Synthesis of benzofuran derivatives through the coupling of conjugated dienynes with Fischer carbene complexes

Article abstract of DOI:10.1016/S0040-4039(00)01574-4

The reaction of Fischer carbene complexes with conjugated dienylacetylene derivatives followed by treatment with iodine leads to benzofuran derivatives in good-to-excellent yields. Equivalent products can be obtained from coupling of conjugated enediynes

Full text of DOI:10.1016/S0040-4039(00)01574-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8687–8690
Synthesis of benzofuran derivatives through the coupling of
conjugated dienynes with Fischer carbene complexes
James W. Herndon,* Yi Zhang, Haixia Wang and Ke Wang
Department of Chemistry & Biochemistry, New Mexico State University, MSC 3C, Las Cruces, NM 88003,
and Department of Chemistry & Biochemistry, University of Maryland, College Park, MD 20742-2021, USA
Received 30 June 2000; revised 10 August 2000; accepted 14 September 2000
Abstract
The reaction of Fischer carbene complexes with conjugated dienylacetylene derivatives followed by
treatment with iodine leads to benzofuran derivatives in good-to-excellent yields. Equivalent products can
be obtained from coupling of conjugated enediynes with Fischer carbene complexes in the presence of
hydrogen atom donors. © 2000 Published by Elsevier Science Ltd.
In several recent publications, annulation processes employing the coupling of Fischer carbene
complexes with highly conjugated acetylene derivatives have been demonstrated. Specific classes
of conjugated acetylenes include arylvinylacetylenes,1 cyclopropylvinylacetylenes,1 enediynes,2
enyne aldehydes,3 and o-alkynylbenzoyl derivatives.4 The coupling of Fischer carbene complex
1 (Scheme 1) with arylvinylacetylenes (e.g. 2A) results in benzannulation, ultimately affording
naphthofuran derivatives 5A or 6A, depending upon the reaction conditions. This process is
mechanistically related to the Do¨tz benzannulation reaction5 in that a chromium carbene-gener-
ated arylvinylketene complex (e.g. 3A) cyclizes to a phenol derivative (4A), which ultimately
converts to the observed products 5A or 6A, depending upon the workup procedure.
Scheme 1. Compounds 2–6: (A) Dashed atoms included (phenyl series). (B) Dashed atoms omitted (vinyl series)
* Corresponding author. E-mail: jherndon@nmsu.edu
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01574-4

8688
In this manuscript the focus is on coupling of Fischer carbene complexes with dienylacetylenes
(e.g. 2B), which should in theory provide simple benzofuran derivatives (6B). The benzofuran
ring system is a very important pharmacophore and is present in numerous biologically-active
natural and synthetic compounds.6 Most syntheses of benzofurans emphasize annulation of a
furan ring onto a preexisting benzene ring,7 however, the synthetic approach in Scheme 1
involves a simultaneous single-pot construction of both the furan and benzene rings which
occurs in conjunction with the formation of three carbonꢀcarbon bonds and one carbonꢀoxygen
bond.
Dienylacetylenes 10A–E (substituent letters for 10, 12 correlate with Table 1 Entry letters)
were prepared according to the synthetic routes in Scheme 2 using readily-available bromo-
aldehyde derivative 7.9 Two general routes were employed, involving either direct palladium-
catalyzed coupling of 7 with an alkyne, followed by Wittig reaction on enyne-aldehyde 11 or
two-step conversion of 7 to bromoenyne 9, followed by Suzuki coupling. The conversion of 8 to
9 was surprisingly efficient (91% yield) even in the presence of the extra bromine atom.
Table 1
Synthesis of benzofurans (12) via the coupling of dienylacetylenes (10) with carbene complex 1
Entry
R1
R2
Cis/trans
Yield 12 (%)
A
B8
C
D
E
H
Bu
H
COOMe
Ph
Ph
Trans
–
Trans
Trans
Cis
71
84
61
81
Bu
Bu
Bu
Bu
63 (12E=12D)
Scheme 2. (i) CBr4/PPh3/Zn (83%). (ii) n-BuLi −78°C, then TBSCl (91%). (iii) (HO)2BꢀCHꢁCHBu/2% (PPh3)2PdCl2,
then Bu4NF (95%). (iv) BuCCH or TMSCCH, 1–5% PdCl2, PPh3/CuI/EtN(i-Pr)2/DMF. (v) For 10B: Ph3PꢁCH2
(55%). (vi) For 10C: Ph3PꢁCHCOOMe (81%). (vii) For 10D,E: Ph3PꢁCHPh (85%), then Bu4NF, then separate
stereoisomers; 10D–53%, 10E–34%

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The reaction of dienynes 10A–E with Fischer carbene complex 1 afforded benzofuran
derivatives (12A–E) in good-to-excellent yields (Table 1) in a very clean reaction. The highest
yields of product were observed after treatment of the crude reaction mixtures with iodine. The
proton NMR spectrum of the crude product prior to iodine treatment showed a complex
reaction mixture consistent with the presence of arene–chromium complexes. Apparently the
complex reaction mixture was converted to a single uncomplexed benzofuran derivative upon
treatment with iodine.
The examples in Table 1 vary in the substitution pattern on the alkyne and the terminating
alkene. The reaction process is tolerant of a variety of substitution patterns within the
terminating alkene. Simple (Entries A and B), as well as further-conjugated systems (Entries
C–E) are tolerated by the reaction. As noted in Entries D and E, the trans isomer provides a
higher yield of benzofuran than the cis isomer. A possible problem with the cis isomer is failure
to obtain the desired conformation (s-cis) for the electrocyclic ring closure.
In an earlier publication, an alternate but low-yielding synthesis of compound 12A using
enediyne 13 and carbene complex 1 was described (Scheme 3).2 This product arises through
Moore cyclization of intermediate vinylketene complex 14,10 followed by reduction of the
resulting diradical 15 by hydrogen abstraction from dioxane, eventually affording 12A. The
major product of this reaction was however the unsaturated analog 18, which arises through a
series of intramolecular hydrogen atom transfers.11 In order to compare the merits of the two
methods for the synthesis of 12A, the coupling of carbene complex 1 with enediyne 13 was
attempted in the presence of the more efficient hydrogen atom donors 1,3-cyclohexadiene or
terpinene.12 Under the optimal conditions using 0.2 M cyclohexadiene in dioxane, compound
12A was obtained in 67% yield accompanied by only trace amounts of unsaturated compound
18; preparation of 12A from 10A (Scheme 3 inset and Table 1, Entry 1) proceeded in
comparable (71%) yield. The less expensive hydrogen atom donor terpinene was also tested,
however this compound was very difficult to separate from the product.
Scheme 3.

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In summary, synthesis of benzofurans through the coupling of conjugated dienynes with
Fischer carbene complexes has been demonstrated for a variety of dienynes. In all cases
examined, formation of the benzofuran was the exclusive reaction pathway. The reaction
process is synthetically equivalent to the coupling of Fischer carbene complexes with enediynes
in the presence of hydrogen atom donors, which proceeds through diradical intermediates.
Acknowledgements
We thank the Petroleum Research Fund, Administered by the American Chemical Society,
the National Science Foundation, and New Mexico State University for financial support. We
thank Ms Caroline Ladd of the University of Maryland for acquisition of mass spectral data.
References
1. Herndon, J. W.; Hayford, A. Organometallics 1995, 14, 1556–1558.
2. Herndon, J. W.; Wang, H. J. Org. Chem. 1998, 63, 4562–4563.
3. Herndon, J. W.; Wang, H. J. Org. Chem. 1998, 63, 4564–4565.
4. Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267–1269.
5. For the latest review of this chemistry, see Do¨tz, K. H.; Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187–198.
6. See: Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V.; Bird, C. W., Eds.; Elsevier Science: Oxford, 1996; Vol. 2, Chapter 8.
7. See: Friedrichsen, W. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.;
Bird, C. W., Eds.; Elsevier Science: Oxford, 1996; Vol. 2, Chapter 7.
8. Sample procedure: A solution of methylcarbene complex 1 (0.212 g, 0.848 mmol) and dienyne 10B (0.123 g,
0.7069 mmol) in dioxane (10 mL) was added dropwise to refluxing dioxane (20 mL) over a 2 h period. After the
addition was complete, the mixture was refluxed for an additional 24 h. The reaction mixture was then allowed
to cool to room temperature and then concentrated in vacuo. Hexane (30 mL) was added and the green
chromium residue was filtered out over a bed of Celite. The solvent was removed on a rotary evaporator. The
crude product was dissolved in chloroform (30 mL) and iodine (225 mg, 0.900 mmol) was added. The mixture
was allowed to stir 12–24 h and the poured into an aqueous sodium thiosulfate solution in a separatory funnel.
The chloroform layer was dried over sodium sulfate and the solvent was removed on a rotary evaporator. Final
purification using flash column chromatography (silica gel/9:1 hexanes:ethyl acetate) yielded benzofuran 12B
(0.138 g, 0.6079 mmol) in 86% yield. IR (CDCl3) 3020, 2955, 2930, 2857, 1733, 1628, 1602 cm−1 1H NMR
;
(CDCl3) l 7.11 (1H, d, J=8.2 Hz), 7.07 (1H, d, J=8.2 Hz), 3.14 (2H, t, J=7.3 Hz), 2.93 (2H, t, J=7.3 Hz), 2.60
(2H, t, J=7.3 Hz), 2.34 (3H, s), 2.15 (2H, quintet, J=7.3 Hz), 1.2–1.6 (4H, m), 0.92 (3H, t, J=7.1 Hz); 13C NMR
(CDCl3) l 153.01, 150.50, 137.75, 134.85, 126.13, 118.75, 114.69, 108.15, 33.58, 32.12, 31.36, 25.79, 23.95, 22.38,
13.93, 11.85; MS (EI): 228 (M+, 88), 227 (39), 226 (11), 186 (24), 185 (100); HRMS calcd for C16H20O 228.15141,
found 228.15174.
9. Prepared in one step from the reaction of cyclopentanone with DMF/PBr3. Wang, K. K.; Liu, B.; Lu, Y.
Tetrahedron Lett. 1995, 36, 3785–3788.
10. This is a well-established reaction pathway for enyne-ketene derivatives. For a review, see: Moore, H. W.;
Benjamin, R. Y. Chemtracts Org. Chem. 1992, 5, 273–313.
11. The formation of compound 18 proceeds with high selectivity if hydrogen atom donors are omitted from the
reaction. Zhang, Y.; Herndon, J. W. Tetrahedron 2000, 56, 2175–2182.
12. Similar intermediates have been successfully trapped using this approach. Rahm, A.; Wulff, W. D. J. Am. Chem.
Soc. 1996, 118, 1807–1808.
.