Synthesis of isoindolinones via palladium-catalyzed C-H activation of N-methoxybenzamides

Article abstract of DOI:10.1039/c1cc15897j

The synthesis of isoindolinones from N-methoxybenzamides and alkenes has been achieved by Pd-catalyzed ortho sp² C-H activation and intramolecular oxidative amidation, which involve the cleavage of four bonds and formation of two bonds.

Full text of DOI:10.1039/c1cc15897j

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COMMUNICATION
Synthesis of isoindolinones via palladium-catalyzed C–H activation of
N-methoxybenzamidesw
Dan-Dan Li, Ting-Ting Yuan and Guan-Wu Wang*
Received 22nd September 2011, Accepted 20th October 2011
DOI: 10.1039/c1cc15897j
The synthesis of isoindolinones from N-methoxybenzamides and
alkenes has been achieved by Pd-catalyzed ortho sp2 C–H
activation and intramolecular oxidative amidation, which involve
the cleavage of four bonds and formation of two bonds.
such as acrylate esters. The Pd-catalyzed reaction of N-methoxy-
benzamide (1a) with methyl acrylate (2a) was chosen as the model
reaction to screen for optimal conditions. No cross-coupling
reaction occurred when Cu(OAc)2 was used as the oxidant
under Miura’s6 or Yu’s7 conditions (Table 1, entries 1 and 2).
Gratifyingly, we found that the reaction of 1a with 2.0 equiv.
of 2a in the presence of 5 mol% of Pd(OAc)2 and 2.0 equiv. of
Cu(OAc)2 in AcOH at 100 1C for 10 h gave product 3aa in 9%
yield (Table 1, entry 3). If Ag2O was employed as the oxidant,
the yield could be increased to 23% (Table 1, entry 4). Other
silver salts such as AgOAc and Ag2CO3 could also promote
the reaction, albeit in slightly lower yields (Table 1, entries 5
and 6 vs. entry 4). However, K2S2O8, PhI(OAc)2 and O2 were
unsuitable for the reaction (see ESIw). p-Benzoquinone (BQ) is
a well-established oxidant for Pd0 and a promoter for C–C bond
formation in a wide range of palladium-catalyzed reactions.8 To
our delight, the yield of 3aa could be improved to 74% yield
when BQ was used as the oxidant (Table 1, entry 7). Prolonging
or shortening the reaction time did not provide higher yield
(Table 1, entries 8 and 9 vs. entry 7). Disappointedly, when
Palladium-catalyzed C–H activation has become one of the
most important methods to construct C–C and C–X (X =
heteroatom) bonds in recent years.1 A directing group is
frequently required to achieve high regioselectivity in a C–H
activation reaction. The CONHOMe group was first exploited
by the Yu group as a directing group in the Pd-catalyzed
arylation of sp3 C–H bonds2 and lactamization of sp2 C–H
bonds.3 We have reported the alkoxylation of N-methoxybenz-
amides via Pd-catalyzed sp2 C–H bond activation,4a and the
synthesis of phenanthridinones from N-methoxybenzamides
and aryl iodides by intermolecular C–C bond formation and
subsequent intramolecular C–N bond formation through
Pd-catalyzed sequential C–H bond activation.4b The same
CONHOMe group could act as both a directing group and
an internal oxidant when a rhodium catalyst was used.5 The
Rh-catalyzed reaction of N-methoxybenzamides with acrylates/
styrenes gave ortho-olefinated products with concurrent N–O bond
cleavage.5a In contrast, replacing the N-methoxy group with the
N-pivalate group led to the formation of 3,4-dihydroisoquinolone
derivatives via a sequence of ortho-olefination and intramolecular
cyclization, concomitant with the N–O bond rupture.5a,b
Intriguingly, we found that the same reaction of N-methoxy-
benzamides with acrylates/acrylamides/styrenes selectively
afforded another type of products, i.e., isoindolinones, without
N–O bond cleavage when catalyzed by Pd(OAc)2. Herein, we
report this novel result.
Table 1 Screening conditions for the Pd-catalyzed reaction of
N-methoxybenzamide and methyl acrylatea
Entry
Oxidant
Solvent
Time/h
Yield (%)
1b
2c
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2O
AgOAc
Ag2CO3
BQ
DMF
DMF
10
10
10
10
10
10
10
8
0
0
9
23
21
17
74
73
70
Our success in the Pd-catalyzed C–H activation reactions of
N-methoxybenzamides with alcohols4a and aryl iodides4b prompted
us to examine their olefination reactions with activated alkenes
AcOH
AcOH
AcOH
AcOH
HOAc
HOAc
HOAc
Hefei National Laboratory for Physical Sciences at Microscale,
CAS Key Laboratory of Soft Matter Chemistry, Joint Laboratory of
Green Synthetic Chemistry and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui 230026,
P. R. China. E-mail: gwang@ustc.edu.cn; Fax: +86 551 3607864;
Tel: +86 551 3607864
w Electronic supplementary information (ESI) available: Experimental
procedures for the synthesis, spectral data and NMR spectra of
products 3. CCDC 832992. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1cc15897j
BQ
BQ
12
a
Unless otherwise specified, all reactions were carried out with 1a
(0.5 mmol), 2a (1.0 mmol), Pd(OAc)2 (0.025 mmol), oxidant
b
(1.0 mmol), solvent (5 mL), 100 1C. Pd(OAc)2 (0.025 mmol),
Cu(OAc)2 (0.025 mmol), KOAc (0.25 mmol), 4 A MS (400 mg),
c
DMF (5 mL), 100 1C. Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.0 equiv.),
LiCl (2.0 equiv.), DMF (5 mL), 120 1C, N2.
c
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DMF, DCE, 1,4-dioxane, CH3CN and toluene were employed
as the solvent, either no or a trace amount of product was
formed (see ESIw). Therefore, 1.0 equiv. of 1a, 2.0 equiv. of 2a,
5 mol% of Pd(OAc)2 and 2.0 equiv. of BQ were chosen as the
optimized conditions for the Pd-catalyzed reaction of 1a with
2a in refluxing AcOH.
Table 2 Synthesis of isoindolinones by Pd-catalyzed reaction of
N-methoxybenzamides with alkenesa
With the optimized reaction conditions in hand, we then
investigated the synthesis of isoindolinones by utilizing various
N-methoxybenzamides and acrylates/acrylamides/styrenes.
The results are listed in Table 2. N-Methoxybenzamides with
either electron-donating or electron-withdrawing groups
afforded isoindolinones 3ba–3ma in moderate to good yields.
N-Methoxybenzamides having electron-donating groups at
the meta-position and/or para-position of the phenyl ring were
generally more reactive and gave higher yields than those
bearing electron-withdrawing groups (62–75% for 3ba–3ha
vs. 40–53% for 3ia–3la). 3,5-Dimethylated benzamide 1m gave
much lower yield than its counterpart 1e due to steric hindrance.
n-Butyl acrylate (2b) could replace methyl acrylate to react with
N-methoxybenzamides 1a–k and afforded products 3ab–3kb in
slightly better yields than the corresponding counterparts of
3aa–3ka. ortho-Substitution on phenyl rings is known to retard
the Pd-catalyzed ortho C–H activations.4,8a Nevertheless, the
o-Me on the phenyl ring of 1d afforded only slightly lower
product yields (67% for 3da and 69% for 3db) relative to those
(71% for 3ba, 72% for 3ca, 75% for 3bb and 77% for 3cb) of
their p- and m-substituted counterparts. The reaction could be
extended to acrylamides such as N,N-dimethyl acrylamide
(2c). For example, the reaction of 1a, 1c, and 1d with 2c
generated 3ac, 3cc and 3dc in 80%, 67% and 82% yields,
respectively. Finally, alkenes with an electron-withdrawing
group was not mandatory, styrene could also be employed,
and 3da was obtained in 46% yield. It should be noted that the
chloro, bromo, ether, nitro and ester groups in the phenyl ring
were tolerated under our conditions, and can be further
manipulated for the functionalization of the corresponding
isoindolinone products. For the meta-substituted N-methoxy-
benzamides (1c, 1e, 1g and 1h), only one regioisomer was
obtained due to the steric factor.
Additional experiments were performed to gain insights for
the reaction mechanism. In our previous work, we found that the
reaction of N-methoxybenzamides 1 with Pd(OAc)2 generated
palladacycles 4.4b The reaction of palladacycle 4 with an acrylate
ester could generate either 5 or 6 as the precursor of the final
product via C–C and C–N bond formation, respectively. When
5aa and 6aa were treated with Pd(OAc)2 (5 mol%) and BQ
(2 equiv.) in AcOH at 100 1C, only 5aa could successfully afford
isoindolinone 3aa (Scheme 1). In addition, Michael adduct 7aa
could not cyclize to 3aa under the same conditions. Thus the
reaction of N-methoxybenzamides 1 with acrylate esters did not
give 6 and 7, instead generated 5 as the intermediate. Intermediate
5 may undergo intramolecular aza-Michael addition to produce
8, which is then oxidized to 3. However, treatment of 8aa with
Pd(OAc)2 (5 mol%) and BQ (2 equiv.) failed to produce 3aa, thus
ruling out the intermediacy of 8 in the formation of 3. The
molecular structure of product 3 was established by the X-ray
crystallography of representative 3aa.
a
Unless otherwise specified, all reactions were carried out with 1
(0.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (0.025 mmol), and BQ (1.0 mmol)
b
in AcOH (5 mL) at 100 1C. 0.05 mmol of Pd(OAc)2 was employed.
c
d
120 1C was employed. 1.5 mmol of 2c was used.
benzamide 1 with Pd(OAc)2 produces the five-membered
palladacycle 4.4b Olefin insertion into 4 generates the seven-
membered palladacycle 9, which undergoes b-hydride elimina-
tion to give ortho-olefinated intermediate 5 together with Pd0.
Coordination of 5 with Pd(OAc)2 furnishes 10, and subsequent
Based on the aforementioned results, a plausible reaction
mechanism is proposed and shown in Scheme 2. Palladation of
c
12790 Chem. Commun., 2011, 47, 12789–12791
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afforded an isoindolinone with retention of the OMe group.
The Pd- or Rh-catalyzed reaction of primary benzamides with
2b gave isoindolinones as the Z-isomers resulting from the
intramolecular anti-aminometallation in low to moderate
yields.10 A similar anti-addition process led to cyclized products
with Z geometry for the Pd-catalyzed hydroxy-directed ortho
C–H olefination.11 Clearly, the CONHOMe group under our
conditions directs the intramolecular cyclization step in a
different pathway.7,9–11
In summary, we have achieved the synthesis of isoindolinones
by a palladium-catalyzed cascade reaction, which involves the
cleavage of three C–H bonds and one N–H bond as well as the
formation of one C–C bond and one C–N bond. The reaction
proceeds initially through the palladium-catalyzed ortho sp2
C–H activation directed by the CONHOMe group of benzamides,
followed by an intramolecular oxidative amidation with acrylates/
acrylamides/styrenes, leading to the isoindolinone products as the
E-isomers rather than the Z-isomers reported in the literature.10,11
Intriguingly, replacing the Rh-catalyzed system5a with our
Pd-catalyzed system switches the reaction pathway leading
to different products for the reaction of N-methoxybenzamides
with acrylate esters.
Scheme 1 Attempted Pd-catalyzed cyclization of 5aa, 6aa, 7aa and 8aa.
We are grateful for the financial support from NSFC
(91021004) and National Basic Research Program of China
(2011CB921402).
Notes and references
1 For most recent reviews on Pd-catalyzed C–H activations, see:
(a) O. Daugulis, H.-Q. Do and D. Shabashov, Acc. Chem. Res.,
2009, 42, 1074; (b) X. Chen, K. M. Engle, D.-H. Wang and
J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (c) K. Muniz,
Angew. Chem., Int. Ed., 2009, 48, 9412; (d) L.-M. Xu, B.-J. Li,
Z. Yang and Z.-J. Shi, Chem. Soc. Rev., 2010, 39, 712;
(e) P. Sehnal, R. J. K. Taylor and I. J. S. Fairlamb, Chem. Rev.,
2010, 110, 824; (f) T. W. Lyons and M. S. Sanford, Chem.
Rev., 2010, 110, 1147; (g) C. S. Yeung and V. M. Dong, Chem.
Rev., 2011, 111, 1215.
2 D.-H. Wang, M. Wasa, R. Giri and J.-Q. Yu, J. Am. Chem. Soc.,
2008, 130, 7190.
3 M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 14058.
4 (a) G.-W. Wang and T.-T. Yuan, J. Org. Chem., 2010, 75, 476;
(b) G.-W. Wang, T.-T. Yuan and D.-D. Li, Angew. Chem., Int. Ed.,
2011, 50, 1380.
Scheme 2 Proposed reaction mechanism.
syn-aminopalladation produces 11. b-Hydride elimination
from 11 after bond rotation provides the final isoindolinone
3 as the E-isomers along with Pd0. Pd0 is oxidized by BQ to
PdII, which re-enters the catalytic cycle. The fact that BQ
behaves as an oxidant is confirmed by observation and isolation
of p-hydroquinone (HQ).
5 (a) S. Rakshit, C. Grohmann, T. Besset and F. Glorius, J. Am.
Chem. Soc., 2011, 133, 2350; (b) N. Guimond, S. I. Gorelsky and
K. Fagnou, J. Am. Chem. Soc., 2011, 133, 6449.
6 M. Miura, T. Tsuda, T. Satoh, S. Pivsa-Art and M. Nomura,
J. Org. Chem., 1998, 63, 5211.
Yu and co-workers reported the palladium-catalyzed olefination
of sp3 C–H bonds directed by N-arylamide (CONHAr), followed
by cyclization to give lactams.7 More recently, Li, Zhu, and their
co-workers described the reaction of benzamides (ArCONHAr0
and ArCONHTs) with electron-deficient alkenes such as acrylate
esters to afford isoindolinones via sp2 C–H olefination and
subsequent cyclization.9 In these reactions, the cyclization
step is an intramolecular aza-Michael addition,7,9 which is
mechanistically distinct from the intramolecular oxidative
amidation step generating an E-configured exocyclic CQC
bond in our case (see Scheme 2). It is noteworthy that the
CONHOMe group was not a suitable directing group in the
above-mentioned reactions because the acidic N–H was essential
and dramatically improved the reactivity under the employed
conditions.7,9 More importantly, the Rh-catalyzed reaction of 1a
with 2b gave a Heck-type product accompanied by the N–O
bond cleavage.5a In sharp contrast, our Pd-catalyzed reaction
7 M. Wasa, K. M. Engle and J.-Q. Yu, J. Am. Chem. Soc., 2010,
132, 3680.
8 For selected examples, see: (a) M. D. K. Boele, G. P. F. van
Strijdonck, A. H. M. de Vries, P. C. J. Kamer, J. G. de Vries and
P. W. N. M. van Leeuwen, J. Am. Chem. Soc., 2002, 124, 1586;
(b) X. Chen, J.-J. Li, X.-S. Hao, C. E. Goodhue and J.-Q. Yu,
J. Am. Chem. Soc., 2006, 128, 78; (c) K. L. Hull and M. S. Sanford,
J. Am. Chem. Soc., 2007, 129, 11904; (d) M. J. Tredwell, M. Gulias,
N. G. Bremeyer, C. C. C. Johansson, B. S. L. Collins and
M. J. Gaunt, Angew. Chem., Int. Ed., 2011, 50, 1076.
9 (a) F. Wang, G. Song and X. Li, Org. Lett., 2010, 12, 5430;
(b) C. Zhu and J. R. Falck, Org. Lett., 2011, 13, 1214.
10 (a) X. Liu and K. K. Hii, Eur. J. Org. Chem., 2010, 5181;
(b) F. W. Patureau, T. Besset and F. Glorius, Angew. Chem., Int.
Ed., 2011, 50, 1064.
11 Y. Lu, D.-H. Wang, K. M. Engle and J.-Q. Yu, J. Am. Chem. Soc.,
2010, 132, 5916.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12789–12791 12791