Stereoselective c(sp3)-c(sp2) negishi coupling of (2-amido-1-phenylpropyl)zinc compounds through the steric control of β-amido group

Article abstract of DOI:10.1007/s11426-013-4880-2

A controllable diastereoselective C(sp²)-C(sp³) Negishi coupling reaction of secondary benzylic zinc reagents with aryl bromides has been demonstrated for the first time, forming medicinally important 1-arylphenylethylamines. In the presence of Pd(OAc)₂ and S-phos, open-chain (2-amido-1-phenylethyl)zinc reagents bearing a β-NHAc or NHCHO group underwent cross-coupling reaction to give syn 1-arylphenylethylamine as the major products, whereas the zinc reagents bearing a sterically hindered β-NHCOC(CH₃)₂OTBS group specifically yielded anti 1-arylphenylethylamines.

Full text of DOI:10.1007/s11426-013-4880-2

SCIENCE CHINA
Chemistry
January 2013 Vol.5 No.1: 1–7
doi: 10.1007/s11426-013-4880-2
• ARTICLES •
doi: 10.1007/s11426-013-4880-2
Stereoselective C(sp3)-C(sp2) Negishi coupling of
(2-amido-1-phenylpropyl)zinc compounds
through the steric control of -amido group
TANG Shi1, 2*, LI ShuHua1, ZHOU Dong1, ZENG HuiQiong1 & WANG NaiXing2
1College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, China
2Technical Institute of Physics and chemistry, Chinese Academy of Sciences, Beijing 100080, China
Received January 27, 2013; accepted March 4, 2013
A controllable diastereoselective C(sp2)-C(sp3) Negishi coupling reaction of secondary benzylic zinc reagents with aryl bro-
mides has been demonstrated for the first time, forming medicinally important 1-arylphenylethylamines. In the presence of
Pd(OAc)2 and S-phos, open-chain (2-amido-1-phenylethyl)zinc reagents bearing a -NHAc or NHCHO group underwent
cross-coupling reaction to give syn 1-arylphenylethylamine as the major products, whereas the zinc reagents bearing a steri-
cally hindered -NHCOC(CH3)2OTBS group specifically yielded anti 1-arylphenylethylamines.
stereoselective, Negishi coupling, benzylic zinc, 1-arylphenylethylamine, aryl bromide
ganozinc reagents, Negishi couplings between secondary
1 Introduction
C(sp3)-hybridized organozinc reagents and aryl halides, or
arylzinc reagents and secondary alkyl halides, to form C–C
bond recently attracted much attention in this regard [4]. In
spite of the significant advances in stereospecific coupling
of secondary alkyl halides with arylzinc reagents (e.g., Fu’s
works) [5], the stereospecific coupling of sencondary alkyl-
zinc reagents with aryl halides remains challenging due to
β-elimination of secondaryl alkylzinc reagents. Recently,
Knochel and co-workers developed the diastereoselective
couplings of several cyclohexylzinc reagents with aryl
halides [6]. The stereoselectivity of this reaction was
controlled through a stable equilibrium conformation of
Phenylethylamines (PEA) and derivatives are pharmaco-
logically interesting compounds that display great potential
bioactivation in many major therapeutic areas, such as stim-
ulants, 5HT2-receptor agonist, bronchodilators, and antide-
pressants [1]. For example, the well-known amphetamines,
one class of psychoanaleptic drugs, usually contain the
phenylethylamine core (Scheme 1). Given the growing
commercial and therapeutic importance of optically en-
riched phenylethylamine bearing an additional functional
group at the benzylic position (e.g., ephedrine), stereospe-
cifical introduction of an aromatic group to the benzylic site
of phenylethylamines becomes popularly noteworthy.
In the past decade, metal-catalyzed cross-coupling reac-
tions have provided a wide variety of synthetical processes
to stereospecifically construct C(sp3)-C(sp2) bond for the
benzylic arylation [2, 3]. Owing to the readily availability
and excellent compatibility with functional groups of or-
Scheme 1 Several phenylethylamine derivations.
*Corresponding author (email: shitang@126.com)
© Science China Press and Springer-Verlag Berlin Heidelberg 2013
chem.scichina.com www.springerlink.com

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Tang S, et al. Sci China Chem January (2013) Vol.56 No.1
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( 7.26 ppm for H NMR and  77.0 ppm for 13C NMR).
Abbreviations for signal coupling are as follows: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet, br, broad.
Column chromatographical purifications were performed
using SiO2 (0.040–0.063 mm, 230–400 mesh ASTM) from
Merck.
cyclohexylic Pd species in the catalytic cycle, which limited
its further application to wider nucleophiles. To the best of
our knowledge, the stereospecific C(sp3)-C(sp2) Negishi
coupling of open-chain alkylzinc species is still unknown
due to the flexible C–C  bond formed in the couplings
(Scheme 2).
Commercially available starting materials were used
without further purification. THF was continuously refluxed
and freshly distilled from sodium benzophenone under ni-
trogen. Diethyl ether was predried over calcium hydride and
dried with the solvent purification system SPS-400-2 from
INNOVATIVE TECHNOLOGIES INC (Al2O3, 1–3 mm,
ICN, Eschwege, Germany). Anhydrous DMSO was pur-
chased from Aldrich and used without further purification.
Zinc reagents were prepared by direct zinc insertion of
benzylic chlorides [10, 11]. Pd(OAc)2 was purchased from
Strem and used without further purification. S-Phos was
purchased from Strem or prepared according to literature
procedure [12].
2.2 Typical procedure to prepare N-(1-chloro-1-phen-
ylpropan-2-yl)acetamide A (TP1)
Scheme 2 Diastereoselective Negishi C(sp3)-C(sp2) coupling.
Compounds A was prepared through the known chlorina-
tion procedure (Eq.(1)) [13]. To a suspension of DL-
norephedrine hydrochloride (1.9 g, 10 mmol) in DCM (2
mL) was added dropwise SOCl2 (2.2 mL, 30 mmol) at 0 °C,
the resulting mixture was stirred at rt for 3–4 h. The mixture
was then basified with 6 M NaOH solution at 0 °C and ex-
tracted with CH2Cl2. The combined organic layers were
dried over anhydrous MgSO4 and concentrated in vacuo. To
a solution of the above crude 1-chloro-1-phenylpropan-2-
amine in DCM (10 mL) were added acetyl chloride (1.1 mL,
15 mmol), and then Et3N (2.0 g, 2 mmol) at 0 °C. After be-
ing stirred at rt overnight, the reaction mixture was washed
with brine. The aqueous layer was extracted with diethyl
ether, and the combined organic layers were dried over an-
hydrous MgSO4 and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel to give the
title compound (1.8 g, 85%) as a white solid. M.p.: 151.1–
On the other hand, the benzyl zinc compounds with
phenylethylamine skeletons can be readily prepared by direct
insertion of zinc into 1-chloro-1-phenylpropan-2-amine from
chlorination of naturally-occurring DL-norephedrine hydro-
chloride [7]. Thus, we envisage that stereospecific Negishi
coupling of (2-amido-1-phenylethyl)zinc reagent with aryl
halides could be achieved for the synthesis of optically en-
riched 1-arylphenthylamines. In fact, the C(sp3)-hybridized
organozincs bearing a chiral -amino group could actually
undergo cross-coupling to produce -substituted amines.
For example, Jackson developed a series of coupling reac-
tions of - and -amino alkylzinc reagents to prepare bio-
logically active - and -amino acids [8]. However, their
methods just provided a non-stereoselective coupling due to
the use of primary C(sp3)-hybridized organozincs. Herein,
we herein want to demonstrate a diastereoselective C(sp3)-
C(sp2) coupling of open-chain secondary C(sp3)-alkylzincs
bearing a chiral -amino group [9].
1
151.5 °C (uncorrected). H NMR (400 MHz, CDCl3) :
7.38–7.26 (m, 5H), 5.75 (br, 1H), 4.99 (d, J = 3.2 Hz, 1H),
4.60–4.43 (m, 1H), 1.95 (s, 3H), 1.20 (d, J = 4.8 Hz, 3H).
13C NMR (101 MHz, CDCl3) : 169.5, 138.0, 128.5, 128.4,
127.6, 66.0, 50.5, 23.2, 18.1. IR (KBr, cm1) ν 3269, 1647,
1559, 1368, 1142, 975, 727. MS (EI, 70 eV): m/z (%) =
211[M+] (5), 175 (7), 134 (12), 125 (15) 117 (26), 86 (100).
HRMS (EI): Cacld for C11H14NClNO: 211.0764, found:
211.0761.
2 Experimental
2.1 Material and methods
All reactions were carried out under argon atmosphere in
flame-dried glassware. Syringes which were used to transfer
anhydrous solvents or reagents were purged with argon pri-
or to use. NMR spectra were recorded on solutions in deu-
terated chloroform (CDCl3) with residual chloroform
(1)

Tang S, et al. Sci China Chem January (2013) Vol.56 No.1
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2.3 Typical procedure to prepare zinc compounds 1a,
1b, 1c, 1d, 1e (TP2)
2.5 Typical procedure to prepare the benzylic zinc re-
agents 1f and 1g (TP4)
A Schlenk-flask equipped with a magnetic stirring bar was
heated with a heating gun (400 °C) for 10 min under high
vacuum. After cooling to room temperature, the flask was
flushed with argon (3 times). Zinc dust (<10 micron, Al-
drich, 1.3 g, 30 mmol ) was added followed by THF (2 mL).
1,2-Dibromethane (5 mol %) was added and the reaction
mixture was heated until ebullition occurred. After cooling
to 25 °C, trimethylsilyl chloride (2 mol %) was added and
the mixture was heated again until ebullition occurred. Re-
lated N-(1-chloro-1-phenylpropan-2-yl)amide (prepared ac-
cording to TP1, 10 mmol) was added at the required tem-
perature (usually 25 °C) as a solution in THF-DMSO (v:v =
2:1, 30 mL). The reaction mixture was stirred at room tem-
perature until capillary GC analysis of a hydrolyzed aliquot
containing an internal standard showed a conversion
of >98% (usually 20 h), the reaction mixture was allowed to
settle down for 1–2 h. The yield of the resulting benzylic
zinc chloride was determined by iodiometric titration (usu-
ally 50–60%).
A Schlenk-flask equipped with a magnetic stirring bar was
heated with a heat gun (400 °C) for 10 min under high vac-
uum. After cooling to 25 °C, the flask was flushed with ar-
gon (3 times). Zinc dust (1.3 g, 30 mmol, < 10 micron, Al-
drich) was added followed by THF (2 mL). 1,2-Dibrome-
thane (5 mol %) was added and the reaction mixture was
heated until ebullition occurred. After cooling to 25 °C,
trimethylsilyl chloride (2 mol %) was added and the mixture
was heated again until ebullition occurred. Corresponding
N-(1-chloro-1-phenylpropan-2-yl)alkylamide (prepared ac-
cording to TP3) was added at the required temperature
(usually 25 °C) as a solution in THF-DMSO (v:v = 2:1, 30
mL). The reaction mixture was stirred at 50 °C until capil-
lary GC analysis of a hydrolyzed aliquot containing an in-
ternal standard showed a conversion of >90% (usually 24 h),
the reaction mixture was allowed to settle down for 1–2 h.
The yield of the resulting benzylic zinc chloride was deter-
mined by iodiometric titration (usually 40–50%).
2.4 Typical procedure to prepare 2-(tert-butyldime-
thylsilyloxy)-N-(1-chloro-1-phenylpropan-2-yl)-2-methyl-
propanamide B (TP3)
2.6 Typical procedure for cross-coupling reactions of
zinc reagents 1f and aryl bromide (TP5)
Following the TPI, the comounds B was prepared according
to Eq. (2) through the amidation of intermediate 1-chloro-
1-phenylpropan-2-amine obtainded from the chlorination of
DL-norephedrine hydrochloride (1.9 g, 10 mmol) with
2-(tert-butyldimethylsilyloxy)-2-methylpropanoyl chloride,
prepared from ethyl 2-(tert-butyldimethylsilyloxy)-2-methyl-
propanoate [14, 15] (3.5 g, 15 mmol) to give the title com-
To a solution of aryl bromide (0.5 mmol) in THF (0.5 mL)
were added S-Phos (12 mg, 6 mol%), Pd(OAc)2 (3.4 mg, 3
mol%). Then, a solution of benzyl zinc chloride 1f (0.75
mmol, 1.5 eq.) in THF-DMSO was added dropwise (Eq.
(3)). The reaction mixture was stirred for 10–24 h at 25 °C,
then quenched by adding sat. aqueous NH4Cl. The layers
were separated and the aqueous layer was extracted with
diethyl ether (5 × 50 mL). The combined organic extracts
were dried over Na2SO4. Evaporation of the solvents in
vacuo and purification by flash chromatography (silica gel,
isohexane/EA = 10:1) afforded the title coupling products
(3a’–3g).
1
pound (2.8 g, 75%) as a yellowish solid. H NMR (400
MHz, CDCl3) : 7.38–7.23 (m, 5H), 7.07 (br, 1H), 5.01 (d,
J = 2.8 Hz, 1H), 4.50–4.41 (m, 1H), 1.38 (s, 3H), 1.32 (s,
3H), 1.25 (d, J = 4.8 Hz, 3H), 0.87(s, 9H), 0.15 (s, 3H), 0.13
(s, 3H): 13C NMR (101 MHz, CDCl3) : 175.7, 138.1, 128.2,
127.6, 66.4, 49.9, 28.0, 27.7, 25.7, 25.7, 18.3, 17.9, 2.3,
2.4, IR (KBr, cm1) ν 3319, 1651, 1520, 1373, 1127, 746.
MS (EI, 70 eV): m/z (%) = 354[M+–CH3] (4), 334 (3), 276
(47), 244 (31), 190 (27), 173 (100), 143 (25), 115 (30), 73
(84). HRMS (EI): calcd for C19H22ClNO2Si: (369.1891),
found: 369.1889.
(3)
Ethyl 4-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropana-
mido)-1-phenylpropyl)benzoate (3a′, according to TP5)
A yellowish oil, d.r. > 5:95 (anti/syn). anti-isomer: 1H NMR
(300 MHz, CDCl3) : 7.95 (d, J = 8.4 Hz, 2H), 7.23 (d, J =
7.6 Hz, 2H),7.33–7.21 (m, 5H), 6.75 (br, 1H), 4.834.79 (m,
(2)

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Tang S, et al. Sci China Chem January (2013) Vol.56 No.1
439 [M+Me] (4), 397 (34), 341 (8), 311 (9), 281 (8),
244(21), 207 (31), 173 (100), 115 (21), 73 (49). HRMS (EI):
calcd for C26H36F3NO2Si: 454.2452, found: 454.2448.
1H), 4.33 (q, J = 7.2 Hz, 2H), 3.84 (d, J = 10.8 Hz, 1H),
1.35 (t, J = 7.2 Hz, 3H), 1.34 (s, 3H), 1.10 (d, J = 6.4 Hz,
3H), 0.79 (s, 9H), 0.05 (s, 3H), 0.07 (s, 3H). 13C NMR
(101 MHz, CDCl3)  175.5, 166.5, 147.8, 141.6, 130.1,
129.0, 128.5, 128.1, 128.0, 126.9, 76.5, 61.0, 59.1, 47.1,
27.7, 27.5, 25.9, 20.5, 18.7, 14.2, 2.4. IR (KBr, cm1) ν
3375, 1720, 1647, 1574, 1227,1180, 1030. MS (EI, 70 eV):
m/z (%) = 468 [M+–Me] (4), 426 (11), 244(25), 173 (100),
115 (12), 73 (42). HRMS (EI): calcd for C28H41NO4Si:
483.2805, found: 483.2801.
2-(Tert-butyldimethylsilyloxy)-N-(1-(4-cyano-3-fluorophenyl)-
1-phenylpropan-2-yl)-2-methylpropanamide (3e, according
to TP5)
1
A yellowish oil, d.r. > 95:5 (anti/syn). Anti-isomers: H
NMR (400 MHz, CDCl3)  7.56 (s, 1H), 7.51–7.39 (m, 2H),
7.28–7.15(m, 5H), 6.74 (br, 1H), 4.914.78 (m, 1H), 3.94 (d,
J = 10.3 Hz, 1H), 1.36 (s, 3H), 1.30 (s, 3H), 1.14 (d, J = 6.6
Hz, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.80 (s, 9H), 0.06 (s,
3H), 0.06 (s, 3H). 13C NMR (151 MHz, CDCl3)  175.7,
143.3, 131.3 (q, J = 31.2 Hz) 129.2, 128.6, 128.2, 128.1,
127.0, 126.9, 125.0, 124.9, 123.7 (q, J = 367 Hz), 76.6, 58.8,
47.0, 46.9, 27.7, 25.7, 20.4, 17.9, 2.6. IR (KBr, cm1) ν
3389, 1656, 1515, 1375, 1197, 1032, 979, 743. MS (EI, 70
eV): m/z (%) = 464 [M+Me] (4), 422 (34), 336 (8), 263 (8),
244(21), 173 (100), 115 (18), 73 (39). HRMS (EI): calcd for
C26H36FN2O2Si: 454.2452, found: 454.2448.
2-(Tert-butyldimethylsilyloxy)-2-methyl-N-(1-(4-(methylthio)
phenyl)-1-phenylpropan-2-yl)propanamide (3b, according
to TP5)
A yellowish oil, d.r.= 93:7 (anti/syn). Anti-isomer: 1H NMR
(400 MHz, CDCl3)  7.32–7.08 (m, 9H), 6.73 (br, 1H),
4.83–4.7 (m, 1H), 3.73 (d, J = 10.4 Hz, 1H), 3.43 (s, 3H),
1.35 ( (s, 3H), 1.04 (d, J = 6.5 HZ, 3 H), 0.99 (s, 3H), 0.79
(s, 9H), 0.05 (s, 3H), 0.07 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 175.5, 141.9, 139.3, 136.5, 128.6, 128.5, 128.0,
127.0, 126.6, 77.6, 58.6, 47.0, 27.7, 27.4, 25.7, 20.4, 17.9,
15.9, 2.6. IR (KBr, cm1) ν 3379, 1674, 1509, 1259, 1032,
969, 807. MS (EI, 70 eV): m/z (%) = 442 [M+–Me] (4), 400
(14), 244 (31), 173 (100), 115 (18), 73 (32). HRMS (EI):
calcd for C26H39NO2SSi: 457.2471, found: 457.2473.
2-(Tert-butyldimethylsilyloxy)-N-(1-(3-isobutyrylphenyl)-1-
phenylpropan-2-yl)-2-methylpropanamide (3f, according to
TP5)
A yellowish oil, d.r. > 95:5 (anti/syn). Anti-isomer: 1H NMR
(400 MHz, CDCl3)  7.91 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H),
7.52 (d, J = 6.4 Hz, 1H), 7.41–7.13 (m, 6H), 6.67 (d, J = 6.6
Hz, 1H), 4.87–4.78 (m, 1H), 3.86 (d, J = 10.4 Hz, 1H),
3.56–3.57 (m, 1H), 3.4 (s, 3H), 1.35 (s, 3H), 1.19 (d, J = 6.8
Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H), 1.12 (J = 6.4 Hz, 3H),
0.99 (s, 3H), 0.80 (s, 9H), 0.06 (s, 3H), 0.08 (s, 3H). 13C
NMR (101 MHz, CDCl3)  204.3, 175.3, 143.3, 141.2,
137.3, 132.4, 128.6, 128.4, 128.3, 127.5, 127.4, 126.3, 76.5,
59.3, 47.2, 36.9, 27.4, 27.2, 25,7, 21.5, 20.5, 17.9, 2.6. IR
(KBr, cm1) ν 3334, 1712, 1682, 1532, 1373, 1092, 976,
795. MS (EI, 70 eV): m/z (%) = 466 [M+Me] (4), 424 (17),
352 (8), 295 (6), 265 (12), 244 (21), 190 (13),173 (100),
115 (18), 73 (39). HRMS (EI): calcd for C29H43NO3Si:
454.2452, found: 454.2448.
2-(Tert-butyldimethylsilyloxy)-N-(1-(4-cyanophenyl)-1-phen-
ylpropan-2-yl)-2-methylpropanamide (3c, according to TP5)
A yellowish oil, d.r. > 95:5 (anti/syn). Anti-isomer: 1H NMR
(600 MHz, CDCl3)  7.57 (d, J = 6.6 Hz, 2H), 7.43 (d, J =
7.8 Hz, 2H),7.29–7.15 (m, 5H), 6.73 (br, 1H), 4.87–4.77 (m,
1H), 3.86 (d, J = 10.3 Hz, 1H), 1.35 (s, 3H), 1.11 (d, J = 6.6
Hz, 3H), 1.06 (s, 3H), 0.78 (s, 9H), 0.05(s, 3H), 0.07 (s,
3H). 13C NMR (151 MHz, CDCl3)  175.7, 147.8, 140.5,
132.5, 128.9, 128.7, 128.1, 127.4, 118.7, 110.7, 76.6, 59.0,
46.6, 27.7, 27.4, 25.7, 20.4, 17.9, 2.6. IR (KBr, cm1) ν
3383, 2230, 1647, 1504, 1032, 837, 753. MS (EI, 70 eV):
m/z (%) = 421 [M+–Me] (4), 379 (31), 244(21), 173 (100),
115 (18), 73 (47). HRMS (EI): calcd for C26H36N2O2Si:
436.2546, found: 436.2546.
2-(Tert-butyldimethylsilyloxy)-2-methyl-N-(1-(3-(trifluoro-
methyl)phenyl)-1-phenylpropan-2-yl)propanamide (3d,
according to TP5)
2-(Tert-butyldimethylsilyloxy)-2-methyl-N-(1-phenyl-1-(pyridin-
3-yl)propan-2-yl)propanamide (3g, according to TP5)
A yellowish oil, d.r. > 95:5 (anti/syn). Anti-isomer: 1H NMR
(400 MHz, CDCl3)  7.58–7.50 (m, 2H), 7.29–7.17 (m, 6H),
6.73 (br, 1H), 4.834.71 (m, 1H), 3.87 (d, J = 9.6 Hz, 1H),
1.35 (s, 3H), 1.35 (s, 3H), 1.13 (d, J = 6.8 Hz, 3H), 0.91 (s,
3H), 0.77 (s, 9H), 0.05(s, 3H), 0.06 (s, 3H). 13C NMR (101
MHz, CDCl3)  175.7, 163.2 (d, J = 260.6 Hz), 151.0 (d, J =
9.7 Hz), 139.7, 133.6, 128.9, 128.2, 127.4, 124.6 (d, J = 3.1
Hz), 116.2 (d, J = 20.1 Hz), 113.8, 76.6, 58.7, 46.4, 29.7,
27.6, 27.4, 25.7, 20.5, 17.9, 2.4. IR (KBr, cm1) ν 3381,
2237, 1651, 1569, 1202, 874, 723. MS (EI, 70 eV): m/z (%) =
A yellowish oil, d.r. > 95:5 (anti/syn). Anti-isomers: 1H NMR
(300 MHz, CDCl3)  8.60 (s, 1H), 8.50 (s, 1H), 7.85 (d, J =
3.0 Hz, 2H), 7.41–7.16 (m, 5H), 6.67 (br, 1H), 4.87–4.78 (m,
1H), 3.86 (d, J = 12.0 Hz, 1H), 1.38 (s, 3H), 1.17 (d, J = 6.6
Hz, 3H), 1.10 (s, 3H), 0.81 (s, 9H), 0.04 (s, 3H), 0.02 (s,
3H). 13C NMR (75 MHz, CDCl3)  175.7, 148.3, 146.5,
136.8, 140.2,128.9, 128.2, 127.3, 126.3, 124.2, 76.6, 56.2,
46.7, 27.7, 27.4, 25.7, 20.4, 17.9, 2.5. IR (KBr, cm1) ν
3378, 1652, 1529, 1396, 1205, 1029, 980, 755. MS (EI, 70
eV): m/z (%) = 412 [M+] (4), 397 (8), 355 (31), 269 (10),

Tang S, et al. Sci China Chem January (2013) Vol.56 No.1
5
240(15), 196(18), 169 (100), 115 (15), 73 (43). HRMS (EI):
calcd for C24H36N2O2Si: 412.2546, found: 412.2546.
steric property and electronic effect of carbonyl group on
the N-atom. Gratifyingly, the coupling reaction provided
exellent yield (85%) and an exceptionally higher diastere-
oselectivity (85:15 d.r., syn/anti) after the N-acetyl group
was switched to the less steric formyl protection. Moreover,
the diastereomeric ratio could, to our surprise, be inversed
when a bulky N-acyl group was examined in our sequential
3 Results and discussion
In the course of our research project aiming at metal-
catalyzed diastereoselective Negishi coupling of open-chain
alkylzinc reagents, we initially screened various parameters
including metal sources, ligands, N-protecting group in zinc
reagent (Table 1) [16]. We observed that the combination of
Pd(OAc)2 and S-Phos is highly effective to catalyze the
C(sp3)-C(sp2) cross-coupling of (N-acetyl-2-amino-1-phen-
ylethyl)zinc chloride 1a with ethyl 4-bromobenzonate 2a
providing the desired product 3a in good yield (78 %) and
moderate diastereoselectivity (78:22 d.r., syn/anti) [17].
With the promising results obtained in our preliminary ex-
periments, we continued our efforts towards improving the
diastereoselectivity. Notably, the coordination of carbonyl
group to zinc species usually forms a cyclic intermediate for
(N-carbonyl-2-amino-1-phenylethyl)zinc reagent [8b]. Thus,
we surmised that the diastereoselectivity could be further
improved through enhancing this coordination by tuning the
i
investigation. For example, when the PrCO- was applied
instead of –Ac group, the diastereomeric selectivity ratio
was inversed partly (46:54 d.r., syn/anti). Sebsequent
screening of more bulky acyl groups including pivaloyl,
2-methyl-2-phenylpropanoyl, –COC(CH3)2OTBS, etc., re-
veal that increasing steric hindrance of acyl group could
further improve the formation of anti-diastereomer. The
zinc reagent with –CO(CH3)2OTBS group underwent the
coupling reaction in good yield with excellent diastereose-
letivity (Table 1, entry 6). In addition, zinc reagents 1h and
1i with COC6H4CH2OTBS, Boc was found to be unstable,
due to the serious β-elimination.
With the diastereoselective C(sp2)-C(sp3) Negishi cou-
pling conditions in hand, we examined the scope of the
reaction using zinc reagent 1f bearing steric hindered acyl
group COC(CH3)2OTBS. Scheme 3 shows the cross-coupling
reactions with a wide array of aryl bromides proceeded
smoothly to yield various anti 1-arylphenylethylamines in
moderate to good yields with high diastereoselectivities. All
aryl bromides, irrespective of their steric and electronic
character of the substituent groups, produced specific anti
1-arylphenylethylamine derivatives in good yields with
excellent diastereoselectivities (d.r. > 95:5, anti/syn). In
addition, different substitutions at aryl bromides including
ester, ester, methylthio, nitrile were well tolerated in the
reaction. Notably, the sterically demanding substituent at
the meta position of aryl bromide were also tolerated to
provide 3f. In addition, fluoro, heteroaromatic ring could also
be tolerated in the coupling, which would provide an alterna-
tive route for the synthesis of pharmaceutically important
fluoro or heterocycle-containing 1-arylphenylethylamines
3d–3g. However, the 2-bromothiophene was observed to
less effective in the reaction.
Table 1 Screening of carbonyl groups on N-atom a)
d.r.
Entry
1 (PG)
Yield of 3 (%) b)
(anti/syn) c)
22:78
1
2
Ac (1a)
81(78)
87
CHO (1b)
19:81
O
(1c)
3
4
76
71
46:54
79:21
i-Pr
O
(1d)
t-Bu
The diastereoselectivity in the coupling can be explained
by the the catalytic cycles shown in Scheme 4. For the zinc
reagent 1a, the coordination of the acetyl group to zinc
forms a six-membered zinc intermediate 1a′ [8b], which is
subjected to the transmetalation with ArPdBr generated
from the insertion of Pd into Ar-Br bond. The resulting Pd
species 1a″ underwent reduction elimination step to gener-
ate the desired syn product 3 and Pd(0) [6a]. On the other
hand, a working pathway b was proposed for the zinc
reagent 1f. The six-membered zinc intermediate 1f″ would
be difficult to form owing to the collision between bulky
NHCOC(Me)2OTBS and proximal zinc species. Instead, a
favored zinc intermediate 1f′ was produced, which was fol-
lowed by subsequent transmetalation and reduction elimina-
tion to afford the desired anti product 3. Obviously, the
O
Ph
5
84
90:10
(1e)
O
O
6
7
(1f)
78
67
> 95:5
88:12
t
SiMe2 Bu
O
(1g)
t
OSiMe2 Bu
OTBDPS
8
9
trace
trace
N.D.d)
N.D.d)
(1h)
O
Boc (1i)
a) Reaction conditions: zinc reagent (0.45 mmol), ethyl 4-bromobenzoate
(0.3 mmol), Pd(OAc)2 (3 mol%), S-Phos (6 mol%) in THF (0.5 mL) for
24 h; b) determined by GC, isolated yield is given in parenthesis; c) deter-
mined by GC or 1H NMR; d) N.D. = Not detected.

6
Tang S, et al. Sci China Chem January (2013) Vol.56 No.1
Scheme 3 High diastereoseletive Negishi coupling of zinc compound 1f with aryl bromides. a) Reaction conditions: 1f (0.75 mmol), aryl bromides (0.5
mmol), Pd(OAc)2 (3 mol%), S-Phos (6 mol%) in THF for 24 h; b) isolated yield; c) diastereomer ratio (anti:syn) was determined by GC or 1H NMR.
Scheme 4 Proposed reaction mechanism.

Tang S, et al. Sci China Chem January (2013) Vol.56 No.1
7
tive cross-coupling of 1,1-diboron compounds, Nat Chem, 2011, 3:
894–899; (k) Maity P, Shacklady-Mcatee DM, Yap GPA, Sirianni
ER, Watson MP. Nickel-catalyzed cross couplings of benzylic am-
monium salts and boronic acids: stereospecific formation of dia-
rylethanes via C–N bond activation. J Am Chem Soc, 2013, 135(1):
280–285
carbonyl group in COC(Me)2OTBS on N-atom is crucial in
achieving high diastereoselectivity in the transformation,
and it is possible that this amide bond could be cleaved to
give practically important primary amines [18].
4
For representative references, see: (a) Han C, Buchwald SL. Negishi
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4 Conclusion
In summary, we developed a diastereoselective Negishi
coupling reaction of open-chain zinc compounds with aryl
bromides for the first time. It would open a door for
diastereoselective C(sp3)-C(sp2) cross-coupling of open-chain
alkylzinc compounds with aryl halides, providing a novel
stereospecific approach to prepare important 1-arylphenyle-
thylamines. The detailed mechanism and application of this
novel reaction to more complex targets are currently under
study in our laboratory.
The research was financially supported by the National Natural Science
Foundation of China (21172227) and Jishou University (2012).
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