Stereospecific palladium-catalyzed decarboxylative C(sp3)- C(sp2) Coupling of 2,5-Cyclohexadiene-1-carboxylic Acid Derivatives with Aryl Iodides

Article abstract of DOI:10.1002/anie.201103450

Walk on the same side! The title reaction occurs by means of highly stereospecific 1,3-metal migration. The starting carboxylic acids are readily prepared by Birch reduction, and the developed protocol provides an efficient route to enantiomerically pure

Full text of DOI:10.1002/anie.201103450

Communications
DOI: 10.1002/anie.201103450
Decarboxylative Coupling
3
2
À
Stereospecific Palladium-Catalyzed Decarboxylative C(sp ) C(sp )
Coupling of 2,5-Cyclohexadiene-1-carboxylic Acid Derivatives with
Aryl Iodides**
Chih-Ming Chou, Indranil Chatterjee, and Armido Studer*
3
been reported,[8] to our knowledge stereoselective C(sp )
À
During the past few years we have shown that metalated
cyclohexadienes are useful intermediates in asymmetric syn-
thesis. Chiral cyclohexadienyl titanium derivatives, readily
obtained by transmetalation of the corresponding lithiated
species, react with various aldehydes with excellent stereose-
lectivities [Eq. (1)].[1] We later found that such desymmetri-
zations[2] can be run with Ag and Cu catalysts in combination
with silylated and stannylated cyclohexadienes as precur-
sors.[3,4] However, all these methods are currently restricted to
the metalation of the parent 1,4-cyclohexadiene; the gener-
ation of substituted cyclohexadienyl metal intermediates has
not been achieved. Moreover, as electrophiles only aldehydes
and sulfinyl imines[5] have shown acceptable reactivities. We
therefore decided to investigate cyclohexadienyl palladium
complexes, which should make it possible to apply aryl halides
electrophiles.
C(sp2) bond formation through metal-catalyzed decarboxy-
lative arylation is unknown.
To evaluate our new concept, we first investigated the
decarboxylative coupling of readily prepared 1-methyl-2,5-
cyclohexadiene-1-carboxylic acid (1a; see the Supporting
Information) with iodobenzene in the presence of 10 mol%
of Pd(OAc)2, 20 mol% of P(o-tol)3, and various bases.
Reactions were conducted in toluene at 1108C for 26 h.
With tBuOK, tBuOLi, and K2CO3 little or no formation of
the targeted phenylated cyclohexadiene 2a was observed
(Table 1, entries 1–3). The yield was improved to 30% by
switching to Cs2CO3 (Table 1, entry 4). We then studied the
Table 1: Decarboxylative coupling of 1a with iodobenzene to give 2a.
Along this line, we planned to use cyclohexadienyl
carboxylic acids as precursors which are readily available by
Birch reduction [Eq. (2)].[6] We note that substituted cyclo-
hexadienyl compounds are easily accessible by the Birch
approach, and generation of organometallic compounds
through decarboxylation of the corresponding metal carbox-
Entry[a] Pd cat.
Base[b]
Solv.
T [oC] Lig.[c]
Yield [%][d]
1
Pd(OAc)2
tBuOK toluene 110
tBuOLi toluene 110
K2CO3
P(o-tol)3
P(o-tol)3
P(o-tol)3 <2
P(o-tol)3
–
PPh3
PCy3
PtBu3
dppb
8
0
ylates has been intensively investigated.[7–9] Substituents R1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[e]
18[f]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd(dba)2]
[Pd2(dba)3] Cs2CO3 toluene 110
[Pd(dba)2] Cs2CO3 toluene 110
[Pd(dba)2] Cs2CO3 NMP
[Pd(dba)2] Cs2CO3 THF
[Pd(dba)2] Cs2CO3 DCE
2
À
toluene 110
and R should strongly influence C C bond formation for
Cs2CO3 toluene 110
Cs2CO3 toluene 110
Cs2CO3 toluene 110
Cs2CO3 toluene 110
Cs2CO3 toluene 110
Cs2CO3 toluene 110
Cs2CO3 toluene 110
Cs2CO3 toluene 110
30
15
12
27
47
<2
<2
63
59
57
<2
41
36
55
41
steric reasons, and this should make it possible to control the
À
regioselectivity of the C C bond formation. Herein, we
present highly stereospecific Pd-catalyzed arylations of cyclo-
hexadienyl carboxylic acids. Whereas stereoselective allyla-
tion through metal-catalyzed decarboxylative metalation has
binap
–
–
[*] Dr. C.-M. Chou, I. Chatterjee, Prof. Dr. A. Studer
Organisch-Chemisches Institut
PtBu3
90
60
80
–
–
–
–
–
Westfꢀlische Wilhelms-Universitꢀt
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: studer@uni-muenster.de
[Pd(dba)2] Cs2CO3 toluene 110
[Pd(dba)2] Cs2CO3 toluene 110
[**] We thank the Alexander von Humboldt-Foundation (stipend to C.-
M.C.) and the NRW Graduate School of Chemistry (stipend to I.C.)
for financial support.
[a] Test experiments conducted at 0.3m. [b] With 1.1 equiv of base.
[c] With 20 mol% of additive. [d] Yield of isolated product. [e] With
5 mol% of Pd. [f] With 1.5 equiv of Cs2CO3.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103450.
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Angew. Chem. Int. Ed. 2011, 50, 8614 –8617

effect of the P ligand, keeping Cs2CO3 as base. The reaction in
the absence of any ligand under otherwise identical con-
ditions was low yielding (Table 1, entry 5). The yield
improved when electron-rich monodentate phosphines were
used (Table 1, entries 6–8), and with bidentate phosphines as
ligands no product was identified (Table 1, entries 9 and 10).
Pleasingly, yields increased significantly when [Pd(dba)2] and
[Pd2(dba)3] were used as precatalysts in the absence of ligands
(Table 1, entries 11 and 12). Addition of PtBu3 led to a slightly
lower yield (Table 1, entry 13), therefore the following
optimizations were conducted without P ligand. Solvent
screening revealed that toluene is best suited for this reaction
(Table 1, entries 14–16). Reducing the [Pd(dba)2] loading or
increasing the amount of Cs2CO3 provided worse results
(Table 1,entries 17 and 18). Based on these initial studies, all
following experiments were conducted with 10 mol% of
[Pd(dba)2], 1.1 equiv of Cs2CO3, and 1.1 equiv of aryl iodide
in toluene at 1108C for 26 h.
In order to evaluate the substrate scope, cyclohexadienyl
carboxylic acids 1b–g were prepared and reacted under
optimized conditions with iodobenzene to give 2b–g (see
Scheme 1 and the Supporting Information). The size of the
enced the reaction outcome. Whereas the decarboxylative
coupling of aryl iodides bearing electron-donating substitu-
ents provided the corresponding products in high yields,
iodobenzene derivatives with electron-deficient groups were
significantly less reactive. 4-Iodobiphenyl, 1-iodonaphtha-
lene, and also N-phenylpyrrole were good substrates for the
decarboxylative coupling (3h, 3i, 3k). Reductive elimination,
which is in competition with aromatization, is known to be
faster for electron-rich aryl groups and this is reflected by the
yields obtained.
Also a heteroarene, 2-iodothiophene, was successfully
reacted to give the corresponding coupling product 3j. We
were pleased to find that ortho-substituted aryl iodides were
also transformed into the corresponding decarboxylation/
coupling products (3l–n). Even sterically hindered 2,6-
disubstituted aryl iodides underwent smooth reaction with
1c (see 3o,p).
Encouraged by these results, we decided to study the
stereospecificity of the decarboxylative coupling reaction. To
this end, the chiral 2-methyl-2,5-cyclohexadiene-1-carboxylic
acids 6a,b were prepared in enantioenriched form by using a
slightly modified procedure of a known asymmetric Birch
reductive alkylation (Scheme 2, see the Supporting Informa-
tion).[10] Amides 5a,b were obtained from chiral amide 4 in
good yields and good to excellent diastereoselectivities.
Amide hydrolysis was achieved by desilylation and subse-
quent amide-to-ester transacylation followed by ester hydrol-
ysis to give acids 6a,b with high ee values and good yields.[11]
For 6a the ee value can be further increased to 99% by
recrystallization. The relative configuration of the major
isomer of 5a was unambiguously assigned after desilylation
by X-ray analysis of the corresponding alcohol (see the
Supporting Information).
Scheme 1. Decarboxylative coupling of substituted 2,5-cyclohexadiene-
1-carboxylates with iodobenzene. dba=trans,trans-dibenzylideneace-
tone.
a substituent influenced the reaction outcome, and the high-
est yields were achieved with isopropyl- and benzyl-substi-
tuted acids 1c,d. Substrates without an a substituent gave low
yields. Thanks to the reliable Birch reduction, the substitution
pattern at the cyclohexadiene core was readily varied. An
additional methyl group either at the 2- or 3-position of the
2,5-cyclohexadiene-1-carboxylate was tolerated, and reac-
tions occurred with excellent regioselectivity to give 2e and
2 f, respectively. Again with the larger iPr group at the 1-
position a higher yield was achieved (see 2g). However, the
2,5-dimethyl derivative 1h did not deliver the corresponding
coupling product, likely for steric reasons.
We then varied the iodoarene component in the Pd-
catalyzed decarboxylative coupling with 1c, and products 3a–
p were obtained in moderate to excellent yields. Aryl iodides
with methoxy, methyl, aminyl, ethoxycarbonyl, trifluoro-
methyl, fluoro, and acyl substituents in the para position
were tolerated. However, electronic effects strongly influ-
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Communications
Scheme 2. Preparation of optically active 2-methyl-2,5-cyclohexadiene-
1-carboxylic acid derivatives 6a,b. TBAF=tetra-n-butylammonium fluo-
ride, TBS=tert-butyldimethylsilyl.
The enantiomerically enriched acid 6a (93% ee after one
recrystallization) was reacted with iodobenzene under opti-
mized conditions to give diene 7a, which was isolated in 62%
yield. We were very pleased to find that 7a was formed in
93% ee, which indicates that decarboxylation coupling oc-
curred with perfect stereospecificity (Table 2, entry 1). Prod-
Scheme 3. Suggested catalytic cycle (Ar=aryl).
cyclohexadienyl palladium species B with retention of
stereochemistry. Stereospecific 1,3-Pd migration likely via
allyl palladium complex C delivers the 2,4-cyclohexadienyl
palladium intermediate D, which upon reductive elimination
eventually affords arylated cyclohexadienes 7 along with the
regenerated Pd0 to complete the catalytic cycle. Alternatively,
decarboxylation of A might directly lead to C. 1,3-Pd
migration from B might also deliver the regiosiomeric
palladium complex E. However, for steric reasons reductive
elimination in E is slow and B can be regenerated through 1,3-
Pd migration. In side reactions, B, D, and E can undergo b-H
elimination to provide the corresponding arene directly (for
D, E) or after tautomerization (for B).
The chiral product dienes are highly interesting building
blocks in synthesis. To show their potential, we subjected
diene 7b to nitrosopyridine in our recently developed Cu-
catalyzed nitroso Diels–Alder reaction (NDA).[12] Face and
also regiochemistry was perfectly controlled, and product 8
was isolated as a single isomer with high yield (Scheme 4).[13]
As previously shown, the chiral center at the diene moiety, in
concert with the chiral Cu catalyst, steers the regioselectivity
of the NDA reaction.[12]
Table 2: Stereospecific Pd-catalyzed decarboxylative coupling of 6a,b
with various aryl iodides.
Entry
R
ee (6) [%][a]
Aryl
Yield [%][b]
ee (7) [%][c]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Bn
93[d]
99[e]
93[d]
99[e]
93[d]
99[e]
99[e]
99[e]
94
Ph
Ph
62
63
66
68
73
72
77
72
81
92
93
93 (7a)
99 (7a)
93 (7b)
99 (7b)
93 (7c)
99 (7c)
99 (7d)
99 (7e)
94 (7 f)
94 (7g)
94 (7h)
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-NH2C6H4
1-naphthyl
Ph
9
10
11
Bn
Bn
94
94
4-MeC6H4
4-NH2C6H4
[a] Determined by GC analysis with a chiral stationary phase. [b] Yield of
isolated product. [c] Determined by HPLC analysis with a chiral sta-
tionary phase. [d] After a single recrystallization. [e] After two recrystal-
lizations.
uct 7a with 99% ee was isolated starting from the highly
enantiomerically enriched acid 6a (Table 2, entry 2). As
expected, also with substituted aryl iodides the reaction
occurred with excellent stereospecificity, and products 7b–d
were isolated in good yields (Table 2, entries 3–7). Reaction
of 1-iodonaphthalene with acid 6a provided 7e with 99% ee
(Table 2, entry 8). Similar results were achieved using the
benzylated acid 6b to give stereospecifically the dienes 7 f–h
in very good yields (Table 2, entries 9–11).
Scheme 4. Regioselective nitroso-Diels–Alder reaction.
Our proposed mechanism for the highly stereospecific Pd-
catalyzed decarboxylative coupling reaction is shown in
Scheme 3. Oxidative addition of aryl iodide to Pd0 provides
ArPdI, which undergoes ligand exchange with the cesium salt
of 6 to give intermediate A. Decarboxylation provides the 2,5-
In conclusion, we have described a highly stereospecific
Pd-catalyzed decarboxylative arylation of 2,5-cyclohexa-
diene-1-carboxylic acids. The resulting 5-arylated-1,3-cyclo-
hexadienes are useful bulding blocks in synthesis.[14] The
starting carboxylic acids are readily prepared by Birch
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2009, 131, 18343; i) B. M. Trost, J. Xu, T. Schmidt, J. Am. Chem.
Soc. 2008, 130, 11852; j) J. T. Mohr, T. Nishimata, D. C. Behenna,
B. M. Stoltz, J. Am. Chem. Soc. 2006, 128, 11348; k) M.
Nakamura, A. Hajra, A. K. Endo, E. Nakamura, Angew.
Chem. 2005, 117, 7414; Angew. Chem. Int. Ed. 2005, 44, 7248;
l) B. M. Trost, B. Schꢁffner, M. Osipov, D. A. A. Wilton, Angew.
Chem. 2011, 123, 3610; Angew. Chem. Int. Ed. 2011, 50, 3548.
reduction. To our knowledge, this is the first report of the
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stereoselective formation of C(sp ) C(sp ) bonds through
decarboxylative arylation.
Received: May 19, 2011
Published online: July 19, 2011
3
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[9] C(sp ) C(sp ), C(sp ) C(sp ), and C(sp) C(sp ) coupling
through metal-catalyzed decarboxylative arylation: a) W. H.
Fields, J. J. Chruma, Org. Lett. 2010, 12, 316; b) R. R. P.
Torregrosa, Y. Ariyarathna, K. Chattopadhyay, J. A. Tunge, J.
Am. Chem. Soc. 2010, 132, 9280; c) R. Shang, Z. Yang, Y. Wang,
S. Zhang, L. Liu, J. Am. Chem. Soc. 2010, 132 , 14391; d) R.
Shang, D.-S. Ji, L. Chu, Y. Fu, L. Liu, Angew. Chem. 2011, 123,
4562; Angew. Chem. Int. Ed. 2011, 50, 4470; e) H.-P. Bi, L. Zhao,
Y.-M. Liang, C.-J. Li, Angew. Chem. 2009, 121, 806; Angew.
Chem. Int. Ed. 2009, 48, 792; f) H.-P. Bi, W.-W. Chen, Y.-M.
Liang, C.-J. Li, Org. Lett. 2009, 11, 3246; g) C. Zhang, D. Seidel,
J. Am. Chem. Soc. 2010, 132, 1798; h) R. Jana, R. Trivedi, J. A.
Tunge, Org. Lett. 2009, 11, 3434.
.
À
Keywords: asymmetric synthesis · Birch reduction · C
.
C bond formation · homogeneous catalysis · palladium
[1] a) F. Schleth, A. Studer, Angew. Chem. 2004, 116, 317; Angew.
Chem. Int. Ed. 2004, 43, 313; b) F. Schleth, T. Vogler, K. Harms,
A. Studer, Chem. Eur. J. 2004, 10, 4171. Application in radical
chemistry: c) J. C. Walton, A. Studer, Acc. Chem. Res. 2005, 38,
794.
[2] A. Studer, F. Schleth, Synlett 2005, 3033.
[3] R. Umeda, A. Studer, Org. Lett. 2007, 9, 2175.
[4] R. Umeda, A. Studer, Org. Lett. 2008, 10, 993.
[10] a) A. G. Schultz, P. Sundararaman, Tetrahedron Lett. 1984, 25,
4591; b) A. G. Schultz, M. Macielag, P. Sundararaman, A. G.
Taveras, M. Welch, J. Am. Chem. Soc. 1988, 110, 7828; c) A. G.
Schultz, P. Sundararaman, M. Macielag, F. P. Lavieri, M. Welch,
Tetrahedron Lett. 1985, 26, 4575; d) A. G. Schultz, Chem.
Commun. 1999, 1263.
[11] During hydrolysis we observed a slight decrease of the ee value
which might be due to a reversible Koch–Haaf reaction, see:
a) H. Koch, W. Haaf, Liebigs Ann. Chem. 1958, 618, 251; b) J. A.
Peters, H. van Bekkum, Recl. Trav. Chim. Pays-Bas 1973, 92,
379; c) J. A. Peters, J. Rog, H. van Bekkum, Recl. Trav. Chim.
Pays-Bas 1974, 93, 248.
[12] a) C. K. Jana, A. Studer, Angew. Chem. 2007, 119, 6662; Angew.
Chem. Int. Ed. 2007, 46, 6542; b) C. K. Jana, A. Studer, Chem.
Eur. J. 2008, 14, 6326; c) C. K. Jana, S. Grimme, A. Studer, Chem.
Eur. J. 2009, 15, 9078. See also: I. Chatterjee, C. K. Jana, M.
Steinmetz, S. Grimme, A. Studer, Adv. Synth. Catal. 2010, 352,
945.
[13] The assignment of the relative configuration is based on
1H NMR analysis. The regiochemistry obtained in the nitroso-
Diels–Alder reaction fits with our model (see Refs. [12a,b]) and
further supports the correct assignment of the absolute config-
uration of 7b.
[5] M. S. Maji, R. Frçhlich, A. Studer, Org. Lett. 2008, 10, 1847.
[6] a) P. W. Rabideau, Tetrahedron 1989, 45, 1579; b) P. W. Rabid-
eau, Z. Marcinow, Org. React. 1992, 42, 1; c) G. S. R. Subba-Rao,
Pure Appl. Chem. 2003, 75, 1443; d) T. Krꢀger, K. Vorndran, T.
Linker, Chem. Eur. J. 2009, 15, 12082.
[7] Reviews: a) L. J. Goossen, N. Rodriguez, K. Goossen, Angew.
Chem. 2008, 120, 3144; Angew. Chem. Int. Ed. 2008, 47, 3100;
b) T. Satoh, M. Miura, Synthesis 2010, 3395; c) J. D. Weaver, A.
Recio III, A. J. Grenning, J. A. Tunge, Chem. Rev. 2011, 111,
1846. Pioneering studies: d) A. G. Myers, D. Tanaka, M. R.
Mannion, J. Am. Chem. Soc. 2002, 124, 11250; e) D. Tanaka, S. P.
Romeril, A. G. Myers, J. Am. Chem. Soc. 2005, 127, 10323;
f) L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662;
g) P. Forgione, M. C. Brochu, M. St-Onge, K. H. Thesen, M. D.
Bailey, F. Bilodeau, J. Am. Chem. Soc. 2006, 128, 11350.
[8] Generation of allyl–metal compounds or enolates through
decarboxylation: a) E. C. Burger, J. A. Tunge, J. Am. Chem.
Soc. 2006, 128, 10002; b) S. R. Waetzig, J. A. Tunge, J. Am.
Chem. Soc. 2007, 129, 4138; c) S. R. Waetzig, J. A. Tunge, J. Am.
Chem. Soc. 2007, 129, 14860; d) J. D. Weaver, J. A. Tunge, Org.
Lett. 2008, 10, 4657; e) A. J. Grenning, J. A. Tunge, Org. Lett.
2010, 12, 740; f) J. D. Weaver, B. J. Ka, D. K. Morris, W.
Thompson, J. A. Tunge, J. Am. Chem. Soc. 2010, 132, 12179;
g) H. He, X.-J. Zheng, Y. Li, L.-X. Dai, S.-L. You, Org. Lett.
2007, 9, 4339; h) B. M. Trost, J. Xu, T. Schmidt, J. Am. Chem. Soc.
[14] S. L. Poe, J. P. Morken, Angew. Chem. 2011, 123, 4275; Angew.
Chem. Int. Ed. 2011, 50, 4189.
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