The asymmetric synthesis of terminal aziridines by methylene transfer from sulfonium ylides to imines

Article abstract of DOI:10.1039/c3ob27271k

A new ylide-based protocol for the asymmetric aziridination of imines via methylene transfer has been developed involving the use of a simple chiral sulfonium salt and an organic strong base. A systematic study identified triisopropylphenyl sulfonylimines as optimal substrates for the process. Unexpectedly, hindered C₂-symmetric sulfonyl salts incorporating bulky ethers at C-2 and C-5-which had previously been useful in the corresponding epoxidation chemistry-decomposed in these aziridination reactions via competing elimination pathways. Under optimised conditions it was found that a simple salt derived from (2R,5R)-2,5-diisopropyl thiolane could mediate asymmetric methylene transfer to a range of imines with uniformly excellent yields with 19-30% ee. Since this is a similar level of enantiomeric excess to that obtained using these same salts in epoxidation chemistry, it was concluded that if more bulky sulfonium salts could be devised which were resistant to decomposition under the reaction conditions, that highly enantioselective aziridine formation by methylene transfer would be possible. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob27271k

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The asymmetric synthesis of terminal aziridines by
methylene transfer from sulfonium ylides to imines†
Cite this: DOI: 10.1039/c3ob27271k
Sarah A. Kavanagh, Alessandro Piccinini and Stephen J. Connon*
A new ylide-based protocol for the asymmetric aziridination of imines via methylene transfer has been
developed involving the use of a simple chiral sulfonium salt and an organic strong base. A systematic
study identified triisopropylphenyl sulfonylimines as optimal substrates for the process. Unexpectedly,
hindered C2-symmetric sulfonyl salts incorporating bulky ethers at C-2 and C-5 – which had previously
been useful in the corresponding epoxidation chemistry – decomposed in these aziridination reactions
via competing elimination pathways. Under optimised conditions it was found that a simple salt derived
from (2R,5R)-2,5-diisopropyl thiolane could mediate asymmetric methylene transfer to a range of imines
with uniformly excellent yields with 19–30% ee. Since this is a similar level of enantiomeric excess to that
obtained using these same salts in epoxidation chemistry, it was concluded that if more bulky sulfonium
salts could be devised which were resistant to decomposition under the reaction conditions, that highly
enantioselective aziridine formation by methylene transfer would be possible.
Received 22nd November 2012,
Accepted 3rd April 2013
DOI: 10.1039/c3ob27271k
www.rsc.org/obc
methylene transfer to imines is an inefficient and relatively
unselective process.
Introduction
Aziridines are 3-membered nitrogen heterocycles of substan-
To date a single report has emerged on this subject:
tial synthetic importance found in a number of pharmaceuti- Aggarwal et al.12c demonstrated that the benzaldehyde-derived
cally relevant molecules,1,2 and natural products.3 Their imines 1a–b could be converted to the corresponding terminal
considerable utility largely derives from ring-strain,4 which aziridines 3a–b in good yields (ca. 70%) and 19–20% ee under
facilitates their participation in highly selective ring-opening Simmons–Smith type conditions involving the use of 2.0
reactions with nucleophiles.5 It is unsurprising therefore, that equivalents of both the chiral sulfide 2 and ICH2Cl in the pres-
the catalytic asymmetric synthesis of chiral aziridines from ence of stoichiometric amount of diethyl zinc (Scheme 1A).
acyclic starting materials has been the subject of intensive
We recently became interested in the corresponding reac-
research endeavour.6 Several methodologies have been develo- tions to form terminal epoxides13 from aldehydes (a process
ped; these can be organised into three general transformation which was also characterised by poor–moderate levels of enan-
classes: (a) addition (formal or otherwise) of either a nitrene or tioselectivity and product yield12c,14) and reported the design
nitrene-equivalent to alkenes,6 (b) the reaction between carbe- of novel, highly hindered sulfonium salts such as 5, which
noids and imines6,7 and (c) the sulfonium ylide-mediated aziri-
dination of imines.6,8
The latter class of reaction is an aza-analogue of the highly
successful asymmetric Johnson–Corey–Chaykovsky process8a,
b,9,10
and has proven particularly useful for the synthesis of di-
and trisubstituted aziridines with excellent levels of enantio-
control and moderate–good diastereoselectivity.11 However, as
has been the case (until recently) with the epoxidation variant
of the process,12 the sulfonium-ylide based methodologies are
bedevilled by an Achilles heel which limits the substrate scope:
the catalytic asymmetric synthesis of terminal aziridines from
Trinity Biomedical Sciences Institute, School of Chemistry, The University of Dublin,
Scheme 1 (A) The literature protocol for sulfonium ylide-mediated asymmetric
aziridination to yield terminal aziridines. (B) Asymmetric epoxidation of benz-
aldehyde to styrene oxide mediated by sulfonium salt 5.
Trinity College, Dublin 2, Ireland. E-mail: connons@tcd.ie; Fax: +353 16712826
†Electronic supplementary information (ESI) available: All procedures and
characterisation data. See DOI: 10.1039/c3ob27271k
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proved capable of mediating these reactions in >90% yield and
Table 1 Asymmetric aziridination involving the chiral salt 8
ee for the first time (Scheme 1B).15
Results and discussion
Naturally therefore, our first approach to tackling the problem
of asymmetric aziridination reactions centred on the use of
sulfonium ions such as 5. To determine if these general reac-
tion conditions involving the use of a strong organic base such
as P2 would be compatible with aziridine formation, we
reacted the N-tosyl-imine 1a with stoichiometric quantities of
the achiral sulfonium salt 7 in the presence of proton sponge
as an auxiliary base to scavenge any traces of triflic acid associ-
ated with the decomposition of 7. We were pleased to observe
clean aziridination of 1 to (rac)-3a in just 30 min. The more
hindered TPS protecting group (i.e. imine 1c) can also be used
to generate the corresponding aziridine efficiently, albeit in
lower product yield (Scheme 2).
Concentration
(M)
Temperature
(°C)
Time
(h)
Yielda
(%)
eeb
(%)
Entry
1
2
3
0.4
0.08
0.01
rt
−78
rt
1.25
17
1.25
70
69c
25
15
19
n.d.d
a Determined by 1H NMR spectroscopy using styrene as an internal
standard. b Determined by CSP-HPLC. c Refers to conversion. d Not
determined due to the formation of multiple products.
Since this base-mediated aziridination protocol is rapid
and furnishes the product in high yield, attention then turned
to the question of enantioselectivity. In preliminary exper-
iments, the aziridination of 1c by the hindered, readily pre-
pared chiral sulfonium salt (R,R)-8 (known to be capable of
enantioselective terminal epoxidation15) was carried out under
a range of conditions. A selection this data is presented in
Table 1.
Under conditions identical to those outlined in Scheme 2,
3c was formed in similar yield but only 25% ee after 75 min
reaction time (entry 1). Somewhat surprisingly, reduction of
either the temperature (entry 2) or the reaction concentration
(entry 3) led to lower enantioselectivity. In addition, while the
reaction at ambient temperature proceeded relatively cleanly,
multiple products were observed at lower temperatures and
higher dilutions. Careful 1H NMR spectroscopic analysis of the
crude material from these reactions indicated that the majority
of (R,R)-8 had decomposed: subsequent chromatography
allowed the identification and isolation of three products
derived from (R,R)-8 (i.e. alkenes 9–10 and allene 11, Fig. 1).
All three products are characterised by the elimination of
methanol and the destruction of at least one (two in the case
of 10) chiral centre. Since all three products are sulfides (as
opposed to sulfonium salts) it would appear reasonable to
suggest that the low observed product ee is due (at least in
part) to decomposition of (R,R)-8 to methylated sulfonium salt
analogues of 9–11 via elimination reactions, with subsequent
base-mediated methylene transfer to the imine, yielding 9–11.
Fig. 1 The isolated decomposition products derived from (R,R)-8.
Since methylene transfer from salts derived from 9–11 would
expected to be inefficient from a stereochemical perspective
(due to the loss of chiral information during decomposition),
low product ee results. It is interesting to note that these
decomposition pathways were not a feature of the analogous
epoxidation chemistry at any temperature or concentration
evaluated.15,16
On the assumption that decomposition could be favourable
due to the highly conjugated nature of the alkene products
9–11, we sought to develop an analogue of (R,R)-8 devoid
of pendant aromatic substituents. Sulfonium salt (R,R)-12
was duly prepared and evaluated in the aziridination of 1c,
resulting in the formation of 3c in low ee (Scheme 3). Again,
Scheme 2 Initial aziridination experiments using the achiral salt 7.
Scheme 3 Asymmetric aziridination involving the chiral salt 12.
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(i.e. imine 1e) resulted in moderate product yield but low enantio-
selectivity (entry 5).
Table 2 Asymmetric aziridination involving the chiral salt (R,R-13)
These experiments indicated that only the TPS- and DPP-
substituted imines (i.e. 1c and 1e) possessed the requisite
activity and steric characteristics to be considered as suitable
candidates for subsequent optimisation studies. The sensi-
tivity of the aziridination of DPP to both temperate and con-
centration were next probed: we found that the unusual
attenuation of enantioselectivity observed earlier (Table 1) at
low temperatures of −78 °C was again a feature (although
without catalyst decomposition on this occasion, entry 6),
while (surprisingly) increasing the reaction temperature led to
a marginal increase in product ee (entry 7). It is perhaps note-
worthy that in the analogous epoxidation chemistry, improved
enantioselectivity at lower temperatures was always observed.
Aziridination of 1e under dilute conditions at low temperature
afforded near-racemic product (entry 8).
More pleasingly, the hindered TPS-substituted imine 1c
underwent more selective aziridination both when the temp-
erature was decreased (entry 9) and when the concentration
was reduced (entry 10). Under these conditions we detected
low levels of styrene oxide product – presumably formed from
hydrolysis of the imine by adventitious water and subsequent
epoxidation mediated by 13 – and therefore we repeated the
experiment in the presence of molecular sieves, which resulted
in improved product yield (94%) and enantiomeric excess
(23% ee, entry 11). Further dilution reduced reaction rates and
failed to improve the enantioselectivity (entry 12). Thus it is
clear from an analysis of the results of these experiments that
the TPS protecting group is superior to others evaluated,
however the improvement in levels of product enantiomeric
Conc.
(M)
Temp.
(°C)
Time
(h)
Yielda
(%)
eeb
(%)
Entry
Imine
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1e
1e
1e
1c
1c
1c
1c
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.08
0.4
0.08
0.08
0.02
rt
rt
rt
rt
rt
−78
60
−78
−78
−78
−78
−78
0.5
0.5
0.5
1.5
1.5
16
0.5
16.5
17
87
8
6
n.d.
14
13
9
2
10
1
18
22
23
23
85
31
70c
87c
98c
96c
90
72
94
85
9
10
11d
12d
16
16
17
a Determined by 1H NMR spectroscopy using styrene as an internal
standard. b Determined by CSP-HPLC. c Refers to conversion. d In the
presence of 3 Å mol. sieves.
1H NMR spectroscopic analysis of the crude material indicated excess resulting from the use of this group is marginal.
significant catalyst decomposition.
With the optimum conditions in hand, we sought to estab-
Thus it is likely that the presence of the alkoxy group is the lish the substrate scope (Table 3). Overall, the scope was found
root-cause of the inherent instability of materials such as 8 to be quite broad – TPS-substituted imines of various steric
and 12 in these aziridination processes. Accordingly, we pre- and electronic characteristics (aromatic, aliphatic and α,β-un-
pared the bis-isopropyl substituted sulfonium salt (R,R)-13 and saturated) could be converted to the corresponding aziridines
reacted it with imines 1a–e under the base-mediated aziridin- efficiently in 87–92% isolated yield.
ation conditions (Table 2).
As expected, imine 1c could be converted to 3c in excellent
The N-tosyl imine proved to be a poor substrate under these yield and 23% ee (entry 1). It is noteworthy that while this level
conditions (ambient temperature, 0.4 M concentration) from of asymmetric induction is modest, the protocol represents a
an asymmetric induction standpoint – the aziridine 3a was small improvement in terms of stereoselectivity and a signifi-
formed in good yield and only 6% ee (entry 1). Significantly, cant advance from an efficacy standpoint over the previous lit-
no evidence of decomposition of the salt (R,R)-13 was erature benchmark (i.e. considerably higher yields using half
observed by 1H NMR spectroscopy, only the clean regeneration the amount of ylide precursor). The more activated imine 14
of the corresponding demethylated sulfide analogue (which underwent slightly less selective aziridination (entry 2). The
could be recovered by column chromatography) was observed. deactivated imine 15 proved a relatively useful substrate (entry
The PMP-protected imine 1b was found to be relatively unreac- 3), while more hindered analogues 16, 17 and 18 formed
tive under these conditions (entry 2). The aziridination of the 23–25 with comparable enantioselectivity (entries 4–6). We
more hindered sulfonylimine 1c proceeded more selectively: were pleased to observe that both electrophilic α,β-unsatu-
the aziridine 3c was formed in a modest yet considerably rated- and base-sensitive aliphatic imines were compatible
improved 14% ee (entry 3). The N-phenyl imine 1d underwent with the methodology – no competing cyclopropanation or
reaction with similar levels of product ee, however, as was the self-condensation through enamide ions (respectively) were
case with the PMP-protected analogue 1b – insufficient acti- observed (entries 7–8).
vation of the imine by the protecting group proved problematic
In summary, we have developed a new protocol for the
(entry 4). The use of the diphenylphosphoryl substituent asymmetric aziridination of imines which is marginally more
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Table 3 Evaluation of substrate scope
Fig. 2 Unsuccessful candidate structures.
Entry
1
Substrate
Product
Yielda (%)
91
eeb (%)
chemistry under optimised conditions (e.g. 13 mediated the
formation of styrene oxide from benzaldehyde in 80% yield
and 18% ee13c). This leads to the conclusion that the there is
nothing inherently problematic with the aziridine substrates
in these reactions from a asymmetric induction standpoint,
and that if the steric bulk of (R,R)-13 could be augmented con-
siderably17 without the structure decomposing during aziridi-
nation, then, as was the case with the epoxidation chemistry
(vide supra), that excellent enantioselectivity should be pos-
sible. As yet we have not been able to devise such a structure.
Avenues we have explored thus far (Fig. 2) include candidate
materials such as 28–30, which fail due to base-sensitivity (28
and 29) and unselective alkylation (30). Efforts to circumvent
these difficulties are underway.
23
2
3
88
92
18
25
4
87
30
5
6
87
92
25
23
Experimental
General
Proton nuclear magnetic resonance spectra were recorded on a
Bruker Avance 400 or 600 MHz spectrometer in CDCl3 refer-
enced relative to residual CHCl3 (δ = 7.26 ppm) or DMSO-d6
referenced relative to residual DMSO-d6 (δ = 2.50 ppm). Chemi-
cal shifts are reported in ppm and coupling constants in
Hertz. Carbon NMR spectra were recorded on the same instru-
ments (100 or 150 MHz) with total proton decoupling. All
melting points are uncorrected. Infrared spectra were obtained
on a Perkin Elmer Spectrum One spectrophotometer. Flash
chromatography was carried out using silica gel, particle size
0.04–0.063 mm. TLC analysis was performed on precoated
60F254 slides, and visualised by UV irradiation, KMnO4, phos-
phomolybdic acid, or anisaldehyde staining. Specific rotation
measurements were made on a Rudolph research analytical
Autopol IV instrument, and are quoted in units of 10−1 deg
cm2 g−1. Anhydrous THF was distilled over sodium–benzophen-
7
8
92
91
18
20
a Isolated yield. b Determined by CSP-HPLC.
selective and considerably more efficient than the literature
benchmark. Highly hindered sulfonium catalysts bearing an one ketyl radical before use. Methylene chloride, toluene and
alkoxy group which proved very successful in the correspond-
ing epoxide chemistry were not useful here due to competing
triethylamine were distilled from calcium hydride. All reac-
tions were carried out under a protective argon atmosphere.
elimination reactions which generate less discriminating sulfo- Analytical CSP-HPLC was performed on Daicel CHIRALCEL
nium salts in situ. The easily prepared and stable salt (R,R)-13
was found to be capable of mediating the highly efficient ylide-
OJ-H (4.6 mm × 25 cm) and CHIRALPAK AD-H (4.6 mm ×
25 cm). Solid reagents for all catalysed reactions were weighed
based synthesis of terminal aziridines (the substrate scope of using a Precisa balance, series 320XR, model XR125SM-FR
this class of process was probed for the first time) with either
comparable or higher levels of product ee to the only previous
example in the literature.
(readability 0.01 mg/0.1 mg). For all known compounds the
spectral characteristics were in agreement with those reported
in the literature. (2R,5R)-2,5-Diisopropyl-thiolane was prepared
according to a literature procedure.13c Imines N-benzylidene-4-
methoxybenzenamine (1b),18 N-(benzylidene)-4-methylbenzene-
It is noteworthy that the degree of enantioinduction
observed in this process is marginally higher than that
obtained from the use of 13 in the corresponding epoxidation sulfonamide (1a),19 P,P-diphenyl-N-(phenylmethylene)phosphinic
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amide (1e)20 and N-phenyl benzaldehyde imine (1d)21 were
prepared according to literature procedures. The spectroscopic
data of the aforementioned compounds were consistent with
those previously reported.
2 Representative Tamiflu syntheses: (a) S. Abrecht,
M. C. Federspiel, H. Estermann, R. Fischer, M. Karpf,
H.-J. Mair, T. Oberhauser, G. Rimmler, R. Trussardi and
U. Zutter, Chimia, 2007, 61, 93; (b) Y. Fukuta, T. Mita,
N. Fukuda, M. Kanai and M. Shibasaki, J. Am. Chem. Soc.,
2006, 128, 6312; (c) T. Mita, N. Fukuda, F. X. Roca,
M. Kanai and M. Shibasaki, Org. Lett., 2007, 9, 259;
(d) N. Satoh, T. Akiba, S. Yokoshima and T. Fukuyama,
Angew. Chem., Int. Ed., 2007, 46, 5734; (e) B. M. Trost and
T. Zhang, Angew. Chem., Int. Ed., 2008, 47, 1.
3 P. A. S. Lowden, in Aziridines and Epoxides in Organic Syn-
thesis, ed. A. K. Yudin, Wiley-VCH, Weinheim, 2006, ch. 11.
4 W. H. Pearson, B. W. Lian and S. C. Bergmeier, in Compre-
hensive Heterocyclic Chemistry II, ed. A. R. Katritzky,
C. W. Rees and E. F. V. Scriven, Elsevier, Oxford, 1996,
vol. 1A.
5 (a) R. S. Atkinson, Tetrahedron, 1999, 55, 1519;
(b) B. Zwanenburg, Pure Appl. Chem., 1999, 71, 423;
(c) D. Tanner, Angew. Chem., Int. Ed., 1994, 33, 599;
(d) X. E. Hu, Tetrahedron, 2004, 60, 2701; (e) A. Padwa, in
Comprehensive Heterocyclic Chemistry III, ed. A. R. Katritzky,
C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier,
Oxford, 2008, ch. 1.
General procedure A: synthesis of imines (1c and 14–20)
An oven dried round bottomed flask was charged with 2,4,6-
triisopropylbenzenesulfonamide (1 equiv.), fitted with
a
septum and placed under an atmosphere of argon (balloon).
CH2Cl2 was then added via syringe followed by triethylamine
(3 equiv.) and the appropriate aldehyde (1 equiv.). The result-
ing solution was cooled to
0 °C. Titanium(IV) chloride
(0.5 equiv.) in CH2Cl2 was then added dropwise to the cooled
solution and the resulting solution was allowed to stir for 1 h
at this temperature. The reaction mixture was filtered through
Celite and washed with CH2Cl2. The filtrate was concentrated
in vacuo and the resulting solid was suspended in toluene and
then filtered. The filtrate was then concentrated under reduced
pressure to afford the desired imine which was purified as
required.
Representative example: synthesis of (R)-2-phenyl-1-
(2,4,6-triisopropylbenzenesulfonyl)aziridine (3c)
6 For a comprehensive recent review see: H. Pellissier, Tetra-
hedron, 2010, 66, 1509.
An oven dried round bottomed flask containing a magnetic
stirring bar and (2R,5R)-13 (21.36 mg, 0.063 mmol) was
charged with proton sponge (13.60 mg, 0.063 mmol), 1c
(23.58 mg, 0.063 mmol) and activated 3 Å molecular sieves.
The flask was placed under vacuum for 1 h and then immedi-
ately flushed with argon, fitted with a rubber septum and
placed under an atmosphere of argon (balloon). Freshly dis-
tilled CH2Cl2 (0.79 cm3 – stored over activated 3 Å molecular
sieves) and styrene (7.3 μL, 0.063 mmol), was then added
sequentially via syringe. The resulting solution was cooled to
−78 °C. P2 base (2.0 M in THF, 31.7 μL, 0.063 mmol) was then
added dropwise. After 16 h, the crude material was purified by
column chromatography (8 : 2 hexane–CH2Cl2) to furnish the
desired aziridine 3c as a white solid (22.20 mg, 91%, 23% ee).
M.p. 82–84 °C. [α]2D0 = −7.9 (c 0.16, CH2Cl2, 23% ee).
CSP-HPLC: Chiralpak AD-H (4.6 mm × 25 cm), hexane–IPA:
9.5/0.5, 0.5 mL min−1, RT, UV detection at 220 nm, retention
times: 10.0 min (minor enantiomer) and 12.2 (major enantio-
mer). δH (400 MHz, CDCl3): 1.23–1.28 (m, 18H), 2.37 (d, J 4.4,
1H), 2.90 (septet, J 6.9, 1H), 3.04 (d, J 7.2, 1H), 3.80 (dd, J 4.4,
7.2, 1H), 4.40 (septet, J 6.8, 2H), 7.17 (s, 2H), 7.18–7.21 (m,
2H), 7.26–7.32 (m, 3H). δC (100 MHz, CDCl3): 23.7, 24.9, 25.1,
29.9, 34.4, 36.3, 40.7, 124.0, 126.6, 128.3, 128.6, 131.4 (q),
135.8 (q), 151.4 (q), 153.7 (q). ν (cm−1): 694, 758, 1151, 1313,
1462, 1562, 1602, 2869, 2929, 2957. HRMS (EI): [M]+ Calcd for
C23H31NO2S 385.2076; found 385.2061.
7 Selected recent organocatalytic examples: (a) T. Hashimoto,
N. Uchiyama and K. Maruoka, J. Am. Chem. Soc., 2008, 130,
14380; (b) Y. Zhang, Z. Lu and W. D. Wulff, Synlett, 2009,
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8 Recent reviews: (a) V. K. Aggarwal, E. M. McGarrigle and
M. A. Shaw, in Science of Synthesis, ed. G. A. Molander,
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V. K. Aggarwal, Chem. Rev., 2007, 107, 5841; (c) J. R. Fulton,
V. K. Aggarwal and J. de Vicente, Eur. J. Org. Chem., 2005,
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9 (a) A. W. Johnson and R. B. LaCount, J. Am. Chem. Soc.,
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Chem. Soc., 1962, 84, 867; (c) V. Franzen and H.-E. Driesen,
Chem. Ber., 1963, 96, 1881; (d) E. J. Corey and
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Commun., 2003, 2644; (c) V. K. Aggarwal and C. L. Winn,
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11 Representative references: (a) T. Saito, M. Sakairi and
D. Akiba, Tetrahedron Lett., 2001, 42, 5451; (b) V. K. Aggarwal,
R. A. Stenson, R. V. H. Jones, R. Fieldhouse and J. Blacker,
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1 V. H. Dahanukar and I. Zavialov, Curr. Opin. Drug Discovery
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12 (a) B. R. Bellenie and J. M. Goodman, Chem. Commun.,
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16 For mechanistic rationales for the formation of 9–11 see
the ESI.†
2004, 1076; (b) V. K. Aggarwal, A. Ali and M. P. Coogan, 17 The bis-tert butyl analogue of 13 is known (ref. 13c), but is
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