Ruthenium(II)/chiral Bronsted acid co-catalyzed enantioselective four-component reaction/cascade aza-michael addition for efficient construction of 1,3,4-tetrasubstituted tetrahydroisoquinolines

Article abstract of DOI:10.1002/chem.201304576

An elegant synergistic catalytic system comprising a ruthenium complex with a chiral Bronsted acid was developed for a four-component Mannich/cascade aza-Michael reaction. The ruthenium-associated ammonium ylides successfully trapped with in situ generated imines indicates a stepwise process of proton transfer in the ruthenium-catalyzed carbenoid Ni￡H insertion reaction. The different decomposition abilities of various ruthenium complexes towards diazo compounds were well explained by the calculated thermodynamic data. The transformation features a mild, rapid, and efficient method for the synthesis of enantiomerically pure 1,3,4-tetrasubstituted tetrahydroquinolines bearing a quaternary stereogenic carbon center from simple starting precursors in moderate yields with high diastereo- and enantioselectivity. An elegant synergistic catalytic system comprising a ruthenium complex with a chiral Bronsted acid was developed for a four-component Mannich/cascade aza-Michael reaction. The transformation features a mild, rapid, and efficient method for the synthesis of enantiomerically pure 1,3,4-tetrasubstituted tetrahydroquinolines from simple starting precursors in moderate yields with high diastereo- and enantioselectivity (see scheme, Cbz=carbobenzyloxy). Copyright

Full text of DOI:10.1002/chem.201304576

DOI: 10.1002/chem.201304576
Communication
&
Organic Synthesis
Ruthenium(II)/Chiral Brønsted Acid Co-Catalyzed Enantioselective
Four-Component Reaction/Cascade Aza-Michael Addition for
Efficient Construction of 1,3,4-Tetrasubstituted
Tetrahydroisoquinolines
Jun Jiang, Xiaochu Ma, Changge Ji, Zhenqiu Guo, Taoda Shi, Shunying Liu,* and
Wenhao Hu*[a]
gant synergistic catalytic systems may provide an opportunity
Abstract: An elegant synergistic catalytic system compris-
to conquer this challenge.
ing a ruthenium complex with a chiral Brønsted acid was
Ruthenium complexes are versatile catalysts for chemical
developed for a four-component Mannich/cascade aza-Mi-
transformations.[3] Due to great compatibility and tolerance to-
chael reaction. The ruthenium-associated ammonium
wards a wide range of organic functionalities including acids
ylides successfully trapped with in situ generated imines
and amines,[4] ruthenium complexes should be ideal catalysts
indicates a stepwise process of proton transfer in the
of choice in developing synergistic catalytic systems in multi-
ruthenium-catalyzed carbenoid NÀH insertion reaction.
component cascade reactions. Nevertheless, only a few catalyt-
The different decomposition abilities of various ruthenium
ic systems combining ruthenium complex and chiral organic
complexes towards diazo compounds were well explained
small molecules have been reported. MacMillan’s group inno-
by the calculated thermodynamic data. The transforma-
vatively merged a synergistic system of a ruthenium complex
tion features a mild, rapid, and efficient method for the
and a chiral imidazolidinone catalyst to accomplish the enan-
synthesis of enantiomerically pure 1,3,4-tetrasubstituted
tioselective intermolecular a-alkylation of aldehydes under
tetrahydroquinolines bearing a quaternary stereogenic
light irradiation, in which the ruthenium complex served as the
carbon center from simple starting precursors in moderate
photoredox catalyst.[5] You and co-workers have reported a se-
yields with high diastereo- and enantioselectivity.
quential catalytic process involving a ruthenium complex and
a chiral phosphoric acid for olefin cross-metathesis/intramolec-
ular Friedel–Crafts alkylation to offer polycyclic indoles, in
The highly efficient construction of chiral polyfunctional mole-
cules has always been one of the most pursued aims in asym-
metric synthesis. Asymmetric multicomponent reactions
(AMCRs) and cascade reactions provide powerful strategies to
construct such molecules in an operationally simple fashion.[1]
Combining AMCRs and cascade reactions, in which, the multi-
component reaction forms the precursor with necessary func-
tionalities ready for the subsequent cascade reaction, should
present the most efficient approach to construct chiral poly-
functional complex molecules with the maximum synthetic ef-
ficiency.[2] In such an attractive approach, the control of reac-
tion selectivity, especially the order control of bond formation
and the stereoselectivity of the desired molecules, is a great
challenge because many possible chemical transformations
may be involved in the reaction systems. The discovery of ele-
which the two catalysts worked separately but in a one-pot
fashion.[6] To the best of our knowledge, no synergistic system
of ruthenium complex and chiral Brønsted acid has been re-
ported. Herein, we develop an enantioselective four-compo-
nent cascade reaction for efficient construction of chiral multi-
substituted tetrahydroisoquinolines (THIQs), and a synergistic
catalytic system of a ruthenium complex with a chiral phos-
phoric acid is discovered to efficiently control the reaction se-
lectivity.
Ruthenium complexes have been reported to be effective
catalysts for the decomposition of diazo compounds.[7,8] Re-
cently, Che and collaborators reported that commercially avail-
able [RuCl2(p-cymene)]2 was an efficient catalyst for the carbe-
noid NÀH insertion reaction and the reaction was tolerant to-
wards oxygen and moisture in the atmosphere.[9] As the mech-
anism of the NÀH insertion reaction was still unclear, a stepwise
process via ruthenium ylide formation and a subsequential
proton transfer was proposed as one possibility (Scheme 1A).
Based on our previous studies in rhodium-catalyzed active
ammonium ylide trapping processes,[10] we envision that it is
highly possible to trap the proposed ruthenium-associated am-
monium ylide with a bifunctional electrophile if the aforemen-
tioned stepwise NÀH insertion operates (Scheme 1B). The suc-
cessful trapping process following a cascade reaction will not
only provide direct experimental evidence to clarify the reac-
[a] Dr. J. Jiang,+ X. Ma,+ Dr. C. Ji, Dr. Z. Guo, T. Shi, Dr. S. Liu, Prof. W. Hu
Shanghai Engineering Research Center of Molecular Therapeutics
and New Drug Development, East China Normal University
Shanghai, 200062 (China)
Fax: (+86)021-62221237
E-mail: syliu@sist.ecnu.edu.cn
whu@chem.ecnu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304576.
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cially
available
[RuCl2(p-
cymene)]2 was a highly compati-
ble catalyst. Decomposition of
the diazo compound 4a went
smoothly in the presence of
1 mol%
[RuCl2(p-cymene)]2.
Trace amounts of the desired
tetrahydroisoquinoline 5a were
exactly detected after treating
the reaction mixture with potas-
sium tert-butoxide. Significant
amounts of NÀH insertion prod-
uct were identified as a side
product. The common catalyst,
Rh2(OAc)4, was also used to de-
Scheme 1. A) Ruthenium-associated ammonium ylides followed by a proposed stepwise or concerted proton
transfer.[9] B) Trapping the ruthenium-associated ammonium ylides by electrophiles to delay proton transfer.
tion pathway for the Ru-catalyzed NÀH insertion, but also vali-
date the ruthenium complex as an effective catalyst in the
multicomponent reaction for efficient construction of polyfunc-
tional molecules.
compose diazo compound in this reaction system as a control.
While in the presence of 1 mol% Rh2(OAc)4, no diazo decom-
position occurred, and only the imine derived from 1a and 2a
was detected.
The designed four-component cascade reaction of bifunc-
tional substrates 1, arylamine 2, benzyl carbamate 3, and aryl
diazoacetate 4 is hypothesized as the following reaction se-
quence (Scheme 2). Bifunctional electrophile A will be generat-
To suppress the side reaction and achieve enantioselective
control of the desired process, chiral phosphoric acid[11] was
employed as a co-catalyst to promote the iminium forma-
tion.[12] In the presence of 1 mol% [RuCl2(p-cymene)]2 and
5 mol% chiral phosphoric acid
(R)-7a, the reaction successfully
afforded a Mannich/aza-Michael
addition product 5a in 47% iso-
lated yield with 78:22 diastereo-
meric ratio (d.r.) and 90:10 enan-
tiomeric ratio (e.r.) of the major
diastereomer (Table 1, entry 1).
Other ruthenium complexes
were then evaluated to catalyze
this reaction under otherwise
identical reaction conditions. No
diazo decomposition occurred
when
[RuCl(cod)]n
or
Ru-
(bpy)3Cl2·6H2O (cod=1,5-cyclo-
octadiene; bpy=2,2’-bipyridine)
was used (Table 1, entries 2 and
3). [RuCl2(PPh3)3] only afforded
a trace of product 5a (Table 1,
Scheme 2. Schematic of the four-component reaction by synergistic catalysis with a ruthenium complex/chiral
Brønsted acid system.
ed in situ, and a Brønsted acid promotes the formation of the
iminium species. Ruthenium(II) complex catalyzes the decom-
position of diazo compound 4 with carbamate 3 to form Ru-
associated ammonium ylide B. We hope that the trapping of
active ammonium ylide B by the bifunctional iminium species
occurs in a Mannich-type addition to provide a four-compo-
nent coupling product C. A subsequent one-pot cascade pro-
cess by an intramolecular aza-Michael addition will readily
afford 1,3,4-multisubstituted THIQ 5 or isoindoline 6 depend-
ing on the reactivity of the two NÀH groups. The challenge of
the designed process is to control the order of the bond for-
mation and the stereoselectivity of the desired products.
entry 4) because the significant amount of diazo compounds
were not decomposed under current conditions.
Other chiral phosphoric acids 7b–e were then investigated
to give comparable yields but much lower d.r. and ee values
(Table 1, entries 5–8). The reaction conditions were further opti-
mized with various solvents and additives at different tempera-
tures. 1,2-Dichloroethane (DCE) was a better solvent than di-
chloromethane or toluene, providing 5a in 51% yield with
85:15 d.r. and 90:10 e.r. (entries 10 vs. 1, 9). Acidic additives
were found to have a pronounced effect on the reaction (en-
tries 11–13). (Æ)-Mandelic acid was identified as the most effec-
tive additive when (R)-7a (5 mol%) was used, evidenced by
the enhancement in the distereoselectivity of the reaction
from 85:15 to 90:10. The relatively lower temperature was fa-
vored to control the reaction selectivity, especially the diastero-
Our initial study began with the reaction of bifunctional sub-
strate 1a, p-bromoaniline 2a, benzyl carbamate 3, and methyl
phenyldiazoacetate 4a. We were pleased to find that commer-
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Communication
the Michael acceptor will offer
Table 1. Optimization of conditions for the one-pot four-component cascade reaction.[a]
a favored product 5a with twist-
boat conformation.
A Re-face
process is unfavored due to the
increased steric hindrance.
Removal of the carboben-
zyloxy (Cbz) protecting group in
the four-component product
with Pd/C under a hydrogen at-
mosphere yielded the corre-
sponding optically active 1,3,4-
tetrasubstituted THIQs bearing
three chiral stereogenic centers
without any loss in enantioselec-
tivity (see the Supporting Infor-
mation).
Entry
7
Additive acid (10 mol%)
[M]
Solvent Yield[b] [%] (major/minor)[c] e.r.[d]
[e]
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7b
7c
7d
7e
7a
7a
–
[RuCl2(p-cymene)]2 toluene 47 (78:22)
90:10
n.d.
n.d.
–
–
–
–
–
–
–
–
–
[RuCl(cod)]n toluene n.d.
[Ru(bpy)3Cl2]·6H2O toluene n.d.
[Ru(PPh3)3Cl2] toluene trace
[RuCl2(p-cymene)]2 toluene 44 (46:54)
[RuCl2(p-cymene)]2 toluene 42 (54:46)
[RuCl2(p-cymene)]2 toluene 54 (74:26)
[RuCl2(p-cymene)]2 toluene 60 (57:43)
–
46:54
54:46
74:26
57:43
78:22
94:6
84:16
90:10
92:8
93:7
97:3
9
[RuCl2(p-cymene)]2 CH2Cl2
[RuCl2(p-cymene)]2 DCE
57 (86:14)
51 (85:15)
42 (90:10)
40 (88:12)
57 (90:10)
52 (96:4)
66 (96:4)
The THIQs ring systems, as an
important class of alkaloids, ex-
hibit a vast array of important
bioactivities.[13] They are typically
present in many complex natural
molecules, such as quinocarcin
10
11
12
13
14[f]
15[f,g]
7a (Æ)-10-camphorsulfonic Acid [RuCl2(p-cymene)]2 DCE
7a (Æ)-tartaric acid
7a (Æ)-mandelic acid
7a (Æ)-mandelic acid
7a (Æ)-mandelic acid
RuCl2(p-cymene)]2 DCE
RuCl2(p-cymene)]2 DCE
RuCl2(p-cymene)]2 DCE
RuCl2(p-cymene)]2 DCE
[a] Unless otherwise noted, all reactions were carried out at room temperature on a 0.2 mmol scale and 1a/
2a/3/4a=1.0:1.1:1.2:1.2. 4 ꢁ MS (100 mg) and 1 mol% [RuCl2(p-cymene)]2 were added, and tBuOK (0.22 mmol)
was added after the Mannich-type reaction was completed. [b] Isolated yields were obtained after purification
by column chromatography. [c] The diastereomeric ratio was detected by 1H NMR (400 MHz) spectroscopy.
[d] Determined by HPLC analysis. [e] No additive acid. [f] Reactions were carried out at À108C. [g] The reaction
was carried out with 10 mol% of (R)-7a.
(QNC),[14]
ecteinascidin 743,[15]
and renieramycin G.[16] Conse-
quently, the merging of poten-
tial biological activity with the
challenging complexity of mo-
lecular architecture makes THIQs
selectivity, as demonstrated by the results at room tempera-
ture (90:10 d.r.) and at À108C (96:4 d.r., entries 13 vs. 14). The
optimal conditions were estab-
attractive molecules for target-directed synthesis. The most fre-
quently used method for the synthesis of THIQs is asymmetric
lished as 1 mol% of [RuCl2(p-
cymene)], 10 mol% of phospho-
Table 2. Scope of substrates in the one-pot four-component cascade reaction.[a]
ric acid (R)-7a, and 10 mol% of
(Æ)-mandelic acid in DCE at
À108C (entry 15).
The general applicability of
the protocol was investigated
under the optimized reaction
conditions, and the results are
summarized in Table 2. The pro-
cess was tolerant to several aryl-
amines 2 (Table 2, entries 1–7). In
addition, other bifunctional sub-
Entry
R1
Ar1
Ar2
Yield[b]
[%]
d.r.[c]
e.r.[d]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Et
pBrPh
pClPh
pIPh
mMePh
pMePh
pFPh
pEtOPh
pBrPh
pFPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a, 66
5b, 52
5c, 48
5d, 51
5e, 55
5 f, 57
5g, 45
5h, 78
5i, 53
5j, 67
5k, 61
5l, 53
5m, 55
5n, 72
5o, 73
96:4
87:13
92:8
97:3
94:6
94:6
95:5
94:6
97:3
91:9
96:4
96:4
94:6
96:4
95:5
94:6
96:4
96:4
96:4
86:14
80:20
76:24
86:13
95:5
88:12
85:15
85:15
92:8
strates
1 with different ester
groups and additional aryl diazo-
acetates 4 were feasible sub-
strates in this reaction and gave
the corresponding products
with satisfactory d.r. and high
e.r. values (entries 8–15). The
absolute stereochemistry of
(1R,3S,4R)-5a was established by
single-crystal X-ray analysis as
9
Bn
Ph
10
11
12
13
14
15
Me
Me
Me
Et
Bn
Me
pFPh
pFPh
mMeOPh
mMeOPh
mMeOPh
mBrPh
mBrPh
mMePh
pBrPh
pFPh
pBrPh
pBrPh
85:15
86:14
[a] Unless otherwise noted, all reactions were carried out at À108C on a 0.2 mmol scale and 1/2/3/4=
1.0:1.1:1.2:1.2. 4 ꢁ MS (100 mg), and tBuOK (0.22 mmol) was added after the Mannich-type reaction was com-
pleted. [b] Isolated yields were obtained after purification by column chromatography. [c] Diastereomeric ratio
a
twist-boat
conformation
(Scheme 3). After deprotonating
1
was detected by H NMR (400 MHz) spectroscopy. [d] Determined by HPLC analysis.
by base, a Si-face attacking to
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Carbenoid formation through
transition-metal-catalyzed diazo
decomposition is a key step in
the current process. Here, we
tried to explore the catalytic effi-
ciency of Ru complexes in this
process through quantum chem-
ical calculations.[20] The comput-
ed free energies for transition-
metal-catalyzed decomposition
of diazo compounds are À9.1,
12.8, and À13.1 kcalmolÀ1 for
the
catalysis
of
[RuCl2(p-
cymene)],
[RuCl2(bpy)3]·6H2O,
Scheme 3. Proposed processes for the formation of observed stereochemical structures.
and [RuCl2(PPh3)3], respectively,
which indicates that [RuCl2(p-
cymene)] and [RuCl2(PPh3)3] can
hydrogenation of the isoquinoline frameworks.[17] Despite the
great advance of this protocol, only 1-alkyl-substituted or 1,3-
disubstituted THIQs have been obtained with high enantiose-
lectivity.[17a,b] In addition, due to the easy racemization of 1 or
4-substituted THIQs,[17b,18] the methods for asymmetric synthe-
sis of multisubstituted THIQs, especially 1,3,4-tetrasubstituted
THIQs, are considerably rare.[19] Taking advantage of the unique
reactivity of the ammonium ylide, the reaction can proceed
under mild and neutral conditions allowing rapid construction
of structurally constrained chiral 1,3,4-tetrasubstituted THIQs
without any racemization of the products.
catalyze the decomposition of the diazo compound. [RuCl2-
(bpy)3]·6H2O does not work (see the Supporting Information,
Table 1S). However, due to the large ligand of [RuCl2(PPh3)3]
with the reaction barrier of up to approximately 30 kcalmolÀ1
(Figure 1A), the substrate cannot approach the metal center
easily (Figure 1B), which suggests it is very difficult to push the
formation of Ru-associated carbenoid forward. These theoreti-
cal predictions agree well with our experimental results:
[RuCl2(p-cymene)] efficiently catalyzed the decomposition of
the diazo compound to provide the desired tetrahydroisoqui-
nolines, whereas [RuCl2(PPh3)3] only afforded a trace amount of
product.
In conclusion, we have developed an elegant synergistic cat-
alytic system comprising a ruthenium complex with chiral
Brønsted acid for a four-component Mannich/cascade aza-Mi-
chael reaction. The ruthenium-associated ammonium ylides
were successful trapped by in situ generated iminiums, which
indicates a stepwise process for the ruthenium-catalyzed car-
benoid NÀH insertion reaction. The calculated thermodynamic
data facilitates a better understanding of the decomposition
ability of ruthenium complexes towards diazo compounds in
this reaction. The transformation features a mild, rapid, and ef-
ficient method to synthesize 1,3,4-tetrasubstituted THIQs bear-
ing a quaternary stereogenic carbon center from simple start-
ing precursors in moderate yields with high diastereo- and
enantioselectivity. The synergistic catalytic system of ruthenium
complexes and chiral Brønsted acids should have a wide appli-
cation in other ruthenium-catalyzed asymmetric transforma-
tions.
Experimental Section
General procedure
A
25 mL flask was charged with bifunctional aldehyde
1 (0.22 mmol), aromatic amine 2 (0.2 mmol), chiral phosphoric acid
7a (10 mol%), (Æ)-mandelic acid (10 mol%), and 4 ꢁ MS (0.1 g) in
Cl(CH2)2Cl (4 mL) and the resulting mixture was stirred at RT for
1 h. [RuCl2(p-cymene)]2 (1.0 mol%) and benzyl carbamate
3
(2.22 mmol) were then added, and the flask was cooled down to
Figure 1. Relaxed potential energy surface along the reaction path for the
[RuCl2(PPh3)3]-catalyzed reaction.
À108C. Diazo compound 4 (0.24 mmol) in Cl(CH2)2Cl (4 mL) was
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added to the reaction mixture over a 1 h time period by a syringe
pump. After completion of the addition, potassium tert-butoxide
(0.24 mmol) was added all at once. After the reaction mixture had
been stirred for another 1 h at À108C, product 5 from the crude
reaction mixture was subjected to 1H NMR spectroscopic analysis
for the determination of diastereoselectivity. The reaction mixture
was purified by flash chromatography on silica gel (eluent: EtOAc/
light petroleum ether 1:10 to 1:5) to give pure 5
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Acknowledgements
We are grateful for financial support from the NSFC (21125209
and 21332003), the MOST of China (2011CB808600), STCSM
(12JC1403800), and Fostering Project for National Top Hundred
Doctoral Dissertations (PY2011015).
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Keywords: Brønsted acid
ruthenium · synergistic catalysis · tetrahydroisoquinolines
· multicomponent reactions ·
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Received: November 22, 2013
Published online on January 16, 2014
Chem. Eur. J. 2014, 20, 1505 – 1509
www.chemeurj.org
1509
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