A convenient synthesis of ortho-ortho disubstituted biphenyls containing an eight-membered lactam ring using radical chemistry

Article abstract of DOI:10.1016/j.tetlet.2009.02.031

Compound 4 prepared from Isatin in two steps underwent an unusual radical-induced rearrangement reaction to yield 9 as the major product and 10 as the minor component. Compound 9 shows structural similarities to the antimitotic agent rhazinilam and the ga

Full text of DOI:10.1016/j.tetlet.2009.02.031

Tetrahedron Letters 50 (2009) 1879–1881
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A convenient synthesis of ortho–ortho disubstituted biphenyls containing
an eight-membered lactam ring using radical chemistry
*
C. H. Wang , S. Alluri, A. K. Ganguly
Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Compound 4 prepared from Isatin in two steps underwent an unusual radical-induced rearrangement
reaction to yield 9 as the major product and 10 as the minor component. Compound 9 shows structural
similarities to the antimitotic agent rhazinilam and the gamma secretase inhibitor LY411575. The scope
of the reaction has been studied by changing the substitutions on the aromatic rings and the mechanism
for the formation of 9 and 10 from 4 is suggested.
Received 14 January 2009
Revised 21 January 2009
Accepted 2 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Radical reaction
Ortho–ortho disubstituted biphenyls
1. Introduction
bromide, indium metal, and sodium iodide in dimethyl formamide
to yield 4. Compound 4 on heating in toluene solution with tributyl
There has been considerable interest1 in the literature regarding
the synthesis of ortho–ortho disubstituted biphenyls incorporating
a median size (six- to nine-membered) lactam ring. Several of
these compounds possess biological activities of interest, for exam-
ple, rhazinilam2,3 which shows antimitotic activity by inducing
inhibition of polymerization and depolymerization of tubulin and
LY 411575,4 a gama secretase inhibitor for possible use in Alzhei-
mer patients (Fig. 1). Other compounds possessing ortho–ortho
disubstituted biphenyls and incorporating a carbocyclic ring3a are
represented in the structures of the antimitotic agents colchicine
and steganacin. Synthesis of these classes of compounds involve
the assembly of the suitably ortho–ortho disubstituted biphenyls
followed by the ring closure to form the median-sized ring.
tin hydride and AIBN yielded 9 as the major compound7 and 10 as a
minor component.8
A plausible mechanism for the formation of 9 and 10 is also
summarized in Scheme 1. The initial radical 5 adds to the aromatic
ring of the oxindole moiety to yield 6 which then undergoes fur-
ther rearrangement to form radicals 7 and 8. Capture of hydrogen
radical yields 9 from 7 and similarly 10 is obtained from 8. It
should be noted that in this reaction there was no evidence for
the formation of 26. Methylation of 10 yielded 11.
2. Present work
OH
O
H
N
F
N
CH3
N
In this Letter, we wish to disclose the synthesis of compound 9
and it’s analogs using an unusual radical-induced rearrangement
reaction. These compounds5,6 are novel. They have certain similar-
ities to the structures mentioned above. For example, they possess
ortho–ortho disubstituted biphenyls containing an eight-mem-
bered lactam ring, however, in addition they have an extra nitro-
gen atom in the lactam ring.
The synthetic scheme for compound 9 is shown in Scheme 1.
Thus, isatin 1 is treated with 2-bromo aniline 2 yielding the unsta-
ble imine 3 which without purification was treated with cinnamyl
H
O
O
O
CH3
F
LY411575
O
OAc
H
NH
O
MeO
N
H
O
O
MeO
MeO
(-)-rhazinilam
Steganacin
* Corresponding author. Tel.: +1 201 216 8175; fax: +1 201 216 8240.
E-mail address: cwang0001@gmail.com (C.H. Wang).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.031

1880
C. H. Wang et al. / Tetrahedron Letters 50 (2009) 1879–1881
H
NH2
O
N
Br
Br
EtOH
In, NaI, DMF
HN
O
Br
N
TBTH
AIBN
Br
N
O
O
O
4
H
5
N
H
N
N
2
1
(50.0%)
H
H
3
H
H
H
N
N
6
NH
H
8
O
O
O
N
H
N
N
H
H
26
H
N
O
7
N
H
H
H
H
H
N
N
e
e
NH
CS2CO3, CH3I
DMF
c
H
H
b
d
d
O
b
O
N
HN
f
a
N
H
c
a
O
CH3
11 (90.5%)
10 (17.6%)
9 (70.6%)
Scheme 1.
R1
R1
R1
R1
NH
O
R
R1
O
In, NaI, DMF
Br
R
TBTH
AIBN
O
Br
R1
Br
N
N
HN
R
HN
H
R
O
O
N
19: R=R1=H (93.1%)
3: R=R1=H
15: R=R1=H (58.5%)
N
20: R=OCF3 R1=H (61.3%)
21: R=F, R1=H (93.9%)
22: R=H, R1=F (87.0%)
H
12: R=OCF3 R1=H
13: R=F, R1=H
14: R=H, R1=F
16: R=OCF3 R1=H (52.9%)
17: R=F, R1=H (54.4%)
18: R=H, R1=F (48.9%)
H
CS2CO3,
allyl bromide
Grubbs' I catalyst
toluene, reflux
Compound 19
NaI, DMF
N
N
N
N
CS2CO3, CH3I DMF
O
O
24 (72.5%)
25
isolated yield 12.1%
CH3
N
N
23 (83.3%)
H3C
O
Scheme 2.
To explore the scope of the above reaction, we have converted
the Schiff’s bases 3, 12, 13, and 14 to their corresponding C-allyl
adducts 15 to 18 using allyl bromide, sodium iodide, and indium
metal in dimethyl formamide. Heating in toluene solution, these
adducts with tributyltin hydride in the presence of AIBN yielded
compounds 19 to 22, thus establishing that a variety of aromatic
substitutions are well tolerated in the reaction disclosed in the
present Letter (see Scheme 2). Methylation of compound 19
yielded 23.
As compounds such as 19 are obtained in three easy steps start-
ing with commercially available starting materials, we investigated
its conversion to another novel heterocycle 25. Thus compound 19
was converted to the diallyl derivative 24, which was submitted to
ring-closing metathesis in the presence of Grubbs’ I catalyst to
yield 25. Although compound 25 could be isolated in pure condi-
tion, it underwent slow decomposition on standing at room tem-
perature. Obviously 25 could be further functionalized to impart
drug like properties.

C. H. Wang et al. / Tetrahedron Letters 50 (2009) 1879–1881
1881
Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem. 2002, 67,
1199–1207.
Acknowledgments
4. Fuwa, H.; Okamura, Y.; Morohashi, Y.; Tomita, T.; Iwatsubo, T.; Kan, T.;
Fukuyama, T.; Natsugari, H. Tetrahedron Lett. 2004, 45, 2323–2326.
5. The purity of the compounds was established using various chromatographic
techniques. NMR and high resolution mass spectra of all the compounds
described in this letter were consistent with the assigned structures.
Assignments were further confirmed using 2D NMR and NOE experiments.
6. Excepting compounds 10, 11, 16, 20, 24, and 25, all the other compounds
described in this Letter were crystalline. Crystals were obtained from dichloro-
methane and hexane. The melting points of compounds 4, 9, 15, 17, 18, 19, 21,
22, and 23 were 163–165, 195–197, 180–182, 160–162, 187–189, 179–181,
191–193, 156–158, and 101–103 °C, respectively. Yields are indicated in
parentheses.
We wish to thank Schering-Plough Research Institute for gener-
ous financial assistance and Dr. T.M. Chan (Schering-Plough Re-
search Institute) for helpful discussion. One of us (C.H.W.) would
also like to thank Stevens Institute of Technology for the award
of a postdoctoral fellowship.
References and notes
1. (a) Brecht, A.; Seitz, G.; Guenard, D.; Thoret, S. Bioorg. Med. Chem. 2000, 8, 557–
562; (b) Bergemann, S.; Brecht, S.; Buttner, F.; Guenard, D.; Gust, R.; Seitz, G.;
Stubbsa, M.; Thoret, S. Bioorg. Med. Chem. 2003, 11, 1269–1281; (c) Bringmann,
G.; Günther, C.; Ochse, M.; Schupp, O.; Tasler, S.. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Falk, H., Kirby, G. W., Moore, R. E., Eds.;
Springer: Vienna, 2001; Vol. 82, pp 1–249; (d) Baudoin, O.; Guéritte, F.. In Studies
in Natural Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2003;
Vol. 29, pp 355–417.
7. The 1H NMR spectrum of compound 9 showed the presence of two vinyl
hydrogens at d 6.4 (d, J = 15.8 Hz, 1H, H-a) and d 6.1 (td, J = 15.8 Hz, J = 7.0 Hz,
1H, H-b), a CH2 group at d 2.7–2.5 (m, 2H, H-c), and a CH group at d 4.4 (td,
J = 9.3 Hz, J = 7.1 Hz, 1H, H-d). The amine proton H-e appeared at d 3.9 (d,
J = 9.3 Hz, 1H) and the amide hydrogen H-f showed a singlet at d 8.0.
8. The 1H NMR spectra of compound 10 showed three vinyl hydrogens
representing the diene system at
d 5.5 (d, J = 5.3 Hz, 1H, H-a), d 6.1 (dd,
2. Baudoin, O.; Guenard, D.; Gueritte, F. J. Org. Chem. 2000, 65, 9268–9271.
3. (a) Pasquinet, E.; Rocca, P.; Richalot, S.; Guéritte, F.; Guénard, D.; Godard,
A.; Marsais, F.; Quéguiner, G. J. Org. Chem. 2001, 66, 2654–2661; (b)
J = 9.4 Hz, J = 5.3 Hz, 1H, H-b), and d 5.7 (dd, J = 9.4 Hz, J = 5.5 Hz, 1H, H-c). In the
13CNMR spectrum, the two quaternary carbons appeared at d 60.1 (C-d) and d
78.0 (C-e).