Nickel(0)-catalyzed cyclization of N -benzoylaminals for isoindolinone synthesis

Article abstract of DOI:10.1021/ol201248c

A nickel(0) catalyst effectively mediates the cyclization of N-benzoyl aminals in the presence of a stoichiometric Lewis acid. This method enables preparation of a variety of isoindolinones with substitution on the benzoyl fragment and C-3 carbon. This reaction likely proceeds via an α-amidoalkylnickel(II) intermediate, which then may cyclize via either an electrophilic aromatic substitution or an insertion pathway.

Full text of DOI:10.1021/ol201248c

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3490–3493
Nickel(0)-Catalyzed Cyclization of
N-Benzoylaminals for Isoindolinone
Synthesis
Danielle M. Shacklady-McAtee, Srimoyee Dasgupta, and Mary P. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark,
Delaware 19716, United States
mpwatson@udel.edu
Received May 10, 2011
ABSTRACT
A nickel(0) catalyst effectively mediates the cyclization of N-benzoyl aminals in the presence of a stoichiometric Lewis acid. This method enables
preparation of a variety of isoindolinones with substitution on the benzoyl fragment and C-3 carbon. This reaction likely proceeds via an
R-amidoalkylnickel(II) intermediate, which then may cyclize via either an electrophilic aromatic substitution or an insertion pathway.
Efficient formation of nitrogen heterocycles from
readily available starting materials is crucial for the
synthesis of various pharmaceutical compounds, agro-
chemicals, and materials. One privileged substructure is
the isoindolinone, or phthalimidine, nucleus. Isoindoli-
nones with carbon substitution at C-3 are found in a
number of biologically active molecules and natural
products,1 including the anxiolytic pagoclone2 and
naturally occurring pestalachloride A3 (Figure 1). There
are a variety of methods for building this important
structure from 1,2-disubstituted benzenes, such as
1,2-diacylbenzenes, unsubstituted isoindolinones, and
o-halobenzoic amides.4 Isoindolinones can also be pre-
pared via CꢀH functionalization of a monosubstituted
benzene ring by directed ortho lithiation5 or transition-
metal-catalyzed carbonylations.6 More recently, palla-
dium- and rhodium-catalyzed oxidative olefinations of
benzoic amides have been developed.7 CꢀH functiona-
lization has also been accomplished via triflic acid
promoted aza-Nazarov cyclizations of N-benzoyl imi-
nium chlorides.8
(4) (a) Gabriel, S. Ber. 1885, 18, 3470. (b) Chen, M.-D.; He, M.-Z.;
Huang, L.-Q.; Ruan, Y.-P.; Huang, P.-Q. Chin. J. Chem. 2002, 20, 1149.
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Zhang, L.; Collard, S.; Keep, A. Can. J. Chem. 2005, 83, 990. (d) Khan,
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Xia, C.; Huang, H. Angew. Chem., Int. Ed. 2010, 49, 2728. (f) Campbell,
J. B.; Dedinas, R. F.; Trumbower-Walsh, S. Synlett 2010, 3008. (g) Pin,
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Handlon, A. L.; Hyman, C. E.; Oplinger, J. A.; Rabinowitz, M. H.;
Turnbull, P. S. Intl. Pat. Appl. WO 03,076,440 (2003); Chem. Abstr.
2003, 139, 261291. (c) Wood, J. L.; Petsch, D. T.; Stoltz, B. M.; Hawkins,
E. M.; Elbaum, D.; Stover, D. R. Synthesis 1999, 1529. (d) Comins,
D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95. (e) Belliotti, T. R.;
Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow, D. J.; Zoski, K. T.;
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Nishimura, S.; Morishima, H. J. Med. Chem. 2001, 44, 4615.
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(b) Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.; Blagg, J. Tetra-
hedron Lett. 1990, 31, 5015. (c) Campbell, J. B.; Dedinas, R. F.;
Trumbower-Walsh, S. A. J. Org. Chem. 1996, 61, 6205. (d) Epsztajn,
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J.; Jozwiak, A.; Koluda, P.; Sadokierska, I.; Wilkowska, I. D. Tetra-
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Future 2001, 26, 651. (b) Stuk, T. L.; Assink, B. K.; Bates, R. C., Jr.;
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Chem. 2008, 16, 7894. (b) Slavov, N.; Cvengros, J.; Neudoerfl, J.-M.;
Schmalz, H.-G. Angew. Chem., Int. Ed. 2010, 49, 7588.
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r
10.1021/ol201248c
Published on Web 06/06/2011
2011 American Chemical Society

lead to efficient cyclization (not shown). With MgBr2 OEt2,
3
1,10-bis(diphenylphosphino)ferrocene (dppf) was found to
be the optimal ligand (entry 6). To minimize formation of 4
further, the reaction temperature was lowered to 95 °C(entry
7).15 Reducing the catalyst loading led to lower yields (entry
8), and a small increase in yield was observed with higher
catalyst loading (entry 9). Using the conditions shown in
entry 7 (bold), 3a was isolated in 67% yield with minimal
formation of undesired 4.
Figure 1. Examples of bioactive and natural isoindolinones.
Aminals are attractive starting materials that can be
easily accessed from acid chlorides, imines, and primary
amines.9,10 However, there are few methods for using transi-
tion metal catalysts to activate aminals despite their potential
to promote novel reactivity.11 The Arndtsen group has
shown that the addition of Pd catalysts to such aminals
allows unique reaction pathways via catalytic formation of
R-amidoalkylpalladium intermediates.12 Very recently,
Doyle has shown that Ni catalysts can be used to couple
aryl boroxines with aminal substrates.13
Table 1. Optimization of Isoindolinone Formationa
Ni
(mol %)
ligand
(mol %)
temp
(°C)
time
(h)
yield
(%)b
entry
1c
2
3
4
5
6
7
8
NiCl2 DME (10)
P(o-Tol)3 (22)
P(o-Tol)3 (22)
PCyPh2 (22)
bpy (12)
dppp (12)
dppf (12)
dppf (12)
dppf (6)
110
110
110
110
110
110
95
95
95
95
95
4
4
4
4
4
(60)
31
35
37
36
60
(67)
61
74
56
0
3
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (5)
Ni(cod)2 (20)
Ni(cod)2 (10)
(0)
Scheme 1. Ni-Catalyzed Synthesis of Isoindolinones via
Intramolecular CꢀH Functionalization
5
24
24
24
24
24
24
4
9
dppf (22)
BINAP (12)
(0)
10
11c
12
13d
(0)
(0)
95
110
5
0
NiCl2 DME (10)
P(o-Tol)3 (22)
3
a Conditions: Substrate 1a (0.064 mmol), [Ni], Ligand, Lewis acid
(0.127 mmol, 2.2 equiv), PhMe (0.2 mL, 0.3 M). b Yield of 3a, determined
by NMR analysis using 1,3,5-trimethoxybenzene as an internal stan-
dard. Numbers in parentheses are isolated yields. c AlMe3 was used
Herein, we describe a process for preparing isoindoli-
nones 3via intramolecular cyclization of N-benzoylaminals 1
(Scheme 1). This Ni-catalyzed process involves aromatic
CꢀH functionalization of the benzoyl group and offers a
convergent, 3-step approach for preparing isoindolinones
from benzoyl chorides, primary amines, and aldehydes.
Optimization of the reaction conditions focused on cycli-
zation of substrate 1a, which can be readily prepared in 82%
yield by benzoylation and trapping of the N-benzylimine of
p-tolualdehyde.12,14 When 1a was heated in the presence
instead of MgBr2 OEt2. d No Lewis acid used.
3
Both a nickel catalyst and Lewis acid are required for high
yields of isoindolinone 3a. In the absence of nickel, use of
AlMe3 resulted in no desired product and significant decom-
position (Table 1, entry 11). MgBr2 OEt2 alone produced
3
only trace amounts of product 3a (entry 12). In addition, no
product forms in the absence of a Lewis acid (entry 13).
As shown in Table 2, isoindolinones 3with a variety of aryl
substituents at R2 could be prepared by this method, includ-
ing that with a sterically demanding 3,5-dimethylphenyl
substituent (entry 2) and those with electronically different
aryl groups (entries 3ꢀ6). However, substrates with moder-
ately electron-poor substituents required longer reaction
times (entries 3, 4). The cyclization of substrates with very
electron-poor groups, such as p-trifluoromethylphenyl, was
not possible under these conditions (not shown). Further,
aminals with heteroaromatic R2 substituents, such as 2-furyl,
decomposed under the optimized conditions (not shown).
of NiCl2 DME, P(o-Tol)3 and AlMe3, isoindolinone 3a
3
formed in 60% yield, as was undesired amide 4 (Table 1,
entry 1). To enable greater functional group tolerance, we
examined a variety of milder Lewis acids. An extensive screen
revealed that MgBr2 OEt2 could replace the harsher AlMe3,
albeit in reduced yield (entry 2). With MgBr2 OEt2,Ni(cod)2
was required as the Ni source; the use of NiCl2 DME did not
3
3
3
(9) Enantioenriched aminals can also be prepared by the addition of
alcohol to an imine. See: Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am.
Chem. Soc. 2008, 130, 12216.
(10) Aminals can also be prepared from the amide and acetal. See:
Downey, C. W.; Johnson, M. W.; Tracy, K. J. J. Org. Chem. 2008, 73, 3299.
(11) (a) Yao, B.; Zhang, Y.; Li, Y. J. Org. Chem. 2010, 75, 4554. (b)
Huang, H.-L.; Sung, W.-H.; Liu, R.-S. J. Org. Chem. 2001, 66, 6193.
(12) (a) Lu, Y.; Arndtsen, B. A. Org. Lett. 2007, 9, 4395. (b) Lu, Y.;
Arndtsen, B. A. Angew. Chem., Int. Ed. 2008, 47, 5430. (c) Arndtsen,
B. A. Chem.;Eur. J. 2009, 15, 302.
The use of MgBr2 OEt2 allowed preparation of p-bromo-
3
phenylsubstituted product 3c; with AlMe3 cross-coupling of
the bromide resulted in formation of product 3a in 33%
(15) The Arndtsen group has attributed amide formation to thermal
decomposition of the iminium ion. See: Siamaki, A. R.; Arndtsen, B. A
J. Am. Chem. Soc. 2006, 128, 6050.
(13) Graham, T.; Shields, J.; Doyle, A. Chem. Sci. 2011, 2, 980.
(14) See Supporting Information for full experimental details.
Org. Lett., Vol. 13, No. 13, 2011
3491

which was isolated in 84% yield.16 The effect of the Ni(0)
catalyst on the product distribution highlights the unique
role that Ni has in the formation of the isoindolinones.
Table 2. Scope of Cyclizationa
Scheme 2. Cyclizations of N-(m-Methoxybenzoyl)aminal 1o
with and without Ni(0) Catalyst
3
yield
(%)b
entry
R1
R2
Lewis acid
1
2
3d
4d
5
6
7
8
9
10
11e
12e
13e
14
15f
H
H
H
H
H
H
H
H
Me
OMe
NMe2
NMe2
Br
p-Tol
a
b
c
d
e
f
g
g
h
i
j
k
l
m
n
MgBr2 OEt2
70
67c
73
66
76c
45c
0
69
69
74
62
65
68
0
3
3,5-(Me)2C6H3
4-BrC6H4
4-FC6H4
3-(OMe)C6H4
4-(OMe)C6H4
t-Bu
t-Bu
p-Tol
p-Tol
p-Tol
MgBr2 OEt2
3
3
3
MgBr2 OEt2
MgBr2 OEt2
MgBr2 OEt2
3
AlMe3
MgBr2 OEt2
3
AlMe3
MgBr2 OEt2
3
3
3
3
3
3
3
MgBr2 OEt2
The Ni(0) catalyst may either have a role in activating the
CꢀO bond of the aminal substrate or in the CꢀC bond-
forming step of the cyclization. To begin to differentiate
between these possibilities, we determined that the cyclization
of enantioenriched aminal 1a (>99% ee) results in racemic
isoindolinone 3a (eq 1),14 suggesting that the reaction likely
proceeds via an N-benzoyl iminium ion. Further, heating
enantioenriched 1a with only a Lewis acid resulted in race-
mization of the recovered aminal (eq 2).17,18 From this
experiment, a Lewis acid alone seems sufficient to form the
iminium ion. The Ni(0) catalyst then is likely involved in the
CꢀC bond-forming step. Although it is somewhat surprising
that the postulated iminium ion does not cyclize without the
Ni(0) catalyst, this result is consistent with Klumpp’s ob-
servation that cyclization of N-benzoyl iminium ions requires
stoichiometric TfOH to form a superelectrophile, or doubly
cationic, intermediate, which then cyclizes via a lowered
transition state barrier.8a,b Under our conditions, Ni(0)
may play a similar role in providing a lower-energy pathway
for cyclization. Notably, however, Klumpp observes compet-
ing cyclization of the benzyl group to form isoindolines,
instead of isoindolinones, with substrates similar to 1. Under
the Ni-catalyzed conditions, isoindolines are not observed.
MgBr2 OEt2
Ph
p-Tol
p-Tol
p-Tol
MgBr2 OEt2
MgBr2 OEt2
CF3
H
MgBr2 OEt2
MgBr2 OEt2
43
a Conditions: Substrate 1 (0.138 mmol), Ni(cod)2 (0.014 mmol, 10 mol
%), dppf (0.017 mmol, 12 mol %), MgBr2 OEt2 (0.304 mmol, 2.2 equiv),
3
PhMe (0.5 mL, 0.3 M), 95 °C, 24 h, R3 = Bn, unless otherwise noted.
b Average isolated yield from duplicate experiments unless otherwise noted
((3%). c Yield from a single experiment. d Heated for 48 h. e Heated for
36 h. f R3 = PMB.
isolated yield from bromide 1c. Although most substrates
cyclized in higher yield when MgBr2 OEt2 was used instead
3
of AlMe3, aminals 1f and 1g did not cyclize under the stan-
dard conditions. The stronger Lewis acid, AlMe3, was
required for these substrates (entries 6ꢀ8). In addition, a
variety of substituents (R1) were tolerated on the benzoyl
fragment, including electron-rich substituents (entries
10ꢀ12) and a bromide group (entry 13). However, substrates
with electron-withdrawing groups, such as trifluoromethyl,
on the benzoyl fragment failed to produce any of the
corresponding isoindolinone (entry 14). Heteroaromatic am-
inals, such as that derived from pyrazinecarboxylic acid, also
failed to cyclize under the optimized reaction conditions and
instead decomposed (not shown). Finally, p-methoxybenzyl
can be used as an alternative nitrogen protecting group, albeit
in lower yield under these conditions (entry 15).
Under the Ni(0)-catalyzed conditions, aminals with
meta-substituted benzoyl rings cyclized to give nearly
equimolar mixtures of both possible regioisomeric products.
For example, aminal 1o cyclized to give 3o and 3o0 in 46%
and 32% yield, respectively (Scheme 2). Preliminary calcula-
tions suggested that the electron-donating methoxy substi-
tuent might enable cyclization in the absence of nickel.
Remarkably, cyclization of aminal 1o not only occurred
Possibilities for how Ni(0) may be involved in the CꢀC
bond formation are shown in Scheme 3. Based on precedent
using only MgBr2 OEt2 but also gave only isoindolinone 3o,
3
(17) AlMe3 was used for this experiment, because MgBr2 OEt2
3
resulted in complete decomposition of aminal 1a. Significant decom-
position of aminal 1a to amide 4 was observed under these conditions,
but no isoindolinone 3a was observed.
(18) This result is consistent with observations of Doyle’s Ni-cata-
lyzed cross-coupling of related aminal substrates. See ref 13.
(16) The electron-donating group must be meta for cyclization to
occur in high yield without Ni(0). In the presence of only MgBr2 OEt2
3
and no Ni(0) catalyst, the cyclization of N-(p-methoxybenzoyl)aminal 1i
resulted in only 3% yield of isoindolinone 3i.
3492
Org. Lett., Vol. 13, No. 13, 2011

Scheme 3. Potential Mechanisms for the Nickel-Catalyzed Cyclization
from the Arndtsen lab,12 the electron-rich Ni(dppf) catalyst
likely reacts with iminium ion 5 to form alkylnickel bromide
2. Three distinct pathways are then possible for the CꢀC
bond formation.19 Via Path A, CꢀH activation of the
benzoyl ring leads to metallocycle 6. Subsequent reductive
elimination results in isoindolinone 3. Alternatively, electro-
philic aromatic metalation of the benzoyl ring would lead to
arenium ion 7 (Path B).20 Rearomatization of intermediate
7 via deprotonation followed by reductive elimination
delivers product 3. Finally, alkylnickel species 2 may under-
go a 5-exo-trig cyclization via an insertion pathway to give
nickel enolate 8 (Path C). Isomerization of nickel enolate 8
via tautomer 9 would then allow isoindolinone 3 to form by
β-hydride elimination. Because Pd-based catalysts can also
be used for this cyclization,14 single-electron pathways seem
unlikely for this cyclization.
affects both iminium formation and subsequent cycliza-
tion. Although we cannot exclude either possibility, we
favor Path B, because electron-withdrawing groups on
the benzoyl ring inhibit cyclization. In Path B, cyclization
of the benzoyl ring may be favored over cyclization of
the benzyl ring due to the conformational constraint
imposed by the amide.
In summary, we have developed a 3-step procedure for
the conversion of an aldehyde, amine, and benzoyl chlor-
ide to a variety of isoindolinones. The key step of this route
relies on the use of an electron-rich Ni(0) catalyst to
chaperone the iminium ion intermediate to the cyclized
product. Studies toward exploiting this reactivity for other
reactions as well as an asymmetric synthesis of isoindoli-
nones are ongoing in our laboratory.
Acknowledgment. To Prof. Douglas A. Klumpp
(Northern Illinois University) for comparative spectral
data, Dr. Glenn Yap (University of Delaware) for X-ray
crystallography, Dr. Olga Dmitrenko (University of
Delaware) for preliminary computational studies, Dr.
Prantik Maity (University of Delaware) for discussions,
and to Kaitlin Papson (University of Delaware) for mass
spectrometry. Acknowledgement is also made to the Do-
nors of the American Chemical Society Petroleum Re-
search Fund and the University of Delaware for partial
support of this research.
Totest thelikelihood ofPath A, monodeuterated aminal
1p was subjected to the cyclization conditions (eq 3). No
intramolecular kinetic isotope effect was observed, sug-
gesting that Path A is not the operable mechanism.21
Despite the different electronic requirements on the
benzoyl ring, Paths B and C are more difficult to distinguish,
because the electronic character of the benzoyl fragment
Supporting Information Available. Experimental pro-
cedures, X-ray crystal structure, characterization data
and spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Similar mechanistic quandries have been proposed for related
Pd-catalyzed cyclizations. See: (a) Martın-Matute, B.; Mateo, C.;
´
ꢀ
Cardenas, D.; Echavarren, A. Chem.;Eur. J. 2001, 7, 2341. (b) Hughes,
C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569. (c) Glover, B.;
Harvery, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett.
2003, 5, 301. (d) Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.;
Arakawa, M.; Ihara, M. Org. Lett. 2002, 4, 4293. (e) Park, C.-H.;
Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett.
2004, 6, 1159. (f) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. (g) Catellani, M.;
Chiusoli, G. P. J. Organomet. Chem. 1992, 425, 151.
(20) (a) Kleiman, J.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
(b) Cope, A.; Siekman, R. J. Am. Chem. Soc. 1965, 87, 3272. (c) Valk, J.;
Maassarani, F.; Vandersluis, P.; Spek, A.; Boersma, J.; van Koten, G.
Organometallics 1994, 13, 2320. (d) Canty, A.; van Koten, G. Acc. Chem.
Res. 1995, 28, 406.
(21) Significant intramolecular KIEs have been observed in similar
reactions that do proceed via CꢀH activation. See: Hennessey, E. J.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084.
Org. Lett., Vol. 13, No. 13, 2011
3493