Convenient synthesis of chiral non-racemic S-mesityl sulfinimines

Article abstract of DOI:10.1016/j.tetlet.2007.12.067

A direct multi-component coupling of (2S,4R,5S)-N-tosyl-4-methyl-5-phenyl-1,2,3-oxathiozolidine-2-oxide with mesityl magnesium bromide, LHMDS and a range of aldehydes produces chiral sulfinimines in essentially optically pure form in an operationally simp

Full text of DOI:10.1016/j.tetlet.2007.12.067

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Tetrahedron Letters 49 (2008) 1129–1132
Convenient synthesis of chiral non-racemic S-mesityl sulfinimines
Leonid Sasraku-Neequaye a, David MacPherson b, Robert A. Stockman a,*
a School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
b GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 16 October 2007; revised 3 December 2007; accepted 12 December 2007
Abstract
A direct multi-component coupling of (2S,4R,5S)-N-tosyl-4-methyl-5-phenyl-1,2,3-oxathiozolidine-2-oxide with mesityl magnesium
bromide, LHMDS and a range of aldehydes produces chiral sulfinimines in essentially optically pure form in an operationally simple
single pot procedure.
Ó 2008 Elsevier Ltd. All rights reserved.
The first sulfinimine was synthesised by Davis over 30
years ago1 and was found to have unusual stability towards
hydrolysis and deprotonation when compared to N-ali-
phatic imines and N-sulfonyl imines. This ease of handling,
coupled with the stereogenic sulfur atom, led to Davis and
more latterly Ellman employing the N-sulfinyl group as a
directing group for the nucleophilic addition to sulfini-
mines.2 This methodology has become probably the most
common and effective method for the synthesis of chiral
non-racemic amines, and is further enhanced by the ease
of removal of the p-tolyl (Davis) and t-butyl (Ellman) sul-
finyl groups from the product amino compounds by simple
acid hydrolysis.2
enantioselectivities.4 When Ellman introduced the tert-
butylsulfinyl directing group, he also introduced a proce-
dure for the synthesis of enantiopure tert-butylsulfinamide5
and condensed this with aldehydes and ketones with either
copper sulfate or titanium tetraethoxide as the dessicant.6
More recently the groups of Senanayake and Han have
described a very general and high yielding approach to
the synthesis of sulfinamides, which employs cheap and
readily available materials and uses straightforward proce-
dures to synthesise chiral sulfinamides7 via a modification
of Wudl’s sulfoxide synthesis (Scheme 1).8
These sulfinamides are then condensed with aldehydes
and ketones using the Davis et al.9 and Ellman and
The synthesis of these versatile chiral building blocks
has received relatively little attention compared to the large
body of work exploring their reactivity. Cinquini was the
first to report an asymmetric synthesis of sulfinimines by
the addition of aromatic metalloimines with the Andersen
reagent.3 Davis’ subsequent method also used the Ander-
sen reagent, which was reacted with LHMDS and a range
of aldehydes in a one-pot procedure to produce p-tolylsul-
finimines in moderate to excellent yields and excellent
O
S
HO
Ph
NH2.HCl
1. TsCl, NaHCO3
2. SOCl2, py
O
NTs
Ph
1
95%
RMgBr,
THF, -78 ºC
O
S
O
S
R
LiNH2, NH3/THF
or LHMDS
O
NHTs
R
NH2
*
Corresponding author at present address: School of Chemistry,
Ph
University of Nottingham, University Park, Nottingham NG7 2RD,
UK. Tel.: +44 (0) 115 9513252; fax: +44 (0) 115 9513564.
80-92% from 1
Scheme 1. Senanayake synthesis of sulfinamides.
E-mail address: robert.stockman@nottingham.ac.uk (R. A. Stockman).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.067

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L. Sasraku-Neequaye et al. / Tetrahedron Letters 49 (2008) 1129–1132
co-workers6 techniques. Qin et al. used a related method to
develop a 51% yielding three step synthesis of tert-butylsul-
finamide.10 Senanayake and Han then refined their method
further to a kilo-scale synthesis of tert-butylsulfinamide
from N-tosylnorephedrine in 75% yield and also adapted
this approach for the synthesis of a wide range of sulfin-
amides11 including the recently introduced mesityl sulfin-
amide,12 which combines the high selectivity of the
Ellman sulfinyl group with the additional benefits of the
Davis p-tolylsulfinyl group, which can be removed with
either acid or Grignard reagents.
All of the Ellman, Han/Senanayake and Qin/Jiang
methods require the use of large volumes of liquid ammo-
nia in the formation of the sulfinamide, which can lead to
difficulty in isolation of the sulfinamide due to its high sol-
ubility in water. These methods also require an extra con-
densation step to form the sulfinimine, unlike Davis’
earlier one-pot procedure.
Herein we report a one-pot synthesis of mesityl sulfini-
mines from 1,2,3-thiazoxazole oxide 1 using an amalgama-
tion of the Senanayake one-pot sulfoxide formation11 and
the Davis one-pot sulfinamide4 formation (Table 1).
Table 1
Synthesis of S-mesityl sulfinimines
O
S
O
S
1. MesMgBr, THF, -78 ºC
2. LHMDS, rt
O
NTs
N
Mes
3. R'CHO, Ti(OEt)
4
R'
Ph
1
2a-g
Entry
1
Aldehyde
Product
Yield (%)
54
eea (%)
>99.5
O
S
O
Mes
Mes
N
N
2a
O
S
O
O
2
3
50
35
>99.5
>99.5
2b
OMe
OMe
O
S
Mes
Mes
N
2c
NO
2
NO
2
O
S
O
O
N
4
5
44
57
>99.5
>99.5
O
2d
O
S
O
Mes
Mes
N
N
Ph
2e
Ph
O
S
O
O
6
60
46
>99.5
>99.5
2f
O
S
7
Mes
N
2g
a
Determined by HPLC.

L. Sasraku-Neequaye et al. / Tetrahedron Letters 49 (2008) 1129–1132
1131
Thiazoxazole oxide 1 was prepared using Sananayake’s
procedure. Treatment of 1 with mesityl magnesium bro-
mide at ꢀ78 °C is followed by warming to room tempera-
ture and the addition of lithium hexamethyldisilazide. Once
the intermediate (related to 3, Scheme 2) was judged to be
fully reacted by TLC, aldehyde and titanium tetraethoxide
were added to the reaction solution, which was stirred at
room temperature until judged complete by TLC. As can
be seen from Table 1, the coupling reaction gives moderate
to good yields of a wide range of sulfinimines13 in essen-
tially optically pure form as judged by chiral HLPC. Elec-
tron rich and electron poor aldehydes are tolerated, as are
easily enolisable aldehydes. X-Ray crystallographic analy-
sis of cinnamyl derived imine 2e confirms the stereochemi-
cal outcome of the reactions (Fig. 1). Whilst the yields of
product at first glance seem underwhelming, comparison
with the stepwise procedure shown in Scheme 2 shows that
yields are in fact superior for the one-pot procedure.
In conclusion, the one-pot four-component coupling is a
convenient and useful method for the preparation of opti-
cally pure mesityl sulfinimines, which uses relatively inex-
pensive reagents and is practically simple. A wide range
of aldehyde coupling partners are tolerated. Investigations
into the range of Grignard coupling partners and the explo-
ration of a five-component coupling are on-going in these
laboratories and will be disclosed in due course.
Acknowledgements
We are grateful to Dr. David Hughes, UEA X-ray suite,
for carrying out the crystal structure determination. We are
also grateful to GlaxoSmithKline for the award of CASE
funding (L.S.N.).
References and notes
1. For a review of Davis’ work on sulfur–nitrogen chemistry see: Davis,
F. A. J. Org. Chem. 2006, 71, 8993.
2. For a recent review on the chemistry of chiral sulfinimines see:
Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869.
3. Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc., Perkin Trans.
1 1982, 339.
4. Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.;
Carroll, P. J. J. Org. Chem. 1997, 62, 2555.
5. Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317; and references
cited therein.
6. Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A. J. Am.
Chem. Soc. 1998, 120, 8011.
7. (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senana-
yake, C. H. J. Am. Chem. Soc. 2002, 124, 7880; (b) Han, Z.;
Krishnamurthy, D.; Pflum, D.; Grover, P.; Wald, S. A.; Senanayake,
C. H. Org. Lett. 2002, 4, 4025; (c) Han, Z.; Krishnamurthy, D.;
Grover, P.; Wilkinson, H. S.; Fang, Q. K.; Su, X.; Lu, Z.-H.;
Magiera, D.; Senanayake, C. H. Angew. Chem., Int. Ed. 2003, 115,
2078; (d) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.;
Pflum, D. A.; Senanayake, C. H. Tetrahedron Lett. 2003, 44, 4195.
8. Wudl, F.; Lee, T. B. K. J. Am. Chem. Soc. 1973, 95, 6349.
9. Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
O
S
O
MesMgBr,THF, -78 ºC
90%
S
O
NTs
O
NHTs
Ph
Ph
3
LHMDS,
10. Qin, Y.; Wang, C.; Huang, Z.; Xiao, X.; Jiang, Y. J. Org. Chem. 2004,
69, 8533.
11. Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, K. Q.; Su, X.;
Wilkinson, H. S.; Lu, Z.-H.; Magiera, D.; Senanayake, C. H.
Tetrahedron 2005, 61, 6386.
THF, -78 ºC
72%
Mes
O
O
S
RCHO, Ti(OEt)4
THF, r.t
S
12. Davis, F. A.; Ramachandar, T.; Wu, Y. J. Org. Chem. 2003, 68, 6894.
13. General procedure for the synthesis of S-mesitylsulfinyl imines
from 4-methyl-5-phenyl-3-(toluene-4-sulfonyl)-[1,2,3]oxathiazolidine-
2-oxide (1). In a 100 mL one-neck, round-bottomed flask equipped
with a magnetic stirring bar, rubber septum, and argon inlet was
placed 1 (1 equiv) in THF (40 mL). The reaction mixture was cooled
to ꢀ78 °C, followed by the addition of MesMgBr (1.15 equiv of a 1 M
solution in diethyl ether) slowly via a syringe. After the addition, the
reaction was stirred at ꢀ78 °C for 1 h and the reaction mixture was
warmed to ꢀ45 °C and monitored by TLC analysis. After completion,
a solution of lithium hexamethyldisilazane (2 equiv of a 0.5 M
solution in THF) was added dropwise via syringe and the reaction
mixture was warmed to room temperature. The reaction was stirred at
room temperature for 1 h and monitored for completion by TLC. The
aldehyde (1.1 equiv) and titanium tetraethoxide (4 equiv) were then
added to the reaction mixture, which was stirred at room temperature.
Conversion was monitored by TLC after which the mixture was
quenched with a saturated aqueous solution of sodium hydrogencar-
bonate with rapid stirring. The resulting suspension was filtered
through a plug of Celite, and the filter cake was washed with ethyl
acetate. The filtrate was transferred to a separatory funnel and the
phases were separated. The organic layer was then washed with brine
and the combined aqueous layer was extracted once with ethyl
acetate. The combined organic portions were dried over sodium
sulfate (Na2SO4), filtered and concentrated. The sulfinyl imines, 2a–g,
N
Mes
NH2
R
R=Ph, 60% (38.9% over 3 steps)
R=Cy, 73% (47.3% over 3 steps)
Scheme 2. Stepwise synthesis of sulfinimines.
Fig. 1. X-ray structure of 2e.

1132
L. Sasraku-Neequaye et al. / Tetrahedron Letters 49 (2008) 1129–1132
were purified by silica gel chromatography (ethyl acetate/hexanes
s), 2.27 (3H, s); dC (100 MHz, CDCl3) 150.5, 148.8, 147.1, 141.8,
gradient elution). N-(Benzylidene)-2,4,6-trimethylphenylsulfinamide
138.6, 135.1, 130.9, 119.0, 112.6, 21.1, 18.9; HRMS calculated for
25
(2a): ½aꢁD ꢀ150.7 (c 0.52, CHCl3); found IR (neat) 2981, 2879,
C14H15NO2S: [M+H]: 262.0896, found: 262.0893. N-(3-Phenyl-allyl-
25
1602, 1572, 1448 cmꢀ1; dH (400 MHz, CDCl3) 8.82 (1H, s), 7.83–7.85
(2H, m), 7.46–7.47 (3H, m), 6.85 (2H, s), 2.49 (6H, s), 2.27 (3H, s); dC
(100 MHz, CDCl3) 161.9, 141.9, 138.7, 135.5, 134.1, 132.7, 131.1,
idene)-2,4,6-trimethylphenylsulfinamide (2e): ½aꢁD ꢀ401.7 (c 0.53,
CHCl3); found: IR (neat) 2976, 1827, 1623, 1598, 1566, 1448, 1071,
995, 753 cmꢀ1; dH (400 MHz, CDCl3) 8.53 (1H, d, J = 9.2), 7.44–7.47
(2H, m), 7.31–7.38 (2H, m), 7.18–7.19 (1H, m), 7.02 (2H, m), 6.79
(2H, s), 2.42 (6H, s), 2.20 (3H, s); dC (100 MHz, CDCl3) 162.6, 146.5,
141.8, 138.4, 135.0, 131.0, 130.4, 129.1, 128.6, 128.0, 125.5, 21.0, 18.7;
129.1, 21.3, 19.1; HRMS calculated for
C16H17NOS: [M+H]:
272.1104, found: 272.1102. N-(4-Methoxy-benzylidene)-2,4,6-trimethyl-
25
benzenesulfinamide (2b): ½aꢁD ꢀ86.7 (c 0.5, CHCl3); found: IR
(neat) 2964, 2931, 3863, 1597, 1563, 1420, 1247, 1081 cmꢀ1; dH
(400 MHz, CDCl3) 8.75 (1H, s), 7.79–7.81 (2H, m), 6.94–6.97 (2H, m),
6.85 (2H, s), 3.86 (3H, s), 2.50 (6H, s), 2.28 (3H, s); dC (100 MHz,
CDCl3) 163.1, 160.8, 141.6, 138.5, 135.8, 131.5, 130.8, 127.1, 114.3,
HRMS calculated for C18H19NOS: [M+H]: 298.1260, found:
298.1261. N-(Cyclohexylmethylene)-2,4,6-trimethylphenylsulfinamide
25
(2f): ½aꢁD ꢀ237.9 (c 0.52, CHCl3); found: IR (neat) 2925, 2855,
1595, 1449, 1431, 1092 cmꢀ1; dH (400 MHz, CDCl3) 8.15 (1H, d,
J = 5.2), 6.81 (2H, s), 2.42 (6H, s), 2.24 (3H, s), 1.49–1.84 (4H, m),
1.13–1.41 (4H, m, H2), 0.82–0.87 (3H, m, 11-H); dC (100 MHz,
CDCl3) 171.4, 141.6, 138.4, 135.4, 130.9, 43.0, 21.2, 25.7, 25.2, 20.9,
18.6; HRMS calculated for C16H23NOS: [M+H]: 278.1573, found:
55.5, 21.1, 18.9; HRMS calculated for
C17H19NO2S: [M+H]:
302.1209, found: 302.1211. N-(4-Nitro-benzylidene)-2,4,6-trimethyl-
25
benzenesulfinamide (2c): ½aꢁD ꢀ43.1 (c 0.5, CHCl3); found: IR (neat)
3110, 2993, 1737, 1582, 1516, 1088, 1078 cmꢀ1; dH (400 MHz, CDCl3)
8.91 (1H, s), 8.29–8.33 (2H, m), 8.00–8.04 (2H, m), 6.88 (2H, s), 2.50
(6H, s), 2.30 (3H, s); dC (100 MHz, CDCl3) 159.3, 149.9, 142.5, 138.9,
138.5, 134.5, 131.0, 130.2, 124.2, 21.1, 18.9; HRMS calculated for
25
278.1577. N-(Hexylidene)-2,4,6-trimethylphenylsulfinamide (2g): ½aꢁD
ꢀ239.6 (c 0.52, CHCl3); found: IR (neat) 2954, 2926, 1732, 1617,
1087, 619 cmꢀ1; dH (400 MHz, CDCl3) 8.22 (1H, t, J = 5.1), 6.77 (2H,
s), 2.42–2.47 (2H, m), 2.38 (6H, s), 2.19 (3H, s), 1.51–1.57 (2H, m),
1.15–1.30 (4H, m), 0.76–0.85 (3H, m); dC (100 MHz, CDCl3) 168.5,
141.8, 138.4, 135.3, 131.0, 36.1, 31.6, 25.6, 22.6, 21.3, 19.0, 14.1;
HRMS calculated for C15H23NOS: [M+H]: 266.1573, found:
266.1575.
C
16H16N2O3S: [M+H]: 317.0954, found: 317.0949. N-(Furan-2-yl-
25
methylene)-2,4,6-trimethyl-benzenesulfinamide (2d): ½aꢁD ꢀ127.1 (c
0.52, CHCl3); found: IR (neat) 3128, 2971, 1737, 1604, 1546, 1473,
1076, 791, 763 cmꢀ1; dH (400 MHz, CDCl3) 8.64 (1H, s), 7.62–7.63
(1H, m), 7.04–7.05 (1H, m), 6.84 (2H, s), 6.56–6.57 (1H, m), 2.49 (6H,