Efficient palladium-catalyzed double carbonylation of o-dibromobenzenes: Synthesis of thalidomide

Article abstract of DOI:10.1039/c4ob00796d

We describe here a convenient and mild procedure for double carbonylation of o-dibromobenzenes with various 2-amino pyridines and naturally occurring amines, thus providing in good to excellent yields N-substituted phthalimides by using this palladium-catalyzed carbonylation procedure. Furthermore, for the first time we have applied the developed synthetic protocol for the synthesis of biologically active molecule thalidomide via a single step carbonylative cyclization reaction in excellent yield. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00796d

Organic &
Biomolecular Chemistry
View Article Online
View Journal
COMMUNICATION
Efficient palladium-catalyzed double
carbonylation of o-dibromobenzenes:
synthesis of thalidomide†
Cite this: DOI: 10.1039/c4ob00796d
Received 16th April 2014,
Accepted 29th April 2014
DOI: 10.1039/c4ob00796d
Jianbin Chen,‡ Kishore Natte,‡ Anke Spannenberg, Helfried Neumann,
Matthias Beller and Xiao-Feng Wu*
www.rsc.org/obc
We describe here a convenient and mild procedure for double palladium-catalyzed carbonylation of 1,2-diiodoarenes with
carbonylation of o-dibromobenzenes with various 2-amino pyridines primary amines under CO pressure (∼6.2 bar) at 115 °C.
and naturally occurring amines, thus providing in good to excellent Recently, Cao and Alper reported an interesting Pd-catalyzed
yields N-substituted phthalimides by using this palladium-catalyzed carbonylative synthesis of phthalimides under atmospheric
carbonylation procedure. Furthermore, for the first time we have pressure of CO in ionic liquids. Bhanage and co-workers have
applied the developed synthetic protocol for the synthesis of bio- reported an elegant Pd/C as a recyclable catalyst and applied
logically active molecule thalidomide via a single step carbonylative this catalytic species in the carbonylation of o-diiodoarenes
6
cyclization reaction in excellent yield.
with primary amines as well. More recently, some of us
reported a palladium-catalyzed procedure for obtaining N-sub-
stituted phthalimides with molybdenum hexacarbonyl as a
Imide derivatives especially phthalimides carrying additional
substituents are an important class of compounds with
various biological activities such as antimicrobial, anticonvul-
sant, antihistaminic, anti-inflammatory, antitumor, anxiolytic
and hypolipidemic and they are used predominantly as chiral
building blocks in organic synthesis and have numerous appli-
cations in dyes, liquid crystals, functional materials and pesti-
7
carbon monoxide precursor. Nevertheless, the use of 2-amino-
pyridines as substrates was scarcely described which can
provide N-pyridinyl phthalimides as a class of biologically
active compounds.
On the other hand, as it was said, N-substituted phthali-
mides represent an important class of biologically active mole-
cules. In this regard, thalidomide (see Fig. 1) was reported to
act as a hypnotic/sedative agent but was withdrawn from the
market because of its teratogenicity. However, even with its
teratogenic effects, thalidomide continued to be used clini-
cally. In 1991, Kaplan and co-workers reported thalidomide as
1
cides. Also, the related pyromellitic diimide is an important
structure in high-performance polymers like Kapton.
Ever since the pioneering work of Heck and Schoenberg in
8
1
974, palladium-catalyzed carbonylations using CO enabled
2
the synthesis of a variety of carbonyl compounds. Nowadays,
these reactions are routinely applied for constructing carbonyl-
containing compounds, such as aldehydes, amides, esters, etc.
9
an inhibitor of the production of TNF. Later in 1995, clinical
trials using TNF-α antibodies have shown its efficacy in
the treatment of rheumatoid arthritis and Crohn’s disease,
3
Due to the wide range and applicability of phthalimides
and their related derivatives in medicinal chemistry and the
pharmaceutical industry, their synthesis has received great
attention. Typically, the synthesis of N-substituted phthali-
mides involves the dehydrative condensation of a phthalic acid
anhydride with a primary amine and the cyclization of the
amic acid in the presence of acidic reagents. However, these
reactions require relatively high temperature and long reaction
10
confirming the role of TNF-α in these diseases. In 2001,
4
time. Interestingly, carbonylation reactions were applied in
5
phthalimide preparation as well. Perry and Turner reported a
Leibniz-Institut für Katalyse an der Universität Rostock, Albert-Einstein-Straße 29a,
18059 Rostock, Germany. E-mail: xiao-feng.wu@catalysis.de
†
Electronic supplementary information (ESI) available. CCDC 999881.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob00796d
Fig. 1 Selected structures of pharmaceutically important phthalimide
‡
These authors contributed equally to this work.
derivatives.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
a
Table 1 Optimization of the palladium-catalyzed double carbonylation
reaction
Table 2 Carbonylative reactions of o-dibromobenzenes with amines
a
b
Entry
1
Amine 2
Product 3
Yield
b
Entry
Base
Solvent
3a Yield (%)
84%
c
1
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DiPEA
DMAc
DMAc
Toluene
Dioxane
MeCN
THF
DMSO
DMAc
DMAc
51
65
20
5
5
5
2
3
4
5
6
7
8
9
2
82%
3
46
85
90
NEt
3
3
4
5
6
74%
83%
73%
65%
1
0
NEt
3
DMAc (degassed)
a
Reaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), base (3.0 mmol),
b
solvent (5 mL), CO (30 bar), time (20 h). GC yield using hexadecane
as an internal standard. 1.2 mmol of Mo(CO) as the CO source.
6
c
Petit and co-workers reported that phthalimidic containing
additional nitrogen atom allow significant improved property in
inhibition of TNF-α production.
and our continuous interest in carbonylations, we describe
herein a facile and convenient palladium-catalyzed procedure
for the synthesis of N-pyridinyl phthalimides. To the best of
our knowledge, until now there has been no brief report about
the carbonylative synthesis of N-pyridinyl phthalimides.
1d,11
Inspired by these reports
As the starting point for the optimization, the reaction of
o-bromobenzene (1a) with 2-aminopyridine (2a) and CO in the
presence of a base and a solvent was chosen as a model reac-
7
8
9
67%
77%
72%
61%
69%
tion (Table 1). Preliminary experiments showed that Pd(OAc)
and CataCXium A [di(1-adamantyl)-n-butylphosphine; BuPAd
2
2
]
proved to be the optimal catalyst system. A series of exper-
iments were performed to optimize various reaction para-
meters such as the effects of solvents and bases. The results
obtained are summarized in Table 1. As shown in Table 1,
9
0% of the corresponding N-substituted phthalimide was
obtained under the optimized reaction conditions (Table 1,
entry 10).
Having identified our active catalytic system, we tested 10
various amines with o-dibromobenzene to afford N-substituted
phthalimide derivatives (Table 2). Excellent activities were
observed with methyl substituted 2-amino pyridines (Table 2,
entries 1–4). Remarkably, chloro-substituted amino pyridines
can be applied as substrates in this reaction as well and suc-
ceeded in providing the desired products in good yields
1
1
(
Table 2, entries 5 and 6). Noticeably, electron-withdrawing
c
1
2
88%
cyano substituted amino pyridine was also obtained in good
yield (Table 2, entry 7). In the case of trifluoroethyl amine
hydrochloride, the reaction worked well and the corresponding
product was isolated in excellent yield (Table 2, entry 12).
Excited by the facile synthesis of phthalimide derivatives
a
Reaction conditions: o-dibromobenzene (1 mmol), amine (1.1 equiv.),
(2 mol%), CataCXium A (6 mol%), NEt (3 equiv.), 30 bar CO,
Pd(OAc)
2
3
b
c
from o-dibromobenzene, various substituted o-dibromobenzenes DMAc (5 mL), 100 °C, 20 h. Isolated yield. 30 h.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
General information
Reactions were run under an argon/N
2
atmosphere with exclu-
sion of moisture from reagents and autoclaves. All substrates
were purchased from Sigma-Aldrich and 3-aminopiperidine-
2,6-dione from Fluorochem, and they were used as received.
Solvents were dried from molecular sieves and kept under
argon. NMR spectra were recorded on Bruker AV 300 spec-
trometers. All chemical shifts (δ) are reported in parts per
million (ppm) and coupling constants (J) in Hz. All chemical
Fig. 2 Molecular structure of 5-methyl-2-(pyridin-2-yl)isoindoline-
1
,3-dione. Displacement ellipsoids correspond to 50% probability.
shifts are reported relative to tetramethylsilane (δ 0.0 for
1
H NMR in DMSO-d
6
, CDCl
3
) and d-solvent peaks (δ 77.00 for
, δ 40.00), respectively.
1
3
C NMR, chloroform and for DMSO-d
6
All measurements were carried out at room temperature unless
otherwise stated. Mass spectra were recorded on an AMD 402/3
or a HP 5989A mass selective detector. Gas chromatographic
analysis was performed on an Agilent HP-5890 instrument
with an FID detector and an HP-5 capillary column (poly
(dimethylsiloxane) with 5% phenyl groups, 30 m, 0.32 mm
i.d., 0.25 mm film thickness) with argon as the carrier gas.
Scheme 1 Synthesis of thalidomide.
Experimental section
The reaction was carried out on a Parr Instruments 4560 series
3
4
00 mL autoclave containing an alloy plate with wells for six
mL Wheaton vials. Pd(OAc)2 (4.49 mg, 2.0 mol%), CataC-
Xium A (21.48 mg, 6.0 mol%), amino pyridine (1.1 mmol), and
a magnetic stir bar were placed in each vial, which were then
capped with a septum equipped with an inlet needle and
Scheme 2 Synthesis of phthalimides with naturally occurring amines.
3
flushed with argon. Then NEt (3 mmol, 3.0 equiv.), o-dibromo-
benzene (1.0 mmol) and DMAc (5 mL) were added to the vial
via a syringe. The vials were placed in an autoclave, which was
then purged several times with argon. Subsequently it was
filled with 30 bars of CO at room temperature and heated at
were also screened and generated their corresponding phthali-
mides in good yields (Table 2, entries 8–11). The product was
further confirmed by X-ray analysis (Fig. 2).
100 °C for 20 h. After the reaction, the autoclave was cooled to
room temperature and vented to discharge N . The product
2
In order to make this procedure useful for the synthesis of
biological compounds containing phthalimide groups, for the
first time we applied the developed synthetic protocol reaction
conditions to synthesise thalidomide, which resulted in excel-
lent yield (87%; Scheme 1). In addition to this, we also syn-
thesised various biological N-substituted phthalimides from
different naturally occurring amines such as tryptamine and
tyramine. The reactions were accomplished with ease whereby
these two naturally occurring amines were quite capable of
providing good to excellent yields of the expected products
was extracted with ethyl acetate (5 × 3 mL). The organic layers
were washed with brine, dried over Na SO , and evaporated to
2
4
yield the crude reaction mixture. The purification was done by
flash chromatography on silica gel (eluent: heptane–EtOAc
50 : 50).
Acknowledgements
We thank the state of Mecklenburg-Vorpommern and the
Bundesministerium für Bildung und Forschung (BMBF) for
financial support. We also thank Dr W. Baumann, Dr C. Fischer,
and S. Buchholz (LIKAT) for analytical support.
(Scheme 2).
In conclusion, we have demonstrated that N-pyridyl phthali-
mides and their derivatives can be synthesized directly from
o-dibromobenzenes. A wide range of different amino pyridines
and naturally occurring amines as well as a variety of miscella-
neous o-dibromobenzenes can be applied as substrates, and
the corresponding phthalimides were obtained in moderate to
excellent yields. This facile and versatile procedure helps to
synthesize the valuable thalidomide and could also be applied
to other drug molecules like pomalidomide, etc.
Notes and references
1 (a) M. K. Hargreaves, J. G. Pritchard and H. R. Dave, Chem.
Rev., 1970, 70, 439–469; (b) Y. Kamitori, M. Hojo,
R. Masuda, T. Kimura and T. Yoshida, J. Org. Chem., 1986,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
5
1, 1427–1431; (c) K. Rad-Moghadam and L. Kheyrkhah,
(c) S. M. Capitosti, T. P. Hansen and M. L. Brown, Org. Lett.,
2003, 5, 2865–2867; (d) S. Y. Yeung, S. Kampmann,
K. A. Stubbs, B. W. Skelton, B. J. Kaskow, L. J. Abraham and
S. G. Stewart, MedChemComm, 2011, 2, 1073–1078;
(e) G. W. Muller, W. E. Konnecke, A. M. Smith and
V. D. Khetani, Org. Process Res. Dev., 1999, 3, 139–140.
5 (a) R. J. Perry and S. R. Turner, J. Org. Chem., 1991, 56,
6573–6579; (b) H. Cao and H. Alper, Org. Lett., 2010, 12,
4126–4129; (c) M. Mori, K. Chiba, N. Ohta and Y. Ban,
Heterocycles, 1979, 13, 329–332; (d) A. Takács, P. Ács and
L. Kollár, Tetrahedron, 2008, 64, 983–987.
Synth. Commun., 2009, 39, 2108–2115; (d) X. Collin,
J. Robert, G. Wielgosz, G. Le Baut, C. Bobin-Dubigeon,
N. Grimaud and J. Petit, Eur. J. Med. Chem., 2001, 36, 639–
6
2
49; (e) H. Teisseire and G. Vernet, Pestic. Biochem. Physiol.,
001, 69, 112–117; (f) F. B. Miguel, D. Gema, S. Beatriz,
R. Cynthia, R. Simmon and B. Teresa, Eur. J. Med. Chem.,
002, 37, 541–551; (g) A. A. Abdel-Hafez, Arch. Pharmacal.
2
Res., 2004, 27, 495–501; (h) C. Shinji, T. Nakamura,
S. Maeda, M. Yoshida, Y. Hashimoto and H. Miyachi,
Bioorg. Med. Chem. Lett., 2005, 15, 4427–4431;
(
i) J. Ungwitayatorn, C. Wiwat, C. Matayatsuk, J. Pimthon
and S. Piyaviriyakul, Chin. J. Chem., 2008, 26, 379–387;
j) U. Sharma, P. Kumar, N. Kumar and B. Singh, Mini-Rev.
6 (a) M. V. Khedkar, S. R. Khan, D. N. Sawant, D. B. Bagal
and B. M. Bhanage, Adv. Synth. Catal., 2011, 353, 3415–
3422; (b) D. N. Sawant, Y. S. Wagh, K. D. Bhatte and
B. M. Bhanage, Eur. J. Org. Chem., 2011, 6719–6724.
7 X.-F. Wu, S. Oschatz, M. Sharif, A. Flader, L. Krey, M. Beller
and P. Langer, Adv. Synth. Catal., 2013, 355, 3581–3585.
8 M. Reist, P.-A. Carrupt, E. Francotte and B. Testa, Chem.
Res. Toxicol., 1998, 11, 1521–1528.
(
Med. Chem., 2010, 10, 678–704.
(a) A. Schoenberg, I. Bartolet and R. F. Heck, J. Org. Chem.,
1
Chem., 1974, 39, 3327–3331; (c) A. Schoenberg and
R. F. Heck, J. Am. Chem. Soc., 1974, 96, 7761–7764.
2
3
974, 39, 318–326; (b) A. Schoenberg and R. F. Heck, J. Org.
(a) A. Brennführer, H. Neumann and M. Beller, Angew.
Chem., Int. Ed., 2009, 48, 4114–4133; (b) X.-F. Wu,
9 E. P. Sampaio, E. N. Sarno, R. Gallily, Z. A. Cohn and
G. J. Kaplan, Exp. Med., 1991, 173, 699–703.
H. Neumann and M. Beller, Chem. Soc. Rev., 2011, 40, 10 (a) R. A. Van Hogezand and H. W. Verspaget, J. Scand. Gastro-
4
986–5009; (c) X.-F. Wu, H. Neumann and M. Beller, Chem.
enterol., 1997, 32(Suppl. 223), 105–107; (b) M. J. Elliott,
M. Feldmann and R. N. Maini, Int. J. Immunopharmacol.,
1995, 17, 141–145.
Rev., 2013, 113, 1–35; (d) X.-F. Wu, H. Neumann and
M. Beller, ChemSusChem, 2013, 6, 229–241; (e) Q. Liu,
H. Zhang and A. Lei, Angew. Chem., Int. Ed., 2011, 50, 11 For selected examples, see ref. 1d, (a) X. Collin,
1
5
0788–10799; (f) C. F. J. Barnard, Organometallics, 2008, 27,
402–5422.
J. M. Robert, S. Robert-Piessard, G. Le Baut, C. Bobin-Dubi-
geon, L. Vernhet, F. Lang and J. Y. Petit, Pharm. Pharmacol.
Commun., 1998, 4, 27–31; (b) J. M. Robert, S. Robert-Pies-
sard, J. Courant, G. Le Baut, B. Robert, F. Lang, J. Y. Petit,
N. Grimaud and L. Welin, Eur. J. Med. Chem., 1995, 3,
915–924.
4
(a) A. Da Settimo, G. Primofiore, F. Da Settimo, F. Simorini,
C. La Motta, A. Martinelli and E. Boldrini, Eur. J. Med.
Chem., 1996, 31, 49–58; (b) N. B. Mehta, A. P. Phillips,
F. F. Lui and R. E. Brooks, J. Org. Chem., 1960, 25, 1012–1015;
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014