The trapping of 6,6-Dimethylisobenzofulvene by its 1,3-dipolar precursor: A rare example of a dipolar [6+4] cycloaddition

Article abstract of DOI:10.1081/SCC-100104000

A new route to isobenzofuran and isobenzofulvene is reported that is proposed to involve the 14e electrocyclic fragmentation of a transient 1,3-dipolar intermediate formed by ring-opening of a fused aziridinocyclobutane. 6,6-Dimethylisobenzofulvene generated in this way reacts with its 1,3-dipole precursor to form a [10π+4π] cycloadduct, the first of this type involving the participation of a 1,3-dipolar species.

Full text of DOI:10.1081/SCC-100104000

This article was downloaded by: [Boston University]
On: 07 October 2014, At: 17:01
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number:
1072954 Registered office: Mortimer House, 37-41 Mortimer Street,
London W1T 3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
THE TRAPPING OF 6,6-
DIMETHYLISOBENZOFULVENE
BY ITS 1,3-DIPOLAR
PRECURSOR: A RARE
EXAMPLE OF A DIPOLAR [6+4]
CYCLOADDITION
Ronald N. Warrener a , Malcom L. A. Hammond a &
Douglas N. Butler a
a Centre for Molecular Architecture, Central
Queensland University , Rockhampton,
Queensland, 4702, Australia
Published online: 09 Nov 2006.
To cite this article: Ronald N. Warrener , Malcom L. A. Hammond & Douglas
N. Butler (2001) THE TRAPPING OF 6,6-DIMETHYLISOBENZOFULVENE BY ITS 1,3-
DIPOLAR PRECURSOR: A RARE EXAMPLE OF A DIPOLAR [6+4] CYCLOADDITION,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:8, 1167-1175, DOI: 10.1081/SCC-100104000
To link to this article: http://dx.doi.org/10.1081/SCC-100104000
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our

platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(8), 1167–1175 (2001)
THE TRAPPING OF 6,6-
DIMETHYLISOBENZOFULVENE
BY ITS 1,3-DIPOLAR PRECURSOR:
A RARE EXAMPLE OF A DIPOLAR [6 þ 4]
CYCLOADDITION
Ronald N. Warrener,* Malcom L. A. Hammond,
and Douglas N. Butler
Centre for Molecular Architecture, Central Queensland
University, Rockhampton, Queensland, 4702, Australia
ABSTRACT
A newroute to isobenzofuran and isobenzofulvene is
reported that is proposed to involve the 14e electrocyclic
fragmentation of a transient 1,3-dipolar intermediate formed
by ring-opening of
a fused aziridinocyclobutane. 6,6-
Dimethylisobenzofulvene generated in this way reacts with
its 1,3-dipole precursor to form a [10ꢀ þ 4ꢀ] cycloadduct,
the first of this type involving the participation of a 1,3-
dipolar species.
Isobenzofulvenes have been prepared by the 14e electrocyclic fragmen-
tation of dihydropyridazine compounds formed by the treatment of benzo-
norbornadienes with s-tetrazines.1,2 The reaction is general and has been
used to prepare 6,6-dimethyl,1 6,6-diethyl,2 6,6-diphenyl,3 and the parent
isobenzofulvenes.4 An alternative route involves a similar 14e electrocyclic
* Corresponding author. E-mail: r.warrener@cqu.edu.au
1167
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1168
WARRENER, HAMMOND, AND BUTLER
process from fused dihydrobenzenes generated in situ by the thermal dec-
arbonylation of cyclone adducts of benzonorbornadiene.2
None of the isobenzofulvenes has been isolated as monomers, but they
can be trapped as [4ꢀ þ 2ꢀ] cycloadducts with a variety of electron-deficient
alkenes,1 heterocyclic dienophiles,5 or higher order products with cyclic
polyene reagents, e.g., [8ꢀ þ 6ꢀ] cycloaddition with tropone and 7,7-dicya-
nofulvalene,6 and [10ꢀ þ 8ꢀ] cycloaddition with isobenzofurans.7,8 In the
absence of other cycloaddition partners, isobenzofulvenes undergo self-
dimerization8,9 with one molecule acting as the 10ꢀ reagent and another
as its 8ꢀ partner. Accordingly, the credentials of isobenzofulvenes to act
as cycloaddition reagents have been well-established. In spite of this, no
reactions with 1,3-dipolar reagents have been reported, to the best of our
knowledge, prior to the present study.10
In the course of reactions involving the intermolecular trapping of
Scheme 1. Series a X is O Series b X is C ¼ CMe2 Series c X is CH2
aziridinocyclobutanes with benzonorbornenes (vide infra),11 we uncovered
an unexpected fragmentation of 1a,b,12 which caused the yields of [4 þ 2]
products to drop in favor of the formation of pyrrole 5, and other products
derived from isobenzofuran 3 or 6,6-dimethylisobenzofulvene 4 (Schemes
1–3). In the case of the isopropylidene-bridged aziridinocyclobutene 1b, a
newminor compound ( m/z ¼ 585.2881, C39H39NO4 requires 585.2879) was
isolated, which has been assigned the structure 10 (Scheme 2) on the basis of

DIPOLAR [6 þ 4] CYCLOADDITION
1169
1H NMR evidence (see Scheme 2 for chemical shift and nOe data). Dimers4
of 6,6-dimethylisobenzofulvene 4 were also identified.8,9
Scheme 2.
Analysis of the cycloaddition step proposed for the formation of 10 in
Scheme 2 indicated a dual role for the 1,3-dipole 2b, in which it acted as
both the source of 6,6-dimethylisobenzofulvene 4 and also as its trapping
reagent. The generation of the isobenzofulvene 4 by the 14e electrocyclic
fragmentation of the dipolar intermediate 2b found good analogy in the
isoelectronic fragmentation of the dihydropyridazines 8a,b (Scheme 1)1,2,14
but the reaction of 4 with a 1,3-dipole was without precedent. This reaction
was also noteworthy since it involved the reaction of two transient species,
neither of which could be characterized definitively. The color developed by
heating 1c in toluene (reversed on cooling) provided support for 1,3-dipole
2c, whereas Wentrup et al. showed that very low temperature spectroscopy
was required to provide evidence for the existence of monomeric
isobenzofulvene.16
The success of the intermolecular reaction of 4 with 2b leading to the
[10 þ 4] adduct 10 depended very much on the high reactivity and electro-
cyclic compatibility of each species and the short but real lifetime of the
1,3-dipolar species 2b. The fact that dimers of 4 were also obtained in this
reaction indicated that the reactivity of 1,3-dipole 2b with 4 must be
comparable with the rate of dimerization of 4, which is known too fast at

1170
WARRENER, HAMMOND, AND BUTLER
1
room temperature to afford H NMR evidence of monomeric isobenzoful-
vene 4.
Other experiments confirmed the special features that were necessary
for the observed formation of 10. When aziridine 1b was heated in the
presence of a powerful dipolarophilic reagent such as 7-oxabenzonorborna-
diene 6a, the intermediate 1,3-dipole 2b was trapped exclusively to form the
[4 þ 2] adduct 11a in 94% yield (Scheme 3),17 i.e., trapping was faster than
fragmentation.
Me
Me
Reactants
Me
Me
O
E
E
O
+
+
NBn
NB n
-
-
1b
1a
E
E
2a
2b
6a
6b
Bn
N
Me
X
Products
Me
E
Bn
N
X
X is O
X is C=CMe
Series a
Series b
E
E
2
Me
E
Me
11a,b
12a,b
2b + 11b + 12b + 10
(4)
Reactions
1b + 6a
2b + 11a
1b + 6b
reference 15
1a + 6b 2a + 11a + 12a + 13 + 14
1b
2b + 10 +
2
E=CO Me; Bn =CH Ph
2
2
2a
-5
Ph
Me
Me
Me
Me
Ph
O
O
Ph
6b
∆
diglyme
3
IBF
+
O
O
Ph
15
13
14
Scheme 3.
In the related reaction in which aziridine 1b was heated with the less re-
active dipolarophile 6b, direct [4 þ 2] dipolar cycloaddition of 2b with 6b
occurred to form adducts 11b and 12b, but this reaction competed with the
[10 þ 8] electrocyclic fragmentation of intermediate 1,3-dipole 2b to form pyrrole
5 and isobenzofulvene 4 and trapping of 2b with 4 to give adduct 10. Thermolysis
of 2b in the absence of 6b raised the yield of 10 to 8%, however formation of the
syn- and anti-dimers of 6,6-dimethylisobenzofulvene dominated.
Heating the oxa-bridged aziridinocyclobutene 1a in the presence of 7-
isopropylidenebenzonorbornadiene 6b produced the 1,3-dipolar adducts 11a
(12%) and 12a (18%) by addition to 1,3-dipole 2a. In this case, no evidence
for the reaction of isobenzofuran (IBF) 3 with 1,3-dipolar intermediate 2a
was observed (only a [4 þ 2]reaction is symmetry allowed). Instead, addition
of IBF 3 with the 7-isopropylidenebenzonorbornadiene 6b (acting as dieno-

DIPOLAR [6 þ 4] CYCLOADDITION
1171
phile) occurred to form the Diels-Alder adducts 13 and 14. These structures
were confirmed by spectroscopy and separate synthesis from the addition of
IBF, generated by the Fieser method18 from 15,19 with 6b.
This study has uncovered a newfragmentation route to 6,6-dimethyl
isobenzofulvene 4 and isobenzofuran 3. The reaction of 4 with the 1,3-
dipolar species 2b is an exceptional example of serendipitous timing, as
1
breakdown of the intermediate 2b (too fast to observe by H NMR) is
still slowenough to allowits offspring 4 (itself a transient species) time to
attack its forebear. This reaction is a rare example of a symmetry-allowed
[6 þ 4] cycloaddition involving a 1,3-dipolar species; the only earlier ex-
amples of which we are aware10 are the dipolar addition to diazomethane22
or benzonitrile oxide23 to fulvenes, and the addition of diphenylnitrileimine
to tropone.24 A [6 þ 4] reaction has also been implicated in the reaction of
carbethoxyformonitrileoxide with dihydrocyclopenta[c]pyran.25
EXPERIMENTAL
Reaction of Aziridinocyclobutanes 1a,b with Benzonorbornadienes
Generation and Trapping of 6,6-Dimethylisobenzofulvene
A layer of aziridine 1b (57 mg, 0.13 mmol) was deposited inside a flask
from chloroform by evaporation and heated at 120ꢀC for 20 m. The residue
was chromatographed on silica gel (gradient elution light petroleum b.p.
40ꢀ–60ꢀ/ethyl acetate) to afford the pyrrole 5 (17 mg, 49%), a mixture of
6,6-dimethylisobenzofulvene dimers (4 mg, 19%; 1:4 exo:endo), and the
[10 þ 8] adduct 10 (3 mg, 8%).
Dimethyl N-benzylpyrrole-2,6-dicarboxylate (5)
M.p. 98ꢀ–99ꢀC; 1H NMR (400 MHz, CDC13) d 3.80 (6H, s), 6.17 (2H,
s), 6.97 (2H, s), 7.00 (2H, d, J¼7.2 Hz), 7.18 (1H, d, J¼7.2 Hz), 7.25 (2H, m).
13C NMR d 49.21, 51.60, 117.04, 126.14, 126.88, 127.67, 128.37, 138.71,
160.99; HRMS m/z found 273.1003, C15H15O4N requires 273.1001.
Dimethyl (1ꢀ,11ꢀ,12ꢀ,13ꢁ,14ꢀ,21ꢀ,22ꢁ)-23-benzyl-24-isopropylidene-
]
23-aza-heptacyclo[10.10.1.14,21 .03,11 .05,10 .013,22 .015,25
tetracosa-3,5,7,9,15,17,19-heptaene-1,12-dicarboxylate (10)
M.p. 227ꢀ–228ꢀC; 1H NMR (400 MHz, CDCl3) d 0.98 (1H, d
J ¼ 7.3 Hz), 1.39 (3H, s), 1.56 (3H, s), 1.62 (3H, s), 1.69 (3H, s), 2.19 (1H,

1172
WARRENER, HAMMOND, AND BUTLER
d J ¼ 7.3 Hz), 3.02 (3H, s), 3.58 (1H, s), 3.85 (3H, s) 4.24 (1H, s), 4.34 (1H, d
J ¼ 15.65 Hz), 4.49 (1H, s), 4.74 (1H, d J ¼ 15.65 Hz), 6.47 (1H, s), 6.85
(2H, m) 6.95 (1H, t J ¼ 7.3 Hz), 7.06 (2H, t J ¼ 7.3 Hz), 7.18 (3H, m), 7.28
(3H, t J ¼ 7.3 Hz), 7.45 (2H, d J ¼ 7.3 Hz), 13C NMR d 20.99 (2 lines), 26.40,
28.54, 46.45, 47.43, 47.55, 47.75, 48.79, 51.47, 51.69, 53.14, 54.00, 73.18,
78.33, 112.10, 119.44, 120.56 (2 lines), 120.90, 124.18, 124.66, 125.34 (2
lines), 126.82, 127.51, 126.02, 128.05, 141.50, 143.40, 145.84, 146.70,
148.32, 149.08, 154.44, 170.92, 172.27 HRMS m/z found 585.2881,
C39H39O4N requires 585.2879.
Generation and Trapping of Isobenzofuran
Aziridine 1a (180 mg, 0.46 mmol) and 7-isopropyliden-benzonorbor-
nadiene 6a were heated under reflux in benzene (1.5 mL) for 30 h. The
reaction mixture was evaporated to dryness and the products separated
by radial chromatography (silica, gradient elution light petroleum/metha-
nol).
(1ꢀ,2ꢁ,3ꢀ,10ꢀ,11ꢁ,12ꢀ,13ꢁ,14ꢀ,21ꢀ,22ꢁ) Dimethyl 23-benzyl-23-
aza-25-isopropylidene-2-oxadecacyclo[10.10.1.114,21
.02,11 .04,9.013,22 .015,20]pentaconta-4,6,8,15,17,19-hexaene-
1,12, dicarboxylate (11)
M.p. 145ꢀ–146ꢀC. 1H NMR d: 1.40 (6H, s, CH3); 1.90 (2H, s, H13,22);
2.29 (2H, s, H2,11); 3.57 (2H, s, H14,21); 3.79 (6H, s, OCH3); 3.93 (2H, s,
HCH2Ph); 5.49 (2H, s, H3,10); 6.92–7.43 (13H, m). 13C NMR d 20.33;
46.44; 50.62; 54.00; 57.57; 58.06; 76.39; 79.25; 111.29; 119.36; 119.84;
125.42; 125.61; 126.73; 127.15; 128.82; 142.80; 143.35; 146.82; 147.79;
171.25. M/z found 573.2524, C37H35O5N requires 573.2515.
(1ꢀ,2ꢀ,3ꢁ,10ꢁ,11ꢀ,12ꢀ,13ꢁ,14ꢀ,21ꢀ,21ꢀ,22ꢁ) Dimethyl
23-benzyl-25-isopropylidene-23-aza-oxadecacyclo[10.10.1.13,10
.114,21 .02,11 .04,9 .013,22 .015,20] pentaconta-4,6,8,15,17,
19-hexaene-1,12-dicarboxylate (12)
M.p. 208ꢀ–209ꢀC 1H NMR d: 1.05 (6H, s, CH3); 2.11 (2H, s, H13,22);
2.75 (2H, s, H2,11); 3.57 (6H, s, OCH3); 3.71 (2H, s, H3,10); 3.82 (2H, s,
NCH2Ph); 5.38 (2H, s, H14,21); 7.00–7.50 (13H, m) 13CNMR d 20.07;
45.08; 48.63; 49.15; 51.79; 54.50; 74.82; 80.47; 113.84; 118.85; 120.22;

DIPOLAR [6 þ 4] CYCLOADDITION
1173
125.58; 125.76; 126.68; 127.55; 127.60; 141.65; 146.17; 147.62; 149.38;
171.75. M/z found ¼ 573.2512 C37H25O5N requires 573.2515.
Reaction of Isobenzofuran (3) with 7-Isopropylidene
Benzonorbornadiene (6b)
18
A solution of the Fieser adduct 15 (1.1 g, 2.08 mmol) in chloroform
(2 mL) and diglyme (5 mL) was added dropwise over 15 m to a refluxing
solution of 6b (0.4 g, 2.2 mmol) in diglyme (3 mL). After a further 5 m at
reflux, the mixture was poured into water and extracted with ether. The
white solid obtained from the ether extract was separated by preparative
thick layer chromatography on silica by development with 50% methylene
chloride in hexane (adduct 14 was more mobile than its isomer 13).
Tetraphenylbenzene was also identified but not quantified.
(1ꢀ,2ꢁ,3ꢀ,6ꢀ,7ꢁ,8ꢀ) 20-isopropylidene-19-oxahexacyclo
[10.6.1.1 3,10.02,11.04,9.013,18]eicosa-4,6,8,13,14,17-hexaene (13).
M.p. 241ꢀ–242ꢀC. H NMR d 1.69 (6H, s, CH3); 1.88 (2H, s, H2,11);
1
3.86 (2H, s, H3,10); 5.19 (2H, s, H1,12); 6.96 (2H, m, H6,7); 7.04 (2H, m,
H15,16); 7.09 (2H, m, H5,8); 7.16 (2H, m, H14,17). 13C NMR d 20.33,
47.30, 51.89, 82.00, 112.49, 118.80, 120.09, 125.48, 126.28, 145.51, 146.79,
148.17. M/z Found 300.1514 calc. for C22H20O 300.1514. Found C 87.66, H
6.57 requires C 87.96, H 6.71%.
(1ꢀ,2ꢀ,3ꢁ,6ꢀ,7ꢀ,8ꢁ) 20-isopropylidene-19-oxahexacyclo[10.6.1.13,10
.02,11 .04,9 .013,18]eicosa-4,6,8,13,14,17-hexaene (14)
M.p. 226ꢀ–227ꢀC. H NMR d 1.03 (6H, s, CH3); 2.63–2.70 (2H, m,
1
H2,11); 3.36 (2H, s, H3,10); 5.17–5.24 (2H, m, H1,12); 6.96–7.24 (8H, m,
ArH). Found C 87.92, H 6.79, C22H20O requires C 87.96, H 6.71%.
ACKNOWLEDGMENT
M.L.A.H. thanks the Center for Molecular Architecture for the award
of an honors scholarship. This project was supported by funds from the

1174
WARRENER, HAMMOND, AND BUTLER
CQU Merit Research Program. We thank Dr. Ian Pitt for performing the
experiment involving the addition of isobenzofuran to 7-isopropylidene-
benzonorbornadiene well ahead of its time (ANU, 14/9/82).
REFERENCES
1. Watson, P.L.; Warrener, R.N. Aust. J. Chem. 1973, 26,1725.
2. Tanida, H.; Irie, T.; Torie, K. Bull. Chem. Soc., Japan 1972, 45, 1999.
3. Gell, K.I.; Warrener, R.N. unpublished results.
4. Warrener, R.N.; Russell, R.A.; Collin, G.J. Tetrahedron Lett. 1978,
4447.
5. Warrener, R.N.; Harrison, P.A.; Russell, R.A. Electronic Conference
0
on Heterocyclic Chemistry 98, 1998, Rzepa, H.S.; Kappe, O.: Eds;
Imperial College Press: 081. (http://www.ch.ic.ac.uk/ectoc/echet98/
pub/081/index.htm)
6. Paddon-Row, M.N.; Warrener, R.N. Tetrahedron Lett. 1974, 382.
7. Warrener, R.N.; Evans, D.A.C.; Paddon-Row, M.N.; Russell, R.A.
Aust. J. Chem. 1982, 35, 757.
8. Russell, R.A.; Longmore, R.W.; Warrener, R.N. J. Chem. Ed. 1992,
34, 403.
9. Warrener, R.N.; Paddon-Row, M.N.; Russell, R.A.; Watson, P.L.
Aust. J. Chem. 1981, 34, 397.
10. A SciFinder Scholar search on isobenzofulvenes plus 1,3-dipoles regis-
tered no hits (March, 2000).
11. Butler, D.N.; Malpass, J.R.; Margetic, D.; Russell, R.A.; Sun, G.;
Warrener, R.N. Synlett 1998, 588–589.
12. The ruthenium-catalyzed [2ꢂ þ 2ꢂ] addition of dimethyl acetylene
dicarboxylate to 7-oxabenzonorbornadiene 6a has been described.13
The resultant cyclobutene was treated with benzyl azide (benzene,
RT, 48 h) and the triazolidine adduct so formed, deazetised by ultra-
violet irradiation (300 nm, benzene) to give 1a. Aziridine 1b was pre-
pared in a similar way from 6b.17
13. Mitsudo, T.; Kokuryo, K.; Shinsugi, T.; Nakagawa, Y.; Wantanabe,
Y.; Takegami, Y. J. Org. Chem. 1979, 44, 4492–4496.
14. Isobenzofulvenes are conveniently prepared using our s-tetrazine route
outlined in Scheme 1. This 14e electrocyclic fragmentation approach
was first described15 for the preparation of isobenzofuran 3 (Scheme 1)
and later used for the production of isobenzofulvenes 4.1
15. Warrener, R.N. J. Am. Chem. Soc. 1971, 93, 2346.
16. Gross, G.; Schulz, R.; Scheig, A; Wentrup, C. Angew. Chem. 1981,
93, 1078.

DIPOLAR [6 þ 4] CYCLOADDITION
1175
17. Butler, D.N.; Hammond, M.L.A.; Johnston, M.R.; Sun, G.; Malpass,
J.R.; Fawcett, J.; Warrener, R.N. Org. Letters 2000, 2, 721–724.
18. Fieser, L.F.; Haddadin, M.J. Can. J. Chem. 1965, 43, 1599.
19. The structure of this adduct has been recently been established by x-ray
crystallography.20 The structure was in no doubt, having been assigned
by a long-range CO-H coupling method reported by us in 1979.21
20. Packe-Wirth, R.; Enkelmann, V. J. Mol. Structure 1998, 448, 1.
21. Tan, R.Y.S.; Russel, R.A.; Warrener, R.N. Tetrahedron Lett. 1979,
5031.
22. Houk, K.N.; Luskus, L.J. Tetrahedron Lett. 1970, 46, 4029.
23. Caramella, P.; Frattini, P.; Gruenanger, P. Tetrahedron Lett. 1971, 41,
3817.
24. Houk, K.N.; Watts, C.R. Tetrahedron Lett. 1970, 46, 4025.
25. Alazard, J.P.; Leboff, A.; Thal, C. Tetrahedron 1986, 42, 1407.
Received April 26, 2000