Synthesis and reactivity of non-activated 2-(chloromethyl)aziridines

Article abstract of DOI:10.1016/j.tetlet.2011.06.062

An efficient synthesis of non-activated 2-(chloromethyl)aziridines and 2-chloromethyl-2-methylaziridines as new representatives of the class of 2-(halomethyl)aziridines was developed. Furthermore, the reactivity of these azaheterocycles was assessed and compared to that of their brominated counterparts, pointing to a similar profile for 2-(chloromethyl)aziridines and 2-(bromomethyl)aziridines on the one hand, and a different behaviour of 2-chloromethyl-2-methylaziridines versus 2-bromomethyl-2-methylaziridines concerning their aptitude towards ring expansion to azetidines on the other hand.

Full text of DOI:10.1016/j.tetlet.2011.06.062

Tetrahedron Letters 52 (2011) 4529–4532
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Tetrahedron Letters
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Synthesis and reactivity of non-activated 2-(chloromethyl)aziridines
⇑
⇑
´
Sonja Stankovic, Matthias D’hooghe , Jo Dewulf, Piet Bogaert, Robrecht Jolie, Norbert De Kimpe
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of non-activated 2-(chloromethyl)aziridines and 2-chloromethyl-2-methylaziri-
dines as new representatives of the class of 2-(halomethyl)aziridines was developed. Furthermore, the
reactivity of these azaheterocycles was assessed and compared to that of their brominated counterparts,
pointing to a similar profile for 2-(chloromethyl)aziridines and 2-(bromomethyl)aziridines on the one
hand, and a different behaviour of 2-chloromethyl-2-methylaziridines versus 2-bromomethyl-2-methy-
laziridines concerning their aptitude towards ring expansion to azetidines on the other hand.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 April 2011
Revised 9 June 2011
Accepted 15 June 2011
Available online 23 June 2011
Keywords:
Aziridines
Azetidines
Ring expansion
Imines
Selectivity
Aziridines represent a valuable class of strained compounds in
azaheterocyclic chemistry with diverse synthetic and biological
applications.1 The interest in aziridines as synthons in organic
chemistry is due to the general influence of ring strain on chemical
reactivity, making them important building blocks for the prepara-
tion of a large variety of ring-opened and ring-expanded amines.2
It is known that the nucleofugality of the ring nitrogen and thus
the reactivity of aziridines is dependent on the nature of the sub-
stituent at the nitrogen atom. For example, aziridines bearing an
electron-withdrawing substituent at nitrogen (activated aziri-
dines) are known to be reactive towards a large number of nucle-
ophiles with respect to ring opening.3 On the other hand, electron-
donating groups at nitrogen render the aziridine more stable, and
activation towards an aziridinium intermediate is, in most cases,
required prior to nucleophilic ring opening.4
The synthesis of 2-(bromomethyl)aziridines 4 is well estab-
lished and comprises cyclization of b,
-dibromoamines 3 (R2 = H),
c
obtained through NaBH4-mediated reduction of N-alkylidene-
2,3-dibromopropylamines 1 (R2 = H), in methanol under reflux
(Scheme 1).8,11b Surprisingly, structurally similar b,
c-dibromoam-
ines 3 bearing an additional methyl group (R2 = Me), prepared via
NaBH4-reduction of both N-alkylidene-(2,3-dibromo-2-methylpro-
pyl)amines
1
(R2 = Me) or N-(2,3-dibromo-2-methylpropylid-
ene)amines 2 (R2 = Me), have recently been shown to be easily
convertible into 3-methoxy-3-methylazetidines 6 through rear-
rangement of 2-bromomethyl-2-methylaziridines 5 applying the
same reaction conditions (NaBH4, MeOH,
D), pointing to a pro-
found influence of the additional methyl group in amines 3 on
the reaction outcome.12 Next to aziridines, azetidines are also of
interest due to their diverse applications from both a synthetic
and a biological point of view.13
Within the class of 2-substituted, non-activated aziridines, the
use of 2-(bromomethyl)aziridines as substrates for ring-opening
reactions and nucleophilic substitutions has found great applica-
tion in synthetic chemistry. In particular, 2-(bromomethyl)aziri-
A detailed analysis of the latter transformation revealed the syn-
thesis of azetidines 6 to proceed via the initial formation of
2-bromomethyl-2-methylaziridines 5, obtained as the sole reaction
products in the kinetically-controlled cyclization of amines 3
(R2 = Me) using NaBH4 in methanol at room temperature. Under
thermodynamic conditions, 2-bromomethyl-2-methylaziridines 5
have been shown to completely rearrange into 3-methoxy-
3-methylazetidines 6 upon treatment with sodium borohydride in
methanol under reflux for 48 h.12 In contrast to this clean aziridine
(5) to azetidine (6) rearrangement, no reports on the transformation
of 2-(bromomethyl)aziridines 4 (without an additional methyl
group at the aziridine ring) into the corresponding azetidines are
available in the literature. From these observations, it was clear that
2-bromomethyl-2-methylaziridines 5 exhibit a totally different
reactivity as compared to 2-(bromomethyl)aziridines 4.12
dines
4 have been shown to be suitable synthons for the
preparation of, for example, cyclopropanes,5 morpholines,6 pyrro-
lizidines,7 pyrrolidines,7 2-imino-1,3-thiazoli(di)nes8 and piperi-
dine derivatives.9 In addition, the nucleophilic substitution of
bromide in 2-(bromomethyl)aziridines with various heteroatom
nucleophiles6,8,10 and carbon nucleophiles5,11 has provided a con-
venient access towards a variety of 2-substituted aziridines.
⇑
Corresponding authors.
E-mail addresses: matthias.dhooghe@UGent.be (M. D’hooghe), norbert.dekim-
pe@UGent.be (N. De Kimpe).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.062

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S. Stankovic et al. / Tetrahedron Letters 52 (2011) 4529–4532
R1
N
N
Br
2 Br
Br
H
R
Br R2
R
H
1
2
NaBH4
MeOH
R1
R1
N
R1
N
NaBH4
R1
NaBH4
N
N
Br
H
MeOH, Δ
R2 Br
MeOH, Δ
Br
Br
OMe
R2 = Me
R
2 = H
4
5
3
6
Scheme 1. Reactivity of b,c
-dibromoamines 3 (R2 = H or Me) towards NaBH4 Ref. 12.
In contrast to the widely explored chemistry of 2-(bromo-
methyl)aziridines 4, the synthesis of their chlorinated counterparts
received only limited interest in the literature.14,15 In these reports,
the preparation of non-activated N-t-butyl-, N-isopropyl- and N-
cyclohexyl-2-(chloromethyl)aziridine has been described through
nucleophilic displacement of amines bearing a good leaving group
the crude product was then treated with one equiv of sodium
hydroxide in water (2 M) with the intention to isolate the free
amine 9, but only small amounts of this amine 9 were obtained in
this way (10–15%). Finally, using a more concentrated solution of
sodium hydroxide in water (7 M), 2,3-dichloropropylamine 9 was
obtained in acceptable yields (40–45%) (Scheme 2). After nucleo-
philic addition of the latter amine 9 across aldehydes 10a–f in
dichloromethane under reflux in the presence of MgSO4, the corre-
sponding novel N-arylmethylidene- and N-alkylidene-2,3-dichloro-
propylamines 11a–f were formed in good yields and used as such in
the next step due to their lability (Scheme 2). Subsequently, novel
2-(chloromethyl)aziridines 12a–f were obtained in high yields
and purity as a result of NaBH4-mediated reduction of imines 11
in methanol after 22 h under reflux.17 It should be noted that the
reductive cyclization of N-arylmethylidene- and N-alkylidene-
2,3-dichloropropylamines 11a–f required a prolonged reaction
time (22 h) as compared to the cyclization of the corresponding
N-arylmethylidene-2,3-dibromopropylamines (2 h),18 which can
be rationalized considering the weaker leaving group capacity of
chloride as compared to bromide.
With regard to their reactivity, it was shown that 2-(chloro-
methyl)aziridines 12 display the same reactivity towards LiAlH4
and NaOMe as their brominated counterparts.19,20 Indeed, N-ben-
zyl-N-isopropylamine 13 was obtained upon treatment of aziridine
12a with 2 equiv of LiAlH4 in diethyl ether after 6 h under reflux
(Scheme 3), and 2-(methoxymethyl)aziridine 14 was formed
through nucleophilic substitution of chloride by methoxide after
treatment of aziridine 12a with 5 equiv of NaOMe (2 M) in metha-
nol under reflux for 48 h (Scheme 3). As compared to the reactivity
of 2-(bromomethyl)aziridines 4, more drastic reaction conditions,
such as prolonged reaction times and heating under reflux, were
required in order to drive these reactions to completion. The
above-described results show that 2-(chloromethyl)aziridines 12
can be prepared in an efficient and straightforward way and point
in b-position,14 or through reductive cyclization of
a,a,b-trichlori-
nated N-alkylimines using lithium aluminium hydride.15 The syn-
thesis of 2-chloromethyl-2-methylaziridines, however, has not
been reported in the literature so far.
In the present Letter, a new and efficient synthesis of non-acti-
vated 2-(chloromethyl)aziridines through reductive cyclization of
N-alkylidene- and N-arylmethylidene-2,3-dichloropropylamines
is described, as well as the synthesis of 2-chloromethyl-2-methy-
laziridines applying an analogous methodology, that is, the reduc-
tive cyclization of N-(2,3-dichloro-2-methylpropylidene)amines.
Whereas 2-(chloromethyl)aziridines were shown to have a similar
(and as expected slightly reduced) reactivity as compared to
the corresponding 2-(bromomethyl)aziridines, the behaviour of
2-chloromethyl-2-methylaziridines was demonstrated to be
intrinsically different than that of their brominated analogues.
In the first part of this work, the synthesis and reductive cycli-
zation of N-alkylidene- and N-arylmethylidene-2,3-dichloropro-
pylamines into 2-(chloromethyl)aziridines was evaluated. After
unsuccessful attempts towards the chlorination of N-(phenylme-
thylidene)allylamine16 in dichloromethane or carbon tetrachloride
using 1 equiv of chlorine gas, an alternative approach to access N-
alkylidene- and N-arylmethylidene-2,3-dichloropropylamines 11
en route to aziridines 12 was applied.
Thus, the synthesis of 2-(chloromethyl)aziridines 12 com-
menced with the chlorination of allylamine 7 in water by introduc-
ing 1 equiv of chlorine gas at 0 °C for 2 h after initial treatment with
1 equiv of HCl in water (6 M) at 0 °C (Scheme 2). Since attempted
crystallization of 2,3-dichloropropylamine hydrochloride 8 failed,
1) 1 equiv
HCl/H2O (6M), 0 o
C
Cl
NH2
Cl
NH2 • HCl
2) 1 equiv Cl2/H2O
0°C, 2 h
7
8
1 equiv
NaOH (7M)
H2O, 0°C
(40-45%)
Cl
R
Cl
NH2
1 equiv
3 equiv NaBH4
Cl
N
O
9
N
Cl
MeOH, Δ, 22 h
Cl
R
H
R
H
MgSO4, CH2Cl2
Δ, 15 min
10a-f
11a (R = Ph, 76%)
12a (R = Ph, 84%)
11b (R = 4-MeC6H4, 93%)
11c (R = 4-ClC6H4, 93%)
11d (R = iPr, 93%)
12b (R = 4-MeC6H4, 90%)
12c (R = 4-ClC6H4, 97%)
12d (R = iPr, 77%)
11e (R = CHEt2, 95%)
11f (R = nPr, 92%)
12e (R = CHEt2, 85%)
12f (R = nPr, 67%)
Scheme 2. Synthesis of 2-(chloromethyl)aziridines 12.

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S. Stankovic et al. / Tetrahedron Letters 52 (2011) 4529–4532
4 equiv LiAlH4
Et2O, Δ, 8 h
N
N
5 equiv
NaOMe (2M)
+
+
N
Cl
N
H
2 equiv LiAlH4
Cl
H
Cl
Cl
NH
Cl
19 (22%)
Cl
17d
Et2O, Δ, 6 h
N
N
MeOH, Δ, 48 h
21 (18%)
18d (60%)
OMe
Cl
12a
13 (98%)
14 (93%)
Scheme 5. Reactivity of imine 17d towards LiAlH4.
Scheme 3. Reactivity of 2-(chloromethyl)aziridine 12a towards NaOMe and LiAlH4.
In view of these results, and in light of a recently established
to a similar and—as expected—reduced reactivity profile of these
azaheterocycles as compared to the analogous 2-(bromo-
methyl)aziridines 4.
Given the recently reported successful and efficient synthesis of
2-bromomethyl-2-methylaziridines 5,12 the same synthetic meth-
odology was applied for the preparation of novel 2-chloromethyl-
2-methylaziridines. The chlorination of methacrolein 15 with chlo-
rine gas (neat) furnished 2,3-dichloro-2-methylpropanal 16 in
nearly quantitative yield after 1.5 h. Treatment of the latter alde-
hyde 16 with 1.1 equiv of a primary amine in dichloromethane in
aziridine to azetidine rearrangement,12 the formation of 3-
chloro-3-methylazetidine 19 in both the above-mentioned reac-
tions might be the result of the ring expansion of the initially
formed 2-chloromethyl-2-methylaziridine 18d under thermody-
namic conditions through chloride-induced ring opening of bicy-
clic aziridinium intermediate 22 (Scheme 6). It should be
mentioned that the formation of intermediate 22 from aziridine
18d is more difficult than from 2-bromomethyl-2-methylaziri-
dines 5 because of the less pronounced leaving group capacity of
chloride as compared to bromide. Furthermore, the presence of
azetidine 20 (Scheme 4) can be explained by nucleophilic attack
of methanol at the more hindered carbon atom of the same inter-
mediate bicyclic aziridinium salt 22. The comparable nucleophilic-
ity of chloride and methanol can account for the competing
pathways yielding a mixture of azetidines 19 and 20 (Scheme 6).
The different reactivity of 1-t-butylaziridine 18d as compared to
1-alkylaziridines 18a–c (R = cHex, iPr, iBu) might be attributed to
the slightly increased electron density of the nitrogen atom in
the former due to the higher electron-donating capacity of the t-
butyl group, rendering the aziridine nitrogen atom in aziridine
18d more reactive in terms of nucleophilicity.
the presence of MgSO4 afforded a,b-dichloroimines 17a–d. Subse-
quently, the reaction of aldimines 17a–c with 1.1 equiv of NaBH4 in
methanol under reflux for 4 h provided new 2-chloromethyl-2-
methylaziridines 18a–c in high yields (Scheme 4).21
Interestingly, in contrast to the preparation of 2-bromomethyl-
2-methylaziridines 5, the synthesis of aziridines 18a–c required
heating under reflux in order to achieve reductive cyclization of
a,b-dichloroimines 17. In addition, when aziridine 18b was treated
with NaBH4 in methanol for 62 h under reflux, no traces of the cor-
responding 3-methoxyazetidine were found, pointing to a high sta-
bility of these aziridines towards ring expansion. It should be
stressed that 2-bromomethyl-2-methylaziridines
shown to rearrange smoothly into 3-methoxy-3-methylazetidines
6 applying the same reaction conditions (NaBH4, MeOH,
).12
5 have been
The influence of an additional methyl group in aziridines 18 as
compared to 2-(chloromethyl)aziridines 12 was demonstrated by
the reactions of aziridine 18b with NaOMe and LiAlH4. Treatment
of aziridine 18b with 2 equiv of LiAlH4 in Et2O or THF at both room
temperature and under reflux gave only the starting compound,
and the nucleophilic substitution of aziridine 18b with 5 equiv of
NaOMe in methanol (2 M) also resulted in the full recovery of
the starting material, even after heating for 62 h under reflux.
Treatment of 2-bromomethyl-2-methylaziridines 5 with NaOMe
in methanol under reflux, however, has previously been shown
to furnish 3-methoxyazetidines.12
D
In contrast to the synthesis of 2-chloromethyl-2-methylaziri-
dines 18a–c, N-(2,3-dichloro-2-methylpropylidene)-t-butylamine
17d was transformed into a rather complex mixture upon treat-
ment with NaBH4 in methanol for 26 h under reflux (Scheme 4),
consisting of 3-chloroazetidine 19 (36%), 3-methoxyazetidine 20
(44%), b,c-dichloroamine 21 (12%) and small amounts of N-t-bu-
tyl-2,3-dichloro-2-methylpropionamide (<8%), formed by reaction
of 2,3-dichloro-2-methylpropionyl chloride (obtained during the
chlorination of methacrolein) with t-butylamine.
In conclusion, the present Letter provides efficient syntheses of
2-(chloromethyl)aziridines and 2-chloromethyl-2-methylaziri-
dines as new representatives of the class of 2-(halomethyl)aziri-
dines. It was elucidated that 2-(chloromethyl)aziridines 12 show
a similar (and as expected a slightly reduced) reactivity profile as
compared to the corresponding 2-(bromomethyl)aziridines 4, re-
flected in the nucleophilic substitution using NaOMe and the ring
Furthermore, when the same imine 17d was treated with an ex-
cess (4 equiv) of LiAlH4 in Et2O for 8 h under reflux, a complex mix-
ture was obtained in which the presence of aziridine 18d (60%),
azetidine 19 (22%) and b,c-dichloroamine 21 (18%) was observed
by means of NMR and GC analysis (Scheme 5). Apparently, the
presence of the sterically hindered t-butyl group at nitrogen has
a strong influence on the outcome in these reactions.
O
O
Cl2
H
Cl
H
-5-0oC, 1.5 h
neat
Cl
15
16 (98%)
1.1 equiv RNH2
MgSO4, CH2Cl2, r.t., 2 h
R
R
N
N
1.1 equiv NaBH4
1.1 equiv NaBH4
N
N
Cl
H
+
+
Cl
Cl
N
H
MeOH, Δ, 4 h
MeOH, Δ, 26 h
Cl
Cl
Cl
19 (36%)
OMe
20 (44%)
R = tBu
18a (R = cHex, 98%)
18b (R = iPr, 84%)
18c (R = iBu, 89%)
17a (R = cHex, 78%)
17b (R = iPr, 88%)
17c (R = iBu, 86%)
17d (R = tBu, 85%)
(12%)
21
Scheme 4. Synthesis of 2-chloromethyl-2-methylaziridines 18.

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S. Stankovic et al. / Tetrahedron Letters 52 (2011) 4529–4532
2010, 75, 885–896; (e) Kim, Y.; Ha, H.-J.; Yun, H.; Lee, B. K.; Lee, W. K.
Tetrahedron 2006, 62, 8844–8849.
N
5. (a) Vervisch, K.; D’hooghe, M.; Törnroos, K. W.; De Kimpe, N. Org. Biomol. Chem.
2009, 7, 3271–3279; (b) D’hooghe, M.; Vervisch, K.; Törnroos, K. W.; De Kimpe,
N. J. Org. Chem. 2007, 72, 7329–7332.
6. D’hooghe, M.; Vanlangendonck, T.; Törnroos, K. W.; De Kimpe, N. J. Org. Chem.
2006, 71, 4678–4681.
a
b
Cl
19
N
N
Cl
a
b
7. (a) De Smaele, D.; Bogaert, P.; De Kimpe, N. Tetrahedron Lett. 1998, 39, 9797–
9800; (b) D’hooghe, M.; Van Nieuwenhove, A.; Van Brabandt, W.; Rottiers, M.;
De Kimpe, N. Tetrahedron 2008, 64, 1064–1070.
8. D’hooghe, M.; Waterinckx, A.; De Kimpe, N. J. Org. Chem. 2005, 70, 227–232.
9. Vervisch, K.; D’hooghe, M.; Törnroos, K. W.; De Kimpe, N. J. Org. Chem. 2010, 75,
7734–7744.
Cl
HOMe
N
18d
22
OMe
20
10. (a) Sheikha, G. A.; La Colla, P.; Loi, A. G. Nucleosides Nucleotides Nucl. 2002, 21,
619–635; (b) D’hooghe, M.; Kenis, S.; Vervisch, K.; Lategan, C.; Smith, P. J.;
Chibale, K.; De Kimpe, N. Eur. J. Med. Chem. 2011, 46, 579–587; (c) D’hooghe,
M.; De Kimpe, N. Chem. Commun. 2007, 1275–1277.
11. (a) D’hooghe, M.; Mangelinckx, S.; Persyn, E.; Van Brabandt, W.; De Kimpe, N. J.
Org. Chem. 2006, 71, 4232–4236; (b) D’hooghe, M.; Rottiers, M.; Jolie, R.; De
Kimpe, N. Synlett 2005, 931–934.
Scheme 6. Formation of azetidines 19 and 20 from 18d.
R
R
R
N
N
NaBH4
NaBH4
N
X
H
MeOH, Δ
MeOH, Δ
Cl
´
12. Stankovic, S.; Catak, S.; D’hooghe, M.; Goossens, H.; Abbaspour Tehrani, K.;
X
OMe
18
Bogaert, P.; Waroquier, M.; Van Speybroeck, V.; De Kimpe, N. J. Org. Chem.
2011, 76, 2157–2167.
X = Cl
X = Br
23
6
13. (a) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79, 331–358; (b) Moore, J. A.;
Ayers, R. S. In Chemistry of Heterocyclic Compounds-Small Ring Heterocycles;
Hassner, A., Ed.; Wiley: New York, NY, 1983; pp 1–217. Part 2; (c) Davies, D. E.;
Storr, R. C. In Comprehensive Heterocyclic Chemistry; Lwowski, W., Ed.;
Pergamon: Oxford, 1984; Vol. 7, pp 237–284. Part 5; (d) Singh, G. S.;
D’hooghe, M.; De Kimpe, N. Azetidines, Azetines, and Azetes: Monocyclic In
Comprehensive Heterocyclic Chemistry III, A Review of the Literature 1995–2007;
Katritzky, A., Ramsden, C., Scriven, E., Taylor, R., Eds.; Elsevier: Oxford, 2008;
Vol. 2, pp 1–110; (e) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,
A. J.; Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12, 136–139; (f) Feula, A.; Male,
L.; Fossey, J. S. Org. Lett. 2010, 12, 5044–5047; (g) Brown, M. J.; Clarkson, G. J.;
Inglis, G. G.; Shipman, M. Org. Lett. 2011, 13, 1686–1689; (h) Couty, F.; Durrat,
F.; Prim, D. Tetrahedron Lett. 2003, 44, 5209–5212; (i) Couty, F.; Evano, G.
Synlett 2009, 3053–3064; (j) Couty, F. Sci. Synth. 2009, 773–817; (k) Couty, F.;
Durrat, F.; Evano, G. Targets Heterocycl. Syst. 2005, 9, 186–210; (l) Couty, F.;
Evano, G. Org. Prep. Proced. Int. 2006, 38, 427–465; (m) Mangelinckx, S.;
R
N
Br
5
Scheme 7. Different reactivity of imines 23 with respect to NaBH4 depending on
the substituent X (X = Cl or Br).
opening by means of LiAlH4. On the other hand, the behaviour of
2-chloromethyl-2-methylaziridines 18 was shown to be intrinsi-
cally different than that of their brominated analogues 5. While
2-bromomethyl-2-methylaziridines 5 have previously been shown
to be the kinetic products in the formation of 3-methoxy-3-methy-
ˇ
ˇ
Zukauskaite, A.; Buinauskaite, V.; Šackus, A.; De Kimpe, N. Tetrahedron Lett.
˙
˙
2008, 49, 6896–6900.
14. Gaertner, V. R. J. Org. Chem. 1970, 35, 3952–3959.
lazetidines 6 upon treatment of
(X = Br) with NaBH4 in methanol under reflux,
a
,b-dibrominated imines 23
15. D’hooghe, M.; De Meulenaer, B.; De Kimpe, N. Synlett 2008, 2437–2442.
16. (a) Lumbroso, A.; Chevallier, F.; Beaudet, I.; Quintard, J.-P.; Besson, T.; Le
Grognec, E. Tetrahedron 2009, 65, 9180–9187; (b) Dekeukeleire, S.; D’hooghe,
M.; Müller, C.; Vogt, D.; De Kimpe, N. New J. Chem. 2010, 34, 1079–1083.
a
,b-dichloroaldi-
mines 23 (X = Cl) were converted into 2-chloromethyl-2-methylaz-
iridines 18 applying the same reaction conditions (with the
exception of the t-butyl derivative), pointing to the relative stabil-
ity of these aziridines 18 towards ring expansion as a result of the
less pronounced leaving group capacity of chloride as compared to
bromide (Scheme 7).
17. As
a representative example, the synthesis of 1-(4-chlorobenzyl)-2-
(chloromethyl)aziridine 12c is described here. N-(4-Chlorobenzylidene)-2,3-
dichloropropylamine 11c (2.51 g, 10 mmol) was dissolved in methanol (30 ml),
after which NaBH4 (1.13 g, 3 mol equiv) was added in small portions at 0 °C,
and the mixture was stirred for 22 h under reflux. The reaction mixture was
poured into water (20 ml) and extracted with CH2Cl2 (3 Â 20 ml). The
combined organic extracts were washed with H2O (2 Â 15 ml) and brine
(20 ml). Drying (MgSO4), filtration of the drying agent and evaporation of the
solvent afforded 1-(4-chlorobenzyl)-2-(chloromethyl)aziridine 12c (2.10 g,
97%), which was purified by distillation (Bp = 86–92 °C/0.09 mmHg) in order
to obtain an analytically pure sample. 1-(4-Chlorobenzyl)-2-(chloromethyl)
aziridine 12c: Bp = 86–92 °C/0.09 mmHg; Yield 97%; 1H NMR (60 MHz, CCl4) d
1.30–2.00 (3H, m), 2.90–3.80 (4H, m), 7.28 (4H, s). 13C NMR (125 MHz, CDCl3) d
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34.0, 40.2, 46.8, 63.5, 128.5, 129.4, 133.0, 137.1. IR (NaCl, cmÀ1
) mmax = 1597,
1492, 1408, 1354, 1268, 1088, 1018. MS m/z (%) 215/7/9 (M+, 6), 180/2 (40),
126/8 (9), 125/7 (100), 98 (5), 92 (17), 90 (56), 89 (16), 75 (5), 63 (7), 55 (8).
18. De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc., Chem. Commun. 1994, 1221–
1222.
´
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4273.
20. D’hooghe, M.; De Kimpe, N. Arkivoc 2008, 9, 6–19.
21. As a representative example, the synthesis of 2-chloromethyl-1-cyclohexyl-2-
methylaziridine 18a is described here. N-(2,3-Dichloro-2-methylpropylidene)
cyclohexylamine 17a (2.22 g, 10 mmol) was dissolved in methanol (30 ml),
after which NaBH4 (0.42 g, 1.1 mol equiv) was added in small portions at 0 °C,
and the mixture was stirred for 4 h under reflux. The reaction mixture was
poured into a 0.5 M solution of NaOH in H2O (20 ml) and extracted with CH2Cl2
(3 Â 20 ml). The combined organic extracts were washed with H2O (2 Â 15 ml)
and brine (20 ml). Drying (MgSO4), filtration of the drying agent and evaporation
of the solvent afforded 2-chloromethyl-1-cyclohexyl-2-methylaziridine 18a
(1.84 g, 98%), which was purified by distillation (Bp = 120–134 °C/19 mmHg)
in order to obtain an analytically pure sample. 2-Chloromethyl-1-cyclohexyl-2-
methylaziridine 18a: Bp = 120–134 °C/19 mmHg; Yield 98%; 1H NMR (60 MHz,
CDCl3) d 0.9–2.4 (13H, m), 1.33 (3H, s), 3.1–3.8 (2H, m). 13C NMR (125 MHz,
3. Hu, X. E. Tetrahedron 2004, 60, 2701–2743.
4. (a) Lee, W. K.; Ha, H.-J. Aldrichim. Acta 2003, 36, 57–63. and references cited
therein; (b) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama, K. J.
Org. Chem. 1999, 64, 7323–7329; (c) D’hooghe, M.; Van Speybroeck, V.;
Waroquier, M.; De Kimpe, N. Chem. Commun. 2006, 1554–1556; (d) Catak, S.;
D’hooghe, M.; De Kimpe, N.; Waroquier, M.; Van Speybroeck, V. J. Org. Chem.
CDCl3) d 12.5, 24.6, 24.9, 26.2, 32.8, 33.9, 38.2, 40.0, 54.7, 60.3. IR (NaCl, cmÀ1
max = 2922, 2850, 1450, 1383, 1259. MS m/z (%) 187/9 (M+, 5), 152 (100), 144/6
)
m
(6), 108 (6), 106 (13), 104 (17), 96 (6), 83 (10), 82 (8), 81 (8), 77 (99), 70 (98), 69
(13), 68 (10), 67 (8), 56 (26), 55 (51), 54 (11), 53 (9), 49 (11).