Synthesis of imides via palladium-catalyzed three-component coupling of aryl halides, isocyanides and carboxylic acids

Article abstract of DOI:10.1039/c9cc08438j

A palladium-catalyzed three-component synthesis of acyclic imides from feedstock aryl halides, carboxylic acids and isocyanides through the intermediacy of isoimides has been developed. The key to the success of this approach was controlled isocyanide slow addition and organic/aqueous biphasic conditions. This transition-metal-catalyzed approach features readily available starting materials, atom- and step-economy, good functional group compatibility and gram-scale synthetic capability. Utilization of this new method is illustrated in the late-stage functionalization of drugs Carprofen, Loxoprofen and Flurbiprofen. This strategy has also been successfully applied in the synthesis of cyclic imides including phthalimide, homophthalimide, and 2H-2-benzazepine-1,3-dione derivatives.

Full text of DOI:10.1039/c9cc08438j

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COMMUNICATION
Synthesis of imides via palladium-catalyzed three-
component coupling of aryl halides, isocyanides
and carboxylic acids†
Cite this:DOI: 10.1039/c9cc08438j
Received 29th October 2019,
Accepted 11th December 2019
Bo Wang,‡ Dan He,‡ Beige Ren and Tuanli Yao
*
DOI: 10.1039/c9cc08438j
rsc.li/chemcomm
A palladium-catalyzed three-component synthesis of acyclic imides
from feedstock aryl halides, carboxylic acids and isocyanides
through the intermediacy of isoimides has been developed. The
key to the success of this approach was controlled isocyanide slow
addition and organic/aqueous biphasic conditions. This transition-
metal-catalyzed approach features readily available starting materials,
atom- and step-economy, good functional group compatibility and
gram-scale synthetic capability. Utilization of this new method is
illustrated in the late-stage functionalization of drugs Carprofen,
Loxoprofen and Flurbiprofen. This strategy has also been successfully
applied in the synthesis of cyclic imides including phthalimide, homo-
phthalimide, and 2H-2-benzazepine-1,3-dione derivatives.
Imides are present as a core structural motif in natural products and
pharmaceutical agents. For example, natural products penimide
1
a
1b
1c
A, berkeleyamide C, and pestalamides A, and approved drugs
1d
1e
thalidomide, anircetam, and ethosuximide all contain an imide
moiety (Scheme 1a). Imides also have a wide range of applications
in agrochemicals and materials science. In addition, imides are
versatile synthetic building blocks. The wide occurrence and high Scheme 1 Examples of biologically relevant imides, traditional Mumm
value of imides have driven the continuous development of new
2a
2b
3
rearrangement and palladium-catalyzed three-component synthesis of imides.
synthetic methods.
Mumm rearrangement of isoimides (Scheme 1b) is a traditional
4
method for the synthesis of imides, in which the use of reactive greatly limits the scope of applicable carboxylic acids. An ideal
reagents (POCl3 and SOCl ) leads to limited functional group solution to overcome these limitations would be the development
2
compatibility and creates significant chemical waste. Transition- of a general and practical transition-metal-catalyzed process that
metal catalysed Mumm rearrangement has been developed utilizes feedstock chemicals such as aryl halides and carboxylic
recently. Unfortunately, these methods are limited to the synthesis acids to arrive at acyclic imides. To the best of our knowledge,
5
of only specific imides such as N-acyl propiolamides, N-acetyl- there is no example of catalytic imide synthesis employing
6
7
indole-3-carboxamides and a-amio imides. Furthermore, these aryl halides and carboxylic acids. Herein, we disclose the first
methods require the use of pre-prepared carboxylic salts, which palladium(0) catalyzed three-component coupling of aryl halides,
isocyanides and carboxylic acids, which enables straightforward
Shaanxi Key Laboratory of Chemical Additives for Industry, College of Chemistry
and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an,
synthesis of a broad range of acyclic imides. This strategy has also
been successfully applied in the synthesis of cyclic imides such
as phthalimide, homophthalimide and 2-benzazepine-1,3-dione
derivatives.
Our investigation of this Pd-catalyzed tandem process was
commenced by surveying reaction conditions using isocyanide
7
10021, China. E-mail: yaotuanli@sust.edu.cn
†
Electronic supplementary information (ESI) available. CCDC 1962679. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc08438j
‡
These authors contributed equally.
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a
a
Table 1 Reaction optimization
Table 2 Scope of aryl halides
b
Entry
Pd catalyst
Pd(OAc)
Ligand
Solvent
4aaa (yield) (%)
1
2
3
4
5
6
7
8
9
2
PPh
PPh
PPh
3
3
3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
0
7
14
3
Pd (dba)
2
3
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
P(o-tol)
3
n
Ad
2
P Bu
0
BINAP
dppm
dppe
29
36
12
43
0
24
45
70
73
21
57
0
DEPhos
DEPhos
DEPhos
dppm
BINAP
BINAP
BINAP
BINAP
BINAP
Toluene
DMF
10
11
12
13
14
15
16
17
c
Toluene/H
Toluene/H
Toluene/H
Toluene/H
Toluene/H
Toluene/H
Toluene/H
2
2
2
2
2
2
2
O
O
O
O
O
O
O
c
c
a
Performed on a 0.20 mmol scale using the standard reaction conditions
the same as Table 1, entry 13.
c,d
c,e
c,d,f
c,d,g
(compare Table 1, entries 14 and 17). We reasoned that slow
a
addition of isocyanides would restrict the highly coordinating
Reaction conditions: isocyanide 1a (0.2 mmol) in solvent (1 mL) was
9
added by syringe pump to a solution of aryl iodide 2a (0.3 mmol, nature of isocyanides, which facilitated their insertion by the
.5 equiv.), CsPiv (0.24 mmol, 1.2 equiv.), Pd catalyst (10 mol%), and
ligand (20 mol%) in solvent (1 mL) over 1 h at 100 1C and was further
1
phenylpalladium intermediate and protected the catalyst from
10
b
c
poisoning at the same time (see Scheme 3).
stirred for 0.5 h after addition. Isolated yield. PivOH (0.24 mmol,
.2 equiv.), Cs CO (0.12 mmol, 0.6 equiv.) and n-Bu NCl (1.0 equiv.) in
O (0.4 ml) were used. 80 1C. 60 1C. Pd(dba) (5 mol%) and
1
H
2
3
4
We first examined the substrate scope with respect to the
aryl halides under the optimized reaction conditions (Table 1,
entry 13), and the results are shown in Table 2. Aryl iodides with
either an electron-withdrawing or an electron–donating group
worked smoothly in this chemistry (4aba–4aha). The structure
d
e
f
2
2
g
BINAP (10 mol%). 1a was added in one portion.
1
a, aryl iodide 2a and cesium pivalate (3a) as the model. In the
presence of Pd(OAc) (10 mol%) and PPh (20 mol%), no
detectable imide 4a was produced (Table 1, entry 1). To our
delight, changing the palladium precatalyst to Pd (dba)
or Pd(dba) afforded 4a in 7% and 14% isolated yields, respec-
11
of 4ada was confirmed by single crystal X-ray diffraction. It should
be noted that 2-iodobiphenyl reacted chemoselectively, affording
imide 4aha in 70% yield without the formation of the previously
2
3
2
3
12
reported fluorenone imine product. 1-Iodonaphthalene was also a
2
tively (Table 1, entries 2 and 3). The previously known indole
3
product from isocyanide insertion/benzylic C(sp )–H activation
a
8
Table 3 Scope of isocyanides
was not observed. More sterically hindered P(o-tol)
3
and
n
sterically demanding and electron-rich phosphine Ad
2
P Bu
are detrimental to the reaction (Table 1, entries 4 and 5). On
the other hand, bidentate phosphines were more efficient and
DEPhos afforded a 43% yield of 4a (Table 1, entries 6–9).
Switching the solvent to more polar DMF was inferior
(
Table 1, entry 10). Since CsOPiv is very hydroscopic, an organic/
aqueous biphasic condition (toluene/water) using pivalic acid,
Cs CO and phase transfer reagent n-Bu NCl was developed to
2
3
4
facilitate operation and extend the reaction to more complex
carboxylic acids (Table 1, entries 11–13). Remarkably, the isolated
yield of 4a was increased to 70% upon using BINAP as the ligand
(Table 1, entry 13) and no corresponding amide from reacting with
water was observed. Decreasing the reaction temperature to 80 1C
did not affect the result (Table 1, entry 14). Further decreasing the
reaction temperature (Table 1, entry 15) or reducing the loading
of the Pd catalyst (Table 1, entry 16) all led to lower yields of 4a. It
should be noted that slow addition of isocyanide 1a is the key
to the success of the reaction. When adding 1a in one portion, no
a
Performed on a 0.20 mmol scale using the standard reaction conditions
4a was produced at all under otherwise identical conditions the same as Table 1, entry 13.
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a
a
Table 4 Scope of carboxylic acids
Table 5 Synthesis of cyclic imides
a
Performed on a 0.20 mmol scale using the standard reaction condi-
tions the same as Table 1, entry 13.
9H-xanthene-9-carboxylic acid afforded imide 4adj in a 40% yield.
Interestingly, when employing Cl CCO H, F CCO H or N-protected
3
2
3
2
amino acid Boc-Ala-OH in the reaction, amide 4adk was obtained
due to hydrolysis of the corresponding imide products. Gratifyingly,
this method has been successfully applied in the late-stage
functionalization of drugs Carprofen, Loxoprofen and Flurbiprofen
(4adl–adn).
This strategy has also been successfully applied in the
synthesis of cyclic imides by using 2-halobenzoic acids (Table 5).
Various phthalimides were prepared in moderate to good yields
(6a–f). Homophthalimide 6g and 2H-2-benzazepine-1,3-dione 6h
can also be prepared in useful yields from 2-(2-iodophenyl)acetic
acid and 2-(3-iodobenzo[b]thiophen-2-yl)benzoic acid, respectively.
Since the imide products possess N-Ar axial chirality when
using asymmetric aryl isocyanides, we performed the reaction
using unsymmetrical isocyanides 1f and 1k and chiral carboxylic
acid (S)-3h (Scheme 2). Slightly enantioenriched products 4fdh
and 4kdh were obtained. The diastereoselectivity was not
a
Performed on a 0.20 mmol scale using the standard reaction condi-
tions the same as Table 1, entry 13.
13
improved when employing (R)-BINAP as the ligand.
We propose a mechanism for this process as illustrated in
Scheme 3 by employing iodobenzene (2a) as an example. Pd(0) adds
oxidatively to iodobenzene to generate the phenylpalladium(II) inter-
mediate I. Isocyanide insertion of this intermediate followed by
halide/carboxylate exchange affords imidoylpalladium(II)-carboxylate
suitable substrate, providing imide 4aia in 71% yield. We were
pleased to find that hetero aromatic halides were compatible with
the reaction conditions. Thus, 4-bromoquinoline and 3-iodo-2-
methoxy pyridine provided the corresponding imide products
4aja and 4aka in good yields.
Both bis-ortho-substituted and mono-ortho-substituted iso-
cyanides afforded good yields of imide products and functional
groups such as chloride, methoxy group and acrylate are all well
tolerated (Table 3). No imide product 4hda was obtained when
employing isocyanobenzene. This observation demonstrated
the importance of steric hindrance of isocyanides, which might
promote the reductive elimination of an aryl imidoyl palladium
carboxylate intermediate (see Scheme 3). 1-Isocyanonaphthalene
afforded imide 4jda in 79% yield.
The reaction proceeded very well with various carboxylic
acids such as aromatic, vinylic, saturated carbocyclic and benzyl
carboxylic acids, providing the corresponding imide products
(4adb–adi) in good to excellent yields (Table 4). Even very bulky Scheme 2 Diastereoselectivity of palladium-catalyzed Mumm rearrangement.
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Notes and references
1
(a) T. Pacher, A. Raninger, E. Lorbeer, L. Brecker, P. P.-H. But and
H. Greger, J. Nat. Prod., 2010, 73, 1389; (b) A. A. Stierle, D. B. Stierle
and B. Patacini, J. Nat. Prod., 2008, 71, 856; (c) G. Ding, L. Jiang,
L. Guo, X. Chen, H. Zhang and Y. Che, J. Nat. Prod., 2008, 71, 1861;
(
d) K. Nakamura, CNS Drug Rev., 2002, 8, 70; (e) S. J. Flatters and
G. J. Bennett, Pain, 2004, 109, 150.
(a) Y. Hisada and A. Fujinami, Agric. Biol. Chem., 1987, 51, 1547;
2
3
(
2
b) Z. Cheng, X. Zhu, E. T. Kang and K. G. Neoh, Macromolecules,
006, 39, 1660.
(a) C. Patzelt, A. P o¨ thig and T. Gulder, Org. Lett., 2016, 18, 3466;
b) S. Takebayashi, J. M. John and S. H. Bergens, J. Am. Chem. Soc.,
010, 132, 12832.
(
2
4
5
6
(a) O. Mumm, H. Hesse and H. Volquartz, Ber. Dtsch. Chem. Ges.,
1915, 48, 379; (b) J. S. P. Schwarz, J. Org. Chem., 1972, 37, 2906.
Y. He, Y. Wang, X. Liang, B. Huang, H. Wang and Y.-M. Pan, Org.
Lett., 2018, 20, 7117.
Scheme 3 Proposed mechanism.
(a) G. Qiu, C. Chen, L. Yao and J. Wu, Adv. Synth. Catal., 2013,
complex III, whose reductive elimination leads to isoimide IV and
regenerates the Pd(0) catalyst. 1,3(O–N) acyl transfer of isoimide IV
355, 1579; (b) Z. Hu, D. Liang, J. Zhao, J. Huang and Q. Zhu, Chem.
Commun., 2012, 48, 7371; (c) S. Chen, W.-X. Wei, J. Wang, Y. Xia,
Y. Shen, X.-X. Wu, H. Jing and Y.-M. Liang, Adv. Synth. Catal., 2017,
(Mumm rearrangement) produces imide product 4.
3
59, 3538; (d) J. Peng, L. Liu, Z. Hu, J. Huang and Q. Zhu, Chem.
In summary, we have developed a general and efficient
method to prepare acyclic imides by palladium-catalyzed
three-component coupling of aryl halides, isocyanides and
carboxylic acids. Key to the success of this approach was
controlled isocyanide slow addition and organic/aqueous
Commun., 2012, 48, 3772.
7
(a) M. Rueping and C. Vila, Org. Lett., 2013, 15, 2092; (b) X. Ye, C. Xie,
Y. Pan, L. Han and T. Xie, Org. Lett., 2010, 12, 4240; (c) I. Guerrero,
S. S. Marcos and A. Correa, Chem. Commun., 2018, 54, 1627.
T. Nanjo, C. Tsukano and Y. Takemoto, Org. Lett., 2012, 14, 4270.
Y. Yamamoto, Coord. Chem. Rev., 1980, 32, 193.
8
9
biphasic conditions. This transition-metal-catalyzed approach 10 For selected references using controlled slow addition in Pd-catalyzed
reactions, see: (a) R. J. Sullivan, G. P. R. Freure and S. G. Newman, ACS
features readily available starting materials, atom- and step-
Catal., 2019, 9, 5623; (b) X. Hua, J. Masson-Makdissi, R. J. Sullivan and
economy and good functional group compatibility. Additionally,
we have also demonstrated expansion of this strategy to the
synthesis of cyclic imides.
We are grateful for financial support from Shaanxi Univer-
sity of Science and Technology (BJ15-33).
S. G. Newman, Org. Lett., 2016, 18, 5312; (c) M. Giannerini, M. Fa n˜ an ´a s-
Mastral and B. L. Feringa, Nat. Chem., 2013, 5, 667; (d) V. Hornillos,
M. Giannerini, C. Vila, M. Fa n˜ an ´a s-Mastral and B. L. Feringa, Org. Lett.,
2013, 15, 5114.
1
1
1
1 CCDC 1962679† contains the supplementary crystallographic data
for 4ada.
2 M. Tobisu, S. Imoto, S. Ito and N. Chatani, J. Org. Chem., 2010,
75, 4835.
3 For racemization of chiral imides via N-Ar bond rotation, see:
K. Kondo, T. Iida, H. Fujita, T. Suzuki, K. Yamaguchi and
Y. Murakami, Tetrahedron, 2000, 56, 8883.
Conflicts of interest
There are no conflicts to declare.
Chem. Commun.
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