A facile one-pot synthesis of acyclic β-enamino ketones, an important class of versatile synthetic intermediates

Article abstract of DOI:10.1016/j.tetlet.2007.02.115

A one-pot sequential process consisting of nucleophilic substitution of the lithiated acetylides with Weinreb amides followed by a Michael reaction of the extruded N-methoxy-N-methylamine after quenching with saturated NH₄Cl, provided β-enamino ketones in high yield and in a single geometrical isomeric form. It has been demonstrated that this method is applicable to a wide variety of such amides and to different acetylides.

Full text of DOI:10.1016/j.tetlet.2007.02.115

Tetrahedron Letters 48 (2007) 3069–3072
A facile one-pot synthesis of acyclic b-enamino ketones,
an important class of versatile synthetic intermediates
Anusuya Choudhury,a,* Michael Breslav,b Jeffrey S. Grimm,a Tong Xiao,a
Dawei Xua and Kirk L. Sorgia
aChemical Development, Johnson & Johnson Pharmaceutical Research & Development,
L.L.C. 1000 Route 202 Raritan, NJ 08869, USA
bAnalytical Development, Johnson & Johnson Pharmaceutical Research & Development,
L.L.C. Welsh & McKean Roads, PA 19477, USA
Received 16 January 2007; revised 21 February 2007; accepted 23 February 2007
Available online 1 March 2007
Abstract—A one-pot sequential process consisting of nucleophilic substitution of the lithiated acetylides with Weinreb amides fol-
lowed by a Michael reaction of the extruded N-methoxy-N-methylamine after quenching with saturated NH4Cl, provided b-ena-
mino ketones in high yield and in a single geometrical isomeric form. It has been demonstrated that this method is applicable to
a wide variety of such amides and to different acetylides.
Ó 2007 Elsevier Ltd. All rights reserved.
A long-standing problem in organic synthesis has been
the lack of an effective, clean reduction method of
carboxylic acid derivatives to their corresponding
aldehydes without over-reduction. Weinreb’s group
has solved this problem in recent years via the use of
the corresponding N-methoxy-N-methylamide (Weinreb
amide) as the reduction precursor. Origin of such
control has been attributed to a tetrahedral chelate (as
shown in A, Scheme 1) involving the –OMe group of
the substrate amide with the metal cation, which pre-
vents further reduction.1 This concept has been also
extended to carbon nucleophiles for ketone formation.
While use of this methoxyamine segment in regulating
nucleophilic attack is the key to prevent over-reduction
M
R
O
OMe
a
Cl
Cl
OMe
O
N
N
+
Me
Cl
Me
H
R
2a
1a
Cl
A
c
a, b
NH2
R
O
O
O
Cl
Cl
Cl
Cl
R
Cl
Cl
d
OMe
N
R
H
H
Me
5a
3
4a
R = O-THP
Scheme 1. Reagents and condition: (a) Li-HMDS, THF, À10 °C to +10 °C; (b) dilute HCl; (c) saturated NH4Cl; (d) prolonged stirring.
Keywords: b-Enamino ketones; Weinreb amide.
*
Corresponding author. Tel.: +1 908 704 4975; fax: +1 908 231 7429; e-mail: achoudhu@prdus.jnj.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.115

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A. Choudhury et al. / Tetrahedron Letters 48 (2007) 3069–3072
Table 1. One-pot sequential transformation of Weinreb amides (1a–g)
to enamino ketones (4a–g) via the addition of propargyl-Li (from 2a)
followed by satd NH4Cl quench
or reaction, its role in the post-reaction mixture has not
been fully explored. This Letter is a subject of such
work, which describes a facile preparation of b-enamino
ketones, a versatile class of synthetic intermediates.
Entry Amidea
Productb
Yieldc
(%)
We were interested in preparing a propargylic ketone
bearing an acid sensitive tetrahydropyranyloxy (OTHP)
functionality (3, R = OTHP, Scheme 1) via lithium
acetylide addition to Weinreb amide 1a. When this reac-
tion was carried out following standard conditions
(LiHMDS added to a mixture of 1a and 2a in THF at
À10 to +10 °C followed by a saturated NH4Cl quench),
we were surprised to find none of the expected acetylenic
ketone 3. The major product formed in this reaction was
characterized as the isomerically pure (E) N-methoxy-N-
methyl-b-enamino ketone 4a.2 This unwanted reaction
product was considered to arise from the Michael addi-
tion of N-methoxy-N-methylamine with the desired
acetylenic ketone 3. We were intrigued by the ease of
which this Michael addition took place and the potential
synthetic utility of b-enamino ketone products.
O
OTHP
O
Cl
Me
Me
N
N
1
86
Cl
Cl
OMe
Cl
1a
OMe
4a
OTHP
Me
O
O
Me
2
3
4
5
N
86
72
85
93
N
OMe
1b
4b
OMe
OTHP
NO2
O
NO2
O
Me
Me
N
N
OMe
1c
4c
OMe
OTHP
O
O
Me
Me
N
N
To test the usefulness of this synthetic method, we pre-
pared a wide variety of Weinreb amides (1a–g) and
reacted each with lithium acetylide of 2a followed by
a saturated NH4Cl quench. The results are recorded in
Table 1. In all cases, high yields of the (E) N-meth-
oxy-N-methyl-b-enamino ketones were obtained. The
electronic influence of the substituents on the aromatic
ring seem to have little or no impact on the yield and
nature of the reaction (entries 1–4). Heterocyclic (entry
5), alicyclic and aliphatic amides (entries 6 and 7) also
led to moderate to high yields, clearly demonstrating
the versatility of this synthetic method. We also exam-
ined several lithiated acetylides and found that good
yields were obtained as well (Table 2). 3,4-Dichloro-
carboxamide (1a) was used as a model substrate, and
reacted with different lithiated acetylides, derived from
the corresponding acetylenes (entries 1–4). In all cases,
the yields were high and a single geometrical isomer
was formed.
1d
OMe
4d
MeO
OMe
MeO
OTHP
O
1e
O
O
Me
Me
N
N
OMe
N
4e
OMe
N
OTHP
O
Me
Me
N
6d
81
65
N
OMe
1f
OMe
4f
OTHP
O
O
Me
Me
N
7
H3C
N
H3C
1g
4g
OMe
OMe
a For a general preparation of the Weinreb amides see Ref. 9.
b For a general procedure see Ref. 10, a single geometrical isomer was
obtained in each case, NOE experiment for 4a indicated E configu-
ration for the double bond, for 4b–g double bond configuration was
assumed to be E.
While this work was in progress, we came across a
similar type of sequential Micheal addition product
involving N-methoxy-N-methylamine (B) but with a
vinylic system (Fig. 1) to generate b-amino ketones.3
c Isolated crude yield, purity was >95% in each case.
d The second addition step was carried out at 40 °C.
While continuing to explore the scope and limitations of
preparing N-methoxy-N-methyl-b-enamino ketones,4 we
found that prolonged stirring (48–72 h) of the NH4Cl
quenched reaction mixture led to an exchange of the
amines and resulted in the generation of b-enamino
ketones (Table 3). Thus the N-methoxy-N-methylamine
unit in the substrates does not remain as an imposing
structural feature, but rather can be exchanged with
other amines to introduce novel amine segments to the
vinylic system. More interestingly, a reversal in double
bond configuration was noticed in all cases (Table 1 vs
Table 3). The Z-isomer was obtained, presumably via
an addition elimination process to form the thermody-
namically more stable product that enjoys an intra-
molecular hydrogen bond between the amino group
and the b-carbonyl group (Fig. 1, 5a–k).
In general, the synthesis of b-enamino ketones is not
straightforward. Metal mediated reduction of oxazo-
lines5 and reaction of 1,3-diketones with amines are
the major synthetic methods to generate them. Recently,
Muller et al. have shown a sequential protocol which
uses the reaction of an acid chloride and acetylenes un-
der Sonogashira condition (Pd(PPh3)3Cl2, CuI) followed
by an attack of primary or secondary amines to generate
these important intermediates.6 In contrast to these
methods, our present method is extremely simple, versa-
tile and generates high yields of isomerically pure b-ena-
mino ketones which are strategic precursors useful in
preparing a wide variety of compounds.
Mechanistically, the formation of the N-methoxy-N-
methyl-b-enamino ketone7 can be explained by a

A. Choudhury et al. / Tetrahedron Letters 48 (2007) 3069–3072
3071
Table 2. The products from the addition of different lithiated
acetylides (2b–e) with 3,4-dichlorocarboxamide (1a) followed by satd
NH4Cl quench
Table 3. One-pot synthesis of b-enamino ketones: prolonged stirring
of the quenched propargylation reaction mixture
Entry
Amide
Producta
Yieldb (%)
94
Entry Acetylenea
Productb
Yieldc (%)
O
NH2
1
4a
O
COOMe
Cl
COOMe
Me
1
77
Cl
Cl
N
OTHP
Cl
5a
2b
OMe
O
NH2
4h
c
c
OAc
2
3
4
5
6
7
4b
4c
4d
4e
4f
Me
O
O
Me
OTHP
NH2
5b
5c
Cl
Cl
N
O
2
3
4
83
85
83
NO2
O
OMe
2c
4i
OTHP
NH2
O
Ph
Me
Ph
2d
Cl
Cl
O
N
OMe
83
83
81
91
4j
5d
OTHP
MeO
O
O
NH2
O
Cl
Me
Cl
Cl
Cl
N
5e
OTHP
NH
N
OMe
2e
4k
2
a LiHMDS was used as the base to generate the corresponding
acetylides.
OTHP
b Based on 4a, the configuration of the double bond was assumed to be
5f
E.
O
NH2
c Isolated crude yield, purity was >95% in each case.
4g
H3C
5g
OTHP
O
O
NH2
COOMe
Me
Cl
Cl
R
O
N
8
4h
77
MgBr
(ref. 3)
B
OMe
5h
H
O
H2O
O
R
NH
Me
O
O
O
NH2
R
N
R'
Cl
Cl
1a-k
OMe
9
4i
4j
83
85
5a-k
Sat. NH4Cl
OAc
NH2
Ph
R'
Li
5i
R
Satd. NH4Cl
O
R'
R'
Me
C
H
Me
N
Cl
Cl
N
R
10
OMe
OMe
4a-k
5j
5k
NH2
Figure 1.
Cl
Cl
11
4k
83
three-step process.8 The first step involves a nucleophilic
substitution of a lithium acetylide to a Weinreb amide
followed by a second step generation of the propargylic
ketone via quenching of the tetrahedral intermediate. In
the third step, a Michael addition occurs between the
liberated N-methoxy-N-methyl amine and the ketone
(Fig. 1). Evidence for this mechanism comes from mon-
itoring the reaction by 1H NMR. When the reaction was
carried out with lithium phenyl acetylide and 1a, the
acetylenic ketone was observed after immediate quench-
ing (satd NH4Cl) and workup. Further monitoring by
1H NMR showed the eventual formation of the corre-
sponding b-enamino ketone 4j.
Cl
a NOE experiment and X-ray structure determination for 5a proved
the configuration of the double bond to be Z, for other enamino
ketones the double bond configuration was assumed to be Z, for a
general procedure see Ref. 11.
b Isolated crude yield.
c Quantitative.
clean formation of the corresponding b-enamino ketone.
The origin of selective formation of a single geometrical
isomer, however, is not clearly understood. We presume
that N-methoxy-N-methylamine dictates the selective
protonation of the Michael addition intermediate,
resulting in the E geometrical isomer.
In a separate experiment we reacted N-methoxy-N-
methylamine with acetylenic ketone 3 and observed

3072
A. Choudhury et al. / Tetrahedron Letters 48 (2007) 3069–3072
8. (a) Qu, B.; Collumn, D. J. Org. Chem. 2006, 71, 7117; (b)
Other possible mechanisms cannot be ruled out. For
example, an allene formation (via a selective 1,4-addition)
could be a possible intermediate to explain the single
geometric isomer. However, we were unable to detect an
allene peak in an in situ FTIR study.
In conclusion, we have demonstrated a mild and efficient
synthetic method to transform carboxamides to b-en-
amino ketones in one reaction flask. Further potential
of this synthetic methodology is currently ongoing and
will be reported.
9. Synthesis of 3,4-dichloro-N-methoxy-N-methyl-benzam-
ide (1a): N,O-Dimethylhydroxylamine hydrochloride
(1.48 kg, 14.88 mol) was suspended in EtOAc (16 L) and
warmed to 35 °C. A solution of 3,4-dichlorobenzoyl
chloride (3.00 kg, 13.88 mol) in EtOAc (8 L) was added,
followed by addition of diisopropylethyl amine (5.45 ml,
31.2 mol) while maintaining the temperature below 40 °C.
The reaction suspension was stirred for 1 h. When TLC
analysis confirmed reaction completion by the disappear-
ance of starting material, the reaction mixture was cooled
to room temperature and water (10 L) was added to
achieve a two-phase clear solution. After removing the
aqueous layer, the organic layer was dried (Na2SO4) and
concentrated to afford 1a (3.38 kg) as an oil. Upon sitting
at room temperature the product crystallized. HPLC
area% purity 99.3%. mp: 43.2 °C. Yield: quantitative. IR
(KBr pellet): 3445.0, 3258.0, 3091.6, 2981.4, 2945.5,
1942.4, 1645.6, 1588.6, 1557.4, 1462.9, 1414.5, 1368.0,
1386.2, 1262.0, 1209.0, 1130.0, 1112.5, 1071.8, 1030.9,
Acknowledgements
We are thankful to Ryan Callahan, Angelo Fields and
Nicole Le Fur for running several experiments. We
thank Dr. Donald Walker for useful discussions and
Ms. Emma Huang for analytical support.
References and notes
1. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815; see (b) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25,
15.
2. (a) Choudhury, A; Grimm, J. S.; Jones, T. K.; Liang, J. T.;
Mani, N; Sorgi, K. L. WO 2005/005393; (b) The content
of this manuscript and related work were presented at the
following symposiums: (1) A facile one-pot synthesis of
b-enamino ketones: A masked diketone with distinct
reactivity difference. Choudhury, A; Grimm, J. S.; Sorgi,
K. L; Xiao, T; Breslav, M; Xu, D.; Presented at the 230th
ACS National Meeting, Washington, DC, United States,
August 28–September 1, 2005. (2) Novel and highly
regioselective synthesis of substituted pyrazoles. Grimm,
J. S.; Callahan, R.; Choudhury, A.; Segmuller, B.; Sorgi,
K. L.; Xiao, T; Xu, D. Presented at the 229th ACS
National Meeting, San Diego, CA, United States, March
13–17, 2005; (c) Very recently, we came across a commu-
nication, which describes synthesis of a substrate similar to
4a via analogous method as disclosed in our patent
application, WO 2005/005393 (Persson, T., Nielsen, J.
Org. Lett. 2006, 8, 3219).
.
100.9, 893.8 cmÀ1 1H NMR (CDCl3): 7.8 (d, 1H,
J = 2 Hz), 7.54 (dd, 1H, J = 2 and 8.4 Hz), 7.46 (d, 1H,
J = 8.3 Hz), 3.54 (s, 3H), 3.34 (s, 3H). 13C NMR (CDCl3):
167.2, 135.0, 133.9, 132.4, 130.7, 130.2, 127.9, 61.5 and
33.0.
10. General procedure for the sequential transformation of
the amides to b-enamino ketones: To a solution of amide
1a (0.79 g, 3.33 mmol) and propargyl-THP (0.48 mL,
3.4 mmol) in dry THF (3 mL), lithium hexamethyldisilaz-
ide (LiHMDS, 3.4 mL, 1 M/THF) was added between
À10 and +10 °C. The reaction mixture was stirred for 1 h
at that temperature range and quenched with 10 mL of
saturated NH4Cl. The mixture was warmed to ambient
temperature and 10 mL of EtOAc was added to facilitate
the layer separation. The organic layer was separated and
dried over anhydrous MgSO4 and filtered. The filtrate was
concentrated in vacuum and dried at high vacuum to
afford 1.07 g (86%) of 4a as a thick oil. Compound 4a: MS
(ES+): mass calcd for C17H21Cl2NO4, 373.08; m/z found,
374.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.95 (d,
J = 2.1 Hz, 1H), 7.69 (dd, J = 8.4, 2.1 Hz, 1H), 7.44 (d,
J = 8.3 Hz, 1H), 6.12 (s, 1H), 5.13 (d, J = 12 Hz, 1H),
4.79–4.77 (m, 1H), 4.76 (d, J = 11.5 Hz, 1H), 3.70 (s, 3H),
3.88–3.86 (m, 1H), 3.30 (s, 3H), 1.83–1.50 (m, 3H), 1.49–
1.21 (m, 4H).
3. Gomtsyan, A. Org. Lett. 2000, 2, 11.
4. Jeong, I. H.; Jeon, S. L.; Min, Y. K.; Kim, B. T.
Tetrahedron Lett. 2002, 43, 7171.
5. The methods for the synthesis of b-enamino ketones see
(a) Alberola, A.; Gonzalez, A. M.; Laguna, M. A.; Pulido,
F. J. Synth. Commun. 1986, 16, 673; (b) De La Cal, M. T.;
Cristobal, B. I.; Cuadrado, P.; Gonzalez, A. M.; Pulido, F.
J. Synth. Commun. 1989, 19, 1039; (c) Gonzalez, B.;
Gonzalez, A.; Pulido, F. J. Synth. Commun. 1995, 25,
1005; (d) Smirnova, Y. V.; Krasnaya, Z. A.; Zelinsky, N.
D. Russ. Chem. Rev. 2000, 69, 1021; Amination of a,b-
unsaturated ketones see (e) Seko, S.; Tani, N. Tetrahedron.
Lett. 1998, 39, 8117; For a review on b-enaminones (f)
Michael, J. P.; Konig, C. B.; Gravestock, D.; Hosken, G.
D.; Howard, A. S.; Jungmann, C. M.; Krause, R. W. M.;
Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure Appl.
Chem. 1999, 71, 979.
11. Prolonged stirring of the reaction mixture after the quench
with saturated NH4Cl (Ref. 10) for 48–72 h generated
cleanly the b-enamino ketone 5a in 94% yield (Table 3,
entry 1). (ES+): mass calculated for C14H15Cl2NO3,
1
329.06; m/z found, 330.1 [M+H]+. H NMR (400 MHz,
CDCl3): 10.2 (br s, 1H), 8.19 (m, 1H), 7.77 (d, J = 2 Hz,
1H), 7.47 (d, J = 2.8 Hz, 1H), 6.33 (br s, 1H), 5.62 (s, 1H),
4.68–4.66 (m, 1H), 4.45 (d, J = 15 Hz, 1H), 4.4 (d,
J = 15 Hz, 1H), 3.91–3.83 (m, 1H), 3.60–3.53 (m, 1H),
3.30 (s, 3H), 2.0–1.6 (2 m, 6H).
6. Karpov, A.; Muller, T. J. J. Synthesis 2003, 18, 2815.
7. All compounds were characterized by H NMR and mass
1
spectral analysis.