A sequential Pd/norbornene-catalyzed process generates o- biaryl carbaldehydes or ketones via a redox reaction or 6 h -dibenzopyrans by C-O ring closure

Article abstract of DOI:10.1021/ol302889t

o-Biaryl carbaldeydes and ketones are obtained through the one-pot reaction of o-aryl iodides with o-bromobenzyl alcohols under the catalytic action of Pd and norbornene, in the presence of a base. The same reaction can also give dibenzopyrans by Pd and norbornene catalysis with a different termination, leading to C-O ring closure. In both cases the process first leads to a five-membered palladacycle, which controls C-C coupling, then to a seven-membered oxapalladacycle, which gives aldehydes and ketones or dibenzopyrans.

Full text of DOI:10.1021/ol302889t

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5792–5795
A Sequential Pd/Norbornene-Catalyzed
Process Generates o-Biaryl
Carbaldehydes or Ketones via a Redox
Reaction or 6H‑Dibenzopyrans by CꢀO
Ring Closure
Elena Motti,† Nicola Della Ca’,† Di Xu,†,‡ Anna Piersimoni,† Elena Bedogni,†
Zhi-Ming Zhou,‡ and Marta Catellani*,†
ꢀ
Dipartimento di Chimica and CIRCC, Universita di Parma, Parco Area delle Scienze,
17/A, 43124 Parma, Italy, and R&D Centre for Pharmaceuticals, School of Chemical
Engineering and the Environment, Beijing Institute of Technology, Beijing, P. R. China,
100081
marta.catellani@unipr.it
Received October 19, 2012
ABSTRACT
o-Biaryl carbaldeydes and ketones are obtained through the one-pot reaction of o-aryl iodides with o-bromobenzyl alcohols under the catalytic
action of Pd and norbornene, in the presence of a base. The same reaction can also give dibenzopyrans by Pd and norbornene catalysis with a
different termination, leading to CꢀO ring closure. In both cases the process first leads to a five-membered palladacycle, which controls CꢀC
coupling, then to a seven-membered oxapalladacycle, which gives aldehydes and ketones or dibenzopyrans.
In the course of our studies aimed at working out new
methods to achieve ordered reaction sequences by means
of Pd and norbornene joint catalysis,1 we have shown
that a variety of biphenyl derivatives can be prepared by
reaction of ortho-substituted aryl iodides with aryl bro-
mides, followed by irreversible termination steps leading to
CꢀC, CꢀN, or CꢀO bond formation.
derivative under catalysis of Pd and norbornene in the
presence of a base leads to o-biaryl carbaldehyde 3 and to
6H-dibenzo[b,d]pyran 4, the former by an intramolecular
oxidationꢀreduction process involving hydrogen migra-
tion from the benzylic group to the aromatic carbon of the
other ring and the latter by CꢀO coupling (Scheme 1).
Amazingly, the hydroxymethyl group of the bromoben-
zyl alcohol remains unaffected through the series of steps
leading to unsymmetrical arylꢀaryl coupling and even-
tually reacts with the biaryl-bonded Pd intramolecularly.
In the effort to optimize the reaction conditions we
observed that the use of PPh3 as a ligand negatively affected
the yield due to the formation of byproducts and set out to
work out a ligandless reaction. We varied the base, the
solvent, and norbornene equivalents as well as the tempera-
ture. We were delighted to find that the use of CsO2CCMe3
(cesium pivalate) allowed us to obtain o-biaryl carbaldehyde
3 selectively and in satisfactory to excellent yield.
We have now found that the one-pot reaction of an
ortho-substituted aryl iodide with a 2-bromobenzyl alcohol
†
ꢀ
Universita di Parma.
‡ Beijing Institute of Technology.
(1) (a) Catellani, M.; Motti, E.; Della Ca’, N. Acc. Chem. Res. 2008,
41, 1512. (b) Catellani, M. In Palladium in Organic Synthesis; Tsuji, J.,
Ed.; Springer: Berlin, 2005, 21. (c) Martins, A.; Mariampillai, B.; Lautens,
M. Top. Curr. Chem. 2010, 292, 1. (d) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174. (e) Sehnal, P.; Taylor,
R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010, 110, 824. (f) Xu, L.-M.;
~
Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (g) Muniz,
K. Angew. Chem., Int. Ed. 2009, 48, 9412. (h) Johnson, J. B.; Rovis, T.
Angew. Chem., Int. Ed. 2008, 47, 840. (i) Jiao, L.; Herdtweck, E.; Bach,
Thorsten J. Am. Chem. Soc. 2012, 134, 14563.
r
10.1021/ol302889t
Published on Web 11/07/2012
2012 American Chemical Society

using CsO2CCMe3 in DMF, at 105 °C for 24 h, led to the
formation of 30-isopropyl[1,10]-biphenyl-2-carbaldehyde
(3; R1 = i-Pr; R2, R3, R4 = H) in 90% yield, together
with a small amount, if any, of the corresponding dibenzo-
[b,d]pyran derivative (Table 1).
Scheme 1. o-Biaryl Carbaldehyde and 6H-Dibenzo[b,d]pyran by
Pd/Norbornene Catalysis2
As shown in Table 1, the reaction led to compounds 3
with good to excellent yields, which are significantly
enhanced in the presence of bulky groups ortho to the aryl
iodide (e.g., entries 6 and 9) as well as in the presence of
electron-releasing groups in the aromatic ring of both the
iodide (entries 4 and 13) and the bromide (entries 14
and 15). Electron-releasing substituents in the iodoarene
are required since, with the exception of CF3,3 electron-
withdrawing groups favor the reaction with a second mole-
cule of iodoarene rather than with the bromobenzyl alcohol.
As pointed out in our previous works,1 norbornene,
although acting catalytically, must be used in excess to Pd
to counteract competitive reactions. A too large excess has
a negative effect, however, because of the tendency of
certain substrates to retain norbornene and incorporate
it into organic compounds.1 Different ratios to Pd (from 5
to 20:1 molar ratio), depending on substituents on both
aryl halides, have therefore to be used. As previously pointed
out, the base of choice turned out to be CsO2CCMe3, with
poorer results being obtained, in terms of both conversion
and selectivity, with other bases such as KO2CCMe3, K2CO3,
Cs2CO3, or Na2CO3, and NaOAc or KOAc, used in excess
over that required for neutralizing acidity.
This procedure allows access to a large number of
substituted o-biaryl carbaldehydes, which are useful inter-
mediates for fragrances, pharmaceutical compounds, and
other fine chemicals;4 moreover, in view of the simplicity of
the one-pot procedure, the availability of the starting
materials, and the modular approach, which allows a facile
change of the building blocks, this ligandless Pd-catalyzed
sequence offers a valuable alternative toother procedures.5
At this point, we wondered how aryl bromides, contain-
ing a substituted hydroxymethyl group in the ortho posi-
tion, as in the case of 5 (Table 2) would behave. As shown
in Table 2 the reaction led tothe expected ketone 6 together
with 6H-dibenzopyran derivative 7. K2CO3 proved to be
the base of choice and allowed us to obtain the ketone with
a yield up to 85% (entry 3; R5 = Me). Passing from the
methyl group to the phenyl one (entry 6; R5 = Ph) led to
the dibenzopyran derivative predominantly. The decrease
of the norbornene ratio to Pd had a beneficial effect in
entries 1 and 2. Other variations of reaction conditions did
not exert a positive influence on the outcome.
Table 1. Synthesis of o-Biaryl Carbaldehydesa
entry
R1
R2
R3
R4
3 (yield %)b
1
Me
Me
H
Me
H
H
H
H
H
H
H
H
66 (78)c
66 (79)
92 (99)
91 (99)c
68 (80)d
90 (99)
91 (99)
62 (78)d
93 (99)
74 (86)
90 (98)
68 (81)d
92 (98)c
88 (95)d
95 (99)
2
H
3
Me
Me
OMe
H
4
Me
H
5
Et
H
6
i-Pr
i-Pr
i-Pr
sec-Bu
H
H
7
H
H
OMe
8
H
H
Cl
9
H
H
H
10
11
12
13
14
15
(CHdCH)2
(CHdCH)2
H
H
OMe
H
H
CF3
H
OMe
H
H
Me
n-Pr
i-Pr
OMe
H
H
4,5-OMe
4,5-OMe
H
H
a Reaction conditions: molar ratio of 1, 2, Pd(OAc)2, norbornene,
and CsO2CCMe3 20:20:1:10:50; 105 °C for 24 h. DMF as solvent, under
N2; 2.2 ꢁ 10ꢀ3 mmol Pd(OAc)2/mL DMF. b Isolated yield on the
amount of charged aryl iodide. In parentheses: yield based on reacted
aryl bromide. Dibenzopyrans 4, when present, have been estimated by
1H NMR to range from 1 to 5%. Byproducts mainly derive from the
reaction of aryl iodide with norbornene and have been reported pre-
viously.1a,3 c Molar ratio of norbornene to Pd = 5:1. d Molar ratio of
norbornene to Pd = 20:1.
Thus, reaction of 2-isopropyliodobenzene and 2-bromo-
benzyl alcohol, in the presence of Pd(OAc)2 and norbornene,
Finally, we carried out the reaction using tertiary benzyl
alcohols 8, as reported in Table 3. In this case, as could be
expected in view of the lack of hydrogen to be abstracted,
the reaction was found to be very selective and led, with
good to excellent yields, to the dibenzopyran derivative 9.
Ring closure to dibenzopyran derivative was also
strongly favored by the geminal group effect (Table 3).7
The base of choice turned out to be K2CO3. The trend
(2) See the Supporting Information for details.
(3) (a) Motti, M.; Ippomei, G.; Deledda, S.; Catellani, M. Synthesis
2003, 2671. (b) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc.
2004, 126, 78.
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2000001389, 2000. (b) Murugesan, N.; Tellew, J. E.; Macor, J. E.; Gu, Z.
WO 2001044239, 2001.
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€
€
€
2009, 10, 865 and references therein. (b) Gurbuz, N.; Ozdemir, I.;
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Gulias, M.; Gaunt Bremeyer, N.; Johansson, C. C. C.; Collins, B. S. L.;
Gaunt, M. J. Angew. Chem. Int. Ed. 2011, 50, 1076.
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1969, 34, 2401.
Org. Lett., Vol. 14, No. 22, 2012
5793

appears to be compatible with a variety of R5 and R6
substituents. No reaction is observed in the absence of
norbornene.
Table 2. Synthesis of o-Biaryl Ketones and Dibenzo[b,d]pyransa
Dibenzopyrans are widely present in natural substances
and in pharmaceuticals. Their basic structure is contained
in the important class of cannabinoids.8
The proposed reaction pathway for the reactions shown
in Tables 1ꢀ3 is outlined in Scheme 2. The aryl iodide
oxidatively adds to Pd(0),9 and then norbornene stereo-
selectively inserts into the CꢀC bond of I giving II,10 which
cyclizes to III11 through Csp2ꢀH activation.12 Oxidative
addition of the aryl bromide has been recently shown to
proceed through the Pd(IV) complex IV13 thanks to the
presence of an ortho substituent in palladacycle III.14 This
step is followed by reductive elimination leading to inter-
mediate V, which, owing to steric factors, readily under-
goes norbornene deinsertion to the aryl-Pd(II) species VII
(via VI).15 In the presence of the appropriate base inter-
mediate VII generates both the cyclic (7 and 9) and the
carbonyl (3 and 6) containing species together with Pd(0).
6
7
entry
R1
R2
R3
R5
(yield %)b
(yield %)b
1
Me
Me
Me
H
H
H
Me
Me
Me
Me
Me
Ph
43c
78c
85
24
80
11
37c
8c
2
OMe
OMe
H
3
OMe
9
4
(CHdCH)2
(CHdCH)2
49
16
50
5
6d
OMe
H
Me
H
a Reaction conditions: molar ratio of 1, 5 (R4 = H), Pd(OAc)2,
norbornene, and K2CO3 20:20:1:20:50; 105 °C for 24 h. DMF as solvent,
under N2; 2.2 ꢁ 10ꢀ3 mmol of Pd(OAc)2/mL of DMF. b Isolated yield.
c Molar ratio of norbornene to Pd = 10:1. d 1-Methyl-9-phenylfluoren-
9-ol6 was also formed in 11% isolated yield likely through coupling of
the activated hydroxymethyl carbon with the Pd-bonded aryl carbon.
Scheme 2. Proposed Reaction Pathway
Table 3. Synthesis of Dibenzo[b,d]pyransa
entry
R1
R2
R3
R4
R5
R6
9 (yield %)b
1
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
79c
75c
66
98
84c
90
92
98
95c
98
80
90
99
99
98
97
2
i-Pr
H
3
(CHdCH)2
H
4
Me
Me
H
H
5
H
H
H
H
6
n-Pr
i-Pr
H
7
H
8
(CHdCH)2
H
9
Me
H
H
10
11
12
13
14
15
16
n-Pr
H
H
Et
(CHdCH)2
H
Et
OMe
Me
H
H
Et
H
H
OMe
OMe
OMe
Cl
Et
n-Pr
Et
Oxapalladacycles, condensed with simple arenes instead
of the biaryl unit of VI and VII, have been prepared by
(CHdCH)2
Me
Et
H
Et
a Reaction conditions as in Table 2. b Isolated yield. c Molar ratio of
the substrate to Pd = 50:1.
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observed for the substituent effect is the same as that
previously mentioned for Table 1. In addition the reaction
5794
Org. Lett., Vol. 14, No. 22, 2012

trapping them with tertiary phosphines or other stabilizing
ligands.15 Cyclic ether formation has been the object of
much work in the past years.16
groups, which occurs between the two carbon atoms
originally bonded to the bromide. Biarylaldehydes or
ketones have been found to be not accessible through this
procedure because, if primary or secondary bromobenzyl
alcohols are used, β-hydrogen elimination readily occurs
with formation of aldehydes or ketones16cꢀe,17 before
coupling to biaryls might take place; for example, the
following reaction (Scheme 3) has been reported.17
Recently the formation of dibenzopyrans starting from
tertiary o-bromobenzyl alcohols similar to 9, using
Pd(OAc)2 as the catalyst, Cs2CO3 as a base, and phosphines
as ligands, was reported by Satyanarayana et al.17 This
methodology substantially differs from ours, because of
the presence of phosphines, the absence of norbornene, the
use of only bromobenzyl alcohol for the construction of
the biaryl structure, and the termination step (ipso sub-
stitution). As a consequence, the dibenzopyrans formed
differ by the substituents, which belong only to the bro-
mobenzyl alcohols, and also by the junction of the two aryl
Scheme 3. Benzaldehyde from o-Bromobenzyl Alcohol
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This problem does not arise in our case, as no benzalde-
hyde is being formed. The aryl iodide indeed reacts with
Pd(0) in preference to the poorly reactive bromobenzyl
alcohol to give I. Hydrogen transfer from the hydroxy-
methyl group through a redox process does not occur until
VII is formed. Although intermolecular hydrogen transfer
reactions18 able to terminate a Pd-catalyzed reaction se-
quence have been reported by us and others,19 the bromo-
benzaldehyde expected to result from such a process was
not detected. Thus, the behavior observed in the present
research, which involves oxidation to aldehyde in one ring
of the biaryl unit and reduction of the CꢀPd bond in the
other, appears to be unprecedented.
In summary, we have reported a new one-pot method
for preparing o-biaryl carbaldehydes and ketones or con-
densed 6H-dibenzo[b,d]pyrans, in most cases with good to
excellent selectivity, through oxapalladacycles formed in
the final stage of the reaction sequence that leads to bi-
arylpalladium intermediates.
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Acknowledgment. We thank MIUR and Parma Univer-
sity for financial support. D.X. is a recipient of a fellowship
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The authors declare no competing financial interest.
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