Novel synthesis of oxocine derivatives by Wittig olefination and intramolecular Heck reaction via 8-endo trig cyclization

Article abstract of DOI:10.1016/j.tetlet.2007.12.096

A concise and efficient method for the preparation of oxocine derivatives is described via sequential Wittig and intramolecular Heck reactions. The method is highly regioselective and affords high yields of the products.

Full text of DOI:10.1016/j.tetlet.2007.12.096

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1319–1322
Novel synthesis of oxocine derivatives by Wittig olefination
and intramolecular Heck reaction via 8-endo trig cyclization
K. C. Majumdar *, B. Chattopadhyay, B. Sinha
Department of Chemistry, University of Kalyani, Kalyani 741 235, India
Received 8 October 2007; revised 12 December 2007; accepted 19 December 2007
Available online 14 January 2008
Abstract
A concise and efficient method for the preparation of oxocine derivatives is described via sequential Wittig and intramolecular Heck
reactions. The method is highly regioselective and affords high yields of the products.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Pd-catalyst; Heck reaction; Wittig reaction; 8-endo trig; Oxocine
The Heck reaction has become a useful synthetic tool
due to its excellent functional group tolerance and high
stereoselectivity. The Heck reaction was introduced to
organic chemists in the late 1960s,1 but only in the past
decade or so it has witnessed rapid development and wide
applications in carbon–carbon bond-forming reactions.2
Generally, many natural products such as rhazinilam3
and its congener rhazinal,4 and naphthoxepin5 that contain
medium-sized heterocyclic rings fused to aryl rings have
attracted the attention of both biologists and synthetic
organic chemists.6 Oxepin is an important structural sub-
unit present in numerous biologically active molecules
and has received considerable attention over the last 20
years. For example, naphthoxepin derivatives such as 17
have been used as antipsychotic drugs (Fig. 1).
In continuation of our interest in the Pd-catalyzed
synthesis of heterocycles, we have devised an approach
for construction of the oxepin ring employing a Wittig
reaction followed by a highly regioselective intramolecular
Heck reaction. We envisioned that this route would not
only lead to the naphthoxepin derivatives, but also to a
variety of new analogs possessing modification around
the aryl ring.
Me
N
O
O
1a
1b
O
Fig. 1.
The synthesis of heterocyclic compounds utilizing
organometallic compounds such as ruthenium or palla-
dium-complexes has been studied recently in our labora-
tory.8–15
The
palladium-catalyzed
intramolecular
cyclizations seemed to be particularly fascinating, since a
number of different nucleophiles are known to react with
olefinic compounds to afford useful natural and unnatural
heterocyclic compounds.
The intramolecular Heck reaction has two possible
modes of ring closing, that is, exo- and endo-cyclization.
Small to medium size (5–8) ring formation is usually
favored by exo-cyclization16–18 since the corresponding endo-
cyclization is sterically very demanding; endo-cyclization
requires that the olefinic bond moves into the loop of the
substrate generating an energetically favorable substituted
alkene product. Thus large size ring (ꢀ20) formation with
a flexible tether generally favors endo-cyclization.19–22
*
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 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.096

1320
K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 1319–1322
Table 1
To the best of our knowledge, only a limited number of
examples of endo-cyclization for the formation of med-
ium-sized rings have appeared in the literature.23,24
The required Heck precursors 6a–h were synthesized in
89–93% yields by the Wittig reaction of substrates 5a–h.
The Wittig reagent was prepared from PPh3MeI in dry
THF in the presence of nBuLi at 0 °C–rt for about 1 h. Sub-
strates 5a–h were in turn prepared in almost quantitative
yields by the reaction of hydroxy-aldehydes 3a–d with
either 2-bromobenzyl bromide 4a or 2-bromo-5-methoxy-
benzyl bromide 4b in dry acetone in the presence of anhy-
drous potassium carbonate and a small amount of sodium
iodide25 (Scheme 1). Compounds 3a–d were prepared by
the Reimer–Tiemann reaction.
Optimization of the palladium-catalyzed cyclizationa of 7a from 6a
Br
O
O
6a
Catalyst
7a
Solvent
Entry
Base
Yield (%)
1b
2b
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)2Cl2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
KOAc
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Et3N
86
<5
63
NR
NR
43
K2CO3
Ag2CO3
Cs2CO3
KOAc
KOAc
KOAc
KOAc
Et3N
6b
7b
8b
9b
10
11
12
13
a
When the intramolecular Heck reaction was performed
with precursor 6a26 in the presence of Pd(OAc)2 as a cata-
lyst, KOAc as a base, and tetrabutylammonium bromide
(TBAB) as an additive in dry DMF as solvent for 2 h under
a nitrogen atmosphere, the eight-membered naphthoxocine
compound 7a27,28 was obtained in excellent yield (86%).
21
36
NR
NR
NR
<5
<5
Et3N
Et3N
KOAc
MeCN
Dioxane
Dioxane
1
Only the Z-isomer was formed as indicated by H NMR
analysis (JHaÀHb = 13.8 Hz). Molecular models also show
that the compound can be considered as a bridged cis-stil-
bene. The optimum conditions for the cyclization were
found through a series of experiments where various
changes were made to the catalyst, base, additive, and sol-
vent (Table 1).
All reactions were carried out at 100 °C and the amount of catalyst
used in the reaction was 10 mol %.
b
TBAB was used as an additive. NR indicates no reaction.
6–9). In the absence of TBAB, the reactions (entries 1, 2,
and 6–9) did not occur.
During the course of the optimization of the exo-Heck
reaction, we found that the catalyst, base, additive, and sol-
vent had a profound effect on the reaction yield. The cata-
lyst Pd(PPh3)2Cl2, which is used mostly in this type of Heck
cyclization,23 provided a 21% yield of the product, whereas
Pd(PPh3)4 provided 7a in 43% yield. Therefore, we exam-
ined the results of the reaction taking Pd(OAc)2 as a cata-
lyst and succeeded in obtaining excellent yields in the
intramolecular Heck cyclization. The reaction did not pro-
ceed under the reaction conditions described in Table 1,
entries 4, 5, 9–11. The catalyst PdCl2 was also found to
be effective but the yield of the reaction was only 36%.
Here, it is important to note that the additive plays an
important role in the Heck cyclization. We performed the
reaction in the presence of TBAB, Table 1 (entries 1, 2,
The effect of base on the reaction was also investigated.
The use of the organic base Et3N dramatically reduced the
rate of reaction (entries 2 and 12) and no reaction was
observed in the case of entries 10 and 11. Replacement of
the organic base with inorganic KOAc was found to be
highly effective and excellent yields of products were
obtained. Other inorganic bases, for example, K2CO3,
Ag2CO3, and Cs2CO3 were explored, and K2CO3 was
found to be effective (entry 3); however, the use of Ag2CO3
and Cs2CO3 led to no reaction.
A study of the influence of various solvents (DMF,
CH3CN, Et3N, and dioxane) suggested that DMF was
the best choice.
Substrates 6b–h when treated under optimized reaction
conditions [Pd(OAc)2/TBAB/KOAc/DMF/100 °C] affor-
Br
Br
Br
CHO
CHO
OH
(i)
O
OH Br
O
R1
R1
(ii)
(iii)
+
R1
2a
3a
4a,b
6a,b
5a,b
Br
R
CHO
O
R
R
CHO
R
Br
(i)
OH
Br
R1
(ii)
Br
R1
(iii)
+
OH
R = H
R1
O
R1 = H
2b-d
5c-h
3b-d
R = OMe
R = Me
6c-h
4a,b
R1 = OMe
Scheme 1. Reagents and conditions: (i) aq NaOH, CHCl3, reflux, 4 h; (ii) acetone, K2CO3, NaI, 3–4 h; (iii) PPh3MeI, nBuLi, THF, 0 °C–rt. Yields: 6a,
88%; 6b, 91%; 6c, 94%; 6d, 87%; 6e, 90%; 6f, 95%; 6g, 88%; 6h, 89%.

K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 1319–1322
1321
Table 2
Results of the Heck reactionsa
Entry
Heck precursor
Product
Time (h)
Yieldb(%)
Br
Br
1
2
86
O
O
6a
O
7a
2
3
4
5
6
7
3.5
67
76
70
69
66
71
68
OMe
6b
OMe
O
7b
Br
Br
Me
O
O
4
6c
O
7c
Me
Me
5
OMe
OMe
6d
O
7d
Me
Br
MeO
MeO
O
O
5
6e
O
7e
MeO
MeO
Br
3.5
OMe
OMe
6f
O
7f
Br
Br
4
O
O
O
O
6g
6h
7g
8
5
OMe
OMe
7h
a
All the reactions were carried out using the optimized reaction conditions.
Isolated yields.
b
ded the corresponding eight-membered cyclized oxocine
derivatives 7b–h. Only the Z-isomer was formed as indi-
cated by 1H NMR analysis (JHa–Hb = 13.8 Hz). The results
are summarized in Table 2.
The mechanistic rationalization for the regioselective
formation of the oxocine derivatives by the 8-endo trig
cyclization is unusual. Denieul and Skrydstrup23 recently
showed that during intramolecular Heck cyclization, the
7-exo trig mode of cyclization of a compound having a
vinyl group attached to an aromatic ring was favored over
the 8-endo trig mode. In the present instance, we obtained
exclusively the eight-membered heterocyclic compounds,
that is, the oxocine derivatives via 8-endo trig cyclization.
In conclusion, we have developed an efficient and regio-
selective method for the synthesis of eight-membered
heterocyclic compounds via 8-endo trig cyclization using
a Wittig reaction followed by intramolecular Heck cycli-
zation as the key steps. This method constitutes a simple
synthetic protocol for the formation of fused oxocine
derivatives in high yields.
Acknowledgments
We thank the CSIR (New Delhi) for financial assistance.
Two of us (B.C. and B.S.) are grateful to the CSIR
(New Delhi) for a Senior and a Junior research fellowship,

1322
K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 1319–1322
19. Denieul, M. P.; Laursen, B.; Hazell, R.; Skrydstrup, T. J. Org. Chem.
2000, 65, 6052.
20. Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427.
21. Ma, S.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 6345.
22. Stocks, M. J.; Harrison, R. P.; Teague, S. J. Tetrahedron Lett. 1995,
36, 6555.
respectively. We also thank the DST (New Delhi) for pro-
viding the FT-IR Spectrometer under the DST-FIST
program.
References and notes
23. Denieul, M.-P.; Skrydstrup, T. Tetrahedron Lett. 1999, 40, 4901.
24. Gibson, S. E.; Guillo, N.; Middleton, R. J.; Thuilliez, A.; Tozer, M. J.
J. Chem. Soc., Perkin Trans. 1 1997, 447.
1. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518.
2. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
3. Abraham, D. J.; Rosenstein, R. D.; Lyon, R. L.; Fong, H. H. S.
Tetrahedron Lett. 1972, 909.
4. Kam, T.-S.; Tee, Y.-M.; Subramaniam, G. Nat. Prod. Lett. 1998, 12,
307.
5. Kotha, S.; Mandak, K. Tetrahedron Lett. 2004, 45, 1391.
6. Baudoin, O.; Guenard, D.; Gueritte, F. Mini-Rev. Org. Chem. 2004, 1,
333.
7. Carl, K.; Joseph, L. U.S. Patent 4,073,912, 1972; Chem. Abstr. 1978,
89, 24156.
8. Majumdar, K. C.; Islam, R.; Rahaman, H.; Roy, B. Org. Biomol.
Chem. 2006, 4, 2393.
9. Majumdar, K. C.; Muhuri, S.; Rahaman, H.; Islam, R.; Roy, B.
Chem. Lett. 2006, 35, 1430.
10. Majumdar, K. C.; Rahaman, H.; Muhuri, S.; Roy, B. Synlett 2006,
466.
25. Gazith, M.; Noys, R. M. J. Am. Chem. Soc. 1955, 77, 6091.
26. Compound 6a: Yield 88%; solid; mp 44–45 °C; IR (KBr):
m
max = 2850, 2921 cmÀ1 1H NMR (CDCl3, 400 MHz): dH = 5.27
;
(s, 2H, OCH2), 5.75 (dd, 1H, J = 11.2 Hz, J = 2.0 Hz, @CHaHb),
5.80 (dd, 1H, J = 17.7 Hz, J = 2.0 Hz, @CHaHb), 7.13 (m, 2H,
CH2@CH and ArH overlapped), 7.27 (d, 1H, J = 9.0 Hz, ArH), 7.31
(t, 1H, J = 7.5 Hz, ArH), 7.36 (t, 1H, J = 7.2 Hz, ArH), 7.46 (t, 1H,
J = 7.0 Hz, ArH), 7.59 (m, 2H, ArH), 7.74 (d, 1H, J = 9.0 Hz, ArH),
7.77 (d, 1H, J = 8.1 Hz, ArH), 8.20 (d, 1H, J = 8.6 Hz, ArH). 13C
NMR (CDCl3, 75 MHz): dC = 70.6, 114.7, 121.0, 121.9, 122.2, 123.7,
124.4, 126.4, 127.5, 128.2, 128.7, 128.8, 129.1, 129.5, 130.3, 132.4,
132.5, 136.6, 152.9. HRMS: calcd for C19H15BrO: 339.0379 [M+H];
341.0361 [MH+2]. Found: 339.0391 [M+H]; 341.0391 [MH+2].
Anal. Calcd for C19H15BrO: C, 67.27; H, 4.46. Found: C, 67.39; H,
4.54.
27. Compound 7a: Yield 86%; solid, mp 115–116 °C; IR (KBr):
11. Majumdar, K. C.; Rahaman, H.; Islam, R.; Roy, B. Tetrahedron Lett.
2006, 47, 2111.
m
max = 2851, 2922 cmÀ1 1H NMR (CDCl3, 400 MHz): dH = 5.47 (s,
;
2H, OCH2), 6.97 (d, 1H, J = 13.8 Hz, @CHaHb), 7.04 (d, 1H,
J = 13.8 Hz, @CHaHb), 7.13–7.21 (m, 4H, ArH), 7.29–7.35 (m, 2H,
ArH), 7.44 (t, 1H, J = 7.3 Hz, ArH), 7.61 (d, 1H, J = 8.9 Hz, ArH),
7.69 (d, 1H, J = 8.0 Hz, ArH), 7.89 (d, 1H, J = 8.5 Hz, ArH). 13C
NMR (CDCl3, 75 MHz): dC = 73.9, 120.4, 121.8, 123.8, 124.0, 126.2,
127.1, 127.3, 127.8, 128.1, 129.1, 129.2, 129.3, 129.6, 131.3, 133.2,
134.8, 138.5, 152.8. HRMS: calcd for C19H14O: 258.1045 [M+].
Found: 258.1045 [M+]. Anal. Calcd for C19H14O: C, 88.34; H, 5.46.
Found: C, 88.41; H, 5.61.
12. Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2007, 48, 6951.
13. Majumdar, K. C.; Pal, A.; Taher, A.; Debnath, P. Synthesis 2007,
1707.
14. Majumdar, K. C.; Chattopadhyay, B.; Ray, K. Tetrahedron Lett.
2007, 48, 7633.
15. Majumdar, K. C.; Chattopadhyay, B.; Taher, A. Synthesis 2007,
3647.
16. Overman, L. E. Pure Appl. Chem. 1994, 66, 1423.
17. Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53,
7371.
28. Compound 7g was earlier synthesized by Wittig reaction. See:
Begasse, B.; Corre, M. L. Synthesis 1981, 197.
18. Negishi, E.; Coperet, C.; Ma, S. M.; Liou, S. Y.; Liu, F. Chem. Rev.
1996, 96, 365.