An easy access to pyrimidine-fused azocine derivatives by thiophenol-mediated radical cyclization via 8-endo-trig mode

Article abstract of DOI:10.1016/j.tetlet.2009.11.020

An efficient route for the synthesis of eight-membered nitrogen heterocycles has been developed via a thiophenol-mediated intramolecular 8-endo-trig radical cyclization. The radical precursors were prepared using BF₃·Et₂O-catalyzed aza-Claisen rearrangement followed by the reaction with propargyl bromide. The alkenyl radicals are generated from thiophenol initiated by the benzoyl peroxide instead of commonly used AIBN for easy and facile isolation of the pure products.

Full text of DOI:10.1016/j.tetlet.2009.11.020

Tetrahedron Letters 51 (2010) 348–350
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An easy access to pyrimidine-fused azocine derivatives by
thiophenol-mediated radical cyclization via 8-endo-trig mode
*
K. C. Majumdar , Shovan Mondal, Debankan Ghosh
Department of Chemistry, University of Kalyani, Kalyani 741 235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route for the synthesis of eight-membered nitrogen heterocycles has been developed via a
thiophenol-mediated intramolecular 8-endo-trig radical cyclization. The radical precursors were pre-
pared using BF3ÁEt2O-catalyzed aza-Claisen rearrangement followed by the reaction with propargyl bro-
mide. The alkenyl radicals are generated from thiophenol initiated by the benzoyl peroxide instead of
commonly used AIBN for easy and facile isolation of the pure products.
Received 24 September 2009
Revised 4 November 2009
Accepted 6 November 2009
Available online 12 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Uracil
Aza-Claisen rearrangement
Thiophenol
Radical cyclization
Medium-sized N-containing fused ring systems, in particular
eight-membered rings (azocine) are core structures of various
structurally remarkable natural products.1–3 They constitute an
important class of compounds which are used as precursors in
the synthesis of biologically active compounds. Annulated azocines
have recently been demonstrated to possess substantial bioactivity
as preventives of urinary disturbances,4 AChE inhibitors,5 and 17-
b-hydroxysteroid dehydrogenase inhibitors.6 As the direct forma-
tion of this ring system from acyclic precursors is entropically
and enthalpically not favoured, an efficient construction of this
ring is a challenging problem.
ular cyclization has also been applied for the synthesis of azocine
derivatives.12 However, any radical-mediated cyclization method
has not been so far explored in their preparation. In continuation
of our work on radical chemistry and the synthesis of biologically
active heterocycles,13 we have recently reported14 an efficient
synthesis of 9-deazaxanthines. This success has prompted us to
undertake a study on the use of benzoyl peroxide in the thiophe-
nol-mediated 8-endo-trig radical cyclization for the synthesis of
pyrimidine-annulated azocine derivatives. Herein, we report our
results.
The required precursors 3(a–d) for the synthesis of pyrimidine-
fused azocine derivatives by the thiophenol-mediated radical cycli-
zation were prepared in 90–93% yields by the reaction of 2(a–d)
with propargyl bromide in the presence of anhydrous K2CO3 in
refluxing acetone for 4–5 h. The compounds 2(a–d) were in turn
There are several classical cyclization approaches available for
synthesizing azocine, for example, cycloaddition,7 fragmentation
reaction,8 Dieckmann cyclization,9 tandem hydroboration reac-
tion,10 and Michael reaction.11 Recently, Pd-catalyzed intramolec-
O
Ts
N
O
O
Ts
R1
O
NH2
R1
O
R1
O
NH
N
N
(ii)
(i)
N
N
N
N
R
1a-d
R
3a-d
R
2a-d
a, R = R1 = Me
a, R = R1 = Me, 92%
b, R = R1 = Et, 91%
c, R = Et, R1 = Me, 93%
a, R = R1 = Me, 90%
b, R = R1 = Et, 97%
c, R = Et, R1 = Me, 95%
1
b,
c,
R = R = Et
1
R = Et, R = Me
d, R = Et, R1 = H
1
1
d,
d,
R = Et, R = H, 90%
R = Et, R = H, 98%
Scheme 1. Synthesis of precursors 3a–d. Reagent and conditions: (i) TsCl, Py, 80 °C, 1-2 h; and (ii) propargyl bromide, K2CO3, acetone, reflux, 4–5 h.
* Corresponding author. Tel.: +91 33 2582 7521, fax: +91 33 25828282.
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.020

K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 348–350
349
Table 1
Ts
N
O
O
N
Ts
N
SPh
H
Synthesis of pyrimidine containing azocine derivatives 4a–d
(i)
80%
Me
O
Me
O
N
N
Entry
Azocine precursor 3
Azocine derivative4
Yield (%)
(ii)
85%
N
O
Ts
N
Ts
O
SPh
H
Me
4a
Me
O
N
Me
3a
Me
N
N
1
85
82
N
O
N
Scheme 2. Synthesis of azocine derivative 4a. Reagent and conditions: (i) dry t-
butanol, PhSH, AIBN, reflux, 2 h; and (ii) dry t-butanol, PhSH, benzoyl peroxide,
reflux, 2 h.
Me
Me
3a
4a
O
Ts
Ts
N
O
SPh
H
Et
N
Et
N
N
2
O
N
O
N
Et
Et
3b
4b
O
Ts
Ts
O
SPh
H
Me
N
N
Me
N
N
3
4
83
70
O
N
O
N
Et
Et
3c
4c
O
Ts
Ts
N
O
SPh
H
H
N
H
N
N
O
N
O
N
Et
3d
Et
4d
tyronitrile). Interestingly, the amount of the initiator played a cru-
cial role in this reaction. The use of 2 equiv of AIBN with respect to
the substrate proved to be the best compromise between the addi-
tion of thiophenol and the cyclization. The cyclized product 4a was
isolated as a white solid in 80% yield. However, the use of higher
AIBN excess caused the difficulty during the separation of the
product 4a from an appreciable amount of starting initiator. To
avoid this problem, we have used 2 equiv of benzoyl peroxide as
initiator in place of AIBN. The reaction was complete within 2 h
to afford 85% yield of 4a16 (Scheme 2). In contrast, a stoichiometric
amount of radical initiator with respect to thiophenol indicated
that the radical process was not efficient. Dimerization of thiyl rad-
icals leading to diphenyl disulfide could explain this inefficiency.
The use of a stoichiometric amount of radical initiator allows
regeneration of the thiyl radicals from either the thiophenol or
disulfide.17
Figure 1. Ortep diagram of compound 4a.
prepared in excellent yields (90–98%) by tosylation of 1(a–d) using
p-TsCl and pyridine at 80 °C for 1–2 h. Compounds 1(a–d) were ac-
cessed following published procedure.14,15 The synthetic route for
the preparation of precursors 3(a–d) is depicted in Scheme 1.
We next turned our attention to the synthesis of azocine deriv-
atives. For this purpose, the alkenyl radicals were generated by the
addition of thiophenol to the terminal alkynes. We then examined
their efficiency in tandem cyclization. Initially, substrate 3a was
investigated under different conditions. The reaction was con-
ducted in refluxing t-butanol with slow addition of thiophenol
(2 equiv) in the presence of the radical initiator AIBN (azobisisobu-
The product of 4a was characterized from its spectral data and
the cis-(Z)-configuration of the exocyclic double bond was settled
by single crystal X-ray diffraction18 (Fig. 1).
O
Ts
N
Ts
O
O
Ts
N
R1
O
R1
O
SPh
R1
O
N
SPh
N
N
SPh
7-exo-trig
path b
N
b
a
N
R
N
R
N
R
5
6
3
8-endo-trig
path a
Neophyl
rearrangement
Ts
Ts
O
O
SPh
H
Ts
O
SPh
N
SPh
H
R1
R1
O
N
R1
N
N
N
N
O
N
R
N
R
O
N
R
8
4
7
Scheme 3. Proposed reaction pathway for thiophenol-mediated radical cyclization reaction for synthesizing azocine derivatives.

350
K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 348–350
8. Grob, C. A.; Kunz, W.; Marbet, P. R. Tetrahedron Lett. 1975, 16, 2613–2616.
Encouraged by this result, other enynes 3(b–d) were similarly
9. (a) Leonard, N. J.; Oki, M.; Chiavarelli, S. J. Am. Chem. Soc. 1955, 77, 6234–6236;
(b) Leonard, N. J.; Oki, M. J. Am. Chem. Soc. 1955, 77, 6241–6244; (c) Leonard, N.
J.; Sato, T. J. Org. Chem. 1969, 34, 1066–1070.
treated to afford 4(b–d) in 70–83% yields. The results are summa-
rized in Table 1.
10. Garst, M. E.; Bonfiglio, J. N.; Marks, J. J. Org. Chem. 1982, 47, 1494–1500.
11. (a) Nakatsubo, F.; Cocuzza, A. J.; Keeley, D. E.; Kishi, Y. J. Am. Chem. Soc. 1977,
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Tetrahedron Lett. 1977, 18, 4295–4298.
12. (a) Majumdar, K. C.; Chattopadhyay, B.; Samanta, S. Tetrahedron Lett. 2009, 50,
3178–3181; (b) Majumdar, K. C.; Chattopadhyay, B. Curr. Org. Chem. 2009, 13,
731–757; (c) Cropper, E. L.; White, A. J. P.; Ford, A.; Hii, K. K. J. Org. Chem. 2006,
71, 1732–1735; (d) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287–1289;
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13. (a) Majumdar, K. C.; Debnath, P. Tetrahedron 2008, 64, 9799–9820; (b)
Majumdar, K. C.; Mondal, S.; De, N. Synlett 2008, 2851–2855; (c) Majumdar,
K. C.; Mondal, S. Tetrahedron Lett. 2007, 48, 6951–6953; (d) Majumdar, K. C.;
Mondal, S. Tetrahedron Lett. 2008, 49, 2418–2420; (e) Majumdar, K. C.; Mondal,
S.; Ghosh, D. Tetrahedron Lett. 2009, 50, 4781–4784; (f) Majumdar, K. C.; Alam,
S. Org. Lett. 2006, 8, 4059–4062; (g) Majumdar, K. C.; Chattopadhyay, B.; Ray, K.
Tetrahedron Lett. 2007, 48, 7633–7636; (h) Majumdar, K. C.; Das, U.; Jana, N. K.
J. Org. Chem. 1998, 63, 3550–3553; (i) Majumdar, K. C.; Biswas, A.;
Mukhopadhyay, P. P. Synthesis 2005, 1164–1168; (j) Majumdar, K. C.; Sinha,
B.; Maji, P. K.; Chattopadhyay, S. K. Tetrahedron 2009, 65, 2751–2756; (k)
Majumdar, K. C.; Basu, P. K.; Gonzalez, A. Curr. Org. Chem. 2009, 13, 599–645; (l)
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826.
The phenylsulfanyl radical, generated from thiophenol and ben-
zoyl peroxide, adds to the terminal alkynes of enynes 3 to form vi-
nyl radicals 5. These vinyl radicals may undergo an 8-endo-trig
intramolecular cyclization with the adjacent alkene to form the
hypothetical intermediate 8 which may afford product 4 by
abstraction of a H radical from thiophenol. An alternative pathway
(path b), a 7-exo-trig cyclization followed by 1,2-alkenyl migration
via a cyclopropyl methyl radical 7 (neophyl rearrangement)19
would also lead to the same product 4. This may be an indication
that the reaction proceeds via a ring expansion process (Scheme
3, path b), that is ring opening of the cyclopropylmethyl radical
intermediate may be stereoselective. The proposed mechanism of
the thiophenol-mediated reaction is depicted in Scheme 3.
In conclusion, we have developed a new efficient methodology
for the synthesis of azocine derivatives via sulfanyl radical addi-
tion–cyclization reaction. To the best of our knowledge, this is
the first example for the synthesis of azocine derivatives by thio-
phenol-mediated radical cyclization. The use of benzoyl peroxide
in the place of usual radical initiator AIBN offers easy and facile
separation of the pure products. Application of this strategy to
the synthesis of other bioactive azocine derivatives is under way,
and a full account will be communicated in due course.
14. Majumdar, K. C.; Mondal, S. Tetrahedron 2009, 65, 9604–9608.
15. Majumdar, K. C.; Das, T. K.; Jana, M. Synth. Commun. 2005, 35, 1961–1969.
16. General procedure for the synthesis of azocine derivatives 4(a–d) by thiophenol-
mediated radical cyclization:
A
deoxygenated solution of thiophenol
(0.40 mmol, 0.04 mL) in dry t-butanol (3 mL) was added dropwise to
a
Acknowledgments
solution of compound 3a (0.20 mmol, 100 mg) in refluxing anhydrous t-
butanol (3 mL) under a nitrogen atmosphere. The radical initiator benzoyl
peroxide (0.40 mmol, 97 mg) was added and 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 Â 15 mL), and the combined organic extracts were
washed with water (2 Â 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 azocine derivative 4a (109 mg, 85%) as a white solid. The other
substrates 3(b–d) were similarly treated to give products 4(b–d).
We thank DST (New Delhi) and CSIR (New Delhi) for financial
assistance. We thank the Material Science Department of the IACS
(Kolkata) for XRD data of compound 4a. We also thank Professor
Surajit Chattopadhyay, of this department, for solving the crystal
structure. Two of us (S.M. and D.G.) are thankful to DST (New Del-
hi) and CSIR (New Delhi), respectively, for fellowships.
(Z)-1,3-Dimethyl-7-(phenylthiomethylene)-5-tosyl-5,6,7,8,9,10- hexahydropyrimido-
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(KBr, cmÀ1 max: 2927, 1707, 1655; 1H NMR (CDCl3, 400 MHz) d 2.23–2.27 (m,
) m
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