Molybdenum-Catalyzed Deoxygenative Cyclopropanation of 1,2-Dicarbonyl or Monocarbonyl Compounds

Article abstract of DOI:10.1002/anie.202103429

The transition-metal-catalyzed cyclopropanation of alkenes by the decomposition of diazo compounds is a powerful and straightforward strategy to produce cyclopropanes, but is tempered by the potentially explosive nature of diazo substrates. Herein we report the Mo-catalyzed regiospecific deoxygenative cyclopropanation of readily available and bench-stable 1,2-dicarbonyl compounds, in which one of the two carbonyl groups acts as a carbene equivalent upon deoxygenation and engages in the subsequent cyclopropanation process. The use of a commercially available Mo catalyst afforded an array of valuable cyclopropanes with exclusive regioselectivity in up to 90 % yield. The synthetic utility of this method was further demonstrated by gram-scale syntheses, late-stage functionalization, and the cyclopropanation of a simple monocarbonyl compound. Preliminary mechanistic studies suggest that phosphine (or silane) acts as both a mild reductant and a good oxygen acceptor that efficiently regenerates the catalytically active Mo catalyst through reduction of the Mo-oxo complexes.

Full text of DOI:10.1002/anie.202103429

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Accepted Article
Title: Molybdenum-Catalyzed Deoxygenative Cyclopropanation of 1,2-
Dicarbonyl or Mono-carbonyl Compounds
Authors: Li-Ya Cao, Jian-Nan Luo, Jia-Sheng Yao, De-Ku Wang,
Yuan-Qing Dong, Chao Zheng, and Chun-Xiang Zhuo
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10.1002/anie.202103429
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COMMUNICATION
Molybdenum-Catalyzed Deoxygenative Cyclopropanation of 1,2-
Dicarbonyl or Mono-carbonyl Compounds
Li-Ya Cao, Jian-Nan Luo, Jia-Sheng Yao, De-Ku Wang, Yuan-Qing Dong, Chao Zheng, and Chun-
Xiang Zhuo*
[*]
L.-Y. Cao, J.-N. Luo, J.-S. Yao, D.-K. Wang, Y.-Q. Dong, Prof. Dr. C.-X. Zhuo
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
E-mail: cxzhuo@xmu.edu.cn
Prof. Dr. C. Zheng
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R.
China
Supporting information for this article is given via a link at the end of the document.
Abstract: The transition-metal catalyzed cyclopropanation of alkenes
via the decomposition of diazo compounds is a powerful and
straightforward strategy to produce cyclopropanes. However, the
potentially explosive nature of the diazo substrates tempers the
appeal of further application of this strategy. Herein we report the first
Mo-catalyzed regiospecifically deoxygenative cyclopropanation
reaction of the readily available and bench stable 1,2-dicarbonyl
compounds, in which one of the two carbonyl groups acts as a
carbene equivalent upon deoxygenation, thus engaging in the
subsequent cyclopropanation process. With a commercially available
molybdenum catalyst, an array of valuable cyclopropanes were
obtained in up to 90% yield and exclusive regioselectivity. The
synthetic utility of this method is further demonstrated by gram-scale
syntheses, late-stage functionalization, and application to the
cyclopropanation of a simple mono-carbonyl compound. Preliminary
mechanistic studies suggest that phosphine (or silane) is both a mild
Figure 1. Representative cyclopropane ring-containing natural products and
pharmaceuticals.
reductant and
a good oxygen acceptor that could efficiently
The 1,2-dicarbonyl compounds are readily available and often
serve as valuable building blocks in organic synthesis.[10]
Specifically, these bench stable compounds may be used to
prepare the ɑ-diazo carbonyl compounds.[7] Accordingly, we
questioned whether the 1,2-dicarbonyl compounds could be
directly utilized as carbene equivalents through transition-metal-
catalyzed regioselective deoxygenation for the syntheses of
cyclopropanes, thus avoiding the tedious preparation and use of
the hazardous diazo compounds (Scheme 1B). Although
conceptually simple in design, several fundamental requirements
need to be met to achieve such a transition-metal-catalyzed
regioselectively deoxygenative cyclopropanation reaction.
Specifically, a powerful transition-metal catalyst that is capable of
promoting a regioselective deoxygenation process of a 1,2-
dicarbonyl compound and inhibiting side reactions such as
dimerization and competitive C−H bond insertion when allylic
substrates are applied has to be identified. In addition, a mild
reductant and an oxygen acceptor that will not directly reduce the
1,2-dicarbonyl group, but could efficiently regenerate the
catalytically active transition-metal catalyst through reduction of
the metal-oxo complexes should be realized. Furthermore, the
generation of carbene equivalents through transition-metal-
catalyzed regioselectively direct deoxygenation of 1,2-dicarbonyl
compounds is challenging. In practice, carbonyl compounds
rarely served as direct precursors of carbenes except a few
examples using either stoichiometric metal reagents and
reductants[11] or low-valent transition-metal complexes.[12] In
regenerate the catalytically active Mo-catalyst through reduction of the
Mo-oxo complexes.
As a unique and important structure motif, cyclopropane ring is
widely occurred in many biologically active natural products and
pharmaceuticals,[1,2] such as mitrephorone A,[2a-b] ingenol,[2c-d]
duocarmycin A,[2e-f] saxagliptin,[2g] and beclabuvir[2h] (Figure 1). To
this end, numerous efforts have been devoted to the syntheses of
functionalized cyclopropanes.[3] Among the various synthetic
strategies for the generation of these unique carbocycles, the
cyclopropanation of alkenes with transition-metal carbene
species is powerful and straightforward (Scheme 1A).[4,5] The
metal carbene species, usually generated in situ through the
decomposition of ɑ-diazo carbonyl compounds promoted by
transition-metal catalysts (Rh, Pd, Cu, Au, etc.), are deemed as
key intermediates in these processes.[6] Unfortunately, the highly
energetic diazo compounds are potentially explosive. In addition,
hazardous reagents and multiple synthetic steps are often
required for the preparation of the diazo substrates.[4,7] Therefore,
developing operationally safe and readily available alternatives to
the diazo carbonyl compounds as carbene precursors would
benefit the synthetic applications, especially in the industrial scale
synthesis.[8,9]
1
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addition, to the best of our knowledge, there is no general method
for the generation of carbene equivalents via transition-metal-
catalyzed regioselective deoxygenation of 1,2-dicarbonyl
compounds, thereby engaging in subsequent cyclopropanation
with unactivated alkenes to produce cyclopropanes. Herein, we
describe the first Mo-catalyzed deoxygenative cyclopropanation
of 1,2-dicarbonyl or mono-carbonyl compounds (Scheme 1C).
With the commercially available molybdenum catalyst and
diphosphine or silane as a mild reductant as well as an oxygen
acceptor, various substituted cyclopropanes were obtained in up
to 90% yield and exclusive regioselectivity.
NMR yield and the 1,3-oxazine derivative 3a which was formed
via a keto-ene/cyclization tandem reaction[14] in 18% NMR yield.
The structures of compounds 2a and 3a were unambiguously
confirmed by X-ray crystallographic analyses.[15] Notably, the
probably competitive C-H insertion product 2a’’ was not detected
at all under these Mo-catalytic conditions.
Scheme 2. Proof of concept.
Encouraged by these results, we carried out further
optimization of the reaction conditions (Table 1). Various
commercially available molybdenum catalysts were then
investigated (entries 2−7). Interestingly, a Mo-catalytic system
derived from Mo(CO)6 and 3,5-di-tert-butyl-o-benzoquinone,
which was elegantly developed by Asako, Takai and coworkers
for the syntheses of indolines, indoles and pyridoisoindoles,[12j,k]
was found to be able to catalyze the deoxygenative
cyclopropanation of 1a efficiently in the presence of 60 mol% of
DPPB (entry 7). The o-quinone was proposed to oxidize the
Mo(CO)6 to the catalytically active molybdenum(II) species.[12f,j]
Next, reductants such as phosphine, HBpin, silane and Me6Si2
were examined (entries 8−15). Pleasingly, Ph2MeSiH was
discovered to promote the reaction also in good yield (entry 14).
To be noted, the cyclopropanation reaction also proceeded well
when the reaction temperature was decreased or the catalyst
loading was reduced (entries 16−17). In addition, among other
transition-metal carbonyl complexes {W(CO)6,Cr(CO)6, Fe2(CO)9,
Ru3(CO)12, and Mn2(CO)10} screened, none of them were capable
of promoting the transformation, which demonstrated the unique
efficiency of the Mo-catalytic system towards this reaction.[16]
Finally, the conditions {10 mol% of Mo(CO)6, 10 mol% of o-
quinone, and 0.6 equiv of DPPB in toluene at 120 oC} were
identified to be optimal in terms of yield, chemoselectivity and
efficiency. Under these conditions, the cyclopropane 2a was
obtained in 83% yield (entry 7).
Scheme 1. 1,2-Dicarbonyl or mono-carbonyl compounds directly serve as
surrogates for diazo compounds in the Mo-catalyzed deoxygenative
cyclopropanation reactions.
Table 1. Optimization of the reaction conditions.[a]
The general feasibility of our hypothesis for the Mo-catalyzed
regiospecifically deoxygenative cyclopropanation was evaluated
using 1,2-dicarbonyl compound 1a as a model substrate, 10 mol%
of commercially available MoO2Cl2 as a catalyst[13] and 60 mol%
of 1,4-bis(diphenylphosphino)butane (DPPB) as both a reductant
and an oxygen acceptor (Scheme 2). Intriguingly, under these
reaction conditions, the deoxygenative cyclopropanation reaction
of 1a occurred in moderate conversion, providing the desired
cyclopropane 2a as a single regio-isomer (2a:2a’ > 99:1) in 30%
2
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cyclopropane products in moderate to good yields (2x−2ac). The
reaction of 1-naphthylamine containing 1,2-dicarbonyl substrate
1ad proceeded smoothly as well. Furthermore, the reaction of the
2,2-disubstituted alkene 1ae also occurred, providing the desired
cyclopropane 2ae with two contiguous quaternary carbon centers.
Unfortunately, when the 2-phenyl substituted (R4 = Ph) or the 1-
propyl substituted alkene substrates were used under these
reaction conditions, complicated mixtures were obtained.[16]
Table 2. The substrate scope.[a]
[a] Reaction conditions: Mo-cat. (x mol%), reductant (y equiv), and 1a (0.2
mmol) in toluene (2.0 mL) at 120 ℃. [b] Yield was determined by 1H NMR
analysis using CH2Br2 as internal standard. [c] Not detected. [d] 10 mol% of 3,5-
di-tert-butyl-o-benzoquinone (o-quinone) was added. [e] Isolated yield in the
parenthesis. [f] The reaction was performed at 100 ℃. [g] The reaction was
performed with 5 mol% of Mo(CO)6 and 5 mol% of o-quinone. DPPE: 1,2-
bis(diphenylphosphino)ethane; DCPB: 1,4-bis(dicyclohexylphosphino)butane.
With the optimized reaction conditions in hand, various
substituted 1,2-dicarbonyl compounds 1 were tested to establish
the generality of the process (Table 2). Reactions of 1,2-
dicarbonyl substrates containing either electron-donating or
electron-withdrawing groups on the aromatic ring (R1) attached
to the 2-carbonyl moiety all gave the corresponding products in
moderate to good yields (2b−2n). Notably, different kinds of aryl
halides (F, Cl, Br, 2g−2i & 2m−2n), acetyl moiety (2k) and ester
group (2l) were well tolerated under these mild reductive
conditions. Interestingly, substrate 2o, bearing a Bpin group that
could be easily utilized in the following functionalization, also
reacted smoothly, affording the desired product 2o in 85% yield.
In addition, the reaction also proceeded smoothly with either
heteroaromatic substituted substrates 1q & 1r or substrates 1p &
1s−1t in which 2-naphthyl or alkyl substituents were directly
attached to the 2-carbonyl moiety (2p−2t). The reaction also
occurred when the ɑ-keto ester substrate 1u was applied. In
addition, reactions of substrates bearing different alkyl
substituents on the nitrogen atom of aniline moiety (R3) also
underwent smoothly, affording the corresponding cyclopropane
products in moderate yields (2v−2w). Moreover, substrates
containing either electron-donating or electron-withdrawing
groups on the aromatic ring of the aniline moiety (R2) were probed.
The reactions occurred smoothly, affording the corresponding
3
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and readily to accept two oxygen atoms from the 1,2-dicarbonyl
substrate (eq 2, Scheme 6). In contrast, with 0.6 equiv of DPPB,
the Mo-catalyzed cyclopropanation reaction of 1a occurred in full
conversion, affording the desired product 2a in 78% yield along
with 44% yield of diphosphine oxide P1 and 6% yield of
diphosphine monoxide P2 (yields calculated based on substrate
1a), which indicated the one of the two carbonyl oxygen atoms in
substrate 1a was almost completely transferred to the
diphosphine (eq 3, Scheme 6). These results clearly demonstrate
that DPPB is a good oxygen acceptor and plays an important role
in the regeneration of the catalytically active molybdenum
complex.
[a] Reaction conditions: 10 mol% of Mo(CO)6, 10 mol% of o-quinone, 0.2 mmol
of 1, 0.12 mmol of DPPB in toluene (2.0 mL) at 120 oC. Isolated yields are
reported. [b] The reaction was performed on 0.1 mmol scale. [c] 30 mol% of
Mo(CO)6 and o-quinone were used.
Pleasingly, the present method was able to be applied to the
late-stage functionalization of the derivatives of natural products
and drug molecules, providing an easy access to several
cyclopropane-containing complex molecules (2af−2ai, Table 2) in
good yields. Intriguingly, this molybdenum-based system was
also capable of promoting the deoxygenative cyclopropanation of
a simple mono-carbonyl compound (1aj, Scheme 3).
Scheme 3. Deoxygenative cyclopropanation of
a simple mono-carbonyl
compound.
To further demonstrate the synthetic utility of the present
methodology, gram-scale syntheses and several transformations
of the heterocycle fused cyclopropanes were carried out. Under
the Mo-catalytic conditions, the gram-scale production of
cyclopropane 2c was obtained in excellent yields using either
diphosphine or silane as the reductant (Scheme 4). In addition,
these cyclopropane products are readily transformed to other
valuable building blocks through m-CPBA oxidation, Sonogashira
cross-coupling, and Suzuki cross-coupling (paths a-c, Scheme 5).
Interestingly, the amide 4 instead of the Baeyer-Villiger oxidation
product 5 was obtained in 54% yield when the reaction was
performed under the Baeyer-Villiger oxidation conditions.[17,18]
Scheme 5. Synthetic transformations. Reaction conditions: a) m-CPBA, TsOH,
CH2Cl2, rt, 54% yield. b) Pd(PPh3)4 (10 mol%), CuI (20 mol%), phenylacetylene,
Et3N, rt−80 oC, 94% yield. c) Pd(PPh3)4 (10 mol%), pyridin-4-ylboronic acid,
Na2CO3, toluene/MeOH/H2O, 80 oC, 94% yield.
Scheme 4. Gram-scale syntheses of cyclopropane product 2c.
To shed light on the reaction mechanism, preliminary
mechanistic studies were carried out. Initially, the control
experiment showed that cyclopropane 2a was not observed when
the cyclopropanation reaction was carried out in the absence of
the Mo-catalyst (eq 1, Scheme 6). These results clearly exclude
the plausible reaction pathway involving the Kukhtin–Ramirez
adducts[19] which are often formed via the addition of a trivalent
phosphorus to 1,2-dicarbonyl compounds. Intriguingly, 20% yield
of the desired cyclopropane 2a was obtained when the reaction
was carried out without DPPB, which indicates the Mo-catalyst
generated in situ from 10 mol% of Mo(CO)6 and o-quinone is
capable of promoting the cyclopropanation for two catalytic cycles
Scheme 6. Control experiments.
4
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Based on the above experimental observations and
computational studies,[20-21] a plausible reaction pathway was
proposed, as shown in Scheme 7. Firstly, the formation of oxo-
Mo-carbene complex I-1 is promoted by the Mo-complex M-1 via
a regioselective C=O double bond cleavage transition state
TS1.[12f, j-k] Then, the oxo-Mo-carbene complex I-1 undergoes the
concerted intramolecular cyclopropanation via TS2 to afford the
product 2a and the oxo-Mo-complex M-2. Finally, the Mo-catalyst
M-1 is regenerated through reduction of the oxo-Mo-complex M-
2 with either phosphine[22] or silane as a reductant.
Keywords: deoxygenative cyclopropanation • molybdenum
catalysis • carbene equivalent • 1,2-dicarbonyl compound •
regiospecific deoxygenation
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valuable substituted cyclopropanes in up to 90% yield. The
reaction is distinguished by its broad substrate scope,
commercially available Mo-catalytic system, use of either
phosphine or silane as both a mild reductant and an oxygen
acceptor, operationally safe and simple procedure, and
application to the late-stage functionalization and gram-scale
syntheses. Moreover, the 1,2-dicarbonyl compounds could be
directly utilized as carbene equivalents through the Mo-catalyzed
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the preparation of cyclopropanes via catalytic cyclopropanation of
the readily available and bench stable 1,2-dicarbonyl or mono-
carbonyl compounds instead of the potentially explosive diazo
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development of other diazo-free transformations are ongoing in
our laboratory.
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Acknowledgements
We are grateful for financial support from the Recruitment Pro-
gram of Global Experts and Xiamen University. We thank Mr.
Zanbin Wei for solving the X-ray structure.
Conflict of interest
The authors declare no conflict of interest.
5
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10.1002/anie.202103429
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The first Mo-catalyzed regiospecifically deoxygenative cyclopropanation reaction of the readily available and bench stable 1,2-
dicarbonyl compounds is described. An array of valuable cyclopropanes were obtained in up to 90% yield and exclusive
regioselectivity. This strategy could further be applied to a cyclopropanation reaction of a simple mono-carbonyl compound.
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