Practical cleavage of trifluoroacetamides with p-toluensulfonic acid

Article abstract of DOI:10.1016/j.tetlet.2008.12.050

A practical and efficient cleavage of trifluoroacetamides with p-TsOH·H₂O has been developed. The deprotected amines are isolated directly from the reaction mixture as tosylate salts. This method can be applied to both secondary and tertiary tr

Full text of DOI:10.1016/j.tetlet.2008.12.050

Tetrahedron Letters 50 (2009) 1010–1012
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Practical cleavage of trifluoroacetamides with p-toluensulfonic acid
*
Cierra Spencer, Jaume Balsells, Hongmei Li
Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and efficient cleavage of trifluoroacetamides with p-TsOHÁH2O has been developed. The
deprotected amines are isolated directly from the reaction mixture as tosylate salts. This method can
be applied to both secondary and tertiary trifluoroacetamides in good isolated yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 October 2008
Revised 9 December 2008
Accepted 11 December 2008
Available online 24 December 2008
The trifluoroacetamide group is synthetically useful in the pro-
tection of primary and secondary amines due to its ease of intro-
duction and, more importantly, easy cleavage.1,2 The most
commonly used cleavage method involves basic hydrolysis in
aqueous MeOH using bases such as K2CO3 or Na2CO3, NH3 or
Ba(OH)2.3–9
K2CO3, 40 oC
MeOH -H2O
F
F
H
N
NH2
CF3
N
90% assay
N
51% isolated
O
2
1
Under these reaction conditions, the isolation of the amine
products requires an extractive workup, which is typically fol-
lowed by solvent switches or concentrations. This isolation work
greatly reduces the efficiency of an otherwise extremely simple
reaction. Moreover, the resulting amines may have significantly
high solubility in water, making it very difficult to recover the de-
sired product from the aqueous washes.
We recently encountered this problem in the preparation of
amine 2 from trifluoroacetamide 1 (Scheme 1). Although the
deprotection reaction takes place in 90% yield at 40 °C using
K2CO3 as the base, extracting the free amine from the aqueous
layer during the reaction workup proved extremely difficult,
resulting in almost 40% loss in yield in the aqueous layers.
In order to design a more efficient process for this reaction, we
decided to attempt an acidic non-aqueous deprotection of trifluo-
roacetamide 1.10 Hydrochloric acid in methanol had been used pre-
viously11 to promote this reaction. However, handling and use of
HCl at multi-kilogram scale require safety measures such as use
of scrubbers to scavenge acidic vapors. In order to avoid handling
and exposure to HCl vapors, we decided to look for an alternative
acid for this chemistry.
Scheme 1.
F
F
p-TsOH H2O, MeOH
86%
H
N
CF3
NH3
TsO
N
N
O
1
2
Scheme 2.
trifluoroacetamide 1 under these conditions takes place in 86% iso-
lated yield.
We have examined the generality of this deprotection method
for other heterocycle containing trifluoroacetamides. We felt that
these substrates would have a higher tendency to be water soluble
and thus more prone to isolation problems under base-catalyzed
deprotection conditions. The results are summarized in Tables 1
and 2. All the substrates examined afforded upon deprotection
crystalline tosylate salts that could be recovered in high yield by
crystallization from the reaction mixture after addition of an
appropriate weak solvent.
Deprotection of aminomethyl pyridines (Table 1, entries 1 and
2) is slow and required over 48 h of reflux in MeOH. By contrast,
cleavage of aminopyridines (Table 1, entries 3–6) is fast, requiring
only 2–3 h of reflux in MeOH. Deprotection of tertiary trifluoroac-
etamides12 was uniformly fast. All reactions were complete after
2–3 h of refluxing in MeOH (Table 2, entries 1–4). We found that
the isolation of secondary amine tosylate salts was best performed
from an iPrOH/iPrOAc solvent system. This required performing a
solvent switch from MeOH to iPrOH after reaction completion,
We were glad to find that refluxing a methanol solution of tri-
fluoroacetamide 1 with 1 equiv of p-toluenesulfonic acid for 24 h
cleanly afforded amine 2 as a tosylate salt (Scheme 2). This salt
can be directly isolated from the reaction mixture by crystalliza-
tion upon addition of MTBE as weak solvent. This procedure avoids
aqueous conditions and workup, and the direct isolation of the tos-
ylate salt makes the process highly efficient. The deprotection of
* Corresponding author. Tel.: +1 7325944707; fax: +1 7325941499.
E-mail address: Hongmei_li@merck.com (H. Li).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.050

C. Spencer et al. / Tetrahedron Letters 50 (2009) 1010–1012
1011
Table 1
Table 2
p-TsOHÁH2O deprotection of secondary trifluoroacetamides13,14
p-TsOHÁH2O deprotection of tertiary trifluoroacetamides13,14
R1
N
R1
N
H2
N
p-TsOH H2O, MeOH
H3N
p-TsOH H2O, MeOH
R1
TsO
CF3
CF3
R2
R1
TsO
H
R2
O
O
Entry Starting material
Product
Isolated yield (%)
Entry Starting material
Product
Isolated yield
(%)
F
F
H
NH3
TsO
1
2
3
4
5
6
86
N
CF3
N
H2
N
N
N
O
2
1
81
N
CF3
N
N
N
TsO
O
NH3
TsO
N
8
O
O
96
99
86
94
92
N
H
CF3
3
H2
N
H
N
N
N
CF3
NH3
N
N
N
N
2
3
4
87
77
88
CF3
N
N
TsO
TsO
N
N
TsO
TsO
O
O
4
9
H2
N
NH3
N
CF3
N
N
N
H
CF3
CF3
5
N
N
H
N
O
N
10
NH3
N
N
N
N
TsO
NH3
O
6
H2
N
S
N
H
N
S
N
S
S
N
O
CF3
CF3
N
N
TsO
TsO
N
11
N
N
N
N
O
7
were filtered, washed with MTBE, and dried under vacuum at 20 °C. Yield of 2
was 86%. 1H NMR (CDCl3, 400 MHz) d 1.47 (d, J = 6.8 Hz, 3H), 2.28 (s, 3H), 4.56
(q, J = 6.8 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.60 (dd,
J1 = 4.4 Hz, J2 = 8.7 Hz, 1H), 7.81 (td, J1 = 3.0 Hz, J2 = 8.7 Hz, 1H), 8.34 (b, 3H),
8.60 (d, J = 2.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 20.3, 21.1, 50.2, 123.7 (d,
J = 10 Hz), 124.8 (d, J = 20 Hz), 125.9, 128.5, 137.3 d, J = 30 Hz), 138.3, 145.6,
154.2 (d, J = 10 Hz), 159.2 (d, J = 250 Hz).
followed by the addition of iPrOAc to crystallize the desired prod-
ucts in 77–88% yield.
In summary, a practical non-aqueous cleavage of trifluoroaceta-
mides with p-TsOHÁH2O in methanol has been developed to afford
tosylate salts that can be isolated directly from the reaction mix-
ture. By avoiding an aqueous workup, the reactions are much more
efficient and amenable to large scale work. This method can be ap-
plied to both secondary and tertiary trifluoroacetamides with good
isolated yields.
14. All compounds isolated gave consistent 1H NMR, 13C NMR, and GCMS or LCMS
data. 3: 1H NMR (DMSO-d6, 500 MHz) d 2.29 (s, 3H), 4.20–4.23 (d, J = 5.6 Hz,
2H), 7.13–7.11 (d, J = 7.9 Hz, 2H), 7.43–7.52 (m, 4H), 7.88–7.92 (dt, J = 7.7 Hz,
J = 1.6 Hz, 1H), 8.29 (b, 3H), 8.63–8.64 (d, J = 4.6 Hz, 1H); 13C NMR (DMSO-d6,
125 MHz)
d 20.76, 42.56, 122.72, 123.53, 125.47, 128.07, 137.63, 137.74,
145.45, 148.58, 152.91.
Compound 4: 1H NMR (DMSO-d6, 500 MHz) d 2.28 (s, 3H), 6.82–6.85 (dt,
J1 = 7.1 Hz, J2 = 1 Hz, 1H), 7.01–7.03 (d, J = 9.0, 1H), 7.14–7.16 (d, J = 8.0 Hz, 2H),
7.57–7.56 (d, J = 8.0 Hz, 2H), 7.89–7.93 (m, 2H), 8.09 (b, 2H), 13.43 (b, 1H); 13C
NMR (DMSO-d6, 125 MHz) d 20.77, 112.13, 113.50, 125.47, 128.31, 135.84,
138.36, 144.11, 144.63, 153.99.
References and notes
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; John
Wiley & Sons, 1999.
2. Moussa, Z.; Romo, D. Synlett 2006, 3294.
3. Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637.
4. Bergeron, R. J.; McManis, J. J. J. Org. Chem. 1988, 53, 3108.
5. Newman, H. J. Org. Chem. 1965, 30, 1287.
6. Quick, J.; Meltz, C. J. Org. Chem. 1979, 44, 573.
7. Schwartz, M. A.; Rose, B. F.; Vishnuvajjala, B. J. Am. Chem. Soc. 1973, 95, 612.
8. Imazawa, M.; Eckstein, F. J. Org. Chem. 1979, 44, 2039.
Compound 5: 1H NMR (DMSO-d6, 500 MHz) d 2.28 (s, 6H), 6.30 (b, 2H), 7.14–
7.12 (d, J = 8.0 Hz, 2H), 7.53–7.55 (dd, J1 = 6.6 Hz, J2 = 1.5 Hz, 2H), 7.59–7.58 (d,
J = 5.7 Hz, 1H), 7.97–7.95 (d, J = 5.7 Hz, 1 Hz), 8.04 (s, 1H), 14.81 (b, 1H); 13C
NMR (DMSO-d6, 125 MHz) d 18.26, 21.26, 124.54, 125.98, 127.84 128.22,
128.69, 138.52, 140.23, 145.64, 146.92.
Compound 6: 1H NMR (DMSO-d6, 500 MHz) d 2.29 (s, 3H), 7.13–7.11 (dd,
J1 = 10.4 Hz, J2 = 0.9 Hz, 2H), 7.47–7.50 (dd, J1 = 10.1 Hz, J2 = 2.1 Hz, 2H), 7.81–
7.82 (d, J = 4.2 Hz, 1H), 7.92–7.93 (dd, J1 = 3.4 Hz, J2 = 1.3 Hz, 1H), 8.18–8.19 (d,
J = 1.7 Hz, 1H); 13C NMR (DMSO-d6, 125 MHz) d 2.74, 125.45, 128.18, 129.18,
132.48, 137.42, 138.07, 144.94, 150.76.
9. Weygand, F.; Swodenk, W. Chem. Ber. 1957, 90, 639.
10. An alternative approach to avoid aqueous workup by trapping the amine
product with an acidic resin has been described: Liu, Y.-S.; Zhao, C.;
Bergbreiter, D. E.; Romo, D. J. Org. Chem. 1998, 63, 3471.
Compound 7: 1H NMR (DMSO-d6, 500 MHz) d 1.33 (s, 9H), 2.29 (s, 3H), 7.13–
7.14 (d, J = 7.7 Hz, 2H), 7.52–7.50 (d, J = 8.2 Hz, 2H); 13C NMR (DMSO-d6,
125 MHz) d 20.75, 29.40, 36.06, 125.47, 128.14, 137.97, 145.11, 167.85, 169.51.
Compound 8: 1H NMR (DMSO-d6, 500 MHz) d 2.28 (s, 3H), 5.45 (s, 2H), 6.95–
6.98 (dt, J1 = 6.9 Hz, J2 = 1.1 Hz, 1H), 7.13–7.10 (m, 3H), 7.25–7.23 (d, J = 7.1 Hz,
2H), 7.43–7.37 (m, 3H), 7.49–7.48 (d, J = 8.0 Hz, 2H), 7.94–7.91 (dt, J1 = 8.5 Hz,
J2 = 1.2 Hz, 1H), 8.16–8.15 (d, J = 6.1 Hz, 1H), 8.49 (b, 2H); 13C NMR (DMSO-d6,
11. King, S. B.; Ganem, B. J. Am. Chem. Soc. 1994, 116, 562.
12. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373.
13. Typical deprotection procedure: Trifluoroacetamide 1 was dissolved in MeOH
(5 mL/g trifluoroacetamide). p-TsOHÁH2O (1 equiv) was added and the
resulting solution was heated to ꢀ65 °C and aged at that temperature until
HPLC or TLC showed complete reaction. The reaction mixture was then cooled
to 20 °C, and MTBE (10 mL/g trifluoroacetamide) was added over 1 h. The
slurry was aged for 1 h at 20 °C, then cooled to 5 °C, and held for 1 h. The solids
125 MHz)
d 20.72, 55.08, 113.22, 115.26, 125.44, 127.28, 128.00, 128.38,
128.92, 133.28, 137.56, 140.05, 142.62, 145.69, 153.98.

1012
C. Spencer et al. / Tetrahedron Letters 50 (2009) 1010–1012
Compound 9: 1H NMR (CDCl3, 500 MHz) d 2.31 (s, 3H), 5.61 (s, 2H), 6.64–6.62
J2 = 1.7 Hz, 1H), 8.02–8.02 (d, J = 4.3 Hz, 1H), 8.09–8.10 (d, J = 4.2 Hz, 1H),
8.49–8.50 (d, J = 4.7 Hz, 1H), 8.65 (s, 1H), 9.23 (b, 2H); 13C NMR (DMSO-d6,
(t, J1 = 6.8 Hz, J2 = 6.2 Hz, 1H), 7.08–7.10 (d, J = 8 Hz, 2H), 7.24–7.26 (m, 1H),
7.50–7.42 (m, 2H), 7.73–7.67 (m, 4H), 7.93–7.92 (d, J = 6.7 Hz, 1H), 8.45–8.44
(d, J = 4.9 Hz, 1H), 8.64 (s, 2H); 13C NMR (CDCl3, 125 MHz) d 21.40, 57.29,
113.19, 116.73, 124.37, 124.81, 126.03, 128.97, 139.17, 139.98, 140.25, 141.90,
142.84, 148.40, 151.36, 155.26.
125 MHz)
d 20.72, 56.13, 122.97, 123.54, 125.42, 128.03, 130.06, 131.26,
137.35, 137.65, 142.78, 145.53, 148.48, 149.26, 151.24.
Compound 11: 1H NMR (DMSO-d6, 500 MHz) d 1.31 (s, 9H), 2.29 (s, 3H), 5.56 (s,
2H), 7.11–7.12 (d, J = 7.8 Hz, 2H), 7.38–7.40 (dd, J = 1.8 Hz, J = 7.7 Hz, 1H), 7.45–
7.49 (m, 3H), 7.86–7.90 (dd, J = 1.8 Hz, J = 7.7Hz, 1H), 8.54–8.55 (d, J = 3.4 Hz, 1 H),
9.99 (b, 1H); 13C NMR (DMSO-d6, 125 MHz) d 20.73, 29.10, 36.23, 53.89, 122.14,
123.40, 125.44, 128.02, 137.33, 137.64, 145.55, 149.30, 152.64, 166.53, 168.18.
Compound 10: 1H NMR (DMSO-d6, 500 MHz) d 2.29 (s, 3H), 5.58 (s, 2H), 7.12–
7.10 (d, J = 7.7 Hz, 2H), 7.38–7.40 (dt, J1 = 7.2 Hz, J2 = 2 Hz, 1H), 7.47–7.49 (d,
J = 8.1 Hz, 2H), 7.55–7.57 (d, J = 7.8 Hz, 1H), 7.88–7.91 (dt, J1 = 7.7 Hz,