Catalytic Enantioselective Cyclopropenation of Internal Alkynes: Access to Difluoromethylated Three-Membered Carbocycles

Article abstract of DOI:10.1002/anie.201911701

Herein we described an efficient Rh^II-catalyzed enantioselective cyclopropenation reaction of internal alkynes with a masked difluorodiazoethane reagent (PhSO₂CF₂CHN₂, Ps-DFA). This asymmetric transformation offers efficient access to a broad range of enantioenriched difluoromethylated cyclopropenes (40 examples, up to 99 % yield, 97 % ee). The synthetic utility of obtained strained carbocycles is demonstrated by subsequent stereodefined processes, including cross-couplings, hydrogenation, Diels–Alder reaction, and Pauson–Khand reaction.

Full text of DOI:10.1002/anie.201911701

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Accepted Article
Title: Catalytic Enantioselective Cyclopropenation of Internal Alkynes:
Access to Difluoromethylated Three-Membered Carbocycles
Authors: Zhi-Qi Zhang, Meng-Meng Zheng, Xiao-Song Xue, Ilan
Marek, Fa-Guang Zhang, and Jun-An Ma
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911701
Angew. Chem. 10.1002/ange.201911701
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Angewandte Chemie International Edition
10.1002/anie.201911701
COMMUNICATION
Catalytic Enantioselective Cyclopropenation of Internal Alkynes:
Access to Difluoromethylated Three-Membered Carbocycles
[a]
[b]
[b]
[c]
[a]
Zhi-Qi Zhang, Meng-Meng Zheng, Xiao-Song Xue, Ilan Marek,* Fa-Guang Zhang,* and Jun-An
Ma*[a, b]
Abstract: Herein we described an expeditious Rh(II)-catalysed
enantioselective cyclopropenation reaction of internal alkynes with a
2 2 2
masked difluorodiazoethane reagent (PhSO CF CHN , Ps-DFA).
This asymmetric transformation offers efficient access to a broad
range of enantioenriched difluoromethylated cyclopropenes (40
examples, up to 99% yield, 97% ee). The synthetic utility of obtained
strained carbocycles is demonstrated by subsequent stereo-defined
processes including cross-couplings, hydrogenation, Diels-Alder
reaction, and Pauson−Khand reaction.
Enantioenriched cyclopropenes have drawn increasingly
considerable synthetic interest owing to their versatile reactivity.[1]
In this context, catalytic enantioselective cyclopropenation
reactions arguably represent one of the most straightforward and
Scheme 1. Catalytic enantioselective cyclopropenation reactions
of internal alkynes with diazo compounds.
commonly-used
transformations
to
access
chiral
cyclopropenes.[ Pioneered by the elegant studies from Doyle,
Corey,[3] Davies,[4] among others,[5] this [2+1]-cycloaddition
reaction with terminal alkyne has witnessed substantial advances
in the past two decades. In sharp contrast, the extension of this
chemistry for internal alkynes has proved extremely challenging,
mainly due to the attenuated reactivity and difficult stereo-control
associated with growing steric hindrance.[6] Until now, only the
research group of Huw Davies has successfully used internal
alkynes in a cooperative gold/silver-catalyzed enantioselective
cyclopropenation reaction with donor/acceptor-substituted
diazoesters (Scheme 1a).[ In the same vein, Carreira and
Morandi have reported a powerful racemic cyclopropenation
reaction of internal alkynes by using trifluorodiazoethane as
reaction partner (Scheme 1b).[8] As fluorinated diazo compounds
have emerged as an attractive building block for the efficient
1]
[2]
be realized by taking advantage of our recently developed
2 2 2
difluorodiazo reagent (PhSO CF CHN
, Ps-DFA).[12] Herein we
report our investigations toward this goal through a Rh(II)-
catalyzed highly enantioselective cyclopropenation of Ps-DFA
with a broad range of readily accessible unbiased internal alkynes
(
Scheme 1c). This reaction represents the first example of
catalytic asymmetric addition of acceptor-(only) carbene
precursor with internal alkynes.
In our preliminary experiments, [Rh (OAc) ] was first evaluated
2 4
as potential catalyst with 1-phenyl-1-propyne 1a, as model
substrate. However, in this condition, only a trace amount of the
desired product 2a was detected (Table 1, entries 1–3). To our
7]
2 2
delight, when the Du Bois catalyst [([Rh (esp) ])] was added to the
same two substrates, cycloproprene 2a was smoothly produced
at –30 °C in decent yield (Table 1, entry 4).[13] Encouraged by
these results, we have subsequently investigated the asymmetric
variant of this carbene transfer reaction by screening an array of
chiral Rh(II) complexes (entries 5–11). Although the Davies’s
construction of numerous
fluoroalkylated carbocycles,
[
9]
heterocycles, and acyclic architectures, the development of
catalytic asymmetric [2+1]-cycloaddition of fluorodiazo derivatives
with internal alkynes is still in its infancy.[10]
As part of our continuing interest in the realm of fluorinated
carbene chemistry,[11] we hypothesized that the catalytic and
enantioselective cyclopropenation of inert internal alkynes might
2 4 2 3
(S-DOSP) (OAc)(DPTI)
][14] and Corey’s [Rh ][3] catalysts
[
Rh
gave low enantiodiscrimination in this transformation (Table 1,
entries 5 and 6, respectively), the Hashimoto’s catalyst ([Rh (S-
TCPTTL)
])[15] delivered 2a in good yield with high asymmetric
2
4
induction (Table 1, entry 9, 80% yield, 96% ee). Further
optimizations allowed to decrease the catalyst loading to only 1.5
mol% with 1.5 equivalent of Ps-DFA to provide the expected
cyclopropene in only 40 min at –30 °C (Table 1, entry 16, 88%
yield, 96% ee). At the outset, a scale-up experiment established
our confidence in the robustness of the current method as 2a
could be prepared on a gram scale in 91% yield and 96%
[
a]
Z.-Q. Zhang, Prof. Dr. F.-G. Zhang, and Prof. Dr. J.-A. Ma
Department of Chemistry, Tianjin Key Laboratory of Molecular
Optoelectronic Sciences, and Tianjin Collaborative Innovation
Centre of Chemical Science & Engineering, Tianjin University,
Tianjin 300072; and Joint School of NUS & TJU, International
Campus of Tianjin University, Fuzhou 350207, P. R. of China
Email: zhangfg1987@tju.edu.cn, majun_an68@tju.edu.cn
Homepage: http://tjmos.tju.edu.cn/majunan/
M.-M. Zheng, Prof. Dr. X.-S. Xue, Prof. Dr. J.-A. Ma
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071, P. R. of China
Prof. Dr. I. Marek E-mail: chilanm@technion.ac.il
Schulich Faculty of Chemistry, Technion-Israel Institute of
Technology, Haifa, 3200009, Israel
enantiomeric
excess.
Remarkably,
constant
high
[
b]
c]
enantioselectivities were observed even when the reaction was
performed in a short period of time (i.e. 5 minutes) albeit at the
expense of slightly decreased yields (Table 1, entries 17–18).
Alternatively, cyclopropene 2a could also be obtained with 96%
enantiomeric excess in practical yield while Ps-DFA was
employed as the limiting starting material, thus providing a
[
Supporting information for this article is given via a link at the end
of the document. ((Please delete this text if not appropriate))
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Angewandte Chemie International Edition
10.1002/anie.201911701
COMMUNICATION
Table 1. Optimization of the reaction conditions. [a]
complementary protocol for future applications
(
Table 1, entry 19). In addition, this reaction is
also well compatible with other solvents, such
as chloroform, tetrahydrofuran, and diethyl
ether (entries 20–23).
Entry
Catalyst (mol%)
Solvent
Temperature
Yield
(%)[b]
trace
5
ee
(%)[c]
-
With the optimized reaction conditions in
hand (Table 1, entry 15), a wide variety of
disubstituted alkynes were evaluated in the
cyclopropenation reaction (Scheme 2). Alkyl
substituents in ortho, meta or para position of
the aromatic ring (Scheme 2, 2b–2d
respectively) were equally tolerated and in all
cases, good to high yields and high
enantioselectivities were consistently observed.
The absolute configuration of compound 2d
(ºC) / Time (h)
1
2
3[e]
Rh
2
(OAc)
4
(2.5)
(2.5)
(2.5)
(2.5)
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0 / 3
Rh
2
(esp)
2
0 / 3
-
Rh
Rh
2
(OAc)
4
–20 / 3
6
-
4
2
(esp)
2
–30 / 2
63
50
30
85
85
80
59
53
80
72
69
82
88
79
74
69
85
63
65
50
-
5
Rh
Rh (OAc)(DPTI)
Rh (S-PTTL) (2.5)
Rh (S-TFPTTL) (2.5)
Rh (S-TCPTTL)
Rh (S-TBPTTL)
Rh (S-NTTL)
2
(S-DOSP)
4
(2.5)
–30 / 2
50
14
64
93
96
93
57
96
95
96
96
96
96
96
96
94
96
98
98
6
2
3
(2.5)
–30 / 2
7
2
4
–30 / 2
8
2
4
–30 / 2
9
2
4
(2.5)
(2.5)
–30 / 2
was unambiguously determined by X-ray
crystallography analysis,[16] and the absolute
10
11
12
13
14
2
4
–30 / 2
2
4
(2.5)
–30 / 2
configuration of all other cyclopropenes were
assigned by analogy. Similarly, various halogen
substituents at different positions of the phenyl
ring could be tolerated under identical
conditions (Scheme 2, 2h–2m). It was found
that substrates bearing strong electron-
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
2
2
2
2
2
2
2
2
2
2
2
2
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
(S-TCPTTL)
4
4
4
4
4
4
4
4
4
4
4
4
(1.5)
–30 / 2
(1.0)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
–30 / 2
–40 / 2
1
1
1
1
1
2
2
2
2
5[d]
6[d]
7[d]
8[d]
9[e]
0[d]
1[d]
2[d]
3[d]
–30 / 1
–30 / 40 min
–30 / 20 min
–30 / 5 min
–30 / 40 min
–30 / 40 min
–30 / 40 min
–30 / 40 min
–30 / 40 min
3
withdrawing groups such as -CF , -CN, and -
NO , are also compatible in this reaction, giving
2
rise to the corresponding cyclopropenes 2n–2r
with 92–96% ee. This Rh(II)-catalyzed
cycloaddition reaction could be extended to
naphthyl-, thienyl-, and pyridinyl-substituted
ClCH
CHCl
THF
Et
2
CH
2
Cl
3
2
O
alkynes
as
demonstrated
by
the
[
a] Reaction was conducted as following unless otherwise noted: To a stirred solution of Rh(II)
enantioselective formation of 2s–2u. Notably,
the current protocol also exhibits high level of
tolerance toward a broad range of alkyl groups
as regards to the second substituent of the
internal alkyne (Scheme 2, products 2v–2ae). It
is interesting to note that this carbene transfer
reaction is chemoselective as the C-H insertion
at the benzylic as well as the methylene sites
next to the alkoxy group was not observed
catalyst and internal alkyne 1a (0.3 mmol, 1 equiv) in solvent (1 mL) was added diazo compound
Ps-DFA (0.6 mmol, 2 equiv) in 1 mL of corresponding solvent dropwise at indicated temperature.
[
b] Yield of isolated product. [c] Determined by HPLC on a chiral stationary phase using a Daicel
Chiralpak column. [d] 1.5 equiv of Ps-DFA was employed. [e] Ps-DFA (0.3 mmol, 1 equiv) with
alkyne 1a (0.6 mmol, 2 equiv) was employed.
(
Scheme 2, 2z and 2aa).
As one of the limitations[17] of our proposed
strategy concerned the catalytic and
enantioselective cyclopropenation of diaryl
acetylenes en route to the formation of diaryl
cyclopropenes (2ai could only be formed in 5% yield), we were
interested to develop an alternative substrate that would be able
to provide subsequently the desired diaryl cyclopropenes. In this
context, we were pleased to observe that the treatment of
halogenated internal alkynes 1af–1ah in our experimental
condition led to the corresponding halogeno-cyclopropenes 2af–
boronic acids (Scheme 3b), whereas an array of previously
inaccessible chiral vinyl cyclopropenes (Scheme 3c, products
2al–2ap) could also be readily prepared under mild conditions by
a Heck reaction on 2af with easily available styrenyl or acrylate
derivatives. In all cases, the products are obtained with the same
enantiomeric excess than that the initial starting material 2af.
The developed cyclopropenation reaction provides a viable
route to access densely functionalized cyclopropenes containing
enantioenriched fluoroalkyl carbon stereogenic centers, which
should find a range of applications as useful chiral building blocks
for stereoselective organic syntheses. Therefore, the phenyl
sulfone moiety was smoothly cleaved by using magnesium under
2ah in 86–93% ee (Scheme 3a). Having now access to
cyclopropenyl bromide 2af, smooth cross-coupling reactions have
been performed to lead to the expected dissymmetric 1,2-
disubstituted
cyclopropenes
2ai–2ap.[18] For
instance,
enantioenriched diaryl cyclopropenes 2ai–2ak were obtained
from 2af via a Suzuki cross-coupling reaction with different aryl
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Angewandte Chemie International Edition
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COMMUNICATION
Scheme 3. Preparation and reactivity of halogeno-cyclopropenes.
Scheme 2. Rh-catalysed enantioselective cyclopropenation
reaction of internal alkynes with Ps-DFA.
acidic conditions, leading to the formation of CF
with very minor epimerization of the stereogenic center
Scheme 4a). Furthermore, we showed that 2a could easily be
reduced to cyclopropane 4 as a single diastereoisomer in almost
quantitative yield upon simple treatment with Pd/C/H at room
temperature without again any loss of the enantiopurity (Scheme
b). Next, a Diels–Alder reaction of 2a with 2,3-dimethylbutadiene
2
H-cyclopropene
3
(
2
4
was found to proceed smoothly to produce the fused-bicycle 5 in
high yield and selectivities (>20:1, Scheme 4c). The absolute
configuration of 5 was determined by X-ray crystallography
analysis.[16] Finally, cyclopropene 2a was also subjected to an
intermolecular Pauson−Khand reaction,[19] furnishing the bicyclic
cyclopentenone 6 in high yield without any erosion of its
enantiopurity (Scheme 4d).[16]
Scheme 4. Synthetic transformations with cyclopropene 2a.
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COMMUNICATION
To better understand the origin of the selectivity for the
cyclopropenation on disubstituted alkynes,[20] the reaction
mechanism was investigated by density functional theory
calculation[
[
21]
for the cycloaddition of Ps-DFA with 1a using
Rh (S-TCPTTL)
2 4
] as the catalyst (Scheme 5).[22] The theoretical
calculations indicate that the reaction is highly exergonic by 47.6
kcal/mol, and the rate-determining step among the whole catalytic
process could be the extrusion of nitrogen (Int1 to TS1, 12.5
kcal/mol). The difluoroalkyl-substituted rhodium carbenoid Int2 is
stabilized relative to the starting reactants by 11.7 kcal/mol. This
in-situ-formed organometallic intermediate is very electrophilic
and tends to cyclopropenate with internal alkyne 1a in a step-wise
process involving a zwitterionic intermediate Int3. Based on these
results and the previously reported C4-symmetry-like chiral crown
conformation
of
[Rh
2
(S-TCPTTL)
4
],[20]
the
origin
of
enantioselectivity was proposed in Scheme 5b. In the located two
transition states, the alkyne approaches the Rh-carbenoid with a
tilted side-on trajectory preferentially from the hydrogen side. The
calculated lengths of the forming C−C bonds are 3.16 Å in TS2
and 3.35 Å in TS2’, implying that this step has a relatively early
transition state (Δbond length(TS-product) = 1.65 and 1.84 Å,
respectively). The Gibbs free energy of TS2 (leading to product
S-2a) is 2.7 kcal/mol lower than that of TS2’ (leading to product
R-2a), which is consistent with the observed sense of asymmetric
induction. The preferential formation of TS2 over TS2’
presumably results from the considerable steric repulsion
Scheme 5. Free energy profile for the Rh-catalysed
cyclopropenation reaction between Ps-DFA and alkyne 1a
calculated
at
the
SMD-B3LYP-D3/6-311+G**(Rh:
SDD)//B3LYP/6-31G*(Rh: lanl2dz) level of theory and plausible
stereochemical mode for enantioselective cyclopropenation. The
selected bond lengths are in Å.
between the aryl group located on the alkyne and the
tetrachlorophthalimido group in TS2’.[22]
In summary, we have developed the first highly
enantioselective Rh(II)-catalyzed cyclopropenation reaction of
unactivated internal alkynes with a fluorinated diazo reagent (Ps-
DFA) providing a facile route for the construction of a broad range
of enantioenriched densely functionalized unsaturated three-
membered carbocycles. This study brings an easy and
straightforward answer to the long-standing challenge of catalytic
enantioselective cyclopropenation of internal alkynes with
acceptor-(only) carbene precursors. Furthermore, the synthetic
utility of the obtained novel strained molecules has been
demonstrated through versatile stereocontrolled transformations.
Future investigations including substrate scope expansion and
synthetic applications are ongoing in our laboratory, and these
results will be reported in due course.
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E. A. Shapiro, J. Am. Chem. Soc. 1994, 116, 8492-8498.
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Briones, J. Hansen, K. I. Hardcastle, J. Autschbach, H. M. L. Davies, J.
Am. Chem. Soc. 2010, 132, 17211-17215.
a) T. Goto, K. Takeda, N. Shimada, H. Nambu, M. Anada, M. Shiroo, K.
Ando, S. Hashimoto, Angew. Chem. Int. Ed. 2011, 50, 6803-6808;
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Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2011, 133, 3304-3307; c) M.
Uehara, H. Suematsu, Y. Yasotumi, T. Katsuki, J. Am. Chem. Soc. 2011,
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21532008, 21772142, and 21901181)
[
6]
7]
Davies et al demonstrated that the terminal hydrogen of alkynes may
play a crucial role through interactions with carboxylate ligands, see ref
and Tianjin Municipal Science
19JCQNJC04700).
& Technology Commission
(
4b and J. F. Briones, H. M. L. Davies, Org. Lett. 2011, 13, 3984-3987.
[
J. F. Briones, H. M. L. Davies, J. Am. Chem. Soc. 2012, 134, 11916-
11919. The electron-donating group in the donor/acceptor carbene is
assumed to stabilize the dirhodium-carbene intermediates and renders
better stereo-control in the C-C bond forming step. In addition, Doyle et
al also reported some preliminary results on the catalytic asymmetric
Keywords: cyclopropenes • difluoromethyl group• diazo
compounds• metal carbenes • internal alkynes
[
1]
a) I. Marek, S. Simaan, A. Masarwa, Angew. Chem. Int. Ed. 2007, 46,
364-7376; Angew. Chem. 2007, 119, 75087520; b) M. Rubin, M. Rubina,
7
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Angewandte Chemie International Edition
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COMMUNICATION
cyclopropenation of internal alkynes with ethyl diazoacetate, albeit with
low yield and low enantioselectivity. For details, see ref 2.
[15] a) M. Anada, N. Watanabe, S. Hashimoto, Chem. Commun. 1998, 1517-
1518; b) S. Kitagaki, M. Anada, O. Kataoka, K. Matsuno, C. Umeda, N.
Watanabe, S. Hashimoto, J. Am. Chem. Soc. 1999, 121, 1417-1418; c)
M. Yamawaki, H. Tsutsui, S. Kitagaki, M. Anada, S. Hashimoto,
Tetrahedron Lett. 2002, 43, 9561–9564.
[8]
a) B. Morandi, E. M. Carreira, Angew. Chem. Int. Ed. 2010, 49, 4294-
296; Angew. Chem. 2010, 122, 4390-4392; For two other examples,
4
see: b) D. Gladow, S. Doniz-Kettenmann, H.-U. Reissig, Helv. Chim.
Acta 2014, 97, 808-821; c) R. Barroso, A. Jimenez, M. C. Perez-Aguilar,
M.-P. Cabal, C. Valdes, Chem. Commun. 2016, 52, 3677-3680.
[16] CCDC 1934783 (2d), 1934959 (5), and 1934966 (6) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
[9]
a) O. O. Grygorenko, O. S. Artamonov, I. V. Komarov, P. K. Mykhailiuk,
Tetrahedron 2011, 67, 803-823; b) D. Qiu, M. Qiu, R. Ma, Y. Zhang, J.
Wang, Acta Chim. Sinica 2016, 74, 472-487; c) L. Mertens, R. M.
Koenigs, Org. Biomol. Chem. 2016, 14, 10547-10556; d) M. Bos, T.
Poisson, X. Pannecoucke, A. B. Charette, P. Jubault, Chem. Eur. J. 2017,
2 2
Centre. HF CCHN was also employed to react with 1-phenyl-1-propyne
1a under otherwise identical reaction conditions, but resulted in the
formation of desired product 2a in trace amount (<10% yield) with only
30% ee.
2
9
6
3, 4950-4961; e) X. Wang, X. Wang, J. Wang, Tetrahedron 2019, 75,
49-964; f) P. K. Mykhailiuk, R. M. Koenigs, Chem. Eur. J. 2019, 25,
053-6063.
[17] Two terminal alkynes (phenyl acetylene and 4-phenyl-1-butyne) have
been evaluated in this reaction under otherwise identical conditions. In
the case of 4-phenyl-1-butyne, the desired cyclopropene 2aq was
obtained in 70% yield, but with no enantioselectivity. No desired
cyclopropene was observed when phenyl acetylene was employed
(unidentified complex mixtures).
[
10] There is no reported study of enantioselective reactions with CF
2
HCHN
2
until now. For reported catalytic enantioselective reactions with CF
3
CHN ,
2
see: a) B. Morandi, B. Mariampillai, E. M. Carreira, Angew. Chem. Int.
Ed. 2011, 50, 1101-1104; Angew. Chem. 2011, 123, 1133-1136; b) Z.
Chai, J.-P. Bouillon, D. Cahard, Chem. Commun. 2012, 48, 9471-9473;
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4
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[22] See the supporting information (SI) for calculation details. Noncovalent
interaction (NCI) analysis on TS2 and TS2’ has also been conducted. As
shown in Scheme S2 in the SI, the NCIPLOT suggests a steric repulsion
between the aryl group of the alkyne and the tetrachlorophthalimido
group in transition state TS2’. Therefore, the enantioselectivity is
assumed to be mainly controlled by the steric effect of the alkyne-
insertion step, which is in line with the proposed stereo-control model in
Scheme 5b.
1
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Zheng, Z.-Q. Zhang, X.-S. Xue, F.-G. Zhang, J.-A. Ma, Org. Lett. 2019,
2
1, DOI: 10.1021/acs.orglett.9b02989.
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[
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Angewandte Chemie International Edition
10.1002/anie.201911701
COMMUNICATION
Zhi-Qi Zhang, Meng-Meng Zheng, Xiao-
Song Xue, Ilan Marek*, Fa-Guang
Zhang*, and Jun-An Ma*
Page No. – Page No.
Catalytic
Enantioselective
Cyclopropenation of Internal Alkynes:
Access to Difluoromethylated Three-
Membered Carbocycles
Overcoming Internal Alkynes:
cyclopropenation reaction of difluorodiazoethane (PhSO
internal alkynes is disclosed (up to 99% yield, 97% ee). Versatile stereoselective
transformations of these unique strained cyclopropenes is also demonstrated.
A
Rh(II)-catalysed highly enantioselective
CF CHN ) with challenging
2
2
2
This article is protected by copyright. All rights reserved.