Manganese dioxide-methanesulfonic acid promoted direct dehydrogenative alkylation of sp3 C-H bonds adjacent to a heteroatom

Article abstract of DOI:10.1021/jo4000674

A manganese dioxide (MnO₂)-methanesulfonic acid (CH ₃SO₃H) oxidation system has been developed to efficiently promote direct coupling of benzylic ethers and carbamates with simple ketones via oxidative C-H bond activation.

Full text of DOI:10.1021/jo4000674

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Article
Manganese Dioxide-Methanesulfonic Acid Promoted Direct
Dehydrogenative Alkylation of sp3 C–H Bonds Adjacent to a Heteroatom
Xigong Liu, Bin Sun, Zhiyu Xie, Xiaojun Qin, Lei Liu, and Hongxiang Lou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4000674 • Publication Date (Web): 18 Mar 2013
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Manganese Dioxide-Methanesulfonic Acid Promoted Direct
Dehydrogenative Alkylation of sp3 C–H Bonds Adjacent to a
Heteroatom
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Xigong Liu,†,§ Bin Sun,‡ ,§ Zhiyu Xie,† Xiaojun Qin,† Lei Liu,*,† Hongxiang
Lou*,†
†Department of Natural Products Chemistry, Key Lab of Chemical Biology (MOE),
School of Pharmaceutical Sciences and ‡National Glycoengineering Research Center,
Shandong University, Jinan 250012, P. R. China
leiliu@sdu.edu.cn, louhongxiang@sdu.edu.cn
R4
R4
n
n
R3
R3
X
X
MnO2, CH3SO3H
Et2O, air, rt
H
O
R1
R2
H
R1
O
n = 0, 1
X = O, S, NC(O)R5
R2
53%-87%
Abstract: A manganese dioxide (MnO2)ꢀmethanesulfonic acid (CH3SO3H) oxidation
system has been developed to efficiently promote direct coupling of benzylic ethers and
carbamates with simple ketones via oxidative C–H bond activation. The alkylation
proceeds smoothly under air atmosphere to afford the corresponding products in good to
excellent yields (53ꢀ87%). The employment of the combination of MnO2 and CH3SO3H
is attractive based on economical and environmental issues.
■ INTRODUCTION
Carbon–carbon (C–C) bond forming reactions are fundamental transformations in organic
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synthesis. While these processes are most frequently achieved through reactive functional
group transformations, precise one step substitution of carbon–hydrogen (C–H) bonds,
the most ubiquitous bonds in organic molecules, with C–C bonds opens a new synthetic
strategy for modern synthesis.1ꢀ4 Among these, the crossꢀdehydrogenative coupling (CDC)
reaction, namely, the direct coupling of two different C–H bonds between two reactants,
has attracted much interest in recent years.5ꢀ10 The majority of such CDC reactions
involve oxidative alkylation of benzylic C–H bonds adjacent to an Nꢀaryl group.11ꢀ26 In
sharp contrast, for the oxidation of corresponding less reactive benzylic C–H bonds next
to an oxygen atom or an Nꢀacyl group, only a few oxidation systems have been reported
so far (Scheme 1). The four oxidants utilized for isochroman substrates are
2,3ꢀdichloroꢀ5,6ꢀdicyanobenzoquinone (DDQ),27ꢀ34 NHPI (Nꢀhydroxyphthalimide),35
organic peroxides,36ꢀ37 and TEMPO oxoammonium salt (T+BF4ꢀ)38ꢀ39; the two oxidants for
Nꢀacyl THIQs are organic peroxides36ꢀ37 and T+BF4ꢀ38ꢀ39. These oxidation systems
required either intensive heating or expensive reagents. While moderate to high reaction
efficiency (up to 81%) was observed for Nꢀacyl THIQs, only low to moderate reaction
efficiency (23ꢀ52%) was reported for isochromans when using either tertꢀbutyl
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ꢀ
hydroperoxide (tBHP) or T+BF4 as the oxidant. Considering that isochroman moieties are
core units within a multitude of biologically active compounds,40ꢀ44 and the synthetic
efficiencies of such compounds through CDC are still far from satisfactory, the
development of mild, economic and efficient oxidation system is still a worthwhile
project to pursue.
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Scheme 1. Four reported oxidation systems for CDCs between isochroman or N-acyl
THIQ and carbon nucleophiles
5
6
nucleophile
oxidant
7
8
X
X
9
Nu
X = O, NBoc
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Nu:
X = O
ketones, indoles
oxidative
systems:
DDQ
1)
2)
3)
4)
, neat, 100 °C.
NHPI
(OMe)n
n = 2-4
, Cu(OTf)2, InCl3, O2, neat, 75 °C.
TBHP
, Cu(NO3)2, neat, 80 °C.
T+BF
4-, Cu(OTf)2, TFA, CH2Cl2, rt.
X = NBoc
Nu:
β
-dicarbonyls, indoles
oxidative
systems:
TBHP
1)
, Fe(NO3)3, neat, 50 °C.
T+BF
2)
O
4-, Fe(OTf)2, CH2Cl2, rt.
(OMe)n
n = 2-4
O
NC
NC
Cl
Cl
N OH
N
O
OOH
TBHP
O
NHPI
(
BF4
O
-
)
(
)
T+BF
(
)
4
(DDQ)
Manganese moieties like manganese(III) porphyrins and (salen)manganese(III)
complexes have long been known to selectively catalyze benzylic hydroxylation through
a P450ꢀlike C–H oxidation mechanism (Scheme 2).45ꢀ49 However, direct C–C bond
formations have not been achieved via such systems to date. Activated MnO2 is an
inexpensive, less toxic, easily handled, and environmentally benign reagent.50ꢀ51 It has
been utilized as an efficient and mild reagent for selective oxidation of activated alcohols
(benzylic, allylic, propargylic, etc.). However, to the best of our knowledge, MnO2 has
not been reported to promote corresponding oxidation of activated ethers, leading to C–C
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Scheme 2. Well-accepted mechanisms of manganese species-induced benzylic C–H
oxidation
Ar
O
Ar
Ar
OH
+
Mn
H
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OH
Mn
Mn
[ ] = solvent cage
= manganese(III) porphyrins or
(salen)manganese(III) complexes
manganese(III) complexes catalyzed benzylic C-H oxidation
IV
Mn
O
O
H
Ar
O
MnO2
Ar
O
adsorbed
species
H
H
H
adsorption
coordination
hydrogen atom
abstraction
single electron
oxidation
III
Mn
H
H
O
O
Ar
MnO/HOH
+
Ar
O
O
MnO2-mediated benzyl alcohol oxidation
bond formation.52 While the mechanism of benzylic alcohol oxidation is not fully
understood, a widely accepted rationale53ꢀ55 involves an adsorption and coordination of
the alcohol onto MnO2, followed by a rateꢀdetermining hydrogen abstraction to produce a
free benzylic radical, and subsequent a oneꢀelectron oxidation to afford the desired
aldehyde (Scheme 2). Utilizing the mechanistic rationale, we proposed that a suitable acid
might be able to activate MnO2 thereby initiating a C–H oxidation of the benzylic ether.
Herein, we document a MnO2ꢀmediated oxidative crossꢀcoupling of cyclic benzylic
ethers and carbamates with simple ketones in the presence of CH3SO3H at room
temperature.
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■ RESULTS AND DISCUSSION
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We selected the coupling of isochroman and acetophenone as a starting point for our
initial studies. Isochroman was known to be readily oxidized when exposed to the air,
especially in an acidic environment and under elevated oxygen pressure.56ꢀ59 Therefore,
reactions were conducted under a nitrogen atmosphere in a glove box to get rid of the
involvement of oxygen. A variety of Brønsted acids as well as Lewis acids were applied
to the model reaction employing activated MnO2 as the oxidant in CH2Cl2 (Table 1).
Lewis acids like BF3ꢁOEt2 and Brønsted acids like AcOH and pꢀtoluenesulfonic acid
(PTSA) resulted in no reaction at all (entries 2ꢀ4, Table 1). Camphorsulfonic acid (CSA),
Trifluoroacetic acid (TFA) and trifluoromethanesulfonic acid (TfOH) can promote the
coupling, and CH3SO3H proved to be the best choice for the coupling (entries 5ꢀ8). No
reaction took place if MnO2 or CH3SO3H alone was employed (entries 1 and 9).
Subsequently, various metal oxidants were investigated for the reaction. While
manganeseꢀbased candidates like Mn(OAc)3,60 Mn(OAc)2ꢁ4H2O and Ba(MnO4)2 can also
effect the coupling, MnO2 worked best, and was selected for further reaction optimization
(entries 10ꢀ17). The reaction was also highly dependent on the solvent choice. Solvents
such as hexane, THF and 1,4ꢀdioxane inhibited the reaction (entries 18, 20 and 21);
CH2Cl2 afforded a fair amount of the desired product at the beginning stage, but product
decomposition was observed during the reaction, giving irreproducible results (entry 8);
products in toluene and Et2O were well compatible with the oxidation system and Et2O
proved to be the best choice (entries 19 and 22). Reaction optimization experiments
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Table 1. Optimization of the oxidation systema
5
6
7
8
oxidant
acid
solvent
O
O
O
+
O
rt
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2a
3a
1a
entry oxidant
acid
—
solvent
CH2Cl2
time (h) yield (%)b
1
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
—
12
12
12
12
12
3
0
2
BF3ꢁOEt2 CH2Cl2
0
3
AcOH
PTSA
CSA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
4
0
5
15
28
33
45
<5
38
15
36
<5
<5
<5
<5
<5
<5
77
<5
10
83
81
63
80
57
<5
82
81
<5
6
TFA
7
TfOH
3
8
CH3SO3H CH2Cl2
CH3SO3H CH2Cl2
2
9
12
3
10
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12
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14
15
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17
18
19
20
21
22
23c
24d
25e
26f
27e,g
Mn(OAc)3 CH3SO3H CH2Cl2
Mn(OAc)2 CH3SO3H CH2Cl2
Ba(MnO4)2 CH3SO3H CH2Cl2
3
3
FeCl3
RuCl3
CoF3
CH3SO3H CH2Cl2
CH3SO3H CH2Cl2
CH3SO3H CH2Cl2
CH3SO3H CH2Cl2
CH3SO3H CH2Cl2
CH3SO3H hexane
CH3SO3H toluene
CH3SO3H THF
3
3
3
CuCl2
PdCl2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
—
3
3
3
4
4
CH3SO3H 1,4ꢀdioxane 4
CH3SO3H Et2O
CH3SO3H Et2O
CH3SO3H Et2O
CH3SO3H Et2O
CH3SO3H Et2O
CH3SO3H Et2O
CH3SO3H Et2O
CH3SO3H Et2O
CH3SO3H Et2O
3
8
24
24
48
96
24
24
24
28e,g MnO2
29e,h MnO2
30e,h,i MnO2
aGeneral conditions: 1a (0.2 mmol), 2a (0.4 mmol), oxidant (600 mol%), acid (0.4 mL),
b
c
solvent (1.5 mL) in a glove box, unless stated otherwise. Isolated yield. CH3SO3H (0.3
mL). dCH3SO3H (0.2 mL). eCH3SO3H (0.3 mL) and MnO2 (300 mol%). fCH3SO3H (0.3 mL)
and MnO2 (200 mol%). gReaction under O2. hReaction under air. i50 mol% BHT added.
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identified decreased MnO2 (300 mol%) and CH3SO3H (0.3 mL) as ideal conditions (entry
25), although a prolonged reaction time was necessary. The involvement of oxygen did
not bring down the reaction efficiency. Even after four days, little conversion was
observed when the reaction was performed under atmospheric pressure of oxygen in the
absence of MnO2 (entry 27). When MnO2 was introduced to the oxygen atmosphere, the
reaction went to completion to give an 82% yield (entry 28). The reaction under air
afforded comparable result, and this optimized condition will be applied for further
studies for convenience (entry 29). Addition of substoichiometric amounts (50 mol%) of
a radical inhibitor, 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) completely blocked the
transformation (entry 30).
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With the optimized oxidative crossꢀcoupling conditions in hand, the effect of various
nucleophiles on the transformation was studied (Table 2). A variety of ketones with
electronically varied aromatic and heteroaromatic substituents, as well as propiophenone
were accommodated. The coupling reaction was found to be sensitive to the electronic
substituents. Electronꢀrich ketones provided products in slightly reduced yields relative to
acetophenone (entries 1ꢀ3, Table 2), while electronꢀdeficient one like
4’ꢀbromoacetophenone afforded a better result (entry 4). The reaction efficiency was also
influenced by the steric encumbrance of the nucleophile, which well explained the mild
decrease in yields for 2’ꢀchloroacetophenone and propiophenone (entries 1 and 4ꢀ6). A
heteroaromatic ketone like 2ꢀfuryl methyl ketone was also compatible with the system,
though only a moderate yield was observed (entry 7). Aliphatic ketones proved to be less
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Table 2. Cross-coupling between isochroman and ketone derivativesa
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7
8
9
MnO2 (300 mol%)
CH3SO3H (0.3 mL)
O
Et2O (1.5 mL)
rt, air
R1
+ R2
O
R1
O
R2
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O
3
1a
2
entry
ketone
yield (%)b
series
2a
2b
2c
2d
2e
2f
2g
2h
2i
1
2
3
4
5
6
7
8
9
acetophenone
81
75
71
87
75
71
51
30
13
4'ꢀmethylacetophenone
4’ꢀmethoxyacetophenone
4’ꢀbromoacetophenone
2’ꢀchloroacetophenone
propiophenone
2ꢀfuryl methyl ketone
3ꢀpentanone
cyclopentanone
aGeneral conditions: 1a (0.2 mmol), 2 (0.4 mmol), MnO2 (300 mol%), acid (0.3 mL),
Et2O (1.5 mL) under air for 24 h. bIsolated yield.
effective than the aromatic ones, and relative low yields were obtained (entries 8 and 9).
The substituent effect of isochroman on the coupling reaction was subsequently
investigated (Table 3). Alkylꢀsubstituents like methyl and tertꢀbutyl at C7 of isochroman
performed equally well as the model reaction (entries 1ꢀ3, Table 3). In accordance with
Todd’s result,28 the methoxy substituent afforded no reaction (entry 4). This can be
explained by Floreancig’s mechanistic studies,61 that substrates with lower oxidation
potentials have higher bond dissociation energy of the scissile C–H bond, if reactions
proceed through a radical mechanism. The reaction went smoothly when a
bromoꢀsubstituent was placed at C7 position, and 72% yield was obtained (entry 5). A
bromoꢀsubstituent at C6 position resulted in a slightly reduced yield (entry 6), and the
yield of substituent at C8 dropped to 55% (entry 7) probably due to the increased steric
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Table 3. Cross-coupling between acetophenone and isochroman derivativesa
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7
8
MnO2 (300 mol%)
CH3SO3H (0.3 mL)
Et2O (1.5 mL)
R4
n
X
O
R3
R4
+
n
X
R3
rt, air
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n = 0, 1
X = O, S
O
2a
5
4
entry
1
series
4a
isochroman derivatives
yield (%)b
81
O
2
3
4
5
6
7
4b
4c
4d
4e
4f
76
74
0
O
H3C
O
tBu
O
MeO
72
66
55
O
Br
Br
O
4g
O
Br
8
4h
4i
78
40
18
0
O
O
9
10
11
4j
S
4k
OMe
MeO
aGeneral conditions: 4 (0.2 mmol), 2a (0.4 mmol), MnO2 (300 mol%),
acid (0.3 mL) in Et2O (1.5 mL) under air for 24 h. bIsolated yield.
bulk. The compatibility of a bromoꢀsubstituent with the oxidation system will be
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beneficial for further diversifications. The reaction of 3ꢀsubstituted isochroman with
acetophenone gave the product in 78% yield (entry 8). Other active methylene
compounds were also applied to the protocol. Phthalan and isothiochroman can be
oxidized by the protocol (entries 9 and 10), although both of them proved to be less
reactive than isochroman. No desired product was observed when acyclic benzylic ether
4k was subjected to the reaction (entry 11).
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Figure 1. Proposed roles of MnO2 and the acid in the coupling
role 1
role 2
H
O
O
Mn
MnO2 + Acid
new Mn(III)
(IV) species
or
(IV)
6b
6a
The presence of a suitable acid is the key issue to the coupling. Although the exact role of
the acid is still unclear, we proposed two possible roles in which MnO2 and acid acted in
the oxidation (Figure 1). In the first one, MnO2 is the real oxidant and the role of the acid
is activating the MnO2 like 6a62. In the other one (6b), the acid might react with MnO2 to
form a new reactive manganese species, which might be the essential oxidant.63 Although
the formula of 6b is unclear, the fact that manganese species like Mn(OAc)3 and
Ba(MnO4)2 afforded comparable results to MnO2 in the presence of CH3SO3H in CH2Cl2
(entries 8, 10 and 12, Table 1), and the precedent64 that Mn2(SO4)3 is a reasonably stable
oneꢀelectron oxidant, indicates that the presence of 6b should be possible. According to
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the above analysis, the reactivity difference of a variety of acids in table 1 could be well
explained. For example, enough acidity and solubility are required for the acid to activate
or react with the MnO2 to initiate the oxidation process, which could explain the
reactivity difference between AcOH and TFA (entries 3 and 6, table 1), and PTSA and
CSA (entries 4 and 5, table 1), respectively. TfOH is less effective than CH3SO3H for the
process (entries 7 and 8, table 1), which could be attributed to the strong acidity of TfOH,
resulting in a poor compatibility of TfOH with reactive intermediates or products;
moreover, in reactive species 6b, the counterion of the acid like sulfonate
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ꢀ
(methanesulfonate for CH3SO3 and trifluoromethanesulfonate for TfOH) could affect the
reactivity of 6b by coordinating to the manganese center. This counterion effect could
also explain the observation that CSA is not as efficient as CH3SO3H for the process
(entries 5 and 7, table 1), probably because the coordination of a bulky counterion to the
manganese center might result in a less reactive oxidant.65
While the mechanism is not yet fully understood, radical intermediates should be
involved in the reaction since substoichiometric amounts (50 mol%) of BHT completely
blocked the transformation (entry 30, table 1); therefore, oneꢀstep hydride transfer
process from isochroman to the oxidant should be excluded. Two mechanisms have been
postulated for the generation of stabilized carbocation 9 through MnO2ꢀCH3SO3H
mediated C–H oxidation (Scheme 3). The first pathway proceeds through an initial
benzylic hydrogen atom abstraction from 1a to 6a or 6b to form free radical 7;66 the
radical diverges either via hydroxyl rebound to form 8 or oneꢀelectron oxidation to
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directly generate cationic intermediate 9. Indeed, employing synthesized 8 as a substrate
under the standard oxidation conditions67 provided the alkylation product 3a in 93% yield
(Scheme 3), indicating that 8 could be a potential intermediate. The other pathway
proceeds through an initial electron transfer from isochroman to 6a or 6b to form the
radical cation 10.68 Carbocation 9 can then be accessed through hydrogen atom
abstraction or proton abstraction followed by a second electron transfer.68ꢀ69
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Scheme 3. Proposed mechanism for MnO2-mediated oxidative cross-coupling
OH
rebound
O
H
8
H+
OH
abstraction
O
6a
6b
or
7
O
O
single-electron
oxidation
O
O
O
9
Ph
Ph
1a
3a
H
abstraction
6a
6b
or
O
O
single-electron
oxidation
or H+ abstraction
then electron
transfer
9
10
H
O
O
new Mn(III)
(IV) species
or
MnO2, CH3SO3H
Et2O, rt, air
O
Mn
O
(IV)
Ph
OH
6b
6a
3a
93%
8
O
The success of the MnO2/CH3SO3H system on ether alkylation led us to explore the
corresponding nitrogenated substrates because tetrahydroisoquinoline (THIQ) derivatives
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Table 4. Cross-coupling between THIQ derivatives and ketonesa
5
6
7
8
9
MnO2 (600 mol%)
CH3SO3H (0.5 mL)
N
O
PG
O
Et2O (1.5 mL)
+
N
rt, air
PG
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R6
11
PG = protecting group
12
13
R6
entry
PG
Bn
R
Yield (%)b
c
c
c
1
2
3
4
5
6
7
8
H
—
—
—
60
20
16
65
62
Ph
H
Boc
Cbz
Ac
H
H
H
Bz
H
Cbz
Br
Cbz
MeO
aGeneral conditions: 11 (0.2 mmol), 12 (0.4 mmol), MnO2 (600 mol%), CH3SO3H
(0.5 mL) in Et2O (1.5 mL) under air. bIsolated yield. cdecomposition.
are common subunits in numerous natural products and pharmaceutically active
compounds.70ꢀ72 NꢀAlkyl and Nꢀaryl THIQs proved to be incompatible with the acid
system, and substrate decomposition occurred immediately after the additions (entries 1
and 2, Table 4). Protecting groups bearing carbonyl functions were also investigated
(entries 3ꢀ6). While similar decomposition was observed with the tertꢀbutyl carbamate
(Boc) substituent (entry 3), benzyl carbamate (Cbz) and amide moieties like acyl (Ac)
and benzoyl (Bz) gave the corresponding alkylation products (entries 4ꢀ6); among these,
the Cbz protecting group worked the best. Cbzꢀprotected THIQ displayed lower reactivity
compared to the oxygenated analogs and more MnO2 and CH3SO3H were required for
reaction completion. 4’ꢀBromo and 4’ꢀmethoxyacetophenone were selected to simply test
the nucleophilic scope and both of them afforded desired products in good chemical
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yields (entries 7 and 8). While the C–H functionalization of Nꢀarylated THIQs was
wellꢀstudied, a vital limitation of such protocols is the difficulty in removing the Nꢀaryl
group, often requiring harsh conditions,73ꢀ75 and therefore resulting in poor functional
group tolerance and synthetic applications. In sharp contrast, although the Cbz group can
be easily removed under a variety of mild conditions,36,76ꢀ78 only two examples of such
couplings were reported, probably due to the reduced reactivity (Scheme 1).36ꢀ37,39 While
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ꢀ
moderate to good chemical yields (up to 81%) were achieved using tBHP or T+BF4 as the
oxidant, either intensive heating or the expensive T+BF4 was requisite for the coupling.
ꢀ
Herein, the successful alkylation of NꢀCbz THIQs under very mild conditions affords
efficient access to structurally diverse THIQs through further functionalization.
■ CONCLUSION
In summary, we have developed an oxidative crossꢀcoupling protocol simply employing
the inexpensive reagents CH3SO3H and MnO2 under air at room temperature. The
oxidation system efficiently promotes the alkylation of isochroman and Cbzꢀprotected
THIQ derivatives with simple ketones in good to excellent yields with high functional
group tolerance on both reactants. The low cost, negligible toxicity, and ease of handling
combined with the absence of hazardous byproducts, are attractive. The method does not
require intensive heating and the workup consists of simple filtration and solvent
evaporation. To the best of our knowledge, this is the first example of the use of MnO2 to
promote benzylic ether or carbamate oxidation, leading to C–C bond formation. The
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development of potential manganese(III)ꢀcatalyzed oxidative alkylation of benzylic
ethers and carbamates is currently under investigation and will be disclosed in due
course.
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■ EXPERIMENTAL SECTION
General Experimental Methods. Proton (1H NMR) and carbon (13C NMR) nuclear
magnetic resonance spectra were recorded at 600 MHz and 125 MHz, respectively. The
chemical shifts are given in parts per million (ppm) on the delta (δ) scale.
Tetramethylsilane (TMS) or the solvent peak was used as a reference value, for 1H NMR:
TMS (in CDCl3) = 0.00 ppm, for 13C NMR: TMS (in CDCl3) = 0.00. Infrared spectra
were recorded on a FTꢀIR spectrometer with KBr discs. Analytical TLC was performed
on preꢀcoated silica gel GF254 plates. HRMS were carried out on an Orbitrap analyzer.
Active MnO2 was heated at 200 °C under vacuum before use.
General procedure A for oxidative couplings between benzylic ethers with ketones.
To a solution of benzylic ethers (0.2 mmol, 1.0 equiv) and ketones (0.4 mmol, 2.0 equiv)
in Et2O (1.5 mL) were added activated MnO2 (52.2 mg, 3.0 equiv) followed by CH3SO3H
(0.3 mL) dropwise under air. The reaction mixture was stirred at rt until TLC analysis
showed complete starting material consumption. The above mixture was directly
purified by flash chromatography to give the desired products.
2-(Isochroman-1-yl)-1-phenylethanone (3a). The general procedure A for the oxidative
coupling was followed, affording the title compound in 81% yield (40.8 mg) as colorless
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oil. 1H NMR (CDCl3, 600 MHz) δ 8.03 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.2 Hz, 2H), 7.49
(t, J = 7.8 Hz, 1H), 7.23ꢀ7.19 (m, 2H), 7.18ꢀ7.14 (m, 1H), 7.15ꢀ7.11 (m, 1H), 5.52 (dd, J
= 3.0, 9.0 Hz, 1H), 4.13 (ddd, J = 3.6, 7.2, 9.6 Hz, 1H), 3.83 (ddd, J = 3.6, 9.6, 11.4Hz,
1H), 3.63 (dd, J = 8.4, 16.2 Hz, 1H), 3.34 (dd, J = 3.0, 16.2 Hz, 1H), 3.06ꢀ3.02 (m, 1H),
2.73 (dt, J = 3.0, 16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 198.2, 137.5, 137.2, 134.0,
133.2, 129.1, 128.6, 128.3, 126.5, 126.3, 124.5, 72.7, 63.5, 45.5, 28.9; IR: νmax 1685,
1596, 1579, 1493, 1449, 1427, 1399, 1366, 1340, 1282, 1203, 1181, 1160, 1107, 1073,
1039, 1013, 1002, 986 cmꢀ1; HRMS (EI) m/z calcd for C17H16O2 [M + H]+ 253.1223,
found 253.1222.
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2-(Isochroman-1-yl)-1-(p-tolyl)ethanone (3b). The general procedure A for the
oxidative coupling was followed, affording the title compound in 75% yield (39.9 mg) as
colorless oil. 1H NMR (CDCl3, 600 MHz) δ 7.92 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 7.2 Hz,
2H), 7.20 (s, 2H), 7.15 (s, 1H), 7.12 (s, 1H), 5.51 (d, J = 1.8 Hz, 1H), 4.15ꢀ4.09 (m, 1H),
3.85ꢀ3.79 (m, 1H), 3.60 (dd, J = 9.0, 16.2 Hz, 1H), 3.31 (d, J = 16.2 Hz, 1H), 3.06ꢀ3.00
13
(m, 1H), 2.72 (d, J = 16.2 Hz, 1H), 2.42 (s, 3H); C NMR (CDCl3, 125 MHz) δ 197.8,
144.0, 137.7, 134.7, 134.0, 129.3, 129.0, 128.5, 126.5, 126.3, 124.6, 72.7, 63.5, 45.4, 28.9,
21.7; IR: νmax 1700, 1590, 1566, 1492, 1468, 1432, 1365, 1339, 1286, 1200, 1106, 1078,
1037, 990, 960, 799 cmꢀ1; HRMS (EI) m/z calcd for C18H18O2 [M + H]+ 267.1380, found
267.1382.
2-(Isochroman-1-yl)-1-(4-methoxyphenyl)ethanone (3c). The general procedure A for
the oxidative coupling was followed, affording the title compound in 71% yield (40.1 mg)
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as colorless oil. H NMR (CDCl3, 600 MHz) δ 8.01 (d, J = 7.8 Hz, 2H), 7.20 (s, 2 H),
7.14 (d, J = 6.0 Hz, 2 H), 6.85 (d, J = 7.2 Hz, 2H), 5.50 (d, J = 7.8 Hz, 1H), 4.16ꢀ4.08 (m,
1H), 3.88 (s, 3H), 3.82 (t, J = 10.2 Hz, 1H), 3.62ꢀ3.54 (m, 1H), 3.27 (d, J = 16.2 Hz, 1H),
3.07ꢀ2.99 (m, 1H), 2,72 (d, J = 16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 196.6,
163,5, 137.7, 134.0, 130.7, 130.3, 129.0, 126.5, 126.2, 124,6, 113.7, 72.8, 63.5, 55.5, 45.1,
28.9; IR: νmax 1675, 1600, 1575, 1511, 1455, 1421, 1366, 1260, 1171, 1106, 1028, 987,
846,754 cmꢀ1; HRMS (EI) m/z calcd for C18H18O3 [M + H]+ 283.1329, found 283.1328.
1-(4-Bromophenyl)-2-(isochroman-1-yl)ethanone (3d). The general procedure A for the
oxidative coupling was followed, affording the title compound in 87% yield (57.6 mg) as
colorless oil. 1H NMR (CDCl3, 600 MHz) δ 7.88 (d, J = 6.6 Hz, 2H), 7.62 (d, J = 6.6 Hz,
2 H), 7.26ꢀ7.05 (m, 4 H), 5.48 (d, J = 7.2 Hz, 1H), 4.15ꢀ4.07 (m, 1H), 3.81 (t, J = 10.2 Hz,
1H), 3.58 (dd, J = 10.2, 15.6 Hz, 1H), 3.29 (d, J = 15.6 Hz, 1H), 3.04 (dd, J = 4.8, 8.4 Hz,
1H), 2.72 (d, J = 16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 197.3, 137.2, 135.9, 134.0,
131.8, 129.9, 129.1, 128.3, 126.7, 126.29, 124.4, 72.7, 63.5, 45.3, 28.9; IR: νmax 1686,
1581, 1495, 1396, 1368, 1283, 1196, 1174, 1105, 1070, 1012, 990, 847, 805, 754 cmꢀ1;
HRMS (EI) m/z calcd for C17H15BrO2 [M + H]+ 331.0328, found 331.0331.
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1-(2-Chlorophenyl)-2-(isochroman-1-yl)ethanone (3e). The general procedure A for the
oxidative coupling was followed, affording the title compound in 75% yield (43.0 mg) as
colorless oil. 1H NMR (CDCl3, 600 MHz) δ 7.55 (d, J = 6.0 Hz, 1H), 7.44ꢀ7.32 (m, 3H),
7.26ꢀ7.05 (m, 4H), 5.37 (s, 1H), 4.15ꢀ4.07 (m, 1H), 3.82ꢀ3.74 (m, 1H), 3.49 (s, 2H),
2.99ꢀ2.93 (m, 1H), 2.71 (d, J = 16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 201.5,
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139.5, 136.9, 133.9, 131.7, 130.7, 130.3, 129.4, 129.1, 127.0, 126.7, 126.3, 124.5, 72.8,
63.1, 49.7, 28.7; IR: νmax 1680, 1606, 1572, 1492, 1453, 1406, 1366, 1339, 1284, 1200,
1181, 1106, 1039, 1013, 983, 805 cmꢀ1; HRMS (EI) m/z calcd for C17H15ClO2 [M + H]+
287.0833, found 287.0835.
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2-(Isochroman-1-yl)-1-phenylpropan-1-one (3f). The general procedure A for the
oxidative coupling was followed, affording the title compound in 71% yield (37.8 mg, dr
1
= 3:1). H NMR (CDCl3, 600 MHz) of the mixture: δ 8.03ꢀ7.93 (m, 2H), 7.61ꢀ7.53 (m,
1H), 7.53ꢀ7.43 (m, 2H), 7.25ꢀ7.02 (m, 4H), 5.33ꢀ5.23 (m, 1H), 4.17ꢀ4.09 (m, 1H),
4.08ꢀ3.96 (m, 1H), 3.71ꢀ3.57 (m, 1H), 3.08ꢀ2.90 (m, 1H), 2.69ꢀ2.56 (m, 1H), 1.24ꢀ1.07
(m, 3H); 13C NMR (CDCl3, 125 MHz) of the mixture: δ 202.6, 201.8, 137.2, 136.7, 136.1,
135.5, 135.0, 134.9, 132.7 (two peaks), 129.1, 128.7, 128.6, 128.5, 128.4 (two peaks),
126. 6, 126.5, 126.4, 125.8 (two peaks), 124.5, 77.5, 76.6, 64.0, 63.3, 47.3, 47.8, 29.3,
28.9, 13.6, 9.9; IR: νmax 1722, 1686, 1597, 1579, 1492, 1451, 1426, 1374, 1343, 1276,
1240, 1220, 1161, 1114, 1075, 1061, 976 cmꢀ1; HRMS (EI) m/z calcd for C18H18O2H [M
+ H]+ 267.1380, found 267.1382.
1-(Furan-2-yl)-2-(isochroman-1-yl)ethanone (3g). The general procedure A for the
oxidative coupling was followed, affording the title compound in 50% yield (24.2 mg) as
colorless oil. 1H NMR (CDCl3, 600 MHz) δ 7.62 (s, 1H), 7.26 (s, 1H), 7.20 (s, 2H), 7.14
(d, J = 15.0 Hz, 2H), 6.56 (s, 1H), 5.47 (d, J = 9.0 Hz, 1H), 4.13 (d, J = 7.2 Hz, 1H),
3.85ꢀ3.76 (m, 1H), 3.49ꢀ3.41 (m, 1H), 3.20 (d, J = 15.6 Hz, 1H), 3.04ꢀ2.96 (m, 1H), 2.73
13
(d, J = 16.2 Hz, 1H); C NMR (CDCl3, 125 MHz) δ 187.0, 153.0, 146.6, 137.2, 134.0,
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129.1, 126.6, 126.3, 124.6, 117.8, 112.4, 72.6, 63.2, 45.3, 28.8; IR: νmax 1721, 1663, 1563,
1493, 1468, 1430, 1393, 1342, 1294, 1246, 1164, 1100, 1057, 1030, 1006, 987, 911, 881
cmꢀ1; HRMS (EI) m/z calcd for C15H14O3 [M + H]+ 243.1016, found 243.1015.
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2-(Isochroman-1-yl)pentan-3-one (3h). The general procedure A for the oxidative
coupling was followed, affording the title compound in 30% yield (13.1 mg) as colorless
1
oil. H NMR (CDCl3, 600 MHz) δ 7.24ꢀ7.02 (m, 4H), 5.32 (s, 0.75H), 4.99 (s, 0.25H),
4.21ꢀ4.09 (m, 1H), 3.75ꢀ3.64 (m, 1H), 3.14ꢀ2.95 (m, 2H), 2.72ꢀ2.24 (m, 3H), 1.22 (d, J =
4.2 Hz, 0.75H), 1.11 (s, 2.25H), 0.96 (d, J = 5.4 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ
212.6, 212.5, 136.0 (two peaks), 134.9, 134.4, 129.0, 126.6, 126.3 (two peaks), 126.0,
125.2, 124.3, 77.8, 76.7, 64.0, 63.6, 51.7, 51.5, 35.0, 33.9, 29.0, 28.9, 13.8 (two peaks),
9.1, 7.8 (two peaks), 7.6; IR: νmax 1710, 1604, 1580, 1494, 1453, 1411, 1373, 1284, 1192,
1160, 1113, 1073, 1042, 980, 942, 906, 804, 748 cmꢀ1; HRMS (EI) m/z calcd for
C14H18O2 [M + H]+ 219.1380, found 219.1377.
2-(Isochroman-1-yl)cyclopentanone (3i). The general procedure A for the oxidative
coupling was followed, affording the title compound in 13% yield (5.6 mg) as colorless
oil. 1H NMR (CDCl3, 600 MHz) δ 7.22ꢀ7.02 (m, 4H), 5.30 (s, 1H), 4.12 (dd, J = 6.0, 10.8
Hz, 1H), 3.72 (t, J = 11.4 Hz, 1H), 3.12ꢀ2.96 (m, 1H), 2.81ꢀ2.68 (m, 1H), 2.64ꢀ2.54 (m,
1H), 2.39ꢀ2.29 (m, 1H), 2.28ꢀ1.98 (m, 2H), 1.97ꢀ1.83 (m, 1H), 1.82ꢀ1.62 (m, 2H); 13C
NMR (CDCl3, 125 MHz) δ 220.0, 218.9, 136.5, 135.8, 134.9, 134.7, 128.9, 126.4, 126.3,
126.1, 124.6, 124.1, 75.6, 75.4, 64.5, 64.2, 55.3, 53.5, 39.5, 29.3, 29.0, 25.3, 23.3, 20.8,
20.6; IR: νmax 1741, 1604, 1493, 1452, 1427, 1404, 1376, 1329, 1278, 1158, 1111, 1060,
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1010, 983, 944 cmꢀ1; HRMS (EI) m/z calcd for C14H16O2 [M + H]+ 217.1223, found
217.1221.
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2-(7-Methylisochroman-1-yl)-1-phenylethanone (5b). The general procedure A for the
oxidative coupling was followed, affording the title compound in 76% yield (40.4 mg) as
colorless oil. 1H NMR (CDCl3, 600 MHz) δ 8.03 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.2 Hz,
1H), 7.49 (d, J = 7.2 Hz, 2H), 7.04 (q, J = 7.2 Hz, 2H), 6.93 (s, 1H), 5.48 (d, J = 8.4 Hz,
1H), 4.15ꢀ4.07 (m, 1H), 3.80 (dd, J = 3.0, 12.0 Hz, 1H), 3.62 (dd, J = 9.0, 16.2 Hz, 1H),
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3.36ꢀ3.30 (m, 1H), 3.31ꢀ2.95 (m, 1H), 2.68 (d, J = 16.2 Hz 1H), 2.32 (s, 3H); C NMR
(CDCl3, 125 MHz) δ 198.2, 137.3, 137.2, 135.8, 133.1, 131.0, 128.9, 128.6, 128.4, 127.5,
125.0, 72.7, 63.6, 45.6, 28.6, 21.2; IR: νmax 1679, 1596, 1578, 1504, 1446, 1366, 1284,
1263, 1202, 1095, 1060, 1010, 809, 758 cmꢀ1; HRMS (EI) m/z calcd for C18H18O2
[M+H]+ 267.1380, found 267.1382.
2-(7-(Tert-butyl)isochroman-1-yl)-1-phenylethanone (5c). The general procedure A for
the oxidative coupling was followed, affording the title compound in 74% yield (45.6 mg)
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as colorless oil. H NMR (CDCl3, 600 MHz) δ 8.03 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.8
Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.26 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 5.53
(d, J = 9.0 Hz, 1H), 4.15ꢀ4.07 (m, 1H), 3.81 (dd, J = 9.6, 16.8 Hz, 1H), 3.66 (dd, J = 9.0,
15.6 Hz, 1H), 3.30 (d, J = 16.2 Hz,1H), 3.03ꢀ2.95 (m, 1H), 2.70 (d, J = 16.2 Hz 1H), 1.30
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(s, 9H); C NMR (CDCl3, 125 MHz) δ 198.5, 149.2, 137.4, 137.0, 133.1, 131.0, 128.7,
128.6, 128.4, 123.8, 121.2, 73.0, 63.4, 45.6, 34.5, 31.3, 28.5; IR: νmax 1726, 1685, 1597,
1580, 1503, 1449, 1364, 1280, 1202, 1102, 1073, 1018, 988, 930, 821 cmꢀ1; HRMS (EI)
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m/z calcd for C21H24O2 [M + H]+ 309.1849, found 309.1846.
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2-(7-Bromoisochroman-1-yl)-1-phenylethanone (5e). The general procedure A for the
oxidative coupling was followed, affording the title compound in 72% yield (47.7 mg) as
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colorless oil. H NMR (CDCl3, 600 MHz) δ 8.05ꢀ7.99 (m, 2H), 7.59 (t, J = 7.2 Hz, 1H),
7.49 (t, J = 7.8 Hz, 2H), 7.33 (dd, J = 1.2, 8.4 Hz, 1H), 7.26 (s, 1H), 7.03 (d, J = 7.2 Hz,
1H), 5.45 (dd, J = 1.8, 7.8 Hz, 1H), 4.12 (ddd, J = 3.6, 5.4, 9.0 Hz, 1H), 3.78 (ddd, J = 3.6,
9.6, 14.4 Hz, 1H), 3.62 (dd, J = 9.0, 16.2 Hz, 1H), 3.30 (dd, J =3.6, 16.2 Hz, 1H),
3.00ꢀ2.92 (m, 1H), 2.67 (dt, J = 3.6, 16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 197.6,
139.7, 137.0, 133.3, 133.0, 130.7, 129.7, 128.6, 128.3, 127.5, 119.8, 72.2, 63.4, 45.2, 28.4;
IR: νmax 1685, 1596, 1580, 1483, 1402, 1368, 1331, 1280, 1109, 1017, 987, 919, 813, 691
cmꢀ1; HRMS (EI) m/z calcd for C17H15BrO2 [M + H]+ 331.0328, found 331.0330.
2-(6-Bromoisochroman-1-yl)-1-phenylethanone (5f). The general procedure A for the
oxidative coupling was followed, affording the title compound in 66% yield (43.7 mg) as
colorless oil. 1H NMR (CDCl3, 600 MHz) δ 8.06 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.2 Hz,
1H), 7.49 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.15ꢀ7.07 (m, 2H), 5.66 (d, J = 9.6
Hz, 1H), 4.10 (ddd, J = 4.2, 12.0, 12.6 Hz, 1H), 3.88ꢀ3.84 (m, 1H), 3.71 (d, J = 15.6 Hz,
1H), 3.44 (dt, J = 10.2, 16.2 Hz, 1H), 2.96ꢀ2.90 (m, 1H), 2.80 (dt, J = 4.2, 16.2 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ 197.3, 136.9, 136.8, 136.48, 133.1, 131.1, 128.6, 128.4,
128.3, 128.1, 121.2, 71.6, 59.8, 42. 6, 28.6; IR: νmax 1731, 1685, 1596, 1562, 1451, 1439,
1403, 1355, 1280, 1203, 1177, 1100, 1059, 1005, 965, 905, 816, 767 cmꢀ1; HRMS (EI)
m/z calcd for C17H15BrO2 [M+H]+ 331.0328, found 331.0331.
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2-(8-Bromoisochroman-1-yl)-1-phenylethanone (5g). The general procedure A for the
oxidative coupling was followed, affording the title compound in 55% yield (36.4 mg) as
colorless oil. 1H NMR (CDCl3, 600 MHz) δ 8.01 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.8 Hz,
1H), 7.48 (t, J = 7.8 Hz, 2H), 7.31 (d, J = 9.6 Hz, 2H), 6.99 (d, J = 8.4 Hz, 1H), 5.44 (d, J
= 6.0 Hz, 1H), 4.13ꢀ4.07 (m, 1H), 3.82ꢀ4.76 (m, 1H), 3.60 (dd, J = 8.4, 16.2 Hz, 1H),
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3.29(dd, J = 3.6, 16.2 Hz, 1H), 3.04ꢀ2.96 (m, 1H), 2.70 (d, J = 16.2 Hz, 1H); C NMR
(CDCl3, 125 MHz) δ 197.8, 137.0, 136.6, 136.4, 133.3, 131.8, 129.37, 128.6, 128.3,
126.3, 120.3, 72.4, 63.2, 45.2, 28.7; IR: νmax 1731, 1673, 1595, 1484, 1449, 1431, 1359,
1336, 1280, 1238, 1106, 1080, 1038, 967, 888, 825 cmꢀ1; HRMS (EI) m/z calcd for
C17H15BrO2 [M + H]+ 331.0328, found 331.0330.
2-(3-Methylisochroman-1-yl)-1-phenylethanone (5h). The general procedure A for the
oxidative coupling was followed, affording the title compound in 78% yield (41.5 mg, dr
= 1:1) as colorless oil. 1st isomer: 1H NMR (CDCl3, 600 MHz) δ 8.03 (d, J = 7.2 Hz, 2H),
7.58 (t, J = 7.2 Hz, 1 H), 7.48 (t, J = 7.2 Hz, 2 H), 7.19 (d, J = 1.8 Hz, 2H), 7.11 (s, 2H),
5.51 (s, 1H), 3.91ꢀ3.81 (m, 1H), 3.59 (dd, J = 7.8, 16.2 Hz, 1H), 3.39 (d, J = 16.2 Hz, 1H),
2.80ꢀ2.67 (m, 2H), 1.28 (d, J = 6.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 198.4, 137.7,
137.4, 134.4, 133.0, 128.9, 128.5, 128.4, 126.6, 126.2, 124.1, 73.5, 70.6, 45.9, 36.5, 21.7;
IR: νmax 1725, 1687, 1597, 1492, 1450, 1357, 1279, 1207, 1146, 1108, 1083, 1042, 987,
955, 822, 750 cmꢀ1; HRMS (EI) m/z calcd for C18H18O2 [M + H]+ 267.1380, found
267.1381. 2nd isomer: 1H NMR (CDCl3, 600 MHz) δ 8.01 (d, J = 7.2 Hz, 2H), 7.59 (t, J =
7.2 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 2 H), 7.20 (m, 2H), 7.13 (s, 2H), 5.64 (d, J = 9.0 Hz,
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1H), 4.12ꢀ4.06 (m, 1H), 3.75 (dd, J = 9.6, 15.6 Hz, 1H), 3.23 (d, J = 9.6 Hz, 1H), 2.77 (d,
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124.1, 73.5, 70.6, 45.9, 36.5, 21.7; IR: νmax 1725, 1682, 1597, 1492, 1450, 1383, 1355,
1281, 1204, 1123, 1107, 1076, 1039, 984, 940, 815 cmꢀ1; HRMS (EI) m/z calcd for
C18H18O2 [M + H]+ 267.1380, found 267.1380.
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2-(1,3-Dihydroisobenzofuran-1-yl)-1-(furan-2-yl)ethanone (5i). The general procedure
A for the oxidative coupling was followed, affording the title compound in 40% yield
1
(18.3 mg) as colorless oil. H NMR (CDCl3, 600 MHz) δ 8.00 (d, J = 7.8 Hz, 2H), 7.58
(t, J = 7.2 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 2H), 7.33ꢀ7.22 (m, 4H), 5.91 (s, 1H), 5.16 (d, J =
12.6 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 3.55 (dd, J = 7.2, 16.2 Hz, 1H), 3.36 (dd, J = 5.4,
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16.8 Hz, 1H); C NMR (CDCl3, 125 MHz) δ 197.8, 141.4, 139.2, 137.0, 133.3, 128.6,
128.3, 127.8, 127.4, 121.5, 121.0, 80.1, 72.6, 45.6; IR: νmax 1700, 1682, 1599, 1476, 1450,
1361, 1281, 1231, 1208, 1107, 1042, 983, 936, 878 cmꢀ1; HRMS (EI) m/z calcd for
C16H14O2 [M + H]+ 239.1067, found 239.1066.
2-(Isothiochroman-1-yl)-1-phenylethanone (5j). The general procedure A for the
oxidative coupling was followed, affording the title compound in 18% yield (9.7 mg). 1H
NMR (CDCl3, 600 MHz) δ 7.98 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.48 (t, J =
7.8 Hz, 2H), 7.22ꢀ7.14 (m, 4H), 4.71ꢀ4.65 (m, 1H), 3.74 (dd, J = 9.0, 17.4 Hz, 1H), 3.49
(dd, J = 3.0, 17.4 Hz, 1H), 3.10 (t, J = 6.0 Hz, 2H), 3.01ꢀ2.95 (m, 1H), 2.90ꢀ2.84 (m, 1H);
13C NMR (CDCl3, 125 MHz) δ 197.3, 137.8, 136.8, 136.7, 133.3, 129.6, 128.7, 128.2,
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127.3, 126.9, 126.6, 47.1, 36.1, 30.9, 24.7; IR: νmax 1677, 1594, 1491, 1445, 1410, 1357,
1299, 1274, 1238, 1205, 1186, 977, 913 cmꢀ1; HRMS (EI) m/z calcd for C17H16SO [M +
H]+ 269.0995, found 269.0996.
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General procedure B for oxidative couplings between tetrahydroisoquinoline
(THIQ）derivatives and ketones. To a solution of THIQ derivatives (0.2 mmol, 1.0
equiv) and ketones (0.4 mmol, 2.0 equiv) in Et2O (1.5 mL) were added activated MnO2
(104 mg, 6.0 equiv) followed by CH3SO3H (0.5 mL) dropwise. The reaction mixture
was stirred at rt until TLC analysis showed complete starting material consumption.
The reaction was quenched with saturated aqueous NaHCO3, and extracted with
CH2Cl2 (3X). The combined organic layers were dried and concentrated under
reduced pressure. The residue was purified by flash chromatography to give the
desired products.
Benzyl-1-(2-oxo-2-phenylethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (13a). The
general procedure B for the oxidative coupling was followed, affording the title compound
in 60% yield (46.3 mg). 1H NMR (CDCl3, 600 MHz, rotamers seen ) δ 8.01 (d, J = 6.6 Hz,
1H), 7.89 (d, J = 6.6 Hz, 1H), 7.60ꢀ7.30 (m, 5H), 7.30ꢀ7.10 (m, 7H), 5.85 (d, J = 4.8 Hz,
1H), 5.14 (s, 1H), 5.09 (d, J = 12.6 Hz, 0.5H), 4.95 (d, J = 12.6 Hz, 0.5H), 4.18 (d, J =
12.6 Hz, 0.5H), 3.99ꢀ3.89 (m, 0.5H), 3.77ꢀ3.53 (m, 1H), 3.47 (d, J = 9.6 Hz, 1H), 3.37 (dd,
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J = 6.0, 15.0 Hz, 1H), 3.05ꢀ2.83 (m, 2H); C NMR (CDCl3, 125 MHz, rotamers seen) δ
197.3, 155.0, 137.0, 136.8, 136.7, 136.6, 136.3, 134.2, 133.1, 129.0, 128,6, 128.4, 128.3,
128.1, 127.9, 127.9, 127.2, 127.1, 126.9, 129.4, 67.3, 51.9, 46.5, 38.8, 28.3; IR: νmax 1687,
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1607, 1492, 1454, 1381, 1333, 1275, 1205, 1095, 1075, 1051, 1006, 995, 957, 917, 776
cmꢀ1; HRMS (EI) m/z calcd for C25H23NO3 [M + H]+ 386.1751, found 386.1740.
Benzyl-1-(2-(4-bromophenyl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylat
e (13b). The general procedure B for the oxidative coupling was followed, affording the
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title compound in 65% yield (60.1 mg) as colorless oil. H NMR (CDCl3, 600 MHz,
rotamers seen) δ 7.87 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 7.8 Hz,
1H), 7.50 (d, J = 7.8 Hz, 1H), 7.42ꢀ7.28 (m, 4H), 7.26ꢀ7.10 (m, 5H), 5.79 (d, J = 6.0 Hz,
1H), 5.13 (s, 1H), 5.08ꢀ4.95 (m, 1H), 4.21ꢀ4.15 (m, 0.5H), 3.95ꢀ3.89 (m, 0.5H), 3.61 (s,
0.5H), 3.55ꢀ3.37 (m, 1.5H), 3.34ꢀ3.28 (m, 1H), 3.04ꢀ2.82 (m, 2H); 13C NMR (CDCl3, 125
MHz, rotamers seen) δ 196.2, 154.9, 136.6, 136.2, 136.1, 135.7, 135.4, 134.2, 132.0,
129.9, 129.6, 129.1, 128.7, 128.4, 128.0, 127.9, 127.2, 127.1, 126.8, 126.4, 67.4, 52.0,
46.5, 38.7, 28.3; IR: νmax 1697, 1584, 1453, 1425, 1327, 1294, 1225, 1204, 1120, 1097,
1006, 947, 834, 753 cmꢀ1; HRMS (EI) m/z calcd for C25H22BrNO3 [M + H]+ 464.0856,
found 464.0837.
Benzyl-1-(2-(4-methoxyphenyl)-2-oxoethyl)-3,4-dihydroisoquinoline-2(1H)-carboxyl
ate (13h). The general procedure B for the oxidative coupling was followed, affording
the title compound in 62% yield (51.5 mg) as colorless oil. 1H NMR (CDCl3, 600 MHz,
rotamers seen) δ 8.02 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.41ꢀ7.23 (m, 5H),
7.22ꢀ7.12 (m, 4H), 6.95 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 5.82 (m, 1H), 5.14
(s, 1H), 5.08 (d, J = 12.6 Hz, 0.5H), 4.96 (d, J = 12.0 Hz, 0.5H), 4.22ꢀ4.16 (m, 0.5H),
3.96ꢀ3.90 (m, 0.5H), 3.87 (s, 3H), 3.65ꢀ3.29 (m, 2H), 3.32ꢀ3.24 (m, 1H), 3.04ꢀ2.82 (m,
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2H); 13C NMR (CDCl3, 125 MHz, rotamers seen) δ 195.8, 163.5, 155.1, 136.7, 136.6,
136.5, 134.2, 130.7, 130.5, 130.1, 129.9, 129.0, 128.6, 128.4, 128.0, 127.2, 127.1, 126.4,
113.8, 67.3, 55.5, 52.2, 46.3, 38.7, 28.4; IR: νmax 1698, 1600, 1454, 1425, 1294, 1258,
1227, 1170, 1119, 1026, 1003, 839 cmꢀ1; HRMS (EI) m/z calcd for C26H25NO4 [M+H]+
416.1856, found 416.1844.
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General procedure C for the synthesis of isochroman derivatives (4b-h, 4j).
Substrates 4b-h, 4j were prepared following Johansen79 and Watson80 protocols. A
mixture of the substituted phenylethyl alcohol (1.0 equiv), (2ꢀmethoxyethoxy)methyl
(MEM) chloride (1.5 equiv) and N,Nꢀdiisopropylethylamine (1.5 equiv) in dry CH2Cl2
(120 mL) was stirred under N2 for 2.5 h at rt. The reaction mixture was then washed with
1 M HCl, dried over MgSO4 and the solvent was removed in vacuo. The residue was
purified by flash chromatography to provide the desired acetal for next step.
To the MEM acetal (1.0 equiv) in CH3CN at 0 °C was added TMSOTf (0.25 equiv)
dropwise. After striing at rt for 10 h, it was quenched by saturated aqueous NaHCO3. The
CH3CN was removed under reduced pressure, and the resulting mixture was diluted with
saturated aqueous NaHCO3 and then partitioned with Et2O. The ethereal layer was dried
over MgSO4, filtered, and concentrated to give the crude product, which was purified by
flash chromatography to afford the corresponding isochroman derivatives as colorless
oil.21
7-Methylisochroman (4b). The general procedure C was followed, affording the title
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compound in 80% yield (1.2 g) over two steps as colorless oil. H NMR (CDCl3, 600
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= 4.8 Hz, 2H), 2.32 (s, 3H); C NMR (CDCl3, 125 MHz) δ 135.5, 134.7, 130.1, 128.7,
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1227, 1152, 1126, 1104, 1069, 1005, 986, 946, 916, 853, 810, 747 cmꢀ1; HRMS (EI) m/z
calcd for C10H12O [M + H]+ 149.0960, found 149.0957.
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7-(tert-Butyl)isochroman (4c). The general procedure C was followed, affording the title
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compound in 80% yield (1.5 g) over two steps as colorless oil. H NMR (CDCl3, 600
MHz) δ 7.29ꢀ7.25 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 4.84 (s, 2H), 4.02 (t, J
= 5.4 Hz, 2H), 2.88 (t, J = 5.4 Hz, 2H), 1.37 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ148.9,
134.3, 130.2, 128.5, 123.5, 121.0, 68.2, 65.4, 34.4, 31.3, 31.3, 31.3, 27.9; IR: νmax 1506,
1462, 1376, 1362, 1266, 1194, 1138, 1105, 1067, 989, 945, 878, 824, 810 cmꢀ1; HRMS
(EI) m/z calcd for C13H18O [M + H]+ 191.1430, found 191.1426.
7-Methoxyisochroman (4d). The general procedure C was followed, affording the title
compound in 40% yield (600 mg) over two steps as colorless oil. 1H NMR (CDCl3, 600
MHz) δ 7.05 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 1.8, 8.4 Hz, 1H), 6.53 (d, J = 1.8 Hz, 1H),
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4.76 (s, 2H), 3.97 (t, J = 6.0 Hz, 2H), 3.78 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H); C NMR
(CDCl3, 125 MHz) δ 157.7, 135.8, 129.8, 125.2, 112.7, 109.0, 68.0, 65.6, 55.2, 27.5; IR:
νmax 1725, 1612, 1589, 1504, 1464, 1429, 1320, 1271, 1253, 1226, 1098, 1035, 991, 850,
814 cmꢀ1; HRMS (EI) m/z calcd for C10H12O2 [M + H]+ 165.0944, found 165.0938.
7-Bromoisochroman (4e). The general procedure C was followed, affording the title
compound in 40% yield (750 mg) over two steps as colorless oil. 1H NMR (CDCl3, 600
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MHz) δ 7.28 (m, 1H), 7.14 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.73 (s, 2H), 3.96 (t, J = 6.0
Hz, 2H), 2.80 (t, J =5.4 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 137.0, 132.1, 130.5,
129.4, 127.3, 119.4, 67.4, 65.1, 27.8; IR: νmax 1484, 1426, 1412, 1190, 1101, 986, 944,
877, 807 cmꢀ1; HRMS (EI) m/z calcd for C9H9BrO [M + H]+ 212.9910, found 212.9905.
6-Bromoisochroman (4f). The general procedure C was followed, affording the title
compound in 15% yield (200 mg) over two steps as colorless oil. 1H NMR (CDCl3, 600
MHz) δ 7.38 (d, J = 7.8 Hz, 1H), 7.11ꢀ7.03 (m, 2H), 4.71 (s, 2H), 3.94 (t, J = 6.0 Hz, 2H),
2.86 (t, J =5.4 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 136.1, 134.0, 130.0, 127.9, 127.6,
120.7, 68.6, 64.8, 28.3; IR: νmax 1566, 1461, 1434, 1200, 1111, 1067, 1003, 954, 823, 771
cmꢀ1; HRMS (EI) m/z calcd for C9H9BrO [M + H]+ 212.9910, found 212.9905.
8-Bromoisochroman (4g). The general procedure C was followed, affording the title
compound in 45% yield (600 mg) over two steps as colorless oil. 1H NMR (CDCl3, 600
MHz) δ 7.27 (d, J = 6.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.71 (s, 2H), 3.95 (t, J = 5.4
Hz, 2H), 2.83 (t, J =6.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 135.4, 133.7, 131.6,
129.0, 126.0, 119.8, 67.5, 64.9, 28.0; IR: νmax 1592, 1573, 1481, 1431, 1379, 1327, 1231,
1103, 1066, 1005, 990, 943, 865, 810 cmꢀ1; HRMS (EI) m/z calcd for C9H9BrO [M + H]+
212.9910, found 212.9907.
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3-Methylisochroman (4h). The general procedure C was followed, affording the title
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compound in 80 % yield (1.2 g) over two steps as colorless oil. H NMR (CDCl3, 600
MHz) δ 7.20ꢀ7.14 (m, 2H), 7.11 (s, 1H), 7.01 (d, J = 2.4 Hz, 1H), 4.88ꢀ4.82 (m, 2H), 3.84
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(dd, J = 5.4, 11.4 Hz, 1H), 2.73 (d, J = 7.2 Hz, 2H), 1.37 (d, J = 6.0 Hz, 3H); C NMR
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(CDCl3, 125 MHz) δ 134.6, 133.5, 128.7, 126.3, 125.9, 124.1, 70.9, 68.1, 35.7, 21.6; IR:
νmax 1497, 1451, 1383, 1369, 1203, 1139, 1124, 1103, 1084, 1040, 821 cmꢀ1; HRMS (EI)
m/z calcd for C10H12O [M + H]+ 149.0961, found 149.0956.
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Isothiochroman (4j). The general procedure C was followed, affording the title
compound in 40% yield (400 mg) over two steps as colorless oil. 1H NMR (CDCl3, 600
MHz) δ 7.26ꢀ7.10 (m, 4H), 3.77 (s, 2H), 3.04 (t, J = 6.0 Hz, 2H), 2.92 (t, J =6.0 Hz, 2H);
13C NMR (CDCl3, 125 MHz) δ 136.8, 135.0, 129.2, 127.6, 126.8, 126.2, 30.4, 29.2, 26.4;
IR: νmax 1696, 1579, 1492, 1446, 1423, 1289, 1189, 1102, 1046, 945, 903, 814, 744 cmꢀ1;
HRMS (EI) m/z calcd for C9H10S [M + H]+ 151.0554, found 151.0548.
Isochroman-1-ol (8). The title compound was prepared through the Harling route.81 1
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NMR (CDCl3, 600 MHz) δ 7.37ꢀ7.31 (m, 1H), 7.30ꢀ7.23(m, 2H), 7.15 (d, J = 7.2 Hz, 1H),
5.99 (d, J = 5.4 Hz, 1H), 4.23 (td, J = 3.6, 12.6 Hz, 1H), 3.97 (ddd, J = 2.4, 5.4, 11.4 Hz,
1H), 3.02 (d, J = 5.4 Hz, 1H), 2.70 (d, J = 16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
134.9, 134.1, 128.5, 128.3, 127.3, 126.5, 91.5, 58.3, 28.0; IR: νmax 3377， 1606，1494,
1458，1424，1384，1269，1199，1078，1066，1011，984，950，938，885，784，
740，664，572，439 cmꢀ1; HRMS (EI) m/z calcd for C9H10O2 [M + H]+ 151.0754, found
151.0748.
2-(Isochroman-1-yl)-1-phenylethanone (3a).
To a solution of hemiacetal 8 (30.0 mg, 0.2 mmol) and acetophenone (46.7 uL, 0.4 mmol)
in Et2O (1.5 mL) were added activated MnO2 (52.2 mg, 0.6 mmol) followed by
CH3SO3H (0.3 mL) dropwise under air. The reaction mixture was stirred at rt for 3 h,
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