A highly practical instant catalyst for cyclotrimerization of alkynes to substituted benzenes

Article abstract of DOI:10.1021/ol0602295

A 2-(2,6-diisopropylphenyl)iminomethylpyridine (1a)/CoCl ₂·6H₂O/Zn reagent has been developed as an effective instant catalyst for the intra- and intermolecular cyclotrimerization of alkynes to substituted benzenes, making the method

Full text of DOI:10.1021/ol0602295

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1439-1442
A Highly Practical Instant Catalyst for
Cyclotrimerization of Alkynes to
Substituted Benzenes
Naoko Saino, Fumihiro Amemiya, Emi Tanabe, Kouki Kase, and
Sentaro Okamoto*
Department of Applied Chemistry, Kanagawa UniVersity, 3-27-1 Rokkakubashi,
Kanagawa-ku, Yokohama 221-8686, Japan
okamos10@kanagawa-u.ac.jp
Received January 26, 2006
ABSTRACT
A 2-(2,6-diisopropylphenyl)iminomethylpyridine (1a)/CoCl2‚6H2O/Zn reagent has been developed as an effective instant catalyst for the intra-
and intermolecular cyclotrimerization of alkynes to substituted benzenes, making the method extremely practical since the reagent, 1a/CoCl2
‚
6H2O/Zn, is inexpensive and easy to handle and the reaction is less sensitive to moisture and is reasonably general.
Cyclotrimerization of alkynes,1,2 which can be classified into
three types, i.e., an intramolecular reaction (type I, Scheme
1) and two intermolecular reactions (types II and III),
substituted and annulated benzenes as synthetic intermediates.
After the pioneering work of Reppe,1 complexes of many
transition metals have been developed as effective catalysts
or precursors for the transformation.
Among them, CpCoL complexes (Cp ) cyclopentadienyl)
involving CpCo(CO)2, CpCo(alkene)2, and CpCo(PPh3)2 have
been used most widely,4 where the nature of ligand L
influences the starting behavior of the catalyst: too effective
stabilization retards initiation of the catalyst, while, with too
weak stabilizing ligand(s), the complex tends to undergo
decomposition reactions. To avoid the difficulty and waste
associated with isolation and initiation of the catalyst, efforts
Scheme 1
continues to attract considerable attention by virtue of its
intrinsic atom economy,3 as well as the importance of
(3) Trost, B. M. Science 1991, 254, 1471. Trost. B. M. Acc. Chem. Res.
2002, 35, 695.
(1) Reppe, W.; Schweckendiek, W. J. Justus Liebigs Ann. 1948, 560,
104.
(4) Chang, C. A.; Francisco, C. G.; Gadek, T. R.; King, J. J. A.; Sternberg,
E. D.; Vollhardt, K. P. C. In Organic Synthesis Today and Tomorrow; Trost,
B. M., Hutchinson, C. R., Eds.; Pergamon Press: Oxford, 1981; pp 71-
83. Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 536.
Vollhardt, K. P. C. Pure Appl. Chem. 1985, 57, 1819. Vollhardt, K. P. C.
Pure Appl. Chem. 1993, 65, 153. Eickmeier, C.; Holmes, D.; Junga, H.;
Matzger, A. J.; Scherhag, F.; Shim, M.; Vollhardt, K. P. C. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 800. Aubert, C.; Buisine, O.; Petit, M.; Slowinski,
F.; Malacria, M. Pure Appl. Chem. 1999, 71, 1463. Slowinski, F.; Aubert,
C.; Malacria, J. Org. Chem. 2003, 68, 378 and references cited therein.
(2) Grotjahn, D. B. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Hegedus, L. S., Eds.; Pergamon:
Oxford, 1995; Vol. 12, p 741. Schore, N. E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon:
Oxford, 1991; Vol. 5, p 1129. Saito, S.; Yamamoto, Y. Chem. ReV. 2000,
100, 2901. Malacria, M.; Aubert, C.; Renaud, J. L. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; Lautens, M., Trost,
B. M., Eds.; Georg Thieme Verlag: Stuttgart, 2001; Vol. 1, pp 439-530.
10.1021/ol0602295 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/25/2006

in applications to synthesis of complex molecules2,4 and have
often been used as a benchmark reaction to evaluate the
synthetic potential of the method.
In this context, we wished to focus our investigation on
utilization of a stable cobalt salt, CoCl2‚6H2O, for the instant
generation of a catalyst, aiming to develop a user-friendly
and environmentally benign method at low cost. We intro-
duced 2-(2,6-diisopropylphenyl)iminomethylpyridine (1a)12
as a ligand into a CoCl2‚6H2O/Zn system and found that
this inexpensive, easily handled combination reagent, 1a/
CoCl2-6H2O/Zn, is an effective catalyst to perform the
reaction of types I-III with unique chemo- and regioselec-
tivity (see Figure 1 for the ligands and substrates employed
in the present study).
The results in Table 1 show the feasibility of a 1a/CoCl2‚
6H2O/Zn reagent for the partially intramolecular reactions
of type II. Thus, to a mixture of diyne 3a and alkyne 4a
(1.3 equiv) and zinc dust (10 mol %) in THF was added a
solution of a ligand and CoCl2‚6H2O in THF.13 After being
stirred for 5 min at 35-40 °C, the mixture was stirred at
room temperature (∼25 °C). As revealed in Table 1, although
the reaction without a ligand and that with PPh3, TMEDA,
2,2′-bipyridinyl, or 1,2-diimine 1d did not afford benzene
derivative 5aa at all (entries 1, 2, 5, 6, and 7), the reaction
with dppe (entry 3) or 2-iminomethylpyridine 1a (entry 8)
proceeded smoothly to provide 5aa quantitatively. The results
of the reactions with use of 2-iminomethylpyridines as a
ligand (entries 8-18) revealed the following characteris-
tics: Use of less bulky ligand 1b instead of 1a was not
effective (entry 13).14 Interestingly, use of 2 equiv of 1a to
CoCl2‚6H2O did not work (entry 9).15 The amount of catalyst
precursor could be reduced to 1 mol %, although a higher
temperature (∼40 °C) was applied to complete the reaction
in a reasonable amount of time (entry 10). Anhydrous CoCl2
could be used as well as its hydrate (entry 11). The reaction
is less sensitive to moisture so that it could proceed in
aqueous THF [THF/H2O ) 40/1 (v/v)] (entry 12). The
reaction with arylacetylene such as 4a and 4b proceeded
Figure 1.
have recently been made to generate an active catalyst in
situ by reduction of cobalt (II) halides in the presence of
substrate(s). This “instant” protocol requires a weak and
minimal amount of stabilizing ligand(s), and therefore, the
catalyst can be initiated under milder conditions and can be
expected to exhibit high reactivity. Regarding such concept,
Boennemann et al. reported a CoCl2‚6H2O/NaBH4 reagent
as a catalyst system for intermolecular reaction (type III).5
CoCl2/Mn and CoI2/PPh3/Mn have been developed as a
catalyst system for the intramolecular reaction (type I) by
Chiusoli et al.6 and Malacria et al.,7 respectively. We have
introduced a CoCl2/imidazolium carbene/Zn reagent for the
reaction of type I.8 Most recently, Hilt et al. have described
that a CoBr2/2PR3, disulfide, or diimine/Zn/ZnI2 reagent can
effectively catalyze intermolecular cyclotrimerization of
alkynes.9 However, it is somewhat surprising that no reaction
has been investigated for partially intramolecular reactions
(type II),10,11 which are synthetically useful as can be seen
(10) For the related instant procedures for Co-catalyzed Diels-Alder,
homo-Diels-Alder, pyridine formation, and allene-diyne-[2 + 2 + 2]
cycloaddition reactions, see: Co(acac)n/dppe/Et2AlCl: Lautens, M.; Tam,
W.; Lautens, J. C.; Edwards, L. G.; Crudden, C. M.; Smith, A. C. J. Am.
Chem. Soc. 1995, 117, 6863. Lyons, J. E.; Myers, H. K.; Schneider, A. J.
Chem. Soc., Chem. Commun. 1978, 636. CoX2(dppe)/Zn/ZnI2: Achard, M.;
Tenaglia, A.; Buono, G. Org. Lett. 2005, 7, 2353. Hilt, G.; Galbiati, F.
Synlett 2005, 829. Hilt, G.; Lueers, S.; Harms, K. J. Org. Chem. 2004, 69,
624. CoX2(PR3)2/Zn: Wu, M.-S.; Rayabarapu, D. K.; Cheng, C.-H.
Tetrahedron 2004, 60, 10005. Wu, M.-S.; Shanmugasundaram, M.; Cheng,
C.-H. Chem. Commun. 2003, 718. Pardigon, O.; Tenaglia, A.; Buono, G.
J. Org. Chem. 1995, 60, 1868. Duan, I. F.; Cheng, C. H.; Shaw, J. S.;
Cheng, S. S.; Liou, K. F. J. Chem. Soc., Chem. Commun. 1991, 1347.
(11) A NiBr2(dppe)/Zn system has been reported for the alkyne-
cyclotrimerization: Turek, P.; Kotora, M.; Tislerova´, I.; Hocek, M.; Votruba,
I.; C´ısarova´, I. J. Org. Chem. 2004, 69, 9224 and cited therein.
(12) Prepared from commercially available 2,6-diisopropylaniline and
pyridine-2-carboxaldehyde. For the results of the reactions with related
ligands other than 1a, see the Supporting Information.
(13) The solution prepared by simply mixing 1 and CoCl2‚6H2O in THF
could be stored at room temperature for more than 1 month under Ar.
(14) Probably generated less hindered species, 1b‚CoCl or 1c‚CoCl, by
reduction with Zn would be unstable and may decompose and/or precipitate
via the reactions such as dimerization and disproportionation.
(15) Presumably due to generation of stable (1a)2CoCl (formal 18-
electron complex), which would not form a metallacyclopentadiene
intermediate.
(5) Boennemann, H.; Brinkmann, R.; Schenkluhn, H. Synthesis 1974,
575.
(6) Chiusoli, G. P.; Costa, M.; Reverberi, S.; Terenghi, M. G. Transition
Met. Chem. 1989, 14, 238. Chiusoli, G. P.; Terenghi, G. Transition Met.
Chem. 1984, 9, 360.
(7) Slowinski, F.; Aubert, C.; Malacria, M. AdV. Synth. Catal. 2001, 343,
64.
(8) Saino, N.; Kogure, D.; Okamoto, S. Org. Lett. 2005, 7, 3065.
(9) Hilt, G.; Vogler, T.; Hess, W.; Galbiati, F. Chem. Commun. 2005,
1474. Hilt, G.; Hess, W.; Vogler, T.; Hengst, C. J. Organomet. Chem. 2005,
690, 5170.
1440
Org. Lett., Vol. 8, No. 7, 2006

Table 1. Type II Reactions with Various Ligandsa
Table 2. Representative Examples of Type II Reactiona
a Conditions: 3a (1.0 mmol), 4 (1.3 or 3.0 mmol), ligand, CoCl2‚6H2O
or CoCl2 (5 mol %), Zn dust (10 mol %), solvent(s) (4 mL). Reactions
were performed at room temperature (∼25 °C) after 5 min of stirring at
35-40 °C. b Unless otherwise indicated, 1H NMR yield. c Isolated yield.
selectively to give the corresponding 5 even with use of a
nearly stoichiometric amount of 4 (entries 8, 10-12, 14).
On the other hand, a 1:1 mixture of diyne 3a and alkylacety-
lene 4c provided 37% of product 5ac with formation of
dimerization product(s) derived from 3a (total 24%, for the
structures, see the Supporting Information) (entry 15). An
increase of the amount of 4c improved the yield of 5 to a
synthetically useful level (entry 16). Under similar conditions,
5ad and 5af were obtained in good yield (entries 17 and
18).
As revealed from Table 2, summarizing other representa-
tive examples of the 1a/CoCl2‚6H2O/Zn-catalyzed intermo-
lecular reaction of type II, a variety of 1,6- and 1,7-diynes
could couple with various alkynes 4 to provide the corre-
sponding tetra-, penta-, and hexasubstituted benzenes in good
to excellent yields, where high functional group compatibility
was attained and the formation of heterocyclic compounds
as well as carbocyclic ones proceeded smoothly. It was
noteworthy that the reactions of unsymmetrical diynes 3c
and 3d with terminal alkynes proceeded regioselectively and
the reaction with alkyl or aryl acetylenes showed an opposite
regioselectivity (entries 8-11).16 Although simple internal
a Conditions: 3 (1.0 mmol), 4 (1.3 or 3.0 mmol), 1a (6 mol %),
CoCl2‚6H2O (5 mol %), Zn dust (10 mol %), THF (4 mL). Reactions were
performed at room temperature (∼25 °C) after 5 min of stirring at 35-40
°C. b Isolated yield or yield of a mixture of regioisomers. c Regioisomeric
ratio. d Meta isomer was major. e Ortho isomer was major.
alkynes such as 4-octyne did not couple with diynes 3 (data
not shown), internal alkynes having an oxygen atom attached
to the propargyl carbon(s) such as propargyl alcohols 4g-k
(entries 1-5), propargyl ether 4l (entry 6), and R,â-acetylenic
ester 4m (entry 7) were good substrates.17 This feature
enables the chemoselective reaction of poly-ynes: the
reaction of diynes 4n-p with 3a proceeded selectively at
the propargyl alcohol moiety to yield benzyl alcohols with
an alkyne substitution (entries 18-20).17,18
Table 3 summarizes the results of the intermolecular
reaction (type III)5,9 with a 1a/CoCl2‚6H2O/Zn. The reagent
catalyzed effectively the reaction of 1-alkynes to yield 1,2,4-
trisubstituted benzenes 6 selectively or exclusively (entries
(17) For a directing effect with a hydroxyl group, see: Witulski, B.;
Stengel, T.; Ferna´ndez-Herna´ndez, J. M. Chem. Commun. 2000, 1965 and
references therein.
(16) Regioselectivity in catalytic cyclotrimerization reactions has been
well-documented: Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am.
Chem. Soc. 2003, 125, 12143.
(18) Ni-catalyzed selective reaction of 1,4-disubstituted 1,3-diynes has
been reported: Jeevanandam, A.; Korivi, R. P.; Huang, I.; Cheng, C. Org.
Lett. 2002, 5, 807.
Org. Lett., Vol. 8, No. 7, 2006
1441

Table 3. Type III Reactionsa
Table 4. Type I Reactionsa
a Conditions: 2 (1.0 mmol), 1 (6 mol %), CoCl2‚6H2O (5 mol %), Zn
dust (10 mol %), THF (4 mL)/0.25 M solution. Reactions were performed
at room temperature (∼25 °C) after 5 min stirring at 35-40 °C. b Carried
out in a 0.025 M solution (40 mL of THF) for 36 h.
a Conditions: 4 (1.0 mmol), ligand, CoCl2‚6H2O (5 mol %), Zn dust
(10 mol %), solvent(s) (4 mL). Reactions were performed at room
temperature (∼25 °C) after 5 min of stirring at 35-40 m °C. b Unless
otherwise indicated, isolated (total) yield. c 1H NMR yield.
moiety such as 2b and 2c could be converted to the
corresponding 10 in good to excellent yield even under high
concentration conditions (entries 4 and 5). It was observed
again that use of less bulky ligand 1c instead of 1a was not
effective (entry 3).14
In conclusion, we have developed a new cobalt-based
instant catalyst, 1a/CoCl2‚6H2O/Zn, for alkyne cycloisomer-
ization of types I-III.19 The method is extremely practical
since it is inexpensive, easy to handle, less sensitive to
moisture, and reasonably general, where unique regio- and
chemoselectivities were observed.
1-3). 4-Octyne could not be trimerized at all (entry 4) but
but-2-ynedioic acid dimethyl ester was quickly trimerized
to 8 quantitatively (entry 5). As can be seen in entry 6, dppe/
CoCl2‚6H2O/Zn catalyst could not be used for cyclotrimer-
ization of type III, where the reaction provided enyne 9
mainly, although dppe and 2-iminomethylpyridine 1a could
equally be utilized for the reactions of type II as mentioned
above. Similar results to entry 6 have been reported by Hilt
et al., who have pointed out that addition of ZnI2 to a CoBr2/
2PR3, disulfide, or diimine/Zn system is important to perform
the cyclotrimerization of alkynes. However, the catalyst 1a/
CoCl2‚6H2O/Zn developed here could work without any
additive.
Finally, we applied the present method to an intramolecular
reaction (type I)6-8 (Table 4). As shown in entry 1,
intramolecular cyclotrimerization of triyne 2a in a 0.25 M
(1.0 mmol of 2a in 4 mL of THF) solution provided
annulated benzene 10a in 62% yield, but intermolecular-
coupled compounds were coproduced. With lower concen-
tration (0.025 M), the yield of 10a was improved to 93%
(entry 2). The reaction of triynes having no terminal alkyne
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Science and Technology (Japan) for financial
support.
Supporting Information Available: Experimental pro-
cedures and characterization of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0602295
(19) Although confirmation of the reaction mechanism must await further
study, based on those proposed for the reported metal-catalyzed reactions
we postulate that the reaction might proceed via a Co(I)-Co(III) catlytic
cycle, involving formation of metallacyclopentadiene followed by insertion
or cycloaddition of alkyne and reductive elimination reaction. Further
investigation is underway in our laboratory.
1442
Org. Lett., Vol. 8, No. 7, 2006