Unified approach to isoindolinones and THIQs via lewis acid catalyzed domino mukaiyama-mannich Lactamization/Alkylations: Application in the synthesis of (±)-homolaudanosine

Article abstract of DOI:10.1021/acs.orglett.5b01197

A novel and efficient synthesis of a variety of isoindolinones and tetrahydroisoquinolines via a Lewis acid catalyzed domino Mukaiyama-Mannich lactamization/alkylation is achieved. This transformation comprises a sequential formation of three new bonds through a one-pot, three-component procedure to afford product in moderate to high yields. A concise synthesis of (±)-homolaudanosine (2b) has been achieved using this method.

Full text of DOI:10.1021/acs.orglett.5b01197

Letter
pubs.acs.org/OrgLett
Unified Approach to Isoindolinones and THIQs via Lewis Acid
Catalyzed Domino Mukaiyama−Mannich Lactamization/Alkylations:
Application in the Synthesis of ( )-Homolaudanosine
Sivasankaran Dhanasekaran,§ Anirban Kayet,† 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 novel and efficient synthesis of a variety of isoindolinones and tetrahydroisoquinolines via a Lewis acid catalyzed
domino Mukaiyama−Mannich lactamization/alkylation is achieved. This transformation comprises a sequential formation of
three new bonds through a one-pot, three-component procedure to afford product in moderate to high yields. A concise
synthesis of ( )-homolaudanosine (2b) has been achieved using this method.
eterocyclic compounds like isoindolinones (1a−d; Figure
1) and tetrahydroisoquinolines (THIQs 2a−d; Figure 1)
hydrazones,14 reactions of acyliminium ion,15 exploitation of
carbanion methodology,16 and various enantioselective ap-
proaches.17,18 On the other hand, synthesis of THIQs involves
various multistep processes11,19 and few enantioselective
processes.20 Although few elegant approaches to these targets
have been reported, there is still a need to develop a
straightforward synthesis of isoindolinones and THIQs employ-
ing a common strategy from cheaply available simple starting
materials. Toward this end, we recently reported an efficient
allylation−lactamization/alkylation21 cascade in the synthesis of
THIQ alkaloid ( )-crispine 2a. Herein, we envisioned an
expeditious approach to these targets following a direct Lewis
acid catalyzed domino Mukaiyama−Mannich lactamization/
alkylation of o-formyl methylbenzoates 3 and o-formyl-2-
arylethyl bromide 8 to afford isoindolinones 6 and 7 and
THIQs 9, respectively (Scheme 1).22
Initially, we began our optimization studies by using o-formyl
methylbenzoate 3a and silyl enol ether 4a in the presence of
several potential catalysts to ultimately identify the most efficient
catalytic system. We used p-methoxyphenylamine (PMPNH2) as
an amine component so as to obtain PMP-protected compound
6a, which can be oxidatively cleaved,18,21,23 leading to an N-
protecting group free isoindolinone. It was observed that 10 mol
% of In(OTf)3, Zn(OTf)2, and Cu(OTf)2 afforded the expected
isoindolinone 6a in 73−77% isolated yields along with
uncyclized 10a in 10−11% (entries 1−3, Table 1). We
envisioned that conversion of 10a to 6a may depend on
H
Figure 1. Selected active isoindolinones and THIQs.
are important structural scaffolds from a synthetic perspective.
Substituted isoindolinones are useful advanced intermediates in
the synthesis of a variety of drugs1 and complex natural
products.2 Their biological properties such as antihypertensive,3
antipsychotic,4 anti-inflammatory,5 anesthetic,6 antiulcer,7 vaso-
dilatory,8 antiviral,9 and antileukemic10 activities makes them
attractive synthetic targets. Similarly, tetrahydroisoquinolines
(THIQs 2a−d)11 exist widely in alkaloids and, because of their
fascinating biological activities, they also attract special synthetic
interest.
Existing approaches toward isoindolinone synthesis include
Received: April 23, 2015
Heck cyclization,12 Diels−Alder approach,13 ring-closure of
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01197
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Organic Letters
Letter
Scheme 1. Proposed Mukaiyama−Michael Lactamization/
Alkylation
a
Table 1. Selected Optimization Studies
Figure 2. Scope of reaction with various amines.
anilines might be inhibiting the formation of isoindolinones.
Aliphatic amines such as allyl- and benzylamines were also found
to be good substrates to furnish 6h,i in 66−71% yields. However,
electron-deficient amines such as p-TsNH2 and CbzNH224 were
not suitable for the one-pot process, and only starting aldehyde
3a was recovered in 85−89% yields.
Notably, 3,4-(methylenedioxy)aniline as amine partner
afforded isoindolinone 6l only in 40−46% yields. In this case,
however, we isolated quinoline 11a in 25−28% yields under
optimized conditions. Interestingly, 3,4-dimethoxyaniline, when
used as aromatic amine, afforded quinolines 11b,c as the sole
products in 78−86% yields (Figure 3). A proposed mechanism
for the synthesis of 11a−c involving Mukaiyama−Mannich
Friedel−Crafts alkylation−condensation followed by aerial
oxidation is shown in Scheme 2.25
Lewis acid
(mol %)
time
(h)
10a (% yield) 6a (% yield)
b
b
entry
solvent
c
1
In(OTf)3 (10)
Zn(OTf)2 (10)
Cu(OTf)2 (10)
In(OTf)3 (10)
Zn(OTf)2 (10)
Cu(OTf)2 (10)
Sc(OTf)3 (10)
Bi(OTf)3 (10)
Zn(OTf)2 (5)
Cu(OTf)2 (5)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
24
24
24
35
30
28
33
28
35
35
10
11
10
0
73
77
76
76
92
90
83
85
80
79
c
2
c
3
4
5
0
6
0
7
0
8
0
9.
10
0
0
a
All of the reactions were performed with 1 equiv of aldehyde, 1 equiv
of amine, and 1.3 equiv of silyl enol ether under argon atmosphere.
b
c
Isolated yields. Reactions were carried out in the absence of TBAF.
Conditions A: 10 mol % of Zn(OTf)2. Conditions B: 10 mol % of
Cu(OTf)2.
inefficient deprotection of the N-silyl group, and thus, we
decided to use TBAF as an additive in the reaction. Following
exhaustive optimization (see the Supporting Information for
details), we found that 10 mol % of Zn(OTf)2 and Cu(OTf)2
furnished 6a in 90−92% yields (entries 5 and 6). Other metal
triflates such as In(OTf)3, Sc(OTf)3, and Bi(OTf)3 also afforded
6a in 76−85% yields (entries 4, 7, and 8). A brief solvent studies
showed that chloroform was the most efficient (see the
Supporting Information for details). Gratifyingly, it was observed
that 5 mol % of Zn(OTf)2 and Cu(OTf)2 also afforded 6a in 79−
80% yields (entries 9 and 10). On the basis of optimization
studies, it was decided to carry out further studies using 10 mol %
of Zn(OTf)2 (conditions A) and Cu(OTf)2 (conditions B) in
combination with a stoichiometric amount of TBAF as an
additive in chloroform at rt. Interestingly, a gram-scale synthesis
of 6a under conditions A also afforded product in 75% (30 h)
isolated yield (see the Supporting Information), thus making the
strategy synthetically viable.
We then studied various amines in the domino Mukaiyama−
Mannich lactamization. Gratifyingly, all aromatic amines,
including electron-donating and electron-deficient ones, afforded
isoindolinones 6b−g in 76−92% isolated yields (Figure 2). The
X-ray structure analysis of 6d (CCDC no. 1057396)
unambiguously proved the formation of an isoindolinone
motif. Surprisingly, ortho-substituted anilines afforded only
Mukaiyama−Mannich products 10b,c in 71−89% yields,
probably indicating that the sterics at the o-position of the
Figure 3. Scope of reaction with various amines.
Scheme 2. Plausible Mechanism of Quinoline Synthesis
Later, the Mukaiyama−Mannich lactamization was carried out
with differently substituted o-formyl methylbenzoate 3, silyl enol
ether 4a, and PMPNH2 under both conditions A and B (Figure
4). To our delight, a variety of o-formyl methylbenzoates
containing various electronic natures at the 4- and 5-positions of
3 (Figure 4) afforded isoindolinones 7a−h in good to excellent
yields. In addition, electron-donating groups at the 3- and 6-
positions of 3 also afforded products 7i−l in synthetically useful
yields (65−89%, Figure 4).
B
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Scheme 3. Substrate Scope of THIQ Synthesis
the synthesis of THIQs 9f,g (65−88% yields in 18 h).
Gratifyingly, 9f was synthesized in gram scale under conditions
A, which afforded THIQ in 65% (24 h) yield (see the Supporting
Information). One of these THIQs, 9f, was then converted to 13
under reductive hydrogenolysis in the presence of a Pd−C,
AcOH/TFA mixture to afford 13 in 75% yield (Scheme 3). This
was later converted to ( )-2b in 78% yield following N-
methylation using HCHO and NaBH3CN, thus completing a
concise total synthesis of ( )-homolaudanosine (2b).
Further, isoindolinones 6a and 7m were reacted with CAN to
form protecting group free 15a,b in 85−89% yield (Scheme
4).18,21 Unprotected isoindolinone 15b was converted to 17a in
Figure 4. Substrate scope of isoindolinone synthesis.
Scheme 4. Synthetic Elaborations to Important Intermediates
Next, a variety of silyl enol ethers were selected for the domino
Mukaiyama−Mannich lactamization using different o-formyl
methylbenzoates 3 and PMPNH2 (Figure 4). Rewardingly, silyl
enol ethers (see the Supporting Information for synthetic
details) of acetophenone derivatives furnished isoindolinones
7m−r in synthetically useful yields. Silyl enol ethers of acetone
afforded products 7s,t in 64−72% yields. The silyl enol ether of
methyl acetate was also found to be a good substrate and afforded
7u−v in 72−85% yields, which could be an advanced
intermediate for the synthesis of derivatives of medicinally
important 1a−c in a few steps (Figure 1). Gratifyingly, our
optimized strategy works fine with silyl enol ethers of 2-
hydroxyfuran and cyclohexanone, which afforded products 7w
and 7x in 60% (dr = 2.9:1) and 67% (dr = 5.5:1), respectively
(Figure 4).
70% yield under the Baeyer−Villiger oxidation conditions.
Compound 15a was further reduced with NaBH4, followed by
treatment with methanesulfonic acid (MsOH), which afforded
16 in 85% yield over two steps (Scheme 4). The latter was then
hydrogenated to furnish medicinally important 1-alkylisoindoli-
none 17b in 96% yield.
In another sequence, isoindolinone 16 on reductive ozonolysis
afforded 17c, which has hydroxymethyl functionality in 78%
yield (Scheme 4). The latter could be used for the syntheses of
( )-1a−c shown in Figure 1. Finally, the reactivity of the
electron-donating PMP group of isoindolinone 6a was explored
in the synthesis of tetracyclic tetrahydroquinoline derivative 14
following a two-step sequence (87% overall yield) via NaBH4
reduction followed by treatment with methanesulfonyl chloride.
In summary, we have shown an efficient Mukaiyama−
Mannich lactamization/alkylation sequence for an expeditious
synthesis of a variety of isoindolinones and THIQs under mild
conditions. A variety of silyl enol ethers were utilized, and the
Next, we became interested in applying our strategy in the
synthesis of C1-substituted THIQs (Figure 1). Toward this end,
we have utilized a variety of o-formyl-2-arylethyl bromides 8 in
the presence of a few silyl enol ethers and PMPNH2 (Scheme 3).
To our delight, a variety of THIQs were synthesized under
optimized conditions A and B, where TBAF was not essential.
This is probably indicative of the high reactivity of the
2
intermediate Mukaiyama−Mannich product toward SN reac-
tions, and thus, reaction times were also reduced as compared to
isoindolinone synthesis. Our strategy can be applied further in
the efficient synthesis of THIQs 9a−e in 78−87% isolated yields
(Scheme 3). In particular, THIQ 9d could be an advanced
intermediate for the syntheses of ( )-2a−c (Figure 1) following
further synthetic elaboration. However, for a direct synthesis of
( )-2b,c, we synthesized silyl enol ethers of 3,4-dimethox-
yacetophenone and 3,4,5-trimethoxyacetophenone (see the
Supporting Information for procedure) and utilized them in
C
DOI: 10.1021/acs.orglett.5b01197
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analytical data (1H, 13C NMR
spectra and HRMS) for all new compounds, and X-ray data for
6d (CIF). The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01197.
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: vinodks@iitk.ac.in.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support through the J. C. Bose fellowship (DST,
Government of India) and SERB, DST (SB/FT/CS-011/2014),
are 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 SRF fellowships. Facilities from the
Department of Chemistry, IISER Bhopal, and IIT Kanpur are
gratefully acknowledged.
DEDICATION
■
This work is dedicated to Professor Tavarekere K. Chandra-
shekar on the occasion of his 60th birthday.
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