Rhodium/diene-catalyzed asymmetric arylation of N-Boc-protected α,β-unsaturated δ-lactam with arylboronic acids: Enantioselective synthesis of 4-aryl-2-piperidinones

Article abstract of DOI:10.1016/j.tet.2012.09.001

Utilizing toluene/isopropanol (20:1 to 40:1) as a solvent and KHF ₂ as an additive, the rhodium/diene-catalyzed asymmetric arylation (RCAA) reaction of arylboronic acids to N-Boc-protected α,β- unsaturated δ-lactam proceeded smoothly to afford chiral 4-aryl-2-piperidinones with high to excellent yields (up to 94%) and enantioselectivities (up to >99% ee). Further conversion of adduct (R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-2-piperidone to (R)-Homobaclofen hydrochloride was also presented.

Full text of DOI:10.1016/j.tet.2012.09.001

Tetrahedron 68 (2012) 9186e9191
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rhodium/diene-catalyzed asymmetric arylation of N-Boc-protected
a,
b-unsaturated
d-lactam with arylboronic acids: enantioselective
synthesis of 4-aryl-2-piperidinones
*
Zhi-Tao He, Ya-Bing Wei, Hong-Jie Yu, Cai-Yun Sun, Chen-Guo Feng, Ping Tian ,
*
Guo-Qiang Lin
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 August 2012
Received in revised form 31 August 2012
Accepted 1 September 2012
Available online 7 September 2012
Utilizing toluene/isopropanol (20:1 to 40:1) as a solvent and KHF2 as an additive, the rhodium/diene-
catalyzed asymmetric arylation (RCAA) reaction of arylboronic acids to N-Boc-protected
a,b-unsaturated
d
-lactam proceeded smoothly to afford chiral 4-aryl-2-piperidinones with high to excellent yields (up to
94%) and enantioselectivities (up to >99% ee). Further conversion of adduct (R)-1-(tert-butyloxycarbonyl)-
4-(4-chlorophenyl)-2-piperidone to (R)-Homobaclofen hydrochloride was also presented.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Rhodium/chiral diene catalyzed
Asymmetric arylation
Arylboronic acids
a
,
b-Unsaturated
d-lactam
Baclofen
1. Introduction
Rhodium-catalyzed asymmetric arylation (RCAA) reactions
provide one of the most straightforward and powerful ways to
introduce aryl fragments into specific molecules in an enantiose-
lective manner. During the last decade, significant efforts have been
devoted to the discovery of novel chiral ligands and catalytic sys-
tems.1 On the other hand, exploring suitable aryl-acceptors is also
a major focus in this field. We have previously reported the RCAA of
arylboronic acids to
a,b-unsaturated g-lactams with excellent
enantioselectivities (usually over 97% ee) and demonstrated much
better enantioselectivities for lactams with electron-withdrawing
N-Boc-protecting group than its N-Bn- or N-PMB-analogues.2
Herein, we wish to extend this asymmetric methodology to N-
Boc-protected a,b-unsaturated d-lactam, affording a novel and ef-
ficient entry to optically active 4-aryl-2-piperidinones.
Optically pure 4-aryl-2-piperidinones (1) are key intermediates
for the synthesis of pharmacologically active molecules such as
Femoxetine,3 Paroxetine,3a,4 S-Riva-Paroxetine,5 and Homo-
baclofen6 (Scheme 1). Despite considerable efforts have been made
for the synthesis of 1,7 reports on catalytic asymmetric arylation
variants have been rare.8 In 2001, Hayashi and co-workers first
* Corresponding authors. Tel.: þ86 21 54925169; fax: þ86 21 64166263; e-mail
Scheme 1. Pharmacologically active 4-aryl-piperidine derivates and RCAA to
saturated -lactams.
a,b-un-
addresses: tianping@sioc.ac.cn (P. Tian), lingq@sioc.ac.cn (G.-Q. Lin).
d
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.001

Z.-T. He et al. / Tetrahedron 68 (2012) 9186e9191
9187
described the RCAA reaction to -unsaturated
a
,
b
d
-lactam 2a and N-
RCAA of arylboronic acids to nitroalkenes, the acidic additive KHF2
showed remarkably helpful to enhance the yields.13 Accordingly,
excellent yield and enantioselectivity were achieved, when KHF2
applied as an additive in this case (Table 1, entry 12). To our delight,
the switch of co-solvent from toluene/water to toluene/isopropanol
dramatically improved the yield and enantioselectivity (92% yield,
95% ee), probably due to the suppression of corresponding proto-
deboration (Table 1, entry 16).14 Moreover, the RCAA reaction could
proceed smoothly at room temperature and maintain the same
excellent results (Table 1, entry 18). Several attempts to change the
co-solvents led to lower yields (Table 1, entries 13e15 and 17).
Bn-protected -unsaturated d
a,b
-lactam 2b.9 However, in order to
suppress the fast hydrolysis of the arylboronic acids, the large excess
amount of arylboroxines was necessarily used in place of arylboronic
acids for the completion of the reaction possibly due to the relatively
lower aryl-accepting capability of 2a and 2b. To address these dis-
advantage and pursue more reactive aryl-acceptor,10 we started to
explore rhodium/diene-catalyzed asymmetric arylation of arylbor-
onic acids to N-Boc-protected a,b-unsaturated d-lactam 2c.
2. Results and discussion
2.1. Evaluation of chiral bicyclo[3.3.0]octadiene ligands and
optimization of reaction conditions
2.2. RCAA of arylboronic acids to N-Boc-protected
saturated -lactam
a,b-un-
d
At the outset, various chiral bicyclo[3.3.0]octadiene ligands
With the optimal reaction conditions in hand, the scope of RCAA
to 2c was investigated using various arylboronic acids with diverse
steric and electronic properties. The results are summarized in
Table 2. Most 4-substituted phenylboronic acids gave excellent
yields (90e93%) and enantioselectivities (92e93% ee, Table 2, en-
tries 2e6). The reaction of 4-bromophenylboronic acid (3g, Table 2,
entry 7) resulted in a little lower yield, which might be attributed to
its relatively lower reactivity and faster protodeboration.9 The same
observation was also met with 3-chlorophenylboronic acid (3h),
however, the enantioselectivity was still excellent (96% ee, Table 2,
entry 8). It should be noted that the reactions were carried out in
the absence of KHF2 additive for the electron-deficient arylboronic
acids at 40 ꢀC (Table 2, entries 5e8). High yields and excellent
enantioselectivities were achieved for the 3-substituted arylbor-
onic acids (Table 2, entries 8e10). As for the more sterically hin-
dered 2-substituted arylboronic acids, the reactions could still
proceed at room temperature, giving excellent enantioselectivities
albeit a little loss in yields (Table 2, entries 12 and 13). Especially, for
1-naphthylboronic acid (3n), it reached excellent yield and perfect
enantioselectivity (>99% ee, Table 2, entry 14).
(L1eL8) have been examined in the RCAA of phenylboronic acid (3a)
11
to 2c using [Rh(C2H4)2Cl]2 as a precatalyst (Table 1, entries
1e8). Taking into account the results in both enantioselectivity and
yield, the chiral diene ligand, (S,S)-1,3a,4,6a-tetrahydro-3,6-
diphenylpentalene (L1, (S,S)-Ph-thpe),12 provided the best outcome
(Table 1, entry 1). The application of chiral diene ligands L2eL4
bearing more sterically hindered aromatic groups led to different
levels of erosion in enantioselectivities (Table 1, entries 2e4). Addi-
tionally, significant losses in yields were observed when either the
electron-deficient diene ligands (L5eL7) or electron-sufficient diene
ligand (L8) were employed, albeit a little bit higher enantioselectivity
was reached for the reaction using ligand L8 (Table 1, entries 5e8).
Next several reaction parameters including additives, solvents,
and temperature were screened in order to further improve both
enantioselectivity and yield by directly utilizing more reactive
[Rh(L1)OH]2 as the catalyst. We found that a base additive such as
Et3N, Na2CO3 or NaHCO3 was destructive to the high yields, possibly
due to the decomposition of the substrate 2c or product 4a under
basic conditions (Table 1, entries 9e11). In our previous report on
Table 1
Evaluation of chiral bicyclo[3.3.0]octadiene ligands and optimization of reaction conditionsa
Entry
Catalyst
Additiveb
Co-solvent
T (ꢀC)
Time
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
[Rh(C2H4)2Cl]2/L1
[Rh(C2H4)2Cl]2/L2
[Rh(C2H4)2Cl]2/L3
[Rh(C2H4)2Cl]2/L4
[Rh(C2H4)2Cl]2/L5
[Rh(C2H4)2Cl]2/L6
[Rh(C2H4)2Cl]2/L7
[Rh(C2H4)2Cl]2/L8
[Rh(L1)(OH)]2
[Rh(L1)(OH)]2
[Rh(L1)(OH)]2
[Rh(L1)(OH)]2
[Rh(L1)(OH)]2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
Et3N
Na2CO3
NaHCO3
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Toluene/H2O (20:1)
Dioxane/H2O (20:1)
Toluene/MeOH (20:1)
Toluene/EtOH (20:1)
toluene/i-PrOH (20:1)
Toluene/t-BuOH (20:1)
Toluene/i-PrOH (20:1)
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
rt
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
30 h
16 h
6 h
55
37
61
44
9
90
87
70
89
73
77
n.d.
92
94
91
77
92
94
88
90
95
96
95
12
Trace
23
76
37
19
93
50
41
53
92
74
92
9
10
11
12
13
14
15
16
17
18
9 h
[Rh(L1)(OH)]2
[Rh(L1)(OH)]2
[Rh(L1)(OH)]2
[Rh(L1)(OH)]2
23 h
23 h
45 min
36 h
2 h
[Rh(L1)(OH)]2
a
The reaction was carried out with 2c (0.2 mmol), phenylboronic acid 3a (0.4 mmol), [Rh(C2H4)2Cl]2 (0.0050 mmol)/diene (L1eL8) (0.011 mmol, 1.1 equiv to Rh) or [Rh(L1)
OH]2 (0.0050 mmol), and additive in 2 mL of co-solvent at 40 ꢀC or rt, unless otherwise noted.
b
Additives of 20 mol %.
Yield of isolated product.
Determined by chiral HPLC analysis.
c
d

9188
Z.-T. He et al. / Tetrahedron 68 (2012) 9186e9191
Table 2
RCAA of arylboronic acids to 1-N-Boc-2-oxo-5,6-dihydropyridine (2c)a
Entry
3 (Ar¼)
Time
Yieldf (%)
eeg (%)
1
3a (Ph)
2 h
8 h
45 min
2 h
10 min
10 min
25 min
25 min
2 h
1.5 h
8 min
1.5 h
2 h
92
90
92
91
93
92
80
76
94
90
85
84
88
92
95
93
92
93
93
92
93
96
94
95
96
96
97
>99
2
3b (4-MeePh)
3c (4-t-Bu-Ph)
3d (4-MeOePh)
3e (4-FePh)c,d,e
3f (4-ClePh)c,d,e
3g (4-Br-Ph)c,d,e
3h (3-ClePh)c,d,e
3i (3-MeePh)
3j (3-MeOePh)
3k (2-Naphthyl)
3l (2-MeOePh)
3m (2-MeePh)
3n (1-Naphthyl)
3b
4
5b
6b
7b
8b
9b
10b
11
12
13
14
Scheme 2. Asymmetric synthesis of (R)-Baclofen hydrochloride 6.
6 min
Scheme 3. RCAA to 1-N-Boc-7-oxo-2,3,4,7-tetrahydro-1H-azepine (7).
a
The reaction was carried out with 2c (0.2 mmol), arylboronic acid 3 (0.4 mmol),
[Rh(L1)OH]2 (0.0050 mmol), and KHF2 (0.04 mmol) in 2 mL of toluene/isopropanol
(20:1) at rt, unless otherwise noted.
b
c
d
e
f
3. Summary
At 40 ꢀC.
Arylboronic acids of 3 equiv.
No additive.
Toluene/isopropanol (40:1).
Yield of isolated product.
Determined by chiral HPLC analysis.
In summary, we have developed a RCAA of arylboronic acids to
N-Boc-protected -unsaturated -lactam or -lactam using a chi-
a
,b
d
3
ral diene, (S,S)-Ph-thpe as ligand. Utilizing toluene/isopropanol as
solvent and KHF2 as additive, the reaction proceeded uniformly
with high to excellent yields and enantioselectivities, affording
a synthetically useful chiral 4-aryl-2-piperidinones.
g
The absolute configuration of arylated adducts 4 was un-
ambiguously assigned as R by comparison of optical rotation of the
known Boc-protected piperidinone (R)-4f,6 which was further
confirmed by X-ray crystal structure of (R)-4g (Fig. 1).
4. Experimental
4.1. General methods
All solvents were dried before use following the standard pro-
cedures. Unless otherwise indicated, all starting materials were
obtained from commercial suppliers and were used without further
purification. The 1H and 13C NMR spectra were recorded on 300 or
400 MHz spectrometer in the indicated solvents. Chemical shifts
are reported in
d (ppm) referenced to an internal TMS standard for
1H NMR and CDCl3
(d
¼77.05 ppm) for 13C NMR. Optical rotations
were measured on a JASCO P-1030 polarimeter.
4.2. General procedure for RCAA of arylboronic acid to 1-N-
Boc-2-oxo-5,6-dihydropyridine (2c)
A dried Schlenk flask was charged with arylboronic acid (3,
0.4 mmol), [Rh(L1)(OH)]2 (L1¼(S,S)-Ph-thpe, 3.8 mg, 0.005 mmol),
KHF2 (3.2 mg, 0.04 mmol), and 1 mL of anhydrous toluene under
argon. The resulting mixture was stirred at room temperature for
30 min. 1-N-Boc-2-oxo-5,6-dihydropyridine15 (2c, 39.4 mg,
0.2 mmol) in toluene (1 mL) was added. Seven minutes later, 0.1 mL
of isopropanol was added. After being stirred at room temperature
for 2 h, the reaction was quenched with saturated aq NH4Cl,
extracted with ethyl acetate (20 mLꢁ3), and the combined organic
phases were washed with brine, dried with anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by silica gel
(300e400 mesh) column chromatography to afford 4.
Fig. 1. X-ray crystal structure of 4g.
2.3. Asymmetric synthesis of (R)-Baclofen and RCAA to N-
Boc-protected
a,
b
-unsaturated -lactam
3
The chiral adducts, 4-aryl-2-piperidinones (4) are very useful
building blocks for assembling some bioactive compounds.3e6 Thus,
the synthetic application of this methodology is demonstrated by
a simple synthesis of a GABAB receptor agonist, (R)-Homobaclofen
hydrochloride.6 After a single recrystallization, the optical pure
adduct 4f was obtained with >99% ee and then converted to (R)-
Homobaclofen in two steps in 93% overall yield (Scheme 2).
Further extension of this methodology to N-Boc-protected
unsaturated -lactam (7) was also successful. Boronic acid of 5.0 equiv
was required in this case, owing to the low reactivity of -lactam
substrate.AsshowninScheme3, theRCAAof1-naphthyl-boronicacid
(3n) provided chiral 4-aryl -lactam 8n in 68% yield and 98% ee.
a
,
b
-
4.2.1. (R)-1-(tert-Butyloxycarbonyl)-4-phenyl-2-piperidone
(4a,
3
Table 2, entry 1). White solid, 50.7 mg, 92% yield; mp 95.1e96.6 ꢀC;
27
3
[
d
a
]
þ16.7 (c 1.00, CHCl3) for 95% ee; 1H NMR (400 MHz, CDCl3)
D
(ppm) 7.36e7.33 (m, 2H), 7.27e7.19 (m, 3H), 3.88 (dt, J¼12.8,
3
4.4 Hz, 1H), 3.62 (ddd, J¼12.8, 10.8, 4.0 Hz, 1H), 3.16e3.09 (m, 1H),

Z.-T. He et al. / Tetrahedron 68 (2012) 9186e9191
9189
2.84 (ddd, J¼17.2, 5.2, 2.0 Hz, 1H), 2.64 (dd, J¼17.2, 11.2 Hz, 1H),
2.22e2.17 (m, 1H), 2.01e1.91 (m, 1H), 1.55 (s, 9H); 13C NMR
(FTMS-ESI): [MþNa]4 calcd for C16H20NO3FNa4 316.1319, found
316.1327; IR (KBr) n
(cmꢂ1) 2981, 2926, 1709, 1604, 1513, 1400, 1368,
(100 MHz, CDCl3)
d
(ppm) 170.4, 152.8, 143.2, 128.9, 127.0, 126.5,
1298, 1149, 837, 770; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2)
Column; detected at 214 nm; n-hexane/i-propanol¼90:10; flow
rate¼0.7 ml/min; retention time: 27.5 min (S), 29.0 min (R).
83.0, 45.7, 42.1, 38.4, 30.4, 28.1; ESI-MS: [MþNa]4 298.1; HRMS
(FTMS-ESI): [MþNa]4 calcd for C16H21NO3Na4 298.1414, found
298.1413; IR (KBr) n
(cmꢂ1) 3057, 2996, 2932, 1717, 1701, 1603, 1494,
1302, 1147, 890, 760, 701; HPLC: Phenomenex Lux 5u Cellulose-2
(PC-2) Column; detected at 214 nm; n-hexane/i-propanol¼90:10;
flow rate¼0.7 ml/min; retention time: 30.5 min (S), 34.8 min (R).
4.2.6. (R)-1-(tert-Butyloxycarbonyl)-4-(4-chlorophenyl)-2-
piperidone6 (4f, Table 2, entry 6). White solid, 57.0 mg, 92% yield;
mp 106.0e106.8 ꢀC; [
a]
29 þ15.4 (c 1.00, CHCl3) for 92% ee; 1H NMR
D
(400 MHz, CDCl3)
d
(ppm) 7.31 (d, J¼8.4 Hz, 2H), 7.13 (d, J¼8.4 Hz,
4.2.2. (R)-1-(tert-Butyloxycarbonyl)-4-(4-methylphenyl)-2-
piperidone (4b, Table 2, entry 2). White solid, 52.1 mg, 90% yield; mp
2H), 3.87 (dt, J¼12.8, 4.4 Hz, 1H), 3.61 (ddd, J¼12.8, 11.2, 4.4 Hz, 1H),
3.15e3.07 (m,1H), 2.82 (ddd, J¼16.8, 5.2,1.6 Hz,1H), 2.58 (dd, J¼16.8,
11.2 Hz, 1H), 2.20e2.16 (m, 1H), 1.98e1.88 (m, 1H), 1.54 (s, 9H); 13C
28
94.7e95.0 ꢀC; [
(400 MHz, CDCl3)
a]
D
þ13.2 (c 1.00, CHCl3) for 93% ee; 1H NMR
d
(ppm) 7.15 (d, J¼8.0 Hz, 2H), 7.09 (d, J¼8.0 Hz, 2H),
NMR (100 MHz, CDCl3) d (ppm) 170.0,152.7,141.6,132.8,129.0,127.9,
3.86 (dt, J¼12.8, 4.4 Hz, 1H), 3.61 (ddd, J¼12.8, 11.2, 4.4 Hz, 1H),
3.13e3.05 (m, 1H), 2.82 (ddd, J¼17.2, 5.2, 2.0 Hz, 1H), 2.61 (dd, J¼17.2,
11.2 Hz, 1H), 2.33 (s, 3H), 2.19e2.16 (m, 1H), 1.99e1.88 (m, 1H), 1.54 (s,
83.2, 45.5, 42.0, 37.9, 30.3, 28.0; ESI-MS: [MþNa]4 332.0; HRMS
(FTMS-ESI): [MþNa]4 calcd for C16H20NO3ClNa4 332.1024, found
332.1036; IR (KBr) n
(cmꢂ1) 3419, 2977, 2931, 1768, 1667, 1494, 1389,
9H); 13C NMR (100 MHz, CDCl3)
d
(ppm) 170.5, 152.8, 140.2, 136.6,
1365, 1310, 1159, 846, 777; HPLC: Phenomenex Lux 5u Cellulose-2
(PC-2) Column; detected at 214 nm; n-hexane/i-propanol¼90:10;
flow rate¼0.7 ml/min; retention time: 32.5 min (S), 36.9 min (R).
129.5, 126.3, 83.0, 45.7, 42.2, 38.1, 30.5, 28.1, 21.0; ESI-MS: [MþNa]4
312.1; HRMS (FTMS-ESI): [MþNa]4 calcd for C17H23NO3Na4 312.1570,
found 312.1581; IR (KBr) n
(cmꢂ1) 3050, 2974, 2923, 1708, 1516, 1457,
1393,1295,1152, 855, 808, 785; HPLC:Phenomenex Lux 5u Cellulose-2
(PC-2) Column; detected at 214 nm; n-hexane/i-propanol¼90:10;
flow rate¼0.7 ml/min; retention time: 17.9 min (S), 21.4 min (R).
4.2.7. (R)-1-(tert-Butyloxycarbonyl)-4-(4-bromophenyl)-2-
piperidone (4g, Table 2, entry 7). White solid, 56.7 mg, 80% yield; mp
28
98.2e98.7 ꢀC; [
(400 MHz, CDCl3)
a]
D
þ11.2 (c 1.00, CHCl3) for 93% ee; 1H NMR
(ppm) 7.46 (d, J¼8.4 Hz, 2H), 7.08 (d, J¼8.4 Hz,
d
4.2.3. (R)-1-(tert-Butyloxycarbonyl)-4-(4-(tert-butyl)phenyl)-2-
piperidone (4c, Table 2, entry 3). White solid, 61.0 mg, 92% yield; mp
2H), 3.87 (dt, J¼13.2, 4.4 Hz, 1H), 3.61 (ddd, J¼13.2, 10.8, 4.4 Hz, 1H),
3.13e3.05 (m,1H), 2.82 (ddd, J¼17.2, 5.6, 2.0 Hz,1H), 2.58 (dd, J¼17.2,
11.2 Hz, 1H), 2.21e2.14 (m, 1H), 1.97e1.87 (m, 1H), 1.54 (s, 9H); 13C
28
121.1e122.3 ꢀC; [
(400 MHz, CDCl3)
a]
þ12.1 (c 1.00, CHCl3) for 92% ee; 1H NMR
D
d
(ppm) 7.36 (d, J¼8.4 Hz, 2H), 7.13 (d, J¼8.4 Hz,
NMR (100 MHz, CDCl3) d (ppm) 170.0,152.7,142.1,132.0,128.2,120.8,
2H), 3.87 (dt, J¼12.4, 4.8 Hz, 1H), 3.61 (ddd, J¼13.2, 10.8, 4.4 Hz, 1H),
3.14e3.06 (m, 1H), 2.83 (ddd, J¼17.2, 5.2, 2.0 Hz, 1H), 2.62 (dd,
J¼16.8, 11.2 Hz, 1H), 2.22e2.15 (m, 1H), 1.99e1.89 (m, 1H), 1.55 (s,
83.2, 45.5, 41.9, 38.0, 30.2, 28.0; ESI-MS: [MþNa]4 376.0; HRMS
(FTMS-ESI): [MþNa]4 calcd for C16H20NO3BrNa4 376.0519, found
376.0509; IR (KBr) n
(cmꢂ1) 3064, 2977, 2931, 1767, 1667, 1489, 1400,
9H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
(ppm) 170.6, 152.8,
1301, 1158, 845, 828, 775; HPLC: Phenomenex Lux 5u Cellulose-2
(PC-2) Column; detected at 214 nm; n-hexane/i-propanol¼90:10;
flow rate¼0.7 ml/min; retention time: 37.4 min (S), 45.4 min (R).
149.9, 140.1, 126.1, 125.7, 83.0, 45.7, 42.1, 37.9, 34.5, 31.3, 30.5, 28.1;
ESI-MS: [MþNa]4 354.2; HRMS (FTMS-ESI): [MþNa]4 calcd for
C20H29NO3Na4 354.2040, found 354.2024; IR (KBr)
n
(cmꢂ1) 3008,
2959, 2867, 1713, 1518, 1459, 1369, 1294, 1153, 830, 780; HPLC:
Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at
214 nm; n-hexane/i-propanol¼90:10; flow rate¼0.7 ml/min; re-
tention time: 12.2 min (S), 14.0 min (R).
X-ray structural data for 4g (CCDC 888969)
Crystal data
C
16H20BrNO3
F000¼728
Mr¼354.24
Dcalcd¼1.446 Mg/m3
Monoclinic, C2
Hall symbol: none
Mo Ka radiation
Cell parameters from 1330
4.2.4. (R)-1-(tert-Butyloxycarbonyl)-4-(4-methoxyphenyl)-2-
piperidone (4d, Table 2, entry 4). White solid, 55.6 mg, 90% yield;
reflections
27
a
]
D
þ14.1 (c 1.00, CHCl3) for 93% ee; 1H NMR
ꢀ
ꢀ
mp 87.4e87.6 ꢀC; [
a¼22.956(5) A
l
¼0.717073 A
¼1.80e26.00ꢀ
ꢀ
b¼7.7296(15) A
q
(400 MHz, CDCl3)
d
(ppm) 7.12 (d, J¼8.4 Hz, 2H), 6.88 (d, J¼8.4 Hz,
¼2.535 mmꢂ1
ꢀ
c¼9.2996(18) A
m
2H), 3.88e3.83 (m, 1H), 3.80 (s, 3H), 3.64e3.57 (m, 1H), 3.11e3.04
(m, 1H), 2.81 (dd, J¼16.8, 5.6 Hz, 1H), 2.59 (dd, J¼17.2, 11.2 Hz, 1H),
2.18e2.14 (m, 1H), 1.97e1.86 (m, 1H), 1.54 (s, 9H); 13C NMR
a
b
¼90ꢀ
T¼293(2) K
¼99.558(4)ꢀ
Prismatic, colorless
0.311ꢁ0.215ꢁ0.167 mm
Z¼4
g
¼90ꢀ
3
ꢀ
V¼1627.2(5) A
(100 MHz, CDCl3)
d (ppm) 170.6, 158.6, 152.8, 135.3, 127.4, 114.2,
83.0, 55.3, 45.6, 42.4, 37.6, 30.6, 28.0; ESI-MS: [MþNa]4 328.1;
Data collection
HRMS (FTMS-ESI): [MþNa]4 calcd for C17H23NO4Na4 328.1519,
Bruker SMART APEX diffractometer 1330 Reflections with I>2s(I)
found 328.1512; IR (KBr) n
(cmꢂ1) 2982, 2936, 1767, 1716, 1612, 1513,
Radiation source: fine-focus
sealed tube
Rint¼0.0319
1345, 1248, 1150, 838, 768; HPLC: Phenomenex Lux 5u Cellulose-2
(PC-2) Column; detected at 214 nm; n-hexane/i-propanol¼90:10;
flow rate¼0.7 ml/min; retention time: 43.2 min (S), 54.8 min (R).
Graphite
4 and
qmax¼26.00o
h¼ꢂ27/28
k¼ꢂ9/9
u scans
Absorption correction: empirical
Tmin¼0.53517, Tmax¼1.00000
l¼ꢂ11/5
4.2.5. (R)-1-(tert-Butyloxycarbonyl)-4-(4-fluorophenyl)-2-
piperidone (4e, Table 2, entry 5). White solid, 54.6 mg, 93% yield; mp
Refinement
Refinement on F2
Matrix type: full
H atoms treatment: constrained
w ¼ 1=½s2ðFo2Þ þ ð0:0282PÞ2 þ 0:0000Pꢃ
where P ¼ ðFo2 þ 2Fc2Þ=3
29
76.9e77.1 ꢀC; [
a]
D
þ162.1 (c 0.99, CHCl3) for 93% ee; 1H NMR
(400 MHz, CDCl3)
d
(ppm) 7.16 (dd, J¼8.4, 5.2 Hz, 2H), 7.03 (t, J¼8.4 Hz,
2H), 3.87 (dt, J¼13.2, 4.4 Hz, 1H), 3.61 (ddd, J¼12.8, 11.2, 4.4 Hz, 1H),
3.15e3.07 (m, 1H), 2.82 (ddd, J¼16.8, 5.6, 2.0 Hz, 1H), 2.59 (dd, J¼17.2,
11.2 Hz, 1H), 2.20e2.15 (m, 1H), 1.98e1.88 (m, 1H), 1.55 (s, 9H); 13C
R[F2>2
s
(F2)]¼0.0449
(D
/s)
¼0.004
max
wR(F2)¼0.1029
S¼0.990
Drmax¼0.488 e A
ꢀꢂ3
ꢀꢂ3
Drmin¼ꢂ0.60 e A
3191 Reflections
193 Parameters
1 Restraints
Absolute structure: Flack HD (1983)
Absolute structure parameter: 0.025(15)
NMR (100 MHz, CDCl3)
d
(ppm) 170.2, 161.8 (d, JCF¼244.3 Hz), 152.7,
138.9 (d, JCF¼3.6 Hz), 128.0 (d, JCF¼8.0 Hz), 115.7 (d, JCF¼21.1 Hz),
83.2, 45.5, 42.3, 37.8, 30.5, 28.0; ESI-MS: [MþNa]4 298.1; HRMS

9190
Z.-T. He et al. / Tetrahedron 68 (2012) 9186e9191
4.2.8. (R)-1-(tert-Butyloxycarbonyl)-4-(3-chlorophenyl)-2-
4.2.12. (R)-1-(tert-Butyloxycarbonyl)-4-(2-methoxyphenyl)-2-
piperidone (4h, Table 2, entry 8). White solid, 47.1 mg, 76% yield;
piperidone (4l, Table 2, entry 12). White solid, 51.3 mg, 84% yield;
28
22
mp 80.0e80.2 ꢀC; [
a]
D
þ13.8 (c 1.00, CHCl3) for 96% ee; 1H NMR
mp 59.7e60.6 ꢀC; [
a
]
D
þ26.7 (c 0.91, CHCl3) for 96% ee; 1H NMR
(400 MHz, CDCl3)
d
(ppm) 7.30e7.19 (m, 3H), 7.08 (d, J¼7.2 Hz,
(400 MHz, CDCl3)
d
(ppm) 7.25e7.21 (m, 1H), 7.11 (dd, J¼7.2,
1H), 3.89 (dt, J¼13.2, 4.4 Hz, 1H), 3.65e3.58 (m, 1H), 3.13e3.06 (m,
1H), 2.83 (dd, J¼16.8, 4.0 Hz, 1H), 2.60 (dd, J¼16.8, 11.2 Hz, 1H),
2.20e2.18 (m, 1H), 1.99e1.89 (m, 1H), 1.55 (s, 9H); 13C NMR
1.2 Hz, 1H), 6.94 (t, J¼7.2 Hz, 1H), 6.88 (d, J¼8.0 Hz, 1H),
3.89e3.82 (m, 4H), 3.63 (ddd, J¼12.8, 10.8, 4.4 Hz, 1H), 3.50e3.42
(m, 1H), 2.85 (ddd, J¼17.2, 5.6, 1.6 Hz, 1H), 2.60 (dd, J¼17.2,
10.8 Hz, 1H), 2.16e2.10 (m, 1H), 2.04e1.94 (m, 1H), 1.55 (s, 9H);
(100 MHz, CDCl3)
d (ppm) 169.9, 152.7, 145.2, 134.7, 130.2, 127.3,
126.8, 124.7, 83.2, 45.5, 41.9, 38.2, 30.2, 28.0; ESI-MS: [MþNa]4
13C NMR (100 MHz, CDCl3)
d (ppm) 171.2, 156.9, 152.8, 131.3,
332.1; HRMS (FTMS-ESI): [MþNa]4 calcd for C16H20NO3ClNa4
127.9, 126.5, 120.8, 110.6, 82.9, 55.2, 45.8, 40.7, 32.6, 28.6, 28.1;
332.1024, found 332.1031; IR (KBr)
n
(cmꢂ1) 3063, 2973, 2927,
ESI-MS: [MþNa]4 328.1; HRMS (FTMS-ESI): [MþNa]4 calcd for
1770, 1760, 1599, 1475, 1367, 1283, 1150, 788, 696; HPLC:
Phenomenex Lux 5u Cellulose-1 (PC-1) Column; detected at
214 nm; n-hexane/i-propanol¼70:30; flow rate¼0.7 ml/min; re-
tention time: 13.4 min (S), 14.6 min (R).
C17H23NO4Na4 328.1519, found 328.1513; IR (KBr) (cmꢂ1) 2977,
n
2932, 1719, 1703, 1600, 1495, 1391, 1367, 1291, 1149, 855, 758;
HPLC: Phenomenex Lux 5u Cellulose-1 (PC-1) Column; detected
at 214 nm; n-hexane/i-propanol¼50:50; flow rate¼0.7 ml/min;
retention time: 8.1 min (S), 9.0 min (R).
4.2.9. (R)-1-(tert-Butyloxycarbonyl)-4-(3-methylphenyl)-2-
piperidone (4i, Table 2, entry 9). White solid, 54.4 mg, 94% yield;
4.2.13. (R)-1-(tert-Butyloxycarbonyl)-4-(2-methylphenyl)-2-
28
mp 61.9e63.2 ꢀC; [
a]
þ15.0 (c 1.00 CHCl3) for 94% ee; 1H NMR
piperidone (4m, Table 2, entry 13). White solid, 50.9 mg, 88% yield;
D
29
(400 MHz, CDCl3)
d
(ppm) 7.23 (t, J¼7.6 Hz, 1H), 7.07 (d, J¼7.6 Hz,
mp 81.4e81.8 ꢀC; [
(400 MHz, CDCl3)
a
d
]
þ33.9 (c 0.95, CHCl3) for 97% ee; 1H NMR
D
1H), 7.00(s, 1H), 6.99 (d, J¼7.6 Hz, 1H), 3.87 (dt, J¼12.8, 4.4 Hz, 1H),
3.61 (ddd, J¼12.8, 11.2, 4.4 Hz, 1H), 3.12e3.04 (m, 1H), 2.82 (ddd,
J¼17.2, 5.2, 2.0 Hz, 1H), 2.62 (dd, J¼17.2, 11.2 Hz, 1H), 2.35 (s, 3H),
2.21e2.14 (m, 1H), 2.00e1.90 (m, 1H), 1.55 (s, 9H); 13C NMR
(ppm) 7.24e7.14 (m, 4H), 3.89 (dt, J¼12.8,
4.4 Hz, 1H), 3.65 (ddd, J¼12.8, 10.8, 4.4 Hz, 1H), 3.37e3.29 (m, 1H),
2.80 (ddd, J¼17.2, 5.6, 2.0 Hz, 1H), 2.58 (dd, J¼17.2, 11.2 Hz, 1H), 2.34
(s, 3H), 2.17e2.10 (m, 1H), 2.02e1.92 (m, 1H), 1.55 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d
(ppm) 170.5, 152.8, 143.2, 138.5, 128.8,
(100 MHz, CDCl3) d (ppm) 170.7, 152.7, 141.3, 135.3, 130.8, 126.8,
127.8, 127.3, 123.5, 83.1, 45.7, 42.2, 38.4, 30.4, 28.1, 21.5; ESI-
126.7, 124.9, 83.1, 45.7, 41.6, 34.2, 29.5, 28.1, 19.3; ESI-MS: [MþNa]4
MS: [MþNa]4 312.1; HRMS (FTMS-ESI): [MþNa]4 calcd for
312.2; HRMS (FTMS-ESI): [MþNa]4 calcd for C17H23NO3Na4
C17H23NO3Na4 312.1570, found 312.1557; IR (KBr)
n
(cmꢂ1) 3031,
312.1570, found 312.1584; IR (KBr) n
(cmꢂ1) 3000, 2976, 2931, 1766,
1767, 1669, 1609, 1488, 1391, 1284, 1149, 849, 816, 703; HPLC:
Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at
214 nm; n-hexane/i-propanol¼90:10; flow rate¼0.7 ml/min; re-
tention time: 19.0 min (S), 20.3 min (R).
1714,1672,1483,1367,1305,1150, 855, 761; HPLC: Phenomenex Lux
5u Cellulose-2 (PC-2) Column; detected at 214 nm; n-hexane/
i-propanol¼90:10; flow rate¼0.7 ml/min; retention time: 17.8 min
(S), 25.1 min (R).
4.2.10. (R)-1-(tert-Butyloxycarbonyl)-4-(3-methoxyphenyl)-2-
4.2.14. (R)-1-(tert-Butyloxycarbonyl)-4-(naphthalen-1-yl)-2-
piperidone (4j, Table 2, entry 10). White solid, 55.0 mg, 90%
piperidone (4n, Table 2, entry 14). White solid, 59.9 mg, 92% yield;
22
22
yield; mp 48.4e48.9 ꢀC; [
a
]
þ15.6 (c 0.96 CHCl3) for 95% ee; 1H
mp 99.3e100.4 ꢀC; [
a
]
þ .3 (c 1.02, CHCl3) for >99% ee; 1H
(ppm) 8.02 (d, J¼8.0 Hz, 1H), 7.89 (d,
D
D
NMR (400 MHz, CDCl3)
d
(ppm) 7.28e7.24 (m, 1H), 6.81e6.74
NMR (400 MHz, CDCl3) d
(m, 3H), 3.88 (dt, J¼12.8, 4.4 Hz, 1H), 3.81 (s, 3H), 3.61 (ddd, J¼12.8,
11.2, 4.4 Hz, 1H), 3.13e3.05 (m, 1H), 2.84 (ddd, J¼17.2, 5.2, 2.0 Hz,
1H), 2.62 (dd, J¼17.2, 11.2 Hz, 1H), 2.22e2.16 (m, 1H), 2.00e1.90
J¼8.0 Hz, 1H), 7.77 (d, J¼8 Hz, 1H), 7.57e7.45 (m, 3H), 7.33 (d,
J¼6.8 Hz, 1H), 4.00e3.92 (m, 1H), 3.87 (dt, J¼12.8, 4.8 Hz, 1H),
3.75 (ddd, J¼12.8, 10.4, 4.4 Hz, 1H), 3.04 (ddd, J¼17.2, 5.2, 2.0 Hz,
1H), 2.75 (dd, J¼17.2, 10.4 Hz, 1H), 2.39e2.32 (m,1H), 2.17e2.08
(m, 1H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3)
d (ppm) 170.4,
160.0, 152.8, 144.8, 129.9, 118.8, 112.7, 112.0, 83.1, 55.2, 45.7,
42.1, 38.5, 30.3, 28.1; ESI-MS: [MþNa]4 328.2; HRMS (FTMS-
MALDI): [MþNa]4 calcd for C17H23NO4Na4 328.1519, found
(m, 1H), 1.57 (s, 9H); 13C NMR (100 MHz, CDCl3)
d (ppm) 170.7,
152.7, 138.8, 134.0, 131.0, 129.2, 127.6, 126.4, 125.8, 125.6, 122.6,
122.4, 83.2, 45.5, 41.82 33.4, 29.8, 28.1; ESI-MS: [MþNa]4 348.1;
HRMS (FTMS-ESI): [MþNa]4 calcd for C20H23NO3Na4 348.1570,
328.1530; IR (KBr)
n
(cmꢂ1) 3060, 3002, 2983, 2932, 1705, 1597,
1492, 1396, 1369, 1162, 790, 700; HPLC: Phenomenex Lux 5u
Cellulose-1 (PC-1) Column; detected at 214 nm; n-hexane/i-prop-
anol¼50:50; flow rate¼0.7 ml/min; retention time: 17.2 min (S),
19.0 min (R).
found 348.1574; IR (KBr) n
(cmꢂ1) 3049, 2978, 2931, 1702, 1598,
1486, 1392, 1370, 1148, 855, 799, 773; HPLC: Phenomenex Lux 5u
Cellulose-2 (PC-2) Column; detected at 214 nm; n-hexane/
i-propanol¼95:5; flow rate¼0.7 ml/min; retention time: 42.9 min
(R), 48.1 min (S).
4.2.11. (R)-1-(tert-Butyloxycarbonyl)-4-(naphthalen-2-yl)-2-
piperidone (4k, Table 2, entry 11). White solid, 55.3 mg, 85% yield;
4.3. Preparation of (R)-Baclofen hydrochloride 6
mp 104.6e105.2 ꢀC; [
a]
29 þ13.0 (c 1.00 CHCl3) for 96% ee; 1H NMR
D
(400 MHz, CDCl3)
d
(ppm) 7.84e7.80 (m, 3H), 7.62 (s, 1H), 7.51e7.44
4.3.1. (R)-5-((tert-Butoxycarbonyl)amino)-3-(4-chlorophenyl)penta-
28
(m, 2H), 7.33 (dd, J¼8.4, 2.0 Hz, 1H), 3.90 (dt, J¼12.8, 4.8 Hz, 1H),
3.67 (ddd, J¼12.8, 10.8, 4.0 Hz, 1H), 3.34e3.26 (m, 1H), 2.93 (ddd,
J¼17.2, 5.2, 2.0 Hz, 1H), 2.75 (dd, J¼17.2, 11.2 Hz, 1H), 2.32e2.25 (m,
1H), 2.12e2.02 (m, 1H), 1.56 (s, 9H); 13C NMR (100 MHz, CDCl3)
noic acid (5).6 Optically pure 4f (135.9 mg, 69% yield, >99% ee, [
a]
D
þ14.9 (c 0.18, CH2Cl2)) was obtained after single recrystallization
from 197.0 mg of 4f (92% ee) in 10 mL of hexane/EtOAc (2:1). To
a solution of 4f (52.3 mg, 0.169 mmol, >99% ee) in methanol
(2.5 mL) was added an aqueous solution of NaOH (1 M, 3.0 mL), and
the resulting mixture was stirred at room temperature for 30 min.
The pH of the aqueous solution was adjusted to 1 using 1 M HCl.
The aqueous phase was extracted with Et2O (20 mLꢁ3), and the
combined organic phases were washed with brine, dried with an-
hydrous Na2SO4, filtered, and concentrated. The residue was puri-
fied by silica gel (300e400 mesh) column chromatography to afford
5 (53.7 mg, 97%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
(ppm) 170.4, 152.8, 140.5, 133.5, 132.5, 128.7, 127.7, 127.7, 126.4,
125.9, 125.0, 124.8, 83.1, 45.6, 42.0, 38.5, 30.4, 28.0; ESI-MS:
[MþNa]4 348.2; HRMS (FTMS-ESI): [MþNa]4 calcd for
C20H23NO3Na4 348.1570, found 348.1578; IR (KBr)
n
(cmꢂ1) 3061,
2976, 2925, 1712, 1599, 1476, 1390, 1370, 1292, 1149, 850, 824, 750;
HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at
214 nm; n-hexane/i-propanol¼90:10; flow rate¼0.7 ml/min; re-
tention time: 32.8 min (S), 41.6 min (R).

Z.-T. He et al. / Tetrahedron 68 (2012) 9186e9191
9191
d
(ppm) 12.00 (s, 1H), 7.33 (d, J¼8.4 Hz, 2H), 7.26 (d, J¼8.4 Hz, 2H),
at 214 nm; n-hexane/i-propanol¼80:20; flow rate¼0.7 ml/min;
retention time: 13.4 min (minor), 14.8 min (major).
6.78 (s, 1H), 3.04e3.02 (m, 1H), 2.75e2.70 (m, 2H), 2.62e2.43 (m,
2H), 1.75e1.59 (m, 2H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
(ppm) 173.4, 156.0, 143.5, 131.3, 129.9, 128.6, 77.9, 41.1, 39.0, 38.5,
Acknowledgements
36.3, 28.7.
Financial support for this work was generously provided by the
NSFC (21102161), SMSTC (11ZR1445800), CAS, and the 973 Program
(2010CB833302). We thankDr. HanqingDong forhelpful discussions.
4.3.2. (R)-Homobaclofen hydrochloride salt (6). To
a 4 mL of
1,4-dioxane solution of HCl (gas, 5 M) was added 5 (53.7 mg,
0.164 mmol). The resulting mixture was stirred at room tempera-
ture for 24 h and concentrated to give 6 (41.5 mg, 96%) as a yellow
solid. Mp 176.8e178.4 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d (ppm)
References and notes
12.15 (br s, 1H), 7.85 (br s, 3H), 7.38 (s, J¼8.8 Hz, 2H), 7.31
1. For recent reviews on RCAA reactions, see: (a) Tian, P.; Dong, H.-Q.; Lin, G.-Q.
ACS Catal. 2012, 2, 95; (b) Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. Synlett 2011, 1345; (c)
Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost, C. G. Chem. Soc. Rev. 2010, 39,
2093; (d) Shintani, R.; Hayashi, T. Aldrichimica Acta 2009, 42, 31; (e) Defieber, C.;
(s, J¼8.8 Hz, 2H), 3.11e3.09 (m, 1H), 2.68e2.62 (m, 2H), 2.55e2.42
(m, 2H), 1.92e1.79 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
d (ppm)
173.2, 142.6, 131.6, 129.9, 128.8, 40.9, 38.7, 37.4, 33.5;
€
Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482; (f)
ESI-MS: [MꢂHClþH]4 228.1; HRMS (FTMS-ESI): [MꢂHClþH]4
Johnson, J. B.; Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840.
2. Shao, C.; Yu, H.-J.; Wu, N.-Y.; Tian, P.; Wang, R.; Feng, C.-G.; Lin, G.-Q. Org. Lett.
2011, 13, 788.
calcd for C11H15ClNO42 228.0786, found 228.0795; IR (KBr) (cmꢂ1
n )
3178(brs), 2926, 1717, 1702, 1673, 1613, 1495, 1342, 1176, 1092,
829, 707.
ꢁ
ꢂ
ꢁ
ꢂ
3. (a) Cíhalova, S.; Valero, G.; Schimer, J.; Humpl, M.; Dracínsky, M.; Moyano, A.;
ꢂ
Rios, R.; Vesely, J. Tetrahedron2011, 67, 8942; (b) Brandau, S.; Landa, A.; Franzen, J.;
Marigo, M.; Jøgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305; (c) Johnson, T. A.;
Jang, D. O.; Slafer, B. W.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2002, 124, 11689.
4. Kim, M.-H.; Park, Y.; Jeong, B.-S.; Park, H.-G.; Jew, S.-S. Org. Lett. 2010, 12, 2826;
(b) Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389; (c) Bower, J.
F.; Riis-Johannessen, T.; Szeto, P.; Whitehead, A. J.; Gallagher, T. Chem. Commun.
2007, 728; (d) Takasu, K.; Nishida, N.; Tomimura, A.; Ihara, M. J. Org. Chem.
2005, 70, 3957; (e) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11253; (f) Greenhalgh, D. A.; Simpkins, N. S. Synlett 2002, 2074; (g)
Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004; (h) Liu, L.-
T.; Hong, P.-C.; Huang, H.-L.; Chen, S.-F.; Jeff Wang, C.-L.; Wen, Y.-S. Tetrahedron:
Asymmetry 2001, 12, 419.
5. Rupniak, N. M. J.; White, J. F. (Colucid Pharmaceuticals, Inc.). WO 2010009316, 2010.
6. Karla, R.; Ebert, B.; Thorkildsen, C.; Herdeis, C.; Johansen, T. N.; Nielsen, B.;
Krogsgaard-Larsen, P. J. Med. Chem. 1999, 42, 2053.
7. Ito, M.; Sakaguchi, A.; Kobayashi, C.; Ikariya, T. J. Am. Chem. Soc. 2007, 129, 290;
(b) Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62, 4907; (c) Yu, M. S.; Lantos, I.;
Peng, Z.-Q.; Yu, J.; Cacchio, T. Tetrahedron Lett. 2000, 41, 5647.
4.4. Preparation of 8n
4.4.1. 1-(tert-Butyloxycarbonyl)-4-(naphthalen-1-yl)-2-oxoazepane
(8n). A dried Schlenk flask was charged with naphthalen-1-
ylboronic acid (3n, 172 mg, 1.0 mmol), [Rh(L1)(OH)]2 (L1¼(S,S)-
Ph-thpe, 3.8 mg, 0.005 mmol), KHF2 (3.2 mg, 0.04 mmol), and
1 mL of anhydrous toluene under argon. The resulting mixture
was stirred at room temperature for 30 min. 1-N-Boc-7-oxo-
2,3,4,7-tetrahydro-1H-azepine (7, 42.3 mg, 0.2 mmol) in 1 mL of
toluene was added. Seven minutes later, 0.1 mL of isopropanol
was added. After being stirred at 40 ꢀC for 1.5 h, the reaction
was quenched with saturated aq NH4Cl, extracted with ethyl
acetate (20 mLꢁ3), and the combined organic phases were
washed with brine, dried with anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by silica gel (300e400
8. (a) Jin, S.-S.; Wang, H.; Xu, M.-H. Chem. Commun. 2011, 7230; (b) Gini, F.;
Hessen, B.; Feringa, B. L.; Miniaard, A. J. Chem. Commun. 2007, 710; (c) Nakao, Y.;
Chen, J.-S.; Imanaka, H.; Hiyama, Y.; Ichikawa, Y.; Duan, W.-L.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2007, 129, 9137.
mesh) column chromatography to afford 8n (46 mg, 68%) as
9. Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852.
10. RCAA to a,b-unsaturated amides see: (a) Sakuma, S.; Miyaura, N. ˇ J. Org. Chem.
2001, 66, 8944; (b) Pucheault, M.; Michaut, V.; Darses, S.; Geneet, J.-P. Tetra-
hedron Lett. 2004, 45, 4729.
11. Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc.
1998, 120, 5579.
12. Recent works on chiral diene ligand (S,S)-Ph-thpe see: (a) Cui, Z.; Yu, H.-J.;
Yang, R.-F.; Gao, W.-Y.; Feng, C.-G.; Lin, G.-Q. J. Am. Chem. Soc. 2011, 133, 12394;
(b) Wang, L.; Wang, Z.-Q.; Xu, M.-H.; Lin, G.-Q. Synthesis 2010, 3263; (c) Feng,
C.-Q.; Wang, Z.-Q.; Tian, P.; Xu, M.-H.; Lin, G.-Q. Chem. Asian J. 2008, 3, 1511; (d)
Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336;
(e) Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W. Adv. Synth.
Catal. 2007, 349, 2331.
28
a colorless oil. [
a
]
þ13.1 (c 1.01, CHCl3) for 98% ee; 1H NMR
(ppm) 8.10 (d, J¼8.4 Hz, 1H), 7.86 (d,
D
(400 MHz, CDCl3)
d
J¼8.0 Hz, 1H), 7.74 (d, J¼8.4 Hz, 1H), 7.58e7.41 (m, 3H), 7.32 (d,
J¼7.2 Hz, 1H), 4.42 (dd, J¼15.2, 6.8 Hz, 1H), 3.77 (t, J¼10.8 Hz, 1H),
3.50 (dd, J¼15.2, 10.4 Hz, 1H), 3.18 (dd, J¼13.2, 11.2 Hz, 1H), 2.92
(d, J¼13.6 Hz, 1H), 2.26 (d, J¼13.6 Hz, 1H), 2.19e2.13 (m, 1H),
1.95e1.75 (m, 2H), 1.58 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
(ppm) 174.2, 153.0, 142.1, 134.0, 130.6, 129.1, 127.3, 126.4, 125.7,
125.4, 122.9, 122.2, 83.1, 46.4, 46.0, 37.2, 35.7, 28.9, 28.1; ESI-MS:
[MþNa]4 362.1; HRMS (FTMS-ESI): [MþNa]4 calcd for
13. Wang, Z.-Q.; Feng, C.-G.; Zhang, S.-S.; Xu, M.-H.; Lin, G.-Q. Angew. Chem., Int. Ed.
C21H25NO3Na4 362.1727, found 362.1727; IR (KBr)
n
(cmꢂ1) 2979,
2010, 49, 5780.
14. Brock, S.; Hose, D. R. J.; Moseley, J. D.; Parker, A. J.; Patel, I.; Williams, A. J. Org.
Process Res. Dev. 2008, 12, 496.
15. Winter, D. K.; Drouin, A.; Lessard, J.; Spino, C. J. Org. Chem. 2010, 75, 2610.
2931, 1766, 1731, 1597, 1392, 1367, 1345, 1150, 854, 778, 753;
HPLC: Phenomenex Lux 5u Cellulose-4 (PC-4) Column; detected