Pd-Catalyzed Highly Regio- and Stereoselective Formation of C-C Double Bonds: An Efficient Method for the Synthesis of Benzofuran-, Dihydrobenzofuran-, and Indoline-Containing Alkenes

Article abstract of DOI:10.1021/acs.joc.5b01024

A highly regio- and stereoselective C-C double bond formation reaction via Pd-catalyzed Heck-type cascade process with N-tosylhydrazones has been developed. Various N-tosylhydrazones derived from both ketones and aldehydes are found to be efficient substrates to provide di- and trisubstituted olefins with high regio- and stereoselectivity. Furthermore, this reaction has a good functional group tolerance and different benzofuran-, dihydrobenzofuran-, and indoline-containing alkene products were obtained with high selectivity.

Full text of DOI:10.1021/acs.joc.5b01024

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Pd-Catalyzed Highly Regio- and Stereoselective Formation
of C–C Double Bonds: An Efficient Method for the Synthesis
of Benzofuran-, Dihydrobenzofuran- and
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Indoline-Containing Alkenes
Yang Gao, Wenfang Xiong, Huoji Chen, Wanqing Wu*, Jianwen Peng, Yinglan Gao, Huanfeng
Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
cewuwq@scut.edu.cn, jianghf@scut.edu.cn
ABSTRACT: A highly regioꢀ and stereoselective C‒C double bond formation
reaction via Pdꢀcatalyzed Heckꢀtype cascade process with Nꢀtosylhydrazones has
been developed. Various Nꢀtosylhydrazones derived from both ketones and aldehydes
are found to be efficient substrates to provide diꢀ and triꢀsubstituted olefins with high
regioꢀ and stereoselectivity. Furthermore, this reaction has a good functional group
tolerance and different benzofuranꢀ, dihydrobenzofuranꢀ and indolineꢀcontaining
alkene products were obtained with high selectivity.
INTRODUCTION
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Carbonꢀcarbon double bond is one of the most fundamental and versatile functional
groups in synthetic organic chemistry,1ꢀ4 owing to its widespread presence and highly
developed chemistry.5ꢀ9 In the past few years, a novel type of palladiumꢀcatalyzed
crossꢀcoupling reactions involving carbene migratory insertion process has emerged
as a powerful method for the construction of CꢀC double bonds.10ꢀ14 As shown in
Scheme 1a, palladiumꢀcatalyzed crossꢀcoupling reaction based on carbene migratory
insertion includes the following common processes:15 (1) metal species A is captured
by the diazo compound to generate metal carbene species B; (2) migratory insertion
occurs to produce a new metal species C which undergoes further transformations,
typically βꢀhydride elimination; (3) the reaction releases coupling product D and
regenerates the metal catalyst. According to this sequence, various alkene formation
reactions have been designed and developed.16ꢀ29 Nevertheless, despite the efficiency
of these methods, the regioꢀ and stereoselectivities of this type of reaction is still a
challenge and has rarely been discussed. Actually, when alkylꢀPd species A’ is
employed, metal species C’ bearing two βꢀhydride atoms Ha and Hb, which are
electronically similar, is generated and two regioisomers D-1 and D-2 may be formed
without selectivity in the position of the double bond (Scheme 1b). In the previous
work,30ꢀ34 Nꢀtosylhydrazones derived from nonꢀenolizable carbonyls (aldehydes
or/and ketones bearing no αꢀhydride) are chosen as the coupling partners to avoid the
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regioselective
problem.
Significantly,
to
promote
the
regioselective
βꢀhydrideꢀelimination on alkylpalladium complex C’ is the crucial step to improve the
regioselectivity of this type of reaction. Therefore, we envision that the discovery of a
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catalyst system sensitive to the steric effect and capable of distinguishing
electronically nonbiased Ha and Hb on the basis of their relative steric environments
might be a strategy to solve the regioselective problem.
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On the other hand, the intramolecular carbometalation of alkenes35ꢀ48 initiated from
the oxidative addition of C(sp2)ꢀX provides an efficient method to construct
benzoꢀfused saturated nitrogen/oxygen heterocycles such as indolines35ꢀ40 and
dihydrobenzofurans,41ꢀ48 which are prominent in a variety of natural products and
biologically active compounds.49ꢀ55 In 2002, Grigg and coꢀworkers reported an
interesting Pdꢀcatalyzed queuing processes by employing allene as a relay switch and
secondary amines as nucleophiles.39 Inspired by these precedents and our continued
interest in the palladiumꢀcatalyzed crossꢀcoupling of Nꢀtosylhydrazones,56ꢀ59 we
conceived that the alkylꢀPd species generated from intramolecular carbopalladation of
alkene may be trapped by a diazo substrate to form a Pd carbene species, which would
undergo migratory insertion and βꢀhydride elimination to afford the polysubstituted
olefins (Scheme 1c). Herein, we present our recent progress in palladiumꢀcatalyzed
Heckꢀtype cascade reaction with various Nꢀtosylhydrazones for the synthesis of
functionalized olefins with high selectivity. It is worth mentioning that this reaction
proceeds in a regioꢀ and stereoselective manner which is a crucial issue in the
construction of polysubstituted olefins.60
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Scheme 1. Pd-catalyzed Heck-type cascade reaction with N-tosylhydrazone.
RESULTS AND DISCUSSION
Our initial investigations of this Pdꢀcatalyzed Heckꢀtype cascade reaction were
commenced with substrate (1a) and Nꢀtosylhydrazone (2a) derived from
acetophenone as model substrates under conditions that 1a (0.3 mmol), 2a (0.45
mmol), Pd(OAc)2 (5 mol %), PPh3 (15 mol %) and LiOtBu (0.9 mmol) in 1,4ꢀdioxane
(2 mL) at 90 °C. To our delight, the desired product was obtained as a mixture of
diastereomers (5:1) in 66% yield. The structure of the major isomer was confirmed to
be 3aa by the NMR analysis and the byꢀproduct was the doubleꢀbond isomer 4.
Meanwhile, a small amount of 5 was also formed. Encouraged by this promising
regioselectivity, we thought that the selective formation of 3aa could be obtained
through the careful screening of base, Pd source, solvent and ligand. Among various
bases tested, LiOtBu gave the highest yield (entry 1), however, the selectivity of the
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dominant product 3aa was still unsatisfactory. The formation of the doubleꢀbond
isomer 4 remained an issue and indicated the competition of two βꢀhydride
elimination pathways. The judicious choice of a bulky ligand would promote the
required selective βꢀhydride elimination61 and afford the best selectivity for 3aa.
Further optimization studies revealed that more bulky Xphos gave the highest
selectivity for 3aa (entry 10) and the presence of 5 equivalents of water could further
promote the ratio of 3aa to 95% (entry 11). In addition, diphosphine ligand Xanphos
and dppp were found to be effective for this reaction, but the selectivity is no better
than that of Xphos (entries 12 and 13).
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Table 1. Optimization of Reaction Conditionsa
Entry
1
2
3
4
5
6
7
8
Base
Ligand
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
ꢀ
Solvent
3aa/4/5b
77:18:5
83:12:5
76:21:3
70:26:4
66:24:10
54:28:18
75:20:5
61:37:2
83:17:5
90:5:5
Yield (%)c
tBuOLi
tBuONa
tBuOK
K2CO3
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
MeCN
66
53
59
35
45
62
37
80
78
toluene
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4-dioxane
1,4ꢀdioxane
1,4ꢀdioxane
TFP
9
PtBu3
Xphos
Xphos
Xanphos
Dppp
10
11d
12e
13e
82
95:4:1
83:11:6
78:12:10
88 (83)
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a Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), Pd(OAc)2 (5 mol %), ligand (15 mol %)
b
and base (3.0 equiv) in indicated solvent (2 mL) at 90 °C for 8 h. The ratio was determined by
c
GC analysis. Combined yield of 3a and 4. Dodecane is used as the internal standard. Data in
parentheses is isolated yield. d 5.0 equivalent of water was added. e 7.5 mol % ligand was used.
With the optimal reaction conditions in hand, we then examined the scope of this
palladiumꢀcatalyzed
Heckꢀtype
cascade
reaction.
Generally,
various
Nꢀtosylhydrazones with different substituents were found to be suitable reaction
partner for this transformation. As shown in Table 2, a series of paraꢀsubstituted
Nꢀtosylhydrazones including both electronꢀdonating groups (EDGs) (3aeꢀ3ah) and
electronꢀwithdrawing groups (EWGs) (3ai and 3aj) could be converted to the
corresponding polysubstituted olefins in good to excellent yields. Halo substituents,
such as ꢀCl, and ꢀBr, were well tolerated, which provided the possibility for further
functionalization (3abꢀ3ad). It was found no significant effect for the substituents at
the para, meta, and ortho positions of the aromatic ring (3ag, 3ak and 3am). When
polysubstituted Nꢀtosylhydrazones were used for this transformation, the
corresponding products could be obtained in good yields (3an and 3ao). To our
delight, heterocyclic Nꢀtosylhydrazones such as furan and thiophene (3ap and 3aq)
were found to be a suitable reaction partner for this reaction. The naphthyl
Nꢀtosylhydrazone 2r also proceeded well under the optimal conditions. Notably,
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cyclic Nꢀtosylhydrazones underwent the transformation smoothly to afford the desired
products (3asꢀ3au) in good yields. It should be noted that the stereochemistry is a
crucial issue in the construction of polysubstitued olefins. In this context, various
trisubstituted olefins (3avꢀ3ax) were obtained in this reaction with high
stereoselectivity (E/Z > 10:1 determined by NOSEY analysis, see the Supporting
Information for details).
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Table 2. Substrate Scope of N-Tosylhydrazones Derived from Aryl Ketonesa, b
Pd(OAc)2 (5 mol %)
Ar
Xphos (15 mol %)
H2O (5.0 equiv)
I
NNHTs
R1
+
tBuOLi (3.0 equiv)
O
R1
Ar
O
1,4-dioxane, 90 o
C
1a
2
3
R
R
O
O
O
O
3ak, R = OMe, 80%
3al, R = NHAc, 88%
3aa, R = H, 83%
3ab, R = F, 85%
3ac, R = Cl, 80%
3ad, R = Br, 82%
3ae, R = Me, 89%
3af, R = Ph, 81%
3ag, R = OMe, 86%
3am, 85%
Cl
Cl
O
O
O
3ah, R = morpholine, 86%
3ai, R = CN, 78%
3aj, R = NO2, 72%
O
3an, 81%
3ao, 76%
S
O
O
O
O
3ap, 68%
3aq, 83%
3ar, 85%
O
O
O
O
3as, 84%
3at, 80%
3au, 86%
O
Ph
O
O
3av, 88%
3aw, 78%
3ax, 78%
a Reaction conditions: all reactions were performed with 1a (0.3 mmol), 2 (0.45 mmol), Pd(OAc)2
(5 mol %), Xphos (15 mol %), H2O (5.0 equiv) and LiOtBu (3.0 equiv) in 2 mL 1,4ꢀdioxane at
90 °C for 8 h. b Isolated yields are given.
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Table 3. Substrate Scope of Organic Halide Substratesa, b
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a Reaction conditions: all reactions were performed with 1 (0.3 mmol), 2 (0.45 mmol), Pd(OAc)2
(5 mol %), Xphos (15 mol %), H2O (5.0 equiv) and LiOtBu (3.0 equiv) in 2 mL 1,4ꢀdioxane at
90 °C for 8 h. b Isolated yields are given.
Next, the generality of the reaction was additionally explored by employing various
organic halide substrates to the optimized reaction conditions. Substrates bearing
4ꢀtꢀBu or 4ꢀCl underwent a smooth reaction to afford the corresponding products (3ba
and 3ca) in good yields. 1ꢀIodoꢀ2ꢀ(2ꢀmethylallyloxy)naphthalene was also shown to
be a good substrate and gave product 3da in 73% yield. The reaction of NꢀAc
protected amide 1f afforded the desired product 3fa in 80% yield, while an amide
bearing free NꢀH failed to undergo this crossꢀcoupling reaction. Acrylamide 1h was
proved to be an efficient substrate for this reaction and 3hi was obtained in 89% yield.
Moreover, we were pleased to find that the transformations of the substrates with
βꢀOMe, or ꢀPh functional group underwent the reaction efficiently and furnished the
corresponding products (3ea and 3ia) in good yields.
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To further highlight the versatility of this reaction, various Nꢀtosylhydrazones
derived from benzaldehyde were applied in this reaction. As shown in Table 4, a
series of nonterminal olefins were prepared and different functional groups such as
(Cl, Br, NMe2, SO2Me and furyl) were tolerated. It is worth mentioning that this
reaction was tested to be efficient for the synthesis of sixꢀmembered chorman
substituted alkenes (6j and 6k).
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Table 4. Substrate Scope of N-Tosylhydrazones Derived from Benzaldehydea ,b
a Reaction conditions: all reactions were performed with 1 (0.3 mmol), 2 (0.45 mmol), Pd(OAc)2
(5 mol %), Xphos (15 mol %), H2O (5.0 equiv) and LiOtBu (3.0 equiv) in 2 mL 1,4ꢀdioxane at
90 °C for 8 h. b Isolated yields are given.
The analogous reactions with aryl bromide or chloride starting materials were
found to be inefficient, giving only a trace amount of the desired products.
Interestingly, the arylꢀPd species generated from the oxidative addition of C(sp2)ꢀBr
was firstly trapped by a diazo substrate and afforded 5 in 84% isolated yield [Eq (1)].
This may be caused by the slow oxidative addition of C(sp2)ꢀBr and the fast formation
of aryl palladium carbene species. Furthermore, the failure of 1m to give the desired
products indicated that βꢀhydride elimination should be faster than the carbene
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insertion and blocking βꢀH elimination by the choice of substrate is critical for the
5
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success of this reaction [Eq (2)].
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In the light of the above experimental results, we envisioned that the formation of a
relatively stable alkyl palladium species is the crucial process of this reaction. And the
allene substrates were then tested under the standard conditions (Table 5). As we
expected, various benzofuranꢀcontaining alkene products were isolated in good yields
(8aꢀ8f). Furthermore, nonterminal olefins 9 could also be prepared via applying the
Nꢀtosylhydrazone derived from benzaldehyde in this reaction [Eq (3)].
Table 5. Substrate Scope of Allene Substratesa ,b
a Reaction conditions: all reactions were performed with 1i (0.3 mmol), 2 (0.45 mmol), Pd(OAc)2
(5 mol %), Xphos (15 mol %), H2O (5.0 equiv) and LiOtBu (3.0 equiv) in 2 mL 1,4ꢀdioxane at
90 °C for 8 h. b Isolated yields are given.
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Cl
4
5
Pd(OAc)2 (5 mol %)
NNHTs
6
7
8
9
Xphos (15 mol %)
H2O (5.0 equiv)
I
(3)
+
tBuOLi (3.0 equiv)
1,4-dioxane, 90 o
•
O
Cl
O
9
, 80%
C
1n
2
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On the basis of the above results, a tentative mechanism for this
palladiumꢀcatalyzed intramolecular Heckꢀtype cascade reaction is proposed (Scheme
2). It was initiated by the oxidative addition of 1, affording the ary palladium species I.
Subsequently, the intramolecular alkene insertion into the carbon–palladium bond led
to intermediate II, which was then captured by the diazo compound III to generate
metal carbene species IV.10ꢀ15 Next, the migratory insertion occurred to give
intermediate V, which would undergo regioselective synꢀβꢀhydride elimination to
form the polysubstituted olefins 3 and 6. When 2 was derived from benzaldehyde and
only Ha exists, the elimination of Ha occured to afford the disubstituted alkenes 6 and
this result is in consist with Gu’s work.34 As for substrates derived from ketone with
both Ha and Hb, the regioselective elimination of Hb was favored under the optimal
reaction conditions, thus leading to the formation of the lessꢀsubstituted terminal
olefins 3. If allene substrates were employed, 8 and 9 were obtained via the process
indicated in the right cycle. The high regioꢀ and stereoselectivity for the CꢀC
doubleꢀbond formation observed in this reaction could be explained by the syn
arrangement required for the βꢀhydride elimination in intermediate V, and the
conformation with less steric hindrance was favored to undergo the βꢀhydride
elimination and the use of a bulky ligand could further promote the selectivity.62, 63
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Scheme 2. A Tentative Mechanism for the Pd-Catalyzed Intramolecular
Heck-Type Cascade Reaction
CONCLUSION
In conclusion, we have developed a mild and efficient palladiumꢀcatalyzed
Heckꢀtype cascade reaction with various Nꢀtosylhydrazones for the synthesis of
functionalized olefins with high selectivity. This transformation involves the
processes of olefin insertion/alkyl palladium carbene migratory insertion and
regioselective βꢀhydride elimination. Different types of functionalized olefins were
obtained via the switch of substrates; both inactive alkenes and allenes were proved to
be efficient for this Heckꢀtype cascade reaction. The high regioꢀ and stereoselectivity,
good functional group tolerance as well as the mild reaction conditions and good to
excellent yields make the present protocol very attractive. Therefore, this reaction is
an attractive method to prepare benzofuranꢀ, dihydrobenzofuranꢀ and
indolineꢀcontaining alkene products and will find its potential applications in the
synthesis of more complex and significant pharmaceuticals.
EXPERIMENTAL SECTION
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1
General Methods H NMR 400 MHz spectra were recorded in CDCl3 at 400 MHz
and 13C NMR spectra were recorded in CDCl3 at 100 MHz respectively, and the
chemical shifts (d) were referenced to TMS. GC–MS was obtained using electron
ionization. EIꢀHRMS for 6k, 7a, 7d, APCIꢀHRMS for 6b, 6h and ESIꢀHRMS for
others were obtained with a LCMSꢀITꢀTOF mass spectrometer. IR spectra were
obtained as potassium bromide pellets or as liquid films between two potassium
bromide pellets. TLC was performed using commercially prepared 100ꢀ400 mesh
silica gel plates (GF254), and visualization was effected at 254 nm.
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Typical Procedure for Synthesis of Aryl Iodides 1a-1d, 1g, 1i, 1l, 1m.42 The starting
phenol (5 mmol, 1 equiv) and K2CO3 (10 mmol, 2 equiv) were suspended in DMF
(0.2 M). Methallyl chloride (6.5 mmol, 1.3 equiv) was added by syringe and the
reaction was heated to 70 °C overnight. After cooling, the mixture was diluted with
EtOAc and transferred to a seperatory funnel. The organic phase was washed twice
with H2O and once with brine. Drying over MgSO4, filtration, and rotary evaporation
provided the crude material. The residue was separated by column chromatography on
a silica gel with petroleum ether/ethyl acetate as the eluent to afford the corresponding
aryl iodides products 1a-1d, 1g, 1i, 1l, 1m.
1-Iodo-2-(2-methylallyloxy)benzene (1a)42 Colorless oil (1.23 g, 90% yield); Rf 0.70
(petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.8 Hz, 1H), 7.31 (t, J =
7.8 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 5.25 (s, 1H), 5.07 (s,
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1H), 4.52 (s, 2H), 1.92 (s, 3H). C NMR (100 MHz, CDCl3) δ 157.0, 140.1, 139.3,
128.9, 122.4, 112.8, 112.2, 86.5, 72.4, 19.4. MS (EI, 70 eV) m/z 274, 259, 220, 147,
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4-Chloro-2-iodo-1-(2-methylallyloxy)benzene (1b) Colorless oil (1.24 g, 80% yield);
Rf 0.66 (petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.27 (d, J = 9.5
Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.20 (s, 1H), 5.05 (s, 1H), 4.48 (s, 2H), 1.88 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 156.0, 139.8, 138.5, 129.0, 126.3, 113.2, 112.6, 86.6,
72.8, 19.4. MS (EI, 70 eV) m/z 308, 254, 181, 145, 97.
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4-(tert-Butyl)-2-iodo-1-((2-methylallyl)oxy)benzene (1c) Colorless oil (1.45 g, 88%
yield); Rf 0.71 (petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.27 (d,
J = 8.5 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 5.18 (s, 1H), 5.00 (s, 1H), 4.45 (s, 2H), 1.86
(s, 3H), 1.27 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 154.9, 145.5, 140.3, 136.4, 126.1,
112.7, 111.7, 86.4, 72.6, 33.9, 31.3, 19.4. MS (EI, 70 eV) m/z 330, 315, 274, 203, 173,
105, 91, 57.
1-Iodo-2-(2-methylallyloxy)naphthalene (1d) Colorless oil (1.46 g, 90% yield); Rf
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0.72 (petroleum ether); H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.6 Hz, 1H), 7.80
(d, J = 8.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 7.3
Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 5.28 (s, 1H), 5.08 (s, 1H), 4.66 (s, 2H), 2.07 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 155.7, 140.3, 135.6, 131.1, 130.0, 129.8, 128.1, 127.9,
124.3, 114.1, 113.1, 88.2, 73.3, 19.5. MS (EI, 70 eV) m/z 324, 269, 241, 197, 142,
114.
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2-Iodo-N-(2-methylallyl)aniline (1g)64 Colorless oil (0.54 g, 40% yield); Rf 0.68
(petroleum ether/EtOAc 30/1); 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 1H),
7.17 (t, J = 7.7 Hz, 1H), 6.52 (d, J = 8.2 Hz, 1H), 6.42 (t, J = 7.5 Hz, 1H), 4.93 (d, J =
20.1 Hz, 2H), 4.46 (s, 1H), 3.72 (s, 2H), 1.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
147.1, 141.8, 138.9, 129.3, 118.6, 111.1, 110.9, 85.2, 49.9, 20.3. MS (EI, 70 eV) m/z
273, 232, 146, 130, 91.
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1-Iodo-2-(2-(methoxymethyl)allyloxy)benzene (1i) Colorless oil (1.21 g, 80% yield);
Rf 0.74 (petroleum ether/EtOAc 50/1); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.7
Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.70 (t, J = 7.5 Hz, 1H),
5.44 (s, 1H), 5.29 (s, 1H), 4.58 (s, 2H), 4.07 (s, 2H), 3.36 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 157.0, 140.7, 139.4, 129.3, 122.6, 115.0, 112.3, 86.5, 73.3, 69.4, 58.1.
MS (EI, 70 eV) m/z 304, 272, 259, 145, 131, 85, 55.
1-Bromo-2-(2-methylallyloxy)benzene (1l)43 Colorless oil (1.04 g, 92% yield); Rf
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0.70 (petroleum ether); H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.8 Hz, 1H), 7.24
(d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 5.16 (s, 1H),
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5.01 (s, 1H), 4.49 (s, 2H), 1.86 (s, 3H). C NMR (100 MHz, CDCl3) δ 155.0, 140.2,
133.4, 128.3, 121.8, 113.4, 112.8, 112.3, 72.4, 19.3. MS (EI, 70 eV) m/z 226, 211, 172,
147, 133, 91, 63.
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1-(Allyloxy)-2-iodobenzene (1m)42 Colorless oil (1.17 g, 90% yield); Rf 0.72
(petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.8 Hz, 1H), 7.31 – 7.23
(m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.70 (t, J = 7.5 Hz, 1H), 6.06 (ddd, J = 15.7, 10.0,
4.7 Hz, 1H), 5.52 (d, J = 17.3 Hz, 1H), 5.31 (d, J = 10.6 Hz, 1H), 4.59 (d, J = 3.8 Hz,
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2H). C NMR (100 MHz, CDCl3) δ 157.1, 139.5, 132.6, 129.3, 122.6, 117.6, 112.5,
86.7, 69.7. MS (EI, 70 eV) m/z 260, 220, 191, 133, 105, 92.
Typical Procedure for Synthesis of Phenyl Propiolates 1h, 1j.34 Methacryloyl
chloride (0.12 mL, 1.2 mmol, 1.2 equiv) was added to a mixture of 2ꢀiodoaniline
(0.219 g, 1.0 mmol, 1.0 equiv), DMAP (6.0 mg, 0.05 mmol, 5 mol %), Et3N (0.28 mL,
2.0 mmol, 2.0 equiv) in CH2Cl2 (2.0 mL) at ꢀ20 °C dropwise. After stirring at ꢀ20 °C
for 30 min and room temperature overnight, the mixture was quenched with saturated
NaHCO3. The mixture was extracted with CH2Cl2, washed with brine, and dried over
Na2SO4. After filtration and concentration, the obtained crude amide was used in next
step without purification. NaH (80 mg, 60% in mineral oil, 2.0 mmol, 2.0 equiv) was
added to a solution of the above crude amide in THF (4.0 mL) at 0 °C in portions.
After stirring for 20 min at 0 °C MeI (0.19 mL, 3.0 mmol, 3.0 equiv) added dropwise
and the reaction mixture was allowed to warm to room temperature and stirred for
another 2 h. The reaction was quenched with water and the resulting mixture was
extracted with ethyl acetate twice. The combined organic phase was washed with
brine, dried over Na2SO4, filtered and concentrated. The residue was separated by
column chromatography on a silica gel with petroleum ether/ethyl acetate as the
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N-(2-Iodophenyl)-N-methylmethacrylamide (1h)34 Solid (0.18 g, 58% yield); Rf
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0.47 (petroleum ether/EtOAc 4/1); H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 8.0,
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1.2 Hz, 1 H), 7.35 (dd, J = 7.6, 7.2 Hz, 1 H), 7.18 (d, J = 7.6 Hz, 1 H), 7.07ꢀ6.91 (m, 1
H), 5.05 (s, 1H), 4.98 (s, 1 H), 3.24 (s, 3H), 1.82 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 171.6, 146.6, 140.0, 139.8, 129.2, 129.1, 129.1, 118.9, 98.8, 36.7, 20.3. MS (EI, 70
eV) m/z 301, 245, 174, 134, 69.
N-(2-Iodophenyl)-N-methyl-2-phenylacrylamide (1j) 34 Solid (0.26 g, 70% yield);
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Rf 0.50 (petroleum ether/EtOAc 4/1); H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.9
Hz, 1H), 7.21 (d, J = 4.4 Hz, 3H), 7.13 (d, J = 4.4 Hz, 2H), 7.03 (dd, J = 14.4, 6.9 Hz,
1H), 6.86 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.62 (s, 1H), 5.34 (s, 1H), 3.29
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.1, 145.6, 145.3, 139.8, 136.9, 129.7,
129.0, 128.7, 128.2, 127.9, 126.0, 117.3, 99.1, 36.3. MS (EI, 70 eV) m/z 363, 263,
208, 103, 77.
Typical Procedure for Synthesis of 1-Iodo-2-(2-phenylallyloxy)benzene 1e, 1k.42 A
solution of diethyl azodicarboxylate (DEAD) (0.3 mL, 0.98 mmol, 1.3 equiv) in
CH2Cl2 (3.0 mL) was added slowly to a mixture of 2ꢀphenylpropꢀ2ꢀenꢀ1ꢀol (0.27 g,
0.98 mmol, 1.3 equiv), PPh3 (0.34 g, 2 mmol, 1.3 equiv), 2ꢀiodophenol (0.160 g, 1.5
mmol, 1.0 equiv) in CH2Cl2 (3.0 mL) at 0 °C. The resulted solution was allowed to
warm to room temperature and stirred for 1 h. The reaction was quenched with water
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and extracted with EtOAc twice. The combined organic layer was washed with brine
and dried over Na2SO4, filtered and concentrated. The residue was separated by
column chromatography on a silica gel with petroleum ether/ethyl acetate as the
eluent to afford the corresponding products 1e, 1k.
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1-Iodo-2-(2-phenylallyloxy)benzene (1e)42 Colorless oil (0.25 g, 76% yield); Rf 0.69
(petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.7 Hz, 1H), 7.48 (d, J =
7.4 Hz, 2H), 7.32 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 5.62 (d, J
= 3.6 Hz, 2H), 4.93 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 157.0, 142.4, 139.5, 138.3,
129.3, 128.4, 128.0, 126.1, 122.7, 114.6, 112.5, 86.6, 70.4. MS (EI, 70 eV) m/z 336,
259, 220, 209, 91, 64.
1-Iodo-2-(3-methylbut-3-enyloxy)benzene (1k)65 Colorless oil (0.23 g, 80% yield);
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Rf 0.68 (petroleum ether); H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.7 Hz, 1H),
7.27 (t, J = 7.9 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.69 (t, J = 7.5 Hz, 1H), 4.85 (d, J =
8.2 Hz, 2H), 4.11 (t, J = 6.8 Hz, 2H), 2.56 (t, J = 6.8 Hz, 2H), 1.86 (d, J = 13.8 Hz,
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3H). C NMR (100 MHz, CDCl3) δ 157.5, 142.0, 139.5, 129.3, 122.4, 112.4, 112.1,
86.7, 68.0, 37.1, 23.0. MS (EI, 70 eV) m/z 288, 274, 259, 228, 147, 69.
Typical Procedure for Synthesis of N-(2-Iodophenyl)-N-(2-methylallyl)acetamide
1f.34 To a suspension of NaH (100 mg, 60% in oil, 2 mmol) in DMF (10 mL) were
added 0.52 g (2 mmol) of Nꢀ(2ꢀiodophenyl)acetamide in DMF (5 mL). When the
evolution of H2 has ceased, methallyl chloride (0.4 mL, 4 mmol) was added. The
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reaction mixture was heated to 80 °C overnight. The reaction mixture was quenched
with water and extracted with Et2O. The organic phase was dried over MgSO4 and
concentrated in vacuo. The residue was separated by column chromatography on a
silica gel with petroleum ether/ethyl acetate as the eluent to afford the corresponding
product 1f.
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N-(2-Iodophenyl)-N-(2-methylallyl)acetamide (1f)34 Solid (0.54 g, 87% yield); Rf
0.66 (petroleum ether/EtOAc 3/1); 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.9 Hz,
1H), 7.38 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 5.00
(d, J = 14.9 Hz, 1H), 4.84 (s, 1H), 4.67 (s, 1H), 3.35 (d, J = 14.8 Hz, 1H), 1.82 (s, 3H),
1.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.1, 144.7, 140.3, 140.2, 130.2, 129.7,
129.3, 114.1, 100.0, 53.8, 22.8, 20.6. MS (EI, 70 eV) m/z 315, 273, 188, 146, 130, 91.
Typical Procedure for Synthesis of 2-Iodophenyl Propadienyl Ether 1n.66
A
suspension of 2ꢀiodophenol (2.20 g, 10 mmol), propargyl bromide (1.79 g, 12 mmol)
and potassium carbonate (1.66 g, 12 mmol) in THF (25 mL) was boiled under reflux
for 16 h. Water (50 mL) and ethyl acetate (20 mL) were then added and the organic
layer separated, dried (Na2SO4) , evaporated under reduced pressure and the residue
was dissolved in 3:1 v/v tꢀbutyl alcoholꢀTHF (20 mL). Potassium tꢀbutoxide (1.35 g,
12 mmol) was then added and the resulting mixture was stirred at room temperature
for 16 h. When the solvent was evaporated under reduced pressure and
dichloromethane (20 mL) was added. The organic layer was separated and washed
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with water (20 mL), dried (Na2SO4) and evaporated under reduced pressure. The
residue was separated by column chromatography with petroleum ether/ethyl acetate
as the eluent on a silica gel to afford the corresponding product 1n.
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1-Iodo-2-(propa-1,2-dienyloxy)benzene (1n)66 Colorless oil (1.4 g, 55% yield); Rf
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0.75 (petroleum ether); H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.29
(t, J = 7.7 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.84 – 6.76 (m, 2H), 5.43 (d, J = 5.9 Hz,
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2H); C NMR (100 MHz, CDCl3) δ 202.3, 156.2, 139.6, 129.8, 124.7, 118.4, 116.8,
90.4, 87.2. MS (EI, 70 eV) m/z 258, 219, 190, 131, 103, 91.
Typical Procedure for Synthesis of N-Tosylhydrazones 2a-2x.27ꢀ29, 57ꢀ59 A solution
of pure TsNHNH2 (5 mmol) in methanol (5 mL) was stirred and heated to 60 °C until
the TsNHNH2 was completely dissolved. Then carbonyl compounds were dropped to
the mixture slowly. After approximately 5ꢀ30 min the crude products was obtained as
precipitates. The residue was separated by column chromatography on a silica gel to
afford the corresponding Nꢀtosylhydrazone products 2a-2x with petroleum ether/ethyl
acetate as the eluent.
Typical Procedure for the Synthesis of 3-Methyl-3-(2-phenylallyl)-2,3-
dihydrobenzofuran. To a Schlenk tube were added 1a (0.3 mmol), 2a (0.45 mmol),
Pd(OAc)2 (5 mol %), Xphos (15 mol %), H2O (5.0 equiv) and LiOtBu (3.0 equiv) in 2
mL 1,4ꢀdioxane and stirred at 90 °C for the desired reaction time. After completed, the
reaction was quenched with aqueous NH4Cl and extracted the crude product with
ethyl acetate. The organic extracts were concentrated in vacuum, and the resulting
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ether/ethyl acetate as eluent to afford the desired product 3aa-3ia, 5, 6a-6k, 8a-8f and
9.
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3-Methyl-3-(2-phenylallyl)-2,3-dihydrobenzofuran (3aa). Colorless oil (62 mg,
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83% yield); Rf 0.58 (petroleum ether/EtOAc 100/1); H NMR (400 MHz, CDCl3) δ
7.32 – 7.19 (m, 5H), 7.07 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.80 (t, J = 7.4
Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.24 (s, 1H), 4.99 (s, 1H), 4.27 (d, J = 8.8 Hz, 1H),
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3.87 (d, J = 8.7 Hz, 1H), 2.86 (q, J = 13.7 Hz, 2H), 1.23 (d, J = 11.4 Hz, 3H). C
NMR (100 MHz, CDCl3) δ 159.2, 145.8, 142.6, 135.3, 128.2, 128.0, 127.3, 126.5,
122.9, 120.3, 117.4, 109.6, 81.7, 45.8, 45.6, 25.3; IR (KBr, cmꢀ1): 3085, 2926, 1630,
1540, 1224, 1098, 745; ESIꢀHRMS calcd for C18H18NaO [M + Na]+ 273.1250; found,
273.1253.
3-(2-(4-Fluorophenyl)allyl)-3-methyl-2,3-dihydrobenzofuran (3ab). Colorless oil
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(68 mg, 85% yield); Rf 0.60 (petroleum ether/EtOAc 100/1); H NMR (400 MHz,
CDCl3) δ 7.23 (dd, J = 7.5, 5.2 Hz, 2H), 7.05 (t, J = 7.7 Hz, 1H), 7.00 – 6.90 (m, 3H),
6.77 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.20 (s, 1H), 4.97 (s, 1H), 4.28 (d, J
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= 8.7 Hz, 1H), 3.90 (d, J = 8.7 Hz, 1H), 2.91 – 2.69 (m, 2H), 1.23 (s, 3H); C NMR
(100 MHz, CDCl3) δ 162.2 (d, J = 238.0 Hz), 159.2, 144.9, 138.6 (d, J = 4.0 Hz),
135.0, 128.1 (d, J = 3.0 Hz), 128.0, 123.0, 120.3, 117.4, 115.0 (d, J = 21.0 Hz), 109.6,
81.7, 45.9, 45.8, 25.4. IR (KBr, cmꢀ1): 3074, 2964, 1600, 1508, 1227, 1014, 749;
ESIꢀHRMS calcd for C18H17FNaO [M + Na]+ 291.1156; found, 291.1156.
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3-(2-(4-Chlorophenyl)allyl)-3-methyl-2,3-dihydrobenzofuran (3ac). Colorless oil
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(68 mg, 80% yield); Rf 0.58 (petroleum ether/EtOAc 100/1); H NMR (400 MHz,
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CDCl3) δ 7.24 – 7.17 (m, 4H), 7.06 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.77
(t, J = 7.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.22 (s, 1H), 4.99 (s, 1H), 4.28 (d, J = 8.8
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Hz, 1H), 3.90 (d, J = 8.8 Hz, 1H), 2.88 – 2.73 (m, 2H), 1.23 (s, 3H); C NMR (100
MHz, CDCl3) δ 159.2, 144.7, 141.0, 134.8, 133.1, 128.3, 128.1, 127.8, 123.0, 120.3,
117.9, 109.6, 81.6, 45.8, 45.7, 25.4. IR (KBr, cmꢀ1): 3084, 2968, 1612, 1504, 1198,
745; ESIꢀHRMS calcd for C18H17ClNaO [M + Na]+ 307.0860; found, 307.0857.
3-(2-(4-Bromophenyl)allyl)-3-methyl-2,3-dihydrobenzofuran (3ad). Colorless oil
1
(80 mg, 82% yield); Rf 0.59 (petroleum ether/EtOAc 100/1); H NMR (400 MHz,
CDCl3) δ 7.37 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.06 (t, J = 7.7 Hz, 1H),
6.97 (d, J = 7.4 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.23 (s,
1H), 4.99 (s, 1H), 4.28 (d, J = 8.8 Hz, 1H), 3.90 (d, J = 8.8 Hz, 1H), 2.87 – 2.70 (m,
13
2H), 1.24 (d, J = 10.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 159.2, 144.8, 141.4,
134.8, 131.3, 128.1, 128.1, 122.9, 121.2, 120.3, 117.9, 109.6, 81.6, 45.8, 45.7, 25.4.
IR (KBr, cmꢀ1): 3078, 2964, 1597, 1508, 1226, 748; ESIꢀHRMS calcd for
C18H17BrNaO [M + Na]+ 351.0355; found, 351.0353.
3-Methyl-3-(2-p-tolylallyl)-2,3-dihydrobenzofuran (3ae). Colorless oil (70 mg,
1
89% yield); Rf 0.58 (petroleum ether/EtOAc 100/1); H NMR (400 MHz, CDCl3) δ
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7.21 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 7.9 Hz, 3H), 7.04 (d, J = 7.6 Hz, 1H), 6.81 (t, J =
7.3 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 5.22 (s, 1H), 4.94 (s, 1H), 4.27 (d, J = 8.8 Hz,
1H), 3.85 (d, J = 8.7 Hz, 1H), 2.96 – 2.71 (m, 2H), 2.33 (s, 3H), 1.23 (d, J = 20.3 Hz,
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3H); C NMR (100 MHz, CDCl3) δ 159.2, 145.6, 139.7, 137.1, 135.6, 129.0, 128.0,
126.4, 122.9, 120.3, 116.7, 109.6, 81.8, 45.8, 45.6, 25.3, 21.0. IR (KBr, cmꢀ1): 3132,
2966, 1598, 1472, 1130, 750; ESIꢀHRMS calcd for C19H20NaO [M + Na]+ 287.1406;
found, 287.1409.
3-(2-(Biphenyl-4-yl)allyl)-3-methyl-2,3-dihydrobenzofuran (3af). Colorless oil (79
mg, 81% yield); Rf 0.62 (petroleum ether/EtOAc 100/1); 1H NMR (400 MHz, CDCl3)
δ 7.58 (d, J = 7.7 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.34 (dd,
J = 16.6, 7.9 Hz, 3H), 7.05 (dd, J = 17.2, 7.8 Hz, 2H), 6.79 (t, J = 7.4 Hz, 1H), 6.73 (d,
J = 7.9 Hz, 1H), 5.31 (s, 1H), 5.00 (s, 1H), 4.33 (d, J = 8.7 Hz, 1H), 3.91 (d, J = 8.7
13
Hz, 1H), 2.88 (q, J = 13.7 Hz, 2H), 1.24 (d, J = 10.9 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 159.2, 145.3, 141.4, 140.6, 140.1, 135.2, 128.7, 128.0, 127.3, 126.9, 126.9,
123.0, 120.3, 117.3, 109.6, 81.8, 45.8, 45.6, 25.4. IR (KBr, cmꢀ1): 3033, 2964, 1680,
1477, 1127, 747; ESIꢀHRMS calcd for C24H22NaO [M + Na]+ 349.1563; found,
349.1570.
3-(2-(4-Methoxyphenyl)allyl)-3-methyl-2,3-dihydrobenzofuran (3ag). Yellow oil
1
(72 mg, 86% yield); Rf 0.68 (petroleum ether/EtOAc 30/1); H NMR (400 MHz,
CDCl3) δ 7.24 (d, J = 7.7 Hz, 2H), 7.10 – 7.00 (m, 2H), 6.82 – 6.77 (m, 3H), 6.73 (d,
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J = 7.9 Hz, 1H), 5.19 (s, 1H), 4.91 (s, 1H), 4.28 (d, J = 8.7 Hz, 1H), 3.86 (d, J = 8.7
Hz, 1H), 3.79 (s, 3H), 2.87 – 2.74 (m, 2H), 1.22 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 159.2, 159.0, 145.1, 135.5, 135.0, 128.0, 127.6, 122.9, 120.3, 116.0, 113.6, 109.6,
81.8, 55.2, 45.8, 45.6, 25.3. IR (KBr, cmꢀ1): 3090, 2959, 1605, 1510, 1246, 749;
ESIꢀHRMS calcd for C19H20NaO2 [M + Na]+ 303.1356; found, 303.1361.
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4-(4-(3-(3-Methyl-2,3-dihydrobenzofuran-3-yl)prop-1-en-2-yl)phenyl)morpholine
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(3ah). Colorless oil (86 mg, 86% yield); Rf 0.69 (petroleum ether/EtOAc 30/1); H
NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.1 Hz, 2H), 7.06 (dd, J = 17.1, 7.8 Hz, 2H),
6.82 (dd, J = 12.7, 7.5 Hz, 3H), 6.73 (d, J = 7.9 Hz, 1H), 5.20 (s, 1H), 4.90 (s, 1H),
4.29 (d, J = 8.8 Hz, 1H), 3.89 – 3.82 (m, 5H), 3.20 – 3.13 (m, 4H), 2.82 (q, J = 13.7
Hz, 2H), 1.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 150.5, 145.1, 135.6,
133.9, 128.0, 127.3, 122.9, 120.3, 115.5, 115.2, 109.5, 81.8, 66.8, 49.1, 45.8, 45.4,
25.3. IR (KBr, cmꢀ1): 3084, 2931, 1603, 1248, 751; ESIꢀHRMS calcd for C22H26NO2
[M + H]+ 336.1958; found, 336.1962.
4-(3-(3-Methyl-2,3-dihydrobenzofuran-3-yl)prop-1-en-2-yl)benzonitrile
(3ai).
Colorless oil (64 mg, 78% yield); Rf 0.43 (petroleum ether/EtOAc 5/1); 1H NMR (400
MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.02 – 6.96 (m, 1H),
6.90 (d, J = 7.4 Hz, 1H), 6.70 (t, J = 7.4 Hz, 1H), 6.65 (t, J = 6.3 Hz, 1H), 5.30 (s, 1H),
5.12 (s, 1H), 4.31 (d, J = 8.8 Hz, 1H), 3.96 (d, J = 8.8 Hz, 1H), 2.83 (q, J = 13.8 Hz,
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2H), 1.28 (s, 3H); C NMR (100 MHz, CDCl3) δ 159.3, 147.0, 144.5, 133.9, 131.8,
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128.2, 127.0, 123.0, 120.3, 119.9, 118.8, 110.6, 109.6, 81.39, 45.74, 25.36. IR (KBr,
cmꢀ1): 3079, 2964, 1602, 1476, 751; ESIꢀHRMS calcd for C19H17NNaO [M + Na]+
298.1202; found, 298.1204.
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3-Methyl-3-(2-(4-nitrophenyl)allyl)-2,3-dihydrobenzofuran (3aj). Yellow oil (63
1
mg, 72% yield); Rf 0.52 (petroleum ether/EtOAc 3/1); H NMR (400 MHz, CDCl3) δ
8.05 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.99 (t, J = 7.7 Hz, 1H), 6.91 (d, J =
7.4 Hz, 1H), 6.69 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 5.16 (s,
1H), 4.34 (d, J = 8.8 Hz, 1H), 3.98 (d, J = 8.8 Hz, 1H), 2.86 (q, J = 13.8 Hz, 2H), 1.30
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 149.0, 146.8, 144.3, 133.8, 128.3,
127.1, 123.3, 123.0, 120.5, 120.3, 109.6, 81.4, 46.0, 45.8, 25.4. IR (KBr, cmꢀ1): 3071,
2969, 1596, 1401, 751; ESIꢀHRMS calcd for C18H17NNaO3 [M + Na]+ 318.1101;
found, 318.1106.
3-(2-(3-Methoxyphenyl)allyl)-3-methyl-2,3-dihydrobenzofuran (3ak). Colorless
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oil (67 mg, 80% yield); Rf 0.66 (petroleum ether/EtOAc 30/1); H NMR (400 MHz,
CDCl3) δ 7.19 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H),
6.90 (d, J = 7.5 Hz, 1H), 6.84 – 6.76 (m, 3H), 6.73 (d, J = 8.0 Hz, 1H), 5.25 (s, 1H),
4.98 (s, 1H), 4.29 (d, J = 8.8 Hz, 1H), 3.89 (d, J = 8.8 Hz, 1H), 3.80 (d, J = 7.2 Hz,
13
3H), 2.84 (q, J = 13.7 Hz, 2H), 1.23 (s, 3H); C NMR (100 MHz, CDCl3) δ 159.4,
159.2, 145.7, 144.1, 135.3, 129.2, 128.0, 123.0, 120.3, 119.1, 117.4, 112.6, 112.5,
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109.6, 81.7, 55.2, 45.8, 45.7, 25.3. IR (KBr, cmꢀ1): 3073, 2960, 1597, 1479, 751;
ESIꢀHRMS calcd for C19H20NaO2 [M + Na]+ 303.1356; found, 303.1358.
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N-(4-(3-(3-Methyl-2,3-dihydrobenzofuran-3-yl)prop-1-en-2-yl)phenyl)acetamide
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(3al). Colorless oil (81 mg, 88% yield); Rf 0.48 (petroleum ether/EtOAc 3/1); H
NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.1 Hz, 2H), 7.35 (s, 1H), 7.21 (t, J = 7.8 Hz,
1H), 7.11 – 6.95 (m, 3H), 6.79 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 5.25 (s,
1H), 4.98 (s, 1H), 4.29 (d, J = 8.7 Hz, 1H), 3.89 (d, J = 8.7 Hz, 1H), 2.89 – 2.76 (m,
13
2H), 2.16 (s, 3H), 1.24 (s, 3H); C NMR (100 MHz, CDCl3) δ 168.3, 159.2, 145.3,
143.4, 137.9, 135.2, 128.9, 128.0, 123.0, 122.5, 120.3, 118.8, 118.0, 117.8, 109.5,
81.7, 45.8, 45.6, 25.4, 24.6. IR (KBr, cmꢀ1): 3302, 3082, 2964, 1667, 1600, 1481, 748;
ESIꢀHRMS calcd for C20H22NO2 [M + H]+ 308.1645; found, 308.1649.
3-(2-(2-Methoxyphenyl)allyl)-3-methyl-2,3-dihydrobenzofuran (3am). Colorless
1
oil (71 mg, 85% yield); Rf 0.65 (petroleum ether/EtOAc 30/1); H NMR (400 MHz,
CDCl3) δ 7.20 (d, J = 7.9 Hz, 1H), 7.11 – 6.96 (m, 3H), 6.87 (t, J = 7.4 Hz, 1H), 6.78
(t, J = 7.4 Hz, 2H), 6.69 (d, J = 7.9 Hz, 1H), 5.10 (d, J = 4.1 Hz, 2H), 4.15 (d, J = 8.7
Hz, 1H), 3.82 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.06 (d, J = 13.7 Hz, 1H), 2.82 (d, J =
13.7 Hz, 1H), 1.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 156.3, 145.6, 135.8,
132.0, 130.1, 128.6, 127.8, 122.7, 120.7, 120.2, 119.0, 110.5, 109.4, 81.8, 55.2, 46.3,
45.6, 26.0. IR (KBr, cmꢀ1): 3072, 2960, 1597, 1479, 751; ESIꢀHRMS calcd for
C19H20NaO2 [M + Na]+ 303.1356; found, 303.1360.
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3-(2-(3,4-Dichlorophenyl)allyl)-3-methyl-2,3-dihydrobenzofuran (3an). Colorless
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oil (77 mg, 81% yield); Rf 0.60 (petroleum ether/EtOAc 100/1); H NMR (400 MHz,
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CDCl3) δ 7.32 – 7.25 (m, 2H), 7.04 (t, J = 8.4 Hz, 2H), 6.95 (d, J = 7.3 Hz, 1H), 6.75
(t, J = 7.4 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 5.24 (s, 1H), 5.03 (s, 1H), 4.32 (d, J = 8.8
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Hz, 1H), 3.96 (d, J = 8.8 Hz, 1H), 2.78 (q, J = 13.8 Hz, 2H), 1.27 (s, 3H); C NMR
(100 MHz, CDCl3) δ 159.3, 143.8, 142.4, 134.2, 132.2, 131.1, 130.0, 128.4, 128.2,
125.8, 123.0, 120.3, 118.7, 109.6, 81.5, 45.8, 45.8, 25.4. IR (KBr, cmꢀ1): 3086, 2926,
1598, 1400, 1200, 750; ESIꢀHRMS calcd for C18H16Cl2NaO [M + Na]+ 341.0470;
found, 341.0467.
5-(3-(3-Methyl-2,3-dihydrobenzofuran-3-yl)prop-1-en-2-yl)benzo[d][1,3]dioxole
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(3ao). Colorless oil (67 mg, 76% yield); Rf 0.65 (petroleum ether/EtOAc 20/1); H
NMR (400 MHz, CDCl3) δ 7.11 – 6.98 (m, 2H), 6.79 (dd, J = 15.8, 7.3 Hz, 3H), 6.72
(t, J = 8.0 Hz, 2H), 5.93 (s, 2H), 5.17 (s, 1H), 4.91 (s, 1H), 4.30 (d, J = 8.8 Hz, 1H),
3.89 (d, J = 8.8 Hz, 1H), 2.90 – 2.67 (m, 2H), 1.24 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.2, 147.5, 146.9, 145.3, 136.8, 135.3, 128.0, 122.9, 120.2, 120.0, 116.5,
109.6, 108.0, 107.2, 101.0, 81.7, 45.9, 45.8, 25.3. IR (KBr, cmꢀ1): 3090, 2850, 1650,
1490, 1250, 750; ESIꢀHRMS calcd for C19H18NaO3 [M + Na]+ 317.1148; found,
317.1156.
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3-(2-(Furan-2-yl)allyl)-3-methyl-2,3-dihydrobenzofuran (3ap). Yellow oil (49 mg,
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68% yield); Rf 0.53 (petroleum ether/EtOAc 50/1); H NMR (400 MHz, CDCl3) δ
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6.35 – 6.29 (m, 1H), 6.20 (d, J = 3.0 Hz, 1H), 5.60 (s, 1H), 4.83 (s, 1H), 4.47 (d, J =
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8.7 Hz, 1H), 4.05 (d, J = 8.7 Hz, 1H), 2.78 – 2.59 (m, 2H), 1.34 (s, 3H); C NMR
(100 MHz, CDCl3) δ 159.3, 155.1, 141.8, 135.2, 133.8, 128.1, 123.1, 120.4, 113.7,
111.2, 109.7, 106.6, 82.0, 45.7, 42.8, 24.7. IR (KBr, cmꢀ1): 3064, 2918, 1630, 1427,
1111, 717; ESIꢀHRMS calcd for C16H16NaO2 [M + Na]+ 263.1043; found, 263.1040.
3-Methyl-3-(2-(thiophen-2-yl)allyl)-2,3-dihydrobenzofuran (3aq). Yellow oil (63
mg, 83% yield); Rf 0.48 (petroleum ether/EtOAc 50/1); 1H NMR (400 MHz, CDCl3) δ
7.15 – 7.03 (m, 3H), 6.90 (d, J = 4.0 Hz, 2H), 6.84 – 6.73 (m, 2H), 5.45 (s, 1H), 4.84
(s, 1H), 4.44 (d, J = 8.8 Hz, 1H), 4.01 (d, J = 8.7 Hz, 1H), 2.85 – 2.73 (m, 2H), 1.32
(d, J = 9.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 146.2, 138.2, 135.1, 128.1,
127.3, 124.4, 123.9, 123.0, 120.3, 115.6, 109.7, 82.0, 45.9, 45.5, 24.9. IR (KBr, cmꢀ1):
3091, 2968, 2360, 1646, 1017, 747; ESIꢀHRMS calcd for C16H16NaOS [M + Na]+
279.0814; found, 279.0814.
3-Methyl-3-(2-(naphthalen-1-yl)allyl)-2,3-dihydrobenzofuran (3ar). Colorless oil
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(76 mg, 85% yield); Rf 0.52 (petroleum ether/EtOAc 100/1); H NMR (400 MHz,
CDCl3) δ 8.06 – 7.92 (m, 1H), 7.81 (dd, J = 6.1, 3.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H),
7.44 (dd, J = 6.3, 3.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.25 – 7.19 (m, 1H), 7.02 (t, J
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= 7.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 8.0 Hz,
1H), 5.35 (s, 1H), 5.23 (s, 1H), 4.09 (d, J = 8.8 Hz, 1H), 3.85 (d, J = 8.8 Hz, 1H), 3.04
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CDCl3) δ 159.1, 145.1, 141.1, 135.4, 133.8, 130.8, 128.4, 127.9, 127.5, 125.8, 125.6,
125.4, 125.2, 122.7, 120.2, 109.5, 81.3, 48.5, 45.9, 26.2. IR (KBr, cmꢀ1): 3092, 2964,
2863, 1640, 1054, 749; ESIꢀHRMS calcd for C22H20NaO [M + Na]+ 323.1406; found,
323.1412.
3-((3,4-Dihydronaphthalen-1-yl)methyl)-3-methyl-2,3-dihydrobenzofuran (3as).
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Colorless oil (69 mg, 84% yield); Rf 0.56 (petroleum ether/EtOAc 100/1); H NMR
(400 MHz, CDCl3) δ 7.20 (d, J = 7.7 Hz, 1H), 7.15 – 7.00 (m, 5H), 6.85 – 6.71 (m,
2H), 5.72 (t, J = 4.5 Hz, 1H), 4.47 (d, J = 8.7 Hz, 1H), 3.99 (d, J = 8.7 Hz, 1H), 2.83
(d, J = 14.0 Hz, 1H), 2.75 (s, 1H), 2.71 – 2.64 (m, 2H), 2.17 (dd, J = 12.4, 7.7 Hz, 2H),
1.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 136.5, 135.5, 135.4, 133.1, 129.4,
128.0, 127.5, 126.5, 126.1, 123.1, 123.0, 120.2, 109.6, 82.2, 46.1, 41.7, 28.6, 25.0,
23.2. IR (KBr, cmꢀ1): 3059, 2927, 1598, 1478, 925, 745; ESIꢀHRMS calcd for
C20H20NaO [M + Na]+ 299.1406; found, 299.1402.
4-((3-Methyl-2,3-dihydrobenzofuran-3-yl)methyl)-2H-chromene (3at). Colorless
1
oil (66 mg, 80% yield); Rf 0.61 (petroleum ether/EtOAc 50/1); H NMR (400 MHz,
CDCl3) δ 7.08 (dt, J = 13.2, 6.8 Hz, 4H), 6.81 (dt, J = 14.0, 5.2 Hz, 4H), 5.43 (t, J =
3.7 Hz, 1H), 4.65 (d, J = 3.7 Hz, 2H), 4.46 (d, J = 8.7 Hz, 1H), 4.06 (d, J = 8.7 Hz,
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1H), 2.76 (d, J = 14.1 Hz, 1H), 2.67 (d, J = 14.1 Hz, 1H), 1.35 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 159.3, 154.3, 135.0, 130.8, 128.8, 128.2, 124.4, 123.7, 123.2, 122.2,
121.0, 120.4, 116.2, 109.7, 82.1, 65.0, 45.9, 40.3, 24.8. IR (KBr, cmꢀ1): 3053, 2928,
1596, 1109, 743; ESIꢀHRMS calcd for C19H18NaO2 [M + Na]+ 301.1199; found,
301.1198.
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3-((1H-Inden-3-yl)methyl)-3-methyl-2,3-dihydrobenzofuran (3au). Colorless oil
1
(67 mg, 86% yield); Rf 0.57 (petroleum ether/EtOAc 100/1); H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 3.7 Hz, 2H), 7.18 (dd, J = 10.7, 6.6 Hz,
1H), 7.13 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 6.80
(d, J = 8.0 Hz, 1H), 6.08 (s, 1H), 4.55 (d, J = 8.7 Hz, 1H), 4.12 (d, J = 8.7 Hz, 1H),
3.32 (s, 2H), 2.97 – 2.80 (m, 2H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4,
146.0, 143.9, 140.3, 135.4, 131.7, 128.2, 126.0, 124.5, 123.6, 123.0, 120.4, 119.2,
109.7, 82.2, 45.9, 38.0, 37.5, 25.4. IR (KBr, cmꢀ1): 3058, 2925, 1599, 974, 750;
ESIꢀHRMS calcd for C19H18NaO [M + Na]+ 285.1250; found, 285.1254.
(E)-3-Methyl-3-(2-phenylbut-2-enyl)-2,3-dihydrobenzofuran (3av). Colorless oil
1
(69 mg, 88% yield); Rf 0.55 (petroleum ether/EtOAc 100/1); H NMR (400 MHz,
CDCl3) δ 7.29 – 7.18 (m, 5H), 7.13 – 7.01 (m, 2H), 6.81 (t, J = 7.4 Hz, 1H), 6.74 (d, J
= 8.0 Hz, 1H), 5.73 (q, J = 6.9 Hz, 1H), 4.16 (d, J = 8.7 Hz, 1H), 3.81 (d, J = 8.7 Hz,
1H), 2.95 (d, J = 13.8 Hz, 1H), 2.79 (d, J = 13.8 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H),
1.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 145.0, 138.0, 135.4, 128.2, 128.0,
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