Synthesis of gem-difluorocyclopropa(e)nes and O-, S-, N-, and P-difluoromethylated compounds with TMSCF2Br

Article abstract of DOI:10.1002/anie.201306703

Two-in-one: Me₃SiCF₂Br is an efficient difluorocarbene source and is compatible with both neutral and aqueous basic conditions. Bromide-ion-initiated [2+1] cycloaddition with alkenes/alkynes and hydroxide ion promoted α-addition with (thio)phenols, (thio)alcohols, sulfinates, heterocyclic amines, and H-phosphine oxides give the corresponding gem-difluorinated compounds with broad functional-group tolerance. Copyright

Full text of DOI:10.1002/anie.201306703

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DOI: 10.1002/anie.201306703
Synthetic Methods
Hot Paper
Synthesis of gem-Difluorocyclopropa(e)nes and O-, S-, N-, and P-
Difluoromethylated Compounds with TMSCF2Br**
Lingchun Li, Fei Wang, Chuanfa Ni, and Jinbo Hu*
Selective incorporation of fluorine atoms or fluorinated
moieties into organic molecules has become a routine and
powerful strategy in drug design and new functional-material
development.[1] Among various fluorinated moieties that are
employed to modify the property of a molecule, difluoro-
methylene (-CF2-) and difluoromethyl (-CF2H) groups are
two of the most prevailing ones.[1,2] The past decade has
witnessed an increasing demand for structurally diverse gem-
difluorocyclopropa(e)nes (A) and heteroatom difluoro-
methyl compounds (B).[3] Although these compounds can
be synthesized in various ways,[4,5] the difluoromethylenation
of alkenes/alkynes and difluoromethylation of heteroatom
Scheme 1. Examples of difluorocarbene sources and their application.
nucleophiles with a difluorocarbene reagent are the most
widely used approaches.[1a] On one hand, the reactions of
difluorocarbene with all but the most electron-rich alkynes/
alkenes usually proceed at sufficiently high temperatures to
overcome their substantial activation barriers.[4a] On the other
hand, the reactions of difluorocarbene with heteroatom
nucleophiles are relatively insensitive to the reaction temper-
atures. However, an alkaline base (such as KOH) is usually
needed to activate the pronucleophiles (Nu-H) by deproto-
nation.[6–11] These interesting and unique features of difluoro-
carbene chemistry have led to the extensive studies of various
reagents which are suitable to generate difluorocarbene
under various conditions (Scheme 1).
However, a major limitation of most of the difluorocar-
bene sources is that they focus on only one type of reaction,
either [2+1] cycloaddition with alkenes/alkynes under non-
basic conditions (Category A)[12–18] or a-addition with Nu-H
under basic conditions (Category C).[6–11] Although diflu-
orocarbene generated from FSO2CF2CO2H[19] and
FSO2CF2CO2TMS (TFDA; Category B)[20] under nonbasic
conditions is reactive towards both alkenes/alkynes and Nu-
H, the synthesis of difluoromethyl compounds with these
reagents is subject to low yields[19] or narrow substrate
scope.[20b–d] As the most commonly used reagent for heter-
HFPO=hexafluoropropylene oxide, TMS=trimethylsilyl, Ts=tosyl.
oatom difluoromethylation, HCF2Cl (Category B) itself is an
ozone-depleting substance (ODS) and its [2+1] cycloaddition
only works with electron-rich alkenes.[21] Sodium chlorodi-
fluoroacetate (Category B) has found practical applications in
both gem-difluorocyclopropanation (usually at 1808C)[22a,b]
and O and N difluoromethylation (> 808C).[22c,d] However,
the reactions suffer from disadvantages such as high temper-
atures or large excess of reagent. Although TMSCF2Cl is
arguably one of the most versatile difluorocarbene
reagents,[23] its preparation from ozone-depleting BrCF2Cl[24]
makes its wide application less attractive. Therefore, the
development of an operationally simple and environmentally
benign difluorocarbene precursor which is effective with
a broad substrate scope under relatively mild conditions is
highly desirable. Herein, we report the use of (bromodiflu-
oromethyl)trimethylsilane (TMSCF2Br; 1)[25] as a general
difluorocarbene source for the difluoromethylenation of
alkenes/alkynes initiated by a bromide salt as well as the
difluoromethylation of O-, S-, N-, and P-nucleophiles pro-
moted by the alkaline bases.
Our research started with the development of a Freon-
free method to prepare TMSCF2Br (1). We found that 1 could
be obtained by an extremely fast halogen–exchange reaction
between TMSCF3 (Ruppert–Prakash reagent) and BBr3.
Meanwhile, dibromofluoro- and tribromomethylated silanes
were also produced in varying yields under different reaction
conditions. TMSCF2Br (1) was isolated in 52% yield by
reacting 1.0 equivalent of TMSCF3 and 0.4 equivalent of BBr3
at 158C for 2 minutes [Eq. (1)]. Prolonging reaction time
could result in a decrease of the yield of 1. Moreover, heating
the mixture of N-bromosuccinimide (NBS)[26] and TMSCF2H
[*] L. Li,[+] Dr. F. Wang,[+] Dr. C. Ni, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai, 200032 (China)
E-mail: jinbohu@sioc.ac.cn
[+] These authors contributed equally to this work.
[**] Support of our work by the National Basic Research Program of
China (2012CB215500 and 2012CB821600), the National Natural
Science Foundation of China (20825209 and 21202189), and the
Chinese Academy of Sciences is gratefully acknowledged.
TMS=trimethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306703.
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could also afford 1 in 75% yield [Eq. (2)].[27] However,
TMSCF2Cl could not be prepared using similar methods
because of the sluggish reaction between TMSCF3 and BCl3,
and the undesired chlorination of the methyl group (CH3) in
TMSCF2H by N-chlorosuccinimide (NCS).
Table 1: Difluoromethylenation of various alkynes 2 and alkenes 4 using
1.[a]
À
We first carried out the difluoromethylenation of C C
multiple bonds with 1. In a previous report, the unoptimized
reaction between the alkyne 2a and 1 catalyzed by tetrabu-
tylammonium chloride gave the gem-difluorocyclopropene
3a in only 67% yield (based on 19F NMR spectroscopy).[23a] In
this research, we observed that tetrabutylammonium bromide
(TBAB) was a better catalyst (Scheme 2; for details, see the
Scheme 2. Screen of reaction conditions for the difluoromethylenation
of alkyne 2a using 1.
Supporting Information). When the reaction employing
2.0 equivalents of 1 was performed in a sealed tube at
1108C for 2 hours, 3a was obtained in 85% yield (Condi-
tion A). A decrease of the amount of 1 from 2.0 to
1.5 equivalents gave a higher yield of 3a (Condition B). The
relatively lower yield of 3a with 2.0 equivalents of 1 probably
arose from the formation of the unstable bicyclobutane
through an additional [2+1] cycloaddition.[14b] A comparison
of the reaction temperatures (Conditions B and C) showed
that a high temperature is beneficial for this reaction. Finally,
we chose Condition B to perform most of the reactions with
alkynes.
[a] All reactions were performed on 0.5 mmol scale in a pressure tube.
Yields given refer to the yields of isolated product. [b] Yields within
parentheses were determined by 19F NMR spectroscopy using an internal
standard. [c] Yield of product after recrystallization. [d] Reactions were
performed at 808C. [e] d.r.>99:1. [f] Used 2.5 equiv of 1.
As shown in Table 1, 1 could react with a variety of
structurally diverse alkynes and alkenes. Both mono- and
disubstituted alkynes were readily converted into gem-
difluorinated cyclopropenes (3b–k) in high yields. Not only
alkynes with electron-donating groups, but also those with
electron-withdrawing groups could undergo the reactions.
Note that propiolates and alkynyl sulfides are also reactive
under these reaction conditions (3g–i), and this had never
been demonstrated in the previously reported difluoro-
methylenation of alkynes. Although alkenes are known to
be less reactive than alkynes towards difluorocarbene,[28] our
protocol could be extended to various alkenes by simply
prolonging the reaction time to 4 hours. The [2+1] cyclo-
addition of the aryl- and alkyl-substituted alkenes with
difluorocarbene proceeded smoothly, thus affording the
gem-difluorocyclopropanes 5a–j in moderate to excellent
yields. In the cases of alkenes bearing an OH, only difluoro-
carbene under the neutral conditions, wherein the nucleo-
philic ROÀ could not be generated. It is remarkable that the
electron-deficient alkene such as benzyl acrylate was also
successfully difluoromethylenated to give 5k in 43% yield.
Subsequently, we investigated the difluoromethylation of
heteroatom nucleophiles with 1 by using the phenol 6a as
a model substrate to optimize the reaction conditions
(Table 2). Initial results with CH3CN as the solvent and
KOH aqueous solution as the base showed that 1 was reactive
towards 6a even at 08C, and the reaction was complete within
0.5 hours (entries 1–3). Such a low reaction temperature and
short reaction period indicate that this protocol would
tolerate base-sensitive functional groups. A screening of the
solvents revealed that CH2Cl2 was the best choice among
various solvents (entries 4–11). As for the base, in addition to
KOH, NaOH was also suitable for this reaction (entry 12).
However, K2CO3 was not efficient to activate 1 in a short
period of time because of its weak basicity (entry 13). Finally,
=
methylenation of the C C bond was observed (5i and 5j).
This result indicates that the OH is inert towards difluoro-
2
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Table 2: Screen of reaction conditions for the difluoromethylation of
phenol 6a using 1.[a]
Table 3: Difluoromethylation of O-, S, and N nucleophiles using 1.[a]
Entry
6a/1/Base[b]
Base[c]
Solvent
T [8C]
Yield [%][d]
1
2
3
4
5
6
7
8
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:2.5:8.0
1.0:1.5:8.0
1.0:2.0:3.0
1.0:2.0:6.0
1.0:2.0:10.0
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaOH
K2CO3
KOH
KOH
KOH
KOH
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
PhCH3
DCE
Et2O
THF
DMF
DME
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50
RT
0
0
RT
0
0
0
0
0
0
0
0
0
0
0
0
44 (>99)
40 (>99)
63 (>99)
84 (>97)
78 (>99)
74 (95)
77 (93)
65 (>99)
28 (>99)
0 (>99)
23 (>99)
84 (78)
28 (34)
77 (>99)
66 (82)
9
10
11
12
13
14
15
16
17
83 (>97)
85 (>99)
[a] Reactions were performed on 0.5 mmol scale. [b] Molar ratio.
[c] Concentration of the bases used: KOH (20 wt%); NaOH (15 wt%);
K2CO3 (38 wt%). [d] Yields were determined by 19F NMR spectroscopy
using PhCF3 as an internal standard. Conversions of 1 are given within
the parentheses. DME=1,2-dimethoxyethane; DCE=1,2-dichloro-
ethane.
using a 20% KOH aqueous solution as the base and CH2Cl2 as
the solvent, the optimal molar ratio of 6a, 1, and KOH was
identified as 1.0:2.0:6.0 (entry 16).
With the optimized reaction conditions in hand (Table 2,
entry 16), we studied the substrate scope of this heteroatom
difluoromethylation (Table 3). The results for O nucleophiles
showed that this reaction is compatible with both phenols and
alcohols (7b–r). The difluoromethylation of mono- and
multisubstituted phenols occurred in moderate to excellent
yields and with high functional-group tolerance (7b–n). Both
electron-rich functional groups such as ether (7b and 7e),
amide (7m), and alkenyl (7n), and electron-deficient ones
such as nitro (7c), nitrile (7d), ester (7i), carbonyl (7j and 7r),
and aldehyde (7k and 7l) are amenable to this reaction. The
chemoselective reaction of difluorocarbene with OH rather
=
=
than with the C C bond (see 7n and 7r) indicates that the C
C bond is less reactive towards difluorocarbene under basic
conditions, which is interesting especially when compared
with the chemoselective reactions affording 5i and 5j (see
Table 1). Furthermore, the difluoromethylation of a primary
alcohol using 1 afforded the corresponding difluoromethyl
ether in moderate yields (7p and 7q). This protocol is suitable
for the late-stage O difluoromethylation of complex mole-
cules. (+)-d-Tocopherol underwent the difluoromethylation
reaction to give the difluoromethyl ether 7o in 70% yield.
The secondary alcohol pregnenolone reacted to form 7r in
synthetically useful yields. The S difluoromethylation with
1 could also be achieved under similar reaction conditions
(9a–k). Various aryl thiols with electron-donating or electron-
[a] All reactions were performed on 0.5 mmol scale. Yields given refer to
those of isolated products. [b] Yields within parentheses were deter-
mined by 19F NMR spectroscopy using an internal standard. [c] Yield of
isolated product when 1 (4.0 equiv) and KOH (10 equiv) were used.
[d] The starting material was PhSO2Na.
withdrawing substituents and alkyl thiols afforded difluoro-
methyl thioethers in good to excellent yields (9a–e and 9i–k).
The heteroarylthiols benzo[d]thiazole-2-thiol and 1-phenyl-
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1H-tetrazole-5-thiol were difluoromethylated regioselectively
at the S atoms (9 f and 9g). It is noteworthy that the sulfinates
were also reactive substrates, for example, the reaction of
phenylsulfinate gave the difluoromethyl sulfone 9h in 61%
yield.
In contrast with the difluoromethylation of (thio)phenols
and (thio)alcohols, the difluoromethylation of heterocyclic
amines with 1 is more complicated. Although several
imidazoles could undergo the reaction, the yields of the N-
difluoromethyl compounds 11a–c were only moderate (31–
49%; see Table 3). The low yields presumably arose from
a further difluoromethylation of the desired products, thus
forming unstable difluoromethyl ammonium salts. The reac-
tion of 1H-benzo[d]-1,2,3-triazole (10d) and 5-phenyl-1H-
tetrazole (10e) provided the N-difluoromethyl products in
high yields. However, two separable regiomers, 11 e and 11e’,
were obtained in the latter case (see Table 3). In the case of
the pyrazolone 10 f, both N- and O-difluoromethylation
products 11 f and 12 f, respectively, were obtained when the
reaction was conducted at 08C [Eq. (3)].[29] In the case of the
Scheme 3. Difluoromethylation of the hydrophosphine oxides 14 using
1.
Scheme 4. Proposed mechanism for difluoromethylation of hetero-
atom nucleophiles using 1.
(such as HOÀ) and subsequent a elimination of a bromide
ion. The protonation of the bromodifluoromethyl anion
À
(BrCF2 ) at 08C should be much slower than its fragmenta-
tion to difluorocarbene, as was determined by the observation
of only trace amounts (ca. 1% based on 19F NMR spectros-
copy) of HCF2Br during the difluoromethylation of 6a. The
formed HCF2Br, if any, would also participate in the reaction
in the presence of base.
In conclusion, we have developed a highly efficient
method for the difluoromethylenation of C–C multiple
bonds and difluoromethylation of heteroatom nucleophiles
with TMSCF2Br (1) as the single difluorocarbene source. This
method allows gem-difluorocyclopropa(e)nes and O-, S-, N-,
and P-difluoromethylated compounds to be prepared using
very simple procedures. The bromide catalyzes the fragmen-
tation of 1 at a higher temperature (1108C) to generate
difluorocarbene, which is reactive towards both electron-rich
and electron-deficient alkynes and alkenes. Compared with
the difluoromethylenation protocols using the common
pyrazolidinone 10g, the reaction at 08C not only gave the
heterocyclic ether 12g, but also the ring-opening product 13g
[Eq. (4)]. The formation of 13g is proposed to proceed by
reagent TFDA,[20] and the newly developed TMSCF3 and
[14]
FSO2CF2CO2Me (MDFA),[16] this homogeneous reaction is
much safer and more convenient for large-scale application
because of the avoidance of the gaseous by-products. The
hydroxyl-ion-promoted fragmentation of 1 at a lower temper-
ature (08C) facilitates the difluoromethylation of (thio)phe-
nols with broad functional-group tolerance. The mild reaction
conditions of this reaction are also applicable for the
difluoromethylation of (thio)alcohols, sulfinates, heterocyclic
amines, and even hydrophosphine oxides. Since 1 is readily
available from TMSCF3 but more robust than the latter,[30]
this new synthetic method is expected to found many
applications in the synthesis of difluoromethylene- and
difluoromethyl-containing compounds.
a Hofmann elimination of the 1-difluoromethyldihydropyr-
azolium salt of 12g with subsequent hydrolysis of the N’-CF2H
group (for details, see the Supporting Information).
To further extend the synthetic utility of 1, we tested the
reactivity of P nucleophiles. It was found that the phosphinite
anions were less reactive than any other heteroatom nucle-
ophile investigated. When a weak base K2CO3 was used
instead of KOH, the hydrolysis of difluorocarbene was
minimized, and the reactions of the hydrophosphine oxides
14a and 14b proceeded smoothly, thus giving difluoromethyl
phosphine oxides 15a and 15b in 82 and 50% yield,
respectively (Scheme 3).
Concerning the mechanism of the difluoromethylation of
heteroatom nucleophiles with 1, the reaction is believed to
occur by an anionic chain reaction involving the addition of
difluorocarbene to the nucleophile anion (NuÀ)
(Scheme 4).[28] The generation of difluorocarbene from 1 is
postulated to proceed through initial desilylation with a base
Received: July 31, 2013
Published online: && &&, &&&&
Keywords: carbenes · cycloaddition · heterocycles · fluorine ·
.
synthetic methods
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[14] a) F. Wang, T. Luo, J. Hu, Y. Wang, H. S. Krishnan, P. V. Jog, S. K.
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
Angewandte
Communications
Communications
Synthetic Methods
Two-in-one: Me3SiCF2Br is an efficient
difluorocarbene source and is compatible
with both neutral and aqueous basic
conditions. Bromide-ion-initiated [2+1]
cycloaddition with alkenes/alkynes and
hydroxide-ion-promoted a-addition with
(thio)phenols, (thio)alcohols, sulfinates,
heterocyclic amines, and H-phosphine
oxides give the corresponding gem-
difluorinated compounds with broad
functional-group tolerance.
L. Li, F. Wang, C. Ni,
J. Hu*
&&&& — &&&&
Synthesis of gem-
Difluorocyclopropa(e)nes and O-, S-, N-,
and P-Difluoromethylated Compounds
with TMSCF2Br
6
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!