General and Chemoselective N-transacylation of secondary amides by means of perfluorinated anhydrides

Article abstract of DOI:10.1002/anie.200906055

A direct route: The N-transacylation of secondary amides to their perfluorinated analogues with the possibility of subsequent conversion into a normal amide is reported (see scheme). This reaction occurs in the presence of a variety of functional groups that are labile to the hydrolysis conditions required by classical N-transacylation. Chemical equation representation

Full text of DOI:10.1002/anie.200906055

Communications
DOI: 10.1002/anie.200906055
Transacylation
General and Chemoselective N-Transacylation of Secondary Amides
by Means of Perfluorinated Anhydrides**
Paola Rota,* Pietro Allevi, Raffaele Colombo, Maria L. Costa, and Mario Anastasia
Examples of direct N-transacylations of amides are very rare
and lacking in general applicability. For instance, earlier
attempts at N-transacylation were performed under harsh
conditions.[1] Other procedures required prolonged treatment
with an equimolar mixture of trifluoroacetic acid (TFA) and
trifluoroacetic anhydride (TFAA; 1008C, 48 h),[2,3] or even
running the reaction in TFAA followed by the addition of a
strong base, reported as necessary to abstract the hydrogen
atom in the alpha position to the eliminated acyl group.[4]
Finally, some acetanilides were treated with chloroacetyl
chloride under acid catalysis of zeolites or AlCl3 at 838C for
16 h,[5] or in refluxing pyridine containing dimethylaminopyr-
idine for 5 h.[6]
Thus, N-transacylations are usually accomplished by
hydrolysis of the acylamides and successive re-acylation of
the formed amines,[7] a procedure that does not allow the
simultaneous presence, in the amide molecule, of functional
groups labile to the basic or acidic conditions of the hydro-
lysis.[7d,8] Herein, we report the first direct, general, and
chemoselective procedure for the N-transacylation of secon-
dary acylamides to their perfluorinated analogues, in high
yields, with perfluorinated anhydrides. Remarkably, the
perfluorinated amide formed could then be directly converted
to a different amide by simple treatment with the desired acyl
chloride, followed by a very mild aqueous process of the
reaction mixture.
5 min, in CH3CN),[10] we did not obtain the expected
derivative 1b but the lactone 2b, which could be quantita-
tively transformed into lactone 2a by treatment of the
reaction mixture with methanol at room temperature.
Prompted by these initial results, we explored the scope of
this new reaction (Table 1). Because of the particular utility of
the reaction in carbohydrate chemistry,[7a] we started with
some sialic acid and amido sugar derivatives of interest in
organic synthesis and in biological studies.[11] In particular, we
were interested in testing molecules containing groups labile
to the commonly used conditions of amide hydrolysis and re-
acylation. In effect, our reaction conditions allowed the
successful N-transacylation of several compounds containing
a great variety of functional groups (often within the same
molecule), such as hydroxy groups, lactones, benzyloxycar-
bonyls (OCbz), methyl esters, acetates, tert-butyldimethylsilyl
(TBDMS) groups, and acyclic and cyclic acetals as their
2-methoxyethoxymethyl (MEM), methyl, and benzylidene
derivatives (Table 1, entries 1–18). Moreover, to test possible
anomerizations resulting from the perfluorinated acid liber-
ated in the reaction, we tested a- and b-glycosidic compounds
as well as a b-disaccharide. Finally, we selected carbohydrates
with an equatorial or an axial acetamido group, to test the
possible influence of the amide geometry.
The study was first performed with HFBAA,[10a] then the
reaction was repeated on some representative samples with
TFAA, which gave comparable results (Table 1, entries 3, 13,
14, and 17). In all cases, except for entry 7, the reaction
occurred in good yields, chemoselectively, and involving
exclusively the amido group independently of its equatorial or
axial geometry. Other functional groups present in the treated
compounds were conserved, with the exception of free
hydroxy, alcoholic, or acetalic groups, which, as expected,
were perfluoroacylated (mass spectrometry (MS) and NMR
evidence) under the reaction conditions employed. However,
they could be easily regenerated by simple, short treatment of
the crude reaction mixture with a solution of aqueous TFA in
THF.
Our work originated while studying sialic acid 1,7-lactone
1a.[9] Surprisingly, on reacting the lactone 1a with heptafluor-
obutyric anhydride (HFBAA) to volatilize it (1358C for
Only acyclic acetals appeared to be labile under the
reaction conditions, as observed for the MEM group (Table 1,
entry 7). Remarkably, analysis of the 1H NMR spectra of
compounds 4, 6, 8, 10, 12, 14, and 16 clearly showed in all cases
that the reaction does not modify the configuration of the
anomeric centers (see the Supporting Information). The
anomeric geometry for the sialic acid derivative 8a, which
lacks the anomeric proton, was established on the basis of the
values of the heteronuclear vicinal coupling constant (3JC1,H3ax
and 2JC2,H3ax).[12,13]
[*] Dr. P. Rota, Prof. Dr. P. Allevi, Dr. R. Colombo, Dr. M. L. Costa,
Prof. Dr. M. Anastasia
Department of Medical Chemistry, Biochemistry, and Biotechnology
University of Milan
via Saldini 50, 20133 Milano (Italy)
Fax: (+39)02-5031-6040
E-mail: paola.rota@unimi.it
[**] This work was financially supported by the Italian Ministero
dell’Universitꢀ e della Ricerca (MiUR).
To further study the general applicability of the reaction,
we tested it on other non-carbohydrate compounds, including
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906055.
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Table 1: N-Transacylation of secondary amides by the action of perfluorinated anhydrides.[a]
Entry Substrate
Product
t
Yield
[min] [%][b]
1
2
3
3a: R1 =H
3b: R1 =Ac
3b
4a: R1 =H;n=2[c]
4b: R1 =Ac;n=2
4c: R1 =Ac;n=0
5
5
5
79
82
80
4
5
6
7
5a: R1 =R2 =H
6a: R1 =R2 =H[c]
5
5
5
5
89
84
78
–
5b: R1 =R2 =Ac
6b: R1 =R2 =Ac
5c: R1 =Ac;R2 =TBDMS
5d: R1 =Ac;R2 =MEM
6c: R1 =Ac;R2 =TBDMS
mixture of compounds
8
9
7a: R1 =OMe[e]
7b: R1 =H
8a: R1 =OMe[e]
8b: R1 =H
5
5
53
82
10
11
12
13
14
9a: R1 =R2 =H;R3 =OH[d]
9b: R1 =Ac;R2 =H;R3 =OAc[e]
9c: R1 =Ac;R2 =OAc;R3 =H[e]
9b[e]
10a: R1 =R2 =H;R3 =OH;n=2[c,d]
10b: R1 =Ac;R2 =H;R3 =OAc;n=2[e]
10c: R1 =Ac;R2 =OAc;R3 =H;n=2[e]
10d: R1 =Ac;R2 =H;R3 =OAc;n=0[e]
10e: R1 =R2 =H;R3 =OH;n=0[c,d]
5
5
5
5
5
83
87
92
85
86
9a[d]
15
11[e]
12[e]
5
63
16
17
13[f]
13[f]
14a: n=2[f]
14b: n=0[f]
5
5
81
79
18
15[e]
16[e]
5
90
19
20
21
17a: R=Ac
17b: R=tBuCO
17c: R=Bn
18a: R=Ac
18b: R=tBuCO
18c: R=Bn
15
15
15
88
84
56
22
23
24
19a: R=Ac
19b: R=tBuCO
19c:R=iPrCO
20a: R=Ac
20b: R=tBuCO
20c: R=iPrCO
15
15
15
91
84
88
25
26
21
21
22a: n=2
22b: n=0
90
90
92
89
27
23
24
30
87
[a] Reaction conditions: acylamide (0.2 mmol) in MeCN (600 mL) was reacted with the perfluorinated anhydride (0.6–1.4 mmol) at 1358C in a sealed
tube. [b] Yield of isolated compound. [c] Isolated, by hydrolysis after 1 h of treatment of the final reaction mixture with TFA in H2O/THF at 608C.
[d] Anomeric mixture, a/b 85:15. [e] a Anomer. [f] Anomeric mixture, a/b 18:82.
their protective groups and also the benzyl (Bn) group
(Table 1, entries 19–27). Some of these compounds allowed
validation that the reaction is not limited to acetyl amides, but
could be successfully performed on hindered acylamides and
with amides lacking an a-hydrogen atom (Table 1, entries 20,
23, and 24). Other examples were chosen to verify that the
reaction was not limited to compounds bearing a substituent
(acetoxy or hydroxy group) at the a position of the amidic
nitrogen atom (Table 1, entries 25 and 26). Interestingly, the
reaction also worked with protected amino acids such as the
acetyl phenylalanine methyl ester 23 (Table 1, entry 27),
which is transformed into its heptafluorobutyrate analogue 24
in satisfactory yields and without any racemization, as
demonstrated by its gas–liquid chromatography (GLC)
analysis on a chiral column (see the Supporting Information).
This latter result shows that the new reaction, besides being
crucial for amino acid analysis, may represent a tool to
selectively regenerate the amino group of acetylated amino
esters.[2,14]
Finally, we performed some additional experiments to
rationalize the reaction course and suggest a possible
mechanism. For this purpose, we chose the 1,3,4,6-tetra-O-
acetyl-2-acetamido-2-deoxy-a-d-glucopyranoside
(9b)
(Scheme 1) as a model compound, and reacted it with
TFAA in CD3CN at room temperature. By monitoring the
reaction course with 1H NMR spectroscopy, we observed
from some diagnostic changes in the 1H NMR spectrum of the
reaction mixture that the starting amide 9b was almost
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Communications
Scheme 2. N-transperfluoroacylation of acetanilide.
Scheme 1. N-transperfluoroacylation of N-acetylglucosamine.
27. In fact, in the final reaction mixture, the imide 27 was only
accompanied by minor amounts of the starting imide 26 (ca.
3%) and by trace amounts (0.6%) of the acetanilide 21 (GLC
analysis). Moreover, when the reaction mixture was heated at
1358C for 5 min, it afforded the transacylated amide 22a as
expected.
All this evidence describes the observed N-transacylation
as a consecutive reaction, with a fast pre-equilibrium between
the starting amide A and the intermediary mixed imide B,
which is more slowly transformed into the perfluorinated
amide C (Scheme 3).
instantly transformed into the mixed imide 25 (90% yield,
accompanied by 10% of the starting amide 9b). Interestingly,
the mixed imide 25 was stable in the reaction mixture but
completely reverted to the starting amide 9b when the more
volatile TFAA and TFA were removed from the reaction
mixture by a direct stream of nitrogen. This suggested that the
amide 9b and the imide 25 were in a rapid equilibrium and
that the removal of TFAA, which is more volatile than its
acid, drives the reaction back to the starting acetyl amide 9b.
On the contrary, when the reaction mixture containing the
imide 25 was heated at 1358C for 5 min, or kept at room
temperature for 6 days, the trifluoroacetamide 10d was
quantitatively obtained (Scheme 1). Moreover, while mon-
itoring the reaction course by 1H NMR spectroscopy at 258C,
we observed a slow increase of the final amide 10d which was
accompanied by a parallel progressive decrease of the imide
25 and of the starting amide 9b, although they maintained a
constant reciprocal ratio during the entire reaction course.
Furthermore, we also observed that the final fluorinated
acylamide 10d was practically irreversibly formed. In fact, it
could not be converted into the imide 25 or into the non-
fluorinated analogue 9b by treatment with acetic anhydride
or other non-fluorinated anhydrides, or with the mixed
anhydride CF3COOCOCH3 under various conditions. In
addition, the trifluoroacetylated amide 10d did not react
with TFAA or HFBAA.
The existence of a rapid equilibrium between the amide
9b and the imide 25 was also confirmed by a different
experiment, in which we first formed the imide 25 (1H NMR,
in CD3CN) and then added a strong excess of HFBAA
(40 molar equiv) to the reaction mixture and heated it for
5 min at 1358C. Under these conditions, we obtained the
heptafluorobutyrate amide 10b as the main product, together
with trace amounts of the trifluoroacetate analogue 10d.
A parallel result was reached upon studying the reaction
of the acetanilide 21, which formed the trifluoroacetylated
imide 26 that was stable and isolable by distillation (Sch-
eme 2).[1e] In this case, we prepared the pure imide 26 and
subjected it to a short treatment (5 min) with a strong excess
of HFBAA (40 molar equiv) at room temperature. Under
these conditions the trifluoroacetate imide was quantitatively
transformed into the homologous heptafluorobutyrate imide
Scheme 3. Suggested mechanism of the N-transacylation of amides,
with k2 <k1 and kÀ1
.
This rationalization of the reaction mechanism suggested
the possibility of reverting the N-transacylation and trans-
forming the fluorinated amide C into the starting non-
fluorinated (normal) amide A, or into a different acylamide.
This remarkable and unprecedented goal could be achieved
as long as appropriate acylation reagents were found to attack
the poorly reactive perfluorinated amide C. In fact, at the
beginning of our work we observed that by the action of
water, imides such as B lose the perfluorinated acyl group
affording the parent amide A. In effect, after some unsuc-
cessful attempts, we reached a positive result by reacting, in
separate experiments, the trifluoroacetylanilide 22b with
acetyl, propionyl, and pivaloyl chlorides in the presence of
triethylamine (Table 2, entries 1–3).
Under these conditions, after a short reaction time
(20 min), we observed the disappearance of the starting
amide 22b and the appearance of the intermediary mixed
imides (GLC–MS evidence) which, by simple aqueous
workup of the reaction mixtures, afforded the non-fluorinated
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Table 2: N-Transacylation of perfluorinated amides by the action of acyl
chlorides.
Keywords: amides · chemoselectivity ·
perfluorinated anhydrides · synthetic methods · transacylation
.
Entry Substrate R1
R2
Product Yield [%][a]
[1] a) G. S. Kulikova, V. E. Kirichenko, K. I. Pashkevich, Zh. Anal.
Khim. 1989, 44, 1148; b) S. Nagubandi, G. Fodor, Heterocycles
1981, 15, 165; c) M. Michman, D. Meidar, J. Chem. Soc. Perkin
Trans. 2 1972, 300; d) M. Michman, S. Patai, I. Shenfeld, J. Chem.
Soc. C 1967, 1337, and references therein; e) E. J. Bourne, S. H.
Henry, C. E. M. Tatlow, J. C. Tatlow, J. Chem. Soc. 1952, 4014.
[2] B. Nilsson, S. Svensson, Carbohydr. Res. 1978, 62, 377.
[3] Under these conditions some 2-acetamido-2-deoxy sugars are
severely degraded, see: a) B. Nilsson, S. Svensson, Carbohydr.
Res. 1978, 65, 169; b) B. Nilsson, S. Svensson, Carbohydr. Res.
1979, 72, 183.
1
2
3
22b
22b
22b
Ph
Ph
Ph
Me
Et
Me3C
21
28
29
65[b]
60[b]
64[b]
4
5
4c
Me
Me
3b
9b
71[c]
70[c]
10d
[4] A. G. M. Barrett, J. Chem. Soc. Perkin Trans. 1 1979, 1629.
[5] a) H. R. Sonawane, A. V. Pol, P. P. Moghe, A. Sudalai, S. S.
Biswas, Tetrahedron Lett. 1994, 35, 8877; b) H. R. Sonawane,
A. V. Pol, B. S. Nanjundiah, A. Sudalai, J. Chem. Res. Synop.
1998, 90.
[a] Yield of isolated compound. [b] Reaction conditions: the acyl chloride
(0.6 mmol) was added at 08C to a solution of trifluoroacetyl anilide (22b,
0.2 mmol) and triethylamine (0.64 mmol) in CH2Cl2 (500 mL). [c] Reac-
tion conditions: the acetyl chloride (0.6 mmol) was added at 08C to a
solution of trifluoroacetamide (4c or 10d, 0.1 mmol) and diisopropyle-
thylamine (2.0 mmol) in CH2Cl2 (500 mL).
[6] Y. Li, C. Li, P. Wang, S. Chu, H. Guan, B. Yu, Tetrahedron Lett.
2004, 45, 611.
[7] For some examples of multistep transacylations, see: a) C.
De Meo, U. Priyadarshani, Carbohydr. Res. 2008, 343, 1540;
b) I. Hemeon, A. J. Bennet, Synthesis 2007, 1899; c) H. Myszka,
D. Bednarczyk, M. Najder, W. Kaca, Carbohydr. Res. 2003, 338,
133; d) M. Oba, M. Tanaka, M. Kurihara, H. Suemune, Helv.
Chim. Acta 2002, 85, 3197; e) K. Ikeda, K. Konishi, K. Sano, K.
Tanaka, Chem. Pharm. Bull. 2000, 48, 163.
[8] See, for example: a) T. Q. Gregar, J. Gervay-Hague, J. Org.
Chem. 2004, 69, 1001; b) H. Ando, Y. Koike, H. Ishida, M. Kiso,
Tetrahedron Lett. 2003, 44, 6883; c) A. A. Sherman, O. N.
Yudina, A. S. Shashkov, V. M. Menshov, N. E. Nifantiev, Carbo-
hydr. Res. 2002, 337, 451; d) T. Axenrod, J. Sun, K. K. Das, P. R.
Dave, F. Forohar, M. Kaselj, N. J. Trivedi, R. D. Gilardi, J. L.
Flippen-Anderson, J. Org. Chem. 2000, 65, 1200.
amides (21, 28, or 29). The applicability of the reaction to
more complex molecules was then satisfactorily proved by
operating on N-trifluoroacetyl lactone 4c (Table 2, entry 4)
and N-trifluoroacetylglucosamine 10d (Table 2, entry 5), and
performing the reaction with acetyl chloride in the presence
of excess diisopropylethylamine.
All these results permit the conclusion that our
N-transacylation reaction is general in scope and of high
utility in organic chemistry. Moreover, the two-step replace-
ment of an acyl group of a secondary amide with a different
one through the formation of a trifluorinated intermediate
allows one to prepare in a simple way the acyl analogues of a
variety of molecules having synthetic or pharmaceutical
applications.[15] Not less importantly, the disclosure of this
reaction is of high utility in analytical protocols where the
overlooking of this N-transacylation may be a pitfall affording
puzzling results. Work is ongoing in our laboratory to apply
the new knowledge to synthetic and analytical protocols.
[9] R. Colombo, M. Anastasia, P. Rota, P. Allevi, Chem. Commun.
2008, 5517.
[10] a) D. Bratosin, C. Palii, A. D. Moicean, J. P. Zanetta, J.
Montreuil, Biochemie 2007, 89, 355; b) J. P. Zanetta, V. Sriniva-
san, R. Shauer, Biochemie 2006, 88, 171, and references therein.
[11] For an interesting review on sialic acid chemistry, see: a) F.
Kimio, Trends Glycosci. Glycotechnol. 2004, 89, 143.
[12] J. Haverkamp, T. Spoormaker, L. Dorland, J. F. G. Vliegenthart,
R. Schauer, J. Am. Chem. Soc. 1979, 101, 4851.
[13] a) S. Prytulla, J. Lambert, J. Lauterwein, M. Klessinger, J. Thiem,
Magn. Reson. Chem. 1990, 28, 888; b) S. Prytulla, J. Lauterwein,
M. Klessinger, J. Thiem, Carbohydr. Res. 1991, 215, 345.
[14] D. J. Silva, H. Wang, N. M. Allanson, R. K. Jain, M. J. Sofia, J.
Org. Chem. 1999, 64, 5926.
Experimental Section
General procedure: The acylamide (0.2 mmol) dissolved in CH3CN
(600 mL) was reacted with the perfluorinated anhydride (0.6–
1.4 mmol) at 1358C for the time reported in Table 1. Then the
reaction mixture was ice-cooled, methanol (200 mL) was added, and
the solvent was removed under vacuum to afford the crude
N-transacylated amidic compound, which was purified by column
chromatography. More specific workup is reported in the Supporting
Information. Comparable results were obtained at room temperature
but with longer reaction times (1 week).
[15] a) J. C. Biffinger, H. W. Kim, S. G. DiMagno, ChemBioChem
2004, 5, 622; b) J. Jubert, S. Roussel, C. Christophe, T. Billard,
B. R. Langlois, T. Vidal, Angew. Chem. 2003, 115, 3241; Angew.
Chem. Int. Ed. 2003, 42, 3133.
Received: October 28, 2009
Revised: December 1, 2009
Published online: February 9, 2010
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