Orthogonal synthesis of isoindole and isoquinoline derivatives from organic azides

Article abstract of DOI:10.1021/ol802816k

(Chemical Equation Presented) α-Azido carbonyl compounds bearing a 2-alkenylaryl moiety at the α-position are found to be promising precursors for synthesis of isoindole and isoquinoline derivatives via 1,3-dipolar cycloaddrtion of azides onto alkenes and fcrelectrocyclization of N-H imine intermediates, respectively.

Full text of DOI:10.1021/ol802816k

ORGANIC
LETTERS
2009
Vol. 11, No. 3
729-732
Orthogonal Synthesis of Isoindole and
Isoquinoline Derivatives from Organic
Azides
Benjamin Wei-Qiang Hui and Shunsuke Chiba*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received December 6, 2008
ABSTRACT
r-Azido carbonyl compounds bearing a 2-alkenylaryl moiety at the r-position are found to be promising precursors for synthesis of isoindole
and isoquinoline derivatives via 1,3-dipolar cycloaddition of azides onto alkenes and 6π-electrocyclization of N-H imine intermediates, respectively.
Among numerous diverse approaches toward the synthesis
of azaheterocycles, both 1,3-dipolar cycloaddition of azides
onto alkenes1 and 6π-electrocyclization of azatrienes2,3 have
proven to be versatile methods for providing ready access
to azaheterocycles. Herein, we report an orthogonal meth-
odology for the synthesis of isoindole and isoquinoline
derivatives from R-azido carbonyl compounds possessing a
2-alkenylaryl moiety at the R-position, in which either
azide-alkene cycloaddition for isoindoles or 6π-electrocy-
clization for isoquinolines can be induced selectively by
slight modification of the reaction conditions.
Isoindoles and their derivatives are attractive candidates
for organic light-emitting devices (OLEDs) due to their high
fluorescent and electroluminescent properties,4 and they are
regarded as highly reactive substrates in [4+2]-cycloadditions
with various dienophiles for preparation of oligoacenes.5 We
envisaged that the intramolecular azide-alkene cycloaddition
reaction of 1 and subsequent elimination of dinitrogen from
(1) (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247. (b) Padwa,
A. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed; Wiley-
Interscience: New York, 1984; Vol. 2, p 316. (c) Feldman, K. S.; Iyer,
M. R.; Lo´pez, C. S.; Faza, O. N. J. Org. Chem. 2008, 73, 5090. (d) Zhou,
Y.; Murphy, P. V. Org. Lett. 2008, 10, 3777. (e) Kim, S.; Lee, Y. M.; Lee,
J.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.; Kim, D. J. Org. Chem. 2007, 72,
4886. (f) Huang, X.; Shen, R.; Zhang, T. J. Org. Chem. 2007, 72, 1534.
(g) Feldman, K. S.; Iyer, M. R.; Hester, D. K., II. Org. Lett. 2006, 8, 3116.
(h) Feldman, K. S.; Iyer, M. R. J. Am. Chem. Soc. 2005, 127, 4590. (i)
Hassner, A.; Amarasekara, A. S.; Andisik, D. J. Org. Chem. 1988, 53, 27.
(j) Liu, J.-M.; Young, J.-J.; Li, Y.-J.; Sha, C.-K. J. Org. Chem. 1986, 51,
1120. (k) Sundberg, R. J.; Pearce, B. C. J. Org. Chem. 1982, 47, 725. (l)
Smith, P. A. S.; Chou, S. P. J. Org. Chem. 1981, 46, 3970, and references
therein.
(3) For recent examples of 6π-electrocyclization of azatriene, see: (a)
Manning, J. R.; Davies, H. M. L. J. Am. Chem. Soc. 2008, 130, 8602. (b)
Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (c) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645.
(d) Meketa, M. L.; Weinreb, S. M.; Nakao, Y.; Fusetani, N. J. Org. Chem.
2007, 72, 4892. (e) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S.
J. Org. Chem. 2001, 66, 3099, and references therein.
(4) (a) Mi, B.-X.; Wang, P.-F.; Liu, M.-W.; Kwong, H.-L.; Wong, N.-
B.; Lee, C.-S.; Lee, S.-T. Chem. Mater. 2003, 15, 3148. (b) Ding, Y.; Hay,
A. S. J. Polym. Sci. Part A: Polym. Chem. 1999, 37, 3293. (c) Gauvin, S.;
Santerre, F.; Dodelet, J. P.; Ding, Y.; Hlil, A. R.; Hay, A. S.; Anderson, J.;
Armstrong, N. R.; Gorjanc, T. C.; D‘Iorio, M. Thin Sold Films 1999, 353,
218. (d) Matuszewski, B. K.; Givens, R. S.; Srinivasachar, K.; Carlson,
R. G.; Higuchi, T. Anal. Chem. 1987, 59, 1102. (e) Zweig, A.; Metzler, G.;
Maurer, A.; Roberts, B. G. J. Am. Chem. Soc. 1967, 89, 4091.
(2) For reviews of 6π-electrocyclization, see: (a) Okamura, W. H.; de
Lera, A. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 5, p 699. (b) Marvell, E. N.
Thermal Electrocyclic Reactions; Academic Press: New York, 1980
.
10.1021/ol802816k CCC: $40.75
Published on Web 01/05/2009
2009 American Chemical Society

the resulting triazolines6,7 would produce isoindoles as shown
in Scheme 1.8,9
Table 1. Synthesis of Isoindole Derivativesa
Scheme 1. Synthetic Plan of Isoindoles
First, azide 1a was prepared from aryl bromide 3a as
shown in Scheme 2. Treatment of Grignard reagent prepared
from 3a with diethyl oxalate followed by reduction of the
resulting R-keto ester with NaBH3CN afforded R-hydroxy
ester 4a. Mesylation of 4a gave 5a, which was treated with
NaN3 in DMF at 0 °C to lead to azide 1a. Next, isoindole
formation via the intramolecular azide-alkene cycloaddition
was investigated. As expected, the reaction proceeded
smoothly by heating of azides 1a in toluene or DMF (0.1 M
concentration) at 100 °C to give isoindole 2a10 in good yield
(Scheme 2).11
a Reaction conditions: treatment of azide 1 in toluene (0.1 M) at 100
°C for 3 h. b The two-step-yield from mesylate 5 is in parentheses. Reaction
conditions: treatment of mesylate 5 with NaN3 (1.2 equiv) in DMF (0.3 M)
at 0 °C; then after work up, exposure of resulting crude azide in toluene
(0.1 M) at 100 °C for 3-5 h. c Z:E ) 5.4:1.
Scheme 2. Synthesis of Isoindole 1a
cloalkyl moieties (entries 1-6). The reaction of azide 1h
having a 4-methylbenzoyl group instead of ethoxycarbonyl
also proceeded smoothly to afford isoindole 2h in 85% yield
(entry 7). A fluorine or a bromine atom also could be
introduced at the C5- or C4-position on an isoindole ring,
respectively (entries 8 and 9). It is noteworthy that a
heterocyclic framework such as 6H-pyrrolo[3,4-b]pyridine
could be readily accessible using this method (entry 10).
(8) One of the most common synthetic methods of isoindoles are the
reactions of phthalaldehyde and amine in the presence of reductants or
nucleophiles. For examples, see: (a) Watanabe, Y.; Shim, S. C.; Uchida,
H.; Mitsudo, T.; Takegami, Y. Tetrahedron 1979, 35, 1433. (b) Simons,
S. S., Jr.; Johnson, D. F. J. Chem. Soc., Chem. Commun. 1977, 374. (c)
Bonnett, R.; Brown, R. F. C. J. Chem. Soc., Chem. Commun. 1972, 393.
(9) For recent reports on isoindole formation by the other methods, see:
(a) Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008, 47, 7040.
(b) Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker, G. Chem. Commun.
2006, 661. (c) Murashima, T.; Tamai, R.; Nishi, K.; Nomura, K.; Fujita,
K.; Uno, H.; Ono, N. J. Chem. Soc., Perkin Trans. 1 2000, 995. (d) Dialer,
H.; Polborn, K.; Beck, W. J. Organomet. Chem. 1999, 589, 21.
(10) The structure of 2a was secured by X-ray crystallographic
analysis (see Supporting Information). CCDC-710407 contains the
supplementary crystallographic data for compound 2a. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Center via www.ccdc.cam.ac.uk/conts/retrieving.html.
A variety of substituted isoindoles 2 were synthesized as
shown in Table 1.12 At the C3-position of isoindoles were
installed methyl and benzyl groups as well as some cy-
(5) (a) Duan, S.; Sinha-Mahapatra, D. K.; Herndon, J. W. Org. Lett.
2008, 10, 1541. (b) Chen, Y.-L.; Lee, M.-H.; Wong, W.-Y.; Lee, A. W. M.
Syntlett 2006, 2510. (c) Chen, Z.; Mu¨ller, P.; Swager, T. M. Org. Lett.
2006, 8, 273. (d) LeHoullier, C. S.; Gribble, G. W. J. Org. Chem. 1983,
48, 2364.
(6) For reports on the mechanism of the elimination of dinitrogen
from triazoline intermediates with heterolytic cleavage of the N-N bond,
see: (a) Shea, K. J.; Kim, J.-S. J. Am. Chem. Soc. 1992, 114, 4864. (b)
Wladkowski, B. D.; Smith, R. H., Jr.; Michejda, C. J. J. Am. Chem. Soc.
1991, 113, 7893, and references therein.
(7) A radical pathway via homolytic cleavage of the N-N bond of
triazoline intermediates is also proposed, for examples, see references1c,g,h
and: Broeckx, W.; Overbergh, N.; Samyn, C.; Smets, G.; L’abbe´, G.
Tetrahedron 1971, 27, 3527.
(11) The introduction of a carbonyl moiety at the C1-position on
isoindoles is indispensable for this isoindole formation. For an example,
the reaction of 2′-vinylbenzyl azide under same reaction conditions gave a
complex mixture without desired isoindoles.
730
Org. Lett., Vol. 11, No. 3, 2009

Upon this discovery of the formation of isoindoles 2, we
next attempted a direct transformation of mesylate 5a to
isoindole 2a by treatment of 5a with 1.5 equiv of NaN3 in
DMF at 100 °C (Scheme 3). However, in this case, the major
product was not isoindole 2a (26% yield) but dihydroiso-
quinoline 6a (72% yield). In this reaction, the formation of
azide 1a as an intermediate was confirmed by monitoring
the reaction with TLC. This unprecedented isoquinoline
formation prompted us to investigate the reaction course and
optimize the reaction conditions.13
Scheme 4. Proposed Reaction Mechanisms
Scheme 3. Competitive Formation of Dihydroisoquinoline
deprotonation and subsequent protonation to afford N-H imine
8a,15 which then undergoes an intramolecular 6π-electrocy-
clization to afford dihydroisoquinoline 6a (Scheme 4).16,17
Thus, for selective synthesis of dihydroisoquinoline 6a,
the formation of N-H imine 8a should be achieved at
relatively low temperature to prevent the intramolecular 1,3-
dipolar cycloaddition. It was realized that treatment of azide
1a with K2CO3 (5 equiv as a base) and EtOH (10 equiv as
a proton source)18 in 1,3-dimethyl-2-imidazolidinone (DMI)
(0.3 M concentration) can provide N-H imine 8a at 40 °C.
Subsequent 6π-electrocyclization was found to be promoted
by dilution of the concentration with toluene (0.1 M) and
heating at 100 °C (Scheme 5a). On the basis of the above
findings, a direct transformation of mesylates 5a to dihy-
droisoquinoline 6a was finally achieved in 90% yield by
treatment of 5a with NaN3 (1.2 equiv), K2CO3 (5 equiv),
and EtOH (10 equiv) in DMI at 40 °C followed by
cyclization of the resulting imine 8a in toluene-DMI at
100 °C (Scheme 5b).
The reactions of azide 1a with some additives were
examined as shown in Table 2. Treatment of 1a with 1 equiv
of NaN3 gave isoindole 2a and dihydroisoquinoline 6a in
9% and 87% yield, respectively (entry 1). Addition of 1 equiv
of NaOAc14 also gave almost the same results as that of
NaN3 (entry 2). When the reaction of 1a with NaOAc was
quenched by addition of 1 M aq. HCl within 1 h, R-keto
ester 7a was isolated in 70% yield (entry 3).
Table 2. Investigation of Additivesa
Scheme 5. Optimized Reaction Conditions
entry
additive
time/h
2a (%)a
6a (%)a
7a (%)a
1
2
3
NaN3
NaOAc
NaOAc
10
10
1b
9
6
5
87
85
13
0
0
70
a Isolated yield. b The reaction was quenched with 1 M aq. HCl and
stirred for 1 h.
We have found the scope of this method to be quite broad
and have synthesized a range of structurally diverse iso-
From this experimental evidence, it was concluded that NaN3
or NaOAc induces elimination of dinitrogen from azide 1a by
(12) The starting materials were prepared by almost the same procedures
as Scheme 2; see Supporting Information.
(15) For generation of imine from R-azido ketones and esters under the
strong basic conditions, see: (a) Manis, P. A.; Rathke, M. W. J. Org. Chem.
1980, 45, 4952. (b) Edwards, O. E.; Purushothaman, K. K. Can. J. Chem.
1964, 42, 712.
(13) For recent reviews on isoqunoline derivatives, see: (a) Keller, P. A.
In ComprehensiVe Heterocyclic Chemistry III; Katritzky, A. R., Ramsden,
C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Pergamon: Oxford, 2008;
Vol. 7, p 217. (b) Jones, G. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.;
Pergamon: Oxford, 1996; Vol. 5, p 167. (c) Blently, K. W. Nat. Prod. Rep.
2006, 23, 444. (d) Kartsev, V. G. Med. Chem. Res. 2004, 13, 325. (e)
Chrzanowska, M.; Rozwadowska, M. D. Chem. ReV. 2004, 104, 3341.
(14) The pKa value of the conjugate acid of NaN3 (HN3) is almost same
as that of NaOAc (HOAc).
(16) For preparation of isoquinoline by 6π-electrocyclization of oxime
derivatives, see: Kumemura, T.; Chosi, T.; Yukawa, J.; Hirose, A.; Nobuhiro,
J.; Hibino, S. Heterocycles 2005, 66, 87.
(17) 6π-Electrocyclization of 1-azatriene possessing N-H imine moiety
is quite rare. For an example, see: Jutz, C.; Lo¨bering, H.-G.; Trinkl, K.-H.
Synthesis 1977, 326.
(18) H2O (10 equiv) can be used as a proton source, giving dihydroiso-
quinoline 6a in 88% yield from azide 1a.
Org. Lett., Vol. 11, No. 3, 2009
731

styryl moiety afforded 3-phenylisoquinoline 6c in 52% yield
along with 4-phenylisoquinoline 6c′ (16% yield), which may
be formed via rearrangement of the phenyl group during
oxidation of the resulting dihydroisoquinoline (entry 2).
Mesylate 5d bearing a 4-methoxyphenyl group, which has
higher migratory aptitude than a phenyl group,19 however,
gave nearly identical distribution of products (entry 3).
Dihydroisoquinoline 6e having a spiro-cyclohexyl moiety
was successfully prepared in excellent yield from mesylate
5e (entry 4). Mesylate 5f having a cyclobutylidenemethyl
moiety gave spiro-dihydroisoquinoline 6f20 in 71% yield
along with 13% yield of 3-propylisoquinoline 6f′ via ring
opening of a cyclobutyl moiety/aromitization (entry 5). The
reaction of mesylate 5g with a cyclopropylidenemethyl group
resulted in only 3-ethylisoquinoline 6g in 88% yield (entry
6).21 Replacement of the ethoxycarbonyl with a 4-methyl-
benzoyl group and introduction of halogen atoms on the aryl
ring did not affect this transformation, giving the desired
isoquinoline derivatives in good yield (entries 7-9). 1,6-
Naphthyridine derivative 6k could be synthesized in good
yield from mesylate 5k (entry 10). Finally, the reaction of
mesylate 5l having an R-methylvinyl group was examined,
and the corresponding 4-methylisoquinoline 6l was obtained
in 65% yield (entry 11).
Table 3. Synthesis of Isoquinoline and Dihydroisoquinoline
Derivativesa
In summary, an orthogonal method has been developed
for the synthesis of isoindole and isoquinoline derivatives
using R-azido carbonyl compounds bearing a 2-alkenylaryl
moiety. Further studies on the scope and synthetic applica-
tions of these reactions are currently in progress.
Acknowledgment. This work was supported by funding
from Nanyang Technological University, Singapore Ministry
of Education, and Science & Engineering Research Council
(A*STAR grant No. 082 101 0019). We thank Dr. Yongxin
Li and Ms. Siew Ping Yeo (Division of Chemistry and
Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University) for assistance
in X-ray crystallographic analysis.
Supporting Information Available: Experimental pro-
cedures, characterization of new compounds, and CIF files
giving crystallographic data for compounds 2a and 6f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Reaction conditions unless otherwise noted: treatment of mesylate 5
with NaN3 (1.2 equiv), K2CO3 (5 equiv), and EtOH (10 equiv) in DMF
(0.3 M) at 40 °C for 1-3 h; then addition of toluene (0.1 M) and heat at
100 °C for 8 h. b After consumption of imine 8, purge of O2 and heat at
100 °C. c Z:E ) 5.4:1.
OL802816K
(19) Curtin, D. Y.; Crew, M. C. J. Am. Chem. Soc. 1955, 77, 354.
(20) The structure of 6f was secured by X-ray crystallographic analysis
(see Supporting Information). CCDC-710406 contains the supplementary
crystallographic data. These data can be obtained free of charge from The
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/conts/
retrieving.html.
(21) The ring-opening reactions to lead isoquinolines 6f′ and 6g seem
to occur just after 6π-electrocyclization, not from the corresponding
dihydroisoquinolines like 6f. The detailed investigation is discussed in
Supporting Information.
quinoline and dihydroisoquinoline derivatives from the
corresponding mesylates 5 (Table 3). From the mesylate 5b
having a vinyl group, the 6π-cyclization followed by
oxidation of the resulting dihydroisoquinoline under an
oxygen atmosphere gave ethyl isoquinoline-1-carboxylate
(6b) in 82% yield (entry 1). The reaction of 5c possessing a
732
Org. Lett., Vol. 11, No. 3, 2009