Highly Chemo- and Stereoselective Catalyst-Controlled Allylic C?H Insertion and Cyclopropanation Using Donor/Donor Carbenes

Article abstract of DOI:10.1002/anie.201805676

The highly chemo-, enantio-, and diastereoselective catalyst-controlled intramolecular allylic C?H insertion and cyclopropanation of donor/donor carbenes are reported. The Ru^II/Pybox complex selectively catalyzed the intramolecular allylic C?H

Full text of DOI:10.1002/anie.201805676

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Accepted Article
Title: Catalyst-Controlled Highly Chemo- and Stereoselective Allylic C-
H Insertion and Cyclopropanation of Donor/Donor-Carbenes
Authors: Shifa Zhu, Dong Zhu, Lianfen Chen, He Zhang, Zhiqiang Ma,
and Huanfeng Jiang
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Angewandte Chemie International Edition
10.1002/anie.201805676
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Asymmetric Catalysis
Catalyst-Controlled Highly Chemo- and Stereoselective Allylic
C-H Insertion and Cyclopropanation of Donor/Donor-Carbenes**
Dong Zhu, Lianfen Chen, He Zhang, Zhiqiang Ma, Huanfeng Jiang, and Shifa Zhu*
Abstract: Catalyst-controlled highly chemo-, enantio-, and
diaseteroselective intramolecular allylic C−H insertion and
cyclopropanation of donor/donor-carbenes were reported. The
Ru(II)/Pybox complex selectively catalyzed the intramolecular
allylic C−H insertion, providing vinyl-substituted dihydroindoles
with > 20:1 chemoselectivity and up to > 99% ee. Chiral
dirhodium(II) tetracarboxylates, however, selectively promoted the
intramolecular cyclopropanation, giving rise to cyclopropane-
fused tetrahydroquinoline derivatives in excellent yields with >
Scheme 1. Chemoselectivity of cyclopropanation and C-H insertion.
Recently, carbene transfer reactions via non-diazo approaches
have received a lot of attention due to the obvious advantages of
safety (no gas emission) and practicality (no slow addition
required).[ These new methods are particularly useful in the
transformation of donor- and donor/donor-carbenes, as the
corresponding diazo precursors are potentially explosive and easy
9
9:1 chemoselectivity and up to 97%ee.
8]
C
hemoselectivity has long been a significant problem in organic
[1]
synthesis. Efficient control of chemoselectivity could afford
[9]
to dimerize. In 2016, we reported a Rh2(II)-catalyzed highly
[2]
access to different products from the same starting materials. As
one of the most important and useful intermediates, carbene offers
abundant and selectable methods to construct various C-C and C-
heteroatom bonds in both intramolecular and intermolecular
patterns. Among numerous reactions involving a transition-metal
carbene, cyclopropanation and C-H insertion represent the two
most common processes and have found wide applications in
chemical transformations.[4] However, cyclopropanation and C-H
insertion often take place competitively when using an allylic
substrate to trap the carbene intermediate, which severely limits the
practical applications of this process in synthetic chemistry
enantioselective intramolecular benzylic C-H insertion with
enynones as the donor- and donor/donor-carbene source.
[10]
However, cyclopropanation occurred selectively when it came to
N-allylic enynone substrates (Scheme 2, path a). Compared with
the facile cyclopropanation, realizing the C-H insertion of N-allylic
enynones, especially with high chemo- and stereoselectivity, would
be a great challenge. Herein, we would like to report a catalyst-
controlled highly chemo-, enantio-, and diastereoselective allylic
C-H insertion with N-allylic enynones as the donor/donor-carbene
precursors (Scheme 2, path b).
[3]
[5]
(Scheme 1). Over the past decades, extensive efforts have been
devoted to achieving chemoselective allylic C-H insertion and
cyclopropanation, especially with donor/acceptor-carbenes.[6]
However, establishment of chemo- and stereoselective approaches
to divergently acquire both cyclopropanation and C-H insertion
products from the same reactant pool still remains challenging but
[7]
highly desirable.
Scheme 2. Divergent reaction pathways of allylic substrate.
Initially, N-allylic enynone 1a was chosen as the model
substrate to screen the reaction conditions. As shown in Table 1,
cyclopropane 2a was obtained in 99% yield and 91% ee under the
catalysis of 1 mol% Rh2(S-PTAD)4 at room temperature (Table 1,
[
] D. Zhu, Dr. L. Chen, H. Zhang, Prof. Dr. Z. Ma, Prof. Dr. H. Jiang,
[10]
entry 1), which was consistent with our previous report.
For
Prof. Dr. S. Zhu
other chiral Rh2(II) complexes, such as Rh2(S-DOSP)4, Rh2(S-
PTTL)4 and Rh2(5S-MEPY)4, the cyclopropanation reaction
dominated as well, giving the cyclopropane product 2a in 84-99%
yields and 4-77% ee (entries 2-4). These results suggested that for
the dirhodium(II) system, the cyclopropanation reaction is more
likely to take place than C-H insertion. It’s well known that
ruthenium complexes are good catalysts for carbene transfer
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
[] We are grateful to Ministry of Science and Technology of the
People’s Republic of China (2016YFA0602900), the NSFC
(
21672071), Natural Science Foundation of Guangdong Province
2016A030310433), the Guangdong Natural Science Foundation
2018B030308007), Science and Technology Program of Guangzhou
201707010316), and the Fundamental Research Funds for the
[11]
reactions. Different combinations of [Ru(p-cymene)Cl2]2/Pybox
(
were then tested for this transformation as well (entries 5-10).
When Pyboxes L1-L4 were applied as chiral ligands for Ru(II), the
reaction also gave exclusively cyclopropane 2a with good yields
but low enantioselectivities (entries 5-8). Interestingly, when
bulkier ligand L5 was used, C-H insertion product 3a was obtained
with 91% ee, albeit in low yield (ca. 8%, entry 9). It is gratifying to
(
(
Central Universities, SCUT.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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Angewandte Chemie International Edition
10.1002/anie.201805676
system might be ascribed to π-π interaction between C=C double
bond of the allyl group in the substrate and the benzene ring of
ligand L6, thus the allylic CH2 group was exposed to the carbene
carbon center for C-H insertion (see the Supporting Information for
proposed chemoselective model of Ru(II)/L6 system).
Table 1. Optimization of the reaction conditions.[a]
Based on the optimized reaction conditions for chemoselective
asymmetric allylic C-H insertion (Table 1, entry 15), the substrate
scope of the [Ru(p-cymene)I2]2/L6 catalytic system was then
examined. It was shown that this Ru(II)-catalyzed system could be
successfully applied to different N-allylic enynone substrates, and
the enantioselectivities were typically higher than 96% (Table 2).
In addition to non-substituted N-allylic enynone 1a, enynones
containing different functional groups at the allylic double bond
could also be selectively converted to the desired dihydroindoles
2
a
3a
Entry [M]
L
2a/3a
>99:1
>99:1
5.2: 1
>20:1
>99:1
>99:1
>99:1
>99:1
4.3:1
Yield
ee
Yield
ee
1[b]
-
99%[c] 91%
-
-
Rh2(S-PTAD)4
2[b]
Rh2(S-DOSP)4
-
99%
84%
96%
81%
85%
69%
74%
34%
19%
11%
13%
-
10%
4%
77%
10%
0%
25%
-6%
64%
nd
-
-
3[b]
Rh2(S-PTTL)4
-
16%
4%
-
nd
4[b]
5[d]
6[d]
-
nd
Rh2(5S-MEPY)4
(3b-f). When methyl allylic enynones were employed as the
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
L1
L2
L3
L4
L5
L6
L6
L6
L6
-
substrates, in which the newly introduced methyl groups provided
additional competitive allylic C-H insertion sites, the reactions
selectively took place at the desired N-C-H position and led to the
products 3b-c in 73-81% yields with > 96% ee. 2-Isopropyl-
substituted enynone showed decreased yield (57%), probably due
to the steric hindrance. However, the enantioselectivity was not
affected at all (98% ee, 3d). 2-Bromo-substituted allylic enynone
was also an effective substrate for C-H insertion, giving the desired
product 3e in 61% yield and 92% ee. The bromine atom would
allow further useful transformations. It is noted that the reaction
was even compatible with 2-ethoxycarbonyl-substituted allylic
enynone, furnishing the product 3f in 52% yield, but with 25% ee.
The inferior result may be attributed to the steric effect (reducing
yield) and electronic interference (reducing ee) of the ester group.
The enynones with different carbonyl substituents showed good
reactivities, which delivered the desired dihydroindole products 3g-
k in 49-85% yields and > 97% ee. Moreover, various substituents
-
-
7[d]
-
-
8[d]
-
-
9[d]
8%
69%
75%
68%
9%
-
91%
98%
> 99%
99%
99%
-
0[d] [Ru(p-cymene)Cl2]2
1[d] [Ru(p-cymene)I2]2
1
1
1
1
1
1:3.6
1:6.8
nd
2[e] Ru(cod)Cl2
1:5.2
nd
3[e] Ru(PPh3)3Cl2
<1:20
-
4[e] CpRu(PPh3)2Cl
L6
L6
>99:1
96%
0%
1 [
f]
76%[c] > 99%
5
[Ru(p-cymene)I2]2
<1:20
trace nd
Table 2. Scope of allyllic C-H insertion.[a]
[
a] The reaction was performed in DCE under N2, 1a = 0.2 mmol, [1a] = 0.1 M,
1
the yields and the ratio of 2a/3a were determined by H NMR of the crude
reaction mixture. [b] Rh2(II) = 1 mol %, 25 °C . [c] isolated yield. [d] [Ru(p-
cymene)X2]2 = 5 mol %, L = 10 mol%, 80 °C . [e] [Ru] = 5 mol%, L = 5 mol%,
8
0 °C . [f] [1a] = 0.025 M, [Ru(p-cymene)X2]2 = 5 mol %, L = 15 mol%, 80 °C .
find that the indane-fused Pybox L6, a more rigid ligand,
significantly improved both chemo- and stereoselectivity of C-H
insertion, leading to 3a as the major product in 69% yield and 98%
ee (entry 10, 2a:3a = 1:3.6). Subsequently, other Ru(II) complexes
associated with ligand L6 were also examined to improve the
reaction performance (entries 11-14). [Ru(p-cymene)I2]2/L6
showed better chemoselectivity towards the allylic C-H insertion
(2a:3a = 1:6.8) and afforded product 3a in 75% yield and > 99% ee
(entry 11). Ru(cod)Cl2 was a good ruthenium source as well,
providing 3a in 68% yield and 99% ee with good chemoselectivity
entry 12, 2a:3a = 1:5.2). Ru(PPh3)3Cl2 was an inferior catalyst for
(
both cyclopropanation and C-H insertion (entry 13).
CpRu(PPh3)2Cl showed excellent catalytic activity for
cyclopropanation reaction but without asymmetric induction (entry
14), which indicated that the chiral ligand L6 might not coordinate
with ruthenium center. The chemoselectivity could be further
improved (2a:3a < 1:20) by decreasing the substrate concentration
and increasing the amount of L6, and the product 3a was furnished
in 76% yield and > 99% ee (entry 15). The significant
chemoselectivity of C-H insertion in the Ru(II)/L6-catalyzed
[
a] Reaction conditions: 1 = 0.2 mmol, [1] = 0.025 M, isolated yield, dr was
1
determined by H NMR spectrum of the crude reaction mixture.
2
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Angewandte Chemie International Edition
10.1002/anie.201805676
Table 4. Scope of other alkyl C-H insertion.[a]
6
of R at different positions of the phenylene group were also well
tolerated, producing 3l-o in 63-87% yields and 96-99% ee. It’s
worth mentioning that cyclopropanation products 2 were not
observed in most cases under the [Ru(p-cymene)I2]2/L6 catalytic
conditions. Furthermore, the diastereoselectivities for all the C-H
insertion products 3 in Table 2 were higher than 99:1.
As shown in entry 1 of Table 1, Rh2(S-PTAD)4 was capable of
catalyzing the asymmetric cyclopropanation of enynone 1a with
excellent chemoselectivity (> 99:1) and enantioselectivity (91%).[10]
Further studies revealed that the Rh2(II) catalytic system could be
successfully extended to various enynones with different
substituents, giving cyclopropane 2 as the sole product in
quantitative yields (Table 3). The enantioselectivities were higher
than 90% ee for those substrates without substituents on the allyl
group (2a-e). However, enantioselectivity of the Rh2(II)-based
system seems more sensitive to the steric hindrance of substrates
than the Ru(II)-based one, as 2-bromo-substituted allylic enynone
was cyclopropanated in only 59% ee (2f).
Table 3. Scope of allylic cyclopropantion.[a]
[
a] Reaction conditions: 1 = 0.2 mmol, [1] = 0.1 M, isolated yield, dr was
1
[
a] Reaction conditions: 1 = 0.2 mmol, [1] = 0.1 M, isolated yield, dr was
determined by H NMR spectrum of the crude reaction mixture. [b] 80°C.
1
determined by H NMR spectrum of the crude reaction mixture. [b] 0 °C .
the demanding asymmetric alkyl C-H insertion with N-
alkylacetamide enynones 4 as the starting materials. To our delight,
under conditions similar to the allylic C-H insertion, but at an
elevated temperature (120 ºC), various N-alkyl substituted
enynones 4 with diverse functional groups could be transferred to
the desired dihydroindoles in excellent enantioselectivities (> 96%)
and good diastereoselectivities (Table 4). For example, the
enynones with both linear and branched alkyl groups were
effective substrates, affording the desired products 5a-c in 57-63%
yields with 96-99% ee and > 95:5 dr. Furthermore, when different
functional groups, such as cyclopropyl, alkenyl, phenyl, methoxyl,
and even bromo were introduced onto the alkyl side chain, the
reactions proceeded smoothly to give the products 5d-h in
moderate yields (43-68%) with excellent enantioselectivities (>
Except for chemo- and enantioselective allylic C-H insertion,
carbene-involved asymmetric alkyl C-H insertion is another
formidable task in carbene chemistry as it often results in much
lower diastereo- and enantioselectivity.[12] For example, in our
previous work of Rh2(S-PTAD)4-catalyzed enantioselective
Scheme 3. Rh2(S-PTAD)4-catalyzed asymmetric alkyl C-H insertion of 4a.
intramolecular benzylic C-H insertion with enynone as the carbene
source, both diastereoselectivity (dr) and enantioselectivity (ee)
dropped significantly when enynone 4a bearing N-alkylacetamide
9
7% ee). Additionally, this system could be extended to the N-
2
3
4
group served as the substrate (Scheme 3, dr = 50:50, ee = 71%).[10]
alkyl enynones having different R , R and R groups, delivering
the desired products 5i-m without loss of yields (56-71%),
enantioselectivities (> 97% ee), and diastereoselectivities (> 91:9
dr). Lastly, this Ru(II)-catalytic reaction was also a highly efficient
system for N-benzylic enynone substrates, which furnished the
Having established [Ru(p-cymene)I2]2/L6 as a reliable system
for catalyzing the allylic C-H insertion of enynone 1 with excellent
chemo-, diastereo-, and enantioselectivity (Table 2), we were then
very curious about the possibility of applying this system to resolve
3
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Angewandte Chemie International Edition
10.1002/anie.201805676
Maguire, M. A. McKervey, Chem. Rev. 2015, 115, 9981; k) Y. Xia,
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(82-97%) and stereoselectivities (> 97% ee and > 99:1 dr).
With the allylic C-H insertion products 3 in hand, further
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indole 7 in good yield (65%).
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In summary, we have developed a catalyst-controlled highly
chemo-, enantio-, and diaseteroselective intramolecular allylic C-H
insertion and cyclopropanation of donor/donor-carbenes by a
nondiazo approach. All the reactions were conducted in a one-pot
manner without slow addition of the carbene precursors. The
Ru(II)/Pybox complex selectively catalyzed the intramolecular
allylic C−H insertion, providing vinyl-substituted dihydroindoles
with > 20:1 chemoselectivity and up to > 99% ee. Chiral
dirhodium(II) tetracarboxylates, however, selectively promoted the
intramolecular cyclopropanation, giving rise to cyclopropane-fused
tetrahydroquinoline derivatives in excellent yields with > 99:1
chemoselectivity and up to 97% ee. In addition, this Ru(II)/L6
catalytic system was also applied to the challenging alkyl C-H
insertion of N-alkyl substituted enynones and afforded the desired
products with excellent diastereoselectivity and enantioselectivity.
We believe that this unique catalyst-controlled carbene transfer
reaction should not only help understanding the behaviors of
different types of metal carbenes but also provide appealing
methodologies for organic synthesis.
1
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Entry for the Table of Contents (Please choose one layout)
Asymmetric Catalysis
Dong Zhu, Lianfen Chen, He Zhang,
Zhiqiang Ma, Huanfeng Jiang, and Shifa
Zhu*
_
_________ Page – Page
Catalyst-Controlled Highly Chemo- and
Stereoselective Allylic C-H Insertion and
Cyclopropanation of Donor/Donor-
Carbenes
Catalyst-controlled highly chemo-, enantio-, and diaseteroselective intramolecular
allylic C−H insertion and cyclopropanation of donor/donor-carbenes were reported.
The Ru(II)/Pybox complex selectively catalyzed the intramolecular allylic C−H
insertion, providing vinyl-substituted dihydroindoles with > 20:1 chemoselectivity
and up to > 99% ee. Chiral dirhodium(II) tetracarboxylates, however, selectively
catalyzed the intramolecular cyclopropanation, giving rise to cyclopropane-fused
tetrahydroquinoline derivatives in excellent yields with > 99:1 chemoselectivity and
up to 97% ee.
6
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