AlMe3-promoted formation of amides from acids and amines

Article abstract of DOI:10.1021/ol203007s

In the presence of AlMe₃, amines can be directly coupled with acids through dimethylaluminum amide intermediates to form the corresponding amides. A wide range of amines and acids including less nucleophilic amines, bulky amines, unprotected se

Full text of DOI:10.1021/ol203007s

ORGANIC
LETTERS
2012
Vol. 14, No. 1
214–217
AlMe3-Promoted Formation of Amides
from Acids and Amines
Jianqing Li,*,† Krishnananthan Subramaniam,† Daniel Smith,† Jennifer X. Qiao,‡
Jie Jack Li,† Jingfang Qian-Cutrone,§ John F. Kadow,§ Gregory D. Vite,† and Bang-Chi Chen†
Bristol-Myers Squibb Company, Research and Development, P.O. Box 4000, Princeton,
New Jersey 08543-4000, United States, 311 Pennington-Rocky Hill Road, Pennington,
New Jersey 08534, United States, and 5 Research Parkway, Wallingford, Connecticut
06492, United States
*Jianqing.li@bms.com
Received November 7, 2011
ABSTRACT
In the presence of AlMe3, amines can be directly coupled with acids through dimethylaluminum amide intermediates to form the corresponding
amides. A wide range of amines and acids including less nucleophilic amines, bulky amines, unprotected secondary amino acids, and acids with
poor solubility were coupled smoothly to give the desired products in 55À98% yields.
Amide formation from acids and amines is one of the
most fundamental reactions in organic synthesis. It plays a
key role in peptide synthesis and medicinal chemistry. The
general strategy for amide bond formation is the activation
of carboxylic acids as acyl halides, acylimidazoles, acyla-
zide, anhydrides, and active esters followed by aminolysis.
Although numerous activating reagents have been devel-
oped to facilitate amide formation, they all have advan-
tages and limitations due to the structural diversity of the
substrates.1 The development of new coupling reagents
and conditions is still needed, especially for less nucleo-
philic amines, bulky amines, unprotected amino acids, and
acids with poor solubility.
converted to ureas.5 To the best of our knowledge, the
direct synthesis of amides from acids and amines using
AlMe3 as a coupling reagent has not been reported.6
Herein, we wish to report a highly efficient AlMe3-pro-
moted coupling reaction between acids and amines to give
amides (Scheme 1).
Scheme 1. AlMe3-Promoted Formation of Amides 5 from
Amines 1 and Acids 4
Since Weinreb and co-workers reported AlMe3 pro-
moted amide synthesis from esters and amines in 1977,2
the AlMe3-mediated amide and lactam formation from
esters has found many applications in organic synthesis.3,4
Using aluminum amides, carbamates can be directly
† Bristol-Myers Squibb Company, Princeton, New Jersey.
‡ Bristol-Myers Squibb Company, Pennington, New Jersey.
§ Bristol-Myers Squibb Company, Wallingford, Connecticut.
(1) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827
and references therein.
(5) Lee, S.-H.; Matsushita, H.; Clapham, B.; Janda, K. D. Tetrahe-
dron 2004, 60, 3439.
(2) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 48,
4171.
(3) Bracher, F. J. Prakt. Chem. 1999, 341, 88.
(4) Ooi, T.; Maruoka, K. Sci. Synth. 2004, 7, 230.
(6) After the original presentation of this work at the 240th ACS
National Meeting August 22À26, 2010, another transformation was
reported: Chung, W.; Uccello, D. P.; Choi, H.; Montgomery, J. I.; Chen,
J. Synlett 2011, 14, 2072À2074
r
10.1021/ol203007s
Published on Web 12/07/2011
2011 American Chemical Society

In one of our research projects, we attempted to use
AlMe3 to selectively transform an ester group to an amide
while keeping an acid function intact in the same molecule.
Surprisingly, a substantial amount of diamide formation
was observed. This discovery prompted us to investigate
the direct coupling of acids withamines to giveamides. In a
model study (Table 1), (2R,6S)-2,6-dimethyl-morpholine
(1a) (2 equiv) was treated with 2 equiv of AlMe3 in toluene
atrtunder N2 for30min, followed by addition of1 equivof
benzoic acid (4a). The reaction mixture was stirred at rt for
18h. LCMS indicated∼60% conversion (Table 1, entry1).
The reaction mixture was further heated at 80 °C for 18 h.
However, the conversion was not increased. When 3 equiv
of AlMe3 and 3 equiv of the amine 1a were used and the
reaction was run at rt for 2 days, 80% conversion was
observed (Table 1, entry 2). Quickly, we found that the
reaction completed after 3 equiv of the amine 1a was
treated with 3 equiv of AlMe3 for 30 min at rt followed
by the reaction with 1 equiv of the acid 4a at 80 °C for 16 h
(Table 1, entry 3).
Furthermore, primary and secondary aromatic and
aliphatic amines 1aÀm were also transferred to the corre-
sponding amides. Even highly hindered 8-methyl-1,2,3,
4-tetrahydroquinoline (1e) coupled with benzoic acid (4a)
gave amide 5e in 68% isolated yield (Table 2, entry 5). In
contrast, this bulky amine 1e was reported to couple with
an acid using EDAP/HOBt/Hunig’s base to give an amide
in 39% yield.8 The weak amine such as 2-fluoro-5-amino-
pyridine 1k required the acid component to be activated to
acyl halide in order to form the corresponding amide in
good yield.9 However, assisted by AlMe3, 1k coupled with
1-benzylpyrrolidine-2-carboxylic acid (4g) to afford the
amide 5l in 68% yield (Table 2, entry 12).
Encouraged by the above results, we were interested in
applying the method to the synthesis of N-(perfluoro-
phenyl)aliphatic amides which are useful substrates for
Pd(II)-catalyzed olefination of sp3 CÀH bonds. Because
of the strong electron-withdrawing nature of the perfluor-
ophenyl ring, this kind of amide formation required acid
chloride formation followed by aminolysis under basic
conditions at high temperature.10 It is also interesting to
see if racemization could occur when a chiral acid is
employed under our AlMe3 conditions. Scheme 2 showed
that AlMe3 promoted the coupling of pentafluoroaniline
(1n) with (S)- and (R)-2-phenylpropanoic acids (4i and 4j),
yielding the corresponding (S)- and (R)-N-(perfluoro-
phenyl)-2-phenylpropanamides (5o and 5p) in excellent
yields, remarkably, with no racemization.
Table 1. Reaction Condition Screen for the AlMe3-Promoted
Direct Coupling of Benzoic Acid (4a) with (2R,6S)-2,6-Di-
methylmorpholine (1a)
Scheme 2. AlMe3-Promoted Coupling of (S)- and (R)-
2-Phenylpropanoic acid (4i and 4j) with Pentafluoroaniline (1n)
equiv of
amine
time
(h)
conversion
(%)
entry
and AlMe3
temp
1
2
3
2
3
3
rt
18
48
16
60
80
rt
80 °C
100
Based on the above results from Table 2 and Scheme 2,
we proposed the reaction mechanism illustrated in Scheme 3.
Dimethylaluminun amide 3 generated from the reac-
tion of amine 1 with AlMe3 reacted with acids 4 to form
With the above conditions in hand, we examined a range
of acids and amines. As shown in Table 2, aromatic,
heteroaromatic, and aliphatic acids 4aÀh all can be tran-
ferred to the corresponding amides 5aÀn in good to
excellent yields. As reported previously, 5-bromoorotic
acid (4h) coupled to an acid chloride (an amide precursor)
proved to be problematic due to the insolubility of the acid
in a variety of solvents appropriate for chlorination.7
Under our current conditions using toluene as the solvent,
the amides 5m and 5n (Table 2, entry 13 and 14) were
obtained easily by quenching the reaction mixture with
MeOH and 1 N HCl followed by filtration.
(8) Chong, J. A.; Fanger, C.; Larsen, G. R.; Lumma, W. C.; Moran,
M. M.; Ripka, A.; Underwood, D. J.; Weigele, M.; Zhen, X. U.S. Pat.
Appl. Publ., 2007213321, 13 Sep 2007.
(9) Wittman, M. D.; Carboni, J. M.; Yang, Z.; Lee, F. Y.; Antman,
M.; Attar, R.; Balimane, P.; Chang, C.; Chen, C.; Discenza, L.;
Frennesson, D.; Gottardis, M. M.; Greer, A.; Hurlburt, W.; Johnson,
W.; Langley, D. R.; Li, A.; Li, J.; Liu, P.; Mastalerz, H.; Mathur, A.;
Menard, K.; Patel, K.; Sack, J.; Sang, X.; Saulnier, M.; Smith, D.;
Stefanski, K.; Trainor, G.; Velaparthi, U.; Zhang, G.; Zimmermann, K.;
Vyas, D. M. J. Med. Chem. 2009, 52, 7360.
(10) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
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(7) Decicco, C. P.; Nelson, D. J. Tetrahedron Lett. 1993, 34, 8213.
Org. Lett., Vol. 14, No. 1, 2012
215

Table 2. AlMe3-Promoted Formation of Amides 5aÀn from Acids and Amines
intermediate 6. The formation of 3 and 6 was evidenced by
the observation of gas evolution (presumably methane).
Intermediate 6 was then reacted with another equivalent of
3 to give the tetrahedral intemediate 7, which upon treat-
ment with MeOH afforded amide 5.
According to the reaction pathway of Scheme 3, we
envisioned that if the AlÀN bond of 3 were relatively
stable, unprotected amino acid could couple with acids
without cross-coupling. Indeed, we found unprotected
L- and D-prolines (4k and 4l) reacted with the aluminun
anisidine (1o) complex to give the products 5q and 5r in
excellent yields (Scheme 4). No cross-coupling products
were observed. However, 6.4% to 13.2% racemization
occurred. The coupling of primary amino acids such as
2-phenylglycine with anisidine (1o) became complicated
since cross-coupling products appeared to be predomi-
nated based on LCMS. Most likely, in the proline case, the
secondary amino group from proline was much slower to
216
Org. Lett., Vol. 14, No. 1, 2012

Scheme 3. Proposed Mechanism
Scheme 4. Direct Coupling of Unprotected L- and D-Prolines
(4k and 4l) with Anisidine (1o)
replace the anisidine group in complex 3 due to steric
hindrence. These results also confirmed that complex 3 is
labile.11 Nevertheless, the results from Scheme 4 could be
potentially useful.
In summary, we have developed a highly efficient
AlMe3-promoted amide formation from acids and amines.
The advantages of this method include the following: a
wide range of acids and amines were coupled in good to
excellent yields; weak nucleophilic and bulky amines can
be transferred to the corresponding amide in high yields;
and unprotected secondary amino acids can be converted
to primary amides. The limitations of this method include
functional groups such as esters, nitro, and cyano groups
are not tolerated under these conditions and 3 equiv of
amines and AlMe3 are required.
Note Added after ASAP Publication. This paper was
published ASAP on December 7, 2011. A new reference 6
was added and it reposted December 15, 2011.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(11) Sidler, D. R.; Lovelace, T. C.; McNamara, J. M.; Reider, P. J.
J. Org. Chem. 1994, 59, 1231.
Org. Lett., Vol. 14, No. 1, 2012
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