Rhodium(III)-Catalyzed Annulation of Acetophenone O-Acetyl Oximes with Allenoates through Arene C-H Activation: An Access to Isoquinolines

Article abstract of DOI:10.1021/acs.joc.8b03092

Rhodium(III)-catalyzed annulation of acetophenone O-acetyl oximes with allenoates was achieved, affording isoquinolines in good to excellent yields with high regioselectivities under redox-neutral conditions. Allenoates acted as the C2 synthons in the annulation reaction. The present synthetic methodology features good functional group tolerance and avoids metal salts as the external oxidants. The proposed mechanism suggests that the reaction proceeds through arene C-H activation, allene insertion, and C-N coupling.

Full text of DOI:10.1021/acs.joc.8b03092

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Article
Rhodium(III)-Catalyzed Annulation of Acetophenone O-Acetyl Oximes with
Allenoates through Arene C-H Activation: An Access to Isoquinolines
Quannan Wang, Jiang Lou, Zilong Huang, and Zhengkun Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03092 • Publication Date (Web): 24 Jan 2019
Downloaded from http://pubs.acs.org on January 24, 2019
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Rhodium(III)-Catalyzed Annulation of Acetophenone O-Acetyl Oximes with
Allenoates through Arene CH Activation: An Access to Isoquinolines
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Quannan Wang,†,‡ Jiang Lou,†,‡ Zilong Huang,†,‡ and Zhengkun Yu*,†,§
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†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023,
People’s Republic of China
‡University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, People’s Republic of China
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
_____________________________________________________________________
R1
R1
2 mol % [Cp*RhCl2]2
10 mol % AgSbF6
R2
H
N
OAc
CO2R3
N
+
•
R2
20 mol % PivOH
DCE, 60 oC, 24 h
R
H
R4 CO2R3
R
R4
up to 93% yield
ABSTRACT: Rhodium(III)-catalyzed annulation of acetophenone O-acetyl oximes
with allenoates was achieved, affording isoquinolines in good to excellent yields with
high regioselectivities under redox-neutral conditions. Allenoates acted as the C2
synthons in the annulation reaction. The present synthetic methodology features good
functional group tolerance and avoids metal salts as the external oxidants. The
proposed mechanism suggests that the reaction proceeds through arene CH
activation, allene insertion, and CN coupling.
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INTRODUCTION
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Isoquinoline motif exists in a variety of biologically active molecules,
pharmaceuticals, and functional materials1a For example, (R)-(+)-Crispine A1b shows
significant cyctotoxic activity, PK 111951c can be used as an inhibitor of [3H]MeTRH,
and Pareitropone1d is the most potent anticancer agent among the relatively small
family of tropoloiso-quinoline alkaloids (Scheme 1). Considerable efforts have
recently been devoted to the synthesis of isoquinolines, and nitrogen-containing
directing group-assisted transition-metal catalyzed CH activation seems to be a
promising route to reach this goal.2 Among the nitrogen-containing directing groups
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Scheme 1. Structures of (R)-(+)-Crispine A, PK 11195, and Pareitropone
O
Cl
MeO
MeO
(R)-(+)-Crispine A1b
N
MeO
N
N
N
O
MeO
Pareitropone1d
PK 111951c
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for CH activation, oxime ester has been paid much attention due to its ready
availability,
easy
removal
and
transformation.3
In
this
regard,
transition-metal-catalyzed CH annulation of acetophenone O-acetyl oximes with
alkynes has been developed to access isoquinolines.4 However, such a protocol is
limited to internal alkynes, and only a few examples using terminal alkynes have been
reported.5 To synthesize isoquinolines, vinyl acetates,6a 1,3-dienes,6b and diazo
compounds7 have been explored as the coupling partners to react with acetophenone
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O-acetyl oximes through arene CH annulation. Although progress has been achieved,
more powerful and elegant synthetic methods are strongly desired in this area.
Allenes, which can exhibit high reactivity in comparison to similar alkenes, have
been demonstrated as useful building blocks for the construction of complex
skeletons.8 Much attention has been paid to allene-involved, transition-metal-
catalyzed CH transformations. In the relevant catalytic cycle, allene is usually
inserted into the metal-carbon bond of an in-situ generated organometallic species to
form an alkenyl-metal or π-allyl-metal intermediate. Protonation or β-hydride
elimination then occurs to give an allylation9 or allenylation10 product. Coupling such
an intermediate with the nucleophilic atom in the directing group has recently been
documented to build a heterocycle. Various nitrogen-containing directing groups have
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Scheme 2. Transition-Metal-Catalyzed CH Activation with Allenes
(a) Previous work20
10 mol % Cp*Co(CO)I2
20 mol % AgSbF6
20 mol % Cu(OAc)2•H2O
H
Ac
N
H
N
Ar
Ar
Ac
+
+
R
•
R
R
1 equiv Ag2CO3
CH3NO2, 80 oC, 15 h
H
(b) This work
R1
R1
R2
2 mol % [Cp*RhCl2]2
10 mol % AgSbF6
H
N
CO2R3
OAc
R2
R4 CO2R3
up to 93% yield
N
•
R
20 mol % PivOH
DCE, 60 oC, 24 h
H
R4
high regioselectivity
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been explored in the CH annulation with allenes for the synthesis of N-heterocycles.
Ding11a and Cramer,11b,c et al. reported an imine-directed CH annulation of ketimines
with allenes for the synthesis of 1-aminoindanes, respectively. Wang group realized a
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Mn/Ag catalyzed CH activation of ketimines with allenes for the synthesis of
polycyclic products.11d Pyrimidine-directed, Mn-catalyzed 1,2-diheteroarylation of
allenes formed bicyclic and tricyclic heterocycles.12 Transition-metal-catalyzed CH
annulation of arylamides with allenes have been well explored to produce diverse
isoquinolones by Rao,13 Ackermann,10a,14 Volla,15 Glorius,16 Cheng17, Ma,10b,18 and
other groups19. Cheng, et al. recently developed a cobalt(III)-catalyzed oxidative [3+3]
annulation of anilides with allenes to access 1,2-dihydroquinolines (Scheme 2a).20
However, this reaction required silver(I) salt Ag2CO3 as the external oxidant. It has
been known that the NO functionality of oximes can act as an internal oxidant in the
relevant CH functionalization reactions,4,5 and the C=N functionality in the C=N-OR
moiety is a potential directing group. During our continuous investigation of CH
activation,21 we were intrigued by the structural features of O-acyl oximes, and
reasonably envisioned the direct CH annulation of aromatic O-acyl oximes with
allenes. Herein, we disclose a rhodium(III)-catalyzed [4+2] annulation of
acetophenone O-acetyl oximes with allenoates for the synthesis of isoquinoline
derivatives under redox-neutral conditions (Scheme 2b).
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RESULTS AND DISCUSSION
Initially, the reaction of (E)-acetophenone O-acetyl oxime (1a) with ethyl
2-methylbuta-2,3-dienoate (2a) was conducted to screen the reaction conditions
(Table 1). With 2 mol % RhCl3·3H2O/8 mol % AgSbF6 as the catalyst, 20 mol %
PivOH as the additive, the reaction of 1a with 2a in a 1:2 molar ratio did not occur in
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o
1,2-dichloroethane (DCE) at 60 C for 24 h under a nitrogen atmosphere (Table 1,
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entry 1). Changing the catalyst to 2 mol % [Cp*RhCl2]2/8 mol % AgSbF6 led to
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Table 1. Optimiation of Reaction Conditionsa
H
N
OAc
conditions
CO2Et
N
+
•
H
CO2Et
1a
2a
3a
[Ag]
PivOH
Temp
(oC)
yieldb
(%)
entry
(mol %)
(mol %)
1c
2
20
0
66
AgSbF6 (8)
60
60
60
60
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60
60
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60
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50
70
60
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60
20
20
20
20
20
20
30
10
20
20
20
20
20
AgSbF6 (8)
AgPF6 (8)
3
40
4
51
AgBF4 (8)
5
87
AgSbF6 (9)
AgSbF6 (10)
AgSbF6 (11)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
AgSbF6 (10)
6
91
7
90
8
90
9
88
10d
11
12
13f
14
15
92 (86)e
83
92
0
0
86
AgSbF6 (10)
a Conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (2 mol %), DCE (2 mL),
b
0.1 MPa N2, 60 oC, 24 h.
Determined by 1H NMR analysis with
1,3,5-trimethyloxylbenzene as the internal standard. c RhCl3·3H2O (2 mol %) 1a
d
e
f
(0.3 mmol), 2a (0.6 mmol), DCE (3 mL). Isolated yield given in parentheses.
Without [Cp*RhCl2]2。
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isoquinoline derivative 3a in 66% yield by 1H NMR determination (Table 1, entry 2).
Both silver salts AgPF6 and AgBF4 were less effective than AgSbF6 (Table 1, entries
3 and 4). Use of 10 mol % AgSbF6 improved the product yield to 91% (Table 1,
entries 5-7). The highest yield (92%) was reached, and the target product was
obtained in 86% isolated yield from a 0.3 mmol-scale reaction (Table 1, entry 10).
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o
Lowering the temperature to 50 C diminished the yield to 83%, and elevating the
temperature to 70 oC did not further enhance the product yield (Table 1, entries 11 and
12). The control experiments revealed that the reaction could not occur in the absence
of [Cp*RhCl2]2 or AgSbF6 (Table 1, entries 13 and 14). It is noteworthy that the
reaction could also occur in the absence of PivOH to give product 3a in 86% NMR
yield (Table 1, entry 15). The reaction of 1a and 2a was conducted under the optimal
conditions with 2 mol % Cp*Co(CO)I2 as the catalyst, but the reaction did not occur.
Under the optimized conditions, the scope of O-acetyl oximes 1 was investigated
(Table 2). The substituted acetophenone O-acetyl oximes also efficiently reacted with
2a to form the target products of type 3. The para-methoxy substituent on the aryl
ring of acetophenone O-acetyl oxime 1b facilitated formation of 3b (92%). Due to
presence of two different reactive sites on the aryl ring of meta-methoxy
acetophenone-based oxime substrate 1c two isomeric products 3c (52%) and 3c
(35%) were generated. However, ortho-MeO group exhibited an obvious steric effect
on the yield of 3d (43%), and the reaction had to be performed at an elevated
temperature (80 oC). Both 4-methyl and 4-ethyl substituents facilitated the reaction to
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produce 3e and 3f (88-90%), respectively. The halogen substituents F, Cl, and Br
deteriorated the reaction efficiency to yield 3g-i (62-64%). It is noteworthy that
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Table 2. Scope of O-Acetyl Oximes 1a
R1
R1
H
2 mol % [Cp*RhCl2]2
10 mol % AgSbF6
H
N
OAc
CO2Et
N
R
+
•
R
20 mol % PivOH
DCE, 60 oC, 24 h
CO2Et
1
2a
3
MeO
N
N
N
N
+
MeO
CO2Et
CO2Et
OMe
3c
CO2Et
CO2Et
, 35%
3a
, 86%
3c'
3b
, 92%
, 52%
OMe
N
N
N
N
F
Et
CO2Et
c
CO2Et
CO2Et
, 88%
CO2Et
3d
, 43%
b
3g
, 62%
3e
3f
, 90%
N
N
N
Br
MeO2C
Cl
CO2Et
CO2Et
CO2Et
c
c
c
3i
, 64%
3j
, 51%
3j
X-ray structure of
N
3h
, 64%
OMe
OMe
N
N
N
CO2Et
CO2Et
, 80%
CO2Et
CO2Et
, 69%
3k
, 84%
3m
3n
, 80%
3l
Ph
Et
N
N
N
N
S
CO2Et
3r
, 79%
CO2Et
CO2Et
, 78%
CO2Et
3p
, 68%
3q
, 83%
3o
O
S
N
N
CO2Et
CO2Et
3s
, 0%
3t
, 0%
a
Conditions: 1 (0.3 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (0.006 mmol), AgSbF6
(0.03 mmol), PivOH (0.06 mol), DCE (3 mL), 0.1 MPa N2, 60 oC, 24 h. Yields refer
to the isolated products. b 80 oC. c [Cp*RhCl2]2 (0.012 mmol), AgSbF6 (0.06 mmol).
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electron-withdrawing groups such as F and CO2Me remarkably reduced the product
yields of 3g (62%) and 3j (51%), respectively. The negative impact from the
ortho-substituent was also observed that 2,5-dimethoxy-acetophenone O-acetyl oxime
(1l) reacted with 2a to give 3l (69%), while its 3,4-dimethyl-substituted analog 1k
almost kept the same reactivity as 1a did, forming 3k in 84% yield. Both
2-acetonaphthone and 2-acetylfluorene O-acetyl oximes (1m and 1n) reacted
efficiently with 2a, yielding 3m (80%) and 3n (80%), respectively. Increasing the
steric hindrance of the acyl group in the starting ketones, that is, using propiophenone
and benzophenone O-acetyl oximes 1o and 1p as the substrates, led to 3o and 3p in
78% and 68% yields, respectively, demonstrating a negative steric effect on the
reaction efficiency. Unexpectedly, α-tetralone O-acetyl oxime 1q reacted well with 2a
to afford tricyclic isoquinoline 3q (83%). It should be noted that (E)-1-(thiophen-3-
yl)ethanone O-acetyl oxime (1r) also efficiently reacted with 2a to exclusively
produce the corresponding product 3r (79%). However, both 1-(benzofuran-2-yl)-
ethanone and 1-(thiophen-2-yl)ethanone O-acetyl oximes 1s and 1t did not react with
2a under the same conditions, which is presumably attributed to the bidentate
coordination of the vicinal N,O or N,S heteroatoms in the oxime substrate 1s or 1t to
the rhodium atom of the catalyst that inhibits activation of the ortho-(hetero)arene
CH bond by the catalyst. The molecular structure of compound 3j was further
confirmed by the X-ray single crystal crystallographic determination (See the
Supporting Information for details). It should be noted that in the cases of using
p-NO2, p-CN, and p-CF3-substituted aryl oxime derivatives as the substrates, the
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reactions with 2a could not effectively occur and no target products were obtained.
N-Hetercycles such as (E)-1-(pyridin-4-yl)ethanone and (E)-1-(1-benzyl-1H-indol-
3-yl)ethanone O-acetyl oximes could not react with 2a under the same conditions
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either.
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Table 3. Scope of Allenoates 2a
H
R2
2 mol % [Cp*RhCl2]2
10 mol % AgSbF6
N
OAc
CO2R3
N
R2
+
•
MeO
20 mol % PivOH
DCE, 60 oC, 24 h
MeO
H
N
R4 CO2R3
R4
4
1b
2
N
N
MeO
MeO
MeO
CO2nPr
CO2iPr
CO2Bn
4a
, 93%
4b
, 90%
4c
, 91%
N
N
N
nBu
MeO
MeO
MeO
CO2Et
CO2Et
CO2tBu
4d
, 81%
4e
4h
4f
4i
, 78%
, 79%
N
N
N
n-hexyl
CO2Et
i-pentyl
MeO
MeO
MeO
MeO
Ph
CO2Et
CO2Et
4g
, 64%
, 57%
, 86%
N
N
N
+
CO2Et
MeO
CO2Et
MeO
CO2Et
CO2Et
4j
, 78%
4k
, 50%
4k'
, 43%
N
N
N
+
MeO
CO2Et
MeO
MeO
Bn CO2Et
CO2Bn
Bn
, 84%
b
4l
4m
, 44%
4l'
, 14%
N
N
N
R
MeO
MeO
MeO
Ph
4p
4q
(R = MeO), 0%
(R = cyclohexyl), 0%
b
4n
, 47%
4o
, 0%
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a
Conditions: 1b (0.3 mmol), 2 (0.6 mmol), [Cp*RhCl2]2 (0.006 mmol), AgSbF6
(0.03 mmol), PivOH (0.06 mol), DCE (3 mL), 0.1 MPa N2, 60 oC, 24 h. Yields refer
to the isolated products. b [Cp*RhCl2]2 (0.012 mmol), AgSbF6 (0.06 mmol).
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Next, the protocol generality was investigated by testing various allenoates 2 as
the coupling partners (Table 3). With para-methoxy-acetophenone O-acetyl oxime 1b
as the substrate, its reactions with n-propyl, isopropyl, benzyl, and tert-butyl
allenoates 2b-d efficiently underwent to afford the corresponding isoquinoline
products 4a-d (81-93%), respectively, only tert-butyl group exhibited an obvious
steric effect. Altering the 2-substituent of allenoates to ethyl, n-butyl, n-hexyl or
isopentyl diminished the product yields of 4e-h to 57-79%, demonstrating a negative
steric effect in comparison to the formation of 3b (92%, see Table 2). Ethyl
2-benzylbuta-2,3-dienoate (2j) exhibited a good reactivity to 1b, producing the target
product 4i in 86% yield. Diethyl 2-vinylidenesuccinate (2k) also underwent the
reaction well with 1b to form 4j (78%). Unexpectedly, ethyl penta-2,3-dienoate (2l)
reacted with 1b to afford two separable isomers 4k (50%) and 4k (43%), and ethyl
5-phenylpenta-2,3-dienoate (2m) behaved the same way to yield separable 4l (84%)
and 4l (14%). However, unsubstituted allenoate 2n only exhibited a poor reactivity to
undergo the reaction with 1b, giving 4m in 44% yield, while the reaction of 2d with
1b formed 4c in an excellent yield (91%). This result suggests that a 2-substituent is
crucial to efficiently execute the desired reaction. Buta-2,3-dien-2-ylbenzene (2o) was
also tested as the substrate to react with 1b, generating the target product 4n in 47%
yield, implicating that a terminal ester group is also a crucial functionality in the
allene-type substatrates 2. It is noteworthy that electron-donating group-substituted
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allenes such as 1,1-dimethylallene, methoxy allene, and cyclohexylallene could not
undergo the same type of annulation reactions with 1b to give the corresponding
products 4o-p under the stated conditions.
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H
2 mol % [Cp*RhCl2]2
10 mol % AgSbF6
OAc
N
N
CO2Et
(1)
(2)
+
•
MeO
20 mol % PivOH
DCE, 60 oC, 24 h
MeO
H
CO2Et
1b
(4 mmol)
2a
(8 mmol)
3b
, 1.0 g, 92%
LiAlH4 (2 equiv)
THF, 25 oC, 30 min
N
N
R
R
CO2Et
OH
5a
(R = H), 62%
3a
3b
(R = H)
5b
(R = OMe), 64%
(R = OMe)
To demonstrate the utility of the synthetic protocol, a gram-scale reaction of
oxime 1b and allenoate 2a was performed, affording the target product 3b in 92%
yield (eq 1). Chemoselective reduction of isoquinolines 3a and 3b was readily
conducted to give the corresponding alcohols 5a (62%) and 5b (64%), respectively
(eq 2).
_____________________________________________________________________
Scheme 3. Mechanism Studies.
(a) H/D exchange
(35% D)
H
H/D
2 mol % [Cp*RhCl2]2
OAc
OAc
10 mol % AgSbF6
N
N
PivOD (2 equiv)
DCE, 60 oC, 4 h
H
(35% D)
H/D
-dn
1a
1a
(b) KIE studies
H/D
H/D
H/D
H/D
2 mol % [Cp*RhCl2]2
10 mol % AgSbF6
OAc
H/D
H/D
N
N
2a
+
H/D
H/D
H/D
PivOH (20 mol %)
DCE, 60 oC
CO2Et
1a 1a-d
or
3a
3a-d4
or
5
time (min)
5
10
15
3a
yield of
yield of
26.7%
8.5%
32.1%
9.9%
36.1%
11.3%
kH/kD = 3.2
3a-d
4
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To gain insight into the reaction mechanism, control experiments were carried
out. Significant H/D exchange was observed for the ortho CH of the aryl ring in
(E)-acetophenone O-acetyl oxime (1a) in the presence of PivOD under the reaction
conditions, revealing reversibility of the CH bond cleavage (Scheme 3a). The kinetic
isotope effect (KIE) was measured from the parallel experiments using 1a and its
deuterated form 1a-d5 with 2a as the coupling partner (Scheme 3b). A primary isotope
effect was obtained with kH/kD = 3.2, which suggests that arene CH bond
activation/cleavage is likely involved in the rate-determining step in the overall
catalytic cycle.
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A plausible mechanism13-18,24 is proposed in Scheme 4. With the assistance of
coordination of the oxime moiety to the rhodium center, cyclorhodation of 1a initially
occurs to form intermediate A. The rhodium center is then coordinated by allenoate
2a to give Rh(III) cation intermediate B. Regioselective migratory insertion of the
_____________________________________________________________________
Scheme 4. Proposed Reaction Mechanism
[Cp*RhCl2]2
Cp*RhCl2
AgSbF6
3a
H
OAc
N
1,3-hydrogen shift
AgCl
H
Cp*RhX2
X = SbF6
1a
HOAc
+
N
C-H activation
HX
D
CO2Et
N-O bond cleavage
and C-N coupling
HX
OAc
N
OAc
Rh
X
N
Cp*
Cp*
Rh
A
X
CO2Et
C
OAc
X-
N
CO2Et
2a
•
Rh
migratory insertion
allene
coordination
Cp*
CO2Et
•
B
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activated allenoate into the RhC(aryl) bond delivers a seven-membered rhodacycle
intermediate C. Subsequent CN bond formation and NO bond cleavage of
intermediate C affords intermediate D and regenerates the catalytically active Rh(III)
species, accomplishing a catalytic cycle. Eventually, intermediate D undergoes 1,3-
hydrogen shift13,15 to accompolish aromatization, yielding the more stable product 3a.
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In summary, we have successfully realized rhodium(III)-catalyzed C–H
annulation of acetophenone O-acetyl oximes with allenoates to efficiently access
isoquinoline derivatives under redox-neutral conditions. The [4+2] annulation
reaction proceeds with high regioselectivities, broad scopes, and avoids metal salts as
the external oxidants. The present synthetic protocol provides a convenient and mild
route to functionalized isoquinolines.
EXPERIMENTAL SECTION
General Considerations. The solvents were dried and distilled prior to use by the
1
literature methods. H and 13C{1H} NMR spectra were recorded on a 400 MHz
spectrometer and all chemical shift values refer to δTMS = 0.00 ppm or CDCl3 (δ(1H),
7.26 ppm and δ(13C), 77.16 ppm). The HRMS analysis was obtained on a GC-TOF
mass spectrometer. All the chemical reagents were purchased from commercial
sources and used as received unless otherwise indicated. Known compounds 1a and
1b,4b 1c and 1d,4f 1e-i,4b 1j,22 1k and 1m,23 1n,24 1o,4b 1p,4f 1q and 1r4b 1t,4f 2a, 2d,
and 2f-m,25 2n,26 and 2o25 were prepared by the literature procedures, and their
spectroscopic features are in good agreement with those reported in the literatures.
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General Procedure for the Synthesis of Acetophenone O-Acetyl Oximes (1). A
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mixture of the aryl ketone (5 mmol), NH2OH·HCl (521 mg, 7.5 mmol) and pyridine
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9
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(1.1 mL, 14 mmol) in 2 mL EtOH was stirred at 60 C for 1 h. After cooled to
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ambient temperature, the reaction was quenched by water (10 mL). The resultant
mixture was extracted with ethyl acetate (3×5 mL). The combined organic phase was
washed with aqueous 1 N HCl (2×10 mL), dried over anhydrous MgSO4, filtered, and
evaporated all the volatiles under reduced pressure. The resultant residue was treated
with Ac2O (0.9 mL, 10 mmol) and a catalytic amount of 4-dimethylaminopyridine
(1.2 mg, 0.01 mmol) in pyridine (2.5 mL) with stirring at ambient temperature for 1 h.
The reaction was then quenched by water (10 mL) and the mixture was extracted with
ethyl acetate (3×5 mL). The combined organic phase was washed with aqueous 1 N
HCl (2×10 mL), dried over anhydrous MgSO4, filtered, and evaporated all the
volatiles under reduced pressure. The resulting residue was purified by silica gel
o
column chromatography (eluent: petroleum ether (60-90 C)/ether = 10:1, v/v) to
afford 1.
(E)-1-(2,5-Dimethoxyphenyl)ethanone O-acetyl oxime (1l). 0.87 g, 74% yield;
white solid; m.p. 76-78 oC. 1H NMR (400 MHz, CDCl3) δ 6.89 (m, 2 H), 6.82 (d, J =
13
8.7 Hz, 1 H), 3.75 (d, J = 5.7 Hz, 6 H), 2.30 (s, 3 H), 2.21 (s, 3 H). C{1H} NMR
(100 MHz, CDCl3) δ 168.9, 164.7, 153.4, 151.7, 125.9, 116.4, 115.2, 112.4, 56.1,
55.9, 19.8, 17.7. HRMS (EI) calcd for C12H15NO4 [M+H]+: 238.1079; Found:
238.1079.
(E)-1-(Benzofuran-2-yl)ethanone O-acetyl oxime (1s): 0.81 g, 74% yield; white
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solid; m.p. 82-84 oC. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.8 Hz, 1 H), 7.55 (d,
J = 8.3 Hz, 1 H), 7.37 (t, J = 7.3 Hz, 1 H), 7.26 (m, 2 H), 2.41 (s, 3 H), 2.29 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 168.3, 155.7, 154.4, 150.0, 127.6, 126.9, 123.5,
121.9, 112.1, 109.9, 19.7, 13.4. HRMS (EI) calcd for C12H11NO3 [M+H]+: 218.0817;
Found: 218.0819.
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General Procedure for the Synthesis of Allenoates (2). A mixture of the
corresponding basified ylied (31 mmol) and CH3I (5.7 g, 40 mmol) in 50 mL
chloroform was stirred at reflux for 25 h. After cooled to ambient temperature, the
mixture was evaporated all the volatiles under reduced pressure. 50 mL CH2Cl2 and
Et3N (6.3 g, 62 mmol) were then added with stirring, and followed by slow addition
o
of acetyl chloride (2.9 g, 37 mmol) at 0 C over half an hour. The reaction mixture
was allowed to warm up to ambient temperature and stirred overnight. After
evaporated all the volatiles under reduced pressure, the resulting residue was
o
dissolved in 100 mL petroleum ether (60-90 C), stirred for 2 h, and filtered. The
filtrate was evaporated all the volatiles under reduced pressure and purified by silica
o
gel column chromatography (eluent: petroleum ether (60-90 C)/ether = 20:1, v/v) to
afford 2.
1
Propyl 2-methylbuta-2,3-dienoate (2b): 2.4 g, 57% yield; colourless liquid. H
NMR (400 MHz, CDCl3) δ 5.04 (q, J = 3.2 Hz, 2 H), 4.08 (t, J = 6.7 Hz, 2 H), 1.85 (t,
13
J = 3.2 Hz, 3 H), 1.65 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H). C{1H} NMR (100 MHz,
CDCl3) δ 214.1, 167.7, 95.6, 77.8, 66.6, 22.1, 14.8, 10.4. HRMS (EI) calcd for
C8H12O2 [M+H]+: 141.0916; Found: 141.0915.
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Isopropyl 2-methylbuta-2,3-dienoate (2c): 2.8 g, 67% yield; colourless liquid. 1H
NMR (400 MHz, CDCl3) δ 5.00 (m, 3 H), 1.82 (t, J = 3.2 Hz, 3 H), 1.21 (d, J = 6.3
7
8
9
13
Hz, 6 H). C{1H} NMR (100 MHz, CDCl3) δ 214.0, 167.1, 95.8, 77.7, 68.3, 21.8,
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14.8. HRMS (EI) calcd for C8H12O2 [M+H]+: 141.0916; Found: 141.0913.
tert-Butyl 2-methylbuta-2,3-dienoate (2e): 1.6 g, 52% yield; colourless liquid. 1H
NMR (400 MHz, CDCl3) δ 4.99 (q, J = 3.2 Hz, 2 H), 1.82 (t, J = 3.2 Hz, 3 H), 1.46 (s,
13
9 H). C{1H} NMR (100 MHz, CDCl3) δ 214.0, 167.0, 96.9, 80.9, 77.4, 28.2, 14.8.
HRMS (EI) calcd for C9H14O2 [M+H]+: 155.1072; Found: 155.1073.
A Typical Procedure for the Synthesis of 3 and 4  Synthesis of Ethyl
2-(1-Methylisoquinolin-3-yl)propanoate (3a): A mixture of 1a (53 mg, 0.3 mmol),
allenoate 2a (76 mg, 0.6 mmol), [Cp*RhCl2]2 (3.7 mg, 0.006 mmol), AgSbF6 (10.3
mg, 0.03 mmol), and PivOH (6.1 mg, 0.06 mmol) in 3 mL 1,2-dichloroethane (DCE)
o
was stirred at 60 C for 24 h under a nitrogen atmosphere. After cooled to ambient
temperature, the mixture was evaporated all the volatiles under reduced pressure. The
resultant residue was purified by silica gel column chromatography (eluent: petroleum
o
ether (60-90 C)/ethyl acetate = 10:1, v/v) to afford 3a as a colorless liquid (63 mg,
86%).
Ethyl 2-(1-methylisoquinolin-3-yl)propanoate (3a): 62 mg, 86% yield; colourless
1
oil. H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.3 Hz, 1), 7.74 (d, J = 8.2 Hz, 1 H),
7.61 (t, J = 7.1 Hz, 1 H), 7.52 (m, 1 H), 7.46 (s, 1 H), 4.17 (qd, J = 7.1, 2.3 Hz, 2 H),
4.04 (q, J = 7.2 Hz, 1 H), 2.92 (s, 3 H), 1.62 (d, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3
H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.4, 158.5, 152.6, 136.6, 130.0, 127.3,
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126.7, 126.5, 125.6, 116.2, 60.8, 47.8, 22.4, 17.8, 14.2. HRMS (EI) calcd for
C15H17NO2 [M+H]+: 244.1338; Found: 244.1337.
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Ethyl 2-(6-methoxy-1-methylisoquinolin-3-yl)propanoate (3b): 75 mg, 92% yield;
pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.2 Hz, 1 H), 7.45 (s, 1 H),
7.18 (dd, J = 9.2, 2.5 Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 4.16 (m, 3 H), 3.91 (s, 3 H),
2.94 (s, 3 H), 1.60 (d, J = 7.2 Hz, 3 H), 1.19 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100
MHz, CDCl3) δ 174.4, 160.6, 157.8, 153.2, 138.7, 127.4, 122.1, 119.4, 115.6, 104.9,
60.8, 55.4, 47.8, 22.2, 17.8, 14.2. HRMS (EI) calcd for C16H19NO3 [M+H]+: 274.1443;
Found: 274.1443.
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Ethyl 2-(5-methoxy-1-methylisoquinolin-3-yl)propanoate (3c): 43 mg, 52% yield;
colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1 H), 7.61 (d, J = 8.5 Hz, 1 H),
7.42 (t, J = 8.1 Hz, 1 H), 6.94 (d, J = 7.7 Hz, 1 H), 4.17 (m, 2 H), 4.05 (q, J = 7.2 Hz,
1 H), 3.97 (s, 3 H), 2.91 (s, 3 H), 1.62 (d, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 174.4, 157.8, 154.9, 152.3, 129.2, 127.2, 126.6,
117.4, 110.6, 107.3, 60.7, 55.6, 48.0, 22.7, 17.8, 14.2. HRMS (EI) calcd for
C16H19NO3 [M+H]+: 274.1443; Found: 274.1442.
Ethyl 2-(7-methoxy-1-methylisoquinolin-3-yl)propanoate (3c): 28 mg, 35% yield;
colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.9 Hz, 1 H), 7.40 (s, 1 H),
7.28 (m, 2 H), 4.16 (m, J = 7.1, 3.0 Hz, 2 H), 4.00 (q, J = 7.2 Hz, 1 H), 3.93 (s, 3 H),
2.88 (s, 3 H), 1.60 (d, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100
MHz, CDCl3) δ 174.6, 158.1, 156.7, 150.7, 132.2, 128.9, 127.5, 122.7, 116.0, 103.6,
60.8, 55.5, 47.6, 22.5, 17.9, 14.3. HRMS (EI) calcd for C16H19NO3 [M+H]+: 274.1443;
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Found: 274.1446.
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Ethyl 2-(8-methoxy-1-methylisoquinolin-3-yl)propanoate (3d): 35 mg, 43% yield;
pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (t, J = 8.0 Hz, 1 H), 7.36 (s, 1 H),
7.29 (d, J = 8.1 Hz, 1 H), 6.83 (d, J = 7.8 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 3.99 (m,
4 H), 3.07 (s, 3 H), 1.60 (d, J = 7.2 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR
(100 MHz, CDCl3) δ 174.4, 158.4, 158.2, 152.7, 139.6, 130.3, 119.6, 119.4, 115.8,
106.0, 60.8, 55.5, 47.7, 28.8, 17.7, 14.3. HRMS (EI) calcd for C16H19NO3 [M+H]+:
274.1443; Found: 274.1441.
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Ethyl 2-(1,6-dimethylisoquinolin-3-yl)propanoate (3e): 68 mg, 88% yield; pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.6 Hz, 1 H), 7.51 (s, 1 H), 7.35
(m, 2 H), 4.17 (m, 2 H), 4.02 (q, J = 7.2 Hz, 1 H), 2.89 (s, 3 H), 2.50 (s, 3 H), 1.61 (d,
J = 7.2 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.4,
158.1, 152.6, 140.2, 137.0, 128.9, 126.2, 125.4, 124.9, 115.8, 60.8, 47.8), 22.3, 21.9,
17.8, 14.2. HRMS (EI) calcd for C16H19NO2 [M+H]+: 258.1494; Found: 258.1490.
Ethyl 2-(6-ethyl-1-methylisoquinolin-3-yl)propanoate (3f): 73 mg, 90% yield;
colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.6 Hz, 1 H), 7.53 (s, 1 H,),
7.38 (m, 2 H), 4.17 (m, 2 H), 4.02 (q, J = 7.2 Hz, 1 H), 2.89 (s, 3 H), 2.80 (q, J = 7.6
Hz, 2 H), 1.61 (d, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.6 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 174.4, 158.0, 152.6, 146.3, 137.0, 127.9, 125.5,
125.1, 124.9, 115.9, 60.7, 47.8, 29.1, 22.3, 17.8, 15.2, 14.2. HRMS (EI) calcd for
C17H21NO2 [M+H]+: 272.1651; Found: 272.1648.
Ethyl 2-(6-fluoro-1-methylisoquinolin-3-yl)propanoate (3g): 48 mg, 62% yield;
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colourless oil. 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 9.2, 5.5 Hz, 1 H), 7.41 (s, 1
H), 7.35 (dd, J = 9.4, 2.5 Hz, 1 H), 7.28 (td, J = 8.8, 2.9 Hz, 1 H), 4.18 (m, 2 H), 4.01
(q, J = 7.2 Hz, 1 H), 2.91 (s, 3 H), 1.60 (d, J = 7.2 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 163.15 (d, J = 251.8 Hz), 158.4 (d, J = 0.9
Hz), 153.8, 138.4 (d, J = 10.3 Hz), 128.7 (d, J = 9.6 Hz), 123.7, 117.0 (d, J = 25.1 Hz),
116.0 (d, J = 5.0 Hz), 110.5 (d, J = 20.5 Hz), 60.9, 47.8, 22.5, 17.7, 14.3. HRMS (EI)
calcd for C15H16FNO2 [M+H]+: 262.1243; Found: 262.1245.
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Ethyl 2-(6-chloro-1-methylisoquinolin-3-yl)propanoate (3h): 53 mg, 64% yield;
pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.9 Hz, 1 H), 7.69 (d, J =
2.1 Hz, 1 H), 7.41 (dd, J = 8.9, 2.1 Hz, 1 H), 7.35 (s, 1 H), 4.16 (m, 2 H), 4.00 (q, J =
7.2 Hz, 1 H), 2.87 (s, 3 H), 1.59 (d, J = 7.2 Hz, 3 H), 1.20 (t, J = 7.1 Hz, 3 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 174.1, 158.6, 153.9, 137.6, 136.2, 127.7, 127.4, 126.0,
124.7, 115.5, 60.9, 47.8, 22.4, 17.7, 14.3. HRMS (EI) calcd for C15H16ClNO2 [M+H]+:
278.0948; Found: 278.0950.
Ethyl 2-(6-bromo-1-methylisoquinolin-3-yl)propanoate (3i): 61 mg, 64% yield;
colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 5.3, 3.4 Hz, 2 H), 7.59 (dd,
J = 9.0, 1.8 Hz, 1 H), 7.36 (s, 1 H), 4.17 (m, 2 H), 4.02 (q, J = 7.2 Hz, 1 H), 2.90 (s, 3
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H), 1.60 (d, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz,
CDCl3) δ 174.1, 158.7, 153.9, 137.9, 130.3, 129.4, 127.4, 125.0, 124.8, 115.4, 61.0,
47.9, 22.4, 17.7, 14.3. HRMS (EI) calcd for C15H16BrNO2 [M+H]+: 322.0443; Found:
322.0443.
Methyl 3-(1-ethoxy-1-oxopropan-2-yl)-1-methylisoquinoline-6-carboxylate (3j):
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46 mg, 51% yield; white solid; m.p. 70-72 oC. 1H NMR (400 MHz, CDCl3) δ 8.49 (s,
1 H), 8.10 (m, 2 H), 7.54 (s, 1 H), 4.17 (q, J = 7.0 Hz, 2 H), 4.03 (m, 4 H), 2.94 (s, 3
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H), 1.62 (d, J = 7.2 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz,
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CDCl3) δ 174.1, 166.6, 158.7, 153.6, 136.0, 131.2, 130.1, 128.0, 126.2, 126.0, 117.2,
60.9, 52.6, 47.8, 22.5, 17.7, 14.3. HRMS (EI) calcd for C17H19NO4 [M+H]+: 302.1392;
Found: 302.1394.
Ethyl 2-(1,6,7-trimethylisoquinolin-3-yl)propanoate (3k): 68 mg, 84% yield;
colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1 H), 7.49 (s, 1 H), 7.34 (s, 1 H),
4.17 (m, 2 H), 4.01 (q, J = 7.2 Hz, 1 H), 2.88 (s, 3 H), 2.43 (s, 3 H), 2.41 (s, 3 H), 1.60
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(d, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ
174.5, 157.3, 151.8, 140.2, 136.5, 135.6, 126.7, 125.8, 125.0, 115.3, 60.7, 47.8), 22.3,
20.5, 20.4, 17.8, 14.2. HRMS (EI) calcd for C17H21NO2 [M+H]+: 272.1651; Found:
272.1654.
Ethyl 2-(5,8-dimethoxy-1-methylisoquinolin-3-yl)propanoate (3l): 63 mg, 69%
yield; colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1 H), 6.81 (d, J = 8.5 Hz,
1 H), 6.69 (d, J = 8.5 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 4.02 (q, J = 7.2 Hz, 1 H),
3.89 (d, J = 13.7 Hz, 6 H), 3.06 (s, 3 H), 1.60 (d, J = 7.2 Hz, 3 H), 1.20 (t, J = 7.1 Hz,
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3 H). C{1H} NMR (100 MHz, CDCl3) δ 174.4, 157.8, 152.6, 151.8, 148.4, 131.3,
119.6, 109.9, 107.4, 105.1, 60.7, 55.8, 55.7, 47.9, 28.6, 17.6, 14.2. HRMS (EI) calcd
for C17H21NO4 [M+H]+: 304.1549; Found: 304.1549.
Ethyl 2-(1-methylbenzo[g]isoquinolin-3-yl)propanoate (3m): 70 mg, 80% yield;
pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1 H), 8.25 (s, 1 H), 8.02 (d, J =
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8.3 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.49 (m, 3 H), 4.22 (q, J = 7.1 Hz, 2 H), 4.08
(q, J = 7.1 Hz, 1 H), 3.05 (s, 3 H), 1.68 (d, J = 7.2 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 174.5, 160.1, 150.3, 134.0, 132.9, 131.9, 129.1,
127.8, 127.3, 125.8, 125.5, 125.3, 125.0, 115.5, 60.8, 47.7, 22.8, 17.6, 14.3. HRMS
(EI) calcd for C19H19NO2 [M+H]+: 294.1494; Found: 294.1494.
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Ethyl 2-(1-methyl-10H-indeno[1,2-g]isoquinolin-3-yl)propanoate (3n): 79 mg,
80% yield; pale yellow solid; m.p. 104-106 oC. 1H NMR (400 MHz, CDCl3) δ 8.08 (s,
1 H), 7.99 (s, 1 H), 7.87 (m, 1 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.39 (m, 2 H), 4.22 (m, 2
H), 4.08 (q, J = 7.2 Hz, 1 H), 3.99 (s, 2 H), 2.93 (s, 3 H), 1.67 (d, J = 7.2 Hz, 3 H),
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1.26 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 174.5, 157.9, 152.0,
144.3, 144.1, 142.0, 140.2, 136.3, 128.5, 127.2, 125.8, 125.4, 121.2, 121.0, 116.8,
116.5, 60.8, 47.7, 36.6, 22.6, 17.8, 14.3. HRMS (EI) calcd for C22H21NO2 [M+H]+:
332.1651; Found: 332.1652.
Ethyl 2-(1-ethylisoquinolin-3-yl)propanoate (3o): 60 mg, 78% yield; colourless
liquid. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.3 Hz, 1 H), 7.76 (d, J = 8.2 Hz, 1
H), 7.61 (m, 1 H), 7.52 (m, 1 H), 7.45 (s, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.05 (q, J =
7.2 Hz, 1 H), 3.30 (q, J = 7.5 Hz, 2 H), 1.63 (d, J = 7.2 Hz, 3 H), 1.41 (t, J = 7.6 Hz, 3
H), 1.22 (t, J = 7.1 Hz, 3 H).13C{1H} NMR (100 MHz, CDCl3) δ 174.4, 162.9, 152.7,
137.0, 129.8, 127.5, 126.6, 125.6, 125.2, 116.1, 60.7, 47.8, 28.4, 17.7, 14.3, 13.7.
HRMS (EI) calcd for C16H19NO2 [M+H]+: 258.1494; Found: 258.1496.
Ethyl 2-(1-phenylisoquinolin-3-yl)propanoate (3p): 62 mg, 68% yield; colourless
liquid. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 1 H), 7.85 (d, J = 8.2 Hz, 1
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H), 7.68 (m, 4 H), 7.52 (m, 4 H), 4.21 (m, 3 H), 1.69 (d, J = 7.2 Hz, 3 H), 1.25 (t, J =
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7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 174.4, 160.3, 153.0, 139.6, 137.7,
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130.2, 130.1, 128.6, 128.4, 127.6, 127.1, 126.9, 125.7, 117.0, 60.9, 47.9, 18.0, 14.3.
HRMS (EI) calcd for C20H19NO2 [M+H]+: 306.1494; Found: 306.1495.
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Ethyl 2-(8,9-dihydro-7H-benzo[de]quinolin-2-yl)propanoate (3q): 67 mg, 83%
yield; pale yellow solid; m.p. 64-66 oC. 1H NMR (400 MHz, CDCl3) δ 7.53 (m, 2 H),
7.42 (s, 1 H), 7.25 (d, J = 6.7 Hz, 1 H), 4.18 (m, 2 H), 4.03 (q, J = 7.2 Hz, 1 H), 3.22
(m, 2 H), 3.07 (t, J = 6.1 Hz, 2 H), 2.16 (m, 2 H), 1.61 (d, J = 7.2 Hz, 3 H), 1.21 (t, J =
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7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 174.4, 160.1, 152.6, 138.7, 136.8,
130.0, 124.6, 124.4, 124.2, 115.8, 60.8, 47.9, 34.4, 30.5, 23.3, 17.8, 14.2. HRMS (EI)
calcd for C17H19NO2 [M+H]+: 270.1494; Found: 270.1496.
Ethyl 2-(4-methylthieno[3,4-c]pyridin-6-yl)propanoate (3r): 59 mg, 79% yield;
pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1 H), 7.39 (s, 2 H), 4.15 (m, 2
H), 4.01 (q, J = 7.2 Hz, 1 H), 2.80 (s, 3 H), 1.58 (d, J = 7.2 Hz, 3 H), 1.20 (t, J = 7.1
Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 153.6, 153.0, 148.0, 133.5,
126.3, 122.0, 112.7, 60.9, 48.0, 22.8, 18.0, 14.2. HRMS (EI) calcd for C13H15NO2S
[M+H]+: 250.0902; Found: 250.0903.
Propyl 2-(6-methoxy-1-methylisoquinolin-3-yl)propanoate (4a): 80 mg, 93%
yield; colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.2 Hz, 1 H), 7.36 (s,
1 H), 7.14 (dd, J = 9.2, 2.5 Hz, 1 H), 7.00 (d, J = 2.5 Hz, 1 H), 4.07 (m, 2 H), 4.01 (q,
J = 7.2 Hz, 1 H), 3.90 (s, 3 H), 2.86 (s, 3 H), 1.60 (m, 5 H), 0.84 (t, J = 7.4 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 174.5, 160.6, 157.7, 153.3, 138.7, 127.4, 122.1,
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119.4, 115.7, 104.9, 66.4, 55.5, 47.8, 22.2, 22.0, 17.8, 10.3. HRMS (EI) calcd for
C17H21NO3 [M+H]+: 288.1600; Found: 288.1598.
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yield; pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.2 Hz, 1 H), 7.36 (s,
1 H), 7.14 (dd, J = 9.2, 2.6 Hz, 1 H), 7.01 (d, J = 2.5 Hz, 1 H), 5.06 (hept, J = 6.3 Hz,
1 H), 3.96 (q, J = 7.2 Hz, 1 H), 3.91 (s, 3 H), 2.86 (s, 3 H), 1.58 (d, J = 7.2 Hz, 3 H),
1.23 (d, J = 6.3 Hz) and 1.16 (d, J = 6.2 Hz) (3:3 H). 13C{1H} NMR (100 MHz,
CDCl3) δ 174.0, 160.6, 157.7, 153.5, 138.7, 127.4, 122.1, 119.4, 115.6, 104.9, 68.0,
55.5, 47.9, 22.3, 21.9, 21.7, 17.9. HRMS (EI) calcd for C17H21NO3 [M+H]+: 288.1600;
Found: 288.1599.
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Benzyl 2-(6-methoxy-1-methylisoquinolin-3-yl)propanoate (4c): 91 mg, 91%
yield; colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 9.2 Hz, 1 H), 7.29 (m,
6 H), 7.16 (dd, J = 9.1, 2.4 Hz, 1 H), 6.96 (d, J = 2.4 Hz, 1 H), 5.19 (m, 2 H), 4.09 (q,
J = 7.2 Hz, 1 H), 3.91 (s, 3 H), 2.87 (s, 3 H), 1.64 (d, J = 7.2 Hz, 3 H). 13C{1H} NMR
(100 MHz, CDCl3) δ 174.2, 160.6, 157.8, 153.0, 138.7, 136.3, 128.4, 128.0, 128.0,
127.4, 122.1, 119.4, 115.8, 104.9, 66.4, 55.5, 47.8, 22.3, 17.7. HRMS (EI) calcd for
C21H21NO3 [M+H]+: 336.1600; Found: 336.1599.
tert-Butyl 2-(6-methoxy-1-methylisoquinolin-3-yl)propanoate (4d): 73 mg, 81%
yield; colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.2 Hz,1 H), 7.35 (s,
1 H), 7.12 (dd, J = 9.2, 2.5 Hz, 1 H), 7.00 (d, J = 2.5 Hz, 1 H), 3.90 (m, 4 H), 2.85 (s,
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3 H), 1.54 (d, J = 7.2 Hz, 3 H), 1.42 (s, 9 H). C{1H} NMR (100 MHz, CDCl3) δ
173.8, 160.5, 157.5, 153.8, 138.7, 127.4, 122.0, 119.3, 115.4, 104.8, 80.5, 55.4, 48.6,
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28.1, 22.2, 17.9. HRMS (EI) calcd for C18H23NO3 [M+H]+: 302.1756; Found:
302.1759.
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Ethyl 2-(6-methoxy-1-methylisoquinolin-3-yl)butanoate (4e): 67 mg, 78% yield;
pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.2 Hz, 1 H), 7.40 (s, 1 H),
7.13 (dd, J = 9.2, 2.5 Hz, 1 H), 7.01 (d, J = 2.4 Hz, 1 H), 4.16 (m, 2 H), 3.89 (s, 3 H),
3.78 (m, 1 H), 2.86 (s, 3 H), 2.15 and 2.00 (m each, 1:1 H), 1.21 (t, J = 7.1 Hz, 3 H),
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0.95 (t, J = 7.4 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 173.9, 160.6, 157.7,
152.0, 138.6, 127.4, 122.2, 119.4, 116.2, 104.8, 60.7, 55.5, 55.4, 26.2, 22.3, 14.3, 12.3.
HRMS (EI) calcd for C17H21NO3 [M+H]+: 288.1600; Found: 288.1601.
Ethyl 2-(6-methoxy-1-methylisoquinolin-3-yl)hexanoate (4f): 75 mg, 79% yield;
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.2 Hz, 1 H), 7.41 (s, 1 H), 7.13
(dd, J = 9.2, 2.5 Hz, 1 H), 7.01 (d, J = 2.5 Hz, 1 H), 4.15 (m, 2 H), 3.90 (s, 3 H), 3.85
(dd, J = 8.2, 7.1 Hz, 1 H), 2.86 (s, 3 H), 2.13 and 1.96 (m each, 1:1 H), 1.32 (m, 4 H),
1.21 (t, J = 7.1 Hz, 3 H), 0.87 (t, J = 7.0 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3)
δ 174.0, 160.6, 157.7, 152.2, 138.6, 127.4, 122.2, 119.4, 116.1, 104.8, 60.7, 55.4, 53.9,
32.7, 30.0, 22.7, 22.3, 14.3, 14.0. HRMS (EI) calcd for C19H25NO3 [M+H]+: 316.1913;
Found: 316.1911.
Ethyl 2-(6-methoxy-1-methylisoquinolin-3-yl)octanoate (4g): 66 mg, 64% yield;
pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.2 Hz, 1 H), 7.41 (s, 1 H),
7.14 (dd, J = 9.2, 2.4 Hz, 1 H), 7.01 (d, J = 2.4 Hz, 1 H), 4.16 (m, 2 H), 3.91 (s, 3 H),
3.86 (m, 1 H), 2.86 (s, 3 H), 2.12 and 1.95 (m each, 1:1 H), 1.27 (m, 11 H), 0.85 (t, J
= 6.8 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.1, 160.6, 157.7, 152.2, 138.7,
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127.4, 122.2, 119.4, 116.2, 104.9, 60.7, 55.5, 53.9, 33.0, 31.7, 29.2, 27.7, 22.7, 22.3,
14.3, 14.2. HRMS (EI) calcd for C21H29NO3 [M+H]+: 344.2226; Found: 344.2224.
Ethyl 2-(6-methoxy-1-methylisoquinolin-3-yl)-5-methylhexanoate (4h): 57 mg,
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57% yield; colourless oil. H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.2 Hz, 1 H),
7.41 (s, 1 H), 7.14 (dd, J = 9.2, 2.5 Hz, 1 H), 7.02 (d, J = 2.5 Hz, 1 H), 4.16 (m, 2 H),
3.91 (s, 3 H), 3.82 (dd, J = 8.3, 6.9 Hz, 1 H), 2.87 (s, 3 H), 2.13, 1.96 (m each, 1:1 H),
1.57 (m, 1 H), 1.22 (m, 5 H), 0.87 (dd, J = 6.6, 5.2 Hz, 6 H). C{1H} NMR (100
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MHz, CDCl3) δ 174.1, 160.6, 157.7, 152.2, 138.7, 127.4, 122.2, 119.4, 116.2, 104.9,
60.7, 55.5, 54.2, 36.9, 31.0, 28.1, 22.6, 22.3, 14.3. HRMS (EI) calcd for C20H27NO3
[M+H]+: 330.2069; Found: 330.2067.
Ethyl 2-(6-methoxy-1-methylisoquinolin-3-yl)-3-phenylpropanoate (4i): 90 mg,
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86% yield; pale yellow oil. H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.2 Hz, 1 H),
7.39 (s, 1 H), 7.23 (m, 4 H), 7.17 (m, 2 H), 7.00 (d, J = 2.5 Hz, 1 H), 4.21 (m, 1 H),
4.10 (m, 2 H), 3.91 (s, 3 H), 3.47 (dd, J = 13.8, 8.9 Hz) and 3.34 (dd, J = 13.8, 6.6 Hz)
(1:1 H), 2.90 (s, 3 H), 1.12 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ
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173.1, 160.6, 157.9, 151.2, 139.5, 138.6, 129.1, 128.3, 127.4, 126.3, 122.2, 119.5,
116.7, 104.9, 60.8, 55.5, 55.4, 38.7, 22.3, 14.1. HRMS (EI) calcd for C22H23NO3
[M+H]+: 350.1756; Found: 350.1754.
Diethyl 2-(6-methoxy-1-methylisoquinolin-3-yl)succinate (4j): 81 mg, 78% yield;
yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 9.2 Hz, 1 H), 7.35 (s, 1 H), 7.13
(dd, J = 9.2, 2.5 Hz, 1 H), 6.98 (d, J = 2.5 Hz, 1 H), 4.34 (dd, J = 9.4, 5.6 Hz, 1 H),
4.16 (m, 4 H), 3.89 (s, 3 H), 3.26 and 2.92 (m each, 1:1 H), 2.83 (s, 3 H), 1.20 (td, J =
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7.1, 4.7 Hz, 6 H). 13C{1H} NMR (100 MHz, CDCl3) δ 172.6, 171.9, 160.7, 158.1,
150.3, 138.5, 127.3, 122.2, 119.6, 116.8, 104.8, 61.1, 60.6, 55.4, 49.4, 36.8, 22.2, 14.2,
14.1. HRMS (EI) calcd for C19H23NO5 [M+H]+: 346.1654; Found: 346.1655.
Ethyl 4-ethyl-6-methoxy-1-methylisoquinoline-3-carboxylate (4k): 41 mg, 50%
yield; pale yellow solid; m.p. 77-79 oC. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 9.1
Hz, 1 H), 7.30 (d, J = 2.4 Hz, 1 H), 7.25 (dd, J = 9.1, 2.4 Hz, 1 H), 4.48 (q, J = 7.1 Hz,
2 H), 3.95 (s, 3 H), 3.12 (q, J = 7.5 Hz, 2 H), 2.88 (s, 3 H), 1.43 (t, J = 7.1 Hz, 3 H),
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1.35 (t, J = 7.5 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 168.2, 160.9, 156.2,
141.8, 136.9, 131.3, 128.2, 123.7, 119.8, 103.1, 61.7, 55.5, 22.5, 21.8, 15.0, 14.4.
HRMS (EI) calcd for C16H19NO3 [M+H]+: 274.1443; Found: 274.1444.
Ethyl 2-(6-methoxy-1,4-dimethylisoquinolin-3-yl)acetate (4k): 35 mg, 43% yield;
yellow solid; m.p. 83-85 oC. 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 8.5, 1.0 Hz,
1 H), 7.16 (m, 2 H), 4.17 (q, J = 7.1 Hz, 2 H), 4.02 (s, 2 H), 3.94 (s, 3 H), 2.84 (s, 3
H), 2.49 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 171.3,
160.6, 155.3, 144.8, 138.1, 128.0, 123.1, 122.1, 118.4, 102.1, 60.9, 55.4, 42.3, 22.1,
14.3, 14.3. HRMS (EI) calcd for C16H19NO3 [M+H]+: 274.1443; Found: 274.1442.
Ethyl 6-methoxy-1-methyl-4-phenethylisoquinoline-3-carboxylate (4l): 88 mg,
84% yield; pale yellow solid; m.p. 90-92 oC. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J
= 9.1 Hz, 1 H), 7.26 (m, 7 H), 4.47 (q, J = 7.1 Hz, 2 H), 3.91 (s, 3 H), 3.41 and 3.01
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(m each, 2:2 H), 2.90 (s, 3 H), 1.43 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz,
CDCl3) δ 167.9, 161.0, 156.4, 141.9, 137.1, 129.4, 128.6, 128.4, 128.2, 126.2, 123.7,
120.0, 103.0, 61.7, 55.4, 36.8, 30.6, 22.5, 14.4. HRMS (EI) calcd for C22H23NO3
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[M+H]+: 350.1756; Found: 350.1757.
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Ethyl 2-(4-benzyl-6-methoxy-1-methylisoquinolin-3-yl)acetate (4l): 15 mg, 14%
yield; yellow solid; m.p. 76-78oC. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 9.1 Hz,
1 H), 7.17 (m, 8 H), 4.38 (s, 2 H), 4.11 (q, J = 7.1 Hz, 2 H), 4.00 (s, 2 H), 3.75 (s, 3
H), 2.90 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 171.4,
160.7, 156.6, 146.3, 139.6, 138.1, 128.7, 128.2, 128.0, 126.3, 125.1, 122.6, 118.6,
103.0, 61.0, 55.4, 42.2, 34.1, 22.4, 14.3. HRMS (EI) calcd for C22H23NO3 [M+H]+:
350.1756; Found: 350.1758.
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Benzyl 2-(6-methoxy-1-methylisoquinolin-3-yl)acetate (4m): 42 mg, 44% yield;
pale yellow solid; m.p. 68-70 oC. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.2 Hz, 1
H), 7.32 (m, 6 H), 7.17 (dd, J = 9.2, 2.5 Hz, 1 H), 6.98 (d, J = 2.5 Hz, 1 H), 5.20 (s, 2
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H), 3.97 (s, 2 H), 3.92 (s, 3 H), 2.88 (s, 3 H). C{1H} NMR (100 MHz, CDCl3) δ
171.2, 160.8, 158.0, 147.1, 138.7, 136.1, 128.6, 128.3, 128.2, 127.5, 122.1, 119.6,
118.1, 104.8, 66.7, 55.5, 43.7, 22.3. HRMS (EI) calcd for C20H19NO3 [M+H]+:
322.1443; Found: 322.1440.
6-Methoxy-1-methyl-3-(1-phenylethyl)isoquinoline (4n): 39 mg, 47% yield; white
solid; m.p. 104-106 oC. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.1 Hz, 1 H), 7.40
(d, J = 7.4 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.23 (dd, J = 14.1, 6.8 Hz, 1 H), 7.13 (m,
2 H), 6.94 (d, J = 2.5 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 1 H), 3.89 (s, 3 H), 2.90 (s, 3 H),
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1.78 (d, J = 7.2 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 160.5, 158.5, 157.5,
145.5, 138.7, 128.4, 128.1, 127.4, 126.2, 121.8, 119.0, 115.5, 104.8, 55.4, 47.2, 22.5,
21.4. HRMS (EI) calcd for C19H19NO [M+H]+: 278.1545; Found: 278.1544.
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Gram-Scale Preparation of the Target Products: Synthesis of Ethyl
2-(6-methoxy-1-methylisoquinolin-3-yl)propanoate (3b): A mixture of 1b (0.83 g, 4
mmol), allenoate 2a (1.01 g, 8 mmol), [Cp*RhCl2]2 (49 mg, 0.08 mmol), AgSbF6
(137 mg, 0.4 mmol), and PivOH (81 mg, 0.8 mmol) in 3 mL 1,2-dichloroethane (DCE)
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was stirred at 60 C for 24 h under a nitrogen atmosphere. After cooled to ambient
temperature, the mixture was evaporated all the volatiles under reduced pressure. The
resultant residue was purified by silica gel column chromatography (eluent: petroleum
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ether (60-90 C)/ethyl acetate = 20:1, v/v) to afford 3b as a pale yellow oil (1.00 g,
92%).
A
Typical Procedure for the Synthesis of
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
Synthesis of
2-(1-Methylisoquinolin-3-yl)propan-1-ol (5a): A mixture of 3a (73 mg, 0.3 mmol)
and LiAlH4 (23 mg, 0.6 mmol) in 2 mL THF was stirred at 25 oC for 30 min under an
argon atmosphere. The resulting mixture was poured into ice water (25 mL) and
extracted with CH2Cl2 (3×10 mL). The combined organic phase was dried over
anhydrous Na2SO4, filtered, and evaporated all the volatiles under reduced pressure.
The resultant residue was purified by silica gel column chromatography (eluent:
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petroleum ether (60-90 C)/ethyl acetate = 1:1, v/v) to afford 5a as a colorless liquid
(37 mg, 62%).
2-(1-Methylisoquinolin-3-yl)propan-1-ol (5a): 37 mg, 62% yield; colourless oil.
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.2 Hz, 1 H),
7.64 (m, 1 H), 7.53 (ddd, J = 8.1, 6.9, 1.1 Hz, 1 H), 7.35 (s, 1 H), 3.99 (dd, J = 10.6,
3.6 Hz) and 3.86 (dd, J = 10.6, 6.7 Hz) (1:1 H), 3.16 (m, 1 H), 2.92 (s, 3 H), 1.41 (d, J
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= 7.1 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.9, 157.1, 136.8, 130.3, 127.1,
126.6, 126.2, 125.7, 116.0, 68.0, 41.3, 22.5, 17.1. HRMS (EI) calcd for C13H15NO
[M+H]+: 202.1232; Found: 202.1230.
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2-(6-Methoxy-1-methylisoquinolin-3-yl)propan-1-ol (5b): 44 mg, 64% yield;
white solid; m.p. 110-112 oC. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.1 Hz, 1 H),
7.26 (s, 1 H), 7.15 (m, 1 H), 7.00 (d, J = 2.1 Hz, 1 H), 3.97 (m) and 3.83 (dd, J = 10.5,
6.7 Hz) (4:1 H), 3.12 (m, 1 H), 2.86 (s, 3 H), 1.39 (d, J = 7.1 Hz, 3 H). 13C{1H} NMR
(100 MHz, CDCl3) δ 160.9, 157.8, 157.1, 138.9, 127.5, 121.8, 119.3, 115.4, 104.7,
68.1, 55.5, 41.1, 22.4, 17.1. HRMS (EI) calcd for C14H17NO2 [M+H]+: 232.1338;
Found: 232.1335.
H/D Exchange in acetophene O-acetyl oxime (1a): A mixture of 1a (35 mg, 0.2
mmol), [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), AgSbF6 (6.9 mg, 0.02 mmol), and PivOD
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(41 mg, 0.4 mmol) in 2 mL 1,2-dichloroethane (DCE) was stirred at 60 C for 4 h
under a nitrogen atmosphere. After cooled to ambient temperature, the mixture was
evaporated all the volatiles under reduced pressure. The resultant residue was purified
by silica gel column chromatography (eluent: petroleum ether (60-90 oC)/ethyl acetate
= 20:1, v/v). The H/D exchange was determined by 1H NMR analysis.
Kinetic isotope effect (KIE) experiments: The reactions with 1a or its
deuterated form 1a-d5 were carried out in a parallel manner under the standard
conditions as follows. A mixture of 1a (35 mg, 0.2 mmol) or 1a-d5 (36 mg, 0.2 mmol),
2a (50 mg, 0.4 mmol), [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), AgSbF6 (6.9 mg, 0.02
mmol), and PivOH (4.1 mg, 0.04 mmol) in 2 mL 1,2-dichloroethane (DCE) was
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