Effect of deuterated solvents toward 2,2,2-trichloroethyl esters with a benzylic methylene moiety

Article abstract of DOI:10.1016/j.tetlet.2010.09.039

The indium-promoted chemoselective deprotection of 2,2,2-trichloroethyl esters containing a benzylic methylene was successfully achieved by employing deuterated solvents.

Full text of DOI:10.1016/j.tetlet.2010.09.039

Tetrahedron Letters 51 (2010) 6045–6048
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Effect of deuterated solvents toward 2,2,2-trichloroethyl esters
with a benzylic methylene moiety
Tomoko Mineno a, , Haruyasu Hirayama a, Kazuhide Nakahara a, Mitsuaki Yamashita b, Hisao Kansui c,
⇑
Hiroshi Moriwaki d
a Laboratory of Medicinal Chemistry, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui, Takasaki, Gunma 370-0033, Japan
b Laboratory of Organic Chemistry for Life Sciences, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui, Takasaki, Gunma 370-0033, Japan
c Laboratory of Organic Chemistry, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
d Division of Applied Biology, Faculty of Textile Science and Technology, Shinshu University, 3-15-1 Tokita, Ueda, Nagano 386-8567, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2010
Revised 4 September 2010
Accepted 14 September 2010
Available online 17 September 2010
The indium-promoted chemoselective deprotection of 2,2,2-trichloroethyl esters containing a benzylic
methylene was successfully achieved by employing deuterated solvents.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2,2,2-Trichloroethyl esters
Benzylic methylene moiety
Deuterated solvents
Indium
A number of protecting groups have been introduced over the
past few decades,1 and the 2,2,2-trichloroethyl moiety has been
used as a convenient protecting unit for alcohols and amines, as
well as for carboxylic acids.2,3 Among the many available proce-
dures used to deprotect the 2,2,2-trichloroethoxycarbonyl (Troc)
group, we have employed mild methods for its removal from alco-
hols4 and amines5 by utilizing indium powder and ammonium
chloride. In addition, the 2,2,2-trichloroethyl moiety is known to
be routinely cleaved from 2,2,2-trichloroethyl esters using Zn/
AcOH,2 electrolysis,6 SmI2,7 Se/NaBH4,8 and Cd/AcOH.9 We also
have continuously explored the use of indium-mediated reactions
for 2,2,2-trichloroethyl esters.10 We have recently reported a mild
method to deprotect 2,2,2-trichloroethyl esters and furnish the
carboxylic acids in good to excellent yields. However, the method
was unsuccessful for substrates wherein a benzylic methylene
moiety was present, which is a limitation.
In this case, demonochlorination proceeded in an exclusive for-
mation of 2,2-dichloroethyl esters with negligible amounts of the
deprotected form. To overcome this shortcoming, we have now
discovered the conditions that could efficiently cleave 2,2,2-
trichloroethyl esters containing a benzylic methylene moiety and
yield the deprotected forms of the free carboxylic acids by using
deuterated solvents (Scheme 1).
To begin, benzene, toluene, and chlorobenzene were selected as
the solvents, and the reaction mixtures containing 4-tolylacetic
acid 2,2,2-trichloroethyl ester and indium metal powders were
heated at reflux, applying the reaction conditions from our previ-
ous work. However, none of the experimental procedures
produced any chemical transformations leaving the starting mate-
rial in the solution intact after 5 days, even when high boiling
points of toluene and chlorobenzene were used. We then
approached the problem from a different perspective. Regarding
the choice of tetrahydrofuran (THF) in our previous report,
THF-d8 was considered as a promising solvent that could deprotect
2,2,2-trichloroethyl esters with a benzylic methylene moiety. Also,
the reductive stability of radicals/anions was reviewed.10–12 When
dissociation of a C–H bond of THF is responsible for the demono-
chlorination of 2,2,2-trichloroethyl esters, the rate of the reaction
should be slowed when THF is replaced by THF-d8, due to the
kinetic isotope effect of the corresponding C–D bond. Based on
the previously mentioned study concerning reaction rates, the
reaction rate involving the C–H bond is five to six times faster than
that involving the corresponding C–D bond.13,14
O
CCl3
OH
indium
R
R
O
O
⇑
Corresponding author. Tel.: +81 27 352 1180; fax: +81 27 352 1118.
E-mail address: mineno@takasaki-u.ac.jp (T. Mineno).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.039

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T. Mineno et al. / Tetrahedron Letters 51 (2010) 6045–6048
Table 1
Reactions using THF-d8 as the solventa
indium, ND4Cl
O
O
O
R
R
R
+
D
O
CCl3
OH
O
THF-d8
n
n
n
Cl
(n = 1, 2)
Cl
Entry
1
Substrate
Products and yieldsb
Time (h)
30
O
O
O
D
Cl
23%
67%
60%
OH
O
O
O
CCl3
Cl
O
O
D
Cl
2
13%
30
O
CCl3
OH
O
Cl
a
All reactions were conducted at reflux using 2 equiv of In, 5 equiv of ND4Cl, and THF-d8 as the solvent.
Isolated yields and the free carboxylic acids were indicated after silica gel separation.
b
Table 2
Reactions using THF-d8/D2O (10:1) as the solventa
indium, ND4Cl
THF-d8/D2O
O
O
O
R
R
R
+
D
O
CCl3
OH
O
n
n
n
Cl
(n = 1, 2)
Cl
Entry
1
Substrate
Products and yieldsb
Time (h)
40
O
O
80%
72%
—
ND
ND
O
O
CCl3
OH
O
2
3
—
40
40
O
CCl3
OH
Br
Br
Br
O
O
O
D
Cl
54%
3%
O
CCl3
OH
O
Cl
O
O
4
5
32%
70%
—
ND
24
40
HO
O
CCl3
O
HO
OH
O
O
O
D
Cl
28%
TBDPSO
OH
TBDPSO
O
TBDPSO
CCl3
O
Cl
i-Pr
i-Pr
i-Pr
i-Pr
O
6
7
52%
85%
—
ND
6%
90
40
SO3
O
O
CCl3
SO3
OH
i-Pr
i-Pr
H3C
H3C
H3C
O
O
D
Cl
O
O
CCl3
O
O
OH
O
Cl
CH3
CH3
CH3
H3C
H3C
H3C
H3C
H3C
8
9
81%
76%
8%
40
40
D
Cl
OH
O
CCl3
O
Cl
CH3
CH3
CH3
H3C
O
O
O
14%
D
Cl
O
CCl3
OH
O
CH3
CH3
CH3
Cl

T. Mineno et al. / Tetrahedron Letters 51 (2010) 6045–6048
6047
Table 2 (continued)
Entry
Substrate
Products and yieldsb
Time (h)
CH3
N
CH3
N
CH3
N
H3C
O
H3C
O
H3C
O
10
63%
70%
8%
8%
22
D
Cl
OH
O
O
CCl3
O
Cl
O
O
O
O
O
D
Cl
11
110
O
CCl3
O
OH
Cl
a
All reactions were conducted at reflux using 2 equiv of In, 5 equiv of ND4Cl, and THF-d8/D2O (10:1) as the solvent.
Isolated yields and the free carboxylic acids were indicated after silica gel separation.
b
To determine the applicability of THF-d8 as the solvent, several
phy on silica gel furnished analytically pure products, which were
confirmed by spectroscopy.
substrates having representative structures were tested with an in-
dium-mediated reaction using deuterated ammonium chloride
(Table 1).15 Although the reaction conditions were very mild, and
some improvement was found, the obtained results were quite
unsatisfactory, furnishing deuterated forms as the major products
and deprotected free carboxylic acids as the minor. Since the total
yields, as shown in Table 1, were not inferior, a modification of the
reaction conditions was envisioned. After experimental study,
the addition of deuterium oxide was found to effectively smooth
the deprotection of 2,2,2-trichloroethyl esters with a benzylic
methylene unit. The results are summarized in Table 216 and in-
clude various substrates possessing diverse functionalities. The
compounds with representative structures were reevaluated (Ta-
ble 2, entries 1 and 2). The reaction conditions were mild, and dra-
matic improvement was observed. In both cases, the free
carboxylates were furnished exclusively in good yields. A silyl pro-
tection of the tert-butyldiphenylsilyl (TBDPS) group was resistant
to the reaction conditions, although 28% of the deuterated form
of demonochlorination was generated (Table 2, entry 5) with an
evident 1H NMR spectra, by comparison with our previous data.10
Meanwhile, derivatives with protected hydroxyl groups (Table 2,
entries 5 and 6) displayed higher yields than the unprotected sub-
strate (Table 2, entry 4). Among phenyl acetic acid derivatives,
those with electron donating units, such as alkyl groups (Table 2,
entries 7–9), showed high yields of the corresponding carboxyl-
ates, whereas those with electron-withdrawing groups, such as
halogen and sulfonyloxy groups (Table 2, entries 3 and 6), dis-
played medium yields. In the case of 4-phenoxy derivative, the
reaction furnished 70% of the corresponding carboxylate. It should
be noted that separation of these two products, free carboxylates
and 2-deuterio-2,2-dichloroethyl esters, was easily performed
through ordinary silica gel flash chromatography.
In summary, by using deuterated solvents, we have substan-
tially improved the mild indium-mediated deprotection of 2,2,2-
trichloroethyl esters with a benzylic methylene moiety. We also
have determined the applicability with respect to various sub-
strates possessing diverse functionalities. Even when a small
amount of 2-deuterio-2,2-dichloroethyl esters were formed, these
minor products were easily separated. The deprotection of 2,2,2-
trichloroethyl esters with a benzylic methylene moiety is now a
simple process. To our knowledge, it represents the first attempt
to utilize deuterated solvents in this type of chemical transforma-
tion. Research on further applications and utility is now being
conducted.
General experimental procedure: The trichloroethyl esters
(1 mmol) were dissolved in THF-d8/D2O (10:1, w/w, 11 g), and
indium powder17 (2 mmol) and ND4Cl (5 mmol) were added at
room temperature. The reaction mixture was heated at reflux
and monitored for completion by TLC. Flash column chromatogra-
Acknowledgment
The authors thank Professor T. Kunieda (Sojo University) for his
suggestions and comments. This study was partially supported by
a grant from The Naito Foundation.
References and notes
1. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th
ed.; John Wiley & Sons: New Jersey, 2007.
2. Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.;
Ranganathan, S.; Vorbrüggen, H. J. Am. Chem. Soc. 1966, 88, 852–853.
3. Windholz, T. B.; Johnston, D. B. R. Tetrahedron Lett. 1967, 27, 2555–2558.
4. Valluri, M.; Mineno, T.; Hindupur, R. M.; Avery, M. A. Tetrahedron Lett. 2001, 42,
7153–7154.
5. Mineno, T.; Choi, S.-R.; Avery, M. A. Synlett 2002, 883–886.
6. Semmelhack, M. F.; Heinsohn, G. E. J. Am. Chem. Soc. 1972, 94, 5139–5140.
7. Pearson, A. J.; Lee, K. J. Org. Chem. 1994, 59, 2304–2313.
8. Huang, Z.-Z.; Zhou, X.-J. Synthesis 1989, 693–694.
9. Genisson, Y.; Tyler, P. C.; Young, R. N. J. Am. Chem. Soc. 1994, 116, 759–760.
10. Mineno, T.; Kansui, H.; Kunieda, T. Tetrahedron Lett. 2007, 48, 5027–5030.
11. Mitsuo, N.; Kunieda, T.; Takizawa, T. J. Org. Chem. 1973, 38, 2255–2257.
12. Mitchell, T. A.; Romo, D. Heterocycles 2005, 66, 627–637.
13. Lynch, R. A.; Vincenti, S. P.; Lin, Y. T.; Smucker, L. D.; Subba Rao, S. C. J. Am.
Chem. Soc. 1972, 94, 8351–8356.
14. Wiberg, K. B.; Slaugh, L. H. J. Am. Chem. Soc. 1958, 80, 3033–3039.
15. Experimental data for Table 1.
Phenylacetic acid 2-deuterio-2,2-dichloroethyl ester (Table 1, entry 1): 1H NMR
(500 MHz, CDCl3): d 7.36–7.27 (m, 5H), 4.46 (s, 2H), 3.70 (s, 2H); 13C NMR
(125 MHz, CDCl3): d 170.6, 133.1, 129.3, 128.6, 127.3, 68.4, 68.2 (t, J = 27.8 Hz),
40.8.
Phenypropionic acid 2-deuterio-2,2-dichloroethyl ester (Table 1, entry 2): 1H NMR
(500 MHz, CDCl3): d 7.30–7.27 (m, 5H), 4.42 (s, 2H), 2.97 (t, 2H, J = 7.6 Hz), 2.71
(t, 2H, J = 7.6 Hz); 13C NMR (125 MHz, CDCl3): d 172.0, 140.1, 128.7, 128.4,
126.5, 68.5, 68.3 (t, J = 27.8 Hz), 35.5, 30.8.
16. Experimental data for Table 2.
4-Bromophenylacetic acid 2-deuterio-2,2-dichloroethyl ester (Table 2, entry 3): 1
H
NMR (500 MHz, CDCl3): d 7.46 (d, 2H, J = 8.6 Hz), 7.17 (d, 2H, J = 8.6 Hz), 4.40 (s,
2H), 3.59 (s,2H); 13C NMR (125 MHz, CDCl3): d 170.1, 132.0, 131.8, 131.0, 121.5,
68.5, 68.1 (t, J = 27.8 Hz), 40.2.
3-(tert-Butyldiphenylsilyloxy)phenylacetic acid 2-deuterio-2,2-dichloroethyl ester
(Table 2, entry 5): 1H NMR (500 MHz, CDCl3): d 7.72–7.71 (m, 4H), 7.45–7.42
(m, 2H), 7.38–7.36 (m, 4H), 7.03 (t, 1H, J = 8.1 Hz), 6.80–6.76 (m, 2H), 6.64 (dd,
1H, J = 8.1, 2.3 Hz), 4.36 (s, 2H), 3.52 (s, 2H), 1.10 (s, 9H); 13C NMR (125 MHz,
C6D6): d 170.0, 156.6, 136.2, 135.6, 133.5, 130.6, 130.0, 128.7, 122.9, 121.5,
119.3, 68.9 (t, J = 27.5 Hz), 68.6, 41.0, 27.0, 20.0.
4-Tolylacetic acid 2-deuterio-2,2-dichloroethyl ester (Table 2, entry 7): 1H NMR
(500 MHz, CDCl3): d 7.18 (d, 2H, J = 8.0 Hz), 7.15 (d, 2H, J = 8.0 Hz), 4.45 (s, 2H),
3.66 (s, 2H), 2.34 (s 3H); 13C NMR (125 MHz, CDCl3): d 170.8, 137.0, 130.1,
129.3, 129.1, 68.4, 68.0 (t, J = 27.7 Hz), 40.4, 21.1.
4-Isopropylphenylacetic acid 2-deuterio-2,2-dichloroethyl ester (Table 2, entry 8):
1H NMR (500 MHz, CDCl3): d 7.21–7.19 (m, 4H), 4.45 (s, 2H), 3.66 (s, 2H), 2.89
(sept, 1H, J = 6.8 Hz), 1.24 (d, 6H, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3): d
170.8, 148.0, 130.4, 129.2, 126.7, 68.4, 68.0 (t, J = 27.8 Hz), 40.4, 33.7, 23.9.
2,4,6-Trimethylphenylacetic acid 2-deuterio-2,2-dichloroethyl ester (Table 2, entry
9): 1H NMR (500 MHz, CDCl3): d 6.86 (s, 2H), 4.43 (s, 2H), 3.71 (s, 2H), 2.29 (s,
6H), 2.26 (s, 3H); 13C NMR (125 MHz, C6D6): d 170.4, 137.5, 137.0, 129.7, 128.7,
69.0 (t, J = 27.8 Hz), 68.5, 35.2, 21.3, 20.6.

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T. Mineno et al. / Tetrahedron Letters 51 (2010) 6045–6048
4-Dimethylaminophenylacetic acid 2-deuterio-2,2-dichloroethyl ester (Table 2,
1H NMR (500 MHz, CDCl3): d 7.36–7.32 (m, 2H), 7.27–7.24 (m, 2H), 7.11 (t, 1H,
J = 7.5 Hz), 7.02–6.96 (m, 4H), 4.47 (s, 2H), 3.67 (s, 2H); 13C NMR (125 MHz,
CDCl3): d 170.7, 157.0, 156.6, 130.6, 129.7, 127.8, 123.4, 118.94, 118.92, 68.4,
68.0 (t, J = 27.5 Hz), 40.1.
entry 10): 1H NMR (500 MHz, CDCl3): d 7.15 (d, 2H, J = 8.5 Hz) , 6.99 (d, 2H,
J = 8.5 Hz), 4.44 (s, 2H), 3.59 (s, 2H), 2.94 (s, 6H); 13C NMR (125 MHz, CDCl3): d
171.3, 149.9, 129.9, 120.8, 112.7, 68.4, 68.1 (t, J = 27.5 Hz), 40.6, 39.9.
4-Phenoxyphenylacetic acid 2-deuterio-2,2-dichloroethyl ester (Table 2, entry 11):
17. Indium powder, 99.99%. Aldrich Chemical Company, Catalog # 277959.