Copper-Mediated Deuterotrifluoromethylation of α?Diazo Esters

Article abstract of DOI:10.1002/cjoc.201600004

A copper-mediated deuterotrifluoromethylation of α?diazo esters under the promotion of deuterium oxide (D₂O) has been developed for the synthesis of deuterium-labeled trifluoromethyl compounds. This deuterotrifluoromethylation reaction is of broad scope and can afford the deuterated products with higher than 99% isotopic purity. Moreover, the results of this investigation also provide some experimental evidences to support our previously proposed trifluoromethylation mechanism.

Full text of DOI:10.1002/cjoc.201600004

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DOI: 10.1002/cjoc.201600004
Copper-Mediated Deuterotrifluoromethylation of
α‑Diazo Esters
Mingyou Hu, Qiqiang Xie, Xinjin Li, Chuanfa Ni, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
A copper-mediated deuterotrifluoromethylation of α‑diazo esters under the promotion of deuterium oxide (D2O)
has been developed for the synthesis of deuterium-labeled trifluoromethyl compounds. This deuterotrifluoromethyl-
ation reaction is of broad scope and can afford the deuterated products with higher than 99% isotopic purity. More-
over, the results of this investigation also provide some experimental evidences to support our previously proposed
trifluoromethylation mechanism.
Keywords copper, trifluoromethylation, deuterium, diazo compounds
Introduction
I: (i) β-fluoride elimination under anhydrous conditions
to give 1,1-difluoroalkenes 2;[8,9] and (ii) protonation in
the presence of water to afford α-trifluoromethylesters
3.[8] When a trifluoromethylthiocopper reagent was used,
the corresponding hydrotrifluoromethylthiolation can
also be achieved.[10] To expand the synthetic application
of this copper promoted trifluoromethylation and to find
more evidences to support our proposed mechanism, we
investigated the capturing of intermediate I with other
agents. Herein, we report copper-mediated deuterotri-
fluoromethylation of α‑diazo esters under the promotion
of deuterium oxide (D2O) (Scheme 1).
Fluorine-containing organic molecules are widely
applied in pharmaceuticals, agrochemicals and func-
tional materials due to their improved lipophilicity,
metabolic stability and bioavailability endowed by the
unique fluorine atom.[1] As one of the most common
fluorinated moieties, trifluoromethyl group (CF3) is
frequently used in pharmaceutical and agrochemical
research to enhance the bioactivity of organic mole-
cules.[2] Exploring new methods for introducing CF3
into organic molecules is remarkably one of the hotspots
in modern organic chemistry. Recently, many break-
throughs on the Cu- and Pd-catalyzed/mediated trifluo-
romethylation of aromatic carbons have been
achieved.[3] However, transition-metal-assisted trifluo-
romethylation of aliphatic carbons is less developed.[4]
Isotopic substitution can be used to determine the
mechanism of a chemical reaction via the kinetic iso-
tope effect.[5] Isotopic labeled compounds, are often
used as isotope tracer in medical diagnostics, age-
determination of radioisotope-containing materials,
quantifying proteins, etc.[6] The late-stage introduction
of isotopes is often based on isotope-exchanging meth-
od, which always gives impure isotope labeled chemi-
cals.[7]
Scheme 1 Reaction of CuCF3 with diazo esters
CF3
CO2R2
3
R1
Ref. 8
H2O
CF2
CO2R2
Anhydrous
[CuCF3]
F3C Cu
N2
1
CO2R2
R1
R1
CO2R2
Refs. 8 & 9
R1
2
I
This work
D2O
F3C D
CO2R2
Previously, we reported a Cu-mediated trifluoro-
methylation of α‑diazo esters (Scheme 1).[8] The mech-
anism investigation suggested that the reaction involves
a migratory insertion of carbene ligand into trifluoro-
methyl-copper bond, giving an α-trifluoromethyl-α-
copper ester intermediate I. There are two reaction
pathways for the further transformation of intermediate
R1
4
Results and Discussion
In previous work, we developed two methods for the
trifluoromethylation of α-diazo esters with pre-regener-
*
E-mail: jinbohu@sioc.ac.cn; Tel.: 0086-021-54925174; Fax: 0086-021-64166128
Received January 3, 2016; accepted March 7, 2016; published online April 25, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600004 or from the author.
Chin. J. Chem. 2016, 34, 469—472
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
469

Hu et al.
COMMUNICATION
ated “CuCF3” reagent (prepared from CuI/TMSCF3/CsF
in a ratio of 1.0∶1.1∶1.1).[8] One is the added
CuI-promoted reaction (with adventitious water as the
proton source), and the other is the added water pro-
moted reaction. At the outset of this work, to probe the
formation of trifluoromethylated organocopper interme-
diate I, D2O was used to quench the CuI-promoted tri-
fluoromethylation reaction, and a 18% yield of deuter-
ated product 4a was obtained (Scheme 2, Eq. 1).[11]
However, we soon realized that intermediate I can read-
ily undergo protonation by water, the deuterated product
4a may be generated from the H-D exchange of the
original formed product 3a under the action of the un-
reacted CuCF3, which served as a base. To test the pos-
sibility of H-D exchange, pure deuterated 4a was sub-
jected to the standard conditions of water-promoted tri-
fluoromethylation reaction.[8] Interestingly, the H-D
exchange indeed took place; however, only a conversion
of about 80% was observed (Scheme 2, Eq. 2). When
non-deuterated compound 3a was subjected to the H-D
exchange reaction conditions, a similar conversion was
observed (Eq. 3). These results indicate that the H-D
exchange can take place under the standard trifluoro-
methylation conditions, and the deuteration yield is only
moderate due to the equilibrium reaction.
Since the trifluoromethylated organocopper interme-
diate I in our reaction system could not be observed or
trapped by various other electrophiles such as allyl bro-
mide, iodine, diphenyl disulfide, and α,β-unsaturated
compounds,[12] to verify the formation of this intermedi-
ate during the trifluoromethylation, we performed the
added D2O-promoted reaction. Initially, 0.2 mmol scale
starting material 1a and 0.5 mL solvent NMP were used,
and a randomly selected amount of D2O (90 equiv.) was
used to test the viability of the reaction. Gratifyingly,
the reaction proceeded smoothly to give the desired
deuterated product in 36% yield with higher than 99%
purity (Table 1, Entry 1). However, reducing the
amount of D2O to 1 equiv. is inferior to the reaction
(Table 1, Entry 2). Because the viscosity of D2O is larg-
er than H2O, we envisioned that a higher temperature
may promote the reaction. Indeed we found that raising
the temperature to 40 ℃, the yield increased dramati-
cally from 36% to 68% when 90 equiv. of D2O were
used as the promoter (Table 1, Entry 3). Further opti-
mization of the reaction conditions showed that a 75%
yield can be achieved by using 100 equiv. of D2O as
promoter (Table 1, Entries 4－8). More interestingly,
simply increasing the concentration of the starting ma-
terial 1a can improve the yield to 89% (Table 1, Entry
9). Further screening the quantity of D2O showed that
4a could be obtained in a yield as high as 96% when 60
equiv. of D2O was used (Table 1, Entries 9－12).
Table 1 Optimization of the reaction conditionsa
(1) CuI (x equiv.), TMSCF3 (y equiv.)
N2
1a
CsF (y equiv.), r.t., NMP, 10 min
F3C
D
(2) 1a (1 equiv.) and D2O, Temp.
Ph
COOEt
Ph
COOEt
4a
Entryb D2O (equiv.)
Temp./℃
r.t.
Time/h Yieldc/%
1
D2O (90)
D2O (1)
15
65
15
14
16
16
16
11
11
11
11
11
36
11
68
37
75
69
52
75
89
96
93
90
2
r.t.
3
D2O (90)
D2O (50)
D2O (100)
D2O (120)
D2O (220)
D2O (100)
D2O (40)
D2O (60)
D2O (80)
D2O (100)
40
4
40
5
40
6
40
7
40
8
40
9
40
10
11
12
40
40
40
a All reactions were performed by adding 1a and additive into the
b
pre-generated “CuCF3”. Entries 1－8 were performed on 0.2
mmol sacle (x＝1.5, y＝1.8) in NMP (3 mL＋3 mL) under N2
atmosphere; Entries 9－12 were performed on 0.5 mmol sacle
(x＝1.5, y＝1.65) in NMP (3 mL＋3 mL) under N2 atmosphere.
c The yields were determined by 19F NMR with PhCF3 as an in-
ternal standard.
Scheme 2 H-D exchange experiments of α-trifluoromethyl esters
(1) CuI (1.2 equiv.),
NMP, 6 h
CF3
F3C D
CO2Et
4a, 18%
N2
(1)
(2)
+
+
[CuCF3]
CO2Et
3a, 62%
Ph
Ph
(2) D2O (0.5 mL), r.t., 1 h
Ph
CO2Et
1a
H2O (44 equiv.),
NMP, r.t., 20 h
CF3
F3C D
F3C D
Ph CO2Et
4a
+ [CuCF3]
+ [CuCF3]
+
+
Ph
CO2Et
96% recovered
CO2Et
3a
Ph
Ph
4a/3a = 1.00:4.03
4a
D2O (44 equiv.),
NMP, r.t., 20 h
CF3
CF3
F3C D
Ph CO2Et
4a
(3)
quant. recovered
CO2Et
3a
CO2Et
3a
Ph
4a/3a = 3.98:1.00
470
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 469—472

Copper-Mediated Deuterotrifluoromethylation of α‑Diazo Esters
intermediate I (see Scheme 1). Compared with the H-D
exchange reaction (see Eqs 1 and 3), the high isotope
purities of 4 in this reaction probably arise from the
avoidance of adventitious water, which prevents the
competitive hydrotrifluoromethylation reaction. More-
over, compared with previously reported hydrotrifluo-
romethylation, this D2O-promoted deuterotrifluoro-
methylation required more D2O than H2O, and higher
reaction temperature, probably due to the higher viscos-
ity of D2O than H2O, and the isotope effect of water
used to hydrolyze the intermediate I.[8]
With the optimized reaction conditions in hand (Ta-
ble 1, Entry 10), we further investigated the versatility
of the deuterotrifluoromethylation reaction with di-
versely substituted α ‑ diazo esters, the results were
summarized in Table 2. The reaction was of similar
functional group tolerance and electronic effect with
previously reported hydrotrifluoromethylation.[8] For
example, there occurred no aromatic trifluoromethyla-
tion when the aryl ring was substituted by halogens (F-,
Cl-, Br) (Table 2, 4g－4m, 4t, and 4u), and the substit-
uents on the orth-, meta-, or para-position of the phenyl
group had no significant influence on the yields (Table 2,
4b－4m). Similarly, the electron-donating groups sub-
stituted on the phenyl groups, afforded better yields than
electron-deficient ones (Table 2, 4c－4m). Due to the
competitive β-H elimination of Cu-carbene intermediate,
the benzyl substituted diazo esters rendered comparably
lower yield than phenyl substituted ones (Table 2, En-
tries 4n－4t). The aliphatic substituted diazo esters gave
good yields similar to previous reported hydrotrifluoro-
methylation (Table 2, Entries 4u－4w).[8]
Conclusions
In conclusion, we have developed a D2O-promoted
deuterotrifluoromethylation reaction, which can be used
to synthesize isotopically pure α-deuterium-α-trifluoro-
methyl esters. The highly pure deuterated products are
potentially useful for mechanistic research and other
isotope-involved applications. Compared to previously
reported water-promoted hydrotrifluoromethylation, this
deuterotrifluoromethylation is of similar electronic ef-
fect. Moreover, the results of this investigation also pro-
vide some experimental evidences to support our previ-
ously proposed trifluoromethylation mechanism.
According to the results that the deuterotrifluoro-
methylation products were produced in high yields and
purities higher than 99%, we confirmed the formation of
Table 2 Deuterotrifluoromethylation of α-diazo estersa
(1) CuI (1.5 equiv.), TMSCF3 (1.65 equiv.),
CsF (1.65 equiv.), NMP, r.t., 10 min
N2
F3C
R1
D
R1
CO2Et
(2) 1 (1 equiv.) in NMP, D2O (60 equiv.),
40 oC, 11 h
CO2Et
1
4
F3C
F3C
F3C
F3C
F3C
D
D
D
D
D
MeO
MeO
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Me
Me
4d, 92%
4e, 95%
4a, 90%
4b, 89%
4c, 91%
F3C
F3C
D
F3C
F3C
D
F3C
D
D
D
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
MeO
Cl
F
Br
Br
4f, 92%
4j, 79%
4g, 96%
4h, 72%
4i, 76%
F3C
F3C
F3C
D
D
D
F3C
Cl
Cl
Cl
D
CF3
CO2Et
CO2Et
CO2Et
CO2Et
4n, 56%
F3C
D
CO2Et
Cl
4m, 68%
4o, 70%
4k, 76%
4l, 73%
F3C
t-Bu
Br
F3C
MeO
Me
Me
D
D
F3C
F3C
D
D
D
CO2Et
CO2Et
CO2Et
CO2Et
Me
CO2Et
4s, 73%
4t, 80%
4r, 61%
4p, 73%
4q, 76%
F3C
F3C
D
F3C
D
D
MeO
MeO
Cl
Cl
CO2Et
CO2Et
CO2Et
4w, 83%
4u, 84%
4v, 88%
a All reactions were performed on 0.5 mmol scale by adding 1 and D2O into the pre-generated CuCF3. Yields given refer to isolated yields
of the analytically pure products.
Chin. J. Chem. 2016, 34, 469—472
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
471

Hu et al.
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(b) Fluorine in Pharmaceutical and Medicinal Chemistry: From Bi-
ophysical Aspects to Clinical Applications, Eds.: Gouverneur, V.;
Müller, K., Imperial College Press, London, 2012; (c) Fluorine in
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Acknowledgement
Support of this work by the National Basic Research
Program of China (Nos. 2015CB931900 and
2012CB821600), the National Natural Science Founda-
tion of China (Nos. 21372246, 21421002 and
21472221), Shanghai Science and Technology program
(No. 15XD1504400), the Chinese Academy of Sciences,
and MSD China R&D Postdoc Fellowship (to H.M.) is
gratefully acknowledged.
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Typical procedures for D2O-promoted deuterotri-
fluoromethylation of α‑diazo esters (Table 2)
In a glovebox, to an oven-dried 25-mL Schlenk tube
equipped with a stir bar were added CuI (143 mg, 0.75
mmol) and CsF (125 mg, 0.825 mmol). Then the
Schlenk tube was sealed with a septum and brought to
the bench. TMSCF3 (117 mg, 0.825 mmol) in NMP (3
mL) was added via syringe. After stirring at room tem-
perature for 10 min, ethyl 2-diazo-2-phenylacetate (1a)
(95 mg, 0.5 mmol) in NMP (3 mL) was added, then D2O
(0.54 mL, 30 mmol) was added. The resulting mixture
was heated to 40 ℃ and stirred under N2 atmosphere
for 11 h. After the addition of 5－10 mL HCl (1 mol/L),
the mixture was extracted with Et2O (15 mL×3). The
combined organic layer was washed with H2O (20 mL
×2), then brine (20 mL), dried over MgSO4 and con-
centrated in vacuo. The residue was purified by chro-
matography on silica gel (petroleum ether/AcOEt, 30∶
1, V/V) to afford 4a (105 mg, 90% yield) as a yellow oil.
1H NMR (300 MHz, CDCl3/TMS) δ: 7.45－7.40 (m,
5H), 4.34－4.18 (m, 2H), 1.26 (t, J＝6.9 Hz, 3H); 19F
NMR (282 MHz, CDCl3/CFCl3) δ: 67.5 (s, 3F); 13C
NMR (100 MHz, CDCl3/TMS) δ: 166.2, 129.4, 129.2,
128.9, 123.8 (q, J＝280.4 Hz), 62.0, 13.8; IR (film) ν:
3068, 2986, 1748, 1453, 1369, 1262, 1198, 1166, 1052,
700 cm1; MS (EI, m/z): 233 (M＋, 32.39), 160 (100.00).
HRMS (EI): exact mass calcd for C11H10DF3O2 (M＋):
233.0774, found 233.0779.
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Chin. J. Chem. 2016, 34, 469—472