Toward Pyrrolo[2,3- d ]pyrimidine scaffolds

Article abstract of DOI:10.1021/jo100759b

(Figure presented) Herein, we present a new route to highly substituted pyrrolo[2,3-d]pyrimidines featuring a Ugi-Smiles/Sonogashira cascade followed by an efficient base-catalyzed intramolecular cyclization. When formaldehyde is chosen as input in the Ugi-Smiles step, aromatic fused systems are eventually obtained through the isomerization of an exo-alkylidene intermediate.

Full text of DOI:10.1021/jo100759b

pubs.acs.org/joc
SCHEME 1. Ugi-Smiles Access to Pyrimidoalkyne Precursors
Toward Pyrrolo[2,3-d]pyrimidine Scaffolds
Laurent El Kaım,* Laurence Grimaud,* and
Simon Wagschal*
ꢀ ꢀ
Laboratoire Chimie et procedes, UMR 7652, Ecole Nationale
ꢀ
Superieure de Techniques Avancees, 32 Bd Victor,
ꢀ
Paris 75015, France
laurent.elkaim@ensta.fr; laurence.grimaud@ensta.fr;
simon.wagschal@ensta.fr
Received April 23, 2010
palladium-catalyzed processes as previously featured in a
one-pot, two-step formation of indoles.4 Similarly, a Sono-
gashira coupling5 could allow an easy access to acetylenic
Ugi-Smiles adducts, providing us with some interesting
opportunities for potential cyclizations. We report herein a
new formation of fused pyrrolopyrimidine systems through a
formal five-component coupling followed by a deprotona-
tion alpha to the amide and a subsequent cyclization.
The Ugi-Smiles adducts 2 presenting an alkyne moiety can
be prepared by a Ugi-Smiles reaction of ortho iodopyrimidin-
4-ol derivatives followed by a Sonogashira coupling (Scheme 1,
path A). The alternative path B starting with alkynepyrimi-
dinol was unsuccessful due to its lack of reactivity in the
Ugi-Smiles coupling step.
Herein, we present a new route to highly substituted pyr-
rolo[2,3-d]pyrimidines featuring a Ugi-Smiles/Sonogashira
cascade followed by an efficient base-catalyzed intra-
molecular cyclization. When formaldehyde is chosen as
input in the Ugi-Smiles step, aromatic fused systems are
eventually obtained through the isomerization of an exo-
alkylidene intermediate.
Several pyrimido alkynes 2 were prepared through modi-
fications of the various partners of the couplings (Table 1)
and following Hu’s conditions for the Sonogashira step.6 We
had already exploited the acidity of aryl-substituted Ugi-Smiles
adducts to trigger a palladium-induced cyclization.7 The
proposed mechanism for this previous study featured a sta-
bilized anion formation in the R position of the amide. This
intermediate cyclized onto a remote alkene activated by the
palladium catalyst.
With these acetylenic pyrimidines 2 in hand, we next
examined their behavior under basic conditions. In the case
of the adducts 2, we chose to first investigate aromatic
aldehydes so that the stabilized anion can react with the
alkyne to form the fused pyrrolidinopyrimidine derivatives.
Indeed, a similar cyclization pattern was observed by Cacchi
et al. when working on N-aryl-substituted glycine esters to
form indole derivatives.8
The most acidic adducts 2a-g were then submitted to
different basic conditions as reported in Table 2. The first
trials with the substrate 2a (Table 2, entry 1) and various
amounts of DBU in acetonitrile gave the compound 3a as a
mixture of two diastereomers. Both isomers can be selectively
Multicomponent reactions (MCRs), in which three or
more substrates react in a one-pot procedure, have become
powerful tools to easily prepare large libraries of highly
substituted molecules.1 Over the past decades, the Ugi reac-
tion has become the leading reaction of this field thanks to its
great versatility. An even higher degree of diversity may be
reached when these processes are coupled with postconden-
sation transformations, such cascades having been inten-
sively explored by many research groups. We have recently
disclosed a new Ugi-type reaction using electron-deficient
phenols and heteroaromatic phenols (pyridines, pyrimidines)
as the acidic partners.2 Considering that phenols substituted
by halogens at the ortho position are efficient partners in this
coupling,3 we developed this chemistry in association with
(4) El Kaim, L.; Gizzi, M.; Grimaud, L. Org. Lett. 2008, 10, 3417–3419.
For an Ugi/Heck reaction toward indoles, see: Kalinski, C.; Umkehrer, M.;
Schmidt, J.; Ross, G.; Kold, J.; Burdack, C.; Hiller, W.; Hoffmann, S. D.
Tetrahedron Lett. 2006, 47, 4683–4686.
ꢀ
(5) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874–922.
(6) Liu, Z.; Li, D.; Li, S.; Bai, D.; He, X.; Hu, Y. Tetrahedron 2007, 63,
€
ꢀ
(1) Domling, A. Chem. Rev. 2006, 106, 17–89. Zhu, J.; Bienayme, H.
Multicomponent Reactions; Wiley-VCH: Weinheim, 2005. Orru, R. V. A.;
De Greef, M. Synthesis 2003, 1471–1499.
(2) El Kaim, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44,
7165–7169. El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem.
2007, 72, 4169–4180. For a review on Ugi-Smiles reactions, see: El Kaım, L.;
Grimaud, L. Mol. Diversity DOI 10.1007/s11030-009-9175-3.
(3) Oble, J.; El Kaım, L.; Gizzi, M.; Grimaud, L. Heterocycles 2007, 73,
503–517.
1931–1936.
~
(7) El Kaim, L.; Gamez-Montano, R.; Grimaud, L.; Ibarra-Rivera, T.
Chem. Commun. 2008, 1350–1352.
(8) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2000, 5, 647–
649.
DOI: 10.1021/jo100759b
r
Published on Web 07/01/2010
J. Org. Chem. 2010, 75, 5343–5346 5343
2010 American Chemical Society

El Kaım et al.
JOCNote
TABLE 1. Ugi-Smiles/Sonogashira Cascade Results
entry
Ugi-Smiles adduct (yield, %)
alkyne RCCH, R =
Sonogashira adduct (yield, %)
1
2
3
1a (65)
1a
1a
Ph
p-MePh
Bu
2a (62)
2b (64)
4
5
6
7
8
9
10
11
12
13
14
1b (42)
1c (68)
1d (22)
1d
1e (59)
1f (50)
1g (64)
1g
o-CF3Ph
Ph
o-CF3Ph
p-MeOPh
TMS
o-CF3Ph
Ph
o-CF3Ph
Ph
2c (76)
2d (58)
2e (74)
2f (70)
2ga
2h (61)
2i (74)
2j (64)
2k (73)
2l (63)
2m (63)
1h (27)
1i (30)
1j (33)
p-MePh
Ph
a2g could not be isolated; the following cyclization was directly performed on the crude mixture.
formed using a catalytic amount of either DBU in refluxing
methanol (conditions A) or potassium tert-butoxide in ref-
luxing tetrahydrofuran (conditions B). For most starting
alkynes, only one diastereomer can be isolated under condi-
tions A, but the conditions B gave a mixture of both (the
opposite is observed for trifluoropyrrolidinopyrimidine 3c
and 3e). The diastereomers formed under conditions A show a 1
ppm 1H NMR downfield shift of the methyl pyrimidine moiety
compared to the major ones obtained under B. A NOESY
experiment performed on both isomers of 3d was consistent with
a Z configuration of the alkene formed under condition A. All
isomers could be separated, but some of these (Table 2, entries 3
and 5) appeared to be quite unstable and difficult to isolate as
they can easily isomerize within a few days (a few hours in a
CDCl3 solution). In the case of the silyl-substituted alkyne 2g
(Table 1, entry 8, and Table 2, entry 7), it should be noted that
the cyclization and the TMS deprotection occurred at the same
time with potassium carbonate, giving a fused pyrrolidinopy-
rimidine bearing an exo-methylene.
More interestingly, a one-pot procedure can be performed
for the Sonogashira/cyclization step by adding DBU in the
mixture after the palladium-catalyzed step. Under these con-
ditions, the substrate 2a afforded both isomers 3a(Z)/3a(E)
in a 4:3 ratio in a 60% overall yield.
When formaldehyde was used in the Ugi-Smiles reaction,
one would expect the resulting formation of less acidic adducts
(Table 1, entries 9-14). Indeed, the treatment of 2h with various
amounts of DBU in methanol does not lead to any cyclization,
nor do substoichiometric amounts of sodium hydride in DMF.
However, the expected cyclization occurred at room tempe-
rature with 2 equiv of NaH, affording good yields for pyr-
rolo[2,3-d]pyrimidines (Table 3, entries 1-6). It is noteworthy
that, in the case of o-trifluoromethylaryl alkynes 2h and 2j
(Table 3, entries 1 and 3), the increased stability of the ben-
zylic anion probably favors the oxidation of this position as
the ketones 4h and 4j can be isolated.9
A plausible pathway starts with the deprotonation of the
amide, forming a poorly reactive anion for a 7-exo-dig cycliza-
tion. The further addition of base results in the formation of
a reactive dianion, prone to undergo a fast 5-exo-dig cyclization.
Nevertheless, with an aromatic moiety as the aldehyde input,
the acidities of the amide and the R-CH are quite similar,
allowing an equilibrium between the two anionic sites so that
the cyclization can be observed with a catalytic amount of base.
As already shown for aromatic derivatives, the whole
process;Sonogashira coupling-cyclization-isomerization;
can be performed according to a one-pot two-step procedure
using acetonitrile as solvent. Under these conditions, the com-
pound 3i is obtained from 1g in a 39% isolated yield, compared
with 65% if the intermediate 2i is separated (Table 1, entry 10,
and Table 3, entry 2).
In conclusion, we have developed a new multicomponent
synthesis of pyrrolopyrimidines, which are potentially relevant
(9) For a related oxidation, see: Bernini, R.; Cacchi, S.; Fabrizi, G.;
Filisti, E.; Sferrazza, A. Synlett 2009, 1245–1250.
5344 J. Org. Chem. Vol. 75, No. 15, 2010

El Kaım et al.
JOCNote
TABLE 2. Pyrrolidinopyrimidines from Pyrimidines 2a-g
entry
1
R1
R2
R3
R4
R5
3
conditions (yield, %; ratio)
p-ClBn
p-FPh
p-ClPh
i-Pr
Ph
3a
A (91)
B (100; 4:1)
A (84)
B (94; 4:1)
A (87; 2:1)a
B (72)
2
3
4
5
6
7
p-ClBn
p-ClBn
p-ClBn
Cy
p-FPh
p-ClPh
Ph
p-ClPh
(CH2)2OMe
n-Bu
i-Pr
Ph
p-MePh
o-CF3Ph
Ph
3b
3c
3d
3e
3f
i-Pr
i-Pr
i-Pr
i-Pr
A (73)
B (86; 3:1)
A (97; 2:1)a
B (83)
p-FPh
p-FPh
p-FPh
p-ClPh
p-ClPh
p-ClPh
o-CF3Ph
p-MeOPh
H
Cy
A (66)
B (75; 1.2:1)
p-MeOBn
3g
(36)b
aFast isomerization of both isomers after a few hours in CDCl3 solutions. bYield given directly from 1e and cyclization performed using K2CO3.
TABLE 3. Pyrrolopyrimidines from Pyrimidines 2h-m
N-(4-Chlorobenzyl)-2-[(4-chlorobenzyl)(5-iodo-2-isopropyl-6-
methylpyrimidin-4-yl)amino]-2-(4-fluorophenyl)acetamide (1a).
General procedure for this Ugi-Smiles adduct using p-fluorobenz-
aldehyde (110 μL, 1.0 mmol), p-chlorobenzylamine (120 μL, 1.0
mmol), p-chlorobenzyl isocyanide (130 μL, 1.0 mmol), and 5-iodo-
2-isopropyl-6-methylpyrimidin-4-ol (280 mg, 1.0 mmol): Purifica-
tion by flash chromatography (petroleum ether-diethyl ether,
70:30) afforded 1a as a colorless oil: yield 65% (440 mg); Rf 0.3
(70:30 petroleum ether/diethyl ether); 1H NMR (CDCl3, 400 MHz)
δ 7.32 (dd, JH-H, H-F=8.6, 5.3 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H),
7.13 (d, J= 8.3 Hz, 2H), 7.04 (t, J= 8.6 Hz, 2H), 6.98-6.89 (m,
3H), 6.75 (d, J=8.3 Hz, 2H), 5.27 (s, 1H), 4.50-4.42 (m, 2H), 4.27
(d, J=15.2 Hz, 1H), 4.16 (dd, J=14.7, 4.8 Hz, 1H), 2.90 (sept, J=
6.8 Hz, 1H), 2.68 (s, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8
Hz, 3H); 13C NMR (CDCl3, 100.6 MHz) δ 173.6, 171.3, 170.3,
167.7, 163.0 (d, J=248.9 Hz), 136.8, 134.8, 133.8, 133.7, 131.5 (d,
J=2.9 Hz), 130.9 (d, J=8.1 Hz), 130.3, 129.4, 129.2, 128.7, 116.0
(d, J = 21.2 Hz), 89.4, 68.4, 53.8, 43.1, 37.0, 30.4, 22.0, 21.7; IR
(ATR) 1670, 1541, 1508, 1490 cm-1; HRMS calcd for [C30H28Cl2-
FIN4O - C8H7ClNO] 508.0453, found 508.0460.
entry
R1
R2
n-Bu
p-ClPh
p-ClPh
p-ClPh
R3
R4
3 (yield, %) (A/B)
1
2
3
4
5
6
p-MeOPh
p-ClPh
p-ClPh
t-Bu
i-Pr o-CF3Ph
i-Pr Ph
i-Pr o-CF3Ph
i-Pr Ph
4h (88)
3i (90)
4j (57)
3k (82)
3l (69)
3m (75)
Cy
ArCH2CH2a n-Bu
aAr = 3,4-dimethoxyphenyl.
(CH2)2OMe i-Pr p-MePh
Ph Ph
scaffolds for use in the pharmaceutical industry.10 More inter-
estingly, this study underlines the potential of Ugi adducts in
the alkylation of amide enolates and the necessity to address the
relative acidities of the N-HandC-H protons. Several studies
by Marcaccini et al. have already shown a possible control of
the cyclization paths by a proper selection of the Ugi starting
partners.11 We are further studying the behavior of such
Ugi-Smiles adducts under basic conditions.
2-[Butyl-(5-iodo-2-isopropyl-6-methylpyrimidin-4-yl)amino]-
N-(4-methoxybenzyl)acetamide (1f). General procedure for this
Ugi-Smiles adduct using formaldehyde (180 μL, 2.0 mmol), butyl-
amine (200 μL, 2.0 mmol), p-methoxybenzylisocyanide (300 μL,
2.0 mmol), and 5-iodo-2-isopropyl-6-methylpyrimidin-4-ol (560 mg,
2.0 mmol): Purification by flash chromatography (petroleum
ether-diethyl ether, 50:50) afforded 1f as a colorless oil: yield
Experimental Section
1
50% (510 mg); Rf 0.3 (50:50 petroleum ether/diethyl ether); H
General Procedure for Pyrimidine-Induced Ugi-4CR. To a 1 M
solution of pyrimidine in methanol were successively added 1.0
equiv of aldehyde, 1.0 equiv of amine, and 1.0 equiv of isocyanide
under inert atmosphere. The resulting mixture was stirred at 60 °C
for 3 days. It was then concentrated under reduced pressure, and
the crude product was purified by flash chromatography on silica
gel.
NMR (CDCl3, 400 MHz) δ7.16-7.10 (m, 3H), 6.83 (d, J=8.3Hz,
2H), 4.39 (d, J=5.6 Hz, 2H), 4.17 (s, 2H), 3.80 (s, 3H), 3.41-3.35
(m, 2H), 2.97 (sept, J=6.8 Hz), 2.66 (s, 3H), 1.65-1.55 (m, 2H),
1.33-1.25 (m, 2H), 1.23 (d, J= 6.8 Hz, 6H), 0.90 (t, J=7.3 Hz,
3H); 13C NMR (CDCl3, 100.6 MHz) δ 173.4, 171.2, 170.4, 167.0,
159.4, 130.5, 129.5, 114.4, 84.0, 55.7, 54.8, 53.5, 43.2, 37.0, 30.8,
30.2, 22.0, 20.5, 14.3; IR (ATR) 1668, 1539, 1513, 1490 cm-1
;
HRMS calcd for C22H31IN4O2 510.1492, found 510.1510.
General Procedure for Sonogashira Adducts. To a 0.1 M
solution of Smiles adduct in acetonitrile were successively added
1.2 equiv of alkyne, 5 mol % of dichlorobis(triphenylphosphine)-
palladium, 5 mol % of CuI, and 1 equiv of a diisopropylethyl-
amine. The resulting mixture was stirred at 70 °C overnight. The
solution was filtered under reduced pressure, and the filtrate was
washed with methanol. The solvent was removed afterward under
reduced pressure to afford Ugi-Smiles products after purification
by flash chromatography on silica gel.
(10) Bundy, G. L.; Ayer, D. E.; Banitt, L. S.; Belonga, K. L.; Mizsak,
S. A.; Palmer, J. R.; Tustin, J. M.; Chin, J. E.; Hall, E. D. J. Med. Chem. 1995,
38, 4161–4163. Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer,
T.; Lydon, N. J. Med. Chem. 1996, 39, 2285–2292. Weisner, J. B.; Ugarkar,
B. G.; Castellino, A. J.; Barankiewicz, J.; Dumas, D. P.; Gruber, H. E.;
Foster, A. C.; Erion, M. D. J. Pharmacol. Exp. Ther. 1999, 289, 1669–1677.
(11) Marcaccini, S.; Pepino, R.; Pozo, M. C. Tetrahedron Lett. 2001, 42,
2727–2728. Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Hetero-
cycles 1997, 45, 1589–1592. Bossio, R.; Marcos, C. F.; Marcaccini, S.;
Pepino, R. Synthesis 1997, 1389–1390.
J. Org. Chem. Vol. 75, No. 15, 2010 5345

El Kaım et al.
JOCNote
N-(4-Chlorobenzyl)-2-[(4-chlorobenzyl)-(2-isopropyl-6-methyl-
5-phenylethynylpyrimidin-4-yl)amino]-2-(4-fluorophenyl)acetamide
(2a). General procedure for this Sonogashira adduct using 1a
(615 mg, 0.91 mmol), phenylacetylene (120 μL, 1.09 mmol),
dichlorobis(triphenylphosphine)palladium (32 mg, 0.05 mmol),
CuI (9 mg, 0.05 mmol), and diisopropylethylamine (160 μL, 0.91
mmol): Purification by flash chromatography (petroleum
ether-diethyl ether, 60:40) afforded 2a as a yellow oil: yield
65% (385 mg); Rf 0.3 (60:40 petroleum ether/diethyl ether); 1H
NMR (CDCl3, 400 MHz) δ 7.32-7.23 (m, 6H), 7.17-7.15 (m,
4H), 7.10 (d, J = 8.3 Hz, 2H), 6.99-6.91 (m, 6H), 5.91 (s, 1H),
5.29 (d, J=16.9 Hz, 1H), 4.93 (d, J=16.9 Hz, 1H), 4.43 (dd, J=
14.7, 5.8 Hz, 1H), 4.36 (dd, J=14.7, 5.7 Hz, 1H), 2.90 (sept, J=
6.9 Hz, 1H), 2.66 (s, 3H), 1.12 (d, J=6.9 Hz, 3H), 1.08 (d, J=6.9
Hz, 3H); 13C NMR (CDCl3, 100.6 MHz) δ 171.7, 171.2, 170.5,
162.9, 162.8 (d, J =248.1 Hz), 137.5, 136.8, 133.8, 133.0, 131.4
(d, J=8.1 Hz) 131.4 (d, J=2.9 Hz), 131.2, 129.6, 129.2, 129.1,
129.0, 128.7, 128.7, 123.0, 115.8 (d, J = 22.0 Hz), 102.3, 100.5,
84.3, 66.6, 52.4, 43.5, 37.8, 24.5, 21.8, 21.6; IR (ATR) 1664, 1528,
1491, 1430 cm-1; HRMS calcd for C38H33Cl2FN4O 650.2015,
found 650.2024.
133.1, 132.8 (d, J = 3.7 Hz), 131.6 (d, J = 8.1 Hz), 130.5, 129.5,
129.2, 128.7, 128.4, 128.4, 128.3, 115.2 (d, J=20.5 Hz), 112.6, 76.0,
44.8, 43.6, 38.0, 24.1, 22.2, 22.1.
Condition B. To a 0.3 M solution of Sonogashira adduct in
THF was added 0.1 equiv of t-BuOK. The resulting mixture
was stirred until TLC showed no trace of the starting materials.
The solvent was then removed under reduced pressure to afford
5-benzylidene-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidines after
purification by flash column chromatography on silica gel.
5-Benzylidene-7-(4-chlorobenzyl)-6-(4-fluorophenyl)-2-isopropyl-
4-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylic
Acid 4-Chlorobenzylamide (3a-E-Isomer). General procedure for
this benzylidene-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine using
Sonogashira adduct 2a (90 mg, 0.14 mmol) and t-BuOK (2 mg,
0.02 mmol): Purification by flash chromatography (petroleum
ether-diethyl ether, 60:40) afforded E-3a as a colorless oil, yield
80% (72 mg). Z-3a was also isolated in a 20% yield: Rf 0.4 (50:50
petroleum ether/diethyl ether); 1H NMR (CDCl3, 400 MHz) δ
7.40 (dd, JH-H, H-F = 8.6, 5.6 Hz, 2H), 7.37-7.29 (m, 3H),
7.21-7.13 (m, 8H), 7.04 (t, J=8.6 Hz, 2H), 6.94 (d, J=8.3 Hz,
2H), 6.77 (s, 1H), 6.43 (t, J=5.9 Hz, 1H), 4.64 (d, J=15.3 Hz,
1H), 4.36 (dd, J=14.9, 6.3 Hz, 1H), 4.26 (d, J=15.3 Hz, 1H),
4.13 (dd, J=14.9, 5.9 Hz, 1H), 3.05 (sept, J=6.8 Hz, 1H), 1.74
2-[Butyl[2-isopropyl-6-methyl-5-(2-trifluoromethylphenylethynyl)-
pyrimidin-4-yl]amino]-N-(4-methoxybenzyl)acetamide (2h). Gene-
ral procedure for this Sonogashira adduct using 1f (490 mg, 0.96
mmol), 1-ethynyl-2-trifluoromethylbenzene (160 μL, 1.2 mmol),
dichlorobis(triphenylphosphine)palladium (34 mg, 0.05 mmol),
CuI (10 mg, 0.05 mmol), and diisopropylethylamine (170 μL,
0.96 mmol): Purification by flash chromatography (petroleum
ether-diethyl ether, 50:50) afforded 2h as a colorless oil: yield
(s, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H); 13
C
NMR (CDCl3, 100.6 MHz) δ 175.9, 170.5, 168.5, 163.0 (d, J=
249.6 Hz), 158.7, 138.8, 137.8, 137.2, 136.4, 135.2 (d, J=2.9 Hz),
133.8, 133.7, 132.0 (d, J = 8.1 Hz), 130.5, 129.2, 129.2, 129.0,
128.9, 128.8, 128.3, 115.9 (d, J=20.5 Hz), 111.3, 80.8, 46.0, 43.6,
37.9, 25.6, 22.2, 22.0; IR (ATR) 1670, 1569, 1541, 1506, 1492 cm-1
;
1
51% (270 mg); Rf 0.3 (50:50 petroleum ether/diethyl ether); H
HRMS calcd for C38H33Cl2FN4O 650.2015, found 650.1991.
General Procedure for Pyrrolo[2,3-d]pyrimidines. To a 0.2 M
solution of Sonogashira adduct in DMF was added 2.2 equiv of
NaH (95%). The resulting mixture was stirred overnight at
room temperature. The solvent was then removed by extraction,
and the organic phases were collected and concentrated in vacuo
to afford pyrrolo[2,3-d]pyrimidines after purification by flash
column chromatography on silica gel.
NMR (CDCl3, 400 MHz) δ7.70(d,J=7.8 Hz, 1H), 7.61 (d, J=7.8
Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.12 (d,
J=8.3 Hz, 2H), 6.84-6.76(m, 3H), 4.45(s,2H),4.36(d,J=5.8Hz,
2H), 3.87-3.79 (m, 2H), 3.77 (s, 3H), 2.95 (sept, J=6.8 Hz, 1H),
2.60 (s, 3H), 1.68 (m, 2H), 1.32-1.23 (m, 2H), 1.21 (d, J=6.8 Hz,
6H), 0.85 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz) δ
172.7, 171.6, 170.3, 161.9, 159.4, 134.0, 132.1, 131.0 (q, J=30.7 Hz),
130.4, 129.5, 128.6, 126.3 (q, J=5.1 Hz), 124.0 (q, J=273.7 Hz),
121.6 (q, J= 2.9 Hz), 114.4, 97.6, 96.4, 90.5, 55.6, 54.5, 51.4, 43.3,
37.8, 30.5, 24.4, 21.8, 20.4, 14.2; IR (ATR) 1663, 1537, 1515, 1409
cm-1; HRMS calcd for C31H35F3N4O2 552.2712, found 552.2723.
General Procedure for 5-Benzylidene-6,7-dihydro-5H-pyrrolo-
[2,3-d]pyrimidine Derivatives. Conditions A. To a 0.3 M solution
of Sonogashira adduct in methanol was added 0.1 equiv of DBU.
The resulting mixture was stirred until TLC showed no trace of
the starting materials. The solvent was then removed under redu-
ced pressure to afford 5-benzylidene-6,7-dihydro-5H-pyrrolo-
[2,3-d]pyrimidines after purification by flash column chromato-
graphy on silica gel.
7-Butyl-2-isopropyl-4-methyl-5-(2-trifluoromethylbenzoyl)-7H-
pyrrolo[2,3-d]pyrimidine-6-carboxylic Acid 4-Methoxybenzylamide
(3h). General procedure for this pyrrolo[2,3-d]pyrimidine using
Sonogashira adduct 2h (100 mg, 0.18 mmol) and sodium hydride
(10 mg, 0.40 mmol): Purification by flash chromatography
(petroleum ether-diethyl ether, 50:50) afforded 3h as a colorless
oil: yield 88% (88 mg); Rf 0.3 (50:50 petroleum ether/diethyl
ether); 1H NMR (CDCl3, 400 MHz) δ 7.87 (d, J=7.6 Hz, 1H),
7.67 (dd, J=7.6, 7.4 Hz, 1H), 7.59 (dd, J=7.6, 7.4 Hz, 1H), 7.54
(d, J=7.4 Hz, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.5 Hz,
2H), 6.75 (t, J=5.1 Hz, 1H), 4.08 (br s, 2H), 4.49 (t, J=7.3 Hz,
2H), 3.80 (s, 3H), 3.26 (sept, J = 6.8 Hz, 1H), 2.58 (s, 3H),
1.76-1.66 (m, 2H), 1.39 (d, J=6.8 Hz, 6H), 1.32-1.21 (m, 2H),
0.90 (t, J=7.6 Hz, 2H); 13C NMR (CDCl3, 100.6 MHz) δ 190.6,
171.1, 162.9, 160.8, 159.6, 152.2, 139.5, 138.7, 132.2, 132.1,
131.8, 129.8, 128.9 (q, J = 32.2 Hz), 127.8 (q, J = 5.1 Hz),
124.2 (q, J=273.7 Hz), 121.6 (q, J=2.9 Hz), 114.5, 113.1, 55.7,
43.8, 43.5, 37.8, 32.6, 24.9, 22.4, 20.3, 14.0; IR (ATR) 1650, 1548,
1514, 1400 cm-1; HRMS calcd for C31H33F3N4O3 566.2505,
found 566.2500.
5-Benzylidene-7-(4-chlorobenzyl)-6-(4-fluorophenyl)-2-isopropyl-
4-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylic
Acid 4-Chlorobenzylamide (3a-Z-Isomer). General procedure
for this benzylidene-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine
using Sonogashira adduct 2a (110 mg, 0.17 mmol) and DBU
(one drop, 0.02 mmol): Purification by flash chromatography
(petroleum ether-diethyl ether, 50:50) afforded Z-3a as a color-
less oil: yield 91% (100 mg); Rf 0.2 (50:50 petroleum ether/diethyl
1
ether); H NMR (CDCl3, 400 MHz) δ 7.48 (dd, JH-H, H-F
=
8.8, 5.6 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.16 (s, 1H), 7.12-7.08
(m, 5H), 7.06 (d, J=7.8 Hz, 2H), 6.91 (d, J=7.8 Hz, 2H), 6.86 (d,
J=8.4 Hz, 2H), 6.78 (t, J=8.8 Hz, 2H), 6.39 (t, J=6.1 Hz, 1H),
4.66 (d, J=15.6 Hz, 1H), 4.46 (d, J=15.6 Hz, 1H), 4.26 (dd, J=
14.8, 6.6 Hz, 1H), 3.87 (dd, J=14.8, 5.0 Hz, 1H), 3.04 (sept, J=
6.8 Hz, 1H), 2.66 (s, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.30 (d, J=6.8
Hz, 3H); 13C NMR (CDCl3, 100.6 MHz) δ 175.8, 167.8, 165.5,
162.7 (d, J = 248.8 Hz), 157.6, 139.1, 136.9, 136.1, 134.9, 133.8,
Acknowledgment. We thank ICSN for NOESY experi-
ments and the French Ministry of Defense for financial support.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
5346 J. Org. Chem. Vol. 75, No. 15, 2010