Addition of amines to nitriles catalyzed by ytterbium amides: An efficient one-step synthesis of monosubstituted N-arylamidines

Article abstract of DOI:10.1021/ol702739c

A one-step synthesis of monosubstituted N-arylamidinates via addition of amines to nitriles catalyzed by ytterbium amides is reported. The reactions with various substrates give the products in good to excellent yields with 5 mol % ytterbium at 100 °C under solvent-free conditions.

Full text of DOI:10.1021/ol702739c

ORGANIC
LETTERS
2008
Vol. 10, No. 3
445-448
Addition of Amines to Nitriles Catalyzed
by Ytterbium Amides: An Efficient
One-Step Synthesis of Monosubstituted
N-Arylamidines
Junfeng Wang,† Fan Xu,† Tao Cai,† and Qi Shen*,†,‡
Key Laboratory of Organic Synthesis of Jiangsu ProVince, Department of Chemistry
and Chemical Engineering, Dushu Lake Campus, Suzhou UniVersity,
Suzhou 215123, People’s Republic of China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China
qshen@suda.edu.cn
Received November 14, 2007
ABSTRACT
A one-step synthesis of monosubstituted N-arylamidinates via addition of amines to nitriles catalyzed by ytterbium amides is reported. The
reactions with various substrates give the products in good to excellent yields with 5 mol % ytterbium at 100 C under solvent-free conditions.
°
Amidinates are of interest as structural units with wide utility
in drug design1 and as synthons for the synthesis of
heterocyclic compounds.2 Several synthetic strategies have
been developed3,4 in which the nucleophilic addition of amine
to nitrile is the most convenient and atom-economic method.3
The one-step synthesis of amidines from nitriles and amines
can be realized only if the nitriles are activated by electron-
withdrawing groups3a or under more forcing conditions in
the presence of Lewis acids3b or with aluminum amides3c
for unactivated nitriles. Trivalent lanthanide triflates have
been employed successfully as catalysts in the condensation
(2) (a) Dunn, P. J. In ComprehensiVe Organic Functional Group
Transformations II; Katritzky, A. R., Taylor, R. J., Eds.; Elsevier: Oxford,
2005; Vol. 5, pp 655-698. (b) Yokoyama, M.; Menjo, Y.; Wei, H.; Togo,
H. Bull. Chem. Soc. Jpn. 1995, 68, 2735. (c) Lerestif, J. M.; Bazureau, J.
P.; Hamelin, J. Tetrahedron Lett. 1993, 34, 4639. (d) Doise, M.; Blondeau,
D.; Sliwa, H. Synth. Commun. 1992, 22, 2891. (e) Neunhoeffer, H.; Karafiat,
U.; Ko¨hler, G.; Sowa, B. Liebigs Ann. Chem. 1992, 115. (f) Alanine, A. I.
D.; Fishwick, C. W. G. Tetrahedron Lett. 1989, 30, 4443.
† Suzhou University.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Taveras, A. G.; Chao, J.; Biju, P. J.; Yu, Y.; Fine, J. S.; Hipkin,
W.; Aki, C. J.; Merritt, J. R.; Li, G.; Baldwin, J. J.; Lai, G.; Wu, M.; Hecker,
E. A. WO-2004033440, 2004. (b) Varghese, J.; Maillard, M.; Jagodzinska,
B.; Beck, J. P.; Gailunas, A.; Fang, L.; Sealy, J.; Tenbrink, R.; Freskos, J.;
Mickelson, J.; Samala, L.; Hom, R. WO-2003040096, 2003. (c) Sugino,
M.; Sugita, S. JP-2004175720, 2004. (d) Takamuro, I.; Honma, K.; Ishida,
A.; Taniguchi, H.; Onoda, Y. JP-2004115450, 2004. (e) Maguire, M. P.;
Dai, M.; Vos, T. J. WO-2002062766, 2002. (f) Sunagawa, M.; Hebeisen,
P. WO-2002048149, 2002. (g) Lin, Y. I.; Wang, B. S.; Ruszala-Mallon, V.
M.; Bitha, P.; Fields, T. L. EP-354303, 1990. (h) Moeller, H.; Gloxhuber,
C. DE-2364437, 1975. (i) Zhu, B.-Y.; Su, T.; Li, W.; Goldman, E. A.;
Zhang, P.; Jia, Z. J.; Scarborough, R. M. WO-2002026734, 2002. (j) Bullock,
W. H.; Kluender, H. C. E.; Collibee, W. L.; Dally, R.; Rodriguez, M. E.;
Wang, M. WO-2002020526, 2002. (k) Ito, K.; Spears, G. W.; Yamada, A.;
Toshima, M.; Kato, M. JP-2001220375, 2001.
(3) (a) Grivas, J. C.; Taurins, A. Can. J. Chem, 1961, 39, 761. (b) Oxiey,
P.; Partridge, M. W.; Short, W. F. J. Chem. Soc. 1947, 1110. (c) Garigipati,
R. S. Tetrahedron Lett. 1990, 31, 1969. (d) Fersberg, J. H.; Spaziano, V.
T.; Balasubramanian, T. M. J. Org. Chem. 1987, 52, 1017. (e) Xu, F.; Sun,
J.; Shen, Q. Tetrahedron Lett. 2002, 43, 1867. (f) Rousselet, G.; Capdevielle,
P.; Maumy, M. Tetrahedron Lett. 1993, 34, 6395. (g) Anbazhagan, M.;
Boykin, D. W.; Stephens, C. E. Tetrahedron Lett. 2001, 43, 9089. (h)
Anbazhagan, M.; Stephens, C. E.; Boykin, D. W. Tetrahedron Lett. 2002,
43, 4221. (i) Khanna, I. K.; Yu, Y.; Huff, R. M.; Weier, R. M.; Xu, X.;
Koszyk, F. J.; Collins, P. W.; Cogburn, J. N.; Isakson, P. C.; Koboldt, C.
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J.; Yang, D.-C.; Zhang, Y. Y. J. Med. Chem. 2000, 43, 3168. (j) Zhou, S.;
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10.1021/ol702739c CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/04/2008

Scheme 1. Tested Amides
of nitriles with primary amines and diamines into N,N′-
for controlled polymerization of lactide.9 Thus, complex I
was first tested in the condensation reactions of nitriles and
amines, and several reaction conditions were examined in
the model reaction of 1a with 2a (Table 1). The reactions
disubstituted and cyclic amidines, but monosubstituted
amidines cannot be synthesized, and the reaction with
secondary amines afforded triazines or pyrimidines via
further condensations.3d SmI2 can also catalyze the condensa-
tion reaction as a precatalyst, and the same problem as in
the case with lanthanide triflates remains to be solved.3e
Recently, the selective synthesis of monosubstituted alky-
lamidines from amines and nitriles can be achieved in the
presence of CuCl. However, 1.2 equiv of CuCl to amines is
needed in this process.3f Thus, the development of catalytic
addition of amines to nitriles is still a challenge in mono-
substituted amidine synthesis.
Table 1. Optimization of the Reaction Conditionsa
entry cat. (mol %) solvent 1a/2a T (°C) time (h) % yieldb
Prompted by recent successes obtained in C-N bond
formation, reactions catalyzed by lanthanide amide com-
plexes, including hydroamination,5 monocoupling reaction
of isocyanides with terminal alkynes,6 a Cannizzaro-type
disproportionation of aromatic aldehydes,7 and the guany-
lation of amines8 and amidination of alkyne,3j,k we turned
our attention to the possible use of lanthanide amides as
catalysts for addition reaction of amines to nitriles.
1
2
3
4
5
6
7
8
9
5
5
10
10
5
5
5
5
5
toluene 1:1
toluene 1:1
60
60
60
60
80
100
100
100
100
100
100
100
12
24
12
12
24
24
24
24
24
24
24
12
35
45
45
80
55
65
75
88
84
83
65
97
THF
1:1
toluene 1:1
toluene 1:1
toluene 1:1
1:1
1:2
1:3
1:4
1:10
1:2
We have recently synthesized the novel amide complexes
supported by a bridged bis(amidinate) I-III (Scheme 1) and
found that amide complexes I and II show high reactivity
10
11
12
5
5
10
a All data were obtained using 1.90 mmol of nitrile. b Isolated yields.
(4) Recent examples: (a) Yet, L. A SurVey of Amidine Synthesis;
Technical Report No. 3; Albany Molecular Research, Inc.: New York, 2000;
Vol. 4. (b) Tidwell, R. R.; Boykin, D. W. In Dicationic DNA Minor GrooVe
Binders as Antimicrobial Agents in Small Molecule DNA and RNA
Binders: From Synthesis to Nucleic Acid Complexes; Demeunynck, M.,
Bailly, C., Wilson, W. D., Eds.; Wiley-VCH: Hoboken, NJ, 2002. (c)
Tucker, J. A.; Clayton, T. L.; Chidester, C. G.; Schulz, M. W.; Harrington,
L. E.; Conrad, S. J.; Yagi, Y.; Oien, N. L.; Yurek, D.; Kuo, M.-S. Bioorg.
J. Med. Chem. 2000, 8, 601. (d) Stephens, C. E.; Tanious, F.; Kim, S.;
Wilson, D. W.; Schell, W. A.; Perfect, J. R.; Franzblau, S. G.; Boykin, D.
W. J. Med. Chem. 2001, 44, 1741. (e) Werbovetz, K.; Brendle, J.; Stephens,
C. E.; Boykin, D. W. US Patentc60/246,330, filed 11/7/00. (f) Kusturin, C.
L.; Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4, 983.
(5) For general reviews on hydroamination reactions, see: (a) Mu¨ller,
T. E.; Beller, M. Chem. ReV. 1998, 98, 675. (b) Nobis, M.; Driessen-
Ho¨lscher, B. Angew. Chem., Int. Ed. 2001, 40, 3983. (c) Brunet, J. J.;
Neibecker, D. In Catalytic Heterofunctionalization from Hydroaminationto
Hydrozirconation; Togni, A., Gru¨tzmacher, H., Eds.; Wiley-VCH: Wein-
heim, Germany, 2001; pp 91-141. (d) Roesky, P. W.; Mu¨ller, T. E. Angew.
Chem., Int. Ed. 2003, 42, 2708. (e) Pohlki, F.; Doye, S. Chem. Soc. ReV.
2003, 32, 104. (f) Beller, M.; Tillack, A.; Seayad, J. In Transition Metals
for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; Vol. 2, pp 403-414.
took place smoothly under solvent free conditions or in
toluene to afford the monosubstituted amidine 3aa in
moderate to excellent yields depending on the conditions
used. The reaction in THF provided the lowest yield (Table
1, entry 3). With the increasing temperature, the yields
increased (Table 1, entries 2, 5, and 6). The ratio of amine
to nitrile showed an effect on the reactivites, and the
maximum yields were obtained in the range of 2-4 (Table
1, entries 8-10). The yields increased when the catalyst
loading increased and an almost quantitative yield was
obtained with 10 mol % of ytterbium (based on 1a) under
solvent-free conditions for 12 h (Table 1, entry 12).
Since I performed well in this reaction, we screened other
lanthanide amides II-IV10 (Scheme 1) in the reactions with
several substrates. All reactions were conducted with 5 mol
% of ytterbium at 100 °C in the absence of solvent (Table
2).
(6) (a) Komeyama, K.; Sasayama, D.; Kawabata, T.; Takehira, K.; Takali,
K. J. Org. Chem. 2005, 70, 10679. (b) Komeyama, K.; Sasayama, D.;
Kawabata, T.; Takehira, K.; Takaki, K. Chem. Commun. 2005, 634.
(7) Zhang, L.; Wang, S.; Zhou, S.; Yng, G.; Sheng, E. J. Org. Chem.
2006, 71, 3149.
(8) (a) Li, Q.; Wang, S.; Zhou, S.; Yang, G.; Zhu, X.; Liu, Y. J. Org.
Chem. 2007, 72, 6763. (b) Zhang, W.-X.; Nishiura, M.; Hou, Z. Synlett
2006, 8, 1213. (c) Zhang, W.-X.; Nishiura, M.; Hou, Z. Chem. Eur. J. 2007,
13, 4037.
(9) Wang, J.; Cai, T.; Yao, Y.; Zhang, Y.; Shen, Q. Dalton Trans. 2007,
5275.
(10) Zhou, S.; Wang, S.; Yang, G.; Liu, X.; Sheng, E.; Zhang, K.; Cheng,
L.; Huang, Z. Polyhedron 2003, 22, 1019.
446
Org. Lett., Vol. 10, No. 3, 2008

Scheme 2. Proposed Mechanism for the Reaction of Nitriles
Table 2. Addition of Amines to Nitriles Catalyzed by
Ytterbium Amides I-IVa
with Amines
amidesb (%)
entry
1
1
2
product
I
II
90
III
IV
1a
2a
3aa
88
55
(80c)
70
0
55
45
(70c)
20
35d
45
2
1b
2a
3ba
4b
3cb
3ac
4a
83
0
55
84
0
62
3
4
1c
1a
2b
2c
n.r.
n.r.
n.r.
0
30d
0
activity. They reacted with 2b to give the corresponding
amidines in 55% and 45% yields, respectively (Table 2, entry
3, and Table 3, entry 7). The reactions with 2a (Table 3,
5
1a
2d
3ad
4a
55
0
58
0
45
0
60d
a The reaction was performed by treating 1 equiv of nitrile with 2 equiv
of amine. b Isolated yields. c 48 h. d The yield based on nitrile.
Table 3. One-Step Synthesis of Monosubstituted Amidines by
I: Substrate Scopea
Inspection of Table 2 clearly revealed that I and II were
the desired catalysts, displaying the best catalytic activity
and selectivity giving monosubstituted amidines as the only
products for all reactions tested. In general, the bimetallic
amide III and amide IV were less active and required an
extended period of reaction time for getting good yields
(Table 2, entry 1). Quite interestingly, the product depen-
dence on the amide complexes used were observed in some
reactions (Table 2, entries 2, 4, and 5). For example, the
addition reaction of 2a to 1b with IV gave a mixture of
monosubstituted amidine and triazine in 1:1.7 mole ratio,
while the same reaction with I(II) afforded only monosub-
stituted amidine 3ab in 83(84)% yield (Table 2, entry 2);
the reaction of 1a with 2d gave the amidine in 55% yield
for I and 58% for II, and no triazine was detected for both
cases, while the same reaction with IV gave triazine as the
only product; the reaction of 1a with 2c by IV gave the
triazine in 30% yield, whereas the same reaction by I and II
went sluggishly. The different catalytic behavior observed
between I(II) and IV might be attributed to the different
coordinate environment around the center metal which leads
to a difference in reactivity between the reactions of the
active intermediate with amine and with nitrile (see Scheme
2).
entry
1
2
product
% yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
1c
1d
1a
1c
1d
1e
1f
1g
1a
1a
1a
1a
1h
2a
2a
2b
2b
2b
2b
2b
2b
2c
2e
2f
3ca
3da
3abc
3cb
3dbc
3ebc
3fb
30 (75d)
92
97
87d
98
95
45 (75d)
95
trace
94
91
trace
trace
4g
3ae
3af
2g
2b
a The reaction was performed by treating 1 equiv of nitrile with 2 equiv
of amine under the given conditions. b Isolated yields. c 12 h. d Catalyst
loading 10 mol %, 48 h.
According to the optimized conditions a range of other
substrates were surveyed for the synthesis of monosubstituted
amidines with I (Table 3). All tested aromatic nitriles which
have electron-drawing or electron-donating groups at the
meta and para position on the aryl ring, except 4-cyanopy-
ridine, reacted smoothly with primary aromatic amines to
give the corresponding monosubstituted aromatic amidines
in isolated yields of 91-98%. The reaction with 4-cyan-
opyridine afforded triazine in 95% yield; no amidine was
detected (Table 3, entry 8). The reaction with o-methoxy-
benzonitrile proceeded sluggishly (Table 3, entry 13).
Aliphatic nitriles, such as 1c and 1g, showed much less
entry 1) were similar and required an extended period of
reaction time and an increased catalytic loading for getting
high yields (Table 3, entries 4 and 7). Apparently, the less
active cyano group of aliphatic nitriles, in comparison with
that of aromatic nitriles, retarded the reaction rate. The
reaction of aromatic nitriles with aliphatic amines proceeded
sluggishly, and only a trace of product was isolated (Table
3, entries 9 and 12). This may be attributed to much slower
protonation reaction by aliphatic amines compared to that
by aromatic amines, which was included in catalytic cycles
Org. Lett., Vol. 10, No. 3, 2008
447

(see the mechanism proposed, Scheme 2). All products were
characterized by 1H NMR and 13C NMR to be amidines via
1,3-H shift and the structure of 3aa was further confirmed
by X-ray structural analysis (Figure 1). The crystal structure
Intermediate C underwent protonation by amine to release
the product and to generate the lanthanide amide active
species A. When the reaction of intermediate C with
additional nitrile is more favorable than that with amine,
triazine E was produced as the main product.
In summary, we have developed an efficient protocol to
the one-step synthesis of monosubstituted amidines in good
to excellent yields via a nucleophilic addition of amines to
nitriles catalyzed by ytterbium amides under solvent free
conditions. The reactions of aromatic nitriles with aromatic
primary amines proceed very well to give excellent yields.
The present strategy can be viewed as a compensative
method for the published intramolecular nucleophilic addition
of amine to activated nitrile methods with Ln(OTf)3 and/or
SmI2 as the catalysts,3d,e which frequently suffered from
difficulty in synthesis of monosubstituted amidines. However,
the reaction with aliphatic amines has not yet been successful.
Efforts in this direction are ongoing in our laboratory.
Acknowledgment. We are grateful to the National
Natural Science Foundation of China (Grant No. 20632042)
for financial support.
Figure 1. Molecular structure of 3aa, drawn with 30% thermal
ellipsoids.
Supporting Information Available: Experimental pro-
1
cedures and characterization data; copies of H NMR and
13C NMR of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
showed a double-bond character for the N(2)-C(1) bond
with a distance of 1.290(3) Å.
OL702739C
The reaction mechanism was proposed as shown in
Scheme 2. Reaction of an aniline with the lanthanide amide
gave the new amido intermediate A through an acid-base
reaction.11 A nitrile then was coordinated to the center metal
forming a complex B. An intramolecular insertion of amide
to cyano of nitrile gave the corresponding intermediate C
as reported previously.12
(11) (a) Schuetz, S. A.; Day, V. W.; Sommer, R. D.; Rheingold, A. L.;
Belot, J. A. Inorg. Chem. 2001, 40, 5292. (b) Bradley, D. C.; Ghotra, J. S.;
Hart, F. A. J. Chem. Soc., Dalton Trans. 1973, 1021. (c) Alyea, E. C.;
Bradley, D. C.; Copperthwaite, R. G. J. Chem. Soc., Dalton Trans. 1972,
1580.
(12) (a) Bercaw, J. E.; Davies, D. L.; Wolczanski, P. T. Organometallics
1986, 5, 443. (b) Evans, W. J.; Fujimoto, C. H.; Ziller, J. W. Organome-
tallics 2001, 20, 4529.
448
Org. Lett., Vol. 10, No. 3, 2008