Regioselectivity in the Au-catalyzed hydration and hydroalkoxylation of alkynes.

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Regioselectivity in the Au-Catalyzed Hydration and Hydroalkoxylation of Alkynes Justin A. Goodwina and Aaron Aponick*a

Received 00th January 2015, Accepted 00th January 2015

Over the past decade and a half, homogenous gold catalysis has emerged as a diverse and rich field of research resulting in the continuous development of new methods for organic synthesis. The activation of alkynes towards nucleophilic attack by AuI and AuIII complexes is a well-established mode of reactivity and the gold-catalyzed hydration and hydroalkoxylation of alkynes are two of the more well-explored reaction pathways. Although these classes of reactions have seen continuous development since their initial reports, achieving regioselectivity persists as one of the most challenging issues for this chemistry. This article aims to draw attention to the general problem of regioselectivity in these reactions. A select set of examples is presented to highlight the challenges and survey some of the strategies employed to address this problem.

DOI: 10.1039/x0xx00000x www.rsc.org/chemcomm

1. Introduction The addition of oxygen nucleophiles to carbon-carbon triple bonds is a classic research area that has generated many highly useful transformations for organic synthesis. These reactions can be catalyzed by a variety of metal complexes including mercury,1 palladium,2 ruthenium,3 rhodium,4 platinum,5 and other metals with varying levels of success.6 In addition to catalysts based on these metals, the gold-catalyzed hydration and hydroalkoxylation of alkynes is a well-developed general class of reactions that has been brought to the forefront of organic synthesis over the past 15 years.7 A variety of AuI and AuIII catalyst systems have been shown to effect these transformations with such high efficiency that they might now be considered the standard for alkyne hydration and hydroalkoxylation.8

[M]

X H + R

R R

1

X H

X R

[M] 2

OH O

X

-[M] R

[M]3

R

R H 4

Au[P(t-Bu)2(o-biphenyl)]SbF 6 O

O

OTBS

H

R

The high atom economy coupled with the ability for rapid generation of structural complexity and high functional group tolerance has established Au-catalyzed alkyne addition as an invaluable synthetic tool. For example, a recent report from Fürstner and coworkers demonstrated the power of these transformations in their formal synthesis of (-)-polycavernoside A.10 The AuI-catalyzed hydroalkoxylation of alkyne 5 afforded the advanced intermediate 6 that could be further elaborated to the desired natural product (Scheme 1).11

5

DCM MS 4Å rt

O

O

O

O

OTBS 6 67%

Scheme 1. Gold-catalyzed hydroalkoxylation in the formal synthesis of (-)-polycavernoside A

Figure 1. General Metal-catalyzed addition to C-C triple bonds

The utility of this class of reactions has been demonstrated by a multitude of examples in natural product total syntheses.9

This journal is © The Royal Society of Chemistry 2015

Although this research platform has been greatly advanced in recent times, there is significant room for improvement, particularly in the area of the regioselective hydration and

Chem. Commun. , 2015, 00, 1-‐3 | 1


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FEATURE ARTICLE

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FEATURE ARTICLE

ChemComm DOI: 10.1039/C5CC00120J

2. Hydration of Alkynes

[(Ipr)AuCl]/AgSbF 6

R1

O

R2 1,4-dioxane/H 2O 120 °C

9

R1

R2 9

(1)

R2

(2)

10

[{Au(NHC)}2(µ-OH)[BF4]

R1

R2

Dioxane/H 2O 80 °C

O R1 10

Low Temp. ppm catalyst loading

Scheme 2. Current state-of-the-art conditions for goldcatalyzed alkyne hydration

2.1 General Introduction/Current State-Of-The-Art Although the gold-catalyzed hydration of alkynes was first reported over 100 years ago,12 further exploration of this significant finding was not undertaken until 1976 when Thomas and coworkers reported the conversion of phenylacetylene to acetophenone using tetrachloroauric acid.13 Over the past decade and a half, much progress has been made in the goldcatalyzed hydration of alkynes.6,14 This methodology provides rapid access to a variety of ketone products. It is well known that hydration of terminal alkynes 7 proceeds with a high level of regioselectivity to furnish predominately the Markovnikov products 8 (Figure 2); however, hydration of internal alkynes often results in multiple regioisomeric products and the problem is illustrated by the hydration of 9 to form 10 and 11. Terminal Alkynes; Highly Selective:

O

Au Cat.

R1

H

H 2O

7

H

R1

H H 8

Internal Alkynes; Generally not regioselective: O Au Cat. R2 R1 R 2 H 2O 1 R H H

9

10

O R1

R2

H H 11

Figure 2. Gold-Catalyzed hydration of alkynes

Currently, a recent report by Nolan and coworkers could be considered the benchmark in the hydration of alkynes with respect to reaction conditions (Scheme 2, eq 1). Through the use of N-heterocyclic carbene (NHC) ligands, they were able to develop a highly efficient catalyst system requiring only partper-million loadings for addition to internal alkyl and aryl alkynes.15 This mild catalytic system provides a significant advantage as it obviates the need for high temperatures or acid additives. In a subsequent report, they later demonstrated that the process could also be conducted without a silver salt (Scheme 2, eq 2). This was achieved by activating a mononuclear gold hydroxide complex with HBF4 to generate a dinuclear gold hydroxide species that efficiently catalyzed the hydration of alkynes.16

2 | Chem. Commun., 2015, 00, 1-‐3

While great strides have been made in terms of improving the catalytic efficiency of the title transformation, there is room for further development in this class of reactions. Specifically, internal alkyne hydration leaves much to be desired with respect to regioselectivity. 2.2 Hydration of Internal Alkynes As mentioned above, the hydration of terminal alkynes has been well established and proceeds with high levels of selectivity; however, in contrast, the hydration of internal alkynes often leads to the formation of regioisomeric products. Several factors appear to influence which position of the alkyne is attacked including both the steric and electronic nature of the substituents. As a general observation, the selectivity for the intramolecular hydration of internal alkynes is low and is highly substrate dependent. This observation was made early on and, in their initial report, Utimoto and coworkers reported the hydration of internal alkynes 9 to generate a mixture of the desired ketone products 10 and 11 (Scheme 3).17 1-Phenyl-1butyne was treated with NaAuCl4 in water and methanol to afford a mixture of ketones 10a and 11a in low yield with a slight preference for attack at the phenyl substituted alkyne carbon. It should be noted that this level of selectivity requires only a very small difference in energy between the two productforming pathways. Interestingly, hydration of 2-nonyne gave a mixture of 10b and 11b in high yield with a similar level of selectivity, modestly favoring the formation of the methyl ketone. NaAuCl 4 R1

O

R2 MeOH/H 2O reflux

9

O

R1

Ph O

Ph 10a

10

R1 11

R2

28% 10a:11a = 57:43

11a

O

94% 10b:11b 60:40

O 10b

O R2

11b




hydroalkoxylation of internal alkynes. Our interest in this chemistry stems from our own attempts to develop a tandem hydroalkoxylation / Claisen rearrangement sequence that proved to be extremely challenging (vide infra). This article is not intended to be a comprehensive review of gold-catalyzed alkyne hydration and hydroalkoxylation, but aims to use select recent examples to outline the inherent challenge of this issue and to highlight some of the unique strategies employed to address this problem.

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FEATURE ARTICLE DOI: 10.1039/C5CC00120J

Scheme 3. Early example of Au(III)-catalyzed alkyne hydration

While Utimoto’s work is one of the earliest reports in this area, recent examples further illustrate the persistence of regiochemical issues with internal alkyne hydration. Exploring different ligands and counterions, Leyva and Corma observed that both yield and selectivity could be increased to varying extents in the hydration of internal alkyne 12 (Scheme 4).18 A series of cationic gold complexes bearing phosphine ligands were screened. In all examples, a mixture of ketone products 13 and 14 was observed. Employing the catalytic Ph3PAuNTf2 complex gave a 50:50 mixture of products in low yield. Switching to more highly donating phosphines such as SPhos, greatly improved the reaction yield but provided the products in a 60:40 ratio favoring the aryl ketone 13. This small enhancement in selectivity may arise from either the increased steric bulk or enhanced electron donating ability of the phosphine ligand.

( )5

Ph 12

Catalyst AuPPh3NTf 2 AuSPhosNTf2 AuSPhosOTf

Catalyst, H 2O

O

MeOH rt

( )6 Ph 13

% yield 30 100 100

13:14 50:50 60:40 60:40

O Ph

O

Pcy 2 OMe

SPhos

Scheme 4. Phosphine ligand effects in gold (I) catalyzed alkyne hydration

R1

10

81% 10a:11a = 19:81

O 10a

R2 11

Ph

Ph

11a 74% 10c:11c = 69:31

O O 10c

11c 99%a OH 10d:11d = 0 : > 99

O OH 10d

O 11d

a

Conditions: [(IPr)AuOH], HSbF6, 24h Scheme 5. Employment of a NHC gold catalyst system to furnish regioselective alkyne hydration

Although a general solution to the regioselective hydration of internal alkynes remains an unsolved problem, several strategies employing either substrate or catalyst design have been implemented to address this challenge. One particular strategy that has proven to be successful is the manipulation of the alkyne substituents to direct attack of the incoming nucleophile. By including a directing group as a substituent on the alkyne, selective hydration can be achieved generating a single regioisomer (Figure 3). H2O Au cat. R2

Interestingly, using a gold NHC catalyst system, Nolan and coworkers reported higher, albeit modest, selectivities for the hydration of internal alkynes 9 (Scheme 5).15,19 Hydration of 1phenyl-1-butyne gave a mixture of ketones 10a and 11a in a 19:81 ratio. It is noteworthy that this selectivity is opposite of that reported by Utimoto and coworkers. Hydration of 2-octyne afforded a mixture of 10c and 11c, favoring formation of the methyl ketone, while hydration of non-4-yn-1-ol exclusively gave product 10d in high yield. The exquisite selectivity observed with this substrate is presumably due to a directing effect of the alkyne substituent.


O R2

R1

1,4-dioxane/H 2O 120°C

9

O

[(Ipr)AuCl]/AgSbF 6

2.3.1 Substrate directing group strategies ( )5

14

MeO

R2

9

H2O = directing group

O R2 10

Figure 3. Directing group strategy for alkyne hydration

As briefly described above, one particularly effective method used to induce selectivity is the inclusion of a tethered nucleophile as a substituent on the alkyne (Figure 4). Initial selective intramolecular attack by the pendant nucleophile onto the alkyne 15 would lead to intermediate 17 and the selectivity of this initial attack would be governed by Baldwin’s rules.20 This intermediate could then be attacked by water to liberate the directing group. Upon protodeauration, ketone 16 would be generated regioselectively. This strategy has been effectively used with a variety of nucleophilic directing groups and several examples are described below.

Chem. Commun., 2015, 00, 1-‐3 | 3



R1

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FEATURE ARTICLE

R1


[Au]

XH

O

( )n

()

R1

n

XH

[Au] 15

X

R1

via

systems have been reported, but to the best of our knowledge, this has not yet been achieved. Differences in selectivity based

( )n

R

H 2O 17

16

Figure 4. Regioselective alkyne hydration directed by pendant nucleophile

R Ph 3PAuCl AgOTf

EtO 2C EtO 2C

1,4-dioxane/H 2O rt

O EtO 2C CO2Et

21

R O

Hammond and coworkers demonstrated that esters 18 could be employed to furnish alkyne hydration products 19 with complete selectivity (Scheme 6).21 The authors proposed that an initial attack of the ester group would generate intermediate 20 via a 5-endo-dig cyclization, which is favored over the alternative 4-exo-dig process. Hydrolysis of the resulting oxonium ion and protodeauration would then form the desired γ-keto esters 19.

R2 R3

R1

CO2Et

[Au]

NaAuCl 4•H 2O EtOH/H 2O rt

O R2 R3 R1

O Me (CH 2)2COOMe CO2Et Me

CO2Et

O

20

19

O Me

19a 58%

OR4 R1

H 2O

18

Ph

via

CO2Et

R2 R3

O

O Me Et CO2Et C6H13

C6H13

19b 80%

19c 74%

CO2Et 19d 78%

Scheme 6. Use of a neighboring ester to direct alkyne hydration

In a similar fashion, Oh and coworkers showed that aldehydes were suitable directing groups for the regioselective hydration of internal alkynes (Scheme 7).22 Treatment of orthoalkynyl arylaldehydes 21 under cationic gold conditions in the presence of water generated hydration products 22 selectively. An initial 6-endo-dig cyclization by the aldehyde was proposed to direct the attack of water. When the aldehyde substituent on the aromatic ring was changed to a ketone, a complete reversal of selectivity was observed, suggesting that the reaction proceeded through an unexpected 5-exo-dig pathway to produce the opposite regioisomer. Interestingly, when a substrate lacking a directing group was treated under the reaction conditions, the authors report that no reaction occurred. 2.3.2 Catalyst design strategies While including directing groups in the substrate can provide highly regioselective examples, by definition the selectivity observed using this approach will always be directly related to the functional groups incorporated into each substrate. A more general approach may be achieved if a catalyst could be designed to provide regioselectivity based either on steric or electronic considerations. Many examples of different catalyst

4 | Chem. Commun., 2015, 00, 1-‐3

R = CHO 87% R =H 0% R = COMe 85%

22a : 22b = 100:0 22a : 22b = 0:100

EtO 2C

Scheme 7. hydration

CO2Et

22b

Use of an aldehyde directing group for alkyne

on catalyst, albeit small, have been observed suggesting that this may be possible with further development. During their studies on bulkier NHC ligands, Cavell and coworkers screened a variety of sterically imposing six and seven membered ring ligands.23 The steric demand imparted by these ligands was shown to be beneficial in the hydration of substrates such as 4-octyne, which was previously shown to be ineffective under similar conditions employing 5-membered ring NHC ligands bearing mesityl substituents.15 Hydration of 2-hexyne was accomplished in high yields but only moderate levels of selectivity were observed (Scheme 8). Interestingly, the bulkier DIPP ligand 27 gave slightly higher selectivity than the less bulky Mes ligand 26, suggesting that this could eventually be an effective strategy for addressing regioselectivity issues. The development of selective new ligands could lead to vast improvements in this field. O NR n

( )2

AuCl NR

AgBF 4 1,4-dioxane/H 2O 80 °C

23

24

O 25

R=

i-Pr

Mes 26

i-Pr DIPP 27

Cat. 26a 27a 26b 27b

n=1 R=Mes n=1 R=DIPP n=2 R=Mes n=2 R=DIPP

24:25 = 63:37 24:25 = 68:32 24:25 = 61:39 24:25 = 65:35

Scheme 8. Effect of bulky NHC ligands on alkyne hydration

3. Hydroalkoxylation of Alkynes 3.1 Introduction A similar class of reactions, the metal-catalyzed addition of alcohol nucleophiles to alkynes (hydroalkoxylation) has been




22a

+

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extensively explored with a variety of metal catalysts,24 and a gold-catalyzed version of this reaction was first reported by Utimoto in 1991.17 Over the past two decades, this goldcatalyzed variant has been well explored.25 Recently, several experimental studies have been performed to gain insight into the mechanism of this transformation26 as well as to determine the effect of a silver salt27 and its counterion28 when employed in gold-catalyzed additions to alkynes. In general, addition to terminal alkynes occurs at the internal carbon to give the corresponding ketal 29 or enol ether 30 products (Figure 5). In contrast, internal alkynes can potentially furnish the two possible enol ether products. Depending on which position of the alkyne is attacked by the nucleophile, 31a and 31b, in addition to the corresponding ketals 32a and 32b, could all be formed. There are several considerations for determining the selectivity of these reactions including sterics, electronics, and the identity of the nucleophile, but the effects of these factors can often be difficult to predict. Au Cat.

R1

H

ROH

H H

R1 H

28

7

OR

RO OR

29

H

R1 H 30

OR

OR R2

R1

R1

H R1

R2 9

ROH 28

Au Cat.

RO OR R1

H H 32a

DCM rt

O

via

33

34

X X 35

OMe

OMe

Cl MeO

MeO

OMe

OMe

OMe

O

O

34a 84%

O

O

O

34a 92%

34a 90%

Scheme 9. Tandem Au (I)-catalyzed hydroalkoxylation Prinstype cyclization

In similar fashion, Hashmi and co-workers also demonstrated nucleophilic attack exclusively at the internal position.32 Treatment of diyne-diols 36 with the acyclic carbene complex I initiated a hydroalkoxylation sequence to form bisenol ethers via 5-exo-dig cyclization. These intermediates were trapped with an external nucleophile such as water to afford the bis-ketal products 37 (Scheme 8).

R2

R1

2 mol% I AgNTf2

HO R 2

31b RO OR

R2

O

ArH

X

H

31a

Ar

Ph 3PAuCl AgOTf

OH

DCM H 2O or RNH 2 rt

HO R1 36

R2

X O

O

R1

R2

Cl Au N

37

N H I

H H 32b

Figure 5. Gold-catalyzed hydroalkoxylation of alkynes

O

O O

O

O

Ph N

O O

O

O

O

O

CH 3

37a 82%

Terminal Alkynes The intramolecular hydroalkoxylation of terminal alkynes generally proceeds through the initial attack of a tethered alcohol nucleophile and a wide variety of gold-catalyzed intramolecular cyclizations have been developed in recent times.29 These reactions have been shown to proceed with selectivity for attack at the internal position to generate a vinyl gold intermediate that is often used in an additional tandem process. Barluenga and coworkers demonstrated the selective attack in their tandem hydroalkoxylation/Prins-type cyclization (Scheme 9).30 Initial gold-catalyzed exo addition of the hydroxyl group in alkynols 33 selectively furnished enol ether 35 via protodeauration of the organogold intermediate. A subsequent Prins-type cyclization31 involving the allyl group then afforded the desired products 34 in high yield.


Br

Br

3.2 Intramolecular Hydroalkoxylation

37b 79%

37c 48%

37d 80%

Scheme 10. Double intramolecular hydroalkoxylation of terminal alkynes

Manzo and coworkers further demonstrated this selectivity pattern in their intramolecular hydroalkoxylation of 2-alkynylsubstituted phenols 38 (Scheme 11).33 Treatment with AuCl and potassium carbonate induced a 6-exo-dig cyclization of the phenol onto the tethered alkyne to exclusively afford the corresponding enol ether products 39.

Chem. Commun., 2015, 00, 1-‐3 | 5



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FEATURE ARTICLE

ChemComm DOI: 10.1039/C5CC00120J butyrolactone products 43 upon treatment with AuCl3 (Scheme 13).35 Selective attack at the bromine bearing terminal position of the alkyne exclusively afforded the five-membered lactones.

O

AuCl K 2CO 3 CH 3CN 81 °C

N OH R 38

N R 39

OH R1 R2

Br

42

O

O

O

O

O

O

O

toluene / H 2O rt

O

O

O

AuCl3

O R1 R2 43

O

O Me

O


nPr

N H

N Bz

39a 72%

N Ac

39b 63%

N Ts

39c 61%

43a 87%

Internal Alkynes In contrast to their terminal alkyne counterparts, internal alkynes pose a more significant regiochemical problem for intramolecular hydroalkoxylations because attack at both positions of the alkyne is frequently observed unless the substrates are engineered such that the ring size formed or electronics of the alkyne favor the formation of one regiosisomer. When there is little electronic bias, the initial cyclization generally adheres to Baldwin’s rules. Krause and coworkers demonstrated that, in the presence of an external nucleophile, hydroalkoxylation of homopropargyl alcohols 40 proceeds to give the five-membered acetals 41 selectively (Scheme 12).34 An initial 5-endo cyclization furnished a dihydrofuran intermediate, which could be further converted to the desired products by the Brønsted acid catalyst and external nucleophile. Ph 3PAuCl AgBF4

OH R2

OMe

R2

O 41a 50%

EtO

O 41b 36%

MeO

R1 O2C

OH ( )n

AuCl3

R2

BnO 2C

O

45

rt

MeO BnO 2C 45b 85%

O

R2 n

R 3OH

44 MeO

OR3 O

R1 O2C

MeO BnO 2C 45c 34%

O

MeO EtO 2C

O

Ph

45d 82%

Scheme 14. Hydroalkoxylation of conjugated ynoates

41 CO2Me R 4O

EtO

43d 75%

Tuning the electronic nature of the alkyne substituents can greatly influence the regioselectivity of the intramolecular attack of a pendant nucleophile onto an internal alkyne. Vazquez and colleagues demonstrated the gold-catalyzed synthesis of five-, six-, and seven-membered cyclic acetals 45 via an oxo Michael-type reaction sequence (Scheme 14).36 Treatment of the corresponding hydroxyalkyneoates 44 with AuCl3 initiated the selective alkyne hydroalkoxylation and conversion to the corresponding acetal product in the presence of the external alcohol nucleophile. 7-hydroxyheptynoates proceeded through a 6-exo cyclization whereas 6hydroxyhexynoates followed a 5-exo pathway. The electronic nature of the ester substituent favored the conjugate addition to the ester β-carbon, dictating the selectivity of the cyclization.

45a 80%

R1 O

p-TsOH R 3OH rt

40 Me

R 3O

43c 45%

43b 85%

Scheme 13 . Hydroalkoxylation of 4-bromo-3-yn-1-ols

39d 91%

Scheme 11. Intramolecular hydroalkoxylation of 2-(prop-2yn-1-ylamino)phenols

R1

NO 2

nBu O CH 3

O 41c 71%

41d 44% 3:2 dr

Scheme 12. Tandem cycloisomerization/hydroalkoxylation of homopropargylic alcohols

With less biased systems, controlling the regioselectivity is much more problematic. The double hydroalkoxylation of internal alkynes, which is an example of this, is a useful transformation to rapidly generate complex structures from alkynes. A variety of metal-catalyzed strategies to convert alkynes into spiroketals have been developed.37 In terms of regioselectivity, the gold-catalyzed addition of the two nucleophiles has been reported to produce mixtures of spiroketal products, as observed by several groups (Scheme 15).38

Further highlighting the preference for formation of the favored ring size, Reddy and coworkers showed that 4-bromo3-yn-ols 42 were smoothly converted to the corresponding γ-

6 | Chem. Commun., 2015, 00, 1-‐3



H

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FEATURE ARTICLE DOI: 10.1039/C5CC00120J OH

7-endo 6-exo

OR

HO

[M]

O

O

O

5-exo 6-endo

46

OH OH

O

OTBDPS HO

( )4 59

47

48

JohnPhosAuCl AgOTf THF MS 4Å 0 °C 80% 60:61:62 = 38:38:24

O O

RO +

60 RO


In their spiroketalization studies, De Brabander and coworkers showed that the identity of the catalyst and having the alcohols protected plays a significant role in the product distribution.39 The [6.6]-spiroketal motif 47 is more commonly found in natural products and is often the desired product of this reaction; however, treatment of the diol 46a favors formation of the [7.5]-spiroketal 48 (Scheme 16). Monoprotected diols were explored and it was found that when R1=TBS and R2=H (46b), the [7.5]-spiroketal 48 is still the major product. In contrast, when the protecting group is placed on the other alcohol, R2=THP (46c-e), the [6,6]-spiroketal 47 was then favored over spiroketal 48.

()

R1 O

3

OR2

1. [Au] rt 2. CSA

( )4

46

46a1R1 46b R1 46c R1 46d R1 46e R1

= R2 = H = TBS R 2 = H = H R 2 = THP = H R 2 = THP = H R 2 = THP

O O

O

O 47

Catalyst MeAuPPh 3, AgPF61 MeAuPPh 3, AgPF61 MeAuPPh 3, TfOH1 PPh 3AuCl, AgOTf1 AuCl31

48 92%1 73%1 40%1 36%1 41%1

47:48 21:791 13:87 1 57:431 67:331 69:311

Scheme 16. Substituent effect on alkynediol spiroketalization

Aponick and coworkers recently reported a strategy for controlling the regiochemistry of spiroketalization of alkyne triols emoloying an acetonide protecting group.40 Previously, the group reported that the gold-catalyzed cyclization of triol 59 gave a mixture of the three regioisomeric spiroketal products 60-62 in a combined 80% yield (Scheme 17).41 By masking one of the alcohol nucleophiles as an acetonide (63), the regioselectivity of the reaction could be completely controlled and spiroketal 60 was formed exclusively in comparable yield. As illustrated, this approach offers an alternative strategy for spiroketalization when regiochemistry problems arise.

O OTBDPS

HO

( )4

63

AuCl THF rt

61

O O 62

Scheme 15. Spiroketalization of alkynediols O

O O OH

OR O O 60 74%

Scheme 17. Regiochemical control of alkyne hydroalkoxylation using an acetonide; JohnPhos= [P(t-Bu)2(obiphenyl)] In other systems, such as arene containing spiroketals, additional problems may arise. During their studies on the synthesis of the spiroketal core of the rubromycin class of natural products, Li and coworkers screened a variety of substrates in a gold-catalyzed double intramolecular hydroalkoxylation of substituted alkynes (Scheme 18).42 When bisphenol 49 was treated under cationic gold conditions only spiroketal 50 was observed along with the aromatized product, benzofuran 51. The authors also screened a series of benzyl alcohol nucleophiles. Diols 52 and 57 cyclized smoothly to give the corresponding spiroketal products 53 and 58 as single regioisomers. Conversely, diol 54 cyclized with poor selectivity and afforded a mixture of regioisomeric spiroketals 55 and 56 in a 60:40 ratio. O O

OH

Ph 3PAuCl AgOTf DCM rt

49 HO

HO 51, 28% Ph 3PAuCl AgOTf

OH

52

50, 62% + O

DCM rt

OH

O O 53 75% O

Ph 3PAuCl AgOTf

OH OH 54

O

55 + O

DCM rt

O

56 86%, 55:56 = 60:40 OH

57


Ph 3PAuCl AgOTf

OH

DCM rt

O O 58 84%

Chem. Commun., 2015, 00, 1-‐3 | 7


OH

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FEATURE ARTICLE


Scheme 18. Spiroketalization studies on the γ-rubromycin core Recently, Hashmi and co workers reported the use of gold(I) catalysts bearing phosphite ligands with sterically imposing substituents for the intramolecular hydroalkoxylation of alkynediols.43 Spiroketalization of diol 54 afforded a mixture of spiroketals 55 and 56 with the formation of 55 being favored in a 67:33 ratio (Scheme 19). This preference is consistent with the previous findings of Li and coworkers, but the level of selectivity is somewhat improved. O R 3OPAuCl AgSbF6

OH

O 55

OH 54 R = III R = IV R=V

AdO

CD2Cl2 TTBB rt

55:56 = 67:33 55:56 = 67:33 55:56 = 67:33

+ O

O

56 100 % conversion

MeO OMe H ()

MeO OMe H ( )9

MeO OMe H Ph

64a 85%

64b 86%

64c 96%

5

III

In a subsequent report, Teles and coworkers further demonstrated the high selectivity of the hydroalkoxylation of terminal alkynes.44 Treatment of terminal alkynes 7 with a gold (I) catalyst in the presence of an acid co-catalyst and an alcohol nucleophile provided the corresponding dimethyl acetals 65 with exclusive selectivity for addition at the more substituted position (Scheme 21). Acetal formation was observed in nearly all cases. Interestingly, reaction of phenylacetylene with bulkier alcohol nucleophiles such as isopropanol resulted in a mixture of the acetal product 65 and enol ether product 66.

R= IV

Ph 3PAuMe MsOH

H

MeOH 40 °C

7

V

Scheme 19. Sterically imposing ligand effects in alkynediol spiroketalization

Although the problem of controlling the regiochemistry of intramolecular alkyne hydroalkoxylation has yet to be completely resolved, a significant amount of progress has been made in the development of strategies to address this issue. Further progress in this area could lead to more widespread use of this transformation in a variety of settings. 3.3 Intermolecular Hydroalkoxylation

OR

RO OR H

R1

H

R1 H 66

65

Scheme 21. Gold (I)-catalyzed hydroalkoxylation Corma and co-workers demonstrated that diol nucleophiles also selectively added to the internal carbon of terminal alkynes.45 Treatment of the alkynes 7 under cationic gold (I) conditions in the presence of a diol produced the desired cyclic ketals 67 (Scheme 22). Nucleophilic attack of unsubstituted diols occurred exclusively at the more substituted position of the alkyne and the corresponding 5-, 6-, 7-, and 8-membered ketals 67a-d could be generated. When diols bearing an additional substituent were employed with phenylactylene, the desired ketals 67g-h were isolated as the major product but a small amount of the cyclic acetal (68g-h) was also observed.

Terminal Alkynes The gold-catalyzed intermolecular hydroalkoxylation of alkynes is extremely challenging from a regioselectivity standpoint; however, as expected, terminal alkynes have been shown to exhibit very high selectivities. In their seminal report, Utimoto and coworkers demonstrated that terminal alkynes 7 reacted in the presence of NaAuCl4 in refluxing methanol to afford the corresponding dimethyl acetals 64, (Scheme 20).17 Only a single regioisomer resulting from addition at the internal carbon was observed.

MeO OMe H ( )6 HO 64d 93%

Scheme 20. Gold (III)-catalyzed hydroalkoxylation

R1

R=

MeOH 65 °C

7

BnO

R=

MeO OMe H R1 64

NaAuCl 4

H

Ph 3PAuCl AgBF4 toluene 100 °C

H + diol

R1

R3 R2 ( )n O O +

7

( )n O O

O

R1 67 O

R4 67a-d 67a n = 1 87% 67b n = 2 82% 67c n = 3 76% 67d n = 4 68%

67e-f 67e R 4 = Cl 41% 67f R 4 = OMe 65%

R2

R1

R2 R3 ( )n O O H 68

R3

R2

R3

O O O O + R1 H R1 67g-h 68g-h R 2 = R 3 = Me 78% 67:68 97:3a R 2 = H, R 3 = Et 85% 67:68 94:6a

a

dr not indicated Scheme 22. Gold-catalyzed addition of diols to alkynes

8 | Chem. Commun., 2015, 00, 1-‐3




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R1

R2

H 7

O

n-C8H17

O

71

O Me

Ph

70a 90%

OCOR2

R1 70

O Ph

R1

R2

O

toluene 60°C

OH 69

O

O

Ph 3PAuCl AgPF6

O

O

R2

Ph OCOR2

Ph 70b 82%

70c-d

71c-d

R 2 = Ph 86% 70c:71c = 83:17 R 2 = CH2 Ph 72% 70d:71d = 71:29

Scheme 23. Gold-catalyzed hydroacylation of terminal alkynes

While the examples mentioned above involved studies on different types of nucleophiles, the catalyst may also affect product distribution and aspects such as the ratio of acetal to enol could also be influenced.47 To this end, a series of gold catalysts were screened for the addition of n-BuOH to phenyl acetylene 72 (Scheme 24). In these examples, the predicted product of addition to the internal carbon was observed; however, the results demonstrate that the electronic nature of the phosphine ligand greatly affects the product distribution. Although both electronic and steric factors may affect the selectivity, when catalysts containing phosphine ligands with all aryl substituents were employed, the enol ether product 73 was heavily favored (entries 1,2). Conversely, complexes containing an electron donating alkyl phosphines favored the formation of the ketal product 74 (entries 3-5).

Au Cat n-BuOH

Ph

H 72

DCM rt

OBu

Although addition to terminal alkynes has been shown to be highly regioselective for nucleophilic attack at the internal alkyne position, a gold-catalyzed variant favoring addition to the terminal carbon has yet to be reported. Further development in this area would provide a valuable addition to this class of reactions. Internal Alkynes In contrast to the selectivity observed for terminal alkynes, internal alkynes can generally be attacked by the nucleophile at both positions. The substituents on the alkyne as well as the identity of the nucleophile play a large role in the regioselectivity. In the earliest example of regioselective addition to an internal alkyne, Teles and coworkers reported the selective addition of methanol to alkyne 75 (Scheme 25).44 Limited details are described, but the authors state that the nucleophile added exclusively to the methyl substituted position to give dimethyl ketal 76 as the major product with only a small amount of enol ether 77 detected. The authors suggest that this selectivity is derived from the steric nature of the substituents with attack being favored at the least sterically hindered position. CH 3

Ph 3PAuMe MsOH

CH 3

MeOH 40 °C

H 3C 75

74

Scheme 24. Effect of the nature of phosphine ligands on regioselectivity of mono-hydroalkoxylation; DavePhos=2Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl


77 minor

R3

Ph 3AuCl /AgBF4a toluene, 100 °C R 2 + diol

R1 9

Entry Catalyst % conversion 73:74 1 AuPPh3NTf 2 98 88:5 2 AuP[(2,4,6-tris-CF 3)C6H 2]3NTf 2 96 92:2 3 AuDavePhosNTf2 >99 10:88 4 AuSPhosNTf2 98 34:63 5 AuP(t-Bu) 3NTf 2 97 28:69

iPr

H 3C

Corma and coworkers also demonstrated that bisaddition to internal alkynes to form a cyclic ketal was possible, but led to a mixture of products (Scheme 26).45,47 Addition of diols to alkynes 9 afforded the corresponding cyclic ketal products 78 and 79. When R1 = alkyl, R2 = aryl, addition was selective for the alkyl substituted carbon of the alkyne in all reported examples. The identity of the diol substituent had a moderate effect on the regioselectivity of the reaction. Employing ethylene glycol afforded the corresponding cyclic ketals 78a and 78c with a slight enhancement in regioselectivity when compared to substituted glycols.

BuO OBu

73

OMe

Scheme 25. Steric effect on regioselective hydroalkoxylation

Ph

Ph

MeO OMe iPr H 3C 76 major

O

or PPh 3AuNTf2b CH 3CN, 80 °C

R1

O

R 2 + R1

O

O

Ph

O

O

H 3C

Ph

O

78

O 79

Et

H 3C

R3

R2

CH2OH O

O

n-Bu

O Ph n-Bu

O

Ph

78aa

78ba

78cb

78db

78:79 68:32

78:79 66:34

78:79 76:24

78:79 66:34

15% c

60%c

50%c,d

65%c,d

Chem. Commun., 2015, 00, 1-‐3 | 9



Carboxylic acids can also be used as nucleophiles and this was recently demonstrated by the Kim lab.46 Treatment of terminal alkynes 7 with a gold (I) salt and silver activator catalyzed the selective addition of carboxylic acids 69 to give the corresponding enol esters 70 (Scheme 23). For alkyl substituted terminal alkynes only the Markovnikov addition products 70a/b were observed. Reactions employing phenylacetylene gave a mixture of products with a significant amount of the anti-Markovnikov product 71 seen.

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FEATURE ARTICLE


a

Conditions A; b Conditions B; c % conversion of alkyne (GC); % conversion includes formation of hydrolysis products Scheme 26. Regioselective alkyne hydroalkoxylation with diols

AuCl3 II

During their studies on the addition of carboxylic acids to internal alkynes, Kim and coworkers reported excellent regioselectivities with aryl alkynes.46 Addition of carboxylic acids 80 to internal alkynes 9 resulted in vinyl acetate products 81 in high yields as single regioisomers (Scheme 27). Addition to the β-carbon of an ynoate occurred selectively to afford 81a. Interestingly, addition to 1-phenylpropyne also afforded the vinyl acetate 81b as a single product.

R1

R2 2.0 eq

1.0 eq

9

82

O R1

R3

R2 9

OH 80

toluene 60 °C

O 81a 78%

O Ph

O R1

O Ph

MeO

O

83a

37:63

93%

32:68

94%

38:62

63%

91:9

35%

30:70

84a

O2N

NO 2 O Ph

H 3C

H 3C

Ph 84b

83b O2N

NO 2 O

Sahoo and coworkers reported the gold (III) catalyzed intermolecular addition of substituted phenol nucleophiles 82 to unsymmetrical internal alkynes 9 to generate vinyl ethers 83 and 84 (Scheme 28).48 The authors varied the electronics of both the alkyne substituents as well as the substituents on the phenol nucleophile and the effect on regioselectivity can be observed. When an electron rich unsymmetrical alkyne was employed using 4-nitrophenol as the nucleophile a slight preference for attack at the phenyl substituted position to give enol ether 84a was observed. Phenyl alkyl acetylenes reacted with similar regioselectivity to give enol ethers 84b and 84c as the major products. When a meta-substituted phenol was employed with an unsymmetrical electron rich alkyne, the selectivity was reversed to give enol ether 83d in tenfold excess. Addition of para-phenylphenol to an electron deficient alkyne showed modest selectivity for formation of enol ether 84e, albeit in low yield.

94%

Ph

81b 72%

Scheme 27. Gold-catalyzed hydroacylation of internal alkynes

84

MeO

O

Ph CH 3

R1

R2

NO 2 Combined yield 83:84 Ph

81

83

O2N

O CH 3 CO2Et

Ag2CO 3/K2CO 3 DCM/THF 100 *C

OR3 R2

R1

II

O

R3 R2

OR3

P(t-Bu)2

O Ph 3PAuCl AgPF6

R 3OH

O Ph

n-Bu

n-Bu

83c

MeO

Ph 84c

O Ph

MeO

O

OMe Ph

MeO 83d

84d

Ph Ph O O

Ph F 3C

Ph

CF 3 83e

84e

Scheme 28. Au(III)-catalyzed intermolecular hydroalkoxylation of alkynes

Catalyst modification also imparts changes to the level of regioselectivity in this reaction. In a recent report, Nolan and coworkers demonstrated the use of cooperative gold catalysis for the hydrophenoxylation of alkynes (Scheme 29).49 Reaction of unsymmetrical internal alkynes 9 with a dinuclear gold hydroxide species and phenol nucleophiles 82 afforded the corresponding vinyl ethers 83 and 84. The assorted substituents on both the alkyne as well as the phenol nucleophile were screened to assess the regioselectivity of the transformation. Alkynes bearing a p-methoxyaryl substituent demonstrated moderate regioselectivities with attack at the electron rich aromatic substituted position to give vinyl ethers 83f and 83h as

10 | Chem. Commun., 2015, 00, 1-‐3




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the major products. Treatment of 1-phenylpropyne gave the opposite regioselectivity observed by Sahoo and coworkers to generate enol ethers 83i and 83b, when phenol and 4nitrophenol were employed as nucleophiles. The dependence of regioselectivity on the nucleophile employed (85:15 versus 74:26) indicates that the electronic nature of both the alkyne and the nucleophile plays a role in determining the regioselectivity of the transformation. The authors also demonstrated that the regioselectivity could be controlled by the inclusion of directing group substituents to give single regioisomeric products 83j and 83k, albeit in reduced yields. OR

[{Au(NHC)}2(µ-OH)[BF4] R1

R2

R 3OH

9

82

Ag2CO 3/K2CO 3 DCM/THF 100 °C

MeO

O

OR R2

R1

R1

R2

83

84

Combined yield

83:84

93%

78:22

93%

61:39

O

MeO 83f

84f Cl

O

O

Cl 83g

alkynes 9 under cationic Au(I) conditions in the presence of an allylic alcohol generated the desired ketone products 86 (Scheme 30). A variety of unsymmetrical internal alkynes with varying alkyne substituents were screened. Interestingly, an electron rich alkyl aryl alkyne afforded the aryl ketone as the major product but, when electron deficient alkynes were employed, the selectivity was reversed to give the α-aryl ketone (e.g. 86a vs. 86b). When an ether or acetate substituent was incorporated on electron rich alkynes, the selectivity was improved to give ketones 86d and 86e as the major products in a 90:10 and 89:11 ratio respectively. When ester or phthalimide substituents were included, the regioselectivity was vastly improved and the corresponding ketones 86f and 86g were produced as single regioisomers. This dramatic improvement in regioselectivity could be attributed to an inductive effect and or neighboring group participation. When the authors subjected 1-phenyl-1-propyne to their conditions, the opposite regioselectivity from Sahoo and coworkers48 (Scheme 28) was observed with attack at the alkyl substituted position to generate ketone 86h favored in an 80:20 ratio. Nolan and coworkers later reported a solvent and silver free variant of this tandem hydroalkoxylation/Claisen rearrangement.51 The authors observed similar levels of regioselectivity for addition to unsymmetrical alkynes.

84g

OH Cl

O

MeO

R1

O

94%

MeO

R2 + 9

81:19

85

R3

(IPr)AuCl AgBF4 THF 65° C then 120° C

R4

O R3 R4 R1 R2 86

Cl 83h

90%

H 3C

85:15

H 3C 83i

86a 70% 67:33

NO 2 O

O

O 90%

H 3C

74:26

H 3C 83b

O

86c 79% 75:25

O N

O

34%

100:0

Ph(MeO-4) OAc 86f 50% 100:0

O

n-octyl

OCOCF3

n-octyl

Ph(MeO-4)

H3C NPhth

86g 72% 100:0

nBu

O

Ph(MeO-4) OMe 86e 65% 89:11

Ph(MeO-4)

84j

O

O

O

100:0

N

83j

83k

62%

nBu N

Ph(MeO-4) 86d 87% 90:10

84b

O

nBu

OMe

Ph(4-NO2) 86b 99% 11:89

n-hexyl

84i

O2N

nBu

Ph

n-hexyl

(4-OMe)Ph O

O

O

O

O

84h

Ph 86h 78% 20:80

NPhth 86i 59% 100:0

Scheme 30. Tandem hydroalkoxylation Claisen rearrangement

N 84k

Scheme 29. Au(I)-catalyzed intermolecular hydroalkoxylation

4. Conclusions Enol ethers are valuable synthetic intermediates and they are easily produced in these reactions. Aponick and coworkers reported a tandem hydroalkoxylation/Claisen rearrangement in which the first step of the transformation was the Au(I) catalyzed hydroalkoxylation of internal alkynes.50 Treatment of


Over the past decade and a half, gold-catalyzed hydration and hydroalkoxylation reactions of alkynes have been extensively explored and vast improvements in these research platforms have been made. Overall, these transformations have been demonstrated to be reliable synthetic tools for the rapid and atom economical generation of valuable synthetic building

Chem. Commun., 2015, 00, 1-‐3 | 11



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blocks or complex natural products. Various highly efficient catalyst systems have been developed to effect these transformations, but in general these classes of reactions are still plagued by selectivity issues. The regioselectivity has been shown to vary depending on the catalyst system, nature of the substituents on the alkyne, and identity of the incoming nucleophile. Much progress has been made in developing measures to control the regioselectivity of these reactions and inventive solutions have been devised for many substrate classes. Scheme 31 attempts to classify these reactions by substrate class and reaction type in a general sense as follows: Terminal alkynes have been widely shown to give almost exclusively the Markovnikov products. While regioselectivity issues still plague the hydration of alkyl-alkyl substituted alkynes in the absence of directing groups (e.g. Schemes 3-5), the hydroalkoxylation of alkyl-alkyl substituted alkynes can offer moderate levels of selectivity. Although not always entirely, regioselectivity in intramolecular reactions can be dictated by the size of the ring being formed (e.g. schemes 12, 16) or the electronic nature of the substituents (e.g. schemes 13, 14). Intermolecular variants employing alkyl-alkyl substituted alkynes have not been widely reported, but limited examples suggest that differentiation based on the steric nature of the substituents could be possible (e.g. scheme 25). When the substituents are relatively dissimilar, such as the case of alkylaryl substituted alkynes, product distribution for alkyne hydration can be difficult to control (e.g. schemes 3, 4), but moderate levels of selectivity can be observed under carefully developed conditions and well designed substrates (e.g. scheme 5). Hydroalkoxylation reactions offer similar challenges with regards to regioselective addition (e.g. schemes 28-30). The product distribution for these reactions seems to be very substrate dependent. Intermolecular hydroalkoxylation of arylaryl substituted alkynes offers modest control of regioselectivity (e.g. schemes 28-30). The electronic nature of the substituents plays a key role in product distribution with attack at the more electron deficient alkyne position usually favored. Directing group strategies have been developed for to control hydration of both alkyl and aryl substituted alkynes, but there is still room for development of directing groups for hydroalkoxylation reactions. While it may be difficult to engineer a catalyst system that can offer high levels of selectivity when the alkyne substituents are very similar, there is still ample room for improvement and ideally a general catalytic system to control regioselectivity for alkynes with differing substituents could be realized. Advances in this area are likely to be made in the future as innovative new ligand systems are developed. Alkyne Substituents

Hydration

Intramolecular Intermolecular Hydroalkoxylation Hydroalkoxylation

+ + + +/n/a Alkyl Aryl +/+/+/Aryl Aryl n/a n/a +/Alkyl Directing + + n/a Aryl Directing + n/a + + = high levels of selectivity, +/- = moderate levels achieved but highly substrate dependent, - = little to no selectivity, n/a = not enough reported examples to generalize. Terminal Alkynes

Alkyl

Alkyl

Scheme 31. Overview of selectivity

Acknowledgements 12 | Chem. Commun., 2015, 00, 1-‐3

We thank the Herman Frasch Foundation (647-HF07) and the James and Ester King Biomedical Research Program (09KN01) for their generous support of our programs

Notes and references a

Department of Chemistry, Center for Heterocyclic Compounds,

University of Florida, Gainesville, Florida 32611; [email protected] 1

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The mechanism of gold(I)-catalyzed hydroalkoxylation of alkynes: an extensive experimental study.

Amide Oxygen-Assisted Palladium-Catalyzed Hydration of Alkynes.

On the regioselectivity of the mononuclear copper-catalyzed cycloaddition of azide and alkynes (CuAAC). A quantum chemical topological study.

Broad-spectrum catalysts for the ambient temperature anti-Markovnikov hydration of alkynes.

Reactivity switch enabled by counterion: highly chemoselective dimerization and hydration of terminal alkynes.

A highly active and air-stable ruthenium complex for the ambient temperature anti-Markovnikov reductive hydration of terminal alkynes.

Inverse regioselectivity in the silylstannylation of alkynes and allenes: copper-catalyzed three-component coupling with a silylborane and a tin alkoxide.

Enzyme-Catalyzed Intramolecular Enantioselective Hydroalkoxylation.

Copper-promoted hydration and annulation of 2-fluorophenylacetylene derivatives: from alkynes to benzo[b]furans and benzo[b]thiophenes.

Atomic Zero Steric Potential and the Regioselectivity of Reactions.

Regioselectivity in sulfation of galactosides by sulfuric acid and dicyclohexylcarbodiimide.

Regioselectivity in the nucleophile trapping of arynes: the electronic and steric effects of nucleophiles and substituents.

Copper(I)-catalyzed intramolecular hydroalkoxylation of unactivated alkenes.

Organocatalytic Synthesis of Alkynes.

Origins of Regioselectivity in Iridium Catalyzed Allylic Substitution.

The hydration shell of myoglobin.

Siloxy alkynes in annulation reactions.

Water Intake and Hydration Indices in Healthy European Adults: The European Hydration Research Study (EHRS).

The role of tea in hydration.

Regioselectivity in the sulfation of some chemically-modified heparins, and observations on their cation-binding characteristics.

Mechanistic insight into the ruthenium-catalysed anti-Markovnikov hydration of alkynes using a self-assembled complex: a crucial role for ligand-assisted proton shuttle processes.

Hydration-dependent dynamic crossover phenomenon in protein hydration water.

Hydration Stickers - Improving oral hydration in vulnerable patients.

Regioselectivity in the formation of di- and tri-6-O-mesitylenesulfonates of α-cyclodextrin.