Intermolecular domino reaction of two Aryl iodides involving two C-H functionalizations

Article abstract of DOI:10.1002/anie.201400807

A palladium-catalyzed intermolecular cross-coupling of two aryl iodides is reported, giving polycyclic ring systems with a high level of convergence and efficiency. Pendulum Reaction: 1 Pd complex catalyzes the intermolecular reaction of 2 aryl iodides to

Full text of DOI:10.1002/anie.201400807

Angewandte
Chemie
DOI: 10.1002/anie.201400807
À
C H Activation
Intermolecular Domino Reaction of Two Aryl Iodides Involving Two
À
C H Functionalizations**
Marcel Sickert, Harald Weinstabl, Brendan Peters, Xiao Hou, and Mark Lautens*
Abstract: A palladium-catalyzed intermolecular cross-cou-
pling of two aryl iodides is reported, giving polycyclic ring
systems with a high level of convergence and efficiency.
a pioneering study, Larock and co-workers[8] illustrated the
utility of an in situ generated neopentyl–PdII species A for the
À
synthesis of complex fused biaryls 2 through a sequence of C
H activations, which is facilitated by a net 1,4-palladium shift
to form intermediate B (Scheme 1a and Scheme 2).
Related to Larockꢀs report,[9–11] Jia and co-workers
recently described the intermolecular functionalization of
the palladacycle intermediate E, in which aryl, hetaryl, nitrile,
and Heck acceptors may be introduced on either position
(C(sp2) versus C(sp3), Scheme 1b) depending on the reaction
conditions.[12]
T
he rapid construction of complex heteroatom-containing
carbon frameworks has become an attractive challenge in the
past years. For this reason, domino reactions represent
a powerful strategy for the rapid formation of multiple
bonds in a single flask.[1,2] In recent years, this class of
À
reactions, involving transition-metal-catalyzed C H bond
activation, have emerged as an important field of research
in organic synthesis. Metals, including palladium, rhodium,
We now illustrate that both positions of the six-membered
palladacycle E can be functionalized in a single step through
and iridium, have been used to access a variety of ortho- or
[3]
À
meta-directed C H activations. For over a decade, our
group[4] has used variants of the palladium-catalyzed Catellani
reaction[5] to direct C H functionalization by generating the
À
directing group in situ and catalytically. This task has been
accomplished by using norbornene as the shuttle to direct the
À
desired C H palladation. The power of this reaction was
recently demonstrated in the total syntheses of two distinct
classes of natural products.[6]
The key to success of the norbornene-facilitated trans-
formation is the lack of suitable syn-b-hydrogen atoms in the
À
carbopalladated intermediate, which prompts the C H acti-
vation and initiates the subsequent steps. The utilization of
other olefins following similar principles was rarely reported,
and in most cases an incorporation of the double-bond
scaffold in the final product structure was observed.[7,8] In
[*] Dr. M. Sickert, Dr. H. Weinstabl, B. Peters, X. Hou,
Prof. Dr. M. Lautens
Department of Chemistry, University of Toronto
80 St. George St. Toronto, Ontario, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
Scheme 1. a) Intramolecular arylation through [1,4]-Pd shift and final
2
3
À
C H activation by Larock (2004). b) C(sp ) or C(sp ) functionalization
of s-alkyl/PdII intermediate E by Jia (2010). c) This work: C(sp2) and
C(sp3) arylation of intermediate E with an aryl iodide. FG=functional
group.
Homepage: http://www.chem.utoronto.ca/staff/ML/index.php
[**] We thank the Natural Sciences and Engineering Research Council of
Canada (NSERC), the Killam Foundation, Alphora Inc., and the
University of Toronto for financial support. NSERC/Merck-Frosst
Canada is thanked for an Industrial Research Chair. M.S. thanks the
Alexander von Humboldt Foundation for a Feodor-Lynen postdoc-
toral fellowship. H.W. thanks the Austrian Science Fund (FWF):
J3250-N19 for an Erwin Schroedinger postdoctoral fellowship. B.P.
thanks NSERC for a postgraduate scholarship (CGS-M). The
authors wish to acknowledge CFI project number 19119 for funding
the CSICOMPNMR Facility. Dr. Timothy Burrow and Dr. Alan Lough
(Chemistry Department, University of Toronto) are sincerely
thanked for their single-crystal X-ray structure analysis and
dedicated assistance with NMR analyses, respectively. We thank
Johnson Matthey for kind gifts of QPhos, [Pd(QPhos)2], and
[Pd(crotyl)QPhosCl].
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400807.
Scheme 2. Proposed PdII intermediates A to E of transformations
shown in Scheme 1.
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an intermolecular domino reaction of an aryl iodide. These
positions react selectively in a sequence of carbopalladations
À
and cross C H activations, furnishing complex fused biaryls
(Scheme 1c). Our interest in this particular area was driven
by recent studies on the Pd0-catalyzed carboiodination
reaction.[13] We initially set out to capture intermediate E
with an alkyl iodide,[14] however, we observed the formation
of the dimerization product 6a (see Scheme 4) in modest
yields. Intrigued by the complexity of this product we set out
to investigate the transformation in detail.
Upon optimization,[15] synthetically useful levels of dimer
6a could be obtained. However, a by-product (7a) remained
an issue and indicated the presence of an additional and
competing reaction pathway.[16] Interestingly, the extent of by-
product formation depended on the nature of the base, the Pd
source, and the ligand.[15] By using Buchwaldꢀs palladacycle
precatalyst Pd-1 (Scheme 3) and Cs2CO3 in DMF, the highest
selectivity for 6a:7a was 7:1, and 6a was isolated in 68%
yield. With the optimized reaction conditions in hand, we
began to explore the scope of the transformation.
Scheme 4. Substrate scope of the dimerization of 3.[a] [a] When R1, R2,
or R3 were H, they were omitted for clarity in the table. Yields are
reported with respect to 0.30 mmol of 3. Conditions: 0.60 mmol
scale.[17] Pd-1 or Pd-2 (1.5 mol%), 3 (1.0 equiv), Cs2CO3 (2.5 equiv),
DMF (0.4m), 1008C, 18–22 h. [b] Yields of isolated products. [c] Ratio
1
determined by H NMR analysis of the crude reaction mixture.
[d] 2.45 mmol scale (0.60 mmol scale resulted in 67% yield of 6b).
[e] Isolation of clean 7b failed because of coeluting impurities [f] Com-
bined yield of 6g and 7g.
synthetically useful yields (9i, 9k). Aryl iodides substituted
with sterically different groups on the meta position gave
divergent selectivity. More sterically demanding electron-
À
withdrawing groups, such as CF3 (9l), favored the C H
activation in the para position (HA, Scheme 5), whereas
Scheme 3. Privileged Pd precatalysts.
À
a meta-fluoro substituent allowed the final C C formation at
À
When the aromatic ring contained either an electron-
donating or an electron-withdrawing group, a marginal
impact on the yield was observed and yields higher than
50% were typically obtained (entries b–d, Scheme 4). The
effect of varying the alkyl chain was also investigated. Both
ethyl and butyl groups were tolerated, giving the correspond-
ing products 6e and 6 f in 59% and 61% yield, respectively;
however, the application of Pd-2 was necessary to achieve
good selectivities in these cases (Scheme 4). The selectivity of
the reaction (6 vs. 7) ranged between 5:1 and 7:1, and by-
products 7a–f were generally obtained in 8–9% yield
(Scheme 4).
We next studied a heteroaryl cross-coupling (Scheme 5).
We successfully obtained the desired product 9, accompanied
by smaller amounts of the dimerization product 6a. The
highest yields were obtained using Cs2CO3 in DMF, however,
efficient suppression of 6a was only observed when palladium
precatalyst Pd-3 was used.[15] An increase in the reaction rate
was observed when a catalytic amount of CsOPiv was added,
even with a catalyst loading of 3 mol%.[18]
Under the optimized reaction conditions, para-substituted
aryl iodides formed the desired products in up to 71% yield.
In general, electron-donating substituents on the aryl iodide,
such as alkoxy groups, protected amines, or acetals, resulted in
higher yields compared to their electron-deficient counter-
parts (Scheme 5). In the case of the electron-withdrawing
CF3-containing substrate, it was necessary to increase the
catalyst loading to 6 mol%. Bis-meta-substituted aryl iodides
were also tolerated and the products were afforded in
the C HB position with a regioselectivity of 8:1 (9n).
Although, substituents at the ortho position generally gave
poor results,[20] a fluoro group at the ortho position was
tolerated and the corresponding product 9p and by-product
9n were afforded in 56% and 6% yield, respectively.
Variations on the aromatic ring of the methallyl ether
were also studied (Scheme 5). The reaction of methyl- and
dioxolane-substituted methallyl ethers with para-methoxy
iodobenzene furnished products 10a and 10c in yields of 58%
and 56% yield, respectively. Additionally, a fused bipyridyl
structure was accessible by the reaction of electron-deficient
pyridyl-substituted methallyl ether 3g with the 4-iodopyri-
dine, and 10 f was isolated in 64% yield. However, the
introduction of 3g enhanced both the by-product formation
(up to 10%) and the dimerization process (up to 20%).
Substitution of the vinylic methyl group with longer alkyl
chains did not seem to affect the reaction. Similarly high
yields of 70% and 69% were observed for both the ethyl- and
the butyl-substituted systems (10h and 10i). In order to have
a handle for post-synthesis modification, a silyl ether was
subjected to the reaction conditions and 10k was obtained in
47% yield after 21 hours.
The scalability of the heterodimerization reaction was
demonstrated for the reaction of 6a with 4-methyl iodoben-
zene. When run on a 3.7mmol scale, the desired product 9b
was obtained in 72% yield.
On the basis of these preliminary results, a proposed
mechanism is outlined in Scheme 6, in which two reaction
pathways (A: PdIV versus B: PdII–PdII) are considered in
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Scheme 6. Proposed simplified mechanism: I) generation of active Pd0
species; II) competitive oxidative addition; III) oxidative addition;
À
IV) carbopalladation; V) C H activation; VIa) transmetalation;
VIIa) reductive elimination; VIb) second oxidative addition;
À
VIIb) reductive elimination; VIII) second C H activation; IX) second
reductive elimination.
Scheme 5. Substrate scope of domino reactions with aryl iodides.[a]
[a] When R1, R2, or R3 were H, they were omitted for clarity in the table.
Conditions: 0.40–0.45 mmol scale, Pd-3 (3 mol%), KOtBu
(6 mol%),[18b] CsOPiv (25 mol%), Cs2CO3 (5.0 equiv), 3 (1.0 equiv), 8
(1.3 equiv), DMF (0.2m), 1008C. [b] 3.70mmol scale (0.40 mmol scale
resulted in 65% yield). [c] 80 h. [d] 3–8% of 6a observed. [e] Pd-3
(6 mol%), KOtBu (12 mol%). [f] 8 (1.5 equiv). [g] 48 h. [h] Combined
yield; r.r.=7:1. [i] 120 h. [k] Combined yield; r.r.=8:1. [l] 6% of 9p’
(9n) was observed. [m] 13% of 6b was observed. [n] 72 h. [o] 13 h.
[p] 25% of 6c was observed.[19] [q] 6% of 10e’ was isolated. [r] 10% of
10 f’ was isolated. [s] 18% of 6g was observed. r.r.=regioisomeric
ratio.
reductive elimination, the Pd0 catalyst is regenerated and the
fused bicycle 9 is formed.
Despite the similarities to the Catellani reaction, the
selective formation of the fused biaryls 9/10 gave rise to
intriguing questions regarding: 1) the apparent selectivity in
oxidative addition in the presence of aryl iodides 3 and 8;[23,24]
2) the origin of a selective heterodimerization to 9/10,
preventing dimerization to 6 with the QPhos ligand;[25] and
3) the mechanism leading to the formation of regioisomer 9’/
10’.[26]
analogy to the proposed mechanisms of the Catellani
reaction.[21,22] After oxidative addition, carbopalladation,
In conclusion, we have developed a novel Pd0-catalyzed
intermolecular domino reaction, in which two structurally
distinguishable aryl iodides react together through a carbo-
À
and C H activation of 3a (steps III–V, Scheme 6), the
À
palladacyle E may follow one of two pathways: The oxidative
addition of E with a second aryl iodide 8 may form a PdIV
complex FA, which upon aryl–aryl reductive elimination
generates intermediate G (Scheme 6, pathway A). Another
plausible sequence (pathway B) may occur by the reaction of
E with an additional PdII species 8’[23] through transmetalation
between both PdII centers to form the dinuclear complex FB,
which generates intermediate G following aryl–aryl reductive
elimination (Scheme 6, pathway B). Finally, the 7-membered
palladation and a sequence of C H activations to form three
[27]
À
new C C bonds.
The reaction allows an efficient and
convergent synthesis of fused biaryls with high complexity
based on a dihydrodibenzoisochromene framework.
Experimental Section
Representative procedure for 9c: [Pd(crotyl)QPhosCl] (Pd-3)
(3.0 mol%), KOtBu (6.0 mol%), cesium pivalate (25 mol%), and
cesium carbonate (5.0 equiv) were weighed into a dry microwave vial
and purged with argon for ten minutes. The contents were suspended
palladacycle H could be formed by a second intramolecular
II
À
C H activation of the alkyl Pd species G. Upon the final
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in anhydrous DMF (0.4 mL) and after 10 min, a DMF solution
(1.6 mL) of methallyl ether 3a (0.40 mmol, 1.0 equiv) and 4-methoxy
iodobenzene 8c (1.3 equiv) was added. The vial was sealed, purged
with argon for 5 min and heated for 18 h in a preheated oil bath at
1008C. Following standard work-up procedures (see the Supporting
Information), the crude product was purified by flash column
chromatography on silica gel using a gradient of hexanes to EtOAc/
hexanes (1:10, v:v) as eluent, and 9c was isolated as white solid
(73.5 mg, 0.276 mmol, 69%).
e) R. Grigg, J. Sansano, V. Santhakumar, V. Sridharan, R.
Thangavelanthum, M. Thornton-Pett, D. Wilson, Tetrahedron
1997, 53, 11803 – 11826; for reports on cyclopropane intermedi-
ates, see: f) F. Liron, P. Knochel, Tetrahedron Lett. 2007, 48,
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2
3
À
À
[10] For reports on a sequence of C(sp ) H and C(sp ) H activa-
tions, see: a) T. Piou, A. Bunescu, Q. Wang, L. Neuville, J. Zhu,
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Received: January 24, 2014
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[12] a) Initial study: O. Renꢃ, D. Lapointe, K. Fagnou, Org. Lett.
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[13] a) S. G. Newman, M. Lautens, J. Am. Chem. Soc. 2011, 133,
1778 – 1780; b) S. G. Newman, J. K. Howell, N. Nicolaus, M.
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Petrone, M. Lischka, M. Lautens, Angew. Chem. 2013, 125,
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[14] An ortho butylation accompanied by a reductive carbopallada-
tion was observed by using nBu-I, giving a yield of 30–40% (see
the Supporting Information).
Published online: && &&, &&&&
À
Keywords: carbopalladation · C H activation ·
domino reactions · fused-ring systems · palladium
.
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[15] Detailed optimization studies are summarized in the Supporting
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[16] X-Ray structures of 6c, 7c, 9c, and 10c support the proposed
assignment; see Supporting Information. CCDC 982746 (7c),
982747 (9c), 982748 (10c), and 982749 (6c) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[17] For selected examples, experiments were also conducted with 3
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[18] a) By using 5 equiv of CsOPiv, an enhanced formation of by-
product 9’ was observed (see the Supporting Information).
b) The addition of KOtBu leads to a more reproducible reaction.
[19] An enhanced formation of 6c was detected in the final phase of
the reaction.
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[21] Notably, the precise mechanism of the Catellani reaction with
the possible formation of PdIV is still under investigation and an
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Chem. 2013, 78, 1323 – 1328; b) K. MuÇiz, Angew. Chem. 2009,
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an alternative regeneration process from 8’ is reported by
4
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formation of biaryl species, which were also detected in the
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[25] The bulkiness of QPhos may cause the preferential reaction of E
with less hindered 8/8’, rather than 3.
[26] The formation of 9’/10’ and 7, respectively, can be rationalized by
3
3
2
À
a C(sp ) arylation step. The C(sp ) C(sp ) reductive elimination
from PdIV is proposed as an exceptional process in the Catellani
reaction, see Ref. [11b].
À
[24] A reversible oxidative addition to carbon halogen bonds by
bulky ligands such as QPhos has recently been reported and may
play a role in the catalytic process. For reversible oxidative
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Communications
À
C H Activation
M. Sickert, H. Weinstabl, B. Peters,
X. Hou, M. Lautens*
&&&& — &&&&
Intermolecular Domino Reaction of Two
À
Aryl Iodides Involving Two C H
Functionalizations
Pendulum Reaction: 1 Pd complex cata-
lyzes the intermolecular reaction of 2 aryl
biaryls with a high level of convergence
and efficiency. The key to success lies in
the choice of an appropriate bulky Pd
catalyst, which allows the aryl iodides to
be distinguished in the key step.
À
iodides to form 3 new C C bonds
À
through 2 C H activations and 1 carbo-
palladation. The intermolecular domino
reaction of two aryl iodides gives fused
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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