Single-step synthesis of pyrimidine derivatives

Article abstract of DOI:10.1021/ja066405m

We describe a single-step conversion of various N-vinyl and N-aryl amides to the corresponding pyrimidine and quinazoline derivatives, respectively. The process involves amide activation with 2-chloropyridine and trifluoromethanesulfonic anhydride followe

Full text of DOI:10.1021/ja066405m

Published on Web 10/12/2006
Single-Step Synthesis of Pyrimidine Derivatives
Mohammad Movassaghi* and Matthew D. Hill
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139
Received September 4, 2006; E-mail: movassag@mit.edu
Table 1.
The pyrimidine substructure is ubiquitous in natural products,
pharmaceuticals, and functional materials.1 The majority of synthetic
routes to this family of azaheterocycles involve strategies based
on the condensation of amines and carbonyl compounds.1,2
A
complementary approach to substituted derivatives involves the use
of recent advances in cross-coupling chemistry to introduce
substituents on activated heterocycles.3 Herein we report a mild,
convergent, and single-step procedure for the conversion of readily
available N-vinyl and N-aryl amides4 to the corresponding substi-
tuted pyrimidines and quinazolines, respectively (eq 1).
We recently reported a mild procedure for electrophilic activation
of sensitive amides en route to pyridine derivatives.5,6 We recog-
nized the unique reactivity associated with electrophilic activation
of amides using 2-chloropyridine (2-ClPyr)7 in combination with
trifluoromethanesulfonic anhydride (Tf2O).8 The current study
concerns the trapping of highly activated amide derivatives with
weakly nucleophilic nitriles to directly provide the corresponding
pyrimidine derivatives (eq 1).
entry
base additive
equiv
isolated yield (%)a
1
2
3
4
5
6
7
8
none
0
29
0
Et3N
1.2
1.2
1.2
1.2
1.0
1.2
3.0
iPr2Net
14
26
28
72
90
81
pyridine
2,6-lutidine
2-chloropyridine
2-chloropyridine
2-chloropyridine
a Tf2O (1.1 equiv), C6H11CN (1.1 equiv), 45 °C, 16 h.
c
temperature activation of the amide is essential for optimum
results.10b In the case of highly reactive amides, excess nitrile was
found to increase the yield of the desired pyrimidine product (Table
2, entry 17).10c
The dehydration of primary amides to the corresponding nitriles
using Tf2O and triethylamine has been reported.13 Under optimum
conditions, treatment of a solution of secondary amide 1a (1 equiv),
primary amide 4 (1.1 equiv), and 2-ClPyr (2.6 equiv) with Tf2O
(2.3 equiv) at -78 °C followed by microwave heating for 20 min,
directly gave quinazoline 3a in 74% yield (eq 2).14 The ready
availability of primary amides and their use as nitrile surrogates
adds to the utility of this chemistry.
Benzamide 1a and cyclohexanecarbonitrile (2a) were used to
identify the optimum reagent combination (Table 1). The use of
2-ClPyr and Tf2O allowed direct conversion of benzamide 1a to
the corresponding quinazoline 3a (Table 1, entry 7).9 Other base
additives largely returned the starting amide 1a after aqueous
workup. A large excess of 2-chloropyridine was found to have an
inhibitory effect (Table 1, entry 8), perhaps by competing with the
addition of the weakly nucleophilic nitrile 2a (vide infra). Under
optimal conditions, the addition of Tf2O (1.1 equiv) to a cold
solution of amide 1a (1 equiv), nitrile 2a (1.1 equiv), and 2-ClPyr
(1.2 equiv) in dichloromethane followed by warming afforded the
desired quinazoline 3a in 88-90% isolated yield.
We next explored the substrate scope with a variety of secondary
amides and nitriles (Table 2). While electron rich N-vinyl and N-aryl
amides proceeded to afford the corresponding pyrimidine derivatives
at ambient temperatures (Table 2, condition A), less reactive
substrates required heating (Table 2, conditions B and C).10a
Electron donating and electron withdrawing substituents were
tolerated in N-aryl benzamide derivatives (Table 2, entries 1-9).
A wide range of nitriles, including electron rich and electron
deficient benzonitriles in addition to saturated and unsaturated
nitriles (Table 2, entries 10-16) were compatible with this
chemistry. A variety of sensitive N-vinyl amides (Table 2, entries
14-21) served as substrates, giving the corresponding pyrimidine
derivatives. Significantly, the use of epimerizable substrates (Table
2, entries 20 and 21) provided the corresponding pyrimidine
derivatives without any loss in optical activity.11,12 For the most
reactive substrates, the introduction of the nitrile prior to the low
As illustrated in Scheme 1, amide activation and addition of
2-ClPyr to a protonated imidoyl triflate is envisioned to give the
highly electrophilic 2-chloropyridinium adduct 5. In contrast to
pyridine, 2-ClPyr was found not to add to Tf2O.6,11 Monitoring of
the reaction in entry 1 of Table 2 by 19F NMR spectroscopy revealed
the presence of trifluoromethanesulfonate (-79.6 ppm, CD2Cl2)
throughout the reaction, without involvement of a persistent imidoyl
triflate. In situ 13C NMR monitoring of the amide activation using
1a-13CdO (166.0 ppm, CD2Cl2) led to observation of a new broad
resonance (149.8 ppm, CD2Cl2) prior to addition of the nitrile.
React-IR monitoring during activation of amide 1a with Tf2O in
the absence of nitrile 2a revealed the consumption of 2-ClPyr (1580
cm-1) with concomitant appearance of a new absorption band (1600
cm-1). Introduction of the nitrile 2a to this mixture led to loss of
this absorption band and simultaneous release of 2-chloropyridinium
trifluoromethane-sulfonate (1620 cm-1) and the trifluoromethane-
sulfonate salt of the desired product 3a (1575 cm-1).11 The broad
9
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10.1021/ja066405m CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. a
ion 6 is expected to occur en route to pyrimidine derivative 3.16
The inhibitory effect of more nucleophilic base additives and excess
2-ClPyr in addition to the benefit of superstoichiometric quantities
of nitrile are consistent with the proposed mechanism.
We describe a single-step and convergent procedure for the
synthesis of pyrimidine derivatives. This chemistry is applicable
to a wide range of secondary amides and nitriles and allows for
unique transformations including that in eq 2. This methodology
not only alleviates the need for isolation of activated amide
derivatives but also does not require the additional use of stoichio-
metric Lewis acids.9 The use of this chemistry with sensitive and
epimerizable substrates is noteworthy and offers a valuable ad-
dendum to methodology for azaheterocycle synthesis.
Acknowledgment. M.M. is a Dale F. and Betty Ann Frey
Damon Runyon Scholar supported by the Damon Runyon Cancer
Research Foundation (Grant DRS-39-04). This study was supported
by NSF (Grant 547905). We acknowledge additional support by
Amgen, Firmenich, and Boehringer Ingelheim Pharmaceutical Inc.
Supporting Information Available: Experimental procedures and
spectroscopic data for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
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(1.2 equiv), nitrile (1.1 equiv), CH2Cl2, heating: A ) 23 °C, 1 h; B ) 45
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c 18 h. d An amount of 5 equiv of nitrile. e Gram-scale reaction. f Time )
1 h. g TBAF (1 equiv) used to desilylate the product. h An amount of 3
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Scheme 1
(11) See Supporting Information for details.
(12) The use of the N-4-methoxyphenyl variant of the amide in entry 21 of
Table 2 provided the corresponding quinazoline in 58% yield but with
complete racemization. Please see Supporting Information for details.
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(16) The conversion of 6 to 3 may be facilitated by net addition of
2-chloropyridinium triflate to the nitrilium ion.
1H, 13C, and 19F NMR resonances observed for the activated
intermediate prior to addition of the nitrile suggests equilibration
of 5 with the corresponding triflate adduct.11 Reversible addition
of nitrile15 and expulsion of 2-ClPyr‚HOTf to provide the nitrilium
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