Cyclobutenone as a highly reactive dienophile: Expanding upon diels-alder paradigms

Article abstract of DOI:10.1021/ja1056888

Cyclobutenone was employed as a dienophile in Diels-Alder cycloadditions, provide diverse and complex cycloadducts in good yields. Experimental outcomes indicated cyclobutenone to be more reactive than either cyclopentenone or cyclohexenone. In addition, cycloadducts bearing a strained cyclobutanone moiety were able to undergo regioselective ring expansions to produce corresponding cyclopentanones, lactones, and lactams, which are otherwise difficultly obtained by direct Diels-Alder reactions.

Full text of DOI:10.1021/ja1056888

Published on Web 07/27/2010
Cyclobutenone as a Highly Reactive Dienophile: Expanding Upon Diels-Alder
Paradigms
Xiaohua Li† and Samuel J. Danishefsky*,†,‡
Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway, New York, New York 10027 and Laboratory
for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue, New York, New York 10065
Received June 28, 2010; E-mail: s-danishefsky@ski.mskcc.org
Table 1. Diels-Alder Reaction of Various Dienes with Cyclobutenone
Abstract: CyclobutenonewasemployedasadienophileinDiels-Alder
cycloadditions, provide diverse and complex cycloadducts in good
yields. Experimental outcomes indicated cyclobutenone to be more
reactive than either cyclopentenone or cyclohexenone. In addition,
cycloadducts bearing a strained cyclobutanone moiety were able
to undergo regioselective ring expansions to produce corresponding
cyclopentanones, lactones, and lactams, which are otherwise dif-
ficultly obtained by direct Diels-Alder reactions.
The power of the Diels-Alder cycloaddition reaction in organic
synthesis is widely appreciated.1 The six-membered rings created
through Diels-Alder technology can be substructures of relatively
simple targets or may be of value in building molecules of
considerable complexity. Indeed, the Diels-Alder reaction has
proven to be a valuable resource in reaching many natural products
of novel architecture.2
Access to higher levels of complexity might well be facilitated
if the dienophilic double bond in a Diels-Alder reaction is already
housed in an existing ring. However, under strictly thermal
conditions, parent cyclenones such as cyclohexenone and cyclo-
pentenone are relatively unreactive unless the diene contains
strategically placed activating groups.3 While both of these dieno-
philes are known to undergo Lewis acid catalyzed Diels-Alder
cycloaddition with less activated dienes, such applications require
substrates which are stable to Lewis acids.
Remarkably, although cycloadditions of substituted cyclobuten-
ones have been reported,4 we were unable to find a report of a
Diels-Alder reaction of the parent cyclobutenone (1, Table 1). We
anticipated that perhaps the ring strain of 1 might well serve to
enhance its dienophilicity relative to corresponding cyclopentenones
or cyclohexenones. Moreover, we could foresee that the products
of such Diels-Alder reactions (cf. 3) could well represent
particularly useful platforms for further elaborations (vide infra).
Sieja5 had actually described a preparation of cyclobutenone 1,
followingaveryharshHunsdiecker-typedecarboxylation-bromination
of 3-oxo-cyclobutanecarboxylic acid6 and subsequent elimination.
We developed a modified version of the Sieja protocol in which a
much milder Hunsdiecker-type decarboxylation-bromination was
utilized, leading to gram-scale quantities of 1.7a,b Cyclobutenone
(1) was found to be prone to polymerization when stored in the
a Isolated yield. b A mixture of cycloadducts (endo/exo ) 4:1) was
neat state, even at very low temperatures. Accordingly, it was stored
as a solution in chloroform.
Activated acyclic dienes 2a-c were explored and found to be quite
reactive in Diels-Alder reactions with 1 (Table 1). Dienes 2a, b, and
d gave rise, predominantly, to endo products (entries 1, 2, 4). Not
isolated in 90% combined yield. When the reaction was conducted at
-30 °C for 48 h, the endo/exo ratio was increased to 13:1 (52% yield
based on 60% conversion). c The minor adduct was isolated in 8% yield.
d Cycloadduct 3h was isolated in 40% yield in the absence of ZnCl2.
surprisingly, dienes 2c, 2e, and 2f require higher temperatures (45 °C)
and longer reaction times to produce cycloadducts (entries 3, 5-6).
The structure of 3e was confirmed by X-ray crystallographic analysis.7c
† Columbia University.
‡ Sloan-Kettering Institute for Cancer Research.
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11004 J. AM. CHEM. SOC. 2010, 132, 11004–11005
10.1021/ja1056888  2010 American Chemical Society

C O M M U N I C A T I O N S
Reactions of cyclobutenone with less reactive dienes 2g-j were
conducted with Lewis acid activation (ZnCl2)8 to produce cycloadducts
in moderate to good yields (entries 7-10).7a
as the equivalent of a Diels-Alder reaction between 2f and 1,5-
dihydropyrrol-2-one (12), which is, in reality, a nonfunctional dienophile.
Similarly, exposure of 3h to the conditions described afforded cyclopen-
tanone 7, lactone 8, and lactam 9 (entries 4-6).
These studies represent a potentially valuable approach to the
assembly of complex substructure types by combining Diels-Alder
reactions of the now available and highly reactive 1 with a range
of dienes to provide cycloadducts of the type 3, which serve as
substrates for appropriate ring expansions.13
In summary, as a consequence of improved methods for its synthesis
and management, the parent cyclobutenone (1) has become available
as a reagent for chemical synthesis. In thermally driven Diels-Alder
cycloadditions, it is far more reactive than ∆2 cyclopentenone, which
is notably more reactive than ∆2 cyclohexenone. For instance, 1 reacts
with cyclopentadiene at room temperature with high endo selectivity.
Diels-Alder reactions can be readily conducted with other, less reactive
diene types (remarkably, with furanoid dienes, high exo selectivity
pertains). Ring expansion reactions following Diels-Alder cycload-
ditions can be used to generate structure types which correspond to
cycloadducts of hypothetical but, in reality, nonfunctional dienophiles.
In this way, the logic of the Diels-Alder reaction is extendable to
reaching hitherto inaccessible structural types.
In our estimation, 1 is quite similar in its Diels-Alder reactivity
profile to maleic anhydride. This is remarkable in that vicinal
diactivation is a common rate enhancing feature in Diels-Alder
cycloadditions. While the magnitude of the effect could not have
been predicted in advance, the rate enhancement with 1 must reflect
the favorable effects of rehybridization of two particularly strained
sp2 carbons in the cycloaddition transition state.9 By contrast,
noncatalyzed Diels-Alder reactions of cyclopentenone or cyclo-
hexenone as dienophiles typically require much higher temperatures
(180-250 °C).10 In fact, in our hands, the uncatalyzed reaction of
cyclopentadiene with cyclopentenone was only 40% complete after
36 h at 150 °C. The results provided in Table 1 clearly demonstrate
that cyclobutenone 1 is a far more reactive dienophile than are the
analogous unsubstituted five- and six-membered cycloalkenones.
Given the now enhanced availability of 1 and its powerful
dienophilicity, we explored some aspects of the chemistry of adducts
3 with a view to reaching otherwise inaccessible target structures via
Diels-Alder logic (Table 2). For instance, treatment of cycloadduct
Table 2. Representative Ring Expansions of Cycloadducts
Acknowledgment. Support was provided by the NIH (HL25848
to S.J.D.). We thank Aaron Sattler and Wesley Sattler (Parkin group,
Columbia University) for help with X-ray experiments (NSF, CHE-
0619638); Mr. Zhang Wang, Drs. Jianglong Zhu and William F.
Berkowitz for helpful discussions, and Dr. Fay W. Ng and Ms.
Rebecca M. Wilson for editorial assistance and consultations.
Supporting Information Available: Experimental procedures,
copies of spectral data, and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100. (b) Corey, E. J.
Angew. Chem., Int. Ed. 2002, 41, 1650. (c) Bear, B. R.; Sparks, S. M.;
Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820. (d) Williams, R. M.;
Stocking, E. M. Angew. Chem., Int. Ed. 2003, 42, 3078. (e) Jørgensen,
K. A. Angew. Chem., Int. Ed. 2000, 39, 3558.
(2) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668. (b) Danishefsky, S. Acc. Chem.
Res. 1981, 14, 400.
(3) Karthikeyan, M.; Kamakshi, R.; Sridar, V.; Reddy, B. S. R. Synth. Commun.
2003, 33, 4199.
(4) (a) Bienfait, B.; Coppe-Motte, G.; Mere´nyi, R.; Viehe, H. G. Tetrahedron 1991,
47, 8167. (b) Kelly, T. R.; McNutt, R. W. Tetrahedron Lett. 1975, 16, 285.
(5) Sieja, J. B. J. Am. Chem. Soc. 1971, 93, 2481.
(6) 3-Oxo-cyclobutanecarboxylic acid is commercially available or can be
synthesized on a large scale: Pigou, P. E.; Schiesser, C. H. J. Org. Chem.
1988, 53, 3841.
(7) See Supporting Information for details: (a) synthesis, (b) spectral docu-
mentation, (c) crystallography.
a Key. A: Trimethylsulfoxonium iodide, NaH, DMF, then LiI, THF;
B: CF3CH2OH, H2O2; C: O-Mesitylenesulfonyl-hydroxylamine, CH2Cl2,
0 °C, then Al2O3, PhH/MeOH (3:1).
(8) Dols, P. P M. A.; Kluder, A. J. H.; Zwanenburg, B. Tetrahedron 1994, 50, 8515.
(9) Computational studies into the amenability of unsubstituted cycloalkenones
to Diels-Alder cycloaddition are in progress.
3f with trimethylsulfoxonium iodide and NaH in DMF (A) afforded
the spiroepoxide11 which, upon exposure to lithium iodide, underwent
rearrangement to produce cyclopentanone 4, apparently as a single
regioisomer (entry 1). Thus, methylene insertion had occurred exclu-
sively at the more substituted C-C bond, as consistent with the findings
of Marko´ and co-workers.11 It is appropriate to note that 4 corresponds
to the cycloadduct of a hypothetical Diels-Alder reaction of 2f and
the nonfunctional dienophile, 3-cyclopentenone (10).
Correspondingly, 3f was converted to lactone 5 in 70% yield (entry
2). In this case, oxygen insertion had occurred, as anticipated, at the more
substituted C-C bond. It is of note that lactone 5 corresponds to the
equivalent of a Diels-Alder reaction between 2f and butenolide 11. Once
again, butenolide 11 is not a useful dienophile in chemical synthesis.
Finally, reaction of 3f with O-mesitylenesulfonyl-hydroxylamine (MSH)
in CH2Cl2, followed by Al2O3-promoted rearrangement (C),12 afforded
lactam 6 in 80% yield as a single isomer (entry 3). Lactam 6 may be seen
(10) Computational studies explaining these results will be disclosed in due
course. (a) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Halls, T. D. J.; Wenkert,
E. J. Org. Chem. 1982, 47, 5056. (b) Karthikeyan, M.; Kamakshi, R.; Sridar,
V.; Reddy, B. S. R. Synth. Commun. 2003, 33, 4199.
(11) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–1364.
(b) Maulide, N.; Marko´, I. E. Org. Lett. 2007, 9, 3757.
(12) Greene, A. E.; Depre`s, J. P.; Nagano, H.; Crabbe´, P. Tetrahedron Lett.
1977, 18, 2365.
(13) It should be noted that ring expansion reactions of unique compound 3d
are not regiospecific and, in fact, occur in the sense shown. This finding is
in line with the precedent of Miller and co-workers: (a) Miller, R. D.; Dolce,
D. L.; Merritt, V. Y. J. Org. Chem. 1976, 41, 1221.
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