The Palladium-Catalyzed C-H Activation of Benzylic gem-Dialkyl Groups

Article abstract of DOI:10.1002/anie.200352461

Palladacyclic intermediates effectively lower the high energy barrier to cleavage of a C(sp³)-H bond. C-H activation of benzylic gem-dialkyl groups of bromo- and iodobenzenes produces olefins and cyclobutabenzenes, respectively, without homocoupling (see scheme).

Full text of DOI:10.1002/anie.200352461

Communications
Organometallic Chemistry
The Palladium-Catalyzed C–H Activation of
Benzylic gem-Dialkyl Groups
Olivier Baudoin,* Audrey Herrbach, and
Françoise GuØritte
3
ꢀ
The activation of C(sp ) H bonds is one of the current
challenges in chemistry that is expected to have a major
impact on both industrial and academic research. In the past
ꢀ
years, it was shown that C H bond activations in alkanes can
be performed by low- and high-valent transition-metal
complexes and in stoichiometric and catalytic processes,
giving rise to synthetically useful and structurally diverse
functionalized hydrocarbons.[1]
ꢀ
The high energy barrier of C H bond cleavage is lowered
when it is preceded by cyclometalation, which is initiated by
precoordination of the metal complex to a carbon or
heteroatom in the molecule. This precoordination directs
[*] Dr. O. Baudoin, Dr. A. Herrbach, Dr. F. GuØritte
Institut de Chimie des Substances Naturelles, CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Fax : (+33)1-6907-7247
E-mail: baudoin@icsn.cnrs-gif.fr
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200352461
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ꢀ
the metal center to the vicinity of the C H bond to be broken.
large cone angles—PPh3 (1458), P(o-tol)3 (1948), and P(mesi-
Among transition metals, it was shown that palladium(o) is
particularly suitable for this process since the precoordination
step can arise from the oxidative insertion into a carbon–
halogen bond, such as that occurring in cross-coupling
reactions. Indeed, a number of intramolecular arylations
tyl)3 (2128) (entries 3, 6, and 7)[7]— P(o-tol)3 seems to have the
optimal bulkiness for this reaction. Interestingly aldehyde 1d
was formed in substantial amounts when PPh3 and dppp were
employed as ligands (entries 3 and 5). In most other cases 1d,
which probably arises from desilylation and dehydrogenation
of the resulting primary alcohol, was formed in negligible
quantities. The influence of the base was then assessed
(entries 8–11). Among the bases tested, K2CO3 (entry 8) and
K3PO4 (entry 9) gave the highest yields of 1b and the highest
1b:1c ratio. Besides, high-boiling solvents other than DMF
(e.g. dimethyl sulfoxide, xylenes) gave lower yields of 1b
(data not shown). In DMF, the reaction did not proceed at
temperatures below140–150 8C. Repeating the reaction
under the optimal conditions (entries 8–9) with 5 mol%
palladium acetate and 10 mol% phosphane gave the same
results as with 10 mol% palladium. However, lower yields
were obtained when less than 5 mol% palladium was
employed (data not shown).
ꢀ
that proceed by catalytic C H activation of arenes have been
described.[2] Much less data is available regarding catalytic
3
ꢀ
activation of a C(sp ) H bond through cyclometalation. In
ꢀ
particular, it was shown that benzylic or a-benzylic C H
bonds can be cleaved through cyclometalation from PdII
intermediates, giving rise to homo- or cross-coupling prod-
ucts.[3–6] In this report, we describe our own findings regarding
ꢀ
the catalytic C H activation of benzylic gem-dialkyl groups,
which occurs by formation of five- and six-membered
palladacycles, and gives rise to benzocylobutadienes and
olefins, respectively, without formation of homo- or cross-
coupling products.
During the course of our studies directed to the synthesis
of bridged biaryls with antimitotic properties, we found that a
mixture of olefin 1b, the protodeiodinated compound 1c, and
aldehyde 1d was obtained in different ratios when phenyl
iodide 1a was heated at 1508C in DMF in the presence of a
palladium catalyst and a base [Eq. (1), Table 1]. Initially,
cesium carbonate was used as base, and different palladium
catalysts were tested (entries 1–7). Thus, in the presence of a
phosphane-free catalyst, olefin 1b was the major product,
accompanied by starting material 1a and by-product 1c
(entry 1). When a phosphane ligand was added, the starting
iodide was completely converted into the mixture of 1b
(major product) and 1c (entries 2–7). Among the ligands
tested, tri-o-tolylphosphane gave the highest yield of 1b
(entry 6). From these results, it seems that a bulky triarylmo-
nophosphane gives better results than other types of phos-
phanes in this reaction. Among triarylmonophosphanes with
Using the optimal conditions, i.e. Pd(OAc)2/P(o-tol)3 as
the catalyst and K2CO3 as the base, we evalulated the scope of
this newdehydrogenation reaction with a number of different
substrates (Table 2).[8] These were obtained in few steps from
commercially available iodo- or bromobenzenes according to
procedures described in our previous reports.[9] First, the
influence of the benzylic R substituent and of the halogen X
was studied (entries 1–8). As shown with iodides 1a, 2a, 3a,
and 4a, substrates with relatively large R groups gave higher
yields of olefin than those with smaller groups. Remarkably,
phenyl bromides 5a and 6a gave olefins 1b and 4b,
respectively, in high yield and with no protodehalogenated
by-products (entries 5 and 6), in contrast to the reactions of
the corresponding iodides 1a and 4a. The same temperature
(1508C) was required for the reactions of bromides and
iodides. In contrast, the chloro ethyl ester (R = CO2Et, X =
Cl) was not reactive under these
conditions. The fact that the reac-
tion of bromides is more efficient
than that of iodides may be related
to the high reactivity of the latter at
this temperature and consequently
their higher propensity to undergo
protodehalogenation. Nitrile 7a
gave olefin 7b as the sole product
in 65% yield, indicating again that
substrates with smaller R groups
give lower yields. The methoxyme-
Table 1: Optimization of the reaction conditions.[a]
Entry
Catalyst[a]
Base
1a [%][b]
1b [%][b]
1c [%][b]
1d [%]
1
2
3
4
5
6
7
8
Pd(OAc)2
[PdCl2(dppf)]
Pd(OAc)2/PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
19
0
0
0
0
0
0
0
0
55
57
39
58
32
82
75
82
83
42
32
6
18
7
6
10
8
6
4
5
nd
nd
<5
<5
28[c]
<5
28[c]
<5
<5
<5
<5
<5
<5
thyl(MOM)-protected
tertiary
alcohol 8a gave only 11% yield of
olefin 8b. In this case, the use of
protecting groups other than
MOM (Me, Ac, TES) did not
prove more satisfactory. These
data indicate that the reaction is
quite dependent on the nature of
the benzylic R substituent, with
poor reactivity when an oxygen
atom is directly attached to the
quaternary carbon atom, perhaps
Pd(OAc)2/P(tBu)3
Pd(OAc)2/dppp
Pd(OAc)2/P(o-tol)3
Pd(OAc)2/P(mesityl)3
Pd(OAc)2/P(o-tol)3
Pd(OAc)2/P(o-tol)3
Pd(OAc)2/P(o-tol)3
Pd(OAc)2/P(o-tol)3
9
10
11
DBU
KOAc
47
56
[a] Reaction conditions: 10 mol% palladium, 20 mol% phosphane (when used), 2 equiv base, DMF
(0.1 mmol 1aLꢀ1), 1508C, 30 min. Abbreviations: dppf=1,1’-bis(diphenylphosphanyl)ferrocene,
dppp=1,3-bis(diphenylphosphanyl)propane, TIPS=triisopropylsilyl. [b] Yields after flash chromatog-
raphy; 1a:1b:1c ratio was determined by GC and 1H NMR analysis. [c] Yield of isolated product.
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Table 2: Dehydrogenation of phenyliodides and bromides. [a]
[b]
Entry
Phenylhailde
Products
Yield [%][c]
1
2
3
4
5
6
7
8
1a: R=CH2OTIPS, X=I
1b
2b
3b
4b
1b
4b
7b
8b
82 (4)
12 (2)
47 (8)
62 (6)
83 (0)
83 (0)
65 (0)
11 (7)
2a: R=CH2OTES, X=I
3a: R=CO2Me, X=I
4a: R=CO2Et, X=I
5a: R=CH2OTIPS, X=Br
6a: R=CO2Et, X=Br
7a: R=CN, X=Br
8a: R=OMOM, X=Br
9
93
10
11
–
0
60[d]
12
13
71
75
14
74
15
16
78
80
[a] Reaction conditions: 10 mol% Pd(OAc)2, 20 mol% P(o-tol)3, 2 equiv K2CO3, DMF, 1508C, 30 min.[8] Abbreviation: TES=triethylsilyl. [b] The ratio of
regioisomers was determined by GC analysis. [c] After flash chromatography; yields in brackets refer to the protodehalogenated by-product (see 1c,
Table 1). [d] Reaction time: 90 min.
due to electronic effects. By contrast, as shown with bromide
9a, it seems that substituted benzenes can be employed
successfully, though more examples are still needed.
Next, the influence of different benzylic alkyl groups was
evaluated (entries 10–16) starting from bromophenyl ethyl
esters 10a–16a. When only one ethyl group was present, no
reaction occurred (entry 10). With a gem-dimethyl group,
substrate 11a (entry 11) is obviously unable to undergo
double-bond formation. The benzocyclobutene 11b was
formed exclusively in 60% yield, and a longer time (90 min)
was necessary for the reaction to reach completion. A related
example of benzocyclobutene formation, concomitant with
homocoupling, was described by Dyker.[3d] The controlled
formation of 11b (without homocoupling) may provide
convenient access to functionalized benzocyclobutenes,
which are traditionally difficult to synthesize and which, in
particular, are useful substrates for Diels–Alder reactions and
intermediates in the synthesis of natural products.[10] Starting
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from dissymmetric methyl ethyl bromide 12a, a 95:5 mixture
of the two possible products 12b and 12c was obtained in
71% yield, showing that the formation of the cyclobutarene is
much preferred over the olefin. When the ethyl propyl
bromide 13a was employed, a 73:19:8 mixture of regioiso-
meric olefins 13b, 13c, and 13d was obtained in 75% yield,
showing that the dehydrogenation of the less substituted alkyl
group is predominant. With the symmetrical dipropyl bro-
mide 14a, a 81:19 mixture of regioisomers 14b and 14c was
obtained in 74% yield, and 14b has exclusively the E
geometry (like 13c). Thus, as shown with 13a and 14a, it
seems that the dehydrogenation of the n-propyl group occurs
such as to give the thermodynamically more stable product
with the more substituted double bond.
In order to determine whether palladacycle C or D is
involved in the formation of olefin G, the dehydrogenation
was conducted with deuterated bromides 17a and 18a
(Scheme 2). The corresponding olefins 17b and 18b, having
Finally, the two-carbon homologated compounds 15a and
16a were reacted in order to determine whether the
conjugated double bond was formed preferentially as a
consequence of thermodynamic factors. In the case of gem-
dimethyl bromide 15a, the benzocyclobutene 15b was formed
exclusively in 78% yield. Similarly, with gem-diethyl bromide
16a, both olefins 16b and 16c were formed (80% yield), but
in a 86:14 ratio in favor of the nonconjugated product 16b.
These data suggest again that steric factors prevail in this
reaction.
Scheme 2. Deuterium-labeling experiments.
a deuterium atom and an hydrogen atom, respectively, in the
place of the bromine, were obtained in good yield.[12] These
experiments showthat the deuterium or hydrogen atom
incorporated on the benzene ring originated from the carbon
a to the quaternary benzylic position and lends support for
the six-membered palladacycle intermediate D in Scheme 1.
The observation of terminal olefins 13d and 14c in the
dehydrogenation of propyl-containing substrates (Table 2)
also argues in favor of intermediate D (with b-elimination
from the terminal position).[11] Thus, it appears that benzo-
cyclobutenes F and olefins G are formed initially through
A plausible mechanism for the formation of olefins (when
alkyl groups have at least two carbons) or benzocyclobutenes
(when at least one alkyl group is a methyl) is shown in
Scheme 1. The oxidative addition of Pd0 to phenyl bromide A
ꢀ
gives rise to intermediate B, which would undergo C H
ꢀ
activation of one of the alkyl C H bonds to give either the
ꢀ
five-membered palladacycle C or the six-membered pallada-
cycle D. If a methyl group is present (R1 = H), intermediate C
is formed and gives directly benzocyclobutene F by reductive
elimination. If alkyl groups having at least two carbons are
present (R1 = Me, Et), both five- and six-membered pallada-
cycles can explain the formation of olefin G by b-elimination
followed by reductive elimination from the palladium hydride
intermediate E.[11]
C H activation at the a- and b-benzylic position, respectively,
(B!C or D). When the competition between the two routes
leading to F and G is allowed (Table 2, entries 12, 15), the
route leading to cyclobutarene F is preferred, perhaps
because of steric factors or because in this case no b-
elimination step is involved.
In conclusion, we have reported a novel palladium-
ꢀ
catalyzed C H activation of gem-dialkyl groups on bromo-
and iodobenzenes to give olefins or benzocyclobu-
tenes. This process is simple, efficient, and regiose-
lective and utilizes common reagents. The reaction
products are valuable molecules containing a qua-
ternary stereocenter as well as a new chemical
function (olefin, cyclobutene) potentially useful for
further reactions. A full description of the synthesis
and physical data of reaction substrates and prod-
ucts as well as further development of the method-
ology will be reported in due course.
Received: July 24, 2003 [Z52461]
ꢀ
Keywords: alkenes · C H activation · catalysis ·
dehydrogenation · palladium
.
[1] For reviews, see: a) A. E. Shilov, G. B. Shul'pin,
Chem. Rev. 1997, 97, 2879 – 2932; b) G. Dyker,
Angew. Chem. 1999, 111, 1808 – 1822; Angew.
Chem. Int. Ed. 1999, 38, 1698–1712; c) Y. Guari, S.
Scheme 1. Mechanistic proposal for the formation of olefins and benzocyclo-
butenes.
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Communications
Sabo-Etienne, B. Chaudret, Eur. J. Inorg. Chem. 1999, 1047 –
1055; d) J. A. Labinger, J. E. Bercaw,Nature 2002, 417, 507 – 514.
[2] a) J. Hassa, M. Sꢀvignon, C. Gozzi, E. Schultz, M. Lemaire,
Chem. Rev. 2002, 102, 1359 – 1470; b) A. M. Echavarren, B.
Gꢁmez-Lor, J. J. Gonzꢂlez, O. de Frutos, Synlett 2003, 585 – 597.
[3] a) G. Dyker, Angew. Chem. 1992, 104, 1079 – 1081; Angew.
Chem. Int. Ed. Engl. 1992, 31, 1023 – 1025; b) G. Dyker, J. Org.
Chem. 1993, 58, 6426 – 6428; c) G. Dyker, Chem. Ber. 1994, 127,
739 – 742; d) G. Dyker, Angew. Chem. 1994, 106, 117 – 119;
Angew. Chem. Int. Ed. Engl. 1994, 33, 103 – 105.
[4] M. Catellani, E. Motti, S. Ghelli, Chem. Commun. 2000, 2003 –
2004.
[5] a) J. L. Portscheller, H. C. Malinakova, Org. Lett. 2002, 4, 3679 –
3681; b) J. L. Portscheller, S. E. Lilley, H. C. Malinakova,
Organometallics 2003, 22, 2961 – 2971.
[6] a) B. D. Dangel, K. Godula, S. W. Youn, B. Sezen, D. Sames, J.
Am. Chem. Soc. 2002, 124, 11856 – 11857; b) B. Sezen, R. Franz,
D. Sames, J. Am. Chem. Soc. 2002, 124, 13372 – 13373.
[7] C. A. Tolman, Chem. Rev. 1977, 77, 313 – 348.
[8] Representative procedure:
A dry resealable Schlenk tube
containing a magnetic rod was charged with bromide 6a
(145 mg, 0.48 mmol), palladium acetate (11 mg, 0.048 mmol),
tri-o-tolylphosphane (30 mg, 0.097 mmol), and potassium car-
bonate (134 mg, 0.97 mmol). The Schlenk tube was evacuated
and backfilled with argon twice, then capped with a rubber
septum. Dry N,N-dimethylformamide (3 mL) was injected under
argon, then the septum was replaced by a screwcap and the
mixture was stirred at 1508C (preheated oil bath) for 30 min.
After cooling, the mixture was diluted with diethyl ether and
filtered through celite. The organic solution was washed with
water, dried over magnesium sulfate, and concentrated to
dryness. The residue was purified by flash chromatography
(silica gel, heptanes) to afford olefin 4b as an oil (88 mg, 83%);
1H NMR (CDCl3, 300 MHz): d = 0.86 (t, J = 7.3 Hz, 3H), 1.22 (t,
J = 7.2 Hz, 3H), 2.18 (m, 2H), 4.18 (q, J = 7.2 Hz, 2H), 5.03 (d,
J = 17.7 Hz, 1H), 5.31 (d, J = 11.1 Hz, 1H), 6.38 (dd, J = 17.7,
10.8 Hz, 1H), 7.27 ppm (m, 5H); 13C NMR (CDCl3, 62.9 MHz):
d = 9.2, 14.0, 29.3, 57.9, 60.8, 115.9, 126.6, 127.3, 128.1, 139.6,
142.0, 174.3 ppm; IR (film) n = 2975, 1729 cmꢀ1; HRMS (ESI)
~
calcd for C14H18NaO2 [(M+Na)+]: 241.1204, found: 241.1212.
[9] a) C. Pascal, J. Dubois, D. Guꢀnard, F. Guꢀritte, J. Org. Chem.
1998, 63, 6414 – 6420; b) C. Pascal, J. Dubois, D. Guꢀnard, L.
Tchertanov, S. Thoret, F. Guꢀritte, Tetrahedron 1998, 54, 14737 –
14756.
[10] a) G. Mehta, S. Kotha, Tetrahedron 2001, 57, 625 – 659; b) A. K.
Sadana, R. K. Saini, W. E. Billups, Chem. Rev. 2003, 103, 1539 –
1602.
[11] In the case of propyl groups (R1 = Et), it could be possible that
ꢀ
the terminal methyl C H bond is activated selectively to form a
seven-membered palladacycle giving the terminal olefin, and
that isomerization of the double bond occurs afterwards to give
the mixture of olefins.
[12] Selected physical data: 17b: 1H NMR (300 MHz, CDCl3): d =
0.78 (s, 3H), 0.99 (m, 21H), 3.86 (d, J = 9.9 Hz, 1H), 3.96 (d, J =
9.3 Hz, 1H), 5.02 (m, 1H), 5.21 (m, 1H), 7.15–7.33 ppm (m, 4H);
13C NMR (62.9 MHz, CDCl3): d = 8.5, 12.0, 18.0, 26.5, 50.1, 68.7,
113.8, 125.9 (CH-Ar), 127.3 (CD-Ar), 127.7 (CH-Ar), 127.8
(CH-Ar), 128.0 (CH-Ar), 143.3, 144.2 ppm (Cq-Ar); HRMS
(EI) calcd for C18H25D4OSi [(MꢀiPr)+]: 293.2239; found:
1
293.2242. 18b: H NMR (250 MHz, CDCl3): d = 0.98 (m, 21H),
1.91 (m, 2H), 3.86 (d, J = 8.8 Hz, 1H), 3.95 (d, J = 9.2 Hz, 1H),
6.01 (m, 1H), 7.14–7.35 ppm (m, 5H); 13C NMR (75.5 MHz,
CDCl3): d = 8.5, 11.9, 17.9, 26.8, 50.1, 68.6, 113.9, 125.8 (CH-Ar),
127.7 (CH-Ar), 127.9 (CH-Ar), 143.2, 144.1 ppm (Cq-Ar);
HRMS (EI) calcd for C18H24D5OSi [(MꢀiPr)+]: 294.2302;
found: 294.2312.
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