Novel tandem cyclizations/reaction with electrophiles of α-aminoalkyl radicals

Full text of DOI:10.1021/jo981735d

J . Org. Chem. 1999, 64, 3335-3338
3335
Sch em e 1
Novel Ta n d em Cycliza tion s/Rea ction w ith
Electr op h iles of r-Am in oa lk yl Ra d ica ls
Alan R. Katritzky,*,‡ Daming Feng,‡ Ming Qi,‡
J ose´ M. Aurrecoechea,*,§ Rube´n Suero,§ and
Natalia Aurrekoetxea§
Center for Heterocyclic Compounds, Department of
Chemistry, University of Florida, Gainesville, Florida
32611-7200, and Departamento de Quı´mica Orga´nica,
Facultad de Ciencias, Universidad del Pa´ıs Vasco,
Apartado 644, 48080 Bilbao, Spain
Received August 24, 1998
Sch em e 2
Construction of carbon-carbon bonds adjacent to
nitrogen is of great importance for the synthesis of many
nitrogen-containing compounds of biological significance,
including interalia alkaloids and amino acids. Such
carbon-carbon bond formation usually occurs via one of
three different types of intermediates: (i) iminium ions,1
(ii) R-amino-substituted carbanions,2 and (iii) R-amino-
substituted radicals.3
Regarding the last of these routes, electron-rich
R-aminoalkyl radicals (1a,b, Scheme 1), which are strongly
nucleophilic, react readily with electron-deficient CdC
bonds (e.g., formation of products 4a ).3,4,5b However,
attempted intramolecular additions of nonstabilized
R-amino radicals (1a ) to unactivated CdC bonds (Scheme
1) mostly give reduction products 25 or very low yields of
cyclization products4a,6a (for an exception see ref 6b). By
contrast, R-amino radicals (1c) with stabilizing groups
(e.g., acyl,7 sulfonyl5a,6) or a quaternized8 nitrogen un-
dergo intramolecular cyclization to unactivated CdC
bonds (Scheme 1).
substituent in the transition state leading to cyclization,
(ii) the nucleophilic nature of the radical, and (iii) the
tendency for dimerization of the R-aminoalkyl radical.
However, the previously reported4a,6 formation of small
amounts of the cyclized products and the dependence of
the cyclization stereochemistry on the stability of the
R-amino radical5b suggested to us that an equilibrium
exists between the acyclic radical and the cyclized one
(cf. 7 T 8, Scheme 2). Normally, the acyclic radical
undergoes reduction3,5 or dimerization.5b,9 We reasoned
that an additional driving force, such as the rapid
reduction of the cyclized radical to the corresponding
organosamarium (cf. 8 f 9), could favor the formation
of cyclized products. As justification of these speculations,
we now report a novel reaction sequence comprising site
specific formation of an R-aminoalkyl radical, regioselec-
tive addition of this radical to an unactivated double
bond, further reduction to a carbanion, and finally
carbanion trapping by an electrophile.10
The cyclization of an R-aminoalkyl radical onto an
unactivated CdC bond is difficult due to (i) partial loss
of the stabilization provided to the radical by the amino
‡ University of Florida.
§ Universidad del Pa´ıs Vasco.
(1) Kleinman, E. F. In Comprehensive Organic Synthesis: Selectivity,
Strategy and Efficiency in Modern Organic Chemistry; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 893.
(2) (a) Beak, P.; Zajdel, W. J .; Reitz, D. B. Chem. Rev. 1984, 84, 471.
(b) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552. (c) Kessar, S. V.; Singh, P. Chem.
Rev. 1997, 97, 721. (d) Katritzky, A. R.; Qi, M. Tetrahedron 1998, 54,
2647.
(3) Renaud, P.; Giraud, L. Synthesis 1996, 913.
(4) (a) Aurrecoechea, J . M.; Lo´pez, B.; Ferna´ndez, A.; Arrieta, A.;
Coss´ıo, F. P. J . Org. Chem. 1997, 62, 1125. (b) Yoon, U. C.; Mariano,
P. S. Acc. Chem. Res. 1992, 25, 233.
(5) (a) Padwa, A.; Nimmesgern, H.; Wong, G. S. K. J . Org. Chem.
1985, 50, 5620. (b) Aurrecoechea, J . M.; Ferna´ndez-Acebes, A. Synlett
1996, 39.
N-(R-Aminobutyl)benzotriazole (6a ) was prepared from
the condensation of a secondary amine 5,11 butyralde-
hyde, and benzotriazole (Scheme 2). Crude 6a was
treated directly with samarium diiodide in THF-HMPA
(6) (a) Padwa, A.; Dent, W.; Nimmesgern, H.; Venkatramanan, M.
K.; Wong, G. S. K. Chem. Ber. 1986, 119, 813. (b) Robertson, J .; Peplow,
M. A.; Pillai, J . Tetrahedron Lett. 1996, 37, 5825.
(7) (a) Bachi, M. D.; Hoornaert, C. Tetrahedron Lett. 1981, 22, 2693.
(b) Hart, D. J .; Tsai, Y.-M. J . Am. Chem. Soc. 1982, 104, 1430. (c)
Kametani, T.; Honda, T. Heterocycles 1982, 19, 1861. (d) Keck, G. E.;
Enholm, E. J . Tetrahedron Lett. 1985, 26, 3311. (e) Beckwith, A. L. J .;
Boate, D. R. Tetrahedron Lett. 1985, 26, 1761. (f) Kano, S.; Yuasa, Y.;
Asami, K.; Shibuya, S. Heterocycles 1988, 27, 1437. (g) Arya, P.;
Wayner, D. D. M. Tetrahedron Lett. 1991, 32, 6265. (h) Kuzmich, D.;
Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S.; Atarashi, S.; Choi, J .-K.;
Hart, D. J . J . Am. Chem. Soc. 1994, 116, 6943.
(8) (a) Martin, S. F.; Yang, C.-P.; Laswell, W. L.; Ru¨eger, H.
Tetrahedron Lett. 1988, 29, 6685. (b) Della, E. W.; Knill, A. M.; Smith,
P. A. Chem. Commun. 1996, 14, 1637. (c) Rios, L. A.; Dolbier, W. R.,
J r.; Paredes, R.; Lusztyk, J .; Ingold, K. U.; J onsson, M. J . Am. Chem.
Soc. 1996, 118, 11313.
(9) Aurrecoechea, J . M.; Ferna´ndez-Acebes, A. Tetrahedron Lett.
1992, 33, 4763.
(10) The use of radical cyclizations in organic synthesis is of
increasing importance; see: J asperse, C. P.; Curran, D. P.; Fevig, T.
L. Chem. Rev. 1991, 91, 1237. Samarium diiodide-mediated sequencing
reactions have been reviewed recently; see: Molander, G. A.; Harris,
C. R. Chem. Rev. 1996, 96, 307. Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321.
(11) Brands, K. M. J .; Meekel, A. A. P.; Pandit, U. K. Tetrahedron
1991, 47, 2005.
10.1021/jo981735d CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/14/1999

3336 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
Ta ble 1. Sequ en tia l Rea ction s fr om 6 to 10
the major isomers of 10a -j C-2 and C-3 were shielded
in the 13C NMR spectrum when compared with the
corresponding resonances of the minor isomers.4a,13
The introduction of larger isopropyl or tert-butyl groups
at C-2 resulted in almost no difference in diastereose-
lectivity for the former (Table 1, 2.8:1 for 10l, similar to
compound 10e) but a large increase for the latter (19.7:1
for 10m ). However the sense of the diastereoselection
changed dramatically in the case of the tert-butyl group
as the trans isomer was now found to predominate. The
reaction also afforded significant amounts of byproduct
10n , the result of protonation with high stereoselectivity
(10:1) of a carbanionic intermediate 9 found in the second
stage of the reaction. The trans stereochemistry in the
major isomer 10n was indicated by its downfield shifted
C-2 when compared with the minor isomer; compound
10m should possess the same stereochemistry of 10n for
mechanistic reasons (vide infra). The low yield obtained
for 10m , as well as the changes in the sense and amount
of diastereoselectivity, should obviously be attributed to
steric hindrance factors that render the formation of the
normally preferred cis isomer a slow process. Thus, the
generally preferred cis stereochemistry in products 10
was expected on the basis of Beckwith’s model for radical
ring closures,14 and the only moderate diastereoselectivity
observed for small R groups is in line with previous
results obtained with the hex-5-enyl radical.14 This
relatively low stereoselectivity is in contrast to that found
in related R-aminoalkyl radical ring closures leading to
cyclopentylamines, which are much more selective.4a In
this latter case, the cis-TS benefits additionally from a
secondary stabilizing orbital interaction between SOMO
and LUMO p-type orbitals that cannot take place during
formation of pyrrolidines due to the endocyclic nature of
the N-C bond throughout cyclization. For R ) t-Bu,
however, the greater steric congestion associated to the
cis-TS overwhelms the normal stereoelectronic factors
that usually favor cis products and high trans selectivity
results.15
Two possible intermediates, a radical or a carbanion,
could be involved in the cyclization step. Previously, we
showed that N-(R-aminomethyl)benzotriazoles are easily
transformed into the corresponding nonstabilized R-ami-
nocarbanions by treatment with SmI2.16 However, when
the NCH2Bt methylene group carries an alkyl or aryl
group substituent (e.g., compound 6), the corresponding
radical is more stable and cannot be further reduced by
SmI2;17 rather, hydrogen transfer or dimerization is
observed.16 This appears to exclude the possibility of a
carbanion cyclization in the present reaction, and we
believe that the radical was the active intermediate in
our new reactions. The whole process comprises the
formation of an R-aminoalkyl radical 7, addition of 7 to
the CdC bond to generate the primary pyrrolidin-3-
ylmethyl radical 8, the reduction of 8 by SmI2 to carban-
cis/trans ratiob
by GC
products 10
R
electrophile
E
yielda (%) by NMR
a
b
c
d
e
f
Pr
H2O
MeOD
H
D
58
71
60
65
46
53
38
41
43
45
37
68
51
36
34
2.6/1
2.0/1
2.4/1c
2.0/1c
2.2/1
2.3/1
2.2/1
5.8/1c
4.1/1c
2.3/1
2.5/1
1.5/1
2.8/1
1/19.7
1/10.0
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
MeCOEt
MeCOPr
EtCOEt
(CH2)5CO
(CH2)5CO
i-PrCHO
PhCHO
I2
MeC(OH)Et
MeC(OH)Pr
Et2COH
(CH2)5COH
(CH2)5COH
i-PrCHOH
PhCHOH
I
i-PrNHCO
H
Et2CHOH
Et2CHOH
H
fd
g
h
i
j
k
l
i-PrNCO
i-Pr H2O
i-Pr EtCOEt
t-Bu EtCOEt
t-Bu EtCOEt
m
n e
a
Protonated pyrrolidines (10a ,n , etc.) were always isolated with
the expected products, sometimes in substantial amounts (e.g.,
b
43% of 10a with 10j, 34% of 10n with 10m ). Determined by GC
or 1H NMR. c The 13C spectra showed the presence of four isomers,
d
but the GC separated only two peaks. Benzotriazole substrate
and cyclohexanone were added to SmI2 solution simultaneously.
e Obtained as a byproduct from the preparation of 10m .
under argon to form, via radical intermediates 7a and
8a , carbanion 9a , which was quenched by H2O (Scheme
2). Pyrrolidine 10a (Table 1) was isolated as a mixture
of cis and trans isomers in 58% yield. When methyl
alcohol-d was used as electrophile to trap carbanion 9a ,
deuterium was incorporated to give cis- and trans-
pyrrolidines 10b. The cis and trans ratios (Table 1) were
determined by GC or integration of the H-2 signals in
the 1H NMR spectrum. Ketones worked well in this
sequence to form pyrrolidines 10c-f in 38-65% yields,
even when the ketone was added together with 6 to SmI2
(Table 1). Symmetrical ketones gave mixtures of cis and
trans isomers (Table 1). Unsymmetrical ketones formed
four isomers for 10c and 10d : GC separated only the cis
and trans forms, but the presence of the additional chiral
center in the side chain was obvious from the 13C spectra,
which showed the presence of all four isomers. This
general stepwise procedure was utilized with other
electrophiles: aliphatic and aromatic aldehydes gave 10g
and 10h (each as four isomers), iodine gave 10i, and
isopropyl isocyanate formed pyrrolidines 10j in moderate
yields (Table 1).
The yields reported in Table 1 are based on the amount
of starting amine 5 used and are, therefore, overall yields
for a two-pot, three-step process (a small amount of amine
5 was usually detected by NMR in crude benzotriazole
derivatives 6). The formation of 10b-j was always
accompanied by compound 10a (ca. 10-43%), probably
arising from protonation by traces of adventitious water
of the intermediate organosamarium reagent 9 before it
could be trapped by the electrophile; similar speculations
have been proposed by Molander and Harris.12 Alterna-
tively, it could be the result of competitive enolization
by the intermediate organosamarium, especially when
aliphatic ketones were used. The cis derivative predomi-
nated in products 10a -j. The cis:trans ratios for com-
pounds 10a -f,i,j were ca. 2:1, while those for pyrrolidines
10g,h derived from aldehydes were higher at 4:1 and 6:1.
The assignment of a cis stereochemistry for the major
cyclized product followed from the observation that for
(13) RajanBabu, T. V.; Fukunaga, T.; Reddy, G. S. J . Am. Chem.
Soc. 1989, 111, 1759.
(14) (a) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41,
3925. (b) Spellmeyer, D. C.; Houk, K. N. J . Org. Chem. 1987, 52, 959.
(c) Beckwith, A. L. J .; Cliff, M. D.; Schiesser, C. H. Tetrahedron 1992,
48, 4641. (d) Beckwith, A. L. J .; Chem. Soc. Rev. 1993, 22, 143.
(15) See ref 14c for a related case in the hex-5-enyl radical system.
We thank a reviewer for calling this point to our attention.
(16) Katritzky, A. R.; Qi, M.; Feng, D.; Nichols, D. A. J . Org. Chem.
1997, 62, 4121.
(17) Secondary carbanions can be prepared from N-(R-aminoalkyl)-
benzotriazoles by using the more powerful reducing agent Li/LiBr; see
ref 16.
(12) Molander, G. A.; Harris, C. R. J . Am. Chem. Soc. 1996, 118,
4059.

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3337
oil; 1H NMR (CDCl3, 300 MHz) δ 0.78-1.07 (m, 6H), 1.08-1.20
(m, 3H), 1.21-1.75 (m, 12H), 1.86-2.68 (m, 4H), 2.78-2.98 (m,
1H), 3.06 (d, J ) 12.8 Hz) and 3.37 (d, J ) 13.2 Hz) (total 1H),
3.99 (d, J ) 13.0 Hz) and 4.01 (d, J ) 12.6 Hz) (total 1H), 7.13-
7.43 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 14.5, 14.6, 14.8, 17.0,
17.2, 17.3, 17.4, 18.1, 19.9, 20.0, 27.1, 27.2, 27.4, 27.8, 30.7, 31.0,
31.2, 31.4, 32.4, 33.8, 36.3, 36.5, 38.1, 38.3, 41.0, 44.9, 45.1, 45.2,
46.0, 46.8, 47.0, 52.8, 58.8, 60.1, 66.9, 67.0, 70.8, 70.9, 72.9, 73.0,
73.2, 126.6, 128.1, 128.7, 128.8, 139.8, 139.9, 140.0. Anal. Calcd
for C20H33NO: C, 79.15; H, 10.96; N, 4.62. Found: C, 78.74; H,
11.26; N, 5.09.
ion 9, and the quenching of carbanion 9 by an electrophile
to afford as final product pyrrolidine 10.
In conclusion, we now report the tandem cyclization
of R-aminoalkyl radicals, which provides a new strategy
for the synthesis of pyrrolidines18 with a functional group
at C-3. The new reaction enlarges the synthetic potential
of R-aminoalkyl radicals and suggests its potential scope
in the preparation of alkaloids and other nitrogen-
containing heterocycles.
N-Ben zyl-2-p r op yl-3-(2-h yd r oxy-2-et h ylb u t yl)p yr r oli-
d in e (10e): obtained as a mixture of diastereoisomers; colorless
oil; 1H NMR (CDCl3, 250 MHz) δ 0.84-1.04 (m, 9H), 1.20-1.68
(m) and 2.59-2.67 (m, cis) (total 12H), 1.87-2.03 (m, 2H), 2.04-
2.30 (m, 2H), 2.82-2.94 (m, 1H), 3.40 (d, J ) 13.1 Hz, cis) and
3.08 (d, J ) 12.8 Hz, trans) (total 1H), 3.99 (d, J ) 13.1 Hz, cis)
and 4.02 (d, J ) 12.8 Hz, trans) (total 1H), 7.19-7.37 (m, 5H);
13C NMR (CDCl3, 62.9 MHz) δ 7.6, 7.8, 8.1, 14.6, 14.8, 18.0, 20.0,
30.5, 31.0, 31.3, 31.5, 31.8, 32.5, 33.7, 36.0, 37.6, 43.3, 52.8, 52.9,
58.8, 60.3, 66.9, 70.9, 74.9, 75.0, 126.6, 126.7, 128.1, 128.7, 128.8,
139.8, 140.1; HRMS calcd for C20H33NO 303.2562, found 303.2549.
N-Ben zyl-2-p r op yl-3-[(1-h yd r oxycycloh exyl)m eth yl]p yr -
r olid in e (10f): obtained as a mixture of diastereoisomers;
colorless oil; 1H NMR (CDCl3, 250 MHz) δ 0.93-0.96 (m, 3H),
1.21-1.69 (m, 17H), 1.85-2.04 (m, 2H), 2.10-2.33 (m, 2H), 2.58
(m, 1H), 2.90 (ddd, J ) 3.1, 7.9, 10.9 Hz, cis) and 2.84 (m, trans)
(total 1H), 3.36 (d, J ) 13.1 Hz, cis) and 3.08 (d, J ) 12.8 Hz,
trans) (total 1H), 4.00 (d, J ) 13.1 Hz, cis) and 4.02 (d, J ) 12.8
Hz, trans) (total 1H), 7.21-7.36 (m, 5H); 13C NMR (CDCl3, 62.9
MHz) δ 14.6, 14.8, 18.2, 19.9, 22.1, 22.2, 25.8, 31.0, 31.4, 32.3,
33.9, 35.7, 37.5, 37.6, 37.8, 38.1, 38.7, 41.9, 48.1, 52.7, 52.8, 58.8,
60.0, 67.0, 70.9, 71.6, 71.8, 126.6,126.7, 128.1, 128.7, 128.8, 139.8,
140.0; IR (CHCl3) ν 3420, 2930, 2860, 2780, 1495, 1450, 1360,
1250, 1140, 1070, 1025, 970, 700 cm-1; LRMS (EI) m/z 315 (M+),
272 (100); HRMS calcd for C21H33NO 315.2562, found 315.2569.
N-Ben zyl-2-p r op yl-3-(2-h yd r oxy-3-m eth ylbu tyl)p yr r oli-
d in e (10g): obtained as a mixture of four isomers; colorless oil;
1H NMR (one single isomer was enriched by column chroma-
tography, CDCl3, 300 MHz) δ 0.75-1.10 (m, 9H), 1.10-1.75 (m,
9H), 1.81-1.96 (m, 1H), 2.10-2.20 (m, 1H), 2.22-2.47 (m, 1H),
2.48-2.59 (m, 1H), 2.86-2.97 (m, 1H), 3.26 (d, 1H, J ) 13.2 Hz),
3.32-3.45 (m, 1H), 4.02 (d, 1H, J ) 13.2 Hz), 7.17-7.43 (m, 5H);
13C NMR (CDCl3, 75 MHz) δ 14.6, 17.5, 18.8, 20.1, 29.0, 32.2,
34.3, 34.5, 36.6, 52.9, 59.5, 66.6, 74.9, 126.6, 128.1, 128.8, 140.0.
Anal. Calcd for C19H31NO: C, 78.84; H, 10.79; N, 4.84. Found:
C, 78.61; H, 11.14; N, 5.18.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were determined on a
hot stage apparatus without correction. 1H (300 MHz) and 13C
NMR (75 MHz) spectra were recorded in CDCl3 with TMS,
respectively, as the internal reference. Elemental analyses and
high-resolution mass spectra were performed within the depart-
ment. Column chromatography was carried out on MCB silica
gel (200-425 mesh). Tetrahydrofuran (THF) was freshly distilled
from sodium benzophenone. The commercial HMPA was used
as received.
Gen er a l P r oced u r es for th e P r ep a r a tion of P yr r olid in es
10. A mixture of N-benzyl-N-but-3-en-1-ylamine (5, 2 mmol),
butyraldehyde (3 mmol), and benzotriazole (3 mmol) in dry
benzene (8 mL) was refluxed for 90 min with azeotropic
separation of water. The reaction mixture was washed with
aqueous Na2CO3 and vacuum-dried for 2 h to give crude 6, which
was dissolved in THF (20 mL) and added to SmI2/THF-HMPA
solution (60 mL 0.1 N SmI2 in THF, 6 mL HMPA) at 0 °C over
30 min. The mixture was stirred for an additional 10 min, and
then the appropriate electrophile (4 mmol) was added. The
mixture was stirred overnight. Water was added to quench the
reaction, followed by ether extraction. The residue, after solvent
evaporation, was purified by column chromatography on silica
gel (saturated with Et3N, hexanes-EtOAc-Et3N as eluent) to
give the title compound.
N-Ben zyl-2-p r op yl-3-m eth ylp yr r olid in e (10a ): obtained as
a mixture of diastereoisomers; colorless oil; 1H NMR (CDCl3, 250
MHz) δ 0.94-1.05 (m, 6H), 1.22-1.58 (m) and 2.35-2.42 (m,
cis) (total 5H), 1.81-1.99 (m, 2H), 2.07-2.26 (m, 2H), 2.89-2.97
(ddd, J ) 3.5, 8.1, 11.6 Hz, cis) and 2.81-2.87 (m, trans) (total
1H), 3.22 (d, J ) 13.2 Hz, cis) and 3.14 (d, J ) 12.9 Hz, trans)
(total 1H), 4.05 (d, J ) 13.2 Hz, cis) and 4.03 (d, J ) 12.9 Hz,
trans) (total 1H), 7.20-7.37 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 14.6, 14.7, 15.9, 18.6, 19.9, 20.5, 31.3, 31.5, 31.8, 34.4, 35.0,
37.3, 52.4, 52.7, 58.9, 66.6, 71.9, 126.4, 126.5, 127.9, 128.0, 128.6,
128.7, 139.9, 140.2; IR (CHCl3) ν 2960, 2930, 2880, 2780, 1490,
1450, 1370, 1140, 1070, 1025, 910, 730, 700 cm-1; LRMS (EI)
N-Ben zyl-2-p r op yl-3-(2-h yd r oxy-2-p h en yleth yl)p yr r oli-
d in e (10h ): obtained as a mixture of four isomers; colorless oil;
1H NMR (CDCl3, 300 MHz) δ 0.79-1.06 (m, 3H), 1.13-1.56 (m,
5H), 1.57-2.08 (m, 4H), 2.14 (q, 1H, J ) 8.7 Hz), 2.32-2.60 (m,
2H), 2.81-3.05 (m, 1H), 3.03 (d, J ) 12.4 Hz) and 3.25 (dd, J )
12.9 and 2.5 Hz) (total 1H), 4.00 (d, J ) 13.1) and 4.27 (d, J )
12.4 Hz) (total 1H), 4.70 (dd, 1H, J ) 8.9 and 2.3 Hz), 7.12-
7.46 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 14.6, 19.9, 20.0, 25.0,
28.8, 29.8, 32.1, 36.9, 37.8, 39.6, 39.7, 52.6, 52.8, 58.2, 59.5, 66.4,
67.3, 70.1, 72.7, 125.6, 125.9, 126.6, 126.8, 127.1, 127.3, 128.1,
128.2, 128.3, 128.4, 128.7, 128.9, 138.2, 140.0, 145.7, 146.0. Anal.
Calcd for C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C, 81.28;
H, 9.27; N, 4.75.
m/z 216 (M+), 174 (91), 91 (100); HRMS calcd for C15H23
216.1752, found 216.1751.
N-Ben zyl-2-p r op yl-3-(m et h yl-d )p yr r olid in e (10b ): ob-
tained as a mixture of diastereoisomers; colorless oil; H NMR
N
1
(CDCl3, 300 MHz) δ 0.80-1.09 (m, 5H), 1.15-2.45 (m, 9H), 2.75-
2.98 (m, 1H), 3.12 (d, J ) 12.9 Hz) and 3.20 (d, J ) 13.2 Hz)
(total 1H), 4.01 (d, J ) 12.9 Hz) and 4.02 (d, J ) 13.3 Hz) (total
1H), 7.12-7.42 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 14.7, 14.8,
15.4, 15.7, 16.0, 18.7, 20.0, 20.3, 20.6, 31.4, 31.5, 31.8, 34.4, 34.5,
35.1, 37.3, 37.4, 52.5, 52.8, 58.9, 59.0, 66.7, 72.0, 126.5, 126.6,
128.0, 128.1, 128.7, 128.8, 140.0, 140.3.
N-Ben zyl-2-p r op yl-3-(2-h yd r oxy-2-m eth ylbu tyl)p yr r oli-
d in e (10c): obtained as a mixture of four isomers; colorless oil;
1H NMR (one single isomer was enriched by column chroma-
tography, CDCl3, 300 MHz) δ 0.78-1.03 (m, 6H), 1.17 (s, 3H),
1.22-1.76 (m, 10H), 1.85-2.06 (m, 1H), 2.23 (q, 2H, J ) 8.5 Hz),
2.54-2.66 (m, 1H), 2.71-2.96 (m, 1H), 3.37 (d, 1H, J ) 13.0 Hz),
3.99 (d, 1H, J ) 13.1 Hz), 7.15-7.43 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 8.4, 14.6, 20.0, 27.2, 31.5, 32.4, 35.0, 36.3, 40.6, 52.8,
N-Ben zyl-2-p r op yl-3-iod om et h ylp yr r olid in e (10i): ob-
1
tained as a mixture of diastereoisomers; colorless oil; H NMR
(CDCl3, 300 MHz) δ 0.78-1.08 (m, 3H), 1.20-1.78 (m, 5H), 1.88-
2.08 (m, 1H), 2.10-2.35 (m, 2H), 2.44-2.70 (m, 2H), 2.77-3.04
(m, 1H), 3.05-3.46 (m, 2H), 3.97 (d, J ) 12.9 Hz) and 3.99 (d, J
) 13.2 Hz) (total 1H), 7.11-7.48 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 10.7, 14.5, 14.6, 18.6, 19.9, 30.7, 30.9, 31.3, 34.8, 44.1,
45.8, 51.8, 52.2, 58.6, 59.0, 67.0, 70.0, 126.7, 126.8, 128.1, 128.6,
128.7, 139.3, 139.6; HRMS calcd for C15H22NI 343.0797, found
343.0796.
N-Ben zyl-2-p r op yl-3-(isop r op ylca r b a m oylm et h yl)p yr -
r olid in e (10j): obtained as a mixture of diastereoisomers; white
solid; mp 66-68 °C; 1H NMR (CDCl3, 300 MHz) δ 0.95 (t, 3H, J
) 7.1 Hz), 1.08 (d, J ) 6.6 Hz) and 1.13 (d, J ) 6.5 Hz) (total
6H), 1.21-1.70 (m, 5H), 1.81-1.98 (m, 1H), 2.00-2.68 (m, 5H),
2.78-2.96 (m, 1H), 3.19 (d, 1H, J ) 12.9 Hz), 3.93-4.18 (m, 1H),
4.03 (d, 1H, J ) 13.3 Hz), 5.43 (d, J ) 6.0 Hz) and 6.18 (d, J )
60.2, 67.0, 73.2, 126.6, 128.1, 128.7, 140.1. Anal. Calcd for C19H31
NO: C, 78.84; H, 10.79; N, 4.84. Found: C, 78.70; H, 11.19; N,
4.95.
N-Ben zyl-2-p r op yl-3-(2-h yd r oxy-2-m eth ylp en tyl)p yr r o-
lid in e (10d ): obtained as a mixture of four isomers; colorless
-
(18) For
a recent survey of the synthesis of pyrrolidines, see:
Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1993, 58, 3857.

3338 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
6.5 Hz) (total 1H), 7.15-7.38 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 14.5, 14.6, 18.4, 19.9, 22.7, 28.2, 29.1, 31.7, 34.7, 36.7, 37.6,
39.7, 41.0, 41.2, 42.4, 52.1, 52.7, 58.4, 58.8, 66.1, 69.3, 126.7,
128.1, 128.7, 128.8, 139.4, 170.9, 171.5. Anal. Calcd for
C19H30N2O: C, 75.45; H, 10.00; N, 9.26. Found: C, 75.07; H,
10.16; N, 9.47.
N-Ben zyl-2-ter t-bu tyl-3-(2-h yd r oxy-2-eth ylbu tyl)p yr r o-
lid in e (10m ): obtained as a mixture of diastereoisomers; color-
less oil; H NMR (CDCl3, 300 MHz) δ 0.87 (t, 6H, J ) 7.4 Hz),
0.96 (s, 9H), 1.06-1.35 (m, 2H), 1.37-1.59 (m, 5H), 1.60-1.73
(m, 1H), 1.74-1.93 (m, 1H), 2.08-2.25 (m, 2H), 2.35-2.48 (m,
1H), 2.77-2.90 (m, 1H), 3.55 (d, 1H, J ) 14.0 Hz), 4.07 (d, 1H,
J ) 14.0 Hz), 7.18 (m, 1H), 7.29 (t, 2H, J ) 7.3 Hz), 7.39 (d, 2H,
J ) 7.3 Hz); 13C NMR (CDCl3, 75 MHz) δ 7.8, 8.1, 27.2, 30.8,
31.7, 32.0, 36.0, 36.7, 45.8, 53.6, 63.6, 75.5, 82.3, 126.4, 128.1,
141.4. Anal. Calcd for C21H35NO: N, 4.41. Found: N, 4.51.
1
N-Ben zyl-2-isop r op yl-3-m et h ylp yr r olid in e (10k ): ob-
1
tained as a mixture of diastereoisomers; colorless oil; H NMR
(CDCl3, 300 MHz) δ 0.75-1.15 (m, 9H), 1.18-2.57 (m, 6H), 2.75-
3.02 (m, 1H), 3.20 (d, J ) 13.2 Hz) and 3.37 (d, J ) 13.7 Hz)
(total 1H), 4.00 (d, J ) 13.5 Hz) and 4.04 (d, J ) 13.5 Hz) (total
1H), 7.12-7.50 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 15.8, 16.9,
19.6, 19.9, 21.1, 22.6, 29.7, 29.9, 32.5, 32.8, 32.9, 36.4, 52.5, 53.3,
59.7, 61.9, 71.9, 77.6, 126.4, 126.5, 128.1, 128.3, 128.5, 140.8,
141.2. Anal. Calcd for C15H23NO: C, 82.89; H, 10.67; N, 6.44.
Found: C, 82.83; H, 10.86; N, 7.02.
N-Ben zyl-2-isop r op yl-3-(2-h yd r oxy-2-eth ylbu tyl)p yr r o-
lid in e (10l): obtained as a mixture of diastereoisomers; color-
less oil; 1H NMR (CDCl3, 300 MHz) δ 0.71-0.92 (m, 6H), 0.93-
1.15 (m, 6H), 1.17-1.32 (m, 1H), 1.35-1.65 (m, 7H), 1.66-1.95
(m, 2H), 2.08 (br s, 1H), 2.15-3.01 (m, 3H), 3.24 (d, J ) 13.2
Hz) and 3.57 (d, J ) 13.6 Hz) (total 1H), 3.99 (d, J ) 13.2 Hz)
and 4.09 (d, J ) 13.6 Hz) (total 1H), 7.09-7.45 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 7.8, 7.9, 8.0, 8.1, 18.1, 18.5, 19.6, 22.3, 26.9,
30.5, 30.6, 31.0, 31.5, 31.6, 31.7, 33.4, 34.6, 37.3, 37.4, 45.3, 49.6,
52.9, 54.3, 60.3, 63.4, 71.5, 75.2, 75.4, 77.5, 126.4, 126.5, 127.6,
N-Ben zyl-2-ter t-b u t yl-3-m et h ylp yr r olid in e (10n ): ob-
1
tained as a mixture of diastereoisomers; colorless oil; H NMR
(CDCl3, 300 MHz) δ 0.94 (br s, 9H),1.01 (d, 3H, J ) 6.0 Hz),
1.30-1.44 (m, 1H), 1.55-1.92 (m, 1H), 2.03-2.58 (m, 3H), 2.77-
3.03 (m, 1H), 3.54 (d, 1H, J ) 14.0 Hz), 4.15 (d, 1H, J ) 14.0
Hz), 7.14-7.53 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 22.8, 27.0,
28.5, 33.0, 35.0, 53.6, 63.8, 81.7, 126.4, 126.8, 128.0, 128.1, 141.6.
Anal. Calcd for C16H25N: C, 83.06; H, 10.89; N, 6.05. Found: C,
82.38; H, 10.81; N, 6.04.
Ack n ow led gm en t. The group at UPV acknowledges
financial support by Direccio´n General de Ensen˜anza
Superior (DGES PB95-0344) and Universidad del Pa´ıs
Vasco (UPV 170.310-EC216/97).
128.1, 128.2, 128.5, 130.8, 140.8, 141.2. Anal. Calcd for C20H33
-
NO: C, 79.15; H, 10.96; N, 4.62. Found: C, 79.47; H, 10.93; N,
4.75.
J O981735D