Cobalt-catalyzed versus uncatalyzed intramolecular Diels-Alder cycloadditions

Article abstract of DOI:10.1016/j.tetlet.2017.11.052

The intramolecular [4+2] cycloadditions of dienynes was investigated using cobalt-based catalysts. Substrates without substitution on alkyne moiety were found to react under thermal activation. The use of a cobalt salt as catalyst made reactions cleaner by limiting the formation of byproducts. Cycloadditions with dienynes possessing a substituent on the alkyne pattern occurred only in presence of a cobalt catalyst which displayed a moderate to good activity depending on the substrate patterns.

Full text of DOI:10.1016/j.tetlet.2017.11.052

Accepted Manuscript
Cobalt-Catalyzed Versus Uncatalyzed Intramolecular Diels-Alder Cycloaddi-
tions
Bohdan Biletskyi, Alphonse Tenaglia, Hervé Clavier
PII:
S0040-4039(17)31486-7
https://doi.org/10.1016/j.tetlet.2017.11.052
TETL 49495
DOI:
Reference:
Tetrahedron Letters
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11 October 2017
24 November 2017
28 November 2017
Please cite this article as: Biletskyi, B., Tenaglia, A., Clavier, H., Cobalt-Catalyzed Versus Uncatalyzed
Intramolecular Diels-Alder Cycloadditions, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.11.052
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Cobalt-Catalyzed Versus Uncatalyzed
Intramolecular Diels-Alder Cycloadditions
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Bohdan Biletskyi, Alphonse Tenaglia, Hervé Clavier

1
Tetrahedron Letters
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Cobalt-Catalyzed Versus Uncatalyzed Intramolecular Diels-Alder Cycloadditions
Bohdan Biletskyia , Alphonse Tenagliaa and Hervé Claviera, ∗
a Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France
ARTICLE INFO
ABSTRACT
Article history:
Received
The intramolecular [4+2] cycloadditions of dienynes was investigated using cobalt-based
catalysts. Substrates without substitution on alkyne moiety were found to react under thermal
activation. The use of a cobalt salt as catalyst made reactions cleaner by limiting the formation
of byproducts. Cycloadditions with dienynes possessing a substituent on the alkyne pattern
occurred only in presence of a cobalt catalyst which displayed a moderate to good activity
depending on the substrate patterns.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Cobalt
Cycloaddition
Cycloisomerization
Dienyne
Carbocycle
Cycloisomerizations are valuable transformations to prepare
straightforwardly cyclic, bicyclic or polycyclic compounds from
simple and readily available acyclic materials.1 Moreover, they
belong to the class of atom-economy processes since no formal
gain or loss of any atom takes place.2 However they are generally
promoted by transition metals which allow to activate
polyunsaturated substrates and trigger the formation of the new
C-C bonds under mild reaction conditions.3,4 For example, the
intramolecular [4+2] cycloaddition of dienynes was successfully
investigated with various transition metals (Scheme 1). Wender
reported first an efficient Ni(0)-based catalytic system under mild
reaction conditions which unfortunately gave a rather modest
endo/exo preference (1.8-2.2/1).5 Shortly after, Livinghouse
demonstrated that Rh(I)-based catalysts showed an even better
efficiency since [4+2] cycloadducts were isolated with good to
excellent diastereoselectivity6 and the use of chiral phosphines
allowed to perform this transformation in an enantioselective
fashion.7 Then, efforts focused on the study and improvement of
Rh-catalysis,8 and the transposition to iridium-catalysis did not
led to better results.9 Recently, Chung reported that [4+2]
cycloadditions of dienynes can be achieved at room temperature
with a gold(I) catalyst but only for substrates featuring terminal
alkynes (R2 = H).10
R2
R2
R1
Z
[M]
Z
R1
[M] = [Ni], Wender 1989
H
[M] = [Rh], Livinghouse 1990, Gilbertson 1998
[M] = [Ir], Shibata 2002
[M] = [Au], Chung 2011
[M] = [Co], This work
Scheme 1. Transition metal-promoted intramolecular Diels-
Alder cycloadditions of dienynes.
intramolecular Diels-Alder cycloadditions have been described
so far.13
Based on our previous studies on the cobalt-mediated [6+2]
cycloaddition between cycloheptatriene and 2π-partners (alkynes
or allenes),14 we started to explore the cycloaddition of dienyne
1a with CoI2 as cobalt source, 1,2-bis(diphenylphoshino)ethane
(dppe), zinc metal as reducing agent and ZnI2 as Lewis acid
(Table 1, entry 1). With this catalytic system, at 80 °C in
dichloroethane, after 20 h of reaction, 34% of the expected [4+2]
cycloadduct 2a was isolated (entry 1). Pleasingly, the reaction
proceeded with a high diastereoselectivity, and tipycally 2a was
isolated with high diastereomeric ratio >20:1.15 Importantly, the
solvent needed to be degassed to avoid the formation of
substantial amounts of dimerization products16 or oxidized
product 3a. In the absence of ZnI2, the catalytic system
performed better and 60% of 2a was isolated (entry 2). Then,
many bidentate ligands were tested, among them dppe, 1,2-
bis(diphenylphoshino)methane (dppm) or 1,10-phenanthroline
(entries 2-4) but only minor changes in chemical yields and
Given the costs associated with the use of noble transition metals
and chiral phosphines, it will be interesting to develop a new
catalytic system for this transformation based on an earth
abundant transition metal. Considering that cobalt showed a good
ability to catalyze various cycloadditions,11 it seems to be a good
candidate to investigate. Of note, whereas several examples of
cobalt-mediated intermolecular [4+2] cycloadditions have been
reported in the literature,12 to the best of our knowledge, no
———
∗ Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron Letters
diastereoselectivies were observed. As an additional evidence of
the little impact of the ligand structure, when chiral ligands were
used no chiral induction was detected.17 The nature of the
cobalt(II) source was also found to be a minor parameter since
only little differences were obtained with CoI2, CoBr2, CoCl2 and
Co(OAc)2 (entries 2, 5-7). As the ligand structure did not impact
significantly the course of the reaction, we carried out
experiments without ligands (entries 8 and 9). Surprisingly, the
catalytic system Co(OAc)2 and zinc metal performed well with
the formation of 57% of 2a. Control experiments without
reducing agent were also achieved (entries 10-13). Whereas in
the case of CoI2 the yield slightly decreased, with Co(OAc)2 a
significant improvement was observed and 68% of 2a was
isolated. Co(OAc)2·4H2O and Co(OBz)2 exhibited somewhat
lower activities. Importantly, we performed a control experiment
without catalyst and, at 80 °C, 36% of cycloadduct 2a with an
excellent diastereoselectivity (dr > 20:1) along with 41% of 3a
(entry 14).18 Of note, in the reactions carried out in presence of
cobalt, less than 10% of 3a was generally observed. The
oxidation process affording 3a took place only during the
reaction, since the purification step did not increase its quantity
and cyclohexadiene derivatives were found stable in solution few
days at room temperature. Thus, it appeared that the use of
Co(OAc)2 allowed to reduce the oxidation process more than
improve the reaction itself.
Table 1. Optimization of reaction conditions for the cobalt-
mediated [4+2] cycloadditiona
Entry
1
Catalytic system
CoI2, Zn, dppe, ZnI2
Yield %
34
2
CoI2, Zn, dppe
CoI2, Zn, dppm
CoI2, Zn, 1,10-phenanthroline
CoBr2, Zn, dppe
CoCl2, Zn, dppe
Co(OAc)2, Zn, dppe
CoI2, Zn
60
3
65
4
54
5
60
6
53
7
53
8
36
9
Co(OAc)2, Zn
CoI2
57
10
11
12
13
14
21
Co(OAc)2
68
Co(OAc)2·4H2O
Co(OBz)2
57
59
Then, we started to compare the uncatalyzed and cobalt-mediated
intramolecular Diels-Alder cycloadditions of various dienynes
featuring a terminal alkyne 1 (Table 2). Both reaction conditions
gave [4+2] cycloadducts 2 with high diastereoselectivities.
Compared to 1a, C- and O-tethered dienynes were found less
reactive. For example, 1b gave only 11% of corresponding
cycloadduct 2b under thermal activation along with 22% of 3b.
In presence of Co(OAc)2, the reaction performed better with less
oxidation competing (entries 3 and 4). Similar results were
obtained with dienyne 1c to the exception that this time the use of
none
36b
a
Conditions: [Co] (5 mol%), Zn (15 mol%), Ligand (5 mol%), ZnI2 (10
mol%), dienyne 1a (0.5 mmol), ClCH2CH2Cl (2 mL), 80 °C, 20 h.
b 41% of oxidized product 3a was also isolated.
Table 2. Comparison between uncatalyzed and cobalt-mediated intramolecular Diels-Alder cycloadditions of various dienynes 1a
Products
Entry
Substrate
Catalyst
[4+2] Cycloadduct 2b
Yield (%)
Oxidized product 3
Yield (%)
41
1
2
None
36
68
Co(OAc)2
<10
3
4
None
11
27
22
Co(OAc)2
<10
5
6
None
11
23
21
31
Co(OAc)2
7
8
None
60
60
15
TsN
Co(OAc)2
<10
1d
Ph
9
None
63
68
17
12
10
Co(OAc)2
a Conditions: Co(OAc)2 (4.4 mg, 5 mol%), dienyne 1 (0.5 mmol), ClCH2CH2Cl (2 mL) 80 °C, 20 h.
b Major diastereomer depicted.

3
Co(OAc)2 improved yields of both cycloadduct and oxidized
product (entries 5 and 6). Better outcomes were obtained for
dienynes 1d and 1e bearing a phenyl substituent at the terminal
position of the dienic moiety but no significant difference
between uncatalyzed and cobalt-catalyzed reactions could be
noticed (entries 7-10).
Table 3. Optimization of reaction conditions for substituted
dienyne 4aa
When the dienyne 4a with a methyl substituent on the alkyne
pattern was tested no reaction occurred either under thermal
conditions nor in presence of Co(OAc)2 or CoI2 (Table 3, entries
1-3). Therefore, we decided to reinvestigate the catalytic system
for this type of substrate. The catalytic system CoI2, Zn, dppe and
ZnI2 was found competent to give cycloadduct 5a (69%) along
with small amount of 6a (11% yield) (entry 4). It turned out that
the use of Co(OAc)2 instead of CoI2 led to a substantial decrease
of the activity with only 10% of isolated cycloadduct 5a and 16%
of 6a (entry 5). Additional experiments proved the need of ZnI2
that upgraded the efficiency of the cobalt-based catalyst but did
not exhibit any activity itself (entries 6-8). Having in hands the
optimized reaction conditions, several substituted dienynes 4
have been tested (Table 4). Despite a good diastereoselectivity,
the catalytic system exhibited a reduced activity C- and O-
tethered dienynes and only low yields of 5b and 5c were obtained
along with higher quantities of aromatic products (entries 2 and
3). For 4d bearing a phenyl substituent at the terminal position of
the dienic moiety, only traces of cycloadduct 4d were isolated
(entry 4) whereas with the O-tethered analogous 4e a better yield
compared to dienyne 4c was reached (entry 5). Finally, with
trimethylsilyl-substituted dienyne 4f the catalytic system led to
the formation of 72% of the expected cycloadduct 5f and only
10% of oxidized product 6f (entry 6).
Entry
Catalytic system
Yield %
NR
1
2
3
4
5
6
7
8
None
Co(OAc)2
CoI2
NR
NR
CoI2, Zn, dppe, ZnI2
Co(OAc)2, Zn, dppe, ZnI2
CoI2, Zn, dppe
CoI2, Zn
69b
10c
NR
NR
ZnI2
NR
a Conditions: [Co] (5 mol%), Zn (15 mol%), dppe (5 mol%), ZnI2 (10 mol%),
dienyne 4a (0.5 mmol), ClCH2CH2Cl (2 mL), 80 °C, 20 h. NR = No
Reaction;
b 11% of oxidized product 3a was also isolated.
c 16% of 6a.
Table 4. 4 Scope investigation of cobalt-mediated intramolecular Diels-Alder cycloadditions of substituted dienynes 4a
Products
Entry
1
Substrate
[4+2] Cycloadduct 5b
Yield (%)
69
Oxidized product 6
Yield (%)
11
2
3
4
37
19
6
26
18
-
Me
MeO2C
MeO2C
4b
Me
5
6
31
72
Me
17
10
Ph
O
6e
TMS
Me
TMS
Me
TsN
TsN
H
6f
5f (dr > 20:1)
a Conditions: CoI2 (5 mol%), Zn (15 mol%), dppe (5 mol%), ZnI2 (10 mol%), dienyne 4 (0.5 mmol), ClCH2CH2Cl (2 mL), 80 °C, 20 h.

4
Tetrahedron
b Major diastereomer depicted.
(k) Canlas, G. M. R.; Gilbertson, S. R. Chem. Commun. 2014, 50, 5007-
5010.
In summary, cobalt-based catalysts promoted the intramolecular
[4+2] cycloaddition of dienynes. An important difference has
been noticed as a function of substrates structure. With dienynes
containing a terminal alkyne moiety, reactions performed without
catalyst gave the expected cycloadducts along with substantial
amounts of products resulting from their dehydrogenation. The
use of a cobalt salt as catalyst; here the best was found to be sole
Co(OAc)2; improved slightly the yields of [4+2] cycloadducts but
made reactions cleaner by lowering the oxidation process
whereas unwanted resulting dimerization16 can be circumvent by
the use of degassed solvents. With dienynes possessing a
substituent on the alkyne pattern, no reaction occurred without
cobalt and even ZnI2 as Lewis acid was required to activate the
catalyst. Once again, the nature of the tether as well as the one of
the substituents on both alkyne and diene moieties were found to
strongly influence the outcome of the highly diastereoselective
[4+2] cycloadditions. The development of more active cobalt-
based catalysts is currently underway in our laboratory.
9. Shibata, T.; Takasaku, K.; Takesue, Y.; Hirata, N.; Takagi, K. Synlett
2002, 1681-1682.
10. Kim, S. M.; Park, J. H.; Chung, Y. K. Chem. Commun. 2011, 47, 6719-
6721.
11. (a) Röse, P.; Hilt, G. Synlett 2016, 48, 463-492; (b) Amatore, M.; Aubert,
C.; Malacria, M.; Petit, M. In Science of Synthesis, Vol. 1 Update 2012/3,
Pliekter, B., Ed.; Thieme: Stuttgart, 2012, 1-121; (c) Hess, W.,
Treutwein, J.; Hilt, G. Synthesis 2008, 22, 3537-3562.
12. For selected examples, see: (a) Kuttner, J. R.; Warratz, S.; Hilt, G.
Synthesis 2012, 44, 1293-1303; (b) Pünner, F.; Hilt, G. Chem. Commun.
2012, 48, 3617-3619; (c) Hilt, G.; Hengst, C. J. Org. Chem. 2007, 72,
7337-7342; (d) Hilt, G.; Lüers, S.; Harms, K. J. Org. Chem. 2004, 69,
624-630.
13. [4+2] cycloadducts were observed as side products in intramolecular
Pauson-Khand reactions of dienynes, see: (a) Park, K. H.; Choi, S. Y.;
Kim, S. Y.; Chung, Y. K. Synlett 2006, 527-532; (b) Choi, S. Y.; Lee, S.
I.; Park, K. H.; Chung, Y. K. Synlett 2007, 1857-1862; For an
unsuccessful attempt, see reference 8e.
14. (a) Achard, M.; Tenaglia, A.; Buono, G. Org. Lett. 2005, 7, 2353–2356;
(b) Toselli, N.; Martin, D.; Achard, M.; Tenaglia, A.; Bürgi, T.; Buono,
G. Adv. Synth. Catal. 2008, 350, 280-286; (c) Clavier, H. Le Jeune, K.;
De Riggi, E.; Tenaglia, A.; Buono, G. Org. Lett. 2011, 13, 308-311.
15. Lower diastereomeric ratios were observed with substrates containing
little impurities.
Acknowledgments
This work was supported by the Ministère de l’Enseignement
Supérieur et de la Recherche (B. B. Ph.D. grant), the CNRS,
AMU, and Centrale Marseille.
16. For a more detailed discussion on the formation of dimers using
rhodium-based catalysts, see: reference 8b.
17. See the supporting information.
18. For a rare example of thermal intramolecular [4+2] cycloaddition of
dienyne, see: Karabiyikoglu, S.; Merlic, C. A. Org. Lett. 2015, 17, 4086-
489.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at.
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5
Highlights
Cobalt-promoted intramolecular [4+2]
cycloadditions of dienynes
Important differences as a function of substrates
structures have been noticed.
Excellent diastereoselectivities were obtained.