Personal Account DOI: 10.1002/tcr.201500009
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Recent Advances in the Base-Induced Sommelet–Hauser Rearrangement of Amino Acid Derived Ammonium Ylides Eiji Tayama Department of Chemistry, Faculty of Science, Niigata University, 2-8050 Ikarashi, Nishi-ku Niigata 950-2181 (Japan), E-mail: [email protected]
Received: February 19, 2015 Published online: July 14, 2015
ABSTRACT: The Sommelet–Hauser rearrangement of N-benzylic ammonium ylides generated from ammonium salts is an interesting and useful transformation that enables one to convert a readily accessible C–N bond into a new C–C bond to an aromatic ring. The rearrangement was discovered by Sommelet in 1937, studied in detail by Hauser, and applied to organic synthesis by Sato until 1999. Further studies have not advanced because several competitive side reactions and structural limitations of the products severely limit the substrate scope and synthetic applications. In this Personal Account, a history of the research in problem solving and recent advances in the base-induced Sommelet–Hauser rearrangement are described. This synthetic method developed by my group provides efficient access to various types of a-aryl-a-amino acid and a-aryl-b-amino acid derivatives. Keywords: amino acids, ammonium salts, ammonium ylides, rearrangement, synthetic methods
1. Introduction With regard to the rearrangement of tetraalkylammonium ylides (R3N1C2R2), the [2,3]-Stevens rearrangement of Nallylic ammonium ylides and the [1,2]-Stevens rearrangement of N-benzylic ammonium ylides are known as representative reactions. In the rearrangement of N-benzylic ammonium ylides, the [2,3]-rearrangement process with an aromatic double bond is also a possible pathway and is known as a Sommelet–Hauser (S–H) rearrangement (Scheme 1).[1] The S–H rearrangement frequently competes with the [1,2]-Stevens rearrangement, and the distribution of products is dependent on the reaction conditions. In general, the S–H rearrangement prefers to occur in a polar solvent, such as liquid ammonia, DMSO, or HMPA, at a lower temperature. By contrast, the [1,2]-Stevens rearrangement prefers to occur in a nonpolar solvent at a higher temperature.
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In 1937, Sommelet reported the first example of the S–H rearrangement of an ammonium ylide.[2] Later, initial studies on the rearrangement were reported by Hauser et al.[3] The representative example of the S–H rearrangement is the baseinduced transformation of benzyltrimethylammonium salt A into (2-methylbenzyl)dimethylamine D (Scheme 2). [3h] Treatment of A with a base affords ylide B by deprotonation followed by a [2,3]-sigmatropic rearrangement with an aromatic double bond, generating the dearomatized intermediate C. Finally, the isomerization of C leads to D. This reaction enables the conversion of a readily accessible C–N bond into a new C–C bond to an aromatic ring. However, the utility of this rearrangement is severely limited because of the competition from several side reactions. The following points must be achieved for success of the base-induced S–H rearrangement: (i) regioselective deprotonation followed by the corresponding
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Scheme 1. [2,3]-Stevens, [1,2]-Stevens, rearrangements of ammonium ylides.
and
Sommelet–Hauser
Scheme 3. Regioselective formation of the ammonium ylide.
Scheme 2. A representative example of the base-induced S–H rearrangement.
Scheme 4. Stabilized rearrangement.
ylide formation, and (ii) inhibition of the competitive [1,2]Stevens rearrangement as a main side reaction. The most acidic protons in A are the two benzylic methylene protons, which may be removed with base (path b) to form ylide E (Scheme 3). However, in the case of the reaction depicted in Scheme 2, one of the nine methyl protons is removed to form the desired ylide B for kinetic reasons (path a). This is one of the successful examples of the S–H rearrangement; however, the regioselective deprotonation followed by ylide formation does not proceed, depending on the structure of the ammonium salt. The resulting mixture of various ylides
would afford several side products. Thus, a study on the baseinduced S–H rearrangement is difficult to advance.[4] To solve this limitation, Sato and Shirai’s group reported the regioselective formation of ammonium ylide B by the desilylation of asilylammonium salts F with fluoride, which was a transformation originally developed by Vedejs,[5] followed by S–H rearrangement.[6t] This method enabled the generation of the desired ammonium ylide without using a strong base. Various studies on this fluoride-induced S–H rearrangement have been reported by Sato et al.[6]
Eiji Tayama was born in Hokkaido in 1974 and received his B.Sc. (1997) from Utsunomiya University. He received his M.Sci. (1999) and Ph.D. (2002) degrees from Hokkaido University under the direction of Prof. Keiji Maruoka. He worked as a postdoctoral fellow (2002– 2003) in the Chemistry Department of the University of Toronto (Prof. Mark Lautens). He was appointed to Assistant
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ammonium
ylide
leads
to
a
[1,2]-Stevens
Professor (2003) and Associate Professor (2008) at Niigata University. His research interests are the development of synthetic methods in organic synthesis and the chemistry of asymmetric nitrogen compounds.
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Scheme 5. Base-induced asymmetric Stevens rearrangements of L-prolinederived ammonium salts via N-to-C chirality transmission. Scheme 7. Base-induced [1,2]-Stevens versus S–H rearrangements of Lproline-derived ammonium salt 5b.
Scheme 6. Effects of reaction conditions on the base-induced asymmetric [1,2]-Stevens rearrangement of L-proline-derived ammonium salt 5a.
By contrast, the desired ammonium ylide can be generated by the regioselective removal of an acidic proton activated by an electron-withdrawing group (EWG), such as the a proton of the carbonyl of N-benzylic amino acid or ketone derived ammonium salts (Scheme 4). However, S–H rearrangement of the resulting stabilized ylides tends not to proceed, and the competitive [1,2]-Stevens rearrangement proceeds preferentially to give the a-benzylated product. Therefore, several rearrangements of N-benzylic a-amino acid or a-aminoketone derived ammonium ylides have been examined previously; however, most of them are examples of [1,2]-Stevens rearrangements.[1,7] From this background, my group could demonstrate successful examples of the base-induced S–H rearrangement that employ N-benzylic amino acid derived ammonium ylides. The results could be applied to the synthesis of various types of aaryl amino acid derivatives.
2. Base-Induced Sommelet–Hauser Rearrangement of Amino Acid Derived Ammonium Ylides 2.1. Discovery of the First Successful Example of a BaseInduced Asymmetric Sommelet–Hauser Rearrangement My group became interested in the asymmetric version of the rearrangement of ammonium ylides,[8,9] particularly the rear-
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Scheme 8. Base-induced asymmetric [2,3]-Stevens and S–H rearrangements of glycine-derived ammonium salts.
rangement involving the transmission of nitrogen-centered chirality to newly formed carbon-centered chirality (N-to-C chirality transmission).[10–12] In 1999, West reported that the asymmetric Stevens rearrangement of L-proline-derived ammonium ylides generated from 1 and 3 proceeded with Nto-C chirality transmission (Scheme 5).[10e] The concerted [2,3]-Stevens rearrangement of the single diastereomer 1 proceeded with a perfect level of N-to-C chirality transmission to afford the enantiopure 2. In addition, the [1,2]-Stevens rearrangement of the single diastereomer 3, which involves a radical cleavage–recombination pathway, proceeded with a moderate level (54%) of N-to-C chirality transmission. I expected that the degree of chirality transmission in the [1,2]Stevens rearrangement of 3 would be improved by
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Table 1. Base-induced asymmetric S–H rearrangement of para-substituted N-benzylic ammonium salts.
Entry 1 2 3 4 5 6 7 8
R CN (b) CN (b) CO2Me (c) COPh (d) CF3 (e) H (f ) H (f ) OMe (g)
Temp./8C 240 260 260 260 260 260 240 240
Time/h
Yield/%[a]
dr[b]
4 8 8 8 15 15 15 15
84 82 92 95 93 0 46 0
87:13 97:3 >98:2 >98:2 >98:2 – >98:2 –
[a] Isolated yield. [b] Determined by 1H NMR assay.
Fig. 1. Molecular structure of 11c. Hydrogen atoms are omitted for clarity. Gray: carbon; red: oxygen; blue: nitrogen.
1,2-dichloroethane at 2108C proceeded with a perfect level (>99%) of N-to-C chirality transmission to afford 6b in a low yield. Interestingly, when the rearrangement was performed with solid tBuOK in THF at room temperature, the aarylproline 7b was obtained as the corresponding S–H rearrangement product in a low yield (27%) along with 6b. The S–H rearrangement proceeded exclusively with a perfect level (>99%) of N-to-C chirality transmission at 2408C to give 7b.[13] This result was the first successful example of a baseinduced asymmetric S–H rearrangement. 2.2. Base-Induced Asymmetric Sommelet–Hauser Rearrangement of N-Benzylic Glycine Ester Derived Ammonium Ylides
Scheme 9. Base-induced asymmetric S–H rearrangement of ortho- and metasubstituted N-benzylic ammonium salts.
optimization of the reaction conditions. The reaction of the tert-butyl ester derivative 5a was examined under the same conditions (Scheme 6), and the [1,2]-rearranged product 6a was obtained with an improved enantioselectivity (72% ee). When the reaction was carried out under solid–liquid biphasic conditions, a degree of chirality transmission of 92% ee was reached.[10b] With the result in hand, substituent effects on the N-benzylic aromatic ring were investigated (Scheme 7). The reaction of N-para-(tert-butoxycarbonyl)benzylammonium salt 5b in
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My group started to investigate the base-induced S–H rearrangement to expand the synthetic scope and utility. In 2005, Sweeney et al. reported the base-induced asymmetric [2,3]-Stevens rearrangement of glycine-derived N-allylic ammonium ylides using camphorsultam as a chiral auxiliary (Scheme 8).[8g] This result encouraged me that the asymmetric S–H rearrangement of glycine-derived N-benzylic ammonium ylides could also be achieved. Thus, we selected (2)-8-phenylmenthol as a chiral auxiliary and examined the rearrangement. Very fortunately, the reaction of 10a with solid tBuOK under an argon atmosphere proceeded to give the desired S–H product 11a in 95% yield with perfect diastereoselectivity (>98:2 dr). The substrate scope with a para substituent on the N-benzylic aromatic ring is shown in Table 1. A lack of diastereoselectivity was observed in the reaction of the para-cyano derivative 10b at 2408C, because epimerization of the product 11b proceeded by deprotonation of the acidic a proton with an excess amount of tBuOK (entry 1). This epimerization
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Scheme 12. Rearrangement of the a-arylglycine-derived ammonium salt 25. Scheme 10. Base-induced asymmetric S–H rearrangement of L- or D-alaninederived ammonium salts 18.
levels of yield and selectivity (Scheme 9). When ortho-substituted substrates 12 were subjected to the rearrangement conditions, the 2,3-regioisomers 13 were obtained without isolation of the dearomatized products 14.[14] Reactions of the metasubstituted substrates 15 gave 2,4-regioisomers 16 as the main products. The formation of a small amount of 2,6-regioisomer 17a was observed in the reaction of the meta-cyano derivative 15a. The stereochemistry of the product 11 could be determined by a single-crystal X-ray analysis of 11c. The crystal was obtained by recrystallization from n-hexane (Figure 1).[15] 2.3. Base-Induced Asymmetric Sommelet–Hauser Rearrangement of a-Substituted Amino Acid Derived Ammonium Ylides
Scheme 11. Rearrangements of the a-allylglycine-derived ammonium salt 22 prepared by a [2,3]-Stevens rearrangement of 20.
could be minimized at 2608C (entry 2). An EWG on the Nbenzylic aromatic ring (10c–e) was necessary for sufficient yields of the S–H rearrangement product (entries 3–5, 11c–e). Without an EWG, such as in 10f, the reaction did not proceed at all at 2608C (entry 6) and resulted in a lower yield of 11f at 2408C (entry 7). When an electron-donating-group (EDG), such as para-methoxy, was attached to the N-benzylic aromatic ring, the desired S–H rearrangement did not proceed (entry 8). The rearrangements of ortho- and meta-substituted Nbenzylic derivatives 12 and 15 also proceeded with the same
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The base-induced asymmetric S–H rearrangement could be applied to the L- and D-alanine-derived ammonium ylides generated from salts 18 to construct a chiral quaternary stereogenic center. Reactions of L- and D-18 with solid tBuOK proceeded via formation of the same ylide to afford the aarylalanine derivative 19 in good yields with similar diastereoselectivities (Scheme 10).[16] However, a substituent larger than methyl at the aposition inhibited the desired S–H rearrangement by steric repulsion, and the competitive [1,2]-Stevens rearrangement proceeded preferentially (Scheme 11). The reaction of the aallyl-N-benzylic ammonium salt 22, prepared from the N-allyl ammonium salt 20 via a [2,3]-Stevens rearrangement, gave a 1:2 mixture of S–H (23) and [1,2]-rearrangement (24) products. Similarly, reaction of the a-aryl-N-benzylic ammonium salt 25, prepared from 11a, did not afford the S–H product 26 at all (Scheme 12). The corresponding [1,2]-Stevens product 27 was obtained exclusively.
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Table 2. Effects of tBuOK source and carbonyl substituents on the competition of base-induced S–H and [1,2]-Stevens rearrangements.
Entry
Substrate
1 2 3 4 5
28a 28a 31a 31a 34a
t
BuOK
S–H/%[a]
[1,2]-Stevens/%[a]
solid THF solution solid THF solution THF solution
11 (29a) 80 (29a) 56 (32a) 83 (32a) 0[b] (35a)
32 (30a) 8 (30a) 15 (33a) 0 (33a) 40[b] (36a)
[a] Isolated yield unless otherwise noted. [b] Determined by 1H NMR assay of the crude product using mesitylene as an internal standard.
3. Synthetic Applications of the Base-Induced Sommelet–Hauser Rearrangement As described in Section 2, my group demonstrated that the base-induced S–H rearrangement of N-benzylic ammonium salts proceeds in excellent yields and with high selectivity. However, this rearrangement has serious disadvantages for further synthetic transformations for the following reasons: (i) an EWG on the migrating benzylic aromatic ring is necessary for sufficient reaction conversion; (ii) the products are generally N,N-dialkyl-a-aryl amino acid derivatives, which are difficult to convert into the primary amines; and (iii) the a-aryl substituent of the products must be an o-tolyl component. The disadvantages of (i) and (ii) could be solved by our further studies. The results are described in this section. 3.1. The Rate Enhancement Effect of a tBuOK–THF Solution in the Base-Induced Sommelet–Hauser Rearrangement In the base-induced S–H rearrangement, the competitive [1,2]-Stevens rearrangement could be minimized at lower temperatures using an electron-deficient N-benzylic substituent as the migrating group. With this information in hand, my group investigated the rearrangement to further develop the synthetic method. During the experiments, we used a commercially available tBuOK–THF solution, which can be added precisely by a syringe to prevent the contamination by oxygen under more conventional procedures, instead of solid tBuOK. Surprisingly, when the reaction was performed using the tBuOK– THF solution, the desired S–H rearrangement was found to proceed preferentially with minimal undesired [1,2]-Stevens rearrangement.[17] For example, the treatment of the N-benzy-
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Table 3. Effect of the type of base in the competition between the base-induced S–H and [1,2]-Stevens rearrangements of 28a.
Base[a]
29a/%[b]
30a/%[b]
BuOK–THF solution BuOK solid t BuOK solid[c] t BuONa–THF solution t BuONa solid KHMDS–toluene solution KOH powder[d] LDA–THF–hexane solution[e] PhLi–cyclohexane–Et2O solution
80 22 40 36 19 15 0 6 0
8 43 36 35 43 34 22 29 15
Entry 1 2 3 4 5 6 7 8 9
t t
[a] Unless otherwise noted, the base was added to a THF solution of 28a. [b] Isolated yield. [c] A THF solution of 28a was added to a suspension of tBuOK in THF. [d] Five equivalents were used. [e] Prepared from nBuLi and diisopropylamine.
lammonium salt 28a with solid tBuOK gave the S–H rearrangement product 29a in only 11% yield along with the [1,2]-rearrangement product 30a in 32% yield (Table 2, entry 1). However, when the same reaction was carried out using a t BuOK–THF solution, the S–H rearrangement proceeded preferentially to afford 29a in 80% yield (entry 2). The reactions of the amide-derived ammonium ylide generated from 31a preferred to give the S–H product 32a (entry 3), and the same rate enhancement effect from the tBuOK–THF solution was observed (entry 4). By contrast, the reaction of the aminoketone-derived ammonium ylide generated from 34a preferred to give the [1,2]-Stevens product 36a from the use of a tBuOK–THF solution (entry 5). The desired S–H product 35a was not obtained. The effect of the type of base in the competition between the base-induced S–H and the [1,2]-Stevens rearrangement is summarized in Table 3. The results clearly show that the S–H rearrangement proceeded specifically from the use of the t BuOK–THF solution (entry 1).[18] Reactions with other bases did not show any remarkable results (entries 2–9). The rate enhancement effect of the tBuOK–THF solution in the S–H rearrangement was further demonstrated in the rearrangement of the N-(para-substituted)benzylammonium salts 28 (Table 4). The reaction of the para-chloro derivative 28b with solid tBuOK gave a mixture of S–H (29b) and [1,2]rearrangement (30b) products (entry 1); however, the yield of
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Table 4. Effect of the tBuOK source on the base-induced S–H rearrangement of the N-(para-substituted)benzylammonium salts 28.
Entry 1 2 3 4 5 6
t
BuOK
29/%[a]
30/%[a]
solid THF solution solid THF solution solid THF solution
60 87 8 68 0 45
22 4 59 20 53 37
R Cl (b) Cl (b) Me (c) Me (c) OMe (d) OMe (d)
Scheme 13. Diastereoselective base-induced S–H rearrangement of the amino acid amide derived N-benzylammonium salts 37.
[a] Isolated yield.
Table 5. S–H rearrangement of the amino acid amide derived ammonium salts 31 using tBuOK–THF solution.
Scheme 14. Removal of N,N-diallyl substituents, as in 41, after the Stevens rearrangement of the N,N,N-triallylammonium salt 40.
Entry 1 2 3 4 5 6
NR12
R2
32/%[a]
pyrrolidin-1-yl (b) NHnBu (c) NHPh (d) NHtBu (e) pyrrolidin-1-yl (f ) NHnBu (g)
H H H H CO2tBu CO2tBu
58 29 20 83 92 99
[a] Isolated yield.
the desired 29b was improved by using a tBuOK–THF solution (entry 2). The effect was also observed using substrates deactivated by an EDG on the N-benzylic aromatic ring, such as a para-methyl (28c, entries 3 and 4) or a para-methoxy (28d, entries 5 and 6) substituent. As described in Table 2, the reaction of the diethylamidederived ammonium ylide generated from 31a proceeded to afford the corresponding S–H rearrangement product preferentially. With the results in hand, the base-induced S–H rearrangement of various types of amide-derived ammonium salts with a tBuOK–THF solution was examined to define the scope
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and limitations (Table 5). The reaction of the cyclic tertiary amide 31b proceeded slowly to give the S–H product 32b in a moderate yield (entry 1). The rearrangement of the secondary amide derivatives 31c and 31d resulted in low yields (entries 2 and 3); however, the sterically hindered tert-butyl amide derivative 31e rearranged to 32e in a good yield (entry 4). By activation of the N-benzylic aromatic ring with an EWG (CO2tBu), the yields were improved (entries 5 and 6). The diastereoselective S–H rearrangements of the N-benzyl amino acid amide derived ammonium ylides obtained from 37 with tBuOK–THF solution using an (R)-4-substituted-2,2-dimethyloxazolidine as a chiral auxiliary are shown in Scheme 13. The corresponding a-(o-tolyl) derivatives 38 were obtained in good yields followed by acid hydrolysis, which gave the peptide alcohols 39. 3.2. A Formal Method for the N,N-Didealkylation of Sommelet–Hauser Rearrangement Products The S–H rearrangement of amino acid derived ammonium ylides generally affords an N,N-dialkyl-a-aryl-a-amino acid
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Scheme 15. Removal of an N-methyl substituent, as in 4, via formation of an N-alkoxycarbonyl ammonium ion. Scheme 17. Amine dealkylation of 48 with BrCN.
Scheme 16. Amine dealkylation of 45 with an acid halide.
derivative as the product. No successful methods for the removal of the N,N-dialkyl substituents to yield the corresponding free NH derivatives have been reported. As removable N,N-dialkyl substituents, the N,N-diallyl and N,Ndibenzyl substituents are known as representative. For example, Sweeney et al. successfully demonstrated the removal of N,N-diallyl substituents, as in 41, derived from a [2,3]-Stevens rearrangement of the N,N,N-triallylglycine-derived ammonium salt 40, to obtain the primary amine 42 (Scheme 14).[8g] However, allylic and benzylic substituents also function as reactive migrating groups. Unless the same N,N,N-substituents are used, undesirable [1,2]- or [2,3]-Stevens rearrangements may proceed to give a mixture of rearrangement products. These migrations severely restrict the scope of substrates that can be used in the S–H rearrangement. On the other hand, West et al. reported the removal of an N-methyl substituent, as in the N-methylproline 4, prepared by the [1,2]-Stevens rearrangement of 3, with 1-chloroethyl chloroformate to afford the corresponding secondary amine 44 (Scheme 15).[10e] This transformation proceeds via formation of the N-alkoxycarbonyl ammonium chloride followed by substitution with chloride at the N-methyl carbon to produce the N-alkoxycarbonyl derivative 43. Elimination of the Nalkoxycarbonyl substituent gave the desired 44 in 31% yield.
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Scheme 18. Preparation of a-amino-a-arylaldehydes 56 via the S–H rearrangement and the von Braun reaction.
This type of dealkylation, such as the transformation of 4 into 43, is well known and similar reactions have been developed using various types of acyl halides.[19] At the beginning of this research, I was of the opinion that the transformation would be limited to monodealkylation; however, the low yield of 44 suggested to me that a side reaction, such as nucleophilic
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Scheme 19. Preparation of N-Boc-b-amino-a-arylaldehyde 59 via the S–H rearrangement and the von Braun reaction.
attack at the cyclic carbon, might occur to produce the ringopened product. Therefore, I drew a reaction scheme using the N,N-dialkyl-a-amino acid ester 45 with an acyl halide to clarify the possible reactions (Scheme 16). Substitution at the Nmethyl carbon would proceed to afford the monodemethylated N-acyl derivative 46 preferentially, because the reaction site is the less sterically hindered of the two N-methyl carbons of the intermediate. However, when the substrate 45 has an aryl substituent at the a-position (R1), whose structure is obtainable by an S–H rearrangement, the substitution is expected to proceed at the benzylic carbon to form the ahaloester 47 as a deaminated product. Further transformation of 47 may be possible by substitution with various nucleophiles. Thus, I decided to investigate the transformation of 45 into 47. My group selected the methyl (N,N-dialkylamino)phenylacetates 48 as model compounds for the S–H product and investigated the reactions (Scheme 17). The reaction of the N,N-dimethyl derivative 48a with BrCN (von Braun reaction)[20] was found to proceed smoothly to give a mixture of monodemethylated 49a and a-bromoester 50.[21] Interestingly, the 49:50 product ratio was dramatically reversed by changing the structure of the N,N-substituents. The reaction of the pyrrolidinyl derivative 48b afforded the ring-opened (monodealkylated) product 49b exclusively. By contrast, the reaction of the piperidinyl derivative 48c afforded the SN2 substitution product 50 as the sole product. The results were applied to the preparation of a-aryl amino acid derivatives via the S–H rearrangement (Scheme 18). The rearrangement of the N-benzylic ammonium salts 51 derived from a-piperidinyl morpholine acetamides followed by deamination of 52 gave the a-aryl-a-bromoamides 53. Substitution with azide followed by hydrogenation afforded the desired a-aryl-a-amino acid amides 54. A formal method for
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Scheme 20. Preparation of the a-aryl-N-cyanopipecolinic acid derivative 63 via the S–H rearrangement and the von Braun reaction.
the N,N-didealkylation from the S–H rearrangement products was successfully achieved. The amide moiety could be transformed into the aldehyde 56 by Boc protection of 54 followed by reduction of the N-Boc-a-aryl amino acid amides 55 with DIBAH.[22] Furthermore, N-Boc-b-amino-a-arylaldehydes 59 were also prepared via the S–H rearrangement (Scheme 19). Substitution of 53a with NaCN followed by hydrogenation gave the b-amino-a-arylamide 57. Boc protection and reduction of 58 with LiAlH4 gave the desired product 59. 3.3. Preparation of a-Arylpipecolinic Acid Esters via the Sommelet–Hauser Rearrangement The result of the ring-opening reaction affording 49b depicted in Scheme 17 was applied to the preparation of aarylpipecolinic acid esters.[23] For example, S–H rearrangement of pyrrolidinium salt 60 followed by von Braun reaction of the resulting product 61 afforded the ring-opened product 62 (Scheme 20). Intramolecular alkylation with KHMDS gave the desired cyclized product 63. The N-cyano substituent, as in 63, could be removed in two steps (Scheme 21). Hydrogenation into the corresponding amidine 64 followed by reductive hydrolysis with sodium borohydride gave the desired secondary amine 65 with a side product of the N-methyl derivative 66.
4. The Effect of Ring Size of the Cyclic Amino Acid Derived Ammonium Ylides on the BaseInduced Sommelet–Hauser Rearrangement Section 3 described how my group demonstrated the rate enhancement effect of a tBuOK–THF solution on the baseinduced S–H rearrangement. Additionally, amide-derived ammonium ylides preferred to afford the S–H rearrangement
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Scheme 24. Competition between the S–H and [1,2]-Stevens rearrangements in the reaction of the N-benzylazetidine-2-carboxylic acid ester derived ammonium salt 72.
Scheme 21. Removal of an N-cyano group, as in 63.
Scheme 22. Competition between the S–H and [1,2]-Stevens rearrangements in the reaction of the N-benzyl-L-proline ester and amide derived ammonium salts 5.
Interestingly, when reactions of the N-benzylazetidine-2carboxylic acid ester derived ammonium salt 72[24] were examined with tBuOK, the desired S–H rearrangement proceeded exclusively to afford 73 without formation of the [1,2]-Stevens product 74 (Scheme 24). The same results were obtained using a tBuOK–THF solution or the solid as the base. Additionally, my group also examined the reaction of an aziridine carboxylic acid ester derived ammonium salt (threemembered ring); however, the reaction was unsuccessful and a complex mixture was obtained. The exact reason for the difference in reactivity depending on the ring size cannot be advanced at present. Further studies may expand the synthetic scope of the S–H rearrangement.
5. Conclusion and Outlook
Scheme 23. Competition between the S–H and [1,2]-Stevens rearrangements in the reaction of the N-benzylic pipecolinic acid ester derived ammonium salts 69.
product. With these results in hand, the rearrangement of cyclic amino acid derived ammonium ylides was investigated to clarify the effect of ring size. First, my group re-examined the reactions of the N-benzyl-L-proline ester derived ammonium salt 5a depicted in Scheme 6 and the amide analog 5b with a tBuOK–THF solution (Scheme 22). However, the desired 67 was not obtained in either case without an EWG on the N-benzylic aromatic ring. The reactions of the N-benzylpipecolinic acid derived ammonium salts 69 (racemic diastereomeric mixture), affording the S–H product 70 and the [1,2]-Stevens product 71, also gave results similar to those of 5a (Scheme 23). An EWG on the N-benzylic aromatic ring and a lower reaction temperature were necessary for sufficient yields of the S–H rearrangement.
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In this Personal Account, I have described the recent advances in the base-induced S–H rearrangement of N-benzylic amino acid derived ammonium ylides. The rearrangement of ammonium ylides was originally discovered by Sommelet in 1937 and initial studies were reported by Hauser in 1951–1967. Next, the fluoride-induced S–H rearrangement was developed and studied by Sato and Shirai’s group in 1985–1999. Later, further reports on this rearrangement were quite limited.[25] In 2007, my co-workers and I successfully demonstrated that the asymmetric rearrangements of N-benzylic ammonium ylides using a chiral auxiliary undergo exclusively the S–H rearrangement. The rearrangement proceeds in excellent yields with minimal competition from the [1,2]-Stevens rearrangement under mild conditions. Although the S–H rearrangement has structural limitations in that it requires the product to have an o-tolyl component, the method provides efficient access to various types of a-aryl amino acid derivatives and expands the synthetic utility of the rearrangement. These studies should afford valuable information in the area of analogous rearrangements, such as the transitionmetal-catalyzed S–H rearrangement[25] and the Lewis acid mediated rearrangement of tertiary amines.[9,11] Recently, the Lewis base catalyzed asymmetric [2,3]-rearrangement of Nallylic ammonium ylides was reported by Smith’s group.[26] Although the ylide generated by Lewis base would be stabilized and unfavorable for the [2,3]-rearrangement with an aromatic
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double bond, this methodology might be applicable to the base-induced S–H rearrangement. The catalytic asymmetric S–H rearrangement, which has never been reported to date, could be achieved in the future.
[5]
[6]
Acknowledgements I would like to thank all co-workers for their significant contributions and Prof. Dr. Takeshi Nakai for valuable support at the beginning of this research. This work was supported by KAKENHI (Grant-in-Aid for Young Scientists (B), 23750037, 19750029, 17750034), the Mitsubishi Chemical Corporation Foundation, the Asahi Glass Foundation, the Union Tool Scholarship Foundation, the Foundation for Japanese Chemical Research, and the Uchida Energy Science Promotion Foundation.
REFERENCES [1] For reviews: a) G. Lahm, J. C. O. Pacheco, T. Opatz, Synthesis 2014, 46, 2413–2421; b) J. Clayden, M. Donnard, J. Lefranc, D. J. Tetlow, Chem. Commun. 2011, 47, 4624–4639; c) J. B. Sweeney, Chem. Soc. Rev. 2009, 38, 1027–1038; d) L. K€ urti, B. Czako, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier, Amsterdam, 2005; e) Nitrogen, Oxygen and Sulfur Ylide Chemistry (Ed.: J. S. Clark), Oxford University Press, Oxford, 2002; f) I. E. Marko, Comprehensive Organic Synthesis (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, Vol. 3, Chapter 3.10. [2] M. Sommelet, C. R. Hebd. Seances Acad. Sci. 1937, 205, 56– 58. [3] a) K. P. Klein, D. N. Van Eenam, C. R. Hauser, J. Org. Chem. 1967, 32, 1155–1160; b) W. H. Puterbaugh, C. R. Hauser, J. Am. Chem. Soc. 1964, 86, 1108–1110; c) W. H. Puterbaugh, C. R. Hauser, J. Am. Chem. Soc. 1964, 86, 1105–1107; d) G. C. Jones, W. Q. Beard, C. R. Hauser, J. Org. Chem. 1963, 28, 199–203; e) W. Q. Beard, Jr., C. R. Hauser, J. Org. Chem. 1961, 26, 371–375; f) W. Q. Beard, Jr., C. R. Hauser, J. Org. Chem. 1960, 25, 334–343; g) D. Lednicer, C. R. Hauser, J. Am. Chem. Soc. 1957, 79, 4449–4451; h) W. R. Brasen, C. R. Hauser, Org. Synth. 1954, 34, 61–63; i) S. W. Kantor, C. R. Hauser, J. Am. Chem. Soc. 1951, 73, 4122–4131. [4] Previous examples of S–H rearrangement of ammonium ylides: a) S. Hanessian, C. Talbot, P. Saravanan, Synthesis 2006, 723–734; b) J. M. Klunder, J. Heterocycl. Chem. 1995, 32, 1687–1691; c) S. M. Weinreb, F. Z. Basha, S. Hibino, N. A. Khatri, D. Kim, W. E. Pye, T.-T. Wu, J. Am. Chem. Soc. 1982, 104, 536–544; d) Y. Sato, Y. Yagi, M. Koto, J. Org. Chem. 1980, 45, 613–617; e) C. L. Bumgardner, H.-B. Hsu, F. Afghahi, W. L. Roberts, S. T. Purrington, J. Org. Chem. 1979, 44, 2348–2353; f ) Y. Sato, H. Sakakibara, J. Organomet. Chem. 1979, 166, 303–307; g) E. B. Sanders, H. V. Secor, J. I. Seeman, J. Org. Chem. 1978, 43, 324–330; h) L. N. Mander, J. V. Turner, J. Org. Chem. 1973, 38, 2915–2916; i) G. Wittig,
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H. Tenhaeff, W. Schoch, G. Koenig, Liebigs Ann. Chem. 1951, 572, 1–22. a) E. Vedejs, F. G. West, Chem. Rev. 1986, 86, 941–955; b) E. Vedejs, G. R. Martinez, J. Am. Chem. Soc. 1979, 101, 6452– 6454. a) T. Nishimura, C. Zhang, Y. Maeda, N. Shirai, S. Ikeda, Y. Sato, Chem. Pharm. Bull. 1999, 47, 267–272; b) K. Narita, N. Shirai, Y. Sato, J. Org. Chem. 1997, 62, 2544–2549; c) C. Zhang, Y. Maeda, N. Shirai, Y. Sato, J. Chem. Soc., Perkin Trans. 1 1997, 25–28; d) Y. Maeda, Y. Sato, J. Org. Chem. 1996, 61, 5188–5190; e) Y. Maeda, N. Shirai, Y. Sato, J. Chem. Soc., Perkin Trans. 1 1994, 393–398; f ) A. Sakuragi, N. Shirai, Y. Sato, Y. Kurono, K. Hatano, J. Org. Chem. 1994, 59, 148–153; g) Y. Sato, N. Shirai, Y. Machida, E. Ito, T. Yasui, Y. Kurono, K. Hatano, J. Org. Chem. 1992, 57, 6711–6716; h) T. Kitano, N. Shirai, M. Motoi, Y. Sato, J. Chem. Soc., Perkin Trans. 1 1992, 2851–2854; i) T. Kitano, N. Shirai, Y. Sato, Chem. Pharm. Bull. 1992, 40, 768–769; j) T. Tanaka, N. Shirai, Y. Sato, Chem. Pharm. Bull. 1992, 40, 518–520; k) T. Tanaka, N. Shirai, J. Sugimori, Y. Sato, J. Org. Chem. 1992, 57, 5034–5036; l) T. Kitano, N. Shirai, Y. Sato, Synthesis 1991, 996–998; m) F. Sumiya, N. Shirai, Y. Sato, Chem. Pharm. Bull. 1991, 39, 36–40; n) N. Shirai, Y. Watanabe, Y. Sato, J. Org. Chem. 1990, 55, 2767–2770; o) N. Shirai, F. Sumiya, Y. Sato, M. Hori, J. Org. Chem. 1989, 54, 836–840; p) H. Sugiyama, Y. Sato, N. Shirai, Synthesis 1988, 988–990; q) N. Shirai, F. Sumiya, Y. Sato, M. Hori, J. Chem. Soc., Chem. Commun. 1988, 370; r) N. Shirai, Y. Sato, J. Org. Chem. 1988, 53, 194–196; s) M. Nakano, Y. Sato, J. Org. Chem. 1987, 52, 1844–1847; t) M. Nakano, Y. Sato, J. Chem. Soc., Chem. Commun. 1985, 1684–1685. Studies on competition in base-induced S–H and [1,2]-Stevens rearrangements: a) A. Jo nczyk, D. Lipiak, J. Org. Chem. 1991, 56, 6933–6937; b) A. Jo nczyk, D. Lipiak, K. Sienkiewicz, Synlett 1991, 493–496. Base-induced asymmetric rearrangement: a) E. Tayama, N. Naganuma, H. Iwamoto, E. Hasegawa, Chem. Commun. 2014, 50, 6860–6862; b) E. Tayama, K. Takedachi, H. Iwamoto, E. Hasegawa, Tetrahedron Lett. 2012, 53, 1373– 1375; c) T.-S. Zhu, M.-H. Xu, Chem. Commun. 2012, 48, 7274–7276; d) K. Tomooka, J. Sakamaki, M. Harada, R. Wada, Synlett 2008, 683–686; e) M.-H. Gonc¸alves-Farbos, L. Vial, J. Lacour, Chem. Commun. 2008, 829–831; f ) J. B. Sweeney, A. Tavassoli, J. A. Workman, Tetrahedron 2006, 62, 11506–11512; g) J. A. Workman, N. P. Garrido, J. Sanc¸on, E. Roberts, H. P. Wessel, J. B. Sweeney, J. Am. Chem. Soc. 2005, 127, 1066–1067. Lewis acid mediated asymmetric rearrangement: J. Blid, O. Panknin, P. Tuzina, P. Somfai, J. Org. Chem. 2007, 72, 1294– 1300. Base-induced rearrangement via N-to-C chirality transmission: a) E. Tayama, S. Otoyama, H. Tanaka, Tetrahedron: Asymmetry 2009, 20, 2600–2608; b) E. Tayama, S. Nanbara, T. Nakai, Chem. Lett. 2006, 35, 478–479; c) E. Tayama, H. Tanaka, T. Nakai, Heterocycles 2005, 66, 95–99; d) A. P. A. Arbore, D. J. Cane-Honeysett, I. Coldham, M. L. Middleton, Synlett 2000,
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236–238; e) K. W. Glaeske, F. G. West, Org. Lett. 1999, 1, 31– 33; f ) K. Hiroi, K. Nakazawa, Chem. Lett. 1980, 9, 1077– 1080. Lewis acid mediated rearrangement via N-to-C chirality transmission: P. Tuzina, P. Somfai, Org. Lett. 2009, 11, 919–921. Electro-induced rearrangement via N-to-C chirality transmission: L. Palombi, Catal. Commun. 2011, 12, 485–488. E. Tayama, H. Kimura, Angew. Chem. Int. Ed. 2007, 46, 8869–8871. In base-induced S–H rearrangement of S-benzylic sulfonium ylides, the dearomatized products were obtained. R. Berger, J. W. Ziller, D. L. Van Vranken, J. Am. Chem. Soc. 1998, 120, 841–842. CCDC-1046313 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_request/cif. E. Tayama, K. Orihara, H. Kimura, Org. Biomol. Chem. 2008, 6, 3673–3680. E. Tayama, K. Takedachi, H. Iwamoto, E. Hasegawa, Tetrahedron 2010, 66, 9389–9395. We used commercially available reagent (1.0 M in THF) from Aldrich or TCI. Representative examples: a) A. D. Jones, R. E. Zelle, I. R. Silverman, PCT Int. Appl. WO 2009035652, 2009; b) M. Vargas-Sanchez, S. Lakhdar, F. Couty, G. Evano, Org. Lett. 2006, 8, 5501–5504; c) R. G. Bhat, Y. Ghosh, S. Chandrasekaran, Tetrahedron Lett. 2004, 45, 7983–7985; d) P. R. Dave, K. A. Kumar, R. Duddu, T. Axenrod, R. Dai, K. K.
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Das, X.-P. Guan, J. Sun, N. J. Trivedi, R. D. Gilardi, J. Org. Chem. 2000, 65, 1207–1209; e) M. W. Miller, S. F. Vice, S. W. McCombie, Tetrahedron Lett. 1998, 39, 3429–3432; f ) M. E. Kopach, A. H. Fray, A. I. Meyers, J. Am. Chem. Soc. 1996, 118, 9876–9883; g) J. R. Ferguson, K. W. Lumbard, F. Scheinmann, A. V. Stachulski, P. Stjernl€of, S. Sundell, Tetrahedron Lett. 1995, 36, 8867–8870; h) B. V. Yang, D. O’Rourke, J. Li, Synlett 1993, 195–196. A review: i) J. H. Cooley, E. J. Evain, Synthesis 1989, 1–7. a) H. W. J. Cressman, Org. Synth. 1947, 27, 56–57; b) J. v. Braun, K. Heider, E. M€ uller, Chem. Ber. 1918, 51, 273–282; c) J. v. Braun, Chem. Ber. 1900, 33, 1438–1452. E. Tayama, R. Sato, K. Takedachi, H. Iwamoto, E. Hasegawa, Tetrahedron 2012, 68, 4710–4718. R. Martın, P. Romea, C. Tey, F. Urpı, J. Vilarrasa, Synlett 1997, 1414–1416. E. Tayama, R. Sato, M. Ito, H. Iwamoto, E. Hasegawa, Heterocycles 2013, 87, 381–388. Studies on rearrangement of azetidinium ylides: a) B. Drouillat, E. d’Aboville, F. Bourdreux, F. Couty, Eur. J. Org. Chem. 2014, 1103–1109; b) F. Couty, B. Drouillat, G. Evano, O. David, Eur. J. Org. Chem. 2013, 2045–2056; c) B. Drouillat, F. Couty, J. Marrot, Synlett 2009, 767–770. Transition-metal-catalyzed S–H rearrangement was also studied: a) Y. Li, Y. Shi, Z. Huang, X. Wu, P. Xu, J. Wang, Y. Zhang, Org. Lett. 2011, 13, 1210–1213; b) M. Liao, L. Peng, J. Wang, Org. Lett. 2008, 10, 693–696. T. H. West, D. S. B. Daniels, A. M. Z. Slawin, A. D. Smith, J. Am. Chem. Soc. 2014, 136, 4476–4479.
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Recent Advances in the Base-Induced Sommelet–Hauser Rearrangement of Amino Acid Derived Ammonium Ylides Eiji Tayama Department of Chemistry, Faculty of Science, Niigata University, 2-8050 Ikarashi, Nishi-ku Niigata 950-2181 (Japan), E-mail: [email protected]
Received: February 19, 2015 Published online: July 14, 2015
ABSTRACT: The Sommelet–Hauser rearrangement of N-benzylic ammonium ylides generated from ammonium salts is an interesting and useful transformation that enables one to convert a readily accessible C–N bond into a new C–C bond to an aromatic ring. The rearrangement was discovered by Sommelet in 1937, studied in detail by Hauser, and applied to organic synthesis by Sato until 1999. Further studies have not advanced because several competitive side reactions and structural limitations of the products severely limit the substrate scope and synthetic applications. In this Personal Account, a history of the research in problem solving and recent advances in the base-induced Sommelet–Hauser rearrangement are described. This synthetic method developed by my group provides efficient access to various types of a-aryl-a-amino acid and a-aryl-b-amino acid derivatives. Keywords: amino acids, ammonium salts, ammonium ylides, rearrangement, synthetic methods
1. Introduction With regard to the rearrangement of tetraalkylammonium ylides (R3N1C2R2), the [2,3]-Stevens rearrangement of Nallylic ammonium ylides and the [1,2]-Stevens rearrangement of N-benzylic ammonium ylides are known as representative reactions. In the rearrangement of N-benzylic ammonium ylides, the [2,3]-rearrangement process with an aromatic double bond is also a possible pathway and is known as a Sommelet–Hauser (S–H) rearrangement (Scheme 1).[1] The S–H rearrangement frequently competes with the [1,2]-Stevens rearrangement, and the distribution of products is dependent on the reaction conditions. In general, the S–H rearrangement prefers to occur in a polar solvent, such as liquid ammonia, DMSO, or HMPA, at a lower temperature. By contrast, the [1,2]-Stevens rearrangement prefers to occur in a nonpolar solvent at a higher temperature.
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In 1937, Sommelet reported the first example of the S–H rearrangement of an ammonium ylide.[2] Later, initial studies on the rearrangement were reported by Hauser et al.[3] The representative example of the S–H rearrangement is the baseinduced transformation of benzyltrimethylammonium salt A into (2-methylbenzyl)dimethylamine D (Scheme 2). [3h] Treatment of A with a base affords ylide B by deprotonation followed by a [2,3]-sigmatropic rearrangement with an aromatic double bond, generating the dearomatized intermediate C. Finally, the isomerization of C leads to D. This reaction enables the conversion of a readily accessible C–N bond into a new C–C bond to an aromatic ring. However, the utility of this rearrangement is severely limited because of the competition from several side reactions. The following points must be achieved for success of the base-induced S–H rearrangement: (i) regioselective deprotonation followed by the corresponding
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Scheme 1. [2,3]-Stevens, [1,2]-Stevens, rearrangements of ammonium ylides.
and
Sommelet–Hauser
Scheme 3. Regioselective formation of the ammonium ylide.
Scheme 2. A representative example of the base-induced S–H rearrangement.
Scheme 4. Stabilized rearrangement.
ylide formation, and (ii) inhibition of the competitive [1,2]Stevens rearrangement as a main side reaction. The most acidic protons in A are the two benzylic methylene protons, which may be removed with base (path b) to form ylide E (Scheme 3). However, in the case of the reaction depicted in Scheme 2, one of the nine methyl protons is removed to form the desired ylide B for kinetic reasons (path a). This is one of the successful examples of the S–H rearrangement; however, the regioselective deprotonation followed by ylide formation does not proceed, depending on the structure of the ammonium salt. The resulting mixture of various ylides
would afford several side products. Thus, a study on the baseinduced S–H rearrangement is difficult to advance.[4] To solve this limitation, Sato and Shirai’s group reported the regioselective formation of ammonium ylide B by the desilylation of asilylammonium salts F with fluoride, which was a transformation originally developed by Vedejs,[5] followed by S–H rearrangement.[6t] This method enabled the generation of the desired ammonium ylide without using a strong base. Various studies on this fluoride-induced S–H rearrangement have been reported by Sato et al.[6]
Eiji Tayama was born in Hokkaido in 1974 and received his B.Sc. (1997) from Utsunomiya University. He received his M.Sci. (1999) and Ph.D. (2002) degrees from Hokkaido University under the direction of Prof. Keiji Maruoka. He worked as a postdoctoral fellow (2002– 2003) in the Chemistry Department of the University of Toronto (Prof. Mark Lautens). He was appointed to Assistant
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ammonium
ylide
leads
to
a
[1,2]-Stevens
Professor (2003) and Associate Professor (2008) at Niigata University. His research interests are the development of synthetic methods in organic synthesis and the chemistry of asymmetric nitrogen compounds.
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Scheme 5. Base-induced asymmetric Stevens rearrangements of L-prolinederived ammonium salts via N-to-C chirality transmission. Scheme 7. Base-induced [1,2]-Stevens versus S–H rearrangements of Lproline-derived ammonium salt 5b.
Scheme 6. Effects of reaction conditions on the base-induced asymmetric [1,2]-Stevens rearrangement of L-proline-derived ammonium salt 5a.
By contrast, the desired ammonium ylide can be generated by the regioselective removal of an acidic proton activated by an electron-withdrawing group (EWG), such as the a proton of the carbonyl of N-benzylic amino acid or ketone derived ammonium salts (Scheme 4). However, S–H rearrangement of the resulting stabilized ylides tends not to proceed, and the competitive [1,2]-Stevens rearrangement proceeds preferentially to give the a-benzylated product. Therefore, several rearrangements of N-benzylic a-amino acid or a-aminoketone derived ammonium ylides have been examined previously; however, most of them are examples of [1,2]-Stevens rearrangements.[1,7] From this background, my group could demonstrate successful examples of the base-induced S–H rearrangement that employ N-benzylic amino acid derived ammonium ylides. The results could be applied to the synthesis of various types of aaryl amino acid derivatives.
2. Base-Induced Sommelet–Hauser Rearrangement of Amino Acid Derived Ammonium Ylides 2.1. Discovery of the First Successful Example of a BaseInduced Asymmetric Sommelet–Hauser Rearrangement My group became interested in the asymmetric version of the rearrangement of ammonium ylides,[8,9] particularly the rear-
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Scheme 8. Base-induced asymmetric [2,3]-Stevens and S–H rearrangements of glycine-derived ammonium salts.
rangement involving the transmission of nitrogen-centered chirality to newly formed carbon-centered chirality (N-to-C chirality transmission).[10–12] In 1999, West reported that the asymmetric Stevens rearrangement of L-proline-derived ammonium ylides generated from 1 and 3 proceeded with Nto-C chirality transmission (Scheme 5).[10e] The concerted [2,3]-Stevens rearrangement of the single diastereomer 1 proceeded with a perfect level of N-to-C chirality transmission to afford the enantiopure 2. In addition, the [1,2]-Stevens rearrangement of the single diastereomer 3, which involves a radical cleavage–recombination pathway, proceeded with a moderate level (54%) of N-to-C chirality transmission. I expected that the degree of chirality transmission in the [1,2]Stevens rearrangement of 3 would be improved by
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Table 1. Base-induced asymmetric S–H rearrangement of para-substituted N-benzylic ammonium salts.
Entry 1 2 3 4 5 6 7 8
R CN (b) CN (b) CO2Me (c) COPh (d) CF3 (e) H (f ) H (f ) OMe (g)
Temp./8C 240 260 260 260 260 260 240 240
Time/h
Yield/%[a]
dr[b]
4 8 8 8 15 15 15 15
84 82 92 95 93 0 46 0
87:13 97:3 >98:2 >98:2 >98:2 – >98:2 –
[a] Isolated yield. [b] Determined by 1H NMR assay.
Fig. 1. Molecular structure of 11c. Hydrogen atoms are omitted for clarity. Gray: carbon; red: oxygen; blue: nitrogen.
1,2-dichloroethane at 2108C proceeded with a perfect level (>99%) of N-to-C chirality transmission to afford 6b in a low yield. Interestingly, when the rearrangement was performed with solid tBuOK in THF at room temperature, the aarylproline 7b was obtained as the corresponding S–H rearrangement product in a low yield (27%) along with 6b. The S–H rearrangement proceeded exclusively with a perfect level (>99%) of N-to-C chirality transmission at 2408C to give 7b.[13] This result was the first successful example of a baseinduced asymmetric S–H rearrangement. 2.2. Base-Induced Asymmetric Sommelet–Hauser Rearrangement of N-Benzylic Glycine Ester Derived Ammonium Ylides
Scheme 9. Base-induced asymmetric S–H rearrangement of ortho- and metasubstituted N-benzylic ammonium salts.
optimization of the reaction conditions. The reaction of the tert-butyl ester derivative 5a was examined under the same conditions (Scheme 6), and the [1,2]-rearranged product 6a was obtained with an improved enantioselectivity (72% ee). When the reaction was carried out under solid–liquid biphasic conditions, a degree of chirality transmission of 92% ee was reached.[10b] With the result in hand, substituent effects on the N-benzylic aromatic ring were investigated (Scheme 7). The reaction of N-para-(tert-butoxycarbonyl)benzylammonium salt 5b in
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My group started to investigate the base-induced S–H rearrangement to expand the synthetic scope and utility. In 2005, Sweeney et al. reported the base-induced asymmetric [2,3]-Stevens rearrangement of glycine-derived N-allylic ammonium ylides using camphorsultam as a chiral auxiliary (Scheme 8).[8g] This result encouraged me that the asymmetric S–H rearrangement of glycine-derived N-benzylic ammonium ylides could also be achieved. Thus, we selected (2)-8-phenylmenthol as a chiral auxiliary and examined the rearrangement. Very fortunately, the reaction of 10a with solid tBuOK under an argon atmosphere proceeded to give the desired S–H product 11a in 95% yield with perfect diastereoselectivity (>98:2 dr). The substrate scope with a para substituent on the N-benzylic aromatic ring is shown in Table 1. A lack of diastereoselectivity was observed in the reaction of the para-cyano derivative 10b at 2408C, because epimerization of the product 11b proceeded by deprotonation of the acidic a proton with an excess amount of tBuOK (entry 1). This epimerization
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Scheme 12. Rearrangement of the a-arylglycine-derived ammonium salt 25. Scheme 10. Base-induced asymmetric S–H rearrangement of L- or D-alaninederived ammonium salts 18.
levels of yield and selectivity (Scheme 9). When ortho-substituted substrates 12 were subjected to the rearrangement conditions, the 2,3-regioisomers 13 were obtained without isolation of the dearomatized products 14.[14] Reactions of the metasubstituted substrates 15 gave 2,4-regioisomers 16 as the main products. The formation of a small amount of 2,6-regioisomer 17a was observed in the reaction of the meta-cyano derivative 15a. The stereochemistry of the product 11 could be determined by a single-crystal X-ray analysis of 11c. The crystal was obtained by recrystallization from n-hexane (Figure 1).[15] 2.3. Base-Induced Asymmetric Sommelet–Hauser Rearrangement of a-Substituted Amino Acid Derived Ammonium Ylides
Scheme 11. Rearrangements of the a-allylglycine-derived ammonium salt 22 prepared by a [2,3]-Stevens rearrangement of 20.
could be minimized at 2608C (entry 2). An EWG on the Nbenzylic aromatic ring (10c–e) was necessary for sufficient yields of the S–H rearrangement product (entries 3–5, 11c–e). Without an EWG, such as in 10f, the reaction did not proceed at all at 2608C (entry 6) and resulted in a lower yield of 11f at 2408C (entry 7). When an electron-donating-group (EDG), such as para-methoxy, was attached to the N-benzylic aromatic ring, the desired S–H rearrangement did not proceed (entry 8). The rearrangements of ortho- and meta-substituted Nbenzylic derivatives 12 and 15 also proceeded with the same
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The base-induced asymmetric S–H rearrangement could be applied to the L- and D-alanine-derived ammonium ylides generated from salts 18 to construct a chiral quaternary stereogenic center. Reactions of L- and D-18 with solid tBuOK proceeded via formation of the same ylide to afford the aarylalanine derivative 19 in good yields with similar diastereoselectivities (Scheme 10).[16] However, a substituent larger than methyl at the aposition inhibited the desired S–H rearrangement by steric repulsion, and the competitive [1,2]-Stevens rearrangement proceeded preferentially (Scheme 11). The reaction of the aallyl-N-benzylic ammonium salt 22, prepared from the N-allyl ammonium salt 20 via a [2,3]-Stevens rearrangement, gave a 1:2 mixture of S–H (23) and [1,2]-rearrangement (24) products. Similarly, reaction of the a-aryl-N-benzylic ammonium salt 25, prepared from 11a, did not afford the S–H product 26 at all (Scheme 12). The corresponding [1,2]-Stevens product 27 was obtained exclusively.
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Table 2. Effects of tBuOK source and carbonyl substituents on the competition of base-induced S–H and [1,2]-Stevens rearrangements.
Entry
Substrate
1 2 3 4 5
28a 28a 31a 31a 34a
t
BuOK
S–H/%[a]
[1,2]-Stevens/%[a]
solid THF solution solid THF solution THF solution
11 (29a) 80 (29a) 56 (32a) 83 (32a) 0[b] (35a)
32 (30a) 8 (30a) 15 (33a) 0 (33a) 40[b] (36a)
[a] Isolated yield unless otherwise noted. [b] Determined by 1H NMR assay of the crude product using mesitylene as an internal standard.
3. Synthetic Applications of the Base-Induced Sommelet–Hauser Rearrangement As described in Section 2, my group demonstrated that the base-induced S–H rearrangement of N-benzylic ammonium salts proceeds in excellent yields and with high selectivity. However, this rearrangement has serious disadvantages for further synthetic transformations for the following reasons: (i) an EWG on the migrating benzylic aromatic ring is necessary for sufficient reaction conversion; (ii) the products are generally N,N-dialkyl-a-aryl amino acid derivatives, which are difficult to convert into the primary amines; and (iii) the a-aryl substituent of the products must be an o-tolyl component. The disadvantages of (i) and (ii) could be solved by our further studies. The results are described in this section. 3.1. The Rate Enhancement Effect of a tBuOK–THF Solution in the Base-Induced Sommelet–Hauser Rearrangement In the base-induced S–H rearrangement, the competitive [1,2]-Stevens rearrangement could be minimized at lower temperatures using an electron-deficient N-benzylic substituent as the migrating group. With this information in hand, my group investigated the rearrangement to further develop the synthetic method. During the experiments, we used a commercially available tBuOK–THF solution, which can be added precisely by a syringe to prevent the contamination by oxygen under more conventional procedures, instead of solid tBuOK. Surprisingly, when the reaction was performed using the tBuOK– THF solution, the desired S–H rearrangement was found to proceed preferentially with minimal undesired [1,2]-Stevens rearrangement.[17] For example, the treatment of the N-benzy-
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Table 3. Effect of the type of base in the competition between the base-induced S–H and [1,2]-Stevens rearrangements of 28a.
Base[a]
29a/%[b]
30a/%[b]
BuOK–THF solution BuOK solid t BuOK solid[c] t BuONa–THF solution t BuONa solid KHMDS–toluene solution KOH powder[d] LDA–THF–hexane solution[e] PhLi–cyclohexane–Et2O solution
80 22 40 36 19 15 0 6 0
8 43 36 35 43 34 22 29 15
Entry 1 2 3 4 5 6 7 8 9
t t
[a] Unless otherwise noted, the base was added to a THF solution of 28a. [b] Isolated yield. [c] A THF solution of 28a was added to a suspension of tBuOK in THF. [d] Five equivalents were used. [e] Prepared from nBuLi and diisopropylamine.
lammonium salt 28a with solid tBuOK gave the S–H rearrangement product 29a in only 11% yield along with the [1,2]-rearrangement product 30a in 32% yield (Table 2, entry 1). However, when the same reaction was carried out using a t BuOK–THF solution, the S–H rearrangement proceeded preferentially to afford 29a in 80% yield (entry 2). The reactions of the amide-derived ammonium ylide generated from 31a preferred to give the S–H product 32a (entry 3), and the same rate enhancement effect from the tBuOK–THF solution was observed (entry 4). By contrast, the reaction of the aminoketone-derived ammonium ylide generated from 34a preferred to give the [1,2]-Stevens product 36a from the use of a tBuOK–THF solution (entry 5). The desired S–H product 35a was not obtained. The effect of the type of base in the competition between the base-induced S–H and the [1,2]-Stevens rearrangement is summarized in Table 3. The results clearly show that the S–H rearrangement proceeded specifically from the use of the t BuOK–THF solution (entry 1).[18] Reactions with other bases did not show any remarkable results (entries 2–9). The rate enhancement effect of the tBuOK–THF solution in the S–H rearrangement was further demonstrated in the rearrangement of the N-(para-substituted)benzylammonium salts 28 (Table 4). The reaction of the para-chloro derivative 28b with solid tBuOK gave a mixture of S–H (29b) and [1,2]rearrangement (30b) products (entry 1); however, the yield of
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Table 4. Effect of the tBuOK source on the base-induced S–H rearrangement of the N-(para-substituted)benzylammonium salts 28.
Entry 1 2 3 4 5 6
t
BuOK
29/%[a]
30/%[a]
solid THF solution solid THF solution solid THF solution
60 87 8 68 0 45
22 4 59 20 53 37
R Cl (b) Cl (b) Me (c) Me (c) OMe (d) OMe (d)
Scheme 13. Diastereoselective base-induced S–H rearrangement of the amino acid amide derived N-benzylammonium salts 37.
[a] Isolated yield.
Table 5. S–H rearrangement of the amino acid amide derived ammonium salts 31 using tBuOK–THF solution.
Scheme 14. Removal of N,N-diallyl substituents, as in 41, after the Stevens rearrangement of the N,N,N-triallylammonium salt 40.
Entry 1 2 3 4 5 6
NR12
R2
32/%[a]
pyrrolidin-1-yl (b) NHnBu (c) NHPh (d) NHtBu (e) pyrrolidin-1-yl (f ) NHnBu (g)
H H H H CO2tBu CO2tBu
58 29 20 83 92 99
[a] Isolated yield.
the desired 29b was improved by using a tBuOK–THF solution (entry 2). The effect was also observed using substrates deactivated by an EDG on the N-benzylic aromatic ring, such as a para-methyl (28c, entries 3 and 4) or a para-methoxy (28d, entries 5 and 6) substituent. As described in Table 2, the reaction of the diethylamidederived ammonium ylide generated from 31a proceeded to afford the corresponding S–H rearrangement product preferentially. With the results in hand, the base-induced S–H rearrangement of various types of amide-derived ammonium salts with a tBuOK–THF solution was examined to define the scope
Chem. Rec. 2015, 15, 789–800
and limitations (Table 5). The reaction of the cyclic tertiary amide 31b proceeded slowly to give the S–H product 32b in a moderate yield (entry 1). The rearrangement of the secondary amide derivatives 31c and 31d resulted in low yields (entries 2 and 3); however, the sterically hindered tert-butyl amide derivative 31e rearranged to 32e in a good yield (entry 4). By activation of the N-benzylic aromatic ring with an EWG (CO2tBu), the yields were improved (entries 5 and 6). The diastereoselective S–H rearrangements of the N-benzyl amino acid amide derived ammonium ylides obtained from 37 with tBuOK–THF solution using an (R)-4-substituted-2,2-dimethyloxazolidine as a chiral auxiliary are shown in Scheme 13. The corresponding a-(o-tolyl) derivatives 38 were obtained in good yields followed by acid hydrolysis, which gave the peptide alcohols 39. 3.2. A Formal Method for the N,N-Didealkylation of Sommelet–Hauser Rearrangement Products The S–H rearrangement of amino acid derived ammonium ylides generally affords an N,N-dialkyl-a-aryl-a-amino acid
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Scheme 15. Removal of an N-methyl substituent, as in 4, via formation of an N-alkoxycarbonyl ammonium ion. Scheme 17. Amine dealkylation of 48 with BrCN.
Scheme 16. Amine dealkylation of 45 with an acid halide.
derivative as the product. No successful methods for the removal of the N,N-dialkyl substituents to yield the corresponding free NH derivatives have been reported. As removable N,N-dialkyl substituents, the N,N-diallyl and N,Ndibenzyl substituents are known as representative. For example, Sweeney et al. successfully demonstrated the removal of N,N-diallyl substituents, as in 41, derived from a [2,3]-Stevens rearrangement of the N,N,N-triallylglycine-derived ammonium salt 40, to obtain the primary amine 42 (Scheme 14).[8g] However, allylic and benzylic substituents also function as reactive migrating groups. Unless the same N,N,N-substituents are used, undesirable [1,2]- or [2,3]-Stevens rearrangements may proceed to give a mixture of rearrangement products. These migrations severely restrict the scope of substrates that can be used in the S–H rearrangement. On the other hand, West et al. reported the removal of an N-methyl substituent, as in the N-methylproline 4, prepared by the [1,2]-Stevens rearrangement of 3, with 1-chloroethyl chloroformate to afford the corresponding secondary amine 44 (Scheme 15).[10e] This transformation proceeds via formation of the N-alkoxycarbonyl ammonium chloride followed by substitution with chloride at the N-methyl carbon to produce the N-alkoxycarbonyl derivative 43. Elimination of the Nalkoxycarbonyl substituent gave the desired 44 in 31% yield.
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Scheme 18. Preparation of a-amino-a-arylaldehydes 56 via the S–H rearrangement and the von Braun reaction.
This type of dealkylation, such as the transformation of 4 into 43, is well known and similar reactions have been developed using various types of acyl halides.[19] At the beginning of this research, I was of the opinion that the transformation would be limited to monodealkylation; however, the low yield of 44 suggested to me that a side reaction, such as nucleophilic
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Scheme 19. Preparation of N-Boc-b-amino-a-arylaldehyde 59 via the S–H rearrangement and the von Braun reaction.
attack at the cyclic carbon, might occur to produce the ringopened product. Therefore, I drew a reaction scheme using the N,N-dialkyl-a-amino acid ester 45 with an acyl halide to clarify the possible reactions (Scheme 16). Substitution at the Nmethyl carbon would proceed to afford the monodemethylated N-acyl derivative 46 preferentially, because the reaction site is the less sterically hindered of the two N-methyl carbons of the intermediate. However, when the substrate 45 has an aryl substituent at the a-position (R1), whose structure is obtainable by an S–H rearrangement, the substitution is expected to proceed at the benzylic carbon to form the ahaloester 47 as a deaminated product. Further transformation of 47 may be possible by substitution with various nucleophiles. Thus, I decided to investigate the transformation of 45 into 47. My group selected the methyl (N,N-dialkylamino)phenylacetates 48 as model compounds for the S–H product and investigated the reactions (Scheme 17). The reaction of the N,N-dimethyl derivative 48a with BrCN (von Braun reaction)[20] was found to proceed smoothly to give a mixture of monodemethylated 49a and a-bromoester 50.[21] Interestingly, the 49:50 product ratio was dramatically reversed by changing the structure of the N,N-substituents. The reaction of the pyrrolidinyl derivative 48b afforded the ring-opened (monodealkylated) product 49b exclusively. By contrast, the reaction of the piperidinyl derivative 48c afforded the SN2 substitution product 50 as the sole product. The results were applied to the preparation of a-aryl amino acid derivatives via the S–H rearrangement (Scheme 18). The rearrangement of the N-benzylic ammonium salts 51 derived from a-piperidinyl morpholine acetamides followed by deamination of 52 gave the a-aryl-a-bromoamides 53. Substitution with azide followed by hydrogenation afforded the desired a-aryl-a-amino acid amides 54. A formal method for
Chem. Rec. 2015, 15, 789–800
Scheme 20. Preparation of the a-aryl-N-cyanopipecolinic acid derivative 63 via the S–H rearrangement and the von Braun reaction.
the N,N-didealkylation from the S–H rearrangement products was successfully achieved. The amide moiety could be transformed into the aldehyde 56 by Boc protection of 54 followed by reduction of the N-Boc-a-aryl amino acid amides 55 with DIBAH.[22] Furthermore, N-Boc-b-amino-a-arylaldehydes 59 were also prepared via the S–H rearrangement (Scheme 19). Substitution of 53a with NaCN followed by hydrogenation gave the b-amino-a-arylamide 57. Boc protection and reduction of 58 with LiAlH4 gave the desired product 59. 3.3. Preparation of a-Arylpipecolinic Acid Esters via the Sommelet–Hauser Rearrangement The result of the ring-opening reaction affording 49b depicted in Scheme 17 was applied to the preparation of aarylpipecolinic acid esters.[23] For example, S–H rearrangement of pyrrolidinium salt 60 followed by von Braun reaction of the resulting product 61 afforded the ring-opened product 62 (Scheme 20). Intramolecular alkylation with KHMDS gave the desired cyclized product 63. The N-cyano substituent, as in 63, could be removed in two steps (Scheme 21). Hydrogenation into the corresponding amidine 64 followed by reductive hydrolysis with sodium borohydride gave the desired secondary amine 65 with a side product of the N-methyl derivative 66.
4. The Effect of Ring Size of the Cyclic Amino Acid Derived Ammonium Ylides on the BaseInduced Sommelet–Hauser Rearrangement Section 3 described how my group demonstrated the rate enhancement effect of a tBuOK–THF solution on the baseinduced S–H rearrangement. Additionally, amide-derived ammonium ylides preferred to afford the S–H rearrangement
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Scheme 24. Competition between the S–H and [1,2]-Stevens rearrangements in the reaction of the N-benzylazetidine-2-carboxylic acid ester derived ammonium salt 72.
Scheme 21. Removal of an N-cyano group, as in 63.
Scheme 22. Competition between the S–H and [1,2]-Stevens rearrangements in the reaction of the N-benzyl-L-proline ester and amide derived ammonium salts 5.
Interestingly, when reactions of the N-benzylazetidine-2carboxylic acid ester derived ammonium salt 72[24] were examined with tBuOK, the desired S–H rearrangement proceeded exclusively to afford 73 without formation of the [1,2]-Stevens product 74 (Scheme 24). The same results were obtained using a tBuOK–THF solution or the solid as the base. Additionally, my group also examined the reaction of an aziridine carboxylic acid ester derived ammonium salt (threemembered ring); however, the reaction was unsuccessful and a complex mixture was obtained. The exact reason for the difference in reactivity depending on the ring size cannot be advanced at present. Further studies may expand the synthetic scope of the S–H rearrangement.
5. Conclusion and Outlook
Scheme 23. Competition between the S–H and [1,2]-Stevens rearrangements in the reaction of the N-benzylic pipecolinic acid ester derived ammonium salts 69.
product. With these results in hand, the rearrangement of cyclic amino acid derived ammonium ylides was investigated to clarify the effect of ring size. First, my group re-examined the reactions of the N-benzyl-L-proline ester derived ammonium salt 5a depicted in Scheme 6 and the amide analog 5b with a tBuOK–THF solution (Scheme 22). However, the desired 67 was not obtained in either case without an EWG on the N-benzylic aromatic ring. The reactions of the N-benzylpipecolinic acid derived ammonium salts 69 (racemic diastereomeric mixture), affording the S–H product 70 and the [1,2]-Stevens product 71, also gave results similar to those of 5a (Scheme 23). An EWG on the N-benzylic aromatic ring and a lower reaction temperature were necessary for sufficient yields of the S–H rearrangement.
Chem. Rec. 2015, 15, 789–800
In this Personal Account, I have described the recent advances in the base-induced S–H rearrangement of N-benzylic amino acid derived ammonium ylides. The rearrangement of ammonium ylides was originally discovered by Sommelet in 1937 and initial studies were reported by Hauser in 1951–1967. Next, the fluoride-induced S–H rearrangement was developed and studied by Sato and Shirai’s group in 1985–1999. Later, further reports on this rearrangement were quite limited.[25] In 2007, my co-workers and I successfully demonstrated that the asymmetric rearrangements of N-benzylic ammonium ylides using a chiral auxiliary undergo exclusively the S–H rearrangement. The rearrangement proceeds in excellent yields with minimal competition from the [1,2]-Stevens rearrangement under mild conditions. Although the S–H rearrangement has structural limitations in that it requires the product to have an o-tolyl component, the method provides efficient access to various types of a-aryl amino acid derivatives and expands the synthetic utility of the rearrangement. These studies should afford valuable information in the area of analogous rearrangements, such as the transitionmetal-catalyzed S–H rearrangement[25] and the Lewis acid mediated rearrangement of tertiary amines.[9,11] Recently, the Lewis base catalyzed asymmetric [2,3]-rearrangement of Nallylic ammonium ylides was reported by Smith’s group.[26] Although the ylide generated by Lewis base would be stabilized and unfavorable for the [2,3]-rearrangement with an aromatic
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double bond, this methodology might be applicable to the base-induced S–H rearrangement. The catalytic asymmetric S–H rearrangement, which has never been reported to date, could be achieved in the future.
[5]
[6]
Acknowledgements I would like to thank all co-workers for their significant contributions and Prof. Dr. Takeshi Nakai for valuable support at the beginning of this research. This work was supported by KAKENHI (Grant-in-Aid for Young Scientists (B), 23750037, 19750029, 17750034), the Mitsubishi Chemical Corporation Foundation, the Asahi Glass Foundation, the Union Tool Scholarship Foundation, the Foundation for Japanese Chemical Research, and the Uchida Energy Science Promotion Foundation.
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![An isothiourea-catalyzed asymmetric [2,3]-rearrangement of allylic ammonium ylides.](/assets/img/hold.png)
