A novel highly site-selective synthesis of 2,4,7-triarylpyrrolo[2,3-d] pyrimidines by a combination of palladium(0)-, nickel(0)-, and copper(I)-catalyzed cross-coupling reactions

Article abstract of DOI:10.1055/s-0033-1338951

An efficient highly site-selective synthesis of 2,4,7-triarylpyrrolo[2,3-d] pyrimidines from 4-chloro-2-methylthiopyrrolo[2,3-d]pyrimidine has been developed. The proposed synthetic pathway is based on three sequential arylation reactions: Suzuki coupling at position 4 of pyrrolo[2,3-d]pyrimidine, copper(I)-catalyzed N(7)-arylation and nickel(0)-catalyzed desulfitative reaction of 2-methylthio group with aryl Grignard reagents. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338951

LETTER
▌1383
lAetteNr ovel Highly Site-Selective Synthesis of 2,4,7-Triarylpyrrolo[2,3-d]pyrimi-
dines by a Combination of Palladium(0)-, Nickel(0)-, and Copper(I)-Catalyzed
Cross-Coupling Reactions
Synthesis of 2,4,7-Triarylpyrrolo[2,3-d]pyrimidines
Rytis V. Urbonas, Vilius Poskus, Jonas Bucevicius, Jelena Dodonova, Sigitas Tumkevicius*
Vilnius University, Faculty of Chemistry, Department of Organic Chemistry, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: sigitas.tumkevicius@chf.vu.lt
Received: 25.03.2013; Accepted after revision: 25.04.2013
d]pyrimidine scaffold it had some limitations. A major
Abstract: An efficient highly site-selective synthesis of 2,4,7-tri-
drawback of this method is a complicated control of the
arylpyrrolo[2,3-d]pyrimidines from 4-chloro-2-methylthiopyrro-
monocoupling reaction of 2,4-dichloropyrrolo[2,3-d]py-
rimidine with arylboronic acids and low yields of 4-aryl-
lo[2,3-d]pyrimidine has been developed. The proposed synthetic
pathway is based on three sequential arylation reactions: Suzuki
coupling at position 4 of pyrrolo[2,3-d]pyrimidine, copper(I)-cata- 2-chloropyrrolo[2,3-d]pyrimidines. Moreover, the 4-aryl-
lyzed N(7)-arylation and nickel(0)-catalyzed desulfitative reaction
of 2-methylthio group with aryl Grignard reagents.
2-chloropyrrolo[2,3-d]pyrimidine intermediates appeared
to be inert towards arylboronic acids.
Key words: arylation, cross-coupling, heterocycles, transition met-
In this communication we present an alternate and im-
als, catalysis, desulfitative C-arylation
proved method for the synthesis of 2,4,7-triarylpyrro-
lo[2,3-d]pyrimidines starting from an easily accessible 4-
chloro-2-methylthiopyrrolo[2,3-d]pyrimidine (1).6 The
synthetic strategy is based on three orthogonal, and thus
fully chemoselective, reactions. The first one was the C-
arylation at position 4 of pyrrolo[2,3-d]pyrimidine by a
Suzuki coupling. The second reaction involved the cop-
per(I)-catalyzed N-arylation reaction at position 7 of the
heterocycle. The third reaction of choice was the nick-
Pyrrolo[2,3-d]pyrimidine and its aryl- and heteroaryl de-
rivatives display a broad spectrum of biological activities,
such as antimycobacterial,1a antimicrobial,1b inhibition of
protein kinases,1c–f and dihydrofolate reductase,1g antago-
nist effects to receptors,1h,i cytostatic effects.1j,k Some pyr-
rolo[2,3-d]pyrimidine nucleosides bearing fluorescent
subunits were shown to be good substrates for DNA poly-
el(0)-catalyzed Kumada-type cross-coupling reaction that
merases and have found applications for DNA labeling.2
allows substitution of sulfur-containing groups with aryl
Recently, we have shown that oligoarylenes with a pyrro-
moieties.7 The Kumada-type reaction, to the best of our
lo[2,3-d]pyrimidine core exhibit strong UV-blue fluores-
knowledge, has not been employed for the arylation of a
cence and are promising candidates as fluorescent
pyrrolopyrimidine moiety thus far.
functional materials.3 Therefore, introduction of different
Initially, introduction of aryl moieties into pyrrolo[2,3-
aryl functionalities at various positions of pyrrolo[2,3-
d]pyrimidine using compound 1 as starting material was
d]pyrimidine is highly warranted and important for the
attempted. However, neither C-arylation nor N-arylation
synthesis of combinatorial libraries of compounds and
reaction of 1 gave desirable results.
tuning of structure and photophysical properties of the
pyrrolo[2,3-d]pyrimidine derivatives as well.
For example, N-arylation of 1 with iodobenzene in the
presence of CuI, trans-cyclohexane-1,2-diamine, and
K3PO4 gave 4-chloro-2-methylthio-7-phenylpyrrolo[2,3-
d]pyrimidine in only 23% yield. Therefore, the N(7)-posi-
tion of pyrrolo[2,3-d]pyrimidine was protected with a Boc
group by the reaction of 1 with Boc2O in the presence of
DMAP and DIPEA to give compound 2 in 95% yield8
(Scheme 1). N-Boc derivative 2 easily reacted with the se-
lected arylboronic acids in the presence of Pd(OAc)2,
P(2-biPh)Cy2, and K3PO4 as catalyst system to afford the
corresponding 4-arylpyrolo[2,3-d]pyrimidines 3a–c in
reasonable yields9 (Table 1, entries 1–3).
One of the most efficient approaches for the introduction
of aryl groups into heteroaromatic scaffolds that does not
involve the preparation of specific intermediates needed
in the synthesis via cyclization procedures is arylation us-
ing metal-catalyzed cross-coupling reactions.4 However,
methods of site-selective arylation reactions in a pyrro-
lo[2,3-d]pyrimidines series have been insufficiently ex-
plored. Recently, we reported on the synthesis of 2,4,7-
triarylpyrrolo[2,3-d]pyrimidines by a combination of pal-
ladium(0)- and copper(I)-catalyzed cross-couplings of
2,4-dichloropyrrolo[2,3-d]pyrimidine with arylboronic
acids and aryl halogenides, respectively.5 Although the
proposed method allowed the introduction of different
aryl groups into positions 2, 4, and 7 of the pyrrolo[2,3-
After deprotection of 3a–c with TFA at room
temperature10 the 4-arylpyrrolopyrimidines 4a–c so ob-
tained (Table 1, entries 4–6) were allowed to react with
aryl halogenides to give 4,7-diaryl-2-methylthiopyrrolo
[2,3-d]pyrimidines 5a–g11 in good to excellent yields
(Table 2).
SYNLETT 2013, 24, 1383–1386
Advanced online publication: 06.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338951; Art ID: ST-2013-D0264-L
© Georg Thieme Verlag Stuttgart · New York

1384
R. V. Urbonas et al.
LETTER
Finally, in the case of compounds 5a,c,d the nickel(0)-cat-
alyzed Kumada-type coupling has been studied. It was
found that 2-methylthiopyrrolopyrimidines 5a,c,d easily
Cl
N
Ar1
Cl
N
i
ii
N
N
N
N
N
N
N
MeS
MeS
MeS
H
Table 1 Preparation of 4-Aryl-2-methylthiopyrrolo[2,3-d]pyrimi-
dines 3a–c and 4a–c
Boc
Boc
1
2
3a–c
iii
Entry
Compound
Ar1
Yield (%)
Ar1
Ar1
N
Ar1
1
2
3
4
5
6
3a
3b
3c
4a
4b
4c
Ph
83
87
68
86
99
74
iv
MeS
v
N
N
N
4-PhC6H4
4-MeOC6H4
Ph
N
N
N
Ar2
Ar3
N
N
Ar2
MeS
H
5a–g
6a–h
4a–c
Scheme 1 Reagents and conditions: i) Boc2O, DMAP, DIPEA,
CH2Cl2, r.t.; ii) Ar1B(OH)2, Pd(OAc)2, P(2-biPh)Cy2, K3PO4, 1,4-di-
oxane, reflux, argon; iii) TFA, CH2Cl2, r.t.; iv) CuI, Ar2I(Br), trans-
cyclohexane-1,2-diamine, 1,4-dioxane, reflux, argon; v) Ar3MgBr,
NiCl2(dppp), THF, r.t., argon.
4-PhC6H4
4-MeOC6H4
Table 2 Preparation of 4,7-Diaryl-2-methylthiopyrrolo[2,3-d]py-
rimidines 5a–g
reacted with an excess of arylmagnesium halogenides in
THF at room temperature in the presence of NiCl2(dppp)
to afford the title 2,4,7-triarylpyrrolo[2,3-d]pyrimidines
6a–h12 (Table 3).
Entry Compound 5 Ar1
Ar2
Yield (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
Ph
99
84
82
89
71
94
71
In summary, starting with 4-chloro-2-methylthiopyrro-
lo[2,3-d]pyrimidine we have developed a new protocol
for the synthesis of 2,4,7-triarylpyrrolo[2,3-d]pyrimidines
based on a sequential Suzuki, N-arylation, and nickel-cat-
alyzed reactions. The protocol allows the introduction of
different aryl groups into the positions 2, 4, and 7 of the
pyrrolo[2,3-d]pyrimidine moiety and to obtain 2,4,7-tri-
arylpyrrolo[2,3-d]pyrimidines in good yields. The combi-
nation of the palladium-, nickel-catalyzed cross-coupling
and N-arylation reactions makes it a powerful alternative
Ph
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-Ph2NC6H4
4-CNC6H4
Ph
4-PhC6H4
4-PhC6H4
4-PhC6H4
4-PhC6H4
4-MeOC6H4
5g
Table 3 Preparation of 2,4,7-Triarylpyrrolo[2,3-d]pyrimidines 6a–h
Entry
1
Compound 6 Ar1
Ar2
Ar3
Reaction time (h) Yield (%)
6a
6b
6c
6d
Ph
Ph
Ph
Ph
Ph
1.5
2
92
83
83
90
Me
2
3
4
Ph
Ph
Ph
1.5
1
F
Me
5
6e
Ph
Ph
2
87
Me
Me
6
7
8
6f
Ph
2
2
2
79
62
40
Me
6g
6h
MeO
Ph
Synlett 2013, 24, 1383–1386
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,4,7-Triarylpyrrolo[2,3-d]pyrimidines
1385
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regio- and chemoselectivities. Further optimization of
nickel-catalyzed desulfitative C2-arylation of pyrro-
lo[2,3-d]pyrimidines with Grignard reagents bearing re-
acting groups and study of photoluminescent properties of
the synthesized compounds with estimation of the fluores-
cence quantum yields and decay times is currently being
carried out, and the results will be reported in due course.
Acknowledgment
The study was funded from the European Community’s social foun-
dation under Grant Agreement No. VP1-3.1-ŠMM-08-K-01-
004/KS-120000-1756.
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(8) 7-(tert-Butoxycarbonyl)-4-chloro-2-methylthio-7H-
pyrrolo[2,3-d]pyrimidine (2)
To a solution of 1 (100 mg, 0,50 mmol) in anhyd CH2Cl2 (2
mL) DIPEA (77.4 mg, 0.60 mmol), DMAP (12.2 mg, 0.10
mmol), and Boc2O (164 mg, 0,752 mmol) was added. The
reaction mixture was stirred at r.t. for 30 min. After
evaporation of CH2Cl2 the residue was dissolved in CHCl3
and filtered through a layer of silica gel. After evaporation of
the CHCl3 the solid was recrystallized to give 142 mg (95%)
of compound 2; mp 104–105 °C (from 2-PrOH). IR (KBr):
ν = 1748 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.71
[s, 9 H, C(CH3)3], 2.67 (s, 3 H, SCH3), 6.57 (d, J = 4 Hz, 1
H, 5-H), 7.61 (d, J = 4 Hz, 1 H, 6-H). 13C NMR (75 MHz,
CDCl3): δ = 14.9, 28.4, 85.8, 103.1, 116.3, 126.2, 147.9,
152.7, 152.8, 167.6. Anal. Calcd for C12H14ClN3O2S: C,
48.08; H, 4.71; N, 14.02. Found: C, 48.07; H, 4.73; N, 13.68.
(9) Representative Procedure for the Preparation of 4-Aryl-
7-tert-butoxycarbonyl-2-methylthio-7H-pyrrolo[2,3-
d]pyrimidines 3a–c
Compound 3a: A solution of 2 (100 mg, 0.33 mmol) in
anhyd dioxane (2 mL) was flushed with argon and 2-
biphenyldicyclohexylphosphine (4 mol%) and Pd(OAc)2 (2
mol%) were added. The mixture was stirred for 10 min, then
phenylboronic acid (48.8 mg, 0.4 mmol) and K3PO4 (169.8
mg, 0.8 mmol) were added under argon flow, and the
reaction mixture was refluxed for 1 h. After cooling the
solvent was removed to dryness, the residue dissolved in
H2O (5 mL), and the solution obtained was extracted with
CHCl3. The extract was dried over Na2SO4, filtered, and the
CHCl3 was removed on the rotary evaporator. The residue
was purified by column chromatography (eluent CHCl3) to
give 93.5 mg (83%) of compound 3a; mp 82.5–83 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.72 [s, 9 H, C(CH3)3], 2.73
(s, 3 H, SCH3), 6.78 (d, J = 4 Hz, 1 H, 5-H), 7.52–7.54 (m, 3
H, ArH), 7.62 (d, J = 4 Hz, 1 H, 6-H), 8.05 (d, J = 9 Hz, 2 H,
ArH). 13C NMR (75 MHz, CDCl3): δ = 14.9, 85.2, 104.3,
125.9, 129.0, 129.2, 130.6, 137.5, 148.4, 153.8, 158.6,
167.4. Anal. Calcd for C18H19N3O2S: C, 63.32; H, 5.61; N,
12.31. Found: C, 62.95; H, 5.63; N, 12.03.
(4) (a) Anctil, E. J.-G.; Snieckus, V. In Metal-Catalyzed Cross-
Coupling Reactions; Vol. 2; de Meiejere, A.; Diederich, F.,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1383–1386

1386
R. V. Urbonas et al.
LETTER
103 °C. 1H NMR (300 MHz, CDCl3): δ = 2.70 (s, 3 H,
SCH3), 6.92 (d, J = 4 Hz, 1 H, 5-H), 7.40 (t, J = 8 Hz, 1 H,
ArH), 7.47 (d, J = 4 Hz, 1 H, 6-H), 7.53–7.62 (m, 5 H, ArH),
7.84 (d, J = 8 Hz, 2 H, ArH), 8.18 (d, J = 8 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 14.8, 102.6, 113.6, 123.8,
126.9, 127.3, 129.0, 129.3, 129.6, 130.5, 137.9, 138.1,
152.7, 158.4, 165.5. ESI-HRMS: m/z [M + H]+ calcd for
C19H16N3S: 318.1059; found: 318.1056.
(10) Representative Procedure for the Preparation of 4-Aryl-
2-methylthio-7H-pyrrolo[2,3-d]pyrimidines 4a–c
Compound 4a: To a solution of 3a (270 mg, 0.79 mmol) in
anhyd CH2Cl2 (5 mL) TFA (8.5 mL, 114.6 mmol) was
added. The reaction mixture was stirred for 30 min, then
concentrated to dryness under reduced pressure. H2O was
added to the residue, and the solid obtained was
recrystallized to give 165 mg (86%) of compound 4a; mp
221–222 °C (from 2-PrOH). 1H NMR (300 MHz, CDCl3 +
DMSO-d6): δ = 2.59 (s, 3 H, SCH3), 6.66 (dd, J = 4, 2 Hz, 1
H, 5-H), 7.21 (dd, J = 4, 2 Hz, 1 H, 6-H), 7.44–7.51 (m, 3 H,
ArH), 8.08 (d, J = 8 Hz, 2 H, ArH), 11.69 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3 + DMSO-d6): δ = 14.8, 100.6,
112.3, 125.9, 129.0, 129.1, 130.4, 138.4, 154.3, 156.8,
163.6. ESI-HRMS: m/z [M + H]+ calcd for C13H12N3S:
242.0746; found: 242.0745.
(12) Representative Procedure for the Preparation of 2,4,7-
Triaryl-7H-pyrrolo[2,3-d]pyrimidines 6a–h
Compound 6f: To a suspension of 5c (100 mg, 0.25 mmol)
and NiCl2(dppp) (5 mol%) in anhyd THF (2 mL) a solution
of PhMgBr prepared from bromobenzene (0.13 mL, 1.24
mmol) and Mg (31 mg, 1.3 mmol) in anhyd THF (1 mL) was
added under stirring and argon flow. For activation of
magnesium 1,2-dibromoethane (0.005 mL, 0.06 mmol) was
used. The reaction mixture was stirred at r.t. for 2 h. Then
poured into 15% NH4Cl aq solution (15 mL) and extracted
with CHCl3. The extract was dried over Na2SO4. After
evaporation of CHCl3 the residue was purified by column
chromatography using a mixture CHCl3–hexane (2:1) as an
eluent to give 86 mg (79%) of compound 6f; mp 232–
233 °C. 1H NMR (300 MHz, CDCl3): δ = 2.51 (s, 3 H, CH3),
7.06 (d, J = 4 Hz, 1 H, 5-H), 7.42–7.55 (m, 3 H, ArH), 7.60
(d, J = 4 Hz, 1 H, 6-H), 7.86 (m, 2 H, ArH), 8.42 (d, J = 8
Hz, 2 H, ArH), 7.57–7.88 (m, 9 H, ArH), 8.73 (d, J = 8 Hz,
2 H, ArH). 13C NMR (75 MHz, CDCl3): δ = 21.4, 102.2,
115.1, 124.0, 127.5, 127.7, 128.0, 128.5, 128.6, 129.1,
129.2, 129.8, 130.0, 130.2, 135.6, 136.8, 137.8, 139.1,
140.9, 143.1, 152.9, 157.4, 158.5. ESI-HRMS: m/z [M + H]+
calcd for C31H24N3: 438.1965; found: 438.1956.
(11) Representative Procedure for the Preparation of 4,7-
Diaryl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidines 5a–g
Compound 5a: To a solution of 4a (100 mg, 0.41 mmol) in
anhyd dioxane (2 mL) CuI (1 mol%), K3PO4 (154 mg, 0,72
mmol), iodobenzene (71.4 mg, 0,35 mmol), and trans-
cyclohexane-1,2-diamine (10 mol%) were added. The
reaction mixture was refluxed for 4 h. Then every hour CuI
(1.0 mol%) was added to the mixture until the total amount
of CuI reached 10 mol%. The total reaction time was 13 h.
Then, after cooling to r.t., EtOAc (5 mL) was added to the
reaction mixture and the resulting solution was filtered
through a layer of silica gel, eluting with EtOAc. The filtrate
was concentrated under reduced pressure, and the residue
was purified by column chromatography using CHCl3 as
eluent to give 110 mg (99%) of compound 5a; mp 102–
Synlett 2013, 24, 1383–1386
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