Reaction of Nitric Oxide with Amines

Article abstract of DOI:10.1021/jo962101e

Reactions of nitric oxide (NO) with amines in organic solvents were studied using Hantzsch dihydropyridines and aromatic primary amines as substrates. Hantzsch dihydropyridines are readily oxidized by nitric oxide to give the corresponding pyridines in quantitative yields. The addition of oxygen accelerates the reaction rate considerably. On the other hand, aromatic primary amines give deaminated products by the reaction with nitric oxide only in the presence of oxygen in ethereal solvents or chloroform.

Full text of DOI:10.1021/jo962101e

3
582
J . Org. Chem. 1997, 62, 3582-3585
Rea ction of Nitr ic Oxid e w ith Am in es
Takashi Itoh, Kazuhiro Nagata, Y uˆ ji Matsuya, Michiko Miyazaki, and Akio Ohsawa*
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, J apan
Received November 11, 1996X
Reactions of nitric oxide (NO) with amines in organic solvents were studied using Hantzsch
dihydropyridines and aromatic primary amines as substrates. Hantzsch dihydropyridines are
readily oxidized by nitric oxide to give the corresponding pyridines in quantitative yields. The
addition of oxygen accelerates the reaction rate considerably. On the other hand, aromatic primary
amines give deaminated products by the reaction with nitric oxide only in the presence of oxygen
in ethereal solvents or chloroform.
Because of the well-recognized importance of nitric
Ta ble 1. Ar om a tiza tion of Ha n tzsch Dih yd r op yr id in es 1
w ith Nitr ic Oxid e u n d er Ar Atm osp h er e
1
oxide (NO), many papers have been presented concern-
ing biological and cytotoxic roles of NO. Studies on the
chemical reactivity of NO were also begun only recently.
The reported reactions can be divided into two categories,
sub-
yield
(%)
entry strate
R1
R2
H
condns
product
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
CO
2
Et
benzene, rt, 3 h
2a
96
99
96
97
96
97
95
100
2
3
ClCH
Et Me benzene, rt, 4.5 h
ClCH CH Cl, rt, 2.5 h
benzene, rt, 3 h
ClCH CH Cl, rt, 1 h
benzene, rt, 3 h
ClCH CH Cl, rt, 3 h
Et 3-CHa benzene, rt, 2 h
ClCH CH Cl, rt, 1 h
Et Ph benzene, rt, 3 h
2 2
CH Cl, rt, 3 h
those using NO under oxygen atmosphere and others
CO
2
2b
2c
2d
that are performed only with NO in the presence or
2
2
4
absence of an inert gas. Recently, we reported two
CO Et
Et
Pr
2
reactions of NO with amino compounds that involve
2
2
5
6
CO
CO
CO
2
2
2
Et
Hantzsch dihydropyridines and aromatic primary amines
2
2
as substrates in organic solvents. The reaction was
clarified with respect to the influence of oxygen, and it
was found that a catalytic amount of oxygen affected
these two reactions in different manners. This paper
describes these results.
b
2e (2a ) 34 (47)
10
2
2
29 (67)
96
1
1
1
1
1
2
3
4
2f
ClCH
2
2
2
CH
CH
CH
2
2
2
Cl, rt, 5.5 h
Cl, rt, 1 h
Cl, rt, 2 h
92
99
92
1g
1h
CN
i-Pr ClCH
2g
2h
CN 3-CHa ClCH
The oxidation of Hantzsch 1,4-dihydropyridines 1 is an
old reaction in general organic chemistry. Even in recent
years, several groups have reported new methods for
aromatization including oxidations with ferric or cupric
a
-Cyclohexenyl is abbreviated as 3-CH. b In the case of 1e, 2a
3
was obtained in 47% (in benzene) and 67% (in ClCH2CH2Cl) yields
other than 2e.
7
8
all these reactions require different workup procedures.
In our experiments, we found that NO oxidized Hantzsch
dihydropyridines to give the corresponding pyridine
derivatives in quantitative yields.
nitrates on a solid support, ceric ammonium nitrate,
clay-supported cupric nitrate accompanied by ultrasound-
9
10
promotion, or pyridinium chlorochromate. There has
also been a general method using nitric acid,11 although
X
Resu lts a n d Discu ssion
Abstract published in Advance ACS Abstracts, May 1, 1997.
(
1) Methods in Nitric Oxide Research; Feelisch, M., Stamler, J . S.,
Ed.; J ohn Wiley &Sons: Chichester, 1996.
2) (a) de la Breteche, M.-L.; Servy, C.; Lenfant, M.; Ducrocq, C.
Rea ction of Ha n tzsch 1,4-Dih yd r op yr id in es w ith
NO. Compound 1 was dissolved in benzene or 1,2-
dichloroethane under Ar atmosphere, and NO was in-
troduced to the reaction system with a gas-tight syringe
(eq 1). After the consumption of the starting material,
the solvent was evaporated to leave almost pure product
except in the case of 1e (Table 1).
(
Tetrahedron Lett. 1994, 35, 7231. (b) Nagano, T.; Takizawa, H.; Hirobe,
M. Tetrahedron Lett. 1995, 36, 8239. (c) d’Ischia, M. Tetrahedron Lett.
1
995, 36, 8881. (d) d’Ischia, M. Tetrahedron Lett. 1996, 37, 5773.
3) (a) Korth, H.-G.; Ingold, K. U.; Sustmann, R.; de Groot, H.; Sies,
(
H. Angew. Chem., Int. Ed. Engl. 1992, 31, 891. (b) Wilcox, A. L.;
J anzen, E. G. J . Chem. Soc., Chem. Commun. 1993, 1377. (c) J anzen,
E. G.; Wilcox, A. L.; Manoharan, V. J . Org. Chem. 1993, 58, 3597. (d)
Freeman, F.; Huang, B.-G.; Lin, R. I.-S. J . Org. Chem. 1994, 59, 3227.
(
e) Mukaiyama, T.; Hata, E.; Yamada, T. Chem. Lett. 1995, 505. (f)
Hata, E.; Yamada, T.; Mukaiyama, T. Bull. Chem. Soc. J pn. 1995, 68,
629.
4) Pryor et al. reported that a small amount of oxygen changes the
3
v
(
reactivity of NO toward thiols: (a) Pryor, W. A.; Church, D. F.;
Govindan, C. K.; Crank, G. J . Org. Chem. 1982, 47, 156. Related papers
were published recently; see: (b) Kharitonov, V. G.; Sundquist, A. R.;
Sharma, V. S. J . Biol. Chem. 1995, 270, 28158. (c) Goldstein, S.;
Czapski, G. J . Am. Chem. Soc. 1996, 118, 3419. There have been some
reports that suggest that minute quantities of O
2
, which was not added
Substrate 1e was transformed to a mixture of 4-(3-
cyclohexenyl)pyridine 2e and 4H-pyridine 2a , which were
separated by silica gel chromatography. Substrates 1g
and 1h have poor solubilities in benzene; thus, the
reaction was performed only in 1,2-dichloroethane solu-
tion (Table 1, entries 13 and 14). The influence of oxygen
on the reaction yield was investigated using 1a as a
to the reaction mixtures deliberately, might bring about reactions of
substrates with NO; see: (d) Challis, B. C.; Kyrtopoulos, S. A. J . Chem.
Soc., Perkin Trans. 1 1979, 299. (e) Afzal, M.; Walton, J . C. BioMed.
Chem. Lett. 1996, 6, 2329.
(
5) Itoh, T.; Nagata, K.; Okada, M.; Ohsawa, A. Tetrahedron Lett.
995, 36, 2269.
6) Itoh, T.; Matsuya, Y.; Nagata, K.; Ohsawa, A. Tetrahedron Lett.
996, 37, 4165.
7) Balogh, M.; Hermecz, I.; Meszaros, Z.; Laszlo, P. Helv. Chim.
Acta 1984, 67, 2270.
1
1
(
(
(
8) Pfister, J . R. Synthesis 1990, 689.
(10) Eynde, J .-J . V.; Mayence, A.; Maquestiau, A. Tetrahedron 1992,
48, 463.
(9) Maquestiau, A.; Mayence, A.; Eynde, J .-J . V. Tetrahedron Lett.
1
991, 32, 3839.
(11) B o¨ cker, R. H.; Guengerich, F. P. J . Med. Chem. 1986, 29, 1596.
S0022-3263(96)02101-9 CCC: $14.00 © 1997 American Chemical Society

Reaction of Nitric Oxide with Amines
J . Org. Chem., Vol. 62, No. 11, 1997 3583
Ta ble 2. Effect of Oxygen on th e Rea ction Yield of 2a a
Ta ble 4. Ar om a tiza tion of Ha n tzsch Dih yd r op yr id in es 1
w ith Nitr ic Oxid e u n d er O2 Atm osp h er e
amount of
O2 (µL)
ratio of
O2/NO
yield of
2a (%)
entry
amount of NO
(equiv to 1)
yield
(%)
entry substrate
condns
product
1
2
3
4
0
5
12.5
20
0
39
56
66
0.0002
0.0005
0.0008
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
0.2
0.6
0.7
0.6
0.5
0.7
benzene rt,
under O2,
10 min
2a
2b
2c
2d
98
84
89
97
100
a
The reaction of 1a was carried out with 10 equiv of NO in
a
2e (2a ) 0 (97)
2f
dichloroethane for 2 h.
95
Ta ble 3. In flu en ce of th e Solven t on th e Rea ction of 1a
7
1a
0.001
benzene, rt,
under O2,
2a
93
a
w ith NO (20 equ iv) u n d er Ar
7
days
solvent
yield of 2a (%)
solvent
yield of 2a (%)
a
In the case of 1e, 2a was obtained as a sole product.
benzene
DCE
CHCl3
96
99
94
CH3CN
CH3OH
THF
91
20
18
4. A radical coupling of 4 with NO might form N-nitroso
derivative 5, which eliminates HNO to afford the aro-
a
The reaction time is 3 h for all the reactions.
matized product. In the case of N
seems reasonable that N should react with 1 in
catalytic fashion. Thus, the reaction of 1 with N
might release NO , which regenerates another N
the reaction with excess NO.
2 3
O as an oxidant, it
Sch em e 1
2 3
O
2
O
3
O by
2 3
2
Other nitrogen oxides are also reactive toward
Hantzsch dihydropyridines. Thus, 1a was aromatized
with 1 equiv of NO under Ar to give 94% of 2a after 44
h reaction. The stoichiometry of the reaction suggests
-
that HNO (or NO ) might also react with 1a , although
the reaction mechanism remains unclear.
The use of a smaller amount of NO completed the
reaction in a similar manner when excess O
see Table 4). There is, however, one noticeable differ-
ence between the results of Tables 1 and 4. Namely,
substrate 1e afforded 2a as a sole product under O
atmosphere (Table 4, entry 5), while it gave a mixture of
a and 2e under Ar (Table 1, entries 9 and 10). In this
2
was used
(
2
substrate. The results obtained show that a trace
amount of oxygen highly accelerates the reaction rate
2
system, an active species might be NO
2
, which oxidizes
(Table 2, entries 2-4).
1
accompanied by the formation of NO, and NO thus
It is well known that NO rapidly reacts with O
2
to give
16
obtained is reoxidized to NO
2
2
by excess O .
nitrogen dioxide NO
formed to nitrous anhydride N
excess NO.12 Therefore, the acceleration shown above is
probably due to the higher reactivity of N (or NO
than that of NO; N (or NO ) is supposed to react with
in a catalytic fashion. Provided that O added to the
reaction system is transformed to N (or NO ) stoichi-
ometrically, the reactivity of N (or NO ) toward 1a
2
, and NO
2
thus formed is trans-
Rea ction of Ar om a tic P r im a r y Am in es w ith Ni-
tr ic Oxid e in th e P r esen ce of a Ca ta lytic Am ou n t
of Oxygen . The above results prompted us to initiate
an investigation of the reactivity of nitric oxide with other
amines. Although aromatic primary amines were re-
2
3
O in the presence of
2
O
3
2
)
2
O
3
2
1
2
2
ported to react with NO in the presence of excess O to
2
O
3
2
2b
afford triazene derivatives in benzene solution, it was
found that the same substrates reacted with NO in the
2
13
O
3
2
3
14
may be about 10 times higher than that of NO.
The investigation of solvent effects (Table 3) shows that
basic solvents give poor reaction yields, which is in accord
with the results reported previously for the reaction of
2
presence of a catalytic amount of O to give deaminated
6
products in ethereal solvents or chloroform. Our previ-
ous communication6 did not include any information
about the influence of oxygen. Further investigations
3
e,f
NO with alkenes.
revealed that ca. 0.000 05 equiv of O
for the reaction progress (1 µL of O
2
in NO was crucial
in 22.4 mL of NO).
The presumed reaction mechanism is shown in Scheme
. The reaction might commence with a hydrogen
abstraction from the NH group in dihydropyridine or
one-electron transfer from 1 to NO to give the ammoni-
umyl radical 3, and both paths lead to an aminyl radical
2
1
The reaction proceeded in moderate to high yields except
for aromatic amines, which have an electron-donating
1
5
17
group in their meta position (eq 2 and Table 5).
v
(
12) Von Gratzel, M.; Taniguchi, S.; Henglein, A. Ber. Bunsenges.
Phys. Chem. 1970, 74, 488.
13) For example, in the case of entry 2 in Table 2, N
formed at 1/2500 of NO, and the reaction yield was 1.435 times higher
than that in the absence of oxygen. Thus, the reactivity of N might
(
2 3
O might be
2
O
3
be 1087 times higher (0.435 × 2500) than that of NO. The calculations
using data of Table 2, entries 3 and 4, give the values 692 and 978,
respectively.
The reaction produced a transient precipitate, which
slowly dissolved in the solvent to afford the deaminated
product. When the precipitate in THF was isolated and
dissolved in water followed by the addition of N,N-
2
(14) Korth et al. reported that NO reacts at least 200 times as
rapidly as NO with 7,7,8,8-tetramethyl-o-quinodimethane: Korth, H.-
G.; Sustman, R.; Lommes, P.; Ernst, A.; de Groot, H.; Hughes, L.;
Ingold, K. U. J . Am. Chem. Soc. 1994, 116, 2767. The result is in
agreement in the order of magnitude with our estimation.
2
(16) The organic reactions using NO and excess dioxygen were
(
15) When 1 was methylated at N-1, it was inert to this reaction.
throughly investigated by Kochi et al. including detailed reaction
mechanisms; see: Bosch, E; Kochi, J . K. J . Am. Chem. Soc. 1996, 118,
1319 and references cited therein.
Thus, we supposed that an initial hydrogen abstraction might not occur
at the C-4 position.

3
584 J . Org. Chem., Vol. 62, No. 11, 1997
Itoh et al.
Ta ble 7. Solven t Effects on th e Dea m in a tion of
Ta ble 5. Dea m in a tion of Ar om a tic Am in es 6 w ith NO in
THF u n d er Ar Atm osp h er e w ith a Ca ta lytic Am ou n t of O2
(Meth ylth io)a n ilin e (6d ) Usin g NO in th e P r esen ce of a
Ca ta lytic Am ou n t of Oxygen a
entry
substrate
X
time (h)
product
yield (%)
solvent
yield of 7d (%)
solvent
yield of 7d (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
2
6
24
2
5
3
3
2
2
2
7a
7b
7c
7d
7e
7f
7g
7h
7i
86a
71
20
74
o-SMe
m-SMe
p-SMe
o-Cl
m-Cl
p-Cl
o-NO2
m-NO2
p-NO2
o-OMe
m-OMe
p-OMe
THF
82
80
81
benzene
CH3CN
CDCl3
tracee
22
CHCl3
b
f
DME
56
a
DCEc
d
88
87
82
43
a
a
a
The reaction time is 2 h except in the case of CDCl3 (24 h).
b
,2-Dimethoxyethane. c 1,2-Dichloroethane. d In addition to 7d ,
1
93
78
90
55
trace
64
e
trace amount of methyl phenyl sulfoxide was detected. 4-(Meth-
ylthio)biphenyl was obtained in 28% yield. f p-Deuteriated 7d was
obtained as a sole product.
1
1
1
1
6j
7j
7k
7l
b
6k
5
24
7
b
6l
Ta ble 8. In flu en ce of NO Am ou n t on th e Rea ction Yield s
b
6m
7m
amount of
NO (equiv)
reaction
time (h)
yield of
7 (%)
a
Determined by HPLC analysis. Other yields were obtained
substrate
b
from the NMR data. The reactions were carried out in the
presence of 2 µL of O2. The other experiments were with 1 µL of
O2.
6g
6g
3
2
3
96
144
96
87
35
66
6
d
Sch em e 2
v
stituent. In contrast, the deaminated products were
obtained in higher yields when an electron-withdrawing
substituent exists on the aniline ring (Table 5), which
indicates that the second step involves a reductive
process that requires a trace amount of oxygen.
The effect of solvent was examined for the deamination
of 6d (Table 7). Ethereal solvents and chloroform af-
forded good results. On the other hand, 1,2-dichloro-
ethane and benzene, which were used for the reaction of
Ta ble 6. In flu en ce of Oxygen on th e Rea ction Yield s of 7
1
NO,
, and previously reported solvents for the reaction of
2
b,3e,f
amount of O2
(equiv to NO)
yield of
7 (%)
recovery of
were less effective in the deamination. In
entry
substrate
6 (%)
benzene solution, 4-(methylthio)biphenyl was obtained
in 28% yield as a side product. When CDCl was used
for the solvent, the reaction proceeded more slowly than
with CHCl , and the product isolated was p-deuterio-
thioanisole. The results show that hydrogen abstraction
from the solvent (CHCl ) is required to form the deami-
1
2
3
4
5
6
7
6d
6d
6g
6g
6g
6g
6g
0
trace
82
8
82
91
0
0
68
0
0
0
3
0.000 05
0
0.000 05
0.005
0.05
0.5
3
86
66
3
0
nated product. Thus, a phenyl radical was suggested to
be one of the intermediates of the reaction.
dimethylaniline, an azo product 8a18 was obtained (Scheme
In addition, when the reaction of 6d was carried out
in carbon tetrachloride, 4-chlorothioanisole was obtained
in 52% yield. Moreover, in the presence of diphenyl
disulfide in benzene, compound 6d afforded 1-(meth-
ylthio)-4-(phenylthio)benzene in 29% yield along with
2
). This result indicates that the deaminated product is
1
9
formed via the intermediacy of a diazonium salt.
2
Influence of O on the reaction yields was studied using
6
d (X ) p-SMe) and 6g (X ) p-Cl) as substrates, and the
results are summarized in Table 6 (eq 3). Even without
3
8% of 4-(methylthio)biphenyl. These facts also support
the intermediacy of a phenyl radical.
v
In order to estimate the stoichiometry, the reaction was
carried out using a decreased amount of NO in the
presence of oxygen. It was necessary to lengthen the
reaction time under these conditions. Thus, p-chloro-
aniline (6g), which is the most susceptible substrate in
the reaction, was treated with 3 equiv of NO for 96 h in
the addition of O
2
, consumption of 6 was observed (Table
6
, entries 1 and 3). Compound 6d , which has an electron-
the presence of 0.1 equiv of O
7% yield. Compound 6d afforded the product in 66%
2
to give chlorobenzene in
donating group, was consumed more completely than 6g.
Thus, the first step is suggested to involve an oxidative
process that is accelerated by an electron-donating sub-
8
yield under the same conditions (Table 8). Thus, 3 equiv
of NO is sufficient for the completion of the reaction,
although the reaction rate was too slow to clarify the real
stoichiometry.
The above reaction seems to proceed by two steps, that
is, the formation of phenyl diazonium salts and succeed-
ing reductive denitrogenation. In addition, the necessity
(17) It was reported that phenyldiazonium salts that have an
electron-donating group on the meta position were unstable compared
to their o- or p-substituted counterparts. See: Swain, C. G.; Sheats, J .
E.; Harbison, K. G. J . Am. Chem. Soc. 1975, 97, 783.
(
18) Westheimer, F. H.; Segel, E.; Schramn, R. J . J . Am. Chem. Soc.
947, 69, 773.
19) The low yield of the azo product 8a suggests the possibility that
1
(
of a trace amount of O
catalytic amounts of N
2
for the deamination indicates that
(or NO ) plays a crucial role
all of the precipitate may not be the corresponding diazonium salt.
Drago et al. have shown that primary and secondary amines reacted
with NO at -78 °C in ether to form precipitates that were characterized
as complexes of amines and NO: (a) Drago, R. S.; Paulik, F. E. J . Am.
Chem. Soc. 1960, 82, 96. (b) Drago, R. S.; Karstetter, B. R. J . Am.
Chem. Soc. 1961, 83, 1819. Our precipitate might comprise this type
of complex, although it was reported in ref 19b that aniline did not
form the stable one.
2
O
3
2
for the reaction. Furthermore, 3 equiv of NO seems to
be necessary, although there remains the possibility that
a smaller amount is sufficient for completion of the
reaction. Therefore, the total reaction scheme may be
summarized as shown in Scheme 3. A detailed reaction

Reaction of Nitric Oxide with Amines
J . Org. Chem., Vol. 62, No. 11, 1997 3585
Sch em e 3
4-8 mesh soda lime to remove NO
x
impurities. Hantzsch
dihydropyridines were synthesized by the reported methods.
9
,24
Gen er a l P r oced u r e for th e Ar om a tiza tion of Ha n tzsch
Dih yd r op yr id in es. A Hantzsch dihydropyridine 1 (50 µmol)
was placed in a two-necked flask (vol. ca. 35 mL) equipped
with a septum ruber and three-way stopcock, one way of which
was attached to an Ar balloon, and the other jointed to a pump.
The flask was degassed under vacuo and filled with Ar gas.
These operations were repeated five times. Freshly distilled
1
,2-dichloroethane (2.5 mL) was added, the solution was
bubbled with dry Ar gas for 20 min, and then the flask was
sealed. NO gas was through a column of soda lime, measured
at 22.4 mL using a Hamilton gas-tight syringe, and then added
to the reaction vessel. The inner pressure is estimated at
about 160 kPa. The reaction mixture was allowed to react for
several hours at room temperature. Then Ar was bubbled for
degassing of excess NO, and the solvent was evaporated to
leave almost pure compound 2, which was further purified
with a short column of alumina. Among the aromatized
mechanism is now under investigation.
Su m m a r y a n d Con clu sion s
In this paper, we have described two reactions of
amines with NO and the effect of O
Hantzsch dihydropyridines aromatize in quantitative
yields by the reaction with NO in the absence of O . The
2
on these reactions.
2
products, 2a -d ,f,h were identified by comparing their physical
reaction proceeded smoothly without any side reaction,
and the products are isolated as almost pure compounds
only after solvent evaporation. Thus, this reaction
system might be superior to previous methods for aro-
matization. Aromatic primary amines react with NO in
and spectrometric data with reported data.1
0, 24
Compound 2g
was a known compound as an oil, but its spectral data were
not reported. 2g: 1H-NMR (CDCl
) δ 1.53 (6H, d, J ) 7.3 Hz),
13
3
2
2
.80 (6H, s), 3.59 (1H, sep, J ) 7.3 Hz); C-NMR (CDCl ) δ
0.34, 24.56, 33.88, 106.43, 115.29, 164.13; HRMS m/ z (M )
3
+
THF in the presence of catalytic amounts of O
deamination. This reaction is unique in that N
NO ) acts as a reductant-like species and that the
2
to undergo
12
calcd for C H13N3 199.1109, found 199.1119. Compound 2e
1
O
3
(or
is a new compound obtained as an oil. 2e: H-NMR (CDCl
3
)
2
δ 1.37 (6H, t, J ) 7.2 Hz), 1.78-2.22 (6H, m), 2.48 (6H, s),
2
1
3
2
(
1
.77 (1H, m), 4.39 (4H, q, J ) 7.2 Hz), 5.68 (2H, bs); C-NMR
addition of a sufficient amount of oxygen decreases the
reaction yields instead. It was reported that nitrosoal-
kanes reacted with NO to bring about the formation of
CDCl ) δ 14.02, 22.66, 26.26, 26.81, 31.22, 40.00, 61.65, 126.35,
26.54, 127.14, 148.29, 154.80, 169.23; HRMS m/ z (M ) calcd
331.1783, found 331.1754.
3
+
for C19
H25NO
4
2
0
alkyl radicals via diazonium intermediates. Our reac-
tion might proceed through a similar mechanism, though
the details need further investigation. Deamination of
Gen er a l P r oced u r e for th e Dea m in a tion of Ar om a tic
Am in es. The sampling and degassing processes were as same
as those of Hantzsch dihydropyridines. Freshly distilled THF
(2.5 mL) was added, and the solution was bubbled with dry
aromatic primary amines is an important substitution
reaction,21 and there are many reports concerning the
Ar gas for 20 min. Then the flask was sealed, and O (1 µL)
2
was added with a micro syringe. NO gas was added to the
reaction vessel, and the reaction mixture was allowed to stand
for several hours at room temperature. During this time,
formation of a precipitate was observed in the solvent, which
was dissolved through the reaction progress. Then Ar was
bubbled for degassing of excess NO. Thereafter, the solvent
was evaporated off, and the product yield was determined by
NMR using mesitylene as an internal standard or was
estimated by HPLC using naphthalene as an internal stan-
dard.
hydrogen donors including hypophosphorous acid as a
standard.22 Our reaction system seems to be of synthetic
use since the reaction is performed under mild condi-
tions23 using a gaseous reagent. The applications of these
reactions to other amino compounds are now in progress.
Exp er im en ta l Section
A melting point was taken on a B u¨ chi 535 micro melting
point apparatus and is uncorrected. The mass spectrum was
recorded on J EOL J MS-SX102A instrument. The nuclear
magnetic resonance spectra (NMR) were measured with J EOL
GX400 and LA500 spectrometers using tetramethylsilane as
an internal standard. HPLC analysis was performed using
J ASCO TRI ROTAR-V pump and J ASCO UVIDEC-100-V UV
spectrophotometer.
Ma ter ia ls. All chemicals are of analytical grade and were
used as received. It was necessary, however, to distill the
reaction solvents freshly in order to obtain reproducible results.
Nitric oxide gas (99.9%) was purchased from Takachiho
Chemical Company Ltd. and was passed through a column of
Dia zo Cou p lin g of a n In ter m ed ia te of 6a . Aniline (0.2
mmol) was allowed to react in THF (10 mL) with NO (90 mL)
and O
(1 µL) under the same conditions mentioned above for
2
10 min. A precipitate thus formed was filtered and dissolved
in 5 mL of 25% aqueous NaOAc solution. Then dimethyl-
aniline (0.2 mmol) was added, and the mixture was allowed
to react for 10 min at room temperature. The solution was
made basic with 1 N aqueous NaOH, and the mixture was
extracted with CH
MgSO and evaporated off to leave a residue, which was
chromatographed on silica gel to give 2.5 mg (6%) of orange
2 2
Cl . The organic layer was dried over
4
1
8
1
needles 8a : mp 113-115 °C (lit. mp 114-117 °C); H-NMR
(
CDCl ) δ 3.08 (6H, s), 6.76 (2H, d, J ) 8.0 Hz), 7.38 (1H, m),
7.47 (2H, m), 7.83 (2H, m), 7.88 (2H, d, J ) 8.0 Hz).
3
(20) (a) Brown, J . F., J r. J . Am. Chem. Soc. 1957, 79, 2480. (b)
Birchall, J . M.; Bloom, A. J .; Haszeldine, R. N.; Willis, C. J . J . Chem.
Soc. 1962, 3021. (c) Tuaillon, J .; Perrot, R. Helv. Chim. Acta 1978, 61,
Th e R ea ct ion of 6d in t h e P r esen ce of Dip h en yl
Disu lfid e. The reaction was carried out under the same
conditions as mentioned in the above general procedure except
that 2 equiv of diphenyl disulfide was added in the reaction
mixture and benzene was used as solvent. The structures of
4-(methylthio)biphenyl and 1-(methylthio)-4-(phenylthio)ben-
zene were determined by comparing physical and spectromet-
5
58.
21) Wulfman, D. S. The Chemistry of Diazonium and Diazo Groups.
(
In The Chemistry of the Functional Groups; Patai, S., Ed.; Wiley: New
York, 1978; pp 286-287.
(
22) Wassmundt, F. W.; Kiesman, W. F. J . Org. Chem. 1995, 60,
1
713 and references cited therein.
23) It was revealed that the same reaction process was applied to
-aminothiazole and 3-amino-1,2,4-triazines, which gave poor results
(
2
25,26
ric data with the reported data.
by the use of the conventional methods, to give the corresponding
deamination products in good yields. The detailed results will be
reported in a near future.
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture of
J apan.
(
24) Loev, B.; Snader, K. M. J . Org. Chem. 1965, 30, 1914.
(25) Supniewski, J .; Rogoz, F.; Krupinska, J . Bull. Acad. Polon. Sci.,
Ser. Sci. Biol. 1961, 9, 235.
26) Torii, S.; Matsuyama, Y.; Kawasaki, K.; Uneyama, K. Bull.
Chem. Soc. J pn. 1973, 46, 2912.
(
J O962101E