Synthesis of 2,3-disubstituted pyrroles and pyridines from 3-halo-1-azaallylic anions

Article abstract of DOI:10.1021/jo000724t

A new synthesis of 2,3-disubstituted pyrroles and pyridines is described. The reaction of 3-halo-1-azaallylic carbanions, regiospecifically generated from α-halogenated ketimines, with ω-iodoazides led to the regiospecific formation of ω-azido-α-haloketimines. Treatment of these functionalized imines with tin(II) chloride afforded halogenated five- and six-membered cyclic imines, which were transformed under mild conditions into 2,3-disubstituted pyrroles and pyridines. The stereoselective reduction of 2,3-dialkyl-3-chloro-1-pyrrolines to afford cis-2,3-dialkyl-3-chloropyrrolidines is also reported.

Full text of DOI:10.1021/jo000724t

J . Org. Chem. 2001, 66, 53-58
53
Syn th esis of 2,3-Disu bstitu ted P yr r oles a n d P yr id in es fr om
3-Ha lo-1-a za a llylic An ion s
Wim Aelterman,† Norbert De Kimpe,*,† Vladimir Tyvorskii,‡ and Oleg Kulinkovich‡
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences,
Ghent University, Coupure Links 653, B-9000 Ghent, Belgium, and Department of Organic Chemistry,
Belarussian State University, Fr. Scorina Avenue 4, 220050 Minsk, Belarus
norbert.dekimpe@rug.ac.be
Received May 12, 2000
A new synthesis of 2,3-disubstituted pyrroles and pyridines is described. The reaction of 3-halo-
1-azaallylic carbanions, regiospecifically generated from R-halogenated ketimines, with ω-iodoazides
led to the regiospecific formation of ω-azido-R-haloketimines. Treatment of these functionalized
imines with tin(II) chloride afforded halogenated five- and six-membered cyclic imines, which were
transformed under mild conditions into 2,3-disubstituted pyrroles and pyridines. The stereoselective
reduction of 2,3-dialkyl-3-chloro-1-pyrrolines to afford cis-2,3-dialkyl-3-chloropyrrolidines is also
reported.
Sch em e 1
In tr od u ction
Pyrroles and pyridines, and their di- and tetrahydro
derivatives, are very important compounds as they occur
in a large number of natural products and display a
variety of physiological activities.1,2
In the present paper, a new entry into 2,3-disubstituted
pyrroles (also containing a chloro atom at the 3-position)
and pyridines is disclosed.
Several types of these N-heterocycles are used in
agrochemistry and in the pharmaceutical field, which
explains the interest in new and better strategies for the
construction of these compounds. For example, roseo-
phillin 1 is a 2-substituted-3-chloropyrrole containing
antileukemic compound, isolated from Streptomyces
griseoviridis,3 while 3-chloro-2-(3-nitro-4-chlorophenyl)
pyrrole 2 has bactericidal properties.4
synthesis of physiologically active products, such as
antitumor compounds.5 Some simple 2- and 3-alkyl(aryl)-
pyridines also have been identified as natural flavor
compounds of cocoa,6 tobacco,6 and orange oil.7
From a retrosynthetic point of view, 2,3-disubstituted
pyrroles and pyridines 8 or 9 can be synthesized via a
reaction sequence involving R-alkylation of carbonyl
compounds 5 (Z ) O) or imines 5 (Z ) NR) with suitable
N-protected ω-bromoamines, subsequent N-deprotection,
ring closure, and final oxidation or dehydrohalogenation
(Scheme 1). This seems to be a very attractive route
because of the wide variety of substituents (R1 and R2)
that can be used, originating from readily accessible
starting materials. However, nonhalogenated 1-pyrro-
lines 7 (n ) 1) and 2,3,4,5-tetrahydropyridines 7 (n ) 2)
(3) Hayakawa, Y.; Kawasaki, K.; Seto, H. Tetrahedron Lett. 1992,
33, 2701-2704.
On the other hand, 2-alkyl-3-arylpyridines 3 and
2-aryl-3-methylpyridines 4 are intermediates in the
(4) Umio, S.; Kariyone, K.; Tanaka, K. J apan 67 13,946, 1967;
Chem. Abstr. 1968, 69, 51887j.
† Ghent University.
(5) (a) Lin, L.-F.; Lee, S.-J .; Chen, C.-T. Heterocycles 1977, 7, 347-
352. (b) Du Priest, M. T.; Schmidt, C. L.; Kuzmich, D.; Williams, S. B.
J . Org. Chem. 1986, 51, 2021-2023.
(6) Maarse, H.; Visscher, C. A. In Volatile Compounds in Food;
Grafische Industrie Kreon Zeist: The Netherlands, 1989; Vol II, pp
648, 703, 1059.
‡ Belarussian State University.
(1) Yates, F. S. In Comprehensive Heterocyclic Chemistry; Boulton,
A. J ., Mc. Killop, A., Eds.; Pergamon: Oxford, 1984; Vol 2, Part 2A, pp
511-524.
(2) J ones, R. A. In Pyrroles, Part II, The Synthesis, Reactivity and
Physical Properties of Substituted Pyrroles; J . Wiley and Sons, New
York, 1992.
(7) Thomas, A. F.; Bassols, F. J . Agric. Food Chem. 1992, 40, 2236-
2243.
10.1021/jo000724t CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/14/2000

54 J . Org. Chem., Vol. 66, No. 1, 2001
Aelterman et al.
(R2 ) H), which are for example accessible via an
intramolecular aza-Wittigreaction of ω-azidoketones,8 can
only be oxidized under harsh conditions such as pal-
ladium on alumina in refluxing nitrobenzene9 or reflux
in mesitylene in the presence of selenium.10 Aromatiza-
tion of cyclic imines can also be achieved by a halogena-
tion-dehydrohalogenation sequence, but during the first
step often mixtures of mono- and dihalogenated cyclic
imines are obtained.11 Cyclic imines can also be synthe-
sized by R-alkylation of imines with ethylenetetrameth-
yldisilyl-protected ω-bromoamines, followed by ring clo-
sure.12 However, this method does not seem to be
applicable to aliphatic R-halogenated imines.
Sch em e 2
In this paper, a straightforward and versatile synthetic
route to 2,3-disubstituted pyrroles and pyridines via
halogenated cyclic imines is disclosed. The latter are
obtained in one step from ω-azidoketimines, synthesized
by regiospecific R-alkylation of R-halogenated imines with
ω-iodoazides.
Resu lts a n d Discu ssion
R-Halo-ω-azidoketimines 13 were synthesized by re-
giospecific alkylation of R-haloketimines 10 with ω-iodo-
alkyl azides 12 via the intermediacy of 3-halo-1-azaallylic
anions 11,13 generated with lithium diisopropylamide in
tetrahydrofuran (Scheme 2, Table 1). The primary amino-
protected electrophilic reagents 12 were easily prepared
in good yields from 2-chloroethanol (n ) 1) and 3-chloro-
propanol (n ) 2) by successive reaction with sodium
azide, tosylation, and substitution with sodium iodide.14
The azides were purified by distillation and could be
stored at -20 °C for several months without noticeable
decomposition. To obtain good conversions of the 3-halo-
1-azaallylic carbanions 11 into the R-alkylated imines 13,
after initial deprotonation with LDA at 0 °C, hexameth-
ylphosphoramide (HMPA) was added at -78 °C and the
ω-iodoazides 12 were added neat. The R,γ- and R,δ-
difunctionalized ketimines 13 thus obtained were purified
by vacuum distillation (except the derivatives with a too
high boiling point) and have a reasonable shelf life when
stored at -20 °C (Table 1).
The chemoselective reduction of the azides 13 with 1.5
equiv of tin(II) chloride15 in methanol at room tempera-
ture led directly to the halogenated 1-pyrrolines 14 (n )
1) and 2,3,4,5-tetrahydropyridines 14 (n ) 2). The
transient primary amines could not be detected as the
reaction resulted in an immediate transimination.
The cyclic imines 14 were obtained in pure form in good
to excellent yields after flash chromatography (48-97%).
For the reduction-cyclization of the aromatic δ-azido-
ketimine 13f, a tandem Staudinger-intramolecular aza-
Ta ble 1. Syn th esis of r-Ha lo-ω-a zid ok etim in es 13 by
Dep r oton a tion a n d Su bsequ en t Alk yla tion of
r-Ha lok etim in es 10 w ith ω-Iod oa zid es 12a
product
entry
R
R1
R2
X
nb (yield, %) bp (°C/mmHg)
1
2
3
4
5
6
7
i-Pr Me Me
t-Bu Et Me
i-Pr Cl C6H5
i-Pr Me Me
t-Bu Et Me
i-Pr Cl C6H5
Cl
Cl
Cl
Cl
Cl
Cl
1
1
1
2
2
2
2
13a (81)c 51-52/0.02-0.03
13b (77)c 55-59/0.05
13c (96)d
13d (62)c 47-51/0.01
13e (66)c 62-63/0.01
13f (100)d
i-Pr Me 4-MeC6H4 Br
13 g (93)d
a
Deprotonation conditions: 1.2 equiv of LDA/THF, 25 min 0
°C; cooling to -78 °C, addition of 1 equiv of HMPA; 30 min at
-78 °C. Alkylation conditions: 1 equiv of 10; 5 h -78 f 0 °C.
b
Alkylation with 2-iodoethyl azide 12 (n ) 1) or 3-iodopropyl azide
d
12 (n ) 2). c Yield after distillation. Crude yield.
Wittig reaction8 with triphenylphosphine in the presence
of water in THF gave better results (62% isolated yield)
than reaction with tin(II) chloride in methanol. Some-
what surprisingly, reaction of the R-bromoketimine 13g
(R ) i-Pr, R1 ) Me, R2 ) 4-MeC6H5, n ) 2) with tin(II)
chloride in methanol mainly led to the hydrodebromina-
tion product 18 which was isolated in 44% yield after
flash chromatography. Alternatively, the 5-bromo-2,3,4,5-
tetrahydropyridine 14g could be synthesized by treat-
ment of the R-bromo ketone 19, obtained by acid hydrol-
ysis of imine 13g, with triphenylphosphine in pentane
via an intramolecular aza-Wittig reaction (Scheme 3).
The R-bromo imine unit is apparently more rapidly
reduced by tin(II) chloride than the δ-azido function,
necessitating a modification of the tin(II) chloride type
reductive cyclization.
(8) (a) Lambert, P. H.; Vaultier, M.; Carrie´, R. J . Chem. Soc., Chem.
Commun. 1982, 1224-1225. (b) Vaultier, M.; Lambert, P. H.; Carrie´,
R. Bull. Soc. Chim. Fr. 1985, 83-92.
(9) Schmidle, C. J .; Mansfield, R. C. J . Am. Chem. Soc. 1956, 78,
1702-1705.
(10) Francis, R. F.; Howell, H. M.; Fetzer, D. T. J . Org. Chem. 1981,
46, 2213-2216.
(11) De Kimpe, N.; Abbaspour Tehrani, K.; Stevens, C.; De Cooman,
P. Tetrahedron 1997, 53, 3693-3706.
(12) De Kimpe, N.; Keppens, M.; Stevens, C. Tetrahedron Lett. 1993,
34, 4693-4696.
(13) De Kimpe, N.; Sulmon, P.; Schamp, N. Angew. Chem. 1985,
97, 878-879.
(14) Khoukhi, M.; Vaultier, M.; Carrie´, R. Tetrahedron Lett. 1986,
27, 1031-1034.
In a final step, treatment of 1-pyrrolines 14a ,b (n )
1) with sodium methoxide in methanol under reflux
(15) Maiti, S. N.; Singh, M. P.; Micetich, R. G. Tetrahedron Lett.
1986, 27, 1423-1424.

2,3-Disubstituted Pyrroles and Pyridines
J . Org. Chem., Vol. 66, No. 1, 2001 55
Ta ble 2. Syn th esis of Cyclic Im in es 14 fr om ω-Azid ok etim in es 13 a n d Th eir Con ver sion in to P yr r oles 15 a n d P yr id in es
16 a n d 17
entry
R
R1
R2
X
n
reaction conditions
cyclic imine (yield, %)
reaction conditions
product (yield, %)
a
1
2
3
4
5
6
7
i-Pr
t-Bu
i-Pr
i-Pr
t-Bu
i-Pr
i-Pr
Me
Et
Cl
Me
Et
Cl
Me
Me
C6H5
Me
Me
C6H5
4-MeC6H4
Cl
Cl
Cl
Cl
Cl
Cl
Br
1
1
1
2
2
2
2
SnCl2
SnCl2
SnCl2
SnCl2
14a (97)d
14b (84)d
14c (76)d
14d (48)d
14e (56)d
14f (62)d
14g (35)d,e
NaOMef
NaOMef
NaOMef
KOt-Bug
KOt-Bug
NaOMef
KOt-Bug
15a (98)h
15b (78)d
15c (95)h
16a (80)d
16b (73)d
17 (91)d
a
a
a
a
SnCl2
(C6H5)3Pb
(C6H5)3Pc
Me
16c (80)d
a
b
Imines 13 were reacted with 1.5 equiv of SnCl2 in MeOH at room temperature for 5 h. Imine 13f was reacted with 1 equiv of both
(C6H5)3P and H2O in THF at room temperature for 20 h. c See, for example, Scheme 3. Yields after flash chromatography. e Starting
d
from ketone 19. f Cyclic imines 14 were treated with 3 equiv of NaOMe in methanol (2 N) under reflux for 2 h. Cyclic imines 14 were
g
h
treated with 3 equiv of KOt-Bu in THF under reflux for 1 h and further stirred at room temperature for 20 h. Crude yields.
Sch em e 3
Sch em e 5
Sch em e 4
furnished 2,3-disubstituted pyrroles 15, which were
obtained in pure form after flash chromatography (Table
2). When R,R-dichloro ketimines were used as starting
compounds, 2-alkyl- or 2-aryl-3-chloropyrroles, such as
15c, could be prepared via this synthetic strategy. These
halogenated pyrroles are particularly interesting because
of their potential biological activities.3,4,11 1,2-Dehydro-
halogenation of the corresponding halogenated six-
membered cyclic imines 14 (n ) 2) with potassium tert-
butoxide in THF led to the formation of pyridines 16.
During this reaction, spontaneous oxidation takes place
as the intermediate dihydropyridines could not be de-
tected. 5,5-Dichloro-2,3,4,5-tetrahydropyridine 14f was
converted to 2-phenylpyridine 17 (R2 ) C6H5) by reaction
with sodium methoxide in methanol most probably by a
successive 1,2- and 1,4-dehydrochlorination.
In addition, 2,3-dialkyl-3-chloro-1-pyrrolines 14 could
be converted stereoselectively into the corresponding cis-
pyrrolidines 20 by treatment with sodium borohydride
in methanol at room temperature for 2 h. The cis-2-alkyl-
3-chloropyrrolidines 20 were obtained as colorless oils in
excellent isolated yields (Scheme 4). The relative stereo-
chemistry of compounds 20 was established by NOE
NMR experiments. Irradiation of the R-protons of the
alkylsubstituent at C3 resulted in a NOE effect of the
methine proton at C2. It is quite remarkable that no trace
of the corresponding trans isomer was present in the
reaction mixture, culminating in a stereospecific synthe-
sis of chlorinated cis-pyrrolidines 20.
Alternatively, the synthesis of ω-azido-R-haloketimines
was tried via R,ω-dihalogenated imines in order to get
an alternative access to pyrroles and pyridines. These
dihalogenated imines, as demonstrated with imine 22,
are easily accessible by alkylation of R-chloroketimines,
e.g., 21, with 1-bromo-3-chloropropane. However due to
the low chemoselectivity of the substitution reaction with
sodium azide, the R-chloro-ω-azidoketimine 13d was
isolated in a low yield (28% after distillation). Also 3,6-
dichloro-3-methyl-2-hexanone (23), obtained by hydroly-
sis of the corresponding imine 22b, led to mixtures of
mono- and diazidoketones, after treatment with 1.5 equiv
of sodium azide in DMSO (Scheme 5).
Only R,δ-diazidoketone 24 could be obtained in pure
form by treatment of the dihalide 23 with an excess of
sodium azide in DMSO. Via a tandem Staudinger-aza-
Wittig reaction with triphenylphosphine in THF the azido

56 J . Org. Chem., Vol. 66, No. 1, 2001
Aelterman et al.
(CH2N3), 52.4 (CHMe2), 88.2 (CCl2), 127.1, 128.0 and 128.2
(CHd’s), 132.4 (dCquat), 162.8 (CdN); IR (NaCl, cm-1) 2100
(N3), 1639 (CdN). MS m/z (%) no M+, 235/7(5), 208(7), 146-
(20), 104(100), 77(10). Anal. Calcd for C13H16Cl2N4: C, 52.18;
H, 5.39; N, 18.72. Found: C, 52.03; H, 5.44; N, 18.76.
N-(6-Azid o-3-ch lor o-3-m eth yl-2-h exylid en e)isop r op yl-
a m in e (13d ): 1H NMR (CDCl3) δ 1.08 (6H, d, J ) 6.27 Hz,
Me2CH), 1.66 (3H, s, MeCC1), 1.52-1.90 (2H, m, CH2CH2N3),
1.90-2.26 (2H, m, CH2CCl), 1.98 (3H, s, MeCdN), 3.28 and
3.30 (2H, ABxdxd, J ) 12.12, 6.76, 2.64 Hz, CH2N3), 3.63 (1H,
septet, J ) 6.27 Hz, CHMe2); 13C NMR (CDCl3) δ 13.0 (MeCd
N), 23.1 and 23.2 (2xMeCH), 24.8 (CH2CH2Cl), 28.1 (MeCC1),
39.0 (CH2CCl), 50.8 (NCH), 51.5 (CH2N3), 76.2 (CCl), 164.4
(CdN); IR (NaCl, cm-1) 2098 (N3), 1650 (CdN); MS m/z (%)
no M+, 195(M+ - Cl, 4), 188/190(M+ - N3, 17), 147(11), 134-
(7), 84(50), 42(100). Anal. Calcd for C10H19ClN4: C, 52.05; H,
8.30; N, 24.28. Found: C, 52.27; H, 8.22; N, 24.20.
N-(6-Azid o-3 ch lor o-3-eth yl-2-h exylid en e)-ter t-bu tyl-
a m in e (13e): 1H NMR (CDCl3) δ 0.88 (3H, t, J ) 7.26 Hz,
MeCH2), 1.26 (9H, s, Me3), 1.54-1.86 (2H, m, CH2CH2CC1),
1.80-2.25 (4H, m, MeCH2CC1CH2), 2.05 (3H, s, MeCdN), 3.27
(2H, t, J ) 6.8 Hz, CH2N3); 13C NMR (CDCl3) δ 9.2 (MeCH2),
17.5 (MeCdN), 24.6 (CH2CH2CC1), 30.2 (Me3C), 34.0 and 36.3
(CH2CC1CH2), 51.7 (CH2N3), 55.1 (CMe3), 82.2 (CC1), 163.1
(CdN); IR (NaCl, cm-1) 2080-2100 (N3), 1660 (CdN); MS m/z
(%) no M+, 216/8(4), 177(5), 162(9), 98(25), 57(100). Anal. Calcd
for C12H23ClN4: C, 55.70; H, 8.96; N, 21.65. Found: C, 55.86;
H, 7.04; N, 21.55.
N -(5-Azid o -2,2-d ic h lo r o -1-p h e n y l)is o p r o p y la m in e
(13f): 1H NMR (CDCl3) δ 1.06 (2 × 3H, 2xd, J ) 6.93 Hz, Me2-
CH), 2.00-2.13 (2H, m, CH2CH2N3), 2.70-2.76 (2H, m, CH2-
CCl2), 3.32 (1H, septet, J ) 6.93 Hz, Me2CH), 3.43 (2H, t, J )
6.27 Hz, CH2N3), 7.23-7.31 (2H, m, m-CHd), 7.39-7.47 (3H,
m, o- and p-CHd); 13C NMR (CDCl3) δ 23.1 (Me2CH), 25.5 (CH2-
CH2N3), 42.1 (CH2CCl2), 50.9 (CH2N3), 53.1 (Me2CH), 91.7
(CCl2), 127.8 (o-CHd), 128.5 (p-CHd), 128.9 (m-CHd), 133.7
(dCsCdN), 164.0 (CdN); IR (NaCl, cm-1) 2100 (N3), 1643 (Cd
N). Anal. Calcd for C14H18Cl2N4: C, 53.68; H, 5.79; N, 17.89.
Found: C, 53.76; H, 5.77; N, 17.80.
ketone 24 was mainly converted into 5-azido-2,3,4,5-
tetrahydropyridine (25) which was obtained in 28% yield
after flash chromatography.
In conclusion, it was demonstrated that 3-halo-1-
azaallylic anions, derived from R-halogenated ketimines,
are versatile intermediates in the synthesis of nitrogen-
containing heterocycles, e.g., pyrrolines, tetrahydropyri-
dines, pyrroles, pyrrolidines, and pyridines. These 3-halo-
1-azaallylic anions were regiospecifically R-alkylated with
ω-iodoazides to give ω-iodoketimines which were trans-
formed in two steps into 2,3-disubstituted pyrroles and
pyridines.
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were recorded at 270
and 68 MHz, respectively. The type of carbon and hydrogen
1
atom was determined via DEPT and 13C-1H and H-1H COSY
NMR techniques. Mass spectra were obtained at 70 eV (only
major and diagnostic peaks are given). Thin-layer chromatog-
raphy was carried out on plates coated with a 0.25 mm layer
of silica gel. Column chromatography was performed using
silica gel 60 of 40-63 µm particle size. THF was freshly
distilled from sodium benzophenone ketyl.
Syn th esis of r-Ch lor o-ω-a zid o Ketim in es 13. A solution
of LDA was prepared by addition of 2.5 M n-butyllithium (12
mL, 30 mmol) in hexane to an ice-cooled solution of diisopro-
pylamine (3.28 g, 33 mmol) in dry THF (35 mL) under a
nitrogen atmosphere. This solution was treated by syringe with
a solution of R-haloketimine 10 (25 mmol) in THF (25 mL).
After 25 min of stirring at 0 °C, the reaction mixture was
cooled to -78 °C, hexamethylphosphoramide (CAUTION!)
(4.48 g, 25 mmol) was added, and the mixture was stirred
additionally for 30 min at -78 °C. Then, ω-iodoazide 12 (25
mmol) was added dropwise. The mixture was gradually
warmed to 0 °C over 5 h then poured into an ice-cooled 0.5 M
NaOH solution (100 mL), extracted with ether, and the
combined organic extracts were dried with K2CO3. After
filtration and removal of the solvents in vacuo, the crude
R-chloro-ω-azido ketimines 13 were distilled in vacuo behind
a safety shield (CAUTION) (Table 1) or were used as such in
the next step (derivatives 13c, 13f, 13g).
N-(5-Azid o-3-ch lor o-3-m eth yl-2-p en tylid en e)isop r op yl-
a m in e (13a ): 1H NMR (CDCl3) δ 1.07 and 1.09 (2 × 3H, 2xd,
J ) 6.1 Hz, Me2CH), 1.67 (3H, s, MeCCl), 1.97 (3H, s, MeCd
N), 2.18 (1H, ABxdxd, J ) 13.86, 9.8, 5.61 Hz, HCHCCl), 2.48
(1H, ABxdxd, J ) 13.86, 9.57, 5.28 Hz, HCHCCl), 3.34 (1H,
ABxdxd, J ) 12.0, 9.57, 5.61 Hz, HCHN3), 3.51 (1H, ABxdxd,
J ) 12.0, 9.8, 5.28 Hz, HCHN3), 3.62 (1H, septet, J ) 6.1 Hz,
CHMe2); 13C NMR (CDCl3) δ 13.0 (MeCdN), 23.1 (2xMe2CH),
28.9 (MeCCl), 40.3 (CH2CCl), 48.1 (CH2N3), 50.8 (CHMe2), 74.4
(CCl), 164.0 (CdN); IR (NaCl, cm-1) 2095 (N3), 1658 (CdN);
MS m/z (%) no M+, 154(5), 127(14), 84(33), 55(3), 42(100). Anal.
Calcd For C9H17ClN4: C, 49.88; H, 7.91; N, 25.85. Found: C,
50.02; H, 7.85; N, 25.76.
N-[5-Azid o-2-br om o-2-m eth yl-2-(4-m eth ylp h en yl)-1-bu -
tylid en e]isop r op yla m in e (13g): 1H NMR (CDCl3) δ 1.00
(6H, d, J ) 6.26 Hz, Me2CH), 1.69-1.94 (2H, m, CH2CH2-
CH2N3), 1.82 (3H, s, MeCBr), 2.22-2.28 (2H, m, CH2CBr), 2.38
(3H, s, MeC6H4), 3.16 (1H, septet, J ) 6.26 Hz, CHMe2), 3.31
(2H, m, CH2N3), 7.02-7.26 (4H, m, C6H4); 13C NMR (CDCl3) δ
21.6 (MeC6H4), 23.2 and 23.3 (Me2CH), 26.0 (CH2CH2CH2N3),
29.3 (MeCBr), 40.0 (CH2CBr), 51.4 (CH2N3), 52.8 (CHMe2), 70.5
(CBr), 128.1 and 128.6 (CHd’s), 132.6 and 137.8 (Cquat.arom.),
167.7 (CdN); IR (NaCl, cm-1) 2098 (N3), 1632 (CdN); MS m/z
(%) no M+, 308/10 (M+ - N3), 160(16), 118(100), 91(8). Anal.
Calcd for C16H23BrN4: C, 54.71; H, 6.60; N, 15.95. Found: C,
54.59; H, 6.63; N, 15.91.
Syn th esis of 1-P yr r olin es 14a -c a n d 2,3,4,5-Tetr a h y-
d r op yr id in es 14d -g. The synthesis of 3-chloro-2,3-dimethyl-
1-pyrroline (14a ) is representative. To a solution of R-chloro-
ω-azidoketimine 13a (2.16 g, 10 mmol) in methanol (30 mL)
was added SnCl2 (2.84 g, 15 mmol). The mixture was stirred
under nitrogen for 5 h at room temperature, poured into a 0.5
N NaOH solution, and extracted with ether. The combined
organic extracts were dried (MgSO4) and evaporated in vacuo
to yield 1.27 g (97%) of crude 14a (purity > 95%, 1H NMR)
(light red oil) which was used as such in the next step.
3-Ch lor o-2,3-dim eth yl-1-pyr r olin e (14a): 1H NMR (CDCl3)
δ 1.75 (3H, s, MeCCl), 2.11 (3H, t, J ) 1.98 Hz, MeCdN), 2.03-
2.15 (1H, m, overlap, HCHCCl), 2.47 (1H, ABxt, J ) 14.19,
4.95 Hz, HCHCCl), 3.81 (2H, txq, J ) 4.95, 1.98 Hz, NCH2);
13C NMR (CDCl3) δ 14.4 (MeCdN), 27.6 (MeCCl), 41.9 (CH2-
N-(5-Azid o-3-ch lor o-3-eth yl-2-p en tylid en e)-ter t-bu tyl-
a m in e (13b): 1H NMR (CDCl3) δ 0.89 (3H, t, J ) 7.4 Hz,
MeCH2), 1.27 (9H, s, Me3C), 2.04 (3H, s, MeCdN), 1.91-2.10
(3H, m, CH2 Me and CH2HCH), 2.55 (1H, ABxdxd, J ) 16.08,
10.1, 5.28 Hz, NCH2HCH), 3.32 and 3.51 (2H, ABxdxd, J )
11.88, 10.1, 5.28 Hz, NHCH). 13C NMR (CDCl3) δ 10.0
(MeCH2), 17.9 (MeCdN), 31.0 (Me3C), 35.9 (CH2Me), 38.5 (CH2-
CH2N3), 49.1 (CH2N3), 56.2 (Me3C), 80.9 (CCl), 163.6 (CdN);
IR (NaCl, cm-1) 2096 (N3), 1664 (CdN); MS m/z (%) no M+,
181(4), 154(3), 98(18), 94(3), 57(100). Anal. Calcd For C11H21
-
CCl), 57.0 (CH2N), 76.1 (CCl), 174.7 (CdN); IR (NaCl, cm-1
)
ClN4: C, 53.98; H, 8.65; N, 22.89. Found: C, 54.23; H, 8.56; N,
23.02.
1638 (CdN); MS m/z (%) 131/3(M+, 6), 96(M+ - Cl, 10), 92-
(14), 90(37), 55(100). Anal. Calcd for C6H10ClN: C, 54.76; H,
7.66; N, 10.64. Found: C, 54.60; H, 7.51; N, 10.48.
N-(4-Azid o-2,2-d ich lor o-1-p h en yl-1-bu tylid en e)isop r o-
p yla m in e (13c): 1H NMR (CDCl3) δ 1.05 (6H, d, J ) 6.1 Hz,
Me2), 3.00 (2H, ∼t, J ) 7.59 Hz, CH2CCl2), 3.22 (1H, septet, J
) 6.1 Hz, CHMe2), 3.70 (2H, ∼t, J ) 7.59 Hz, CH2N3), 7.22-
7.29 (2H, m. and o. CHd’s), 7.38-7.46 (3H, m, m. and p. CHd
’s); 13C NMR (CDCl3) δ 22.4 (Me2), 43.0 (CH2CC12), 47.5
3-Ch lor o-3-eth yl-2-m eth yl-1-p yr r olin e (14b): purifica-
tion by flash chromatography hexane/ether 9/1 (Rf ) 0.26); 1H
NMR (CDCl3) δ 1.05 (3H, t, J ) 7.26 Hz, MeCH2), 1.79 (1H,
ABxq, J ) 14.36, 7.26 Hz, HCHMe), 2.02-2.18 (2H, m,

2,3-Disubstituted Pyrroles and Pyridines
J . Org. Chem., Vol. 66, No. 1, 2001 57
HCHMe and HCHCH2N), 2.09 (3H, t, J ) 1.98 Hz, MeCdN),
2.33 (1H, ABxt, J ) 14.19, 6.95 Hz, HCHCH2N), 3.82 (2H, txq,
J ) 6.95, 1.98 Hz, NCH2); 13C NMR (CDCl3) δ 9.4 (MeCH2),
14.7 (MeCdN), 32.8 (CH2Me), 38.1 (NCH2CH2), 57.3 (CH2N),
81.3 (CCl), 174.3 (CdN); IR (NaCl, cm-1) 1640 (CdN); MS m/z
(%) 145/7(M+, 21), 104/6(78), 89(10), 69(78), 55(100). Anal.
Calcd for C7H12ClN: C, 57.73; H, 8.31; N, 9.62. Found: C, 57.88;
H, 8.30; N, 9.54.
5-C h lo r o -5,6-d im e t h y l-2,3,4,5-t e t r a h y d r o p y r id in e
(14d ): purification by flash chromatography hexane/ether 4/1
(Rf ) 0.20); 1H NMR (CDCl3) δ 1.56-1.74 and 1.82-2.00 (2 ×
1H, 2xm, NCH2CH2), 1.71 (3H, s, MeCCl), 1.82-2.00 and 2.18-
2.29 (2 × 1H, 2xm, CH2CCl), 2.12 (3H, dxd, J ) 2.18, 1.48 Hz,
MeCdN), 3.43 and 3.79 (2H, ABxm, J AB ≈ 18.1 Hz, NCH2);
13C NMR (CDCl3) δ 19.2 (NCH2CH2), 21.9 (MeCdN), 29.9
(MeCCl), 38.3 (CH2CCl), 49.6 (NCH2), 63.7 (CCl), 166.4 (Cd
N); IR (NaCl, cm-1) 1650 (CdN); MS m/z (%) 145/7(M+, 27),
110(M+ - Cl, 44), 76/8(97), 69(69), 56(44), 42(100). Anal. Calcd
for C7H12ClN: C, 57.73; H, 8.31; N, 9.62. Found: C, 57.92; H,
8.22; N, 9.56.
5-Ch lor o-5-eth yl-6-m eth yl-2,3,4,5-tetr a h yd r op yr id in e
(14e): purification by flash chromatography hexane/ether 92/8
(Rf ) 0.25); 1H NMR (CDCl3) δ 0.98 (3H, t, J ) 7.26 Hz,
MeCH2), 1.56-2.00 (2H, m, NCH2CH2), 1.78-2.20 (4H, m,
(CH2)2CCl), 2.08 (3H, dxd, J ) 2.31, 1.32 Hz, MeCdN), 3.33
and 3.81 (2H, ABxm, J AB ≈ 17.7 Hz, NCH2); 13C NMR (CDCl3)
δ 8.6 (MeCH2), 18.7 (NCH2CH2), 21.9 (MeCdN), 34.0 and 34.2
(each CH2CCl), 49.5 (NCH2), 68.0 (CCl), 166.4 (CdN); IR
(NaCl, cm-1) 1645 (CdN); MS m/z (%) 159/61(M+, 19), 124-
to give 0.86 g of crude pyridine 16a , which was purified by
flash chromatography (pentane/ether 1/1, Rf ) 0.17) to afford
0.68 g (80%) of the pure substance as a colorless oil.
2,3-Dim eth ylp yr id in e (16a ): 1H NMR (CDCl3) δ 2.28 and
2.50 (2 × 3H, 2xs, 2xMe), 7.03 (1H, dxd, J ) 7.4 Hz, NCHCH),
7.39 (1H, broad d, J ) 7.4 Hz, NCHCHCH), 8.32 (1H, dxd, J
) 4.7, 0.99 Hz, NCH); 13C NMR (CDCl3) δ 19.2 and 22.6
(2xMe), 121.2 (NCHCH), 131.4 (CHCMe), 137.0 (NCHCHCH),
146.5 (NCH), 157.1 (NCMe); IR (NaCl, cm-1) 1575, 1470, 1450,
1435; MS m/z (%) 107(M+, 100), 106(69), 92(19), 79(24), 66-
(27). See ref 18. Anal. Calcd for C7H9N: C, 78.46; H, 8.47; N,
13.07. Found: C, 78.32; H, 8.40; N, 12.92.
3-Eth yl-2-m eth ylp yr id in e (16b): Purified by flash chro-
matography pentane/ether 1/1 (Rf ) 0.23); 1H NMR (CDCl3) δ
1.22 (3H, t, J ) 7.59 Hz, MeCH2), 2.54 (3H, s, MeCN), 2.63
(2H, q, J ) 7.59 Hz, CH2Me), 7.07 (1H, dxd, J ) 7.7, 4.8 Hz,
NCHCH), 7.43 (1H, dxd, J ) 7.7, 1.4 Hz, NCHCHCH), 8.33
(1H, dxd, J ) 4.8, 1.4 Hz, NCH); 13C NMR (CDCl3) δ 13.8
(MeCH2), 22.0 (MeCN), 25.6 (CH2), 121.4 (NCHCH), 135.4
(NCHCHCH), 137.1 (CCH2Me), 146.3 (NCH), 156.5 (NCMe);
IR (NaCl, cm-1) 2960, 1600, 1490; MS m/z (%) 121(M+, 87),
120(43), 106(100), 92(12), 79(34), 77(16). Anal. Calcd for
C8H11N: C, 79.29; H, 9.15; N, 11.56. Found: C, 79.20; H, 9.01;
N, 11.46.
Syn th esis of N-[5-Azid o-2-m eth yl-2-(4-m eth ylp h en yl)-
1-bu tylid en e]isop r op yla m in e (18). The same procedure as
described for the preparation of 14 provided 18 as a light
yellow oil in 44% yield after flash chromatography (hexane/
ethyl acetate 9/1, Rf ) 0.25). For 18: 1H NMR (CDCl3) δ 1.03
and 1.04 (2 × 3H, 2xd, J ) 5.94 Hz, Me2CH), 1.06 (3H, d, J )
6.93 Hz, MeCH), 1.31-1.40 and 1.63-1.73 (4H, m, CH2CH2-
CH2N3), 2.37 (3H, s, MeC6H4), 2.58 (1H, ∼sextet, J ≈ 6.7 Hz,
CH2CHMe), 3.27 (2H, t, J ) 6.3 Hz, CH2N3), 3.31 (1H, septet,
J ) 5.94 Hz, CHMe2), 6.90 and 7.19 (4H, AB, J AB ) 7.9 Hz,
C6H4); 13C NMR (CDCl3) δ 18.4 (MeCHCH2), 21.2 (MeC6H4),
23.7 and 23.9 (Me2CH), 26.9 and 31.0 (CH2CH2CH2N3), 44.4
(CHCdN), 51.6 (CH2N3), 52.0 (CHMe2), 126.4 and 128.9 (CHd
’s), 134.7 and 137.5 (Cquat), 172.6 (CdN); IR (NaCl, cm-1) 2098
(N3), 1641 (CdN); MS m/z (%) no M+, 230(M+ - N3, 7), 229-
(36), 188(11), 181(12), 118(100), 84(19), 44(24). Anal. Calcd for
(82), 90/2(100), 69(19), 56(34), 55(89). Anal. Calcd for C8H14
-
ClN: C, 60.18; H, 8.84; N, 8.77. Found: C, 60.30; H, 8.74; N,
8.70.
Syn th esis of P yr r oles 15 a n d P yr id in e 17 by Rea ction
of Cyclic Im in es 14 w ith Sod iu m Meth oxid e in Meth a n ol.
The synthesis of 2,3-dimethylpyrrole 15a is representative
(Table 2). To 1.04 g (8 mmol) of 1-pyrroline 14a was added 12
mL (24 mmol) of a 2 M solution of sodium methoxide in
methanol. The mixture was stirred for 2 h at reflux, poured
into water, and extracted with ether. The combined organic
extracts were dried (MgSO4) and evaporated in vacuo to give
0.74 g (98%) of pure (>97%; GC) pyrrole 15a (light red oil).
2,3-Dim eth ylp yr r ole 15a : 1H NMR (CDCl3) δ 2.02 and 2.16
(2 × 3H, 2xs, 2xMe), 5.98 (1H, t, J ) 2.64 Hz, NCHdCH), 6.56
C
16H24N4: C, 70.55; H, 8.88; N, 20.57. Found: C, 70.70; H, 8.84;
N, 20.50.
Syn th esis of 6-Azid o-3-br om o-3-m eth yl-1-(4-m eth yl-
(1H, t, J ) 2.64 Hz, NCHd), 7.60-7.85 (1H, broad s, NH); 13
C
p h en yl)-2-h exa n on e (19). A solution of 1.34 g (3.8 mmol) of
ketimine 13g in 15 mL of dichloromethane was stirred with
3.8 mL of a 1 M aqueous solution of HCl under reflux for 2 h.
The organic layer was separated, and the water phase was
extracted with CH2Cl2. The combined organic extracts were
dried with MgSO4, filtered, and concentrated in vacuo to yield
1.05 g (89%) of the crude ketone 19 (purity > 90%) which was
used as such in the next step. For 19: 1H NMR (CDCl3) δ 1.49-
1.92 (2H, m, CH2CH2N3), 2.01 (3H, s, MeCBr), 2.15-2.46 (2H,
m, CH2CBr), 2.41 (3H, s, MeC6H4), 3.29 (2H, t, J ) 6.8 Hz,
CH2N3), 7.24 and 8.04 (4H, AX, J AX ) 8.25 Hz, C6H4); 13C NMR
(CDCl3) δ 21.6 (MeC6H4), 25.4 (CH2CH2N3), 28.7 (MeCBr), 40.1
(CH2CBr), 51.1 (CH2N3), 64.6 (CBr), 128.9 and 130.1 (CHd’s),
132.3 and 143.4 (Cquat), 196.1 (CdO); IR (NaCl, cm-1) 2100 (N3),
1672 (CdO); MS m/z (%) no M+, 160(2), 119(100), 91(21), 65-
(8), 55(3), 43(7).
Syn t h esis of 5-Br om o-5-m et h yl-6-(4-m et h ylp h en yl)-
2,3,4,5-tetr a h yd r op yr id in e (14g). A solution of 0.93 g (3
mmol) of δ-azidoketone 19 in 10 mL of pentane was treated
with 0.79 g (3 mmol) of triphenylphosphine. The reaction
mixture was stirred for 6 h at room temperature, and the
precipitate that formed was filtered off. The filtrate was
evaporated, and 15 mL of pentane was added. The solution
was stored overnight at -20 °C, and the precipitate that
formed was again filtered off. The filtrate was purified by flash
chromatography using hexane/ethyl acetate (70/30) as eluent
(Rf ) 0.31) yielding 0.28 g (35%) of pure 2,3,4,5-tetrahydro-
pyridine 14g as a semisolid colorless product: 1H NMR (CDCl3)
NMR (CDCl3) δ 10.8 (2xMe, overlap), 109.8 (NCHdCH), 113.9
(NHCdCMe), 114.9 (NCHd), 123.6 (NCMe); IR (NaCl, cm-1
)
3370 (NH), 2915, 1466, 1102, 712; MS m/z (%) 95(M+, 100),
93(14), 80(22), 67(12), 53(12). See ref 16. Anal. Calcd for
C6H9N: C, 75.74; H, 9.53; N, 14.72. Found: C, 75.88; H, 9.44;
N, 14.68.
3-Eth yl-2-m eth ylp yr r ole (15b): purified by flash chroma-
tography hexane/ethyl acetate 9/1 (Rf ) 0.34); 1H NMR (CDCl3)
δ 1.16 (3H, t, J ) 7.59 Hz, MeCH2), 2.18 (3H, s, MeCdC), 2.42
(2H, q, J ) 7.59 Hz, CH2), 6.04 (1H, t, J ) 2.64 Hz, NCHd
CH), 6.59 (1H, t, J ) 2.64 Hz, NCHd), 7.56-7.95 (1H, broad
s, NH); 13C NMR (CDCl3) δ 11.0 (MeCdC), 15.6 (MeCH2), 19.0
(CH2Me), 108.2 and 114.9 (2x dCH), 121.1 and 122.8 (Cquat);
IR(NaCl, cm-1) 3360-3390 (NH), 1451, 1105, 899; MS m/z (%)
109(M+, 48), 94(100), 67(11), 53(9). See ref 17. Anal. Calcd for
C7H11N: C, 77.01; H, 10.16; N, 12.83. Found: C, 77.18; H, 10.08;
N, 12.76.
Syn th esis of P yr id in es 16 by Rea ction of Cyclic Im i-
n es 14 w ith P ota ssiu m ter t-Bu toxid e in THF . The syn-
thesis of 2,3-dimethylpyridine 16a is representative (Table 2).
To a solution of 1.16 g (8 mmol) of 2,3,4,5-tetrahydropyridine
14d in THF (20 mL) was added potassium tert-butoxide (2.69
g, 24 mmol). The reaction mixture was stirred for 1 h under
reflux, cooled to room temperature, and further stirred for 20
h, poured into water, and extracted with ether. The combined
organic extracts were dried (MgSO4) and evaporated in vacuo
(16) Wang, N.; Teo, K.; Anderson, H. Can. J . Chem. 1977, 55, 4112-
4116.
(17) Korostova, S.; Shevchenko, S.; Sigalov, M.; Sobenina, L. Izv.
Akad. Nauk. USSR Ser. Khim 1990, 2659.
(18) Vijn, R.; Arts, H.; Green, R.; Castelijns, A. Synthesis 1994, 573-
578.

58 J . Org. Chem., Vol. 66, No. 1, 2001
Aelterman et al.
δ 1.81 (3H, s, MeCBr), 1.72-1.99 and 2.17-2.46 (4H, m,
CH2CH2CBr), 2.36 (3H, s, MeC6H4), 3.75 (1H, Abxdxd, J )
18.9, 11.7, 5.61 Hz, NCHCH), 4.18 (1H, Abxdxt, J ) 18.9, 5.94,
1.32 Hz, NHCH), 7.15 and 7.63 (4H, AX, J AX ) 8.1 Hz, C6H4);
13C NMR (CDCl3) δ 19.7 (NCH2CH2), 21.2 (MeC6H4), 32.3
(MeCBr), 39.4 (CH2CBr), 50.0 (NCH2), 57.3 (CBr), 128.5 (CHd
), 136.1 and 138.5 (Cquat), 167.8 (CdN); IR (NaCl, cm-1) 1610,
1620 (CdN, CdC); MS m/z (%) no M+, 182(46), 181(100), 166-
(27), 151(4), 90(7), 89(7), 83(9). Anal. Calcd for C13H16BrN: C,
58.66; H, 6.06; N, 5.26. Found: C, 58.76; H, 6.18; N, 5.13.
Syn th esis of 3-Meth yl-2-(4-m eth ylph en yl)pyr idin e (16c).
The same procedure as described for the preparation of 16a
and 16b gave 16c as a colorless oil in 80% yield after flash
chromatography (hexane/ethyl acetate 4/1, Rf ) 0.30): 1H
NMR (CDCl3) δ 2.36 and 2.41 (2 × 3H, 2xs, 2xMe), 7.15 (1H,
(NCH2CH2), 43.2 (CH2NH), 64.3 (NCH), 85.8 (CCl); IR (NaCl,
cm-1) 3100-3580 (NH), 2968, 1460, 1379, 848; MS m/z (%)
147/9(M+, 5), 112(7), 82(6), 69(3), 57(100). Anal. Calcd for
C7H14ClN: C, 56.94; H, 9.56; N, 9.49. Found: C, 56.83; H, 9.46;
N, 9.56.
Syn th esis of 3,6-Dich lor o-3-m eth yl-2-h exa n on e (23). A
solution of imine 22 (9.55 g, 42.6 mmol) in 100 mL of CH2Cl2
was stirred with 43 mL of a 1 M aqueous solution of oxalic
acid. The two-phase mixture was refluxed for 1.5 h, the organic
layer was separated, and the water layer was extracted two
times with CH2Cl2. After drying (MgSO4), filtration, and
evaporation of the solvent in vacuo, the crude ketone 23 was
distilled to yield 6.23 g (80%) of pure compound 23: bp 33-38
°C (0.04-0.05 mmHg); 1H NMR (CDCl3) δ 1.66 (3H, s, MeCCl),
1.80-2.22 (4H, m, CH2CH2CCl), 2.39 (3H, s, MeCdO), 3.51-
3.62 (2H, m, CH2Cl); 13C NMR (CDCl3) δ 25.1 (MeCdO), 26.6
(MeCCl), 27.9 (CH2CH2Cl), 38.1 (CHCCl), 44.5 (CH2Cl), 74.2
(CCl), 204.7 (CdO); IR (NaCl, cm-1) 1714 (CdO); MS m/z (%)
no M+, 148(M+, 0.3), 146(1), 141(1), 108(2), 106(5), 103(3), 67-
(5), 43(100). Anal. Calcd for C7H12Cl2O: C, 45.92; H, 6.61.
Found: C, 45.80; H, 6.52.
Syn th esis of 3,6-Dia zid o-3-m eth yl-2-h exa n on e (24). To
a solution of ketone 23 (1.28 g, 7 mmol) in DMSO (20 mL)
was added sodium azide (1.63 g, 21 mmol). The mixture was
stirred for 24 h at room temperature, poured into water, and
extracted with diethyl ether. The combined organic extracts
were dried (MgSO4) and evaporated to yield 1.22 g (89%) of
crude diazido ketone 24 (purity > 95%, 1H NMR): 1H NMR
(CDCl3) δ 1.45 (3H, s, MeCN3), 1.47-1.94 (4H, m, CH2CH2-
CN3), 2.25 (3H, s, MeCdO), 3.31 (2H, t, J ) 6.4 Hz, CH2N3);
13C NMR (CDCl3) δ 20.9 (MeCN3), 23.3 (CH2CH2N3), 25.4
(MeCdO), 34.2 (CH2CN3), 50.9 (CH2N3), 70.7 (CN3), 207.0 (Cd
O); IR (NaCl, cm-1) 2090-2110 (N3), 1718 (CdO); MS m/z (%)
no M+, 154(1), 125(2), 107(3), 84(2), 71(3), 69(9), 56(17).
Syn th esis of 5-Azid o-5,6-d im eth yl-2,3,4,5-tetr a h yd r o-
p yr id in e (25). An analoguous procedure as described for the
preparation of 14g afforded 25 in 28% yield after flash
chromatography (pentane/ether 40/60, Rf ) 0.13): 1H NMR
(CDCl3) δ 1.41 (3H, s, MeCN3), 1.60-2.02 (4H, m, NCH2-
CH2CH2), 2.03 (3H, t, J ) 1.98 Hz, MeCdN), 3.50-3.62 (2H,
m, NCH2); 13C NMR (CDCl3) δ 19.6 (NCH2CH2), 22.1 (MeCd
N), 23.9 (MeCN3), 33.4 (CH2CN3), 49.3 (NCH2), 60.4 (CN3),
166.7 (CdN); IR (NaCl, cm-1) 2100 (N3), 1656 (CdN); MS m/z
(%) 152(M+, 1), 124(3), 109(2), 96(2), 83(24), 69(18), 42(100).
Anal. Calcd for C7H12N4: C, 55.24; H, 7.95; N, 36.81. Found:
C, 55.38; H, 7.75; N, 36.69.
dxd, J ) 7.8, 4.78 Hz, NCHCH), 7.26 and 7.42 (4H, AB, J AB
)
7.92 Hz, C6H4), 7.56 (1H, dxd, J ) 7.8, 0.99 Hz, NCHCHCH),
8.51 (1H, dxd, J ) 4.78, 0.99 Hz, NCH); 13C NMR (CDCl3) δ
20.2 and 21.3 (2xMe), 121.8 (NCHCHCH), 128.8 and 128.9
(CH’s of C6H4), 138.4 (NCHCHCH), 146.9 (NCH), 130.8, 137.6,
137.7, and 159.7 (Cquat); IR (NaCl, cm-1) 1447, 1425, 829, 790,
770; MS m/z (%) 183(M+, 50), 182(100), 167(25), 83(8), 65(5).
See ref 19. Anal. Calcd for C13H13N: C, 85.21; H, 7.15; N, 7.64.
Found: C, 85.32; H, 7.03; N, 7.59.
Syn th esis of 3-Ch lor op yr r olid in es 20. To an ice-cooled
solution of 1-pyrroline 14 (2 mmol) in methanol (10 mL) was
added 3 mmol of sodium borohydride. After 2 h of stirring at
room temperature, the mixture was poured into water and
extracted with CH2Cl2. The combined extracts were dried with
MgSO4, filtered, and concentrated in vacuo yielding pure
1
3-chloropyrrolidines 20 (purity > 98%; H NMR).
cis-3-Ch lor o-2,3-d im eth ylp yr r olid in e (20a ): 1H NMR
(CDCl3) δ 1.18 (3H, d, J ) 6.27 Hz, MeCH), 1.63 (3H, s,
MeCCl), 1.9-2.1 (1H, broad s, NH), 2.00 (1H, ABxdxd, J )
14.0, 9.89, 8.5 Hz, HCHCCl), 2.34 (1H, Abxdxd, J ) 14.0, 8.5,
2.97 Hz, HCHCl), 2.75 (1H, q, J ) 6.27 Hz, CHMe), 2.95 (1H,
ABxdxd, J ) 11.56, 9.89, 2.97 Hz, HCHN), 3.16 (1H, ABxt, J
) 11.53, 8.5 Hz, HCHN); 13C NMR (CDCl3) δ 14.5 (MeCH),
26.2 (MeCCl), 43.2 (CH2NH), 44.1 (CH2CCl), 64.8 (CHMe), 80.4
(CCl); IR (NaCl, cm-1) 3100-3320 (NH), 1443, 1378, 1112; MS
m/z (%) 133/5(M+, 13), 118/20(4), 98(11), 82(7), 69(4), 57(100).
Anal. Calcd for C6H12ClN: C, 53.92; H, 9.05; N, 10.48. Found:
C, 54.03; H, 8.98; N, 10.40.
cis-3-Ch lor o-3-eth yl-2-m eth ylpyr r olidin e (20b): 1H NMR
(CDCl3) δ 1.13 (3H, t, J ) 7.26 Hz, MeCH2), 1.18 (3H, d, J )
6.27 Hz, MeCH), 1.62 and 1.93 (2H, ABxq, J ) 13.5, 7.26 Hz,
CH2Me), 1.88-2.11 (2H, m, NH en NCH2HCH), 2.29 (1H,
ABxdxd, J ) 15.88, 8.41, 3.1 Hz, NCH2HCHl), 2.72-2.84 (1H,
m, CHMe), 2.86-3.04 and 3.08-3.24 (2H, m, NCH2); 13C NMR
(CDCl3) δ 10.3 (MeCH2), 14.7 (MeCH), 32.4 (CH2Me), 41.2
Ack n ow led gm en t. The authors are indebted to the
IWT, Ghent University, and the FWO Flanders for
financial support.
(19) Prostakov, N.; Pleshakov, V.; Seitenbetov, T.; Fresenko, D.;
Olubajo, L. Zh. Org. Khim. 1977, 13, 1484-1494.
J O000724T