Palladium-catalyzed highly diastereoselective cascade dihalogenation of alkyne-Tethered cyclohexadienones: Via Umpolung of palladium enolate

Article abstract of DOI:10.1039/c9cc07164d

Herein, we report a highly diastereo-and regioselective dihalogenation of alkyne-Tethered cyclohexadienones for the synthesis of cis-hydrobenzofurans. One carbon-carbon and two carbon-halogen bonds were formed in an efficient manner and three contiguous s

Full text of DOI:10.1039/c9cc07164d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Palladium-catalyzed highly diastereoselective
cascade dihalogenation of alkyne-tethered
cyclohexadienones via Umpolung of palladium
enolate†
Cite this: Chem. Commun., 2019,
55, 13442
Received 12th September 2019,
Accepted 13th October 2019
Anurag Singh, Rahul K. Shukla and Chandra M. R. Volla
*
DOI: 10.1039/c9cc07164d
rsc.li/chemcomm
Herein, we report a highly diastereo- and regioselective dihalo-
genation of alkyne-tethered cyclohexadienones for the synthesis of
cis-hydrobenzofurans. One carbon–carbon and two carbon–halogen
bonds were formed in an efficient manner and three contiguous
stereocenters were generated. The reaction proceeds through cis-
halopalladation, migratory insertion followed by a nucleophilic attack
of a halide anion on a palladium enolate.
cis-Hydrobenzofurans belong to a class of privileged structural
motifs that are present in various natural products and exhibit
a wide range of biological activities including antimicrobial,
anti-inflammatory and antiviral activities.1 Consequently,
tremendous efforts have been made for the construction of these
Scheme 1 Overview of the work.
motifs in a straightforward and efficient synthetic manner. In this meet its high demand.8 Among these transformations, halo-
context, functionalization of cyclohexadienones via cascade cycli- palladation of alkynes was found to be rather appealing as it
zation represents a powerful strategy and has captured a lot of leads to the construction of C–C and C–halogen bonds in a
attention in the past few years.2 In particular, alkyne-tethered single step, often with high stereo- and regioselectivities.9 Vinyl-s-
cyclohexadienones, which are easily accessible by the oxidative palladium(II) species, formed by the halopalladation of alkynes, can
dearomatization of phenols, were utilized in a variety of Rh,3 be trapped with a variety of electrophiles and also by nucleophiles
Pd,4 Ni5 and Cu6 catalyzed reactions (Scheme 1a). Majority of under oxidative conditions.10 Despite the elegant advances in
these reports involve formation of mono-functionalized cis- both the Pd-catalyzed cascade cyclizations and halopalladation
hydrobenzofuran derivatives leaving the cyclohexanone moiety chemistry, dihalogenation of alkyne-tethered cyclohexadienones
unfunctionalized. In sharp contrast, only a single report exists still remains unexplored. In view of the wide applicability of vinyl-
depicting the synthesis of di-functionalized benzofurans by Sasai halides and a-halo-carbonyl derivatives in organic synthesis and
and co-workers.4b They illustrated a diacetoxylative carbocycliza- our recent studies on cyclohexadienones,11 we envisioned that the
tion under Pd(II) catalysis in AcOH. Apart from this elegant work, oxa-p-allyl palladium(II) intermediate generated by the cascade
nucleophilic interception of oxa-p-allyl palladium species is an halopalladation/alkene insertion could be trapped with a halide
uncharted territory in spite of its ability to install a variety of anion leading to difunctionalized cis-hydrobenzofurans (Scheme 1b).
functional groups at the a-carbon of the carbonyl group.
Initial challenges associated with the envisioned protocol include
Discovery of transition metal catalyzed cross coupling reactions the competing facile b-hydride elimination or protonation of the
has made alkenyl halide a major workhorse and valuable building oxa-p-allyl palladium enolate. An additional challenge would be to
block.7 Therefore, several new strategies have been developed to control the stereoselectivity at the a-carbonyl centre by suppressing
the epimerization of palladium-enolate.
We commenced our investigation of the cascade halopalladation/
conjugate addition by choosing 1a as a model substrate. On
treatment of 1a with 10 mol% of Pd(OAc)2 and 2 equiv. of CuCl2
Department of Chemistry, Indian Institute of Technology Bombay, Powai,
Mumbai-400076, India. E-mail: chandra.volla@chem.iitb.ac.in
† Electronic supplementary information (ESI) available. CCDC 1913321, 1913346,
at 50 1C, dichlorinated product 2a was observed, albeit in a
lower yield of 18% (see the ESI† for the full optimization table).
1913347, 1913363, 1922338, 1922346, 1922350, and 1934494. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c9cc07164d
13442 | Chem. Commun., 2019, 55, 13442--13445
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
After careful screening of the various reaction parameters like aliphatic-alkyne-tethered cyclohexadienones were also found to
ligands, solvents, temperature and Pd-catalysts, we were delighted be amenable substrates furnishing the dihalogenated products
to observe the best yield of 93% using 10 mol% of Pa(OAc)2, (2m and 2n, 73 and 74%). The single crystal X-ray diffraction
12 mol% of 2-20-bpy along with 2 equiv. of CuCl2, at 70 1C in analysis of 2d, 2f, 2k and 2l unambiguously confirmed the regio-
THF. Nitrogen-containing ligands such as 2,20-bpy and 1,10-phen- and diastereoselectivity of the dichlorinated products 2. Next, we
anthroline were found to be advantageous for the dichlorination, screened various substituents at the quaternary center of the
probably because of their ability to accelerate the intramolecular cyclohexadienone to understand the steric effect on the cascade
migratory insertion and at the same time to suppress the undesired dichlorination (2o-2v). While primary alky groups gave products
b-hydride elimination (see the ESI†). Remarkably, the whole 2o-2r in comparable yields (71–82%), the yields decreased signifi-
sequence consists of efficient formation of one carbon–carbon cantly in the case of secondary alkyl groups (2s and 2t, 63 and 51%)
and two carbon–halogen bonds with three contiguous stereo- and a tert-butyl group led to the product only in traces, indicating a
centers. Pleasingly, only one diastereomer was observed in the crude prominent steric effect of the substituent on the reactivity. This
1H NMR spectrum of the reaction mixture. The stereospecific can be due to the Umpolung attack of chloride ions from the
(E)-configuration of the exocyclic double bond supports the expected opposite face, on the oxa-p-allyl palladium intermediate and the
cis-chloropalladation. The chloride at the a-carbon of the carbonyl chloride nucleophile approaches from the same face of the sub-
group was found to be trans to the fused furan ring.
stituent on the quaternary center. Subsequently, 3- and 2-methyl
With the optimized reaction conditions in hand, we started substituted cyclohexadienones 1w and 1x were examined to study
to probe the versatility of the developed protocol against a the regioselectivity of the cascade cyclization and we were pleased
variety of alkyne-tethered cylcohexadienones 1 (Table 1). We were to see that the migratory insertion takes place selectively with the
pleased to find that electron-donating and electron-withdrawing less substituted double bond of cyclohexadienones affording
groups, as well as halogen substituents like chloro and bromo, 2w and 2x as single regioisomers in 75% and 46% respectively.
which are sensitive to oxidative addition, were compatible on the Unfortunately, N-tethered cyclohexadienones were not found to be
aromatic ring of the alkyne, affording the corresponding products amenable substrates for the transformation.
in good to excellent yields (2b-2l, 68–91%). Heteroaryl- and
The superior reactivity of alkenyl bromides in metal-catalyzed
cross-coupling reactions due to their facile oxidative addition and
the importance of a-bromo carbonyl compounds encouraged us to
study the cascade dibromination of alkyne-tethered cyclohexadie-
nones. With this in mind, we investigated the reaction using
2 equiv. of CuBr2 for bromopalladation and also as the bromide
nucleophile, and we were delighted that under our standard
conditions 1a afforded the corresponding dibrominated cis-
hydrobenzofuran 3a in 89% yield (Table 2). The substrate scope
for the dibromination was also found to be wide as different aryl-,
thiophenyl- and aliphatic-alkyne tethered cyclohexadienones 1
reacted smoothly to form the corresponding dibromo-hydro-
benzofurans 3b-3n in good to excellent yields (54–89%). The
structure and regio- and diastereoselectivity of the dibrominated
products were also similar to that of dichlorinated products as
confirmed by the single-crystal X-ray diffraction analysis of 3b, 3d
and 3f (see the ESI†). Of particular note is the effect of substituents
at the quaternary center on the dibromination. Primary alkyl and
phenyl substituents led to the corresponding products 3o-3s in
51–71%. However, in the case of the i-propyl group, the reaction
did not go to completion even after prolonged reaction time
(3t, 45%). Furthermore, sec-butyl derived alkyne 1t, which gave
the dichlorination product 2t in 51% yield, failed to give any
dibromination. This could be due to the increased steric hindrance
in the case of bulky bromide, exerted by the substituent at the
quaternary center. Similar to dichlorination, dibromination also was
highly regio-selective in the case of unsymmetrical cyclohexa-
dienones (3v and 3w in 69% and 38%).
Table 1 Substrate scope of cascade dichlorinationa
Next, we carried out gram scale reactions of 1a under the
optimized reaction conditions to isolate 1.05 g (81%) of 2a and
1.29 g (78%) of 3a (Scheme 2a). The synthetic utility of the
dihalogenation products was illustrated by converting them
into other useful products. Upon treatment of 3a with a strong
a
Reaction conditions: 1 (0.2 mmol), CuCl2 (2 equiv.), Pd(OAc)2 (10 mol%),
2,20-bpy (12 mol%), THF (2 mL). 70 1C, 16 h, under nitrogen.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 13442--13445 | 13443

View Article Online
ChemComm
Communication
Table 2 Substrate scope of cascade dibrominationa
The (E)-geometry of the exo-olefin and the stereochemistry at
the a-position of the carbonyl group provided crucial information
about the cis-halopalladation pathway. In order to gain more
insights into the reaction mechanism, control studies were carried
out. Reaction of 1a with stoichiometric amounts of PdCl2 in the
absence of CuCl2 led to a complex mixture and 2a was observed in
o5%, indicating the essential role of CuCl2 as the chloride source
(Scheme 3a). This also sheds light on the operative mechanism
and a Pd(II)/Pd(0) mechanism involving reductive elimination
can be ruled out. Furthermore, to understand the nature of the
oxa-p-allyl palladium species, the reaction was carried out in the
presence of 8 equiv. H2O. Remarkably, 2a was formed exclusively
and no protonation was observed, illustrating the Umpolung
behavior of the palladium enolate (Scheme 3b). When the stoichio-
metric control experiment was done in a 7 : 1 THF/H2O mixture,
interestingly a fused tricycle 9 was isolated in 40% (Scheme 3c).
Notably, the stereochemistry at the a-carbon of 9 was opposite (cis
to the fused furan ring) to that of dihalogenation products 2 (trans
to the furan ring). Sluggish reactivity of cyclohexadienone 10 having
bulky t-butyl substituents at the 2,6-positions also supports the
back face attack of a halide nucleophile on the palladium enolate,
similar to the Tsuji–Trost reaction (Scheme 3d).12 To exclude the
possibility of a-chlorination directly with CuCl2 as the Cl2 source, 7
was treated with 1 equiv. of CuCl2 and no reaction was observed
(Scheme 3e, see the ESI† for more details).13 Finally, addition of
a radical scavenger such as (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO) did not hamper the reaction, suggesting the absence of
radical intermediates.
a
Reaction conditions: 1 (0.2 mmol), CuBr2 (2 equiv.), Pd(OAc)2 (10 mol%),
2,20-bpy (12 mol%), THF (2 mL). 70 1C, 16 h, under nitrogen.
base like KOtBu at room temperature cyclohexadienone-fused
hydro-furan 4 was isolated in 85% (Scheme 2b). Interestingly,
under catalytic hydrogenation conditions, both the cyclohexe-
none double bond and a-halogen were selectively reduced
leaving the exo-olefin untouched furnishing 5 and 7 in excellent
yields. Selective reduction of the carbonyl group under Luche
reaction conditions (NaBH4, CeCl3ꢀ7H2O in MeOH at rt)
resulted in alcohol 6 as a single diastereomer in 92%.
Scheme 2 Gram-scale synthesis and functionalization.
13444 | Chem. Commun., 2019, 55, 13442--13445
Scheme 3 Mechanistic studies.
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
Notes and references
1 (a) J. M. Castro, S. Salido, J. Altarejos, M. Nogueras and A. Sanchez,
Tetrahedron, 2002, 58, 5941; (b) M. J. Uddin, S. Kokubo, K. Ueda,
K. Suenaga and D. Uemura, J. Nat. Prod., 2001, 64, 1169; (c) K. F. Nielsen,
M. Mansson, C. Rank, J. C. Frisvad and T. O. Larsen, J. Nat. Prod., 2011,
74, 2338; (d) Y.-Q. Chen, Y. H. Shen, Y. Q. Su, L.-Y. Kong and
W. D. Zhang, Chem. Biodiversity, 2009, 6, 779.
2 (a) Y. Hayashi, H. Gotoh, T. Tamura, H. Yamaguchi, R. Masui and
M. Shoji, J. Am. Chem. Soc., 2005, 127, 16028; (b) Q. Liu and T. Rovis,
J. Am. Chem. Soc., 2006, 128, 2552; (c) N. T. Vo, R. D. M. Pace,
F. O’Har and M. Gaunt, J. Am. Chem. Soc., 2008, 130, 404; (d) Q. Gu
and S.-L. You, Chem. Sci., 2011, 2, 1519; (e) M.-Q. Jia and S.-L. You,
Chem. Commun., 2012, 48, 6363; ( f ) S. Takizawa, T. M.-N. Nguyen,
A. Grossmann, D. Enders and H. Sasai, Angew. Chem., Int. Ed., 2012,
51, 5423; (g) W. Wu, X. Li, H. Huang, X. Yuan, J. Lu, K. Zhu and J. Ye,
´
Angew. Chem., Int. Ed., 2013, 52, 1743; (h) C. Martın-Santos, C. Jarava-
´
Barrera, S. del Pozo, A. Parra, S. Dıaz-Tendero, R. Mas-Balleste and
S. Cabrera, Angew. Chem., Int. Ed., 2014, 53, 8184; (i) W. Yao, X. Dou,
S. Wen, J. Wu, J. J. Vittal and Y. Lu, Nat. Commun., 2016, 7, 13024.
3 (a) K. K. Gollapelli, S. Donikela, N. Manjula and R. Chegondi, ACS Catal.,
2018, 8, 1440; (b) Z.-T. He, B. Tian, Y. Fukui, X. Tong, P. Tian and G.-Q.
Lin, Angew. Chem., Int. Ed., 2013, 52, 5314; (c) J. Keilitz, S. G. Newman and
M. Lautens, Org. Lett., 2013, 15, 1148; (d) C.-L. Duan, Y.-X. Tan, J.-L.
Zhang, S. Yang, H.-Q. Dong, P. Tian and G.-Q. Lin, Org. Lett., 2019,
21, 1690.
Scheme 4 Proposed mechanism.
4 (a) A. S. Murthy, S. Donikela, C. S. Reddy and R. Chegondi, J. Org.
Chem., 2015, 80, 5566; (b) K. Takenaka, S. C. Mohanta and H. Sasai,
Angew. Chem., Int. Ed., 2014, 53, 4675; (c) R. Tello-Aburto and
A. M. Harned, Org. Lett., 2009, 11, 3998; (d) K. Kondo, M. Sodeoka,
M. Mori and M. Shibasaki, Tetrahedron Lett., 1993, 34, 4219.
5 (a) C. Clarke, C. A. Incerti-Pradillos and H. W. Lam, J. Am. Chem.
Soc., 2016, 138, 8068; (b) R. Kumar, Y. Hoshimoto, E. Tamai,
M. Ohashi and S. Ogoshi, Nat. Commun., 2017, 8, 32.
6 P. Liu, Y. Fukui, P. Tian, Z.-T. He, C.-Y. Sun, N.-Y. Wu and G.-Q. Lin,
J. Am. Chem. Soc., 2013, 135, 11700.
7 (a) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011,
111, 1417; (b) G. Evano, N. Blanchard and M. Toumi, Chem. Rev.,
2008, 108, 3054; (c) K. C. Nicolaou, P. G. Bulger and D. Sarlah,
Angew. Chem., Int. Ed., 2005, 44, 4442.
8 D. A. Petrone, J. Ye and M. Lautens, Chem. Rev., 2016, 116, 8003.
9 (a) J. Derosa, A. L. Cantu, M. N. Boulous, M. L. O’Duill, J. L. Turnbull,
Z. Liu, D. M. De La Torre and K. M. Engle, J. Am. Chem. Soc., 2017,
139, 5183; (b) G. Zhu and Z. Zhang, J. Org. Chem., 2005, 70, 3339;
(c) X.-C. Huang, F. Wang, Y. Liang and J.-H. Li, Org. Lett., 2009, 11, 1139;
(d) S. Ma and X. Lu, J. Org. Chem., 1991, 56, 5120; (e) D. Chen, Y. Cao,
Z. Yuan, H. Cai, R. Zheng, L. Kong and G. Zhu, J. Org. Chem., 2011,
76, 4071; ( f ) P. Zhou, M. Zheng, H. Jiang, X. Li and C. Qi, J. Org. Chem.,
2011, 76, 4759; (g) G. Yin and G. Liu, Angew. Chem., Int. Ed., 2008,
47, 5442; (h) R. Shukla, K. Pal and C. M. R. Volla, Chem. – Asian. J., 2018,
13, 2435.
10 (a) Z. Zhang, W. Wu, J. Liao, J. Li and H. Jiang, Chem. – Eur. J., 2015,
21, 6708; (b) L. Huang, Q. Wang, W. Wu and H. Jiang, Adv. Synth.
Catal., 2014, 356, 1949; (c) Z. Zhang, L. Ouyang, W. Wu, J. Li,
Z. Zhang and H. Zhang, J. Org. Chem., 2014, 79, 10734; (d) S. Ye,
K. Gao, H. Zhou, X. Yang and J. Wu, Chem. Commun., 2009, 5406;
(e) Y. Liang, S. Tang, X.-D. Zhang, L.-Q. Mao and J.-H. Li, Org. Lett.,
2006, 8, 3017; ( f ) S. Ma, B. Wu, X. Jiang and Z. Zhao, J. Org. Chem.,
2005, 70, 2568; (g) K. Takenaka, S. Hashimoto, S. Takizawa and
H. Sasai, Adv. Synth. Catal., 2011, 353, 1067.
On the basis of our mechanistic studies, a plausible mechanism
for the Pd-catalyzed dihalogenation of cyclohexadienones is
depicted (Scheme 4). Initial coordination of Pd(II)-salt with the
alkyne and alkene units of 1 forms intermediate B. Regioselective
cis-halopalladation of the alkyne would lead to the formation of
vinylpalladium(II) species C. Intramolecular syn-migratory insertion
with the less-substituted double bond would form the palladium-
enolate D. Nucleophilic attack of a halide ion on rather electrophilic
oxa-p-allyl intermediate E from the back side affords 2 and Pd(0).
Re-oxidation of Pd(0) with CuCl2 generates Pd(II)-salt and completes
the catalytic cycle.
In conclusion, we have developed a widely applicable Pd-
catalyzed cascade dihalogenation of alkyne-tethered cyclo-
hexadienones using CuX2 as the halide source. The protocol
was highly regio- and diastereoselective affording densely
functionalized cis-hydrobenzofuranone derivatives with three
stereocenters. Key control experiments and mechanistic studies
revealed the involvement of an unusual electrophilic palladium
enolate illustrating Umpolung behaviour. The practical utility
of cascade cyclization has been further demonstrated with the
gram scale reaction and further functionalization of these
derivatives into other useful compounds.
This work is supported by SERB, India (EMR/2015/002047).
A. S. and R. K. S. would like to thank the Council of Scientific &
Industrial Research (CSIR) and University Grants Commission
(UGC) respectively for the fellowship.
11 (a) A. Nair, S. Kumar and C. M. R. Volla, Adv. Synth. Catal., 2019,
DOI: 10.1002/adsc.201900874; (b) G. Sontakke, K. Pal and
C. M. R. Volla, J. Org. Chem., 2019, 84, 12198.
12 B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921.
13 E. M. Kosower, W. J. Cole, G. S. Wu, D. E. Cardy and G. Meisters,
J. Org. Chem., 1963, 28, 630.
Conflicts of interest
There are no conflicts to declare.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 13442--13445 | 13445