Dual Catalysis: Proton/Metal-Catalyzed Tandem Benzofuran Annulation/Carbene Transfer Reaction

Article abstract of DOI:10.1021/acs.orglett.6b00260

An efficient proton/metal-catalyzed tandem benzofuran annulation/carbene transfer reaction for the synthesis of various benzofuryl-substituted cyclopropanes and cycloheptatrienes has been developed. The reaction was proposed to proceed through two key int

Full text of DOI:10.1021/acs.orglett.6b00260

Letter
pubs.acs.org/OrgLett
Dual Catalysis: Proton/Metal-Catalyzed Tandem Benzofuran
Annulation/Carbene Transfer Reaction
Jun Ma,† Kai Chen,† Hongguang Fu,‡ Li Zhang,‡ Wanqing Wu,† Huanfeng Jiang,† and Shifa Zhu*,†
†School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, P. R. China
‡School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, 510275, P. R. China
S
* Supporting Information
ABSTRACT: An efficient proton/metal-catalyzed tandem
benzofuran annulation/carbene transfer reaction for the
synthesis of various benzofuryl-substituted cyclopropanes and
cycloheptatrienes has been developed. The reaction was
proposed to proceed through two key intermediates, o-
quinone methide (o-QM) and benzofuryl carbene. The DFT-based computational studies indicated that the reaction was
initiated through the dehydration of o-HBA via a Brønsted acid mediated proton shuttle transition state, forming the key
intermediate o-QM.
Scheme 2. Formation of Furyl Carbene from Enynal/
Enynone or o-HBA
ual catalysis is a powerful catalytic strategy in modern
organic synthesis. It is particularly useful in the
D
generation and trapping of those highly reactive transient
species.1
o-Quinone methide (o-QM), a transient short-lived and
highly reactive species, has attracted extensive interest from
organic chemists for over 100 years.2 Many of the synthetic
techniques for producing o-QMs have been developed in the
past decades, such as tautomerization, thermolysis, photolysis,
and acid facilitation.3,4 Among them, acid facilitation probably
is one of the most useful strategies, and many tautomerization
and thermal processes can be induced to occur at much lower
temperature by addition of an acid catalyst. For example, in the
presence of an acid catalyst, o-QM can be formed smoothly
from the reaction of o-hydroxyl-benzyl alcohol (o-HBA) at
room temperature,4 whereas without the help of an acid
catalyst, the reaction is largely decelerated and o-QM can be
generated at much higher temperature (>100 °C)3 (Scheme 1).
made to systematically investigate various catalytic reaction
conditions for the tandem benzofuran annulation/cyclopropa-
nation reaction. The metals used most commonly in carbene
transformations, such as Cu, Ag, Au, and Rh, were then tested.
It was found that the desired product 2a has not been detected
when the metal catalysts were used alone, indicating that they
are inefficient for this transformation (entries 1−4). We
speculated that it might be the consequence of inefficiency of
the formation of o-QM. The attempt to facilitate the generation
of the o-QM intermediate by enhancing the temperature
resulted in a complex system. The product 2a could be detected
in 18% yield when 1 mol % Rh2(OPiv)4 was used as the catalyst
at 80 °C (entry 5). To examine whether the addition of acids
could promote the formation of o-QM, the reactions in the
presence of different acids as the cocatalyst of Rh2(OPiv)4 have
been carried out (entries 6−8). The addition of TsOH has no
obvious positive effects (entry 6), whereas the yield of 2a was
increased to 44% when PhCOOH was applied (entry 7).
Gratifyingly, the yield was sharply enhanced to 88% when 50
Scheme 1. Generation of o-QM by Thermolysis or Acid
Facilitation
Recently, enynal/enynone has proved to be a new, safe, and
practical carbenoid precursor.5 We speculated that alkynyl-
substituted o-HBA might be used as the benzofuryl carbene
precursor under the dual catalysis of an acid and a transition
metal via o-QM as the proposed intermediate (Scheme 2).6
With this in mind, o-HBA (1a) with a tethered enyne side
chain was then chosen as the model substrate for this
investigation, aiming at producing the cyclopropyl-fused
pyrrolidine7 (2a). As shown in Table 1, initial efforts were
Received: January 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00260
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Scope of Cyclopropanation Reaction
entry
cat.-1 (mol %)
cat.-2 (mol %)
yield (%) (2a)
1
2
3
4
CuCl2 (5)
−
−
−
−
ND
ND
ND
ND
18
AgNTf2 (5)
PPh3AuNTf2 (5)
Rh2(OPiv)4 (1)
Rh2(OPiv)4 (1)
Rh2(OPiv)4 (1)
Rh2(OPiv)4 (1)
Rh2(OPiv)4 (1)
CuCl2 (5)
b
5
−
6
TsOH (50)
PhCOOH (50)
TFA (50)
TFA (50)
TFA (50)
TFA (20)
TFA (100)
TFA (50)
20
7
44
c
8
88
9
77
10
11
12
13
AgNTf2 (5)
trace
60
Rh2(OPiv)4 (1)
Rh2(OPiv)4 (1)
−
65
ND
a
The reaction was conducted with 1a (0.2 mmol) in DCE (1 mL), rt,
1
under N2, 3 h. The yield was determined by H NMR analysis using
b
CH3NO2 as an internal standard; TFA: CF3COOH. 80 °C, 12 h.
c
Isolated yield.
mol % TFA was added instead (entry 8). The combination of
CuCl2/TFA is another good choice for this transformation,
albeit in a relatively lower yield (entry 9). However, only a trace
amount of the desired product 2a was detected when AgNTf2/
TFA was employed (entry 10). Neither increasing nor
decreasing the amounts of TFA in the rhodium-catalytic
system can give better results (entries 11−12). TFA alone does
not catalyze the formation of 2a at all (entry 13).
With the optimized reaction conditions (Table 1, entry 8) in
hand, the substrate scope was then examined (Table 2). It was
found that the Rh2(OPiv)4/TFA catalytic system could be
successfully applied to the reaction of a variety of o-HBA
derivatives 1. The aryl substituents R1 have little effect on the
yields (2a−f, 74−93%). In addition to the o-HBAs 1 with a
simple terminal alkene, the substrates with a di- or
trisubstituted alkene unit could also be effectively converted
into the desired cyclopropane products in satisfied yields (2g−
k, 64−87%), although the reactions were accomplished at
elevated temperature (e.g., 80 °C). Furthermore, the reaction
could be extended to the o-HBA with a tertiary alcohol (R2 =
Me), giving the product in excellent yield (2l, 88%). A bulky
substrate (R6 = R7 = Me) transferred to the product in
moderate yield (2m, 43%). Moreover, the o-HBAs with a
longer side chain (n = 2, 3) could also be used as effective
substrates, leading to the desired products 2n and 2o in 73%
and 36% yields, respectively. For the latter case, a C−H
insertion product 2o′ could be isolated in 40% yield as well,
indicating that the reaction probably proceeded through the
Rh-carbene intermediate (excluding the carbon cation mech-
anism7).8 In all cases in Table 2, only one diastereoisomer was
observed.
a
Conditions: Rh2(OPiv)4 (1 mol %), TFA (50 mol %), DCE (1 mL),
b
1 (0.2 mmol), rt, 3−12 h, isolated yield. 80 °C.
typically higher than 60%. For examples, both electron-rich and
-deficient substituents of R1 functioned well. It seems that
electron-donating groups of R1 (4a−4c) gave better results
than electron-withdrawing ones (4d, 4f). However, the
electron-donating group methoxy (MeO−) led to product 4e
only in 44% yield, presumably due to the potential interaction
between the electron-rich phenyl ring and the rhodium catalyst.
The electronic effects of R2 on the benzyl group had relatively
little effect on this reaction, giving the desired products 4g−4k
in 41%−78% yields. Furthermore, the reaction could be
extended to the o-HBA with a tertiary alcohol (R3 = Me) as
well, giving the product 4l in 74% yield.
Besides the intramolecular reaction, the proton/Rh-catalyzed
system could be extended to the intermolecular cyclo-
propanation as well. For instance, styrene could be cyclo-
propanated by the Rh2(OPiv)4/TFA in dichloroethane with o-
HBA 5 as a carbene source at room temperature, affording the
desired product 6 in 55% yield, accompanied by a 15% yield of
chroman 7. The latter should come from the [4 + 2]
cycloaddition of the in situ generated o-QM with styrene
[Scheme 3, eq 1].4 Actually, chroman 7 could be produced
solely in 74% yield when the reaction was promoted merely by
TFA eq 2. Furthermore, when o-HBA 5 was subjected to
In addition to the cyclopropantion reaction, another
representative carbene-transfer reaction, a Buchner ring-
expansion reaction, was also investigated for this dual catalysis.9
For this purpose, various N-benzyl derived substrates o-HBA 3
were then tested. As shown in Table 3, the reaction has good
substrate scope. A variety of different substituents R1, R2, and
R3 were well tolerated for this reaction system. The yields were
B
DOI: 10.1021/acs.orglett.6b00260
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 3. Scope of Buchner Reaction
Scheme 4. Proposed Reaction Mechanism15
a
Conditions: Rh2(OPiv)4 (1 mol %), TFA (50 mol %), DCE (1 mL),
b
c
3 (0.2 mmol), rt, 3−12 h, isolated yield. 72 h. 80 °C, without TFA.
Scheme 3. Intermolecular Reaction
the dehydration process. Similar to Chen and co-workers’
theoretical study,13 the following cyclopropanation step is
concerted but asynchronous. This step requires an activation
free energy of 12.3 kcal/mol, while its reverse requires 45.6
kcal/mol, which indicates an irreversible process. Furthermore,
the direct attack of phenolic oxygen to the Rh-alkyne complex
pathway14 was also considered (Mechanism II), but not as
favorable as the acid assisted dehydration pathway. The energy
barrier for the nucleophilic attack of the phenolic oxygen (sp2
hybridization) to the Rh-alkyne complex is about 25.8 kcal/mol
in Gibbs free energy, which is higher than that of the acid
assisted dehydration process (21.2 kcal/mol). It is notable that
the energy barrier for the nucleophilic attack of the o-QM
oxygen (sp2 hybridization) to the Rh-alkyne complex (2.9 kcal/
mol) is much lower than the phenolic oxygen attack process
(25.8 kcal/mol). (See Supporting Information for the details of
the calculation.)
In summary, we have developed an efficient proton/metal-
catalyzed tandem benzofuran annulation/cyclopropanation and
Buchner reaction for the synthesis of various benzofuryl-
substituted cyclopropanes and cycloheptatrienes. The reaction
was proposed to proceed through two key intermediates, o-QM
and benzofuryl carbene. Full analysis of the reaction
mechanistic pathway by DFT-based computational methods
revealed that the reaction was initiated through the dehydration
of o-HBA via a Brønsted acid mediated proton shuttle
transition state, forming the key intermediate o-QM. Such a
Brønsted acid mediated proton shuttle model may provide
useful insight in understanding the reaction process and
designing new reactions. Investigations on the asymmetric
Rh2(OPiv)4 without the addition of TFA, neither 7 nor 5 could
be detected.10
A possible reaction mechanism was proposed based on the
reaction results and was also rationalized by DFT-based
methods.11 Taking the cyclopropanation reaction as example,
the reaction starts with the dehydration of o-HBA 1a via a
Brønsted acid mediated proton shuttle transition state,12
forming the key intermediate o-QM (Scheme 4, Mechanism
I). Under the catalysis of CF3COOH, both cis-o-QM I and
trans-o-QM I′ could be easily generated, with the energy
barriers of 21.2 and 18.3 kcal/mol, respectively (Scheme 4).
However, only cis-o-QM could be consumed through the
rhodium-catalyzed benzofuran annulation/cyclopropanation
tandem reaction, which drives the reaction to the right
direction. The energy barrier for benzofuran annulation step
is about 2.9 kcal/mol, which is almost negligible compared to
C
DOI: 10.1021/acs.orglett.6b00260
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
D.; McClintock, S. P.; Haley, M. M. Chem. Soc. Rev. 2008, 37, 343.
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value is up to 82% when Rh2(S-TFPTTL)4 was used as a chiral
catalyst. See Supporting Information for detail.
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version and additional applications of this reaction are
underway in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00260.
Typical experimental procedure and characterization for
all products (PDF)
(10) When the reaction was conducted with 10 mol % Rh2(OPiv)4 as
a catalyst at rt for 24 h, only alcohol 8 could be detected in less than
10% yield. For a similar catalytic process, see: (a) Harkat, H.; Blanc,
A.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2008, 73, 1620. (b) Yu, M.;
Lin, M.-D.; Han, C.-Y.; Zhu, L.; Li, C.-J.; Yao, X.-Q. Tetrahedron Lett.
2010, 51, 6722.
AUTHOR INFORMATION
■
Corresponding Author
* E-mail: zhusf@scut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate financial support from the NSFC (21372086 and
21422204), Guangdong NSF (2014A030313229), SRF for
ROCS, State Education Ministry, The Fundamental Research
Funds for the Central Universities, SCUT, and China
Postdoctoral Science Foundation (Grant No. 2015M582378).
(11) All structures were optimized in Gaussian09 using a hybrid
B3LYP functional in conjugation with the LANL2DZ basis set for
rhodium, augmented with a 4f function and the 6-31g(d) basis set for
the other atoms at 298 K. Frequency calculations were performed at
the same theoretical level to obtain the thermal corrections.
(12) (a) Xu, B.; Li, M.-L.; Zuo, X.-D.; Zhu, S.-F.; Zhou, Q.-L. J. Am.
Chem. Soc. 2015, 137, 8700. (b) Xu, B.; Zhu, S.-F.; Xie, X.-L.; Shen, J.-
J.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2011, 50, 11483. (c) Liang, Y.;
Zhou, H.; Yu, Z.-X. J. Am. Chem. Soc. 2009, 131, 17783. (d) Xu, B.;
Zhu, S.-F.; Zhang, Z.-C.; Yu, Z.-X.; Ma, Y.; Zhou, Q.-L. Chem. Sci.
2014, 5, 1442. (e) Xu, B.; Zhu, S.-F.; Zuo, X.-D.; Zhang, Z.-Z.; Zhou,
Q.-L. Angew. Chem., Int. Ed. 2014, 53, 3913. (f) Kisan, H. K.; Sunoj, R.
B. Chem. Commun. 2014, 50, 14639. (g) Kisan, H. K.; Sunoj, R. B. J.
Org. Chem. 2015, 80, 2192.
(13) Xue, Y.-S.; Cai, Y. P.; Chen, Z.-X. RSC Adv. 2015, 5, 57781.
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(15) Optimized transition structures are illustrated using CYLView.
Tosyl groups are simplified as S atoms, and some atoms are set to be
transparent for clarity. Selected bond lengths are given in Å, and atoms
of C, H, O, N, F, and S are colored in gray, light gray, red, blue, green,
and yellow, respectively.
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DOI: 10.1021/acs.orglett.6b00260
Org. Lett. XXXX, XXX, XXX−XXX