Palladium(0)-catalyzed intramolecular dearomative arylation of pyrroles

Article abstract of DOI:10.1039/c3cc44631j

The palladium(0)-catalyzed dearomative arylation of pyrroles has been accomplished to afford the spironaphthalenepyrrole derivatives in good to excellent yields.

Full text of DOI:10.1039/c3cc44631j

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Palladium(0)-catalyzed intramolecular dearomative
arylation of pyrroles†
Cite this: Chem. Commun., 2013,
49, 8620
Ke-Jia Wu, Li-Xin Dai and Shu-Li You*
Received 20th June 2013,
Accepted 27th July 2013
DOI: 10.1039/c3cc44631j
www.rsc.org/chemcomm
The palladium(0)-catalyzed dearomative arylation of pyrroles has
been accomplished to afford the spironaphthalenepyrrole deriva-
tives in good to excellent yields.
Dearomatization1 of aromatic compounds has made great
progress in developing molecular complexity in recent years.2
Beyond the traditional methods such as oxidation,3 electro-
philic alkylation4 and cycloaddition,5 in which a stoichiometric
Scheme 1 Dearomative arylation of 2,5-disubstituted pyrroles.
amount of reagents is indispensable, transition-metal-catalyzed we envision that the dearomatization of pyrroles could be
dearomatization reaction6 is an attractive approach in which achieved through the Pd-catalyzed intramolecular dearomative
only a catalytic amount of metal complex is required. Among arylation reaction (Scheme 1), providing the spironaphthalene-
them, Pd-catalyzed cross-coupling reaction has been demon- pyrrole compounds. Herein we report our results on this subject.
strated to be successful in dearomative processes. Since 2009,
With substrate 1a, we began to examine the palladium
Buchwald and co-workers have realized the Pd-catalyzed dearo- precursors and the ligands in the dearomative arylation reac-
matization reaction of aniline derivatives and phenols.7 Bedford tion. The results are summarized in Table 1. With the cata-
et al. have also independently accomplished this type of reaction lytic system consisting of [Pd(Z3-C3H5)Cl]2 (2.5 mol%), PPh3
by employing anilines and 2-amino-1-methylindoles as suitable (7.5 mol%), and K2CO3 (1.5 equiv.), the dearomative arylation of
substrates.8 In 2012, we reported the Pd-catalyzed intramolecular 1a in refluxing toluene (0.2 M) afforded the desired product 2a
dearomative arylation of indoles.9
in 81% yield (entry 1). Other readily available palladium sources
On the other hand, the pyrrole and pyrroline structural cores led to much lower yields (entries 2–4). Various ligands such as
exist widely in bioactive compounds and pharmaceuticals (Fig. 1).10 SIPrꢀHBF4, phosphoramidite L1, XPhos, XPhos(tBu), QPhos,
Therefore, great efforts have been made for the synthesis of and P1 were then screened (entries 5–10). Phosphoramidite
pyrroles, pyrrolines and their derivatives.11 With our continuing L1 performed best to give the dearomatization product in 91%
interest in developing catalytic dearomatization reactions,12 yield (entry 6).
In the presence of 2.5 mol% of [Pd(Z3-C3H5)Cl]2 and 7.5 mol%
of L1, reaction parameters such as bases and solvents were
further optimized. Among the inorganic bases tested, K2CO3
remained to be the best option (entries 11–15). The use
of organic bases such as Et3N did not lead to the formation
of the desired product (entry 16). The reaction in dioxane or
DMF could give the dearomatization product in good yields
(entries 17 and 18). It is worth mentioning that the reaction
Fig. 1 Selected bioactive compounds bearing spironaphthalene-pyrrolidine units. proceeded smoothly in refluxed THF (entry 19). The desired
product could be obtained in 90% yield with 2 mol% of catalyst
(entry 20), while 1 mol% of catalyst resulted in only 49% con-
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
version (entry 21).
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China.
Under the optimized reaction conditions, {[Pd(Z3-C3H5)Cl]2
E-mail: slyou@sioc.ac.cn; Fax: +86 21-5492-5087
(1.0 mol%), L1 (3.0 mol%), and K2CO3 (1.5 equiv.) in refluxed
toluene (0.2 M)}, the substrate scope was investigated. The results
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. See DOI: 10.1039/c3cc44631j
c
8620 Chem. Commun., 2013, 49, 8620--8622
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope of dearomative arylation of pyrrolesa,b
Entry [Pd]
L
Base
Solvent Yieldb (%)
1
[Pd(Z3-C3H5)Cl]2 PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
Toluene
81
66
2
Pd(OAc)2
Pd2(dba)3
Pd(PPh3)4
PPh3
PPh3
—
3c
4
Toluene o5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
24
82
91
62
19
52
15
83
66
11
37
a
Reaction conditions: [Pd(Z3-C3H5)Cl]2 (1.0 mol%), rac-L1 (3.0 mol%),
5
6
7
8
[Pd(Z3-C3H5)Cl]2 SIPrꢀHBF4
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 XPhos
K2CO3 (1.5 equiv.) and 1a (0.4 mmol) in toluene (0.2 M) at reflux.
b
c
Isolated yields. XPhos was used as the ligand.
[Pd(Z3-C3H5)Cl]2 XPhos(tBu) K2CO3
9
[Pd(Z3-C3H5)Cl]2 QPhos
[Pd(Z3-C3H5)Cl]2 P1
K2CO3
K2CO3
Cs2CO3 Toluene
K3PO4 Toluene
10
11
12
13
14
15c
16c
17
18
19d
20e
21f
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
[Pd(Z3-C3H5)Cl]2 rac-L1
Li2CO3 Toluene
NaOAc Toluene
KOtBu
Et3N
Toluene o5
Toluene
Dioxane
DMF
N.D.
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
87
74
80
90
49
THF
Toluene
Toluene
a
Scheme 2 Transformations of dearomatization product 2a.
Reaction conditions: [Pd] (5.0 mol%), L (7.5 mol%), base (1.5 equiv.)
b
and 1a (0.2 mmol) in solvent (0.2 M) at 110 1C. Isolated yields.
c
d
e
Determined by 1H NMR. Refluxed at 75 1C. [Pd(Z3-C3H5)Cl]2
(1.0 mol%) was used. [Pd(Z3-C3H5)Cl]2 (0.5 mol%) was used.
f
desired product 2i was obtained in 79% yield. When the
malonate diester linked substrates were used, much higher
are summarized in Table 2. 2-Aryl pyrrole substrates bearing reactivity was observed. The dearomatization products were
either an electron-donating group (40-MeO, 2b) or an electron- obtained in excellent yields (87–93% in 10 h, 2j–2l).
withdrawing group (40-F, 2c) on the benzene ring were well
To explore the utility of the product obtained here, several
tolerated to afford dearomatization products in excellent yields transformations of the dearomatization product 2a were then
(91–93%). Notably, alkyl substituents could also be present on carried out. As summarized in Scheme 2, hydrogenation of 2a
the pyrrole ring without attenuating its nucleophilicity. When by using Pd/C as the catalyst under 1 atm of hydrogen atmo-
the phenyl group was replaced by an ethyl group (5-Et, 2d), the sphere smoothly led to product 3a in 61% yield, with the imine
reaction proceeded smoothly, giving the desired product in functionality intact (eqn (1)). The dearomatization product 2a
84% yield. In the case of product 2e featuring more steric could also be subjected to 3 equivalents of NaBH3CN in acetic
hindrance due to the 3-methyl substituent, only 32% yield acid, and the spironaphthalenepyrroline product 3b was
was obtained with rac-L1 as a ligand. To our delight, the yield obtained in 58% yield with >20 : 1 dr (eqn (2)).13
could be improved to 73% when XPhos was utilized instead
of rac-L1.
In summary, we have realized the Pd-catalyzed intramolecular
dearomative arylation of 2-substituted pyrroles, leading to
Substrates having substituents (R2) on the bromobenzene spironaphthalene-1,20-pyrrole derivatives in good to excellent
ring varying the electronic properties (2f–2h) were all tolerated, yields. Further extension of the reaction scope and develop-
leading to the dearomatized products in 87–94% yields. The ment of an enantioselective variant are currently under inves-
naphthyl ring containing substrate was also applicable, and the tigation in our lab.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 8620--8622 8621

View Article Online
ChemComm
Communication
51, 2448; (g) M. Yoshida, T. Nemoto, Z. Zhao, Y. Ishige and
Y. Hamada, Tetrahedron: Asymmetry, 2012, 23, 859; (h) Q. Xiao,
J. J. Jackson, A. Basak, J. M. Bowler, B. G. Miller and A. Zakarian,
Nat. Chem., 2013, 5, 410; (i) J. Chen and M. J. Cook, Org. Lett., 2013,
15, 1088; ( j) T. D. Montgomery, Y. Zhu, N. Kagawa and V. H. Rawal,
Org. Lett., 2013, 15, 1140; (k) T. Nemoto, R. Wu, Z. Zhao, T. Yokosaka
and Y. Hamada, Tetrahedron, 2013, 69, 3403; (l) T. Nemoto, R. Wu,
Z. Zhao, T. Yokosaka, Y. Suzuki, R. Wu and Y. Hamada, Angew.
Chem., Int. Ed., 2013, 52, 2217; (m) Q.-L. Xu, L.-X. Dai and S.-L. You,
Chem. Sci., 2013, 4, 97; (n) Y. Liu and H. Du, Org. Lett., 2013, 15, 740;
For Rh-catalyzed dearomatization reactions: (o) R. P. Reddy and
H. M. L. Davies, J. Am. Chem. Soc., 2007, 129, 10312; (p) J. V. Mulcahy
and J. Du Bois, J. Am. Chem. Soc., 2008, 130, 12630; (q) Y. Lian and
H. M. L. Davies, J. Am. Chem. Soc., 2010, 132, 440; (r) C. Nadeau,
S. Aly and K. Belyk, J. Am. Chem. Soc., 2011, 133, 2878; (s) J. E.
Spangler and H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 6802; For
The National Basic Research Program of China (973 Program
2009CB825300) and the National Natural Science Foundation of
China (20923005, 20932008, 21025209, 21121062) are acknowl-
edged for generous financial support.
Notes and references
1 For recent reviews: (a) S. P. Roche and J. A. Porco Jr, Angew. Chem.,
Int. Ed., 2011, 50, 4068; (b) C.-X. Zhuo, W. Zhang and S.-L. You,
Angew. Chem., Int. Ed., 2012, 51, 12662; (c) D.-S. Wang, Q.-A. Chen,
S.-M. Lu and Y.-G. Zhou, Chem. Rev., 2012, 112, 2557For recent
selected examples: (d) L. M. Repka, J. Ni and S. E. Reisman, J. Am.
Chem. Soc., 2010, 132, 14418; (e) S. B. Jones, B. Simmons,
A. Mastracchio and D. W. C. MacMillan, Nature, 2011, 475, 183;
( f ) R. R. Knowles, J. Carpenter, S. B. Blakey, A. Kayano,
I. K. Mangion, C. J. Sinz and D. W. C. MacMillan, Chem. Sci.,
2011, 2, 308; (g) O. Lozano, G. Blessley, T. Martinez del Campo,
A. L. Thompson, G. T. Giuffredi, M. Bettati, M. Walker, R. Borman
and V. Gouverneur, Angew. Chem., Int. Ed., 2011, 50, 8105; (h) B. Tan,
´
´
´˜
Cu-catalyzed dearomatization reactions: (t) M. A. Fernandez-Ibanez,
´
B. Macia, M. G. Pizzuti, A. J. Minnaard and B. L. Feringa, Angew.
Chem., Int. Ed., 2009, 48, 9339; (u) S. Zhu and D. W. C. MacMillan,
J. Am. Chem. Soc., 2012, 134, 10815; (v) H. Xiong, H. Xu, S. Liao,
Z. Xie and Y. Tang, J. Am. Chem. Soc., 2013, 135, 7851; For
Au-catalyzed dearomatization procedure: (w) G. Cera, M. Chiarucci,
A. Mazzanti, M. Mancinelli and M. Bandini, Org. Lett., 2012, 14, 1350.
´
G. Hernandez-Torres and C. F. Barbas III, J. Am. Chem. Soc., 2011,
133, 12354; (i) M. E. Kieffer, K. V. Chuang and S. E. Reisman, Chem.
´
´
7 (a) J. Garcıa-Fortanet, F. Kessler and S. L. Buchwald, J. Am. Chem.
Sci., 2012, 3, 3170; ( j) H. Jiang, C. Rodrıguez-Escrich, T. K.
´
Johansen, R. L. Davis and K. A. Jøgensen, Angew. Chem., Int. Ed.,
2012, 51, 10271; (k) Z. Zhang and J. C. Antilla, Angew. Chem., Int. Ed.,
2012, 51, 11778; (l) M. E. Kieffer, K. V. Chuang and S. E. Reisman,
J. Am. Chem. Soc., 2013, 135, 5557; (m) B. D. Horning and D. W. C.
MacMillan, J. Am. Chem. Soc., 2013, 135, 6442.
2 (a) L. N. Mander, Synlett, 1991, 134; (b) T. Bach, Angew. Chem., Int.
Ed. Engl., 1996, 35, 729; (c) S. Cacchi and G. Fabrizi, Chem. Rev.,
Soc., 2009, 131, 6676; (b) S. Rousseaux, J. Garcıa-Fortanet, M. A. Del
Aguila Sanchez and S. L. Buchwald, J. Am. Chem. Soc., 2011,
133, 9282.
8 (a) R. B. Bedford, C. P. Butts, M. F. Haddow, R. Osborne and R. F.
Sankey, Chem. Commun., 2009, 4832; (b) R. B. Bedford, N. Fey,
M. F. Haddow and R. F. Sankey, Chem. Commun., 2011, 47, 3649.
9 K.-J. Wu, L.-X. Dai and S.-L. You, Org. Lett., 2012, 14, 3772.
2005, 105, 2873; (d) S. Cacchi and G. Fabrizi, Chem. Rev., 2011, 10 For reviews: (a) H. Hoffmann and T. Lindel, Synthesis, 2003, 1753;
111, PR215; (e) L. Joucla and L. Djakovitch, Adv. Synth. Catal., 2009,
351, 673; ( f ) M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed.,
2009, 48, 9608; (g) G. Bartoli, G. Bencivenni and R. Dalpozzo, Chem.
Soc. Rev., 2010, 39, 4449.
(b) A. Fu¨rstner, Angew. Chem., Int. Ed., 2003, 42, 3582; (c) G. Balme,
Angew. Chem., Int. Ed., 2004, 43, 6238; (d) H. Fan, J. N. Peng,
M. T. Hamann and J. F. Hu, Chem. Rev., 2008, 108, 264; For
examples: (e) J. A. Johnson, N. Li and D. Sames, J. Am. Chem. Soc.,
2002, 124, 6900; ( f ) P. S. Baran, J. M. Richter and D. W. Lin, Angew.
Chem., Int. Ed., 2005, 44, 609; (g) A. Fu¨rstner, K. Radkowski and
H. Peters, Angew. Chem., Int. Ed., 2005, 44, 2777.
´
3 For recent reviews: (a) S. Quideau, L. Pouysegu and D. Deffieux,
´
Synlett, 2008, 467; (b) L. Pouysegu, D. Deffieux and S. Quideau,
Tetrahedron, 2010, 66, 2235; For a recent example: (c) J.-B. Peng,
Y. Qi, A.-J. Ma, Y.-Q. Tu, F.-M. Zhang, S.-H. Wang and S.-Y. Zhang, 11 (a) D. Berney and K. Schuh, Helv. Chim. Acta, 1979, 62, 1268; (b) D. A.
Chem.–Asian J., 2013, 8, 833.
Burnett and D. J. Hart, J. Org. Chem., 1987, 52, 5662; (c) A. A. Bahajaj,
P. D. Bailey, M. H. Moore, K. M. Morgan and J. M. Vernon, J. Chem.
Soc., Chem. Commun., 1994, 2511; (d) H. Walter and J. Schneider,
Heterocycles, 1995, 41, 1251; (e) V. Gandon, P. Bertus and
J. Szymoniak, Synthesis, 2002, 1115; ( f ) P. D. Bailey, K. M. Morgan,
D. I. Smith and J. M. Vernon, Tetrahedron, 2003, 59, 3369; (g) M. A.
Siddiqui, C.-Y. Dai, U. F. Mansoor, L.-P. Yang, L.-D. Vitharana and
A. R. Angeles, [P] WO 2009/061597 A1, 2009.
4 For selected recent examples: (a) N. A. McGrath, E. S. Bartlett,
S. Sittihan and J. T. Njardarson, Angew. Chem., Int. Ed., 2009,
48, 8543; (b) J. D. Trzupek, D. Lee, B. M. Crowley, V. M. Marathias
and S. J. Danishefsky, J. Am. Chem. Soc., 2010, 132, 8506; (c) K. Iwasaki,
R. Kanno, T. Morimoto, T. Yamashita, S. Yokoshima and T. Fukuyama,
Angew. Chem., Int. Ed., 2012, 51, 9160.
5 For selected recent examples: (a) E. L. Campbell, A. M. Zuhl,
C. M. Liu and D. L. Boger, J. Am. Chem. Soc., 2010, 132, 3009; 12 (a) Q.-F. Wu, H. He, W.-B. Liu and S.-L. You, J. Am. Chem. Soc., 2010,
(b) D. Kato, Y. Sasaki and D. L. Boger, J. Am. Chem. Soc., 2010,
132, 3685; (c) Y. Sasaki, D. Kato and D. L. Boger, J. Am. Chem. Soc.,
2010, 132, 13533; (d) S. Levin, R. R. Nani and S. E. Reisman,
Org. Lett., 2010, 12, 780.
6 For Pd-catalyzed dearomatization reactions: (a) M. Kimura,
M. Futamata, R. Mukai and Y. Tamaru, J. Am. Chem. Soc., 2005,
127, 4592; (b) B. M. Trost and J. Quancard, J. Am. Chem. Soc., 2006,
128, 6314; (c) N. Kagawa, J. P. Malerich and V. H. Rawal, Org. Lett.,
2008, 10, 2381; (d) T. Nemoto, Y. Ishige, M. Yoshida, Y. Kohno,
M. Kanematsu and Y. Hamada, Org. Lett., 2010, 12, 5020;
(e) D.-S. Wang, Z.-S. Ye, Q.-A. Chen, Y.-G. Zhou, C.-B. Yu, H.-J. Fan
132, 11418; (b) Q.-F. Wu, W.-B. Liu, C.-X. Zhuo, Z.-Q. Rong, K.-Y. Ye
and S.-L. You, Angew. Chem., Int. Ed., 2011, 50, 4455; (c) Q. Cai,
C. Zheng and S.-L. You, Angew. Chem., Int. Ed., 2011, 50, 8665;
(d) C.-X. Zhuo, W.-B. Liu, Q.-F. Wu and S.-L. You, Chem. Sci., 2012,
3, 205; (e) C. Liu, W. Zhang, L.-X. Dai and S.-L. You, Org. Biomol.
Chem., 2012, 10, 7177; ( f ) Q.-F. Wu, C. Zheng and S.-L. You, Angew.
Chem., Int. Ed., 2012, 51, 1680; (g) Q. Cai and S.-L. You, Org. Lett.,
2012, 14, 3040; (h) C. Liu, W. Zhang, L.-X. Dai and S.-L. You,
Org. Lett., 2012, 14, 4525; (i) Q. Cai, C. Liu, X.-W. Liang and
S.-L. You, Org. Lett., 2012, 14, 4588; ( j) X. Zhang, Z.-P. Yang,
C. Liu and S.-L. You, Chem. Sci., 2013, 4, 3239.
and Y. Duan, J. Am. Chem. Soc., 2011, 133, 8866; ( f ) T. Cao, J. Deitch, 13 The relative configuration of compound 3b was determined by H–H
E. C. Linton and M. C. Kozlowski, Angew. Chem., Int. Ed., 2012,
COSY and 2D NOESY NMR analysis, see the ESI.†
c
8622 Chem. Commun., 2013, 49, 8620--8622
This journal is The Royal Society of Chemistry 2013