Efficient Difluoromethylation of Alcohols Using TMSCF2Br as a Unique and Practical Difluorocarbene Reagent under Mild Conditions

Article abstract of DOI:10.1002/anie.201611823

A general method for the efficient difluoromethylation of alcohols using commercially available TMSCF₂Br (TMS=trimethylsilyl) as a unique and practical difluorocarbene source is developed. This method allows primary, secondary, and even tertiary alkyl difluoromethyl ethers to be synthesized under weakly basic or acidic conditions. The reaction mainly proceeds through the direct interaction between a neutral alcohol and difluorocarbene, which is different from the difluoromethylation of phenols. Moreover, alcohols containing other moieties that are also reactive toward difluorocarbene can be transformed divergently by using TMSCF₂Br. This research not only solves the synthetic problem of difluorocarbene-mediated difluoromethylation of alcohols, it also provides new insights into the different reaction mechanisms of alcohol difluoromethylation and phenol difluoromethylation with difluorocarbene species.

Full text of DOI:10.1002/anie.201611823

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201611823
German Edition: DOI: 10.1002/ange.201611823
Carbenes
Efficient Difluoromethylation of Alcohols Using TMSCF2Br as
a Unique and Practical Difluorocarbene Reagent under Mild
Conditions
Qiqiang Xie, Chuanfa Ni,* Rongyi Zhang, Lingchun Li, Jian Rong, and Jinbo Hu*
Abstract: A general method for the efficient difluoromethyla-
tion of alcohols using commercially available TMSCF2Br
(TMS = trimethylsilyl) as a unique and practical difluorocar-
bene source is developed. This method allows primary,
secondary, and even tertiary alkyl difluoromethyl ethers to be
synthesized under weakly basic or acidic conditions. The
reaction mainly proceeds through the direct interaction
between a neutral alcohol and difluorocarbene, which is
different from the difluoromethylation of phenols. Moreover,
alcohols containing other moieties that are also reactive toward
difluorocarbene can be transformed divergently by using
TMSCF2Br. This research not only solves the synthetic
problem of difluorocarbene-mediated difluoromethylation of
alcohols, it also provides new insights into the different reaction
mechanisms of alcohol difluoromethylation and phenol
difluoromethylation with difluorocarbene species.
To access difluoromethyl ethers,[8–11] the difluoromethyla-
tion of alcohols and phenols with difluorocarbene (:CF2) is
a facile approach owing to the ready availability of many
reagents.[10,11] However, current syntheses of difluoromethyl
ethers with :CF2 reagents mainly focus on the difluorome-
thylation of phenols under basic conditions;[10] the difluoro-
methylation of alcohols under similar reaction conditions is
usually less productive as a result of the competitive reactions
caused by the base. To date, only several reagents, including
HCF2Cl,[12] BrCF2P(O)(OEt)2,[13] and TMSCF2Br,[14] have
been reported for difluoromethylation of alcohols under
basic conditions with limited functional group compatibility
(Scheme 1a, basic). Although some methods that can avoid
a-Fluoroethers, as a valuable class of organofluorine
compounds, have found wide application in pharmaceuticals,
agrochemicals, and functional materials, owing to the impres-
sive conformational changes and maximal shifts in electron
distribution brought by fluorine.[1,2] Moreover, the a-fluorine
À
substitution of alkyl ethers shortens and strengthens the C O
bond[3] and thus improves the in vivo oxidative stability of the
ether moiety of a drug.[4] Among various a-fluoroethers,
difluoromethyl ethers are of particular interest as the
difluoromethyl group is capable of acting as a lipophilic
hydrogen-bond donor.[5] In the past decades, difluoromethyl
ethers have been applied in developing enzyme inhibitors/
activators, anti-HIV agents, antimicrobial agents, and anes-
thetic drugs.[2b,c,6,7] For instances, Desflurane, a widely used
anesthetic drug,[7a] and Roflumilast, a newly approved respi-
ratory system drug for treatment of chronic obstructive
pulmonary disease (COPD) exacerbations,[7b] are both
difluoromethyl ethers.
Scheme 1. Difluoromethylation of alcohols with various difluorocar-
bene reagents. HFPO=hexafluoropropylene oxide, TMS=trimethyl-
silyl.
strongly basic conditions by the use of special :CF2 reagents,
such as CF2N2,[15] HFPO,[16] and CF3ZnBr·2CH3CN,[17] have
been exploited for alcohol difluoromethylation, these meth-
ods usually require excess amounts of alcohols and suffer
from narrow substrate scope (Scheme 1a, neutral). Recently,
a modification of Chenꢀs method has led to an effective
difluoromethylation of primary and secondary alcohols with
FSO2CF2CO2H (Scheme 1a, acidic);[18] however, the reaction
with tertiary alcohols is still unmet. Furthermore, the elution
of SO2, an air pollutant,[19] as a byproduct may prohibit this
method from wide application. In general, efficient difluoro-
methylation of structurally diverse alcohols with :CF2 still
remains a challenge, which is strikingly different from the
difluoromethylation of phenols.[10] Therefore, it is not only of
great demand, but also of immense fundamental interest to
seek a mild and general approach for the difluoromethylation
of alcohols with readily available :CF2 reagents.
[*] Q. Xie, Dr. C. Ni, R. Zhang, Dr. L. Li, J. Rong, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai, 200032 (China)
E-mail: nichuanfa@sioc.ac.cn
jinbohu@sioc.ac.cn
R. Zhang, Prof. Dr. J. Hu
School of Physical Science and Technology
ShanghaiTech University
100 Haike Road, Shanghai 201210 (China)
Previously, we developed TMSCF2Br as a versatile :CF2
reagent for difluoromethylation/difluoromethylenation of
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611823.
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phenols, thiols, amines, alkenes, and alkynes, among
others.[10,14] During our continuous pursuit of alcohol difluoro-
methylation with TMSCF2Br, we found that the reaction
conditions for generating :CF2 are crucial, and mild con-
ditions are optimal for the conversion of alcohols (Sche-
me 1b). Thus, the difluoromethylation of alcohols can be
achieved as easily as that of phenols, provided that proper
conditions for the generation of :CF2 are chosen. Herein, we
report the development of KOAc- or KHF2-promoted highly
efficient difluoromethylation of alcohols with TMSCF2Br as
a unique :CF2 source, a reaction proceeding through a mech-
anism different from the difluoromethylation of phenols.
Our research started with optimization of the difluoro-
methylation of alcohols with TMSCF2Br under commonly
used strongly basic conditions.[10,14] Experiments were con-
ducted by adding an aqueous KOH solution to an organic
solution of model substrate 1a and TMSCF2Br (Table 1,
entries 1–9). Under our reported conditions,[14a] the desired
product 2a was obtained in a low yield (entry 1). Solvent
screening showed that PhCH3 and CH2Cl2 were superior to
acetonitrile, and the reaction could be somewhat improved by
using PhCH3 instead of CH2Cl2. After exhaustive optimiza-
tion on the reaction parameters, we found that when using
PhCH3 or CH2Cl2 as the solvent, the reaction was sensitive to
the concentration of the reactants (entries 1, 8, and 9;
entries 4–7). Increasing the concentration of the organic
phase significantly enhanced the yield of 2a, indicating an
improvement on the transfer of in-situ-generated :CF2 to the
alcohol substrate. This concentration effect was not observed
in the difluoromethylation of (thio)phenols/thioalcohols
under similar conditions. We inferred that alcohols and
(thio)phenols/thioalcohols may react with :CF2 in different
pathways. In the cases of (thio)phenols/thiols, which are acidic
enough to be efficiently deprotonated by a strong base such as
KOH, the corresponding anions should be the major nucle-
ophilic species to react with :CF2 (Scheme 2a). However, in
Scheme 2. a,b) Proposed mechanisms of phenol and alcohol difluoro-
methylation. c) Difluoromethylation of phenol under mild conditions.
the case of alcohols, which are less acidic than (thio)phenols/
thiols, the alcoholate anion presents in weak equilibrium even
in the presence of KOH, thus both the alcoholate anion
(Scheme 2a, path a) and the alcohol (Scheme 2a, path b)
would react with :CF2, with the reaction of the alcohol being
the major pathway. The remarkable concentration effect of
alcohols should arise from the lower nucleophilicity of
alcohols than that of phenolate anions. Based on the above
rationalizations, we further investigated the difluoromethyla-
tion of 1a by using many other activators, ranging from
strongly basic NaOH to weakly acidic KHF2 (Table 1,
entries 10–16). To our delight, all of the reactions proceeded
smoothly, giving 2a in good to excellent yields. For compar-
ison, we performed the reaction between phenol 4 and
TMSCF2Br by using KOAc or KHF2 as the mild activator
(Scheme 2c); however, although TMSCF2Br was consumed
completely, product 5 was formed in very low yield.[20] It is
obvious that alcohols can react with :CF2 directly without pre-
deprotonation (Scheme 2b, path b), which is distinct from the
reaction of (thio)phenols/thioalcohols with difluorocarbene
(Scheme 2a).
We also investigated the role of water in this reaction
(Table 1, entries 17–19). When NaOH or KOAc was used in
the absence of water, the complete conversion of TMSCF2Br
needed 24 hours and led to low yields of 2a (entries 17 and
18). The difluorocarbene mainly reacted with the activator to
form the hydrolysis product or AcOCF2H. When KHF2 was
used without water, although a high yield of 2a could be
obtained, it required much longer reaction time (entry 19).
These results indicate that the two-phase system consisting of
an organic solution of the alcohol/TMSCF2Br and an aqueous
solution of the activator not only promoted the formation and
Table 1: Screen of reaction conditions for the difluoromethylation of
alcohol 1a with TMSCF2Br.[a]
Entry Additive [equiv]
Solvent [mL] T [8C] t [h] Yield [%]
1
2
3
4
5
6
7
8
20% aq. KOH (6.0)
20% aq. KOH (6.0)
20% aq. KOH (6.0)
20% aq. KOH (6.0)
20% aq. KOH (6.0)
20% aq. KOH (6.0)
20% aq. KOH (6.0)
20% aq. KOH (6.0)
20% aq. KOH (5.0)
20% aq. NaOH (5.0) CH2Cl2 (0.3)
8% aq. LiOH (5.0) CH2Cl2 (0.3)
30% aq. Na2CO3 (4.0) CH2Cl2 (0.3)
NH4OAc (4.0)
KOAc (4.0)
KF (4.0)
CH2Cl2 (2.0)
MeCN (2.0)
PhCH3 (2.0)
PhCH3 (2.0)
PhCH3 (1.0)
PhCH3 (0.5)
PhCH3 (0.3)
CH2Cl2 (0.3)
CH2Cl2 (0.3)
0
0
0
0
0
0
0
0
0
0.5 33
0.5 13
0.5 45
1
36
65
76
78
82
85
86
81
70
86
92
69
88
29
48
87
1
2
2
2
9
2
2
2
10
11
12
13
14
15
16
17
18
19
0
0
RT
10
10
10
10
10
24
24
48
CH2Cl2 (0.3)[b] RT
CH2Cl2 (0.3)[b] RT
CH2Cl2 (0.3)[b] RT
CH2Cl2 (0.3)[b] RT
CH2Cl2 (0.3)
CH2Cl2 (0.3)
CH2Cl2 (0.3)
KHF2 (4.0)
NaOH (4.0)
KOAc (4.0)
KHF2 (4.0)
RT
RT
RT
[a] All of the reactions were performed on 0.5 mmol scale. The yields
were determined by 19F NMR spectroscopy using PhOCF3 as an internal
standard. [b] H2O (0.3 mL) was used as co-solvent.
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transfer of :CF2, but also could confine the base to the
aqueous phase to minimize the competitive consumption of
:CF2.[11c]
Next, we examined the substrate scope by using two mild
activators, weakly basic KOAc and weakly acidic KHF2. For
comparison, we also conducted the reactions using strongly
basic NaOH. As shown in Scheme 3, primary, secondary, and
tertiary alcohols reacted smoothly to give difluoromethyl
ethers in moderate to excellent yields. Mild activators KOAc
and KHF2 were suitable for almost all of the alcohols
examined, although the strongly basic NaOH were only
suitable for the reaction of electron-rich and less sterically
hindered alcohols (2a–f, 2h,i, 2q, 2v, and 2y). Functional
groups such as cyano (2l), nitro (2n), halogen (2h–k), ester
(2m), and protected amino groups (2t and 2z) are well
tolerated under the conditions of KOAc and KHF2. In the
case of alcohol 2p with a boronic ester group, KOAc is
superior to KHF2. Moreover, alkene (2b), alkyne (2c), alkyl
aryl ether (2e–g and 2y), and heteroarene (2r, 2s, and 2q) are
compatible with the difluoromethylation of alcohols, and no
competing reaction occurs. This procedure is also applicable
for the late-stage difluoromethylation of bioactive alcohols.
Idebenone, a drug for treatment of Alzheimerꢀs disease,[21]
was converted to 2ac in excellent yields under all three sets of
conditions. Estradiol benzoate, the first form of estrogen to be
marketed,[22] underwent KOAc-promoted reaction to give
2ad in 86% yield. Note that the reactions can be easily scaled
up to 10-mmol scale (2a and 2ad). Overall, the difluorome-
thylation of alcohols is affected by both the electronic and the
steric effects of the substrates: the electron-rich alcohols
(2e,f) gave somewhat higher yields than the electron-defi-
cient ones (2n,o), and the secondary and tertiary alcohols
were normally less reactive than the primary ones, thus
requiring more excess amounts of TMSCF2Br. The influence
of the steric effect is further demonstrated by the reaction of
1,4-diol 1ae, with the primary alcohol being selectively
difluoromethylated to give 2ae in 86% yield [Eq. (1)].
Scheme 3. Difluoromethylation of alcohols with TMSCF2Br. Unless
To demonstrate the unique feature of TMSCF2Br, we
investigated the difluoromethylation of alcohol 1a by using
other :CF2 sources that have been employed for difluorome-
thylation of phenols.[10,11] Due to the potential substrate
limitation of the strongly basic conditions (such as NaOH), we
only considered reagents that can release :CF2 under mild
conditions (Scheme 4). The acidic reagent FSO2CF2CO2H
(6a) could efficiently difluoromethylate 1a;[18] however, its
slow addition was required to avoid the competing consump-
tion of :CF2 by itself (Supporting Information). As for the
neutral reagents ClCF2CO2Na (6b) and Ph3P+CF2CO2À (6c),
the former reacted very rapidly with :CF2 even when it was
slowly added to the reaction system,[23] while the latter readily
otherwise noted, reactions were performed on 0.5 mmol scale. Meth-
od A1: 3 (2.0 equiv), 20% aq. NaOH (5.0 equiv), CH2Cl2 (0.3 mL), 08C,
2 h; Method A2: 3 (3.0 equiv), 20% aq. NaOH (8.0 equiv), CH2Cl2
(0.3 mL), 08C, 2 h; Method B1: 3 (2.0 equiv), KOAc (4.0 equiv), CH2Cl2
(0.3 mL), H2O (0.3 mL), RT, 10 h; Method B2: 3 (3.0 equiv), KOAc
(6.0 equiv), CH2Cl2 (0.3 mL), H2O (0.3 mL), RT, 10 h; Method B3: 3
(3.8 equiv), KOAc (7.6 equiv), CH2Cl2 (0.3 mL), H2O (0.3 mL), RT,
15 h; Method C1: 3 (2.0 equiv), KHF2 (4.0 equiv), CH2Cl2 (0.3 mL),
H2O (0.3 mL), RT, 10 h; Method C2: 3 (3.0 equiv), KHF2 (6.0 equiv),
CH2Cl2 (0.3 mL), H2O (0.3 mL), RT, 10 h; Method C3: 3 (3.8 equiv),
KHF2 (7.6 equiv), CH2Cl2 (0.3 mL), H2O (0.3 mL), RT, 15 h. The yields
were determined by 19F NMR spectroscopy using PhOCF3 as an
internal standard. The isolated yields of analytically pure compounds
are given in the parentheses.
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Scheme 5. Divergent transformation of functionalized alcohols with
TMSCF2Br. [a] The bis(difluoromethylation) product was formed in 6%
yield. [b] The bis(difluoromethylation) product was formed in 15%
yield.
Scheme 4. Difluoromethylation of alcohol 1a with other difluorocar-
bene reagents. For details of the reaction conditions, see the Support-
ing Information. Conversions of reagent 6 and yields of 2a (the data in
the parentheses) were determined by 19F NMR spectroscopy.
[a] Reagent 6 was added during a period of 20 min.
ethers to be synthesized using very simple procedures.
Compared with other reagents, TMSCF2Br is particularly
suitable for the generation of difluorocarbene in the organic
phase of a two-liquid-phase system, which reduces the contact
between difluorocarbene and the aqueous solution of the
activator and promotes the difluoromethylation of alcohols.
We also showed that TMSCF2Br is able to transform
ambident substrate such as alcohol-phenol divergently by
switching its activation methods. This work not only solves the
synthetic problem of difluorocarbene-mediated difluorome-
thylation of alkyl alcohols, it also provides new insights into
the different reaction mechanisms of alcohol difluoromethy-
lation and phenol difluoromethylation with difluorocarbene.
underwent decarboxylative protonation to afford the difluor-
omethyl phosphonium salt. Comparing TMSCF2Cl (6d) with
TMSCF2Br (3), we found that the different halogen-substitu-
tions can affect the reaction of 1a, with 3 being more effective
owing to the better leaving ability of the bromide ion. When
reagents 6e–g were used to generate :CF2 in two-liquid-phase
systems, the low yields of 2a probably arose from the high
hydrophilicity of the activated :CF2 precursors, which resulted
in more contact between :CF2 and the aqueous base.
Because :CF2 is of diverse reactivity and can be generated
from TMSCF2Br under a variety of mild conditions, we
considered that it would react divergently with ambident
substrates. Thus, we finally investigated the transformation of
several functionalized alcohols with TMSCF2Br as a :CF2
source (Scheme 5). The reactions of phenol-alcohol 1af and
thiophenol-alcohol 1ag under weakly acidic conditions
afforded predominantly the alcohol difluoromethylation
products, whereas their reactions under strongly basic con-
ditions preferred the (thio)phenol difluoromethylation (Sche-
me 5a,b). These results further supported different mecha-
nisms of difluoromethylation of alcohols and (thio)phenols
with :CF2. In the case of unsaturated alcohol 1c (Scheme 5c),
the two-phase system consisting of water and CH2Cl2
facilitated the difluoromethylation of alcohol at 08C, while
the homogenous organic system of PhCH3 at 1108C promoted
the selective difluorocyclopropanation of the alkene.
Acknowledgements
This work was supported by the National Basic Research
Program of China (2015CB931900), the National Natural
Science Foundation of China (21632009, 21421002, 21472221,
21372246), Shanghai Academic Research Leader Program
(15XD1504400),
Shanghai
Rising-Star
Program
(16QA1404600), the Youth Innovation Promotion Associa-
tion CAS (2014231), and the Chinese Academy of Sciences.
J.H. thanks Professor Long Lu (SIOC) for helpful discussions.
Conflict of interest
In summary, we have developed a general method for the
efficient difluoromethylation of alcohols by using TMSCF2Br
as a unique and practical difluorocarbene source under very
mild conditions. The reaction proceeds through a mechanism
that is different from the difluoromethylation of phenols, and
allows primary, secondary, and tertiary alkyl difluoromethyl
The authors declare the following competing financial
interest: The Shanghai Institute of Organic Chemistry holds
a patent on the chemistry described herein.
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Keywords: alcohols · difluorocarbene · difluoromethyl ethers ·
fluorine · synthetic methods
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Manuscript received: December 5, 2016
Revised: January 24, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Carbenes
A general method for difluoromethylation
of alcohols with difluorocarbene under
weakly basic or acidic aqueous conditions
by using TMSCF2Br as a unique and
practical difluorocarbene reagent is
developed. This method is efficient for
the selective synthesis of alkyl difluoro-
methyl ethers from functionalized alco-
hols, and a mechanism different from
difluoromethylation of phenols is dis-
closed.
Q. Xie, C. Ni,* R. Zhang, L. Li, J. Rong,
J. Hu*
&&&& — &&&&
Efficient Difluoromethylation of Alcohols
Using TMSCF2Br as a Unique and
Practical Difluorocarbene Reagent under
Mild Conditions
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!