Synthesis of naphthothiazolium salts from binol

Article abstract of DOI:10.3987/COM-05-10579

Naphthothiazolium salts with axial chirality were prepared from (S)-BINOL through introduction of a thiol group in place of the hydroxyl group by the Newmann-Kwart rearrangement and construction of the thiazolium ring by treatment of the air-sensitive N-a

Full text of DOI:10.3987/COM-05-10579

HETEROCYCLES, Vol. 68, No. 1, 2006
101
HETEROCYCLES, Vol. 68, No. 1, 2006, pp. 101 – 110. © The Japan Institute of Heterocyclic Chemistry
Received, 27th September, 2005, Accepted, 28th October, 2005, Published online, 1st November, 2005. COM-05-10579
SYNTHESIS OF NAPHTHOTHIAZOLIUM SALTS FROM BINOL
Osamu Hara,b Taiju Nakamura,a Kazuishi Makino, a and Yasumasa
Hamada*a
a
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho,
b
Inage-ku, Chiba, 263-8522, Japan. E-mail: hamada@p.chiba-u.ac.jp
Faculty
of Pharmacy, Meijo University, 150 Yagotoyama Tempaku-ku, Nagoya
460-8503, Japan
Abstract – Naphthothiazolium salts with axial chirality were prepared from
(S)-BINOL through introduction of a thiol group in place of the hydroxyl group
by the Newmann-Kwart rearrangement and construction of the thiazolium ring by
treatment of the air-sensitive N-alkylated aminothionaphthol with triethyl
orthoformate in the presence of hydrogen chloride.
Organocatalysis has been shown to be an expedient and environmentally benign procedure for a variety
of transformations and recent examples using chiral organocatalysts have demonstrated their crucial role
in asymmetric synthesis, for example, asymmetric aldol reaction catalyzed with proline, asymmetric
Diels- Alder reaction and 1,3-dipolar cycloaddition catalyzed with chiral imidazolidinones, and so on.1
Recently, our interest has focused on development of new organocatalysis for the benzoin reaction and
the Stetter reaction.2 An asymmetric version of these reactions by use of chiral tetrazolium salts has been
demonstrated.3 Generally, these reactions are catalyzed by a nucleophilic carbene species generated from
azolium salts and a base. Although thiazolium salts are a pioneer of organocatalysts, there have so far
been no efficient chiral thiazolium salts in terms of chemical yield and enantiomeric excess in the benzoin
reaction and the Stetter reaction.4 Recently, Enders and coworkers screened a number of thiazolium salts
with an extended conjugate system and observed that in the formoin reaction catalyzed by thiazolium
salts like the benzoin reaction,5 the thiazolium salt derived from benzothiazole with a conjugate system
was an especially excellent catalyst better than that of thiazole itself.6 These results led us to develop a
new chiral thiazolium salt with an extended conjugate system. We envisioned that chiral thiazolium salt
(1) from BINOL depicted in Figure 1 should have both the reactivity reported by Enders and the
enantioselectivity by the shielding effect of the bottom aryl group. To date, there are no chiral thiazolium

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HETEROCYCLES, Vol. 68, No. 1, 2006
salts derived from BINOL as a chiral template.7 Herein we report the synthesis of new chiral
naphthothiazolium salts from (S)-BINOL.
R
R
NH2
N+
X-
S
OH
Ar
OH
OH
SH
Ar
Ar
1
2
3: R = NO2
4: R = H
5
Figure 1
Our synthetic plan for the new thiazolium salts is shown in Figure 1. The thiazolium salts can be
constructed from the corresponding aminothiophenol (2), which should be obtained from the nitrophenol
(3) through the Newmann-Kwart rearrangement and reduction. The nitrophenol (3) can be derived from
the corresponding phenol (4), which would be constructed from (S)-BINOL (5) through monoactivation
of two phenol functions and palladium-catalyzed cross-coupling reaction with an organometallic reagent.
Synthesis of 1 started with palladium-catalyzed cross-coupling reaction of the known (S)-BINOL
monotriflate8 with phenylmagnesium bromide according to the literature method as shown in Scheme 1.
(A) 30 % HNO3, Ac2O,
1) Me2NCSCl
0°C, 0.3 h, 43 %
R1
R2
DABCO, DMF Br
0 - 23°C, 22 h
100 %
NO2
60 % HNO , Et O,
-10°C - rt, 1 h, 100 %
(B)
3
2
O
S
Ph
Ref. 8
OH
Ph
OH
Ph
NMe2
5
2) Ph2O
200°C
92 %
(C) i) NBS, MeCN
-45 °- 0°C, 26 h, 72 %
(rac)-11
ii) 35 % HNO3, CH2Cl2
40°C, 24 h, 92 %
(rac)-7: R1= NO2, R2= NO2
(rac)-8: R1 = NO2, R2 = H
9: R1= Br, R2= H
6
(rac)-10: R1 = Br, R2 = NO2
Scheme 1
With large quantities of binaphthol (6) in hand, the regioselective nitration of 6 was attempted. When this
reaction was carried out with treatment of 30% nitric acid in acetic anhydride (method A), overreacted
3,6-dinitro derivative (7) was generated in 43% yield. Careful treatment of 6 with 1 equivalent of 60%
nitric acid at –10 to 23°C in ether (method B) again resulted in undesired 6-nitro derivative (8) in
quantitative yield. Since the attempts for ortho-selective nitration failed, we turned our attention to
protection against electrophiles at the C6-reactive position of 6. Selective protection at the C6 position
was carried out by treatment with 1 equivalent of N-bromosuccinimide (NBS) at -40°C to 23°C in
acetonitrile to afford the 6-bromo derivative (9) in 72% yield (method C). Introduction of a bromide
group is very useful for the synthesis of naphthothiazolium analogues because of not only the easy
removal by hydrogenolysis but also the conversion to other function groups through palladium-catalyzed

HETEROCYCLES, Vol. 68, No. 1, 2006
103
cross-coupling reaction. The bromide (9) was reacted with 1.2 equivalent of 30% nitric acid at 40°C in
methylene chloride to furnish the desired 3-nitro derivative (10) in 92% yield. The thus-obtained 10,
however, was found to completely racemize on the axial chirality.9 Although this was a serious problem,
we decided to synthesize 1 as a racemic compound and examine its reactivity. Conversion of the hydroxy
group to a thiol group in (rac)-10 was carried out by the Newmann-Kwart rearrangement. Thus, (rac)-10
was coupled with dimethylthiocarbamoyl chloride (Me2NCSCl) in the presence of
diazabicyclo[2.2.2]octane (DABCO) in dimethylformamide (DMF) to give the O-thiocarbamate in
quantitative yield. The rearrangement of the O-thiocarbamate was performed at 200°C in diphenyl ether
to afford the desired S-thiocarbamate [(rac)-11] in 92% yield.10 Deprotection of the S-dimethylcarbamoyl
group, however, was unexpectedly difficult. After some trials and errors, we were pleased to find
chemoselective reduction of the 3-nitro group in (rac)-11 with stannous chloride in the presence of
hydrochloric acid and acetic acid and spontaneous conversion to thiazolinone [(rac)-12] through
intramolecular attack of the resulting amine to the S-dimethylcarbamoyl group in 83% yield. Since
(rac)-12 resisted alkaline hydrolysis and reductive cleavage, the thiazolinone [(rac)-12] was first
N-ethylated with n-butyllithium and iodoethane at 60°C for 24 h in THF to give N-ethylthiazolinone
[(rac)-13] in 94% yield. Removal of the 6-bromo group was performed under transfer hydrogenolysis
conditions to give (rac)-14 in 78% yield. Cleavage of the N-ethylthiazolinone ring in (rac)-14 was
accomplished by alkaline hydrolysis with 5M sodium hydroxide in ethylene glycol-diglyme to give the
aminothiophenol derivative. Unsurprisingly, this product was very sensitive to air or oxygen. Therefore,
this step was carried out under oxygen-free conditions and the product was used for the next step without
any purification. The crude aminothiophenol was treated with triethyl orthoformate in ethyl acetate in the
presence of hydrogen chloride at 23°C for 4 h to produce the desired thiazolium salt [(rac)-15] in 80%
Et
N
Et
R
N
Br
i) SnCl2, HCl
AcOH, 90 °C
30 min, 83 %
N+
5% Pd/C
HCO2NH4
O 1) 5M NaOH, 150°C, 4 h
ethylene glycol - diglyme
O
S
S
S
Cl-
(rac)-11
Ph
Ph
Ph
DMF
100°C, 16 h
78%
2) HC(OEt)3, 2M HCl-EtOAc
23°C, 4 h, 80 % from 9
ii) n-BuLi, EtI
THF, 60°C
2 h, 94 %
(rac)-12: R = H
(rac)-13: R = Et
(rac)-14
(rac)-15
Pd(OAc)2, BINAP
NaOBu-t, pyrrolidine
toluene, 75°C, 3 h, 91 %
Et
Et
Et
Br
N
N+
N
N+
N
O
S
S
S
Cl-
Cl-
Ph
Ph
Ph
(rac)-16
(rac)-17
(rac)-18
Scheme 2

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HETEROCYCLES, Vol. 68, No. 1, 2006
yield.11 For demonstration of the utility concerning the C6-bromo protection in (rac)-13, Buchwald’s
amination reaction12 with Pd catalyst in the presence of BINAP was applied to the bromide [(rac)-13] to
provide the corresponding amine [(rac)-16] in 91% yield. Finally, these compounds (rac)-13 and (rac)-16
were converted to the corresponding thiazolium salts (rac)-18 and (rac)-17, respectively, by a similar
procedure. The thus-obtained chiral naphthothiazolium salts (rac)-15, (rac)-17, and (rac)-18 were applied
to the asymmetric benzoin reaction as a bench-mark reaction. Unfortunately, the reaction failed to afford
the desired compound.
In summary, we have demonstrated the first synthetic approach to new chiral naphthothiazolium salts
with axial chirality from BINOL. Although the reactivity of these new naphthothiazolium salts remains to
be improved, the present method described here will be useful for synthesis of other new thiazolium salts
with a conjugate system. Further modification of naphthothiazolium salts is currently under way.
EXPERIMENTAL
General.
Melting points were determined on a Yamato MP-21 apparatus and are uncorrected. IR spectra were
1
measured with a Perkin-Elmer 1600 FTIR spectrophotometer. H-NMR and 13C-NMR spectra were
recorded on a JEOL JNM-ALPHA 400 or JEOL JNM-AL 400 spectrometer with tetramethylsilane or
CHCl3 as an internal standard. Optical rotations were measured with a JASCO DIP-1000 digital
polarimeter. TLC was performed using precoated (0.25 mm) Merck silica gel F-254 plates. Column
chromatography was performed using silica gel (FL-100D; Fuji Silysia Chemical Ltd.).
6-Nitro-2'-phenyl-1,1'-binaphthalen-2-ol (8)
To a solution of 6 (346.4 mg, 1.00 mmol) in ether (9.5 mL), aqueous HNO3 (60%, 76 μL, 1.00 mmol)
was added at –10°C under nitrogen atmosphere. After stirring the mixture for 1 h at 0°C, the reaction was
quenched with saturated aqueous NaHCO3 and extracted with ether. The organic extract was washed with
water and saturated aqueous brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo
and the residue was purified by column chromatography on silica gel (n-hexane/EtOAc = 1/0 then 9/1) to
give 8 (396 mg, 100%) as yellow crystals: mp 96°C (EtOAc/n-hexane); IR (KBr) 1637, 1654, 1685, 1735,
3433 cm-1; 1H-NMR (400 MHz, CDCl3) δ 5.64 (1H, s), 7.00-7.09 (5H, m), 7.14 (1H, d, J = 9.2 Hz), 7.22
(1H, d, J = 8.6 Hz), 7.27-7.36 (2H, m), 7.51 (1H, dd, J = 6.6, 8.4 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.89-7.92
(2H, m), 7.97 (1H, d, J = 8.6 Hz), 8.16 (1H, d, J = 8.3 Hz), 8.68 (1H, s); 13C-NMR (100 MHz, CDCl3) δ
118.6, 119.5, 120.1, 125.0, 125.6, 126.2, 126.7, 126.8, 127.1, 127.3, 127.6, 127.9, 128.4, 128.5, 128.6,
130.1, 132.7, 133.3, 136.9, 140.3, 142.0, 143.6, 154.5. HRMS (FAB) calcd for C26H17NO3: 391.1208
(M+H+). Found: 391.1213.

HETEROCYCLES, Vol. 68, No. 1, 2006
105
(S)-6-Bromo-2'-phenyl-1,1'-binaphthalen-2-ol (9)
To a solution of 6 (3.74 g, 10.8 mmol) in MeCN (75 mL) at –45°C under nitrogen atmosphere, NBS (2.02
g, 11.3 mmol) was added and the mixture was gradually warmed to 0°C for 26 h. The reaction was
quenched with water and extracted with EtOAc. The organic extract was washed with water and saturated
aqueous brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo and the resulting
residue was purified by column chromatography on silica gel (n-hexane/EtOAc = 1/0 then 97/3) to give 9
(3.30 g, 72%) as pale yellow amorphous powder: mp 85°C (EtOAc/n-hexane); [α]20 –48.1° (c 1.01,
D
1
CHCl3); IR (KBr) 763, 820, 874, 934, 1045, 1242, 1373, 1494, 1588, 1731 cm-1; H-NMR (400 MHz,
CDCl3) δ 4.89 (1H, bs), 6.95 (1H, d, J = 9.0 Hz), 7.03-7.11 (5H, m), 7.14 (1H, d, J = 8.8 Hz), 7.23-7.26
(2H, m), 7.33 (1H, ddd, J = 12.0, 6.8, 1.2 Hz), 7.51 (1H, ddd, J = 8.1, 6.8, 1.2 Hz), 7.66 (1H, d, J = 9.0
Hz), 7.68 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 2.0 Hz), 7.97 (1H, d, J = 8.1 Hz), 8.07 (1H, d, J = 8.5 Hz);
13C-NMR (100 MHz, CDCl3) δ 117.0, 118.0,118.3, 126.0, 126.5, 126.8, 127.1, 127.3, 127.8, 128.3, 128.5,
128.6, 128.9, 129.6, 129.79, 129.84, 130.0, 132.6, 132.9, 133.2, 140.6, 141.7, 151.3. HRMS (FAB)
calcd for C26H17OBr: 424.0463 (M+H+). Found: 424.0498.
6-Bromo-3-nitro-2'-phenyl-1,1'-binaphthalen-2-ol (10)
To a solution of 9 (1.30 g, 3.07 mmol) in CH2Cl2 (5.2 mL), aqueous HNO3 (35%, 0.82 mL, 3.68 mmol)
was added at 23°C under nitrogen atmosphere and the mixture was heated at 40°C for 24 h. Heptane (24
mL) was added to the mixture and the resulting precipitates were collected by filtration to give 10 (1.32 g,
92%) as orange crystals: mp 294°C (EtOAc/n-hexane); IR (KBr) 762, 822, 938, 1066, 1192, 1313, 1353,
1
1443, 1489, 1520, 1598, 1622 cm-1; H-NMR (400 MHz, CDCl3) δ 7.01 (1H, d, J = 9.1 Hz), 7.04-7.08
(3H, m), 7.13-7.16 (3H, m), 7.33 (1H, ddd, J = 1.2, 6.8, 8.3 Hz), 7.38 (1H, dd, J = 2.0, 9.0 Hz), 7.50 (1H,
ddd, J = 1.0, 6.8, 8.1 Hz), 7.65 (1H, d, J = 8.5 Hz), 7.99 (1H, d, J = 8.5 Hz), 8.00 (1H, d, J = 2.0 Hz), 8.07
(1H, d, J = 8.3 Hz), 8.67 (1H, s), 10.13 (1H, s); 13C-NMR (100 MHz, CDCl3) δ 119.2, 124.9, 125.5, 125.7,
126.1, 126.9, 126.96, 127.02, 127.2, 127.7, 128.3, 128.4, 128.7, 129.1, 131.6, 132.3, 132.9, 134.0, 134.6,
136.4, 140.8, 141.3, 147.5. HRMS (FAB) calcd for C26H16NO3Br: 469.0313 (M+H+). Found: 469.0297.
O-(6-Bromo-3-nitro-2'-phenyl-1,1'-binaphthalene-2-yl)dimethylthiocarbamate
To a solution of 10 (0.97 g, 2.07 mmol) in DMF (10 mL), DABCO (0.46 g, 4.14 mmol) and N,
N-dimethylthiocarbamoyl chloride (0.51 g, 4.14 mmol) were added at 0°C under nitrogen atmosphere and
the mixture was stirred at 23°C for 24 h. Water (20 mL) was added and the resulting precipitates were
collected by filtration to give pure O-thiocarbamate (1.15 g, 100%) as pale yellow crystals: mp 293°C
(EtOAc/n-hexane); IR (KBr) 762, 822, 914, 1112, 1172, 1227, 1283, 1346, 1396, 1527, 1592 cm-1;
1H-NMR (The spectrum could not be assigned for the presence of the rotational isomers); 13C-NMR (100
MHz, CDCl3) δ 38.3, 38.7, 43.1, 43.2, 121.6, 124.6, 126.4, 126.5, 126.9, 127.0, 127.1, 127.5, 127.7,

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HETEROCYCLES, Vol. 68, No. 1, 2006
127.8, 127.9, 128.2, 128.38, 128.41, 128.5, 128.7, 129.2, 129.5, 130.2, 130.3, 131.6, 132.1, 132.5, 133.3,
134.6, 140.2, 141.00, 141.02, 142.5, 184.8. Anal. Calcd for C29H21N2O3BrS: C, 62.48; H 3.80; N 5.03.
Found: C, 62.29; H, 3.93; N, 5.03.
S-(6-Bromo-3-nitro-2'-phenyl-1,1'-binaphthalene-2-yl)dimethylthiocarbamate (11)
A suspension of O-thiocarbamate (1.11 g, 1.99 mmol) in diphenyl ether (11 mL) was heated to 200°C
under nitrogen atmosphere for 7.5 h. After cooling the mixture, the resulting residue was purified by
column chromatography on silica gel (n-hexane/EtOAc = 95/5) to give 11 (1.02 g, 92%) as colorless
crystals: mp 263°C (EtOAc/n-hexane); IR (KBr) 764, 822, 924, 1097, 1255, 1364, 1534, 1560, 1671
1
cm-1; H-NMR (400 MHz, DMSO-d6) δ 2.64 (6H, s), 6.96 (1H, dd, J = 0.6, 8.4 Hz), 7.00-7.09 (6H, m),
7.31 (1H, ddd, J = 1.2, 6.8, 8.4 Hz), 7.52 (1H, ddd, J = 1.2, 6.8, 8.0 Hz), 7.62 (1H, dd, J = 2.0, 8.8 Hz),
7.64 (1H, d, J = 8.0 Hz), 8.06 (1H, d, J = 8.4 Hz), 8.18 (1H, d, J = 8.4 Hz), 8.46 (1H, d, J = 2.0 Hz), 8.67
13
(1H, s); C-NMR (100 MHz, DMSO-d6) δ 35.9, 121.5, 121.6, 123.6, 123.7, 125.1, 125.6, 126.3, 126.4,
127.0, 127.4, 127.6, 127.9, 128.4, 128.6, 128.7, 130.8, 130.9, 131.4, 131.8, 132.0, 138.9, 139.9, 144.3,
150.2, 162.4. Anal. Calcd for C29H21N2O3BrS: C, 62.48; H 3.80; N 5.03. Found: C, 62.10; H, 3.93; N,
5.04.
6-Bromo-9-(2-phenyl-1-naphthyl)naphtho[2,3-d]thiazol-2(3H)-one (12)
To a suspension of 11 (1.02 g, 1.84 mmol) in acetic acid (28 mL) at 23°C were added concd HCl (4.0 mL,
47.7 mmol, 10.0 equiv) and SnCl2•H2O (3.49 g, 10.8 mmol). After stirring the mixture at 90°C for 30 min,
the reaction mixture was cooled to 0°C and the resulting precipitates were collected by filtration to give
12 (0.73 g, 83%) as colorless crystals: mp >300°C (EtOAc); IR (KBr) 760, 818, 886, 930, 1028, 1073,
1
1217, 1415, 1493, 1619, 1683 cm-1; H-NMR (400 MHz, CDCl3) δ 6.99-7.10 (7H, m), 7.20 (1H, d, J =
9.2 Hz), 7.28-7.32 (3H, m), 7.51 (1H, ddd, J = 1.5, 7.3, 7.6 Hz), 7.65 (1H, d, J = 8.6 Hz), 7.94 (1H, d, J =
1.5 Hz), 7.99 (1H, d, J = 8.3 Hz), 8.08 (1H, d, J = 8.6 Hz); 13C-NMR (100 MHz, CDCl3) , 105.8, 112.1,
120.3, 125.7, 126.3, 127.1, 127.2, 127.4, 127.7, 128.4, 128.5, 128.6, 128.9, 129.5, 131.0, 131.5, 133.0,
134.1, 138.8, 140.1, 140.6, 168.1. HRMS (ESI) calcd for C27H17NOBrS: 482.0214 (M+H+). Found:
482.0219.
6-Bromo-9-(2-phenyl-1-naphthyl)-3-ethylnaphtho[2,3-d]thiazol-2(3H)-one (13)
To a solution of 12 (1.00 g, 2.07 mmol) in THF (10 mL), n-BuLi (1.55M in hexane, 1.3 mL, 2.07 mmol)
and iodoethane (199 μL, 2.49 mmol) were added dropwise. After stirring the mixture at 60°C for 24 h,
the reaction was quenched with aqueous 1M HCl and extracted with EtOAc. The organic extract was
washed with water, saturated aqueous NaHCO3, and saturated aqueous brine, dried over MgSO4, and
filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by column

HETEROCYCLES, Vol. 68, No. 1, 2006
107
chromatography on silica gel (n-hexane/EtOAc = 95/5 then 82/18) to give 13 (0.99 g, 94%) as colorless
crystals: mp >300°C (EtOAc/n-hexane); IR (KBr) 761, 828, 850, 1051, 1226, 1246, 1295, 1428, 1446,
1458, 1510, 1620, 1678 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.39 (3H, d, J = 7.3 Hz), 3.92-4.01 (1H, m),
4.05-4.13 (1H, m), 7.00-7.15 (6H, m), 7.20 (1H, d, J = 9.0 Hz), 7.25-7.32 (3H, m), 7.51 (1H, dd, J = 7.1,
7.8 Hz), 7.65 (1H, d, J = 8.3 Hz), 7.99 (1H, d, J = 8.1 Hz), 8.03 (1H, d, J = 2.0 Hz), 8.09 (1H, d, J = 8.5
13
Hz); C-NMR (100 MHz, CDCl3) δ 12.6, 37.9, 104.9, 120.2, 125.7, 126.3, 126.5, 127.0, 127.3, 127.6,
128.2, 128.3, 128.5, 128.6, 128.9, 129.5, 129.6, 131.2, 131.4, 132.9, 133.0, 136.2, 140.1, 140.6, 169.9 .
HRMS (ESI) calcd for C29H21NOBrS: 510.0527(M+H+). Found: 510.0526.
3-Ethyl-9-(2-phenyl-1-naphthyl)naphtho[2,3-d]thiazol-2(3H)-one (14)
To a solution of 13 ( 51mg, 0.1 mmol) in DMF (1 mL) under argon atmosphere were added 5% Pd-C (11
mg, 0.005 mmol) and HCO2NH4 (125 mg, 1.97 mmol). After stirring at 100°C for 16 h, the mixture was
filtered through a pad of celite to remove the Pd catalyst. The filtrate was diluted with EtOAc/n-hexane
(4:1), washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated in
vacuo and the residue was purified by column chromatography on silica gel (n-hexane/EtOAc = 5:1) to
give 14 (34 mg, 78%) as colorless solids: mp 247-250°C (EtOAc/n-hexane); IR (KBr) 3048, 2961, 1685,
1616, 1494, 1429, 1378, 1304, 1227, 1144, 822, 767, 715 cm-1 ; 1H-NMR (400 MHz, CDCl3) δ 1.39 (3H,
t, J = 7.2 Hz), 3.94-4.15 (2H, m), 7.00-7.04 (3H, m), 7.12 (3H, dd, J = 1.6, 7.2 Hz), 7.22-7.30 (2H, m),
7.34-7.36 (2H, m) 7.44 (1H, ddd, J = 1.2, 8.4, 14 Hz), 7.49 (3H, ddd, J = 0.8, 7.2, 14 Hz), 7.55 (1H, d, J =
8.4 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.97 (1H, d, J = 8.4 Hz), 8.07 (1H, d, J = 8.4 Hz); 13C-NMR (100 MHz,
CDCl3) δ 12.7, 37.8, 106.0, 125.0, 125.6, 125.9, 126.0, 126.1, 126.8, 126.9, 127.5, 127.6, 128.2, 128.5,
128.7, 129.3, 130.5, 131.1, 131.7, 131.9, 132.9, 135.3, 140.0, 140.8, 169.5. LRMS (EI) m/z 431 (M+).
HRMS (FAB, NBA) calcd for C29H22NOS: 432.1344 (M+H+). Found: 432.1449.
3-Ethyl-9-(2-phenyl-1-naphthyl)naphtho[2,3-d]thiazol-3-ium chloride (15)
A carefully degassed suspension of 14 (1.33g, 3.08 mmol) in aqueous 5M NaOH (20 mL), ethylene
glycol (20 mL), and diglyme (20 mL) was heated at 150°C for 4 h under nitrogen atmosphere. The
reaction mixture was cooled to 23°C and diluted with EtOAc. The organic extract was washed with
saturated aqueous NH4Cl and water, dried over MgSO4, and filtered. The filtrate was concentrated in
vacuo to give the crude aminothionaphthol (1.22 g). The crude aminothionaphthol was suspended in
triethyl orthoformate (7 mL) under nitrogen atmosphere and HCl (2.1 M in EtOAc, 5 mL) was added at
23°C. After stirring the mixture for 4 h, the mixture was diluted with n-hexane (6mL) and stirred for 1 h.
The resulting precipitates were collected by filtration to give 15 (1.11g, 80%) as pale brown solids. The
pure sample was obtained by reprecipitation from CH2Cl2/ether as slightly yellow crystals: mp >178°C
(decomp) (CH2Cl2/ether); IR (KBr) 3403, 3055, 2918, 1655, 1562, 1525, 1493, 1443, 1343, 893, 823, 768,

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1
704 cm-1; H-NMR (400 MHz, CD3OD) δ 1.72 (3H, t, J = 7.1 Hz), 4.94 (2H, q, J = 7.3 Hz), 6.84-7.03
(4H, m) 7.02 (2H, m), 7.25 (1H, ddd, J = 1.2, 7.2, 14.0 Hz), 7.51 (1H, ddd, J = 0.9, 7.1, 15.0 Hz),
7.60-7.64 (2H, m), 7.71-7.76 (2H, m), 8.06 (1H, d, J = 8.1 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.33 (1H, d, J =
8.4 Hz), 8.97 (1H, s), 10.4 (1H, s). HRMS (FAB, NBA) calcd for C29H22NS: 416.1473 (M+-Cl). Found:
416.1490.
3-Ethyl-9-(2-phenyl-1-naphthyl)-6-(1-pyrrolidinyl)naphtho[2,3-d]thiazol-2(3H)-one (16)
A suspension of 13 (411 mg, 0.805 mmol), Pd(OAc)2 (9.0 mg, 0.040 mmol), BINAP (75.2 mg, 0.121
mmol), sodium t-butoxide (108 mg, 1.13 mmol) and pyrrolidine (134 μL, 1.61 mmol) in toluene (8 mL)
was heated at 75°C for 3 h with stirring under nitrogen atmosphere. After cooling the mixture to 23°C, the
mixture was quenched with aqueous 1 M HCl and extracted with toluene. The organic extract was
washed with water, saturated aqueous NaHCO3, and saturated aqueous brine, dried over MgSO4, and
filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography
on silica gel (n-hexane/EtOAc = 1/0 then 9/1) to give 16 (366 mg, 91%) as pale yellow crystals: mp
283°C (decomp) (EtOAc/n-hexane); IR (KBr) 701, 760, 806, 838, 849, 1140, 1225, 1294, 1421, 1446,
1458, 1510, 1620, 1676 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.37 (3H, t, J = 7.1 Hz), 2.02-2.06 (4H, m),
3.36-3.42 (4H, m), 3.88-3.97 (1H, m), 4.02-4.12 (1H, m), 6.75 (1H, d, J = 8.8 Hz), 7.02-7.06 (3H, m),
7.15-7.20 (5H, m), 7.24-7.30 (2H, m), 7.47 (1H, ddd, J = 1.5, 6.8, 8.2 Hz), 7.64 (1H, d, J = 8.5 Hz), 7.95
13
(1H, d, J = 8.1 Hz), 8.04 (1H, d, J = 8.3 Hz); C-NMR (100 MHz, CDCl3) δ 12.8, 25.6, 37.7, 47.7,
104.07, 104.14, 114.6, 120.1, 123.7, 125.9, 126.2, 127.5, 128.0, 128.5, 128.7, 128.9, 130.8, 131.9, 132.4,
133.9, 135.7, 139.6, 140.9, 145.6, 170.0. HRMS (FAB, NBA) calcd for C33H28N2OS: 500.1922 (M+H+).
Found: 500.1934.
3-Ethyl-9-(2-phenyl-1-naphthyl)-6-(1-pyrrolidinyl)naphtho[2,3-d]thiazol-3-ium chloride (17)
A carefully degassed suspension of 16 (806 mg, 1.61 mmol) in aqueous 2M KOH (8.1 mL), ethylene
glycol (8.1 mL) and diglyme (8.1 mL) was heated at 160°C for 2 h under nitrogen atmosphere. The
reaction mixture was cooled to 23°C and diluted with EtOAc. The whole was washed with saturated
aqueous NH4Cl and water, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give
the crude aminothionaphthol (1.04 g). The crude aminothionaphthol was suspended in triethyl
orthoformate (16 mL) under nitrogen atmosphere and HCl (4M in EtOAc, 4 mL) was added at 23°C.
After stirring for 18 h, the resulting precipitates were collected by filtration to give 17 (693 mg, 81%) as
pale yellow crystals. The pure sample was obtained by reprecipitation from CH2Cl2/ether as slightly
yellow crystals: mp 284°C (decomp) (CH2Cl2/ether); IR (KBr) 701, 762, 831, 1032, 1248, 1382, 1451,
1
1506, 1541, 1615 cm-1; H-NMR (400 MHz, CDCl3) δ 1.77 (3H, t, J = 7.1 Hz), 2.10-2.14 (4H, m),
3.46-3.50 (4H, m), 4.99 (1H, dt, J = 7.1, 14.2 Hz), 5.28 (1H, dt, J = 7.3, 14.4 Hz), 6.93-7.07 (7H, m), 7.14

HETEROCYCLES, Vol. 68, No. 1, 2006
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(1H, dd, J = 2.4, 9.2 Hz), 7.29 (1H, ddd, J = 1.2, 6.8, 11.5 Hz), 7.52-7.56 (2H, m), 7.72 (1H, d, J = 8.3
Hz), 8.03-8.05 (2H, m), 8.18 (1H, d, J = 8.8 Hz), 12.35 (1H, s); 13C-NMR (100 MHz, CDCl3) δ 14.8, 25.5,
47.7, 48.2, 103.1, 110.1, 120.0, 125.4, 126.6, 126.8, 127.3, 127.49, 127.53, 128.0, 128.4, 128.50, 128.54,
130.1, 130.5, 131.7, 132.9, 135.4, 137.2, 140.0, 167.0. HRMS (FAB, NBA) calcd for C33H29N2S:
485.2051 (M+-Cl). Found: 485.2084.
6-Bromo-3-ethyl-9-(2-phenyl-1-naphthyl)naphtho[2,3-d]thiazol-3-ium chloride (18)
A carefully degassed suspension of 13 (388 mg, 0.761 mmol) in aqueous 2M NaOH (6.1 mL), ethylene
glycol (6.1 mL) and diglyme (6.1 mL) was heated at 150°C for 2 h under nitrogen atmosphere. The
reaction mixture was cooled to 23°C and diluted with EtOAc. The organic extract was washed with
saturated aqueous NH4Cl and water, dried over MgSO4, and filtered. The filtrate was concentrated in
vacuo to give the crude aminothionaphthol (412.4 mg). The crude aminothinaphthol was suspended in
triethyl orthoformate (2.3 mL) under nitrogen atmosphere and HCl (4M in EtOAc, 0.76 mL) was added at
23°C. After stirring for 18 h, the resulting precipitates were collected by filtration to give 18 (382 mg,
95%) as pale yellow crystals. The pure sample was obtained by reprecipitation from CH2Cl2/ether as
slightly yellow crystals: mp 150°C (decomp) (CH2Cl2/ether); IR (KBr) 703, 764, 820, 893, 919, 1065,
1308, 1335, 1425, 1494, 1482, 1574, 1610 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.81 (3H, t, J = 7.3 Hz),
5.15 (1H, m), 5.36 (1H, m), 6.83 (1H, d, J = 8.5 Hz), 6.95-7.06 (5H, m), 7.30 (1H, ddd, J = 1.2, 6.8, 8.3
Hz), 7.56 (1H, ddd, J = 1.0, 6.8, 8.1 Hz), 7.61 (1H, s), 7.67 (1H, dd, J = 2.0, 9.3 Hz), 7.74 (1H, d, J = 8.5
Hz), 8.06 (1H, d, J = 8.1 Hz), 8.22 (1H, d, J = 8.5 Hz), 8.44 (1H, d, J = 1.7 Hz), 8.45 (1H, s), 12.73 (1H,
s); 13C-NMR (100 MHz, CDCl3) δ 14.9, 49.0, 13.5, 123.2, 124.8, 126.7, 127.6, 127.7, 127.8, 128.0, 128.2,
128.4, 128.6, 128.8, 130.0, 130.9, 131.0, 131.3, 132.6, 132.8, 133.4, 135.8, 137.0, 139.6, 140.4, 170.0.
HRMS (FAB, NBA) calcd for C29H21NBrS: 494.0578 (M+-Cl). Found: 494.0534.
ACKNOWLEDGEMENTS
This work was financially supported in part by a Grant-in-Aid for Scientific Research (C) from the
Ministry of Education, Culture, Sports, Science, and Technology, Japan. We are grateful to Eisai Co., Ltd.
for partial support of this research and financial support to TN.
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