Synthesis of oxathiocine derivatives by palladium-catalyzed intramolecular Heck reaction

Article abstract of DOI:10.2174/157017809789124803

A novel approach towards the synthesis of hitherto unreported oxathiocine derivatives has been described by utilizing palladium-catalyzed intramolecular Heck reaction starting from deactivated allylic compounds.

Full text of DOI:10.2174/157017809789124803

Letters in Organic Chemistry, 2009, 6, 453-455
453
Synthesis of Oxathiocine Derivatives by Palladium-Catalyzed Intramol-
ecular Heck Reaction
K.C. Majumdar*, Buddhadeb Chattopadhyay and Biswajit Sinha
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B., India
Received February 25, 2009: Revised July 18, 2009: Accepted July 23, 2009
Abstracts: A novel approach towards the synthesis of hitherto unreported oxathiocine derivatives has been described by
utilizing palladium-catalyzed intramolecular Heck reaction starting from deactivated allylic compounds.
Keywords: Heck reaction, sulfur heterocycles, 2-bromobenzene sulfonyl chloride, palladium catalyst, oxathiocine, 8-exo-trig.
During the last decades palladium-catalyzed Heck
reaction became an extremely powerful tool to synthetic
organic chemists for the synthesis of a number of target
molecules including different interesting heterocyclic
compounds [1,2]. This is because of its functional group
tolerance and high regioselectivity. Formation of the
medium-sized ring [3-5] is an ongoing challenge to the
organic chemists as these types of fragments are frequently
found in a number of naturally occurring compounds [6,7].
Different protocols are available in literature for constructing
medium-sized rings [8-15], among which transition-metal
catalyzed cyclization is well known. Recently, we have
reported some interesting medium-sized oxa-heterocycles
utilizing palladium-catalyzed intramolecular Heck reaction
[16-18]. Sulfones and sultones are two important classes of
organosulfur compounds that are used as important
intermediates in modern organic syntheses [19]. A number of
cyclic sulfones are the key subunit for the construction of
biologically active molecules e.g., proteases and ꢀ-lactamase
inhibitors [20-22]. Medium ring cyclic sulfones are
frequently used for the construction of cyclic olefines [23-
25]. On the other hand sultones have some toxicological [26]
and antiviral properties [27]. There are fewer examples of
palladium-catalyzed Heck reactions of sulfur compounds
[28,29] in literature and to the best of our knowledge
synthesis of medium-sized heterocycles containing sulfur
atom at the appropriate position has been rare. Probably
there is only one example to construct eight-membered
sultones by Heck reaction conditions starting from highly
activated vinylic system [30]. But, there is no such example
available in literature for the synthesis of sulfone or sultone
derivatives from the unactivated allylic systems. This is why
the synthesis of medium sized sulfur heterocycles by the Pd-
catalyzed cyclization is a challenge to the organic chemists.
Recently we have reported interesting oxathiocine
derivatives starting from unactivated vinylic systems with
the help of palladium-catalyzed intramolecular Heck reaction
[31]. So in continuation of our effort to synthesize medium
sized heterocyclic compounds, we decided to enrich the
scope of Heck reaction of different unactivated allylic
systems containing sulfur atom at the key position.
The compounds 1(a-d) were prepared by refluxing ꢁ- and
ꢀ-naphthols with different allyl bromides in acetone in the
presence of anhydrous potassium carbonate and followed by
Claisen rearrangement. The Heck precursors 3(a-d) for our
present investigation were prepared by the process outlined
in (Scheme 1). Reaction of compound 1a with 2-
bromobenzenesulfonyl chloride 2 in dry dichloromethane in
the presence of triethylamine and a catalytic amount of
o
DMAP at 0 C for 2 h afforded the compound 3a in 81%
yield. Similarly, compounds 3(b-d) were prepared from
compounds 1(b-d) in 74-84% yields. The compound 3a,
when subjected to the intramolecular Heck reaction in the
presence of 10 mol% Pd(OAc)2 as catalyst, KOAc as base,
o
TBAB as promoter in dry DMF at 100 C for 3 h using the
Jeffery’s two-phase protocol [32] the exo- cyclized 8-
membered oxathiocene derivative 4a was obtained
regioselectively, in 97% yield (Scheme 2). Generally, in this
type of reaction, there is always a chance to yield mixture of
regioisomeric products [18]. But, in this case, we obtained
the exo-Heck product 4a, as the sole product. Increasing the
reaction temperature to 150-160 oC did not improve the yield
of the cyclized product and on further increasing the
temperature considerable decomposition of the product was
observed. The use of Pd(PPh3)2Cl2 as catalyst was also found
to be effective but the yield of the cyclized product 4a was
reduced to some extent whereas the catalyst Pd(PPh3)4
showed very poor catalytic activity. Here it is important to
note that in the absence of the base the reaction did not occur
at all. Optimization of the reaction was achieved through a
series of experiments and it was observed that the base
Cs2CO3 or NaOAc showed lower activity compared to that
of KOAc. It is interesting to note that the phosphine ligands,
such as triphenyl phosphine or tri-o-tolylphosphine did not
show any effect upon the yield of the reaction. Therefore, it
is clear that our developed protocol is quite simple because it
is known that the ligand free approach does not work well
for the aryl bromides and this is obviously due to the fact
that in almost all the cases a palladium black is precipitated
and the reaction is stopped before the completion of the
reaction. To test the generality of the reaction, compounds
3(b-d) were subjected to the Heck reaction at optimized
*Address correspondence to this author at the Department of Chemistry,
University of Kalyani, Kalyani 741235, W.B., India; Fax: 91-033-2582
8282; E-mail: kcm_ku@yahoo.co.in
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

454 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Majumdar et al.
O
O
S
OH
R
SO2Cl
O
Br
Br
(i)
R
R = H, Me
1a,b
3a,b
2
R
Br
S
SO2Cl
R
Br
OH
O
(i)
R = H, Me
O
O
1c,d
2
3c,d
Scheme 1. Reagents and conditions: (i) Dry DCM, Et3N, DMAP, 0 °C.
O
O
S
O
S
O
O
O
Br
(i)
3a
4a
Scheme 2. Reagents and conditions: (i) Pd(OAc)2, KOAc, TBAB, DMF, 100 °C.
Table 1. Summarized Results of the Heck Reaction
Entry
Precursors
Time(h)
Products
Yield(%)
O
O
O
S
O
S
O
O
Br
1
3
97
3a
4a
O
S
O
S
O
O
O
O
Br
2
3.5
91
CH3
CH3
3b
4b
Br
O
O
S
3
3.2
95
S
O
O
O
O
3c
4c

Synthesis of Oxathiocine Derivatives
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
455
(Table 1). Contd…..
Yield(%)
Entry
Precursors
Time(h)
Products
H3C
Br
S
H3C
O
O
S
4
3.4
84
O
O
O
O
3d
4d
[7]
Moody, C. J. Studies in Natural Products Chemistry, Rahaman, A.;
Ed.; Elsevier: Amsterdam, 1992, p. 201.
Petasis, N. A.; Patane, M. A. Tetrahedron, 1992, 48, 5757.
Mehta, G.; Singh, V. Chem. Rev., 1999, 99, 881.
Roxburg, C. J. Tetrahedron, 1993, 49, 10749.
Rousseau, G. Tetrahedron, 1995, 51, 2777.
Evans, P. A.; Holmes, A. B. Tetrahedron, 1991, 47, 9131.
Yet, L. Tetrahedron, 1999, 55, 9349.
Hoberg, J. O. Tetrahedron, 1998, 54, 12631.
Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.;
Rahaman, H.; Roy, B. Tetrahedron, 2007, 63, 3919.
Majumdar, K. C.; Chattopadhyay, B.; Ray, K. Tertahedron Lett.,
2007, 48, 7633.
Majumdar, K. C. Chattopadhyay, B.; Sinha, B. Tetrahedron Lett.,
2008, 49, 1319.
Majumdar, K. C.; Chattopadhyay, B. Synlett, 2008, 979.
Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon:
Oxford, 1993.
Kim, C. U.; McGee, L. R.; Krawczyk, S. H.; Harwood, E.; Harada,
Y.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Cherrington,
J. M.; Xiong, S. F.; Griffin, L.; Cundy, K. C.; Lee, A.; Yu, B.;
Gulnik, S.; Erickson, J. W. J. Med. Chem., 1996, 39, 3431.
Richter, H. G.; Angehrn, P.; Hubschwerlen, C.; Kania, M.; Page,
M. G.; Specklin, J.-L.; Winkler, F. K. J. Med. Chem., 1996, 39,
3712.
conditions to afford the cyclized products 4(b-d) in 84-95%
yields. The results are summarized in (Table 1). The
exclusive formation of benzoxathiocine derivatives 4a-d [33]
via 8-exo mode of cyclization is quite unusual. Because,
Beletskaya and Cheprakov reported [34] that the exo-Heck
cyclization can occur only in case of the substrate which
generates small to common ring system; otherwise mixture
of products of exo-cyclization and endo-cyclization is
formed. However, in the present instance, exclusively the
eight-membered oxathiocine derivatives via 8-exo trig mode
of cyclization are obtained.
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
In conclusion, we have developed an efficacious
regioselective method for the construction of eight-
membered oxathiocine derivatives via an 8-exo trig
cyclization using a Claisen rearrangement followed by
intramolecular Heck cyclization as the key steps. The
method represents a simple synthetic protocol for the
formation of fused oxathiocine derivatives.
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
Buynak, J. D.; Vogeti, L.; Chen, H. Org. Lett., 2001, 3, 2953.
MaGee, D. I.; Beck, E. J. J. Org. Chem., 2000, 65, 8367.
Vedejs, E.; Singer, S. P. J. Org. Chem., 1978, 43, 4884.
McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett., 2001, 42,
1197.
Roberts, D. W.; Williams, D. L. Tetrahedron, 1987, 43, 1027.
Pérez-Pérez, M.-J.; Balzarini, J.; Hosoya, M.; Clercq, E. D.;
Camarasa, M. J. Bioorg. Med. Chem. Lett., 1992, 2, 647.
Jin, Z.; Fuchs, P. L. Tetrahedron Lett., 1993, 34, 5205.
Fu, C.; Ma, S. Org. Lett., 2005, 7, 1605.
ACKNOWLEDGEMENT
We thank the CSIR (New Delhi) and the DST (New
Delhi) for financial assistance. Two of us (B. C. and B. S.)
are grateful to the CSIR (New Delhi) for their CSIR-NET
fellowships.
[26]
[27]
[28]
[29]
[30]
[31]
SUPPLEMENTARY MATERIAL
Arnold, L. A.; Luo, W.; Guy, R. K. Org. Lett., 2004, 6, 3005.
Majumdar, K. C.; Chattopadhyay, B.; Sinha, B. Synthesis, 2008,
3857.
Supplementary material is available on the publishers
Web site along with the published article.
[32]
[33]
Jeffery, T. J. Chem. Soc., Chem. Commun., 1987, 1288.
Compound 4a: Yield: 97%; yellow solid; mp 130-131 0C; IR
(KBr, cm-1): 1188, 1369; 1H NMR (CDCl3, 400 MHz): ꢀH = 3.91 (s,
2H, =CHCH2), 5.34 (s, 2H, =CH2), 7.28 (d, 1H, J = 8.2 Hz, ArH),
7.36 (d, 1H, J = 7.6 Hz, ArH), 7.42 (t, 1H, J = 7.4 Hz, ArH), 7.48
(dt, 1H, J = 7.8 Hz, J = 1.0 Hz, ArH), 7.57-7.63 (m, 2H, ArH),
7.70 (d, 1H, J = 8.4 Hz, ArH), 7.80 (d, 1H, J = 8.2 Hz, ArH), 8.06
(d, 1H, J = 2.3 Hz, ArH). 8.36 (d, 1H, J = 8.6 Hz, ArH). 13C NMR
(CDCl3, 100 MHz): ꢀC = 40.1, 119.8, 120.3, 122.7, 126.8, 127.5,
127.8, 127.9, 128.0, 128.4, 129.6, 130.8, 134.2, 134.5, 145.2,
145.6. HRMS: Calculated for C19H14O3S: 345.0561 (M+Na)+.
Found: 345.0561 (M+Na)+. Anal. Calcd. for C19H14O3S: C, 70.79;
H, 4.38%. Found: C, 70.98; H, 4.09%.
REFERENCES AND NOTES
[1]
Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring
Compounds; Academic Press: New York and London, 1972; Vol.
II.
[2]
Faulkner, D. J. Nat. Prod. Rep., 1984, 1, 251, 551; 1986, 3, 1;
1987, 4, 539; 1989, 5, 613.
[3]
[4]
[5]
[6]
Denieul, M. P.; Skrydstrup, T. Tetrahedron Lett., 1999, 40, 4901.
Kricka, L. J.; Ledwith, A. Chem. Rev., 1974, 74, 101.
Hoberg, J. O. Tetrahedron, 1998, 54, 12631.
Oishi, T.; Ohtsuka, Y. Studies in Natural Products Chemistry;
Rahaman, A.; Ed.; Elsevier: Amsterdam, 1989, p. 73.
[34]
Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev., 2000, 100, 3009.