Multicomponent synthesis of chiral sulfinimines

Article abstract of DOI:10.1002/chem.201003222

Two oxathiozolidine-S-oxide templates have been developed and used in a four-component coupling protocol for the synthesis of a wide range of chiral sulfinimines in high enantiomeric excesses. The templates can be synthesized from cheap commodity chemicals in three steps in high yields. Furthermore the template is easily recovered in high yields for recycling.

Full text of DOI:10.1002/chem.201003222

DOI: 10.1002/chem.201003222
Multicomponent Synthesis of Chiral Sulfinimines
Caroline Roe,[a] Heather Hobbs,[b] and Robert A. Stockman*[a]
Abstract: Two oxathiozolidine-S-oxide templates have been developed and used in
a four-component coupling protocol for the synthesis of a wide range of chiral sul-
finimines in high enantiomeric excesses. The templates can be synthesized from
cheap commodity chemicals in three steps in high yields. Furthermore the tem-
plate is easily recovered in high yields for recycling.
Keywords: butanesulfinimine
·
imines · mesitylsulfinimine · multi-
component reactions · sulfinimines
Introduction
finamides with aldehydes, as pioneered by Ellman and co-
workers for the synthesis of tert-butylsulfinimines.[3] This
method is quite general, and various desiccants such as
copper sulfate or titanium tetraethoxide can be used. The
synthesis of the chiral sulfinamides can be achieved either
by a catalytic asymmetric oxidation of di-tert-butyldisulfide
followed by ammonolysis in liquid ammonia and sodium
amide,[3] or by Senanayake and co-workersꢀ adaptation of
Wudlꢀs sulfoxide synthesis, which uses a chiral amino-alco-
hol template for the addition of lithium amide and Grignard
reagents to generate chiral sulfinamides.[6]
Recently we disclosed a convenient synthesis of chiral
non-racemic S-mesitylsulfinimines using a four-component
coupling[7] based on Senanayakeꢀs norephedrine-derived
template 1 (Scheme 1). This method generated chiral sulfini-
mines in a single reaction procedure in excellent enantiose-
lectivities and greater yields than the multistep route. The
disadvantage to this method was that template 1 is derived
from norephedrine, which is relatively expensive and on the
controlled precursor list.
Chiral amines are high value commodities that can be found
in a large number of natural products and active pharma-
ceutical ingredients (e.g. Tamiflu, Plavix, Januvia). Over the
past two decades chiral sulfinimines have come to the fore
as versatile chiral building blocks for the synthesis of chiral
amines by addition of a suitable nucleophile or by reduction
with a hydride reagent.[1] First developed by Davis and co-
workers[2] and subsequently by Ellman and co-workers,[3]
both p-tolylsulfinimines (Davis)[1d] and tert-butylsulfinimines
(Ellman)[1a] have changed the way in which chemists synthe-
size chiral amines. Sulfinimines are significantly more stable
to hydrolysis when compared with N-sulfonyl and N-carba-
moyl imines,[1a] and the stereogenic sulfur group is able to
confer a high degree of stereocontrol in many cases upon re-
action with a wide range of nucleophiles. Furthermore the
N-sulfinyl group is usually cleaved easily from the formed
chiral amine by simple acid treatment.[1]
Whilst the chemistry of sulfinimines has been well ex-
plored over the past three decades, the synthesis of chiral
sulfinimines has seen fewer developments. The original syn-
thesis developed by Davis and co-workers used an oxidation
of sulfenimines, which gave racemic sulfinimines.[2] Subse-
quently both Cinquini et al.[4] and Davis et al.[5] reported on
the use of the Anderson reagent for the synthesis of chiral
sulfinimines by reaction with either metalloimines (Cin-
quini) or LiHMDS and aldehydes in a three-component re-
action (Davis). These methods suffered due to the difficulty
in recycling the sugar-based chiral auxiliary. The most
common method, however, is the condensation of chiral sul-
Scheme 1. Four-component synthesis of chiral S-mesitylsulfinimines.
Results and Discussion
[a] Dr. C. Roe, Dr. R. A. Stockman
School of Chemistry, University of Nottingham
Nottingham, NG7 2RD (UK)
Herein we describe a versatile multicomponent reaction
(MCR) methodology for the synthesis of chiral sulfinimines
using a template derived from l-phenylalanine, an inexpen-
sive, chiral, readily available starting material. Template 3
(Scheme 2) is prepared in three steps from l-phenylalanine
or in two steps from l-phenylalaninol. Since our initial prep-
aration of 3 its formation as a diastereomeric mixture has
Fax : (+44)115-9513564
E-mail: robert.stockman@nottingham.ac.uk
[b] Dr. H. Hobbs
GlaxoSmithKline
Gunnels Wood Road, Stevenage, SG1 2NY (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003222.
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Chem. Eur. J. 2011, 17, 2704 – 2708

FULL PAPER
good yields of 59% and 80%, respectively. All of these ex-
amples had high enantiomeric excess, with the mesityl sulfi-
nimine having the highest at 97.6%. It was found in all
cases to be important to add just one equivalent of the
Grignard reagent—any more and double addition to give
the sulfoxide would predominate. The use of two equiva-
lents of LiHMDS and raising the temperature of the reac-
tion to room temperature were found to be necessary to
drive the second step to completion. Two equivalents of al-
dehyde with titanium(IV) ethoxide were found to be the op-
timum conditions for the third (condensation) step. Amino
alcohol 2 was easily recovered from the reaction mixture by
chromatography, and was found to be unchanged in optical
rotation, thus allowing easy recycling (e.g. it was recovered
in 94% yield in entry 4, Table 1, Method A).
In their synthesis of S-tert-butylsulfinamide, Han, Sena-
nayake and their co-workers[6a] noted that changing the
order of the first two steps using template 1 (LiHMDS and
tert-butylmagnesium bromide) was found to give a high
yield and stereoselectivity. Thus we investigated the use of
template 3 with this reversal of addition (Method B). We
found that only one equivalent of LiHMDS and one equiva-
lent of Grignard reagent were necessary to obtain good
yields for all four examples of sulfinimine (Table 1). This
was a great improvement in yield for the p-tolyl and tert-
butyl sulfinimines, but on further analysis the products were
all found to be near-racemic. We also found that with the re-
verse addition a by-product formed that was inseparable by
flash chromatography, which we identified as alcohol 2 with
trimethylsilyl protection of the alcohol. This could be con-
veniently removed by the addition of TBAF prior to
workup so as to change the RF of the impurity and enable
separation.
Scheme 2. Formation of chiral template 3.
been published by Gallagher and Rujirawanich[8] using thio-
nyl chloride and pyridine. The issue of the formation of the
diastereomeric mixture was overcome by the avoidance of
an aqueous workup, which we found gave rise to the partial
epimerization of oxathiazolidine-S-oxide 3. Thus, rather
than using an aqueous quench, we found that concentration
of the reaction mixture, and purification using an ISOLUTE
CN cartridge[9] cleanly gave one diastereoisomer in 77%
yield (Scheme 2), for which the stereochemistry was con-
firmed by X-ray crystallography (see the Supporting Infor-
mation).
We decided to test the efficacy of the new template 3 by
the synthesis of a range of S-functionalized benzylidenesulfi-
nimines. The results of the synthesis of four sulfinimines
(tert-butyl, p-tolyl, iso-propyl, mesityl) that are most com-
monly seen in the literature using the template 3 in the
MCR (Method A) are shown in Table 1.
Table 1. Multicomponent synthesis of benzaldimines.
To explore scope of the reaction further, a range of
Grignard reagents were then applied to the MCR keeping
benzaldehyde as the fourth component using Method A
(Table 2). The cyclopentyl and cyclohexyl examples
Entry
Grignard
Method A
Method B
yield
ee
yield
ee
[%]
[%]
[%]
[%]
1
2
3
4
tBuMgCl
p-TolMgBr
iPrMgCl
20
27
59
80
95.2
94.3
89.1
97.6
63
52
63
56
0.9
8.6
2.6
1.3
Table 2. Synthesis of sulfinimines.
MesMgBr
Our initial method (Method A) involved the addition of
the Grignard reagent followed by LiHMDS and finally ben-
zaldehyde and titanium tetraethoxide. We found that tert-
butyl magnesium chloride successfully added into the oxa-
thiazolidine oxide but the subsequent addition of LiHMDS
was extremely slow, and only a low yield of tert-butylsulfini-
mine (20%) was isolated even when a large excess (six
equivalents) of LiHMDS was used. The p-tolylmagnesium
bromide reacted to give the p-tolylsulfinimine in 27% yield,
in this case the lower yield observed being due to double ad-
dition of the Grignard reagent to 3 giving an unwanted sulf-
oxide by-product. The isopropyl and mesityl Grignards gave
Entry
R
4
Yield
[%]
ee
[%]
1
2
3
4
5
6
2-thienyl
cyclopentyl
cyclohexyl
4-chloro-3-fluorophenyl
4a
4b
4c
4d
4e
4 f
43
53
66.3
93.2
93.0
96.6
81.8
96.8
67
29[a]
29
AHCTUNGTRENNUNG
59
[a] The sulfinimine product had gained a trimethylsilyl group at the
ortho-position next to the fluoro group.
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R. A. Stockman et al.
Table 4. Synthesis of S-mesitylsulfinimines.
(Table 2, entry 2 and 3) unsuprisingly gave similar results to
the isopropyl Grignard. The main product isolated from the
4-chloro-3-fluorophenyl example (Table 2, entry 4) had
gained a trimethylsilyl group on the aromatic ring in the 2-
position (presumably by ortho-lithiation and subsequent re-
action with HMDS). Although isolated in low yield, this
product had a high enantiomeric excess (96.6%), and poten-
tially leads the way to further diversification by use of other
traps, although this will not be discussed here. The 2-biphen-
yl sulfinimine (Table 2, entry 6) was prepared in a good
yield (59%) and high enantiomeric excess (96.8%). Thus
template 3 gives greater stereocontrol when the Grignard
used is more sterically hindered at the nucleophilic carbon.
We next investigated the synthesis of S-isopropylsulfini-
mines[10] (Table 3). It was found that the aromatic sulfini-
mines were formed in moderate to good yields and enantio-
meric excesses in the region of 90%. However, alkylsulfini-
mines were isolated in significantly lower yields due to hy-
drolysis in the workup/purification conditions.
Entry Aldehyde
6
Yield ee
[%] [%]
1
2
3
4
5
6
7
8
9
benzaldehyde
6a 80
6b 62
6c 46
6d 62
6e 60
6 f 72
6g 71
6h 52
97.6
99.2
98.3
98.6
99.1
88.6
99.2
99.2
95.0
4-methoxybenzaldehyde
4-nitrobenzaldehyde
furfural
trans-cinnamaldehyde
cyclopropanecarboxaldehyde
cyclohexanecarboxaldehyde
hexanal
1,1-dimethylethyl 3-formyl-1H-indole-1-carbox- 6i 50
ylate
10
11
12
13
14
15
16
17
1,3-oxazole-4-carboxaldehyde
1,3-thiazole-5-carbaldehyde
pivaldehyde
6j 72
6k 81
6l 61
6m 33
6n 84
6o 60
6p 85
6q 73
99.0
98.3
99.0
100
93.8
98.9
96.4
97.1
2-pyridinecarboxaldehyde
1-benzofuran-2-carbaldehyde
6-((tert-butyldimethyl-silyl)oxy)hexanal
5-bromo-2-thiophenecarbox-aldehyde
3-chloro-4-fluorobenzaldehyde
Table 3. Synthesis of S-isopropylsulfinimines.
hyde condensation step had to be shortened due to reaction
of 6h with excess hexanal.
Entry
Aldehyde
5
Yield
[%]
ee
[%]
To improve the yields for the p-tolyl sulfinimine synthesis
a more sterically hindered oxathiazolidine oxide 8 was in-
vestigated, which could also be prepared from l-phenylala-
nine in four steps. The formation of the oxathiazolidine
oxide 8 was straightforward from 7[12] giving only one diaste-
reoisomer in 90% yield (Scheme 3), the structure of which
was confirmed by X-ray crystallography (see the Supporting
Information).
1
2
3
4
5
6
7
8
benzaldehyde
5a
5b
5c
5d
5e
5 f
5g
5h
59
48
32
61
50
17
12
19
89.1
92.5
89.4
89.5
92.0
89.9
90.4
91.5
4-methoxybenzaldehyde
4-nitrobenzaldehyde
furfural
trans-cinnamaldehyde
cyclopropanecarboxaldehyde
cyclohexanecarboxaldehyde
hexanal
With moderate success with the S-isopropylsulfinimines,
we next turned our attention to S-mesitylsulfinimines
(Table 4), which were introduced by Davis and co-workers
in 2003[11] who found they have better stereodirecting ability
than the p-tolylsulfinimines but, like their tolyl cousins, S-
mesitylsilfinamide products can be deprotected with methyl
magnesium chloride as well as strong acid, making their de-
protection more flexible than tert-butylsulfinamides. In gen-
eral it was found that the MCR produced S-mesitylsulfini-
mines in good to excellent yields and excellent enantiomeric
excesses. The lowest yields at 33% and 46% (Table 4,
entry 3 and 13) were observed with electron-withdrawing ar-
omatic aldehydes, where the susceptibility to coordinate the
titanium tetraethoxide is greatest, slowing the condensation
stage and accelerating hydrolysis in the workup. Alkyl alde-
hydes performed well in the one-pot reaction, as long as
four equivalents of aldehyde were used. In the case of the
hexanal MCR (Table 4, entry 8), it was found that the alde-
Scheme 3. Synthesis of template 8.
Comparison of the performance of all three templates (1,
3, and 8) for the formation of S-functionalized benzylidene-
sulfinimines is set out in Table 5. The templates 1 and 3
gave comparable results for the synthesis of all sulfinimines,
with low yields being observed for S-p-tolyl and S-tert-butyl
benzylidenesulfinimines, the former case being due to un-
wanted double addition of the Grignard forming a sulfoxide.
The more sterically hindered template 8 was able to over-
come this issue, enabling the S-p-tolyl and S-isopropyl ben-
zylidenesulfinimines to be generated in good yields and ex-
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Chem. Eur. J. 2011, 17, 2704 – 2708

Multicomponent Synthesis of Chiral Sulfinimines
FULL PAPER
Table 5. Synthesis of S-isopropylsulfinimines.
Table 7. Synthesis of S-isopropylsulfinimines.
Oxathiazolidine oxide
Entry
Aldehyde
5
Yield
[%]
ee
[%]
1
3
8
Entry
RMgX
yield
[%]
ee
[%]
yield
[%]
ee
[%]
yield
[%]
ee
[%]
1
2
3
benzaldehyde
furfural
cyclopropanecarboxaldehyde
5a
5d
5 f
71
61
53
98.9
100
98.7
1
2
3
4
tBuMgCl
p-TolMgBr
iPrMgCl
0
–
20
27
59
80
95.2
94.3
89.1
97.6
0
–
27
49
65
98.6
98.7
99.2
49
71
8
99.8
98.9
–
MesMgBr
Conclusion
cellent enantiomeric excess. The S-tert-butyl and S-mesityl
benzylidenesulfinimines were not formed well due to the
steric bulk of the Grignard reagents used.
With an enhanced method for the formation of S-p-tolyl-
sulfinimines, we investigated the scope of the MCR
(Table 6). It was found that a range of S-p-tolylsulfinimines
were produced in moderate to good yields and high stereo-
selectivity.
In conclusion, we have developed a versatile multicompo-
nent reaction capable of generating a wide range of chiral
sulfinimines from simple commercially available reagents in
good yields and high enantioselectivities. We are further de-
veloping the template-directed multicomponent reaction for
the versatile one-pot synthesis of chiral sulfinamides and
will report our findings in due course.
Experimental Section
Table 6. Synthesis of S-p-tolylsulfinimines.
The entire experimental section can be found in the Supporting Informa-
tion, including compound characterization data and copies of NMR spec-
tra.
Acknowledgements
Entry
Aldehyde
9
Yield
[%]
ee
[%]
Financial support from EPSRC/GSK (EP/F068352/1) is gratefully ac-
knowledged. Eric Hortense (GSK) is thanked for carrying out chiral
HPLC analyses, and William Lewis is thanked for X-ray crystallographic
analyses.
1
2
3
4
5
6
7
benzaldehyde
9a
9b
9c
9d
9e
9 f
9g
49
82
33
31
59
62
19
99.8
99.1
99.0
98.8
99.7
97.8
98.8
4-methoxybenzaldehyde
4-nitrobenzaldehyde
furfural
trans-cinnamaldehyde
cyclopropanecarboxaldehyde
cyclohexanecarboxaldehyde
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Received: November 9, 2010
Published online: January 26, 2011
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Chem. Eur. J. 2011, 17, 2704 – 2708