Organocatalytic direct difluoromethylation of aldehydes and ketones with TMSCF2H

Article abstract of DOI:10.1039/c5ra04472c

An organic Lewis base promoted direct difluoromethylation reaction of carbonyl compounds with Me₃SiCF₂H has been studied. The Schwesinger's superbase can efficiently activate the Si-CF₂H bond and initiate the difluoromethy

Full text of DOI:10.1039/c5ra04472c

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Organocatalytic direct difluoromethylation of
aldehydes and ketones with TMSCF2H†
Cite this: RSC Adv., 2015, 5, 35421
b
b
b
b
Guang-Fen Du,ab Ying Wang, Cheng-Zhi Gu, Bin Dai and Lin He
*
*
Received 13th March 2015
Accepted 13th April 2015
DOI: 10.1039/c5ra04472c
www.rsc.org/advances
An organic Lewis base promoted direct difluoromethylation reaction of remove the auxiliary groups of the diuoromethylated adducts.
carbonyl compounds with Me3SiCF2H has been studied. The Schwe- Silylated reagent TMSCF2H can be easily prepared from Rup-
singer's superbase can efficiently activate the Si–CF2H bond and pert–Prakash reagent (TMSCF3).8 In 1995, Fuchikami and
initiate the difluoromethylation of aldehydes and ketones under very Hagiwara documented9 that KF can initiate the direct diuor-
mild conditions, producing difluoromethyl adducts in 42–99% yields.
omethylation reaction of TMSCF2H and carbonyl compounds.
However, unlike the analogous Si–CF3 bond, harsh reaction
conditions are required for the cleavage of the relatively inert Si–
CF2H bond, which restricts the applications of this diuor-
omethylating reagent for long time. Until recently, Hu and co-
workers10 found that CsF or stoichiomeric t-BuOK can activate
the Si–CF2H bond efficiently and initiate the diuor-
omethylation of carbonyl compounds and imines. However, to
the best of our knowledge, no other catalysts have been devel-
oped for the activation of TMSCF2H and efficient protocol for
the direct diuoromethylation is still highly desirable.
Organouorine compounds have found widespread applica-
tions in pharmaceuticals, agrochemicals and medicinal chem-
istry.1 In particular, the introduction of uorinated moieties
into organic molecules has become a powerful strategy in new
drug discovery. As a result, tremendous efforts have been exer-
ted to develop efficient methodologies for the synthesis of u-
oroorganics.
Among
various
uorinated
moieties,
diuoromethyl group (CF2H) has attracted considerable atten-
tion in recent years.2 CF2H is isosteric to hydroxy group (OH)
and compared to OH and NH groups, this uorinated moiety
can serve as a lipophilic hydrogen bond donor through
hydrogen bonding.3 These unique properties make the CF2H
group to be particularly interesting with respect to the design of
biologically active molecules. However, compared to the exten-
sively studied triuoromethylation reactions,4 efficient methods
for the introduction of CF2H group are scarce. Similar with the
direct nucleophilic triuoromethylation reactions, the direct
diuoromethylation reaction is the most straightforward
method for the introduction of CF2H group into organic mole-
cules. However, diuoromethylated organometallic reagents are
inefficient for diuoromethylation of carbonyl compounds.5
In recent years, several organic Lewis bases such as Bu4N+
alkoxides,11 tris(2,4,6-trimethoxyphenyl)phosphine,12 sodium
phenoxide–phosphine oxides13 and N-heterocyclic carbenes14
have been utilized successfully for the activation of different
silylated reagents. As an important class of superbases, proa-
zaphosphatranes exhibit high reactivity toward the activation of
silylated nucleophiles and a variety of transformations have
been developed by Verkade and co-workers15 in the past decade.
As another important type of superbases, phosphazenes16 have
been applied successfully in deprotonative reactions.17
However, phosphazenes catalysed transformations of organo-
silanes are farless examined. Until recently, Kondo and co-
workers18 disclosed that phosphazene bases can be utilized to
activate several silylated nucleophiles efficiently. We envisioned
that phosphazenes and other organic Lewis bases can be
utilized to activate TMSCF2H to initiate the direct diuor-
omethylation reaction of carbonyl compounds. Herein, we
would like to disclose these interesting results.
Diuoromethyl
phenylsulfone6
and
several
diuor-
omethylsilanes7 can undergo indirect diuoromethylation with
carbonyl compounds, but additional reactions are needed to
aSchool of Chemical Engineering and Technology, Tianjin University, Tianjin 300072,
P. R. China
bSchool of Chemistry and Chemical Engineering, Shihezi University, Xinjiang Uygur
Autonomous Region, 832000, P. R. China. E-mail: db_tea@shzu.edu.cn; helin@
shzu.edu.cn; Fax: +86-993-2057270
Our study commenced with the reaction of TMSCF2H and p-
chlorobenzaldehyde. To our delight, we found that the reaction
proceed smoothly in the presence of 10 mol% t-Bu-P4 (4a),
producing diuoromethyl carbinol 3a in 52% yield aer 12 h
(Table 1, entry 1). Phosphazene bases 4b and 4c can also
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra04472c
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Table 1 Screening of reaction conditionsa
Table 2 Evaluation of aldehydesa
Entry
R
Time (h)
0.5
Product
Yieldb (%)
1
2
3a
3b
91
99
0.5
3
4
5
6
0.5
1
3c
3d
3e
3f
99
99
99
99
1
Entry
Conditions
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
4a, THF
4b, THF
4c, THF
12
12
12
72
72
72
72
12
0.5
2
52
34
18
11
12
<10
<10
0
91
73
48
23
<10
<10
63
1
5a, tBuOK, THF
5b, tBuOK, THF
5c, tBuOK, THF
5d, tBuOK, THF
6, THF
7
0.5
0.5
0.5
0.5
0.5
3g
3h
3i
92
92
99
99
99
9
4a, DMF
4b, DMF
4c, DMF
4a, PhCH3
4a, CH2Cl2
4a, CH3CN
4a, DMF
8
10
11
12
13
14
15c
2
12
12
12
12
9
a
b
1 (1.5 equiv.), 2a (1.0 equiv.). Isolated yield. c Using 5 mol% 4a.
10
11
3j
promote the addition reaction, but in relatively low efficiency
(Table 1, entries 2 and 3). To our surprise, N-heterocyclic car-
benes 5a–5d, which were proved to be highly efficient catalysts
for triuoromethylation of aldehydes,19 only showed very low
efficiency for diuoromethylation reaction of aldehydes (Table
1, entries 4–7). Whereas DBU can't catalyse the addition reac-
tion (Table 1, entry 8). The evaluation of other reaction media
indicated the high polar solvent of DMF was the best choice
with respect to the reaction yield (Table 1, entries 9–14).
Reduction of catalyst loading to 5 mol% led to dramatic
decrease of reaction rate (Table 1, entry 15).
3k
12
3
3l
95
13
14
3
1
3m
3n
88
99
With the optimized reaction conditions in hand, the
substrate scope and the generality of the reaction were subse-
quently investigated, and the results are summarized in Table 2.
Aromatic aldehydes bearing electron-withdrawing, -neutral, and
-donating groups can participate in the direct diuor-
omethylation reaction in excellent yields (Table 2, entries 1–6).
Additionally, the substituents on the ortho-, meta-, and para-
positions of the aromatic ring showed no obvious effects on the
reaction yields (Table 2, entries 7–11). Interestingly,
15c
16c
0.5
3
3o
3p
87
68
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Table 2 (Contd.)
Entry
17c
R
Time (h)
6
Product
Yieldb (%)
66
3q
Scheme 2 Proposed reaction mechanism.
18c
19c
6
3
3r
3s
72
95
cinnamaldehyde can also undergo the reaction smoothly to
produce 3u in 81% yield (Table 2, entry 21). However, for
aliphatic aldehyde 2v, the strong basicity of t-Bu-P4 can cause
undesired side reactions, which led to moderate yield of the
nal uorinated product (Table 2, entry 22).
20
2
3t
99
81
We further applied this protocol to the more challenging
ketones. Gratifyingly, under the standard reaction conditions,
non-enolizable ketones such as biaryl ketone 7a and uo-
renone 7b react with TMSCF2H smoothly to afford the corre-
sponding products in 43% and 46% yields, respectively
(Scheme 1).
21c,d
0.5
3u
22c
1
3v
42
Based on the pioneering work of Kondo18 and Verkade,15
a
plausible mechanism is proposed and illustrated in Scheme 2. t-
Bu-P4 attacks the silicon atom of TMSCF2H to form a hexavalent
species I, which might trigger the addition to carbonyl
compounds and produce oxy anion II. The following migration
of TMS from t-Bu-P4 to II led to the formation of III with release
of the catalyst. And acidic work up produces the diuoromethyl
carbinol.
a
Reaction conditions: 10 mol% of 4a, 1.5 equiv. of 1, 0.5 mol LÀ1 of 2,
room temperature for 0.5–3 h. b Isolated yield. c Using 2.0 equiv. TBAF
instead of HCl for desilication. d Using 20 mol% of 4a.
Conclusions
In conclusion, we have demonstrated an organocatalytic
diuoromethylation reaction of aldehydes and ketones. The
mild conditions, simple procedure and high yields provide an
efficient and novel protocol for the introduction of the signi-
cantly important diuoromethyl group into organic molecules,
which paves the new way for direct diuoromethylation reac-
tions, although the protocol is not suitable for aliphatic alde-
hydes and enolizable ketones. Further study of the reaction
scope and the applications of this methodology in bioactive
compounds synthesis are on-going in our group.
Scheme 1 Difluoromethylation of ketones.
naphthaldehyde and heliotropin were proved to be excellent
candidates for the reaction, producing the corresponding
diuoromethyl carbinols in excellent yields (Table 2, entries 12–
14). A variety of heterocyclic aldehydes, such as furfural, 2-
thienal, pyrrole-2-carboxaldehyde, indole-4-carboxaldehyde,
Acknowledgements
isoquinoline-5-carboxaldehyde
and
5-coumarancarbox- This work was supported by the National Natural Science
aldehyde can participate in the reaction smoothly, producing Foundation of China (no. 21262027) and the Natural Science
the corresponding products in good to high yields (Table 2, Foundation of Shihezi university (no. 2011ZRKETD-04,
entries 15–20). Increasing the catalyst loading to 20 mol%, 2012ZRKXJQ06).
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J. Hu, J. Fluorine Chem., 2008, 129, 382; (f) M. Pohmakotr,
D. Panichakul, P. Tuchinda and V. Reutrakul, Tetrahedron,
2007, 63, 9429; (g) S. Mizuta, N. Shibata, S. Ogawa,
H. Fujimoto, S. Nakamura and T. Toru, Chem. Commun.,
2006, 2575; (h) G. K. S. Prakash, J. Hu, Y. Wang and
G. A. Olah, J. Fluorine Chem., 2005, 126, 527; (i) C. Ni and
J. Hu, Tetrahedron Lett., 2005, 46, 8273; (j) Y.-Y. Qin, X.-L. Qiu,
Y.-Y. Yang, W.-D. Meng and F.-L. Qing, J. Org. Chem., 2005,
70, 9040.
Notes and references
´
´
˜
1 (a) J. Wang, M. Sanchez-Rosello, J. Luis Acena, C. del Pozo,
A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu,
Chem. Rev., 2014, 114, 2432; (b) P. Kirsch, Modern
uoroorganic chemistry: synthesis, reactivity, applications,
Wiley-VCH, Weinheim, 2nd edn, 2013; (c) I. Ojima, J. Org.
Chem., 2013, 78, 6358; (d) K. Uneyama, J. Fluorine Chem.,
¨
2008, 129, 550; (e) K. Muller, C. Faeh and F. Diederich,
´
´
8 A. A. Tyutyunov, V. E. Boyko and S. M. Igoumnov, Fluorine
Notes, 2011, 74, 1.
9 T. Hagiwara and T. Fuchikami, Synlett, 1995, 1995, 717.
10 Y. Zhao, W. Huang, J. Zheng and J. Hu, Org. Lett., 2011, 13,
5342.
11 (a) M. Das and D. F. O'Shea, J. Org. Chem., 2014, 79, 5595; (b)
T. Kitazawa, T. Minova and T. Mukaiyama, Chem. Lett., 2006,
35, 1002.
Science, 2007, 317, 1881; (f) J. P. Begue and D. Bonnet-
Delpon, Bioorganic and medicinal chemistry of uorine,
Wiley-VCH, Weinheim, 2008; (g) Fluorine in Medicinal
Chemistry and Chemical Biology, ed. I. Ojima, Wiley-
Blackwell, Chichester, 2009; (h) Fluorine in Pharmaceutical
and Medicinal Chemistry: From Biophysical Aspects to
Clinical Applications, ed. V. Gouverneur and K. Muller,
Imperial College Press, London, 2012.
12 (a) S. Matsukawa and E. Kitazaki, Tetrahedron Lett., 2008, 49,
2982; (b) S. Matsukawa and T. Sekin, Synth. Commun., 2009,
39, 1718.
13 M. Hatano, E. Takagi and K. Ishihara, Org. Lett., 2007, 9, 4527.
14 For reviews on NHCs mediated transformations of silylated
reagents, see: (a) M. J. Fuchter, Chem.–Eur. J., 2010, 16,
12286; (b) L. He, H. Guo, Y. Wang, G.-F. Du and B. Dai,
Tetrahedron Lett., 2015, 56, 972.
2 For reviews, see: (a) C.-F. Ni, L.-G. Zhu and J.-B. Hu, Acta Chim.
Sin., 2015, 73, 90; (b) B. Gao, C. Ni and J. Hu, Chimia, 2014, 68,
414; (c) P. Xu, S. Guo, L. Wang and P.-P. Tang, Synlett, 2015, 26,
36; (d) T. Besset, T. Poisson and X. Pannecoucke, Chem.–Eur.
J., 2014, 20, 16830; (e) Y.-L. Liu, J.-S. Yu and J. Zhou, Asian J.
Org. Chem., 2013, 2, 194; (f) J.-B. Hu, W. Zhang and F. Wang,
Chem. Commun., 2009, 7465; (g) C. Ni, M. Hu and J.-B. Hu,
Chem. Rev., 2015, 115, 765.
15 For reviews, see: (a) J. G. Verkade and P. B. Kisanga,
Tetrahedron, 2003, 59, 7819–7858; (b) J. G. Verkade and
P. B. Kisanga, Aldrichimica Acta, 2004, 37, 3–14; (c)
S. Urgaonkar and J. G. Verkade, Spec. Chem., 2006, 26, 36–
39, for selected examples, see: (d) K. Wadhwa and
J. G. Verkade, J. Org. Chem., 2009, 74, 5683; (e) K. Wadhwa,
V. R. Chintareddy and J. G. Verkade, J. Org. Chem., 2009,
74, 6681; (f) V. R. Chintareddy, K. Wadhwa and
J. G. Verkade, J. Org. Chem., 2009, 74, 8118; (g) K. Wadhwa
and J. G. Verkade, J. Org. Chem., 2009, 74, 4368.
3 (a) G. K. S. Prakash, M. Mandal, S. Schweizer, N. A. Petasis
and G. A. Olah, J. Org. Chem., 2002, 67, 3718; (b)
J. A. Erickson and J. I. McLoughlin, J. Org. Chem., 1995, 60,
1626; (c) Y. Li and J. Hu, Angew. Chem., Int. Ed., 2005, 44,
5882–5886; (d) G. K. S. Prakash, C. Weber, S. Chacko and
G. A. Olah, Org. Lett., 2007, 9, 1863.
´
4 For selected reviews, see: (a) M. Medebielle and W. R. Dolbier Jr,
J. Fluorine Chem., 2008, 129, 930; (b) J. A. Ma and D. Cahard,
Chem. Rev., 2008, 108, PR1; (c) J. Nie, H. C. Guo, D. Cahard
and J. A. Ma, Chem. Rev., 2011, 111, 455; (d) G. Valero,
´
16 R. Schwesinger and H. Schlemper, Angew. Chem., Int. Ed.
Engl., 1987, 26, 1167–1169.
X. Companyo and R. Rios, Chem.–Eur. J., 2011, 17, 2018; (e)
O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111,
4475; (f) X.-F. Wu, H. Neumann and M. Beller, Chem.–Asian J.,
2012, 7, 1744; (g) T. Besset, C. Schneider and D. Cahard,
Angew. Chem., Int. Ed., 2012, 51, 5048; (h) T. Liang,
C. N. Neumann and T. Ritter, Angew. Chem., Int. Ed., 2013, 52,
8214; (i) J. Xu, X. Liu and Y. Fu, Tetrahedron Lett., 2014, 55,
585; (j) E. Merino and C. Nevado, Chem. Soc. Rev., 2014, 43,
6598; (k) L. Chu and F.-L. Qing, Acc. Chem. Res., 2014, 47, 1513.
5 (a) G. A. Hartgraves and D. J. Burton, J. Fluorine Chem., 1988,
39, 425; (b) D. J. Burton, G. A. Hartgraves and J. Hsu,
Tetrahedron Lett., 1990, 31, 3699; (c) D. J. Burton and
G. A. Hartgraves, J. Fluorine Chem., 2007, 128, 1198.
6 G. K. S. Prakash and J. Hu, Acc. Chem. Res., 2007, 40, 921.
7 For an excellent review, see: (a) K. Uneyama, J. Fluorine Chem.,
2008, 129, 550, for selected examples, see: (b) J. Liu, C. Ni,
F. Wang and J. Hu, Tetrahedron Lett., 2008, 49, 1605; (c)
L. Zhu, Y. Li, Y. Zhao and J. Hu, Tetrahedron Lett., 2010, 51,
6150; (d) T. Bootwicha, D. Panichakul, C. Kuhakarn,
S. Prabpai, P. Kongsaeree, P. Tuchinda, V. Reutrakul and
M. Pohmakotr, J. Org. Chem., 2009, 74, 3798; (e) Y. Li and
17 For an excellent review, see: (a) T. Ishikawa, Superbases for
Organic Synthesis, John Wiley & Sons Ltd, Chichester, 2009,
for selected examples, see: (b) T. Imahori and Y. Kondo, J.
Am. Chem. Soc., 2003, 125, 8082; (c) K. Kobayashi, M. Ueno
and Y. Kondo, Chem. Commun., 2006, 3128; (d) M. Ueno,
M. Yonemoto, M. Hashimoto, A. E. H. Wheatley, H. Naka
and Y. Kondo, Chem. Commun., 2007, 2264; (e)
K. Kobayashi, M. Ueno, H. Naka and Y. Kondo, Chem.
Commun., 2008, 3780; (f) K. Kobayashi, M. Ueno, H. Naka
and Y. Kondo, Chem.–Eur. J., 2009, 15, 9805; (g) Y. Araki,
K. Kobayashi, M. Yonemoto and Y. Kondo, Org. Biomol.
Chem., 2011, 9, 78; (h) H. Kawai, Z. Yuan, E. Tokunaga and
N. Shibata, Org. Biomol. Chem., 2013, 11, 1446–1450.
18 (a) M. Ueno, C. Hori, K. Suzawa, M. Ebisawa and Y. Kondo,
Eur. J. Org. Chem., 2005, 2005, 1965–1968; (b) K. Suzawa,
M. Ueno, A. E. H. Wheatley and Y. Kondo, Chem.
Commun., 2006, 4850–4852; (c) H. Naka, D. Koseki and
Y. Kondo, Adv. Synth. Catal., 2008, 350, 1901.
19 J. J. Song, Z. Tan, J. T. Reeves, F. Gallou, N. K. Yee and
C. H. Senanayake, Org. Lett., 2005, 7, 2193.
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