A general catalytic route to isoindolinones and tetrahydroisoquinolines: Application in the synthesis of (±)-crispine A

Article abstract of DOI:10.1021/ol502842f

An unprecedented highly efficient Lewis acid catalyzed one-pot cascade has been demonstrated as a general catalytic system for the synthesis of diversely substituted isoindolinones and tetrahydroisoquinolines. The cascade effects one C-C and two C-N bond-

Full text of DOI:10.1021/ol502842f

Letter
pubs.acs.org/OrgLett
A General Catalytic Route to Isoindolinones and
Tetrahydroisoquinolines: Application in the Synthesis of
( )-Crispine A
Sivasankaran Dhanasekaran,† Vishnumaya Bisai,‡ Rajshekhar A. Unhale,‡ Arun Suneja,‡
and Vinod K. Singh*,†,‡
†Department of Chemistry, Indian Institute of Technology Kanpur-208 016, UP, India
‡Department of Chemistry, Indian Institute of Science Education and Research Bhopal-462 066, MP, India
S
* Supporting Information
ABSTRACT: An unprecedented highly efficient Lewis acid catalyzed one-pot cascade has been demonstrated as a general
catalytic system for the synthesis of diversely substituted isoindolinones and tetrahydroisoquinolines. The cascade effects one C−
C and two C−N bond-forming events in one pot. Several interesting transformations of the products into valuable synthetic
intermediates are featured with the successful total synthesis of ( )-crispine A.
soindolinone- and tetrahydroisoquinoline-based N-hetero-
cyclic scaffolds comprise the key structural feature of a wide
range of synthetically and biologically active molecules (1 and 2;
active natural products and pharmaceuticals.10 Although there
are several reports in the literature for the synthesis of these
compounds11−13 there exists no precedence to access both of
these two important classes of compounds employing a more
generalized and common catalytic system in one-pot. To address
this, we propose herein a practical approach to isoindolinones
and tetrahydroisoquinolinones using a Lewis acid catalyzed one-
pot three-component allylation−lactamization cascade of readily
available o-formyl methyl benzoates and o-formyl methyl
arylacetates as shown in Scheme 1.14
I
Figure 1). 3-Alkyl-2,3-dihydro-1H-isoindolin-1-ones 1a−d man-
In order to determine what structural parameters affect catalyst
performance and to ultimately identify a more efficient catalyst,
we performed a systematic optimization of a one-pot three-
component allylation−lactamization cascade using various Lewis
acids with methyl 2-formyl benzoate (3a), p-methoxyaniline, and
Scheme 1. Proposed One-Pot Cascade
Figure 1. Selected isoindolinones and tetrahydroisoquinolines.
ifest activities such as antihypertensive,1 antipsychotic,2 anti-
inflammatory,3 anesthetic,4 antiulcer,5 vasodilatory,6 antiviral,7
and antileukemic8 and are also used in the synthesis of various
drugs.9
On the other hand, 1-substituted 1,2,3,4-tetrahydroisoquino-
lines 2a−d are immensely prominent in diverse biologically
Received: September 26, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
allyltributylstannane (see the Supporting Information for
details).
We then looked forward to the possible substrate scope of our
one-pot strategy with diversely substituted o-formyl methyl
benzoates possessing an entirely different electronic and steric
environment. Interestingly, it was found that various o-formyl
methyl benzoates such as 3b−i undergo the one-pot cascade
without event to afford products 5a−l in synthetically viable
yields (Scheme 3). The X-ray crystal structure of compound 5a is
shown in Figure 2.
Exhaustive optimization studies in various solvents with
different mol % of various metal triflates as Lewis acids (see
the Supporting Information for details) at 35 °C indicated that
10 mol % of Cu(OTf)2, Zn(OTf)2, Sn(OTf)2, Sc(OTf)3, and
In(OTf)3 afforded allylation−lactamization product 4a in 88%,
90%, 71%, 68%, and 93% yields, respectively (entries 1−5, Table
1, Supporting Information) in chloroform. Based on these
observations, we eventually set forth with two best conditions for
further studies viz. 10 mol % of In(OTf)3 (conditions A) and
Zn(OTf)2 (conditions B).
Scheme 3. Reaction Scope with Different Substrates
Next, a variety of amines were studied under optimized
conditions in the allylation/lactamization cascade. To our
delight, almost all aromatic amines such as aniline, o-
methoxyphenyl (OMP), p-(thiomethoxy)phenyl (PTMP), 3,4-
(methylenedioxy)phenyl, 3,4-dimethoxyphenyl, 3,5-dimethyl-
phenyl, and p-bromophenyl afforded the required product 4b−
h in up to 93% yields (Scheme 2) applying conditions A and B. It
a
Scheme 2. Scope of Reaction with Various Amines
a
All of the reactions were performed with 1 equiv each of aldehyde,
amine, and allyltributylstannane (ratio of 1:1:1.5).
Figure 2. X-ray crystal structure of compound 5a.
is important to note that isoindolinones with N-aryl groups
having electron-donating groups (such as 4a and 4c−f) can easily
be cleaved under oxidative conditions.15
Having secured the synthesis of a wide range of isoindolinones,
we next attempted a one-pot, three-component synthesis of
isoquinolinones using PMPNH2 as per our hypothesis (Scheme
1) with o-formyl methyl arylacetates. However, in this case, the
cascade was not facilitated and the reaction stopped at the
allylation step to afford solely uncyclized product 8 in excellent
yields. Nevertheless, one can utilize amino ester 8 to access a
diverse array of tetrahydroisoquinoline alkaloids following a two-
step synthetic protocol viz. reduction of ester in the presence of
LiAlH4 followed by mesylation and nucleophilic displacement
(Scheme 4).13
In the case of o-bromoaniline, instead of the expected
isoindolinone, we obtained the uncyclized benzylamine 4i as a
sole product in 86−90% yields. This might be due to the bulky
Br-substituent at the ortho-position, which hampers the
formation of isoindolinone (Scheme 2). This is probably also
responsible for an inefficient reaction in the case of o-
methoxyaniline (see 4c). Further, we tested easily removable
aliphatic amines such as allyl and benzyl for the one-pot cascade.
Gratifyingly, isoindolinones 4j−k having N-allyl and N-benzyl
protecting groups were successfully obtained in 73−85% yields.
CbzNH2 as amine source,16 however, led to a multitude of spots
on TLC, indicating nucleophilicity of amines plays a crucial role
in the allylation−lactamization cascade.
The hunt for a more suitable substrate which could install the
tetrahydroisoquinoline skeleton directly in one pot made us see
the application of our catalytic protocol on substituted o-
formylphenethyl bromides 11a−c (Scheme 5), which may follow
B
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Organic Letters
Letter
Scheme 4. One-pot three-component allylation of 6
Scheme 6. Synthesis of Useful Synthetic Intermediates
Scheme 7. Total Synthesis of ( )-Crispine A and Related
Structures
Scheme 5. Scope of Reaction with Various Bromoaldehydes
synthesis of 3,4-dihydroisoquinolinium salts which act as
fungicides for treating skin infections.17 Further, N-deprotected
tetrahydroisoquinoline 15 was obtained in 87% yield by
debenzylation. Eventually, we applied our catalytic protocol in
the synthesis of ( )-crispine A18a (Figure 1, 2a) following a
three-step sequence viz. hydroboration−oxidation, tosylation,
and N-debenzylation-cyclization in overall 66% yield. In
addition, compound 16 could serve as an advanced intermediate
for the synthesis of crispine C (2c) and crispine E (2d) after
simple synthetic elaboration.18b
Further utility of the method has been shown by exploiting the
reactivity of the olefinic moiety through ring-closing metathesis
(RCM)19 to construct synthetically useful N-heterocycle
benzodehydro[a]quinolizidine20 17 in good yield (Scheme 8).
an allylation−N-alkylation cascade to effect this cyclization.
Interestingly, these aldehydes, when employed in a one-pot,
three-component allylation−N-alkylation cascade, led to a
straightforward access to a variety of N-protected tetrahydroi-
soquinolines in 75−96% yields as shown in Scheme 5. In this
process, we found that 10 mol % of Cu(OTf)2 (conditions C) is a
better choice than 10 mol % Zn(OTf)2 (conditions B) in
addition to 10 mol % of In(OTf)3 (conditions A). In this case
also, three different easily removable amines viz. p-methoxyani-
line, allylamine, and benzylamine were used to ultimately utilize
the products for the synthesis of biologically active tetrahy-
droisoquinoline (THIQ) alkaloids. Under optimized conditions
A and C, products 12a−g were obtained in good to excellent
yields (Scheme 5).
Scheme 8. Synthetic Elaborations via RCM
Next, to illustrate the synthetic viability of our methodology,
we converted the isoindolinones 4 and tetrahydroisoquinolines
12 into various synthetically useful intermediates. Toward this,
the olefinic functionality of the allyl group was converted into an
aldehyde and alcohol functionality following ozonolysis and
reductive ozonolysis, respectively (see 13a and 13c, Scheme 6).
The N-protecting PMP group of 4b was oxidatively cleaved using
ceric ammonium nitrate (CAN) to afford 13b in 95% yield
(Scheme 6). In another sequence, hydrogenation of the double
bond and cleavage of N-PMP group afforded 13d in 91% yield
over two steps.
In conclusion, we report a highly efficient Lewis acid catalyzed
one-pot cascade process for the synthesis of isoindolinones as
well as tetrahydroisoquinolines applying a common catalytic
route. The reaction is operationally simple and proceeds under
mild conditions in high yields. The methodology has been
successfully exploited in the synthesis of ( )-crispine A and
related structures. The usefulness of the methodology has also
been demonstrated by cleavage of N-PMP and N-benzyl groups
and exploiting the unique reactivity of the double bond
functionality. Further synthetic exploration toward the enantio-
selective variant of this strategy is currently under active
investigation and will be reported in due course.
Interestingly, an attempt at oxidative removal of N-PMP in the
presence of 4.0 equiv of ceric(IV)ammonium nitrate, after
hydrogenation of 12b, led to aromatized isoquinoline moiety 14
(Scheme 7) which could serve as an important synthon for the
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
General experimental procedures and analytical data for all new
compounds and crystallographic data file (CIF) for 5a. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
S
(13) (a) Sun, L. X.; Zeng, T.; Jiang, D.; Dai, L.-Y.; Li, C.-J. Can. J. Chem.
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2014, 53, 10737.
AUTHOR INFORMATION
Corresponding Author
■
(14) For allylation of aldehydes and imines, see: (a) Lu, J.; Hong, M.-
L.; Ji, S.-J.; Loh, T.-P. Chem. Commun. 2005, 1010. (b) Lu, J.; Hong, M.-
L.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Chem. Commun. 2005, 4217. (c) Lu, J.;
Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 159. (d) Itoh, T.;
Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8,
1295. (e) Wei, X. N.; Liu, L. Y.; Wang, B.; Chang, W. X.; Li, J. Chin.
Chem. Lett. 2009, 20, 40. (f) Naodovic, M.; Wadamoto, M.; Yamamoto,
H. Eur. J. Org. Chem. 2009, 5129.
(15) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409. (b) Fu, P.; Snapper, M. L.; Hoveyda,
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*E-mail: vinodks@iitk.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.K.S. thank the DST, Government of India, for generous
financial support through the J. C. Bose Fellowship. Research
facilities by Indian Institute of Technology Kanpur and Indian
Institute of Science Education and Research Bhopal are gratefully
acknowledged. D.S., R.A.U., and A.S. thank the CSIR, New
Delhi, for SRF, SPM, and JRF Fellowships. We sincerely thank
Mr. Dhananjay Dey and Dr. Deepak Chopra, IISER Bhopal, for
assistance with X-ray crystallography.
(17) (a) Kido, K.; Watainabe, Y. Chem. Pharm. Bull. 1987, 35, 4964.
(b) Jungho, K.; Sangphil, L.; Junyoung, C.; Youngki, P.; Yousuk, L.;
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(19) (a) Chandra, K. L.; Chandrasekhar, M.; Singh, V. K. J. Org. Chem.
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DEDICATION
■
This work is dedicated to Professor Kankan Bhattacharyya on the
occasion of his 60th birthday.
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