Coupling of 1-alkyl-2-(bromomethyl)aziridines with lithium dialkylcuprates towards 1,2-dialkylaziridines

Article abstract of DOI:10.1055/s-2005-864801

The reactivity of 1-alkyl-2-(bromomethyl)aziridines with respect to lithium dialkylcuprates (Gilman reagents) has been evaluated for the first time, pointing to the conclusion that these substrates can be applied successfully as synthetic equivalents for

Full text of DOI:10.1055/s-2005-864801

LETTER
931
Coupling of 1-Alkyl-2-(bromomethyl)aziridines with Lithium Dialkylcuprates
towards 1,2-Dialkylaziridines
C
M
oupling of 1-Alkyl-2
a
-(bromome
t
thyl)az
t
s
h
w
ith Lithium
i
D
ialk
a
ylcupratess D’hooghe, Mario Rottiers, Robrecht Jolie, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent,
Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 6 December 2004
Ar
O S
Ar
Abstract: The reactivity of 1-alkyl-2-(bromomethyl)aziridines
with respect to lithium dialkylcuprates (Gilman reagents) has been
evaluated for the first time, pointing to the conclusion that these
substrates can be applied successfully as synthetic equivalents for
the aziridinylmethyl cation synthon towards, e.g. 2-ethyl-, 2-pentyl-
and 2-(phenylmethyl)aziridines in good yields.
SO2
N
2
NH
Br
Br
1
2
R
R
Key words: 2-(bromomethyl)aziridines, organometallics, nucleo-
philic substitution, 1,2-dialkylaziridines
N
N
3
4
In the past decade, aziridines acquired a prominent place Figure 1
in organic chemistry due to their broad synthetic utility.1
In analogy with epoxides, N-activated aziridines are prone
4
be synthesized from the corresponding amino alcohol, by
to ring-opening, which allows the synthesis of a large va-
riety of functionalized amines upon reaction with nucleo-
philes. In a former communication, it has been
demonstrated that 1-arenesulfonyl-2-(bromomethyl)aziri-
dines 1 can be applied successfully as synthetic equiva-
lents for the 2-aminopropane dication synthon 2 towards
5
reaction of organoboranes with organic azides, by amino-
palladation of alkenes followed by oxidation by bromine6
and by reduction of a-halogenated imines or a,a-dihalo-
genated imines. 1,2-Dialkylaziridines have been used as
substrates for the synthesis of a whole range of cyclic and
acyclic compounds with various applications. An interest-
ing conversion of 1,2-dialkylaziridines comprises the syn-
thesis of biologically and medically important 1,2-
7
1
-tosyl-2-alkylaziridines on the one hand and a-branched
symmetrical and unsymmetrical N-tosylamides on the
2
other hand, depending on the amount of reagent used. A
8
diamines. Also a variety of ring expansions towards b-
similar ring-opening was observed for the closely related
N,O-bis(diphenylphosphinyl)hydroxymethylaziridine in
ring-opening reactions with copper(I)-modified Grignard
lactams9 and five-membered heterocycles have been
established, furnishing different synthetically and biolog-
ically relevant compounds.10 Therefore, a new and syn-
thetically useful approach towards 1,2-dialkylaziridines is
reported here.
3
reagents. In this report, the chemistry of 1-alkyl-2-(bro-
momethyl)aziridines 3, a hitherto scarcely investigated
class of b-halo amines, is evaluated in terms of their reac-
tivity with regard to carbon-centered nucleophiles. Con- 1-Alkyl-2-(bromomethyl)aziridines 3 are very easily
trary to the above-mentioned N-activated aziridines, the accessible substrates for further syntheses, prepared in a
focus here will be on the absence of ring-opening in order three-step procedure starting from the appropriate alde-
to develop a method for aziridine synthesis. Up to now, no hydes.11 Condensation of benzaldehydes 5a,b with 1
information is available in the literature concerning the equivalent of allylamine in dichloromethane in the pres-
behavior of 1-alkyl-2-(bromomethyl)aziridines upon ence of magnesium sulfate afforded the corresponding
reaction with organocuprate reagents such as lithium N-allylimines, which were subsequently brominated by
dialkylcuprates. Although closely related to N-(arene- bromine in dichloromethane to give N-(arylidene)-2,3-di-
sulfonyl)aziridines, N-alkylaziridines 3 appeared to be bromopropylamines in a quantitative yield. The latter di-
suitable equivalents for the aziridinylmethyl cation 4, bromoimines were used as such because of their
allowing the selective synthesis of different 1,2-dialkyl- instability and hence treated with sodium borohydride in
aziridines in good yields (Figure 1).
methanol under reflux, furnishing 1-arylmethyl-2-(bro-
momethyl)aziridines 3a,b in high yields (Scheme 1).11
Other approaches towards 1-benzylaziridines have been
described in the literature.12
1
,2-Dialkylaziridines are versatile substrates in organic
synthesis, hence the interest in a straightforward strategy
for their preparation. Generally, 1,2-dialkylaziridines can
In the case of the synthesis of aziridine 3c, isobutanal 5c
was condensed with 1 equivalent of 2,3-dibromo-1-pro-
pylammonium bromide in dichloromethane in the pres-
ence of 1 equivalent of triethylamine and magnesium
SYNLETT 2005, No. 6, pp 0931–0934
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864801; Art ID: G45704ST
0
6.
0
4.
2
0
0
5
©
Georg Thieme Verlag Stuttgart · New York

9
32
M. D’hooghe et al.
LETTER
.
NH2 HBr
Br
1
) 1 equiv
Br
1
) 1 equiv allylamine, CH2Cl2
R
1 equiv Et N, CH Cl
3
2
2
O
2) 1 equiv Br , CH Cl
O
2
2
2
1.5 equiv MgSO4, ∆, 2h
N
R
H
R
H
Br
3) 2 equiv NaBH4, MeOH
2) 2 equiv NaBH , MeOH
4
∆, 3 h
5
5
a (R = Ph)
b (R = 4-ClC6H4)
3a (R = Ph, 89%)
3b (R = 4-ClC6H4, 83%)
5c (R = i-Pr)
3c (R = i-Pr, 87%)
Scheme 1
sulfate as drying agent. Reduction of the dibromoimine, The synthesis of 1,2-di(phenylmethyl)aziridine 6e re-
thus obtained, with sodium borohydride in methanol af- quired a higher amount of lithium diphenylcuprate, since
forded aziridine 3c in 87% yield after reflux for 3 hours.13 only with 3 equivalents of Ph CuLi the reaction could be
2
driven to completion, whereas the addition of 2 equiva-
Treatment of aziridines 3 with 1.5–5 equivalents of lithi-
um dimethylcuprate, lithium dibutylcuprate and lithium
diphenylcuprate in diethyl ether for 3–20 hours afforded
lents of Ph CuLi resulted in the recovery of most of the
2
starting material (Table 1, entries 6 and 7).
the corresponding 2-alkylaziridines 6 in high yields of the Attempts to functionalize aziridines 3 with lithium
crude product (85–95%), which were subsequently bis(isopropenyl)cuprate and lithium bis(allyl)cuprate in
purified by means of column chromatography to obtain diethyl ether were unsuccessful, and only the correspond-
1
4
analytically pure samples (Table 1). When lithium di- ing allylamines were isolated (Table 1, entries 9–11).
methylcyanocuprate (1.05 equiv) was used in diethyl Complete conversion of aziridine 3 into allylamine 7 was
ether at –78 °C instead of lithium dimethylcuprate, a observed after 6 hours at room temperature upon
similar result was obtained after 15 hours at room temper- treatment with bis(isopropenyl)cuprate in diethyl ether at
ature, affording 2-ethyl-1-[4-(chlorophenyl)methyl]aziri- –78 °C, whereas after reaction with bis(allyl)cuprate in di-
dine 6c in 77% yield. In the reaction mixtures, obtained ethyl ether also some starting material (ca. 50%) was
after treatment of aziridines 3 with lithium dibutylcuprate present in the reaction mixture, even upon a prolonged
or lithium diphenylcuprate, the formation of the corre- reaction time of 17 hours (Table 1, entry 10). Further-
sponding allylamine 7 was observed as a by-product in more, also lithium bis(phenylethynyl)cuprate was used as
small quantities (5–10%, Table 1), except for entry 8 a possible carbon-centered nucleophile. However, no re-
(
25%, Table 1), possibly due to the presence of some action was observed after 20 hours at room temperature
remaining phenyllithium, used for the in situ preparation upon treatment of aziridine 3b with 1.5 equivalents of this
of lithium diphenylcuprate. Allylamines 7 (Scheme 2) are organocuprate in diethyl ether at –78 °C, and the starting
probably formed due to the lower nucleophilicity of these material was entirely recovered (Table 1, entry 12). The
Gilman reagents as compared to lithium dimethylcuprate. use of lithium phenylacetylide appeared to be no suitable
Apparently, a small amount of the organocuprate reagent alternative for lithium bis(phenylethynyl)cuprate, and
provokes metal–halogen exchange or induces electron- again the starting aziridine 3b was recovered after reac-
transfer, and the resulting aziridinylmethyl carbanion 8 or tion with 1.1 or 1.2 equivalents of lithium phenylacetylide
radical intermediate 9 suffers ring-opening to form the in THF after 1 or 3 hours at room temperature, even when
allylamines 7 (Scheme 3).
HMPA was added as a co-solvent (THF–HMPA, 4:1).
In conclusion, 1-alkyl-2-(bromomethyl)aziridines are
suitable synthetic equivalents for the aziridinylmethyl
cation, providing an easy access to 1,2-dialkylaziridines
as substrates for further elaboration. In this way, 2-ethyl-,
R
R
R′2CuLi
N
N
+
R
N
H
Br
R'
Et2O
2
-pentyl- and 2-(phenylmethyl)aziridines have been pre-
3
6
7
pared in a preparative way via a new route starting from
1-alkyl-2-(bromomethyl)aziridines upon treatment with
the appropriate lithium dialkylcuprate reagent. Further-
more, it was demonstrated that 1-alkyl-2-(bromo-
methyl)aziridines are considerably less reactive than the
structurally related 1-arenesulfonyl-2-(bromomethyl)azi-
ridines, which creates the possibility to develop new
synthetic strategies with different applications. In contrast
with 2-alkyl-1-(arenesulfonyl)aziridines, the aziridine
ring of 1,2-dialkylaziridines is not susceptible to ring-
opening upon treatment with an excess of lithium cuprate
reagent.
Scheme 2
R
N
8
R
NH
R
7
N
9
Scheme 3
Synlett 2005, No. 6, 931–934 © Thieme Stuttgart · New York

LETTER
Coupling of 1-Alkyl-2-(bromomethyl)aziridines with Lithium Dialkylcuprates
933
Table 1 Reactions of 2-(Bromomethyl)aziridines 3 with Lithium Dialkylcuprates
Entry
R
R¢
Conditionsa
Yield of 6 (%)b
6a (76)
6a (65)
6b (54)
6c (67)
6d (47)
6e (<5)c
6e (76)
6f (45)
6g (–)
Yield of 7 (%)c
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Me
Me
Bu
1.5 equiv R¢ CuLi, 0 °C to r.t., 3.5 h
7a (–)
7a (–)
7b (10)
7c (–)
2
3 equiv R¢ CuLi, –78 °C to r.t., 16 h
2
3 equiv R¢ CuLi, –78 °C to r.t., 19 h
2
4-ClC H
Me
Bu
3 equiv R¢ CuLi, –78 °C to r.t., 6 h
6
4
4
2
4-ClC H
3 equiv R¢ CuLi, –78 °C to r.t., 20 h
7d (<5)
7e (–)
6
2
Ph
Ph
Ph
2 equiv R¢ CuLi, –78 °C to r.t., 5 h
2
Ph
3 equiv R¢ CuLi, –78 °C to r.t., 19 h
7e (<5)
7f (25)
7g (40)
7g (40)
7h (78)
7i (–)
2
4-ClC H
Ph
5 equiv R¢ CuLi, –78 °C to r.t., 20 h
6
4
2
Ph
Ph
Allyl
Allyl
1.5 equiv R¢ CuLi, –78 °C to r.t., 6 h
2
10
11
12
13
14
15
1.5 equiv R¢ CuLi, –78 °C to r.t., 17 h
6g (–)
2
4-ClC H
CH =C(Me)
1.5 equiv R¢ CuLi, –78 °C to r.t., 6 h
6h (–)
6
4
4
2
2
4-ClC H
PhC≡C
Me
1.5 equiv R¢ CuLi, –78 °C to r.t., 20 h
6i (–)
6
2
i-Pr
i-Pr
i-Pr
1.5 equiv R¢ CuLi, 0 °C to r.t., 3 h
6j (83)
6k (63)
6l (–)
7j (–)
2
Bu
1.5 equiv R¢ CuLi, 0 °C to r.t., 4 h
7k (–)
7l (–)
2
Ph
1.5 equiv R¢ CuLi, 0 °C to r.t., 4 h
2
a
b
c
All reactions were performed in dry Et O.
2
Yield after column chromatography.
1
Derived from H NMR and/or GC.
Acknowledgment
(7) (a) De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N.
Synth. Commun. 1975, 5, 269. (b) Duhamel, L.; Valnot, J.
Y. Tetrahedron Lett. 1974, 36, 3167. (c) De Kimpe, N.;
Moens, L. Tetrahedron 1990, 46, 2965. (d) De Kimpe, N.;
Schamp, N.; Verhé, R. Synth. Commun. 1975, 5, 403.
The authors are indebted to the ‘Fund for Scientific Research –
Flanders (Belgium)’ (F.W.O. Vlaanderen) and Ghent University
(GOA) for financial support.
(e) De Kimpe, N.; Verhé, R.; De Buyck, L.; Dejonghe, W.;
Schamp, N. Bull. Soc. Chim. Belg. 1976, 85, 763.
8) (a) Hancock, M. T.; Pinhas, A. R. Tetrahedron Lett. 2003,
References
(
4
4, 7125. (b) Hancock, M. T.; Pinhas, A. R.
(
1) (a) Hu, X. E. Tetrahedron 2004, 60, 2701. (b) Sweeney, J.
B. Chem. Soc. Rev. 2002, 31, 247. (c) Zwanenburg, B.; ten
Holte, P. Top. Curr. Chem. 2001, 216, 93. (d)McCoull, W.;
Davis, F. A. Synthesis 2000, 1347. (e) Lindström, U. M.;
Somfai, P. Synthesis 1998, 109. (f) Somfai, P.; Ahman, J.
Targets in Heterocyclic Systems, Vol. 3; Italian Chemical
Society: Rome, Italy, 1999, 341.
Organometallics 2002, 21, 5155. (c) Chandrasekhar, M.;
Sekar, G.; Singh, V. K. Tetrahedron Lett. 2000, 41, 10079.
9) Chamchaang, W.; Pinhas, A. R. J. Org. Chem. 1990, 55,
(
2
943.
10) (a) Hancock, M. T.; Pinhas, A. R. Tetrahedron Lett. 2003,
4, 5457. (b) Nomura, R.; Nakano, T.; Nishio, Y.; Ogawa,
(
(
4
S.; Ninagawa, A.; Matsuda, H. Chem. Ber. 1989, 122, 2407.
11) (a) De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc.,
Chem. Commun. 1994, 1221. (b) Abbaspour Tehrani, K.;
Van Nguyen, T.; Karikomi, M.; Rottiers, M.; De Kimpe, N.
Tetrahedron 2002, 58, 7145. (c) De Kimpe, N.; De Smaele,
D.; Szakonyi, Z. J. Org. Chem. 1997, 62, 2448.
(
2) D’hooghe, M.; Kerkaert, I.; Rottiers, M.; De Kimpe, N.
Tetrahedron 2004, 60, 3637.
(
(
3) Sweeney, J. B.; Cantrill, A. A. Tetrahedron 2003, 59, 3677.
4) (a) Sekar, G.; Vinod, K. S. J. Org. Chem. 1999, 64, 2537.
(
b) Kelly, J. W.; Anderson, N. L.; Evans, S. A. Jr. J. Org.
Chem. 1986, 51, 95.
(
12) (a) Davoli, P.; Caselli, E.; Bucciarelli, M.; Forni, A.; Torre,
G.; Prati, F. J. Chem. Soc., Perkin Trans. 1 2002, 1948.
(
5) Brown, H. C.; Midland, M. M.; Levy, A. B.; Suzuki, A.;
Sono, S.; Itoh, M. Tetrahedron 1987, 43, 4079.
6) (a) Bäckvall, J.-E. J. Chem. Soc., Chem. Commun. 1977, 12,
(
b) Jahnisch, K. Liebigs Ann. Recl. 1997, 757. (c) Lohray,
B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989, 30,
623.
(
413. (b) Barelle, M.; Apparu, M. Tetrahedron 1977, 33,
2
1309.
(
13) Synthesis of 2-(Bromomethyl)-1-isobutylaziridine (3c).
To a solution of isobutanal (5c, 0.14 g, 2 mmol) in CH Cl
2
2
(10 mL) was added 2,3-dibromo-1-propylammonium
bromide (0.60 g, 2 mmol, 1 equiv), MgSO (0.5 g) and Et N
4
3
(
0.20 g, 2 mmol, 1 equiv) at 0 °C, and the mixture was heated
Synlett 2005, No. 6, 931–934 © Thieme Stuttgart · New York

9
34
M. D’hooghe et al.
LETTER
for 30 min at –78 °C, a solution of 1-benzyl-2-(bromo-
under reflux for 2 h. After evaporation of the solvent, dry
Et O (20 mL) was added, the resulting precipitate was
methyl)aziridine (3a, 0.90g, 4 mmol) in Et O (10 mL) was
2
2
filtered and the solvent evaporated, affording the
added at –78 °C, and the resulting suspension was further
corresponding dibromoimine in 94% yield. This imine was
used as such in the next step due to its lability. To a solution
of N-(isobutylidene)-2,3-dibromopropylamine (0.54 g, 2
stirred for 6 h at r.t. The reaction mixture was quenched with
®
a sat. solution of NH Cl (20 mL), filtered over Celite and
4
washed with Et O (2 ꢀ 20 mL). The filtrate was poured into
2
mmol) in MeOH (2 mL) was added NaBH (0.15 g, 4 mmol,
H O (100 mL), extracted with Et O (2 ꢀ 75 mL), and the
4
2
2
2
equiv) in small portions at 0 °C, and the mixture was
combined organic extracts were washed with sat. NH Cl (50
4
heated under reflux for 3 h. Extraction with CH Cl (2 ꢀ 10
mL) and brine (50 mL). Drying (MgSO ), filtration and
2
2
4
mL), drying (MgSO ) and filtration afforded 2-(bromo-
methyl)-1-isobutylaziridine (3c, 0.33 g, 87%), which was
evaporation of the solvent afforded 2-ethyl-1-(phenyl-
methyl)aziridine (6a), which was purified by means of
column chromatography on silica gel (EtOAc–hexane, 1:4).
Spectroscopic data of, e.g. 1-(phenylmethyl)-2-pentyl-
4
purified by distillation (65–69 °C/11–12 mmHg); colorless
1
liquid, bp 65–69 °C/11–12 mmHg. H NMR (300 MHz,
CDCl ): d = 0.92 and 1.01 [6 H, 2 d, J = 6.6 Hz, (CH ) ], 1.47
aziridine (6b): yield 54%, colorless liquid. Flash chromato-
3
3 2
1
[
1 H, d, J = 6.1 Hz, (H CH)N], 1.68–1.76 (1 H, m, CHMe ),
graphy on silica gel: EtOAc–hexane, 1:4, R = 0.32. H NMR
cis
2
f
1.75 [1 H, d, J = 3.0 Hz, (HCHtrans)N], 1.80–1.93 (1 H, m,
(270 MHz, CDCl ): d = 0.84 (3 H, t, J = 6.2 Hz, CH ), 1.22–
3
3
CHN), 2.05 and 2.17 [2 H, 2 dd, J = 5.8, 8.1, 11.6 Hz,
1.47 [10 H, m, (H CH)N, CHN and (CH ) CH ], 1.60 [1 H,
cis 2 4 3
N(HCH)CHMe ], 3.27 and 3.36 [2 H, 2 dd, J = 5.4, 7.3, 10.3
d, J = 2.9 Hz, (HCHtrans)N], 3.30 and 3.49 [2 H, 2 d, J = 13.2
2
1
3
13
Hz, (HCH)Br]. C NMR (75 MHz, CDCl ): d = 20.80 and
Hz, (HCH)C H ], 7.22–7.35 (5 H, m, C H ). C NMR (68
3
6
4
6
5
2
0.92 [(CH ) ], 28.99 (CHMe ), 35.77 and 36.00 (NCH CH
MHz, CDCl ): d = 14.00 (CH ), 22.62, 27.12, 31.57 and
3
2
2
2
3
3
and CH Br), 40.03 (NCH CH), 69.18 (NCH i-Pr). IR
32.96 [(CH ) CH ], 34.07 (NCH CH), 39.82 (NCH CH),
2 4 3 2 2
2
2
2
–
1
(
(
NaCl): n = 3040, 1469, 1383, 1364, 1238, 1220 cm . MS
70 eV): m/z (%) = 191/193 (1) [M ], 148/150 (20), 119/121
65.00 (CH C H ), 126.95 (HCpara), 128.17 and 128.26 (2
2 6 4
+
HCortho and 2 HCmeta), 139.40 (Carom,quat). IR (NaCl):
–
1
(
18), 112 (100), 70 (7), 68 (5), 57 (41), 56 (77), 42 (73), 41
n = 1607, 1496, 1454 cm . MS (70 eV): m/z (%) = 203 (6)
+
(
45). Anal. Calcd for C H BrN (%): C, 43.77; H, 7.35; N,
[M ], 202 (9), 174 (11), 173 (20), 161 (26), 160 (51), 147
7
14
7
.29. Found: C, 43.94; H, 7.55; N, 7.17.
(19), 146 (39), 121 (23), 112 (22), 92 (56), 91 (100), 65 (13).
Anal. Calcd for C H N (%): C, 82.70; H, 10.41; N, 6.89.
(
14) As a representative example, the synthesis of 2-ethyl-1-
1
4
21
(
phenylmethyl)aziridine (6a) is described. To a suspension
Found: C, 82.84; H, 10.55; N, 6.74.
Spectroscopic data of aziridines 6a,c–f,j,k are available
upon request.
of CuI (1.52 g, 8 mmol, 2 equiv) in dry Et O (40 mL) was
added slowly MeLi (10 mL, 4 equiv, 1.6 M in Et O) via a
2
2
syringe at –78 °C under nitrogen atmosphere. After stirring
Synlett 2005, No. 6, 931–934 © Thieme Stuttgart · New York