Temperature-controlled selectivity toward [1,3]- or [3,3]-sigmatropic rearrangement: Regioselective synthesis of substituted 3,4-dihydrocoumarins

Article abstract of DOI:10.1055/s-0029-1218280

Either [1,3]- or [3,3]-sigmatropic rearrangements were selectively accessed by controlling the reaction temperature in the gold(III)-catalyzed tandem rearrangement/cyclization of (E)-2-(aryloxymethyl)alk-2-enoates to afford diversely substituted 3,4-dihyd

Full text of DOI:10.1055/s-0029-1218280

LETTER
2971
Temperature-Controlled Selectivity toward [1,3]- or [3,3]-Sigmatropic
Rearrangement: Regioselective Synthesis of Substituted
3,4-Dihydrocoumarins
R
egioselective Syn
u
thesis of Sub
n
stituted 3,4-
k
D
ihydrocoum
u
arins i Liu,* Jianqiang Qian, Shaojie Lou, Zhenyuan Xu*
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology,
Hangzhou 310014, P. R. of China
E-mail: ykuiliu@zjut.edu; E-mail: greensyn@zjut.edu.cn
Received 21 July 2009
synthesis of 3,4-dihydrocoumarin (3,4-DHC) derivatives
with diverse substituted patterns in moderate to good
yields via a tandem rearrangement/cyclization strategy.
Abstract: Either [1,3]- or [3,3]-sigmatropic rearrangements were
selectively accessed by controlling the reaction temperature in the
gold(III)-catalyzed tandem rearrangement/cyclization of (E)-2-
(aryloxymethyl)alk-2-enoates to afford diversely substituted 3,4-di-
hydrocoumarin derivatives in moderate to good yields and in excel-
lent regioselectivity.
Initially, we selected (E)-methyl 3-(4-chlorophenyl)-2-(2-
naphthyloxymethyl)-2-enoate (1a) as a model substrate
for the tandem rearrangement/cyclization reaction and ex-
pected the formation of 3a (Scheme 1, Table 1). The reac-
tion indeed proceeded when 1a was treated with
Ph3PAuCl–AgOTf (3 mol% based on 1a) in DCE at 80 °C
for eight hours. However, 3-arylidene-3,4-DHC 2a, ap-
parently generated via a [1,3]-sigmatropic rearrangement/
cyclization process (see intermediate A), was unexpected-
ly isolated as the sole product in 16% yield (entry 1). The
yield of 2a was increased to 87% in the presence of AuCl–
AgOTf at the same temperature for five hours (entry 2).
The best result (up to 96% yield of 2a) was obtained when
a combination of AuCl3 and AgOTf was used in DCE or
DCB (1,2-dichlorobenzene) at 80 °C for four hours (entry
3). Interestingly, when the same reaction was conducted at
120 °C for two hours, 4-aryl-3-methylene-3,4-DHC 3a,
arising from normal Claisen rearrangement/cyclization
process (see intermediate B),3j was exclusively obtained
in 93% yield (entry 3). It was found that solvent had fun-
damental influence on the activity and the selectivity of
the catalytic system (entry 3). DCE and DCB were equally
suitable solvent for the tandem reaction, but DCB was
preferred to be used at 120 °C because its higher boiling
point allowed the operation to be more easily handled.
Shifting solvent to toluene, MeCN, THF or 1,4-dioxane
led to a decrease in the yield of products and/or the regi-
oselectivity of the reaction. The reaction could hardly take
place without a catalyst (entry 16), or in the presence of
AuCl, Ph3PAuCl, AuCl3 or AgOTf alone at both 80 °C
and 120 °C (entries 4–7), indicating that cationic gold(III)
or gold(I) species were essential for the reaction due to
their more electrophilic properties.13,14 Catalyst screening
experiments revealed that the tandem rearrangement/
cyclization of 1a in the presence of other conventional
Lewis and Brønsted acids as catalyst was less effective
(entries 8–15).
Key words: [1,3]-sigmatropic rearrangement, [3,3]-sigmatropic re-
arrangement, gold catalyst, tandem reaction, 3,4-dihydrocoumarin
After being neglected in catalysis field for a long time,
gold catalysis has become a hot topic in chemistry over
the past few years as witnessed by a focus of attention on
gold-catalyzed organic transformations recently.1 Among
various gold-catalyzed reactions, those involving sigmat-
ropic skeletal rearrangements have received much atten-
tion and served as powerful and highly selective tools to
generate molecular diversity and structural complexity.2–5
The Claisen rearrangement6 is a 97-year-old reaction, yet
it still plays a very important role in modern organic syn-
thesis.7 Normally, the reaction proceeds via a [3,3]-sigma-
tropic rearrangement process to afford products with high
chemo-, regio- and stereoselectivity. In some cases, how-
ever, the reaction may be concomitant with other patterns
of rearrangement deviating from the normal [3,3]-sigmat-
ropic rearrangement (e.g. [1,3]-, [2,3]-, [3,5]-rearrange-
ments), often leading to reduced selectivities.8 On the
other hand, we believe that such rearrangements should
also be useful tools for organic synthesis provided that se-
lectivity could be well controlled by proper optimization
of catalysts, solvents and temperatures. Unfortunately, so
far, such efforts have been still limited.9 As part of our on-
going interest in the application of Baylis–Hillman
adducts10,11 in organic synthesis and gold-catalyzed skel-
etal rearrangements,11e we herein report the first example
of gold(III)-catalyzed regiospecific [1,3]-sigmatropic
rearrangement9a–9e of aryl allyl ethers 112,3j derived from
Baylis–Hillman adducts (Tables 1 and 2). Furthermore,
our studies disclose that [1,3]- or [3,3]-sigmatropic rear-
rangement of 1 could be selectively accessed by control-
ling the reaction temperature, leading to regioselective
With optimized reaction conditions in hand, a study of the
scope of this temperature-controlled regioselective trans-
formation of 1 into 3,4-DHCs with diverse substituted
patterns (2 vs. 3) was then undertaken (Scheme 2,
Table 2).15,16 Under conditions A (3 mol% AuCl3 plus
9 mol% AgOTf, DCE, 80 °C), a variety of 1 could be
SYNLETT 2009, No. 18, pp 2971–2976
x
x
.x
x
.2
0
0
9
Advanced online publication: 08.10.2009
DOI: 10.1055/s-0029-1218280; Art ID: W11409ST
© Georg Thieme Verlag Stuttgart · New York

2972
Y. Liu et al.
LETTER
Cl
CO2Me
OH
A
Cl
Cl
+
CO2Me
O
O
catalyst
solvent
O
Cl
O
O
1a
3a
2a
Cl
CO2Me
OH
B
Scheme 1
R1
R1
O
O
CO2Me
R1
O
conditions A or B
O
+
O
Ar
R2
R2
1
2
3
conditions A: AuCl3/3AgOTf (3 mol%), DCE, 80 °C
conditions B: AuCl3/3AgOTf (3 mol%), DCE or DCB, 120 °C
Ar =
R2
Scheme 2
OMe
[1,3]
O
[Au]
O
OMe
AuX3
O
O
O
R1
R1
OMe
AuX3
O
R1
[3,3]
8
5
[1,3]-rearrangement
(favored)
[3,3]-rearrangement
4
MeO
MeO
[Au]
O
[Au]
OH
O
MeO
[Au]
O
O
MeO
O
[Au]
O
OH
R1
R1
R1
R1
9
10
6
7
path a
path b
AuX3
AuX3
1
3
2
Scheme 3 Possible mechanism for the selective formation of 2 or 3
Synlett 2009, No. 18, 2971–2976 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of Substituted 3,4-Dihydrocoumarins
2973
regiospecifically converted into 2 in moderate to good On the basis of previous reports,4a,8b a proposed mecha-
yields (65–96%, entries 1–12). When R1 was a phenyl nism to rationalize the regioselectivity in the gold(III)-cat-
ring substituted with electron-withdrawing groups, the re- alyzed tandem reactions of 1 is depicted in Scheme 3.
action produced 2 in slightly higher yield than those sub- Under conditions A, the ether oxygen atom of 1 was coor-
stituted with electron-donating groups (entries 1 and 2 vs. dinated to the cationic gold(III) center, resulting in cleav-
12; entries 6–9 vs. 4 and 5). As for the substituent Ar, sub- age of the ether bond to generate an ion pair intermediate
strates containing electron-rich aryl groups (entries 1–9, 5 between the gold(III) phenolate and the corresponding
11 and 12) usually afforded the corresponding products in allylic cation. The ease of attack of the a-carbon of the
better yields than those possessing electron-deficient aryl gold(III) phenolate onto the less substituted carbon of the
rings (entry 10). Under conditions B (3 mol% AuCl3 plus allylic cation led to selective [1,3]-sigmatropic rearrange-
9 mol% AgOTf, DCE or DCB, 120 °C), allyl ethers 1 de- ment (see intermediate 5), thus 2 could be eventually
rived from 2-naphthol could be regiospecifically trans- formed via cyclization of intermediate 7 (Path a). The ion
formed into the corresponding products 3 in good yields pair mechanism was proven by allylic cation trapping ex-
(entries 1, 2 and 13–15) while those derived from phenol periment, in which a Friedel–Crafts allylation product 12
or 4-methylphenol were converted into 3 as major product was also detected besides the desired 2a when 1a and p-
together with a small amount of 2 (entries 3 and 4).
xylene (11) were subjected to reaction under conditions A
(Scheme 4).
Table 1 Optimization of Reaction Conditions for the Selective Access to 3,4-DHC Derivatives 2a and 3aa
Entry
Catalyst
Solvent
Time (h)
Yield (%)b
(0.03 mmol)
at T1
at T2
T1
T2
2a
3a (2a)
1
2
3
Ph3PAuCl–AgOTf
AuCl–AgOTf
DCE
DCE
8.0
5.0
3.5
3.5
16
87
79
86 (3)
AuCl3–3AgOTf
DCE
4.0
4.0
4.0
4.5
6.0
6.0
2.0
2.0
2.5
2.0
2.5
3.0
96
96
68
72
30
53
93
93
63 (10)
62 (25)
89 (<1)
65 (20)
DCBc
toluene
MeCN
THF
dioxane
4
5
AuCl
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
0
0
3
AuCl3
7
6
Ph3PAuCl
AgOTfd
0
0
7
0
0
e
8
FeCl3
15
0
0 (35)
0
e
9
AlCl3
e
10
11
12
13
14
15
16
ZnCl2
0
7 (15)
11 (18)
29 (35)
10 (54)
4 (32)
27 (28)
0g
e
BiCl3
5
e
SnCl4
0
e
Cu(OTf)2
0
HCle,f
HOTfe
none
0
0
0g
a The reaction was carried out at temperature T1 (80 °C) or T2 (120 °C) using 1a (1.0 mmol), catalyst (3 mol% unless otherwise stated) in solvent
(3 mL) under N2 atmosphere.
b Isolated yield.
c DCB = 1,2-dichlorobenzene.
d The amount of catalyst was 0.09 mmol.
e The amount of catalyst was 0.3 mmol.
f Aqueous HCl (37%wt) was used.
g Compound 1a was recovered quantitatively.
Synlett 2009, No. 18, 2971–2976 © Thieme Stuttgart · New York

2974
Y. Liu et al.
LETTER
nant, thus 3 could be selectively formed via cyclization of
intermediate 10 (Path b). In the process, gold(III) might
play a key role in helping to trigger the [3,3]-sigmatropic
rearrangement via activation of the R1-substituted carbon
through coordination to the internal C=C bond and/or the
carbonyl oxygen atom in 1 (see intermediate 8).
Table 2 Tandem Rearrangement/Cyclization Reactions of (E)-2-
(Aryloxymethyl)alk-2-enoates 1 Catalyzed by Gold(III)
Entry R1, Ar (1)
Time Conditions Yield (%)a
(h)
of 2 or 3
1
2
3
4
5
4-ClC6H4,
2-naphthyl (1a)
3.5
2.0
A
96 (only 2a)
B (DCE) 93 (only 3a)
The 3,4-dihydrocoumarin framework occurs frequently in
natural compounds and shows important pharmacological
activities.17 Besides, DHCs serve as important flavor and
fragrance compounds in both food and cosmetics.18 Sev-
eral methods19 have been reported for the preparation of
functionalized DHCs, the main drawback of some of these
methods can be attributed to using harsh reaction condi-
tions, multistep procedures, not easy availability of sub-
strates, poor selectivities or low yields. The present
method has characteristic features of high efficiency to
tunably produce diversely substituted patterns of 3,4-
DHCs with excellent regioselectivities, high yields and
easy availability of the starting materials.
4-BrC6H4,
2-naphthyl (1b)
3.5
2.0
A 94 (only 2b)
B (DCE) 95 (only 3b)
Ph, Ph (1c)
4.0
3.0
A
81 (only 2c)
B (DCB) 59/29 (3c/2c)b
Ph, 4-MeC6H4 (1d)
3.5
2.5
A 72 (only 2d)
B (DCB) 69/19 (3d/2d)b
3,4-OCH2OC6H3,
4.0
A
83 (only 2e)
Ph (1e)
6
4-ClC6H4, Ph (1f)
2-BrC6H4, Ph (1g)
4-BrC6H4, Ph (1h)
2,4-Cl2C6H3, Ph (1i)
Ph, 4-ClC6H4 (1j)
Ph, 4-MeC6H4 (1k)
4.0
5.0
4.0
4.0
4.5
4.0
4.0
A
A
A
A
A
A
A
93 (only 2f)
87 (only 2g)
89 (only 2h)
91 (only 2i)
65 (only 2j)
87 (only 2k)
90 (only 2l)
7
8
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
9
10
11
12
Acknowledgment
Financial support from the Natural Science Foundation of Zhejiang
Province (No. Y407168), the Foundation of Education of Zhejiang
Province (No. Z200803599) and the Opening Foundation of
Zhejiang Provincial Top Key Discipline is gratefully acknowled-
ged.
4-MeOC6H4,
2-naphthyl (1l)
13
14
Ph, 2-naphthyl (1m)
2.0
2.0
B (DCE) 86 (only 3m)
B (DCB) 90 (only 3n)
4-MeC6H4,
2-naphthyl (1n)
References and Notes
15
4-CF3C6H4,
2.5
B (DCB) 89 (only 3o)
2-naphthyl (1o)
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a Isolated yield based on 1.
b The individual isomers were separated by column chromatography.
CO2Me
3 mol% AuCl3/3AgOTf
+
DCE, 80 °C, 4 h
Cl
O
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11 (1.4 mmol)
1a (1 mmol)
Cl
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CO2Me
O
+
Cl
O
2a (39%)
12 (35%)
Scheme 4 Trapping of allylic cation
On the other hand, under conditions B, a thermally con-
certed [3,3]-sigmatropic rearrangement may be predomi-
Synlett 2009, No. 18, 2971–2976 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of Substituted 3,4-Dihydrocoumarins
2975
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(15) Typical Experimental Procedure for the Synthesis of 2
under Condition A: AuCl3 (9.1 mg, 0.03 mmol), AgOTf
(23.1 mg, 0.09 mmol), and DCE (2 mL) were added to a 10-
mL flask. The mixture was stirred at r.t. for 5 min before a
DCE solution of 1a (0.35 g, 1.0 mmol diluted in 1 mL of
solvent) was added. Then the reaction mixture was stirred at
80 °C for 4 h. Upon completion of the reaction, the resulting
mixture was diluted with CH2Cl2 (10 mL) and filtered
through Celite. After evaporation of the solvent under
vacuum, the residue was purified by column chromatog-
raphy on silica gel (200–300 mesh) using cyclohexane–
EtOAc (12:1) as eluent to give pure 2a.
Typical Experimental Procedure for the Synthesis of 3
under Condition B: AuCl3 (9.1 mg, 0.03 mmol), AgOTf
(23.1 mg, 0.09 mmol), and DCE or DCB (2 mL) were added
to a 10-mL sealed vessel. The mixture was stirred at r.t. for
5 min before a DCE or DCB solution of 1a (0.35 g, 1.0 mmol
diluted in 1 mL of solvent) was added. Then the reaction
mixture was stirred at 120 °C for 2 h. Upon completion of the
reaction, the resulting mixture was diluted with CH2Cl2 (10
mL) and filtered through Celite. After evaporation of the
solvent under vacuum, the residue was purified by column
chromatography on silica gel (200–300 mesh) using
cyclohexane–EtOAc (12:1) as eluent to give pure 3a.
(16) Representative Data for Compound 2 and 3:
Compound 2b: white solid; Rf 0.46 (cyclohexane–EtOAc,
12:1); mp 198.3–201.0 °C. 1H NMR (500 MHz, CDCl3): d =
4.32 (d, 2 H, J = 2.5 Hz, CH2), 7.25 (d, 1 H, J = 8.5 Hz, ArH),
7.43–7.85 (m, 9 H, ArH), 8.03 (t, 1 H, J = 2.5 Hz, ArCH=).
13C NMR (125 MHz, CDCl3): d = 26.12, 112.14, 117.50,
122.28, 122.91, 124.27, 125.25, 127.33, 128.87, 129.25,
130.76, 130.91, 131.74, 132.17, 133.55, 142.13, 147.77,
163.60. IR (KBr): 1711 (C=O), 1630 (C=C) cm–1. GC–MS:
m/z = 364 [M+], 366 [M+ + 2]. HRMS (EI): m/z calcd for
C20H13O2Br: 364.0099; found: 364.0113.
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Compound 3c: white solid; Rf 0.56 (cyclohexane–EtOAc,
12:1); mp 114.5–114.6 °C. 1H NMR (500 MHz, CDCl3): d =
2.28 (s, 3 H, Me), 4.90 (s, 1 H), 5.72 (s, 1 H), 6.44 (s, 1 H),
6.89–7.33 (m, 8 H, ArH). 13C NMR (125 MHz, CDCl3): d =
20.80, 48.26, 117.04, 124.28, 127.52, 127.76, 128.96,
129.08, 129.26, 129.43, 134.53, 136.88, 140.77, 148.59,
163.26. IR (KBr): 1746 (C=O), 1627 (C=C) cm–1. GC–MS:
m/z = 250 [M+]. HRMS (EI): m/z calcd for C17H14O2:
250.0994; found: 250.1001.
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Synlett 2009, No. 18, 2971–2976 © Thieme Stuttgart · New York

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