Cobalt catalysis at the crossroads: cobalt-catalyzed alder-ene reaction versus [2 + 2] cycloaddition

Article abstract of DOI:10.1021/ol100266u

(Figure Presented) The application of bidentate phosphine ligands in cobalt-catalyzed transformations of cyclic alkenes such as cyclopentene and cycloheptene with internal alkynes led to a chemoselective Alder-ene or a [2 + 2] cycloaddition reaction depending on the electronic nature of the alkyne and the bite angle of the ligand used.

Full text of DOI:10.1021/ol100266u

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1536-1539
Cobalt Catalysis at the Crossroads:
Cobalt-Catalyzed Alder-Ene Reaction
versus [2 + 2] Cycloaddition
Gerhard Hilt,* Anna Paul, and Jonas Treutwein
Fachbereich Chemie, Philipps-UniVersita¨t Marburg, Hans-Meerwein-Strasse,
35043 Marburg, Germany
hilt@chemie.uni-marburg.de
Received February 2, 2010
ABSTRACT
The application of bidentate phosphine ligands in cobalt-catalyzed transformations of cyclic alkenes such as cyclopentene and cycloheptene
with internal alkynes led to a chemoselective Alder-ene or a [2 + 2] cycloaddition reaction depending on the electronic nature of the alkyne
and the bite angle of the ligand used.
The application of cobalt complexes in modern organic
synthesis for the atom-economic formation of new carbon-
carbon bonds is of great interest.1 Cycloadditions are a
prototype transformation, and several different types of such
transformations have been described by us2 and other groups3
over the past decade. We recently reported the cobalt-
catalyzed [2 + 2] cycloaddition of mono- and bicyclic
alkenes with alkynes4 and the Alder-ene reaction utilizing
similar starting materials.5 The [2 + 2] cycloaddition of
cyclopentene with internal alkynes such as diphenyl acetylene
was the first example of a transition-metal-catalyzed forma-
tion of a cyclobutene derivative utilizing a monocyclic
alkene. Product 1 was obtained with an excellent yield of
91% utilizing cobalt bromide bis-1,2-diphenylphosphino-
propane [CoBr2(dppp)] as the catalyst (20 mol %) (Scheme
1). On the other hand, the Alder-ene product 2 was observed
as the main product accompanied by 1 (1/2 ) 25:75) as an
inseparable mixture when cobalt bromide 1,2-bis(diphe-
nylphoshino)ethane [CoBr2(dppe)] was applied.
(3) (a) Achard, M.; Tenaglia, A.; Buono, G. Org. Lett. 2005, 7, 2353.
(b) Pardigon, O.; Buono, G. Tetrahedron: Asymmetry 1993, 4, 1977. (c)
Pardigon, O.; Tenaglia, A.; Buono, G. J. Org. Chem. 1995, 60, 1868. (d)
Tenaglia, A.; Pardigon, O.; Buono, G. J. Org. Chem. 1996, 61, 1129. (e)
Pardigon, O.; Tenaglia, A.; Buono, G. J. Mol. Catal. A: Chem. 2003, 196,
157. (f) Ma, B.; Snyder, J. K. Organometallics 2002, 21, 4688. (g) Chen,
Y.; Kiattansakul, R.; Ma, B.; Snyder, J. K. J. Org. Chem. 2001, 66, 6932.
(h) Doszczak, L.; Tacke, R. Organometallics 2007, 26, 5722. (i) Doszczak,
L.; Fey, P.; Tacke, R. Synlett 2007, 753. (j) Goswami, A.; Ito, T.; Okamoto,
S. AdV. Synth. Catal. 2007, 349, 2368. (k) Xu, B. H.; Wu, D.-H.; Li, Y.-Z.;
Yan, H. Organometallics 2007, 26, 4344. (l) Field, L. D.; Ward, A. J. J.
Organomet. Chem. 2003, 681, 91. (m) Yong, L.; Butenscho¨n, H. Chem.
Commun. 2002, 2852. (n) Sugihara, T.; Wakabayashi, A.; Nagai, Y.; Takao,
H.; Imagawa, H.; Nishizawa, M. Chem. Commun. 2002, 576. (o) Montilla,
F.; Aviles, T.; Casimiro, T.; Ricardo, A. A.; Nunes da Ponte, M. J.
Organomet. Chem. 2001, 632, 113. (p) Field, L. D.; Ward, A. J.; Turner,
P. Aust. J. Chem. 1999, 52, 1085. (q) Sigman, M. S.; Fatland, A. W.; Eaton,
B. E. J. Am. Chem. Soc. 1998, 120, 5130. (r) Rhyoo, H.-Y.; Lee, B. Y.;
Yu, H. K. B.; Chung, Y. K. J. Mol. Catal. 1994, 92, 41. (s) Kotha, S.;
Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. (t) Yamamoto,
Y. Curr. Org. Chem. 2005, 9, 503. (u) Chang, H. T.; Jeganmohan, M.;
Cheng, C. H. Org. Lett. 2007, 9, 505. (v) Saino, N.; Amemiya, F.; Tanabe,
E.; Kase, K.; Okamoto, S. Org. Lett. 2006, 8, 1439. (w) Wu, M. S.;
Shanmugasundaram, M.; Cheng, C. H. Chem. Commun. 2003, 718.
(4) Treutwein, J.; Hilt, G. Angew. Chem., Int. Ed. 2008, 47, 6811.
(5) Hilt, G.; Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8500.
(1) (a) Hess, W.; Treutwein, J.; Hilt, G. Synthesis 2008, 3537. (b) Omae,
I. Appl. Organomet. Chem. 2007, 21, 318. (c) Laschat, S.; Becheanu, A.;
Bell, T.; Baro, A. Synlett 2005, 2547. (d) Varela, J. A.; Saa´, C. Chem. ReV.
2003, 103, 3787. (e) Malacria, M.; Aubert, C.; Renaud, J. L. In Science of
Synthesis: Houben-Weyl Methods of Molecular Transformations; Lautens,
M., Trost, B. M., Eds.; Thieme: Stuttgart, 2001; Vol. 1, p 439. (f) Welker,
M. E. Curr. Org. Chem. 2001, 5, 785. (g) Saito, S.; Yamamoto, Y. Chem.
ReV. 2000, 100, 2901. (h) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan,
R. J. Chem. ReV. 1996, 96, 635. (i) Lautens, M.; Klute, W.; Tam, W. Chem.
ReV. 1996, 96, 49.
(2) (a) Hilt, G.; Janikowski, J. Org. Lett. 2009, 11, 773. (b) Treutwein,
J.; Hilt, G. Angew. Chem., Int. Ed. 2008, 47, 6811. (c) Hilt, G.; Paul, A.;
Harms, K. J. Org. Chem. 2008, 73, 5187. (d) Hilt, G.; Janikowski, J. Angew.
Chem., Int. Ed. 2008, 47, 5243. (e) Hilt, G.; Janikowski, J.; Hess, W. Angew.
Chem., Int. Ed. 2006, 45, 5204. (f) Hilt, G.; Vogler, T.; Hess, W.; Galbiati,
F. Chem. Commun. 2005, 1474. (g) Hilt, G.; Korn, T. J. Tetrahedron Lett.
2001, 42, 2783. (h) Hilt, G.; Hengst, C.; Hess, W. Eur. J. Org. Chem. 2008,
2293.
10.1021/ol100266u  2010 American Chemical Society
Published on Web 03/02/2010

previously, the use of pyridine-imine ligands2a,d,e as well
as diaryl sulfide ethane-type ligands2h led selectively to the
cyclotrimerization product even if larger amounts of cyclo-
pentene were applied. Other phosphine ligands utilized in
this reaction (see Figure 1) gave no conversion of the starting
materials and were disregarded for further investigation.
Scheme 1. Cobalt-Catalyzed [2 + 2] Cycloaddition and
Alder-Ene Reaction with Diphenyl Acetylene as Substrate
This situation became more interesting when we used 1,4-
dimethoxybut-2-yne as substrate (Scheme 2). In these
Figure 1. Other ligands tested in the reaction of cyclopentene with
1,4-dimethoxybut-2-yne.
Scheme 2. Cobalt-Catalyzed [2 + 2] Cycloaddition and
Alder-Ene Reaction with 1,4-Dimethoxybut-2-yne as Substrate
To investigate the chemoselectivity for both cobalt com-
plexes the reaction between cyclopentene and symmetrical
as well as unsymmetrical internal alkynes was performed
(Scheme 3). The cycloaddition/Alder-ene ratios were de-
Scheme 3. Cobalt-Catalyzed Alder-Ene Reaction or [2 + 2]
Cycloaddition of Cyclopentene with Unsymmetrical Alkynes
reactions, the chemoselectivity was altered significantly.
Now, the [2 + 2] cycloaddition product 3 was obtained as
a mixture of products 3 and 4 in 23% yield (3/4 ) 56:44)
utilizing the [CoBr2(dppp)] catalyst while product 4 was
generated in 99% yields as the sole product utilizing the
[CoBr2(dppe)] complex.
Therefore, we propose that the chemoselectivity of the
transformation is determined at the crossroad of a common
intermediate. Early on in this investigation we realized that
depending on the nature of the substituents on the alkyne
and the bite angle of the bidentate phosphine ligands both
pathways were possible. Therefore, we were interested in
investigating which parameters controlled the chemoselec-
tivity of these reactions.
termined via 1H NMR spectroscopy or GC analysis and the
results are presented in Table 1.
It turned out that in almost every case by applying the
CoBr2dppp complex the formation of the cycloaddition
products of type 5 is favored while the cobalt dppe complex
predominantly forms the Alder-ene adducts of type 6 as
the major product. However, the nature of the alkyne also
seems to have an effect on the selectivity of the reaction
since alkynes which exclusively form the cyclobutene
derivative with the cobalt dppp complex generate a mixture
of both products when the cobalt dppe complex is used and
vice versa. With diphenyl acetylene (Table 1, entry 1) or
2-(phenylethynyl)thiophene (entry 5) and the cobalt dppp
complex the cyclobutenes 5a and 5c are obtained as the only
product, whereas the 1,4-dienes 6a and 6c are formed as
mixtures with cyclobutenes 5a and 5c when the cobalt dppe
complex is used.
To this end, we examined the dependency of the cobalt-
catalyzed transformation of cyclopentene with 1,4-dimethoxy-
but-2-yne (Scheme 2) on the ligand system.
A rather low conversion was observed (∼5%) for the test
reaction using 1,2-bis(diphenylphosphino)benzene as ligand.
Surprisingly, smaller bite angles as obtained with 1,2-
bis(diphenylphosphino)methane (dppm) as well as larger bite
angles obtained with 1,2-bis(diphenylphosphino)butane (dppb),
1,2-bis(diphenylphosphino)hexane (dpph), and BINAP led
to no conversion of the starting materials. While 1,1′-
bis(diphenylphosphino)ferrocene (dppf) gave about 33%
conversion, the cyclotrimerization product of the alkyne was
found to be the predominant product. As we demonstrated
In the case of (cyclohexenylethynyl)benzene (entry 3), the
conversion with the cobalt dppp as well as the cobalt dppe
Org. Lett., Vol. 12, No. 7, 2010
1537

Table 1. Results of the Cobalt-Catalyzed Reactions of Internal Alkynes with Cyclopentenea
a Catalyst system A: CoBr2(dppp) (20 mol %), zinc dust (40 mol %), zinc iodide (40 mol %). Catalyst system B: CoBr2(dppe) (20 mol %), zinc dust (40
mol %), zinc iodide (40 mol %). b The ratio of the regioisomers (5:6) is given in parentheses. c cHex ) cyclohexyl. d 6c consists of a mixture of regioisomers,
see text.
complex leads to the cyclobutene product 5b without any
traces of the 1,4-diene. In the cases when 1,3-diynes are used
(entries 7 and 9), the type of substituent (phenyl or SiMe3)
on the diynes influences the chemoselectivity drastically. A
rationale could be the better stabilization of intermediate III
(see Scheme 4) by a silyl substituent. Alkynes bearing bulky
substituents such as 1,2-bis(trimethylsilyl)acetylene were
unreactive under these conditions (entries 11 and 12).
When alkyl-aryl-substituted alkynes are used, products
of type 5 are predominantly formed utilizing catalyst system
A. On the other hand, products of type 6 are generated with
catalyst system B. Exceptions are those alkynes where an
oxygen is in the propargylic position (entries 21 and 25)
where the Alder-ene products 6k and 6m are formed
predominantly by catalyst system A as well. In these cases,
additional coordination of the oxygen functionalities might
influence the reaction pathway. In contrast, sulfur and
nitrogen in a propargylic position (entries 27 and 29) as well
as oxygen functional groups further removed from the triple
bond did not exhibit this effect on catalyst system A (entry
23).
As already noted above, we assume that the starting
materials coordinate to the cobalt center (I) to begin with
(Scheme 4). The common cobaltacylopentene intermediate
II is obtained upon formal oxidative addition. At this stage,
the interplay of substituents and ligands applied determine
the chemoselectivity of the reaction.
With the dppp ligand, reductive elimination leads to the
cyclobutene derivatives of type 5. For the formation of the 1,4-
dienes a ꢀ-hydride elimination leading to intermediate III takes
1538
Org. Lett., Vol. 12, No. 7, 2010

substituent in the main product is adjacent to the cyclopen-
tenyl substituent. In all other cases, a single regioisomer is
formed.
Scheme 4. Cobalt-Catalyzed Alder-Ene Reaction or [2 + 2]
Cycloaddition of Cyclopentene with Unsymmetrical Alkynes
In addition to cyclopentene, we were also interested if
other cyclic alkenes could be used in the cobalt catalyzed
transformations. Therefore, 1,4-dimethoxybut-2-yne as a
representative alkyne was reacted with cyclic alkenes. To
our surprise, reactions with cyclohexene were unsuccessful
whereas the conversions with cycloheptene gave the desired
products. The results for the conversions of cycloheptene
with alkynes are summarized in Scheme 5. The reactivity
of cycloheptene is lower than cyclopentene so that the
trimerization of the alkyne becomes predominant. Neverthe-
less, the Alder-ene products of type 7/8 are formed in
acceptable yields while the corresponding products 9 of the
[2 + 2] cycloaddition are always the minor component.
When mixtures were obtained, the separation of the
products could only be realized for the products 7a/9a and
7e/9e. The general characteristics of the reaction of cyclo-
heptene are similar to those with cyclopentene in terms of
E/Z selectivity and regioselectivity. A mixture of the two
regioisomers 7c and 8c was obtained only with 2-(phenyl-
ethynyl)thiophene as starting material. Concerning the
chemoselectivities, changes can be identified with respect
to the reactions with cyclopentene, indicating that the ring
size of the alkene also plays an important role influencing
whether reductive elimination or ꢀ-hydride elimination is the
predominant reaction taking place. In the reactions of
substrates with functional groups in the propargylic position
only single Alder-ene isomers were detected.
place and the Alder-ene products of type 6 are formed. This
pathway is favored when the dppe ligand is utilized.
The first step of the catalytic cycle leading to cobaltacy-
clopentene II is decisive for the regioselectivity in the
Alder-ene product (Scheme 5). Only when 2-(phenylethy-
Scheme 5. Cobalt-Catalyzed Alder-Ene Reaction or [2 + 2]
Cycloaddition of Cyclopentene with Unsymmetrical Alkynes
In conclusion, we have demonstrated that the cobalt-
catalyzed transformation of cyclopentene and, to a lesser
extent, cycloheptene with internal alkynes leads to the desired
adducts in acceptable to excellent yields. The chemoselec-
tivity toward the Alder-ene or the [2 + 2] cycloaddition
products is dependent on the alkyne substituents as well as
on the diphosphine ligand used.
Acknowledgment. This work was partly supported by the
BASF SE and the German Science Foundation. Their support
is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full characterization of the compounds obtained
in pure form. This material is available free of charge via
the Internet at http://pubs.acs.org.
nyl)thiophene was used were both regioisomers of 6c
detected with a 79:21 ratio. In this case, the thiophene
OL100266U
Org. Lett., Vol. 12, No. 7, 2010
1539