1,2-dihydropentalenes from fulvenes by [6 + 2] cycloadditions with 1-isopropenylpyrrolidine

Article abstract of DOI:10.1021/ol202222d

In situ generated acetone pyrrolidine enamine undergoes [6 + 2] cycloadditions with fulvenes to give 1,2-dihydropentalenes. This ring annulation method works particularly well with 6-monosubstituted fulvenes and is subject to steric hindrance at C-6 of th

Full text of DOI:10.1021/ol202222d

ORGANIC
LETTERS
2011
Vol. 13, No. 22
5952–5955
1,2-Dihydropentalenes from Fulvenes
by [6 þ 2] Cycloadditions with
1-Isopropenylpyrrolidine
§
€
Necdet Cos-kun, Jingxiang Ma, Saeed Azimi, Christian Gartner, and Ihsan Erden*
Department of Chemistry and Biochemistry, San Francisco State University,
1600 Holloway Avenue, San Francisco, California 94132, United States
ierden@sfsu.edu
Received August 19, 2011
ABSTRACT
In situ generated acetone pyrrolidine enamine undergoes [6 þ 2] cycloadditions with fulvenes to give 1,2-dihydropentalenes. This ring annulation
method works particularly well with 6-monosubstituted fulvenes and is subject to steric hindrance at C-6 of the fulvene. On the basis of
mechanistic studies, optimal conditions have been developed for a one-pot synthesis of 1,2-dihydropentalenes using catalytic amounts of
pyrrolidine.
1,2-Dihydropentalenes (1,2-DHPs) are of considerable
theoretical and synthetic interest and have served as versa-
tile substrates in diverse modes of cycloadditions as well as
complex ligands in organometallic chemistry.1
under Thiele conditions to give, among others, two iso-
meric diphenyl-1,2-dihydropentalenes. This latter method
was more recently extended to β-phenylenones using the
pyrrolidine method giving 1-phenyl-3-alkyl-substituted
1,2-dihydropentalenes in low to moderate yields.4 Inspired
by Hafner’s intramolecular enamine cyclization method,
Houk et al. reported formal intramolecular [6 þ 2] enamineꢀ
fulvene cycloadditions to give linearly fused tricyclic 1,2-
dihydropentalenes in low to moderate yields.5,6 In our
continued effort to extend the photooxygenation chemis-
try of fulvenes7 to bicyclic analogues, we required a con-
venient synthesis of the only dihydropentalene isomers,
1,2-dihydropentalenes, that contain the fulvene moiety.
There are basically two routes to 1,2-dihydropentalenes;
Hafner’s method2 appears to be most general and takes
advantage of a thermal intramolecular cyclization of 6-(20-
aminovinyl)fulvenes to 3-N,N-dialkylamino-1,2-dihydro-
pentalenes in boiling piperidine followed by regiospecific
LiAlH4 or RLi addition at C-3 and subsequent hydro-
lysis and amine elimination to give the parent system or
3-mono- or 1,3-disubstituted 1,2-dihydropentalenes. The
other method, first reported by Nenitzescu et al.,3 takes
advantage of a Michael addition of the cyclopentadienide ion
on chalcone and subsequent intramolecular condensation
(4) (a) Griesbeck, A. G. J. Org. Chem. 1989, 54, 4981–4982.
(b) Griesbeck, A. G. Chem. Ber. 1991, 403–405.
(5) Wu, T. C.; Houk, K. N. J. Am. Chem. Soc. 1985, 107, 5308–5309.
(6) Wang, Y.; Mukherjee, D.; Birney, D.; Houk, K. N. J. Org. Chem.
1990, 55, 4504–4506. (b) In two isolated cases, 1,2-dihydropentalenes
were obtained from a 2-sulfur-substituted 6,6-dimethylfulvene and a
cyclopentadienylphosphane, respectively: (a) Hartke, K.; Timpe, C.
§ On leave from Uludag University, Department of Chemistry, 16059
Bursa, Turkey.
(1) (a) Macomber, D. W.; Spink, W. C.; Rausch, M. D. J. Organo-
met. Chem. 1983, 250, 311–318. (b) Alves, N. P.; Maia, A. d. S.;
de Oliveira, W. J. Alloys Compd. 2000, 303ꢀ304, 178–181and references
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Heterocycles 1993, 35, 77–80. (b) Petrov, A. R.; Elfferding, M.; Mobus,
J.; Harms, K.; Rufanov, K. A.; Sundermeyer, J. Eur. J. Inorg. Chem.
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cited therein. (c) Greger, I.; Kehr, G.; Frohlich, R.; Erker, G. Organo-
metallics 2010, 29, 3210–3221. (d) Boul, P. J.; Reutenauer, P.; Lehn,
J.-M. Org. Lett. 2005, 7, 15–18. (e) Reutenauer, P.; Buhler, E.; Boul,
P. J.; Candau, S. J.; Lehn, J.-M. Chem.;Eur. J. 2009, 15, 1893–1900.
(2) (a) Kaiser, R.; Hafner, K. Angew. Chem., Int. Ed. Engl. 1970, 9,
892–893. (b) Hafner, K.; Kaiser, R. German Patent 2050404, 1972.
(c) Hafner, K.; Kaiser, R. Angew. Chem., Int. Ed. Engl. 1973, 12, 335–337.
(3) Cioranescu, E.; Bucur, A.; Mihai, G.; Mateescu, G.; Nenitzescu,
C. D. Chem. Ber. 1962, 2325–2580.
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34, 1255–1258. (d) Erden, I.; Drummond, J.; Alstad, R.; Xu, F. J. Org.
Chem. 1993, 58, 3611–3612. (e) Erden, I.; Xu, F.; Cao, W. Angew. Chem.,
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r
10.1021/ol202222d
Published on Web 10/26/2011
2011 American Chemical Society

Herein we report a general and versatile synthesis of 1,
2-dihydropentalenes based on intermolecular fulveneꢀ
enamine [6 þ 2] cycloadditions.8
Table 1. Dihydropentalenes from Fulvenes
Treatment of 6-monosubstituted fulvenes with 30 mol %
of pyrrolidine in acetone solution led cleanly to the forma-
tion of the corresponding 1,2-dihydropentalenes along
with varying amounts of mesityl oxide, formed by base-
catalyzed aldolization of acetone. The products were iso-
lated after removal of solvent and mesityl oxide by rotary
evaporation, purified by flash chromatography on silica
gel, and characterized by NMR, UV, and high-resolution
mass spectral analysis (Scheme 1, Table 1).
Scheme 1. Dihydropentalene Formation from Fulvenes
The optimal conditions for preparative purposes were
established by a series of systematic studies involving the
solvent effects and amount of catalyst by way of initial rate
correlations.
The rates were in the order DMSO > acetonitrile g
acetone > THF > toluene and correlate with solvent pola-
rity index in a linear fashion pointing to polar intermedi-
ates in the reactions. We found that the solvents CH3CN,
DMSO, and acetone appear to be ideal for 1,2-DHP
synthesis. The reported yields in Table 1 were obtained in
acetone solvent.
In regard to the catalyst amount, the best ratio was
determined to be 30 mol % of pyrrolidine since greater
proportions of base only slightly accelerated the reactions
at the expense of using larger amounts of a highly toxic and
malodorous compound and a more tedious workup
procedure.
Next, mechanistic details of these reactions were eluci-
dated. The 1,2-dihydropentalene formation in acetonitrile
solvent with 20 mol % of catalyst was determined to be
bimolecular, as determined by a rate study: doubling the
concentrations of either acetone or the fulvene doubled
the rate, respectively. Similarly, lowering the concentration
of acetone by 1/10 resulted in a 10-fold rate decelaration.
After optimization of the conditions for 1,2-DHP synth-
esis, the substitutent effects were studied by conducting the
experiments in acetone (fulvene/acetone ratio 1/65) with
30% catalyst with a series of 6-aryl-substituted fulvenes by
initial rate measurements. The plot of log(r)X versus the σþ
constants produced a linear correlation (R2 = 0.996) with
a For the synthesis of fulvenes 1aꢀk, see ref 9. b For spectral
characterization of all new products, see the Supporting Information.
c Isolated yields after chromatography on silica gel. d Fulvene (2 mmol),
20 mol % pyrrolidine, 10 mL of acetone, stirred overnight at rt; products
isolated by flash chromatography on SiO2.
F constant equal to 0.46 according to the equation log(r)X=
0.46σþ ꢀ 0.77.10 The only product in each case after 1 h
(8) Although 6,6-dimethylfulvene was reported to react with enam-
ines, the authors were not able to characterize the products because of
their instability; see ref 5, footnote 6. In our hands, 6,6-dimethylfulvene
undergoes clean reaction with in situ generated 1-isopropenylpyrroli-
dine 5 to give dihydropentalene 2i and 3 (see entry 9, Table 1) both of
which were stable under the reaction conditions and isolable by either
chromatography or fractional distillation.
(9) (a) Coskun, N.; Erden, I. Tetrahedron 2011, 67, 8607–8614.
(b) Erden, I.; Xu, F. P.; Sadoun, A.; Smith, W. A.; Sheff, G.; Ossun,
M. J. Org. Chem. 1995, 60, 813–820.
Org. Lett., Vol. 13, No. 22, 2011
5953

was the respective 1,2-DHP. The order of initial rates were
4-Cl > H > 4-Me > 3,4-dimethoxy = 4-methoxy, indicat-
ingatrendwhereingreaterelectrondeficiencyatthefulvene
6-position enhances attack by the nucleophile (vide infra).
In the aliphatic series (6-alkyl or 6,6-dialkyl), a similar
study revealed that steric factors affect the 1,2-DHP for-
mation rates. Whereas after 1 h 6-methyl- and 6-ethylful-
venes were completely consumed togive the corresponding
1,2-DHPs, the conversion of 6-isopropyl derivative was
only 25%. 6,6-Dimethylfulvene was reacted much more
slowly than the 6-monosubstituted analogues and also
gave rise to 2-isopropenyl-6,6-dimethylfulvene.
Scheme 2. Mechanism of Fulveneꢀenamine [6 þ 2] Cycloaddition
The 6-cyclopentylidene derivative 1k did not give any
1,2-DHP; instead, product 4 was isolated from this reac-
tion. The formation of 311 and 4 presumably arises from
initial base-catalyzed isomerization to alkenylcyclopenta-
dienide followed by condensation with acetone, respec-
tively. The tendencey of 1k to undergo facile isomerization
to cyclopent-1-enylcyclopentadiene has also been noted by
Scheme 3. Condensation of 1j with Acetone-d6 and Pyrrolidine
Alder and Ruhmann, as well as Nair et al.12 On the basis of
€
the studies described above, a plausible multistep mechan-
ism emerges, consistent with our results. The 1,2-dihydro-
pentalenes arise from a formal [6 þ 2] cycloaddition of a
fulvene with 1-isopropenylpyrrolidine 5,13 formed in situ
from acetone and pyrrolidine. Nucleophilic attack at
fulvene C-6 (the most electrophilic site in fulvenes, as
documented in various examples)14 gives rise to a zwitter-
ionic intermediate incorporating a cyclopentadienyl anion
and an iminium ion. The latter species cyclizes to a bicyclo-
[3.3.0]octadienyl derivative before eliminating pyrrolidine
to give the final product (Scheme 2).
In order to exclude the possibility of a 1-isopropenylfulvene
formation followed by an 8π-electrocyclization to give the
1,2-DHP, we conducted the reaction of 1i in acetone-d6
with catalytic base.
The 1H NMR spectrum of the reaction mixture clearly
showed that the signal for the C-2 protons (dihydropen-
talene numbering) in 2i at 2.9 ppm, now a CD2 group, had
disappeared (Scheme 3); likewise, the C-6 methyl groups
in 3 were also not visible, confirming the mechanism
proposed in Scheme 2.
On an interesting note, 1,4-diphenylcyclopentadiene
under the same conditions (acetone solvent/pyrrolidine
catalyst) underwent a tandem condensation with acetone
and subsequent dihydropentalene formation to give 11
(Scheme 4).
Obviously, the condensation with acetone did not take
place at the position between the phenyl groups. The
intermediate fulvene 10 was not isolated; under the condi-
tions, it underwent attack by 5 to give the 1,2-DHP
derivative 11. Similarly, the direct condensation of 1,3-
cyclopentadiene in acetone solution in the presence of
catalytic pyrrolidine led to the same mixture as obtained
from 1i by way of a domino condensation with acetone.
Scheme 4. One-Pot Fulveneꢀ1,2-DHP Formation from 9
(10) (a) Jaffe, H. H. Chem. Rev. 1953, 53, 191–261. (b) Hansch, C.;
Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195. (c) March, J.
Advanced Organic Chemistry Reactions Mechanism and Structure, 3rd
ed.; Wiley & Sons: New York, 1985; p 244.
(11) (a) Fenton, D. M.; Hurwitz, M. J. J. Org. Chem. 1963, 28, 1646–
1651. (b) Weyschardt, H.; Plenio, H. Organometallics 2008, 27, 1479–
1485. (c) Smith, W. B.; Gonzales, C. J. Org. Chem. 1963, 28, 3541–3542.
(12) (a) Alder, K.; Ruhmann, R. Justus Liebigs Ann. 1950, 566, 1–27.
(b) Nair, V.; Nair, J. S.; Kumar, S.; Rath, N. P.; Williard, P. G.;
Eigendorf, G. K. Tetrahedron Lett. 1998, 39, 460–4606.
The scope and limitations of the 1,2-DHP synthesis were
also studied. The use of methyl isopropyl ketone, aceto-
phenone, and cyclopentanone in the presence of pyrroli-
dine did not result in 1,2-DHP formation. Likewise,
increased steric bulk at C-6 in the starting fulvene impeded
fulvene formation, e.g., fulvenes derived from cyclopropyl
methyl ketone or p-methylacetophenone were also unreac-
tive toward acetone/pyrrolidine. However, the use of a pre-
formed enamine, i.e., 1-pyrrolidino-1-cyclopentene with1c
gave a mixture of the corresponding [6 þ 2] cycloadducts
12a and b; pyrrolidine did not eliminate spontaneously in
these cases. Preliminary results show that treatment of 1c
(13) The progress of the reactions was monitored by 1H NMR; in
each case, the presence of in situ formed enamine 5 was detected, as
confirmed by comparison of its 1H NMR signals (CDCl3) with those of a
sample formed in situ from acetone and pyrrolidine. The vinyl protons
have characteristic peaks (narrow multiplets) at δ 4.74 and 4.62 ppm in
the 1H NMR spectra of the crude reaction mixtures as well as a mixture
of pyrrolidine and acetone which we ascribe to the methylene protons in
5.
(14) (a) Yates, P. Fulvenes. In Advanced Alicyclic Chemistry; Aca-
demic Press: New York, 1968; Vol. 2, pp 59ꢀ184. (b) Zeller, K. P.
Pentafulvenes. Methoden Org. Chem. (Houben-Weyl) 1985, 5/2C,
504–684. (c) Neuenschwander, M. Fulvenes. In The Chemistry of
Double-Bonded Functional Groups, Supplement A; Patai, S., Ed.; Wiley:
New York, 1989, pp 1131ꢀ1268. (d) Buchi, G.; Decorzant, D. B. R.;
Grieder, A.; Hauser, A. J. Org. Chem. 1976, 41, 3208–3209.
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Org. Lett., Vol. 13, No. 22, 2011

with malonic acid in the presence of NaOAc in ether/H2O
delivers the tricyclic 1,2-dihydropentalene 13, albeit in low
yield (Scheme 5).
Scheme 6. Enamineꢀfulvene Reaction in the Presence of H2O
Scheme 5. Dihydropentalene with a Preformed Enamine
In conclusion, we have developed a convenient general
synthesisof 1,2-dihydropentalenes from fulvenesinvolving
a formal stepwise [6 þ 2] cycloaddition with an in situ
generated enamine.15 By way of mechanistic studies, we
elucidated the mechanism of the reaction and optimized
the reaction conditions. With a variety of 1,2-dihydropen-
talenes now readily accessible, we plan to explore various
aspects of the chemistry of these interesting bicyclic ful-
venes, including cycloadditions, singlet oxygenation,16 as
well as applications to natural product synthesis.
In order to test the dipolar nature of the [6 þ 2] cyclo-
addition, and in hopes of trapping an intermediate pro-
posed in Scheme 2, we conducted the reaction of 1c with
in situ-generated acetone pyrrolidine enamine in DMSO
containing 2% H2O. Under the conditions, in addition to
the dihydropentalene 2c, a small amount of a product was
isolated that was identified as fulvene 15 (Scheme 6). Its
formation can be rationalized in terms of a second enamine
addition to 2c; the resulting iminium ion 14 is hydrolyzed
to give the corresponding ketone. The resulting cyclopen-
tadiene undergoes pyrrolidine-catalyzed condensation with
acetone to give 15. Since no 1,2-DHP-enamine cycloaddi-
tion was observed previously in the absence of H2O, the
second enamine attack is reversible since the cyclization of
the intermediate is geometrically not feasible and the alter-
native four membered ring formation would also be un-
favorable. Thus, when no H2O is present, 14 reverts to 2c.
Acknowledgment. This paper is dedicated to the mem-
ory of Professor Emmanuel Vogel. Support of this work by
funds from the National Institutes of Health (Grant No.
1SC1GM082340) is gratefully acknowledged. Funding
from the National Science Foundation (Grant Nos.
DBO-0521342 and DUE-9451624) for the purchase of
300 and 500 MHz NMR spectrometers is also acknowl-
edged. N.C. acknowledges a BIDEP-2219 fellowship from
the Turkish Scientific and Technological ResearchCouncil
(TUBITAK).
:
(15) This work was presented at the 43rd IUPAC World Congress in
San Juan, Puerto Rico, paper no. 589, Aug 1, 2011.
Supporting Information Available. General experimen-
tal procedures, spectral data, and 1H and 13C NMR
spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
€
(16) Erden, I.; Gartner, C. Inter- and Intramolecular Trapping of
Cyclopropanone Intermediates in the Photooxygenation of 1,2-Dihy-
dropentalenes. Presented at the Pacifichem conference in Honolulu,
HW, Symposium No. 1 (Reactive Intermediates andUnusual Molecules),
paper no. 1354, Dec 18, 2010.
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