Highly cis-selective synthesis of iodo-aziridines using diiodomethyllithium and in situ generated N-Boc-imines

Article abstract of DOI:10.1039/c2cc37029h

The first preparation of iodoaziridines is described. The addition of diiodomethyllithium to N-Boc-imines affords these novel aziridines in high yields. The reaction proceeds in one-pot via a highly diastereoselective cyclisation of an amino gem-diiodide

Full text of DOI:10.1039/c2cc37029h

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COMMUNICATION
Highly cis-selective synthesis of iodo-aziridines using diiodomethyllithium
and in situ generated N-Boc-iminesw
James A. Bull,* Tom Boultwood and Thomas A. Taylor
Received 27th September 2012, Accepted 2nd November 2012
DOI: 10.1039/c2cc37029h
The first preparation of iodoaziridines is described. The addition
of diiodomethyllithium to N-Boc-imines affords these novel
aziridines in high yields. The reaction proceeds in one-pot via
a highly diastereoselective cyclisation of an amino gem-diiodide
intermediate.
Scheme 1 Proposed route to iodoaziridines.
of bromide.15 Mono- and di-fluoroaziridines have also been
recently reported.16
Aziridines continue to provide both structural fascination,1 and
important synthetic intermediates for wide ranging applications
in chemical synthesis.2 Consequently, diverse synthetic methods
for their preparation have been disclosed.3 In recent years the
functionalisation of intact aziridine rings has become important,
allowing access to a variety of aziridine derivatives from single
precursors. In particular, anionic functionalisation of
aziridines,4 in the absence of a stabilising group, has been
mediated either by functional group exchange,5 or by direct
deprotonation at the most acidic site.6 Recently, Vedejs and
co-workers reported the palladium catalysed cross coupling of
aziridine metal species, formed by Bu3Sn–Li exchange, with
aryl halides.7 We envisaged that more efficient routes to
suitably functionalised aziridines, that would enable regiocon-
trolled and diverse derivatisation of the intact ring, could find
numerous applications in synthesis.
Iodoaziridines, on the other hand, are unknown in the literature
to date. We chose to explore the possibility of forming
iodoaziridines, as a potential reactive substrate for cross
coupling, which should also provide precursors for anionic
or radical functionalisation. Here we report the preparation of
this new functional group, in high yields and excellent cis-
stereoselectivity in one step from simple N-Boc-imine–sulfinic
acid adducts.
We proposed an addition-cyclisation protocol to access
iodoaziridines from imines using diiodomethyllithium, analogous
to the aza-Darzens reaction (Scheme 1).17,18 Recently Charette
and Bull utilised diiodomethane anions at À78 1C to prepare alkyl
diiodides by alkylation,19 and to form styryl halides by alkylation/
elimination,20 but diiodomethyllithium remains an underutilised
reagent.21 Importantly, whereas in the aza-Darzens reaction itself
the diastereochemistry of the aziridine product is determined in
the initial addition, here, due to the symmetrical nature of the
diiodomethyllithium nucleophile the cyclisation step would be
diastereodetermining.
C-Heteroatom substituted aziridines can dramatically influ-
ence the reactivity and stability of the 3-membered ring.8
Chloro-aziridines, in particular dichloroaziridines, often formed
by the reaction of dichlorocarbenes and imines,9,10 are widely
used in the preparation of N-containing heterocycles.8 Bromo-
aziridines are more difficult to access, and have been reported
on only a few occasions. Ziegler first formed bromoaziridines by
a Barton decarboxylation–bromination from aziridine carboxy-
lates, affording a mixture of cis/trans-isomers.11 These were used as
radical precursors in the synthesis of mitomycin-like anti-
tumour agents.12 Yudin has reported bromoaziridines through
an N-transfer approach, generating a nitrene under oxidative
conditions,13 as has Huang using TsNBr2.14 Additionally,
Oshima reported the intermediacy of bromoaziridines in the
preparation of silyl aziridines, proposing an in situ elimination
The stability of potential iodoaziridines was naturally a
significant concern, due to potential loss of iodide amongst
other potential decomposition routes. We elected to examine
N-Boc imines to provide an electron-withdrawing group on N
as well as offering potential for further functionalisation or
ring opening.
Initial investigations concentrated on the addition of diiodo-
methyllithium to phenyl N-Boc imine to afford the amino-
diiodide. Diiodomethyllithium was preformed by deprotonation
of CH2I2 with LiHMDS at À78 1C prior to addition of the
imine.22 Both the imine and imine–HO2STol adduct 1a were
examined, with the latter preferred for practical simplicity,
generating the imine in situ by deprotonation with excess
base.23,24 Careful optimisation of the reaction conditions was
undertaken, including the equivalents of base and CH2I2, the use
of Lewis basic additives, as well as concentration and the solvent
ratio (a mixture of THF and ether was essential).19a The optimal
Department of Chemistry, Imperial College London, South
Kensington, London SW7 2AZ, UK. E-mail: j.bull@imperial.ac.uk;
Tel: +44 (0)207 594 5811
w Electronic supplementary information (ESI) available: Experimental
and characterization data and NMR spectra (1H and 13C) for all novel
compounds. See DOI: 10.1039/c2cc37029h
c
12246 Chem. Commun., 2012, 48, 12246–12248
This journal is The Royal Society of Chemistry 2012

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Table 2 Scope of one-pot synthesis of iodoaziridinesa
Scheme 2 Formation of amino-diiodide 2a.
d.r.b
Entry
Ar
Ph
Yield (%)
1
2
83
88c
96
89
92
67
51
52
42
76
77
13
49
>95 : 5
>95 : 5
>95 : 5
3a
3
4-Tolyl
2-Tolyl
2-Napthyl
4-tBuPh
4-ClPh
2-ClPh
4-BrPh
4-FPh
3-OMePh
4-CF3Ph
3-Pyridyl
3b
3c
3d
3e
3f
3g
3h
3i
4d
5
90 : 10 (>95 : 5)
>95 : 5
>95 : 5
Scheme 3 Cyclisation to iodoaziridine 3a promoted by Cs2CO3.
6
7
>95 : 5
8d
9
87 : 13 (88 : 12)e
>95 : 5
>95 : 5
conditions (3.0 equiv. CH2I2, 2.6 equiv. LiHMDS, THF/Et2O,
À78 1C) provided amino-diiodide 2a in 80% yield (Scheme 2).
We next assessed the conversion of diiodide 2a to aziridine
3a using a variety of bases and Lewis acids to promote the
cyclisation. Under these conditions, multiple pathways could
be conceived: the desired cyclisation may occur to form either
syn or anti-aziridines, cyclisation to the oxazoline, or alternatively
elimination to the vinyl iodide. Pleasingly, the use of Cs2CO3 in
DMF produced an effective cyclisation, providing iodoaziridine
3a (54% yield, Scheme 3).25 Remarkably, aziridine 3a was stable
to isolation and could be purified on silica gel without decom-
position.26 Furthermore, exclusive formation of the cis-aziridine
was observed indicating a highly stereoselective cyclisation step
was occurring.
10
11f
12
13
>95 : 5
>95 : 5
>95 : 5
3j
3k
3l
a
Imine–HO2STol adduct 1 (0.6 mmol), CH2I2, (3 equiv.), LiHMDS
b
(2.6 equiv.), THF/Et2O (3 : 1), À78 1C to 30 1C. d.r. of crude
mixture by 1H NMR. Where >95 : 5 is stated, the minor diastereo-
isomer could not be observed by 1H NMR. d.r. of purified compound
c
indicated in parentheses where relevant. Reaction performed on a
d
3 mmol scale. Warmed to 30 1C for 30 min as required to induce
cyclisation. Also contained diiodide 2 g in crude mixture, which was
f
isolated in 5% yield. Purified on neutral alumina due to decomposi-
e
tion on silica gel.
Having proved iodoaziridine 3a was indeed a viable structure,
the possibility of a one-pot synthesis was investigated. Cyclisation
could be promoted by subsequent warming of the reaction
mixture, after the initial addition of LiCHI2 was complete, under
otherwise similar reaction conditions. Subtle control of the reaction
temperature profile proved to be critical.
rate of warming was shown to be crucial in avoiding elimination.
Therefore the cyclisation was performed in a water bath at
30 1C, to ensure rapid and reproducible warming. This completely
prevented the elimination pathway and iodoaziridine 3a could
be isolated cleanly in excellent yield (Table 1, entry 5, Table 2
entry 1).29 Performing the reaction on a 3 mmol scale afforded
similarly excellent yield and selectivity (Table 2, Entry 2).
The addition of LiCHI2 to the generated imine occurred very
rapidly at À78 1C,27,28 but the intermediate was stable at this
temperature (Table 1, Entry 1). Warming to rt by removing the
flask from the dry ice bath led to inseparable mixtures of
iodoaziridine 3a with the elimination product 4a. Cyclisation
was observed to occur only slowly at À20 1C, with diiodide 2a
the major product after 60 min. At 0 1C the diiodide reacted
completely to afford a 3 : 1 mixture of iodoaziridine 3a and the
elimination product iodide 4a, and rapid warming to rt in a
water bath gave an improved ratio (entries 2–4). Ultimately the
Variation of the aromatic group of the imine with alkyl and
napthyl substituents gave the corresponding iodoaziridines in
high yields, and exclusively as the cis-isomers (Table 2, entries
3–6). The ortho-tolyl substrate displayed more reluctance to cyclise,
requiring a longer time at the elevated temperature (30 min) to
achieve complete cyclisation from the amino-diiodide (entry 4),
presumably due to unfavourable steric interactions.
Next halogenated aromatics were examined, which were well
tolerated by the reaction conditions (entries 7–10). With ortho-
chlorophenyl (Entry 8) cyclisation was more significantly slowed
presumably due to coordination of the lone pairs on the ortho-
substituent with the lithium cation in the intermediate. Notably
in this example the trans-iodoaziridine was observed.30 All other
examples were isolated in >95 : 5 cis-selectivity by 1H NMR.
The 3-methoxyphenyl bearing imine was also tolerant of the
reaction conditions but required the short reaction times to
prevent decomposition (Entry 11). As electron rich N-Boc
aziridines are prone to SN1-type opening, purification required
chromatography on neutral alumina to prevent decomposition.
Electron poor aryl-imines were successful (entries 12–13) but
with lower yields due to increased amounts of elimination and
other side product formation. Alkyl imines were generally not
successful, for example with cyclohexyl imine-adduct (1m), only
the corresponding diiodide (2m) was isolated in 29% yield. The
use of CH2Br2 in the place of CH2I2 under otherwise identical
Table 1 Selected optimisation: one-pot preparation of iodoaziridinesa
Time at
À78 1Cb (min)
Time
at T2 (min)
Product ratio
2a : 3a : 4a
Entry
T2 (1C)
c
1
2
3
4
5
60
30
30
20
10
—
À20
—
60
90
90
10
2a onlyd
6 : 2 : 1
À : 3 : 1
À : 10 : 1
3a onlye
0
rt
30
a
Imine–HO2STol adduct 1 (0.3 mmol), CH2I2, (3 equiv.), LiHMDS
b
(2.6 equiv.), THF/Et2O (3 : 1), À78 1C to 30 1C. Time following
c
d
addition of 1a. Reaction quenched at À78 1C. As Scheme 2; yield
e
80%. 83% yield.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 12246–12248 12247

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Scheme 4 Orientation for cyclisation; A preferred (Ar and I cis).
conditions with 1a led to the formation of the corresponding
bromoaziridine (5) with exclusive cis-stereochemistry in an
unoptimised yield of 30%.
Our proposal for the cis-selectivity in forming the iodoazir-
idines is based on steric factors (Scheme 4).31 The aryl and Boc
groups are likely to adopt an anti-orientation preferentially,
providing two conformations (A and B) with N and I in an
anti-periplanar arrangement appropriate for cyclisation. We
propose that an unfavourable interaction between the non-
displaced iodide with the Boc group is dominant in the
cyclisation transition state where the N-atom becomes sp3
hybridised. Hence the non-displaced iodine prefers to adopt
a position away from the bulk of the Boc group and so gauche
to the Ph group, resulting in the cis-aziridine configuration.
In summary, we report the first examples of iodoaziridines.
The use of diiodomethyllithium with careful temperature control
allows either the isolation of the amino-diiodide or complete
cyclisation to the iodoaziridine with very high cis-selectivity, and
both with excellent yields. We are currently developing methods
for the functionalisation of iodoaziridines to various aziridine
derivatives, which will be reported in due course.
11 F. E. Ziegler and M. Belema, J. Org. Chem., 1994, 59, 7962.
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17 For the formation of terminal aziridines using iodomethyllithium
see: (a) J. M. Concello
C. Simal, J. Org. Chem., 2009, 74, 2452; (b) J. M. Concello
H. Rodrıguez-Solla and C. Simal, Org. Lett., 2008, 10, 4457.
´
n, H. Rodrı
´
guez-Solla, P. L. Bernad and
´
n,
´
18 For a related reaction using LiCHCl2 see: (a) J. A. Deyrup and
R. B. Greenwald, Tetrahedron Lett., 1965, 321; (b) Also see ref. 15.
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22 The use of NaHMDS to form NaCHI2 resulted in decomposition.
23 M. Petrini, Chem. Rev., 2005, 105, 3949.
24 For the preparation of imine sulfinic acids: A. G. Wenzel and
E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 12964.
25 Compound 3a was assigned as the cis-aziridine on the basis of IR
stretch (CQO; 1724 cmÀ1) and characteristic 1H NMR coupling
constants (J = 5.4 for aziridine CH).
For financial support we gratefully acknowledge the
EPSRC (Career Acceleration Fellowship to JAB), the Ramsay
Memorial Trust (Research Fellowship 2009–2011 to JAB),
The Royal Society for a research grant, the Nuffield foundation
and Pfizer for UG bursaries (TT, TB), and Imperial College
London. Thank you to Prof Alan Armstrong for generous
support and advice.
Notes and references
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26 Iodoaziridine 3a was stable to silica gel and in solution. On
concentration the neat compound showed significant sensitivity
to light leading to decomposition. Iodoaziridines were stored as
stock solutions in dichloromethane at À20 1C. Under these
conditions 3a was stable for >4 weeks.
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27 Low temperature is required for the initial addition to ensure the
stability of LiCHI2.
28 See ESIw for further details on 1H NMR sampling studies into the
rate of addition and cyclisation. This supports our mechanistic
hypothesis of addition followed by cyclisation at elevated temperatures,
rather than an alternative mechanism via diiodocarbene. Quenching the
reaction at À78 1C with D2O (forming 2a) did not lead to any
incorporation of deuterium in place of the CHI2 proton, but partial
incorporation at NH. This suggests that the intermediate diiodide is not
deprotonated to the carbenoid under the reaction conditions.
29 A possible explanation for effect of rate of warming on product
distribution is that elimination is caused by excess LiCHI2 which
decomposes rapidly on warming to non-basic species, preventing
the undesired elimination reaction.
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31 Alternative explanations involving electronic factors may be possible.
See ESIw for further discussion.
c
12248 Chem. Commun., 2012, 48, 12246–12248
This journal is The Royal Society of Chemistry 2012