Intercepting palladacycles derived by C-H insertion. A mechanism-driven entry to heterocyclic tetraphenylenes

Article abstract of DOI:10.1021/ja056964d

Mechanistic support for the intermediacy of a palladacycle, which has been implicated in the crossover Heck reaction, has been obtained by intercepting this species using biphenylene. This leads to the formation of heterocyclic tetraphenylene derivatives. Three examples of this process are reported, and in two cases, the product structures have been confirmed by X-ray crystallographic analysis. Copyright

Full text of DOI:10.1021/ja056964d

Published on Web 12/23/2005
Intercepting Palladacycles Derived by C-H Insertion. A Mechanism-Driven
Entry to Heterocyclic Tetraphenylenes
David Masselot, Jonathan P. H. Charmant, and Timothy Gallagher*
School of Chemistry and Structural Chemistry Laboratory, UniVersity of Bristol, Bristol BS8 1TS, United Kingdom
Received October 12, 2005; E-mail: t.gallagher@bristol.ac.uk
We recently described the efficient Heck reactions of pyridyl-
based biaryl halides 1a-c, which lead to the formation of the
expected adducts 3 as well as the more unusual isomeric “crossover”
products 4 (Scheme 1).1,2 This “crossover Heck” process is
mechanistically significant, involving as it does a C-H cleavage
step, with palladacycle 2 as a plausible intermediate. A role for 2,
however, raises a number of issues. For example, 1a (X ) NO2)
leads to a higher proportion of crossover adduct than 1c (X )
OMe): 3a:4a ) 3:1 versus 3c:4c ) 10:1. These substituent effects
are not consistent with palladacycle formation via electrophilic
aromatic substitution (EAS), that is, more crossover is observed
with the more electron-deficient substrate.3-5
variants11 is not straightforward, so new synthetic approaches to
such systems merit investigation.
We focused initially on the 4-nitrophenyl derivative 1a, given
that this substrate showed the highest propensity to undergo C-H
insertion (as judged by the level of crossover adduct 4a observed).
Using conditions similar to those employed in Scheme 1 with 1
equiv of biphenylene 5, the desired tetracycle 8a was observed in
addition to 4-(4′-nitrophenyl)pyridine 9, the product of C-Br
reduction. This reaction was slow (which may account for formation
of significant amounts of 9), so this process was subjected to further
optimization.12a Our current conditions (5 (1000 mol %), Pd(OAc)2
(10 mol %), (o-Tol)3P (20 mol %), NEt3 (1000 mol %), MeCN,
sealed tube, at either 125 °C for 20 h or 110 °C for 3 days) gave
the target tetraphenylene 8a in 36% isolated yield after chroma-
tography (Scheme 2).
Scheme 1. “Crossover Heck” Reaction
Scheme 2
The mechanism5 associated with the formation and reaction of
the postulated palladacycle 2 is still under study, but to date, we
have been unable to isolate or observe directly this intermediate.6
An alternative approach is to gain indirect support for the
involvement of 2, and this paper focuses on methods aimed at
intercepting this palladacycle. This would provide a mechanistic
insight into the process outlined in Scheme 1, but also offers an
unusual synthetic entry to novel polyarene variants.
Of particular relevance to this objective is the elegant work of
Jones, who showed that Pd(0) or Pt(0) will catalyze the dimerization
of biphenylene 5 to give tetraphenylene 7.7 This occurs via
sequential C-C insertion reactions, and the intermediacy of a
metallacycle 6 (M ) Pt or Pd) was demonstrated.
Given the novel nature of this process, the structure of tetraphe-
nylene 8a was also established by single-crystal X-ray crystal-
lographic analysis (Figure 1).
Interestingly, we did not observe formation of tetraphenylene 7
in any appreciable amounts under these conditions, but dimerization
of 5 to give 7 is reported to be slow.7 A number of important control
experiments were carried out, with a major mechanistic issue
concerning the timing of the individual steps. Does 1a undergo
oxidative addition faster than biphenylene 5; that is, does the
formation of 8a involve 2a or 6? Also, is evidence available for
the second step being the formation of palladacycle 2a followed
by reaction of this species with biphenylene 5? First, the process
shown in Scheme 2 does require palladium, and tetraphenylene 8a
was not observed in the absence of catalyst. Second, and in order
to identify which component (1a vs 5) was undergoing oxidative
addition more rapidly, we ran a competition between 1a and 5 under
Heck conditions.12b Only Heck adducts derived from 1a (i.e., 3a
and 4a) were observed, and no Heck adducts7 derived from 5 were
detected.12c This demonstrates clearly that aryl bromide 1a under-
goes selective (faster) oxidative addition in preference to biphe-
nylene 5. Third, we observed no reaction between 3-bromopyridine
and biphenylene 5 under the conditions shown in Scheme 2. This
indicates that formation of tetraphenylene 8a requires an aryl ring
ortho to the site of oxidative addition (i.e., a role for palladacycle
This observation raises the possibility that palladacycle 2 (derived
from biaryls 1, Scheme 1) could also be intercepted by biphenylene
5.8 This would not only provide valuable evidence and support for
the intermediacy of 2, but should generate a novel synthetic entry
to “mixed” (i.e., unsymmetrical) tetraphenylene derivatives. Sub-
stituted tetraphenylenes are of significant interest given the unusual
electronic properties associated with these systems.9,10 However,
access to either unsymmetrical or heterocyclic tetraphenylene
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10.1021/ja056964d CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
14327. For other, related Pd-mediated migration processes, see: (b)
Campo, M. A.; Huang, Q. H.; Yao, T. L.; Tian, Q. P.; Larock, R. C. J.
Am. Chem. Soc. 2003, 125, 11506-11507. (c) Huang, Q. H.; Campo, M.
A.; Yao, T. L.; Tian, Q. P.; Larock, R. C. J. Org. Chem. 2004, 69, 8251-
8257. (d) Huang, Q. H.; Fazio, A.; Dai, G. X.; Campo, M. A.; Larock, R.
C. J. Am. Chem. Soc. 2004, 126, 7460-7461. For an earlier example of
products derived by a formal Pd migration within a biaryl system, see:
(e) Rice, J. E.; Cai, Z. W. J. Org. Chem. 1993, 58, 1415-1424.
(3) Reviews: (a) Handbook of CH Transformations; Dyker, G., Ed.; Wiley-
VCH: Weinheim, Germany, 2005. (b) Jia, C. G.; Kitamura, T.; Fujiwara,
Y. Acc. Chem. Res. 2001, 34, 633-639. (c) Dyker, G. Angew. Chem.,
Int. Ed. 1999, 38, 1699-1712. (d) Ryabov, A. D. Chem. ReV. 1990, 90,
403-424.
(4) For other studies involving intramolecular palladium-catalyzed arylations
other than with biaryls, see: (a) Campeau, L.-C.; Parisien, M.; Leblanc,
M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126, 9186-9187. (b) Go´mez-
Lor, B.; Gonza´lez-Cantalapiedra, E.; Ruiz, M.; de Frutos, OÄ .; Ca´rdenas,
D. J.; Santos, A.; Echavarren, A. M. Chem. Eur. J. 2004, 10, 2601-
2608.
Figure 1. Structure of tetraphenylene 8a.
(5) For studies relating to EAS versus other mechanistic options associated
with palladacycle formation, see: (a) Gonza´lez, J. J.; Garc´ıa, N.; Go´mez-
Lor, B.; Echavarren, A. M. J. Org. Chem. 1997, 62, 1286-1291. (b)
Mart´ın-Matute, B.; Mateo, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem.
Eur. J 2001, 7, 2341-2348. (c) Go´mez-Lor, B.; Echavarren, A. M. Org.
Lett. 2004, 6, 2993-2996. For recent computational studies of C-H
insertions that favor an agostic C-H complex and do not invoke EAS or
Pd(IV), see: (d) Mota, A. J.; Dedieu, A.; Bour, C.; Suffert, J. J. Am.
Chem. Soc. 2005, 127, 7171-7182. (e) Davies, L. D.; Donald, S. M. A.;
Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754-13755.
(6) We have characterized the related platinacycle generated using Pt(PPh3)4.
This metallacycle undergoes the Heck reaction (as Scheme 1) leading to
both 3a and 4a but decomposes under conditions required for tetraphe-
nylene formation.
(7) (a) Edelbach, B. L.; Lachicotte, R. J.; Jones, W. D. J. Am. Chem. Soc.
1998, 120, 2843-2853. Jones has shown that palladacycle 6 undergoes
Heck and Suzuki couplings: (b) Satoh, T.; Jones, W. D. Organometallics
2001, 20, 2916-2919.
(8) Palladacycles based on a biaryl scaffold (cf 6) have been characterized
by X-ray crystallography: (a) Retbøll, M.; Edwards, A. J.; Rae, A. D.;
Willis, A. C.; Bennett, M. A.; Wenger, E. J. Am. Chem. Soc. 2002, 124,
8348-8360. Similar metallacycles have been implicated in the Pd(0)-
mediated cyclotrimerization of benzynes: (b) Pen˜a, D.; Escudero, S.;
Pe´rez, D.; Guitia´n, E.; Castedo, L. Angew. Chem., Int. Ed. 1998, 37, 2659-
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C. ComprehensiVe Supramolecular Chemistry; MacNicol, D. D., Toda,
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(10) For more recent approaches to substituted tetraphenylenes, see: (a) Peng,
H. Y.; Lam, C. K.; Mak, T. C. W.; Cai, Z. W.; Ma, W. T.; Li, Y. X.;
Wong, H. N. C. J. Am. Chem. Soc. 2005, 127, 9603-9611. (b) Wen, J.
F.; Hong, W.; Yuan, K.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem.
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Hasegawa, M.; Kuwatani, Y.; Yoshida, M.; Matsuyama, H.; Iyoda, M. J.
Chem. Soc., Perkin Trans. 1 2001, 159-165.
(11) Heterocyclic tetraphenylenes incorporating furan, thiophene, pyrazine,
pyrimidine, pyrazole, and pyridone units are known. (a) Marsella, M. J.;
Reid, R. J.; Estassi, S.; Wang, L.-S. J. Am. Chem. Soc. 2002, 124, 12507-
12510. (b) Brettreich, M.; Bendikov, M.; Chaffins, S.; Perepichka, D. F.;
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and references therein.
(12) (a) An excess of 5 is important to limit C-Br reduction. With 1a, the
mass balance is made up of 8a (36%) and 9 (55%). (b) Jones7 has shown
that 6 derived from 5 participates in Heck reactions, and our control
experiment indicates that 1a undergoes oxidative addition more rapidly
than 5. (c) We did not observe 7, 8a, or 9 under these Heck conditions,
and increasing the concentration of 5 made no impact. This control reaction
(see Supporting Information) also shows an induction period prior to
consumption of 1a, and addition of liquid mercury to this Heck process
very significantly reduced the rate of reaction of 1a. The implications of
this are not clear; the active catalyst is not immediately present, and
mercury is either preventing the formation of or removing the catalytically
competent Pd species. For a related application of a catalytic species
derived from Pd black, see: Campeau, L.-C.; Thansandote, P.; Fagnou,
K. Org. Lett. 2005, 7, 1857-1860. (d) A more open-ended question relates
to how the Pd insertion into biphenylene might be accelerated. This has
implications for the efficiency of formation of tetraphenylenes 8.
2a) and excludes the direct interaction of the oxidative addition η1
complex (i.e., ArPdBrL2) with biphenylene 5.
Taken together with these control experiments, the formation of
tetraphenylene 8a indicates the selective formation of a reactive
palladacycle 2a from 1a, which arises via C-Br oxidative addition
followed by C-H insertion into the adjacent aryl ring prior to
reaction with biphenylene 5.12d
To extend the scope of tetraphenylenes available, two other
4-aryl-3-bromopyridines 1b1 and 1c1 have been examined. Using
similar conditions, tetraphenylenes 8b and 8c were isolated in 16
and 13% yields, respectively.13 Our earlier work1 had indicated a
similar trend, that is, both 1b and 1c were less effective than 1a
with respect to the formation of crossover Heck adducts 4, and
this moderated level of reactivity is apparent in their reactions with
with 5. This observationsan effect associated with the 4′-X
substituentstaken together with the control experiments mentioned
earlier provides additional support for the intermediacy of a
palladacycle 2 in both Schemes 1 and 2.
In summary, we have provided new evidence to support the
conclusion that palladacycle 2 is implicated in the process illustrated
in Scheme 1. This assertion is based on an ability to intercept 2
with biphenylene 5, which, in turn, demonstrates a novel strategy
for the construction of heterocyclic tetraphenylene derivatives 8.
The latter are preliminary synthetic results but importantly serve
to validate the basic concept involved, and improved mechanistic
understanding will be a factor in making this an effective synthetic
process. The mechanism associated with conversion of 1 to 2 (and
3/4) does remain open to debate, but our results show that a Pd(II)
species needs to be considered in the catalytic cycle. A Pd(IV)
hydride intermediate or EAS both appear less plausible, and the
electronic effects observed with 1a-c endorse recent computational
studies.5 Further, given the role of 2 and the feasibility of a Heck
reaction involving this species, ring opening of 2 (or migration of
palladium) is not required to explain the formation of crossover
adducts 4.
Acknowledgment. We thank Professors Guy C. Lloyd-Jones
and Antonio Echavarren for advice.
Supporting Information Available: Experimental procedures,
product characterization, and Heck-based control experiment between
1a and 5. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Karig, G.; Moon, M. T.; Thasana, N.; Gallagher, T. Org. Lett. 2002, 4,
3115-3118. Products 3 and 4 are also obtained with the isomeric biaryl
halides (i.e., 1-substituted 3-bromo-4-(4′-pyridyl)benzenes). In these cases,
the ratio of expected to crossover adducts is not dependent on the nature
of the X substituent.
(2) This crossover process was subsequently reported for other biaryls: (a)
Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002, 124, 14326-
(13) Tetraphenylene 8b was characterized by X-ray crystallography (see
Supporting Information) and was obtained in a similar (12%) yield using
3-bromo-4-(4′-pyridyl)benzene1 (the regioisomer of 1b). While this
establishes an alternative entry to a common palladacycle (2b), these
isomeric halides are synthetically less readily accessible than 1.
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