Approach to Isoindolinones, Isoquinolinones, and THIQs via Lewis Acid-Catalyzed Domino Strecker-Lactamization/Alkylations

Article abstract of DOI:10.1021/acs.orglett.5b03331

A one-pot, three-component synthesis of widely substituted isoindolinones and isoquinolinones, featuring a Lewis acid-catalyzed efficient Strecker reaction and lactamization sequence, affording products in good to high yields is reported. The method has also been extended to the synthesis of tetrahydroisoquinolines (THIQs) in high yields. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b03331

Letter
pubs.acs.org/OrgLett
Approach to Isoindolinones, Isoquinolinones, and THIQs via Lewis
Acid-Catalyzed Domino Strecker-Lactamization/Alkylations
Sivasankaran Dhanasekaran,†,§ Arun Suneja,‡,§ Vishnumaya Bisai,‡,¶ and Vinod K. Singh*,†,‡
‡Department of Chemistry, Indian Institute of Science Education and Research, Bhopal, MP - 462 066, India
†Department of Chemistry, Indian Institute of Technology, Kanpur, UP - 208 016, India
S
* Supporting Information
ABSTRACT: A one-pot, three-component synthesis of
widely substituted isoindolinones and isoquinolinones, featur-
ing a Lewis acid-catalyzed efficient Strecker reaction and
lactamization sequence, affording products in good to high
yields is reported. The method has also been extended to the
synthesis of tetrahydroisoquinolines (THIQs) in high yields.
soindolinones are an important class of heterocycles found
in many biologically active natural products1 and are also
synthesize them applying a general catalytic route. To this
end, recently, we reported the Lewis acid-catalyzed allylation-
lactamization domino process25 for synthesis of diversely
substituted isoindolinones and THIQs. Herein, we report a
practical approach to isoindolinones, isoquinolinones, and
THIQs via a Lewis acid-catalyzed domino Strecker-lactamiza-
tion/alkylations of readily available o-formyl methylbenzoates,
o-formyl methylarylacetates, and o-formyl arylethyl bromides
(Scheme 1).
I
useful intermediates in the synthesis of a variety of drug
molecules2 (1a−b; Figure 1) having important biological
Scheme 1. Proposed Strecker-Lactamization/Alkylations
Figure 1. Selected active isoindolinones and THIQs.
activities such as antihypertensive,3 antipsychotic,4 anti-
inflammatory,5 anesthetic,6 antiulcer,7 vasodilatory,8 antiviral,9
and antileukemic10 agents. In addition, a few members of this
class are known to have platelet aggregation inhibitory activity11
and are shown to induce dose-dependent p53-dependent gene
transcription in MDM2-amplified SJSA human sarcoma cell
lines.12 On the other hand, tetrahydroisoquinolines13 (THIQs)
(2a−g; Figure 1) are widespread in nature and have interesting
biological activities. They are also found to be the building
blocks for synthesis of many complex alkaloids.14
Approaches in literature for isoindolinone synthesis include
Heck cyclization,15 Diels−Alder approach,16 ring-closure of
hydrazones,17 reactions of acyliminium ion,18 exploiting
carbanion methodology,19 and various enantioselective ap-
proaches20 including our recent domino21 Cu(I)-catalyzed
enantioselective propargylation/lactamization and organocata-
lytic Mannich/lactamization sequence.22 On the other hand,
synthesis of isoquinolines involves various diastereoselective
processes13c,23 and catalytic enantioselective processes.21,24
Although some elegant approaches to these targets have been
reported, still there exist a fewer number of reports to
At the outset, optimization of domino Strecker-lactamization
was performed by taking 1.0 equiv of each ester-aldehyde 3a
and PMPNH2 (p-anisidine) with 1.5 equiv of TMSCN without
any catalyst. We found that only Strecker product 10a was
formed in 28−42% yields, and no trace of isoindolinone 4a
were observed (Scheme 2). Following extensive optimization, it
was found that 10 mol % of Zn(OTf)2 and In(OTf)3 each
afforded 4a in 93% yield (condition A) and 91% yield
(condition B), respectively, when 1.0 equiv of TFA was used
(see the SI for details).
Scheme 2. Domino Strecker-Lactamization Process
Received: November 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03331
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a c
Scheme 4. Substrate Scope of Isoindolinone Synthesis −
With optimized conditions, a variety of amines such as
aromatic, aliphatic, and amine having an electron-withdrawing
group (Cbz-NH2) were studied. To our delight, various
aromatic amines, such as aniline, o-methoxyphenyl (OMP), p-
thiomethoxyphenyl (PTMP), 3,4-methylenedioxyphenyl, 3,4-
dimethoxyphenyl, 3,5-dimethylphenyl, and p-bromophenyl, all
afforded expected Strecker-lactamization products 4b−h in up
to 95% yield (Scheme 3) under conditions A and B. It is
a c
Scheme 3. Scope of Reaction with Various Amines −
a
b
Condition A: 10 mol % Zn(OTf)2. Condition B: 10 mol %
c
In(OTf)3. 1.0 equiv of TFA was used after 12 h as additive. LA =
Lewis acid, TFA = trifluoroacetic acid.
p-position of aldehyde such as 3b−d, all afforded products 6a−
c in high yields (Scheme 4).
Methyl o-formyl benzoates having cyano substitution at the
p-position of an ester such as 3e also afforded products 6d−f in
good to excellent yields (Scheme 4). Importantly, less reactive
methyl o-formyl benzoates having the −OMe group as an
electron-rich substituent at the p-positions of aldehyde, such as
3f−i, also underwent a domino Strecker-lactamization sequence
efficiently to afford 6g−r in synthetically viable yields (Scheme
4).
Having secured the synthesis of isoindolinones, we
attempted a one-pot, three-component synthesis of isoquino-
linones using various amine partners as per our hypothesis
(Scheme 1). As most of the naturally occurring THIQ alkaloids
contain the dimethoxy substituent, we explored the possibility
of the formation of domino Strecker-lactamization using o-
formyl methylarylacetate 5 (Scheme 5). To our delight, we
were able to synthesize a variety of isoquinolinones 7a−e in
synthetically useful yields, following our optimized conditions A
and B (Scheme 5).
a
b
Condition A: 10 mol % Zn(OTf)2. Condition B: 10 mol %
c
In(OTf)3. 1.0 equiv of TFA was used after 12 h as an additive. LA =
Lewis acid, TFA = trifluoroacetic acid.
important to note that isoindolinones with N-aryl groups
having electron-donating groups (such as 4a, 4c−d, and 4g−h)
in the ring can be cleaved under oxidative conditions so as to
obtain free amines.26 To our surprise, in the case of o-
bromophenylamine, we could only isolate the expected
isoindolinone in 21% yield, where uncyclized benzylamine 4j
was obtained in 57−60% yields. We speculate that this could be
because of the −I effect of the −Br group at the ortho-position
of the aryl ring, which hampers the formation of isoindolinone
(Scheme 3).27
Then, we turned our attention to domino Strecker-
lactamization using an aliphatic amine having easily removable
groups such as allyl and benzyl. Gratifyingly, under optimized
conditions we were able to synthesize isoindolinones 4k−l
having N-allyl and N-benzyl protecting groups in 80−92%
yields. We also used CbzNH2 as a protected amine source
having an electron-withdrawing group;28 however, to our
displeasure, we were not able to assess expected isoindolinone
4m, and this led to a multitude of spots on the TLC, indicating
the nucleophilicity of amines plays a crucial role in the domino
Strecker-lactamization process.
a c
Scheme 5. Substrate Scope of Isoquinolinone Synthesis −
a
b
Condition A: 10 mol % Zn(OTf)2. Condition B: 10 mol %
c
In(OTf)3. 1.0 equiv of TFA was used after 12 h as additive. LA =
Further, we investigated the substrate scope of domino
Strecker-lactamization using different amines viz. aniline (R =
Ph), p-methoxyphenylamine (R = PMP), and p-thiomethox-
yphenylamine (R = PTMP) with various o-formyl benzoates
under optimized conditions A and B (Scheme 4). Gratifyingly,
it was found that various o-formyl benzoates such as 3b−i are
suitable substrates under optimized conditions. In the presence
of 10 mol % Zn(OTf)2 (condition A) and In(OTf)3 (condition
B) followed by treatment with 1.0 equiv of TFA as an additive,
these o-formyl benzoates afforded a variety of products having
N-aryl groups in synthetically viable yields. Methyl o-formyl
benzoates, having bromo, phenyl, and nitro substitution at the
Lewis acid, TFA = trifluoroacetic acid.
Further, we thought to apply the domino Strecker-N-
alkylation sequence for the synthesis of tetrahydroisoquinolines
(THIQs). Toward this, a few o-formyl phenethyl bromides 8a−
c were employed in the domino Strecker-N-alkylation which
afforded a variety of N-protected THIQs 9a−l in 70−92%
yields (Scheme 6). Interestingly, in these cases an additive
(TFA) is not required, thus indicating SN2 type N-alkylation is a
faster process than a lactamization (Schemes 3−5).
B
DOI: 10.1021/acs.orglett.5b03331
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Scheme 6. Substrate Scope Using Various Bromo
Aldehydes
Scheme 8. Synthesis of ( )-PZQ 2a and ( )-Calycotomine
2d
a b
,
a
b
Condition A: 10 mol % Zn(OTf)2. Condition B: 10 mol %
In(OTf)3.
Scheme 9. Synthesis of Tetracyclic Structures 16a−b and
17a−b
The domino Strecker-lactamization was also carried out on a
1.0 g scale of o-formyl methylbenzoates 3a and o-formyl
arylacetate 5 under condition A, which afforded products 4a,
7b, and 7d in 90%, 78%, and 93% yields, respectively (see the
SI for details). Similarly, a gram scale reaction of
bromoaldehyde 8b with p-methoxyphenylamine and 8a with
benzylamine under condition A afforded THIQs 9d and 9b in
76% and 78% yields, respectively (see the SI for details).
To show versatility, compounds 4l and 7d were treated
under hydrogenolysis separately to obtain amine compounds
11a and 11c in 60% and 67% yields, respectively (Scheme 7),
Scheme 7. Synthetic Elaborations
(2g) (Figure 1). In these transformations, we have shown that
Friedel−Crafts type C−C bond-forming reactions can be
performed on nitrile functionality.
In conclusion, we report a Lewis acid-catalyzed highly
efficient domino Strecker-lactamization for the synthesis of
isoindolinones and isoquinolinones. The reaction itself is
operationally simple and proceeds under mild conditions to
afford isoindolinones with high yields. A variety of valuable
intermediates have been synthesized utilizing the aforemen-
tioned method. Further exploration of the enantioselective
version of this process is currently under active investigation.
where N-benzyl groups were found to be untouched. We also
reacted compounds 4a and 7b in the presence of aqueous
H2SO4 to afford carboxamides 12a and 12b in 62% and 75%
yields, respectively (Scheme 7). Esters 13a and 13b can be
obtained from 4a and 7b, respectively, when reactions were
carried out in MeOH. Oxidative cleavage of the PMP group can
simply be accomplished with CAN to afford isoindolinone 13c
(Scheme 7). Later, synthesis of the anthelmintic drug
( )-praziquantel 2a29 and alkaloid ( )-calycotomine 2d13d
has been accomplished from 9b and 7d via intermediacy of 14a
and 13d, respectively (Scheme 8).
Nevertheless, Lewis acid-catalyzed domino Strecker-lactam-
ization was applied for the synthesis of isoindolinones 6s−t,
which on subsequent treatment with triflic acid (TfOH)
afforded tetracyclic structures 16a−b (Scheme 9), resembling
the core structure of lennoxamine 1b (Figure 1). Along similar
lines isoquinolinones 7f−g can also be utilized for the synthesis
of tetracyclic structures 17a−b (Scheme 9), which are common
structural features of the protoberberine alkaloid, xylopinine
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03331.
Experimental procedures and analytical data (1H, 13C
NMR spectra and HRMS) for all new compounds
(PDF)
CIF file of 4a (CIF)
CIF file of 9d (CIF)
C
DOI: 10.1021/acs.orglett.5b03331
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vinodks@iitk.ac.in.
Present Address
¶Department of Chemistry, Indian Institute of Science
Education and Research Tirupati, Tirupati - 517 507, Andhra
Pradesh, India.
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Author Contributions
§S.D. and A.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support through the SERB, DST (EMR/2014/
001165) is gratefully acknowledged. We thank Ms. Anusha
Upadhyay, IISER Bhopal for X-ray structure analysis. S.D. and
A.S. thank the CSIR, New Delhi for fellowships (SRF).
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