Multicomponent multicatalyst reactions (MC)2R: One-pot synthesis of 3,4-dihydroquinolinones

Article abstract of DOI:10.1021/ol4006008

A Rh/Pd/Cu catalyst system led to an efficient synthesis of dihydroquinolinones in one-pot, two operations. The reaction features the first triple metal-catalyzed transformations in one reaction vessel, without any intermediate workup. The conjugate-addition/amidation/amidation reaction sequence is highly modular, divergent, and practical.

Full text of DOI:10.1021/ol4006008

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Multicomponent Multicatalyst
Reactions (MC)2R: One-Pot
Synthesis of 3,4-Dihydroquinolinones
Lei Zhang, Lorenzo Sonaglia, Jason Stacey, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto,
80 St George Street, Toronto, Ontario M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received March 6, 2013
ABSTRACT
A Rh/Pd/Cu catalyst system led to an efficient synthesis of dihydroquinolinones in one-pot, two operations. The reaction features the first triple
metal-catalyzed transformations in one reaction vessel, without any intermediate workup. The conjugate-addition/amidation/amidation reaction
sequence is highly modular, divergent, and practical.
In addition to the development of new methods in
synthetic organic chemistry, efficiency remains a major
objective. Ultimately, factors that significantly hinder
efficiency include workup and purification, which require
time and generate waste. Thus, the development of cascade
and one-pot reactions provides ideal solutions that address
this challenge. Within this paradigm, there is room for
further increase in efficiency through the development of
multimetal-catalyzed processes.1 While chemists have yet
to achieve Nature’s capacity to have multiple catalysts
operate within the same “vessel”, the development of
multimetal-catalyzed cascade reactions can afford highly
modular and divergent syntheses.
(1) For selected examples of the use of two transition-metal catalysts
in a domino transformation, see: (a) Zimmermann, B.; Herwig, J.;
Beller, M. Angew. Chem., Int. Ed. 1999, 38, 2372–2375. (b) Jeong, N.;
Seo, S. D.; Shin, J. Y. J. Am. Chem. Soc. 2000, 122, 10220–10221. (c)
Komon, Z. J. A.; Diamond, G. M.; Leclerc, M. K.; Murphy, V.;
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Org. Lett. 2003, 5, 459–462. (f) Nishibayashi, Y.; Yoshikawa, M.; Inada,
Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2004, 126, 16066–16072. (g)
Goldman, A. S.; Roy, A. H.; Huang, Z.; Ahuja, R.; Schinski, W.;
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G.; Gaillard, T.; Madec, D.; Poli, G. Org. Lett. 2008, 10, 405–408. (i)
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2009, 131, 18022–18023. (k) Takahashi, K.; Yamashita, M.; Ichihara, T.;
Nakano, K.; Nozaki, K. Angew. Chem. 2010, 122, 4590–4592. Angew.
Chem., Int. Ed. 2010, 49, 4488–4490. For selected examples of multi-
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J. Am. Chem. Soc. 1996, 118, 3309–3310. (m) Gooßen, L. J.; Deng, G.;
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r
10.1021/ol4006008
XXXX American Chemical Society

We obtained excellent yields using K3PO4, t-BuOH, and
tert-amyl alcohol (entries 2 and 3).
We next focused our attention on the development of
Pd-catalyzed intramolecular amidation. The Pd-catalyzed
amidation of aryl chlorides is a challenging reaction, but
we were able to realize the reaction employing Pd(OAc)2
and XPhos L2 in the presence of K3PO4 and t-BuOH
(entry 4).6 We tested the compatibility of both metal-
catalyzed reactions in one synthetic operation and were
pleased with an initial conversion to 3 and 4a in a yield of
49 and 35%, respectively (entry 5). Elevating the reaction
temperature to 110 °C gave a smooth reaction to afford the
desired dihydroquinolinone 4a in 74% yield (entry 6). We
opted for the use of t-am-OH as solvent due to its ease of
handling. Further improvements in yield were achieved by
switching the Pd-catalyst to [Pd(allyl)Cl]2 (entry 7). We
also observed a benefit by omitting BINAP (entry 8).
Consequently, no catalyst premixing was required in the
reaction setup, which significantly improved the opera-
tional practicality of the reaction. Lowering the amount of
boronic acid to just 1.05 equiv not only improved the
efficiencyof the conjugateaddition but alsothe subsequent
step. This effect probably resulted from diminished proto-
deborolation to form chlorobenzene, a possible inhibitory
byproduct for the Pd-catalyzed reaction. Finally, the use
of a more cost-effective catalyst, [Rh(cod)Cl]2, provided
favorable reactivity (entry 9).
Figure 1. Developments in Rh/Pd dual catalysis.
Due to the highly versatile and orthogonal catalytic
reactivity of rhodium and palladium,2 we decided to apply
the Rh/Pd system in a new conjugate addition/amidation
catalytic multimetal method. We further expanded the
modularity of this method with a subsequent Cu-catalyzed
amidation that exhibited highly complementary reactivity
(Figure 1). We could access quinolinones, which are
ubiquitous scaffolds of drugs and natural products that
possess potent biological properties (Figure 2).3
Table 1. Optimization of Reaction Conditionsa
Figure 2. Drugs containing the 3,4-dihydroquinolinone scaffold.
sol/MeOH
(10:1)
% yield
We began our study with the optimization of Rh-catalyzed
conjugate addition of o-chloroarylboronic acid 1a onto
acrylamide 2a (Table 1).4 In general, the presence of an ortho
substituent had a negative impact on the reaction but follow-
ing optimization, a conjugate addition product 3, employing
catalytic amounts of [Rh(cod)OH]2 and BINAP L1 with
dioxane/MeOH as solvent (entry 1) was found to afford
the desired product in good yields. We then tested the com-
patibility of the conjugate addition with conditions that are
typically employed in Pd-catalyzed amidation reactions.5,6
entry
[Rh]/L1
[Pd]/L2
t (°C)
3a/4a
1b
2
[Rh(cod)OH]2
[Rh(cod)OH]2
[Rh(cod)OH]2
ꢀ
ꢀ
ꢀ
ꢀ
Dioxane
t-BuOH
t-am-OH
t-BuOH
t-BuOH
t-BuOH
100 84/ꢀ
100 89/ꢀ
100 92/ꢀ
100 ꢀ/99
110 49/35
110 ꢀ/74
110 ꢀ/73
110 ꢀ/76
110 ꢀ/89 (87)
3
4c
5d
6
[Pd(OAc)2]
[Pd(OAc)2]
[Pd(OAc)2]
[Rh(cod)OH]2
[Rh(cod)OH]2
[Rh(cod)OH]2
7
8e
[Pd(allyl)Cl2] t-am-OH
[Rh(cod)OH]2 no L1 [Pd(allyl)Cl2] t-am-OH
9e,f [Rh(cod)Cl]2 no L1 [Pd(allyl)Cl2] t-am-OH
a Yields were determined by 1H NMR spectroscopy. [Rh] and L1
were premixed separately from [Pd] and L2, each in 1 mL of solvent for
15 min. The mixtures were transferred to a vial containing 1a (1.5 equiv),
2a (0.4 mmol), base (2.2 equiv) under argon atmosphere. The vial was
stirred at rt for 15 min, sealed, and heated at the described temperature
for 16 h. b K2CO3 was used instead of K3PO4. c Reaction conducted with
3 as substrate. d No MeOH as cosolvent. e No catalyst premixing; 1.05
equiv 1a. f Isolated yield in parentheses. X-Phos =2-dicyclohexylpho-
sphino-20,40,60-triisopropylbiphenyl, t-am-OH = 2-Methyl-2-butanol
(tert-amyl alcohol).
(4) For reviews on Rh-catalyzed conjugate addition, see: (a) Hayashi,
T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844. (b) Edwards, H. J.;
Hargrave, J. D.; Penrose, S. D.; Frost, C. G. Chem. Soc. Rev. 2010, 39,
2093–2105. (c) Berthon, G.; Hayashi, T. Rhodium- and Palladium-
Catalyzed Asymmetric Conjugate Additions. In Catalytic Asymmetric
ꢀ
Conjugate Reactions; Cordova, A., Ed.; Wiley: Weinheim, 2010; p 1ꢀ70.
For selected examples of conjugate addition onto amides, see: (d)
Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000,
65, 5951–5955. (e) Frost, C. G.; Penrose, S. D.; Gleave, R. Org. Biomol.
Chem. 2008, 6, 4340–4347.
B
Org. Lett., Vol. XX, No. XX, XXXX

and easily from phenols.7 Good to high yields were
observed with a variety of substituted boronic esters. The
reaction tolerated substituents at various positions on the aryl
ring. While electron-poor aryl groups afforded the highest
yields, electron neutral aryl groups gave modest yields.
Employing functionalized aryl boronates such as 1h to 1j,
tricyclic lactams can be accessed (entries 7ꢀ9).
Table 2. Reaction Scope of Rh/Pd Conjugate Addition/
Amidationa
We sought to achieve the goal of conducting additional
metal-catalyzed reactions in the same vessel without any
workup/purification stages. Doing so would further add a
level of efficiency. Thus, we attempted to perform a Cu-
catalyzed arylation of the secondary lactam8 immediately
after Rh/Pd-catalysis. Following optimization, we could
perform the Cu-catalysis in the same reaction solvent with
CuI, a diamine ligand, an aryl iodide, molecular sieves, and
the same base at an elevated temperature. Control studies
on this step indicated the necessity of Cu, since Pd did not
promote the reaction.
The Cu-catalyzed amidation (Table 3) offers highly com-
plementary reactivity toward the Pd-catalyzed reaction.
Iodoanilines and iodohalobenzenes (entries 6ꢀ8) can be
used even in the presence of Pd and the desired reactivity
for Cu catalysis was observed. Products over three catalytic
cycles can be accessed in good to high yields.
Upon examination of substitutions on the acrylamide
acceptor, the reaction seemed to be limited due to the Rh-
catalyzed step. We observed a complex mixture once the
acrylamide was N-alkyl or aryl substituted (Figure 3, eq 1).
In addition, β-substituted acrylamides exhibited no reac-
tivity (Figure 3, eq 2). Whereas arylboronic acids lacking
ortho-halo substitution reacted smoothly with the afore-
mentioned acrylamides,4d the o-chloro moiety was respon-
sible for the lack of reactivity. Indeed, reports of conjugate
a Reaction conducted at 0.4 mmol scale. See Supporting Information
for detailed procedures. To a vial under argon atmosphere was added
[Rh], [Pd], XPhos, 2a, arylboronic acid (1.05 equiv), K3PO4 (2.2 equiv),
followed by 2.2 mL of t-am-OH/MeOH (10:1). The vial was sealed,
stirred at rt for 5 min, and heated at 110 °C for 16 h.
We next examined the scope of the (MC)2R (Table 2).
Good reactivity was observed with pinacol protected
boronic esters and these boronates can be accessed reliably
Table 3. Two-Step One-Pot (MC)2Ra
(5) For reviews on CꢀN coupling, see: (a) Prim, D.; Campagne,
J. M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041–2075. (b)
Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626. For
selected examples of amidation of aryl chlorides, see: (c) Hartwig, J. F.;
Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman,
L. M. J. Org. Chem. 1999, 64, 5575–5580. (d) Arterburn, J. B.; Rao,
K. V.; Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3, 1351–1354. (e)
Ghosh, A.; Sieser, J. E.; Riou, M.; Cai, W.; Rivera-Ruiz, L. Org. Lett.
2003, 5, 2207–2210. (f) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2004, 6,
2433–2435. (g) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2005, 44, 1371–1375. (h) Shi, F.; Smith, M. R.,
III; Maleczka, R. E., Jr. Org. Lett. 2006, 8, 1411–1414. Examples of the
intramolecular amidation of aryl chlorides: (i) Poondra, R. R.; Turner,
N. J. Org. Lett. 2005, 7, 863–866. (j) McLaughlin, M.; Palucki, M.;
Davies, I. W. Org. Lett. 2006, 8, 3311–3314.
(6) For the use of XPhos and similar bulky biaryl phosphines in
amination of aryl chlorides, see: (a) Anderson, K. W.; Tundel, R. E.;
Ikawa, T.; Altman, R. A.; Buchwald, S. L. Angew. Chem. 2006, 118,
6673–6677. Angew. Chem., Int. Ed. 2006, 45, 6523–6527. (b) Charles,
M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7, 3965–3968. (c)
Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 13978–13980. (d) Fors, B. P.; Krattiger, P.; Strieter, E.;
Buchwald, S. L. Org. Lett. 2008, 10, 3505–3508. (e) Fors, B. P.;
Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L. Tetrahedron 2009, 65,
6576–6583.
entry
R1
H, la
Ar
5
% yield
1
Ph
5a
5b
5c
5d
5e
5f
80
75
74
71
60
77
53
62
57
54
47
59
58
2
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
3-CF3ꢀC6H4
3-NH2ꢀC6H4
4ꢀBr-C6H4
3,4-(CI)2-C6H3
Ph
3
4
5
6
7
5g
5h
5i
8
9
3-Me, 1b
1b
10
11
12
13
4-MeO-C6H4
Ph
5j
3-OMe, 1c
3-F, 1e
5k
5l
Ph
5-CF3, 1g
Ph
5m
a See Supporting Information for detailed reaction procedures.
Reaction conducted on 0.4 mmol scale.
(7) For the preparation of ortho-chloroboronates, see: Barluenga, J.;
ꢀ
ꢀ
Jimenez-Aquin, A.; Aznar, F.; Valdes, C. J. Am. Chem. Soc. 2009, 131,
4031.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Reaction Scope of Rh/Pd-Catalysis with Respect
to R-Substituted Acrylamides/Acrylatesa
Figure 3. Reactivity of Rh-catalyzed conjugate addition of o-chloro
phenylboronic acid onto substituted acrylamides.
of the aforementioned acrylamides, we investigated an
alternative approach with acrylates bearing an R-methyl
amino group (2d and 2e). The more electrophilic acrylates
facilitated the conjugate addition while the amino group
can efficiently cyclize after the conjugate addition. This
annulation strategy provided access to tetrahydroquino-
lines 4mꢀo in good yields.
In summary, we have developed an efficient Rh/Pd
conjugate addition/amidation sequence useful in the syn-
thesis of dihydroquinolinones. We have also developed a one-
pot triple metal catalyzed reaction. The use of ortho-halo
arylboronates and acrylamides provides an annulation
strategy which also can be applied to substituted acrylates
to access tetrahydroquinolines. Combining compatible and
complementary reactivity of metals should further high-
light the potential, operational practicality, and efficiency of
(MC)2R.
a See Supporting Information and Table 2 for reaction procedures.
Reaction conducted on a 0.2ꢀ0.4 mmol scale. b Performed with stepwise
addition of [Pd(allyl)Cl]2/XPhos after completion of Rh-catalyzed step.
c Reaction performed with dioxane/MeOH as solvent. d RuPhos was
used instead of XPhos.
additions of ortho-substituted arylboronic acids to acyclic
R,β-unsaturated Michael acceptors are rare.9 Even more
scarce are reports on the ortho-halo-substituted arylboro-
nic acids.10
However, we did identify a number of R-alkyl-substi-
tuted acrylamides and acrylates that displayed useful
reactivity (Table 4). While methacrylamide (2b) provided
the desired quinolinone (entry 1), larger R-alkyl substitu-
ents were less reactive in the Rh-catalyzed step. R-Phenyl
acrylamide (2c) gave smooth conversion in the conjugate
addition. The poor reactivity of the amidation step was the
main obstacle, even with the use of a sequential catalyst/
ligand addition protocol. Due to the attenuated reactivity
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC) and Merck for
an Industrial Research Chair, and the University of Toronto
for financial support. L.Z. thanks OGS for a scholarship.
L.S. thanks University of Genova for a scholarship and
Prof. Andrea Basso (University of Genova) for the oppor-
tunity of working abroad for PhD. J.S. thanks NSERC for
a scholarship.
Supporting Information Available. Detailed experimen-
tal procedures and full compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) For reviews of Cu-catalyzed cross coupling, see (a) Kunz, K.;
Cholz, U.; Ganzer, D. Synlett 2003, 2428–2439. (b) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337–2364. (c) Evano,
G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054–3131.
(9) (a) Otomura, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org.
Chem. 2005, 70, 2503–2508. (b) Liao, Y.-X.; Xing, C.-H.; Israel, M.; Hu,
Q.-S. Org. Lett. 2011, 13, 2058–2061. (c) Wei, W.-T.; Yeh, J.-Y.; Kuo,
T.-S.; Wu, H.-L. Chem.;Eur. J. 2011, 17, 11405–11409. (d) Yamamoto,
Y.; Kurihara, K.; Takahashi, Y.; Miyaura, N. Molecules 2013, 18,
14–26.
(10) (a) Morimoto, T.; Yamasaki, K.; Hirano, A.; Tsutsumi, K.;
Kagawa, N.; Kakiuchi, K.; Harada, Y.; Fukumoto, Y.; Chatani, N.;
Nishioka, T. Org. Lett. 2009, 11, 1777–1780. (b) Harada, Y.; Nakanishi,
J.; Fujihara, H.; Tobisu, M.; Fukumoto, Y.; Chatani, N. J. Am. Chem.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX