Direct synthesis of chiral aziridines from N-tert-butyl-sulfinylketimines

Article abstract of DOI:10.1039/b601527a

The direct preparation of a range of variously substituted chiral tert-butylsulfinylketimines was achieved in good yield (41-90%), with relatively rapid reaction times (4-15 hours); their synthetic application was examined through the reaction with the yl

Full text of DOI:10.1039/b601527a

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Direct synthesis of chiral aziridines from N-tert-butyl-sulfinylketimines
Daniel Morton,a David Pearson,{b Robert A. Fielda and Robert A. Stockman*a
Received (in Cambridge, UK) 1st February 2006, Accepted 16th March 2006
First published as an Advance Article on the web 27th March 2006
DOI: 10.1039/b601527a
The direct preparation of a range of variously substituted chiral
tert-butylsulfinylketimines was achieved in good yield (41–90%),
with relatively rapid reaction times (4–15 hours); their synthetic
application was examined through the reaction with the ylides
derived from trimethylsulfonium iodide and S-allyl tetrahy-
drothiophenium bromide, affording convenient access to a
Fig. 1 Synthesis of chiral aziridines from tert-butyl-sulfinylketimines.
diverse range of highly substituted chiral aziridines in up to 78%
yield and . 90% d.e.
tert-butyl-sulfinyl-ketimines in good yield. Our results are
summarized in Table 1.
Amines, and particularly chiral amines, are key structural
functionalities throughout natural products and drug candidates.
Perhaps the most direct method of synthesis of functionalised
amines is through 1,2-nucleophilic addition to imines. What makes
this avenue particularly attractive is the vast pool of readily
available inexpensive aldehydes and ketones which can be easily
transformed into imines. However, the reactive nature of imines is
such that an electron withdrawing N-substituent is required to
domesticate their character. In this role the N-sulfonyl substituent
has found widespread application.1 A significant limitation to the
chemistry of N-sulfonylimines is the problematic preparation of
sulfonyl ketimines.2 Thus, while sulfonyl-aldimines have enjoyed
facile preparation and reaction, the chemistry of their more
substituted counterparts is significantly less developed.
At room temperature the condensation of many of the
substrates was observed to be sluggish. The formation of tert-
butyl-sulfinyl-ketimines is known to be accelerated at elevated
temperatures.5 The extent of warming was found to be dependent
on the thermal stability of the product; in many of our preliminary
investigations thermal decomposition of the ketimine was
observed. The temperatures reported in Table 1 reflect the
optimum conditions found for the synthesis of the ketimines.
Thus the tert-butyl-sulfinyl-ketimines were prepared in good yield
(41–90%), with the ketimines found to be stable to flash column
chromatography.
The high propensity for the tert-butyl-sulfinyl-aldimines to
reside in the E-conformation has been observed throughout the
plethora of publications within this field.1,2 This tendency is also
evident for the tert-butyl-sulfinyl-ketimines, albeit to a lesser
extent, particularly in substrates with less pronounced steric
differentiation between the substituents. Our findings were in
agreement with this literature precedent; the E-isomer predomi-
nated in all instances. There were only two cases where the
Recent reports have detailed the emergence and application of
chiral sulfoxides as N-protecting groups for imines.3 Methods have
been developed for the direct preparation of these enantiopure
building blocks. Both the p-tolyl- and tert-butyl- chiral sulfinyl
moieties have been demonstrated to be successful directing/
protecting groups for a large variety of transformations,4 in
addition both the sulfinyl-aldimines and sulfinyl-ketimines are
readily accessible.4
Table 1 Summary of the preparation of a range of chiral tert-butyl-
sulfinylketimines
A particular class of asymmetric amines that has great potential
for further elaboration are chiral aziridines.5 Our previous
investigations have focused on the suitability of tert-butyl
sulfinyl-aldimines as substrates for aziridination via reaction with
both dimethylsulfonium methylide6 and allylic sulfur ylides.7
We report the extension of the scope of this methodology by
demonstrating the suitability of tert-butyl-sulfinyl-ketimines as
aziridination substrates (Fig. 1).
Yield
Entry R1, R2
Temp./uC Time/h (%)
E/Z
Prod.
Using an adaptation of the methods established by Ellman et al.
for the condensation of tert-butyl-sulfinamide with carbonyl
compounds8 provided direct access to a comprehensive range of
1
2
3
4
5
6
7
8
9
Ph, Ph
55
55
45
55
55
55
4
6
6
4
5
8
12
7
15
7
10
69
90
41
61
55
62
48
51
60
44
51
—
1a
Me, Ph
Me, Et
–(CH)4–
–(CH)5–
–(CH)6–
Et, 2-methyl Bu 45
Et, 2-thiophene 45
Et, Cy
Et, 2-thiazole
Me, n-hexyl
. 10/1 1b
. 10/1 1c
—
—
—
. 10/1 1g
y 5/1 1h
. 10/1 1i
y 6/1 1j
. 10/1 1k
1d
1e
1f
aSchool of Chemical Sciences and Pharmacy, University of East Anglia,
Norwich, UK NR4 7TJ. E-mail: r.stockman@uea.ac.uk
bMillennium Pharmaceuticals, Granta Park, Great Abington,
Cambridge, UK CB1 6ET
{ Present address: Millennium Pharmaceuticals, Inpharmatica Ltd, 127
Science Park, Milton Road, Cambridge, UK CB4 0DG
45
50
45
10
11
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Chem. Commun., 2006, 1833–1835 | 1833

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three of the nine ketimines exposed to the reaction conditions
Table 2 Summary of the reaction of tert-butyl-sulfinyl-ketimines with
dimethylsulfonium methylide
furnished significant amounts of the desired aziridines. While
many of the reactions yielded little or none of the desired aziridine,
those that were synthesised were formed in excellent diastereo-
selectivity. It is thought that the low yields observed in the reaction
of dimethylsulfonium methylide and the tert-butyl-sulfinyl-keti-
mines are due to the harsh reaction conditions employed; the
strained, relatively unstable nature of the ketimines led to a
multitude of undesired side reactions upon exposure to sodium
hydride, hence we chose to investigate the use of the less basic ylide
derived from S-allyl tetrahydrothiophenium bromide accessible
under much milder conditions.
Entry
Substrate
Time/h
Yield (%)
d.e. (%)
Prod.
1
2
3
4
5
1a
1a
1c
1d
1f
4
12
24
24
8
73
69
trace
—
—
. 95
. 95
—
—
—
2a
2a
2c
2d
2f
The reaction of tert-butyl-sulfinyl-aldimines with the allylic ylide
during previous studies was optimised to provide efficient access to
chiral vinyl aziridines.8 The aziridines were synthesised in high
yield9 with excellent diastereoselectivities and good stereocontrol
when the reaction was carried out in THF. However, it was found
that by employing DMSO as the solvent aziridines were
synthesised in higher yield, albeit with lower stereocontrol.
Consideration of the reduced reactivity caused by the greater
steric presence inherent in the tert-butyl-sulfinyl-ketimines
prompted us to investigate the use of both THF and DMSO as
the solvent for aziridination. Our results are summarised in Table 3.
The implementation of the allylic ylide proved to provide a
more substituent tolerant procedure.10 The highly strained vinyl
aziridines were prepared in good yield (42–85%), excellent
diastereoselectivity (between 90– . 95%) and reasonable cis/trans
selectivity. In comparison to the reaction of ketimines with
dimethylsulfonium methylide, the yields are significantly improved,
with the distinction particularly pronounced for ketimines bearing
an enolisable proton.
6
7
8
9
10
1g
1h
1i
1j
1k
5
8
8
4
12
—
—
47
trace
36
—
—
. 95
—
. 95
2g
2h
2i
2j
2k
Z-isomer was present to any significant extent (entries 8 and 10,
Table 1), and in these instances the major isomer could be isolated.
We have previously demonstrated the suitability of tert-butyl-
sulfinyl-aldimines as substrates for the Corey–Chaykovsky azir-
idination with dimethylsulfonium methylide, furnishing the
aziridines in high yield, and in addition with high stereocontrol
gained through the influence of the chiral sulfinyl group.6 Table 2
summarises our investigations into the suitability of tert-butyl-
sulfinyl-ketimines as substrates for the optimized Corey–
Chaykovsky aziridination procedure.
In contrast to our previous findings with the tert-butyl-sulfinyl-
aldimines, the ketimines were, in general, found not to be suitable
substrates for reaction with dimethylsulfonium methylide. Only
There are many routes for the elaboration of aziridines,11 a good
proportion of which require deprotection of the aziridine nitrogen.
Table 3 Summary of the reaction of chiral tert-butyl-sulfinyl-ketimines with the ylide derived from S-allyl tetrahydrothiophenium bromide
Entry
Substrate
Solvent
Time/h
Yield (%)
trans/cis
d.e. (%)a
Prod.
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1d
1d
1e
1f
1h
1h
1j
1j
1k
THF
DMSO
THF
DMSO
THF
DMSO
DMSO
DMSO
THF
DMSO
THF
2
1.5
2.5
2
6
4
48
48
3
3
4
52
85
72
78
trace
55
—
—
55
72
42
56
55
—
—
80/20
75/25
—
. 95
. 95
. 95
. 95
—
. 95
—
—
. 95
. 95
—
90
. 95
3a
3a
3b
3b
3d
3d
3e
3f
3h
3h
3j
3j
3k
—
—
—
72/28
60/40
50/50
55/45
69/31
10
11
12
13
a
DMSO
DMSO
2
3
Diastereomeric excess stated is that measured of the major trans-isomer determined from the 1H NMR of the crude reaction mixture.
1834 | Chem. Commun., 2006, 1833–1835
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Notes and references
1 S. M. Weinreb, Top. Curr. Chem., 1997, 190, 131.
2 For a comprehensive discussion on the syntheses of N-sulfonylketimines
and an elegant solution involving the formation and oxidation of
N-sulfinylketimines, see: J. L. Garc´ıa Ruano, J. Alema´n, M. B. Cid and
A. Parra, Org. Lett., 2005, 7, 179.
3 For reviews on this subject see: (a) F. A. Davis, R. R. Reddy,
J. M. Szewczyk, G. V. Reddy, P. S. Portonovo, H. Zhang, D. Fanelli,
R. T. Reddy, P. Zhou and P. J. Carrol, J. Org. Chem., 1997, 62, 2555;
(b) D. A. Cogan, G. Liu and J. A. Ellman, Tetrahedron, 1999, 55, 8883;
(c) J. A. Ellman, T. D. Owens and T. P. Tang, Acc. Chem. Res., 2002,
35, 984; (d) B.-C. Chen, F. A. Davis and P. Zhou, Tetrahedron, 2004, 60,
8003; (e) G. Liu, D. A. Cogan, T. D. Owens, T. P. Tang and
J. A. Ellman, J. Org. Chem., 1999, 64, 1278.
4 (a) P. Zhou, B. C. Chen and F. A. Davis, Tetrahedron, 2004, 60, 8003;
(b) J. A. Ellman, Pure Appl. Chem., 2003, 75, 39.
Fig. 2 Influence of the tert-butyl-sulfinyl group on the topicity of attack
of nucleophiles on sulfinimines.
5 For reviews on this subject see: (a) D. Tanner, Angew. Chem., Int. Ed.
Engl., 1994, 33, 599; (b) R. S. Atkinson, Tetrahedron, 1999, 55, 1519; (c)
J. B. Sweeney, Chem. Soc. Rev., 2002, 103, 2905; (d) X. E. Hu,
Tetrahedron, 2004, 60, 2701.
6 D. Morton, D. Pearson, R. A. Field and R. A. Stockman, Synlett, 2003,
13, 1985.
7 D. Morton, D. Pearson, R. A. Field and R. A. Stockman, Org. Lett.,
2004, 6, 2377.
8 G. Liu, D. A. Cogan and J. A. Ellman, J. Am. Chem. Soc., 1997, 119,
9913.
Encouraged by our previous results7 and further reports detailing
the deprotection of tri-substituted tert-butyl-sulfinyl-aziridines10 we
investigated the removal of the sulfinyl group. Deprotection of tri-
substituted aziridine 3a using saturated HCl in diethyl ether was
successful, yielding the corresponding aziridinium salt in 83% yield
with the remaining mass balance accounted for by the ring-opened
product, wherein chloride ion has attacked the aziridine ring on the
carbon bearing the vinyl group (15%).
9 Representative procedure for the synthesis of tert-butyl sulfinyl vinyl
aziridines: An oven-dried 25 mL round-bottomed flask was charged
with a 0.1 M solution of S-allyl tetrahydrothiophenium bromide,
(2.5 eq.), in anhydrous DMSO, and the solution stirred at ambient
temperature under an atmosphere of argon. To which was added a
solution of N-[tert-butyl-(RS)-sulfinyl]-ketimine, (1 eq.), in anhydrous
DMSO, portionwise, and the reaction allowed to stir for 30 minutes. To
the clear reaction mixture was added lithium tert-butoxide, (2.5 eq.), and
the progress was monitored by TLC. Once the reaction was complete,
ice-cold brine was added, and the biphasic mixture stirred for 10 minutes.
Filtration of the cloudy mixture through Celite, and extraction of the
solids with EtOAc, afforded a biphasic solution which was separated,
the aqueous layer extracted with EtOAc and the combined organic
fractions concentrated under reduced pressure. The organic residues
were then partitioned between a 1 : 1 petrol/Et2O solution and brine.
The organic fractions were then dried over sodium sulfate, and
concentrated under reduced pressure to yield the crude aziridine.
Purification was achieved through column chromatography over
alumina. N-[tert-butyl-(RS)-sulfinyl]-2-diphenyl-3-vinyl-aziridine: Rf 0.54
(4 : 1 petrol/EtOAc); m.p. 81–83 uC (from hexane/EtOAc); nmax (Nujol)/
cm21 2921, 1450, 1370, 1282, 1089 (s) (SLO stretch); dH (400 MHz;
CDCl3) 7.80–7.20 (10H, m, Ar-H), 5.49–5.43 (1H, m, –CH C-4), 5.25
(1H, d, J = 16.8, C-5-HA), 5.19 (1H, d, J = 10.1, C-5-HB), 3.68 (1H, d,
J = 6.4, –CH C-3), 1.23 (9H, s, tbutyl-H); dC (100 MHz; CDCl3) 139.6,
137.1, 133.3 (2 6 C), 130.3 (2 6 C), 128.8 (2 6 C), 128.2 (2 6 C),
127.5 (2 6 C), 121.5, 120.9, 58.3, 57.1, 49.8, 23.2 (3 6 C); MS (CI): m/z
[M + H]+ 326.2 (100%); HRMS calculated for C20H24NOS (M + H)
326.1573, found 326.1572.
The exceptional diastereoselectivity observed in the formation of
the aziridines is thought to be due to the high stereo-directing
nature of the chiral tert-butyl-sulfinyl group (Fig. 2). The
nucleophilic sulfur ylide can approach the ketimine from either
face, however, the large tert-butyl group effectively blocks one face
of the imine to attack from the nucleophile, directing the addition
of the sulfur ylide.
The origins of the cis/trans selectivity observed in sulfur ylide
addition to carbonyls and imines has been the focus of much work.
In a series of enlightening articles Aggarwal et al. and others
outline the key factors contributing to the selectivity of this
reaction. Our observations are in agreement with the trends
detailed within.12
Overall we have demonstrated the suitability of tert-butyl-
sulfinylketimines as substrates for ylide mediated aziridination.
While the reaction of tert-butyl-sulfinylketimines under Corey–
Chaykovsky conditions was disappointing, with more sensitive,
enolisable substrates not forming the desired aziridine, high
diastereoselectivities for those synthesised were observed. The
reaction with the ylide derived from S-allyl tetrahydrothiophenium
bromide was found to furnish the desired chiral vinyl aziridines for
a much wider range of substrates and in improved yield. Both
excellent diastereoselectivities and good stereocontrol were
observed. Studies of the exploitation of these highly substituted
aziridines as chiral building blocks for synthesis of complex
molecules are ongoing, and our results will be reported in due
course.
10 For other approaches to substituted aziridines from sulfinyl ketimines,
albeit with only a limited number of substrates, see: (a) F. Chemla and
F. Ferreira, Synlett, 2004, 6, 983; (b) F. Chemla and F. Ferreira, J. Org.
Chem., 2004, 69, 8244; (c) J.-C. Cheng, W.-W. Liao, X.-X. Sun,
X.-L. Sun, Y. Tang, L.-X. Dai and J.-G. Deng, Org. Lett., 2005, 7, 5789.
11 X. F. Hu, Tetrahedron, 2004, 60, 2701.
12 (a) V. K. Aggarwal, J. P. H. Charmant, C. Ciampi, J. M. Hornby,
C. J. O’Brien, G. Hynd and R. Parsons, J. Chem. Soc., Perkin Trans. 1,
2001, 3159; (b) V. K. Aggarwal, J. N. Harvey and J. Richardson, J. Am.
Chem. Soc., 2002, 124, 5747; (c) R. Robiette, J. Org. Chem., 2006, 71,
2726.
The authors wish to thank Millennium Pharmaceuticals and
BBSRC/EPSRC BMS for funding and the EPSRC Mass
Spectrometry service, Swansea. We also acknowledge the use of
the EPSRC’s Chemical Database Service at Daresbury.13
13 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput.
Sci., 1996, 36, 746.
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Chem. Commun., 2006, 1833–1835 | 1835