One pot preparation of amides from azo compounds by Sm/TiCl4

Article abstract of DOI:10.1002/jccs.200500175

Azo compounds were conveniently reduced by a system consisting of Sm/TiCl₄ to produce aniline anions. This anion species reacted smoothly with aliphatic acyl chlorides or acid anhydrides to afford corresponding amides under mild and neutral conditions.

Full text of DOI:10.1002/jccs.200500175

Journal of the Chinese Chemical Society, 2005, 52, 1219-1222
1219
One Pot Preparation of Amides from Azo Compounds by Sm/TiCl4
Xue Lia (
) and Yong-Min Zhanga,b* (
)
aDepartment of Chemistry, Zhejiang University at XiXi Campus, Hangzhou 310028, P. R. China
bState Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
Azo compounds were conveniently reduced by a system consisting of Sm/TiCl4 to produce aniline an-
ions. This anion species reacted smoothly with aliphatic acyl chlorides or acid anhydrides to afford corre-
sponding amides under mild and neutral conditions.
Keywords: Amides; Azo compound; Sm/TiCl4; Reduction.
INTRODUCTION
Amides are important commercial and biological com-
readily identified. Azo compounds can also be reductive
cleavages of an azo linkage of either symmetric or unsym-
metric azoarenes that permits two functional groups to be in-
troduced into the aromatic nuclei, and this is one of the easi-
est methods for the preparation of substituted aminoarenes.
As azoarenes are easily accessible, it would be valuable to de-
velop an easier and simpler method for the reduction of the
N=N bond without affecting the substituents. Previous re-
ports on the reductive cleavage of azoarenes to aminoarenes
have been reviewed.6a The reduction of azo compounds is
pounds. Because amides constitute the backbone of protein
molecules, their chemistry is of extreme importance. The
peniciline and cephalosporin antibiotics are among the best-
known products of the pharmaceutical industry.1 For this rea-
son, the development of new and simple methods for the syn-
thesis of the peptide bond always constitute an important ad-
dition to the field of natural products synthesis. Several gen-
eral methods are available for the preparation of amides,1
such as starting amines with acyl chlorides, acid anhydrides,
esters, carboxylic acids, and carboxylic salts. All of these
methods involve nucleophilic addition-elimination reaction
by ammonia or an amine at an acyl carbon. Amides can also
be made from Beckmann rearrangement2 of ketoximes and
conversion of thioamides into amides.3
usually achieved with Pd/Cyclohexene,6b multimetallic clus-
6c
ter (Mox-1, Wx-1
)
center, KBH4/Cu2Cl2,6d Pd/C,6e NaBH4/
Cp2TiBH4,6f PdMCM-416g and Al/NH2NH2 to form ani-
lines. Kagan6i reported that azobenzene can be reduced by
SmI2 to give moderate yields of amines if methanol is pres-
ent. In our previous work, Li7 reported synthesis of amidines
from azobenzene and nitriles promoted by SmI2 in THF.
To the best of our knowledge, there is no data on syn-
thesis of amides from azobenzene by Sm/TiCl4 directly; here-
in, we wish to present the Sm/TiCl4 mediated reductive cleav-
age of N=N bond in azobenzene and successive acylation to
prepare amides. This reaction can be finished in one pot with-
out separating the intermediate aniline, and the reaction con-
ditions were mild and neutral.
6h
Samarium diiodide (SmI2) has played an ever-increas-
ing role in organic synthesis since its introduction by Kagan’s
group.4 Though SmI2 is a useful reductive reagent, its appli-
cation in organic synthesis is limited to some extent. For ex-
ample, Sm2+ only gives one electron in the reaction, which se-
riously restricts its application in large scale use.
However, metallic samarium is stable in air, and its
strong reducing power (Sm3+/Sm = -2.41 V), is comparable
with that of magnesium (Mg2+/Mg = -2.37 V), and superior to
that of zinc (Zn2+/Zn = -0.71 V). Therefore, the direct use of
metallic samarium as a reducing agent in organic transforma-
tions has attracted considerable attention in recent years.5
On the other hand, azo compounds serve as suitable
models because they are easy to handle and the products are
RESULTS AND DISCUSSION
In order to optimize the reaction, various reactions in
THF solvent using azobenzene (1b) and propanoic anhydride
(2b) as model substrates were studied (Scheme I). Interest-
* Corresponding author. E-mail: yminzhang@mail.hz.zj.cn

1220 J. Chin. Chem. Soc., Vol. 52, No. 6, 2005
Li and Zhang
Table 2. Synthesis of amides from acid anhydrides
ingly, the best proportion of the substrate employed 1:2 = 1:4.
Just as Table 1 shows when 1b:2b = 1:1, the yield of N-phen-
yl propionamide (3b) was only 42%, while when 1b:2b = 1:4,
the yield of 3b was 82%. Notably, temperature influences the
reaction remarkably. Hardly any 3b was observed in such re-
action systems after 5 min at room temperature, and on the
other hand, 3b noticeably increased when the reaction tem-
perature exceeded 65 °C. Generally, according to the results
of the experiment, the ideal temperature for this reaction was
65 °C. And Table 1 also indicated that when the reaction fin-
ished in 5 min, the yield of 3b didn’t improve greatly when
prolonging the reaction time.
Temp. Time Yielda
Entry
Ar1
R1
(°C)
(min)
3 (%)
a
b
c
d
e
f
Ph
Ph
Ph
CH3
65
65
65
65
rt
rt
rt
rt
5
5
5
5
8
74(3a)
82(3b)
81(3c)
83(3d)
75(3e)
85(3f)
84(3g)
81(3h)
CH2CH3
(CH2)2CH3
(CH2)4CH3
CH3
CH2CH3
(CH2)2CH3
(CH2)4CH3
Ph
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
8
8
g
h
100
a Isolated yields based on azobenzene.
Table 3. Synthesis of amides from acyl chlorides
Temp.
Scheme I
Time Yielda
Entry
Ar1
R2
(°C)
(min)
3 (%)
Sm/TiCl
Ar1N=NAr1 (R1CO)2O
1a-1h 2a-2h
Ar1NHCOR1
4
a
b
c
d
e
f
g
h
i
Ph
Ph
Ph
CH3
65
65
65
65
rt
rt
rt
rt
65
6
7
6
76(3a)
85(3b)
83(3c)
80(3d)
79(3e)
87(3f)
89(3g)
84(3h)
95(3i)
3a-3h
CH2CH3
(CH2)2CH3
(CH2)4CH3
CH3
CH2CH3
(CH2)2CH3
(CH2)4CH3
CH2Ph
3a: Ar1= Ph-, R1= CH3-;
3c: Ar1= Ph-, R1= CH3(CH2)2-; 3d: Ar1= Ph-, R1= CH3(CH2)4-;
3e: Ar1= p-MeC6H4-, R1= CH3-;
3f: Ar1= p-MeC6H4-, R1= CH3CH2-;
3g: Ar1= p-MeC6H4-, R1= CH3(CH2)2-;
3h: Ar1= p-MeC6H4-, R1= CH3(CH2)4-.
3b: Ar1= Ph-, R1= CH3CH2-;
Ph
6
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
Ph
100
100
120
150
6
a Isolated yields based on azobenzene.
To explore the generality of this reaction, a series of
aliphatic acyl chlorides and acid anhydrides were subjected
to the acylation with 1 and 2; as anticipated, a variety of
amides were obtained in good to excellent yields in the
Sm/TiCl4 system, as shown in Table 2 and Table 3. Both acyl
chlorides and acid anhydrides could react smoothly to yield
corresponding amides. When acetyl chloride (4a) was used
instead of acetic anhydride (2a) in the reaction, the same
product N-phenylacetamide (3a) was obtained at a higher
yield. This is attributed to the more reactive substrate of acyl
Scheme II
Sm/TiCl
Ar1NHCOR2
R2COCl
Ar1N=NAr1
4
3a-3i
4a-4i
1a-1i
3a: Ar1= Ph-, R1= CH3-;
3c: Ar1= Ph-, R1= CH3(CH2)2-; 3d: Ar1= Ph-, R1= CH3(CH2)4-;
3e: Ar1= p-MeC6H4-, R1= CH3-;
3f: Ar1= p-MeC6H4-, R1= CH3CH2-;
3g: Ar1= p-MeC6H4-, R1= CH3(CH2)2-;
3h: Ar1= p-MeC6H4-, R1= CH3(CH2)4-;
3i: Ar1= Ph-, R1= PhCH2-.
3b: Ar1= Ph-, R1= CH3CH2-;
Table 1. Reactions of 1b and 2b in different conditions
Molar ratio of the
reactants
Temp.
(°C)
Time
(min)
Yielda of 3b
Entry
(%)
chloride than that of the acid anhydride. And all products
were characterized by IR, 1H NMR and MS.
a
b
c
d
e
f
1b:2b = 1:1
1b:2b = 1:2
1b:2b = 1:3
1b:2b = 1:4
1b:2b = 1:4
1b:2b = 1:4
1b:2b = 1:4
65
65
65
65
40
rt
05
05
05
05
10
10
15
42
60
73
82
20
In conclusion, amides can be obtained from moderate
to good yield by Sm/TiCl4 mediated reductive cleavage of the
N=N bond in azo and successive acylation by acyl chloride or
acid anhydride. This one-pot method offers a facile, efficient
and novel route for the synthesis of amides.
trace
85
g
65
a Isolated yields based on azobenzene.

Synthesis of Amides by Sm/TiCl4
J. Chin. Chem. Soc., Vol. 52, No. 6, 2005 1221
163 (M+), 93 (100), 43.
EXPERIMENTAL SECTION
Melting points were uncorrected. Infrared spectra were
PhNHCO(CH2)4CH3 (3d)
mp 97-98 °C (Lit.11 97-98 °C); IR (KBr) u: 3295, 1675
cm-1; 1H NMR d: 0.90 (3H, t, J = 7.2 Hz), 1.30-1.71 (6H, m),
2.33 (2H, t, J = 7.2 Hz), 7.03-7.65 (5H, m), 9.57 (1H, br, s,
NH); MS (m/z): 191 (M+), 93 (100), 77, 43.
1
recorded on a Bruker Vector 22 spectrometer in KBr. H
NMR spectra was measured in d6-DMSO solutions on a
Bruker AC-400 spectrometer with TMS as the internal stan-
dard. Mass spectra were recorded on a HP 5989B MS spec-
trometer (70 eV). THF was distilled from sodium-benzo-
phenone immediately prior to use. Metallic samarium and
other reagents were purchased from commercial sources and
were used without further purification.
p-MeC6H4NHCOCH3 (3e)
mp 148-150 °C (Lit.12 150 °C); IR (KBr) u: 3250, 1655
1
cm-1; H NMR d: 2.13 (s, 3H), 2.31 (s, 3H), 7.03-7.45 (m,
4H), 9.70 (s, 1H); MS (m/z): 149 (M+), 107 (100), 91, 77.
General Procedure
p-MeC6H4NHCOCH2CH3 (3f)
Under nitrogen atmosphere, 1 mmol of azo compound
(1) dissolved in dry THF (1 mL) was added to the solution of
2.2 mmol Sm/TiCl4 in THF (10 mL). The deep blue color of
the solution changed to brown immediately. After 4 mmol
acid anhydrides (2) were added to the mixture, the color of
the solution changed to yellow gradually. When the reaction
was completed (the reaction was monitored by TLC), the re-
action mixture was quenched with 0.1 M hydrochloric acid (2
mL) and extracted with ether (3 ´ 20 mL). The organic phase
was successively washed with water (20 mL), brine (15 mL)
and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure to give crude products, which were
purified by preparative TLC using ethyl acetate and cyclo-
hexane (1:3) as eluent.
mp 124-126 °C (Lit.13 121-123 °C); IR (KBr) u: 3296,
1675 cm-1; 1H NMR d: 1.07 (t, 3H, J = 7.2 Hz), 2.24 (s, 3H),
2.30 (q, 2H), 7.07-7.46 (m, 4H), 9.73 (s, 1H); MS (m/z): 163
(M+), 107 (100), 91, 77, 57.
p-MeC6H4NHCO(CH2)2CH3 (3g)
mp 74-76 °C (Lit.14 74.6-74.8 °C); IR (KBr) u: 3297,
1665 cm-1; 1H NMR d: 0.90 (t, 3H, J = 7.6 Hz), 1.60 (m, 2H),
2.23 (s, 3H), 2.26 (t, 2H, J = 7.2 Hz), 7.08-7.47 (m, 4H), 9.73
(s, 1H); MS (m/z): 177 (M+), 107 (100), 91, 77, 43.
p-MeC6H4NHCO(CH2)4CH3 (3h)
mp 74-75 °C (Lit.15 74-75 °C); IR (KBr) u: 3305, 1669
cm-1; 1H NMR d: 0.87 (t, 3H, J = 7.6 Hz), 1.28 (m, 4H), 1.57
(m, 2H), 2.23 (s, 3H), 2.28 (t, 2H, J = 7.6 Hz), 7.08-7.47 (m,
4H), 9.73 (s, 1H); MS (m/z): 205 (M+), 107 (100), 91, 77,
43.
DATA OF THE PRODUCTS
PhNHCOCH3 (3a)
PhNHCOCH2Ph (3i)
mp 113-115 °C (Lit.8 115-116 °C); IR (KBr) u: 3295,
1665 cm-1; 1H NMR d: 2.03 (s, 3H), 7.02-7.56 (m, 5H), 9.90
(s, 1H); MS (m/z): 135 (M+), 93 (100), 43.
mp 116-118 °C (Lit.16 118-119 °C); IR (KBr) u: 3295,
1
1664 cm-1; H NMR d: 3.63 (s, 2H), 7.05-7.61 (m, 10H),
10.14 (s, 1H); MS (m/z): 211 (M+), 93 (100), 77, 51.
PHNHCOCH2CH3 (3b)
mp 106-108 °C (Lit.9 105-106 °C); IR (KBr) u: 3305,
1665 cm-1; 1H NMR d: 1.08 (t, 3H, J = 6.0 Hz), 2.32 (q, 2H, J
= 6.0 Hz), 7.01-7.60 (m, 5H), 9.82 (s, 1H); MS (m/z): 149
(M+), 93 (100), 57.
ACKNOWLEDGEMENTS
We are grateful to the National Natural Science Foun-
dation of China (Project No: 20072033) and Specialized Re-
search Fund for the Doctoral Program of Higher Education of
China.
PhNHCOCH2CH2CH3 (3c)
mp 91-93 °C (Lit.10 91-92 °C); IR (KBr) u: 3297, 1660
cm-1; 1H NMR d: 0.91 (t, 3H, J = 7.6 Hz), 1.62 (m, 2H), 2.28
(t, 2H, J = 7.6 Hz), 7.03-7.60 (m, 5H), 8.57 (s, 1H); MS (m/z):
Received May 9, 2005.

1222 J. Chin. Chem. Soc., Vol. 52, No. 6, 2005
Li and Zhang
Commun. 1989, 19, 3047. (e) Alper, H.; Vasapollo, G. Tet-
rahedron Lett. 1992, 33, 7477. (f) Dosa, P.; Kronish, I.;
McCallum, J.; Schivartz, J.; Barden, M. C. J. Org. Chem.
1996, 61, 4886. (g) Selvam, P.; Sonavane, S. V.; Mohapatra,
S. K.; Jayaram, R. V. Tetrahedron Lett. 2004, 45, 3071. (h)
Pasha, M. A.; Nanjundaswamy, H. M. J. Chem. Res(s).
2004, 750. (i) Souppe, J.; Danon, L.; Namy, J. L.; Kagan, H.
B. J. Organomet. Chem. 1983, 250, 227.
REFERENCES
1. Atkins, R. C.; Carey, F. A. Organic Chemistry, A Brief
Course; McGraw-Hill: New York, 1997, 362.
2. (a) Donaruma, L .G.; Heldt, W. Z. Org. React. 1960, 11, 1.
(b) Gawley, R. E. Org. React. 1988, 35, 1.
3. Movassagh, B.; Meibodi, F.; Sobhani, S. Indian J. Chem.
2002, 41B, 1296.
7. Li, Z. F.; Zhang, Y. M. Chin. Chem. Lett. 2000, 495.
8. Dictionary of Organic Compounds. 5th Ed. Chapman and
Hall: New York, 1982.
9. Weast, R. C.; Graffelli, J. G. Handbook of Data on Organic
Compounds; 2nd Ed.; 1989.
4. (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc.
1980, 102, 2693-2698. (b) Krief, A.; Laval, A. M. Chem.
Rev. 1999, 99, 745-777. (c) Molander, G. A. Acc. Chem. Res.
1998, 31, 603-609. (d) Molander, G. A.; Harris, C. R. Tetra-
hedron 1998, 54, 3321-3354. (e) Molander, G. A.; Harris, C.
R. Chem. Rev. 1996, 96, 307-338.
5. (a) Reviews see: Banik, B. K. Eur. J. Org. Chem. 2002,
2431-2444. (b) Li, X.; Zhang, S.; Wang, Y.; Zhang, Y. J.
Chin. Chem. Soc. 2002, 49, 1111. (c) Li, X.; Zhang, S.;
Zhang, X.; Wang, X. J. Chin. Chem. Soc. 2003, 50, 1043. (d)
Li, X.; Zhang, S.; Zhang, Y. J. Chin. Chem. Soc. 2004, 51,
347.
10. Cruess, W. V.; Alsberg, C. L. J. Am. Chem. Soc. 1934, 56,
2117.
11. Ueda, M.; Kawaharasaki, N.; Imai, Y. Synthesis 1982, 933.
12. Sharghi, H.; Hosseini, M. Synthesis 2002, 1057.
13. DE Feo, R. J.; Strickler, P. D. J. Org. Chem. 1963, 28, 2915.
14. Urry, W. H.; Nishihara, A.; Niu, H. Y. J. Org. Chem. 1967,
32, 347.
15. Underwood, H. W.; Gale, J. C. J. Am. Chem. Soc. 1934, 56,
117.
16. Shioiri, T.; Yokoyama, Y.; Kasai, Y.; Yamada, S. Tetrahe-
dron 1976, 32, 2211.
6. (a) Gilchrist, T. L. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Ed.; Pergamon Press: Oxford,
1991, 8, 381. (b) Ho, T. L.; Olah, G. A. Synthesis 1977, 169.
(c) Sobota, P.; Pluzi½ski, T.; Rummel, S. Tetrahedron 1981,
37, 939. (d) He, Y.; Zhao, H.; Pan, X.; Wang, S. Synth.