Efficient base catalyzed alkylation reactions with aziridine electrophiles

Article abstract of DOI:10.1039/b802447b

N-Mesitylene sulfonyl and N-tosyl aziridines have been identified as effective electrophiles in alkylation reactions of carbon acids catalyzed by the organic phosphorine base BEMP; yields of up to 99% for a range of pro-nucleophiles under mild reaction co

Full text of DOI:10.1039/b802447b

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Efficient base catalyzed alkylation reactions with aziridine electrophilesw
Thomas A. Moss,a Aurelie Alba,a David Hepworthb and Darren J. Dixon*a
Received (in Cambridge, UK) 12th February 2008, Accepted 3rd March 2008
First published as an Advance Article on the web 27th March 2008
DOI: 10.1039/b802447b
N-Mesitylene sulfonyl and N-tosyl aziridines have been identi-
fied as effective electrophiles in alkylation reactions of carbon
acids catalyzed by the organic phosphorine base BEMP; yields
of up to 99% for a range of pro-nucleophiles under mild reaction
conditions are reported.
Scheme 1 Concept of a catalyzed aziridine alkylation reaction.
Compounds containing the ethylene amino group attached to
a stereogenic quaternary carbon (R1R2R3CCH2CH2N) are
we reasoned that a base-catalyzed aziridine alkylation reaction
widespread amongst natural products such as those belonging
would be possible. Herein we present our findings.
to the indole alkaloid family, of which horsfiline is represen-
Preliminary studies using a range of N-sulfonyl aziridines
tative. The impressive bioactivities of many of these com-
(2a–f) with ethyl phenylcyanoacetate 1a as a representative
pounds encouraged us to investigate a synthetic strategy that
pro-nucleophile were performed to assess the viability of the
was simple in concept but broad in applicability. Our plan,
concept.
outlined in Scheme 1, required a base-catalyzed addition of a
The results of the preliminary studies are presented in
suitably protected form of aziridine 2 to various methine pro-
Table 1. After a base screen, the organic phosphorine base
nucleophiles 1. This alkylation reaction would allow direct
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-
access to the desired product 3 in one step from simple starting
diazaphosphorine (BEMP) was identified as the most effective,
materials.
catalyzing the alkylation of 1a with N-tosyl aziridine 2a to
N-Substituted aziridines are mildly electrophilic reagents
afford 3a in a 93% yield, with a reaction time of 19 h at room
previously employed for the homologation of a range of
temperature (entry 2). The high yield and relatively short
carbon and heteroatom nucleophiles.1 Their ready preparation
reaction time was attributed to the strong basic nature (pKa
from inexpensive commercial materials2 and ease of handling
¼ 27.5) and low nucleophilicity of BEMP. N-Nosyl aziridine
2d was completely insoluble in THF at room temperature and
no reaction was observed whilst N-phosphoryl aziridine 2e was
soluble but unreactive under our conditions. Interestingly,
when N-2-(trifluoromethane)benzenesulfonyl aziridine 2f was
used as the electrophile under base-catalyzed conditions, only
makes them attractive in synthetic strategies.3
Owing to their moderate reactivity and their ability to
readily polymerize, most efforts with carbon-centred nucleo-
philes have concentrated on the use of stoichiometric quan-
tities of reactive metal enolates or organometallic reagents,
and little attention has been devoted to facilitating the reaction
under mild and catalytic conditions.4–6 Furthermore, to the
best of our knowledge there have been no reports of aziridine
ring opening,7 enantioselective8 or otherwise, with carbon
acids under base-catalyzed conditions.
To be catalytic in base and synthetically useful, the balance
of pKa values and the reactivity of the aziridine electrophile is
critical; following alkylation of carbanion 4 with aziridine 2,
the adduct 5 must be sufficiently basic to deprotonate another
molecule of pro-nucleophile 1 and thus complete the catalytic
cycle (Scheme 2). As the same adduct is also nucleophilic at
nitrogen, the equilibrium must be weighted towards 4 to
suppress polymerization of the aziridine. By careful choice of
pro-nucleophile, aziridine protecting group and base catalyst,
a School of Chemistry, The University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: Darren.Dixon@man.ac.uk;
Fax: þ44 (0)161 2754939; Tel: þ44 (0)161 2751426
b Pfizer Global Research & Development, Ramsgate Road, Sandwich
Kent, UK CT13 9NJ
w Electronic supplementary information (ESI) available: Experimental
procedures, and spectral data for compounds 2b, 2f, 3a–p, 6, 7 and
8a–b. See DOI: 10.1039/b802447b
Scheme 2 Initiation, propagation and polymerization pathways in
the base-catalyzed alkylation of carbon acids with aziridine electro-
philes.
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Table 1 Preliminary studies into the base-catalyzed alkylation of
ethyl phenylcyanoacetate 1a with aziridine electrophiles
Scheme 4 Spirocyclization of 3d.
Entry
P
Base
Time/h Product Yield (%)
1
2
3
4
5
6
7
a
Tosyl (2a)
Tosyl (2a)
SO2Mes (2b)
Cbz (2c)
p-Nosyl (2d)
PO(OEt)2 (2e)
o-CF3C6H4SO2 (2f) BEMP
DABCO
BEMP
BEMP
BEMP
DABCO
BEMP
72
19
24
672
1
3a
3a
3b
3c
—
—
—
69
93
99
83
0ab
0b
168
1
0c
Scheme 5 One pot activation–cleavage of the N-SO2Mes group.
b
Aziridine was insoluble in THF at 25 1C. No reaction occurred.
Polymeric products were obtained.
c
1 will effectively stall, and the dominant reaction pathway will
be polymerization of the aziridine. Successful alkylation was
observed with carbamate-protected aziridines (entry 4), how-
ever the reaction was prohibitively slow. That no significant
polymerization of the aziridine was observed in this reaction
despite the long reaction time suggests proton transfer in the
catalytic cycle was fast, the sluggish reaction being a result of
weaker inductive activation of the aziridine when compared to
its sulfonyl analogues. A further enhancement in reaction
efficiency was noted when N-mesitylsulfonyl aziridine 2b was
employed (entry 3). Overall, the optimal conditions employed
2 equivalents of pro-nucleophile 1a to 1 equivalent of 2b with
10 mol% BEMP in THF at 25 1C.
polymerization products were rapidly formed (entry 7). This
can be rationalized from the various reaction pathways pre-
sented in Scheme 2. If the adduct 5 resulting from ring opening
of the aziridine is relatively stable, as one could envisage by
virtue of the ortho placement of an electron-withdrawing
trifluoromethyl group, proton transfer from the parent acid
With the optimal conditions established, the scope of the
alkylation reaction was surveyed by probing changes to the
pro-nucleophile (Scheme 3). A range of carbonyl compounds,
including esters, lactams, acetates, and nitriles, in addition to
cyanoacetates, amides and oxindoles, were screened. Yields
ranged from 73–99% with the exception of entry 3k where
appreciable oxygen alkylation was also observed; the total
yield for alkylation (C and O) was 67%. At 25 1C in THF
reaction times typically ranged from 24–48 h. 2-Acetyl cyclo-
pentanone was less reactive than its ester analogues, presum-
ably reflecting the enhanced stability of the enolate.
With the scope of the reaction established, the synthetic
utility of the alkylation adducts was investigated in the pre-
paration of azaspirocycles. Adduct 3d was synthesized on a
gram scale with no reduction in chemical yield. Reduction of
the b-keto ester adduct 3d furnished the di-alcohol 6 as 2
diastereoisomers (5 : 2 ratio) in an 88% overall yield. This
could be further elaborated into the N-protected spiro adduct
7 (dr ¼ 2 : 1) by a one-pot tosylation–cyclization reaction
(Scheme 4).
Finally, for this method to be synthetically useful, the robust
sulfonyl protecting group has to be removed under non-
destructive conditions. Of the methods reported in the litera-
ture9 we found that the trifluoroacetamide exchange protocol
of Moussa and Romo to be the most effective. Thus, subjec-
tion of the selected adducts 3b and 3d to a one-pot activa-
tion–cleavage reaction using TFAA and SmI2,10 resulted in
smooth exchange of the sulfonamide protecting group to the
readily manipulated trifluoroacetamide11 in good yield
(Scheme 5).
Scheme 3 BEMP catalyzed alkylation reactions with N-sulfonyl
aziridines 2a and 2b. aReaction performed at 65 1C. b23% O-Alkylated
product was also isolated.
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In conclusion, we have presented the first base-catalyzed
ring opening alkylation of a range of pro-nucleophiles with
N-sulfonyl aziridines under mild reaction conditions. Removal
of the N-sulfonyl group under non-destructive conditions has
also been demonstrated. Work to further expand the nucleo-
phile and electrophile range, and to develop an enantioselec-
tive variant of this methodology is currently underway and
will be reported in due course.
(d) S. S. Murphree and A. Padwa, Prog. Heterocycl. Chem., 2001,
13, 52.
3 For reviews, see: (a) Aziridines and Epoxides in Organic Synthesis,
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Baumann, B. Buckholz and H. Stamm, Synthesis, 1995, 44.
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(b) J. S. Yadav, B. V. S. Reddy, S. Abraham and G. Sabitha,
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recently described: (a) E. V. Blyumin, H. J. Gallon and A. K.
Yudin, Org. Lett., 2007, 9, 4677.
7 Cyclic sulfamidates have been widely used as alternates to azir-
idines as C-2 nitrogen containing electrophiles. For a review, see:
(a) R. E. Melendez and W. D. Lubell, Tetrahedron, 2003, 59, 2581.
´
For recent methodologies and application in synthesis, see: (b) J.
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This journal is The Royal Society of Chemistry 2008
2476 | Chem. Commun., 2008, 2474–2476