Chemoselective reactions of amidines: Selective formation of iminopyrimidine regioisomers

Article abstract of DOI:10.1021/ol006499j

(matrix presented) The dramatic effect of base on the chemoselectivity of the reaction of amidines with substituted 3-phenyl-2-propynylnitriles is demonstrated. Amidine 1 can be added to cyanoalkyne 2 to give iminopyrimidine isomer 3 with high selectivity

Full text of DOI:10.1021/ol006499j

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ORGANIC
LETTERS
2000
Vol. 2, No. 21
3389-3391
Chemoselective Reactions of Amidines:
Selective Formation of Iminopyrimidine
Regioisomers
John A. McCauley,* Cory R. Theberge, and Nigel J. Liverton
Department of Medicinal Chemistry, Merck Research Laboratories,
West Point, PennsylVania 19486
john_mccauley@merck.com
Received August 24, 2000
ABSTRACT
The dramatic effect of base on the chemoselectivity of the reaction of amidines with substituted 3-phenyl-2-propynylnitriles is demonstrated.
Amidine 1 can be added to cyanoalkyne 2 to give iminopyrimidine isomer 3 with high selectivity. The addition of 2 equiv of NaHMDS completely
reverses the selectivity of the reaction, yielding isomer 4 almost exclusively. This method has been used to prepare a variety of substituted
4-iminopyrimidines.
During recent work in our laboratories we became interested
in the synthesis of 4-iminopyrimidines fused to carbocycles
(e.g., 4). 4-Pyrimidones analogous to 4 have been synthesized
by the addition of cyclic amidines to â-ketoesters;1 however,
the conversion of the resultant pyrimidone to the imino-
pyrimidine was nontrivial. To circumvent this problem, we
tried to access the iminopyrimidine directly by adding an
amidine to a â-ketonitrile, but this strategy failed.2
We then reasoned that Michael addition of an amidine to
a cyanoalkyne followed by ring closure would be an
alternative route to this structural class. 3-Phenyl-2-pro-
pynenitrile (2, Scheme 1)3 was prepared via a published
Scheme 1
(1) (a) Le Berre, A.; Renault, C. Bull. Soc. Chim. Fr. 1969, 3139-3146.
(b) Le Berre, A.; Renault, C. Bull. Soc. Chim. Fr. 1969, 3146-3151. (c)
Langlois, M.; Guilloneau, C.; VoVan, T.; Jolly, R.; Maillard, J. J.
Heterocycl. Chem. 1983, 20, 393-398.
(2) For the synthesis of iminopyrimidines, see: (a) Brown, D. J.; Ienega,
K. J. Chem. Soc., Perkin Trans. 1 1974, 372-378. (b) Wamhoff, H.;
Thiemig, H.-A. Chem. Ber. 1986, 119, 1070-1076.
procedure and exposed to 2-iminopiperidine in THF.4,5 The
reaction proceeded very cleanly, and of the two possible
regioisomeric products that can be formed in this reaction,
the 1,2-cyclic isomer (3) predominated in a 97:3 ratio.6 We
were very pleased with this straightforward route to the
4-iminopyrimidine class of compounds; however, we were
also interested in a synthesis of regioisomer 4.
(3) Luo, F.-T.; Wang, M.-W.; Wang, R.-T. Org. Synth. 1997, 75, 146-
152.
(4) 3-Phenyl-2-propynenitrile (2) has been used in a similar fashion for
the preparation of 5-aminopyrazoles and 3-aminothiophene-2-carbonitriles;
see: (a) Fomum, Z. T.; Ifeadike, P. N. J. Heterocycl. Chem. 1985, 22, 1611-
1614. (b) Ren, W.-Y.; Rao, K. V. B.; Klein, R. S. J. Heterocycl. Chem.
1986, 23, 1757-1763.
(5) Identical selectivity was observed when the solvent was 5% MeCN/
THF.
10.1021/ol006499j CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/14/2000

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Our attempts to alter the selectivity of this reaction began
with protection of the secondary amine of 1 followed by
addition to cyanoalkyne 2. This reaction cleanly gave the
Michael adduct; however, attempts to remove a variety of
protective groups [allyl, benzyl, silyl] in the presence of the
nitrile failed. During these investigations we noticed that the
addition of base affected the distribution of reaction prod-
ucts.7 After optimization, we have found that using 2 equiv
of NaHMDS in 5% MeCN/THF completely reverses the
selectivity of the reaction, giving 4 as the major product in
a 97:3 ratio (Entry 1, Table 1).
involving NaHMDS; when 100% THF is employed as
solvent, the reaction gives many side products. Furthermore,
if less than 2 equiv of NaHMDS is used, the reaction
proceeds well but seems to be nonchemoselective. This
information has led us to hypothesize that the dianion of the
amidine is formed and that the acetonitrile aids in solubility
of the dianion.
Cyclic amidines seem to react more quickly and give
higher yields. Preliminary investigation indicates that the ring
closure step is slower in the case of acyclic amidines. The
reaction is also tolerant of substituents on the phenyl ring of
the cyanoalkyne,3 as shown in Table 2.
Table 1. Reaction of 3-Phenyl-2-propynenitrile with Amidines
Table 2. Reaction of 2-Iminopiperidine with Cyanoalkynes
We have extended this methodology to include 2-imino-
4-phenylpyrrolidine8 (20, entry 2), as well as unsymmetrical
monosubstituted acyclic amidines (entries 3 and 4). All of
the cases were run under the same conditions9 and show a
similar reversal of selectivity in the presence of base.10,11
Addition of MeCN is crucial to the success of the reaction
The reactions recorded in entries 4 and 8, however,
behaved somewhat differently than the other examples. In
the absence of base, the selectivity and yield both degraded
substantially. We believe this is due to the steric congestion
associated with the ring closing step to form compounds 9
and 17. After the Michael addition occurs, the aryl group at
position 6 (pyrimidine numbering) and the substituent on
N-1 must come into close proximity in order to close the
(6) Ratios were measured by HPLC with UV detection at 214 nM. Data
for compound 3‚TFA: 1H NMR (500 MHz, CDCl3) δ 9.42 (br s, 1 H),
7.58-7.50 (m, 3 H), 7.38-7.35 (m, 2 H), 6.81 (s, 1 H), 6.73 (br s, 1 H),
3.84 (t, J ) 5.8 Hz, 2 H), 3.10 (t, J ) 6.6 Hz, 2 H), 2.03-1.94 (m, 4 H)
ppm; 13C NMR (125 MHz, CDCl3) δ 163.5, 163.0, 157.4, 131.5, 130.6,
129.5, 128.3, 106.6, 50.3, 31.5, 21.8, 18.1 ppm; HRMS m/z 226.1353 [(M
+ H)+, calcd for C14H16N3 226.1339]. Data for compound 4‚TFA: 1H NMR
(500 MHz, CDCl3) δ 9.74 (br s, 1 H), 9.18 (br s, 1 H), 8.04 (dd, J ) 7.8,
1.5 Hz, 2 H), 7.56-7.43 (m, 4 H), 4.10 (t, J ) 6.2 Hz, 2 H), 3.13 (t, J )
6.5 Hz, 2 H), 2.18-2.11 (m, 2 H), 2.02-1.98 (m, 2 H) ppm; 13C NMR
(125 MHz, CDCl3) δ 161.2, 158.3, 157.7, 132.2, 129.1, 129.0, 127.5, 101.4,
47.0, 32.3, 21.4, 18.1 ppm; HRMS m/z 226.1351 [(M + H)+, calcd for
C14H16N3 226.1339].
(8) The starting amidine for entry 2 (20) was prepared from 4-phenyl-
2-pyrrolidinone (19)12 as shown:
(7) Similar observations in the case of amidine additions to â-ketoesters
have been made (see ref 1a); however, the conditions reported for selectivity
reversal [EtONa, EtOH, reflux], when applied to our system, gave primarily
Michael addition of ethoxide to the cyanoalkyne.
3390
Org. Lett., Vol. 2, No. 21, 2000

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
pyrimidine ring. In the case of compound 17, the 2-Cl
substituent seems to have a greater steric effect than a
4-substituent. A major byproduct in both of these reactions
is one in which both amidine nitrogens undergo Michael
addition to a cyanoalkyne. This observation is consistent with
a slow ring-closing step. In the presence of base, as expected,
compounds 10 and 18 are formed selectively and in satisfac-
tory yield.
In conclusion, we have developed a facile one-step
synthesis of regioisomeric 4-iminopyrimidines and have
shown the effect of base and solvent on chemoselectivity.
Further investigation of the scope and mechanism of this
reaction is underway in these laboratories.
Acknowledgment. We thank Ms. Joan Murphy and Dr.
Steve Pitzenberger for NMR structural assignment of com-
pounds 3 and 4. We also thank Dr. David A. Claremon for
helpful discussions.
(9) Procedure A. Amidine 1 (60 mg, 0.61 mmol) was dissolved in 5%
MeCN/THF (5 mL) at room temperature. Cyanoalkyne 2 (77 mg, 0.61
mmol) was added in one portion, and the reaction mixture was stirred for
2 h. The reaction mixture was poured onto ethyl acetate and aqueous
NaHCO3, and the layers were separated. The organic layer was dried over
Na2SO4, filtered, and concentrated. The residue was purified by preparative
reverse-phase HPLC to give 3‚TFA (134 mg, 65% yield) as a white solid.
Procedure B. Amidine 1 (60 mg, 0.61 mmol) was dissolved in 5% MeCN/
THF (5 mL) at room temperature. NaHMDS (1.0 M/THF, 1.22 mL, 1.22
mmol) was added dropwise, and the solution was stirred at room temperature
for 5 min. Cyanoalkyne 2 (77 mg, 0.61 mmol) was then added in one
portion. The reaction mixture turned dark red and was stirred for 5 min.
The reaction mixture was poured onto ethyl acetate and aqueous NaHCO3,
and the layers were separated. The organic layer was dried over Na2SO4,
filtered, and concentrated. The residue was purified by preparative reverse-
phase HPLC to give 4‚TFA (107 mg, 52% yield) as a white solid.
OL006499J
(10) Unsubstituted amidines have been used as dinucleophiles in the
preparation of iminopyrimidine and pyrimidone derivatives; however, these
cases do not have the possibility of regioisomeric products. See: (a) Todd,
A. R.; Bergel, F. J. Chem. Soc. 1937, 364-367. (b) Foldi, Z.; Salamon, A.
Chem. Ber. 1941, 1126-1128. (c) Nishigaki, S.; Aida, K.; Senga, K.;
Yoneda, F. Tetrahedron Lett. 1969, 4, 247-250. (d) Wamhoff, H.; Materne,
C. Ann. Chem. 1971, 754, 113-118.
(11) For a recent example of the effect of solvent on addition reactions
of biselectrophiles, see: Vasudevan, A.; Mavandadi, F.; Chen, L.; Gangjee,
A. J. Org. Chem. 1999, 64, 634-638.
(12) Zelle, R. E. Synthesis 1991, 1023-1026.
Org. Lett., Vol. 2, No. 21, 2000
3391