Palladium(II)-copper(I) mediated homotrimerization and homotetramerization of terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2014.01.146

Alkyne homocoupling is commonly observed in cross coupling reactions; however, self trimerization and homotetramerization of alkynes to form branched products through cross-coupling reactions are rarely reported. We describe herein homotrimerization and h

Full text of DOI:10.1016/j.tetlet.2014.01.146

Tetrahedron Letters 55 (2014) 1883–1885
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium(II)–copper(I) mediated homotrimerization
and homotetramerization of terminal alkynes
⇑
Ravi Shekar Yalagala, Ningzhang Zhou, Hongbin Yan
Department of Chemistry, Brock University, 500 Glenridge Ave., St. Catharines, Ontario L2S 3A1, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkyne homocoupling is commonly observed in cross coupling reactions; however, self trimerization and
homotetramerization of alkynes to form branched products through cross-coupling reactions are rarely
reported. We describe herein homotrimerization and homotetramerization of terminal alkynes under
the Sonogashira reaction conditions that gave the corresponding modified enediynes. Substrate scope
for this reaction was explored.
Received 9 November 2013
Revised 21 January 2014
Accepted 28 January 2014
Available online 6 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Alkynes
Enediynes
Sonogashira coupling
Homotrimerization
Bergman cyclization
In cross coupling reactions, alkyne homocoupling is commonly
observed.1 Similarly transition metal catalyzed [2+2+2] cyclization
of alkynes is also a well-known process that has found applications
in the synthesis of substituted benzene derivatives.2,3 This process
allows for the rapid construction of highly derived benzene
analogues in reasonable yields. However, self-trimerization and
tetramerization of alkynes to form branched products under
cross-coupling reaction conditions are rarely reported. To the best
Table 1
Optimization of reaction conditions for the reaction described in Scheme 1b (1a ? 4)
Entry Reaction
temperature
Solvent
Base
Catalyst
Isolated
yield (%)
and time
1
2
45 °C,
overnight
Benzene n-Butylamine
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
40
45 °C,
overnight
Benzene No base
n/o
3
4
5
45 °C,
overnight
45 °C,
overnight
45 °C,
Benzene n-Butylamine
Benzene n-Butylamine
Benzene n-Butylamine
CuI (5 mol %)
n/o
n/o
37
Pd(PPh3)2Cl2
(5 mol %)
Pd(PPh3)4
overnight
(15 mol %),
CuI
(15 mol %)
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
6
7
8
9
Rt, overnight Benzene n-Butylamine
30
n/o
28
10
75 °C,
Benzene n-Butylamine
overnight
45 °C, 3 h
THF
n-Butylamine
n-Butylamine
Scheme 1. Reagents and conditions: (i) Pd(PPh3)3Cl2, CuI, base.
45 °C,
MeOH
overnight
⇑
Corresponding author. Tel.: +1 905 688 5550x3545; fax: +1 905 682 9020.
E-mail address: tyan@brocku.ca (H. Yan).
(continued on next page)
http://dx.doi.org/10.1016/j.tetlet.2014.01.146
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1884
R. S. Yalagala et al. / Tetrahedron Letters 55 (2014) 1883–1885
Table 2
Table 1 (continued)
Homocoupling products of terminal alkynes under Sonogoshira coupling conditions
Entry Reaction
Solvent
DMF
Base
Catalyst
Isolated
yield (%)
Entry
Substrate 1
Product yield (%)
temperature
and time
5
6
7
10
11
12
13
45 °C,
overnight
n-Butylamine
n-Butylamine
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
Pd(PPh3)2Cl2
(5 mol %), CuI
(5 mol %)
14
36
20
10
1
2
3
4
5
6
7
8
a; R = –CH2NHBoc
b; R = –CH2OH
10
53
20
60
20
n/o
69
40
40 (i.e. 4)
31
61
10
30
n/o
n/o
n/o
n/o
n/o
n/o
10
c; R = –(CH2)2NHAc
d; R = –(CH2)2NHBoc
e; R = –(CH2)2OH
f; R = –CH2OCH3
g; R = –Ph
45 °C,
overnight
1,4-
Dioxane
23
n/o
n/o
n/o
45 °C,
overnight
Benzene DBU
h; R = –(CH2)4CH3
45 °C,
Benzene Hünig’s base
n/o: not detected.
overnight
Note: DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; n/o: not observed.
Figure 1. Possible structures of trimerized product.
In our effort to prepare enediynes as Bergman cyclization pre-
cursors, attempts to couple 1,2-dihaloalkenes 2 with N-Boc pro-
tected propargylamine 1a under the Sonogashira conditions, that
is Pd/Cu(I)/base, invariably failed to give the corresponding Sono-
gashira coupling product 3 (Scheme 1a). Indeed, a survey of the lit-
erature reveals that synthesis of enediynes with functional groups
on the alkenes by Sonogoshira coupling reactions remains elusive.
One of the closest examples was demonstrated by Myers et al.,
where enediynes bearing an ester functionality on alkene were
prepared by the Sonogoshira coupling reaction in a sequential
manner.7,8 In our hands, these Sonogashira coupling reactions led
Scheme 2. Reagents and conditions: (i) Pd(PPh3)3Cl2, CuI, base.
of our knowledge, there are only three such examples reported in
the literature. Rossi et al.4 first reported the formation of tetramer-
ized products when aliphatic alkynes were treated under the Sono-
gashira conditions in the presence of chloroacetone as a reoxidant.
Two other similar reactions were catalyzed by palladium(0)5 or
zirconocene6 in the presence of an oxidant such as p-chloranil or
dichlorodicyanobenzoquinone.
Figure 2. 1D NMR spectra of compound 6b in DMSO-d6. Top: NOE spectrum of compound 6b excited at 3.98 ppm (CH2(9-)); bottom: 1H NMR spectrum of 6b.

R. S. Yalagala et al. / Tetrahedron Letters 55 (2014) 1883–1885
1885
Figure 3. HMBC spectrum of compound 6b in DMSO-d6.
to the isolation of the same homotrimerization product 4 in low to
Supplementary data
moderate yields.
It then became obvious that formation of the branched homo-
trimerized products, for example 4, does not involve dihaloalkenes
2 altogether. Indeed, when N-Boc protected propargylamine 1a
alone was treated under the Sonogashira conditions (Scheme 1b),
the same homotrimerized product 4 was isolated in yields compa-
rable to those in the presence of dihaloalkene.9 Additional reaction
conditions were explored for this transformation (Scheme 1b), and
the results are summarized in Table 1. It was noted that this tri-
merization was not observed when the reaction was carried out
in the absence of either Pd(PPh3)3Cl2, CuI, or base. While virtually
no reaction was observed in the absence of CuI, only homocoupling
alkyne dimer 5a was isolated in the absence of palladium catalysts.
Coupling reactions were then carried out using various
commercially available terminal alkynes (Scheme 2). Results are
summarized in Table 2.
Structures of trimerized products 6 were confirmed by NMR
spectroscopy. The presence of an NOE signal (Fig. 2) between the
two protons indicated by the arrow in 6b (Fig. 1) excludes 8 as
the product; whereas the cross peak between CH(5) and C(3)
[but not between CH(5) and C(6)] in the HMBC spectrum (Fig. 3)
confirmed 6b but not 9.
To conclude, treatment of terminal alkynes with substituted 1,
2-dihaloalkenes under the Sonogashira coupling conditions invari-
ably failed to give corresponding enediyne products. Homocoupling
products derived from alkynes were isolated. When terminal
alkynes were treated under the same conditions, homocoupling
dimer, trimer, and tetramer products were obtained.
Supplementary data (NMR spectra for the compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.01.146.
References and notes
1. Stefani, H. A.; Guarezemini, A. S.; Cella, R. Tetrahedron 2010, 66, 7871–7918.
2. Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830–2834.
3. Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741–4767.
4. Rossi, R.; Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26, 523–526.
5. Chen, C.; Ai, Z.; Lin, J.; Hong, X.; Xi, C. Synlett 2006, 2454–2458.
6. Xi, C.; Liu, Y.; Yan, X.; Chen, C. J. Organomet. Chem. 2007, 692, 4612–4617.
7. Myers, A. G.; Alauddin, M. M.; Fuhry, M. A. M.; Dragovich, P. S.; Finney, N. S.;
Harrington, P. M. Tetrahedron Lett. 1989, 30, 6997–7000.
8. Myers, A. G.; Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1991, 113, 694–695.
9. Typical procedure: To a solution of propargyl alcohol 1b (0.100 g, 1.78 mmol) in
dry benzene (9.0 mL) were added Pd(PPh3)3Cl2 (119 mg, 10 mol %) and n-
butylamine (2 mL). The mixture was frozen followed by addition of CuI (32 mg,
10 mol %). The mixture was evacuated and purged with argon. After this
degasing procedure was repeated two more times, the mixture was stirred at
45 °C overnight in an argon atmosphere. The solvents were removed under
reduced pressure and the residue was purified by column chromatography on
silica gel without aqueous work up. The appropriate fractions, which were
eluted with dichloromethane–methanol (93:7 v/v), were combined and
evaporated under reduced pressure to give the trimerized product 6b as a
light yellow oil (30 mg, 31%). Homo coupling product 5b was also obtained as a
light yellow solid (50 mg, 53%).
Dimer 5b: Rf = 0.55 [dichloromethane–methanol (92:8, v/v)]. dH (DMSO-d6): 4.17
(s, 4 H), 5.40 (2H, s, br s Ex); dC (DMSO-d6): 49.8, 68.4, 80.0; HRMS: C6H6O2
requires 110.03678, EI found 110.03661.
Trimer 6b: Rf = 0.38 [dichloromethane–methanol (92:8, v/v)]. dH (DMSO-d6):
3.98 (2H, dd, J = 5.8 and 1.7), 4.25 (2H, dd, J = 5.9 and 1.7), 4.26 (2H, d, J = 5.8),
5.27 (1H, t, J = 5.9, ex), 5.32 (1H, t, J = 5.9, ex), 5.36 (1H, t, J = 5.9, ex), 6.00 (1H, t,
J = 1.9); dC (DMSO-d6): 49.9, 50.0, 63.7, 81.2, 81.8, 96.2, 97.7, 112.4, 135.5. Mass
spectrometric analysis of this trimer was unsuccessful, however, upon
acetylation, the corresponding triacetyl analogue gave correct mass. HRMS(EI)
found 292.07806, C15H16O6 requires 292.09469.
Acknowledgment
This work was funded by the Natural Science and Engineering
Research Council of Canada.