Benzylic C-H activation and C-O bond formation via aryl to benzylic 1,4-palladium migrations

Article abstract of DOI:10.1016/j.tet.2008.01.144

A procedure for benzylic C-H activation has been developed using a palladium 1,4-aryl to benzylic migration as a key step. Carboxylates and phenoxides readily trap the resulting benzylic palladium intermediates obtained from palladium 'through space' migration. Aryl bromides and iodides have been successfully employed in this reaction, furnishing moderate to good yields. The mechanism of this reaction has been studied by deuterium-labeling experiments, which suggest that the migration of palladium from an aryl to a benzylic position occurs reversibly. The reaction conditions developed for the migration process also oxidize the neighboring benzylic alcohols to the corresponding aldehydes and ketones.

Full text of DOI:10.1016/j.tet.2008.01.144

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6090e6102
www.elsevier.com/locate/tet
Benzylic CeH activation and CeO bond formation via aryl
to benzylic 1,4-palladium migrations
*
Tanay Kesharwani, Richard C. Larock
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 15 October 2007; accepted 7 January 2008
Available online 4 March 2008
Abstract
A procedure for benzylic CeH activation has been developed using a palladium 1,4-aryl to benzylic migration as a key step. Carboxylates
and phenoxides readily trap the resulting benzylic palladium intermediates obtained from palladium ‘through space’ migration. Aryl bromides
and iodides have been successfully employed in this reaction, furnishing moderate to good yields. The mechanism of this reaction has been
studied by deuterium-labeling experiments, which suggest that the migration of palladium from an aryl to a benzylic position occurs reversibly.
The reaction conditions developed for the migration process also oxidize the neighboring benzylic alcohols to the corresponding aldehydes and
ketones.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
having been recently reported. We have earlier demonstrated
that in o-iodobiaryls, palladium can migrate from one ring
to the other and the resulting palladium intermediate can be
trapped by Heck, as well as Suzuki, cross-coupling reactions
or direct arylation.6 The aryl palladium intermediate formed
by alkyl to aryl palladium migration can also be trapped by
Heck olefination or arylation.7 Cesium pivalate, a crucial
base for these Pd migration reactions, can also be used for
the trapping, as we have demonstrated in vinylic to aryl to
allylic migrations to form the corresponding allylic esters.8
Metal migration reactions provide an alternate way to intro-
duce a palladium moiety into a specific position in an organic
molecule, which has proven to be a useful tool for the synthe-
sis of many heterocyclic ring systems. Vinylic to aryl migra-
tions have been employed for the synthesis of alkylidene
fluorenes,5a,b dibenzofurans,5c,d carbazoles,5c,d and indoles,5d
whereas alkyl to aryl and aryl to aryl migrations have proven
useful for the synthesis of fused polycycles.6,7 Recently, we
have also utilized aryl to imidoyl palladium migrations for
the synthesis of fluoren-9-ones and xanthones.10 Dyker has
successfully applied the CeH activation of a methoxy group
for the synthesis of 6H-dibenzo[b,d]pyrans.11
Metal-catalyzed CeC bond forming reactions and CeH
activation are well studied areas of growing interest.1 These
reactions have been increasingly applied to the synthesis of
natural products.1eeh Among all of the transition metals
known to undergo such processes, the CeC bond forming
reactions of palladium have received the most attention. In
recent years, palladium-catalyzed CeH activation has been
used extensively in organic synthesis.2 Many examples of
cyclopalladation proceeding through alkyl/aryl palladacycles
have been reported. They have proven to be a good model
for CeH activation.3 Lautens, Catellani, and others have
successfully employed these reactions for the formation of
a variety of heterocyclic ring systems.3
Transition metal-catalyzed intramolecular CeH activation
via ‘through space’ migration of a metal has been recently
disclosed.1b,2b,c,4 It appears that the ‘through space’ migration
is quite a general reaction in the case of palladium, examples
of vinylic to aryl,5 aryl to aryl,6 alkyl to aryl,7 vinylic to aryl to
allylic,8 benzylic to aryl,9 and aryl to imidoyl10 migration
The reported palladium migration reactions are presumed
to proceed through a five- or six-membered palladacycle.
* Corresponding author. Tel.: þ1 515 294 4660; fax: þ1 515 294 0105.
E-mail address: larock@iastate.edu (R.C. Larock).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.144

T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
6091
Table 1
Effect of the nucleophile on the reaction in Scheme 2a
The mechanism suggested for these Pd migrations by our
group involves a palladacycle(IV) hydride i or a palladacy-
cle(II) intermediate ii (Scheme 1).5aed,6a,b,d,7,8 In contrast to
our observations, a theoretical study published by Bour and
co-workers suggests the possibility of intermediate iii, which
they suggest is energetically favored.5e,f However, this mech-
anism fails to account for HeD exchange processes observed
in our present work as well as many of our earlier migration
reactions.6a,8
Entry
Nucleophile
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
a
(CH3)3CCO2Cs
PhONa
EtONa
6
12
24
24
24
24
24
24
2
3
4
5
6
7
8
9
64
40
0
Ph2NH
n-Bu2NH
0
0
NaN3
Diethyl sodium malonate
Sodium phthalimide
0
0
0
Reaction conditions: all reactions were performed using 0.25 mmol of aryl
halide 1a, 5 mol % of Pd(OAc)2, 5 mol % of dppm, 3 equiv of the nucleophile,
and 4 mL of DMF at 120 ꢀC.
HX
PdII
H
X
+
PdIV
H
PdX
XPd
H
n
n
n
n
compared with our earlier reported migration reactions and
is very clean. Only a trace amount of the protodehalogenated
by-product 1-methylnaphthalene was observed.
ii
i
n = 0,1
X
PdII
H
To study the scope of this migration process, different
nucleophiles other than cesium pivalate have been employed
as potential traps for the presumed benzylic palladium inter-
mediate. It seemed most reasonable to try nucleophiles, which
have been used to trap p-benzylic13 and p-allylic14 intermedi-
ates. As mentioned earlier, cesium pivalate has proven crucial
for migration of the palladium in our earlier work. However,
we were surprised to observe that sodium phenoxide also
allows the migration of palladium. Nucleophilic displacement
of palladium by this nucleophile gave a 40% yield of the cor-
responding benzylic aryl ether 3 (Scheme 2 and Table 1, entry
2). However, most other nucleophiles examined failed to give
the desired product, including an alkoxide, amines, azide,
malonate, and a phthalimide anion (Table 1, entries 3e8).
Since the cation present in such reactions can often have
a profound effect on the overall yield, we have examined the
effect of various alkali metal pivalates on the process shown
in Scheme 2 (see Table 2). In contrast to cesium pivalate,
sodium pivalate gave a poor yield of 27% (Table 2, compare
entries 1 and 2). We also tried the corresponding potassium
and lithium salts, but they also failed to give better yields
when compared with cesium. Potassium pivalate only gave
a 15% yield of the desired product and lithium pivalate failed
to give any of the desired product even after 1 day (entries 3
and 4). No correlation is observed between the size of the
cation and the yield of the reaction.
n
iii
Scheme 1.
Wang and co-workers have reported the migration of palla-
dium from a benzylic to an aryl position and subsequent trap-
ping of the resulting intermediates by a Heck reaction.9 Their
reaction conditions required that relatively electron-rich
alkenes be employed in order for the Pd migration to take
place prior to the Heck reaction. A mixture of isomeric olefins
was produced, reducing the synthetic utility of the overall
process. Moreover, they did not demonstrate the actual migra-
tion of the palladium from an aryl to a benzylic position.
Herein, we report a number of aryl to benzylic palladium
migrations and subsequent trapping of the benzylic palladium
intermediate by oxygen nucleophiles to form benzylic esters
and ethers. The advantage of our methodology is that the ben-
zylic position can be selectively activated, resulting in good
clean reactions, producing a single product in good yields.
2. Results and discussion
2.1. Benzylic CeH activation
We have found that 1-bromo-8-methylnaphthalene (1), pre-
pared by the reduction of commercially available (8-bromo-
naphthalen-1-yl)methanol using NaBH3CN and BF3$Et2O,12
when subjected to our standard palladium migration condi-
tions employing cesium pivalate as a base furnished the corre-
sponding benzylic ester 2 in 64% yield (Scheme 2 and Table 1,
entry 1). The reaction requires a shorter reaction time (6 h)
To further study the scope of this methodology, other aryl
halides along with several other phenoxides and carboxylates
have been subjected to our migration reaction conditions
(Table 3). In the pivalate reactions, we have found that
Table 2
Effect of the cation on the reaction in Scheme 2a
Entry
Base
Time (h)
Yield (%)
X
Br Me
1
2
3
4
a
(CH3)3CCO2Cs
(CH3)3CCO2Na
(CH3)3CCO2K
(CH3)3CCO2Li
6
12
12
24
64
27
15
0
cat. Pd(OAc)2, dppm
(CH3)3CCO2Cs or NaOPh
DMF, 120 °C
1
X = O2CCMe3 (2) 64%
X = OPh (3) 40%
Reaction conditions: all reactions were performed using 0.25 mmol of aryl
halide 1a, 5 mol % of Pd(OAc)2, 5 mol % of dppm, 3 equiv of the base, and
4 mL of DMF at 120 ꢀC.
Scheme 2.

6092
T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
Table 3
Scope of the benzylic CeH activationa
Entry
Aryl halide
Base
Time (h)
Product
Yieldb (%)
O
C(CH3)3
I
CH3
O
1
2
1
10
(CH3)3CCO2Cs
(CH3)3CCO2Cs
6
4
2
2
64
81
O
3
4
5
6
1
12
12
12
4
3
40
52
39
64
ONa
10
1
3
ONa
OCs
3
O
CH3
O
10
CH3CO2Cs
11
O
7
8
10
10
4
4
12
13
61
CO2Cs
O
Cl
O
38c
Cl
CO2Cs
O
OMe
O
9
10
4
14
67
MeO
CO2Cs
O
O
10
11
10
10
12
12
15
16
57
44
MeO
Cl
ONa
ONa
OMe
O
Cl
O
C(CH3)3
Br Me
O
12
13
17
19
(CH3)3CCO2Cs
6
4
18
18
37
66
Me
Me
Me
I
Me
(CH3)3CCO2Cs

T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
6093
Table 3 (continued)
Entry
Aryl halide
Base
Time (h)
4
Product
Me
Me
Yieldb (%)
Me
I
Me
14
20
22
24
(CH3)3CCO2Cs
21
75c
15
(CH3)3CCO2Cs
(CH3)3CCO2Cs
24
24
23
0
0
Br
OPiv
or
Br
16
25 or 26
Me
a
Unless otherwise stated, all reactions were performed using 0.25 mmol of the aryl halide, 5 mol % of Pd(OAc)2, 5 mol % of dppm, 3 equiv of the base, and
4 mL of DMF at 120 ꢀC.
b
Isolated yield.
The yield was determined by quantitative 1H NMR spectroscopic analysis.
c
1-iodo-8-methylnaphthalene (10) gives a better yield and
a cleaner reaction than the corresponding bromide (Table 3, en-
tries 1 and 2). Similar results have been obtained with phenoxide
as the nucleophile. Thus, iodoarene 10 gave aryl ether 3 in a 52%
yield, while the corresponding aryl bromide furnished the
desired product in only a 40% yield (entries 3 and 4). Surpris-
ingly, aryl bromide 1 when subjected to our migration condi-
tions using cesium phenoxide as the nucleophile failed to give
a higher yield of the desired aryl ether 3 (entry 5).
When cesium acetate was employed, instead of cesium piv-
alate, the yield of the reaction dropped from 81% to 64%
(compare entries 2 and 6). Substituted cesium benzoates
have also been successful in these benzylic CeH activation
processes (entries 7e9). However, the yields are lower than
those obtained using pivalate anion. Cesium p-chlorobenzoate
(entry 8) produced a lower yield than cesium benzoate (entry
7). However, cesium p-methoxybenzoate resulted in a higher
yield (entry 9). This observation can be attributed to the
relative nucleophilicity of the corresponding anions. The
nucleophilicity of the phenoxides has also been found to be
a crucial factor in the yields of the reactions (compare entries
4, 10, and 11). Phenoxide gave a lower yield of ether 3 than
p-methoxyphenoxide, which gave a 57% yield of the desired
product 15 (entry 10) whereas p-chlorophenoxide gave 16 in
only a 44% yield (entry 11).
when such hydrogens are available, as observed in the case of
aryl iodide 20, where the expected product 21 was formed in
a good yield of 75% (entry 14). Our efforts to extend this
methodology to a limited number of other systems have failed.
For example, no migration/hydride elimination product 23 was
observed when bibenzyl 22 was subjected to the usual migra-
tion reaction conditions (entry 15). In similar systems, Olivier
and co-workers have demonstrated the CeH activation of an
alkyl position.15 However, the presence of a benzylic gem-
dialkyl group in their systems reduces the bond angle and
enhances the possibility of forming the necessary five-mem-
bered ring palladacycle. Our one attempt to activate a benzylic
CeH bond by a 1,5-palladium migration also failed, as biphe-
nyl derivative 24 failed to furnish any of the desired product 25
or 26, instead producing only protodehalogenated product
(entry 16).
Possible mechanisms for these reactions are depicted in
Scheme 3. After oxidative addition of the aryl halide to Pd(0),
the resulting intermediate A can insert into the neighboring Ce
H bond to form palladium(IV) intermediate B or a palladium(II)
intermediate C. Intermediate C can also be produced by loss of
HBr from palladacycle B. Palladacycles B and C both can form
Pd(0)
2
1
Our methodology has an advantage over typical benzylic
oxidations or brominations as these latter reactions are usually
not very selective if more than one benzylic group is present.
Our methodology can be used for selective CeH activation as
observed in the case of aryl halides 17 and 19, where the
benzylic CeH, which is in close proximity to the halide is
selectively activated and furnishes only the corresponding
ether (entries 12 and 13). Analogous to our earlier observation,
aryl bromide 17 furnished the corresponding ester 18 in a lower
yield (37%) than aryl iodide 19, which gave a 66% yield of
ester 18 (entries 12 and 13).
BrPd
Br
Pd CH3
Pd CH2
- HBr
HBr
A
D
C
-HBr
H
Br Pd
CH2
B
The benzylic palladium intermediate formed after palla-
dium migration can also undergo facile b-hydride elimination
Scheme 3.

6094
T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
D, which results in migration of the palladium to the benzylic
position. Previous work on benzylic to aryl palladium migrations
reported by Wang and co-workers9 suggested that the steps to
obtain D from A could be reversible.
the six possible products formed, the mechanism for the
formation of 2e and 2c is outlined in Scheme 5. As discussed ear-
lier, palladacycles B and C could be obtained from Avia cyclo-
palladation. These two cyclic intermediates can undergo HeD
exchange to form E. Benzylic intermediate F can be obtained
from reductive elimination of E or from palladium(II) pallada-
cycle C directly. Nucleophilic substitution of F ultimately pro-
duces the deuterated compound 2e. Similar steps can be written
for the formation of 2c starting from G. The formation of G can
take place from E via reductive elimination. G, which can also
be obtained from C directly, can undergo benzylic CeH activa-
tion similar to that of A. The steps for the formation of 2c from G
are expected to be similar to those required for the formation of
2e. Again, they may proceed through palladium(II) intermediate
H or palladium(IV) intermediate I. Equivalent processes can be
written starting from H and J for the formation of the other deu-
terated products.
To study the mechanism in detail, we decided to employ
a deuterated version of compound 1 (1a) under our standard
reaction conditions, since such reactions should result in the
migration of deuterium from the benzylic position to the
aryl position (Scheme 4). To our surprise, we did not see
any deuterium incorporation in the aromatic ring when 1a
was allowed to react with cesium pivalate in DMF straight
from the bottle (Scheme 4, Eq. 1). This observation might
be attributed to HeD exchange between the palladium(IV)
deuteride or DBr formed in the reaction with spurious H2O
present in the reaction system. However, we observed 100%
deuterium incorporation into one aryl position when the
same reaction was performed with 10 equiv of D2O added to
anhydrous DMF (Scheme 4, Eq. 2). The outcome of the above
studies strongly suggests that the HeD exchange reactions
arise by the equilibria indicated in Scheme 3. This encouraged
us to check the reversibility of the steps that might exist
between intermediates D and A.
To do this, we decided to carry out the reaction with non-
deuterated 1-bromo-8-methylnaphthalene in the presence of
10 equiv of D2O using anhydrous DMF (Scheme 4, Eq. 3).
Proton NMR spectroscopic analysis of the product showed
that incorporation of the deuterium occurs not only in the aryl
position (30% of one aromatic hydrogen), but also in the
benzylic position (70% of two benzylic hydrogens). This pro-
vides strong evidence that the palladium migration occurs
reversibly between the aryl and benzylic positions. Increasing
the amount of D2O from 10 to 20 equiv did not change the
amount of deuterium incorporation in either the aryl or the ben-
zylic position. Interestingly, we have found that not only an Mþ
(MW¼242) peak was observed in the GCeMS, but also Mþ1,
Mþ2 and Mþ3 peaks were present in significant amounts.
These four peaks in the GCeMS suggest that six possible
compounds have been formed as illustrated in Figure 1. Out of
The deuterated compound 1a used for the mechanistic
study was prepared in two steps. We started from 8-bromo-
1-naphthoyl chloride (27) (Scheme 6), which was prepared
O
C(CH3)3
O
C(CH3)3
O
C(CH3)3
H D2C
D DHC
H H2C
O
O
O
2b
2c
2
MW = 242
MW = 244
O
C(CH3)3
O
C(CH3)3
O
C(CH3)3
D H2C
H DHC
D D2C
O
O
O
2d
2e
2a
MW = 245
MW = 243
Figure 1.
0% D
O
O
C(CH3)3
O
H D2C
(1)
(2)
(3)
5% Pd(OAc)2, 5% dppm
(CH3)3CCO2Cs
Br CD3
DMF, 120 °C
2a
49%
40%
0% H
C(CH3)3
O
D D2C
5% Pd(OAc)2, 5% dppm
1a
(CH3)3CCO2Cs
10 equiv D2O
anhydrous DMF, 120 °C
2b
70% D
O
30% D
C(CH3)3
O
Br CH3
H H2C
5% Pd(OAc)2, 5% dppm
(CH3)3CCO2Cs
10 equiv D2O
anhydrous DMF, 120 °C
43%
2-2e
1
Scheme 4.

T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
6095
D
PdBr
Br CH3
PdBr CH3
Br Pd
CHD
D DHC
(CH3)3CCO2Cs
K
A
1
J
D2O
DBr
H
H
O
C(CH3)3
DBr
-HBr
-HBr
D H2C
Pd
CH2
Br Pd
CH2
Br Pd
CHD
O
C(CH3)3
Pd
CHD
D DHC
O
O
-HBr
DBr
2e
2c
C
I
B
H
-HBr
D2O
CH2
DBr
D
Pd
CH2
PdBr
(CH3)3CCO2Cs
PdBr CDH2
D H2C
Br Pd
DBr
G
C
E
F
Scheme 5.
from 8-bromo-1-naphthoic acid using a literature procedure.16
Reduction of the acid chloride 27 to the corresponding ben-
zylic alcohol 28a using LiAlD4 resulted in a 79% yield of
28a with 100% deuterium incorporation in both of the ben-
zylic positions. The reduction of 28a with NaBD3CN and
BF3$Et2O gave the desired deuterated compound 1a in
a 50% yield with 93% deuterium incorporation in the three
benzylic positions.
R
O
R
X
OH
5% Pd(OAc)2, 5% dppm
3 (CH3)3CCO2Cs
DMF, 120 °C, 2 h
entry aryl alcohol
X
R
product
yield (%)
1
2
3
4
5
6
28
30
31
32
34
36
Br
H
I
H
29
29
29
33
35
37
71
0
H
H
73
70
67
52
100% D
93% D
PhCH2CH2
I
Br
Br
n-Hex
Br COCl
Br CD2OH
Br CD3
Ph
LiAlD4
NaBD3CN
Scheme 7.
THF, r. t.
BF3 Et2O
THF, reflux
27
1a
50%
28a 79%
36 was also successfully oxidized, but in a lower yield of 52%
(entry 6).
Scheme 6.
This redox chemistry could potentially occur via two
different pathways. One possible route to the product could
be the usual oxidation mechanism suggested by Turner and
co-workers (Scheme 8).17c Palladacycle L, obtained after
oxidative insertion of palladium into aryl halide 28, can react
with the neighboring alcohol group to form the Pd(IV) palla-
dacycle M or Pd(II) intermediate N. Aryl palladium interme-
diate O can then be obtained via b-hydride elimination from
N and can undergo reductive elimination to form the corre-
sponding product 29. A second possible route based upon
a methoxy CeH activation process reported by Dyker11 and
our present aryl to benzylic palladium migration is outlined
in Scheme 9. Aryl palladium intermediate L could also
undergo benzylic CeH activation to form palladacycles P or
Q. Intermediate P can also lead to the formation of Q via
loss of HBr. Benzylic palladium intermediate R, which might
be obtained from P and/or Q could easily undergo b-hydride
elimination to give aldehyde 29.
2.2. Oxidation of benzylic alcohols
The palladium-catalyzed oxidation of alcohols has been
well studied.17 Generally, these reactions require a palladium
catalyst with an aryl halide or O2 as the oxidant.17bei When
aryl halide 28 was subjected to our standard palladium migra-
tion conditions, 1-naphthaldehyde (29) was obtained in a 71%
yield (Scheme 7). Since the reaction was performed under
argon, the absence of O2 suggests that the aryl bromide present
in the starting material must be acting as an oxidant. To check
the involvement of the aryl bromide in the reaction, we
performed the same reaction using 1-naphthylmethanol (30)
(Scheme 7, entry 2), which did not give any aldehyde product.
Aryl iodide 31 gave a cleaner reaction than 28 and a slightly
higher yield of aldehyde when compared with the correspond-
ing bromo derivative 28 (compare entries 1 and 3). We have
also found that aryl halide-containing secondary benzylic
alcohols can be oxidized to the corresponding ketones in
good yields (entries 4 and 5). The relatively hindered alcohol
If the reaction proceeds through the pathway mentioned in
Scheme 8, then it should also be possible to oxidize aryl iodide

6096
T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
Pd(0)
38 under these conditions (Scheme 10, Eq. 1). Moreover, the
29
28
formation of five-membered ring palladacycles similar to M
and N might be favored. However, we observe only a 10% yield
of benzaldehyde (41) from this reaction. Even though the for-
mation of five-membered rings is more favorable than six-
membered ring formation, it is not a favorable geometry for
the b-hydride elimination. Analogous to our above observation,
the aryl bromide 42 also failed to furnish the desired product in
a good yield, affording only a 17% yield of ketone 45 (Scheme
10, Eq. 2). In this case, the formation of a seven-membered ring
palladacycle is not very favorable, even though it is probably
a more favorable geometry for b-hydride elimination.
OH
O
PdBr
PdH CHO
Pd
- HBr
O
N
L
-HBr
H
O
Pd
Br
We have also subjected aryl halide 46 to our standard
migration conditions hoping to perhaps see heterocycle 47
or pivalate 48, the formation of which would suggest the pos-
sibility of benzylic CeH activation next to the electron-with-
drawing oxygen (Scheme 11). Cyclization of the resulting
benzylic palladium intermediate onto the remote aryl group
would lead to heterocycle 47, whereas nucleophilic substitu-
tion of the benzylic palladium by pivalate anion should
produce compound 48. To our surprise, only 1-naphthaldehyde
(29) was formed in a poor 12% yield. This observation
suggests the possible formation of 48, which has hydrolyzed
to give the observed aldehyde or perhaps Pd-benzyl elimina-
tion from an intermediate formed by benzylic CeH activation.
However, all attempts to isolate 48 have failed.
M
Scheme 8.
Pd(0)
29
28
OH
OH
HBr
HO
PdBr
PdBr
Pd
H
+ HBr
- HBr
R
Q
L
-HBr
When the deuterium-labeled compound 28a was subjected
to our usual palladium migration conditions, 100% migration
of one deuterium to the aryl position was observed (Scheme
12). This reaction was unaffected by HeD exchange with
solvent, even when H2O is added. This would presumably
not be the case if the reaction is taking place by the mecha-
nism depicted in Scheme 9. The deuterium-labeling experi-
ments and the possibility of strong coordination between
H
OH
Br Pd
P
Scheme 9.
CHO
OH
- HBr
O
5% Pd(OAc)2, 5% dppm
O
(1)
Pd
+ HBr
Pd
3 (CH3)3CCO2Cs
DMF, 120 °C, 6 h
I
Br
H
39
38
41 10%
40
Br
- HBr
5% Pd(OAc)2, 5% dppm
H
H
Me
(2)
+ HBr
H
Me
3 (CH3)3CCO2Cs
DMF, 120 °C, 6 h
Me
O
Br
O
HO
O
Me
Pd
H
Pd
44
17%
42
45
43
Scheme 10.
O
O
O
Piv
CHO
12%
I
5% Pd(OAc)2, 5% dppm
+
+
3 (CH3)3CCO2Cs
DMF, 120 °C, 12 h
46
48
0%
47
0%
29
Scheme 11.

T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
6097
100% D
100% D
washed with saturated aqueous NaHCO3 and brine. The result-
ing mixture was dried over anhydrous Na2SO4. Evaporation of
the solvent and purification of the crude mixture on silica gel
afforded the desired product 1 (234 mg, 53%) as a white solid:
OH
Br D2C
D
COD
5% Pd(OAc)2, 5% dppm
1
mp 78e80 ꢀC (lit.21 79e80 ꢀC); H NMR (400 MHz, CDCl3)
3 (CH3)3CCO2Cs
DMF, 120 °C, 2 h
d 3.14 (s, 3H), 7.23 (t, J¼7.6 Hz, 1H), 7.34e7.41 (m, 2H),
7.70e7.76 (m, 1H), 7.79 (d, J¼8.0 Hz, 1H), 7.86 (d,
J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 26.2, 120.0,
125.6, 126.0, 128.1, 129.3, 131.0, 131.3, 133.4, 135.4,
136.6; IR (neat, cmꢁ1) 3055, 2968, 2930, 2861, 1563, 1497,
1441, 1381, 1357, 1248, 1192, 1070, 893, 807, 756; HRMS
calcd for C11H9Br: 219.98876, found: 219.98916.
28a
29a
66 %
Scheme 12.
palladium and oxygen suggest that the pathway outlined in
Scheme 8 is more favorable for this particular reaction.
3. Conclusions
4.1.2. 1-Bromo-8-(trideuteromethyl)naphthalene (1a)
8-Bromo-1-naphthoyl chloride16 (525 mg, 2.0 mmol) in an-
hydrous THF (2 mL) was added to lithium aluminum hydride
(92.4 mg, 2.2 mmol) suspended in anhydrous THF (3 mL). Af-
ter the addition was complete, the mixture was stirred at room
temperature for 1 h and hydrolyzed with saturated aqueous so-
dium sulfate. The resulting solution was extracted with ethyl
ether (2ꢂ10 mL). The ether layer was dried over Na2SO4
and concentrated under reduced pressure. The residue was ob-
tained as a pale yellow solid, which was further purified using
column chromatography to furnish deuterated alcohol 28a
(376 mg, 79%) as a white solid: mp 83e85 ꢀC; 1H NMR
(400 MHz, CDCl3) d 2.43 (br s, 1H), 7.25 (t, J¼7.6 Hz, 1H),
7.44 (t, J¼7.2 Hz, 1H), 7.66 (dd, J¼1.6, 7.2 Hz, 1H), 7.77e
7.88 (m, 2H); 13C NMR (100 MHz, CDCl3) d 64.4 (m),
118.1, 125.9, 126.2, 129.8, 129.9, 130.2, 130.3, 133.8,
136.7, 136.8; IR (neat, cmꢁ1) 3048, 2961, 1738, 1364, 1227,
1023, 798, 776; HRMS calcd for C11H7D2BrO: 237.99623,
found: 237.99655. The deuterated aryl bromide 1a was pre-
pared using the procedure described for the preparation of 1,
but using alcohol 28a and NaBD3CN, and was obtained as
A benzylic CeH activation procedure has been developed
using ‘through space’ migration of palladium as a key step.
This process is not only very interesting from the point of
view of mechanism, but it is also very useful for selective
CeH activation. Carboxylates and phenoxides have been
employed to prepare the corresponding benzylic esters and
ethers in moderate to good yields. It is observed that the more
nucleophilic aromatic phenoxides and carboxylates give better
yields. The mechanism of the reaction involving palladium(II)
or palladium(IV) intermediates has been discussed. Deuterium-
labeling experiments suggest that the key step is reversible.
That is aryl to benzylic and benzylic to aryl migrations are
both possible. The reaction conditions developed for these mi-
gration processes also oxidize aryl-containing benzylic alco-
hols to the corresponding aldehydes and ketones in good
yields with simultaneous reduction of halogen. Two possible
mechanisms for the oxidation of these alcohols are discussed.
4. Experimental section
1
a white solid: mp 78e80 ꢀC; H NMR (400 MHz, CDCl3)
4.1. General
d 7.23 (t, J¼7.6 Hz, 1H), 7.32e7.42 (m, 2H), 7.68e7.75 (m,
1H), 7.79 (d, J¼8.0 Hz, 1H), 7.85 (d, J¼7.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 25.6 (m), 120.0, 125.7, 126.0,
128.1, 129.4, 131.0, 131.3, 133.4, 135.3, 136.6; IR (neat,
cmꢁ1) 3055, 2968, 2930, 2861, 1563, 1497, 1441, 1381,
1357, 1248, 1192, 1070, 893, 807, 756; HRMS calcd for
C11H9D3Br: 223.00759, found: 223.00802.
1
The H and 13C NMR spectra were recorded at 300 and
75.5 MHz or 400 and 100 MHz, respectively. All melting points
are uncorrected. High-resolution mass spectra were recorded on
a Kratos MS50TC double focusing magnetic sector mass spec-
trometer using EI at 70 eV. (8-Bromonaphthalen-1-yl)methanol
(28), 30, (8-iodonaphthalen-1-yl)methanol (31), and 38 were
obtained commercially. All reagents were used directly as-
obtained commercially unless otherwise noted. The following
starting materials were made according to literature procedures:
8-bromo-1-naphthoyl chloride (27),16 10-bromo-1,3-dimethyl-
phenanthrene (17),18 1-bromo-2-(phenethyl)benzene (22),19
and 1,8-diiodonaphthalene.20
4.1.3. 1-Iodo-8-methylnaphthalene (10)
Trifluoroacetic acid (1.3 g, 12 mmol) was added to a solu-
tion of (8-iodonaphthalen-1-yl)methanol (568 mg, 2.0 mmol)
and 5 mL of dry CH2Cl2 at 0 ꢀC. A solution of triethylsilane
(277 mg, 4.4 mmol) in 1 mL of anhydrous CH2Cl2 was added
to the reaction mixture. The reaction mixture was allowed to
reach room temperature and stirred overnight under nitrogen.
After completion of the reaction, the CH2Cl2 was removed un-
der reduced pressure and the resulting solution was diluted
with 20 mL of ether and washed with saturated aqueous so-
dium bicarbonate solution. The resulting organic layer was
washed with brine and dried over Na2SO4. Evaporation of
the solvent under reduced pressure and purification of the
crude mixture using column chromatography furnished the
4.1.1. Preparation of 1-bromo-8-methylnaphthalene (1)
To a stirred solution of (8-bromonaphthalen-1-yl)methanol
(472 mg, 2.0 mmol) and BF3$Et2O (2.39 mL, 6.0 mmol) in
dry THF (10 mL), sodium cyanoborohydride (240 mg,
4.0 mmol) was added. The reaction mixture was allowed to re-
flux for 2 days and was monitored by TLC. After completion
of the reaction, 20 mL of ether was added and the solution was

6098
T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
desired product 10 (219 mg, 41% yield) as a white solid: mp
1
reduced pressure and purification of the crude mixture using
column chromatography furnished the desired product 20
(130 mg, 14%) as a colorless liquid: 1H NMR (400 MHz,
CDCl3) d 0.90 (d, J¼6.8 Hz, 6H), 2.08 (q, J¼6.4 Hz, 1H),
3.44 (d, J¼7.2 Hz, 2H), 7.03 (t, J¼7.6 Hz, 1H), 7.33e7.45
(m, 2H), 7.74 (dd, J¼2.0, 7.6 Hz, 1H), 7.84 (d, J¼8.0 Hz,
1H), 8.56 (dd, J¼1.2, 7.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 22.0, 31.0, 44.5, 89.9, 125.5, 126.1, 129.0, 130.8,
131.9, 132.4, 136.5, 138.4, 142.9; IR (neat, cmꢁ1) 3054,
2951, 2927, 2864, 1558, 1364, 1191, 1009, 801, 762; HRMS
calcd for C14H15I: 310.021845, found: 310.02887.
62e64 ꢀC; H NMR (400 MHz, CDCl3) d 3.21 (s, 3H), 7.03
(t, J¼7.6 Hz, 1H), 7.32e7.44 (m, 2H), 7.72 (d, J¼7.6 Hz,
1H), 7.81 (d, J¼8.0 Hz, 1H), 8.31 (d, J¼7.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 26.6, 90.4, 125.8, 126.2, 128.7,
130.3, 131.0, 133.1, 135.0, 135.9, 142.2; IR (neat, cmꢁ1
)
3051, 2964, 2927, 2860, 1558, 1494, 1440, 1380, 1191,
1038, 805, 756; HRMS calcd for C11H9I: 267.97490, found:
267.97553.
4.1.4. 10-Iodo-1,3-dimethylphenanthrene (19)
To a stirred solution of 1718 (284 mg, 1.0 mmol) in THF
(5 mL) at ꢁ78 ꢀC, n-BuLi (2.5 M in hexanes, 0.4 mL,
1.0 mmol) was added. The resulting solution was stirred for
15 min. To the resulting solution, I2 (508 mg, 2.0 mmol) in
THF (1 mL) was slowly added by syringe over a period of
5 min. The solution was then allowed to reach room tempera-
ture and treated with a saturated aqueous Na2S2O3 solution.
The resulting mixture was extracted with diethyl ether
(2ꢂ10 mL). The extracted organic layer was washed with
brine, dried over Na2SO4 and concentrated in vacuum. The
residue was purified by flash chromatography to provide 19
4.1.6. 2-Bromo-20-methylbiphenyl (22)
2-Bromophenylboronic acid (220 mg, 1.1 mmol) was
added to a solution of o-iodotoluene (218 mg, 1.0 mmol),
Pd(PPh3)4 (24 mg, 0.02 mmol), K2CO3 (276 mg, 2.0 mmol),
4 mL of DMF, and 1 mL of H2O. The reaction vial was sealed
and flushed with argon and then allowed to stir at room tem-
perature for 24 h. The resulting reaction mixture was diluted
with 20 mL of Et2O and washed several times with water to
remove DMF. The resulting organic solution was dried over
Na2SO4, concentrated in vacuum, and purified by column
chromatography using hexanes as the eluent to furnish the de-
sired product 22 (189 mg, 77%) as a colorless liquid: 1H NMR
(400 MHz, CDCl3) d 2.12 (s, 3H), 7.12 (d, J¼7.6 Hz, 1H),
7.17e7.40 (m, 6H), 7.66 (d, J¼7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 19.9, 123.8, 125.5, 127.2, 127.9, 128.8,
129.3, 129.8, 130.9, 132.6, 136.0, 141.2, 142.7; IR (neat,
cmꢁ1) 3055, 3017, 2941, 2882, 1466, 1403, 1119, 1064,
1004, 779; HRMS calcd for C11H9D3Br: 246.00441, found:
246.00481.
1
as a brown solid (209 mg, 63%): mp 65e67 ꢀC; H NMR
(400 MHz, CDCl3) d 2.56 (s, 3H), 3.19 (s, 3H), 7.32 (s, 1H),
7.54 (t, J¼7.6 Hz, 1H), 7.62 (t, J¼7.2 Hz, 1H), 7.68 (d,
J¼7.6 Hz, 1H), 8.41 (s, 1H), 8.55e8.63 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 21.7, 27.1, 88.8, 121.8, 123.3, 127.0,
127.2, 127.4, 128.7, 130.3, 132.5, 132.7 133.6, 135.8, 136.2,
142.1; IR (neat, cmꢁ1) 3076, 3052, 2966, 2926, 1613, 1566,
1453, 1378, 1164, 1033, 901, 874, 779; HRMS calcd for
C16H13I: 332.00620, found: 332.00662.
4.1.5. 1-Iodo-8-isobutylnaphthalene (20)
4.1.7. 1-(8-Iodonaphthalen-1-yl)-3-phenylpropan-1-ol (32)
A 100 mL round bottom flask containing 1,8-diiodonaph-
thalene20 (1.14 g, 3.0 mmol) was flushed with argon and
charged with 50 mL of anhydrous Et2O. The pale yellow solu-
tion was cooled to ꢁ30 ꢀC and n-BuLi (1.2 mL of 2.5 M solu-
tion in hexane, 3.0 mmol) was added over a period of 3 min.
After 30 min, a solution of 3-phenylpropanal (603 mg,
4.5 mmol) in 5 mL of anhydrous Et2O was added by a syringe.
The reaction mixture was allowed to warm to room tempera-
ture overnight and then poured into 30 mL of 10% aqueous
HCl. The aqueous layer was separated and extracted with three
10 mL portions of Et2O. The combined organic layer was
washed with 30 mL of H2O and 30 mL of saturated aqueous
NaCl. After drying over Na2SO4, the organic layer was con-
centrated and the crude product was purified by column chro-
matography to give the desired alcohol 32 (453 mg, 39%) as
A 100 mL round bottom flask containing 1,8-diiodonaph-
thalene20 (1.14 g, 3.0 mmol) was flushed with argon and
charged with 50 mL of anhydrous Et2O. The pale yellow solu-
tion was cooled to ꢁ30 ꢀC and n-BuLi (1.2 mL of 2.5 M solu-
tion in hexane, 3.0 mmol) was added over a period of 3 min.
After 30 min, isobutyraldehyde (324 mg, 4.5 mmol) in 5 mL
of anhydrous Et2O was added by a syringe. The reaction mix-
ture was allowed to warm to room temperature overnight and
was then poured into 30 mL of 10% aqueous HCl. The aque-
ous layer was separated and extracted with three 10 mL por-
tions of Et2O. The combined organic layer was washed with
30 mL of aqueous NaCl. After drying over Na2SO4, the or-
ganic layer was concentrated to afford a yellow oil. Without
purification this crude alcohol was added to a stirred solution
of trifluoroacetic acid (975 mg, 9.0 mmol) and 5 mL of dry
CH2Cl2 at 0 ꢀC. A solution of triethylsilane (415 mg,
6.6 mmol) in 1 mL of anhydrous CH2Cl2 was added to the re-
action mixture. The reaction mixture was allowed to warm to
room temperature and stirred overnight under nitrogen. After
completion of the reaction, the CH2Cl2 was removed under re-
duced pressure. The resulting solution was diluted with 30 mL
of ether and washed with saturated aqueous sodium bicarbon-
ate solution. The separated organic layer was washed with
brine and dried over Na2SO4. Evaporation of the solvent under
1
a yellow liquid: H NMR (400 MHz, CDCl3) d 1.98e2.10
(m, 1H), 2.11e2.25 (br s, 1H), 2.28e2.41 (m, 1H), 2.95
(t, J¼8.8 Hz, 2H), 7.84 (dd, J¼2.8, 9.6 Hz, 1H), 7.04 (t,
J¼8.0 Hz, 1H), 7.13e7.32 (m, 5H), 7.53 (t, J¼7.6 Hz, 1H),
7.74 (dd, J¼1.2, 8.0 Hz, 1H), 7.85 (d, J¼8.0 Hz, 1H), 8.04
(d, J¼7.2 Hz, 1H), 8.29 (dd, J¼1.2, 7.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 32.5, 41.8, 67.6, 87.7, 125.8, 125.9,
126.0, 126.1, 128.4, 128.6, 129.6, 130.7, 131.2, 136.0,
141.3, 142.2, 143.0; IR (neat, cmꢁ1) 3320, 3056, 2951,

T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
6099
2924, 2854, 1563, 1463, 1035, 802, 761; HRMS calcd for
C19H17IO: 388.03242, found: 388.03309.
4.0 mmol), 8 mL of DMF, and 2 mL of H2O. The reaction
vial was sealed and flushed with argon and allowed to stir at
room temperature for 24 h. The resulting reaction mixture
was diluted with 30 mL of Et2O and washed several times
with water to remove DMF. The resulting organic solution
was dried over Na2SO4 and concentrated in vacuum. The
crude product was further purified by column chromatography
using hexanes as the eluent to furnish the desired product 20-
bromobiphenyl-2-carbaldehyde (848 mg, 82%) as a colorless
4.1.8. 1-(8-Bromonaphthalen-1-yl)heptan-1-ol (34)
Manganese(IV) oxide (352 mg, 4.0 mmol) was added to
a solution of the alcohol (8-bromonaphthalen-1-yl)methanol
(470 mg, 2.0 mmol) in chloroform (10 mL) and the stirred
mixture was allowed to reflux for 24 h. The suspension was fil-
tered through Celite and washed with chloroform. The filtrate
was washed with water (5 mL), dried over Na2SO4, and con-
centrated in vacuum to give 8-bromo-1-naphthaldehyde
(369 mg, 79% yield) as a white solid: mp 81e83 ꢀC; 1H
NMR (400 MHz, CDCl3) d 7.19 (t, J¼8.0 Hz, 1H), 7.50 (t,
J¼8.0 Hz, 1H), 7.81e7.96 (m, 3H), 8.22 (d, J¼7.6 Hz, 1H),
11.66 (s, 1H); 13C NMR (100 MHz, CDCl3) d 89.9, 126.0,
127.8, 129.8, 130.2, 133.7, 134.3, 135.7, 136.5, 141.4,
191.7; IR (neat, cmꢁ1) 2878, 2861, 1672, 1609, 1553, 1493,
1335, 1234, 1197, 1063, 824, 790, 747; HRMS calcd for
C11H7BrO: 233.96803, found: 233.96836. At 0 ꢀC, a 1 M so-
lution of hexylmagnesium bromide (1.5 mL, 1.5 mmol) was
added dropwise to a solution of 8-bromo-1-naphthaldehyde
(233 mg, 1.0 mmol) in THF (10 mL). The mixture was stirred
for 4 h at room temperature and then hydrolyzed with H2O
(3 mL). The organic phase was separated and the water phase
was extracted with ether (2ꢂ10 mL). The combined extracts
were dried over Na2SO4 and the solvent was evaporated under
reduced pressure. The crude product was further purified by
flash chromatography on silica gel to give the required alcohol
34 (153 mg, 48% yield) as a yellow liquid: 1H NMR
(400 MHz, CDCl3) d 0.89 (t, J¼6.8 Hz, 3H), 1.20e1.45 (br
m, 6H), 1.50e1.75 (m, 3H), 1.98e2.18 (m, 2H), 6.60e6.67
(m, 1H), 7.23 (t, J¼7.6 Hz, 1H), 7.51 (t, J¼7.6 Hz, 1H),
7.76 (d, J¼7.6 Hz, 1H), 7.79e7.88 (m, 2H), 8.02 (d,
J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 14.3, 22.8,
26.5, 29.6, 32.0, 40.7, 69.8, 117.9, 125.6, 125.8, 126.2,
1
liquid: H NMR (400 MHz, CDCl3) d 7.28e7.38 (m, 3H),
7.42 (dt, J¼1.2, 7.6 Hz, 1H), 7.56 (t, J¼7.6 Hz, 1H), 7.63e
7.73 (m, 2H), 8.05 (dd, J¼1.2, 8 Hz, 1H), 9.80 (s, 1H); 13C
NMR (100 MHz, CDCl3) d 124.0, 127.5, 127.6, 128.7,
130.0, 131.0, 131.8, 132.9, 133.8, 133.9, 139.0, 144.6,
191.7; IR (neat, cmꢁ1) 3058, 2916, 2847, 2750, 1693, 1597,
1464, 1393, 1268, 1196, 1003, 826, 754; HRMS calcd for
C13H9BrO: 259.98368, found: 259.98402. At 0 ꢀC, a 1 M so-
lution of methylmagnesium bromide (1.5 mL, 1.5 mmol) was
added dropwise to a solution of 20-bromobiphenyl-2-carbalde-
hyde (259 mg, 1.0 mmol) in THF (10 mL). The mixture was
stirred for 4 h at room temperature and then hydrolyzed with
H2O (3 mL). The organic phase was separated and the water
phase was extracted with ether (2ꢂ10 mL). The combined ex-
tracts were dried over Na2SO4 and the solvent was evaporated
under reduced pressure. The crude product was further puri-
fied by flash chromatography on silica gel to give alcohol 42
(184 mg, 67% yield) as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) d 1.30 (d, J¼6.4 Hz, 3H), 1.42 (d,
J¼6.4 Hz, 3H), 2.01 (br s, 2H), 4.64e4.78 (m, 2H), 7.09 (d,
J¼7.6 Hz, 1H), 7.13 (d, J¼7.6 Hz, 1H), 7.20e7.42 (m, 8H),
7.44e7.53 (m, 2H), 7.63e7.77 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 24.3, 24.6, 66.9, 67.2, 123.7, 124.2,
125.3, 125.4, 127.2, 127.3, 127.3, 127.5, 128.7, 128.9,
129.2, 129.2, 129.3, 129.9, 131.1, 131.5, 132.6, 132.8,
138.8, 139.4, 141.6, 141.7, 143.0, 144.0; IR (neat, cmꢁ1
)
129.2, 129.3, 129.9, 134.4, 136.7, 142.5; IR (neat, cmꢁ1
)
3350 (br), 3055, 3023, 2971, 2924, 1464, 1444, 1080, 1001,
754; HRMS calcd for C14H13BrO: 276.01498, found:
276.01531.
3388 (br), 3056, 2951, 2924, 2854, 1563, 1463, 1192, 1059,
818, 761; HRMS calcd for C17H21BrO: 320.07758, found:
320.07806.
4.1.11. 1-(Benzyloxymethyl)-8-iodonaphthalene (46)
4.1.9. (8-Bromonaphthalen-1-yl)(phenyl)methanol (36)
Compound 36 was prepared as described for the synthesis
of 34 using 8-bromo-1-naphthaldehyde and phenylmagnesium
bromide and was obtained as a colorless liquid (240 mg, 77%
NaH (54 mg, 2.2 mmol) was added in small portions to
a stirred solution of (8-iodonaphthalen-1-yl)methanol (566 g,
2.0 mmol) in dry DMF (50 mL) at 0 ꢀC. After 20 min, benzyl
bromide (0.42 mL, 4.0 mmol) was added dropwise to the solu-
tion at 0 ꢀC and stirring was continued for 1 h at room temper-
ature. The reaction was quenched with saturated aqueous
NH4Cl and the resulting mixture was diluted with Et2O
(30 mL). The organic layer was washed with water and brine,
and then dried over MgSO4. Evaporation of the solvent in vac-
uum afforded a residue, which was purified by column chro-
matography to furnish ether 46 (658 mg, 88%) as a yellow
1
yield): H NMR (400 MHz, CDCl3) d 2.50e2.80 (br s, 1H),
7.25e7.32 (m, 2H), 7.33e7.42 (m, 4H), 7.46 (t, J¼7.6 Hz,
1H), 7.68 (dd, J¼1.2, 7.2 Hz, 1H), 7.80e7.94 (m, 4H); 13C
NMR (100 MHz, CDCl3) d 70.9, 117.9, 125.9, 126.1, 127.4,
127.6, 128.4, 129.5, 130.0, 130.1, 130.2, 134.7, 136.7,
140.1, 144.1; IR (neat, cmꢁ1) 3319, 3083, 3057, 3028, 1561,
1450, 1193, 1035, 761; HRMS calcd for C17H13BrO:
312.01498, found: 312.01548.
1
solid: mp 76e78 ꢀC; H NMR (400 MHz, CDCl3) d 4.73 (s,
2H), 5.50 (s, 2H), 7.07 (t, J¼7.6 Hz, 1H), 7.28e7.53 (m,
6H), 7.74e7.84 (m, 2H), 7.85 (d, J¼8.0 Hz, 1H), 8.33 (d,
J¼7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 71.6, 72.3,
125.6, 126.3, 127.6, 128.0, 128.4, 129.6, 130.3, 130.3,
132.7, 133.9, 136.2, 138.3, 142.6; IR (neat, cmꢁ1) 3055,
4.1.10. 1-(20-Bromobiphenyl-2-yl)ethanol (42)
2-Bromophenylboronic acid (440 mg, 2.2 mmol) was
added to a solution of o-iodobenzaldehyde (462 mg,
1.0 mmol), Pd(PPh3)4 (48 mg, 0.04 mmol), K2CO3 (552 mg,

6100
T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
3024, 2971, 2868, 1495, 1483, 1451, 1351, 1212, 1193, 1064,
1001, 815, 767, 757; HRMS calcd for C18H15IO: 374.01676,
found: 374.01709.
4.2.5. Naphthalen-1-ylmethyl 4-chlorobenzoate (13)
The product was obtained as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) d 5.84 (s, 2H), 7.38 (d, J¼8.8 Hz, 2H),
7.47e7.63 (m, 3H), 7.65 (d, J¼6.8 Hz, 1H), 7.87e7.95 (m,
2H), 8.00 (d, J¼8.8 Hz, 2H), 8.13 (d, J¼8.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 65.5, 123.7, 125.4, 126.2, 126.8,
127.8, 128.6, 128.8, 128.9, 129.6, 131.3, 131.4, 131.9,
133.9, 139.6, 165.7; IR (neat, cmꢁ1) 3048, 2962, 1720,
1594, 1478, 1400, 1268, 1171, 1100, 1014, 792, 758; HRMS
calcd for C17H13ClO: 296.06041, found: 296.06080.
4.2. General procedure for the CeH activation chemistry
To a stirred solution of 0.25 mmol of the aryl halide,
dppm
Pd(OAc)2
(2.8 mg,
0.012 mmol),
(4.8 mg,
0.012 mmol), and 4 mL of DMF, 3 equiv of the desired base
was added. The reaction vial was sealed, flushed with argon,
heated at 120 ꢀC, and monitored by TLC. After completion
of the reaction, the mixture was diluted with 20 mL of Et2O
and washed several times with small amounts of water to re-
move DMF. The resulting organic solution was dried over
Na2SO4, concentrated in vacuum, and purified by column
chromatography using hexanes and ethyl acetate as the eluent.
4.2.6. Naphthalen-1-ylmethyl 4-methoxybenzoate (14)
1
The product was obtained as a yellow liquid: H NMR
(400 MHz, CDCl3) d 3.84 (s, 3H), 5.81 (s, 2H), 6.90 (d,
J¼8.8 Hz, 2H), 7.45e7.62 (m, 3H), 7.65 (d, J¼6.8 Hz, 1H),
7.89 (d, J¼8.4 Hz, 1H), 7.92 (d, J¼8.4 Hz, 1H), 8.13 (d,
J¼8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 55.5, 64.9,
113.7, 122.5, 123.7, 125.4, 126.0, 126.6, 127.4, 128.8,
4.2.1. Naphthalen-1-ylmethyl pivalate (2)
The product was obtained as a pale yellow oil: H NMR
1
129.3, 131.8, 131.8, 133.8, 163.5, 166.3; IR (neat, cmꢁ1
)
(400 MHz, CDCl3) d 1.24 (s, 9H), 5.58 (s, 2H), 7.47 (t,
J¼7.2 Hz, 1H), 7.51e7.60 (m, 3H), 7.83e7.94 (m, 2H), 8.01
(d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 27.4, 39.2,
64.8, 123.8, 125.4, 126.1, 126.6, 127.2, 128.9, 129.2, 131.8,
132.0, 133.9, 178.6; IR (neat, cmꢁ1) 3049, 2972, 2934,
2871, 1726, 1599, 1479, 1397, 1281, 1148, 963, 795; HRMS
calcd for C16H18O2: 242.13068, found: 242.13116.
3050, 3007, 2960, 2934, 2838, 1710, 1605, 1511, 1256,
1167, 1100, 1028, 770; HRMS calcd for C19H16O3:
292.10994, found: 292.11036.
4.2.7. 1-[(4-Methoxyphenoxy)methyl]naphthalene (15)
The product was obtained as a white solid: mp 72e74 ꢀC;
1H NMR (400 MHz, CDCl3) d 3.80 (s, 3H), 5.46 (s, 2H), 6.89
(d, J¼8.8 Hz, 2H), 7.01 (d, J¼8.8 Hz, 2H), 7.48 (t, J¼7.2 Hz,
2H), 7.52e7.65 (m, 3H), 7.84e7.94 (m, 2H), 8.08 (d,
J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 55.9, 69.6,
114.9, 116.1, 123.9, 125.5, 126.0, 126.6, 126.7, 128.8,
4.2.2. 1-(Phenoxymethyl)naphthalene (3)
The product was obtained as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) d 5.52 (s, 2H), 7.03 (t, J¼7.2 Hz, 1H), 7.05
(d, J¼8.0 Hz, 2H), 7.36 (t, J¼7.6 Hz, 2H), 7.45e7.62 (m, 3H),
7.63 (d, J¼6.8 Hz, 1H), 7.85e7.96 (m, 2H), 8.09 (d,
J¼8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 68.8, 115.1,
121.3, 123.9, 125.5, 126.1, 126.6, 126.8, 128.9, 129.2,
129.8, 131.7, 132.5, 134.0, 159.1; IR (neat, cmꢁ1) 3053,
2986, 1598, 1495, 1421, 1265, 1173, 1029, 739; HRMS calcd
for C17H14O: 234.10447, found: 234.10483.
129.1, 131.7, 132.7, 133.9, 153.2, 154.3; IR (neat, cmꢁ1
)
3051, 3001, 2954, 2911, 2834, 1507, 1465, 1265, 1227,
1037, 826, 738; HRMS calcd for C18H16O2: 264.11503, found:
264.11547.
4.2.8. 1-[(4-Chlorophenoxy)methyl]naphthalene (16)
The product was obtained as a pale yellow solid: mp 83e
1
85 ꢀC; H NMR (400 MHz, CDCl3) d 5.48 (s, 2H), 5.58 (s,
4.2.3. Naphthalen-1-ylmethyl acetate (11)
The product was obtained as a yellow liquid: H NMR
1
2H), 6.99 (d, J¼8.2 Hz, 2H), 7.28 (d, J¼9.2 Hz, 2H), 7.48
(t, J¼7.2 Hz, 1H), 7.52e7.63 (m, 3H), 7.85e7.95 (m, 2H),
8.05 (dd, J¼2.4, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 69.2, 116.4, 123.8, 125.5, 126.2, 126.7, 126.8, 128.9,
(400 MHz, CDCl3) d 2.23 (s, 3H), 5.59 (s, 2H), 7.47 (t,
J¼8.0 Hz, 1H), 7.51e7.64 (m, 3H), 7.87 (d, J¼8.4 Hz, 1H),
7.90 (d, J¼8.4 Hz, 1H), 8.03 (d, J¼8.4 Hz, 1H). Other physi-
cal and spectral data are consistent with those reported in the
literature.22
129.4, 129.6, 131.6, 132.1, 134.0, 157.6; IR (neat, cmꢁ1
)
3055, 2924, 2872, 1592, 1509, 1468, 1377, 1279, 1236,
1007, 917, 797; HRMS calcd for C17H13ClO: 268.06549,
found: 268.06583.
4.2.4. Naphthalen-1-ylmethyl benzoate (12)
The product was obtained as a yellow liquid; H NMR
1
(400 MHz, CDCl3) d 5.85 (s, 2H), 7.43 (t, J¼7.6 Hz, 2H),
7.47e7.63 (m, 4H), 7.67 (d, J¼6.8 Hz, 1H), 7.90 (d,
J¼9.6 Hz, 1H), 7.93 (d, J¼9.6 Hz, 1H), 8.08 (d, J¼8.0 Hz,
2H), 8.15 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 65.3, 123.8, 125.5, 126.2, 126.8, 127.7, 128.6, 128.9,
129.5, 129.9, 130.3, 131.7, 131.9, 133.2, 133.9, 166.7; IR
(neat, cmꢁ1) 3061, 3010, 2961, 2900, 1923, 1719, 1600,
1511, 1451, 1314, 1270, 957, 710; HRMS calcd for
C18H14O2: 262.09938, found: 262.09974.
4.2.9. (3-Methylphenanthren-1-yl)methyl pivalate (18)
The product was obtained as a brown solid: mp 74e76 ꢀC;
1H NMR (400 MHz, CDCl3) d 1.22 (s, 9H), 2.63 (s, 3H), 5.57
(s, 2H), 7.49 (s, 1H), 7.55e7.70 (m, 2H), 7.76 (d, J¼8.8 Hz,
1H), 7.85e7.95 (m, 2H), 8.52 (s, 1H), 7.78 (d, J¼8.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 22.2, 27.4, 39.1, 65.2,
122.3, 123.0, 123.4, 126.7, 126.7, 126.8, 128.5, 128.7,
130.0, 130.4, 131.0, 131.9, 132.4, 135.8, 178.6; IR (neat,
cmꢁ1) 2967, 2920, 2852, 1725, 1478, 1281, 1147, 1033,

T. Kesharwani, R.C. Larock / Tetrahedron 64 (2008) 6090e6102
6101
950, 864, 819, 750; HRMS calcd for C21H22O2: 306.16198,
found: 306.16244.
4.3.4. 1-(Naphthalen-1-yl)heptan-1-one (35)
The product was obtained as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) d 0.90 (t, J¼6.8 Hz, 3H), 1.20e1.45 (m,
6H), 1.79 (quintet, J¼7.2 Hz, 2H), 3.05 (t, J¼7.2 Hz, 2H),
7.46e7.65 (m, 3H), 7.81e7.92 (m, 2H), 7.98 (d, J¼8.0 Hz,
1H), 8.55 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.1, 22.6, 24.8, 29.1, 31.7, 42.4, 124.4, 125.8, 126.4,
127.2, 127.8, 128.4, 130.1, 132.3, 134.0, 136.5, 205.2; IR
(neat, cmꢁ1) 2953, 2926, 2855, 1677, 1507, 1462, 1278,
1233, 1171, 1086, 799, 775; HRMS calcd for C17H20O:
240.15142, found: 240.15173.
4.2.10. 1-(2-Methylprop-1-enyl)naphthalene (21)
The product was obtained as a colorless liquid: H NMR
1
(400 MHz, CDCl3) d 1.74 (s, 3H), 2.04 (s, 3H), 6.68 (s, 1H),
7.30 (d, J¼7.0 Hz, 1H), 7.48e8.05 (m, 6H). The other physi-
cal and spectral data are consistent with those reported in the
literature.23
4.3. General procedure for the alcohol oxidations
4.3.5. Naphthalen-1-yl(phenyl)methanone (37)
The product was obtained as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) d 7.45e7.51 (m, 2H), 7.51e7.56 (m, 3H),
7.56e7.63 (m, 2H), 7.86e7.89 (q, J¼3.3 Hz, 2H), 7.92e7.94
(t, J¼4.8 Hz, 1H), 8.00e8.02 (d, J¼8.0 Hz, 1H), 8.09e8.11
(d, J¼8.0 Hz, 1H). The other physical and spectral data are
consistent with those reported in the literature.25
To the stirred solution of 0.25 mmol of the aryl halide,
(2.8 mg,
Pd(OAc)2
0.012 mmol),
dppm
(4.8 mg,
0.012 mmol), and 4 mL of DMF, cesium pivalate (175 mg,
0.75 mmol) was added. The reaction vial was sealed, flushed
with argon, heated at 120 ꢀC, and monitored using TLC. After
completion of the reaction, the mixture was diluted with
20 mL of Et2O and washed several times with small amounts
of water to remove the DMF. The resulting organic solution
was dried over Na2SO4, concentrated in vacuum, and purified
by column chromatography using hexanes and ethyl acetate as
the eluent.
4.3.6. 1-(Biphenyl-2-yl)ethanone (45)
The product was obtained as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) d 2.03 (s, 3H), 7.35e7.47 (m, 7H), 7.53
(dt, J¼1.4, 7.5 Hz, 1H), 7.58 (dd, J¼1.2, 7.6 Hz, 1H). The
other physical and spectral data are consistent with those re-
ported in the literature.26
4.3.1. 1-Naphthaldehyde (29)
The product was obtained as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) d 7.59 (m, 2H), 7.67 (t, J¼8.5 Hz, 1H),
7.90 (d, J¼8.5 Hz, 1H), 7.95 (d, J¼8.2 Hz, 1H), 8.06 (d,
J¼8.2 Hz, 1H), 9.25 (d, J¼8.5 Hz, 1H), 10.36 (s, 1H). The
other physical and spectral data are consistent with those re-
ported in the literature.24
Acknowledgements
We thank the National Science Foundation for support of
this research and Johnson Matthey, Inc., and Kawaken Fine
Chemicals Co., Ltd., for donations of palladium catalysts, as
well as Frontier Scientific for a gift of 3,5-dimethylphenylbor-
onic acid and 2-bromophenylboronic acid used in the synthesis
of compounds 17, 19, 24, and 42.
4.3.2. (8-Deuteronaphthalen-1-yl)deuterocarb-
aldehyde (29a)
The product was obtained as a pale yellow liquid: 1H NMR
(400 MHz, CDCl3) d 7.58e7.68 (m, 2H), 7.71 (d, J¼6.8 Hz,
1H), 7.94 (dd, J¼1.2, 8.0 Hz, 1H), 8.01 (dd, J¼1.2, 6.8 Hz,
1H), 8.11 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 124.6, 124.9, 127.0, 128.5, 129.0, 130.5, 131.3 (m), 133.7,
135.4, 136.7, 193.3 (m); IR (neat, cmꢁ1) 3054, 2951, 2927,
2864, 1558, 1364, 1191, 1009, 801, 762; HRMS calcd for
C11H6D2O: 158.07007, found: 158.07033.
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