Preparation of secondary and tertiary amides under neutral conditions by photochemical acylation of amines

Article abstract of DOI:10.1055/s-2001-18760

The smooth and neutral acylation of amines to form amides by photoactivation of N-acyl-5,7-dinitroindolines is described. An improved acylation of nitroindolines allows the convenient preparation of N-acylnitroindolines. This reaction makes possible the recycling of the nitroindoline released during the photoactivation.

Full text of DOI:10.1055/s-2001-18760

1968
LETTER
Preparation of Secondary and Tertiary Amides under Neutral Conditions by
Photochemical Acylation of Amines
Preparation of
Se
é
condary an
l
d
T
erti
i
ry
A
m
n
ide
s
under
N
e
eutral ConditionsHelgen, Christian G. Bochet*
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
Fax +41(22)3287396; E-mail: Christian.Bochet@chiorg.unige.ch
Received 17 August 2001
ly.5,6 The 5,7-dinitroindoline 4 studied here offers several
Abstract: The smooth and neutral acylation of amines to form
amides by photoactivation of N-acyl-5,7-dinitroindolines is de-
scribed. An improved acylation of nitroindolines allows the conve-
nient preparation of N-acylnitroindolines. This reaction makes
advantages over its Bni analog.7 Faster reaction times
were observed (up to a factor of 4), most probably due to
an increased electrophilic character arising from the two
possible the recycling of the nitroindoline released during the pho- electron-withdrawing groups,8 combined with a signifi-
cantly higher quantum yield.11 The separation of the
toactivation.
amide and free indoline is greatly facilitated by the insol-
ubility of the latter in cyclohexane, thus avoiding chro-
matographic purification.
Key words: acylations, amides, indoles, photochemistry, protect-
ing groups
The primary aliphatic amines 5a–c reacted smoothly upon
irradiation at 300 nm12 with N-acetyl-dinitroindoline13 2a
to give secondary amides in excellent yields (Scheme 2;
Table 1, entries 1–3). Secondary amines 5d–h also pro-
vided tertiary amides in excellent yields (entries 4–8), ex-
cept in the case of particular steric hindrance (entry 5).
The presence of an adjacent and unprotected alcohol did
not detrimentally interfere, as shown by the acetylation of
(S)-ephedrine 5h in quantitative yield (entry 8). On the
other hand, the poorly nucleophilic aniline derivatives
failed to react (entries 10 and 11), except in the case of the
cyclic indoline 5i (entry 9), although in low yield. Poten-
tially reactive groups such as olefins are tolerated (entry
12). This reactivity pattern parallels the overall trend ob-
served for the acylation of amines with classical meth-
ods.2 The photochemical nature of the reaction was
confirmed by the complete lack of reaction of the amines
in the absence of light (heating at 40 °C in the dark for 16
hours).
The amide functional group is of central importance in or-
ganic chemistry, as it is the linking element between the
amino acids in peptides and proteins.1 The classical routes
to access amides all involve the reaction of an amine with
an activated carboxyl group (anhydride, acid halide or ac-
tivated ester). These reactions have advantages and draw-
backs, extensively described recently by Katritzky et al.2
A desirable feature for this reaction would be a neutral
medium, mild temperature, great tolerance towards nu-
cleophilic centers other than amines, and the possibility of
mixing both reactants and trigger the process at the appro-
priate time. The photoacylation reaction fulfills many of
these requirements (Scheme 1). The very recent commu-
nication by Nicolaou et al. on the use of this reaction for
solid-support chemistry prompted us to disclose now our
recent results in solution phase.3
R1R2NH
no reaction
no light
O
O
NO2
NO2
H
X
R
R1R2NH 5
O
hν
N
N
+
R1R2NH
O
R1R2N
hν (300 nm)
MeCN, 1h
+ XH
R1R2N
R
R
R
6
3 R=Br
4 R=NO2
1a R=Br
2a R=NO2
Scheme 1
Scheme 2
The photoacylation reaction was developed a few decades
ago by Amit and Patchornik,4 with the introduction of the
5-bromo-7-nitroindoline (Bni, 3) photoactivable leaving
group. In this context, the attachment of two peptidic moi-
eties was promoted by UV-irradiation at 360 nm. The ex-
act nature of the mechanism is still unclear, but the
transfer of the acyl group from the indoline nitrogen to
one of the oxygens of the nitro group at C-7 seems like-
In most of the cases, the indoline and the amides were sep-
arated by simple trituration in cyclohexane. The recovery
of the indoline is typically greater than 80%, and recycling
by reacylation did not erode the efficiency of the reaction.
However, the overall efficiency of this process would be
greatly reduced by a cumbersome preparation of the
acylindolines, or by the use of harsh conditions incompat-
ible with many functional groups. To date, three strategies
have been utilized for introducing the acyl group. The
original method involved the acylation of the indoline be-
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1968,1970,ftx,en;G17901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Preparation of Secondary and Tertiary Amides under Neutral Conditions
1969
Table 1 Acetylation of Amines with N-Acetyl-5,7-dinitroindoline
2a
succinic anhydride (1 equiv), followed by esterification
with trimethylsilyl diazomethane (75% overall yield).
Entry
1
Amine R1
R2
Yielda (%)
99 (90)
83 (81)
91 (85)
96 (96)
0
O
NO2
R
H
NO2
5a
5b
5c
5d
5e
5f
n-C12H25
H
O
AlCl3
N
N
+
ClCH2CH2Cl
reflux, 2-6 h
Cl
R
2
c-Hex
H
NO2
NO2
7
4
2
3
PhCH(Me)
H
Scheme 3
Table 2 Preparation of Acylindolines 2 under mild Conditions
4
n-C5H11
n-C5H11
c-Hex
5
c-Hex
6
-(CH2)5-
79 (57)
81 (62)
100 (68)
15 (9)
0
Entry
Acid Chloride
R
Yielda (%)
100 (89)
93 (81)
60
7
5g
5h
5i
-(CH2)2-O-(CH2)2-
PhCH(OH)CH(Me)
-(CH2)2-o-(C6H4)-
4-MeO-(C6H4)
2,6-Me2-(C6H3)
H2C=CH-CH2
1
2
3
4
5
7a
7b
7c
7d
7e
CH3
8
Me
CH2CH3
C11H23
C6H5
9
10
11
12
5j
H
H
H
88 (64)
67
5k
5l
0
(CH2)3Cl
81 (57)
a Determined by 1H NMR; isolated yields in parentheses.20
a Determined by 1H NMR; isolated yields in parentheses.14
N-acyl-5,7-dinitroindolines 2a–f were used to acylate N-
dodecylamine using our standard protocol. In all cases,
high yields of amide were obtained, as shown in Table 3
and Scheme 4. Functionalized side chains were well toler-
ated (entries 5 and 6).
fore the introduction of the nitro group at C-7;6 this meth-
od does not allow the recycling of the indoline, and is
quite inconvenient when dealing with a series of different
acyl groups. The second approach consisted in heating the
Bni indoline 3 in the presence of an acid chloride in tolu-
ene or xylene;15,16 in our hands, the very poorly nucleo-
philic indoline 4 failed to react under classical
acylation.6,11 The last method involved heating the indo-
line with acetyl chloride in acetic acid.17 Although very
successful, this approach is by essence limited to the intro-
duction of an acetyl group. Under these conditions, the
use of propionyl chloride afforded a mixture of the N-
acetyl and N-propionyl compounds.
O
R
NO2
O
hν (300 nm)
N
C12H25NH2
+
C12H25
N
R
MeCN, 1 h
H
NO2
2a-e
8a-e
Scheme 4
In conclusion, we have described a convenient photoacy-
lation reaction leading to high yields of amides by using
only 1 equivalent of both the acylating species and amine.
By using a Lewis acid-promoted reaction, we showed that
the drawbacks associated with the formation of N-acyl-ni-
Hence, we endeavored to optimize the formation of N-
acylindolines to proceed under relatively mild conditions.
The deprotonation of 4 with various strong bases followed
by the addition of an acid chloride failed to afford yields
higher than 30%. We believe that partial O-acylation of
the nitro group, and spontaneous hydrolysis upon workup
were responsible for this observation. As a consequence,
we decided to avoid the basic conditions by choosing in-
stead to activate the acid chloride with a Lewis acid and to
use the neutral indoline. Hence, heating 4 with a slight ex-
cess of an acid chloride 7 (2 equiv)18 in the presence of
aluminum trichloride (2.5 equiv) in 1,2-dichloroethane af-
forded the N-acylindolines 2 in good to excellent yields
(Scheme 3, Table 2). It is worth mentioning that the
choice of the solvent is critical.19 This protocol is compat-
ible with functionalized chains, thus keeping the possibil-
ity for post-modification as shown by Nicolaou et al.3
(entry 5). In addition, we prepared the succinate monom-
ethyl ester derivative 2f by a similar procedure, but using
Table 3 Preparation of Amides using Indolines 2a–f and N-dode-
cylamine
Entry
Indoline
2a
R
Yielda (%)
99 (90)
1
2
3
4
5
6
CH3
2b
CH2CH3
C11H23
100 (99)
98 (86)
2c
2d
C6H5
100 (97)
95 (87)
2e
(CH2)3Cl
CH2CH2COOMe
2f
100 (99)
a Determined by 1H NMR; isolated yields in parentheses.14
Synlett 2001, No. 12, 1968–1970 ISSN 0936-5214 © Thieme Stuttgart · New York

1970
C. Helgen, C. G. Bochet
LETTER
(10) Bamford, C. H.; Norrish, R. G. W. J. Chem. Soc. 1935, 1504.
(11) Adams, S. R.; Kao, J. P. Y.; Tsien, R. Y. J. Am. Chem. Soc.
1989, 111, 7957.
(12) This wavelength was selected for practical reasons (higher
light intensities with a RPR3000 source). We nevertheless
also successfully performed one of the reactions (entry 1) up
to 420 nm (although with a significantly longer reaction time
at this wavelength).
troindolines could be circumvented. The extension of this
method to other types of nucleophiles is currently under
development, and will be disclosed in due course.
Acknowledgement
This work was supported by the Swiss National Science Foundation
grant 2100-57044.99, and by the Fonds Frédéric Firmenich et Phil-
ippe Chuit. The generous support to C. H. by the Janggen-Pöhn Stif-
tung is gratefully acknowledged.
(13) Mortensen, M. B.; Kamounah, F. S.; Christensen, J. B. Org.
Prep. Proc. Int. 1996, 28, 123.
(14) Typical Experimental Procedure: The N-acylated indoline
(0.14 mmol) and the amine (0.14 mmol) were dissolved in
UV-grade anhyd acetonitrile (15 mL) in a quartz vessel, and
the mixture was briefly de-aerated by a stream of argon. The
mixture was then irradiated at 300 nm in a Rayonet®
apparatus equipped with 16 RPR3000 fluorescent tubes for
1 h. Evaporation of the solvent and trituration in cyclo-
hexane gave the pure amide and deacylated nitroindoline 4.
All new compounds were fully characterized by 1H NMR,
13C NMR, IR and MS analysis.
(15) Pass, S.; Amit, B.; Patchornik, A. J. Am. Chem. Soc. 1981,
103, 7674.
(16) Amit, B.; Ben-Efraim, D. A.; Patchornik, A. J. Chem. Soc.,
Perkin Trans. 1 1976, 57.
(17) Gall, W. G.; Astill, B. D.; Boekelheide, V. J. Org. Chem.
1955, 20, 1538.
(18) The excess is small when compared to the other existing
methods. With only 1 equiv of 7a, a yield of 52% of 2a was
obtained.
References
(1) In Amino Acids, Peptides and Proteins. A Specialist
Periodical Report, Vol. 31; Davies, J. S., Ed.; Royal Society
of Chemistry: Oxford, 2000.
(2) Katritzky, A. R.; He, H. Y.; Suzuki, K. J. Org. Chem. 2000,
65, 8210.
(3) Nicolaou, K. C.; Safina, B. S.; Winssinger, N. Synlett 2001,
900.
(4) (a) Amit, B.; Ben-Efraim, D. A.; Patchornik, A. J. Am.
Chem. Soc. 1976, 98, 843. (b) For other types of
photoacylation reactions, see: Burton, L. P. J.; White, J. D.
Tetrahedron Lett. 1980, 21, 3147. (c) See also: Confalone,
P. N.; Woodward, R. B. J. Am. Chem. Soc. 1983, 105, 902.
(d) For synthetic applications, see ref. 15.
(5) Papageorgiou, G.; Ogden, D. C.; Barth, A.; Corrie, J. E. T. J.
Am. Chem. Soc. 1999, 121, 6503.
(6) Goissis, G.; Erickson, B. W.; Merrifield, R. B. Pept., Proc.
Am. Pept. Symp. 5th 1977, 559.
(19) Many solvents were found inappropriate, such as EtOAc,
DMSO, acetonitrile or THF.
(20) Typical Experimental Procedure: A solution of indoline 4
(0.21 mmol), aluminum trichloride (0.51 mmol) and acid
chloride 7 (0.41 mmol) was refluxed in 1,2-dichloroethane
(5 mL) for 2 to 6 h. Extraction and washing the solid with
cyclohexane gave the indolines 2. All new compounds were
fully characterized by 1H NMR, 13C NMR, IR and MS
analysis.
(7) Such dinitroindoline underwent aminolysis when irradiated
in an ammonia-containing solvent. See ref.4a.
(8) When other reactive chromophores are present on the
substrate, it is critical to maintain reaction times as short as
possible.9 For example, carbonyl groups can react with UV-
light by Norrish-type reactions.10
(9) (a) Bochet, C. G. Tetrahedron Lett. 2000, 41, 6341.
(b) Bochet, C. G. Angew. Chem. Int. Ed. 2001, 40, 2071.
Synlett 2001, No. 12, 1968–1970 ISSN 0936-5214 © Thieme Stuttgart · New York