An unusual reactivity of BBr3: Accessing tetrahydroisoquinoline units from N-phenethylimides

Article abstract of DOI:10.1039/c0ob00269k

Isoindoloisoquinalinone, pyrroloisoquinolinone and benzo[a]quinolizinone units are constructed via intramolecular cyclization of the methoxy substituted N-phenethylimides using BBr₃.

Full text of DOI:10.1039/c0ob00269k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
An unusual reactivity of BBr3: Accessing tetrahydroisoquinoline units from
N-phenethylimides†
Jayaraman Selvakumar,a Alexandros Makriyannisb and Chinnasamy Ramaraj Ramanathan*a
Received 16th June 2010, Accepted 1st July 2010
First published as an Advance Article on the web 21st July 2010
DOI: 10.1039/c0ob00269k
Isoindoloisoquinalinone,
benzo[a]quinolizinone
pyrroloisoquinolinone
units are constructed
and
via
intramolecular cyclization of the methoxy substituted
N-phenethylimides using BBr3.
The heterocycles containing a tetrahydroisoquinoline unit consti-
tute a major class in the pharmacologically active isoquinoline al-
kaloid family1 and hence attracted the great attention of synthetic
chemists.2 Molecules containing tetrahydroisoquinoline skeleton
have generally been constructed through the synthetic proto-
cols such as Pictet–Spengler,3 Bischler–Napieralski,4 Pomeranz-
Fritsch-Bobbitt,5 N-acyliminium ion cyclization,6 Parham type
cyclization,7 base induced aryl mediated cyclization,8 and other
sophisticated methods.9 These methods either involve the harsh
condition or multiple steps to effect the cyclization.
During the course of our investigation on the preparation of re-
sorcinol 1 from dimethoxyderivative 2a (Fig. 1) on treatment with
boron tribromide, a reagent commonly used for the demethylation
of aryl methyl ether,10 we have observed an unusual reactivity.
The methyl group remained unaffected even with excess of BBr3;
instead, the reaction proceeded smoothly to afford the cyclized
product, isoindoloisoquinolinone derivative, 3a.
Scheme 1 Screening of Lewis acids for cyclization.
Table 1 Cyclization of 2a using common Lewis acids
Entry
Lewis Acid
Equiv.
Reaction time/h
3a (%)a
1
2
3
4
5
6
7
8
BF3·OEt2
FeCl3
TiCl4
AlCl3
AlBr3
BBr3
2
2
2
2
2
4
2
1
96
6.5
12
58
53
72
75
83
88
91
46
8
4.5
0.5
0.5
0.5
BBr3
BBr3
a Isolated yield.
equivalent led to incomplete reaction. To examine the efficacy of
other Lewis acids to effect this cyclization process, the reactions
were carried out with substrate 2a in presence of other Lewis
acids (LA) such as BF3·OEt2, FeCl3, TiCl4, AlCl3, ClTi(OiPr)3,
Ti(OiPr)4, ZnCl2, SnCl4 and AlBr3 (Scheme 1). The results are
summarized in Table 1.
When 2a was treated with 2 equivalents of Lewis acids such
as ClTi(OiPr)3, Ti(OiPr)4, ZnCl2 and SnCl4 the reactions failed to
afford the cyclized product and revealed that the Lewis acidities of
these reagents are not sufficient enough to facilitate the cyclization
process. Whereas, the Lewis acids AlCl3, AlBr3, FeCl3, TiCl4 and
BBr3 were successfully afforded the cyclized product. Depending
on the Lewis acids the time required for the completion of the
reaction and yield varied. For example, the Lewis acids TiCl4,
AlCl3, FeCl3 and AlBr3 required 12 h, 8 h, 6.5 h and 4.5 h for
complete conversion of the starting material 2a to the cyclized
product 3a in 72%, 75%, 53% and 83% yield respectively. The
reaction was sluggish when BF3·OEt2 was used as a Lewis acid;
the reaction was incomplete even after 3 days of stirring at room
temperature (entry no. 1; Table no. 1). The cyclization of 2a using
Fig. 1
This observation prompted us to investigate the feasibility
of this unexpected reaction of BBr3 with methoxy substituted
phenethylimides and herein we report the first single step synthesis
of tetrahydroisoquinoline derivatives such as isoindoloisoquino-
linone, pyrroloisoquinolinone and benzo[a]-quinolizinone units
using BBr3. Preliminary experiments revealed that the cyclization
reaction required two equivalents of BBr3 with 2a, while the lesser
aDepartment of Chemistry, Pondicherry University, Puducherry, 605014,
India. E-mail: crrnath.che@pondiuni.edu.in; Fax: +91-413-2655987;
Tel: +91-413-2654416
◦
BBr3 (in CH2Cl2 at -15 C to room temperature) was fast, clean
and gave the cyclized product within 30 min.
bCenter for Drug Discovery, 360 Huntington Avenue, 116 Mugar Hall,
Northeastern University, Boston, MA 02115, USA
Further utility of BBr3 for this cyclization reaction was exam-
ined by treating mono/di/tri methoxy substituted phenethylph-
thalimides and the results are summarized in Table 2 (Scheme 2).
For example, the substrates 2b and 2e underwent regioselective
cyclization at C-6 position which is para to the C-3 methoxy
† Electronic supplementary information (ESI) available: Detailed synthetic
procedure and characterization of all compounds; 1H, 13C NMR spectra
and crystallographic data for selected compounds. CCDC reference
numbers 768894–768899. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob00269k
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Scheme 2 Cyclization of 2a–e using BBr3.
Fig. 2 1H NMR spectra of a) 2a + BBr3; b) 3a + BBr3.
Table 2 Cyclization of 2a–e using 2 equiv. of BBr3
Substitutions
S. No.
Entry
R1
R2
R3
R4
3 (%)a
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
H
H
OMe
H
H
H
H
OMe
OMe
OMe
OMe
OMe
–OCH2O–
H
H
OMe
H
OMe
H
OMe
H
H
OMe
H
H
3a (91)
3b (72)
3c (37)
3d (42)
3e (81)
b
—
2g
H
H
N.R.c
a Isolated yield. b Only demethylenated product was obtained. c No reac-
tion.
group to afford 3b and 3e respectively. The reaction of N-[2-(3,4-
dimethoxyphenyl)ethyl]phthalimide 2b gave 72% of the cyclized
product 3b along with a mixture of both mono and di demethylated
products. Reaction temperature (-78 ◦C and 27 ◦C) as well as
the quantity of BBr3 did not alter the yields of both cyclized
and demethylated product from 2b. Similarly, 2,3-dimethoxy and
3,4,5-trimethoxy derivatives furnished the corresponding cyclized
products 3c and 3d in 37% and 42% yield respectively; along with
demethylated products. Methylenedioxy phenethylphthalimide 2f
underwent complete ether cleavage to the catechol derivative.
The success of the cyclization depend on the relative position of
the methoxy groups with respect to the phenyl ring carbon that
participates in the cyclization; a methoxy group must be present at
C-3/C-5 positions so that the phenyl carbons C-6/C-2 respectively
participate in the C–C bond forming reaction (Scheme 2). When
methoxy group was present at C-4 carbon, demethylation was a
competing reaction (2b–d).
Scheme 3 Proposed reaction mechanism.
Next we turned our attention to examine the applicability of
this methodology to the methoxy substituted phenethyl aliphatic
imides such as N-[2-(3,5-dimethoxyphenyl)- ethyl]succinimide 5a
(Scheme 4). On treatment with BBr3, 5a furnished the cyclized
product 6a, which underwent dehydration readily to a very
unstable compound 7a in 60% yield.7a Hence the in situ gen-
erated intermediate II, N-acyliminium ion, was reduced with
NaBH4/CH3OH instead of quenching with water in a one pot
fashion to deliver the tricyclic lactam, pyrroloisoquinolinone 8a in
88% yield.12 Similarly, the imide 5c gave 8c in 69% yield along with
demethylated products. Glutarimides 5b and 5d gave the cyclized
tricyclic lactams, tetrahydroisoquinoline core 8b and 8d, present
in the a-glucosidase inhibitors schulzeine-A/B/C,13 in 89% and
71% yields respectively.
Unsubstituted phenethylphthalimide failed to give the cyclized
product even after stirring 2g with BBr3 for the extended period
of time. These examples revealed that the sufficient mesomeric
activation of the reacting nucleophilic carbon is important for a
successful cyclization.
Preferential coordination of BBr3 with imide carbonyl group
1
over methoxy group was evidenced from the H NMR studies11
of the reaction mixture and the mixture of hydroxy lactam 3a and
BBr3 in CDCl3 (Fig. 2). This complexation facilitated the elec-
trophilic substitution at C-6 via nucleophilic addition on the imide
carbonyl group to furnish the boron derivative of hydroxylactam
A prior to the N-acyliminium ion formation. With the expulsion of
boron species (Br2BO-) from A produced the stable intermediate I
the N-acyliminium ion (Scheme 3). Further, this speculation was
supported by the fact that the phenethylphthalimide 2g failed to
give the cyclized product; the reactivity generally observed for the
N-acyliminium ion cyclization.
The formation of hydroxy lactam from phthalimides and lactam
from aliphatic imides were unambiguously confirmed through
spectral techniques as well as single crystal X-ray structural
analysis of selected molecules (Fig. 3).14
In conclusion we have documented a simple methodology to
construct the tetrahydroisoquinoline containing skeleton, employ-
ing the boron tribromide as Lewis acid. Applicability of this reac-
tion towards the synthesis of tetrahydroisoquinoline unit present
in the alkaloid schulzeine-A/B/C was successfully carried out.
Further investigations on extending the scope of this cyclization
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FT-IR and 400 MHz NMR data. X-ray analysis were carried
out at National single crystal X-ray facility, School of Chemistry,
University of Hyderabad; SAIF, IITM, Chennai and Single crystal
X-ray facility, DST-FIST sponsored, Department of Chemistry,
Pondicherry University.
References
1 K. W. Bentley, The Isoquinoline Alkaloids, Harwood Academic Pub-
lishers, Amsterdam, 1998; J. D. Scott and R. M. Williams, Chem. Rev.,
2002, 102, 1669.
2 F. Zhang, N. S. Simpkins and A. J. Blake, Org. Biomol. Chem., 2009, 7,
1963; S. N. Gaskell, L. J. Duffy and S. M. Allin, Nat. Prod. Commun.,
2008, 3, 1825.
3 A. Pictet and T. Spengler, Ber., 1911, 44, 2030; J. Royer, M. Bonin and
L. Micouin, Chem. Rev., 2004, 104, 2311.
4 A. Bischler and B. Napieralski, Ber., 1893, 26, 1903; M. D. Rozwad-
owska, Heterocycles, 1994, 39, 903; M. Chrzanowska and M. D.
Rozwadowska, Chem. Rev., 2004, 104, 3341.
5 C. Pomeranz, Monatsh. Chem., 1893, 14, 116; P. Fritsch, Ber., 1893,
26, 419; J. M. Bobbitt, J. M. Kiely, K. L. Khanna and R. Ebermann,
J. Org. Chem., 1965, 30, 2247; B. Zhou, J. Guo and S. J. Danishefsky,
Org. Lett., 2002, 4, 43.
Scheme 4 One pot conversion of aliphatic imides to lactam.
6 B. E. Maryanoff, H. C. Zhang, J. H. Cohen, I. J. Turchi and C. A.
Maryanoff, Chem. Rev., 2004, 104, 1431; E. Garcia, E. Lete and N.
Sotomayor, J. Org. Chem., 2006, 71, 6776; W. N. Speckamp and H.
Hiemstra, Tetrahedron, 1985, 41, 4367; S. M. Allin, C. J. Northfield,
M. I. Page and A. M. Z. Slawin, Tetrahedron Lett., 1998, 39, 4905.
7 W. E. Parham and C. K. Bradsher, Acc. Chem. Res., 1982, 15, 300;
M. I. Collado, I. Manteca, N. Sotomayor, M. J. Villa and E. Lete,
J. Org. Chem., 1997, 62, 2080.
8 A. Moreau, A. Couture, E. Deniau and P. Grandclaudon, Eur. J. Org.
Chem., 2005, 3437.
9 G. Kim, J. H. Kim, W. J. Kim and Y. A. Kim, Tetrahedron Lett., 2003,
44, 8207; Y. Yamamoto, K. Kinpara, T. Saigoku, H. Nishiyama and
K. Itoh, Org. Biomol. Chem., 2004, 2, 1287.
Fig. 3 ORTEP diagram of 3a and 8b (50% probability ellipsoids).
10 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3rd ed.; John Wiley & Sons, New York, 1999; S. Punna, S. Meunier and
M. G. Finn, Org. Lett., 2004, 6, 2777.
process as well as the modification of Lewis acids to facilitate
cyclization reaction is in progress.
11 For complete 1H NMR spectrum see ESI.
12 J. Quirante, C. Escolano, A. Merino and J. Bonjoch, J. Org. Chem.,
1998, 63, 968.
Acknowledgements
13 K. Takada, T. Uehara, Y. Nakao, S. Matsunaga, R. W. M. van Soest
and N. Fusetani, J. Am. Chem. Soc., 2004, 126, 187; M. K. Gurjar, C.
Pramanik, D. Bhattasali, C. V. Ramana and D. K. Mohapatra, J. Org.
Chem., 2007, 72, 6591; G. Liu and D. Romo, Org. Lett., 2009, 11, 1143;
E. G. Bowen and D. J. Wardrop, J. Am. Chem. Soc., 2009, 131, 6062.
14 See the ESI for details.
This research work was funded by the Council of Scientific and
Industrial Research, Government of India, New Delhi (Grant
No. 01(2141)/07/EMR-II). J. S. thanks CSIR, New Delhi for
research fellowship. We thank CIF, Pondicherry University for
4058 | Org. Biomol. Chem., 2010, 8, 4056–4058
This journal is
The Royal Society of Chemistry 2010
©