Asymmetric Transfer Hydrogenation of Arylidene-Substituted Chromanones and Tetralones Catalyzed by Noyori-Ikariya Ru(II) Complexes: One-Pot Reduction of C═C and C═O bonds

Article abstract of DOI:10.1021/acs.joc.0c02981

3-Arylidenechroman-4-ones and 2-arylidene-1-tetralones are hydrogenated to cis-benzylic alcohols in dr's and er's up to 99:1 via a C═C and C═O one-pot reduction in the presence of 2-5 mol % Noyori-Ikariya-type RuII chiral complexes and HCO2Na as a hydroge

Full text of DOI:10.1021/acs.joc.0c02981

pubs.acs.org/joc
Note
Asymmetric Transfer Hydrogenation of Arylidene-Substituted
Chromanones and Tetralones Catalyzed by Noyori−Ikariya Ru(II)
Complexes: One-Pot Reduction of CC and CO bonds
Guilherme S. Caleffi, Juliana de O. C. Brum, Angela T. Costa, Jorge L. O. Domingos,*
and Paulo R. R. Costa*
Cite This: J. Org. Chem. 2021, 86, 4849−4858
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: 3-Arylidenechroman-4-ones and 2-arylidene-1-tet-
ralones are hydrogenated to cis-benzylic alcohols in dr’s and er’s up
to 99:1 via a CC and CO one-pot reduction in the presence
of 2−5 mol % Noyori−Ikariya-type RuII chiral complexes and
HCO2Na as a hydrogen source under asymmetric transfer
hydrogenation−dynamic kinetic resolution (ATH-DKR) condi-
tions. The oxidation of theses substrates resulted in the
enantioselective synthesis of the natural homoisoflavanone
dihydrobonducellin and its carba-analogues.
kinetic resolution (ATH-DKR) reaction catalyzed by (R,R)-
1a was reported by Seo et al. in two works29,30 (Scheme 1c).
First, the exocyclic CC bond in arylidenechromanones was
reduced by hydrogenation with Pd/C, followed by the ATH-
DKR of the resulting saturated ketones using a large catalytic
loading of (R,R)-1a (30 mol %) and a HCO2H/DBU mixture.
Therefore, we envisioned that the CC and CO bonds
in arylidene-substituted chromanones (2) and tetralones (3)
could be reduced by (R,R)-1 through an one-pot procedure to
the corresponding saturated benzylic alcohols (Scheme 1d),
avoiding the previous step of the hydrogenation of the CC
bond.31−36 Xiao discloses that when HCO2Na is used as the
hydrogen source instead of HCO2H/Et3N at a pH around 7,
much faster rates and higher turnover numbers can be
delivered with (R,R)-1 in the ATH of ketones without
significative losses of ee.37−41 This trend was also found in
our preliminary screening of the hydrogen source for the ATH.
Only traces of the saturated alcohol were obtained for the
more deactivated substrates using HCO2H/Et3N mixtures
(Table S1).
he asymmetric transfer hydrogenation (ATH) of carbon-
Tyl compounds catalyzed by chiral transition-metal
complexes is a powerful tool for obtaining key intermediates
in the synthesis of optically pure pharmaceutical and natural
products.1−10 The Noyori−Ikariya-type RuII complexes (1a−
e) (Figure 1) have been used in water and organic solvents to
promote the ATH of pro-chiral CO and CN groups in
high ee’s.11−20
Figure 1. η6-Arene-N-arylsulfonyldiamine RuII complexes 1a−e.
Concerning the ATH of enones, allylic alcohols are usually
formed using these catalysts.21−26 Deng et al.27 reported the
reduction of α,β-unsaturated methyl ketones to allylic alcohols
using (R,R)-1a (Scheme 1a). However, the reduction of
chalcone was an exception, resulting in the saturated ketone as
the major product (75%) along with the corresponding
benzylic alcohol (23%) in a 93% ee. Just recently, Wills et
al.28 reported the preferential 1,4-reduction of chalcones,
which was promoted by (R,R)-1e and a HCO2H/Et3N mixture
(Scheme 1b).
The hydrogenation of enone 2a using 5 equiv of HCO2Na in
water with 5 mol % (R,R)-1a and 20 mol % of cationic
cetyltrimethylammonium bromide (CTAB) as phase-transfer
catalyst (PTC) at 45 °C (Table 1, entry 1) led, after 20 h, to a
Received: December 19, 2020
Published: March 8, 2021
The enantioselective synthesis of homoisoflavanones
through an asymmetric transfer hydrogenation−dynamic
https://dx.doi.org/10.1021/acs.joc.0c02981
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 4849−4858
4849

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
process and resulting the cis-4a alcohol with an (R,R)-
configuration as the major product.30 In methanol (Table 1,
entry 2) the full conversion of the intermediate 6a was
observed (as for all other entries in Table 1) and 4a was
formed with a higher enantioselectivity (97:3 er), but the cis/
trans ratio remained the same (72:28). In MeOH/H2O, the
cis/trans ratio decreased (Table 1, entry 3), while DCE/H2O
improved the diastereoselectivity to 82:18 but with a decrease
in the er (Table 1, entry 4). Attempts to improve the
stereoselectivity in DCE/H2O resulted in tests with neutral
and anionic PTC (Table 1, entries 5 and 6, respectively; see
also Table S2) as well as tests under acid and basic conditions
using, respectively, HCO2H and Na2CO3 as additives (Table 1,
entries 7 and 8, respectively); however, no significant
improvements were achieved. The decrease in the reaction
time from 20 to 5 h did not affect the conversion of 2a
(compare Table 1, entries 4 and 9, respectively), but an
increase in the stereoselectivity was observed.
Scheme 1. ATH of α,β-Unsaturated Ketones Using (R,R)-1
Catalysts
Then, the precatalysts (R,R)-1b−d were tested under the
same conditions (Table 1, entries 10−12, respectively). A
better er was found in all cases compared to that with (R,R)-
1a. However, despite the excellent er achieved by (R,R)-1d
(>99:1), a significant loss of diastereoselectivity was observed
(Table 1, entry 12). Thus, (R,R)-1c was considered the best
complex (92:8 cis/trans, 95:5 er). The efficacy of this η6-
mesitylene precatalyst was already reported due to its ability to
form multiple electrostatic CH−π interactions with the
substrate.42 A decrease in the temperature from 45 °C to rt
showed no effect on the reaction stereoselectivity (Table 1,
entry 13). Finally, Lewis acids and Brønsted acids were used as
additives43−45 (Table S3), and 10 mol % Cu(OTf)2 resulted in
mixture of 4a and 6a, showing that the catalyst was able to
promote the total reduction of the enone through a DKR
a
Table 1. Optimization of ATH-DKR Conditions for 2a
b
c
d
e
e
f
g
entry
(R,R)-1
T (°C)
t (h)
PTC
solvent
H2O
MeOH
additive
4a/6a
4a cis/trans
yield (%)
er (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1c
1c
1c
45
45
45
45
45
45
45
45
45
45
45
45
rt
20
20
20
20
20
20
20
20
5
5
5
5
20
5
CTAB
CTAB
CTAB
CTAB
73:27
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
72:28
72:28
62:38
82:18
81:19
85:15
74:26
80:20
86:14
74:26
92:8
34
54
57
71
66
83
72
72
73
74
85
60
69
66
65
93:7
97:3
95:5
MeOH/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
88:12
89:11
85:15
73:27
89:11
92:8
Tween 20
OSAS
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
HCO2H
Na2CO3
9
10
11
12
13
14
15
95:5
95:5
>99:1
95:5
97:3
62:38
92:8
90:10
90:10
45
rt
Cu(OTf)2
Cu(OTf)2
20
98:2
a
b
All reactions were carried out on a 0.1 mmol scale using (R,R)-1 (5 mol %) and HCO2Na (5 equiv). PTC (phase-transfer catalyst, 20 mol %):
c
CTAB, cetyltrimethylammonium bromide; Tween 20, polyoxyethylenesorbitan monolaurate; and OSASS, octane-1-sulfonic acid sodium salt. At
d
0.25 M using the pure solvent or a 1:1 mixture with water. Using HCO2H (5 equiv), Na2CO3 (1.25 equiv), and Cu(OTf)2 (10 mol %) when
e
specified. Ratios were determined by the analysis of the 1H NMR spectrum of the crude mixture. The full conversion of 2a was achieved in all tests
f
except entry 2 (63%). The corresponding allylic alcohol was found as a minor product (<5%) in entries 1, 3, 9, 11, and 15. Isolated yield for the
major diastereoisomer (cis-4a) after preparative TLC. Determined by HPLC analysis using a chiral stationary phase column for the major
g
diastereoisomer.
4850
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
a
Table 2. Scope of the ATH-DKR of 2 and 3 Catalyzed by (R,R)-1c
a
All reactions were carried out on a 0.1 mmol scale using (R,R)-1c (5 mol %), HCO2Na (5 equiv), Cu(OTf)2(10 mol %), CTAB (20 mol %), and
b
DCE/H2O (1:1, 0.25 M) at rt for either 20 (2a−d) or 72 h (3a−h). Determined by the analysis of the 1H NMR spectrum of the crude mixture;
c
d
conversions ≥95% were achieved. Isolated yield for the major diastereoisomer (cis-4/5) after preparative TLC. Determined by HPLC analysis for
e
the major diastereoisomer. At 45 °C for 20 h.
a good increase of the er from 95:5 to 98:2 for the ATH-DKR
of 2a compared to tests without the additive at 45 °C or rt
(Table 1, compare entries 10 and 13 against 14 and 15).
Next, the hydrogenation of different homoisoflavones 2b−d
was also investigated (Table 2, entries 1−3, respectively).
These substrates were oxygenated at the 7-position of the A-
ring with different protecting groups, which could be removed
after an oxidative step of the resulting alcohols 4b−d to
enantioselectively obtain the natural homoisoflavanone dihy-
drobonducellin (10c). The electron-donating groups in 2b
(OMe) and 2c (OMOM) decreased the substrate reactivity,
and the intermediate ketones 6b and 6c were found in the
reaction crude in 15 and 9% yields, respectively, after 20 h.
Moreover, to our delight higher diastereoselectivities (>95:5)
and excellent er’s (up to 99:1) were achieved in alcohols 4b
and 4c. In contrast, the reaction with 2d (7-OAc) resulted in a
decrease in the reaction stereoselectivity, and 9% of the allylic
alcohol 8d was also formed (Table 2, entry 3).
alcohols cis-5 as major products in high diastereo- and
enantioselectivities. For substrates unsubstituted at the A-ring
(3a−d) (Table 2, entries 4−7, respectively), considerable
amounts of allylic alcohols 9a−d were obtained with high
enantioselectivities, for instance, 9b with a 96:4 er. The
decrease in the reactivity was even more pronounced in enones
substituted by methoxy groups on the A-ring in the para- or
ortho-position to the carbonyl group (Table 2, entries 8−12),
resulting in 29−35% yields of ketones 7e−h in the same
reaction time. Interestingly, in these cases only small amounts
of allylic alcohols 8e−h were formed in the crude reaction.
With the aim of improving the chemical yields of alcohols cis-5,
additional tests were performed with the enone 3f. With the
increase in temperature from rt to 45 °C, the alcohol cis-5f was
isolated in a 59% yield in 20 h at a similar level of
stereoselectivity (Table 2, entry 10), while a 48% yield was
found after 72 h at rt (Table 2, entry 9). Besides, the beneficial
effect of Cu(OTf)2 over the reaction outcome could be proven
again, since without the additive the enantioselectivity dropped
to an 89:11 ratio at 45 °C (Table S6).
The substitution of the oxygen atom at the chromanone ring
by the methylene group in enones 3a−h significantly decreases
the chemical reactivity (Table 2). Therefore, the reaction times
were set at 72 h at rt to achieve higher conversions rates.
Interestingly, the lower reactivity of these substrates resulted in
The alcohols cis-4a and cis-5c, which were obtained through
reduction with the (S,S)-1c catalyst, were oxidized to ketones
(S)-6a and (R)-7c using Dess−Martin periodinane (DMP)
4851
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
without an erosion of the ee (Scheme 2a).46 Next, (R,S)-5f was
also oxidized under the same reaction conditions, resulting in
Scheme 3. Mechanistic Proposal for the Reductions of 2 and
3
Scheme 2. Enantioselective Synthesis of Homoisoflavanones
and Carba-Analogues
the 1,2-reduction that leads to allylic alcohols 8 or 9. The
resulting ketones 6 or 7 are reduced through DKR to the
saturated alcohols cis-4 or cis-5, respectively, as major products.
Interestingly, nonconsumed ketones 6c (Table 2, entry 2)
and 7f (Table 2, entry 10) were not racemic but instead
enantiomerically enriched with their less-reactive enantiomers
(S)-6c and (R)-7f, respectively. These er’s are the result of the
combination of the rate of the enantiomer interconversion and
the rate of the consumption (R)-6 and (S)-7 to the
corresponding cis-alcohols cis-4 and cis-5. On the other hand,
alcohols trans-4 or trans-5 would originate from (S)-6 or (R)-
7.
(S)-7f in a 94:6 er (Scheme 2b). This ketone belongs to a
family of synthetic compounds that displays antiproliferative
activity against MCF-7 tumor cells.47 Then, for the synthesis of
the natural dihydrobonducellin,48 the arylenone 2c was
reduced in an excellent dr and er to alcohol (R,R)-4c using
only 2 mol % precatalyst (R,R)-1c at rt for 20 h. After an
oxidation step to (R)-6c, followed by MOM removal under
mild conditions,49 (R)-10c48 was obtained with a 50% overall
yield and a 92:8 er. (Scheme 2c).
Once 8 or 9 were present in some of our crude products and
the transformation of allylic alcohols into enantiomeric-
enriched saturated alcohols was reported using RuII complexes,
we considered that these alcohols could be the precursors of
saturated alcohols 4 and 5.50−53 To check this possibility, the
allylic alcohols (rac)-8a and (rac)-9c were prepared by the
reduction of 2a and 3a, respectively, with NaBH4 and
submitted to the same reaction conditions at rt. Interestingly,
these allylic alcohols did not lead to saturated alcohols 4a and
5c (Scheme S1). Therefore, we assume that the ratio between
the saturated alcohols and the allylic alcohols observed in our
reactions reflects the relative rate of 1,4- vs 1,2-addition in the
first step of the reduction of enones 2 or 3.
In conclusion, the RuII chiral complex (R,R)-1c acts as dual
precatalyst in the total reduction of enones 2 and 3 through the
reduction of CC bonds, followed by ATH-DKR of the
resulting saturated ketones. By using low catalyst loadings (2−
5 mol %) in a biphasic aqueous media under neutral
conditions, the isolated yields ranged from moderate to high
with high diastereo- and enantiomeric ratios. Finally, the
developed protocol proved to be practical and suitable for a
scaled-up reaction (Scheme S3). Additional mechanistic
studies, synthetic applications, and the antiproliferative activity
evaluation of the synthesized compounds are under inves-
tigation in our laboratories.
EXPERIMENTAL SECTION
■
General Information. All commercially available reagents and
solvents were used without further purification. The (R,R)-1a−d
precatalysts were purchased from Sigma-Aldrich. Analytical thin layer
chromatography (TLC) was performed on 0.25 mm silica gel 60 F254
plates and visualized either under UV light (254 or 365 nm) or by
staining with vanillin/H2SO4. Preparative TLC was performed on 20
cm × 20 cm glass-backed plates bearing a 0.5 mm layer of silica gel 60
F254(15−40 μm). Flash column chromatography was performed on
All these results (Tables 1 and 2) are in agreement with the
mechanistic proposal showed in Scheme 3. In the first step,
enones 2 or 3 are hydrogenated to ketones 6 or 7 (1,4-
reduction), respectively, and the resulting enantiomers are in
equilibrium through the enol tautomers. This step is faster than
4852
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
silica gel 60 (230−400 mesh) SiliaFlash. Optical rotations were
measured on a Jasco P-2000 polarimeter at approximately 27 °C, and
concentrations (c) are given in grams per 100 mL. Enantiomeric
excesses were determined using a Shimadzu LC 20AT Prominence
HPLC system equipped with a UV detector (SPD-M20A), a system
controller (CBM-20A), a column oven (CTO-20A), an autosampler
(SIL-20AHT), an online degasser (DGU-20A), and a chiral column
(CHIRALPAK-IA) using mixtures of n-hexane/isopropyl alcohol as
the mobile phase at 28 °C. NMR spectra were recorded on Varian
Unity 400 and 500 MHz instruments at 25 °C. Chemical shifts are
expressed in ppm relative to TMS or the deuterated solvent, and the
coupling constants (J) are expressed in Hertz. High-resolution mass
spectra were obtained with a Bruker Maxis Impact mass spectrometer
with an eletrospray ionization (ESI) source coupled to quadrupole
Time-Of-Flight (qTOF) hybrid mass analyzer.
yield): 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 1H), 7.81
(d, J = 2.0 Hz, 1H), 7.31−7.23 (m, 2H), 6.97 (d, J = 8.8 Hz, 2H),
6.63 (dd, J = 8.9, 2.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 5.36 (d, J =
2.0 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H).
(E)-3-(4-Methoxybenzylidene)-7-(methoxymethoxy)chroman-4-
one (2c).5 8 To
a solution of (E)-7-hydroxy-3-(4-
methoxybenzylidene)chroman-4-one (1 mmol, 282 mg) in dry
DCM (4 mL) at 0 °C under an argon atmosphere was added
DIPEA (3 mmol, 0.52 mL). After stirring for 10 min, MOMCl (3
mmol, 0.23 mL) was added to the solution dropwise. The resulting
mixture was stirred for 16 h at rt. Afterward, the solution was poured
into saturated aq NH4Cl (30 mL), then DCM (30 mL) was added to
the mixture. The organic layer was washed with brine (30 mL), dried
over Na2SO4, and concentrated under reduced pressure. The resulting
crude was purified by flash chromatography (n-hexane/AcOEt 75:25)
1
P r e p a r a t i o n o f t h e C o m p o u n d s . ( E ) - 3 - ( 4 -
Methoxybenzylidene)chroman-4-one (2a).54 4-Chromanone (1.0
mmol, 148 mg) was dissolved in methanol (6 mL), followed by the
addition of 4-methoxybenzaldehyde (1.05 mol, 128 μL) and
concentrated hydrochloric acid (3 mL). The mixture was refluxed
for 24 h and then diluted with water. Filtration afforded the crude
product, which was crystallized from methanol to give 2a as a pure
to afford the pure product as a yellow solid (222 mg, 68% yield): H
NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.8, 1.0 Hz, 1H), 7.79 (s,
1H), 7.25 (d, J = 8.8 Hz, 2H), 7.00−6.92 (m, 2H), 6.71 (ddd, J = 8.8,
2.4, 1.0 Hz, 1H), 6.58 (t, J = 1.6 Hz, 1H), 5.34 (s, 2H), 5.19 (s, 2H),
3.83 (s, 3H), 3.47 (s, 3H).
(E)-3-(4-Methoxybenzylidene)-4-oxochroman-7-yl acetate
(2d).59 To a MW tube equipped with a standard cap (CEM
Discover) were added (E)-7-hydroxy-3-(4-methoxybenzylidene)-
chroman-4-one (1 mmol, 282 mg), pyridine (2 mL), and acetic
anhydride (8 mmol, 882 μL). The tube was sealed, and the sample
was irradiated at 100 °C for 1 h. Then, methanol (10 mL) was added
at rt to remove the acetic anhydride under reduced pressure. Toluene
(10 mL × 4) was added and evaporated to remove the pyridine.
Finally, methanol (10 mL × 4) was added and evaporated off to
remove the remaining toluene, resulting in 2d (279 mg, 86% yield) as
1
product (215 mg, 81% yield): H NMR (500 MHz, CDCl3) δ 8.02
(dd, J = 7.8, 1.7 Hz, 1H), 7.84 (s, 1H), 7.48 (ddd, J = 8.3, 7.2, 1.8 Hz,
1H), 7.29 (d, J = 8.7 Hz, 2H), 7.07 (ddd, J = 8.0, 7.2, 1.1 Hz, 1H),
7.00−6.94 (m, 3H), 5.38 (d, J = 1.8 Hz, 2H), 3.86 (s, 3H).
Synthesis of 7-Hydroxy-chromanon-4-one.55 Step 1. The
trifluoromethanesulfonic acid (24 mmol, 2.12 mL) was added to a
mixture of Resorcinol (8 mmol, 881 mg) and 3-chloropropionic acid
(9.6 mmol, 1042 mg). The resulting solution was stirred at 80 °C for
1 h, cooled to room temperature over 10 min, and poured into
chloroform (50 mL). Then, the solution was washed with water (50
mL x 2), and the aqueous layer was extracted with chloroform (25 mL
× 2). The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
resulting product 3-chloro-1-(2,4-dihydroxyphenyl) propan-1-one
(911 mg, 56% yield) was used crude in the next step: 1H NMR
(500 MHz, CDCl3) δ 12.46 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 6.41
(dd, J = 8.7, 2.5 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 5.46 (s, 1H), 3.91
(t, J = 6.8 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H). Step 2. A NaOH solution
(2 M, 40 mL) was added to a round-bottom flask containing 3-chloro-
1-(2,4-dihydroxyphenyl) propan-1-one (4.5 mmol, 903 mg), and the
resulting mixture was left under stirring at rt for 2 h. Then, a H2SO4
solution (6 M) was added until pH < 2, and the mixture was extracted
with AcOEt (60 mL × 2). The resulting organic phase was washed
with brine (120 mL), dried over Na2SO4, and concentrated under
reduced pressure, resulting in 7-hydroxy-chroman-4-one (705 mg,
54% yield for the two steps) that was used without further purification
in the following step: 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.7
Hz, 1H), 6.52 (dd, J = 8.7, 2.3 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.03
(s, 1H), 4.51 (t, J = 6.4 Hz, 2H), 2.82−2.71 (m, 2H).
1
a light-yellow solid that was used without further purification: H
NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.6 Hz, 1H), 7.84 (s, 1H),
7.28 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.81 (dd, J = 8.6,
2.1 Hz, 1H), 6.76 (d, J = 2.1 Hz, 1H), 5.40 (d, J = 1.6 Hz, 2H), 3.87
(s, 3H), 2.31 (s, 3H).
General Procedure for the Synthesis of 3a−g.60 The
corresponding 1-tetralone (1.0 mmol) was dissolved in ethanol (6
mL), followed by the addition of the appropriate benzaldehyde (1.0
mol). The 10% aq solution of NaOH was added dropwise to the
mixture at 0 °C. After 20 min, the mixture was stirred for 24 h at
room temperature. Filtration afforded the products 3a−h as pure
products.
(E)-2-Benzylidene-3,4-dihydronaphthalen-1(2H)-one (3a).61
1
Yielded 221 mg, 94%: H NMR (400 MHz, CDCl3) δ 8.14 (dd, J
= 7.8, 1.4 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.54−7.32 (m, 6H),
7.29−7.21 (m, 2H), 3.14 (ddd, J = 6.8, 5.6, 1.8 Hz, 2H), 2.95 (dd, J =
7.5, 5.4 Hz, 2H).
(E)-2-(4-Chlorobenzylidene)-3,4-dihydronaphthalen-1(2H)-one
(3b).62 Yielded 215 mg, 80%: H NMR (500 MHz, CDCl3) δ 8.01
1
(dd, J = 7.8, 1.4 Hz, 1H), 7.68 (s, 1H), 7.37 (td, J = 7.5, 1.5 Hz, 1H),
7.30−7.20 (m, 5H), 7.13 (d, J = 7.6 Hz, 1H), 2.97 (td, J = 6.5, 1.9 Hz,
2H), 2.83 (dd, J = 7.6, 5.3 Hz, 2H).
(E)-7-Hydroxy-3-(4-methoxybenzylidene)chroman-4-one.56 7-
hydroxy-chroman-4-one (1.0 mmol, 164 mg) was dissolved in
methanol (6 mL) followed by the addition of 4-methoxybenzaldehyde
(1.05 mol, 128 μL) and concentrated hydrochloric acid (3 mL). The
mixture was refluxed for 24 h and then diluted with water. Filtration
afforded the crude product, which was crystallized from methanol to
(E)-2-(4-Methoxybenzylidene)-3,4-dihydronaphthalen-1(2H)-
one (3c).63 Yielded 240 mg, 91%: H NMR (400 MHz, CDCl3) δ
1
8.12 (dd, J = 7.8, 1.4 Hz, 1H), 7.85 (s, 1H), 7.48 (td, J = 7.5, 1.4 Hz,
1H), 7.44 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6
Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H), 3.15 (td, J = 6.5, 1.8
Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H).
1
give the pure product (175 mg, 62% yield): H NMR (500 MHz,
DMSO-d6) δ 10.65 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.64 (s, 1H),
7.41 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.55 (dd, J = 8.7,
2.2 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 5.36 (d, J = 1.6 Hz, 2H), 3.82
(s, 3H).
(E)-2-(3,4-Dimethoxybenzylidene)-3,4-dihydronaphthalen-
1(2H)-one (3d).64 Yielded 183 mg, 62%: 1H NMR (500 MHz,
CDCl3) δ 8.12 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.49 (tt, J = 7.5, 1.1
Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.28−7.22 (m, 1H), 7.13−7.06 (m,
1H), 6.99 (d, J = 1.9 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H),
3.91 (s, 3H), 3.21−3.14 (m, 2H), 2.96 (t, J = 6.5 Hz, 2H).
(E)-2-Benzylidene-6-methoxy-3,4-dihydronaphthalen-1(2H)-one
(3e).65 Yielded 154 mg, 58%: 1H NMR (400 MHz, CDCl3) δ 8.12 (d,
J = 8.7 Hz, 1H), 7.84 (s, 1H), 7.47−7.31 (m, 5H), 6.88 (dd, J = 8.7,
2.6 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 3.88 (s, 3H), 3.12 (ddd, J = 6.9,
5.7, 1.8 Hz, 2H), 2.97−2.89 (m, 2H).
(E)-7-Methoxy-3-(4-methoxybenzylidene)chroman-4-one (2b).57
To a solution of (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-
one (1 mmol, 282 mg) in acetone (5 mL) at rt were added
iodomethane (3 mmol, 0.19 mL) and K2CO3 (3 mmol, 415 mg). The
mixture was refluxed for 2 h, then the acetone was evaporated, and the
crude was diluted in AcOEt (25 mL). The mixture was washed with
water (25 mL) and brine (25 mL), dried over Na2SO4, and
concentrated under reduced pressure, resulting in 2b (240 mg, 81%
4853
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(E)-6-Methoxy-2-(4-methoxybenzylidene)-3,4-dihydronaphtha-
2.4 Hz, 1H), 5.12 (s, 2H), 4.45 (d, J = 3.0 Hz, 1H), 4.09−4.03 (m,
2H), 3.80 (s, 3H), 3.45 (s, 3H), 2.80 (dd, J = 13.8, 8.5 Hz, 1H), 2.61
(dd, J = 13.8, 7.2 Hz, 1H), 2.29−2.20 (m, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 158.4, 158.1, 155.3, 131.1, 131.0, 130.0, 118.2, 113.9,
109.1, 104.1, 94.3, 65.1, 64.5, 56.0, 55.4, 40.2, 32.0; HRMS(ESI) m/z
[M + Na]+ calcd for C19H22O5Na+ 353.1359, found 353.1360.
(3R,4R)-4-Hydroxy-3-(4-methoxybenzyl)chroman-7-yl Acetate
(cis-4d). Purified by PTLC (n-hexane/EtOAc 70:30) as a pale yellow
oil (21 mg, 63% yield): [α]2D7 = +29.9 (c = 1, CHCl3); the
enantiomeric ratio (93:7 er) was determined by HPLC analysis using
a Chiralpack IA column, n-hexane/isopropyl alcohol 80:20, 1 mL/
min, 28 °C, tRmaj = 10.1 min, tRmin = 17.0 min, 277 nm; 1H NMR (400
MHz, CDCl3) δ 7.18 (t, J = 8.2 Hz, 3H), 6.87 (d, J = 8.5 Hz, 2H),
6.62 (dd, J = 8.2, 2.3 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 4.48 (s, 1H),
4.07 (d, J = 7.6 Hz, 2H), 3.80 (s, 3H), 2.80 (dd, J = 13.8, 8.5 Hz, 1H),
2.61 (dd, J = 13.8, 7.2 Hz, 1H), 2.27 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 169.5, 158.2, 155.3, 151.7, 131.0, 130.9, 130.2, 122.1,
114.1, 110.3, 65.2, 64.6, 55.4, 40.1, 31.9, 21.2; HRMS(ESI) m/z [M +
Na]+ calcd for C19H20O5Na+ 351.1203, found 351.1208
len-1(2H)-one (3f).66 Yielded 138 mg, 47%: H NMR (500 MHz,
1
CDCl3) δ 8.10 (d, J = 8.7 Hz, 1H), 7.81 (s, 1H), 7.41 (d, J = 8.6 Hz,
2H), 6.94 (d, J = 8.8 Hz, 2H), 6.87 (dd, J = 8.7, 2.5 Hz, 1H), 6.70 (d,
J = 2.5 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.12 (ddd, J = 6.9, 5.8, 1.8
Hz, 2H), 2.91 (dd, J = 7.6, 5.5 Hz, 2H).
(E)-2-(3,4-Dimethoxybenzylidene)-6-methoxy-3,4-dihydronaph-
thalen-1(2H)-one (3g).66 Yielded 84 mg, 26%: H NMR (400 MHz,
1
CDCl3) δ 8.11 (d, J = 8.7 Hz, 1H), 7.80 (s, 1H), 7.11−7.03 (m, 1H),
6.98 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.88 (dd, J = 8.7,
2.6 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.87
(s, 3H), 3.14 (ddd, J = 7.0, 5.8, 1.8 Hz, 2H), 2.92 (t, J = 6.5 Hz, 2H).
(E)-5,8-Dimethoxy-2-(4-methoxybenzylidene)-3,4-dihydronaph-
thalen-1(2H)-one (3h).53 5,8-Dimethoxy-1-tetralone (1.0 mmol, 206
mg) was dissolved in methanol (6 mL), followed by the addition of 4-
methoxybenzaldehyde (1.05 mol, 128 μL) and concentrated hydro-
chloric acid (3 mL). The mixture was refluxed for 24 h and then
diluted with water. Filtration afforded the crude product, which was
crystallized from methanol to give 3h as a pure product (234 mg,
1
72%): H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.43 (d, J = 8.7
(1R,2S)-2-Benzyl-1,2,3,4-tetrahydronaphthalen-1-ol (cis-5a). All
spectra were in agreement with reported data.68 Purified by PTLC (n-
Hz, 2H), 6.99 (d, J = 9.1 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.83 (d, J
= 9.0 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 2.99 (ddd, J =
6.8, 5.3, 1.8 Hz, 2H), 2.86 (dd, J = 7.7, 5.1 Hz, 2H).
hexane/EtOAc 90:10) as a white solid (13 mg, 53% yield): [α]D27
=
+31.8 (c = 0.8, CHCl3); the enantiomeric ratio (92:8 er) was
determined by HPLC analysis using a Chiralpack IA column, n-
hexane/isopropyl alcohol 90:10, 1 mL/min, 28 °C, tRmaj = 6.4 min,
General Procedure for the Synthesis of (R,R)-4 or (R,S)-5. To
a Pyrex tube were added the substrate 2 or 3 (0.1 mmol),
RuCl[(R,R)-TsDPEN](mesitylene) 1c (0.005 mmol, 3.1 mg),
Cu(OTf)2 (0.010 mmol, 3.6 mg), CTAB (0.020 mmol, 7.3 mg),
and dichloroethane (0.2 mL), and the resulting mixture was stirred at
rt for 15 min under an argon atmosphere. Then, a solution of sodium
formate (0.5 mmol, 34 mg) in water (0.2 mL) was added, and the
reaction mixture was stirred at room temperature for either 20 (2a−
d) or 72 h (3a−i), diluted in AcOEt (10 mL), dried over Na2SO4 ,and
filtered through a small pad of silica. The resulting crude was then
purified by preparative thin-layer chromatography (in n-Hexane/
AcOEt), yielding the pure products (R,R)-4 or (R,S)-5.
1
tRmin = 7.4 min, 208 nm; H NMR (500 MHz, CDCl3) δ 7.48−7.11
(m, 9H), 4.56 (d, J = 3.0 Hz, 1H), 3.00 (dd, J = 13.5, 7.8 Hz, 1H),
2.93 (dd, J = 17.3, 5.4 Hz, 1H), 2.85−2.73 (m, 2H), 2.07 (dtd, J =
10.9, 7.5, 3.5 Hz, 1H), 1.88 (qd, J = 12.3, 5.6 Hz, 1H), 1.80−1.70 (m,
1H); 13C{1H} NMR (101 MHz, CDCl3) δ 140.8, 138.6, 137.0, 130.2,
129.4, 129.3, 128.5, 128.1, 126.3, 126.0, 69.5, 41.9, 38.3, 29.3, 22.7.
HRMS (ESI) m/z [M + Na]+ calcd for C17H18ONa+ 261.1250, found
261.1263.
(1R,2S)-2-(4-Chlorobenzyl)-1,2,3,4-tetrahydronaphthalen-1-ol
(cis-5b). This compound was only partially characterized.69 Purified
by PTLC (n-hexane/EtOAc 90:10) as an off-white solid (20 mg, 75%
yield): [α]2D7 = +45.4 (c = 0.6, CHCl3); the enantiomeric ratio (91:9
er) was determined by HPLC analysis using a Chiralpack IA column,
n-hexane/isopropyl alcohol 90:10, 1 mL/min, 28 °C, tRmaj = 6.6 min,
(3R,4R)-3-(4-Methoxybenzyl)chroman-4-ol (cis-4a). All spectra
were in agreement with reported data.67 Purified by PTLC (n-hexane/
EtOAc 75:25) as a white solid (18 mg, 65% yield): [α]2D7 = +30.2 (c =
1, CHCl3); the enantiomeric ratio (98:2 er) was determined by
HPLC analysis using a Chiralpack IA column, n-hexane/isopropyl
alcohol 90:10, 1 mL/min, 28 °C, tRmaj = 10.6 min, tRmin = 14.6 min,
1
tRmin: 7.8 min, 208 nm; H NMR (400 MHz, CDCl3) δ 7.32−7.10
(m, 8H), 4.47 (d, J = 3.1 Hz, 1H), 2.98−2.83 (m, 2H), 2.81−2.64 (m,
2H), 1.97 (dtd, J = 10.8, 7.6, 7.1, 3.5 Hz, 1H), 1.82 (qd, J = 12.4, 5.6
Hz, 1H), 1.75−1.64 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
139.3, 138.5, 136.9, 131.8, 130.7, 130.1, 129.3, 128.6, 128.3, 126.4,
69.3, 41.86, 37.7, 29.3, 22.7; HRMS (ESI) m/z [M + Na]+ calcd for
C17H17ClONa+ 295.0860, found 295.0860.
1
284 nm; H NMR (500 MHz, CDCl3) δ 7.23−7.16 (m, 4H), 6.91−
6.82 (m, 4H), 4.50 (d, J = 3.1 Hz, 1H), 4.12−4.04 (m, 2H), 3.80 (s,
3H), 2.82 (dd, J = 13.8, 8.5 Hz, 1H), 2.62 (dd, J = 13.8, 7.3 Hz, 1H),
2.28 (ttd, J = 8.6, 7.2, 3.2 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 158.2, 154.5, 131.2, 130.3, 130.1, 123.0, 124.3, 120.6, 117.0,
114.1, 65.1, 65.0, 55.4, 40.2, 32.0; HRMS(ESI) m/z [M + Na]+ calcd
for C17H18O3Na+ 293.1148, found 293.1149.
(1R,2S)-2-(4-Methoxybenzyl)-1,2,3,4-tetrahydronaphthalen-1-ol
(cis-5c). This compound was characterized only in a diastereoisomeric
mixture (50:50).70 Purified by PTLC (n-hexane/EtOAc 80:20) as a
white solid (14 mg, 52% yield): [α]2D7 = +20.0 (c = 1, CHCl3); the
enantiomeric ratio (98:2 er) was determined by HPLC analysis using
a Chiralpack IA column, n-hexane/isopropyl alcohol 90:10, 1 mL/
min, 28 °C, tRmaj = 8.3 min, tRmin = 10.0 min, 278 nm; 1H NMR (400
MHz, CDCl3) δ 7.31−7.07 (m, 6H), 6.86 (d, J = 8.5 Hz, 2H), 4.50
(d, J = 3.0 Hz, 1H), 3.80 (s, 3H), 2.94−2.82 (m, 2H), 2.79−2.61 (m,
2H), 2.05−1.91 (m, 1H), 1.81 (qd, J = 12.3, 5.6 Hz, 1H), 1.69 (ddd, J
= 12.5, 6.1, 2.9 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 158.0,
138.7, 137.1, 132.8, 130.3, 130.2, 129.2, 128.1, 126.3, 113.8, 69.5,
55.5, 42.0, 37.4, 29.4, 22.7; HRMS (ESI) m/z [M + Na]+ calcd for
C18H20O2Na+ 291.1356, found 291.1355.
(1R,2S)-2-(3,4-Dimethoxybenzyl)-1,2,3,4-tetrahydronaphthalen-
1-ol (cis-5d). Purified by PTLC (n-hexane/EtOAc 70:30) as a yellow
oil (18 mg, 59% yield): [α]2D7 = +27.0 (c = 1, CHCl3); the
enantiomeric ratio (98:2 er) was determined by HPLC analysis using
a Chiralpack IA column, n-hexane/isopropyl alcohol 90:10, 1 mL/
min, 28 °C, tRmaj = 13.4 min, tRmin = 18.8 min, 278 nm; 1H NMR (400
MHz, CDCl3) δ 7.31−7.06 (m, 4H), 6.87−6.72 (m, 3H), 4.52 (d, J =
3.0 Hz, 1H), 3.88 (s, 6H), 2.97−2.85 (m, 2H), 2.76 (ddd, J = 17.4,
11.7, 6.2 Hz, 1H), 2.68 (dd, J = 13.6, 7.3 Hz, 1H), 2.00 (dddd, J =
13.6, 10.7, 7.6, 3.0 Hz, 1H), 1.89−1.77 (m, 1H), 1.75−1.67 (m, 1H);
(3R,4R)-7-Methoxy-3-(4-methoxybenzyl)chroman-4-ol (cis-4b).
Purified by PTLC (n-hexane/AcOEt 70:30) as a light brown waxy
solid (18 mg, 61% yield): [α]2D7 = +37.0 (c = 1, CHCl3); the
enantiomeric ratio (97:3 er) was determined by HPLC analysis using
a Chiralpack IA column, n-hexane/isopropyl alcohol 90:10, 1 mL/
min, 28 °C, tRmaj = 16.8 min, tRmin = 26.1 min, 284 nm; 1H NMR (500
MHz, CDCl3) δ 7.18 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H),
6.87 (d, J = 8.6 Hz, 2H), 6.47 (dd, J = 8.4, 2.5 Hz, 1H), 6.37 (d, J =
2.5 Hz, 1H), 4.45 (d, J = 3.0 Hz, 1H), 4.09−4.03 (m, 2H), 3.80 (s,
3H), 3.75 (s, 3H), 2.81 (dd, J = 13.8, 8.5 Hz, 1H), 2.61 (dd, J = 13.8,
7.2 Hz, 1H), 2.30−2.20 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3)
δ 161.1, 158.2, 155.5, 131.2, 131.1, 130.1, 117.0, 114.1, 107.9, 101.3,
65.2, 64.6, 55.5, 55.4, 40.4, 32.2; HRMS(ESI) m/z [M + Na]+ calcd
for C18H20O4Na+ 323.1254, found 323.1257.
(3R,4R)-3-(4-Methoxybenzyl)-7-(methoxymethoxy)chroman-4-ol
(cis-4c). Purified by PTLC (n-hexane/EtOAc 70:30) as a pale yellow
oil (23 mg, 71% yield): [α]2D7 = +59.5 (c = 1, CHCl3); the
enantiomeric ratio (99:1 er) was determined by HPLC analysis using
a Chiralpack IA column, n-hexane/isopropyl alcohol (90:10, 1 mL/
1
min), tRmaj = 18.4 min, tRmin = 28.1 min, 284 nm; H NMR (500
MHz, CDCl3) δ 7.17 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.4 Hz, 1H),
6.86 (d, J = 8.5 Hz, 2H), 6.58 (dd, J = 8.4, 2.5 Hz, 1H), 6.53 (d, J =
4854
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
13C{1H} NMR (101 MHz, CDCl3) δ 148.9, 147.3, 138.6, 137.1,
133.3, 130.2, 129.3, 128.2, 126.3, 121.2, 112.5, 111.3, 69.5, 56.1, 55.9,
41.9, 37.9, 29.4, 22.7; HRMS (ESI) m/z [M + Na]+ calcd for
C19H22O3Na+ 321.1461, found 321.1468.
temperature for either 20 (2a) or 72 h (3c), diluted in AcOEt (60
mL), dried over Na2SO4, and filtered through a small pad of silica.
The resulting crude was then purified by flash chromatography (in n-
hexane/AcOEt), yielding the pure products (R,R)-4a (205.4 mg, 76%
yield, 96:4 er) or (R,S)-5c (123.2 mg, 46% yield, 92:8 er).
(1R,2S)-2-Benzyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol
(cis-5e). Purified by PTLC (n-hexane/EtOAc 80:20) as a pale yellow
oil (14 mg, 51% yield); the enantiomeric ratio (98:2 er) was
determined by HPLC analysis using a Chiralpack IA column, n-
hexane/isopropyl alcohol 95:5, 1 mL/min, 28 °C, tRmaj = 15.4 min,
General Procedure for the Synthesis of ketones 6 and 7.46
To a solution of corresponding enantioenriched saturated alcohol cis-
4 or cis-5 (0.05 mmol) in dichloromethane (2.5 mL, 0.02 M) at 0 °C
was added Dess−Martin periodinane (DMP) (0.15 mmol, 3 equiv, 64
mg), and the mixture was stirred for 1 h at 0 °C. Then, the reaction
was diluted in dichloromethane (15 mL) and washed with a 1:1
mixture of saturated solutions of Na2S2O3 (10 mL) and NaHCO3 (10
mL), dried over Na2SO4, and concentrated under reduced pressure.
The resulting crude was purified by preparative thin layer
chromatography (n-hexane/AcOEt), yielding the products 6 or 7
without significant losses of the enantiomeric excess.
t
Rmin = 16.5 min, 206 nm; 1H NMR (400 MHz, CDCl3) δ 7.29−7.17
(m, 5H), 7.18−7.09 (m, 2H), 6.66 (dd, J = 8.4, 2.7 Hz, 1H), 6.56 (d,
J = 2.6 Hz, 1H), 4.40 (d, J = 2.9 Hz, 1H), 3.70 (s, 3H), 2.87 (dd, J =
13.5, 7.8 Hz, 1H), 2.77 (ddd, J = 17.2, 5.8, 2.3 Hz, 1H), 2.71−2.59
(m, 2H), 1.92 (dddd, J = 10.5, 7.6, 4.6, 2.9 Hz, 1H), 1.74 (qd, J =
12.4, 5.7 Hz, 1H), 1.61 (ddd, J = 13.2, 5.9, 2.8 Hz, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 159.3, 140.9, 138.5, 131.3, 129.4, 128.5,
126.0, 113.5, 112.6, 69.1, 55.3, 42.1, 38.5, 29.8, 22.6; HRMS (ESI) m/
z [M + Na]+ calcd for C18H20O2Na+ 291.1356, found 291.1360.
(1R,2S)-6-Methoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-
naphthalen-1-ol (cis-5f). Purified by PTLC (n-hexane/EtOAc 80:20)
as a waxy yellow solid (14 mg, 48% yield): [α]2D7 = +28.3 (c = 0.5,
CHCl3); the enantiomeric ratio (97:3 er) was determined by HPLC
analysis using a Chiralpack IA column, n-hexane/isopropyl alcohol
90:10, 1 mL/min, 28 °C, tRmaj = 13.0 min, tRmin = 19.3 min, 206 nm;
1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.5 Hz, 3H), 6.86 (d, J =
(S)-3-(4-Methoxybenzyl)chroman-4-one ((S)-6a). All spectra were
in agreement with reported data.71 Purified by PTLC (n-hexane/
EtOAc 90:10) as a white solid (9 mg, 70% yield): the enantiomeric
ratio (95:5 er) was determined by HPLC analysis using a Chiralpack
IA column, n-hexane/isopropyl alcohol 90:10, 0.5 mL/min, 28 °C,
1
tRmaj = 16.8 min, tRmin = 16.2 min, 284 nm; H NMR (500 MHz,
CDCl3) δ 7.93 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 (ddd, J = 8.4, 7.1, 1.8
Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 7.03 (ddd, J = 8.0, 7.1, 1.1 Hz,
1H), 6.97 (dd, J = 8.4, 1.0 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 4.37
(dd, J = 11.5, 4.3 Hz, 1H), 4.18 (dd, J = 11.5, 8.1 Hz, 1H), 3.80 (s,
3H), 3.21 (dd, J = 14.1, 4.6 Hz, 1H), 2.88 (ddt, J = 10.3, 8.1, 4.4 Hz,
1H), 2.69 (dd, J = 14.1, 10.3 Hz, 1H). HRMS (ESI) m/z [M + Na]+
calcd for C17H16O3Na+ 291.0992, found 291.0994.
8.6 Hz, 2H), 6.73 (dd, J = 8.5, 2.7 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H),
4.46 (d, J = 2.9 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 2.92−2.80 (m,
2H), 2.77−2.62 (m, 2H), 1.99−1.89 (m, 1H), 1.86−1.73 (m, 1H),
1.67 (ddt, J = 9.9, 6.3, 2.7 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 159.3, 157.9, 138.6, 132.8, 131.4, 131.3, 130.3, 113.9, 113.4,
112.6, 69.0, 55.4, 55.3, 42.2, 37.6, 29.8, 22.6; HRMS (ESI) m/z [M +
Na]+ calcd for C19H22O3Na+ 321.1461, found 321.1461.
(1R,2S)-2-(3,4-Dimethoxybenzyl)-6-methoxy-1,2,3,4-tetrahydro-
naphthalen-1-ol (cis-5g). Purified by PTLC (n-hexane/EtOAc
70:30) as a yellow solid (15 mg, 44% yield): [α]2D7 = +22.8 (c = 1,
CHCl3); the enantiomeric ratio (>99:1 er) was determined by HPLC
analysis using a Chiralpack IA column, n-hexane/isopropyl alcohol
80:20, 1 mL/min, 28 °C, tRmaj = 11.1 min, tRmin = 27.7 min, 222 nm;
1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 1H), 6.85−6.79
(R)-3-(4-Methoxybenzyl)-7-(methoxymethoxy)chroman-4-one
((R)-6c). Purified by PTLC (n-hexane/EtOAc 85:15) as a white solid
(14 mg, 87% yield): the enantiomeric ratio (97:3 er) was determined
by HPLC analysis using a Chiralpack IA column, n-hexane/isopropyl
alcohol 90:10, 1 mL/min, 28 °C, tRmaj = 14.3 min, tRmin = 16.7 min,
1
268 nm; H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.8 Hz, 1H),
7.15 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.69 (dd, J = 8.8,
2.3 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 5.20 (s, 2H), 4.34 (dd, J = 11.5,
4.2 Hz, 1H), 4.16 (dd, J = 11.4, 7.6 Hz, 1H), 3.80 (s, 3H), 3.48 (s,
3H), 3.19 (dd, J = 13.9, 4.4 Hz, 1H), 2.80 (ddt, J = 11.8, 8.2, 4.0 Hz,
1H), 2.67 (dd, J = 13.9, 10.5 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 192.90, 163.53, 163.40, 158.46, 130.39, 130.20, 129.34,
115.36, 114.15, 111.12, 103.45, 94.19, 69.78, 56.56, 55.36, 47.77,
31.90; HRMS (ESI) m/z [M + Na]+ calcd for C19H20O5Na+
351.1203, found 351.1203.
(m, 3H), 6.74 (dd, J = 8.5, 2.6 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 4.47
(d, J = 2.9 Hz, 1H), 3.88 (s, 6H), 3.77 (s, 3H), 2.92−2.82 (m, 2H),
2.74 (dt, J = 11.8, 6.0 Hz, 1H), 2.67 (dd, J = 13.6, 7.3 Hz, 1H), 1.96
(dtd, J = 13.4, 7.6, 7.2, 3.4 Hz, 1H), 1.81 (qd, J = 12.3, 5.7 Hz, 1H),
1.72−1.65 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.3,
148.9, 147.3, 138.5, 133.4, 131.4, 131.3, 121.2, 113.5, 112.6, 112.7,
111.2, 69.0, 56.1, 55.9, 55.4, 42.2, 38.1, 29.7, 22.6. HRMS (ESI) m/z
[M + Na]+ calcd for C20H24O4Na+ 351.1567, found 351.1577.
(1R,2S)-5,8-Dimethoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-
naphthalen-1-ol (cis-5h). Purified by PTLC (n-hexane/EtOAc
70:30) as a waxy yellow solid (14 mg, 42% yield): [α]2D7 = +66.3 (c
= 1, CHCl3); the enantiomeric ratio (99:1 er) was determined by
HPLC analysis using a Chiralpack IA column, n-hexane/isopropyl
alcohol 90:10, 1 mL/min, 28 °C, tRmaj = 15.4 min, tRmin = 19.2 min,
(R)-2-(4-Methoxybenzyl)-3,4-dihydronaphthalen-1(2H)-one ((R)-
7c). All spectra were in agreement with reported data;72 Purified by
PTLC (n-hexane/EtOAc 90:10) as a colorless oil (10 mg, 78% yield):
[α]2D7 = +7.5 (c = 1, CHCl3); the enantiomeric ratio (94:6 er) was
determined by HPLC analysis using a Chiralpack IA column, n-
hexane/isopropyl alcohol 99:1, 0.5 mL/min, 28 °C, tRmaj = 24.0 min,
t
Rmin = 25.5 min, 243 nm; 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J
= 7.9, 1.4 Hz, 1H), 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz,
1H), 7.22 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 6.85 (d, J =
8.3 Hz, 2H), 3.80 (s, 3H), 3.40 (dd, J = 13.6, 3.9 Hz, 1H), 2.93 (dt, J
= 9.5, 4.7 Hz, 2H), 2.70 (ddt, J = 10.9, 8.1, 4.1 Hz, 1H), 2.62 (dd, J =
13.6, 9.5 Hz, 1H), 2.11 (dt, J = 13.5, 4.5 Hz, 1H), 1.78 (ddt, J = 15.9,
10.8, 5.4 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 199.7, 158.1,
144.2, 133.4, 132.6, 132.1, 130.3, 128.81, 127.7, 126.8, 113.9, 55.4,
49.7, 34.9, 28.7, 27.7.; HRMS (ESI) m/z [M + Na]+ calcd for
C18H18O2Na+ 289.1199, found 289.1194.
(S)-6-Methoxy-2-(4-methoxybenzyl)-3,4-dihydronaphthalen-
1(2H)-one ((S)-7f). This compound was only partially described;73
Purified by PTLC (n-hexane/EtOAc 85:15) as a waxy pale yellow
solid (13 mg, 87% yield): [α]2D7 = −11.2 (c = 1, CHCl3); the
enantiomeric ratio (94:6 er) was determined by HPLC analysis using
a Chiralpack IA column, n-hexane/isopropyl alcohol 90:10, 1 mL/
min, 28 °C, tRmaj = 11.8 min, tRmin = 13.0 min, 269 nm; 1H NMR (400
MHz, CDCl3) δ 8.04 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H),
6.92−6.78 (m, 3H), 6.66 (d, J = 2.5 Hz, 1H), 3.85 (s, 3H), 3.79 (s,
3H), 3.40 (dd, J = 13.1, 3.3 Hz, 1H), 2.99−2.81 (m, 2H), 2.72−2.55
1
207 nm: H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H),
6.87 (d, J = 8.6 Hz, 2H), 6.68 (q, J = 8.8 Hz, 2H), 4.83 (d, J = 3.3 Hz,
1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 2.98 (dd, J = 13.6, 7.3
Hz, 1H), 2.95−2.89 (m, 1H), 2.71 (dd, J = 13.8, 7.5 Hz, 1H), 2.38
(ddd, J = 18.1, 11.3, 6.8 Hz, 1H), 1.83 (qt, J = 8.7, 4.3 Hz, 1H), 1.78−
1.66 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.8, 151.8,
151.5, 133.3, 130.3, 128.8, 127.7, 113.7, 108.9, 107.1, 63.7, 55.8, 55.6,
55.4, 41.4, 37.4, 24.3, 21.9; HRMS (ESI) m/z [M + Na]+ calcd for
C20H24O4Na+ 351.1567, found 351.1578.
Synthesis of (cis)-4a and (cis)-5c on a Larger Scale
Catalyzed by 2 mol % (R,R)-1c. To a round-bottom flask were
added the substrate 2a or 3c (1.0 mmol), RuCl[(R,R)-TsDPEN]-
(mesitylene) 1c (0.02 mmol, 12.4 mg), Cu(OTf)2(0.04 mmol, 14.5
mg), CTAB (0.2 mmol, 72.9 mg), and dichloroethane (2 mL,) and
the resulting mixture was stirred at rt for 15 min under an argon
atmosphere. Then, a solution of sodium formate (5 mmol, 340 mg) in
water (2 mL) was added, and the reaction mixture was stirred at room
4855
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(m, 2H), 2.08 (dq, J = 13.6, 4.5 Hz, 1H), 1.83−1.70 (m, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 198.5, 163.6, 158.1, 146.7,
132.3, 130.4, 130.2, 126.3, 113.9, 113.2, 112.6, 55.5, 55.3, 49.4, 35.0,
Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil;
orcid.org/0000-0001-9703-3404
Juliana de O. C. Brum − Laboratório de Química
+
29.1, 27.7; HRMS (ESI) m/z [M + H]+ calcd for C19H21O3
̂
Bioorganica, Instituto de Pesquisas de Produtos Naturais,
297.1485, found 297.1486.
Universidade Federal do Rio de Janeiro, 21941-902 Rio de
Janeiro, Brazil; Instituto Militar de Engenharia, 22290-270
Rio de Janeiro, Brazil; orcid.org/0000-0003-2039-2075
(R)-7-Hydroxy-3-(4-methoxybenzyl)chroman-4-one ((R)-10c).49
To a solution of (R)-6c (0.05 mmol) in DCM (0,5 mL) were
added ZnBr2 (0.075 mmol, 17 mg) and n-BuSH (0.15 mmol, 16 μL).
The reaction mixture was stirred at 0 °C for 1 h under an argon
atmosphere. Then, the resulting mixture was diluted in DCM (10
mL) and filtered through a small pad of silica. The resulting crude was
the purified by PTLC (n-hexane/AcOEt 70:30), yielding the pure
product as a yellow solid (11 mg, 78% yield): [α]2D7 = −15.4 (c = 0.7,
MeOH). All spectra were in agreement with reported data.11 The
enantiomeric ratio (92:8 er) was determined by HPLC analysis using
a Chiralpack IA column, n-hexane/isopropyl alcohol 90:10, 1 mL/
min, 28 °C, tRmaj = 20.1 min, tRmin = 22.7 min, 275 nm: 1H NMR (400
MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H),
6.86 (d, J = 8.7 Hz, 2H), 6.52 (dd, J = 8.7, 2.3 Hz, 1H), 6.39 (d, J =
2.3 Hz, 1H), 4.35 (dd, J = 11.4, 4.2 Hz, 1H), 4.16 (dd, J = 11.4, 7.8
Hz, 1H), 3.80 (s, 3H), 3.20 (dd, J = 14.0, 4.4 Hz, 1H), 2.88−2.77 (m,
1H), 2.68 (dd, J = 13.9, 10.2 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 193.3, 163.8, 163.1, 158.4, 130.4, 130.2, 120.0, 114.6, 114.7,
110.8, 103.2, 69.7, 55.8, 47.7, 32.0; HRMS (ESI) m/z [M + Na]+
calcd for C17H16O4Na+ 307.0941, found 307.0942.
̂
Angela T. Costa − Laboratório de Química Bioorganica,
Instituto de Pesquisas de Produtos Naturais, Universidade
Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil;
orcid.org/0000-0002-3450-6099
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02981
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was financed in part by the Coordenaca
̧
o
̃
de
Aperfeic
̧oamento de Pessoal de Nível Superior−Brasil
(CAPES), Finance Code 001, for the scholarships of G.S.C.
̂
and J.O.C.B. and the Programa de Cooperaca̧ o Academica−
̃
PROCAD for the scholarship of A.T.C. P.R.R.C. would like to
thank the financial support of Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq; PQ-
(E)-3-(4-Methoxybenzylidene)chroman-4-ol (rac-8a).74 Com-
pound 2a (0.2 mmol) was dissolved in methanol (2 mL), followed
by the addition of NaBH4 (0.6 mol, 3 equiv, 23 mg). The mixture was
stirred for 1 h at rt, diluted in AcOEt (10 mL), and filtered through a
small pad of silica. The resulting crude, a yellow solid (49 mg, 91%
yield), was then used without further purification. All spectra were in
agreement with reported data:20 1H NMR (400 MHz, CDCl3) δ 7.39
(dd, J = 7.7, 1.7 Hz, 1H), 7.26−7.11 (m, 3H), 6.96 (t, J = 7.4 Hz,
1H), 6.89 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 7.2 Hz, 2H), 5.15 (s, 1H),
4.92 (q, J = 12.5 Hz, 2H), 3.81 (s, 3H); HRMS (ESI) m/z [M + Na]+
calcd for C17H16O3Na+ 291.0992, found 291.0991.
(S,E)-3-(4-Methoxybenzylidene)chroman-4-ol ((S)-8a). All spectra
were in agreement with reported data;74 Isolated as the remaining
starting material after the ATH of rac-8a under the conditions
described in Scheme S2 . Purified by PTLC (n-hexane/EtOAc 80:20)
as a yellow solid (7.5 mg, 28% yield): [α]2D7 = −29.6 (c = 0.75,
CHCl3); the enantiomeric ratio (99:1 er) was determined by HPLC
analysis using a Chiralpack IA column, n-hexane/isopropyl alcohol
90:10, 1 mL/min, 28 °C, tRmaj = 18.6 min, tRmin: 17.5 min, 284 nm.
2017/311070/2017-5) and the Fundaçao Carlos Chagas
̃
̀
Filho de Amparo a Pesquisa do Estado do Rio de Janeiro
(FAPERJ; CNE-FAPERJ E-26/203059/2016). We are grateful
to Pontifícia Universidade Católica do Rio de Janeiro for NMR
analyses and the Instituto de Química−UFRJ for NMR and
optical rotation analyses. Universidade Federal do Rio do
Janeiro, Universidade do Estado do Rio de Janeiro, and
Instituto Militar de Engenharia are also acknowledged.
REFERENCES
■
(1) Vyas, V. K.; Clarkson, G. J.; Wills, M. Sulfone Group as a
Versatile and Removable Directing Group for Asymmetric Transfer
Hydrogenation of Ketones. Angew. Chem., Int. Ed. 2020, 59 (34),
14265−14269.
(2) Xiong, Z.; Tian, J.; Xue, P.; Zhang, X.; Lv, H. Enantioselective
Synthesis of Chiral Multicyclic γ-Lactones via Dynamic Kinetic
Resolution of Racemic γ-Keto Carboxylic Acids. Org. Chem. Front.
2020, 7 (1), 104−108.
(3) Touge, T.; Sakaguchi, K.; Tamaki, N.; Nara, H.; Yokozawa, T.;
Matsumura, K.; Kayaki, Y. Multiple Absolute Stereocontrol in
Cascade Lactone Formation via Dynamic Kinetic Resolution Driven
by the Asymmetric Transfer Hydrogenation of Keto Acids with Oxo-
Tethered Ruthenium Catalysts. J. Am. Chem. Soc. 2019, 141 (41),
16354−16361.
(4) Touge, T.; Kuwana, M.; Komatsuki, Y.; Tanaka, S.; Nara, H.;
Matsumura, K.; Sayo, N.; Kashibuchi, Y.; Saito, T. Development of
Asymmetric Transfer Hydrogenation with a Bifunctional Oxo-
Tethered Ruthenium Catalyst in Flow for the Synthesis of a
Ceramide (d-Erythro-CER[NDS]). Org. Process Res. Dev. 2019, 23
(4), 452−461.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02981.
■
sı
General information and procedures, HPLC analysis,
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
Paulo R. R. Costa − Laboratório de Química Bioorganica,
■
̂
Instituto de Pesquisas de Produtos Naturais, Universidade
Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil;
orcid.org/0000-0001-9541-1707; Email: prrcosta2011@
gmail.com
(5) Sun, G.; Jian, W.; Luo, Z.; Sun, T.; Li, C.; Zhang, J.; Wang, Z.
Development of an Efficient and Scalable Asymmetric Synthesis of
Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydro-
genation. Org. Process Res. Dev. 2019, 23 (6), 1204−1212.
(6) Cotman, A. E.; Modec, B.; Mohar, B. Stereoarrayed 2,3-
Disubstituted 1-Indanols via Ruthenium(II)-Catalyzed Dynamic
Kinetic Resolution-Asymmetric Transfer Hydrogenation. Org. Lett.
2018, 20 (10), 2921−2924.
̂
Jorge L. O. Domingos − Departamento de Química Organica,
Instituto de Química, Universidade do Estado do Rio de
Janeiro, 20550-900 Rio de Janeiro, Brazil; orcid.org/
0000-0002-9131-7649; Email: jlo.domingos@gmail.com
Authors
̂
Guilherme S. Caleffi − Laboratório de Química Bioorganica,
Instituto de Pesquisas de Produtos Naturais, Universidade
(7) Keßberg, A.; Lubken, T.; Metz, P. Enantioselective Total
̈
Synthesis of Natural Isoflavans: Asymmetric Transfer Hydrogenation/
4856
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Deoxygenation of Isoflavanones with Dynamic Kinetic Resolution.
Org. Lett. 2018, 20 (10), 3006−3009.
(8) Ashley, E. R.; Sherer, E. C.; Pio, B.; Orr, R. K.; Ruck, R. T.
Ruthenium-Catalyzed Dynamic Kinetic Resolution Asymmetric
Transfer Hydrogenation of β-Chromanones by an Elimination-
Induced Racemization Mechanism. ACS Catal. 2017, 7 (2), 1446−
1451.
(9) Qin, T.; Metz, P. Enantioselective Synthesis of Isoflavanones by
Catalytic Dynamic Kinetic Resolution. Org. Lett. 2017, 19 (11),
2981−2984.
(10) Sun, G.; Zhou, Z.; Luo, Z.; Wang, H.; Chen, L.; Xu, Y.; Li, S.;
Jian, W.; Zeng, J.; Hu, B.; et al. Highly Enantioselective Synthesis of
syn-β-Hydroxy α-Dibenzylamino Esters via DKR Asymmetric Trans-
fer Hydrogenation and Gram-Scale Preparation of Droxidopa. Org.
Lett. 2017, 19 (16), 4339−4342.
(11) Molina Betancourt, R.; Echeverria, P.-G.; Ayad, T.; Phansavath,
P.; Ratovelomanana-Vidal, V. Recent Progress and Applications of
Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer
Hydrogenation of Ketones and Imines through Dynamic Kinetic
Resolution. Synthesis 2021, 53 (01), 30−50.
(12) Seo, C. S. G.; Morris, R. H. Catalytic Homogeneous
Asymmetric Hydrogenation: Successes and Opportunities. Organo-
metallics 2019, 38 (1), 47−65.
(13) Baráth, E. Hydrogen Transfer Reactions of Carbonyls, Alkynes,
and Alkenes with Noble Metals in the Presence of Alcohols/Ethers
and Amines as Hydrogen Donors. Catalysts 2018, 8 (12), 671.
(14) Matsunami, A.; Kayaki, Y. Upgrading and Expanding the Scope
of Homogeneous Transfer Hydrogenation. Tetrahedron Lett. 2018, 59
(6), 504−513.
(15) Nedden, H. G.; Zanotti-Gerosa, A.; Wills, M. The Develop-
ment of Phosphine-Free “Tethered” Ruthenium(II) Catalysts for the
Asymmetric Reduction of Ketones and Imines. Chem. Rec. 2016, 16
(6), 2623−2643.
(16) Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Transition-
Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydro-
genation: Sustainable Chemistry to Access Bioactive Molecules.
Chem. Rec. 2016, 16 (6), 2754−2771.
(17) Echeverria, P.-G.; Ayad, T.; Phansavath, P.; Ratovelomanana-
Vidal, V. Recent Developments in Asymmetric Hydrogenation and
Transfer Hydrogenation of Ketones and Imines through Dynamic
Kinetic Resolution. Synthesis 2016, 48 (16), 2523−2539.
(18) Foubelo, F.; Nájera, C.; Yus, M. Catalytic Asymmetric Transfer
Hydrogenation of Ketones: Recent Advances. Tetrahedron: Asymmetry
2015, 26 (15−16), 769−790.
(19) Wang, D.; Astruc, D. The Golden Age of Transfer
Hydrogenation. Chem. Rev. 2015, 115 (13), 6621−6686.
(20) Cotman, A. E. Escaping from Flatland: Stereoconvergent
Synthesis of Three-Dimensional Scaffolds via Ruthenium(II)-
Catalyzed Noyori-Ikariya Transfer Hydrogenation. Chem. - Eur. J.
2021, 27 (1), 39−53.
(21) Farrar-Tobar, R. A.; Dell’Acqua, A.; Tin, S.; de Vries, J. G.
Metal-Catalysed Selective Transfer Hydrogenation of α,β-Unsatu-
rated Carbonyl Compounds to Allylic Alcohols. Green Chem. 2020, 22
(11), 3323−3357.
(22) Liu, S.; Cui, P.; Wang, J.; Zhou, H.; Liu, Q.; Lv, J. Asymmetric
Transfer Hydrogenation of Cycloalkyl Vinyl Ketones to Allylic
Alcohols Catalyzed by Ruthenium Amido Complexes. Org. Biomol.
Chem. 2019, 17 (2), 264−267.
(23) Son, S.-M.; Lee, H.-K. Dynamic Kinetic Resolution Based
Asymmetric Transfer Hydrogenation of α-Alkoxy-β-Ketophospho-
nates. Diastereo- and Enantioselective Synthesis of Monoprotected
1,2-Dihydroxyphosphonates. J. Org. Chem. 2014, 79 (6), 2666−2681.
(24) Bizet, V.; Pannecoucke, X.; Renaud, J.-L.; Cahard, D.
Ruthenium-Catalyzed Redox Isomerization of Trifluoromethylated
Allylic Alcohols: Mechanistic Evidence for an Enantiospecific
Pathway. Angew. Chem., Int. Ed. 2012, 51 (26), 6467−6470.
(25) Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.;
Campbell, L.; Walsgrove, T.; Wills, M. Asymmetric Transfer
Hydrogenation of α,β-Unsaturated, α-Tosyloxy and α-Substituted
Ketones. Tetrahedron 2006, 62 (8), 1864−1876.
(26) Hannedouche, J.; Kenny, J. A.; Walsgrove, T.; Wills, M.
Asymmetric Reduction of Cyclic Enones to Allylic Alcohols. Synlett
2002, 2002 (02), 0263−0266.
(27) Xue, D.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C.
Transfer Hydrogenation of Activated C = C Bonds Catalyzed by
Ruthenium Amido Complexes: Reaction Scope, Limitation, and
Enantioselectivity. J. Org. Chem. 2005, 70 (9), 3584−3591.
(28) Hall, T. H.; Adams, H.; Vyas, V. K.; Michael Chu, K. L.; Wills,
M. Asymmetric Transfer Hydrogenation of Unsaturated Ketones;
Factors Influencing 1,4- vs 1,2- Regio- and Enantioselectivity, and
Alkene vs Alkyne Directing Effects. Tetrahedron 2021, 77, 131771.
(29) Kwon, S.; Lee, S.; Heo, M.; Lee, B.; Fei, X.; Corson, T. W.; Seo,
S.-Y. Total Synthesis of Naturally Occurring 5,7,8-Trioxygenated
Homoisoflavonoids. ACS Omega 2020, 5 (19), 11043−11057.
(30) Heo, M.; Lee, B.; Sishtla, K.; Fei, X.; Lee, S.; Park, S.; Yuan, Y.;
Lee, S.; Kwon, S.; Lee, J. Enantioselective Synthesis of Homoiso-
flavanones by Asymmetric Transfer Hydrogenation and Their
Biological Evaluation for Antiangiogenic Activity. J. Org. Chem.
2019, 84, 9995.
(31) Ciesielski, P.; Metz, P. Asymmetric One-Pot Transformation of
Isoflavones to Pterocarpans and Its Application in Phytoalexin
Synthesis. Nat. Commun. 2020, 11 (1), 3091.
(32) Ma, Y.; Li, J.; Ye, J.; Liu, D.; Zhang, W. Synthesis of Chiral
Chromanols via a RuPHOX-Ru Catalyzed Asymmetric Hydro-
genation of Chromones. Chem. Commun. 2018, 54 (96), 13571−
13574.
(33) Arai, N.; Satoh, H.; Komatsu, R.; Ohkuma, T. Double
Asymmetric Hydrogenation of Linear β,β-Disubstituted α,β-Unsatu-
rated Ketones into γ-Substituted Secondary Alcohols Using a Dual
Catalytic System. Chem. - Eur. J. 2017, 23 (37), 8806−8809.
(34) He, B.; Phansavath, P.; Ratovelomanana-Vidal, V. Rh-Mediated
Asymmetric-Transfer Hydrogenation of 3-Substituted Chromones: A
Route to Enantioenriched cis-3-(Hydroxymethyl)Chroman-4-Ol
Derivatives through Dynamic Kinetic Resolution. Org. Lett. 2019,
21 (9), 3276−3280.
(35) Tang, L.; Lin, Z.; Wang, Q.; Wang, X.; Cun, L.; Yuan, W.; Zhu,
J.; Deng, J. Rh(II)-Cp-TsDPEN Catalyzed Aqueous Asymmetric
Transfer Hydrogenation of Chromenones into Saturated Alcohol: C =
C and C = O Reduction in One Step. Tetrahedron Lett. 2012, 53 (30),
3828−3830.
(36) Liu, Y. T.; Chen, J. Q.; Li, L. P.; Shao, X. Y.; Xie, J. H.; Zhou,
Q. L. Asymmetric Hydrogenation of Tetrasubstituted Cyclic Enones
to Chiral Cycloalkanols with Three Contiguous Stereocenters. Org.
Lett. 2017, 19 (12), 3231−3234.
(37) Wu, X.; Wang, C.; Xiao, J. Transfer Hydrogenation in Water.
Chem. Rec. 2016, 16 (6), 2772−2786.
(38) Wu, X.; Liu, J.; Di Tommaso, D.; Iggo, J. A.; Catlow, C. R. A.;
Bacsa, J.; Xiao, J. A Multilateral Mechanistic Study into Asymmetric
Transfer Hydrogenation in Water. Chem. - Eur. J. 2008, 14 (25),
7699−7715.
(39) Wu, X.; Xiao, J. Aqueous-Phase Asymmetric Transfer
Hydrogenation of Ketones - A Greener Approach to Chiral Alcohols.
Chem. Commun. 2007, No. 24, 2449−2466.
(40) Wu, X.; Li, X.; King, F.; Xiao, J. Insight into and Practical
Application of pH-Controlled Asymmetric Transfer Hydrogenation of
Aromatic Ketones in Water. Angew. Chem., Int. Ed. 2005, 44 (22),
3407−3411.
(41) Wu, X.; Li, X.; Hems, W.; King, F.; Xiao, J. Accelerated
Asymmetric Transfer Hydrogenation of Aromatic Ketones in Water.
Org. Biomol. Chem. 2004, 2 (13), 1818.
(42) Matsuoka, A.; Sandoval, C. A.; Uchiyama, M.; Noyori, R.;
Naka, H. Why P- Cymene? Conformational Effect in Asymmetric
Hydrogenation of Aromatic Ketones with a η 6 -Arene/Ruthenium-
(II) Catalyst. Chem. - Asian J. 2015, 10 (1), 112−115.
(43) Wang, D.-S.; Zhou, Y.-G. Asymmetric Hydrogenation of
Quinolines Activated by Brønsted Acids. Tetrahedron Lett. 2010, 51
(22), 3014−3017.
4857
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(44) Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval,
C.; Noyori, R. The Hydrogenation/Transfer Hydrogenation Net-
work: Asymmetric Hydrogenation of Ketones with Chiral H6-Arene/
N-Tosylethylenediamine- Ruthenium(II) Catalysts. J. Am. Chem. Soc.
2006, 128 (27), 8724−8725.
Electron Demand Diels-Alder Reaction. Chem. Commun. 2018, 54
(88), 12463−12466.
(61) Cheng, X.-M.; Huang, Z.-T.; Zheng, Q.-Y. Topochemical
Photodimerization of (E)-3-Benzylidene-4-Chromanone Derivatives
from β-Type Structures Directed by Halogen Groups. Tetrahedron
2011, 67 (47), 9093−9098.
(62) Kayal, S.; Mukherjee, S. Catalytic Enantioselective Cascade
Michael/Cyclization Reaction of 3-Isothiocyanato Oxindoles with
Exocyclic α,β-Unsaturated Ketones En Route to 3,2′-Pyrrolidinyl
Bispirooxindoles. Org. Biomol. Chem. 2016, 14 (43), 10175−10179.
(63) Feng, Y.; Ding, X.; Chen, T.; Chen, L.; Liu, F.; Jia, X.; Luo, X.;
Shen, X.; Chen, K.; Jiang, H.; et al. Design, Synthesis, and Interaction
Study of Quinazoline-2(1 H)-Thione Derivatives as Novel Potential
Bcl-x L Inhibitors. J. Med. Chem. 2010, 53 (9), 3465−3479.
(64) Lokhande, P. D.; Hasanzadeh, K.; Khaledi, H.; Mohd Ali, H.
Aromatization and Halogenation of 3,3a,4,5-Tetrahydro-3-Aryl-2-
Phenyl-2 H -Benzo[g]Indazole Using I2/DMSO, CuCl2/DMSO,
and N-Bromosuccinimide. J. Heterocycl. Chem. 2012, 49 (6), 1398−
1406.
(65) Xu, W.-Z.; Huang, Z.-T.; Zheng, Q.-Y. Synthesis of Benzo[ c
]Xanthones from 2-Benzylidene-1-Tetralones by the Ultraviolet
Radiation-Mediated Tandem Reaction. J. Org. Chem. 2008, 73 (14),
5606−5608.
(66) Abdelsalam, E. A.; Zaghary, W. A.; Amin, K. M.; Abou Taleb,
N. A.; Mekawey, A. A. I.; Eldehna, W. M.; Abdel-Aziz, H. A.;
Hammad, S. F. Synthesis and in Vitro Anticancer Evaluation of Some
Fused Indazoles, Quinazolines and Quinolines as Potential EGFR
Inhibitors. Bioorg. Chem. 2019, 89, 102985.
(67) Fava, E.; Nakajima, M.; Nguyen, A. L. P.; Rueping, M.
Photoredox-Catalyzed Ketyl-Olefin Coupling for the Synthesis of
Substituted Chromanols. J. Org. Chem. 2016, 81 (16), 6959−6964.
(68) Thorey, C.; Bouquillon, S.; Helimi, A.; Hénin, F.; Muzart, J.
Palladium on Charcoal plus Enantiopure Amino Alcohols as Catalytic
Systems for the Enantioselective 1,4-Reduction of α-Substituted α,β-
Unsaturated Ketones. Eur. J. Org. Chem. 2002, 2002 (13), 2151.
(69) Shriner, R. L.; Teeters, W. O. Substituted Tetrahydronaph-
thalenes. I. 1-Keto- and 1-Hydroxy-2-(p-Dialkyl-Aminobenzyl)-
Tetrahydronaphthalenes. J. Am. Chem. Soc. 1938, 60 (4), 936−939.
(70) Satyanarayana, P.; Reddy, G. M.; Maheswaran, H.; Kantam, M.
L. Tris(Acetylacetonato)Rhodium(III)-Catalyzed α-Alkylation of
Ketones, β-Alkylation of Secondary Alcohols and Alkylation of
Amines with Primary Alcohols. Adv. Synth. Catal. 2013, 355 (9),
1859−1867.
(71) Simon, L.; Abdul Salam, A. A.; Madan Kumar, S.; Shilpa, T.;
Srinivasan, K. K.; Byrappa, K. Synthesis, Anticancer, Structural, and
Computational Docking Studies of 3-Benzylchroman-4-One Deriva-
tives. Bioorg. Med. Chem. Lett. 2017, 27 (23), 5284−5290.
(72) Gao, B.; Feng, X.; Meng, W.; Du, H. Asymmetric Hydro-
genation of Ketones and Enones with Chiral Lewis Base Derived
Frustrated Lewis Pairs. Angew. Chem., Int. Ed. 2020, 59 (11), 4498−
4504.
(45) Hartmann, R.; Chen, P. Noyori’s Hydrogenation Catalyst
Needs a Lewis Acid Cocatalyst for High Activity We Thank Mr.
Christian Dambouwy, Thales Technologies AG, Zurich, Switzerland,
̈
for Experimental Work to Compare the Effects of Various
Combinations of Bases and Salts. Addition. Angew. Chem., Int. Ed.
2001, 40 (19), 3581.
(46) Sanichar, R.; Carroll, C.; Kimmis, R.; Reiz, B.; Vederas, J. C.
Dess-Martin Periodinane Oxidative Rearrangement for Preparation of
α-Keto Thioesters. Org. Biomol. Chem. 2018, 16 (4), 593−597.
(47) Yee, S. W.; Jarno, L.; Gomaa, M. S.; Elford, C.; Ooi, L.-L.;
Coogan, M. P.; McClelland, R.; Nicholson, R. I.; Evans, B. A. J.;
Brancale, A.; et al. Novel Tetralone-Derived Retinoic Acid
Metabolism Blocking Agents: Synthesis and in Vitro Evaluation
with Liver Microsomal and MCF-7 CYP26A1 Cell Assays. J. Med.
Chem. 2005, 48 (23), 7123−7131.
(48) Zhao, P.; Iwamoto, Y.; Kouno, I.; Egami, Y.; Yamamoto, H.
Stimulating the Production of Homoisoflavonoids in Cell Suspension
Cultures of Caesalpinia Pulcherrima Using Cork Tissue. Phytochem-
istry 2004, 65 (17), 2455−2461.
(49) Han, J. H.; Kwon, Y. E.; Sohn, J.-H.; Ryu, D. H. A Facile
Method for the Rapid and Selective Deprotection of Methoxymethyl
(MOM) Ethers. Tetrahedron 2010, 66 (9), 1673−1677.
(50) Scalambra, F.; Lorenzo-Luis, P.; de los Rios, I.; Romerosa, A.
Isomerization of Allylic Alcohols in Water Catalyzed by Transition
Metal Complexes. Coord. Chem. Rev. 2019, 393, 118−148.
(51) Cahard, D.; Gaillard, S.; Renaud, J.-L. Asymmetric Isomer-
ization of Allylic Alcohols. Tetrahedron Lett. 2015, 56 (45), 6159−
6169.
(52) Shoola, C. O.; DelMastro, T.; Wu, R.; Sowa, J. R. Asymmetric
Transfer Hydrogenation of Secondary Allylic Alcohols. Eur. J. Org.
Chem. 2015, 2015 (8), 1670−1673.
(53) Cadierno, V.; Crochet, P.; Francos, J.; García-Garrido, S. E.;
Gimeno, J.; Nebra, N. Ruthenium-Catalyzed Redox Isomerization/
Transfer Hydrogenation in Organic and Aqueous Media: A One-Pot
Tandem Process for the Reduction of Allylic Alcohols. Green Chem.
2009, 11 (12), 1992.
(54) Cheng, X. M.; Huang, Z. T.; Zheng, Q. Y. Topochemical
Photodimerization of (E)-3-Benzylidene-4-Chromanone Derivatives
from β-Type Structures Directed by Halogen Groups. Tetrahedron
2011, 67 (47), 9093−9098.
(55) Koch, K.; Biggers, M. S. General Preparation of 7-Substituted
4-Chromanones: Synthesis of a Potent Aldose Reductase Inhibitor. J.
Org. Chem. 1994, 59 (5), 1216−1218.
(56) Siddaiah, V.; Rao, C. V.; Venkateswarlu, S.; Subbaraju, G. V. A
Concise Synthesis of Polyhydroxydihydrochalcones and Homoiso-
flavonoids. Tetrahedron 2006, 62 (5), 841−846.
(57) Siddaiah, V.; Rao, C. V.; Venkateswarlu, S.; Krishnaraju, A. V.;
Subbaraju, G. V. Synthesis, Stereochemical Assignments, and
Biological Activities of Homoisoflavonoids. Bioorg. Med. Chem.
2006, 14 (8), 2545−2551.
(58) Feng, L.; Maddox, M. M.; Alam, M. Z.; Tsutsumi, L. S.; Narula,
G.; Bruhn, D. F.; Wu, X.; Sandhaus, S.; Lee, R. B.; Simmons, C. J.;
et al. Synthesis, Structure-Activity Relationship Studies, and
Antibacterial Evaluation of 4-Chromanones and Chalcones, as Well
as Olympicin A and Derivatives. J. Med. Chem. 2014, 57 (20), 8398−
8420.
(73) Juday, R. E. Synthetic Estrogens. II. 1 Derivatives of 2-
Phenylphenanthrene and 1-Ethyl-2-Benzylnaphthalene. J. Am. Chem.
Soc. 1953, 75 (16), 4071−4074.
(74) Yıldız, T. An Oxazaborolidine-Based Catalytic Method for the
Asymmetric Synthesis of Chiral Allylic Alcohols. Tetrahedron:
Asymmetry 2015, 26 (8−9), 497−504.
(59) Das, B.; Thirupathi, P.; Kumar, R. A.; Laxminarayana, K. Part
148 in the Series “Studies on Novel Synthetic Methodologies:”
Selective Acetylation of Alcohols, Phenols and Amines and Selective
Deprotection of Aromatic Acetates Using Silica-Supported Phospho-
molybdic Acid. Adv. Synth. Catal. 2007, 349 (17−18), 2677−2683.
(60) Fathimath Salfeena, C. T.; Basavaraja, B.; Ashitha, K. T.;
Kumar, V. P.; Varughese, S.; Suresh, C. H.; Sasidhar, B. S. Synthesis of
Symmetrical and Unsymmetrical Triarylpyrylium Ions via an Inverse
4858
https://dx.doi.org/10.1021/acs.joc.0c02981
J. Org. Chem. 2021, 86, 4849−4858