Intermolecular Oxidative Radical Addition to Aromatic Aldehydes: Direct Access to 1,4- and 1,5-Diketones via Silver-Catalyzed Ring-Opening Acylation of Cyclopropanols and Cyclobutanols

Article abstract of DOI:10.1021/acs.joc.8b00666

A novel silver-catalyzed ring-opening acylation of cyclopropanols and cyclobutanols is described. The reaction proceeds under mild and neutral conditions and provides a facile access to nonsymmetric 1,4- and 1,5-diketones in promising yields with broad substrate scope. Mechanistic studies including DFT calculations suggest the involvement of an uncommon water-assisted 1,2-HAT process, which is strongly exothermic and thus promotes addition of carbon radicals to aldehydes. In contrast to traditional reductive radical addition protocols, this work represents the first example of the intermolecular oxidative radical addition to aldehydes, thus offering a novel strategy for the direct synthesis of acyclic ketones from readily accessible aldehydes.

Full text of DOI:10.1021/acs.joc.8b00666

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Intermolecular Oxidative Radical Addition to Aromatic Aldehydes:
Direct Access to 1,4- and 1,5-Diketones via Silver-Catalyzed
Ring-Opening Acylation of Cyclopropanols and Cyclobutanols
Chao Che, Zhaosheng Qian, Mingchang Wu, Ying Zhao, and Gangguo Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00666 • Publication Date (Web): 23 Apr 2018
Downloaded from http://pubs.acs.org on April 23, 2018
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Intermolecular Oxidative Radical Addition to Aromatic Aldehydes: Direct Access to 1,4ꢀ and
1,5ꢀDiketones via SilverꢀCatalyzed RingꢀOpening Acylation of Cyclopropanols and Cyclobutanols
Chao Che,† Zhaosheng Qian,† Mingchang Wu, Ying Zhao, and Gangguo Zhu*
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of
Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China
gangguo@zjnu.cn
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O
n
AgNO3, Na2S2O8
DMSO/H2O (1:1), 50 oC
Ar
+ ArCHO
R
n
R
OH
O
n = 1, 2
up to 92% yield
A novel silverꢀcatalyzed ringꢀopening acylation of cyclopropanols and cyclobutanols is described. The
reaction proceeds under mild and neutral conditions and provides a facile access to nonsymmetric 1,4ꢀ
and 1,5ꢀdiketones in promising yields with broad substrate scope. Mechanistic studies including DFT
calculations suggest the involvement of an uncommon waterꢀassisted 1,2ꢀHAT process, which is
strongly exothermic and thus promotes addition of carbon radicals to aldehydes. In contrast to
traditional reductive radical addition protocols, this work represents the first example on the
intermolecular oxidative radical addition to aldehydes, thus offering a novel strategy for the direct
synthesis of acyclic ketones from readily accessible aldehydes.
INTRODUCTION
Among the ketone family, 1,4ꢀ and 1,5ꢀdiketones are common substructures of natural products,
medicinal compounds, and functional materials. Moreover, they are versatile building blocks for the
assembly of fiveꢀ or sixꢀmembered cycles, including cyclopentenone, thiophene, furan, pyrrole,
cyclohexenone, and pyridine derivatives.1 Therefore, the exploration of efficient methods for the
creation of these entities, especially from readily accessible starting materials, has received
considerable attention in organic chemistry.2ꢀ7 So far, traditional methods include the conjugate
addition of acyl anions or enolates to Michael acceptors,2 nucleophilic substitution3 or metalꢀcatalyzed
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crossꢀcoupling of αꢀhaloketones,4 oxidative coupling of enolates,5 radical addition to alkenes,6 and
Rhꢀcatalyzed hydroacylation.7 Despite the great progress achieved in this field, the previous reports
have focused on the synthesis of either 1,4ꢀ or 1,5ꢀdiketones, and the development of general methods
allowing the construction of both 1,4ꢀ and 1,5ꢀdiketones remains unexplored.
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Over the past decades, catalytic radical reactions have become very powerful tools for chemical
synthesis. With the rapid development of this area, expanding the scope of radical acceptors is highly
demanded. So far, CꢀC double bonds are the most widely used acceptors for radical addition. In
contrast, CꢀO double bonds have been rarely employed as radical acceptors, since addition of radicals
to aldehydes is reversible and the equilibrium lies in favor of βꢀscission, hence converting the alkoxy
radical A back into aldehydes (Scheme 1a, top).8 To facilitate the addition, fast reduction of the alkoxy
radical A is a common strategy.9,10 For example, Ryu and coꢀworkers achieved an unprecedented
hydroxymethylation of alkyl halides using paraformaldehyde as the radical acceptor and
tetrabutylammonium cyanoborohydride as the hydrogen source.10c However, the intermolecular
addition of carbon radicals to advanced aldehydes still constitutes an unmet goal. Very recently,
Glorius disclosed a wellꢀdesigned strategy for the intermolecular radical addition to carbonyls through
visibleꢀlight photoredox initiated hole catalysis and in situ Brønsted acid activation of CꢀO double
bonds (Scheme 1a, bottom).11 It should be noted that these methods fall into the type I reaction,
reductive radical addition, thus delivering alcohols as final products. On the other hand, oxidative
radical addition to aldehydes affording ketones (type II), instead of alcohols, still poses a significant
challenge. By taking advantage of the intramolecular strategy, we have developed a new
methodology12 for the direct synthesis of cyclic ketones via oxidative radical addition to aldehydes
(Scheme 1b, top).12a However, the intermolecular oxidative radical addition to aldehydes, permitting
the formation of acyclic ketones, is more challenging and has not been achieved yet.
Scheme 1. Intermolecular Addition of Carbon Radicals to Aldehydes
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radical addition to C=Y double bonds (Y = C, O)
H
R
R
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O
R
R
R
irreversible addition
well-known acceptors
reversible addition
to be developed
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(a) type I: reductive radical addition, forming alcohols
a common strategy: fast reduction
O
R2
R1
O
OH
R2
addition
M-H
R1
+
R1
H
R2
H
-scission
M = Sn, Si, B
A
Ryu's work: first intermolecular reductive radical addition to (HCHO)n
OH
Pyrex/AIBN/Hg lamp
R1X +
(HCHO)n
+ n-Bu4NBH3CN
R1
MeCN, rt-90 oC
Glorius's strategy: Bronsted acid activation
OH OR4
O
-
MesAcr+BF4 , R4OH
R3
R1
+
R1
R2
CH2Cl2, blue LED, rt
R2
R3
Ar
R2 = R, H
Ar
(b) type II: oxidative radical addition, forming ketones
previous work: intramolecular oxidative radical addition to aldehydes
O
R1
Cu(OAc)2, DEAD
PMDETA
MeCN, 80 oC
R3
E
CHO
+ R1
Z = CH2 or (CH2)2
Z
Br
Z
E
R3
this work: first intermolecular oxidative radical addition to aldehydes
O
n
AgNO3, Na2S2O8
DMSO/H2O (1:1), 50 oC
Ar
+ ArCHO
R
n
R
OH
O
n = 1, 2
The radical ringꢀopening of cyclopropanols and cyclobutanols, has emerged as a highly appealing
method for the synthesis of functionalized ketones.13,14 For example, Zhu et. al discovered a series of
protocols for the efficient preparation of βꢀ or γꢀfluoro, azido, cyano, alkynyl, or thiolated ketones,
through Mnꢀ or Agꢀcatalyzed CꢀC bond cleavage of cyclopropanols or cyclobutanols.13 Chen and
coꢀworkers achieved a novel visibleꢀlightꢀinduced alkynylation or alkenylation of cyclopropanols and
cyclobutanols using cyclic iodine(III) reagent catalysis.14h Inspired by these elegant works, we
envisioned that the strain release might offer an opportunity for the realization of intermolecular
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addition of carbon radicals to aldehydes. Herein, we report the first intermolecular oxidative radical
addition to aromatic aldehydes, initiated by Agꢀcatalyzed ringꢀopening of cyclopropanols and
cyclobutanols, which produces both 1,4ꢀ and 1,5ꢀdiketones under mild and neutral reaction conditions
(Scheme 1b, bottom). DFT calculations indicate that an unusual waterꢀassisted 1,2ꢀHAT is involved in
the catalytic cycle. Moreover, the waterꢀassisted 1,2ꢀHAT is strongly exothermic, thus offering a
driving force for achieving the thermodynamically unfavorable addition of carbon radicals to
aldehydes. Clearly, it will be valuable for the development of novel reactions using aldehydes as
radical acceptors.
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RESULTS AND DISCCUSION
Table 1. Optimization of Reaction Conditionsa
CHO
O
O
[M], oxidant
solvent, 50 oC
+
OH
MeO
CN
MeO
CN
1a
2a
3aa
entry
[M]
oxidant
solvent
yield (%)b
1c
2d
3
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9
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Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgBF4
AgOTf
AgOAc
AgNO3
AgNO3
none
none
BIOH
MeCN
MeCN
MeCN
MeCN
MeCN/H2O (1:1)
acetone/H2O (1:1)
DMF/H2O (1:1)
DMSO/H2O (1:1)
DMSO
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
nr
nr
nr
nr
PhI(OAc)2
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
5
16
10
85
12
68
31
45
45
23
trace
nr
Na2S2O8
none
AgNO3
aReaction conditions: 1a (0.75 mmol), 2a (0.25 mmol), [M] (10 mol %), oxidant (0.75 mmol), solvent,
o
b
c
d
o
under N2, 50 C, 16 h. Isolated yield. 0.75 mmol of Mn(OAc)2 was used. Run at 70 C. nr = No
reaction.
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Initially, we chose the cyclobutanol 1a and aldehyde 2a as model substrates to evaluate the reaction
parameters. In the presence of 3 equiv of Mn(OAc)3, no detectable product 3aa was observed (Table 1,
entry 1). Zhu's conditions, including the Mn(OAc)3/BIOH13b and Mn(OAc)3/PhI(OAc)2
combination,13c were totally ineffective for the reaction (entries 2 and 3). To our delight, upon
treatment with 10 mol % of AgNO3 and 3 equiv of Na2S2O8 in a 1:1 mixture of DMSO and H2O at 50
oC for 16 h, 85% yield of the 1,5ꢀdiketone 3aa was obtained (entry 8). In contrast, a dramatic decrease
in the yield (12%) was observed when the reaction was conducted in dry DMSO (entry 9), thus
highlighting the crucial role of water in this reaction. Other silver salts, such as AgBF4, AgOTf, and
AgOAc, were less efficient for the transformation (entries 10ꢀ12). Switching the oxidant from
Na2S2O8 to K2S2O8 or (NH4)2S2O8 resulted in a decline of the yield (entries 13 and 14). Both the silver
catalyst and oxidant are essential for the transformation, since no reaction occurred in the absence of
AgNO3 or Na2S2O8 (entries 15 and 16). Therefore, the optimized reaction conditions for Agꢀcatalyzed
cycloalkanol ringꢀopening acylation comprised 10 mol % of AgNO3 and 3 equiv of Na2S2O8 in a 1:1
mixture of DMSO and H2O at 50 oC for 16 h.
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Scheme 2. Scope of Cyclopropanols and Cyclobutanolsa
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aReaction conditions: 1 (0.75 mmol), 2 (0.25 mmol), AgNO3 (10 mol %), Na2S2O8 (0.75 mmol),
DMSO/H2O (v/v = 1:1), under N2, 50 oC, 16 h. Isolated yields were reported. b12 h.
With the optimized reaction conditions in hand, the scope of this reaction with respect to
cyclopropanols and cyclobutanols were explored, and the results are summarized in Scheme 2. A
variety of cyclobutanols were first tested. Compared with the reaction of 1a, the orthoꢀmethoxy
substrate 1b led to the production of 3ba in a relatively lower yield (51%). The increased steric
hindrance of 1b may account for the decline of yield. Halogen atoms including fluoro, chloro, and
bromo were well tolerated under the reaction conditions, which may be attractive for further
manipulations via transitionꢀmetalꢀcatalyzed crossꢀcoupling reactions (3faꢀ3ha). In addition,
heterocycles, such as thiophene, benzo[b]thiophene, and benzofuran, were also compatible for the
process (3kaꢀ3la). The reaction of alkylꢀsubstituted cyclobutanols took place smoothly as well,
producing 3maꢀ3oa in good yields. Besides tertial cyclobutanols, secondary cyclobutanols also
worked well for this reaction. For example, the coupling of 1p with 2a formed 3pa in 37% yield. In
contrast, the cyclopentanol 1q was incompatible with the reaction. For cyclopropanols, the reaction
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with the aldehyde 2b occurred efficiently to afford a set of 1,4ꢀdiketones in promising yields
(3rbꢀ3wb). Therefore, we have developed a broadly applicable method for the construction of both
1,4ꢀ and 1,5ꢀdiketones.
9
In the meantime, we examined the reactivity of various aldehydes (Scheme 3). As compared to 2a,
the reaction of 2c led to the generation of 1,5ꢀdiketone 3ac in a slightly lower yield (67%), again
highlighting the influence of steric hindrance. Benzaldehydes possessing strong electronꢀwithdrawing
groups, such as CO2Me, CHO, Ms, and Ac, were excellent coupling partners, giving 3ab, and 3adꢀ3af
in 70ꢀ92% yields. In contrast, PhCHO (2g) was transformed into the desired 1,5ꢀdiketone 3ag in 59%
yield. These results indicated that the electronic effect of the aryl ring of 2 has an important impact on
the reaction efficiency. Furthermore, 2h, a compound with a free hydroxy group, was also suitable
substrate, albeit in a moderate yield (3ah). Unfortunately, 4ꢀmethoxybenzaldehyde (2i) and alkyl
aldehyde 2j were ineffective substrates (3ai and 3aj).
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Scheme 3. Scope of Aldehydesa
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O
O
AgNO3, Na2S2O8
R
+ RCHO
OH
DMSO/H2O (1:1)
MeO
MeO
1a
2
3
9
O
O
O
O
O
O
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MeO
CN
MeO
MeO
MeO
CO2Me
CHO
Ac
3aa, 85%
3ab, 80%
O
CN
O
O
O
MeO
MeO
3ac, 67%
3ad, 92%
O
O
Ms
3ae, 85%
3af, 70%
O
O
O
O
O
O
OH
Et
MeO
MeO
MeO
3ag, 59%
3ah, 36%
Et
O
O
n-C5H11
OMe MeO
3ai, 0%
3aj, 0%
aReaction conditions: 1a (0.75 mmol), 2 (0.25 mmol), AgNO3 (10 mol %), Na2S2O8 (0.75 mmol),
DMSO/H2O (v/v = 1:1), under N2, 50 oC, 16 h. Isolated yields were reported.
As mentioned before, 1,4ꢀ and 1,5ꢀdiketones are versatile building blocks for the synthesis of
carboꢀ and heterocycles. As such, the transformation of resultant 1,4ꢀ or 1,5ꢀdiketones was then
conducted (Scheme 4). Upon treatment of 3tb with Lawesson's reagent in refluxing toluene for 6 h,
the 2,5ꢀdisubstituted thiophene 4a was obtained in 80% yield. In the presence of TfOH, 3tb was
converted into the furan product 4b in 91% yield. Cyclization of 3tb with either NH4OAc or nꢀBuNH2
successfully produced the pyrrole derivatives 4c and 4d in 75% and 55% yield, respectively.
Additionally, treating 3ag with NH4OAc in HOAc at reflux provided the pyridine derivative 4e in a
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high yield.
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Scheme 4. Synthetic Utility
7
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O
O
Ph
Lawesson's reagent
Ph
S
PhMe, reflux
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O
O
CO2Me
CO2Me
CO2Me
3tb
3tb
4a, 80%
Ph
Ph
Ph
TfOH
Ph
Ph
Ph
O
MeCN, reflux
CO2Me
CO2Me
4b, 91%
O
O
NH4OAc, HOAc
MeOH, reflux
N
H
O
O
CO2Me
CO2Me
3tb
3tb
4c, 75%
n-BuNH2
N
HOAc, reflux
n-Bu
CO2Me
OMe
4d, 55%
Ph
NH4OAc
Ph
N
HOAc, reflux
O
O
OMe
3ag
4e, 77%
To gain insights into the reaction mechanism, the standard reaction between 1a and 2a was
conducted with addition of TEMPO (5 equiv). As a result, the TEMPOꢀadduct 5a was obtained in
22% yield, accompanied by the formation of 5b and 5c in 16% and 5% yield, respectively, while the
acyl adduct 5d could not be detected, even in the absence of 1a (eqs 1 and 2). These results implied
that the formation of acyl radical intermediate shoud be less likely. When a 1:1 mixture of 1a and 1d
was subjected to the reaction conditions, a 4.1:1 mixture of 3aa and 3da was obtained after 3.5 h,
indicating that introducing electronꢀdonating groups onto the aryl ring of 1 is beneficial for the
reaction (eq 3). Additionally, the competitive reaction of 2a and 2g with 1a afforded a mixture of 3aa
and 3ag in a 4.7:1 ratio, pointing out that the electronic effect of aldehyde plays a key role in this
reaction (eq 4).
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CHO
O
O
TEMPO (5 equiv)
standard conditions
OH
+
+
MeO
CN
MeO
MeO
CN
2a
1a
3aa, 0%
O
O
O
O
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OTEMP
(1)
(2)
+
OTEMP
+
+
NC
4
MeO
MeO
5a, 22%
5b, 16%
5c, 6%
5d, 0%
CHO
O
TEMPO (2 equiv)
standard conditions
OTEMP
71% of 2a recovered
NC
O
5d, 0%
CN
2a
O
2a
standard conditions
OH
(3)
(4)
3.5 h
R
CN
R
R = OMe (1a), Me (1d)
1a/1d = 1:1
R = OMe (3aa), Me (3da)
60% yield, 3aa/3da = 4.1:1
CHO
O
O
1a
standard conditions
1 h
MeO
R
R
R = CN (2a), H (2g)
R = CN (3aa), H (3ag)
63% yield, 3aa/3ag = 4.7:1
2a/2g = 1:1
Based on the above results and our previous reports,12 a possible mechanism for this Agꢀcatalyzed
ringꢀopening acylation of cyclopropanols and cyclobutanols is portrayed in Scheme 5 using 1a and 2a
as the representative starting materials. Initially, a cycloalkanoxyl radical I is produced via oxidation
of the cyclobutanol 1a, either by Ag(II) species13e or sulfate radical (SO4•ꢀ)14d (paths 1A and 1B), both
of which can be generated by the reaction between AgNO3 and Na2S2O8 (eq 5).15 The ringꢀopening of
I followed by an intermolecular addition to the aldehyde 2a affords a new alkoxy radical III.
Increasing the electrophilic property of the carbonyl group of 2 may be beneficial for the
intermolecular addition. Subsequently, the alkoxy radical III can be converted into the αꢀhydroxy
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carbon radical IV via a direct or waterꢀassisted 1,2ꢀhydrogen atom transfer (1,2ꢀHAT) (paths 2A and
2B).16 The lack of conjugation effect between the carbon radical and aryl ring may be responsible for
the failure of the reaction of aliphatic aldehydes. Finally, a single electron transfer (SET) oxidation of
IV by Ag(II) species like AgSO4, either via a stepwise electron transfer/proton transfer (ET/PT, path
3A) or concerted protonꢀcoupled electron transfer (PCET, path 3B) pathway,17 results in the formation
of 3aa and Ag(I) catalyst, which can be reꢀoxidized to Ag(II) species by Na2S2O8.
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Scheme 5. Proposed Mechanism
A computational study with density functional theory (DFT) at the M06/6ꢀ311+G(d,p) level was
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performed to shed light on the mechanism (Scheme 6). The oxidation of 1a by AgSO4 (path 1A) is
•ꢀ
exothermic by 13.0 kcal/mol, while the energy release enabled by sulfate radical (SO4 ) (path 1B) is
only 6.4 kcal/mol. Although both Ag(II) species13e and sulfate radical14d have been suggested as the
oxidant for the generation of cycloalkanoxyl radicals, our data support Ag(II) species like AgSO4 to be
the preferred choice. After a small energy barrier (2.5 kcal/mol), the radical I is transformed to a
carbonꢀcentered radical II with a release of 23.9 kcal/mol energy. Consistent with the previous
reports,8 addition of II to the aldehyde 2a yielding the alkoxy radical III is thermodynamically
unfavorable, as it is endothermic by 10.0 kcal/mol. As for the 1,2ꢀHAT, the energy barrier for an
intramolecular 1,2ꢀHAT, directly transforming the radical III to IV (path 2A), is 21.1 kcal/mol, while
that for the waterꢀassisted 1,2ꢀHAT16c proceeding via a fiveꢀmembered ring like transition state TS3'
(path 2B) is 16.0 kcal/mol. Therefore, the waterꢀassisted 1,2ꢀHAT, instead of the direct intramolecular
1,2ꢀHAT, is suggested for the pathway, which may be responsible for the crucial role of water in this
reaction. It is noteworthy that the waterꢀassisted 1,2ꢀHAT is exothermic by 29.9 kcal/mol, thus
offering a driving force for moving the equilibrium from II to III. Hence, in addition to the traditional
fast reduction strategy, 1,2ꢀHAT may serve as an alternative strategy for facilitating the radical
addition to aldehydes. After the release of H2O, the intermediate IV can be formed, followed by an
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ꢀ
electron transfer to AgSO4 (ꢁG‡ = ꢀ31.1 kcal/mol) and a subsequent proton transfer with AgSO4 (ꢁG‡
= ꢀ39.1 kcal/mol) to give 3aa as the final product (path 3A). Of course, the concerted PCET between
IV and AgSO4 (ꢁG‡ = ꢀ70.2 kcal/mol) is also feasible for the transformation (path 3B).
Scheme 6. Free Energy Profile for the Transformation from I to 3aa. Bond Lengths Are Shown
in Å.
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CONCLUSION
In conclusion, we have developed an unprecedented intermolecular oxidative radical addition to
aldehydes via a silverꢀcatalyzed ringꢀopening acylation of cyclopropanols and cyclobutanols. Both
1,4ꢀ and 1,5ꢀdiketones can be efficiently synthesized via this protocol. The reaction proceeds under
mild and neutral conditions and tolerates a wide range of functional groups. A mechanism involving
the radicalꢀmediated CꢀC bond cleavage, intermolecular addition to aldehyde, waterꢀassisted 1,2ꢀHAT,
and SET oxidation has been proposed. As compared to the traditional reductive radical addition
protocols that deliver alcohols, this reaction provides a novel strategy for the stepꢀ and atomꢀeconomic
approach to acyclic ketones from readily available aldehydes. DFT calculations indicate that the
waterꢀassisted 1,2ꢀHAT is strongly exothermic, thus offering a driving force for the promotion of the
thermodynamically unfavorable addition of carbon radicals to aldehydes, a formidable challenge for
the potential use of aldehydes as radical acceptors. With this advance, new reactions using aldehydes
as radical acceptors will be feasible in the near feature.
EXPERIMENTAL SECTION
General. The column chromatography was performed with silica gel (300−400 mesh) using
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petroleum ethers/EtOAc as the eluent. H, C, and F NMR spectra were measured on a 600 or 400
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MHz NMR spectrometer using CDCl3 as the solvent. The chemical shifts are given in δ relative to
TMS, and the coupling constants are given in Hertz. The highꢀresolution mass spectra (HRMS)
analyses were conducted using a TOF MS instrument with an ESI source. Melting points were
measured by a melting point instrument and were uncorrected.
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General Procedure for the Silver-Catalyzed Ring-Opening Acylation of Cyclopropanols and
Cyclobutanols. To a mixture of AgNO3 (4.2 mg, 0.025 mmol) and Na2S2O8 (178.6 mg, 0.75 mmol)
was added a solution of 1a (133.6 mg, 0.75 mmol) and 2a (32.8 mg, 0.25 mmol) in 3 mL of
o
DMSO/H2O (v/v = 1:1) under a nitrogen atmosphere. After stirring at 50 C for 16 h, the reaction
mixture was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous
Na2SO4, and concentrated. Column chromatography on silica gel (EtOAc/petroleum ether = 1:5) gave
65 mg of 3aa (yield: 85%) as a white solid, mp 118–120 oC. 622 mg (yield: 81%) of 3aa was obtained
1
from 2a (328 mg, 2.5 mmol) using the general procedure. H NMR (600 MHz, CDCl3) δ 2.16−2.22
(m, 2H), 3.08 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 7.0 Hz, 2H), 3.87 (s, 3H), 6.94 (d, J = 8.9 Hz, 2H), 7.77
(d, J = 8.5 Hz, 2H), 7.92−7.98 (m, 2H), 8.04−8.10 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 18.5, 36.8,
38.0, 55.4, 113.7, 116.2, 117.9, 128.4, 129.8, 130.2, 132.4, 139.6, 163.5, 198.1, 198.5; HRMS (ESI)
calcd for C19H17NO3Na (M + Na)+ 330.1101, found 330.1096.
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Compound 3ba. 51% yield (39 mg); white solid, mp 109–111 C; H NMR (600 MHz, CDCl3) δ
2.11−2.18 (m, 2H), 3.06−3.16 (m, 4H), 3.89 (s, 3H), 6.95−7.14 (m, 2H), 7.44−7.50 (m, 1H), 7.71 (dd,
J = 1.8, 7.7 Hz, 1H), 7.74−7.79 (m, 2H), 8.05−8.10 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 18.7, 38.2,
42.5, 55.5, 111.6, 116.2, 118.0, 120.7, 128.0, 128.5, 130.2, 132.5, 133.6, 139.8, 158.6, 198.7, 201.9;
HRMS (ESI) calcd for C19H17NO3Na (M + Na)+ 330.1101, found 330.1108.
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Compound 3ca. 70% yield (65 mg); white solid, mp 99–101 C; H NMR (600 MHz, CDCl3) δ
2.15−2.23 (m, 2H), 3.04−3.16 (m, 4H), 6.97−7.09 (m, 2H), 7.04−7.09 (m, 2H), 7.18−7.22 (m, 1H),
7.37−7.42 (m, 2H), 7.76−7.78 (m, 2H), 7.91−7.98 (m, 2H), 8.04−8.09 (m, 2H); 13C NMR (151 MHz,
CDCl3) δ 18.4, 37.0, 37.9, 116.2, 117.2, 117.9, 120.1, 124.6, 128.4, 130.0, 130.2, 131.3, 132.4, 139.6,
155.3, 162.0, 198.1, 198.4; HRMS (ESI) calcd for C24H19NO3Na (M + Na)+ 392.1257, found
392.1268.
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Compound 3da. 79% yield (58 mg); white solid, mp 124–126 C; H NMR (600 MHz, CDCl3) δ
2.15−2.18 (m, 2H), 2.41 (s, 3H), 3.07−3.15 (m, 4H), 7.26 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H),
7.87 (d, J = 8.1 Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 18.4, 21.6, 37.1,
38.0, 116.3, 117.9, 128.1, 128.5, 129.3, 132.5, 134.2, 139.7, 144.0, 198.5, 199.2; HRMS (ESI) calcd
for C19H17NO2Na (M + Na)+ 314.1151, found 314.1148.
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Compound 3ea. 64% yield (52 mg); white solid, mp 120–122 C; H NMR (600 MHz, CDCl3) δ
2.14−2.24 (m, 2H), 2.52 (s, 3H), 3.06−3.15 (m, 4H), 7.24−7.28 (m, 2H), 7.75−7.78 (m, 2H),
7.86−7.90 (m, 2H), 8.05−8.08 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 14.7, 18.4, 37.0, 37.9, 116.2,
117.9, 124.9, 128.4, 128.4, 132.5, 132.9, 139.6, 146.0, 198.4, 198.5; HRMS (ESI) calcd for
C19H17NO2SNa (M + Na)+ 346.0872, found 346.0859.
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Compound 3fa. 61% yield (45 mg); white solid, mp 107–109 C; H NMR (600 MHz, CDCl3) δ
2.16−2.23 (m, 2H), 3.08−3.17 (m, 4H), 7.11−7.16 (m, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.98−8.03 (m,
2H), 8.08 (d, J = 8.3 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 18.3, 37.1, 37.8, 115.7 (d, J = 21.8 Hz),
116.3, 117.9, 128.4, 130.6 (d, J = 9.3 Hz), 132.5, 133.10 (d, J = 3.1 Hz), 139.6, 165.7 (d, J = 255.1
Hz), 197.9, 198.3; 19F NMR (565 MHz, CDCl3) δ –105.0; HRMS (ESI) calcd for C18H14FNO2Na (M
+ Na)+ 318.0901, found 318.0892.
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Compound 3ga. 63% yield (49 mg); white solid, mp 111–113 C; H NMR (400 MHz, CDCl3) δ
2.15−2.24 (m, 2H), 3.07−3.16 (m, 4H), 7.42ꢀ7.47 (m, 2H), 7.76ꢀ7.80 (m, 2H), 7.90ꢀ7.94 (m, 2H),
8.06ꢀ8.09 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 18.2, 37.2, 37.8, 116.3, 117.9, 128.4, 128.9, 129.3,
129.4, 132.5, 134.9, 139.6, 198.3, 198.3; HRMS (ESI) calcd for C18H14ClNO2Na (M + Na)+ 334.0605,
found 334.0591.
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Compound 3ha. 60% yield (53 mg); white solid, mp 116–118 C; H NMR (600 MHz, CDCl3) δ
2.15−2.25 (m, 2H), 3.04−3.17 (m, 4H), 7.58−7.80 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.80−7.87 (m,
2H), 8.07 (d, J = 8.4 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 18.2, 37.2, 37.8, 116.4, 117.9, 128.5,
129.4, 129.5, 132.0, 132.5, 138.0, 139.6, 198.3, 198.5; HRMS (ESI) calcd for C18H14BrNO2Na (M +
Na)+ 378.0100, found 378.0109.
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Compound 3ia. 76% yield (53 mg); white solid, mp 130–132 C; H NMR (600 MHz, CDCl3) δ
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2.16−2.25 (m, 2H), 3.09−3.17 (m, 4H), 7.43−7.51 (m, 2H), 7.54−7.60 (m, 1H), 7.77 (d, J = 8.3 Hz,
2H), 7.98 (d, J = 7.4 Hz, 2H), 8.08 (d, J = 8.3 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 18.3, 37.2, 37.9,
116.3, 117.9, 128.0, 128.5, 128.6, 132.5, 133.2, 136.7, 139.7, 198.4, 199.5; HRMS (ESI) calcd for
C18H16NO2 (M + H)+ 278.1176, found 278.1181.
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Compound 3ja. 46% yield (33 mg); white solid, mp 90–92 C; H NMR (600 MHz, CDCl3) δ
2.16−2.24 (m, 2H), 3.08 (t, J = 6.8 Hz, 2H), 3.14 (t, J = 7.0 Hz, 2H), 7.14 (dd, J = 3.8, 4.9 Hz, 1H),
7.65 (dd, J = 1.1, 4.9 Hz, 1H), 7.75 (dd, J = 1.1, 3.8 Hz, 1H), 7.72−7.80 (m, 2H), 8.02−8.10 (m, 2H);
13C NMR (151 MHz, CDCl3) δ 18.6, 37.8, 37.9, 116.3, 117.9, 128.2, 128.5, 132.0, 132.5, 133.7, 139.6,
144.0, 192.6, 198.3; HRMS (ESI) calcd for C16H13NO2SNa (M + Na)+ 306.0559, found 306.0558.
Crystal data for 3ja (C16H13NO2S, 283.33): triclinic, space group P2(1)/n, a = 14.755(2) Å, b =
6.0419(7) Å, c = 16.653(2) Å, U = 1428.3(3) Å3, Z = 4, T = 296(2) K, absorption coefficient 0.226
mmꢀ1, reflections collected 21063, independent reflections 3399 [R(int) = 0.088], refinement by
fullꢀmatrix leastꢀsquares on F2, data/restraints/parameters 3399/0/181, goodnessꢀofꢀfit on F2 = 1.152,
final R indices [I>2σ(I)] R1 = 0.0874, wR2 = 0.1472, R indices (all data) R1 = 0.1683, wR2 = 0.1776,
largest diff. peak and hole 0.249 and –0.224e. Å–3. Crystallographic data for the structure 3ja have
been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 1580484.
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Compound 3ka. 35% yield (29 mg); white solid, mp 115–117 C; H NMR (600 MHz, CDCl3) δ
2.21−2.28 (m, 2H), 3.14−3.20 (m, 4H), 7.39−7.50 (m, 2H), 7.75−7.78 (m, 2H), 7.86−7.90 (m, 2H),
8.00 (s, 1H), 8.05−8.09 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 18.6, 37.7, 37.8, 116.4, 117.9, 123.0,
125.1, 125.9, 127.5, 128.5, 129.2, 132.5, 139.1, 139.6, 142.4, 143.4, 194.1, 198.3; HRMS (ESI) calcd
for C20H15NO2SNa (M + Na)+ 356.0716, found 356.0708.
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Compound 3la. 50% yield (40 mg); white solid, mp 113–115 C; H NMR (600 MHz, CDCl3) δ
2.20−2.27 (m, 2H), 3.11−3.17 (m, 4H), 7.29−7.34 (m, 1H), 7.45−7.50 (m, 1H), 7.53−7.58 (m, 2H),
7.69−7.78 (m, 3H), 8.05−8.08 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 18.2, 37.5, 37.7, 112.3, 112.9,
116.3, 117.9, 123.3, 123.9, 126.9, 128.3, 128.4, 132.4, 139.6, 152.3, 155.5, 190.7, 198.2; HRMS (ESI)
calcd for C20H15NO3Na (M + Na)+ 340.0944, found 340.0940.
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Compound 3ma. 62% yield (37 mg); white solid, mp 103–105 C; H NMR (400 MHz, CDCl3) δ
0.85−0.92 (m, 2H), 1.00−1.05 (m, 2H), 1.90−2.09 (m, 3H), 2.72 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 7.1 Hz,
2H), 7.77 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 8.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 10.7, 18.1, 20.5,
37.9, 41.9, 116.2, 117.9, 128.4, 132.5, 139.7, 198.4, 210.2; HRMS (ESI) calcd for C15H16NO2 (M +
H)+ 242.1176, found 242.1175.
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Compound 3na. 55% yield (40 mg); white solid, mp 97–99 C; H NMR (600 MHz, CDCl3) δ
1.95−2.02 (m, 2H), 2.61 (t, J = 6.7 Hz, 2H), 2.94 (t, J = 7.1 Hz, 2H), 3.70 (s, 2H), 7.18−7.35 (m, 5H),
7.73−7.76 (m, 2H), 7.97−8.01 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 17.9, 37.6, 40.4, 50.2, 116.3,
117.9, 127.1, 128.4, 128.7, 129.3, 132.4, 133.9, 139.6, 198.3, 207.8; HRMS (ESI) calcd for
C19H17NO2Na (M + Na)+ 314.1151, found 314.1146.
Compound 3oa. 53% yield (34 mg); white solid, mp 94–96 oC; 1H NMR (600 MHz, CDCl3) δ 0.90 (t,
J = 7.4 Hz, 3H), 1.30−1.34 (m, 2H), 1.52−1.59 (m, 2H), 1.98−2.04 (m, 2H), 2.41 (t, J = 7.5 Hz, 2H),
2.56 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 7.1 Hz, 2H), 7.75−7.79 (m, 2H), 8.04−8.07 (m, 2H); 13C NMR
(151 MHz, CDCl3) δ 13.8, 18.0, 22.3, 25.9, 37.9, 41.2, 42.6, 116.3, 117.9, 128.5, 132.5, 139.6, 198.4,
210.7; HRMS (ESI) calcd for C16H19NO2Na (M + Na)+ 280.1308, found 280.1303.
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Compound 3pa. 37% yield (19 mg); white solid, mp 104–106 C; H NMR (600 MHz, CDCl3) δ
2.04−2.13 (m, 2H), 2.63 (td, J = 1.0, 6.9 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H), 7.75−7.81 (m, 2H),
8.02−8.08 (m, 2H), 9.82 (t, J = 0.9 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 16.2, 37.6, 42.8, 116.4,
117.9, 128.4, 132.5, 139.5, 198.0, 201.7; HRMS (ESI) calcd for C12H11NO2Na (M + Na)+ 224.0682,
found 224.0679.
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Compound 3rb. 62% yield (51 mg); white solid, mp 121–123 C. H NMR (600 MHz, CDCl3) δ
3.41−3.48 (m, 4H), 3.88 (s, 3H), 3.96 (s, 3H), 6.92−6.98 (m, 2H), 7.99−8.04 (m, 2H), 8.09 (d, J = 8.4
Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 32.2, 33.0, 52.4, 55.5, 113.7, 128.0,
129.7, 129.8, 130.4, 133.8, 140.0, 163.6, 166.3, 196.9, 198.5; HRMS (ESI) calcd for C19H19O5 (M +
H)+ 327.1227, found 327.1232.
Compound 3sb. 72% yield (56 mg); white solid, mp 124–126 oC; 1H NMR (600 MHz, CDCl3) δ 2.42
(s, 3H), 3.41−3.50 (m, 4H), 3.96 (s, 3H), 7.24−7.29 (m, 2H), 7.94 (d, J = 8.0 Hz, 2H), 8.09 (d, J = 8.1
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Hz, 2H), 8.14 (d, J = 8.1 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 21.6, 32.4, 32.9, 52.4, 128.0, 128.2,
129.3, 129.8, 133.8, 134.1, 140.0, 144.0, 166.2, 198.0, 198.3; HRMS (ESI) calcd for C19H18O4Na (M
+ Na)+ 333.1097, found 333.1096.
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Compound 3tb. 61% yield (45 mg); white solid, mp 110–112 C; H NMR (600 MHz, CDCl3) δ
3.43−3.52 (m, 4H), 3.95 (s, 3H), 7.46−7.50 (m, 2H), 7.56−7.60 (m, 1H), 8.02−8.16 (m, 6H); 13C NMR
(151 MHz, CDCl3) δ 32.5, 32.8, 52.4, 128.0, 128.0, 128.6, 129.8, 133.2, 133.8, 136.6, 139.9, 166.2,
198.2, 198.4; HRMS (ESI) calcd for C18H16O4Na (M + Na)+ 319.0941, found 319.0924.
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Compound 3ub. 50% yield (39 mg); white solid, mp 100–102 C; H NMR (600 MHz, CDCl3) δ
2.89−2.94 (m, 2H), 3.25−3.29 (m, 2H), 3.83 (s, 2H), 3.95 (s, 3H), 7.23−7.37 (m, 5H), 7.99−8.02 (m,
2H), 8.09−8.12 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 32.8, 35.6, 50.2, 52.5, 127.1, 127.9, 128.7,
129.5, 129.8, 133.9, 134.1, 139.8, 166.2, 198.1, 206.9; HRMS (ESI) calcd for C19H18O4Na (M + Na)+
333.1097, found 333.1094.
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Compound 3vb. 56% yield (42 mg); white solid, mp 98–100 C; H NMR (600 MHz, CDCl3) δ
1.18−1.43 (m, 5H), 1.65−1.71 (m, 1H), 1.77−1.83 (m, 2H), 1.91−1.95 (m, 2H), 2.43−2.50 (m, 1H),
2.89−2.94 (m, 2H), 3.26−3.31 (m, 2H), 3.95 (s, 3H), 8.01−8.05(m, 2H), 8.10−8.13 (m, 2H); 13C NMR
(151 MHz, CDCl3) δ 25.6, 25.8, 28.5, 32.6, 34.1, 50.8, 52.4, 127.9, 129.7, 133.8, 139.9, 166.2, 198.3,
212.4; HRMS (ESI) calcd for C18H22O4Na (M + Na)+ 325.1410, found 325.1407.
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Compound 3wb. 65% yield (45 mg); white solid, mp 107–109 C; H NMR (600 MHz, CDCl3) δ
1.81−1.87 (m, 1H), 1.95−2.03 (m, 1H), 2.17−2.34 (m, 4H), 2.81−2.84 (m, 2H), 3.28−3.31 (m, 2H),
3.35−3.41 (m, 1H), 3.95 (s, 3H), 8.03−8.05 (m, 2H), 8.11−8.14 (m, 2H); 13C NMR (151 MHz, CDCl3)
δ 17.8, 24.4, 32.5, 33.4, 45.4, 52.4, 127.9, 129.8, 133.8, 139.9, 166.2, 198.3, 210.2; HRMS (ESI) calcd
for C16H18O4Na (M + Na)+ 297.1097, found 297.1093.
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Compound 3ab. 80% yield (68 mg); white solid, mp 98–100 C; H NMR (600 MHz, CDCl3) δ
2.16−2.22 (m, 2H), 3.07 (t, J = 6.9 Hz, 2H), 3.14 (t, J = 7.0 Hz, 2H), 3.87 (s, 3H), 3.95 (s, 3H), 6.93 (d,
J = 8.9 Hz, 2H), 7.96 (d, J = 8.9 Hz, 2H), 8.00−8.05 (m, 2H), 8.09−8.13 (m, 2H); 13C NMR (151 MHz,
CDCl3) δ 18.7, 37.0, 38.0, 52.4, 55.4, 113.7, 127.9, 129.8, 129.8, 130.3, 133.7, 140.0, 163.4, 166.2,
198.3, 199.4; HRMS (ESI) calcd for C20H20O5Na (M + Na)+ 363.1203, found 363.1198.
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Compound 3ac. 67% yield (51 mg); white solid, mp 112–114 C; H NMR (600 MHz, CDCl3) δ
2.17−2.23 (m, 2H), 3.10 (t, J = 6.8 Hz, 2H), 3.16 (t, J = 6.9 Hz, 2H), 3.87 (s, 3H), 6.90−6.96 (m, 2H),
7.65 (td, J = 1.2, 7.6 Hz, 1H), 7.71 (td, J = 1.4, 7.7 Hz, 1H), 7.82 (dd, J = 1.2, 7.6 Hz, 1H), 7.92−7.97
(m, 2H), 7.99 (dd, J = 0.9, 7.9 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 18.6, 36.8, 38.7, 55.4, 110.9,
113.7, 118.1, 129.4, 129.8, 130.3, 132.3, 132.5, 135.3, 139.6, 163.5, 198.2, 198.2; HRMS (ESI) calcd
for C19H17NO3Na (M + Na)+ 330.1101, found 330.1095.
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Compound 3ad. 92% yield (71 mg); white solid, mp 122–124 C; H NMR (600 MHz, CDCl3) δ
2.16−2.24 (m, 2H), 3.09 (t, J = 6.8 Hz, 2H), 3.16 (t, J = 7.0 Hz, 2H), 3.87 (s, 3H), 6.91−6.96 (m, 2H),
7.93−8.00 (m, 4H), 8.11−8.14 (m, 2H), 10.10 (s, 1H); 13C NMR (151 MHz, CDCl3) δ 18.6, 36.9, 38.1,
55.4, 113.7, 128.5, 129.8, 130.2, 138.9, 140.9, 163.4, 191.6, 198.2, 199.3; HRMS (ESI) calcd for
C19H18NaO4 (M + Na)+ 333.1097, found 333.1090.
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Compound 3ae. 85% yield (77 mg); white solid, mp 99–101 C; H NMR (600 MHz, CDCl3) δ
2.15−2.22 (m, 2H), 3.04−3.12 (m, 5H), 3.15 (t, J = 7.0 Hz, 2H), 3.87 (s, 3H), 6.94 (d, J = 8.8 Hz, 2H),
7.96 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 8.15 (d, J = 8.4 Hz, 2H); 13C NMR (151 MHz,
CDCl3) δ 18.5, 36.8, 38.1, 44.2, 55.4, 113.7, 127.7, 128.9, 129.7, 130.2, 140.6, 144.0, 163.5, 198.1,
198.6; HRMS (ESI) calcd for C19H20SO5Na (M + Na)+ 383.0924, found 383.0912.
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Compound 3af. 70% yield (57 mg); white solid, mp 102–104 C; H NMR (600 MHz, CDCl3) δ
2.16−2.22 (m, 2H), 2.65 (s, 3H), 3.08 (t, J = 6.9 Hz, 2H), 3.15 (t, J = 7.0 Hz, 2H), 3.87 (s, 3H),
6.91−6.96 (m, 2H), 7.94−7.99 (m, 2H), 8.00−8.08 (m, 4H); 13C NMR (151 MHz, CDCl3) δ 18.7, 26.8,
37.0, 38.0, 55.4, 113.7, 128.2, 128.4, 129.8, 130.3, 140.0, 140.0, 163.5, 197.5, 198.2, 199.4; HRMS
(ESI) calcd for C20H20O4Na (M + Na)+ 347.1254, found 347.1247.
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Compound 3ag.18 59% yield (42 mg); H NMR (600 MHz, CDCl3) δ 2.15−2.22 (m, 2H), 3.03−3.14
(m, 4H), 3.86 (s, 3H), 6.93 (d, J = 8.8 Hz, 2H), 7.42−7.58 (m, 3H), 7.90−8.00 (m, 4H); 13C NMR (151
MHz, CDCl3) δ 18.9, 37.2, 37.6, 55.4, 113.7, 128.0, 128.5, 130.0, 130.3, 133.0, 136.9, 163.4, 198.5,
199.9.
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Compound 3ah. 36% yield (33 mg); white solid, mp 95–97 C; H NMR (600 MHz, CDCl3) δ
0.73−0.79 (m, 6H), 1.81−1.94 (m, 4H), 2.17−2.24 (m, 2H), 3.00−3.16 (m, 4H), 3.88 (s, 4H),
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6.92−6.97 (m, 2H), 7.45−7.52 (m, 2H), 7.91−8.01 (m, 4H); 13C NMR (151 MHz, CDCl3) δ 7.7, 19.0,
35.1, 37.3, 37.6, 55.4, 77.5, 113.7, 125.8, 127.9, 130.3, 135.0, 151.3, 163.4, 198.5, 199.7; HRMS (ESI)
calcd for C23H28O4Na (M + Na)+ 391.1880, found 391.1879.
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Experimental Procedure for the Synthesis of Compound 4a. To a solution of 3ta (74.0 mg, 0.25
mmol) in 1.5 mL of toluene was added Lawesson's reagent (121.3 mg, 0.30 mmol). After stirring at
reflux for 6 h, the reaction mixture was cooled to room temperature then quenched with water,
extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated. Column
chromatography on silica gel (EtOAc/petroleum ether = 1:10) gave 59 mg of 4a (yield: 80%) as a
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white solid, mp 150–152 C. H NMR (400 MHz, CDCl3) δ 3.93 (s, 3H), 7.23−7.34 (m, 3H),
7.36−7.44 (m, 3H), 7.61−7.71 (m, 3H), 8.01−8.09 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 52.1,
124.2, 125.1, 125.5, 125.7, 127.9, 128.7, 129.0, 130.3, 134.0, 138.5, 142.1, 145.2, 166.7; HRMS (ESI)
calcd for C18H14SO2Na (M + Na)+ 317.0607, found 317.0613.
Experimental Procedure for the Synthesis of Compound 4b. To a solution of 3ta (74.0 mg, 0.25
mmol) in 2.5 mL of MeCN was added TfOH (43.1 mg, 0.25 mmol) dropwise under a nitrogen
atmosphere. After stirring at 85 oC for 1 h, the reaction mixture was cooled to room temperature then
quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and
concentrated. Column chromatography on silica gel (EtOAc/petroleum ether = 1:10) gave 63 mg of 4b
(yield: 91%) as a white solid, mp 154–156 oC. 1H NMR (600 MHz, CDCl3) δ 3.92 (s, 3H), 6.75 (d, J =
3.5 Hz, 1H), 6.85 (d, J = 3.5 Hz, 1H), 7.26−7.32 (m, 1H), 7.37−7.44 (m, 2H), 7.72−7.79 (m, 4H),
8.04−8.07 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 52.1, 107.5, 109.5, 123.2, 123.9, 127.8, 128.4,
128.7, 130.1, 130.3, 134.6, 152.2, 154.4, 166.8; HRMS (ESI) calcd for C18H14O3Na (M + Na)+
301.0835, found 301.0834.
Experimental Procedure for the Synthesis of Compound 4c. To a mixture of NH4OAc (192.8 mg,
2.5 mmol) and AcOH (150.3 mg, 2.5 mmol) was added a solution of 3ta (74.0 mg, 0.25 mmol) in 2.5
mL of MeOH. After stirring at reflux for 3 h, the reaction mixture was cooled to room temperature
then quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4,
and concentrated. Column chromatography on silica gel (EtOAc/petroleum ether = 1:3) gave 52 mg of
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4c (yield: 75%) as a white solid, mp 161–163 C. H NMR (600 MHz, CDCl3) δ 3.92 (s, 3H),
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8.01−8.07 (m, 2H), 8.74 (br s, 1H); C NMR (151 MHz, CDCl3) δ 52.1, 108.4, 109.9, 123.0, 124.0,
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126.8, 127.4, 129.0, 130.4, 131.9, 132.1, 134.5, 136.5, 166.9; HRMS (ESI) calcd for C18H15NO2Na
(M + Na)+ 300.0995, found 300.1004.
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Experimental Procedure for the Synthesis of Compound 4d. To a solution of 3ta (74.0 mg, 0.25
mmol) in 1.5 mL of HOAc was added nꢀBuNH2 (21.9 mg, 0.3 mmol). After stirring at 120 oC for 2 h,
the reaction mixture was cooled to room temperature then quenched with water, extracted with EtOAc,
washed with brine, dried over anhydrous Na2SO4, and concentrated. Column chromatography on silica
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gel (EtOAc/petroleum ether = 1:8) gave 46 mg of 4d (yield: 55%) as a white solid, mp 143–145 C.
1H NMR (600 MHz, CDCl3) δ 0.53 (t, J = 7.4 Hz, 3H), 0.76−0.88 (m, 2H), 1.10−1.19 (m, 2H), 3.93 (s,
3H), 4.10 (t, J = 7.2 Hz, 2H), 6.27 (d, J = 3.5 Hz, 1H), 6.35 (d, J = 3.5 Hz, 1H), 7.30−7.35 (m, 1H),
7.38−7.48 (m, 4H), 7.53 (d, J = 8.2 Hz, 2H), 8.09 (d, J = 8.2 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ
13.3, 19.2, 32.6, 45.2, 52.0, 110.8, 120.9, 127.1, 128.0, 128.1, 128.4, 129.0, 129.8, 133.7, 135.4, 138.1,
138.6, 166.9; HRMS (ESI) calcd for C22H23NO2Na (M + Na)+ 356.1621, found 356.1618.
Experimental Procedure for the Synthesis of Compound 4e.6e To a solution of 3ag (70.5 mg, 0.25
mmol) in 1.5 mL of HOAc was added NH4OAc (192.8 mg, 2.5 mmol). After stirring at 120 oC for 3 h,
the reaction mixture was cooled to room temperature then quenched with water, extracted with EtOAc,
washed with brine, dried over anhydrous Na2SO4, and concentrated. Column chromatography on silica
gel (EtOAc/petroleum ether = 1:3) gave 50 mg of 4e (yield: 77%) as a white solid, mp 168–170 oC. 1H
NMR (600 MHz, CDCl3) δ 3.82 (s, 3H), 6.96−7.02 (m, 2H), 7.37−7.50 (m, 3H), 7.54−7.60 (m, 2H),
7.67−7.73 (m, 1H), 8.06−8.16 (m, 4H); 13C NMR (151 MHz, CDCl3) δ 55.3, 114.0, 117.7, 117.8,
126.9, 128.2, 128.6, 128.8, 132.0, 137.3, 139.5, 156.3, 156.5, 160.4; HRMS (ESI) calcd for C18H16NO
(M + H)+ 262.1226, found 262.1229.
Compound 5a. It was obtained from 1a and 2b under the standard reaction conditions in the presence
of 5 equivalents of TEMPO in 22% yield (54 mg), based on 1a, as a colorless oil; 1H NMR (600 MHz,
CDCl3) δ 1.09 (s, 6H), 1.15 (s, 6H), 1.28−1.61 (m, 6H), 1.92−2.00 (m, 2H), 3.01−3.07 (m, 2H), 3.82 (t,
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J = 6.2 Hz, 2H), 3.86 (s, 3H), 6.90−6.96 (m, 2H), 7.93−7.99 (m, 2H); C NMR (151 MHz, CDCl3) δ
17.0, 20.0, 23.7, 33.0, 35.0, 39.5, 55.3, 59.6, 75.5, 113.6, 130.0, 130.2, 163.2, 198.6; HRMS (ESI)
calcd for C20H32NO3 (M + H)+ 334.2377, found 334.2372.
Compound 5b.19 It was obtained from 1a and 2b under the reaction conditions in the presence of 5
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equivalents of TEMPO in 16% yield (21 mg), based on 1a, as a colorless oil. H NMR (600 MHz,
CDCl3) δ 2.07−2.15 (m, 2H), 2.58−2.62 (m, 2H), 2.92 (t, J = 6.1 Hz, 2H), 3.85 (s, 3H), 6.70 (d, J = 2.4
Hz, 1H), 6.82 (dd, J = 2.5, 8.7 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H).
Compound 5c.20 It was obtained from 1a and 2b under the reaction conditions in the presence of 5
equivalents of TEMPO in 5% yield (7 mg), based on 1a, as a colorless oil. 1H NMR (600 MHz, CDCl3)
δ 1.00 (t, J = 7.4 Hz, 3H), 1.70−1.80 (m, 2H), 2.89 (t, J = 7.3 Hz, 2H), 3.86 (s, 3H), 6.90−6.96 (m, 2H),
7.91−7.97 (m, 2H).
Supporting Information. Spectroscopic data of products 3-5, crystallographic data for 3ja, and
computational data. This material is available free of charge via the Internet at http://pubs.acs.org.
ORCID
Gangguo Zhu: 0000ꢀ0003ꢀ4384ꢀ824X
Zhaosheng Qian: 0000ꢀ0002ꢀ2134ꢀ8300
Author Contributions
†These two authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by the National Natural Science Foundation of China (21672191).
REFERENCES
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(3) Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.; Baba, A. CrossꢀCoupling Reaction of αꢀChloroketones and
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Synthesis of WaterꢀTolerant Indium Homoenolate in Aqueous Media and Its Application in the
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TitaniumꢀMediated Synthesis of 1,4ꢀDiketones from Grignard Reagents and Acyl Cyanohydrins.
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(5)
For
selected
examples,
see:
(a)
Ryter,
K.;
Livinghouse,
T.
Dichloro(2,2,2ꢀtrifluoroethoxy)oxovanadium(V). A Remarkably Effective Reagent for Promoting
OneꢀElectron Oxidative Cyclization and Unsymmetrical Coupling of Silyl Enol Ethers. J. Am. Chem.
Soc. 1998, 120, 2658. (b) DeMartino, M. P.; Chen, K.; Baran, P. S. Intermolecular Enolate
Heterocoupling: Scope, Mechanism, and Application. J. Am. Chem. Soc. 2008, 130, 11546. (c) Clift,
M. D.; Thomson, R. J. Development of a Merged Conjugate Addition/Oxidative Coupling Sequence.
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Application to the Enantioselective Total Synthesis of Metacycloprodigiosin and Prodigiosin R1. J.
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Selective Intermolecular Oxidative CrossꢀCoupling of Enolates. J. Am. Chem. Soc. 2015, 137, 10072.
For a review, see: (e) Guo, F.; Clift, M. D.; Thomson, R. J. Oxidative Coupling of Enolates, Enol
Silanes, and Enamines: Methods and Natural Product Synthesis. Eur. J. Org. Chem. 2012, 4881.
(6) For selected examples, see: (a) Miura, K.; Tojino, M.; Fujisawa, N.; Hosomi, A.; Ryu, I.
Cascade Carbonylation Methods Leading to βꢀDiketones and βꢀFunctionalized δꢀDiketones. Angew.
Chem., Int. Ed. 2004, 43, 2423. (b) Roessle, M.; Werner, T.; Baro, A.; Frey, W.; Christoffers, J.
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