Palladium-catalyzed reactions of N-allylbenzotriazoles with amines: Intramolecular allylamination routes to 2-vinylpyrrolidines and 2- vinylpiperidines

Article abstract of DOI:10.1021/jo990181r

Reactions of allylbenzotriazole (4a-d) with 1-bromo-3-chloropropane, 1- bromo-2-methyl-3-chloropropane, epibromohydrin (8), and 1-bromo-4- chlorobutane afforded the corresponding α-substituted allylbenzotriazoles (5a-d, 9, and 16a,b), which with primary amines in one-pot sequences produce 2-vinylpyrrolidines (7a-i), 2-ethylpyrrole (13), and 2-vinylpiperidines (18a- c) in good yields under mild conditions.

Full text of DOI:10.1021/jo990181r

6066
J . Org. Chem. 1999, 64, 6066-6070
P a lla d iu m -Ca ta lyzed Rea ction s of N-Allylben zotr ia zoles w ith
Am in es: In tr a m olecu la r Allyla m in a tion Rou tes to
2-Vin ylp yr r olid in es a n d 2-Vin ylp ip er id in es
Alan R. Katritzky,* J iangchao Yao, and Baozhen Yang
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received February 1, 1999
Reactions of allylbenzotriazole (4a -d ) with 1-bromo-3-chloropropane, 1-bromo-2-methyl-3-chloro-
propane, epibromohydrin (8), and 1-bromo-4-chlorobutane afforded the corresponding R-substituted
allylbenzotriazoles (5a -d , 9, and 16a ,b), which with primary amines in one-pot sequences produce
2-vinylpyrrolidines (7a -i), 2-ethylpyrrole (13), and 2-vinylpiperidines (18a -c) in good yields under
mild conditions.
Sch em e 1
In tr od u ction
2-Vinylpyrrolidines and 2-vinylpiperidines are useful
intermediates in organic synthesis,1 and their structures
are present in biologically active alkaloids.2 Common
routes to 2-vinylpyrrolidines and 2-vinylpiperidines in-
clude (i) silver(I), organolanthanide, or palladium-
catalyzed cyclization of allenic amines;1e,f,3 (ii) palladium-
catalyzed transformations of N-tosyl-2-(1,3-butadien-
yl)aziridine;4 (iii) ceric ammonium nitrate oxidative in-
tramolecular amination of allylsilanes;1i (iv) Wittig reac-
tion of 2-carboxyaldehydes;1j,k,5 (v) intramolecular Mit-
sunobu reaction of γ-aminoallyl alcohols;1h and (vi)
transition metal-catalyzed intramolecular allylamination
of allyl acetates or allyl halides.1f,6 Transition metal-
catalyzed allylaminative cyclizations have led to impor-
tant alkaloid skeletons,6b,7 but the convenience of such
reactions depends on the availability of the starting
materials.
Benzotriazole is a useful synthetic auxiliary in organic
synthesis.8 Transition metal-catalyzed allylic substitu-
tions using benzotriazole as a leaving group are poten-
tially advantageous because of the ease of preparation
of R-substituted allylbenzotriazoles. Lithiation of allyl-
benzotriazole followed by reaction with various electro-
philes (alkyl bromides or iodides, aldehydes, ketones,
epoxides, imines, acyl chlorides, and isocyanates) affords
a diversity of allylic substrates.9 We previously reported
that benzotriazole can be used as a leaving group in
intermolecular palladium-catalyzed allylic aminations
used to prepare substituted allylamines.10 Intramolecular
(1) (a) Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1998,
39, 3505. (b) Hiral, Y.; Watanabe, J .; Nozaki, T.; Yokoyama, H.;
Yamaguchi S. J . Org. Chem. 1997, 62, 776. (c) Heintzelman, G. R.;
Weinreb, S. M. J . Org. Chem. 1996, 61, 4594. (d) Diederich, M.;
Nubbemeyer, U. Angew. Chem., Int. Ed. Engl. 1995, 34, 1026. (e)
Takao, K. I.; Nigawara, Y.; Nishino, E.; Takagi, I.; Maeda, K.; Tadano,
K. I.; Ogawa, S. Tetrahedron 1994, 50, 5681. (f) Fox, D. N. A.; Lathbury,
D.; Mahon, M. F.; Molloy, K. C.; Gallagher, T. J . Am. Chem. Soc. 1991,
113, 2652. (g) Edstrom, E. D. J . Am. Chem. Soc. 1991, 113, 6690. (h)
Bernotas, R. C. Tetrahedron Lett. 1990, 31, 469. (i) Wilson, S. R.;
Augelli-Szafran, C. E. Tetrahedron 1988, 44, 3983. (j) Vedejs, E.;
Hagen, J . P.; Roach, B. L.; Spear, K. L. J . Org. Chem. 1978, 43, 1185.
(k) Vedejs, E.; Arco, M. J .; Powell, D. W.; Renga, J . M.; Singer, S. P. J .
Org. Chem. 1978, 43, 4381. (l) Deur, C. J .; Miller, M. W.; Hegedus, L.
S. J . Org. Chem. 1996, 61, 2871. (m) Vedejs, E.; Gingras, M. J . Am.
Chem. Soc. 1994, 116, 579. (n) Tanaka, K. I.; Suzuki, H.; Sawanishi,
H. Heterocycles 1996, 43, 205.
(2) (a) Poerwono, H.; Higashiyama K.; Takahashi, H. J . Org. Chem.
1998, 63, 2711. (b) Cook, G. R.; Beholz, L. G.; Stille, J . R. J . Org. Chem.
1994, 59, 3575. (c) Dolle, R. E.; Osifo, K. I.; Li, C. S. Tetrahedron 1991,
32, 5029. (d) Yamazaki, N.; Kibayashi, C. J . Am. Chem. Soc. 1989,
111, 1396.
(3) (a) Davies, I. W.; Gallagher, T.; Lamont, R. B.; Scopes, D. I. C.
J . Chem. Soc., Chem. Commun. 1992, 335. (b) Fox, D. N. A.; Gallagher,
T. Tetrahedron 1990, 46, 4697. (c) Kinsman, R.; Lathbury, D.; Vernon,
P.; Gallagher, T. J . Chem. Soc., Chem. Commun. 1987, 243. (d)
Lathbury, D.; Gallagher, T. J . Chem. Soc., Chem. Commun. 1986, 114.
(e) Arredondo, V. M.; McDonald, F. E.; Marks, T. J . J . Am. Chem. Soc.
1998, 120, 4871. (f) J acques Gore, S. A. Tetrahedron Lett. 1983, 24,
3997.
(7) (a) Metz, P. In Stereoselective Synthesis: Formation of C-N
Bonds by Allylic Substitution Catalyzed by Palladium Complexes;
Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.;
Thieme Stuttgart: New York, 1996; Vol. 9, p 5643. (b) Godleski, S. A.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991; Vol. 4, p 585. (c)
Harrington, P. J . In Comprehensive Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Hegedus, L. S., Eds.; Pergamon:
Oxford, 1995; Vol. 12, p 799. (d) Trost, B. M.; Godleski, S. A.; Belletitre,
J . L. J . Org. Chem. 1979, 44, 2052. (e) Trost, B. M.; Godleski, S. A.;
Genet, J . P. J . Am. Chem. Soc. 1978, 100, 3930. (f) Trost, B. M.; Genet,
J . P. J . Am. Chem. Soc. 1976, 98, 8516. (g) J ohannsen, M.; J orgensen,
K. A. Chem. Rev. 1998, 98, 1689. (h) Andriamialisoa, R. Z.; Langlois,
N.; Langlois, Y. Heterocycles 1980, 14, 1457.
(8) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. Chem. Rev.
1998, 98, 409.
(9) (a) Katritzky, A. R.; Musgrave, R. P.; Breytenbach, J . C. J .
Heterocycl. Chem. 1996, 33, 1637. (b) Katritzky, A. R.; Chang, H. X.;
Verin, S. V. Tetrahedron Lett. 1995, 36, 343. (c) Katritzky, A. R.;
Shcherbakova, I. V. Synth. Commun. 1996, 26, 1385. (d) Katritzky, A.
R.; Soloducho, J .; Musgrave, R. P.; Breytenbach, J . C. Tetrahedron Lett.
1995, 36, 5491. (e) Katritzky, A. R.; Wu, H.; Xie, L.; Rachwal, S.;
Rachwal, B.; J iang, J .; Zhang, G.; Lang, H. Synthesis 1995, 1315. (f)
Katritzky, A. R.; Li, J .; Malhotra, N. Liebigs Ann. Chem. 1992, 843.
(4) Fugami, F.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1985, 26, 857.
(5) Nazabadioko, S.; Perez, R. J .; Brieva, R.; Gotor, V. Tetrahedron:
Asymmetry 1998, 9, 1597.
(6) (a) Yokoyama, H.; Otaya, K.; Yamaguchi, S.; Hirai, Y. Tetrahe-
dron Lett. 1998, 39, 5971. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl.
1989, 28, 1173.
10.1021/jo990181r CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/09/1999

N-Allylbenzotriazole/Amine Pd-Catalyzed Reactions
J . Org. Chem., Vol. 64, No. 16, 1999 6067
Ta ble 1. P r ep a r a tion of 2-Vin ylp yr r olid in es 7a -i
substituents
R2
cyclization conditions
starting
materials
overall
yield (%)
R1
R3
catalyst
temperature (°C)
products
5a
5a
5a
5a
5a
5b
5a
5a
5c
5a
5d
5a
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
n-C12H25
Pd(OAc)2/Ph3P
(Ph3P)4Pd
70
70
70
25
25
25
25
25
25
50
25
50
7a
7a
7a
7a
7b
7c
7d
7e
7f
85a
80b
85b
95b
70c
85c
65c
70c
70c
85c
75c
80c
(Ph3P)2PdCl2
Pd(OAc)2/Ph3P
Pd(OAc)2/Ph3P
(Ph3P)2PdCl2
Pd(OAc)2/Ph3P
Pd(OAc)2/Ph3P
Pd(OAc)2/Ph3P
Pd(OAc)2/Ph3P
Pd(OAc)2/Ph3P
Pd(OAc)2/Ph3P
c-C6H11
C6H5CH(CH3)
(R)-C6H5CH(CH3)
C6H5CH2
EtOCH2CH2
C6H5CH2
CH3
H
C6H5CH2
H
H
H
H
7g
7h
7i
Et2NCH2CH2
From 6. By GC from 6. c Isolated yield from 5.
a
b
Sch em e 2
24 h, while its intermolecular counterpart did not proceed
at room temperature.10 Catalysts such as (Ph3P)4Pd or
(Ph3P)2PdCl2 can be used instead of Pd(OAc)2/Ph3P (Table
1). However, the use of other solvents (THF, DMF or
toluene) without methanol inhibited the reaction; this is
consistent with the previous conclusion10 that methanol
is the preferred solvent. The sequence 5a f 6a f 7a can
also proceed in one pot without purification of the
intermediates 6a simply by adding excess methanol (four
volumes) and Pd(OAc)2/Ph3P to the intermediate 6a in
DMF solution. Since the major solvent is methanol
(methanol:DMF ) 4:1, v/v) and the cyclization did not
proceed in DMF, we concluded that the best cyclization
conditions were to use methanol as solvent, Pd(OAc)/Ph3P
as catalyst, K2CO3 as base to perform the reaction at
room temperature and not to purify the intermediate
amine 6.
The reactions between chlorides 5a -d and other
amines were all carried out in DMF at 80 °C to give the
expected 6 in situ, followed by the addition of methanol,
Pd(OAc)2/Ph3P, and K2CO3, which resulted in the cycliza-
tion of 6 to 7. The combined sequence of substitution and
cyclization proceeded well at room temperature when the
long chained molecules dodecylamine, cyclohexylamine,
and R-methylbenzylamine were used to produce 7b-d
(65-85%). The sequence 5 f 6 f 7 was thus carried out
successfully with a methyl group present in the γ-position
(5b) or with a methyl (5c) or benzyl group (5d ) on the
R-carbon in the benzotriazole starting compounds; the
products 7c,f,h were each isolated in good yield. For
2-ethoxy-1-ethanamine and N1,N1-diethyl-1,2-ethanedi-
amine, the cyclization step needed a higher temperature
(50 °C) in order to form products 7g and 7i at a
reasonable rate. Possibly the â-oxygen or â-nitrogen atom
coordinates with the palladium, making complex 15
(Scheme 4) more stable and thus requiring a higher
temperature for a reductive elimination to give 7g,i.
However, the cyclization of 10, which has a free hydroxy
group on the γ-carbon to benzotriazole, proceeded at room
temperature (Scheme 3). The reason may be that the
hydroxy group is conformationally unfavorable for coor-
dination with the palladium in complex 15 (Scheme 4,
R2 ) OH). No diasterioselectivity was observed in the
cyclization step; product 7c was formed as a mixture of
cis- and trans-isomers (approximately 1:1 by GC analy-
sis). We also tested the enantioselective induction of the
cyclization step. Reaction of 5a and optically active (R)-
R-methylbenzylamine afforded the chiral precursor amine
(6e), which cyclized in situ to give 7e with low enantio-
selective induction (57:43 by GC analysis).3b,12 Com-
aminations of 2 could afford two types of heterocycles 1
or 3 (Scheme 1), depending on whether the amine attacks
the R- or γ-position to benzotriazole. Structures of type
1 and 3 are both common structures in biologically active
alkaloids.2,11 We now document that intramolecular reac-
tions of 2 (n ) 3 or 4) indeed allow the syntheses of
2-vinylpyrrolidines (1, n ) 3) and 2-vinylpiperidines (1,
n ) 4).
Resu lts a n d Discu ssion
Syn th eses of 2-Vin ylpyr r olidin es. Compounds 4a-c
were prepared as described in our previous papers.9f,10
Lithiation of 4a -c with n-BuLi at -78 °C followed by
alkylation with 1-bromo-3-chloropropane or 1-bromo-3-
chloro-2-methylpropane afforded the corresponding chlo-
rides 5a -d in good yields. Compound 5a was reacted
with benzylamine in DMF at 80 °C for 15 h to give
compound 6a . We used amine 6a (R1 ) R2 ) H, R3
)
C6H5CH2) as a model compound to optimize the intramo-
lecular allylic amination conditions (Scheme 2, Table 1,
entries i-iv). We found that 6a cyclized under the
previous10 intermolecular reaction conditions (refluxing
with K2CO3 and Pd(OAc)2/Ph3P in methanol for 24 h) to
provide 2-vinylpyrrolidine (7a ) in 85% yield. However,
the conversion 6a f 7a was also completed at 25 °C in
(10) Katritzky, A. R.; Yao, J .; Qi, M. J . Org. Chem. 1998, 63, 5323.
(11) (a) Balasubramanian, T.; Hassner, A. Tetrahedron: Asymmetry
1998, 9, 2201. (b) Keck, G. E.; Cressman, E. N. K.; Enholm, E. J . J .
Org. Chem. 1989, 54, 4345. (c) Meyers, A. I.; Dickman, D. A.; Bailey,
T. R. J . Am. Chem. Soc. 1985, 107, 7974.

6068 J . Org. Chem., Vol. 64, No. 16, 1999
Katritzky et al.
Sch em e 3
Sch em e 5
intermediate in the synthesis of indolizidinones and nine-
membered ring lactams.1d,g,15
The reaction mechanism is evidently similar to that
of previously reported allylic aminations.6b,7h,16 Oxidative
addition of allylbenzotriazole (6) to palladium(0) first
forms complex 15 (Scheme 4), which can react with an
intramolecular amine in two ways: (i) R-position attack
to form a five-membered ring product 7 or (ii) γ-position
attack to form a seven-membered ring compound 14. In
a recent paper, it was reported that a tertiary amine in
the homoallylic position directed nucleophilic substitution
to the terminus of the allylic moiety proximal to the
tertiary amine.17 This is consistent with our results. In
the above reactions, the amino group regioselectively
attacks the R-position to give five-membered ring prod-
ucts 7a -i. The region selectivity of the intramolecular
reaction is controlled by the favorably entropy of forma-
tion of a five- or six-membered ring, while in the
intermolecular reaction the amine prefers to attack the
less substituted carbon.10
Syn th eses of 2-Vin ylp ip er id in es. Similar intramo-
lecular reactions were used for the synthesis of 2-vinyl-
piperidines (18a -c) (Scheme 5). Compounds 16a ,b were
prepared from 1-bromo-4-chlorobutane and 4a ,d , respec-
tively. The reactions of 16a ,b with benzylamine and
n-hexylamine gave the corresponding intermediates 17.
Cyclizations of 17 under the standard conditions afforded
the six-membered ring 2-vinylpiperidines (18a -c) in good
yields. The reaction mechanism is similar to that for the
formation of 7 (Scheme 4).
Sch em e 4
pounds 7a -i were characterized by 1H and 13C NMR
spectra and by either CHN analysis or HRMS. Initially,
compound 7f, while showing a small peak at M - 1
together with large peaks at M - 15 and M - 31 on the
mass spectrum, displayed nothing above M - 15 in the
high-resolution mass spectrum. Possibly, under these
conditions the loss of CH3 from the initially formed
radical cation proceeds easily to form the conjugated
eniminium cation.
The presence of a hydroxy group on the γ-carbon to
benzotriazole does not preclude the palladium-catalyzed
cyclization. In fact, in the literature a hydroxy group was
used to direct the regioselectivity of a transition metal-
catalyzed allylic alkylation.13 Compound 9 was prepared
from 4a and epibromohydrin (8) in 85% yield. Reaction
of 9 and benzylamine in ethanol formed the â-hy-
droxyamine (10), which when subjected to the above
cyclization conditions at room temperature for 48 h gave
compound 11, as detected by GC-MS. On column chro-
matography, compound 11 was converted into the 2-eth-
ylpyrrole (13, Scheme 3), probably by elimination of water
to give 12, and subsequent isomerization to 13.14 2-Vinyl-
4-hydroxypyrrolidine (11) is potentially useful as an
In conclusion, we have extended our benzotriazole
methodology to palladium-catalyzed intramolecular al-
lylamination reactions, which can readily be applied to
the synthesis of five- and six-membered nitrogen hetero-
cycles. The presence of a substitutent at the R- or
γ-position to benzotriazole did not affect the cyclization,
and both R- and â-substituted primary amines can be
used.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were measured on a
(12) For the case of chiral amines and chiral amino acids in reductive
eliminations of palladium complex with the formation of C-N bonds,
see: (a) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J . Am. Chem. Soc.
1997, 119, 8451. (b) Ma, D.; Yao, J . Tetrahedron: Asymmetry 1996, 7,
3075. (c) Humphries, M. E.; Clark, B. P.; Williams, J . M. J . Tetrahe-
dron: Asymmetry 1998, 9, 749.
hot-stage microscope and are uncorrected. 1H and 13C NMR
(15) Sudau, A.; Nubbemeyer, U. Angew. Chem., Int. Ed. Engl. 1998,
37, 1140.
(16) Reductive eliminations of palladium complexes with the forma-
tion of C-N bonds have recently been reviewed by Hartwig, J . F.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2047.
(13) Genet, J . P.; Balabane, M.; Legras, Y. Tetrahedron Lett. 1982,
23, 331.
(14) Genet, J . P.; Balabane, M.; Backvall, J . E.; Nystrom, J . E.
Tetrahedron Lett. 1983, 24, 2745.
(17) Krafft, M. E.; Wilson, A. M.; Fu, Z.; Procter, M. J .; Dasse, O. A.
J . Org. Chem. 1998, 63, 1748.

N-Allylbenzotriazole/Amine Pd-Catalyzed Reactions
J . Org. Chem., Vol. 64, No. 16, 1999 6069
data were collected on a Gemini 300 MHz NMR spectrometer
(300 and 75 MHz, respectively) using CDCl3 as solvent.
Compounds 4a -d were prepared using literature methods.10
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
5a -d , 9, a n d 16a ,b. Under the protection of N2, allylbenzo-
triazole (4a , 4.0 g, 25.2 mmol) was dissolved in anhydrous THF
(150 mL) and cooled to -78 °C with a dry ice-acetone bath.
This was followed by addition of n-BuLi (1.5 N in hexanes, 18
mL, 27 mmol) over 30 min; the resulting deep blue mixture
was stirred at this temperature for another 2 h. Then 1-bromo-
3-chloropropane (5.0 g, 34 mmol) was added and the reaction
mixture was allowed to warm to room temperature overnight.
The solvents were removed under vacuum, and the residue
was dissolved in CH2Cl2 (80 mL) and then washed with a
saturated NH4Cl aqueous solution (40 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 60 mL). The combined organic
layer was dried over MgSO4, concentrated, and purified by
column chromatography on silica gel (eluent: hexanes:EtOAc
100:5) to afford 5a (5.3 g, 89%).
62.2, 109.9, 118.0, 120.0, 123.9, 127.1, 135.6, 139.3, 145.9.
Anal. Calcd for C13H16N3Cl: C, 62.52; H, 6.46; N, 16.83.
Found: C, 62.44; H, 6.69; N, 17.13.
1-[1-Bu tyl-1-(4-ch lor obu tyl)-2-p r op en yl]-1H-1,2,3-ben -
1
zotr ia zole (16b): colorless oil (70%); H NMR δ 0.83 (t, 3H,
J ) 7.1 Hz), 1.28-1.34 (m, 4H), 1.44-2.02 (m, 4H), 2.25-2.41
(m, 4H), 3.48 (t, 2H, J ) 3.5 Hz), 5.27 (dd, 1H, J ) 3.3, 17.8
Hz), 5.48 (dd, 1H, J ) 3.3, 11.0 Hz), 6.22 (dd, 1H, J ) 10.7,
17.5 Hz), 7.34-7.41 (m, 2H), 7.64 (d, 1H, J ) 8.3 Hz), 8.08 (d,
1H, J ) 8.1 Hz); 13C NMR δ 13.8, 20.7, 22.7, 25.2, 32.5, 35.8,
36.2, 44.5, 68.9, 112.5, 116.3, 120.0, 123.5, 126.4, 132.4, 140.0,
146.8. Anal. Calcd for C17H24N3Cl: C, 66.76; H, 7.91; N, 13.74.
Found: C, 66.54; H, 7.99; N, 13.94.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Vin ylp yr -
r olid in es 7a -i 13 a n d 2-Vin ylp ip er id in es 18a -c. Under
N2, 5a -d , 9 (the reaction of 9 and benzylamine was conducted
in ethanol instead of DMF) or 16a ,b (2.1 mmol), the amine
(2.8 mmol), and K2CO3 in DMF (5 mL) were heated to 80 °C
for 12 h, after cooling to room temperature, Pd(OAc)2 (20 mg,
0.09 mmol), Ph3P (100 mg, 0.4 mmol), K2CO3 (0.8 g), and
methanol (20 mL) were added under argon, and the resulting
mixture was stirred at room temperature for 24 h. Water (20
mL) was added to the reaction mixture followed by extraction
with CH2Cl2 (3 × 40 mL). The solvent was removed, and the
residual oil was purified by chromatography (neutral alumina)
to give the desired product.
1-Ben zyl-2-vin ylp yr r olid in e (7a ):1j colorless oil; 1H NMR
δ 1.62-1.72 (m, 3H), 1.82-2.02 (m, 1H), 2.10 (q, 1H, J ) 8.8
Hz), 2.78 (q, 1H, J ) 7.9 Hz), 2.91 (t, 1H, J ) 7.1 Hz), 3.06
and 4.02 (AB q, 2H, J ) 12.9 Hz), 5.13 (dd, 1H, J ) 1.4, 10.2
Hz), 5.17 (d, 1H, J ) 17.0 Hz), 5.79 (ddd, 1H, J ) 1.5, 9.5,
17.6 Hz), 7.21-7.30 (m, 5H); 13C NMR δ 22.0, 31.5, 53.2, 58.1,
68.4, 116.5, 126.7, 128.1, 129.0, 139.8, 141.0.
1-Dod eca n yl-2-vin ylp yr r olid in e (7b): colorless oil; 1H
NMR δ 0.88 (t, 3H, J ) 6.7 Hz), 2.60 (t, 1H, J ) 8.3 Hz), 2.66-
2.79 (m, 1H), 3.18 (t, 1H, J ) 7.8 Hz), 1.22-2.25 (m, 26H),
5.07 (d, 1H, J ) 10.5 Hz), 5.12 (d, 1H, J ) 19.5 Hz), 5.63-
5.78 (m, 1H); 13C NMR δ 14.1, 22.1, 22.7, 27.8, 28.8, 29.3, 29.6
(br), 29.7, 31.5, 31.9, 53.6, 54.5, 69.3, 118.2, 141.1; HRMS (EI)
calcd for C18H35N 265.2769, found 265.2740.
1-Cycloh exyl-4-m eth yl-2-vin ylp yr r olid in e (7c): mixture
of cis- and trans-isomers (about 1:1 by GC analysis), colorless
oil; 1H NMR δ 0.99 (d, 3H, J ) 6.5 Hz) [minor isomer 1.01 (d,
3H, J ) 6.3 Hz), 1.08-1.42 (m, 6H), 1.45-1.85 (m, 5H), 2.05-
2.25 (m, 2H), 2.45-2.55 (m, 2H), 3.07 (t, 1H, J ) 7.2 Hz) [2.89
(t, 1H, J ) 8.4 Hz)], 3.28-3.42 (m, 1H), 4.99 (dd, 1H, J ) 9.6,
8.5 Hz), 5.07 (d, 1H, J ) 17.2 Hz), 5.71-5.80 (m, 1H); 13C NMR
δ 19.4 (minor isomer 20.4), 25.5 (25.6), 26.0 (26.21), 26.4 (27.1),
30.5 (31.2), 32.8 (32.9), 40.6 (41.6), 56.6 (54.5), 58.9 (57.6), 63.2
(64.3), 114.1 (114.8), 142.6 (141.2); HRMS (EI) calcd for
1-[1-(3-Ch lor op r op yl)-2-p r op en yl]-1H-1,2,3-ben zotr ia -
1
zole (5a ): colorless oil; H NMR δ 1.81-1.84 (m, 2H), 2.49-
2.53 (m, 2H), 3.50-3.57 (t, 2H, J ) 5.2 Hz), 5.26 (dd, 1H, J )
3.6, 17.2 Hz), 5.33 (dd, 1H, J ) 4.2, 10.6 Hz), 5.38-5.42 (m,
1H), 6.25-6.38 (m, 1H), 7.37-7.56 (m, 3H), 8.09 (d, 1H, J )
7.1 Hz); 13C NMR δ 28.8, 30.7, 44.0, 61.6, 109.9, 118.2, 120.0,
123.9, 127.1, 135.3, 138.4, 146.2. Anal. Calcd for C12H14N3Cl:
C, 61.15; H, 5.99; N, 17.83. Found: C, 61.17; H, 6.09; N, 18.02.
1-[1-(3-Ch lor o-2-m et h ylp r op en yl)-1H-1,2,3-b en zot r ia -
zole (5b): mixture of two isomers, colorless oil (81%); 1H NMR
δ 1.07 (d, 3H, J ) 6.6 Hz) [minor isomer 0.99 (d, 3H, J ) 6.5
Hz), 1.52-1.62 (m, 1H), 1.96-2.05 (m, 1H), 2.59-2.69 (m, 1H),
3.41 (d, 2H, J ) 5.1 Hz), 5.18 (d, 1H, J ) 17.1 Hz), 5.28 (d,
1H, J ) 11.6 Hz), 5.42-5.53 (m, 1H), 6.17 (ddd, 1H, J ) 6.1,
10.9, 17.8 Hz), 7.36 (t, 1H, J ) 7.8 Hz), 7.46 (t, 1H, J ) 7.8
Hz), 7.54 (d, 1H, J ) 8.4 Hz), 8.07 (d, 1H, J ) 8.1 Hz); 13C
NMR δ 17.0 (minor isomer 18.0), 31.6, 37.4 (37.3), 50.8 (50.0),
59.8 (60.0), 109.9, 117.8, 120.1, 123.9, 127.2, 132.2, 135.6
(135.5), 146.1. Anal. Calcd for C13H16N3Cl: C, 62.52; H, 6.46;
N, 16.83. Found: C, 62.54; H, 6.92; N, 17.04.
1-[1-(3-Ch lor op r op yl)-1-m et h yl-2-p r op en yl]-1H -1,2,3-
ben zotr ia zole (5c): colorless oil (80%); 1H NMR δ 1.48-1.54
(m, 1H), 1.95-2.02 (m, 4H), 2.41-2.61 (m, 2H), 3.42-3.58 (m,
2H), 5.25 (dd, 1H, J ) 2.5, 17.6 Hz), 5.41 (dd, 1H, J ) 2.8,
10.1 Hz), 6.22 (dd, 1H, J ) 10.7, 17.5 Hz), 7.34-7.41 (m, 2H),
7.64 (d, 1H, J ) 8.3 Hz), 8.06 (d, 1H, J ) 8.1 Hz); 13C NMR δ
24.9, 26.7, 36.6, 44.6, 65.5, 112.2, 115.6, 119.8, 123.4, 126.5,
131.9, 140.4, 146.5. Anal. Calcd for C13H16N3Cl: C, 62.52; H,
6.46; N, 16.83. Found: C, 62.78; H, 6.77; N, 16.35.
1-[1-(3-Ch lor op r op yl)-1-b en zyl-2-p r op en yl]-1H -1,2,3-
ben zotr ia zole (5d ): colorless oil (85%); 1H NMR δ 1.52-1.62
(m, 1H), 1.75-1.85 (m, 1H), 2.32-2.45 (m, 1H), 2.52-2.61 (m,
1H), 3.52 (t, 2H, J ) 6.9 Hz), 3.58 and 3.68 (ABq, 2H, J )
13.8 Hz), 5.26 (d, 1H, 17.6 Hz), 5.54 (d, 1H, 10.9 Hz), 6.21 (dd,
1H, J ) 10.9, 17.6 Hz), 6.68 (d, 2H, J ) 7.3 Hz), 7.21-7.30
(m, 3H), 7.35-7.48 (m, 2H), 7.60 (d, 1H, J ) 7.9 Hz), 8.09 (d,
1H, J ) 7.5 Hz); 13C NMR δ 26.8, 34.2, 43.6, 44.8, 68.9, 112.6,
117.2, 120.2, 123.7, 126.7, 128.0, 130.3, 132.8, 134.6, 139.1,
146.5. Anal. Calcd for C19H20N3Cl: C, 70.04; H, 6.19; N, 12.90.
Found: C, 70.08, H, 6.17; N, 12.85.
C
13H23N 193.1830, found: 193.1590.
N-r-Meth ylben zyl-2-vin ylp yr r olid in e (7d ):3b mixture of
two isomers, colorless oil; 1H NMR δ 1.36 (dd, 3H, J ) 6.5, 6.5
Hz) [1.46 (dd, 3H, J ) 6.6, 6.9 Hz, minor isomer)], 1.58-1.68
(m, 4H), 2.45-3.25 (m, 3H), 3.75-3.95 (m, 1H), 4.96 (dd, 1H,
J ) 2.1, 11.5 Hz), 5.12 (dd, 1H, J ) 1.5, 18.5 Hz), 5.65-5.85
(m, 1H), 7.25-7.45 (m, 5H); 13C NMR δ 16.2, 22.4 (minor
isomer 22.1), 31.9 (31.7), 48.2 (48.1), 58.6, 64.4 (63.9), 114.5
(115.4), 126.5 (126.7), 127.8 (127.9), 128.3, 141.1 (141.9), 142.3.
(R)-N-r-Meth ylben zyl-2-vin ylp yr r olid in e (7e):3b mix-
ture of two isomers, colorless oil; 1H NMR δ (1.46 (d, 3H, J )
7.1 Hz) [minor isomer 1.35 (d, 3H, J ) 6.8 Hz)], 1.55-1.95
(m, 4H), 2.32-2.52 (m, 1H), 2.88-2.98 (m, 1H), 3.25-3.35 (m,
1H) [2.68-2.78 (m, 1H)], 3.88 (q, 1H, J ) 6.9 Hz) [3.83 (q, 1H,
J ) 6.8 Hz), 5.05 (m, 2H), 5.84 (ddd, 1H, J ) 8.4, 9.2, 17.6 Hz)
[5.72 (dd, 1H, J ) 10.1, 17.9 Hz)], 7.15-7.35 (m, 5H); 13C NMR
δ 16.2 (minor isomer 21.6), 22.1 (22.4), 31.7 (31.9), 47.7 (48.2),
58.6 (58.7), 63.9 (64.4), 114.5 (115.4), 126.5 (126.7), 127.7
(127.8), 127.9 (128.3), 141.1 (141.9), 150.2 (142.5).
1-[1-(2-Oxir a n ylm eth yl)-2-p r op en yl]-1H-1,2,3-ben zotr i-
a zole (9): mixture of two isomers, colorless oil (88%); 1H NMR
δ 2.42-3.05 (m, 5H), 5.29-5.40 (m, 2H), 5.52-5.54 (m, 1H),
6.21-6.42 (m, 1H), 7.36-7.51(m, 2H), 7.56 (d, 1H, J ) 8.4 Hz),
8.08 (d, 1H, J ) 8.3 Hz); 13C NMR δ 36.6 (minor isomer 36.8),
47.0 (47.2), 48.9, 59.7 (59.5), 109.7, 117.0 (117.1), 118.9, 119.9,
123.9 (124.0), 127.2, 134.7 (135.3), 146.5. Anal. Calcd for
C
12H13N3O: C, 66.96; H, 6.09; N, 19.52. Found: C, 66.61; H,
6.26; N, 19.81.
1-[1-(4-Ch lor ob u t yl)-2-p r op e n yl]-1H -1,2,3-b e n zot r i-
a zole (16a ): colorless oil (80%); 1H NMR δ 1.31-1.54 (m, 2H),
1.74-1.85 (m, 2H), 2.19-2.40 (m, 2H), 3.46 (t, 2H, J ) 6.5
Hz), 5.20 (d, 1H, J ) 17.3 Hz), 5.28 (d, 1H, J ) 10.5 Hz), 5.30-
5.35 (m, 1H), 6.17 (ddd, 1H, J ) 6.6, 10.5, 17.1 Hz), 7.36 (t,
1H, J ) 8.1 Hz), 7.46 (t, 1H, J ) 8.3 Hz), 7.53 (d, 1H, J ) 8.2
Hz), 8.06 (d, 1H, J ) 8.3 Hz); 13C NMR δ 23.4, 31.9, 32.8, 44.4,
1-Ben zyl-2-m eth yl-2-vin ylp yr r olid in e (7f): colorless oil;
1H NMR δ 1.16 (s, 3H), 1.65-1.92 (m, 2H), 2.8-2.85 (m, 1H),
2.99-3.04 (m, 1H), 3.58 and 3.83 (AB q, 2H, J ) 12.8 Hz),
5.09-5.18 (m, 2H), 5.88-5.98 (m, 1H), 7.30 (m, 5H); 13C NMR
δ 17.5, 21.1, 39.0, 50.4, 53.4, 62.2, 113.0, 126.5, 128.1, 128.4,

6070 J . Org. Chem., Vol. 64, No. 16, 1999
Katritzky et al.
140.5, 144.6; GCMS(EI) 200 (M - 1), 186, 170, 91; HRMS (EI)
calcd for C14H19N 186.1282 (M+ - 15), found 186.1286.
1-(2-E t h yloxyet h yl)-2-vin ylp yr r olid in e (7g): colorless
oil; 1H NMR δ 1.21 (t, 3H, J ) 6.9 Hz), 1.55-1.95 (m, 4H),
2.15-2.35 (m, 2H), 2.71 (q, 1H, J ) 7.7 Hz), 2.96-3.04 (m,
1H), 3.21-3.27 (m, 1H), 3.47-3.58 (m, 4H), 5.09 (d, 1H, J )
10.1 Hz), 5.16 (d, 1H, J ) 17.1 Hz), 5.72 (ddd, 1H, J ) 7.6,
9.8, 16.9 Hz); 13C NMR δ 15.1, 22.3, 31.2, 53.5, 54.3, 66.3, 69.4,
69.6, 116.4, 140.8; HRMS (EI) calcd for C10H19NO 168.1388
(M+ - 1), found 168.1416.
105.1, 107.1, 120.9, 126.3, 127.3, 128.7, 134.8, 138.2. Anal.
Calcd for C13H15N: C, 84.28; H, 8.16; N, 7.56. Found: C, 84.36;
H, 8.71; N, 7.62.
1-Ben zyl-2-vin ylp ip er id in e (18a ):1k colorless oil; 1H NMR
δ 1.25-1.95 (m, 7H), 2.64-2.71 (m, 1H), 2.78-2.83 (m, 1H),
3.05 and 4.06 (AB q, 2H, J ) 13.5 Hz), 5.10 (dd, 1H, J ) 1.7,
10.2 Hz), 5.19 (d, 1H, J ) 17.3 Hz), 5.90 (ddd, 1H, J ) 1.6,
10.1, 17.6 Hz), 7.31 (m, 5H); 13C NMR δ 24.0, 25.8, 33.7, 52.1,
59.8, 66.7, 115.5, 126.6, 128.0, 129.0, 139.6, 142.6.
1
1-Hexyl-2-vin ylp ip er id in e (18b): colorless oil; H NMR
1,2-Diben zyl-2-vin ylp yr r olid in e (7h ): colorless oil; 1H
NMR δ 1.59-1.68 (m, 3H), 1.7-1.95 (m, 1H), 2.42-2.45 (m,
1H), 2.80-2.83 (m, 1H), 2.89 and 3.01 (AB q, 2H, J ) 13.2
Hz), 3.49 and 4.01 (AB q, 2H, J ) 13.5 Hz), 5.08 (d, 1H, J )
17.6 Hz), 5.23 (d, 1H, J ) 11.0 Hz), 5.98 (dd, 1H, J ) 10.8,
17.4 Hz), 7.26-7.41 (m, 10 H); 13C NMR δ 20.8, 33.7, 41.9,
50.7, 53.0, 67.6, 114.2, 125.9, 126.6, 127.6, 128.2, 128.4, 130.7,
139.5, 139.8, 140.2; HRMS (EI) calcd for C20H23N 277.1830,
found 277.1805.
δ 0.88 (t, 3H, J ) 6.5 Hz), 1.27-1.73 (m, 14H), 1.99-2.25 (m,
2H), 2.54-2.74 (m, 2H), 2.95-2.99 (m, 1H), 5.03 (d, 1H, J )
10.2 Hz), 5.12 (d, 1H, J ) 14.2 Hz), 5.72-5.84 (m, 1H); 13C
NMR δ 14.1, 22.6, 23.9, 25.8, 26.0, 27.4, 31.8, 33.6, 52.1, 55.7,
66.6, 115.0, 142.2; HRMS (EI) calcd for C13H25N 195.1987,
found 195.1990.
1-Ben zyl-2-bu tyl-2-vin ylp yr r olid in e (18c): colorless oil;
1H NMR δ 0.93 (t, 3H, J ) 6.8 Hz), 1.35-1.85 (m, 12H), 2.38-
2.45 (m, 2H), 3.48 and 3.65 (AB q, 2H, J ) 14.3 Hz), 5.13 (d,.
1H, J ) 17.9 Hz), 5.20 (d, 1H, J ) 11.1 Hz), 6.01 (dd, 1H, J )
11.1, 17.9 Hz), 7.21-7.38 (m, 5H); 13C NMR δ 14.2, 20.8, 23.6,
25.9, 26.0, 33.9, 46.6, 53.5, 60.2, 114.1, 126.3, 128.1, 128.2,
141.4, 142.3. Anal. Calcd for C18H27N: C, 83.99; H, 10.57; N,
5.44. Found: C, 83.87; H, 11.04; N, 5.46.
N,N-Dieth yla m in oeth yl-2-(2-vin yl-1-pyr r olidin e)-1-eth -
1
a n a m in e (7i): colorless oil; H NMR δ 1.04 (t, 6H, J ) 7.2
Hz), 1.5-1.95 (m, 4H), 2.12-2.22 (m, 2H), 2.56 (q, 4H, J )
6.8 Hz), 2.58-2.72 (m, 3H), 2.86-2.95 (m, 1H), 3.18-3.25 (m,
1H), 5.10 (d, 1H, J ) 10.2 Hz), 5.16 (d, 1H, J ) 19.0 Hz), 5.72
(ddd, 1H, J ) 9.9, 10.2, 19.0 Hz); 13C NMR δ 11.6, 22.2, 31.2,
47.4, 51.7, 52.2, 53.9, 69.4, 116.4, 140.7; HRMS (EI) calcd for
C
12H24N2 196.1936, found 196.1999.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and HRMS
spectra for compounds 7b,c,f-i and 18b. This material is
available free of charge via the Internet at http://pubs.acs.org.
1-Ben zyl-2-eth ylp yr r ole (13): colorless oil (52%); 1H NMR
δ 1.20 (t, 3H, J ) 7.3 Hz), 2.47 (q, 2H, J ) 7.4 Hz), 5.03 (s,
2H), 5.98 (br, 1H), 6.15 (br, 1H), 6.63 (br, 1H), 6.98 (d, 2H, J
) 6.9 Hz), 7.26-7.30 (m, 3H); 13C NMR δ 12.9, 19.4, 50.2,
J O990181R