Design and development of a new chelating bis(phosphinite)-based palladium(II) catalyst and its application to the heck reaction

Article abstract of DOI:10.1055/s-2007-970750

A new sterically demanding and bulky bis(phosphinite) ligand derived from salicylaldehyde and 2-amino-3-hydroxy pyridine and its palladium(II) complex has been synthesized and characterized. The utility of this palladium complex has been demonstrated in the Heck reaction between a variety of aryl halides and olefin substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970750

LETTER
757
Design and Development of a New Chelating Bis(phosphinite)-Based
Palladium(II) Catalyst and Its Application to the Heck Reaction
Development of
a
.
Ne
w
Chelati
D
ngBis
(
phosphinite
.
)-Base
d
Palla
P
dium(II)
C
ata
a
lyst thak,*a H. Maheswaran,*b K. Leon Prasanth,b M. Lakshmi Kantamb
a
Department of Applied Chemistry, Indian School of Mines, Dhanbad 826 004, India
b
Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
Fax +91(40)27160921; E-mail: maheswaran_dr@yahoo.com
Received 10 October 2006
chemistry employing both palladium colloids and palladi-
um acetate is of limited scope; in particular, they are not
good catalysts for the Heck reaction involving unactivated
aryl chlorides and unactivated aryl bromides as substrates.
Abstract: A new sterically demanding and bulky bis(phosphinite)
ligand derived from salicylaldehyde and 2-amino-3-hydroxy
pyridine and its palladium(II) complex has been synthesized and
characterized. The utility of this palladium complex has been de-
monstrated in the Heck reaction between a variety of aryl halides In this case, the palladium catalysts based on special
and olefin substrates.
ligands (bulky electron-rich phosphines or NHCs) are
essential and should be used to effect the Heck reaction
Key words: palladium, Heck reaction, phosphorus, alkenes, cross-
coupling
reliably under mild conditions.11,12
OH
N
HO
The Heck reaction,1 essentially a palladium-catalyzed
cross-coupling of an aryl halide with an olefin
(Scheme 1), is one of the most versatile methods for car-
bon–carbon bond formation in the armoury of an organic
chemist, giving access to a wide range of olefin products
owing to its broad functional group tolerance.2,3
OH
OH
+
stirring, 16 h
EtOH
N
CHO
N
NH2
1
NaBH4 MeOH
reflux
P
P
O
O
OH HO
2 (C6H11)2PCl
Et3N, THF
N
N
N
H
N
H
2
R
R
"Pd"
+
Base·HX
+
Ar–X
Base
3
CH2Cl2
Pd(MeCN)2Cl2
Cl
Ar
Scheme 1
Cl
Pd
P
P
A variety of ligands such as electron-rich phosphines,4 N-
heterocyclic nucleophilic carbenes (NHCs),5 phosphinite-
based PCP pincer ligands6 and iminophosphines having
phosphorus–nitrogen and carbon–nitrogen architectures7
have been used as ligands for effecting the Heck reaction.
In addition, phosphine-containing palladacycles8 and
phosphine-free palladacycles9 as well as ligand-free palla-
dium (palladium acetate)10 have also been employed for
the Heck reaction. Nevertheless, it has been shown ele-
gantly by de Vries and Beletskaya et al. that in most Heck
reactions at high temperatures, certainly above 120 °C, the
palladium catalyst, irrespective of the nature of its precur-
sor, is rapidly reduced to metallic Pd(0) which has a
strong tendency to form soluble colloids.11,12 It has been
shown conclusively that palladium nanoparticles, that are
present in these colloids, catalyze the Heck reaction.
Thus, there is no obvious advantage in the application of
palladacycles, or any palladium complexes as compared
to palladium acetate. However, such phosphine-free
O
O
N
N
H
4
Scheme 2 Synthesis of the complex {Pd[bis(phosphinite)]–Cl2}, 4
We present a new sterically demanding and electron-rich
bis(phosphinite) ligand and its Pd(II) complex for use in
the Heck reaction. The new ligand, N-[2-(dicyclo-
hexylphosphinooxy)benzyl]-3-(dicyclohexylphosphino-
oxy)pyridine-2-amine (3) was readily accessible in three
steps as depicted in Scheme 2. The first step involves con-
densation of salicylaldehyde with 2-amino-3-hydroxy-
pyridine to form the corresponding Schiff base 1. In step
2, this compound was reduced to its corresponding amine
form 2, an off-white solid, using sodium borohydride in
methanol, so as to impart flexibility to the backbone.
Finally, the bis(phosphinite) ligand 3 was then isolated as
a white crystalline solid by reacting 2 with chlorodicyclo-
hexylphosphine in tetrahydrofuran in the presence of two
equivalents of triethylamine. The ligand 3 was then
reacted with [Pd(MeCN)2Cl2] in dichloromethane to yield
SYNLETT 2007, No. 5, pp 0757–0760
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970750; Art ID: D29506ST
© Georg Thieme Verlag Stuttgart · New York

758
D. D. Pathak et al.
LETTER
{Pd[bis(phosphinite)]Cl2} 4, as a pale-yellow crystalline 4-iodoanisole with various olefin substrates including
solid. All compounds 1–4 were fully characterized by a acrylonitrile, styrene, and 4-methylstyrene (Table 1, en-
combination of several spectroscopic techniques.13
tries 1–4). Thus, this reaction is very tolerant of reactive
or sensitive functional groups such as nitrile and ester.
However, aryl bromide substrates required a slightly
higher temperature range (115–120 °C) to afford the cor-
responding Heck products in good yields (Table 1, entries
5–12). As can be seen in Table 1, the reaction proceeded
smoothly with unactivated aryl bromides such as bromo-
benzene (Table 1, entries 9–12) and is tolerant of reactive
acetyl groups as well (Table 1, entries 5–8). It is to be
noted that during the course of the reaction, the color of
the solution remained yellow, which is the characteristic
color of the Pd(II) complex. Thus, it is less likely that
neither Pd nanoparticles nor Pd(0) colloids formed in the
reaction could have played a major role in effecting the
Heck reactions involving aryl iodides and aryl bromides
as substrates. Finally, as a test to evaluate the efficiency of
the catalyst 4 in promoting the Heck reaction, very inert
chlorobenzene was evaluated as a substrate by employing
conditions similar to those employed for aryl bromides.
As anticipated, the reaction of chlorobenzene with styrene
gave no product in the temperature range 115–120 °C.
However, at 130 °C, when neat non-aqueous ionic liquid
(NAIL) Bu4NBr was used as solvent with tri-n-butyl-
amine as base, we observed that chlorobenzene could be
activated in the reaction with styrene to afford trans-
stilbene in 20% yield (Table 1, entry 13).
Complex 4 was first screened for its activity in the Heck
reaction between 4-iodoanisole and methyl acrylate in a
number of solvents including DMSO, MeCN, NMP, and
DMF using tri-n-butylamine as a base. For these screen-
ing studies we initially used 10 mol% of complex 4 (rela-
tive to the substrate) as catalyst. Of the solvents screened
the best results were obtained in DMF, which gave the de-
sired Heck product in six hours and 90% yield (Table 1,
entry 1 in parenthesis). Encouraged by this result, we re-
duced the loading of the catalyst to 5 mol% and observed
that the reaction was complete within ten hours, giving the
product in 86% yield (Table 1, entry 1). However, further
reduction in the catalyst amount to 2 mol%, increased the
reaction time to almost 30 hours; thus, further studies
were carried out using 5 mol% of complex 4 relative to the
substrate. With optimized conditions in hand, the scope of
the reaction was explored (Table 1).
In general, good yields of Heck products were obtained
at 85–90 °C using DMF as the solvent for the reaction of
Table 1 Heck Reaction Between Alkenes and Aryl Halides
Catalyzed by 4a,14
R2
X
catalyst
R2
+
DMF, ∆
R1
R1
In conclusion, we have synthesized and characterized a
new bis(phosphinite) ligand and its Pd(II) complex. We
have shown this complex is an efficient catalyst in the
Heck reaction. To the best of our knowledge, this is the
first report of a palladium(II)bis(phosphinite) complex
catalyzing the Heck reaction of a very unreactive substrate
(chlorobenzene) although moderate yields were obtained
for the corresponding Heck product.
Entry R1
X
I
R2
Time (h) Yield (%)b
1
2
OMe
COOMe
CN
10 (6)
12
86 (90)
82
OMe
OMe
OMe
Ac
Ac
Ac
Ac
H
I
3
I
Ph
28
89
4
I
4-tolyl
Ph
28
84
5
Br
Br
Br
Br
Br
Br
Br
Br
Cl
30
70c
83c
86c
81c
74c
72c
69c
71c
20d
Acknowledgment
6
4-tolyl
COOMe
CN
24
K.L.P. thanks both IICT & CSIR, New Delhi, for the award of a
Junior Research Fellowship. D.D.P. wishes to thank the Indian
National Science Academy (INSA), New Delhi for the award of a
Visiting Fellowship, the Director, Indian School of Mines, Dhanbad
for sanctioning the leave, and the Director, Indian Institute of
Chemical Technology, Hyderabad for providing the necessary
research facilities.
7
16
8
18
9
COOMe
CN
17
10
11
12
13
H
19
H
Ph
22
References and Notes
H
4-tolyl
Ph
22
(1) (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518. (b)Heck,
R. F. Palladium Reagents in Organic Syntheses; Academic
Press: London, 1985.
H
36
a Reaction conditions: Haloarene (0.50 mmol), alkene substrate
(0.60 mmol), n-Bu3N (0.60 mmol), catalyst (0.025 mmol, 5 mol%),
85–90 °C, DMF. Values in parenthesis indicate yield and time with
10 mol% catalyst.
(2) For reviews on Heck Reactions, see: (a) Shibakashi, M.;
Vogl, E. M.; Oshima, T. Adv. Synth. Catal. 2004, 346, 1533.
(b) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004,
1559. (c) Whitcombe, N. J.; Hii, K. K. M.; Gibson, S. E.
Tetrahedron 2001, 57, 7449. (d) Beletskaya, I. P.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (e) Crisp,
G. T. Chem. Soc. Rev. 1998, 27, 427. (f) Heck, R. F. Acc.
Chem. Res. 1979, 12, 146. (g) Heck, R. F. Org. React. 1982,
27, 345.
b Isolated yields after column chromatography. All products were
fully characterized by 1H NMR.
c 115–120 °C, DMF.
d n-Bu3N, TBAB, 130 °C.
Synlett 2007, No. 5, 757–760 © Thieme Stuttgart · New York

LETTER
Development of a New Chelating Bis(phosphinite)-Based Palladium(II) Catalyst
759
(3) For recent work on Heck reactions, see: (a) Hagiwara, H.;
Sugawara, Y.; Hoshi, T.; Suzuki, T. Chem. Commun. 2005,
2942. (b) Calo, V.; Nacci, A.; Monopoli, A.; Leva, E.;
Cioffi, N. Org. Lett. 2005, 7, 617. (c) Mukhopadhyay, S.;
Rothenberg, G.; Joshi, A.; Baidossi, M.; Sasson, Y. Adv.
Synth. Catal. 2002, 344, 348. (d) Pröckl, S. S.; Kleist, W.;
Gruber, M. A.; Köhler, K. Angew. Chem. Int. Ed. 2004, 43,
1881. (e) Riina, K.; Nicholas, A. E. L. J. Org. Chem. 2004,
70, 1786. (f) Yao, Q.; Kinney, E. P.; Zheng, C. Org. Lett.
2004, 6, 2997. (g) Choudary, B. M.; Madhi, S.; Chowdari,
N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002,
124, 14117.
(4) (a) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc.
2002, 124, 6343. (b) Littke, A. F.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 6989. (c) Stambulli, J. P.; Stuffer, S. R.;
Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 2677. (d) Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J.
Am. Chem. Soc. 1999, 121, 2123.
2-(2-Hydroxybenzylamino)pyridine-3-ol (2): To a stirred
brick-red suspension of Schiff’s base (1, 2.95 g, 13.8 mmol)
in MeOH (40 mL), solid NaBH4 (2.47 g, 65.3 mmol) was
added in small portions gradually over a period of 4 h to give
an almost colorless solution. The reaction mixture was
quenched with cold H2O, the product extracted with CH2Cl2
(3 × 75 mL) and dried over anhydrous Na2SO4. Removal of
the solvent under reduced pressure afforded the desired
compound as an off-white crystalline solid (1.96 g, 66%);
mp 108–110 °C; 1H NMR (300 MHz, CDCl3): d = 7.60 (d,
J = 6 Hz, 1 H, Ar-H), 7.26–7.17 (m, 2 H, Ar-H), 6.79–6.74
(m, 3 H, Ar-H), 6.42–6.35 (m, 1 H, Ar-H), 5.58 (unresolved
m, 1 H, NH), 4.47 (d, J = 6 Hz, 2 H, CH2); IR (KBr): 3415
(n OH + n NH merging), 3058 (n C–H Ar), 2925 (n C–H
aliphatic), 1621 (s), 1579 (w), 1518 (s), 1452 (m), 1352 (w),
1255 (s), 1185 (m), 1105 (m), 1039 (m), 848 (w), 755 (s),
580 (w), 534 (w) cm–1; MS (EI+): m/z [M+] calcd for
C12H12N2O2: 216.23; found: 216.
(5) (a) Herrmann, W. A.; Böhm, V. P. W.; Reisinger, C. P. J.
Organomet. Chem. 1999, 576, 23. (b) Weskamp, T.; Böhm,
V. P. W.; Herrmann, W. A. J. Organomet. Chem. 2001, 585,
348.
(6) Morales-Morales, D.; Redon, R.; Yumg, C.; Jensen, C. M.
Chem. Commun. 2000, 1619.
N-[2-(Dicyclohexylphosphinooxy)benzyl]-3-
(dicyclohexylphoshinooxy)pyridin-2-amine (3): Diol (2,
290 mg, 1.34 mmol) and chlorodicyclohexylphosphine (623
mg, 2.68 mmol) were dissolved in freshly distilled dry THF
(40 mL) under high-purity nitrogen. To this suspension at
r.t., a THF solution (5 mL) of Et3N (272 mg, 2.69 mmol) was
added dropwise over a period of 30 min via a syringe.
Immediately, a white precipitate formed. The reaction
mixture was stirred at r.t. overnight, filtered under nitrogen
and the solvent was removed under reduced pressure to give
a colorless sticky compound. Trituration with n-pentane (10
mL) initiated the formation of a white precipitate which was
filtered and dried under vacuum to yield the desired ligand
(334 mg, 41%); mp 126–128 °C; 1H NMR (300 MHz,
CDCl3): d = 7.58 (d, J = 6 Hz, 1 H, Ar-H), 7.18–7.05 (m, 2
H, Ar-H), 6.90–6.70 (m, 3 H, Ar-H), 6.45–6.38 (m, 1 H, Ar-
H), 5.82 (unresolved m, 1 H, NH), 4.50 (d, J = 6 Hz, 2 H,
CH2); 31P [1H] NMR (162 MHz, CDCl3): d = 70.58 (s); IR
(KBr): 3387 (n NH), 3061 (n Ar C–H), 2926 and 2847 (n
C–H antisymmetric and symmetric of c-Hex), 1613 (s), 1585
(w), 1524 (s), 1445 (m), 1346 (w), 1254 (s), 1183 (m), 1118
(m), 1068 (w), 999 (w), 960 (w), 939 (w), 887 (m), 844 (w),
752 (m), 723 (w), 695 (w), 593 (w), 511 (m), 485 (w);
MS(FAB): m/z [M+] calcd for C36H54N2O2P2: 608; found:
443 [M+1n – 2 × C6H11].
(7) Schultz, T.; Schmees, N.; Pfaltz, A. Appl. Organometal.
Chem. 2004, 18, 595.
(8) Herrmann, W. A.; Brossmer, C.; Reisinger, C. P.; Riermeier,
T. H.; Ofele, K.; Beller, M. Chem. Eur. J. 1997, 3, 1357.
(9) Ohff, M.; Ohff, A.; Milstein, D. Chem. Commun. 1999, 357.
(10) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Jeffery, T. J.
J. Chem. Soc., Chem. Commun. 1984, 1287. (c) Jeffery, T.
In Advances in Metal-Organic Chemistry 5; Liebeskind, L.
S., Ed.; Jai Press Inc.: London, 1996, 153. (d) de Vries, A.
H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.;
Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5,
3285. (e) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004,
1559.
(11) de Vries, J. G. J. Chem. Soc., Dalton Trans. 2006, 421.
(12) Beletskeya, I. P.; Cheprakov, A. V. J. Organomet. Chem.
2004, 689, 4055.
(13) All chemicals were obtained from commercial sources and
used without further purification. All solvents were dried
and distilled prior to use according to literature procedures.
All known compounds were characterized by comparing
their physical data with those in the literature. FT–IR spectra
were recorded on a Perkin–Elmer spectrophotometer using
KBr discs. 1H NMR spectra were recorded on a Bruker (300
MHz) spectrophotometer using CDCl3 as solvent and TMS
as the internal standard. 31P[1H] NMR were recorded on a
Bruker 400 MHz instrument using 85% H3PO4 as an internal
standard. FAB(MS) was obtained using a VG-AUTOSPEC
Micromass (UK) equipment using MNBA as matrix.
(Z)-2-(2-Hydroxybenzlideneamino)pyridine-3-ol (1):
2-Amino-3-hydroxypyridine (2.11 g, 19.16 mmol) and
salicylaldehyde (2.34 g, 19.16 mmol) in EtOH (60 mL) were
stirred for 16 h at r.t. to give a brick-red suspension. The
reaction mixture was concentrated (20 mL) and filtered
under vacuum, washed with n-hexane and dried to afford a
brick-red powder (2.96 g, 72%); mp 180 °C; 1H NMR (300
MHz, CDCl3): d = 9.42 (s, 1 H, CH=N, pyridine), 8.03 (d,
J = 6 Hz, 1 H, N=CH), 7.55–6.93 (overlapping m, 6 H, Ar-
H); IR (KBr): 3442 (n OH), 3048 (n C–H), 2924 (n C–H
aliphatic), 1620 (n C=N– aliphatic), 1570 (C=N– of C5H5N),
1528 (m), 1458 (s), 1287 (m), 1182 (s), 1133 (m), 1091 (m),
1024 (w), 905 (w), 764 (m), 546 (m), 477 (w) cm–1; MS
(EI+): m/z [M+] calcd for C12H10N2O2: 214.23; found: 214.
Dichloro{N-[2-(dicyclohexylphosphinooxy)benzyl]-3-
(dicyclohexylphoshinooxy)pyridin-2-
amine}palladium(II) (4): To a solution of [Pd(MeCN)2Cl2]
(125 mg, 0.48 mmol)in CH2Cl2 (15 mL), the bis(phos-
phinite) ligand (294 mg, 0.48 mmol) was added under a
nitrogen atmosphere. The resultant orange solution was
stirred for 2 h at r.t. to give a brown solution. The solution
was filtered through celite, concentrated (5 mL) and PE (40–
60 °C fraction; 5 mL) was added to precipitate the product
as a pale yellow crystalline solid (330 mg, 87%); 1H NMR
(300 MHz, CDCl3): d = 7.90–6.60 (m, 7 H, Ar-H), 4.65 (d,
J = 6 Hz, 2 H, CH2), 2.60–0.95 (m, 44 H, 4 × C6H11); 31P[1H]
NMR (162 MHz, CDCl3): d = 112.84 (s); IR (KBr): 3382 (n
NH), 3059 (n Ar C–H), 2927 and 2850 (n C–H antisym-
metric and symmetric of c-Hex), 2312 (w), 1735 (w) (s),
1590 (m), 1520 (w), 1446 (s), 1347 (w), 1248 (m), 1211 (w),
1176 (w), 1112 (w), 1043 (w), 1005 (w), 970 (w), 919 (w),
887 (w), 849 (w), 818 (w), 753 (m), 570 (w), 527 (w), 448
(w), 408 (w) cm–1; MS(FAB): m/z [M+] calcd for
C36H54N2O2Cl2P2Pd: 785; found: 750 [M+1n – Cl], 553
[M+1n – Cl–PCy2].
Synlett 2007, No. 5, 757–760 © Thieme Stuttgart · New York

760
D. D. Pathak et al.
LETTER
(Table 1). After completion, the reaction mixture was
diluted with H2O, the product was extracted with EtOAc
(3 × 10 mL) and the resultant organic layer was dried over
anhydrous Na2SO4. After removal of the solvent, the residue
was subjected to column chromatographic separation on
silica gel using EtOAc and hexane mixtures to afford the
Heck product in high purity.
(14) General Procedure for the Heck Reaction: Aryl halide
(0.50 mmol), olefinic substrate (0.60 mmol), n-Bu3N (0.60
mmol) and catalyst (0.025 mmol, 5 mol%) were placed
sequentially in a two-necked Schlenk flask, followed by the
addition of DMF (2 mL), under a nitrogen atmosphere. The
reaction mixture was stirred, gradually allowed to warm to
ambient temperature for the specified reaction time
Synlett 2007, No. 5, 757–760 © Thieme Stuttgart · New York

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