Enantioselective synthesis of allenamides via sulfimide [2,3]-sigmatropic rearrangement

Article abstract of DOI:10.1021/ol900146s

Chiral allenamides are prepared with high levels of enantiomeric purity by [2,3]-sigmatropic rearrangement of propargylic sulfimides. The required branched propargylic sulfides are prepared by an enantioselective organocatalytic aldehyde α-sulfenylation followed by Corey-Fuchs alkynylation.

Full text of DOI:10.1021/ol900146s

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1547-1550
Enantioselective Synthesis of
Allenamides via Sulfimide
[2,3]-Sigmatropic Rearrangement
Alan Armstrong* and Daniel P. G. Emmerson
Department of Chemistry, Imperial College London, South Kensington,
London SW7 2AZ, U.K.
a.armstrong@imperial.ac.uk
Received January 23, 2009
ABSTRACT
Chiral allenamides are prepared with high levels of enantiomeric purity by [2,3]-sigmatropic rearrangement of propargylic sulfimides. The
required branched propargylic sulfides are prepared by an enantioselective organocatalytic aldehyde r-sulfenylation followed by Corey-Fuchs
alkynylation.
The chemistry of allenamides is currently attracting consider-
able interest,1 and several potentially useful synthetic trans-
formations have been studied. For example, allenamides have
been used in [2 + 2],2,3 [3 + 2],4 [4 + 2],3,5 [4 + 3],6 and
Pauson-Khand7 cycloadditions, radical cyclizations,8 acid-9
and gold-catalyzed10 intramolecular cyclizations, and various
processes proceeding via epoxidation.11 Among several
methods for allenamide synthesis,12 the most popular is base-
catalyzed isomerization of propargylic amines.5b,13 This
method has been used to make allenamides bearing a chiral
auxiliary5a,14 and has been adapted to give allenamides with
an additional, axial element of chirality with high dia-
stereoselectivities.15 More recently, Hsung16 and Trost17
independently published copper-catalyzed coupling reactions
of allenyl halides with various nitrogen nucleophiles. Hsung’s
work is notable as it includes the first example of enantio-
(1) Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. ReV. 2003, 36, 773–
782.
(2) Kimura, M.; Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru, Y.
(10) Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2006, 71, 8658–
J. Am. Chem. Soc. 1997, 119, 10869–10870
(3) Horino, Y.; Kimura, M.; Tanaka, S.; Okajima, T.; Tamaru, Y.
Chem.sEur. J. 2003, 9, 2419–2438
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8660.
(11) (a) Rameshkumar, C.; Xiong, H.; Tracey, M. R.; Berry, C. R.; Yao,
.
L. J.; Hsung, R. P. J. Org. Chem. 2002, 67, 1339–1345. (b) Rameshkumar,
C.; Hsung, R. P. Angew. Chem., Int. Ed. 2004, 43, 615–618.
(4) Broggini, G.; Bruche, L.; Zecchi, G.; Pilati, T. J. Chem. Soc., Perkin
Trans. 1 1990, 533–9.
(12) Other methods, which have provided racemic allenamides, or ones
with no element of axial chirality, include [3,3]-sigmatropic rearrangements:
(a) Overman, L. E.; Marlowe, C. K.; Clizbe, L. A. Tetrahedron Lett. 1979,
599–600. (b) Padwa, A.; Cohen, L. A. J. Org. Chem. 1984, 49, 399–406.
Elimination of enol triflates: (c) Tanaka, H.; Kameyama, Y.; Sumida, S.;
Yamada, T.; Tokumaru, Y.; Shiro, T.; Sasaoka, M.; Taniguchi, M.; Torii,
S. Synlett 1991, 888–890. (d) Kant, J.; Farina, V. Tetrahedron Lett. 1992,
33, 3563–3566. Palladium-catalyzed aminocyclization: (e) Kimura, M.;
Wakamiya, Y.; Horino, Y.; Tamaru, Y. Tetrahedron Lett. 1997, 38, 3963–
3966. (f) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869–4873.
(5) (a) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah,
N. T. Org. Lett. 1999, 1, 2145–2148. (b) Wei, L.-L.; Xiong, H.; Douglas,
C. J.; Hsung, R. P. Tetrahedron Lett. 1999, 40, 6903–6907. (c) Berry, C. R.;
Rameshkumar, C.; Tracey, M. R.; Wei, L. L.; Hsung, R. P. Synlett 2003,
791–796. (d) Rameshkumar, C.; Hsung, R. P. Synlett 2003, 1241–1246.
(e) Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629–7636. (f) Song,
Z.; Hsung, R. P. Org. Lett. 2007, 9, 2199–2202. (g) Song, Z.; Hsung, R. P.;
Lu, T.; Lohse, A. G. J. Org. Chem. 2007, 72, 9722–9731
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(6) Antoline, J. E.; Hsung, R. P. Synlett 2008, 739–744.
(7) An˜orbe, L.; Poblador, A.; Dom´ınguez, G.; Pe´rez-Castells, J. Tetra-
hedron Lett. 2004, 45, 4441–4444.
(g) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43, 1499–1502
.
(13) (a) Dickinson, W. B.; Lang, P. C. Tetrahedron Lett. 1967, 3035–
3040. (b) Corbel, B.; Paugam, J. P.; Dreux, M.; Savignac, P. Tetrahedron
Lett. 1976, 835–838. (c) Bogentoft, C.; Ericsson, O.; Stenberg, P.;
(8) Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775–778.
(9) (a) Navarro-Va´zquez, A.; Rodr´ıguez, D.; Mart´ınez-Espero´n, M. F.;
Garc´ıa, A.; Saa´, C.; Dom´ınguez, D. Tetrahedron Lett. 2007, 48, 2741–
2743. (b) Berry, C. R.; Hsung, R. P.; Antoline, J. E.; Petersen, M. E.;
Challeppan, R.; Nielson, J. A. J. Org. Chem. 2005, 70, 4038–4042.
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C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459–466
.
.
10.1021/ol900146s CCC: $40.75
Published on Web 03/02/2009
2009 American Chemical Society

merically enriched allenamides with respect to axial chirality
without any external chiral elements. However, a limitation
is the lack of methods for preparing the allenyl halide
precursors in high ee.18 It would therefore be beneficial to
develop a general method of preparing axially chiral alle-
namides without the need for chiral auxiliaries.
nation/rearrangement of R-branched substrates as well as an
asymmetric organocatalytic approach for the synthesis of the
R-branched propargylic sulfide precursors, allowing an
effective route to enantiomerically enriched axially chiral
allenamides.
In order to find higher yielding conditions for allenamide
synthesis, we began our investigation by exploring some of
the most commonly used reagents for sulfimidation,26 namely
chloramine-T27 and PhINTs.28 Although we found a small
improvement in the yield of allenamide from amination/
rearrangement of challenging R-branched sulfide 3b (e.g.,
Table 1: 31% 5b for PhINTs (entry 5), cf. 13% 4b using 2
In connection with an ongoing research program in our
laboratory on the synthesis and reactions of sulfimides,19-21
we recently22 described the synthesis of allenamides via
[2,3]-sigmatropic rearrangement23 of propargylic sulfimides
generated in situ by amination of the corresponding prop-
argylic sulfides using the novel aminating agent 2, developed
in our laboratory (Scheme 1). This rearrangement was first
Table 1. Sulfimidation/Rearrangement Using Different
Sulfimidation Reagents
Scheme 1
.
Synthesis of Allenamides via Sulfimidation/
[2,3]-Sigmatropic Rearrangement
entry
3
R′
reagent
[PG]
4-6
yielda (%)
1
2
3
4
5
6
a
b
a
b
b
b
H
Me
H
Me
Me
Me
2b
2b
Boc
Boc
Ts
Ts
Ts
4a
4b
5a
5b
5b
6b
37c
13c
49
29
31
54
chloramine-Td
chloramine-Td
PhINTse
1bf
Cbz
a After column chromatography. b CH2Cl2, -78 °C to rt. c See ref 22.
e
d MeCN, -15 to 0 °C. MeCN, CuIOTf·PhMe (2:1 complex) cat., rt.
reported by Tamura and Ikeda,24 who used the aminating
agent EtO2CNHOTf (1a), and was more recently studied by
Van Vranken25 using an Fe(II)-catalyzed sulfimidation with
BocN3. Our previously published results,22 as well as Van
Vranken’s work, suffered from the limitation that high yields
could only be obtained for propargylic sulfides without
further R-substitution. We attributed this limitation in our
own work to competing N vs O transfer from 2. Furthermore,
the possibility of central-to-axial transfer of chirality in this
reaction has not been studied and would provide an efficient
synthesis of axially chiral allenamides. Here, we report new
amination conditions which give good yields for the ami-
f CH2Cl2, rt, 1 h, then NaHCO3 (aq) 16 h.
(entry 2)), these results were unsatisfactory. Noting Ikeda
and Tamura’s 1981 report24 of the reagent EtO2CNHOTf
(1a) for sulfimidation, in particular, a single example of high
yielding sulfimidation/[2,3]-sigmatropic rearrangement of
phenyl propargyl sulfide, we felt that this type of reagent
might suit our purposes if we could prepare an analogue with
a synthetically more useful N-protecting group. Although
we were not successful in preparing the Boc-protected
variant, we were able to synthesize the Cbz analogue of this
reagent using a method similar to the one reported by Ikeda
and Tamura: preparation of the thallium salt of the corre-
sponding N-hydroxycarbamate, followed by treatment with
triflic anhydride. Although the CbzNHOTf (1b) thus prepared
proved to be unstable to attempted purification, the crude
material was found to effect efficient sulfimidation of a range
of simple aryl and alkyl sulfides (see Supporting Informa-
tion). It was then tested in the sulfimidation/ rearrangement
of 3b. Upon treatment with 1b followed by aqueous sodium
bicarbonate, the desired allenamide 6b was obtained in 54%
yield (Table 1, entry 6).
(15) (a) Gaul, C.; Seebach, D. HelV. Chim. Acta 2002, 85, 963–978. (b)
Ranslow, P. B. D.; Hegadus, L. S.; de los Rios, C. J. Org. Chem. 2004, 69,
105–111. (c) Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2005, 70,
8628–8630.
(16) Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org.
Lett. 2005, 7, 3081–3084.
(17) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117–2120.
(18) (a) Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W. J. Org.
Chem. 1985, 50, 364–367. (b) Marshall, J. A.; Grant, C. M. J. Org. Chem.
1999, 64, 8214–8219.
(19) Armstrong, A.; Cooke, R. S. Chem. Commun. 2002, 904–905
.
(20) Armstrong, A.; Challinor, L.; Cooke, R. S.; Moir, J. H.; Treweeke,
N. R. J. Org. Chem. 2006, 71, 4028–4030
(21) Armstrong, A.; Challinor, L.; Moir, J. H. Angew. Chem., Int. Ed.
2007, 46, 5369–5372
.
.
(22) Armstrong, A.; Cooke, R. S.; Shanahan, S. E. Org. Biomol. Chem.
2003, 1, 3142–3143.
(26) Reviews: (a) Gilchrist, T. L.; Moody, C. J. Chem. ReV. 1976, 77,
409–435. (b) Taylor, P. C. Sulfur Rep. 1999, 21, 241–280.
(27) Marzinzik, A. L.; Sharpless, K. B. J. Org. Chem. 2001, 66, 594–
596.
(23) Reviews: (a) Back, T. G. Tetrahedron 2001, 57, 5263–5302. (b)
Braverman, S.; Cherkinsky, M. Top. Curr. Chem. 2007, 275, 67–101.
(24) Tamura, Y.; Ikeda, H.; Mukai, C.; Morita, I.; Ikeda, M. J. Org.
Chem. 1981, 46, 1732–1734.
(28) (a) Takada, H.; Nishibayashi, Y.; Ohe, K.; Uemura, S. J. Chem.
Soc., Chem. Commun. 1996, 931–932. (b) Takada, H.; Nishibayashi, Y.;
Ohe, K.; Uemura, S.; Baird, C. P.; Sparey, T. J.; Taylor, P. C. J. Org.
Chem. 1997, 62, 6512–6518.
(25) Bacci, J. P.; Greenman, K. L.; Van Vranken, D. L. J. Org. Chem.
2003, 68, 4955–4958.
1548
Org. Lett., Vol. 11, No. 7, 2009

Encouraged by this result, a series of R-branched prop-
argylic sulfides 3c-j was prepared to establish the scope of
the reaction. Pleasingly, we were able to isolate the corre-
sponding allenamides 6c-i in 47-84% yield (Table 2). The
Scheme 2
.
Synthesis of Enantiomerically Enriched Allenamide
6c from (S)-Methyl Lactate
Table 2. Synthesis of Allenamides from R-Branched Propargylic
Sulfides 3a-h
entry
R
R′
Me
CH2OH
I
Ph
H
CH2OH
H
CH2OH
CO2Me
3/6
yielda (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Et
b
c
d
e
f
g
h
i
54
84
63
47
65
81
71
74
Et
The absolute configuration of the allenamide product has
not been determined unambiguously but is assigned based
on the expected suprafacial nature of the rearrangement, as
observed for other propargylic [2,3]-sigmatropic processes.30
Although a mixture of diastereomeric sulfimide intermediates
A and B is possible due to the formation of a stereocenter at
sulfur, the stereochemical course of the rearrangement is
likely to be determined solely by the carbon chiral center.31
As depicted in Scheme 3, it might be expected that
i-Pr
Bn
Me
b
j
-
a After column chromatography. b Alkyne 7 was isolated in 48% yield;
only a trace of the desired allenamide 6j was isolated.
results indicate that the more sterically demanding R-sub-
stituents such as isopropyl (entry 7) are tolerated. Several
different acetylenic substituents could also be tolerated,
including CH2OH, methyl, phenyl, and iodine. Interestingly,
in the case of the acetylenic ester 3j, the isolated product
was the alkyne 7, presumed to arise from isomerization of
the initially formed allenamide.
Scheme 3
In order to pursue the enantioselective synthesis of
allenamides, a reliable method to prepare enantiomerically
enriched propargylic sulfides was now required. We first
developed a route starting from a chiral pool starting material,
(S)-methyl lactate (Scheme 2). Tosylation and SN2 displace-
ment by hexanethiol gave methyl ester 8.20 To avoid
racemization of the intermediate aldehyde, a one-pot reduc-
tion/alkynylation method was now considered necessary. The
Corey-Fuchs synthesis was chosen as the most versatile
alkynylation method since the resulting lithium acetylide may
be quenched in situ with a variety of electrophiles. DIBAL-H
reduction of 8 followed by in situ dibromoolefin formation29
gave 9 in 67% yield. The dibromoolefin 9 was treated with
n-BuLi followed by paraformaldehyde to give propargylic
sulfide 3c, which was of 95% ee according to HPLC analysis
of the corresponding Mosher’s ester. Reaction of enantio-
merically enriched 3c with 1b under the same conditions as
before gave 6c with 93% ee (chiral HPLC), demonstrating
>98% conservation of enantiomeric purity in the rearrange-
ment.
diastereomer B, which would suffer from a steric interaction
between the R- and S-hexyl substituents in the reactive
conformation, would undergo rearrangement more slowly
than A. We have some evidence that diastereomeric sulfimide
intermediates are indeed formed and undergo rearrangement
at different rates. Thus, in the reaction of racemic sulfide 3b
(29) (a) Mukai, C.; Kasamatsu, E.; Ohyama, T.; Hanaoka, M. J. Chem.
Soc., Perkin Trans. 1 2000, 737–744. (b) Romo, D.; Johnson, D. D.;
Plamondon, L.; Miwa, T.; Schreiber, S. L. J. Org. Chem. 1992, 57, 5060–
5063.
(30) (a) Stirling, C. J. M.; Smith, G. J. Chem. Soc. C 1971, 1530–1535.
(b) Marshall, J. A.; Robinson, E. D.; Zapata, A. J. Org. Chem. 1989, 54,
5854–5855.
(31) Hoffmann, R. W. Angew. Chem., Int. Ed. 1979, 91, 563–574.
Org. Lett., Vol. 11, No. 7, 2009
1549

1
with 1b, H NMR analysis of the reaction mixture before
(Table 3). Treatment of 12a-c with n-BuLi and an electro-
phile (water or paraformaldehyde) then gave 3f-i in
50-83% yield.
These enantiomerically enriched propargylic sulfides 3f-i
were then subjected to our sulfimidation conditions, and the
enantiomeric purity of the resulting chiral allenamides 6f-i
was determined by chiral HPLC (Table 4). The ee levels
the addition of base indicated the presence of a ca. 3:2
mixture of diastereomeric azasulfonium salts. One hour after
addition of base, 1H NMR showed the desired allene product
6b as well as the sulfimide, now as a single diastereomer. A
prolonged reaction time after addition of base was required
for full conversion to 6b.
Although the demonstration of effective chirality transfer
was pleasing, the chiral pool approach used for the asym-
metric synthesis of propargylic sulfide 3c is limited to
R-methyl substitution. We therefore wished to develop a
more general route. Prompted by our recently published
preparation of allylic sulfides,21 we envisaged organocatalytic
R-sulfenylation of aldehydes followed by alkynylation. An
adapted version of Jørgensen’s32 method using the prolinol
organocatalyst 10 and the sulfur electrophile 11 was em-
ployed in the R-sulfenylation step.
Table 4. Sulfimidation/Rearrangement of Enantiomerically
Enriched Propargylic Sulfides 3
entry
R
R′
3/6
yielda (%)
eeb (%)
1
2
3
4
Et
H
f
76
83
71
74
87
88
89
81
Et
i-Pr
Bn
CH2OH
H
CH2OH
g
h
i
a After column chromatography. b Determined by chiral HPLC.
For the alkynylation, the Corey-Fuchs reaction was again
chosensthe dibromoolefination initially being performed in
situ after the organocatalytic R-sulfenylation step to avoid
the need to isolate the potentially racemizable intermediate
R-sulfenyl aldehyde. Unfortunately, with this procedure, the
yield of dibromoolefins 12a-c was compromized by the
formation of byproduct (see Supporting Information). Better
results were obtained by filtering the sulfenylation reaction
mixture over silica prior to the addition of the dibromoole-
fination reagents, and yields of 52-59% could be achieved
(81-89%) were good although slightly lower than usually
observed in organocatalytic R-sulfenylation of aldehydes.21,32
In view of the high levels of chirality transfer seen for the
chiral pool-derived substrate 3c, it is likely that this reflects
the tendency of the intermediate R-sulfenyl aldehydes to
undergo racemization rather than a loss of enantiomeric
purity during the rearrangement.
In conclusion, we have demonstrated for the first time that
chiral propargylic sulfides undergo amination/[2,3]-sigmat-
ropic rearrangement with a high level of chirality transfer,
affording enantiomerically enriched allenamides. As part of
the work, we developed the novel sulfimidation reagent 1b
bearing a synthetically useful carbamate protecting group,
as well as a new approach for the synthesis of the propargylic
sulfide precursors using organocatalysis. Further development
of the method and study of synthetic applications of the
allenamide products is currently underway.
Table 3. Synthesis of Enantiomerically Enriched Sulfides 3f-i
via Organocatalytic R-Sulfenylation of Aldehydes
Acknowledgment. We thank the EPSRC (EP/E010598/
1) for their support of this work. We are also grateful to
Merck Sharpe and Dohme and Pfizer for support of our
research programs.
Supporting Information Available: General experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
yield (%)a,b
yieldb (%)
entry
R
12
12
X
R′
3
of 3
1
2
3
4
Et
Et
i-Pr
Bn
a
a
b
c
52
52
59
54
H2O
H
f
62
83
72
50
CH2O CH2OH
H2O
CH2O CH2OH
g
h
i
OL900146S
H
(32) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794–797. (b) Franze´n, J; Marigo, M;
Fielenbach, D; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296–18304.
a Reaction mixture filtered over silica prior to dibromoolefination step.
b Yield after column chromatography.
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Org. Lett., Vol. 11, No. 7, 2009