Tandem Rh(III)-catalyzed oxidative acylation of secondary benzamides with aldehydes and intramolecular cyclization: The direct synthesis of 3-hydroxyisoindolin-1-ones

Article abstract of DOI:10.1021/ol2034228

The rhodium-catalyzed oxidative acylation between secondary benzamides and aryl aldehydes via sp² C - H bond activation followed by an intramolecular cyclization is described. This method results in the direct and efficient synthesis of 3-hydro

Full text of DOI:10.1021/ol2034228

ORGANIC
LETTERS
2012
Vol. 14, No. 3
906–909
Tandem Rh(III)-Catalyzed Oxidative
Acylation of Secondary Benzamides with
Aldehydes and Intramolecular
Cyclization: The Direct Synthesis of
3-Hydroxyisoindolin-1-ones
Satyasheel Sharma, Eonjeong Park, Jihye Park, and In Su Kim*
Department of Chemistry, University of Ulsan, Ulsan, 680-749, Republic of Korea
insukim@ulsan.ac.kr
Received December 22, 2011
ABSTRACT
The rhodium-catalyzed oxidative acylation between secondary benzamides and aryl aldehydes via sp2 CÀH bond activation followed by an
intramolecular cyclization is described. This method results in the direct and efficient synthesis of 3-hydroxyisoindolin-1-one building blocks.
3-Hydroxyisoindolin-1-ones are ubiquitous structural
motifs in a number of synthetic and naturally occurring bio-
active compounds, such as the synthetic diuretic and anti-
hypertensive agent chlorthalidone,1 the natural product
isoquinoline fumadensine,2 and isoindolobenzazepine
chilenine,3 and a synthetic antibacterial compound.4 3-
Hydroxyisoindolin-1-ones are conventionally synthesized
by the site-selective addition of organometallic reagents or
other nucleophilic agents to phthalimide derivatives.5 The
condensation of pseudo acid chlorides (Ψ-acid chlorides)
with amines provides an efficient protocol for the synthesis
of 3-hydroxyisoindolin-1-ones.6 FriedelÀCrafts acylation
of compounds containing secondary amide moieties with
carboxylic acid derivatives (e.g., acid chlorides) followed by
intramolecular cyclization has also been reported.7 Re-
cently, Liu et al. described a tandem transformation for
the construction of 3-hydroxyisoindolin-1-ones from o-
(substituted ethynyl)benzoic acids and primary amines
using a phase transfer catalyst.8 However, from a syn-
thetic point of view, these approaches have intrinsic draw-
backs, which include strict handling requirements for the
organometallic reagent (e.g., Grignard reagents), poor func-
tional group tolerance, harsh reaction conditions, and the
need for prefunctionalization of the coupling partners.
Therefore, it is highly desirable to develop novel and ef-
ficient protocols that involve fewer synthetic steps and
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r
10.1021/ol2034228
Published on Web 01/20/2012
2012 American Chemical Society

readily available starting materials for the synthesis of 3-
hydroxyisoindolin-1-ones.
Deng and Li demonstrated a palladium-catalyzed oxidative
acylation reaction of 2-arylpyridines and alcohols in the pre-
sence of tert-butyl hydroperoxide as an oxidant.16c Li and
Kwong also reported a palladium-catalyzed oxidative cou-
pling of acetanilides and aldehydes to provide ortho-acyl
acetanilides.16d Recently, we described the rhodium-catalyzed
oxidative acylation of tertiary benzamides and aldehydes to
afford aryl ketones (Scheme 1).17
Scheme 1. Transition-Metal-Catalyzed Oxidative Acylation
and Intramolecular Cyclization
As part of an ongoing research program directed toward
the development of transition-metal-catalyzed carbonÀ
carbon bond forming reactions,18 we became interested
in developing an efficient synthetic route to 3-hydroxy-
isoindolin-1-ones from secondary benzamides and alde-
hydes via CÀH bond activation followed by amino-
cyclization. In this paper, we report the rhodium-catalyzed
regioselective ortho-acylation and intramolecular cyclization
sequence in the presence of silver carbonate as an oxidant to
prepare 3-hydroxyisoindolin-1-ones in good to high yields.
We initiated our investigation by exploring the coupling
of a variety of N-substituted benzamides (1aÀh) with
4-(trifluoromethyl)-benzaldehyde (2a); selected results are
summarized in Table 1. The cationic rhodium complex
derived from [Cp*RhCl2]2 and AgSbF6 catalyzed the cou-
pling of N-methyl benzamide (1a) and aryl aldehyde 2a in the
presence of Ag2CO3 as an oxidant to yield compound 3a in
34% yield (Table 1, entry 1). Further screening of N-mono-
substituted amides indicated that N-isopropyl benzamide
(1b) was the most effective in affording the 3-hydroxyiso-
indolin-1-one 3b, as shown in entries 2À8. However, the use
of other oxidants, such as AgOAc, K2S2O8, benzoquinone,
and t-BuO2H, was relatively ineffective in the coupling of 1b
and 2a (Table 1, entries 9À12). A screening of solvents re-
vealed that the best yield was obtained with THF and that
other oxygen-containing solvents, such as 1,4-dioxane and
THP, were less effective (Table 1, entries 13 and 14). After
further optimization, the best results were obtained by
increasing the amount of Ag2CO3 (300 mol %) and
the reaction temperature (150 °C) to afford the desired
3-hydroxyisoindolin-1-one 3b in 83% yield, as shown in
entry 16.
Having established the optimized reaction conditions,
the substrate scope was examined with respect to the
aldehyde (Scheme 2). The coupling of benzamide 1b and
aldehydes 2iÀm with para- or meta-substituted electron-
withdrawing groups afforded the corresponding products
3iÀm in moderate to high yields. This reaction was also
compatible with halogen-substituted aldehydes 2nÀp fur-
nishing the corresponding products 3nÀp in good yields.
Particularly noteworthy was the tolerance of the reaction
conditions to chloro and bromo groups, which provide a
versatile synthetic handle for further functionalization of
the products. In addition, 2-naphthaldehyde 2q and benz-
aldehyde 2r also smoothly underwent reaction to gener-
ate the corresponding products 3q and 3r, respectively.
Transition-metal-catalyzed CÀH bond functionaliza-
tions have emerged as powerful tools in organic synthesis,
since such methods avoid the necessity of multistep pre-
paration of preactivated starting materials and lead to an
improved overall efficiency of the desired transformation.9
In particular, the combination of transition metals and
directing groups is a useful strategy for facilitating CÀH
bond cleavage10 and has provided valuable conversions of
CÀH bonds to CÀX (X = carbon,11 oxygen,12 nitogen,13
and halogen14) bonds. Recently, remarkable progress has
been made in the transition-metal-catalyzed oxidative cou-
pling of two different aryl CÀH bonds for the construction
of areneÀarene linkages.15 However, cross-coupling reac-
tions between aryl CÀH and aldehyde CÀH bonds to form
corresponding aryl ketones remain relatively unexplored.16
Cheng et al. described a palladium-catalyzed cross-coupling
reaction of aromatic compounds containing a pyridine
directing group and aldehydes to afford aryl ketones.16a Li
and co-workers reported the palladium-catalyzed sp2Àsp2
coupling of 2-phenylpyridine with aliphatic aldehydes.16b
(9) (a) Dyker, G. Handbook of CÀH Transformations: Application in
Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Yu, J. Q.; Shi, Z. J.
CÀH Activation; Springer: Berlin, Germany, 2010.
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Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740.
(b) Ackermann, L. Chem. Rev. 2011, 111, 1315. (c) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (d) Mkhalid, I. A. I.; Barnard, J. H.;
Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
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Ellman, J. A. Chem. Rev. 2010, 110, 624. (g) Beck, E. M.; Gaunt, M. J. Top.
Curr. Chem. 2010, 292, 85.
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K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2011, 50, 4169. (b) Lu, Y.;
Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916.
(c) Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am.
Chem. Soc. 2010, 132, 468. (d) Patureau, F. W.; Glorius, F. J. Am. Chem.
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Science 2010, 327, 315. (f) Guimond, N.; Gouliaras, C.; Fagnou, K.
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Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
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Org. Lett., Vol. 14, No. 3, 2012
907

Table 1. Selected Optimization of the Reaction Conditionsa
Scheme 2. Scope of Aldehydesa
yield
entry
R3
benzamide
oxidant
Ag2CO3
solvent
(%)b
1
methyl
1a
1b
1c
1d
1e
1f
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
1,4-
34
64
48
23
35
12
0
2
isopropyl
isobutyl
tert-butyl
benzyl
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
3
4
5
6
phenyl
7
methoxy
tosyl
1g
1h
1b
1b
1b
1b
1b
8
0
9
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
0
10
11
12
13
K2S2O8
0
benzoquinone
t-BuO2H
Ag2CO3
18
0
19
dioxane
THP
THF
THF
a Reaction conditions: 1b (0.3 mmol), aldehydes 2a and 2iÀs
(0.6 mmol), [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), Ag2CO3
(0.9 mmol), THF (1 mL) at 150 °C for 20 h under N2 in 13 Â 100 mm2
pressure tubes. bYield isolated by column chromatography.
14c
15d
16e
isopropyl
isopropyl
isopropyl
1b
1b
1b
Ag2CO3
Ag2CO3
Ag2CO3
40
72
83
a Reaction conditions: 1aÀh (0.3 mmol), 2a (0.6 mmol), [Cp*RhCl2]2
(5 mol %), AgSbF6 (20 mol %), oxidant (0.6 mmol), solvent (1 mL) at
110 °C for 20 h under N2 in 13 Â 100 mm2 pressure tubes. b Yield isolated
by column chromatography. c THP = tetrahydropyrane. d Ag2CO3
(0.9 mmol) was used. e 150 °C.
directing groups such as in compound 1s, as shown in
Scheme 4. Unfortunately, the Pd-catalyzed oxidative acyl-
ation conditions reported by Li and Kwong did not yield
ortho-acyl acetanilide from the coupling of acetanilide 1s
with aldehyde 2a.16d However, compound 1s under our
optimal reaction conditions was converted to the 3-hydroxy-
isoindolin-1-one 4s with excellent regioselectivity in 48%
yield. Thus, Rh catalysis could provide efficient regioselec-
tivity in the CÀH bond functionalization reaction.
In contrast, electron-rich aldehyde 2s was less reactive
under the reaction conditions presumably due to the
difficulty of metal insertion into the aldehyde CÀH
bond.19
Couplings with a variety of benzamides 1iÀr and alde-
hyde 2a under identical reaction conditions were examined
to further explore the substrate scope and limitations of
this process (Scheme 3). Electron-neutral and -donating
benzamides 1iÀm were readily converted to the corre-
sponding products 4iÀm. In particular, the reaction of
benzamides 1jÀm with a meta-substituent preferentially
occurred at the more sterically accessible position. In addi-
tion, benzamides 1nÀp with halogen groups (Br and Cl)
in the para- or meta-positions were found to be favor-
able in the reaction and provided products which would
be amenable to further cross-coupling reactions. How-
ever, ortho-substituted benzamides 1q and 1r showed
relatively decreased reactivity since coplanar confor-
mation between the aromatic ring and the amide moiety
was not available.
To probe the catalytic mechanism, we carried out a
competition experiment between equimolar amounts of
deuterio-1b and benzamides 1b with aldehyde 2i under our
standard conditions for 10 min, which results in the
intermolecular kinetic isotope effect (kH/kD) of 1.1
(Scheme 5). Interestingly, the reaction of deuterio-1b
with aldehyde 2i in THF (condition A) provided sig-
nificant deuterium loss (27% D) at the ortho-position of
deuterio-3i as well as partial deuteration (10% D) of the
internal sp3 CÀH bond of the isopropyl group. In
addition, the use of either condition B (2i-d1 in THF)
or condition C (2i-d1 in THF-d8) afforded isotope
results very similar to those obtained through the use
of condition A. These results may arise from a fast
and reversible metalationÀproto(deutero)demetala-
tion step of deuterio-1b prior to the cross-coupling reaction
Encouraged by these results, we further examined the
influence of both the acetamido and N-isopropyl amide
(20) For detailed mechanistic studies of Rh(III)-catalyzed CÀH
bond functionalization, see: (a) Stuart, D. R.; Bertrand-Laperle, M.;
Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
(b) Stuart, D. R.; Alsaben, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 18326.
(19) (a) Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am.
Chem. Soc. 2002, 124, 3806. (b) Kwong, F. Y.; Li, Y. M.; Lam, W. H.;
Qiu, L.; Lee, H. W.; Yeung, C. H.; Chan, K. S.; Chan, A. S. C. Chem.;
Eur. J. 2005, 11, 3872.
908
Org. Lett., Vol. 14, No. 3, 2012

Scheme 3. Scope of Benzamidesa
Scheme 5. Mechanistic Studies
reversible protonationÀdeuteration step of the aryl ketone
intermediate obtained from the oxidative acylation re-
action. To gain insight into the catalytic pathway, we
again conducted a competition reaction between equi-
molar amounts of electron-deficient aldehyde 2i and
electron-rich aldehyde 2s with benzamide 1b for 1 h,
affording about 2.5 times more 3i than 3s. Thus, it
seems that the insertion of aldehyde to a cyclo-rhodated
intermediate is most likely involved in the rate-limiting
step of this transformation (see Supporting Informa-
tion for plausible reaction mechanism).
a Reaction conditions: benzamide 1iÀr (0.3 mmol), 2a (0.6 mmol),
[Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %), Ag2CO3 (0.9 mmol), THF
(1 mL) at 150 °C for 20 h under N2 in 13 Â 100 mm2 pressure tubes.
bYield isolated by column chromatography.
Scheme 4. Regioselectivity of Pd vs Rh
Acknowledgment. This work was supported by Na-
tional Research Foundation of Korea (No. 2010-
0002465 and 2011-0005400) funded by the Ministry of
Education, Science and Technology.
a Reaction conditions: 1s (0.3 mmol), 2a (0.6 mmol), [Cp*RhCl2]2
(5 mol %), AgSbF6 (20 mol %), Ag2CO3 (0.9 mmol), THF (0.3 M) at
150 °C for 20 h. bReaction conditions: 1s (0.3 mmol), 2a (0.6 mmol),
Pd(TFA)2 (5 mol %), tert-butyl hydroperoxide (1.2 mmol), toluene (0.5 M)
at 90 °C for 18 h.
Supporting Information Available. Spectroscopic data
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
with aldehyde 2i or 2i-d1.20 Partial deuteration (8% D) of
the aromatic ring sp2 CÀH bond may be the result of a
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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