Acid mediated deprotection of N-isopropyl tertiary amides

Article abstract of DOI:10.1016/j.tetlet.2015.01.161

Tertiary amides containing an N-isopropyl group were selectively deprotected by heating in methanesulfonic acid. The N-isopropyl group was removed selectively in the presence of other groups on the amide nitrogen such as methyl, primary alkyl, or aryl. The putative isopropyl cation was trapped by Friedel-Crafts alkylation of anisole when the latter was included as a co-solvent.

Full text of DOI:10.1016/j.tetlet.2015.01.161

Tetrahedron Letters 56 (2015) 1280–1282
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Tetrahedron Letters
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Acid mediated deprotection of N-isopropyl tertiary amides
⇑
Chris Lorenc, Jonathan T. Reeves , Carl A. Busacca, Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/PO Box 368, Ridgefield, CT 06877-0368, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Tertiary amides containing an N-isopropyl group were selectively deprotected by heating in methanesulf-
onic acid. The N-isopropyl group was removed selectively in the presence of other groups on the amide
nitrogen such as methyl, primary alkyl, or aryl. The putative isopropyl cation was trapped by Friedel–
Crafts alkylation of anisole when the latter was included as a co-solvent.
Received 9 January 2015
Accepted 24 January 2015
Available online 31 January 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Amides
Acid
Deprotection
Dealkylation
The amide functional group is ubiquitous in natural and syn-
thetic products.1 The utility of tertiary amides as directing groups
for ortho-metallation has been amply demonstrated by the work
of Snieckus and co-workers.2 The sterically hindered N,N-diisopro-
pyl carboxamide, in particular, has shown excellent ability as a
directing group. The steric hindrance provided by the two isopro-
pyl groups is advantageous in lithiation reactions, but can make
subsequent modifications of the amide difficult. The selective
removal of one or both of the isopropyl groups could facilitate sub-
tronic effects. A benzyl group (entry 4) was selectively removed
over the isopropyl group at a lower temperature (40 °C, 2 h).5 Sub-
jecting the N-isopropyl-N-phenyl amide 11 to the reaction condi-
tions resulted in slow conversion to the N-phenyl amide 12
(entry 5). Cyclohexyl groups were found to behave similarly to iso-
propyl groups, as the N,N-dicyclohexyl amide 13 gave a clean and
complete conversion to the N-cyclohexyl secondary amide 14 after
2 h (entry 6). In addition to the 1-adamantyl carboxamides
employed in entries 1–6, the reaction was extended to enolizable
sequent transformations. We recently subjected
a
-amino amide 1
amides bearing either one or two a-hydrogens. Both the cyclohex-
to heating in methanesulfonic acid with the intention of removing
the N-tert-butyl group.3 Instead, these reaction conditions selec-
tively removed one isopropyl group from the amide to give 2 in
52% yield.4 Herein we describe the scope of this acid mediated
deprotection of various N-isopropyl amides.
anecarboxamide 15 (entry 7) and the n-decanecarboxamide 17
(entry 8) underwent complete conversion after 5 h to give the
respective secondary amides in good yields. The reaction was next
investigated for aryl carboxamides.6 Interestingly, these amides
underwent N-isopropyl deprotection much more slowly than the
alkyl carboxamides of entries 1–8. The unsubstituted N,N-diisopro-
pyl benzamide 19 (entry 9) and the para-methoxy analog 21 (entry
10) required 24 h and 21 h, respectively, for complete reaction. The
para-nitro benzamide 23 (entry 11) reacted extremely slowly,
requiring 72 h for complete deprotection. The trend among not
only the benzamides but also the alkyl carboxamides is that a more
electron deficient carbonyl group causes the reaction to proceed
more slowly.
The proposed mechanism of deprotection is depicted in
Scheme 2. Protonation of the amide carbonyl group gives com-
pound B, which may undergo an SN1-type ionization to give C,
which tautomerizes to the product secondary amide F. An isopro-
pyl cation D is also produced, which may undergo E1 elimination
to give propene E. It is also possible that B undergoes E1 fragmen-
tation to give propene E directly. The fate of the isopropyl cation is
likely as polypropylene G.
Various N-isopropyl tertiary amides were prepared from 1-ada-
mantane carbonyl chloride and different secondary amines
(Table 1). The amides were subjected to the conditions described
in Scheme 1 (MsOH, 90 °C). The reactions were monitored by LC–
MS for complete conversion of the starting material. As observed
for compound 2, the N,N-diisopropyl amide 3 was mono-deprotec-
ted cleanly after 2 h to provide 4 in 92% isolated yield (entry 1).
Amides bearing two different groups on nitrogen were then exam-
ined (entries 2–5). The isopropyl group was removed selectively
over an ethyl (entry 2) and a methyl (entry 3) group. The reaction
required longer to reach completion as the size of the group
decreased. This could be attributable to a greater release of steric
strain for the substrates with larger groups, or possibly to elec-
⇑
Corresponding author. Tel.: +1 203 778 7703.
E-mail address: jonathan.reeves@boehringer-ingelheim.com (J.T. Reeves).
http://dx.doi.org/10.1016/j.tetlet.2015.01.161
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

C. Lorenc et al. / Tetrahedron Letters 56 (2015) 1280–1282
1281
Table 1
Deprotection of N-isopropyl amides with MsOHa
Entry
Substrate
Product
Time (h)
2
Yieldb (%)
92
O
O
O
O
O
O
N
N
N
N
N
N
H
1
4
3
5
7
9
O
N
H
2
4
18
2
86
90
76
71
6
O
N
H
3
8
O
4c
5
N
H
Ph
10
O
Ph
N
H
18
Ph
12
11
O
O
N
N
H
6
2
5
88
79
14
13
O
O
N
N
7
8
H
16
15
O
O
n-C9H21
17
N
n-C9H21
N
H
18
5
83
O
O
N
N
H
X
X
9
10
11
19: X = H
21: X = OMe
23: X = NO2
20: X = H
22: X = OMe
24: X = NO2
24
21
72
72
75
63
a
b
c
Reaction conditions: Amide (1.0 equiv), MsOH (10 volumes), 90 °C.
Isolated yield.
Reaction conducted at 40 °C.
H
O
O
OH
H+
-H+
-H+
H+
NH
NH
+
N
N
N
H
N
R
R
R
MsOH
C
D
N
E
A
90 °C, 2 h
B
O
O
Br
Br
O
52%
1
2
N
R
n
H
Scheme 1. Attempted tert-butyl deprotection of 1 results in N-isopropyl deprotec-
tion to give 2.
F
G
Scheme 2. Proposed mechanism of deprotection.
We have employed anisole as a co-solvent to trap the 4-meth-
oxyphenethyl cation generated from the deprotection of an N-(4-
methoxyphenyl)ethyl secondary amide.7 It seemed plausible that
the isopropyl cation could also be trapped with anisole. The depro-
tection of amide 3 was run in a 1:1 mixture of MsOH and anisole
(Scheme 3). This cleanly gave the product 4 as well as a 6:1 mix-
ture of 4-isopropylanisole 26 and 2-isopropylanisole 27 as deter-
mined by 1H NMR analysis of the crude product mixture.
In conclusion, the deprotection of N-isopropyl tertiary amides
with MsOH has been demonstrated.8 The isopropyl group may be
removed selectively in the presence of other alkyl and aryl groups.
The reaction was demonstrated for alkyl carboxamides with 0, 1, or
2
a-hydrogens to the carbonyl group, as well as for aryl amides.
The cyclohexyl group was shown to deprotect in a similar manner
to the isopropyl group. The isopropyl cation generated in the reac-
tion was trapped with anisole.

1282
C. Lorenc et al. / Tetrahedron Letters 56 (2015) 1280–1282
O
O
MsOH, anisole (1:1 v/v)
N
N
H
+
+
90 °C, 5 h
3
4
OMe
OMe
26
27
Scheme 3. Trapping of the isopropyl cation with anisole.
N-phenyladamantane-1-carboxamide (12):12 white solid; 1H NMR (400 MHz,
CDCl3) d 7.55–7.53 (m, 2H), 7.38–7.28 (m, 3H), 7.10–7.06 (m, 1H), 2.12–2.06
(m, 3H), 1.96 (d, J = 2.6 Hz, 6H), 1.79–1.71 (m, 6H); 13C NMR (100 MHz, CDCl3) d
176.1, 138.1, 128.9, 124.1, 120.0, 41.5, 39.3, 36.5, 28.2; LC–MS (m/z) [M+H]+:
256 (C17H22NO: 256.17).
References and notes
1. (a) Arthur, G. The Amide Linkage: Selected Structural Aspects in Chemistry,
Biochemistry, and Materials Science; Wiley-Interscience, 2000; (b) Pattabiraman,
V. R.; Bode, J. W. Nature 2011, 480, 471–479.
2. (a) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34–46; (b) Beak, P.; Snieckus, V.
Acc. Chem. Res. 1982, 15, 306–312; (c) Snieckus, V. Chem. Rev. 1990, 90, 879–
933.
N-cyclohexyladamantane-1-carboxamide (14):13 white solid; 1H NMR (400 MHz,
CDCl3) d 5.42 (br s, 1H), 3.82–3.70 (m, 1H), 2.06–2.00 (m, 3H), 1.92–1.81
(m, 8H), 1.77–1.65 (m, 8H), 1.64–1.57 (m, 1H), 1.43–1.31 (m, 2H), 1.23–1.04
(m, 3H); 13C NMR (100 MHz, CDCl3) d 176.9, 47.6, 40.4, 39.3, 36.6, 33.2, 28.2,
25.6, 24.9; LC–MS (m/z) [M+H]+: 262 (C17H28NO: 262.22).
3. Reeves, J. T.; Lorenc, C.; Camara, K.; Li, Z.; Lee, H.; Busacca, C. A.; Senanayake, C.
H. J. Org. Chem. 2014, 79, 5895–5902.
N-isopropylcyclohexanecarboxamide (16):14 white solid; 1H NMR (400 MHz,
CDCl3) d 5.32 (br s, 1H), 4.03–4.07 (m, 1H), 2.02–1.97 (m, 1H), 1.89–1.05 (m,
10H), 1.12 (d, J = 6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 175.1, 45.6, 41.0,
29.7, 25.7, 22.8; LC–MS (m/z) [M+H]+: 170 (C10H20NO: 170.15).
4. The deprotection of N-(1-phenylethyl) amides using MsOH in toluene at reflux
has been reported: Paik, S.; Lee, J. Y. Tetrahedron Lett. 2006, 47, 1813–1815.
5. The deprotection of N-benzyl amides using acidic conditions has been
reported: Chern, C.-Y.; Huang, Y.-P.; Kan, W. M. Tetrahedron Lett. 2003, 44,
1039–1041.
6. The deprotection of N-isopropyl benzamides with Na or Li metal under
ultrasound conditions has been reported: Karaman, R.; Fry, J. L. Tetrahedron
Lett. 1990, 31, 941–944.
7. Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Song, J. J.; Rodriguez, S.; Qu, B.; Kim, S.;
Niemeier, O.; Li, Z.; Byrne, D.; Campbell, S.; Chitroda, A.; DeCroos, P.; Fachinger,
T.; Fuchs, V.; Gonnella, N. C.; Grinberg, N.; Haddad, N.; Jäger, B.; Lee, H.; Lorenz,
J. C.; Ma, S.; Narayanan, B. A.; Nummy, L. J.; Premasiri, A.; Roschangar, F.;
Sarvestani, M.; Shen, S.; Spinelli, E.; Sun, X.; Varsolona, R. J.; Yee, N.; Brenner,
M.; Senanayake, C. H. J. Org. Chem. 2013, 78, 3616–3635.
N-isopropyldecanamide (18):15 white solid; 1H NMR (400 MHz, CDCl3) d 5.93–
5.91 (br, 1H), 4.05–3.93 (m, 1H), 2.05 (t, J = 7.4 Hz, 2H), 1.57–1.49 (m, 2H),
1.21–1.15 (m, 12H), 1.06 (d, J = 6.6 Hz, 6H), 0.80 (m, 3H); 13C NMR (100 MHz,
CDCl3) d 172.3, 41.0, 36.8, 31.8, 29.4, 29.3, 29.26, 29.21, 25.9, 22.6, 13.9; LC–MS
(m/z) [M+H]+: 214 (C13H28NO: 214.22).
N-isopropylbenzamide (20):16 tan solid; 1H NMR (400 MHz, CDCl3)
d 7.75
(d, J = 8.3 Hz, 2H), 7.47–7.37 (m, 3H), 6.10 (br s, 1H), 4.34–4.22 (m, 1H), 1.24
(d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 166.8, 134.9, 131.2, 128.3,
126.8, 41.8, 22.7; LC–MS (m/z) [M+H]+: 164 (C10H14NO: 164.11).
N-isopropyl-4-methoxybenzamide (22):17 white solid; 1H NMR (400 MHz, CDCl3)
d 7.72 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.95 (br s, 1H), 4.31–4.23 (m,
1H), 3.82 (s, 3H), 1.25 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 165.5,
161.2, 128.0, 126.6, 113.0, 54.6, 41.1, 22.2; LC–MS (m/z) [M+H]+: 194
(C11H16NO2: 194.12).
8. General procedure for N-isopropyl amide deprotection with MsOH.
N-isopropyladamantane-1-carboxamide (4):9
A round bottomed flask was
charged with amide 3 (400 mg, 1.52 mmol) and methanesulfonic acid (10 vol-
umes, 4.00 mL). The mixture was heated at 90 °C under nitrogen until complete
consumption of starting material was observed by LC–MS and TLC analysis (see
Table 1 for specific reaction times). The reaction mixture was cooled to rt,
diluted with CH2Cl2, and the solution was washed with water twice, dried over
Na2SO4, filtered, and concentrated. The crude product was purified by
chromatography on SiO2 using hexanes/EtOAc to give 4 (308 mg, 92% yield)
as an off-white solid. 1H NMR (400 MHz, CDCl3) d 5.36 (br s, 1H), 4.12–4.00 (m,
1H), 2.06–2.01 (m, 3H), 1.83 (d, J = 2.6 Hz, 6H), 1.76–1.67 (m, 6H), 1.13 (d,
J = 6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 177.0, 40.8, 40.4, 39.3, 36.6, 28.2,
22.8; LC–MS (m/z) [M+H]+: 222 (C14H24NO: 222.19).
N-isopropyl-4-nitrobenzamide (24):17 tan solid; 1H NMR (400 MHz, CDCl3) d
8.28 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 6.01 (br s, 1H), 4.34–4.28 (m,
1H), 1.29 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 165.2, 150.0, 141.0,
128.6, 124.6, 43.0, 23.2; LC–MS (m/z) [M+H]+: 209 (C10H13N2O3: 209.09).
9. Baugh, L. S.; Sissano, J. A. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 1633–
1651.
10. Szostak, M.; Spain, M.; Procter, D. J. Angew. Chem., Int. Ed. 2013, 52, 7237–7241.
11. Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319–329.
12. Brancour, C.; Fukuyama, T.; Mukai, Y.; Skrydstrup, T.; Ryu, I. Org. Lett. 2013, 15,
2794–2797.
13. Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817–
12819.
14. Itsenko, O.; Kihlberg, T.; Langstrom, B. J. Org. Chem. 2004, 69, 4356–4360.
15. Ohta, T.; Kamiya, M.; Nobutomo, M.; Kusui, K.; Furukawa, I. Bull. Chem. Soc. Jpn.
2005, 78, 1856–1861.
N-ethyladamantane-1-carboxamide (6):10 white solid; 1H NMR (400 MHz,
CDCl3) d 5.59 (br s, 1H), 3.31–3.24 (m, 2H), 2.04 (br s, 3H), 1.85 (br s, 6H),
1.76–1.68 (m, 6H), 1.13 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 177.8,
40.5, 39.3, 36.6, 34.1, 28.2, 14.9; LC–MS (m/z) [M+H]+: 208 (C13H22NO: 208.17).
N-methyladamantane-1-carboxamide (8):11 white solid; 1H NMR (400 MHz,
CDCl3) d 5.60 (br s, 1H), 2.80 (d, J = 4.6 Hz, 3H), 2.07–2.01 (m, 3H), 1.85 (d,
J = 2.7 Hz, 6H), 1.78–1.66 (m, 6H); 13C NMR (100 MHz, CDCl3) d 178.6, 40.6,
39.3, 36.6, 28.1, 26.3; LC–MS (m/z) [M+H]+: 194 (C12H20NO: 194.15).
16. Jiang, H.; Liu, B.; Li, Y.; Wang, A.; Huang, H. Org. Lett. 2011, 13, 1028–1031.
17. Przychodzen, W. Heteroat. Chem. 2006, 17, 676–684.