Palladium-catalysed coupling of 4-halopyrrolo[2,3-d]pyrimidines with arylacetylenes: Synthesis of a new heterocyclic system - 4H-pyrrolo[2,3,4-de] pyrimido[5′,4′:5,6][1,3]diazepino[1,7-a]indole

Article abstract of DOI:10.1055/s-2004-832820

Palladium-catalysed reaction of methyl 5-amino-4-chloro(or iodo)-7-methyl-2-methylthiopyrrolo[2,3-d]pyrimidine-6-carboxylate with arylacetylenes affords the corresponding 4-(arylethynyl)pyrrolopyrimidines. Reaction of 5-amino-4-iodopyrrolopyrimidine with

Full text of DOI:10.1055/s-2004-832820

LETTER
2327
Palladium-Catalysed Coupling of 4-Halopyrrolo[2,3-d]pyrimidines with
Arylacetylenes: Synthesis of a New Heterocyclic System – 4H-Pyrrolo[2,3,4-
de]pyrimido[5¢,4¢:5,6][1,3]diazepino[1,7-a]indole
C
oupling of 4-
i
H
alopy
g
r
rolo[2,3-
d
]
i
t
ines
w
a
ithArylace
s
tylenes 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 2004
Sonogashira reaction in the pyrrolo[2,3-d]pyrimidine se-
Abstract: Palladium-catalysed reaction of methyl 5-amino-4-chlo-
ro(or iodo)-7-methyl-2-methylthiopyrrolo[2,3-d]pyrimidine-6-car-
boxylate with arylacetylenes affords the corresponding 4-
(arylethynyl)pyrrolopyrimidines. Reaction of 5-amino-4-iodopyr-
ries has not been studied extensively yet. To the best of
our knowledge, there are only few examples of function-
alisation of a pyrrole moiety of pyrrolo[2,3-d]pyrimidine
rolopyrimidine with 2-ethynyl-N-mesylaniline in the presence of via the Sonogashira reaction5 and no work has been done
PdCl2(PPh3)2 and CuI led to the formation of 5-amino-4-(1-me-
sylindol-2-yl)pyrrolopyrimidine which after the removing of mesyl
with pyrrolo[2,3-d]pyrimidines bearing halogeno groups
in a pyrimidine moiety. In this context and as continuation
group cyclised with ethyl orthoformate to give the first representa-
of our ongoing program aimed at the synthesis of the py-
tive of
a novel heterocycle – 4H-pyrrolo[2,3,4-de]pyrimi-
rimidine moiety containing heterosystems6 we report
herein the synthesis of 4-(arylethynyl)pyrrolo[2,3-d]pyri-
midines and implementation of the obtained results for the
synthesis of a novel heterocycle – pyrrolo[2,3,4-de]py-
rimido[5¢,4¢:5,6][1,3]diazepino[1,7-a]indole. The work
was also stimulated by reports that 6-alkenyl and 6-(2-
arylethyl)purines are highly active as cytokinins.7
do[5¢,4¢:5,6][1,3]diazepino[1,7-a]indole.
Key words: palladium, catalysis, arylacetylenes, pyrrolopyrim-
idines, cyclisation, pyrrolo[2,3,4-de]pyrimido[5¢,4¢:5,6][1,3]diaze-
pino[1,7-a]indole
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 alkynyl group introduction into organic molecules
is an important target. For this purpose the Sonogashira
reaction has enjoyed tremendous success because of the
mild reaction conditions and great tolerance of nearly all
types of functional groups.3 As the pyrrolo[2,3-d]pyrimi-
dine heterosystem represents a 7-deazaanalogue of bio-
genic purine it is an important class of compounds
possessing notable biological activities.4 Nevertheless the
An easily available methyl 5-amino-4-chloro-7-methyl-2-
methylthiopyrrolo[2,3-d]pyrimidine-6-carboxylate6b (1a)
reacted with arylacetylenes 2a–c at 60–70 °C in the pres-
ence 10 mol% PdCl2(PPh3)2 and 20 mol% CuI to form the
corresponding 4-(arylethynyl)pyrrolopyrimidines 3a–c in
56–60% yields (Scheme 1).
Although the coupling reactions were carried out under
argon, the Sonogashira reaction between 1a and arylacet-
ylenes was always accompanied by the formation of some
amount of diacetylenes 4. Formation of by-products 4 was
R
X
NH2
NH2
O
O
i
N
N
R
+
+ R
OMe
R
N
OMe
N
MeS
N
MeS
N
Me
Me
1a,b
2a–d
4
3a–d
1a, X = Cl
1b, X = I
Yield
2, 3
R
ii
a
b
c
d
C6H5
60%
60%
56%
62%
4-Me-C6H4
4-F-C6H4
2-NH2-C6H4
Scheme 1 Reagents: i) PdCl2(PPh3)2, PPh3, CuI, Et3N, DMF; ii) 67% HI, Me2CO, r.t., 8 h.
SYNLETT 2004, No. 13, pp 2327–2330
0
3
.1
1
.2
0
0
4
Advanced online publication: 24.09.2004
DOI: 10.1055/s-2004-832820; Art ID: G27404ST
© Georg Thieme Verlag Stuttgart · New York

2328
S. Tumkevicius, V. Masevicius
LETTER
found to depend on the nature of substituent in benzene the formed 4-(2-mesylaminophenylethynyl) derivative 6
ring and solvent. For example, in the reaction of 1a with occurred to give 4-(1-mesyl-2-indolyl)pyrrolopyrimidine
4-fluorophenylacetylene (2c) performed in DMF using 2 (7). This prompted us to develop a one-pot synthesis of 7
equivalents of Et3N only traces of diacetylene were ob- from 4-iodopyrrolopyrimidine (1b): when coupling reac-
served, whereas in the reaction of 1a with 4-methylphe- tion at room temperature between 1b and 2-ethynyl-N-
nylacetylene (2b) under the same reaction conditions the mesylaniline had completed additional amount of CuI was
target compound 3b and the corresponding diacetylene 4 added and the reaction temperature was raised to 50–
were isolated in 60% and 15% yield, respectively.8 More- 60 °C. 4-(1-Mesyl-2-indolyl)pyrrolopyrimidine (7) was
over, the corresponding diacetylene 4 (R = 4-MeC6H4) isolated in 78% yield.14 N-Mesyl derivative 7 was depro-
was obtained as the main reaction product when the reac- tected to give 4-(2-indolyl)pyrrolopyrimidine (5) by heat-
tion was carried out only in Et3N. To synthesise the de- ing with KOH in methanol.15
sired 4-(arylethynyl)pyrrolopyrimidines 3a–c from 1a in
reasonable yields an excess (10 equiv) of acetylenes 2a–c
had to be used. However, synthesis of compound 3d was
Heating 5 with an excess of ethyl orthoformate at 100–
110 °C in the presence of ammonium chloride furnished
methyl 4-methyl-2-methylthio-4H-pyrrolo[2,3,4-de]py-
achieved only from 4-iodo derivative 1b, which was ob-
rimido[5¢,4¢:5,6][1,3]diazepino[1,7-a]indole-5-carboxyl-
tained in 91% yield by the reaction of 1a with 67% hy-
ate (8) – the first representative of a novel heterocyclic
droiodic acid in acetone.9 The best results for the synthesis
1
system.16 In the H NMR spectrum of compound 8 a
3d were obtained when the reaction was carried out in
signal for C7-H appeared at d = 8.48 ppm, while charac-
Et3N and 1.4 equivalents of 2-ethynylaniline (2d), 2 mol%
teristic signals of the NH and NH2 groups, which in the 1H
of PdCl2(PPh3)2 and 20 mol% CuI were used.10
NMR spectrum of compound 5 are correspondingly
Among the most efficient procedures for indole system observed at d = 9.6 ppm and 5.59 ppm, disappears from
1
synthesis are methods starting from 2-ethynylaniline de- the H NMR spectrum. IR spectrum of 8 also does not
rivatives, which can be heteroannulated to deliver indoles contain absorption bands for the amino groups. The 13C
by many types of reagents, among the most frequently NMR and elemental analysis data are consistent with the
used being palladium complexes11 and, more recently, structure of 8.
copper salts.12 However, heating 3d with CuI in DMF at
In summary, we have developed a simple and efficient
100 °C led to a complex reaction mixture from which 4-
synthesis of a novel pentacyclic heterosystem – pyrro-
(2-indolyl)pyrrolo[2,3-d]pyrimidine (5) was isolated only
lo[2,3,4-de]pyrimido[5¢,4¢:5,6][1,3]diazepino[1,7-a]in-
in 6% yield (Scheme 2). On the other hand, electron-with-
dole, containing structural units of indole, pyrrolo[2,3-
drawing groups such as mesyl, acetyl, trifluoroacetyl or
d]pyrimidine and 1,3-diazepine. Work is now in progress
ethoxycarbonyl groups attached to the amino group of 2-
to establish the scope and limitations of this novel route to
ethynylanilines can facilitate their cyclisation into the ap-
the synthetic target 8 as well as application of 4-(arylethy-
nyl)pyrrolopyrimidines for the preparation of 4-alkenyl-
and 4-(2-arylethyl)pyrrolopyrimidines as structural ana-
logues of the naturally occurring and synthetic purines
propriate indoles.13 Therefore, 4-iodopyrrolopyrimidine
(1b) was allowed to react with 2-ethynyl-N-mesylaniline
in the presence of PdCl2(PPh3)2 and CuI at room tempera-
ture. It was noticed that along with the cross-coupling re-
with cytokinin properties.
action of 1b with 2-ethynyl-N-mesylaniline cyclisation of
NHMs
NH
N
Ms
NH2
NH2
NH2
i
iii
O
O
O
N
3 d
N
N
(6%)
(73%)
N
N
OMe
OMe
MeS
N
MeS
N
N
OMe
MeS
N
Me
Me
Me
5
7 (78%)
6
iv
ii
SMe
2
I
3
NH2
1
N
N
12
O
11
4
N
N
Me
10
N
N
OMe
MeS
N
5
N
6
Me
9
8
7
CO2Me
1b
8 (81%)
Scheme 2 Reagents: i) CuI, DMF, 100 °C, 12 h; ii) 1. 2-ethynyl-N-mesylaniline, PdCl2(PPh3)2, CuI, Et3N, DMF, r.t., 3 h, 2. CuI, 50–60 °C,
3 h; iii) KOH, MeOH, reflux, 45 min; iv) HC(OEt)3, NH4Cl, 100–110 °C, 8 h.
Synlett 2004, No. 13, 2327–2330 © Thieme Stuttgart · New York

LETTER
Coupling of 4-Halopyrrolo[2,3-d]pyrimidines with Arylacetylenes
2329
(10) Methyl 5-Amino-4-(2-aminophenylethynyl)-2-methyl-
thiopyrrolo[2,3-d]pyrimidine-6-carboxylate (3d).17
Through a mixture of compound 1b (0.40 g, 1.060 mmol),
CuI (40 mg, 0.210 mmol), PdCl2(PPh3)2 (16 mg, 0.023
mmol) and Et3N (15 mL) was bubbled Ar for 10 min. The
mixture was heated to 50 °C (bath temperature) and then a
solution of acetylene 2d (0.17 g, 1.450 mmol) in Et3N (5 mL)
was added dropwise. The reaction mixture was stirred under
Ar at 55–60 °C for 1 h. The precipitate was filtered off and
recrystallised to give 0.24 g (62%) of compound 3d, mp
227–230 °C (from CHCl3).
Acknowledgment
The work was supported by Lithuanian Science and Study
Foundation, Grant No. T-04220.
References
(1) (a) Modern Acetylene Chemistry; Stang, P. J.; Diederich, F.,
Eds.; VCH: Weinheim, Germany, 1995. (b) Chemistry of
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New York, 1994.
(11) (a) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54,
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Tetrahedron Lett. 1998, 39, 9347. (c) Arcadi, A.; Cacchi,
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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,
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L.; Estevez, R. J. Synlett 2003, 1603.
(13) (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.
(14) Methyl 5-Amino-4-(1-mesylindol-2-yl)-2-methylthio-
pyrrolo[2,3-d]pyrimidine-6-carboxylate (7).
(2) Chemistry and Biology of Naturally-Occurring Acetylenes
and Related Compounds; Lam, J.; Breteler, H.; Arnason, T.;
Hansen, L., Eds.; Elsevier: Amsterdam, 1988.
(3) (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.
(4) (a) Townsend, L. B.; Lewis, A. F.; Roti Roti, L. W. U. S. Pat.
Appl. 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.;
Mavandadi, F.; Kisliuk, R. L.; Queener, S. F. J. Med. Chem.
1999, 42, 2272. (d) 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. (e) Edstrom,
E. D.; Wei, I. J. Org. Chem. 1993, 58, 403.
A mixture of compound 1b (0.24 g, 0.63 mmol), CuI (0.06
g, 0.32 mmol), Et3N (25 mL), DMF (2.5 mL), PdCl2(PPh3)2
(0.045 g, 0.064 mmol) and 2-ethynyl-N-mesylaniline13a
(0.15 g, 0.77 mmol) was stirred under Ar at r.t. for 3 h. Then
CuI (0.18 g, 0.95 mmol) was added and the reaction mixture
was stirred for additional 3 h at 50–60 °C (bath temperature).
The reaction mixture was diluted with H2O and extracted
with Et2O (3 × 70 mL). The combined organic extracts were
dried over Na2SO4, evaporated and purified using dry
column vacuum chromatography19 (eluent: CHCl3). The
solid was recrystallised to give 0.22 g (78%) of compound 7,
mp 197.5–199.0 °C (from 2-PrOH). 1H NMR (300 MHz,
CDCl3): d = 2.60 (s, 3 H, SCH3), 3.71 (s, 3 H, SO2CH3), 3.96
(s, 3 H, NCH3), 4.00 (s, 3 H, OCH3), 5.25 (s, 2 H, NH2), 7.06
(d, J = 0.5 Hz, 1 H, C3¢-H), 7.41–7.35 (m, 1 H, C5¢-H), 7.49
(ddd, J = 1.3 Hz, J6¢-5¢ = 7.3 Hz, J6¢-7¢ = 8.5 Hz, 1 H, C6¢-H),
7.70 (d, J4¢-5¢ = 7.7 Hz, 1 H, C4¢-H), 8.13 (dd, J = 0.6 Hz,
(5) (a) Seela, F.; Zulauf, M. Synthesis 1996, 726. (b) Seela, F.;
Zulauf, M.; Deimel, M. Helv. Chim. Acta 2000, 83, 910.
(6) (a) Susvilo, I.; Brukstus, A.; Tumkevicius, S. Synlett 2003,
1151. (b) Tumkevicius, S.; Sarakauskaite, Z.; Masevicius,
V. Synthesis 2003, 1377. (c) Tumkevicius, S.; Agrofoglio,
L. A.; Kaminskas, A.; Urbelis, G.; Zevaco, T. A.; Walter, O.
Tetrahedron Lett. 2002, 43, 695. (d) Kaminskas, A.;
Dailide, M.; Tumkevicius, S. Polish J. Chem. 2002, 76, 725.
(7) Brathe, A.; Gundersen, L.; Rise, F.; Eriksen, A. B.; Vollsnes,
A. V.; Wang, L. Tetrahedron 1999, 55, 211.
(8) Typical Procedure for the Synthesis of Methyl 5-Amino-
4-(arylethynyl)-2-methylthiopyrrolo[2,3-d]pyrimidine-
6-carboxylates (3a–c).17
Through a mixture of compound 1a6b (0.20 g, 0.70 mmol),
CuI (26 mg, 0.14 mmol), PPh3 (0.10 g, 0.38 mmol),
PdCl2(PPh3)2 (49 mg, 0.07 mmol), Et3N (0.2 mL, 0.14 g,
1.4 mmol) and DMF (3.0 mL) was bubbled Ar for 10 min.
Then 4-methylphenylacetylene (2b) (0.80 g, 6.95 mmol)
was added dropwise at 60–70 °C (bath temperature). The
reaction mixture was stirred at 60–70 °C for 1 h and then
cooled to –5 °C. The precipitate was filtered off, washed
with cold 2-PrOH and purified by chromatography on silica
gel eluting with CHCl3 to give 0.12 g (15%, calculated in
respect of 2b) of di(4-methylphenyl)-1,3-butandiyne (4b),
mp 180–181 °C (from 1-BuOH), Rf = 0.5 (CHCl3), lit.18 mp
183 °C, and 0.15 g (60%) of compound 3b, mp 157.0–
158.5 °C (from MeCN), Rf = 0.4 (CHCl3).
J
7¢-6¢ = 8.4 Hz, 1 H, C7¢-H). 13C NMR (75.4 MHz, CDCl3):
d = 14.4, 31.0, 43.7, 51.5, 104.5, 107.9, 113.9, 114.9, 122.3,
124.2, 126.5, 128.7, 135.1, 136.0, 137.9, 151.4, 153.3,
163.5, 168.1. IR (nujol): 3460, 3361 (NH2), 1677 (CO) cm–1.
Anal. Calcd for C19H19N5O4S2: C, 51.22; H, 4.30; N, 15.72.
Found: C, 51.55; H, 4.36; N, 15,76.
(15) Methyl 5-Amino-4-(indol-2-yl)-2-methylthiopyrrolo[2,3-
d]pyrimidine-6-carboxylate (5).17
A solution of compound 3 (50 mg, 0.11 mmol) in 5% KOH
solution in MeOH (25 mL) was refluxed for 45 min, then
cooled to r.t., poured into H2O and extracted with Et2O.
Extract was dried over Na2SO4 and evaporated. The solid
was recrystallised to give 30 mg (73%) of compound 5, mp
172–174°C (from 2-PrOH).
(9) Methyl 5-Amino-4-iodo-2-methylthiopyrrolo[2,3-
d]pyrimidine-6-carboxylate (1b).17
To a mixture, prepared by slow addition of 67% HI (15 mL)
to acetone (15 mL), compound 1a (1.5 g, 5.23 mmol) was
added. The mixture was stirred for 8 h at r.t., then poured
onto ice (24 g) and 20% NaOH solution (33 mL) was added.
The reaction mixture was stirred for 2–5 h till the colour of
precipitate turned into bright yellow. The solid was filtered,
dried and recrystallised to give 1.8 g (91%) of compound 1b,
mp 160.5–161.0 °C (from 2-PrOH).
(16) Methyl 4-Methyl-2-methylthio-4H-pyrrolo[2,3,4-
de]pyrimido[5¢,4¢:5,6][1,3]diazepino[1,7-a]indole-5-
carboxylate (8).
A mixture of compound 5 (30 mg, 0.08 mmol) and ethyl
orthoformate (10 mL) was heated at 100–110 °C (bath
temperature) for 2 h and NH4Cl (5 mg, 0.09 mmol) was
added. The reaction mixture was heated for additional 6 h
and then cooled to r.t. The precipitate was filtered off,
washed with cold EtOH and recrystallised to give 26 mg
Synlett 2004, No. 13, 2327–2330 © Thieme Stuttgart · New York

2330
S. Tumkevicius, V. Masevicius
LETTER
(84%) of compound 8, mp 267.0–268.5 °C (from DMF). 1H
NMR (300 MHz, CDCl3): d = 2.75 (s, 3 H, SCH3), 4.10 (s, 3
H, NCH3), 4.11 (s, 3 H, OCH3), 7.39 (ddd, J = 0.9 Hz,
J10-9 = 7.3 Hz, J10-11 = 8.0 Hz, 1 H, C10-H), 7.51 (ddd,
J = 1.3 Hz, J9-10 = 7.2 Hz, J9-8 = 8.5 Hz, 1 H, C9-H), 7.73 (d,
J8-9 = 8.3 Hz, 1 H, C8-H), 7.78 (d, J11-10 = 8.0 Hz, 1 H, C11-
H), 8.01 (s, 1 H, C12-H), 8.48 (s, 1 H, C7-H). 13C NMR (75.4
MHz, CDCl3): d = 14.7, 31.4, 52.7, 106.3, 110.8, 113.6,
120.9, 123.2, 124.5, 127.1, 127.9, 128.6, 135.8, 137.1, 140.1,
150.1, 151.0, 162.2, 169.7. IR (nujol): 1694 (CO) cm–1. Anal.
Calcd for C19H15N5O2S: C, 60.47; H, 4.01; N, 18.56. Found:
C, 60.85; H, 3.95; N, 18.24.
(17) Compounds 3a–d, 1b and 5 were fully characterised by IR,
1H NMR, 13C NMR spectroscopy and microanalytical data.
(18) Kunckell, F. Chem. Zentralbl. 1913, 1, 1768.
(19) Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 2431.
Synlett 2004, No. 13, 2327–2330 © Thieme Stuttgart · New York