Regioselective Domino Synthesis of 2-Alkylflavans via Hidden Br?nsted Acid Catalysis

Article abstract of DOI:10.1055/s-0036-1589004

A range of alkyl-substituted flavans, which are important structural elements in natural products and pharmaceutical molecules, were prepared by successive hidden Br?nsted acid catalyzed domino reaction, intermolecular hydroarylation, and intramolecular hydroalkoxylation. 1,1-Disubstituted allenes were activated under mild acidic AgOTf/t-BuCl condition to initiate the regioselective Friedel-Crafts reaction with phenol derivatives, and the consecutive reaction triggered by the 6 -endo cyclization led to the formation of a new type of 2-alkylflavan. Mechanistic study of the reaction intermediates and control experiments support the catalytic pathway and advantage of hidden Bronsted acid catalysis.

Full text of DOI:10.1055/s-0036-1589004

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
H. J. Jin et al.
Paper
Synthesis
Regioselective Domino Synthesis of 2-Alkylflavans via Hidden
Brønsted Acid Catalysis
Ha Jeong Jin
R1
•
AgOTf, t-BuCl
R3
R3
Jae Hyung Kim
Eun Joo Kang*
R1
R2
+
R2
R1 = aryl, alkyl
2 = alkyl, H
DCE, r.t.
O
HO
Hidden Brønsted Acid
Catalysis
13 new examples
up to 95% yield
R
Department of Applied Chemistry, Kyung Hee University,
Yongin 17104, Korea
ejkang24@khu.ac.kr
Cl
OH
O
O
Cl
tocopherol moiety
antibiotic BW-683C
Received: 25.01.2017
Accepted after revision: 24.03.2017
Published online: 25.04.2017
Cl
OH
O
OMe
O
DOI: 10.1055/s-0036-1589004; Art ID: ss-2017-f0047-op
HO
Cl
4',6-dichloroflavan
OH
Abstract A range of alkyl-substituted flavans, which are important
structural elements in natural products and pharmaceutical molecules,
were prepared by successive hidden Brønsted acid catalyzed domino
reaction, intermolecular hydroarylation, and intramolecular hy-
droalkoxylation. 1,1-Disubstituted allenes were activated under mild
acidic AgOTf/t-BuCl condition to initiate the regioselective Friedel–
Crafts reaction with phenol derivatives, and the consecutive reaction
triggered by the 6-endocyclization led to the formation of a new type of
2-alkylflavan. Mechanistic study of the reaction intermediates and con-
trol experiments support the catalytic pathway and advantage of hid-
den Brønsted acid catalysis.
OH
morusyunnansin E
O
HO
HO
OH
OH
O
O
OH
OH
OH
7-O-galloyltricetiflavan
HO
HO
O
OMe
griffinoid D
Key words 2-alkylflavan, hidden Brønsted acid catalyst, arylallene,
domino cyclocoupling, regioselectivity
Figure 1 Representative structures of biologically active flavan com-
pounds
Flavans with a 2-arylchroman structure are naturally
occurring materials found extensively throughout the plant
kingdom, with more than 17 000 compounds that show in-
teresting biological and pharmacological activities.1,2 For
example, 4′,6-dichloroflavan inhibits rhinovirus replication
in vitro,1a and the antiviral component, 7-O-galloyltriceti-
flavan, from P. clypearia exhibits activity against respiratory
syncytial virus and Herpes simplex virus type I (Figure 1).1b
Tyrosinase inhibitory agents, morusyunnansins, were iso-
lated from the leaves of M. yunnanensis,1c and griffinoid D
from the stems of Combretum griffithii shows antiplasmo-
dial activity and cytotoxicity toward cancer cell lines.1d
From these various bioactivities, flavans have attracted the
attention of many synthetic chemists; therefore, general
procedures for their synthesis have been developed, as
shown in Scheme 1.
reaction between a substituted alkene and o-quinone
methide. o-Acetoxymethylphenol, 4H-1,2-benzoxazine, and
o-hydroxybenzyl alcohol were employed as o-quinone
methide precursors under thermal and acidic conditions,
which reacted with styrene to provide flavan derivatives.3a–c
o-Quinone methides were also generated as methylene in-
termediates from phenol and formaldehyde in a three-com-
ponent reaction.3d–f Intramolecular C–O bond formation of
o-bromophenylpropanols using copper catalysis4 and alke-
nyl phenols under acidic media were developed;5 moreover,
gold-catalyzed hydroarylation of allenyl ethers afforded
chroman derivatives.6 Tandem C–C and C–O coupling be-
tween various C3 units and phenol have been extensively
investigated for construction of the chroman structure. Sil-
ver or copper triflate catalyzed the addition of phenols to
1,3-dienes, and Hintermann proposed this type of condi-
tion as ‘hidden Brønsted acid catalysis’ in which Brønsted
acid (TfOH) was released from metal triflate in dichlo-
A variety of methods for flavan synthesis have been de-
veloped. An early approach utilized a hetero-Diels–Alder
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
H. J. Jin et al.
Paper
Synthesis
OH/OAc
•
R
R'
HO
O
Alkene
Hydroarylation
R
HO
HO
R'
Diene
Hydroalkoxylation
Hydroarylation &
Hydroalkoxylation
R
R'
O
Ullmann type
condensation
Ar
•
R
Diels–Alder
HO
HO
This work
Allene
Alk
Br
•
O
NTs
R
R'
HO
O
O
Scheme 1 Various approaches for the synthesis of flavans
roethane (DCE) or t-BuCl.7 The 1,3-dienes tested in previous
reports were limited to few commercial sources, and inap-
propriate to construct the flavan (2-arylchroman) skeleton.
Molybdenum or indium complexes catalyzed the reaction
of allylic alcohols/acetates with phenols.8 Allene as a C3
component also underwent a tandem reaction under
Brønsted acid catalysis (2.5 mol% Tf2NH). However, allenes
possessing an electron-withdrawing group, allene sulfon-
amides, were solely examined to provide functionalized
chromans.9 As part of our ongoing interest in economical
domino reactions with allenes, interesting substrates to
control stereo- and regioselectivities, we report a short and
efficient procedure for the first synthesis of 2-alkylflavans
from aryl- and alkyl-substituted allenes, employing hidden
Brønsted acid catalyzed intermolecular hydroarylation and
intramolecular hydroalkoxylation reactions. This one-pot
synthesis exhibited high regioselectivity for both hydroary-
lation at the terminal allene position and hydroalkoxylation
forming six-membered pyran derivatives.
To examine the feasibility of a domino reaction of allene
and phenol, 1,1-disubstituted allene 1a and 4-methoxyphe-
nol (2a) were selected as representative substrates in the
investigation of various Lewis acid catalysts. In a prelimi-
nary investigation, reaction of a monosubstituted allene
and phenol provided the product mixture of the desired
flavan and two hydroarylated regioisomers (Table S1 in
Supporting Information). It was thought that the additional
methyl substituent on 1a might promote the C–O bond for-
mation reaction and the use of 4-methoxyphenol (2a)
might control the regioselectivity and increase the reactivi-
ty in the hydroarylation step. As shown in Table 1, the cata-
lytic activities of iron salts were tested first, and exhibited
efficiency in the hydrofunctionalization reaction of al-
lenes.10 Various iron catalysts led to formation of flavan 3aa
in moderate yield after long reaction times (Table 1, entries
1–4). Other metal triflate salts, such as Ga(III), Sc(II), Cu(II),
Sn(II), and Ag(I), resulted in low to good yields (entries 5–
9). Bearing in mind some ambiguity that the counteranion
of the metal salt could generate Brønsted acid by proton
transfer,11 the hidden Brønsted acid system was also intro-
Table 1 Optimization of Conditions for Flavan Synthesisa
OMe
cat.
(10 mol%)
OMe
•
+
O
DCE (0.5 M)
r.t.
HO
1a
2a
3aa
Entry
Catalyst
Time (h)
Yield (%)b
1
2
FeCl3
24
24
72
72
15
72
72
15
40
2
15
0
Fe(acac)3
Fe(OTs)3
Fe(OTf)3
Ga(OTf)3
Sc(OTf)2
Cu(OTf)2
Sn(OTf)2
AgOTf
3
45
15
78
0
4
5
6
7
71
80
60
82
90
37
64
16
0
8
9
10c
11d
12
13
14
15
AgOTf, t-BuCl
AgOTf, t-BuCl
TfOH
2
72
72
72
72
TsOH
CF3CO2H
AcOH
a Reaction conditions: allene 1a (1.5 mmol), 4-methoxyphenol (2a; 1.0
mmol), catalyst (10 mol%), DCE (0.5 M) under N2, unless otherwise speci-
fied.
b Isolated yield.
c Reaction with 10 mol% AgOTf and 40 mol% t-BuCl.
d Reaction with 3 mol% AgOTf and 12 mol% t-BuCl.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
H. J. Jin et al.
Paper
Synthesis
duced to these substrates.12 Mildly generated TfOH from
AgOTf and t-BuCl was found to efficiently perform the se-
quential transformation of allene 1a with 3 mol% AgOTf in
shorter time (entry 11). It is of interest to note that t-BuCl
was found to be a better co-agent for the hidden acid for-
mation than dichloroethane, in terms of the reaction effi-
ciency (entries 9 and 10). Direct treatment with TfOH led to
decomposition of the starting allene, the corresponding in-
termediate, and the product, presumably due to the strong
acidity of TfOH; moreover, low conversion was observed
under these conditions with other types of Brønsted acid
catalysts (entries 12–15).
With AgOTf (3 mol%) and t-BuCl (12 mol%) as the select-
ed catalyst system, the scope of the tandem reaction was
examined with a variety of phenol derivatives (Table 2). For
substituted phenols 2a–d, with electron-donating groups
such as MeO, BnO, Me, or t-Bu at the para-position, the cor-
responding flavan derivatives 3aa–ad were isolated in 66–
95% yield; however, an electron-withdrawing chloro-sub-
stituent significantly retarded the rate of reaction. Phenol
2g bearing a methoxy substituent at the meta-position is
presumably not sufficiently electron-rich to undergo the
first hydroarylation reaction. 2,3,5-Trimethylbenzene-1,4-
diol (2h) also participated in the reaction to afford flavan
3ah, which has the α-tocopherol core structure.
Table 2 Domino Synthesis of Flavan Derivatives from Various Phenols
R1
AgOTf (3 mol%)
t-BuCl (12 mol%)
R1
•
+
O
DCE (0.5 M), r.t.
HO
1a
2a–h
3aa–ah
Entry
Phenol
Product (time, yield)a
1
2
3
4
5
2a (R1 = OMe)
2b (R1 = OBn)
2c (R1 = Me)
2d (R1 = t-Bu)
2e (R1 = Cl)
3aa (1 h, 90%)
3ab (12 h, 95%)
3ac (1 h, 66%)
3ad (2 h, 68%)
3ae (12 h, 36%)
6
O
HO
2f
3af (2 h, 90%)
O
OMe
OMe
7
HO
OMe
The allene substrate scope was next explored (Table 3).
With 4-methoxyphenol (2a), a broad range of allenes with
methyl- or bromo-substituted benzene, naphthalene, and
thiophene substituents (1b, 1d–f) proved to be suitable
substrates for the current catalytic system, giving the corre-
sponding products in good yields. However, the presence of
a methoxy group, electron-donating through conjugation,
seemed to significantly decrease the efficiency of the reac-
tion, presumably due to formation of a quite stable and de-
localized carbocation intermediate (Table 3, entry 2). Ethyl-,
isopropyl-, and dialkyl-substituted allenes were also com-
patible with the reaction, delivering the corresponding fla-
vans in up to 80% yield (entries 6–8). Additionally, com-
pound 3ja with two chroman units was also prepared, albe-
it in low yield, due to the chemical lability of diallene 1j.
According to two identical methyl (CH3) peaks in 1H NMR, a
mixture of meso compound and diastereomer of 3ja
seemed to be produced in a similar amount.
Remarkably, the one-pot construction of 3ke was
achieved by reacting mono-substituted allene 1k with p-
chlorophenol (2e) (Scheme 2). Although the yield was mod-
erate, the formation of antibiotic 4′,6-dichloroflavan 3ke
(BW-683C) showcases this highly attractive method for fla-
van synthesis from readily accessible starting materials.
The increased reactivity of electron-rich phenols and
more highly substituted allene derivatives suggests that the
reaction mechanism involves carbocation intermediates in
the presence of hidden Brønsted acid. Flavan 3aa can be ob-
tained from 1a and 2a by two different reaction pathways:
2g
O
3ag + 3ag′ (3:1, 48 h, 64%)
OH
OH
8
O
HO
2h
a Isolated yield.
3ah (2 h, 80%)
the first route involves intermolecular hydroarylation to
4aa, followed by intramolecular hydroalkoxylation;7 an al-
ternative route involves the same reactions but in the oppo-
site order (Scheme 3; eq. 1). However, the preliminary re-
sults of phenyl allene (1l, see Table S1 in Supporting Infor-
mation) with phenol, forming two hydroarylated
regioisomers (4li and 4li′) indicated a more favorable inter-
molecular hydroarylation, while no intermediate resulting
from intermolecular hydroalkoxylation was observed un-
AgOTf
(3 mol%)
Cl
t-BuCl
(12 mol%)
Cl
Cl
+
O
•
DCE (0.1 M)
r.t.
HO
Cl
1k
2e
3ke (24 h, 48%)
Scheme 2 Synthesis of the antibiotic 4′,6-dichloroflavan
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
H. J. Jin et al.
Paper
Synthesis
Table 3 Domino Synthesis of Flavan Derivatives from Various Allenes
AgOTf
R2
(3 mol%)
t-BuCl
OMe
OMe
(12 mol%)
+
•
O
DCE (0.5 M)
HO
r.t.
R2
1b–j
2a
3ba–ja
Entry
Allene
Product (time, yield)a
1
2
3
1b (R2 = Me)
3ba (17 h, 58%)
3ca (20 h, 5%)
3da (48 h, 49%)
1c (R2 = OMe)
1d (R2 = Br)
OMe
•
4
5
6
O
1e
3ea (5 h, 60%)
OMe
OMe
•
S
O
S
1f
3fa (48 h, 49%)
•
O
1g
3ga (12 h, 80%)
OMe
•
7
8
O
3ha (12 h, 37%)
1h
OMe
H11C5
•
H11C5
O
C5H11
H11C5
1i
3ia (48 h, 72%)
MeO
OMe
•
•
9
O
O
3ja (1 h, 13%)
1j
a Isolated yield.
der various conditions. This mechanism is further support-
ed by the reaction of 4aa, which was quantitatively convert-
ed to 3aa in the presence of hidden Brønsted acid catalyst
(Scheme 3; eq. 2). Additionally, the reactions did not pro-
ceed in the presence of the non-coordinating base 2,6-di-
tert-butylpyridine, which only binds to protons.
A catalytic cycle involving Brønsted acid catalysis has
been proposed to explain the observed pattern of reactivity
(Scheme 4). The addition of t-BuCl to a stirred solution of
AgOTf at ambient temperature in DCE immediately pro-
duced a white precipitate of AgCl, and TfOH was generated
in situ by E1 elimination.7c The hidden Brønsted acid cata-
lyst reacted with allene to form the carbocation intermedi-
ate I, which was resonance-stabilized as a tertiary benzylic
carbocation. Hydroarylation and subsequent intermolecu-
lar hydroalkoxylation afforded the alkyl-substituted flavan
derivative.
In conclusion, a highly efficient catalytic system is pre-
sented for the construction of the flavan skeleton via inter-
molecular hydroarylation and intramolecular hydroalkox-
ylation reactions of allenes and phenols. AgOTf and t-BuCl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
H. J. Jin et al.
Paper
Synthesis
230 mesh ASTM). NMR spectra were recorded in CDCl3 using one of
several JEOL 300 MHz spectrometers. Mass spectra were recorded us-
ing electron impact (EI) method.
OMe
HO
OMe
(1)
4aa
Flavan Derivatives 3; General Procedure
1a + 2a
O
The hidden Brønsted acid catalyst was prepared first as follows:
AgOTf (3 mol%) and t-BuCl (12 mol%) were stirred for 10 min at r.t.
and any volatiles were removed under reduced pressure. The result-
ing concentrated mixture was diluted in DCE (0.5 M) and treated with
allene 1 (1.5 mmol) and phenol 2 (1.0 mmol) at r.t. The reaction prog-
ress was monitored by TLC analysis, and quenched by the addition of
sat. aq NH4Cl (3 mL). The organic layer was separated, extracted with
CH2Cl2 (3 × 3 mL), dried (MgSO4), and concentrated. Silica gel column
chromatography provided the desired flavan 3. All the products were
fully characterized by 1H and 13C NMR spectroscopy and HRMS analy-
sis.
OMe
3aa
O
5aa
AgOTf
(3 mol%)
t-BuCl
OMe
OMe
(12 mol%)
(2)
O
DCE (0.5 M)
r.t.
HO
4aa
3aa
100% conversion on 1H NMR
Scheme 3 Mechanistic investigation
6-Methoxy-2-methyl-2-phenylchroman (3aa)
According to the general procedure, a yellow oil (0.23 g, 90%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
1H NMR (300 MHz, CDCl3): δ = 7.37–7.15 (m, 5 H), 6.90 (d, J = 8.8 Hz, 1
H), 6.70 (dd, J = 9.0, 3.1 Hz, 1 H), 6.48 (d, J = 3.1 Hz, 1 H), 3.69 (s, 3 H),
2.61 (dt, J = 15.9, 4.3 Hz, 1 H), 2.47–2.31 (m, 2 H), 2.10–1.99 (m, 1 H),
1.61 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.1, 148.2, 145.7, 128.4, 126.7, 125.0,
122.1, 117.5, 113.8, 113.5, 78.0, 55.5 32.7, 30.1, 22.9.
HRMS (EI): m/z [M]+ calcd for C17H18O2: 254.1307; found: 254.1304.
as hidden Brønsted acid precursors catalyzed regioselective
domino reactions from readily accessible aryl allenes and
phenols under mild conditions to prepare a variety of un-
known flavans, in expectation of wide industrial applicabil-
ity. Further studies on consecutive functionalization reac-
tions using various accumulated multiple bond systems
and chiral flavan synthesis is underway.
(E)-4-Methoxy-2-(3-phenylbut-2-enyl)phenol (4aa)
Unless otherwise specified, all reactions were conducted under a
slight positive pressure of dry nitrogen. All solvents were reagent
grade and other commercially available reagents were used as re-
ceived. Flash chromatography was carried out using silica gel (70–
During the preparation of 3aa under the hidden Brønsted acid cataly-
sis, the formation of the intermediate 4aa was observed, which could
be isolated as a mixture with p-methoxyphenol.
R2
R1
TfOH
•
O
1
R2
3
AgCl + t-BuOTf
AgOTf + t-BuCl
R2
R1
R2
H
H
+
O
+
+
I
H
R2
V
R1
Hydroarylation
Hydroalkoxylation
HO
2
R1
R1
+
+
R2
HO
R2
HO
II
IV
R1
H+
H+
R2
HO
III
Scheme 4 Plausible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
H. J. Jin et al.
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Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.41–7.29 (m, 4 H), 7.26–7.22 (m, 1 H),
6.82–6.78 (m, 1 H), 6.74–6.71 (m, 1 H), 6.68–6.65 (m, 1 H), 5.93 (t, J =
7.3 Hz, 1 H), 3.75 (s, 3 H), 3.53 (d, J = 7.3 Hz, 2 H), 2.16 (s, 3 H).
3-Methyl-3-phenyl-2,3-dihydro-1H-benzo[f]chromene (3af)3d
According to the general procedure, a white solid (0.25 g, 90%) was
obtained after column chromatography on silica gel (hexane/EtOAc
80:1); mp 94–97 °C.
13C NMR (75 MHz, CDCl3): δ = 147.9, 143.4, 137.0, 128.3, 128.0, 127.9,
1H NMR (300 MHz, CDCl3): δ = 7.76–7.65 (m, 3 H), 7.44–7.38 (m, 3 H),
7.32–7.15 (m, 5 H), 3.04 (dt, J = 16.2, 4.3 Hz, 1 H), 2.67–2.52 (m, 2 H),
2.23 (ddd, J = 15.4, 9.7, 4.4 Hz, 1 H), 1.70 (s, 3 H).
127.0, 125.8, 125.3, 116.2, 115.8, 112.1, 55.7, 29.9, 15.9.
6-(Benzyloxy)-2-methyl-2-phenylchroman (3ab)
13C NMR (75 MHz, CDCl3): δ = 151.5, 145.3, 132.9, 128.8, 128.4, 127.9,
126.8, 126.2, 124.9, 123.1, 122.0, 119.4, 113.5, 78.1, 32.5, 29.9, 19.2.
HRMS (EI): m/z [M]+ calcd for C20H18O: 274.1358; found: 274.1355.
According to the general procedure, a yellow solid (0.31 g, 95%) was
obtained after column chromatography on silica gel (hexane/EtOAc
80:1); mp 122–123 °C.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.17 (m, 10 H), 6.90 (d, J = 8.8 Hz,
1 H), 6.78 (dd, J = 8.8, 2.9 Hz, 1 H), 6.58 (d, J = 2.9 Hz, 1 H), 4.95 (s, 2 H),
2.62 (dt, J = 17.2, 5.3 Hz, 1 H), 2.49–2.33 (m, 2 H), 2.16–2.01 (m, 1 H),
1.62 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.6, 148.6, 145.9, 137.7, 128.7, 128.5,
128.0, 127.7, 126.9, 125.2, 122.4, 117.6, 115.2, 114.6, 78.2, 70.7, 32.9,
30.3, 23.0.
7-Methoxy-2-methyl-2-phenylchroman (3ag)
According to the general procedure, a yellow oil (0.17 g, 64%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1) as a 3:1 mixture of 3ag and its regioisomer 3ag′ (5-methoxy-2-
methyl-2-phenylchroman).
1H NMR (300 MHz, CDCl3): δ = 7.38–7.21 (m, 5 H), 6.84 (d, J = 8.0 Hz, 1
H), 6.56 (d, J = 2.2 Hz, 1 H), 6.41, (dd, J = 8.4, 2.6 Hz, 1 H), 3.80 (s, 3 H),
2.62–2.55 (m, 1 H), 2.41–2.30 (m, 2 H), 2.10–2.00 (m, 1 H), 1.64 (s, 3
H).
HRMS (EI): m/z [M]+ calcd for C23H22O2: 330.1620; found: 330.1621.
2,6-Dimethyl-2-phenylchroman (3ac)8a
13C NMR (75 MHz, CDCl3): δ = 159.4, 155.0, 145.8, 130.0, 128.5, 126.8,
125.1, 113.9, 107.1, 101.7, 78.6, 55.4, 33.2, 30.1, 21.9.
HRMS (EI): m/z [M]+ calcd for C17H18O2: 254.1307: found: 254.1311.
According to the general procedure, a yellow oil (0.16 g, 66%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
1H NMR (300 MHz, CDCl3): δ = 7.38–7.15 (m, 5 H), 6.93 (d, J = 8.4 Hz, 1
H), 6.87 (d, J = 8.1 Hz, 1 H), 6.75 (s, 1 H), 2.59 (dt, J = 16.7, 5.0 Hz, 1 H),
2.45–2.31 (m, 2 H), 2.21 (s, 3 H), 2.04 (ddd, J = 15.2, 9.9, 4.0 Hz, 1 H),
1.62 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 152.0, 145.9, 129.9, 129.5, 128.5, 128.2,
126.8, 125.1, 121.4, 116.8, 78.3, 33.0, 30.3, 22.6, 20.5.
HRMS (EI): m/z [M]+ calcd for C17H18O: 238.1358; found: 254.1355.
2,5,7,8-Tetramethyl-2-phenylchroman-6-ol (3ah)13
According to the general procedure, a yellow oil (0.23 g, 80%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
1H NMR (300 MHz, CDCl3): δ = 7.36–7.16 (m, 5 H), 4.17 (s, 1 H), 2.64–
2.56 (m, 1 H), 2.43–2.24 (m, 2 H), 2.29 (s, 3 H), 2.19 (s, 3 H), 2.07 (ddd,
J = 12.5, 6.6, 3.1 Hz, 1 H), 2.00 (s, 3 H), 1.59 (s, 3 H).
6-(tert-Butyl)-2-methyl-2-phenylchroman (3ad)
13C NMR (75 MHz, CDCl3): δ = 146.3, 145.8, 145.0, 128.5, 126.7, 125.0,
According to the general procedure, a yellow solid (0.19 g, 68%) was
obtained after column chromatography on silica gel (hexane/EtOAc
80:1); mp 68–71 °C.
122.4, 121.2, 118.6, 117.7, 76.7, 32.8, 30.2, 21.1, 12.3, 12.0, 11.3.
HRMS (EI): m/z [M]+ calcd for C19H22O2: 282.1620; found: 282.1622.
1H NMR (300 MHz, CDCl3): δ = 7.10–7.20 (m, 5 H), 7.16 (dd, J = 8.4, 2.5
Hz, 1 H), 6.94 (d, J = 2.5 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 2.65 (dt, J =
15.9, 4.7 Hz, 1 H), 2.50–2.32 (m, 2 H), 2.07 (ddd, J = 14.1, 8.8, 4.2 Hz, 1
H), 1.63 (s, 3 H), 1.26 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 152.0, 146.1, 142.7, 128.5, 126.8, 126.2,
125.2, 124.6, 120.8, 116.4, 78.3, 34.0, 33.2, 31.6, 30.1, 22.9.
6-Methoxy-2-methyl-2-(p-tolyl)chroman (3ba)
According to the general procedure, a yellow oil (0.16 g, 58%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.4
Hz, 2 H), 6.89 (d, J = 9.0 Hz, 1 H), 6.70 (dd, J = 8.6, 2.7 Hz, 1 H), 6.48 (d,
J = 3.1 Hz, 1 H), 3.71 (s, 3 H), 2.65–2.58 (m, 1 H), 2.53–2.31 (m, 2 H),
2.30 (s, 3 H), 2.04 (ddd, J = 14.6, 9.1, 4.3 Hz, 1 H), 1.67 (s, 3 H).
HRMS (EI): m/z [M]+ calcd for C20H24O: 280.1827; found: 280.1828.
6-Chloro-2-methyl-2-phenylchroman (3ae)
13C NMR (75 MHz, CDCl3): δ = 153.2, 148.4, 142.9, 136.4, 129.2, 125.1,
According to the general procedure in DCE (0.1 M), a yellow oil (94
mg, 36%) was obtained after column chromatography on silica gel
(hexane/EtOAc 70:1).
122.3, 117.6, 114.0, 113.7, 78.1, 55.7, 32.8, 30.4, 23.0, 21.0.
HRMS (EI): m/z [M]+ calcd for C18H20O2: 268.1463; found: 268.1461.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.16 (m, 5 H), 7.08 (dd, J = 8.6, 2.4
Hz, 1 H), 6.92 (d, J = 2.2 Hz, 1 H), 6.90, (d, J = 8.8 Hz, 1 H), 2.62 (dt, J =
17.0, 5.0 Hz, 1 H), 2.47–2.34 (m, 2 H), 2.05 (ddd, J = 15.2, 9.9, 4.0 Hz, 1
H), 1.63 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.0, 145.3, 129.1, 128.6, 127.5, 127.1,
125.0, 124.8, 123.4, 118.4, 78.8, 32.5, 30.3, 22.6.
6-Methoxy-2-(4-methoxyphenyl)-2-methylchroman (3ca)
According to the general procedure in DCE (0.1 M), a yellow oil (22
mg, 5%) was obtained after column chromatography on silica gel
(hexane/EtOAc 80:1).
1H NMR (300 MHz, CDCl3): δ = 7.28 (d, J = 8.1 Hz, 2 H), 6.89 (d, J = 8.8
Hz, 1 H), 6.82 (d, J = 8.8 Hz, 2 H), 6.71 (dd, J = 8.1, 2.9 Hz, 1 H), 6.49 (d,
J = 2.6 Hz, 1 H), 3.77 (s, 3 H), 3.72 (s, 3 H), 2.70–2.53 (m, 1 H), 2.53–
2.41 (m, 1 H), 2.41–2.29 (m, 1 H), 2.12–1.97 (m, 1 H), 1.60 (s, 3 H).
HRMS (EI): m/z [M]+ calcd for C16H15ClO: 258.0811; found: 258.0813.
13C NMR (75 MHz, CDCl3): δ = 158.5, 153.3, 148.4, 138.0, 126.4, 122.3,
117.6, 114.0, 113.9, 113.7, 77.9, 55.7, 55.3, 32.9, 30.4, 23.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
H. J. Jin et al.
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HRMS (EI): m/z [M]+ calcd for C18H20O3: 284.1412; found: 284.1407.
1H NMR (300 MHz, CDCl3): δ = 7.29–7.14 (m, 5 H), 6.89 (d, J = 8.8 Hz, 1
H), 6.68 (dd, J = 8.8, 2.9 Hz, 1 H), 6.41, (d, J = 3.3 Hz, 1 H), 3.69 (s, 3 H),
2.57–2.42 (m, 1 H), 2.40–2.30 (m, 2 H), 2.16–2.01 (m, 2 H), 0.95 (d, J =
7.0 Hz, 3 H), 0.87 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.1, 148.6, 142.8, 128.0, 126.8, 126.6,
122.8, 117.6, 113.9, 113.6, 28.6, 55.7, 38.7, 27.8, 22.9, 17.3, 16.9.
2-(4-Bromophenyl)-6-methoxy-2-methylchroman (3da)
According to the general procedure, a yellow oil (0.17 g, 49%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
HRMS (EI): m/z [M]+ calcd for C19H22O2: 282.1620; found: 282.1622.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.38 (m, 2 H), 7.26–7.21 (m, 2 H),
6.88 (d, J = 8.8 Hz, 1 H), 6.71 (dd, J = 9.1, 2.9 Hz, 1 H), 6.48 (d, J = 2.9 Hz,
1 H), 3.72 (s, 3 H), 2.64 (dt, J = 16.7, 4.6 Hz, 1 H), 2.47–2.29 (m, 2 H).
2.05 (ddd, J = 14.6, 9.3, 4.0 Hz, 1 H), 1.59 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.4, 148.0, 145.0, 131.7, 127.1, 122.1,
120.8, 117.7, 114.0, 113.8, 77.8, 55.7, 32.6, 30.3, 22.9.
6-Methoxy-2,2-dipentylchroman (3ia)
According to the general procedure, a yellow oil (0.22 g, 72%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
HRMS (EI): m/z [M]+ calcd for C17H17BrO2: 332.0412; found: 332.0412.
1H NMR (300 MHz, CDCl3): δ = 6.68–6.58 (m, 3 H), 3.74 (s, 3 H), 2.69
(t, J = 7.0 Hz, 2 H), 1.78, (t, J = 6.8 Hz, 2 H), 1.38–1.20 (m, 16 H), 0.88, (t,
J = 7.0 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 152.9, 134.7, 122.1, 117.9, 114.1, 113.4,
77.9, 55.8, 36.3, 32.4, 28.9, 23.0, 22.7, 22.3, 14.1.
6-Methoxy-2-methyl-2-(naphthalen-2-yl)chroman (3ea)
According to the general procedure, a yellow oil (0.18 g, 60%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
HRMS (EI): m/z [M + H]+ calcd for C20H33O2: 305.2481; found:
1H NMR (300 MHz, CDCl3): δ = 7.81–7.75 (m, 4 H), 7.50 (dd, J = 2.0, 8.6
Hz, 1 H), 7.45–7.41 (m, 2 H), 6.97 (d, J = 8.8 Hz, 1 H), 6.74 (dd, J = 8.8,
2.9 Hz, 1 H), 6.47 (d, J = 2.4 Hz, 1 H), 3.70 (s, 3 H), 2.66 (dt, J = 17.0, 5.2
Hz, 1 H), 2.54–2.42 (m, 2 H), 2.14 (ddd, J = 15.5, 10.0, 4.1 Hz, 1 H), 1.70
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.3, 148.4, 143.2, 133.4, 132.5, 128.3,
128.7, 126.2, 125.9, 124.1, 123.5, 122.3, 117.7, 114.0, 113.8, 18.3, 55.7,
32.8, 30.3, 23.1.
305.2484.
1,3-Bis(6-methoxy-2-methylchroman-2-yl)benzene (3ja)
According to the general procedure using p-methoxyphenol (96 mg,
0.77 mmol, 2.0 equiv) and 1,3-di(buta-2,3-dien-2-yl)benzene (1j; 69
mg, 0.38 mmol, 1.0 equiv), a yellow oil (21 mg, 13%) was obtained af-
ter column chromatography on silica gel (hexane/EtOAc 50:1).
1H NMR (300 MHz, CDCl3): δ = 7.34 (d, J = 12.1 Hz, 1 H), 7.20–7.19 (m,
3 H), 6.88 (d, J = 8.8 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 1 H), 6.72–6.66 (m, 2
H), 6.45 (d, J = 2.9 Hz, 1 H), 6.41 (d, J = 2.9 Hz, 1 H), 3.71 (s, 6 H), 2.63–
1.96 (m, 8 H), 1.60 (s, 3 H), 1.53 (s, 3 H).
HRMS (EI): m/z [M]+ calcd for C21H20O2: 304.1463; found: 304.1460.
6-Methoxy-2-methyl-2-(thiophen-2-yl)chroman (3fa)
13C NMR (75 MHz, CDCl3): δ = 165.1, 148.2, 148.1, 145.7, 145.3, 128.5,
128.3, 123.5, 123.4, 122.4, 122.1, 121.9, 117.5, 113.8, 113.5, 113.4,
78.1, 55.6, 32.8, 32.5, 30.3, 30.0, 22.8, 22.6.
According to the general procedure, a yellow oil (0.13 g, 49%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
HRMS (EI): m/z [M]+ calcd for C28H30O4: 430.2144; found: 430.2140.
1H NMR (300 MHz, CDCl3): δ = 7.22–7.14 (m, 1 H), 6.91–6.83 (m, 3 H),
6.70 (dd, J = 9.0, 3.1 Hz, 1 H), 6.53 (d, J = 3.3 Hz, 1 H), 3.73 (s, 3 H),
3.73–2.66 (m, 1 H), 2.37–2.29 (m, 1 H), 2.18–2.08 (m, 1 H), 1.71 (m, 1
H).
13C NMR (75 MHz, CDCl3): δ = 130.0, 127.3, 126.8, 124.1, 123.0, 121.8,
117.8, 114.0, 113.7, 77.3, 55.7, 34.1, 30.7, 23.0.
6-Chloro-2-(4-chlorophenyl)chroman (3ke)14
According to the general procedure in DCE (0.1 M), a white solid (0.11
g, 48%) was obtained after column chromatography on silica gel
(hexane/EtOAc 80:1); mp 94–97 °C.
HRMS (EI): m/z [M]+ calcd for C15H16O2S: 260.0871; found: 260.0874.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.31 (m, 4 H), 7.07 (d, J = 9.0 Hz, 2
H), 6.82 (d, J = 9.2 Hz, 1 H), 5.02 (dd, J = 10.0, 2.5 Hz, 1 H), 2.95 (ddd, J =
16.8, 11.0, 6.0 Hz, 1 H), 2.81–2.70 (m, 1 H), 2.24–2.13 (m, 1 H), 2.09–
1.94 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 153.7, 140.0, 133.9, 129.3, 128.9, 127.6,
127.5, 125.4, 123.4, 118.4, 77.2, 29.5, 24.8.
2-Ethyl-6-methoxy-2-phenylchroman (3ga)
According to the general procedure, a yellow oil (0.22 g, 80%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
HRMS (EI): m/z [M]+ calcd for C16H15ClO: 258.0811; found: 258.0813.
1H NMR (300 MHz, CDCl3): δ = 7.33–7.17 (m, 5 H), 6.91 (d, J = 8.8 Hz, 1
H), 6.71 (dd, J = 8.8, 2.9 Hz, 1 H), 6.47, (d, J = 2.9 Hz, 1 H), 3.71 (s, 3 H),
2.60 (dt, J = 16.5, 4.2 Hz, 1 H), 2.47–2.29 (m, 2 H), 2.08 (ddd, J = 14.7,
9.2, 3.8 Hz, 1 H), 1.91 (dq, J = 23.3, 7.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 153.1, 148.3, 144.1, 128.3, 126.7, 125.9,
122.6, 117.6, 113.9, 113.6, 80.6, 55.7, 35.7, 30.9, 22.8, 7.7.
Funding Information
This study was supported by the Kyung Hee University Research Fund
(KHU-20130575)
HRMS (EI): m/z [M]+ calcd for C18H20O2: 268.1463; found: 268.1466.
2-Isopropyl-6-methoxy-2-phenylchroman (3ha)
Supporting Information
According to the general procedure, a yellow oil (0.11 g, 37%) was ob-
tained after column chromatography on silica gel (hexane/EtOAc
80:1).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589004.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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H. J. Jin et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H