Biaryl formation from 5-(2-bromobenzyl)-substituted piperidin-2-ones via palladacycles

Article abstract of DOI:10.1021/ol800330d

(Chemical Equation Presented) The reaction of piperdin-2-ones with a 2-bromobenzyl substituent in the 5-position in the presence of a palladium catalyst leads to biaryl compounds. Their formation can be explained via initial C-H insertion of the aryl pall

Full text of DOI:10.1021/ol800330d

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2361-2364
Biaryl Formation from
5-(2-Bromobenzyl)-Substituted
Piperidin-2-ones via Palladacycles
Gedu Satyanarayana and Martin E. Maier*
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen, Auf der Morgenstelle 18,
72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received February 13, 2008
ABSTRACT
The reaction of piperdin-2-ones with a 2-bromobenzyl substituent in the 5-position in the presence of a palladium catalyst leads to biaryl
compounds. Their formation can be explained via initial C-H insertion of the aryl palladium species into the allylic C-H bond of the piperidinone.
This eventually leads to a metallacycle containing Pd(II) that inserts another aryl bromide, promoting the formation of the biaryl bond.
Transition-metal catalysis allows transformations on organic
substrates that are otherwise not possible or difficult to
achieve. One of the prominent metals in this regard is
palladium which is used for hydrogenations and cross-
coupling reactions. Some classical cross-coupling reactions
mediated by palladium are the Heck,1 Stille,2 Suzuki,3 and
Sonogashira4 coupling. Furthermore, in recent years, C-H
insertion reactions via organopalladium intermediates have
enriched the repertoire of methods for organic synthesis. The
Heck reaction is characterized by the insertion of an alkene
into a Pd-C bond. Commonly, alkenes with an electron-
withdrawing substituent are used in a Heck reaction.5,6
However, terminal alkenes or even electron-rich alkenes,
such as enol ethers and enamides, have been employed as
well. Generally, enamides undergo coupling with the carbon
next to the nitrogen atom with an organopalladium species.
In connection with the synthesis of annulated ring systems,
we planned to implement an intramolecular Heck reaction
on an aryl bromide of type A (Scheme 1). Accordingly,
insertion7–9 of the enamide double bond into the aryl-Pd bond
of B should eventually lead to D or a double-bond isomer
thereof. However, the expected products such as D were not
observed. In this paper, we show that 5-(2-bromobenzyl)-
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A. J. Org. Chem. 2003, 68, 6639–6645. (b) Harrison, P.; Meek, G.
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.
10.1021/ol800330d CCC: $40.75
Published on Web 05/21/2008
2008 American Chemical Society

Scheme 1
.
Intended Annulation Reaction Using Cyclic
Enamides
Table 1. Yields for the Transformations Leading to
Piperidinones 5a-f
coupling
step (%)
Michael
addition (%)
cyclization
to enamide (%)
R1
R2
H
H
H
OMe
OMe
H
H
Me
CO2Me
H
OMe
OMe
2a(80)
2b(70)
2c(75)
2d(70)
2e(70)
2f (74)
4a(75)
4b(72)
4c(72)
4d(73)
4e(73)
4f (64)
5a(85)
5b(78)
5c(79)
5d(83)
5e(85)
5f (89)
substituted-3,4-dihydro-2(1H)-pyridinones, which contain a
cyclic enamide function, enter into a completely different
pathway in presence of a palladium catalyst.
ously,16 the 4-formyl esters provide piperidinones by reduc-
tiveaminationwithbenzylamineandsodiumcyanoborohydride.
If the less powerful reducing agent sodium triacetoxy boro-
hydride was employed, the piperidinones were accompanied
by the cyclic enamide. If the reducing agent was omitted and
the formyl esters were simply reacted with benzylamine in
refluxing dichloroethane, the cyclic enamides 5a-f were the
sole product. The yields for the individual steps of the sequence
shown in Scheme 2 are listed in Table 1.
The required substrates were easily prepared from bro-
moiodobenzenes10–13 1a-f (Scheme 2, Table 1). Via
Scheme 2. Synthesis of the Cyclic Enamides 5a-f via Heck
Coupling, Michael Addition of the Enamines 3a-f to Ethyl
Acrylate and Cyclization of the 4-Formyl Esters 4a-f with
Benzylamine
In an attempt to perform a palladium-catalyzed ring
annulation reaction, the 5-(2-bromobenzyl)-substituted py-
ridinone 5a was stirred with Pd(OAc)2 (0.1 equiv), Ph3P (0.2
equiv), and Cs2CO3 (4 equiv) in hot DMF (Table 2, entry
1). After 24 h, some starting material was left, but two new
compounds 7a and 8a were isolated. The base K2CO3 gave
almost the same results (25% 5a, 21% 7a, 41% 8a). Longer
reaction times (entry 2) also produced some of the debro-
minated pyridinone 6a. The highest yield for the biaryl
compound 8a was obtained by running the reaction at higher
temperature for 48 h (entry 3). Comparable ratios of the three
compounds 6a-8a were obtained using HMPA as solvent
(entry 4). Using binap as ligand, and K2CO3 as base, the
amount of the simple debromination product 6a increased
at the expense of 7a and 8a (entry 5). The sterically hindered
and electronrich Buchwald phosphine ligand N-[2′-(dicyclo-
hexylphosphino)-1,1′-biphenyl-2-yl]-N,N-dimethylamine (dav-
ephos) also favored the debrominated compound 6a (entry
6). Among the dipolar solvents, DMF turned out to be the
best one. In DMSO, the formation of the biaryl compound
is suppressed with the 1,5-dibenzyl-2(1H)-pyridinone (7a)
being the major product (entry 7). The palladium source may
also be varied without significant changes in the product
ratios as illustrated with entries 8 and 9.
Jeffery-Heck coupling14 with allyl alcohol, these aryl
iodides were extended to 3-(2-bromo)phenylpropanals 2a-f.
The obtained aldehydes 2a-f were then converted to the
corresponding enamines using pyrrolidine in presence of
K2CO3. Treatment of the crude enamines with ethyl acrylate
followed by acidic workup furnished the 4-formyl esters
4a-f.15 These modified conditions are a significant improve-
ment over the previously reported ones. As shown previ-
The formation of pyridin-2(1H)-one 7a and the biphenyl-
substituted pyridinone 8a can only be explained by C-H
insertion of the arylpalladium species E into the allylic C-H
bond, yielding palladacycle F (Scheme 3). Via elimination of
(8) (a) For some intramolecular Heck reactions of enamide containing
substrates, see: Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595–602.
(b) Padwa, A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem. 2001, 66,
1716–1724. (c) Arthuis, M.; Pontikis, R.; Florent, J.-C. Tetrahedron Lett.
2007, 48, 6397–6400.
(9) For the Heck reaction using pyrroles, see: Beck, E. M.; Grimster,
N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528–2529.
(10) (a) Compound 1b: Bard, R. R.; Bunnett, J. F.; Traber, R. P. J.
Org. Chem. 1979, 44, 4918–4924. (b) van Klink, G. P. M.; de Boer, H. J. R.;
Schat, G.; Akkerman, O. S.; Bickelhaupt, F.; Spek, A. L. Organometallics
(12) Compound 1d: Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 12202–12206.
(13) Compound 1e, 1f: Orito, K.; Hatakeyama, T.; Takeo, M.; Suginome,
H. Synthesis 1995, 127, 3–1277.
(14) (a) Jeffery, T. Tetrahedron Lett. 1991, 32, 2121–2124. (b) Wolfe,
J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525–7546.
(c) Tietze, L. F.; Kahle, K.; Raschke, T. Chem. Eur. J. 2002, 8, 401–407.
(d) Bruye`re, D.; Bouyssi, D.; Balme, G. Tetrahedron 2004, 60, 4007–4017.
(15) Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheehan, S. M. J.
Org. Chem. 1997, 62, 78–87.
2002, 21, 2119–2135
.
(11) Compound 1c: Vu, C. B.; Corpuz, E. G.; Merry, T. J.; Pradeepan,
S. G.; Bartlett, C.; Bohacek, R. S.; Botfield, M. C.; Eyermann, C. J.; Lynch,
B. A.; MacNeil, I. A.; Ram, M. K.; van Schravendijk, M. R.; Violette, S.;
Sawyer, T. K. J. Med. Chem. 1999, 42, 4088–4098.
2362
Org. Lett., Vol. 10, No. 12, 2008

G could undergo a ꢀ-elimination to give the palladium
hydride J. Expulsion of Pd(0) would lead to the pyridin-
2(1H)-one 7a. Formation of the pyridin-2(1H)-one 7a could
also occur via reductive elimination from F followed by
elimination of PdHBr from the pyridinone intermediate.
The mechanism suggested in Scheme 3 is reminiscent of
the classical Catellani process where an initial arylpalladium
species inserts norbornene which allows a subsequent formal
C-H insertion to produce a palladacycle [Pd(II)] that is ready
for further coupling reactions.20–24
Table 2. Reaction of the Piperidinone 5a with Pd(OAc)2, Base,
and Ph3P under Various Conditions
In all, the conditions found in entry 3 of Table 2 turned
out to be the best with regard to the yield of biaryl compound
8a. Therefore, these conditions were applied to the other
enamides 5b-f from Scheme 1. Thus, the enamides were
reacted in presence of Pd(OAc)2 (0.1 equiv), PPh3 (0.2
equiv), and Cs2CO3 (4 equiv) in DMF for 48 h at 100 or
120 °C. As can be seen from Table 3, the biaryl derivatives
8 were formed in yields ranging from 35-48%. With the
byproducts 6 and 7 taken into consideration the mass balance
is quite good. The pyridine derivatives 7 show a characteristic
doublet (3-H) at around 6.5 ppm. In the dimers 8, the
corresponding signal (J ) 9.4 Hz) appears at slightly higher
field, typically at around 6.4 ppm. In all cases of Table 3,
the crude reaction mixture contains some triphenylphosphine
oxide as an impurity. For entries 3 and 5 (8c and 8e) it is
easily removed during chromatography. With biaryls 8a and
8b this separation is more difficult. However, for these
compounds the Buchwald ligand N-[2′-(dicyclohexylphos-
phino)-1,1′-biphenyl-2-yl]-N,N-dimethylamine (0.2 equiv)
may be used instead of Ph3P. Then the biaryl compounds
can be separated from phosphine oxide impurities, even
though the yields are slightly lower. For entries 4 and 6 (8d
and 8f), the Ph3PdO impurity can be removed almost
completely. In these cases, the impurity from the Buchwald
ligand coelutes with the biaryl products.
entry solvent T (°C) time (h) 6a (%) 7a (%) 8a (%)
1a
2b
3
DMF
DMF
DMF
HMPA
DMF
DMF
DMSO
DMF
DMF
100
100
120
140
120
120
120
120
120
12
24
48
48
48
48
48
48
48
24
20
30
21
15
16
26
28
24
43
42
48
47
16
28
9
17
10
15
24
25
23
12
14
4
5c
6d
7
8e
9f
46
42
a Recovered starting material ) 25%. b Recovered starting material )
7%. c binap (0.15 equiv) was used as ligand. d N-[2′-(Dicyclohexyl-
phosphino)-1,1′-biphenyl-2-yl]-N,N-dimethylamine (0.2 equiv) was used
as ligand. e Pd(PPh3)2Cl2 (10 mol %) as catalyst, without additional Ph3P.
f Pd(PPh3)4 (10 mol %).
H-Br the reactive palladium species G might form.17 The key
palladacycle G could undergo insertion into the C-Br bond of
a second molecule of 5a leading to the Pd(IV) complex H.18,19
Reductive elimination should lead to formation of the biaryl
bond providing intermediate I. Elimination of PdHBr would
complete the catalytic cycle. As another option, palladacycle
Scheme 3
.
Proposed Mechanisms Explaining the Formation of
The insertion of the palladium (cf. E, Scheme 3) into the
allylic C-H bond of the pyridinone ring only seems to occur
due to the lack of other reagents (Scheme 4). In a control
experiment, the reaction of aryl bromide 5b was run under
identical conditions (see Table 3) but with added ethyl
acrylate (2 equiv). In this case, the normal Heck product 9
turned out to be the major product (48%) along with some
debrominated 6b (25%).
6a-8aa
In summary, we could demonstrate the facile synthesis of
5-substituted 3,4-dihydro-1H-pyridin-2-ones from easily ac-
(16) Satyanarayana, G.; Maier, M. E. Tetrahedron 2008, 64, 356–363.
(17) For a review about palladacycles, see: Dupont, J.; Consorti, C. S.;
Spencer, J. Chem. ReV. 2005, 105, 2527–2571.
(18) (a) For the chemistry of Pd(IV) complexes, see: Canty, A. J. Acc.
Chem. Res. 1992, 25, 83–90. (b) Canty, A. J.; Hoare, J. L.; Davies, N. W.;
Traill, P. R. Organometallics 1998, 17, 2046–2051.
(19) For an alternative, see: Cardenas, D. J.; Martin-Matute, B.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 5033–5040.
(20) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem. 1997,
109, 142–145; Angew. Chem., Int. Ed. 1997, 36, 119-122. (b) Catellani,
M.; Cugini, F. Tetrahedron 1999, 55, 6595–6602. (c) Catellani, M.; Motti,
E.; Minari, M. Chem. Commun. 2000, 157–158. (d) Faccini, F.; Motti, E.;
Catellani, M. J. Am. Chem. Soc. 2004, 126, 78–79
.
(21) (a) For reviews, see: Catellani, M. Synlett 2003, 298–313. (b)
Catellani, M.; Motti, E.; Della Ca, N.; Ferraccioli, R. Eur. J. Org. Chem.
2007, 4153–4165. (c) Johnson, J. B.; Rovis, T. Angew. Chem. 2008, 120,
aFor simplicity, phosphine ligands are omitted.
852–884; Angew. Chem., Int. Ed. 2008, 47, 840-871
.
Org. Lett., Vol. 10, No. 12, 2008
2363

Table 3. Palladium-Catalyzed Transformation of the
5-(2-Bromobenzyl)-substituted-3,4-dihydro-2(1H)-pyridinones
5a-fa
Scheme 4
.
Classical Heck Coupling of Aryl Bromide 5b with
Ethyl Acrylate
in presence of a palladium catalyst. Thus, with the 2-bro-
mobenzyl substituent, the arylpalladium species undergoes
a C-H insertion reaction to a palladium intermediate, which
can react with another arylbromide leading to biaryl com-
pounds such as 8a. This sequence is unprecedented and
further illustrates the power of transition metal catalyzed
reactions. In fact, biaryl compounds are of great importance
in many areas of chemistry.25 Thus, chiral biaryls function
as efficient ligands in asymmetric synthesis.26 In addition,
the biaryl subunit can be found in many natural products,
like alkaloids or unusual peptide-based compounds.27 More-
over, biaryl compounds are widely used in material science28
and medicinal chemistry.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank Graeme
Nicholson (Institute of Organic Chemistry) for measuring
the HRMS spectra. G.S. thanks the Alexander von Humboldt
foundation for a postdoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds reported
and copies of NMR spectra for important intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800330D
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a Reaction conditions: Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), Cs2CO3
(4 equiv), DMF (0.18-0.2 M), 120 °C, 48 h. b K2CO3 (4 equiv) was used
as base; with Cs2CO3 the yields were 9% (6c), 21% (7c), 23% (8c).
c Temperature ) 100 °C.
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cessible 4-formyl esters with a 2-bromophenyl group at the
terminus. These enamides enter into a novel reaction pathway
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