N-heterocyclic carbene-catalyzed amidation of unactivated esters with amino alcohols

Article abstract of DOI:10.1021/ol050773y

(Chemical Equation Presented) A catalytic amidation of unactivated esters with amino alcohols is described. A series of solution studies in addition to the first X-ray structure of a carbene-alcohol complex support a carbene-base nucleophile activation mechanism.

Full text of DOI:10.1021/ol050773y

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2453-2456
N-Heterocyclic Carbene-Catalyzed
Amidation of Unactivated Esters with
Amino Alcohols
Mohammad Movassaghi* and Michael A. Schmidt
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
moVassag@mit.edu
Received April 10, 2005
ABSTRACT
A catalytic amidation of unactivated esters with amino alcohols is described. A series of solution studies in addition to the first X-ray structure
of a carbene alcohol complex support a carbene-base nucleophile activation mechanism.
−
Synthesis of amides is important in many areas of chemistry,
including peptide, polymer, and complex molecule synthesis.1
Condensation products of optically active amino alcohols and
carboxylic acids are of particular significance due to their
impact in stereoselective synthesis.2 Dehydration (and oxida-
tion) of N-hydroxyalkyl amides affords valuable heterocycles
that are present in many biologically active natural products.3
Mild methods for the synthesis of amides rely on activation
of carboxylic acid derivatives using stoichiometric quantities
of condensation or activating reagents.1 Direct coupling of
amines and alcohols with unactivated carboxylic acid deriva-
tives is of current interest.4 Herein, we report the development
of a carbene-catalyzed amidation of unactivated esters with
amino alcohols (eq 1). Additionally, we describe preliminary
mechanistic studies that suggest an uncharted mode of
catalysis for stable carbenes via a carbene-alcohol hydrogen-
bond interaction.
The discovery of stable nitrogen-heterocyclic carbenes
(NHCs)5 has had a significant impact on the development
of new methodologies for organic synthesis.6 NHCs have
served both as ligands in organometallic catalyst systems7
(4) For reviews on transesterification, see: (a) Otera, J. Chem. ReV. 1993,
93, 1449-1470. (b) Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis 2004,
7, 971-985. For catalytic condensation of carboxylic acids and alcohols,
see: (c) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000, 290, 1140-
1142. For catalytic transamidation, see: (d) Eldred, S. E.; Stone, D. A.;
Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422-3423. For
a cyanide-catalyzed aminolysis of esters, see: Ho¨gberg, T.; Stro¨m, P.; Ebner,
M.; Ra¨msby, S. J. Org. Chem. 1987, 52, 2033-2036. (e) For representative
use of amino alcohols in amidation reactions, see: Arai, K.; Shaw, C.-h.;
Nozawa, K.; Kawai, K.-i.; Nakajima, S. Tetrahedron Lett. 1987, 28, 441-
442, Diana, G. D.; Cutcliffe, D.; Oglesby, R. C.; Otto, M. J.; Mallamo, J.
P.; Akullian, V.; McKinlay, M. A. J. Med. Chem. 1989, 32, 450-455, and
Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc.
1997, 119, 656-673. (f) For an electrochemical method for benzoylation
of amino alcohols, see: Arai, K.; Tamura, S.; Masumizu, T.; Kawai, K.-i.;
Nakajima, S.; Ueda, A. Can. J. Chem. 1990, 68, 903-907.
(1) (a) Benz, G. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6, Chapter 2.3. (b)
Albericio, F.; Chinchilla, R.; Dodsworth, D. J.; Najera, C. Org. Prep. Proced.
Int. 2001, 33, 203-303.
(2) (a) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J. Am. Chem.
Soc. 1976, 98, 567-576. (b) Larcheveque, M.; Ignatova, E.; Cuvigny, T.
J. Organomet. Chem. 1979, 177, 5-15. (c) Evans, D. A.; Takacs, J. M.
Tetrahedron Lett. 1980, 21, 4233-4236. (d) Evans, D. A.; Ennis, M. D.;
Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737-1739. (e) Myers, A. G.;
Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361-
9362. (f) Hintermann, T.; Seebach, D. HelV. Chim. Acta 1998, 81, 2093-
2126.
(3) (a) Wipf, P. Chem. ReV. 1995, 95, 2115-2134. (b) Jin, Z. Nat. Prod.
Rep. 2003, 20, 584-605.
10.1021/ol050773y CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/17/2005

and as organic catalysts.8 Furthermore, fascinating reports
regarding the use of NHCs as nucleophilic catalysts9 for
polymerization of lactones and transesterification reactions
have appeared.10
Table 1. Catalytic Amidation of Esters with Amino Alcohols
As part of a program directed at the discovery of new and
efficient methods for target-oriented synthesis, we sought
the development of a single-step and catalytic amidation of
unactivated esters. In preliminary studies focused on carbene-
catalyzed amidation of esters, we discovered that amino
alcohols were particularly reactive. A combination of superb
reactivity, ready availability, and ease of storage of N,N-
bismesitylimidazolylidene5b (3, IMes) led to its selection as
the catalyst for our amidation studies. Under optimal
conditions (tetrahydrofuran, 1.0 M initial concentration of
substrates, 23 °C), treatment of an equimolar amount of an
amino alcohol and an unactivated ester with IMes (3, 5 mol
%) affords the corresponding amide in high yield (Table 1).
Under standard conditions, the coupling of methyl phenyl-
acetate (1a) and ethanolamine (2a) was complete in 8 h,
while the corresponding reaction with methyl benzoate (1b)
gave the desired amide in 75% yield after 24 h (Table 1,
entries 1 and 2, respectively).11
Both aromatic and aliphatic esters with a wide range of
functional groups may be employed in this amidation
reaction. The amidation reaction is sensitive to both electronic
and steric factors (Table 1, entries 2-7 and 8-11, respec-
(5) For the first successful isolation of an NHC, see: (a) Arduengo, A.
J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361-363.
(b) Arduengo, A. J., III; Dias, H. V. R.; Harlow, R. L.; Kline, M. J. Am.
Chem. Soc. 1992, 114, 5530-5534. For early studies, see: (c) Wanzlick,
H.-W.; Schikora, E. Angew. Chem. 1960, 72, 494. (d) Wanzlick, H.-W.;
Kleiner, H.-J. Angew. Chem. 1961, 73, 493.
(6) (a) Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem.
ReV. 2000, 100, 39-92. (b) Carbene Chemistry. From Fleeting Intermedi-
ates to Powerful Reagents; Bertrand, G., Ed.; Marcel Dekker: New York,
2002.
(7) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309. (c)
Yong, B. S.; Nolan, S. P. Chemtracts: Org. Chem. 2003, 16, 205-227.
(d) Burgess, K.; Perry, M. C. Tetrahedron: Asymmetry 2003, 14, 951-
961. (e) Kremzow, D.; Seidel, G.; Lehmann, C.; Fu¨rstner, A. Chem. Eur.
J. 2005, 11, 1833-1853.
(8) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726. (b) Stetter,
H.; Kuhlmann, H. Synthesis 1975, 379-380. (c) Murry, J. A.; Frantz, D.
E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem.
Soc. 2001, 123, 9696-9697. (d) Burstein, C.; Glorius, F. Angew. Chem.,
Int. Ed. 2004, 43, 6205-6208. (e) Sohn, S. S.; Rosen, E. L.; Bode, J. W.
J. Am. Chem. Soc. 2004, 126, 14370-14371. For reviews, see: (f) List, B.
Tetrahedron 2002, 58, 5573-5590. For reviews, see: (g) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-5175. (h) Enders, D.;
Balensiefer, T. Acc. Chem. Res. 2004, 37, 534-541.
(9) (a) Steglich, W.; Ho¨fle, G. Angew. Chem., Int. Ed. Engl. 1969, 8,
981-983. (b) Vedejs, E.; Diver, S. T. J. Am. Chem. Soc. 1993, 115, 3358-
3359. (c) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230-7231.
(10) (a) Connor, E. F.; Nyce, G. W.; Myers, M.; Mock, A.; Hedrick, J.
L. J. Am. Chem. Soc. 2002, 124, 914-915. (b) Grasa, G. A.; Kissling, R.
M.; Nolan, S. P. Org. Lett. 2002, 4, 3583-3586. (c) Nyce, G. W.; Lamboy,
J. A.; Connor, E. F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett. 2002, 4,
3587-3590. (d) Grasa, G. A.; Gueveli, T.; Singh, R.; Nolan, S. P. J. Org.
Chem. 2003, 68, 2812-2819. (e) Nyce, G. W.; Glauser, T.; Connor, E. F.;
Moeck, A.; Waymouth, R. M.; Hedrick, J. L. J. Am. Chem. Soc. 2003,
125, 3046-3056. (f) Singh, R.; Kissling, R. M.; Letellier, M.-A.; Nolan,
S. P. J. Org. Chem. 2004, 69, 209-212. (g) For resolution of alcohols using
vinyl esters, see: Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7,
1347-1349.
a Reaction times 1.5-24 h; isolated yield after purification. b In situ
generation of IMes (6.5 mol % IMes‚HCl, 5.0 mol % tBuOK). c Anhydrous
LiCl (5 mol %) used as an additive. d >94% de, >98% ee.
tively).12 The presence of heterocycles is tolerated both on
the ester and the amino alcohol components (Table 1, entries
16-19 and 22-23, respectively). The IMes (3)-catalyzed
(11) (a) In the absence of 3, incubation of equimolar amounts of esters
1a and 1b with 2a at 23 °C provides less than 2 and 1%, respectively, of
the corresponding amides in 12 h. (b) The use of sodium methoxide and
potassium tbutoxide in place of IMes (3) in the coupling of 1a and 2a gave
60 and 74% yield of 4aa, respectively. See Supporting Information.
(12) Introduction of anhydrous lithium chloride (5 mol %) to the reaction
mixture increases the rate of this coupling (Table 1, entries 2, 7, and 13).
2454
Org. Lett., Vol. 7, No. 12, 2005

condensation of optically active N-Boc-1-methyl-L-tryp-
tophan methyl ester and L-phenylalaninol provided the
corresponding amide in good yield (Table 1, entry 23).13 This
catalytic amidation reaction does not require use of excess
coupling components, heat, vacuum, molecular sieves, or
activated esters for completion.10 The high reactivity of amino
alcohols can be used to an advantage in their selective
coupling with unactivated esters in the presence of amines
(eq 2).
2, entry 2).17 Significantly, the C2 resonance of complex 8b
at 209.7 ppm is upfield by 9.7 ppm as compared to the C2
resonance of carbene 3.18 We have also prepared the
hexadeuterated variant of this complex, IMes-d2-methanol-
d4 (8b-d6),14 that displays a C4 resonance (δ 121.1, triplet,
J1 ) 27.0 Hz) and a C2 resonance (δ 203.9, singlet) in
CD
C6D6, most consistent with an imidazolylidene-d2 fragment
rather than an imidazolium-d3 substructure.19 The hydroxyl
t
proton of other alcohols, including butanol, ethanolamine,
and benzyl alcohol, display a similar downfield shift upon
complex formation with IMes (Table 2).20 Samples contain-
ing unequal ratios of IMes to alcohol(s) exhibit averaged
resonances suggesting dynamic systems with exchange rates
faster than the NMR time scale. Benzylamine does not show
a significant interaction with IMes (3), while mixing benzyl
mercaptan with 3 leads to rapid precipitation of imidazolium
thiolate salts under conditions described in Table 2. These
observations are consistent with the expected basicity of
IMes.21
Significantly, this amidation reaction proceeds with equal
efficiency when a solution of catalyst, IMes (3), is prepared
by the addition of potassium tert-butoxide (5 mol %) to a
suspension of N,N-bismesitylimidazolium chloride (6.5 mol
%) in tetrahydrofuran (Table 1, entry 1).10c,d This method is
particularly effective for use of NHCs that are more difficult
to isolate.14 Despite the clear practical advantage of using
in situ-generated carbene samples, we have relied on
recrystallized samples of IMes (3) in these preliminary
studies to allow thorough mechanistic investigation.
The IMes-methanol complex 8b represents the first X-ray
structure of a carbene-alcohol hydrogen-bonded complex
(Figure 1).22 The distance between the carbene C2 and the
These carbene catalysts have been previously proposed
to act as nucleophilic catalysts in transesterification reactions
(through activated C2-acylimidazolium intermediates).10a-f,15
However, our observations regarding the surprising stability
of carbene-alcohol complexes prompt consideration of an
additional mode of catalysis for NHCs. Mixing an equimolar
amount of IMes (3) and anhydrous methanol (7b) in C6D6
(0.05 M, 20 °C) leads to immediate formation of N,N-
bismesityl-imidazolylidene-methanol complex 8b (Table 2,
Figure 1. ORTEP drawing of complex 8b.
oxygen (C- -H-O) is 2.832(2) Å. The oxygen atom resides
only 0.04 Å above the plane defined by the imidazolylidene-
ring, thus allowing a nearly linear (174°) hydrogen bond
interaction. Significantly, the N-C-N bond angle of 102.5°
found in complex 8b is much closer to the same bond angle
Table 2. Alcohol-Carbene Complexes 8a-da
(17) For a review, see: Steiner, T. Angew. Chem., Int. Ed. 2002, 41,
48-76.
entry
R
δ Ha (ppm) δ Hb (ppm) ∆ (ppm)
(18) For reference, the C2 and C4 resonances of carbene 3 (C6D6, 20
°C) are found at 219.4, and 120.9 ppm, respectively.
1
2
3
4
a, tBu
b, Me
0.67
0.05
∼0.70
2.81
4.37
5.24
2.14
4.32
∼4.5
(19) (a) While the C2 resonance of imidazolium salts are typically >60
ppm upfield relative to the corresponding carbene C2 resonance, the
reversible formation of an undetectable concentration of imidazolium
alkoxide cannot be ruled out. (b) In THF-d8, the C2 and C4 resonances of
carbene 3 and complex 8b-d6 are found at 219.9 and 121.6 and at 212.4
c, CH2CH2NH2
d, Bn
0.89
∼6.0
∼5.1
a
1H NMR (500 MHz) data were separately recorded for the alcohols
and 121.6 (t, J1 ) 29.4 Hz) ppm, respectively.
and the IMes-alcohol complexes in C6D6 (0.05 M) at 20 °C.
CD
(20) In the case of the more acidic alcohols, i.e., trifluoroethanol, our
preliminary spectroscopic data clearly indicate a greater degree of proton
transfer and the presence of multiple equilibrating complexes that include
imidazolium alkoxide derivatives.
entry 2).16 The hydroxyl proton of complex 8b displays a
significant downfield shift in the 1H NMR spectrum (Table
(21) (a) Arduengo, A. J., III; Gamper, S. F.; Tamm, M.; Calabrese, J.
C.; Davidson, F.; Craig, H. A. J. Am. Chem. Soc. 1995, 117, 572-573. (b)
Alder, R. W.; Allen, P. R.; Williams, S. J. J. Chem. Soc., Chem. Commun.
1995, 1267-1268. (c) Kim, Y.-J.; Streitwieser, A. J. Am. Chem. Soc. 2002,
124, 5757-5761. (d) Filipponi, S.; Jones, J. N.; Johnson, J. A.; Cowley,
A. H.; Grepioni, F.; Braga, D. Chem. Commun. 2003, 2716-2717.
(22) For the structure of a carbene-diphenylamine complex, see: Cowan,
J. A.; Clyburne, J. A. C.; Davidson, M. G.; Harris, R. L. W.; Howard, J. A.
K.; Ku¨pper, P.; Leech, M. A.; Richards, S. P. Angew. Chem., Int. Ed. 2002,
41, 1432-1434.
(13) N-Fmoc-protected glycine methyl ester was found to undergo
deprotection in the presence of either 3 or 2a.
(14) See Supporting Information for details.
(15) (a) Ohta, S.; Hayakawa, S.; Okamoto, M. Tetrahedron Lett. 1984,
25, 5681-5684. (b) Davies, D. H.; Hall, J.; Smith, E. H. J. Chem. Soc.,
Perkin Trans. 1 1989, 837-838.
(16) Similar results were found in THF-d8.
Org. Lett., Vol. 7, No. 12, 2005
2455

of 101.4° present in the parent IMes (3)5b as compared to
the bond angle of 108.6° found in the corresponding
bismesitylimidazolium chloride.21a Our results to date confirm
the expectation that the degree of proton transfer in these
IMes-alcohol complexes is sensitive to steric interactions,
alcohol acidity, carbene basicity, and solvent. This carbene-
alcohol interaction merits further consideration alongside
previously reported modes of reactivity and catalysis for
NHCs.
the addition of an authentic sample of ester 12ba (0.12 equiv)
to an amidation reaction of methyl benzoate (1b) with
ethanolamine (2a) in progress (at 2 h, 41% conversion) under
optimal reaction conditions led to rapid OfN acyl-transfer
within minutes, providing amide 4ba (Table 1, entry 2) in
90% yield upon completion of the experiment (8 h).14 The
poor reactivity of 6-aminohexan-1-ol, 2-hydroxymethyla-
niline, and (2S,3S)-pseudoephedrine in coupling with methyl
phenylacetate (1a) under our standard conditions may be due
to a slow OfN acyl-transfer24 and/or an unfavorable initial
transesterification10f in the latter case.
The chemistry reported here provides a catalytic method
for the amidation of unactivated esters with amino alcohols
under mild reaction conditions with wide functional group
tolerance. Our preliminary mechanistic investigations have
identified a carbene-alcohol interaction that is supported by
a series of solution studies in addition to the first X-ray
structure of a hydrogen-bonded carbene-alcohol complex.
These data taken together suggest an unexplored mode of
catalysis for stable carbenes with potential mechanistic
impact in other transformations. Current efforts are directed
toward the development of asymmetric25 variants of related
transformations and will be reported in due time.
We propose a carbon-centered Brønsted base21b nucleo-
phile activation for an initial transesterification followed by
a rapid NfO acyl-transfer reaction (Scheme 1) to be
Scheme 1. Proposed Reaction Mechanism
Acknowledgment. M.M. is a Dale F. and Betty Ann Frey
Damon Runyon Scholar supported by the Damon Runyon
Cancer Research Foundation (DRS-39-04). M.M. is a Fir-
menich Assistant Professor of Chemistry. Acknowledgment
is made to the Donors of the American Chemical Society
Petroleum Research Fund for partial support of this research.
M.A.S. acknowledges partial support by the Milas fund. We
thank Dr. P. Mueller for X-ray crystallographic assistance.
We are grateful for generous financial support by MIT and
Amgen, Inc.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all products and crystal-
lographic data of complex 8b (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
operational in our chemistry. Monitoring the IMes-catalyzed
coupling of γ-lactone 1m (Table 1, entry 15, CdO, 1779
cm-1) with ethanolamine (2a) by React-IR proceeded to give
amide 4ma (Table 1, entry 15, CdO, 1648 cm-1), while a
weak absorbance for a fleeting O-(acyl)ethanolamine ester
12ma (Scheme 1, 12 R ) (CH2)3OH, CdO, 1736 cm-1)
was observed during the reaction.14 Additionally, monitoring
the IMes-catalyzed amidation of methyl benzoate (1b) with
OL050773Y
(23) Anhydrous lithium chloride was not used in this experiment.
(24) Kemp, D. S.; Vellaccio, F., Jr. J. Org. Chem. 1975, 40, 3464-
3465.
(25) For use of NHCs in asymmetric catalysis, see refs 7d and 8e in
addition to: (a) Sheehan, J. C.; Hunneman, D. H. J. Am. Chem. Soc. 1966,
88, 3666-3667. (b) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126,
8876-8877. (c) Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J. J.
Am. Chem. Soc. 2005, 127, 1654-1655. (d) Chan, A.; Scheidt, K. A. Org.
Lett. 2005, 7, 905-908.
1
ethanolamine (2a) in THF-d8 by H NMR spectroscopy
clearly demonstrated the intermediacy of O-(benzoyl)-
ethanolamine 12ba (Scheme 1, 12 R ) Ph).14,23 Furthermore,
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Org. Lett., Vol. 7, No. 12, 2005