A Modular Synthesis of 2-Alkyl- and 2-Arylchromans via a Three-Step Sequence

Article abstract of DOI:10.1055/s-0036-1588075

A convergent three-step method for the synthesis of 2-substituted chromans is described. These results have been accomplished via the Heck coupling of readily accessible allylic alcohols and 2-iodophenols, followed by reduction and Mitsunobu cyclization. The utility and generality of this method is demonstrated through the synthesis of a series of 2-aryl-, 2-heteroaryl- and 2-alkylchromans, as well as an azachroman derivative. The asymmetric version of this approach via a Noyori-catalyzed ketone reduction and subsequent cyclization is likewise highlighted.

Full text of DOI:10.1055/s-0036-1588075

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
R. K. Orr et al.
Paper
Synthesis
A Modular Synthesis of 2-Alkyl- and 2-Arylchromans via a Three-
Step Sequence
Robert K. Orr*a
OH
OH
1. Heck reaction
2. reduction
R1
O
Louis-Charles Campeaua
Harry R. Chobanianb
Jamie M. McCabe Dunna
Barbara Piob
Christopher W. Plummerb
Andrew Noltingc
I
R1
R2
R2
+
3. SN2
R1 = alkyl, aryl
R2 = EWG or EDG
modular & convergent approach
14 examples up to 76% yields
amenable to asymmetric synthesis
Rebecca T. Rucka
a Department of Process Chemistry, Merck Research Laboratories,
126 E Lincoln Ave, Rahway, NJ 07065, USA
b Department of Medicinal Chemistry, Merck Research Laboratories,
2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA
c Department of Process Chemistry, Merck Research Laboratories,
2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA
robert.orr@merck.com
Received: 12.07.2016
Me
Accepted after revision: 02.09.2016
Published online: 14.10.2016
DOI: 10.1055/s-0036-1588075; Art ID: ss-2016-m0494-op
HO
Me
Me
Me
i-Pr
O
Me
Me
Abstract A convergent three-step method for the synthesis of 2-sub-
stituted chromans is described. These results have been accomplished
via the Heck coupling of readily accessible allylic alcohols and 2-io-
dophenols, followed by reduction and Mitsunobu cyclization. The utility
and generality of this method is demonstrated through the synthesis of
a series of 2-aryl-, 2-heteroaryl- and 2-alkylchromans, as well as an
azachroman derivative. The asymmetric version of this approach via a
Noyori-catalyzed ketone reduction and subsequent cyclization is like-
wise highlighted.
Me
Vitamin E (1)
OH
H
H
Me
Me
O
Me
Tetrahydrocannabinol (2)
F
F
O
N
O
Key words asymmetric synthesis, chromans, catalysis, Heck reaction,
Mitsunobu reaction, heterocycles
H
OH
OH
Nebivolol (3)
Me
Me
Functionalized chroman derivatives represent an im-
portant class of pharmacologically active compounds ex-
hibiting a broad range of biological activity.1 The most well-
known examples include active natural products such as
the antioxidant, vitamin E (1), and the psychoactive, tetra-
hydrocannabinol (THC, 2).2 Medicinal chemists have also
reported a variety of active pharmaceutical ingredients
containing the chroman core, such as the marketed antihy-
pertensive, nebivolol (3),3 along with the antidiabetic, tro-
glitazone (Figure 1).4
We became interested in the synthesis of chromans as
part of a medicinal chemistry effort in which the chroman
moiety represented a key pharmacophore. As part of that
effort, a highly convergent and modular racemic synthesis
of 2-aryl- and 2-alkyl-substituted chromans was sought to
expedite the SAR efforts. Initially, we investigated the classi-
cal synthesis of chromans via the inverse-electron-demand
Diels–Alder reaction between in situ generated ortho-qui-
HO
O
O
NH
S
Me
O
Me
O
Troglitazone
Figure 1 Biologically active chroman natural products and pharma-
ceuticals
none methides 4 and styrenes (Scheme 1).5 While conver-
gent, this approach suffered from limited reaction scope
and low yields, possibly due to the harsh reaction condi-
tions and competitive decomposition of the ortho-quinone
methide 4, which were unable to be further optimized ac-
cording to literature protocols. While a number of other
conventional methods of chroman synthesis were investi-
gated, all failed to meet the objectives to fully prosecute the
SAR of the target.6 Faced with this challenge, we set out to
develop a convergent, general and robust racemic chroman
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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R. K. Orr et al.
Paper
Synthesis
synthesis to best enable thorough evaluation of the diverse
chemical matter. Targeting the use of readily available start-
ing materials, an approach was designed involving an initial
Heck coupling reaction between an allylic alcohol 5 and 2-
halophenol 6 to form the desired carbon framework. A re-
duction of the newly formed ketone 7, followed by cycliza-
tion, would then afford the desired chroman ring 11
(Scheme 1). In this paper, we disclose our findings on this
novel method for chroman synthesis.
modest yield.7 Upon careful analysis of the reaction mix-
ture, it was established that formation of undesired allylic
alcohol byproduct 8 and ketone 9 was responsible for the
mass balance.10 Unsatisfied with this result, we set out to
optimize this Heck reaction in order to develop a robust and
efficient reaction to support our chroman synthesis strate-
gy.11 Bulky electron-rich phosphine ligand palladium pre-
cursors were screened, with modified Fu conditions afford-
ing excellent conversion into product and a 73% assay yield
along with a significant amount of propiophenone (9) (Ta-
ble 1, entry 1).12,13 Further investigation of Buchwald-type
phosphines revealed a preference for very bulky derivatives
bearing di-tert-butyl groups on phosphorus (Table 1, en-
tries 2–5).14 In particular, tBuXPhos generation 2 palladium
precatalyst (tBuXPhos Pd G2) afforded an improved yield of
ketone 7 due to reduced formation of the two major by-
products 8 and 9 (<10% combined; Table 1, entry 6). With
ortho-Quinone Methide Approach:
AcO
Ph
O
HO
Ph
O
4
11
Heck–Reduction–Cyclization Approach:
OH
O
OH
OH
Ph
O
I
Ph
Ph
11
i. NaBH4
5
6
7
OH
OH
O
OH
Ph
O
DIAD
MeOH, THF
Scheme 1
Ph
Ph
0 °C to r.t.
R3 P
ii. aq H3PO4
EtOAc, 0 °C
CH
2Cl2
7
10
11
Previous work at Merck has demonstrated the utility of
Heck reactions between allylic alcohols and aryl halides to-
wards a robust, large-scale synthesis of montelukast.7 The
corresponding transformation with 2-halophenols, howev-
er, has limited application due to the formation of complex
reaction mixtures and poor reaction scope.8,9 We started
our foray into an improved 2-substituted chroman synthe-
sis by investigation of literature conditions [Pd(OAc)2,
Cs2CO3 or Et3N] which revealed that 2-iodophenol (6) un-
derwent a coupling with 1-phenylprop-2-en-1-ol (5) in
R3P
Ph3P
yield (%)
79
P
77
86
Bu3P
Scheme 2
Table 1 Optimization of the Heck Reaction
OH
OH
O
OH
OH
OH
O
base (equiv)
catalyst (mol%)
I
Ph
Ph
Ph
Ph
Et
solvent, temp
5 (1.25 equiv)
6
7
8
9
Entry
Catalyst (mol%)
Base (equiv)
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8c
tBu3P Pd G2 (3)
Cy2NMe (1.25)
Cy2NMe (1.25)
Cy2NMe (1.25)
Cy2NMe (1.25)
Cy2NMe (1.25)
Cs2CO3 (1.25)
Cy2NMe (1.25)
Cy2NMe (2.5)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
100
100
100
100
100
100
100
100
3
3
3
3
3
3
3
1
73 (89b)
72 (88b)
77 (86b)
84 (93b)
84 (93b)
86 (97b)
65 (78b)
93, 88d (99b)
BrettPhos Pd G3 (3)
tBuBrettPhos Pd G3 (3)
RockPhos Pd G3 (3)
tBuXPhos Pd G3 (3)
tBuXPhos Pd G2 (3)
tBuXPhos Pd G2 (3)
tBuXPhos Pd G2 (5)
a Yield of reaction by HPLC assay, determined by comparison to the product standard.
b Conversion of 2-iodophenol into product, determined by HPLC at 210 nm.
c Allylic alcohol 5 (2 equiv) was used.
d Isolated yield after silica gel chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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R. K. Orr et al.
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the optimal ligand in hand, bases and reagent stoichiome-
try were explored in the Heck reaction (Table 1, entries 6
and 7). Utilizing a combination of tBuXPhos Pd G2 precata-
lyst, 2.0 equivalents of allylic alcohol 5 and 2.5 equivalents
of N,N-dicyclohexylmethylamine in toluene at 100 °C for 1
hour, a 93% assay yield was achieved. Gram-scale demon-
stration of these conditions afforded the desired product 7
in 88% isolated yield (Table 1, entry 8).15
reduced with sodium borohydride, and mild acidic workup
afforded the diol intermediate 10.16 Crude intermediate 10
was then subjected to Mitsunobu conditions to provide
chroman 11 in good yield (Scheme 2). A slight increase in
yield was observed with the use of tributylphosphine com-
pared to triphenylphosphine and the polymer-bound ver-
sion of triphenylphosphine.17
To test the scope and robustness of the newly developed
conditions, a series of allylic alcohols 5a–g was investigated
in the Heck reaction with 2-iodophenol (6) (Table 2). Simi-
lar to the optimization substrate, a significant increase in
With improved conditions for the Heck reaction in
hand, the conversion of ketone 7 into the desired 2-phenyl-
chroman product 11 was then investigated. Ketone 7 was
Table 2 Scope of the Allylic Alcohol Component
OH
t-BuXPhos Pd G2 (5 mol%)
O
OH
I
R
O
Cy2NMe (2.5 equiv)
1) NaBH4, MeOH, THF
2) DIAD, R3P, CH2Cl2
OH
R
+
toluene, 100 °C
R
11a–g
5a–g
6
7a–g
Entry Allylic alcohol
Heck product
Yield Chroman product
(%)
Yield
(%)
O
OH
O
O
OH
OH
O
O
O
O
O
1
88
79a
O
5a
7a
11a
NC
OH
O
2
71
75
56
87b
62b
62b
NC
5b
NC
7b
11b
O
O
OH
OH
O
O
O
3
5c
11c
7c
Me
N
O
OH
OH
O
4
Me
N
Me
N
5d
7d
11d
Cl
O
OH
OH
N
O
5
6
7
74
75
70
65b
71b
74a
Cl
N
Cl
N
5e
7e
11e
O
OH
H15C7
O
OH
H15C7
H15C7
5f
11f
7f
Boc
O
OH
OH
N
O
N
N
Boc
Boc
5g
7g
11g
a With n-Bu3P.
b With Ph3P.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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R. K. Orr et al.
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yield was observed with electron-rich allylic alcohol 5a,
while the Heck yield using electron-deficient benzonitrile
5b was only slightly improved due to what is tentatively as-
signed as the allylic alcohol byproduct 8b (15%; Table 2, en-
tries 1 and 2).18 On the contrary, a slight increase in yield
was observed for the electron-deficient substrate 7b during
the reduction and cyclization sequence, thus providing a
comparable overall yield for the sequence.
The synthesis of 2-heteroaryl- and 2-alkylchromans
11c–g has proven challenging by existing literature meth-
ods.19 For instance, utilizing conditions specified in Table 1,
entries 1–3, complex mixtures were observed with consid-
erable amounts of unreacted starting material (>30%). Us-
ing our methodology, heteroaryl-substituted allylic alco-
hols 5c–e proved competent in the Heck, reduction and cy-
clization reactions, affording the corresponding products
11c–e in good yields (Table 2, entries 3–5). Notably, the
standard Heck conditions demonstrated the selectivity for
the monosubstituted olefin and iodide of the highly func-
tionalized allylic alcohol 5e en route to montelukast (Table
2, entry 5). Finally, both linear and branched aliphatic allyl-
ic alcohols 5f,g performed well as starting materials in this
sequence, vastly increasing the scope of this transformation
and allowing for a high degree of chemical diversity of
chromans produced by this method (Table 2, entries 6 and
7).20,21
Next, the impact of substituents on the 2-iodophenol
component, 6h–m, was investigated for the formation of 2-
phenylchromans 11h–m (Table 3).20 Electron-deficient 2-
iodophenols 6h–j were suitable substrates under standard
reaction conditions with 1-phenylprop-2-en-1-ol (5) as the
reaction partner in the Heck reaction (Table 3, entries 1–3).
However, the use of 2-hydroxy-3-iodopyridine 6k led to
significant amounts of protodehalogenation byproduct un-
der the standard reaction conditions, and <10% of product
7k was obtained. Investigation of additional bases revealed
that phosphazene superbases, notably P2-Et, significantly
suppressed this byproduct formation, and afforded Heck
product 7k in 67% yield (Table 3, entry 4).22
Table 3 Scope of the Iodophenol Component
OH
OH
R1
O
OH
1) NaBH4
MeOH, THF
2) DIAD
R3P, CH2Cl2
I
Heck conditions
O
R2
R2
R2
R1
R1
5, 5l,m
6h–m
7h–m
11h–m
Entry
1
Allylic alcohol R1 Iodophenol
Heck product
Yield (%) Chroman product
Yield (%)
66d
O
OH
OH
Ph
O
I
Ph
H (5)
76a
70a
63a
CF3
11h
CF3
OH
CF3
6h
7h
O
OH
Ph
O
CO2Me
I
Ph
2
3
H (5)
75d
CO2Me
CO2Me
11i
6i
7i
OH
O
OH
I
Ph
O
Ph
H (5)
72d
CO2Me
11j
CO2Me
CO2Me
6j
7j
O
OH
OH
N
I
Ph
O
N
N
Ph
4
H (5)
67b
85e
CO2Me
11k
CO2Me
CO2Me
6k
7k
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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R. K. Orr et al.
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Table 3 (continued)
Entry
5
Allylic alcohol R1 Iodophenol
Heck product
O
Yield (%) Chroman product
Yield (%)
OH
OH
Cl
I
4-ClC6H4
O
Cl (5l)
60a
50e
Cl
Cl
Cl
11l
6l
7l
MeO
OH
O
OH
I
O
OMe
6
MeO (5m)
46c
60f
OMe
MeO
OMe
6m
7m
11m
a tBuXPhos Pd G2 (5 mol%), Cy2NMe (2.0 equiv), toluene, 100 °C.
b tBuXPhos Pd G2 (5 mol%), P2-Et (1.1 equiv), allylic alcohol 5 (1.1 equiv), toluene, 80 °C.
c tBuXPhos Pd G2 (7 mol%), slow addition of P2-Et (1.1 equiv), DMA, 80 °C.
d R3P = polymer-bound Ph3P.
e Ph3P.
f Cyclization occurred during H3PO4 workup.
To further establish the modular nature of this ap-
proach, substrates substituted on both the allylic alcohol
and iodophenol were utilized in this chemistry. For exam-
ple, application to the synthesis of the antibiotic 4′,6-di-
O
OH
i. RuCl(p-cymene)[(S,S)-TsDPEN] (12)
HCO2H, Et3N, ACN
Ph
Ph
O
ii. DIAD, Ph3P
CH2Cl2, 0 °C
(R)-11
54% yield; 96:4 er
7
chloroflavan (BW-683C, 11l; Table 3, entry 5) was accom-
plished in high yield utilizing chlorinated starting materials
5l and 6l.23 The core of the natural product tupichinol C
(11m; Table 3, entry 6) was also prepared in modest yield
via allylic alcohol 5m and iodophenol 6m.24 With this high-
ly electron-rich substrate, similar to the aza substrate 6k,
the Heck reaction required the use of P2-Et as base, along
with slow addition of the base and DMA as solvent. Upon
reduction of the ketone and acidic workup, the correspond-
ing diol underwent spontaneous cyclization to form the
chroman 11m.25
While a racemic synthesis was desirable for initial bio-
logical evaluation of both enantiomers of the chroman
product, an asymmetric approach was required to prepare
multigram quantities of individual enantiomers of these
compounds for in vivo studies. The asymmetric reduction
of aryl alkyl ketones is well-documented utilizing the
Noyori conditions; however, erosion of enantioselectivity is
a known issue with the Mitsunobu reaction of chiral ben-
zylic substrates.26,27 The use of the readily available RuCl(p-
cymene)[(S,S)-TsDPEN] catalyst (12) and in situ hydrogen
generation from transfer hydrogenation conditions with
substrate 7 afforded the corresponding chiral alcohol (S)-10
in good enantioselectivity (95:5 er).28 To our delight, no loss
in enantiomeric excess was observed upon cyclization,
when utilizing slow addition of the DIAD and temperature
control at 0 °C, to form (R)-chroman 11 (Scheme 3).
Scheme 3 Asymmetric synthesis of chroman 11
the Heck reaction between allylic alcohols and iodophenols
allowed for the use of a variety of substrates previously in-
accessible by other methods. This modular chemistry func-
tions on a broad range of substrates, including pharmaceu-
tically relevant and natural product examples. Our chemis-
try has been readily applied to the gram-scale synthesis of
chromans. In addition, application of the asymmetric ver-
sion of this sequence has been demonstrated, with efforts
underway to apply this asymmetric method to prepare
more advanced chroman derivatives.
Commercial grade reagents and solvents were used without further
1
purification. H NMR and 13C NMR spectra were measured with 400,
500 or 600 MHz Bruker Avance spectrometers. 1H NMR chemical
shifts are expressed in parts per million (δ) downfield from TMS
(with the CHCl3 peak at 7.27 used as a reference). 13C NMR chemical
shifts are expressed in parts per million (δ) downfield from TMS
(with the central peak of CDCl3 at 77.0 ppm used as a reference).
High-resolution mass spectrometry was performed on a Waters Ac-
quity UPLC for the LC and Waters Xevo G2 for MS, except for samples
11a, 11b and 11h which were analyzed by GC-MS on an Agilent 6890
GC and a Waters GCT Premier mass detector. Purifications were car-
ried out by flash column chromatography on a Teledyne Isco Combi-
Flash Rf system using a gradient elution of 0–40% EtOAc/hexanes.
In summary, we have discovered a novel synthesis of 2-
substituted chromans from allylic alcohols and 2-iodophe-
nols via a three-step sequence. Significant optimization of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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3-(2-Hydroxyphenyl)-1-phenylpropan-1-one (7); Typical Proce-
dure for Heck Products 7, 7a–m
1H NMR (400 MHz, CDCl3): δ = 2.03 (s, 1 H), 3.10 (t, J = 6.14 Hz, 2 H),
3.50 (t, J = 6.15 Hz, 2 H), 6.89 (td, J = 7.41, 1.22 Hz, 1 H), 6.96 (d,
J = 8.04 Hz, 1 H), 7.19–7.13 (m, 2 H), 7.52–7.44 (m, 3 H), 7.67 (d,
J = 8.54 Hz, 1 H), 7.76–7.73 (m, 2 H), 7.81 (d, J = 7.73 Hz, 1 H), 7.95 (d,
J = 7.89 Hz, 1 H), 8.16–8.11 (m, 2 H), 8.29 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 23.9, 40.5, 117.3, 119.7, 119.7, 120.7,
125.8, 127.0, 127.1, 127.5, 127.7, 128.0, 128.1, 128.5, 128.8, 129.3,
130.6, 132.4, 136.7, 154.6, 201.7.
To a flask were added 1-phenylprop-2-en-1-ol (5) (1.196 mL, 9.09
mmol), 2-iodophenol (6) (1 g, 4.55 mmol) and tBuXPhos Pd G2 prec-
atalyst (0.156 g, 0.227 mmol). Then toluene (18 mL) was added to the
flask and the solvent was degassed by bubbling N2 through the solu-
tion for 15 min. Cy2NMe (2.420 mL, 11.36 mmol) was then added to
the flask and the solvent was degassed by bubbling N2 through the
solution for an additional 5 min. The reaction mixture was heated to
100 °C for 1 h, cooled to r.t. and concentrated to 1/3 volume. The resi-
due was purified by silica gel chromatography to give 0.91 g (88%) of
compound 7 as a colorless oil. The spectroscopic data obtained for
this compound are in accordance with the previously prepared mate-
rial.7
HRMS (TOF-MS): m/z [M + H]+ calcd for C26H21ClNO2: 414.1255;
found: 414.1249.
1-(2-Hydroxyphenyl)decan-3-one (7f)
Yield: 1.02 g (75%); colorless liquid.
1H NMR (500 MHz, CDCl3): δ (~10% ketal form) = 0.88 (m, 3 H), 1.26
(m, 8 H), 1.55 (m, 2 H), 2.41 (m, 2 H), 2.86 (m, 4 H), 6.84 (m, 1 H), 6.90
(m, 1 H), 7.05 (d, J = 7.34 Hz, 1 H), 7.12 (m, 1 H), 7.77 (s, 1 H).
1-(Benzo[d][1,3]dioxol-5-yl)-3-(2-hydroxyphenyl)propan-1-one
(7a)
Yield: 1.341 g (88%).
13C NMR (150 MHz, CDCl3): δ (~10% ketal form) = 14.0, 22.6, 23.2,
23.8, 28.9, 29.0, 31.6, 42.6, 44.3, 117.4, 120.6, 127.7, 128.0, 130.5,
154.4, 214.3.
The spectroscopic data obtained for this compound are in accordance
with the previously prepared material.7
HRMS (TOF-MS): m/z [M – H]– calcd for C16H23O2: 247.1704; found:
247.1707.
4-(3-(2-Hydroxyphenyl)propanoyl)benzonitrile (7b)
Yield: 1.02 g (71%).
tert-Butyl 3-(3-(2-Hydroxyphenyl)propanoyl)azetidine-1-carbox-
ylate (7g)
The spectroscopic data obtained for this compound are in accordance
with the previously prepared material.7
According to the general procedure, treatment of tert-butyl 3-(1-hy-
droxyallyl)azetidine-1-carboxylate (5g) (1.236 g, 5.80 mmol) with 2-
iodophenol (6) (0.85 g, 3.86 mmol) in the presence of tBuXPhos Pd G2
precatalyst (0.133 g, 0.193 mmol) and Cy2NMe (2.06 mL, 9.6 mmol)
afforded 0.828 g (70%) of 7g as a colorless liquid.
1H NMR (500 MHz, CDCl3): δ (~70% ketal form) = 0.88 (m, 3 H), 1.26
(m, 8 H), 1.55 (m, 2 H), 2.41 (m, 2 H), 2.86 (m, 4 H), 6.84 (m, 1 H), 6.90
(m, 1 H), 7.05 (d, J = 7.34 Hz, 1 H), 7.12 (m, 1 H), 7.77 (s, 1 H).
1-(Furan-2-yl)-3-(2-hydroxyphenyl)propan-1-one (7c)
Yield: 0.229 g (75%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 3.02 (t, J = 6.12 Hz, 2 H), 3.32 (t,
J = 6.12 Hz, 2 H), 6.54 (s, 1 H), 6.86 (t, J = 7.37 Hz, 1 H), 6.91 (d, J = 8.34
Hz, 1 H), 7.12 (t, J = 6.83 Hz, 2 H), 7.61 (d, J = 7.07 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 23.5, 39.8, 112.6, 117.2, 118.3, 120.7,
127.6, 128.0, 130.6, 147.0, 152.3, 154.4, 190.8.
HRMS (TOF-MS): m/z [M – H]+ calcd for C13H11O3: 215.0714; found:
215.0715.
13C NMR (150 MHz, CDCl3): δ (~70% ketal form) = 14.0, 22.6, 23.2,
23.8, 28.9, 29.0, 31.6, 42.6, 44.3, 117.4, 120.6, 127.7, 128.0, 130.5,
154.4, 214.3.
HRMS (TOF-MS): m/z [M – H]+ calcd for C17H22NO4: 304.1554; found:
304.1540.
3-(2-Hydroxyphenyl)-1-(6-methylpyridin-3-yl)propan-1-one (7d)
According to the general procedure, treatment of 1-(6-methylpyridin-
3-yl)prop-2-en-1-ol (5d) (0.814 g, 5.45 mmol) with 2-iodophenol (6)
(0.800 g, 3.64 mmol) in the presence of tBuXPhos Pd G2 precatalyst
(0.125 g, 0.182 mmol) and Cy2NMe (1.94 mL, 9.09 mmol) afforded
0.491 g (56%) of 7d as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 2.65 (s, 3 H), 3.08 (t, J = 6.13 Hz, 2 H),
3.45 (t, J = 6.13 Hz, 2 H), 6.93–6.87 (m, 2 H), 7.14 (dd, J = 11.14, 7.43
Hz, 2 H), 7.70 (br s, 1 H), 8.17 (dd, J = 8.16, 2.29 Hz, 1 H), 9.10 (d,
J = 2.25 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 23.6, 24.8, 40.4, 117.3, 120.8, 123.4,
127.4, 128.1, 129.2, 130.6, 136.0, 149.5, 154.4, 163.9, 200.5.
HRMS (TOF-MS): m/z [M + H]+ calcd for C15H16NO2: 242.1176; found:
241.1169.
3-(2-Hydroxy-5-(trifluoromethyl)phenyl)-1-phenylpropan-1-one
(7h)
Yield: 0.272 g (76%); colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 3.10 (t, J = 5.83 Hz, 2 H), 3.52 (t,
J = 5.84 Hz, 2 H), 7.01 (d, J = 8.31 Hz, 1 H), 7.40 (d, J = 11.43 Hz, 2 H),
7.49 (t, J = 7.69 Hz, 2 H), 7.62 (t, J = 7.42 Hz, 1 H), 8.02–8.00 (m, 2 H),
8.76 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 23.2, 40.3, 117.9, 122.8 (q, J = 32.4 Hz),
124.5 (q, J = 271.4 Hz), 125.4 (q, J = 3.7 Hz), 127.9 (q, J = 3.8 Hz), 128.0,
128.4, 128.8, 134.2, 135.7, 157.6, 202.2.
HRMS (TOF-MS): m/z [M – H]– calcd for C16H12F3O2: 293.0795; found:
293.0801.
(E)-1-(3-(2-(7-Chloroquinolin-2-yl)vinyl)phenyl)-3-(2-hydroxy-
phenyl)propan-1-one (7e)
Methyl 3-Hydroxy-4-(3-oxo-3-phenylpropyl)benzoate (7i)
Yield: 0.308 g (70%); colorless liquid.
Yield: 1.4 g (74%); white solid; mp 145–147 °C. This material was pu-
rified for analytical purposes by crystallization from MTBE (45% yield,
without optimization of the crystallization).
1H NMR (500 MHz, CDCl3): δ = 3.10 (t, J = 6.20 Hz, 2 H), 3.47 (t,
J = 6.21 Hz, 2 H), 3.90 (s, 3 H), 7.21 (d, J = 7.89 Hz, 1 H), 7.47 (t, J = 7.70
Hz, 2 H), 7.62–7.53 (m, 3 H), 8.00–7.98 (m, 2 H), 8.14 (s, 1 H).
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13C NMR (126 MHz, CDCl3): δ = 23.9, 39.8, 52.1, 118.3, 121.9, 128.4,
128.7, 129.8, 130.6, 133.4, 133.9, 136.0, 154.6, 167.1, 201.6.
HRMS (TOF-MS): m/z [M – H]– calcd for C17H15O4: 283.0976; found:
283.0976.
mL). The organic layers were combined and washed with sat. aqueous
NaCl. The organic solution was dried with Na2SO4, filtered and con-
centrated in vacuo. This material was used in the following step with-
out further purification.
The crude material was then dissolved in CH2Cl2 (4 mL) and n-Bu3P
(0.368 mL, 1.492 mmol) was added. To this mixture was added DIAD
(0.212 mL, 1.094 mmol) in CH2Cl2 (1 mL) slowly over 1 h at r.t. The
reaction mixture was then stirred at r.t. overnight, filtered and con-
centrated in vacuo. The residue was purified by silica gel chromatog-
raphy to give 0.180 g (86%) of compound 11 as a colorless oil. The
spectroscopic data obtained for this compound are in accordance
with the previously prepared material.29
Methyl 4-Hydroxy-3-(3-oxo-3-phenylpropyl)benzoate (7j)
Yield: 0.277 g (63%); colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 3.08 (t, J = 5.95 Hz, 2 H), 3.49 (t,
J = 5.95 Hz, 2 H), 3.89 (s, 3 H), 6.94 (d, J = 8.46 Hz, 1 H), 7.47 (t, J = 7.73
Hz, 2 H), 7.59–7.56 (m, 1 H), 7.82 (dd, J = 8.45, 2.20 Hz, 1 H), 7.89 (d,
J = 2.20 Hz, 1 H), 8.00–7.98 (m, 2 H), 8.88 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 23.9, 39.8, 52.1, 118.3, 121.9, 128.4,
128.5, 128.7, 129.8, 130.6, 133.4, 133.9, 136.0, 154.6, 167.1, 201.6.
HRMS (TOF-MS): m/z [M – H]– calcd for C17H15O4: 283.0976; found:
283.0964.
2-(Benzo[d][1,3]dioxol-5-yl)chromane (11a)
According to the general procedure, treatment of 1-(benzo[d][1,3]di-
oxol-5-yl)-3-(2-hydroxyphenyl)propan-1-one (7a) (1.4 g, 5.18 mmol)
with NaBH4 (0.295 g, 7.8 mmol) followed by quenching with 1.0 M
aqueous H3PO4 afforded the crude diol intermediate. Treatment of
this crude material with n-Bu3P (1.1 mL, 4.6 mmol) followed by slow
addition of DIAD (1.02 mL, 5.2 mmol) afforded 0.91 g (79%) of 11a as a
colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 2.10–2.02 (m, 1 H), 2.27 (ddt, J = 13.70,
5.89, 3.02 Hz, 1 H), 2.82 (dt, J = 16.51, 4.36 Hz, 1 H), 3.04 (ddd,
J = 16.48, 11.18, 5.93 Hz, 1 H), 5.16 (dd, J = 10.06, 2.45 Hz, 1 H), 6.97–
6.93 (m, 2 H), 7.21–7.13 (m, 2 H), 7.58 (d, J = 8.10 Hz, 2 H), 7.71 (d,
J = 8.14 Hz, 2 H).
Methyl 6-Hydroxy-5-(3-oxo-3-phenylpropyl)nicotinate (7k)
Yield: 0.293 g (67%); colorless liquid.
1H NMR (500 MHz, DMSO-d6): δ = 3.56 (t, J = 7.31 Hz, 2 H), 4.11 (t,
J = 7.34 Hz, 2 H), 4.57 (s, 3 H), 8.32 (t, J = 7.63 Hz, 2 H), 8.44 (t, J = 7.38
Hz, 1 H), 8.54 (d, J = 2.44 Hz, 1 H), 8.79–8.74 (m, 3 H), 12.93 (s, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 26.2, 37.5, 53.0, 109.2, 129.2,
130.0, 132.3, 134.4, 137.0, 137.8, 139.4, 163.8, 165.8, 200.5.
HRMS (TOF-MS): m/z [M + H]+ calcd for C16H16NO4: 286.1074; found:
286.1064.
13C NMR (126 MHz, CDCl3): δ = 24.8, 30.0, 77.4, 111.6, 116.9, 118.8,
120.9, 121.6, 126.6, 127.6, 129.7, 132.4, 147.1, 154.5.
HRMS (ESI-MS): m/z [M]+ calcd for C16H14O3: 254.0937; found:
254.0941.
3-(5-Chloro-2-hydroxyphenyl)-1-(4-chlorophenyl)propan-1-one
(7l)
Yield: 0.348 g (60%); colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 3.00 (t, J = 5.95 Hz, 2 H), 3.42 (t,
J = 5.96 Hz, 2 H), 6.86 (d, J = 8.54 Hz, 1 H), 7.11–7.07 (m, 2 H), 7.45 (d,
J = 8.31 Hz, 2 H), 7.92 (d, J = 8.31 Hz, 2 H), 7.99 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 23.3, 40.2, 118.9, 125.3, 127.9, 129.1,
129.3, 129.8, 130.2, 134.2, 140.6, 153.2, 200.7.
4-(Chroman-2-yl)benzonitrile (11b)
According to the general procedure, treatment of 4-(1-hydroxyal-
lyl)benzonitrile (7b) (1.1 g, 4.38 mmol) with NaBH4 (0.25 g, 6.57
mmol) followed by quenching with 1.0 M aqueous H3PO4 afforded the
crude diol intermediate. Treatment of this crude material with Ph3P
(1.25 g, 4.78 mmol) followed by slow addition of DIAD (1.1 mL, 5.4
mmol) afforded 0.896 g (87%) of 11b as a colorless liquid.
HRMS (TOF-MS): m/z [M – H]– calcd for C15H11Cl2O2: 293.0142; found:
293.0144.
1H NMR (500 MHz, CDCl3): δ = 2.13–2.06 (m, 1 H), 2.20 (ddt, J = 13.66,
5.93, 2.83 Hz, 1 H), 2.84 (ddd, J = 16.47, 5.19, 3.11 Hz, 1 H), 3.05–2.98
(m, 1 H), 5.00 (dd, J = 10.30, 2.38 Hz, 1 H), 6.94–6.85 (m, 4 H), 6.98 (d,
J = 1.68 Hz, 2 H), 7.17–7.11 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 25.2, 30.0, 77.7, 101.1, 106.8, 108.2,
117.0, 119.6, 120.4, 121.8, 127.4, 129.6, 135.7, 147.3, 147.9, 155.1.
3-(2-Hydroxy-4-methoxyphenyl)-1-(4-methoxyphenyl)propan-1-
one (7m)
Yield: 0.289 g (46%); colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 2.97 (t, J = 5.83 Hz, 2 H), 3.37 (t,
J = 5.85 Hz, 2 H), 3.76 (s, 3 H), 3.87 (s, 3 H), 6.46 (dd, J = 8.26, 2.70 Hz,
1 H), 6.53 (d, J = 2.60 Hz, 1 H), 6.93–6.91 (m, 2 H), 7.02 (d, J = 8.37 Hz,
1 H), 7.98–7.96 (m, 2 H), 8.60 (s, 1 H).
HRMS (GC-MS): m/z [M]+ calcd for C16H13NO: 235.0992; found:
235.1002.
13C NMR (126 MHz, CDCl3): δ = 23.0, 40.3, 55.3, 55.5, 102.8, 106.8,
113.8, 120.3, 129.1, 130.8, 131.1, 155.7, 159.6, 164.1, 200.9.
2-(Furan-2-yl)chromane (11c)
HRMS (TOF-MS): m/z [M – H]+ calcd for C17H17O4: 285.1132; found:
285.1127.
According to the general procedure, treatment of 1-(furan-2-yl)-3-(2-
hydroxyphenyl)propan-1-one (7c) (0.140 g, 0.647 mmol) with NaBH4
(0.0245 g, 0.647 mmol) followed by quenching with 1.0 M aqueous
H3PO4 afforded the crude diol intermediate. Treatment of this crude
material with Ph3P (0.255 g, 0.971 mmol) followed by slow addition
of DIAD (0.138 mL, 0.712 mmol) afforded 0.080 g (62%) of 11c as a
colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 2.34–2.27 (m, 2 H), 2.86 (dt, J = 16.49,
4.62 Hz, 1 H), 2.98 (ddd, J = 16.53, 10.29, 6.63 Hz, 1 H), 5.14 (dd,
J = 9.28, 3.10 Hz, 1 H), 6.40 (s, 2 H), 6.92–6.88 (m, 2 H), 7.15–7.09 (m,
2 H), 7.46 (s, 1 H).
2-Phenylchromane (11); Typical Reduction/Cyclization Procedure
for Products 11, 11a–m
To 3-(2-hydroxyphenyl)-1-phenylpropan-1-one (7) (225 mg, 0.994
mmol) in THF (4 mL) and MeOH (4 mL) at 0 °C was added NaBH4 (37.6
mg, 0.994 mmol). The reaction mixture was warmed to r.t. and stirred
for 1 h. After cooling to 0 °C, EtOAc (5 mL) was added and then the
reaction was quenched with 1 N aqueous H3PO4 (5 mL). The organic
layer was removed and the aqueous layer was extracted with EtOAc (5
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R. K. Orr et al.
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13C NMR (126 MHz, CDCl3): δ = 24.6, 26.0, 71.2, 107.3, 110.3, 117.0,
tert-Butyl 3-(Chroman-2-yl)azetidine-1-carboxylate (11g)
120.6, 121.6, 127.4, 129.6, 142.5, 153.8, 154.5.
HRMS (GC-MS, EI): m/z [M]+ calcd for C13H12O2: 200.0837; found:
200.0841.
According to the general procedure, treatment of tert-butyl 3-(3-(2-
hydroxyphenyl)propanoyl)azetidine-1-carboxylate (7g) (0.150 g,
0.491 mmol) with NaBH4 (0.0288 g, 0.762 mmol) followed by quench-
ing with 1.0 M aqueous H3PO4 afforded the crude diol intermediate.
Treatment of this crude material with n-Bu3P (0.188 mL, 0.737 mmol)
followed by slow addition of DIAD (0.105 mL, 0.540 mmol) afforded
0.105 g (74%) of 11g as a colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 1.46 (s, 9 H), 1.60 (m, 1 H), 1.96 (m, 1
H), 2.75 (m, 2 H), 2.80 (m, 1 H), 3.86 (m, 1 H), 3.99 (m, 1 H), 4.08 (m, 3
H), 6.87 (m, 2 H), 7.12 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 24.5, 24.6, 28.1, 28.3, 32.9, 79.2, 116.6,
120.2, 121.5, 127.2, 129.3, 154.5, 156.2.
HRMS (TOF-MS): m/z [M + H]+ calcd for C17H24NO3: 290.1751; found:
290.1760.
5-(Chroman-2-yl)-2-methylpyridine (11d)
According to the general procedure, treatment of 3-(2-hydroxyphe-
nyl)-1-(6-methylpyridin-3-yl)propan-1-one (7d) (0.305 g, 1.264
mmol) with NaBH4 (0.048 g, 1.264 mmol) followed by quenching with
1.0 M aqueous H3PO4 and washing with sat. aq NaHCO3 afforded the
crude diol intermediate. Treatment of this crude material with tri-
phenylphosphine (0.497 g, 1.896 mmol) followed by slow addition of
DIAD (0.270 mL, 1.390 mmol) afforded 0.177 g (62%) of 11d as a col-
orless liquid.
1H NMR (500 MHz, CDCl3): δ = 2.10 (m, 1 H), 2.21 (m, 1 H), 2.58 (s, 3
H), 2.81 (m, 1 H), 3.02 (m, 1 H), 5.08 (dd, J = 1.96, 10.76 Hz, 1 H), 6.89
(m, 2 H), 7.10 (d, J = 7.34 Hz, 1 H), 7.14 (m, 1 H), 7.19 (d, J = 8.31 Hz, 1
H), 7.67 (dd, J = 1.96, 7.83 Hz, 1 H), 8.55 (m, 1 H).
2-Phenyl-6-(trifluoromethyl)chromane (11h)
According to the general procedure, treatment of 3-(2-hydroxy-5-
(trifluoromethyl)phenyl)-1-phenylpropan-1-one (7h) (0.225 g, 0.765
mmol) with NaBH4 (0.0289 g, 0.765 mmol) followed by quenching
with 1.0 M aqueous H3PO4 afforded the crude diol intermediate.
Treatment of this crude material with resin-bound Ph3P (0.384 g,
1.147 mmol) followed by slow addition of DIAD (0.149 mL, 0.765
mmol) afforded 0.140 g (66%) of 11h as a colorless liquid.
13C NMR (126 MHz, CDCl3): δ = 24.1, 24.9, 29.7, 75.5, 116.9, 120.6,
121.5, 123.1, 127.4, 129.5, 134.1, 134.1, 147.1, 154.7, 158.0.
HRMS (TOF-MS): m/z [M + H]+ calcd for C15H16NO: 226.1226; found:
226.1218.
(E)-7-Chloro-2-(3-(chroman-2-yl)styryl)quinoline (11e)
1H NMR (500 MHz, CDCl3): δ = 2.19–2.11 (m, 1 H), 2.31 (ddt, J = 13.84,
5.85, 3.00 Hz, 1 H), 2.88 (dt, J = 16.58, 4.29 Hz, 1 H), 3.06 (ddd,
J = 16.55, 11.27, 5.87 Hz, 1 H), 5.17 (dd, J = 10.08, 2.50 Hz, 1 H), 7.03
(d, J = 8.34 Hz, 1 H), 7.46–7.37 (m, 7 H).
13C NMR (126 MHz, CDCl3): δ = 24.9, 29.4, 78.2, 117.3, 122.2, 122.5 (q,
J = 32 Hz), 124.6 (q, J = 271 Hz), 124.6 (q, J = 3.9 Hz), 126.0, 126.9 (q,
J = 3.9 Hz), 128.1, 128.7, 141.0, 157.7.
According to the general procedure, treatment of (E)-1-(3-(2-(7-chlo-
roquinolin-2-yl)vinyl)phenyl)-3-(2-hydroxyphenyl)propan-1-one (7e)
(0.100 g, 0.242 mmol) with NaBH4 (0.0091 g, 0.242 mmol) followed
by quenching with 1.0 M aqueous H3PO4 and washing of the organic
layer with sat. aqueous NaHCO3 afforded the crude diol intermediate.
Treatment of this crude material with Ph3P (0.089 g, 0.338 mmol) fol-
lowed by slow addition of DIAD (0.052 mL, 0.266 mmol) afforded
0.065 g (65%) of 11e as a colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 2.15 (dtd, J = 13.73, 10.89, 5.19 Hz, 1
H), 2.29 (ddt, J = 13.71, 5.84, 2.87 Hz, 1 H), 2.86 (dt, J = 16.46, 4.03 Hz,
1 H), 3.09–3.02 (m, 1 H), 5.13 (dd, J = 10.26, 2.37 Hz, 1 H), 6.97–6.90
(m, 2 H), 7.20–7.13 (m, 2 H), 7.48–7.41 (m, 4 H), 7.68–7.62 (m, 2 H),
7.75 (t, J = 8.82 Hz, 3 H), 8.13–8.10 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 25.2, 29.8, 30.1, 77.6, 117.0, 119.6,
120.5, 121.8, 125.0, 125.7, 126.6, 126.9, 127.3, 127.5, 128.0, 128.6,
128.7, 129.1, 129.6, 135.3, 136.4, 136.6, 142.5, 155.0, 156.8.
HRMS (TOF-MS): m/z [M + H]+ calcd for C26H21ClNO: 398.1306; found:
398.1299.
HRMS (ESI-MS): m/z [M]+ calcd for C16H13F3O: 278.0913; found:
278.0924.
Methyl 2-Phenylchromane-7-carboxylate (11i)
According to the general procedure, treatment of methyl 3-hydroxy-
4-(3-oxo-3-phenylpropyl)benzoate (7i) (0.207 g, 0.728 mmol) with
NaBH4 (0.0275 g, 0.728 mmol) followed by quenching with 1.0 M
aqueous H3PO4 afforded the crude diol intermediate. Treatment of
this crude material with resin-bound Ph3P (0.366 g, 1.092 mmol) fol-
lowed by slow addition of DIAD (0.142 mL, 0.728 mmol) afforded
0.147 g (75%) of 11i as a colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 2.16–2.08 (m, 1 H), 2.28 (ddt, J = 13.79,
5.87, 3.01 Hz, 1 H), 2.89–2.84 (m, 1 H), 3.04 (ddd, J = 17.02, 11.10, 5.95
Hz, 1 H), 3.92 (s, 3 H), 5.13 (dd, J = 10.02, 2.38 Hz, 1 H), 7.17 (d, J = 7.91
Hz, 1 H), 7.45–7.34 (m, 5 H), 7.58 (dd, J = 7.90, 1.65 Hz, 1 H), 7.63 (s, 1
H).
13C NMR (126 MHz, CDCl3): δ = 25.2, 29.5, 52.1, 77.8, 118.3, 121.4,
125.9, 127.3, 128.0, 128.6, 129.5, 129.6, 141.3, 155.0, 167.0.
2-Heptylchromane (11f)
According to the general procedure, treatment of 1-(2-hydroxyphe-
nyl)decan-3-one (7f) (1.03 g, 4.15 mmol) with NaBH4 (0.235 g, 6.22
mmol) followed by quenching with 1.0 M aqueous H3PO4 afforded the
crude diol intermediate. Treatment of this crude material with Ph3P
(1.63 g, 6.22 mmol) followed by slow addition of DIAD (0.887 mL,
4.56 mmol) afforded 0.684 g (71%) of 11f as a colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 0.92 (m, 3 H), 1.35 (m, 8 H), 1.47 (s, 1
H), 1.61 (m, 4 H), 2.02 (m, 1 H), 2.89 (m, 2 H), 4.00 (m, 1 H), 6.84 (m, 2
H), 7.27 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 14.0, 22.6, 24.7, 25.2, 27.3, 29.2, 29.6,
31.8, 35.4, 75.8, 116.6, 119.8, 121.9, 127.0, 129.4, 155.0.
HRMS (GC-MS, EI): m/z [M]+ calcd for C16H24O: 232.1827; found:
232.1816.
HRMS (TOF-MS): m/z [M + H]+ calcd for C17H17O3: 269.1172; found:
269.1168.
Methyl 2-Phenylchromane-6-carboxylate (11j)
According to the general procedure, treatment of methyl 4-hydroxy-
3-(3-oxo-3-phenylpropyl)benzoate (7j) (0.100 g, 0.352 mmol) with
NaBH4 (0.0133 g, 0.352 mmol) followed by quenching with 1.0 M
aqueous H3PO4 afforded the crude diol intermediate. Treatment of
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this crude material with resin-bound Ph3P (0.177 g, 0.528 mmol) fol-
lowed by slow addition of DIAD (0.0684 mL, 0.352 mmol) afforded
0.0679 g (72%) of 11j as a colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 2.12 (dddd, J = 13.81, 11.26, 10.09, 5.16
Hz, 1 H), 2.28 (ddt, J = 13.82, 5.81, 3.00 Hz, 1 H), 2.86 (dt, J = 16.48,
4.31 Hz, 1 H), 3.03 (ddd, J = 16.46, 11.29, 5.83 Hz, 1 H), 3.91 (s, 3 H),
5.16 (dd, J = 10.08, 2.51 Hz, 1 H), 6.97–6.95 (m, 1 H), 7.45–7.35 (m, 5
H), 7.86–7.84 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 24.9, 29.6, 51.9, 78.3, 116.9, 121.7,
122.2, 126.0, 128.1, 128.6, 129.3, 131.7, 141.0, 159.2, 167.1.
HRMS (TOF-MS): m/z [M + H]+ calcd for C17H17O3: 269.1172; found:
(R)-2-Phenylchromane [(R)-11]
To 3-(2-hydroxyphenyl)-1-phenylpropan-1-one (7) (50 mg, 0.221
mmol) and RuCl(p-cymene)[(S,S)-TsDPEN] (12) (7.04 mg, 0.011
mmol) in MeCN (2210 μL) at 0 °C were added Et3N (55.4 μL, 0.398
mmol) and formic acid (46.6 μL, 1.215 mmol). The reaction mixture
was warmed to r.t. and stirred for 3 d. Then, the reaction was
quenched with EtOAc and aqueous pH 7 phosphate buffer. The organ-
ic layer was washed with brine, dried with Na2SO4, filtered and con-
centrated. The material was analyzed by chiral HPLC (Waters ACQUI-
TY UPC2; sCO2/MeOH 5–50% gradient over 10 min, AD-3 column) and
then used crude in the following step.
To (S)-2-(3-hydroxy-3-phenylpropyl)phenol [(S)-10] (50.4 mg, 0.221
mmol) in CH2Cl2 (2 mL) was added Ph3P (81 mg, 0.309 mmol) at 0 °C.
Then, a solution of DIAD (60.1 μL, 0.309 mmol) in CH2Cl2 (1 mL) was
added dropwise over 30 min. The reaction mixture slowly warmed to
r.t. and was stirred overnight. The crude material was chromato-
graphed to afford (R)-2-phenylchromane [(R)-11] (25.07 mg, 0.119
mmol, 54%). A sample was analyzed by chiral HPLC (Waters ACQUITY
UPC2; sCO2/MeOH 5–50% gradient over 10 min, OD-3 column).
269.1161.
Methyl 2-Phenyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carbox-
ylate (11k)
According to the general procedure, treatment of methyl 6-hydroxy-
5-(3-oxo-3-phenylpropyl)nicotinate (7k) (0.055 g, 0.193 mmol) with
NaBH4 (0.0073 g, 0.193 mmol) followed by quenching with 1.0 M
aqueous H3PO4 afforded the crude diol intermediate. Treatment of
this crude material with Ph3P (0.076 g, 0.289 mmol) followed by slow
addition of DIAD (0.0375 mL, 0.193 mmol) afforded 0.044 g (85%) of
11k as a colorless liquid.
Acknowledgment
The authors would like to thank Peter Dormer for help with the 1H
and 13C NMR interpretations, Scott Borges for assistance with chiral
HPLC analysis, and Jeff Kuethe and Ian Davies for advice and guidance
given during the preparation of this manuscript.
1H NMR (500 MHz, CD3OD): δ = 3.56 (t, J = 7.31 Hz, 2 H), 4.11 (t,
J = 7.34 Hz, 2 H), 4.57 (s, 3 H), 8.32 (t, J = 7.63 Hz, 2 H), 8.44 (t, J = 7.38
Hz, 1 H), 8.54 (d, J = 2.44 Hz, 1 H), 8.79–8.74 (m, 3 H), 12.93 (s, 1 H).
13C NMR (126 MHz, CDCl3): 24.3, 28.9, 52.1, 79.3, 116.6, 120.1, 125.8,
128.1, 128.6, 139.7, 140.0, 164.5, 165.8.
HRMS (TOF-MS): m/z [M + H]+ calcd for C16H16NO3: 270.1125; found:
270.1125.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588075.
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6-Chloro-2-(4-chlorophenyl)chromane (11l)
According to the general procedure, treatment of 3-(5-chloro-2-hy-
droxyphenyl)-1-(4-chlorophenyl)propan-1-one (7l) (0.248 g, 0.840
mmol) with NaBH4 (0.0318 g, 0.840 mmol) followed by quenching
with 1.0 M aqueous H3PO4 afforded the crude diol intermediate.
Treatment of this crude material with Ph3P (0.308 g, 1.176 mmol) fol-
lowed by slow addition of DIAD (0.163 mL, 0.840 mmol) afforded
0.117 g (50%) of 11l as a colorless liquid. The spectroscopic data ob-
tained for this compound are in accordance with the previously pre-
pared material.6a
References
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7-Methoxy-2-(4-methoxyphenyl)chromane (11m)
According to the general procedure, treatment of 3-(2-hydroxy-4-
methoxyphenyl)-1-(4-methoxyphenyl)propan-1-one (7m) (0.150 g,
0.524 mmol) with NaBH4 (0.0198 g, 0.524 mmol) followed by quench-
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orless liquid.
1H NMR (500 MHz, CDCl3): δ = 2.20–2.07 (m, 2 H), 2.77 (ddd,
J = 16.08, 5.19, 3.14 Hz, 1 H), 2.98–2.92 (m, 1 H), 3.79 (s, 3 H), 3.85 (s,
3 H), 5.02 (dd, J = 10.23, 2.43 Hz, 1 H), 6.52–6.50 (m, 2 H), 7.01–6.93
(m, 3 H), 7.38 (d, J = 8.48 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 24.6, 30.0, 55.3, 55.4, 77.7, 101.6,
107.4, 113.9, 114.0, 127.4, 130.0, 133.8, 156.0, 159.1, 159.4.
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HRMS (TOF-MS): m/z [M + H]+ calcd for C17H19O3: 271.1329; found:
271.1326.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

J
R. K. Orr et al.
Paper
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(18) In comparison, the literature conditions afforded the product 7b
in 63% yield. No further attempts were made to improve the
ratio.
(19) For more information, see ref. 6c (Boronic acid and Grignard
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(20) The R3P reagent was optimized for each substrate.
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M.; Luthman, K. J. Med. Chem. 2012, 55, 7104.
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iodophenol (6) afforded a diminished yield of ketone 7. For
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(25) See ref. 16. No attempts were made to investigate alternative
conditions for the workup.
(12) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
(13) Assay yield refers to quantitative HPLC analysis using a product
standard.
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(28) Absolute stereochemistry based on the model by Noyori and co-
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(15) <7% and 5% of allylic alcohol 8 and ketone 9 were observed.
(16) The use of stronger acids, such as HCl, led to cyclization of the
crude diol product 10 to the chroman 11. This observation was
further investigated in an effort to develop a one-pot reductive
cyclization sequence. For instance, use of Et3SiH (10 equiv) and
catalytic TFA afforded the desired 2-phenylchroman product in
diminished yields along with a variety of uncharacterized
byproducts. See: Mazimba, M.; Masesane, I. B.; Majinda, R. R.
Tetrahedron Lett. 2011, 52, 6716.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J