Enantioselective Intramolecular C?H Insertion of Donor and Donor/Donor Carbenes by a Nondiazo Approach

Article abstract of DOI:10.1002/anie.201604211

The first enantioselective intramolecular C?H insertion and cyclopropanation reactions of donor- and donor/donor-carbenes by a nondiazo approach are reported. The reactions were conducted in a one-pot manner without slow addition and provided the desired

Full text of DOI:10.1002/anie.201604211

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Communications
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International Edition: DOI: 10.1002/anie.201604211
German Edition: DOI: 10.1002/ange.201604211
Asymmetric Catalysis
À
Enantioselective Intramolecular C H Insertion of Donor- and Donor/
Donor-Carbenes by a Nondiazo Approach
Dong Zhu, Jun Ma, Kui Luo, Hongguang Fu, Li Zhang,* and Shifa Zhu*
À
Abstract: The first enantioselective intramolecular C H
insertion and cyclopropanation reactions of donor- and
donor/donor-carbenes by a nondiazo approach are reported.
The reactions were conducted in a one-pot manner without
slow addition and provided the desired dihydroindole, dihy-
drobenzofuran, tetrahydrofuran, and tetrahydropyrrole deriv-
atives with up to 99% ee and 100% atom efficiency.
been made in the past century, most work has been focused on
the transformations of acceptor-, donor/acceptor-, and
acceptor/acceptor-carbenes for their relatively good stabil-
ity.[1,2] In comparison, fewer examples have been reported for
donor- and donor/donor-carbenes because of safety (potential
explosiveness) and practicality (easy dimerization) problems
associated with the diazo compounds (Scheme 2, path a).[3–5]
I
n the past decades, few intermediates have attracted as
much interest as carbenes.[1] The versatile reactivities of
carbenes, especially metal carbenoids, make it one of the most
important and useful intermediates since it was first discov-
ered. Among different carbene sources, diazo compounds are
one of the most commonly used carbene precursors. The
diazo compounds can be classified into five types:[2] acceptor-
carbene, acceptor/acceptor-carbene, donor/acceptor-carbene,
donor-carbene and donor/donor-carbene (Scheme 1).
Although great achievements in both the theories and
technologies of carbene chemistry by a diazo approach have
Scheme 2. Carbene chemistry based on different approaches.
To meet these challenges, the reactions were typically
conducted on small scale and the diazo compounds were
added slowly, whereas these requirements severely limit the
further application of the donor- and donor/donor-carbenes.
To solve the inherent disadvantages of the diazo chemis-
try, a more promising trend has been to move away from
a traditional diazo-based carbene strategy but focus on
a nondiazo approach instead. Recently, transition-metal-
catalyzed activation and cyclization reactions of alkynes by
metal carbenoid intermediates have become a very popular
alternative pathway to realize different carbene-transfer
reactions (Scheme 2, Path b).[6] Such a strategy would be
particularly useful for donor- and donor/donor-carbenes
because it is safe (no gas emission), practical (no slow
addition required), and highly atom-efficient (up to 100%
atom efficiency).
Scheme 1. Different types of metal carbenoids.
[*] D. Zhu, J. Ma, K. Luo, Prof. Dr. S. Zhu
Key Laboratory of Functional Molecular Engineering of Guangdong
Province, School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (China)
E-mail: zhusf@scut.edu.cn
As part of our continuous efforts to develop safe and
practical carbene chemistry based on enynals/enynones as
efficient carbene precursors,[7,8] we report herein the first
Prof. Dr. S. Zhu
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (China)
À
enantioselective intramolecular C H insertion and cyclo-
H. Fu, Prof. Dr. L. Zhang
propanation reactions of donor- and donor/donor-carbenes by
a nondiazo approach. As dihydroindole and dihydrobenzo-
furan are core structures of a variety of natural and bioactive
School of Chemistry and Chemical Engineering
Sun Yat-sen University, Guangzhou, 510275 (P.R. China)
E-mail: zhli99@mail.sysu.edu.cn
À
compounds, our first target was to explore C H insertion
reactions of donor/donor-metal carbenoids, which are gen-
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604211.
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erated from the cyclization of enynones (1; see Table 1), thus
giving rise to a range of enantioenriched dihydroindoles and
dihydrobenzofurans.
phthalimide-based catalysts proved to be better choices for
the reaction, thus resulting in the desired 2a in quantitative
yield and with enantioselectivities within the 38–94% range
(entries 5–9). For example, the enantioselectivity reached to
70% when [Rh2(S-PTTL)4] was applied as the catalyst
(entry 5). The use of a bulkier dirhodium catalyst, [Rh2(S-
BPTTL)4], further increased the enantioselectivity to 85%
(entry 6). Electron-deficient dirhodium catalysts, [Rh2(S-
TCPTTL)4] and [Rh2(S-TFPTTL)4], gave 38 and 75% ee,
respectively (entries 7and 8). [Rh2(S-PTAD)4] gave the high-
est enantioselectivity of 94% ee (entry 9). N-naphthaloylteth-
ered chiral dirhodium tetracarboxylates such as [Rh2(S-
NTTL)4] performed good activity but with only moderate
enantioselectivity (entry 10). In the tested solvents, DCE
proved to be the optimal one (entries 11–13). Lowering the
reaction temperature to À208C further improved the enan-
tioselectivity to 97% ee (entry 14).
À
We optimized the C H insertion reaction conditions by
using the enynone 1a, tethered to a N-benzylacetamide, as
a standard substrate (Table 1). The desired dihydroindole 2a
could be obtained in quantitative yield and with larger than
99:1 diastereoselectivity when the reaction was conducted at
Table 1: Optimization of the reaction conditions.[a]
Entry
RhII
Solvent
Yield [%][b]
ee [%][c]
Based on the optimized reaction conditions (Table 1,
entry 14), the substrate scope of the asymmetric intramolec-
1
2
3
4
5
6
7
8
9
10
11
12
13
14[e]
[Rh2(OPiv)4]
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
toluene
hexane
DCE
99
99
8[d]
21[d]
99
99
99
99
99
99
99
99
90
99
–
22
À66
4
À
ular C H insertion was then examined. It was shown that the
[Rh2(S-DOSP)4]
[Rh2(S-BTPCP)4]
Rh2(5S-MEPY)4]
[Rh2(S-PTTL)4]
[Rh2(S-BPTTL)4]
[Rh2(S-TCPTTL)4]
[Rh2(S-TFPTTL)4]
[Rh2(S-PTAD)4]
[Rh2(S-NTTL)4]
[Rh2(S-PTAD)4]
[Rh2(S-PTAD)4]
[Rh2(S-PTAD)4]
[Rh2(S-PTAD)4]
catalytic process could be successfully applied to different
enynone substrates bearing N-alkylacetamide side chains
(Table 2). For example, in addition to 1a, various enynone
derivatives (1) containing N-arylmethylacetamides could be
effectively converted into the desired dihydroindoles 2 with
excellent enantioselectivities (91–99% ee; 2a–l). The yields
were typically higher than 90% for most substrates. The
substrates with electron-rich aryl groups have higher reac-
tivity, thus furnishing the dihydroindole products 2a–e in
70
85
38
75
94
56
88
73
80
97
À
almost quantitative yields. This C H insertion reaction could
be easily scaled up to gram scale without the loss of the yield
and enantioselectivity by using only 0.1 mol% catalyst, which
afforded the product 2 f in 96% yield and 99% ee. The
functional groups MeO, NO2, CN, and ester were all well-
tolerated (2e, 2j, 2k, 2l). Furthermore, the enynone with
N-alkylacetamide also served as a substrate, thus affording
the desired product 2m in good yield, but both the diastereo-
and enantioselectivity fell significantly (1:1 d.r., 71% ee).
Moreover, enynones with different substituents on the
carbonyl groups were also suitable substrates for this trans-
formation, and led to the dihydroindoles 2n and 2o in 94 and
80% ee, respectively.
[a] Reaction conditions: [Rh2L4]/1a=0.002: 0.2 (mmol) in 2 mL of
solvent at 258C. [b] Yield of isolated product. [c] The ee value of 2a was
determined by HPLC using a chiral stationary phase. [d] Determined by
1H NMR spectroscopy. [e] À208C, 36 h. DCE=1,2-dichloroethane.
In addition to the enynones with an N-alkylacetamide
À
substituent, we also investigated the C H insertion of
enynones having an ether side chain, thus producing the
corresponding chiral dihydrobenzofuran or tetrahydrofuran
(Table 3). Like the N-alkylacetamide enynones 1, the ether
À
counterparts also underwent the C H insertion reaction
smoothly, thus producing the corresponding products in good
yields (65–99%), whereas the ether counterparts were more
sensitive to the electronic and steric factors of R3. For
example, the enynones 1 tethered to an electron-deficient
benzylic ether functioned better than an electron-rich one
(2aa–ae). While enynones with bulkier benzylic ether moi-
room temperature with 1 mol% [Rh2(OPiv)4] in a one-pot
manner (Table 1, entry 1). Dirhodium N-sulfonylprolinates
such as [Rh2(S-DOSP)4] resulted in high yield, but with only
22% ee (entry 2). Dirhodium triarylcyclopropane carboxylate
catalysts such as [Rh2(S-BTPCP)4] led to higher enantiose-
lectivity (À66% ee), but much lower reactivity (entry 3). The
result using the rhodium(II) carboxamide catalyst [Rh2(5S-
MEPY)4] was discouraging (entry 4). To our delight, the
eties
exhibited higher enantioselectivity
(2af–ak).
Pentafluorobenzylic ether, which is an extremely electron-
deficient substrate, showed excellent stereo- and enantiose-
lectivity but with somewhat lower reactivity (2aj). In addition
to benzylic ethers, an allylic ether, aliphatic ether, and even
2
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Table 2: Synthesis of dihydroindoles.[a]
Table 3: Synthesis of dihydrobenzofurans or tetrahydrofurans.[a]
[a] [Rh2(PTAD)4]/1=0.002: 0.2 (mmol) in 2 mL of DCE. Yield is that of
isolated product. [b] 08C. [c] Determined by 1H NMR spectroscopy.
[d] The E-configured enynone 1 was used.
À
ester-containing ether also reacted smoothly in the C H
[a] [Rh2(PTAD)4]/1=0.002: 0.2 (mmol) in 2 mL of DCE. Yield is that of
isolated product. [b] The E-configured enynone 1 was used. [c] The
ee value of the major isomer.
insertion process (2al–an). In the case of allylic ether, only
insertion was observed with no detectable cyclopropane
product (2al). The aliphatic ether and 2-ethoxy-2-oxoethyl
ether had good reactivities but with moderate enantioselec-
tivities (2am). The successful preparation of dihydroindole
and dihydrobenzofuran through the insertion of a donor/
donor-carbene prompted us to explore the insertion of a more
challenging donor-carbene. As shown in Table 2, enynones
substituted with alkyl groups at the alkynyl carbon atom,
which react with the catalyst to form the donor-metal
carbenoids, are also efficient in this reaction. Both benzylic
and allylic ethers produced the desired tetrahydrofurans in
quantitative yields, albeit with somewhat lower enantioselec-
tivities (2ao–aq). In all cases shown in Tables 2 and 3, the
reactions were conducted in a one-pot manner, and it is
surprising that there were no detectable products of dimeri-
zation.
À
Having established the intramolecular C H insertion as
a reliable and efficient synthetic protocol, we then proceeded
to develop the intramolecular cyclopropanation reactions
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Table 4: Intramolecular cyclopropanation.[a]
[a] Reaction conditions: [Rh2L4]/1=0.002: 0.2 (mmol) in 2 mL of DCE at
À208C. Yield is that of the isolated product. [b] 1 mol% [Rh2(S-BPTTL)4],
À308C, 12 h.
Scheme 3. Further transformation of 2 f. mCPBA=m-chloroperbenzoic
acid, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
aimed at the cyclopropane-fused polycyclic structures. To
realize this, the enynones 1, with tethered alkenyl side chains,
were then employed. As shown in Table 4, an enynone
tethered to an N-allylic acetamide reacted smoothly, thus
giving the desired cyclopropane 3a in 98% yield and good
cyclopentenone 6 was formed, presumably by an oxidation/
aldol reaction sequence.
In summary, we have developed the first enantioselective
À
intramolecular C H insertion and cyclopropanation reactions
of donor- and donor/donor-carbenes by a nondiazo approach.
The reactions were conducted in a one-pot manner without
slow addition and provided the desired dihydroindole,
dihydrobenzofuran, tetrahydrofuran, and tetrahydropyrrole
derivatives with up to 99% ee and 100% atom efficiency. We
À
selectivity. No allylic C H insertion product was detected.
À
Interestingly, a competition between C H insertion and
cyclopropanation occurred when 3,3-dimethyl allylic acet-
amide was chosen as the substrate, with the insertion product
dominated. The reaction afforded the insertion product 2p
and cyclopropane product 3b. Such results may be attributed
to the steric effect of the dimethyl groups, which impeded the
cyclopropanation. This proposal was supported by the results
in which the sole cyclopropane 3c was formed in quantitative
yield when a less bulky substrate, 2-methyl allylic acetamide,
was applied as the substrate. However, the enantioselectivity
of 3c dropped dramatically to 47%. Similarly with the
insertion reactions, the cyclopropanation could be extended
to a donor-carbene as well. For example, when an enynone
with a nonaromatic amide side chain was utilized as the
donor-carbene precursor, the desired cyclopropane 3d was
produced in quantitative yield and good selectivity by using
1 mol% [Rh2(S-BPTTL)4] as the catalyst instead.
À
believe that these safe and practical asymmetric C H
insertion and cyclopropanation reactions of the donor- and
donor/donor-carbenes by a non-diazo approach, without the
formation of the dimerization alkene side-products and the
requirement of slow addition, should provide appealing
methodologies for organic synthesis. Investigations on further
applications of these reactions are underway in our labora-
tory.
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).
À
With the C H insertion products 2 in hand, further
chemical transformations were also carried out to demon-
strate the potential applications of these molecules
(Scheme 3). Take 2 f as an example, for the N-acetyl group
could be easily removed under acidic conditions in 90% yield.
Furthermore, the furan moiety of the product is a good diene
and reacted with benzyne to form the product 5 through
a [4+2] cycloaddition. In the above-mentioned transforma-
tions, both the diastereo- and enantioselectivity remained
unchanged. More interestingly, when 2 f was subjected to
oxidation conditions with mCPBA as the oxidant,[9] the spiro-
Keywords: asymmetric catalysis · carbenes · heterocycles ·
insertion · rhodium
4
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À
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Received: April 30, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
D. Zhu, J. Ma, K. Luo, H. Fu, L. Zhang,*
S. Zhu*
&&&& — &&&&
À
Enantioselective Intramolecular C H
Insertion of Donor- and Donor/Donor-
Carbenes by a Nondiazo Approach
Generous donor: Enantioselective intra-
ducted in a one-pot manner without slow
addition and provided the desired dihy-
droindole, dihydrobenzofuran, tetrahy-
drofuran, and tetrahydropyrrole deriva-
tives with up to 99% ee.
À
molecular C H insertion and cyclopro-
panation reactions of donor- and donor/
donor-carbenes by a nondiazo approach
are reported. The reactions were con-
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!