Iodination of remote ortho-C-H bonds of arenes via directed S EAr: A streamlined synthesis of tetrahydroquinolines

Article abstract of DOI:10.1021/ol4015078

A new strategy for the synthesis of tetrahydroquinolines (THQs) via the sequential functionalizations of remote C-H bonds is reported. This method uses a single picolinamide directing/protecting group to effect Pd-catalyzed γ-C(sp³)-H arylation, metal-free ε-C(sp²)-H iodination, and Cu-catalyzed intramolecular C-N cross-coupling. The overall sequence is efficient and versatile, and offers a streamlined synthesis of THQs with complex substitution patterns from readily available aryl iodide and aliphatic amine precursors.

Full text of DOI:10.1021/ol4015078

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iodination of Remote Ortho-CꢀH Bonds of
Arenes via Directed SEAr: A Streamlined
Synthesis of Tetrahydroquinolines
William A. Nack, Gang He, Shu-Yu Zhang, Chengxi Lu, and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park,
Pennsylvania 16802, United States
guc11@psu.edu
Received May 29, 2013
ABSTRACT
A new strategy for the synthesis of tetrahydroquinolines (THQs) via the sequential functionalizations of remote CꢀH bonds is reported. This
method uses a single picolinamide directing/protecting group to effect Pd-catalyzed γ-C(sp3)ꢀH arylation, metal-free ε-C(sp2)ꢀH iodination, and
Cu-catalyzed intramolecular CꢀN cross-coupling. The overall sequence is efficient and versatile, and offers a streamlined synthesis of THQs with
complex substitution patterns from readily available aryl iodide and aliphatic amine precursors.
Tetrahydroquinoline (THQ) is a privileged N-hetero-
cyclic scaffold found in many natural products and phar-
maceutical agents.1 In contrast to most conventional
synthesis strategies, which typically begin from prefunc-
tionalized arene or arylamine precursors, we envisioned
that THQs could be quickly assembled by connection at
the C2ꢀCγ and C1ꢀN positions throughdirectedCꢀHfunc-
tionalization reactions from simple aryl halide and alkyl
amine precursors (Scheme 1A).2ꢀ4 The picolinamide (PA)
group has been shown to effect the palladium-catalyzed
arylation of γ-C(sp3)ꢀH bonds of N-alkylpicolinamides
(e.g., 1) with aryl iodides, providing γ-arylpropylamine
products (e.g., 2, Scheme 1B).5ꢀ7 We postulated that the
installation of a halogen group at the ortho position of 2,
followed by intramolecular CꢀN cross coupling could
afford the desired THQ product in two discrete steps.8ꢀ10
Herein, we report a highly efficient and readily applicable
(1) (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
ꢀ
48, 15031. (b) Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C. Chem.
(5) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012,
133, 7. (c) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012,
134, 18237.
(6) (a) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192. (b)
Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850. (c) He, G.; Zhao, Y.;
Zhang, S.-Y.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (d)
Zhang, S.-Y.; He, G.; Zhao, Y.-S.; Wright, K.; Nack, W. A.; Chen, G.
J. Am. Chem. Soc. 2012, 134, 7313. (e) He, G.; Lu, C.; Zhao, Y.-S.; Nack,
W. A.; Chen, G. Org. Lett. 2012, 14, 2944. (f) Zhao, Y.; He, G.; Nack,
W. A.; Chen, G. Org. Lett. 2012, 14, 2948. (g) Zhang, S.-Y.; He, G.;
Nack, W. A.; Zhao, Y.-S.; Qiong, L.; Chen, G. J. Am. Chem. Soc. 2013,
135, 2124.
Rev. 2011, 111, 7157.
(2) For selected recent syntheses of THQs, see: (a) Akiyama, T.;
Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070. (b) Liu, H.;
Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc.
2008, 131, 4598. (c) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z.
ꢀ
J. Am. Chem. Soc. 2009, 131, 9182. (d) Rousseaux, S.; Liegault, B.;
Fagnou, K. Chem. Sci. 2012, 3, 244. For an elegant recent study on
enantioselective THQ synthesis via Pd-catalyzed CꢀH functionalization
approach, see: (e) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51,
12842.
(3) For an excellent review on CꢀH functionalization in the synthesis
of N-heterocycles, see: Thansandote, P.; Lautens, M. Chem.;Eur. J.
2009, 15, 5874.
(7) Recently, we found that PA-directed Pd-catalyzed γ-C(sp3)ꢀH
arylation could be notably improved with the application of catalytic
amount of (BnO)2PO2H. Detailed studies will be reported in a separate
account.
(8) Direct formation of THQs from γ-arylpropylpicolinamides via
Pd-catalyzed intramolecular dehydrogenative ε-C(sp2)ꢀH amination is
under current investigation.
(4) For selected recent reviews on C(sp3)ꢀH functionalization, see:
(a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2009, 48, 5094. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147. (c) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (d) Newhouse, T. R.; Baran,
P. S. Angew. Chem., Int. Ed. 2011, 50, 3362.
r
10.1021/ol4015078
XXXX American Chemical Society

method for the selective iodination of the ε-C(sp2)ꢀH
bonds of these γ-arylpropyl picolinamides under metal-
free conditions. The ortho-iodinated products can be
cyclized under copper catalysis to give tetrahydroquino-
lines (THQs) in high yields.
Table 1. Iodination of ε-o-CꢀH Bonds of 2 via SEAr
Neighboring group-directed halogenation of the ortho-
C(sp2)ꢀH bonds of arenes has been achieved under a
variety of metal-catalyzed or directed lithiation condi-
tions.11,12 However, generally applicable methods for the
selective halogenation of ortho-CꢀH bonds at the more
remote ε position are very rare.13,14 In our initial attempts,
CꢀH iodination of substrate 2 under an extensively opti-
mized Pd-catalyzed condition gave a mixture of mono-
ortho-iodinated product 3 and di-ortho-iodinated product
5 (entry 1, Table 1).15
yield (%)a
temp
solvents (°C)/h
entry
1
reagents (equiv)
3
4/5
Pd(OAc)2 (10%),
PhI(OAc)2 (2),
2 (2) KHCO3 (1)
DMF
130/24 44
<2/37
I
2
3
IPy2 BF4 (1.5),
T/D (1:10)b,c rt/2
T/D (1:10)c rt/2
60
88
5/24
6/3
3
HBF4 OEt2 (3)
3
IPy2 BF4 (1.1),
3
HBF4 OEt 2 (2.2)
3
4
5
6
7
8
NIS (1.1), HBF4 OEt2 (4) T/D (1:9)
0/4
0/4
0/4
0/4
0/4
90 (83)d 4/3
3
NIS (1.1), TfOH (4)
T/D (1:9)
T/D (1:9)
41
68
48
30
26/4
28/<2
4/26
Scheme 1. New Synthetic Strategy for THQs
NIS (1.1), BF3 OEt2 (4)
3
NIS (1.5), HBF4 OEt2 (4) T/D (1:9)
3
NIS (1.1)
T/D (1:9)
24/<2
a All screening reactions were carried out on a 0.2 mmol scale at
6.7 mM concentration unless noted; yields are based on 1H NMR
analysis of the reaction mixture after workup. b T/D: TFA(T)/CH2Cl2
(D). c Performed at 4.5 mM concentration. d Isolated yield.
a very rare example of remote functional group-directed
ε-ortho-CꢀH functionalization of arenes via an electro-
philic aromatic substitution (SEAr) pathway.17 Inspired by
Barluenga’s seminal discovery, we proceeded to evaluate
whether the ε-C(sp2)ꢀH bond of γ-arylpropylpicolina-
mide 2 could be iodinated in a similar fashion (Table 1).18
In 2007, the Barluenga laboratory reported that the
ortho-C(sp2)ꢀH bonds of γ-phenylpropyl trifluoroacet-
amide (57 in Scheme 4) can be selectively monoiodinated
with bis(pyridine) iodonium(I) tetrafluoroborate (IPy2.
BF4) under metal-free conditions.16 This reaction presents
Following Barluenga’s protocol (1.5 equiv of IPy2 BF4,
3
3 equiv of HBF4 OEt2 in mixed solvent of TFA/CH2Cl2
3
at room temperature), substrate 2 generated a mixture of
mono- and di-ortho-iodinated product (3 and 5, entry 2).
The selectivity was improved when only 1.1 equiv of
IPy2 BF4 was applied (entry 3). To augment the utility
3
of this reaction, we next surveyed more economical and
convenient to handle Iþ precursors.19 Gratifyingly, we
found that 1.1 equiv of N-iodosuccinimide (NIS)20,21
provided excellent iodination results with further im-
proved o/p selectivity when the reaction was performed
at 0 °C (entry 4). No iodination of the PA group was
observed. NCS and NBS gave monohalogenated products
in a nonselective fashion. Notably, the addition of the
(9) For an excellent study on the synthesis of indolines and tetra-
hydroisoquinolines via Pd-catalyzed CꢀH activation, see: Li, J.-J.; Mei,
T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452.
(10) γ-C(sp3)ꢀH arylation using o-arene dihalide precursors usually
proceeds in low yield under the standard conditions. Preparation of the
o-dihalides often requires a multistep sequence.
(11) For selected examples of metal-catalyzed halogenation of neigh-
boring o-CꢀH bonds, see: (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.;
Sanford, M. S. Tetrahedron 2006, 62, 11483. (b) Wan, X.; Ma, Z.; Li, B.;
Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416.
(c) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed.
2008, 47, 5215. (d) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.;
Brønsted acid HBF4 OEt2 is critical to the ortho selectiv-
ity of the reaction (entry 8).
3
€
Webster, R. L. Angew. Chem., Int. Ed. 2011, 50, 5524. (e) Schroder, N.;
Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc. 2012, 134, 8298.
(12) (a) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306. (b)
Snieckus, V. Chem. Rev. 1990, 90, 879.
(13) For selected examples of the metal-catalyzed functionalization
of remote CꢀH bonds, see: (a) Hennings, D. D.; Iwasa, S.; Rawal, V. H.
J. Org. Chem. 1997, 62, 2. (b) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7,
2849. (c) Shi, F.; Larock, R. C. Top. Curr. Chem. 2010, 292, 123. (d)
Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518.
(14) For pioneering work on remote CꢀH functionalization by
Breslow, see: Breslow, R. Acc. Chem. Res. 1980, 13, 170.
(17) For another example of functional group-directed halogenation
of remote CꢀH bonds via SEAr, see: (a) O’Connell, J. L.; Simpson, J. S.;
Dumanski, P. G.; Simpson, G. W.; Easton, C. J. Org. Biomol. Chem.
2006, 4, 2716. For an elegant study on peptide-mediated regio and
enantioselective bromination of biaryl compounds, see: (b) Gustafson,
J. L.; Lim, D.; Miller, S. J. Science 2010, 328, 1251.
(18) A single example of iodination of the δ-o-CꢀH bond of
β-phenylethyl picolinamide was first demonstrated in Barluenga’s
2007 paper as a control substrate; see ref 16a.
(15) Similar conditions were originally applied in Yu’s Pd-catalyzed
iodination of remote ortho C(sp2)ꢀH bonds; see: (a) Li, J.-J.; Giri, R.;
(19) IPy2 BF4 is commercially available (1 g/$76 from Aldrich).
Freshly prepared or recrystallized IPy2.BF4 is often recommended for
use in reactions.
3
Yu, J.-Q. Tetrahedron 2008, 64, 6979. (b) ref 9.
ꢀ
(16) (a) Barluenga, J.; Alvarez-Gutierrez, J. M.; Ballesteros, A.;
ꢀ
(20) NIS (97%, Alfa Aesar) was used without further purification.
(21) Prakash, S.; G., K.; Mathew, T.; Hoole, D.; Esteves, P. M.;
Wang, Q.; Rasul, G.; Olah, G. A. J. Am. Chem. Soc. 2004, 126, 15770.
ꢀ
~
Gonzalez, J. M. Angew. Chem., Int. Ed. 2007, 46, 1281. (b) Espuna,
ꢀ
G.; Arsequell, G.; Valencia, G.; Barluenga, J.; Alvarez-Gutierrez, J. M.;
ꢀ
ꢀ
Ballesteros, A.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2004, 43, 325.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Substrate Scope of PA-Directed Sequential
C(sp3)ꢀH Arylation and C(sp2)ꢀH Iodinationa
Scheme 3. Cu-Catalyzed Formation of THQsa
a All reactions were carried out on a 0.2 mmol scale; yields are based
on isolated product. b Yield of PA-deprotected product is shown in
parentheses.
meta substituents were iodinated with excellent selectivity
at the less hindered ortho position.
Treatment of ortho-iodinated compound
3 with
Cu-catalyzed cyclization conditions (10 mol % of CuI,
2.5 equiv of CsOAc in DMSO at 90 °C) afforded
the desired THQ product 38 in excellent yield (eq 4,
Scheme 3).9,22 THQ products 39ꢀ47 were also obtained
in high yields under the same conditions. The PA group of
the cyclized THQ products, linked through an aromatic
tertiary amide bond, can be readily removed with nucleo-
philic bases or metal hydride reagents (eq 5).23 The PA
group of THQs bearing electron-withdrawing groups was
partially removed during the Cu-mediated cyclization step
(see 44 in Scheme 3).
To investigate the mechanism of this PA-directed ortho-
iodination reaction, control substrates 51ꢀ58 were
evaluated (Scheme 4). Substrates 59ꢀ62 are equipped
with auxiliary groups known to direct metal-catalyzed
C(sp3)ꢀH functionalization.24 All reactions proceeded
with >90% conversion under the standard conditions
(A), giving predominately monoiodinated products. For
benzamide 51 and picolinic ester 52, we observed 2:3 ortho/
para selectivity, indicating that both N atoms of the PA
a All reactions were carried out on a 0.2 mmol scale; yields are based
on isolated product. See the Supporting Information for experimental
details pertaining to CꢀH arylations and iodinations. b o-di: ortho-
diiodinated isomer. x: unidentified iodinated products. c Conditions B:
NIS (3.3 equiv), HBF4.OEt2 (12 equiv), 2.5 mM, rt, 16 h. d 13% of 26
recovered.
As shown in Scheme 2, γ-arylpropylpicolinamides bear-
ing different substituents at the R, β and γ positions (10, 14,
18, and 22) were readily prepared from the corresponding
aryl iodides and N-alkylpicolinamides via Pd-catalyzed
C(sp3)ꢀH arylation.7 Good to excellent iodination yields
were obtained for these substrates under the standard
conditions (A). Excellent ortho-selectivities were observed
for substrates bearing moderately electron-donating or
-withdrawing substitutents such as alkyl and halogen
groups (see 11, 15, and 37). In general, electron-deficient
arene substrates such as 26 and 33 were less reactive;
moderate to good yields were obtained under more forcing
(22) (a) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama,
H.; Fukuyama, T. Tetrahedron 2008, 64, 11230. For previous reports on
Cu-catalyzed CꢀN cross-coupling, see: (b) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (c) Ma,
D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120,
12459.
(23) (a) Tanaka, H.; Ogasawara, K. Tetrahedron Lett. 2002, 43, 4417.
(b) Reference 5b.
(24) (a) For directing group (DG) in 59, see: Rodrıguez, N.; Romero-
ꢀ
ꢀ
ꢀ~
Revilla, J. A.; Fernandez-Ibanez, M. A.; Carretero, J. C. Chem. Sci.
2013, 4, 175. (b) For DG in 60, see: Wasa, M.; Engle, K. M.; Yu, J.-Q.
J. Am. Chem. Soc. 2009, 131, 9886. (c) For DG in 61, see ref 5a. (d) For
DG in 62, see: Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am.
Chem. Soc. 2009, 131, 6898.
conditions (B) with excess NIS and HBF4 OEt2 at room
temperature. Sterics also strongly influence the regioselec-
tivity of the reaction; substrates 10, 14, 30, and 36 bearing
3
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Mechanistic Study of SEAr-Mediated Iodinationa
Scheme 5. Total Synthesis of (þ)-Angustureine
In summary, we have developed a new strategy to
synthesize tetrahydroquinolines via the sequential functio-
nalization of two different types of remote CꢀH bonds.
This method uses only the picolinamide directing/protecting
group to effect Pd-catalyzed γ-C(sp3)ꢀH arylation, metal-
free ε-C(sp2)ꢀH iodination, and Cu-catalyzed intramole-
cular CꢀN cross-coupling. The PA group of cyclized
products could be easily removed. The overall sequence is
efficient and versatile and allows for the streamlined synth-
esis of THQs with complex substitution patterns at both
arene and aliphatic positions from readily available aryl
iodide and alkylamine precursors. The monoselective ortho-
iodination of γ-arylalkyl picolinamides with NIS/HBF4
presents a generally applicable synthetic method for remote
CꢀH functionalization based on the underexplored reac-
tion pathway of directed SEAr.
a All reactions were performed under the standard conditions (A) for
4 h. Yields and selectivities are based on 1H NMR analysis of reaction
mixture after workup. b ∼10% unidentified iodinated product formed.
See the Supporting Information for experimental details.
group were involved in the directed ortho-iodination
process. N-methylpicolinamide 53 also underwent ortho-
iodination, with diminished selectivity relative to non-
alkylated picolinamide 6, suggesting that O- iodoimidate
50 is likely the critical intermediate in this intramolecular
SEAr reaction, rather than N-iodoamidate 49.17a Interest-
ingly, the quinolyl carboxamide substrate 615a also under-
went ortho-selective monoiodination in excellent yield and
selectivity.
Acknowledgment. We gratefully acknowledge financial
support from The Pennsylvania State University, the US
National Science Foundation (CHE-1055795), and ACS-
PFR (51705-DNI1).
To demonstrate the utility of this new THQ synthesis
strategy, we applied it to the synthesis of the natural
product (þ)-angustureine (66, Scheme 5).25 Commercially
available (S)-(þ)-3-octanol 63 was converted to picolina-
mide 64 via Mitsunobo chemistry, followed by deprotection
and amide coupling. The standard sequence of PA-directed
CꢀH arylation followed by iodination, and cyclization gave
intermediate 65 in 67% yield. Deprotection of the PA group
of 65 followed by N-methylation, furnished 66 in good yield.
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.
(25) Lin, X.-F.; Li, Y.; Ma, D.-W. Chin. J. Chem. 2004, 22, 932.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX