A regioselective approach to trisubstituted 2 (or 6)-arylaminopyrimidine-5- carbaldehydes and their application in the synthesis of structurally and electronically unique G∧C base precursors

Article abstract of DOI:10.1021/jo7021422

(Chemical Equation Presented) An efficient regioselective synthesis of trisubstituted 2(or 6)-arylaminopyrimidine-5-carbaldehydes has been developed via an S_NAr reaction of 2,4,6-trichloropyrimidine-5-carbaldehyde with aniline, methylamine, and alkoxide nucleophiles using a combination of phase-transfer catalysis and more traditional S_NAr reaction conditions. We demonstrate that in a few synthetic steps, highly functionalized fused-bicyclic pyrimidine substrates can be accessed from the trisubstituted 2-arylaminopyrimidine-5-carbaldehydes. Furthermore, these fused-bicyclic compounds are readily derivatized using the Suzuki cross-coupling reaction to generate electronically and structurally unique G∧C base precursors.

Full text of DOI:10.1021/jo7021422

A Regioselective Approach to Trisubstituted 2 (or
6)-Arylaminopyrimidine-5-carbaldehydes and Their Application in
the Synthesis of Structurally and Electronically Unique G∧C Base
Precursors
Rachel L. Beingessner,† Bo-Liang Deng,‡ Phillip E. Fanwick,§ and Hicham Fenniri*,†
National Institute for Nanotechnology and Department of Chemistry, UniVersity of Alberta, 11421
Saskatchewan DriVe, Edmonton, Alberta, T6G 2M9, Canada, Nektar Therapeutics, 490 DiscoVery DriVe,
HuntsVille, Alabama 35806, and Department of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
hicham.fenniri@ualberta.ca
ReceiVed October 2, 2007
An efficient regioselective synthesis of trisubstituted 2(or 6)-arylaminopyrimidine-5-carbaldehydes has
been developed via an SNAr reaction of 2,4,6-trichloropyrimidine-5-carbaldehyde with aniline, methy-
lamine, and alkoxide nucleophiles using a combination of phase-transfer catalysis and more traditional
SNAr reaction conditions. We demonstrate that in a few synthetic steps, highly functionalized fused-
bicyclic pyrimidine substrates can be accessed from the trisubstituted 2-arylaminopyrimidine-5-
carbaldehydes. Furthermore, these fused-bicyclic compounds are readily derivatized using the Suzuki
cross-coupling reaction to generate electronically and structurally unique G∧C base precursors.
SCHEME 1. General 2- and 6-Arylaminopyrimidines
Introduction
Substituted pyrimidines such as those displaying an arylamine
at position 2 or 6 as illustrated in Scheme 1 are an interesting
class of heterocycles that are widely distributed in natural
products and synthetic analogues thereof.1 They display a range
* Address correspondence to this author. Phone: (780)-641-1750. E-mail:
hicham.fenniri@ualberta.ca.
† University of Alberta.
‡ Nektar Therapeutics.
of significant biological properties and, as a result, have many
important applications in the area of therapeutics. For example,
certain 2-arylaminopyrimidines have been designed to serve as
reverse transcriptase inhibitors for HIV2 as well as angiogenesis
inhibitors for the treatment of cancer.3 Many 6-arylaminopyri-
midines have equally important roles given their potential for
§ Purdue University.
(1) For reviews on pyrimidines see: (a) Brown, D. J.; Evans, R. F.;
Cowden, W. B.; Fenn, M. D. The Pyrimidines; Wiley: New York, 1994.
(b) Brown, D. J. The Chemistry of Heterocyclic Compounds; Vol. 16, The
Pyrimidines; Weissberger, A., Ed.; Wiley-Interscience: New York, 1970.
(c) Hurst, D. T. An Introduction to the Chemistry and Biochemistry of
Pyrimidines, Purines and Pteridines; Wiley: Chichester, UK, 1980.
10.1021/jo7021422 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/08/2008
J. Org. Chem. 2008, 73, 931-939
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Beingessner et al.
SCHEME 2. Synthetic Approach to G∧C Bases 4a/4b
SCHEME 3. Imine Formation and Hydrolysis
preventing carcinomatous disorders4 and their ability to activate
caspases and induce apoptosis,5 to name a few.
molecules 3a/3b were to contain an arylamine such as aniline,
4-iodoanilin, or 4-bromoaniline at position 6 (or 2), an alkyl
ether at position 4, as well as methylamine at position 2 (or 6).
Furthermore, a formyl group at position 5 was to serve as a
building block for further elaboration of the pyrimidine core to
generate 4a/4b.
During the course of our investigations on the self-assembly6
of G∧C bases into rosette nanotubes (RNTs),7 we aspired to
have a flexible, reproducible, and scalable synthetic approach
to 6-arylaminopyrimidine 3a and 2-arylaminopyrimidine 3b, in
order to prepare G∧C bases of the general form 4a and 4b,
respectively (Scheme 2). These tetrasubstitued heterocyclic
Although methodologies for the synthesis of substituted
pyrimidines have been developed, many involve the construction
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Kovalenko, A.; Fenniri, H. J. Am. Chem. Soc. 2007, 129, 5735-5743.
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Samano, V. A.; Ray, J. A.; Freeman, G. A.; Boyd, F. L., Jr.; Sexton, C. J.;
Selleseth, D. W.; Creech, K. L.; Moniri, K. R. Bioorg. Med. Chem. 2005,
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Byth, K. F.; Culshaw, J. D.; Green S.; Oakes, S. E.; Thomas, A. P. Bioorg.
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Lett. 2007, 48, 1205-1207. (f) Font, D.; Heras, M.; Villalgordo, J. M. J.
Comb. Chem. 2003, 5, 311-321. (g) Chhabria, M. T.; Bhatt, H. G.; Raval,
H. G.; Oza, P. M. Bioorg. Med. Chem. Lett. 2007, 17, 1022-1024. (h)
Mesguiche, V.; Parsons, R. J.; Arris, C. E.; Bentley, J.; Boyle, F. T.; Curtin,
N. J.; Davies, T. G.; Endicott, J. A.; Gibson, A. E.; Golding, B. T.; Griffin,
R. J.; Jewsbury, P.; Johnson, L. N.; Newell, D. R.; Noble, M. E. M.; Wang,
L. Z.; Hardcastle, I. R. Bioorg. Med. Chem. Lett. 2003, 13, 217-222.
(3) (a) Sammond, D. M.; Nailor, K. E.; Veal, J. M.; Nolte, R. T.; Wang,
L.; Knick, V. B.; Rudolph, S. K.; Truesdale, A. T.; Nartey, E. N.; Stafford,
J. A.; Kumar, R.; Cheung, M. Bioorg. Med. Chem. Lett. 2005, 15, 3519-
3523. (b) Dev, I. K.; Dornsife, R. E.; Hopper, T. M.; Onori, J. A.; Miller,
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(4) Geisen, K. U.S. Patent 6,156,755, 2000.
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Int. Appl WO 02/47690 A1, 2002
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Turkenburg, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35, 2204-2206. (b)
Marsh, A.; Silvestri, M.; Lehn, J.-M. Chem. Commun. 1996, 1527-1528.
(c) Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin, D.
N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37-44. (d)
Kolotuchin, S. V.; Zimmerman, S. C. J. Am. Chem. Soc. 1998, 120, 9092-
9094. (e) Mele´ndez, R. E.; Hamilton, A. D. Top. Curr. Chem. 1998, 198,
97-129. (f) Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem.,
Int. Ed. 2001, 40, 2382-2426. (g) Stoddart, J. F.; Tseng, H.-R. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 4797-4800. (h) Lehn, J.-M. NATO ASI Series,
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Angew. Chem., Int. Ed. 1999, 38, 1018-1033. (j) Hof, F.; Craig, S. L.;
Nuckolls, C.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2002, 41, 1488-1508.
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N. A. J. M. Chem. ReV. 2001, 101, 4039-4070. (m) Reinhoudt, D. N.;
Crego-Calama, M. Science 2002, 295, 2403-2407. (n) Mascal, M.
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932 J. Org. Chem., Vol. 73, No. 3, 2008

Synthesis of Substituted Arylaminopyrimidine DeriVatiVes
SCHEME 4. Synthetic Approach to G∧C Base Precursor 10
of the heterocyclic ring using building blocks already displaying
the required substituents.8 Alternatively, a potentially more
concise and flexible synthetic approach is the direct introduction
of functional groups into the pyrimidine ring via displacement
of halides and other leaving groups. Unfortunately, this approach
can lead to moderate or low yields of the desired product,
especially when using aniline nucleophiles, since high temper-
atures, excess nucleophile (which can lead to disubstitution and
other side reactions), and extended reaction lengths are often
necessary.9 In addition to the aforementioned obstacles, the
presence of a 5-formyl group on the pyrimidine ring (i.e., 3a/
3b), which can serve as a handle for functionalization, consti-
tutes a further challenge. O’Brien and co-workers reported, for
example, that treatment of pyrimidine 5 with 2 equiv of
4-bromoaniline led to the formation of imine 6, which required
an additional hydrolysis step under refluxing conditions in order
to generate the desired aldehyde 7 (Scheme 3).10 The overall
yield for the two steps was 36%. Clearly, a methodology that
would provide rapid entry into substituted pyrimidines contain-
ing a 2(or 6)-arylamine group without troublesome side reactions
would be of great value.
the 6-substituted compound 11 under the conditions described
is attributed to the directing influence of the aldehyde through
either the formation of a hydrogen bond with the allylamine
nucleophile or the formation of a transient intermediate aminol
that delivers the amine selectively to position 6. It is important,
however, to monitor the reaction temperature and length closely
since side products such as the disubstituted product can often
form.
By using the same approach described in eq 1, the synthesis
of 6-arylaminopyrimidine 3a (Ar ) 4-iodoaniline) was com-
menced by treating 2,4,6-trichloropyrimidine-5-carbaldehyde (8)
with 2.0 equiv of 4-iodoaniline in THF at -78 °C as illustrated
in eq 2. A complex mixture of products formed that, surpris-
ingly, were not easily separated and characterized due to their
poor solubility in hexane, acetone, chloroform, CH2Cl2, and
DMSO. The EI and CI mass spectra of the mixture, however,
revealed the peaks 392.9/394.90 (18%/13%), 575.90/577.85
(31%/10%), 593.85/595.85 (47%/32%), which were tentatively
assigned to compounds 12a, 13, and 14, respectively (eq 2).
Herein, we demonstrate that through the judicious choice of
reaction conditions, highly functionalized trisubstituted ary-
laminopyrimidine-5-carbaldehydes 3a and 3b can be obtained
in an efficient and scalable manner from 2,4,6-trichloropyrimi-
dine-5-carbaldehyde (8) via direct, sequential introduction of
nucleophilic reagents. Moreover, we describe the assembly of
tricyclic compound 9 from pyrimidine 3b and the subsequent
implementation of a Pd cross-coupling reaction as a flexible
strategy to generate structurally and electronically unique G∧C
base precursors 10 (Scheme 4).
Results and Discussion
On the basis of the notion that imine 14 was present in the
mixture, the crude material was refluxed in a 0.1 N solution of
HCl10 to hydrolyze the imine to the monosubstituted pyrimidine
12a. Unfortunately, the CI and EI mass spectra obtained after
the hydrolysis reaction were not very encouraging. The [M]+
peak corresponding to imine 14 still remained and the [M]+
peak for the desired compound 12a (or its expected fragmenta-
tion pattern) was no longer evident. The SNAr reaction was
subsequently repeated by treating 2,4,6-trichloropyrimidine-5-
carbaldehyde (8) with 1.0 equiv of 4-iodoaniline and 1.0 equiv
Synthesis of the 2-Methylamino-4-chloro-6-arylaminopy-
rimidine Regioisomer (3a). We have shown from our previous
work7b that pyrimidine 11 shown in eq 1 can be readily accessed
via an SNAr reaction of 2,4,6-trichloropyrimidine-5-carbaldehyde
(8)11 in the presence of allylamine. The exclusive formation of
(10) O’Brien, D. E.; Weinstock, L. T.; Cheng, C. C. J. Med. Chem. 1968,
11, 387-388.
(11) Yoneda, F.; Sakuma, Y.; Mizumoto, S.; Ito, R. J. Chem. Soc., Perkin
Trans. 1 1976, 1805-1808.
J. Org. Chem, Vol. 73, No. 3, 2008 933

Beingessner et al.
SCHEME 5. Synthesis of 15a-c under PTC Conditions
of Et3N in THF at -78 °C in an attempt to minimize the
disubstituted product 13. This reaction was also unsuccessful
as a mixture of products were obtained. It was therefore apparent
that alternative conditions for this reaction were necessary in
order to avoid the synthesis of imine 14 during the course of
generating 12a. In particular, it was important to neutralize the
aniline hydrohalide byproduct of the reaction since this was
required for imine formation.
The SNAr reaction was thus explored under phase transfer
catalysis (PTC) conditions. PTC in general has proven to be a
powerful tool in organic synthesis, having the advantage of mild
reaction conditions, being operationally simple and adaptable
to larger scale production and offering environmental and cost
benefits.12 Although phase transfer catalyst have been widely
implemented in nucleophilic displacement reactions involving
aliphatic substrates, their use in SNAr reactions have been
explored to a lesser extent.13
14 would therefore be prevented due to the absence of acid,
and the presence of water in the medium. This reaction also
offered the advantage of requiring only 1.0 equiv of amine
nucleophile (unlike eq 2), which would minimize the possibility
of forming the disubstituted product 13.
Gratifyingly, in practice, treatment of 2,4,6-trichloropyrimi-
dine-5-carbaldehyde (8) with 4-iodoaniline (1.0 equiv) in the
presence of TBAI (0.05 equiv) and KHCO3 (1.2 equiv) in a
2:1 mixture of CH2Cl2/H2O for 24 h at rt generated pyrimidine
12a in nearly quantitative yield (Scheme 5). The structure of
12a was successfully verified by single-crystal X-ray diffraction
analysis. High yields of 12b and 12c were also obtained with
4-bromoaniline (81%) and aniline (75%) nucleophiles, respec-
tively. This reaction was readily adapted to larger scales, as
exemplified by the synthesis of 12c, which was conducted on
a 45 g (212 mmol) scale. Substituting CH2Cl2 with toluene,
which is a more environmentally acceptable solvent for larger
scale preparation, had little impact on the yields as 12a, 12b,
and 12c were obtained in 86%, 87%, and 84% yield, respec-
tively, after 24 h at rt.
We envisioned the SNAr reaction of 2,4,6-trichloropyrimidine-
5-carbaldehyde (8) with 4-iodoaniline to occur in a biphasic
system (organic solvent/H2O) containing a weak base (i.e.,
KHCO3) and a phase transfer catalyst such as tetrabutylammo-
nium iodide (TBAI).14 Under these conditions it was feasible
that the bicarbonate anion present as the TBA salt (i.e.,
Bu4N+HCO3-) would neutralize the aniline hydrohalide byprod-
uct of the SNAr reaction, possibly at the interface between the
two solvent phases, to produce Bu4N+Cl- and H2CO3, the later
The second aromatic substitution reaction at position 2 of
pyrimidine 12a-c was subsequently effected in high yields in
the presence of methylamine (3.0 equiv), TBAI (0.05 equiv),
and KHCO3 (1.2 equiv) in a 1:1 solution of toluene/H2O at rt
for 48 h (Scheme 5).15 The products of the reaction, 15a-c,
precipitated out of solution and were simply collected via
filtration. Although the reactions did proceed with only 1.0 equiv
of methylamine, a significant quantity of starting material
remained after 48 h (i.e., 67% yield for 15a with 19% recovered
starting material 12a), which is a direct result of the decreased
electrophilicity of the pyrimidine core relative to compound 8.
-
of which would dissociate into H2O and CO2. The Bu4N+HCO3
could then be regenerated from Bu4N+Cl-, thereby permitting
the neutralization reaction to be repeated. The formation of imine
(12) (a) Starks, C. M.; Liotta, C. L.; Halpern, M. Phase-Transfer
Catalysis: Fundamentals, Applications, and Industrial PerspectiVes; Chap-
man and Hall: New York, 1994. (b) Dehmlow, E. V.; Dehmlow, S. S.
Phase-Transfer Catalysis, 3rd ed.; VCH: Weinheim, Germany, 1993. (c)
Shioiri, T. Chiral Phase-Transfer Catalysis. In Handbook of Phase-Transfer
Catalysis; Sasson, Y., Neumann, R., Eds.; Blackie: London, UK, 1997,
Chapter 14.
(13) For examples see: (a) Ye, C.; Gao, H.; Boatz, J. A.; Drake, G. W.;
Twamley, B.; Shreeve, J. M. Angew. Chem., Int. Ed. 2006, 45, 7262-
7265. (b) Vlasov, V. M. Russ. J. Org. Chem. 1998, 34, 1310-1321. (c)
Stuart, A. M.; Vidal, J. A. J. Org. Chem. 2007, 72, 3735-3740. (d) Calafat,
S. V.; Durantini, E. N.; Chiacchiera, S. M.; Silber, J. J. J. Org. Chem. 2005,
70, 4659-4666. (e) Desai, N. D.; Shah, R. D. Synthesis 2006, 19, 3275-
3279. (f) Feldman, D.; Segal-Lew, D.; Rabinovitz, M. J. Org. Chem. 1991,
56, 7350-7354. (g) Singh, P.; Arora, G. Tetrahedron, 1988, 44, 2625-
2632. (h) Landini, D.; Montanari, F.; Rolla, F. J. Org. Chem. 1983, 48,
604-605. (i) Landini, D.; Maia, A.; Montanari, F. J. Chem. Soc., Perkin
Trans. 2 1983, 461-466. (j) Neumann, R.; Sasson, Y. Tetrahedron 1983,
39, 3437-3440.
Synthesis of the 2-Arylamino-4-chloro-6-methylaminopy-
rimidine-5-carbaldehyde Regioisomer (3b). Having estab-
lished a simple and efficient methodology for the synthesis of
2-methylamino-6-arylaminopyrimidine derivatives 15a-c, it was
envisioned that by simply reversing the order of the two
nucleophilic substitution reactions the other regiosiomer 3b
could be obtained. Indeed, 2,4-dichloro-6-(methylamino)pyri-
midine-5-carbaldehyde (16) was readily prepared from com-
pound 8 in 92% yield in the presence of methylamine (1.0 equiv)
under our standard PTC conditions (TBAI (0.05 equiv), KHCO3
(1.2 equiv), toluene/H2O (1:1)) as illustrated in Scheme 6. A
brief comparison study was also performed whereby 2,4,6-
(14) For examples of using KHCO3 as a base in PTC see: (a) Kiser, E.
J. PCT Int. Appl WO 136910, A1, 2006. (b) Perlman, N.; Gilboa, E. PTC
INT. Appl. WO 044648, A1, 2006. (c) Mafatlal, K. B.; Ambalal, M. I.;
Chandrakant, S. M.; Kashyapbhai, P. K.; Prabhakar, D. S.; Ravi, P.; Jagdish,
D. S.; Raman, J. V. PCT Int. Appl WO 114676, A2, 2006.
(15) Position 2 of 6-substituted-2,4-dichloropyrimidine-5-carbaldehyde
is the most reactive site for the SNAr reaction since a negative charge can
be delocalized on the two nitrogen atoms in the ring. Position 4, alternatively,
is less reactive since there is little directing effect from the aldehyde group
as it is already hydrogen bonded to the amine hydrogen at position 6.
934 J. Org. Chem., Vol. 73, No. 3, 2008

Synthesis of Substituted Arylaminopyrimidine DeriVatiVes
SCHEME 6. Synthesis of 17a/17b Using PTC Conditions
trichloropyrimidine-5-carbaldehyde (8) was treated with me-
thylamine (2.0 equiv) in a solution of THF, CH2Cl2, or toluene
at -78 °C. In these three different solvent environments, the
desired product 16 was isolated in only 49%, 34%, and 1.3%16
yield, respectively, thus highlighting the efficacy of PTC for
these transformations.
favorable yield, the additional hydrolysis step was not very
convenient and thus other conditions were explored. In par-
ticular, a more polar solvent such as THF/H2O was considered
since this was expected to enhance the rate of the substitution
reaction which in turn would permit a lower reaction temper-
ature. Such conditions were predicted to be less conducive for
imine formation because of the miscibility of THF and water.
This rational proved valid as treatment of 2,4-dichloro-6-
(methylamino)pyrimidine-5-carbaldehyde (16) with 4-iodoa-
niline (1.0 equiv) and KHCO3 (1.2 equiv) in THF/H2O (1:1) at
rt provided 4-chloro-2-(4-iodophenylamino)-6-(methylamino)-
pyrimidine-5-carbaldehyde (17a) in 85% yield (Condition C).
Installation of the 4-Alkoxy Substitutent. With the amine
substituents at the 2- and 6-position of the pyrimidine ring
Following the isolation of pyrimidine 16, the second aromatic
substitution reaction at position 2 was attempted using 4-bro-
moaniline as illustrated in Scheme 6, Condition A. Quite
unexpectedly, only starting material was present after 24 h at rt
in a 1:1 mixture of toluene/H2O, TBAI (0.05 equiv), and KHCO3
(1.2 equiv). Refluxing the reaction in a more polar solvent
mixture (CH2Cl2/H2O (2:1)) led to the same outcome. It was
therefore evident that more forcing conditions were necessary
to induce the transformation given the reduced electrophilicity
of the pyrimidine ring (due to the electron-donating methylamine
substituent) and the use of a relatively weak nucleophile.17 Thus,
the reaction was repeated in a 1:1 mixture of toluene/H2O and
refluxed for 24 h as illustrated in Scheme 6 (Condition B, X )
Br). Although the yield of 17b was more acceptable at 85%,
these forcing conditions also generated imine 18b, albeit in only
12% yield.
SCHEME 7. Installation of the 4-Alkoxy Substituent
Repeating the reaction of 4-iodoaniline under identical
conditions (Scheme 6, Condition B, X ) I) led to 17a in only
60% yield as a yellow solid, which was collected from the
1
reaction mixture via filtration. A H NMR spectrum of the
remaining filtrate that had been extracted with EtOAc revealed
the presence of imine 18a. Our attempts to hydrolyze the imine
using a 5% solution of HCl proved to be quite fruitful since
the overall yield of 17a was improved to 70%. Despite this more
(16) The disubstituted product, 4-chloro-2,6-bis(methylamino)pyrimidine-
5-carbaldehyde, was isolated in 76% yield.
(17) Henderson, W. A., Jr.; Schultz, C. J. J. Org. Chem. 1962, 27, 4643-
4646.
J. Org. Chem, Vol. 73, No. 3, 2008 935

Beingessner et al.
SCHEME 8. Synthetic Route to Hydroxylimines 22a-d
established, the installation of the 4-alkoxy moieties in 15a-c
and 17a/17b was next attempted. This functional group was to
become the carbonyl group in G∧C bases 4a/4b, eventually
playing a key role as a hydrogen bond acceptor in the self-
assembly process.6 All of the 4-chloro-2,6-disubstituted pyri-
midine-5-carbaldehydes 15a-c and 17a/17b were readily
transformed into their corresponding 4-alkoxy-2,6-disubstituted
pyrimidine-5-carbaldehydes 19a-d or 20a/20b in the presence
of 2-trimethylsilylethyl alkoxide or benzyl alkoxide under
refluxing conditions (Scheme 7). The structures of 19a and 19c
were confirmed by single-crystal X-ray diffraction analysis.
Attempted Synthesis of the G∧C Bases from Pyrimidines
19a-d. With a practical, scalable, and reproducible methodol-
ogy for the preparation of 2(or 6)-arylaminopyrimidines 19a-d
and 20a/20b in a regioselective manner, the preparation of the
G∧C bases 4a/4b was next embarked upon.7b The synthesis
was thus initiated using compounds 19a-d, by protecting the
secondary methylamine groups with Boc2O in the presence of
Et3N and DMAP (Scheme 8). The corresponding products
21a-d were isolated in good yields. Subsequent treatment of
aldehydes 21a-d with the HCl salt of hydroxylamine in the
presence of KHCO3 furnished hydroxylimines 22a-d in yields
ranging from 73% to 84%. The structures of 21b and 22c were
confirmed by single-crystal X-ray diffraction analysis.
These hydroxylimines 22a-d were then converted to nitriles
23a-d by refluxing in a solution of TFAA, Et3N in THF as
illustrated in Scheme 9. Unfortunately, moderate yields of the
desired products were obtained due to the competing formation
of bicyclic compounds 24a-c, which we proposed formed via
nucleophilic attack of an in situ formed amide anion onto the
nitrogen atom of imine ester 25.18 The structure of the undesired
cyclized adduct 24c was confirmed by X-ray crystal analysis.
Nitriles 23a-d were then treated with N-chlorocarbonyl iso-
cyanate and DMAP in a solution of CH2Cl2 to provide
carbamides 26a-d in good yields.
With use of carbamide 26c, the cyclization reaction to
generate the fused heterobicyclic structure 27c was next explored
as illustrated in Table 1. Unfortunately in the presence of NH3
(entries 1-3, Table 1), a soft Lewis acid (entry 4, Table 1) or
basic conditions (entries 5 and 6, Table 1), the cyclized adduct
27c was not observed. Rather, the CONH2 group was liberated
to regenerate 23c. Such was the case for the cyclization attempts
with 26a and 26d as well. Given these observations, it is likely
that the phenyl ring plays an important role in the dissociation
of the carbamide by stabilizing the resulting amide species.
Synthesis of the G∧C Base from Compounds 20a/20b. In
light of the challenges experienced with the cyclization described
in Table 1, we were hopeful that pyrimidines 20a/20b, which
contained a more electron-rich methylamine substituent in lieu
of the arylamine, would be less prone to liberate CONH2 in the
analogous cyclization reaction. Thus, the synthetic sequence was
repeated using substrates 20a/20b to provide 31a/31b as
described in Scheme 10. As anticipated, treatment of the crude
carbamides 31a/31b with 7 N ammonia in MeOH at rt afforded
the desired cyclized adducts 32a/32b in 88% and 65% yield,
respectively (for the two steps beginning from 30a/30b). The
primary amines of the bicyclic products 32a/32b were subse-
quently protected using Boc2O under standard conditions to
afford 33a/33b in good yields. The structures of 33a and 33b
were confirmed by single-crystal X-ray diffraction analysis.
Suzuki Cross-Coupling Reaction. Generation of Highly
Functionalized Pyrimidine Substrates. Although the goal of
preparing tricyclic compounds 33a/33b was realized, it was
important to have the flexibility to access electronically and
structurally unique G∧C bases derived from 33a/33b, in order
to effectively study the self-assembly process. By employing
the aromatic iodide or bromide of 33a or 33b as the coupling
partner in a palladium-catalyzed cross-coupling reaction, it was
suspected that such flexibility could be attained. Thus, a Suzkui
cross-coupling reaction19 of 33a with a variety of commercially
available boronic acids was performed. As presented in Table
2, the coupled adducts 34a-g were assembled in moderate to
excellent yields under the conditions described (Pd2(dba)3, P(t-
Bu)3, KF, THF, rt).20 In entries 2 and 3, a side product of little
(18) A side product was also observed during the synthesis of 23d,
although it was only isolated in 1% yield and with insufficient purity for
1
characterization purposes. H NMR and ESI-mass spectral data strongly
suggest the bicyclic product analogous to 24a-c.
936 J. Org. Chem., Vol. 73, No. 3, 2008

Synthesis of Substituted Arylaminopyrimidine DeriVatiVes
SCHEME 9. Synthetic Route to Nitriles 26a-d
TABLE 1. Cyclization Attempts of Carbamide 26c to Generate
27c
SCHEME 10. Synthetic Route to G∧C Base Precursors
33a/33ba
entry
reagent
solvent
dioxane
temp (°C)
time (h)
1
2
3
4
5
6
7 N NH3 in MeOH
0.5 M NH3
7 N NH3 in MeOH/urea
PdCl2(PPh3)2, Et3N
LiHMDS
0 to rt
7
3
3
19
4
1
rt
rt
THF
THF
THF
rt
-78
NaH
rt
consequence was also observed whereby one of the Boc
protecting groups on the nitrogen atom had been removed (i.e.,
35b/35c). In any case, in addition to the interesting electronic
or structural impact that the iodide atom on the aromatic amine
of 33a may have on the self-assembly process of the G∧C bases,
it also serves as a proficient handle in which to prepare many
unique derivatives for the purpose of our studies.
a Reagents and conditions: (a) Boc2O, Et3N, THF (28a, 90%; 28b, 81%).
(b) NH2OH‚HCl, KHCO3, MeOH (29a, 68%, 29b, 73%). (c) TFAA, Et3N,
THF (30a, 88%; 30b, 81%). (d) N-Chlorocarbonyl isocyanate, DMAP,
CH2Cl2. (e) 7 N NH3, MeOH (32a, 88%, 2 steps; 32b, 65%, 2 steps). (f)
Boc2O, Et3N, DMAP (33a, 77%, 33b, 92%).
Conclusion
An efficient, scalable, and high-yielding method for the
regioselective synthesis of 4-alkoxy-2(or 6)-arylamino-6(or 2)-
methylaminopyrimidine-5-carbaldehydes from 2,4,6-trichloro-
pyrimidine-5-carbaldehyde (8) has been established. In a bi-
phasic mixture (toluene/H2O) containing a PTC catalyst (TBAI)
and KHCO3, the SNAr reaction of compound 8 with aniline
nucleophiles proceeds smoothly without the deleterious forma-
tion of imines and disubstituted products. A second SNAr reac-
tion using 12a-c and methylamine generates 6-arylamino-2-
methylaminopyrmidines 15a-c in excellent yields. The other
regioisomers 17a/17b were also obtained in equally high yields
by simply reversing the order of the nucleophilic addition under
optimized reaction conditions. Furthermore, 15a-c and 17a/
17b were readily transformed into their 4-alkoxy derivatives in
a refluxing solution with the chosen alkoxide. We have also
demonstrated that highly functionalized pyrimidine derivatives
33a/33b can be constructed and these are capable of further
functionalization using a Suzuki cross-coupling reaction.
J. Org. Chem, Vol. 73, No. 3, 2008 937

Beingessner et al.
TABLE 2. Sukuki Cross-Coupling Reactions of 33a
filtered, and concentrated in vacuo. The residue was recrystallized
with EtOAc to provide 11.49 g of 12a (C11H6Cl2IN3O, 99%) as
yellow needles. Rf 0.62 (SiO2, 30% EtOAc/hexane). Mp 137.5-
138 °C. 1H NMR (300 MHz, CDCl3) δ (ppm): 11.16 (NHC6, br s,
3
1H), 10.35 (C5H, s, 1H), 7.68 (C8H, C10H, d, J ) 8.5 Hz, 2H),
7.39 (C7H, C11H, d, 3J ) 8.5 Hz, 2H).13C NMR (75 MHz, CDCl3)
δ (ppm): 190.7 (C5), 166.5 (C2), 162.8 (C1), 159.3 (C4), 138.2 (C8,
C10), 136.0 (C6), 124.2 (C7, C11), 107.1 (C3), 90.0 (C9). EI-MS:
expected mass for M+/z 392.89/394.89, obsd 392.80/394.80 (M+/
z, 28%/18%), 76 (C6H4+, 100%). CI-MS: expected mass for M+/z
392.89/394.89, obsd 393.45/395.50 (M+, 100%). The structure of
12a is confirmed by X-ray crystallography.
Representative Example of the Installation of the 4-Alkoxy
Substituent. 4-(Benzyloxy)-6-(4-iodophenylamino)-2-(methy-
lamino)pyrimidine-5-carbaldehyde (19a). Benzyl alcohol (2.2 mL,
21 mmol) was added dropwise to a stirred suspension of NaH (0.68
g, 95%, 27 mmol) in THF (70 mL) over a period of 30 min at rt
under nitrogen atmosphere. After stirring for 15 min, the mixture
was cooled to 0 °C and 15a (4.03 g, 10.4 mmol) was added. The
resulting mixture was warmed to rt and refluxed for 24 h. After
cooling to 0 °C, the reaction mixture was carefully quenched with
a saturated aqueous solution of NH4Cl and the solvent was removed
under reduced pressure. The residue was diluted with EtOAc,
washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated. Purification by flash chromatography on silica gel
(1-2% EtOAc/hexane) provided 3.12 g of 19a (C19H17IN4O2, 65%)
as a brown solid. Rf 0.61 (SiO2, 30% EtOAc/hexane). Mp 161-
1
162 °C. H NMR (300 MHz, CDCl3) δ (ppm): 11.46 (C6NH, s,
br, 1H), 11.23 (C6NH, s, br, 1H, minor isomer) (due to the possible
hydrogen bond between C5O and C6NH, this compound displays
two sets of peaks for certain protons), 10.00 (C5H, s, 1H), 7.58-
7.37 (C7H-C11H, C15H-C19H, m, 9H), 5.48 (C12NH, s, br, 1H),
5.37 (C13H, s, 2H), 3.01 (C12H, d, 3J ) 3.0 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ (ppm): 186.4 (C5), 171.3 (C4), 163.0 (C2), 161.3
(C1), 138.7 (C6), 137.5 (C8, C10), 136.3 (C14), 128.5, 128.1, 127.8
(C15-C19), 123.5, 123.3 (C7, C11), 93.1 (C3), 86.6 (C9), 67.7 (C13),
28.5 (C12). ESI-MS: expected mass for [M + H+]/z 461.05, obsd
460.9 ([M + H+]/z, 100%). High-resolution ESI-MS: calcd mass
461.0475, actual mass 461.0474. The structure of 19a is confirmed
by X-ray crystallography.
a Isolated yield. b 70% based on recovered starting material. c 60% based
on recovered starting material
Future efforts will be focused on the transformation of the
cross-coupled adducts 34a-g into their respective G∧C bases
via a global deprotection of the Boc and Bn groups. Preliminary
results using 34f (eq 3) are quite promising, providing 36 in
95% yield. The resulting deprotected adducts of 34a-g will
then be implemented in the self-assembly studies which will
be reported in due course.
Representative Example of the Monoprotection of the Sec-
ondary Amine. tert-Butyl 4-(Benzyloxy)-5-formyl-6-(4-iodophe-
nylamino)pyrimidin-2-yl(methyl)carbamate (21a). Triethylamine
(0.9 mL, 6.4 mmol) was added to a solution of 19a (0.89 g, 1.9
mmol) and DMAP (74 mg, 0.60 mmol) in THF (20 mL) at rt under
nitrogen atmosphere. After stirring for 5 min, Boc2O (0.63 g, 2.8
mmol) was added and the resulting mixture was stirred at rt for 19
h. The reaction was then quenched with H2O and the solvent was
removed under reduced pressure. The residual solid was dissolved
in EtOAc and washed with 10% aqueous citric acid, H2O, 5%
aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and con-
centrated in vacuo. Purification by flash chromatography on silica
gel (1% EtOAc/hexane) provided 0.78 g of 21a (C24H25IN4O4, 72%)
as a white solid. Rf 0.14 (SiO2, 5% EtOAc/hexane). Mp 117.5-
118.5 °C. 1H NMR (300 MHz, CDCl3) δ (ppm): 11.23 (C6NH, br
Experimental Section
Representative Example of the Nucleophilic Aromatic Substi-
tution Reaction. 2,4-Dichloro-6-(4-iodophenylamino)pyrimidine-
5-carbaldehyde (12a). A mixture of 2,4,6-trichloropyrimidine-5-
carbaldehyde (8) (6.21 g, 29.4 mmol), KHCO3 (3.53 g, 35.3 mmol),
tetrabutylammonium iodide (542 mg, 1.47 mmol), and 4-iodoaniline
(6.43 g, 29.4 mmol) in CH2Cl2/H2O (200 mL/100 mL) was stirred
at rt for 24 h. The organic layer was then separated and the aqueous
layer was extracted with CH2Cl2. The combined organic extracts
were washed with H2O and brine, dried over anhydrous Na2SO4,
3
s, 1H), 10.15 (C5H, s, 1H), 7.61-7.53 (C7H-C11H, q, J ) 9.0
Hz, 4H), 7.44-7.33 (C15H-C19H, m, 5H), 5.49 (C13H, s, 2H), 3.40
(C12H, s, 3H), 1.55 (C22H, s, 9H). 13C NMR (75 MHz, CDCl3) δ
(ppm): 187.7 (C5), 171.2 (C4), 161.6 (C2), 160.1 (C1), 152.9 (C20),
138.0 (C6), 137.5 (C8, C10), 135.9 (C14), 128.5 (C16, C18), 128.3
(C17), 128.0 (C15, C19), 123.4 (C7, C11), 94.5 (C3), 87.2 (C9), 82.2
(C21), 68.5 (C13), 34.7 (C12), 28.0 (C22). ESI-MS: expected mass
for [M + Na+]/z 583.08, obsd 582.7 ([M + Na+]/z, 100%), 482.8
([M - Boc + Na+]/z, 7%). Negative: 559.0 (31%), 459.0 (35%).
Representative Example of the Synthesis of the Hydroxy-
limine. tert-Butyl 4-(Benzyloxy)-5-((hydroxyimino)methyl)-6-(4-
(19) For reviews see: (a) Suzuki, A. J. Organomet. Chem. 1999, 576,
147-168. (b) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419-
2440. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (d)
Suzuki, A. Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998; Chapter 2.
(20) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028.
938 J. Org. Chem., Vol. 73, No. 3, 2008

Synthesis of Substituted Arylaminopyrimidine DeriVatiVes
iodophenylamino)pyrimidin-2-yl(methyl)carbamate (22a). A
solution of aldehyde 21a (5.21 g, 9.29 mmol) in anhydrous methanol
(100 mL) was treated with KHCO3 (3.74 g, 37.4 mmol) and
hydroxylamine hydrochloride (1.30 g, 18.7 mmol) at rt under
nitrogen atmosphere. The mixture was then refluxed for 4 h. After
cooling to rt, the reaction was quenched with H2O and the solvent
was removed under reduced pressure. The product was extracted
with EtOAc and the combined organic layers were washed with
H2O and brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo to provide 4.49 g of 22a (C24H26IN5O4, 84%)
as a yellow solid. The material was used in the next step without
further purification. Rf 0.54 (SiO2, 30% EtOAc/hexane). Mp 143.5-
After drying under high vacuum, 0.773 g of 26a (C25H25IN6O4,
51%) was obtained as a white solid. Rf 0.13 (SiO2, 30% EtOAc/
hexane). Mp 149.5-150 °C. 1H NMR (300 MHz, CDCl3) δ
(ppm): 7.75 (C8H, C10H, d, 3J ) 8.4 Hz, 2H), 7.35-7.29 (C15H-
C19H, m, 5H), 7.04 (C7H, C9H, d, 3J ) 8.4 Hz, 2H), 5.44 (C13H, s,
2H), 3.42 (C12H, s, 3H), 1.54 (C22H, s, 9H). 13C NMR (75 MHz,
CDCl3) δ (ppm): 171.9 (C4), 162.3 (C2), 158.3 (C1), 154.5 (C23),
152.4 (C20), 138.5 (C6, C8, C10), 135.1 (C14), 132.2 (C7, C11), 128.6
(C16, C18), 128.4 (C17), 127.6 (C15, C19), 110.8 (C5), 95.1 (C9), 83.6
(C21), 69.6 (C3, C13), 34.4 (C12), 28.0 (C22). ESI-MS: expected mass
for [M + H+]/z 601.10, obsd 600.7 ([M + H+]/z, 100%), 500.9
([M - Boc + H+]/z, 35%), 1199.6 (dimer, 29%). Negative: 556.1
(100%).
1
145 °C. H NMR (300 MHz, CDCl3) δ (ppm): 9.99 (C6NH, br s,
3
1H), 8.56 (C5H, s, 1H), 7.58 (C8H, C10H, d, J ) 9.0 Hz, 2H),
Representative Example of the Suzuki Cross-Coupling Reac-
tion. tert-Butyl 4-(Benzyloxy)-5-(di(tert-butoxycarbonyl)amino)-
8-methyl-7-oxo-7,8-dihydropyrimido[4,5-d]pyrimidin-2-yl(4′-
formylbiphenyl-4-yl)carbamate (34a). A screw-capped vial was
charged with 33a (291 mg, 0.363 mmol), 4-formylphenylboronic
acid (109 mg, 0.726 mmol), potassium fluoride (74 mg, 1.3 mmol),
and tris(dibenzylideneacetone)dipalladium(0) (17 mg, 0.018 mmol).
THF (1.0 mL) was then added followed by tri-tert-butylphosphine
(0.36 mL solution of 41 mg/2.0 mL THF). The vial was subse-
quently flushed with nitrogen and capped. After stirring at rt for
71 h, the mixture was diluted with Et2O, filtered through a pad of
Celite, and eluted with EtOAc and MeOH. The solution was
concentrated in vacuo and the product was purified by flash column
chromatography on silica gel (3-30% EtOAc/hexane) to provide
166 mg of 34a (C42H46N6O9, 59%) as white foam. Rf 0.43 (SiO2,
50% EtOAc/hexane). Mp 129-130 °C. 1H NMR (300 MHz,
7.51 (C7H, C11H, d, 3J ) 9.0 Hz, 2H), 7.42-7.34 (C15H-C19H, m,
5H), 7.08 (NOH, s, 1H), 5.42 (C13H, s, 2H), 3.36 (C12H, s, 3H),
1.51 (C22H, s, 9H). 13C NMR (75 MHz, CDCl3) δ (ppm): 167.1
(C4), 158.6 (C2), 157.8 (C1), 154.0 (C20), 145.4 (C5), 138.8 (C6),
137.3 (C8, C10), 136.4 (C14), 128.4 (C16, C18), 128.0 (C17), 127.9
(C15, C19), 122.8 (C7, C11), 89.1 (C3), 86.1 (C9), 81.8 (C21), 68.3
(C13), 34.8 (C12), 28.1 (C22). ESI-MS: expected mass for [M +
Na+]/z 598.09, obsd 597.8 [M + Na+]/z, 73%) 475.9 ([M - Boc
+ H+]/z, 100%). Negative: 573.9 (100%).
Representative Example of the Synthesis of the Nitrile. tert-
Butyl 4-(Benzyloxy)-5-cyano-6-(4-iodophenylamino)pyrimidin-
2-yl(methyl)carbamate (23a). A solution of hydroxylimine 22a
(4.32 g, 7.51 mmol) and Et3N (3.2 mL, 23 mmol) in THF (40 mL)
at 0 °C was slowly treated with trifluoroacetic anhydride (1.7 mL,
12 mmol). After stirring for 15 min, the mixture was warmed to rt
and then refluxed for 2 h. The reaction was quenched at rt with
H2O and the solvent was removed under reduced pressure. The
residue was diluted with EtOAc, washed with H2O, 10% aqueous
citric acid, H2O, 5% aqueous NaHCO3, and brine, dried over
anhydrous Na2SO4, filtered, and concentrated. Purification by flash
chromatography on silica gel (3% EtOAc/hexane) provided 1.91 g
of 23a (C24H24IN5O3, 46%) as white solid. Rf 0.59 (SiO2, 30%
EtOAc/ hexane). Mp 152.4-154.6 °C. 1H NMR (300 MHz, CDCl3)
δ (ppm): 7.59 (C8H, C10H, d, 3J ) 8.4 Hz, 2H), 7.46-7.32 (C7H,
C11H, C15H-C19H, C6NH, m, 8H), 5.48 (C13H, s, 2H), 3.35 (C12H,
s, 3H), 1.51 (C22H, s, 9H). 13C NMR (75 MHz, CDCl3) δ (ppm):
170.4 (C4), 161.6 (C1), 160.5 (C2), 152.9 (C20), 137.6 (C8, C10),
137.5 (C6), 135.6 (C14), 128.5 (C16, C18), 128.3 (C17), 127.9 (C15,
C19), 123.1 (C7, C11), 114.2 (C5), 87.7 (C9), 82.4 (C21), 70.5 (C3),
68.9 (C13), 34.7 (C12), 28.0 (C22). ESI-MS: expected mass for [M
+ Na+]/z 580.37, obsd ([M + Na+]/z, 579.9, 100%). Negative:
556.1 (91%), 456.1 (49%).
3
CDCl3) δ (ppm): 10.11 (C36H, br s, 1H), 8.03 (C32H, C34H, d, J
) 8.4 Hz, 2H), 7.86 (C8H, C12H, d, 3J ) 8.1 Hz, 2H), 7.78 (C31H,
C35H, d, 3J ) 8.4 Hz, 2H), 7.40 (C9H, C11H, d, 3J ) 8.1 Hz, 2H),
7.31-7.29 (C15H, C17H, C19H, m, 3H), 7.23-7.20 (C16H, C18H,
m, 2H), 5.37 (C13H, s, 2H), 3.64 (C6H, s, 3H), 1.57 (C22H, s, 9H),
1.39 (C26H, C29H, s, 18H). 13C NMR (75 MHz, CDCl3) δ (ppm):
191.6 (C36), 165.7 (C4), 161.2, 160.8, 160.1 (C1, C2, C5), 155.8
(C23), 151.7 (C20), 149.1 (C24, C27), 145.7 (C30), 140.3 (C14), 138.8
(C7), 135.3 (C33), 134.5 (C10), 130.2 (C32, C34), 128.6 (C9, C11),
128.3, 128.2, 128.18 (C15-C19), 127.8 (C8, C12), 127.4 (C31, C35),
93.2 (C3), 83.7 (C25, C28), 83.5 (C21), 69.8 (C13), 30.0 (C6), 27.7
(C22), 27.7 (C26, C29). ESI-MS: expected mass for [M + H+]/z
779.34, obsd 778.9 ([M + H+]/z, 5%), 800.8 ([M + Na+]/z, 65%).
High-resolution ESI-MS: calcd mass 779.3405, actual mass
779.3425.
4-Amino-1-methyl-7-(4-(naphthalen-1-yl)phenylamino)py-
rimido[4,5-d]pyrimidine-2,5(1H,6H)-dione (36). Thioanisole (0.6
mL, 5 mmol) and TFA (9.4 mL, 127 mmol) were added to
compound 34f (300 mg, 0.374 mmol) under nitrogen atmosphere
and the solution was stirred for 27.5 h. Et2O was then added and
the precipitate was centrifuged, collected, and washed with Et2O
to provide 189 mg of 36 (C25H20F3N6O4.5, 95%) as a white solid.
1H NMR (300 MHz, DMSO) δ (ppm): 10.49 (NH, s, 1H), 9.28
(NH, s, H), 8.64 (NH, s, 1H), 8.08-7.28 (C8H, C9H, C11H, C12H,
C31H-C33H, C35H-C38H, m, 11H), 3.47 (C6H, s, 3H). Due to the
solubility in DMSO, no 13C NMR was recorded. Anal. Calcd for
C25H20F3N6O4.5 (M + TFA + 1/2H2O): C, 56.29; H, 3.78: N, 15.75.
Found: C, 56.64; H, 3.98: N, 15.37. High-resolution ESI-MS:
calcd mass 411.1561, actual mass 411.1564.
tert-Butyl 4-(Benzyloxy)-1-(4-iodophenyl)-1H-pyrazolo[3,4-d]-
pyrimidin-6-yl(methyl)carbamate (24a). A 1.19 g yield of 24a
(C24H24IN5O3, 28%) was also isolated as a white solid. Rf 0.74
1
(SiO2, 30% EtOAc/hexane). Mp 124-125.5 °C. H NMR (300
3
MHz, CDCl3) δ (ppm): 8.09 (C8H, C10H, d, J ) 8.7 Hz, 2H),
3
8.08 (C5H, s, 1H), 7.78 (C7H, C11H, d, J ) 8.7 Hz, 2H), 7.51-
7.35 (C15H-C19H, m, 5H), 5.60 (C13H, s, 2H), 3.48 (C12H, s, 3H),
1.54 (C22H, s, 9H). 13C NMR (75 MHz, CDCl3) δ (ppm): 163.1
(C4), 158.8 (C1), 155.7 (C20), 153.9 (C2), 138.9 (C6), 138.0 (C8,
C10), 135.7 (C14), 133.1 (C5), 128.6, 128.5, 128.4 (C16-C19), 122.3
(C7, C11), 100.9 (C3), 90.4 (C9), 81.6 (C21), 68.7 (C13), 35.3 (C12),
28.3 (C22). ESI-MS: expected mass for [M + Na+]/z 580.37, obsd
([M + Na+]/z, 579.9, 100%). Negative: 556.1 (28%), 456.1 (100%).
Representative Example of the Synthesis of the Carbamide.
tert-Butyl 4-(Benzyloxy)-5-cyano-6-(1-(4-iodophenyl)ureido)py-
rimidin-2-yl(methyl)carbamate (26a). N-Chlorocarbonyl isocy-
anate (0.43 mL, 5.3 mmol) was added to a solution of 23a (1.41 g,
2.53 mmol) and DMAP (709 mg, 5.8 mmol) in anhydrous CH2Cl2
(10 mL) at 0 °C. The contents of the flask were stirred at 0 °C for
75 min, followed by rt for 2 h. The reaction was quenched with
10% aqueous NaHCO3 then diluted with H2O and the product was
extracted with CH2Cl2. The combined organic phases were washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
Acknowledgment. We thank the National Institute for
Nanotechnology, the University of Alberta, the U.S. National
Science Foundation, and Purdue University for supporting this
program.
Supporting Information Available: Experimental procedures
and full spectroscopic data for all new compounds and single-crystal
X-ray structures. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO7021422
J. Org. Chem, Vol. 73, No. 3, 2008 939