Synthesis of Trifluoromethylated Tetrasubstituted Allenes via Palladium-Catalyzed Carbene Transfer Reaction

Article abstract of DOI:10.1021/acs.orglett.0c02638

Herein, we report on the palladium-catalyzed synthesis of trifluoromethylated, tetrasubstituted allenes from vinyl bromides and trifluoromethylated diazoalkanes in good to excellent yield. This reaction proceeds via oxidative addition of a Pd(0) complex w

Full text of DOI:10.1021/acs.orglett.0c02638

pubs.acs.org/OrgLett
Letter
Synthesis of Trifluoromethylated Tetrasubstituted Allenes via
Palladium-Catalyzed Carbene Transfer Reaction
Chao Pei, Zhen Yang, and Rene M. Koenigs*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02638
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Herein, we report on the palladium-catalyzed
synthesis of trifluoromethylated, tetrasubstituted allenes from
vinyl bromides and trifluoromethylated diazoalkanes in good to
excellent yield. This reaction proceeds via oxidative addition of a
Pd(0) complex with vinyl bromide. Subsequent base-promoted reductive elimination generates the allene. This methodology
provides an efficient strategy even on gram scale to valuable trifluoromethylated, tetrasubstituted allenes under mild reaction
conditions. The allene products can be used in acid catalyzed cyclization reactions to give trifluoromethylated indene products.
llenes are an intriguing class of polyunsaturated hydro-
carbons and feature distinct properties that render allenes
fins,10a,13 trifluoromethylated heterocycles,10c,14 and other
important trifluoromethylated building blocks15 (Scheme 1b)
and possess distinct properties to conventional ester-
substituted donor/acceptor diazoalkanes.
A
an important strategic building block for a diverse array of
organic synthesis applications.1,2 Among these, the activation
with Lewis acids is among the most important reactions to
quickly increase molecular complexity.3 A particularly intrigu-
ing group of allenes are fluorinated or trifluoromethyl-
substituted allenes that are valuable hydrocarbons for further
derivatization.4−7 Owing to the importance of fluorine in
pharmaceutical, agrochemical, and materials chemistry,8 the
synthesis of fluorinated allenes is thus of high interest, as they
can be readily functionalized for further applications. Currently
available strategies for the synthesis of fluorinated allenes
comprise the utilization of fluorinated, unsaturated building
blocks that can be transformed to allenic products5,6 or the
introduction of either fluoride or a trifluoromethyl group onto
an appropriately functionalized, unsaturated reagent to access
mono-, di-, and trisubstituted fluorinated allenes.7 Despite this
progress, the catalytic synthesis of tetrasubstituted trifluor-
omethylated allenes still remains a synthetic challenge. One of
the rare examples for the synthesis of such allene derivatives
involves the use of propargylic alcohols that undergo
dehydration in the presence of Lewis acids, yet with strict
limitations in yield and the utilization of highly specialized
fluorinated, propargylic alcohols (Scheme 1a).6 The synthesis
of tetrasubstituted allenes even today represents an important
task in organic synthesis methodology.8,9 In this context, the
Lin group recently reported on the palladium-catalyzed
coupling of aryldiazoacetates with vinyl bromides to access
ester-substituted, tetrasubstituted allene products 11 (Scheme
1c, top).9
We hypothesized that vinyl bromides are suitable precursors
to access tetrasubstituted allenes via a metal-catalyzed cross-
coupling reaction with fluorinated donor/acceptor diazoal-
kanes that could then serve as a platform for further
derivatization, e.g. by intramolecular acid catalyzed cyclization,
to access trifluoromethylated indene derivatives. We therefore
initiated our investigations by studying the reaction of vinyl
bromide 9a with the trifluoromethylated donor/acceptor
diazoalkane 4a using palladium-based catalysts. The latter
should allow oxidative insertion into the C(sp2)−Br bond of
vinyl bromide, which should be a suitable intermediate for a
subsequent cross-coupling reaction step.
Moreover, we assumed that basic additives are a pivotal
component to promote the reductive elimination step and to
capture HBr that is released in the coupling reaction. Indeed,
the base had a significant influence on the reaction yield (Table
1, entries 1−7). Of all bases studied, only K2CO3 proved
compatible and the desired allene product 12a was obtained in
72% yield when using dpph as the ligand and Pd(OAc)2 as the
palladium source (Table 1, entry 7). Further studies then
focused on the role of the phosphine ligand. No significant
influence on the reaction yield was observed with different
variants of the dpph ligand (Table 1, entries 8−10).
Surprisingly, BINAP proved incompatible and only a very
low yield was observed (Table 1, entry 11, 5%). To further
Based on our interest in fluorine chemistry,10 we became
intrigued in the synthesis of trifluoromethylated, tetrasub-
stituted allenes using trifluoromethylated donor/acceptor
diazoalkanes (Scheme 1c, bottom).11 The latter have emerged
in recent years as important reagents in the synthesis of
trifluoromethylated cyclopropa(e)nes,10b,12 gem-difluoro ole-
Received: August 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02638
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Synthesis of Fluorinated Allenes and
Applications of Trifluoromethyl-Substituted Donor/
Acceptor Diazoalkanes
Table 1. Optimization of Reaction Conditions
a
b
c
no.
ligand
dpph
base
yield (%)
1
2
3
4
5
6
7
8
CsOAc
KOH
K2CO3
Li2CO3
LiOH
15
9
72
8
dpph
dpph
dpph
dpph
dpph
dpph
dppb
dppe
dppf
3
5
8
NaOAc
NEt3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
74
76
71
5
9
10
11
12
13
14
15
16
17
18
19
20
rac-BINAP
DavePhos
SPhos
XPhos
RuPhos
PoTol3
PAd2nBu
PFur3
4
traces
traces
traces
6
72
67
95
traces
8
PPh3
−
PPh3
d
21
a
Reaction condtions: 9a (0.2 mmol), 4a (0.3 mmol, 1.5 equiv),
catalyst (10 mol %), ligand (15 mol %), and base (0.3 mmol, 1.5
equiv) were dissolved in the solvent indicated (2.5 mL) and stirred at
b
60 °C for 12 h. dppf, 1,1′-bis(diphenylphoshino)ferrocene; dpph,
1,6-bis(diphenylphoshino)hexane; dppb, 1,6-bis(diphenylphoshino)
butane; dppe, 1,6-bis(diphenylphoshino)ethane; XPhos, 2-Dicyclo-
hexylphosphino-2′,4′,6′-triisopropylbiphenyl; SPhos, 2-Dicyclohexyl-
phosphino-2′,6′-dimethoxybiphenyl; RuPhos 2-Dicyclohexylphos-
improve the reaction yield, we next studied different
monodentate phosphine ligands. Buchwald-type ligands
proved inferior in this transformation, and low yields of the
allene product were observed, at best (Table 1, entry 12−15).
Similarly, tri-o-tolyl phosphine gave only a poor yield (Table 1,
entry 16). Very unexpectedly, the most simple and readily
available triphenyl phosphine gave by far the best yields and
allene 12a was obtained in excellent yield (Table 1, entry 19,
95%).16 When the reaction was studiend in the absence of a
ligand, only trace amounts of the allene were observed (Table
1, entry 20). Similarly, the use of Pd2(dba)3 resulted in a
significantly reduced yield (Table 1, entry 21), which might be
reasoned by inefficient catalyst formation.
After establishing reaction conditions to access trifluorome-
thylated, tetrasubstituted allenes in high yields, we next
embarked on the substrate scope and first studied the influence
of the 2,2-diaryl vinyl bromide (9) reaction partner (Scheme
2). Different symmetrically substituted vinyl bromides reacted
in excellent yield to the trifluoromethyl-substituted allene
product, and both halogen and electron-donating groups were
well tolerated under the present conditions. Similarly, different
unsymmetrically substituted vinyl bromides reacted smoothly
and the tetrasubstituted allene was obtained in all cases in
excellent yield, disregarding the substitution pattern of one of
the aromatic rings of the vinyl bromide reaction partner. Even
ortho substituents were well tolerated under the present
conditions, and the allene products were obtained in very good
yield. Only in the case of a bromo-substituent, the yield of the
allene product 12i was slightly reduced, which might be
c
phino-2′,6′-diisopropoxybiphenyl. Yields by 19F NMR spectroscopy
d
of the crude reaction mixture using PhCF3 as internal standard. With
5 mol % Pd2(dba)3 as catalyst precursor.
reasoned by competitive oxidative insertion of the palladium
catalyst into the Aryl−Br bond. Importantly, carbocyclic or
sulfur-containing heterocycles proved compatible to the
present reaction conditions and the corresponding tetrasub-
stituted allene products were obtained in very high yield. We
further studied the application of exocyclic vinyl bromides
using dibenzosubera(e)ne derived vinyl bromides. In both
cases, the coupling reaction with trifluoromethylated donor/
acceptor diazoalkane proceeded to give 12s,t in high yields
(Scheme 3). In this context, we also studied the application of
different substitution patterns of the trifluoromethyl-substi-
tuted diazoalkane and could obtain the coupling product in
excellent yield.
Next, we studied the limitations and applicability on gram
scale of the present methodology (Scheme 4). To test the
applicability of vinyl chlorides, we studied the coupling
reaction of 2,2-diphenyl vinyl chloride (13); however, the
reaction yield dropped significantly and only 32% of the allene
product 12a was obtained. When trans-β-bromo-styrene 14
was studied, the allene product was not formed and only the
decomposition of the diazoalkane 4a was observed, which
might be reasoned by a hampered migration step of the
fluorinated carbene that results in a preferred decomposition
B
https://dx.doi.org/10.1021/acs.orglett.0c02638
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. Evaluation of the Substrate Scope
Scheme 4. Limitations and Application on Gram Scale
Last, we studied the application of the tetrasubstituted allene
product in acid-catalyzed cyclization reactions. In the presence
of triflic acid, allene 12b smoothly underwent chemoselective
cyclization to give the trifluoromethylated indene product 16
in excellent yield. When employing 5 mol % of Yb(OTf)3 as a
Lewis acid catalyst, the allene could be activated toward
intramolecular Friedel−Crafts reaction to give the indene
product 16 and 17 in high yield (Scheme 5).
Scheme 5. Application in Indene Synthesis
Scheme 3. Further Evaluation of Substrate Scope
From a mechanism perspective, we assume that the present
reaction proceeds via a Pd(0) catalyst that undergoes an initial
oxidative insertion reaction with vinyl bromide 9a to give an
intermediate Pd(II) complex 19. This complex can now react
with the trifluoromethylated donor/acceptor diazoalkane 4a
followed by 1,2-migration to give the Pd-allyl complex 21/21′
that finally undergoes base-assisted reductive elimination to
regenerate the catalyst and the tetrasubstituted allene product
10a (Scheme 6). A potential β-fluoride elimination would lead
to the formation gem-difluoro olefins, yet this step would result
in formation of an unfavorable high oxidation state Pd(II)BrF
complex, for which it is difficult to regenerate the Pd catalyst.
In summary, we herein report on the palladium-catalyzed
synthesis of trifluoromethylated, tetrasubstituted allenes. A
simple and readily available palladium catalyst and phosphine
ligand provide an easy-to-handle procedure to challenging
tetrasubstituted allenes in excellent yield (24 examples, up to
96% yield). Gram-scale experiments and application of
trifluoromethylated tetrasubstituted allenes further present
the practicality of this method. A possible mechanism was
reaction of the palladium carbene intermediate. The reaction
of alkyl-aryl vinyl bromide 15 led to formation of a complex,
inseparable mixture. The major products could not be isolated,
yet NMR data indicate the formation of an allene and a diene
product, the latter resulting from β-H elimination. Finally,
when performing the reaction on gram scale, the desired
tetrasubstituted allene could be obtained with almost identical
yield as above (cf. Scheme 2, 12b).
C
https://dx.doi.org/10.1021/acs.orglett.0c02638
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
and computational chemistry: from bonding situations to reaction
Scheme 6. Putative Reaction Mechanism
mechanisms. Chem. Soc. Rev. 2014, 43, 3041−3105.
́
(2) (a) Orłowska, K.; Rybicka-Jasinska, K. R.; Krajewski, P.; Gryko,
D. Photochemical Doyle−Kirmse Reaction: A Route to Allenes. Org.
Lett. 2020, 22, 1018−1021. (b) Wei, X.-F.; Wakaki, T.; Itoh, T.; Li,
H.-L.; Yoshimura, T.; Miyazaki, A.; Oisaki, K.; Hatanaka, M.; Shimizu,
Y.; Kanai, M. Catalytic Regio- and Enantioselective Proton Migration
from Skipped Enynes to Allenes. Chem. 2019, 5, 585−599. (c) Yang,
Y.; Liu, Z.; Porta, A.; Zanoni, G.; Bi, X. Alkynyl N-Nosylhydrazones:
Easy Decomposition to Alkynyl Diazomethanes and Application in
Allene Synthesis. Chem. - Eur. J. 2017, 23, 9009−9013. (d) Chu, W.-
D.; Zhang, L.; Zhang, Z.; Zhou, Q.; Mo, F.; Zhang, Y.; Wang, J.
Enantioselective Synthesis of Trisubstituted Allenes via Cu(I)-
Catalyzed Coupling of Diazoalkanes with Terminal Alkynes. J. Am.
Chem. Soc. 2016, 138, 14558−14561. (e) Yang, Y.; Qin, A.; Zhao, K.;
Wang, D.; Shi, X. Rhodium-Catalyzed Regio- and Stereoselective [2 +
2] Cycloaddition of Allenamides. Adv. Synth. Catal. 2016, 358, 1433−
1439. (f) Nella, N.; Parker, E.; Hitce, J.; Larini, P.; Jazzar, R.; Baudoin,
O. Efficient Pd-Catalyzed Allene Synthesis from Alkynes and Aryl
Bromides through an Intramolecular Base-Assisted Deprotonation
(iBAD) Mechanism. Chem. - Eur. J. 2014, 20, 13272−13278.
(g) Nun, P.; Gaillard, S.; Slawin, A. M. Z.; Nolan, S. P. Ligand
influence in the selective gold-mediated synthesis of allenes. Chem.
Commun. 2010, 46, 9113−9115. (h) Kolakowski, R. V.; Manpadi, M.;
Zhang, Y.; Emge, T. J.; Williams, L. J. Allene Synthesis via C-C
Fragmentation: Method and Mechanistic Insight. J. Am. Chem. Soc.
2009, 131, 12910−12911. (i) Kobayashi, K.; Naka, H.; Wheatley, A.
E. H.; Kondo, Y. Organozinc Reagents in DMSO Solvent:
Remarkable Promotion of SN2’ Reaction for Allene Synthesis. Org.
Lett. 2008, 10, 3375−3377.
(3) (a) Yang, W.; Hashmi, A. S. K. Mechanistic insights into the gold
chemistry of allenes. Chem. Soc. Rev. 2014, 43, 2941−2955.
(b) Munoz, M. P. Silver and platinum-catalysed addition of O−H
and N−H bonds to allenes. Chem. Soc. Rev. 2014, 43, 3164−3183.
(c) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. A Powerful
Chiral Counterion Strategy for Asymmetric Transition Metal
Catalysis. Science 2007, 317, 496−499. (d) Haydl, A. M.; Breit, B.
Atom-Economical Dimerization Strategy by the Rhodium-Catalyzed
Addition of Carboxylic Acids to Allenes: Protecting-Group-Free
Synthesis of Clavosolide A and Late-Stage Modification. Angew.
Chem., Int. Ed. 2015, 54, 15530−15534.
(4) (a) Holmes, M.; Nguyen, K. D.; Schwartz, L. A.; Luong, T.;
Krische, M. J. Enantioselective Formation of CF3-Bearing All-Carbon
Quaternary Stereocenters via C-H Functionalization of Methanol:
Iridium Catalyzed Allene Hydrohydroxymethylation. J. Am. Chem.
Soc. 2017, 139, 8114−8117. (b) Akiyama, S.; Nomura, S.; Kubota, K.;
Ito, H. Copper(I)-Catalyzed Boryl Substitution of 1-Trifluoromethyl
Allenes for the Synthesis of 3-Boryl-Substituted 1,1-gem-Difluor-
odienes. J. Org. Chem. 2020, 85, 4172−4181.
(5) (a) Boreux, A.; Lonca, G. H.; Riant, O.; Gagosz, F. Synthesis of
Trifluoromethyl-allenes by Gold-Catalyzed Rearrangement of Prop-
argyl Benzyl Ethers. Org. Lett. 2016, 18, 5162−5165. (b) Ambler, B.
R.; Peddi, S.; Altman, R. A. Ligand-Controlled Regioselective Copper-
Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)-
allenes. Org. Lett. 2015, 17, 2506−2509. (c) Yamazaki, T.;
Yamamoto, T.; Ichihara, R. Preparation of CF3-containing 1,3-Di-
and 1,1,3-trisubstituted allenes. J. Org. Chem. 2006, 71, 6251−6253.
(d) Oh, K.; Fuchibe, K.; Yokota, M.; Ichikawa, J. Facile synthesis of
substituted 1,1-difluoroallenes via carbonyl difluorovinylidenation.
Synthesis 2012, 44, 857−861.
proposed involving oxidative addition of a Pd(0) complex with
vinyl bromide and a β-H elimination process to regenerate the
active palladium catalyst and the final tetrasubstituted allenes
product.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02638.
Experimental procedures, characterizations, analytical
data, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Rene M. Koenigs − RWTH Aachen University, Institute of
Organic Chemistry, D-52074 Aachen, Germany; orcid.org/
0000-0003-0247-4384; Email: rene.koenigs@rwth-
aachen.de
Authors
Chao Pei − RWTH Aachen University, Institute of Organic
Chemistry, D-52074 Aachen, Germany
Zhen Yang − RWTH Aachen University, Institute of Organic
Chemistry, D-52074 Aachen, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02638
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.M.K. thanks the German Science Foundation for financial
support. C.P. thanks the China Scholarship Council for the
support with a PhD scholarship.
(6) Noel, F.; Vukovic, V. D.; Yi, J.; Richmond, E.; Kravljanac, P.;
Moran, J. Catalytic Synthesis of Trifluoromethylated Allenes, Indenes,
Chromenes and Olefins from Propargylic Alcohols in HFIP. J. Org.
Chem. 2019, 84, 15926−15947.
(7) (a) Qi, S.; Gao, S.; Xie, X.; Yang, J.; Zhang, J. Palladium-
Catalyzed Fluoroarylation of gem-Difluoroenynes to Access Trisub-
stituted Trifluoromethyl Allenes. Org. Lett. 2020, 22, 5229−5234.
(b) Zhang, Q.; Muhammad, M. T.; Chiou, M.-F.; Jiao, Y.; Bao, H.; Li,
Y. 1,4-Fluoroamination of 1,3-Enynes en Route to Fluorinated
REFERENCES
■
(1) (a) Huang, X.; Ma, S. Allenation of Terminal Alkynes with
Aldehydes and Ketones. Acc. Chem. Res. 2019, 52, 1301−1312.
(b) Tejedor, D.; Mendez-Abt, G.; Cotos, L.; Garcia-Tellado, F.
Propargyl Claisen rearrangement. Allene synthesis and beyond. Chem.
Soc. Rev. 2013, 42, 458−471. (c) Soriano, E.; Fernandez, I. Allenes
D
https://dx.doi.org/10.1021/acs.orglett.0c02638
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Allenes. Org. Lett. 2020, 22, 5261−5265. (c) Song, T.; Zhu, L.; Li, H.;
Tung, C.-H.; Lan, Y.; Xu, Z. Kinetically Controlled Radical Addition/
Elimination Cascade: From Alkynyl Aziridine to Fluorinated Allenes.
Org. Lett. 2020, 22, 2419−2424. (d) Ji, Y.-L.; Luo, J.-J.; Lin, J.-H.;
Xiao, J.-C.; Gu, Y.-C. Cu-Catalyzed C-H Trifluoromethylation of 3-
Arylprop-1-ynes for the Selective Construction of Allenic Csp2-CF3
and Propargyl Csp3-CF3 Bonds. Org. Lett. 2016, 18, 1000−1003.
(e) Ji, Y.-L.; Kong, J.-J.; Lin, J.-H.; Xiao, J.-C.; Gu, Y.-C. Copper-
mediated trifluoromethylation of propargyl acetates leading to
trifluoromethyl-allenes. Org. Biomol. Chem. 2014, 12, 2903−2906.
(f) Zhao, T. S. N.; Szabo, K. J. Trifluoromethylation of Propargylic
Halides and Trifluoroacetates Using (Ph3P)3Cu(CF3) Reagent. Org.
Lett. 2012, 14, 3966−3969.
(8) References on the synthesis of tetrasubstituted allenes:
(a) Padwa, A.; Kennedy, G. D. Cyclopropane photochemistry. 27.
Cycloaddition reactions of strained ring systems. Photochemistry of 1-
phenyl-2-carbomethoxy-3,3-dimethylcyclopropene. J. Org. Chem.
1984, 49, 4344−4252. (b) Tang, Y.; Xu, J.; Yang, J.; Lin, L.; Feng,
X.; Liu, X. Asymmetric Three-Component Reaction for the Synthesis
of Tetrasubstituted Allenoates via Allenoate-Copper Intermediates.
Chem. 2018, 4, 1658−1672. (c) Guo, K.; Kleij, A. W. Cu-Catalyzed
Synthesis of Tetrasubstituted 2,3-Allenols through Decarboxylative
Silylation of Alkyne-Substituted Cyclic Carbonates. Org. Lett. 2020,
22, 3942−3945.
azoles. Org. Lett. 2018, 20, 4843−4847. (b) Mertens, L.; Hock, K. J.;
Koenigs, R. M. Fluoroalkyl-substituted Diazomethanes and their
Application in a General Synthesis of Pyrazoles and Pyrazolines.
Chem. - Eur. J. 2016, 22, 9542−9545.
(15) (a) Carreras, V.; Besnard, C.; Gandon, V.; Ollevier, T.
Asymmetric Cu(I)-Catalyzed Insertion Reaction of 1-Aryl-2,2,2-
trifluoro-1-diazoethanes into Si−H Bonds. Org. Lett. 2019, 21,
9094−9098. (b) Hyde, S.; Veliks, J.; Liegault, B.; Grassi, D.;
Taillefer, M.; Gouverneur, V. Copper-Catalyzed Insertion into
Heteroatom-Hydrogen Bonds with Trifluorodiazoalkanes. Angew.
Chem., Int. Ed. 2016, 55, 3785−3789. (c) Emer, E.; Twilton, J.;
Tredwell, M.; Calderwood, S.; Collier, T. L.; Liegault, B.; Taillefer,
M.; Gouverneur, V. Diversity-Oriented Approach to CF3CHF-,
CF3CFBr-, CF3CF2-, (CF3)2CH-, and CF3(SCF3)CH-Substituted
Arenes from 1-(Diazo-2,2,2-trifluoroethyl)arenes. Org. Lett. 2014,
16, 6004−6007.
(16) For further details on the reaction optimization, see the
Supporting Information.
(9) Zhang, G.; Xue, Z.-J.; Zhang, F.; Zhang, S.-S.; Li, M.-Y.; Zhu, B.-
B.; Feng, C.-G.; Lin, G.-Q. Synthesis of tetrasubstituted allenes via
palladium-catalyzed cross-coupling of vinyl bromides with diazo
compounds. ChemRxiv 2019, DOI: 10.26434/chemrxiv.11316842.v1.
(10) (a) Yang, Z.; Moller, M.; Koenigs, R. M. Syntheis of gem-
difluoro Olefins through C-H Functionalization and β-fluoride
Elimination Reaction. Angew. Chem., Int. Ed. 2020, 59, 5572−5576.
(b) Tran, U. P. N.; Hommelsheim, R.; Yang, Z.; Empel, C.; Hock, K.
J.; Nguyen, T. V.; Koenigs, R. M. Chem. - Eur. J. 2020, 26, 1254−
1257. (c) Hock, K. J.; Mertens, L.; Metze, F. K.; Schmittmann, C.;
Koenigs, R. M. Difluoro- and trifluoro diazoalkanes - complementary
approaches in batch and flow and their application in cycloaddition
reactions. Green Chem. 2017, 19, 905−909. (d) Hock, K. J.;
Hommelsheim, R.; Mertens, L.; Ho, J.; Nguyen, T. V.; Koenigs, R.
M. Corey-Chaykovsky Reactions of Nitro Styrenes Enable cis-
Configured Trifluoromethyl Cyclopropanes. J. Org. Chem. 2017, 82,
8220−8227.
(11) (a) Mertens, L.; Koenigs, R. M. Fluorinated diazoalkanes - a
versatile class of reagents for the synthesis of fluorinated compounds.
Org. Biomol. Chem. 2016, 14, 10547−10556.
(12) (a) Morandi, B.; Carreira, E. M. Iron-Catalyzed Cyclo-
propanation with Trifluoroethylamine Hydrochloride and Olefins in
Aqueous Media: In Situ Generation of Trifluoromethyl Diazo-
methane. Angew. Chem., Int. Ed. 2010, 49, 938−941. (b) Barroso, R.;
Jimenez, A.; Perez-Aguilar, M. C.; Cabal, M.-P.; Valdes, C. Synthesis
of 1,3-diaryl-3-trifluoromethylcyclopropenes by transition-metal-free
reaction of 2,2,2-trifluoroacetophenone tosylhydrazones with alkynes:
the effect of the trifluoromethyl group. Chem. Commun. 2016, 52,
3677−3680. (c) Briones, J. F.; Davies, H. M. L. Silver Triflate-
Catalyzed Cyclopropenation of Internal Alkynes with Donor-/
Acceptor-Substituted Diazo Compounds. Org. Lett. 2011, 13,
3984−3987. (d) Uehara, M.; Suematsu, H.; Yasutomi, Y.; Katsuki,
T. Enantioenriched Synthesis of Cyclopropenes with a Quaternary
Stereocenter, Versatile Building Blocks. J. Am. Chem. Soc. 2011, 133,
170−171.
̈
(13) (a) Wang, S.; Cheng, B.-Y.; Srsen, M.; Konig, B. Umpolung
Difunctionalization of Carbonyls via Visible-Light Photoredox
Catalytic Radical-Carbanion Relay. J. Am. Chem. Soc. 2020, 142,
7524−7531. (b) Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang,
Y.; Wang, J. Cu(I)-Catalyzed Cross-Coupling of Terminal Alkyne
with Trifluoromethyl Ketone N-Tosylhydrazones: Access to 1,1-
Difluoro-1,3-enynes. Org. Lett. 2015, 17, 2474−2477.
(14) (a) Lv, X.; Kang, Z.; Xing, D.; Hu, W. Cu(I)-Catalyzed Three-
Component Reaction of Diazo Compound with Terminal Alkyne and
Nitrosobenzene for the Synthesis of Trifluoromethyl Dihydroisox-
E
https://dx.doi.org/10.1021/acs.orglett.0c02638
Org. Lett. XXXX, XXX, XXX−XXX