Mild conversion of esters lacking acidic α-hydrogens into amides via samarium(III) tris[hexamethyldisilazide] and amines

Article abstract of DOI:10.1055/s-0030-1259508

Samarium(III) tris[hexamethyldisilazide] (Sm[(Me³Si) ²N]³ = Sm[HMDS]³) promotes the direct conversion of an ester admixed with an amine into the corresponding carboxamide under exceptionally mild conditions (≤0°) and in high yields. Only a slight excess of amine and the lanthanide complex are required to effect complete conversion of the ester into the amide. Esters with acidic α-hydrogens undergo a competing Claisen-like condensation along with the desired conversion into amides. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259508

LETTER
357
Mild Conversion of Esters Lacking Acidic a-Hydrogens into Amides via
Samarium(III) Tris[hexamethyldisilazide] and Amines
M
ildConv
a
ersionof
E
m
sters es B. Campbell,* Richard B. Sparks, Robert F. Dedinas
Lead Generation Department, CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, DE 19850-5437, USA
Fax +1(302)8851453; E-mail: campbelljim.jbc@gmail.com
Received 22 October 2010
thereby appeared promising for accommodating a broader
range of substrates for our amide compound library.
Therefore, we initially evaluated the Roskamp procedure
in an effort to develop such a sequence (Table 1). Thus,
Abstract: Samarium(III) tris[hexamethyldisilazide] (Sm[(Me3Si)2N]3
= Sm[HMDS]3) promotes the direct conversion of an ester admixed
with an amine into the corresponding carboxamide under excep-
tionally mild conditions (£0 °C) and in high yields. Only a slight ex-
cess of amine and the lanthanide complex are required to effect the reaction of benzyl b-naphthoate (1) with two represen-
complete conversion of the ester into the amide. Esters with acidic
tative primary amines and morpholine using the Roskamp
a-hydrogens undergo a competing Claisen-like condensation along
with the desired conversion into amides.
procedure afforded the desired amides 2 in modest (entry
3) to excellent yields. The reaction was initiated by adding
1.2 equivalents each of Sn[HMDS]2 and amine to the ester
Key words: esters, amides, lanthanides, HMDS, samarium
followed by heating. A second addition of reagents (1.2
equiv each of amine plus Sn[HMDS]2) followed after ca.
The direct conversion of esters into amides is often ac- eight hours to help drive the reactions to completion.
complished by heating amines with esters typically using
Table 1 Roskamp Tin Amide Procedure for Conversion of Esters
into Amides
a large excess of the amine or ester. Improvements in the
transformation were introduced by Weinreb et al. using
aluminum amides formed by reaction of amines1 or amine
hydrochloride salts2 with trimethylaluminum. Heating an
ester with the aluminum amide reagent (80–110 °C) pro-
motes the conversion. A more recent variation of the
Weinreb procedure has been reported in which catalytic
lanthanide salts are added purportedly to coordinate to the
ester carbonyls as Lewis acids enhancing their electrophi-
licity.3 Roskamp described alternative procedures using
weaker Lewis acidic reagents; Sn(II)[HMDS]2 plus an
amine or a chlorostannylene variant of the reagent with an
amine, to directly convert esters into amides.4 Yoon has
reported the use of sodium diethyldiamidoaluminates,
pre-formed from the reaction of two equivalents of an
amine with sodium diethylaluminodihydride, for the di-
rect conversion of esters into amides.5 Most of these pro-
cedures require heat and an excess of both the metal
complex reagent and amine. Extended reaction times (ca.
24 h) are often required as well to drive the reactions to
completion. Herein we describe our efforts to improve
upon the existing reagents for effecting conversion of es-
ters into amides. Our work culminated in the identifica-
tion of Sm[HMDS]3 admixed with an amine to promote
the transformation under exceedingly mild conditions and
in high yield.
O
O
R2
R1R2NH
N
R1
O
[HMDS]2Sn
toluene, Δ
1
2
Entry R1
R2
Reaction
conditions
Product 2 Yield (%)a
1
2
3
-(CH2)2O(CH2)2- 80 °C, 2 h
2a
98
88
35
Bn
Pr
H
H
100 °C, 22 h 2b
80 °C, 22 h 2c
a Yields are isolated products, purified by radial chromatography.
The poor conversion of 1 into amide 2c using propyl-
amine (Table 1, entry 3) may be attributed to the partial
loss of the volatile amine (bp 48 °C) from the extended re-
action time at elevated temperature.
Tin(II) is a relatively poor Lewis acid, which may overly
moderate the reactivity of Sn[HMDS]2. The chlorostan-
nylene variant of the tin HMDS complex does show en-
hanced reactivity enabling reactions at room temperature,
presumably due, in part, to the increased Lewis acidity of
the complex.4c Lanthanide-based reagents, such as
La[HMDS]3, appeared as interesting alternatives to im-
prove the reaction.6 First, the steric demands of three
bulky hexamethyldisilazide groups around the metal cen-
ter forces an unusual coordination number for lanthanides
of three. These monomeric, three-coordinate homoleptic
lanthanide complexes have a unique trigonal pyramidal
geometry with a vacant apical coordination site at the non-
ligated pyramid vertex. A Lewis acidic hybrid LUMO
At the outset of our work, we were interested in devising
a synthetic sequence generalized for preparation of a
small library of amides from esters. The tin-based re-
agents promote the ester-into-amide conversion under
milder conditions compared to the aluminum reagents and
SYNLETT 2011, No. 3, pp 0357–0360
x
x.
x
x.
2
0
1
1
Advanced online publication: 25.01.2011
DOI: 10.1055/s-0030-1259508; Art ID: S08010ST
© Georg Thieme Verlag Stuttgart · New York

358
J. B. Campbell et al.
LETTER
projects from this empty apical site for interaction with plexes were prepared and evaluated for the conversion of
Lewis bases, and the potential for coordination and activa- benzyl b-naphthoate into the morpholinoamide including
tion of a carbonyl group.7 Structurally analogous trigonal HMDS complexes of La, Pr, Nd, Sm, Eu, and Yb.12 Sev-
pyramidal platinum(II) complexes with exceptionally eral were effective in promoting the conversion of ester
high Lewis acidity have been recently described.8 The into amide under mild conditions (e.g., La, Sm, and Yb),
LUMO of these Pt complexes projects from an apical co- but did show some variation in reactivity. A further as-
ordination site, analogously to the lanthanide HMDS sessment of the reactivity of the different reagents re-
complexes, and was demonstrated to be a coordination vealed the samarium-based reagent to be particularly
site for pyridine via the nitrogen lone pair.
reactive and preferred. Thus, the conversion of benzyl b-
naphthoate (1) into amide 2a using morpholine and fresh-
ly prepared Sm[HMDS]3 was complete within one hour at
–15 °C. The procedure required only a 10% excess each
of the samarium complex and morpholine. The procedure
was then applied to the conversion of several esters 3 into
the corresponding amides 4 carrying out the reaction at
0 °C, for convenience (Table 3).
Further evidence of Lewis acid/base interactions of lan-
thanide HMDS complexes include a report of stable ad-
ducts of CO2 with Pr[HMDS]3 and Nd[HMDS]3 in which
CO2 reversibly coordinates to the metals via one of the
carbonyl oxygens.9 Stable triphenylphosphine oxide ad-
ducts are also known for a number of Ln[HMDS]3 com-
plexes. Single-crystal X-ray diffraction reveals ligation of
the phosphine oxide oxygen with the metal center to form
nearly linear LnOP bonds.10 The PO ligand occupies the
apical coordination site of the complex to give an overall
distorted tetrahedral geometry. The known oxophilic na-
ture of lanthanides taken together with the literature cited
above for the interaction of Ln[HMDS]3 complexes with
Lewis bases via the metal-complex LUMO, prompted us
to investigate their utility for conversion of esters into
amides.
We were pleased to find that La[HMDS]3,11 prepared in
situ, promotes the conversion of benzyl b-naphthoate (1),
in the presence of added amine, into the corresponding
carboxamides 2 under mild conditions and in high yields
(Table 2). Furthermore, only a slight excess of the re-
agents (1.4 equiv each of amine and lanthanide complex)
provide near quantitative conversion into the amides.
18,19
Table 3 Ester-into-Amide Conversion Using Sm[HMDS]3
O
O
R2R3NH
R3
R1
R1
N
R2
OMe
Sm[HMDS]3
THF, 0 °C
3
4
Entry R in 3
Amine
Product 4 Yield (%)a
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
morpholine
4a
4a
4b
4c
4d
4e
4f
99
91b
78
82
0c
morpholine
benzylamine
aniline
diisopropylamine
4-BrC6H4 morpholine
4-MeOC6H4 morpholine
3-CNC6H4 morpholine
3-pyridyl morpholine
98
87
0d
Table 2 La[HMDS]3-Promoted Conversion of 1 into Amides 2
R1R2NH
4g
4h
1
2
La[HMDS]3
THF
79
a Isolated yields by radial chromatography.
LaCl3
+
3 LiHMDS
b Reaction conducted at –15 °C requiring 1 h for completion.
c Starting material recovered.
Entry R1
R2
Reaction
Conditions
Product 2
Yield (%)a
d Possible competing addition of amine to nitrile to form the guani-
dine.13
1
2
3
-(CH2)2O(CH2)2- r.t., 2 h
2a
2b
2c
91
97
95
Bn
Pr
H
H
r.t., 2 h
r.t., 2 h
During the course of investigating different substrates, we
observed the formation of Claisen-like condensation
products when using esters containing acidic a hydrogens
along with formation of the desired amides. Thus, reaction
of ethyl hydrocinnamate (5) with 1.1 equivalents each of
Sm[HMDS]3 and morpholine at 0 °C afforded the desired
morpholinoamide 6 in 37% isolated yield, along with con-
densation product 7 in 22% yield (Equation 1). Interest-
ingly, we did not find any products derived from self-
condensation of 5.
a Isolated yields by radial chromatography.
The reaction is high yielding for three representative
amines evaluated with 1, requiring just 2 hours for com-
pletion of the reaction at room temperature. Notably, the
propyl analogue afforded the amide 2c in high yield in
contrast to poor yield obtained with the tin-based reagent
(Table 1, entry 3 cf. Table 2, entry 3)
In fact, Sm[HMDS]3 has been reported as a catalyst for
promoting cross-aldol reactions between aldehydes and a-
chloroketones.14 While this competing side reaction is a
current limitation in the scope of the transformation, the
conversion of substrates not containing acidic a-hydro-
Following the success using La[HMDS]3 for conversion
of esters into amides, we explored optimizing the reagent
and reaction conditions. Thus, several Ln[HMDS]3 com-
Synlett 2011, No. 3, 357–360 © Thieme Stuttgart · New York

LETTER
Mild Conversion of Esters
359
O
ligand exchange of morpholine for a HMDS. An ester car-
bonyl lone pair could then coordinate with the empty
Lewis acidic hybrid orbital on Sm producing an equili-
brating ensemble of complexes, represented by 11 and 12.
Attack of the amine in 12 at the ester carbonyl carbon
would be consistent with a Burgi–Dunitz trajectory into a
p*-frontier orbital of the carbonyl group.17 The resulting
tetrahedral intermediate 13 could then rotate to coordinate
a methoxy oxygen lone pair with the oxophilic samarium
to provide 14. Elimination of MeOSm[HMDS]2 would
then afford amide 15. This proposed mechanism suggests
that a fully catalytic variation of the ester to amide reac-
tion may be precluded. However, the potential still exists
for substoichiometric requirements for the Sm reagent.
N
N
O
O
O
6
+
morpholine (1.1 equiv)
OEt
Sm[HMDS]3
THF
O
O
5
7
Equation 1
OMe
gens is remarkably facile and high-yielding. The presence
of adventitious lithium hexamethyldisilazide remaining
from the in situ preparation of the lanthanide reagent may
contribute to the apparent base-catalyzed cross-condensa-
tion reaction.
OMe
O
R
O
R
Sm
Sm
(Me3Si)2N
(Me3Si)2N
N
N
(Me3Si)2N
O
(Me3Si)2N
O
A very recent communication described the use of
Ln[HMDS]3 complexes grafted onto mesoporous silica as
hydroamination catalysts.15 This new application of
Ln[HMDS]3 complexes further highlights their potential
in developing novel synthetic applications involving acti-
vation of amino groups as nucleophiles. Furthermore, we
were intrigued from a mechanistic perspective by possible
parallels between the hydroamination reaction and our
ester-into-amide conversion. One mechanistic interpreta-
tion we considered for the hydroamination reaction is de-
picted in Scheme 1.
11
12
OMe
R
R
O
N
O
O
N
OMe
Sm
Sm
(Me3Si)2N
(Me3Si)2N
O
(Me3Si)2N
N(SiMe3)2
13
14
– [HMDS]2SmOMe
O
NH2
La
(Me3Si)2N
N(SiMe3)2
– HMDS
R
N
O
(Me3Si)2N
15
8
H
N
Scheme 2 Proposed mechanism for Sm[HMDS]3-induced ester-
into-amide conversion
La
(Me3Si)2N
N
H
10
In summary, we have described a novel approach for con-
version of esters with nonacidic a-hydrogens into amides.
The reaction proceeds in high yield under very mild con-
ditions, even as low as –15 °C, with readily accessible re-
agents and with nearly stoichiometric amounts of reaction
partners.
(Me3Si)2N
9
Scheme 1 Proposed mechanism for the hydroamination reaction me-
diated by the lanthanideHMDS complex
Ligand exchange of the penten-1-amine and a HMDS
from lanthanide complex 8 would produce 9. The double
bond may be activated by a p-interaction with the apical
Lewis acidic hybrid orbital on the lanthanide as illustrated
in structure 9. The geometry for the nucleophilic addition
of the amine to the double bond appears favorable via a 5-
exo-trig ring closure to ultimately produce pyrrolidine
10.16
Acknowledgement
The authors wish to thank Janet Forst for help with preparation of
the manuscript.
References
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By analogy, Scheme 2 illustrates a proposed mechanistic
pathway for the ester-into-amide conversion using
Sm[HMDS]3 and morpholine. The first step would require
1977, 18, 4171.
(2) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
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Synlett 2011, No. 3, 357–360 © Thieme Stuttgart · New York

360
J. B. Campbell et al.
LETTER
1.0 M solution in THF, 2.20 mmol) was added dropwise.
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procedure of Bradley et al.6 Briefly, to a suspension of anhyd
lanthanum chloride12 in THF at r.t. was added dropwise 3
equiv of LiHMDS (Aldrich) as a 1.0 M solution in THF.
Following completion of the addition, the mixture was
warmed to 50 ¡C for 15 min and then cooled to the
prescribed temperature for use in the amidation reactions.
Other lanthanide HMDS complexes were prepared by an
analogous procedure.
(12) (a) Preparation of anhyd lanthanide halides can be capricious
as cited in ref. 12b. We found no difference in reactivity of
the Ln[HMDS]3 complexes using lanthanide chlorides
prepared by the Taylor procedure compared with using salts
treated by drying of the commercially available LnCl3⋅7H2O
salts under high vacuum at 140 °C overnight (b) Taylor, M.
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The suspension was placed in a 50 °C bath and stirred 15
min. The heating bath was removed and the suspension
allowed to cool back to ambient temperature over 30 min.
Morpholine (0.065 mL, 0.73 mmol) was then added as a neat
liquid and the mixture stirred 15 min at ambient temperature.
The reaction flask was placed in an ice-bath and stirred 15
min to equilibrate. Methyl benzoate (0.082 mL, 0.66 mmol)
was added dropwise as a neat liquid, and the reaction was
stirred for 1 h in the ice bath. MeOH (1 mL) was added to
quench the reaction. The mixture was poured directly onto a
short plug of silica gel using EtOAc washes (5 × 5 mL) for
elution. The combined extracts were concentrated, and the
residual green oil was chromatographed [Chromatotron
radial chromatography, silica gel, elution solvent EtOAc–
hexanes (1:5)]. The combined eluent was concentrated to
provide 0.126 g of a clear, colorless oil (ca. 99% yield). 1H
NMR (300 MHz, CDCl3): d = 3.33 (br s, 4 H), 3.59 (br s, 4
H), 7.387.46 (m, 5 H). 13C NMR (75 MHz, CDCl3): d =
40.31, 66.04, 126.97, 128.41, 129.55, 135.57, 166.90. MS:
m/z = 192 [M+].
(19) Most of the products are simple amides previously described
in the literature and/or commercially available. Thus,
products were characterized by NMR (1H, 13C) and MS
comparing data to authentic samples or data acquired from
the literature.
Selected Examples with Data
N-Benzylbenzamide (4b)
1H NMR (300 MHz, CDCl3): d = 4.48 (d, 2 H, J = 6.02 Hz),
7.23 (m, 1 H), 7.31 (m, 4 H), 7.51 (m, 3 H), 7.88 (m, 2 H),
9.04 (t, 1 H, J = 5.70 Hz). 13C NMR (75 MHz, CDCl3):
d = 42.59, 126.73, 127.19, 127.25, 128.29, 128.33, 131.26,
134.33, 139.72, 166.19. MS: m/z = 212 [M+].20a
(4-Bromophenyl)(morpholino)methanone (4e)
1H NMR (300 MHz, CDCl3): d = 2.49 (br s, 4 H), 3.58 (br s,
(13) Lanthanide triflates have been reported to promote the
addition of amines to nitriles. See: Forsberg, J. H.; Spaziano,
V. T.; Balasubramanian, T. M.; Liu, G. K.; Kinsley, S. A.;
Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller, J. L.
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Chem. Soc. 2010, 132, 16368.
4 H), 7.36 (d, 2 H, J = 8.68), 7.64 (d, 2 H, J = 8.58). 13
C
NMR (75 MHz, CDCl3): d = 66.03, 122.99, 129.29, 131.47,
134.75, 168.09.20b
(4-Methoxyphenyl)(morpholino)methanone (4f)
1H NMR (300 MHz, CDCl3): d = 3.48 (br s, 4 H), 3.82 (br s,
4 H), 3.79 (s, 3 H), 6.98 (d, 2 H, J = 6.68 Hz), 7.38 (d, 2 H,
J = 6.76). 13C NMR (75 MHz, CDCl3): d = 55.25, 66.11,
113.66, 127.47, 129.13, 160.24, 169.02. MS: m/z = 206
[M+].20c
(16) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
(17) (a) Burgi, H. B.; Dunitz, J. P.; Lehn, J. M.; Wipff, G.
Tetrahedron 1974, 30, 1563. (b) Bartlett, G. J.; Choudary,
A.; Raines, R. T.; Woolfson, D. N. Nat. Chem. Biol. 2010, 6,
615.
Morpholino(pyridin-3-yl)methanone (4h)
1H NMR (300 MHz, CDCl3): d = 3.64 (br s, 8 H), 7.49 (m, 1
H), 7.85 (m, 1 H), 8.64 (m, 2 H). 13C NMR (75 MHz,
CDCl3): d = 66.04, 123.59, 131.48, 134.96, 147.76, 150.55,
166.90. MS: m/z = 192 [M+].20d
(18) Procedure for Conversion of Esters into Amides Using
Sm[HMDS]3 Synthesis of Amide 4a
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Anhyd samarium chloride (0.280 g, 0.73 mmol) was dried
under high vacuum at 140 °C for 15 h, then cooled to
ambient temperature under argon. The residue was
suspended in anhyd THF (4 mL) and LiHMDS (2.2 mL of a
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