One-pot synthesis of benzolactones and lactams via a cobalt-catalyzed regioselective [2 + 2 + 2] cocyclotrimerization of alkynyl alcohols and amines with propiolates

Article abstract of DOI:10.1039/b509731b

An efficient method for the synthesis of benzolactones and benzolactams via a cobalt-catalyzed [2 + 2 + 2] cocyclotrimerization of alkynyl alcohols and alkynyl amines with propiolates is described. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b509731b

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One-pot synthesis of benzolactones and lactams via a cobalt-catalyzed
regioselective [2 + 2 + 2] cocyclotrimerization of alkynyl alcohols and
amines with propiolates{
Hong-Tai Chang, Masilamani Jeganmohan and Chien-Hong Cheng*
Received (in Cambridge, UK) 8th July 2005, Accepted 16th August 2005
First published as an Advance Article on the web 8th September 2005
DOI: 10.1039/b509731b
Substituted benzolactone 3a was successfully prepared in 91%
of isolated yield from the reaction of propargyl alcohol (1a)
(1.00 mmol) with DMAD (2) (2.2 mmol) in the co-solvent CH3CN
and THF (2.0 + 2.0 mL) in the presence of CoI2(dppe) (5.0 mol%)
and zinc metal powder (2.75 mmol) (Scheme 1). It is necessary that
the solution was initially stirred at room temperature for 1 h to
reduce the Co(II) complex (pale green) to the active species (dark
green) and then at 80 uC for 12 h to obtain high yield of product
3a. Presumably, the formation of 3a is via a [2 + 2 + 2]
cocyclotrimerization of two molecules of 2 and a molecule of
1a followed by transesterification. Product 3a was thoroughly
characterized by its 1H, 13C NMR and mass spectral data. Control
experiments revealed that in the absence of the cobalt catalyst or
Zn powder, no 3a was obtained.
An efficient method for the synthesis of benzolactones and
benzolactams via a cobalt-catalyzed [2 + 2 + 2] cocyclotrimer-
ization of alkynyl alcohols and alkynyl amines with propiolates
is described.
The transition metal catalyzed [2 + 2 + 2] cycloaddition reaction of
unsaturated molecules is an efficient method to construct six-
membered cyclic compounds with the formation of three new
carbon–carbon bonds.1 This cycloaddition reaction has been
known for the past few decades. Of these cycloadditions, the
intramolecular and partially intermolecular modes of cyclotrimer-
ization have been established as powerful synthetic methods.2
However, completely intermolecular versions of [2 + 2 + 2]
cycloaddition generally have encountered difficulties in the control
of chemo- and regioselectivity. When two or three different alkynes
are used for the cycloaddition, in most cases, a mixture of several
benzene derivatives was obtained.3 Therefore, the search for a
highly chemo- and regioselective intermolecular [2 + 2 + 2]
cycloaddition reaction of two or three different monoynes is
greatly challenging. Recently, several groups have devoted
substantial effort in this area.4 We demonstrated a nickel-catalyzed
regio- and chemoselective [2 + 2 + 2] cocyclotrimerization of
propiolates with allenes.5 Takeuchi and Nakaya reported a
iridium-catalyzed [2 + 2 + 2] cycloaddition reaction of DMAD
with substituted propargyl alcohols to afford substituted benzo-
lactones,4d but only few examples were studied. Our continuous
interest in this type of cycloaddition reactions6 prompted us to
explore the possibility of alkynyl alcohols with propiolates. Herein,
we wish to report that cobalt catalyzed the [2 + 2 + 2] cycloaddition
reactions of alkynyl alcohols and amines with propiolates to give
various substituted benzolactones and lactams in a highly chemo-
and regioselective fashion.
To understand the nature of the catalytic reaction and to deter-
mine optimal reaction conditions, the activities of various cobalt
phosphine complexes and the effect of solvents on the [2 + 2 + 2]
cocyclotrimerization of 1a with 2 were examined. Monodentate
phosphine complexes CoCl2(PPh3)2 and CoI2(PPh3)2 exhibited low
catalytic activity, affording 3a in 47 and 41% yields, respectively.
Cobalt complexes with bidentate phosphine ligands dppm and
dppp, gave 3a in 53 and 58% yields. The highest yield of 3a in 95%
was obtained using CoI2(dppe) as the catalyst. The solvent used is
critical to the catalytic reaction. Of the solvents tested, the co-
solvent acetonitrile and THF (2 + 2 mL) was most effective.
Acetonitrile alone was also efficient, affording product 3a in 78%
yield. The other solvents, THF, toluene, ethyl acetate and NMP,
were not active for present catalytic reaction.
Under similar reaction conditions, substituted alkynyl alcohols
1b–d also underwent the [2 + 2 + 2] cocyclotrimerization reaction
with 2 to afford the corresponding benzolactone derivatives
in excellent yields (Table 1). Thus, the reaction of 2 with
1-ethynylcyclohexanol (1b) afforded product 3b in 77% yield
(entry 2), whereas but-2-yn-1-ol (1c) gave 3c in 85% yield (entry 3).
Similarly, but-2-yne-1,4-diol (1d) undergoing reaction with 2
affording bislactone 3d in 50% yield (entry 4).
Benzolactones and lactams are found in plants and they show
several pharmacological effects, such as fungicidal, bactericidal,
herbicidal and analgesic activities.7 The present catalytic reaction
provides a convenient method for the synthesis of various
substituted benzolactones and lactams in one pot with good to
excellent yields.
Department of Chemistry, National Tsing Hua University, Hsinchu,
30013, Taiwan. E-mail: chcheng@mx.nthu.edu.tw; Fax: 886-3-5724698;
Tel: 886-3-5721454
{ Electronic supplementary information (ESI) available: General experi-
mental procedure, melting point, spectral data (IR, 1H, 13C NMR and
HRMS) and copy of 1H and 13C NMR spectra of all compounds. See
http://dx.doi.org/10.1039/b509731b
Scheme 1
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Chem. Commun., 2005, 4955–4957 | 4955

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Table 1 Results of cobalt-catalyzed cocyclotrimerization of alkynyl
alcohols 1 and DMAD 2a
Entry
1
1
2
2
Product
3
Yieldb (%)
1a
3a
91 (95)
2
3
1b
1c
2
2
3b
3c
77
85
Scheme 3
4
5
1d
1e
2
2
3d
3e
50
91
(Scheme 3). The reaction of 1a with pentylpropiolate 4a afforded
highly substituted benzolactone 5a in 45% yield (Table 2, entry 1).
The NOE data of product 5a support the proposed structure in
entry 1 and exclude the other possible regioisomers. Similarly,
phenylpropiolate 4b underwent cycloaddition reaction with 1a and
1h to afford products 5b,c in 40 and 35% yields, respectively. Again,
NOE studies of these products were consistent with the proposed
structures with the two phenyl groups ortho to each other.
6
1f
2
2
3f
82
80
In a similar manner, methyl propiolate (4c) reacts smoothly
with 1a, 1h and 1e catalyzed by the CoI2(dppe)/Zn system to
yield products that contain a five- and six-membered lactone ring
5d–f in 70–80% yields (Table 2, entries 4–6). The reaction is
completely regioselective; in each case only one regioisomer of the
7
1g
3g
Table 2 Results of cobalt-catalyzed cocyclotrimerization of alkynyl
alcohols 1a, 1e and 1h and propiolates 4a–ca
a
All reactions were carried out using alkynyl alcohols 1 (1.00 mmol),
DMAD (2) (2.2 mmol), CoI2(dppe) (5.0 mol%), Zn (2.75 mol%) and
CH3CN and THF (2.0 + 2.0 mL) at room temperature for 1 h and
Entry
1
1
4
5
Yieldb (%)
b
then at 80 uC for 12 h. Isolated yields: the yields in parenthesis was
determined by 1H NMR integration method.
1a
4a
5a
45
The cobalt-catalyzed [2 + 2 + 2] cocyclotrimerization reaction
can also be used for the preparation of six- and seven-membered
benzolactones (Scheme 2). Thus, treating but-3-yn-1-ol (1e)
and pent-4-yn-1-ol (1f) with 2 under the standard conditions
afforded lactones 3e–f in 91 and 82% yields, respectively (Table 1,
entries 5–6). However, an attempt to make an eight-membered
lactone ring from the reaction of hex-5-yn-1-ol 1g and 2 afforded
only the noncyclized product 3g in 80% yield (entry 7).
2
3
1a
1h
4b
4b
5b
5c
50
35
The present protocol can be further applied to propiolates 4a–c
with alkynyl alcohols 1a, 1e and 1h under the similar reaction
conditions to give highly regio- and chemoselective [2 + 2 + 2]
cycloaddition and transesterification products 5a–f in good yields
4
5
1a
1h
4c
4c
5d
5e
80
74
6
1e
4c
5f
70
a
All reactions were carried out using alkynyl alcohols
1
(1.00 mmol), propiolate 4 (2.2 mmol), CoI2(dppe) (5.0 mol%), Zn
(2.75 mol%) and CH3CN and THF (2.0 2.0 mL) at room
+
b
temperature for 1 h and then at 80 uC for 16 h. Isolated yields.
Scheme 2
4956 | Chem. Commun., 2005, 4955–4957
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Scheme 6
Scheme 4
to the hydroxymethyl group and thus, no transesterification could
occur. The difference of regioselectivity in the oxidative cyclome-
talation of propiolates to nickel and cobalt complexes should
account for these results. A tail–tail (pentyl group R4) oxidative
cyclometalation of pentyl propiolate 4a with the nickel complexes
to give intermediate 12 is known.1,2,5,6 We have observed the
same type of regioselective products in our pervious nickel-
catalyzed [2 + 2 + 2] cycloaddition of propiolates and allenes.5
In conclusion, we have developed a cobalt-catalyzed [2 + 2 + 2]
cyclotrimerization of alkynyl alcohols with propiolates. The
reaction is highly regio- and chemoselective affording benzolactone
derivatives in good to excellent yields. Further extension of this
cycloaddition product was observed and the structure was
confirmed by NOE studies. In all of these reactions, the homo
cyclotrimerization products of propiolates were observed in 5–20%
yields.
In addition to propargyl alcohols, the reaction was further
extended into propargyl amines (Scheme 4). The reaction of
propiolate 4c with N-propargyl p-toluenesulfoneamide 6a in the
presence of CoI2(dppe)/Zn afforded benzolactam derivative 7a in
75% yield. Under similar reaction conditions, propargyl amine 6b
also underwent [2 + 2 + 2] cocyclotrimerization with 4c, but the
expected product appears to react further with a propiolate
molecule to give 7b in 72% yield.
work into partially intermolecular version and
mechanistic study is underway.
a detailed
The regioselectivity of propargyl alcohol 1a in the present
cobalt-catalyzed [2 + 2 + 2] cycloaddition was demonstrated with
unsymmetrical diyne 8 under the standard reaction conditions
affording phthalide derivative 9 in 79% yield as the exclusive
product. The other possible product 10 was not detected in the 1H
NMR spectrum of the crude reaction mixture indicating excellent
regioselectivity of 1a in the reaction (Scheme 5).
We thank the National Science Council of Republic of China
(NSC-93-2113-M-007-033) for support this research.
Notes and references
1 (a) K. P. C. Vollhardt, Angew. Chem., Int. Ed. Engl., 1984, 23, 539; (b)
N. E. Schore, Chem. Rev., 1988, 88, 1081; S. Saito and Y. Yamamoto,
Chem. Rev., 2000, 100, 2901; (c) S. Ikeda, Acc. Chem. Res., 2000, 33, 511;
(d) J. A. Varela and C. Saa, Chem. Rev., 2003, 103, 3787.
2 (a) S. Kotha and E. Brahmachary, Tetrahedron Lett., 1997, 38, 3561; (b)
A. Jeevanandam, R. P. Korivi, I.-W. Huang and C.-H. Cheng, Org.
Lett., 2002, 5, 807; (c) M. Shanmugasundaram, M.-S. Wu,
M. Jeganmohan, C.-W. Huang and C.-H. Cheng, J. Org. Chem., 2002,
67, 7724; (d) M.-S. Wu, M. Shanmugasundaram and C.-H. Cheng,
Chem. Commun., 2003, 718.
3 (a) J. C. Sauer and T. L. Cairns, J. Am. Chem. Soc., 1957, 79, 2659; (b)
L. S. Meriwether, E. C. Colthup, G. W. Kennerly and R. N. Reusch,
J. Org. Chem., 1961, 26, 5155; (c) A. F. Donda and G. Moretti, J. Org.
Chem., 1966, 31, 985; (d) Y. Wakatsuki, T. Kuramitsu and H. Yamazaki,
Tetrahedron. Lett., 1974, 4549.
The origin of formation of benzolactones 3, 5 and lactams 7
from the present cobalt-catalyzed cycloaddition of alkynyl
alcohols or amines 1 or 6 with propiolates 2 or 4 is likely from
the regioselective head to head (R4) oxidative cyclometalation of
propiolates to give cobaltacyclopentadiene intermediate 11.1
Insertion of a molecule of alkynyl alcohol (or amine) into a
Co–carbon bond of 11 in which the two ester groups are next to
the metal center, followed by reductive elimination and trans-
esterification afforded the final product 3, 5 or 7.
It is known that nickel complexes also catalyze the [2 + 2 + 2]
cycloaddition of alkynes. To compare the regioselectivity in the
nickel- and cobalt-catalyzed reaction, the cycloaddition of 1a with
4a catalyzed by the NiBr2(dppe)/Zn system was studied. As shown
in Scheme 6, an entirely different product 13 in 62% yield was
observed. In this product, the two ester groups are meta and para
4 (a) S. Ikeda, H. Watanabe and Y. Sato, J. Org. Chem., 1998, 63, 7026; (b)
Y. Yamamoto, H. Kitahara, R. Ogawa and K. Itoh, J. Org. Chem., 1998,
63, 9610; (c) B. Witulski and C. Alayrac, Angew. Chem., Int. Ed., 2002,
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D. Pena, D. Perez, E. Guitian and L. Castedo, J. Am. Chem. Soc., 1999,
121, 5827.
5 M. Shanmugasundaram, M.-S. Wu and C.-H. Cheng, Org. Lett., 2001, 3,
4233.
6 (a) D.-J. Huang, T. Sambaiah and C.-H. Cheng, New J. Chem., 1998, 22,
1147; (b) T. Sambaiah, L.-P. Li, D.-J. Huang, C.-H. Lin,
D. K. Rayabarapu and C.-H. Cheng, J. Org. Chem., 1999, 64, 3663;
(c) M.-S. Wu, D. K. Rayabarapu and C.-H. Cheng, Tetrahedron., 2004,
60, 10005; (d) T. T. Jayanth, M. Jeganmohan and C.-H. Cheng, J. Org.
Chem., 2004, 69, 8445; (e) J.-C. Hsieh, D. K. Rayabarapu and
C.-H. Cheng, Chem. Commun., 2004, 532.
7 (a) T. Aoki, T. Furusho, T. Kimura, S. Satake and S. Funayama, Jpn.
Pat., 7324724, 1973 (Chem. Abstr., 1974, 80, 129246); (b) M. Lacova,
Chem. Zvesti., 1973, 27, 525, Chem. Abstr., 1974, 80, 59757; (c)
R. C. Elderfield, Hetrocyclic Compounds., Wiley, New York, 1951,
vol. 2, ch. 2.
Scheme 5
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 4955–4957 | 4957