Thiophenol mediated radical cyclization: An expedient approach to 2H-pyrrolo[3,2-d]pyrimidines (9-deazaxanthine analogs)

Article abstract of DOI:10.1016/j.tetlet.2010.07.163

A new efficient route for the synthesis of substituted 2H- pyrrolopyrimidines (9-deazaxanthine analogs) via thiophenol mediated radical cyclization has been achieved. The stereochemistry of the newly synthesised compounds has been settled from NOE data.

Full text of DOI:10.1016/j.tetlet.2010.07.163

Tetrahedron Letters 51 (2010) 5273–5276
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thiophenol mediated radical cyclization: an expedient approach
to 2H-pyrrolo[3,2-d]pyrimidines (9-deazaxanthine analogs)
*
K. C. Majumdar , Shovan Mondal, Debankan Ghosh
Department of Chemistry, University of Kalyani, Kalyani 741 235, WB, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new efficient route for the synthesis of substituted 2H-pyrrolopyrimidines (9-deazaxanthine analogs)
via thiophenol mediated radical cyclization has been achieved. The stereochemistry of the newly syn-
thesised compounds has been settled from NOE data.
Received 16 May 2010
Revised 26 July 2010
Accepted 29 July 2010
Available online 5 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Uracil
Thiophenol
Radical cyclization
9-Deazaxanthine
Pyrimidines, being an integral part of DNA and RNA, exhibit
diverse pharmacological properties as effective bactericides,
fungicides, viricides, insecticides, and medicides.1–3 Numerous
pyrimidine and uracil-based molecules,4 for example, 30-azido-
30-deoxythymidine (AZT), 20,30-dideoxycytidine (DDC), (E)-5-[2-
(bromovinyl)-20-deoxyuridine] (BVDU), active against cancer
and AIDS viruses,5 have already been synthesised. Particularly,
pyrrolo[3,2-d]pyrimidines (9-deazaxanthines) are important due
to their proven biological activity and medicinal utility. 9-Deazax-
anthines showed structure-activity relationships that are similar
to those of xanthines. They were shown to be more or less
equipotent to the corresponding xanthines at A2a adenosine recep-
tors. 9-Deazaxanthines are generally at least 2–3-fold more potent
than xanthines at A1 receptors and, therefore, exhibit higher A1
selectivities compared to the xanthines.6 Moreover, pyrrolopyrimi-
dine ring system has aroused considerable interest due to its
presence in several natural products like toyocamycin, sangivamy-
cin, tubercidin etc.7,8
C6H5
(C6H5CO)2O2
O
O
O
R'
NH2
R'
NH2
H
R'
NH2
N
N
N
O
N
R
O
N
R
O
N
R
3
C6H5
1
2
O
O
O
H
N
H
H
H
R'
R'
R'
N
N
H
N
N
N
H
+
O
N
R
O
N
R
O
N
R
6
5
4
On the other hand, free radical cyclization is regarded as a
versatile route for the construction of carbocycles as well as het-
erocycles.9 In particular; the formation of C–S bonds by the inter-
H
molecular addition of S-centerd radicals to
p-systems is a major
O
challenge in organic synthesis. Intermolecular addition of radicals
to terminal alkynes offers an attractive strategy for the generation
of alkenyl radicals10 and thiophenol11 is a very efficient reagent for
this purpose. Moreover, during the cyclization process a phenylthio
moiety is incorporated into the final cyclized products, which is
H
R'
N
N
O
N
R
7
* Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582 8282.
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
Scheme 1. Synthesis of 9-deazaxanthines by benzoyl peroxide mediated radical
cyclization.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.163

5274
K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 5273–5276
O
N
R2
O
N
R2
R1
O
NH
R1
O
N
O
Me
N
O
Me
N
nOe
H
nOe
H
(i)
N
N
Me
O
Me
O
N
N
H
H
H
SPh
R
8a-f
R
9a-f
N
N
Me
SPh
Me
H
a, R = R1 = R2 = Me, 95%
b, R = R1 = Me, R2 = Et, 93%
c, R = R1 = Et, R2 = Me, 91%
d, R = R1 = R2 = Et, 90%
R = Et, R = Me, R = Me, 92%
R = Et, R = Me, R = Et, 94%
a, R = R1 = R2 = Me
(E)-trans configuration
(Z)-cis configuration
b, R = R1 = Me, R2 = Et
c, R = R1 = Et, R2 = Me
d, R = R1 = R2 = Et
1
2
1
2
e,
f,
e,
f,
R = Et, R = Me, R = Me
1
2
1
2
R = Et, R = Me, R = Et
Scheme 2. Synthesis of precursors 9a–f. Reagents and conditions: (i) propargyl
bromide, K2CO3, acetone, reflux, 10–12 h.
particularly
attractive
for
further
transformation/
functionalization.11b,11c
In our previous report12 we have published a new synthetic
route for the synthesis of substituted 9-deazaxanthines in excel-
lent yields via aza-Claisen rearrangement followed by benzoyl per-
oxide mediated radical cyclization which is shown in Scheme 1.
Therefore, in continuation of our work in radical chemistry and
the synthesis of biologically active heterocycles,13 we became
interested in the synthesis of novel pyrrolo[3,2-d]pyrimidine
(9-deazaxanthine derivatives) via thiophenol mediated radical
cyclization and herein we report our results.
The requisite starting materials for our study, 9a–f were syn-
thesised in 90–95% yield by refluxing various substituted 5-amino
uracil derivatives 8a–f and propargyl bromide in dry acetone-
K2CO3 for 10–12 h. The amino uracil derivatives 8a-f were in turn
prepared from the bromouracil derivatives according to our earlier
published procedure.13g The synthetic route of the aforesaid pre-
cursors is shown in Scheme 2.
The thiophenol mediated cyclization was then carried out with
9a under standard conditions [PhSH (2 equiv), AIBN (1.5 equiv)] in
dry benzene for 2 h to afford compound 10a in only 30% yield along
with the depropargylated product 8a in 60% yield. Therefore to
establish the optimized conditions of the radical cyclization we
have performed a series of experiments where sequential changes
were made to the radical initiator, amount of thiophenol and the
solvent used. Very slow addition of PhSH (2 equiv) and use of AIBN
(1.5 equiv) as radical initiator in refluxing t-butanol afforded the
cyclized product 10a14 as a white solid, mp 114–116 °C in 65%
yield along with some depropargylated product 8a (25%). The opti-
mization results are shown in Table 1.
Figure 1. nOe of compound 10a.
the methylene proton (–NCH2) at d = 4.15 ppm and the –N–CH3
proton at d = 3.79 ppm. There is no nOe correlation between the
methylene proton (–NCH2) at d = 4.15 ppm with the exocyclic pro-
ton at d = 6.63 ppm (Fig. 1).
Encouraged by this result, the other substrates 9b–f were sim-
ilarly treated to give 10b–f in 60–63% yields. The results are sum-
marized in Table 2.
The configuration of the exocyclic double bond in 10a was
found to be trans on the basis of only nOe correlation between
A
probable mechanistic rationalization of the thiophenol
mediated radical reaction is shown in Scheme 3. The formation
Table 1
Optimization of the radical cyclization of 9aa
O
Me
N
O
Me
N
O
N
Me
NH
Me
O
Me
O
Me
O
N
N
N
+
SPh
N
N
Me
9a
Me
H
Me
8a
10a
Entry
Reaction conditions
Time (h)
10a (%)
8a (%)
1
2
3
4
5
PhSH (2 equiv), AIBN (1.5 equiv), benzene, reflux
2
30
—
30
65
62
60
65
30
25
25
PhSH (2 equiv), benzoyl peroxide (1.5 equiv), benzene, reflux
PhSH (1.5 equiv), benzoyl peroxide (1.2 equiv), t-BuOH, reflux
PhSH (2 equiv), AIBN (1.5 equiv), t-BuOH, reflux
1.5
1.5
2
PhSH (4 equiv), AIBN (3 equiv), t-BuOH, reflux
2
a
All the reactions were carried out under nitrogen atmosphere.

K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 5273–5276
5275
O
R2
N
O
R2
N
O
R2
N
R1
O
R1
O
R1
O
N
N
4-exo-trig
N
N
R
N
R
N
R
SPh
SPh
SPh
12
11
9
5-endo-trig
R2
N
O
R2
N
O
O
R2
N
R1
R1
O
R1
O
-H
N
N
N
SPh
SPh
SPh
O
N
R
14
N
R
N
R
H
H
13
10
Scheme 3. Probable mechanistic path for the formation of 9-deazaxanthines 9.
of the products 10 from 9 may be explained by the generation of
alkenyl radical 11 by radical addition of thiophenol to the terminal
alkyne 9. The alkenyl radical 11 may undergo either a 4-exo-trig or
a 5-endo-trig cyclization at the double bond of the uracil moiety. A
5-endo-trig cyclization of radical 11 may produce the inter-
mediate radical 14, while 4-exo-trig cyclization may give the
spiroheterocyclic radical 12, followed by neophyl rearrangement
of 12 to radical intermediate 13. Oxidative elimination of a hydro-
gen from 14 may afford 10.
In conclusion, we have successfully achieved a practical method
for the synthesis of 2H-pyrrolo[3,2-d]pyrimidine (9-deazaxanthine
analogs) derivatives. We are continuing this work to extend the
scope of this methodology to the synthesis of other bio-active het-
erocycles and the results will be communicated in due course.
Table 2
2H-Pyrrolo[3,2-d]pyrimidine derivatives
Acknowledgments
Entry
1
Precursors
Products
Yields (%)
O
Me
N
O
Me
We thank DST (New Delhi) and CSIR (New Delhi) for financial
assistance. Two of us (S.M. and D.G.) are thankful to CSIR (New Del-
hi) for Senior and Junior research fellowships respectively.
Me
N
Me
O
N
N
65
O
N
N
References and notes
9a Me
Me
SPh
SPh
SPh
SPh
SPh
SPh
10a
H
O
N
Et
N
O
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2
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62
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N
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9b
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10b Me
H
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H
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O
N
O
N
Et
Et
9d
10d
H
O
Me
N
O
Me
Me
Me
O
N
N
N
O
N
N
9e Et
10e Et
H
O
N
Et
N
O
N
Et
Me
O
Me
O
N
N
N
9f
Et
10f Et
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K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 5273–5276
Almendros, P.; Aragoncillo, C. J. Org. Chem. 2001, 66, 1612; (d) Beaufils, F.;
thiophenol (0.97 mmol, 0.1 mL) in dry t-butanol (3 mL) was added dropwise to
a solution of compound 9a (0.48 mmol, 100 mg) and radical initiator AIBN
(0.72 mmol, 119 mg) in refluxing anhydrous t-butanol (3 mL) under a nitrogen
atmosphere for a period of 1 h and then the reaction mixture was further
refluxed for 2 h. The solvent was removed under reduced pressure. The residue
was dissolved in CH2Cl2 (10 mL) and stirred with saturated NaHCO3 solution
(10 mL) for 2 h. The aqueous layer was extracted with CH2Cl2 (3 ꢀ 15 mL) and
the combined organic extracts were washed with water (2 ꢀ 15 mL), brine
solution (10 mL) and dried (Na2SO4). The solvent was evaporated under
reduced pressure. The crude product was purified by silica gel column
chromatography using 10% EtOAc/Pet. ether as eluent to afford the
2H-pyrrolo[3,2-d]pyrimidine derivative 10a (99 mg, 65%) as a white solid.
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14. General procedure for the synthesis of 2H-pyrrolo[3,2-d]pyrimidine derivatives 10
(a–f) by thiophenol-mediated radical cyclization: A deoxygenated solution of
Compound 10a: white solid, mp 114–116 °C; yield 65%. IR (KBr, cmꢁ1
) mmax:
1689, 1656; 1H NMR (CDCl3, 400 MHz) d: 3.40 (3H, s, CONCH3CO), 3.79 (3H, s,
CH3NCH2–), 3.90 (3H, s, CONCH3C), 4.15 (2H, s, NCH2C), 6.63 (1H, s, @CH–),
7.23–7.31 (5H, m, ArH); 13C NMR (CDCl3, 100 MHz) d: 27.9, 30.9, 31.9, 35.8,
103.9, 111.8, 127.1, 129.1, 130.6, 131.3, 132.4, 135.4, 152.0, 155.9; MS: m/
z = 315 [M+]. Anal. Calcd for C16H17N3O2S: C, 60.93; H, 5.43; N, 13.32. Found: C,
60.79; H, 5.61; N, 13.20.