Synthesis and reactivity of novel α,α,β- and α,α,δ-trichlorinated imines

Article abstract of DOI:10.1055/s-2008-1078171

A variety of different N-(2,2,3-trichloropropylidene)amines, N-(2,2,3-trichlorobutylidene)amines, and N-(2,2,5-trichloropentylidene)amines were synthesized for the first time, and their reactivity with regard to hydride reagents was investigated. In this way, N-(2,2,5-trichloropentylidene)amines were evaluated as substrates for the synthesis of piperidines, and N-(2,2,3-trichloropropylidene)amines and N-(2,2,3-trichlorobutylidene)amines were reduced efficiently into the corresponding novel β,β,γ- trichloroamines by means of sodium cyanoborohydride in methanol in the presence of acetic acid. Furthermore, N-(2,2,3-trichloropropylidene)amines were transformed into 2-(chloromethyl)aziridines by lithium aluminium hydride in Et₂O, and N-(2,2,5-trichloropentylidene)acetamide was used for the first time as a suitable substrate for the addition of oxygen, nitrogen, and sulfur nucleophiles in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078171

LETTER
2437
Synthesis and Reactivity of Novel a,a,b- and a,a,d-Trichlorinated Imines
Synthesis of
T
richlorin
a
atedImine
t
s
thias D’hooghe, Bruno De Meulenaer, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
E-mail: norbert.dekimpe@UGent.be
Received 21 May 2008
trichloropentanal were evaluated for the synthesis of pip-
eridine derivatives, and N-(2,2,5-trichloropentylidene)ac-
etamide was shown to be a suitable substrate for the
addition of oxygen, nitrogen, and sulfur nucleophiles
Abstract: A variety of different N-(2,2,3-trichloropropyli-
dene)amines, N-(2,2,3-trichlorobutylidene)amines, and N-(2,2,5-
trichloropentylidene)amines were synthesized for the first time, and
their reactivity with regard to hydride reagents was investigated. In
this way, N-(2,2,5-trichloropentylidene)amines were evaluated as across the imino moiety. Furthermore, the reactivity of N-
substrates for the synthesis of piperidines, and N-(2,2,3-trichloro-
propylidene)amines and N-(2,2,3-trichlorobutylidene)amines were
reduced efficiently into the corresponding novel b,b,g-trichloro-
investigated, affording a simple method for their reduc-
amines by means of sodium cyanoborohydride in methanol in the
presence of acetic acid. Furthermore, N-(2,2,3-trichloropropyli-
dene)amines were transformed into 2-(chloromethyl)aziridines by
lithium aluminium hydride in Et2O, and N-(2,2,5-trichloropentyl-
idene)acetamide was used for the first time as a suitable substrate
for the addition of oxygen, nitrogen, and sulfur nucleophiles in good
yields.
(2,2,3-trichloropropylidene)amines and N-(2,2,3-trichlo-
robutylidene)amines with regard to hydride reagents was
tion towards trichlorinated amines by means of sodium
cyanoborohydride and a novel entry into 2-(chlorometh-
yl)aziridines using lithium aluminium hydride.
2,2,5-Trichloropentanal (2) can be prepared from tetrahy-
dropyran (1) by means of a straightforward three-step ap-
proach, involving treatment with 1.2 equivalents of acetyl
chloride in the presence of 0.5 mol% of zinc(II) chloride,
p-toluenesulfonic acid catalyzed transesterification by
means of methanol, and finally oxidation of the alcohol
and a,a-dichlorination by reaction with chlorine gas in
DMF and chloroform (Scheme 1).13 Subsequently, 2,2,5-
trichloropentanal (2) was transformed into the corre-
sponding novel N-alkylaldimines 3 upon condensation
with different primary amines (Scheme 1). N-Isopropyl-
and N-tert-butylaldimines 3a,b were prepared upon treat-
ment of aldehyde 2 with four equivalents of the corre-
sponding amine in diethyl ether in the presence of 0.5
equivalents of titanium(IV) chloride at room temperature
for two hours, whereas N-cyclohexyl- and N-benzylaldi-
mines 3c,d were synthesized by reaction with one equiv-
alent of the required amine in the presence of three
equivalents of triethylamine and 0.5 equivalents of titani-
um(IV) chloride in diethyl ether at room temperature
(Scheme 1).14 N-(2,2,5-Trichloropentylidene)amines 3
comprise a novel class of compounds, as no representa-
tives of this type of aldimines have been described in the
literature up to now [only N-(2,2,5-trichloro-1-phenylpen-
tylidene)isopropylamine is known].15
Key words: trichlorinated imines, hydride reagents, trichloro-
amines, 2-(chloromethyl)aziridines
a-Halogenated imines have found widespread use in or-
ganic synthesis since the first reports on this type of chem-
istry,1 for example, towards the synthesis of aziridines,2 2-
imidazolidinethiones,3 a-cyanoenamines,4 2-imidazoli-
dinones,5 allylamines,6 2-aza-1,3-dienes and 3-aza-1,3,5-
trienes,7 pyrrolidines8 and b-lactams.9 Among a-halo-
imines, the class of a,a-dichloroimines10 has been evalu-
ated to a lesser extent, although some valuable
transformations have been described previously.11 Re-
cently, the Lewis acid promoted Mannich-type reaction of
a,a-dichloroaldimines with potassium organotrifluorobo-
rates towards functionalized propargylamines and ally-
lamines has been described.12
In the present report, the synthesis and reactivity of three
novel classes of trichlorinated imines is discussed, that is,
N-(2,2,3-trichloropropylidene)amines, N-(2,2,3-trichlo-
robutylidene)amines,
and
N-(2,2,5-trichloropentyl-
idene)amines. N-Alkylimines derived from 2,2,5-
RNH2 (4 equiv)
TiCl4 (0.5 equiv)
Et2O, r.t., 2 h
R
H
1. AcCl (1.2 equiv)
ZnCl2 (0.5 mol%)
70 °C, 5 h
N
O
Cl
Cl
H
or
2. PTSA (4 mol%)
Cl Cl
Cl Cl
2 48%
O
RNH2 (1 equiv)
Et3N (3 equiv)
TiCl4 (0.5 equiv)
Et2O, r.t., 2 h
MeOH, r.t., 16 h
3. Cl2 (5 equiv), DMF
3a (R = i-Pr) 93%
3b (R = t-Bu) 88%
3c (R = Cy) 70%
3d (R = Bn) 75%
1
CHCl3, 65–75 °C, 2 h
Scheme 1
SYNLETT 2008, No. 16, pp 2437–2442
x
x
.x
x
.2
0
0
8
Advanced online publication: 10.09.2008
DOI: 10.1055/s-2008-1078171; Art ID: G16908ST
© Georg Thieme Verlag Stuttgart · New York

2438
M. D’hooghe et al.
LETTER
At first, the application of d-chloroimines 3 for the synthe-
sis of piperidine derivatives was investigated due to the
relevance of the piperidine ring in many agrochemicals
and pharmaceuticals.16 In order to evaluate the reactivity
of aldimines 3 with regard to hydride reagents, N-(2,2,5-
trichloropentylidene)isopropylamine (3a) was treated
with 1.5 equivalents of lithium aluminium hydride in THF
upon reflux for three hours, resulting in a complex reac-
tion mixture. When diethyl ether was used instead of
THF, again a rather complex mixture was obtained. Pre-
parative gas chromatographic analysis of the latter mix-
ture resulted in the isolation of 3-chloropiperidine 4,17
although this heterocycle was not present in the original
O
HN
O
AcNH2 (1.2 equiv)
95 °C, 2 h
Cl
H
Cl
OH
Cl Cl
Cl Cl
6 70%
2
SOCl2
(1.2 equiv)
benzene
Δ, 2 h
O
H
O
N
HN
Et3N (1.1 equiv)
Cl
Cl
Cl
1
benzene, r.t., 15 min
Cl Cl
8 95%
Cl Cl
7 90%
reaction mixture as judged by H NMR. Apparently, cy-
Δ, 15 min
clization of a suitable precursor occurred during gas chro-
matography. Thus, the reaction mixture obtained after
treatment of aldimine 3a with 1.5 equivalents of LiAlH4
in diethyl ether was further treated with five equivalents
of potassium carbonate in chloroform for 16 hours at
room temperature, affording the reactive 3-chloro-1-iso-
propylpiperidine (4) in 32% yield (Scheme 2). Unfortu-
nately, the application of analogous reaction conditions to
N-tert-butylimine 3b did not resulted in the isolation of
the corresponding 3-chloropiperidine. As 3-chloropipe-
ridines belong to the reactive class of b-haloamines, their
instable nature can account for the difficulties associated
with their preparation and isolation. Besides the use of hy-
dride, the reactivity of N-(2,2,5-trichloropentylidene)iso-
propylamine (3a) with regard to methanol was
investigated. Treatment of the latter imine 3a with five
equivalents of sodium methoxide in methanol at reflux for
18 hours resulted in a complex reaction mixture, whereas
no reaction occurred upon stirring for 18 hours at room
temperature. Also the combination of potassium carbon-
ate (3 equiv) and methanol gave a complex reaction mix-
ture after reflux for 18 hours. On the other hand, heating
of imine 3a in methanol for 15 hours under reflux afforded
3,3-dichloro-2-methoxypiperidine 5, which was isolated
by means of distillation (Scheme 2).
Scheme 3
triethylamine in benzene furnished N-(2,2,5-trichloropen-
tylidene)acetamide (8) in excellent yield after 15 minutes
at room temperature and reflux for 15 minutes
(Scheme 3).
The activated imine 8 was found to be an excellent sub-
strate for the addition of a variety of nucleophiles across
the imino moiety, providing an easy access to N-(2,2,5-
trichloropentyl)acetamides bearing a heteroatom at the 1-
position in the N-pentyl chain (Scheme 4). N-[1-(Hetero-
atom)pentyl]amides have been reported before as medici-
nally relevant target compounds, for example, for the
treatment of gastritis and neurodegenerative disorders.19
Treatment of imine 8 with one equivalent of phenol or
pentachlorophenol in diethyl ether at room temperature
afforded the corresponding N-(1-aryloxypentyl)acet-
amides 9a and 9b after 16 hours,20 whereas N-(1-methox-
ypentyl)acetamide (9c) was prepared upon stirring of the
imine 8 in methanol for 16 hours (Scheme 4). In analogy
with the synthesis of the phenol derivative 9a, N-(1-phen-
ylaminopentyl)acetamide (10) and N-(1-phenylsulfanyl-
pentyl)acetamide (11) were prepared in high yields from
imine 8 upon addition of one equivalent of aniline or
thiophenol in diethyl ether after 16 hours at room temper-
ature (Scheme 4). Despite the electrophilic nature of N-
acetylimines, only a limited number of reports dealing
with the systematic addition of the nucleophile across the
imino bond of this type of imines is available.21 Unfortu-
nately, the cyclization of acetamides 9 towards the corre-
sponding N-acetylpiperidines utilizing sodium hydride in
DMF under various reaction conditions was not success-
ful.
In addition to N-alkylimines 3, 2,2,5-trichloropentanal (2)
was transformed into the corresponding activated N-
acetylimine 8 in an efficient three-step approach adapted
from literature protocols.18 Reaction of aldehyde 2 with
1.2 equivalents of acetamide at 95 °C for two hours af-
forded the adduct 6, which was subsequently transformed
into N-(1,2,2,5-tetrachloropentyl)acetamide (7) upon
treatment with 1.2 equivalents of thionyl chloride in ben-
zene under reflux for two hours (Scheme 3). Finally, de-
hydrochlorination of amide 7 through the action of
1. LAH (1.5 equiv)
N
N
N
OMe
Cl
MeOH
Et2O, Δ, 2 h
Cl
H
Δ, 15 h
2. K2CO3 (5 equiv)
CHCl3, r.t., 16 h
Cl
Cl Cl
3a
Cl
5 73%
4 32%
Scheme 2
Synlett 2008, No. 16, 2437–2442 © Thieme Stuttgart · New York

LETTER
Synthesis of Trichlorinated Imines
2439
O
O
H
O
HN
N
HN
ROH (1 equiv)
Et2O, r.t., 16 h
PhNH2 (1 equiv)
Et2O, r.t., 16 h
Cl
OR
Cl
Cl
NHPh
or
Cl Cl
Cl Cl
Cl Cl
MeOH, r.t., 16 h
9a (R = Ph) 88% (in Et2O)
9b (R = C6Cl5) 80% (in Et2O)
9c (R = Me) 88% (in MeOH)
8
10 85%
PhSH (1 equiv)
Et2O, r.t., 16 h
O
HN
Cl
SPh
Cl Cl
11 85%
Scheme 4
In a second stage, the synthesis of different novel a,a,b- Again, the reactivity of aldimines 14 towards hydride re-
trichloroimines was contemplated. Chlorination of ac- agents was evaluated. Whereas no reaction occurred upon
roleine 12 by means of chlorine gas at –10 °C to 0 °C for treatment of N-isopropylimine 14a with 1.5 equivalents of
one hour afforded 2,3-dichloropropanal in 71% yield after sodium borohydride in refluxing methanol for 72 hours
distillation, which was subsequently a-chlorinated with (recovery of the starting material), the addition of 1.5
respect to the carbonyl group towards 2,2,3-trichloropro- equivalents of lithium aluminium hydride to imines 14a,c
panal (13) using 1.1 equivalents of Cl2 with DMF in in diethyl ether afforded 2-(chloromethyl)aziridines 15a,b
chloroform22 and reflux for one hour (Scheme 5). Imina- as selected examples after two hours at room temperature
tion of aldehyde 13 in diethyl ether in the presence of 0.5 (Scheme 6).25 Apparently, the initially formed 2-chloro-2-
equivalents of titanium(IV) chloride furnished novel aldi- (chloromethyl)aziridines 16 through hydride addition and
mines 14a,b upon treatment with four equivalents of the subsequent cyclization are transformed spontaneously
required primary amine, and aldimines 14c,d upon treat- into intermediate azirinium salts 17 upon expulsion of
ment with one equivalent of the corresponding amine in chloride, which are reduced by hydride towards aziridines
the presence of three equivalents of triethylamine and 0.5 15 (Scheme 6).26 2-(Halomethyl)aziridines comprise use-
equivalents of TiCl4 (Scheme 5).23 Up to now, only N- ful substrates for further elaboration in organic chemis-
acyl-substituted
N-(2,2,3-trichloropropylidene)amines try,27 usually prepared via reduction of dihaloaldimines
are known in the literature,24 and no reports on the synthe- towards the corresponding 1-(arylmethyl)- or 1-(alkylme-
sis of a,a,b-trichlorinated N-alkylimines 14 are available. thyl)aziridines.28 Only one method is known to date for
the synthesis of 2-(chloromethyl)aziridines bearing an a-
RNH2 (4 equiv)
TiCl4 (0.5 equiv)
Et2O, r.t., 1 h
R
H
O
N
O
1. Cl2, –10 to 0 °C, 1 h
Cl
H
Cl
or
H
2. Cl2 (1.1 equiv), DMF
CHCl3, Δ, 1 h
Cl Cl
Cl Cl
RNH2 (1 equiv)
Et3N (3 equiv)
TiCl4 (0.5 equiv)
Et2O, r.t., 1 h
12
13 50%
14a (R = i-Pr) 94%
14b (R = t-Bu) 92%
14c (R = Cy) 70%
14d (R = Bn) 73%
Scheme 5
R
H
N
R
NaCNBH3 (0.7 equiv)
AcOH (1 equiv)
LAH (1.5 equiv)
Et2O, r.t., 2 h
N
Cl
NHR
Cl
Cl
Cl Cl
Cl Cl
14
MeOH, r.t., 2 h, or Δ, 2 h
18a (R = i-Pr) 90%
18b (R = t-Bu) 93%
18c (R = Cy) 91%
15a (R = i-Pr) 63%
15b (R = Cy) 61%
R
N
R
+
N
Cl
Cl
Cl
H–
16
17
Scheme 6
Synlett 2008, No. 16, 2437–2442 © Thieme Stuttgart · New York

2440
M. D’hooghe et al.
LETTER
1. Cl2, CCl4
–10 to 0 °C, 1–1.5 h
O
substituent in the N-alkyl group, involving the synthesis
of 1-(alkylamino)-3-chloropropan-2-ols followed by me-
sylation and ring closure in basic medium.29
Cl
O
H
H
2. Cl2 (1.1 equiv), DMF
CHCl3, Δ, 1.5 h
Cl Cl
The addition of other nucleophiles such as methanol and
cyanide onto imine 14a resulted in either the recovery of
the starting material (96 hours reflux in MeOH in the pres-
ence of 3 equiv of Et3N) or in complex reaction mixtures
(2 equiv of KCN in MeOH, r.t. or reflux).
19
20 66%
RNH2 (1 equiv)
Et3N (3 equiv)
TiCl4 (0.5 equiv)
Et2O, r.t., 1 h
RNH2 (4 equiv)
TiCl4 (0.5 equiv)
Et2O, r.t., 1 h
or
If secondary b,b,g-trichloroamines 18 are contemplated,
the use of 0.7 equivalents of sodium cyanoborohydride in
the presence of one equivalent of acetic acid in methanol
proved to be a suitable methodology, affording 2,2,3-
trichloropropylamines 18a–c as selected examples in high
yields (Scheme 6).30 In this transformation, acetic acid fa-
cilitates hydride addition across the imino moiety (elec-
trophilic activation) on the one hand, and reduces the
nucleophilicity of the in situ formed amino group (proto-
nation) on the other hand. b-Halogenated amines com-
prise an extensive class of reactive organic compounds
with plentiful applications, mainly as synthons in organic
chemistry and as anticancer agents in medical chemis-
try.31 Treatment of trichloroamine 18b with sodium hy-
dride in DMF at 70 °C for two hours did not result in the
formation of an aziridine derivative (recovery of the start-
ing material).
R
Cl
Cl
N
NaCNBH3 (0.7 equiv)
AcOH (1 equiv)
NHR
H
Cl Cl
Cl Cl
MeOH, r.t., 2 h, or Δ, 2 h
21a (R = i-Pr) 91%
21b (R = t-Bu) 92%
21c (R = Cy) 70%
21d (R = Bn) 73%
22a (R = t-Bu) 89%
22b (R = Cy) 93%
22c (R = Bn) 91%
Scheme 7
acetic acid in methanol after two hours at room tempera-
ture or reflux (Scheme 7).35
In summary, novel N-(2,2,3-trichloropropylidene)amines,
N-(2,2,3-trichlorobutylidene)amines, and N-(2,2,5-tri-
chloropentylidene)amines were synthesized through imi-
nation of the corresponding aldehydes. Subsequently,
their reactivity with regard to hydride reagents was inves-
tigated, affording a convenient entry into b,b,g-trichloro-
amines through reduction of a,a,b-trichloroimines by
means of cyanoborohydride in methanol in the presence
of acetic acid. The use of lithium aluminium hydride en-
abled the synthesis of a 3-chloropiperidine and 2-(chlo-
romethyl)aziridines starting from the corresponding
trichloroimines. Furthermore, N-(2,2,5-trichloropentyl-
idene)acetamide was used for the first time as a suitable
substrate for the addition of oxygen, nitrogen, and sulfur
nucleophiles across the imino bond in good yields.
Finally, the synthesis of imines derived from 2,2,3-
trichlorobutanal (20) was envisaged. The latter trichlori-
nated butanal 20 could be easily prepared in 66% overall
yield starting from crotonaldehyde 19 following the same
procedure as described for the synthesis of 2,2,3-trichlo-
ropropanal (13), that is, chlorination by means of chlorine
gas at –10 °C to 0 °C, followed by a-chlorination using
1.1 equivalents of Cl2 and DMF in chloroform under re-
flux (Scheme 7). Again, imination of aldehyde 20 in di-
ethyl ether in the presence of 0.5 equivalents of
titanium(IV) chloride furnished novel aldimines 21a,b
utilizing four equivalents of the required primary amine
and 0.5 equivalents of TiCl4, and aldimines 21c,d upon
treatment of aldehyde 20 with one equivalent of the corre-
sponding amine in the presence of three equivalents of tri-
ethylamine and 0.5 equivalents of TiCl4 (Scheme 7).32
Very few information is available in the literature regard-
ing this class of trichlorinated imines, except for a few
imines derived from 2,2,3-trichlorobutanal and, for exam-
ple, 7-aminocephalosporins33 or amides and carbamates.34
Acknowledgment
The authors are indebted to the ‘Fund for Scientific Research –
Flanders (Belgium)’ (FWO.-Vlaanderen) and to Ghent University
(GOA) for financial support.
References and Notes
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(4) De Kimpe, N.; Verhe, R.; De Buyck, L.; Hasma, H.;
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(5) De Kimpe, N.; Verhe, R.; De Buyck, L.; Schamp, N. Bull.
Soc. Chim. Belg. 1977, 86, 663.
Treatment of aldimines 21 with 1.5 equivalents of sodium
borohydride in methanol under reflux for 24 hours led to
the recovery of starting material, and the reaction with 1.5
equivalents of lithium aluminium hydride in diethyl ether
resulted in complex reaction mixtures. Again, the use of
sodium methoxide or potassium cyanide did not afford
any cyclization products. On the other hand, trichlorinated
imines 21 could be easily reduced towards the corre-
sponding secondary b,b,g-trichloroamines 22a–c as se-
lected examples utilizing 0.7 equivalents of sodium
cyanoborohydride in the presence of one equivalent of
(6) De Kimpe, N.; Stanoeva, E.; Verhe, R.; Schamp, N.
Synthesis 1988, 587.
(7) De Kimpe, N.; Yao, Z.; Boeykens, M.; Nagy, M.
Tetrahedron Lett. 1990, 31, 2771.
Synlett 2008, No. 16, 2437–2442 © Thieme Stuttgart · New York

LETTER
Synthesis of Trichlorinated Imines
2441
(8) De Kimpe, N.; Stevens, C.; Virag, M. Tetrahedron 1996, 52,
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Parsons, A. F.; Pinetti, A. Synthesis 2003, 2173.
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(22) De Buyck, L.; Verhe, R.; De Kimpe, N.; Courtheyn, D.;
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(23) N-(2,2,3-Trichloropropylidene)isopropylamine (14a)
Bp 24–26 °C (0.01 Torr). 1H NMR (270 MHz, CDCl3): d =
1.19 (6 H, d, J = 6.3 Hz), 3.52 (1 H, sept, J = 6.3 Hz), 4.26
(2 H, s), 7.77 (1 H, s). 13C NMR (68 MHz, CDCl3): d = 23.3,
51.8, 59.8, 85.0, 155.3. IR (NaCl): n = 1667 (C=N) cm–1.
MS (70 eV): m/z (%) = 201/203/205/207 (1) [M+], 186/188/
190/192 (9), 124/126/128 (20), 116/118 (10), 111 (17), 96/
98 (12), 70 (42), 63 (16), for chlorine isotopes, the reported
relative intensity (%) represents the largest peak.
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1974, 316, 443. (b) Zinner, H.; Siems, W. E.; Erfurt, G.
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329.
(14) N-(2,2,5-Trichloropentylidene)isopropylamine (3a)
Bp 41–42 °C (0.10 Torr). 1H NMR (270 MHz, CDCl3): d =
1.19 (6 H, d, J = 6.3 Hz), 2.18–2.22 (2 H, m), 2.57–2.62 (2
H, m), 3.49 (1 H, septd, J = 6.3, 0.7 Hz), 3.64 (2 H, t, J = 5.9
Hz), 7.75 (1 H, d, J = 0.7 Hz). 13C NMR (68 MHz, CDCl3):
d = 23.5, 28.4, 40.9, 44.2, 59.8, 88.5, 157.1. IR (NaCl):
n = 1667 (C=N) cm–1. MS (70 eV): m/z (%) = 229/231/233/
235 (0.3) [M+], 194/196/198(16), 70(100); for chlorine
isotopes, the reported relative intensity (%) represents the
largest peak.
(15) Sulmon, P.; De Kimpe, N.; Schamp, N. Synthesis 1989, 8.
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3693. (c) Källström, S.; Leino, R. Bioorg. Med. Chem. 2008,
16, 601.
(17) (a) Hammer, C. F.; Heller, S. R.; Craig, J. H. Tetrahedron
1972, 28, 239. (b) Alabugin, I. V.; Manoharan, M.; Zeidan,
T. A. J. Am. Chem. Soc. 2003, 125, 14014.
(18) (a) Ulrich, H.; Tucker, B.; Sayigh, A. A. R. J. Org. Chem.
1968, 33, 2887. (b) Zinner, H.; Siems, W. E.; Erfurt, G.
J. Prakt. Chem. 1974, 316, 63. (c) De Kimpe, N.; Verhé, R.;
De Buyck, L.; Dejonghe, W.; Schamp, N. Bull. Soc. Chim.
Belg. 1976, 85, 763.
(19) (a) Akiyama, Y.; Nakao, M.; Nagahara, N.; Nara, E. JP
09104640 A, 1997; Chem. Abstr. 1997, 127, 44971.
(b) Kundu, M.; Narayana, L.; Kotame, P. M.; Khairatkar-
Joshi, N.; Karnik, P. WO 2007086080 A2, 2007; Chem.
Abstr. 2007, 147, 235166.
(20) N-(2,2,5-Trichloro-1-phenoxypentyl)acetamide (9a)
Mp 130 °C. 1H NMR (270 MHz, CDCl3): d = 2.07 (3 H, s),
2.10–2.60 (4 H, m), 3.59 (2 H, t, J = 6.3 Hz), 6.18 (1 H, d,
J = 10.1 Hz), 6.47 (1 H, d, J = 10.1 Hz), 7.01–7.06 (3 H, m),
7.26–7.34 (2 H, m). 13C NMR (68 MHz, CDCl3): d = 23.3,
27.9, 41.4, 44.0, 81.3, 93.7, 115.9, 122.8, 129.9, 155.5,
170.2. IR (NaCl): n = 3270 (NH), 1660 (C=O) cm–1. MS (70
eV): m/z (%), no [M+] = 149 (19), 112 (18), 110 (20), 77
(100), 49 (22); for chlorine isotopes, the reported relative
intensity (%) represents the largest peak. Anal. Calcd for
C13H16Cl3NO2: C, 48.10; H, 4.97; N, 4.31. Found: C, 48.33;
H, 5.20; N, 4.15.
(25) 2-Chloromethyl-1-isopropylaziridine (15a)
Bp 40–43 °C (15 Torr). Purity: 90% (based on GC). 1H
NMR (270 MHz, CDCl3): d = 1.12 (3 H, d, J = 6.3 Hz), 1.18
(3 H, d, J = 6.3 Hz), 1.40–1.46 (1 H, m), 1.73–1.75 (1 H, m),
1.46 (1 H, sept, J = 6.3 Hz), 1.68–1.74 (1 H, m), 3.31 (1 H,
dd, J = 11.2, 7.6 Hz), 3.58 (1 H, dd, J = 11.2, 4.5 Hz). 13
C
NMR (68 MHz, CDCl3): d = 21.8, 22.3, 33.3, 39.6, 47.2,
60.7. MS (70 eV): m/z (%) = 133/135 (3) [M+], 118/120 (10),
99 (15), 98 (69), 90/92 (15), 56 (100), 55 (10); for chlorine
isotopes, the reported relative intensity (%) represents the
largest peak.
(26) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007,
107, 2080.
(27) (a) D’hooghe, M.; Van Brabandt, W.; De Kimpe, N. J. Org.
Chem. 2004, 69, 2703. (b) D’hooghe, M.; Waterinckx, A.;
De Kimpe, N. J. Org. Chem. 2005, 70, 227. (c) D’hooghe,
M.; Waterinckx, A.; Vanlangendonck, T.; De Kimpe, N.
Tetrahedron 2006, 62, 2295. (d) D’hooghe, M.;
Vanlangendonck, T.; Törnroos, K. W.; De Kimpe, N. J. Org.
Chem. 2006, 71, 4678. (e) D’hooghe, M.; De Kimpe, N.
Synlett 2006, 2089. (f) D’hooghe, M.; De Kimpe, N. Chem.
Commun. 2007, 1275. (g) D’hooghe, M.; Vervisch, K.; De
Kimpe, N. J. Org. Chem. 2007, 72, 7329. (h) D’hooghe,
M.; De Kimpe, N. Arkivoc 2008, (ix), 6.
(28) De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc., Chem.
Commun. 1994, 1221.
(29) Gaertner, V. R. J. Org. Chem. 1970, 35, 3952.
(30) N-(2,2,3-Trichloropropyl)isopropylamine (18a)
Bp 28.5 °C (0.2 Torr). 1H NMR (270 MHz, CDCl3): d = 1.07
(6 H, d, J = 6.3 Hz), 1.10–1.30 (1 H, m), 2.90 (1 H, sept,
J = 6.3 Hz), 3.29 (2 H, s), 4.14 (2 H, s). 13C NMR (68 MHz,
CDCl3): d = 23.2, 48.8, 50.9, 56.6, 90.7. IR (NaCl): n = 3330
(NH) cm–1. MS (70 eV): m/z (%) = 203/205/207/209 (1)
[M+], 188/190/192/194 (23), 72 (100). Anal. Calcd for
C6H12Cl3N: C, 35.23; H, 5.91; N, 6.85. Found: C, 35.11; H,
6.09; N, 6.74; for chlorine isotopes, the reported relative
intensity (%) represents the largest peak.
(21) (a) Shin, C.-G.; Sato, Y.; Yoshimura, J. Bull. Chem. Soc.
Jpn. 1976, 49, 1909. (b) Koeppen, J.; Matthies, D.;
Schweim, H. Liebigs Ann. Chem. 1985, 2383. (c) Sicker,
D.; Hartenstein, H. Z. Chem. 1989, 29, 169. (d) Zabirov,
N. G.; Galyautdinov, N. I.; Shcherbakova, V. A.; Cherkasov,
R. A. Zh. Obshch. Khim. 1990, 60, 1247; Chem. Abstr. 1991,
114, 6634. (e) Zabirov, N. G.; Cherkasov, R. A. Zh. Obshch.
Khim. 1990, 60, 1251; Chem. Abstr. 1990, 113, 231520.
(f) Booth, B. L.; Cabral, I. M.; Dias, A. M.; Freitas, A. P.;
(31) D’hooghe, M.; De Kimpe, N. Tetrahedron 2008, 64, 3275.
(32) N-(2,2,3-Trichlorobutylidene)isopropylamine (21a)
1H NMR (270 MHz, CDCl3): d = 1.21 (6 H, d, J = 6.3 Hz),
1.78 (3 H, d, J = 6.5 Hz), 3.55 (1 H, sept, J = 6.3 Hz), 4.69
(1 H, q, J = 6.5 Hz), 7.78 (1 H, s). 13C NMR (68 MHz,
CDCl3): d = 20.5, 23.3, 23.4, 60.2, 62.3, 89.8, 156.6. IR
(NaCl): n = 1663 (C=N) cm–1. MS (70 eV): m/z (%) = 215/
217/219/221 (2) [M+], 57 (100), 56 (3); for chlorine isotopes,
Synlett 2008, No. 16, 2437–2442 © Thieme Stuttgart · New York

2442
M. D’hooghe et al.
LETTER
the reported relative intensity (%) represents the largest
peak.
(33) Atsumi, K.; Katano, K.; Nishihata, K.; Kai, F.; Akita, E.;
Niida, T. Tetrahedron Lett. 1982, 23, 2977.
(34) Drach, B. S.; Mis’kevich, G. N. Zh. Org. Khim. 1975, 11,
316; Chem. Abstr. 1975, 82, 125017.
(35) N-(2,2,3-Trichlorobutyl)-tert-butylamine (22a)
1H NMR (270 MHz, CDCl3): d = 1.11 (9 H, s), 1.55 (1 H, br
s), 1.76 (3 H, d, J = 6.5 Hz), 3.26 and 3.44 (2 × 1 H, 2 d,
J = 13.2 Hz), 4.75 (1 H, q, J = 6.5 Hz). 13C NMR (68 MHz,
CDCl3): d = 20.2, 29.3, 50.6, 55.1, 60.5, 96.4. IR (NaCl):
n = 3330 (NH) cm–1. MS (70 eV): m/z (%), no [M+] = 216/
218/220/222 (61), 181/183/185 (15), 140/142/144 (11), 118/
120 (17), 87 (13), 86 (100), 70 (14), 58 (45), 57 (45), 53 (11).
Anal. Calcd for C8H16Cl3N: C, 41.31; H, 6.93; N, 6.02.
Found: C, 41.47; H, 7.13; N, 5.92; for chlorine isotopes, the
reported relative intensity (%) represents the largest peak.
Synlett 2008, No. 16, 2437–2442 © Thieme Stuttgart · New York