One-pot novel regioselective cycloisomerization synthesis of 2-substituted or 3-substituted 4 H-furo[3,2- c ]chromene through the intermediate cyclopropenes of 3-diazochroman-4-one and phenylacetylene

Article abstract of DOI:10.1021/ol502854y

A new class of cyclopropenes containing a chroman-4-one motif were synthesized using 3-diazochroman-4-one and phenylacetylene with rhodium(II) catalyst and followed by cycloisomerization to give 2-substituted or 3-substituted 4H-furo[3,2-c]chromene, respe

Full text of DOI:10.1021/ol502854y

Letter
pubs.acs.org/OrgLett
One-Pot Novel Regioselective Cycloisomerization Synthesis of
2‑Substituted or 3‑Substituted 4H‑Furo[3,2‑c]chromene through the
Intermediate Cyclopropenes of 3‑Diazochroman-4-one and
Phenylacetylene
Jin Gong, Zhensheng Zhao, Fuming Zhang, Songyun Wu, Guangqi Yan, Yingjie Quan, and Baochun Ma*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A new class of cyclopropenes containing a chroman-4-one
motif were synthesized using 3-diazochroman-4-one and phenylacetylene
with rhodium(II) catalyst and followed by cycloisomerization to give 2-
substituted or 3-substituted 4H-furo[3,2-c]chromene, respectively. Using
BF3·Et2O as catalyst, 2-substituted 4H-furo[3,2-c]chromene was
exclusively obtained in 70% yield. Using Cu(OTf)2 as catalyst, 3-
substituted 4H-furo[3,2-c]chromene was obtained in 95% yield with 98:2
regioselectivity. A one-pot cascade addition−cycloisomerization process
was also developed with no need to isolate cyclopropenes of chroman-4-one intermediates.
yclopropenes,1 highly strained but readily accessible
Ccarbocyclic molecules, have been shown to possess useful
reactivity in organic synthesis. Functionalized cyclopropenes as
bioorthogonal chemical reporters can be used to target
biomolecules in vitro and in live cells owing to their rigorous
and highly strained structure. Although rhodium-catalyzed
intermolecular cyclopropenation with donor−acceptor carbe-
noids is a well-established process,2,3 there have been rare
reports on the cyclopropeneation of 3-diazochroman-4-one and
phenylacetylene.
catalyst, 3-substituted 4H-furo[3,2-c]chromene was obtained
with 98:2 regioselectivity. We also developed a one-pot cascade
addition−cycloisomerization process to synthesize 4H-furo[3,2-
c]chromene with no need to isolate cyclopropenes of chroman-
4-one intermediates (Scheme 1).
Scheme 1. Synthesis of Multisubsituted Furan
As part of our ongoing efforts4 toward the asymmetric
synthesis of 3,3′-biflavanones, we have exclusively obtained
cyclopropenes of 3-diazochroman-4-one in the presence of
rhodium catalyst accompanied by no cycloisomerization
products. Cyclopropenes containing the chroman-4-one motif
have a unique structure with much more ring strain. After a
cycloisomerization reaction catalyzed by BF3·Et2O or Cu-
(OTf)2, 2-trisubstituted or 3-trisubstituted furo[3,2-c]chromene
was obtained with good efficiency and regioselectivity. This
class of cyclopropenes containing a chroman-4-one motif has
not been employed as a substrate for cycloisomerizations to
synthesize the 4H-furo[3,2-c]chromene skeleton.
The 4H-furo[3,2-c]chromene skeleton5 can be found in
many natural products and exhibits potential biological activity.
Most synthetic methods have focused on the construction of a
pterocarpan system which is the combination of benzofuran
and chromene scaffold.6−13 Herein, we report the synthesis of
unique cyclopropenes containing a chroman-4-one motif using
3-diazochroman-4-one and phenylacetylene with rhodium(II)
catalyst, followed by regioselectively cycloisomerization to give
2-substituted or 3-substituted 4H-furo[3,2-c]chromene, respec-
tively. Using BF3·Et2O as catalyst, 2-substituted 4H-furo[3,2-
c]chromene was exclusively obtained. Using Cu(OTf)2 as
On the basis of the initial results, a number of different
catalysts, solvents, and operating procedures were tested to
optimize the cyclopropene reaction conditions (Table 1).
When Rh2(OAc)4 was used as catalyst, a benchmark catalyst in
metal carbenoid chemistry (Table 1, entry 1−4), the yield of
the reaction was decreased greatly after completion of the
reaction in 3 h as determined by TLC. Rh2(Oct)4 at −5 °C
Received: July 18, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502854y | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
a b
,
Table 1. Optimization for the Reaction Conditions
Scheme 2. Substrate Scope for the Formation of 3
entry
catalyst
Rh2(OAc)4
solvent
CCl4
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
rt
rt
20
c
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(Oct)4
CH2Cl2
CH3CHCl2
n-hexane
CCl4
NR
NR
NR
26
rt
rt
rt
Ru(BYP)3
CCl4
rt
NR
NR
NR
57
(Ph3P)3RuCl2
[(p-cymene)Ru]2Cl4
Rh2(Oct)4
CCl4
rt
CCl4
rt
CCl4
−5
−20
Rh2(Oct)4
CCl4
85
a
Reaction conditions: The reaction was carried out using 1 (0.2
mmol), 2 (0.2 mmol), and catalyst (0.1 mol %) in the solvent (5 mL).
b
c
Isolated yields. NR = not reaction.
could promote the reaction efficiency to afford 3a in 57% yield
(Table 1, entry 9), while at room temperature, the yield
dropped to 26% (Table 1, entry 5). Among other transition-
metal catalysts, Ru(BYP)3, (Ph3P)3RuCl2, and [(p-cymene)-
Ru]2Cl4 could not proceed the reaction (Table 1, entry 6,7,8).
After screening commonly used solvents, CCl4 was superior to
CH2Cl2, CH3CHCl2, and n-hexane. After numerous screenings,
we found that the reaction of 1 and 2 applying Rh2(Oct)4 (0.1
mol %) in CCl4 (5 mL) at −20 °C to give the expected
products 3a in 85% yield (Table 1, entry 10). Attempts to add
in more RhII catalyst failed to generate cycloisomerization
product 4H-furo[3,2-c]chromene, this may be due to the
specific structure of chroman-4-one precursor.8h,i
With the optimal reaction conditions in hand (Table 1, entry
10), we then tested the functional group tolerance of the newly
developed [2 + 1] cycloaddition reactions of 2,2-dimethyl-3-
diazochroman-4-one 1 and phenylacetylene. Some typical
examples for this regioselective transformation are summarized
in Scheme 2.
a
All reactions were performed by addition of the 1 (0.2 mmol) in 3
mL of CCl4 over 3 h to a stirred solution of 2 (0.2 mmol) and
b
Rh2(Oct)4 (0.1 mol %) in CCl4 (2 mL) at −20 °C. Isolated yields.
c
Low solubility of substrate 2t in CCl4
period of months and should be stored at −20 °C to avoid
decomposition.
With the cyclopropenes of chroman-4-one in hand, the
generality of the reaction and different substituent effects were
subsequently investigated. With 1 mol % of BF3·Et2O as the
catalyst, we developed a novel Lewis acid catalyzed cyclo-
isomerization of cyclopropenes of chroman-4-one, and some of
the typical results are summarized in Scheme 3. When the
substrate 3a derived from 2,2-dimethyl-3-diazochroman-4-one
and acetylene was employed, the anticipated chroman-4-one
derivative 4a was obtained in 70% yield (Scheme 3). All
cyclopropenes (Scheme 3, 3a−p) could exclusively cyclo-
isomerize to corresponding 2-substituted-4H-furo[3,2-c]-
chromene in tolerance with R1 as an alkyl benzyl, aryl, or
vinyl group, while cyclopropane, 5-benzyl, and 5-phenyl groups
gave low yield due to some portion of unidentified products.
With the cyclopropenes of chroman-4-one in hand, the
feasibility of Cu(II)-catalyzed cycloisomerization to 4H-furo-
[3,2-c]chromene was also investigated (Scheme 4). This
method furnished a straightforward route to 3-substituted
4H-furo[3,2-c]chromene and with Pd(II) or Cu(I) catalysts 2-
substituted 4H-furo[3,2-c]chromene could be obtained.9b,10b
The regioselectivity difference should be attributed to our
unique chroman-4-one skeleton.
Obviously, the R2 group with electronic and steric variation
on the acetylene moiety afforded the corresponding cyclo-
propene product in good to moderate yields. The effect of R1
group was investigated. The result showed the steric effect on
the reaction obviously. When R1 was methyl or ethyl group, the
reaction was finished as reasonable yield (Table 2, such as 3a,
3b, and 3c). The sterically hindered group decreased the yield
(Scheme 2, such as 3r and 3s). Compared with electronic
effects on aromatic substitution of chroman-4-one, the
electronics of 3-diazo-2-substituted chroman-4-one should be
similar; this dramatic difference in reactivity can be rationalized
on the basis of steric interference. R3 with an electron-donating
group (Scheme 2, such as 3f, 3h) or electron-withdrawing
group (Scheme 2, such as 3g and 3t) showed no significant
electronic effect; this difference in reactivity can be rationalized
on the basis of steric interference. Because of the slight steric
effects of R2, 3p was obtained in 63% yield. Significantly, the
cyclopropene reaction is compatible with various benzocyclic
systems (Scheme 2, such as 3d, 3e, 3h, and 3p).
Benzocyclopentanone and benzocyclohexanone can also be
compatible. Cyclopropene bearing a chroman-4-one motif was
slowly decomposed on standing at room temperature over a
We chose 3c as the model substrate to test Cu-catalyzed
cycloisomerization. The reactions did occur smoothly under
these catalytic conditions, and 3-substituted 4H-furo[3,2-
c]chromene 5c could be obtained in 95% yield with 98:2
B
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Organic Letters
Letter
ab
,
A possible mechanism for this regioselectivity cycloisomeri-
zation was depicted in Scheme 5 on the basis of previous
Scheme 3. Substrate Scope for the Formation of 4
Scheme 5. Proposed Reaction Mechanism
work14 and our experimental results. 3-Diazochroman-4-one
was reacted with acetylene under rhodium(II) catalyst to form
cyclopropene chroman-4-one. In the presence of the Cu(II)
catalyst, the copper cation attacks the less substituted sp2
carbon atom of cyclopropenone compounds, undergoing a
ring-opening reaction to afford copper carbene intermediate,
and then the carbonyl oxygen atom attacks the metal carbene
carbon atom to afford the corresponding 3-substituted 4H-
furo[3,2-c]chromene product. With BF3·Et2O as catalyst, BF3·
Et2O chelated to the carbonyl group as a driving force to induce
cyclopropene ring opening and a reclosure process, resulting in
2-substituted 4H-furo[3,2-c]chromene product.
a
All reactions were performed by addition of the BF3·Et2O (1 mol %)
to a stirred solution of 3 (0.2 mmol) in dry CCl4 (3 mL) at 0 °C. The
b
reaction mixture naturally warmed to room temperature. Isolated
yields.
a d
−
Scheme 4. Substrate Scope for the Formation of 5
With the optimized cycloisomerization reaction conditions in
hand, we attempted to test a one-pot cascade addition−
cycloisomerization reaction between 3-diazochroman-4-one
and acetylene without isolating the intermediate cyclopropene
chroman-4-one. Compound 1a was treated with phenyl-
acetylene under 0.1% equiv of rhodium catalysts in CCl4 at
−20 °C for 3 h, and then 1% equiv of BF3·Et2O was added to
the reaction mixture at 0 °C. After the reaction mixture was
stirred for 2 h at room temperature, the desired 2-substituted
4H-furo[3,2-c]chromene 4a was obtained in 60% yield.
We also attempted a Cu(OTf)2 catalyzed one-pot cascade
addition−cycloisomerization; compound 1c was treated with
phenylacetylene under 0.1% equiv of rhodium catalyst in CCl4
at −20 °C for 3 h, 5% equiv of Cu(OTf)2 was added to the
reaction mixture at 0 °C, the reaction was stirred at 40 °C, and
the desired 3-substituted-4H-furo[3,2-c]chromene 5c was
obtained in 83% yield.
In summary, we have developed a novel one-pot cascade
addition−cycloisomerization of 3-diazochroman-4-one and
phenylacetylene for the regioselective synthesis of 2-substituted
4H-furo[3,2-c]chromene or 3-substituted 4H-furo[3,2-c]-
chromene by using the catalyst BF3·Et2O or Cu(OTf)2,
respectively. The method is efficient (up to 95% yield and
98:2 regioselectivity), and there is no need to isolate the
cyclopropenes of chroman-4-one. The reaction could be
applied to the synthesis of various natural product skeletons.
Further studies into the scope, mechanism, and synthetic
applications of this transformation are being carried out in our
laboratory.
a
All reactions were performed by a solution of 3 (0.2 mmol) and
Cu(OTf)2 (5 mol %) in dry CCl4 (3 mL), stirred at 40 °C. The
b
reaction mixture naturally warmed to room temperature. Isolated
c
yields. Unless otherwise specified, isolated yields of two isomers.
d
The ratio was determined by 1H NMR analysis of the crude reaction
mixture.
regioselectivity with 5 mol % of Cu(OTf)2 as the catalyst. We
tried more typical substrates such as 3c, 3d, 3g, 3h, 3j, 3m, and
3o to test copper(II)-catalyzed cycloisomerization and obtained
the desired 3-substituted 4H-furo[3,2-c]chromene 5c, 5d, 5g,
5h, 5j, 5m, and 5o with high regioselectivity.
C
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Organic Letters
Letter
Tetrahedron Lett. 2000, 41, 4795. (g) Muller, P.; Allenbach, Y. F.;
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, full characterization of new products,
and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
Bernardinelli, G. Helv. Chim. Acta 2003, 86, 3164. (h) Briones, J. F.;
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AUTHOR INFORMATION
Corresponding Author
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(c) Song, C.; Ju, L. Chem.Eur. J. 2013, 19, 3584.
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*E-mail: mabaochun@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (grant no 21172098, 21173105),
the Fundamental Research Funds for the Central Universities
(lzujbky-2013-50, lzujbky-2013-ct02), and the 111 Project of
Chinese Ministry of Education.
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