Synthesis of enantioenriched homopropargylic sulfonamides by a three component reaction of aldehydes, sulfonamides, and chiral allenylsilanes

Article abstract of DOI:10.1021/ol901692n

Enantloenriched allenylsilanes are used as carbon nucleophiles In three-component reactions with in situ generated N-sulfonylimines to selectively form syn-homopropargylic sulfonamides. The reactions proceed with a variety of aldehyde and sulfonamide reac

Full text of DOI:10.1021/ol901692n

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4362-4365
Synthesis of Enantioenriched
Homopropargylic Sulfonamides by a
Three Component Reaction of
Aldehydes, Sulfonamides, and Chiral
Allenylsilanes
Ryan A. Brawn and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, 590 Commonwealth
AVenue, Boston UniVersity, Boston, Massachusetts 02215
panek@bu.edu
Received July 23, 2009
ABSTRACT
Enantioenriched allenylsilanes are used as carbon nucleophiles in three-component reactions with in situ generated N-sulfonylimines to selectively
form syn-homopropargylic sulfonamides. The reactions proceed with a variety of aldehyde and sulfonamide reaction partners. These novel
reaction products are obtained with useful levels of diastereoselectivity, and the axial chirality of the allenylsilane is fully transferred to point
chirality, forming products with >97% ee.
Recent developments in the synthesis and use of allenylmetal
reagents have allowed their re-emergence as an important
class of reagents for a variety of organic transformations,
capable of producing highly functionalized alkynes and
heterocycles.1 In particular, allenylsilanes have been used
as carbon nucleophiles in additions to a variety of oxonium
ions, producing homopropargylic alcohols,2 homopropargylic
ethers,3 furans,4 and dihydrofurans.5 In cases where enan-
tioenriched allenylsilane reagents were used, the axial
chirality of the allene was typically fully transferred into point
chirality in the products, leading to a variety of highly
enantioenriched building blocks for organic synthesis.
The reaction of allenylmetal reagents with iminium ions
has been underdeveloped. The addition of allenylsilanes to
N-acyliminium ions has been shown to favor either a [3 +
2] annulation pathway, providing dihydropyrroles, or a [3
+ 3] pathway to provide dihydrooxazines.5,6 Achiral alle-
nylsilanes and stannanes have also been used in a [3 + 2]
annulation with a N-sulfonylimines,7 and in the case of the
stannane7a the formation of the acyclic propargylation
(1) For recent reviews on allene chemistry, see: (a) Hassan, H. H. A. M.
Curr. Org. Synth. 2007, 4, 413–439. (b) Ma, S. Chem. ReV. 2005, 105,
2829–2872. (c) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem.
ReV. 2000, 100, 3067–3125.
(4) Danheiser, R. L.; Stoner, E. J.; Koyama, H.; Yamashita, D. S.; Klade,
C. A. J. Am. Chem. Soc. 1989, 111, 4407–4413.
(5) Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y.-M. J. Am. Chem. Soc.
1985, 107, 7233–7235.
(2) (a) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem.
1986, 51, 3870–3878. (b) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000,
65, 630–633.
(6) Brawn, R. A.; Panek, J. S. Org. Lett. 2009, 11, 473–476.
(7) (a) Fuchibe, K.; Hatemata, R.; Akiyama, T. Tetrahedron Lett. 2005,
46, 8563–8566. (b) Daidouji, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2005,
7, 1051–1053.
(3) Brawn, R. A.; Panek, J. S. Org. Lett. 2007, 9, 2689–2692.
10.1021/ol901692n CCC: $40.75
Published on Web 08/28/2009
 2009 American Chemical Society

product was favored under certain reaction conditions. In
these reported cases, a single imine reaction partner was used.
Experiments with allenylboranes have been shown to specif-
ically form homopropargylic amines,8 and in one case where
enantioenriched allenylboranes were used, highly enantioen-
riched products were obtained.9
ions mediated by TMSOTf, followed by reaction with
allenylsilane (Ra)-1, the result was nearly exclusive formation
of homopropargylic sulfonamides 3a-h. This reaction was
effective for a variety of aldehyde partners, including
secondary aliphatic aldehydes (Table 1, entries 1 and 2),
In our continued interest in developing chiral carbon
nucleophiles as reagents to enhance the field of acyclic
stereocontrol, we sought to acquire a method for the synthesis
of homopropargylic amines from enantioenriched allenylsi-
lanes. We have previously reported a multigram synthesis
of enantioenriched allenylsilane 1.3 In exploring the [3 + 2]
annulation of this reagent with N-acyliminium ions we
learned that the acyclic propargylation product was obtained
as a byproduct under certain conditions. This led us to seek
reaction conditions that would selectively lead to homopro-
pargylic amines. Herein we report the achievement of that
objective, forming the desired products in high yields with
full transfer of chirality (axial to point), thereby complement-
ing existing methods utilizing allyl and crotyl silanes that
produce homoallylic amines.10
Table 1. Enantioselective Propargylations with
Methanesulfonamide
When allenylsilane (Sa)-1 was reacted with an iminium ion
formed in situ from methyl carbamate and 2-bromobenzalde-
hyde in the presence of TMSOTf, the result was a mixture of
homopropargylic amine 2a (Scheme 1) and dihydrooxazine 2b.
Scheme 1. Reactions with N-Acyliminium Ions
a Isolated yields after purification over silica gel. b Diastereomeric ratios
determined by 1H NMR analysis on crude material. c Reaction run at -45
°C in MeCN.
When the solvent was changed from EtCN to DCM the oxazine
was formed almost exclusively; however, after considerable
experimentation we were unable to find conditions that led to
selective formation of the homopropargylic amine. Accordingly,
a number of amine sources were screened, with the hope of
finding conditions that would result in an exclusive propargy-
lation pathway. The most promising amine source for these
reactions proved to be sulfonamides.11
which gave high yields and formed the products as a single
diastereomer. Primary aliphatic aldehydes (entries 3-6) gave
moderate to high yields and lower but still useful levels of
diastereoselectivity. Tertiary aliphatic aldehydes (entries 7
and 8) also gave high yields and a single diastereomer,
although the reactions required slightly higher temperatures
to reach completion.
Propargylation reactions with aliphatic aldehydes were also
tolerant to a number of different sulfonamides, in each case
exclusively forming the homopropargylic sulfonamide. For
instance, reactions with p-toluenesulfonamide, benzene-
sulfonamide, and 4-nitrobenzenesulfonamide all afforded the
desired propargylation products in moderate to high yield,
with a single diastereomer observed for branched systems
and moderate diastereoselectivity for unbranched aliphatic
systems (Table 2). Reactions with cyclohexanecarboxalde-
hyde and hydrocinnamaldehyde gave higher yields when
conducted at lower temperature (-78 °C), while experiments
When the combination of aliphatic aldehydes and meth-
anesulfonamide was used for the in situ formation of iminium
(8) (a) Yamamoto, Y.; Ito, W.; Maruyama, K. J. Chem. Soc., Chem.
Commun. 1984, 1004–1005. (b) Nikam, S. S.; Wang, K. K. J. Org. Chem.
1985, 50, 2193–2195. (c) Brown, H. C.; Khire, U. R.; Narla, G.; Racherla,
U. S. J. Org. Chem. 1995, 60, 544–549.
(9) Gonzalez, A. Z.; Soderquist, J. A. Org. Lett. 2007, 9, 1081–1084.
(10) (a) Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59, 2674–2675.
(b) Schaus, J. V.; Jain, N.; Panek, J. S. Tetrahedron 2000, 56, 10263–
10274. (c) Lipomi, D. J.; Panek, J. S. Org. Lett. 2005, 7, 4701–4704. (d)
Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125,
9596–9597. (e) Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am. Chem.
Soc. 2004, 127, 2858–2859. (f) Veenstra, S. J.; Schmid, P. Tetrahedron
Lett. 1997, 38, 997–1000. (g) Phukan, P. J. Org. Chem. 2004, 69, 4005–
4006.
(11) In addition to carbamates and sulfonamides, benzylamines, ally-
lamines, acetamides, and anilines were screened, but all of these nitrogen
sources showed little or no reactivity.
Org. Lett., Vol. 11, No. 19, 2009
4363

Table 2. Enantioselective Propargylations with Other
Sulfonamides
Scheme 2. ee Analysis of Each Enantiomer of Product 4b
yield
entry
aldehyde (R1)
R2
(%)a drb product
1
2
3
4
5
6
7
8
9
cyclohexanecarboxaldehyde p-tolyl
80
>20:1
4a
4b
4c
4d
4e
4f
4g
4h
4i
trimethylacetaldehyde
hydrocinnamaldehyde
p-tolyl
p-tolyl
76c >20:1
68
72
5:1
>20:1
cyclohexanecarboxaldehyde Ph
trimethylacetaldehyde
hydrocinnamaldehyde
Ph
Ph
83c >20:1
more difficult, with diminished reaction rate and selectivity.
For instance, when many aromatic aldehydes were treated
with TMSOTf in the presence of a sulfonamide, a large
amount of an unidentified precipitate was observed, and
product formation was sluggish or not observed. While small
amounts of the desired products could be obtained by
increasing the reaction temperature, this typically led to
decomposition of the starting materials. Despite these
78
5:1
>20:1
cyclohexanecarboxaldehyde 4-NO2Ph 69
trimethylacetaldehyde
4-NO2Ph 74c >20:1
hydrocinnamaldehyde
4-NO2Ph 71
6:1
a Isolated yields after purification over silica gel. b Diastereomeric ratios
determined by 1H NMR analysis on crude material. c Reaction run at -45
°C in MeCN.
with trimethylacetaldehyde needed to be run at higher
temperatures to help drive the reactions to completion.
The observed syn stereochemistry can be rationalized by
open transition states using antiperiplanar or synclinal
orientations of reaction partners (Figure 1), where allenyl-
Table 3. Propargylations with Aryl Sulfonyl Imines
Figure 1. Transition states.
silane (Ra)-1 is shown to add to the Re face of the iminium
ion. While either transition state nicely illustrates the
stereochemical course of the reaction, the synclinal transition
state, where the destabilizing interaction between the R group
on the iminium ion and the methylene and ester groups of
the allene is minimized, may be the best illustration.12
Chiral HPLC analysis was used to confirm that the axial
chirality in the allenylsilane was transferred into point chirality
in the homopropargylic sulfonamide products. In that context,
select products have been used to show how the chirality of
either enantiomer of allenylsilane 1 is fully transferred to the
propargylation products (Scheme 2). All of the homopropargylic
sulfonamides were found to have >97% ee. The relative and
absolute stereochemistry of the homopropargylic amines was
confirmed by comparison to known compounds.12
a Isolated yields after purification over silica gel. b Diastereomeric ratios
determined by H NMR analysis on crude material.
1
While the propargylation reactions with aliphatic aldehydes
were very effective, aromatic aldehydes have proven to be
4364
Org. Lett., Vol. 11, No. 19, 2009

setbacks, we were able to isolate the desired homopropargylic
sulfonamide products in moderate yields and diastereose-
lectivities (Table 3). The lower yields in the propargylations
with aromatic aldehydes may be a result of several factors,
ranging from sluggish reactions, extensive decomposition of
reactants and products, and a competing reaction, which
resulted in the formation of lactone 6.
Scheme 3. Proposed Mechanism for γ-Lactone Formation
When MeCN or EtCN was used as solvent, lactone 6 was
obtained as a minor byproduct, but it became the predominant
product when the solvent was switched to DCM. The use of
preformed aromatic imines resulted in the formation of
lactone 6 in moderate to high yields (Table 4).13 The structure
attacks the iminium ion, which explains the addition to the
central allene carbon, which has not been observed in
allenylmetal chemistry to the best of our knowledge. Pro-
tonation of the trisubstituted olefin results in a tertiary
carbocation, which is trapped by the ester, resulting in the
quaternary center and formation of the observed lactone upon
aqueous workup. For these examples transfer of chirality is
lost, as racemic products are observed, which most likely
arises from a steric argument, as the silyl ketene acetal cannot
differentiate between the π-faces of the iminium ion.
In summary, we have described a three-component reac-
tion of aldehydes, sulfonamides, and enantioenriched alle-
nylsilanes, resulting in the selective formation of syn
homopropargylic sulfonamides. The products were formed
in high yield and moderate to high selectivity when aliphatic
aldehydes were used. The formation of a γ-lactone is also
described by a new reaction pathway for allenylmetal
reagents. Current work is focused on expanding the func-
tionality of the allenylsilane, which would expand the
diversity of the resulting reaction products.
Table 4. Reactions with Pre-Formed Aryl Sulfonyl Imines
entry
R1
R2
yielda (%)
productb
1
2
3
4
5
6
7
8
9
Ph
2-BrPh
Ph
2-BrPh
4-MePh
2,3-OMePh
2-NO2Ph
2-BrPh
t-Bu
Me
Me
47
72
82
77
69
55
47
49
0
6a
6b
6c
6d
6e
6f
6g
6h
-
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-NO2Ph
p-tolyl
b
a Isolated yields after purification over silica gel. [R]2D0 ) 0.00.
of this material was assigned based on 2-D NMR studies
and confirmed by X-ray crystallography of compound 6h
(Scheme 3).12
Interestingly, when a preformed aliphatic imine was used
under identical reaction conditions, no reaction was observed,
and the starting materials were recovered (Table 4, entry 9).
A proposed mechanism for the formation of lactone 6
begins with silyl ketene acetal formation, promoted by
TMSOTf (Scheme 3). The resulting silyl ketene acetal then
Acknowledgment. Financial support was obtained from
NIH CA 53604. We are grateful to Will Youngsaye, Yun
Zhang, and Dr. Paul Ralifo at Boston University for helpful
discussions and assistance with 2D NMR experiments and
gratefully acknowledge Professor Karen Allen and Dr. Ezra
Peisach (Boston University) for obtaining X-ray crystal data.
Supporting Information Available: Experimental data
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) See the Supporting Information for expanded transition-state
analysis, HPLC traces, ee analysis, crystal structure data, and assignment
of the relative and absolute stereochemistry of the products.
(13) Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2003, 44,
1231–1234.
OL901692N
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