2-(Dichloromethylene)azetidines: Stable strained cyclic enamines

Article abstract of DOI:10.1055/s-2008-1072747

2-(Dichloromethylene)azetidines constitute a new class of stable exocyclic enamines. The synthesis of these inductively stabilized N-alkyl-2- methyleneazetidines entails the imination of β-halo ketones, followed by α′,α′-dichlorination and subsequent 1,4- dehydrohalogenation. The synthesis of these azetidines is easy and can be performed on multigram scale in good yield. 2-(Dichloromethylene)azetidines undergo smooth reactions towards electrophilic reagents as evidenced by the ready alkoxyhalogenation and hydrolysis to pyrrolidin-3-ones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072747

1394
LETTER
2-(Dichloromethylene)azetidines: Stable Strained Cyclic Enamines
2
-(Dichlorome
v
thylene)aze
t
e
idines: Stab
n
le Strained Cyclic
M
E
namines angelinckx,1 Marc Boeykens, 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 5 February 2008
es specific reactivity to the 2-(dichloromethylene)azet-
Abstract: 2-(Dichloromethylene)azetidines constitute a new class
idines. The combination of an enamine and a vinyl halide
offers additional synthetic possibilities. In the present re-
port, the straightforward synthesis of 2-(dichloromethyl-
of stable exocyclic enamines. The synthesis of these inductively sta-
bilized N-alkyl-2-methyleneazetidines entails the imination of b-
halo ketones, followed by a¢,a¢-dichlorination and subsequent 1,4-
dehydrohalogenation. The synthesis of these azetidines is easy and ene)azetidines, as useful new building blocks, by base-
can be performed on multigram scale in good yield. 2-(Dichloro-
methylene)azetidines undergo smooth reactions towards electro-
philic reagents as evidenced by the ready alkoxyhalogenation and
induced ring closure of b-chloro N-alkylketimines is de-
scribed.
The synthesis of b-chloro ketimines 1 from the corre-
sponding b-chloro ketones through condensation with a
primary amine occurs in the presence of titanium(IV)
chloride.9 a¢,a¢,b-Trichloro ketimines 2 form a group of
unknown compounds that are easily prepared in high
yields from b-chloro ketimines 1 through reaction with N-
chlorosuccinimide in CCl4 under reflux (Scheme 1).10 The
reaction of trichloro imines 2a,b with sodium methoxide
in methanol (2 M) resulted in the formation of 1-alkyl-2-
(dichloromethylene)-3,3-dimethylazetidines 3, without
the formation of side products.11 These functionalized
azetidines 3 are stable and can be distilled in vacuo with-
out decomposition, upon which a colorless, clear liquid is
obtained with high purity (up to 25 g). The mechanism of
this reaction to new 2-methyleneazetidines 3 involves ini-
tial deprotonation in a¢-position to form an ambident nu-
cleophilic 1-azaallylic anion,12 and cyclization through
N–C bond formation. The nucleophilic character of a de-
localized N-anion seems insufficient to overcome the ri-
gidity of a cyclohexyl group in a-position as in 2c.
hydrolysis to pyrrolidin-3-ones.
Key words: imines, methyleneazetidines, enamines, cyclizations,
heterocycles
2-Methyleneazetidines, as the higher homologues of the
more intensively investigated 2-methyleneaziridines,2
form a class of constrained cyclic enamines which remain
rather unexplored due to their limited stability. Only 2-
methyleneazetidines substituted with electron-withdraw-
ing groups at nitrogen, e.g., N-tosyl,3 N-acyl,4 N-alkoxy-
carbonyl, or N-aryl,5 or a group which conjugates with the
carbon–carbon double bond (e.g., alkoxycarbonyl, ni-
trile),6 are stable. It was envisaged that, in contrast with 2-
methyleneazetidines unsubstituted at the double bond,7 or
with electron-donating groups at the double bond,8 2-
(dichloromethylene)azetidines bearing N-alkyl substitu-
ents would be stable. This stability is imparted by the elec-
tron-withdrawing effect of both halogens. It is also clear
that the presence of the b,b-dihaloenamine moiety impos-
R2
NCS
N
2 M NaOMe
(5 equiv)
R2
Cl
Cl
N
(2.1 equiv)
R1
R1
R1
R1
Cl
MeOH
Δ, 3.5–4 h
R2
CCl4
N
Δ, 1.5–4 h
Cl
Cl
Cl
1a R1 = Me, R2 = Et
2a–c (78–97%)
3a (58–64%)
3b (75%)
1b R1 = Me, R2 = i-Pr
1c R1–R1 = (CH2)5, R2 = Et
1) 2 M HCl (10 equiv)
H2O/CH2Cl2
r.t. or Δ, 1 h
2) NaOH
O
O
Cl
+
OH
Cl
NHR2
N
4a (–)
5a (80%)
4b (no yield determined, unstable in pure form)
Scheme 1
SYNLETT 2008, No. 9, pp 1394–1398
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072747; Art ID: G05008ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
2-(Dichloromethylene)azetidines: Stable Strained Cyclic Enamines
1395
CHCl2
N
CCl3
N
LiAlH4 (1 equiv)
NaCNBH3 (2 equiv)
Et2O, Δ, 17 h
AcOH (1 equiv)
MeOH, 0 °C, 1 h
(97%)
6 (74–97%)
9 (74%)
Cl
Cl
MeO
CCl3
N
NaCNBH3 (2 equiv)
NCS (1 equiv)
N
AcOH (1 equiv)
MeOH, r.t., 2 h
MeOH, r.t., 30 min
3a
7 (86%)
Cl
Cl
Hg(OAc)2
(1.2 equiv)
PhSeBr (1.1 equiv)
MeOH, r.t., 30 min
MeO
MeO
COOMe
N
X
1) BuLi (1.2 equiv)
THF, –78 °C, 1 h
2) MeI (1.2 equiv)
N
MeOH, r.t.
or
NBS (1.05 equiv)
MeOH, r.t., 30 min
THF, –78 °C – r.t., 1 h
8 (X = Br, SePh)
10
Hg(OAc)2 (2 equiv)
MeOH, r.t., 17 h
O
Cl
OMe
OMe
SiO2
r.t.
N
N
O
N
13 (61%)
11 (52–85%)
12 (75%) E/Z = 85:15
Scheme 2
Prolonged heating and/or the use of stronger bases (KOt- duced smoothly by NaCNBH3 generating the 2-(dichlo-
Bu in THF or t-BuOH, LDA in THF) also cannot establish romethyl)azetidine
in good yield (Scheme 2).14
any reaction leading to a complete recovery of the starting Combination of azetidine 3a with N-halo succinimides
6
material 2c.
(NXS, X = Cl, Br) or phenylselenyl bromide in methanol
yielded the alkoxyhalogenation and alkoxyselenenylation
adducts as reactive intermediates (8 when X = Br or SePh)
or as stable end product, that is, 2-methoxy-2-(trichlorom-
ethyl)azetidine 7. In an attempt to reductively replace
methoxide in adduct 7, the reluctance towards hydride re-
duction was encountered again. Also in this case
NaCNBH3 was the reagent of choice to establish the con-
version into 2-(trichloromethyl)azetidine 9 in 74% yield.
Moreover, azetidine 6 results from the reduction of the 2-
trichloromethyl derivative 9 by LiAlH4 in diethyl ether
under reflux for 17 hours. Because the adducts 8 arising
from the reaction with NBS and PhSeBr occurred to be
more reactive and less prone to isolation, they were used
in situ for further transformation. With the addition of
mercury(II) acetate to these adducts, a metal-assisted sol-
volysis into the azetidine-2-carboxylic ester 10 was postu-
lated.9b,15 Both adducts followed another reaction path
leading to 2-pyrrolidinone 11.16 Under the same reaction
conditions the more stable 2-(trichloromethyl)-2-meth-
oxyazetidine 7 did not react. A last topic concerning 2-
(dichloromethylene)azetidines 3 involved lithiation at the
b-carbon atom in the presence of alkyllithiums via halo-
gen–metal exchange.17 Reaction of azetidine 3a with a
small excess of n-butyllithium at low temperature creates
a highly reactive species that was alkylated with methyl
iodide. The methyleneazetidine 12 (E/Z = 85:15) formed
turned out to be quite unstable and hydrolyzed completely
on silica gel chromatography yielding the 3-pyrrolidinone
The elusiveness of 2-(dichloromethylene)azetidines 3
made them attractive to evaluate their chemical behavior.
Azetidines 3, behaving as b-halo enamines,13 are apt to
undergo smooth reactions towards electrophilic reagents
as evidenced by the ready hydrolysis of these compounds
to b-amino ketone 4 or pyrrolidin-3-one 5 (Scheme 1).
The first isolated compound, after acid hydrolysis of 3a
for one hour under reflux and neutralization, was identi-
fied as 1-ethyl-4,4-dimethyl-2-hydroxypyrrolidine-3-one
(5a). The presumption that pyrrolidine-3-one 5 is already
a secondary reaction product, obtained through ring clo-
sure of the intermediate formed b-(N-alkyl)amino ketone
4a, was confirmed by subjecting azetidine 3a briefly to
the hydrolytic conditions (1 min) and 1H NMR analysis of
the reaction mixture, after neutralization, without further
work up. In this way, b-(N-alkyl)amino ketone 4a was
identified as the only reaction product present, as a labile
compound. Acid hydrolysis of N-isopropyl-2-(dichloro-
methylene)-3,3-dimethylazetidine (3b) afforded, after
neutralization, the corresponding free amine 4b as the
only reaction product, which did not further cyclize like
the ethyl-substituted derivative 4a.
Due to the extreme lability of amine 4b it had to be stored
in solution (CH2Cl2) and at low temperature (–20 °C).
Azetidines 3 lack reactivity towards nucleophilic re-
agents, for example, hydride donors such as LiAlH4 and
NaBH4. However, in the presence of acetic acid N-ethyl-
2-(dichloromethylene)-3,3-dimethylazetidine (3a) is re-
Synlett 2008, No. 9, 1394–1398 © Thieme Stuttgart · New York

1396
S. Mangelinckx et al.
LETTER
OMe
OMe
2 M NaOMe
(5 equiv)
N
N
NaOMe
Br
OMe
MeOH, Δ, 2 h
N
Cl
Cl
14a
15a
16a
H2O
O
O
O
Na2CO3 or
K2CO3, MeOH
1) HCl (g)
Et2O
OMe
OMe
OR
N
Cl
or
2) SO2Cl2
(1.1 equiv)
NHEt.HCl
NHEt
NaOH, H2O
CH2Cl2
r.t., 15 h
18
17a (85%)
5a R = H (79%)
5b R = Me (68%)
Scheme 3
Scheme 4
Scheme 5
1) 2 M NaOMe
(5 equiv)
MeOH, Δ, 2 h
N
N
O
Br
OMe
OMe
+
2) H2O
Cl
Cl
NHEt
14b
15b (50%)
17b (50%)
Cl
Cl
N
N
MeO
MeO
MeO
KOt-Bu (2 equiv)
NCS (2.1 equiv)
Cl
MeO
MeO
N
CCl4, r.t., 6 h
t-BuOH, Δ, 17 h
MeO
Cl
Br
Br
19
20 (97%)
21 (60%)
13 via an acid-catalyzed sequence of ring opening and ylpyrrolidin-3-one (5a) or its methyl ether 5b were
ring closure.
formed, respectively. Also in this case, the reaction course
was influenced by the rigidity of the cyclohexyl group.
Under similar reaction conditions as applied for the dime-
thyl derivative 14a, only half of the a-alkoxy imine 15b
underwent rearrangement into the corresponding b-amino
ketone 17b (Scheme 4).
To broaden the scope, attempts were made to cyclize other
a¢,b-halogenated imines into halogenated 2-methylene-
azetidines. Compared with the dichloro derivatives 2, the
reaction path for the a¢-monobrominated ketimines 14 is
altered.9b Treatment of a-bromo-b¢-chloroketimine 14a
with an excess of 2 M NaOMe in MeOH results in the for- With the synthesis of the b-bromo-a,a-dimethoxy
mation of the b-(N-alkylamino) ketone 17a in 85% yield ketimines 19 again a new type of bifunctional imino com-
(Scheme 3). The latter is formed by an initial displace- pound was introduced.18 The presence of an acetal moiety
ment of bromine. The intermediate a¢-alkoxy imine 15a created new possibilities for further transformations.
cyclizes through nucleophilic addition of methoxide Treatment of b-bromo imine 19 with 2.1 equivalents of
across the imine bond and subsequent intramolecular sub- NCS in CCl4 at room temperature afforded the dichloro-
stitution. The resulting hemiaminal 16a is unstable and methyl ketimine 20 in nearly quantitative yield
opens during workup to form the b-amino ketone 17a.
(Scheme 5). The synthesis of the corresponding 2-
(dichloromethylene)azetidine 21, under the conditions ap-
plied formerly for the conversion of trichloro ketimines 2,
could not be established when applied to the dimethoxy
ketimine 20. A stronger base and higher temperature was
necessary to induce the cyclization of the halogenated
imine 20 into 3,3-dimethoxy-2-(dichloromethylene)azeti-
dine 21, which was obtained in 60% yield.19
The use of sterically hindered bases only leads to complex
reaction mixtures. Chlorination of the a-alkoxy ketone
17a is sluggish and only complete after stirring overnight.
The protection of the amino moiety as its hydrochloride is
necessary to prevent it from interacting with sulfuryl chlo-
ride. Upon neutralization of the a-chloro ether 18 ring clo-
sure spontaneously occurred. Depending on whether the
reaction mixture is neutralized by addition of 1 M NaOH In conclusion, starting from a¢,a¢-dichloro-b-halo imines,
or Na2CO3 in MeOH, N-ethyl-2-hydroxy-4,4-dimeth- new and surprisingly stable 2-(dichloromethylene)azet-
Synlett 2008, No. 9, 1394–1398 © Thieme Stuttgart · New York

LETTER
2-(Dichloromethylene)azetidines: Stable Strained Cyclic Enamines
evaporation of the solvent in vacuo afforded the
1397
idines were made accessible by a base-induced cycliza-
tion. These stable strained azaheterocycles were prone to
react with electrophilic species as exemplified by rear-
rangement into pyrrolidinones upon acid hydrolysis or
mercuric acetate induced solvolysis of alkoxybrominated
or alkoxyselenenylated adducts. Acid-mediated reduction
of 2-(dichloromethylene)azetidines or their alkoxychlori-
nated adduct with sodium cyanoborohydride led to 2-
(dichloromethyl)- and 2-(trichloromethyl)azetidines.
trichloroketimines 2 in high purity (>96%), which were used
as such in the next step.
N-(1,1,4-Trichloro-3,3-dimethyl-2-butylidene)isopropyl-
amine (2b): yield 95–97%; mp 42 °C.1H NMR (270 MHz,
CDCl3): d = 1.18 [d, 6 H, J = 6 Hz, (CH3)2CH], 1.28 [s, 6 H,
(CH3)2], 3.67 (s, 2 H, CH2Cl), 4.70 [sept, 1 H, J = 6 Hz,
CH(CH3)2], 6.23 (s, 1 H, CHCl2). 13C NMR (68 MHz,
CDCl3): d = 22.8, 23.4, 44.8, 50.9, 53.7, 59.3, 161.2. IR
(KBr): nC=N = 1655 cm–1. MS (EI, 70 eV): m/z (%) = 242/4/
6/8(1) [M+], 228/30/2/4 (1), 208/10/2 (2), 207/9/11/3 (1),
192/4/6/8 (1), 166 (1), 160/2 (19), 152/4/6 (3), 130/2 (1),
118/20 (100), 110 (2), 91/3 (36), 82 (7), 77 (3), 75 (7), 69 (7),
68 (4), 67 (3), 66 (3), 65 (4), 63 (4), 56 (11), 55 (34), 54 (4),
53 (6), 51 (4), 49 (4), 44 (6), 43 (70), 42 (13), 41 (41), 40 (4),
39 (19).
Acknowledgment
The authors are indebted to the Research Foundation - Flanders
(FWO-Vlaanderen) and Ghent University (GOA) for financial sup-
port of this research.
(11) General Procedure
Trichloroketimine 2 (0.005 mol) was dissolved in 2 M
NaOMe in MeOH (12.5 mL, 0.025 mol). The solution was
stirred under reflux for 4 h, after which the reaction mixture
was poured into a mixture of H2O (30 mL) and CH2Cl2 (20
mL). The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (2 × 15 mL). The combined
organic layers were dried (K2CO3), filtered, and evaporated
under reduced pressure to afford the 2-methyleneazetidine 3
(purity >96%). Distillation under vacuum afforded the
analytically pure 2-methyleneazetidine 3.
References and Notes
(1) Postdoctoral Fellow of the Research Foundation – Flanders
(FWO-Vlaanderen).
(2) (a) Montagne, C.; Shiers, J. J.; Shipman, M. Tetrahedron
Lett. 2006, 47, 9207. (b) Montagne, C.; Prevost, N.; Shiers,
J. J.; Prie, G.; Rahman, S.; Hayes, J. F.; Shipman, M.
Tetrahedron 2006, 62, 8447. (c) Shiers, J. J.; Clarkson, G.
J.; Shipman, M.; Hayes, J. F. Chem. Commun. 2006, 649.
(d) Hayes, J. F.; Shipman, M.; Twin, H. J. Org. Chem. 2002,
67, 935. (e) Prevost, N.; Shipman, M. Org. Lett. 2001, 3,
2383.
(3) (a) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365. (b) Zhao, G.-L.;
Shi, M. J. Org. Chem. 2005, 70, 9975. (c) Zhao, G.-L.;
Huang, J.-W.; Shi, M. Org. Lett. 2003, 5, 4737.
(d) Martinez, I.; Howell, A. R. Tetrahedron Lett. 2000, 41,
5607.
(4) Van Eijk, P. J. S. S.; Trompenaars, W. P.; Reinhoudt, D. N.;
Harkema, S. Recl. Trav. Chim. Pays-Bas 1988, 107, 52.
(5) (a) Sulmon, P.; De Kimpe, N.; Schamp, N. J. Org. Chem.
1988, 53, 4462. (b) De Kimpe, N.; Boeykens, M. J. Org.
Chem. 1994, 59, 5189. (c) Abbaspour Tehrani, K.;
De Kimpe, N. Tetrahedron Lett. 2000, 41, 1975.
(6) (a) Pifferi, G.; Consonni, P.; Testa, E. Ann. Chim. (Rome,
Italy) 1968, 58, 1283; Chem. Abstr. 1969, 70, 68015j.
(b) Pifferi, G.; Vigevani, A.; Consonni, P. Ann. Chim.
(Rome, Italy) 1969, 59, 658; Chem. Abstr. 1970, 72,
90159x. (c) Schaumann, E.; Mrotzek, H. Tetrahedron 1979,
35, 1965. (d) Baldwin, J. E.; Edwards, A. J.; Farthing, C. N.;
Russell, A. T. Synlett 1993, 49. (e) Lee, H. K.; Kim, J.; Pak,
C. S. Tetrahedron Lett. 1999, 40, 2173. (f) Jiang, J.; Shah,
H.; DeVita, R. J. Org. Lett. 2003, 5, 4101. (g) Ishar, M. P.
S.; Kumar, K.; Kaur, S.; Kumar, S.; Girdhar, N. K.; Sachar,
S.; Marwaha, A.; Kapoor, A. Org. Lett. 2001, 3, 2133.
(h) Peng, W.; Zhao, J.; He, P.; Zhu, S. Synlett 2006, 296.
(i) Danion-Bougot, R.; Danion, D.; Carrié, R. Tetrahedron
1985, 41, 1953.
1-Ethyl-2-(dichloromethylene)-3,3-dimethylazetidine (3a):
yield 58–64%; bp 40–43 °C (0.075 mmHg). 1H NMR (270
MHz, CDCl3): d = 1.06 (t, 3 H, J = 7.2 Hz, CH2CH3), 1.37
[s, 6 H, (CH3)2], 3.18 (s, 2 H, CH2), 3.22 (q, 2 H, J = 7.2 Hz,
CH2CH3). 13C NMR (68 MHz, CDCl3): d = 12.0, 23.2, 41.2,
41.9, 60.4, 86.5, 152.8. IR (NaCl): nC=C = 1665 cm–1. MS
(EI, 70 eV): m/z (%) = 193/5/7 (30) [M+], 178/80/2 (7), 158/
60 (8), 137/9/41 (12), 109/11/3 (36), 101/3 (30), 97 (100), 69
(94), 65 (15), 58 (15), 57 (24), 56 (18), 55 (13), 54 (9), 42
(76), 41 (27), 39 (21). Anal. Calcd (%) for C8H13Cl2N: C,
49.50; H, 6.75; N, 7.22. Found: C, 49.32; H, 6.98; N, 7.16.
(12) Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. Rev.
2004, 104, 2353.
(13) For a review on b-haloenamines see: De Kimpe, N.;
Schamp, N. Org. Prep. Proced. Int. 1983, 15, 71.
(14) Synthesis of 1-Ethyl-2-(dichloromethyl)-3,3-
dimethylazetidine (6)
To an ice-cooled solution of 1-ethyl-2-(dichloromethylene)-
3,3-dimethylazetidine (3a, 3.9 g, 20 mmol) in MeOH was
added NaCNBH3 (2.5 g, 40 mmol), followed by AcOH (1.2
g, 20 mmol). The mixture was stirred for 1 h at 0 °C, poured
into H2O, and extracted with CH2Cl2. The combined organic
extracts were dried (MgSO4) and evaporated under reduced
pressure to yield 3.81 g (97%) of 2-(dichloromethyl)-3,3-
dimethylazetidine (6). Purification can be performed by
means of flash chromatography: Rf = 0.47 (Et2O–pentane,
1:2). 1H NMR (270 MHz, CDCl3): d = 0.95 (d × d, 3 H,
J = 7.03, 7.41 Hz, CH2CH3), 1.19 and 1.26 [each s, each 3 H,
(CH3)2], 2.31 [d × q, 1 H, J = 11.41, 7.03 Hz, CH(H)CH3],
2.46 [d, 1 H, J = 6.56 Hz, CH(H)N], 3.07 (d, 1 H, J = 9.84
Hz, CHN), 3.11 [d, 1 H, J = 6.58 Hz, CH(H)N], 3.19 [d × q,
1 H, J = 11.41, 7.41 Hz, CH(H)CH3], 5.70 (d, 1 H, J = 9.84
Hz, CHCl2). 13C NMR (68 MHz, CDCl3): d = 11.6, 21.6,
28.2, 35.4, 52.4, 62.7, 73.3, 79.4. IR (NaCl): n = 2965, 2825,
1463, 1382, 1368, 1350, 1252, 1208, 1163, 1142, 1108,
1012, 790, 730 cm–1. MS (EI, 70 eV): m/z (%) = 195/7/9 (4)
[M+], 180/2/4 (2), 160/2 (2), 140/2/4 (12), 112 (63), 103/5
(6), 75 (3), 67 (5), 58 (31), 57 (31), 56 (100), 55 (8), 43 (5),
42 (63), 41 (21). Anal. Calcd (%) for C8H15Cl2N: C, 48.99;
H, 7.71; N, 7.14. Found: C, 48.76; H, 7.90; N, 7.01.
(7) Sulmon, P.; De Kimpe, N.; Schamp, N. Tetrahedron 1989,
45, 2937.
(8) Wasserman, H. H.; Lipshutz, B. H.; Tremper, A. W.; Wu, J.
S. J. Org. Chem. 1981, 46, 2991.
(9) (a) Sulmon, P.; De Kimpe, N.; Verhé, R.; De Buyck, L.;
Schamp, N. Synthesis 1986, 192. (b) Boeykens, M.;
De Kimpe, N.; Abbaspour Tehrani, K. J. Org. Chem. 1994,
59, 6973.
(10) General Procedure
To a solution of imine 1 (3 mmol) in CCl4 (10 mL) was
added NCS (0.84 g, 6.3 mmol) and the heterogeneous
mixture was stirred under reflux for 1.5–4 h. Filtration and
Synlett 2008, No. 9, 1394–1398 © Thieme Stuttgart · New York

1398
S. Mangelinckx et al.
LETTER
(18) Salgado, A.; Dejaegher, Y.; Verniest, G.; Boeykens, M.;
(15) Boeykens, M.; De Kimpe, N. Synth. Commun. 1992, 22,
3285.
Gauthier, C.; Lopin, C.; Abbaspour Tehrani, K.; De Kimpe,
(16) Synthesis of 1-Ethyl-3,3-dimethoxy-4,4-
dimethylpyrrolidin-2-one (11)
N. Tetrahedron 2003, 59, 2231.
(19) Synthesis of 1-Isopropyl-2-(dichloromethylene)-3,3-
dimethoxyazetidine (21)
To a solution of 1-ethyl-2-(dichloromethylene)-3,3-
dimethylazetidine (3a, 0.97 g, 5 mmol) in MeOH was added
PhSeBr (1.3 g, 5.5 mmol) followed after 30 min by
Hg(OAc)2 (3.18 g, 10 mmol). The mixture was stirred for
17 h, filtered, and the solvent evaporated partially under
reduced pressure. The residue was poured into H2O and
extracted with CH2Cl2. The combined organic extracts were
dried (MgSO4) and evaporated in vacuo. The residual oil is
chromatographed on silica gel to yield 0.52 g (52%) of
pyrrolidin-2-one (11). Rf = 0.17 (EtOAc–hexane, 1:1). 1H
NMR (270 MHz, CDCl3): d = 1.09 (t, 3 H, J = 7.08 Hz,
CH2CH3), 1.15 [s, 6 H, (CH3)2], 2.89 (s, 2 H, CH2N), 3.33 (q,
To a solution of KOt-Bu (3.37 g, 0.03 mol) in t-BuOH (50
mL) was added N-(4-bromo-1,1-dichloro-3,3-dimethoxy-2-
butylidene)isopropylamine (20, 4.82 g, 0.015 mol) and the
resulting mixture was stirred at reflux for 17 h. After
cooling, pentane (100 mL) was added as a result of which a
fine suspension was formed. The suspension was stored at
–20 °C for 15 h, decanted, and the residue washed again with
some pentane (20 mL). The pentane fractions are combined
and the solvent was evaporated in vacuo. The residue, still
containing some t-BuOH, was distilled, affording 2.15 g
(60%) of pure 1-isopropyl-2-(dichloromethylene)-3,3-
dimethoxyazetidine (21); bp 65–67 °C (0.01 mmHg). 1H
NMR (270 MHz, CDCl3): d = 1.08 [d, 6 H, J = 6.60 Hz,
CH(CH3)2], 3.41 [s, 6 H, (OCH3)2], 3.43 (s, 2 H, NCH2), 4.10
(sept, 1 H, J = 6.60 Hz, NCH). 13C NMR (68 MHz, CDCl3):
d = 18.8, 45.8, 51.8, 53.6, 89.5, 100.4, 145.1. IR (NaCl):
2 H, J = 7.08 Hz, CH2CH3), 3.37 [s, 6 H, C(OMe)2]. 13
C
NMR (68 MHz, CDCl3): d = 12.3, 21.5, 37.4, 41.3, 50.7,
56.6, 101.6, 168.3. IR (NaCl): nC=O = 1700 (br) cm–1. MS
(EI, 70 eV): m/z (%) = no [M+], 171 (63), 156 (86), 116 (36),
115 (30), 102 (70), 101 (47), 99 (91), 88 (13), 87 (20), 85
(26), 75 (84), 74 (35), 73 (2), 70 (13), 69 (31), 67 (13), 59
(96), 58 (14), 57 (11), 56 (100), 55 (69), 45 (15), 44 (22), 43
(41), 42 (61), 41 (87), 40 (70). Anal. Calcd (%) for
C10H19NO3: C, 59.68; H, 9.52; N, 6.96. Found: C, 59.65; H,
9.38; N, 7.04.
n
C=C = 1663 cm–1. MS (EI, 70 eV): m/z (%) = 239/41/43 (55)
[M+], 224/6/8 (63), 208/10/12 (29), 182/4/6 (100), 166/68/70
(11), 151/3/5 (23), 150/2/4 (60), 139/41/43 (13), 133/5 (33),
125 (13), 124 (21), 123 (23), 122 (29), 109/11/13 (51), 88
(35), 87 (19), 59 (25), 58 (23), 57 (19), 56 (15), 45 (38), 44
(10), 42 (27), 41 (46), 40 (21). Anal. Calcd (%) for
C9H15Cl2NO2: C, 45.02; H, 6.30; N, 5.83. Found: C, 44.83;
H, 6.51; N, 5.71.
(17) (a) Richards, K. D.; Kolar, A. J.; Srinivasan, A.; Stephenson,
R. W.; Olsen, R. K. J. Org. Chem. 1976, 41, 3674.
(b) Duhamel, L.; Poirier, J.-M. J. Am. Chem. Soc. 1977, 99,
8356. (c) Duhamel, L.; Poirier, J.-M. J. Org. Chem. 1979,
44, 3585.
Synlett 2008, No. 9, 1394–1398 © Thieme Stuttgart · New York

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