Synthesis of novel palladium OCN-pincer complexes: Unprecedented sequential C(sp3)-H activation and aerobic oxidation in the reaction of N,N-dialkyl-3-[(N,N-dimethylamino)methyl]-2-iodoanilines with Pd 2(dba)3

Article abstract of DOI:10.1039/b502854j

The reaction of N,N-dialkyl-3-[(N,N-dimethylamino)methyl]-2-iodoanilines with Pd₂(dba)₃ under O₂ gives palladium OCN-pincer complexes by means of an unprecedented process that involves the formal aerobic oxidation of C(sp<

Full text of DOI:10.1039/b502854j

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COMMUNICATION
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Synthesis of novel palladium OCN-pincer complexes: unprecedented
sequential C(sp3)–H activation and aerobic oxidation in the reaction of
N,N-dialkyl-3-[(N,N-dimethylamino)methyl]-2-iodoanilines with
Pd2(dba)3{
Daniel Sole´,*a Llu´ıs Vallverdu´,a Xavier Solansb and Merce´ Font-Bardiab
Received (in Cambridge, UK) 25th February 2005, Accepted 7th April 2005
First published as an Advance Article on the web 15th April 2005
DOI: 10.1039/b502854j
hydrodehalogenation and demethylation of the starting material
(Scheme 1). After an unsuccessful survey of reaction conditions
while trying to prepare our original target, we fortuitously found
that treatment of 3a with Pd2(dba)3 in the presence of PPh3
(1 equiv.) in open air (benzene, rt, 9 h) afforded the palladium
OCN-pincer complex 5a, which was isolated in 43% yield by ‘flash’
chromatography. Some studies to optimise this unexpected
oxidation process were performed and it was found that the
addition of Et3N under an O2 atmosphere resulted in clean
reaction mixtures and increased the yield of 5a up to 53%. The
structure of complex 5a was confirmed by X-ray crystallography
(Fig. 1).{
The reaction of N,N-dialkyl-3-[(N,N-dimethylamino)methyl]-2-
iodoanilines with Pd2(dba)3 under O2 gives palladium OCN-
pincer complexes by means of an unprecedented process that
involves the formal aerobic oxidation of C(sp3)–H bonds at the
a position of the aniline N atom.
Transition metal complexes containing ECE pincer-type ligands
(where E is a neutral two-electron donor) have recently attracted
considerable attention owing to their usefulness in different areas,
including bond activation, catalysis, and the stabilisation of
otherwise unstable compounds.1 Consequently, many pincer
complexes with a great variety of pendant ligands have been
reported during the last years.2
To evaluate the scope of this unprecedented transformation,
other differently substituted haloanilines were examined. As
summarised in Table 1, substrates 3a–d reacted under the
optimised conditions to afford palladium OCN-pincer complexes
5a–d in moderate yields. As expected, bromoaniline 3b was less
reactive than 3a in the reaction with Pd2(dba)3. However, after
heating a benzene solution of 3b and Pd2(dba)3 at 50 uC for 3 days,
palladium complex 5b was obtained in 57% yield. Reaction of
substrates 3c and 3d showed high selectivity for the functionali-
sation of primary C(sp3)–H bonds in lieu of secondary carbon
centres, as the only palladacycles we obtained were those resulting
from the oxidation at the methyl group, 5c and 5d respectively.
Substrates 6–8, which contain two methylene carbons at the a
position of the aniline N atom, provided further information about
the oxidation reaction. Thus, under optimised conditions iodoani-
lines 6 and 7 afforded the palladium complexes 9 and 10,
respectively, both resulting from the oxidation at secondary
In the context of our studies on the Pd(0)-catalysed coupling of
aryl halides and ketones,3,4a we have recently described a new
family of four-membered azapalladacycles of general structure 1,
which are obtained by reaction of N,N-dialkyl-2-iodoanilines with
Pd(0) complexes.4 Continuing our research on this chemistry, we
were interested to see whether the introduction of an additional
chelating group at the ortho-position of the palladated carbon was
compatible with the four membered metallacycle and if so,
whether palladium pincer complexes containing a four-membered
ring such as 2 could be obtained.
In this communication we report that the introduction of a
(dimethylamino)methyl group at the ortho-position severely
changes the reactivity of 2-haloanilines with Pd2(dba)3. This led
us to obtain palladium OCN-pincer complexes by means of an
unprecedented process involving sequential C(sp3)–H activation at
the a position of the aniline N atom, and aerobic oxidation of the
transient palladium complex thus formed.
Instead of the expected palladium complex 2a, the reaction
of iodoaniline 3a with Pd2(dba)3 (benzene, rt) under an
argon atmosphere gave aniline 4a (40%), resulting from the
{ Electronic supplementary information (ESI) available: experimental
details, characterization data of compounds 2c, 4a,c–d, 5a–d, 9 and 10, and
crystallographic information. See http://www.rsc.org/suppdata/cc/b5/
b502854j/
*dsole@ub.edu
Scheme 1
2738 | Chem. Commun., 2005, 2738–2740
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To our surprise, subjecting iodoaniline 8 to the same reaction
conditions provided the NCN9-pincer derivative 2c (40%) instead
of the corresponding OCN-pincer complex. Longer reaction times
resulted in the formation of the hydrodehalogenation–dealkylation
product 4c together with 2c, the OCN-pincer complex still not
being detected. The structure of the pincer complex 2c was
assigned from its spectroscopic data. Unfortunately, we failed to
obtain a single crystal suitable for X-ray studies because of the
instability of this palladium complex.
Fig. 1 Molecular structure of 5a (ORTEP view). Selected bond distances
˚
(A) and angles (u): Pd–C1 5 1.948(3), Pd–N1 5 2.083(2), Pd–O 5 2.031(2),
Pd–I 5 2.7405(7), C1–Pd–N1 5 83.32(10), C1–Pd–O 5 89.11(9), N1–Pd–
I 5 97.32(7), O–Pd–I 5 90.04(6).
The selectivity of the oxidation reaction can be rationalised on
the basis of the requirements of C–H activation at Pd(II).5 Thus,
selective oxidation at primary versus secondary carbon centres
(entries 3 and 4) probably results from a strong steric preference
for the formation of less hindered primary Pd-alkyls. Additionally,
the high regioselectivity for the oxidation at the benzylic position
(entry 6) reflects that the dissociation energy of benzylic C–H
bonds is lower than that of alkyl C–H bonds.
Table 1 Synthesis of palladium pincer complexesa
Entry 2-Haloaniline
Pd–pincer complex
Yieldb
Although further studies will be necessary to determine the
mechanistic features of the oxidation reported in this communica-
tion, the results obtained in the above reactions may be tentatively
explained by considering the multi-step process shown in Scheme 2.
Thus, the oxidative addition of Pd(0) to the carbon–halogen bond
of the haloaniline gives rise to the corresponding NCN9-pincer
complex (2), which would undergo activation at one of the C–H
bonds at the a position of the aniline N atom6 to give palladacycle
A.7–9 Palladium complex A could undergo reaction with O2 to give
an alkylperoxo palladium complex, which would then give alkoxo
complex B and OPPh3 (path a).10 A control reaction with
iodoaniline 3a argues in favour of an active role of PPh3 in this
process, as no oxidation compound could be obtained when the
reaction was carried out in the absence of PPh3, although the
starting material was consumed and significant amounts of 4a
were obtained. Finally, b-hydride elimination11 from B would
afford a hydrido-palladium complex C, which could react with O2
and the acid formed in situ12 to give the OCN-pincer complex.13,14
On the other hand, palladacycle A can undergo sequential
reductive elimination and hydrolysis to give 4 (path b).15 This
process is the usual reaction pathway in the absence of O2, and
becomes a competitive reaction when the oxidation step is
hampered by steric factors. The isolation of significant amounts
of benzaldehyde together with the hydrodehalogenation–
dealkylation by-products 4d and 4c in the reactions from 6 and
7 (entries 5 and 6) supports this sequence of events.
1
2
3
4
3a, X 5 I, R1 5 Me
5a, X 5 I, R1 5 Me
5b, X 5 Br, R1 5 Me
5c, X 5 I, R1 5 Pr
5d, X 5 I, R1 5 Bn
53%
57%c
60%
45%
3b, X 5 Br, R1 5 Me
3c, X 5 I, R1 5 Pr
3d, X 5 I, R1 5 Bn
5
6
7
6, R2 5 R3 5 Bn
7, R2 5 Bn, R3 5 Pr
8, R2 5 R3 5 Pr
9, R3 5 Bn
10, R3 5 Pr
39%d,e
46%d,f
40%d
a
Reaction conditions: Pd2(dba)3 (0.55 equiv.), PPh3 (1 equiv.), Et3N
(5 equiv.), benzene, rt, 9 h, O2. Yield refers to pure products
b
c
isolated by ‘flash’ chromatography. 50 uC for 3 days in open air.
24 h. 4d (38%) was also isolated. 4c (35%) was also isolated.
d
e
f
Finally, the isolation of the NCN9-pincer complex 2c is a
consequence of its greater stability, which is probably due to the
propyl groups hampering the C(sp3)–H activation that gives A
(vide supra). On the other hand, although the formation of 4c from
the NCN9-pincer complex 2c could also be explained by the steric
hindrance that prevents the oxidation of intermediate A (R1 5 Pr,
R4 5 Et) and forces path b, an alternative pathway (not
benzylic positions. Especially interesting is the reaction of
iodoaniline 7, in which the oxidation took place regioselectively
at the benzylic position. Additionally, it should be noted that
significant amounts of the hydrodehalogenation–dealkylation by-
products, 4d and 4c respectively, were also obtained.
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Chem. Commun., 2005, 2738–2740 | 2739

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Scheme 2
3 (a) D. Sole´, L. Vallverdu´ and J. Bonjoch, Adv. Synth. Catal., 2001, 343,
439; (b) D. Sole´, L. Vallverdu´, E. Peidro´ and J. Bonjoch, Chem.
Commun., 2001, 1888.
4 (a) D. Sole´, L. Vallverdu´, X. Solans, M. Font-Bardia and J. Bonjoch,
J. Am. Chem. Soc., 2003, 125, 1587; (b) D. Sole´, L. Vallverdu´, X. Solans,
M. Font-Bardia and J. Bonjoch, Organometallics, 2004, 23, 1438.
5 L. V. Desai, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2004,
126, 9542.
6 For a recent mechanistic study of the Pd(II) activation of C–H bonds
adjacent to the N atom, see: C. C. Lu and J. C. Peters, J. Am. Chem.
Soc., 2004, 126, 15818.
7 A related palladacycle has been proposed as the key intermediate in the
C–H activation of 2-iodoanisole: G. Dyker, J. Org. Chem., 1993, 58,
6426.
8 For the Pd-catalysed C(sp3)–H activation of benzylic gem-trialkyl
groups on halobenzenes, see: (a) G. Dyker, Angew. Chem. Int., Ed.
Engl., 1994, 33, 103; (b) O. Baudoin, A. Herrbach and F. Gue´ritte,
Angew. Chem., Int. Ed., 2003, 42, 5736.
9 For cyclopalladation processes involving the activation of acidic
C(sp3)–H bonds, see: (a) J. Vicente, M.-T. Chicote, C. Rubio,
M. C. Ram´ırez de Arellano and P. G. Jones, Organometallics, 1999,
18, 2750; (b) J. L. Portscheller and H. C. Malinakova, Org. Lett., 2002,
4, 3679.
represented) seems more likely, due to the presence of b hydrogens.
It would involve b-hydride elimination from A to give an enamine,
followed by reductive elimination of the Pd-hydride, and finally
hydrolysis of the enamine.
In summary, we have shown that the palladium NCN9-pincer
complexes that have simultaneously four- and five-membered
metallacycles are not stable and undergo C–H activation at the a
position of the aniline N atom. The sequential C(sp3)–H activation
and aerobic oxidation at this position led to the novel palladium
OCN-pincer complexes. Further investigation will be conducted to
gain deeper insight into the mechanism of the oxidation process
and to expand the activation reaction to other substrates.
We gratefully acknowledge financial support from Spanish
Ministry of Education and Science (Project CTQ2004-04701) and
from DURSI-Catalonia (Grant 2001SGR-00083).
Daniel Sole´,*a Llu´ıs Vallverdu´,a Xavier Solansb and Merce´ Font-Bardiab
aLaboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Universitat de
Barcelona, Av. Joan XXIII s/n, 08028-Barcelona, Spain.
10 The insertion of one oxygen atom into the C–Pd bond of acyl palladium
complexes under aerobic conditions in a process in which OPPh3 is also
formed has been reported: J. Vicente, J.-A. Abad, A. D. Frankland and
M. C. Ram´ırez de Arellano, Chem. Eur. J., 1999, 5, 3066.
11 For a related b-hydride elimination, see: C. Ferna´ndez-Rivas,
D. J. Ca´rdenas, B. Mart´ın-Matute, A. Monge, E. Gutie´rrez-Puebla
and A. M. Echavarren, Organometallics, 2001, 20, 2998.
12 As observed in the optimisation studies, no exogenous base is required
to promote this sequence of reactions. In fact, as the base is recovered in
the final step, the benzylamino moiety of a second molecule could
promote the elimination of HI.
13 The hydride donor ability of palladium hydride complexes greatly
depends on the Pd-ligands, see for example: J. W. Raebiger,
A. Miedaner, C. J. Curtis, S. M. Miller, O. P. Anderson and
D. L. DuBois, J. Am. Chem. Soc., 2004, 126, 5502.
14 For a theoretical study of the reaction of Pd-hydrides with O2, see:
T. Privalov, C. Linde, K. Zetterberg and C. Moberg, Organometallics,
2005, 24, 885.
E-mail: dsole@ub.edu; Fax: +34 93 402 45 39; Tel: +34 93 402 45 40
bDepartament de Cristallografia, Mineralogia i Dipo`sits Minerals,
Universitat de Barcelona, Mart´ı i Franque`s s/n, 08028-Barcelona, Spain
Notes and references
{ Crystal data for 5a: C11H15IN2OPd, M 5 424.55, monoclinic, space
˚
group P21/a, a 5 10.190(8), b 5 11.219(3), c 5 11.646(2) A, b 5 100.37 (3)u,
V 5 1309.6 (11) A , Z 5 4, T 5 293 K, m 5 3.756 mm21; 3977 data, 3767
3
˚
unique (Rint 5 0.0509). R1 5 0.0321 [I .2s(I)], wR2 5 0.0705 on F2.
CCDC 265336. See http://www.rsc.org/suppdata/cc/b5/b502854j/ for crys-
tallographic data in CIF or other electronic format.
1 For recent reviews, see: (a) M. Albrecht and G. van Koten, Angew.
Chem., Int. Ed., 2001, 40, 3750; (b) M. E. van der Boom and D. Milstein,
Chem. Rev., 2003, 103, 1759; (c) J. T. Singleton, Tetrahedron, 2003, 59,
1837.
2 See for example: (a) E. D´ıez-Barra, J. Guerra, I. Lo´pez-Solera,
S. Merino, J. Rodr´ıguez-Lo´pez, P. Sa´nchez-Verdu´ and J. Tejeda,
Organometallics, 2003, 22, 541; (b) E. Poverenov, M. Gandelman, L. J.
W. Shimon, H. Rozenberg, Y. Ben-David and D. Milstein, Chem. Eur.
J., 2004, 10, 4673 and references therein.
15 A similar reaction has been observed in some Pd-catalysed processes:
M. Qadir, R. E. Priestley, T. W. D. F. Rising, T. Gelbrich, S. J. Coles,
M. B. Hursthouse, P. W. Sheldrake, N. Whittall and K. K. Hii,
Tetrahedron Lett., 2003, 44, 3675; T. Harayama, T. Sato, A. Hori,
H. Abe and Y. Takeuchi, Synthesis, 2004, 1446. See also ref. 3a.
2740 | Chem. Commun., 2005, 2738–2740
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