N-Cyanomethyl-β-chloroamines: A convenient source of aziridinium ions

Article abstract of DOI:10.1016/j.tetlet.2005.02.016

N-Cyanomethyl-β-chloroamines smoothly react with a range of alcohols or amines to give regio- and stereoselectively 1,2-aminoethers or 1,2-diamines. The reaction proceeds through the formation of an intermediate aziridinium ion. The N-cyanomethyl group can then be cleaved easily.

Full text of DOI:10.1016/j.tetlet.2005.02.016

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2253–2257
N-Cyanomethyl-b-chloroamines: a convenient
source of aziridinium ions
Franc¸ois Couty,* Gwilherm Evano and Damien Prim
´ ´
SIRCOB, UMR CNRS 8086, Universite de Versailles, 45, avenue des Etats-Unis, 78035 Versailles Cedex, France
Received 5 January 2005;revised 31 January 2005;accepted 2 February 2005
Abstract—N-Cyanomethyl-b-chloroamines smoothly react with a range of alcohols or amines to give regio- and stereoselectively
1,2-aminoethers or 1,2-diamines. The reaction proceeds through the formation of an intermediate aziridinium ion. The N-cyano-
methyl group can then be cleaved easily.
Ó 2005 Elsevier Ltd. All rights reserved.
Due to the discovery of efficient methods for the asym-
metric synthesis of aziridines,1 and systematic studies of
their nucleophilic opening,2 these compounds have
emerged as useful electrophilic synthons within the past
decades. In contrast, N,N-dialkyl aziridinium ions 3, de-
spite their stronger electrophilic character compared to
neutral aziridines, have only scarcely been used as key
intermediates in organic synthesis.3 This can be ex-
plained by the lack of availability of a stable and easy
to handle precursor to these highly electrophilic ammo-
nium salts that would allow for a smooth and direct
generation.
Scheme 1.
As a matter of fact, N,N-dialkyl aziridinium ions are
most often produced by mesylation of the correspond-
ing b-amino alcohol.4 Beside the problem of regioselec-
tivity in the course of the nucleophilic opening of the
aziridinium, this activation affords various mixtures of
a matter of fact a carbamate would act as an internal
nucleophile to produce oxazolidinones5 and N-sulfonyl
protecting groups, in addition to their difficult cleavage,6
would deactivate the nucleophilic character of the nitro-
gen atom and prevent the formation of the aziridinium
ion.
aziridinium ion 3 and of b-chloro amine 4, the sense
of the equilibrium depicted in Scheme 1 depending of
different factors such as the steric hindrance around
the dialkyl amine and the electrophilic character (e.g.,
a benzylic position) of the chlorine bearing carbon.
We wish to describe herein the use of N-cyanomethyl b-
chloroamines 5 as stable precursors of aziridinium ions
In addition to producing difficult to handle mixtures of
neutral b-chloroamines and charged aziridinium ions,
this method does not allow for the introduction of com-
mon and easy to cleave protecting groups (R1 or R2 in 1)
on the amine moiety of the starting b-amino alcohol. As
Keywords: 1,2-Aminoethers;1,2-Diamines.
*
Corresponding author. Tel.: +33 1 39254455;fax: +33 1 39254452;
e-mail: couty@chimie.uvsq.fr
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.016

2254
F. Couty et al. / Tetrahedron Letters 46 (2005) 2253–2257
6, able to smoothly produce these electrophilic species
and react further with alcohols or amines to give N-
cyanomethyl protected b-aminoethers 7 or 1,2-diamines
8 (Scheme 2).
Table 1. Reaction of N-cyanomethyl b-chloroamines with alcohols
Entry
Substrate
Nucleophile
Conditions
Product
Yielda (%)
Ph
Ph
OMe
Cl
91
CN
CN
CN
1
MeOH
Neat, 0.5 h, 70 °C
N
N
Me
9
Me
Me
Me
12
Ph
OEt
2
3
9
EtOH
Neat, 0.5 h, 70 °C
71
N
Me
13
Me
Me
Me
Me
CN
Cl
N
Ph
O
N
Me
14
+
9
i-PrOH
Neat, 1 h, 100 °C
65 (for 14)b
14/15: 6.5/2.5
CN
Ph
Me
M
e
15
OH
Ph
O
OH
4
5
9
9
Neat, 0.5 h, 80 °C
70
80
CN
HO
HO
N
Me
16
Me
O
Ph
O
OH
OH
Neat, 1 h, 80 °C
O
CN
N
Me
Me
17
O
Ph
O
N
O
O
O
6
7
9
Neat, 1 h, 80 °C
82
77
CN
Me
Me
OH OH
HO
18
Ph
Ph
Cl
N
OMe
CN
MeOH
Neat, reflux, 3 h
CN
N
Me
Me
Me
10
19
Me
O
Me
+
CN
Ph
Cl
8
10
i-PrOH
Neat, reflux, 4 h
16 (for 20)b
20/21: 1.6/4.4
CN
N
Me
N
Me
20
Ph
21
Me
Me
Ph
Cl
N
Bn
11
Ph
O
N
CN
9
MeOH
Neat, reflux, 24 h
90
CN
Bn
22
a Yield of isolated products.
b Crude yield determined by NMR: see text.

F. Couty et al. / Tetrahedron Letters 46 (2005) 2253–2257
2255
In order to circumvent the formation of regioisomers in
the above reaction, we focused our study on chlorides 5
in which R3 is an aromatic, since it is well-established
that in this case the benzylic position in the produced
aziridinium ion is attacked regioselectively.4 Therefore,
reaction of chlorides 9–11, easily prepared from
(1R,2S)-ephedrine, (1S,2S)-pseudo-ephedrine and (R)-
phenylglycinol, respectively,7 with different alcohols
was studied and the results are collected in Table 1.
versible reaction of the ion with the nucleophile, com-
peting the attack of the chloride anion. Considering
that the overall rate of this reaction depends essentially
on the concentration of the produced aziridinium ion,
the relative stabilities of these ions has to be considered
in order to explain the differences of reactivity of the
starting chlorides. By comparing the reaction times re-
quired for completion for the reaction of the different
chlorides with methanol, it appears clearly that 9 is the
most reactive, followed by 10 and 11, since protracted
times of reaction are needed to reach completion. This
difference of reactivity can be attributed to the relative
stabilities of aziridinium ions 23, 24, 25, derived from
9, 10, 11, respectively. Aziridinium ion 23 (from 9) is
probably more stable than 24 (from 10), in which the
cis relationship of the substituents brings a steric strain.4a
Logically, aziridinium 25 derived from the less reactive
chlorides 11 should be the less stable. The reason for this
is less clear, but it can be attributed to the introduction
of the large N-benzyl group on the amine, that brings a
steric strain in the produced ion (Fig. 1).
Before commenting these results, the ease of preparation
of the starting chlorides as well as their stability should
be emphasized: these crystalline compounds can be
stored for long periods without detectable degradation
and they do not show any propensity to give aziridin-
iums ions at room temperature. This can be ascribed
to the N-cyanomethyl protecting group, which deacti-
vates the nucleophilic character of the amine moiety
by anomeric effect.10e,8
In spite of this deactivation, chlorides 9–11 reversibly
produce under moderate heating low concentrations of
aziridinium ions able to smoothly react with alcohols
or amines, as demonstrated by the results collected in
Table 1. As shown in this Table, aminoethers are easily
produced by simply heating the starting chlorides in the
required alcohol for a few hours, and the new amino-
ethers are produced with high regio- and stereoselecti-
vity. The stereospecificity observed for this reaction, to-
gether with our previously reported work demonstrating
that chlorides 9–11 exclusively react with azide anions
via aziridiniums ions secure here the occurrence of such
mechanism. The kinetic of this reaction depends of two
main factors: the ability of the substrate to form an
aziridinium ion, and the rate of the subsequent irre-
When comparing different alcohols, it appears that the
steric hindrance of the nucleophilic alcohol strongly
influences the rate of the second step: while primary
alcohols react in a highly regio- and stereoselective man-
ner with 9–11 at a reasonable rate (entries 1, 2, 4–7 and
Figure 1.
Table 2. Reaction of N-cyanomethyl b-chloro amines with amines
Entry
1
Substrate
Nucleophile
Conditions
Product
Yielda (%)
Ph
NH-nHex
CN
N
9
n-HexNH2
Neat, 2 h, 70 °C
90
Me
Ph
Me
26
N
2
3
9
9
Pyrrolidine
Neat, 1 h, 40 °C
75
76
CN
N
Me
27
OH
Ph
OH
NH
N
Neat, 0.5 h, 60 °C
NH
Me
CN
Me
Me
28
Me
Me
Ph
Ph
OH
Ph
N
OH
CN
4
9
1 equiv, DMF, 1.5 h, 110 °C
20
NH
Me
N
Me
30
Me
Me
29
a Yield of isolated pure products.

2256
F. Couty et al. / Tetrahedron Letters 46 (2005) 2253–2257
9), a secondary alcohol (i-PrOH) reacted in a much
more sluggish manner (entries 3 and 8). Thus, upon
heating in i-PrOH at 100 °C for 1 h, 9 gave a crude
inseparable mixture of starting compound 9, the ex-
pected product 14 and rearranged chloride 15 in a 1/
6.5/2.5 respective ratio (entry 3). Similarly, when this
reaction was conducted with less reactive 10 (entry 8),
a 4/1.6/4.4 respective ratio of 10, 20 and rearranged
chloride 21 was obtained. Chlorides 15 and 21 result
from an attack of the aziridinium by the chloride anion
at the nonbenzylic position. It should be mentioned that
in the case of 9, addition of silver(I) nitrate (1 equiv) as
an aziridinium ion promoter induced completion of the
reaction with i-PrOH at 50–60 °C within 0.5 h and gave
14 in a 76% isolated yield, albeit with a slight erosion (de
84%) of the diastereoselectivity.
In conclusion, this methodology affords a convenient
and flexible preparation of chiral b-aminoethers and
1,2-diamines. The produced compounds can be envi-
sioned as valuable starting material for the synthesis of
peraza8 or azacrown9 chiral macrocycles, as well as
di- or polyamine chiral bases10 used in asymmetric
synthesis.
Acknowledgements
CNRS is acknowledged for generous support (soutien
´
jeune equipe).
Supplementary data
Next was studied the reactions with amines: results are
collected in Table 2. In this case, both primary and sec-
ondary amines reacted efficiently (entries 1 and 2) and
with high chemoselectivity (entry 3). The use of a
crowded secondary amine ((1R,2S)-ephedrine 29, entry
4) used in this case as an equimolecular mixture with 9
in DMF gave the substitution product 30 in modest
yield, again accompanied by rearranged chloride 15. In
this case, nor solvent screening, nor addition of silver(I)
nitrate allowed for an optimisation of the yield.
Supplementary data contains experimental procedures
and characterisation for new compounds. Supplemen-
tary data associated with this article can be found, in
the online version at doi:10.1016/j.tetlet.2005.02.016.
References and notes
1. Osborn, H. M. I.;Sweeney, J. Tetrahedron: Asymmetry
1997, 8, 1693–1715.
2. Hu, E. X. Tetrahedron 2004, 60, 2701–2743.
3. For recent examples, see: (a) Mulvihill, M. J.;Cesario, C.;
Smith, V.;Beck, P.;Nigro, A. J. Org. Chem. 2004, 69,
5124–5127;(b) Chuang, T-H.;Sharpless, K. B. Org. Lett.
1999, 1, 1435–1437;(c) Chuang, T-H.;Sharpless, K. B.
Org. Lett. 2000, 2, 3555–3557, and references cited therein;
(d) Rowlands, G. J.;Barnes, W. K. Tetrahedron Lett.
2004, 45, 5347–5350;(e) Periasamy, M.;Seenivasaperu-
mal, M.;Dharma Rao, V. Tetrahedron: Asymmetry 2004,
15, 3847–3852;(f) Andrews, D. R.;Dahanukar, V. H.;
Eckert, J. M.;Gala, D.;Lucas, B. S.;Schumacher, D. P.;
Zavialov, I. A. Tetrahedron Lett. 2002, 43, 6121–6125;(g)
Graham, M. A.;Wadswoth, A. H.;Thornton-Pett, M.;
Rayner, C. M. Chem. Commun. 2001, 966–967.
4. (a) Dieter, R. K.;Deo, N.;Lagu, B.;Dieter, K. W. J. Org.
Chem. 1992, 57, 1663–1671;(b) de Sousa, S. E.;O ÕBrien, P.
Tetrahedron Lett. 1997, 38, 4885–4888;(c) Fulton, D. A.;
Gibson, C. L. Tetrahedron Lett. 1997, 38, 2019–
2022.
Finally, deprotection of the N-cyanomethyl group was
studied. We found that it could be achieved either ther-
mally, which allowed to perform the substitution/depro-
tection process in a one pot sequence, as exemplified
starting with chloride 31 and 11. In these cases, the chlor-
ides were simply refluxed with methanol and then
heated after removal of the solvent, to give 32 or 33.
Alternatively, silver(I)-promoted hydrolytic cleavage of
the N-cyanomethyl moiety was also operative and gave
33 and 34 from 16 and 22, respectively (Scheme 3).
5. Agami, C.;Couty, F. Tetrahedron 2002, 58, 2701–2724.
6. Greene, T. W.;Wuts, P. G. M. Protective Groups in
Organic Synthesis;John Wiley and Sons, Inc., 1999;pp
603–607.
7. For a previously reported use of these chlorides as
azetidines precursors, see: (a) Agami, C.;Couty, F.;
Evano, G. Tetrahedron: Asymmetry 2002, 13, 297–302;
For a study of their reactivity with azide anions, see: (b)
Couty, F.;Durrat, F.;Prim, D. Tetrahedron Lett. 2004,
45, 3725–3728.
8. Perhaps the more spectacular illustration of this deactiva-
tion is the fact that trials of dicyanomethylation of a b-
amino alcohols such as (S)-alaninol, even under forcing
conditions, cleanly stops at the monoalkylation step:
Scheme 3.

F. Couty et al. / Tetrahedron Letters 46 (2005) 2253–2257
2257
Kim, M. B.;So, S. M.;Choi, H. J. Org. Lett. 2002, 4, 949–
952, and references cited therein.
9. Lee, C.-W.;Jung, E. J.;Lee, S. J.;Ahn, K. H.;Kim, K. S.
J. Org. Chem. 2000, 65, 7225–7227, and references cited
therein.
10. See inter alia: (a) Bassindale, M. J.;Crawford, J. J.;
Henderson, K. W.;Kerr, W. J. Tetrahedron Lett. 2004,
45, 4175–4179;(b) Hutchinson, P. C.;Heightman, T. D.;
Procter, D. J. J. Org. Chem. 2004, 69, 790–801;
¨
(c) Johansson, A. J.;Abrahamsson, P.;Davidsson, O
Tetrahedron: Asymmetry 2003, 14, 1261–1266;(d)
Amedjkouh, M.;Pettersen, D.;Lill, S. O. N.;Davidsson,
.
¨
O.;Ahlberg, P. Chem. Eur. J. 2001, 7, 4368–4377;
(e) Colman, B.;de Sousa, S. E.;O ÕBrien, P.;Towers, T.
D.;Watson, W. Tetrahedron: Asymmetry 1999, 10, 4175–
4182.