Facile Synthesis of Amidines via the Intermolecular Reductive Coupling of Nitriles with Nitro Compounds Induced by Samarium(II) Iodide

Article abstract of DOI:10.1039/a803011a

The intermolecular reductive coupling of nitriles with nitro compounds induced by Sml₂ was studied; amidine derivatives are prepared in good yields under neutral and mild conditions.

Full text of DOI:10.1039/a803011a

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596 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 596±597$
Facile Synthesis of Amidines via the Intermolecular
Reductive Coupling of Nitriles with Nitro
Compounds Induced by Samarium(II) Iodide$
Longhu Zhou% and Yongmin Zhang*
Department of Chemistry, Hangzhou University, Hangzhou, 310028, PR China
The intermolecular reductive coupling of nitriles with nitro compounds induced by SmI2 was studied; amidine derivatives
are prepared in good yields under neutral and mild conditions.
Applications of samarium diiodide in organic synthesis
have grown signi®cantly in the last decade.1 Pioneering
work performed by Kagan2 with SmI2 has served to outline
the uses of this reagent in synthetic organic chemistry.
Kagan's investigations have been followed by reports from
other scientists, revealing that SmI2 is an exceedingly
reliable, mild, neutral, selective and versatile single electron
transfer reagent for promoting reductive coupling reactions
dicult to accomplish by any other existing methodologies.
For instance, Barbier reactions, Reformatsky reactions,
pinacol couplings and ketone±ole®n reductive couplings
have been reported using SmI2 as a reagent substitute. The
reactivity of SmI2 towards various nitrogen compounds
including nitro compounds,3 azo compounds,4 hydra-
Table 1 Intermolecular reaction of nitro compounds with
nitriles induced by SmI2
a
Entry
R1
R2
t/h
Yield (%)b
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
C6H5
C6H5
C6H5
C6H5
C6H5CH2
C6H5CH2
C6H5CH2
p-ClC6H4
p-ClC6H4
p-ClC6H4
C6H5
2
4
1
1
4
4
2
2
2
1
4
3
1
2
2
69
67
62
57
67
59
70
82
87
78
74
71
72
0c
p-CH3C6H4
o-CH3C6H4
C6H5
p-CH3C6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4
C6H5
p-ClC6H4
p-ClC6H4
p-CH3C6H4
C6H5
CH3
CH3
m-CH3C6H4
m-CH3C6H4
m-CH3C6H4
C6H5
3b
3b
zones,3b,5 oximes,
imines,
azides6 and hydroxylamines7
C6H5CH2
0c
has been examined. Recently, we have reported a novel
cyclodimerization of arylidenecyanoacetates promoted by
SmI2.8
Amidines are the nitrogen analogues of carboxylic acids
and this unit is part of several compounds of biological
interest.9 They can be prepared by reacting aromatic amines
with nitriles under intensive reaction conditions,10 such as
high temperatures and long reaction times, using sodium or
lithium.
Nitro groups are known to be easily reduced by SmI2.
The cyano group, however, is more stable to SmI2 than the
nitro group and could not be coupled by this reagent.
Souppe and Kagan3b reported that aromatic and aliphatic
nitriles are inert in the presence of SmI2, but m- or p-
nitrobenzonitrile could be selectively reduced to the corre-
sponding cyanoanilines in almost quantitative yields. We
considered that the intermediate derived from a more active
nitro group by SmI2 treatment could perhaps attack the
more stable cyano group, which does not react with SmI2.
Therefore, we have studied the behavior of the cyano group
and the nitro group when reacted with SmI2 in tetrahydro-
furan (THF) at room temperature.
a1 equiv. nitro compounds, 1.2 equiv. nitriles and 6 equiv. SmI2
were used. bIsolated yield. cThe reaction was studied under
below 0, at 25 8C and under refluxing conditions.
duce amidines in good yields. However, aliphatic nitro
compounds failed to react with aromatic or aliphatic nitriles
to give similar amidines as products under the same con-
ditions, at low temperature or under re¯uxing conditions.
Amidines 3 are not derived from the reaction of the nitriles
with amines produced by the reduction of nitro compounds,
since treatment of nitriles with amines under the same reac-
tion conditions did not lead to a reaction taking place and
no amidines could be detected.
Although the detailed mechanism of the above reaction
has not yet been clari®ed, amidine formation can be
explained by the putative mechanism presented in Scheme 2.
When aromatic nitro compounds 1 and nitriles 2 were
treated with SmI2 in dry THF, the intermolecular reductive
cross coupling products, amidines 3 were found (Scheme 1).
Table 1 summarizes our results on the reaction of nitro
compounds and nitriles with SmI2. Aromatic nitro com-
pounds reacted with aromatic or aliphatic nitriles to pro-
Scheme 2
In conclusion, with high yields, mild and neutral con-
ditions as well as a straightforward procedure, we think
that the present work provides a useful method for the
preparation of amidines. Further studies to develop other
new uses for SmI2 are now in progress in our laboratory.
Scheme 1
*To receive any correspondence.
Experimental
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
%Permanent address: Department of Chemistry, Xuzhou Normal
University, Jiangsu, 221009, China.
Tetrahydrofuran was distilled from sodium±benzophenone
immediately prior to use. All reactions were conducted under a
nitrogen atmosphere. Melting points are uncorrected. Infrared spec-
tra were recorded on a Perkin-Elmer 683 spectrometer in KBr with

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J. CHEM. RESEARCH (S), 1998 597
1
absorptions in cm
.
1H NMR spectra were determined on a JEOL
860, 790, 710. dH 2.26 (3 H, s, CH3), 2.33 (3 H, s, CH3), 5.00 (2 H,
.
PMX 60 SI spectrometer as CDCl3 solutions. Chemical shifts are
expressed in ppm down®eld from internal tetramethylsilane. Mass
spectra were recorded on a Finnigan MAT GC±MS spectrometer.
Microanalyses were carried out on a Carlo±Erba 1106 instrument.
General procedure for the synthesis of Amidines 3.ÐA solution of
nitro compound 1 (1 mmol) and nitrile 2 (1.2 mmol) in anhydrous
THF (3 ml) was added dropwise to a solution of SmI2 (6 mmol) in
THF (40 ml) at room temperature under a dry nitrogen atmosphere
and the reaction stirred under N2. At completion, the reaction
mixture was poured into 10% K2CO3 (50 ml) and extracted with
diethyl ether (3Â30 ml). The combined extracts were washed with a
saturated solution of Na2S2O3 (15 ml) and a saturated solution of
NaCl (15 ml), and dried over anhydrous Na2SO4. After evaporating
the solvent under reduced pressure, the crude product was puri®ed
by preparative TLC on silica gel using ethyl acetate±cyclohexane
(1:3) as eluent.
br s, NH, C NH), 6.75±7.85 (8 H, m, ArH). MS m/z: 225 (M ‡ 1,
‡
27), 224 (M , 94), 209 (11), 133 (9), 118 (30), 107 (100), 106 (75), 91
(66), 77 (23). Anal. Calc. for C15H16N2: C, 80.32, H, 7.19, N, 12.49;
Found: C, 80.54, H, 7.03, N, 12.52%.
1
3-Methyl-N-phenylbenzamidine 3m. mp 104±106 8C. ꢀ/cm 3460,
3320, 1640, 1590, 1490, 1390, 1240, 1170, 1020, 840, 800, 770, 720,
.
695. dH 2.37 (3 H, s, CH3), 5.20 (2 H, br s, NH, C NH), 6.90±7.80
‡
(9 H, m, ArH). MS m/z: 211 (M ‡ 1, 19), 210 (M , 100), 195
(10), 194 (29), 118 (33), 93 (92), 91 (42), 77 (8). Anal. Calc. for
C14H14N2: C, 79.97, H, 6.71, N, 13.32; Found: C, 79.86, H, 6.87,
N, 13.38%.
We are grateful to the National Natural Science
Foundation of China (Project No. 294938004 and 29672007)
and the Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, and the Chinese Academy
of Sciences for ®nancial support.
N-Phenylbenzamidine 3a. mp 115±117 8C (lit.,11 112 8C). ꢀ/cm
1
3500, 3380, 1630, 1600, 1580, 1490, 1450, 1380, 1240, 1170, 1080,
.
1020, 835, 770, 750, 700. dH 5.30 (2 H, br s, NH, C NH), 6.87±7.83
(10 H, m, ArH).
4-Methyl-N-phenylbenzamidine 3b. mp 99±100 8C (lit.,12 100.5±
Received, 22nd April 1998; Accepted, 28th May 1998
Paper E/8/03011A
1
101 8C) ꢀ/cm 3470, 3310, 1640, 1610, 1580, 1510, 1380, 1235, 860,
.
790. dH 2.30 (3 H, s, CH3), 5.23 (2 H, br s, NH, C NH), 6.70±7.95
(9 H, m, ArH).
N-(2-methylphenyl)benzamidine 3c. mp 102±104 8C (lit.,12 105 8C).
References
1
ꢀ/cm 3470, 3320, 1640, 1575, 1490, 1390, 1240, 740, 720. dH 2.15
(3 H, s, CH3), 4.90 (2 H, br s, NH, C NH), 6.68±7.90 (9 H, m,
1 For reviews see: (a) G. A. Molander and C. R. Harris, Chem.
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1995, 53, 987; (c) G. A. Molander, Org. React., 1994, 46, 221;
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2 (a) P. Girard, J. L. Namy and H. B. Kagan, J. Am. Chem. Soc.,
1980, 102, 2693; (b) J. L. Namy, P. Girard and H. B. Kagan,
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3 (a) Y. Zhang and R. Lin, Synth. Commun., 1987, 17, 329;
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1699.
.
‡
ArH). MS: m/z 211 (M ‡ 1, 45), 210 (M , 100), 107 (78), 106
(88), 104 (88), 91 (36), 77 (86), 76 (22). Anal. Calc. for C14H14N2:
C, 79.97, H, 6.71, N, 13.32; Found: C, 79.81, H, 6.83, N, 13.40%.
N-Phenylphenylacetamidine 3d. mp 128±130 8C (lit.,12 127±130 8C).
1
ꢀ/cm 3470, 3320, 1650, 1610, 1490, 1400, 1070, 860, 790. dH 3.63
.
(2 H, s, CH2), 4.80 (2 H, br s, NH, C NH), 6.80±7.73 (10 H, m,
ArH).
N-( p-Tolylphenyl)phenylacetamidine 3e. mp 118±119 8C (lit.,12
1
119 8C). ꢀ/cm 3480, 3320, 1650, 1510, 1390, 1290, 1250, 850, 740,
700. dH 2.27 (3 H, s, CH3), 3.60 (2 H, s, CH2), 4.73 (2 H, br s, NH,
.
C NH), 6.70±7.55 (9 H, m, ArH).
N-( p-Chlorophenyl)phenylacetamidine 3f. mp 114±116 8C (lit.,13
1
114±116 8C). ꢀ/cm 3450, 3320, 1650, 1590, 1490, 1430, 1400, 1300,
1230, 1090, 835, 750, 720, 700. dH 3.57 (2 H, s, CH2), 4.70 (2 H,
.
br s, NH, C NH), 6.67±7.50 (9 H, m, ArH).
4-Chloro-N-(4-chlorophenyl)benzamidine 3g. mp 177±179 8C (lit.,14
1
179 8C). ꢀ/cm 3530, 3430, 1650, 1590, 1495, 1410, 1380, 1240,
1085, 1010, 860, 840, 790. dH 5.17 (2 H, br s, NH, C NH),
6.80±7.73 (8 H, m, ArH).
.
5 M. J. Burk and J. E. Feaster, J. Am. Chem. Soc., 1992, 114,
6266.
4-Chloro-N-(4-methylphenyl)benzamidine 3h. mp 129±131 8C.
6 N. R. Natale, Tetrahedron Lett., 1982, 23, 5009; (b) L. Benati,
P. C. Monievecohi, D. Nanni, P. Spagnolo and M. Volta,
Tetrahedron Lett., 1995, 36, 7313; (c) C. Goulaouic-Dubois and
M. Hesse, Tetrahedron Lett., 1995, 36, 7427.
7 G. E. Keck, S. F. McHardy and T. T. Wager, Tetrahedron Lett.,
1995, 36, 7419.
8 L. Zhou and Y. Zhang, Tetrahedron Lett., 1997, 38, 8063.
9 (a) S. Patai and Z. Rappoport, The Chemistry of Amidines
and Imidates, Wiley, New York, 1991, vol. 27, p. 226; (b)
A. Kreutzberger, Progress in Drug Research, ed. E. Jucker,
Birklauser Verlag, Basel, 1968, pp. 356±445.
10 (a) Lottermoser, J. Prakt. Chem., 1896, 54, 116; (b) F. C.
Cooper and M. W. Partridge, J. Chem. Soc., 1953, 255; (c)
N. A. Kalashnikova, G. N. Kul'bitskii, B. V. Passet and B. Z.
Askinazi, Zh. Org. Khim., 1974, 10(7), 1529.
1
ꢀ/cm
3500, 3360, 1640, 1565, 1510, 1380, 1240, 1110, 1090,
.
1010, 840, 795. dH 2.30 (3 H, s, CH3), 5.07 (2 H, br s, NH, C NH),
6.70±8.00 (8 H, m, ArH). MS m/z: 246 (M ‡ 2, 32), 245 (M ‡ 1,
‡
21), 244 (M , 100), 229 (15), 138 (88), 111 (44), 107 (94), 91 (36).
Anal. Calc. for C14H12ClN2: C, 69.00, H, 4.96, N, 1.49; Found:
C, 69.30, H, 4.81, N, 1.59%.
4-Chloro-N-phenylbenzamidine 3i. mp 107±109 8C (lit.,15 106±
1
110 8C). ꢀ/cm 3480, 3350, 1640, 1600, 1565, 1500, 1440, 1380,
1230, 1180, 1090, 1010, 840, 825, 760. dH 5.10 (2 H, br s, NH,
.
C NH), 6.80±7.90 (9 H, m, ArH).
N-(4-Chlorophenyl)benzamidine 3j. mp 114±116 8C (lit.,16 112±
1
115 8C). ꢀ/cm 3500, 3380, 1630, 1610, 1575, 1490, 1450, 1380,
.
1240, 1100, 1010, 860, 755, 700. dH 5.00 (2 H, br s, NH, C NH),
6.70±8.00 (9 H, m, ArH).
3-Methyl-N-(4-chlorophenyl)benzamidine 3k. mp 98±100 8C.
ꢀ/cm 3490, 3340, 1630, 1590, 1495, 1380, 1250, 1100, 1010, 855,
11 P. Oxley, M. W. Partridge and W. F. Short, J. Chem. Soc.,
1947, 1110.
1
810, 790, 760, 720. dH 2.33 (3 H, s, CH3), 4.90 (2 H, br s, NH,
12 P. Oxley and W. F. Short, J. Chem. Soc., 1946, 147.
13 O. Motoi, T. Shigeo and O. Ryohei, Yuki Gosei Kagadu Kyokai
Shi, 1966, 24, 562.
.
C NH), 6.68±7.80 (8 H, m, ArH). MS m/z: 246 (M ‡ 2, 32), 245
‡
(M ‡ 1, 35), 244 (M , 100), 229 (9), 127 (97), 118 (60), 111 (35),
91 (58). Anal. Calc. for C14H12ClN2: C, 69.00, H, 4.96, N, 11.49;
Found: C, 69.23, H, 5.12, N, 11.37%.
14 Beilstein I (12), 611.
15 N. A. Kalashnikova, G. N. Kul'bitskii, B. V. Passet and B. Z.
Askinazi, Zh. Org. Khim., 1974, 10(7), 1529.
16 L. Citero, M. L. Saccarello and R. Stradi, Synthesis, 1979, 594.
3-Methyl-N-(4-methylphenyl)benzamidine 3l. mp 88±90 8C.
1
ꢀ/cm 3490, 3300, 1650, 1580, 1510, 1380, 1240, 1100, 1020, 920,