Asymmetric α-2-tosylvinylation of in situ-generated N-2-tosylvinyl proline-derived ammonium ylides

Article abstract of DOI:10.1016/j.tetlet.2011.02.040

Asymmetric α-2-tosylvinylation of N-substituted proline esters using ethynyl tolyl sulfone as an electrophile was shown to proceed in good yield with high enantioselectivities without the addition of any bases. The reaction proceeds via the formation of N-2-tosylvinyl ammonium ylides.

Full text of DOI:10.1016/j.tetlet.2011.02.040

Tetrahedron Letters 52 (2011) 1819–1821
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Asymmetric
a-2-tosylvinylation of in situ-generated N-2-tosylvinyl
proline-derived ammonium ylides
⇑
Tomohito Igarashi, Eiji Tayama , Hajime Iwamoto, Eietsu Hasegawa
Department of Chemistry, Faculty of Science, Niigata University, 950-2181, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric a-2-tosylvinylation of N-substituted proline esters using ethynyl tolyl sulfone as an electro-
Received 21 December 2010
Revised 3 February 2011
Accepted 9 February 2011
Available online 13 February 2011
phile was shown to proceed in good yield with high enantioselectivities without the addition of any
bases. The reaction proceeds via the formation of N-2-tosylvinyl ammonium ylides.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ylide
Zwitterion
Amino acid
Asymmetric synthesis
Ethynyl tolyl sulfone (1) is a compound of interest in organic
synthesis because it works as a powerful Michael acceptor and re-
acts with various nucleophiles to produce 2-tosylvinyl deriva-
tives.1 The reactions are applied for the ring-expansion of
nitrogen-containing heterocycles using cyclic tertiary amines as
substrates.2,3 Weston and Back et al., reported that the conjugate
addition of the cyclic tertiary amines to 1 afforded N-2-tosylvinyl
ammonium zwitterion A under mild conditions and that A rear-
ranged to the ring-expansion product B via 3-aza Cope rearrange-
ment (Scheme 1, Eq. 1).3 These results suggest that the reaction of
in various solvents to improve the yield and stereoselectivity.
The use of toluene, THF, ethyl acetate, DMF decreased the chemical
yields (17–34%); however, the enantioselectivities were improved
to moderate levels (entries 2–5, 69–80% ee). Protic solvents, such
as isopropanol, could also be used (entry 6, 50%, 42% ee). The use
of excess amount of 1 (1.5–2.0 equiv) improved the chemical yield
without affecting the enantioselectivity (entries 7–10). When the
reaction of 2a was carried out with 2.0 equiv of 1 in DMF, adduct
3a was obtained in 59% yield with 80% ee (entry 10).
With the optimized conditions (Table 1, entry 10) in hand, we
prepared a series of N-substituted proline esters 2b–g to determine
steric effects of the N-(R1) and ester-(R2) substituents on the yield
and the enantioselectivity (Table 2). When the reaction of N-benzyl
proline cyclohexyl ester 2b was carried out under the same condi-
tions, the enantioselectivity was slightly improved (entry 1, 3b:
45%, 89% ee). Reactions of primary esters, such as n-butyl (2c) or
N-substituted L-proline ester 2 with 1 would give the correspond-
ing zwitterion C, which would then be converted into an ammo-
nium ylide D via intramolecular hydrogen transfer (Eq. 2). The
ylide D might afford
a-substituted proline esters by [1,2] Stevens
or Sommelet–Hauser rearrangements.4,5
We investigated the reaction of N-benzyl-L-proline tert-butyl
ester (2a) with 1.0 equiv of 1 in dichloromethane at 0 °C for 4 h
(Table 1, entry 1). The unreacted 1 was quenched by the addition
of methylamine to prevent undesirable reactions. Contrary to our
expectations, no detectable amount of the [1,2] Stevens rearrange-
ment products, such as
a-benzylproline derivatives, were ob-
tained. However, the -2-tosylvinyl adduct 3a was obtained in
a
52% yield with 34% ee. Assignments of the structure and (R)-config-
uration of 3a were determined by a comparison of the 1H NMR
chemical shifts and specific rotation value with the authentic sam-
ple.6 Thus, we decided to expand the scope and limitation of this
asymmetric
a-2-tosylvinylation, and we examined the reactions
⇑
Corresponding author. Tel.: +81 25 262 7740; fax: +81 25 262 7741.
E-mail address: tayama@chem.sc.niigata-u.ac.jp (E. Tayama).
Scheme 1. Reactions of N-substituted pyrrolidines with ethynyl tolyl sulfone (1).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.040

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T. Igarashi et al. / Tetrahedron Letters 52 (2011) 1819–1821
Table 1
Enantioselective
a-2-tosylvinylation of 2a in various solvents
Entry
Solvent
Equiv of 1
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
CH2Cl2
toluene
THF
EtOAc
DMF
i-PrOH
CH2Cl2
CH2Cl2
DMF
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
1.5
2.0
52
34
17
22
34
50
85
89
44
59
34
69
69
73
80
42
27
25
79
80
DMF
a
Isolated yield.
Determined by chiral HPLC analysis.
b
Table 2
Effects of the substituent on the nitrogen in asymmetric
with 1
a-2-tosylvinylation of 2
Scheme 3. Reactions of the cyclic amino acid esters with 1.
tive 2e did not react at all (entry 4). The initial formation of the
zwitterion C might have been inhibited in this case. In contrast,
the reaction of sterically less-demanding N-methyl (2f) or N-allyl
(2g) derivatives proceeded smoothly to afford 3f or 3g in moderate
yields with good enantioselectivities (entry 5, 78%, 93% ee; entry 6,
70%, 95% ee). The reactions of 2f and 2g with 1.0 equiv of 1 resulted
in lower yields (entry 7, 57%; entry 8, 57%). We found that
2.0 equiv of 1 should be used to obtain 3 in acceptable yield. It is
worth noting that the reaction of the N-allyl substrate 2g gave 3g
in moderate yield with excellent enantioselectivity (entry 6) with-
out the formation of [2,3] Stevens7 or 3-aza Cope rearrangement8
products.
Entry
R1
R2
Equiv of 1
Yielda (%)
eeb,c (%)
1
2
3
4
5
6
7
8
CH2Ph
CH2Ph
CH2Ph
CHPh2
Me
allyl
Me
allyl
c-Hex
n-Bu
b
c
d
e
f
g
f
g
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
45
39
39
0
78
70
57
57
89
96
>99
—
93
95
93
96
CH2Ph
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
a
b
c
Isolated yield.
Determined by chiral HPLC analysis.
The absolute configurations of 3b–g were determined by analogy with 3a.
The high stereoselectivity, although its exact origin is unclear at
present, might be rationalized as the result of the stereoselective
formation of N-(2-tosylvinyl)proline-derived ammonium ylide D
and the diastereoselective addition of D to 1 to form zwitterion E
(Scheme 2). N-Substituted-L-proline ester 2 is in equilibrium be-
tween the syn- and anti-conformational isomers. The anti-isomer
of 2 would be desirable for conjugate addition to 1 and affords
zwitterion C.9 The zwitterion C deprotonates more the acidic pro-
ton at
a-position of the ester-carbonyl to form ammonium ylide
D. Conjugate addition of D to reactive electrophile 1 would give
zwitterion E diastereoselectively because of the steric repulsion
of the N-2-tosylvinyl substituent. Finally, the N-2-tosylvinyl
substituent is eliminated by the reaction with nucleophiles to form
a-adduct (R)-3. The reaction proceeds via the formation of a
mixture of diastereomeric intermediates. Decomposition of unde-
sirable intermediates which leads to (S)-3 might proceed in DMF
and (R)-3 was obtained with high enantioselectivities. Use of
dichloromethane or isopropanol might minimize the decomposi-
tion and (R)-3 was obtained with low enantioselectivities.
In order to define the scope and limitations of this reaction, we
applied our reaction to other types of the cyclic amino acid esters
(Scheme 3). Reactions of trans-4-tert-butyldimethylsilyloxy- (4a)
and 4-methoxy- (4b) L-proline derivatives with 1 under optimized
Scheme 2. Proposed mechanism for the asymmetric a-2-tosylvinylation of 2.
reaction conditions (DMF, 0 °C, 4 h) gave the corresponding
adducts 5a or 5b with lower stereoselectivities (5a: 71%, 78% de;
5b: 80%, 74% de) than the 4-nonsubstituted analog 3f (Table 2, en-
try 5, 93% ee).10 However, a reaction of cis-stereoisomer 4a0 under
the same conditions afforded the corresponding diastereomer 5a0
with a higher stereoselectivity (5a0: 93%, 88% de). These results
benzyl (2d) afforded 3c or 3d in excellent enantioselectivities;
however, the yields were lower (entry 2, 3c: 39%, 96% ee; entry
3, 3d: 39%, >99% ee). Sterically hindered N-diphenylmethyl deriva-

T. Igarashi et al. / Tetrahedron Letters 52 (2011) 1819–1821
1821
S.; Varlamov, A. V. Tetrahedron 2008, 64, 10443–10452; (c) Voskressensky, L.
G.; Listratova, A. V.; Borisova, T. N.; Alexandrov, G. G.; Varlamov, A. V. Eur. J. Org.
Chem. 2007, 6106–6117; (d) Voskressensky, L. G.; Akbulatov, S. V.; Borisova, T.
N.; Kleimenov, A. V.; Varlamov, A. V. Russ. Chem. Bull., Int. Ed. 2007, 56, 2323–
2329; (e) Voskressensky, L. G.; Borisova, T. N.; Listratova, A. V.; Kulikova, L. N.;
Titov, A. A.; Varlamov, A. V. Tetrahedron Lett. 2006, 47, 4585–4589.
3. (a) Weston, M. H.; Parvez, M.; Back, T. G. J. Org. Chem. 2010, 75, 5402–5405; (b)
Weston, M. H.; Nakajima, K.; Back, T. G. J. Org. Chem. 2008, 73, 4630–4637; (c)
Weston, M. H.; Nakajima, K.; Parvez, M.; Back, T. G. Chem. Commun. 2006,
3903–3905.
4. (a)For reviews: Nitrogen, Oxygen, and Sulfur Ylide Chemistry; Clark, J. S., Ed.;
Oxford University Press: Oxford, 2002; (b) Markó, I. E. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, Chapter
3.10.
5. Recent examples of asymmetric Stevens and Sommelet–Hauser
rearrangements of N-substituted proline esters: (a) Tayama, E.; Kimura, H.
Angew. Chem., Int. Ed. 2007, 46, 8869–8871; (b) Tayama, E.; Nanbara, S.; Nakai,
T. Chem. Lett. 2006, 35, 478–479; (c) Arboré, A. P. A.; Cane-Honeysett, D. J.;
Coldham, I.; Middleton, M. L. Synlett 2000, 236–238; (d) Glaeske, K. W.; West, F.
G. Org. Lett. 1999, 1, 31–33.
Scheme 4. Reductive desulfonylation of 3a and 3b with Mg.
would support our proposed mechanism depicted in Scheme 2. The
4-substituent, which is located on the same face as the N-alkyl (R1)
of ylide D would inhibit the stereoselective conjugated addition of
D to 1 due to steric repulsion. A reaction of the 4-hydroxy (4c)
derivative did not afford the expected product. The
a,O-bis(2-
tosylvinyl) derivative (R = trans-TsCH@CH) was obtained in 26%
yield with a complex mixture of unidentified products. Next, we
attempted the reactions of N-substituted pipecolinic acid tert-butyl
esters 6 with 1. However, the attempts were unsuccessful because
of the lower nucleophilicity of the piperidinyl tertiary amine. The
reaction of N-benzyl derivative 6a did not give the product with
the recovery of the substrate. The sterically less-demanding
N-methyl derivative 6b reacted with 1 to afford 7b in only 21% yield.
Finally, we examined the reductive desulfonylation of 3a and 3b
by a treatment with magnesium metal in THF–methanol at 50 °C
6. The assignments were carried out after conversion of 3a to amino alcohol 9.
The authentic sample of 9 was prepared from (S)-a-ethylproline methyl ester
hydrochloride [(S)-10]. Conditions: (i) LiAlH4, THF, 0 °C–rt.; (ii) H2, Pd–C, EtOAc,
rt.; (iii) PhCH2Br, KHCO3, MeCN, reflux; (iv) LiAlH4, THF, reflux. Details: see
Supplementary data.
(Scheme 4). The corresponding a-vinyl prolines 8a or 8b were ob-
tained in moderate yields (8a: 65%, 8b: 54%).
In conclusion, we have reported the asymmetric a-2-tosylviny-
lation of N-substituted proline esters using ethynyl tolyl sulfone
(1) as an electrophile.11 This reaction was shown to proceed in
good yield with high enantioselectivities without the addition of
any bases. The reaction proceeds via the formation of N-2-tosylvi-
nyl ammonium ylides.
7. Even if the reaction was carried out at ꢀ55 °C for 24 h, the corresponding [2,3]
Stevens rearrangement product (a-allyl proline derivative) was not obtained.
8. We attempted a reaction of 12 with 1 to examine the extent to which N-allyl
pyrrolidine derivatives undergo 3-aza Cope rearrangement (DMF, rt, 4 h). The
corresponding rearrangement product 13 was obtained in only 15% yield.
Compound 2g might not undergo 3-aza Cope rearrangement.
Acknowledgments
This work was supported by The Union Tool Scholarship Foun-
dation, The Foundation for Japanese Chemical Research, and The
Uchida Energy Science Promotion Foundation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.040.
9. N-Quaternization of N-substituted
L-proline esters by treatment with
electrophiles such as alkyl halides proceeds from the same face with the
ester substituents preferably at 2-position. See Ref. 5.
References and notes
10. The stereochemistries of 5a and 5b were assigned by 1H NMR. Details: see
Supplementary data.
1. (a) Back, T. G.; Clary, K. N.; Gao, D. Chem. Rev. 2010, 110, 4498–4553; (b) Back, T.
G. Tetrahedron 2001, 57, 5263–5301; (c) Waykole, L.; Paquette, L. A. Org. Synth.
1989, 67, 149–156.
2. (a) Drouillat, B.; Couty, F.; Razafimahaléo, V. Synlett 2009, 3182–3186; (b)
Voskressensky, L. G.; Listratova, A. V.; Borisova, T. N.; Kovaleva, S. A.; Borisov, R.
11. We attempted reactions using other types of electron-deficient terminal
acetylenes, such as ethyl propiolate or 1-phenylprop-2-yn-1-one. However, the
corresponding a-adducts were not obtained.