Efficient and direct nucleophilic difluoromethylation of carbonyl compounds and imines with Me3SiCF2H at ambient or low temperature

Article abstract of DOI:10.1021/ol202208b

Since 1995, Me₃SiCF₂H has been widely believed to be an inefficient difluoromethylating agent, which requires harsh reaction conditions to cleave its rather inert Si-CF₂H bond. However, it has now been found that, by using

Full text of DOI:10.1021/ol202208b

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5342–5345
Efficient and Direct Nucleophilic
Difluoromethylation of Carbonyl Compounds
and Imines with Me3SiCF2H at Ambient or
Low Temperature
Yanchuan Zhao, Weizhou Huang, Ji Zheng, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China
jinbohu@sioc.ac.cn
Received August 15, 2011
ABSTRACT
Since 1995, Me3SiCF2H has been widely believed to be an inefficient difluoromethylating agent, which requires harsh reaction conditions to cleave
its rather inert SiÀCF2H bond. However, it has now been found that, by using a proper Lewis base activator, Me3SiCF2H can efficiently
difluoromethylate various aldehydes, ketones, and imines to give the corresponding products in good to excellent yields at room temperature or
even at À78 °C.
As the fluoroorganics have found increasing applica-
tions in different fields, such as pharmaceuticals, biochem-
istry, and material science, selectively incorporating a
fluorinated moiety into organic molecules has become a
subject of intense investigation.1 Among various fluori-
nated moieties, the difluoromethyl group (CF2H) is of
particular interest because it is known to be isosteric to a
carbinol group (CH2OH) and behaves as a hydrogen donor
through hydrogen bonding.2 Thus, the difluoromethylated
analogues of biologically active compounds are strong
candidates for pharmaceuticals due to the unique charac-
ter of the difluoromethyl group as a lipophilic bioisostere
of CH2OH.3 Nucleophilic fluoroalkylation has been pro-
ven to be a convenient method for the preparation of
fluorinated compounds.1,4 However, although direct nu-
cleophilic trifluoromethylation reactions are widely used
with the RuppertÀPrakash reagent (Me3SiCF3),4 methods
for direct nucleophilic difluoromethylation (that is, the
direct transfer of a CF2H group) are scarce.3 Difluoro-
methyl organometallic reagents, such as (CF2H)Cu,
(CF2H)2Cd, and (CF2H)2Zn, were unable to efficiently
undergo nucleophilic difluoromethylation of carbonyl
compounds and imines.5 In 1995, Fuchikami et al.
(1) (a) Hiyama, T. Organofluorine Compounds: Chemistry and Appli-
cations; Springer: New York, 2000. (b) Banks, R. E.; Smart, B. E.; Tatlow,
J. C. Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994. (c) M€uller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (d) Hagmann, W. K. J. Med. Chem. 2008, 51,
4359. Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305. (f) Ojima, I.
Fluorine in Medicinal Chemistry and Chemical Biology; Wiley: Chichester,
(3) See a recent review on di- and monofluoromethylation reactions:
Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465.
(4) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (b)
Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613. (c) Prakash,
G. K. S.; Mandal, M. J. Fluorine. Chem. 2001, 112, 123.
(5) (a) Hartgraves, G. A.; Burton, D. J. J. Fluorine Chem. 1988, 39,
425. (b) Burton, D. J.; Hartgraves, G. A.; Hsu, J. Tetrahedron Lett. 1990,
31, 3699. (c) Burton, D. J.; Hartgraves, G. A. J. Fluorine Chem. 2007,
128, 1198.
ꢀ
ꢀ
2009. (g) Begue, J. P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley-VCH: Weinheim, 2008. (h) Uneyama, K.
Organofluorine Chemistry; Blackwell: Oxford, 2006. (i) Uneyama, K. J.
Fluorine Chem. 2008, 129, 550.
(2) (a) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60,
1626. (b) Sasson, R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769 and
references therein. (c) Li, Y.; Hu, J. Angew. Chem. 2005, 117, 6032. (e)
Angew. Chem., Int. Ed. 2005, 44, 5882. (d) Prakash, G. K. S.; Weber, C.;
Chacko, S.; Olah, G. A. Org. Lett. 2007, 9, 1863.
r
10.1021/ol202208b
Published on Web 09/12/2011
2011 American Chemical Society

reported that, unlike the RuppertÀPrakash reagent, both
PhMe2SiCF2H and Me3SiCF2H reagents were unable to
undergo nucleophilic difluoromethylation of carbonyl
compounds at room temperature.6 They found that a
harsh reaction condition (100 °C) was required for the
KF-initiated difluoromethylation withPhMe2SiCF2H and
Me3SiCF2H reagents, and the reaction only worked for
some aldehydes, with the product yields being generally low
(20À35%) for ketones.6 Based on molecular orbital calcula-
tion on (difluoromethyl)- and (trifluoromethyl)fluorotri-
methylsilicates, they found that the bond order of the
SiÀCF2H bond (0.436) is significantly higher than that of
the SiÀCF3 bond (0.220), which supports their conclusion
that cleavage of the SiÀCF2H bond is more difficult than that
of the SiÀCF3 bond and, therefore, “more elevated condi-
tions should be required”.6 Since Fuchikami’s report, difluor-
omethylsilanes (such as Me3SiCF2H andPhMe2SiCF2H) are
generally believed to be inefficient difluoromethylating
agents, and their synthetic utility was largely ignored over
the past 16 years.1i,3,7a Currently, difluoromethyl phenyl
sulfone (PhSO2CF2H)7a as well as functionalized difluor-
Me3SiCF2H (1) can be prepared by Mg-mediated difluor-
omethylation of chlorotrimethylsilane with PhSO2CF2H.8a
Recently, Igoumnov et al. elegantly reported that compound
1 can be readily prepared from commercially available
RuppertÀPrakash reagent (Me3SiCF3) and NaBH4 in
70% isolated yield.8b With reagent 1 in hand, we first
examined its reaction with aldehydes, by using anisaldehyde
(2a) as a model substrate in the presence of various Lewis
base initiators at room temperature (Table 1). As reported
previously,6 KF alone could not cleave the SiÀCF2H bond in
DMF at room temperature (Table 1, entry 1). However, in
the presence of KF/18-crown-6, tetrabutylammonium di-
fluorotriphenylsilicate (TBAT), or CsF, the reaction pro-
ceeded smoothly at room temperature (entries 2À4). Highly
polar solvent DMF was found to be much better than THF
and toluene for the reaction, as the reaction between 1 and 2a
could not occur in THF and toluene when TBAT was used as
an initiator (entries 6 and 7).
Interestingly, tBuOK was found to be able to cleave the
SiÀCF2H bond more efficiently in THF than various
fluoride salts (entries 6, 8 and 9), and this observation
could be attributed to the better solubility of tBuOK in
THF than those of fluoride salts. However, CsF was found
to be the best initiator (entries 4 and 5) when DMF was
used as a solvent. After a quick optimization of the
reactant ratio, we were able to isolate 2,2-difluoro-1-
(4-methoxyphenyl)ethanol (3a) in 91% yield when the
reactant ratio 1/2a/CsF = 2.0:1.0:0.13 (Table 1, entry 5).
By using the optimized reaction conditions (as those in
Table 1, entry 5) as the standard, we next examined the
substrate scope of this difluoromethylation reaction be-
tween 1 and various aldehydes 2. As shown in Table 2,
various aldehydes 2 were treated with 1, smoothly giving
the corresponding difluoromethyl carbinols 3 in good to
excellent yields. This method tolerates various substrates
on aryl aldehydes. It was found that aldehydes with
electron-donating groups gave slightly higher yields than
those with electron-withdrawing groups (entries 1À8),
which is consistent with the initiating ability of the gener-
ated carbinolate species [R1(CF2H)(H)COÀ] (please note
that the reaction is autocatalytic, which is similar to the
reactions with Me3SiCF34a). The reaction is also amenable
toboth aliphatic and conjugated aldehydes (entries 10À12).
It is important to mention that a similar reaction with
7b
osilanes Me3SiCF2SiMe3 and PhXCF2SiMe3 (X =
SO2,7cÀe S,7fÀi Se7j,k) are usually employed as indirect
nucleophilic difluoromethylation reagents, and an addi-
tional step for the removal of the functional or auxiliary
group(s) is required after the fluoroalkylation.3
In our continuing effort to develop efficient nucleophilic
difluoromethylation methods,7a,cÀh we have been inter-
ested in seeking a general and direct nucleophilic difluor-
omethylation method for carbonyl compounds and imines
under mild reaction conditions. Herein, we wish to disclose
our remarkable success in the long-sought-after, efficient,
and direct nucleophilic difluoromethylation of aldehydes,
ketones, and imines with 1 at ambient or even low tem-
perature (À78 °C).
Table 1. Survey of Reaction Conditions
Me3SiCF2H (1)
initiator
(mol %)a
(6) Hagiwara, T.; Fuchikami, T. Synlett 1995, 717.
entry
(equiv)a
solvent 3a (%)b
(7) (a) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921. (b)
Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.;
Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572. (c) Ni, C.; Hu, J.
Tetrahedron Lett. 2005, 46, 8273. (d) Liu, J.; Ni, C.; Wang, F.; Hu, J.
Tetrahedron. Lett. 2008, 49, 1605. (e) Zhu, L.; Li, Y.; Zhao, Y.; Hu, J.
Tetrahedron Lett. 2010, 51, 6150. (f) Prakash, G. K. S.; Hu, J.; Wang, Y.;
Olah, G. A. J. Fluorine Chem. 2005, 126, 527. (g) Pohmakotr, M.;
Panichakul, D.; Tuchinda, P.; Reutrakul, V. Tetrahedron 2007, 63, 9429.
(h) Li, Y.; Hu, J. J. Fluorine Chem. 2008, 129, 382. (i) Bootwicha, T.;
Panichakul, D.; Kuhakarn, C.; Prabpai, S.; Kongsaeree, P.; Tuchinda,
P.; Reutrakul, V.; Pohmakotr, M. J. Org. Chem. 2009, 74, 3798. (j) Qin,
Y.-Y.; Qiu, X.-L.; Yang, Y.-Y.; Meng, W.-D.; Qing, F.-L. J. Org. Chem.
2005, 70, 9040. (k) Mizuta, S.; Shibata, N.; Ogawa, S.; Fujimoto, H.;
Nakamura, S.; Toru, T. Chem. Commun. 2006, 2575.
1
2
3
4
5
6
7
8
9
1 (1.3)
1 (2.0)
1 (1.3)
1 (1.3)
1 (2.0)
1 (1.3)
1 (1.3)
1 (1.3)
1 (2.0)
KF (130)
DMF
0
88
75
87
91
0c
KF/18-crown-6 (100) DMF
TBAT (20)
CsF (130)
CsF (13)
DMF
DMF
DMF
THF
CsF (130)
CsF (130)
TBAT (20)
tBuOK (200)
toluene
THF
0c
0c
THF
63
a The equivalentis relative to that of 2a. b Isolated yield. c Determined
by 19F NMR analysis of the crude reaction mixture using PhCF3 as an
internal standard.
(8) (a) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68,
4457. (b) Tyutyunov, A. A.; Boyko, V. E.; Igoumnov, S. M. Fluorine
Notes, 2011, 74, 1; http://notes.fluorine1.ru/public/2011/1_2011/letters/
letter2.html.
Org. Lett., Vol. 13, No. 19, 2011
5343

(difluoromethyl)dimethyl(phenyl)silane (PhMe2SiCF2H)6
also gave a good yield of the difluoromethylated product
under the current reaction conditions (Table 2, entry 1).
limitations of this nucleophilic difluoromethylation reaction
between 1and ketones 4. It was found that the reactions with
nonenolizable ketones (such as biaryl ketones 4a and 4b)
gave CF2H-carbinols in excellent yields (Scheme 1, eqs 1
and 2), whereas the reaction with enolizable methyl ke-
tones (such as acetophenone) failed to give the correspond-
ing products due to the labile enolization and subsequent
aldol reaction of these substrates under the basic reaction
conditions. It should be mentioned that a stoichiometric
amount of tBuOK must be employed, which suggests that
tBuOK possesses better activating power for SiÀCF2H
bond cleavage than the in situ generated difluoromethyl
carbinolate species. This observation is different from the
autocatalyzed nucleophilic difluoromethylation of alde-
hydes (see Table 2) as well as the autocatalyzed trifluoro-
methylation of aldehydes and ketones with Me3SiCF3.4a
Table 2. Direct Nucleophilic Difluoromethylation of Various
Aldehydes 2 with (Difluoromethyl)trimethylsilane 1
Scheme 1. Difluoromethylation of Ketones 4
We also found that t-BuOK/THF was the best initiating
system to facilitate the nucleophilic difluoromethylation of
Ellman’s N-tert-butylsulfinyl imines9 with 1. With an
optimized reaction condition (reactant ratio 1/6/tBu
OK = 2.9:1.0:2.9), we examined the scope of the current
direct diastereoselective nucleophilic difluoromethylation
of N-tert-butylsulfinyl imines 6. As shown in Table 3, a
variety of structurally diverse N-tert-butylsulfinyl imines 6
could be efficiently difluoromethylated by 1 at À78 °C,
giving the corresponding products 7 in good to excellent
yields and with good diastereoselectivities (dr = 80:20À93:7).
The observed lower diastereoselectivity (compared with
corresponding nucleophilic trifluoromethylation using
Me3SiCF310) may be due to the smaller steric hindrance
of the difluoromethyl group (CF2H) than the trifluoro-
methyl group (CF3). The relativeconfiguration of themain
isomer of product 7a was confirmed by comparison with
the previous report,2c and the configurations of other
products 7bÀ7h were assigned by analogy.
a In all cases, 2.0 equiv of 1 and 13 mol % CsF were used. b Isolated
yield. c 1.5 equiv of PhMe2SiCF2H was used as a difluoromethylation
reagent. d 1.5 equiv of TBAT was used as an initiator.
Encouraged by the above results, we next examined the
difluoromethylation of ketones with reagent 1. Similar to
Fuchikami’sresults,6 when we treatedketoneswith reagent
1 under the same reaction conditions as those described in
Table 2, only low yields of product (30À40%) were
obtained. Careful examination of the reaction products
showed that the Me3SiCF2H/CsF/DMF system tends to
undergo irreversible nucelophilic difluoromethylation of
the carbonyl group of DMF, which causes competition
especially when electrophilicity of the substrate is low.
THF and other non-base-sensitive solvents seemed to be
beneficial to suppress the side reactions; however, CsF and
TBAT could not induce the reaction in those solvents
(Table 1, entries 6À8). As mentioned above (Table 1, entry 9),
certain O-initiators are more efficient in cleaving the
SiÀCF2H bond thanF-initiatorsin THF (Table 1, entry 9),
and therefore, various O-initiators were tried and we were
pleased to find that the reaction beween 1 and ketones 4
could proceed smoothly in the presence of tBuOK in THF
at À78 °C. Under the optimized reaction conditions
(1/4/tBuOK = 2.9:1.0:2.9), we examined the scope and
To demonstrate further synthetic application of the
present difluoromethylation with reagent 1 under mild
conditions, we applied it in the synthesis of tricylic com-
pound 9 (Scheme 2), which is the key structural motif of a
useful HIV reverse transcriptase inhibitor. The trifluoro-
methyl analogue of 9 has been easily prepared by using
(9) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600.
(10) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 40, 589.
5344
Org. Lett., Vol. 13, No. 19, 2011

obtain by using previously reported methods6,12) in good to
excellent yields (Scheme 3). These results suggest that, by
applying a similar protocol, a wide range of biologically
important difluoroorganics can be readily prepared with
corresponding (difluoroalkyl)silanes.
Table 3. Direct Nucleophilic Difluoromethylation of N-tert-
Butylsulfinyl Imines 6 with (Difluoromethyl)trimethylsilane 1
Scheme 3. Direct Nucleophilic 1,1-Difluoroethylation of Alde-
hyde, Ketone, and N-tert-Butylsulfinyl Imine with
(1,1-Difluoroethyl)trimethylsilane 10
In conclusion, we have developed an efficient and direct
nucleophilic difluoromethylation of aldehydes, ketones,
and N-tert-butylsulfinimines with Me3SiCF2H (1). The
reactivity of Me3SiCF2H as a nucleophile has been dis-
closed in detail. We found that the use of a proper Lewis
base and solvent plays a crucial role in activating the
SiÀCF2H bond at ambient or even low temperature. The
present synthetic protocol not only paves the way for a
general and direct nucleophilic difluoromethylation but
also can be extended to other fluoroalkylations with
corresponding fluoroalkylsilanes (as demonstrated in
Scheme 3). Given the high importance of introducing of
the CF2H group into organic molecules,3 the easy prepra-
tionofreagent 1 from commerciallyavailable Me3SiCF3,8b
and the practical simplicity of the reaction procedure, the
present difluoromethylation method promises to find
many applications in life science and material science
related fields.
a In all entries, 2.9 equiv of 1 and 2.9 equiv of tBuOK were used.
b Overall isolatedyield oftwo diastereomers. c Diastereometric ratios were
determined by 19F NMR spectroscopy of the crude reaction mixture.
Me3SiCF3 reagent, while 9 was previously obtained through
a long synthetic procedure partially due to the lack of an
efficient and direct method to introduce a difluoromethyl
group (CF2H).11 We found that by using the reactant ratio
1/8/tBuOK = 2.9:1.0:2.9, compound 9 could be obtained
in 79% yield directly from compound 8 (Scheme 2).
Scheme 2. Synthesis of a Tricyclic Compound 9 [SEM = 2-
(Trimethylsilyl)ethoxymethyl]
Acknowledgment. Dedicated to Professor G. K. Surya
Prakash (University of Southern California) for his pio-
neering contribution of using (fluoroalkyl)silanes as nu-
cleophilic fluoroalkylating agents. J.H. thanks Professor
Alexander Dilman (Zelinsky Institute of Organic Chem-
istry, Russian Academy of Sciences) for helpful discus-
sions. Financial support by the National Natural Science
Foundation of China (20825209, 20832008) and the Chi-
nese Academy of Sciences is gratefully acknowledged.
This Lewis base activation (in a proper solvent) protocol
was also applicable to other (difluoroalkyl)silane reagents.
For instance, a direct nucleophilic 1,1-difluoroethylation
reaction with (1,1-difluoroethyl)trimethylsilane 10 worked
equally well under similar reaction conditions to afford the
corresponding products (which is otherwise very difficult to
Supporting Information Available. Experimental proce-
dures, compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Johnson, B. L.; Patel, M.; Rodgers, J. D.; Wang, H. S. WO
2001029037.
(12) Mogi, R.; Morisaki, K.; Hu, J.; Prakash, G. K. S.; Olah, G. A. J.
Fluorine Chem. 2007, 128, 1098.
Org. Lett., Vol. 13, No. 19, 2011
5345