Heck-Matsuda reaction for allylic nitro compounds: A short asymmetric synthesis of an FTY720 derivative

Article abstract of DOI:10.1002/ejoc.201101703

The Heck-Matsuda reaction for allylic nitro compounds effectively afforded cinnamyl nitro compounds in good yields. Aryldiazonium salts that have an electron-donating substituent underwent a smooth reaction in the presence of Pd₂dba₃

Full text of DOI:10.1002/ejoc.201101703

FULL PAPER
DOI: 10.1002/ejoc.201101703
Heck–Matsuda Reaction for Allylic Nitro Compounds: A Short Asymmetric
Synthesis of an FTY720 Derivative
Toshiki Nakano,[a] Mizuki Miyahara,[b] Toshiyuki Itoh,*[b] and Akio Kamimura*[a]
Keywords: Synthetic methods / C–C coupling / Allylic compounds / Nitro compounds / Palladium
The Heck–Matsuda reaction for allylic nitro compounds ef-
fectively afforded cinnamyl nitro compounds in good yields.
Aryldiazonium salts that have an electron-donating substitu-
ent underwent a smooth reaction in the presence of Pd2dba3.
A palladium complex that coordinated with an electron-rich
ligand was necessary for the reaction to progress with elec-
tron-deficient aryldiazonium salts. An optically active allylic
nitro compound underwent reaction without the loss of op-
tical purity at the stereogenic center. A short synthesis of an
optically active FTY720 derivative was achieved by this
method.
a chiral FTY720 analogue employing the Heck–Matsuda
reaction on a chiral allylic nitro compound.
Introduction
Allylic nitro compounds are valuable synthetic building
blocks, because they are readily prepared and can be con-
verted into various compounds in a short number of steps. Results and Discussion
The nitro group frequently serves as a precursor to a nitro-
Allylic nitro compounds 1 were prepared from nitro-
gen-based functional group, such as an amine.[1] A typical
reaction for allylic nitro compounds is the Tsuji–Trost-type
substitution reaction,[2,3] in which the nitro group is substi-
tuted by various nucleophiles in the presence of palladium-
complex catalysts.[4] In this case, the allylic carbon attached
to the nitro group is sp3 hybridized with a chiral configura-
tion, but the chirality is lost during this SN2Ј-type reaction.
In contrast, if a Heck-type reaction is achieved for the all-
ylic nitro compound,[5] the stereochemistry at the allylic
asymmetric center is maintained as elaboration occurs with
a carbon source at the terminal vinyl group. To the best of
our knowledge, there is no report for employing the Heck
reaction on allylic nitro compounds.
alkene and formaldehyde in the presence of DABCO (1,4-
diazabicyclo[2.2.2]octane).[9] The hydroxy group was pro-
tected by treatment with acetic anhydride. Exposing 1a to
various conditions for the Heck reaction resulted in the de-
sired carbon bond elaboration (see Scheme 1), and these re-
sults are summarized in Table 1.
Scheme 1.
FTY720, 2-amino[2-(4-octylphenyl)ethyl]-1,3-propane-
Initially, we examined 1a under classical conditions for
diol is a potent immunosuppressive agent used therapeuti- the Heck reaction. However, the reaction did not progress,
cally to treat autoimmune diseases such as multiple sclero- and the desired Heck adduct 2a was not observed in the
sis.[6] Chiral analogues of FTY720 are of interest for prob- reaction mixture (Table 1, Entry 1). Changing the additive
ing biological activity that is dependent on the stereogenic and the solvent did not give the desirable results (Table 1,
center.[7] So far, several syntheses of these analogues have Entries 2 and 3), and using iodobenzene also failed to give
been reported, however, they use long preparation se- 2a (Table 1, Entries 4 and 5). The benzenediazonium salt is
quences.[8] In this paper, we report a three-step synthesis for a strong aryl donor and is often used for palladium chemis-
try and in coupling reactions.[5h,10] Therefore, we examined
various conditions for the Heck–Matsuda reaction of 1a
[a] Department of Applied Molecular Bioscience,
with the benzenediazonium salt. The treatment of 1a with
PhN2BF4 in the presence of 5 mol-% Pd(OAc)2 failed to
form 2a (Table 1, Entry 6). The use of Xphos as an additive
gave limited amounts of 2a in only 10% yield (Table 1, En-
try 7). PdCl2(dppf)2 was also ineffective for providing a
good yield of the adduct (Table 1, Entry 8). Recently, Cor-
reia reported that using Pd2dba3 (3a) as the catalyst and
Graduate School of Medicine, Yamaguchi University,
Ube 755-8611, Japan
Fax: +81-836-85-9201
E-mail: ak10@yamaguchi-u.ac.jp
[b] Department of Chemistry and Biotechnology,
Graduate School of Engineering, Tottori University,
Tottori 680-8522, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101703.
Eur. J. Org. Chem. 2012, 2161–2166
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Nakano, M. Miyahara, T. Itoh, A. Kamimura
FULL PAPER
Table 1. Heck reaction of compound 1a.
Table 2. Heck–Matsuda reactions of 1a with various aryldiazonium
salts.
Entry Catalyst[a]
X
Conditions
% Yield
2a[b]
Entry Ar
Time [h]
Temp.
[°C]
% Yield
2[a]
1
Pd(OAc)2 (2)
dppp (31)
Pd(OAc)2 (5)
dppf (5)
Pd(OAc)2 (5)
dppf (5)
Pd(OAc)2 (5)
dppf (5)
Br
Br
Br
I
toluene/Et3N
110 °C/12 h
toluene/Et3N
110 °C/12 h
DMF/Et3N
110 °C/12 h
toluene/Et3N
110 °C/12 h
DMF/Et3N
90 °C/14 h
0
1
2
3
4
5
6
7
8
p-MeC6H4
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3a
3a
3c
3d
3e
3d
24
48
40
240
32
96
124
60
72
144
48
46
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
70
r.t.–50
r.t.
r.t.
60
2b, 89
2c, 100
2d, 95
2e, 0
2f, 71
2g, 0
2h, 40
2i, 77
2i, 0
2i, 84
2j, 35
2j, 10
2j, 62
2j, 73
2j, 20
2k, 0
2
0
p-tBuC6H4
p-MeOC6H4
p-Me2NC6H4
3,4-MeO2C6H3
m-MeOC6H4
m-MeC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-IC6H4
p-IC6H4
p-IC6H4
p-IC6H4
p-IC6H4
3
0
4
0
5
Pd(OAc)2 (5)
PPh3 (10)
I
0
9
6
Pd(OAc)2 (5)
N2BF4 CH3CN/NaOAc
r.t./6 d
trace
10
0
10
11
12
13
14
15
16
7
Pd(OAc)2 (6)
Xphos (10)
N2BF4 CH3CN/NaOAc
r.t./7 d
144
60
96
r.t.
r.t.
r.t.
r.t.
8
PdCl2(dppf)2 (5) N2BF4 CH3CN/NaOAc
r.t./6 d
Pd2dba3 (3a, 5) N2BF4 MeOH/NaOAc
r.t./30 h
9
51
p-CF3C6H4
73
(37)[c]
0
[a] Isolated yield.
10
11
Pd2dba3 (3a, 5) N2BF4 CH3CN/Et3N
r.t./30 h
Pd2dba3 (3a, 5) N2BF4 CH3CN/NaOAc
r.t./30 h
90
tron-donating groups at the para position underwent
smooth Heck–Matsuda reactions in the presence of the cat-
alyst 3a to give the corresponding adducts 2 in good yields
(Table 2, Entries 2, 3, and 5), but the p-(dimethylamino)
benzenediazonium salt was the exception and provided an
unsatisfactory result (Table 2, Entry 4). In contrast, the re-
actions with meta-substituted aryldiazonium salts occurred
at slow rates and afforded poor yields of 2 (Table 2, En-
tries 6 and 7). The presence of an electron-withdrawing
group at the para position slowed the reaction rate and de-
creased the yields of 2. For example, the treatment of the
p-chlorobenzenediazonium salt in the presence of Pd2dba3
(3a) resulted in the formation of 2i in 77% yield (Table 2,
Entry 8), however, at room temperature, the rate for this
reaction was considerably slow. The ligand in the palladium
complex was important for improving the yield of 2. Al-
though reaction progress failed to occur with complex 3b,
palladium complex 3c catalyzed the reaction smoothly at
room temperature and give 2i in 84% yield (Table 2, En-
tries 9 and 10, respectively).[11] Similar results were ob-
served in the formation of 2j. The reaction catalyzed by 3a
afforded 2j in only 35% yield (Table 2, Entry 11), however,
by using palladium complex 3c, the yield of 2j improved to
62%, but the reaction required 144 h for completion. Cata-
lyst 3d, with two methoxy groups on each aryl ring, offered
the best results, and the yield of 2j increased to 73%
(Table 2, Entry 14). However, using complex 3e as the cata-
lyst did not improve the yield of 2j (Table 2, Entry 15).
Furthermore, the aryldiazonium salt substituted with a
strong electron-deficient group failed to give 2k (Table 2,
Entry 16), but gave the allylic substituted products 4 in 25%
(see Scheme 3).
[a] Equivalents are in parentheses. [b] Isolated yield. [c] Recovered
starting material.
benzonitrile as the solvent offered the best results for the
Heck–Matsuda reaction.[10a] Although they employed ben-
zonitrile in the reaction, we used CH3CN instead, because
it is readily removed by evaporation during the workup pro-
cess. The reaction performed in MeOH afforded 2a in 51%
yield along with the recovery of 1a in 37% (Table 1, En-
try 9). The use of Et3N is not recommended, because of the
immediate decomposition of PhN2BF4 (Table 1, Entry 10).
Finally, we found that the reaction proceeded smoothly in
the presence of Pd2dba3 (3a) in CH3CN, and the desired 2a
was obtained in 90% yield (Table 1, Entry 11).
With the optimized reaction conditions, we examined the
Heck–Matsuda reaction in which 1a was treated with vari-
ous aryldiazonium salts (Scheme 2). The results are summa-
rized in Table 2.
Next, we examined the use of chiral allylic nitro com-
pounds in the transformation (see Scheme 4). Optically
active nitro alcohol (R)-1b was obtained by using lipase for
Scheme 2.
For example, exposing the p-toluenediazonium salt to the the optical resolution of racemic 1a.[12] Thus, Cbz (carbo-
optimized conditions resulted in the formation of 2b in 89% benzyloxy) protection of (R)-1b (96%ee) was performed
yield (Table 2, Entry 1). The diazonium salts bearing elec- under standard conditions to give (R)-1c in 95% yield.
2162
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2161–2166

Heck–Matsuda Reaction for Allylic Nitro Compounds
a large scale in three steps by using nitromethane, acetalde-
hyde, and formalin. Because the optical resolution of 1 is
already established,[12] the Heck–Matsuda reaction for chi-
ral 1 provides a new and useful methodology for the prepa-
ration of compounds with a nitrogen-substituted chiral ter-
tiary alkyl functional group. Further application of the
present method for heterocyclic synthesis is currently in
progress.
Scheme 3.
Treatment of (R)-1c with benzenediazonium tetrafluo-
roborate under optimized conditions resulted in the forma-
tion of (R)-2l in 78% yield. The optical purity of (R)-2l was
determined by chiral HPLC analysis to be 96%ee. Thus,
the Heck–Matsuda reaction occurred with the complete re-
tention of configuration at the tertiary nitro C atom (see
Scheme 4).
Conclusions
We have successfully achieved the Heck–Matsuda reac-
tion with allylic nitro compounds, which were readily avail-
able by the condensation reaction of a nitroalkene and for-
malin. Benzenediazonium salts served as good aryl donors
for the reaction. The stereogenic center at the allylic nitro
group was well maintained during the reaction, and chiral
adducts were isolated in good yields. The reaction was effec-
tively applied to the short synthesis of a FTY720 derivative.
Experimental Section
1
General Comments: All H and 13C NMR spectroscopic data were
recorded with a JEOL delta-500 or lamda-500 (500 MHz for 1H
and 126 MHz for 13C) spectrometer. High resolution mass spectra
(HRMS) were recorded at the Integrated Center for Sciences,
Ehime University, Matsuyama, Japan. All of the reactions were
performed under a nitrogen atmosphere unless otherwise men-
tioned. The aryldiazonium salts were prepared by the reported
method.[14] The palladium complexes were prepared by the litera-
ture method.[15] CH3CN was dried with CaH2. Palladium com-
plexes 3 were prepared by the reported method.[11c] Compounds 1a
and 1b were prepared by the method reported in the literature.[9]
The optical resolution of 1b was performed by the reported
method.[12]
Scheme 4.
The Heck–Matsuda reaction was used for the synthesis
of the FTY720 derivative 5 (see Scheme 5). Compound 1c
(96%ee) was treated with p-heptyloxyphenyldiazonium salt
in the presence of 5 mol-% of complex 3a to give the desired
product, that is, optically active 2m in 63% yield. The nitro
group of 2m was readily reduced under hydrogenation con-
ditions catalyzed by Pd-C, resulting in the removal of the
Cbz group in a one-pot process, and the desired 5 was ob-
tained in 97% yield. The optical rotation of the synthetic
sample of 5 was –14.4°, which is in good agreement with
the reported data for (R)-5.[8a,8f] Thus, the absolute configu-
rations of 1b, 1c, 2l, 2m, and 5 were unambiguously deter-
mined to be R, which is reasonable in comparison to the
previous data regarding lipase optical resolutions.[13]
2-Methyl-2-nitrobut-3-en-1-yl Acetate (1a): 1H NMR (500 MHz,
CDCl3): δ = 6.13 (dd, J = 17.4, 10.9 Hz, 1 H), 5.46 (d, J = 10.9 Hz,
2 H), 5.46 (d, J = 17.3 Hz, 1 H), 4.57 (d, J = 11.9 Hz, 1 H), 4.40
(d, J = 12.0 Hz, 1 H), 2.07 (s, 3 H), 1.74 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 170.1, 133.8, 119.6, 89.3, 67.5, 20.6,
19.7 ppm. HRMS (ESI): calcd. for C7H12NO4 [M + H]+ 174.0766;
found 174.0766.
(R)-2-Methyl-2-nitrobut-3-en-1-ol (1b): The enantiomeric purity
was determined by HPLC analysis. HPLC [CHIRALPAK AD
(0.46 cmϫ25 cm) from Daicel Chemical Ind., Ltd.; hexane/iPrOH,
95:5; 0.5 mL/min]: tR (retention time) = 25.5 min [(S)-1b] and
30.0 min [(R)-1b] as 96%ee. [α]2D6 = –80.8 (c = 0.14, CDCl3). 1H
NMR (500 MHz, CDCl3): δ = 6.14 (dd, J = 17.5, 10.9 Hz, 1 H),
5.44 (d, J = 10.9 Hz, 1 H), 5.43 (d, J = 17.5 Hz, 2 H), 4.11 (dd, J
= 12.4, 6.5 Hz, 1 H), 3.82 (dd, J = 12.4, 6.9 Hz, 1 H), 2.17 (s, 1
H), 1.72 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 134.4,
119.0, 92.2, 67.6, 19.2 ppm. HRMS (ESI): calcd. for C5H10NO3 [M
+ H]+ 132.0661; found 132.0688.
Scheme 5.
(E)-2-Methyl-2-nitro-4-phenylbut-3-en-1-yl Acetate (2a): A solution
of 1a (186.0 mg, 1.074 mmol) in dry CH3CN (5 mL) was purged
with nitrogen, and NaOAc (266.0 mg, 3.243 mmol), Pd2dba3
(49.0 mg, 0.054 mmol), and PhN2BF4 (309.0 mg, 1.609 mmol) were
added. The resulting mixture was stirred at room temperature for
This method for the preparation of the FTY720 deriva-
tive provided a short and economical process in which only
two steps were necessary for the total synthesis. The allylic
nitro compound starting materials were easily produced on 24 h. PhN2BF4 (102 mg) was added, and the mixture was stirred
Eur. J. Org. Chem. 2012, 2161–2166
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T. Nakano, M. Miyahara, T. Itoh, A. Kamimura
FULL PAPER
for an additional 6 h. The reaction mixture was concentrated, and
the residue was subjected to flash chromatography (silica gel; hex-
stirred at room temperature for 12 h. 3,4-(MeO)2C6H3N2BF4
(285 mg) was added, and the mixture was stirred for an additional
ane/EtOAc, 12:1 then 10:1 then 6:1) to give 2a (242.0 mg, 90%) as 20 h. The reaction mixture was concentrated, and the residue was
a pale, reddish oil. 1H NMR (500 MHz, CDCl3): δ = 7.44–7.29 (m, subjected to flash chromatography (silica gel; hexane/EtOAc, 12:1
1
5 H), 6.75 (d, J = 16.3 Hz, 1 H), 6.42 (d, J = 16.2 Hz, 1 H), 4.68
then 10:1 then 6:1) to give 2f (125.0 mg, 71%) as a brown oil. H
(d, J = 11.9 Hz, 1 H), 4.49 (s, 1 H), 4.46 (s, 1 H), 2.09 (s, 3 H), NMR (500 MHz, CDCl3): δ = 6.97–6.90 (m, 2 H), 6.84 (d, J =
1.86 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.1, 135.0, 8.3 Hz, 1 H), 6.69 (d, J = 16.1 Hz, 1 H), 6.26 (d, J = 16.3 Hz, 1
134.20, 129.0, 128.8, 126.98, 126.97, 124.3, 89.3, 67.6, 20.5, H), 4.71 (d, J = 11.9 Hz, 1 H), 4.44 (d, J = 11.8 Hz, 1 H), 3.91 (s,
19.9 ppm. C13H15NO4 (249.27): calcd. C 62.64, H 6.07, N 5.62; 3 H), 3.89 (s, 3 H), 2.09 (s, 3 H), 1.85 (s, 3 H) ppm. 13C NMR
found C 62.28, H 6.09, N 5.58.
(126 MHz, CDCl3): δ = 170.2, 150.0, 149.2, 134.1, 127.9, 122.2,
120.7, 111.1, 109.1, 89.4, 67.7, 55.9, 20.5, 19.9 ppm. HRMS (ESI):
calcd. for C15H20NO6 [M + H]+ 310.1291; found 310.1310.
(E)-2-Methyl-2-nitro-4-(p-tolyl)but-3-en-1-yl Acetate (2b): A solu-
tion of 1a (226.0 mg, 1.305 mmol) in dry CH3CN (6 mL) was
purged with nitrogen, and NaOAc (323.0 mg, 3.938 mmol),
Pd2dba3 (61.0 mg, 0.067 mmol), and p-TolN2BF4 (539.0 mg,
2.616 mmol) were added. The resulting mixture was stirred at room
temperature for 24 h. The reaction mixture was concentrated, and
the residue was subjected to flash chromatography (silica gel; hex-
ane/EtOAc, 12:1 then 10:1 then 6:1) to give 2b (305.0 mg, 89%) as
a white solid; m.p. 42–43 °C. 1H NMR (500 MHz, CDCl3): δ =
7.30 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.73 (d, J =
16.3 Hz, 1 H), 6.37 (d, J = 16.2 Hz, 1 H), 4.69 (d, J = 11.9 Hz, 1
H), 4.46 (d, J = 12.0 Hz, 1 H), 2.34 (s, 3 H), 2.07 (s, 3 H), 1.84 (s,
3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.0, 139.0, 134.1,
132.1, 129.4, 126.9, 123.2, 89.3, 67.6, 21.1, 20.4, 19.8 ppm.
C14H17NO4 (263.29): calcd. C 63.87, H 6.51, N 5.32; found C
64.08, H 6.42, N 5.18.
(E)-2-Methyl-2-nitro-4-(m-tolyl)but-3-en-1-yl Acetate (2h): A solu-
tion of 1a (105.0 mg, 0.606 mmol) in dry CH3CN (3 mL) was
purged with nitrogen, and NaOAc (151.0 mg, 1.841 mmol),
Pd2dba3 (29.0 mg, 0.032 mmol), and m-TolN2BF4 (500.0 mg,
2.425 mmol) were added. The resulting mixture was stirred at room
temperature for 70 h. m-TolC6H4N2BF4 (125 mg) was added, and
the mixture was stirred for an additional 24 h. The reaction mixture
was concentrated, and the residue was subjected to flash
chromatography (silica gel; hexane/EtOAc, 12:1 then 10:1 then 6:1)
to give 2h (63.0 mg, 40%) as a pale, reddish oil. 1H NMR
(500 MHz, CDCl3): δ = 7.22 (m, 3 H), 7.13 (d, J = 7.3 Hz, 1 H),
6.72 (d, J = 16.3 Hz, 1 H), 6.40 (d, J = 16.2 Hz, 1 H), 4.68 (d, J =
11.9 Hz, 1 H), 4.47 (d, J = 11.9 Hz, 1 H), 2.35 (s, 3 H), 2.08 (s, 3
H), 1.85 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.2,
138.6, 135.0, 134.4, 130.0, 128.8, 127.7, 124.3, 124.2, 89.4, 67.8,
21.4, 20.7, 20.2 ppm. HRMS (ESI): calcd. for C14H18NO4 [M +
H]+ 264.1236; found 264.1243.
(E)-4-[4-(tert-Butyl)phenyl]-2-methyl-2-nitrobut-3-en-1-yl
Acetate
(2c): A solution of 1a (92.0 mg, 0.531 mmol) in dry CH3CN (3 mL)
was purged with nitrogen, and NaOAc (132.0 mg, 1.609 mmol),
Pd2dba3 (24.0 mg, 0.026 mmol), and p-tBuC6H4N2BF4 (264.0 mg,
1.064 mmol) were added. The resulting mixture was stirred at room
temperature for 48 h. The reaction mixture was concentrated, and
the residue was subjected to flash chromatography (silica gel; hex-
ane/EtOAc, 12:1 then 10:1 then 6:1) to give 2c (163.0 mg, 100%)
(E)-4-(4-Chlorophenyl)-2-methyl-2-nitrobut-3-en-1-yl Acetate (2i): A
solution of 1a (107.0 mg, 0.618 mmol) in dry CH3CN (3 mL) was
purged with nitrogen, and NaOAc (152.0 mg, 1.853 mmol), Pd2(p-
MeOdba)3 (34.0 mg, 0.031 mmol), and p-ClC6H4N2BF4 (419.0 mg,
1.854 mmol) were added. The resulting mixture was stirred at room
temperature for 96 h. p-ClC6H4N2BF4 (140 mg) was added, and the
mixture was stirred for an additional 36 h. The reaction mixture
was concentrated, and the residue was subjected to flash
chromatography (silica gel; hexane/EtOAc, 12:1 then 10:1 then 6:1)
to give 2i (147.0 mg, 84%) as a pale, orange oil. 1H NMR
(500 MHz, CDCl3): δ = 7.34 (s, 4 H), 6.70 (d, J = 16.2 Hz, 1 H),
6.41 (d, J = 16.2 Hz, 1 H), 4.66 (d, J = 11.9 Hz, 1 H), 4.48 (d, J =
11.8 Hz, 1 H), 2.09 (s, 3 H), 1.85 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 170.2, 134.9, 133.5, 133.1, 129.1, 128.3,
125.0, 89.2, 67.6, 20.6, 20.1 ppm. C13H14ClNO4 (283.71): calcd. C
55.04, H 4.97, N 4.94; found C 55.45, H 5.04, N 4.70.
1
as a white solid; m.p. 103–103.5 °C. H NMR (500 MHz, CDCl3):
δ = 7.38 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 6.73 (d, J
= 16.5 Hz, 1 H), 6.37 (d, J = 15.9 Hz, 1 H), 4.68 (d, J = 11.6 Hz,
1 H), 4.46 (d, J = 12.1 Hz, 1 H), 2.09 (s, 3 H), 1.85 (s, 3 H), 1.31
(s, 9 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.1, 152.4,
134.0, 132.2, 126.8, 125.8, 123.6, 89.3, 67.7, 34.6, 31.1, 20.5,
20.0 ppm. C17H23NO4 (305.37): calcd. C 66.86, H 7.59, N 4.59;
found C 67.03, H 7.53, N 4.45.
(E)-4-(4-Methoxyphenyl)-2-methyl-2-nitrobut-3-en-1-yl
Acetate
(2d): A solution of 1a (91.0 mg, 0.525 mmol) in dry CH3CN (2 mL)
was purged with nitrogen, and NaOAc (129.0 mg, 1.573 mmol),
Pd2dba3 (25.0 mg, 0.027 mmol) and p-MeOC6H4N2BF4 (236.0 mg,
1.063 mmol) were added. The resulting mixture was stirred at room
temperature for 40 h. The reaction mixture was concentrated, and
the residue was subjected to flash chromatography (silica gel; hex-
ane/EtOAc, 12:1 then 10:1 then 6:1) to give 2d (139.0 mg, 95%) as
a brown oil. 1H NMR (500 MHz, CDCl3): δ = 7.34 (d, J = 9.1 Hz,
2 H), 6.88 (d, J = 9.1 Hz, 2 H), 6.70 (d, J = 16.1 Hz, 1 H), 6.26 (d,
J = 16.7 Hz, 1 H), 4.69 (d, J = 12.1 Hz, 1 H), 4.44 (d, J = 12.0 Hz,
1 H), 3.82 (s, 3 H), 2.09 (s, 3 H), 1.84 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 170.0, 160.3, 133.7, 128.3, 127.6, 121.9,
114.1, 89.3, 67.7, 55.1, 20.4, 19.8 ppm. HRMS (ESI): calcd. for
C14H18NO5 [M + H]+ 280.1185; found 280.1181.
(E)-4-(4-Iodophenyl)-2-methyl-2-nitrobut-3-en-1-yl Acetate (2j): A
solution of 1a (151.0 mg, 0.872 mmol) in dry CH3CN (3 mL) was
purged with nitrogen, and NaOAc (216.0 mg, 2.633 mmol),
Pd2[3,4-(MeO)2dba]3 (56.0 mg, 0.044 mmol), and p-IC6H4N2BF4
(556.0 mg, 1.749 mmol) were added. The resulting mixture was
stirred at room temperature for 60 h. The reaction mixture was
concentrated, and the residue was subjected to flash chromatog-
raphy (silica gel; hexane/EtOAc, 12:1 then 10:1 then 6:1) to give 2j
(240.0 mg, 73%) as a pale, orange oil. 1H NMR (500 MHz,
CDCl3): δ = 7.69 (d, J = 8.3 Hz, 2 H), 7.14 (d, J = 8.1 Hz, 2 H),
6.66 (d, J = 16.1 Hz, 1 H), 6.43 (d, J = 16.8 Hz, 1 H), 4.65 (d, J =
12.0 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 1 H), 2.09 (s, 3 H), 1.85 (s, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 170.3, 138.1, 134.6,
133.4, 128.8, 125.3, 94.9, 89.3, 67.7, 20.7, 20.2 ppm. C13H14INO4
(375.16): calcd. C 41.62, H 3.76, N 3.73; found C 42.01, H 3.81, N
3.70.
(E)-4-(3,4-Dimethoxyphenyl)-2-methyl-2-nitrobut-3-en-1-yl Acetate
(2f): A solution of 1a (98.0 mg, 0.566 mmol) in dry CH3CN (3 mL)
was purged with nitrogen, and NaOAc (140.0 mg, 1.707 mmol),
Pd2dba3 (26.0 mg, 0.028 mmol), and 3,4-(MeO)2C6H3N2BF4 2-Methyl-4-[4-(trifluoromethyl)phenyl]but-2-en-1-yl Acetate (4): A
(570.0 mg, 2.261 mmol) were added. The resulting mixture was solution of 1a (98.0 mg, 0.566 mmol) in dry CH3CN (3 mL) was
2164
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Heck–Matsuda Reaction for Allylic Nitro Compounds
purged with nitrogen, and NaOAc (139.0 mg, 1.695 mmol),
CDCl3): δ = 154.5, 135.0, 134.8, 134.6, 129.2, 128.9, 128.9, 128.8,
128.6, 127.1, 124.1, 89.3, 70.8, 70.4, 20.1 ppm. HRMS (ESI): calcd.
for C19H20NO5 [M + H]+ 342.1341; found 342.1353.
Pd2[3,4-(MeO)2dba]3
(36.0 mg,
0.028 mmol),
and
p-
CF3C6H4N2BF4 (294.0 mg, 1.131 mmol) were added. The reaction
mixture was stirred for 24 h at room temperature. NaOAc (92 mg)
was added, and the reaction mixture was stirred at room tempera-
ture for an additional 48 h. The resulting mixture was poured into
water, and the aqueous layer was extracted with EtOAc
(3ϫ25 mL). The combined organic layers were washed with brine
(1ϫ15 mL) and HCl (1 m solution, 1ϫ3 mL). After drying with
Na2SO4, the organic phase was concentrated in vacuo, and the resi-
due was purified by flash chromatography (silica gel; hexane/
EtOAc, 12:1 then 10:1 then 6:1) to give 4 (39.0 mg, 25%). 1H NMR
(500 MHz, CDCl3): δ = 7.54 (d, J = 8.1 Hz, 2 H), 7.28 (d, J =
8.0 Hz, 2 H), 5.63 (t, J = 7.4 Hz, 0.75 H), 5.54 (t, J = 7.8 Hz, 0.25
H), 4.67 (s, 0.5 H), 4.51 (s, 1.5 H), 3.49 (d, J = 7.5 Hz, 0.5 H), 3.46
(d, J = 7.4 Hz, 1.5 H), 2.08 (s, 3 H), 1.81 (s, 0.75 H), 1.76 (s, 2.25
H) ppm. 13C NMR (126 MHz, CDCl3, major isomer): δ = 171.1,
144.7, 132.2, 128.7, 126.8, 126.4, 125.5 (q, J = 3.7 Hz), 69.7, 33.8,
21.0, 14.2 ppm. 13C NMR (126 MHz, CDCl3, minor isomer): δ =
171.2, 144.8, 131.9, 128.8, 128.0, 126.8, 125.5 (q, J = 3.7 Hz), 63.0,
(R,E)-Benzyl {4-[4-(Heptyloxy)phenyl]-2-methyl-2-nitrobut-3-en-1-
yl} Carbonate [(R)-2m]:
A solution of (R)-1c (200.0 mg,
0.754 mmol) in dry CH3CN (4 mL) was purged with nitrogen, and
NaOAc (188.0 mg, 2.292 mmol), Pd2dba3 (35.0 mg, 0.038 mmol),
and p-C7H15OC6H4N2BF4 (464.0 mg, 1.516 mmol) were added.
The resulting mixture was stirred at room temperature for 48 h.
The reaction mixture was concentrated, and the residue was sub-
jected to flash chromatography (silica gel; hexane/EtOAc, 12:1 then
10:1 then 6:1) to give (R)-2m (216.0 mg, 63%). [α]2D0 = +80.21 (c =
0.46, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.41–7.35 (m, 5
H), 7.32 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.2 Hz, 2 H), 6.70 (d, J
= 16.0 Hz, 1 H), 6.24 (d, J = 16.8 Hz, 1 H), 5.17 (s, 2 H), 4.80 (d,
J = 11.3 Hz, 1 H), 4.48 (d, J = 11.0 Hz, 1 H), 3.96 (t, J = 6.6 Hz,
2 H), 1.85 (s, 3 H), 1.82–1.75 (m, 2 H), 1.51–1.25 (m, 8 H), 0.90 (t,
J = 6.8 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 160.1,
154.5, 134.3, 128.9, 128.8, 128.6, 128.5, 121.5, 114.8, 89.3, 70.9,
70.3, 68.2, 31.8, 29.2, 29.1, 26.0, 22.6, 19.9, 14.1 ppm. HRMS
(ESI): calcd. for C26H34NO6 [M + H]+ 456.2386; found 456.2404.
33.9, 21.6, 21.0 ppm. IR (neat): ν = 1736, 1321, 1107, 1064,
˜
827 cm–1. HRMS (ESI): calcd. for C14H16F3O2 [M + H]+ 273.1102;
found 273.1112.
(R)-2-Amino-4-[4-(heptyloxy)phenyl]-2-methylbutan-1-ol
[(R)-5]:
(R)-2m (199 mg, 0.0437 mmol) was dissolved in MeOH (3 mL), and
Pd-C (10%, 20 mg) was added. The mixture was placed in an auto-
clave and stirred at room temperature under a hydrogen atmo-
sphere at 5 MPa for 50 h. After filtration, the filtrate was concen-
trated to give (R)-5 (130 mg, 97%) as a colorless oil. [α]2D0 = –14.4
(R)-Benzyl (2-Methyl-2-nitrobut-3-en-1-yl) Carbonate [(R)-1c]: To a
solution of (R)-1b (2.62 g, 19.98 mmol, 96%ee) in CH2Cl2 (30 mL)
were added DMAP (4-dimethylaminopyridine, 2.45 g, 20.06 mmol)
and iPr2NEt (5.1 mL, 30.0 mmol). A solution of CbzCl (3.5 mL,
24.5 mmol) in CH2Cl2 (10 mL) was added dropwise to the solution.
The mixture was stirred at room temperature for 48 h and then
was poured into HCl (1 m solution, 20 mL). The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2
(3ϫ30 mL). The combined organic phases were dried with
Na2SO4. After filtration, the filtrate was concentrated, and the resi-
due was purified by flash chromatography (hexane/EtOAc, 3:1) to
give (R)-1c (5.05 g, 95%) as an oil. The enantiomeric purity was
determined by HPLC analysis. HPLC [CHIRALPAK IC
(0.46 cmϫ25 cm) from Daicel Chemical Ind., Ltd.; hexane/iPrOH,
98:2; 1.0 mL/min]: tR = 10.7 min [(S)-1c] and 11.6 min [(R)-1c] as
95%ee. [α]2D0 = +24.78 (c = 1.67, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 7.39–7.34 (m, 5 H), 6.11 (dd, J = 17.4, 10.9 Hz, 1 H),
5.46 (d, J = 10.9 Hz, 1 H), 5.46 (d, J = 17.4 Hz, 1 H), 5.16 (s, 2
H), 4.69 (d, J = 11.7 Hz, 1 H), 4.42 (d, J = 11.7 Hz, 1 H), 1.75 (s,
3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 154.4, 134.8, 133.5,
128.9, 128.8, 128.6, 120.0, 89.2, 70.5, 70.4, 19.6 ppm. C13H15NO5
(265.27): calcd. C 58.86, H 5.70, N 5.28; found C 58.75, H 5.77, N
5.26.
1
(c = 0.32, MeOH). H NMR (500 MHz, CD3OD): δ = 7.10 (d, J
= 8.5 Hz, 2 H), 6.80 (d, J = 8.6 Hz, 2 H), 3.92 (t, J = 6.4 Hz, 2 H),
3.39 (d, J = 10.6 Hz, 1 H), 3.36 (d, J = 10.9 Hz, 1 H), 2.57 (ddd,
J = 2.4, 7.9, 10.2 Hz, 2 H), 1.81–1.69 (m, 2 H), 1.69–1.58 (m, 2 H),
1.52–1.42 (m, 2 H), 1.42–1.27 (m, 6 H), 1.09 (s, 3 H), 0.91 (t, J =
6.4 Hz, 3 H) ppm. 13C NMR (126 MHz, CD3OD): δ = 157.4, 134.6,
128.9, 114.1, 69.5, 67.7, 52.4, 41.2, 31.7, 29.2, 29.0, 28.9, 25.9, 22.8,
22.4, 13.2 ppm. HRMS (FAB): calcd. for C18H32NO2 [M + H]+
294.2433; found 294.2428.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic charts for compounds 1, 2, 4, and 5.
Acknowledgments
We are grateful for the financial support from Yamaguchi Univer-
sity based on the YU Strategic Program for Fostering Research
Activities (2010–2011).
(R,E)-Benzyl (2-Methyl-2-nitro-4-phenylbut-3-en-1-yl) Carbonate
[(R)-2l]: A solution of (R)-1c (55.0 mg, 0.206 mmol) in dry CH3CN
(1 mL) was purged with nitrogen, and NaOAc (52.0 mg,
0.634 mmol), Pd2dba3 (10.0 mg, 0.011 mmol), and PhN2BF4
(80.0 mg, 0.417 mmol) were added. The resulting mixture was
stirred at room temperature for 168 h. PhN2BF4 (40 mg) was
added, and the mixture was stirred for an additional 24 h. The
reaction mixture was concentrated, and the residue was subjected
to flash chromatography (silica gel; hexane/EtOAc, 12:1 then 10:1
then 6:1) to give (R)-2l (55.0 mg, 78%). The enantiomeric purity
was determined by HPLC analysis. HPLC [CHIRALPAK OD-H
(0.46 cmϫ25 cm) from Daicel Chemical Ind., Ltd.; hexane/iPrOH,
95:5; 1.0 mL/min]: tR = 26.1 min [(R)-2l] and 39.2 min [(S)-2l] as
96%ee. [α]2D0 = +18.04 (c = 2.3, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 7.46–7.29 (m, 10 H), 6.77 (d, J = 16.3 Hz, 1 H), 6.42
(d, J = 16.3 Hz, 1 H), 5.18 (s, 2 H), 4.80 (d, J = 11.6 Hz, 1 H),
4.54 (d, J = 11.6 Hz, 1 H), 1.88 (s, 3 H) ppm. 13C NMR (126 MHz,
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Received: November 28, 2011
Published Online: March 6, 2012
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2161–2166