N-Acylation of amides with acid anhydrides by way of dual activation using MgBr2·OEt2

Article abstract of DOI:10.1016/S0040-4039(01)02208-0

A new practical method for the N-acylation of amides is described. Acylation of various amides with acid anhydrides in the presence of MgBr₂·OEt₂ gave the corresponding N-acylamides in good to moderate yields. The present method is a

Full text of DOI:10.1016/S0040-4039(01)02208-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 647–651
N-Acylation of amides with acid anhydrides by way of dual
activation using MgBr2·OEt2
Shinji Yamada,* Setsuko Yaguchi and Kaori Matsuda
Department of Chemistry, Faculty of Science, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan
Received 18 October 2001; revised 14 November 2001; accepted 16 November 2001
Abstract—A new practical method for the N-acylation of amides is described. Acylation of various amides with acid anhydrides
in the presence of MgBr2·OEt2 gave the corresponding N-acylamides in good to moderate yields. The present method is applicable
to amides that are labile to acids or bases. © 2002 Elsevier Science Ltd. All rights reserved.
An acyclic N-acylamide core constitutes various natural
products such as immunosuppressant microcolin A and
B,1 anticancer agent dolastatin 15,2 antibiotic alth-
iomycin,3 antifeedant ypaoamide,4 and neurotoxin jano-
resonance. Reported methods for the N-acylation by a
combination of amides and acyl donors are as follows:
lithiated amide–acyl chloride,8 trimethylsilylated amide–
acyl chloride,9,10 phosphoramidate–carboxylic acid,11
lithiated amide–pentafluorophenyl esters,12,13 amide–
MeMgBr–acyl chloride,14 amide–p-toluenesulfonic acid–
enol ester,15 amide–LiCl–acid anhydride,16 amide–
sulfuric acid–acid anhydride.17 However, these methods
are not always applicable to amides that are labile to acids
and bases.12a,18,19 Therefore, discovery of a more mild
method continues to attract the attention of researchers.
lusimide.5
In
addition,
N-acyloxazolidinone,6
N-acylsultam7 and related compounds, which have been
utilized in various asymmetric syntheses, also possess an
N-acylamide core. To construct these N-acylamide struc-
tures, activation of amides and/or acyl donors is generally
required, since the nitrogen atom of amides is less basic
than that of the corresponding amines due to amide
Keywords: amides; acylation; lactams; imides; magnesium and compounds.
* Corresponding author. Tel.: +81-3-5978-5349; fax: +81-3-5978-5715; e-mail: yamada@cc.ocha.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02208-0

648
S. Yamada et al. / Tetrahedron Letters 43 (2002) 647–651
We paid attention to a dual activation method for the
acylation of congested alcohols,20 where MgBr2·OEt2
activates both an alcohol and an acid anhydride, and
studied its applicability to the N-acylation of amides.
Thus, MgBr2·OEt2 is expected to generate N-magnesium-
amides and acid bromides from the corresponding
amides and acid anhydrides, respectively (Scheme 1).
Here we report a new practical and mild method for the
N-acylation of amides using MgBr2·OEt2, which is
effective even for amides that are labile to acids or
bases.
acyloxindole 222 as a major product. The use of 3 equiv.
of MgBr2·OEt2 resulted in excellent chemoselectivity.
Their structures were elucidated by IR and 13C NMR
spectroscopies; the IR spectra showed two amide car-
bonyl absorption bands for 2 (1699 and 1620 cm−1) and
an ester carbonyl and NH absorption bands for 3 (1753
and 3381 cm−1); in addition, the 13C NMR spectra
suggested the existence of two carbonyl carbons for 2 (l
182.2 and 174.0) and a carbonyl and an enol carbons
for 3 (l 175.5 and 143.7, respectively). To clarify the
role of MgBr2·OEt2 in this selective acylation reaction,
IR spectroscopic analysis for the reaction intermediate
4 was carried out. The IR spectrum of 4 produced from
oxindole with MgBr2·OEt2 in the presence of Et3N
showed no NH absorption, whereas the carbonyl
absorption band appeared at 1686 cm−1, which is lower
than that of oxindole (1699 cm−1). These observations
suggest that the complex has a structure the N-atom of
which coordinates to MgBr2, as shown in Scheme 2.
The combination of this activated amide 4 and the acid
bromide generated in situ from acid anhydride with
As a model compound, oxazolidinone was selected
because of the significant utility of its N-acyl derivatives
in organic synthesis. The results are shown in Table 1.
The trimethylacetylation with pivalic anhydride or
pivaloyl chloride in the presence of Et3N scarcely gave
the desired product (entries 1 and 2). Remarkable is
that addition of 2.0 equiv. of MgBr2·OEt2 gave a
N-pivaloyloxazolidinone21 in significantly improved
yields (entries 3 and 4); in particular, the combination
of pivalic anhydride and MgBr2·OEt2 resulted in the
highest yield. MgCl2 and CsF were less effective than
MgBr2·OEt2 (entries 5 and 6). Although other acid
anhydrides were also available, the steric bulkiness of
the anhydrides was responsible for the product yields;
as the steric bulkiness decreased (entries 7 and 8), the
product yield decreased.
20
MgBr2·OEt2 would facilitate the N-acylation of oxin-
dole (Scheme 2). On the other hand, acylation with
pivaloyl chloride in the presence of Et3N would proceed
through enol 5 to give an O-acylation product.
It has been well known that acylation of alcohols and
amides possessing an acyloxy group near the fuctionali-
ties often accompanies a migration of the acyl group.
Pivaloylation of (S)-5-oxopyrrolidin-2-yl methyl acetate
6 with pivaloyl chloride using a sodium hydride as a
base yielded a 76:24 mixture of N-pivaloylamide 7 and
N-acetylamide 8 (62% yield), as shown in Scheme 3.
This method is applicable to amides that tend to receive
O-acylation. Acylation of oxindole with pivaloyl chlo-
ride exclusively gave O-acyl compound 322 (Table 2).
In contrast, acylation with pivalic anhydride in the
presence of 2 equiv. of MgBr2·OEt2 afforded N-
O
O
+
R3
O
MgBr2·OEt2
NHR2
NR2MgBr
R1
R1
R1
+
N
R2
O
Et3N
(R3CO)2O
R3COBr
Scheme 1.
Table 1. Acylation of oxazolidinone with an acid chloride or acid anhydrides in the presence of Lewis acids
O
O
O
a : R = tBu
Acyl donor / Lewis acid
i
b
c
: R = Pr
: R = Me
R
HN
O
N
O
Et3N, CH2Cl2, 0°C, 4h
1
Entry
Acyl donor (equiv.)
Lewis acid (equiv.)
Product
Yield (%)a
1
2
3
4
5
6
7
8
(tBuCO)2O (2)
tBuCOCl (2)
–
–
–
N.r.
13
80
58
35
28
68
52
1a
1a
1a
1a
1a
1b
1c
(tBuCO)2O (2)
tBuCOCl (2)
MgBr2·OEt2 (2)
MgBr2·OEt2 (2)
MgCl2 (2)
CsF (2)
MgBr2·OEt2 (2)
MgBr2·OEt2 (2)
(tBuCO)2O (2)
(tBuCO)2O (2)
(iPrCO)2O (3)
(CH3CO)2O (3)
a Isolated yield.

S. Yamada et al. / Tetrahedron Letters 43 (2002) 647–651
Table 2. Acylation of oxindole with pivalic anhydride or pivaloyl chloride
649
Acyl donor / Lewis acid
O
O
OCOtBu
+
CH2Cl2, Et3N, 0°C
N
H
N
N
H
COtBu
2
3
Acyl donor (equiv.)
Lewis acid (equiv.)
Time (h)
Yield (%)a
Ratio (2:3)b
(tBuCO)2O (3)
tBuCOCl (2)
–
–
6
7
7
7
N.r.
–
82 (\99)
47 (55)
67 (91)
0:100
66:34
100:0
(tBuCO)2O (2)
(tBuCO)2O (2)
MgBr2·OEt2 (2)
MgBr2·OEt2 (3)
a Isolated yield. Conversion yield is shown in parenthesis.
b Determined by 1H NMR spectroscopy.
MgBr2
(RCO)2O
RCOBr
2
MgBr2 / Et3N
O
N
MgBr
4
5
O
N
H
Et3N
RCOCl
OH
3
N
H
Scheme 2.
a or b
OCOCH3
OCOtBu
OCOCH3
+
O
O
O
N
H
N
N
COtBu
COCH3
6
7
8
a : tBuCOCl, NaH, THF, 0°C, 6h
b : (tBuCO)2O, MgBr2·OEt2, CH2Cl2, Et3N, r.t., 1.5h
76
:
:
24
0
62%
65%
100
Scheme 3.
been prepared by the reaction of the PFP-ester with
lithiated amide at −78°C.12 Acylation of lactam 9
with acid anhydride 1023 in the presence of
MgBr2·OEt2 at rt for 6 h afforded imide 11 in 73%
yield (Scheme 4),24 the specific rotation of which
([h]D −41, c 0.092, CHCl3) is almost in agreement
with that reported ([h]D −46, c 0.092, CHCl3),12a indi-
cating no isomerization of the chiral center adjacent
to the amide functionality during the acylation reac-
tion.
This by-product 8 would be a result of the initial
O,N-acyl migration through a five-membered transi-
tion state and subsequent O-pivaloylation. In con-
trast, acylation by the present method proceeded
chemoselectively to give 7 in 65% yield without
migration of the acetyl group.
The utility of the present method was demonstrated
by the preparation of a synthetic intermediate 1112 of
immunosuppressant agent microcolin B, which has
O
MgBr2·OEt2
N
+
O
O
CO
N
H
N
CH2Cl2, Et3N, rt
N
O
Cbz
2
Cbz
9
10
11
Scheme 4.

650
S. Yamada et al. / Tetrahedron Letters 43 (2002) 647–651
O
O
O
O
BuLi
HN
R
N
janolusimide
+
R
OC6F5
O
O
12
2.8 : 1
Figure 1. Reported coupling reaction of 12 with a PFP ester.
O
O
References
(RCO)2O / MgBr2·OEt2
R
N
12
1. Koehn, F. E.; Longley, R. E.; Reed, J. K. J. Nat. Prod.
1992, 55, 613.
ClCH2CH2Cl, Et3N,
reflux, 24h
O
2. Pettit, G. R.; Kamano, Y.; Dufresne, C.; Cerny, R. L.;
Herald, C. L.; Schmidt, J. M. J. Org. Chem. 1989, 54,
6005.
13 : R = CH3 52% (67%)
14 : R = CH2CH3 42% (59%)
3. Nakamura, H.; Iitaka, Y.; Sakakibara, H.; Umezawa, H.
J. Antibiot. 1974, 27, 894.
4. Nagle, D. G.; Paul, V. J.; Roberts, M. A. Tetrahedron
Lett. 1996, 37, 6263.
Scheme 5.
5. Sodano, G.; Spinella, A. Tetrahedron Lett. 1986, 27,
2505.
6. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem.
Soc. 1982, 104, 1737.
7. Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett.
1989, 30, 5603.
8. Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83.
9. (a) Rothe, M.; To´th, T.; Daser, R. Chem. Ber. 1966, 99,
3820; (b) Thom, C.; Kocienski, P. Synthesis 1992, 582.
10. Mattern, R.-H.; Gunasekera, S. P.; McConnell, O. J.
Tetrahedron Lett. 1997, 38, 2197.
This method is applicable to amides that are susceptible
to epimerization. Amide 12 is a precursor for the total
synthesis of janolusimide, as shown in Fig. 1,18 where a
coupling of 12 with a pentafluorophenyl ester resulted
in considerable isomerization at the chiral center adja-
cent to the amido moiety (a 2.8:1 mixture of
diastereomers). This means that the amide 12 is
extremely labile to the reaction conditions due to hav-
ing a very acidic hydrogen at the chiral center between
the carbonyl and amido moieties. This prompted us to
investigate the applicability of the present method to
the acylation of 12. Attempts to prepare N-acetylamide
13 from 12 using the present method under the condi-
tions described above gave no desired product. How-
ever, when the reaction was conducted in
dichloroethane at reflux temperature for 24 h, 13 was
obtained in 52% isolated yield (67% conversion yield)
(Scheme 5). Similarly, acylation with propionic anhy-
dride afforded 14 in 42% isolated yield (59% conversion
yield). Comparison of the HPLC chromatogram of 13
with that of the racemic one clarified that the extent of
isomerization is less than 6%.25 It is interesting to note
that an acylation of the lithiated amide with acetyl
chloride exclusively gave an O-acetyl product instead of
N-acetylamide.
11. Kunieda, T.; Higuchi, T.; Abe, Y.; Hirobe, M. Tetra-
hedron 1983, 39, 3253.
12. (a) Andrus, M. B.; Li, W.; Keyes, R. F. J. Org. Chem.
1997, 62, 5542; (b) Andrus, M. B.; Li, W.; Keyes, R. F.
Tetrahedron Lett. 1998, 39, 5465.
13. Tomasini, C.; Villa, M. Tetrahedron Lett. 2001, 42, 5211.
14. Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1988, 110, 1238.
15. Rothman, E. S.; Serota, S.; Swern, D. J. Org. Chem.
1964, 29, 646.
16. Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
17. Baburao, K.; Costello, A. M.; Petterson, R. C.; Sander,
G. E. J. Chem. Soc. (C) 1968, 2779.
18. Giordano, A.; Monica, C. D.; Landi, F.; Spinella, A.;
Sodano, G. Tetrahedron Lett. 2000, 41, 3979.
19. Weinstock, L. M.; Karady, S.; Roberts, F. E.;
Hoinowski, A. M.; Brenner, G. S.; Lee, T. B. K.;
Lumma, W. C.; Sletzinger, M. Tetrahedron Lett. 1975,
16, 3979.
In summary, we have developed a new practical and
mild method for the N-acylation of amides by way of
dual activation of both amides and acid anhydrides
using MgBr2·OEt2. This method was applicable to
amides which tend to receive O-acylation and are sus-
ceptible to racemization and O,N-acyl migration.
20. Vedejs, E.; Daugulis, O. J. Org. Chem. 1996, 61, 5702.
21. Yamada, S. Tetrahedron Lett. 1992, 33, 2171.
22. Spectral data for compound 2: mp 115.5–118.0°C; IR
(KBr) 2967, 1699, 1620, 1473, 1336, 1307, 1239, 1203,
1
1176, 743 cm−1; H NMR (270 MHz, CDCl3) l 1.43 (s,
9H), 3.67 (s, 2H), 7.12 (t, J=7.6 Hz, 1H), 7.24–7.29 (m,
2H), 7.45 (d, J=7.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) l 26.9, 36.6, 43.3, 109.7, 114.2, 122.4, 124.3,
128.8, 142.4, 174.0, 182.7; MS m/z 217 (M+, 38%), 133
(100), 132 (30), 104 (42), 77 (36), 57 (61); HRMS calcd
for C13H15NO2 217.1103, found 217.1153. For compound
3: mp 89.0–91.0°C; IR (KBr) 3381, 2983, 1753, 1547,
Acknowledgements
This work was financially supported by a Grant-in-Aid
for Scientific Research (C) (No. 13650901) from the
Japan Society for the Promotion of Science.

S. Yamada et al. / Tetrahedron Letters 43 (2002) 647–651
651
1459, 1432, 1273, 1142, 1102, 773, 748 cm−1
;
1H NMR
156.0, 176.2, 178.3; MS m/z 480 (M+, 2%), 479 (4), 420
(2), 358 (3), 207 (65), 160 (98), 125 (54), 110 (41), 91
(100), 70 (85).
(270 MHz, CDCl3) l 1.37 (s, 9H), 6.15 (s, 1H), 7.14 (m,
2H), 7.27 (m, 1H), 7.52 (d, J=6.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) l 26.9, 39.4, 87.2, 110.6, 120.2, 120.3,
121.5, 126.5, 131.1, 143.7, 175.5; MS m/z 217 (M+,
100%), 133 (45), 132 (9), 104 (11), 57 (18); HRMS calcd
for C13H15NO2 217.1103, found 217.1143.
24. Representative experimental procedure: To a suspension
of MgBr2·OEt2 (279 mg, 1.08 mmol) in dry CH2Cl2 (3 ml)
was added Et3N (210 ml, 1.51 mmol) under a nitrogen
atmosphere. After cooling the suspension to 0°C, a solu-
tion of 5-methyl-2-pyrrolidinone 9 (51 mg, 0.51 mmol) in
CH2Cl2 (2 ml) was added and stirred for 5 min. Then, a
CH2Cl2 solution (2 ml) of acid anhydride 10 (91.4 mg,
1.04 mmol) was added to the solution and stirred for 6 h
at room temperature. The reaction was quenched by the
addition of H2O, and the reaction mixture was extracted
with CH2Cl2 three times. The combined extracts were
dried over anhydrous MgSO4, and the solvent was evapo-
rated to give a crude oily product. This was subjected to
column chromatography with silica gel using a 1:1 mix-
ture of hexane–ethyl acetate as an eluent solvent to afford
11 as a colorless oil: [h]D −40.7 (c 0.092, CHCl3); Ref.
12a: [h]D −46 (c 0.092, CHCl3).
23. Synthesis of N-Cbz-(S)-pyrrolidine-2-carboxylic anhy-
dride (10). To a solution of N-Cbz-L-proline (1.012 g,
4.06 mmol) in dry CH2Cl2 (25 ml) was added 1,3-
dimethyl-2-chloroimidazolinium chloride (DMC) (407
mg, 2.41 mmol) under a nitrogen atmosphere. Et3N (0.7
ml, 5.04 mmol) was then added dropwise to the solution
at 0°C and the solution was stirred for 3 h at rt. After the
solvent was removed, the residue was purified by silica gel
column chromatography (AcOEt/MeOH=1/1) to afford
10 (980 mg, 2.04 mmol) as white crystals in >99% yield.
Mp 73.0–74.0°C; IR (KBr) 3007, 1759, 1650, 1441, 1338,
1189, 1124, 1090, 857, 756, 704 cm−1 1H NMR (400
;
MHz, CDCl3) l 1.91–2.05 (m, 4H), 2.12–2.31 (m, 4H),
3.44–3.52 (m, 2H), 3.54–3.66 (m, 2H), 4.37 (dd, J=8.6,
3.7 Hz, 1H), 4.42 (dd, J=7.9, 4.0 Hz, 1H), 5.18 (m, 4H),
7.30–7.37 (m, 10H); 13C NMR (100 MHz, CDCl3) l 23.5,
24.3, 29.2, 30.9, 46.7, 46.9, 58.6, 59.3, 67.1, 67.6, 127.7,
127.9, 128.0, 128.2, 128.4, 128.5, 136.2, 136.5, 154.4,
25. The HPLC analysis was performed using a chiral station-
ary phase (CHIRALPAK AS column, 4.6 mm×250 mm;
hexane/2-propanol, 4/1; 0.3 mL min−1; 220 nm; 25°C).
The minor and major enantiomers were appeared at 12.6
and 16.6 min, respectively, the ratio of which was 6:94.