Stereoselective synthesis of N-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides

Article abstract of DOI:10.1016/j.tet.2005.03.110

The stereoselective synthesis of N-acyl- and N-Boc-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides is described. These reactions effect formation of two bonds in a single operation and proceed with generally high levels of diastereoselectivity. In contrast to previously described reactions of γ-(N-arylamino) alkenes, these transformations proceed in high yield and high regioselectivity with both electron-rich and electron-deficient aryl bromides as well as vinyl bromide substrates.

Full text of DOI:10.1016/j.tet.2005.03.110

Tetrahedron 61 (2005) 6447–6459
Stereoselective synthesis of N-protected pyrrolidines via
Pd-catalyzed reactions of g-(N-acylamino) alkenes and
g-(N-Boc-amino) alkenes with aryl bromides
*
Myra Beaudoin Bertrand and John P. Wolfe
Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055, USA
Received 8 November 2004; revised 4 February 2005; accepted 4 March 2005
Available online 11 May 2005
Abstract—The stereoselective synthesis of N-acyl- and N-Boc-protected pyrrolidines via Pd-catalyzed reactions of g-(N-acylamino) alkenes
and g-(N-Boc-amino) alkenes with aryl bromides is described. These reactions effect formation of two bonds in a single operation and
proceed with generally high levels of diastereoselectivity. In contrast to previously described reactions of g-(N-arylamino) alkenes, these
transformations proceed in high yield and high regioselectivity with both electron-rich and electron-deficient aryl bromides as well as vinyl
bromide substrates.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
A diverse array of biologically active molecules contain
substituted pyrrolidine cores.1 Many strategies for the
(1)
synthesis of substituted pyrrolidines employ intramolecular
C–N bond-forming reactions for the construction of the
heterocyclic ring.2 However, very few methods allow for
simultaneous intramolecular C–N bond formation and
intermolecular formation of a C10 carbon–carbon bond;3
existing methods are limited in scope and/or require harsh
reaction conditions or toxic reagents.
Despite the utility of this transformation for the synthesis of
N-aryl pyrrolidines, these products cannot be easily
We recently described a new method for the stereoselective
synthesis of N-aryl pyrrolidines via Pd-catalyzed reactions
of g-(N-arylamino) alkenes with aryl bromides (Eq. 1).4,5
This transformation effects the formation of two bonds
transformed into other N-substituted (or unsubstituted)
pyrrolidine derivatives, as cleavage of the aryl C–N bond
is not readily accomplished.6 In addition, reactions of 1 or
related g-N-(p-methoxyphenyl) aminoalkenes provide only
(one C–C bond and one C–N bond) along with upto two
moderate yields of the desired product when vinyl bromides
stereocenters in a single step. This method is effective for
or electron-deficient aryl bromides are used as coupling
the preparation of a number of N-aryl pyrrolidine deriva-
partners due to competing N-arylation or N-vinylation of the
tives (e.g., 2), and substrates bearing substituents at C-1 or
relatively electron-rich nitrogen.
C-3 are converted to the corresponding cis-2,5-disubsti-
tuted- or trans-2,3-disubstituted pyrrolidines in good yield
To address the limitations described above, we have
with excellent (O20:1) diastereoselectivity. In most reac-
developed conditions to effect the conversion of N-acyl
tions small amounts of regioisomeric products 3 are formed
in addition to the desired product 2, although ratios of 2:3
and N-Boc protected g-aminoalkenes into the correspond-
ing pyrrolidines. The Boc and acyl protecting groups can be
readily cleaved under relatively mild conditions,7 and also
serve to minimize competing N-arylation side reactions by
are typically R10:1.
decreasing the nucleophilicity of the nitrogen atom. Our
preliminary studies on the scope and limitations of these
transformations are described herein.
Keywords: Stereoselective synthesis; Pyrrolidines; Diastereoselectivity;
Palladium; Arylhalide.
*
Corresponding author; e-mail: jpwolfe@umich.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.110

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M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
2. Results and discussion
were converted to the desired pyrrolidines in good yield
with high regioselectivity. In contrast, the Pd-catalyzed
reactions of 2-bromonaphthalene with N-benzyl substituted
substrate 4a and N-(p-trifluoromethylbenzoyl) substituted
derivative 4f failed to provide detectable amounts of
pyrrolidine products.11
2.1. Optimization studies
In order to develop a new route to N-protected pyrrolidines,
we initially examined Pd-catalyzed reactions of 2-bromo-
naphthalene with N-4-pentenylacetamide (4b). Our
previous studies on Pd/phosphine-catalyzed reactions of
g-(N-arylamino) alkenes with aryl bromides showed that the
nature of the phosphine ligand had a pronounced effect on
the yield of the desired pyrrolidine product.4 Thus, 4b was
treated with 2-bromonaphthalene and NaOtBu in the
presence of a catalytic amount of Pd2(dba)3 and various
phosphine ligands. The reactions were heated at 110 8C for
9 h, quenched, and assayed by GC. As shown in Table 1,
dpe-phos8 gave the highest yield in the conversion of 4b to
5b. The use of rigid bidentate phosphine ligands generally
provides higher yields than monodentate ligands. However,
subsequent studies on the scope of these reactions revealed
that the optimal bidentate ligand for a given transformation
is somewhat dependent on substrate structure. The use of
dppe,8 dppb,8 or nixantphos8 provides the highest yields in
some reactions (see below), and in some cases Pd(OAc)2
was found to provide slightly better results than Pd2(dba)3.
The effect of other parameters such as solvent and base was
also examined in several different reactions. In general,
weak bases such as K2CO3 or Cs2CO3 were less effective
than NaOtBu; their use resulted in the formation of large
amounts of Heck-type products. Toluene was found to be
the optimal solvent although ethereal solvents such as DME
and dioxane provided satisfactory results in many instances.
Use of THF as solvent in reactions of Boc-protected
substrates led to diminished product yields due to base-
induced cleavage of the boc-group from the substrate.12,13
2.2. Scope and limitations
Following our initial optimization studies we examined
reactions of N-acyl-protected substrate 4b and N-Boc-
protected substrate 4c with a variety of different aryl and
vinyl bromides. As shown in Table 3, the transformations
proceed in good yield with electron-neutral (entries 1, 2, and
5) and electron-poor (entries 3 and 6) aryl bromides. Use of
an electron-rich aryl bromide afforded a moderate yield of
the desired product, although partial oxidation of the N-acyl
pyrrolidine product to the corresponding 2,3-dihydropyrrole
occurred under the reaction conditions (entry 7).14 In all
cases examined a single product regioisomer was
formed. The major side products observed in reactions
of 4b and 4c derive from competing Heck arylation or
N-arylation of the substrate. The competing Heck arylation
is more problematic in reactions of acetate protected
substrate 4b.
Table 1. Ligand effects
Ligand
% Conversion
GC ratio
5b
6b
Othera
PPh3
59
35
61
91
95
96
34
6
23
8
10
7
5
19
3
—
5
4
6
b
P(o-tol)3
Dppb
Dppf
Xantphos
Dpe-phos
53
76
84
85
Most transformations are efficiently catalyzed by mixtures
of Pd2(dba)3 and dpe-phos. However, use of dppe as ligand
provided higher yields for some substrate combinations
a Small amounts of other side products including regioisomers of 6b and
N-arylated compounds were also formed.
Table 2. N-Substitutent effects
b The reaction was conducted for 20 h.
The effect of N-protecting groups on the efficiency of these
transformations was probed by conducting reactions of
2-bromonaphthalene with various N-protected 5-amino-1-
pentene derivatives in the presence of NaOtBu and a
catalytic amount of Pd2(dba)3/dpe-phos (Table 2). These
transformations afford the desired pyrrolidine 5 along with
Heck-type9 side product 6 and/or N-arylated10 side product
7. As expected, the nature of the N-protecting group has a
large impact on the ratio of 5:6:7. In most cases, as the
electron-withdrawing ability of the protecting group
increased, the amount of N-arylation decreased but the
amount of Heck olefination increased. For example, the
reaction of a substrate bearing an N-phenyl substituent (1)
afforded a 75:25 ratio of 5:7, whereas the analogous
transformation of a N-benzoyl substituted amine (4e)
provided a 58:42 ratio of 5:6; the formation of 7 was not
observed. The best results were obtained in reactions of
N-acyl and N-Boc substituted substrates 4b and 4c, which
N-Substituent
GC ratio (isolated yield)
5
6
7
RZBna (4a)
—
40b
—
12
4b
23
42
89b
34
25
—
—
—
—
—
RZPh (1)
75 (63%)c–e
88 (72%)
82 (77%)
77 (63%)
58 (48%)
—
RZAca (4b)
RZBoca (4c)
RZ4-MeO-Bz (4d)
RZBz (4e)
RZ4-F3C-Bza (4f)
a Other minor, unidentified side products were also observed.
b Mixtures of alkene regioisomers were obtained.
c GC yield.
d This product was obtained as a 15:1 mixture of regioisomers.
e Use of 1,4-bis(diphenylphosphino) butane (dppb) as ligand provided a
94% isolated yield of 5 as a 25:1 mixture of regioisomers. See Ref. 4.

M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
Table 3. Synthesis of N-protected pyrrolidines and indolinesa
6449
Entry
Amine
Aryl bromide
Catalyst
Product
Yield
77b
1
Pd(OAc)2/dpe-phos
5c
4c
2
Pd2(dba)3/dpe-phos
81
8
3
4
5
Pd2(dba)3/dppb
Pd(OAc)2/dppe
Pd2(dba)3/dpe-phos
71
9
75b
10
72
5b
4b
6
7
Pd2(dba)3/dppe
78
11
12
Pd2(dba)3/xantphos
67c
8
Pd2(dba)3/dpe-phos
50
13
15
9
Pd2(dba)3/nixantphos
48
14
16
a Conditions: 1.0 equiv substrate, 1.1–1.2 equiv ArBr, 1.2–2.0 equiv NaOtBu, 2 mol% Pd (1 mol% Pd2(dba)3 or 2 mol% Pd(OAc)2), 2–4 mol% ligand, toluene
(0.25 M), 105 8C.
b The reaction was conducted at 65 8C.
c This material contained ca 15% of the corresponding 2,3-dihydropyrrole (1-[5-(4-dimethylaminobenzyl)-2,3-dihydropyrrol-1-yl]ethanone).
by minimizing competing N-arylation or N-vinylation
processes (Table 3, entries 4 and 6).10 The reaction of the
electron-rich N,N-dimethyl-4-bromoaniline was most effi-
ciently catalyzed by a mixture of Pd2(dba)3 and xantphos
(entry 7).
substituted substrate 1. For example, the Pd-catalyzed
reaction of 4b with 4-bromobenzophenone proceeded in
78% isolated yield (entry 6), whereas the analogous reaction
of 1 provided only a modest 45% yield.4 Additionally, the
reaction of 1 with b-bromostyrene proceeds in low yield due
to competing N-vinylation,15,16 but the reaction of 4c with
this vinyl bromide affords the desired product in 75%
isolated yield (entry 4).
The results obtained in the reactions of 4b and 4c described
above contrast with related transformations of N-phenyl

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M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
Table 4. Stereoselective synthesis of N-protected pyrrolidinesa
Entry
1
Amine
Aryl bromide
Catalyst
Product
drb
Yield
60
Pd2(dba)3/dppb
O20:1
24
25
17
18
2
3
Pd2(dba)3/dppb
O20:1
82
72
Pd2(dba)3/dpe-phos
3:1
19
20
26
27
28
29
4
5
6
Pd(OAc)2/dpe-phos
Pd(OAc)2/dpe-phos
Pd2(dba)3/dpe-phos
O20:1
O20:1
O20:1
66c,d
59c,d
61c
21
22
7
Pd(OAc)2/xantphos
O20:1
53d
30
8
Pd2(dba)3/nixantphos
O20:1
61e,f
23
31
a Conditions: 1.0 equiv substrate, 1.1–1.2 equiv ArBr, 1.2–2.0 equiv NaOtBu, 2 mol% Pd (1 mol% Pd2(dba)3 or 2 mol% Pd(OAc)2), 2–4 mol% ligand, toluene
(0.25 M), 105 8C.
b Diastereomeric ratios described in Table 4 represent ratios of diastereomers for the isolated material upon which the yield is based. These ratios may differ
from diastereomeric ratios observed in crude reaction mixtures as noted below.
c A 10:1 ratio of diastereomers was observed in the crude reaction mixture.
d The reaction was conducted at 65 8C.
e The reaction was conducted using 2.5 mol% Pd2(dba)3.
f
The reaction was stopped at 77% conversion after two days at 110 8C.
The synthesis of N-protected indolines from N-allylaniline
derivatives was also briefly examined (Table 3, entries 8
and 9). Treatment of N-Boc-2-allylaniline (13) with
2-bromonaphthalene under our optimized reaction con-
ditions afforded a 50% yield of the desired indoline product
15. The moderate yield in this transformation was mainly
due to competing base-induced cleavage of the Boc-group
from the substrate12 and/or base-induced olefin isomeriza-
tion of the substrate.17 In contrast to the reactions of
N-benzyl protected aliphatic amine substrates, N-benzyl-2-
allylaniline (14) was converted to the N-benzyl-2-benzyl-
indoline 16 in 48% yield. The major side product obtained

M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
6451
in this reaction was N-benzyl-2-methylindole, which
presumably derives from Pd-catalyzed oxidative amination
of the substrate.18 Attempts to transform N-acyl-2-allyl-
aniline to the corresponding indoline were unsuccessful;
competing Heck arylation was observed.
the Pd–N bond4,22 followed by C–C bond-forming reductive
elimination23 of the resulting intermediate 34 to afford the
observed pyrrolidine with concomitant regeneration of the
Pd(0) catalyst.
This mechanism described above is analogous to that
previously proposed for reactions of g-(N-arylamino)
alkene substrates.4 The formation of products that result
from syn addition of the aryl group and the nitrogen across
the C–C double bond (Table 4, entries 7 and 8) is consistent
with this mechanistic proposal.24 This mechanism also
accounts for the formation of N-benzyl-2-methylindole as a
side product in the reaction of N-benzyl-2-allylaniline
(Table 3, entry 9). The N-benzyl-2-methylindole likely
derives from competing b-hydride elimination of inter-
mediate 34 followed by double bond isomerization.18a
The stereoselective synthesis of disubstituted pyrrolidines
bearing N-Boc or N-acyl groups was achieved via
Pd-catalyzed carboamination of substrates 17–21 bearing
substituents on the tether between the alkene and the
nitrogen (Table 4). Comparable diastereoselectivities were
obtained with both N-acyl and N-Boc protected substrates,
and the nature of the aryl bromide did not have a large effect
on diastereoselectivity in the transformations examined.
The synthesis of trans-2,3-disubstituted pyrrolidines
(entries 4–6) and cis-2,5-disubstituted pyrrolidines (entries
1 and 2) was effected in good yield with good levels of
diastereoselectivity.19,20 In contrast, the reaction of 19 with
tert-butyl-(4-bromo)benzoate afforded a 2,4-disubstituted
pyrrolidine product in 72% yield, but with only modest
(ca 3:1) diastereoselectivity (entry 3). The reactions of
17–21 proceed with similar diastereoselectivities and
significantly higher regioselectivities than transformations
of the analogous N-aryl substituted substrates.4
The regioisomeric products 3 observed in reactions of
N-aryl substituted substrates4 (e.g., 1) are believed to derive
from reversible b-hydride elimination/reinsertion processes
as shown in Scheme 1. The absence of these side products in
reactions of N-Boc and N-acyl protected substrates may
result from a decrease in the rate of b-hydride elimination of
intermediate 34. This may be due to stabilization of 34
through chelation of the metal to the carbonyl of the amide
or carbamate,25 or due to electronic effects induced by the
less electron-donating nature of the protected nitrogen.26,27
The increased yields obtained in reactions of N-Boc and
N-acyl protected amines with electron-deficient aryl
bromides and vinyl bromides is likely due to the fact that
C–N bond-forming reductive elimination of intermediate 33
The yields obtained in reactions of substrates 17–18 bearing
substituents at the 1- or 3-position were slightly lower than
yields obtained in reactions of unsubstituted substrates
4b–c. The diminished yields are due in part to competing
base-induced cleavage of the Boc group from the more
hindered substrates.12 The rate of Boc cleavage is relatively
rapid in THF at 65 8C and toluene at 110 8C, whereas little
or no cleavage occurs in toluene at 65 8C. Competing Heck
arylation also becomes more problematic as steric hindrance
at C-1 or C-3 increases. The Heck side products formed in
reactions of N-acylated substrates were more difficult to
separate from the desired product than the side products
obtained in analogous reactions of Boc-protected substrates,
which also led to slightly diminished yields.
The transformations of substrates 22–23 bearing internal
cyclic alkenes proceeded in moderate yield with excellent
regioselectivity and diastereoselectivity (O20:1) to afford
products 30 and 31 (entries 7 and 8).21 In both reactions the
observed diastereomer derives from syn addition of
the nitrogen and the aryl group across the double bond.20
The yields and regioselectivities in these transformations
sharply contrast with those obtained in the reaction of the
analogous N-(4-methoxyphenyl) substituted substrate,
which afforded a mixture of two regioisomeric products
along with an N-arylated side product and a side
product derived from oxidative amination of the
substrate.4
Figure 1. Proposed catalytic cycle.
2.3. Proposed catalytic cycle and mechanism
A proposed catalytic cycle for this transformation is shown
(Fig. 1). The catalytic cycle presumably commences with
oxidative addition of the aryl bromide to the Pd(0) catalyst
to afford Pd(Ar)(Br) complex 32. Reaction of this complex
with the g-aminoalkene substrate in the presence of NaOtBu
likely results in the formation of palladium aryl(amido)
complex 33,10 which undergoes insertion of the alkene into
Scheme 1.

6452
M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
slows as the nucleophilicity of the amine, amide, or
carbamate decreases.28
separate flask containing aqueous ammonium hydroxide
(100 mL) at 0 8C. The resulting mixture was stirred for 6 h
and then concentrated in vacuo. The mixture was diluted
with H2O (50 mL) and ethyl acetate (100 mL), the layers
were separated and the aqueous layer was extracted
with ethyl acetate (2!100 mL). The combined organic
extracts were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to afford 3.86 g (77%)
of 4-pentenamide35 as a white solid; mp 104–106 8C (lit. mp
106 8C)35 that was used without further purification.
3. Summary and conclusion
In conclusion, the synthesis of N-Boc and N-acyl pyrrolidine
derivatives via reactions of N-protected g-aminoalkenes is
achieved in good yield with excellent regioselectivity and
diastereoselectivities of up to O20:1. In contrast to related
transformations of g-(N-arylamino) alkenes, reactions of
N-Boc or N-acyl protected substrates with vinyl bromides or
electron-deficient aryl bromides proceed in good yield
with minimal competing N-arylation/vinylation. The N-Boc
and N-acyl substituents can be readily cleaved from the
products, which allows for potential access to a broad
variety of pyrrolidine derivatives.
A flame-dried round-bottom flask was cooled under a
stream of nitrogen and charged with 4-pentenamide (3.30 g,
33.3 mmol). The flask was purged with nitrogen, THF
(100 mL) was added via syringe and the resulting solution
was cooled to 0 8C. A solution of LiAlH4 in THF (100 mL,
100 mmol, 1.0 M) was added dropwise via syringe. The
reaction mixture was warmed to rt, and stirred for 36 h, then
was cooled to 0 8C, quenched with H2O (16 mL), and
diluted with ether (200 mL). An aqueous solution of NaOH
(30 mL, 10 M) was added and an insoluble white material
precipitated. The organic supernatant was decanted to a
clean Erlenmeyer flask and the precipitate was washed with
ether (100 mL). The combined organic extracts were dried
over anhydrous sodium sulfate and filtered to afford a
solution of 4-pentenylamine36 in diethyl ether (ca 0.1 M),
which was used without further purification.
4. Experimental
4.1. General
All reactions were carried out under an argon or nitrogen
atmosphere in oven or flame dried glassware. Palladium
acetate, tris(dibenzylideneacetone)dipalladium(0), and all
phosphine ligands were purchased from Strem Chemical
Co. and used without further purification. Acetic anhydride,
di-tert-butyldicarbonate, cyclopent-2-enyl-acetic acid, and
all aryl bromides were obtained from commercial sources
(Aldrich Chemical Co. or Acros Chemical Co.) and were
used as without purification. Pent-4-enylphenylamine (1),4
N-benzyl-4-pentenylamine (4a),29 N-(pent-4-enyl-benz-
amide) (4e),30 and 2-allylaniline31 were prepared according
to published procedures. N-Benzyl-2-allylaniline (14)32 was
prepared by N-benzylation33 of 2-allylaniline. Toluene and
THF were purified using a GlassContour solvent purifi-
cation system. Product regiochemistry was assigned on the
basis of 1H NMR 2-D COSY experiments; stereochemistry
A flame-dried round-bottom flask was cooled under a
stream of nitrogen and charged with a solution of
4-pentenylamine in diethyl ether (165 mL, 16.5 mmol,
0.1 M). The solution was cooled to 0 8C and acetic
anhydride (4.7 mL, 5.10 g, 50 mmol) was added via syringe.
The resulting mixture was stirred for 5 h and then aqueous
NaOH (100 mL, 1.0 M) was added. The biphasic mixture
was vigorously stirred for 12 h and then the layers were
separated. The aqueous layer was extracted with ethyl
acetate (3!75 mL). The combined organic extracts were
dried over anhydrous sodium sulfate, filtered, and concen-
trated in vacuo. The crude product was then purified by flash
chromatography on silica gel to afford 1.36 g (65%) of the
title compound as a colorless oil. 1H NMR (400 MHz,
CDCl3) d 5.86–5.57 (m, 2H), 5.07–4.93 (m, 2H), 3.25 (q,
JZ6.0 Hz, 2H), 2.12–2.02 (m, JZ5.8 Hz, 2H), 1.95 (s, 3H),
1.59 (p, JZ7.7 Hz, 2H).
1
was assigned on the basis of H NMR NOE experiments.
Ratios of regioisomers and/or diastereomers were deter-
mined by either 1H NMR or capillary GC analysis of crude
reaction mixtures. Yields refer to isolated yields of
compounds estimated to be R95% pure as determined by
1H NMR, and either capillary GC (known compounds) or
combustion analysis (new compounds). The yields reported
in Section 4 describe the result of a single experiment,
whereas the yields reported in Tables 2–4 are average yields
of two or more experiments. Thus, the yields reported in the
Section 4 may differ from those shown in Tables 2–4.
4.2.2. Pent-4-enyl-carbamic acid tert-butyl ester (4c).37
A
flame-dried round bottom flask was cooled under a stream of
nitrogen and charged with a solution of 4-pentenylamine
(165 mL, 16.5 mmol, 0.1 M). Di-tert-butyl dicarbonate
(5.4 g, 25 mmol) was added to the solution and the resulting
mixture was stirred for 4 h and then aqueous NaOH
(100 mL, 1.0 M) was added. The biphasic mixture was
vigorously stirred for 12 h and then the layers were
separated. The aqueous layer was extracted with ethyl
acetate (3!75 mL). The combined organic extracts were
dried over anhydrous sodium sulfate, filtered, and concen-
trated in vacuo. The crude product was then purified by flash
chromatography on silica gel to afford 2.05 g (67%) of the
title compound as a colorless oil. 1H NMR (500 MHz,
CDCl3) d 5.80–5.70 (m, 1H), 5.01–4.90 (m, 2H), 4.54 (s, br,
1H), 3.13–2.98 (m, 2H), 2.03 (q, JZ6.6 Hz, 2H), 1.52 (p,
JZ6.6 Hz, 2H), 1.39 (s, 9H).
4.2. Synthesis of N-protected g-aminoalkenes
4.2.1. N-Pent-4-enyl-acetamide (4b).34 A flame-dried flask
was cooled under a stream of nitrogen and charged with
4-pentenoic acid (5.7 mL, 49.8 mmol). The flask was
purged with nitrogen, benzene (100 mL) was added and
the resulting solution was cooled to ca 10 8C using an ice
water bath. Oxalyl chloride (8.7 mL, 100 mmol) was added
dropwise via syringe to the solution and the resulting
mixture was warmed to rt, stirred for 1 h, and then
concentrated in vacuo. The crude 4-pentenoyl chloride
was dissolved in THF (100 mL), and slowly added to a

M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
6453
4.2.3. N-(Pent-4-enyl)-4-methoxybenzamide (4d).30 An
oven-dried round-bottom flask was charged with 1,10-
carbonyldiimidazole (486 mg, 3.0 mmol) and then purged
with argon. THF (15 mL) and 4-methoxybenzoic acid
(456 mg, 3.0 mmol) were added to the flask, and the
resulting mixture was stirred at rt for 1 h. A solution of
4-pentenylamine in ether (30 mL, 3.0 mmol, 0.1 M) was
then added via syringe and the mixture was stirred at rt for
4 h. The reaction mixture was then diluted with ethyl acetate
(15 mL) and H2O (15 mL), the layers were separated, and
the aqueous layer was extracted with ethyl acetate (3!
40 mL). The combined organic extracts were washed with
saturated aqueous NaHCO3 (50 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to afford
438 mg (67%) of the title compound as a white solid; mp
42–44 8C (lit. mp not reported). 1H NMR (400 MHz,
CDCl3) d 7.68 (d, JZ8.8 Hz, 2H), 6.87 (d, JZ8.8 Hz,
2H), 6.10 (br s, 1H), 5.85–5.75 (m, 1H), 5.05–4.95 (m, 2H),
3.80 (s, 3H), 3.41 (q, JZ7.0 Hz, 2H), 2.11 (q, JZ7.0 Hz,
2H), 1.68 (p, JZ7.7 Hz, 2H).
The combined organic extracts were diluted with hexanes
(100 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel to afford 2.1 g (19%) of
1-phenyl-pent-4-enylamine40 as a yellow oil. 1H NMR
(400 MHz, CDCl3) 7.36–7.29 (m, 4H), 7.27–7.21 (m, 1H),
5.87–5.76 (m, 1H), 5.05–4.94 (m, 2H), 3.92–3.87 (m, 1H),
2.14–1.96 (m, 2H), 1.84–1.70 (m, 2H), 1.52 (s, 2H).
Treatment of 1.51 g (9.4 mmol) of 1-phenylpent-4-enyl-
amine with 2.62 g (12.0 mmol) of di-tert-butyl dicarbonate
using a procedure analogous to that described above in the
synthesis of 4c provided 2.26 g (92%) of the title compound
as a white solid; mp 76–78 8C. 1H NMR (500 MHz, CDCl3)
d 7.33–7.16 (m, 5H), 5.83–5.70 (m, 1H), 5.02–4.91 (m, 2H),
4.88–4.74 (s, br, 1H), 4.67–4.52 (s, br, 1H), 2.10–1.92 (m,
2H), 1.90–1.71 (m, 2H), 1.38 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 155.4, 143.0, 137.8, 128.8, 127.4, 126.6, 115.4,
79.6, 54.7, 36.2, 30.6, 28.6; IR (film) 3370, 2978, 1687,
1519 cmK1. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87;
N, 5.36. Found: C, 73.41; H, 8.78; N, 5.32.
4.2.4. N-Pent-4-enyl-4-trifluoromethyl benzamide (4f).
Treatment of 570 mg (3.0 mmol) of 4-(trifluoromethyl)
benzoic acid with a solution of 4-pentenylamine in ether
(30 mL, 3.0 mmol) using a procedure analogous to that
described above in the synthesis of 4d afforded 475 mg
(63%) of the title compound as a white solid; mp 69–71 8C.
1H NMR (500 MHz, CDCl3) d 7.80 (d, JZ8.1 Hz, 2H), 7.60
(d, JZ8.1 Hz, 2H), 6.60 (s, br, 1H), 5.83–5.70 (m, 1H),
5.05–4.90 (m, 2H), 3.45–3.36 (m, 2H), 2.15–2.05 (m, 2H),
1.73–1.62 (m, 2H); 13C NMR (125 MHz, CDCl3) d 166.5,
138.2, 137.8, 133.2 (q, JZ41 Hz), 127.5, 125.7, 123.8 (q,
JZ340 Hz), 115.6, 40.0, 31.4, 28.8; IR (film) 3309, 2930,
1638, 1550 cmK1. Anal. Calcd for C13H14F3NO2: C, 60.70;
H, 5.49; N, 5.44. Found: C, 60.97; H, 5.46; N, 5.40.
4.2.7. N-(1-Phenylpent-4-enyl)-acetamide (18). Treatment
of 517 mg (3.21 mmol) of 4-pentenylamine with 0.8 mL
(8.03 mmol) of acetic anhydride using a procedure
analogous to that described above in the synthesis of 4b
provided 530 mg (81%) of the title compound as a white
1
solid; mp 44–46 8C. H NMR (500 MHz, CDCl3) d 7.31–
7.16 (m, 5H), 6.25 (d, JZ8.1 Hz, 1H), 5.80–5.70 (m, 1H),
4.97–4.90 (m, 3H), 2.09–1.92 (m, 2H), 1.90 (s, 3H), 1.88–
1.73 (m, 2H); 13C NMR (125 MHz, CDCl3) d 169.6, 142.4,
137.8, 128.8, 127.5, 126.8, 115.4, 53.3, 35.5, 30.6, 23.5; IR
(film) 3279, 2934, 1646, 1549 cmK1. MS (ESI) 226.1206
(226.1208 calcd for C13H17NO, MCNaC).
4.2.8. 1-Allylbut-3-enyl-carbamic acid tert-butyl ester
(19). A flame-dried round bottom flask was cooled under a
stream of nitrogen and charged with diisopropylamine
(8.4 mL, 60 mmol) and THF (100 mL). The flask was
cooled to K78 8C and a solution of n-butyllithium in
hexanes (22 mL, 55 mmol, 2.5 M) was added dropwise. The
mixture was stirred at K78 8C for 1 h and then acetonitrile
(2.6 mL, 50 mmol) was added dropwise. The mixture was
warmed to rt and stirred for 3 h, then allyl bromide (4.8 mL,
55 mmol) was added dropwise. The mixture was stirred for
1 h, then a solution of saturated aqueous ammonium
chloride (50 mL) was added. The mixture was extracted
with ether (3!150 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to afford a
mixture of 4-cyano-1-butene, 4-cyano-4-allyl-1-butene, and
4-cyano-4,4-diallyl-1-butene (ca 50 mmol) that was used
without further purification.
4.2.5. (2-Allylphenyl) carbamic acid tert-butyl ester
(13).38 Treatment of 904 mg (6.8 mmol) of 2-allylaniline31
with 2.2 g (10.2 mmol) of di-tert-butyldicarbonate using a
procedure analogous to that described above in the synthesis
of 4c (with THF used in place of diethyl ether as solvent)
afforded 1.11 g (70%) of the title compound as a colorless
oil. 1H NMR (500 MHz, CDCl3) d 7.75 (d, JZ7.7 Hz, 1H),
7.20 (t, JZ8.4 Hz, 1H), 7.11 (d, JZ7.7 Hz, 1H), 7.02 (t, JZ
7.3 Hz, 1H), 6.41 (s, br, 1H), 5.97–5.88 (m, 1H), 5.14–5.00
(m, 2H), 3.33 (d, JZ6.2 Hz, 2H), 1.47 (s, 9H).
4.2.6. (1-Phenylpent-4-enyl) carbamic acid tert-butyl
ester (17). A flame-dried round bottom flask was cooled
under a stream of argon and charged with 1-phenylpent-4-
en-1-one39 (11.0 g, 69.0 mmol), activated 3 A molecular
˚
sieves (10.0 g), and methanol (200 mL). The mixture was
stirred at rt for 5 min and then ammonium acetate (53 g,
690 mmol) and sodium cyanoborohydride (4.3 g, 69 mmol)
were added. The flask was purged with argon and then
stirred at rt for 19 h. Ether (500 mL) was added, the mixture
was decanted, and the organic phase was washed with
200 mL of aqueous NaHCO3. The layers were separated, the
aqueous phase was extracted with ether (1!100 mL), and
the combined organic layers were extracted with 1 M HCl
(3!100 mL). The organic phase was discarded and the
combined acidic aqueous extracts were basicified to pH 10
with 10 M NaOH and extracted with ether (3!100 mL).
A flame-dried round-bottom flask was cooled under a
stream of nitrogen and charged with a mixture of 4-cyano-1-
butene, 4-cyano-4-allyl-1-butene, and 4-cyano-4,4-diallyl-
1-butene (ca 50 mmol). The flask was purged with nitrogen,
ether (200 mL) was added via syringe and the resulting
solution was cooled to 0 8C. A solution of LiAlH4 in ether
(150 mL, 150 mmol, 1.0 M) was added dropwise via
syringe. The reaction mixture was warmed to rt and stirred
for 12 h, then was cooled to 0 8C, quenched with H2O
(30 mL), and diluted with ether (150 mL). An aqueous

6454
M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
solution of NaOH (80 mL, 10 M) was added and an
insoluble white material precipitated. The organic super-
natant was decanted to a clean Erlenmeyer flask and the
solution was dried over anhydrous sodium sulfate and
filtered to afford a mixture of 4-pentenylamine, 3-allyl-4-
pentenylamine, and 3,3-diallyl-4-pentenylamine as a
solution in diethyl ether (550 mL, ca 0.1 M). This mixture
was used without further purification.
for C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C,
67.99; H, 10.06; N, 6.63.
4.2.12. N-(2-Cyclopent-2-enylethyl) acetamide (23).
Cyclopent-2-enyl-acetic acid (2.0 g, 15.9 mmol) was con-
verted to 1.27 g (52%) of the title compound using a four-
step procedure analogous to that described above the
conversion of 4-pentenoic acid to 4b. The product was
1
obtained as a colorless oil. H NMR (500 MHz, CDCl3) d
A solution containing a mixture of 4-pentenylamine, 3-allyl-
4-pentenylamine, and 3,3-diallyl-4-pentenylamine in ether
(100 mL, 10 mmol, 0.1 M) was treated with 2.62 g
(12 mmol) of di-tert-butyl dicarbonate using a procedure
analogous to that described above in the synthesis of 4c. The
three products were separated by flash chromatography on
silica gel to afford 675 mg (30%) of 19 as a pale yellow oil.
1H NMR (500 MHz, CDCl3) d 5.80–5.67 (m, 2H), 5.04–
4.96 (m, 4H), 4.52 (s, br, 1H), 3.03 (t, JZ6.2 Hz, 2H), 2.08–
1.94 (m, 4H), 1.72–1.57 (m, 1H), 1.40 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 156.2, 136.5, 116.8, 79.9, 43.7, 38.3,
36.2, 28.6; IR (film) 3351; 2978, 1694, 1515 cmK1. Anal.
Calcd for C13H23NO2: C, 69.29; H, 10.29; N, 6.22. Found:
C, 69.27; H, 10.26; N, 6.22.
5.99 (s, br, 1H), 5.68–5.63 (m, 1H), 5.59–5.55 (m, 1H), 3.18
(q, JZ7.3 Hz, 2H), 2.65–2.55 (m, 1H), 2.33–2.14 (m, 2H),
2.03–1.93 (m, 1H), 1.89 (s, 3H), 1.59–1.49 (m, 1H), 1.45–
1.28 (m, 2H); 13C NMR (125 MHz, CDCl3) d 170.4, 134.3,
131.1, 43.3, 38.5, 35.8, 32.1, 29.8, 23.4; IR (film) 3289,
2932, 1653, 1559 cmK1. MS (ESI) 153.1154 (153.1153
calcd for C9H15NO).
4.3. General procedures for the Pd-catalyzed synthesis of
pyrrolidines
General procedure A: Palladium-catalyzed synthesis of
pyrrolidines and indolines using Pd(OAc)2. A flame-dried
Schlenk tube was cooled under a stream of nitrogen and
charged with Pd(OAc)2 (2 mol%) and a bidentate phosphine
ligand (4 mol%). The tube was purged with nitrogen and
toluene was added (2 mL/mmol amine). The mixture was
stirred at rt for w2 min then the aryl bromide (1.2 equiv)
was added followed by a solution of the amine (1 equiv) in
toluene (2 mL/mmol amine). The mixture was allowed to
stir w1 min before the addition of NaOtBu (2.0 equiv). The
tube was purged with nitrogen and the sides of the flask
were rinsed with toluene (2 mL/mmol amine; final con-
centrationZ0.17 M). The mixture was heated to 65 8C with
stirring until the starting material had been consumed as
4.2.9. (3-Methylpent-4-enyl)-carbamic acid tert-butyl
ester (20). 3-Methyl-pent-4-enoic acid41 (3.33 g,
29.2 mmol) was converted to 3.0 g (52%) of the title
compound using a four-step procedure analogous to that
described above for the conversion of 4-pentenoic acid to
1
4c. The product was obtained as a colorless oil. H NMR
(400 MHz, CDCl3) d 5.62–5.53 (m, 1H), 4.90–4.82 (m, 2H),
4.59 (s, br, 1H), 3.09–2.91 (m, 2H), 2.15–2.02 (m, 1H),
1.44–1.27 (m, 11H), 0.91 (d, JZ6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 156.1, 143.9, 113.4, 79.0, 38.9, 36.7,
1
35.8, 28.5, 20.3; IR (film) 3351, 2977, 1694, 1526 cmK1
.
judged by GC or H NMR analysis. The reaction mixture
was cooled to rt, quenched with saturated aqueous NH4Cl
and diluted with ethyl acetate. The layers were separated,
the aqueous layer was extracted with ethyl acetate, and the
combined organic extracts were dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The
crude product was then purified by flash chromatography on
silica gel.
Anal. Calcd for C11H21NO2: C, 66.29; H, 10.62; N, 7.03.
Found: C, 66.04; H, 10.60; N, 6.97.
4.2.10. N-(3-Methylpent-4-enyl) acetamide (21). Treat-
ment of a solution of 3-methyl-4-pentenylamine in ether
(100 mL, 10 mmol, 0.1 M) with 3 mL (30 mmol) of acetic
anhydride using a procedure analogous to that described
above in the synthesis of 4b provided 720 mg (51%) of the
title compound as a colorless oil. 1H NMR (500 MHz,
CDCl3) d 6.27 (s, br, 1H), 5.61–5.52 (m, 1H), 4.90–4.82 (m,
2H), 3.15–3.07 (m, 2H), 2.13–2.03 (m, 1H), 1.85 (s, 3H),
1.46–1.32 (m, 2H); 0.90 (d, JZ7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 170.4, 143.8, 113.5, 38.0, 36.2, 35.9,
23.3, 20.4; IR (film) 3290, 2964, 1649, 1558 cmK1. MS
(ESI) 142.1228 (142.1232 calcd for C8H16NO, MCHC).
General procedure B: Palladium-catalyzed synthesis of
pyrrolidines and indolines using Pd2(dba)3. A flame-dried
Schlenk tube was cooled under a stream of nitrogen and
charged with Pd2(dba)3 (1 mol% complex, 2 mol% Pd), a
bidentate phosphine ligand (2 mol%), NaOtBu (1.2 equiv),
and the aryl bromide (1.1 equiv). The tube was purged with
nitrogen and a solution of the amine substrate (1.0 equiv) in
toluene (4 mL/mmol amine) was added. The mixture was
heated to 105 8C with stirring until the starting material had
been consumed as judged by GC or 1H NMR analysis. The
reaction mixture was cooled to rt, quenched with saturated
aqueous NH4Cl and diluted with ethyl acetate. The layers
were separated, the aqueous layer was extracted with ethyl
acetate, and the combined organic extracts were dried over
anhydrous sodium sulfate, filtered and concentrated in
vacuo. The crude product was then purified by flash
chromatography on silica gel.
4.2.11. (2-Cyclopent-2-enylethyl) carbamic acid tert-
butyl ester (22). Cyclopent-2-enyl-acetic acid (3.0 g,
23.8 mmol) was converted to 2.41 g (48%) of the title
compound using a four-step procedure analogous to that
described above the conversion of 4-pentenoic acid to 4c.
1H NMR (400 MHz, CDCl3) d 5.69–5.65 (m, 1H), 5.62–
5.57 (m, 1H), 4.52 (s, br, 1H), 3.16–2.99 (m, 2H), 2.67–2.56
(m, 1H), 2.34–2.15 (m, 2H), 2.06–1.94 (m, 1H), 1.59–1.48
(m, 1H), 1.45–1.31 (m, 11H); 13C NMR (100 MHz, CDCl3)
d 156.1, 134.5, 131.0, 79.2, 43.2, 39.5, 36.4, 32.1, 29.9,
28.6; IR (film) 3351, 2977, 1692, 1524 cmK1. Anal. Calcd
4.3.1. (4-Methoxyphenyl)-(2-naphthalen-2-ylmethyl-
pyrrolidin-1-yl) methanone (5d). Reaction of 52 mg

M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
6455
(0.25 mmol) of 4d with 2-bromonaphthalene (57 mg,
0.28 mmol), dpe-phos (2.7 mg, 0.005 mmol, 2 mol%) and
NaOtBu (29 mg, 0.30 mmol) following general procedure B
afforded 54.3 mg (63%) of the title compound as a pale
yellow oil that was contaminated with ca 5% of Heck-type
side product 6d. The title compound was found to exist as a
ca 9:1 mixture of rotamers as judged by 1H NMR analysis.
Data are for the major rotamer. 1H NMR (400 MHz, CDCl3)
d 7.84–7.58 (m, 4H), 7.57–7.30 (m, 5H), 6.88 (d, JZ8.8 Hz,
2H), 4.62–4.49 (m, 1H), 3.80 (s, 3H), 3.45–3.30 (m, 2H),
3.26–3.14 (m, 1H), 3.13–3.00 (m, 1H), 2.01–1.83 (m, 1H),
1.82–1.51 (m, 3H); 13C NMR (125 MHz, CDCl3) d 169.9,
161.2, 136.4, 133.7, 132.4, 129.6, 128.7, 128.4, 127.9,
127.8, 127.7, 126.1, 125.5, 113.7, 58.7, 55.5, 51.1, 39.0,
29.6, 25.3 (two aromatic signals are incidentally equival-
ent); IR (film) 2967, 1608, 1420 cmK1. MS (ESI) 368.1625
(368.1626 calcd for C23H23NO2, MCNaC).
(5.4 mg, 0.01 mmol, 2 mol%) and NaOtBu (58 mg,
0.6 mmol) following general procedure B afforded 112 mg
(81%) of the title compound as a pale yellow oil. This
compound was found to exist as a 2:1 mixture of rotamers as
1
1
judged by H NMR analysis; data are for the mixture. H
NMR (400 MHz, CDCl3) d 7.10–7.08 (m, 4H), 4.02 (s, br,
1H), 3.42–3.02 (m, 3H), 2.50–2.29 (m, 4H), 1.92–1.59 (m,
4H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) d 154.8;
154.2, 137.9, 137.2, 130.7, 130.5, 126.9, 126.6, 126.1, 79.7,
79.6, 57.5, 46.9. 46.4, 38.5, 37.7, 37.0, 29.7, 29.2, 28.8,
28.7, 23.7, 22.8, 20.0, 19.9 (three sets of signals are
incidentally equivalent); IR (film) 2973, 1693, 1394 cmK1
.
Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09.
Found: C, 73.84; H, 9.16; N, 5.10.
4.3.5. 2-(4-Cyanobenzyl)pyrrolidine-1-carboxylic acid
tert-butyl ester (9). Reaction of 185 mg (1.00 mmol) of
4c with 4-bromobenzonitrile (200 mg, 1.10 mmol), dppb
(8.8 mg, 0.02 mmol, 2 mol%) and NaOtBu (116 mg,
1.20 mmol) following general procedure B afforded
203 mg (71%) of the title compound as a pale yellow oil.
This compound was found to exist as a 1:1 mixture of
4.3.2. (2-Naphthalen-2-ylmethylpyrrolidin-1-yl) phenyl-
methanone (5e). Reaction of 48 mg (0.25 mmol) of 4e with
2-bromonaphthalene (57 mg, 0.28 mmol), dpe-phos
(2.7 mg, 0.005 mmol, 2 mol%) and NaOtBu (29 mg,
0.30 mmol) following general procedure B afforded 38 mg
(48%) of the title compound as a pale yellow oil. This
compound was found to exist as a 4:1 mixture of rotamers as
1
rotamers as judged by H NMR analysis; data are for the
mixture. 1H NMR (400 MHz, CDCl3) d 7.50–7.46 (m, 2H),
7.26–7.22 (m, 2H), 3.80–3.97 (m, 1H), 3.35–2.95 (m, 4H),
2.62–2.55 (m, 1H), 1.81–1.52 (m, 3H), 1.40 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 154.6, 145.1, 132.6, 132.2,
130.4, 128.2, 119.0, 110.3, 79.5, 58.4, 46.81, 46.79, 41.0,
40.1, 30.1, 28.9, 28.7, 23.6, 22.9 (five sets of signals are
incidentally equivalent); IR (film) 2974, 2228, 1690,
1395 cmK1. Anal. Calcd for C17H22N2O2: C, 71.30; H,
7.74; N, 9.78. Found: C, 71.15; H, 7.82; N, 9.69.
1
1
judged by H NMR analysis; data are for the mixture. H
NMR (400 MHz, CDCl3) d 7.86–7.78 (m, 3H), 7.78–7.74
(m, 0.2H), 7.72 (s, 0.8H), 7.70–7.60 (m, 0.8H), 7.56–7.42
(m, 1.4H), 7.50–7.38 (m, 5.8H), 7.19 (s, 0.2H), 6.74–6.68
(m, 0.2H), 4.62–4.52 (m, 1H), 4.20–4.11 (m, 0.2H), 3.78–
3.67 (m, 0.4H), 3.43–3.29 (m, 1.6H), 3.22–3.13 (m, 0.8H),
3.12–3.03 (m, 0.8H), 2.77–2.18 (m, 0.2H), 2.61–2.50 (m,
0.2H), 2.04–1.88 (m, 1H), 1.87–1.73 (m, 1H), 1.72–1.54 (m,
2H); 13C NMR (100 MHz, CDCl3) d 170.2, 137.6, 136.4,
135.8, 133.7, 132.4, 130.2, 129.6, 128.7, 128.5, 128.3,
128.0, 127.8, 127.7, 127.5, 127.3, 126.7, 126.2, 126.1,
125.7, 125.5, 60.9, 58.7, 50.9, 46.0, 41.2, 39.0, 29.9, 29.5,
25.1, 22.1 (three sets of carbons are incidentally equivalent);
IR (film) 2968, 1625, 1412 cmK1. MS (ESI) 338.1519
(338.1521 calcd for C22H21NO, MCNaC).
4.3.6. 2-(3-Phenylallyl)pyrrolidine-1-carboxylic acid tert-
butyl ester (10). Reaction of 93 mg (0.50 mmol) of 4c
with b-bromostyrene (80 mL, 110 mg, 0.60 mmol), dppe
(8 mg, 0.02 mmol, 4 mol%) and NaOtBu (96 mg,
1.00 mmol) following general procedure A afforded
108 mg (79%) of the title compound as a pale yellow oil.
This compound was found to exist as a 1:1 mixture of
1
rotamers as judged by H NMR analysis; data are for the
4.3.3. 2-Napthalen-2-ylmethylpyrrolidine-1-carboxylic
acid tert-butyl ester (5c). Reaction of 93 mg (0.50 mmol)
of 4c with 2-bromonaphthalene (124 mg, 0.60 mmol), dpe-
phos (11 mg, 0.02 mmol 4 mol%) and NaOtBu (96 mg,
1.0 mmol) following general procedure A afforded 120 mg
(77%) of the title compound as a pale yellow oil. This
compound was found to exist as a 1:1 mixture of rotamers as
judged by H NMR analysis; data are for the mixture. H
NMR (400 MHz, CDCl3) d 7.84–7.74 (m, 3H), 7.78–7.58
(m, 1H), 7.51–7.30 (m, 3H), 4.21–4.02 (m, 1H), 3.46–3.18
(m, 3H), 2.78–2.63 (m, 1H), 1.73 (m, 4H), 1.49 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 154.8, 137.0, 133.8, 132.3,
128.5, 128.2, 128.0, 127.8, 127.7, 126.2, 126.1, 125.6 125.5,
79.5, 79.3, 59.0, 47.1, 46.5, 41.0, 39.9, 29.9, 29.1, 28.8,
23.7, 22.9 (nine sets of carbons are incidentally equivalent);
IR (film) 3052, 2973, 1692, 1395 cmK1. Anal. Calcd for
C20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found: C, 76.78; H,
8.24; N, 4.57.
mixture. 1H NMR (400 MHz, CDCl3) d 7.35–7.10 (m, 5H),
6.38 (d, JZ16.0 Hz, 1H), 6.20–6.05 (m, 1H), 3.90–3.78 (m,
1H), 3.42–3.32 (m, 2H), 2.71–2.52 (m, 1H), 2.32–2.23 (m,
1H), 1.95–1.73 (m, 4H); 1.44 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 154.8, 138.0, 137.7, 132.4, 128.7, 127.2, 126.2,
79.39, 79.36, 57.4, 46.9, 46.6, 38.4, 37.6, 30.5, 29.6, 28.8,
23.9, 23.2 (nine sets of signals are incidentally equivalent);
IR (film) 2972, 1693, 1394 cmK1. Anal. Calcd for
C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.24;
H, 8.59; N, 4.81.
1
1
4.3.7.
1-(2-Naphthalen-2-ylmethylpyrrolidin-1-yl)
ethanone (5b). Reaction of 32 mg (0.25 mmol) of 4b with
2-bromonaphthalene (57 mg, 0.28 mmol), dpe-phos
(2.7 mg, 0.005 mmol, 2 mol%) and NaOtBu (29 mg,
0.30 mmol) following general procedure B afforded 44 mg
(70%) of the title compound as a pale yellow oil. This
compound was found to exist as a 7:3 mixture of rotamers as
1
1
judged by H NMR analysis; data are for the mixture. H
NMR (500 MHz, CDCl3) d 7.83–7.78 (m, 3H), 7.66 (s,
0.3H), 7.60 (s, 0.3H), 7.51–7.40 (m, 3H), 4.45–4.38 (m,
0.7H), 4.15–4.08 (m, 0.3H), 3.63–3.48 (m, 0.7H), 3.43–3.31
4.3.4. 2-(2-Methylbenzyl) pyrrolidine-1-carboxylic acid
tert-butyl ester (8). Reaction of 93 mg (0.5 mmol) of 4c
with 2-bromotoluene (66 mL, 94 mg, 0.55 mmol), dpe-phos

6456
M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
(m, 2H), 3.07–3.00 (m, 0.3H), 2.84–2.70 (m, 1H), 2.14–2.03
(m, 3H), 1.96–1.69 (m, 4H); 13C NMR (125 MHz, CDCl3) d
169.5, 169.4, 137.0, 135.7, 135.7, 133.8, 132.5, 132.4,
128.7, 128.4, 128.15, 128.05, 128.03, 127.94, 127.87,
127.76, 127.72, 126.5, 126.2, 126.0, 125.6, 60.3, 58.6,
48.2, 45.8, 41.2, 39.1, 30.3, 28.7, 24.0, 23.4, 22.4, 22.1 (one
set of carbons are incidentally equivalent); IR (film) 2968,
1637, 1417 cmK1. MS (ESI) 276.1359 (276.1364 calcd for
C17H19NO, MCNaC).
CDCl3) d 152.5, 142.2, 135.7, 133.8, 132.5, 130.2, 128.3,
128.2, 128.0, 127.9, 127.7, 127.6, 126.2, 125.7, 125.3,
122.7, 115.6, 81.1, 60.8, 40.6, 31.7, 28.7; IR (film) 2974,
1702, 1483, 1392 cmK1. MS (ESI) 382.1787 (382.1783
calcd for C24H25NO2, MCNaC).
4.3.11. 1-Benzyl-2-(4-methylbenzyl)-2,3-dihydro-1H-
indole (16). Reaction of 65 mg (0.29 mmol) of 14 with
4-bromotoluene (40 mL, 55 mg, 0.32 mmol), nixantphos
(3.2 mg, 0.0058 mmol, 2 mol%) and NaOtBu (34 mg,
0.30 mmol) following general procedure B afforded 44 mg
4.3.8. 1-[2-(4-Benzoylbenzyl)pyrrolidin-1-yl]ethanone
(11). Reaction of 32 mg (0.25 mmol) of 4b with 4-bromo-
benzophenone (72 mg, 0.28 mmol), dppe (2.0 mg,
0.005 mmol, 2 mol%) and NaOtBu (29 mg, 0.30 mmol)
following the general procedure B afforded 61 mg (80%) of
the title compound as a pale yellow oil. This compound was
found to exist as a 3:1 mixture of rotamers as judged by 1H
1
(48%) of the title compound as a pale yellow oil. H NMR
(500 MHz, CDCl3) d 7.36–7.22 (m, 5H), 7.07–6.94 (m, 6H),
6.59 (t, JZ7.0 Hz, 1H), 6.33 (d, JZ7.7 Hz, 1H), 4.46 (d,
JZ16.1 Hz, 1H), 4.24 (d, JZ16.1 Hz, 1H), 3.86–3.78 (m,
1H), 3.12 (dd, JZ4.0, 13.2 Hz, 1H), 2.96–2.89 (m, 1H),
2.78–2.62 (m, 2H), 2.29 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 152.7, 139.2, 136.0, 135.6, 129.33 129.29, 128.69,
128.67 127.56, 127.54, 127.2, 124.4, 117.7, 107.1, 66.7,
51.8, 40.1, 35.1, 21.2; IR (film) 2921, 2360, 1484 cmK1. MS
(ESI) 314.1901 (314.1909 calcd for C23H23N, MCHC).
1
NMR analysis. H NMR (500 MHz, CDCl3) d 7.80–7.64
(m, 4H), 7.58–7.51 (m, 1H), 7.47–7.40 (m, 2H), 7.32–7.22
(m, 2H), 4.34–4.26 (m, 0.75H), 4.08–4.00 (m, 0.25H), 3.60–
3.32 (m, 2H), 3.24 (dd, JZ3.3, 12.8 Hz, 0.75H), 2.92 (dd,
JZ5.1, 13.6 Hz, 0.25H), 2.72 (m, 0.25H), 2.67–2.60 (m,
0.75H), 2.20–2.05 (m, 0.75H), 2.06–1.98 (m, 3H), 1.90–
1.74 (m, 3.25H); 13C NMR (125 MHz, CDCl3) d 196.7,
196.6, 169.6, 169.5, 144.5, 143.0, 138.3, 138.0, 136.2,
135.8, 132.7, 132.5, 130.8, 130.5, 130.2, 129.6, 129.4,
128.5, 128.4, 60.0, 58.4, 48.2, 45.7, 41.1, 39.0, 30.3, 28.7,
24.0, 23.2, 22.3, 22.0 (one set of carbons are incidentally
equivalent); IR (film) 2960, 1638, 1414 cmK1. MS (ESI)
330.1466 (330.1470 calcd for C20H21NO2, MCNaC).
4.3.12. (G)-(2S,5R)-2-(4-Methoxybenzyl)-5-phenyl-
pyrrolidine-1-carboxylic acid tert-butyl ester (24).
Reaction of 261 mg (1.00 mmol) of 17 with 4-bromoanisole
(140 mL, 206 mg, 1.1 mmol), dppb (8.0 mg, 0.02 mmol,
2 mol%) and NaOtBu (116 mg, 1.20 mmol) following
general procedure B afforded 219 mg (60%) of the title
compound as a pale yellow oil. This compound was found to
1
exist as a 7:3 mixture of rotamers as judged by H NMR
analysis. 1H NMR (500 MHz, CDCl3) d 7.33–7.05 (m, 7H),
6.82 (d, JZ8.4 Hz, 2H), 4.97–4.61 (m, 1H), 4.22–3.98 (m,
1H), 3.76 (s, 3H), 3.56–3.29 (m, 1H), 2.59 (t, JZ11.4 Hz,
1H), 2.22 (sx, JZ6.6 Hz, 1H), 1.97–1.81 (m, 1H), 1.82–1.66
(m, 2H), 1.62–1.04 (m, 9H); 13C NMR (125 MHz, CDCl3) d
158.4, 155.1, 131.6, 130.5, 128.5, 128.3, 126.6, 125.8,
114.1, 79.5, 63.3, 61.3, 55.4, 40.6, 34.4, 28.5 (nine sets of
carbons are incidentally equivalent); IR (film) 2974, 1686,
1454 cmK1. MS (ESI) 390.2038 (390.2045 calcd for
C23H29NO3, MCNaC).
4.3.9. 1-[2-(4-Dimethylaminobenzyl)pyrrolidin-1-yl]-
ethanone (12). Reaction of 32 mg (0.25 mmol) of 4b with
N,N-dimethyl-4-bromoaniline (55 mg, 0.28 mmol), xant-
phos (2.9 mg, 0.005 mmol, 2 mol%) and NaOtBu (29 mg,
0.30 mmol) following general procedure B afforded 42 mg
(67%) of the title compound as a pale yellow oil. This
compound was found to exist as a 3:2 mixture of rotamers as
1
judged by H NMR analysis. This material contained ca
15% of the corresponding 2,3-dihydropyrrole (1-[5-(4-
dimethylaminobenzyl)-2,3-dihydropyrrol-1-yl]ethanone),
which could not be separated by chromatography. 1H NMR
(500 MHz, CDCl3) d 7.29–6.95 (m, 2H), 6.72–6.57 (m, 2H),
4.32–4.20 (m, 0.6H), 4.01–3.88 (m, 0.4H), 3.57–3.39 (m,
0.8H), 3.38–3.29 (m, 1.2H), 3.06–2.98 (m, 0.6H), 2.93–2.85
(m, 6H), 2.77–2.70 (m, 0.4H), 2.57–2.43 (m, 1H), 2.07–1.95
(m, 3H), 1.89–1.67 (m, 4H); 13C NMR (125 MHz, CD3OH)
d 170.9, 170.6, 150.1, 149.8, 129.9, 129.8, 113.4 113.3,
112.6, 112.4, 60.9, 59.0, 45.3, 40.1, 40.0, 39.9, 39.8, 39.1,
38.9, 36.9, 23.1, 21.5, 21.33, 21.28, 20.6; IR (film) 2930,
1638, 1417 cmK1. MS (ESI) 269.1361 (269.1630 calcd for
C15H22N2O, MCNaC).
4.3.13. (G)-(2S,5R)-1-(2-Phenyl-5-pyridin-3-ylmethyl-
pyrrolidin-1-yl) ethanone (25). Reaction of 51 mg
(0.25 mmol) of 18 with 3-bromopyridine (27 mL, 43.5 mg,
0.28 mmol), dppb (2.2 mg, 0.005 mmol, 2 mol%) and
NaOtBu (29 mg, 0.3 mmol) following general procedure B
afforded 57.2 mg (82%) of the title compound as a pale
1
yellow oil. H NMR (500 MHz, CDCl3) d 8.49–8.41 (m,
2H), 7.67–7.62 (m, 1H), 7.38–7.18 (m, 6H), 4.85 (t, JZ
7.3 Hz, 1H), 4.41–4.34 (m, 1H), 3.62 (dd, JZ7.3, 12.8 Hz,
1H), 2.59 (dd, JZ10.6, 12.8 Hz, 1H), 2.34 (sx, JZ7.6 Hz,
1H), 2.03–1.94 (m, 1H), 1.80–1.72 (m, 4H), 1.66–1.58 (m,
1H); 13C NMR (125 MHz, CDCl3) d 171.4, 150.6, 148.1,
143.2, 137.0, 134.8, 129.2, 127.6, 125.7, 123.7, 64.1, 60.6,
37.6, 35.5, 28.2, 23.4; IR (film) 2968, 1643, 1404 cmK1. MS
(ESI) 281.1653 (281.1654 calcd for C18H20N2O, MCHC).
4.3.10. 2-Naphthalen-2-ylmethyl-2,3-dihydroindole-1-
carboxylic acid tert-butyl ester (15). Reaction of 59 mg
(0.25 mmol) of 13 with 2-bromonaphthalene (57 mg,
0.28 mmol), dpe-phos (2.7 mg, 0.005 mmol, 2 mol%) and
NaOtBu (29 mg, 0.30 mmol) following general procedure B
afforded 44 mg (50%) of the title compound as a pale yellow
oil. 1H NMR (500 MHz, CDCl3) d 7.84–7.76 (m, 3H), 7.63
(s, 1H), 7.48–7.34 (m, 4H), 7.22–7.30 (m, 2H), 6.94 (t, JZ
7.3 Hz, 1H), 4.71 (s, br, 1H), 3.41 (s, br, 1H) 3.21–3.00 (m,
1H), 2.81–2.67 (m, 2H), 1.59 (s, 9H); 13C NMR (125 MHz,
4.3.14. 4-Allyl-2-(4-tert-butoxycarbonyl-benzyl) pyrroli-
dine-1-carboxylic acid tert-butyl ester (26). Reaction of
57 mg (0.25 mmol) of 19 with 4-bromo-tert-butyl benzoate
(71 mg, 0.28 mmol), dpe-phos (2.7 mg, 0.005 mmol,
2 mol%) and NaOtBu (29 mg, 0.3 mmol) following general
procedure B afforded 80 mg (70%) of the title compound as

M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
6457
a pale yellow oil. This product was isolated as a ca 3:1
mixture of diastereomers. Data are for the mixture. 1H NMR
(500 MHz, CDCl3) d 7.90–7.79 (m, 2H), 7.17 (s, br, 2H),
5.72–5.57 (m, 1H), 4.99–4.86 (m, 2H), 4.06–2.83 (m, br,
3H), 2.76–2.48 (m, 2H), 2.07–1.88 (m, 4H), 1.57–1.40 (m,
18H), 1.27–1.11 (m, 1H); 13C NMR (125 MHz, CDCl3) d
166.0, 157.5, 154.7, 149.5, 146.2, 143.8, 136.4, 130.2,
129.7, 116.3, 116.2, 81.0, 79.4, 77.6, 77.2, 76.9, 58.7, 52.7,
52.1, 51.7, 41.8, 41.0, 40.1, 37.9, 37.7, 37.3, 37.0, 36.3,
35.6, 34.9, 28.8, 28.4; IR (film) 2976, 1712, 1694,
1395 cmK1. Anal. Calcd for C24H35NO4: C, 71.79; H,
8.79; N, 3.49. Found: C, 71.60; H, 8.75; N, 3.45.
pyrrolidin-1-yl]ethanone (29). The reaction of 72 mg
(0.5 mmol) of 21 with 4-bromochlorobenzene (106 mg,
0.55 mmol), dpe-phos (10.8 mg, 0.02 mmol, 4 mol%) and
NaOtBu (58 mg, 1.00 mmol) was conducted following
general procedure B. 1H NMR analysis of the crude product
showed the formation of the desired product as a 10:1
mixture of diastereomers. The minor diastereomer was
separated upon chromatographic purification to afford
69.4 mg (61%) of the title compound as a pale yellow oil
with O20:1 dr. Data are for the major diastereomer, which
was found to exist as a 7:3 mixture of rotamers as judged by
1H NMR analysis. 1H NMR (500 MHz, CDCl3) d 7.27–7.16
(m, 2H), 7.12–7.00 (m, 2H), 3.86–3.78 (m, 0.7H), 3.71–3.60
(m, 0.3H), 3.55–3.48 (m, 0.3H), 3.47–3.29 (m, 1H), 3.26–
3.16 (m, 0.7H), 3.08–2.98 (m, 0.7H), 2.81–2.73 (m, 0.3H),
2.72–2.57 (m, 1H), 2.14–2.08 (m, 0.3H), 2.07–1.95 (m,
3.1H), 1.92–1.84 (m, 1.6H), 1.52–1.38 (m, 1H), 0.89–0.80
(m, 3H); 13C NMR (125 MHz, CDCl3) d 169.8, 169.7,
137.5, 136.5, 132.8, 132.1, 131.1, 130.7, 129.1, 128.6, 67.4,
65.3, 46.9, 44.1, 40.6, 37.7, 37.2, 35.6, 31.4, 29.1, 23.2,
22.2, 19.8, 19.3; IR (film) 2961, 1641, 1417 cmK1. MS
(ESI) 274.0969 (274.0975 calcd for C14H18ClNO, MC
NaC).
4.3.15. (G)-(2R,3S)-3-Methyl-2-naphthalen-2-ylmethyl-
pyrrolidine-1-carboxylic acid tert-butyl ester (27). The
reaction of 100 mg (0.5 mmol) of 20 with 2-bromonaphtha-
lene (124 mg, 0.60 mmol), dpe-phos (10.8 mg, 0.02 mmol,
4 mol%) and NaOtBu (96 mg, 1.00 mmol) was conducted
1
following general procedure A. H NMR analysis of the
crude product showed the formation of the desired product
as a 10:1 mixture of diastereomers. The minor diastereomer
was separated upon chromatographic purification to afford
106 mg (65%) of the title compound as a white solid with
O20:1 dr; mp 107 8C. Data are for the major diastereomer,
which was found to exist as a 1:1 mixture of rotamers as
judged by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) d
7.85–7.73 (m, 3H), 7.62 (d, JZ16.3 Hz, 1H), 7.50–7.28 (m,
3H), 3.78–3.60 (m, 1H), 3.61–3.38 (m, 1H), 3.33–3.08 (m,
2H), 2.96–2.73 (m, 1H), 2.15–2.09 (m, 1H), 1.98–1.80 (m,
1H), 1.53 (s, 9H), 1.49–1.34 (m, 1H), 0.84 (s, br, 3H); 13C
NMR (125 MHz, CDCl3) d 155.0, 136.8, 133.7, 132.3,
128.6, 128.2, 128.0, 127.8, 127.7, 126.2, 126.0, 125.5,
125.4, 79.6, 79.5, 66.0, 65.7, 45.7, 45.0, 40.6, 39.1, 37.0,
36.1, 31.3, 30.4, 28.8, 19.6, 19.4 (seven sets of carbons are
4.3.18. (G)-(3aR,6S,6aS)-6-Biphenyl-4-yl-hexahydro-
cyclopenta[b]pyrrole-1-carboxylic acid tert-butyl ester
(30). Reaction of 53 mg (0.25 mmol) of 22 with 4-bromo-
biphenyl (64 mg, 0.28 mmol), xantphos (5.8 mg,
0.01 mmol, 4 mol%) and NaOtBu (36 mg, 0.38 mmol)
following general procedure A afforded 42.8 mg (47%) of
the title compound as a white solid; mp 128 8C. This
compound was found to exist as a 3:2 mixture of rotamers as
judged by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) d
7.55–7.34 (m, 6H), 7.32–7.16 (m, 3H), 4.54–4.30 (m, 1H),
3.83–3.71 (m, 0.6H), 3.55–3.17 (m, 1.4H), 3.10–2.78 (m,
2H), 2.12–1.98 (m, 1H), 1.97–1.60 (m, 5H), 1.21–0.89 (m,
9H); 13C NMR (125 MHz, CDCl3) d 154.5, 141.6, 141.2,
139.4, 129.6, 128.9, 127.2, 127.1, 127.0, 126.6, 94.6, 79.0,
65.4, 52.3, 51.2, 47.8, 43.5, 42.5, 34.2, 33.7, 32.4, 32.2,
31.8, 28.4, 27.9 (thirteen sets of carbons are incidentally
equivalent); IR (film) 2952, 1689, 1392 cmK1. MS (ESI)
386.2105 (386.2096 calcd for C24H29NO2, MCNaC).
incidentally equivalent); IR (film) 2964, 1692, 1396 cmK1
.
MS (ESI) 348.1943 (348.1939 calcd for C21H27NO2, MC
NaC).
4.3.16. (G)-(2R,3S)-2-(4-tert-Butylbenzyl)-3-methyl-
pyrrolidine-1-carboxylic acid tert-butyl ester (28). The
reaction of 100 mg (0.5 mmol) of 20 with 4-bromo-tert-
butylbenzene (105 mL, 128 mg, 0.60 mmol), dpe-phos
(10.8 mg, 0.02 mmol, 4 mol%) and NaOtBu (96 mg,
1.00 mmol) was conducted following general procedure
A. 1H NMR analysis of the crude product showed the
formation of the desired product as a 10:1 mixture of
diastereomers. The minor diastereomer was separated upon
chromatographic purification to afford 97.4 mg (59%) of the
title compound as a pale yellow oil with O20:1 dr. Data are
for the major diastereomer, which was found to exist as a 3:2
4.3.19. (G)-(3aR,6S,6aS)-1-(6-Naphthalen-2-yl-hexa-
hydrocyclopenta[b]pyrrol-1-yl) ethanone (31). Reaction
of 78 mg (0.25 mmol) of 23 with 2-bromonaphthalene
(114 mg, 0.55 mmol), nixantphos (13.8 mg, 0.025 mmol,
5 mol%), Pd2(dba)3 (11.4 mg, 0.0125 mmol, 2.5 mol%) and
NaOtBu (58 mg, 0.60 mmol) following general procedure B
afforded 85 mg (61%) of the title compound as a pale yellow
oil. This compound was found to exist as a 7:3 mixture of
rotamers as judged by 1H NMR analysis. 1H NMR
(400 MHz, CDCl3) d 7.82–7.69 (m, 3H), 7.57 (s, 1H),
7.48–7.34 (m, 2H), 7.28–7.24 (m, 1H), 4.90 (t, JZ8.6 Hz,
0.3H), 4.43 (t, JZ7.0 Hz, 0.7H), 4.14–4.06 (m, 0.70H), 3.54
(q, JZ8.1 Hz, 0.3H), 3.48–3.20 (m, 2H), 3.13–3.04 (m,
0.7H), 2.92–2.82 (m, 0.3H), 2.17–1.92 (m, 4H), 1.85–1.72
(m, 2H), 1.64 (s, 0.6H), 1.11 (s, 2.4H); 13C NMR (100 MHz,
CDCl3) d 170.6, 168.8, 139.2, 138.2, 133.6, 133.5, 132.7,
132.4, 128.31, 128.29, 128.1, 127.91, 127.90, 129.86,
127.81, 127.2, 127.0, 126.6, 126.4, 125.9, 125.8, 125.3,
67.0, 65.2, 53.4, 49.9, 49.1, 47.4, 44.0, 42.3, 33.7, 32.6,
32.4, 32.3, 32.2, 31.4, 22.5, 21.8; IR (film) 2950, 1638,
1
1
mixture of rotamers as judged by H NMR analysis. H
NMR (500 MHz, CDCl3) d 7.35–7.25 (m, 2H), 7.16–7.06
(m, 2H), 3.69–3.37 (m, 2H), 3.31–2.92 (m, 2H), 2.76–2.56
(m, 1H), 2.05 (s, br, 1H), 1.97–1.79 (m, 1H), 1.51 (s, 9H),
1.45–1.35 (m, 1H), 1.32 (s, 9H), 0.88 (d, JZ6.8 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 155.0, 149.2, 149.0, 136.1,
129.5, 129.3, 125.5, 125.3, 79.4, 79.1, 66.1, 65.6, 45.6, 45.0,
39.9, 38.5, 37.1, 36.0, 34.6, 31.6, 31.2, 30.4, 28.8, 19.7, 19.5
(five sets of carbons are incidentally equivalent); IR (film)
2963, 1696, 1395 cmK1. MS (ESI) 354.2402 (354.2409
calcd for C21H33NO2, MCNaC).
4.3.17. (G)-(2R,3S)-1-[2-(4-Chlorobenzyl)-3-methyl

6458
M. B. Bertrand, J. P. Wolfe / Tetrahedron 61 (2005) 6447–6459
1413 cmK1. MS (ESI) 302.1523 (302.1521 calcd for
12. Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M.
Tetrahedron Lett. 2004, 45, 905–906.
C19H21NO, MCNaC).
13. Control experiments demonstrated the Boc-cleavage is base-
induced (not Pd-catalyzed). See Ref. 12.
14. The product isolated from this reaction contained ca 15% of
the corresponding dihydropyrrole. Similar side reactions have
been previously observed in reactions of 2-allylaniline or g-N-
arylaminoalkenes with electron-rich aryl bromides. See Refs.
4,5a.
Acknowledgements
The authors thank the University of Michigan for generous
financial support of this work. J.P.W. acknowledges the
Camille and Henry Dreyfus Foundation for a New Faculty
Award, and Research Corporation for an Innovation Award.
Additional unrestricted support was provided by Amgen,
3M, and Eli Lilly.
15. Ney, J. E.; Wolfe, J. P. Unpublished results.
16. For recent studies on Pd-catalyzed N-vinylation of amines,
´
See: Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C.
Chem. Eur. J. 2004, 10, 494–507.
17. The base induced substrate olefin isomerization was only
observed in reactions of 2-allylaniline derivatives.
18. For Pd-catalyzed oxidative amination reactions that afford
indole products, see: (a) Hegedus, L. S.; Allen, G. F.; Bozell,
J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100,
5800–5807. (b) Larock, R. C.; Hightower, T. R.; Hasvold,
L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585.
19. Proton NMR analysis of crude reaction mixtures revealed
diastereomer ratios of 10–20:1; the minor diastereomer was
usually readily separated by chromatography to provide
isolated products with O20:1 dr. Thus, diastereomeric ratios
reported in Table 4 represent ratios of diastereomers for the
isolated material upon which the yield is based. The
diastereomeric ratios observed in crude reaction mixtures
were O20:1 for 2,5-disubstituted pyrrolidines, O20:1 for
6-substituted hexahydrocyclopenta[b]pyrroles, and ca 10:1 for
2,3-disubstituted pyrrolidines.
References and notes
1. (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446. (b) Lewis,
J. R. Nat. Prod. Rep. 2001, 18, 95–128.
2. (a) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1
2000, 2862–2892 and earlier reviews in this series. (b) Pichon,
´
M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927–964.
3. For examples of pyrrolidine synthesis that involve intra-
molecular C–N bond formation and intermolecular C–C bond
formation, see: (a) Tamaru, Y.; Kimura, M. Synlett 1997,
749–757. (b) Tamaru, Y.; Hojo, M.; Yoshida, Z.-i. J. Org.
Chem. 1988, 53, 5731–5741. (c) Yorimitsu, H.; Wakabayashi,
K.; Shinokubo, H.; Oshima, K. B. Chem. Soc. Jpn. 2001, 74,
1963–1970. (d) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr,
R. J. J. Org. Chem. 1994, 59, 4172–4178.
20. The relative stereochemistry of the pyrrolidine products was
assigned on the basis of 1H NMR NOE experiments.
Diastereomeric ratios were determined by GC and/or 1H
NMR analysis.
4. Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43,
3605–3608.
5. For related transformations that afford indoline or tetra-
hydrofuran products, see: (a) Lira, R.; Wolfe, J. P. J. Am.
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in some systems.

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