Ring-opening of benzocyclobutenol with mild bases and trapping with dieneophiles

Article abstract of DOI:10.1080/00397910701575269

The treatment of benzocyclobutenol with a mild base has been investigated. This reaction results in an electrocyclic opening of the cyclobutene to the corresponding o-quinodimethane, which has been successfully treated with aldehydes and electron-deficient alkenes to form benzolactols and benzocyclohexenes respectively. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701575269

This article was downloaded by: [McGill University Library]
On: 14 December 2014, At: 13:48
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
Ring‐Opening of Benzocyclobutenol with Mild
Bases and Trapping with Dieneophiles
Simon J. Shaw a
a Kosan Biosciences , Hayward, California, USA
Published online: 10 Dec 2007.
To cite this article: Simon J. Shaw (2007) Ring‐Opening of Benzocyclobutenol with Mild Bases and Trapping
with Dieneophiles, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:23, 4183-4189, DOI: 10.1080/00397910701575269
To link to this article: http://dx.doi.org/10.1080/00397910701575269
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 Communicationsw, 37: 4183–4189, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575269
Ring-Opening of Benzocyclobutenol with
Mild Bases and Trapping with Dieneophiles
Simon J. Shaw
Kosan Biosciences, Hayward, California, USA
Abstract: The treatment of benzocyclobutenol with a mild base has been investigated.
This reaction results in an electrocyclic opening of the cyclobutene to the correspond-
ing o-quinodimethane, which has been successfully treated with aldehydes and
electron-deficient alkenes to form benzolactols and benzocyclohexenes respectively.
Keywords: Diels-Alder reactions, electrocyclic reactions, pericyclic reactions, tandem
reactions
In this article, electrocyclic ring-opening of benzocyclobutenols under mild
basic conditions is studied. It has been used to trap both aldehydes and
electron-deficient alkenes in good yields.
The synthesis, physical chemistry, and synthetic applications of benzocyclo-
butenes have been studied for many years.[1] In particular, they are a common
startingpointforthegenerationofo-quinodimethanes,[2] usuallythroughelectro-
cyclic ring-opening under the action of either heat or light. Recent methodology
from the Danishefsky laboratory[3] employed a heat-activated opening and
Diels–Alder trapping for the synthesis of (+)-rishirilide.[3b]
In 1998, it was reported that the reaction of benzocyclobutenol 1 in the
presence of an alkylating agent and sodium hydride did not produce the
expected ether, but a lactol 2, resulting from ring opening of the benzocyclo-
butenol and Diels–Alder dimerization with a second molecule of the ring-
opened benzocyclobutenol (Fig. 1).[4] Although base-induced ring openings
Received in the USA May 9, 2007
Address correspondence to Simon J. Shaw, Kosan Biosciences, Inc., 3832 Bay
Center Place, Hayward, CA 94545, USA. E-mail: shaw@kosan.com
4183

4184
S. J. Shaw
Figure 1. Base-induced ring opening of benzocyclobutenol.
of this kind have been known for some time, the reaction has been used more
sparingly in the synthetic community than the thermal ring-opening process.
However, it was shown to be comparable with the thermal process for a
small group of dieneophiles by Choy and Yang[5] and was employed by Fitz-
gerald et al. for the synthesis of a set of isocoumarins and isoquinolines.[6]
Further, there has been a study reporting that a variety of substituted benzocy-
clobutenols treated with base favored ring opening to form the o-quinodi-
methane 4 or benzylcarbanion 5 over the aryl anion resulting from cleavage
of the aryl-carbon bond.[7]
The drawback of these systems is the strong bases such as butyllithium
used to effect ring opening. The milder sodium hydride conditions
suggested that weaker bases might also be effective at promoting the ring
opening, which would increase the utility of this method.
Benzocyclobutenol was synthesized by sodium borohydride reduction of
benzocyclobutenone generated as reported by South and Liebeskind,[8] and a
range of bases was screened (Scheme 1, Table 1). As anticipated, the dimer-
ization product was generated in good yield on exposure to both sodium
hydride and potassium hydride in minutes at 08C (entries 1 and 2). Further,
sodium methoxide had the same effect (entry 3). By contrast, no reaction
occurred in the presence of diazabicycloundecene (DBU) even after 24 h
(entry 4). These results suggested that upon formal deprotonation to the ben-
zocyclobutene alkoxide 3, electrocyclic ring opening occurs rapidly to
generate 4 and 5. The facile base-induced ring opening contrasts with the
Scheme 1.

Ring-Opening of Benzocyclobutenol with Mild Bases
4185
Table 1. Screening the ring opening with a range of bases
Yield of 2
(%)
Entry
Base
Temp (8C)
Time
10 min
5 min
1
2
3
4
5
NaH
KH
0
0
79
85
80
NaOMe
DBU
0
40 min
24 hours
90 min
20
20
No reaction
55
K2CO3, 18-
crown-6
elevated temperatures that are required for thermal rearrangement, an effect
that is similar to the oxy-Cope rearrangement. Indeed, it was found that dimer-
ization also occurred under the classic oxy-Cope conditions of potassium
carbonate in the presence of 18-crown-6 (entry 5). The mild conditions
employed in this instance were particularly striking and suggested that this
approach could be a practical route to the generation of o-quinodimethanes.
Given that base-induced ring opening and trapping occurred with a series
of weaker bases, it was necessary to demonstrate that the ring-opened material
could be trapped prior to dimerization, leading to a useful reaction. Olofson
has shown that, in the presence of a strong base, aromatic carboxaldehydes
make good reaction partners.[6a] Thus, this study began by treating benzocy-
clobutenol with sodium hydride in the presence of 4-nitrobenzaldehyde. In
an effort to outcompete the dimerization reaction, an excess of the aldehyde
was used. Surprisingly, no reaction was observed under these conditions,
with starting benzocyclobutenol being returned, even after the addition of
further base. By contrast, reducing the number of equivalents to just more
than stoicheometric (1.2 eq) produced the cycloadduct 6 in just 10 min with
none of the dimerization product observed (Scheme 2).
It is possible that in the presence of an excess of the aldehyde, the hemi-
acetal 7 is produced (Fig. 2), which is returned to starting materials upon
workup.
Having shown that the ring-opened material could be trapped, a series of
aldehydes was investigated using both sodium hydride conditions (Method A)
and potassium carbonate conditions (Method B) (Table 2). Both were effective
with aromatic carboxaldehydes (entries 1–6) and heteroaromatic aldehydes
Scheme 2.

4186
S. J. Shaw
Figure 2. Proposed semi-acetal intermediate 7.
Table 2. Reaction with a range of aldehydes
Yield
(%)a
Entry
1
Aldehyde
Product
Method
4-Nitrobenzaldehyde
A
40
2
3
2-Naphthalenecarboxaldehyde
2-Naphthalenecarboxaldehyde
A
B
68
52
4
5
4-Bromobenzaldehyde
4-Bromobenzaldehyde
A
B
75
60
6
7
4-Methoxybenzaldehyde
4-Methoxybenzaldehyde
A
B
58
43
8
9
Furaldehyde
Furaldehyde
A
B
71
33
10
Propionaldehyde
A
45
11
12
Isobutyraldehyde
Isobutyraldehyde
A
B
15
25
aIsolated yields, purities . 90% based on 1H NMR.
Note. Method A: benzocyclobutenol (1.0 eq), NaH (1.3 eq), aldehyde (1.2 eq), THF
[0.1 M], 08C. Method B: 18-crown-6 (2.0 eq), K2CO3 (1.2 eq), toluene [0.1 M], rt, 1 h
then aldehyde (1.3 eq) and benzocyclobutenol (1.0 eq), rt.

Ring-Opening of Benzocyclobutenol with Mild Bases
4187
(entries 7, 8), giving good conversions to the corresponding diastereomeric
mixture of lactols in high purity after column chromatography. (The
1
isolated products were greater than 90% purity as judged by H NMR.) In
general, the sodium hydride conditions gave superior yields, but both con-
ditions were effective. By contrast, with alkanals (entries 9–12), the
potassium carbonate conditions appear to achieve better conversion to the
lactols. Although yields are lower in these instances, it is a feature of this
methodology that these enolizable aldehydes can be used directly in this
reaction system, something that could only be achieved through careful
control of temperature under stronger conditions.[6a]
To probe further the methodology, the benzocyclobutenol was treated with
sodium hydride in the presence of trans-cinnamaldehyde. Cycloaddition
proceeds in moderate yield to give only a single product resulting from cyclo-
addition with the carbon–carbon double bond followed by elimination of water
to form enal 14 (Table 3, entry 1). The lactol resulting from cycloaddition with
the aldehyde was isolated. Treatment of benzocyclobutenol with sodium
hydride in the presence of benzoquinone failed to effect any reaction;
however, under the potassium carbonate conditions the dihydroanthraquinone
15 was formed, albeit in low yield. The result suggests that there may be
subtle differences between the two reaction conditions. The dihydroanthraqui-
none might be an effective route to the anthraquinone scaffold that could
prove useful in the pursuit of analogs of type II polyketides synthases.
The reaction of benzocyclobutenol with benzonitrile using either the
sodium hydride or potassium carbonate conditions did not result in the
desired isoquinoline but in direct addition to yield the phenyl acetimidate.
This observation may suggest that all three species 3, 4, and 5 exist in equili-
brium. Reaction occurs through the species that is optimally suited for reaction
with each particular substrate. Thus aldehydes and electron-deficient
Table 3. Reactions with carbon dieneophile
Entry
1
Dieneophile
Product
Method
A
Yield (%)a
54
E-Cinnamaldehyde
2
3
Benzoquinone
Benzoquinone
A
B
No reaction
21
1
aIsolated yields, purities .90% based on H NMR.
Note. Method A: benzocyclobutenol (1.0 eq), NaH (1.3 eq), dieneophile (1.2 eq),
THF [0.1 M], 08C. Method B: 18-crown-6 (2.0 eq), K2CO3 (1.2 eq), toluene [0.1 M],
rt, 1 h then dieneophile (1.3 eq) and benzocyclobutenol (1.0 eq), rt.

4188
S. J. Shaw
dieneophiles react through one of the ring-opened species 4 or 5, whereas
nitriles react with the alkoxide 3 under these reaction conditions.
METHOD A REACTION CONDITIONS
To a solution of benzocyclobutenol (0.013 g, 0.118 mmol, 1.0 eq) in tetra-
hydrofuran (1 ml) at 08C, p-bromobenzaldehyde (0.026 g, 0.142 mmol,
1.2 eq), was added, followed by sodium hydride (0.003 g, 0.142 mmol,
1.3 eq) (Figure 2). The solution was stirred at 08C for 15 min before adding
NH4Cl (15 ml). The organics were extracted with CH2Cl2 (3 ꢀ 15 ml),
combined, dried (Na2SO4), and concentrated under reduced pressure.
Column chromatography (20% EtOAc–hexane) yielded the lactol (0.026 g,
75%) as a colorless oil; IR (film, CH2Cl2) 3277, 2896, 1489, 1070, 1012,
980, 815, 747 cm21;1H NMR (400 MHz) d 7.52 (2H, d, J 8.5 Hz, m-
C6H4Br), 7.34 (2H, d, J 8.5 Hz, o-C6H4Br), 7.32–7.27 (3H, m, 3H of
C6H4), 7.15 (1H, m, 1H of C6H4), 6.18 (1Hmaj, d, J 4.0 Hz, H-1), 6.10
(1Hmin, d, J 8.5 Hz, H-1), 5.22 (1Hmaj, dd, J 11.0, 3.5 Hz, H-3), 4.90
(1Hmin, dd, J 11.0, 3.0 Hz, H-3), 3.31 (1Hmin, d, J 9.0 Hz, OH), 3.21
(1Hmaj, d, J 4.5 Hz, OH), 3.07 (2H, m, 2H of H-4); m/z 289, 287 [M þ H-
H2O]þ.
METHOD B REACTION CONDITIONS
To a solution of 18-crown-6 (0.048 g, 0.182 mmol, 2.0 eq) in toluene (1 ml),
freshly ground potassium carbonate (0.015 g, 0.109 mmol, 1.2 eq) was added.
The mixture was stirred at room temperature for 1 h before adding benzocy-
clobutenol (0.010 g, 0.091 mmol, 1.0 eq) and p-bromobenzaldehyde
(0.022 g, 0.118 mmol, 1.3 eq). The resulting mixture was stirred at room
temperature for 1 h before partitioning between EtOAc (15 ml) and NH4Cl
(15 ml). The aqueous phase was extracted with EtOAc (3 ꢀ 15 ml) and the
combined organics dried (Na2SO4) before concentrating under reduced
pressure. Column chromatography (silica, 15% EtOAc–hexane) yielded the
lactol (0.017 g, 60%) as a colorless oil; data agrees with that stated previously.
CONCLUSIONS
In summary, a route to the formation of o-quinodimethanes, through electro-
cyclic ring opening of benzocyclobutenol with a mild base, has been investi-
gated. The reaction appears to be analogous to the oxy-Cope reaction and can
be effected under similar conditions, namely potassium carbonate. The
resulting o-quinodimethanes rapidly undergo cycloaddition with carboxalde-
hydes to give the corresponding lactols. Under these milder conditions,

Ring-Opening of Benzocyclobutenol with Mild Bases
4189
cycloaddition will also occur with alkanals, although the yields are lower, in
contrast to what has been reported previously. It appears that the methodology
can also be extended to Diels–Alder trapping with electron-deficient carbon–
carbon double bonds. The mild reaction conditions may make the anion-
mediated ring-opening of benzocyclobutenes a practical complement to the
thermal opening.
ACKNOWLEDGMENTS
Yong Li is thanked for useful suggestions.
REFERENCES
1. For a review of benzocyclobutarenes, see Sadana, A. K.; Saini, R. K.; Billups, W. E.
Cyclobutarenes and related compounds. Chem. Rev. 2003, 103, 1539–1602.
2. For a review of o-quinodimethanes, see Charlton, J. L.; Alaudin, M. M. Orthoqui-
nodimethanes. Tetrahedron 1987, 43, 2873–2889.
3. (a) Allen, J. G.; Hentemann, M. F.; Danishefsky, S. D. A powerful o-quinone
dimethide strategy for intermolecular Diels–Alder cycloadditions. J. Am. Chem.
Soc. 2000, 122, 571–575; (b) Allen, J. G.; Danishefsky, S. D. The total synthesis
of (+)-rishirilide B. J. Am. Chem. Soc. 2001, 123, 351–352.
4. Craig, D.; Robson, M. J.; Shaw, S. J. Traceless linkers for solid-phase synthesis:
Homo- and hetero-Diels–Alder reactions of o-quinodimethanes. Synlett. 1998,
1381–1383.
5. Choy, W.; Yang, H. Diels–Alder reactions of a-oxy-o-xylylenes. J. Org. Chem.
1988, 53, 5796–5798.
6. (a) Fitzgerald, J. J.; Pagano, A. R.; Sakoda, V. M.; Olofson, R. A. Reaction of
benzocyclobutenoxides with aldehydes: synthesis of peshawarine and other 3,4-
dihydroisocoumarins. J. Org. Chem. 1994, 59, 4117–4121; (b) Fitzgerald, J. J.;
Micheal, F. E.; Olofson, R. A. Reaction of benzocyclobutenoxides with nitriles:
Synthesis of hypecumie and other 3-substituted isoquinolines. Tetrahedron Lett.
1994, 35, 9191–9194.
7. Gokhale, A.; Schiess, P. Regioselectivity of the base-induced ring cleavage of
1-oxygenated derivatives of cyclobutabenzene. Acta Helv. Chim. 1998, 81,
251–267.
8. South, M. S.; Liebeskind, L. S. Practical multigram synthesis of benzocyclobutene-
diones. J. Org. Chem. 1982, 47, 3815–3821.