Rapid synthesis of α-ketoamides using microwave irradiation- simultaneous cooling method

Article abstract of DOI:10.1016/j.tetlet.2003.09.180

Microwave-assisted acyl chloride-isonitrile condensation and CaCO ₃-mediated hydrolysis constitute a one-pot, 2-minute process to prepare α-ketoamides.

Full text of DOI:10.1016/j.tetlet.2003.09.180

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8873–8876
Rapid synthesis of a-ketoamides using microwave
irradiation–simultaneous cooling method
Jack J. Chen* and Seema V. Deshpande
Procter & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45040, USA
Received 26 August 2003; revised 19 September 2003; accepted 19 September 2003
Dedicated to the memory of Professor Arno F. Spatola
Abstract—Microwave-assisted acyl chloride–isonitrile condensation and CaCO3-mediated hydrolysis constitute a one-pot,
2-minute process to prepare a-ketoamides.
© 2003 Published by Elsevier Ltd.
The electron-deficient a-carbonyl group of a-ketoamide
provides exceptional adducting opportunities to nucle-
ophiles such as the hydroxyl and thiol groups that are
abundantly present in the reactive sites of proteolytic
enzymes.1 Because of these enzymes’ crucial roles in
biochemical pathways, a-ketoamide containing natural
products or synthetic agents often deliver profound
biological effects. Structurally related microbial prod-
ucts rapamycin and FK-506 (1) are two well known
instances.2 Both are potent T-cell activation and prolif-
eration blockers and 1 has been approved for use in
organ transplant.3 Many transition-state protease
inhibitors incorporate a-ketoamides into their P1 sites
to affect reversible enzyme modifications. Good exam-
ples include thrombin inhibitor cyclotheonamide 2,4
calpain inhibitor 3,5 and Caspase-3 and 7 inhibitor 4.6
Further development of these compounds could lead to
therapeutic solutions to stroke, Alzheimer’s disease and
muscular dystrophy (Fig. 1).
Synthetically, a-ketoamides are prepared mainly by (1)
oxidation of the corresponding a-hydroxyamides7 or
a-cyanoketones,8 and (2) amidation of a-ketoacids.9
There are also a few less notable protocols including a
Figure 1. Biologically active a-ketoamides.
Keywords: microwave synthesis; a-ketoamide; isocyanide chemistry.
* Corresponding author. Fax: 513-622-0085; e-mail: chen.j.1@pg.com
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.180

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J. J. Chen, S. V. Deshpande / Tetrahedron Letters 44 (2003) 8873–8876
direct synthesis method developed by Ugi in the
1960s.10 In this protocol, an acyl chloride couples with
an isonitrile to form an a-ketoimidoyl chloride interme-
diate, which is then converted to an a-ketoamide upon
hydrolysis (Scheme 1).
nated from the original protocol to reduce environmen-
tal impact and reagent cost. Neat benzoyl chloride and
cyclohexyl isonitrile were mixed in a microwave reac-
tion tube and irradiated at 60 W for 2 minutes. CaCO3–
water suspension was injected and the irradiation
continued at 60 W for 2 more minutes. The LC-MS
analysis indicated that purity of the crude product was
comparable to the original method. Though the yield
after purification was found to be less than the one with
conventional heating,12 the total reaction time was
reduced from 4 h to 4 minutes!
A method was warranted to rapidly prepare struc-
turally diverse a-ketoamides to support our protease-
related discovery projects. After careful assessment of
the available methodologies, we concluded that Ugi’s
approach was more practical for our purpose since it
could generate products directly from commercially
available reagents, whereas others necessitated special
starting materials that require additional synthetic
efforts. However, in Ugi’s method, formation and
hydrolysis of the key intermediate a-ketoimidoyl chlo-
ride demand two to six hours of heating. These lengthy
heating steps compromise reaction throughput and thus
ought to be optimized. We decided to quest microwave
technology for solutions since it has proved to dramat-
ically accelerate heating-involved reactions.11
Because of the short turnover time of microwave syn-
thesis, the reaction conditions were quickly optimized
using preparation of 6 as the model reaction (Table 1).
When the power of irradiation in step 1 was raised to
100 W, only a black tar-like product was produced,
which presumably was caused by overheating (entry b).
The overheating effect was relieved and the reaction
efficiency recovered when air-cooling was engaged dur-
ing the course of irradiation (entry c).13 By applying
100 W irradiation along with air-cooling to both con-
densation and hydrolysis steps, the yield was improved
and the total reaction time was further reduced to 2
The approach was examined in
a
Discovery™
microwave synthesizer (Scheme 1). Solvents were elimi-
Scheme 1. Preparation of a-ketoamide 5 with different heating methods
Table 1. Optimization of microwave conditions
Entry
a
b
c
d
e
f
Step 1
Step 2
t1 (min)a
P1 (W)
Cooling
T1max °Cc
t2 (min)a
P2b(W)
2
60
Off
149
2
60
Off
195
1
1
1
1
1
b
100
Off
150
2
60
Off
195
100
On
100
2
60
Off
180
100
On
100
1
100
On
125
100
On
100
1
100
On
125
100
On
100
1
100
On
125
Cooling
T2max °Cc
Reagent ratiod
%Yield
1
45
1
N/A
1
69
1
74
2/3
70
3/2
77
a Irradiation time of step 1 or 2.
b Wattage of irradiation power.
c Maximal temperature during the irradiation.
d Molar ratio of benzoyl chloride/cyclohexyl isonitrile.

J. J. Chen, S. V. Deshpande / Tetrahedron Letters 44 (2003) 8873–8876
8875
Table 2. a-Ketoamides prepared by the irradiation-simultaneous cooling method
Entry
R1
R2
%Yield (MW)
%Yield (Ugi)a
69
5
Ph
Cyclohexyl
74
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
Ph
Bn
n-Bu
Cyclohexyl
Cyclohexyl
n-Bu
Bn
Cyclohexyl
n-Bu
51
40
53
64
60
21
60
51
p-Anisoyl
1-Napthyl
1-Napthyl
1-Napthyl
PhCH2CH2
PhCH2CH2
PhCH2CH2
Ph
65
Bn
36
N/A
N/A
6j
6h
1,1,3,3-Tetramethylbutyl
2,5-Dimethylphenyl
Ph
a Yields reported in Ref. 10.
W with air-cooling for 1 min. After ensuring the tem-
perature had dropped and pressure was released, anhy-
drous K2CO3 was added to the reaction tube and the
solution filtered. The filtrate was evaporated to dryness
and the final product was purified by flash column
chromatography with hexane–methylene chloride.
minutes (entry d). It is noteworthy that, this is the first
reported instance that demonstrated the practical
benefits of microwave irradiation–simultaneous cooling
method apart from few scarce mentions.11a The alterna-
tive acyl chloride–isonitrile ratios were also investi-
gated. Our results suggested that increasing the amount
of either reagent did not provide significant benefit to
offset the extra reagent cost and purification efforts.
Acknowledgements
The irradiation–simultaneous cooling method was
employed to prepare a series of a-ketoamides listed in
Table 2.14 The final isolation yields of the syntheses
were found at least to be comparable to the conven-
tional heating method. Both aromatic and aliphatic
acyl chlorides provided good to moderate yields. Steri-
cally hindered or less nucleophilic isonitriles, such as
1,1,3,3-tetramethylbutyl isocyanide and 2,5-dimethyl-
phenyl isocyanide did not perform well, the cause of
which is still being investigated.
The authors would like to thank Dr. Bill Seibel and Dr.
Namal Warshakoon for proofreading the manuscript.
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In summary, a microwave-assisted, rapid synthetic
method for a-ketoamides has been developed. The
speed of the reaction and a variety of commercially
available reagents provide a broad access for this class
of compounds. The performance of synthesized
ketoamides in protease inhibition assays and their fur-
ther applications in construction of heterocyclic systems
are under active investigation. We will report those
results in due course.
General procedure for microwave-assisted synthesis of
a-ketoamides: Isocyanide (0.4 mmol) and acyl chloride
(0.4 mmol) were added to a 5 mL reaction tube with a
stirring bar. The tube was sealed and positioned in the
irradiation cavity. The sealed reaction mixture was
stirred and irradiated at 100 W while it was cooled by
pressurized (20 psi) airflow for 1 minute. To the same
reaction tube, a suspension of CaCO3 (24 mg) in ace-
tone (0.8 mL) and water (0.16 mL) was added via a
syringe. The mixture was stirred and irradiated at 100
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8876
J. J. Chen, S. V. Deshpande / Tetrahedron Letters 44 (2003) 8873–8876
6. Lee, D.; Long, S. A.; Murray, J. H.; Adams, J. L.;
188.38, 161.09, 134.60, 134.52, 133.73, 133.68, 131.46,
128.69, 48.70, 32.96, 25.66, 24.99. MS (ESI): m/z 232.26
MH+.
Nuttall, M. E.; Nadeau, D. P.; Kikly, K.; Winkler, J. D.;
Sung, C.-M.; Ryan, M. D.; Levy, M. A.; Keller, P. M.;
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12. Reaction with neat reagents and conventional heating
also provided similar results, but still required total 4 h
reaction time.
1
Compound 6a: H NMR (300 MHz, CDCl3): l 8.41–8.38
(m, 2H), 7.66–7.64 (m, 1H), 7.54–7.49 (m, 2H), 7.42–7.29
(m, 5H), 4.62–4.60 (d, 2H, J=6.0 Hz). 13C NMR (75
MHz, CDCl3): l 187.76, 161.76, 137.34, 134.72, 133.57,
131.51, 129.12, 128.78, 128.17, 128.11, 43.76. MS (ESI):
m/z 240.09 MH+.
1
Compound 6b: H NMR (300 MHz, CDCl3): l 8.37–8.34
(m, 2H), 7.66–7.61 (m, 1H), 7.52–7.49 (m, 2H), 7.14 (s,
1H), 3.44–3.38 (dd, 2H, J1=7.3 Hz, J2=13.1 Hz), 1.64–
1.56 (m, 2H), 1.46–1.38 (m, 2H), 1.00–0.95 (t, 3H, J=7.3
Hz). 13C NMR (75 MHz, CDCl3): l 188.17, 161.99,
134.59, 133.65, 131.46, 128.80, 128.71, 39.40, 31.57, 20.31,
13.94. MS (ESI): m/z 206.10 MH+.
1
Compound 6c: H NMR (300 MHz, CDCl3): l 8.44–8.41
(m, 2H), 6.97–6.94 (m, 2H), 7.06 (s, 1H), 3.90 (s, 3H)
3.88–3.80 (m, 1H), 2.02–1.97 (m, 2H), 1.81–1.63 (m, 3H)
1.49–1.21 (m, 5H). 13C NMR (75 MHz, CDCl3): l
186.30, 164.89, 161.61, 134.18, 126.78, 126.74, 114.03,
55.78, 48.61, 32.96, 25.68, 25.00. MS (ESI): m/z 262.10
MH+.
1
Compound 6d: H NMR (300 MHz, CDCl3): l 8.60–8.58
(d, 1H, J=8.4 Hz), 8.33–8.30 (dd, 1H, J1=0.7 Hz J2=6.9
Hz), 8.10–8.07 (d, 1H, J=8.0 Hz), 7.93–7.90 (dd, 1H,
J1=0.7 Hz, J2=8.0 Hz), 7.67–7.53 (m, 3H), 7.12–7.10 (d,
1H, J=7.3 Hz), 3.99–3.87 (m, 1H), 2.08–2.03 (m, 2H),
1.85–1.78 (m, 2H), 1.71–1.66 (m, 1H), 1.49–1.24 (m, 5H).
13C NMR (75 MHz, CDCl3): l 191.14, 161.46, 134.69,
134.10, 133.32, 131.45, 130.08, 128.95, 128.57, 126.75,
125.59, 124.49, 48.99, 33.04, 25.69, 25.02. MS (ESI): m/z
282.26 MH+.Compound 6g: 1H NMR (300 MHz,
CDCl3): l 7.33–7.22 (m, 5H), 6.87 (s, 1H), 3.81–3.69 (m,
1H), 3.32–3.27 (t, 2H, J1=7.0 Hz, J2=14.6), 2.98–2.93 (t,
2H, J1=7.3 Hz, J2=15.0), 1.94–1.89 (m, 2H), 1.95–1.62
(m, 4H), 1.47–1.16 (m, 5). 13C NMR (75 MHz, CDCl3):
l 198.96, 159.23, 140.72, 128.74, 128.65, 126.48, 48.57,
38.58, 32.91, 29.41, 25.60, 24.92. MS (ESI): m/z 260.10
MH+.
13. The Discovery™ microwave synthesizer features the
option of heating along with spontaneous air-cooling. A
similar approach has been mentioned in Chapter 5 of
Ref. 11a.
14. The spectroscopic data for selected compounds:
1
Compound 5: H NMR (300 MHz, CDCl3): l 8.37–8.34
(m, 2H), 7.66–7.61 (dd, 1H, J1=7.5 Hz, J2=14.8 Hz),
7.52–7.47 (dd, 2H, 2H, J1=7.8 Hz, J2=15.3 Hz), 6.99 (s,
1H), 3.93–3.83 (m, 1H), 2.03–1.78 (m, 2H), 1.77–1.64 (m,
3H), 1.51–1.21 (m, 5H). 13C NMR (75 MHz, CDCl3): l