Tris(pentafluorophenyl)borane-Catalyzed Cyclopropanation of Styrenes with Aryldiazoacetates

Article abstract of DOI:10.1021/acscatal.0c03218

Methods for the synthesis of cyclopropanes are critical for drug discovery, chemical biology, total synthesis, and other fields. Herein, we report the use of the strong sterically encumbered Lewis acid tris(pentafluorophenyl)borane as a catalyst for the cyclopropanation of unactivated alkenes using aryldiazoacetates. The cyclopropane products are synthesized using 10 mol % of the catalyst under mild conditions in up to 90% yield (8:1 to >20:1 dr). We propose that the reaction proceeds via a Lewis acid-activated carbene.

Full text of DOI:10.1021/acscatal.0c03218

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Letter
Tris(pentafluorophenyl)borane-Catalyzed
Cyclopropanation of Styrenes with Aryldiazoacetates
Joseph P Mancinelli, and Sidney Wilkerson-Hill
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c03218 • Publication Date (Web): 10 Sep 2020
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ACS Catalysis
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Tris(pentafluorophenyl)borane-Catalyzed Cyclopropanation of
Styrenes with Aryldiazoacetates.
Joseph P. Mancinelli and Sidney M. Wilkerson-Hill*
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†Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United
States
Keywords: Cyclopropanation, tris(pentafluorophenyl)borane, Lewis acid catalysis, carbene, aryl diazoacetate
Supporting Information Placeholder
highly electrophilic chiral oxazaborolidinium catalysts due to the
low nucleophilicity of diazoacetates.22 At the outset of these
studies, there were no reports of isolating cyclopropanes when
unactivated alkenes were used as a reaction partner in the presence
of Lewis acids. However, during the preparation of this manuscript,
a report by Melen and coworkers appeared disclosing such
reactivity.23
ABSTRACT: Methods for the synthesis of cyclopropanes are
critical for drug discovery, chemical biology, total synthesis and
other fields. Herein, we report the use of the strong sterically
encumbered Lewis acid tris(pentafluorophenyl)borane as a catalyst
for the cyclopropanation of unactivated alkenes using
aryldiazoacetates. The cyclopropane products are synthesized
using 10 mol % of the catalyst under mild conditions in up to 90%
yield (8:1 to >20:1 dr). We propose that the reaction proceeds via a
Lewis acid-activated carbene.
(a) Early stoichiometric experiments using acids and diazocarbonyls
Products obtained
O
O
R
R
R
R
Typical acids Typical nucleophiles employed
OR
O
employed
(most cases intramolecular)
R
R
R
BF3•OEt2
HCl
CF3CO2H
HClO4
R
N
R
R
R
R
N2
-diazoketone
R
ROH
Cyclopropanes are dissonant carbocycles which are typically
synthesized using [2+1] cycloaddition strategies and are used in a
variety of applications.1–7 Consequently, reactions to build these
motifs are enabling for a number of subdisciplines. To date, some
of the most efficient methods for the synthesis of cyclopropanes
rely on the activation of a carbene precursor, such as a diazo
acetate, with a transition-metal catalyst8 generating transient metal
carbene species. These transformations have been optimized
extensively and, in most cases, provide cyclopropanes with high
enantioselectivity and diastereoselectivity and regiocontrol.
Alternatively, stoichiometric transformations utilizing zinc
carbenoids have been developed.9 These transformations, however,
are not without limitations. The use of expensive transition-metal
catalysts can be a deterrent for their use on large scale.
Furthermore, the use of zinc carbenoids requires 1,1-dihaloalkane
precursors, work best when transferring methylene units, and
produces stoichiometric amounts of zinc waste. Thus, transition-
R
R
O
R
N
O
no cyclopropanes
formed when used
R
R
(b) Catalytic activation of diazo compounds without transition-metals.
CF3
F
F
TsOH
Doyle: C–H insetions
Zhang: C–H insertions
Ar
B
TfO
O
N
H
Ar
B
O
N
H
N
CF3
R
H
B(C6F5)3
Hu: - C–H insertions
Tang: - O–H insertions
Melen: - alkenylation
Mattson
Ryu - (activates enaldehyde)
Ar = 3,5-dimethylphenyl
R = 1-naphthyl
nitrodiazoacetates
N–H insertion
O–H insertion
(c) This work- transition-metal-free cyclopropanation with aryldiazoacetates
LA
R
O
O
O
LA
LA
Ar
Ar
Ar
R
R
LA
common for
transition-metal
free
N2
N2
N2
transition-metals
-diazonium
carbonyl species
-diazoketone
alkene diazonium
- N2
metal-free variants of [2+1] cycloaddition reactions are valuable.10–
LA
O
12
MeO2C
Ar
Ar
CO2Me
cat. B(C6F5)3
30 examples
Ar
C
R
+
Harnessing the electrophilic reactivity of diazocarbonyl
compounds catalytically without transition-metals is conspicuously
absent despite the extensive studies on the stoichiometric reactivity
of these compounds with both Brønsted and Lewis acids.13–15 Early
mechanistic studies demonstrated these species are capable of
generating both diazonium ketones, when activated with an acid on
carbon, or an alkenediazonium intermediate when activated on
oxygen instead.16 Interactions of acids with diazo compounds on
nitrogen are also common.17 Typically, the putative diazonium
species are then trapped with a variety of nucleophiles such as
pendant heteroatoms,18 nitriles,19 arenes20 or activated olefins to
give substitution products.21 However, these transformations are
limited in scope and often produce substitution products in low
yields and as a mixture of isomers (Figure 1, A). Organocatalytic
transformations using diazocarbonyls as ylides have only recently
been achieved using enaldehyde Michael acceptors activated by
Ar'
N2
Ar'
Lewis acid -
activated carbene
Figure 1: Summary of the reactivity of Brønsted and Lewis acids
with diazocarbonyl compounds.
Recently, researchers have focused attention on catalytic
activation of diazocarbonyl compounds with Brønsted (including
H–bonding) and Lewis acids. However, these transformations are
mainly limited to X–H insertions (X = C, N, or O).24 For example,
studies by the Mattson group showed that anilines undergo N–H
insertions with -nitrodiazoesters activated by thioureas as
catalyst.25 In 2014, Hu found that treating 3-diazooxindoles with
TfOH results in formal C–H insertion products which arise through
a Friedel–Crafts alkylation of electron-rich arenes (Figure 1, B).26
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Later in 2016, Zhang showed that tris(pentafluorophenyl)borane
With our optimized conditions in hand, we explored the scope of
this transformation, beginning first with substitution on the styrene.
The transformation was amenable to several electron-rich styrene
derivatives producing 4–8 and electron deficient styrene
derivatives producing 9–11 (Chart 1) including those with Lewis
basic functionality that could hinder the reaction by coordinating
with the Lewis acid catalyst (e.g., 8). In all cases we observe a
single diastereomer with the aryl rings cis to each other, except in
the case of α-methyl styrene, where an 8:1 mixture of diastereomers
was observed by proton 1H NMR (E-14).29 Indole groups were also
tolerated giving compound 15 in good yield, and no products
arising from cyclopropanation of the 2,3-bond of the indole unit
were observed. We also tested several unactivated alkenes (Chart
1, inset box) and found these substrates performed poorly with our
optimized conditions producing the desired cyclopropanes in low
yields (< 15%).
1
2
3
4
5
6
7
8
(B(C6F5)3),27 activates aryldiazoacetates to effect an ortho-selective
C–H insertion reaction on phenols, and O–H insertions into water.28
As a part of a research program centered on main-group
catalysis, we became interested in the reactivity of strong sterically
encumbered Lewis acids with aryldiazoacetates. We sought to use
the carbonyl group of aryldiazoacetates as a Lewis base handle for
activation and hypothesized that
a strong, but sterically
encumbered, Lewis acids, such as tris(pentafluorophenyl)borane,
would facilitate catalysts turnover. Furthermore, we envisioned a
Lewis-acid activated carbene intermediate (see inset box in Scheme
1, C) would confer high levels of diasterocontrol. Herein, we report
an additional study on the use of B(C6F5)3 to activate
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donor/acceptor
diazo
compounds
for
the
catalytic
diastereoselective cyclopropanation of styrene derivatives.
We began by studying the reaction of ethyl 4-
bromophenyldiazoacetate with styrene in the presence of catalytic
(5 mol%) tris(pentafluorophenyl)borane.29 We found that
increasing the catalyst loading from 5 to 10 mol % was moderately
beneficial (Table 1, Entries 1–2), but further increases (15 mol %
were deleterious to the reaction efficiency. A control study of the
reaction in the absence of catalyst revealed no conversion to
cyclopropane by 1H NMR. Next, the effect of solvent on the system
was investigated. We observed that non-coordinating solvents such
as benzene gave the best initial results (Table 1, Entry 8), and that
1,2-dichloroethane was optimal (63% yield, Table 1, Entry 9).
Other more coordinating solvents such as tetrahydrofuran and
acetonitrile significantly diminished the yields of cyclopropane
products (< 5%) presumably due to competitive inhibition of the
catalyst by the solvent. Reducing the equivalents of styrene relative
to diazo (2 equiv 1a) gave the best results 83% yield (75% isolated)
of compound 3. We observed increased amounts of poly(styrene)
in the crude reaction mixture when increased amounts of styrene
we used. The reaction was amenable to large batches, providing 3
on gram scale (70% isolated yield with 1.00 mmol styrene).
Notably, BPh3 and other Lewis acid catalyst gave diminished yields
of the cyclopropane product (Table 1, Entries 13–16). The
temperature of the reaction was also investigated and 50 °C was
optimal. Cooling the reaction mixture to room temperature resulted
in slower conversion to product over days while heating the
mixture to 90 ºC resulted in premature thermal decomposition of
the aryldiazoacetate, in accord with previous studies.30
Chart 1. Reaction Scope with Styrene Derivatives
R
Br
2a - 2m
Br
O
MeO2C
(1 equiv)
R
B(C6F5)3 (10 mol%)
1,2-DCE, 50 ºC
14 - 16 h
OMe
N2
(2 equiv)
1a
3 – 15
Br
Br
Br
Me
Me
CO2Me
CO2Me
CO2Me
4
3
5
85% (95%)b yield
75% (83%) yield
90% (93%) yield
Br
Br
Br
OMe
Me
Ph
CO2Me
CO2Me
CO2Me
6
7
8
83% (88%) yield
82% (84%) yield
79% (82%) yield
Br
Br
Br
Cl
Cl
F
CO2Me
CO2Me
CO2Me
9
10
80% (87%) yield
11
90% (97%) yield
73% (83%) yield
Br
Br
Br
H
CO2Me
CO2Me
CO2Me
Table 1. Optimization Studies.
H
Me
12
82% (83%) yield
13
65% (70%) yield
E-14
75% (82%) yield, 8:1 d.r.
Br
O
Br
MeO
O
conditions
Br
OMe
ineffective alkene substrates
Me
16 h
O
N2
1a
2a
3
TsN
CO2Me
temp. (oC)
yield (%) 3aa
Entry
catalyst loading (mol %) 2a (equiv)
solvent
Me
Me
15
59% (75%) yield
B(C6F5)3
27
33
PhMe
PhMe
1
2
5
10
15
5
5
5
5
5
5
5
5
5
5
1
1
1
1
1
1
1
50
50
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
BPh3
21
PhMe
3
50
a Yields determined by 1H NMR of the crude reaction mixture in
37
Et2O
4
50
parenthesis. Product 3 is included for comparison purposes.
Conditions: All reactions were performed on 150 mol 2a–2m
(0.10 M) in a reaction tube. b2-methyl styrene 75.0 mol scale.
<5
THF
5
5
50
<5
MeCN
6
5
50
16
CH2Cl2
PhH
7
5
50
57
8
5
50
63
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
9
5
50
We next explored the scope of the donor/acceptor diazo
compounds. We found that aryl diazoacetates with various
functionalities were reactive using the optimized reaction
conditions (Chart 2). Changing the identity of the ester did not
hinder the reaction, as methyl ester 1b ethyl ester 1h and even the
more sterically encumbered isopropyl ester 1i proved tolerant of
the reaction conditions giving products 16, 22 and 23 respectively.
More deactivated diazo compounds, such as the para-fluoro
derivative 1f, required longer reaction times, giving diminished
yields of cyclopropane 20. The more activated para-methoxy diazo
1e also gave 19 in reasonable yield (60% yield). Diazocarbonyl
70
10
11
12
13
14
15
16
5
50
64
10
10
10
10
10
10
50
83b (75)
< 5
21
50
50
SnCl4
-78 to 25
-78 to 25
-78 to 25
BF3•OEt2
TiCl4
21
decomp.
Standard conditions: 0.10 M, 16 h. aYields are based on 1H NMR
analysis of the crude reaction mixture using 150 mol mesitylene
or hexamethyldisiloxane as an internal standard. b150 mol styrene
2a, 300 mol (2 equiv) diazo 1a.
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ACS Catalysis
Br
compounds without aryl substitution or with two electron
withdrawing groups (e.g., ethyl diazoacetate, ethyl
diazocyanoacetate, or dimethyl diazomalonate) were ineffective
using the optimized conditions giving less than 5% conversion to
product by 1H NMR analysis (Chart 2, inset box).
O
Br
Br
O
O
styrene (2.0 equiv)
1
2
O
O
eq 3
B(C6F5)3 (10 mol%)
1,2-DCE, 50 ºC
14 - 16 h
O
Ph
N2
H
3
4
31
65% yield
(1H NMR)
32
1k
27% yield
(1H NMR)
Chart 2. Cyclopropanation Scope with Diazocarbonyl
5
6
7
8
Compounds
R1
Br
Br
O
O
B(C6F5)3 (1.00 equiv)
R2
O
RO2C
MeO
MeO
sytrene (2a, 2b, or 2h) (1 equiv)
R1
eq 4
OR
B(C6F5)3 (10 mol%)
1,2-DCE, 50 ºC
14 - 16 h
CDCl3, 50 ºC
16 h
N2
16 – 28
OMe
9
(2 equiv)
1b - 1j
3
3
< 5% change by 1H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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49
50
51
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58
59
60
Me
Cl
With these data, the tentatively proposed mechanism for this
transformation is shown in Scheme 1. First, B(C6F5)3 coordinates
reversibly to the Lewis basic ester on diazo compound 1a,
generating the alkene diazonium species A which exists as a
mixture of E- and Z- isomers. The proposed O-bound enol
diazonium ion is in accord with known values for the equilibrium
of C- versus O-bound boron enolates, and is predicted to be ~25
kcal/mol lower in energy than the C-bound isomers.32 Loss of
dinitrogen affords a resonance stabilized Lewis acid-activated
carbene intermediate B, which then undergoes a concerted [2+1]
cycloaddition reaction with the vinyl group on styrene derivative
2a and regenerates the Lewis acid catalyst. Intermediates such as C
have been studied using DFT calculations.27b The concerted nature
of the cycloaddition reaction is suggested by eq 1 and 2. We
hypothesize that the high diastereoselectivity results from steric
interference between the styrene aryl group and the bulky
tris(pentafluorophenyl)borane, however we cannot rule out
favorable π-stacking interactions at this point. Lastly, B(C6F5)3 is
known to have a Lewis acidity intermediate of BF3 and BCl3.33 We
surmise this is an important feature of our catalytic reaction that
prevents ring-opening of the cyclopropane products and facilitates
catalysts turnover suggested by eq 4.
CO2Me
CO2Me
CO2Me
CO2Me
16
17
18
69% (91%)
19
60% (64%)a
69% (71%)a
48% (51%)a
F
t-Bu
Br
Br
CO2Me
CO2Me
CO2Et
CO2i-Pr
22
23
20
21
41 (45%)a
72% (74%)
88% (92%)
66% (77%)
Br
Br
Cl
Cl
Me
Cl
Me
Cl
CO2i-Pr
CO2i-Pr
CO2Me
CO2Me
24
72% (74%)
25
88% (92%)
26
27
72% (74%)
88% (92%)
Br
ineffective diazo compounds
EtO2C
H
EtO2C
CN MeO2C
CO2Me
N2
CO2TCE
N2
N2
28
43% (52%)
Conditions: All reactions were performed on 150 mol 2a (0.10
M). a 24 h reaction time. TCE = 2,2,2-trichloroethyl.
Scheme 1. Proposed Mechanism for the Transformation
Br
Preliminary investigations into the mechanism for this
transformation are outlined in eq 1–2. Reacting diazo 1a with E--
Br
O
O
OMe
methyl styrene (E-2n) and Z--methyl styrene (Z-2n) gave
products 29 and 30 as single diastereomers by 1H NMR, indicating
the reaction is both stereospecific and stereoselective. The reaction
is not limited to Z-alkenes; E-alkenes, which typically react with
diazo carbonyl compounds only using Ag catalysis, also react in
our system, albeit slower.31 When allyl 4-bromophenyldiazoacetate
1k was subjected to the optimized reaction conditions, products 31
and 32 were formed 65% and 27% yield, respectively, by crude 1H
NMR analysis (eq 3). Thus, alkene groups on the diazoester are
allowed during the cyclopropanation reaction. The stereospecific
nature and high levels of diastereoselectivity are in accord with a
concerted cycloaddition process. As shown in eq 4, when purified
cyclopropane product 3 was subjected to the Lewis acid catalyst at
50 ºC, no changes were observed by 1H NMR spectroscopy.
Br
OMe
1a
B(C6F5)3
3
N2
Br
B(C6F5)3
OMe
O
Br
B(C6F5)3
OMe
O
N2
E/Z-A
C
N2
Br
B(C6F5)3
O
2a
OMe
B
Me
1a (2.0 equiv)
In conclusion, we have shown that aryldiazoacetates can be
activated with catalytic amounts of B(C6F5)3 to cyclopropanate
olefins. The reaction is tolerant of a wide variety of styrene
derivatives and diazo compounds with yields comparable to those
reported with transition-metal complexes. Further investigations
into the mechanism of this transformation, extension of the scope
of this transformation to unactivated alkenes, as well as methods
for rendering the transformation enantioselective are currently
underway.
CO2Me
B(C6F5)3 (10 mol%)
1,2-DCE, 50 ºC
eq 1
14 - 16 h
Me
E -2n
29, 18% isolated yield
(25% 1H NMR yield)
Br
1a (2.0 equiv)
Me
CO2Me
eq 2
B(C6F5)3 (10 mol%)
1,2-DCE, 50 ºC
14 - 16 h
Me
Z -2n
30, 42% isolated yield
(45% 1H NMR yield)
ASSOCIATED CONTENT
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5.
a) Rubin, M.; Rubina, M.; Gevorgyan, V. Transition metal
chemistry of cyclopropenes and cyclopropanes. Chem. Rev.
2007, 107, 3117–3179.; b) Chen, Y.; Fields, K. B.; Zhang, X. P.
“Bromoporphyrins as Versatile Synthons for Modular
construction of chiral porphyrins: Cobalt-catalyzed highly
enantioselective and diastereoselective cyclopropanation. J. Am.
Chem. Soc. 2004, 126, 14718–14719.; c) Qin, C.; Boyarskikh,
V.; Hansen, J. H.; Hardcastle, K. I.; Musaev, D. G.; Davies, H.
M. L. D2-Symmetric Dirhodium catalysts derived from a 1,2,2,-
triarylcyclopropanecarboxylate ligand: Design, Synthesis and
application. J. Am. Chem. Soc. 2011, 133, 47, 19198–19204.
Ebner, C.; Carreira, E. M. Cyclopropanation strategies in recent
total synthesis. Chem. Rev. 2017, 117, 11651–11679.; b) Chen,
D. Y.-K.; Pouwer, R. H.; Richard, J.-A. Recent advances in the
total synthesis of cyclopropane-containing natural products.
Chem. Soc. Rev. 2012, 41, 4631–4642.
Supporting Information
1
2
3
4
5
6
7
8
The Supporting Information is available free of charge on the ACS
Publications website.
AUTHOR INFORMATION
Corresponding Author
Sidney M. Wilkerson-Hill–College of Arts and Sciences,
Department of Chemistry, University of North Carolina at Chapel
Hill, Chapel Hill, NC, 27599. Email: smwhill@email.unc.edu.
6.
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58
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60
ORCID
7.
8.
Thibodeaux, C. J.; Chang, W.; Liu, H. Enzymatic chemistry of
cyclopropane, epoxide, and aziridine biosynthesis. Chem. Rev.
2012, 112, 1681–1709.
Sidney M. Wilkerson-Hill: 0000-0002-4396-5596.
Notes
a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides. Wiley: New York, 1998.; b) Diaz-
Requejo, M. M.; Perez, P. J. Copper, silver and gold-based
cactalyts for carbene addition or insertion reactions. J.
Organomet. Chem. 2005, 690, 5441–5450. c) For Ru-catalyzed
reactions, see: Chanthamath, S.; Iwasa, S. Enantioselective
cyclopropanation of a wide variety of olefins catalyzed by
Ru(II)-phenox complexes. Acc. Chem. Res. 2016, 49, 2080–
2090.; d) Pellissier, H. Recent developments in asymmetric
cyclopropanation. Tetrahedron, 2008, 64, 7041–7095.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the University of North Carolina, Chapel Hill chemistry
department for funding. We thank the University of North
Carolina’s Department of Chemistry NMR Core Laboratory for the
use of their NMR spectrometers. This material is based upon work
supported by the National Science Foundation under Grant No.’s
CHE-0922858 and CHE-1828183. We thank the University of
North Carolina’s Department of Chemistry Mass Spectrometry
Core Laboratory, for their assistance with mass spectrometry
analysis. This material is based upon work supported by the
National Science Foundation under Grant No. CHE-1726291. We
also thank the Gagné group for the donation of Piers’ borane in
preliminary studies related to this work and helpful discussions.
9.
Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Stereoselective cyclopropanation reactions. Chem. Rev. 2003,
103, 977–1050.
10. Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Asymmetric ylide
reactions: epoxidations, cyclopropanation, aziridination,
olefination, and rearrangement. Chem. Rev. 1997, 97, 2341–
2372.; b) Aggarwal, V. K.; Smith, H. W.; Jones, R. V. H.;
Fieldhouse, R. Catalytic asymmetric cyclopropanation of
electron deficient alkenes mediated by chiral sulfides. J. Chem.
Soc., Chem. Commun. 1997, 1785–1786.; c) Aggarwal, V. K.;
Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M.
Application of chiral sulfides to catalytic asymmetric
aziridination and cyclopropanation with in situ generation of the
diazo compound. Angew. Chem. Int. Ed. 2001, 41, 1430–1433.
11. Papageorgiou, C. D.; de Dios, M. A. C.; Ley, S. V.; Gaunt, M.
J. Enantioselective organocatalytic cyclopropane via
ammonium ylides. Angew. Chem. Int. Ed. 2004, 43, 4641–4644.
12. Liao, W.-W.; Li, K.; Tang, Y. Controllable diastereoselective
REFERENCES
1.
a) Kulinkovich, O. G. Cyclopropanes in organic synthesis;
Wiley: New Jersey, 2015.; b) Rappoport, Z. The Chemistry of
the Cyclopropyl Group; Wiley: Chinchester, 1987.; c) Pellissier,
H.; Lattanzi, A.; Dalpozzo, R. Asymmetric synthesis of three-
membered rings; Wiley: Weinheim, 2017.; d) Small Ring
Compounds in Organic Synthesis, VI in Topics in Current
Chemistry; de Meijere, A.; Ed.; Vol. 207; Springer: Berlin,
2000.
cyclopropanation.
Enantioselective
synthesis
of
vinylcyclopropanes via chiral telluronium ylides J. Am. Chem.
Soc. 2003, 125, 13030–13031.
2.
a) For the use of cyclopropanes as radical clocks, see: Griller,
D.; Ingold, K. U. Free-radical clocks. Acc. Chem. Res. 1980, 13,
317–323.; b) Kumar, D.; de Visser, S. P.; Sharma, P. K.; Cohen,
S.; Shaik, S. Radical clock substrates, their C–H hydroxylation
mechanism by cytochrome P450, and other reactivity patterns:
What Does Theory Reveal about the Clocks’ Behavior? J. Am.
Chem. Soc. 2004, 126, 1907–1920.; c) Ortiz de Montellano, P.
R.; Substrate oxidation by cytochrome P450 Enzymes. In
Cytochrome p450: Structure, Mechanism, and Biochemistry, 4th
ed.; Ortiz de Montellano, P. R., Ed.; Springer: Switzerland,
2015; Vol. 1, Ch 4.; d) Ortiz de Montellano, P. R. Hydrocarbon
hydroxylation by cytochrome P450 enzymes. Chem. Rev 2010,
110, 932–948 .
13. For the activation of -hydroxydiazo compounds using Lewis
acids to ionize pendant hydroxyl groups, see: a) Pellicciari, R.;
Natalini, B., Sadeghpour, B. M., Marinozzi, M., Snyder, J. P.,
Williamson, B. L., Kuethe, J. T., Padwa, A. The reaction of -
diazo--hydroxy esters with boron trifluoride etherate:
generation and rearrangement of destabilized vinyl cations. A
detailed experimental and theoretical study. J. Am. Chem. Soc.
1996, 118, 1–12.; b) Draghici, C., Brewer, M. Lewis acid
promoted carbon-carbon bond cleavage of -silyloxy--
hydroxy--diazoesters. J. Am. Chem. Soc. 2008, 130, 3766–
3767.; c) Bayir, A., Brewer, M. Fragmentation of bicyclic -
silyloxy--hydroxy--diazolactones as an approach to ynolides
J. Org. Chem. 2014, 79, 6037–6046.; d) Cleary, S., Hensinger,
M., Brewer, M. Remote C–H insertion of vinyl cations leading
to cyclopentenones. Chem. Sci. 2017, 8, 6810-6814.; e) Fang, J.,
Brewer, M. Intramolecular vinylation of aryl rings by vinyl
cations Org. Lett. 2018, 20, 7384–7387.; f) Hensinger, M.J.,
Dodge, N.J., Brewer, M. Substituted -alkylidene
cyclopentenones via the intramolecular reaction of vinyl cations
with alkenes. Org. Lett. 2020, 22, 497–500.
3.
a) Boche, G.; Walborsky, H. M. Cyclopropane Derived Reactive
Intermediates; Rappaport, Z., Ed.; Wiley: New York, 1990.; b)
Schneider, T. F.; Kaschel, J.; Werz, D. B. A new golden age for
donor-acceptor cyclopropanes. Angew. Chem. Int. Ed. 2014, 53,
5504–5523.; c) Grover, H. K.; Emmet, M. R.; Kerr, M. A.
Carbocycles from donor-acceptor cyclopropanes. Org. Biomol.
Chem. 2015, 13, 655–671.; d) Cavitt, M. A.; Phun, L. H.;
France, S. Intramolecular donor-acceptor cyclopropane ring-
opening cyclizations. Chem. Soc. Rev. 2014, 43, 804–818.
Talele, T. T. The ‘cyclopropyl fragment’ is a versatile player that
frequently appears in preclinical/clinical drug molecules. J.
Med. Chem. 2016, 59, 8712–8756.
4.
14. For reviews on the reactivity of diazocarbonyl compounds with
acids, see; Smith, III., A. B., Dieter, R. K. The acid promoted
decomposition of -diazoketones. Tetrahedron 1981, 37, 2407–
2439.
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Page 5 of 7
ACS Catalysis
15. Dumitrescu, L.; Azzouzi-Zriba, K.; Bonnet-Deplon, D.;
23. Dasgupta, A.; Bambaahmadi, R.; Slater, B.; Yates, B. F.;
Ariafard, A.; Melen, R. L. Chem. 2020,
doi.org/10.1016/j.chempr.2020.06.035.
24. Doyle, M. P.; Zheng, H.; Dong, K.; Wherritt, D.; Arman, H.
Brønsted acid catalyzed Friedel–Crafts-type coupling and
dedinitrogenation reactions of vinyl diazo compounds Angew.
Chem. Int. Ed. 2020, 59, 1–6.
Crousse, B. Non-metal catalyzed insertion reactions of
diazocarbonyls to acid derivatives in fluorinated alcohols. Org.
Lett. 2011, 13, 692–695.
1
2
3
4
16. Bott, K. Alkenediazonium salts: A new chapter of classical
organic chemistry. Angew. Chem. Int. Ed. Engl. 1979, 18, 259–
265.
5
6
7
8
17. a) For X-ray crystallographic studies, see: Tang, C.; Liang, Q.;
Jupp, A. R.; Johnstone, T. C.; Neu, R. C.; Song, D.; Grimme, S.;
Stephan, D. W. 1,1-Hydroboration and a boron adduct of
25. a) So, S. S.; Mattson, A. E. Urea activation of -
nitrodiazoesters: an organocatalytic approach to N–H insertion
reactions J. Am. Chem. Soc. 2012, 134, 8798–8801.; b) Auvil,
T. J.; So, S. S.; Mattson, A. E. Double arylation of
nitrodiazoesters via a transient N–H insertion organocascade.
Angew. Chem. Int. Ed. 2013, 52, 11317–11320.; c) So, S. S.;
Mattson, A. E. Enantioselective N–H insertion/Arylation
reactions of nitrodiazoesters. Asian J. Org. Chem. 2014, 3, 425–
428.; d) So. S. S.; Oottikkal, S.; Badjic, J.; Hadad, C. M.;
Mattson, A. E. Urea-catalyzed N–H insertion-arylation
reactions of nitrodiazoesters. J. Org. Chem. 2014, 20, 8283–
8287. e) Fisher, T. J.; Mattson, A. E. Synthesis of -
peroxyesters via organocatalyzed O–H insertion of
hydroperoxides and aryl diazoesters. Org. Lett. 2014, 20, 5316–
5319.
26. Zhai, C.; Xing, D.; Jun Zhou, C. J.; Wang, C.; Wang, D.; Hu,
W. Facile synthesis of 3-aryloxindoles via Brønsted acid
catalyzed Friedel-Crafts Alkylation of Electron-Rich Arenes
with 3-Diazooxindoles. Org Lett. 2014, 16, 2934–2937.
27. a) Yu, Z.; Li, Y.; Shi, J.; Ma, B.; Liu, L.; Zhang, J. (C6F5)3B
catalyzed chemoselective and ortho-selective substitution of
phenols with -aryl -diazoesters. Angew. Chem. Int. Ed. 2016,
55, 14807–14811.; b) For computational studies, see: Zhang, Q.;
Zhang, X.-F.; Li, M.; Li, C.; Liu, J.-Q.; Jiang, Y.-Y.; Ji, X.; Liu,
L.; Wu, Y.-C. Mechanistic insights into the chemo- and
regioselective B(C6F5)3 catalyzed C–H functionalization of
phenols with diazoesters. J. Org. Chem. 2019, 84, 14508–14519.
28. San, H. H.; Wang, S.-J.; Jian, M.; Tang, W.-Y. Boron-Catalyzed
O–H Insertion of -Aryl -Diazo Esters in Water. Org. Lett.
2018, 20, 4672–4676.
29. See the Supporting Information for further details.
30. Ovalles, S. R.; Hansen, J. H.; Davies, H. M. L. Thermally
Induced Cycloadditions of Donor/Acceptor Carbenes. Org. Lett.
2011, 13, 4284–4287.; b) Tortoreto, C.; Rackl, D.; Davies, H.
M. L. Metal-Free C–H Functionalization of Alkanes by
Aryldiazoacetates. Org. Lett. 2017, 19, 770–773. c) Hansen, S.;
Spangler, J. E.; Hansen, J.; Davies, H. M. L. Metal-Free N–H
insertions of donor/acceptor carbenes. Org. Lett. 2012, 14,
4626–4629.
31. Thompson, J. L.; Davies, H. M. L. Enhancement of
cyclopropanation chemistry in the silver-catalyzed reactions of
aryldiazo acetates. J. Am. Chem. Soc. 2007, 129, 6090–6091.
32. For a review, see: He, Z.; Kajdlik, A.; Yudin, A. K. -
Borylcarbonyl compounds: from transient intermediates to
robust building blocks. Dalton. Trans. 2014, 43, 11434–11451.;
b) Despite this, a C-bound intermediate has been proposed for a
related transformation: see, Rao, S.; Kapanaiah, R.; Prabhu, K.
R. Boron-catalyzed C–C functionalization of allylic alcohols.
Adv. Synth. Catal. 2019, 361, 1301–1306.
diphenyldiazomethane:
A Potential prelude to FLP-N2
chemistry.Angew. Chem. Int. Ed. 2017, 129, 16815–16819.; b)
Neu, R. C.; Jiang, C.; Stephan, D. W. Bulky derivatives of
boranes, boronic acids and boronate esters via reaction with
diazomethanes. Dalton Trans. 2013, 42, 726–736.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18. a) For reviews, see: Miller, D. J.; Moody, C. J. Synthetic
applications of the O–H insertion reactions of carbenes and
carbenoids derived from diazocarbonyl and related diazo
compounds. Tetrahedron, 1995, 51, 10811–10843.; b)
Gillingham, D.; Fei, N.; Catalytic X–H insertion reactions based
on carbenoids. Chem. Soc. Rev. 2013, 42, 4918–4931.; c)
Marshall, E. R.; Kuck, J. A.; Elderfield, R. C. Studies on
lactones related to the cardiac aglycones X. Synthesis of simple
hydroxylated -substituted  -butenoldies. J. Org. Chem.
1942, 7, 444–456.; d) Bose, A. K.; Yates, P. The conversion of
-diazo-o-methoxyacetophenone to coumaranone. J. Am.
Chem. Soc. 1952, 74, 4703–4704.
19. Doyle, M. P., Buhro, W.E., Davidson, J. G., Elliot, R. C.,
Hoekstra, J. W., Oppenhuizen, M. Lewis acid promoted
reactions of diazocarbonyl compounds. 3. Synthesis of oxazoles
from nitriles through intermediate -imidatoalkenediazonium
salts. J. Org. Chem. 1980, 45, 3657–3664.
20. a) Hutt, O. E.; Mander, L. N.; Willis, A. C. Ring fragmentation
process resulting from acid catalyzed diazo ketone cyclisations.
Tetrahedron Lett. 2005, 46, 4569–4572.; b) Morris, J. C.;
Mander, L. N.; Hockless, D. C. R. Norcaradienes from the
intramolecular cyclopropanation reactions of diazomethyl
ketones. Valuable intermediates for the synthesis of polycyclic
diterpenes. Synthesis 1998, 455–467.; c) Beames, D. J.; Mander,
L. N. Studies on intramolecular alkylation I: the preparation of
tricyclic intermediates for the synthesis of diterpene alkaloids.
Aust. J. Chem. 1971, 24, 343–351.; d) Mander, L. N.; Pyne, S.
G. A New Strategy for Gibberillin Synthesis. J. Am. Chem. Soc.
1979, 101, 3373–3375.; d) Pour, M.; King, G. R.; Monck, N. J.
T.; Morris, J. C.; Zhang, H.; Mander, L. N. Synthetic and
structural studies of novel gibberellins. Pure and App. Chem.
1998, 70, 351–354.
21. a) Smith III, A. B., Toder, B. H., Branca, S. J., Dieter, R. K.
Lewis acid promoted decomposition of unsaturated -diazo
ketones. 1. An Efficient approach to simple annulated
cyclopentenones. J. Am. Chem. Soc. 1981, 103, 1996–2008. (b)
Smith III, A.B., Dieter, R. K. Lewis acid promoted
decomposition of unsaturated -diazoketones. 2. A new initiator
for polyolefinic cationic cyclization. J. Am. Chem. Soc. 1981,
103, 2009-2016. (c) Smith III, A.B., Dieter, R. K. Lewis acid
promoted decomposition of unsaturated a-diazoketones. 3.
Stereochemical consequences of polyolefinic cyclizations
initiated by the -diazoketone functionality J. Am. Chem. Soc.
1981, 103, 2017-2022.
33. a) Beckett, M. A.; Brassington, D. S.; Coles, S. J.; Hursthouse,
M. B. Lewis acidity of tris(pentafluorophenyl)borane: crystal
and molecular structure of B(C6F3)3•OPEt3. Inorg. Chem.
Commun. 2000, 3, 530–533.; b) Jacobsen, H.; Berke, H.;
Doring, S.; Kehr, G.; Erker, G.; Frohlich, R.; Meyer, O. Lewis
acid properties of Tris(pentafluorophenyl)borane. Structure and
bonding in L-B(C6F5)3 complexes Organometallics 1999, 18,
1724–1735.
22. Shim, S. Y.; Ryu, D. H. Enantioselective carbonyl 1,2- or 1,4-
addition reactions of nucleophilic silyl and diazo compounds
catalyzed by the chiral oxazaborolidinium ion. Acc. Chem. Res.
2019, 52, 2349–2360.
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Lewis acid -
activated carbene
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