Organocatalytic chemo- and regioselective oxyarylation of styrenes via a cascade reaction: Remote activation of hydroxyl groups

Article abstract of DOI:10.1021/jo500859b

The first organocatalytic oxyarylation of styrenes has been established through a cascade of vinylogous Michael addition/alkoxyl transfer reactions of o- or p-hydroxylstyrenes with quinone imine ketals. The process leads to a highly chemo- and regioselective oxyarylation of styrenes and provides access to m-alkylated anilines in generally high yields and excellent diastereoselectivity (up to 99% yield, >95:5 dr). An investigation of the reaction pathway revealed that the existence and position of the hydroxyl group of styrene played crucial roles in the cascade reaction, suggesting that the two reactants were simultaneously activated by binaphthyl-derived phosphoric acid via hydrogen bonding interactions and long-distance conjugative effects. In addition, the activating group of the hydroxyl functionality in the products can be easily removed or transformed, demonstrating the applicability and utility of this strategy in styrene oxyarylation and in the synthesis of styrene-based compounds.

Full text of DOI:10.1021/jo500859b

Article
pubs.acs.org/joc
Organocatalytic Chemo- and Regioselective Oxyarylation of Styrenes
via a Cascade Reaction: Remote Activation of Hydroxyl Groups
Yu-Chen Zhang, Fei Jiang, Shu-Liang Wang,* Feng Shi,* and Shu-Jiang Tu
School of Chemistry and Chemical Engineering and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou 221116, China
S
* Supporting Information
ABSTRACT: The first organocatalytic oxyarylation of styrenes has been
established through a cascade of vinylogous Michael addition/alkoxyl transfer
reactions of o- or p-hydroxylstyrenes with quinone imine ketals. The process
leads to a highly chemo- and regioselective oxyarylation of styrenes and
provides access to m-alkylated anilines in generally high yields and excellent
diastereoselectivity (up to 99% yield, >95:5 dr). An investigation of the
reaction pathway revealed that the existence and position of the hydroxyl
group of styrene played crucial roles in the cascade reaction, suggesting that
the two reactants were simultaneously activated by binaphthyl-derived
phosphoric acid via hydrogen bonding interactions and long-distance
conjugative effects. In addition, the activating group of the hydroxyl
functionality in the products can be easily removed or transformed,
demonstrating the applicability and utility of this strategy in styrene
oxyarylation and in the synthesis of styrene-based compounds.
photoredox-catalyzed coupling of styrenes with aryl groups
and alcohols under mild reaction conditions (eq 5). Despite
these elegant works, the oxyarylation of styrenes, especially
those exploiting organocatalysis, is still relatively under-
developed and therefore highly desirable considering the
importance of styrene functionalization and styrene-based
chemicals.
INTRODUCTION
■
Styrenes are a ubiquitous and fundamental chemical feedstock
in organic, medicinal, and materials chemistry, and their
functionalization is an important research field in both
academia and industry.1 In particular, the arylation of styrenes
has been investigated intensively over the past few decades,
resulting in well-developed procedures, including the Heck
reaction2 and metathesis3 (eq 1). However, in contrast, the
oxyarylation of styrenes has met with little success despite its
great potential in generating a C−C bond and a C−O bond as
well as a new stereocenter in a single transformation (eq 2).4
The tendency of styrenes to polymerize makes their oxy-
arylation particularly challenging.4b,5
Quinone imine ketals (QIKs)6−8 have been recognized as
electrophilic aryl group surrogates that react with various
nucleophiles (eq 6)6 and styrenes (eq 7).7 This recognition
suggested that QIK may be utilized as a latent functionalized
aromatic ring to realize the oxyarylation of styrenes. However,
Some recent breakthroughs have, however, been made in the
oxyarylation of styrenes. Studer et al.4a succeeded in a radical
oxyarylation of styrenes employing aryl diazonium salts as
radical precursors and TEMPONa as a reducing reagent (eq 3).
Lloyd-Jones, Russell, and co-workers4b realized the methoxyar-
ylation of styrenes using aryl silanes in the presence of a Au
catalyst using 2-iodosobenzoic acid (IBA) as a terminal oxidant
(eq 4). Very recently, Greaney et al.4c also reported a
Received: April 17, 2014
Published: June 6, 2014
© 2014 American Chemical Society
6143
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
pioneering work into this concept has revealed several
challenges in controlling the regioselectivity and chemo-
selectivity of QIK-involved reactions because of the existence
of multiple electrophilic sites (C1−C3) in the QIK. Thus,
facilitating the chemo- and regioselective oxyarylation of
styrenes via reactions with QIK remains challenging.
on the styrene double bond over a long distance. This
activating group could then be removed using well-established
procedures.11 This approach also provides easy access to m-
alkylated anilines, which cannot be obtained by simple Friedel−
Crafts reactions of anilines.12
We report herein the first organocatalytic oxyarylation of
styrenes through cascade reactions of o- or p-hydroxylstyrenes
with quinone imine ketals. In the presence of a BA, the two
substrates are simultaneously activated by hydrogen bonds over
a long distance, resulting in a highly chemo- and regioselective
domino sequence of vinylogous Michael addition and alkoxyl
transfer. This procedure is a powerful approach to the
oxyarylation of styrenes and m-alkylated anilines.
RESULTS AND DISCUSSION
■
Our study of the organocatalytic oxyarylation of styrenes
commenced with the reaction of quinone imine ketal (QIK) 1a
with o-hydroxylstyrene 2a catalyzed by 5 mol % Brønsted acid
(BA) 4 in toluene at 30 °C (Table 1). A preliminary screening
of catalysts 4 revealed that the acidity of the BA played an
important role in determining the overall reactivity (entries 1−
6). Specifically, BAs 4a and 4b, which are weakly acidic, could
not catalyze the desired reaction (entries 1 and 2, respectively),
while BAs 4c and 4d, which are stronger acids, promoted the
tandem reactions in moderate to good yields (entries 3 and 4,
respectively). Using the racemic binaphthyl-derived phosphoric
acid (BPA) 4e delivered the target product 3aa in a yield of
88% (entry 5). Exchanging racemic BPA 4e for chiral BPA 4f
led to the same yield, but no enantioselective induction was
observed (entry 6). Note that the BPA-catalyzed tandem
reaction proceeded in a highly chemo- and regioselective
manner, providing the sole product 3aa without other chemo-
or regioisomers. Because BPA 4e is much more easily
synthesized than BPA 4f, the subsequent solvent evaluation
was performed with catalyst 4e. This evaluation showed that
ethyl acetate (EtOAc), dichloromethane (DCM), and tetrahy-
drofuran (THF) were inferior to toluene in terms of reactivity
(entries 7−9, respectively, vs entry 5). Finally, increasing the
stoichiometric ratio of o-hydroxylstyrene 2a led to improve-
ments in yield (entries 10 and 11), and a mole ratio of 1:2
(1a:2a) delivered the model reaction in the highest yield of
99% (entry 10).
Considering these challenges, and the great demand for the
oxyarylation of styrenes, we designed a reaction for the
organocatalytic oxyarylation of styrenes employing QIK as an
aryl group precursor. Brønsted acids (BAs) are privileged
organocatalysts that allow a variety of transformations via the
activation of imino or carbonyl functionalities.9 Because QIK
contains an imine group, it could also be electrophilically
activated by such an acid.6a,7,8c−e Nevertheless, styrenes lacking
an activating group could not be motivated by a BA. Our
previous success in BA-catalyzed reactions showed that double
activation of both of the substrates greatly facilitates the
reaction.10 Therefore, we hypothesized that styrenes substituted
with an o- or p-hydroxyl group could be activated by BAs
through the formation of a hydrogen bond with the hydroxyl
group, which would then undergo a vinylogous Michael
addition to QIK (Scheme 1). Then, one alkoxyl group of
transient intermediate A would attack the enone functionality,
leading to the generation or restoration of two aromatic rings
and thus completing the oxyarylation of the styrene. In this
design, the hydroxyl group would impose a remote activation
Scheme 1. Design of an Organocatalytic Oxyarylation Reaction for Styrenes
6144
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
was evident in previous approaches (eqs 3 and 4).4a,b In some
cases, chiral BPA 4f was employed as a catalyst instead of
racemic BPA 4e to obtain higher yields (entries 4 and 6−11)
because the former showed a higher catalytic activity than the
latter. However, in most of these cases, the enantioselectivity
was poor, with the exception of product 3ga, which was
generated with a moderate enantioselectivity of 55% enantio-
meric excess (ee) (entry 7).
Table 1. Screening of Catalysts and Optimization of
Reaction Conditions
a
Next, the generality of the reaction for o-hydroxylstyrenes 2
was explored by reactions with QIK 1a under optimal
conditions. As shown in Table 3, this protocol was acceptable
over a wide range of o-hydroxylstyrenes 2 with various,
electronically distinct substituents linked to the phenyl ring.
The desired products of oxyarylation were generated in
generally high yields (57−99%, entries 1−7). Basically,
substrates 2a−h, which bear electron-neutral or -donating
groups on their aromatic rings, were beneficial to the desired
tandem reaction (entries 1−4). The exception was 2c, which
bears a bulky tert-butyl group (entry 3). Moreover, the
electronically poor o-hydroxylstyrenes 2e−g also served as
suitable substrates in the oxyarylation reactions with good
yields (60−74%, entries 5−7, respectively). Even α-methyl o-
hydroxylstyrene 2h was a suitable reaction partner and afforded
oxyarylation product 3ah with a quaternary stereocenter in a
considerable yield of 70% (entry 8). Notably, in the presence of
chiral BPA 4f, (E)-β-methyl o-hydroxylstyrene 2i, a type of
nonterminal olefin, was able to participate in the tandem
reaction and gave the desired product 3ai in an acceptable yield
of 52%, considerable enantioselectivity of 72% ee, and an
excellent diastereoselectivity of >95:5 dr (entry 9). These
examples, and in particular the reactions with disubstituted
olefins, greatly expanded the scope of our strategy but also
demonstrated the chemo-, regio-, and stereospecific nature of
this oxyarylation process.
b
entry
4
solvent
1a:2a
yield (%)
c
1
4a
4b
4c
4d
4e
4f
toluene
toluene
toluene
toluene
toluene
toluene
EtOAc
DCM
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:2
−
−
c
2
3
41
77
88
4
5
d
6
88 (<5% ee)
7
4e
4e
4e
4e
4e
69
74
50
99
95
8
9
THF
10
11
toluene
toluene
1:2.5
a
Unless indicated otherwise, the reaction was conducted at the 0.1
mmol scale in solvent (1 mL) at 30 °C for 12 h. Isolated yields. No
reaction occurred. The ee (enantiomeric excess) value was
b
c
d
determined by HPLC.
To obtain insight into the reaction pathway and the
activation mode of BPA 4e on the various substrates, several
control experiments were performed under optimized reaction
conditions (Scheme 2). First, o-methoxylstyrene 2j was
employed as a substrate instead of o-hydroxylstyrene 2a in a
reaction with QIK 1a (eq 8). No reaction (N.R.) occurred,
which indicates that the hydroxyl group plays a crucial role in
the as-designed cascade reaction. Second, m- and p-hydroxyl-
styrenes (2k and 2l, respectively) were used as reactants in the
same reaction. m-Hydroxylstyrene 2k gave only trace amounts
of product (eq 9), while p-hydroxylstyrene 2l generated the
target product 3aj in an excellent yield of 92% (eq 10). These
results suggest that the position of the hydroxyl group was
essential to the success of the reaction, and that hydrogen
bonding of the hydroxyl group with BPA was not enough to
guarantee the desired tandem reaction. The success of p-
hydroxylstyrene 2l in generating the desired product
demonstrates that the hydroxyl group remotely activates the
styrene double bond over a long distance via conjugative
effects. This hydrogen bond therefore facilitates the first step in
the vinylogous Michael addition to QIK. To verify the second
step of the tandem reaction (i.e., the transfer of an alkoxyl
group through an intramolecular rather than intermolecular
pathway), a control experiment was performed using two
different QIKs, 1a and 1k (1:1 mole ratio), to react with 2
equiv of o-hydroxylstyrene 2a (eq 11). As expected, two
corresponding products 3aa and 3ka were produced with no
crossover products, verifying the proposed intramolecular
alkoxyl transfer pathway.
With the optimal reaction conditions in hand, we
investigated the substrate scope of QIKs via tandem vinylogous
Michael addition and alkoxyl transfer reactions with o-
hydroxylstyrene 2a (Table 2). First, the effects of N-
substituents on QIK were studied by employing different
protecting groups, including Boc, Bz, Cbz, and Ac (entries 1−4,
respectively). Among them, N-Boc-protected QIK exhibited the
highest reactivity (entry 1), while N-Cbz-protected QIK (entry
2) yielded a higher reactivity than its N-Bz- and N-Ac-
substituted counterparts (entries 3 and 4, respectively). This
result indicated that the electronic nature of the protecting
group imposed a delicate effect on reactivity. Then, a series of
N-Boc QIKs, with either electronically poor or rich R1 groups,
were utilized in the reaction to generate the desired m-alkylated
anilines in generally high yields (entries 5−8). Thus, the
electronic nature of the R1 group seemed to impose some
influence on the reactivity because QIK substituted with an
electron-donating methyl group facilitated the cascade reaction
in a yield of 82%, which is higher than those obtained with
electron-withdrawing analogues (entry 8 vs entries 5−7). More
importantly, the two alkoxyl groups of the QIKs could be easily
changed from methoxyl (entry 1) to ethoxyl, isopropoxyl, or
butoxyl groups (entry 9, 10, or 11, respectively). Note that
linear alkoxyl groups were superior to branched ones with
regard to reactivity (entries 1, 9, and 11 vs entry 10). These
examples demonstrate the efficiency and applicability of this
strategy to the oxyarylation of styrenes. Furthermore, this
strategy solves the problem of unchangeable alkoxyl groups that
6145
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
a
Table 2. Substrate Scope of QIKs 1
a
Unless indicated otherwise, the reaction was conducted at the 0.1 mmol scale and catalyzed by racemic BPA 4e in toluene (1 mL) at 30 °C for 12 h.
b
c
d
The 1:2a mole ratio was 1:2. Isolated yields. Chiral BPA 4f was employed as the catalyst. The ee value was determined by HPLC.
In accordance with these control experiments, a possible
reaction mechanism was deduced. Scheme 3 uses p-
hydroxylstyrene 2l as an example to illustrate the remote
activation of the hydroxyl group on the styrene double bond via
hydrogen bonding and conjugative effects. BPA 4e acts as a
bifunctional catalyst to activate both p-hydroxylstyrene 2l and
QIK 1a at the same time through hydrogen bonding
interactions, thereby initiating a vinylogous Michael addition.
Subsequent hydrogen elimination and an intramolecular alkoxyl
transfer take place simultaneously under the catalysis of the
BPA anion, which acts as a base, resulting in the experimentally
observed chemo- and regioselective oxyarylation product 3al.
Preliminary derivations of oxyarylation product 3aa were
conducted to explore the potential of this methodology. As
shown in Scheme 4, the hydroxyl activating group in compound
3aa can be easily removed to create product 6 by Pd/C-
catalyzed deoxygenation11 of aryl triflate 5 in 82% yield, which
shows that our approach can be used to oxyarylate various
styrenes. In addition, triflate 5 of compound 3aa is available for
cross-coupling reactions as demonstrated by the formation of
product 7 in a high yield of 88%. This further exhibits the
synthetic utility of the hydroxyl group in compounds 3.
Furthermore, the bromination of compound 3aa regioselec-
tively occurred at the ortho position of the NHBoc group to
6146
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
a
Table 3. Substrate Scope of o-Hydroxylstyrenes 2
a
Unless indicated otherwise, the reaction was conducted at the 0.1 mmol scale and was catalyzed by racemic BPA 4e in toluene (1 mL) at 30 °C for
b
c
d
e
12 h. The 1a:2 mole ratio was 1:2. Isolated yields. Chiral BPA 4f was employed as a catalyst. The ee value was determined by HPLC. The dr was
determined by H NMR.
1
afford product 8, albeit in a moderate yield of 58%.
Nevertheless, this transformation not only provides an
alternative approach to synthesizing this type of compound,
as opposed to using 2-substituted QIKs, but also offers
opportunities for further derivations based on the aryl halide.
organocatalysis and cascade reactions to generate a C−C bond
and a C−O bond as well as a new stereocenter in a single
transformation. Furthermore, the reaction tolerates a wide
range of substrates and provides the target products in generally
high yields and excellent diastereoselectivity (up to 99% yield,
>95:5 dr). The hydroxyl functionality as a remote activating
group can be easily removed to perform further trans-
formations, which demonstrates the applicability and utility of
this strategy in styrene oxyarylation and the synthesis of
styrene-based compounds.
CONCLUSIONS
■
We have demonstrated the first organocatalytic oxyarylation of
styrenes via a cascade of vinylogous Michael addition and
alkoxyl transfer reactions of o- or p-hydroxylstyrenes with
quinone imine ketals. In the presence of a binaphthyl-derived
phosphoric acid, the two types of substrates were simulta-
neously activated via hydrogen bonds and conjugative effects
over a long distance, ultimately resulting in the highly chemo-
and regioselective oxyarylation of styrenes and providing access
to m-alkylated anilines. This approach combines the merits of
EXPERIMENTAL SECTION
■
General Information. NMR spectra were measured at 400 and
100 MHz. The solvent used for NMR spectroscopy was CDCl3, using
tetramethylsilane as the internal reference. HRMS spectra were
recorded on a LTQ-Orbitrap mass spectrometer (ionization mode,
6147
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
Scheme 2. Control Experiments for Exploring the Reaction Pathway
ESI+). Enantiomeric excesses (ee) were determined by chiral high-
performance liquid chromatography (chiral HPLC). The chiral
columns used for the determination of the enantiomeric excess by
chiral HPLC were Chiralpak IC and AD-H columns. Analytical grade
solvents for the column chromatography and commercially available
reagents were used as received. Toluene was dried and distilled prior
to use. Substrates 1 and 2 were synthesized according to the literature
methods.8e,13
Scheme 3. Proposed Reaction Pathway and Activation Mode
General Procedure for the Synthesis of Oxyarylation
Product 3 via Cascade Reactions. After catalyst 4e or 4f (0.005
mmol) had been weighed to a reaction tube, the solution of
hydroxylstyrenes 2 (0.2 mmol) in toluene (0.5 mL) was added to
the tube and stirred. Then, the solution of quinone imine ketals 1 (0.1
mmol) in toluene (0.5 mL) was added to the stirred mixture and the
new mixture stirred at 30 °C for 12 h. After the reaction had been
stopped, the reaction mixture was directly purified via flash column
Scheme 4. Derivations of Oxyarylation Product 3aa
6148
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
chromatography on silica gel (flushed by a 10% Et3N/petrol ether
mixture in advance) to afford pure products 3.
tert-Butyl {3-[2-(2-hydroxyphenyl)-2-methoxyethyl]-5-iodo-4-
methoxyphenyl}carbamate (3fa): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
10:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 55%
(27.7 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H),
7.85 (s, 1H), 7.26−7.15 (m, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.94−6.90
(m, 1H), 6.89−6.86 (m, 1H), 6.85−6.79 (m, 1H), 6.36 (s, 1H), 4.66−
4.53 (m, 1H), 3.75 (s, 3H), 3.35 (s, 3H), 3.30−3.16 (m, 1H), 3.05−
2.89 (m, 1H), 1.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.3,
153.9, 152.5, 135.3, 132.2, 129.2, 128.4, 124.4, 119.8, 116.9, 91.6, 85.3,
61.1, 57.6, 37.9, 28.3; IR (KBr) 3650, 3294, 2928, 2337, 1828, 1700,
1491, 1427, 1368, 1115, 731 cm−1; ESI FTMS exact mass calcd for
(C21H26INO5 + Na)+ requires m/z 522.0753, found m/z 522.0739; ee,
<5%, determined by HPLC (Daicel Chirapak AD-H, 92:8 hexane/2-
propanol, flow rate of 1.0 mL/min, 30 °C, 254 nm); tR = 8.553 min, tR
= 10.797 min.
tert-Butyl {5-[2-(2-hydroxyphenyl)-2-methoxyethyl]-6-methoxy-
[1,1′-biphenyl]-3-yl}carbamate (3ga): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
10:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 72%
(32.3 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H),
7.65−7.50 (m, 2H), 7.51−7.40 (m, 2H), 7.39−7.30 (m, 2H), 7.25−
7.18 (m, 1H), 7.07 (s, 1H), 6.99−6.89 (m, 2H), 6.87−6.78 (m, 1H),
6.45 (s, 1H), 4.79−4.60 (m, 1H), 3.41 (s, 3H), 3.32−3.23 (m, 4H),
3.13−2.91 (m, 1H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.4, 152.9, 151.8, 138.5, 135.1, 133.8, 131.9, 129.0, 128.9, 128.4,
128.2, 127.2, 124.7, 119.7, 116.8, 85.7, 60.4, 57.6, 37.2, 28.3; IR (KBr)
3730, 3294, 2977, 2932, 2361, 1700, 1538, 1376, 1239, 1158, 1080,
755, 698 cm−1; ESI FTMS exact mass calcd for (C27H31NO5 + Na)+
requires m/z 472.2095, found m/z 472.2108; ee, 55%, determined by
HPLC (Daicel Chirapak AD-H, 92:8 hexane/2-propanol, flow rate of
1.0 mL/min, 30 °C, 254 nm); tR = 9.670 min (major), tR = 10.937 min
(minor).
tert-Butyl {3-[2-(2-hydroxyphenyl)-2-methoxyethyl]-4-methoxy-
5-methylphenyl}carbamate (3ha): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
10:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 82%
(31.6 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H),
7.25−7.17 (m, 2H), 6.99−6.76 (m, 4H), 6.33 (s, 1H), 4.72−4.51 (m,
1H), 3.66 (s, 3H), 3.36 (s, 3H), 3.25−3.12 (m, 1H), 3.02−2.90 (m,
1H), 2.30 (s, 3H), 1.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.3, 152.9, 152.8, 133.7, 131.4, 131.2, 129.0, 128.4, 124.8, 119.7,
116.8, 85.8, 60.4, 57.6, 37.0, 28.4, 16.4; IR (KBr) 3731, 3674, 3313,
2977, 2943, 2361, 1700, 1539, 1239, 1153, 1085, 753 cm−1; ESI FTMS
exact mass calcd for (C22H29NO5 + Na)+ requires m/z 410.1922,
found m/z 410.1926; ee, <5%, determined by HPLC (Daicel Chirapak
AD-H, 92:8 hexane/2-propanol, flow rate of 1.0 mL/min, 30 °C, 254
nm); tR = 8.873 min, tR = 11.613 min.
tert-Butyl {4-ethoxy-3-[2-ethoxy-2-(2-hydroxyphenyl)ethyl]-
phenyl}carbamate (3ia): flash column chromatography eluent
(flushed with a 10% Et3N/petrol ether mixture in advance), 8:1
petroleum ether/ethyl acetate; reaction time, 12 h; yield, 62% (24.8
mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.26 (s,
1H), 7.24−7.07 (m, 1H), 6.97−6.85 (m, 2H), 6.78−6.70 (m, 3H),
6.29 (s, 1H), 4.85−4.50 (m, 1H), 4.04−3.79 (m, 2H), 3.66−3.49 (m,
1H), 3.50−3.35 (m, 1H), 3.25−3.07 (m, 1H), 3.06−2.96 (m, 1H),
1.51 (s, 9H), 1.40 (t, J = 6.9 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 155.5, 153.1, 130.7, 128.7, 128.2, 126.9,
119.3, 116.6, 111.5, 83.3, 65.5, 63.8, 37.3, 28.4, 15.0, 14.9; IR (KBr)
3612, 3338, 2976, 2928, 2360, 1698, 1507, 1236, 1161, 1069, 754
cm−1; ESI FTMS exact mass calcd for (C23H31NO5 + Na)+ requires
m/z 424.2094, found m/z 424.2088; ee, 16%, determined by HPLC
(Daicel Chirapak AD-H, 92:8 hexane/2-propanol, flow rate of 1.0 mL/
min, 30 °C, 254 nm); tR = 7.893 min (minor), tR = 11.473 min
(major).
tert-Butyl {3-[2-(2-hydroxyphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (3aa): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
10:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 99%
(37.0 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H),
7.29 (s, 1H), 7.20−7.10 (m, 1H), 7.00−6.83 (m, 2H), 6.80−6.69 (m,
3H), 6.29 (s, 1H), 4.64−4.43 (m, 1H), 3.73 (s, 3H), 3.34 (s, 3H),
3.15−3.08 (m, 1H), 3.04−2.97 (m, 1H), 1.50 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 155.4, 153.7, 131.0, 128.9, 128.4, 126.6, 124.7, 119.4,
116.6, 110.6, 85.0, 57.5, 55.6, 37.0, 28.3; IR (KBr) 3648, 3110, 2930,
2337, 1700, 1507, 1238, 1161, 756 cm−1; ESI FTMS exact mass calcd
for (C21H27NO5 + Na)+ requires m/z 396.1781, found m/z 396.1789.
N-{3-[2-(2-Hydroxyphenyl)-2-methoxyethyl]-4-methoxyphenyl}-
benzamide (3ba): flash column chromatography eluent (flushed with
a 10% Et3N/petrol ether mixture in advance), 10:1 petroleum ether/
ethyl acetate; reaction time, 12 h; yield, 52% (19.6 mg); yellow oil; 1H
NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H),
7.81 (s, 1H), 7.69−7.63 (m, 1H), 7.59−7.53 (m, 1H), 7.49 (t, J = 7.4
Hz, 2H), 7.23−7.14 (m, 2H), 6.94−6.88 (m, 1H), 6.88−6.74 (m, 3H),
4.65−4.54 (m, 1H), 3.79 (s, 3H), 3.37 (s, 3H), 3.24−3.13 (m, 1H),
3.12−3.00 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.4, 154.7,
135.0, 131.6, 130.6, 128.9, 128.7, 128.4, 127.0, 126.7, 124.7, 123.8,
120.2, 119.5, 116.6, 110.6, 84.9, 57.5, 55.6, 36.9; IR (KBr) 3649, 3614,
3291, 2930, 2361, 1651, 1504, 1234, 1080, 704 cm−1; ESI FTMS exact
mass calcd for (C23H23NO4 + Na)+ requires m/z 400.1519, found m/z
400.1510.
Benzyl {3-[2-(2-hydroxyphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (3ca): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
2:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 64%
(26.0 mg); red oil; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.59−
7.28 (m, 6H), 7.22−7.10 (m, 1H), 7.01−6.84 (m, 2H), 6.82−6.69 (m,
3H), 6.54 (s, 1H), 5.19 (s, 2H), 4.71−4.41 (m, 1H), 3.74 (s, 3H), 3.34
(s, 3H), 3.23−3.09 (m, 1H), 3.08−2.94 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 155.4, 136.2, 128.9, 128.6, 128.4, 128.3, 128.2, 126.7,
124.6, 119.4, 116.6, 110.6, 85.0, 57.5, 55.6, 36.9; IR (KBr) 3303, 2933,
2832, 2357, 1707, 1504, 1225, 1808, 753 cm−1; ESI FTMS exact mass
calcd for (C24H25NO5 + Na)+ requires m/z 430.1625, found m/z
430.1628.
N-{3-[2-(2-Hydroxyphenyl)-2-methoxyethyl]-4-methoxyphenyl}-
acetamide (3da): flash column chromatography eluent (flushed with a
10% Et3N/petrol ether mixture in advance), 2:1 petroleum ether/ethyl
acetate; reaction time, 12 h; yield, 46% (14.5 mg); yellow oil; 1H NMR
(400 MHz, CDCl3) δ 8.03 (s, 1H), 7.79−7.60 (m, 1H), 7.52−7.45 (m,
2H), 7.23 (s, 1H), 6.98 (d, J = 2.6 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H),
6.81−6.75 (m, 2H), 4.62−4.47 (m, 1H), 3.74 (s, 3H), 3.33 (s, 3H),
3.18−3.08 (m, 1H), 3.04−2.95 (m, 1H), 2.12 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 168.2, 155.3, 154.5, 132.0, 128.9, 128.4, 126.6, 123.6,
120.1, 119.4, 116.6, 110.5, 84.9, 57.5, 55.6, 36.9, 24.3; IR (KBr) 3671,
3641, 3271, 3270, 2926, 2360, 1740, 1504, 1381, 1233, 1085, 755
cm−1; ESI FTMS exact mass calcd for (C18H21NO4 + Na)+ requires
m/z 338.1363, found m/z 338.1364; ee, <5%, determined by HPLC
(Daicel Chirapak AD-H, 95:5 hexane/2-propanol, flow rate of 1.0 mL/
min, 30 °C, 254 nm); tR = 42.327 min, tR = 47.277 min.
tert-Butyl {3-chloro-5-[2-(2-hydroxyphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (3ea): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
10:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 69%
1
(28.0 mg); yellow oil; H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H),
7.49 (s, 1H), 7.22−7.14 (m, 1H), 6.96−6.72 (m, 4H), 6.40 (s, 1H),
4.57−4.48 (m, 1H), 3.75 (s, 3H), 3.33 (s, 3H), 3.22−3.13 (m, 1H),
3.00−2.91 (m, 1H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.3, 152.5, 150.0, 134.5, 133.1, 129.2, 128.4, 127.9, 124.3, 119.8,
116.9, 85.4, 60.8, 57.6, 37.2, 28.3; IR (KBr) 3474, 3413, 2978, 2934,
2362, 1701, 1526, 1483, 1240, 1159, 1085, 756 cm−1; ESI FTMS exact
mass calcd for (C21H26ClNO5 + Na)+ requires m/z 430.1392, found
m/z 430.1416.
tert-Butyl {3-[2-(2-hydroxyphenyl)-2-isopropoxyethyl]-4-
isopropoxyphenyl}carbamate (3ja): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance), 8:1
petroleum ether/ethyl acetate; reaction time, 12 h; yield, 42% (18.0
mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.33 (s,
6149
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
1H), 7.19−7.08 (m, 1H), 6.92−6.84 (m, 1H), 6.84−6.70 (m, 4H),
6.23 (s, 1H), 4.85−4.68 (m, 1H), 4.60−4.47 (m, 1H), 3.70−3.54 (m,
1H), 3.14−2.98 (m, 1H), 2.99−2.87 (m, 1H), 1.50 (s, 9H), 1.40−1.30
(m, 6H), 1.11 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.6, 153.2, 130.7, 128.7, 128.2, 126.9, 125.4,
119.2, 116.7, 83.6, 69.9, 67.8, 31.5, 28.3, 19.4, 19.1; IR (KBr) 3649,
3332, 2961, 2932, 2361, 1724, 1507, 1389, 1238, 1163, 1078, 755
cm−1; ESI FTMS exact mass calcd for (C25H35NO5 + Na)+ requires
m/z 452.2407, found m/z 452.2381; ee, <5%, determined by HPLC
(Daicel Chirapak AD-H, 92:8 hexane/2-propanol, flow rate of 1.0 mL/
min, 30 °C, 254 nm); tR = 5.890 min, tR = 7.073 min.
tert-Butyl {4-butoxy-3-[2-butoxy-2-(2-hydroxyphenyl)ethyl]-
phenyl}carbamate (3ka): flash column chromatography eluent
(flushed with a 10% Et3N/petrol ether mixture in advance), 8:1
petroleum ether/ethyl acetate; reaction time, 12 h; yield, 75% (34.5
mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.28 (s,
1H), 7.20−7.11 (m, 1H), 6.96−6.83 (m, 2H), 6.81−6.67 (m, 3H),
6.25 (s, 1H), 4.68−4.53 (m, 1H), 3.97−3.85 (m, 2H), 3.59−3.45 (m,
1H), 3.39−3.28 (m, 1H), 3.23−3.07 (m, 1H), 3.04−2.94 (m, 1H),
1.89−1.73 (m, 2H), 1.63−1.53 (m, 2H), 1.50 (s, 9H), 1.49−1.45 (m,
2H), 1.30−1.23 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 155.8, 151.8, 130.5, 128.6,
127.9, 127.9, 126.2, 119.2, 116.8, 113.0, 80.6, 71.3, 70.0, 38.3, 28.3,
22.6, 22.2, 21.1; IR (KBr) 3742, 3614, 3310, 2959, 2930, 2361, 1701,
1508, 1390, 1238, 1163, 754 cm−1; ESI FTMS exact mass calcd for
(C27H39NO5 + Na)+ requires m/z 480.2720, found m/z 480.2720; ee,
14%, determined by HPLC (Daicel Chirapak AD-H, 98:2 hexane/2-
propanol, flow rate of 1.0 mL/min, 30 °C, 254 nm); tR = 15.983 min
(minor), tR = 17.460 min (major).
tert-Butyl {3-[2-(2-hydroxy-5-methylphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (3ab): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
8:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 85%
(32.9 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H),
7.31 (s, 1H), 7.02−6.92 (m, 2H), 6.84−6.74 (m, 2H), 6.65 (d, J = 1.7
Hz, 1H), 6.37 (s, 1H), 4.56−4.44 (m, 1H), 3.78 (s, 3H), 3.34 (s, 3H),
3.17−3.07 (m, 1H), 3.05−2.97 (m, 1H), 2.22 (s, 3H), 1.53 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 153.7, 153.0, 131.0, 129.4, 128.8,
128.6, 126.9, 124.6, 116.4, 110.6, 85.0, 57.5, 55.7, 37.2, 28.4, 20.4; IR
(KBr) 3705, 3647, 3443, 2360, 2336, 1698, 1507, 1389, 1237, 1162,
815 cm−1; ESI FTMS exact mass calcd for (C22H29NO5 + Na)+
requires m/z 410.1938, found m/z 410.1917.
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
8:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 60%
(23.6 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H),
7.26 (s, 1H), 6.97 (s, 1H), 6.88−6.72 (m, 3H), 6.52 (dd, J = 8.7, 2.8
Hz, 1H), 6.32 (s, 1H), 4.50−4.44 (m, 1H), 3.74 (s, 3H), 3.33 (s, 3H),
3.12−3.04 (m, 1H), 3.04−2.96 (m, 1H), 1.50 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 157.3, 155.0, 153.6, 151.3, 151.2, 131.1, 126.3, 117.5,
117.40, 115.2, 115.0, 114.6, 114.4, 110.6, 84.4, 57.7, 55.6, 36.9, 28.4; IR
(KBr) 3650, 3306, 2929, 2361, 1700, 1512, 1236, 1162, 1082, 814, 771
cm−1; ESI FTMS exact mass calcd for (C21H26FNO5 + Na)+ requires
m/z 414.1687, found m/z 414.1649.
tert-Butyl {3-[2-(5-chloro-2-hydroxyphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (3af): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
8:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 60%
(24.3 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H),
7.24 (s, 1H), 7.11 (dd, J = 8.6, 2.6 Hz, 1H), 7.00 (s, 1H), 6.85−6.70
(m, 3H), 6.32 (s, 1H), 4.49−4.43 (m, 1H), 3.73 (s, 3H), 3.32 (s, 3H),
3.10−3.03 (m, 1H), 3.03−2.96 (m, 1H), 1.51 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 154.0, 153.6, 131.0, 128.7, 127.9, 126.5, 126.2, 124.1,
118.0, 110.6, 84.5, 57.7, 55.6, 37.1, 28.4; IR (KBr) 3648, 3618, 3331,
2930, 1261, 1699, 1512, 1390, 1235, 1161 cm−1; ESI FTMS exact mass
calcd for (C21H26ClNO5 + Na)+ requires m/z 430.1392, found m/z
430.1393.
tert-Butyl {3-[2-(5-bromo-2-hydroxyphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (3ag): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
8:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 74%
(33.6 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H),
7.25 (dd, J = 8.8, 2.6 Hz, 2H), 7.00 (s, 1H), 6.91 (d, J = 2.4 Hz, 1H),
6.85−6.65 (m, 2H), 6.31 (s, 1H), 4.49−4.41 (m, 1H), 3.73 (s, 3H),
3.32 (s, 3H), 3.09−3.03 (m, 1H), 3.03−2.98 (m, 1H), 1.51 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 154.6, 153.6, 131.6, 131.0, 130.8,
127.1, 126.2, 118.6, 111.4, 110.6, 84.4, 57.7, 55.6, 37.1, 28.4; IR (KBr)
3731, 3649, 3298, 2929, 2361, 1700, 1508, 1238, 1161, 815, 761 cm−1;
ESI FTMS exact mass calcd for (C21H26BrNO5 + Na)+ requires m/z
474.0886, found m/z 474.0892; ee, 13%, determined by HPLC (Daicel
Chirapak AD-H, 92:8 hexane/2-propanol, flow rate of 1.0 mL/min, 30
°C, 254 nm); tR = 11.920 min (minor), tR = 21.507 min (major).
tert-Butyl {3-[2-(2-hydroxyphenyl)-2-methoxypropyl]-4-
methoxyphenyl}carbamate (3ah): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
8:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 70%
tert-Butyl (3-{2-[5-(tert-butyl)-2-hydroxyphenyl]-2-methoxyeth-
yl}-4-methoxyphenyl)carbamate (3ac): flash column chromatogra-
phy eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
3:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 57%
1
(27.1 mg); yellow oil; H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H),
7.33 (s, 1H), 7.23−7.13 (m, 1H), 6.92−6.87 (m, 1H), 6.86−6.81 (m,
1H), 6.79−6.66 (m, 3H), 6.40 (s, 1H), 3.61 (s, 3H), 3.20 (d, J = 10.3
Hz, 4H), 3.10 (d, J = 13.3 Hz, 1H), 1.53 (s, 3H), 1.50 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 156.1, 154.2, 130.7, 129.2, 127.9, 127.4,
125.6, 119.2, 116.6, 110.6, 83.4, 55.5, 50.7, 39.7, 28.4, 20.6; IR (KBr)
3552, 3413, 2979, 1714, 1616, 1505, 1367, 1243, 1161, 622 cm−1; ESI
FTMS exact mass calcd for (C22H29NO5 + Na)+ requires m/z
410.1938, found m/z 410.1931.
1
(24.3 mg); yellow oil; H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H),
7.28 (s, 1H), 7.23−7.11 (m, 1H), 6.87−6.73 (m, 3H), 6.59 (d, J = 2.4
Hz, 1H), 6.26 (s, 1H), 4.51 (t, J = 7.1 Hz, 1H), 3.74 (s, 3H), 3.42 (s,
3H), 3.29−3.16 (m, 1H), 3.02−2.86 (m, 1H), 1.52 (s, 9H), 1.17 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 153.7, 152.9, 141.8, 131.0,
126.6, 125.6, 125.4, 123.5, 115.9, 110.6, 85.6, 57.5, 55.7, 36.9, 33.8,
31.6, 31.4, 28.4; IR (KBr) 3673, 3649, 3297, 2960, 2361, 1701, 1505,
1234, 1162, 821, 733 cm−1; ESI FTMS exact mass calcd for
(C25H35NO5 + Na)+ requires m/z 452.2407, found m/z 452.2395.
tert-Butyl {3-[2-(2-hydroxy-5-methoxyphenyl)-2-methoxyethyl]-
4-methoxyphenyl}carbamate (3ad): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance), 3:1
petroleum ether/ethyl acetate; reaction time, 12 h; yield, 70% (26.9
mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.28 (s,
1H), 6.94 (s, 1H), 6.89−6.64 (m, 3H), 6.36 (d, J = 3.0 Hz, 1H), 6.33
(s, 1H), 4.50−4.40 (m, 1H), 3.74 (s, 3H), 3.66 (s, 3H), 3.32 (s, 3H),
3.16−3.05 (m, 1H), 3.05−2.92 (m, 1H), 1.50 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 153.7, 152.6, 149.1, 131.0, 126.7, 125.5, 117.1, 114.1,
113.6, 110.6, 84.7, 57.5, 55.7, 55.7, 37.0, 28.3; IR (KBr) 3647, 3612,
3341, 2976, 2934, 2360, 1699, 1457, 1235, 1034, 811, 731 cm−1; ESI
FTMS exact mass calcd for (C22H29NO6 + Na)+ requires m/z
426.1887, found m/z 426.1889.
tert-Butyl {3-[1-(2-hydroxyphenyl)-1-methoxypropan-2-yl]-4-
methoxyphenyl}carbamate (3ai): flash column chromatography
eluent (flushed with a 10% Et3N/petrol ether mixture in advance),
8:1 petroleum ether/ethyl acetate; reaction time, 12 h; yield, 52%
1
(20.1 mg); yellow oil; H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H),
7.26 (s, 1H), 7.23−7.15 (m, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.91−6.83
(m, 2H), 6.80 (t, J = 7.6 Hz, 2H), 6.36 (s, 1H), 4.42 (d, J = 8.7 Hz,
1H), 3.76 (s, 3H), 3.73−3.65 (m, 1H), 3.27 (s, 3H), 1.51 (s, 9H), 1.05
(d, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 155.7, 153.7,
132.5, 131.3, 130.1, 129.0, 123.3, 119.1, 116.8, 111.2, 89.3, 57.6, 55.9,
28.4, 17.1; IR (KBr) 3611, 2975, 2933, 2360, 1698, 1505, 1368, 1241,
1161, 1066, 810, 756 cm−1; ESI FTMS exact mass calcd for
(C22H29NO5 + Na)+ requires m/z 410.1938, found m/z 410.1918;
ee, 72%, determined by HPLC (Daicel Chirapak IC, 95:5 hexane/2-
propanol, flow rate of 1.0 mL/min, 30 °C, 254 nm); tR = 10.010 min
(major), tR = 11.637 min (minor).
tert-Butyl {3-[2-(5-fluoro-2-hydroxyphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (3ae): flash column chromatography
tert-Butyl {3-[2-(4-hydroxyphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (3al): flash column chromatography
6150
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
eluent (flushed with a 10% Et3N/petrol ether mixture in advance), 8:1
petroleum ether/ethyl acetate; reaction time, 12 h; yield, 92% (34.2
mg); red oil; 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.20−7.04
(m, 2H), 6.88 (d, J = 1.9 Hz, 1H), 6.83−6.67 (m, 3H), 6.37 (s, 1H),
6.20 (s, 1H), 4.43−4.29 (m, 1H), 3.74 (s, 3H), 3.18 (s, 3H), 3.11−
2.99 (m, 1H), 2.95−2.80 (m, 1H), 1.52 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 155.5, 153.9, 133.4, 130.7, 128.9, 128.0, 127.9, 127.5, 115.6,
115.1, 110.7, 83.0, 56.5, 55.7, 50.7, 38.9, 28.4; IR (KBr) 3741, 3648,
3306, 2976, 2361, 1698, 1512, 1367, 1241, 1161, 811, 729 cm−1; ESI
FTMS exact mass calcd for (C21H27NO5 + Na)+ requires m/z
396.1781, found m/z 396.1781.
(Al2O3), 4:1 petroleum ether/ethyl acetate; reaction time, 4 h; yield,
88% (20.2 mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.74−7.59
(m, 1H), 7.56−7.37 (m, 1H), 7.37−7.23 (m, 4H), 7.15−7.00 (m, 1H),
6.87 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.19 (s, 1H), 4.52 (t,
J = 6.8 Hz, 1H), 3.49 (s, 3H), 3.10 (s, 3H), 3.06−2.95 (m, 1H), 2.92−
2.73 (m, 1H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.8,
141.0, 139.6, 139.4, 132.7, 130.8, 129.3, 128.1, 127.9, 127.0, 126.6,
126.5, 110.4, 78.2, 56.3, 55.2, 38.8, 29.7, 28.4; IR (KBr) 3672, 3648,
3362, 2925, 2857, 2361, 2337, 1720, 1538, 1508, 1233, 1164, 835, 766
cm−1; ESI FTMS exact mass calcd for (C27H30ClNO4 − H)− requires
m/z 466.1779, found m/z 466.1780.
Procedure for the Synthesis of Compound 8. CCl4 (1 mL)
was added to the mixture of compound 3aa (18.7 mg, 0.05 mmol) and
NBS (9.8 mg, 0.055 mmol). After the mixture had been stirred at
room temperature overnight and the completion of the reaction
indicated by TLC, the reaction mixture was concentrated under
reduced pressure to give the residue, which was purified through flash
column chromatography on silica gel (flushed with a 10% Et3N/petrol
ether mixture in advance) to afford pure product 8 (13.0 mg, 58%
yield).
Procedure for the Synthesis of Compound 5. To the solution
of compound 3aa (374 mg, 1 mmol) in dichloromethane (10 mL) was
added pyridine (237 mg, 3 mmol). Then, the solution of Tf2O (423
mg, 1.5 mmol) in dichloromethane (5 mL) was added dropwise to the
reaction mixture at 0 °C, which was stirred overnight at room
temperature. After the completion of the reaction indicated by TLC,
water (5 mL) was added to the reaction mixture, which was further
extracted by dichloromethane and dried by anhydrous Na2SO4. The
resultant organic layer was concentrated under the reduced pressure to
give the residue, which was purified through flash column
chromatography on silica gel (flushed with a 10% Et3N/petrol ether
mixture in advance) to afford pure products 5 (384 mg, 76% yield).
2-(2-{5-[(tert-Butoxycarbonyl)amino]-2-methoxyphenyl}-1-
methoxyethyl)phenyl trifluoromethanesulfonate (5): flash column
chromatography eluent (flushed with a 10% Et3N/petrol ether mixture
in advance), 12:1 petroleum ether/ethyl acetate; reaction time, 12 h;
tert-Butyl {2-bromo-5-[2-(2-hydroxyphenyl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (8): flash column chromatography eluent
(flushed with a 10% Et3N/petrol ether mixture in advance), 8:1
petroleum ether/ethyl acetate; reaction time, 12 h; yield, 58% (13.0
1
mg); colorless oil; H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.40
(d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 6.92 (s, 1H), 6.80−6.69 (m, 2H),
6.68−6.52 (m, 1H), 6.28 (s, 1H), 4.56 (t, J = 7.0 Hz, 1H), 3.70 (d, J =
1.2 Hz, 3H), 3.34 (d, J = 1.5 Hz, 3H), 3.19−3.06 (m, 1H), 3.05−2.92
(m, 1H), 1.51 (d, J = 1.4 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ
149.0, 147.0, 127.4, 126.2, 122.8, 121.8, 121.5, 115.7, 105.9, 105.8,
79.6, 52.9, 50.8, 32.0, 23.6; IR (KBr) 3737, 3647, 3275, 2930, 2360,
2336, 1700, 1508, 1229, 1161, 882, 774 cm−1; ESI FTMS exact mass
calcd for (C21H26BrNO5 − H)− requires m/z 450.0910, found m/z
450.0936.
1
yield, 76% (384 mg); colorless oil; H NMR (400 MHz, CDCl3) δ
7.60−7.48 (m, 1H), 7.43−7.23 (m, 3H), 7.20 (d, J = 8.1 Hz, 1H), 6.87
(s, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.32 (s, 1H), 4.96−4.69 (m, 1H),
3.70 (s, 3H), 3.19 (s, 3H), 3.06−2.98 (m, 1H), 2.96−2.87 (m, 1H),
1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 149.1, 142.9, 130.5,
126.0, 124.2, 123.8, 123.7, 121.1, 116.0, 105.5, 52.3, 50.5, 33.7, 23.6; IR
(KBr) 3647, 3589, 3443, 2922, 2851, 2360, 1699, 1645, 1510, 1391,
1232, 1161, 755 cm−1; ESI FTMS exact mass calcd for
(C22H26F3NO7S + Na)+ requires m/z 528.1274, found m/z 528.1277.
Procedure for the Synthesis of Compound 6. Methanol (2
mL) was added to the mixture of compound 5 (25.3 mg, 0.05 mmol),
Mg (12 mg, 0.5 mmol), 10% Pd/C (32 mg), and ammonium acetate
(120 mg, 1.55 mmol). After the mixture had been stirred at room
temperature overnight and the completion of the reaction indicated by
TLC, the reaction mixture was filtered, and the filtrate was
concentrated under the reduced pressure to give the residue, which
was then added to water (5 mL), extracted by ethyl acetate, and dried
by anhydrous Na2SO4. The resultant organic layer was again
concentrated under reduced pressure to give pure products 6 (15
mg, 82% yield).
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data (including H and 13C NMR and HPLC
1
spectra) for all products 3 and 5−8. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: fshi@jsnu.edu.cn.
*E-mail: wangsl@jsnu.edu.cn.
Notes
tert-Butyl [4-methoxy-3-(2-methoxy-2-phenylethyl)phenyl]-
The authors declare no competing financial interest.
carbamate (6): reaction time, 12 h; yield, 82% (15.0 mg); yellow
1
oil; H NMR (400 MHz, CDCl3) δ 7.35−7.27 (m, 3H), 7.27−7.21
ACKNOWLEDGMENTS
(m, 3H), 6.87 (d, J = 2.3 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.26 (s,
1H), 4.45−4.35 (m, 1H), 3.72 (s, 3H), 3.18 (s, 3H), 3.08−2.99 (m,
1H), 2.95−2.85 (m, 1H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 153.8, 142.2, 130.8, 128.1, 127.4, 127.3, 126.7, 110.6, 83.3, 56.8, 55.6,
39.2, 28.4; IR (KBr) 3420, 2964, 2929, 1699, 1649, 1509, 1389, 1262,
1161, 1097, 822, 699 cm−1; ESI FTMS exact mass calcd for
(C21H27NO4 + Na)+ requires m/z 380.1832, found m/z 380.1830.
Procedure for the Synthesis of Compound 7. Under an argon
atmosphere, DMF (1.5 mL) was added to the mixture of compound 5
(25.3 mg, 0.05 mmol), 4-chlorophenylboronic acid (11.7 mg, 0.075
mmol), K2CO3 (13.8 mg, 0.1 mmol), and Pd(PPh3)4 (11.6 mg, 0.01
mmol). After the mixture had been stirred at 120 °C for 4 h and the
completion of the reaction indicated by TLC, water (5 mL) was added
to the reaction mixture, which was extracted by ethyl acetate and dried
by anhydrous Na2SO4. The resultant organic layer was concentrated
under reduced pressure to give the residue, which was purified through
column chromatography on aluminum oxide to afford pure products 7
(20.2 mg, 88% yield).
■
We are grateful for financial support from NSFC (21372002
and 21232007), the Open Foundation of Jiangsu Key
Laboratory (K201314), PAPD of Jiangsu Province, and the
Qing Lan Project.
REFERENCES
■
(1) For some examples, see: (a) Haldar, S.; Koner, S. J. Org. Chem.
2010, 75, 6005. (b) Gligorich, K. M.; Cummings, S. A.; Sigman, M. S.
J. Am. Chem. Soc. 2007, 129, 14193. (c) Liang, X.; George, S. M.;
Weimer, A. W.; Li, N.-H.; Blackson, J. H.; Harris, J. D.; Li, P. Chem.
Mater. 2007, 19, 5388. (d) Dong, J. Y.; Manias, E.; Chung, T. C.
Macromolecules 2002, 35, 3439.
(2) For some reviews, see: (a) Heck, R. F. Acc. Chem. Res. 1979, 12,
146. (b) Daves, G. D.; Hallberg, A. Chem. Rev. 1989, 89, 1433.
(c) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442. (e) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106,
4644. (f) Ruan, J.; Xiao, J. Acc. Chem. Res. 2011, 44, 614. (g) Mc
tert-Butyl {3-[2-(4′-chloro[1,1′-biphenyl]-2-yl)-2-methoxyethyl]-4-
methoxyphenyl}carbamate (7): flash column chromatography eluent
6151
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152

The Journal of Organic Chemistry
Article
Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122. (h) Sigman,
M. S.; Werner, E. W. Acc. Chem. Res. 2012, 45, 874.
(3) For some reviews, see: (a) Monfette, S.; Fogg, D. E. Chem. Rev.
2009, 109, 3783. (b) van Otterlo, W. A. L.; de Koning, C. B. Chem.
Rev. 2009, 109, 3743. (c) Choi, S.-K.; Gal, Y.-S.; Jin, S.-H.; Kim, H. K.
Chem. Rev. 2000, 100, 1645. (d) Deiters, A.; Martin, S. F. Chem. Rev.
2004, 104, 2199. (e) McReynolds, M. D.; Dougherty, J. M.; Hanson,
P. R. Chem. Rev. 2004, 104, 2239.
(4) (a) Hartmann, M.; Li, Y.; Studer, A. J. Am. Chem. Soc. 2012, 134,
16516. (b) Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Chem.Eur. J.
2012, 18, 2931. (c) Fumagalli, G.; Boyd, S.; Greaney, M. F. Org. Lett.
2013, 15, 4398. (d) Wang, L.; Fan, R. Org. Lett. 2012, 14, 3596.
(e) Satterfield, A. D.; Kubota, A.; Sanford, M. S. Org. Lett. 2011, 13,
1076.
(5) Urbano, J.; Hormigo, A. J.; Fremont, P. D.; Nolan, S. P.; Diaz-
Requejo, M. M.; Perez, P. J. Chem. Commun. 2008, 759.
(6) (a) Chen, C.-P.; Chou, C.-T.; Swenton, J. S. J. Am. Chem. Soc.
1987, 109, 946. (b) Swenton, J. S.; Bonke, B. R.; Clark, W. M.; Chen,
C.-P.; Martin, K. V. J. Org. Chem. 1990, 55, 2027.
(7) Dalidowicz, P.; Swenton, J. S. J. Org. Chem. 1993, 58, 4802.
(8) (a) Banfield, S. C.; England, D. B.; Kerr, M. A. Org. Lett. 2001, 3,
3325. (b) Chuang, K. V.; Navarro, R.; Reisman, S. E. Chem. Sci. 2011,
2, 1086. (c) Dohi, T.; Hu, Y.; Kamitanaka, T.; Washimi, N.; Kita, Y.
Org. Lett. 2011, 13, 4814. (d) Hu, Y.; Kamitanaka, T.; Mishima, Y.;
Dohi, T.; Kita, Y. J. Org. Chem. 2013, 78, 5530. (e) Hashimoto, T.;
Nakatsu, H.; Takiguchi, Y.; Maruoka, K. J. Am. Chem. Soc. 2013, 135,
16010.
(9) For some reviews on the catalysis of chiral Brønsted acid, see:
(a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem.
Commun. 2008, 35, 4097. (c) Terada, M. Synthesis 2010, 1929. (d) Yu,
J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156.
(10) (a) Shi, F.; Xing, G.-J.; Zhu, R.-Y.; Tan, W.; Tu, S.-J. Org. Lett.
2013, 15, 128. (b) Shi, F.; Tan, W.; Zhu, R.-Y.; Xing, G.-J.; Tu, S.-J.
Adv. Synth. Catal. 2013, 355, 1605. (c) Shi, F.; Zhu, R.-Y.; Dai, W.;
Wang, C.-S.; Tu, S.-J. Chem.Eur. J. 2014, 20, 2597.
(11) Sajiki, H.; Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.;
Hirota, K. Org. Lett. 2006, 8, 987.
(12) Jensen, K. L.; Franke, P. T.; Nielsen, L. T.; Daasbjerg, K.;
Jøgensen, K. A. Angew. Chem., Int. Ed. 2010, 49, 129.
(13) (a) Elias, X.; Pleixats, R.; Man, M. W. C. Tetrahedron 2008, 64,
6770. (b) Chatterjee, A. K.; Toste, F. D.; Goldberg, S. D.; Grubbs, R.
H. Pure Appl. Chem. 2003, 75, 421.
6152
dx.doi.org/10.1021/jo500859b | J. Org. Chem. 2014, 79, 6143−6152