Synthesis of densely substituted pyrimidine derivatives

Article abstract of DOI:10.1021/jo9017149

(Chemical Equation Presented) The direct condensation of cyanic acid derivatives with N-vinyl/aryl amides affords the corresponding C4-heteroatom substituted pyrimidines. The use of cyanic bromide and thiocyanatomethane in this chemistry provides versatil

Full text of DOI:10.1021/jo9017149

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pyrimidine substructures of interest. Additionally, the ad-
Synthesis of Densely Substituted Pyrimidine
Derivatives
vancement of transition metal-catalyzed methodologies for
cross-coupling of activated azaheterocycles offers comple-
mentary access to substituted azaheterocycles.3 We reported
the development of a methodology4 for the convergent
synthesis of pyrimidine and pyridine derivatives in a single
step from the corresponding N-vinyl/aryl5 amides. This
methodology relies on electrophilic amide activation,6 using
the reagent combination of trifluoromethanesulfonic anhy-
dride7 (Tf2O) and 2-chloropyridine8 (2-ClPyr). Herein we
report the use of cyanic acid derivatives as nucleophiles for
rapid synthesis of versatile C4-heteroatom substituted pyri-
midines. Furthermore, we discuss the utility of this chemistry
in the synthesis of a variety of pyrimidine derivatives that are
not directly accessible due to functional group incompat-
ibility with the condensation reaction conditions.
Omar K. Ahmad, Matthew D. Hill, and
Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
movassag@mit.edu
Received August 6, 2009
Scheme 1 illustrates a plausible mechanism for the union
of an N-vinyl/aryl amide 1 with nitrile 2 by interception of an
activated intermediate9 followed by cyclization of the nitri-
lium ion 5 to give the corresponding substituted pyrimidine
6. Among the various nucleophiles we have explored for this
chemistry, nitriles proved to be most sensitive to conditions
for amide activation; their addition being inhibited even by
excess 2-ClPyr additive. The prevalence of C4-heteroatom-
substituted pyrimidine derivatives in fine chemicals and
pharmaceuticals coupled with our observations that more
electron rich σ- and π-nucleophiles served as excellent con-
densation partners prompted our investigation of cyanic
acid derivatives in the context of our pyrimidine synthesis
methodology.4
The direct condensation of cyanic acid derivatives with
N-vinyl/aryl amides affords the corresponding C4-hete-
roatom substituted pyrimidines. The use of cyanic bro-
mide and thiocyanatomethane in this chemistry provides
versatile azaheterocycles poised for further derivatiza-
tion. The synthesis of a variety of previously inaccessible
C2- and C4-pyrimidine derivatives using this methodo-
logy is described.
The use of a variety of cyanic acid derivatives in the direct
synthesis of C4-heteroatom-substituted pyrimidine deriva-
tives is shown in Table 1. Synthesis of the 4-morpholinopyr-
imidine 6a is illustrative: introduction of Tf2O to a solution
of N-vinyl amide 1a, morpholine-4-carbonitrile (2a), and
2-ClPyr in dichloromethane at -78 °C followed by warming
to 23 °C gave the desired azaheterocycle 6a in 87% yield.
Both N-vinyl and N-aryl amides serve as effective coupling
partners with various cyanic acid derivatives to give the
corresponding azaheterocycles. We recommend either sim-
ple warming to 23 °C after electrophilic activation or heating
at 140 °C in a microwave reactor to accelerate the rate of
cyclization. The union of morpholine-4-carbonitrile (2a)
Pyrimidine derivatives are important azaheterocycles that
have inspired the development of new methodologies for
their chemical synthesis for over a century.1 In addition to
reports concerning variation of established protocols, new
methods2 are also described that rely on the union of amine-
and carbonyl-containing fragments to assemble the important
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~
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8460 J. Org. Chem. 2009, 74, 8460–8463
Published on Web 10/07/2009
DOI: 10.1021/jo9017149
r
2009 American Chemical Society

Ahmad et al.
JOCNote
SCHEME 1
TABLE 1. Synthesis of Pyrimidines and Quinazolinesa
with amides 1a, 1b, and 1c gave the corresponding pyrimi-
dines 6a and 6b, and quinazoline 6c, respectively, within an
hour at 23 °C (condition A). The use of the less nucleophilic
1,3-dioxoisoindoline-2-carbonitrile (2b) necessitated the use
of more forcing cyclization conditions (condition B) to
deliver the desired azaheterocycles. Interestingly, while cya-
natobenzene (2c) afforded the targeted pyrimidine 6f and
quinazoline 6g in moderate yield (Table 1), the use of
thiocyanatobenzene failed to provide the corresponding
4-thiophenyl-substituted azaheterocycles in synthetically
useful yields.10 On the basis of our interest in the synthesis
of 4-thio-derivatives as versatile precursors to other com-
pounds of interest11 we were delighted to see the formation of
the desired products 6h-k (Table 1) in good yield using
thiocyanatomethane (2d) as the nucleophile in this chemis-
try. Importantly, even cyanic bromide (2e) can be used as a
starting material in this azaheterocycle synthesis illustrated
by 4-bromoquinazolines 6l and 6m (Table 1).12 The direct
synthesis of azaheterocycles 6h-m is noteworthy as they
offer exciting options for introduction of a wide range of
other substituents at C4.13
The conversion of 4-methylthioquinazoline 6h and
4-bromoquinazoline 6m to azaheterocycles 6s-v (Scheme 2)
is illustrative of the versatility of the products accessed by using
thiocyanatomethane (2d) and cyanic bromide (2e), respec-
tively, as the nucleophilic component in this chemistry. Reduc-
tion of 6h with Raney nickel14 provided the C4-H quinazoline
6s in 59% yield. Alternatively, the free radical-based reduc-
tion15 of C4-Br 6m proceeded cleanly to give product 6s in 99%
yield. It is important to note that the use of trimethylsilyl
cyanide in our condensative synthesis of pyrimidines did not
proceed under optimal conditions.16 Furthermore, the oxida-
tive activation of the 4-methylthiopyrimidines sets the stage
for addition of various nucleophiles.17 For example, oxidation
(10) Treatment of amide 1b with thiocyanatobenzene provided the cor-
responding quinazoline in <15% yield under various reaction conditions.
(11) Jang, M.-Y.; De Jonghe, S.; Gao, L.-J.; Rozenski, J.; Herdewijn, P.
Eur. J. Org. Chem. 2006, 18, 4257.
(12) Treatment of amide 1a with cyanic bromide did give the correspond-
ing 4-bromopyrimidine albeit in low yields (37-56%).
(13) We have considered mechanisms other than direct nucleophilic
addition of 2e to an electrophilic intermediate; however, in the absence of
any contrary data, a plausible mechanism based on our prior studies is used
here.
c
aAll yields are the average of two experiments. Hx = cyclohexyl.
PMB = p-methoxybenzyl. Uniform reaction conditions unless other-
wise noted: Tf2O (1.1 equiv), 2-ClPyr (1.2 equiv), nucleophile (2.0 equiv),
CH2Cl2. Heating: A, 23 °C, 1 h; B, microwave, 140 °C, 5 min; C, 1,2-
dichloroethane, reflux, 2 h, nucleophile (4.0 equiv; large excess required
to compensate for loss of nucleophile due to sublimation). bNucleophile
(1.1 equiv). cHeat in the microwave for 10 min. dExperiment on 6-gram
scale was heated to 45 °C (oil bath) for 6 h, giving 81% yield of 6h.
(14) Roth, B.; Aig, E.; Lane, K.; Rauckman, B. J. Med. Chem. 1980, 23,
535.
of 4-methylthioquinazoline 6h with m-chloroperbenzoic acid
(mCPBA) followed by treatment with butylamine, ammo-
nia, or aqueous sodium hydroxide gave the corresponding
4-butylaminoquinazoline 6t, 4-aminoquinazoline 6u, and the
(15) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2006, 8, 561.
(16) The use of trimethylsilyl cyanide led to decomposition of the
activated amide.
(17) Herrera, A.; Martınez-Alvarez, R.; Chioua, M.; Chatt, R.; Chioua,
ꢀ
R.; Sanchez, A.; Almy, J. Tetrahedron 2006, 62, 2799.
J. Org. Chem. Vol. 74, No. 21, 2009 8461

Ahmad et al.
JOCNote
SCHEME 2
discussed above. Notably, (2H)-quinazolines are impor-
tant kinase inhibitors and are of value in the development
of anticancer drugs.21
The synthesis of 2-aminoazaheterocycles is of interest due
to their prevalence in a variety of pharmacological drug
targets.22 Typically, their synthesis involves condensation of
guanidine derivatives with appropriate coupling partners.
We had previously noted that trisubstituted ureas function
effectively under activation conditions for both pyridine and
pyrimidine synthesis using our methodology.4 However, less
substituted ureas simply undergo dehydration under the
activation conditions.23 In this regard the use of p-methox-
ybenzyl amine derived ureas as substrates provides a solution
for rapid access to the desired 2-aminoazaheterocycles by
simple unraveling of the C2-amino group post azahetero-
cycle synthesis. For example, the direct condensation of
methoxybenzylurea derivative 1g with cyclohexanecarboni-
trile (2f) gave the desired methoxybenzylquinazoline 6p in
84% yield (Table 1). Treatment of the quinazoline 6p with
hydrogen bromide in toluene at reflux results in the desired
2-aminoquinazoline 6x as shown in eq 2.
quinazoline-4(3H)-one 6v, respectively. Importantly, the 4-bro-
moquinazoline 6m obviated the need for oxidative activation
and allowed direct conversion to the desired products 6t-vwith
superior overall efficiency (Scheme 2). It should be noted that
products 6t-v could not be accessed directly by condensation
of amide 1c with the respective cyanamide or cyanate nucleo-
philes.18
We have also been interested in expansion of our chemi-
stry to address the need for synthesis of pyrimidines with
maximum flexibility for the C2-substituent. In prior stu-
dies we have demonstrated the use of various benzoic,
heteroaromatic, alkanoic, and alk-2-enoic amide deriva-
tives in our condensative synthesis of azaheterocycles.4
These substrates offer the corresponding 2-alkyl, aryl,
heteroaryl, and vinyl azaheterocycles. However, we have
noted4b that formamides are not substrates for this azahe-
terocycle synthesis methodology due to competing forma-
tion of isonitriles during the activation of the substrates.7,19
The rapid decarboxylation of pyrimidine-2-carboxylic
acids20 prompted exploration of oxamates as substrates
for our azaheterocycle synthesis. Simple acylation of
amines with use of the commercially available methyl
2-chloro-2-oxoacetate provides the necessary substrates
for the condensative union with various nucleophiles. As
an illustration, the coupling of amide 1f with cyclohexylni-
trile (2f) and thiocyanatomethane (2d) provided the corre-
sponding quinazolines 6n and 6o, respectively (Table 1).
The simple decarboxylation of quinazoline-2-carboxylate
6n to the corresponding quinazoline 6w is shown in eq 1.
The use of readily available oxamates in our azaheterocycle
synthesis followed by decarboxylation affords access
to products that are not viable by using formamides as
Similarly, use of the methoxy-3-(4-methoxyphenyl)-
1-methylurea 1h and the phenyl carbamate 1i in this meth-
odology affords the corresponding 2-dimethylhydroxyami-
noquinazoline 6q and 2-phenoxy 6r, respectively (Table 1).
It should be noted that carbamothioates did not provide
2-thiopyrimidines in synthetically useful yields.24
In summary, the direct condensation of cyanic acid deri-
vatives with N-vinyl/aryl amides affords the corresponding
C4-heteroatom-substituted pyrimidines. In particular, the
use of cyanic bromide and thiocyanatomethane in this chemi-
stry yields versatile azaheterocycles ready for further C4
derivatization. Additionally, we describe the use of oxamates
(21) (a) Thompson, A. M.; Bridges, A. J.; Fry, D. W.; Kraker, A. J.;
Denny, W. A. J. Med. Chem. 1995, 38, 3780. (b) Gibson, K. H.; Grundy, W.;
Godfrey, A. A.; Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Scarlett, L.;
Barker, A. J.; Brown, D. S. Bioorg. Med. Chem. Lett. 1997, 7, 2723. (c) Fry,
D. W. Exp. Cell. Res. 2003, 284, 131. (d) Cascone, T.; Morelli, M. P.;
Ciardiello, F. Ann. Oncol. 2006, 17 (Suppl 2), 44.
(22) For recent studies, see: (a) Collis, A. J.; Foster, M. L.; Halley, F.;
Maslen, C.; McLay, I. M.; Page, K. M.; Redford, E. J.; Souness, J. E.;
Wilsher, N. E. Bioorg. Med. Chem. Lett. 2001, 11, 693. (b) Gangjee, A.;
Adair, O. O.; Pagley, M.; Queener, S. F. J. Med. Chem. 2008, 51, 6195.
(c) Fujiwara, N.; Nakajima, T.; Ueda, T.; Fujita, H.; Kawakami, H. Bioorg,
Med. Chem. 2008, 16, 9804.
(23) Stevens, C. L.; Singhal, G. P.; Ash, A. B. J. Org. Chem. 1967, 32,
2895.
(24) A variety of 2-thiopyrimidine derivatives were synthesized in low
yield (<20%) primarily due to the incomplete activation of the carbamothio-
ates.
(18) Cyanamide, bis(trimethylsilyl)carbodiimide, and potassium cyanate
do not serve as competent nucleophiles under our condensative pyrimidine
synthesis reaction conditions; for example, amide 1c and cyanamide did not
afford 6u.
(19) Baldwin, J. E.; O’Neil, I. A. Tetrahedron Lett. 1990, 3, 2047.
(20) Boger, D. L.; Dang, Q. Tetrahedron 1988, 44, 3379.
8462 J. Org. Chem. Vol. 74, No. 21, 2009

Ahmad et al.
JOCNote
and benzylated ureas to access C2-H and C2-amino aza-
heterocycles, compounds previously inaccessible with this
methodology. This chemistry provides densely substituted
and functionalized pyrimidine derivatives and extends the
scope of this condensative strategy for azaheterocycle
synthesis.
4-Bromo-6-methoxy-2-phenylquinazoline (6m, Table 1). Tri-
fluoromethanesulfonic anhydride (450 μL, 2.67 mmol, 1.10
equiv) was added dropwise to a mixture of amide 1c (552 mg,
2.43 mmol, 1 equiv) and 2-chloropyridine (275 μL, 2.91 mmol,
1.20 equiv) in 1,2-dichloroethane (4.0 mL) at -78 °C. After
5 min, the reaction mixture was allowed to warm to 0 °C. After
5 min, a solution of cyanic bromide (2e, 1.07 g, 10.1 mmol, 4.17
equiv) in 1,2-dichloroethane (4.1 mL) was added via cannula.
After 5 min, the reaction mixture was heated to reflux. After 1 h,
the reaction mixture was allowed to cool to 23 °C, the volatiles
were removed under reduced pressure, and the residue was
purified by flash column chromatography (eluent: 10% EtOAc
and 1% Et3N in hexanes; SiO2: 18 ꢀ 3 cm) on neutralized silica
gel to afford the desired quinazoline derivative 6m as a white
solid (633 mg, 83%). Mp 141-142 °C; TLC (10% EtOAc in
hexanes) Rf 0.30 (UV); 1H NMR (500 MHz, DMSO-d6, 20 °C) δ
8.49 (app. dt, 2H, J=7.5 Hz, 2.0 Hz), 7.92 (d, 1H, J=9.0 Hz),
7.52 (dd, 1H, J =9.0, 3.0 Hz), 7.49-7.44 (m, 3H), 7.36 (d, 1H,
J=2.5 Hz), 3.96 (s, 3H); 13C NMR (125 MHz, DMSO-d6, 20 °C)
δ 159.3, 158.4, 155.4, 147.5, 136.8, 130.9, 130.6, 128.8, 128.5,
127.8, 125.8, 105.3, 56.0; FTIR (nujol) (cm-1) 2855, 2828, 1619,
1553, 1482, 1391; HRMS (ESI) calcd for C15H12BrN2O [M þ
H]þ 315.0128, found 315.0136.
Experimental Section
6-Methoxy-4-(methylthio)-2-phenylquinazoline (6h, Table 1).
Trifluoromethanesulfonic anhydride (4.79 mL, 29.0 mmol, 1.10
equiv) was added via syringe over 2 min to a well-stirred mixture
of amide 1c (6.00 g, 26.4 mmol, 1 equiv) and 2-chloropyridine
(3.00 mL, 31.7 mmol, 1.20 equiv) in dichloromethane (88 mL) at
-78 °C. After 10 min, the reaction mixture was placed in an
ice-water bath and warmed to 0 °C. After 4 min, nucleophile 2d
(2.12 g, 29.0 mmol, 1.10 equiv) was added via syringe over 1 min.
The resulting solution was allowed to warm to 23 °C for 5 min
before the reaction mixture was heated to 45 °C in an oil bath.
After 6 h, the reaction vessel was allowed to cool to 23 °C and
then triethylamine (8.08 mL) was introduced to neutralize the
trifluoromethanesulfonate salts. The volatiles were removed
under reduced pressure and the residue was purified by flash
column chromatography (eluent: 10% EtOAc in hexanes; SiO2:
11 ꢀ 6.5 cm) on neutralized silica gel to give quinazoline
derivative 6h as a white solid (6.05 g, 81%). Mp 104-105 °C;
TLC (20% EtOAc in hexanes) Rf 0.49 (UV); 1H NMR (500 MHz,
CDCl3, 20 °C) δ 8.61-8.57 (m, 2H), 7.91 (d, 1H, J = 9.1 Hz),
7.52-7.43 (m, 4H), 7.25-7.23 (m, 1H), 3.93 (s, 3H), 2.82 (s,
3H); 13C NMR (125 MHz, CDCl3, 20 °C) δ 169.1, 157.8, 157.2,
144.5, 138.4, 130.5, 130.2, 128.5, 128.3, 125.9, 123.2, 101.6,
55.7, 12.8; FTIR (neat) (cm-1) 3059, 1564, 1536, 1493, 1231,
1214; HRMS (ESI) calcd for C16H15N2OS [M þ H]þ 283.0900,
found 283.0898.
Acknowledgment. M.M. is an Alfred P. Sloan Research
Fellow, a Beckman Young Investigator, and a Camille
Dreyfus Teacher-Scholar. We acknowledge financial sup-
port from NSF (547905), Amgen, and DuPont.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 21, 2009 8463