Lactam coupling as a versatile route to indoprofen analogs

Article abstract of DOI:10.1080/00397910903531813

A convergent synthesis of indoprofen via a Buchwald coupling approach is reported. Using this methodology, indoprofen and a set of analogs of indoprofen were readily prepared. Copyright

Full text of DOI:10.1080/00397910903531813

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Lactam Coupling as a Versatile Route to
Indoprofen Analogs
Keith D. Barnes a , Ping Chen a , Yingyan Chang a , Robert M. Lewis
a , Christopher M. Manley a , Nicholas J. Mayhew a , Stephen H.
Steffke a , Guixing Wang a , Yi Wang a , Yuh-Lin A. Yang a & John W.
Lippert III a
a Medicinal Chemistry Department , AMRI , Albany, New York, USA
Published online: 14 Dec 2010.
To cite this article: Keith D. Barnes , Ping Chen , Yingyan Chang , Robert M. Lewis , Christopher
M. Manley , Nicholas J. Mayhew , Stephen H. Steffke , Guixing Wang , Yi Wang , Yuh-Lin A. Yang &
John W. Lippert III (2010) Lactam Coupling as a Versatile Route to Indoprofen Analogs, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:1, 67-72, DOI: 10.1080/00397910903531813
To link to this article: http://dx.doi.org/10.1080/00397910903531813
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Synthetic Communications1, 41: 67–72, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531813
LACTAM COUPLING AS A VERSATILE ROUTE TO
INDOPROFEN ANALOGS
Keith D. Barnes, Ping Chen, Yingyan Chang, Robert M. Lewis,
Christopher M. Manley, Nicholas J. Mayhew,
Stephen H. Steffke, Guixing Wang, Yi Wang,
Yuh-Lin A. Yang, and John W. Lippert III
Medicinal Chemistry Department, AMRI, Albany, New York, USA
A convergent synthesis of indoprofen via a Buchwald coupling approach is reported. Using
this methodology, indoprofen and a set of analogs of indoprofen were readily prepared.
Keywords: Buchwald–Hartwig cross-coupling; indoprofen; palladium
INTRODUCTION
Indoprofen (1), a nonsteroidal anti-inflammatory drug that was withdrawn
from the world market in the 1980s after postmarketing reports of severe gastrointes-
tinal bleeding, has resurfaced within the drug discovery realm.[1] In 2004, Stockwell
and coworkers found through high-throughput screening that indoprofen increases
production of the survival motor neuron protein, suggesting that it may provide
insight into the treatment of spinal muscular atrophy.[1]
A number of syntheses of indoprofen (1) have been reported,[2] but we felt
none of these were attractive for readily preparing an array of analogs. To obtain
a variety of derivatives of indoprofen (1), new synthetic methods were explored.
Herein we report a new convergent approach to obtain the indoprofen scaffold
via a palladium-mediated Buchwald–Hartwig cross-coupling reaction.
RESULTS AND DISCUSSION
The preparation of indoprofen and a small set of analogs substituted on the
aryl portion of isoindolin-1-one was accomplished using a carbon–nitrogen
cross-coupling. Buchwald, Hartwig, and coworkers[3] have previously described both
the palladium- and copper-catalyzed coupling of amides and aryl halides. Using
the Buchwald–Hartwig palladium-catalyzed coupling method, we found that the
indoprofen core structure could be constructed in a quick and efficient manner by
Received September 16, 2009.
Address correspondence to John W. Lippert III, Medicinal Chemistry Department, AMRI,
26 Corporate Circle, P.O. Box 15098, Albany, NY 12212-15098, USA. E-mail: John.Lippert@
amriglobal.com
67

68
K. D. BARNES ET AL.
Figure 1. Indoprofen.
coupling the appropriately substituted isoindolin-1-ones with 2-(4-bromophenyl)-
propanoate. The preparations of the coupling partners were carried out using stan-
dard synthetic organic transformations, and in most cases the isoindolin-1-ones were
commercially available unless otherwise noted in this text. The synthesis of methyl
2-(4-bromophenyl)propanoate has previously been reported.[4]
Table 1 illustrates the results from the palladium-mediated cross-coupling
conditions of isoindolin-1-ones 2a–i utilizing Pd2(dba)3=Xantphos. The methyl ester
of indoprofen 3a was obtained in 56% yield, and products containing the methoxy
groups 3b–e on all positions of the benzo ring gave comparable yields (57–78%) in
the palladium coupling system investigated. With the chloro groups, however, the
yields ranged considerably. In the case of the 4-Cl 3f and 7-Cl 3i analogs, the yields
were poor, 8% and 36%, respectively. In contrast, the 5-Cl 3g and 6-Cl 3h analogs
were obtained in 73% and 59% yields, respectively.
Based on the encouraging biological activities[5] demonstrated by the C-6 sub-
stituted analogs, we further explored substitution at this position with a variety of
substituents (Table 2).
The C-6 substituted isoindolin-1-ones 4c–e, h, and i have been previously
described in the literature, and isoindolin-1-ones 4a, b, f, and g were prepared by
similar methods.
Table 1. Palladium coupling products
Compound
R
Yield (%)
3a
3b
3c
3d
3e
3f
H
56
73
57
78
66
8
4-OCH3
5-OCH3
6-OCH3
7-OCH3
4-Cl
3g
3h
3i
5-Cl
6-Cl
73
59
36
7-Cl

LACTAM COUPLING ROUTE TO INDOPROFEN ANALOGS
69
Table 2. Palladium coupling products of C-6 substituted isoindolin-1-ones
Compound
R
Yield (%)
5a
5b
5c
5d
5e
5f
N(CH3)2
OCH(CH3)2
CH3
78
63
72
70
57
51
16
8
C6H5
F
CF3
5g
5h
5i
CN
SO2CH3
NO2
0
From the results tabulated in Table 2, it was evident that as one moved
from electron-donating to electron-withdrawing groups, the overall yield of the
palladium-catalyzed coupling decreased to the point where no reaction occurred,
as shown in entry 5i. One possible explanation is that strongly electron-withdrawing
groups affect the pKa of the amide, resulting in increased acidity and therefore
reduced nucleophilicity, leading to poor reaction efficiency. Shakespeare[3d] noted
this with the cross-coupling of aliphatic amides.
Indoprofen (1) and the substituted indoprofen analogs were readily obtained
by saponification of the coupled products under conventional conditions using
lithium hydroxide in yields of 72–98%.
In conclusion, a new convergent method based on C-N cross-coupling for the
synthesis of indoprofen and its analogs has been developed. The desired coupling
partners can be prepared in a straightforward manner using standard organic
transformations.
EXPERIMENTAL
Unless otherwise noted, reagents and solvents were used as received from com-
mercial suppliers. Proton nuclear magnetic resonance spectra were obtained on a
Bruker Avance 300 spectrometer at 300 MHz and Bruker Avance 500 spectrometer
at 500 MHz. Spectra are given in parts per million (d), and coupling constants, J
values, are reported in hertz. Tetramethylsilane was used as an internal standard.
Mass spectra were obtained on a Thermo Finnigan AQA Mass Spectrometer (elec-
trospray ionization) or a Finnigan LCQ Duo liquid chromatograph–mass spec-
trometer (APCI). All compounds were purified using ISCO combi-flash column
chromatography.

70
K. D. BARNES ET AL.
General Palladium Coupling Procedure
A mixture of the appropriately substituted isoindolin-1-one (1.2 mmol),
2-(4-bromophenyl)propanoate (1 mmol), tris(dibenzylideneacetone) dipalladium
(3 mol%), Xantphos (8 mol%), cesium carbonate (1.4 mmol), and 1,4-dioxane (2 mL)
was heated under argon in a sealed tube at 120 ꢀC overnight. After cooling to room
temperature, the mixture was diluted with dichloromethane and filtered. The fil-
trate was concentrated, and the residue was purified by chromatography to afford
the desired product. The data for the compounds in Tables 1 and 2 are shown.
Selected Data
1
Compound 3a. White solid: mp 110–111 ꢀC; H NMR (500 MHz, CDCl3) d
7.86 (d, J ¼ 9.0 Hz, 2H), 7.78 (d, J ¼ 7.5 Hz, 1H), 7.68 (m, 2H), 7.54 (t, J ¼ 7.5 Hz,
1H), 7.34 (d, J ¼ 8.5 Hz, 2H), 5.01 (s, 2H), 3.82 (q, J ¼ 7.0 Hz, 1H), 3.59 (s, 3H),
1.41 (d, J ¼ 7.5 Hz, 3H); ESI MS m=z 296 [M þ H]þ.
Compound 3b. Off-white solid: mp 105–106 ꢀC; 1H NMR (500 MHz,
DMSO-d6) d 7.87 (d, J ¼ 8.5 Hz, 2H), 7.52 (t, J ¼ 7.7 Hz, 1H), 7.36 (d, J ¼ 7.5 Hz,
1H), 7.33 (d, J ¼ 8.5 Hz, 2H), 7.28 (d, J ¼ 8.0 Hz, 1H), 4.92 (s, 2H), 3.93 (s, 3H),
3.81 (q, J ¼ 7.0 Hz, 1H), 3.59 (s, 3H), 1.40 (d, J ¼ 7.5 Hz, 3H); ESI MS m=z 326
[M þ H]þ.
Compound 3c. White solid: mp 114–115 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 7.82 (d, J ¼ 8.5 Hz, 2H), 7.78 (d, J ¼ 8.5 Hz, 1H), 7.32 (d, J ¼ 8.5 Hz, 2H), 7.21 (d,
J ¼ 1.5 Hz, 1H), 7.08 (dd, J ¼ 8.5, 2.0 Hz, 1H), 4.94 (s, 2H), 3.87 (s, 3H), 3.81 (q,
J ¼ 7.0 Hz, 1H), 3.59 (s, 3H), 1.41 (d, J ¼ 7.0 Hz, 3H); ESI MS m=z 326 [M þ H]þ.
Compound 3d. White solid: mp 130–131 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 7.84 (d, J ¼ 8.5 Hz, 2H), 7.56 (d, J ¼ 8.5 Hz, 1H), 7.34 (d, J ¼ 9.0 Hz, 2H), 7.27–7.23
(m, 2H), 4.93 (s, 2H), 3.85 (s, 3H), 3.82 (q, J ¼ 7.0 Hz, 1H), 3.60 (s, 3H), 1.41 (d,
J ¼ 7.5 Hz, 3H); ESI MS m=z 326 [M þ H]þ.
Compound 3e. Off-white solid: mp 105–107 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.83 (m, 2H), 7.52 (m, 1H), 7.34 (m, 2H), 7.06 (d, J ¼ 7.4 Hz, 1H), 6.93 (d,
J ¼ 8.3 Hz, 1H), 4.78 (s, 2H), 4.00 (s, 3H), 3.73 (q, J ¼ 7.2 Hz, 1H), 3.67 (s, 3H),
1.51 (d, J ¼ 7.2 Hz, 3H); ESI MS m=z 326 [M þ H]þ.
1
Compound 3f. White solid: mp 160–162 ꢀC; H NMR (500 MHz, CDCl3)
d 7.83–7.81 (m, 3H), 7.56 (dd, J ¼ 7.9, 0.9 Hz, 1H), 7.48 (t, J ¼ 7.7 Hz, 1H),
7.39–7.36 (m, 2H), 4.82 (s, 2H), 3.75 (q, J ¼ 7.2 Hz, 1H), 3.68 (s, 3H), 1.52 (d,
J ¼ 7.2 Hz, 3H); ESI MS m=z 330 [M þ H]þ.
Compound 3g. Off-white solid: mp 160–162 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.85–7.78 (m, 3H), 7.48 (m, 2H), 7.37 (m, 2H), 4.82 (s, 2H), 3.75 (q, J ¼ 7.0 Hz,
1H), 3.67 (s, 3H), 1.52 (d, J ¼ 7.5 Hz, 3H); ESI MS m=z 330 [M þ H]þ.
1
Compound 3h. White solid: mp 160–161 ꢀC; H NMR (300 MHz, CDCl3) d
7.89 (d, J ¼ 1.8 Hz, 1H), 7.79 (dd, J ¼ 6.8, 2.0 Hz, 2H), 7.56 (dd, J ¼ 8.0, 2.0 Hz, 1H),
7.45 (dd, J ¼ 8.1, 0.5 Hz, 1H), 7.37 (dd, J ¼ 7.0, 1.8 Hz, 2H), 4.83 (s, 2H), 3.75 (q,
J ¼ 7.1 Hz, 1H), 3.67 (s, 3H), 1.52 (d, J ¼ 7.2 Hz, 3H); ESI MS m=z 330 [M þ H]þ.

LACTAM COUPLING ROUTE TO INDOPROFEN ANALOGS
71
Compound 3i. Off-white solid: mp 110–113 ꢀC; 1H NMR (500 MHz,
DMSO-d6) d 7.82 (d, J ¼ 8.5 Hz, 2H), 7.66–7.63 (m, J ¼ 7.5, 5.5 Hz, 2H), 7.54 (d,
J ¼ 7.5 Hz, 1H), 7.35 (d, J ¼ 8.5 Hz, 2H), 4.98 (s, 2H), 3.82 (q, J ¼ 7.0 Hz, 1H),
3.59 (s, 3H), 1.41 (d, J ¼ 7.0 Hz, 3H); ESI MS m=z 330 [M þ H]þ.
Compound 5a. Off-white solid: mp 169–170 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.82 (d, J ¼ 8.6 Hz, 2H), 7.35 (d, J ¼ 8.6 Hz, 2H), 7.33 (d, J ¼ 8.2 Hz, 1H), 7.19 (d,
J ¼ 2.4 Hz, 1H), 6.96 (dd, J ¼ 8.4, 2.4 Hz, 1H), 4.74 (s, 2H), 3.74 (q, J ¼ 7.2 Hz, 1H),
3.67 (s, 3H), 3.02 (s, 6H), 1.51 (d, J ¼ 7.2 Hz, 3H); ESI MS m=z 339 [M þ H]þ.
1
Compound 5b. White solid: mp 71 ꢁ 74 ꢀC; H NMR (500 MHz, CDCl3) d
7.81 (d, J ¼ 8.7 Hz, 2H), 7.37 (m, 4H), 7.12 (dd, J ¼ 8.3, 2.4 Hz, 1H), 4.77 (s, 2H),
4.65 (m, 1H), 3.74 (q, J ¼ 7.1 Hz, 1H), 3.67 (s, 3H), 1.52 (d, J ¼ 6.9 Hz, 3H), 1.37
(d, J ¼ 6.1 Hz, 6H); ESI MS m=z 354 [M þ H]þ.
1
Compound 5c. White solid: mp 139–142 ꢀC; H NMR (500 MHz, CDCl3) d
7.82 (d, J ¼ 8.7 Hz, 2H), 7.72 (s, 1H), 7.39 (s, 2H), 7.35 (d, J ¼ 8.6 Hz, 2H), 4.79
(s, 2H), 3.74 (q, J ¼ 7.2 Hz, 1H), 3.67 (s, 3H), 2.46 (s, 3H), 1.51 (d, J ¼ 6.9 Hz,
3H); ESI MS m=z 310 [M þ H]þ.
1
Compound 5d. White solid: mp 155–158 ꢀC; H NMR (500 MHz, CDCl3) d
8.15 (d, J ¼ 1.3 Hz, 1H), 7.84 (m, 3H), 7.66 (m, 2H), 7.58 (d, J ¼ 7.6 Hz, 1H), 7.48 (t,
J ¼ 7.6 Hz, 2H), 7.39 (m, 3H), 4.89 (s, 2H), 3.75 (q, J ¼ 7.3 Hz, 1H), 3.68 (s, 3H), 1.53
(d, J ¼ 6.9 Hz, 3H); ESI MS m=z 372 [M þ H]þ.
1
Compound 5e. White solid: mp 134–136 ꢀC; H NMR (500 MHz, CDCl3) d
7.80 (d, J ¼ 8.6 Hz, 2H), 7.59 (dd, J ¼ 7.6, 2.2 Hz, 1H), 7.48 (dd, J ¼ 8.2, 4.3 Hz, 1H),
7.37 (d, J ¼ 8.6 Hz, 2H), 7.29 (td, J ¼ 4.3, 2.3 Hz, 1H), 4.82 (s, 2H), 3.75 (q,
J ¼ 7.1 Hz, 1H), 3.67 (s, 3H), 1.52 (d, J ¼ 7.3 Hz, 3H); ESI MS m=z 314 [M þ H]þ.
1
Compound 5f. White solid: mp 105–107 ꢀC; H NMR (500 MHz, CDCl3) d
8.20 (s, 1H), 7.86 (dd, J ¼ 7.9, 1.0 Hz, 1H), 7.82–7.79 (m, 2H), 7.66 (d, J ¼ 7.9 Hz,
1H), 7.40–7.37 (m, 2H), 4.92 (s, 2H), 3.76 (q, J ¼ 7.2 Hz, 1H), 3.68 (s, 3H), 1.52
(d, J ¼ 7.0 Hz, 3H); ESI MS m=z 364 [M þ H]þ.
Compound 5g. Off-white solid: mp 186–187 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.21 (s, 1H), 7.88 (dd, J ¼ 7.8, 1.4 Hz, 1H), 7.84 (d, J ¼ 8.7 Hz, 1H), 7.77 (d,
J ¼ 4.4 Hz, 1H), 7.66 (d, J ¼ 7.9 Hz, 1H), 7.39 (d, J ¼ 8.6 Hz, 2H), 4.93 (s, 2H),
3.76 (q, J ¼ 7.2 Hz, 1H), 3.68 (s, 3H), 1.52 (d, J ¼ 7.2 Hz, 3H); ESI MS m=z 321
[M þ H]þ.
Compound 5h. Off-white solid: mp 196–197 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.50 (d, J ¼ 1.3 Hz, 1H), 8.20 (dd, J ¼ 7.9, 1.7 Hz, 1H), 7.80 (d, J ¼ 8.6 Hz, 2H), 7.74
(d, J ¼ 7.9 Hz, 1H), 7.39 (d, J ¼ 8.6 Hz, 2H), 4.96 (s, 2H), 3.76 (q, J ¼ 7.2 Hz, 1H), 3.68
(s, 3H), 3.12 (s, 3H), 1.53 (d, J ¼ 7.2 Hz, 3H); ESI MS m=z 374 [M þ H]þ.
ACKNOWLEDGMENTS
The authors acknowledge Drs. Jill Heemskerk (National Institute of Neuro-
logical Disorders and Stroke), John M. McCall (PharMac LLC), Sabina Robinson
(Science Applications International Corporation), Amelie Gubitz (National Institute

72
K. D. BARNES ET AL.
of Neurological Disorders and Stroke), and James A. Romano Jr. (Science Applica-
tions International Corporation) for their advice, direction, and support on this
project. This project has been funded in whole or in part with federal funds from
the National Institute of Neurological Disorders and Stroke, National Institute of
Health, under Contract No. N01-NS-3-2356.
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