Biaryl synthesis via palladium-catalyzed aryne multicomponent coupling

Article abstract of DOI:10.1021/ol702584t

Aryl iodides have been introduced as electrophiles in the three-component Heck coupling of arynes. Following optimization studies to favor three- versus two-component coupling, the reaction proceeds in good yield to afford a variety of functionalized biaryls.

Full text of DOI:10.1021/ol702584t

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5589-5592
Biaryl Synthesis via Palladium-Catalyzed
Aryne Multicomponent Coupling
Jaclyn L. Henderson,† Andrew S. Edwards,‡ and Michael F. Greaney*,†
UniVersity of Edinburgh, School of Chemistry, Joseph Black Building, King’s
Buildings, West Mains Road, Edinburgh EH9 3JJ, U.K., and Organon Laboratories
Ltd., Newhouse, Lanarkshire ML1 5SH, U.K.
michael.greaney@ed.ac.uk
Received October 26, 2007
ABSTRACT
Aryl iodides have been introduced as electrophiles in the three-component Heck coupling of arynes. Following optimization studies to favor
three- versus two-component coupling, the reaction proceeds in good yield to afford a variety of functionalized biaryls.
The biaryl motif occupies an iconic role in chemistry, being
a key structural feature of natural products, novel optical
and mechanical materials, drugs, agrochemicals, and other
biologically active molecules. The assembly of functionalized
biaryls using transition-metal-catalyzed tandem reactions,
whereby multiple carbon-carbon or carbon-heteroatom
bonds are formed in a single step, is a highly attractive
approach to these valuable compounds that has widespread
application.1 The incorporation of arynes into such multi-
component coupling processes offers a unique entry point
into functionalized aromatics and is a rapidly growing area
of research.2 Pioneering work from the Pere´z/Guitia´n and
Yamamoto groups used π-allyl palladium complexes, alkynes,
and arynes to synthesize naphthalenes and phenanthrenes,3,4
setting the stage for a series of developments in transition-
metal-catalyzed aryne multicomponent couplings.5-11 Until
recently, a limitation of such aryne multicomponent coupling
processes was the requirement for allyl halides as the
electrophilic component. Work from our own laboratory
(4) (a) Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron
Lett. 1999, 40, 7533-7535. (b) Yoshikawa, E.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2000, 39, 173-175. (c) Yoshikawa, E.; Radhakrishnan, K.
V.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 7280-7286.
(5) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. Tetrahedron
Lett. 2000, 41, 729-731.
(6) (a) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Org. Chem. 2000,
65, 6944-6950. (b) Quintana, I.; Boersma, A. J.; Pen˜a, D.; Pe´rez, D.;
Guitia´n, E. Org. Lett. 2006, 8, 3347-3349.
(7) (a) Hsieh, J. C.; Rayabarapu, D. K.; Cheng, C.-H. Chem. Commun.
2004, 532-533. (b) Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2004, 6,
2821-2824. (c) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. C. J. Org.
Chem. 2004, 69, 8445-8450. (d) Jeganmohan, M.; Cheng, C.-H. Synthesis
2005, 10, 1693-1697. (e) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H.
Org. Lett. 2005, 7, 2921-2924. (f) Jayanth, T. T.; Cheng, C.-H. Chem.
Commun. 2006, 894-896. (g) Bhuvaneswari, S.; Jeganmohan, M.; Cheng,
C.-H. Org. Lett. 2006, 8, 5581-5584. (h) Jayanth, T. T.; Cheng, C.-H.
Angew. Chem., Int. Ed. 2007, 46, 5921-5924.
† University of Edinburgh.
‡ Organon Laboratories.
(1) (a) Leclerc, J.-P.; Andre´, P. M.; Fagnou, K. J. Org. Chem. 2006, 71,
1711-1714. (b) Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000,
56, 5959-5989. (c) de Meijere, A.; Brase, S. J. Organomet. Chem. 1999,
576, 88-110. (d) Heumann, A.; Reglier, M. Tetrahedron 1996, 52, 9289-
9346.
(2) Recent reviews: (a) Dyke, A. M.; Hester, A. J.; Lloyd-Jones, G. C.
Synthesis 2006, 4093-4112. (b) Guitia´n, E.; Pe´rez, D.; Pen˜a, D. Top.
Organomet. Chem. 2005, 14, 109.
(8) (a) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127,
15716-15717. (b) Zhang, X.; Larock, R. C. Org. Lett. 2005, 7, 3973-
3976. (c) Liu, Z.; Larock, R. C. J. Org. Chem. 2007, 72, 223-232. (d)
Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007, 46, 2535-2538.
(9) Chatani, N.; Kanitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S. J.
Am. Chem. Soc. 2001, 123, 12686-12687.
(10) Yoshida, H.; Honda, Y.; Shirakawa, E.; Hiyama, T. Chem. Commun.
2001, 1880-1880.
(3) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Am. Chem. Soc. 1999,
121, 5827-5828.
(11) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. J. Am. Chem.
Soc. 2006, 128, 7426-7427.
10.1021/ol702584t CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/22/2007

extended the reaction to include bromoacetates (heteroallyls)
and benzyl bromides in a Heck reaction.11 Biaryl synthesis
via the use of aryl halide electrophiles, however, remains
an unexplored area. The proposed reaction is set out in
Scheme 1 for the insertion of benzyne, generated from the
Table 1. Three-Component Coupling of Aryne, Aryl Iodide,
and Heck Acceptor; Optimization Data
Scheme 1. Three-Component Coupling of Benzyne, Aryl
Halide, and Heck Acceptor
time temp ratio yield yield
entry
Pd/ligand
(h) (°C) 2:3:8 of 9a of 10
1
2
3
4
5
Pd(OAc)2/dppe
48
2
4
4
4
50 1:1:1
50 1:1:1
50 2:1:1.5 55
50 2:1:1.5 48
45 2:1:1.5 62
6
34
74
15
36
29
30
Pd(OAc)2/P(o-tol)3
Pd(OAc)2/P(o-tol)3
Pd(OAc)2/P(t-Bu)3‚HBF4
Pd(OAc)2/P(o-tol)3
of the desired 3CC biaryl 9a. Yields were not improved using
either aryl bromides or chlorides, both proving unproductive
in the reaction.
O-silyl aryl triflate 2, into a Heck reaction to produce the
biaryl 7.
We began an optimization study, aiming to control the
critical 3CC versus 2CC dichotomy.12 An initial coarse
catalyst screen identified Pd(OAc)2/P(o-tol)3 and a shortened
reaction time of 2 h as producing 9a as the major product,
albeit in low overall yield. (Table 1, entry 2).
A major challenge concerns the o-arylpalladium(II) com-
plex 4 generated after oxidative addition to the aryl halide
1, being far more reactive than analogous benzyl or allylpal-
ladium(II) species used with success in previous systems.
Shepherding this reactive intermediate to undergo successful
reaction with an aryne, another reactive intermediate, would
seem to be a demanding requirement. An obvious side
reaction is straight Heck coupling of 4 with acrylate to form
the cinnamate derivative 6. Selectivity for biaryl synthesis
through three-component coupling (3CC, 7) versus cinnamate
formation through two-component coupling (2CC, 6) is
therefore expected to be a significant issue in this chemistry.
Two elegant solutions to multicomponent biaryl bond
synthesis in this area have recently appeared: Larock
described the three-component coupling of an aryl halide,
an alkyne, and an aryne to produce polycyclic aromatics.8d
Two-component coupling was not feasible with this mono-
mer set, and bulky alkynes were used to prevent unwanted
incorporation of multiple alkyne units. Cheng has reported
the nickel-catalyzed union of arynes, acrylates, and boronic
acids whereby the first two components undergo cyclization
to a nickelacycle, followed by final biaryl bond formation.7h
The formal carbopalladation of arynes with arylpalladium-
(II) intermediates, followed by intermolecular C-C bond
formation with a third component (as shown in Scheme 1),
has yet to be achieved and would represent a very direct
and convenient method for accessing highly functionalized
biaryls. Our previous experience in catalyst optimization for
incorporating arynes into the Heck reaction suggested that
it may be possible to engineer the reaction toward this goal.11
Initial studies on coupling m-iodoanisole (8a), benzyne,
and tert-butyl acrylate (3a) produced low yields of the desired
3CC product 9a (Table 1). Using a catalyst system that had
been effective for benzyl bromide coupling (Pd(OAc)2/dppe
5 mol %) in the presence of CsF in MeCN, we isolated the
2CC product 10 (74%), along with a very small amount (6%)
A key parameter proved to be the benzyne stoichiometry.
Assuming a carbopalladation mechanism (vide infra), we
reasoned that 3CC works through successful aryne intercep-
tion of the arylpalladium intermediate formed from oxidative
addition of Pd(0) with the aryl iodide. Clearly, an insufficient
concentration of aryne present in the reaction medium will
lead to high yields of unwanted 2CC. However, simply
adding a large excess of 2 to the reaction in order to promote
3CC is not feasible, as excessive concentrations of benzyne
lead to triphenylene formation via Pd-catalyzed trimerisa-
tion.13 A balance between the two limiting stoichiometries
was struck as 2a:3a:8a ) 2:1:1.5, with the aryne precursor
2 being added in two equal batches at t ) 0 and t ) 1 h
(Table 1, entry 3). Although a slow, steady addition of
benzyne via syringe pump could be envisioned to give further
improvements, we found that this did not significantly
enhance the production of 9a. In our previous work we also
found that the rate of benzyne generation could be controlled
by solvent, and thus a selection of solvents and solvent
mixtures were tested, none giving a better ratio or yield than
100% acetonitrile. Addition of Ag2CO3 to the reaction did
not have any affect on the yield, ruling out any inhibitory
role for the iodide anion. After some additional optimization
of reaction temperature we could isolate the desired 3CC
product 9a in a good 62% yield using the final conditions
shown in entry 5, Table 1. Additional fine-tuning of the
catalyst system did not reveal a superior combination to Pd-
(OAc)2/P(o-tol)3, although Pd(OAc)2/P(t-Bu)3‚HBF4 proved
similarly effective.
(12) See Supporting Information.
(13) Pen˜a, D.; Escudeo, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Angew.
Chem., Int. Ed. 1998, 37, 2659-2661.
5590
Org. Lett., Vol. 9, No. 26, 2007

The scope and limitations of this palladium-catalyzed 3CC
process were next examined, and we were pleased to observe
that the reaction conditions had good generality and could
be applied to a wide variety of aryl iodides for the synthesis
of diverse biaryls. The results are summarized in Scheme 2.
difficult aryl iodide in 8a for initial studies. In point of fact,
the reaction proved less tolerant than previous systems of
electron-rich electrophilic components, with the 2- and 4-
iodomethoxy benzenes failing to produce isolable yields of
3CC products.
The aryne component was varied to include the 1,4-
dimethyl, 5-methyl, and 4,5-methylenedioxy functionalities.
The methyl-substituted arynes worked well (9m and 9n, 70%
and 65% yield), with the formation of 9m as a 1:1 mixture
of regioisomeric biaryls supporting the intermediacy of
benzyne in the coupling process. Methylenedioxy aryne was
less effective, producing 9o in a low 38% yield. It is likely
that focused optimization would improve 3CC of this
electron-rich aryne precursor. The Heck acceptor could be
altered to an enamide without problems, producing the
dimethyl amide and morpholine amide compounds 9r and
9s in high yields. p-Methoxystyrene was also effective as
the nucleophilic component, affording the novel tricyclic
arene 9p in a good 70% yield. It is also worth noting that
no products of either palladium migration14 or benzyne/
benzyne/acrylate trimerization6b were observed during the
course of these investigations.
Scheme 2. 3CC of Aryl Iodides, Arynes and Heck Acceptors
To demonstrate the power of the biaryl 3CC for the rapid
assembly of biologically active compounds, we synthesized
the prostenoid EP3 receptor antagonist 11 recently reported
by Merck-Frosst (Scheme 3).15 3CC of 1,2-dichloro-4-
Scheme 3. 3CC for the Synthesis of EP3 Receptor Antagonist
iodobenzene with tert-butyl acrylate and benzyne proceeded
in an excellent 88% yield. Subsequent ester hydrolysis and
amide bond formation with thiophene-2-sulfonamide then
gave the EP3 antagonist in an overall yield of 60% for the
three steps.
Three possible mechanistic pathways for the reaction are
set out in Scheme 4. Pathways A and B involve Pd0
complexing benzyne as a first step, either in concert with
the acrylate to form a palladacycle 12 (path A),6b or directly
to form the η2-metallocyclopropene 15 (path B).8a-c Path C
shows the conventional carbopalladation of the aryne with
the oxidative addition product 18, followed by a Heck
reaction.
a Product isolated as a 1:1 mixture of 3- and 4-methyl substituted
regioisomers.
Yields were good for aryl iodides having halogenated
functionality in the meta (9c, 9d, 9j; 73-88%) and para
(9b and 9k, 63% and 74%) position of the aryl iodide
component. The production of the bromo-compound 9b is
noteworthy as it provides a facile handle for further elabora-
tion of the biaryl ring system. Electron-poor aryl iodides were
particularly effective, producing some of the highest yields
of 3CC, e.g., the m-nitro and cyano compounds 9f and 9g
in 85% and 90% yields and the p-trifluoromethyl compound
9i in 86% yield. 2CC was not a noticeable problem for this
set of substrates, in hindsight suggesting that we chose a
(14) (a) Campo, M. A.; Zhang, H.; Yao, T.; Ibdah, A.; McCulla, R. D.;
Huang, Q.; Zhao, J.; Jenks, W. S.; Larock, R. C. J. Am. Chem. Soc. 2007,
129, 6298-6307. (b) Masselot, D.; Charmant, J. P. H.; Gallagher, T. J.
Am. Chem. Soc. 2006, 128, 694-695.
(15) Gallant, M.; Belley, M.; Carriere, M.-C.; Chateauneuf, A.; Denis,
D.; Lachance, N.; Lamontagne, S.; Metters, K. M.; Sawyer, N.; Slipetz,
D.; Truchon, J. F.; Labelle, M. Bioorg. Med. Chem. Lett. 2003, 13, 3813-
3816.
Org. Lett., Vol. 9, No. 26, 2007
5591

3), due to the methoxy group providing inductive17 and
dative7h,8b stabilization to the neighboring palladium atom,
subsequently forming product 14a.
Scheme 4. Possible Three-Component Coupling Mechanisms
Carbopalladation mechanism C has been implicated in
several aryne multicomponent couplings.4,5,7b,d,8a-c,9,11 Studies
from Larock have established that stoichiometric amounts
of a preformed arylpalladium complex will produce 2CC
products with benzyne in a related reaction (albeit in lower
yield), giving support to the mechanism.8c
Our own stoichiometric studies have been inconclusive
in the aryl iodide series, with the preformed (p-CF3C6H4)-
PdI(PPh3)2 complex providing the three-component-coupled
product 9i in a low 27% yield after extended reaction times
of 24 h. The benzyl complex BnPdCl(PPh3)2 was more
effective, however, giving a 40% yield of the analogous
phenylbenzyl 3CC product. Given sufficient lifetime in
solution of complex 18, the carbopalladation-Heck pathway
C appears reasonable. In the catalytic manifold, however,
we would favor the alternative pathway B. We have observed
that straight 2CC between aryl iodide and acrylate is sluggish
under the optimized 3CC reaction conditions, giving yields
of 16-22% when no aryne is present over the 4 h reaction
time course.12 If oxidative addition-Heck reaction is slow,
it seems unlikely that oxidative addition-aryne carbopalla-
dation-Heck reaction would be substantially faster, sug-
gesting that the aryne is having a significant effect on the
catalytic pathway in regard to 2CC versus 3CC coupling.
Whether this is through the formation of the η2-metallocy-
clopropene 15 or through another pathway will form the basis
of our future mechanistic studies in this area.
Addition of aryl iodides to palladacycles analogous to 12
is precedented in the norbornene shuttle work of Catellani
and Lautens and implies the formation of a Pd(IV) species
13.16 Subsequent reductive elimination/â-hydride elimination
processes furnish the biaryl 14a. A similar addition of Ar-I
is required for Path B, producing the biaryl σ-palladium
species 16, which undergoes Heck reaction as in path C.
The biaryl 14b is identical to 14a for the symmetrical arynes
employed in our studies thus far. If an unsymmetrical aryne
is used, however, then 14a and 14b will be isomeric. We
have investigated this possibility via the 3CC of 3-methoxy
and 3,4-dimethoxy benzyne precursors 2e and 2f (Scheme
5). The exclusive formation of products 19 and 20, corre-
In conclusion, we have introduced aryl iodides to the 3CC
insertion of arynes into the Heck reaction for the synthesis
of highly functionalized biaryl compounds. The reaction is
effective across a range of structures in each component,
producing diverse, multifunctional arenes in a single step
from commercially available starting materials.
Scheme 5. 3CC of o-Methoxy-arynes
Acknowledgment. We thank Organon and the University
of Edinburgh for funding. Dr Anna Collins (School of
Chemistry, University of Edinburgh) is thanked for assistance
with X-ray crystallography.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL702584T
sponding to the 14b connectivity, allow us to rule out the
cycloisomerization pathway A. Palladacycle formation from
3-methoxy benzyne would be expected to be highly selective
for intermediate 13 having R1 ) OMe and R2 ) H (Scheme
(16) Leading references: (a) Motti, E.; Faccini, F.; Ferrari, I.; Catellani,
M.; Ferraccioli, R. Org. Lett. 2006, 8, 3967-3970. (b) Rudolph, A.;
Rackelmann, N.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 1485-
1488.
(17) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701-730.
5592
Org. Lett., Vol. 9, No. 26, 2007