Synthesis of a tetracyclic GC scaffold for the assembly of rosette nanotubes with 1.7 nm inner diameter

Article abstract of DOI:10.1021/jo101194v

The synthesis of a tetracyclic self-complementary molecule 4 for self-assembly into rosette nanotubes is presented. This new heterocycle has a core structure containing two pyrido[2,3-d]pyrimidine molecules fused together and features the Watson-Crick hyd

Full text of DOI:10.1021/jo101194v

pubs.acs.org/joc
Synthesis of a Tetracyclic G∧C Scaffold for the Assembly of Rosette
Nanotubes with 1.7 nm Inner Diameter
Gabor Borzsonyi, Alaaeddin Alsbaiee, Rachel L. Beingessner, and Hicham Fenniri*
National Institute for Nanotechnology (NINT-NRC) and Department of Chemistry, University of Alberta,
11421 Saskatchewan Drive, Edmonton, Alberta T6G 2M9, Canada
hicham.fenniri@nrc-cnrc.gc.ca
Received July 25, 2010
The synthesis of a tetracyclic self-complementary molecule 4 for self-assembly into rosette nanotubes
is presented. This new heterocycle has a core structure containing two pyrido[2,3-d]pyrimidine
molecules fused together and features the Watson-Crick hydrogen bond donor-acceptor arrays of
both guanine (G) and cytosine (C). Current methods to synthesize pyrido[2,3-d]pyrimidines require
harsh conditions and long reaction times and result usually in low product yields. This is particularly
problematic for the direct incorporation of functional groups that cannot withstand these conditions.
Here, we present an efficient approach to access the multifunctional pyrido[2,3-d]pyrimidine
intermediate 2 under relatively mild conditions using three regioselective SNAr reactions at C2,
C4, and C7 on the trichloro compound 1. The electron-withdrawing group and amino functionalities
€
on 2 are then used as a handle to install the third and fourth rings of 4 using a Friedlander-type
condensation followed by mixed urea synthesis and cyclization.
Introduction
tricyclic ꢀG∧C3 motifs, which should self-assemble into RNTs
via the π-π stacking of intermediate H-bonded hexameric
rosettes (Figure 1). The RNTs assembled from bicyclic
G∧C have an internal diameter of ca. 1 nm,1 whereas with
tricyclic ꢀG∧C, the diameter is extended to ca. 1.4 nm.3
Tetracyclic ꢀꢀG∧C, with its larger core structure, has the
potential to self-assemble into RNTs with an even larger
internal diameter (ca. 1.7 nm), which will be crucial for the
internal functionalization of these architectures and for applica-
tions in biomaterials engineering and drug delivery.4
During the course of our studies of the synthesis and self-
assembly of rosette nanotubes (RNTs),1 we became interested
in tetracyclic ꢀꢀG∧C (Figure 1), which has a highly conjugated
core structure of two pyrido[2,3-d]pyrimidine molecules fused
together. This self-complementary heterotetracycle, which has
not been reported thus far, features the Watson-Crick H-bond
donor/acceptor arrays of both guanine and cytosine (G∧C
motif).1,2 It is an extended version of the bicyclic G∧C1 and
From the synthetic approach perspective, target compound 4
(Scheme 1) may be viewed as the juxtaposition of two pyri-
do[2,3-d]pyrimidine cores and can therefore be approached
from the G face or the C face. A standard procedure for the
preparation of pyrido[2,3-d]pyrimidines and their derivatives
(1) (a) Tikhomirov, G.; Oderinde, M.; Makeiff, D.; Mansouri, A.; Weibing,
L.; Heirtzler, F.; Kwok, D. Y.; Fenniri, H. J. Org. Chem. 2008, 73, 4248–4251.
(b) Beingessner, R.; Deng, B.-L.; Fanwick, P. E.; Fenniri, H. J. Org. Chem.
2008, 73, 931–939. (c) Fenniri, H.; Mathivanan, P.; Vidale, K. L.; Sherman,
D. M.; Hallenga, K.; Wood, K. V.; Stowell, J. G. J. Am. Chem. Soc. 2001, 123,
3854–3855.
(2) For other examples and reviews, see: (a) Marsh, A.; Silvestri, M.;
Lehn, J.-M. Chem. Commun. 1996, 1527–1528. (b) Mascal, M.; Hext, N. M.;
Warmuth, R.; Moore, M. H.; Turkenburg, J. P. Angew Chem., Int. Ed. 1996,
35, 2204–2206. (c) Asadi, A.; Patrick, B. O.; Perrin, D. M. J. Am. Chem. Soc.
2008, 130, 12860–12861. (d) Petersen, P. M.; Wu, W.; Fenlon, E. E.; Kim, S.;
Zimmerman, S. C. Bioorg. Med. Chem. Lett. 1996, 4, 1107–1112. (e) Whitesides,
G. M.; Grzybowski, B. Science 2002, 295, 2418–2421. (f) Prins, L. J.; Reinhoudt,
D. N.; Timmerman, P. Angew. Chem., Int. Ed. 2001,40, 2382–2426. (g) 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.
(3) Borzsonyi, G.; Johnson, R. S.; Myles, A. J.; Cho, J.-Y.; Yamazaki, T.;
Beingessner, R. L.; Kovalenko, A.; Fenniri, H. Chem. Commun. 2010, 46,
6527–6529.
(4) (a) Suri, S. A.; Rakotondradany, F.; Myles, A. J.; Fenniri, H.; Singh,
B. Biomaterials 2009, 30, 3084–3090. (b) Zhang, L.; Rakotondradany, F.;
Myles, A. J.; Fenniri, H.; Webster, T. J. Biomaterials 2009, 30, 1309–1320. (c)
Zhang, L.; Ramsaywack, S.; Webster, T. J. Tissue Eng. Part A 2008, 4, 1353–
1364. (d) Chen, Y.; Song, S.; Fenniri, H.; Webster, T. J. Mater. Res. Soc.
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DOI: 10.1021/jo101194v
r
Published on Web 10/07/2010
J. Org. Chem. 2010, 75, 7233–7239 7233
2010 American Chemical Society

Borzsonyi et al.
JOCArticle
FIGURE 1. (A) Self-complementary G∧C motifs: tetracycle (ꢀꢀG∧C), tricycle (ꢀG∧C), and bicycle (G∧C). (B) Self-assembly of ꢀꢀG∧C
into hexameric rosettes, which π-π stack to form RNTs (R1 = allyl, R2 = H).
SCHEME 1
methods based on the annulation of a pyridine ring on a
pyrimidine (and vice versa) were also reported,11 but they
usually suffer from similar challenges. Thus, alternative and
efficient synthetic strategies that can provide a rapid entry into
fused and nonfused pyrido[2,3-d]pyrimidines functionalized
with a broader range of substituents for further elaboration
are of considerable value.
Regardless of whether we approach the synthesis form the
G or the C side, our strategy for the synthesis of 4 required
the multifunctional pyrido[2,3-d]pyrimidine intermediate 2
(Scheme 1). This molecule contains a protected alcohol at
C4, which becomes the carbonyl group in 4. The NH2 group
at C7 is used as a handle along with the electron-withdrawing
€
group (EWG) to install the third ring using Friedlander-type
condensation, followed by mixed urea synthesis/cyclization
for the final cytosine ring. In order to confer unique chemical
and physical properties upon these RNT architectures, it was
also necessary to have the flexibility to append a variety of
functional groups at the C2 position. Given the challenges
associated with the classical methods for the preparation of
pyrido[2,3-d]pyrimidines,5-11 we chose to explore the for-
mation of 2 using three regioselective SNAr reactions at C2,
C4, and C7 on the trichloro substituted molecule 1. An
earlier report by Broom and co-workers12 suggests that
regioselective SNAr on pyrido[2,3-d]pyrimidine is a viable
involves the condensation of 4-aminouracil with conjugated
alkenes.5 Despite the extensive range of biological activities6-10
associated with this class of heterocycles, current synthetic
approaches suffer from long reaction times and relatively harsh
conditions, result in low product yield, and do not allow for the
direct incorporation of sensitive functional groups. Other
(5) For examples, see: (a) El-Gazzar, A. B. A.; Youssef, M. M.; Youssef,
A. M. S.; Abu-Hashem, A. A.; Badria, F. A. Eur. J. Med. Chem. 2009, 44,
609–624. (b) Bharate, S. B.; Mahajan, T. R.; Gole, Y. R.; Nambiar, M.;
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Balakrishnan, A.; Vishwakarma, R. A. Bioorg. Med. Chem. 2008, 16,
7167–7176. (c) Abdel-Aziz, H. A.; Hamdy, N. A.; Farag, A. M.; Fakhr,
I. M. I. J. Heterocycl. Chem. 2008, 45, 1033–1037.
(6) (a) El-Gazzar, A. B. A.; Aly, A. S.; Zaki, M. E. A.; Hafez, H N.
Phosphorus, Sulfur, Silicon 2008, 183, 2119–2138. (b) Kumar, N.; Singh, G.;
Yadav, A. K. Heteroat. Chem. 2001, 12, 52–56.
(7) (a) Nasr, M. N.; Gineinah, M. M. Arch. Pharm. Pharm. Med. Chem.
2002, 6, 289–295.
(8) Monge, A.; Martinez-Merino, V.; Sanmartin, C.; Fernandez, F. J.;
Ochoa, M. C.; Bellver, C.; Artigas, P.; Fernandez-Alvarez, E. Eur. J. Med.
Chem. 1989, 24, 209–216.
(11) For examples, see: (a) Kanth, S. R.; Reddy, G. V.; Kishore, K. H.;
Rao, P. S.; Narsaiah, B.; Murthy, U. S. N. Eur. J. Med. Chem. 2006, 41,
1011–1016. (b) Wu, Z.; Robinson, R. G.; Fu, S.; Barnett, S. F.; Defeo-Jones,
D.; Jones, R. E.; Kral, A. M.; Huber, H. E.; Kohl, N. E.; Hartman, G. D.;
Bilodeau, M. T. Bioorg. Med. Chem. Lett. 2008, 18, 2211–2214.
(c) Matulenko, M. A.; Lee, C.-H.; Jiang, M.; Frey, R. R.; Cowart, M. D.;
Bayburt, E. K.; DiDomenico, S., Jr.; Gfesser, G. A.; Gomtsyan, A.; Zheng,
G. Z.; McKie, J. A.; Stewart, A. O.; Yu, X.; Kohlhaas, K. L.; Alexander,
K. M.; McGaraughty, S.; Wismer, C. T.; Mikusa, J.; Marsh, K. C.; Snyder,
R. D.; Diehl, M. S.; Kowaluk, E. A.; Jarvis, M. F.; Bhagwat, S. S. Bioorg.
Med. Chem. 2005, 13, 3705–3720. (d) Perner, R. J.; Lee, C.-H.; Jiang, M.; Gu,
Y.-G.; DiDomenico, S.; Bayburt, E. K.; Alexander, K. M.; Kohlhaas, K. L.;
Jarvis, M. F.; Kowaluk, E. L.; Bhagwat, S. S. Bioorg. Med. Chem. Lett. 2005,
15, 2803–2807.
ꢀ
(9) Quintela, J. M.; Peinador, C.; Botana, L.; Estevez, Riguera, R. Bioorg.
Med. Chem. 1997, 5, 1543–1553.
ꢀ
ꢀ
(10) (a) Cordeu, L.; Cubedo, E.; Bandres, Rebollo, A.; Saenz, X.; Chozas,
H.; Domınguez, M. V.; Echeverrıa, M.; Mendivil, B.; Sanmartin, C.; Palop,
J. A.; Font, M.; Garcıa-Foncillas, J. Bioorg. Med. Chem. 1997, 5, 1659–1669.
´
´
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(b) Pochat, F.; Lavelle, F.; Fizames, C.; Zerial, A. Eur. J. Med. Chem. 1987,
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SCHEME 2
SCHEME 3
at C4 in addition to an EWG at C6 that could further enhance
its reactivity, we anticipated the SNAr to occur at C7.
Unexpectedly, when 6 was treated with ammonia in CH2Cl2
at room temperature, compounds 8 and 9 (Scheme 2) were
isolated in ca. 70% and ca. 30% yield, respectively. Whereas 9
was the result of BnO- displacement by ammonia, in the case of
8 we had to carry out an additional transformation to establish
the site of SNAr displacement. Thus, 8 was treated with
allylamine in CH2Cl2 at 50 °C, and the resulting product
(isolated in 55% yield) 10 was characterized by 1D and 2D
NMR (HMBC) techniques. The coupling of HA and HB to C7
confirmed that ammonia had indeed displaced the chloride at
C2. This interesting reversal in reactivity suggests the impor-
tance of electronic/inductive effects on the substitution pattern
of this class of compounds. One may hypothesize in this
case that preferential reaction at C2 is due to the electron-
withdrawing ability of (a) the adjoining deactivated pyridyl ring
and (b) the adjacent pyrimidine ring nitrogens.
To achieve the correct substitution pattern, the order of
nucleophilic addition was therefore reversed. Compound 6
was first treated with allylamine to provide target compound
11 in 64% yield (Scheme 3). Interestingly, however, all
attempts at the SNAr reaction of 11 with ammonia to
generate 12 were unsuccessful, and only starting material
was isolated. This result could be attributed to (a) decreased
nucleophilicity of ammonia relative to allylamine and in
particular (b) ring system deactivation toward SNAr at C7
as a result of the two strong EDG (-OBn, -NHallyl).
strategy, although to the best of our knowledge, C6-sub-
stituted pyrido[2,3-d]pyrimidine have never been reported.
Results and Discussion
The synthesis of tetracycle 4 commenced with the prepara-
tion of 2,4,7-trichloro[2,3-d]pyrimidine-6-carbonitrile 5 accord-
ing to a modified procedure reported by Beck.13 With this
compound in hand, we explored the relative reactivity of
positions C2, C4, and C7 toward SNAr (Scheme 2). On the
basis of earlier work on simple chloro-substituted pyrido[2,3-
d]pyrimidines,12,14 we anticipated that position C4 would be the
most reactive. Thus, reaction with allylamine at -78 °C in
CH2Cl2 yielded compound 7 in 90% yield, whereas reaction
with benzyl alcohol at -40 °C in CH2Cl2 gave the desired
compound 6 in 70% yield.
€
The next step in our strategy called for a Friedlander-type
condensation to build the third ring. It was therefore necessary
to introduce an amino group at C7 and convert the -CN group
at C6 to an aldehyde. Earlier work by Broom and co-workers12
suggests that C7 should be more reactive than C2 toward SNAr
when the molecule is functionalized at C4 with an electron-
donating group (EDG). Since compound 6 has an EDG (OBn)
(13) Beck, G. Ger. Offen. 1988, 3643456.
(14) For example, see: (a) Robins, R. K.; Hitchings, G. H. J. Am. Chem.
Soc. 1955, 77, 2256–2260. (b) Lavecchia, G.; Berteina-Raboin, S.; Guillaumet,
G. Tetrahedron Lett. 2005, 46, 5851–5855.
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SCHEME 4
aCompounds 18-21 correspond to the DMAP (X = Cl-), 4-methoxypyridine (X = Cl-), DABCO (X = NO3-), and 4-(pyrrolidin-1-yl)pyridine (X =
Cl-) adduct, respectively. Condition A: all reactions were performed overnight at room temperature in acetonitrile with DMAP for 18, 4-methox-
ypyridine for 19, DABCO and AgNO3 for 20 and 4-(pyrrolidin-1-yl)pyridine for 21. bCondition B: all reactions were performed overnight at room
temperature in THF for 18 and acetonitrile for 19-21 using ammonia 2 M in i-PrOH (10 equiv).
At this stage we had the option of (a) reducing the
electron density in the ring system by protecting the allyla-
mino group with an EWG (e.g., Boc) and then carrying out
the reduction of the nitrile with DIBAL-H to the corre-
other tertiary amines could act as catalysts for our third SNAr.
That is, addition of DMAP to 16 would generate a stable yet
more reactive intermediate species that may be more amenable
to SNAr with ammonia. We therefore examined DMAP,
4-methoxypyridine, 4-pyrrolidinopyridine, and DABCO as
possible catalysts for this reaction (Scheme 4).
€
sponding aldehyde for the subsequent Friedlander conden-
sation, or (b) the opposite sequence. Unfortunately, all
attempts at protecting the allylamino moiety of 11 with a
Boc group failed. This lack of reactivity was attributed to
the strong electron-withdrawing ability of the neighboring
pyridyl ring (bearing -Cl and -CN groups). These results
prompted us to proceed with the DIBAL-H reduction
(Scheme 3), which gave the desired product 13 in 50% yield
along with recovered starting material 11 (ca. 50%). We
also reasoned that if the Boc protection did not proceed
with compound 13, we could further reduce it to the
corresponding alcohol. Incidentally, the separation of com-
pounds 11 and 13 proved to be very challenging because of
their similar polarities. Therefore to facilitate the isolation
of 13 and to test the reduction of aldehyde 13 to the
corresponding alcohol 14, the mixture was treated with
NaBH4 in MeOH/CHCl3. While the resulting products (14
and 15) were readily separated by silica gel flash chroma-
tography, we did not expect the pyridyl ring of 11 to
undergo reduction to the corresponding dihydropyridine
15 (in 50% yield). This compound could indeed be reox-
idized back to 11 in 72% yield using PDC, whereas 14 could
be converted back to 13 in 74% yield using PCC. It should
be noted at this stage that, as expected, compound 13 did
not undergo SNAr at C7 when treated with ammonia under
a variety of conditions (data not shown). Reaction of 13
with Boc2O in the presence of DMAP and DIPEA furnished
16 in 73% yield (Scheme 3). After numerous attempts, we
determined that treatment of activated compound 16 with 10
equiv of ammonia (2 M in i-PrOH) in THF overnight provided
the desired trisubstituted product 17, but with only a maximum
yield of ca. 30%.
While the addition of tertiary amines to compound 16
were nearly quantitative, subsequent displacement with
ammonia proceeded in poor yields (20-30%) (Scheme 4). For
instance, with 10 equiv of ammonia (2 M in i-PrOH) at room
temperature in THF (optimal conditions) the DMAP adduct
18 gave target compound 17 in only 20% yield. Adduct 20
with DABCO was formed within 10 min but decomposed over
time. Only when this reaction was conducted in the presence of
AgNO3 (to remove the nucleophilic chloride counterion from
solution) was adduct 20 found to be stable when monitored by
1H NMR over a period of 12 h. Unfortunately, subsequent
treatment with ammonia provided the desired product 17, but
only in 20% yield. Adduct 19 with 4-methoxypyridine gave a
moderately better yield of 17 (30%) upon treatment with
ammonia. Finally, subjecting 21 to the same conditions did
not provide the aminated product, but rather the unexpected
hydrolysis product 22 in 46% yield. With these rather low
yields, we further explored a one-pot reaction of 16 with
DABCO, DIPEA, and various ammonia solutions. Interest-
ingly, using 0.5 M ammonia in dioxane provided 17 in only
25% yield along with the ring-opened adduct 23 in 50% yield.
The most favorable results were obtained, however, when
0.5 M ammonia in THF was used to furnish 17 in 52% yield
along with the hydrolysis product 22 in 40% yield. We expect
the outcome of this reaction to improve dramatically under
anhydrous conditions.
€
Our subsequent task was to perform the Friedlander-type
condensation on compound 17 in order to generate the third
(pyridine) ring on compound 24 (Scheme 5). The reaction of
17 with malononitrile was found to occur in good yield
(88%) when conducted in pyridine overnight at room tem-
perature (Scheme 5).
The fourth ring to be synthesized, which was a pyrimidine
ring, was initially attempted by treating 24 with trichloro-
carbonyl isocyanate at 0 °C in dichloromethane for 2 h,
followed by the addition of ammonia (2 M in i-PrOH).
Although these conditions typically result in in situ cycliza-
tion of the urea onto the nitrile,1 an IR vibration at 2200
cm-1 confirmed that the nitrile was still present and thus the
cyclization had not occurred. Ring closure of 25 was subse-
quently attempted using other bases such as 7 M NH3 in
MeOH, NaH, or t-BuONa in THF at various temperatures,
While optimizing the conditions for the Boc protection of
13, we observed that the yield of 16 decreased substantially as
the number of equivalents of DMAP increased. Investiga-
tion of the reaction kinetics and product distribution by 1H
NMR in CD3CN, suggested that the addition of 1 equiv of
DMAP at room temperature led to quantitative conversion
of the starting material to adduct 18 (Scheme 4), which was
apparent by the upfield shift of the aldehyde proton and
downfield shift of the DMAP protons. The formation of 18
was also confirmed by mass spectrometry.
The similarity of this reaction with the first step of the
Baylis-Hillman process led us to postulate that DMAP and
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SCHEME 5
tetracyclic motif and allow for functionalization of the outer
periphery of the corresponding RNTs.
Experimental Section
2-Amino-4-(benzyloxy)-7-chloropyrido[2,3-d]pyrimidine-6-car-
bonitrile (8). Compound 6 (50 mg, 0.15 mmol) was dissolved in
anhydrous CH2Cl2 (6 mL) and treated with a 2 M solution of NH3
in i-PrOH (0.32 mL, 0.64 mmol). The solution was stirred overnight
at room temperature and then concentrated under reduced pres-
sure. Purification by flash chromatography on silica gel (0-2%
MeOH/CH2Cl2) provided 8 (C15H10ClN5O, 33 mg) in 70% yield
as a white solid. Rf = 0.5 (1% MeOH/CH2Cl2). Mp = 227.5-
1
229.1 °C. H NMR (600 MHz, DMSO-d6) δ (ppm) 8.78 (C6H,
sharp s, 1H), 7.99 (NH, brs, 1H), 7.89 (NH, brs, 1H), 7.58-7.37
(C 9-11H, m, 5H), 5.55 (C15H, m, 2H). C NMR (150 MHz,
13
DMSO-d6) δ(ppm) 166.9 164.2 162.4 155.1 (C1) (C2) (C3) (C4), 141.5
135.3 (C5) (C6), 128.4 128.2 128.1 (C9) (C10) (C11), 115.4 104.3 100.5
(C8) (C13) (C14), 68.6 (C15). ESI-MS: calcd for (M þ Hþ)/z, 312.1,
found 312.4 [(M þ Hþ)/z]. HRMS (ESI): calcd for C15H11ClN5O,
312.0647, found 312.0640. 4-Amino-2,7-dichloropyrido[2,3-d]pyri-
midine-6-carbonitrile (9, C8H3Cl2N5, 11 mg) was also isolated in
30% yield from the reaction mixture. Rf = 0.3 (2% MeOH/
1
CH2Cl2). Mp = 218.1-218.7 °C. H NMR (600 MHz, DMSO-
d6) δ (ppm) 9.31 (C6H, sharp s, 1H), 9.17 (NH, broad s, 1H), 8.97
(NH, broad s, 1H). 13C NMR (150 MHz, DMSO-d6) δ(ppm) 163.9
163.7 160.1 154.8 (C1) (C2) (C3) (C4), 143.5 (C6), 114.9 106.9 105.9
(C8) (C13) (C14). ESI-MS: calcd for (M þ Hþ)/z, 240.0, found 240.3
[(M þ Hþ)/z]. HRMS(ESI): calcdfor C8H4Cl2N5, 239.9838, found
239.9841.
7-(Allylamino)-2-amino-4-(benzyloxy)pyrido[2,3-d]pyrimidine-
6-carbonitrile (10). Allylamine (0.044 mL, 0.59 mmol) was added
to a solution of compound 8 (73 mg, 0.23 mmol) in anhydrous
CH2Cl2 (6 mL) in a sealed tube. After stirring overnight at 50 °C,
the solvent was removed in vacuo. Purification by flash chromatog-
raphy on silica gel (0-2% MeOH/CH2Cl2) provided compound
10 (C18H16N6O, 43 mg) in 55% yield as a solid. Rf=0.5 (7.5%
but without success (data not shown). In order to increase the
acidity of HB relative to HA and therefore promote ring
closure, 24 was converted to 26 in the presence of benzoyl
isocyanate in dichloromethane at 0 °C. Subsequent treat-
ment of 26 with DIPEA in dichloromethane at room tem-
perature for 4 days provided the cyclized adduct 27
(Scheme 5). Finally, deprotection of the crude product 27
with 4 M HCl in dioxane at 70 °C afforded our target
tetracyclic adduct 4 in 75% yield (two steps). This product,
which is presented in only one of the many tautomeric forms,
was found to be soluble in DMSO, hot DMF, and protic
acids such as TFA.
1
MeOH/CH2Cl2). Mp = 213.4-215.1 °C. H NMR (300 MHz,
DMSO-d6) δ (ppm) 8.31 (C6H, sharp s, 1H), 7.64-7.62 (NH, brs,
1H), 7.52-7.33 (C 9-11H, m, 5H), 7.22 (NH, brs, 2H), 5.98-5.82
(C 7H, m, 1H), 5.46 (C15H, s, 2H), 5.14-5.03 (C 12H, m, 2H), 4.02
(C16H, s, 2H). 13C NMR (150 MHz, DMSO-d6) δ (ppm) 166.6
163.8 163.4 159.1 (C1) (C2) (C3) (C4), 140.3 (C6), 136.1 (C5), 135.2
(C7), 128.4 128.0 127.9 (C9) (C10) (C11), 116.5 (C14), 115.3 (C12),
97.1 87.8 (C13) (C8), 67.6 (C15), 42.9 (C16). ESI-MS: calcd for (M þ
Hþ)/z, 333.1, found 333.4 [(M þ Hþ)/z]. HRMS (ESI): calcd for
C18H17N6O, 333.1458, found 333.1454.
Conclusion
2-(Allylamino)4-(benzyloxy)-7-chloropyrido[2,3-d]pyrimidine-
6-carbonitrile (11). 4-(Benzyloxy)-2,7-dichloropyrido[2,3-d]pyri-
midine-6-carbonitrile (6) (1.0 g, 3.0 mmol) was dissolved in
CH2Cl2 (125 mL), cooled to 0 °C, and then treated with DIPEA
(1.1 mL, 6.0 mmol) and allylamine (246 μL, 3.3 mmol). After 3 h
of stirring, the precipitate was collected, washed with CH2Cl2,
and dried under high vacuum to yield compound 11 (C18H14-
ClN5O, 688 mg) in 64% yield as a solid. Rf = 0.2 (30% EtOAc/
hexane). Mp = 234.7-235.7 °C. 1H NMR (600 MHz, DMSO-
d6, 90 °C) δ (ppm) 8.70 (C6H, sharp s, 1H), 8.35 (NH, broad s,
1H), 7.54-7.35 (C 9-11H, m, 5H), 5.98-5.83 (C 7H, m, 1H), 5.59
(C15H, s, 2H), 5.24-5.09 (C 12H, m, 2H), 4.08-4.07 (C 16H, m,
2H). 13C NMR (150 MHz, DMSO-d6, 90 °C) δ (ppm) 166.2
162.1 161.9 154.9 (C1) (C2) (C3) (C4), 141.3 135.2 134.4 (C5) (C6)
(C7), 128.2 128.1 128.0 (C9) (C10) (C11), 115.6 115.2 104.9 100.7
(C8) (C12) (C13) (C14), 68.5 (C15), 43.1 (C16). Positive ESI-MS:
calcd for (M þ Hþ)/z, 352.1, found 352.5 [(M þ Hþ)/z]. HRMS
(ESI): calcd for C18H 15ClN5O, 352.0960, found 352.0966.
(2-(Allylamino)-4-(benzyloxy)-7-chloropyrido[2,3-d]pyrimidin-
6-yl)methanol (14). DIBAL-H (21.3 mL, 1 M in CH2Cl2, 21.3
mmol) was added dropwise to a solution of 11 (3 g, 8.5 mmol) in
The synthesis of the tetracyclic self-complementary mole-
cule 4 was achieved. Our approach to preparing the key
trisubstituted pyrido[2,3-d]pyrimidine intermediate 17 involves
three regioselective SNAr reactions on the trichloro pre-
cursor 5. Interestingly, we have determined that the order
of chloride displacement at C4, C2, and C7 of 5 differs from
that reported for a very similar compound.11 Furthermore, a
key step to the success of this strategy is a base-catalyzed
SNAr process that allowed us to effectively install the third
substituent on the pyrido[2,3-d]pyrimidine core. In general,
this strategy should enable the synthesis of a variety of
pyrido[2,3-d]pyrimidine derivatives and in particular pro-
vide rapid access to those which contain one or more fused
rings involving the substitutents at C6 and C7.
Future efforts will be focused on the synthesis and self-
assembly of 4 and its derivatives. For instance, the synthesis
of a bis-allyl version of 4 (R5 = R6 = Allyl), wherein the allyl
groups could serve as a handle for further functionalization1
is currently underway. This will improve the solubility of the
J. Org. Chem. Vol. 75, No. 21, 2010 7237

Borzsonyi et al.
JOCArticle
CH2Cl2 (450 mL). After stirring for 3.5 h at rt, the reaction
was quenched with MeOH (10 mL), followed by 1 M HCl(aq)
(30 mL), and the resulting suspension was stirred for 15 min.
The organic phase was separated, dried over Na2SO4, filtered,
and concentrated in vacuo. The crude mixture was then dissolved in
a 1:1 mixture of CHCl3\MeOH (170 mL) and treated with NaBH4
(643 mg, 17.0 mmol). After 2 h of stirring, dH2O (100 mL) was
added, and the organic phase was extracted and concentrated.
Purification by silica gel flash chromatography (0-1% MeOH/
CH2Cl2) provided compound 14 (C18H17ClN4O2, 1.5 g) in ca. 50%
yield as a solid. Rf = 0.8 (3% MeOH/CH2Cl2). Mp = 166.3-167.9
°C. 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 8.26 (C6H, sharp s,
1H), 7.51-7.33 (C 9-11H, m, 5H), 6.04-5.97 (C 7H, m, 1H), 5.57
(C15H, m, 2H), 5.21 (C12H, dd, J = 1.2 Hz, J = 16.8 Hz, 1H), 5.07
(C12H, dd, J = 1.2 Hz, J = 10.2 Hz, 1H), 4.55 (C14H, s, 2H),
4.04-4.02 (C 16H, m, 2H). 13C NMR (150 MHz, DMSO-d6) δ
(ppm) 167.2 161.5 161.0 154.9 (C1) (C2) (C3) (C4), 136.5 135.9 133.5
(C5) (C6) (C7), 129.8 128.9 128.7 128.6 (C8) (C9) (C10) (C11), 115.7
105.5 68.7 (C12) (C13) (C14), 60.2 (C15), 43.8 (C16). Positive ESI-MS:
calcd for (M þ Hþ)/z, 357.5, found 357.4 [(M þ Hþ)/z]. HRMS
(ESI): calcd for C18H18ClN4O2, 357.1113, found 357.1110.
2-(Allylamino)-4-(benzyloxy)-7-chloro-5,8-dihydropyrido[2,3-d]pyri-
midine-6-carbonitrile (15, C18H16ClN5O, 1.5 g) was also isolated
1.8 Hz, 1H), 5.12 (C12H, dd, J = 10.8 Hz, 1.8 Hz, 1H), 4.74-
4.72 (C 16H, m, 2H), 1.57 (C19H, s, 9H). 1 H NMR (600 MHz,
CD3CN) δ (ppm) 10.33 (C14H, s 1H), 8.75 (C6H, sharp s, 1H),
7.57-7.39 (C 9-11H, m, 5H), 6.02-6.01 (C H, m, 1H), 5.65
7
(C15H, s, 2H), 5.25 (C12H, dd, J = 17.4 Hz, J = 1.8 Hz, 1H),
5.14 (C12H, dd, J = 10.8 Hz, J = 1.8 Hz, 1H), 4.64-4.63 (C 16H,
m, 2H), 1.55 (C19H, s, 9H). 13C NMR (150 MHz, CDCl3) δ
(ppm) 187.9 (C14) 168.3 162.2 161.8 158.3 (C1) (C2) (C3) (C4)
152.6 (C17), 136.9 134.8 133.5 (C5) (C6) (C7), 128.9 128.8 128.7
125.6 (C8) (C9) (C10) (C11), 116.7 107.2 (C12) (C13), 82.7 (C18),
70.3 (C15), 49.9 (C16) 28.1 (C19). Positive ESI-MS: calcd for
(M þ Hþ)/z, 455.5, found 455.4 [(M þ Hþ)/z]. HRMS (ESI):
calcd for C23H24ClN4O4, 455.1481, found 455.1475.
tert-Butyl Allyl(7-amino-4-(benzyloxy)-6-formylpyrido[2,3-d]-
pyrimidin-2-yl)carbamate (17). Compound 16 (100 mg, 0.22
mmol) was dissolved in 0.5 M NH3 in THF (4.4 mL, 2.2 mmol).
DIPEA (0.038 mL, 0.22 mmol) and DABCO (27 mg, 0.24 mmol)
were then added, and the solution was stirred for 13 h. The
solvent was removed in vacuo, and the crude product was
purified by silica gel flash chromatography (0-100% EtOAc/
hexane) to provide compound 17 as a solid (C23H25N5O4, 50
mg) in 52% yield. Rf = 0.5 (5% MeOH/CH2Cl2). Mp =
1
196.7-198.6 °C. H NMR (600 MHz, CDCl3) δ (ppm) 9.86
1
(C14H), 8.49 (C6H, sharp s, 1H), 7.49-7.36 (C 9-11H, m, 5H),
from the reaction mixture in ca. 50% yield as an oil. H NMR
6.05-5.96 (C H, m, 1H), 5.56 (C15H, s, 2H), 5.22 (C12H, dd,
(600 MHz, DMSO-d6) δ (ppm) 10.43 (NH, sharp s, 1H), 7.39-
7.28 (C9-11H, m, 5H), 7.15 (NH, broad s, 1H), 5.85-5.82 (C7H, m,
1H), 5.31 (C15H, s, 2H), 5.12-5.00 (C12H, m, 2H), 3.84-3.82
(C16H, m, 2H), 3.40 (C6H, s, 2H). 13CNMR(150MHz, DMSO-d6)
δ(ppm) 166.9 160.8 156.6 140.2 (C1) (C2) (C3) (C4), 137.3 136.5 (C5)
(C7), 128.9 128.18 128.15 (C9) (C10) (C11), 118.8 115.3 (C12) (C14),
83.3 79.6 (C8) (C13), 67.3 (C15), 43.5 (C16), 23.4 (C6). Positive ESI-
MS: calcd for (M þ Hþ)/z, 354.5, found 354.3 [(M þ Hþ)/z].
HRMS (ESI): calcd for C18H17ClN5O, 354.1116, found 354.1115.
2-(Allylamino)-4-(benzyloxy)-7-chloropyrido[2,3-d]pyrimidine-
6-carbaldehyde (13). PCC (1.2 g, 5.4 mmol) was added to a solu-
tion of 14 (950 mg, 2.7 mmol) in CHCl3 (70 mL). After stirring
overnight, the reaction mixture was filtered through a pad of
Celite, treated with 1 M HCl(aq) (30 mL), and stirred for 15 min.
The organic phase was then separated, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Purification by
silica gel flash chromatography (0-1% MeOH/CH2Cl2) pro-
vided compound 13 as a solid (C18H15ClN4O2, 700 mg) in 74%
yield. Rf = 0.8 (3% MeOH/CH2Cl2). Decomposes >280 °C. 1H
NMR (600 MHz, CDCl3, 50 °C) δ (ppm) 10.37 (C14H, s, 1H),
8.75 (C6H, sharp s, 1H), 7.47-7.37 (C9-11H, m, 5H), 6.25 (NH,
brs, 1H), 6.00-5.97 (C7H, m, 1H), 5.53 (C15H, s, 2H), 5.32-5.21
(C12H, m, 2H), 4.31 (C16H, m, 2H). 13C NMR (150 MHz,
CDCl3, 50 °C) δ (ppm) 188.2 (C14), 168.4 163.9 162.8 158.7
(C1) (C2) (C3) (C4), 136.8 135.3 134.0 (C5) (C6) (C7), 129.04
129.01 128.6 123.7 (C8) (C9) (C10) (C11), 117.3 106.7 (C12) (C13),
69.8 (C15), 44.5 (C16). Positive ESI-MS: calcd for (M þ Hþ)/z,
355.5, found 355.4 [(M þ Hþ)/z]. HRMS (ESI): calcd for
C18H16ClN4O2, 355.0956, found 355.0956.
tert-Butyl Allyl(4-(benzyloxy)-7-chloro-6-formylpyrido[2,3-
d]pyrimidin-2-yl)carbamate (16). Compound 13 (693 mg, 1.95
mmol) was suspended in THF (100 mL) and then treated with
DIPEA (0.68 mL, 3.9 mmol), DMAP (24 mg, 0.2 mmol), and
Boc2O (468 mg, 2.15 mmol). After the mixture stirred overnight,
dH2O (10 mL) was added, and the THF was removed under
reduced pressure (rotavap). The residue was then extracted with
CH2Cl2, and the combined organic extracts were dried over
anhydrous Na2SO4, filtered, and concentrated. Purification by
silica gel flash chromatography (0-15% EtOAc/hexane) pro-
vided compound 16 as a solid (C23H23ClN4O4, 650 mg) in 73%
yield. Rf = 0.9 (3% MeOH/CH2Cl2). Mp = 130.3-131.1 °C. 1
H NMR (600 MHz, CDCl3) δ (ppm) 10.43 (C14H, s, 1H), 8.88
(C6H, sharp s, 1H), 7.50-7.38 (C 9-11H, m, 5H), 6.02-5.98
(C 7H, m, 1H), 5.62 (C15H, s, 2H), 5.25 (C12H, dd, J = 17.4 Hz,
7
J = 17.4 Hz, 1.8 Hz, 1H), 5.09 (C12H, dd, J = 10.2 Hz, 1.2 Hz,
1H), 4.68-4.67 (C 16H, m, 2H), 1.53 (C19H, s, 9H). 13 C NMR
(150 MHz, CDCl3) δ (ppm) 191.2 (C14), 167.6 163.4 162.3 160.7
(C1) (C2) (C3) (C4), 153.1 (C17), 144.2 135.7 134.1 (C5) (C6) (C7),
128.8 128.7 128.7 (C9) (C10) (C11), 116.2 115.2 101.2 (C8) (C12)
(C13), 82.1 (C18), 69.4 (C15), 49.9 (C16), 28.2 (C19). Positive ESI-
MS: calcd for (M þ Hþ)/z, 436.5, found 436.6 [(M þ Hþ)/z].
HRMS (ESI): calcd for C23H26N5O4, 436.1979, found 436.1976.
tert-Butyl Allyl(4-(benzyloxy)-6-formyl-7-hydroxypyrido[2,3-d]-
pyrimidin-2-yl)carbamate (22, C23H24N4O5, 38 mg) was also
isolated in 40% yield from the reaction mixture. Rf = 0.3 (5%
MeOH/CH2Cl2). Mp = 158.1-159.7 °C. 1 H NMR (600 MHz,
CDCl3) δ (ppm) 10.26 (C14H), 8.54 (C6H, sharp s, 1H),
7.43-7.36 (C 9-11H, m, 5H), 5.93-5.88 (C H, m, 1H), 5.50
7
(C15H, s, 2H), 5.21-5.17 (C 12H, m, 2H), 4.54 (C16H, m, 2H),
1.53 (C19H, s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 188.3
(C14), 167.6 162.8 162.3 157.6 (C1) (C2) (C3) (C4), 152.4 (C17),
137.4 135.0 133.4 (C5) (C6) (C7), 128.8 128.7 128.5 (C9) (C10)
(C11), 123.6 116.8 (C8) (C12), 96.0 (C13) 83.1 (C18), 69.8 (C15) 48.8
(C16), 28.1 (C19). Positive ESI-MS: calcd for (M þ Hþ)/z, 437.5,
found 437.4 [(M þ Hþ)/z]. HRMS (ESI): calcd for C23H25N4O5,
437.1819, found 437.1830.
N-(1-(2-(Allyl(tert-butoxycarbonyl)amino)-4-(benzyloxy)-6-for-
mylpyrido[2,3-d]pyrimidin-7-yl)pyridin-4(1H)-ylidene)-N-methyl-
methanaminium Chloride (18). 1H NMR (600 MHz, CD3CN) δ
(ppm) 10.00 (C14H, s 1H), 9.17 (C6H, sharp s, 1H), 8.37 ((C22)-
(C23)H, dd, J=6.0Hz, J= 1.8 Hz, 1H), 8.11 ((C22)(C23)H, dd, J=
5.4 Hz, J = 1.8 Hz, 1H), 7.61-7.45 (C9-11H, m, 5H), 7.04 ((C20)-
(C21)H, dd, J=5.4Hz, J= 1.2 Hz, 1H), 6.55 ((C20)(C21)H, dd, J=
5.4 Hz, J = 1.8 Hz, 1H), 6.02-6.00 (C7H, m, 1H), 5.72 (C15H, s,
2H), 5.24 (C12H, dd, J = 18.0 Hz, J = 1.8 Hz, 1H), 5.16 (C12H, dd,
J=10.8 Hz, J=1.2 Hz, 1H), 4.67 (C16H, m, 2H), 3.32, 2.96 (C25, 26H,
þ
s, 6H), 1.55 (C19H, s, 9H). HRMS (EI): calcd for C30H3N6O4
541.2558, found 541.2556.
1-(2-(Allyl(tert-butoxycarbonyl)amino)-4-(benzyloxy)-6-for-
mylpyrido[2,3-d]pyrimidin-7-yl)-4-methoxypyridinium Chloride
(19). 1H NMR (600 MHz, CD3CN) δ (ppm) 9.99 (C14H, s
1H), 9.00 (C6H, sharp s, 1H), 8.37 ((C20)(C21)H, dd, J = 4.8
Hz, J=1.8 Hz, 1H), 7.91-7.89 ((C20)(C21)H, m, 1H), 7.61-7.39
(C9-11H, m, 5H), 6.88 ((C22)(C23)H, dd, J = 4.8 Hz, J = 1.2 Hz,
1H), 6.29 ((C22)(C23)H, m, 1H), 6.02-6.00 (C7H, m, 1H), 5.69
(C15H, s, 2H), 5.24 (C12H, dd, J=18.0 Hz, J=1.8 Hz, 1H), 5.16
(C12H, dd, J=10.8 Hz, J=1.2 Hz, 1H), 4.65 (C16H, m, 2H),
7238 J. Org. Chem. Vol. 75, No. 21, 2010

Borzsonyi et al.
JOCArticle
4.23 (C25H, s, 3H), 1.55 (C19H, s, 9H). Positive ESI-MS: calcd
for (M þ Hþ)/z, 528.2, found 528.4 [(M þ Hþ)/z]
(60 mg, 0.12 mmol) in CH2Cl2 (9 mL) at 0 °C. After the mixture
stirred for 2 h, NH3 (2 M in i-PrOH, 1 mL, 2 mmol) was added, and
the solution was stirred for an additional 2 h. Upon warming to rt,
the solvent was removed under reduced pressure, and the resulting
crude material was purified by silica gel flash chromatography
(0-3% MeOH/CH2Cl2) to provide compound 25 (C27H26N8O4,
50 mg) in 77% yield as a white solid. Rf =0.3(5%MeOH/CH2Cl2).
Mp = 209.1-211.0 °C. 1HNMR(600MHz, CD2Cl2) δ(ppm) 9.65
(NH, brs, 1H), 8.95 (C6H, sharp s, 1H), 8.60 (C14H, sharp s, 1H),
7.65 (NH, broad s, 1H), 7.58-7.40 (C 9-11H, m, 5H), 6.06-6.03 (C
7H, m, 1H), 5.69 (C15H, s, 2H), 5.65 (NH, bs, 1H), 5.28 (C12H, dd,
J = 17.4 Hz, 1.2 Hz, 1H), 5.18 (C12H, dd, J = 10.2 Hz, 1.8 Hz, 1H),
1-(2-(Allyl(tert-butoxycarbonyl)amino)-4-(benzyloxy)-6-formyl-
pyrido[2,3-d]pyrimidin-7-yl)-4-aza-1-azoniabicyclo[2.2.2]octane
(20). 1H NMR (600 MHz, CD3CN) δ (ppm) 10.07 (C14H, s 1H),
9.32 (C6H, sharp s, 1H), 7.61-7.41 (C9-11H, m, 5H), 6.05-6.01
(C7H, m, 1H), 5.73 (C15H, s, 2H), 5.25 (C12H, dd, J = 17.4 Hz,
J = 1.8 Hz, 1H), 5.16 (C12H, dd, J = 10.8 Hz, J = 1.8 Hz, 1H),
4.69 (C16H, m, 2H), 4.01 (C20H, t, J = 7.8 Hz, 6H), 3.34 (C21H,
t, J = 7.8 Hz, 6H), 1.57 (C19H, s, 9H). Positive ESI-MS: calcd
for Mþ/z, 532.3, found 531.5 [Mþ/z].
1-(1-(2-(Allyl(tert-butoxycarbonyl)amino)-4-(benzyloxy)-6-for-
mylpyrido[2,3-d]pyrimidin-7-yl)pyridin-4(1H)-ylidene)pyrrolidi-
nium Chloride (21). 1H NMR (600 MHz, CD3CN) δ (ppm) 10.00
(C14H, s 1H), 9.17 (C6H, sharp s, 1H), 8.35-8.34 ((C22)(C23)H,
m, 1H), 8.07-8.06 ((C22)(C23)H, m, 1H), 7.61-7.45 (C9-11H, m,
5H), 6.90 ((C20)(C21)H, m, 1H), 6.50-6.49 ((C20)(C21)H, m,
1H), 6.09-6.00 (C7H, m, 1H), 5.72 (C15H, s, 2H), 5.24 (C12H,
dd, J = 18.0 Hz, J = 1.8 Hz, 1H), 5.16 (C12H, dd, J = 10.8 Hz,
13
4.75-4.72 (C 16H, m, 2H), 1.58 (C19H, s, 9H). C NMR (150
MHz, CD2Cl2) δ (ppm) 168.7 163.2 162.3 158.0 154.3 153.9 153.3
(C1) (C2) (C3) (C4) (C17) (C22) (C23), 147.8 138.3 135.8 134.4 (C5)
(C6) (C7) (C14), 129.4 129.3 129.3 (C9) (C10) (C11), 116.7 115.9 114.7
109.1 98.4 (C8) (C12) (C13) (C20) (C21), 83.1 (C18), 70.8 (C15), 50.5
(C16), 28.5(C19). ESI-MS:calcdfor(Mþ Hþ)/z, 527.2, found 527.2
[(M þ Hþ)/z].
J = 1.2 Hz, 1H), 4.67 (C16H, m, 2H), 3.27, 1.98 (C25-26H, s, 8H),
1.55 (C19H, s, 9H). HRMS (ESI): calcd for C32H35N6O4
567.2714, found 567.2714.
tert-Butyl Allyl(4-(benzyloxy)-7-cyano-8-(3-phenylcarbonyl-
ureido)pyrimido[4,5-b][1,8]naphthyridine)carbamate (26). Ben-
zoyl isocyanate (25 mg, 0.17 mmol) was added to a solution of 24
(40 mg, 0.083 mmol) in CH2Cl2 (6 mL) at 0 °C. After 2 h, the reac-
tion mixture was warmed to rt and quenched with dH2O (3 mL).
The organic phase was then extracted with CH2Cl2, dried over
anhydrous Na2SO4, filtered, and concentrated. Purification by silica
gel flash chromatography (0-3% MeOH/CH2Cl2) provided com-
pound 26 (C34H30N8O5, 40 mg) as a yellow foam in 77% yield. Rf =
0.4 (5% MeOH/CH2Cl2). 1H NMR (600 MHz, CD2Cl2) δ (ppm)
8.99 (C6H, sharp s, 1H), 8.66 (C14H, sharp s, 1H), 8.44 (NH, broad
s, 2H), 7.71-7.41 (C9-11H, C26-28H, m, 10H), 6.19-6.05 (C7H, m,
1H), 5.71 (C15H, s, 2H), 5.37-5.22 (C12H, m, 2H), 4.81-4.80
(C16H, m, 2H), 1.61 (C19H, s, 9H). 13C NMR (150 MHz, CD2Cl2)
δ (ppm) 168.7 163.2 162.5 157.6 153.8 153.4 149.2 148.2 (C1) (C2)
(C3) (C4) (C17) (C22) (C23) (C24), 138.5 135.8 134.5 134.0 132.9 132.4
129.7 129.5 129.4 129.3 129.0 (C5) (C6) (C7) (C9) (C10) (C11) (C14)
(C25) (C26) (C27) (C28), 127.9 117.0 116.3 114.6 109.7 (C8) (C12) (C13)
(C20) (C21), 83.2 (C18), 70.8 (C15), 50.8 (C16), 28.4 (C19). Positive
ESI-MS: calcd for (M þ Hþ)/z, 631.2, found 631.4 [(M þ Hþ)/z].
HRMS (ESI): calcd for C34H31N8O5, 631.2412, found 631.2414.
ꢀꢀG∧C Motif (4). A solution of 26 (30 mg, 0.05 mmol) and
DIPEA (0.07 mL, 0.4 mmol) in CH2Cl2 (3 mL) was stirred at rt
for 4 days and then concentrated. The crude product was then
dissolved in 4 M HCl/dioxane (90 mL) and heated at 70 °C for
5 h in a sealed tube. The resulting residue was collected and
washed with CH2Cl2 to give target compound 4 (C15H12N8O2,
12 mg) as a yellow solid in 75% yield (2 steps). Decomposition
þ
,
tert-Butyl Allyl(4-(benzyloxy)-7-(4-(2-chloroethyl)piperazin-
1-yl)-6-formylpyrido[2,3-d]pyrimidin-2-yl)carbamate (23). A
solution of compound 16 (100 mg, 0.22 mmol) in 0.5 M NH3
in dioxane (4.4 mL, 2.2 mmol) was treated with DABCO (27 mg,
0.24 mmol) and DIPEA (0.038 mL, 0.22 mmol). After stirring
for 24 h, the solution was concentrated in vacuo. Purification
by silica gel flash chromatography (0-100% EtOAc/hexane)
offered compound 23 (C29H35ClN6O4, 62 mg) in 50% yield
as a white solid. Rf = 0.2 (30% EtOAc/hexane). Decomposes
1
>200 °C. H NMR (600 MHz, CDCl3) δ (ppm) 9.89 (C14H),
8.59 (C6H, sharp s, 1H), 7.47-7.35 (C9-11H, m, 5H), 5.99-5.88
(C7H, m, 1H), 5.55 (C15H, s, 2H), 5.21 (C12H, dd, J = 16.8 Hz,
1.2 Hz, 1H), 5.17 (C12H, dd, J = 10.2 Hz, 1.2 Hz, 1H), 4.62
(C16H, m, 2H), 3.70 (C20H, t, J = 4.8 Hz, 4H), 3.60 (C23H, t, J =
6.6 Hz, 2H), 2.77 (C22H, t, J = 6.6 Hz, 2H), 2.67 (C21H, t, J =
4.8 Hz, 4H), 1.52 (C19H, s, 9H). 13C NMR (150 MHz, CDCl3) δ
(ppm) 188.1(C14), 167.9 162.4 161.9 153.2, 153.1 (C1) (C2) (C3)
(C4) (C17), 141.9 135.6, 134.3 (C5) (C6) (C7), 128.7 128.6 128.5
(C9) (C10) (C11), 119.4 116.2 102.1 (C8) (C12) (C13), 81.9 (C18),
69.3 (C15), 59.7 53.0 50.0 49.7 39.9 (C16) (C20) (C21) (C22) (C23)
28.2 (C19). ESI-MS: calcd for (M þ Hþ)/z, 567.2, found 567.5
[(M þ Hþ)/z]. HRMS (ESI): calcd for C29H36ClN6O4, 567.2481,
found 567.2469.
tert-Butyl Allyl(8-amino-4-(benzyloxy)-7-cyanopyrimido[4,5-
b][1,8]naphthyridine)carbamate (24). A solution of 17 (150 mg,
0.34 mmol) and malononitrile (25 mg, 0.38 mmol) in pyridine
(15 mL) was stirred for 24 h at rt. The solution was then
concentrated under reduced pressure (rotavap), and the crude
material was purified by silica gel flash chromatography (0-5%
MeOH/CH2Cl2) to provide compound of 24 (C26H25N7O3, 146
mg) as a clear oil in 88% yield. Rf = 0.3 (5% MeOH/CH2Cl2).
1H NMR (600 MHz, CD2Cl2) δ (ppm) 8.81 (C6H, sharp s, 1H),
8.42 (C14H, sharp s, 1H), 7.56-7.39 (C9-11H, m, 5H), 6.15 (NH,
brs, 2H), 6.08-6.03 (C7H, m, 1H), 5.66 (C15H, s, 2H), 5.31
(C12H, dd, J = 17.4 Hz, 1.2 Hz, 1H), 5.15 (C12H, dd, J = 10.2,
1
>400 °C. H NMR (600 MHz, CF3CO2D) δ (ppm) 9.47 9.37
(C6H, C14H, two sharp s, 2H), 5.91-5.89 (C7H, m, 1H), 5.38-
5.32 (C12H, m, 2H), 4.33-4.32 (C16H, m, 2H). 13C NMR (150
MHz, CF3CO2D) δ (ppm) 164.3 163.0 160.5 157.6 157.2 154.9
154.0 (C1) (C2) (C3) (C4) (C20) (C22) (C23), 150.5 146.9 (C6) (C14),
131.6 (C7), 121.6 (C12), 117.7 116.2 113.3 (C8) (C13) (C21), 46.8
(C16). HRMS (ESI): calcd for C15H12DN8O2, 338.1146, found
338.1218.
Acknowledgment. We thank the National Research
Council of Canada (NRC), University of Alberta, Natural
Sciences and Engineering Research Council of Canada
(NSERC), and the Canadian Foundation for Innovation
(CFI). A.A. thanks the Alberta Ingenuity Fund (AIF) for a
Graduate Student Scholarship in Nanotechnology.
1.2 Hz, 1H), 4.73-4.72 (C16H, m, 2H), 1.55 (C19H, s, 9H). 13
C
NMR (150 MHz, CD2Cl2) δ (ppm) 168.7 163.0 161.8 160.5 (C1)
(C2) (C3) (C4), 159.5 (C22), 153.7 (C17), 147.0 (C14), 137.8 136.1
134.8 (C5) (C6) (C7), 129.3 129.24 129.23 (C9) (C10) (C11), 116.6
115.8, 115.4, 107.5, 97.8 (C8) (C12) (C13) (C20) (C21), 82.8 (C18),
70.4 (C15), 50.5 (C16), 28.5 (C19). Positive ESI-MS: calcd for
(M þ Hþ)/z, 484.1, found 484.4 [(M þ Hþ)/z]. HRMS (ESI):
calcd for C26H26N7O3, 484.2092, found 484.2095.
Supporting Information Available: Experimental proce-
dures not described in the Experimental Section and H and
1
tert-Butyl Allyl(4-(benzyloxy)-7-cyano-8-ureidopyrimido[4,5-
b][1,8]naphthyridine)carbamate (25). Trichlorocarbonyl isocya-
nate (0.030 mL, 0.25 mmol) was added to a solution of 24
13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 21, 2010 7239