Trifluoromethylation of Allenes: An Expedient Access to α-Trifluoromethylated Enones at Room Temperature

Article abstract of DOI:10.1002/chem.201805097

A silver(I) catalyzed regioselective trifluoromethylation of allenes using Langlois's salt (NaOSOCF₃) is demonstrated. This transformation enables direct expedient access to α-trifluoromethylated acroleins, which are valuable synthons for a number of pharmaceuticals and agrochemicals containing vinyl-CF₃ moieties. Versatility of this trifluoromethylation method has been established with good yield and excellent regioselectivity. Preliminary experiments and computational studies were carried out to elucidate the mechanistic insight of this protocol.

Full text of DOI:10.1002/chem.201805097

A Journal of
Accepted Article
Title: Trifluoromethylation of Allenes: An Expedient Access to α-
Trifluoromethylated Enones at Room Temperature
Authors: Massimo Brochetta, Tania Borsari, Andrea Gandini, Sandip
Porey, Arghya Deb, Emanuele Casali, Arka Chakraborty,
Giuseppe Zanoni, and Debabrata Maiti
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To be cited as: Chem. Eur. J. 10.1002/chem.201805097
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Trifluoromethylation of Allenes: An Expedient Access to α-
Trifluoromethylated Enones at Room Temperature
Massimo Brochetta,[a] Tania Borsari,[a] Andrea Gandini,[a] Sandip Porey,[b] Arghya Deb,[c] Emanuele
Casali,[a] Arka Chakraborty,[b] Giuseppe Zanoni,*[a] and Debabrata Maiti *[a,b]
ABSTRACT:
A
silver(I)
catalyzed
regioselective
approach could become one of the highly appealing and useful
synthetic strategy.
trifluoromethylation of allenes using Langlois’s salt (NaOSOCF3)
is demonstrated. This transformation enables direct expedient
access to α-trifluoromethylated acroleins which are valuable
synthons for a number of pharmaceuticals and agrochemicals
containing
vinyl-CF3
moieties.
Versatility
of
this
trifluoromethylation method has been established with good
yield and excellent regioselectivity. Preliminary experiments and
computational studies were carried out to elucidate the
mechanistic insight of this protocol.
The ubiquity of trifluoromethyl group (-CF3)[1,2] in myriads of
pharmaceuticals, agrochemicals and functional materials has
inspired chemists to develop numerous trifluoromethylation
strategies over the years.[3,4] Among different protocols,
trifluoromethyl radical based methods were found to be highly
captivating due to their high reactivity, milder reaction conditions
and easily accessible resources.[5-7] In spite of having
advantageous
features,
a
number
of
important
trifluoromethylated scaffold synthesis still remain unaddressed.
In this context, -trifluoromethyl substituted enones is one such
important moiety which has drawn significant attention in recent
years due to its presence in many pharmaceutical and bioactive
molecules. [8,9]
Recently, we have developed a method to access α-CF3
substituted ketones from simple unactivated olefins and alkynes
using an inexpensive radical trifluoromethylating source
Langlois’s reagent (NaOSOCF3) at room temperature (Scheme
1a).[10] We envisaged the possibility of accessing -
trifluoromethyl substituted enones starting from allene. The
highly electrophilic sp hybridized carbon center in allene core
structure is expected to be reactive towards the trifluoromethyl
radical. High regio- and stereo selectivity of product were
expected due to the unique structural feature of allenes. Utilizing
Scheme 1. a) Oxidative trifluoromethylation of allenes. b) Plausible
mechanistic pathway. c) Challenges and possible side products during
trifluoromethylation of allene.
At the outset of this study, phenyl allene was selected as a
model substrate along with Langlois’s reagent (NaOSOCF3) to
examine the feasibility of radical reactions to afford α-
trifluoromethylated acrolein. To our delight, we obtained 26%
yield of -CF3 substituted acrolein which was highly encouraging
to pursue further optimization. After extensive studies with
different silver salts, silver oxide (Ag2O) was found to be the best
catalyst to generate the trifluoromethylated product in 67% yield
with N,N-dimethylformamide (DMF) as solvent under air.
Optimum use of 20 mol% potassium persulfate (K2S2O8) was
resulted from detailed optimization with different oxidants.
However, further attempts to improve the yield of
trifluoromethylated product by increasing the amount of silver
catalyst as well as oxidant was unsuccessful due to the
increased oxidation of allene to the corresponding aldehydes
(Scheme 1c).
these
potential,
development
of
regioselective
trifluoromethylation of allenes to access -trifluoromethyl
substituted enones by direct radical based CH functionalization
[a]
M. Brochetta, T. Borsari, A. Gandini, E. Casali, Prof. Dr. D. Maiti*
and Prof. Dr. G. Zanoni*
Department of Chemistry
University of Pavia
Viale Taramelli 10, 27100 Pavia
E-mail: gz@unipv.it
[b]
[c]
S. Porey, A. Chakraborty and Prof. Dr. D. Maiti*
Department of Chemistry
Indian Institute of Technology Bombay
Powai, Mumbai-400 076 (India)
E-mail: dmaiti@chem.iitb.ac.in
A. Deb, Merkert Chemistry Center, Boston College, Massachusetts
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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10.1002/chem.201805097
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Table 1. Trifluoromethylation of allene.[a]
Table 2. Scope of oxidative trifluoromethylation with allenes
Entry.
Silver saltb
Oxidantb
Solvent
Yieldc
1
2
AgNO3
AgNO3
K2S2O8
K2S2O8
DMF
DMA
26
6
3
4
5
6
7
8
9
Ag2SO4
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
K2S2O8
K2S2O8
Na2S2O8
(NH4)2S2O8
TBHP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
40
70 (67d)
51
53
32
DTBP
28
-
6
[a]All reactions performed at rt, [b]20 mol% w.r.t allene.[c]GC yield except as
noted, [d]Isolated, DMF: N,N-dimethyl formamide, DMAc: N,N-dimethyl
acetamide
With optimized reaction condition, we started to explore the
generality of this radical trifluoromethylation protocol by varying
substituents in the aryl ring of phenyl allenes. Electron rich para-
tolyl and methoxy allenes gave thermodynamically favorable (E)-
selective trifluoromethylated acrolein in 65% and 68% yields,
respectively. Bulky tert-butyl (2e) substituted allene produced
corresponding trifluoromethylated product in synthetically useful
yield.
The product from 1,1‘-biphenyl-4-allene has been
characterized by X-ray crystallography (2g,CCDC1846274).
Electron withdrawing halogen substituted allenes (2h and 2i)
gave the desired product albeit in lower yield. A meta-methoxy
group resulted in exclusive E isomer (2k). However, electron
richness as well as steric influences in the aromatic ring resulted
10:1 E/Z selectivity for 2,4-dimethyl allene (2o). Polyaromatic
allenes like 2-naphthyl (2p) derivative gave the corresponding -
trifluoromethylated acroleins in 61% yields. Synthetic efficiency
of the current protocol has been perceived by accessing
aliphatic α -trifluoromethylated cyclohexyl acrolein in 56% yield
from unactivated cyclohexyl allene (2z).[11]
Investigation into the trifluoromethylation mechanism suggested
that the CF3 radical is likely to be involved in the reaction. Under
the optimized conditions, para-tert-butyl allene did not produce
-CF3 substituted enone in presence of TEMPO (Scheme 2c).
Expectedly, TEMPO-CF3 was detected by GC-MS analysis.
Homocoupling product (3a) was isolated in 90% yield in a closed
cap reaction highlighting the influence of air as the oxidizing
agent (Scheme 2a). Furthermore, attempt for trifluoromethylation
reaction under O2 atmosphere resulted in the oxidation of the
aryl allene into the carbonyl derivative (Scheme 2b).[9] Four
different allenes were tested under oxygen atmosphere, and all
of them produced corresponding aromatic aldehyde. Formation
of aldehyde from allene has previously been reported in the
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literature. Mechanism of trifluoromethylation reaction with
different pathways has been proposed (Scheme 3). We
supposed that the trifluoromethyl radical is produced during the
reaction, which involve silver and NaOSOCF3.
Furthermore the property of the aryl substituents could affect the
trifluoromethylation reaction.
Table 3. Oxidative trifluoromethylation using CF3SO2Na
Scheme 2. Mechanistic studies
[a] GCyield.
The reaction between CF3 radical and the allene proceeds via
formation of radical intermediates
I or II. In particular,
(intermediate II) is less reactive due to the allylic and benzylic
conjugation. Under the reaction condition, O2 promotes oxidation
of I into trifluoromethylated enones. Conversely, closed cap
reaction (N2 atmosphere) afford the homocoupling product (3a).
To investigate the stability of the radical species involved in the
trifluoromethylation reaction, computational calculations were
performed in order to observe the spin density on the atom C1,
C2 and C3. We hypothesize that the benzylic conjugation
increases the spin density on the C1 and the stability of the
species Ⅱ (Table 4). Moreover, the presence of electron-
donating group (methyl, intermediate B) on the arene decreases
the spin density on the benzyl carbon (C1). On the contrary it
was observed that the spin density decreased on C3 in
presence of electron withdrawing group such as bromine or
naphthyl. Thus, we can assume that the reactive species
involved in the oxidation step is the intermediate I because of
lower stability induced by lowest spin density on C3.
Scheme 3. Proposed Mechanism of trifluoromethylation
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Table 4. Spin density on C1, C2 and C3 involved in trifluoromethylation.
Level of
computational theory
spin density
C1
spin density
C2
spin density
C3
6-311++g(d,p)
+0.674
-0.258
+0.506
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[5]
Level of
computational
theory
spin
density
C1
spin
density
C2
spin
density
C3
Intermediate
6-311++g(d,p)
B
C
D
+0.627
+0.631
+0.622
-0.247
-0.247
-0.249
+0.506
+0.497
+0.491
[6]
[7]
In conclusion, we have developed a direct, efficient, and general
method to synthesize -CF3-substituted enones from allenes.
Various functionalized allenes were employed using an
inexpensive trifluoromethylating reagent. Mild reaction condition
and easy availability of starting material make this method
attractive to generate -trifluromethylated enones.
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A. Studer, Angew. Chem. Int. Ed. 2012, 51, 8950; c) A. T. Parsons, S. L.
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Chem. Commun. 2017, 53, 4681.
Keywords: • Trifluoromethylation • Allenes • Enones • E-
selective • Thermodynamically controlled product
[9]
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Acknowledgements
Org. Chem. 2011, 7, 860–865.ꢀ d) A. Das, R. Chaudhuri,
Chem.Commun., 2009, 4046-4048.
R Liu,
This activity is supported by research grant from Lombardy
Region and Cariplo Foundation, Italy (Sottomisura B) and SERB
(EMR/2015/000164).
[10] a) A. Deb, S. Manna, A. Modak, T. Patra, S. Maity, D. Maiti, Angew.
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A highly regio and
sterio selective
M Brochetta,T Borsari, A
Gandini, S Porey, A Deb,
E Casali, A. Chakraborty,
G Zanoni* and D. Maiti*
Page No. – Page No.
Trifluromethylation of
Allene: An Expedient
Access to  –
trifluromethylation of
allenes has been
developed to afford α-
trifluoromethylated
acroleins using
Langlois’s reagent .
Trifluromethylated
Enones at Room
Temperature
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