Diastereoselective synthesis of tetrahydroquinolines via a palladium-catalyzed Heck-Suzuki cascade reaction

Article abstract of DOI:10.1016/j.tetlet.2012.02.096

A method for the diastereoselective synthesis of tetrahydroquinolines via a palladium-catalyzed Suzuki terminated Heck reaction is described. The reaction provides access to tetrahydroquinolines containing both quaternary and tertiary stereocenters. Ligand effects, a rationale for the high level of diastereoselectivity, and a mechanistic hypothesis are discussed.

Full text of DOI:10.1016/j.tetlet.2012.02.096

Tetrahedron Letters 53 (2012) 2308–2311
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective synthesis of tetrahydroquinolines
via a palladium-catalyzed Heck–Suzuki cascade reaction
Jonathan E. Wilson
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the diastereoselective synthesis of tetrahydroquinolines via a palladium-catalyzed Suzuki
terminated Heck reaction is described. The reaction provides access to tetrahydroquinolines containing
both quaternary and tertiary stereocenters. Ligand effects, a rationale for the high level of diastereoselec-
tivity, and a mechanistic hypothesis are discussed.
Received 27 January 2012
Revised 15 February 2012
Accepted 21 February 2012
Available online 28 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalysis
Tetrahydroquinoline
Heck reaction
Suzuki coupling
In the course of a recent medicinal chemistry program we be-
came interested in the synthesis of tetrahydroquinolines (THQs)
containing a quaternary stereocenter at C-4 and an aryl group at
C-2. It was envisioned that these structures may be constructed
from a palladium-catalyzed intramolecular insertion into a 2,2-
disubstituted olefin in which the nascent alkyl-palladium(II) inter-
mediate would be intercepted by transmetallation with an aryl
boronic acid resulting in an alkyl-Suzuki coupling. Formally, this
could be thought of as a Heck/Suzuki cascade (Scheme 1). Previ-
ously, this strategy has been applied to the synthesis of a variety
of heterocycles and carbocycles.1,2 However, diastereoselective
variants and application of this transformation to the synthesis of
THQs are limited. Herein, efforts toward this goal are described.
The reaction in Table 1 was investigated to test the feasibility of
the strategy outlined above. Because Pd2(dba)3/P(t-Bu)3 is known
to be an excellent catalyst for both Heck3 and Suzuki4 couplings,
the initial experiments were performed with this system in combi-
nation with K3PO4 as base. Gratifyingly, these conditions afforded
the THQ in excellent yield and diastereoselectivity (Table 1, entry
1). The reaction also proceeds under anhydrous conditions, which
may be of use when performing couplings with base labile protect-
ing groups (Table 1, entry 2). A ligand is required for the coupling,
but the success of the reaction is not dependent upon the use of
P(t-Bu)3 (Table 1, entry 3). Other ligands such as X-PHOS, PCy3,
BINAP, and PPh3 are also effective, but in most cases deliver the
THQ product with inferior levels of diastereoselectivity.5 The
diastereoselectivity appears to decline as the cone angle of
the phosphine ligand decreases.6 Finally, substrate modifications
have a profound impact on the course of the reaction. Arylchlorides
do not react under the optimized conditions (Table 1, entry 8). If a
secondary amine (N-H instead of N-Bn) is used in the reaction, the
direct Suzuki cross coupling product (product B) is obtained as the
sole product (Table 1, entry 9).
With an effective set of conditions in hand, the scope of the
reaction was investigated. A variety of aryl boronic acids were
effective coupling partners. Both electron-rich (Table 2, entries 3,
4, and 6) and electron-poor (Table 2, entries 5, 10, and 12) boronic
acids coupled smoothly to deliver the THQ products in excellent
yield and diastereoselectivity. Moreover, heterocyclic boronic acids
were effective coupling partners (Table 2, entries 2 and 6). Modifi-
cations, such as addition of a 6-fluoro- or 6-methyl-substituent, to
the bromo-aniline were also tolerated (Table 2, entries 8, 10, and
11). Finally, substrates containing alternative nitrogen substituents
such as N-PMB or N-Me are also effective coupling partners (Table
2, entries 9, 12, and 13).
In contrast to arylboronic acids, styrenylboronic acid did not
provide the desired Heck/Suzuki coupling product under the opti-
mized reaction conditions. Instead, the product from a direct Suzu-
ki cross coupling was observed. This type of product was also
observed with other very electron-rich boronic acids, such as
3-(N-Boc)indoleboronic acid (Scheme 2).7
These observations are consistent with the enhanced nucleo-
philicity of vinyl boronic acids and electron-rich heterocyclic boro-
nic acids relative to aryl boronic acids. Interestingly, the direct
cross coupling product was not observed in any appreciable
amount in the case of any of the arylboronic acids shown in Table
2, with the exception of 3-thienylboronic acid (Table 2, entry 6).
E-mail address: jonathan_wilson@merck.com
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.096

J. E. Wilson / Tetrahedron Letters 53 (2012) 2308–2311
2309
C-4
Ar2
C-2
Ar1
Pd2+
Ar1
Me
Me
Ar2B(OH)2
Pd0 catalyst
X
Me
Ar1
Alkyl Suzuki
Coupling
N
R
N
R
Heck reaction
N
R
Scheme 1. Retrosythetic analysis for tetrahydroquinoline target compounds.
Table 1
Reaction optimization
Me
Ph
3 equiv. 3-OMe-C6H4B(OH)2
Me
Me
2.5% Pd2(dba)3
Br
.
N
Bn
10% P(t-Bu)3 HBF4
OMe
3 equiv. K3PO4
N
Ph
N
Ph
Bn
Bn
toluene:H2O (9:1), 85 o
C
OMe
A
B
Entry
Change from standard conditions
Conversion
Yield (%, product)
d.r.
1a
2b
3b
4b
5b
6b
7b
8b
9a
No change
No water
No ligand
X-PHOS instead of P(t-Bu)3
P(Cy)3 instead of P(t-Bu)3
BINAP instead of P(t-Bu)3
PPh3 instead of P(t-Bu)3
Cl instead of Br
100
100
0
100
100
100
100
0
93 (A)
>99 (A)
0
>99 (A)
>99 (A)
>99 (A)
>99 (A)
0
>20:1
>20:1
n.a.
>20:1
10:1
6:1
3:1
N–H instead of N-Bn
100
95 (B)
a
Isolated yield. Diastereomeric ratio based from 1H NMR analysis of crude reaction mixture.
NMR yield calculated using internal standard of mesitylemne.
b
The reaction is believed to proceed through oxidative addition
acetate, and filtered through a small pad of silica gel eluting with
ethyl acetate. The crude solution was concentrated and purified by
silica gel chromatography (Biotage 25 g SNAP cartridge; 0–10% ethyl
acetate in hexanes) to afford a clear viscous oil (121 mg, 93%). 1H
NMR (500 MHz) d 7.35 (m, 1H), 7.30–7.15 (m, 10H), 7.12 (apparent
t, J = 7.5 Hz, 1H), 6.89 (d, J = 9.3 Hz, 1H), 6.87 (d, J = 9.3 Hz, 1H), 6.79
(dd, J = 8 Hz, J = 2 Hz, 1H), 6.67 (apparent t, J = 7.5 Hz, 1H), 6.59 (d,
J = 2.5 Hz, 1H), 6.32 (s, 1H), 4.75 (d, J = 16 Hz, 1H), 4.68 (dd,
J = 11 Hz, J = 5 Hz, 1H), 4.06 (d, J = 16 Hz, 1H), 3.64 (s, 3H), 3.02 (d,
J = 12.5 Hz, 1H), 2.82 (d, J = 12.5 Hz, 1H), 2.10 (dd, J = 14 Hz,
J = 5 Hz, 1H), 1.98 (dd, J = 14 Hz, J = 12 Hz, 1H), 1.26 (s, 3H). LCMS
calc. for C31H31NO [M+1] 434.24, found 434.3.
followed by the insertion into the olefin to yield the alkyl-palladium
(II)-intermediate. This intermediate then undergoes transmetalla-
tion with boronic acid. Finally, reductive elimination affords
tetrahydroisoquinoline and regenerates the catalyst, Pd(0)-P(t-
Bu)3 (Scheme 3).
A method for the synthesis of tetrahydroquinolines that em-
ploys a Heck–Suzuki cascade reaction has been described. The
reaction tolerates a variety of coupling partners and provides THQs
in good yield and with high levels of diastereoselectivity. A positive
correlation between the cone angle of the phosphine ligand and
the diastereoselectivity of the reaction was observed. Efforts are
underway to apply this strategy to a variety of other highly-substi-
tuted heterocyclic systems.
Substrate preparation
Experimental procedures
2-Bromoaniline (2.18 g, 12.67 mmol) and benzaldehyde (1.287
ml, 12.67 mmol) are combined in DCE (10 ml) with MgSO4 and
heated to 65 °C until the reaction is judged to be complete by
NMR. The MgSO4 is removed by filtration and the crude material
is concentrated and dissolved in THF. The solution is cooled to
0 °C and treated with 2-methyl-allylmagnesium chloride
(27.9 ml, 13.94 mmol). The mixture is stirred until the reaction is
judged to be complete by NMR. The reaction is quenched with sat-
urated ammonium chloride and the product is extracted with ethyl
acetate. The extracts are dried over Na2SO4, filtered, and concen-
trated. The crude material is purified by silica gel chromatography
(Biotage 100 g SNAP cartridge; 0–10% ethyl acetate in hexanes) to
afford 2-bromo-N-(3-methyl-1-phenylbut-3-en-1-yl)aniline as
yellow oil (3.75 g, 94%).
Procedure for the Heck–Suzuki cascade reaction
Me
Me
Ph
NaHMDS, BnBr
1) PhCHO
NH2 2)
Br
Br
Br
N
H
Ph
N
Bn
Me
MgCl
The arylbromide (122 mg, 0.3 mmol), 3-methoxy-phenylbo-
ronic acid (137 mg, 0.900 mmol), potassium phosphate (191 mg,
0.900 mmol), Pd2(dba)3 (6.87 mg, 0.008 mmol), and tri-tert-butyl-
phosphonium tetrafluoroborate (8.70 mg, 0.030 mmol) were com-
bined in a mixture of degassed toluene (0.81 ml) and water
(0.09 ml) and heated to 90 °C for 14 h. At this time LC–MS showed
a complete reaction. The reaction was cooled, diluted with ethyl
Sodium bis(trimethylsilyl)amide (3.83 ml, 3.83 mmol) was
added to a solution of 2-bromo-N-(3-methyl-1-phenylbut-3-en-1-

2310
J. E. Wilson / Tetrahedron Letters 53 (2012) 2308–2311
Table 2
Additional examples of tetrahydroquinolines prepared via the diastereoselective Heck–Suzuki cascade
Entry
Product
Yield (%), d.r.b
93, >20:1
Entry
Product
Yield (%), d.r.b
95, >20:1
Me
Me
F
OMe
OMe
1
8
N
N
Bn
Bn
OMe
N
N
Me
Me
Me
Boc
OMe
2
3
95, >20:1
9
93, >20:1
N
Bn
N
Me
F
Me
Me
CO2t-Bu
88, >20:1
10
97, >20:1
N
N
Bn
Bn
OMe
Me
MeO
Me
Me
Me
Me
4
72, >20:1
11
90, >20:1
Me
N
Bn
N
Bn
OMe
Me
CF3
NO2
F
5
58, >20:1
12
13
99, >20:1
N
PMB
N
Bn
S
Me
Me
Me
6a
63, >20:1
95, >20:1
95, >20:1
OCF3
N
PMB
N
Bn
F
7
OMe
OCF3
N
Bn
a
Isolated with the direct cross coupling product (as in Table 1, product B) in a ratio of 2:1 as an inseparable mixture of compounds. Yield is based on 1H NMR.
Diastereomeric ratio is for the crude reaction mixture.
b
2.5% Pd2(dba)3
10% P(t-Bu)3
Ph
(HO)2B
Me
N
Boc
3 equiv. K3PO4
Br
Me
HO
Ph
B
OH
OCF3
OCF3
toluene:H2O (9:1), 85 °C
53%
N
Bn
N
Bn
B(OH)2
S
Scheme 2. Boronic acid substrates that yield direct Suzuki coupling products.
yl)aniline (1.01 g, 3.19 mmol) in THF (12 ml) cooled to 0 °C. The
reaction was stirred for 1 h at 0 °C and then benzylbromide
(0.399 ml, 3.35 mmol) was added. The reaction was allowed to
warm to rt and stirred overnight. The reaction was quenched with
saturated ammonium chloride solution and the product was ex-
tracted with ethyl acetate. The combined extracts were dried over

J. E. Wilson / Tetrahedron Letters 53 (2012) 2308–2311
2311
Me
Ph
Me
Ar
Br
Pd0Ln
N
N
Ph
Bn
Bn
Oxidative
Addition
Reductive
Elimination
Heck/Suzuki Product
Ar
L
PdBr
Me
Me
Pd
L
N
Bn
Ph
N
Bn
Ph
Trans-
metallation
Olefin
Insertion
Me
H
Me
R
N
ArB(OH)2
N
Ph
Ln
Bn
R
B(OH)2
Ph
Pd
Br
Bn
Direct Suzuki Product
Scheme 3. Proposed mechanism of the diastereoselective tetrahydroquinoline synthesis.
Cossy, J. Tetrahedron 2006, 62, 3882; (f) Arthius, M.; Pontikis, R.; Florent, J.-C.
Tetrahedron Lett. 2007, 48, 6397; (g) Marchal, E.; Cupif, J.-F.; Uriac, P.; van de
Weghe, P. Tetrahedron Lett. 2008, 49, 3713; (h) Guo, L.-N.; Duan, X.-H.; Hu, J.; Bi,
H.-P.; Liu, X.-Y.; Liang, Y.-M. Eur. J. Org. Chem. 2008, 1418; (i) Arthius, M.;
Pontikis, R.; Florent, J.-C. J. Org. Chem. 2009, 74, 2234.
Na2SO4, filtered, and concentrated. The material was recrystallized
from DCM/hexanes (1:9) to afford N-benzyl-2-bromo-N-(3-
methyl-1-phenylbut-3-en-1-yl)aniline as a cream colored solid
(365 mg, 28%). 1H NMR (500 MHz) d 7.59 (apparent d, J = 8 Hz,
1H), 7.36–7.29 (m, 5H), 7.21–7.16 (m, 4H), 7.12 (m, 1H), 7.06
(apparent t, J = 8 Hz, 1H), 6.88 (m, 1H), 6.76 (apparent d, J = 8 Hz,
1H), 4.67 (broad s, 1H), 4.61 (dd, J = 10 Hz, J = 5 Hz, 1H), 4.59 (broad
s, 1H), 4.29 (d, J = 15 Hz, 1H), 3.90 (d, J = 15 Hz, 1H), 2.84–2.82 (m,
2H), 1.63 (s, 3H). LCMS calc. for C31H31NO [M+1] 406.11, found
406.1.
3. (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989; (b) Littke, A. F.; Fu, G.
C. J. Org. Chem. 1999, 64, 10.
4. (a) Lou, S.; Fu, G. C. Adv. Synth. Catalysis 2010, 352, 2081; (b) Littke, A. F.; Fu, G. C.
J. Am. Chem. Soc. 2000, 122, 4020.
5. The cone angles for PPh3, PCy3, and Pt-Bu3 are 145°, 170°, and 182°. These values
were taken from: (a) Tolman, C. A. Chem. Rev. 1977, 77, 313; The cone angle for
BINAP is 189° which does not fit the hypothesis that has been put forward.
However, BINAP is bidentate and other factors may be involved. The cone angle
for BINAP was taken from: (b) Niksch, T.; Gorling, H.; Weigand, W. Eur. J. Inorg.
Chem. 2010, 95.
Acknowledgements
6. The relative stereochemistry was determined by performing a 1H–1H 2D NOE
(NOESY) experiment on product A of Table 1. There was a strong NOE between
Ha and Hb and no NOE observed between Ha and the protons of the methyl
group. This indicates that the benzyl group and Ha are on the same face of the
molecule and that both reside in pseudoaxial positions.
The author would like to thank Mikhail Reibarkh for helpful
NOE studies and Petr Vachal, Harry Chobanian, and Christopher
Plummer for helpful discussions.
Me
References and notes
N
Ph
OMe
1. A similar Heck/Suzuki cascade has been used for the synthesis of a variety of
heterocyclic systems including one example of THQ, see: (a) Lu, Z.; Hu, C.; Guo,
J.; Li, J.; Cui, Y.; Jia, Y. Org. Lett. 2010, 12, 480; For a diastereoselective synthesis
of methylenetetrahydrofurans employing this strategy see: (b) Braun, M.;
Richrath, B. Synlett 2009, 968.
Bn
Hb
Ha
Hb
2. For the use of this strategy for the synthesis of other carbocyclic and
heterocyclic systems, see: (a) Oh, C. H.; Sung, H. R.; Park, S. J.; Ahn, K. H. J.
Org. Chem. 2002, 67, 7155; (b) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Org. Lett.
2004, 6, 2511; (c) Cheung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005, 70,
3741; (d) Yanada, R.; Obika, S.; Inokuma, T.; Yanada, K.; Yamashita, M.; Ohta, S.;
Takemoto, Y. J. Org. Chem. 2005, 70, 6972; (e) Couty, S.; Liegault, B.; Meyer, C.;
7. This side product is observed in
a
related method for the synthesis of
methylenetetrahydrofurans, see Ref. 1b.