Palladium-catalyzed [4+2] cross-benzannulation reaction of conjugated enynes with diynes and triynes

Article abstract of DOI:10.1021/ja990749d

The enyne-diyne [4+2] cross-benzannulation proceeded smoothly in the presence of Pd(0) catalyst to give 1,2,4-trisubstituted benzenes 8a-j, 1,2,3- trisubstituted benzenes 9a-i, 1,2,3,5-tetrasubstituted benzenes 11a-k, 1,2,3,4-tetrasubstituted benzenes 111

Full text of DOI:10.1021/ja990749d

J. Am. Chem. Soc. 1999, 121, 6391-6402
6391
Palladium-Catalyzed [4+2] Cross-Benzannulation Reaction of
Conjugated Enynes with Diynes and Triynes
Vladimir Gevorgyan,*,† Akira Takeda, Miyako Homma, Naoki Sadayori,
Ukkiramapandian Radhakrishnan, and Yoshinori Yamamoto*
Contribution from the Department of Chemistry, Graduate School of Science, Tohoku UniVersity,
Sendai 980-8578, Japan
ReceiVed March 8, 1999
Abstract: The enyne-diyne [4+2] cross-benzannulation proceeded smoothly in the presence of Pd(0) catalyst
to give 1,2,4-trisubstituted benzenes 8a-j, 1,2,3-trisubstituted benzenes 9a-i, 1,2,3,5-tetrasubstituted benzenes
11a-k, 1,2,3,4-tetrasubstituted benzenes 11l,m, and 1,2,3,4,5-pentasubstituted benzenes 11n-p in moderate
to quantitative yields. In all cases the reaction was found to be regiospecific with regard to substitution at the
benzene ring. The palladium-catalyzed [4+2] cycloaddition of monosubstituted conjugated enynes 3a-c and
5a with unsymmetrical diynes 13a-j and triynes 16a-g also proceeded with perfect regiochemistry with
regard to substitution at the benzene ring. However, since two differently substituted triple bonds are present
in the enynophiles 13 and 16, the enyne preference toward either triple bond in the enynophiles became an
issue, and in most cases, two regioisomeric products were obtained. The detailed deuterium-labeling studies
were performed, and the mechanism of this regiospecific [4+2] cycloaddition between enynes and diynes was
proposed.
Introduction
synthesis of benzene derivatives 1 and 2 through thermal7,8 or
Lewis acid-mediated7 enyne-yne [4+2] cycloaddition reaction
(eq 1). However, these cycloaddition methodologies are strictly
It is hard to overstate the importance of aromatic compounds
in most areas of synthetic organic chemistry and material
science. Additionally, these ubiquitous structural units are found
in a wide variety of naturally occurring compounds. Accord-
ingly, much attention has been paid toward the synthesis of these
classes of compounds by synthetic chemists. Although most of
the approaches to date involve various types of modifications
of aromatic precursors,1 certain success has been achieved in
the selective construction of the aromatic frameworks from
different acyclic units.2 Among several cycloaddition method-
ologies, perhaps the Do¨tz metal carbene-alkyne coupling3 and
alkyne [2+2+2] cyclotrimerizations4 are the most general
approaches toward benzene rings. While the last protocol has
proven to be a simple, powerful, and very selective methodology
for intramolecular alkyne trimerizations,5 it still suffers from
the severe drawback of providing low degrees of regio- and
chemoselectivity for the intramolecular [2+2+2] alkyne cy-
cloaddition.6 Furthermore, there are several reports on successful
(1)
limited to the intramolecular version of this reaction.7,8 We have
recently reported a complementary regiospecific intermolecular
method for the construction of the benzene skeleton Via
homodimerization of conjugated enynes under palladium ca-
talysis.9 Thus, R,4-disubstituted styrenes 4 and 2,6-disubstituted
† Present address: Department of Chemistry, University of Illinois at
Chicago, 845 West Taylor Street, Chicago, IL 60607-7061.
(1) For reviews, see: (a) Taylor, R. Electrophilic Aromatic Substitution;
Wiley: New York, 1990. (b) Zoltewicz, J. A. Top. Curr. Chem. 1975, 59,
33. (c) Kobrina, L. S. Russ. Chem. ReV. 1977, 46, 348. (d) Sainsbury, M.
Tetrahedron 1980, 36, 3327. (e) Narasimhan, N. S.; Mali, R. S. Synthesis
1983, 957.
(2) For reviews, see: (a) Schore, N. E. Chem. ReV. 1988, 88, 1081. (b)
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49.
(3) For a review, see: Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1984,
23, 587.
(4) For a review, see: (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed.
Engl. 1984, 23, 539. For the most recent mechanistic study, see: (b) Diercks,
R.; Eaton, B. E.; Gu¨rtzgen, S.; Jalisatgi, S.; Matzger, A. J.; Radde, R. H.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1998, 120, 8247.
(5) Lecker, S. H.; Nguen, N. H.; Vollhardt, K. P. C. J. Am. Chem. Soc.
1986, 108, 856. (b) Negishi, E.; Harring, L. S.; Owczarczyk, Z.; Mohamud,
M. M.; Ay, M. Tetrahedron Lett. 1992, 33, 3253. See also ref 4 and
references therein.
(6) See, for example: (a) Colman, J. P.; Kang, J. W.; Little, W. F.;
Sullivan, M. F. Inorg. Chem. 1968, 7, 1298. (b) Ferreri, R. A.; Wolf, A. P.
J. Phys. Chem. 1984, 88, 2256. (c) Borrini, A.; Diversi, P.; Ingrosso, G.;
Lucherini, A.; Serra, G. J. Mol. Catal. 1985, 30, 181.
(7) (a) Danheiser, R. L.; Gould, A. E.; Fernandez, de la Predilla, R.;
Helgason, A. L. J. Org. Chem. 1994, 59, 5514. For an oxa-version of this
[4+2] cycloaddition reaction, see: (b) Wills, M. S. B.; Danheiser, R. L. J.
Am. Chem. Soc. 1998, 120, 9378.
(8) (a) Burrell, R. C.; Daoust, K. J.; Bradley, A. Z.; DiRico, K. J.;
Johnson, R. P. J. Am. Chem. Soc. 1996, 118, 4218. For dehydro version of
this reaction, see: (b) Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc.
1997, 119, 9917.
(9) (a) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya, N.; Tando, K.;
Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 3970. (b) Gevorgyan, V.;
Tando, K.; Uchiyama, N.; Yamamoto, Y. J. Org. Chem. 1998, 63, 7022.
For intramolecular version of this reaction, see: (c) Saito, S.; Tsuboya, N.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 5042. (d) Weibel, D.; Gevorgyan,
V.; Yamamoto, Y. J. Org. Chem. 1998, 63, 1217.
10.1021/ja990749d CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/25/1999

6392 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
GeVorgyan et al.
styrenes 6 could be now effectively synthesized in one step from
conjugated enynes 3 (eq 2)9a and 5 (eq 3)9b respectively.
Synthesis of 1,2,3-Trisubstituted Benzenes 9. Encouraged
by successful preparation of 1,2,4-trisubstituted benzenes 8 via
the palladium-catalyzed cross-benzannulation of 2-substituted
enynes 3 with diynes 7, we attempted to perform a similar [4+2]
cross-cycloaddition reaction employing 4-susbstituted conju-
gated enyne 5. Overnight stirring of hexyl-substituted enyne
5a with dodecadiyne 7a in the presence of 5 mol % Pd(PPh3)4
in THF at 65 °C (the best conditions found for the cross-
benzannulation of 2-substituted enynes 3) gave cross-benz-
annulation product, benzene 9a, in 52% yield, accompanied with
7% of homo-dimerization product 6a (eq 5). After certain
(2)
(3)
As a further development of this methodology, we also
recently communicated the preparation of multisubstituted
benzenes via the palladium-catalyzed intermolecular enyne-
diyne [4+2] cross-benzannulation protocol.10 In this paper we
report a full account on this palladium-catalyzed enyne-yne
[4+2] cross-benzannulation reaction, involving reactions of
conjugated enynes with unsymmetrical diynes and triynes, as
well as mechanistic studies of this reaction.
(5)
optimization work, it was found that stirring the mixture of the
same reactants in toluene at 80 °C afforded 9a in 66% isolated
yield together with 12% of homodimer 6a (Table 2, entry 1).
Other 4-substituted enynes, possessing aryl- (5b), keto- (5c),
chloro- (5d), and hydroxy- (5e) groups in a side chain underwent
smooth cycloaddition reaction with 7a and diphenyldiyne 7b
to produce 1,2,3-trisubstituted benzenes 9b-i in moderate to
good isolated yields (eq 5, Table 2). Although in all cases the
enyne-diyne cross-benzannulation reaction was absolutely
regiospecific, the chemoselectivity of this reaction was not
perfect, since in all cases the formation of trace to detectable
amounts of enyne homodimers 6 was detected (eq 5, Table 2).
Synthesis of 1,2,3,5-Tetrasubstituted Benzenes 11a-k,
1,2,3,4-Tetrasubstituted Benzenes 11l,m, and 1,2,3,4,5-Pen-
tasubstituted Benzenes 11n-p. To test our palladium-catalyzed
enyne-diyne [4+2] cross-cycloaddition methodology for the
preparation of tetra- and pentasubstituted benzenes, we prepared
2,4-disubstituted enynes 10a-f, 1,4-disubstituted enynes 10g,h,
and 1,2,4-trisubstituted enynes 10i-m. Control experiments
indicated that neither disubstituted enynes 10a-h nor tri-
substituted enynes 10i-m were able to undergo the homo-
dimerization reaction in the presence of Pd(PPh3)4 even under
prolonged heating at 120 °C; no traces of homodimerized
products 12 were detected by GC-MS analyses of the crude
reaction mixtures (eq 6). Encouraged by this fact we examined
Results and Discussion
Synthesis of 1,2,4-Trisubstituted Benzenes 8. After trying
a number of alkynes in a role of enyne partner in the [4+2]
cycloaddition, we discovered that conjugated diynes 7 underwent
regiospecific cross-cycloaddition with 3 (eq 4). The reaction
(4)
of 2-methyl-1-buten-3-yne 3a with dodeca-5,7-diyne 7a in the
presence of 5 mol % Pd(PPh3)4 in THF at 65 °C gave 8a11 in
89% yield (entry 1, Table 1). No traces of 8′ were detected by
NMR and capillary GLC analyses of crude reaction mixtures.
The enyne-diyne cross-annulation reaction of enynes 3b,c
appeared to be much faster than the corresponding enyne-enyne
homo- dimerization;9a thus an equimolar amount of hexyl-(3b)
and benzyl- (3c) enyne reacted with diynes 7a,b,d,e,f not only
in regio-, but also in chemo-selective manner affording the
cross-annulation products 8d-f,h-j exclusively (entries 4-6,
8-10). In contrast, 2-5-fold excess of volatile and less reactive
3a (toward diynes 7) were needed to drive the reaction until
complete conversion of 7 (entries 1-3).12 Bulky diyne 7c
reacted with enynes more slowly in comparison with 7a,b,d-
f; thus the slow addition of the enynes 3a,c was employed in
order to avoid its dimerization (entries 3, 7).
(10) (a) Gevorgyan, V.; Takeda, A.; Yamamoto, Y. J. Am. Chem. Soc.
1997, 119, 11313. (b) Gevorgyan, V.; Sadayori, N.; Yamamoto, Y.
Tetrahedron Lett. 1997, 38, 8603.
(11) The structure of para-oriented 8d was unambiguously confirmed
by 500 MHz NOE- and COLOC NMR analyses. See Supporting Information
(S28-S32).
(12) Excess enyne 3a underwent homo-dimerization, affording 4a, see
also footnote c, Table 1.
2,4-disubstituted enynes 10a-f in the [4+2] cross-cycloaddition
reaction with diynes 7a,b (eq 6, Table 3). We found that dialkyl-
substituted enyne 10a, alkylalkenyl-substituted enyne 10b, and
alkylphenyl-substituted enyne 10c in the presence of 5 mol %
of Pd(PPh3)4 at 80 °C in toluene did not react with 7a,b at all
but underwent rather slow reaction (4-5 days) at 100 °C

Enyne-Diyne [4+2] Cross-Benzannulation
J. Am. Chem. Soc., Vol. 121, No. 27, 1999 6393
Table 1. Palladium-Catalyzed Cross-Benzannulation of 2-Substituted Enynes 3 with Symmetrical Diynes 7
a Isolated yields based on diyne 7, except for where otherwise indicated. b Two equivalents of 3a were utilized. c Excess 3a underwent
homodimerization affording the by-product 4a (R)Me).9 d Recovery of 7 (%). e Five equivalents of 3a was utilized. f 3 was added in 5 portions.
g NMR yield. h One and half equivalents of 3c was added in 10 portions. i Two and half equivalents of 3c was added during 14 hours using syringe
pump.
(Method A), affording 1,2,3,5-tetrasubstituted benzenes 11a-f
in moderate to high chemical yields (eq 6, Table 3, entries 1-6).
Being unsatisfied by the drastic reaction conditions for the
benzannulation of 10a-c, we performed a substantial optimiza-
tion work of the catalyst system. We found that the use of the
catalyst system Pd2(dba)3‚CHCl3 (5 mol %) - P(o-tol)3 (40 mol
%) in toluene (Method B), instead of Pd(PPh3)4, allowed us to
decrease the temperature of the benzannulation reaction from
100 to 50 °C. However the yields of 11a-f in the cases of
employment of the Method B were 10-15% lower than those
for Method A. 2,4-Diaryl-substituted enynes 10d-f, in contrast
to 10a-f, enabled the benzannulation reaction to go very
smoothly. Thus, 2,4-diphenylenyne 10d, 2,4-di(p-tolyl)-enyne
10e, and 2,4-di(p-methoxyphenyl)enyne 10f reacted with 7a,b

6394 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
GeVorgyan et al.
Table 2. Palladium-Catalyzed Cross-Benzannulation of 4-Substituted Enynes 5 with Symmetrical Diynes 7
a Isolated yields.
under conditions of the Method B eVen at room temperature,
affording the corresponding tetrasubstituted benzenes 11g-k
(Table 3, entries 7-11) in good to Virtually quantitatiVe isolated
yields!
Z-1,2,4-Trisubstituted enyne 10i was able to react slowly with
7a under the conditions of Method C, affording pentasubstituted
benzene 11n in 47% yield (entry 14). Remarkably, the replace-
ment of the methyl group in the enyne 10i with electron-
withdrawing substituents, such as ester (10j) or cyano (10l)
groups, exerted a dramatic acceleration effect on the cross-
benzannulation reaction. Thus, Z-1,2,4-trisubstituted enynes
10j,l, in contrast to 10i, smoothly reacted with 7a even under
the conditions of milder Method A (in 6 and 48 h at 100 °C for
10j and 10l, respectively, versus 5 days at 120 °C for 10i) to
give the multisubstituted benzoate 11o and cyanobenzene 11p
in high yields (72% and 81%, respectively, entries 15, 17). Again
surprisingly, in the case of enynes, possessing electron-
withdrawing substituents at the C-1 position, not only Z-isomers
(10j,l) but also the corresponding E-isomers 10k,m were able
to undergo the cycloaddition with 7a to give the pentasubstituted
benzenes 11o,p, although with somewhat lower yields (eq 6,
Table 3, entries 16, 18).
Again, the reactions of the alkyl group-containing Z-1,4-
disubstituted enynes 10g,h with diynes 7a,b even under very
high temperature (120 °C) were rather sluggish and afforded
the desired aromatic products with trace to unsatisfactory low
yields. The main reason of last would be the low stability of
the palladium catalyst under the prolonged heating. This problem
was solved by the addition of excess amounts of phosphine
ligand to the reaction mixture.13 Thus, employment of 20 mol
% of tris(2,6-dimethoxyphenyl)phosphine - 5 mol % of Pd-
(PPh3)4 combination (Method C) allowed us to obtain 1,2,3,4-
tetrasubstituted benzenes 11l,m in 40% and 70% yields,
respectively (Table 3, entries 12, 13). It was interesting to find
that E-isomers of 10g,h practically did not undergo the
benzannulation reaction under similar conditions at all (Table
3, note b).
Cycloaddition of 2-Substituted Enynes 3 with Unsym-
metrical Diynes 13. In all of the above cases the palladium-
catalyzed [4+2] cross-benzannulation reaction between enynes
and diynes was found to be perfectly regiospecific with regard
(13) During our study on palladium-catalyzed enyne-enyne homodimer-
ization reactions9b we found that Pd(0) complexes, bulky phosphine ligands
combinations (4-10-fold excess of phosphine ligands with respect to Pd
content), were rather more thermally stable than Pd(0) complexes alone.

Enyne-Diyne [4+2] Cross-Benzannulation
J. Am. Chem. Soc., Vol. 121, No. 27, 1999 6395
Table 3. Palladium-Catalyzed Cross-Benzannulation of Multisubstituted Enynes 10 with Symmetrical Diynes 7

6396 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
Table 3 (Continued)
GeVorgyan et al.
a Isolated yields. b Reactions employing E-isomers of these enynes produced trace amounts of aromatic products.
to the orientation of the unreacted triple bond in the enynophile
(diyne), since symmetrically substituted diynes were used.
However, in the case if unsymmetrical diynes are employed,
two differently substituted triple bonds would be able to undergo
the cycloaddition reaction. Consequently, in these cases an
additional regiochemistry issue should be considered. To
examine above-mentioned topic, we studied the benzannulation
of monosubstituted enynes 3a,b with unsymmetrical diynes
13a-j (eq 7, Table 4). The experiment demonstrated that in
aromatic ring. Two selective reactions were also observed in
the case of internal diynes; the only triple bond, attached to the
TMS group of unsymmetrical 13f, and that attached to (HO)C-
(CH3)2 group of 13i underwent the benzannulation reaction to
give 14f and 14i as sole reaction products in 78% and 54%
yields, respectively (entries 6, 9). In all other cases tested, both
triple bonds of unsymmetrical diynes (13a,c,e,g,h,j) were
reactive in the palladium-catalyzed benzannulation reaction with
enynes 3a,b to give both isomeric products 14 + 15a,c,e,g,h,j
in moderate to good combined yields (eq 7, Table 4, entries
1,3,5,7,8,10).14 It seems that the reactivity issue of two differ-
(7)
ently substituted triple bonds of unsymmetrical diynes 13a-j
could not be explained by the steric factors only. At this stage
we have a feeling that electronic factors could play some role
in this diverse regioselectivity, as well.15
several cases only one triple bond of unsymmetrical diyne was
reactive toward the cycloaddition with enyne. Thus, terminal
diynes, possessing bulky substituents such as t-Bu- (13b) and
MOMOC(Me)2- (13d), reacted with 3a selectively to produce
the single reaction products, phenylacetylenes 14b and 14d, in
52 and 80 isolated yields, respectively (eq 7, Table 4, entries 2
and 4). In both products, the bulky groups were attached to the
(14) Both triple bonds of 13e exhibited rather similar reactivities toward
4-substituted enyne 5a, as well. Accordingly, trisubstituted benzenes 14k
and 15k were obtained in 36% and 39%, respectively.
(15) Preliminary low level ab initio computations revealed that the triple
bond, attached to the TMS group, of unsymmetrical diyne 13f and of triyne
16g is more electron-rich than the others.

Enyne-Diyne [4+2] Cross-Benzannulation
J. Am. Chem. Soc., Vol. 121, No. 27, 1999 6397
Cycloaddition of Monosubstituted Enynes 3,5 with Triynes
16. Next, we examined the palladium-catalyzed benzannulation
of enynes 3a-c and 5a with conjugated triynes 16a-g (eq 8,
(10)
However, as we have previously mentioned (eqs 4-8, Tables
1-5), in all of the cases of palladium-catalyzed cross- [4+2]
cycloadditions, only one regioisomer 24 (with regard to relative
orientation of enyne and enynophile) was formed, and no traces
of regioisomeric 25 were ever detected in the crude reaction
mixtures (eq 11, AG ) alkyne for enyne-diyne cross-benz-
annulation, and AG ) alkene for enyne-enyne homo-dimer-
ization9).
This fact of remarkable regiospecificity completely eliminates
involvement of the traditional transition metal-assisted mech-
anism of alkynes trimerization (eq 9). Indeed, if the mentioned
mechanism is operative, the formation of two regioisomers 22
and 23 (eq 10) is unavoidable. Consequently, the observed
palladium-catalyzed regiospecific [4+2] enyne-yne cycloaddi-
tion must proceed through an entirely different mechanism.
It is obvious that at a certain stage of this novel palladium-
catalyzed enyne-diyne benzannulation process there should be
the migration of one of the hydrogen atoms of conjugated enyne
to its internal sp carbon (marked as “•”, Figure 1). To figure
out which hydrogen migrates, we performed comprehensive
deuterium-labeling studies. We synthesized the conjugated
enynes 26-30 with a deuterium atom incorporated into all of
the possible positions of them and subjected those deuterated
enynes to the benzannulation reaction with diyne 7a (Figure
1). Thus, the monodeuterated enynes 26 and 27, possessing a
deuterium atom at the C-4 and C-2 positions, afforded the
benzenes 31 and 32, respectively, indicating no migration of D
atom (Figure 1). As expected, the cycloaddition of bis-deuterated
enyne 28 afforded the bis-deuterated benzene 33, indicating a
deuterium migration to the internal sp carbon of enyne. To
clarify which particular D migrates, we examined the cyclo-
addition of Z- (29) and E-deuterated enyne 30. The benzannu-
lation of 29 revealed no deuterium migration, whereas the
reaction of E-deuterated enyne 30 produced deuterated benzene
35, thus unambiguously indicating that the deuterium atom at
E-position of C-1 migrates to the C-3 of 30.
(8)
Table 5). Again, the triynes, possessing bulky (16d-h) and TMS
(16g) substituents,15 reacted with enynes 3a-c regioselectively
to afford the aromatic conjugated diynes 17d-h as a single
reaction product in high isolated yields (Table 5, entries 5-9).
In contrast, both different triple bonds of triyne 16b were
similarly reactive to afford an almost statistical distribution of
17b and 18b (44% and 28%, respectively, entry 2). Similarly,
low regioselectivities were observed in the reactions of triynes
16a,c (entries 1,3). In these cases, the formation of notable
amounts of double-benzannulation products 19a, 20a, and 20b
were observed (entries 1, 3). Furthermore, the employment of
2.2 equiv of 3b completely converted initially formed 17c into
a mixture of 19b and 20b, while the amount of 18c remained
virtually unchanged (entry 4). The 4-susbstituted enyne 5a, as
expected, reacted with triynes much more slowly. The reaction
of 5a with 16b produced a mixture of 17i and 18d in 36% and
9% yields, respectively (entry 10), whereas the benzannulation
with 16d was even more sluggish, although selective, to give
the conjugated diyne 17j only in 29% yield (entry 11).
The results on deuterium-labeling experiments, taken together
with the fact of regiospecific formation of single regioisomer
24 (eq 11), encouraged us to propose the following mechanistic
Mechanistic Study. Analyzing the problems to control the
regioselectiVity of intramolecular trimerization of alkynes
proceeding via the traditional metallocycle i (eq 9),4 we realized
(11)
rationale for this reaction (Scheme 1). The coordination of
palladium with enyne and diyne (36) would produce pallada-
cycle 37,16 stabilized by the coordination of Pd atom with
neighboring η3-propargyl moiety.17 Then 37 either undergoes
sigmatropic shift to form another metallocycle 38, which via
(9)
(16) π-Propargyl palladium complexes have been recently isolated and
fully characterized. See: (a) Ogoshi, S.; Tsutsumi, K.; Kurosawa, H. J.
Organomet. Chem. 1995, 493, C19. (b) Ogoshi, S.; Tsutsumi, K.; Ooi, M.;
Kurosawa, H. J. Am. Chem. Soc. 1995, 117, 10415.
(17) The coordination of palladium to propargyl group in the intermediate
37 is supported not only by the exclusive formation of a sole regioisomer
24 but also by the fact that simple alkynes, such as acetylene and its alkyl-,
aryl-, halo-, and cyanoderivatives which do not possess such an additional
that if a conjugated enyne 21 (as a regiodefined equivalent of
dimerized alkyne) would react with an alkyne in a [4+2]
cycloaddition manner, this reaction could be more regioselective
than [2+2+2] mode of cycloaddition since only the regiose-
lectivity of two bond formation remains questionable (eq 10).

6398 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
GeVorgyan et al.
Table 4. Palladium-Catalyzed Cross-Benzannulation of 2-Substituted Enynes 3 with Unsymmetrical Diynes 13
a Isolated yields.
reductive coupling affords the benzene 40 and regenerates a
Pd(0) catalyst, or forms a strained cyclic cumulene 39 via
consecutive reductive elimination of palladium,18 which is
transformed into the aromatic product 40 via sigmatropic
rearrangement. Although the reasons for observed hydrogen
migration exclusively from E-position of conjugated enynes are
not clearly understood, this fact is in perfect agreement with
the relative reactivities of Z- and E-isomers of enynes 10g,m
in the benzannulation reaction (Table 3). Thus, as it was
mentioned above, the alkyl-substituted Z-enynes 10g-i, which
possess a hydrogen atom in E-position, underwent smooth
cycloaddition, whereas their E-counterparts (with hydrogen atom
in Z-position) did not exhibit any notable reactivity under the
similar reaction conditions (Table 3, note b). In contrast to above
cases, the reactivities of E- and Z-isomers of activated enynes
10j-m are not so different. As a working hypothesis, we assume
that partial E f Z isomerization of activated E-enynes 10k and
10m into their more reactive Z-analogues 10j and 10l, under
alkynyl group, do not act as enynophiles in the mentioned reaction at all.
Accordingly, an alternative explanation for remarkably high reactivity of
diynes in terms of steric effects is discounted by the observation that
acetylene itself did not act as an enynophile in that reaction.
(18) This type of six-membered strained cyclic cumulene has been
proposed as an intermediate in the dehydro Diels-Alder cycloadditions.
(a) For review see: Johnson, R. P. Chem. ReV. 1989, 89, 1111. (b) See
also ref 8.

Enyne-Diyne [4+2] Cross-Benzannulation
J. Am. Chem. Soc., Vol. 121, No. 27, 1999 6399
Table 5. Palladium-Catalyzed Cross-Benzannulation of Monosubstituted Enynes 3 and 5 with Triynes 16
a Isolated yields. b In this case, 2.2 equiv of 3b was used. In all the other cases, one equivalent of 3 was used.
spectra were recorded on a Shimadzu FTIR-8200A spectrometer. High-
the reaction conditions, could be responsible for the surprisingly
low reactivities of E-enynes 10k and 10m (Table 3, entries 16,
18).
resolution mass spectra were recorded on a Hitachi M-2500S spec-
trometer. GC-MS analyses were performed on a Hewlett-Packard Model
6890 GC interfaced to a Hewlett Packard Model 5973 mass selective
detector (30 m × 0.25 mm capillary column, HP-5MS). Capillary GLC
analysis was performed on SHIMADZU GC-18A (30 m × 0.25 mm
capillary column, DB-5). Column chromatography was carried out
employing Merck silica gel (Kieselgel 70-230 mesh), and analytical
thin-layer chromatography (TLC) was performed on 0.2 mm precoated
silica gel plates (Kieselgel 60 F254).
Concluding Remarks. As a brief concluding outlook on
palladium-catalyzed [4+2] cycloaddition reactions of conjugated
enynes to date, we arranged the mono- and multisubstituted
enynes in the order of the decrease of their reactivities (Figure
2). The monosubstituted enynes 3 and 5, as the most reactive
substrates, easily react in both homo- and cross-cycloaddition
manner to afford the enyne-enyne homodimerization products
49a and 69b and enyne-diyne cross-benzannulation products 8
and 9, respectively (Figure 2). In contrast to the above cases,
the di- and trisubstituted enynes 10 did not undergo the homo-
dimerization process; however they reacted with diynes in the
cross-cycloaddition manner, although in most cases their
reactions were slower than that for monosubstituted enynes 3
and 5, affording multisubstituted benzenes 11 not only in highly
regio- but also in highly chemoselectiVe manner (Figure 2).
Although further investigation to settle a precise reaction
mechanism is needed, the present procedure provides a new
regiospecific and synthetically useful route to multisubstituted
arylacetylenes possessing alkyl-, alkynyl-, aryl-, silyl-, cyano-,
and ester functionalities attached to the benzene unit.
Chemicals. Anhydrous solvents were purchased from Kanto Chemi-
cals. All other compounds used were commercially available and
purchased from Aldrich.
Synthesis of Substrates. Enynes 3b,19 3c,20 5a-e, 10a-c,g-i,21
10d-f,22 10j-m,23 26,24 27,25 28,26 29-30,27 diynes 7d,28 7e,f,21 13a,b,29
(19) Klusener, P. A. A.; Kulik, W.; Brandsma, L. J. Org. Chem. 1987,
52, 5261.
(20) Benzyl-substituted enyne 3c was prepared via the following
consecutive transformations: acylation of bis-TMS-acetylene with phenyl-
acetyl chloride,20a Peterson olefination,20b followed by desilylation step.20c
See: (a) Schwab, J. M.; Lin, D. C. T. J. Am. Chem. Soc. 1985, 107, 6046.20a
(b) For a review on Peterson olefination, see for example: Ager, D. J.
Synthesis 1984, 384. (c) Corey, E. J.; Ruden, R. A. Tetrahedron Lett. 1973,
1495.
(21) Brandsma, L. PreparatiVe Acetylenic Chemistry, 2nd ed.; Elsevier:
Amsterdam, The Netherlands, 1988.
(22) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ru¨hter, G. J.
Am. Chem. Soc. 1997, 119, 698.
(23) Ester- 10j,k, and cyano-containing enynes 10l,m were synthesized
from the corresponding alkynyl ketones via Horner-Wadsworth-Emmons
procedure, see: Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
Experimental Section
Instrumentation. NMR spectra were recorded on a JEOL JNM LA-
300 (300 MHz) and JEOL JNM R-500 (500 MHz) instruments. IR

6400 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
GeVorgyan et al.
Figure 1. Deuterium-labeling studies.
13c,21 13e-i,j,30 and 13f31 and triynes 16a-d30 and 16g32 were prepared
according to the standard procedures. Enyne 3a and diynes 7a-c were
commercially available and purchased from Aldrich. All manipulations
were conducted in oven dried Wheaton microreactors under an argon
atmosphere.
Palladium-Catalyzed Enyne-Diyne (Triyne) [4+2] Cross-Benz-
annulatuion (General Procedure). A mixtute of enyne (1.0 mmol),33
diyne (or triyne) (1.0 mmol), and Pd(PPh3)4 (5 mol %), unless otherwise
specified, in THF (2 mL) was stirred under the conditions indicated in
the Tables 1-5. The reaction course was monitored by capillary GLC
analysis. After completion of the reaction (see Tables 1-5 for details),
the mixture was filtered through a short column (silica gel) and
concentrated. Benzannulation products were purified by column chro-
matography (silica gel, eluent-hexane).
Synthesis of 8a (Table 1, Entry 1). To a THF (2 mL) solution of
Pd(PPh3)4 (28.9 mg, 0.025 mmol) under Ar atmosphere were added
3a (66.1 mg, 1.0 mmol) and 7a (81.1 mg, 0.5 mmol), and the resulting
mixture was stirred overnight at 65 °C. GLC analysis revealed
completion of the reaction. The reaction mixture was filtered through
a short florisil column, and the product was purified by a silica gel
column chromatography using hexane as an eluent. 8a was obtained
in 89% yield (101.6 mg).
1
8a. H NMR (300 MHz, CDCl3) δ 7.25 (d, 0H, J ) 7.7 Hz), 6.96
(24) Deuterium-containing enyne 26 was synthesized from 3b19 by means
of deprotonation with n-BuLi, followed by quenching with D2O.
(25) Deuterated enyne 27 was prepared from diyne 13a29 via Pd-catalyzed
hydrostannation-deuteriodestannation (with DClaq) sequence. For Pd-
catalyzed hydrostannation of diynes, see: Zhang, H. X.; Guibe´, F.;
Balavoine, G. J. Org. Chem. 1990, 55, 1857.
(26) Bis-deuterated enyne 28 was synthesized by consecutive acylation
of bis-TMS-acetylene with heptanoyl chloride,20a Wittig olefination with
CD3Ph3PI, followed by desilylation step.20c
(s, 1H), 6.90 (d, 1H, J ) 7.7 Hz), 2.71 (t, 2H, J ) 7.8 Hz), 2.43 (t, 2H,
J ) 6.7 Hz), 2.30 (s, 3H), 1.65-1.32 (m, 8H), 0.944 (t, 3H, J ) 7.0
Hz), 0.938 (t, 3H, J ) 7.3 Hz); 13C NMR (75 MHz, CDCl3) δ 144.6,
137.3, 131.9, 129.4, 126.2, 120.3, 92.8, 79.3, 34.4, 32.9, 31.0, 22.7,
22.0, 21.4, 19.2, 14.0, 13.6; IR (neat) 2957, 2930, 2860, 1611, 1497,
1456, 1379, 1329, 1105, 818 cm-1; HRMS calcd for C17H24 228.1877,
found 228.1883.
8b. 1H NMR (300 MHz, CDCl3) δ 7.68-6.64 (m, 2H), 7.54 (d, 1H,
J ) 7.9 Hz), 7.48-7.23 (m, 9H), 7.14 (dd, 1H, J ) 7.9, 0.7 Hz), 2.40
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.8, 140.6, 138.6, 132.7, 131.2
(×2), 130.2, 129.3 (×2), 128.2 (×2), 127.9 (×2), 127.8 (×2), 127.4,
123.6, 118.6, 91.5, 89.5, 21.5; IR (KBr) 3059, 3030, 2920, 1597, 1493,
1443, 908, 820, 770, 756, 733, 698, 691, 665 cm-1; HRMS calcd for
C21H16 263.1252, found 268.1230. Anal. calcd for C21H16: C, 93.99;
H, 6.01. Found: C, 93.77; H, 6.32.
(27) E-29, and Z-deuterated enyne 30 were prepared via consequtive
haloboration-deuterio (protio) deboration of hexyne-1 (1-deuterio-hexyne-
1),27a followed by Sonogashira coupling 1-ethynylcyclohexene.27b (a) Hara,
S.; Dojo, H.; Takunami, S.; Suzuki, A. Tetrahedron Lett. 1983, 24, 731.
(b) Matsumoto, Y.; Naito, M.; Hayashi, T. Organometallics 1992, 11, 2732.
(28) Diyne 7d was synthesized by oxidative coupling21 of propargyl
alcohol, followed by MOM protection. For MOM protection, see: Stork,
G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275.
(29) Kende, A. S.; Smith, C. A. J. Org. Chem. 1988, 53, 2655.
(30) Blanco, L.; Helson, H. E.; Hirthammer, M.; Mestdagh, H.; Spy-
roudis, S.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1987, 26, 1246.
(31) Miller, J. A.; Zweifel, G. Synthesis 1983, 128.
Synthesis of 9a (Table 2, Entry 1). To a toluene (0.5 mL) solution
of Pd(PPh3)4 (11.6 mg, 0.01 mmol) and (o-tol)3P (30.4 mg, 0.1 mmol)
under Ar atmosphere were added 5a (68.1 mg, 0.5 mmol) and 7a (81.1
mg, 0.5 mmol), and the resulting mixture was stirred for 8 h at 80 °C.
GLC analysis indicated completion of the reaction. The mixture was
filtered through a short alumina column, and the product was purified
as described above. 9a was obtained in 66% yield (98 mg).
(32) Bis-TMS-triyne 16g was synthesized from propargyl alcohol Via
oxidative coupling,21 tosylation,32a and silylation32b sequence. See: (a) Patel,
G. N. J. Polym. Sci. Pol. Phys. Ed. 1979, 17, 1591. (b) Alberts, A. H. Recl.
TraV. Chim. Pays-Bas 1989, 108, 242.
(33) The good scalability of this reaction was demonstrated with an
1
essentially quantitative preparation of 8b (homogeneous by H NMR and
1
9a. H NMR (300 MHz, CDCl3) δ 7.09 (dd, 1H, J ) 8.6, 6.6 Hz),
GLC analyses, isolated yield) in a 5 mmol scale under the mentioned
reaction conditions.
6.99 (d, 2H, J ) 7.5 Hz), 2.76 (t, 2H, J ) 8.3 Hz), 2.75 (t, 2H, J ) 8.3

Enyne-Diyne [4+2] Cross-Benzannulation
J. Am. Chem. Soc., Vol. 121, No. 27, 1999 6401
Scheme 1. Proposed Mechanism for Palladium-Catalyzed Enyne-Diyne Cross-Benzannulation
1
Hz), 2.49 (t, 2H, J ) 6.5 Hz), 1.66-1.31 (m, 16H), 0.95 (t, 3H, J )
6.1 Hz), 0.94 (t, 3H, J ) 7.5 Hz), 0.89 (t, 3H, J ) 7.1 Hz);13C NMR
(75 MHz, CDCl3) δ 145.1, 145.0, 126.9, 125.9, 122.8, 97.5, 77.7, 35.1,
34.8, 32.9, 31.8, 31.1, 30.7, 29.4, 22.7, 22. 7, 22.0, 19.4, 14.1, 14.0,
13.6; IR (neat) 3061, 2957, 2928, 2858, 2361, 1576, 1466, 1456, 1379,
1327, 1105, 752, 669 cm-1. Anal. calcd for C22H34: C, 88.52; H, 11.48.
Found: C, 88.53; H, 11.84.
14f. H NMR (300 MHz, CDCl3) δ 7.52-7.50 (m, 2H), 7.46 (d,
1H, J ) 7.7 Hz), 7.38-7.32 (m, 4H), 7.15 (dd, 1H, J ) 7.8, 1.2 Hz),
2.36 (s, 3H), 0.42 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 142.1, 137.2,
134.7, 132.5, 131.1 (×2), 129.6, 128.4 (×2), 128.0, 125.3, 123.7, 91.32,
91.29, 21.6, -1.0 (×3); IR (neat) 3018, 2955, 2214, 1597, 1493, 1468,
1443, 1246, 1140, 1070, 889, 841, 754, 689 cm-1; HRMS calcd for
C18H20Si 264.1333, found 264.1336.
Synthesis of 11a (Table 3, Entry 1). To a toluene (1.0 mL) solution
of Pd(PPh3)4 (28.9 mg, 0.025 mmol) under Ar atmosphere were added
10a (75.1 mg, 0.5 mmol) and 7a (81.1 mg, 0.5 mmol), and the resulting
mixture was stirred at 100 °C for 5 days. The same procedure as above
was used, giving 11a in 69% yield (107 mg).
Synthesis of 17h (Table 5, Entry 9). To a THF (2 mL) solution of
Pd(PPh3)4 (28.9 mg, 0.025 mmol) under Ar atmosphere were added 3c
(71.1 mg, 0.5 mmol) and 16g (109.2 mg, 0.5 mmol), and the resulting
mixture was stirred at 65 °C for 2 h. The same procedure as above
gave 17h in 86% yield (148.7 mg).
1
11a. H NMR (300 MHz, CDCl3) δ 6.82 (s, 2H), 2.72 (t, 2H, J )
17h. 1H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H, J ) 7.9 Hz), 7.35-
7.15 (m, 6H), 7.08 (d, 1H, J ) 7.7 Hz), 3.97 (s, 2H), 0.35 (s, 9H),
0.23 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 144.3, 141.4, 140.3, 134.6,
134.2, 129.3, 128.9, 128.5, 126.3, 124.1, 90.8, 88.0, 79.1, 76.7, 42.0,
-0.3 (×3), -1.1 (×3); IR (neat) 3028, 2959, 2899, 2201, 2098, 1587,
1495, 1452,1250, 1015, 883, 841, 760, 700, 633 cm-1; HRMS calcd
for C23H28Si2 360.1728, found 360.1721.
7.8 Hz), 2.71 (t, 2H, J ) 8.0 Hz), 2.47 (t, 2H, J ) 6.6 Hz), 2.27 (s,
3H), 1.65-1.31 (m, 16H), 0.95 (t, 3H, J ) 7.2 Hz), 0.94 (t, 3H, J )
7.2 Hz), 0.89 (t, 3H, J ) 6.6 Hz);13C NMR (75 MHz, CDCl3) δ 144.93,
144.86, 136.6, 126.8, 126.7, 119.8, 96.6, 77.7, 35.1, 34.7, 33.0, 31.1,
30.8, 29.4, 22.8, 22.7, 22.0, 21.4, 19.4, 14.1, 14.0, 13.6; IR (neat) 2957,
2930, 2858, 2731, 2667, 2361, 2343, 1609, 1566, 1466, 1377, 1364,
1329, 1300, 1105, 854, 727, 665 cm-1. Anal. calcd for C23H36: C, 88.39;
H, 11.61. Found: C, 88.50; H, 11.66.
Synthesis of 14f (Table 4, Entry 6). To a THF (2 mL) solution of
Pd(PPh3)4 (28.9 mg, 0.025 mmol) under Ar atmosphere were added
3a (66.1 mg, 1.0 mmol) and 13f (99.2 mg, 0.5 mmol), and the resulting
mixture was stirred at 65 °C overnight. Completion of the reaction
was confirmed by GLC analysis, and the mixture was filtered through
a short florisil column. Purification of the product with a silica gel
column chromatography using hexane as an eluent gave 14f in 78%
yield (102.5 mg).
Deuterium-Labeling Studies. The reaction of 26 (97% D-content)
with 7a was carried out in a manner similar to that described for the
synthesis of 8a; 31 (97% D-content) was obtained in 64% yield. The
reaction of 27 (95% D-content) with 7a was carried out in a manner
similar to that described for the synthesis of 9a; 32 (95% D-content)
was obtained in 41% yield. The reaction of 28 (82% D-content for
both deuteriums at C-1 positions) with 7a was carried out as described
above, and 33 was obtained in 61% yield in which D-content at C-3

6402 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
GeVorgyan et al.
Figure 2. Summary on palladium-catalyzed [4+2] benzannulation of conjugated enynes.
was 84% and that at C-5 was 71%. The reaction of 29 and 30 was
carried out as described in Table 3 entry 2, giving the [4+2] adducts
34 and 35, respectively, in ∼70% yield.
32, and 33 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Supporting Information Available: Analytical and spec-
troscopic data of 8, 9, 11, 14, 15, 17, 18, 19, 20, 26, 27, 28, 31,
JA990749D