Rhodium-catalyzed tandem nucleophilic addition/bicyclization of diyne-enones with alcohols: A modular entry to 2,3-fused bicyclic furans

Article abstract of DOI:10.1039/c000883d

A novel, efficient and atom-economic Rh-catalyzed stereoselective tandem nucleophilic addition/bicyclization for the synthesis of 2,3-fused bicyclic furans from readily available acyclic diyne-enones and alcohols has been developed.

Full text of DOI:10.1039/c000883d

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Rhodium-catalyzed tandem nucleophilic addition/bicyclization of
diyne-enones with alcohols: a modular entry to 2,3-fused bicyclic
furansw
Wanxiang Zhaoa and Junliang Zhang*ab
Received 13th January 2010, Accepted 9th April 2010
First published as an Advance Article on the web 10th May 2010
DOI: 10.1039/c000883d
A novel, efficient and atom-economic Rh-catalyzed stereo-
selective tandem nucleophilic addition/bicyclization for the
synthesis of 2,3-fused bicyclic furans from readily available
acyclic diyne-enones and alcohols has been developed.
Table 1 Optimization of the rhodium-catalyzed tandem nucleophilic
cyclizationa
Rhodium-catalyzed reactions are powerful tools for the
construction of organic compounds and have played an
important role in modern organic synthesis.1 Among the
numerous methods for this endeavour, cyclization and nucleo-
philic addition catalyzed by rhodium are receiving much
attention because of their high efficiency in the formation of
carbon–carbon and carbon–heteroatom bonds.1–3 In the past
decade, the rhodium-catalyzed tandem addition/cyclization
has been extensively investigated.4 However, most of the
nucleophiles employed in the addition are organometallic
reagents which transmetalate with the rhodium catalyst to
produce organorhodium species acting as effective nucleo-
philes of alkynes and electron-deficient olefins.3,4 Moreover,
because of the significant role of highly substituted furan not
only in many natural products and important pharmaceuticals
as a key structure, but also in synthetic chemistry as a useful
building blocks, the development of new tandem reactions for
constructing highly functionalized substituted furan from
easily available acyclic starting materials has been stimulated
by their appearance in many bioactive natural products and
important pharmaceuticals.5,6 Herein we now report our
discovery of novel rhodium-catalyzed tandem nucleophilic
addition/bicyclization of acyclic diyne-enones with alcohols to
construct 2,3-fused bicyclic furans with 100% atom-economy.7
Previous studies in our group aimed at the synthesis of
multi-functionalized polysubstituted furan have proved that
2-(1-alknyl)-2-alken-1-ones8,9 is a highly efficient precursor of
furan derivatives. As a continuation of the development of
constructing polycyclic furan scaffold, we envisaged that
diyne-enone might undergo a cascade reaction with nucelo-
philes in the presence of catalytic rhodium species to afford
fused bicyclic furan derivatives.
Yield (%)
of 2aab
Entry
Conditions
1
2
3
4
[RhCl(CO)2]2, DCE, 20 h
27
0
8
0
0
35
41
28
16
59
64
63
RhCl(PPh3)3/AgOTf(10%), DCE, 3 h
[RhCl(cod)2]/AgOTf(10%), DCE, 20 h
[RhCl(CO)2]2, THF, 24 h
5
[RhCl(CO)2]2, 1,4-Dioxane, 24 h
[RhCl(CO)2]2, CO(0.2 atm), DCE, 3.5 h
[RhCl(CO)2]2, CO(1.0 atm), DCE, 4 h
[RhCl(cod)]2, CO(1.0 atm), DCE, 3 h
[RhCl(cod)]2, CO(1.0 atm), MeOH, 4.5 h
[RhCl(cod)]2, CO(1.0 atm), DCE, 1.5 h,
[RhCl(cod)]2, CO(1.0 atm), TCE, 1.5 h
[RhCl(cod)]2, CO(1.0 atm),
DCE/MeOH(10/1), 1.5 h
[RhCl(CO)2]2, CO(0.2 atm),
DCE/MeOH(10/1), 2.5 h
[RhCl(cod)]2, CO(1.0 atm),
6c
7
8
9
10d
11d,e
12
13
14
15
35
75
83
TCE/MeOH(10/1), 2 h
[RhCl(cod)]2, CO(0.2 atm),
TCE/MeOH (10/1), 3 h
a
Conditions (unless other noted): 1a (0.2 mmol, 0.05 M), methanol
b
c
(2.0 equiv.), rhodium (5.0 mol%), 60 1C. Isolated yield. 0.2 atm.
CO = 1 atm. CO/N2 (CO/N2 = 1/4). Methanol (10.0 equiv.) was
d
e
used. TCE = 1,1,2,2-tetrachloroethane.
The starting point for our study was the rhodium-catalyzed
conversion of substrates 1a, which was easily prepared by
Sonogashira cross coupling of 2-bromo-1,3-diphenyl-prop-2-
en-1-one and terminal 1,6-diynes (Table 1). To our delight,
the domino nucleophilic cyclization indeed occurred in
1,2-dichloroethane (DCE) under the catalysis of 5 mol% of
[RhCl(CO)2]2, and afforded the bicyclic furan 2aa in 27% yield
after 20 h at 60 1C (Table 1, entry 1). To further identify
optimal reaction conditions, various rhodium complexes
and different organic solvents were screened. Notably,
[RhCl(cod)2]/AgOTf species were proved to have poor
efficiency and no catalytic activity was observed for
RhCl(PPh3)3/AgOTf and [RhCl(CO)]2 in THF or 1,4-dioxane
at 60 1C (entries 2–5). Gratifyingly, there was a moderate
improvement in the yield under a carbon monoxide atmosphere
with a catalytic amount of [RhCl(CO)]2 or [RhCl(cod)]2
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N, Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: (+86) 21-6223-5039
b State key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
P. R. China
w Electronic supplementary information (ESI) available: Representative
experimental procedure and characterization of reaction products.
CCDC 761108. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c000883d
ꢀc
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Table 2 Screen the reaction scope via variation of nucleophile
componenta
Table
diyne-enone component 1
3
Synthesis of fused bicyclic furan
3
via variation of
Diyne-enone 1
X/R1/R2/R3
Isolated
Time/h Yield(%)a
Entry
ROH
Time/h
Yield (%)
Entry
1
2
3
4
5
6
i-PrOH
BnOH
t-BuOH
H2O
Cyclopropylmethanol
Cyclohexanol
3
3
10
4
5
79 (2ab)
51 (2ac)
—
45 (2ad)
60 (2ae)
63 (2af)
1
2
3
4
5
6
7
8
C(CO2Me)2/Ph/Ph/H (1a)
C(CO2Me)2/Me/Ph/H (1b)
C(CO2Me)2/4-ClC6H4/Ph/H (1c)
C(CO2Me)2/Ph/4-ClC6H4/H (1d)
C(CO2Me)2/Ph/Ph/n-Bu (1e)
C(CO2Me)2/Ph/Ph/Ph (1f)
C(CO2Me)2/Ph/Ph/4-OMeC6H4 (1g)
C(CO2Me)2/Ph/Ph/4-NO2C6H4 (1h)
C(CO2Me)2/Me/n-C4H9/H (1i)
NTs/Ph/Ph/H (1j)
3
1.5
3
2
3
3
3
3
1
83 (2aa)
62 (2ba)
73 (2ca)
70 (2da)
62 (2ea)
81 (2fa)
98 (2ga)
69 (2ha)
60 (2ia)
61 (2ja)
75 (2ka)
0
5
a
Conditions: [RhCl(cod)]2 (5%), TCE (0.05 M), TCE/ROH = 10/1,
60 1C, CO/N2 (1/4, 1 atm).
9
10
11
12
3
3
3
(entries 6–8).10 Higher yields and faster reaction rates were
achieved when 10 equivalents of methanol were used
(entries 10–11). However, the yield decreases sharply when
MeOH was used as a solvent (entry 9). Finally, the mixed
solvent system (TCE/MeOH = 10/1, v/v) was found to be the
best and the reaction furnished 2aa in 83% isolated yield
under a mixed CO/N2 (1/4) atmosphere, while a relatively
lower yield (75%) was obtained when the reaction was run
under the CO atmosphere (entry 14 vs. 15).
NTs/Ph/Ph/Ph (1k)
O/Me/Ph/H (1l)
crystallographic analysis of compound 2ha.11 It is noteworthy
that the reactions of 1j and 1k with a TsN tether, together with
a terminal alkyne (R3 = H) or an internal alkyne (R3
=
phenyl) also proved to be efficient cyclization precursors
(entries 10–11). However, oxygen-tethered substrate was
decomposed under the reaction conditions and could not give
the corresponding product (entry 12).
With the optimal conditions in hand, we started to examine
the scope of this domino process via variation of nucleophile
component and the results are depicted in Table 2. The
reaction of 1a with both primary and secondary alcohol
proceeded smoothly to give the desired products in moderate
to good yields (Table 2, entries 1–2). The bulkyl tertiary
alcohol failed to produce the corresponding product
(entry 3). Interestingly, water can also act as a nucleophile
to afford 45% yield of 2ad with a hydroxy group which is
ready for further functional transformation (entry 4). Finally,
cyclopropyl methanol and cyclohexanol provided the corres-
ponding bicyclic furans in reasonable yields (entries 5–6).
However, the N-based nucleophile failed to react with 1a
under the conditions which was likely due to the strong
interaction between the amine and the rhodium catalyst
leading to catalyst poisoning.
To elucidate the mechanism, CD3OD was employed as a
nucleophile for this transformation. The rhodium nucleophilic
tandem cyclization of 1a with CD3OD furnished the bicyclic
furan product (Z)-D-2a in 72% yield under the optimized
conditions, 96% of deuterium could be incorporated into the
product and located syn to the furan ring (eqn (1)).
ð1Þ
We next investigated the scope of the reaction by testing
various diyne-enones (Table 3). The results indicated that this
cyclization is tolerant of different substitutions on the alkene,
akyne and carbonyl moieties. Alkyl substitution on the
carbonyl position (R1) was less effective than the aryl group
(entries 1 vs. 2). The reaction of substrate 1c and 1d, tethered
with a terminal alkyne (R3 = H) proceeded smoothly to afford
2ca and 2da in good yields (entries 3–4). Fortunately, substrate
1f–h tethered with an internal alkyne (R3 = butyl, aryl)
could also allow for the efficient formation of bicyclic furans
(entries 5–8). Interestingly, the electron-withdrawing group on
R3 gave the corresponding product in higher yield than the
electron-donating substituent one (entries 7 vs. 8). The alkyl
substituent (R2) on the alkene moiety also produced the
desired product 2ia (entry 9). The structure and the stereo-
chemistry of the products were established by the X-ray
Consequently, a plausible mechanism that accounts for the
formation of fused bicyclic furan 2 is outlined in Scheme 1.
Two plausible catalytic cycles are proposed. In cycle A, the
coordination of the rhodium complex to the double alkyne
moieties of 1 would give intermediate A, which would in turn
undergo tandem cyclizations to give a carbocation inter-
mediate B with sp2C–Rh species. The introduction of a strong
p-acid CO to the system would cause the electron density of
the metal lower and thus help the rapid conversion of inter-
mediate A into B. The carbocation of intermediate B could be
rapidly trapped by the nucleophile to produce the intermediate
C. Subsequent protonation of the sp2C–Rh bond would afford
the bicyclic furan product 2 and regenerate the rhodium
catalyst. While in cycle B, nucleophilic addition of nucleophile
to the C–C double bond of intermediate A and subsequent
ꢀc
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Scheme 1 Plausible mechanism for the rhodium-catalyzed nucleo-
philic tandem cyclization.
cyclization would give a furanyl rhodium complex D.8a,9,12
The syn-addition of the sp2C–Rh to the alkyne moiety would
also furnish the intermediate C, which would in turn produce
the final product and regenerate the catalyst as cycle A.
In summary, we have demonstrated a novel rhodium-
catalyzed stereoselective tandem nucleophilic addition/
bicyclization of various alcohols with diyne-enones, which
provides an efficient, atom-economic route to multi-
functionalized 2,3-fused bicyclic furans. Diyne-enones are
easily prepared by the palladium-catalyzed cross-coupling
reactions of a-bromo(iodo)-enones with 1,6-diynes, which will
make this method more practical and useful. Further studies
including the mechanism, expanding the scope of the nucleo-
phile and the development of an asymmetric version are
underway.
6 For examples of 2,3-fused furan as
a key structure, see:
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Soc., 1987, 109, 4717; (b) K. Harada, Y. Tonoi, H. Kato and
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7 A few examples for synthesis of 2,3-fused bicyclic furans, please
see: (a) C. Oh, H. Park and D. Park, Org. Lett., 2007, 9, 1191;
(b) H. Yamamoto, I. Sasaki, H. Imagawa and M. Nishizawa, Org.
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Angew. Chem., Int. Ed., 2008, 47, 1903; (b) Y. Xiao and J. Zhang,
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This research was supported by 973 program (2009CB-
825300), the National Natural Science Foundation of China
(20702015, 20972054), and the Shanghai Municipal Committee
of Science and Technology (08dj1400101).
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11 CCDC 761108 (2ha) contains the supplementary crystallographic
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The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif. The X-structure was enclosed in the ESI.
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ꢀc
This journal is The Royal Society of Chemistry 2010
4386 | Chem. Commun., 2010, 46, 4384–4386