Personal Account
THE CHEMICAL RECORD
Siloxy Alkynes in Annulation Reactions Hui Qian, Wanxiang Zhao, and Jianwei Sun*[a] Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR (P. R. China), E-mail: [email protected]
[a]
Received: May 1, 2014 Published online: August 29, 2014
ABSTRACT: Siloxy alkynes are a family of versatile species in organic synthesis. This account reviews the annulation reactions of siloxy alkynes for the synthesis of a variety of carbo- and heterocyclic products. With various dipolarophiles or dipolarophile-like reaction partners, siloxy alkynes are capable of forming small (three- to six-membered) rings. Recently, we have expanded the scope to the synthesis of medium- and large-ring lactones, enabled by the design of new amphoteric molecules as well as a new ring-expansion strategy. These annulation reactions provide not only practically useful syntheses of cyclic molecules, but also important understanding of the fundamental reactivity of siloxy alkynes. DOI 10.1002/tcr.201402042 Keywords: alkynes, annulation, cyclization, cycloaddition, silanes
1. Introduction Although silyl enol ethers (or enol silanes) have been widely known and utilized in organic synthesis for a long time, such as in Mukaiyama aldol reactions, the exploration of their triplebond siblings, siloxy alkynes (also called silyl ynol ethers or ynol silanes, 1 in Figure 1), has received relatively little attention. However, siloxy alkynes are by no means less important or versatile. In the past few decades, more and more attention has been paid to the study of new reactivity of siloxy alkynes, resulting in the development of a variety of useful processes.[1] The increased interest in the study and subsequent application of these processes has been to some extent facilitated by the development and improvement of reliable and efficient synthesis of siloxy alkynes.[2] In return, the interesting reactivity pattern of siloxy alkynes continues to attract more interest in this area. Today, the exploration of the reactivity of siloxy alkynes has emerged as an important platform for new reaction development. Siloxy alkynes with a bulky silyl group, such as triisopropylsilyl, are thermally stable. However, those with a
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small silyl group can easily isomerize to silyl ketenes and further decompose.[2b] Therefore, the majority of the siloxy alkynes involved in current studies are substituted with the bulky triisopropylsilyl (TIPS) group. It is worth noting that even with the bulky TIPS group, the majority of these siloxy alkynes are prone to decompose upon silica gel chromatography. Therefore, siloxy alkynes are typically purified by distillation and stored in a refrigerator. Several strategies for siloxy alkyne synthesis are known.[2] Among them, the most widely used is the silylation of the corresponding ynolate ions 2. Ynolate ions can be accessed by direct oxidation of lithium acetylides (oxygen transfer from LiOOtBu, Figure 1a),[2e,f ] rearrangement of enolate α,α-dibromoketones dianions 3 generated from (Figure 1b),[2g] or elimination of dianions 4, which can be obtained from α-bromoesters or α,α-dibromoesters (Figure 1c).[2h–j] These methods are reasonably general in terms of the R group and the reaction efficiency is generally high.
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© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
R
O
R3
Si R1
Siloxy alkynes Silyl ynol ethers Ynol silanes
2
R
1
Silylation
R
LiOOt Bu R
Li
O O
a
b
ynolate ions (2)
Br R or Br Br R
3
c CO2R'
LDA; t-BuLi
R
CO2R'
n-BuLi
OLi
Li
Br
R
O
OR' 4
R
Br Br
Fig. 1. General structure of siloxy alkynes and the typical synthetic strategies.
Bearing a siloxy group, the triple bonds of siloxy alkynes are thus electron rich and highly polarized, with the β carbon partially negatively charged and the α carbon partially positively charged (Scheme 1). Therefore, siloxy alkynes are good
Hui Qian was born in 1988 in Yixing, Jiangsu Province (P. R. China). He received a bachelor’s degree in Chemistry from Yangzhou University (P. R. China) in 2011. He is presently enrolled in the Chemistry Ph.D. program at the Hong Kong University of Science and Technology under the supervision of Prof. Jianwei Sun. Wanxiang Zhao received his B.S. degree in Chemistry from Linyi Normal University in 2007, and obtained his M.S. degree in Organic Chemistry from East China Normal University in 2010, where he worked under the guidance of Prof. Junliang Zhang. In 2014, he obtained his Ph.D. degree in Organic Chemistry from the Hong Kong University of Science and Technology, under the supervision of Prof. Jianwei Sun. He is currently a postdoctoral fellow with Prof. John Montgomery at the University of Michigan, Ann Arbor.
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nucleophiles. As a result, electrophiles typically react at the β position, resulting in the formation of silyl ketenium intermediate 5, which is highly electrophilic. Subsequent reaction with a nucleophile forms silyl enol ether 6, which is again
Jianwei Sun graduated with B.S. and M.S. degrees from Nanjing University in 2001 and 2004, respectively. In 2008, he obtained his Ph.D. degree in Organic Chemistry from the University of Chicago, working with Prof. Sergey A. Kozmin. He then worked as a postdoctoral fellow with Prof. Gregory C. Fu at Massachusetts Institute of Technology. In August 2010, he became an Assistant Professor of Chemistry at the Hong Kong University of Science and Technology. He is a recipient of the Asian Core Program Lectureship Award, the Hong Kong Research Grants Council Early Career Award, and the Thieme Chemistry Journal Award.
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δ+ δ−
δ−
OTIPS α
TIPS E1
R β
R Nu E
O
Nu E1
TIPSO
Nu
R
E1 6
5 E2
2.1. [2 + 1] Cycloaddition
Nu
TIPSO R
E 8
Annulation
Nu
TIPSO R
E2
E1
7
Scheme 1. General reactivity of siloxy alkynes and their annulation reactions.
nucleophilic and reactive toward another electrophile to form oxocarbenium 7. Termination of the reactions can be desilylation or reaction with additional nucleophiles. With such a highly organized polarity-switching process, siloxy alkynes are fundamentally useful. In particular, siloxy alkynes have proved versatile in a wide range of annulation reactions with dipolarophiles and dipolarophile-like molecules to form cyclic products 8. This account reviews these annulation reactions.
2. Annulations of Siloxy Alkynes Depending on the reaction partners, siloxy alkynes can participate in a range of annulation reactions to form various cyclic products with different ring sizes ranging from small, medium to large rings. The representative annulation topologies are depicted in Figure 2. With a carbene, siloxy alkynes can undergo [2 + 1] cycloaddition to form three-membered alkene products, which are highly strained and prone to further reactions. With two-atom dipolarophiles, such as aldehydes and imines, the reactions proceed in a [2 + 2] cycloaddition form to generate various four-membered cyclic products. Some of these products, such as β-lactones and β-lactams, are unstable and easily undergo ring opening. Donor–acceptor cyclopropanes are versatile three-carbon dipolarophiles. Their reactions with siloxy alkynes can form highly functionalized cyclopentene derivatives. Aromatic annulation is probably the most studied family of reactions of siloxy alkynes. Pioneered by the Danheiser and Kowalski groups, the initial benzannulation reaction with four-carbon dipolarophile vinyl ketenes to form resorcinols has been applied in several syntheses of natural products. Recently, the Kozmin and Movassaghi groups have further advanced the aromatic annulation of siloxy alkynes
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with different four-atom dipolarophiles. Although various processes have been developed for small-ring synthesis, the use of siloxy alkynes for medium- and large-ring systems has been only recently realized by our group. Other than cycloadditions with intermolecular partners, siloxy alkynes bearing an internal reactive motif may undergo intramolecular cyclizations, such as enyne metathesis and cycloisomerizations.
In 2006, Clark and Woerpel reported a silver-catalyzed silacyclopropenation of siloxy alkynes.[3] The di-tertbutylsilylene was generated in situ from silabicyclo [4.1.0]heptane 10 and reacted with siloxy alkyne 9 to form the [2 + 1] adduct silacyclopropene 11 with high efficiency (Scheme 2). The three-membered strained product could be isolated, purified, and characterized under inert conditions. It could also easily undergo CuI-catalyzed insertion with butyraldehyde to afford oxasilacyclopentene 12, which is a versatile building block toward sequential Mukaiyama aldol reaction and 1,3-Brook rearrangement, leading to the stereoselective formation of a variety of 1,2,4-triols, such as 13. This reaction is the only example of [2 + 1] cycloaddition of siloxy alkynes to date. 2.2. [2 + 2] Cycloadditions In 1959, Arens and co-workers reported the first olefination of carbonyl groups with electron-rich alkynes, in which a [2 + 2] cycloaddition step to form an oxetene intermediate was proposed.[4] In 1965, Middleton proved the intermediacy of the oxetene in this process by isolation and characterization of the oxetene at low temperature and confirmed its subsequent electrocyclic ring opening to form the observed α,β-unsaturated ester.[5] These results provided an important foundation for the following studies of [2 + 2] cycloadditions of siloxy alkynes. 2.2.1. [2 + 2] Cycloaddition with Aldehydes (Carbonyl Olefination) In 1990, Kowalski and Sakdarat reported the first reaction between siloxy alkynes and aldehydes, an extension of the Arens olefination.[6] The reactions proceeded efficiently in the presence of a stoichiometric amount of TiCl4. After transesterification by MeOH, a range of α,β-unsaturated esters could be obtained with moderate efficiency but generally high E stereoselectivity (Scheme 3). It was natural to propose the oxetene intermediate 14, but the attempts to isolate and characterize this intermediate failed. The reaction provided a direct and highly E-selective synthesis of trisubstituted olefins, thereby representing an attractive alternative to the classical Horner–Wadsworth– Emmons reaction. The siloxy alkynes serve as a versatile
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Siloxy Alkynes in Annulation Reactions
X R X Y
OTIPS X Y
OTIPS
X
R = reactive tether
[2+1]
[2+2]
R
intramolecular cyclization
OTIPS R D
D
A
A
X
Y R'
R
[3+2]
OTIPS
B C
[4+2]
B C
A
A D
[n+2] (n>4)
D R OTIPS
B C
A
R
D
OTIPS
R
O O
medium and large lactones
aromatic annulation
Fig. 2. Representative annulation topologies of siloxy alkynes.
OTIPS
t Bu
Si
+
t Bu
n
Bu
t Bu
Ag3PO4 (10 mol%)
n
70 oC
Bu
10
9
Pr
Bu
Si
t Bu
n
CuI 50 oC
Me
t Bu
OH OH n
OTIPS 11
O
Ph
t Bu
Si
O
n
Bu
OH
13
n
Pr
OTIPS 12
Scheme 2. Silacyclopropenation of siloxy alkynes.
surrogate for the phosphonates required in the typical Horner– Wadsworth–Emmons conditions, thus avoiding the generation of stoichiometric amounts of phosphate-containing waste and simplifying the product purification. While the above olefination protocol is efficient and attractive, a stoichiometric amount of the promoter TiCl4 is required. Nevertheless, the process could be catalytic in nature. In 2010, Kozmin and co-workers reported the first catalytic version of this carbonyl olefination.[7] In the presence of 5 mol % of AgNTf2, various siloxy alkynes reacted efficiently with a range of aldehydes under mild conditions to form trisubstituted esters with high efficiency and moderate to excellent stereoselectivity (Scheme 4). Excellent chemoselectivity was also demonstrated in the presence of ketone and ester groups.
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Silver is a good π-acid, so the authors proposed that the reaction might start with a rapid and reversible coordination of silver to the alkyne, followed by aldehyde addition and ring closing to form the oxetene 14. Subsequent electrocyclic ring opening then gave the observed olefination product 15. 2.2.2. [2 + 2] Cycloaddition with Imines Imines can also undergo similar [2 + 2] cycloaddition reactions with siloxy alkynes to form four-membered dihydroazete or lactam products. In 1990, Maas and co-workers reported the first example with kinetically stabilized (hindered) azete 16.[8] Stirring the mixture of siloxy alkyne 17 and 1,2,3-tri-tert-butyl azete 16 under argon for 72 hours afforded the so-called Dewar pyridine 18 in 46% yield (Scheme 5). The cycloaddition displayed very high regioselectivity, which could be explained by steric control of the transition state geometry rather than bond polarization that would favor the opposite regioisomer 19. In this case, 19 was not observed. In 2000, Shindo and co-workers reported a lanthanoidcatalyzed imine olefination reaction with siloxy alkynes.[9] In the presence of a lanthanoid triflate, such as Pr(OTf )3 or Yb(OTf )3, as the Lewis acid catalyst, the reaction between 1-siloxy-1-hexyne 9 and imine 20 gave α,β-unsaturated amides 21 in 43% yield, together with lactam 22 in 22% yield (Scheme 6).[9] The catalyst turnover and yield were moderate, but this process featured good stereoselectivity in terms of the alkene configuration (E only). The observation of lactam 22 confirmed the [2 + 2] pathway, in which the direct adduct 23 might be involved as an intermediate. It is also worth noting
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OTIPS + H
R
O
1) TiCl4 (1 equiv.), CH2Cl2, -78 oC
O R'
R'
R
OMe R
2) TiCl4; MeOH -78 oC to rt OTIPS O R' 14
Ph
O OMe
OMe
n
Ph
OMe
n
C5H11
Ph
63%, E only
OMe n
C5H11
Ph
Bu
65%, E only
O
O
O
62%, E only
64%, E:Z = 93:7
Scheme 3. TiCl4-promoted carbonyl olefination with siloxy alkynes.
OTIPS
AgNTf 2 (5 mol%)
O +
H
O R
OTIPS R'
-78 to 20 oC
R'
R
O
R'
CH2Cl2
14
O
O n
Bu
Ph
OTIPS
15
TIPSO
O Me
OTIPS H
H
OTIPS R
n
Pent
OTIPS
AgNTf 2
14
15
R
H
O2N
O2N 84%, E:Z > 95:5
75%, E:Z = 86:14
O Me
OTIPS
Me 2
H
Me
n
Bu
OTIPS
OTIPS
R
O Ag R'
TIPSO
TIPS
NTf 2
O C
NTf 2 R
C R
Ag
MeOOC 75%, E:Z > 95:5
Ag NTf 2
H
H
O 76%, E:Z = 94:6
TIPS O C
O
O
n
Bu
87%, E:Z > 95:5
O
80%, E:Z = 91:9
H
R'
Scheme 4. Silver-catalyzed carbonyl olefination with siloxy alkynes.
that the regioselectivity of this reaction is opposite to the above example (Scheme 5), and the selectivity in this case is governed by the electronic effect. 2.2.3. [2 + 2] Cycloaddition with Ketenes Besides carbonyl and imine groups, activated C=C bonds can also be the reactive motifs for [2 + 2] cycloadditions with siloxy alkynes. For example, in 1988, Kowalski and Lal reported that
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ketenes can form [2 + 2] cycloadducts with siloxy alkynes and the corresponding cyclobutenones were obtained with excellent efficiency (Scheme 7).[10] Due to the high reactivity of ketenes, the reaction could proceed without a catalyst under mild conditions. In the same paper, the authors demonstrated that these cyclobutenone products could be further converted to other useful molecules, including the transposition of the enone moiety as well as the subsequent application in benzannulation reactions.
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© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
OTIPS N
16
+
N
rt Ph
Ph
OTIPS
pentane
+
N OTIPS
Ph
72 h
17
19 (0%)
18 (46%)
Scheme 5. The Maas cycloaddition of siloxy alkyne 17 with azete 16.
OTIPS
PMP +
N
n
9
n
Bu
MeCN
Ph
Bu
O
Pr(OTf)3 (30 mol%)
Bu N
PMP
21
22 22%
43% (E only) n
Bu
O
Ph
Ph
0 oC to rt
20
n
PMP N + H
OTIPS N
Ph
PMP 23
Scheme 6. Shindo’s imine olefination with siloxy alkynes.
OTIPS
H +
R
H C O
CH2Cl2
O
TIPSO
Me o
0 C 5h
R
O TIPSO
Me
O
77%
n
R = Cy, 92% R = nPent, 88% R = Ph
85%
OTIPS
AgNTf 2 (5 mol%)
Bu
CH2Cl2 20 oC
n
CN
Bu
TIPSO
69%
n
O
Bu O
OMe
Scheme 7. The [2 + 2] cycloaddition of siloxy alkynes with ketenes.
CN
TIPSO
OMe
78%
n
Bu
2.2.4. [2 + 2] Cycloaddition with Activated Alkenes In 2004, Kozmin and co-workers reported the Ag-catalyzed [2 + 2] cycloaddition of siloxy alkynes with simple electrondeficient alkenes.[11] With 5 mol % of AgNTf2 as the catalyst, unsaturated enones, esters, and nitriles all participated in the reaction to form a range of highly functionalized siloxy cyclobutenes with good efficiency (Scheme 8). The reaction could not proceed under thermal conditions. Other Lewis acids, such as TiCl4 and BF3, promoted the reaction with low efficiency. Mechanistic studies suggested a stepwise mechanism. The reaction may be initiated by activation of either the siloxy alkyne or the activated alkenes by the silver catalyst. Complexation of siloxy alkynes with the silver catalyst was also observed by NMR. This reaction demonstrated a new mode of reactivity for siloxy alkynes and also provided a new synthesis of useful cyclobutene products.
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Scheme 8. Ag-catalyzed [2 + 2] cycloaddition with activated alkenes.
2.3. [3 + 2] Cycloaddition Donor–acceptor cyclopropanes are widely used precursors as three-carbon dipolar species for cycloadditions. Various reaction partners, such as indoles, enol ethers, and aryl acetylenes, have been employed for such cycloadditions to form cyclopentane skeletons. Nevertheless, electron-rich alkynes had not been employed until 2008.[12] Ready and co-worker reported that siloxy alkynes and donor–acceptor cyclopropanes 24 reacted convergently to form cyclopentenones 25 with good efficiency and stereoselectivity (Scheme 9). The reaction involved sequential generation of dipolar intermediates 26 followed by cycloaddition to form adducts 27, which then underwent elimination and subsequent desilylation to give the enone products. Cyclopentenones with different substitution patterns
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1) Me2AlCl/air (1 equiv)
OTIPS
CO2Et +
R1 OEt R2
R
R1
2) HF.Pyridine DCM, -78 oC
R
O
EtO2C
R2 25
24
CO2Et
OTIPS
EtO2C
OTIPS
EtO2C
R1 EtO
R1 EtO
R2 26
EtO2C
R
R2
27
O
EtO2C
O
EtO2C
O
EtO2C n
Bu
Bu
Et
O
H
n
Bu
Bu
n
n
77%
R
R1
R2
n
Bu
76%
63%
79%
Scheme 9. The [3 + 2] cycloaddition with donor–acceptor cyclopropanes.
as well as bicyclic scaffolds could be obtained. During the reaction optimization, the authors observed an interesting phenomenon – the catalyst Me2AlCl from a freshly opened bottle gave inferior catalytic activity, while that from an aged bottle could catalyze the reaction with a shorter time and higher efficiency. Further investigation by control experiments suggested that the real active catalyst might be the derivative (MeO)AlMeCl. 2.4. Aromatic Annulation (Formal [4 + 2] Annulation) In 1984, the Danheiser group reported a benzannulation reaction between vinyl ketenes and a range of alkynes, including alkoxy alkynes, ynamines and alkynyl sulfides.[13] In 1988, the Danheiser and Kowalski groups concurrently reported the extension of this annulation to siloxy alkynes, which are typically more reactive than alkoxy alkynes, and thus the scope could be expanded to secondary and tertiary alkyl-substituted alkynes.[2d,10] A wide range of monosilylated resorcinol products 29 were obtained in good to excellent yield (Scheme 10). It was believed that the reaction begins with four-electron electrocyclic opening of cyclobutenone 28 to form the reactive vinyl ketene intermediate 30. Subsequent [2 + 2] cycloaddition between the ketene moiety and the siloxy alkyne formed alkenyl-substituted cyclobutenone 31, which then undergoes sequential electrocyclic ring opening, six-electron electrocyclic ring closure, and tautomerization to give the observed aromatic product 29 via 32. The overall reaction could be regarded as a formal [4 + 2] annulation.
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Later on, Danheiser and co-workers reported a secondgeneration version of the above annulation featuring a new photochemical strategy for the generation of the reactive vinyl or aryl ketene intermediates.[14] Instead of thermal electrocyclic ring opening of cyclobutenones, Wolff rearrangement by irradiation of diazo ketones 33 was employed to generate aryl- and vinylketenes 30 (Scheme 11). Since the diazo ketones 33 could be efficiently obtained from a wide range of readily available aryl and vinyl ketones 34, the new two-step strategy significantly expanded the substrate scope. A range of polycyclic aromatic and heteroaromatic compounds could also be synthesized with this new method. More recently, the Danheiser group also reported that lithium ynolates generated from siloxy alkynes are also reactive towards (trialkylsilyl)vinylketenes in the benzannulation reactions.[15] Due to the reduced reactivity of silyl ketenes, siloxy alkynes are not reactive enough. However, siloxy alkynes are useful precursors of lithium ynolates in these reactions. Owing to its excellent efficiency as well as its unambiguous regioselectivity, which is typically an issue in the more conventional direct aromatic substitution strategy for the synthesis of multisubstituted aromatic compounds, the Danheiser benzannulation has been demonstrated as a key step in the syntheses of various natural products, including cylindrocyclophanes, aegyptinone A, danshexinkun A, (−)cryptotanshinone, etc. (Figure 3).[16] It is worth noting that the Danheiser annulation is one of the few reactions of siloxy alkynes that have been widely applied in natural product synthesis. In the above benzannulations, the reaction partner (i.e., vinyl or aryl ketene) serves as a four-carbon unit to react with the siloxy alkynes to form the all-carbon aromatic ring products. Indeed, the use of heteroatom-containing four-atom variants could result in heterocyclic aromatic compound formation. In 2007, Movassaghi and co-workers reported an elegant pyridine synthesis employing N-vinyl and N-arylamides as the annulation partners with alkynes.[17] The reaction starts with in situ generation of the reactive vinyl- or aryliminiums 37 from amides 35 in the presence of Tf2O (Scheme 12). Subsequent stepwise alkyne addition followed by ring closing and aromatization furnishes the observed pyridines 36 in good yield. In addition to siloxy alkynes, other electronrich alkynes and enol ethers including ynamides and alkoxy alkynes were also suitable substrates. Thus, the method provided a convergent and rapid synthesis of highly substituted pyridines with controlled substitution patterns. Recently, the Kozmin and Rawal groups reported a new benzannulation using 1,2-diazines as the reaction partner.[18a] With the AgNTf2/2,2′-bipyridine catalyst system, the formal inverse electron-demand Diels–Alder reaction between phthalazines 38 and siloxy alkynes proceeded efficiently at room temperature to form naphthalenes 39 in high yield
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Siloxy Alkynes in Annulation Reactions
OTIPS
R1
O
R2
R3
R
Δ
+
OH R3
TIPSO f ormal [ 4+2]
R
R1
28
29 electrocyclic ring-closing; tautomerization
electrocyclic ring-opening R R1
C
R2
electrocyclic ring-opening
O TIPSO [ 2+2] cycloaddition
R2 R3
R
O R1 R2
C O R3
TIPSO R3
31
30
R2
R1 32 n
Bu
n
Bu
nC5H11
OMOM
MOMO
Cl
TIPSO TIPSO
TIPSO
TIPSO OH
i Pr
Me
OH
92% (Ref 2d)
Ph
OH
59% (Ref 2d)
80% (Ref 10)
OH
76% (Ref 10)
Scheme 10. Benzannulation of siloxy alkynes with cyclobutenones.
O R2
N2
photochemical Wolff rearrangement
R1
R1
R3
CH3
O
C
R1 H3C
R3
33
CH3
30
R2
HO
CH3 R2
R R1
R3 34
H
aegyptinones A
(Ref 16g-i)
(Ref 16c)
OH R3
TIPSO R1
O
cylindrocyclophanes
O R2
H3C CH3
CH3
f ormal [ 4+2] R
O
OH
H3C
OTIPS
CH3 O
OH
OH
CH3
O
O OH
O
R2
CH3
O
O
Scheme 11. Second-generation benzannulation using diazo ketones. H3C CH3
CH3
(Scheme 13). The reaction scope is broad in terms of the siloxy alkynes. It is worth noting that electron-demand Diels–Alder reactions of this type are scarce and typically require high temperature under thermal conditions. This reaction represents one the few examples with heterocyclic azadienes using Lewis acid activation. Although other ligands (e.g., BOX, PYBOX, pyridine, and terpyridine) could be used, the best efficiency was obtained with 2,2′-bipyridine. It was proposed that the Lewis acid activates the electrophile by lowering the
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danshexinkun A
(-)-cryptotanshinone
(Ref 16b)
(Ref 16d)
Fig. 3. Selected natural products that were synthesized using the Danheiser annulation.
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R2 HN R1
+
O
R2
Tf 2O 2-ClPy
OTIPS
R3
R3
N R1
R
OTIPS R 36
35 Tf 2O 2-ClPy
− TfOH OTIPS R2
R2
TfO H
R
R3
N
R1
− 2-ClPy − TfOH
OTf
N
R3 OTIPS
N C
R1 R
Cl
OTf
37 OMe O
N Ph
OTIPS
N n
Bu
n
Bu
N
OTIPS n
Bu
c
OMe
Hex
OTIPS Ph
61%
73%
74%
Scheme 12. Pyridine synthesis using vinyl- and arylamides.
LUMO, which facilitates the nucleophilic attack by the alkyne to form ketenium intermediate 40 (path a). Further ring closure forms the formal [4 + 2] adduct 41. Release of nitrogen gas with concomitant aromatization gives the observed products. The formation of 41 might also proceed in a concerted pathway (path b). Later on, the same groups reported that the same reaction partners reacted in a [2 + 2 + 2] cycloaddition manner to form complex heterocyclic products when pyridinium trifluoromethane-sulfonimide was used as the promoter.[18b] In addition to 1,2-diazines as the reaction partner, Kozmin and co-workers later found that other heterocycles, such as 2-pyrones 42 and isoquinoline oxides 44 as well as pyridinium salts 46, were also useful benzannulation partners (Scheme 14).[19,20] Notably, their discovery was enabled by label-assisted mass spectrometry. Different from the reactions with 1,2-diazines where nitrogen was extruded as a leaving group, these new annulations bear hemi cleavable leaving groups. After aromatization from the direct bridged adducts (e.g., 43, 45, and 47), the leaving groups (carboxylate, oxime, and imine) remained as a substituent of the products. Therefore, these reactions provided access to these functionalized aromatic compounds. Although the AgNTf2/2,2′-bipyridine catalyst proved best in the previous reaction, gold/phosphine and silver carboxylate performed better for these new annulations.
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2.5. Medium- and Large-Ring Lactone Synthesis ([n + 2], n > 4) While siloxy alkynes have been very versatile in small-ring annulation reactions, the discovery of their reactivity in forming medium and large rings has only been reported very recently.[21] Enabled by the design of a new family of (1,6)amphoteric molecules, e.g., 48, we discovered the first eightmembered lactone formation using siloxy alkynes. Our design of the (1,6)-amphoteric molecules featured the incorporation of oxetane and aldehyde functionalities in one molecule with an aryl linker (Scheme 15).[21a] The formal [6 + 2] cycloaddition was efficiently catalyzed by the Brønsted acid HNTf2 and proceeded at room temperature. Various aryl-fused eightmembered lactones 49 were synthesized in moderate to good yield. Medium-sized (eight- to eleven-membered) lactone synthesis is a well-known challenge in organic synthesis. This challenge is largely due to the unfavorable ring-closing kinetics and transannular interactions for medium-ring formation.[22] It is particularly problematic for intermolecular reactions due to additional unfavorable entropic change and competitive dimerization side reactions. Typical conventional strategies to enhance the efficiency are slow addition of substrates and/or high dilution, but these only lead to limited and unpredictable improvement. These strategies also have limited utility in largescale synthesis. Notably, our reaction does not require slow addition or high dilution and represents one of the very few examples of intermolecular synthesis of medium-sized lactones. Two possible mechanisms are depicted in Scheme 16. In mechanism a, upon activation by the Brønsted acid catalyst, cyclization of substrate 48 forms oxocarbenium 50. Then, attack of the electron-rich alkyne gives ketenium intermediate 51. Further cyclization forms cyclic silyl ketene acetal 52. Subsequent activation of 52 by protonation of the ether motif initiates the C–O bond cleavage to form lactone 53. Finally, silylation of the free alcohol furnishes the observed eightmembered lactone products. Alternatively, as shown in mechanism b, the alkyne and the aldehyde undergo [2 + 2] cycloaddition to form oxetene 54, followed by electrocyclic ring opening to give α,β-unsaturated ester 55. Next, with acid activation of the oxetane, the carbonyl group can cyclize in an 8-exo-tet manner to give 53 via the intermediacy of 56. Further silylation delivers the product. While the above process proved efficient for a range of aryl-linked (1,6)-amphoteric molecules, the extension to aliphatic linkers between the oxetane and aldehyde moieties resulted in none of the desired lactone formation under the standard conditions. This dramatic decrease in reactivity is probably due to the increased substrate flexibility or loss of the aryl resonance stabilization of the relevant intermediates. Aiming at further developing a more general and practically
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© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
R1
OTIPS N N
AgNTf 2 2,2'-bipyridine
+
R1
OTIPS R
R 38
39 Ag
path a stepwise
N
Tf 2N N N
R1
Ag
[4+2] N N Ag
N N
R
C
40
N2
path b
N
N N
OTIPS
R1
OTIPS
R
41 Cl
OTIPS n
n
n
Bu
82%
OTIPS
OTIPS
Bu
Bu 67%
72% OTIPS
OTIPS
OTIPS Ph
83%
80%
95%
Scheme 13. Formal Diels–Alder reaction with 1,2-diazines.
useful medium- and large-ring lactone synthesis, we employed a different strategy featuring unprecedented bicyclic oxetenium ring expansion.[21b] The new strategy involves a [2 + 2] cycloaddition between cyclic oxocarbenium 58 and ynolate 2, which are derived from cyclic acetal 57 and siloxy alkyne, respectively. The adduct oxetenium 59 next undergoes ring opening to form the observed ring-expansion lactone product 60 (Scheme 17). Promoted by the readily available Lewis acid BF3, this intermolecular process employs mild conditions without high dilution or slow addition. More importantly, compared with the previous reaction, the scope is significantly expanded. Fusion with an aryl group is not required. Moreover, the process is not limited to eight-membered ring formation, and 7-, 9-, 10-, and 18-membered lactones were also obtained with high efficiency. 2.6. Intramolecular Cyclizations In addition to the many intermolecular annulations, intramolecular cyclization has also been studied. These reactions typically required the synthesis of siloxy alkynes tethered with an internal functional group, which could sometimes be
Chem. Rec. 2014, 14, 1070–1085
problematic due to incompatibility of the functional group with the siloxy alkyne synthesis. Currently, these intramolecular reactions include enyne metathesis and cycloisomerizations. 2.6.1. Siloxy Enyne Metathesis In 2001, Kozmin and co-workers reported a ring-closing enyne metathesis of siloxy alkynes.[23] A range of 1,5- and 1,6-enynes 61 were treated with the Ru-based Grubbs catalyst 62 to give silyl dienol ethers 63, which could be isolated or directly desilylated to form the enone products 64 in good to excellent yield (Scheme 18). Mechanistically, it was believed that the reaction follows the typical enyne metathesis mechanism, which is the sequential formation of Ru-alkylidenes, metallacyclobutenes, and vinyl carbenes, etc. This reaction expanded the scope of enyne metathesis. It provided a highly efficient synthesis of a range of five- and six-membered carboand heterocyclic molecules that could be transformed to other useful building blocks. For example, the reaction was later demonstrated as the key step in the synthesis of natural products furanoeremophilane and bakkenolide A.[24]
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t Bu P Au(NCMe) t Bu SbF6
O OTIPS
O
1)
(2.5 mol%)
+
R2
2) HF-pyridine
R1
CO2H OH
R2 R1
R
R
42
O R2
H
O
OTIPS
R1 H
R
R2
CO2H OTIPS
R1
R
43
OH R1 N
OTIPS
R2
R1 N
same as above
O
R2
OTIPS
O
R
45
R1 N
R1
N
H
44
R3
H
R
R2
R3 N
OTIPS 1) PhCO2Ag 2) F- on PS
R2
H
R R3 NH
I 46
R1
HO
R1
R
R2
R2 47
Scheme 14. Aromatic annulation with 2-pyrones, isoquinoline N-oxides, and pyridinium salts.
2.6.2. Cyclization of Arene- and Alkene-Tethered Siloxy Alkynes It was known that siloxy alkynes could be activated by Lewis acids or Brønsted acids to generate electrophilic ketenium species. Therefore, with proper incorporation of an internal nucleophile, intramolecular cyclization should be expected to take place. In 2004, the Kozmin group reported the first example of such cyclizations to synthesize substituted tetralone and cyclohexenone derivatives. After activation of the siloxy alkyne moiety by HNTf2 or MsOH, arene 65 and alkene 66 cyclized smoothly to form the six-membered products in either the silyl enol ether or the desilylated enone form (Scheme 19).[25] In the case of the arene cyclization, a proton could be regenerated efficiently at the rearomatization step, so the whole reaction could be completed with a catalytic amount
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of proton. In contrast, the reaction of alkene 66 required a stoichiometric amount of the acid promoter in order to achieve good efficiency. 2.6.3. Au-Catalyzed Cycloisomerization of 1-Siloxy-1,5-enynes In sharp contrast to the above Brønsted acid promoted siloxy enyne cyclization with direct intramolecular nucleophile interception of the ketenium intermediate, the use of gold(I) chloride as the catalyst for the similar 1,5-enyne substrates 67 resulted in a novel cycloisomerization process featuring an unusual formal position-swapping of the R1 and OTIPS groups (Scheme 20).[26] Only 1 mol % of AuCl was sufficient to catalyze the reaction to completion within 30 min. With a tertiary C(3) position, a mixture of 1,4- and 1,3-cyclohexadienes 68
Chem. Rec. 2014, 14, 1070–1085
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Siloxy Alkynes in Annulation Reactions
OTIPS
O
HNTf 2 (10 mol%)
OTIPS +
Ar
O
O
Ar
DCM, rt
R
O
48
R
49
OTIPS
OTIPS
OTIPS
OTIPS
O
O
O
O
O
O n
Bu
71%
S
O
t Bu
O t Bu
Ph
60%
47%
53%
Scheme 15. Formal [6 + 2] annulation with (1,6)-amphoteric molecules.
OH
Ar
H+
O
O C O R
Ar
H
Ar
O
52
OTIPS OTIPS
R
HNTf 2
O Ar
TIPS
O
R 51
50
NTf 2
TIPS
O
H+ a
O
O
Ar
O
OH
TIPSNTf 2
O
Ar
O
O 48
R
R
R H+
TIPSNTf 2
49
b [2+2]
53
OH
O H+ Ar
OTIPS
O O R
Ar
O TIPS O TIPS
55
O
O
O TIPS
54
Ar
R
56
R
NTf 2
Scheme 16. Plausible mechanisms.
and 69 was formed, with the former being the major product. Introduction of a quaternary center at the C(3) position resulted in exclusive formation of 1,3-cyclohexadienes. The addition of a phosphine ligand could inhibit the reaction, but cationic Au(I) generated from Au(PPh3)Cl in combination with a silver salt (such as AgOTf or AgNTf2) was found to be equally effective. Control experiments also indicated that the presence of the C(1)-siloxy group was crucial to the formation of the cyclohexadiene products.
Chem. Rec. 2014, 14, 1070–1085
The most unusual but general phenomenon in this reaction is the formal migration of the siloxy group from the C(1) to the C(6) position. This could be explained by a series of alkyl shifts. As shown in the proposed mechanism (Scheme 21), the process begins with gold activation of the electron-rich alkyne motif, forming ketenium 70. Intramolecular nucleophilic attack by the alkene followed by back attack forms the cyclopropane intermediate 72 via 71. Next, the electron-donating C(1) siloxy group initiates the subsequent [1,2] alkyl shift to
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R1
BF3-OEt2 2,4,6-collidine
OTIPS n
+ OR2
O
R O
O
DCM
R
HNTf 2 (10 mol%)
R n+2
R1
60
57
CH2Cl2 20 oC
OTIPS
65
R OTIPS
40-99% yield − H
H R1 R1
n
R n
[2+2]
+
(89%)
R=
O
66
O
n O
Bu n=1, 86% (Z) n=2, 88% (Z/ E = 1:1) O n=10, 87% (E)
93%
Scheme 17. Annulation with cyclic acetals for medium and large lactone synthesis.
1) 62 (5 mol%) benzene, Δ
OTIPS
aq. hydrolysis
R1
R3
O
n
n
Pr
O
O
76%
80%
Pr
O 78%
Scheme 19. Brønsted acid promoted cyclization of siloxy alkynes.
O
to give either 1,3-cyclohexadiene 77 or 1,4-cyclohexadiene 78. The proposed mechanism well explains the observed unusual skeletal reorganization. Although the original reaction was limited to siloxy alkynes, Kozmin and co-workers subsequently managed to significantly expand the reaction scope to include normal 1,5-enynes (without siloxy substitution) using a platinum-based catalyst system.[27]
CH3
2) HF, CH3CN 61
64 N Mes Mes N Cl u R Ph Cl PCy3
R2
Ph
O 72%
HNTf 2 or MsOH
OTIPS
n
Bu
OTIPS
R3
O
n
O
Bu
77%
n
H
R1
n
O
75%
Bu
R2
Me
O
O
O TIPS
LA
Bu
TBSO
C
O
n
R = nBu (91%) R = Ph (64%)
O
O
59
2
R
R
O
58
R
R
O
O
OTIPS
HF
62
2.6.4. Cyclization of 1-Siloxy-1,5-diynes
63
O
O Me O
O N
O Me
Bn CH3
O Me
O
MeO 88%
91%
88%
86%
Scheme 18. Ring-closing metathesis of siloxy enynes.
form oxocarbenium ion 73. An additional [1,2] alkyl shift delivers the intermediate 74, leading to gold carbene 75 (or 76) by C–C bond cleavage. Depending on the hydrogen availability at the adjacent position, the final elimination step can occur
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Having established the activation of siloxy alkynes by soft and hard electrophiles followed by subsequent intramolecular attack with arenes and alkenes, Kozmin and Sun further examined the reactivity of 1-siloxy-1,5-diynes in the presence of strong Brønsted acid HNTf2.[28] Interestingly, the reactivity of siloxy diynes 79, particularly the way to terminate the carbocation intermediates, was quite different from that of enynes, typically deprotonation or protodemetalation. Indeed, after activation by acid, diyne 79 cyclizes (via ketenium 80) in a 5-endo-dig mode to form alkenyl cation 81 and then abstracts a halogen atom from the haloalkane solvent, leading to the formation of the halo enone product after acid-promoted protodesilylation of the intermediate silyl dienol ether 82
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© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
R3 R2
R4
R3
R3
R5
AuCl (1 mol%)
R4
R2
R2
R4
R5
or
R1
20 oC CH2Cl2
OTIPS
TIPSO
TIPSO
R1
R1 68
67
n
Ph
Me
Pr
TMS
69
n
Ph
n
Ph
Pr
Pr
+
TIPSO
TIPSO
TIPSO
TIPSO
73%
50%
99% (4:1)
Me
Me Me
Me +
Me
Pent
TIPSO 88%
82% (6:1)
Me Ph
Me
n
TIPSO
TIPSO
TIPSO
Me
Me
Me
89%
Scheme 20. Cycloisomerization of 1-siloxy-1,5-enynes.
R1
R2
R3
R2
R1
R3
R1
R3
or TIPSO
TIPSO 77
OTIPS
78
AuCl R2
R1 C O TIPS
R3
R2
R1
AuCl
R1
AuCl
TIPSO H
70
R3
R2
76
75
R2 = H
R1
R2
R2
R3
AuCl OTIPS
71
R3
R1
AuCl
TIPSO
74
R2
R3
AuCl OTIPS 72
R3 AuCl
TIPSO
R2 = H R1
H
R1
R3 AuCl
OTIPS
73
Scheme 21. Mechanism of Au-catalyzed cycloisomerization of siloxy enynes.
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R2
X
haloalkane (RX, solvent)
OTIPS
R'
R'
O 83-85
79
R2
H C O
R'
R2
R2 NTf 2
NTf 2
RX TIPS
Acknowledgements
X
R'
R'
OTIPS
80
81
OTIPS 82
Me Me
Br
Cl
n
O
83 (60%) RX = CHCl3
Oct
n
O
Oct
n
Bu
84 (71%) RX = CH2Br2
O
[1]
O 85 (69%)
86 (58%)
RX = CH3I
RX = PhH
Scheme 22. HNTf2-promoted cyclization of 1-siloxy-1,5-diynes.
(Scheme 22). HNTf2 is uniquely effective as a promoter in this process, presumably due to its strong acidity in organic solvents as well as the low nucleophilicity of its counteranion. With halogenated solvents, such as CH2Cl2, CHCl3, CH2Br2, and even CH3I, the corresponding halogen atom was abstracted and incorporated into the enone products 83–85 with high efficiency and good E selectivity. More surprisingly, with benzene as the solvent, trapping of the alkenyl cation 81 by benzene (i.e., Friedel–Crafts reaction) was also observed and the tetrasubstituted alkene product 86 was obtained in moderate yield.
[2]
[3] [4] [5] [6] [7]
3. Conclusion and Outlook We have summarized all the annulation reactions of siloxy alkynes. These reactions clearly demonstrate the versatility of siloxy alkynes in the synthesis of small-, medium-, and largering annulation products. These structurally diverse carbo- and heterocyclic products are useful in organic synthesis. Regarding the ring-size distribution of the annulation products, the majority of them are four- and six-membered ring products. Particularly, aromatic annulations to form six-membered ring aromatics have received considerable attention. For example, the Danheiser benzannulation has been applied in several natural product syntheses. In contrast, medium- and large-ring synthesis using siloxy alkynes is still at an early stage, and it is
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Financial support was provided by HKUST and Hong Kong RGC (GRF-604411 and GRF-605812).
REFERENCES
Ph
I
n
Oct
expected that more efforts will be made in this direction. Furthermore, cascade annulations of siloxy alkynes to form polycyclic products are also desirable but scarce. Finally, with the increasing understanding of the fundamental reactivity of siloxy alkynes as well as the new design of their reaction partners,[29] we believe that more and more novel annulation processes will be developed and applied in organic synthesis.
R2
HNTf 2 (1.1 equiv.)
[8] [9] [10] [11] [12] [13]
[14]
Chem. Rec. 2014, 14, 1070–1085
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Siloxy Alkynes in Annulation Reactions
[15]
[16]
[17] [18]
[19]
a) W. F. Austin, Y. Zhang, R. L. Danheiser, Org. Lett. 2005, 7, 3905; b) W. F. Austin, Y. Zhang, R. L. Danheiser, Tetrahedron 2008, 64, 915. a) R. L. Danheiser, D. D. Cha, Tetrahedron Lett. 1990, 31, 1527; b) R. L. Danheiser, D. S. Casebier, J. L. Loebach, Tetrahedron Lett. 1992, 33, 1149; c) R. L. Danheiser, D. S. Casebier, A. H. Huboux, J. Org. Chem. 1994, 59, 4844; d) R. L. Danheiser, D. S. Casebier, F. Firooznia, J. Org. Chem. 1995, 60, 8341; e) R. L. Danheiser, M. P. Trova, Synlett 1995, 573; f ) R. L. Danheiser, A. L. Helgason, J. Am. Chem. Soc. 1994, 116, 9471; g) A. B. Smith, III, S. A. Kozmin, D. V. Paone, J. Am. Chem. Soc. 1999, 121, 7423; h) A. B. Smith, III, S. A. Kozmin, C. M. Adams, D. V. Paone, J. Am. Chem. Soc. 2000, 122, 4984; i) A. B. Smith, III, C. M. Adams, S. A. Kozmin, D. V. Paone, J. Am. Chem. Soc. 2001, 123, 5925. M. Movassaghi, M. D. Hill, O. K. Ahmad, J. Am. Chem. Soc. 2007, 129, 10096. a) Y. E. Türkmen, T. J. Montavon, S. A. Kozmin, V. H. Rawal, J. Am. Chem. Soc. 2012, 134, 9062; b) T. J. Montavon, Y. E. Türkmen, N. A. Shamsi, C. Miller, C. S. Sumaria, V. H. Rawal, S. A. Kozmin, Angew. Chem. Int. Ed. 2013, 52, 13576. J. R. Cabrera-Pardo, D. I. Chai, S. Liu, M. Mrksich, S. A. Kozmin, Nat. Chem. 2013, 5, 423.
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[22] [23] [24] [25]
[26] [27] [28] [29]
J. R. Cabrera-Pardo, D. I. Chai, S. A. Kozmin, Adv. Synth. Catal. 2013, 355, 2495. a) W. Zhao, Z. Wang, J. Sun, Angew. Chem. Int. Ed. 2012, 51, 6209; b) W. Zhao, Z. Li, J. Sun, J. Am. Chem. Soc. 2013, 135, 4680; c) W. Zhao, J. Sun, Synlett. 2014, 25, 303. G. Illuminati, L. Mandolini, Acc. Chem. Res. 1981, 14, 95. M. P. Schramm, D. S. Reddy, S. A. Kozmin, Angew. Chem. Int. Ed. 2001, 40, 4274. D. S. Reddy, S. A. Kozmin, J. Org. Chem. 2004, 69, 4860. a) L. Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2004, 126, 10204; b) L. Zhang, J. Sun, S. A. Kozmin, Tetrahedron 2006, 62, 11371. L. Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2004, 126, 11806. J. Sun, M. P. Conley, L. Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2006, 128, 9705. J. Sun, S. A. Kozmin, J. Am. Chem. Soc. 2005, 127, 13512. For other non-annulation reactions of siloxy alkynes, see: a) J. Sun, S. A. Kozmin, Angew. Chem. Int. Ed. 2006, 45, 4991; b) E. C. Minnihan, S. L. Colletti, F. D. Toste, H. C. Shen, J. Org. Chem. 2007, 72, 6287; c) T. J. Montavon, J. Li, J. R. Cabrera-Pardo, M. Mrksich, S. A. Kozmin, Nat. Chem. 2012, 4, 45.
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Siloxy Alkynes in Annulation Reactions Hui Qian, Wanxiang Zhao, and Jianwei Sun*[a] Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR (P. R. China), E-mail: [email protected]
[a]
Received: May 1, 2014 Published online: August 29, 2014
ABSTRACT: Siloxy alkynes are a family of versatile species in organic synthesis. This account reviews the annulation reactions of siloxy alkynes for the synthesis of a variety of carbo- and heterocyclic products. With various dipolarophiles or dipolarophile-like reaction partners, siloxy alkynes are capable of forming small (three- to six-membered) rings. Recently, we have expanded the scope to the synthesis of medium- and large-ring lactones, enabled by the design of new amphoteric molecules as well as a new ring-expansion strategy. These annulation reactions provide not only practically useful syntheses of cyclic molecules, but also important understanding of the fundamental reactivity of siloxy alkynes. DOI 10.1002/tcr.201402042 Keywords: alkynes, annulation, cyclization, cycloaddition, silanes
1. Introduction Although silyl enol ethers (or enol silanes) have been widely known and utilized in organic synthesis for a long time, such as in Mukaiyama aldol reactions, the exploration of their triplebond siblings, siloxy alkynes (also called silyl ynol ethers or ynol silanes, 1 in Figure 1), has received relatively little attention. However, siloxy alkynes are by no means less important or versatile. In the past few decades, more and more attention has been paid to the study of new reactivity of siloxy alkynes, resulting in the development of a variety of useful processes.[1] The increased interest in the study and subsequent application of these processes has been to some extent facilitated by the development and improvement of reliable and efficient synthesis of siloxy alkynes.[2] In return, the interesting reactivity pattern of siloxy alkynes continues to attract more interest in this area. Today, the exploration of the reactivity of siloxy alkynes has emerged as an important platform for new reaction development. Siloxy alkynes with a bulky silyl group, such as triisopropylsilyl, are thermally stable. However, those with a
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small silyl group can easily isomerize to silyl ketenes and further decompose.[2b] Therefore, the majority of the siloxy alkynes involved in current studies are substituted with the bulky triisopropylsilyl (TIPS) group. It is worth noting that even with the bulky TIPS group, the majority of these siloxy alkynes are prone to decompose upon silica gel chromatography. Therefore, siloxy alkynes are typically purified by distillation and stored in a refrigerator. Several strategies for siloxy alkyne synthesis are known.[2] Among them, the most widely used is the silylation of the corresponding ynolate ions 2. Ynolate ions can be accessed by direct oxidation of lithium acetylides (oxygen transfer from LiOOtBu, Figure 1a),[2e,f ] rearrangement of enolate α,α-dibromoketones dianions 3 generated from (Figure 1b),[2g] or elimination of dianions 4, which can be obtained from α-bromoesters or α,α-dibromoesters (Figure 1c).[2h–j] These methods are reasonably general in terms of the R group and the reaction efficiency is generally high.
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© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
R
O
R3
Si R1
Siloxy alkynes Silyl ynol ethers Ynol silanes
2
R
1
Silylation
R
LiOOt Bu R
Li
O O
a
b
ynolate ions (2)
Br R or Br Br R
3
c CO2R'
LDA; t-BuLi
R
CO2R'
n-BuLi
OLi
Li
Br
R
O
OR' 4
R
Br Br
Fig. 1. General structure of siloxy alkynes and the typical synthetic strategies.
Bearing a siloxy group, the triple bonds of siloxy alkynes are thus electron rich and highly polarized, with the β carbon partially negatively charged and the α carbon partially positively charged (Scheme 1). Therefore, siloxy alkynes are good
Hui Qian was born in 1988 in Yixing, Jiangsu Province (P. R. China). He received a bachelor’s degree in Chemistry from Yangzhou University (P. R. China) in 2011. He is presently enrolled in the Chemistry Ph.D. program at the Hong Kong University of Science and Technology under the supervision of Prof. Jianwei Sun. Wanxiang Zhao received his B.S. degree in Chemistry from Linyi Normal University in 2007, and obtained his M.S. degree in Organic Chemistry from East China Normal University in 2010, where he worked under the guidance of Prof. Junliang Zhang. In 2014, he obtained his Ph.D. degree in Organic Chemistry from the Hong Kong University of Science and Technology, under the supervision of Prof. Jianwei Sun. He is currently a postdoctoral fellow with Prof. John Montgomery at the University of Michigan, Ann Arbor.
Chem. Rec. 2014, 14, 1070–1085
nucleophiles. As a result, electrophiles typically react at the β position, resulting in the formation of silyl ketenium intermediate 5, which is highly electrophilic. Subsequent reaction with a nucleophile forms silyl enol ether 6, which is again
Jianwei Sun graduated with B.S. and M.S. degrees from Nanjing University in 2001 and 2004, respectively. In 2008, he obtained his Ph.D. degree in Organic Chemistry from the University of Chicago, working with Prof. Sergey A. Kozmin. He then worked as a postdoctoral fellow with Prof. Gregory C. Fu at Massachusetts Institute of Technology. In August 2010, he became an Assistant Professor of Chemistry at the Hong Kong University of Science and Technology. He is a recipient of the Asian Core Program Lectureship Award, the Hong Kong Research Grants Council Early Career Award, and the Thieme Chemistry Journal Award.
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δ+ δ−
δ−
OTIPS α
TIPS E1
R β
R Nu E
O
Nu E1
TIPSO
Nu
R
E1 6
5 E2
2.1. [2 + 1] Cycloaddition
Nu
TIPSO R
E 8
Annulation
Nu
TIPSO R
E2
E1
7
Scheme 1. General reactivity of siloxy alkynes and their annulation reactions.
nucleophilic and reactive toward another electrophile to form oxocarbenium 7. Termination of the reactions can be desilylation or reaction with additional nucleophiles. With such a highly organized polarity-switching process, siloxy alkynes are fundamentally useful. In particular, siloxy alkynes have proved versatile in a wide range of annulation reactions with dipolarophiles and dipolarophile-like molecules to form cyclic products 8. This account reviews these annulation reactions.
2. Annulations of Siloxy Alkynes Depending on the reaction partners, siloxy alkynes can participate in a range of annulation reactions to form various cyclic products with different ring sizes ranging from small, medium to large rings. The representative annulation topologies are depicted in Figure 2. With a carbene, siloxy alkynes can undergo [2 + 1] cycloaddition to form three-membered alkene products, which are highly strained and prone to further reactions. With two-atom dipolarophiles, such as aldehydes and imines, the reactions proceed in a [2 + 2] cycloaddition form to generate various four-membered cyclic products. Some of these products, such as β-lactones and β-lactams, are unstable and easily undergo ring opening. Donor–acceptor cyclopropanes are versatile three-carbon dipolarophiles. Their reactions with siloxy alkynes can form highly functionalized cyclopentene derivatives. Aromatic annulation is probably the most studied family of reactions of siloxy alkynes. Pioneered by the Danheiser and Kowalski groups, the initial benzannulation reaction with four-carbon dipolarophile vinyl ketenes to form resorcinols has been applied in several syntheses of natural products. Recently, the Kozmin and Movassaghi groups have further advanced the aromatic annulation of siloxy alkynes
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with different four-atom dipolarophiles. Although various processes have been developed for small-ring synthesis, the use of siloxy alkynes for medium- and large-ring systems has been only recently realized by our group. Other than cycloadditions with intermolecular partners, siloxy alkynes bearing an internal reactive motif may undergo intramolecular cyclizations, such as enyne metathesis and cycloisomerizations.
In 2006, Clark and Woerpel reported a silver-catalyzed silacyclopropenation of siloxy alkynes.[3] The di-tertbutylsilylene was generated in situ from silabicyclo [4.1.0]heptane 10 and reacted with siloxy alkyne 9 to form the [2 + 1] adduct silacyclopropene 11 with high efficiency (Scheme 2). The three-membered strained product could be isolated, purified, and characterized under inert conditions. It could also easily undergo CuI-catalyzed insertion with butyraldehyde to afford oxasilacyclopentene 12, which is a versatile building block toward sequential Mukaiyama aldol reaction and 1,3-Brook rearrangement, leading to the stereoselective formation of a variety of 1,2,4-triols, such as 13. This reaction is the only example of [2 + 1] cycloaddition of siloxy alkynes to date. 2.2. [2 + 2] Cycloadditions In 1959, Arens and co-workers reported the first olefination of carbonyl groups with electron-rich alkynes, in which a [2 + 2] cycloaddition step to form an oxetene intermediate was proposed.[4] In 1965, Middleton proved the intermediacy of the oxetene in this process by isolation and characterization of the oxetene at low temperature and confirmed its subsequent electrocyclic ring opening to form the observed α,β-unsaturated ester.[5] These results provided an important foundation for the following studies of [2 + 2] cycloadditions of siloxy alkynes. 2.2.1. [2 + 2] Cycloaddition with Aldehydes (Carbonyl Olefination) In 1990, Kowalski and Sakdarat reported the first reaction between siloxy alkynes and aldehydes, an extension of the Arens olefination.[6] The reactions proceeded efficiently in the presence of a stoichiometric amount of TiCl4. After transesterification by MeOH, a range of α,β-unsaturated esters could be obtained with moderate efficiency but generally high E stereoselectivity (Scheme 3). It was natural to propose the oxetene intermediate 14, but the attempts to isolate and characterize this intermediate failed. The reaction provided a direct and highly E-selective synthesis of trisubstituted olefins, thereby representing an attractive alternative to the classical Horner–Wadsworth– Emmons reaction. The siloxy alkynes serve as a versatile
Chem. Rec. 2014, 14, 1070–1085
© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
X R X Y
OTIPS X Y
OTIPS
X
R = reactive tether
[2+1]
[2+2]
R
intramolecular cyclization
OTIPS R D
D
A
A
X
Y R'
R
[3+2]
OTIPS
B C
[4+2]
B C
A
A D
[n+2] (n>4)
D R OTIPS
B C
A
R
D
OTIPS
R
O O
medium and large lactones
aromatic annulation
Fig. 2. Representative annulation topologies of siloxy alkynes.
OTIPS
t Bu
Si
+
t Bu
n
Bu
t Bu
Ag3PO4 (10 mol%)
n
70 oC
Bu
10
9
Pr
Bu
Si
t Bu
n
CuI 50 oC
Me
t Bu
OH OH n
OTIPS 11
O
Ph
t Bu
Si
O
n
Bu
OH
13
n
Pr
OTIPS 12
Scheme 2. Silacyclopropenation of siloxy alkynes.
surrogate for the phosphonates required in the typical Horner– Wadsworth–Emmons conditions, thus avoiding the generation of stoichiometric amounts of phosphate-containing waste and simplifying the product purification. While the above olefination protocol is efficient and attractive, a stoichiometric amount of the promoter TiCl4 is required. Nevertheless, the process could be catalytic in nature. In 2010, Kozmin and co-workers reported the first catalytic version of this carbonyl olefination.[7] In the presence of 5 mol % of AgNTf2, various siloxy alkynes reacted efficiently with a range of aldehydes under mild conditions to form trisubstituted esters with high efficiency and moderate to excellent stereoselectivity (Scheme 4). Excellent chemoselectivity was also demonstrated in the presence of ketone and ester groups.
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Silver is a good π-acid, so the authors proposed that the reaction might start with a rapid and reversible coordination of silver to the alkyne, followed by aldehyde addition and ring closing to form the oxetene 14. Subsequent electrocyclic ring opening then gave the observed olefination product 15. 2.2.2. [2 + 2] Cycloaddition with Imines Imines can also undergo similar [2 + 2] cycloaddition reactions with siloxy alkynes to form four-membered dihydroazete or lactam products. In 1990, Maas and co-workers reported the first example with kinetically stabilized (hindered) azete 16.[8] Stirring the mixture of siloxy alkyne 17 and 1,2,3-tri-tert-butyl azete 16 under argon for 72 hours afforded the so-called Dewar pyridine 18 in 46% yield (Scheme 5). The cycloaddition displayed very high regioselectivity, which could be explained by steric control of the transition state geometry rather than bond polarization that would favor the opposite regioisomer 19. In this case, 19 was not observed. In 2000, Shindo and co-workers reported a lanthanoidcatalyzed imine olefination reaction with siloxy alkynes.[9] In the presence of a lanthanoid triflate, such as Pr(OTf )3 or Yb(OTf )3, as the Lewis acid catalyst, the reaction between 1-siloxy-1-hexyne 9 and imine 20 gave α,β-unsaturated amides 21 in 43% yield, together with lactam 22 in 22% yield (Scheme 6).[9] The catalyst turnover and yield were moderate, but this process featured good stereoselectivity in terms of the alkene configuration (E only). The observation of lactam 22 confirmed the [2 + 2] pathway, in which the direct adduct 23 might be involved as an intermediate. It is also worth noting
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OTIPS + H
R
O
1) TiCl4 (1 equiv.), CH2Cl2, -78 oC
O R'
R'
R
OMe R
2) TiCl4; MeOH -78 oC to rt OTIPS O R' 14
Ph
O OMe
OMe
n
Ph
OMe
n
C5H11
Ph
63%, E only
OMe n
C5H11
Ph
Bu
65%, E only
O
O
O
62%, E only
64%, E:Z = 93:7
Scheme 3. TiCl4-promoted carbonyl olefination with siloxy alkynes.
OTIPS
AgNTf 2 (5 mol%)
O +
H
O R
OTIPS R'
-78 to 20 oC
R'
R
O
R'
CH2Cl2
14
O
O n
Bu
Ph
OTIPS
15
TIPSO
O Me
OTIPS H
H
OTIPS R
n
Pent
OTIPS
AgNTf 2
14
15
R
H
O2N
O2N 84%, E:Z > 95:5
75%, E:Z = 86:14
O Me
OTIPS
Me 2
H
Me
n
Bu
OTIPS
OTIPS
R
O Ag R'
TIPSO
TIPS
NTf 2
O C
NTf 2 R
C R
Ag
MeOOC 75%, E:Z > 95:5
Ag NTf 2
H
H
O 76%, E:Z = 94:6
TIPS O C
O
O
n
Bu
87%, E:Z > 95:5
O
80%, E:Z = 91:9
H
R'
Scheme 4. Silver-catalyzed carbonyl olefination with siloxy alkynes.
that the regioselectivity of this reaction is opposite to the above example (Scheme 5), and the selectivity in this case is governed by the electronic effect. 2.2.3. [2 + 2] Cycloaddition with Ketenes Besides carbonyl and imine groups, activated C=C bonds can also be the reactive motifs for [2 + 2] cycloadditions with siloxy alkynes. For example, in 1988, Kowalski and Lal reported that
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ketenes can form [2 + 2] cycloadducts with siloxy alkynes and the corresponding cyclobutenones were obtained with excellent efficiency (Scheme 7).[10] Due to the high reactivity of ketenes, the reaction could proceed without a catalyst under mild conditions. In the same paper, the authors demonstrated that these cyclobutenone products could be further converted to other useful molecules, including the transposition of the enone moiety as well as the subsequent application in benzannulation reactions.
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© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
OTIPS N
16
+
N
rt Ph
Ph
OTIPS
pentane
+
N OTIPS
Ph
72 h
17
19 (0%)
18 (46%)
Scheme 5. The Maas cycloaddition of siloxy alkyne 17 with azete 16.
OTIPS
PMP +
N
n
9
n
Bu
MeCN
Ph
Bu
O
Pr(OTf)3 (30 mol%)
Bu N
PMP
21
22 22%
43% (E only) n
Bu
O
Ph
Ph
0 oC to rt
20
n
PMP N + H
OTIPS N
Ph
PMP 23
Scheme 6. Shindo’s imine olefination with siloxy alkynes.
OTIPS
H +
R
H C O
CH2Cl2
O
TIPSO
Me o
0 C 5h
R
O TIPSO
Me
O
77%
n
R = Cy, 92% R = nPent, 88% R = Ph
85%
OTIPS
AgNTf 2 (5 mol%)
Bu
CH2Cl2 20 oC
n
CN
Bu
TIPSO
69%
n
O
Bu O
OMe
Scheme 7. The [2 + 2] cycloaddition of siloxy alkynes with ketenes.
CN
TIPSO
OMe
78%
n
Bu
2.2.4. [2 + 2] Cycloaddition with Activated Alkenes In 2004, Kozmin and co-workers reported the Ag-catalyzed [2 + 2] cycloaddition of siloxy alkynes with simple electrondeficient alkenes.[11] With 5 mol % of AgNTf2 as the catalyst, unsaturated enones, esters, and nitriles all participated in the reaction to form a range of highly functionalized siloxy cyclobutenes with good efficiency (Scheme 8). The reaction could not proceed under thermal conditions. Other Lewis acids, such as TiCl4 and BF3, promoted the reaction with low efficiency. Mechanistic studies suggested a stepwise mechanism. The reaction may be initiated by activation of either the siloxy alkyne or the activated alkenes by the silver catalyst. Complexation of siloxy alkynes with the silver catalyst was also observed by NMR. This reaction demonstrated a new mode of reactivity for siloxy alkynes and also provided a new synthesis of useful cyclobutene products.
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Scheme 8. Ag-catalyzed [2 + 2] cycloaddition with activated alkenes.
2.3. [3 + 2] Cycloaddition Donor–acceptor cyclopropanes are widely used precursors as three-carbon dipolar species for cycloadditions. Various reaction partners, such as indoles, enol ethers, and aryl acetylenes, have been employed for such cycloadditions to form cyclopentane skeletons. Nevertheless, electron-rich alkynes had not been employed until 2008.[12] Ready and co-worker reported that siloxy alkynes and donor–acceptor cyclopropanes 24 reacted convergently to form cyclopentenones 25 with good efficiency and stereoselectivity (Scheme 9). The reaction involved sequential generation of dipolar intermediates 26 followed by cycloaddition to form adducts 27, which then underwent elimination and subsequent desilylation to give the enone products. Cyclopentenones with different substitution patterns
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1) Me2AlCl/air (1 equiv)
OTIPS
CO2Et +
R1 OEt R2
R
R1
2) HF.Pyridine DCM, -78 oC
R
O
EtO2C
R2 25
24
CO2Et
OTIPS
EtO2C
OTIPS
EtO2C
R1 EtO
R1 EtO
R2 26
EtO2C
R
R2
27
O
EtO2C
O
EtO2C
O
EtO2C n
Bu
Bu
Et
O
H
n
Bu
Bu
n
n
77%
R
R1
R2
n
Bu
76%
63%
79%
Scheme 9. The [3 + 2] cycloaddition with donor–acceptor cyclopropanes.
as well as bicyclic scaffolds could be obtained. During the reaction optimization, the authors observed an interesting phenomenon – the catalyst Me2AlCl from a freshly opened bottle gave inferior catalytic activity, while that from an aged bottle could catalyze the reaction with a shorter time and higher efficiency. Further investigation by control experiments suggested that the real active catalyst might be the derivative (MeO)AlMeCl. 2.4. Aromatic Annulation (Formal [4 + 2] Annulation) In 1984, the Danheiser group reported a benzannulation reaction between vinyl ketenes and a range of alkynes, including alkoxy alkynes, ynamines and alkynyl sulfides.[13] In 1988, the Danheiser and Kowalski groups concurrently reported the extension of this annulation to siloxy alkynes, which are typically more reactive than alkoxy alkynes, and thus the scope could be expanded to secondary and tertiary alkyl-substituted alkynes.[2d,10] A wide range of monosilylated resorcinol products 29 were obtained in good to excellent yield (Scheme 10). It was believed that the reaction begins with four-electron electrocyclic opening of cyclobutenone 28 to form the reactive vinyl ketene intermediate 30. Subsequent [2 + 2] cycloaddition between the ketene moiety and the siloxy alkyne formed alkenyl-substituted cyclobutenone 31, which then undergoes sequential electrocyclic ring opening, six-electron electrocyclic ring closure, and tautomerization to give the observed aromatic product 29 via 32. The overall reaction could be regarded as a formal [4 + 2] annulation.
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Later on, Danheiser and co-workers reported a secondgeneration version of the above annulation featuring a new photochemical strategy for the generation of the reactive vinyl or aryl ketene intermediates.[14] Instead of thermal electrocyclic ring opening of cyclobutenones, Wolff rearrangement by irradiation of diazo ketones 33 was employed to generate aryl- and vinylketenes 30 (Scheme 11). Since the diazo ketones 33 could be efficiently obtained from a wide range of readily available aryl and vinyl ketones 34, the new two-step strategy significantly expanded the substrate scope. A range of polycyclic aromatic and heteroaromatic compounds could also be synthesized with this new method. More recently, the Danheiser group also reported that lithium ynolates generated from siloxy alkynes are also reactive towards (trialkylsilyl)vinylketenes in the benzannulation reactions.[15] Due to the reduced reactivity of silyl ketenes, siloxy alkynes are not reactive enough. However, siloxy alkynes are useful precursors of lithium ynolates in these reactions. Owing to its excellent efficiency as well as its unambiguous regioselectivity, which is typically an issue in the more conventional direct aromatic substitution strategy for the synthesis of multisubstituted aromatic compounds, the Danheiser benzannulation has been demonstrated as a key step in the syntheses of various natural products, including cylindrocyclophanes, aegyptinone A, danshexinkun A, (−)cryptotanshinone, etc. (Figure 3).[16] It is worth noting that the Danheiser annulation is one of the few reactions of siloxy alkynes that have been widely applied in natural product synthesis. In the above benzannulations, the reaction partner (i.e., vinyl or aryl ketene) serves as a four-carbon unit to react with the siloxy alkynes to form the all-carbon aromatic ring products. Indeed, the use of heteroatom-containing four-atom variants could result in heterocyclic aromatic compound formation. In 2007, Movassaghi and co-workers reported an elegant pyridine synthesis employing N-vinyl and N-arylamides as the annulation partners with alkynes.[17] The reaction starts with in situ generation of the reactive vinyl- or aryliminiums 37 from amides 35 in the presence of Tf2O (Scheme 12). Subsequent stepwise alkyne addition followed by ring closing and aromatization furnishes the observed pyridines 36 in good yield. In addition to siloxy alkynes, other electronrich alkynes and enol ethers including ynamides and alkoxy alkynes were also suitable substrates. Thus, the method provided a convergent and rapid synthesis of highly substituted pyridines with controlled substitution patterns. Recently, the Kozmin and Rawal groups reported a new benzannulation using 1,2-diazines as the reaction partner.[18a] With the AgNTf2/2,2′-bipyridine catalyst system, the formal inverse electron-demand Diels–Alder reaction between phthalazines 38 and siloxy alkynes proceeded efficiently at room temperature to form naphthalenes 39 in high yield
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Siloxy Alkynes in Annulation Reactions
OTIPS
R1
O
R2
R3
R
Δ
+
OH R3
TIPSO f ormal [ 4+2]
R
R1
28
29 electrocyclic ring-closing; tautomerization
electrocyclic ring-opening R R1
C
R2
electrocyclic ring-opening
O TIPSO [ 2+2] cycloaddition
R2 R3
R
O R1 R2
C O R3
TIPSO R3
31
30
R2
R1 32 n
Bu
n
Bu
nC5H11
OMOM
MOMO
Cl
TIPSO TIPSO
TIPSO
TIPSO OH
i Pr
Me
OH
92% (Ref 2d)
Ph
OH
59% (Ref 2d)
80% (Ref 10)
OH
76% (Ref 10)
Scheme 10. Benzannulation of siloxy alkynes with cyclobutenones.
O R2
N2
photochemical Wolff rearrangement
R1
R1
R3
CH3
O
C
R1 H3C
R3
33
CH3
30
R2
HO
CH3 R2
R R1
R3 34
H
aegyptinones A
(Ref 16g-i)
(Ref 16c)
OH R3
TIPSO R1
O
cylindrocyclophanes
O R2
H3C CH3
CH3
f ormal [ 4+2] R
O
OH
H3C
OTIPS
CH3 O
OH
OH
CH3
O
O OH
O
R2
CH3
O
O
Scheme 11. Second-generation benzannulation using diazo ketones. H3C CH3
CH3
(Scheme 13). The reaction scope is broad in terms of the siloxy alkynes. It is worth noting that electron-demand Diels–Alder reactions of this type are scarce and typically require high temperature under thermal conditions. This reaction represents one the few examples with heterocyclic azadienes using Lewis acid activation. Although other ligands (e.g., BOX, PYBOX, pyridine, and terpyridine) could be used, the best efficiency was obtained with 2,2′-bipyridine. It was proposed that the Lewis acid activates the electrophile by lowering the
Chem. Rec. 2014, 14, 1070–1085
danshexinkun A
(-)-cryptotanshinone
(Ref 16b)
(Ref 16d)
Fig. 3. Selected natural products that were synthesized using the Danheiser annulation.
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R2 HN R1
+
O
R2
Tf 2O 2-ClPy
OTIPS
R3
R3
N R1
R
OTIPS R 36
35 Tf 2O 2-ClPy
− TfOH OTIPS R2
R2
TfO H
R
R3
N
R1
− 2-ClPy − TfOH
OTf
N
R3 OTIPS
N C
R1 R
Cl
OTf
37 OMe O
N Ph
OTIPS
N n
Bu
n
Bu
N
OTIPS n
Bu
c
OMe
Hex
OTIPS Ph
61%
73%
74%
Scheme 12. Pyridine synthesis using vinyl- and arylamides.
LUMO, which facilitates the nucleophilic attack by the alkyne to form ketenium intermediate 40 (path a). Further ring closure forms the formal [4 + 2] adduct 41. Release of nitrogen gas with concomitant aromatization gives the observed products. The formation of 41 might also proceed in a concerted pathway (path b). Later on, the same groups reported that the same reaction partners reacted in a [2 + 2 + 2] cycloaddition manner to form complex heterocyclic products when pyridinium trifluoromethane-sulfonimide was used as the promoter.[18b] In addition to 1,2-diazines as the reaction partner, Kozmin and co-workers later found that other heterocycles, such as 2-pyrones 42 and isoquinoline oxides 44 as well as pyridinium salts 46, were also useful benzannulation partners (Scheme 14).[19,20] Notably, their discovery was enabled by label-assisted mass spectrometry. Different from the reactions with 1,2-diazines where nitrogen was extruded as a leaving group, these new annulations bear hemi cleavable leaving groups. After aromatization from the direct bridged adducts (e.g., 43, 45, and 47), the leaving groups (carboxylate, oxime, and imine) remained as a substituent of the products. Therefore, these reactions provided access to these functionalized aromatic compounds. Although the AgNTf2/2,2′-bipyridine catalyst proved best in the previous reaction, gold/phosphine and silver carboxylate performed better for these new annulations.
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2.5. Medium- and Large-Ring Lactone Synthesis ([n + 2], n > 4) While siloxy alkynes have been very versatile in small-ring annulation reactions, the discovery of their reactivity in forming medium and large rings has only been reported very recently.[21] Enabled by the design of a new family of (1,6)amphoteric molecules, e.g., 48, we discovered the first eightmembered lactone formation using siloxy alkynes. Our design of the (1,6)-amphoteric molecules featured the incorporation of oxetane and aldehyde functionalities in one molecule with an aryl linker (Scheme 15).[21a] The formal [6 + 2] cycloaddition was efficiently catalyzed by the Brønsted acid HNTf2 and proceeded at room temperature. Various aryl-fused eightmembered lactones 49 were synthesized in moderate to good yield. Medium-sized (eight- to eleven-membered) lactone synthesis is a well-known challenge in organic synthesis. This challenge is largely due to the unfavorable ring-closing kinetics and transannular interactions for medium-ring formation.[22] It is particularly problematic for intermolecular reactions due to additional unfavorable entropic change and competitive dimerization side reactions. Typical conventional strategies to enhance the efficiency are slow addition of substrates and/or high dilution, but these only lead to limited and unpredictable improvement. These strategies also have limited utility in largescale synthesis. Notably, our reaction does not require slow addition or high dilution and represents one of the very few examples of intermolecular synthesis of medium-sized lactones. Two possible mechanisms are depicted in Scheme 16. In mechanism a, upon activation by the Brønsted acid catalyst, cyclization of substrate 48 forms oxocarbenium 50. Then, attack of the electron-rich alkyne gives ketenium intermediate 51. Further cyclization forms cyclic silyl ketene acetal 52. Subsequent activation of 52 by protonation of the ether motif initiates the C–O bond cleavage to form lactone 53. Finally, silylation of the free alcohol furnishes the observed eightmembered lactone products. Alternatively, as shown in mechanism b, the alkyne and the aldehyde undergo [2 + 2] cycloaddition to form oxetene 54, followed by electrocyclic ring opening to give α,β-unsaturated ester 55. Next, with acid activation of the oxetane, the carbonyl group can cyclize in an 8-exo-tet manner to give 53 via the intermediacy of 56. Further silylation delivers the product. While the above process proved efficient for a range of aryl-linked (1,6)-amphoteric molecules, the extension to aliphatic linkers between the oxetane and aldehyde moieties resulted in none of the desired lactone formation under the standard conditions. This dramatic decrease in reactivity is probably due to the increased substrate flexibility or loss of the aryl resonance stabilization of the relevant intermediates. Aiming at further developing a more general and practically
Chem. Rec. 2014, 14, 1070–1085
© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
R1
OTIPS N N
AgNTf 2 2,2'-bipyridine
+
R1
OTIPS R
R 38
39 Ag
path a stepwise
N
Tf 2N N N
R1
Ag
[4+2] N N Ag
N N
R
C
40
N2
path b
N
N N
OTIPS
R1
OTIPS
R
41 Cl
OTIPS n
n
n
Bu
82%
OTIPS
OTIPS
Bu
Bu 67%
72% OTIPS
OTIPS
OTIPS Ph
83%
80%
95%
Scheme 13. Formal Diels–Alder reaction with 1,2-diazines.
useful medium- and large-ring lactone synthesis, we employed a different strategy featuring unprecedented bicyclic oxetenium ring expansion.[21b] The new strategy involves a [2 + 2] cycloaddition between cyclic oxocarbenium 58 and ynolate 2, which are derived from cyclic acetal 57 and siloxy alkyne, respectively. The adduct oxetenium 59 next undergoes ring opening to form the observed ring-expansion lactone product 60 (Scheme 17). Promoted by the readily available Lewis acid BF3, this intermolecular process employs mild conditions without high dilution or slow addition. More importantly, compared with the previous reaction, the scope is significantly expanded. Fusion with an aryl group is not required. Moreover, the process is not limited to eight-membered ring formation, and 7-, 9-, 10-, and 18-membered lactones were also obtained with high efficiency. 2.6. Intramolecular Cyclizations In addition to the many intermolecular annulations, intramolecular cyclization has also been studied. These reactions typically required the synthesis of siloxy alkynes tethered with an internal functional group, which could sometimes be
Chem. Rec. 2014, 14, 1070–1085
problematic due to incompatibility of the functional group with the siloxy alkyne synthesis. Currently, these intramolecular reactions include enyne metathesis and cycloisomerizations. 2.6.1. Siloxy Enyne Metathesis In 2001, Kozmin and co-workers reported a ring-closing enyne metathesis of siloxy alkynes.[23] A range of 1,5- and 1,6-enynes 61 were treated with the Ru-based Grubbs catalyst 62 to give silyl dienol ethers 63, which could be isolated or directly desilylated to form the enone products 64 in good to excellent yield (Scheme 18). Mechanistically, it was believed that the reaction follows the typical enyne metathesis mechanism, which is the sequential formation of Ru-alkylidenes, metallacyclobutenes, and vinyl carbenes, etc. This reaction expanded the scope of enyne metathesis. It provided a highly efficient synthesis of a range of five- and six-membered carboand heterocyclic molecules that could be transformed to other useful building blocks. For example, the reaction was later demonstrated as the key step in the synthesis of natural products furanoeremophilane and bakkenolide A.[24]
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THE CHEMICAL RECORD
t Bu P Au(NCMe) t Bu SbF6
O OTIPS
O
1)
(2.5 mol%)
+
R2
2) HF-pyridine
R1
CO2H OH
R2 R1
R
R
42
O R2
H
O
OTIPS
R1 H
R
R2
CO2H OTIPS
R1
R
43
OH R1 N
OTIPS
R2
R1 N
same as above
O
R2
OTIPS
O
R
45
R1 N
R1
N
H
44
R3
H
R
R2
R3 N
OTIPS 1) PhCO2Ag 2) F- on PS
R2
H
R R3 NH
I 46
R1
HO
R1
R
R2
R2 47
Scheme 14. Aromatic annulation with 2-pyrones, isoquinoline N-oxides, and pyridinium salts.
2.6.2. Cyclization of Arene- and Alkene-Tethered Siloxy Alkynes It was known that siloxy alkynes could be activated by Lewis acids or Brønsted acids to generate electrophilic ketenium species. Therefore, with proper incorporation of an internal nucleophile, intramolecular cyclization should be expected to take place. In 2004, the Kozmin group reported the first example of such cyclizations to synthesize substituted tetralone and cyclohexenone derivatives. After activation of the siloxy alkyne moiety by HNTf2 or MsOH, arene 65 and alkene 66 cyclized smoothly to form the six-membered products in either the silyl enol ether or the desilylated enone form (Scheme 19).[25] In the case of the arene cyclization, a proton could be regenerated efficiently at the rearomatization step, so the whole reaction could be completed with a catalytic amount
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of proton. In contrast, the reaction of alkene 66 required a stoichiometric amount of the acid promoter in order to achieve good efficiency. 2.6.3. Au-Catalyzed Cycloisomerization of 1-Siloxy-1,5-enynes In sharp contrast to the above Brønsted acid promoted siloxy enyne cyclization with direct intramolecular nucleophile interception of the ketenium intermediate, the use of gold(I) chloride as the catalyst for the similar 1,5-enyne substrates 67 resulted in a novel cycloisomerization process featuring an unusual formal position-swapping of the R1 and OTIPS groups (Scheme 20).[26] Only 1 mol % of AuCl was sufficient to catalyze the reaction to completion within 30 min. With a tertiary C(3) position, a mixture of 1,4- and 1,3-cyclohexadienes 68
Chem. Rec. 2014, 14, 1070–1085
© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
OTIPS
O
HNTf 2 (10 mol%)
OTIPS +
Ar
O
O
Ar
DCM, rt
R
O
48
R
49
OTIPS
OTIPS
OTIPS
OTIPS
O
O
O
O
O
O n
Bu
71%
S
O
t Bu
O t Bu
Ph
60%
47%
53%
Scheme 15. Formal [6 + 2] annulation with (1,6)-amphoteric molecules.
OH
Ar
H+
O
O C O R
Ar
H
Ar
O
52
OTIPS OTIPS
R
HNTf 2
O Ar
TIPS
O
R 51
50
NTf 2
TIPS
O
H+ a
O
O
Ar
O
OH
TIPSNTf 2
O
Ar
O
O 48
R
R
R H+
TIPSNTf 2
49
b [2+2]
53
OH
O H+ Ar
OTIPS
O O R
Ar
O TIPS O TIPS
55
O
O
O TIPS
54
Ar
R
56
R
NTf 2
Scheme 16. Plausible mechanisms.
and 69 was formed, with the former being the major product. Introduction of a quaternary center at the C(3) position resulted in exclusive formation of 1,3-cyclohexadienes. The addition of a phosphine ligand could inhibit the reaction, but cationic Au(I) generated from Au(PPh3)Cl in combination with a silver salt (such as AgOTf or AgNTf2) was found to be equally effective. Control experiments also indicated that the presence of the C(1)-siloxy group was crucial to the formation of the cyclohexadiene products.
Chem. Rec. 2014, 14, 1070–1085
The most unusual but general phenomenon in this reaction is the formal migration of the siloxy group from the C(1) to the C(6) position. This could be explained by a series of alkyl shifts. As shown in the proposed mechanism (Scheme 21), the process begins with gold activation of the electron-rich alkyne motif, forming ketenium 70. Intramolecular nucleophilic attack by the alkene followed by back attack forms the cyclopropane intermediate 72 via 71. Next, the electron-donating C(1) siloxy group initiates the subsequent [1,2] alkyl shift to
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THE CHEMICAL RECORD
R1
BF3-OEt2 2,4,6-collidine
OTIPS n
+ OR2
O
R O
O
DCM
R
HNTf 2 (10 mol%)
R n+2
R1
60
57
CH2Cl2 20 oC
OTIPS
65
R OTIPS
40-99% yield − H
H R1 R1
n
R n
[2+2]
+
(89%)
R=
O
66
O
n O
Bu n=1, 86% (Z) n=2, 88% (Z/ E = 1:1) O n=10, 87% (E)
93%
Scheme 17. Annulation with cyclic acetals for medium and large lactone synthesis.
1) 62 (5 mol%) benzene, Δ
OTIPS
aq. hydrolysis
R1
R3
O
n
n
Pr
O
O
76%
80%
Pr
O 78%
Scheme 19. Brønsted acid promoted cyclization of siloxy alkynes.
O
to give either 1,3-cyclohexadiene 77 or 1,4-cyclohexadiene 78. The proposed mechanism well explains the observed unusual skeletal reorganization. Although the original reaction was limited to siloxy alkynes, Kozmin and co-workers subsequently managed to significantly expand the reaction scope to include normal 1,5-enynes (without siloxy substitution) using a platinum-based catalyst system.[27]
CH3
2) HF, CH3CN 61
64 N Mes Mes N Cl u R Ph Cl PCy3
R2
Ph
O 72%
HNTf 2 or MsOH
OTIPS
n
Bu
OTIPS
R3
O
n
O
Bu
77%
n
H
R1
n
O
75%
Bu
R2
Me
O
O
O TIPS
LA
Bu
TBSO
C
O
n
R = nBu (91%) R = Ph (64%)
O
O
59
2
R
R
O
58
R
R
O
O
OTIPS
HF
62
2.6.4. Cyclization of 1-Siloxy-1,5-diynes
63
O
O Me O
O N
O Me
Bn CH3
O Me
O
MeO 88%
91%
88%
86%
Scheme 18. Ring-closing metathesis of siloxy enynes.
form oxocarbenium ion 73. An additional [1,2] alkyl shift delivers the intermediate 74, leading to gold carbene 75 (or 76) by C–C bond cleavage. Depending on the hydrogen availability at the adjacent position, the final elimination step can occur
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Having established the activation of siloxy alkynes by soft and hard electrophiles followed by subsequent intramolecular attack with arenes and alkenes, Kozmin and Sun further examined the reactivity of 1-siloxy-1,5-diynes in the presence of strong Brønsted acid HNTf2.[28] Interestingly, the reactivity of siloxy diynes 79, particularly the way to terminate the carbocation intermediates, was quite different from that of enynes, typically deprotonation or protodemetalation. Indeed, after activation by acid, diyne 79 cyclizes (via ketenium 80) in a 5-endo-dig mode to form alkenyl cation 81 and then abstracts a halogen atom from the haloalkane solvent, leading to the formation of the halo enone product after acid-promoted protodesilylation of the intermediate silyl dienol ether 82
Chem. Rec. 2014, 14, 1070–1085
© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim
Siloxy Alkynes in Annulation Reactions
R3 R2
R4
R3
R3
R5
AuCl (1 mol%)
R4
R2
R2
R4
R5
or
R1
20 oC CH2Cl2
OTIPS
TIPSO
TIPSO
R1
R1 68
67
n
Ph
Me
Pr
TMS
69
n
Ph
n
Ph
Pr
Pr
+
TIPSO
TIPSO
TIPSO
TIPSO
73%
50%
99% (4:1)
Me
Me Me
Me +
Me
Pent
TIPSO 88%
82% (6:1)
Me Ph
Me
n
TIPSO
TIPSO
TIPSO
Me
Me
Me
89%
Scheme 20. Cycloisomerization of 1-siloxy-1,5-enynes.
R1
R2
R3
R2
R1
R3
R1
R3
or TIPSO
TIPSO 77
OTIPS
78
AuCl R2
R1 C O TIPS
R3
R2
R1
AuCl
R1
AuCl
TIPSO H
70
R3
R2
76
75
R2 = H
R1
R2
R2
R3
AuCl OTIPS
71
R3
R1
AuCl
TIPSO
74
R2
R3
AuCl OTIPS 72
R3 AuCl
TIPSO
R2 = H R1
H
R1
R3 AuCl
OTIPS
73
Scheme 21. Mechanism of Au-catalyzed cycloisomerization of siloxy enynes.
Chem. Rec. 2014, 14, 1070–1085
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THE CHEMICAL RECORD
R2
X
haloalkane (RX, solvent)
OTIPS
R'
R'
O 83-85
79
R2
H C O
R'
R2
R2 NTf 2
NTf 2
RX TIPS
Acknowledgements
X
R'
R'
OTIPS
80
81
OTIPS 82
Me Me
Br
Cl
n
O
83 (60%) RX = CHCl3
Oct
n
O
Oct
n
Bu
84 (71%) RX = CH2Br2
O
[1]
O 85 (69%)
86 (58%)
RX = CH3I
RX = PhH
Scheme 22. HNTf2-promoted cyclization of 1-siloxy-1,5-diynes.
(Scheme 22). HNTf2 is uniquely effective as a promoter in this process, presumably due to its strong acidity in organic solvents as well as the low nucleophilicity of its counteranion. With halogenated solvents, such as CH2Cl2, CHCl3, CH2Br2, and even CH3I, the corresponding halogen atom was abstracted and incorporated into the enone products 83–85 with high efficiency and good E selectivity. More surprisingly, with benzene as the solvent, trapping of the alkenyl cation 81 by benzene (i.e., Friedel–Crafts reaction) was also observed and the tetrasubstituted alkene product 86 was obtained in moderate yield.
[2]
[3] [4] [5] [6] [7]
3. Conclusion and Outlook We have summarized all the annulation reactions of siloxy alkynes. These reactions clearly demonstrate the versatility of siloxy alkynes in the synthesis of small-, medium-, and largering annulation products. These structurally diverse carbo- and heterocyclic products are useful in organic synthesis. Regarding the ring-size distribution of the annulation products, the majority of them are four- and six-membered ring products. Particularly, aromatic annulations to form six-membered ring aromatics have received considerable attention. For example, the Danheiser benzannulation has been applied in several natural product syntheses. In contrast, medium- and large-ring synthesis using siloxy alkynes is still at an early stage, and it is
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Financial support was provided by HKUST and Hong Kong RGC (GRF-604411 and GRF-605812).
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Ph
I
n
Oct
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R2
HNTf 2 (1.1 equiv.)
[8] [9] [10] [11] [12] [13]
[14]
Chem. Rec. 2014, 14, 1070–1085
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