Facile benzo-ring construction via palladium-catalyzed functionalization of unactivated sp3 C-H bonds under mild reaction conditions

Article abstract of DOI:10.1021/ol101220x

(Equation Presented). A practical synthetic method for the annulation of benzo-rings by the intramolecular coupling of an aryl iodide and a methylene C-H bond is described. The palladium-catalyzed C-H functionalization is directed by an aminoquinoline carboxamide group, which can be easily installed and removed. High yields and broad substrate scope were achieved. An additive of ortho-phenyl benzoic acid, identified from a systematic screening, functions as a critical ligand for the catalytic process under mild condition, even at near room temperature.

Full text of DOI:10.1021/ol101220x

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3414-3417
Facile Benzo-Ring Construction via
Palladium-Catalyzed Functionalization of
Unactivated sp3 C-H Bonds under Mild
Reaction Conditions
Yiqing Feng, Yuji Wang, Bradley Landgraf, Shi Liu, and Gong Chen*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PensylVania 16802
guc11@psu.edu
Received May 26, 2010
ABSTRACT
A practical synthetic method for the annulation of benzo-rings by the intramolecular coupling of an aryl iodide and a methylene C-H bond
is described. The palladium-catalyzed C-H functionalization is directed by an aminoquinoline carboxamide group, which can be easily installed
and removed. High yields and broad substrate scope were achieved. An additive of ortho-phenyl benzoic acid, identified from a systematic
screening, functions as a critical ligand for the catalytic process under mild condition, even at near room temperature.
Site- and stereoselective functionalization of C-H bonds,
especially of the more prevalent sp3 C-H bonds, under mild
operating conditions would offer tremendous opportunities
for synthesis of complex molecules.1 Despite the significant
progress made over the past decade, the development of
synthetically useful methods via the functionalization of sp3
C-H bonds is still lacking.2,3 Although some novel site-
selective C-H functionalization strategies exploiting the
intrinsic C-H reactivity difference have emerged,4 unbiased
approaches governed by intramolecular directing groups or
tethered auxiliaries can provide more versatile and control-
lable transformations.5 A variety of functional groups,
including amines, ketones, and aldehydes, have proven viable
handles for such directing purposes.6 More recently, free
carboxylic acid groups, ortho-methyl hydroxamic acids,
oxazolines, and arylamides have been successfully utilized
in palladium-catalyzed, directed C-H functionalization.7 The
aminoquinoline carboxamide, a seminal discovery of Dau-
gulis, appears to be a well-behaved auxiliary to enable C-H
functionalization at the ꢀ-methylene position.8,9 Recently,
we successfully applied it as the key C-C bond construction
strategy in a streamlined synthesis of celogentin C.10
Encouraged by the high efficiency and selectivity, we went
(3) Functionalization of sp3 C-H bonds: (a) Dyker, G., Ed. Handbook
of C-H Transformation; Wily-VCH: Weinheim, Germany, 2005; Vols. 1-3.
(b) Chen, H. Y.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000,
287, 1995–1997. (c) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.;
Sames, D. J. Am. Chem. Soc. 2002, 124, 11856–11857. (d) Labinger, J. A.;
Bercaw, J. E. Nature 2002, 417, 507–514. (e) Desai, L. V.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542–9543. (f) Giri, R.; Liang,
J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.; Naggar, I. C.; Guo, C.;
Foxman, B. M.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 7420–7424.
(g) Bergman, R. G. Nature 2007, 446, 391–393. (h) Jazzar, R.; Hitce, J.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.sEur. J. 2010, 16,
2654–2672.
(1) C-H activation in synthesis: (a) Hinman, A.; Du Bois, J. J. Am.
Chem. Soc. 2003, 125, 11510–11511. (b) O’Malley, S. J.; Tan, K. L.;
Watzke, A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
13496–13497. (c) Godula, K.; Sames, D. Science 2006, 312, 67–72. (d)
Chen, K.; Baran, P. S. Nature 2009, 459, 824–828. (e) Chaumontet, M.;
Piccardi, R.; Baudoin, O. Angew. Chem., Int. Ed. 2009, 48, 179–182.
(2) C-H insertion via nitrene and carbene: (a) Espino, C. G.; Wehn,
P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935–6936. (b)
(4) (a) Chen, M. S.; White, M. C. Science 2007, 318, 783–787. (b) Chen,
M. S.; White, M. C. Science 2010, 327, 566–571.
Davies, H. M.; Manning, J. R. Nature 2008, 451, 417–424
.
10.1021/ol101220x  2010 American Chemical Society
Published on Web 06/28/2010

on to explore its synthetic utilization in a more delicate
intramolecular setting. Herein, we report a practical benzo-
ring construction method via the Pd-catalyzed aminoquino-
line carboxamide directed functionalization of sp3 C-H
bonds under mild reaction conditions and the discovery of
ortho-phenyl benzoic acid as a critical ligand to the catalytic
cycle at ambient temperature.
Scheme 1. Benzo-Ring Construction via the
Palladium-Catalyzed Tandem C-H Activation/Intramolecular
Cross Coupling with Aryl Iodidea
As outlined in Scheme 1, we envisioned a new synthetic
strategy for the construction of benzo-ring enabled by the
aminoquinoline auxiliary (Q), which can be easily installed
at the carboxyl terminus via standard amide coupling.
Evidence from Daugulis, Corey, and our previous work
strongly supported the hypothesis that this C-H function-
alization proceeds through a sequential C-H activation/
oxidative addition PdII/IV pathway.11 This served as the initial
working mechanism for our reaction development. Aiming
to achieve an efficient transformation under user-friendly
conditions, the cyclization of precursor 1 was set up at 50 °C,
which is significantly lower than the original operating
temperature, in t-BuOH without exclusion of air or mois-
ture.12
Since the Ag+ salt was believed to act only as an I-
scavenger, our attention was focused on the carboxylic acid
additives, which are known to play the key role in the
concerted palladation-deprotonation C-H activation step
via a three-center agostic interaction (Scheme 1B).13 An
(5) Directed C-H activation: (a) Corey, E. J.; Hertler, W. R. J. Am.
Chem. Soc. 1958, 80, 2903–2904. (b) Barton, D. H. R.; Beaton, J. M.; Geller,
L. E.; Pechet, M. M. J. Am. Chem. Soc. 1960, 82, 2640–2641. (c) Breslow,
R.; Corcoran, R. J.; Snider, B. B. J. Am. Chem. Soc. 1974, 96, 6791. (d)
Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2000, 122, 6321–6322. (e)
Lyons, T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147–1169.
(6) (a) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc.
2001, 123, 8149–8150. (b) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2008, 47, 4882–4886. (c) Chen, K.; Richter, J. M.;
Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247–7249. (d) Desai, L. V.;
Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285–13293.
(7) (a) Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.;
Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Angew. Chem., Int. Ed.
2005, 44, 7420–7424. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.;
Breazzano, S. P.; Sauders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129,
3510–3511. (c) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem.
Soc. 2008, 130, 7190–7191. (d) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–5115. (e) Wasa, M.; Engle,
K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886–9887.
(8) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154–13155. (b) Shabashov, D.; Daugulis, O. Org. Lett. 2005,
7, 3657–3659. (c) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010,
132, 3965–3972.
(9) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391–
3394. A palladacycle intermediate was isolated and characterized.
(10) Feng, Y. Q.; Chen, G. Angew. Chem., Int. Ed. 2010, 49, 958–961.
(11) Pd(IV) chemistry: (a) Canty, A. J. Acc. Chem. Res. 1992, 25, 83–
90. (b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
1997, 36, 119–122. (c) Lautens, M.; Peguel, S. Angew. Chem., Int. Ed.
2000, 39, 1045–1046. (d) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford,
M. S. J. Am. Chem. Soc. 2005, 127, 7330–7331. (e) Xu, L.; Li, B.; Yang,
Z.; Shi, Z. Chem. Soc. ReV. 2010, 39, 712–733.
a Reagents and conditions: 25 µM, 50 °C, 18 h; air and moisture were
not excluded; yields were determined by 1H NMR analysis of the crude
reaction mixture ((3%).
extensive screening of both aliphatic acid and benzoic acids
with varied substituents was carried out to explore their
functional roles.14,15
(12) The original condition was 110-130 °C in neat condition with 1.5
equiv of AgOAc. A newer condition without Ag salt at 90 °C was recently
reported (ref 8c). Although many C-H activations in AcOH and TFA have
been developed, neutral and low boiling point solvents are more favorable
for practical synthesis.
(13) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
Soc. 2005, 127, 13754–13755. (b) Garc´ıa-Cuadrado, D.; de Mendoza, P.;
Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007,
129, 6880–6886. (c) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem.
Soc. 2007, 129, 14570–14571. (d) Gorelsky, S. I.; Lapointe, D.; Fagnou,
K. J. Am. Chem. Soc. 2008, 130, 10848–10849.
(14) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496–
16497. (b) Lebrasseur, N; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926–
2927. (c) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrehedron 2008, 64,
6015–6020
.
(15) research.chem.psu.edu/brpgroup/pKa_compilation.pdf. pKa (in H2O)
data compiled by R. Wiliams.
Org. Lett., Vol. 12, No. 15, 2010
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Gratifyingly, several distinct trends in the acid ligand effect
were revealed from the initial screening: (1) Aliphatic acids
with strong electron-withdrawing substituents (pKa < 3)
resulted in failed reactions with recovery of most of 1. (2)
Benzoic acids with either strong electron-donating or electron-
withdrawing substituents diminished the yield. (3) Sterically
hindered acetic acid derivatives gave higher yields. (4)
Ligands, including PPh3, with strong affinity for palladium
shut down the reaction completely. (5) Most interestingly,
benzoic acids with one weakly electron-donating group,
including methyl, methoxy, tert-butoxyl, phenoxyl, tert-butyl,
and phenyl groups, on the ortho position gave significantly
higher yields than their meta and para counterparts. The
ortho-phenyl benzoic acid (oPBA) stands out as the best
ligand in terms of efficiency and cost. Clearly, electronic
effects alone cannot explain such dramatic differences; we
posited that the steric hindrance from the ortho substituent
must play a critical role.
Table 1. Substrate Scope and Functional Group Tolerancea
Further screening revealed a clear solvent effect: strong
coordinating solvents such as CH3CN, DMF, and DMSO
completely shut down the reaction; THF and dioxane were
comparable to t-BuOH; acetone and CH2Cl2 gave lower
yields. Ag2CO3 (0.6 equiv) was found to be sufficient for
the reaction: excess Ag2CO3 (>1.5 equiv) slightly diminished
the yield. Addition of K2CO3 (0.5 equiv) also diminished
the yield.16 The reaction was well tolerant of air and
moisture. Finally, to our surprise, the cyclization reaction
can take place at even lower temperature and proceeded
cleanly over 72 h at 25 °C in the presence of 1.0 equiv of
oPBA, 1.0 equiv of Ag2CO3, and 0.1 equiv of Pd(OAc)2 in
t-BuOH/CH2Cl2 (2:1) or dioxane/H2O (20:1) (Table 1).17 In
contrast, no reaction occurred in the presence of AcOH, and
much lower yield was obtained with PivOH at 25 °C.18 The
oPBA ligand exhibited an unprecedented level of accelerating
ability to this catalytic cycle at ambient temperature.
The mild conditions of this cyclization reaction suggest that
the oPBA ligand can substantially lower the energy barrier for
the critical C-H activation and/or oxidative addition steps in
this PdII/IV catalytic cycle. While the cyclopalladation at ambient
temperature has been precedented, the oxidative addition of aryl
iodide via PdIV is usually considered kinetically unfavorable
and the rate-limiting step.19,20 We speculate that the ortho
bulky substituent on the benzoic acid might facilitate the
oxidative addition turnover via its facile dissociation from
the PdII center and provide a open coordination site to the
PdII intermediate (16e) (Scheme 1B, e-d).21
a General reaction condition: Pd(OAc)2 (0.1 equiv), Ag2CO3 (1.0 equiv),
oPBA (1.0 equiv), 25 µM in tBuOH, air and moisture were not excluded;
*, 5 µM.
With the optimized conditions established, we began
applying them to the cyclization of substrates with varied
ring sizes and functional groups. We were pleased to observe
moderate to excellent reaction yield and excellent functional
group tolerance (Table 1). All the substrates can be easily
prepared (see Supporting Information). In general, six-
membered rings were readily formed; five and seven-
membered rings were more difficult to form, and elevated
temperatures were needed. Macrocyclization of the 12-
membered ring 8 also worked well under more dilute
conditions. Aryl ethers, tosylamides, and phthalimides at
varied positions were well tolerated, and even the coumarin
(16) See discussion on proton shuttle in ref.14a
(17) CH2Cl2 is added to prevent t-BuOH from freezing.
(18) Higher yield (60-80%) can be achieved with AcOH or PivOH at
110°C.
(19) Activation of sp3 C-H bonds at room temperature: (a) ref 3f. (b)
Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. A.; Hartwig,
J. F. J. Am. Chem. Soc. 2002, 124, 390–391
.
(20) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. ReV. 2005, 105, 2527–
2571
.
(21) The carboxylate ligand dissociation has been proposed to facilitate
the reductive elimination from the PdIV intermediate, and the dissociation
for oxidative addition has not been discussed. See: Racowski, J. M.; Dick,
A. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 10974–10983. The
strong electron-donating bis-N ligand might also facilitate the PdII/IV
oxidative addition.
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Org. Lett., Vol. 12, No. 15, 2010

substrate 21 bearing the unsaturated lactone cyclized cleanly.
Aryl bromide 11 was also unaffected under the reaction
conditions. Interestingly, substrate 15 bearing the ester tether
completely failed the reaction, whereas its amide analogue
13 readily cyclized. The ester might act as an internal ligand
to block the oxidative addition step. Cyclization of substrate
23 bearing the Phth-NR gave a 2:1 diastereomeric mixture
of 24 and 25. Finally, the cyclization of the alkyl iodide 26
also worked but in much lower yield.
Scheme 2. Facile Auxiliary Removal
To make this method truly applicable to the synthesis of
complex molecules, the aminoquinoline auxiliary needs to
be removed or transformed into other functional groups under
mild conditions for further elaboration. To our delight, simple
Boc activation of the amide linkage22 followed by nucleo-
philic replacement provided the corresponding O-ester 29,
free acid 30, and S-ester 31 in excellent yield under mild
conditions (Scheme 2). Furthermore, the S-ester can be easily
converted to the corresponding aldehyde 32.
In summary, we developed a practical method for benzo-
ring construction via the aminoquinoline carboxamide di-
rected palladium-catalyzed functionalization of unactivated
methylene C-H bonds. The ortho-phenyl benzoic acid,
identified from a systematic screening, acts as a critical ligand
for this catalytic process under mild condition, even at near
room temperature. High yields and broad substrate scope
were achieved, and the auxiliary was shown to be amenable
to further transformation. Its application in the synthesis of
complex molecules and development of asymmetric cycliza-
tion is currently under investigation.
Acknowledgment. This work was supported by The
Pennsylvania State University. We thank Professors Kenneth
Feldman, Raymond Funk, Steven Weinreb, and their groups
at Penn State for insightful discussions and general sharing
of chemicals.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424–2426.
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