Metal-free entry to phosphonylated isoindoles by a cascade of 5-exo-dig cyclization, a [1,3]-alkyl shift, and aromatization under microwave heating

Article abstract of DOI:10.1021/ol062817o

When o-ethynylbenzyl α-aminophosphonates are heated under microwave conditions, a rearrangement occurs which results in the formation of phosphonylated isoindoles. The rearrangement consists of a 5-exo-dig cyclization followed by a [1,3]-alkyl shift and finally aromatization.

Full text of DOI:10.1021/ol062817o

ORGANIC
LETTERS
2007
Vol. 9, No. 3
465-468
Metal-Free Entry to Phosphonylated
Isoindoles by a Cascade of 5-exo-dig
Cyclization, a [1,3]-Alkyl Shift, and
Aromatization under Microwave Heating
Nicolai Dieltiens and Christian V. Stevens*
Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience
Engineering, Ghent UniVersity, Coupure links 653, B-9000 Ghent, Belgium
chris.steVens@ugent.be
Received November 20, 2006
ABSTRACT
When o-ethynylbenzyl
r-aminophosphonates are heated under microwave conditions, a rearrangement occurs which results in the formation
of phosphonylated isoindoles. The rearrangement consists of a 5-exo-dig cyclization followed by a [1,3]-alkyl shift and finally aromatization.
Recently, we reported on the synthesis of phosphonylated
benzazepines 3 via a domino enyne metathesis-cross-
metathesis between an appropriately functionalized amino-
phosphonate 1 and an alkene (Scheme 1).1 Studying the
reactivity of 2a, bearing a nonterminal alkene, it became
apparent that this compound was quite inert toward the
second-generation Grubbs’ catalyst,2 even in refluxing
benzene. After two weeks of refluxing, however, spectro-
scopic analysis revealed the formation of a trace amount of
a new compound with a 31P NMR shift around 15 ppm. From
previous experience in azaheterocyclic phosphonates, this
was recognized as a phosphorus attached to an sp2 carbon.3
The trace amount was isolated and identified as isoindole
4a. Phosphonylated isoindoles and related compounds are
rarely described in the literature. In fact, only one entry to
phosphonylated isoindoles could be found from the reaction
of 2,3-benzoxazin-1-ones with trialkyl phosphites at high
temperature.4 Few entries toward phosphonylated dihydro
isoindoles5 and isoindolinones6 have been reported in the
literature. The latter are known for their plant growth
regulating properties.7 Isoindoles possessing an alkoxycar-
Scheme 1
(1) Dieltiens, N.; Stevens, C. V. Synlett 2006, 2771-2776.
(2) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(3) (a) Moonen, K.; Dieltiens, N.; Stevens, C. V. J. Org. Chem. 2006,
71, 4006-4009. (b) Dieltiens, N.; Moonen, K.; Stevens, C. V. Chem.-
Eur. J. 2007, 13, 203-214.
(4) Abdou, W. A.; Kamel, A. A.; Khidre, M. D. Heteroat. Chem. 2004,
15, 77-84.
(5) Failla, S.; Finocchiaro, P. Phosphorus Sulfur 1995, 105, 195-203.
(6) Couture, A.; Deniu, E.; Woisel, P.; Grandclaudon, P. Synthesis 1997,
1439-1445.
10.1021/ol062817o CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/09/2007

bonyl group, the bioisosteric counterpart of the phosphonate,8
on the 1-position have been patented as appetite depressants.9
Scheme 2
The presence of the terminal free double bond in 4a
suggests that the metathesis catalyst is no longer active
because otherwise the product should have been dimerized.
This points to the fact that the rearrangement is thermally
driven rather then catalyzed by a metallic species. Indeed, it
was found that refluxing 2a in benzene results in a very slow
conversion to 4a. This conversion proceeded faster in CH3-
CN. Almost all annulations of alkynes require activation of
the triple bond. This can be achieved by a variety of transition
metals such as Au(III),10 Au(I),11 Cu(II),12 Cu(I),13 Pd,14 Ag,15
and others (W, Pt, Ru).16 Activation can also be achieved
by TBAF,17 TFA,18 and certain electrophiles.19 Addition to
an unactivated carbon-carbon triple bond is rather uncom-
mon but not unknown.20 At first, it was thought that the
reaction proceeded via a [1,5]-shift of the acidic proton in
the R-position of the phosphonate of 2a followed by 5-endo-
dig attack of the nitrogen atom onto the central allene carbon
atom of 5.21 The zwitterionic form 6 could then further
rearrange toward the final product (Scheme 2). The first step
in this sequence is assumed to be rate determining because
aromaticity is lost. The addition of NEt3 to a refluxing
solution of 2a in CH3CN, to facilitate the proton shift, did
not result in an increased reaction rate and caused decom-
position of 4a.
If the reaction is thermally driven, increasing the temper-
ature should result in a faster conversion to 4a. Unfortunately,
refluxing in DMF, DMSO, or NMP did not result in a clean
reaction. Finally a high-temperature, short-time approach
(185 °C/200 min) was achieved by heating 2a in a 1:1
mixture of benzene/CH3CN under microwave conditions
resulting in a 95% conversion to 4a. The proposed reaction
mechanism is depicted in Scheme 3. The first step involves
a direct addition onto the triple bond in a 5-exo-dig fashion.
Although endo-dig cyclizations are more favored than exo-
dig cyclizations, in this case the endo-cyclization would lead
to a less stable secondary anion. The zwitterionic form 7
fragments into anion 8 and cation 9a which is in resonance
with cation 9b.
As a result, anion 8 reacts with the allylic cation at the
phenylated position and the overall result corresponds to a
[1,3]-alkyl shift. Finally, aromatization occurs by a [1,5]-H
shift of 10. To establish the general nature of this rearrange-
ment, a number of substrates 2a-i were prepared by a one-
pot, three-component coupling of 2-ethynylbenzaldehyde,
secondary amines, and P(OMe)3 mediated by LiClO4.22 Table
1 summarizes isolated yields of the isoindoles obtained under
optimized conditions (165 °C).
We were pleased to find that in all cases the isoindoles
were formed. This rearrangement is not limited to these
examples where allylic cations can be formed. If a benzyl
cation can be formed, the rearrangement also occurs. In these
cases, however, an inseparable mixture of two isoindoles in
a variable ratio depending on the applied temperature is
produced in addition to decomposition material.23 The first
is the expected product 4j,k, and the second compound is
11a,b, formed by protonation and aromatization of interme-
diate 8 (Scheme 4). This seems to suggest that the benzyl
cations do not survive long enough in the reaction mixture
to quantitatively react with anions 8.
We observed that during the synthesis of compounds 2
sometimes some isoindole (<10%) was formed if the
reaction was allowed to stir for a prolonged time, probably
by activation of the triple bond by LiClO4. This observation,
together with the fact that only allyl or benzyl cations
migrate, prompted us to try to trap a zwitterionic intermediate
of type 7. A mixture of 2-ethynylbenzaldehyde, pyrrolidine,
(7) Phillips, W. G. CAN 91:175521 (Monsanto CO., U.S.A.), 1979.
(8) For a review concerning azaheterocyclic phosphonates and their
biological activity, see: Moonen, K.; Laureyn, I.; Stevens, C. V. Chem.
ReV. 2004, 104, 6177-6215.
(9) Haunin, R. CAN 91:193175 (Hoffman-La Roche, F., und Co. A.-G.,
Switz.), 1979.
(10) (a) Kadzimirski, D.; Hildebrandt, D.; Merz, K.; Dyker, G. Chem.
Commun. 2006, 661-662. (b) Oh, C. H.; Kim, A.; Park, W.; Park, D. I.;
Kim, N. Synlett 2006, 2781-2784. (c) Asao, N.; Aikama, H.; Yamamoto,
Y. J. Am. Chem. Soc. 2004, 126, 7458-7459. (d) Dyker, G.; Hildebrandt,
D.; Liu, J.; Merz, K. Angew. Chem., Int. Ed. 2003, 42, 4399-4402. (e)
Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 124, 12650-12651.
(11) (a) Buzas, A.; Gagosz, F. Synlett 2006, 2727-2730. (b) Shibata,
T.; Ueno, Y.; Kanda, K. Synlett 2006, 411-414. (c) Nevado, C.; Echavarren,
A. M. Chem.-Eur. J. 2005, 11, 3155-3164.
(12) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69, 5139-5142.
(13) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett.
2006, 8, 2803-2805. (b) Reboredo, F. J.; Treus, M.; Este´vez, J. C.; Castedo,
L.; Este´vez, R. J. Synlett 2003, 1603-1606. (c) Ezquerra, J.; Pedregal, C.;
Lamas, C.; Barluenga, J.; Pe´rez, M.; Garcia-Martin, M. A.; Gonzalez, J.
M. J Org. Chem. 1996, 61, 5804-5812.
(14) (a) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551-1553.
(b) Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Tetrahedron 2003, 59,
6251-6259. (c) Wei, L.-L.; Wei, L.-M.; Pan, W.-B.; Wu, M.-J. Synlett
2004, 1497-1502. (d) Mondal, S.; Nogami, T.; Asao, N.; Yamamoto, Y.
J. Org. Chem. 2003, 68, 9496-9498.
(15) Asao, N.; Yudha, S. S.; Nogami, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 5526-5528.
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Tetrahedron 2001, 57, 9697-9710.
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3381-3388.
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Weingarten, M. D.; Padwa, A. Tetrahedron Lett. 1995, 36, 4717-4720.
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(23) This was also observed when heating 2b to 180 °C.
466
Org. Lett., Vol. 9, No. 3, 2007

Scheme 3
and trimethyl phosphite was stirred in a concentrated solution
of LiClO4 for 4 h and was then quenched by the addition of
react, the allylic cation 15a,b remains attached to the anion
and can react intramolecularly to form an additional six-
membered ring 14a,b.
Table 1. Microwave-Induced Rearrangement of 2a-i to
Isoindoles 4a-i
Scheme 5
time yield of 4
2
R1
R2
R3
R4 (min)
(%)
a
b
c
d
e
f
g
h
i
Bn
Bn
Pr
p-MeBn
CH2CH2Ph
m-FC6H4
CH2CH2-p-ClPh -CH2CH2CH2CH2-
Bu
allyl
H
Ph
H
H
H
H
CH3
H
H
H
H
H
90
70
90
95
80
150
180
80
82
76
68
47
71
63
40
40
98
H
H
H
H
H
p-MeOC6H4
Finally, compound 4i proved to be an excellent substrate
for ring-closing metathesis and was cleanly converted to
azepino isoindole 16 by treatment with 2% second-generation
Grubbs’ catalyst in refluxing benzene (Scheme 7).
In summary, we have uncovered a new unusual rearrange-
ment leading to highly substituted isoindoles that occurs
CH3
iPr
H
CH3 Ph
H
H
60
3 N HCl (Scheme 5). Under these conditions, intermediate
12 did not fragment, because a nonstabilized primary cation
would have been formed, but instead reacted with HCl
producing compound 13.
Scheme 6
It was also possible to prepare more complex isoindoles
by incorporating the allyl group inside a ring structure
(Scheme 6). When these derivatives (2l,m) were allowed to
Scheme 4
Org. Lett., Vol. 9, No. 3, 2007
467

suitable to prepare isoindoles that are fused with an extra
six- or seven-membered ring.
Scheme 7
Acknowledgment. Financial support for this research
from the BOF (Bijzonder Onderzoeksfonds Universiteit Gent,
Research Fund Ghent University) is gratefully acknowledged.
Supporting Information Available: Spectroscopic data
and copies of H NMR and 13C NMR spectra of all new
compounds and general procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
under thermal conditions. The rearrangement starts with an
attack of a tertiary nitrogen on a nonactivated carbon-carbon
triple bond in a 5-exo-dig fashion, followed by a [1,3]-alkyl
shift with eventual aromatization. This strategy is also
OL062817O
468
Org. Lett., Vol. 9, No. 3, 2007