Ni(II)-Catalyzed Highly Stereo- and Regioselective Syntheses of Isoindolinones and Isoquinolinones from in Situ Prepared Aldimines Triggered by Homoallylation/Lactamization Cascade

Article abstract of DOI:10.1021/acs.orglett.5b02932

An efficient route to isoindolinones and isoquinolinones has been achieved via a domino Ni-catalyzed homoallylation/lactamization from in situ prepared imines, derived from o-formyl benzoates and o-formyl arylacetates, with conjugated dienes promoted by diethylzinc. The reaction proceeds smoothly at room temperature for a variety of aldehydes, amines, and dienes. The method involves one C-C and two C-N bond forming events under operationally simple conditions.

Full text of DOI:10.1021/acs.orglett.5b02932

Letter
pubs.acs.org/OrgLett
Ni(II)-Catalyzed Highly Stereo- and Regioselective Syntheses of
Isoindolinones and Isoquinolinones from in Situ Prepared Aldimines
Triggered by Homoallylation/Lactamization Cascade
Raju Karmakar,† Arun Suneja, Vishnumaya Bisai, and Vinod K. Singh*
,§
†,§
†,∥
,†,‡
†Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal - 462
0
66, Madhya Pradesh, India
‡
Indian Institute of Technology Kanpur, Kanpur - 208 016, Uttar Pradesh, India
S Supporting Information
*
ABSTRACT: An efficient route to isoindolinones and isoquinolinones has been achieved via a domino Ni-catalyzed
homoallylation/lactamization from in situ prepared imines, derived from o-formyl benzoates and o-formyl arylacetates, with
conjugated dienes promoted by diethylzinc. The reaction proceeds smoothly at room temperature for a variety of aldehydes,
amines, and dienes. The method involves one C−C and two C−N bond forming events under operationally simple conditions.
soindolinones (1a−d; Figure 1) and tetrahydroisoquinolines
(THIQs 2a−d; Figure 1) are important heterocyclic
structural motif in many biologically active natural products
and have become attractive synthetic targets.
I
Literature on existing approaches toward isoindolinone
1
2
13
15
synthesis include Heck cyclization, Diels−Alder approach,
14
ring closure of hydrazones, reactions of acyliminium ion,
exploitation of carbanion methodology, and various enantio-
16
17,18
selective approaches
developed very recently. On the other
hand, synthesis of THIQs involves various multistep pro-
11,19
20
cesses
and few enantioselective processes. Although few
elegant approaches to these targets have been reported, there is
still a need to develop a straightforward synthesis of
isoindolinones and THIQs employing a unified strategy from
readily available simple starting materials. Toward this, we
recently reported an efficient allylation−lactamization/alkyla-
21
tion cascade in the synthesis of THIQ alkaloid (±)-crispine A
2a). Herein, we envision an expeditious approach to these
(
Figure 1. Selected important isoindolinones and THIQs.
targets following a domino Ni-catalyzed highly stereo- and
regioselective homoallylation of aldimines of o-formyl benzoates
3
and o-formyl arylacetates 4 using 1,3-dienes 5 promoted by
compounds from a synthetic perspective. Many isoindolinones
are useful advanced intermediates in the synthesis of a variety of
drug molecules and complex natural products. Because of their
Et Zn to afford isoindolinones 7−8 and isoquinolinones 9,
2
22
respectively (Scheme 1). Due to the low nucleophilicity and
difficult availability of homoallyl metal species, unlike allylmetals,
homoallylation has been less pursued. However, in the past
decade, it is becoming an emerging method for the formation of
1
2
3
interesting biological properties, such as antihypertensive,
4
5
6
7
antipsychotic, anti-inflammatory, anesthetic, antiulcer, vaso-
8
9
10
dilatory, antiviral, and antileukemic activities, these hetero-
cyclic scaffolds are considered to be attractive synthetic targets.
On the other hand, a wide variety of tetrahydroisoquinolines
23a−e
C−C bonds as evident from Tamaru’s work.
intended to explore the homoallylation strategy in the synthesis
of isoindolinones and isoquinolinones.
Hence, we
1
1
(
THIQs 2a−d) with interesting architecture have been
isolated from different sources. Due to their fascinating biological
activities, THIQs also are of special synthetic interest. Needless
to say, isoindolinones and THIQs constitute a common
Received: October 9, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Working Hypothesis
Scheme 2. Effect of Different Aromatic Amines on
Isoindolinone Synthesis
a
Following a Ni(acac) catalyzed and diethylzinc mediated
2
2
3
domino homoallylation, we set forth to investigate the
potential synthesis of isoindolinones 7−8 and isoquinolinones
9
starting from simple o-formyl benzoates 3 and o-formyl
arylacetates 4 (Scheme 1). We started our optimization studies
by using o-formyl methylbenzoate (3a), p-methoxyphenylamine
(
6a), and diene 5a in the presence of Ni(acac) and Et Zn to
2 2
identify the standard conditions (Table 1). We used p-
a
Table 1. Selected Optimization Studies of Domino Process
a
Reactions were carried out on a 1.0 mmol of each 3a and amine 6 in
the presence of 4.0 equiv of diene 5a in 3 mL of solvent at indicated
temperature. Isolated yields after column purification are shown. dr’s
Ni(acac)2
(mol %)
Et Zn
temp
(°C)
7a
(%)
2
b
c
no.
(equiv)
solvent
dr
1
were determined from H NMR of crude materials.
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
5
3.5
3.5
3.5
2.2
3.0
3.5
3.5
3.5
3.5
3.5
1.8
THF
THF
THF
THF
THF
0−25
0
88
78
93
6.2:1
4.8:1
4.0:1
ND
25
dimethylaniline, 3,4-methylenedioxy aniline, and 3,4,5-trime-
thoxyaniline, were excellent amine partners for the domino
process to afford isoindolinones 7f−h in up to 91% yields with a
maximum of 6.7:1 dr. m-Chloroaniline afforded 7i in 79% yield
with 5.8:1 dr. Interestingly, some anomality was observed in the
case of o-substituted anilines, such as 2-methoxy aniline. Instead
of the desired terminal attack by diene, an internal attack is
observed. This afforded isoindolinone 7j in excellent dr (>20:1)
albeit in low yield (33%), probably indicating that sterics play an
important role in the one-pot homoallylation/lactamization
process.
We further expanded the substrates scope of the domino one-
pot homoallylation/lactamization using a variety o-formyl
benzoates 3 having different electronic properties (Scheme 3).
o-Formyl benzoates 3 having different halogen functionalities
afforded products 7k and 7n−o in synthetically viable yields with
up to 10:1 dr.
d
0−25
0−25
0−25
0−25
0−25
0−25
0−25
0−25
43
90
92
89
96
93
85
72
4.0:1
5.5:1
3.4:1
6.0:1
5.4:1
6.2:1
6.0:1
Et O
2
DME
PhMe
p-xylene
PhMe
PhMe
1
1
0
1
5
a
Reactions were carried out on 1.0 mmol of 3a and PMP-NH 6a in
the presence of 4.0 equiv of diene 5a, 3.5 equiv of Et Zn, and 10 mol
%
yields after column purification. dr’s were determined from H NMR
of crude materials. Decomposition of the rest of the mass balance.
CCDC number of 7a: 1427165 [see Supporting Information for
details].
2
2
b
of Ni(acac) in 3 mL of solvent at indicated temperature. Isolated
2
c
1
d
methoxyphenylamine (PMPNH , 6a) as an amine component
It was also observed that substrate 3 sharing a phenyl ring was
also a good substrate, which afforded products 7l and 7m in up to
76% yields with up to 5.9:1 dr. Substrate 3 having highly electron-
rich functionality furnished 7p−q in 75% and 62% yield
respectively with up to 4.3:1 dr. On the other hand, substrates
2
so as to obtain PMP-protected compound 7a, which in turn can
furnish an N-protecting group free isoindolinone via oxidative
1
8,21,24
cleavage.
Following exhaustive optimization, it was found
that domino homoallylation/lactamization can be realized in the
presence of 10 mol % Ni(acac) and 3.5 equiv of Et Zn in toluene
bearing electron-withdrawing groups (e.g., 5-NO , 4-CN of 3 in
2
2
2
at 0−25 °C to afford 7a in 96% yield with 6:1 dr (standard
conditions: entry 8). Gratifyingly, the reaction operates without
removing water produced during condensation of o-formyl
methylbenzoate (3a) and p-methoxyphenylamine (6a).
With the standard conditions in hand, we explored the
synthetic viability of the domino homoallylation/lactamization
process using o-formyl methylbenzoate (3a) and isoprene (5a),
with a variety of aromatic amines. Scheme 2 demonstrates the
scope of the reaction encompassing different kinds of aromatic
amines to provide isoindolinones 7b−j. Aromatic amines having
electron-deficient as well as electron-rich substituents afforded
products 7b−e in high yields with a maximum of 5.9:1 dr. It was
noteworthy that other electron-rich aromatic amines, such as 3,4-
Scheme 3) failed to provide the desired product, giving a
complex mixture.
Next, different dienes were also employed under standard
conditions, which furnished products in good to excellent yields.
Cyclohexane-1,3-diene afforded 8a in 58% yield with excellent dr
(>20:1; Scheme 4). The reaction is highly regioselective in
nature, where β-myrcene afforded isoindolinones 8b−c in 73−
98% yield (dr up to 7.1:1). A diene consisting of an aromatic ring
viz. trans-1-phenyl-1,3-butadiene also provided the desired
product 8d.
In a few cases, an anomalous reaction was observed during the
reaction. o-Methoxy aniline furnished reductive amination
product 10b (Scheme 5) along with 7j (Scheme 2). In fact,
B
DOI: 10.1021/acs.orglett.5b02932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope of Isoindolinone Synthesis
Scheme 6. Effect of Different Aromatic Amines on
Isoquinolinone Synthesis
a
a
See Scheme 2 footnote for details.
a
a
Reactions were carried out on a 1.0 mmol of each 4a and amine 6 in
the presence of 4.0 equiv of diene 5a in 3 mL of solvent at indicated
temperature. Isolated yields after column purification are shown. dr’s
Scheme 4. Isoindolinone Synthesis with Varied Dienes
1
were determined from H NMR of crude materials.
Scheme 7. Synthetic Elaboration of Domino Product
a
See Scheme 2 footnote for details.
Scheme 5. Reductive Amination under Optimized Condition
to afford 11 in quantitative yield. Again, 7a was converted to
aldehyde 13 via oxidative cleavage of terminal olefin. In another
sequence, we have also shown that deprotection of PMP group of
7a can be carried out to obtain free amide 12 (Scheme 7), which
reductive amination was prominent when an aliphatic amine was
further transformed to 14 in 73% yield, via reductive ozonolysis.
In conclusion, domino Ni-catalyzed regio- and stereoselective
homoallylation/lactamization of aldimines (in situ) of o-formyl
benzoates 3 and aromatic amines has been developed. The
salient features of this process are the highly regio- and
stereoselective nature to provide 1,3-syn-selectivity, the reaction
is completed at room temperature, diverse substrates with
electron-donating and -withdrawing functionality can give
satisfactory results, and the reaction can be operated on a gram
scale (see Supporting Information for details). Further, we have
explored the method for stereoselective synthesis of isoquino-
linones from aldimine prepared from o-formyl arylacetate 4a. We
believe that an enantioselective version of this method would
serve as a potential strategy to access isoindolinones and
isoquinolinones in an enantioenriched form. These are under
active investigation in our laboratory.
used as a coupling partner yielding N-benzylisoindolin-1-one
(
10a), clearly indicating that the basicity/nucleophilicity of
amine partners play a crucial role in switching the reactivities.
Later, the subset of tetrahydroisoquinolines (THIQs; Figure
1
) which constitute a common structural motif in many
biologically active alkaloids drew our attention. We reasoned
that isoquinolinones can play a crucial role in synthesizing a
variety of THIQs via synthetic manipulations. Thus, Ni-catalyzed
domino homoallylation/lactamization of imines prepared from
o-formyl arylacetate 4a and amine 6 with conjugated diene 5a
promoted by diethylzinc was carried out further (Scheme 6).
Delightfully, a variety of isoquinolinones 9a−f with various
amide functionalities were synthesized under the standard
conditions in synthetically useful yields with up to 2.5:1 dr. We
believe that these compounds have the potential for the synthesis
of a range of advanced intermediates for the total synthesis of
isoquinoline alkaloids.
ASSOCIATED CONTENT
Supporting Information
With a synthetically viable route to the isoindolinones and
isoquinolinones in hand, we were inclined to elaborate these
compounds to the various synthetic intermediates (Scheme 7).
Toward this end, we performed hydrogenation of compound 7a
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02932.
C
DOI: 10.1021/acs.orglett.5b02932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Experimental procedures and analytical data ( H, 13C
NMR spectra and HRMS) for all new compounds (PDF)
X-ray data for 7a (CIF)
1
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AUTHOR INFORMATION
■
*
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60, 1247. (b) Chen, M.-D.; Zhou, X.; He, M.-Z.; Ruan, Y.-P.; Huang, P.-
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L.-Y.; Li, C.-J. Can. J. Chem. 2012, 90, 92.
Corresponding Author
E-mail: vinodks@iitk.ac.in.
Present Address
∥Department of Chemistry, Indian Institute of Science
Education and Research Tirupati, Karakambadi Road, Man-
galam, Tirupati - 517 507, Andhra Pradesh, India.
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ard-Viret, J.; Prange, T.; Tomas, A.; Royer, J. Tetrahedron 2002,
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Author Contributions
§R.K. and A.S. contributed equally.
Notes
(18) (a) Bisai, V.; Suneja, A.; Singh, V. K. Angew. Chem., Int. Ed. 2014,
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3, 10737. (b) Bisai, V.; Unhale, R. A.; Suneja, A.; Dhanasekaran, S.;
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The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
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Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87 and references
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■
Financial support through the J. C. Bose fellowship (DST,
Government of India) and SERB, DST (SB/FT/CS-011/2014)
are gratefully acknowledged. A.S. thanks the CSIR, New Delhi for
SRF fellowship. R.K. and V.B. thank the Department of
Chemistry, IISER Bhopal for infrastructure. We thank Mr. Lalit
M. Jha, IISER Bhopal, for single crystal XRD analysis.
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DOI: 10.1021/acs.orglett.5b02932
Org. Lett. XXXX, XXX, XXX−XXX