Non-Diazo C?H Insertion Approach to Cyclobutanones through Oxidative Gold Catalysis

Article abstract of DOI:10.1002/anie.202003698

Cyclobutanones are synthetically versatile compounds that often require extensive effort to access. Herein, we report a facile synthesis of cyclobutanones based on the C(sp³)?H insertion chemistry of oxidatively generated gold carbenes. Various cyclobutanones were obtained in synthetically useful yields from substrates with minimal structural prefunctionalization. This discovery reveals new synthetic utilities of gold-catalyzed oxidative transformations of alkynones.

Full text of DOI:10.1002/anie.202003698

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Accepted Article
Title: Non-Diazo C-H Insertion Approach to Cyclobutanones via
Oxidative Gold Catalysis
Authors: zhitong Zheng, youliang Wang, xu ma, yuxue li, and Liming
Zhang
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Non-Diazo C-H Insertion Approach to Cyclobutanones via
Oxidative Gold Catalysis
Zhitong Zheng,[a]†, Youliang Wang,[a]†‡ Xu Ma,[a] Yuxue Li[*b] and Liming Zhang*[a]
Abstract: Cyclobutanones are synthetically versatile compounds that
often requires extensive effort to access. Herein, we report a facile
synthesis of cyclobutanones based on the C(sp3)-H insertion
chemistry of oxidatively generated gold carbenes. A range of
cyclobutanones was obtained in synthetically useful yields from
substrates with minimal structural prefunctionalization. This discovery
reveals new synthetic utilities of gold-catalyzed oxidative
transformations of alkynones.
tedious and hazardous preparation. Hence, there is a need for
more efficient access to these strained cyclic ketones based on a
safer and more efficient carbene C-H insertion strategy.
We have previously reported facile access to 2-
acylcyclopentanones[1]
via
gold-catalyzed
oxidative
transformations of alkynones.[2] Our preliminary mechanistic
studies are consistent with the generation of a β-diketone-α-gold
carbene (i.e., A, Scheme 1) as the reactive intermediate and its
subsequent insertion into an unactivated C-H bond as the key ring
formation step. This approach permits the use of C-C triple bonds
instead of diazo compounds as precursors to gold carbenes in the
context of synthetically highly valuable C-H insertions.[3] During
the catalyst optimization, we observed, as shown in Scheme 1,
cyclobutanones 3a and 3a’ were formed in combined yields that
are substantially more than those of the intended cyclopentanone
4 when BrettPhos or tBuBrettPhos was used as the gold catalyst
ligand. Moreover, the ratio of 3a and 3a’, the products of insertion
into the C-H bonds of the methyl groups and the β-CH2,
respectively, and the combined yield increase as the ligand
becomes bulkier. The apparent ease of forming the highly
strained four-membered ring in this reaction and its tunability
suggested that the gold carbene intermediate generated can be
highly reactive yet could be coerced via ligand tuning and other
condition optimization into achieving efficient constructions of
cyclobutanones.
Figure 1. Bioactive natural products featuring cyclobutanoid core structures.
Scheme 1. Our previous studies forming cyclobutanones as side products.
Table 1. Initial reaction discovery and optimization.
Of note is that cyclobutanones along with cyclobutanes are
synthetically highly useful structures due to their high ring strain.[4]
Moreover, they are found in bioactive natural products, as
represented in Figure 1.[5] While cyclobutanones can be formed
via Rh/Cu-catalyzed C-H insertive cyclization of diazo ketones,
they are mostly side products along with the desired
cyclopentanones.[6] Consequently, the reaction yields are at best
moderate, and the corresponding diazo substrates often demand
entry
catalyst
N-oxide
conditions
yield[a]
1
2
Ph3PAuNTf2
MorDalPhosAuNTf2
IPrAuNTf2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2b
2b
2b
2b
DCE, rt, 2 h
DCE, rt, 2 h
DCE, rt, 2 h
DCE, rt, 2 h
DCE, rt, 2 h
DCE, rt, 2 h
DCE, rt, 2 h
DCE, rt, 24 h
DCE, rt, 24 h
DCE, rt, 2 h
DCE, 60˚C, 7 h
DCE, 60˚C, 7 h
DCE, rt, 2 h
DCE, rt, 2 h
DCE, rt, 4 h
PhF, rt, 2 h
2%[b]
<1%
< 1%
33%
65%
84%
81%
7%[c]
0[d]
3
4
CyJohnPhosAuNTf2
XPhosAuNTf2
5
6
BrettPhosAuNTf2
tBuBrettPhosAuNTf2
AgNTf2 (10 mol %)
HNTf2 (10 mol %)
BrettPhosAuNTf2
BrettPhosAuNTf2
BrettPhosAuNTf2
BrettPhosAuCl/AgOTf
BrettPhosAuCl/AgPF6
BrettPhosAuCl/NaBARF
BrettPhosAuNTf2
[a]
[b]
Dr. Zhitong Zheng, Dr. Youliang Wang, and Prof. Dr. Liming Zhang
Department of Chemistry and Biochemistry, University of California
Santa Barbara, CA 93106, USA
7
8
E-mail: zhang@chem.ucsb.edu
9
Homepage: http://www.chem.ucsb.edu/~zhang/index.html
Dr. Yuxue Li, CAS Key Laboratory of Energy Regulation Materials,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, P. R. China
These authors contributed equally.
10
11
12
13
14
15
16
92%
64%
60%
92%
87%
87%
90%
†
‡
Current address: College of Science, Xi'an Jiaotong University,
Xi’an 710049, P. R. China
Supporting information for this article is given via a link at the end
1
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17
18
BrettPhosAuNTf2
BrettPhosAuNTf2
2b
2b[e]
PhCF3, rt, 2 h
DCE, rt, 2 h
79%
90%[f]
which upon subsequent hydrolytic decarboxylation led to the
formation of the ketone 5 in 79% yield (entry 2). A cyclopropyl
group, however, had little such side reaction (entry 3). When
alkenyl groups were in the place of the phenyl group, the Wolff
reaction interestingly occurred with a cyclohexen-1-yl (entry 4) but
not with a propen-2-yl (entry 5). In addition, both the electron-
donating 4-methoxy group (entry 6) and the electron-withdrawing
4-trifluoromethyl group (entry 7) were allowed on the phenyl ring,
and the reaction yields were only slightly affected.
[a] Determined by 1H NMR using diethyl phthalate as internal reference. [b]
72% of 1b remained. [c] 56% of 1b remained. [d] Most 1b remained. [e] 1.5
equiv. [f] 82% isolated yield.
Table 3. Reaction scope of different alkyl ketones.[a]
En-
try
ynone
product(s)
catalyst/yield
At the outset, instead of 1a, the tert-butyl alkynyl ketone 1b was
used as the substrate for reaction optimization as the removal of
regioselectivity issues significantly simplified the task at hand.
With Ph3PAuNTf2, MorDalPhosAuNTf2 or IPrAuNTf2 as the gold
catalyst, the desired cyclobutanone 3b was nearly undetectable
(entries 1-3). However, the gold catalysts derived from the
Buchwald ligands were proven uniquely effective (entries 4-7).
Among them, both BrettPhosAuNTf2 and the sterically more
hindered tBuBrettPhosAuNTf2 enabled the highly efficient
formation of 3b, with the former affording an impressive 84% yield
(entry 6). Control experiments with AgNTf2 (entry 8) or HNTf2
(entry 9) as the catalyst led to little or no reaction, respectively,
confirming the indispensable role of gold in this catalysis. Varying
the N-oxide revealed that 8-isopropylquinoline N-oxide 2b is the
best oxidant (entry 10), while the pyridine-based ones, i.e., 2c
(entry 11) and 2d (entry 12), are moderately effective at an
elevated temperature. Other counter anions (entries 13-15) and
different reaction solvents (entries 16-18) had mostly little impact
on the reaction efficiency.
tBuBrettPhos-
AuNTf2
24 h
89%
3j:7 > 16:1
1
AdBrettPhos-
AuNTf2
2 h
86%
3k:3k’:8 =
4.5:1:<0.1
2
AdBrettPhos-
AuNTf2
2 h
80%
3l:3l’ = 7:1
3
4
IMesAuNTf2
7 h
62%
Table 2. Scope of different alkyne substituents.[a]
IMesAuNTf2
7 h
5
42%
1
2
IPrAuNTf2
5 h
45%
6
7
3c, 17 h, 80%
3d, 72 h, 11% (NMR)
5, 79%
6, 36%
BrettPhos-
AuNTf2
4h
3
5
4
6
69%
[a] Reactions were run with the optimal conditions from Table 1. All yields are
isolated yields.
3e, 2 h, 84%
3f, 8 h, 26%
7
Next, we examined how the t-butyl group of 1b could be varied.
As shown in Table 3, entry 1, the ynone 1j possesses the ethyl
counterpart of t-butyl, i.e., 3-ethylpent-3-yl. Its reaction, optimally
t
performed using BuBrettPhosAuNTf2 as the catalyst, was slow
but delivered the cyclobutanone product 3j in 89% yield. The
cyclopentanone product 7, the result of insertion into the methyl
groups was barely detected. The good regioselectivity is
anticipated in light of the results in Scheme 1, where 3a’ and 4
were formed in nearly equal amounts, and the well-precedented
preference of carbene insertion into methylene C-H over methyl
C-H. With the t-pentyl ketone 1k as the substrate,
3g, 7 h, 65%
3h, 4 h, 75%
3i, 4 h, 81%
[a] Reactions were run under the optimal conditions from Table 1, entry 10. All
yields are isolated ones except 3d.
With the optimal conditions (Table 1, entry 10) secured, we
then varied the phenyl group of 1b. As shown in Table 2, an n-
butyl group was tolerated (entry 1), but the substrate with a
cyclohexyl group underwent mostly the Wolff rearrangement,[7]
2
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AdBrettPhosAuNTf2 was the optimal catalyst for a slightly
improved yield (entry 2). The cyclobutanones 3k/3k’ were formed
in a good combined yield, and 3k is favored over 3k’ by a ratio of
4.5:1, which is slightly better than that of 3a’/3a (1:1 and 1.75:1,
Scheme 1) and readily understandable by the fact that ethyl is
smaller than n-hexyl. Again, the cyclopentanone product 8 was
barely formed. We then turned our attention to tertiary cycloalkyl
ketone substrates. In the case of 1l, two cyclobutanones 3l and
3l’ were formed in a combined 79% yield and with a ratio of 3l/3l’
= 7:1. It is remarkable that the inductive deactivation of the ring
C-H bonds β to the carbonyl group is largely inconsequential,
despite literature precedents,[8] while the absence of insertion into
the more deactivated C-H bond α to the ring carbonyl group[1] to
afford a bicyclo[3.2.1]octadione could be readily understood. With
the substrate 1m possessing two 1,4-cis-substituted methyl
groups on the cyclohexane ring, IMesAuNTf2 turned out to be a
better catalyst, and the bicyclo[4.2.0]octanedione 3m was
isolated in 62% yield. On the contrary, in the case of
diastereomeric ketone substrate 1n with trans-methyl groups,
however, the reaction yields the cyclopentanone product 3n as
the major product. Such reactivity divergence must be due to
conformational bias. In the case of 1n, the β-diketone-α-gold
carbene generated resides predominantly at the axial position in
order to avoid positioning both methyl groups at axial positions
and is primed to insert into a cis and axial C-H bond en route to
the bridged cyclopentanone 3n. On the other hand, in the case of
1m, the methyl groups conformationally cancel each other and
hence the carbene moiety prefers the equatorial position, which
could only lead to cyclobutanone formation. In our previous work,
the ynone 1o derived readily from cyclohexanone was
transformed into a bicyclo[3.2.1]octanones selectively in the
presence of LAuNTf2, where L is a P,N-bidentate ligand; in
contrast, when IPrAuNTf2 is the catalyst, the cyclobutanone 3o
was formed in 45% yield, thereby highlighting the critical role of
the ligand in deciding the reaction outcome. This chemistry is also
applicable to the construction of five-membered ring fused
cyclobutanones, and bicyclic ketone 3p was isolated in a
respectable 69% yield (entry 8).
Scheme 2. Mechanistic studies.
To probe the reaction mechanism, we subjected the phenyl
alkynyl ketone 1b’, which differs from 1b by swapping the ynone
moiety substituents, to the optimized reaction conditions. The
reaction was very slow, which could be attributed to the steric
hindrance caused by the bulky t-butyl group in the initial oxidant
nucleophilic attack, but the reaction yield was comparable to that
of 1b, suggesting that a locally symmetric β-diketone-α-gold
carbene moiety of type A is formed. We also prepared the
corresponding α-diazo-β-diketone 9. While its reaction in the
presence of Rh2(TFA)4 required a much longer time, the yield is
nearly identical to that in the presence of BrettPhosAuNTf2 and
the oxidative gold catalysis of 1b. A similar outcome was
observed with α-diazo-β-diketone 10 related to the ynone 1l.
Comparing with our oxidative gold catalysis of 1l, Rh-catalyzed
transformation of 10 gave very similar regioselectivity and a lower
yield at 60 °C and required a longer reaction time. The reaction at
room temperature was, however, sluggish. These results strongly
suggest that the gold carbene of type A is the reactive
intermediate in this gold catalysis. In addition, these comparisons
reveal that the oxidative gold catalysis, in general, undergoes
substantially faster generation of the β-diketone-α-metal carbene
intermediate than dediazotization by Rh complexes.
Figure 2. The calculated carbene intermediate A-3k and the C-H bond insertion transition states that leading to product 3k and 8, respectively. Selected bond
lengths are in angstroms, and bond angles in degrees. Calculated on M06/SDD(Au)/6-311+G**(P)/6-31+G** level in DCE.
To have a better understanding on how the bulky ligands
control the regioselectivity of the C-H bond insertion, we
performed a DFT[9-13] study of the case of the tert-pentyl ketone
1k (Table 3, entry 2) by using M06[10] and SMD[12] methods (DCE
3
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as solvent). The SDD basis set with an Effective Core Potential
(ECP)13 was used for the Au atom, the 6-311+G** basis set for
the P atom, and the 6-31+G** basis set for the other atoms. As
shown in Figure 2, the C-H insertion starts from the β-diketone-α-
gold carbene intermediate A-3k. The calculated transition state,
i.e., TS-Ins-3k, for the formation of the cyclobutanone 3k is 6.9
kcal/mol higher in free energy. This number is 1.1 kcal/mol more
favorable than TS-Ins-8, which is 8.0 kcal/mol higher in free
energy than A-3k and leads to the formation of the
cyclopentanone 8. This result is in line with the experiment
observation, in which 8 is barely formed.
In A-3k, there are steric repulsions between the carbene
fragment and the large AdBrettPhos ligand, which are at least in
part responsible for the compressed angle of P-Au-C1. This angle
is measured at 150.66˚ and substantially bended and deviated
from typical ~180˚. In the transition states, the Au carbene bond
(i.e., Au=C1) length increases from 2.015 Å in A-3k to 2.076 Å in
TS-Ins-3k and 2.073 Å in TS-Ins-8, which are concurrent to the
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that leading to the cyclopentanone 8 and hence experiences less
steric repulsion from the bulky ligand 2,4,6-triisopropylphenyl
group. It is also in line with the difference in the distance between
C6, i.e., the para-carbon on the ligand pendant benzene ring, and
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insertions, leading to preferentially formation of cyclobutanone
products via a sterically less demanding transition state.
In summary, we have exploited the C(sp3)-H insertion
chemistry of oxidatively-generated gold carbenes for the
generation of strained cyclobutanones. The method avoids the
use of diazo precursors and can be highly efficient and applied to
the synthesis of fused bicyclic cyclobutanes. Comparative studies
with rhodium-catalyzed decomposition of α-diazo-β-diketones
strongly suggested the key role of β-diketone-α-gold carbene in
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access to synthetically valuable cyclobutanones.
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[11] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
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Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.;
Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts,
R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
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The experimental work by Z. Z., Y. W. And L.Z. was supported by
NIGMS R01GM123342 and NIH shared instrument grant
S10OD012077 for the purchase of a 400 MHz NMR spectrometer.
The DFT studies by Y.-X. L. is supported by the Natural Science
Foundation of China (Grant No. 21672247).
Keywords: gold carbene• catalysis • cyclobutanone • oxidation •
C-H insertion
4
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5
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Entry for the Table of Contents
COMMUNICATION
Insertion into unactivated C(sp3)-H bonds by
metal carbenes/carbenoids is a reaction of
significant synthetic value. In this study,
easily accessible alkynone substrates are
converted to strained cyclobutanones via
such an insertion by an oxidatively generated
β-diketone-α-gold carbene. This reaction
serves as a benign and more synthetically
expedient alternative to diazo-based
approaches.
Zhitong Zheng, Youliang
Wang, Yuxue Li, and Liming
Zhang*
Page No. – Page No.
Non-Diazo C-H Insertion
Approach to
Cyclobutanones via
Oxidative Gold Catalysis
6
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