Cobalt-catalyzed intermolecular [2 + 2 + 2] cycloaddition for the synthesis of 1,3-cyclohexadienes

Article abstract of DOI:10.1021/jo800735x

(Chemical Equation Presented) A cobalt(I)-catalyzed [2 + 2 + 2] cycloaddition reaction between an internal acceptor-substituted alkyne and a terminal alkene leads to the formation of regiochemically enriched polysubstituted 1,3-cyclohexadiene derivatives in acceptable yields when methyl butynoate is used, whereas regiochemically pure products are formed in good yields form phenyl propyonate. The concurrent cyclotrimerization reaction of the alkyne to the corresponding benzene derivative is dependent on the sterical bulk of the alkyne and is considerably reduced with the sterically more hindered alkyne.

Full text of DOI:10.1021/jo800735x

cycloaddition reactions,2 1,4-hydrovinylation reactions,3 alkyne
cyclotrimerizations,4Alder-enereactions,5[4+2+2]cycload-
ditions,6 and other cobalt-catalyzed transformations have been
under investigation in our group for quite some time.7 Over
the course of our studies, we observed that in some cases the
outcome of the cobalt-catalyzed reactions is dependent on minor
changes in either the precatalyst such as the use of other ligands
or the reaction conditions (solvent effect).8
Cobalt-Catalyzed Intermolecular [2 + 2 + 2]
Cycloaddition for the Synthesis of
1,3-Cyclohexadienes
Gerhard Hilt,* Anna Paul, and Klaus Harms
Fachbereich Chemie, Philipps-UniVersita¨t Marburg,
Hans-Meerwein-Strasse, 35043 Marburg, Germany
While internal alkynes led to a reduced rate in the competing
cyclotrimerization reaction to the corresponding benzene deriva-
tive,9 the reaction with alkenes leads either to the formation of
the Alder-ene reaction product 1 or an unprecedented 1,3-
cyclohexadiene product 2 derived from a [2 + 2 + 2]
cycloaddition process (scheme 1).10 Surprisingly, the chemose-
lectivity was influenced by the ligand as well as by the electron
demand of the alkyne. When a nonacceptor-substituted alkyne
was used (R3 ) alkyl or aryl), the dppp ligand led predominantly
to the Alder-ene product of type 1 and with the dppe ligand to
the 1,3-cyclohexadiene product 2.
hilt@chemie.uni-marburg.de
ReceiVed March 15, 2008
On the other hand, when acceptor-substituted alkynes were
utilized (R3 ) CO2Et), the use of the Co(dppe) complex led
predominantly to the Alder-ene product 1, while the transfor-
A cobalt(I)-catalyzed [2 + 2 + 2] cycloaddition reaction
between an internal acceptor-substituted alkyne and a terminal
alkene leads to the formation of regiochemically enriched
polysubstituted 1,3-cyclohexadiene derivatives in acceptable
yields when methyl butynoate is used, whereas regiochemically
pure products are formed in good yields form phenyl propyo-
nate. The concurrent cyclotrimerization reaction of the alkyne
to the corresponding benzene derivative is dependent on the
sterical bulk of the alkyne and is considerably reduced with
the sterically more hindered alkyne.
(3) (a) Hilt, G.; Lu¨ers, S.; Schmidt, F. Synthesis 2004, 634. (b) Hilt, G.;
Lu¨ers, S. Synthesis 2002, 609. (c) Hilt, G.; du Mesnil, F.-X.; Lu¨ers, S. Angew.
Chem. 2001, 113, 408; Angew. Chem., Int. Ed. 2001, 40, 387. See also: (d)
Grutters, M. M. P.; Mu¨ller, C.; Vogt, D. J. Am. Chem. Soc. 2006, 128, 7414.
(4) (a) Hilt, G.; Hengst, C.; Hess, W. Eur. J. Org. Chem. 2008, 2293. (b)
Hilt, G.; Hess, W.; Vogler, T.; Hengst, C. J. Organomet. Chem. 2005, 690, 5170.
(c) Hilt, G.; Vogler, T.; Hess, W.; Galbiati, F. Chem. Commun. 2005, 1474. See
also: (d) Doszczak, L.; Tacke, R. Organometallics 2007, 26, 5722. (e) Doszczak,
L.; Fey, P.; Tacke, R. Synlett 2007, 753. (f) Goswami, A.; Ito, T.; Okamoto, S.
AdV. Synth. Catal. 2007, 349, 2368. (g) B, H.; Xu, D.-H.; Wu, Y.-Z.; Li; Yan,
H. Organometallics 2007, 26, 4344. (h) Field, L. D.; Ward, A. J. J. Organomet.
Chem. 2003, 681, 91. (i) Yong, L.; Butenscho¨n, H. Chem. Commun. 2002, 2852.
(j) Sugihara, T.; Wakabayashi, A.; Nagai, Y.; Takao, H.; Imagawa, H.; Nishizawa,
M. Chem. Commun. 2002, 576. (k) Montilla, F.; Aviles, T.; Casimiro, T.; Ricardo,
A. A.; Nunes da Ponte, M. J. Organomet. Chem. 2001, 632, 113. (l) Field, L. D.;
Ward, A. J.; Turner, P. Aust. J. Chem. 1999, 52, 1085. (m) Sigman, M. S.;
Fatland, A. W.; Eaton, B. E. J. Am. Chem. Soc. 1998, 120, 5130. (n) Rhyoo,
H.-Y.; Lee, B. Y.; Yu, H. K. B.; Chung, Y. K. J. Mol. Catal. 1994, 92, 41. (o)
Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. (p)
Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503.
The atom-economic generation of complex molecules from
simple building blocks in the context of diversity-oriented
synthesis is of great interest. The cobalt-catalyzed transfor-
mations of alkynes, alkenes, and 1,3-dienes1 in [4 + 2]
(5) (a) Hilt, G.; Treutwein, J. Angew. Chem. 2007, 119, 8653; Angew. Chem.,
Int. Ed. 2007, 46, 8500. (b) Buisine, O.; Aubert, C.; Malacria, M. Chem. Eur.
J. 2001, 7, 3517.
(1) For reviews on cobalt-catalyzed cycloaddition processes, see: (a) Omae,
I. Appl. Organomet. Chem. 2007, 21, 318. (b) Malacria, M.; Aubert, C.; Renaud
J. L. In Science of Synthesis: Houben-Weyl Methods of Molecular Trans-
formations; Lautens, M., Trost, B. M. Eds.; Thieme: Stuttgart, 2001; Vol. 1,
p 439. (c) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (d) Ojima,
I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635. (e)
Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (f) Grotjahn, D. B.In
ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Hegedus, L. Eds.; Pergamon Press: Oxford, 1995; Vol. 12, p
741. (g) Schore, N. E. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Paquette, L. A. Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p
1129. (h) Vollhardt, K. P. C. Angew. Chem. 1984, 96, 525; Angew. Chem., Int.
Ed. 1984, 23, 539.
(2) (a) Hilt, G.; Hengst, C. J. Org. Chem. 2007, 72, 7337. (b) Hilt, G.;
Janikowski, J.; Hess, W. Angew. Chem. 2006, 118, 5328; Angew. Chem., Int.
Ed. 2006, 45, 5204. (c) Hilt, G.; Lu¨ers, S.; Harms, K. J. Org. Chem. 2004,
69, 624. (d) Hilt, G.; Smolko, K. I. Angew. Chem. 2003, 115, 2901; Angew.
Chem. Int. Ed. 2003, 42, 2795. (e) Hilt, G.; Smolko, K. I.; Lotsch, B. V. Synlett
2002, 1081. (f) Hilt, G.; du Mesnil, F.-X. Tetrahedron Lett. 2000, 41, 6757.
See also: (g) Achard, M.; Tenaglia, A.; Buono, G. Org. Lett. 2005, 7, 2353.
(h) Pardigon, O.; Buono, G. Tetrahedron: Asymmetry 1993, 4, 1977. (i)
Pardigon, O.; Tenaglia, A.; Buono, G. J. Org. Chem. 1995, 60, 1868. (j) Tenaglia,
A.; Pardigon, O.; Buono, G. J. Org. Chem. 1996, 61, 1129. (k) Pardigon, O.;
Tenaglia, A.; Buono, G. J. Mol. Catal. A: Chem. 2003, 196, 157. (l) Ma, B.;
Snyder, J. K. Organometallics 2002, 21, 4688. (m) Chen, Y.; Kiattansakul, R.;
Ma, B.; Snyder, J. K. J. Org. Chem. 2001, 66, 6932.
(6) See ref 4a, b and: (a) Hilt, G.; Janikowski, J. Angew. Chem. 2008, 120,
in press; Angew. Chem., Int. Ed. 2008, 47, in press.
(7) (a) Hilt, G.; Hess, W.; Harms, K. Synthesis 2008, 75. (b) Reference 3a;
see also: (c) Achard, M.; Tenaglia, A.; Buono, G. Org. Lett. 2005, 7, 2353. (d)
Achard, M.; Mosrin, M.; Tenaglia, A.; Buono, G. J. Org. Chem. 2006, 71, 2907.
(e) Toselli, N.; Martin, D.; Achard, M.; Tenaglia, A.; Bu¨rgi, T.; Buono, G. AdV.
Synth. Catal. 2008, 350, 280, and references cited therein.
(8) Compare results in ref 2b and ref 2f (regioselective Diels-Alder reaction,
as well as the results in ref 4a and ref 4b (regioselective cyclotrimerization).
(9) (a) Xu, B.-H.; Wu, D.-H.; Li, Y.-Z.; Yan, H. Organometallics 2007, 26,
4344. (b) Field, L. D.; Ward, A. J. J. Organomet. Chem. 2003, 681, 91. (c)
Yong, L.; Butenscho¨n, H. Chem. Commun. 2002, 2852. (d) Sugihara, T.;
Wakabayashi, A.; Nagai, Y.; Takao, H.; Imagawa, H.; Nishizawa, M. Chem.
Commun. 2002, 576. (e) Montilla, F.; Aviles, T.; Casimiro, V.; Ricardo, A. A.;
Nunes da Ponte, M. J. Organomet. Chem. 2001, 632, 113. (f) Field, L. D.; Ward,
A. J.; Turner, P. Aust. J. Chem. 1999, 52, 1085. (g) Sigman, M. S.; Fatland,
A. W.; Eaton, B. E. J. Am. Chem. Soc. 1998, 120, 5130. (h) Rhyoo, H.-Y.; Lee,
B. Y.; Yu, H. K. B.; Chung, Y. K. J. Mol. Catal. 1994, 92, 41. (i) Kotha, S.;
Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. (j) Yamamoto, Y.
Curr. Org. Chem. 2005, 9, 503.
(10) (a) Suzuki, H.; Itoh, K.; Ishii, Y.; Simon, K.; Ibers, J. A. J. Am. Chem.
Soc. 1976, 98, 8494. (b) Suzuki, H.; Itoh, K.; Ishii, Y.; Simon, K.; Ibers, J. A.
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Organometallics 2003, 22, 2267.
10.1021/jo800735x CCC: $40.75
Published on Web 06/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5187–5190 5187

SCHEME 1. Ligand-Dependent Cobalt-Catalyzed
Alder-Ene vs [2 + 2 + 2] Cycloaddtion Reaction
SCHEME 3. Cobalt-Catalyzed [2 + 2 + 2] Cycloaddition
Reaction
cyclohexadienes must be generated in an intermolecular fashion.
The separation from the accompanying cyclotrimerization side
product can be easily accomplished by column chromatography.
Nevertheless, the product consists of a mixture of regioisomers
which could not be separated. In the major isomer, the two
methyl groups are located next to each other in the cyclohexa-
diene ring system as was indicated by NMR spectroscopy and
later confirmed by X-ray analysis of two crystalline compounds.
It should also be noted that the oxidation of the 1,3-cyclohexa-
diene derivative by oxygen is a relatively slow process compared
to the oxidation of 1,4-cyclohexadiene derivatives so that the
dihydroaromatic products can be isolated without extra precau-
tion or exclusion of air. However, oxidation to the corresponding
aromatic products is sometimes encountered. In the case of
product 3c the second double bond does not participate in the
cyclization process, thus opening a new reaction pathway to
other products, nor was it incorporated in a second cycloaddition
process. The steric bulk of the alkenes utilized for the formation
of products 3d and 3e reduced the yields, but the major problem
with this type of product was the concurrent cyclotrimerization
reaction of the alkyne. This process becomes predominant with
terminal alkynes where only 5-10% of the cyclohexadiene
product is obtained, so that these starting materials can not be
applied in this [2 + 2 + 2] cycloaddition reaction. The next set
of experiments was conducted utilizing ethyl phenyl propynoate
(Scheme 3) as the alkyne component. The sterical bulk of the
phenyl group is expected to reduce the reactivity of the cobalt
catalyst, so that the cyclotrimerization reaction of the alkyne
should also be less favorable. We were delighted to find
considerably increased yields of the desired cyclohexadiene
derivatives as well as a reduced amount of the cyclotrimerization
side product.
SCHEME 2. Cobalt-Catalyzed [2 + 2 + 2] Cycloaddition
Reaction
TABLE 1. Cobalt-Catalyzed [2 + 2 + 2] Cycloaddition Utilizing
Ethyl Butynoate as Starting Material
Therefore, we applied the Co(dppp)Br2 catalyst precursor in
the [2 + 2 + 2] cycloaddtion reaction with several terminal
alkenes utilizing ethyl phenyl propynoate. The results are
summarized in Table 2.
Fortunately, in this series of experiments, the regiochemistry
of the products of type 4 is uniform, placing the two phenyl
substituents on the cycloxadiene ring exclusively in a 1,2-
relation. Noteworthy are the products 4c and 4g which provide
rich opportunities for follow-up reactions.
a Combined yields of the regioisomers. The percentage of the other
isomers (methyl groups in 1,3-relation) range from 5 to 15%. b Ratio of
regioisomers. Shown is the major regioisomer. c GC yield of the
cyclotrimerization side products.
Surprisingly, product 4h, which was generated from 3-buten-
1-ol, was obtained in a good yield of 65%, whereas the
corresponding transformation, utilizing 2-propen-1-ol (scheme
4), led to lactonization to afford 6c in 62% overall yield. The
reaction with the corresponding 1-methyl-2-propen-1-ol led to
product 6d in excellent 81% yield when taking into account
that three new carbon-carbon bonds were formed accompanied
by a lactonization reaction to generate a new carbon-oxygen
bond. Intermediates of type 5 were identified as the primary
product by GCMS which subsequently cyclized to the lactone.
In contrast, the transformations of the two alkenoles with ethyl
butynoate led to the corresponding lactones 6a and 6b in
moderate yields in both cases. Unfortunately, an intramolecular
approach utilizing the unsaturated ester 7 did not led to the
desired lactone product. This can be rationalized by the transoid
mation applying the Co(dppp)Br2 catalyst precursor led to the
corresponding 1,3-cyclohexadiene product 2. Therefore, we
applied the Co(dppp)Br2 catalyst precursor in the [2 + 2 + 2]
cycloaddtion reaction with terminal alkenes for the formation
of polysubstituted 1,3-cyclohexadienes (Scheme 2).11
The results of the application of ethyl butynoate are sum-
marized in Table 1.
The yields for the reactions with the butyric ester are moderate
to good when taking into account that polysubstituted 1,3-
(11) (a) For the proposed mechanism of the [2 + 2 + 2] cycloaddition, see
ref 10 and: Agenet, N.; Gandon, V.; Vollhardt, K. P. C.; Malacria, M.; Aubert,
C. J. Am. Chem. Soc. 2007, 129, 8860. (b) Dazinger, G.; Torres-Rodrigues, M.;
Kirchner, K.; Calhorda, M. J.; Costa, P. J. J. Organomet. Chem. 2006, 691,
4434. (c) Diercks, R.; Eaton, B. E.; Gu¨rtzgen, S.; Jalisatgi, S.; Matzger, A. J.;
Radde, R. H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1998, 120, 8247.
5188 J. Org. Chem. Vol. 73, No. 13, 2008

TABLE 2. Cobalt-Catalyzed [2 + 2 + 2] Cycloaddition Utilizing
Ethyl Phenyl Propynoate as Starting Material
SCHEME 4. Cobalt-Catalyzed [2 + 2 + 2] Cycloaddition
Reaction and Lactonization
SCHEME 5. Iron-Initiated Cyclization Reactions
Friedel-Crafts-type cyclization of the second ester functionality
with the less electron rich phenyl substituent was not observed.
However, the transformation of the 1,3-cyclohexadiene
derivative 4d led to different observations. In the presence of
an excess of iron(III) chloride (5.2 equiv) and prolonged reaction
times (96 h), the oxidation of the dihydroaromatic ring to yield
compound 9 in an acceptable yield (49%) was observed
alongside the two Friedel-Crafts-type cyclizations of the ester
functionalities to the phenyl rings.
conformation of the ester 7 which is much more favorable than
adoption of a cisoid conformation. The cisoid conformation
apparently is not adopted during the coordination of unsaturated
groups to the cobalt center. This would lead to the desired
cyclization process. In contrast, for compound 7 cyclotrimer-
ization of the alkynes is found and the alkene functionality is
untouched.
The identity of the products was verified using two-
dimensional NMR techniques and by the X-ray analysis of two
crystalline products 4h and 6a. Nevertheless, the high regiose-
lectivity with which the three starting materials are incorporated
is remarkable. Only very minor signals attributed to regioisomers
were found by NMR analysis (see the Supporting Information).
The cyclohexadiene derivative 4g can be cyclized under mild
reaction conditions utilizing an excess of FeCl3 (5.2 equiv) in
nitromethane/dichloromethane (1:1) (Scheme 5) at ambient
temperature. Under these reaction conditions, the terphenyl
diester intermediate leads to the corresponding dihydroanthrone
derivative 8 which was isolated in 52% yield. A further
Summary
In summary, we have developed an intermolecular, atom-
economic synthetic method that allows prompt access to
polysubstituted 1,3-cyclohexadiene derivatives bearing func-
tional groups suited to interesting follow-up chemistry, such as
the cyclization to anthrone-type products. The chemo- and
regioselectivities of the formation of 1,3-cyclohexadienes from
phenyl propynoates are good to excellent and the yields are in
a preparatively useful range, allowing the exploration of further
applications of these polyfunctionalized and polysubstituted
compounds.
J. Org. Chem. Vol. 73, No. 13, 2008 5189

1.76-1.64 (m, 2H), 1.54-1.44 (m, 1H), 0.96 (dd, 6H, J ) 3.3, 6.3
Hz), 0.81 (dt, 6H, J ) 2.7, 7.1 Hz). 13C NMR (75 MHz, CDCl3):
δ ) 168.8, 168.7, 143.1, 142.3, 138.4, 138.3, 135.6, 128.9, 128.8,
127.7, 127.0, 126.5, 60.2, 39.3, 31.9, 28.8, 25.2, 23.7, 21.5, 13.4.
IR (film, cm-1): 3056, 3025, 2870, 1705, 1603, 1576, 1490, 1465,
1443, 1171, 1100, 1073, 1019, 915, 859, 759. MS (EI): m/z 432
(6, [M+]), 417 (1, [M+ - Me]), 387 (14, [M+ - OEt]), 374 (5),
359 (16), 329 (4), 313 (85), 283 (39), 269 (5), 257 (100), 241 (9),
228 (36), 215 (12), 202 (8), 165 (5). HRMS (EI): m/z calcd for
C28H32O4 432.2301 [M+], found m/z 432.2303.
Experimental Section
General Methods. All reactions were carried out under an argon
atmosphere in flame-dried glassware. Dichloromethane was distilled
under nitrogen from P4O10, and ZnI2 was dried in vacuo at 150 °C
prior to use. Commercially available materials were used without
further purification. Structural assignments were made by NOESY
NMR (mixing time ) 1.5 s).
Representative Procedure for the [2 + 2 + 2] Cycloadditon.
Synthesis of Diethyl 5-Isobutyl-2,3-diphenylcyclohexa-1,3-diene-
1,4-dicarboxylate (4d). Zinc iodide (64 mg, 0.2 mmol, 20 mol %),
zinc dust (13 mg, 0.2 mmol, 20 mol %), and CoBr2 (dppp) (63
mg, 0.1 mmol, 10 mol %) are suspended in 1.0 mL of dichlo-
romethane. Then 4-methyl-1-pentene (0.17 mL, 1.0 mmol) and ethyl
3-phenylpropiolate (0.41 mL, 2.5 mmol) were added to the reaction
mixture, which was stirred for 16 h. The reaction mixture was
filtered over a short pad of silica gel, and then the solvent was
removed under vacuum. Purification by flash column chromatog-
raphy (pentane/methyl tert-butyl ether 5:1) gave the desired product
Acknowledgment. We thank the German Science Foundation
(Deutsche Forschungsgemeinschaft) for financial support.
Supporting Information Available: Experimental proce-
dures detailed X-ray structures of 4h and 6a and full charac-
terization of the compounds 3a-e, 4a-h, 6a-d, 8, and 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
4d (370 mg, 0.86 mmol, 86%) as a colorless oil. H NMR (300
MHz, CDCl3): δ ) 7.04-7.00 (m, 6H), 6.80-6.76 (m, 4H),
3.91-3.82 (m, 4H), 2.96-2.88 (m, 1H), 2.82-2.72 (m, 2H),
JO800735X
5190 J. Org. Chem. Vol. 73, No. 13, 2008