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In Situ trapping of Boc-2-pyrrolidinylmethylzinc hydrogenation of N-acylhydrazonium salts incorporating

Iodide with Aryl Iodides: Direct Synthesis of Enders’ SAMP hydrazone as auxiliary, followed by lactam
reduction;6 and both copper-catalyzed7,8 and palladium-
2-Benzylpyrrolidines catalyzed9 intramolecular asymmetric carboamination of
alkenes. 2-Arylpyrrolidines have been made via asymmetric
Ahmad Reza Massah,† Andrew J. Ross, and deprotonation of Boc-pyrrolidine, transmetalation with
Richard F. W. Jackson* ZnCl2, and subsequent Negishi cross-coupling with aryl
Department of Chemistry, The University of Sheffield, bromides,10,11 although this approach has not yet been
Dainton Building, Sheffield S3 7HF, United Kingdom. extended to 2-benzylpyrrolidines.
†
Present address: Department of Chemistry, In an extension of our general approach to amino acid12,13
Islamic Azad University, Shahreza Branch, and amine synthesis,14,15 it appeared reasonable to consider
Shahreza Isfahan, P.O. Box 86145-311, Iran the possibility that 2-benzylpyrrolidines could be prepared
using protected 2-pyrrolidinylmethylzinc iodides 1. Negishi
[email protected] cross-coupling of 1 with a variety of aryl halides should give
protected 2-benzylpyrrolidines in a single step (eq 1), offering
Received July 30, 2010 a flexible route to these targets.

While the pyroglutamic acid derived zinc reagent 2 is

Addition of (S)-(þ)-tert-butyl 2-(iodomethyl)pyrrolidine- stable enough to undergo copper-catalyzed reaction with
1-carboxylate to activated zinc, aryl halides, and a catalyst propargylic halides,16 bromoallenes, and iodoalkynes,17 two
derived from Pd2(dba)3 (2.5 mol %) and SPhos (5 mol %) groups1,18 have independently reported that attempts to
in DMF allows trapping of the corresponding organozinc prepare the corresponding Boc-protected proline-derived
reagent, with formation of Boc-protected 2-benzylpyrro- zinc reagent 1a were unsuccessful, with the presumed reagent
lidines (20-72%). 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
2-Benzylpyrrolidines feature as structural components of carry out Negishi cross-couplings with this previously elusive
a number of natural products, including the tylophora reagent.
alkaloids which contain a phenanthroindolizidine skeleton.1 Recent work has shown that replacement of the Boc group
Simple 2-benzylpyrrolidines have been shown to be key with the trifluoroacetyl group results in stabilization of
components of orally active dopamine analogues2 and of a protected β-aminoalkylzinc iodides toward elimination.19
series of calcium-sensing receptor antagonists.3 They have We have therefore investigated the preparation of the
also been used as precursors to chiral acyclic diaminocarbene
ligands for use in the Suzuki reaction.4 (6) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron:
Various routes to enantiomerically pure 2-benzylpyrroli- Asymmetry 2003, 14, 2625–2632.
(7) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948–12949.
dines have been developed, with the simplest involving addi- (8) Zeng, W.; Chemler, S. R. J. Org. Chem. 2008, 73, 6045–6047.
tion of Grignard reagents to proline derivatives, followed (9) Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157–12159.
by reduction of the aryl ketone.2,3 Asymmetric syntheses of (10) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen,
C. Y. J. Am. Chem. Soc. 2006, 128, 3538–3539.
2-benzylpyrrolidines include addition of the Grignard reagent (11) Klapars, A.; Campos, K. R.; Waldman, J. H.; Zewge, D.; Dormer,
prepared from 2-(2-bromoethyl)-1,3-dioxane to N-tert- 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.
butanesulfinyl aldimines, followed by cyclization;5 stereoselective (13) Ross, A. J.; Lang, H. L.; Jackson, R. F. W. J. Org. Chem. 2010, 75,
245–248.
(1) F€
urstner, A.; Kennedy, J. W. J. Chem.;Eur. J. 2006, 12, 7398–7410. (14) Hunter, C.; Jackson, R. F. W.; Rami, H. K. J. Chem. Soc., Perkin
(2) Fisher, L. E.; Rosenkranz, R. P.; Clark, R. D.; Muchowski, J. M.; Trans. 1 2000, 219–223.
McClelland, D. L.; Michel, A.; Caroon, J. M.; Galeazzi, E.; Eglen, R.; (15) Deboves, H. J. C.; Hunter, C.; Jackson, R. F. W. J. Chem. Soc.,
Whiting, R. L. Bioorg. Med. Chem. Lett. 1995, 5, 2371–2376. Perkin Trans. 1 2002, 733–736.
(3) Yang, W.; Wang, Y. F.; Roberge, J. Y.; Ma, Z. P.; Liu, Y. L.; (16) Karstens, W. F. J.; Stol, M.; Rutjes, F.; Hiemstra, H. Synlett 1998,
Lawrence, R. M.; Rotella, D. P.; Seethala, R.; Feyen, J. H. M.; Dickson, 1126–1128.
J. K. Bioorg. Med. Chem. Lett. 2005, 15, 1225–1228. (17) Karstens, W. F. J.; Moolenaar, M. J.; Rutjes, F.; Grabowska, U.;
(4) Snead, D. R.; Inagaki, S.; Abboud, K. A.; Hong, S. Organometallics Speckamp, W. N.; Hiemstra, H. Tetrahedron Lett. 1999, 40, 8629–8632.
2010, 29, 1729–1739. (18) Hjelmgaard, T.; Tanner, D. Org. Biomol. Chem. 2006, 4, 1796–1805.
(5) Brinner, K. M.; Ellman, J. A. Org. Biomol. Chem. 2005, 3, 2109–2113. (19) Rilatt, I.; Jackson, R. F. W. J. Org. Chem. 2008, 73, 8694–8704.

DOI: 10.1021/jo101503p Published on Web 11/10/2010 J. Org. Chem. 2010, 75, 8275–8278 8275
r 2010 American Chemical Society
JOC Note Massah et al.

SCHEME 1. Attempted Trapping of TFA-Protected Zinc SCHEME 2. In Situ Trapping of TFA-Protected Zinc Reagent 1b
Reagent 1b

TABLE 1. Synthesis of 2-Benzylpyrrolidine Derivatives 10a-n

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

8276 J. Org. Chem. Vol. 75, No. 23, 2010

Massah et al.
JOC Note
In conclusion, although the zinc reagent 1a is evidently too νmax(film)/cm-1 2969, 1689, 1563, 1493, 1393, 1243, 1161,
unstable to be prepared in a conventional manner, it is 1109; NMR δH (500 MHz) 1.40 (9H, s), 1.55-1.64 (1H, m),
sufficiently reactive that it can be trapped with varying levels 1.63-1.79 (3H, m), 2.61 (1H, dd, J = 13.0 and 8.8 Hz), 2.94 (1H,
of efficiency in situ. This general approach may be applicable dd, J = 13.0, 4.7 Hz), 3.05 (3H, s), 3.17-3.31 (1H, m), 3.97-4.04
to other unstable organozinc reagents. (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,
Experimental Section 77.6, 110.7, 119.9, 126.8, 127.0, 130.3, one quaternary carbon
All NMR spectra were recorded in DMSO-d6 at 80 °C. not observed and one peak obscured; [R]22D þ23.5 (c 1.02,
Negishi Cross-Coupling Using Iodide 9. Zinc dust (190 mg, CHCl3); MS m/z (ES) found MHþ 292.1902, C17H25NO3
3 mmol) was added to a flame-dried, nitrogen-purged, round- requires MHþ 292.1913.
bottom flask. Dry DMF (0.7 mL) was added via syringe, (S )-(þ)-tert-Butyl 2-(3-Chlorobenzyl)pyrrolidine-1-carboxyl-
followed by iodine (40 mg, 0.15 mmol); the yellow color rapidly ate, 10e. The general cross-coupling method using 3-chloroio-
faded. Pd2dba3 (22 mg, 0.025 mmol), SPhos (21 mg, 0.05 mmol), dobenzene (247 μL, 2.0 mmol) gave, after chromatographic
and aryl halide (2.0 mmol) were added to the flask, and the purification (5-10% EtOAc in petrol), 10e (115 mg, 39%) as
reaction mixture was cooled in an ice bath. The iodide 9 (311 mg, a colorless oil: Rf 0.42 (20% EtOAc in petroleum ether); IR νmax
1 mmol) in DMF (0.8 mL) was added in 10 portions, via syringe, (film)/cm-1 2971, 1686, 1389, 1364, 1167; NMR δH (500 MHz)
over 5 h. The reaction mixture was allowed to warm to room 1.41 (9H, s), 1.58-1.66 (1H, m), 1.68-1.75 (2H, m), 1.76-1.85
temperature overnight. The crude reaction mixture was applied (1H, m), 2.65 (1H, dd, J = 13.0 and 8.6 Hz), 2.93 (1H, dd, J =
directly to a silica gel column to give the product 10. In some 13.0 and 3.7 Hz), 3.13-3.20 (1H, m), 3.28 (1H, td, J = 10.2 and
cases, the product coeluted with alkene 11, which could be 7.7 Hz), 3.87-3.95 (1H, m), 7.13 (1H, d, J = 7.5 Hz), 7.21 (1H,
removed by Kugelrohr distillation (90 °C, 0.3 mmHg). s), 7.24 (1H, d, J = 8.2 Hz), 7.30 (1H, t, J = 7.7 Hz); NMR δC
(S )-(þ)-tert-Butyl 2-Benzylpyrrolidine-1-carboxylate, 10a. The (126 MHz) 22.1, 27.8, 28.9, 45.7, 57.6, 77.9, 125.6, 127.4, 128.6,
general cross-coupling method using iodobenzene (224 μL, 2.0 mmol) 129.5, 132.6, 141.2, 153.1, one peak obscured; [R]22D þ6.0 (c 1.0,
gave, after chromatographic purification (10% EtOAc in petroleum CHCl3); MS m/z (ES) found MHþ 296.1431, C16H22NO2Cl
ether) and removal of 11 by Kugelrohr distillation, 10a (112 mg, 43%) requires MHþ 296.1417.
as a colorless oil: Rf 0.5 (20% EtOAc in petroleum ether); IR νmax (S )-(-)-tert-Butyl 2-(3-(Trifluoromethyl)benzyl)pyrrolidine-
(film)/cm-1 2974, 2927, 2862, 1692, 1454, 1392; NMR δH (500 MHz) 1-carboxylate, 10f. The general cross-coupling method using
1.43 (9H, s), 1.55-1.82 (4H, m), 2.60 (1H, dd, J = 13.0, 8.9 Hz), 2.97 3-iodobenzotrifluoride (288 μL, 2.0 mmol) gave, after chroma-
(2H, dd, J = 13.1, 3.6 Hz), 3.23-3.30 (1H, m), 3.14-3.20 (2H, m), tographic purification (7% EtOAc in petrol), 10f (204 mg, 62%)
3.88-3.94 (1H, m), 7.15-7.22 (3H, m), 7.28 (2H, t, J = 7.6 Hz); as an orange oil: Rf 0.47 (20% EtOAc in petroleum ether); IR
NMR δC (500 MHz) 22.1, 28.7, 27.7, 27.9, 45.7, 57.8, 77.8, 125.6, νmax (film)/cm-1 2973, 2928, 2862, 1812, 1769, 1756, 1693, 1456,
127.8, 128.8, 138.6, 153.1, one peak obscured; [R]22D þ9.8 (c 1.02, 1395; NMR δH (500 MHz) 1.41 (9H, s), 1.57-1.75 (4H, m),
CHCl3); MS m/z (ES) found MHþ 262.1815, C16H24NO2 requires 1.76-1.88 (1H, m), 2.78 (1H, dd, J = 13.0 and 8.4 Hz), 3.00 (1H,
MHþ 262.1807. dd, J = 13.2 and 4.1 Hz), 3.22-3.35 (1H, m), 3.91-4.00 (1H, m),
(S)-(þ)-tert-Butyl 2-(2-Methoxybenzyl)pyrrolidine-1-carboxyl- 7.46-7.57 (4H, m); NMR δC (126 MHz) 22.1, 28.9, 77.9, 110.2,
ate, 10b. The general cross-coupling method using 2-iodoanisole 140.1, 153.1, 27.7, 30.9, 45.7, 57.6, 122.4, 125.2, 128.8, 132.9, one
(260 μL, 2.0 mmol) gave, after chromatographic purification (5% peak obscured; [R]22D -18.5 (c 1.08, CHCl3); MS m/z (ES)
EtOAc in petroleum ether), 10b (113 mg, 38%) as a colorless oil: found MNaþ 352.1507, C17H22NO2F3Na requires MNaþ
Rf 0.42 (20% EtOAc in petroleum ether); IR νmax (film)/cm-1 2968, 352.1500.
1687, 1493, 1390, 1364, 1242, 1169, 1107; NMR δH (500 MHz) 1.40 (S )-(þ)-tert-Butyl 2-(4-Methoxybenzyl)pyrrolidine-1-carboxyl-
(9H, s), 1.55-1.63 (1H, m), 1.64-1.80 (3H, m), 2.61 (1H, dd, J = ate, 10g. The general cross-coupling method using 4-iodoanisole
12.8 and 8.9 Hz), 2.94 (1H, dd, J 13.0, 4.7 Hz), 3.17-3.31 (2H, m), (468 mg, 2.0 mmol) gave, after chromatographic purification (7%
3.78 (3H, s), 3.96-4.04 (1H, m), 6.86 (1H, dt, J = 7.3 and 0.9 Hz), EtOAc in petroleum ether), 10g (165 mg, 57%) as a colorless oil:
6.94 (1H, d, J = 8.2 Hz), 7.08 (1H, dd, J = 7.3 and 1.4 Hz), 7.18 (1H, Rf 0.5 (20% EtOAc in petroleum ether); IR νmax (film)/cm-1 2967,
dt, J = 7.9 and 1.7 Hz); NMR δC (126 MHz) 27.8, 45.5, 55.0, 56.7, 1688, 1297, 1363, 1252, 1165, 1112; NMR δH (500 MHz) 1.43 (9H, s),
77.6, 110.7, 119.9, 127.0, 130.3, quaternary carbons are not observed; 1.55-1.81 (4H, m), 2.54 (1H, dd, J = 13.0 and 9.0 Hz), 2.88 (1H, dd,
[R]22D þ30.7 (c 1.14, CHCl3); MS m/z (ES) found MHþ 292.1907, J = 13.2 and 3.4 Hz), 3.11-3.19 (1H, m), 3.21-3.31 (1H, m), 3.73
C17H25NO3 requires MHþ 292.1913. (3H, s), 3.81-3.90 (1H, m), 6.85 (2H, d, J = 8.6 Hz), 7.07 (2H, d, J =
(S )-(þ)-tert-Butyl 2-(2-Hydroxybenzyl)pyrrolidine-1-carboxyl- 8.6 Hz); NMR δC (126 MHz) 22.1, 28.6, 27.9, 45.8, 54.7, 57.9, 77.8,
ate, 10c. The general cross-coupling method using iodobenzene 113.5, 129.7, 130.5, 153.1, 157.5, one peak obscured; [R]22D þ2.4
(226 μL, 2.0 mmol) gave, after chromatographic purification (10- (c 1.04, CHCl3); MS m/z (ES) found MHþ 292.1920, C17H25NO3
15% EtOAc in petroleum ether) and removal of 11 by Kugelrohr requires MHþ 292.1913.
distillation, 10c (112 mg, 40%) as an orange oil: Rf 0.39 (20% EtOAc Using 4-bromoanisole (250 μL, 2.0 mmol) under the same
in petroleum ether); IR νmax(film)/cm-1 3274, 2975, 2926, 2871, 1655, conditions gave 10g (108 mg, 37%).
1595, 1487, 1456, 1417; NMR δH (500 MHz) 1.40 (9H, s), 1.62-1.83 (S )-(-)-tert-Butyl 2-(4-Hydroxybenzyl)pyrrolidine-1-carboxyl-
(4H, m), 2.59 (1H, dd, J = 13.0 and 9.0 Hz), 2.89 (1H, dd, J = 13.2 ate, 10h. The general cross-coupling method using 4-iodophenol
and 3.9 Hz), 3.16-3.31 (2H, m), 3.93-4.02 (1H, m), 6.69 (1H, dt, (440 mg, 2.0 mmol) gave, after chromatographic purification
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 (10-15% EtOAc in petroleum ether), 10h (140 mg, 51%) as a
(126 MHz) 22.2, 27.9, 28.7, 33.0, 45.5, 57.1, 77.7, 114.8, 118.5, 125.0, colorless oil: Rf 0.17 (20% EtOAc in petroleum ether); IR νmax(film)/
126.6, 130.3, 153.2, 155.1; [R]D22 þ40.0 (c 1.0, CHCl3); MS m/z (ES) cm-1 3264, 2970, 1655, 1514, 1410, 1365, 1232, 1164, 1154, 1105;
Found MHþ 278.1762. C16H24NO3 requires MHþ 278.1756. NMR δH (500 MHz) 1.43 (9H, s), 1.56-1.80 (5H, m), 2.84 (1H, dd,
(S)-(þ)-tert-Butyl 2-(3-methoxybenzyl)pyrrolidine-1-carboxyl- J = 13.2 and 3.5 Hz), 3.11-3.19 (1H, m), 3.21-3.30 (1H, m),
ate, 10d. The general cross-coupling method using 3-iodoani- 3.79-3.88 (1H, m), 6.68 (2H, d, J = 8.4 Hz), 6.95 (2H, d, J = 8.4
sole (238 μL, 2.0 mmol) gave, after chromatographic purifica- Hz), 8.87 (1H, s), one peak obscured; NMR δC (126 MHz) 22.1, 27.9,
tion (5% EtOAc in petroleum ether), 10d (127 mg, 44%) as a 28.6, 45.8, 58.0, 114.8, 128.7, 129.5, 155.3, two quaternary carbons are
colorless oil: Rf 0.44 (20% EtOAc in petroleum ether); IR not observed and one peak is obscured; [R]22D -13 (c 1.0, CHCl3);

J. Org. Chem. Vol. 75, No. 23, 2010 8277

JOC Note Massah et al.

MS m/z (ES) found MHþ 278.1755, C16H23NO3 requires MHþ (3H, m), 1.72-1.80 (1H, m), 2.54 (1H, dd, J = 13.1 and 8.8 Hz),
278.1756. 2.87 (1H, dd, J = 13.1 and 3.5 Hz), 3.01-3.07 (1H, m),
(S )-(-)-tert-Butyl 2-(4-Aminobenzyl)pyrrolidine-1-carboxyl- 3.11-3.21 (1H, m), 3.21-3.32 (1H, m), 3.73 (3H, s), 3.74 (3H,
ate, 10i. The general cross-coupling method using 4-iodoaniline s), 3.85-3.91 (1H, m), 6.69 (1H, dd, J = 8.1 and 1.9 Hz), 6.74
(438 mg, 2.0 mmol) gave, after chromatographic purification (1H, d, J = 1.9 Hz), 6.84-6.88 (1H, m); NMR δC (126 MHz)
(10-15% EtOAc in petroleum ether), 10i (112 mg, 41%) as a 22.1, 27.9, 28.7, 45.8, 55.4, 55.6, 57.9, 77.8, 112.5, 113.6, 121.0,
yellow oil: Rf 0.40 (40% EtOAc in petroleum ether); IR νmax(film)/ 131.4, 147.4, 148.7, 153.1, one peak obscured; [R]22D þ4.0 (c 1.0,
cm-1 3391, 3293, 2970, 1655, 1514, 1410, 1365, 1232, 1164, 1154, CHCl3); MS m/z (ES) found MHþ 322.2029, C18H27NO4
1105; NMR δH (500 MHz) 1.44 (9H, s), 1.58-1.77 (4H, m), 2.41 (1H, requires MHþ 322.2018.
dd, J = 13.1 and 9.1 Hz), 2.78 (1H, dd, J = 13.2 and 3.5 Hz), (S )-(þ)-tert-Butyl 2-(Pyridin-2-ylmethyl)pyrrolidine-1-carboxyl-
3.11-3.18 (1H, m), 6.02-6.61 (2H, m), 3.20-3.27 (1H, m), ate, 10m. The general cross-coupling method using 2-bromopyridine
3.76-3.83 (1H, m), 4.62 (2H, s), 6.51 (2H, d, J = 8.4 Hz), 6.82 (191 μL, 2.0 mmol) gave, after chromatographic purification (40%
(2H, d, J = 8.3 Hz); NMR δC (126 MHz) 22.0, 27.9, 28.5, 45.8, 58.1, EtOAc in petroleum ether), 10m (85 mg, 32%) as a pale yellow oil:
77.7, 113.8, 125.7, 129.1, 146.2, 153.1, one peak obscured; [R]22D -2.0 Rf 0.21 (50% EtOAc in petroleum ether); IR νmax(film)/cm-1 2972,
(c 1.0, CHCl3); MS m/z (ES) found MHþ 277.1905, C16H25N2O2 2925, 2862, 1690, 1590, 1563, 1475, 1434, 1394; NMR δH (500 MHz)
requires MHþ 277.1916. 1.40 (9H, s), 1.64-1.83 (4H, m), 2.73 (1H, dd, J = 13.0 and 9.0 Hz),
(S )-(þ)-tert-Butyl 2-(4-(Methoxycarbonyl)benzyl)pyrrolidine- 3.12 (2H, dd, J = 13.0 and 3.7 Hz), 3.14-3.22 (1H, m), 3.22-3.31
1-carboxylate, 10j. The general cross-coupling method using (1H, m), 4.04-4.12 (1H, m), 7.12-7.20 (2H, m), 7.66 (1H, dt, J = 7.7
methyl 4-iodobenzoate (524 mg, 2.0 mmol) and iodide 9 (311 and 1.7 Hz), 8.46 (1H, d, J = 4.1 Hz); NMR δC (126 MHz) 22.1, 27.8,
mg, 1 mmol) gave, after chromatographic purification (5-10% 28.9, 45.7, 56.7, 77.8, 120.8, 123.0, 135.7, 148.5, 153.1, 158.6, one peak
EtOAc in petroleum ether), 10j (96 mg, 30%) as a colorless oil: obscured; [R]22D þ10.0 (c 1.0, CHCl3); MS m/z (ES) found MHþ
Rf 0.32 (20% EtOAc in petroleum ether); IR νmax(film)/cm-1 263.1765, C15H23N2O2 requires MHþ 263.1760.
2930, 1721, 1689, 1610, 1391, 1275, 1103; NMR δH (500 MHz) (S )-(-)-tert-Butyl 2-(Thiophene-3-ylmethyl)pyrrolidine-
1.42 (9H, s), 1.56-1.66 (1H, m), 1.66-1.73 (2H, m), 1.74-1.84 1-carboxylate, 10n. The general cross-coupling method using
(1H, m), 2.71 (1H, dd, J = 13.0 and 8.6 Hz), 3.14-3.20 (1H, m), 3-bromothiophene (187 μL, 2.0 mmol) gave, after chromato-
3.23-3.32 (1H, m), 3.84 (3H, s), 3.91-3.98 (1H, m), 7.32 (2H, d, graphic purification (7% EtOAc in petroleum ether) and removal
J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz); [R]22D þ30.0 (c 1.0, of 11 by Kugelrohr distillation, 10n (53 mg, 20%) as a colorless oil:
CHCl3); MS m/z (ES) found MHþ 320.1876, C18H25NO4 Rf 0.6 (20% EtOAc in petroleum ether); IR νmax(film)/cm-1 2973,
requires MHþ 320.1862. 2924, 1691, 1454, 1393; NMR δH (500 MHz) 1.42 (9H, s),
(S )-(þ)-tert-Butyl 2-(4-Methylbenzyl)pyrrolidine-1-carboxyl- 1.57-1.70 (3H, m), 1.75-1.85 (1H, m), 2.69 (1H, dd, J = 13.6
ate, 10k. The general cross-coupling method using 4-iodoto- and 8.8 Hz), 2.92 (1H, dd, J = 13.6 and 3.3 Hz), 3.11-3.18
luene (436 mg, 2.0 mmol) gave, after chromatographic pur- (1H, m), 3.21-3.29 (1H, m), 3.86-3.93 (1H, m), 6.92 (1H, d, J =
ification (10% EtOAc in petroleum ether) and removal of 11 by 4.9 Hz), 7.09-7.13 (1H, m), 7.40 (1H, dd, J = 4.7 and 2.9 Hz);
Kugelrohr distillation, 10k (104 mg, 38%) as a colorless oil: Rf NMR δC (126 MHz) 22.1, 29.0, 27.9, 45.8, 57.1, 77.8, 121.3, 125.2,
0.49 (20% EtOAc in petroleum ether); IR νmax(film)/cm-1 2964, 128.3, 138.7, 153.1, one peak obscured; [R]22D -9.3 (c 1.07,
2922, 2854, 1695, 1516, 1454, 1392; NMR δH (500 MHz) 1.43 (9H, s), CHCl3); MS m/z (ES) found MHþ 268.1378, C14H22NO2S
1.56-1.80 (4H, m), 2.26 (3H, s), 2.54 (1H, dd, J = 13.1 and 9.0 Hz), requires MHþ 268.1371.
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); Acknowledgment. We thank O. E. S. Johnson and M. L.
NMR δC (126 MHz) 20.1, 22.1, 27.9, 28.7, 45.8, 57.9, 77.8, 128.4, Chilton for preliminary investigations, the Islamic Azad
128.6, 134.6, 135.5, 153.1, one peak obscured; [R]22D þ10.2 University, Shahreza Branch, for financial support during
(c 0.98, CHCl3); m/z (ES) found MNaþ 298.1781, C17H25NO2Na
a period of sabbatical leave (A.R.M.), and the Department
requires MNaþ 298.1783.
(S )-(þ)-tert-Butyl 2-(3,4-Dimethoxybenzyl)pyrrolidine- of Chemistry, The University of Sheffield, for the award of
1-carboxylate, 10l. The general cross-coupling method using an EPSRC DTA studentship (A.J.R.). We also thank the
3,4-dimethoxyiodobenzene (528 mg, 2.0 mmol) and iodide 9 referees for helpful comments.
(311 mg, 1 mmol) gave, after chromatographic purification
(10-15% EtOAc in petroleum ether), 10l (230 mg, 72%) as Supporting Information Available: 1H and 13C NMR spectra
a yellow oil: Rf 0.19 (20% EtOAc in petroleum ether); IR of all compounds and experimental procedures for the preparation
νmax(film)/cm-1 2968, 1686, 1510, 1390, 1364, 1259, 1236, of starting materials and compound 5. This material is available
1154, 1112, 1028; NMR δH (500 MHz) 1.44 (9H, s), 1.61-1.72 free of charge via the Internet at http://pubs.acs.org.

8278 J. Org. Chem. Vol. 75, No. 23, 2010