New seven membered palladacycles: C-Br bond activation of 2-bromo-pyridine derivative by Pd(II)

Article abstract of DOI:10.1039/c1dt11451d

C-Br bond activation followed by a C-C coupling reaction of the 2-bromo-pyridyl unit of [1-phenyl-2-(6-bromopyridin-2-yl)-benzoimidazole] was performed by Pd(CH₂CMe₂-o-C₆H ₄)(η⁴-COD). Two new seven me

Full text of DOI:10.1039/c1dt11451d

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COMMUNICATION
New seven membered palladacycles: C–Br bond activation of
2-bromo-pyridine derivative by Pd(II)†
a
b
a
a
´
Juan Nicasio-Collazo, Eleuterio Alvarez, Jose´ C. Alvarado-Monzo´n, Gabriel Andreu-de-Riquer,
J. Oscar C. Jimenez-Halla,a Luis M. De Leo´n-Rodr´ıguez,a Gabriel Merino,*a Ubaldo Morales,a
Oracio Serranoa and Jorge A. Lo´pez*a
Received 2nd August 2011, Accepted 29th September 2011
DOI: 10.1039/c1dt11451d
C–Br bond activation followed by a C–C coupling reaction of
the 2-bromo-pyridyl unit of [1-phenyl-2-(6-bromopyridin-2-
yl)-benzoimidazole] was performed by Pd(CH2CMe2-o-C6-
H4)(g4-COD). Two new seven membered palladacycles were
obtained. A combined experimental and theoretical DFT
study elucidates the mechanism for this reaction.
Is it possible to use palladacycles to activate a halo-pyridine? In
general, pyridine derivative synthesis involves classic Stille, Suzuki,
Negishi, Kumada, and Hiyama cross couplings.5–12 However, these
reactions show important challenges in (1) the pre-activation
conditions and (2) the coupling reactions. Although arylation
of N-oxide pyridines has been considered as an alternative to
overcome the previous cited cross-coupling problems, and the
coupling of halo-pyridines with aryl boronic acids is known,13–14
the use of non-activated pyridine compounds in coupling reactions
is of great interest given that the pyridine moiety is an important
heterocycle which is present in several natural products and
pharmaceutical agents.
Some twenty years ago, the chemistry of neophyl-derived metalla-
cycles (neophyl = CH2CMe2Ph) of group 10 elements of the type
M(CH2CMe2-o-C6H4)(L2), where L2 represents a diolefin like 1,4-
cyclooctadiene (COD) or two PMe3 (or other tertiary phosphine
ligands), and M = Ni, Pd, Pt, experienced a remarkable growth due
to their facile synthesis and rich chemical properties.1 A number
of synthetically useful transformations of these molecules were
discovered particularly during investigation of their migratory
insertion chemistry toward unsaturated inorganic and organic
molecules (e.g. CO, CS2, SO4, alkynes, etc).1,2 Furthermore, the
Herein we describe an unexpected C–Br bond activation
of a 2-bromopyridine derivative by Pd(II) in the palladacycle
4
Pd(CH2CMe2-o-C6H4)(h -COD). Overall, this transformation
provides a new strategy for pyridyl transfer between Pd(II) centers
to form stable seven-membered palladacycles.
We first prepared Br-PBI 1 through activated carbon promoted
cyclization/oxidation of N-phenyl-1,2-phenylene-diamine and 6-
bromo-2-pyridine-carboxaldehyde (Scheme 1).15 In order to ob-
tain the target complex 2, the subsequent reaction of 1 with
4
palladacycle Pd(CH2CMe2-o-C6H4)(h -COD) has been used as
2
a precursor of cationic k -hydrotrispirazolylborate (Tp) pallada-
cycles utilized in the Pd(IV) complexes synthesis either through
electrochemical or aliphatic C–X bond activation.3 Interestingly,
in the latter case, it has been reported that the reaction of
CH2X2 (X = Br or I) with the cationic palladacycle gives rise
to relatively stable six membered metallacycles, as a result of the
formal insertion of CH2 into the Pd–Caryl bond. However, the
synthesis of palladacycles larger than six members has proven
to be difficult since this type of derivative undergoes facile
reductive elimination. Thus, as a consequence, examples of well-
characterized compounds of this kind are rare.4 Additionally, to
the best of our knowledge, no reports on the use of palladacycles
for activation of halo-heterocyclic (e.g. halo-pyridine) species are
found.
aDepartamento de Qu´ımica, Universidad de Guanajuato, Cerro de la Venada
s/n, Guanajuato, Gto., C.P. 36040, Mexico. E-mail: albinol@ugto.mx;
Fax: 52 47373 26252
bInstituto de Investigaciones Qu´ımicas, Departamento de Qu´ımica In-
orga´nica, CSIC- Universidad de Sevilla, Avda., Ame´rico Vespucio 49, 41092,
Sevilla, Spain
† Electronic supplementary information (ESI) available: Experimental
details and characterization of compounds. CCDC reference number
831992. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1dt11451d
Scheme 1 Synthesis of compounds 1, 2 and 3a–b.
12450 | Dalton Trans., 2011, 40, 12450–12453
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palladacycle I in benzene at 35 ◦C followed, resulting in a yellow
precipitate after stirring for one day (Scheme 1). After filtration
and work-up, the obtained product was isolated as a yellow solid in
good yield. Surprisingly, 1H NMR analysis revealed an unexpected
and complex resonance pattern arising from the neophyl fragment,
which did not correspond to compound 2. So, two doublets series
at d 2.8/2.56 and 2.7/2.4 ppm were observed. These signals were
assigned to the nonequivalent CH2 group protons, suggesting
the presence of two isomers 3a–b. The same was observed for
the methyl protons, giving two singlets for each isomer, which is
in agreement with their non-equivalence. The above assignments
were confirmed by a 2D 1H NMR COSY experiment. Compounds
3a–b were formed in an approximate ratio of 2 : 1. A pure
sample of 3a was successfully obtained when the reaction was
carried out at 25 ◦C and this was further characterized by X-ray
crystallography.‡
quantitative yield (Scheme 1). The 1H NMR spectra showed only
one signal for the CH2 and CH3 groups at 1.39 and 1.12 ppm,
respectively, confirming the formation of 2.
These results indicated the bidentate COD ligand being im-
portant in the formation mechanism of 3. Palladacycles reacting
2
2
2
with aryl Csp –X electrophiles to form Csp –Csp bonds present in
the final product are found in the literature, but no example has
been given using heteroaryl electrophiles and/or the palladacycle
Pd(CH2CMe2-o-C6H4)(h -COD).18 In this area, norbornene de-
4
rived palladacycles have been the most studied systems, providing
most of the mechanistic clues found up to date for this type of
reaction. However, a definite mechanistic path has not been elu-
cidated yet. In general two mechanisms have been proposed: one
2
involves the oxidative addition of the Csp –X electrophile, forming
a Pd(IV) palladacycle, followed by the reductive elimination and
2
2
2
3
formation of the Csp –Csp and Csp –Csp cross coupling products.
The X-ray structure indicated 3a as a new unexpected seven
membered palladacycle (Fig. 1). The formation of this species
resulted from an unexpected cleavage of a C–Br bond in the
pyridine derivative 1, presumably via oxidative addition,16 and
The second suggests a palladium(II) transmetalation,19 involving
the palladacycle. Given that Pd(CH2CMe2-o-C6H4)(h -COD)
4
features similarities with the reported norbornene palladacycles,
it is reasonable to assume that a similar mechanism might be
implicated for the reactions described herein. Moreover, it is
important to highlight that for the norbornene palladacycles, the
oxidative addition/reductive elimination/C–C coupling reactions
usually proceed in coordinating solvents such as DMF and DMA,
and in the absence of phosphines.
2
2
concomitant Csp –Csp reductive coupling to give the seven mem-
bered palladacycle 3a. As expected, the local geometry around
the Pd atom in 3a was square planar and bond lengths and angles
were consistent with those reported for analogous complexes.1,2,4,17
The X-ray structure confirmed that the non-equivalence of the
methylene and methyl protons of the neophyl fragment was due
to the nature of the seven-membered chelate ring.
In order to clarify these initial findings, we carried out a series of
DFT calculations20 to give an insight into the mechanistic details of
the reaction. According to the well accepted mechanistic proposal
for cross-coupling Pd reactions,21 and to the reported charac-
terization of a Pd(IV) species for a phenanthroline norbornene
palladacycle,22 we considered an oxidative addition to be the initial
step for activating the C–Br bond for the reaction presented herein.
We tested several conformations looking first for an interaction of
the substrate with the Pd center but due to the bulkiness of the
COD ligand, either it reverted into a separated set of two molecules
(Reactants) or Br-PBI displaced COD from the coordination
sphere of the metal center. This ligand exchange, namely the (Br-
PBI)neophylpalladacycle + COD, was found to be 1.9 kcal mol-
1
4
higher in energy than Pd(CH2CMe2-o-C6H4)(h -COD) + Br-PBI,
but the consequent C–Br bond activation goes uphill 31.3 kcal
mol-1 without COD (an analogous process Int1¢ → Int2¢ to that
depicted in Fig. 2). So this reaction cannot proceed under mild
conditions without the coordinative effect of COD in an earlier
stage of the reaction mechanism. Then, another possibility was the
Fig. 1 ORTEP representation of 3a; H-atoms are omitted for clar-
◦
˚
ity. Selected bond lengths (A) and angles ( ): Pd(1)–C(1) 2.0217(16),
Pd(1)–N(3) 2.0972(13), Pd(1)–N(1) 2.1692(13), Pd(1)–Br(1) 2.4392(2);
C(1)–Pd(1)–N(3) 100.77(6), C(1)–Pd(1)–N(1) 168.93(7), N(3)–Pd(1)–N(1)
77.97(5), C(2)–C(1)–Pd(1) 121.80(11).
2
h -coordination of a C–C double bond of COD.23 We found that
this process has an energy barrier of 19.1 kcal mol-1 for the isolated
4
Pd(CH2CMe2-o-C6H4)(h -COD) complex but the presence of Br-
In an attempt to understand the mechanism of formation of
3a–b, the reaction was monitored in a NMR tube charged ◦with a
freshly prepared mixture of 1 and I in CDCl3 or C6D6, at 25 C. 1H
NMR spectra were collected every 10 min. Initial proton spectra
revealed resonance signals attributed to the formation of 3a, with
concomitant signals of unbound COD and unreacted 1 and I but
no intermediate species was detected. The reaction was completed
in one day and no significant differences were observed for both
of the solvents used in the NMR experiments.
PBI decreases this barrier to 15.6 kcal mol-1 (see Fig. 2).
Formation of Int1 is a prior condition that generates a coordi-
nation site which can then be occupied by Br-PBI even when an
earlier interaction of this last with palladium is not achieved yet
˚
at this stage (Br–Pd bond distance was 5.343 A and the nearest
˚
N–Pd bond was 4.681 A). The reaction proceeds through the C–Br
bond activation in TS2 with an energy barrier of 9.3 kcal mol-1
where mono-coordinated COD ligand rotates around palladium
into an equatorial position. A similar value of 11.6 kcal mol-1 was
calculated for a bis-triphenyl phosphine Pd complex activating
a C–Br bond.24 This transition state structure is characterized by
To gain further insight, a similar reaction was carried out
between 1 and Pd(CH2CMe2-o-C6H4)(PMe3)2 (II), in C6D6 at
25 ◦C. In this case, compound 2 was obtained after 5 min in
˚
˚
bond distances of C–Br, 2.239 A; Pd–Br, 2.664 A; and Pd–C, 2.222
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Fig. 2 Energy profile of the studied reaction mechanisms calculated at B3LYP/mix-basis level. Enthalpies are expressed as relatives energies with respect
to the reactant.
2
˚
A. The role of COD is still crucial since considering it as a leaving
group in this step raises the energy barrier up to 10.1 kcal mol-1.
This suggests that COD remains attached to the palladium center
filling a coordination site and conferring stability to the complex
when oxidative addition takes place leading to Int2 species.
This intermediate turns out to be the structure where the two
channels for reductive elimination diverge into both reaction
products, Prod_3a and Prod_3b. The pyridine ring can then be
found to be the h -COD-coordination, followed by an oxidative
reaction of the substrate through the C–Br bond giving a Pd(IV)
species. Finally an energetically favored selective intramolecular
C–C cross-coupling followed to give 3a–b. Further investigations
on the role of the substrate (2-halopyridines derivatives), the Pd(II)
complexes and the catalytic activation are underway.
Acknowledgements
2
2
coupled in two fashions: (1) Csp –Csp cross-coupling reaction
2
3
goes through the TS3 transition state, and (2) the Csp –Csp cross-
coupling reaction proceeds via the TS4 transition state, as shown
in Fig. 2. Both reactions are quite exothermic.
This research was supported by grants from the Universidad
de Guanajuato (UG-2008) and SEP/CONACYT (Me´xico) (02-
44420). J. O. C. J.-H. gratefully acknowledges the Carl Trygger
Foundation for support through postdoctoral fellowship (CTS-
09:144). J. N.-C. thanks the CONACYT for a doctoral fellowship
(329449).
Thus, TS3 cross-coupling leading to Prod_3a was favored over
TS4 which was converted into Prod_3b and the energy difference
of 2.4 kcal mol-1 is in excellent agreement with the experimental
findings. The reason behind this preference can be attributed to the
formation of a slightly more strained ring in TS4 when compared
to TS3. This might cause an elongation of Pd–C bonds to reach the
transition state condition for cross-coupling. In fact, by inspecting
the Int2 structure, we found that Pd–Csp (pyridine), Pd–Csp and
Pd–Csp bond distances are 1.993, 2.034, and 2.070 A, respectively.
A comparison with the activated bonds in TS3 (Pd–Csp (pyridine),
2.093 A, and Pd–Csp , 2.108 A) and TS4 (Pd–Csp (pyridine), 2.134
Notes and references
‡ Crystal data for 3a: C28H24BrN3Pd; Monoclinic, P 21/c, Fw = 588.81, a =
13.3675(7); b = 8.5040(4); c = 21.0854(11), b = 90.387(2), V = 2396.9(2), T =
2
2
3
100(2) K, Z = 4, Dc = 1.632 g cm-3, m = 2.463 mm-1, F (000) = 1176, qmax
=
˚
30.48◦, (-17 £ h £ 19, -12 £ k £ 12, -19 £ l £ 30), reflections collected 49938,
unique 7288 [Rint = 0.0241), final R indices [I > 2s(I)] were R1 = 0.0229,
wR2 = 0.0516, R indices (all data) R1 = 0.0294, wR2 = 0.0536, GOF = 1.078.
2
˚
˚
2
2
˚
˚
-3
3
˚
A, and Pd–Csp , 2.276 A), shows that those bond distances are
indeed longer in the latter structure.
Largest diff. peak and hole 0.875 and -0.632 e A .
1 (a) E. Carmona, E. Gutierrez-Puebla, J. M. Marin, A. Monge, M.
Paneque, M. L. Poveda and C. Ruiz, J. Am. Chem. Soc., 1989, 111,
2883; (b) J. Ca´mpora, J. A. Lo´pez, P. Palma, P. Valerga, E. Spillner and
E. Carmona, Angew. Chem., Int. Ed., 1999, 38, 147; (c) J. Ca´mpora, J.
A. Lo´pez, P. Palma, D. del R´ıo, E. Carmona, P. Valerga, C. Graiff and
A. Tiripicchio, Inorg. Chem., 2001, 40, 4116; (d) D. C. Griffiths and G.
B. Young, Organometallics, 1989, 8, 875.
In summary, we report an unusual C–Br bond activa-
tion of a 2-bromopyridine compound by the palladacycle
Pd(CH2CMe2-o-C6H4)(h -COD) under soft conditions. Mech-
anistic studies were performed using both computational and
experimental techniques in order to explain the experimental
results. DFT calculations showed that the reaction reported herein
follows a Pd(II)/Pd(IV) mechanism in which the key step was
4
2 (a) J. Campora, A. Llebaria, J. M. Moreto, M. L. Poveda and
E. Carmona, Organometallics, 1993, 12, 4032; (b) J. Campora, E.
12452 | Dalton Trans., 2011, 40, 12450–12453
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Gutierrez, A. Monge, P. Palma, M. L. Poveda, C. Ruiz and E. Carmona,
Organometallics, 1994, 13, 1728; (c) J. Campora, E. Gutierrez, A.
Monge, M. L. Poveda, C. Ruiz and E. Carmona, Organometallics,
1993, 12, 4025.
H. Salingue, Tetrahedron Lett., 2004, 45, 685; (c) S. Gronowitz, P.
Bjo¨rk, J. Malm and A.-B. Ho¨rnfeldt, J. Organomet. Chem., 1993, 460,
127.
11 (a) F. Tre´court, G. Breton, V. Bonnet, F. Mongin, F. Marsais and G.
Que´guiner, Tetrahedron Lett., 1999, 40, 4339; (b) P. Pierrat, P. Gros and
Y. Fort, Org. Lett., 2005, 7, 697.
12 (a) W. M. Seganish and P. DeShong, J. Org. Chem., 2004, 69, 1137;
(b) K. Tamao, S. Kodama, I. Nakajima, M. Kumada, A. Minato and
K. Suzuki, Tetrahedron, 1982, 38, 3347.
´
3 (a) J. Ca´mpora, P. Palma, D. del R´ıo, J. A. Lo´pez, E. Alvarez and N. G.
Connelly, Organometallics, 2005, 24, 3624; (b) J. Campora, P. Palma,
D. del Rio, J. A. Lopez and P. Valerga, Chem. Commun., 2004, 1490;
(c) J. Ca´mpora, P. Palma, D. del R´ıo, E. Carmona, C. Graiff and A.
Tiripicchio, Organometallics, 2003, 22, 3345.
4 (a) A. E. Kelly, S. A. Macgregor, A. C. Willis, J. H. Nelson and E.
Wenger, Inorg. Chim. Acta, 2003, 352, 79; (b) C. Arlen, M. Pfeffer, O.
Bars and D. Grandjean, J. Chem. Soc., Dalton Trans., 1983, 1535; (c) N.
Gu¨l, J. H. Nelson, A. C. Willis and A. D. Rae, Organometallics, 2002, 21,
2041; (d) F. Maassarani, M. Pfeffer and G. Le Borgne, Organometallics,
1987, 6, 2029; (e) J. Dupont, M. Pfeffer, in Palladacycles: Synthesis
Characterization and Applications Wiley, John & Sons, Weinhem,
Germany, 2008.
5 (a) J. Hassa, M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire, Chem.
Rev., 2002, 102, 1359; (b) J. S. Carey, D. Laffan, C. Thomson and M. T.
Williams, Org. Biomol. Chem., 2006, 4, 2337; (c) V. Bonnet, F. Mongin,
F. Tre´court, G. Breton, F. Marsais, P. Knochel and G. Que´quiner,
Synlett, 2002, 1008.
13 L.-C. Campeau, S. Rousseaux and K. Fagnou, J. Am. Chem. Soc., 2005,
127, 18020.
14 A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000, 122, 4020.
15 Y. Kawashita, N. Nakamichi, H. Kawabata and M. Hayashi, Org. Lett.,
2003, 5, 3713.
16 (a) X. Cui, J. Li, Z.-P. Zhang, Y. Fu, L. Liu and Q.-X. Guo, J. Org.
Chem., 2007, 72, 9342; (b) J. Xu, G. Cheng, D. Su, Y. Liu, X. Wang and
Y. Hu, Chem.–Eur. J., 2009, 15, 13105; (c) K. L. Billingsley and S. L.
Buchwald, Angew. Chem., Int. Ed., 2008, 47, 4695.
17 (a) B. Chiswell, F. Lions and B. S. Morris, Inorg. Chem., 1964, 3, 110;
(b) S. Haneda, Z. Gan, K. Eda and M. Hayashi, Organometallics, 2007,
26, 6551; (c) W. Chen, C. Xi and Y. Wu, J. Organomet. Chem., 2007,
692, 4381.
6 L.-C. Campeau and K. Fagnou, Chem. Soc. Rev., 2007, 36, 1058.
7 I. J. S. Fairlamb, Chem. Soc. Rev., 2007, 36, 1036.
18 H. C. Malinakova, Top. Organomet. Chem., 2011, 503, 85.
19 (a) G. Maestri, E. Motti, N. Della Ca’, M. Malacria, E. Derat and M.
Catellani, J. Am. Chem. Soc., 2011, 133, 8574; (b) D. J. Ca´rdenas, B.
Mart´ın-Matute and A. M. Echavarren, J. Am. Chem. Soc., 2006, 128,
5033; (c) M. Catellani, E. Motti and N. Della Ca’, Acc. Chem. Res.,
2008, 41, 1512.
20 We used Gaussian03 computational package for exploring the potential
energy surface of this reaction by means of the so-called hybrid B3LYP
functional in combination with LANL2TZ+f and 6-311+G(2d,2p)
basis sets (referred as mix-basis). Energies were corrected with sol-
vent effects and by adding long-range DFT-D correction known as
dispersion effects. For further details, the reader is referred to the ESI†.
21 (a) K. Muniz, Angew. Chem., Int. Ed., 2009, 48, 9412; (b) H. Zhang and
A. Lei, Dalton Trans., 2011, 40, 8745.
8 (a) S. Gronowitz, P. Bjo¨rk, J. Malm and A.-B. Ho¨rnfeldt, J. Organomet.
Chem., 1993, 460, 127; (b) M. Reuman, S. J. Daum, B. Singh, M. P.
Wentland, R. B. Perni, P. Pennock, P. M. Carabateas, M. D. Gruett,
M. T. Saindane, P. H. Dorff, S. A. Coughlin, D. M. Sedlock, J. B. Rake
and G. Y. Lesher, J. Med. Chem., 1995, 38, 2531; (c) M. P. Wentland,
R. B. Perni, P. H. Dorff, R. P. Brundage, M. J. Castaldi, T. R. Bailey,
P. M. Carabateas, E. R. Bacon, D. C. Young, M. G. Woods, D. Rosi,
M. L. Drozd, R. K. Kullnig and F. J. Dutko, J. Med. Chem., 1993, 36,
1580.
9 (a) A. Bouillon, J.-C. Lancelot, V. Collot, P. R. Bovy and S. Rault,
Tetrahedron, 2002, 58, 2885; (b) P. R. Parry, C. Wang, A. S. Batsanov, M.
R. Bryce and B. Tarbit, J. Org. Chem., 2002, 67, 7541; (c) A. Bouillon,
J.-C. Lancelot, V. Collot, P. R. Bovy and S. Rault, Tetrahedron, 2002,
58, 4369; (d) A. Bouillon, J.-C. Lancelot, V. Collot, P. R. Bovy and S.
Rault, Tetrahedron, 2002, 58, 3323; (e) P. R. Parry, M. R. Bryce and B.
Tarbit, Synthesis, 2003, 7, 1035.
22 G. Bocelli, M. Catellani and S. Ghelli, J. Organomet. Chem., 1993, 458,
C12–C15.
23 P. Gigler, B. Bechlars, W. A. Herrmann and F. E. Ku¨hn, J. Am. Chem.
Soc., 2011, 133, 1589.
10 (a) A. S. B. Prasad, T. M. Stevenson, J. R. Citineni, V. Nyzam and
P. Knochel, Tetrahedron, 1997, 53, 7237; (b) P. B. Hodgson and F.
24 C. Mollar, M. Besora, F. Maseras, G. Asensio and M. Medio-Simo´n,
Chem.–Eur. J., 2010, 16, 13390.
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The Royal Society of Chemistry 2011
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©