Dramatic Acceleration of Pd-Catalyzed Benzannulation
A R T I C L E S
single chemo- and regioisomers (eq 3).12 This formal [2+2+2]
trimerization proceeds via reductive coupling of two similar
(R1 ) R2, R3 ) H) or different (R1 * R2, R3 ) EWG) alkynes
5 and 6 in situ furnishing requisite enyne 1,13 which under the
same reaction conditions undergoes the [4+2] benzannulation
reaction with a third alkyne component, diyne 2, to give tetra-
or pentasubstituted benzenes 3.12
Table 1. Isomerization of E-1a in the Presence of Various Lewis
Acidsa
no.
Lewis acid
phosphine
time, h
E/Z
material balance, %
1
2
3
4
5
6
7
8
9
Et2AlCl
ZrBr4
ZrCl4
(C6F5)3B
Me3Al
Me3Al
Me3Al
MAOb
MAOb
PPh3
PPh3
PPh3
PPh3
0.5
5
15
15
5
1.5
14
2
1:3
32:1
3:1
15:1
1:3
1:2
100:0
1:1
1:1
75
N/D
N/D
N/D
100
100
N/D
80
PPh3
TDMPP
(o-Tol)3P
PPh3
Despite remarkable selectivity and wide applicability, reac-
tions employing di- and trisubstituted enynes usually required
prolonged heating at temperatures as high as 120 °C to ensure
complete conversion of starting materials.14 As a result, the
overall efficiency of the reaction in these cases was decreased,
leading to only moderate yields of tetra- and pentasubstituted
benzenes. Certain attempts have been made to overcome this
limitation. One of the modifications involved the addition of
an electron-rich phosphine ligand, such as TDMPP (TDMPP
) tris(2,6-dimethoxyphenyl)phosphine), to extend the active
catalyst’s lifetime.14 In the case of the [2+2+2] trimerization
reaction, the most efficient protocol employed two palladium
sources (Pd(II) and Pd(0) catalysts).12 Finally, it was found that
the addition of the AlEt2Cl/PPh3 combination led to a substantial
acceleration of the sequential trimerization reaction. In the single
reported example, a pentasubstituted benzene was obtained after
1 day at 60 °C, in contrast to the analogous reaction under Lewis
acid-free conditions, which required 5 days at 100 °C for
complete conversion.12 This acceleration was attributed to the
facile E/Z isomerization of trisubstituted enyne 1a.15 The
reaction yield, however, was not improved due to the low
stability of reactants under these conditions.14
TDMPP
2
94
a Reaction conditions: E-1a was added to a mixture of Lewis acid (1
equiv), PPh3 (20 mol %), and pentadecane (0.5 equiv, internal standard) at
room temperature; the reaction course was monitored by GC/MS analysis.
b Methylaluminoxane.
the first time, addresses the long held question of stereoselective
hydrogen migration in the benzannulation reaction.
Results and Discussion
Acceleration of the [4+2] Benzannulation and Sequential
[2+2+2] Trimerization Reactions by Lewis Acids. First,
systematic studies on Lewis acid-phosphine-mediated isomer-
ization of enynes have been performed. Efficiency of the new
isomerization conditions were evaluated by reaction time, E/Z
ratio of enyne, and material balance in comparison to that for
the reported system (Table 1, entry 1). Screening various Lewis
acids in combination with triphenylphosphine for the E/Z
isomerization revealed that employment of Me3Al and MAO
allowed for efficient formation of the Z-isomer and maintained
the “living” equilibrium for several hours (Table 1, entries 5,
8). The two most efficient Lewis acids were then tested against
tris(o-tolyl)phosphine ((o-Tol)3P) and TDMPP, phosphines
known to be optimal ligands for the benzannulation reaction.14
Interestingly, it was found that TDMPP promoted E/Z isomer-
ization equally well as PPh3 (entries 6,9), whereas (o-Tol)3P
did not promote any reaction at all (entry 7).
Motivated by the importance of developing a more efficient
[4+2] cyclization methodology, and intrigued by the accelera-
tion effect observed in the presence of a Lewis acid, we
performed systematic studies on the Lewis acid-assisted ben-
zannulation reaction.
Herein, we report several important findings: (1) Pd-catalyzed
benzannulation reaction performed in the presence of methy-
laluminoxane (MAO)/TDMPP additive resulted in dramatic
acceleration of the process, as well as in significant improvement
of the reaction yields; (2) the origins of Lewis acid acceleration
lies not only in assisting the E/Z isomerization of enynes but,
more importantly, in direct acceleration of the [4+2] benzan-
nulation reaction; (3) addition of certain Bronsted bases causes
unprecedented acceleration of the Pd-catalyzed [4+2] benzan-
nulation reaction. The novel experimental findings combined
with deuterium-labeling studies and DFT calculations resulted
in a mechanistic rationale, which both reasonably explains the
observed acceleration by Lewis acid and bases and also, for
The compatibility of the new isomerization conditions (Table
1, entries 6,9) with [4+2] benzannulation reaction was examined
using enyne E-1a and dodecadiyne 2a (Scheme 1). Although
employment of Me3Al as an additive proved unsuccessful, lead-
ing to fast decomposition of the starting materials, to our delight,
the MAO-TDMPP combination allowed for smooth benzan-
nulation at 80 °C, affording product 3aa in 74% yield after 12
h (Scheme 1). This was a significant improvement compared
to the Lewis acid-free conditions, which produced only 55%
of 3aa after a week of heating! Surprisingly, the experiment
involving usually more reactive Z-1a14 under these conditions
provided benzene 3aa in 63% yield only (Scheme 1).
A detailed investigation of the E-1a to Z-1a isomerization in
the presence of the MAO-TDMPP system uncovered the
mystery: it was found that the material balance in the isomer-
ization remained perfect during the first hour of the reaction
and then slowly decreased mainly due to the decomposition of
the Z-enyne (Figure 1). Although the reasons for the lower
stability of Z-1a in the presence of MAO are not clear, this fact
plausibly accounts for the poorer yield obtained in the [4+2]
(12) Gevorgyan, V.; Radhakrishnan, U.; Takeda, A.; Rubina, M.; Rubin, M.;
Yamamoto, Y. J. Org. Chem. 2001, 66, 2835.
(13) (a) Trost, B. M.; Sorum, M. T.; Chen, C.; Harms, A. E.; Ruhter, G. J. Am.
Chem. Soc. 1997, 119, 698. (b) Trost, B. M.; Kottirsch, G. J. Am. Chem.
Soc. 1990, 112, 2816. (c) Brandsma, L. PreparatiVe Acetylenic Chemistry,
2nd ed.; Elsevier: Amsterdam, 1988.
(14) Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.; Radhakrishnan,
U.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 6391.
(15) As it was shown before, trisubstituted Z-enynes reacted much faster than
their E-isomers, see ref 14.
9
J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006 5819