New entry of coupling reaction of phenacylamine derivatives with silylstannane.

Article abstract of DOI:10.1248/cpb.50.441

The new coupling reaction of phenacylamines with silylstannane and lithium diisopropylamide (LDA) is reported. The treatment of a phenacylamine iodide 1 with (trimethylsilyl)tributylstannane (Me3SiSnBu3) and cesium fluoride (CsF) gave a dimerization product 2 having no iodine atom. Reaction of 1 with LDA afforded a dimerization product 3 with an iodine atom. The products 2 and 3 were separated to the meso and racemic isomers, respectively.

Full text of DOI:10.1248/cpb.50.441

March 2002
Notes
Chem. Pharm. Bull. 50(3) 441—443 (2002)
441
New Entry of Coupling Reaction of Phenacylamine Derivatives with
Silylstannane
Yasumasa IWAI, Kumiko KITA, Yoko MATSUSHITA, Aiko YAMAUCHI, and Masaru KIHARA*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-machi,Tokushima 770–8505, Japan.
Received November 26, 2001; accepted January 9, 2002
The new coupling reaction of phenacylamines with silylstannane and lithium diisopropylamide (LDA) is re-
ported. The treatment of a phenacylamine iodide 1 with (trimethylsilyl)tributylstannane (Me3SiSnBu3) and ce-
sium fluoride (CsF) gave a dimerization product 2 having no iodine atom. Reaction of 1 with LDA afforded a
dimerization product 3 with an iodine atom. The products 2 and 3 were separated to the meso and racemic iso-
mers, respectively.
Key words coupling reaction; enolate; silylstannane; phenacylamine
Controlled generation of carbon–carbon bonds forms the 139.5 °C). The structure of each compound 2A and 2B was
1
core of organic synthesis. Coupling reaction of electron-rich confirmed by their IR, H- and 13C-NMR spectra, and HR-
intermediates is an effective methodology for achieving such FAB-MS as described in Experimental. To elucidate their
transformation. Known examples include a variety of eno- stereochemistry, the separated compounds 2A and 2B were
lates1) and dianions2) dimerization. We now report the new analyzed by using HPLC on a chiral stationary phase. The
coupling reactions of N-(2-iodobenzyl)-N-methylphenacyl- HPLC diagrams showed a single peak (9.33 min retention
amine (1) with (trimethylsilyl)tributylstannane (Me3SiSnBu3) time) for 2A and two peaks (10.26, 10.87 min) for 2B, re-
and cesium fluoride (CsF), and lithium diisopropylamide spectively. From these results, the compounds 2A and 2B
(LDA) to the dimeric compounds 2 and 3, and the separation were concluded to be meso and racemic isomer, respectively.
of 2 and 3 to the meso and racemic isomers (Chart 1).
In addition, the integral values of N-methyl protons (d 2.18,
We have reported the synthesis3) of 2-methyl-4-phenyl- 2.37) in the 1H-NMR spectrum of 2 showed a 1 : 2
1,2,3,4-tetrahydroisoquinolin-4-ol (PI-OH) (4) having norad- meso : racemic product ratio.
renaline (NA) potentiating activity due to NA reuptake inhi-
In order to examine the appropriate substrate and reaction
bition as a candidate of antidepressants4) by intramolecular conditions, the bromide 6 and chloride 7 as well as 1 were
Barbier reaction of the phenacylamine 1 with n-BuLi. Opti- treated with Me3SiSnBu3 and CsF in a variety of conditions.
cal resolution of racemic 4 to R-(ϩ)-4 and S-(Ϫ)-4 was car- As shown in Table 1, the treatment of 6 at room temperature
ried out by using HPLC on a chiral stationary phase. The NA for 24 h gave the best result (39.1% yield of 2, run 6),
potentiating activity was found to reside exclusively in R- whereas the reaction of the chloride 7 gave only poor yield of
(ϩ)-4.5)
2 (run 10). This coupling reaction was found to proceed stoi-
This high enantioselectivity of 4 for the NA potentiat- chiometrically from the results of runs 6, 8, and 9. The mech-
ing activity prompted us to perform the asymmetric synthe- anism of this new reaction is not investigated in detail but
sis of R-(ϩ)-4 by intramolecular cyclization of optically ac- may proceed by oxidative coupling of the cesium enolate 9 of
tive chromium complex6) of the phenacylamine 1 with 5, which is formed from the phenyl anion 8 as depicted in
Me3SiSnBu3 and CsF, which are used as a mild and effective Chart 2. The phenyl anion 8 should be formed by attacking
reagent7) for intramolecular carbon–carbon bond formation the iodine atom of 1 with stannyl anion generated from
of ketones possessing halogen atom. As a preliminary experi- Me3SiSnBu3 and CsF since the generation of aryl anion from
ment, we tried to react 1 with Me3SiSnBu3 and CsF to exam- aryl halide with such reagents is well investigated by Mori
ine to produce 4. The product was found to be not an ex- and co-workers.7) This mechanism was supported by the fact
pected compound 4 but a coupling product 2 along with that the deiodinated compound 5 was detected as a sole prod-
deiodinated phenacylamine 5 by the following spectral data. uct on the reaction of 1 for ca. 10 min at room temperature
1
The H-NMR spectrum of 2 showed the presence of two N- by monitoring the TLC behavior of the reaction mixture.
methyl protons (d 2.18, 2.37), two methylene protons as AB- This mixture was successively stirred for 35 h to give the
type doublets (d 4.00, 3.79 and 3.79, 3.59), and two methine coupling product 2 without 5 (run 2). The fact that the reac-
protons (d 5.22, 5.27). The 13C-NMR spectrum of 2 indi- tion of 5 gave no good result (run 11) showed the difficulty
cated the presence of two kinds of N-methyl (d 37.0, 38.2), of the direct enolate formation of 5 with Me3SiSnBu3 and
methylene (d 59.4, 60.4), methine (d 63.2, 63.8), and ketone CsF.
(d 197.8, 198.9) carbons. High resolution (HR)-FAB-MS of
LDA is usually used as a base for the preparation of eno-
2 showed the molecular formula of C32H32N2O2. These spec- lates. Compound 1 was treated with LDA (1.2 eq) at room
tral data suggested that the product should be a dimer 2 with- temperature for 24 h to give the coupling product 3 without
out iodine atom formed by coupling at the active methylene reducing the iodine atom of 1 even in low yield (29%). The
carbon atom of 1 and also suggested the product 2 to be a 1H-NMR spectrum of this product 3 is similar to that of 2 ob-
mixture of meso and racemic isomers. Thus, 2 was separated tained from 1 with Me3SiSnBu3 and CsF except for the aro-
by recrystallization from CH2Cl2 and n-hexane to give two matic protons, and suggested 3 to be a mixture of meso and
compounds, 2A (mp 140—141 °C) and 2B (mp 139— racemic isomers. Crystallization of 3 from CH2Cl2 and n-
To whom correspondence should be addressed. e-mail: mkihara@ph2.tokushima-u.ac.jp
© 2002 Pharmaceutical Society of Japan

442
Vol. 50, No. 3
Table 1. Reaction of Phenacylamines 1, 5—7 with Me3SiSnBu3 and CsF in DMF
Yield (%)
5 Starting material
Run
Compound
Me3SiSnBu3 (eq)
CsF (eq)
Temp.
Time
2
1
2
3
4
5
6
7
8
9
1
1
6
6
6
6
6
6
6
7
5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.1
1.05
2.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
0.16
1.07
3.0
3.0
rta)
rt
60 °C
0 °C
rt
rt
60 °C
rt
70 min
35 h
2 h
7 d
7 h
24 h
24 h
24 h
24 h
14 h
7 h
6.9
33.0
14.5
9.9
30.4
39.1
21.4
4.7
26.1
—
44.4
16.5
27.5
—
—
—
15.1
—
8.8
—
—
—
—
—
—
—
57.2
3.6
—
rt
rt
60 °C
35.1
4.3
1.9
10
11
—
a) rt, room temperature.
stationary phase column (Daicel Chiralcel OJ). IR spectra were recorded on
a Perkin-Elmer 1720 infrared Fourier transform spectrometer.
N-Methyl-N-(2-bromobenzyl)phenacylamine (6) To a mixture of 2-
bromobenzaldehyde (6.12 g, 33.1 mmol) and 3A molecular sieves (5.60 g) in
absolute MeOH (15 ml) was added CH3NH2 (12.8 ml of 40% solution in
MeOH, 165 mmol) under N2. The mixture was stirred for 24 h at room tem-
perature. After cooling to 0 °C, NaBH4 (1.375 g, 32.7 mmol) was added and
the mixture was stirred for 15 min at the same temperature. Water (10 ml)
was added and the mixture was filtered. The filtrate was evaporated in vacuo.
Water (20 ml) was added to the residue. The mixture was extracted with
ethyl acetate (30 mlϫ3). The extracts were washed with water, dried over
MgSO4, and evaporated in vacuo to give an oily product. This was subjected
to flash chromatography on SiO2 with n-hexane–ethyl acetate (9 : 1) to afford
N-methyl-2-bromobenzylamine (6.62 g, 98.2%) as a pale yellow oil. 1H-
NMR (200 MHz, CDCl3) d: 7.55 (1H, dd, Jϭ8.1, 1.2 Hz), 7.35 (1H, ddd,
Jϭ7.6, 6.8, 2.0 Hz), 7.26 (1H, dd, Jϭ7.4, 1.3 Hz), 7.12 (1H, ddd, Jϭ7.6, 7.6,
2.0 Hz), 3.83 (2H, s), 2.45 (3H, s). HR-EI-MS (m/z): Calcd for C8H10BrN
(Mϩ): 200.9976. Found: 200.9978. IR (NaCl) cmϪ1: 3301, 3063, 2936,
2793, 1661, 1568, 1471.
Chart 1
A solution of N-methyl-2-bromobenzylamine (492 mg, 2.46 mmol) ob-
tained as above, phenacyl bromide (467 mg, 2.35 mmol), and propylene
oxide (1.6 ml, 22.8 mmol) in dry dioxane (2 ml) was stirred for 3 h at 50 °C.
The mixture was evaporated in vacuo to give a crude product. This was sub-
jected to flash chromatography on SiO2 with n-hexane–ethyl acetate (20 : 1)
to afford 6 as a pale yellow oil (716 mg, 95.9%). 1H-NMR (200 MHz,
CDCl3) d: 7.29 (2H, dd, Jϭ8.5, 1.7 Hz), 7.38 and 7.59 (5H, m), 7.23 (1H,
ddd, Jϭ7.3, 7.3, 1.5 Hz), 7.11 (1H, ddd, Jϭ7.7, 7.6, 1.7 Hz), 3.90 (2H, s),
3.81 (2H, s), 2.42 (3H, s). HR-EI-MS (m/z): Calcd for C16H16BrNO (Mϩ):
Chart 2
hexane gave two compounds 3A (mp 137—137.5 °C) and 3B
(mp 130—131 °C). HPLC analysis of 3A (single peak, 318.0318. Found: 318.0334. IR (NaCl) cmϪ1: 3060, 2972, 1684, 1598, 1449.
Compounds 1 and 7 were prepared by the method reported in our previ-
10.44 min retention time) and 3B (two peaks, 17.92, 19.54
min) on chiral stationary phase showed their stereochemistry
to be meso and racemic isomers, respectively. HR-FAB-MS
ous papers.8)
General Procedure for the Reaction of Compound 1 with Me3SiSnBu3
and CsF This is exampled by the reaction of run 2 in Table 1. A solution
of 3A and 3B indicated C32H30I2N2O2 of their molecular for-
mulae having iodine atoms. It is interesting to note that the
2 : 1 meso : racemic product ratio of 3 is different from that
(1 : 2 meso : racemic ratio) of 2 obtained with Me3SiSnBu3
and CsF. The coupling reaction of phenacylamines with silyl-
stannane and LDA reported in this study is a first example.
In conclusion, the treatment of phenacylamine 1 with n-
BuLi gave a intramolecular cyclization product 4, whereas
the reaction of 1 with Me3SiSnBu3 and CsF, and with LDA
afforded intermolecular coupling compounds 2 and 3, which
were separated to meso and racemic isomers.
of Me3SiSnBu3 (2.364 g, 6.31 mmol) in dry N,N-dimethylformamide (DMF,
5 ml) was added to a solution of 1 (1.151 g, 3.15 mmol) and CsF (90%)
(1.570 g, 9.31 mmol) in dry DMF (5 ml). The mixture was stirred for 35 h at
room temperature. Water (30 ml) was added and the mixture was basified
with 10% KOH, and extracted with ether (30 mlϫ3). The extracts were
washed with water, dried over MgSO4, and evaporated in vacuo to give a
crude product. This was subjected to column chromatography on SiO2 with
n-hexane–ethyl acetate (10 : 1) to afford 2 as a yellow solid (248 mg, 33.0%).
This was recrystallized from CH2Cl2–n-hexane to give 2A of yellow plates
as a first crop (31.3 mg, mp 140—141 °C) and 2B of yellow plates as a sec-
ond crop (88.4 mg, mp 139—139.5 °C). Compounds 2A and 2B were sub-
mitted to HPLC with a n-hexane–2-propanol (100 : 1) mixture at a flow rate
of 1 ml/min to show a single peak at 9.33 min retention time and two peaks
at 10.26 and 10.87 min, respectively.
1
Experimental
2A: H-NMR (200 MHz, CDCl3) d: 8.05 (4H, d, Jϭ7.7 Hz), 7.47—7.64
Melting points were measured on a Yanako micro melting point apparatus
and uncorrected. 1H- and 13C-NMR spectra were recorded on a JEOL JNM-
FX 200 spectrometer in CDCl3 with tetramethylsilane as a standard. HR-
FAB-MS and HR-EI-MS were recorded on a JEOL JMS SX-102A. HPLC
was run on a Shimadzu LC-6A liquid chromatograph equipped with a chiral
(6H, m), 7.09—7.12 (6H, m), 6.96—6.98 (4H, m), 5.25 (2H, s), 3.79 and
3.59 (each 2H, d, Jϭ13.9 Hz), 2.18 (6H, s). 13C-NMR (100 MHz, CDCl3) d:
197.79, 139.19, 138.77, 133.14, 128.84, 128.46, 128.33, 128.02, 126.79,
63.24, 59.34, 38.19. HR-FAB-MS (m/z): Calcd for C32H33N2O2 (MϩH)ϩ:
477.2542. Found: 477.2527. IR (CHCl3) cmϪ1: 3020, 1668, 1449, 1287,

March 2002
1212.
443
3B: 1H-NMR (200 MHz, CDCl3) d: 7.99 (4H, d, Jϭ6.8 Hz), 7.77 (2H,
Jϭ7.6 Hz), 7.23—7.57 (10H, m), 6.91—6.94 (2H, m), 5.21 (2H, s), 4.06 and
3.89 (each 2H, d, Jϭ14.9 Hz), 2.42 (6H, s). HR-FAB-MS (m/z): Calcd for
C32H31I2N2O2 (MϩH)ϩ: 729.0475. Found: 729.0491. IR (KBr) cmϪ1: 2864,
1671, 1436, 1201.
1
2B: H-NMR (200 MHz, CDCl3) d: 8.05 (4H, d, Jϭ7.3 Hz), 7.43—7.61
(6H, m), 7.24 (10H, s), 5.25 (2H, s), 4.00 and 3.78 (each 2H, d, Jϭ13.7 Hz),
2.37 (6H, s). 13C-NMR (100 MHz, CDCl3) d: 198.86, 139.38, 138.28,
132.90, 128.95, 128.67, 128.53, 128.24, 127.06, 63.84, 60.41, 36.98. HR-
FAB-MS (m/z): Calcd for C32H33N2O2 (MϩH)ϩ: 477.2542. Found:
477.2533. IR (CHCl3) cmϪ1: 3020, 1671, 1449, 1219.
References
The reaction of 5—7 with Me3SiSnBu3 and CsF was carried out in the
same way as for 1 described above (Table 1).
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Reaction of Compound 1 with LDA n-BuLi (5.2 ml of 1.54 M solution
in n-hexane, 7.98 mmol) was added to a solution of diisopropylamine
(1.18 ml, 9.04 mmol) in dry tetrahydrofuran (THF, 5 ml) at Ϫ78 °C under
argon. The mixture was stirred for 1 h under ice-cooling. A solution of 1
(1.947 g, 5.32 mmol) in dry THF (8 ml) was added and the mixture was
stirred for 24 h at room temperature. Water (30 ml) was added under ice-
cooling and the mixture was extracted with ethyl acetate (30 mlϫ3). The ex-
tracts were washed with brine, dried over MgSO4, and evaporated in vacuo
to give an oily product. This was subjected to column chromatography on
SiO2 with n-hexane–ethyl acetate (15 : 1) to afford 3 as a yellow oil (554 mg,
28.5%) and the starting material 1 (114 mg, 5.9%). Crystallization of 3
(205 mg) from CH2Cl2–n-hexane gave 3A of yellow plates as a first crop
(41 mg, mp 137—137.5 °C) and 3B of yellow powder as a second crop
(21 mg, mp 130—131 °C). Compounds 3A and 3B were submitted to HPLC
with a n-hexane–2-propanol (4 : 1) mixture at a flow rate of 0.5 ml/min to
show a single peak at 10.44 min retention time and two peaks at 17.92 and
19.54 min, respectively.
1
3A: H-NMR (200 MHz, CDCl3) d: 7.98 (4H, d, Jϭ7.0 Hz), 7.66 (2H, d,
Jϭ7.8 Hz), 7.43—7.60 (6H, m), 7.01—7.10 (4H, m), 6.77—6.85 (2H, m),
5.19 (2H, s), 3.85 and 3.63 (each 2H, d, Jϭ15.1 Hz), 2.28 (6H, s). HR-FAB-
MS (m/z): Calcd for C32H31I2N2O2 (MϩH)ϩ: 729.0475. Found: 729.0476. IR
(KBr) cmϪ1: 2944, 1669, 1435, 1194.
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