Alkoxide-induced nucleophilic trifluoromethylation using diethyl trifluoromethylphosphonate

Article abstract of DOI:10.1016/j.tetlet.2009.10.135

A novel alkoxide-induced nucleophilic trifluoromethylation of carbonyl compounds, disulfides, and diselenides using diethyl trifluoromethylphosphonate is presented. In these reactions diethyl trifluoromethylphosphonate acts as a [CF₃^-] synthon.

Full text of DOI:10.1016/j.tetlet.2009.10.135

Tetrahedron Letters 51 (2010) 252–255
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Alkoxide-induced nucleophilic trifluoromethylation using diethyl
trifluoromethylphosphonate
*
Prabhakar Cherkupally, Petr Beier
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám 2, 166 10 Prague, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel alkoxide-induced nucleophilic trifluoromethylation of carbonyl compounds, disulfides and disel-
enides using diethyl trifluoromethylphosphonate is presented. In these reactions diethyl trif-
luoromethylphosphonate acts as a ½CF3ꢀꢁ synthon.
Received 23 September 2009
Revised 20 October 2009
Accepted 28 October 2009
Available online 3 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethylation
Phosphonate
Nucleophilic addition
The unique properties of the trifluoromethyl group such as its
powerful electron-withdrawing character, relatively small size, in-
creased lipophilicity and metabolic stability have been exploited
in the design of new targets for pharmaceutical and agrochemical
industries as well as materials science.1 Traditional methods leading
to trifluoromethyl-containing molecules often rely on highly reac-
tive, toxic and hazardous chemicals1c (HF, F2, SF4, halogen fluorides,
high-valence metal fluorides). In recent years, direct CF3 group
introduction by nucleophilic,2 radical3 or electrophilic4 trifluorome-
thylations have been explored.5 Nucleophilic trifluoromethylation
is a powerful strategy despite the inherent instability of CF3M
(M = Na, K, MgX, etc.) reagents which readily decompose to
difluorocarbene and metal fluorides.6 The most efficient, mild and
versatile nucleophilic trifluoromethylating reagent is the Ruppert–
Prakash reagent (Me3SiCF3), which upon initiation, typically with
fluoride ions, oxygen nucleophiles or Lewis bases, delivers the tri-
fluoromethyl group to electrophilic substrates such as aldehydes,
ketones, esters, amides, acid chlorides or anhydrides, imines, nitro-
nes and others.2 Nucleophilic trifluoromethylation has been
achieved using other systems including: (a) trifluoromethane in
the presence of a strong base,7 (b) bromo or iodotrifluoromethane
in the presence of tris(dialkylamino)phosphines8 or tetrakis(dimethyl-
amino)ethylene,9 respectively, (c) trifluoromethyl carbonyl
reagents such as hemiaminals of trifluoroacetaldehyde,10 trifluoro-
acetophenone11 and its aminoketals,12 esters, salts and amides of
trifluoroacetic acid,13 (d) sulfur reagents such as trifluoromethyl sul-
fides in the presence of germyl anions,14 trifluoromethanesulfoxides
and sulfones in the presence of alkoxides,15 and trifluoromethane-
sulfinates and sulfinamides.10f,16 We herein report the use of the
phosphorus-containing nucleophilic trifluoromethylating reagent—
diethyl trifluoromethylphosphonate (1) for the efficient trifluorom-
ethylation of carbonyl compounds and other electrophiles. The only
reported CF3–P-containing nucleophilic trifluoromethylating re-
agents are the phosphonium salts [CF3P(NR2)3]+Br– (R = Me, Et,
n-Pr) prepared by the reaction of CF3Br with P(NR2)3. These phos-
phonium salts were used for the trifluoromethylation of benzalde-
hyde in the presence of fluoride ions.17
O
EtO
P CF3
OEt
1
During the course of our investigation of nucleophilic difluo-
romethylation and difluoromethylenation with diethyl difluoro-
methylphosphonate18 we became interested in the possibility of
analogous nucleophilic trifluoromethylations with diethyl trif-
luoromethylphosphonate (1).19 We expected that addition of a
nucleophilic reagent to 1 would effect cleavage of the carbon–
phosphorus bond to generate an unstable trifluoromethyl carban-
ion, and in the presence of an electrophilic substrate, provide the
corresponding trifluoromethylated product.
Our initial attempts to effect the trifluoromethylation of benzo-
phenone with 1 in the presence of CsF (2 equiv) in DMF at room
temperature led only to recovery of the starting material. Substi-
tuting CsF for t-BuOK did not lead to any improvement and con-
ducting the reaction at ꢀ40 °C or 0 °C for 30 min and quenching
the reaction at that temperature led only to trace amounts of the
* Corresponding author.
E-mail address: beier@uochb.cas.cz (P. Beier).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.135

P. Cherkupally, P. Beier / Tetrahedron Letters 51 (2010) 252–255
253
trifluoromethylated alcohol product. We were gratified to observe
an excellent19 F NMR yield of the trifluoromethylated alcohol prod-
uct when using t-BuOK (2 equiv) in DMF as the solvent at ꢀ40 °C,
and slowly warming to room temperature over 1 h (Table 1, entry
1). Reduction of the amount of base, changing the base to the less
basic potassium phenolate or changing the solvent system to THF–
DMF (9:1) led to dramatic decreases in product yields (5–20%). The
optimized reaction conditions were used for the trifluoromethyla-
tion of a range of non-enolizable ketones and the corresponding
trifluoromethylated alcohols were obtained in very good isolated
yields (Table 1, entries 2–4).
Next, our attention turned to the use of aromatic aldehydes as
electrophilic substrates. Although Prakash et al.15b have demon-
strated the compatibility of aryl aldehydes and t-BuOK in the triflu-
oromethylation using phenyl trifluoromethyl sulfone, in our case,
the use of t-BuOK (2 equiv) (or CsF) with phosphonate 1 and benz-
aldehyde did not lead to any trifluoromethylated product. We
therefore investigated other alkoxides as initiators including the
less sterically demanding MeONa, and the less basic and nucleo-
philic CF3CH2OK, PhOK and C6F5OK. While the use of MeONa or
C6F5OK did not meet with success, the other two alkoxides gave
unexpected products. In the presence of potassium trifluoroethan-
olate the expected 2,2,2-trifluoro-1-phenylethanol was obtained in
15% yield, however a small amount (3%) of diethyl 2,2,2-trifluoro-
1-phenylethyl phosphate was formed. In the presence of potas-
sium phenolate, 2,2,2-trifluoro-1-phenylethanol was obtained in
only 9% NMR yield, while diethyl 2,2,2-trifluoro-1-phenylethyl
phosphate was formed in 81% NMR yield (65% isolated yield)
(Table 1, entry 5). The major product (phosphate) presumably orig-
inates by reaction of the intermediate alcoholate [PhCH(CF3)Oꢀ]
with 1. Therefore we investigated the possibility of using the
nucleophilic initiator in catalytic amounts. However, the use of
0.1 equiv of PhOK under otherwise identical reaction conditions
led to the formation of trace amounts of 2,2,2-trifluoro-1-phenyl-
ethanol and no phosphate. We have evaluated the reaction scope
using the optimized reaction conditions and various aryl aldehydes
(Table 1, entries 6–8). 4-Methylbenzaldehyde and 4-chlorobenzal-
dehyde underwent smooth reaction to give the corresponding tri-
fluoromethyl-containing phosphates as the sole products in good
yields. On the other hand, deactivated 4-methoxybenzaldehde
was found to be unreactive (not shown in Table 1). Even the enol-
izable aldehyde (3-phenylpropanal) provided the trifluoromethyl-
containing phosphate in good yield together with a small quantity
of the trifluoromethylated alcohol.
Attempts to effect trifluoromethylation of enolizable ketones
such as acetophenone or cyclohexanone with 1 under various reac-
tion conditions unfortunately led to low yields (<10%) of the corre-
sponding trifluoromethylated products.
Finally, we briefly evaluated phosphonate 1 for the trifluorom-
ethylation of diphenyl disulfide and diphenyl diselenide. In the
presence of t-BuOK the corresponding trifluoromethyl sulfide and
selenide were obtained in low yields (Table 1, entries 9 and 10).
Table 1
Nucleophilic trifluoromethylation using diethyl trifluoromethylphosphonate (1)a
Entry
1
Substrate
Alkoxide
Product and yieldsb
91%15b
O
HO CF3
Ph Ph
HO CF
t-BuOK
Ph
Ph
Cl
O
3
2
3
4
5
6
7
8
t-BuOK
t-BuOK
t-BuOK
PhOK
99%15b
Cl
Cl
Cl
O
HO CF3
89%10c
91%
O
O
HO CF
3
(83%)20
O
O
81%
OH
(65%)20
Ph
O P OEt
PhCHO
9%15b
CF3
Ph
OEt
CF3
72%
O
P
(57%)20
H3C
CHO
O
OEt
PhOK
H C
OEt
3
CF
3
99%
O
P
(86%)20
Cl
CHO
O
OEt
PhOK
Cl
OEt
CF3
60%
Ph
OH
CF
Ph
O
(53%)20
CHO
Ph
O P OEt
PhOK
16%21
3
OEt
3
CF
9
10
PhSSPh
PhSeSePh
t-BuOK
t-BuOK
PhSCF3
PhSeCF3
26%7c
34%22
a
Reaction conditions: (1) Substrate (0.5 mmol), CF3P(O)(OEt)2 (0.6 mmol), alkoxide (1 mmol), DMF (1.7 mL), ꢀ40 °C to rt, 1 h; (2) HCl, H2O, rt.
b
19F NMR yield using PhCF3 as the internal standard. Yield of isolated product in brackets.

254
P. Cherkupally, P. Beier / Tetrahedron Letters 51 (2010) 252–255
O
O
P OEt
R
OEt
3
RCHO
CF
–
+
PhO K
–
+
O K
OEt
–
+
O
P
OH
CF
O K
+
H O
O
P
3
EtO
OPh
OEt
+
R
R
CF
R
CF
3
3
3
OEt
CF
3
B
C
–
+
O K
O
–
+
RCHO
PhO K
EtO
EtO
P
CF
3
EtO
P CF
3
OPh
OEt
A
1
Scheme 1. A plausible mechanism for the trifluoromethylation of aldehydes with 1 in the presence of potassium phenolate.
The use of PhOK did not result in any improvement in the product
yields.
References and notes
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reaction starts with nucleophilic attack of the alkoxide (PhOK) on
1. In the presence of an aldehyde the alcoholate B is formed
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member.
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Acknowledgements
Support of this work by the Grant Agency of the Czech Republic
(203/08/P310) and the Academy of Sciences of the Czech Republic
(Research Plan AVZ40550506) is gratefully acknowledged.
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1518, 1480, 1267, 1182, 1036, 808; 1H NMR (400 MHz, CDCl3): d = 1.16 (dt, 3H,
3JHH = 7.1 Hz, JHP = 1.1 Hz, CH3), 1.31 (dt, 3H, JHH = 7.1 Hz, JHP = 1.1 Hz, CH3),
3.82–3.99 (m, 2H, CH2), 4.03–4.22 (m, 2H, CH2), 5.52–5.59(m, 1H, CH), 2.38 (s, 3H,
CH3), 7.22 (d, 2H, 3JHH = 8 8.0 Hz, CArH), 7.37 (d, 2H, 3JHH = 8.0 Hz, CArH); 13C {1H}
NMR (100 MHz, CDCl3): d = 15.7–15.9 (m, CH3), 21.2 (s, CH3), 64.1–64.4 (m, CH2),
76.1(dq, 2JCF = 33.8 Hz, 2JCP = 4.4 Hz, CH), 122.9(dq, 1JCF = 281.0 Hz, 3JCP = 10.0 Hz,
CF3), 129.3 (CArH), 128.0 (CArH), 128.5 (CAr), 140.4 (CAr); 19F NMR (376 MHz,
CDCl3): d = ꢀ77.8 (d, 3JFH = 6.5 Hz);31P {1H} NMR (162 MHz, CDCl3): d = ꢀ1.92 (s);
EI MS: m/z 326 (M+, 2%), 306 (60), 230 (100), 258 (39), 249 (40), 173 (63), 123 (49),
119 (36), 91 (30), 77 (15); ESI-HRMS: m/z calcd for C13H19F3O4P (M+H)+:
327.0968; found m/z: 327.0966.
4
3
4
17. Chernega, A. N.; Kolomeitsev, A. A.; Yagupolskij, Y. L.; Gentzsch, A.;
Röschenthaler, G.-V. J. Fluorine Chem. 1995, 70, 271–275.
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64, 10977–10985; (b) Alexandrova, A. V.; Beier, P. J. Fluorine Chem. 2009, 130,
493–500; (c) Beier, P.; Pohl, R.; Alexandrova, A. V. Synthesis 2009, 957–962.
19. Compound 1 was prepared by reaction of CF3I with P(OEt)3 under photolytic
conditions: (a) Burton, D. J.; Flynn, R. M. Synthesis 1979, 615; (b) Mahmood, T.;
Shreeve, J. M. Synth. Commun. 1987, 17, 71–75.
Diethyl 1-(4-chlorophenyl)-2,2,2-trifluoroethyl phosphate (entry 7, Table 1): 86%,
colorless oil; Rf = 0.37 (30% EtOAc in hexane); FTIR (film,
m
max cmꢀ1) 3060, 3040,
2987, 1600, 1582, 1495, 1264, 1187, 1038, 817; 1H NMR (400 MHz, CDCl3):
3
4
3
d = 1.19 (dt, 3H, JHH = 7.1 Hz, JHP = 1.1 Hz, CH3), 1.32 (dt, 3H, JHH = 7.1 Hz,
4JHP = 1.1 Hz, CH3), 3.86–4.02 (m, 2H, CH2), 4.06–4.23 (m, 2H, CH2), 5.55–5.62 (m,
1H, CH), 7.41–7.43 (m, 4H, CArH); 13C {1H} NMR (100 MHz, CDCl3): d = 15.8–15.9
(m, CH3), 64.3–64.6 (m, CH2), 75.5 (dq, 2JCF = 34.1 Hz, 2JCP = 4.3 Hz, CH), 122.7 (dq,
20. General procedure for nucleophilic trifluoromethylation: A solution of alkoxide
(1 mmol) in anhydrous DMF (0.7 mL) was added dropwise to a solution of
substrate (0.5 mmol) and 1 (123.7 mg, 0.6 mmol) in anhydrous DMF (1 mL)
cooled to ꢀ40 °C. The reaction mixture was warmed to room temperature over
1 h and then added slowly to aqueous HCl (5 mL, 0.2 M), followed by extraction
with t-BuOMe (3 ꢂ 10 mL). The combined organic phase was washed with water
(10 mL), brine (10 mL), dried (MgSO4), filtered, and the solvent removed in vacuo.
The crude product was purified by column chromatography over silica gel.
9-Trifluoromethyl-9H-xanthen-9-ol (entry 4, Table 1): 83%, white solid; mp 90–
3
1JCF = 281.2 Hz, JCP = 9.9 Hz, CF3), 129.0 (CArH), 129.3 (CArH), 130.0 (CAr), 136.3
3
(CAr); 19F NMR (376 MHz, CDCl3): d = ꢀ77.8 (d, JFH = 6.3 Hz); 31P {1H} NMR
(162 MHz, CDCl3): d = ꢀ1.93 (s); EI-MS: m/z 346 (M+, 3%), 326 (40), 270 (60), 250
(100), 193 (59), 143 (64), 125 (35), 109 (26), 81 (25); ESI-HRMS: m/z calcd for
C12H15ClF3NaO4P (M+Na)+: 369.0241; found: 369.0242.
Diethyl 3-phenyl-1-trifluoromethylpropyl phosphate (entry 8, Table 1): 53%,
91 °C; Rf = 0.36 (10% EtOAc in hexane); FTIR (film,
m
max cmꢀ1) 3545, 3425, 3077,
colorless oil; Rf = 0.45 (30% EtOAc in hexane); FTIR (film, m
max cmꢀ1) 3088,
3044, 1644, 1606, 1575, 1478, 1452, 1253, 1174, 1057, 756, 717; 1H NMR
3065, 3029, 2985, 1604, 1497, 1481, 1272, 1177, 1037, 751, 700; 1H NMR
(400 MHz, CDCl3): d = 1.33–1.39 (m, 6H, 2 ꢂ CH3), 2.08–2.14 (m, 2H, PhCH2),
2.73–2.81 (m, 1H, PhCH2CHaHb), 2.86–2.94 (m, 1H, PhCH2CHaHb), 4.11–4.22 (m,
4H, 2 ꢂ OCH2), 4.69–4.76 (m, 1H, CH), 7.20–7.24 (m, 3H, CArH), 7.29–7.33 (m, 2H,
(400 MHz, CDCl3): d = 3.16 (s, 1H, OH), 7.18–7.25 (m, 4H, CArH), 7.40–7.46 (m, 2H,
C
ArH), 7.80–7.83 (m, 2H, CArH); 13C {1H} NMR (100 MHz, CDCl3): d = 69.5 (q,
2JCF = 31.2 Hz, COH), 116.6 (CArH), 119.1 (CAr), 123.4 (CArH), 124.3 (q,
1JCF = 286.0 Hz, CF3), 127.9 (CArH), 130.8 (CArH), 151.1 (CAr); 19F NMR (376 MHz,
CDCl3): d = ꢀ81.9 (s); EI-MS: m/z 266 (M+, 5%), 197 (100), 181 (8), 139 (9), 115 (9),
77 (7); ESI-HRMS: m/z calcd for C14H8F3O2 (MꢀH)ꢀ: 265.0482; found: 265.0483.
Diethyl 2,2,2-trifluoro-1-phenylethyl phosphate (entry 5, Table 1): 65%, colorless
C
ArH); 13C {1H}NMR (100 MHz, CDCl3):d = 15.9–16.1(m, CH3), 30.5 (s, CH2), 31.2–
31.3 (m, CH2), 64.4 (d, 2JCP = 6.1 Hz, OCH2), 74.3 (dq, 2JCF = 32.8 Hz, 2JCP = 5.3 Hz,
CH), 123.7 (dq, 1JCF = 281.2 Hz, 3JCP = 6.0 Hz, CF3), 126.4 (CArH), 128.3 (CArH), 128.6
(CArH), 140.2 (CAr); 19F NMR (376 MHz, CDCl3): d = ꢀ78.1 (d, JFH = 6.3 Hz); 31P
3
oil; Rf = 0.14 (20% EtOAc in hexane); FTIR (film,
m
max cmꢀ1) 3070, 3040, 2987,
{1H} NMR (162 MHz, CDCl3): d = ꢀ1.77 (s); EI-MS: m/z 340 (M+, 4%), 186 (39), 155
(50), 127 (25), 117 (100), 99 (42), 91 (36); ESI-HRMS: m/z calcd for C14H21F3O4P
(M+H)+: 341.1124; found: 341.1124.
1606, 1590, 1498, 1481, 1266, 1184, 1039, 704, 635; 1H NMR (400 MHz, CDCl3):
3
4
3
d = 1.15 (dt, 3H, JHH = 7.1 Hz, JHP = 1.1 Hz, CH3), 1.31 (dt, 3H, JHH = 7.1 Hz,
4JHP = 1.1 Hz, CH3), 3.83–3.97 (m, 2H, CH2), 4.06–4.22 (m, 2H, CH2), 5.56–5.64 (m,
1H, CH), 7.40–7.45 (m, 3H, CArH), 7.48–7.50 (m, 2H, CArH); 13C {1H} NMR
(100 MHz, CDCl3): d = 15.7–15.9 (m, CH3), 64.2–64.5 (m, CH2), 76.2 (dq,
21. Kuroki, Y.; Sakamaki, Y.; Iseki, K. Org. Lett. 2001, 3, 457–459.
22. Billard, T.; Roques, N.; Langlois, B. R. J. Org. Chem. 1999, 64, 3913–3920.
23. These phosphates were previously prepared either by the reaction of RC(O)CF3
with HP(O)(OEt)2 in the presence of Et3N or DBU (analytical data not reported):
(a) Kuroboshi, M.; Ishihara, T.; Teiichi, A. J. Fluorine Chem. 1988, 39, 293–298;
(b) El Kaïm, L.; Gaultier, L.; Grimaud, L.; Dos Santos, A. Synlett 2005, 2335–
2336; or from RCH(OH)CF3 and ClP(O)(OR)2 under harsh reaction conditions:
(c) Goryunov, E. I.; Petrovskii, P. V.; Shcherbina, T. M.; Laretina, A. P.; Zakharov,
L. S.; Kabachnik, M. I. Bull. Acad. Sci. USSR, Chem. 1990, 39, 787–794; (d)
Goryunov, E. I.; Zakharov, L. S.; Petrovskii, P. V.; Kabachnik, M. I. Bull. Acad. Sci.
USSR, Chem. 1985, 34, 799–802.
2JCF = 33.9 Hz, JCP = 4.4 Hz, CH), 123.0 (dq, JCF = 281.1 Hz, JCP = 10.0 Hz, CF3),
128.0 (CArH), 128.6 (CArH), 130.1 (CArH), 131.5 (CAr); 19F NMR (376 MHz, CDCl3):
d = ꢀ77.7 (d, 3JFH = 6.4 Hz); 31P {1H} NMR (162 MHz, CDCl3): d = ꢀ1.73 (s); EI-MS:
m/z 312 (M+, 2%), 292 (45), 236 (46), 216 (100), 159 (54), 125 (36), 109 (81), 77
(18); ESI-HRMS: m/z calcd for C12H16F3NaO4P (M+Na)+: 335.0631; found:
335.0630.
2
1
3
Diethyl 2,2,2-trifluoro-1-p-tolylethyl phosphate (entry 6, Table 1): 57%, colorless
oil; Rf = 0.36 (30% EtOAc in hexane); FTIR (film, m
max cmꢀ1) 3044, 2986, 1618,