Tandem Ullmann-Goldberg Cross-Coupling/Cyclopalladation-Reductive Elimination Reactions and Related Sequences Leading to Polyfunctionalized Benzofurans, Indoles, and Phthalanes

Article abstract of DOI:10.1021/acs.orglett.9b02235

On exposure to a combination of Cu[I]- and Pd[0]-based catalysts, compounds such as 1 and 7 engage in tandem Ullmann-Goldberg cross-coupling and cyclopalladation-reductive elimination reactions to give benzofurans such as 8. Related reactions involving hetero-Michael additions of o-halogenated phenols or anilines to propiolates and the Pd[0]-catalyzed cyclization of the resulting conjugates provide, in a one-pot process, alternately functionalized benzofurans, indoles, or phthalanes.

Full text of DOI:10.1021/acs.orglett.9b02235

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tandem Ullmann−Goldberg Cross-Coupling/Cyclopalladation-
Reductive Elimination Reactions and Related Sequences Leading to
Polyfunctionalized Benzofurans, Indoles, and Phthalanes
Faiyaz Khan, Mehvish Fatima, Moheb Shirzaei, Yen Vo, Madushani Amarasiri, Martin G. Banwell,*
Chenxi Ma, Jas S. Ward, and Michael G. Gardiner
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, Australian Capital
Territory 2601, Australia
S
* Supporting Information
ABSTRACT: On exposure to a combination of Cu[I]- and
Pd[0]-based catalysts, compounds such as 1 and 7 engage in
tandem Ullmann−Goldberg cross-coupling and cyclopallada-
tion-reductive elimination reactions to give benzofurans such
as 8. Related reactions involving hetero-Michael additions of
o-halogenated phenols or anilines to propiolates and the
Pd[0]-catalyzed cyclization of the resulting conjugates
provide, in a one-pot process, alternately functionalized
benzofurans, indoles, or phthalanes.
enzofurans and indoles represent privileged heterocyclic
frameworks, not least because they have found extensive
single-crystal X-ray analysis. (See the Supporting Information
for details.) The stepwise addition of the copper salt then
Pd2(dba)3 (entry 2) resulted in a 61% yield of the same
product. Under the same conditions, 3-bromoenone 2 (Y =
Br)10 also coupled to 1 (X = I) (entry 3) to give benzofuran 5,
albeit in somewhat lower (47%) yield. In contrast, the
equivalent process involving o-bromophenol 1 (X = Br) and
iodoenone 2 (Y = I) (entry 4) now just delivered the
Ullmann−Goldberg product 3 (X = Br) in 32% yield.
Similarly, when both coupling partners incorporated bromine
(entry 5), the same product [viz. 3 (X = Br)] was obtained but
now in just 19% yield. The enol triflate 2 (Y = OTf) reacted in
a similar fashion provided that 5 mol % of tetra-n-
butylammonium bromide (TBAB) was added to the reaction
mixture (entry 6), a requirement we attribute to the need for
the in situ formation of 2 (X = Br) (through a halogen for the
pseudohalogen exchange process of some sort) that then
couples in the previously observed manner. On just adding CuI
to the reaction mixture (entry 7) and heating this to 80 °C for
2 h, substrates 1 (X = I) and 2 (Y = I) only engaged in the
Ullmann−Goldberg reaction and thereby formed the enol
ether 3 (X = I) that was obtained in 63% yield. On
resubjecting compound 3 to the same reaction conditions
but now with just Pd[0] present (entry 8), benzofuran 5 was
obtained (91%). Significantly, when a DMSO solution of
substrates 1 (X = I) and 2 (Y = I) was treated with Pd2(dba)3
(0.05 mol equivalents) and triethylamine (no cuprous iodide
present) at 120 °C, no reaction took place. This outcome
suggests that the first step of the successful reaction sequence
B
applications in medicinal chemistry and materials science.1,2
They are also encountered in many biologically active natural
products.3 While numerous methods have been devised for
their assembly,4 new and convergent means for doing so and
that allow for the introduction of novel functionalities remain
of considerable interest.5−7 In this connection, we envisaged
(Scheme 1) that an o-halophenol (1) could be fused with a 3-
halocyclohexenone (2) to give, via an initial and Cu[I]-
catalyzed Ullmann−Goldberg cross-coupling reaction,8 the
ether 3. On exposure of the last compound to Pd[0], the
initially formed oxidative addition product 4 should engage in
a cyclopalladation-reductive elimination reaction sequence and
so deliver the annulated benzofuran 5.6 Overall, a reverse of
the bond-forming steps used in the Larock protocol6a,7e is
involved here, as is a C−H activation step. Compound 5
embodies key structural elements of the benzofuran-containing
and neurologically active ribisin class of natural product,
compound 6 (ribisin C) being a notable example.9 Replacing
the o-halophenol (1) in such a sequence with the analogous
aniline should deliver the corresponding indole.7 Herein we
detail the implementation of such reaction sequences in a
tandem manner and extensions of these to the construction of
a range of alternately substituted benzofurans and indoles as
well as related heterocyclic frameworks.
The outcomes of our initial studies of the proposed process
are shown in Table 1. So, a DMSO solution of a 1:1.5 mixture
of the iodinated substrates 1 (X = I) and 2 (Y = I)10 was
treated with cuprous iodide (0.5 mol equivalents), Pd2(dba)3
(5 mol %), and triethylamine (2 mol equivalents) at 120 °C for
20 h (entry 1), and under such conditions, the benzofuran 511
was obtained in 43% yield, and its structure was confirmed by
Received: June 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02235
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Proposed Tandem Ullmann−Goldberg Cross-
Coupling/Cyclopalladation-Reductive Elimination Reaction
Sequence Leading from Substrates 1 and 2, via
Intermediates 3 and 4, to Benzofuran 5
Figure 1. Further examples of coupling partners that do and do not
engage (see the text) in tandem Ullmann−Goldberg/cyclopallada-
tion-reductive elimination reactions to give benzofurans.
8 (10, 30, and 59%, respectively). Acyclic iodides such as the
crotonate 913 and cinnamate 1011 also couple in an analogous
manner to 1 (X = I), thus affording the 2,3-disubstituted
benzofurans 1114 (42%) and 1214 (84%), respectively, while
the iodinated cyclopentenone 1310 also coupled to the same
phenol to give compound 1415 (47%). Interestingly, the
readily prepared 2-methyl-3-iodoenone10 (15) only coupled to
o-iodophenol 1 (X = I) to give the Ullmann−Goldberg
product 16 (39%). This could not be engaged in a
carbopalladation-reductive elimination sequence, an outcome
that might be attributed to steric effects.
Indoles are also available using the present methods, as
demonstrated by the cross-coupling of o-iodoaniline (17)
(Scheme 2) with enone 7 (Y = Br) to give the cyclo-
hexannulated indole 1816 (60%), the structure of which was
also confirmed by single-crystal X-ray analysis. The non-
isolable enamine 19 is presumably the precursor to the
observed product 18.
Table 1. Optimization of Conditions for Effecting the
Conversion 1 + 2 → 5
a
entry substrates(s)
additives
time/temperature
product (%)
1
2
3
4
5
6
7
1 (X = I)
2 (Y = I)
1 (X = I)
2 (Y = I)
1 (X = I)
2 (Y = Br)
1 (X = Br)
2 (Y = I)
1 (X = Br)
2 (Y = Br)
1 (X = Br)
2 (Y = OTf)
1 (X = I)
2 (Y = I)
3 (X = I)
1 (X = I)
2 (Y = I)
CuI, Pd[0] 20 h/120 °C
5 (43%)
CuI, Pd[0] 2 h then 20 h/
5 (61%)
5 (47%)
c
60 then 120 °C
CuI, Pd[0] 2 h then 20 h/60
c
then 120 °C
CuI, Pd[0] 2 h then 20 h/60
3 (X = Br)
(32%)
c
then 120 °C
CuI, Pd[0] 2 h then 20 h/80
3 (X = Br)
(19%)
c
then 120 °C
CuI, Pd[0] 2 h then 20 h/
5 (15%)
c
b
60 then 120 °C
TBAF
CuI
2 h/80 °C
3 (X = I)
(63%)
Scheme 2. Tandem Ullmann−Goldberg/Cyclopalladation-
Reductive Elimination Reaction Sequence Leading from
Substrates 17 and 7 (Y = Br) to Indole 18 and the Presumed
Intermediate 19
8
9
Pd[0]
Pd[0]
20 h/120 °C
20 h/120 °C
5 (91%)
d
NR
a
0.5 mol equivalents of CuI and 5 mol % of Pd[0] used together with
b
2 mol equiv of Et3N. 5 mole % used except for Entries 4 and 5 where
10 mole % used. Initial reaction mixture containing just the copper
c
salt was stirred for 2 h at 60 °C, then a source of Pd[0] was added and
d
the reaction mixture was heated to 120 °C for 20 h. NR = no
reaction.
(leading to 5) is indeed an Ullmann−Goldberg reaction and
not, for example, a conjugate addition/elimination reaction.
The optimized protocol defined in entry 2 could be
extended to the synthesis of other benzofurans with, for
example, the cyclohexenones 7 (X = I, OTf, or Br)10,12 (Figure
1) coupling to phenol 1 (X = I) to give the anticipated product
B
DOI: 10.1021/acs.orglett.9b02235
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Extensions to this basic process provided indoles 2017
(65%), 2118 (45%), 2219 (63%), and 2320 (52%) (Figure 2)
through the couplings of the reaction partners 17 + 2 (Y = I),
17 + 9, 17 + 10, and 17 + 13, respectively.
Figure 2. Indoles 20−23 arising from the tandem Ullmann−Goldberg
coupling/cyclopalladation-reductive elimination of o-iodoaniline (17)
with iodides 2 (X = I), 9, 10, and 13.
Figure 4. Phthalanes 35 and 36 available through hetero-Michael
addition/Heck cyclization reactions of o-iodobenzyl alcohol (33) with
certain propiolates.
Open-chain analogues of enol ether 3 (X = I) and enamine
19 could, in principle, be obtained through the conjugate
addition of o-halogenated phenols or anilines to, for example,
propiolates and related alkynes incorporating an electron-
withdrawing-group. Consistent with such expectations, when
compounds 1 (X = I) and 17 were treated with dimethyl
acetylenedicarboxylate (DMAD, 24) (Figure 3) in the
terminal alkyne 29 coupled to compound 33 to give phthalane
3626 (41%).
The formation of compound 34 is noteworthy in that an
Au[I] catalyst is required to facilitate the hetero-Michael
addition reaction; in its absence, no product forms.
Furthermore, the Pd[0]-catalyzed Heck-type cyclization of
this enol ether necessarily affords a palladated species that
cannot undergo β-hydride elimination. As such, triethylamine
probably serves as the source of the additional hydrogen
incorporated in product 35.27
The results detailed above reveal that the title and tandem
processes as well as related ones involving an initial hetero-
Michael addition reaction provide an operationally simple and
exceptionally concise means of constructing a range of
heterocyclic compounds possessing useful substitution patterns
or modes of annulation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02235.
Figure 3. Propiolates 24, 29, and 30 that engage in hetero-Michael
addition/cyclopalladation-reductive elimination reactions with com-
pounds 1 (X = I) and 17, leading to 3-substituted and 2,3-
disubstituted benzofurans and indoles.
Experimental procedures, spectroscopic data, copies of
the NMR spectra of compounds 2 (Y = Br, I and OTf),
3 (X = Br and I), 5, 8, 11, 12, 14−16, 18, 20−23, 25−
28, 31, 32, and 34−36 together with the X-ray data and
the derived ORTEPs for compounds 5, 14, 18, 21, 22,
and 26 (PDF)
presence of triethylamine and Pd[0], then benzofuran 2521
(40%) and indole 2622 (67%), respectively, were obtained.
The hetero-Michael addition products 27 (62%) and 2823
(84%) were obtained as single geometric isomers when the
relevant reaction partners were treated with the amine alone.
Furthermore, the exposure of adducts 27 and 28 to Pd[0]
resulted in their cyclization to give heterocycles 25 (37%) and
26 (66%), respectively. Under the same conditions, propiolates
29 and 30 reacted in a regioselective manner with o-
iodophenol (1 (X = I)) to give benzofurans 3124 (42%) and
11 (43%), respectively, while analogous reactions involving o-
iodoaniline (17) afforded indoles 3225 (41%) and 21 (53%).
Phthalanes can be obtained by related means (Figure 4). For
example, when a DMF solution of o-iodobenzyl alcohol (33)
and DMAD (24) was exposed to Au[I] and Pd[0], the isolable
Michael addition product 34 (obtained as a single geometric
isomer of undefined configuration) cyclized, presumably now
in a Heck process, to give product 35 (30%). Similarly, the
Accession Codes
CCDC 1935464−1935469 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Martin.Banwell@anu.edu.au.
ORCID
Martin G. Banwell: 0000-0002-0582-475X
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b02235
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Natural Products Containing Benzofuran Rings. RSC Adv. 2017, 7,
24470−24521.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council and the Institute of
Advanced Studies for financial support including the provision
of scholarships to F.K. and M.A. as well as a postdoctoral
fellowship to Y.V. F.M. thanks the Higher Education Council
of the Government of Pakistan for support, and M.S.
acknowledges the support of the Islamic Government of Iran.
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DOI: 10.1021/acs.orglett.9b02235
Org. Lett. XXXX, XXX, XXX−XXX