Regio- and enantioselective palladium-catalyzed allylic alkylation of nitromethane with monosubstituted allyl substrates: Synthesis of (R)-rolipram and (R)-baclofen

Article abstract of DOI:10.1021/jo301506p

The Pd-catalyzed asymmetric allylic alkylation (AAA) reaction of nitromethane with monosubstituted allyl substrates was realized for the first time to provide corresponding products in high yields with excellent regio- and enantioselectivities. The protocol was applied to the enantioselective synthesis of (R)-baclofen and (R)-rolipram.

Full text of DOI:10.1021/jo301506p

Article
pubs.acs.org/joc
Regio- and Enantioselective Palladium-Catalyzed Allylic Alkylation of
Nitromethane with Monosubstituted Allyl Substrates: Synthesis of
(R)‑Rolipram and (R)‑Baclofen
Xiao-Fei Yang,† Chang-Hua Ding,† Xiao-Hui Li,† Jian-Qiang Huang,† Xue-Long Hou,*,†,‡ Li-Xin Dai,†
and Pin-Jie Wang†
‡
†State Key Laboratory of Organometallic Chemistry and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People's Republic of China
S
* Supporting Information
ABSTRACT: The Pd-catalyzed asymmetric allylic alkylation
(AAA) reaction of nitromethane with monosubstituted allyl
substrates was realized for the first time to provide
corresponding products in high yields with excellent regio-
and enantioselectivities. The protocol was applied to the
enantioselective synthesis of (R)-baclofen and (R)-rolipram.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Our initial investigations on the reaction of nitromethane with
cinnamyl methyl carbonate (1a) was carried out using DABCO
as base under the effect of 2.5 mol % of Pd2(dba)3CHCl3 and
5.0 mol % of (Sc,Rphos,Sa)-SIOCPhox (L1) in dichloromethane
or toluene. However, both experiments failed to afford an
allylated product (entries 1 and 2, Table 1). When DMSO was
applied as solvent, the desired branched product 2a was
acquired in 72% yield with 78% ee (entry 3, Table 1). With
these promising results, other chiral SIOCPhox ligands shown
in Figure 1 were tested. The two SIOCPhox ligands (Rphos,Sa)-
L2 and (Sphos,Sa)-L3, having no chiral center on the oxazoline,
gave the product 2a with opposite configuration, which
suggested the central chirality on the phosphorus atom controls
the configuration of the product (entries 4 and 5, Table 1). The
use of (Sc,Sphos,Sa)-L4 and (Sc,Sphos,Ra)-L5 led to lower regio-
and enantioselectivities in comparison with those for
(Sc,Rphos,Sa)-L1, indicating the chiralities in the two ligands
are mismatched (entries 6 and 7 vs entry 3, Table 1). An
increase in enantioselectivity to 84% was observed using
(Sc,Rphos,Ra)-L6 as ligand, although the regioselectivity was
reduced to 80/20 (entries 8 vs 3, Table 1). On the basis of the
above trials and especially the ee value, (Sc,Rphos,Ra)-L6 was
chosen as the ligand for further investigation of the reaction.
The evaluation of the role of the solvents showed that the
mixed solvents of DMSO and THF could significantly increase
the regioselectivity (entries 9−11, Table 1), while THF proved
to be the solvent of choice, affording the allylated product 2a in
81% yield, the 2a/3a ratio being 92/8 and ee being 95% for 2a
The palladium-catalyzed AAA reaction has become one of the
most powerful tools in organic synthesis to build chiral centers
through carbon−carbon bond-forming reactions.1 Nitro
compounds are valuable intermediates in organic synthesis, as
they are conveniently transformed into a wide variety of
synthetically important compounds such as amines, carboxylic
acids, aldehydes, and nitriles.2 The employment of nitroalkanes
as nucleophiles in Pd-catalyzed asymmetric allylic alkylation has
been reported for more than 15 years. Helmchen reported the
first intermolecular Pd-catalyzed asymmetric allylic alkylation of
nitromethane with 1,3-symmetrically disubstituted allyl sub-
strates in 1995.3 Since then, many reports have appeared for
Pd-catalyzed allylic alkylation reactions using nitroalkanes,
providing corresponding products in high enatioselectivities.4,5
However, the electrophiles used in these reactions are always
limited to those symmetrically 1,3-disubstituted allylic sub-
strates. The use of monosubstituted allyl substrates remains
unexplored and daunting. Recently, we have developed a series
of ferrocene-based chiral ligands, SIOCPhox, and their superior
ability to control regio- and enantioselectivities in Pd-catalyzed
AAA of monosubstituted allyl substrates has been demon-
strated.6 On the basis of these successes, we envisioned that the
regio- and enantioselectivities of Pd-catalyzed AAA of nitro-
methanes with monosubstituted allyl substrates should be
controlled if SIOCPhox is used as a ligand so that the optically
active branched products could be provided. Herein we report
our preliminary results in the Pd-catalyzed AAA reaction of
nitromethane with monosubstituted allyl substrates and apply
the protocol to the enantioselective synthesis of (R)-rolipram
and (R)-baclofen.
Received: July 17, 2012
© XXXX American Chemical Society
A
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Table 1. Impact of Reaction Parameters on the Pd-Catalyzed
Reaction of Cinnamyl Methyl Carbonate (1a) with
Nitromethane
Table 2. Substrate Scope for Pd-Catalyzed Reaction of Allyl
Methyl Carbonate 1 with Nitromethane
a
a
b
c
d
e
entry ligand
solvent
CH2Cl2
2a/3a
yield (%)
ee (%)
1
L1
L1
L1
L2
L3
L4
L5
L6
L6
L6
L6
L7
L8
L9
2
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
b
c
d
entry
R
2/3
2, yield (%)
ee (%)
3
89/11
89/11
82/18
60/40
77/23
80/20
85/15
90/10
92/8
72
62
45
14
18
69
60
73
81
10
58
78
66
1
H
92/8
95/5
97/3
87/13
94/6
85/15
96/4
95/5
96/4
99/1
94/6
2a, 81
2b, 88
2c, 68
2d, 83
2e, 88
2f, 80
2g, 92
2h, 80
2i, 89
2j, 91
2k, 87
97
97
98
96
96
95
96
97
90
93
97
4
2
p-CH3
p-OCH3
p-Cl
f
5
−62
3
f
6
−54
4
f
7
−76
5
p-F
8
84
88
94
97
6
m-Cl
9
THF/DMSO (1/1)
7
m-OCH3
10
11
12
13
14
THF/DMSO (10/1)
8
m-OCH2O-p
o-Br
THF
THF
THF
THF
9
88/12
95/5
10
11
1-naphthyl
p-OCH3; m-cC5H9O
96
87/13
a
Conditions: molar ratio 1/DABCO/Pd2(dba)3CHCl3/L6 = 100/
a
Conditions: molar ratio 1a/DABCO/Pd2(dba)3·CHCl3/L = 100/
b
100/5/10, 0.5 mL of CH3NO2, 2.0 mL of THF. Determined by GC.
b
100/2.5/5.0, 0.5 mL of CH3NO2, 2.0 mL of THF. Reaction time:
c
d
Isolated yield of product 2. Determined by chiral GC or HPLC.
c
entries 3−8, 1 h; entries 9−15, 12 h. Determined by chiral GC.
d
e
f
Isolated yield of product 2a. Determined by chiral GC. A minus
and m-cyclopentyloxy substituents resulted in product 2k with
a slightly reduced regioselectivity but excellent enantioselectiv-
ity (entry 11, Table 2). The absolute configuration of the
product 2a was determined to be R by comparison of retention
time of its HPLC with that in the literature.5
sign means that the product has the opposite configuration.
To showcase the utility of our methodology, syntheses of
(R)-rolipram and (R)-baclofen were undertaken from the
common scaffold 2 (Scheme 1). Rolipram is used as an anti-
inflammatory agent and antidepressant, while baclofen is widely
employed as an antispasmodic agent. The synthesis of optically
Figure 1. P,N-Ferrocene-based SIOCPhox ligands.
Scheme 1. Synthesis of (R)-Baclofen and (R)-Rolipram using
Allylic Alkylated Products 2
(entry 12, Table 1), though it needed more time (entries 12 vs
8, Table 1). The effect of base on the reaction with the ligand
(S,Rphos,R)-L6 uncovered that DABCO is the best among the
bases we screened such as DIPEA, TEA, Cs2CO3, and DMAP
(see the Supporting Information). The influence of substituent
on the oxazoline ring in ligands (S,Rphos,R)-L7−9 was also
studied. The Pd catalysts derived from them showed lower
catalytic activity in the reaction (entries 13−15 vs entry 12,
Table 1).
The substrate generality of this Pd-catalyzed AAA reaction
with nitromethane was examined under the optimized reaction
conditions, and the results are compiled in Table 2. In general,
the reaction proceeded smoothly to afford branched allylated
products in high regio- and enantioselectivities with high yields.
Both electron-donating and -withdrawing groups in the para
position of the aryl ring exerted little influence on
enantioselectivity (entries 2−5, Table 2). However, a strongly
electron withdrawing group, such as a p-NO2 group, resulted in
a complex reaction (not shown in the table). The reaction also
occurred with excellent enantioselectivity for allyl reagents 1
with meta substituents and an o-bromo group on the aryl ring
(entries 6−9, Table 2). The allyl 1 with 1-naphthyl also gave
excellent yields with high regio- and enantioselectivities (entry
10, Table 2). The employment of allyl 1 containing p-methoxy
B
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active rolipram7 and baclofen7f−h,j,k,8 on the basis of asymmetric
catalysis has been accomplished by many groups. Among them,
Michael addition reactions using chiral organometallic or
organocatalytic catalysts are the most common approaches to
constructing the stereocenter of these two drugs. Feng and Lin
approached (R)-baclofen and (R)-rolipram by a two-step
elaboration of products derived from a rhodium/diene-
catalyzed asymmetric addition of arylboronic acids to α,β-
unsaturated γ-lactams.7j Wang completed a three-step synthesis
of chiral baclofen via an enantioselective conjugate addition
reaction of nitromethane with α,β-unsaturated aldehydes.8e
We began the synthesis of (R)-baclofen and (R)-rolipram by
treatment of the alkylated products 2d,k with 9-BBN followed
by oxidation with H2O2/NaOH to afford the alcohols 4
(Scheme 1). Dess−Martin oxidation of alcohols 4 gave the
corresponding aldehydes 5. The aldehyde 5d was subjected to a
Pinnick oxidation to provide the acid 6d in 84% yield, which
was facilely converted to (R)-baclofen according to the
reported procedure in 69% yield.9 The aldehyde 5k was
subjected to an one-pot Pinnick oxidation and ester formation
to furnish ester 6k in 66% overall yield. Further elaboration of
the ester 6k with NaBH4/C2H5OH successfully gave the
desired (R)-rolipram in 85% yield. These results also
demonstrate the R configuration of the allylate product 2k.
petroleum ether and EtOAc as eluent to give product 2 (the products
2 and 3 could be separated by flash chromatography).
(R)-(1-Nitrobut-3-en-2-yl)benzene (2a):5 colorless oil; 81% yield;
20
97% ee. [α]D = −6.1° (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 4.21 (q, J = 8 Hz, 1H), 4.61−4.72 (m, 2H), 5.18 (d, J = 17.2
Hz, 1H), 5.23 (d, J = 10.4 Hz, 1H), 5.99 (ddd, J = 7.2, 10.2, 17.2 Hz,
1H), 7.21−7.39 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 47.7, 79.4,
117.8, 127.5, 127.8, 129.1, 135.7, 138.0; IR (film) 701, 1018, 1087,
1260, 1553, 2963 cm−1; MS (EI) 77 (18), 91 (53), 116 (20), 128 (19),
130 (100), 177 (M+, 0.8); HRMS calcd for C10H11NO2 177.0790,
found 177.0792; chiral GC (CHIRALDEX B-DM column, 30 m ×
0.25 mm × 0.12 μm, carrier gas nitrogen; injector temperature 250 °C,
split ratio 30, constant column flow 1.0 mL/min, column temperature
120 °C (5 min), 120−170 °C (1.5 °C/min, 30 min), FID detector
temperature 250 °C) tR = 28.4 min (major), 28.9 min (minor), chiral
HPLC (Chiralcel OD-H, 0.46 cm × 250 mm, n-hexane/2-propanol =
90/10, flow rate 0.5 mL/min, UV 214 nm) tR = 19.8 min (major), 29.7
min (minor).
(R)-1-Methyl-4-(1-nitrobut-3-en-2-yl)benzene (2b): colorless oil;
20
1
88% yield; 97% ee; [α]D = −4.7° (c = 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ 2.32 (s, 3H), 4.16 (q, J = 8 Hz, 1H), 4.57−4.69 (m,
2H), 5.16 (dd, J = 0.8, 18 Hz, 1H), 5.20 (dd, J = 0.8, 10.8 Hz, 1H),
5.97 (ddd, J = 7.2, 10.2, 18 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.15 (d,
J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.0, 47.4, 79.5,
117.6, 127.4, 129.7, 135.0, 136.0, 137.5; IR (film) 814, 925, 1262,
1376, 1513, 1551, 1727, 2924 cm−1; MS (EI) 65 (6), 77 (8), 91 (19),
115 (29), 129 (100), 144 (87), 191 (M+, 2); HRMS calcd for
C11H13NO2 191.0946, found 191.0941; chiral GC (CHIRALDEX B-
DM column, 30 m × 0.25 mm × 0.12 μm, carrier gas nitrogen;
injector temperature 250 °C, split ratio 30, constant column flow 1.0
mL/min, column temperature 120 °C (5 min), 120−170 °C (1.0 °C/
min, 30 min), FID detector temperature 250 °C) tR = 40.3 min
(major), 41.1 min (minor).
CONCLUSION
■
We have successfully realized the Pd-catalyzed AAA reaction of
monosubstituted allyl substrates with nitromethane, which can
provide the corresponding products in high yields with
excellent regio- and enantioselectivities. The usefulness of the
protocol was demonstrated. Further studies on the extension of
the protocol to other nucleophiles and applications in organic
synthesis are in progress.
(R)-1-Methoxy-4-(1-nitrobut-3-en-2-yl)benzene (2c): colorless oil;
20
1
68% yield, 98% ee; [α]D = +6.1° (c = 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ 3.77 (s, 3H), 4.12−4.17 (m, 1H), 4.56−4.68 (m, 2H),
5.15 (dd, J = 0.8, 18 Hz, 1H), 5.20 (d, J = 10.4 Hz, 1H), 5.95 (ddd, J =
7.2, 10.2, 18 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 47.0, 55.3, 79.6, 114.4, 117.4,
128.6, 129.9, 136.1, 159.1; IR (film) 798, 1030, 1258, 1377, 1512,
1551, 2960 cm−1; MS (EI) 65 (9), 77 (18), 91 (42), 115 (28), 129
(30), 147 (32), 160 (100), 207 (M+, 18); HRMS calcd for C11H13NO3
207.0895, found 207.0898; chiral GC (CHIRALDEX B-DM column,
30 m × 0.25 mm × 0.12 μm, carrier gas nitrogen; injector temperature
250 °C, split ratio 30, constant column flow 1.0 mL/min, column
temperature 120 °C (5 min), 120−170 °C (1.0 °C/min, 30 min), FID
detector temperature 250 °C): tR = 55.7 min (major), 56.6 min
(minor).
EXPERIMENTAL SECTION
■
General Methods. The reactions were carried out in flame-dried
glassware under a dry argon atmosphere. All solvents were purified and
dried by using standard methods prior to use. Commercially available
reagents were used without further purification. 1H NMR spectra were
recorded on a NMR instrument operated at 400 MHz. Chemical shifts
are reported in ppm from tetramethylsilane with the solvent resonance
as the internal standard (CDCl3: δ 7.26 ppm). Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, br = broad, m = multiplet or unresolved), coupling
constants (Hz), and integration. 13C NMR spectra were recorded on a
NMR instrument operated at 100 MHz with complete proton
decoupling. Chemical shifts are reported in ppm from tetramethylsi-
lane with the solvent resonance as the internal standard (CDCl3: δ
77.1 ppm). Infrared spectra were recorded from thin films of pure
samples. Mass and HRMS spectra were measured in EI or ESI mode,
and the mass analyzer of the HRMS was TOF. Thin-layer
chromatography was performed on precoated glass-backed plates
and visualized with UV light at 254 nm. Flash column chromatography
was performed on silica gel. Enantiomer ratios were determined by
chiral HPLC analysis in comparison with authentic racemic materials.
General Experimental Procedure for Table 2. In a flame-dried
Schlenk tube were added Pd2(dba)3·CHCl3 (5.2 mg, 0.005 mmol),
ligand (Sc,Rphos,Ra)-L6 (6.84 mg, 0.010 mmol), and freshly distilled
anhydrous THF (2.0 mL). The resulting mixture was stirred for 30
min. The methyl carbonate 1 (0.1 mmol) and DABCO (0.1 mmol)
were added subsequently, and then 0.5 mL of nitromethane was
added. The resulting reaction mixture was stirred at room temperature
overnight (TLC control). After the ratio of compounds 2 and 3 was
determined by GC, the volatiles were removed in vacuo. The resulting
residue was purified by flash chromatography (FC) on silica gel with
(R)-1-Chloro-4-(1-nitrobut-3-en-2-yl)benzene (2d): colorless oil;
20
1
83% yield, 96% ee; [α]D = −6.5° (c = 1.5, CHCl3); H NMR (400
MHz, CDCl3) δ 4.20 (q, J = 8 Hz, 1H), 4.58−4.70 (m, 2H), 5.17 (dd,
J = 0.8, 17.2 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 5.94 (ddd, J = 7.2,
10.2, 17.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 47.0, 79.1, 118.1, 129.0, 129.2, 133.7,
135.3, 136.5; IR (film) 797, 1015, 1092, 1260, 1492, 1553, 2962 cm−1;
MS (EI) 77 (6), 103 (5), 115 (19), 129 (100), 164 (20), 211 (M+, 1);
HRMS calcd for C10H10NO2Cl 211.0400, found 211.0399; chiral GC
(CHIRALDEX B-DM column, 30 m × 0.25 mm × 0.12 μm, carrier
gas nitrogen; injector temperature 250 °C, split ratio 30, constant
column flow 1.0 mL/min, column temperature 120 °C (5 min), 120−
140 °C (1.0 °C/min, 5 min), 140−165 °C (0.8 °C/min, 5 min), 165−
170 °C (1.0 °C/min, 20 min)): tR =60.3 min (major), 61.6 min
(minor).
(R)-1-Fluoro-4-(1-nitrobut-3-en-2-yl)benzene (2e): colorless oil;
20
1
88% yield, 96% ee; [α]D = +6.0° (c = 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ 4.21 (m, 1H), 4.57−4.70 (m, 2H), 5.17 (dd, J = 0.8,
17.2 Hz, 1H), 5.23 (dd, J = 0.8, 10.4 Hz, 1H), 5.96 (ddd, J = 7.2, 10.2,
17.2 Hz, 1H), 7.02−7.06 (m, 2H), 7.18−7.21 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 46.9, 79.3, 116.0 (d, J = 20 Hz), 117.8, 129.2 (d,
J = 9 Hz), 133.7, 135.6 (d, J = 3 Hz), 161.5 (d, J = 251.5 Hz); 19F
C
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NMR (376 MHz) −114.4 (m); IR (film) 775, 806, 928, 1159, 1224,
1508, 1550, 2925 cm−1; MS (EI) 75 (7), 109 (52), 129 (12), 133 (38),
148 (100), 195 (M+, 1); HRMS calcd for C10H10NO2F 195.0696,
found 195.0694; chiral GC (CHIRALDEX B-DM column, 30 m ×
0.25 mm × 0.12 μm, carrier gas nitrogen; injector temperature 250 °C,
split ratio 30, constant column flow 1.0 mL/min, column temperature
120 °C (5 min), 120−140 °C (1.0 °C/min, 5 min), 140−165 °C (0.8
°C/min, 5 min), 165−170 °C (1.0 °C/min, 20 min)): tR = 37.1 min
(major), 38.2 min (minor).
(R)-1-(1-Nitrobut-3-en-2-yl)naphthalene (2j): colorless oil; 91%
yield, 93% ee; [α]D20 = +29.6° (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 4.76−4.78 (m, 2H), 5.13 (q, J = 8 Hz, 1H), 5.27 (d, J = 17.2
Hz, 1H), 5.30 (d, J = 10.4 Hz, 1H), 6.15 (ddd, J = 7.2, 10.2, 17.4 Hz,
1H), 7.37−39 (m, 1H), 7.45−7.49 (m, 1H), 7.53−7.55 (m, 1H),
7.59−7.63 (m, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H),
8.18 (d, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 42.5, 78.6,
118.1, 122.3, 124.4, 125.2, 125.9, 126.7,128.3, 129.1, 130.8, 133.8,
134.0, 135.4; IR (film) 775, 799, 926, 1375, 1549, 2917, 3047 cm−1;
MS (EI) 82 (10), 115 (15), 152 (22), 165 (100), 181 (29), 227 (M+,
35); HRMS calcd for C14H13NO2 227.0946, found 227.0948; chiral
HPLC (Chiralcel OJ, 0.46 cm × 250 mm, n-hexane/2-propanol 70/30,
flow rate 0.5 mL/min, UV 214 nm): tR = 27.3 min (minor), 29.9 min
(major).
(R)-1-Chloro-3-(1-nitrobut-3-en-2-yl)benzene (2f): colorless oil;
20
1
80% yield, 95% ee; [α]D = −2.3° (c = 0.9, CHCl3); H NMR (400
MHz, CDCl3) δ 4.21 (q, J = 8 Hz, 1H), 4.59−4.71 (m, 2H), 5.20 (d, J
= 17.2 Hz, 1H), 5.26 (d, J = 10.4 Hz, 1H), 5.95 (ddd, J = 7.2, 10.2,
17.2 Hz, 1H), 7.11−7.12 (m, 1H), 7.22−7.31 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 47.3, 79.0, 118.4, 125.8, 127.8, 128.1, 130.3,
134.9, 135.0, 140.0; IR (film) 703, 785, 929, 1376, 1550, 2923 cm−1;
MS (EI) 77 (5), 89 (4), 115 (16), 125 (13), 129 (100), 164 (15), 211
(M+, 0.4); HRMS calcd for C10H10NO2Cl 211.0400, found 211.0399;
chiral GC (CHIRALDEX B-DM column, 30 m × 0.25 mm × 0.12 μm,
carrier gas nitrogen; injector temperature 250 °C, split ratio 30,
constant column flow 1.0 mL/min, column temperature 120 °C (5
min), 120−140 °C (1.0 °C/min, 5 min), 140−165 °C (0.8 °C/min, 5
min), 165−170 °C (1.0 °C/min, 20 min)): tR = 54.0 min (major),
55.7 min (minor).
(R)-2-(Cyclopentyloxy)-1-methoxy-4-(1-nitrobut-3-en-2-yl)-
20
benzene (2k): white solid; mp 56−57 °C; 87% yield, 97% ee; [α]D
=
1
+12.8° (c = 1.3, CHCl3); H NMR (400 MHz, CDCl3) δ 1.60−1.63
(m, 2H), 1.83−1.94 (m, 6H), 3.82 (s, 3H), 4.13 (q, J = 8 Hz, 1H),
4.56−4.68 (m, 2H), 4.75−4.77 (m, 1H), 5.16 (d, J = 17.2 Hz, 1H),
5.21 (d, J = 10.4 Hz, 1H), 5.96 (ddd, J = 7.2, 10.2, 17.4 Hz, 1H), 6.72−
6.75 (m, 2H), 6.82−6.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
24.0, 32.72, 32.75, 47.2, 56.0, 79.6, 80.5, 112.2, 114.5, 117.4, 119.5,
130.2, 136.0, 147.9, 149.6; IR (film) 939, 980, 1017, 1138, 1231, 1259,
1516, 1548, 1589, 2940 cm−1; MS (EI) 41 (21), 91 (14), 103 (17),
117 (32), 144 (36), 161 (24), 176 (100), 223 (11), 291(M+, 18);
HRMS calcd for C16H21NO4 291.1471, found 291.1468; chiral HPLC
(Chiralcel OJ-H, 0.46 cm × 250 mm, hexane/2-propanol 95/5, flow
rate 0.5 mL/min, UV 214 nm): tR = 49.2 min (major), 54.0 min
(minor).
(R)-1-Methoxy-3-(1-nitrobut-3-en-2-yl)benzene (2g): colorless oil;
20
1
92% yield, 96% ee; [α]D = −2.7° (c = 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ 3.81 (s, 3H), 4.18 (q, J = 8 Hz, 1H), 4.60−4.70 (m,
2H), 5.19 (dd, J = 0.8, 18 Hz, 1H), 5.22 (dd, J = 0.8, 10 Hz, 1H), 5.98
(ddd, J = 7.2, 10.2, 18 Hz, 1H), 6.76 (m, 1H), 6.81−6.84 (m, 2H),
7.26−7.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 47.7, 55.2, 79.4,
112.8, 113.6, 117.8, 119.7, 130.1, 135.6, 139.6, 160.0; IR (film) 699,
781, 1039, 1261, 1552, 2838, 2923 cm−1; MS (EI) 65 (9), 77 (15), 91
(40), 115 (36), 129 (60), 145 (35), 160 (100), 207(M+, 55); HRMS
calcd for C11H13NO3 207.0895, found 207.0900; chiral GC
(CHIRALDEX B-DM column, 30 m × 0.25 mm × 0.12 μm, carrier
gas nitrogen; injector temperature 250 °C, split ratio 30, constant
column flow 1.0 mL/min, column temperature 120 °C (5 min), 120−
170 °C (1.0 °C/min, 30 min), FID detector temperature 250 °C): tR =
51.9 min (major), 52.5 min (minor).
(R)-3-(4-Chlorophenyl)-4-nitrobutan-1-ol (4d).10 To a solution
of 2d (21.1 mg, 0.1 mmol) in THF (1 mL) at room temperature was
added 9-borabicyclo[3.3.1]nonane (9-BBN; 0.5 M solution in toluene,
0.4 mmol). The resulting reaction mixture was stirred for 20 h. EtOH
(182 μL) was added to quench the excess 9-BBN, and then 6 N
NaOH (62 μL) and 30% H2O2 (122 μL) was added dropwise. The
resulting mixture was warmed to 50 °C and stirred for another 1 h.
Then 5 mL of water was added. After being extracted with EtOAc, the
organic phase was washed sequentially with H2O, saturated aqueous
Na2SO3, and brine. The organic phase was then dried with MgSO4 and
concentrated in vacuo. Purification of the residual oil by chromatog-
(R)-5-(1-Nitrobut-3-en-2-yl)benzo[d][1,3]dioxole (2h): colorless
1
raphy gave 4d (colorless oil; 17.1 mg, 73%): H NMR (400 MHz,
20
1
oil; 80% yield, 97% ee; [α]D = +12.8° (c = 1.0, CHCl3); H NMR
(400 MHz, CDCl3) δ 4.13 (q, J = 8 Hz, 1H), 4.54−4.67 (m, 2H), 5.16
(dd, J = 0.8, 17.2 Hz, 1H), 5.21 (dd, J = 0.8, 10 Hz, 1H), 5.89−5.98
(m, 3H), 6.66−6.70 (m, 2H), 6.76−6.78 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 47.3, 79.5, 101.2, 107.8, 108.6, 117.4, 120.6, 131.7,
135.8, 147.0, 148.1; IR (film) 809, 927, 1035, 1235, 1487, 1548, 2898,
3670 cm−1; MS (EI) 79 (46), 91 (53), 103 (44), 115 (90), 129 (74),
144 (51), 174 (100), 221 (M+, 49); HRMS calcd for C11H11NO4
221.0688, found 221.0685; chiral GC (CHIRALDEX B-DM column,
30 m × 0.25 mm × 0.12 μm, carrier gas nitrogen; injector temperature
250 °C, split ratio 30, constant column flow 1.0 mL/min, column
temperature 120 °C (5 min), 120−170 °C (1.0 °C/min, 30 min), FID
detector temperature 250 °C): tR = 70.0 min (major), 71.7 min
(minor).
CDCl3) δ 1.65 (br, 1H), 1.85−1.89 (m, 1H), 1.91−1.96 (m, 1H),
3.44−3.47 (m, 1H), 3.60−3.65 (m, 1H), 3.69−3.73 (m, 1H), 4.55−
4.69 (m, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 35.5, 40.4, 59.6, 80.3, 128.9, 129.2, 133.6,
137.4; IR (film) 822, 1013, 1042, 1091, 1260, 1378, 1492, 1547, 1901,
2925 cm−1; MS (ESI) 228 (M − H); HRMS (ESI) calcd for
C10H11ClNO3 (M − H) 228.0433, found 228.0435.
(R)-3-(3-(Cyclopentyloxy)-4-methoxyphenyl)-4-nitrobutan-
1-ol (4k). The experimental procedure was same as that for product
1
4d: white solid; mp 72−73 °C; 25 mg, 67% yield; H NMR (400 M
Hz, CDCl3) δ 1.56−1.65 (m, 2H), 1.78−1.96 (m, 8H), 3.49−3.54 (m,
1H), 3.60−3.65 (m, 1H), 3.82 (s, 3H), 4.55−4.63 (m, 2H), 4.75−4.77
(m, 1H), 6.71−6.75 (m, 2H), 6.81−6.83 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 23.9, 32.7, 35.6, 40.7, 56.0, 59.9, 80.5, 80.3, 112.3,
114.5, 119.5, 131.0, 147.8, 149.5; IR (film) 649, 807, 1047, 1137, 1256,
1511, 1590, 2854, 2926, 3542 cm−1; MS (ESI) 309 (M+); HRMS calcd
for C16H23NO5 309.1576, found 309.1579.
(R)-1-Bromo-2-(1-nitrobut-3-en-2-yl)benzene (2i): colorless oil;
89% yield, 90% ee; [α]D20 = +13.8° (c = 1.0, CHCl3); H NMR (400
1
MHz, CDCl3) δ 4.62−4.72 (m, 2H), 4.75−4.79 (m, 1H), 5.24 (dd, J =
0.8, 17.2 Hz, 1H), 5.30 (dd, J = 0.8, 11.6 Hz, 1H), 5.99 (ddd, J = 7.2,
11.6, 17.2 Hz, 1H), 7.14−7.18 (m, 1H), 7.22−7.26 (m, 1H), 7.30−
7.34 (m, 1H), 7.60−7.62 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
46.1, 77.7, 118.7, 124.5, 128.0, 128.5, 129.2, 133.7, 134.3, 137.1; IR
(film) 794, 1017, 1082, 1259, 1553, 2961 cm−1; MS (EI) 51 (5), 77
(7), 115 (21), 129 (100), 169 (5), 208 (7), 255 (M+, 2); HRMS calcd
for C10H10BrNO2: 254.9895, found 254.9896; chiral GC (CHIR-
ALDEX B-DM column, 30 m × 0.25 mm × 0.12 μm, carrier gas
nitrogen; injector temperature 250 °C, split ratio 30, constant column
flow 1.0 mL/min, column temperature 120 °C (5 min), 120−170 °C
(1.0 °C/min, 30 min), FID detector temperature 250 °C): tR = 51.7
min (minor), 52.1 min (major).
(R)-3-(3-(Cyclopentyloxy)-4-methoxyphenyl)-4-nitrobutanal
(5k). To a solution of 4k (43.2 mg, 0.14 mmol) in dichloromethane (3
mL) at room temperature was added Dess−Martin periodinane (66.1
mg, 0.16 mmol). The resulting mixture was stirred for 0.5 h before the
reaction was quenched with saturated aqueous Na2S2O3 (0.5 mL) and
NaHCO3 (0.5 mL). The aqueous phase was extracted with Et2O. The
combined organic phase was dried with MgSO4 and concentrated in
1
vacuo to afford 5k as a liquid (30.5 mg, 71%): H NMR (400 MHz,
CDCl3) δ 1.59−1.64 (m, 2H), 1.81−1.94 (m, 6H), 2.91 (d, J = 7.2 Hz,
2H), 3.81 (s, 3H), 3.97−4.01 (q, J = 8 Hz, 1H), 4.55−4.67 (m, 2H),
4.74−4.77 (m, 1H), 6.73−6.75 (m, 2H), 6.80−6.82 (m, 1H), 9.69 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 23.9, 32.69, 32.72, 46.5, 56.0,
D
dx.doi.org/10.1021/jo301506p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
79.6, 80.6, 112.3, 114.5, 119.2, 130.3, 147.9, 149.8, 199.0; IR (film)
1014, 1139, 1236, 1257, 1514, 1550, 1732, 2927 cm−1; MS (EI) 55
(12), 97 (13), 114 (100), 164 (10), 192 (8), 239 (3), 307 (M+, 3);
HRMS calcd for C16H21NO5 307.1420, found 307.1417.
80.6, 112.2, 113.8, 118.8, 134.5, 147.9, 149.2, 177.6; MS (EI) 41 (42),
75 (27), 114 (94), 150 (100), 207 (56), 222 (6), 275 (M+, 20);
20
HRMS calcd for C16H21NO3 275.1521, found 275.1520; [α]D
=
−24.6° (c = 0.8, MeOH).
(R)-3-(4-Chlorophenyl)-4-nitrobutanoic Acid (6d).11 To the
crude product 5d (34.9 mg, 0.15 mmol), which was obtained from
compound 4d by the same procedure as that for product 5k, was
added successively NaH2PO4·2H2O (46.8 mg, 0.3 mmol), 2-methyl-2-
butene (0.4 mL), t-BuOH (1.2 mL), and H2O (0.4 mL). To the
resulting mixture was added NaClO2 (40.5 mg, 0.45 mmol) at 0 °C.
After the reaction mixture was stirred for 2 h, the reaction was
quenched by the addition of saturated aqueous NH4Cl (0.5 mL) and
the resulting mixture was stirred for another 10 min. After the solution
was diluted with EtOAc (2 mL), the aqueous phase was extracted with
EtOAc (2 mL). The combined organic phase was dried with
anhydrous magnesium sulfate. The organic layer was filtered through
Celite and concentrated in vacuo. The residue was purified by silica gel
to afford 6d (31.7 mg) in 67% yield (for two steps starting from
ASSOCIATED CONTENT
* Supporting Information
Tables giving additional reaction details and figures giving
spectral data of compounds 2a−k, 4−6, (R)-baclofen hydro-
chloride, and (R)-rolipram. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: xlhou@sioc.ac.cn
Notes
■
1
compound 4d): H NMR (400 MHz, CDCl3) δ 2.73−2.85 (m, 2H),
The authors declare no competing financial interest.
3.93−3.99 (m, 1H), 4.66 (dd, J = 8.4, 12 Hz, 2H), 6.05−6.27 (br, 1H),
7.17 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 37.1, 39.2, 79.0, 128.7, 129.3, 134.0, 136.4, 175.6; MS
(ESI) 242 (M − H)−; HRMS (ESI) calcd for C10H9ClNO4 242.0226,
found 242.0224.
(R)-Methyl 3-(3-(Cyclopentyloxy)-4-methoxyphenyl)-4-nitro-
butanoate (6k). Compound 5k (0.1 mmol) was oxidized to the
corresponding acid by the same procedure as that for compound 5d.
The resulting crude acid was dissolved in MeOH (3 mL), to which was
added 4-dimethylaminopyridine (cat.) and dicyclohexylcarbodiimide
(24.7 mg) at 0 °C. The resulting reaction mixture was stirred at room
temperature until the disappearance of acid (TLC control). The
reaction mixture was concentrated in vacuo. The residue was purified
by silica gel to afford 6k (21.6 mg, 66%): white solid; mp 103−104 °C;
1H NMR (400 MHz, CDCl3) δ 1.67−1.71 (m, 2H), 1.84−1.92 (m,
6H), 2.74 (d, J = 7.2 Hz, 2H), 3.64 (s, 3H), 3.82 (s, 3H), 3.89−3.92
(m, 1H), 4.58−4.63 (m, 1H), 4.67−4.76 (m, 2H), 6.72−6.82 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 24.0, 32.71, 32.74, 37.7, 39.8, 51.9,
55.9, 79.6, 80.5, 112.2, 114.3, 119.1, 130.5, 147.8, 149.7, 171.1; IR
(film) 646, 808, 1140, 1165, 1257, 1514, 1538, 1693, 1730, 2852, 2927
cm−1; MS (EI) 41 (17), 131 (20), 164 (17), 191 (12), 222 (17), 238
(5), 269 (3), 337 (10); HRMS calcd for C17H23NO6 337.1525, found
337.1522.
ACKNOWLEDGMENTS
■
This work was financially supported by the Major Basic
Research Development Program (2010CB833300), National
Natural Science Foundation of China (21121062, 21002113,
21032007), the External Cooperation Program of Chinese
Academy of Sciences (GJHZ200816), the Technology
Commission of Shanghai Municipality, and the Croucher
Foundation of Hong Kong.
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(R)-Baclofen Hydrochloride.9 A mixture of 6d (40 mg, 0.16
mmol), MeOH (5 mL), and Ra−Ni (50% water content, 111 mg) was
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under reduced pressure to give (R)-baclofen hydrochloride (28 mg,
69%): 1H NMR (400 MHz, D2O) δ 2.76 (dd, J = 8.8, 16 Hz, 1H), 2.88
(dd, J = 5.6, 16 Hz, 1H), 3.27 (t, J = 12.4 Hz, 1H), 3.39−45 (m, 2H),
7.36−7.47 (m, 4H); 13C NMR (100 MHz, D2O) δ 38.1, 39.3, 43.6,
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20
[M + H]+, 216.0 [M + 2]+; [α]D = −1.8° (c = 0.28, H2O).
(R)-Rolipram.7i To a stirred solution of 6k (20.2 mg, 0.06 mmol)
and NiCl2·6H2O (23.7 mg, 0.1 mmol) in EtOH (2 mL) was added
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for 2 h before being quenched with saturated aqueous NH4Cl (0.5
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1
was purified by silica gel to afford (R)-rolipram (14.4 mg, 85%): H
Synlett 1999, 1775. (b) Barluenga, J.; Fernan
́
dez-Rodríguez Lic., M. A.;
NMR (400 MHz, CDCl3) δ 1.58−1.65 (m, 2H), 1.82−1.91 (m, 6H),
2.48 (dd, J = 8.8, 16.8 Hz, 1H), 2.72 (dd, J = 8.8, 16.8 Hz, 1H), 3.36−
3.40 (m, 1H), 3.61−3.65 (m, 1H), 3.73−3.78 (m, 1H), 3.83 (s, 3H),
4.75−4.79 (m, 1H), 6.03 (br, 1H), 6.76−6.79 (m, 2H), 6.82−6.84 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 24.0, 32.8, 37.9, 39.9, 49.7, 56.1,
Aguilar, E.; Fernandez-Marí, F.; Salinas, A.; Olano, B. Chem. Eur. J.
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E
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dx.doi.org/10.1021/jo301506p | J. Org. Chem. XXXX, XXX, XXX−XXX