A domino palladium-catalyzed C-C and C-O bonds formation via dual O-H bond activation: Synthesis of 6,6-dialkyl-6 H -benzo[ c ]chromenes

Article abstract of DOI:10.1021/ol2032625

An efficient Pd-catalyzed domino reaction of α,α-dialkyl-(2- bromoaryl)methanols to 6,6-dialkyl-6H-benzo[c]chromenes is presented. Their formation can be explained via a five membered Pd(II)-cycle that efficiently involves a domino homocoupling with the second molecule, β-carbon cleavage, and finally intramolecular Buchwald-Hartwig cyclization. This domino process effectively involves breaking of five σ-bonds (2C-Br, 2O-H, and a C-C) and formation of two new σ-bonds (C-C and C-O). This mechanistic pathway is unprecedented and further illustrates the power of transition metal catalysis.

Full text of DOI:10.1021/ol2032625

ORGANIC
LETTERS
2012
Vol. 14, No. 2
628–631
A Domino Palladium-Catalyzed CÀC and
CÀO Bonds Formation via Dual OÀH
Bond Activation: Synthesis of 6,
6-Dialkyl-6H-benzo[c]chromenes
Lodi Mahendar, Jonnada Krishna, Alavala Gopi Krishna Reddy,
Bokka Venkat Ramulu, and Gedu Satyanarayana*
Department of Chemistry, Indian Institute of Technology, Hyderabad, Ordnance Factory
Estate Campus, Yeddumailaram - 502 205, Medak District, Andhra Pradesh, India
gvsatya@iith.ac.in
Received December 7, 2011
ABSTRACT
An efficient Pd-catalyzed domino reaction of R,R-dialkyl-(2-bromoaryl)methanols to 6,6-dialkyl-6H-benzo[c]chromenes is presented. Their formation can
be explained via a five membered Pd(II)-cycle that efficiently involves a domino homocoupling with the second molecule, β-carbon cleavage, and finally
intramolecular BuchwaldÀHartwig cyclization. This domino process effectively involves breaking of five σ-bonds (2CÀBr, 2OÀH, and a CÀC) and
formation of two new σ-bonds (CÀC and CÀO). This mechanistic pathway is unprecedented and further illustrates the power of transition metal catalysis.
The development of efficient and sustainable synthetic
methods to achieve molecular complexity in one-pot dom-
ino processes is an important and challenging task in
synthetic organic chemistry.1 In this aspect, transition-
metal catalysis is a powerful tool that permits CÀC and
CÀX (heteroatom) bond forming reactions most efficiently.
A metal that in particular has been used for such transfor-
mations is palladium.2,3 A unique method of generating
C(sp)ÀPd, C(sp2)ÀPd species as potential intermediates in
subsequent coupling reactions is via Pd-catalyzed arylative
β-carbon cleavage of tertiary alcohols.4,5 Subsequently,
Yorimitsu, Oshima, and co-workers employed a useful
(3) For recent Pd-catalyzed domino transformations, see: (a)
Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-H. Angew.
Chem. 2008, 120, 9604–9607. Angew. Chem., Int. Ed. 2008, 47, 9462–
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H.-G. Angew. Chem. 2009, 121, 6264–6267. Angew. Chem., Int. Ed.
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Cheng, D. Angew. Chem. 2009, 121, 5556–5559. Angew. Chem., Int. Ed.
2009, 48, 5448–5451. (d) Wang, G.-W.; Yuan, T.-T.; Li, D.-D. Angew.
Chem. 2011, 123, 1416–1419. Angew. Chem., Int. Ed. 2011, 50, 1380–
1383. (e) Levi, Z. U.; Tilley, T. D. J. Am. Chem. Soc. 2009, 131, 2796–
(1) Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
€
€
(2) For reviews on CÀH activations, see: (a) Shibasaki, M.; Vogl,
E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533–1552. (b)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–
2797. (f) Tietze, L. F.; Dufert, A.; Lotz, F.; Solter, L.; Oum, K.; Lenzer,
T.; Beck, T.; Herbst-Irmer, R. J. Am. Chem. Soc. 2009, 131, 17879–
17884. (g) Tietze, L. F.; Redert, T.; Bell, H. P.; Hellkamp, S.; Levy, L. M.
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Hungerland, T.; Oum, K.; Lenzer, T. Chem.;Eur. J. 2011, 17, 8452–
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1512–1522. (f) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res.
2009, 42, 1074–1086. (g) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem. 2009, 121, 5196–5217. Angew. Chem., Int. Ed. 2009, 48,
8461. (i) Satyanarayana, G.; Maichle-Mossmerzb, C.; Maier, M. E.
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r
10.1021/ol2032625
Published on Web 01/11/2012
2012 American Chemical Society

extension where σ-allyl(aryl)palladium intermediates were
generated via retroallylations of homoallylic alcohols through
a six-membered homoalkenyloxy(aryl)palladium transition
state. The obtained arylpalladium intermediates were sui-
table for allylation coupling with aryl moieties.6 Very recently,
Cramer and Waibel reported a novel stereocontrolled
Pd-catalyzed arylative ring-opening reaction on norbornene-
derived tertiary alcohols for the synthesis of highly substituted
acyl cyclohexenes, quinolines, and tetrahydroquinolines.7
Herein, we report a novel protocol, a domino Pd-cata-
lyzed reaction of R,R-disubstituted-(2-haloaryl)-methanols
1,8 for the efficient synthesis of 6,6-dialkyl-6H-benzo-
[c]chromenes 3.9 This domino process effectively involves
breaking of five σ-bonds (2CÀBr, 2OÀH, and a CÀC) and
formation of two new σ-bonds (CÀC and CÀO). In con-
tinuation of our interest in the development of synthetic
methods by Pd-catalysis,10 we became interested in explor-
ing a Pd-catalyzed intramolecular CÀO bond formation
on substrates 1, anticipating the formation of strained four
membered 8,8-dialkyl-7-oxabicyclo[4.2.0]octa-1,3,5-trienes
2 (see Scheme 1). This in fact was presumed based on
previously reported results using Pd-catalyzed synthesis of
strained cyclobutanes, cyclobutanones, and exocyclic cyclo-
butenes.11 However, surprisingly, the only sole product
was understood that the reaction does not permit the
formation of the strained four membered cyclic ether via
an intramolecular ring-closing reaction, but rather prefers
the intermolecular homocoupling followed by cyclization
with a second R,R-disubtituted-(2-haloaryl)-methanol mol-
ecule in a domino fashion. One should note that it is well
documented that Pd-catalyzed intramolecular BuchwaldÀ
Hartwig cyclization, up to the formation of five mem-
bered carbo-cylic ethers and also to cyclic silyl ethers, is
feasible.12
Table 1. Optimization Reaction Conditions for the Synthesis of
6,6-Dimethyl-6H-benzo[c]chromene 3aa
[Pd]
ligand
base
3aa
entrya
(5 mol %)
(10 mol %) solvent
(2 equiv) (%)b
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dppf)2Cl2
Pd(dba)2
PPh3
PPh3
PPh3
AsPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
nil
DMF
DMF
DMF
DMF
K2CO3
42
73
0
2
K3PO4
3
NaHCO3
Cs2CO3
4
51
70
75
79
89
60
62
66
69
5
dioxane Cs2CO3
CH3CN Cs2CO3
toluene Cs2CO3
6
Scheme 1. Unexpected Formation of Homocoupled Biaryl
Cyclic Ether 3
7
8
DMF
DMF
DMF
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
Pd(PPh3)2Cl2
Pd(PPh3)4
a All reaction were performed on a 100 mg (0.46 mmol) scale of 1aa in
a 0.23 M concentration. b Isolated yields of chromatographically pure
products.
The R,R-dialkyl-(2-bromophenyl)-methanols 1, which
are required for this study, could be obtained easily using
a well established one-pot alkyl Grignard addition to the
corresponding o-halobenzoates or alkyl Grignard addi-
tion, oxidation, and alkyl Grignard addition protocol to
o-halobenzaldehydes (see Supporting Information (SI)).
The Pd-catalyzed transformation of the parent R,R-dimethyl-
(2-bromophenyl)-methanol 1aa was explored under var-
ious conditions. Thus, reaction of 1aa in presence of the
catalyst Pd(OAc)2 (5 mol %)/PPh3 (10 mol %) and base
K2CO3 (2 equiv) in hot DMF at 80 °C for 12 h furnished
the product 6,6-dimethyl-6H-benzo[c]chromene 3aa in
42% moderate yield (Table 1, entry 1). Interestingly, base
K3PO4 drastically improved the product yield to 73%
(Table 1, entry 2). Discouragingly, NaHCO3, a weaker
base, lead to complete recovery of the starting material
(Table 1, entry 3). Using ligand AsPh3 and base Cs2CO3
furnished 3aa in moderate yield (51%, Table 1, entry 4).
isolated from performing the reaction on the parent R,
R-dimethyl-(2-bromophenyl)-methanol 1aa was the corre-
sponding 6,6-dialkyl-6H-benzo[c]chromene 3. Therefore, it
(4) Chow, H.-F.; Wan, C.-W.; Low, K.-H.; Yeung, Y.-Y. J. Org.
Chem. 2001, 66, 1910–1913.
(5) (a) Terao, Y.; Wakui, H.; Nomoto, M.; Satoh, T.; Miura, M.;
Nomura, M. J. Org. Chem. 2003, 68, 5236–5243.
(6) (a) Niwa, T.; Yorimitsu, H.; Oshima, K. Angew. Chem. 2007, 119,
2697–2699. Angew. Chem., Int. Ed. 2007, 46, 2643–2645. (b) Hayashi, S.;
Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006, 128,
2210–2211.
(7) Waibel, M.; Cramer, N. Angew. Chem. 2009, 121, 4557–4560.
Angew. Chem., Int. Ed. 2010, 49, 4455–4458.
(8) (a) Saluste, C. G.; Crumpler, S.; Furber, M.; Whitby, R. J.
Tetrahedron Lett. 2004, 45, 6995–6996. (b) Ivica, S.; Jan, U.; Stefan, T.
Synth. Commun. 2004, 34, 3667–3672. (c) Ikeuchi, Y.; Taguchi, T.;
Hanzawa, Y. J. Org. Chem. 2005, 70, 4354–4359.
(9) Wang, B.; Li, M.; Xu, S.; Song, H.; Wang, B. J. Org. Chem. 2006,
71, 8291–8293.
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J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157–15166.
(b) Alvarez-Bercedo, P.; Flores-Gasper, A.; Correa, A.; Martin, R.
(12) For Pd-catalyzed intramolecluar cyclic ether formations, see:
(a) Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202–12206.
ꢁ
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Org. Lett., Vol. 14, No. 2, 2012
629

Interestingly, use of different solvents improved the yield
ofproduct(Table1,entries5À7). Gratifyingly, thereaction
with the catalyst Pd(OAc)2 (5 mol %)/PPh3 (10 mol %),
in the presence of base Cs2CO3, in hot DMF furnished the
product in excellent yield (89%, Table 1 entry 8). A change
of Pd-catalyst for other than Pd(OAc)2, in hot DMF
and base Cs2CO3, showed an incremental effect in yields
(Table 1, entries 9À11). Reaction with Pd(PPh3)4 (5 mol %)
and Cs2CO3 (2 equiv) furnished the product in good yield
(69%, Table 1, entry 12).
methanols 1aaÀag, with furnished products 3baÀ3bg in very
good yields, as depicted in Scheme 3.
Scheme 3. Scope of Homocoupling Reaction on R,
R-Ethylmethyl-(2-bromoaryl)-methanolsa
Scheme 2. Scope of Homocoupling Reaction on R,
R-Dimethyl-(2-bromoaryl)-methanolsa
a Reaction conditions: 1baÀbg (100 mg, 0.20 to 0.45 mmol), Cs2CO3
(2 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), 0.13À0.22 M in DMF,
at 80 °C for 12À27 h. Yields in the parentheses are isolated yields of
chromatographically pure products.
Furthermore, to study the generality of this method,
Pd-catalyzed reaction on R,R-diethyl-(2-bromoaryl)-
methanols 1caÀcf was also explored. Gratifyingly, under
optimized conditions the corresponding products 3caÀcf
were obtained in good yields (Scheme 4).
a Reaction conditions: 1aaÀag (100 mg, 0.21 to 0.47 mmol), Cs2CO3
(2 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), 0.14À0.23 M in DMF,
at 80 °C for 12À27 h. Yields in the parentheses are isolated yields of
chromatographically pure products.
In all, the conditions found in entry 8 of Table 1 turned
out to be the best with regard to the yield of 6,6-dimethyl-
6H-benzo[c]chromene 3aa. Therefore, these optimized
conditions were applied to the other higher substituted
aromatic ring systems of R,R-dimethyl-(2-bromoaryl)-
methanols 1aaÀag to examine the scope and limitations
of the present method. Delightfully, the reaction went
smoothly even with electron-rich substituents and fur-
nished the products 3aaÀag in very good and comparable
yields, as summarized in Scheme 2. The only difference
from the above optimized reaction conditions was the
increase in reaction time (12 to 27 h), which was found to
be essential for complete consumption of the starting
material, especially for higher substituted substrates.
After successful accomplishment of cyclic ethers 3aaÀag,
we turned our attention to checking the scope and limitations
of the method by changing the alkyl substitution pattern of
the tertiary alcohol domain. Thus, Pd-catalysis on R,R-
ethylmethyl-(2-bromoaryl)-methanols 1baÀ1bg was also in-
vestigated. In general, the results were quite consistent with
those observed in the case of R,R-dimethyl-(2-bromoaryl)-
Scheme 4. Scope of Homocoupling Reaction on R,R-Diethyl-
(2-bromoaryl)-methanolsa
a Reaction conditions: 1caÀcf (100 mg, 0.20 to 0.42 mmol), Cs2CO3
(2 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), 0.12À0.20 M in DMF,
at 80 °C for 12À27 h. Yields in the parentheses are isolated yields of
chromatographically pure products.
630
Org. Lett., Vol. 14, No. 2, 2012

The molecular structure of 3 was further confirmed by
the single crystal X-ray diffraction analysis of 3af13 as
shown in Figure 1 (see SI for X-ray data of 3cc as well).
In summary, we have disclosed an efficient domino Pd-
catalyzed homocoupling followed by a ring closing reaction,
for the synthesis of 6,6-dialkyl-6H-benzo[c]chromene. This
mechanistic pathway is unprecedented and further illustrates
the power of transition metal catalysis. Further extension of
this domino process to access various useful heterocyclic
systems is in progress.
Scheme 5. Plausible Reaction Mechanisms for the Formation of
3aaa
Figure 1. X-ray crystal structure of product 3af. Thermal ellip-
soids are drawn at 50% probability level.
The formation of 6,6-dialkyl-6H-benzo[c]chromene 3
can only be explained by insertion of the initially formed
aryl-palladium(II) species A from 1aa to the OÀH bond of
the tertiary alcohol, yielding a five-membered palladacycle
B (Scheme 5). Via elimination of HÀBr the reactive Pd(II)
species C might form. The key palladacycle C could under-
go insertion into the CÀBr bond of a second molecule of1a
leading to the Pd(IV) complex D. Intramolecular transfer
of an aryl group leads to the Pd(II) intermediate E, which
on spontaneous β-carbon cleavage affords Pd(II) species
F. Finally, an intramolecular BuchwaldÀHartwig cycliza-
tion of F with tertiary alcohol via a reductive elimination of
a Pd-catalyst completes the catalytic cycle with the forma-
tion of 6,6-dialkyl-6H-benzo[c]chromene 3aa. The reac-
tion might be driven also by the gem-dialkyl effect to
facilitate the formation of B.14 Surprisingly, we could
determine a practical use for the gem-dialkyl effect in these
cases. This was concluded when the reaction was per-
formed under optimized conditions on simple 2-bromoar-
ylmethanol, which yielded benzaldehyde (not the expected
cyclic ether benzochromene) in about the same time as
compared with substrates with a gem-dialkyl group. Its
formation can be explained via fast cleavage of five a
membered Pd-cycle assisted by β-hydrogen.15 We also
performedthereactionon alkyl-(2-bromoaryl)-methanols.
However, these substrates furnished an inseparable mix-
ture of products.
a For simplicity, phosphine ligands are omitted.
Acknowledgment. This research work dedicated to
Prof. A. Srikrishna, Department of Organic Chemistry,
Indian Institute of Science (IISc), Bangalore. Financial
support by the Department of Science and Technology
[(DST), CHE/2010-11/006/DST/GSN], New Delhi and
Indian Institute of Technology (IIT) Hyderabad is grate-
fully acknowledged. We sincerely thank Prof. Dr. Martin
E. Maier for his valuable suggestions. We also thank
Dr. G. P. Sankar and Dr. T. K. Panda for X-ray analysis.
L.M., J.K., A.G.K., and B.V.R. thank CSIR, New Delhi,
for the award of a research fellowship.
Supporting Information Available. Experimental pro-
cedures and characterization for all new compounds,
copies of NMR spectra, and CIF files for 3af and 3cc
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Crystal data for 3af: CCDC 857035, C17H14O5, M = 298.28,
˚
˚
˚
monoclinic, a = 6.4053(5) A, b = 15.8952(13) A, c = 13.1993(11) A,
(15)
3
˚
R = 90°, β = 101.104(7)°, γ = 90°, V = 1318.71(18) A , T = 150.01 (10)
K, space group P21/n, Z = 4, 4977 reflections measured, 2479 unique
used for calculation (Rint = 0.0270). The final wR2 was 0.1804 (all data)
and R1 was 0.0577 [I > 2σ(I)].
(14) Michael, E. J.; Grazia, P. Chem. Rev. 2005, 105, 1735–1766.
Org. Lett., Vol. 14, No. 2, 2012
631