Synthesis of 4-alkynylpyrrolo[2,3-d]pyrimidines by palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1055/s-2007-990882

The palladium-catalyzed cross-coupling reaction of methyl 5-amino-4-chloro- and 5-amino-4-iodo-7-methyl-2-(methyl-sulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-6- carboxylate with various terminal alkynes has been investigated. The 4-iodo derivative was found to be a good substrate for the synthesis of various 4-alkynylpyrrolopyrimidines. A simple synthesis of 4-(indol-2-yl)pyrrolo[2,3-d] pyrimidines by the reaction of 4-iodopyrrolopyrimidine with 2-ethynyl-N- mesylaniline in the presence dichlorobis(triphenylphosphine)palladium and copper(I) iodide is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990882

PAPER
3815
Synthesis of 4-Alkynylpyrrolo[2,3-d]pyrimidines by Palladium-Catalyzed
Cross-Coupling Reactions
Synthesis of
4
i
g
ylpyrrolo[2,3
i
-
d
]pyr
t
a
s
s Tumkevicius,* Viktoras Masevicius
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: sigitas.tumkevicius@chf.vu.lt
Received 19 July 2007; revised 10 September 2007
tive groups, such as the methylsulfanyl, amino, and ester
groups, that are useful for the functionalization of the mol-
ecule or performing cyclization reactions to give more
complex heterocycles.
Abstract: The palladium-catalyzed cross-coupling reaction of
methyl 5-amino-4-chloro- and 5-amino-4-iodo-7-methyl-2-(methyl-
sulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate with various
terminal alkynes has been investigated. The 4-iodo derivative was
found to be a good substrate for the synthesis of various 4-alky-
nylpyrrolopyrimidines. A simple synthesis of 4-(indol-2-yl)pyrro-
lo[2,3-d]pyrimidines by the reaction of 4-iodopyrrolopyrimidine
with 2-ethynyl-N-mesylaniline in the presence dichlorobis(triphe-
nylphosphine)palladium and copper(I) iodide is described.
Thus, an investigation of the Sonogashira reaction of 1a
was expected to provide information on the tolerance of
the cross-coupling reaction towards groups presented in
the molecule and the possibility of using this reaction for
the synthesis of various 4-alkynylpyrrolo[2,3-d]pyrim-
idines (Scheme 1).
Key words: palladium, alkyne, catalysis, heterocycle, pyrrolopyri-
midine, cyclization
R
Alkynes are versatile intermediates in synthesis1 as well
as an important functional moiety in a wide range of bio-
logically active compounds.2 The development of meth-
ods for the introduction of the alkynyl group into organic
molecules is an important target. For this purpose the So-
nogashira reaction3 has enjoyed tremendous success be-
cause of its mild reaction conditions and great tolerance to
nearly all types of functional groups.4 As the pyrrolo[2,3-
d]pyrimidine heterosystem represents a 7-deaza analogue
of biogenic purine, it is an important class of compounds
possessing notable biological activity.5,6a–e Nevertheless
the Sonogashira reaction in the pyrrolo[2,3-d]pyrimidine
series has not, as yet, been extensively studied.7 To the
best of our knowledge, there are only few examples of the
functionalization of the pyrrole moiety of pyrrolo[2,3-
d]pyrimidine by the Sonogashira reaction6 and no work
has been done with pyrrolo[2,3-d]pyrimidines bearing
halo groups in the pyrimidine moiety. Recently in our
preliminary report,8 we have shown that under the Sono-
gashira reaction conditions 5-amino-4-halo-2-(methyl-
sulfanyl)pyrrolo[2,3-d]pyrimidine-6-carboxylates and
arylacetylenes easily furnish the corresponding cross-cou-
pling products. In the present paper we report a more ex-
tensive study on this palladium-catalyzed reaction with
various terminal alkynes.
R
Cl
NH2
NH2
(2a–c,f)
N
N
PdCl2(PPh3)2
CO2Me
CO2Me
N
N
MeS
N
MeS
N
Me
3a–h
Me
1a
R
+
67% HI, Me2CO
r.t., 8 h
(2a–h)
R
R
PdCl2(PPh3)2
I
4a–h
NH2
N
CO2Me
N
MeS
N
Me
1b
Scheme 1
4-Chloropyrrolopyrimidine 1a reacted with arylacety-
lenes 2a–c at room temperature in N,N-dimethylform-
amide in the presence of 10 mol% dichloro-
bis(triphenylphosphine)palladium and 20 mol% copper(I)
iodide using two equivalents of triethylamine to form the
corresponding 4-(arylethynyl)pyrrolopyrimidines 3a–c in
58–70% yields (method A, Table 1, entries 1–3); the reac-
tion time was 16–28 hours. However the reaction of 1a
with hex-1-yne (2f) or propynol (2h) under these condi-
tions did not give the desired compounds (Table 1, entries
4, 5); full conversion of 1a in the reaction with 2f or 2h
was not achieved even after 48 hours. Performing the re-
action at 60–70 °C and using 0.54 equivalents of triphe-
nylphosphine reduced the conversion time to 1–2 hours
(method B). Although these conditions did not signifi-
cantly affect the yield of 4-(arylethynyl)pyrrolo[2,3-d]py-
rimidines 3a–c (compare entries 1–3 with 6–9) this
procedure allowed 4-hex-1-ynylpyrrolopyrimidine 3f to
be obtained in 65% yield (entry 9). However, reaction of
For the synthesis, methyl 5-amino-4-chloro-7-methyl-2-
(methylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (1a) was
chosen as the starting material. The choice of 1a was
made for several reasons: (1) 1a is easily obtained by a
two-step procedure from 2,4-dichloro-2-(methylsulfa-
nyl)pyrimidine-5-carbonitrile;9 and (2) 1a contains reac-
SYNTHESIS 2007, No. 24, pp 3815–3820
x
x.
x
x
.
2
0
0
7
Advanced online publication: 13.11.2007
DOI: 10.1055/s-2007-990882; Art ID: T11307SS
© Georg Thieme Verlag Stuttgart · New York

3816
S. Tumkevicius, V. Masevicius
PAPER
1a with 2h to give the corresponding 4-alkynylpyrrolopy- equivalents of triethylamine gave only traces of diacety-
rimidine 3h failed (entry 10).
lene 4c, whereas the reaction of 1a with (4-methylphe-
nyl)acetylene (2b) under the same conditions gave the
target compound 3b and the corresponding diacetylene 4b
in 60% and 15% yield, respectively (entry 7). Moreover,
the corresponding diacetylene 4b appeared to be the main
reaction product, and no product of cross-coupling reac-
tion was detected, when the reaction was carried out in tri-
ethylamine (entry 11).
It should be mentioned that in order to achieve 100% con-
version of 1a and to synthesize the desired 4-alkynylpyr-
rolopyrimidines 3a–c,f from 1a in reasonable yields
according to methods A and B an excess (10 equiv) of
alkynes 2a–c,f was used.
Moreover, the Sonogashira reaction between 1a and
alkynes was always accompanied by the formation of an
amount of the diacetylenes 4. Formation of byproducts 4
was found to depend on the nature of alkyne and solvent.
For example, the reaction of 1a with (4-fluorophe-
nyl)acetylene (2c) in N,N-dimethylformamide using two
Since the reaction of 4-chloropyrrolopyrimidine 1a with
some alkynes did not give satisfactory results, 4-iodo de-
rivative 1b, expected to be a more active substrate in the
Sonogashira reaction, was synthesized. Compound 1b
Table 1 Optimization of the Sonogashira Reaction of 4-Chloro- and 4-Iodopyrrolo[2,3-d]pyrimidines 1a,b with Alkynes 2a–h To Give
4-Alkynylpyrrolo[2,3-d]pyrimidines 3a–h
Entry Substrates R
Method CuI
PdCl2(PPh3)2 Alkyne Base, solvent
Temp
(°C)
Time
(h)
Product Yield
(%)
(mol%) (mol%)
(equiv)
1
2
3
4
5
6
1a + 2a
1a + 2b
1a + 2c
1a + 2f
1a + 2h
1a + 2a
Ph
A
A
A
A
A
B
20
20
20
20
20
20
10
10
10
10
10
10
10
Et3N (2 equiv), DMF
Et3N (2 equiv), DMF
Et3N (2 equiv), DMF
Et3N (2 equiv), DMF
Et3N (2 equiv), DMF
r.t.
18
3a
3b
3c
–
65
70
58
–
4-MeC6H4
4-FC6H4
Bu
10
r.t.
16
10
r.t.
28
10
r.t.
48
CH2OH
Ph
10
r.t.
48
–
–
10
Ph3P (0.54 equiv), Et3N
(2 equiv), DMF
60–70
1.25
3a
61
7
8
1a + 2b
1a + 2c
1a + 2f
1a + 2h
4-MeC6H4
4-FC6H4
Bu
B
B
B
B
20
20
20
20
10
10
10
10
10
10
10
10
Ph3P (0.54 equiv), Et3N
(2 equiv), DMF
60–70
60–70
60–70
60–70
1
1.25
2
3b
3c
3f
–
60a
56
65
–
Ph3P (0.54 equiv), Et3N
(2 equiv), DMF
9
Ph3P (0.54 equiv), Et3N
(2 equiv), DMF
10
CH2OH
Ph3P (0.54 equiv), Et3N
(2 equiv), DMF
10
b
b
11
12
13
14
15
16
17
18
19
20
21
1a + 2b
1b + 2a
1b + 2b
1b + 2d
1b + 2e
1b + 2f
1b + 2g
1b + 2f
1b + 2h
1b + 2h
1b + 2h
4-MeC6H4
Ph
20
10
10
20
10
10
10
10
10
10
20
10
2
2
2
2
3
3
3
3
3
6
10
Ph3P (0.54 equiv), Et3N
60–70
55–60
55–60
55–60
55–60
55–60
55–60
r.t.
24
1
–
–
C1
C1
C1
1.5
1.5
1.4
1.5
1.5
2.3
1.5
1.5
10
Et3N
3a
3b
3d
3e
3f
80
72
62
88
79
67
78
31
33
47
4-MeC6H4
2-H2NC6H4
Et3N
1
Et3N
1
2-(EtO2CNH)C6H4 C1
Et3N
1
Bu
C1
C1
C2
C2
C3
D
Et3N
2
SiMe3
Bu
Et3N
1
3g
3f
Et3Nc
3
CH2OH
CH2OH
CH2OH
Et3Nc
r.t.
2.5
1
3h
3h
3h
Et3Nc
r.t.
1.5
Na2CO3 (2 equiv), THF
r.t.
1.5
a Diyne 4 (R = 4-MeC6H4) was isolated in 15% yield.
b Diyne 4 (R = 4-MeC6H4) was the main product (TLC data).
c To increase a solubility of the reaction components, 2–3 drops DMF were added.
Synthesis 2007, No. 24, 3815–3820 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Alkynylpyrrolo[2,3-d]pyrimidines
3817
Table 1, entry 17
was obtained by reaction of 1a with 67% hydroiodic acid
in acetone. The cross-coupling reaction of 4-iodopyrrolo-
pyrimidine 1b with different alkynes proceeded more
smoothly when compared with that of 4-chloropyrrolopy-
rimidine 1a. According to TLC data the formation of
diynes 4 also occurred during the reaction of 1b with
alkynes, but in negligible quantities, thus the use of 1.4–
2.3 equivalents of alkyne was sufficient to achieve full
conversion of 1b. Furthermore, the cross-coupling reac-
tion of 1b with different alkynes to give the corresponding
4-alkynylpyrrolopyrimidines 3a,b,d–g proceeded well
with smaller quantities of copper(I) iodide (10 mol%) and
dichlorobis(triphenylphosphine)palladium (2–3 mol%)
and without the addition of triphenylphosphine (method
C1, entries 12–17). 4-Hex-1-ynylpyrrolopyrimidine 3f
was also obtained from 1b at room temperature (Method
C2, entry 18). Experiments directed to find optimal condi-
tions for the synthesis of 4-(2-hydroxyprop-1-ynyl)pyr-
rolopyrimidine derivative 3h revealed that performing the
reactions at room temperature also gives better results. A
larger excess of prop-2-yn-1-ol shortened the conversion
time of the substrate 1b, but did not affect the yield of 3h
(entries 19, 20). At higher temperatures the cross-cou-
pling reaction of 1b with alkyne 2h proceeded ambigu-
ously. Complex inseparable mixtures of products were
formed. Nevertheless, the best result for the synthesis of
3h was obtained when the reaction was carried out in tet-
rahydrofuran in the absence of triphenylphosphine and us-
ing sodium carbonate as a base (entry 21).
1b
3g
i, 82%
Table 1,
entry 14
NH2
ii
11%
N
3d
CO2Me
N
MeS
N
Me
3i
Scheme 2 Reagents and conditions: (i) KF·2 H2O, dicyclohexano-
18-crown-6, CH2Cl2, r.t., 15 min; (ii) 2-iodoaniline, PdCl2(PPh3)2 (10
mol%), CuI (20 mol%), Et3N, 55–60 °C, 3 h.
appropriate indoles.12 However attempts to cyclize 3e to
N-(ethoxycarbonyl)indolyl derivative 6 failed. In order to
use another electron-withdrawing group, the mesyl group,
4-iodopyrrolopyrimidine 1b was reacted with 2-ethynyl-
N-mesylaniline in the presence of dichlorobis(triphe-
nylphosphine)palladium and copper(I) iodide at room
temperature. It was noticed that together with the cross-
coupling reaction of 1b with 2-ethynyl-N-mesylaniline,
cyclization of the 4-(2-mesylaminophenylethynyl) deriv-
ative 7 occurred to give 4-(1-mesylindol-2-yl)pyrrolopy-
rimidine 8. This prompted us to develop a one-pot, two-
NH
N
Among the most efficient procedures for indole synthesis
are methods starting from 2-ethynylaniline derivatives,
which can be heteroannulated to deliver indoles by many
types of reagents, among the most frequently used being
palladium complexes10 and, more recently, copper salts.11
Since 3d could serve as a key intermediate for the synthe-
sis of the indole moiety in the position 4 of pyrrolopyrim-
idine, it was of interest to examine two possible routes for
the synthesis of 3d from 1b (Scheme 2). In the first route,
4-trimethylsilyl derivative 3g, obtained from 1b as de-
scribed above (Table 1, entry 17), was desilylated to give
4-ethynylpyrrolopyrimidine 3i using potassium fluoride
in the presence of dicyclohexano-18-crown-6. However,
reaction of 3i under the Sonogashira conditions with 2-io-
doaniline gave a complex mixture of products from which
the target compound 3d was isolated only in 11% yield.
Alternatively, 3d was obtained in 62% yield by cross-cou-
pling reaction of 1b with 2-ethynylaniline (2d) using 2
mol% dichlorobis(triphenylphosphine)palladium and 20
mol% copper(I) iodide in triethylamine at 55–60 °C
(Table 1, entry 14).
NH2
N
i
iv
3d
N
N
81%
6%
CO2Me
CO2Me
N
N
MeS
N
MeS
N
5
9
Me
Me
iii
73%
NHMs
NH2
N
Ms
78%
NH2
N
N
CO2Me
CO2Me
N
N
MeS
N
MeS
N
Me
Me
8
7
ii
1b
N
N
EtO2C
MeS
NH2
An attempt to synthesize 4-indolylpyrrolopyrimidine 5 by
reaction of 3d with copper(I) iodide in N,N-dimethylform-
amide at 100 °C led to a complex reaction mixture, from
which the desired compound 5 was isolated only in 6%
yield (Scheme 3).8 It is known that electron-withdrawing
groups such as mesyl, acetyl, trifluoroacetyl, or ethoxy-
carbonyl groups attached to the amino group of 2-ethynyl-
anilines often facilitate their cyclization into the
3e
CO2Me
N
N
Me
6
Scheme 3 Reagents and conditions: (i) CuI (2 equiv), DMF, 100
°C, 12 h; (ii) 1. 2-ethynyl-N-mesylaniline (1.2 equiv), PdCl2(PPh3)2
(10 mol%), CuI (0.5 equiv), Et3N, DMF, r.t., 3 h; 2. CuI (1.5 equiv),
50–60 °C, 3 h; (iii) KOH, MeOH, reflux, 25 min; (iv) HC(OEt)3,
NH4Cl, 100–110 °C, 8 h.
Synthesis 2007, No. 24, 3815–3820 © Thieme Stuttgart · New York

3818
S. Tumkevicius, V. Masevicius
PAPER
mmol), CuI (26 mg, 0.14 mmol), PdCl2(PPh3)2 (49 mg, 0.07 mmol),
Et3N (0.2 mL, 0.14 g, 1.4 mmol), and DMF (3 mL) for 10 min. Then
phenylacetylene (2a, 0.7 g, 6.96 mmol) was added dropwise. The
mixture was stirred at r.t. for 18 h and then cooled to –5 °C. The pre-
cipitate was filtered off, washed with cold i-PrOH and recrystallized
(i-PrOH) to give 3a (0.16 g, 65%); mp 180–181.5 °C.
step synthesis of 8 from 4-iodopyrrolopyrimidine 1b;
when coupling reaction at room temperature between 1b
and 2-ethynyl-N-mesylaniline was complete an additional
amount of copper(I) iodide was added and the reaction
temperature was raised to 50–60 °C. 4-(1-Mesylindol-2-
yl)pyrrolopyrimidine 8 was isolated in 78% yield.8
N-Mesyl derivative 8 was deprotected to give 4-(indol-2-
yl)pyrrolopyrimidine 5 on heating with potassium hy-
droxide in methanol.8
Method B: Argon was bubbled through a mixture of 1a (0.2 g, 0.7
mmol), CuI (26 mg, 0.14 mmol), Ph3P (0.1 g, 0.38 mmol),
PdCl2(PPh3)2 (49 mg, 0.07 mmol), Et3N (0.2 mL, 0.14 g, 1.4 mmol),
and DMF (3 mL) for 10 min. Then phenylacethylene (2a, 0.7 g, 6.96
mmol) was added dropwise at 60–70 °C (bath temperature). The
mixture was stirred at 60–70 °C for 75 min and then cooled to –5
°C. The precipitate was filtered off, washed with cold i-PrOH and
recrystallized (i-PrOH) to give 3a (0.15 g, 61%); mp 180–181.5 °C.
Method C1: Argon was bubbled through a mixture of 1b (0.2 g, 0.53
mmol), CuI (10 mg, 0.054 mmol), PdCl2(PPh3)2 (8 mg, 0.0114
mmol), and Et3N (10 mL) for 10 min. The mixture was heated to 50
°C (bath temperature) and then phenylacetylene (2a, 84 mg, 0.82
mmol) was added dropwise. The mixture was stirred under argon at
55–60 °C for 1 h. After cooling to r.t. the precipitate was collected
by filtration and recrystallized (i-PrOH) to give 3a (0.15 g, 80%);
mp 180–181.5 °C.
Heating 5 with excess ethyl orthoformate at 100–110 °C
in the presence of ammonium chloride furnished methyl
4-methyl-2-(methylsulfanyl)-4H-pyrrolo[2,3,4-de]pyrim-
ido[5¢,4¢:5,6][1,3]diazepino[1,7-a]indole-5-carboxylate
(9), a representative of a fused heterocycle containing the
biologically important pyrrolopyrimidine, 1,3-diazepine,
and indole moieties.8
In conclusion, this investigation provides access to novel
4-alkynylpyrrolo[2,3-d]pyrimidines that are useful pre-
cursors for biologically active compounds and more com-
plex fused heterocycles.
IR (Nujol): 3426, 3331 (NH2), 2211 (C≡C), 1675 cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 2.65 (s, 3 H, SCH3), 3.91 (s, 3 H,
NCH3), 3.95 (s, 3 H, OCH3), 5.63 (s, 2 H, NH2), 7.41–7.52 (m, 3 H,
Ar-H), 7.65–7.68 (m, 2 H, Ar-H).
13C NMR (75 MHz, CDCl3): d = 14.6, 30.8, 51.45, 86.1, 97.1,
106.7, 107.5, 121.1, 129.0, 130.5, 132.5, 136.1, 143.6, 150.7, 163.4,
169.7.
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were run in Nujol mulls or in KBr discs on a Per-
kin-Elmer FTIR spectrophotometer Spectrum BX II. 1H NMR
spectra were recorded with a Varian Unity spectrometer (300
MHz). The MS spectrum was obtained on a LC-ESI-MS spectrom-
eter Agilent 1100 MSD using H2O–MeOH as solvent at 25 °C (pos-
itive scan 50–600 m/z, fragmentator 70 eV). Elemental analyses (C,
H, N) were performed at the Elemental Analysis Laboratory of the
Department of Organic Chemistry of Vilnius University. All reac-
tions and purity of the synthesized compounds were monitored by
TLC using Silica gel 60 F254 aluminum plates (Merck). Visualiza-
tion was accomplished by UV light.
Anal. Calcd for C18H16N4O2S (352.41): C, 61.35; H, 4.58; N, 15.90.
Found: C, 61.22; H, 4.35; N, 15.61.
Methyl 5-Amino-7-methyl-4-[(4-methylphenyl)ethynyl]-2-
(methylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate
(3b)
Following the typical procedures for methods A and C1 gave 3b;
yield: 70% (method A), 72% (method C1); mp 157–158.5 °C
(MeCN).
Synthetic procedures, spectral, and analytical data for methyl 5-
amino-7-methyl-2-(methylsulfanyl)-4-[1-(methylsulfonyl)-1H-in-
dol-2-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (8) and
methyl 4-methyl-2-(methylsulfanyl)-4H-pyrrolo[2,3,4-de]pyrimi-
do[5,¢4¢:5,6][1,3]diazepino[1,7-a]indole-5-carboxylate (9) are de-
tailed in our preliminary report.8
Compound 3b was also obtained using the typical procedure for
method B, using 1a (0.2 g, 0.7 mmol) and (4-methylphenyl)acety-
lene (2b, 0.8 g, 6.95 mmol). The product was isolated as follows:
After cooling the mixture to –5 °C, the precipitate was collected by
filtration, washed with cold i-PrOH and purified by column chro-
matography (silica gel, CHCl3) to give di(4-methylphenyl)buta-1,3-
diyne (4b) (0.12 g, 15%); mp 180–181 °C (BuOH) [Lit.13 183 °C];
Rf = 0.5 (CHCl3); and 3b (0.15 g, 60%); mp 157–158.5 °C (MeCN);
Rf = 0.4 (CHCl3).
Methyl 5-Amino-4-iodo-2-(methylsulfanyl)-7H-pyrrolo[2,3-
d]pyrimidine-6-carboxylate (1b)
To a mixture, prepared by slow addition of 67% HI (15 mL) to
acetone (15 mL), was added 1a9 (1.5 g, 5.23 mmol). The mixture
was stirred at r.t. for 8 h, then poured onto ice (24 g) and 20% NaOH
soln (33 mL) was added. The mixture was stirred for 2–5 h until the
color of precipitate became bright yellow. The solid was filtered,
dried, and recrystallized (i-PrOH) to give 1b (1.8 g, 91%); mp
160.5–161 °C.8
IR (Nujol): 3462, 3352 (NH2), 1681 cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 2.60 (s, 3 H, SCH3), 3.88 (s, 3 H,
NCH3), 3.94 (s, 3 H, OCH3), 5.70 (s, 2 H, NH2).
IR (Nujol): 3435, 3337 (NH2), 2198 (C≡C), 1670 cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H, CH3), 2.66 (s, 3 H,
SCH3), 3.92 (s, 3 H, NCH3), 3.96 (s, 3 H, OCH3), 5.65 (s, 2 H, NH2),
7.25 (d, J3¢-2¢ = 7.9 Hz, 2 H, H3¢, H5¢), 7.56 (d, J2¢-3¢ = 7.9 Hz, 2 H,
H2¢, H6¢).
13C NMR (75 MHz, CDCl3): d = 14.6, 22.0, 30.8, 51.45, 85.7, 97.7,
106.6, 107.4, 118.0, 129.75, 132.5, 136.2, 141.1, 143.9, 150.7,
163.4, 169.7.
13C NMR (75 MHz, CDCl3): d = 14.7, 31.0, 51.5, 107.5, 109.9,
121.6, 136.4, 148.8, 163.3, 168.6.
Anal. Calcd for C19H18N4O2S (366.44): C, 62.28; H, 4.95; N, 15.29.
Found: C, 62.12; H, 4.95; N, 14.90.
Anal. Calcd for C10H11IN4O2S (378.19): C, 31.76; H, 2.93; N,
14.81. Found: C, 31.45; H, 2.85; N, 14.98.
Methyl 5-Amino-4-[(4-fluorophenyl)ethynyl]-7-methyl-2-
(methylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate
(3c)
Methyl 5-Amino-7-methyl-2-(methylsulfanyl)-4-(phenylethy-
nyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (3a); Typical
Procedures
Following the typical procedures for methods A and B gave 3c;
yield: 58% (method A), 56% (method B); mp 193–194.5 °C (i-
Method A: Argon was bubbled through a mixture of 1a (0.2 g, 0.7
Synthesis 2007, No. 24, 3815–3820 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Alkynylpyrrolo[2,3-d]pyrimidines
3819
PrOH).
Methyl 5-Amino-4-hex-1-ynyl-7-methyl-2-(methylsulfanyl)-
7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (3f)
IR (Nujol): 3436, 3343 (NH2), 2205 (C≡C), 1670 cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 2.64 (s, 3 H, SCH3), 3.90 (s, 3 H,
NCH3), 3.94 (s, 3 H, OCH3), 5.60 (s, 2 H, NH2), 7.10–7.17 (m, 2 H,
Ar-H), 7.63–7.70 (m, 2 H, Ar-H).
13C NMR (75 MHz, CDCl3): d = 14.6, 30.8, 51.5, 85.9, 96.0, 106.7,
107.6, 116.5 (d, J3¢-F, J5¢-F = 23.1 Hz, C3¢, C5¢), 117.2, 134.65 (d,
J2¢-F, J6¢-F = 8.5 Hz, C2¢, C6¢), 136.0, 143.5, 150.7, 163.4, 163.9 (d,
J4¢-F = 252.7 Hz, C4¢), 169.7.
Following the typical procedure for methods B, C1 and C2, 3f was
isolated by the following procedure: When the reaction was com-
plete, the solvents were evaporated under reduced pressure and the
residue was purified using dry column vacuum chromatography14
(silica gel 5–40 m, CHCl3) to give 3f; yield: 65% (method B), 79%
(method C1), 78% (Method C2); mp 117–118.5 °C (hexane).
IR (Nujol): 3471, 3344 (NH2), 2223 (C≡C), 1672 cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 0.987 (t, J = 7.27 Hz, 3 H,
CH2CH3), 1.47–1.59 (m, 2 H, CH2CH3), 1.66–1.76 (m, 2 H,
CH2CH2CH3), 2.59 (t, J = 7.13 Hz, 2 H, C≡CCH2), 2.61 (s, 3 H,
SCH3), 3.87 (s, 3 H, NCH3), 3.93 (s, 3 H, OCH3), 5.57 (s, 2 H, NH2).
13C NMR (75 MHz, CDCl3): d = 13.8, 14.5, 19.7, 22.4, 30.4, 30.7,
51.4, 78.3, 100.2, 106.6, 107.0, 136.3, 144.2, 150.7, 163.4, 169.6.
Anal. Calcd for C18H15FN4O2S (370.41): C, 58.37; H, 4.08; N,
15.13. Found: C, 58.12; H, 4.13; N, 14.99.
Methyl 5-Amino-4-[(2-aminophenyl)ethynyl]-7-methyl-2-
(methylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate
(3d)
From 3i and 2-iodoaniline: Argon was bubbled through a mixture
of 2-iodoaniline (44 mg, 0.2 mmol), CuI (7 mg, 0.037 mmol),
PdCl2(PPh3)2 (14 mg, 0.02 mmol), and Et3N (5 mL) for 10 min. The
mixture was heated to 50 °C and 3i (60 mg, 0.22 mmol) was added.
The mixture was stirred at 55–60 °C (bath temperature) for 3 h, then
cooled to r.t. and diluted with CH2Cl2. Solvents were evaporated un-
der reduced pressure and the residue was purified using dry column
vacuum chromatography14 (silica gel 5–40 m, CHCl3) to give 3d (8
mg, 11%); mp 225–228 °C (CHCl3).
Anal. Calcd for C16H20N4O2S (332.43): C, 57.81; H, 6.06; N, 16.85.
Found: C, 58.27; H, 6.00; N, 16.64.
Methyl 5-Amino-7-methyl-2-(methylsulfanyl)-4-[(trimethyl-
silyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (3g)
Following the typical procedure for method C1, with isolation as for
3f; yield: 3g (67%); mp 127–130 °C. Compound 3g was sufficiently
pure to use in the synthesis of 3i; it decomposed partially during
crystallization.
From 1b and 2d by method C1: Alternatively, following the typical
procedure for method C1 using 1b (0.4 g, 1.06 mmol), CuI (40 mg,
0.21 mmol), PdCl2(PPh3)2 (16 mg, 0.023 mmol), and 2-
ethynylaniline10c (2d, 0.17 g, 1.45 mmol) gave 3d (0.24 g, 62%); mp
227–230 °C (CHCl3).
IR (Nujol): 3484, 3398, 3364 (NH2), 2161 (C≡C), 1672 cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 0.33 [s, 9 H, Si(CH3)3], 2.62 (s, 3
H, SCH3), 3.89 (s, 3 H, NCH3), 3.94 (s, 3 H, OCH3), 5.61 (br s, 2 H,
NH2).
13C NMR (75 MHz, CDCl3): d = –0.4, 14.6, 30.7, 51.4, 100.9,
104.6, 106.8, 107.3, 135.9, 143.1, 150.7, 163.3, 169.7.
IR (Nujol): 3491, 3387, 3311, 3214 (2 NH2), 2193 (C≡C), 1699
cm–1 (CO).
MS (ES+): m/z = 349 (M + 1).
1H NMR (300 MHz, CDCl3): d = 2.65 (s, 3 H, SCH3), 3.92 (s, 3 H,
NCH3), 3.95 (s, 3 H, OCH3), 4.50 (s, 2 H, C6H4NH2), 5.64 (s, 2 H,
5-NH2), 6.73–6.79 (m, 2 H, Ar-H), 7.23–7.27 (m, 1 H, Ar-H), 7.43–
7.46 (m, 1 H, Ar-H).
13C NMR (75 MHz, CDCl3): d = 14.6, 30.8, 51.5, 91.6, 94.9, 105.4,
106.5, 107.5, 115.1, 118.4, 132.1, 133.1, 136.0, 143.8, 149.6, 150.7,
163.4, 169.6.
Methyl 5-Amino-4-(3-hydroxyprop-1-ynyl)-7-methyl-2-(meth-
ylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (3h)
Method C2: Argon was bubbled through a suspension of 1b (0.2 g,
0.53 mmol), CuI (10 mg, 0.054 mmol), PdCl2(PPh3)2 (11 mg,
0.0157 mmol), Et3N (4 mL), and DMF (3 drops) for 10 min. Propy-
nol (2h, 45 mg, 0.8 mmol) was added and the mixture was stirred at
r.t. under argon for 2.5 h. The mixture was poured into H2O and the
product was extracted with CH2Cl2. Solvents were evaporated un-
der reduced pressure and the residue was purified using dry column
vacuum chromatography14 (silica gel 5–40 m, CH2Cl2). The ob-
tained product was recrystallized (CHCl3, –5 °C) to give 3h (50 mg,
31%); mp 173–174.5 °C.
Anal. Calcd for C18H17N5O2S (367.42): C, 58.84; H, 4.66; N, 19.06.
Found: C, 58.92; H, 4.67; N, 18.68.
Methyl 5-Amino-4-{[2-(ethoxycarbonylamino)phenyl]ethynyl}-
7-methyl-2-(methylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-6-
carboxylate (3e)
Following the typical procedure for method C1 using 1b (0.45 g,
1.19 mmol), CuI (23 mg, 0.12 mmol), PdCl2(PPh3)2 (18 mg, 0.026
mmol), and ethyl N-(2-ethynylphenyl)carbamate15 (2e, 0.33 g, 1.75
mmol) gave 3e (0.46 g, 88%); mp 179.5–180.5 °C (EtOH).
Method C3: Compound 3h was synthesized analogously to method
C2 with the difference that propynol (10 equiv) was used. The reac-
tion time, 1 h. Yield: 33%; mp 173–174.5 °C (CHCl3).
Method D: To a suspension of 1b (0.1 g, 0.26 mmol), CuI (10 mg,
0.054 mmol), PdCl2(PPh3)2 (11 mg, 0.0157 mmol), and Na2CO3 (56
mg, 0.53 mmol) in THF (5 mL) was added propynol (2h, 22 mg,
0.39 mmol). The mixture was stirred at r.t. under argon for 1.5 h,
then the mixture was filtered through a layer of silica gel (Fluka Sil-
ica Gel 60, Et2O). Et2O was removed, the residue washed with cold
Et2O and recrystallized (CHCl3, –5 °C) to give 3h (38 mg, 47%); mp
173–174.5 °C.
IR (Nujol): 3475, 3364 (NH2), 3165 (OH), 2233 (C≡C), 1672 cm–1
(CO).
1H NMR (300 MHz, CDCl3): d = 2.3 (t, JOH-3 = 6.60 Hz, 1 H, OH),
2.64 (s, 3 H, SCH3), 3.91 (s, 3 H, NCH3), 3.96 (s, 3 H, OCH3), 4.65
(d, J3-OH = 6.60 Hz, 2 H, CH2), 5.59 (s, 2 H, NH2).
IR (KBr): 3487, 3378, 3289 (NH2, NH), 2206 (C≡C), 1739, 1705
cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 1.38 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.67 (s, 3 H, SCH3), 3.92 (s, 3 H, NCH3), 3.96 (s, 3 H, OCH3), 4.30
(q, J = 7.2 Hz, 2 H, CH2), 5.53 (s, 2 H, NH2), 7.11–7.13 (m, 1 H, Ar-
H), 7.47–7.49 (m, 1 H, Ar-H), 7.58–7.61 (m, 2 H, Ar-H, NH), 8.25
(d, J = 8.1 Hz, 1 H, Ar-H).
13C NMR (75 MHz, CDCl3): d = 14.6, 14.8, 30.9, 51.6, 61.9, 92.37,
92.40, 106.9, 108.1, 109.5, 119.0, 123.1, 132.0, 132.9, 135.7, 140.6,
143.1, 150.7, 153.5, 163.3, 169.6.
Anal. Calcd for C21H21N5O4S (439.49): C, 57.39; H, 4.82; N, 15.92.
Found: C, 57.53; H, 5.15; N, 15.58.
13C NMR (75 MHz, CDCl3): d = 14.6, 30.8, 51.5, 51.7, 82.3, 96.0,
106.6, 107.4, 135.9, 142.9, 150.5, 163.4, 169.5.
Synthesis 2007, No. 24, 3815–3820 © Thieme Stuttgart · New York

3820
S. Tumkevicius, V. Masevicius
PAPER
Anal. Calcd for C13H14N4O3S (306.35): C, 50.97; H, 4.61; N, 18.29.
Found: C, 51.20; H, 4.42; N, 18.01.
(2) Chemistry and Biology of Naturally Occurring Acetylenes
and Related Compounds; Lam, J.; Breteler, H.; Arnason, T.;
Hansen, L., Eds.; Elsevier: Amsterdam, 1988.
Methyl 5-Amino-4-ethynyl-7-methyl-2-(methylsulfanyl)-7H-
pyrrolo[2,3-d]pyrimidine-6-carboxylate (3i)
(3) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Sonogashira, K. J. Organomet.
Chem. 2002, 653, 46.
To a soln of 3g (0.5 g, 1.44 mmol) and dicyclohexano-18-crown-6
(0.55 g, 1.48 mmol) in CH2Cl2 (20 mL) was added KF·2H2O (0.35
g, 3.72 mmol). The mixture was stirred at r.t. for 15 min, then
poured into H2O and extracted with CH2Cl2. The solvents were re-
moved from the combined organic extracts under reduced pressure
to give a solid that was washed with Et2O and recrystallized (i-
PrOH) to give 3i (0.33 g, 82%); mp 172–174 °C.
IR (Nujol): 3486, 3440, 3343 (NH2), 2111 (C≡C), 1673 cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 2.62 (s, 3 H, SCH3), 3.65 (s, 1 H,
C≡CH), 3.87 (s, 3 H, NCH3), 3.94 (s, 3 H, OCH3), 5.57 (s, 2 H,
NH2).
(4) (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New
York, 1999. (b) Li, J. K.; Gribble, G. W. Palladium in
Heterocyclic Chemistry; Pergamon: Oxford, 2000.
(5) (a) Townsend, L. B.; Lewis, A. F.; Roti Roti, L. W. US
804601, 1977; Chem. Abstr. 1978, 89, 44130. (b) Porcari,
A. R.; Ptak, R. G.; Borysko, K. Z.; Breitenbach, J. M.;
Vittori, S.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J.
Med. Chem. 2000, 43, 2438. (c) Gangjee, A.; Jain, H. D.;
Phan, J.; Lin, X.; Song, X.; McGuire, J. J.; Kisliuk, R. L. J.
Med. Chem. 2006, 49, 1055. (d) Gangjee, A.; Lin, X.;
Queener, S. F. J. Med. Chem. 2004, 47, 3689. (e) Taylor, E.
C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey, G. B.;
Barredo, J.; Jannatipour, M.; Moran, R. G. J. Med. Chem.
1992, 35, 4450. (f) Edstrom, E. D.; Wei, I. J. Org. Chem.
1993, 58, 403.
13C NMR (75 MHz, CDCl3): d = 14.6, 30.8, 51.5, 80.3, 84.7, 107.0,
107.5, 135.7, 142.3, 150.6, 163.3, 169.6.
Anal. Calcd for C12H12N4O2S (276.32): C, 52.16; H, 4.38; N, 20.28.
Found: C, 51.89; H, 4.51; N, 19.99.
(6) (a) Seela, F.; Zulauf, M. Helv. Chim. Acta 1999, 82, 1878.
(b) Zhang, L.; Zhang, Y.; Li, X.; Zhang, L. Bioorg. Med.
Chem. 2002, 10, 907. (c) Taylor, E. C.; Jennings, L. D.;
Mao, Z.; Hu, B.; Jun, J.-G.; Zhou, P. J. Org. Chem. 1997, 62,
5392. (d) Taylor, E. C.; Chaudhuri, R. P.; Watson, S. E.
Tetrahedron 1999, 55, 1631. (e) Gangjee, A.; Yu, J.;
McGuire, J. J.; Cody, V.; Galitsky, N.; Kisliuk, R. L.;
Queener, S. F. J. Med. Chem. 2000, 43, 3837. (f) Taylor, E.
C.; Young, W. B.; Spanka, C. J. Org. Chem. 1996, 61, 1261.
(g) Hobbs, F. W. J. Org. Chem. 1989, 54, 3420. (h) Seela,
F.; Zulauf, M. Synthesis 1996, 726. (i) Seela, F.; Zulauf, M.;
Deimel, M. Helv. Chim. Acta 2000, 83, 910.
(7) (a) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev.
2003, 103, 1875. (b) Schroter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245.
(8) Tumkevicius, S.; Masevicius, V. Synlett 2004, 2327.
(9) Tumkevicius, S.; Sarakauskaite, Z.; Masevicius, V.
Synthesis 2003, 1377.
(10) (a) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54,
5856. (b) Yu, M. S.; Leon, L. L.; McGuire, M. A.; Botha, G.
Tetrahedron Lett. 1998, 39, 9347. (c) Arcadi, A.; Cacchi,
S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581.
(11) (a) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.;
Perez, M.; Garcia-Martin, M. A.; Gonzalez, J. M. J. Org.
Chem. 1996, 61, 5804. (b) Ma, C.; Liu, X.; Li, X.; Flippen-
Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66,
4525. (c) Reboredo, F. J.; Treus, M.; Estevez, J. C.; Castedo,
L.; Estevez, R. J. Synlett 2003, 1603.
Methyl 5-Amino-4-(1H-indol-2-yl)-7-methyl-2-(methylsulfa-
nyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (5)
Method E: A mixture of 3d (50 mg, 0.14 mmol), DMF (5 mL), and
CuI (52 mg, 0.28 mmol) was stirred at 100 °C for 12 h, then evapo-
rated under reduced pressure to dryness. The residue was purified
by column chromatography (silica gel, CHCl3) to give 5 (3 mg,
6%); mp 172–174 °C (i-PrOH).
Method F:8 To boiling 5% KOH in MeOH (25 mL) was added 8 (50
mg, 0.11 mmol). The mixture was refluxed for 25 min, then cooled
to r.t., poured into H2O and extracted with Et2O. The combined or-
ganic extracts were dried (Na2SO4) and evaporated. The solid was
recrystallized (i-PrOH) to give 5 (30 mg, 73%); mp 172–174 °C.
IR (Nujol): 3428, 3335 (NH2), 1696 cm–1 (CO).
1H NMR (300 MHz, CDCl3): d = 2.69 (s, 3 H, SCH3), 3.96 (s, 3 H,
NCH3), 3.98 (s, 3 H, OCH3), 5.59 (s, 2 H, NH2), 7.20 (ddd, J = 0.9
Hz, J5¢-6¢ = 7.0 Hz, J5¢-4¢ = 7.9 Hz, 1 H, H5¢), 7.35 (ddd, J = 1 Hz,
J
6¢-5¢ = 7.0 Hz, J6¢-7¢ = 8.3 Hz, 1 H, H6¢), 7.52–7.47 (m, 2 H, H3¢,
H7¢), 7.73 (dd, J = 0.7 Hz, J4¢-5¢ = 7.9 Hz, 1 H, H4¢), 9.6 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.6, 31.1, 51.5, 102.8, 107.3,
108.2, 112.0, 120.9, 122.1, 125.0, 128.8, 134.1, 136.3, 137.0, 151.9,
152.8, 163.6, 168.3.
Anal. Calcd for C18H17N5O2S (367.43): C, 58.84; H, 4.66; N, 19.06.
Found: C, 58.54; H, 4.72; N, 19.21.
(12) (a) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata, A.;
Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
1999, 529. (b) Cacchi, S.; Fabrizi, G.; Lamba, D.; Marinelli,
F.; Parisi, L. M. Synthesis 2003, 728.
Acknowledgment
Financial support by Lithuanian Science and Study Foundation
(Grant No. T-04220) is gratefully acknowledged.
(13) Kunckell, F. Chem. Zentralblatt 1913, 1, 1768.
(14) Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 2431.
(15) Forbes, I. T.; Johnson, C. N.; Thompson, M. Synth.
Commun. 1993, 23, 715.
References
(1) (a) Modern Acetylene Chemistry; Stang, P. J.; Diederich, F.,
Eds.; VCH: Weinheim, 1995. (b) Chemistry of Triple-
Bonded Functional Groups; Patai, S., Ed.; Wiley: New
York, 1994.
Synthesis 2007, No. 24, 3815–3820 © Thieme Stuttgart · New York