Intramolecular formal [4 + 2] cycloaddition of nitriles with amides triggered by TMSOTf/Et3N: Highly efficient construction of pyrrolo[1,2-a]-pyrimidin-4(6H)-ones

Article abstract of DOI:10.1021/jo900907h

(Chemical Equation Presented) By treatment with TMSOTf/Et₃N, N-(2-cyanoarylmethyl)-substituted acrylamides or β-ketoamides underwent N-addition cascades under mild conditions to afford the corresponding pyrrolo[1,2-a]pyrimidin-4(6H)-ones as the

Full text of DOI:10.1021/jo900907h

pubs.acs.org/joc
that the water-soluble 14-azacamptothecin (4), a hybrid be-
Intramolecular Formal [4 + 2] Cycloaddition of
Nitriles with Amides Triggered by TMSOTf/Et3N:
Highly Efficient Construction of Pyrrolo[1,2-a]-
pyrimidin-4(6H)-ones
tween luotonin A and the naturally occurring antitumor agent
camptothecin, is also a potent DNA topoisomerase I poison.4
The synthesis of luotonin A and analogues has thus drawn
much attention.5,6 However, most of the literature works
were centered at the construction of the skeleton with an
aromatic E-ring, while few methods were known for the
synthesis of the analogues with a saturated E-ring (as in 3
and 4). Hecht et al. reported the preparation of 3 via the
condensation of 1,2-dihydropyrrolo[3,4-b]quinolin-3-one
with a β-aminoacrylate.3c However, the yield was only 6%.
The intramolecular aryl radical addition to the CdN bond of
pyrimidin-4-ones to form the 5-membered pyrrole ring was
also found to be of low efficiency.4b,4c More recently, Mala-
cria and co-workers reported the one-step construction of
the pyrrolopyrimidinone skeleton via a radical cyclization
cascade with the acyclic N-acyl-N-(2-iodobenzyl)cyana-
mides as the precursors.6c Owing to the important biological
activity of luotonin A derivatives, it is certainly highly
desirable to develop general and efficient methods for their
synthesis. Herein, we report that the trimethylsilyl triflate/
triethylamine-triggered intramolecular reactions between
arylnitriles and acrylamides or β-ketoamides via a formal
[4+2] cycloaddition manner provide a convenient and effi-
cient entry to the synthesis of pyrrolopyrimidinones.
Feng Liu and Chaozhong Li*
Key Laboratory of Synthetic Chemistry of Natural
Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032,
P. R. China
clig@mail.sioc.ac.cn
Received May 1, 2009
By treatment with TMSOTf/Et3N, N-(2-cyanoaryl-
methyl)-substituted acrylamides or β-ketoamides under-
went N-addition cascades under mild conditions to afford
the corresponding pyrrolo[1,2-a]pyrimidin-4(6H)-ones as
the formal [4 + 2] cycloaddition products in high yields.
Pyrrolo[1,2-a]pyrimidin-4(6H)-ones, especially the [7,8]-aryl-
fused ones (1), are a class of heterocyclic compounds of
significant biological interest. A typical example is the naturally
occurring luotonin A (2) isolated from a Chinese medicinal
plant (Peganum nigellastrum) in 1997,1 which is a human DNA
topoisomerase I poison2 and exhibits potent cytotoxicity
against P-388 cells. A number of luotonin A analogues have
thus been evaluated for their ability to stabilize the covalent
binary complex formed between human topoisomerase I and
DNA.3 Among them, the 16,17,18,19-tetrahydroluotonin A (3)
also showed good concentration-dependent cytotoxicity, indi-
cating an aromatic E-ring is not essential for targeting
the topoisomerase I-DNA covalent binary complex.3c More
importantly, Hecht and co-workers have recently discovered
Our initial approach to pyrrolopyrimidinones was to
conduct the intramolecular amidyl radical addition to a
CtN bond as part of our systematic study on N-centered
radical cyclization reactions.7 This idea was vigorously
tested with N-(2-cyanobenzyl)but-2-enamide (5a) as the
(4) (a) Cheng, K.; Rahier, N. J.; Eisenhauer, B. M.; Thomas, S. J.; Gao,
R.; Hecht, S. M. J. Am. Chem. Soc. 2005, 127, 838. (b) Rahier, N. J.; Cheng,
K.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M. Org. Lett. 2005, 7, 835. (c)
Elban, M. A.; Sun, W.; Eisenhauer, B. M.; Gao, R.; Hecht, S. M. Org. Lett.
2006, 8, 3513.
(5) For a review on the synthesis of luotonin A, see: Ma, Z.; Hano, Y.;
Nomura, T. Heterocycles 2005, 65, 2203.
(6) For the latest examples on the synthesis of luotonin A, see: (a)
Bowman, W. R.; Cloonan, M. O.; Fletcher, A. J.; Stein, T. Org. Biomol.
Chem. 2005, 3, 1460. (b) Tangirala, R.; Antony, S.; Agama, K.; Pommier, Y.;
Curran, D. P. Synlett 2005, 2843. (c) Servais, A.; Azzouz, M.; Lopes, D.;
Courillon, C.; Malacria, M. Angew. Chem., Int. Ed. 2007, 46, 576. (d) Zhou,
H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org. Chem. 2007, 72, 6270.
(7) (a) Tang, Y.; Li, C. Org. Lett. 2004, 6, 3229. (b) Chen, Q.; Shen, M.;
Tang, Y.; Li, C. Org. Lett. 2005, 7, 1625. (c) Lu, H.; Li, C. Tetrahedron Lett.
2005, 46, 3574. (d) Hu, T.; Shen, M.; Chen, Q.; Li, C. Org. Lett. 2006, 8, 2647.
(e) Lu, H.; Chen, Q.; Li, C. J. Org. Chem. 2007, 72, 2564. (f) Liu, F.; Liu, K.;
Yuan, X.; Li, C. J. Org. Chem. 2007, 72, 10231. (g) Yuan, X.; Liu, K.; Li, C. J.
Org. Chem. 2008, 73, 6166.
(1) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles 1997, 46,
541.
(2) Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M. J.
Am. Chem. Soc. 2003, 125, 13628.
(3) (a) Ma, Z.; Hano, Y.; Nomura, T.; Chen, Y. Bioorg. Med. Chem. Lett.
2004, 14, 1193. (b) Cagir, A.; Jones, S. H.; Eisenhauer, B. M.; Gao, R.; Hecht,
S. M. Bioorg. Med. Chem. Lett. 2004, 14, 2051. (c) Cagir, A.; Eisenhauer, B.
M.; Gao, R.; Thomas, S. J.; Hecht, S. M. Bioorg. Med. Chem. 2004, 12, 6287.
(d) Lee, E. S.; Park, J. G.; Kim, S. I.; Jahng, Y. Heterocycles 2006, 68, 151.
DOI: 10.1021/jo900907h
r
Published on Web 06/08/2009
J. Org. Chem. 2009, 74, 5699–5702 5699
2009 American Chemical Society

JOCNote
TABLE 1. Optimization of the Synthesis of 6a from 5a
entry
conditions
yielda (%)
1
2
3
4
5
6
7
TMSCl (1.5 equiv), Et3N (1.0 equiv), CH2Cl2, rt, 17 h
TMSCl (1.5 equiv), Et3N (1.0 equiv), (CH2Cl)2, reflux, 8 h
TMSOTf (1.5 equiv), Et3N (1.0 equiv), CH2Cl2, rt, 6 h
TMSOTf (1.5 equiv), Et3N (2.0 equiv), CH2Cl2, rt, 6 h
TMSOTf (0.8 equiv), Et3N (0.8 equiv), CH2Cl2, rt, 6 h
TMSOTf (1.5 equiv), CH2Cl2, rt, 24 h
0
8
94
78
38
0
Et3N (0.5 equiv), CH2Cl2, rt, 24 h
0
a Isolated yield based on 5a.
precursor, which could be readily prepared from the con-
densation of 2-cyanobenzylamine with crotonoyl chloride.
To our disappointment, no desired cyclization product such
as 6a could be observed under various conditions for the
oxidative generation of amidyl radicals.7 However, in an
attempt to generate the amidyl radicals by conversion of 5a
to the corresponding silyl imidate ester8 with TMSCl/Et3N
followed by oxidation with cerium ammonium nitrate
(CAN),9,10 we were surprised to find that, without the
addition of CAN, the cyclized product 6a was obtained in
a low yield (entries 1 and 2, Table 1). Switching TMSCl to the
more reactive TMSOTf led to the formation of 6a in almost
quantitative yield (entry 3, Table 1). Lowering the amount of
TMSOTf resulted in a decrease of product yield, indicating
that a slight excess of TMSOTf was necessary for the
completion of the reaction (entry 5, Table 1). As a compar-
ison, no reaction was observed with the only use of either
TMSOTf or Et3N (entries 6 and 7, Table 1).
TABLE 2. Intramolecular Reactions of Nitriles with Unsaturated
Amides
The above method was then extended to a number of
unsaturated amides, and the results are summarized in
Table 2. Substrates 5a-h with various substitution patterns
all afforded the expected 2,3-dihydropyrrolopyrimidinone
products in high yields. In the case of 5f, an excellent
cis-stereoselectivity was observed (entry 6, Table 2). The
allene 5j furnished the pyrrolopyrimidinone 6j in 85% yield
as the isomerization product (entry 10, Table 2). The reaction
of bromide 5i under the optimized conditions proceeded
sluggishly. However, when the reaction was performed at
refluxing temperature with an increased amount of Et3N
(4 equiv), the 16,17,18,19-tetrahydroluotonin A 3 was
directly achieved in 80% yield (entry 9, Table 2).
The successful formation of the luotonin A derivative 3
from the bromide 5i prompted us to extend the above
method to the reactions of β-ketoamides. Thus, β-ketoamide
7b was chosen as the model substrate for the optimization of
reaction conditions. After the screening of a few combina-
tions, we were pleased to find that the use of TMSOTf
(3 equiv) and Et3N (3 equiv) at room temperature allowed
a Reaction conditions: 5 (0.2 mmol), TMSOTf (55 μL, 0.3 mmol),
Et3N (28 μL, 0.2 mmol), CH2Cl2 (4 mL), rt, 6 h. b Isolated yield based on
5. c Four equivalents of Et3N was used, and the reaction was performed
at refluxing temperature for 10 h.
(8) Mekouar, K.; Genisson, Y.; Leue, S.; Greene, A. E. J. Org. Chem.
2000, 65, 5212.
(9) For the generation of amidyl radicals from imidate esters, see: (a)
Newcomb, M.; Esker, J. L. Tetrahedron Lett. 1991, 32, 1035. (b) Esker, J. L.;
Newcomb, M. J. Org. Chem. 1993, 58, 4933.
(10) For the generation of carbon-centered radicals by oxidation of silyl
ethers with CAN, see: (a) Sinder, B. B.; Kwon, T. J. Org. Chem. 1990, 55,
4786. (b) Paolobelli, A. B.; Ruzziconi, R. J. Org. Chem. 1996, 61, 6434.
the production of pyrrolopyrimidinone 6j in 60% yield.
When the reaction was carried out in 1,2-dichloroethane at
refluxing temperature, 6j was achieved in 96% yield. A
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SCHEME 1. Proposed Mechanisms for the Reactions of
Nitriles with Amides
TABLE 3. Intramolecular Reactions of Nitriles with β-Ketoamides or
R-Ethoxycarbonylamide
number of β-ketoamides were then examined under the
optimized conditions (Table 3). In all cases, clean reactions
were observed, and the expected products were isolated in
excellent yields (entries 1-7, Table 3). Interestingly, this
method was also applicable to malonates such as 7h, albeit
in a lower efficiency (entry 8, Table 3). Thus, the novel [4 + 2]
cycloaddition between amides and nitriles allows the highly
efficient, one-step construction of the pyrrolopyrimidinone
skeleton under mild conditions.
On the basis of the above results, a plausible mechanism
could be drawn as outlined in Scheme 1. The amide 5a was
first converted to the silyl imidate ester A on reaction with
TMSOTf/Et3N, which then underwent tandem conjugate
nucleophilic N-addition to give the cyclized intermediate B.
The treatment of B with water afforded the product 6a. In the
case of β-ketoamide 7a, the di-O-silylation intermediate C
was formed first, which accounts for the use of excess
TMSOTf (3 equiv). The tandem N-addition then took
place to give the intermediate D, which underwent further
β-elimination of TMSOH to furnish 8a. An alternative
mechanism is the Diels-Alder cycloaddition. However, this
seems unlikely in our cases because activated nitriles or
elevated temperatures are typically required for the Diels-
Alder reactions with nitriles as the dienophiles.11
a Reaction conditions: 7 (0.2 mmol), TMSOTf (110 μL, 0.6 mmol),
Et3N (84 μL, 0.6 mmol), ClCH2CH2Cl (4 mL), rt, 4 h, then reflux, 4 h.
b Isolated yield based on 7.
was added into the solution of (E)-N-(2-cyanobenzyl)but-2-
enamide (5a) (40 mg, 0.2 mmol) and triethylamine (28 μL, 0.2
mmol) in CH2Cl2 (4 mL), and the mixture was stirred at rt for 6 h.
Saturated aqueous NaHCO3 solution (5 mL) was then added,
and the two layers were separated. The aqueous phase was
extracted with CH2Cl2 (3 Â 5 mL), and the combined organic
phase was dried over anhydrous MgSO4. After removal of
the solvent under reduced pressure, the crude product was purified
by column chromatography on silica gel with hexane-
ethyl acetate (2:1, v/v) as the eluent to give pure 6a as a white
solid: yield 37.5 mg (94%); mp 154-155 °C (hexane/ethyl acetate);
1H NMR (300 MHz, CDCl3) δ 1.43 (3H, d, J = 6.6 Hz), 2.33
(1H, dd, J = 10.6, 16.9 Hz), 2.67 (1H, dd, J = 5.7, 16.9 Hz),
3.95-4.08 (1H, m), 4.84 (2H, AB, J=16.8 Hz), 7.44-7.49 (2H, m),
7.53-7.59 (1H, m), 7.91 (1H, d, J=8.4 Hz); 13C NMR (75 MHz,
CDCl3) δ 21.9, 36.9, 48.2, 51.3, 123.2, 123.3, 128.4, 132.0,
132.1, 139.8, 154.2, 168.5; IR (KBr) ν (cm-1) 2966, 1697, 1680,
1365, 780, 729; EIMS m/z (rel intensity) 200 (M+, 24), 185 (100),
157 (25), 131 (15), 116 (24), 89 (18), 77 (5), 63 (7). Anal. Calcd for
C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.70; H, 5.91;
N, 14.15.
To provide further evidence on the proposed mechanism,
the R-ketoamide 9 was prepared and subjected to the above
optimized conditions in Table 3. The cyclized silyl ester
product 10 was isolated in 74% yield (eq 1). This strongly
implies that the reactions between nitriles and amides pro-
ceed via the nucleophilic N-addition cascade.
As a summary, the chemistry detailed above has clearly
demonstrated that the intramolecular formal [4+2] cyclo-
addition of nitriles with amides serves as a highly efficient
and convenient route to pyrrolopyrimidinones. This finding
should be of important application in organic synthesis.
2,3-Dimethylpyrimido[2,1-a]isoindol-4(6H)-one (6j). Typical
Procedure. Trimethylsilyl triflate (110 μL, 0.6 mmol) was added
into the solution of N-(2-cyanobenzyl)-2-methyl-3-oxobutana-
mide (7b) (46 mg, 0.2 mmol) and triethylamine (84 μL, 0.6
mmol) in 1,2-dichloroethane (4 mL) at rt, and the mixture was
refluxed for 4 h. The resulting solution was cooled to rt, and the
same workup procedure outlined in the synthesis of 6a was
followed to give the pure 6j as a white solid: yield 41 mg (96%);
Experimental Section
2-Methyl-2,3-dihydropyrimido[2,1-a]isoindol-4(6H)-one (6a).
Typical Procedure. Trimethylsilyl triflate (55 μL, 0.3 mmol)
(11) (a) Dai, W.; Petersen, J. L.; Wang, K. K. Org. Lett. 2006, 8, 4665. (b)
McClure, C. K.; Link, J. S. J. Org. Chem. 2003, 68, 8256. (c) Toyota, M.;
Komori, C.; Ihara, M. Heterocycles 2002, 56, 101. (d) Li, W.-T.; Lai, F.-C.;
Lee, G.-H.; Peng, S.-M.; Liu, R.-S. J. Am. Chem. Soc. 1998, 120, 4520.
1
mp 236-237 °C (hexane/ethyl acetate); H NMR (300 MHz,
J. Org. Chem. Vol. 74, No. 15, 2009 5701

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CDCl3) δ 2.18 (3H, s), 2.45 (3H, s), 5.05 (2H, s), 7.53-7.63 (3H,
m), 8.08 (1H, d, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 11.3,
22.1, 50.1, 117.6, 123.0, 123.4, 128.7, 131.8, 132.7, 139.4, 155.5,
160.2, 161.4; IR (KBr) ν (cm-1) 2941, 1664, 1655, 1603, 1542,
767; EIMS m/z (rel intensity) 212 (M+, 100), 197 (4), 183 (45),
169 (11), 143 (10), 116 (22), 89 (15), 53 (12). Anal. Calcd for
C13H12N2O: C, 73.56; H, 5.70; N, 13.20. Found: C, 73.53; H,
5.71; N, 13.29.
Acknowledgment. This project was supported by the Na-
tional NSF of China (Grant Nos. 20672136, 20702060, and
20832006) and by the Shanghai Municipal Committee of
Science and Technology (Grant No. 07XD14038).
Supporting Information Available: Characterization of 3
and 5-10. This material is available free of charge via the
Internet at http://pubs.acs.org.
5702 J. Org. Chem. Vol. 74, No. 15, 2009