In situ trapping of Boc-2-pyrrolidinylmethylzinc iodide with aryl iodides: Direct synthesis of 2-benzylpyrrolidines

Article abstract of DOI:10.1021/jo101503p

Addition of (S)-(+)-tert-butyl 2-(iodomethyl)pyrrolidine-1-carboxylate to activated zinc, aryl halides, and a catalyst derived from Pd₂(dba) ₃ (2.5 mol %) and SPhos (5 mol %) in DMF allows trapping of the corresponding organozinc rea

Full text of DOI:10.1021/jo101503p

pubs.acs.org/joc
hydrogenation of N-acylhydrazonium salts incorporating
In Situ trapping of Boc-2-pyrrolidinylmethylzinc
Iodide with Aryl Iodides: Direct Synthesis of
2-Benzylpyrrolidines
Enders’ SAMP hydrazone as auxiliary, followed by lactam
reduction;6 and both copper-catalyzed7,8 and palladium-
catalyzed9 intramolecular asymmetric carboamination of
alkenes. 2-Arylpyrrolidines have been made via asymmetric
deprotonation of Boc-pyrrolidine, transmetalation with
ZnCl2, and subsequent Negishi cross-coupling with aryl
bromides,10,11 although this approach has not yet been
extended to 2-benzylpyrrolidines.
Ahmad Reza Massah,† Andrew J. Ross, and
Richard F. W. Jackson*
Department of Chemistry, The University of Sheffield,
Dainton Building, Sheffield S3 7HF, United Kingdom.
Present address: Department of Chemistry,
In an extension of our general approach to amino acid12,13
and amine synthesis,14,15 it appeared reasonable to consider
the possibility that 2-benzylpyrrolidines could be prepared
using protected 2-pyrrolidinylmethylzinc iodides 1. Negishi
cross-coupling of 1 with a variety of aryl halides should give
protected 2-benzylpyrrolidines in a single step (eq 1), offering
a flexible route to these targets.
†
Islamic Azad University, Shahreza Branch,
Shahreza Isfahan, P.O. Box 86145-311, Iran
r.f.w.jackson@shef.ac.uk
Received July 30, 2010
While the pyroglutamic acid derived zinc reagent 2 is
stable enough to undergo copper-catalyzed reaction with
propargylic halides,16 bromoallenes, and iodoalkynes,17 two
groups1,18 have independently reported that attempts to
prepare the corresponding Boc-protected proline-derived
zinc reagent 1a were unsuccessful, with the presumed reagent
undergoing rapid elimination to give the corresponding
alkene. We tried to prepare zinc reagent 1a and also observed
only the product of elimination, in complete agreement with
the previous reports.1,18 We now report a practical method to
carry out Negishi cross-couplings with this previously elusive
reagent.
Addition of (S)-(þ)-tert-butyl 2-(iodomethyl)pyrrolidine-
1-carboxylate to activated zinc, aryl halides, and a catalyst
derived from Pd2(dba)3 (2.5 mol %) and SPhos (5 mol %)
in DMF allows trapping of the corresponding organozinc
reagent, with formation of Boc-protected 2-benzylpyrro-
lidines (20-72%).
2-Benzylpyrrolidines feature as structural components of
a number of natural products, including the tylophora
alkaloids which contain a phenanthroindolizidine skeleton.1
Simple 2-benzylpyrrolidines have been shown to be key
components of orally active dopamine analogues2 and of a
series of calcium-sensing receptor antagonists.3 They have
also been used as precursors to chiral acyclic diaminocarbene
ligands for use in the Suzuki reaction.4
Various routes to enantiomerically pure 2-benzylpyrroli-
dines have been developed, with the simplest involving addi-
tion of Grignard reagents to proline derivatives, followed
by reduction of the aryl ketone.2,3 Asymmetric syntheses of
2-benzylpyrrolidines include addition of the Grignard reagent
prepared from 2-(2-bromoethyl)-1,3-dioxane to N-tert-
butanesulfinyl aldimines, followed by cyclization;5 stereoselective
Recent work has shown that replacement of the Boc group
with the trifluoroacetyl group results in stabilization of
protected β-aminoalkylzinc iodides toward elimination.19
We have therefore investigated the preparation of the
(6) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron:
Asymmetry 2003, 14, 2625–2632.
(7) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948–12949.
(8) Zeng, W.; Chemler, S. R. J. Org. Chem. 2008, 73, 6045–6047.
(9) Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157–12159.
(10) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen,
C. Y. J. Am. Chem. Soc. 2006, 128, 3538–3539.
(11) Klapars, A.; Campos, K. R.; Waldman, J. H.; Zewge, D.; Dormer,
P. G.; Chen, C. Y. J. Org. Chem. 2008, 73, 4986–4993.
(12) Rilatt, I.; Caggiano, L.; Jackson, R. F. W. Synlett 2005, 2701–2719.
(13) Ross, A. J.; Lang, H. L.; Jackson, R. F. W. J. Org. Chem. 2010, 75,
245–248.
€
(1) Furstner, A.; Kennedy, J. W. J. Chem.;Eur. J. 2006, 12, 7398–7410.
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Trans. 1 2000, 219–223.
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Perkin Trans. 1 2002, 733–736.
(16) Karstens, W. F. J.; Stol, M.; Rutjes, F.; Hiemstra, H. Synlett 1998,
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Speckamp, W. N.; Hiemstra, H. Tetrahedron Lett. 1999, 40, 8629–8632.
(18) Hjelmgaard, T.; Tanner, D. Org. Biomol. Chem. 2006, 4, 1796–1805.
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McClelland, D. L.; Michel, A.; Caroon, J. M.; Galeazzi, E.; Eglen, R.;
Whiting, R. L. Bioorg. Med. Chem. Lett. 1995, 5, 2371–2376.
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DOI: 10.1021/jo101503p
r
Published on Web 11/10/2010
J. Org. Chem. 2010, 75, 8275–8278 8275
2010 American Chemical Society

Massah et al.
JOCNote
SCHEME 1. Attempted Trapping of TFA-Protected Zinc
Reagent 1b
SCHEME 2. In Situ Trapping of TFA-Protected Zinc Reagent 1b
TABLE 1. Synthesis of 2-Benzylpyrrolidine Derivatives 10a-n
entry
ArX
product
Ar
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5I
2-MeOC6H4I
2-HOC6H4I
3-MeOC6H4I
3-ClC6H4I
3-F3CC6H4I
4-MeOC6H4I
4-MeOC6H4Br
4-HOC6H4I
4-H2NC6H4I
4-MeO2CC6H4I
4-MeC6H4I
10a
10b
10c
10d
10e
10f
10g
10g
10h
10i
10j
10k
10l
10m
10n
C6H5
43
38
40
44
39
62
57
37
51
41
30
38
72
32
20
TFA-protected proline-derived zinc reagent 1b and sub-
sequent Negishi coupling with aryl iodides using catalysts
incorporating SPhos as ligand.20-22 Such catalysts are highly
effective in Negishi cross-coupling reactions.13,20,23 The nec-
essary precursor 4 was prepared from TFA-protected prolinol
3.24 Attempted formation of the organozinc reagent 1b by
treatment of iodide 4 with activated zinc in DMF at room
temperature, followed by addition of iodobenzene, Pd2(dba)3
(2.5 mol %), and SPhos (5 mol %), gave only trace amounts
of the desired cross-coupled product 5, in addition to the
alkene elimination product 6 (Scheme 1). A reaction at lower
temperature (0-4 °C) showed no improvement.
2-MeOC6H4
2-HOC6H4
3-MeOC6H4
3-ClC6H4
3-F3CC6H4
4-MeOC6H4
4-MeOC6H4
4-HOC6H4
4-H2NC6H4
4-MeO2CC6H4
4-MeC6H4
3,4-(MeO)2C6H3I
2-bromopyridine
3-bromothiophene
3,4-(MeO)2C6H3
2-pyridyl
3-thienyl
The nitrogen protecting group of β-aminoalkylzinc iodides
influences not only the stability of the reagents but also their
reactivity in Negishi cross-coupling reactions.19 For exam-
ple, the TFA-protected aspartic acid derived reagent 7b was
more stable, but less reactive, than the corresponding Boc-
protected reagent 7a, with the result that yields in Negishi
cross-coupling reactions were essentially the same. However,
the TFA-protected glutamic acid-derived reagent 8b was
both more stable, and more reactive, than the corresponding
Boc-protected reagent 8a in Negishi cross-coupling reac-
tions, giving significantly higher yields.19 These observations
demonstrate that apparently small changes in structure can
have a significant influence on the outcome of preparative
reactions.
SCHEME 3. In Situ Preparation of 2-Benzylpyrrolidines 10
the in situ preparation of simple alkylzinc halides in,26 and
on,27 water and elsewhere.28 After extensive optimization,
we established that slow addition of the iodide 4 to activated
zinc and iodobenzene in DMF at 0 °C, in the presence of the
catalyst derived from Pd2(dba)3 (2.5 mol %) and SPhos
(5 mol %), gave the desired product 5 (Scheme 2). This demon-
strated that reagent 1b can be trapped, albeit in poor yield.
Application of the same conditions to the iodide 930 now
allowed the target Boc-2-benzylpyrrolidine 10a to be obtained in
a substantially better yield (43%), together with the alkene 11,
arising from competitive decomposition of the zinc reagent.
This result shows that the Boc-protected reagent 1a can be
trapped more efficiently than the TFA-protected reagent 1b.
The results obtained from in situ trapping of reagent 1a using
a variety of aryl halides are shown in Table 1 and Scheme 3.
While aryl bromides appear to be less suitable substrates
(cf. entries 7 and 8), an electron-poor (entry 14) and an
electron-rich heterocycle (entry 15) can be used. Free phenols
are tolerated (entries 3 and 9).29 In all cases, varying amounts
of the alkene 11 were formed, highlighting the intrinsic
instability of reagent 1a. The yields of the 2-benzylpyrrolidines
10 obtained therefore reflect the relative rates of productive
Negishi cross-coupling and unproductive elimination.
It was clear that neither of the proline-derived reagents 1a
and 1b was sufficiently stable to be prepared in a con-
ventional manner. We therefore attempted to generate the
organozinc reagents 1a and 1b in the same pot as the catalyst
and iodobenzene, so that it could be trapped as soon as it was
formed. One potential advantage of this method is that there
will be an excess of Pd(SPhos)PhI (the likely intermediate)21,25
relative to the zinc reagent, so the residence time of the
zinc reagent in the reaction mixture is minimized. Some
precedent for this approach can be found in recent reports on
(20) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028–
13032.
(21) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685–4696.
(22) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–1473.
(23) Manolikakes, G.; Dong, Z. B.; Mayr, H.; Li, J. S.; Knochel, P.
Chem.;Eur. J. 2009, 15, 1324–1328.
(26) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc. 2009,
131, 15592–15593.
(27) Duplais, C.; Krasovskiy, A.; Wattenberg, A.; Lipshutz, B. H. Chem.
Commun. 2010, 46, 562–564.
(28) Guan, Z. H.; Ren, Z. H.; Zhao, L. B.; Liang, Y. M. Org. Biomol.
Chem. 2008, 6, 1040–1045.
(24) Clark, J. S.; Hodgson, P. B.; Goldsmith, M. D.; Blake, A. J.; Cooke,
P. A.; Street, L. J. J. Chem. Soc., Perkin Trans. 1 2001, 3325–3337.
(25) Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Organometallics 2007,
26, 2183–2192.
(29) Jackson, R. F. W.; Rilatt, I.; Murray, P. J. Org. Biomol. Chem. 2004,
2, 110–113.
(30) Park, S. H.; Kang, H. J.; Ko, S.; Park, S.; Chang, S. Tetrahedron:
Asymmetry 2001, 12, 2621–2624.
8276 J. Org. Chem. Vol. 75, No. 23, 2010

Massah et al.
JOCNote
In conclusion, although the zinc reagent 1a is evidently too
unstable to be prepared in a conventional manner, it is
sufficiently reactive that it can be trapped with varying levels
of efficiency in situ. This general approach may be applicable
to other unstable organozinc reagents.
ν
max(film)/cm-1 2969, 1689, 1563, 1493, 1393, 1243, 1161,
1109; NMR δH (500 MHz) 1.40 (9H, s), 1.55-1.64 (1H, m),
1.63-1.79 (3H, m), 2.61 (1H, dd, J = 13.0 and 8.8 Hz), 2.94 (1H,
dd, J = 13.0, 4.7 Hz), 3.05 (3H, s), 3.17-3.31 (1H, m), 3.97-4.04
(1H, m), 6.86 (1H, dt, J = 7.4 and 0.8 Hz), 6.94 (1H, d, J 8.2 Hz),
7.08 (1H, dd, J = 7.4 and 1.4 Hz), 7.18 (1H, dt, J = 7.8 and
1.7 Hz); NMR δC (126 MHz) 22.1, 27.8, 28.7, 45.5, 55.0, 56.7,
77.6, 110.7, 119.9, 126.8, 127.0, 130.3, one quaternary carbon
Experimental Section
not observed and one peak obscured; [R]22 þ23.5 (c 1.02,
D
CHCl3); MS m/z (ES) found MHþ 292.1902, C17H25NO3
requires MHþ 292.1913.
All NMR spectra were recorded in DMSO-d6 at 80 °C.
Negishi Cross-Coupling Using Iodide 9. Zinc dust (190 mg,
3 mmol) was added to a flame-dried, nitrogen-purged, round-
bottom flask. Dry DMF (0.7 mL) was added via syringe,
followed by iodine (40 mg, 0.15 mmol); the yellow color rapidly
faded. Pd2dba3 (22 mg, 0.025 mmol), SPhos (21 mg, 0.05 mmol),
and aryl halide (2.0 mmol) were added to the flask, and the
reaction mixture was cooled in an ice bath. The iodide 9 (311 mg,
1 mmol) in DMF (0.8 mL) was added in 10 portions, via syringe,
over 5 h. The reaction mixture was allowed to warm to room
temperature overnight. The crude reaction mixture was applied
directly to a silica gel column to give the product 10. In some
cases, the product coeluted with alkene 11, which could be
removed by Kugelrohr distillation (90 °C, 0.3 mmHg).
(S )-(þ)-tert-Butyl 2-(3-Chlorobenzyl)pyrrolidine-1-carboxyl-
ate, 10e. The general cross-coupling method using 3-chloroio-
dobenzene (247 μL, 2.0 mmol) gave, after chromatographic
purification (5-10% EtOAc in petrol), 10e (115 mg, 39%) as
a colorless oil: Rf 0.42 (20% EtOAc in petroleum ether); IR νmax
(film)/cm-1 2971, 1686, 1389, 1364, 1167; NMR δH (500 MHz)
1.41 (9H, s), 1.58-1.66 (1H, m), 1.68-1.75 (2H, m), 1.76-1.85
(1H, m), 2.65 (1H, dd, J = 13.0 and 8.6 Hz), 2.93 (1H, dd, J =
13.0 and 3.7 Hz), 3.13-3.20 (1H, m), 3.28 (1H, td, J = 10.2 and
7.7 Hz), 3.87-3.95 (1H, m), 7.13 (1H, d, J = 7.5 Hz), 7.21 (1H,
s), 7.24 (1H, d, J = 8.2 Hz), 7.30 (1H, t, J = 7.7 Hz); NMR δC
(126 MHz) 22.1, 27.8, 28.9, 45.7, 57.6, 77.9, 125.6, 127.4, 128.6,
129.5, 132.6, 141.2, 153.1, one peak obscured; [R]22D þ6.0 (c 1.0,
CHCl3); MS m/z (ES) found MHþ 296.1431, C16H22NO2Cl
requires MHþ 296.1417.
(S )-(þ)-tert-Butyl 2-Benzylpyrrolidine-1-carboxylate, 10a. The
general cross-coupling method using iodobenzene (224 μL, 2.0 mmol)
gave, after chromatographic purification (10% EtOAc in petroleum
ether) and removal of 11 by Kugelrohr distillation, 10a (112mg,43%)
as a colorless oil: Rf 0.5 (20% EtOAc in petroleum ether); IR νmax
(film)/cm-1 2974, 2927, 2862, 1692, 1454, 1392; NMR δH (500 MHz)
1.43 (9H, s), 1.55-1.82 (4H, m), 2.60 (1H, dd, J = 13.0, 8.9 Hz), 2.97
(2H, dd, J = 13.1, 3.6 Hz), 3.23-3.30 (1H, m), 3.14-3.20 (2H, m),
3.88-3.94 (1H, m), 7.15-7.22 (3H, m), 7.28 (2H, t, J = 7.6 Hz);
NMR δC (500 MHz) 22.1, 28.7, 27.7, 27.9, 45.7, 57.8, 77.8, 125.6,
(S )-(-)-tert-Butyl 2-(3-(Trifluoromethyl)benzyl)pyrrolidine-
1-carboxylate, 10f. The general cross-coupling method using
3-iodobenzotrifluoride (288 μL, 2.0 mmol) gave, after chroma-
tographic purification (7% EtOAc in petrol), 10f (204 mg, 62%)
as an orange oil: Rf 0.47 (20% EtOAc in petroleum ether); IR
ν
max (film)/cm-1 2973, 2928, 2862, 1812, 1769, 1756, 1693, 1456,
127.8, 128.8, 138.6, 153.1, one peak obscured; [R]22 þ9.8 (c 1.02,
1395; NMR δH (500 MHz) 1.41 (9H, s), 1.57-1.75 (4H, m),
1.76-1.88 (1H, m), 2.78 (1H, dd, J = 13.0 and 8.4 Hz), 3.00 (1H,
dd, J = 13.2 and 4.1 Hz), 3.22-3.35 (1H, m), 3.91-4.00 (1H, m),
7.46-7.57 (4H, m); NMR δC (126 MHz) 22.1, 28.9, 77.9, 110.2,
140.1, 153.1, 27.7, 30.9, 45.7, 57.6, 122.4, 125.2, 128.8, 132.9, one
D
CHCl3); MS m/z (ES) found MHþ 262.1815, C16H24NO2 requires
MHþ 262.1807.
(S)-(þ)-tert-Butyl 2-(2-Methoxybenzyl)pyrrolidine-1-carboxyl-
ate, 10b. The general cross-coupling method using 2-iodoanisole
(260 μL, 2.0 mmol) gave, after chromatographic purification (5%
EtOAc in petroleum ether), 10b (113 mg, 38%) as a colorless oil:
Rf 0.42 (20% EtOAc in petroleum ether); IR νmax (film)/cm-1 2968,
1687, 1493, 1390, 1364, 1242, 1169, 1107; NMR δH (500 MHz) 1.40
(9H, s), 1.55-1.63 (1H, m), 1.64-1.80 (3H, m), 2.61 (1H, dd, J =
12.8 and 8.9 Hz), 2.94 (1H, dd, J 13.0, 4.7 Hz), 3.17-3.31 (2H, m),
3.78 (3H, s), 3.96-4.04 (1H, m), 6.86 (1H, dt, J = 7.3 and 0.9 Hz),
6.94 (1H, d, J=8.2Hz), 7.08(1H, dd, J= 7.3 and 1.4 Hz), 7.18 (1H,
dt, J = 7.9 and 1.7 Hz); NMR δC (126 MHz) 27.8, 45.5, 55.0, 56.7,
77.6, 110.7, 119.9, 127.0, 130.3, quaternary carbons are not observed;
[R]22D þ30.7 (c 1.14, CHCl3); MS m/z (ES) found MHþ 292.1907,
C17H25NO3 requires MHþ 292.1913.
(S )-(þ)-tert-Butyl 2-(2-Hydroxybenzyl)pyrrolidine-1-carboxyl-
ate, 10c. The general cross-coupling method using iodobenzene
(226 μL, 2.0 mmol) gave, after chromatographic purification (10-
15% EtOAc in petroleum ether) and removal of 11 by Kugelrohr
distillation, 10c (112 mg, 40%) as an orange oil: Rf 0.39 (20% EtOAc
in petroleum ether); IR νmax(film)/cm-1 3274, 2975, 2926, 2871, 1655,
1595, 1487, 1456, 1417; NMR δH (500 MHz) 1.40 (9H, s), 1.62-1.83
(4H, m), 2.59 (1H, dd, J = 13.0 and 9.0 Hz), 2.89 (1H, dd, J = 13.2
and 3.9 Hz), 3.16-3.31 (2H, m), 3.93-4.02 (1H, m), 6.69 (1H, dt,
J 7.5 and 1.2), 6.77 (1H, d, J 8.2), 6.98 (2H, t, J 7.5), 8.90 (1H, s); δC
(126 MHz) 22.2, 27.9, 28.7, 33.0, 45.5, 57.1, 77.7, 114.8, 118.5, 125.0,
peak obscured; [R]22 -18.5 (c 1.08, CHCl3); MS m/z (ES)
D
found MNaþ 352.1507, C17H22NO2F3Na requires MNaþ
352.1500.
(S )-(þ)-tert-Butyl 2-(4-Methoxybenzyl)pyrrolidine-1-carboxyl-
ate, 10g. The general cross-coupling method using 4-iodoanisole
(468 mg, 2.0 mmol) gave, after chromatographic purification (7%
EtOAc in petroleum ether), 10g (165 mg, 57%) as a colorless oil:
Rf 0.5 (20% EtOAc in petroleum ether); IR νmax (film)/cm-1 2967,
1688, 1297, 1363, 1252, 1165, 1112; NMR δH (500MHz) 1.43(9H, s),
1.55-1.81 (4H, m), 2.54 (1H, dd, J = 13.0 and 9.0 Hz), 2.88 (1H, dd,
J = 13.2 and 3.4 Hz), 3.11-3.19 (1H, m), 3.21-3.31 (1H, m), 3.73
(3H,s),3.81-3.90 (1H, m), 6.85 (2H, d, J=8.6Hz),7.07(2H,d,J=
8.6 Hz); NMR δC (126 MHz) 22.1, 28.6, 27.9, 45.8, 54.7, 57.9, 77.8,
113.5, 129.7, 130.5, 153.1, 157.5, one peak obscured; [R]22 þ2.4
D
(c 1.04, CHCl3); MS m/z (ES) found MHþ 292.1920, C17H25NO3
requires MHþ 292.1913.
Using 4-bromoanisole (250 μL, 2.0 mmol) under the same
conditions gave 10g (108 mg, 37%).
(S )-(-)-tert-Butyl 2-(4-Hydroxybenzyl)pyrrolidine-1-carboxyl-
ate, 10h. The general cross-coupling method using 4-iodophenol
(440 mg, 2.0 mmol) gave, after chromatographic purification
(10-15% EtOAc in petroleum ether), 10h (140 mg, 51%) as a
colorless oil: Rf 0.17 (20% EtOAc in petroleum ether); IR νmax(film)/
cm-1 3264, 2970, 1655, 1514, 1410, 1365, 1232, 1164, 1154, 1105;
NMR δH (500 MHz) 1.43 (9H, s), 1.56-1.80 (5H, m), 2.84 (1H, dd,
J = 13.2 and 3.5 Hz), 3.11-3.19 (1H, m), 3.21-3.30 (1H, m),
3.79-3.88 (1H, m), 6.68 (2H, d, J = 8.4 Hz), 6.95 (2H, d, J = 8.4
Hz), 8.87 (1H, s), one peak obscured; NMR δC (126 MHz) 22.1, 27.9,
28.6, 45.8, 58.0, 114.8, 128.7, 129.5, 155.3, two quaternary carbons are
not observed and one peak is obscured; [R]22D -13 (c 1.0, CHCl3);
22
126.6, 130.3, 153.2, 155.1; [R]D þ40.0 (c 1.0, CHCl3); MS m/z (ES)
Found MHþ 278.1762. C16H24NO3 requires MHþ 278.1756.
(S)-(þ)-tert-Butyl 2-(3-methoxybenzyl)pyrrolidine-1-carboxyl-
ate, 10d. The general cross-coupling method using 3-iodoani-
sole (238 μL, 2.0 mmol) gave, after chromatographic purifica-
tion (5% EtOAc in petroleum ether), 10d (127 mg, 44%) as a
colorless oil: Rf 0.44 (20% EtOAc in petroleum ether); IR
J. Org. Chem. Vol. 75, No. 23, 2010 8277

Massah et al.
JOCNote
MS m/z (ES) found MHþ 278.1755, C16H23NO3 requires MHþ
278.1756.
(3H, m), 1.72-1.80 (1H, m), 2.54 (1H, dd, J = 13.1 and 8.8 Hz),
2.87 (1H, dd, J = 13.1 and 3.5 Hz), 3.01-3.07 (1H, m),
3.11-3.21 (1H, m), 3.21-3.32 (1H, m), 3.73 (3H, s), 3.74 (3H,
s), 3.85-3.91 (1H, m), 6.69 (1H, dd, J = 8.1 and 1.9 Hz), 6.74
(1H, d, J = 1.9 Hz), 6.84-6.88 (1H, m); NMR δC (126 MHz)
22.1, 27.9, 28.7, 45.8, 55.4, 55.6, 57.9, 77.8, 112.5, 113.6, 121.0,
131.4, 147.4, 148.7, 153.1, one peak obscured; [R]22D þ4.0 (c 1.0,
CHCl3); MS m/z (ES) found MHþ 322.2029, C18H27NO4
requires MHþ 322.2018.
(S )-(-)-tert-Butyl 2-(4-Aminobenzyl)pyrrolidine-1-carboxyl-
ate, 10i. The general cross-coupling method using 4-iodoaniline
(438 mg, 2.0 mmol) gave, after chromatographic purification
(10-15% EtOAc in petroleum ether), 10i (112 mg, 41%) as a
yellow oil: Rf 0.40 (40% EtOAc in petroleum ether); IR νmax(film)/
cm-1 3391, 3293, 2970, 1655, 1514, 1410, 1365, 1232, 1164, 1154,
1105; NMR δH (500 MHz) 1.44 (9H, s), 1.58-1.77 (4H, m), 2.41 (1H,
dd, J = 13.1 and 9.1 Hz), 2.78 (1H, dd, J = 13.2 and 3.5 Hz),
3.11-3.18 (1H, m), 6.02-6.61 (2H, m), 3.20-3.27 (1H, m),
3.76-3.83 (1H, m), 4.62 (2H, s), 6.51 (2H, d, J = 8.4 Hz), 6.82
(2H, d, J = 8.3 Hz); NMR δC (126 MHz) 22.0, 27.9, 28.5, 45.8, 58.1,
77.7, 113.8, 125.7, 129.1, 146.2, 153.1, one peak obscured; [R]22D -2.0
(c 1.0, CHCl3); MS m/z (ES) found MHþ 277.1905, C16H25N2O2
requires MHþ 277.1916.
(S )-(þ)-tert-Butyl 2-(Pyridin-2-ylmethyl)pyrrolidine-1-carboxyl-
ate, 10m. The general cross-coupling method using 2-bromopyridine
(191 μL, 2.0 mmol) gave, after chromatographic purification (40%
EtOAc in petroleum ether), 10m (85 mg, 32%) as a pale yellow oil:
Rf 0.21 (50% EtOAc in petroleum ether); IR νmax(film)/cm-1 2972,
2925, 2862, 1690, 1590, 1563, 1475, 1434, 1394; NMR δH (500 MHz)
1.40 (9H, s), 1.64-1.83 (4H, m), 2.73 (1H, dd, J = 13.0 and 9.0 Hz),
3.12 (2H, dd, J = 13.0 and 3.7 Hz), 3.14-3.22 (1H, m), 3.22-3.31
(1H, m), 4.04-4.12 (1H, m), 7.12-7.20 (2H, m), 7.66 (1H, dt, J=7.7
and 1.7 Hz), 8.46 (1H, d, J=4.1Hz);NMRδC (126 MHz) 22.1, 27.8,
28.9, 45.7, 56.7, 77.8, 120.8, 123.0, 135.7, 148.5, 153.1, 158.6, one peak
(S )-(þ)-tert-Butyl 2-(4-(Methoxycarbonyl)benzyl)pyrrolidine-
1-carboxylate, 10j. The general cross-coupling method using
methyl 4-iodobenzoate (524 mg, 2.0 mmol) and iodide 9 (311
mg, 1 mmol) gave, after chromatographic purification (5-10%
EtOAc in petroleum ether), 10j (96 mg, 30%) as a colorless oil:
Rf 0.32 (20% EtOAc in petroleum ether); IR νmax(film)/cm-1
2930, 1721, 1689, 1610, 1391, 1275, 1103; NMR δH (500 MHz)
1.42 (9H, s), 1.56-1.66 (1H, m), 1.66-1.73 (2H, m), 1.74-1.84
(1H, m), 2.71 (1H, dd, J = 13.0 and 8.6 Hz), 3.14-3.20 (1H, m),
3.23-3.32 (1H, m), 3.84 (3H, s), 3.91-3.98 (1H, m), 7.32 (2H, d,
obscured; [R]22 þ10.0 (c 1.0, CHCl3); MS m/z (ES) found MHþ
D
263.1765, C15H23N2O2 requires MHþ 263.1760.
(S )-(-)-tert-Butyl 2-(Thiophene-3-ylmethyl)pyrrolidine-
1-carboxylate, 10n. The general cross-coupling method using
3-bromothiophene (187 μL, 2.0 mmol) gave, after chromato-
graphic purification (7% EtOAc in petroleum ether) and removal
of 11 by Kugelrohr distillation, 10n (53 mg, 20%) as a colorless oil:
Rf 0.6 (20% EtOAc in petroleum ether); IR νmax(film)/cm-1 2973,
2924, 1691, 1454, 1393; NMR δH (500 MHz) 1.42 (9H, s),
1.57-1.70 (3H, m), 1.75-1.85 (1H, m), 2.69 (1H, dd, J = 13.6
and 8.8 Hz), 2.92 (1H, dd, J = 13.6 and 3.3 Hz), 3.11-3.18
(1H, m), 3.21-3.29 (1H, m), 3.86-3.93 (1H, m), 6.92 (1H, d, J =
4.9 Hz), 7.09-7.13 (1H, m), 7.40 (1H, dd, J = 4.7 and 2.9 Hz);
NMR δC (126 MHz) 22.1, 29.0, 27.9, 45.8, 57.1, 77.8, 121.3, 125.2,
J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz); [R]22 þ30.0 (c 1.0,
D
CHCl3); MS m/z (ES) found MHþ 320.1876, C18H25NO4
requires MHþ 320.1862.
(S )-(þ)-tert-Butyl 2-(4-Methylbenzyl)pyrrolidine-1-carboxyl-
ate, 10k. The general cross-coupling method using 4-iodoto-
luene (436 mg, 2.0 mmol) gave, after chromatographic pur-
ification (10% EtOAc in petroleum ether) and removal of 11 by
Kugelrohr distillation, 10k (104 mg, 38%) as a colorless oil: Rf
0.49 (20% EtOAc in petroleum ether); IR νmax(film)/cm-1 2964,
2922, 2854, 1695, 1516, 1454, 1392; NMR δH (500MHz) 1.43(9H, s),
1.56-1.80 (4H, m), 2.26 (3H, s), 2.54 (1H, dd, J = 13.1 and 9.0 Hz),
2.92 (1H, dd, J = 13.1 and 3.4 Hz), 3.13-3.20 (1H, m), 3.21-3.30
(1H, m), 3.83-3.90 (1H, m), 7.06 (4H, dd, J = 18.8 and 8.0 Hz);
NMR δC (126 MHz) 20.1, 22.1, 27.9, 28.7, 45.8, 57.9, 77.8, 128.4,
128.3, 138.7, 153.1, one peak obscured; [R]22 -9.3 (c 1.07,
D
CHCl3); MS m/z (ES) found MHþ 268.1378, C14H22NO2S
requires MHþ 268.1371.
Acknowledgment. We thank O. E. S. Johnson and M. L.
Chilton for preliminary investigations, the Islamic Azad
University, Shahreza Branch, for financial support during
a period of sabbatical leave (A.R.M.), and the Department
of Chemistry, The University of Sheffield, for the award of
an EPSRC DTA studentship (A.J.R.). We also thank the
referees for helpful comments.
128.6, 134.6, 135.5, 153.1, one peak obscured; [R]22 þ10.2
D
(c 0.98, CHCl3); m/z (ES) found MNaþ 298.1781, C17H25NO2Na
requires MNaþ 298.1783.
(S )-(þ)-tert-Butyl 2-(3,4-Dimethoxybenzyl)pyrrolidine-
1-carboxylate, 10l. The general cross-coupling method using
3,4-dimethoxyiodobenzene (528 mg, 2.0 mmol) and iodide 9
(311 mg, 1 mmol) gave, after chromatographic purification
(10-15% EtOAc in petroleum ether), 10l (230 mg, 72%) as
a yellow oil: Rf 0.19 (20% EtOAc in petroleum ether); IR
Supporting Information Available: H and 13C NMR spectra
of all compounds and experimental procedures for the preparation
of starting materials and compound 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
ν
max(film)/cm-1 2968, 1686, 1510, 1390, 1364, 1259, 1236,
1154, 1112, 1028; NMR δH (500 MHz) 1.44 (9H, s), 1.61-1.72
8278 J. Org. Chem. Vol. 75, No. 23, 2010