Copper(II) catalyzed cross-dehydrogenative coupling of cyclic benzylic ethers with simple carbonyl compounds by Na2S2O 8

Article abstract of DOI:10.1016/j.tet.2014.03.074

Copper(II) catalyzed cross-dehydrogenative coupling of cyclic benzylic ethers with a variety of simple carbonyl compounds mediated by Na ₂S₂O₈ is developed. The scope of carbonyl components is broad, including simple aldeh

Full text of DOI:10.1016/j.tet.2014.03.074

Tetrahedron xxx (2014) 1e5
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Tetrahedron
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Copper(II) catalyzed cross-dehydrogenative coupling of cyclic
benzylic ethers with simple carbonyl compounds by Na2S2O8
Xinhui Pan y, Qingwen Hu y, Wenfang Chen, Xigong Liu, Bin Sun, Zhouli Huang,
*
*
Ziyu Zeng, Liguo Wang, Dan Zhao, Mei Ji, Lei Liu , Hongxiang Lou
Department of Natural Product Chemistry, Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences,
Shandong University, Jinan 250012, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper(II) catalyzed cross-dehydrogenative coupling of cyclic benzylic ethers with a variety of simple
carbonyl compounds mediated by Na2S2O8 is developed. The scope of carbonyl components is broad,
including simple aldehydes as well as ketones. The use of Na2S2O8 as the oxidant for the CDC reaction is
attractive based on economical and environmental factors.
Received 31 January 2014
Received in revised form 15 March 2014
Accepted 23 March 2014
Available online xxx
Ó 2014 Published by Elsevier Ltd.
Keywords:
Cross-dehydrogenative coupling
Copper-catalyzed
Peroxydisulfate
Benzylic ether
Simple carbonyl compound
1. Introduction
butyl hydroperoxide (TBHP),7 NHPI (N-hydroxyphthalimide),8
TEMPO oxoammonium salt (TþBF4ꢀ),9 and MnO2/CH3SO3H.10 Mod-
a
-Substituted cyclic ethers are one of the most common struc-
erate to good reaction efficiency was achieved by utilizing these
oxidants together with suitable metal catalysts. However, the ma-
jority of the systems suffer from either economic or environmental
issues. For example, as the most universal oxidant in terms of the
nucleophile scope, DDQ is moderately expensive, with a cost of
$666/mol according to the 2013e2014 Aldrich catalog. In addition
to concerns about cost, DDQ also poses modest toxicity concerns
(LD50¼82 mg/kg),11 the potential for HCN liberation upon exposure
to H2O, and the purification difficulties. As another example, TBHP
in decane costs about $273/mol, and can cause severe skin burns,
eye damage, and an allergic skin reaction. NHPI and TþBF4ꢀ do not
have above problems, though the latter is not commercially avail-
able, and need to be prepared in the bench. While MnO2 only costs
$47/mol, the oxidation requires strong acid to occur, which results
in poor functional group compatibility and also incurs environ-
mental issue. According to the state of art of existing protocols, the
development of an economic and environmentally benign oxida-
tion system is still an attractive project to pursue.
tural motifs spread across biologically active natural products and
synthetic pharmaceuticals, and significant efforts have been de-
voted to their synthesis.1 During the past few years, the direct
cross-dehydrogenative coupling (CDC) reactions to construct new
CeC bond by utilizing two CeH bonds have emerged as an elegant
alternative to the traditional functional group chemistry.2,3 Such
strategy avoids the steps of functional group installation, and
therefore makes the synthetic schemes shorter and more efficient.4
Although remarkable progress including new types of synthetic
transformations as well as oxidation systems has been achieved in
this area, especially in the functionalization of the sp3 CeH bond
adjacent to a heteroatom, the majority of such couplings involve
the functionalization of electron-rich amines.5 For the corre-
sponding ether compounds, important molecules in both academic
and industrial research, the development of CDC reactions is still
far from satisfactory. Till now, five terminal oxidations have been
reported to promote the CDC reactions of benzylic ethers,
including DDQ (2,3-dichloro-5,6-dicyanobenzoquinone),6 tert-
The use of peroxydisulfate (S2O28ꢀ) together with a metal cata-
lyst has long been known to oxidize the benzylic CeH bonds ini-
tiated by a single electron transfer process.12 The oxidant is
inexpensive, less toxic, and easily handled. The price of perox-
ydisulfate salt like Na2S2O8 is only $8.3/mol, with a LD50 of 930 mg/
kg.11 Additionally, the byproduct can be easily removed with
* Corresponding authors. E-mail addresses: leiliu@sdu.edu.cn (L. Liu), lou-
hongxiang@sdu.edu.cn (H. Lou).
y
These authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2014 Published by Elsevier Ltd.
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2
X. Pan et al. / Tetrahedron xxx (2014) 1e5
a simple filtration over Celite. To the best of our knowledge, such
oxidation system has not yet been applied to CDC reactions of
ethers to date. Given the importance of cyclic benzylic ethers in
biologically relevant molecules, we herein report a copper(II) cat-
alyzed CDC reaction of cyclic benzylic ethers with a variety of CeH
nucleophiles employing sodium persulfate as the terminal oxidant.
Na2S2O8 worked the best, and was selected for the further opti-
mization (entries 10, 18 and 19). Either increasing the temperature
to 100 ꢁC or lowering it to 60 ꢁC gave an inferior yield (entries 10,
20, and 21). Microwave-assisted reaction did not give any im-
provement (entry 22). Reaction optimization experiments identi-
fied increased Na2S2O8 (3 equiv) at 80 ꢁC as ideal conditions in the
presence of CuBr2 (20 mol %) without any solvent (entry 23).
Stoichiometric amounts (100 mol %) of 2,6-di-tert-butyl-4-
methylphenol (BHT), completely blocked the oxidative coupling
(entry 24).
2. Results and discussion
Initially, the coupling of isochroman 1a with acetophenone 2a
was examined using Na2S2O8 as the oxidant. The desired product
3a was observed when the reaction was performed in CH3CN at
80 ꢁC (entry 1, Table 1). Inspired by the result, several solvents were
screened for the optimization, and the coupling was found to be
dependent on the solvent choice. While THF, hexane, CH2Cl2, and
1,4-dioxane inhibited the reaction, conducting the reaction without
any solvent provided the best conversion (entries 1e3). As perox-
ydisulfate was most commonly employed with the combination of
a metal catalyst, different additives were investigated next. Gen-
erally speaking, the involvement of metal catalyst afforded high
efficiency compared to that using Na2S2O8 alone, though Cu(OAc)2
and Cu(OTf)2 did not effect the reaction at all (entries 5 and 6).
Among all the metal additives, CuBr2 proved to be the best choice
for the model coupling, affording 3a in 75% yield (entries 4e16). No
reaction occurred if CuBr2 alone was employed even under the
atmosphere of molecular oxygen (entry 17). The counter ion effect
of peroxydisulfate was then studied. The results showed that
With the optimized conditions in hand, the nucleophile scope of
the CDC reaction was explored (Table 2). Various simple ketones
were efficiently coupled with isochroman. Electron-rich ketones
like 2b and 2c afforded comparable results to that of acetophenone,
while electron-deficient one like 2d gave a reduced yield. Propio-
phenone 2e was also a suitable substrate for the oxidative reaction,
delivering the desired 3e in 69% yield with a diastereomeric ratio of
1:1. Heteroaromatic ketone 2f was also compatible with the oxi-
dative condition, resulting in a moderate yield. Besides the aro-
matic ketones, aliphatic ones like linear 2g and cyclic 2h and 2i
were all tolerated with good to excellent efficiency. In addition to
the ketone moieties, we also studied the alkylation of aldehydes,
which would afford the isochroman with multiple stereogenic
centers. Both linear pentanal 2j and sterically hindered branched
Table 2
Scope of the simple carbonyl componentsa,b
Table 1
Reaction condition optimizationa
Entry
Oxidant
Additive
Yieldb (%)
1c
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
d
d
11
<5
25
50
<5
<5
29
56
63
75
46
35
38
31
38
29
<5
36
21
53
62
40
81
<5
2d
3
d
d
4
5
6
7
8
9
CuSO4
Cu(OTf)2
Cu(OAc)2
Cu3(PO4)2
CuCl2
Cu(C2O4)2
CuBr2
CuOTf
CuCl
10
11
12
13
14
15
16
17
18
19
20e
21f
22g
23h
24i
CuBr
CuI
FeSO4
AgNO3
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
K2S2O8
(NH4)2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
a
General conditions: 1a (0.25 mmol), 2a (1.25 mmol), oxidant (0.5 mmol), ad-
ditive (0.05 mmol) at 80 ꢁC for 24 h, unless stated otherwise.
b
Isolated yield.
CH3CN as the solvent.
c
d
THF, hexane, CH2Cl2, and 1,4-dioxane as solvents.
e
Reaction at 60 ꢁC.
f
Reaction at 100 ꢁC.
g
Microwave at 100 ꢁC for 1 h.
h
0.75 mmol oxidant used.
1 equiv of BHT added.
i
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X. Pan et al. / Tetrahedron xxx (2014) 1e5
3
isobutyraldehyde 2k were found to be competent substrates to-
wards the standard conditions.
7). A methyl substituent at the C1 position failed to deliver 5h
probably due to the increased steric bulk (entry 8). In addition to
substituted isochroman, other cyclic ethers were also explored.
Isothiochroman 4i afforded the desired products 5i in reasonable
yields (entry 9). Phthalan 4j was found to be much less reactive
than isochroman 4a with respect to the reaction conversion, pro-
viding mono-substituted 5j in 18% yield (entry 10).14 No reaction
took place when acyclic substrate 4k was applied to the oxidation
condition (entry 11).
While the mechanism is not yet fully understood, radical in-
termediates should be involved in the reaction since stoichiometric
amounts (1 equiv) of BHT completely blocked the transformation
(entry 24, Table 1). This observation indicates that single step hy-
dride transfer pathway from isochroman 1a to the oxidant should
not be applicable to our system (Scheme 1). The oxocarbenium ion
9 was envisioned to be the intermediate for the subsequent nu-
cleophilic addition process. A proposed mechanism for the forma-
tion of carbocation intermediate 9 is shown in Scheme 1. Under
thermal conditions, persulfate may decompose to generate 2 equiv
of SO4 radical anion 6. Two mechanisms have been postulated for
the generation of the carbocation 9 from 1a. The first pathway
proceeds through an initial benzylic hydrogen atom abstraction
from 1a to 6 to give free radical 7 together with 1 equiv of HSOꢀ4 .
Cu(II) is a well-known oxidant for the carbon-centered radicals.15
Therefore, the radical 7 then undergoes one electron oxidation to
generate intermediate 9 together with the generation of Cu(I). Cu(I)
then mediates the collapse of persulfate ion to regenerate Cu(II) and
6. Alternatively, an initial electron transfer from 1a to 6 affords the
radical cation 8 with SO24ꢀ. Then 8 undergoes proton abstraction to
provide radical 7 that will be further oxidized by Cu(II) to afford
intermediate 9.
Next we turned to investigate the scope of benzylic ethers
(Table 3). Isochroman variants with different electronically varied
substituents reacted with acetophenone smoothly under the
standard conditions to afford the desired products in good yields,
though a methoxy substituent at C7 did not effect any reaction
(entries 1e6, Table 3). This observation was identical to that of
DDQ/CuCl2 mediated arylation of isochroman by Todd.6b The result
can be explained according to the Floreancig’s mechanistic studies
of DDQ-mediated ether functionalizations involving a radical
pathway, in which substrates with lower oxidation potentials were
found to possess higher bond dissociation energy of the scissile
CeH bond.13 Therefore, the similar intermediate might also exist in
our reaction pathway. The tolerance of a bromosubstituent towards
the reaction condition will be beneficial for further manipulations.
C3-methyl substituted isochroman 4g was suitable substrate to give
the product 5g in 76% yield with a diastereomeric ratio of 1:1 (entry
Table 3
Scope of the benzylic ethersa,b
Entry
1
Series
Benzylic ethers
Yieldb (%)
81
4a
2
3
4b
4c
78
0
4
5
4d
4e
70
62
6c
7
4f
43
76
4g
8
4h
4i
0
Scheme 1. Proposed catalytic cycle.
3. Conclusion
9
39
In summary, we have developed an efficient copper(II)-
catalyzed oxidative cross-coupling reaction of cyclic benzylic
ethers with a variety of simple carbonyl compounds employing the
inexpensive reagent Na2S2O8 as the terminal oxidant. The low cost,
negligible toxicity, and ease of handling of the oxidant combined
with the absence of hazardous byproducts, are attractive. The
method does not require any solvent, and the workup consists of
simple filtration. To the best of our knowledge, this is the first ex-
ample of the use of Na2S2O8/Cu(II) to promote CDC reaction with
10
4j
18
0
11
4k
a
General conditions: 4 (0.25 mmol), 2a (1.25 mmol), oxidant (0.75 mmol), ad-
ditive (0.05 mmol) at 80 ꢁC for 24 h, unless stated otherwise.
b
Isolated yield.
dr¼1:1.
c
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4
X. Pan et al. / Tetrahedron xxx (2014) 1e5
ethers, leading to CeC bond formation. The development of other
peroxydisulfate-mediated oxidative coupling reactions is currently
under investigation and will be disclosed in due course.
124.5, 77.5, 76.6, 63.9, 63.3, 47.3, 47.8, 29.3, 28.9,13.6, 9.9; HRMS (EI)
m/z calcd for C18H19O2 [MþH]þ 267.1380, found 267.1382.
4.1.6. 1-(Furan-2-yl)-2-(isochroman-1-yl)ethanone 3f.9 Yield 45%;
4. Experimental section
colorless oil; 1H NMR (CDCl3, 600 MHz)
d 7.62 (s, 1H), 7.26 (s, 1H),
7.20 (s, 2H), 7.14 (d, J¼15.0 Hz, 2H), 6.56 (s, 1H), 5.47 (d, J¼9.0 Hz,
1H), 4.13 (d, J¼7.2 Hz, 1H), 3.85e3.76 (m, 1H), 3.49e3.41 (m, 1H),
3.20 (d, J¼15.6 Hz, 1H), 3.04e2.96 (m, 1H), 2.73 (d, J¼16.2 Hz, 1H);
4.1. General procedure for the CDC reaction of benzylic ethers
with carbonyl compounds
13C NMR (CDCl3, 125 MHz)
d 187.0, 153.0, 146.6, 137.2, 134.0, 129.1,
To a solution of 1 or 4 (0.25 mmol, 1 equiv), 2 (1.25 mmol,
5 equiv) and CuBr2 (0.05 mmol, 0.2 equiv) was added Na2S2O8
(0.75 mmol, 3 equiv). Then the mixture was stirred at 80 ꢁC until
the starting material disappeared monitored by TLC. After that, the
above mixture was directly purified by flash chromatography (ethyl
acetate/petroleum ether as eluent) to give the desired product
3 or 5.
126.6, 126.3, 124.6, 117.8, 112.4, 72.6, 63.2, 45.3, 28.8; HRMS (EI) m/z
calcd for C15H15O3 [MþH]þ 243.1016, found 243.1015.
4.1.7. 2-(Isochroman-1-yl)pentan-3-one 3g.10 Yield 56%; colorless
oil; 1H NMR (CDCl3, 600 MHz)
d 7.24e7.02 (m, 4H), 5.32 (s, 0.75H),
4.99 (s, 0.25H), 4.21e4.09 (m, 1H), 3.75e3.64 (m, 1H), 3.14e2.95 (m,
2H), 2.72e2.24 (m, 3H), 1.22 (d, J¼4.2 Hz, 0.75H), 1.11 (s, 2.25H),
0.96 (d, J¼5.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 212.6, 212.5,
4.1.1. 2-(Isochroman-1-yl)-1-phenylethanone 3a.10 Yield 81%; light
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; HRMS (EI) m/z calcd
for C14H19O2 [MþH]þ 219.1380, found 219.1377.
yellow oil; 1H NMR (CDCl3, 600 MHz)
d
8.03 (d, J¼7.8 Hz, 2H), 7.59
(t, J¼7.2 Hz, 2H), 7.49 (t, J¼7.8 Hz, 1H), 7.23e7.19 (m, 2H), 7.18e7.14
(m, 1H), 7.15e7.11(m, 1H), 5.52 (dd, J¼3.0, 9.0 Hz, 1H), 4.13 (ddd,
J¼3.6, 7.2, 9.6 Hz, 1H), 3.83 (ddd, J¼3.6, 9.6, 11.4 Hz, 1H), 3.63 (dd,
J¼8.4, 16.2 Hz, 1H), 3.34 (dd, J¼3.0, 16.2 Hz, 1H), 3.06e3.02 (m, 1H),
4.1.8. 2-(Isochroman-1-yl)cyclopentanone 3h.10 Yield 80%; colorless
2.73 (dt, J¼3.0, 16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
d
198.2,
oil; 1H NMR (CDCl3, 600 MHz)
d 7.22e7.02 (m, 4H), 5.30 (s, 1H), 4.12
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; HRMS (EI) m/z calcd for C17H17O2 [MþH]þ
253.1223, found 253.1222.
(dd, J¼6.0, 10.8 Hz, 1H), 3.72 (t, J¼11.4 Hz, 1H), 3.12e2.96 (m, 1H),
2.81e2.68 (m,1H), 2.64e2.54 (m,1H), 2.39e2.29 (m,1H), 2.28e1.98
(m, 2H), 1.97e1.83 (m, 1H), 1.82e1.62 (m, 2H); 13C NMR (CDCl3,
125 MHz)
d 220.0, 218.9, 136.5, 135.8, 134.9, 134.7, 128.9, 126.4,
4.1.2. 2-(Isochroman-1-yl)-1-(p-tolyl)ethanone 3b.10 Yield 77%;
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; HRMS (EI) m/z calcd for C14H17O2
[MþH]þ 217.1223, found 217.1221.
light yellow oil; 1H NMR (CDCl3, 600 MHz)
d
7.92 (d, J¼7.2 Hz, 2H),
7.28 (d, J¼7.2 Hz, 2H), 7.20 (s, 2H), 7.15 (s, 1H), 7.12 (s, 1H), 5.51 (d,
J¼1.8 Hz, 1H), 4.15e4.09 (m, 1H), 3.85e3.79 (m, 1H), 3.60 (dd, J¼9.0,
16.2 Hz, 1H), 3.31 (d, J¼16.2 Hz, 1H), 3.06e3.00 (m, 1H), 2.72 (d,
4.1.9. 2-(Isochroman-1-yl)cyclohexanone 3i. Yield 86%; colorless
J¼16.2 Hz, 1H), 2.42 (s, 3H); 13C NMR (CDCl3, 125 MHz)
d
197.8,
oil; 1H NMR (600 MHz, CDCl3)
d
7.23e7.14 (m, 2H), 7.11 (d, J¼6.8 Hz,
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; HRMS (EI) m/z calcd for C18H19O2 [MþH]þ
267.1380, found 267.1382.
1H), 7.01 (d, J¼7.0 Hz, 1H), 5.48 (s, 1H), 4.16 (dd, J¼11.0, 5.4 Hz, 1H),
3.75 (t, J¼11.3 Hz, 1H), 3.05e2.97 (m, 1H), 2.75 (dd, J¼11.1, 5.6 Hz,
1H), 2.62e2.53 (m, 2H), 2.3e2.30 (m, 1H), 1.99 (dd, J¼8.2, 4.8 Hz,
1H), 1.89e1.82 (m, 1H), 1.76 (ddd, J¼32.4, 20.4, 12.8 Hz, 2H), 1.64 (d,
J¼7.1 Hz, 1H), 1.54 (t, J¼12.5 Hz, 1H). 13C NMR (151 MHz, CDCl3)
4.1.3. 2-(Isochroman-1-yl)-1-(4-methoxyphenyl)ethanone
3c.10 Yield 75%; light yellow oil; 1H NMR (CDCl3, 600 MHz)
d
8.01
d 210.8, 136.6, 135.5, 128.9, 126.3, 126.2, 123.9, 73.7, 64.3, 55.7, 42.0,
(d, J¼7.8 Hz, 2H), 7.20 (s, 2H), 7.14 (d, J¼6.0 Hz, 2H), 6.85 (d,
J¼7.2 Hz, 2H), 5.50 (d, J¼7.8 Hz, 1H), 4.16e4.08 (m, 1H), 3.88 (s, 3H),
3.82 (t, J¼10.2 Hz, 1H), 3.62e3.54 (m, 1H), 3.27 (d, J¼16.2 Hz, 1H),
3.07e2.99 (m, 1H), 2,72 (d, J¼16.2 Hz, 1H); 13C NMR (CDCl3,
29.3, 26.1, 25.2, 24.5; IRnmax 2938, 2847,1706,1493,1450,1426,1377,
1320, 1280, 1145, 1111, 1054, 981, 748, 717 cmꢀ1; HRMS (EI) m/z
calcd for C15H19O2 [MþH]þ 231.1380, found 231.1386.
125 MHz)
d
196.6, 163.5, 137.7, 134.0, 130.7, 130.32, 129.0, 126.5,
4.1.10. 2-(Isochroman-1-yl)pentanal 3j.16 Yield 71%, dr¼3:1; color-
126.2, 124.6, 113.7, 72.8, 63.5, 55.5, 45.1. 28.9; HRMS (EI) m/z calcd
less oil; 1H NMR (600 MHz, CDCl3):
d 9.52 (s, 1H), 7.25e7.17 (m, 2H),
for C18H19O3 [MþH]þ 283.1329, found 283.1328.
7.14 (dd, J¼7.0, 2.9 Hz, 2H), 5.04 (s, 1H), 4.20 (ddd, J¼11.2, 5.7, 1.5 Hz,
1H), 3.72 (td, J¼11.3, 3.0 Hz, 1H), 3.09e3.01 (m, 1H), 2.86e2.81 (m,
1H), 2.65 (d, J¼16.1 Hz, 1H), 1.97e1.88 (m, 1H), 1.68 (ddd, J¼13.8,
10.1, 6.1 Hz, 1H), 1.50e1.41 (m, 2H), 1.00 (t, J¼7.3 Hz, 3H); 13C NMR
4.1.4. 1-(4-Bromophenyl)-2-(isochroman-1-yl)ethanone 3d.10 Yield
61%; light yellow oil; 1H NMR (CDCl3, 600 MHz)
d
7.88 (d, J¼6.6 Hz,
2H), 7.62 (d, J¼6.6 Hz, 2H), 7.26e7.05 (m, 4H), 5.48 (d, J¼7.2 Hz, 1H),
4.15e4.07 (m, 1H), 3.81 (t, J¼10.2 Hz, 1H), 3.58 (dd, J¼10.2, 15.6 Hz,
1H), 3.29 (d, J¼15.6 Hz, 1H), 3.04 (dd, J¼4.8, 8.4 Hz, 1H), 2.72 (d,
(151 MHz, CDCl3): d 204.2, 136.0, 134.8, 129.4, 127.0, 126.8, 125.0,
76.1, 64.8, 56.9, 29.4, 28.5, 20.8, 14.3; 1H NMR (600 MHz, CDCl3)
d
9.88 (s, 1H), 7.20 (d, J¼2.6 Hz, 2H), 7.14 (d, J¼6.3 Hz, 1H), 7.05 (d,
J¼16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
d
197.4, 137.2, 135.9,
J¼6.5 Hz, 1H), 5.31 (s, 1H), 4.15 (dd, J¼10.9, 5.6 Hz, 1H), 3.70 (t,
J¼11.4 Hz, 1H), 3.11e3.03 (m, 1H), 2.73 (d, J¼9.8 Hz, 1H), 2.60 (d,
J¼16.1 Hz, 1H), 1.86 (dt, J¼14.4, 9.8 Hz, 1H), 1.37e1.31 (m, 1H),
1.22e1.09 (m, 2H), 0.81 (t, J¼6.8 Hz, 3H); 13C NMR (151 MHz, CDCl3)
134.0, 131.8, 129.9, 129.1, 128.3, 126.7, 126.3, 124.4, 72.7, 63.5, 45.3,
28.9; HRMS (EI) m/z calcd for C17H16BrO2 [MþH]þ 331.0328, found
331.0331.
d
205.3, 135.6, 135.3, 129.4, 126.8, 126.7, 124.3, 76.6, 64.7, 56.8, 29.2,
4.1.5. 2-(Isochroman-1-yl)-1-phenylpropan-1-one 3e.10 Yield 69%;
25.3, 21.5, 14.3; HRMS (EI) m/z calcd for C14H19O2 [MþH]þ 219.1380,
colorless oil; 1H NMR (CDCl3, 600 MHz) of the mixture,
d
8.03e7.93
found 219.1376.
(m, 2H), 7.61e7.53 (m, 1H), 7.53e7.43 (m, 2H), 7.25e7.02 (m, 4H),
5.33e5.23 (m, 1H), 4.17e4.09 (m, 1H), 4.08e3.96 (m, 1H), 3.71e3.57
(m, 1H), 3.08e2.90 (m, 1H), 2.69e2.56 (m, 1H), 1.24e1.07 (m, 3H);
4.1.11. 2-(Isochroman-1-yl)-2-methylpropanal 3k. Yield 56%; color-
less oil; 1H NMR (600 MHz, CDCl3)
d 9.73 (s, 1H), 7.23e7.11 (m, 3H),
13C NMR (CDCl3,125 MHz) of the mixture
d
202.6, 201.8,137.2,136.7,
7.05 (d, J¼7.2 Hz, 1H), 5.12 (s, 1H), 4.13 (dd, J¼10.3, 4.5 Hz, 1H), 3.57
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),
(t, J¼11.3 Hz, 1H), 3.04e2.95 (m, 1H), 2.56 (d, J¼15.9 Hz, 1H), 1.10 (s,
3H), 1.00 (s, 3H); 13C NMR (151 MHz, CDCl3)
d 205.4, 136.5, 134.0,
Please cite this article in press as: Pan, X.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.074

X. Pan et al. / Tetrahedron xxx (2014) 1e5
5
129.1, 126.8, 126.0, 126.0, 79.4, 64.0, 52.8, 30.2, 19.1, 17.4; HRMS (EI)
NMR (CDCl3,125 MHz)
d
197.3,137.8,136.8,136.7,133.3,129.6,128.7,
m/z calcd for C13H17O2 [MþH]þ 205.1223, found 205.1219.
128.2, 127.3, 126.9, 126.6, 47.1, 36.1, 30.9, 24.7; HRMS (EI) m/z calcd
for C17H17SO [MþH]þ 269.0995, found 269.0996.
4.1.12. 2-(7-Methylisochroman-1-yl)-1-phenylethanone 5b.10 Yield
78%; colorless oil; 1H NMR (CDCl3, 600 MHz)
d
8.03 (d, J¼7.8 Hz,
4.1.18. 2-(1,3-Dihydroisobenzofuran-1-yl)-1-phenylethanone
2H), 7.58 (t, J¼7.2 Hz, 1H), 7.49 (d, J¼7.2 Hz, 2H), 7.04 (q, J¼7.2 Hz,
2H), 6.93 (s, 1H), 5.48 (d, J¼8.4 Hz, 1H), 4.15e4.07 (m, 1H), 3.80 (dd,
J¼3.0, 12.0 Hz, 1H), 3.62 (dd, J¼9.0, 16.2 Hz, 1H), 3.36e3.30 (m, 1H),
3.31e2.95 (m, 1H), 2.68 (d, J¼16.2 Hz 1H), 2.32 (s, 3H); 13C NMR
5j.10 Yield 18%; colorless oil; 1H NMR (CDCl3, 600 MHz)
d 8.00 (d,
J¼7.8 Hz, 2H), 7.58 (t, J¼7.2 Hz, 1H), 7.47 (t, J¼7.8 Hz, 2H), 7.33e7.22
(m, 4H), 5.91 (s, 1H), 5.16 (d, J¼12.6 Hz, 1H), 5.10 (d, J¼12.0 Hz, 1H),
3.55 (dd, J¼7.2, 16.2 Hz, 1H), 3.36 (dd, J¼5.4, 16.8 Hz, 1H); 13C NMR
(CDCl3, 125 MHz)
d
198.2, 137.3, 137.2, 135.8, 133.1, 131.0, 128.9,
(CDCl3, 125 MHz) d 197.8, 141.4, 139.2, 137.0, 133.3, 128.6, 128.3,
128.6, 128.4, 127.5, 125.0, 72.7, 63.6, 45.6, 28.6, 21.2; HRMS (EI) m/z
127.8, 127.4, 121.5, 121.0, 80.1, 72.6, 45.6; HRMS (EI) m/z calcd for
C
calcd for C18H19O2 [MþH]þ 267.1380, found 267.1382.
16H15O2 [MþH]þ 239.1067, found 239.1066.
4.1.13. 2-(7-Bromoisochroman-1-yl)-1-phenylethanone 5d.10 Yield
Acknowledgements
70%; colorless oil; 1H NMR (CDCl3, 600 MHz)
d 8.05e7.99 (m, 2H),
7.59 (t, J¼7.2 Hz, 1H), 7.49 (t, J¼7.8 Hz, 2H), 7.33 (dd, J¼1.2, 8.4 Hz,
1H), 7.26 (s, 1H), 7.03 (d, J¼7.2 Hz, 1H), 5.45 (dd, J¼1.8, 7.8 Hz, 1H),
4.12 (ddd, J¼3.6, 5.4, 9.0 Hz, 1H), 3.78 (ddd, J¼3.6, 9.6, 14.4 Hz, 1H),
3.62 (dd, J¼9.0, 16.2 Hz, 1H), 3.30 (dd, J¼3.6, 16.2 Hz, 1H), 3.00e2.92
(m, 1H), 2.67 (dt, J¼3.6, 16.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
Financial Support from the National Science Foundation of
China (No. 21202093) and Young Scientist Foundation Grant of
Shandong Province (No. BS2013YY001) and Changjiang Scholars
and Innovative Research Team (IRT13028) is greatly appreciated.
d
197.6, 139.7, 137.0, 133.3, 133.0, 130.7, 129.7, 128.6, 128.3, 127.5,
Supplementary data
119.8, 72.2, 63.4, 45.2, 28.4; HRMS (EI) m/z calcd for C17H16BrO2
[MþH]þ 331.0328, found 331.0330.
The spectra of the compounds in Tables 2 and 3 in this manu-
script can be found. Supplementary data related to this article can
be found at http://dx.doi.org/10.1016/j.tet.2014.03.074.
4.1.14. 2-(6-Bromoisochroman-1-yl)-1-phenylethanone 5e.10 Yield
62%; colorless oil; 1H NMR (CDCl3, 600 MHz)
d
8.06 (d, J¼7.8 Hz,
2H), 7.59 (t, J¼7.2 Hz, 1H), 7.49 (t, J¼7.8 Hz, 2H), 7.44 (d, J¼7.8 Hz,
1H), 7.15e7.07 (m, 2H), 5.66 (d, J¼9.6 Hz, 1H), 4.10 (ddd, J¼4.2, 12.0,
12.6 Hz, 1H), 3.88e3.84 (m, 1H), 3.71 (d, J¼15.6 Hz, 1H), 3.44 (dt,
J¼10.2, 16.2 Hz, 1H), 2.96e2.90 (m, 1H), 2.80 (dt, J¼4.2, 16.2 Hz, 1H);
References and notes
1. (a) Lu, Z.; Lin, Z.; Wang, W.; Du, L.; Zhu, T.; Fang, Y.; Gu, Q.; Zhu, W. J. Nat. Prod.
2008, 71, 543; (b) TenBrink, R. E.; Bergh, C. L.; Duncan, J. N. J. Med. Chem. 1996,
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takoop, P.; Kirtikara, K.; Vichai, V.; Tanticharoen, M.; Thebtaranonth, Y. J. Org.
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Chem. Soc. Rev. 2001, 30, 94; (b) Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45,
6422; (c) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976; (d) Liu, L.;
Floreancig, P. E. Curr. Opin. Drug Discovery Dev. 2010, 13, 733.
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Yoo, W. J.; Li, C. J. Top. Curr. Chem. 2010, 292, 281; (c) Scheuermann, C. J. Chem.
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40; (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
13C NMR (CDCl3, 125 MHz)
d 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; HRMS (EI) m/z
calcd for C17H16BrO2 [MþH]þ 331.0328, found 331.0331.
4.1.15. 2-(8-Bromoisochroman-1-yl)-1-phenylethanone 5f.10 Yield
43%; colorless oil; 1H NMR (CDCl3, 600 MHz)
d
8.01 (d, J¼7.8 Hz,
2H), 7.59 (t, J¼7.8 Hz, 1H), 7.48 (t, J¼7.8 Hz, 2H), 7.31 (d, J¼9.6 Hz,
2H), 6.99 (d, J¼8.4 Hz, 1H), 5.44 (d, J¼6.0 Hz, 1H), 4.13e4.07 (m, 1H),
3.82e4.76 (m, 1H), 3.60 (dd, J¼8.4, 16.2 Hz, 1H), 3.29 (dd, J¼3.6,
16.2 Hz, 1H), 3.04e2.96 (m, 1H), 2.70 (d, J¼16.2 Hz, 1H); 13C NMR
(CDCl3, 125 MHz)
d 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; HRMS (EI) m/z calcd
5. (a) Li, Z.; Li, C. J. J. Am. Chem. Soc. 2004, 126, 11810; (b) Li, Z.; Yu, R.; Li, H. Angew.
Chem., Int. Ed. 2008, 47, 7497; (c) Yang, F.; Li, J.; Xie, J.; Huang, Z. Z. Org. Lett.
for C17H16BrO2 [MþH]þ 331.0328, found 331.0335.
€
2010, 12, 5214; (d) Hari, D. P.; Konig, B. Org. Lett. 2011, 13, 3852; (e) Boess, E.;
ꢀ
4.1.16. 2-(3-Methylisochroman-1-yl)-1-phenylethanone 5g.10 Yield
Sureshkumar, D.; Sud, A.; Wirtz, C.; Fares, C.; Klussmann, M. J. Am. Chem. Soc.
2011, 133, 8106; (f) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012,
134, 5317; (g) Murahashi, S. I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem. Soc.
2008, 130, 11005; (h) Murahashi, S. I.; Komiya, N.; Terai, H.; Nakae, T. J. Am.
Chem. Soc. 2003, 125, 15312; (i) Muramatsu, W.; Nakano, K.; Li, C.-J. Org. Lett.
2013, 15, 3650; (j) Liu, L.; Floreancig, P. E. Org. Lett. 2009, 11, 3152; (k) Liu, L.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 3069; (l) Liu, L.; Floreancig, P. E.
Angew. Chem., Int. Ed. 2010, 49, 5894.
76%, dr¼1:1; colorless oil; 1H NMR (CDCl3, 600 MHz)
d 8.03 (d,
J¼7.2 Hz, 2H), 7.58 (t, J¼7.2 Hz, 1H), 7.48 (t, J¼7.2 Hz, 2H), 7.19 (d,
J¼1.8 Hz, 2H), 7.11 (s, 2H), 5.51 (s, 1H), 3.91e3.81 (m, 1H), 3.59 (dd,
J¼7.8, 16.2 Hz, 1H), 3.39 (d, J¼16.2 Hz, 1H), 2.80e2.67 (m, 2H), 1.28
(d, J¼6.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 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,
6. (a) Zhang, Y. H.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242; (b) Park, S. J.; Price, J.
R.; Todd, M. H. J. Org. Chem. 2012, 77, 949; (c) Zhang, Y. H.; Li, C.-J. Angew. Chem.,
Int. Ed. 2006, 45, 1949.
36.5, 21.7; HRMS (EI) m/z calcd for C18H19O2 [MþH]þ 267.1380,
found 267.1381; 1H NMR (CDCl3, 600 MHz)
d
8.01 (d, J¼7.2 Hz, 2H),
€
7. (a) Ghobrial, M.; Schnurch, M.; Mihovilovic, M. D. J. Org. Chem. 2011, 76, 8781;
€
(b) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schnurch, M. Chem.
7.59 (t, J¼7.2 Hz, 1H), 7.49 (t, J¼7.2 Hz, 2H), 7.20 (m, 2H), 7.13 (s, 2H),
5.64 (d, J¼9.0 Hz, 1H), 4.12e4.06 (m, 1H), 3.75 (dd, J¼9.6, 15.6 Hz,
1H), 3.23 (d, J¼9.6 Hz, 1H), 2.77 (d, J¼15.6 Hz, 1H), 2.67 (dd, J¼9.6,
15.6 Hz, 1H), 1.22 (d, J¼5.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
Commun. 2010, 8836.
8. Yoo, W.-J.; Correia, C. A.; Zhang, Y. H.; Li, C.-J. Synlett 2009, 138.
~
9. (a) Richter, H.; Mancheno, O. G. Eur. J. Org. Chem. 2010, 4460; (b) Richter, H.;
~
Rohlmann, R.; García Mancheno, O. Chem.dEur. J. 2011, 17, 11622.
10. Li, X. G.; Sun, B.; Xie, Z. Y.; Qin, X. J.; Liu, L.; Lou, H. X. J. Org. Chem. 2013, 78, 3104.
11. Rat LD50 values can be found on MSDS sheets.
d
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; HRMS (EI) m/z calcd for C18H19O2
[MþH]þ 267.1380, found 267.1380.
12. (a) Walling, C.; Zhao, C.; El-Taliawi, G. M. J. Org. Chem. 1983, 48, 4910; (b) Par-
liament, T. H.; Parliament, M. W.; Fagerson, I. S. Chem. Ind. (London) 1966, 1845;
(c) Dhar, D. N.; Munjal, R. C. Synthesis 1973, 542; (d) Moritz, C.; Wolffenstein, R.
Chem. Ber. 1899, 32, 432; (e) Bacon, R. G. R.; Doggart, J. R. J. Chem. Soc. 1960,
1332; (f) Austin, P. C. J. Chem. Soc. 1911, 99, 262.
13. Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 10830.
14. Double-alkylated byproduct was observed in less than 5% yield.
15. Kochi, J. K. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York, NY, 1973; p 591.
16. Meng, Z. L.; Sun, S. T.; Yuan, H. Q.; Lou, H. X.; Liu, L. Angew. Chem., Int. Ed. 2014,
53, 543.
4.1.17. 2-(Isothiochroman-1-yl)-1-phenylethanone 5i.10 Yield 39%;
colorless oil; 1H NMR (CDCl3, 600 MHz)
d
7.98 (d, J¼7.2 Hz, 2H), 7.59
(t, J¼7.2 Hz, 1H), 7.48 (t, J¼7.8 Hz, 2H), 7.22e7.14 (m, 4H), 4.71e4.65
(m, 1H), 3.74 (dd, J¼9.0, 17.4 Hz, 1H), 3.49 (dd, J¼3.0, 17.4 Hz, 1H),
3.10 (t, J¼6.0 Hz, 2H), 3.01e3.95 (m, 1H), 2.90e2.84 (m, 1H); 13C
Please cite this article in press as: Pan, X.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.074