Iridium-catalyzed arylative cyclization of alkynones by 1,4-iridium migration

Article abstract of DOI:10.1002/anie.201403271

1,4-Metal migrations enable the remote functionalization of C-H bonds, and have been utilized in a wide variety of valuable synthetic methods. The vast majority of existing examples involve the 1,4-migration of palladium or rhodium. Herein, the stereoselective synthesis of complex polycycles by the iridium-catalyzed arylative cyclization of alkynones with arylboronic acids is described. To our knowledge, these reactions involve the first reported examples of 1,4-iridium migration.

Full text of DOI:10.1002/anie.201403271

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DOI: 10.1002/anie.201403271
À
C H Activation
Iridium-Catalyzed Arylative Cyclization of Alkynones by 1,4-Iridium
Migration**
Benjamin M. Partridge, Jorge Solana Gonzꢀlez, and Hon Wai Lam*
Abstract: 1,4-Metal migrations enable the remote functional-
À
ization of C H bonds, and have been utilized in a wide variety
of valuable synthetic methods. The vast majority of existing
examples involve the 1,4-migration of palladium or rhodium.
Herein, the stereoselective synthesis of complex polycycles by
the iridium-catalyzed arylative cyclization of alkynones with
arylboronic acids is described. To our knowledge, these
reactions involve the first reported examples of 1,4-iridium
migration.
S
ince the early reports of 1,4-palladium migration[1a–d] and
1,4-rhodium migration,[2a,b] numerous catalytic reactions
involving 1,4-metal migration have been developed.[1–5] Such
À
processes enable the remote functionalization of C H bonds,
allowing the introduction of metal centers at positions that
would otherwise be difficult to metalate. To date, reactions
involving the 1,4-migration of palladium,[1] rhodium,[2] plati-
num,[1q] nickel,[4] and cobalt[5] have been achieved. The
demonstration of the ability of other metals to undergo 1,4-
migration would be valuable, as their distinct properties may
offer new opportunities for the development of useful
synthetic methods. Herein, we describe the preparation of
highly functionalized polycycles by the iridium-catalyzed
arylative cyclization of alkynones. One of the key steps in
this transformation is a 1,4-iridium migration, which, to our
knowledge, has not been described previously.
During a program aimed at the stereoselective synthesis
of complex polycycles by the desymmetrization of cyclic 1,3-
diketones,[6,7] we became interested in developing an arylative
cyclization of substrates such as 1a (Scheme 1). We envisaged
that in the presence of a suitable metal complex, an arylboron
Scheme 1. Proposed arylative cyclization of alkynones.
reagent could be employed in an arylmetalation of the alkyne
moiety of 1a to give alkenylmetal species 3. This intermediate
could then undergo an alkenyl-to-aryl 1,4-migration to
provide intermediate 4, which could then participate in the
nucleophilic attack of one of the ketones to give tertiary-
alcohol-containing tricycle 2a.
In view of the success of rhodium catalysis in related
transformations,[2d–g,i,k–q] the reaction of 1a with PhB(OH)2 in
the presence of [{Rh(cod)Cl}2] (1.5 mol%), KF (1.5 equiv) as
a mild base, and tBuOH (1.5 equiv) as a proton source was
examined [Eq. (1)]. Heating the reaction in toluene at 658C
[*] Dr. B. M. Partridge,[+] J. Solana Gonzꢀlez,[+] Prof. H. W. Lam
EaStCHEM, School of Chemistry, University of Edinburgh
Joseph Black Building, The King’s Buildings
West Mains Road, Edinburgh, EH9 3JJ (UK)
and
School of Chemistry, University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
E-mail: hon.lam@nottingham.ac.uk
Homepage: http://www.nottingham.ac.uk/~pczhl
[+] These authors contributed equally to this work.
[**] We thank the ERC (Starting Grant No. 258580) and the EPSRC
(Leadership Fellowship to H.W.L.) for financial support. We thank
Dr. Gary S. Nichol (University of Edinburgh) and Dr. William Lewis
(University of Nottingham) for X-ray crystallography, and Lorna
Eades (University of Edinburgh) for ICP-MS analysis. The EPSRC
National Mass Spectrometry Facility is gratefully acknowledged for
providing high-resolution mass spectra.
for 16 hours did indeed provide tricycle 2a in 41% yield.
However, 2a was accompanied by the simple alkyne hydro-
arylation product 5 (18% yield) and the ring-expansion
product 6 (17% yield), which is formed by initial arylation of
the alkyne with the opposite regioselectivity, followed by
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403271.
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a cyclization–fragmentation process, as described by Mura-
kami and co-workers.[8]
In an effort to increase the yield of 2a, catalyst systems
based upon other metals known to undergo 1,4-migrations
(Pd,[1] Pt,[1q] Ni,[4] and Co[5]) were surveyed. However, no
reaction was observed in these experiments. Fortunately,
[{Ir(cod)Cl}2] (1.5 mol%) was effective, and provided 2a in
72% yield [Eq. (2)]. Interestingly, this experiment also gave
product 7 in 27% yield, the structure of which was deter-
mined by X-ray crystallography.[9] Compound 7 is a 2:1 adduct
of 1a and PhB(OH)2, respectively, resulting from a complex
sequence beginning with the arylmetalation of the alkyne of
1a with the regioselectivity opposite to that seen in the
formation of 2a.[10,11] To our knowledge, this reaction involves
the first reported examples of 1,4-iridium migration. Given
that the yield of 2a was higher using an iridium- rather than
a rhodium-based precatalyst, [{Ir(cod)Cl}2] was selected for
further studies.
The iridium-catalyzed arylative cyclization of various
substrates with PhB(OH)2 was then explored (Scheme 2). In
all reactions, the 2:1 adduct was observed in approximately
Scheme 2. Arylative cyclization of various alkynones. Reactions were
conducted using 0.40 mmol of 1a–n in toluene (4 mL). Cited yields
are of isolated products. [a] Compound 7 was also isolated in 27%
yield. See Equation (2). [b] 2.5 mol% of [{Ir(cod)Cl}2] was used.
1
10–25% yield by H NMR analysis of the reaction mixtures,
but these products were not isolated. Substituents at the para,
meta, or ortho positions of the aryl group on the alkyne were
tolerated (2b–f), though in the case where an ortho-cyano
group was present,
a
higher loading of [{Ir(cod)Cl}2]
from five- to six-membered ring diketones was also possible
(2k–m[9]). In these cases, and in a similar fashion to the five-
membered ring substrates, the reactions of substrates con-
taining more electron-deficient arenes on the alkyne led to
higher yields than those with electron-rich arenes (compare
2k–m). A cyclic b-ketoamide was also tolerated, providing 2n
in 72% yield.
The process is not limited to cyclic 1,3-dicarbonyl
substrates in which both carbonyl groups are part of the
ring; the b-ketoester 8 also underwent arylative cyclization to
give 9 in 72% yield [Eq. (3)]. However, substrate 8 was less
(2.5 mol%) was required for full conversion (2 f). With
para-substituted phenyl groups, electron-poor rather than
electron-rich arenes led to higher yields of the products
(compare 2b–d), which is likely due to a more regioselective
initial arylmetalation of more polarized alkynes. The relative
configurations of the stereogenic centers and the E geometry
of the alkenes in the products were assigned by analogy with
2d, the structure of which was determined by X-ray crystal-
lography.[9] Substrates containing a terminal alkyne or an
alkyne lacking an aryl substituent did not undergo the
reaction and returned only unreacted starting material (2g
and 2h).
Next, variations of the pendant ketone were examined.
An indane-1,3-dione reacted well to give 2i in 67% yield.
Changing the substituent at C2 (between the ketones) from
a methyl to a phenyl group was tolerated, and 2j was obtained
in 63% yield using 2.5 mol% of [{Ir(cod)Cl}2]. Switching
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reactive than those employed in the experiments shown in
Scheme 1, and higher loadings of [{Ir(cod)Cl}2] and the
reagents were required for an acceptable yield of 9.
Next, the arylative cyclization of 1a with pentadeuterio-
phenylboronic acid was conducted [Eq. (4)]. The product
[D5]-2a was deuterated on the alkene (> 95% deuterium
Table 1 presents the results of arylative cyclization of 1a
with various arylboronic acids. The reaction was compatible
with methyl (Table 1, entry 5), methoxy (Table 1, entry 1),
Table 1: Arylative cyclization of 1a with various arylboronic acids.[a]
incorporation by 1H NMR analysis), a result that is consistent
with the proposed mechanism involving alkenyl-to-aryl 1,4-
iridium migration (Scheme 1).
Entry Ar
Product
Yield [%][b]
A possible catalytic cycle for these transformations, using
1a and PhB(OH)2 for illustrative purposes, is shown in
Scheme 3. First, an aryliridium species 12 is generated by
1
2
3
4-MeOC6H4
4-ClC6H4
4-EtO2CC6H4
10a R=OMe
10b R=Cl
69
62[c]
10c R=CO2Et 35[c,d,e]
4
5
3-MeC6H4
3-BrC6H4
10d R=Me
10e R=Br
68[f]
58[c,f]
6
2-naphthyl
10 f
59[c,f,g]
[a] Reactions were conducted with 0.40 mmol of 1a in toluene (4 mL).
[b] Yields of isolated products. [c] 2.5 mol% of [{Ir(cod)Cl}2] was used.
[d] 3.0 equiv each of ArB(OH)2, KF, and tBuOH were used. [e] Substrate
1a was recovered in 41% yield. [f] Single regioisomer observed.
[g] Reaction conducted at 908C.
Scheme 3. Proposed catalytic cycle for the arylative cyclization.
halide (Table 1, entries 1 and 5), or ester groups (Table 1,
entry 3) at either the para or meta positions of the arylboronic
acid. However, with electron-withdrawing substituents,
a higher catalyst loading (5 mol% of Ir) was required for
acceptable yields (Table 1, entries 2, 3, and 5). With a 4-
carboethoxy group, the yield was lower (35%), and unreacted
1a was recovered in 41% yield (Table 1, entry 3). 2-Naph-
thylboronic acid also reacted smoothly to give 10 f in 59%
yield (Table 1, entry 6). Importantly, the reactions of meta-
substituted arylboronic acids were highly regioselective
transmetalation from the arylboronic acid to the iridium
butoxide 11 (or alternatively, an iridium fluoride). Migratory
insertion of the alkyne into 12 then occurs to give alkenyliri-
dium species 13,[13,14] which then undergoes 1,4-migration.
The resulting aryliridium intermediate 14 then undergoes
nucleophilic attack onto one of the ketones to give iridium
alkoxide 15. Protonation of 15 with tBuOH releases the
product 2a and regenerates the iridium butoxide 11.
Preliminary attempts at developing an enantioselective
variant of this process revealed that (R)-Difluorphos (L1)
gave high enantioselectivities. For example, the arylative
cyclization of alkynones 1c and 1i provided (+)-2c and (À)-2i
in 90% ee and 91% ee, respectively, using 10 mol% of the
iridium–bisphosphine complex under slightly modified reac-
1
(ꢀ10:1 regioisomeric ratio, determined by H NMR analysis
of the unpurified reaction mixtures) and provided 10d–f as
the major products (Table 1, entries 4–6). These results
demonstrate that there is a strong preference for iridium to
undergo 1,4-migration to the sterically least hindered site of
the arene.[12]
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quantitites of the starting materials were returned. Interest-
ingly, 2:1 adducts analogous to 7 were not observed in these
reactions.
In summary, we have reported the iridium-catalyzed
arylative cyclization of alkynones with arylboronic acids.[16]
These reactions involve 1,4-iridium migration as a key step,
a mode of reactivity for iridium that, to our knowledge, has
not been reported previously.[17] Efforts to exploit the 1,4-
migration of iridium and other metals in new catalytic
transformations are ongoing in our group.
Received: March 12, 2014
Published online: May 19, 2014
À
Keywords: alkynes · boron · catalysis · C H activation · iridium
.
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[9] CCDC 979585 (7), 979586 (2d), 979587 (2l), and 990617
[(+)-2c] contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
gave 2a and 7 in 79% and 17% yields, respectively. However,
solubility problems were encountered with some of the other
substrates at a 0.4m concentration, so a 0.1m concentration was
used throughout this study.
À
[12] For a recent review on sterically controlled iridium-catalyzed C
H borylation, see: J. F. Hartwig, Acc. Chem. Res. 2012, 45, 864 –
873.
[10] A plausible mechanism for the formation of 7 is illustrated
below.
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compounds, see: a) T. Nishimura, Y. Yasuhara, T. Hayashi,
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[15] The absolute configuration of (+)-2c was determined by X-ray
crystallography. See the Supporting Information for further
details.
[16] To support the conclusion that an iridium species is the active
catalyst, we performed ICP-MS analysis on a standard reaction
mixture (product 2a, Scheme 2). Although trace quantities of Fe
(120 ppb), Ni (29 ppb), Cu (19 ppb), and Pd (62 ppb) were
identified as being present, control experiments carried out with
salts containing these metals at approximately these quantities,
in the absence of [{Ir(cod)Cl}2], did not lead to the formation of
product 2a, as determined by 1H NMR analysis.
[17] After this manuscript was accepted, Ishii and co-workers
reported an example of 1,4-iridium(III) migration. See: Y.
Ikeda, K. Takano, M. Waragai, S. Kodama, N. Tsuchida, K.
Takano, Y. Ishii, Organometallics 2014, 33, 2142 – 2145.
[11] Repeating the reaction shown in Equation (2) at a lower
concentration of 0.04m with respect to 1a rather than at the
standard concentration of 0.1m gave 2a and 7 in 74% and 15%
yields, respectively. A reaction at a higher concentration of 0.4m
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