Hexafluoroisopropanol and Acetyl Chloride Promoted Catalytic Hydroarylation with Phenols

Article abstract of DOI:10.1002/ejoc.201701256

We report a catalytic hydroarylation method to convert phenols to dihydrocoumarins in hexafluoroisopropanol (HFIP) using acid generated from sub-stoichiometric amounts of acetyl chloride as catalyst. Attractive elements include easy set-up and isolation, and applicability to a range of phenols including natural product substrates.

Full text of DOI:10.1002/ejoc.201701256

DOI: 10.1002/ejoc.201701256
Full Paper
Hydroarylation | Very Important Paper |
Hexafluoroisopropanol and Acetyl Chloride Promoted Catalytic
Hydroarylation with Phenols
Sudeshna Roy,[a] Hashim F. Motiwala,[b] Karl M. Koshlap,[a] and Jeffrey Aubé*[a]
Dedicated to Al Padwa on the occasion of his 80th birthday
Abstract: We report a catalytic hydroarylation method to con- of acetyl chloride as catalyst. Attractive elements include easy
vert phenols to dihydrocoumarins in hexafluoroisopropanol set-up and isolation, and applicability to a range of phenols
(HFIP) using acid generated from sub-stoichiometric amounts including natural product substrates.
Introduction
leads to dihydrocoumarin derivatives. A seminal report on
hydroarylation of alkynes and alkenes with arenes in trifluoro-
The hydroarylation of α,ꢀ-unsaturated acids with substituted actetic acid (TFA) by Fujiwara and co-workers invoked electro-
phenols is a variation of Friedel–Crafts alkylation reaction that philic PdII and PtII cationic species as key intermediates
Scheme 1. Methods for hydroarylation of α,ꢀ-unsaturated acids.
(Scheme 1a).[1,2] Although hydroarylation of alkynes requires
activation by PdII or PtII compounds in conjunction with TFA,
[a] Division of Chemical Biology and Medicinal Chemistry and the Center for
Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of
analogous hydroarylation of alkenes requires only TFA. This was
Pharmacy, University of North Carolina,
demonstrated by Tunge and co-workers, who showed that
North Carolina 27599, USA
the TFA-mediated hydroarylation of cinnamic acids did not re-
quire palladium and afforded a range of dihydrocoumarin prod-
ucts at ambient temperature in 16 to 72 h (Scheme 1b).[3]
As expected for electrophilic substitutions, electron-rich
arenes as well as cinnamic acids were preferred, while electron-
neutral and -poor cinnamic acids required elevated reaction
E-mail: jaube@unc.edu
https://pharmacy.unc.edu/news/directory/jaube/
[b] Department of Medicinal Chemistry, University of Kansas,
Delbert M. Shankel Structural Biology Center,
2034 Becker Drive, West Campus, Lawrence, Kansas 66047, USA
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701256.
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Figure 1. (a) Coumarin-containing (highlighted in yellow) natural products and (b) other bioactive compounds obtained from dihydrocoumarins (highlighted
in red).
temperatures (ca. 100 °C) and prolonged reaction times (up to in 1 h at room temperature (Table 1, entry 1). In contrast, re-
72 h).
Coumarins and dihydrocoumarins are common in natural
peating the same reaction in TFA in our laboratory gave a 31 %
yield of 3a after 1 h.[3] We next compared the efficiency of this
reaction to those carried out in other fluorinated solvents. Using
trifluoroethanol (TFE, pKa 12.4) as a solvent resulted in only
18 % conversion to the product (the starting materials were
poorly soluble, even with heating). Perfluoro-tert-butyl alcohol
(PFTB, pKa 5.4) resulted in 81 % conversion, but required initial
heating for about 10 to 20 seconds with a heat gun to dissolve
the starting materials (entry 4). Control experiments, such as
running the reaction solely in acetyl chloride (AcCl) (entry 5) or
leaving out AcCl (entry 6), resulted in no conversion. The
screening results suggested that HFIP would be the solvent of
choice for promoting these hydroarylation reactions.
products and other bioactive agents,[4,5] such as the anti-
coagulant warfarin, suksdorfin (an anti-infective agent), and os-
truthin (an anti-mycobacterial agent) (Figure 1). Furthermore,
coumarin derivatives prepared via hydroarylation have found
biological application as inhibitors of Fad32 as anti-tuberculosis
agents,[6] RORγ inhibitors for treatment of TH17-related auto-
immune diseases,[7] and disruptors of HuR/RNA interactions rel-
evant to many types of cancer.[8] As part of our laboratory's
investigations toward the last class, we sought a convenient
variation of this hydroarylation chemistry. In this paper, we re-
port a hydroarylation reaction that can be carried out in the
strong hydrogen-bond donating solvent hexafluoroisopropanol
(HFIP) using in situ generated HCl from acetyl chloride (AcCl)
(Scheme 1c).
Table 1. Optimization results.[a]
Results and Discussion
Reaction Conditions Development and Examination of
Scope
Entry
Solvent
Pre-catalyst
Yield[b]
1
2
3
4
5
6
HFIP
TFA
TFE
PFTB
AcCl
HFIP
AcCl
none
AcCl
AcCl
none
none
97 %
31 %
18 %[c]
81 %[d]
0 %
The present project arose from our observations that HFIP rep-
resented a particularly attractive solvent for promoting polar
reactions involving in situ generated HCl, such as the intramo-
lecular Schmidt reaction[9] and related chemistry,[10] as well as
the Friedel–Crafts acylation of electron-rich aromatics.[11,12] In
those contexts, using HFIP allowed us to avoid relatively harsh
Lewis acids that often led to product inhibition. The utility of
HFIP in these contexts led us to investigate its use in promoting
the hydroarylation reactions.
0 %
[a] Reaction details: 0.3 mmol of 1a and 0.3 mmol of 2a in 1 mL of solvent
stirred at room temp. for 1 h. [b] NMR yield using benzoyl benzoate (δ =
5.4 ppm in CDCl3) as an internal standard. [c] Starting materials are sparingly
soluble in TFE, even with heating. [d] Initial heating was required to dissolve
the reactants. Boiling point of PFTB = 45 °C.
We first examined the known[3] hydroarylation reaction be-
tween 3,4,5-trimethoxyphenol 1a and p-methoxycinnamic acid
Having demonstrated the utility of AcCl/HFIP for the reac-
2a. Carrying out the reaction in HFIP (pKa 9.3) with 10 mol-% tion, its scope was evaluated by surveying the reactions of se-
of AcCl provided the dihydrocoumarin product 3a in 97 % yield lected phenols and cinnamic acids under these conditions
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(Scheme 2). With electron-rich partners, the reaction went to Moreover, the products containing an aryl chloride (3b, 3f, 3j)
completion in 1 h at ambient temperature furnishing the dihy- or aryl bromide (3c) provide a handle for additional functionali-
drocoumarins in > 95 % yields requiring 5–10 mol-% of AcCl. zation.
Scheme 2. Substrate scope for hydroarylation reactions between phenols and cinnamic acids.
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Tunge and co-workers had previously noted that elevated ple steps.[16] In addition, Jagdale and Sudalai reported a sol-
reaction temperature (100 °C) with prolonged reaction time vent-free variation using p-TSA at 125 °C.[17] Minor quantities of
(16 h to 72 h) were required for cinnamic acid reaction partners the dihydrocoumarin product (5 %) corresponding to the struc-
that are less electron rich than p-methoxycinnamic acid (σp = ture 3d as well as unreacted starting materials (29 %) were also
–0.268).[13] Accordingly, we assessed the efficiency of our cata- isolated in this reaction. Finally, the chemistry of a thiophenol
lytic system for less electron rich substrates. Thus, p-methyl- derivatives were briefly examined. When 4-(tert-butyl)thio-
cinnamic acid (σp = –0.170), resulted in the corresponding phenol was treated with p-methoxycinnamic acid 2a using
dihydrocoumarin products 3j, 3k, and 3l in high yields (> 90 %) 20 mol-% of AcCl in HFIP, 58 % of the 1,4-addition product 7
with 10 mol-% of AcCl (Scheme 2). Using the present reaction and 15 % thiochromanone product 6 were observed after 18 h
conditions, these reactions went to completion in 24–48 h at (Scheme 3b). Reaction of thiophenol with 2a gave similar re-
25–48 °C. Unsubstituted trans-cinnamic acid (electron-neutral) sults (see supporting information Table S1 for details on reactiv-
was more sluggish and required 50 mol-% of AcCl at 48 °C to ity of thiophenols and anilines in the hydroarylation reaction).
furnish the corresponding dihydrocoumarin product 3m in
25 % yield after 60 h along with starting materials that were
recovered (12 %, isolated yield).
Structure and Mechanism
Diversification of drug molecules or natural products to cre-
ate analogs for screening or repurposing is now an established
and vital strategy for medicinal chemists.[14] Toward that end,
we hydroarylated phenol-containing natural products estrone,
eugenol, and δ-tocopherol using the current conditions, afford-
ing derivatives 3p, 3q, and 3r. The estrone derivative 3p was
obtained as a single constitutional isomer but as a 1.3:1 mixture
of epimers as confirmed by NMR analysis. Stereochemistry of
the major epimer was not assigned. On the other hand, the
reaction with δ-tocopherol furnished two isomeric products in a
2.8:1 mixture (determined by NMR) with a 0.19 ppm difference
The utility of HFIP in promoting reactions involving ionic inter-
mediates is generally attributed to its high hydrogen-bonding
ability and ionizing power coupled with low nucleophilicity. We
carried out a concise set of studies to examine the disposition
Table 2. Optimization results replicating the NMR conditions.[a]
1
between the tolyl CH3 peaks in the H NMR spectroscopy. The
constitutional structure of the major isomer 3r was confirmed
by 1D and 2D NOESY studies, but the configuration of the
newly formed stereogenic center was not established. The
minor isomer is most likely an epimer at the newly-formed
benzylic stereocenter in 3r, although we cannot rule out the
possibility of it being a constitutional isomer.
We also examined the scope of the hydroarylation reactions
with a derivative of cinnamic acid and analogues of phenols
(Scheme 3). Thus, the hydroarylation of cinnamide 4 gave the
1,4-addition product 5 in 43 % yield after 56 h, requiring
50 mol-% of AcCl (Scheme 3a). Previous analogous conversions
were reported to require excess of harsh Lewis acids[15] or multi-
Entry
R
HFIP
(equiv.)
CDCl3
(mL)
AcCl
(equiv.) (3l or 3m)
Yield[b]
Yield[b]
(8l or 8m)
1
2
3
4
5
Me 0.31 mL (10)
Me 0.63 mL (20)
Me 0.63 mL (20)
H
H
0.70
0.37
0.37
0.70
0.37
0.1
0.1
0.5
0.1
0.5
42 %[c]
91 %
100 %
0 %
8 %[c]
––[b]
–
0.31 mL (10)
0.63 mL (20)
20 %[b]
–
48 %
[a] All the reactions were carried out at 48 °C for 48 h using 0.3 mmol of 1d
and 2e or 2g, respectively. [a] NMR yield using benzyl benzoate (δ =5.4 ppm
in CDCl3) as an internal standard. [b] Starting materials observed by NMR
spectroscopy. [c] Isolated yield.
Scheme 3. Examination of reactivity of (a) cinnamide and (b) thiophenol derivatives.
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of HFIP as a solvent in these reactions using p-methylcinnamic troscopy. Presence of an additional H-bond acceptor/donor
acid as a representative substrate, chosen because it was easy substituents, such as the methoxy group in p-methoxycinnamic
to monitor its H-bond interactions with HFIP using NMR spec- acid, which reacts faster, complicated these observations. These
Figure 2. (a) Stacked 1H NMR spectra showing the shift of the OH peak of HFIP: (1), in a mixture of 1 equiv. of p-methylcinnamic acid (2), 20 equiv. of HFIP
(3), and upon addition of 0.5 equiv. of AcCl (4), in CDCl3. (b) 1D gradient NOE with Tmix = 500 ms for the mixture of 1 equiv. of p-methylcinnamic acid,
20 equiv. of HFIP, and 0.5 equiv. of AcCl when irradiating H-2 (1) and H-1 (2) of p-methylcinnamic acid; insets contain zoomed-in region of 1D gradient NOE
spectra showing plausible structure of adducts (I and II), and observed NOE interactions with arrows.
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studies generally used 20 equiv. of HFIP because these condi- HFIP (entries 1 and 4), but not in the presence of 20 equiv. of
tions approximated the rates and yields of the reactions carried HFIP (entries 2, 3, and 5).
out in pure HFIP (cf. entries 1 and 2 in Table 2).
We next reacted the cinnamate esters 8l and 8m in HFIP-
A clear shift of the OH signal of pure HFIP in de-acidified conditions to see the effect of the aryl group substituents on
CDCl3 from 4.15 ppm to a broad singlet at δ = 4.65 ppm for a the cyclization (Scheme 4). As anticipated, cinnamate ester with
mixture containing 1 equiv. of p-methylcinnamic acid and a p-methyl substituent 8l afforded the cyclized dihydrocouma-
1
20 equiv. HFIP was observed in H NMR (Figure 2a). HFIP exists rin product 3l in 84 % yield after 24 h (cf. Table 2, entry 2 with
in aggregates,[18] so the chemical shift and broadness of its OH Scheme 4), whereas the reaction of 8m was relatively sluggish.
peak is expected to be concentration dependent. Upon addi- In the case of 8m, 44 % of hydrolysis products of the ester were
tion of 0.5 equiv. of AcCl to this mixture, the broad singlet at also isolated along with 14 % of unreacted starting material;
δ = 4.65 ppm sharpened and moved slightly to 4.67 ppm. These this suggests that cyclized product formation in this case may
results are consistent with H-bonding interactions with the cin- result from an intermolecular pathway, as also suggested by
namic acid, with a greater rate of exchange when HCl is present Tunge and co-workers.[3]
pursuant to the addition of AcCl.
To characterize the putative H-bonded adduct, nuclear Over-
hauser effect (NOE) studies were carried out. Irradiation of the
alkene protons at δ = 6.40 and 7.84 ppm resulted in an NOE
with the HFIP OH signal at δ = 4.67 ppm (Figure 2b). These
results are consistent with H-bonded interactions between the
unsaturated acid and solvent; some possible structures are de-
picted. Related NOEs representing H-bonded adduct between
the HFIP and phenyliodine(III) diacetate have been reported by
Compton and co-workers.[19]
Scheme 4. Effect of aryl substituents on cyclization of cinnamate esters.
In an effort to understand the effect of cinnamic acid substit-
uents on this reaction, conversions and product formations
Based on our observations and NMR studies, we propose the
were examined by comparing the reactions of p-methylcinna- mechanism shown in Scheme 5. Dissolution of para-substituted
mic acid 2e and cinnamic acid 2g, respectively, with 4-(tert- cinnamic acid 2 in HFIP and AcCl generates an oxocarbenium
butyl)phenol 1d (Table 2, entries 1 vs. 4 and 3 vs. 5). Similar intermediate A stabilized by HFIP, HCl, or both. With electron-
concentrations of CDCl3 were added to each reaction in an ef- donating groups such as p-OMe, this carbocation furnishes di-
fort to replicate the NMR conditions. The results indicate a hydrocoumarin 3 via 1,4-addition of the ortho carbon of the
clearly slower reaction for the less electron-rich 2g. In addition, phenol followed by cyclization. However, with poorer electron-
esters resulting from simple acylation but not cyclization were donating groups such as p-Me or the electronically neutral
observed in lieu of or in addition to fully cyclized products trans-cinnamic acid (R = H), the desired reaction is slower and
when the reactions were run in the presence of 10 equiv. of ordinary Fischer esterification competes, generating cinnamate
Scheme 5. Possible mechanism for hydroarylation.
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2 H), 6.92–6.84 (m, 2 H), 6.68 (s, 1 H), 4.22 (X of ABX, J = 8.2, 5.9 Hz,
ester 8. This material can be converted into the desired dihydro-
coumarin product 3 by addition of AcCl in HFIP, but the obser-
vation of a significant amount of hydrolysis product under
these conditions suggests that the reaction may occur by first
ester hydrolysis followed by C–C bond formation as in the stan-
dard intermolecular version (Scheme 2).
1 H), 3.90 (s, 3 H), 3.80 (s, 3 H), 3.02 (A part of ABX system, JAB
15.8, JAX = 5.7 Hz, 1 H), 2.95 (B part of ABX system, JAB = 15.8, JBX
=
=
8.3 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.2, 159.3, 156.1,
151.7, 132.2, 132.0, 128.6, 119.4, 114.8, 106.7, 101.5, 56.7, 55.5, 39.3,
37.4 ppm. IR (solution): ν = 3006, 1773 cm–1. HRMS (ESI): m/z calcd.
˜
for C17H15BrO4 [M + H]+ 363.0226; found 363.0220.
6-(tert-Butyl)-4-(4-methoxyphenyl)chroman-2-one (3d): Follow-
ing the general procedure, 3d was obtained as a colorless viscous
oil (84 mg, 90 %). The 1H NMR of 3d is in agreement with the
literature report.[3] 1H NMR (400 MHz, CDCl3): δ = 7.32 (dd, J = 8.5,
2.4 Hz, 1 H), 7.10–7.06 (m, 3 H), 7.02 (dd, J = 2.5, 0.8 Hz, 1 H), 6.90–
6.84 (m, 2 H), 4.29 (X part of ABX system, m, 1 H), 3.80 (s, 3 H), 3.04
(A part of ABX system, JAB = 15.8, JAX = 5.8 Hz, 1 H), 2.89 (B part of
ABX system, JAB = 15.8, JBX = 7.2 Hz, 1 H), 1.25 (s, 9 H) ppm.
Conclusions
We have demonstrated a catalytic hydroarylation process as an
efficient route to dihydrocoumarins with broad utility. These
reaction conditions in HFIP using AcCl leading to in situ genera-
tion of HCl represents an experimentally attractive means of
accomplishing this useful transformation. Additionally, fast reac-
tion time (within 1 h for most substrates) under ambient tem-
peratures along with the operationally simple chemistry set up
and isolation techniques without the need of any aqueous work
up make this method particularly appealing.
8-(4-Hydroxy-3,5-dimethoxyphenyl)-7,8-dihydro-6H-[1,3]diox-
olo[4,5-g]chromen-6-one (3e): Following the general procedure, a
solution of benzo[d][1,3]dioxol-5-ol (41.5 mg, 0.300 mmol,
1.0 equiv.) and 4-hydroxy-3,5-dimethoxycinnamic acid (67.3 mg,
0.300 mmol, 1.0 equiv.) in HFIP (1.0 mL) was treated with acetyl
chloride (1.07 μL, 0.015 mmol, 0.05 equiv.) for 2 h at room temp.
Reaction mixture was concentrated and a solution of the resulting
residue in DCM was loaded on a silica gel in a sample cartridge.
Purification on a Combiflash purification system using a 12 g of
silica flash column (0–50 % EtOAc/hexanes over 50 min) afforded
3e as an orange-yellow solid (99 mg, 96 %). Mp: 158.5–160.0 °C.
TLC (30 % EtOAc/hexanes): Rf = 0.13. 1H NMR (400 MHz, CDCl3): δ =
6.59 (s, 1 H), 6.38 (m, 1 H), 6.33 (s, 2 H), 5.91 (q, J = 1.3 Hz, 2 H),
5.59 (s, 1 H), 4.10 (X part of ABX system, JAX = 5.9, JBX = 8.0 Hz, 1
H), 3.79 (s, 6 H), 2.97 (A part of ABX system, JAB = 15.8, JAX = 5.7 Hz,
1 H), 2.90 (B part of ABX system, JAB = 15.8, JBX = 8.2 Hz, 1 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 167.7, 147.55, 147.52 (2 C), 146.1,
144.5, 134.3, 131.6, 118.3, 107.3, 104.3 (2 C), 101.8, 99.1, 56.4 (2 C),
Experimental Section
General Procedure for the Hydroarylation Reaction: To a suspen-
sion of phenol (0.30 mmol, 1.0 equiv.) and cinnamic or acrylic acid
(0.30 mmol, 1.0 equiv.) in HFIP (1.0 mL) in a N2-flushed 1-dram vial
at room temp. was added acetyl chloride (0.015 or 0.030 mmol,
0.050 or 0.10 equiv.) and the resulting mixture was continued to
stir at room temp. for 1–24 h. The reaction mixture was concen-
trated under N2 and the resulting residue was dissolved in a mini-
mum quantity of ether, DCM, or hexanes and loaded onto silica
gel in a sample cartridge. Purification on an automated purification
system using a 4 g or 12 g of silica flash column afforded the corre-
sponding product after concentration and drying under vacuum.
40.8, 37.2 ppm. IR (neat): ν = 3482, 1758 cm–1. HRMS (ESI): m/z
˜
calcd. for C18H17O7 [M + H]+ 345.0974; found 345.0940.
5,6,7-Trimethoxy-4-(4-methoxyphenyl)chroman-2-one (3a): Fol-
lowing the general procedure, 3a was obtained as an off-white solid
(98 mg, 95 %). The 1H NMR spectrum of 3a matched reported mate-
4-(Benzo[d][1,3]dioxol-5-yl)-6-chloro-5,7-dimethylchroman-2-
one (3f): Following the general procedure, 3f was obtained as an
off-white oily solid (98 mg, 99 %). The 1H NMR of 3f is in agreement
with the literature report.[3] 1H NMR (400 MHz, CDCl3): δ = 6.92 (s,
1 H), 6.68 (d, J = 8.0 Hz, 1 H), 6.50 (d, J = 1.9 Hz, 1 H), 6.49–6.44 (m,
1 H), 5.90 (AB q, J = 1.4 Hz, ΔνAB = 2.0 Hz, 2 H), 4.36 (m, 1 H), 3.02–
2.92 (complex, 2 H), 2.40 (s, 3 H), 2.24 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 166.9, 150.2, 148.5, 147.2, 137.4, 134.9, 133.7,
131.1, 122.4, 120.3, 117.1, 108.9, 107.5, 101.4, 39.0, 37.9, 21.2, 16.5
ppm.
1
rial. The H NMR of 3a is in agreement with the literature report.[3]
1H NMR (400 MHz, CDCl3): δ = 7.06–6.95 (m, 2 H), 6.84–6.74 (m, 2
H), 6.51 (s, 1 H), 4.57–4.48 (m, 1 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 3.75
(s, 3 H), 3.66 (s, 3 H), 3.01–2.94 (m, 2 H) ppm.
6-Chloro-4-(4-methoxyphenyl)-5,7-dimethylchroman-2-one
(3b): Following the general procedure, 3b was obtained as a color-
less oily solid (94 mg, 99 %). The 1H NMR of 3b is in agreement
with the literature report.[3] 1H NMR (400 MHz, CDCl3): δ = 6.99–
6.89 (m, 3 H), 6.83–6.68 (m, 2 H), 4.42–4.36 (m, 1 H), 3.74 (s, 3 H),
3.03–2.86 (m, 2 H), 2.40 (s, 3 H), 2.24 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = ppm. 13C NMR (101 MHz, CDCl3): δ = 167.1,
159.1, 150.2, 137.2, 134.9, 131.9, 131.0, 128.1, 122.7, 117.1, 114.7,
55.4, 38.5, 37.9, 21.2, 16.5 ppm.
4-(Benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxychroman-2-one
(3g): Following the general procedure, a suspension of 3,4,5-tri-
methoxyphenol (55.3 mg, 0.300 mmol, 1.0 equiv.) and 3,4-(methyl-
enedioxy)cinnamic acid (57.7 mg, 0.300 mmol, 1.0 equiv.) in HFIP
(1.0 mL) was treated with acetyl chloride (2.1 μL, 0.030 mmol,
0.10 equiv.) for 10 h at room temp. Reaction mixture was concen-
trated and a solution of the resulting residue in ether was loaded
6-Bromo-7-methoxy-4-(4-methoxyphenyl)chroman-2-one (3c):
Following the general procedure, a solution of 4-bromo-3-methoxy- on a silica gel in a sample cartridge. Purification on a Combiflash
phenol (61 mg, 0.300 mmol, 1.0 equiv.) and 4-methoxycinnamic purification system using a 12 g of silica flash column (0–30 %
acid (53 mg, 0.300 mmol, 1.0 equiv.) in HFIP (1.0 mL) was treated EtOAc/hexanes over 30 min) afforded 3g as a pale yellow oily solid
with acetyl chloride (2.1 μL, 0.030 mmol, 0.10 equiv.) for 1 h at room (107 mg, 99 %). Mp: 105–110 °C. TLC (30 % EtOAc/hexanes): Rf =
temp. Reaction mixture was concentrated and a solution of the 0.38. 1H NMR (400 MHz, CDCl3): δ = 6.67 (d, J = 8.0 Hz, 1 H), 6.57
resulting residue in ether was loaded on a silica gel in a sample
cartridge. Purification on a Combiflash purification system using a
12 g of silica flash column (0–100 % EtOAc/hexanes over 15 min)
afforded 3c as off-white solid (103 mg, 95 %). Mp: 134–136 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.12 (d, J = 0.8 Hz, 1 H), 7.08–7.01 (m,
(d, J = 1.8 Hz, 1 H), 6.52 (dd, J = 8.0, 1.8 Hz, 1 H), 6.48 (s, 1 H), 5.88
(s, 2 H), 4.48 (X part of ABX system, JAX = 2.9, JBX = 5.8 Hz, 1 H),
3.85 (s, 3 H), 3.81 (s, 3 H), 3.68 (s, 3 H), 2.98–2.88 (AB part of ABX
system, complex, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.4,
153.9, 150.6, 148.2, 147.8, 146.9, 139.1, 135.7, 119.9, 111.1, 108.6,
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107.4, 101.2, 97.0, 61.3, 61.1, 56.3, 37.6, 35.3 ppm. IR (neat): ν =
35.2, 21.1 ppm. IR (solution): ν = 2937, 1767 cm–1. HRMS (ESI): m/z
˜
˜
1755, 1613 cm–1. HRMS (ESI): m/z calcd. for C19H19O7 [M + H]+
calcd. for C19H20O5 [M + H]+ 329.1384; found 329.1376.
359.1131; found 359.1108.
6-(tert-Butyl)-4-(p-tolyl)chroman-2-one (3l): Following the gen-
eral procedure, a solution of 4-(tert-butyl)phenol (45 mg, 0.30 mmol,
1.0 equiv.) and 4-methylcinnamic acid (49 mg, 0.30 mmol,
1.0 equiv.) in HFIP (1.0 mL) was treated with acetyl chloride (2.1 μL,
0.03 mmol, 0.10 equiv.) for 48 h at 48 °C. Reaction mixture was
concentrated and a solution of the resulting residue in ether was
loaded on a silica gel in a sample cartridge. Purification on a Combi-
flash purification system using a 12 g of silica flash column (0–
100 % EtOAc/hexanes over 15 min) afforded 3l as a white solid
(83 mg, 94 %). Mp: 75–77 °C. 1H NMR (400 MHz, CDCl3): δ = 7.32
(dd, J = 8.6, 2.4 Hz, 1 H), 7.16 (d, J = 8.2 Hz, 2 H), 7.09–7.00 (m, 4
H), 4.30 (X part of ABX system, m, 1 H), 3.05 (A part of ABX system,
5,6,7-Trimethoxy-4-(thiophen-2-yl)chroman-2-one (3h): Follow-
ing the general procedure, a suspension of 3,4,5-trimethoxyphenol
(55.2 mg, 0.300 mmol, 1.0 equiv.) and 2-thiopheneacrylic acid
(46.2 mg, 0.300 mmol, 1.0 equiv.) in HFIP (1.0 mL) was treated with
acetyl chloride (2.1 μL, 0.030 mmol, 0.10 equiv.) for 1.5 h at room
temp. Reaction mixture was concentrated and a solution of the
resulting residue in DCM was loaded on a silica gel in a sample
cartridge. Purification on a Combiflash purification system using a
12 g of silica flash column (0–30 % EtOAc/hexanes over 30 min)
afforded 3h as a pale yellow solid (76.0 mg, 79 %). Mp: 132–
134.5 °C. TLC (30 % EtOAc/hexanes) Rf = 0.50. 1H NMR (400 MHz,
CDCl3): δ = 7.13 (dd, J = 5.1, 1.2 Hz, 1 H), 6.87 (dd, J = 5.1, 3.5 Hz,
1 H), 6.73 (dt, J = 3.5, 1.1 Hz, 1 H), 6.46 (s, 1 H), 4.80 (X part of ABX
system, m, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.13 (A part
of ABX system, JAB = 15.9, JAX = 1.8 Hz, 1 H), 2.98 (B part of ABX
system, JAB = 15.9, JBX = 6.7 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 167.2, 154.1, 150.4, 147.5, 145.1, 138.9, 127.2, 124.7,
J
J
AB = 15.8, JAX = 5.9 Hz, 1 H), 2.99 (B part of ABX system, JAB = 15.8,
BX = 7.0 Hz, 1 H), 2.34 (s, 3 H), 1.26 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.1, 149.7, 147.8, 137.8, 137.3, 129.8, 127.4, 125.7,
125.3, 125.1, 116.6, 40.8, 37.6, 34.6, 31.5, 21.2 ppm. IR (solution): ν =
˜
2967, 1763 cm–1. HRMS (ESI): m/z calcd. for C20H22O2 [M + H]+
295.1693; found 295.1689.
124.4, 111.2, 97.0, 61.5, 61.2, 56.3, 37.5, 30.9 ppm. IR (neat): ν =
˜
6-(tert-Butyl)-4-phenylchroman-2-one (3m): Following the gen-
eral procedure, 3m was obtained as an off-white solid (21 mg,
25 %). The 1H NMR of 3m is in agreement with the literature re-
port.[17] 1H NMR (400 MHz, CDCl3): δ = 7.39–7.27 (m, 3 H), 7.19–7.11
(m, 2 H), 7.07 (d, J = 8.5 Hz, 1 H), 7.01 (dd, J = 2.4, 0.8 Hz, 1 H), 4.33
(X part of ABX system, t, J = 6.5 Hz, 1 H), 3.07 (A part of ABX system,
1759 cm–1. HRMS (ESI): m/z calcd. for C16H17O5S [M + H]+ 321.0797;
found 321.0769.
6-(tert-Butyl)-4-(thiophen-2-yl)chroman-2-one (3i): Following the
general procedure, a solution of 4-(tert-butyl)phenol (45 mg,
0.30 mmol, 1.0 equiv.) and 2-thiopheneacrylic acid (46 mg,
0.30 mmol, 1.0 equiv.) in HFIP (1.0 mL) was treated with acetyl chlor-
ide (2.1 μL, 0.03 mmol, 0.10 equiv.) for 1 h at room temp. Reaction
mixture was concentrated and a solution of the resulting residue in
DCM was loaded on a silica gel in a sample cartridge. Purification
on a Combiflash purification system using a 12 g of silica flash
column (0–100 % EtOAc/hexanes over 15 min) afforded 3i as oily
J
AB = 15.8, JAX = 6.0 Hz, 1 H), 3.01 (B part of ABX system, JAB = 15.8,
JBX = 7.0 Hz, 1 H), 1.24 (s, 9 H) ppm.
5,7-Dimethoxy-4-(4-methoxyphenyl)chroman-2-one (3n): Fol-
lowing the general procedure, 3n was obtained as an off-white solid
(81 mg, 85 %). The 1H NMR of 3n is in agreement with the literature
report.[3] 1H NMR (400 MHz, CDCl3): δ = 7.06–6.97 (m, 2 H), 6.82–
6.73 (m, 2 H), 6.31 (d, J = 2.3 Hz, 1 H), 6.28 (d, J = 2.3 Hz, 1 H), 4.51
(t, J = 4.4 Hz, 1 H), 3.81 (s, 3 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 2.97 (d,
J = 4.4 Hz, 2 H) ppm.
1
compound (52 mg, 61 %). H NMR (400 MHz, CDCl3): δ = 7.34 (dd,
J = 8.5, 2.4 Hz, 1 H), 7.23 (dd, J = 5.1, 1.2 Hz, 1 H), 7.20 (d, J = 2.2 Hz,
1 H), 7.05 (d, J = 8.5 Hz, 1 H), 6.94 (dd, J = 5.1, 3.5 Hz, 1 H), 6.80 (dt,
J = 3.6, 1.1 Hz, 1 H), 4.58 (X part of ABX system, t, J = 5.8 Hz, 1 H),
3.14 (A part of ABX system, JAB = 15.9, JAX = 5.7 Hz, 1 H), 3.11 (B
part of ABX system, JAB = 15.9, JBX = 5.9 Hz, 1 H), 1.29 (s, 9 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 167.5, 149.1, 148.0, 144.1, 127.2,
126.1, 125.2, 125.2, 125.1, 124.7, 116.8, 37.7, 36.6, 34.6, 31.5 ppm. IR
7-Methoxy-4-(4-methoxyphenyl)chroman-2-one (3o): Following
the general procedure, a solution of 3-methoxyphenol (33 μL,
0.30 mmol, 1.0 equiv.) and 4-methoxycinnamic acid (53 mg,
0.30 mmol, 1.0 equiv.) in HFIP (1.0 mL) was treated with acetyl chlor-
ide (2.1 μL, 0.03 mmol, 0.10 equiv.) for 1 h at room temp. Reaction
mixture was concentrated and a solution of the resulting residue in
ether was loaded on a silica gel in a sample cartridge. Purification
on a Combiflash purification system using a 12 g of silica flash
column (0–100 % EtOAc/hexanes over 15 min) afforded 3o as off-
white solid (51 mg, 60 %). Mp: 137–140 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.08–7.02 (m, 2 H), 6.91–6.83 (m, 2 H), 6.67 (d, J = 2.5 Hz,
(solution): ν = 1768 cm–1. HRMS (ESI): m/z calcd. for C17H18O2S [M
˜
+ H]+ 287.1100; found 287.1096.
6-Chloro-5,7-dimethyl-4-(p-tolyl)chroman-2-one (3j): Following
the general procedure, 3h was obtained as a colorless solid (86 mg,
95 %). The 1H NMR of 3j is in agreement with the literature report.[3]
1H NMR (400 MHz, CDCl3): δ = 7.08 (d, J = 7.9 Hz, 2 H), 6.97–6.90
(m, 3 H), 4.42 (t, J = 4.4 Hz, 1 H), 3.05–2.97 (complex, 2 H), 2.41 (s,
3 H), 2.29 (s, 3 H), 2.25 (s, 3 H) ppm.
1 H), 6.63 (dd, J = 8.4, 2.6 Hz, 1 H), 4.23 (X part of ABX system, JAX
=
5.9, JBX = 8.0 Hz, 1 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.02 (A part of ABX
system, JAB = 15.8, JAX = 5.8 Hz, 1 H), 3.11 (B part of ABX system,
JAB = 15.8, JBX = 8.1 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
168.0, 160.0, 159.0, 152.5, 132.7, 128.9, 128.6, 118.1, 114.5, 110.8,
5,6,7-Trimethoxy-4-(p-tolyl)chroman-2-one (3k): Following the
general procedure, a solution of 3,4,5-trimethoxyphenol (55 mg,
0.30 mmol, 1.0 equiv.) and 4-methylcinnamic acid (49 mg,
0.30 mmol, 1.0 equiv.) in HFIP (1.0 mL) was treated with acetyl chlor-
ide (2.1 μL, 0.03 mmol, 0.10 equiv.) for 24 h at 48 °C. Reaction
mixture was concentrated and a solution of the resulting residue in
ether was loaded on a silica gel in a sample cartridge. Purification
on a Combiflash purification system using a 12 g of silica flash
column (0–100 % EtOAc/hexanes over 15 min) afforded 3k as an
oily solid (95 mg, 96 %). 1H NMR (400 MHz, CDCl3): δ = 7.09–7.04
(m, 2 H), 7.01–6.96 (m, 2 H), 6.51 (s, 1 H), 4.53 (m, 1 H), 3.87 (s, 3 H),
3.82 (s, 3 H), 3.66 (s, 3 H), 3.02–2.93 (complex, 2 H), 2.28 (s, 3 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 167.6, 153.7, 150.6, 147.8,
139.1, 138.8, 137.0, 129.7, 126.7, 111.3, 96.9, 61.2, 61.1, 56.2, 37.4,
102.6, 55.7, 55.4, 39.4, 37.6 ppm. IR (solution): ν = 1768 cm–1. HRMS
˜
(ESI): m/z calcd. for C17H17O4 [M + H]+ 285.1121; found 285.1122.
(3aS,3bR,11bS,13aS)-10-(4-Methoxyphenyl)-13a-methyl-
2,3,3a,3b,4,5,9,10,11b,12,13,13a-dodecahydrocyclopenta-
[5,6]naphtho[1,2-g]chromene-1,8-dione (3p): Following the gen-
eral procedure, a solution of estrone (45 mg, 0.30 mmol, 1.0 equiv.)
and 4-methoxycinnamic acid (53.4 mg, 0.300 mmol, 1.0 equiv.) in
HFIP (1.0 mL) was treated with acetyl chloride (10.7 μL, 0.15 mmol,
0.50 equiv.) for 1 h at room temp. Reaction mixture was concen-
trated and a solution of the resulting residue in DCM was loaded
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1
on a silica gel in a sample cartridge. Purification on a Combiflash
purification system using a 12 g of silica flash column (0–100 %
EtOAc/hexanes over 15 min) afforded 3p as an oily compound
(90 mg, 70 %) as a 1.3:1 mixture of epimers (determined by integra-
tion in 1H NMR) that could not be separated using column chroma-
tography. H NMR (400 MHz, CDCl3) of major constitutional isomer
3r (full spectrum with all peaks): δ = 6.96 (m, 2 H), 6.83 (s, 1 H),
6.79 (m, 2 H), 4.26 (m, 1 H), 3.75 (s, 3 H), 3.04–2.91 (complex, 2 H),
2.67 (m, 1 H), 2.30 (m, 1 H), 2.20 (s, 3 H), 1.69 (m, 2 H), 1.59–1.01
(complex, 24 H), 0.94–0.68 (complex, 12 H) ppm. 13C NMR (101 MHz,
CDCl3) of major constitutional isomer 3r (full spectrum with all
peaks): δ = 168.0, 158.9, 149.1, 144.6, 132.4, 128.2, 127.3, 120.4,
118.4, 117.0, 114.6, 75.6, 55.4, 40.7, 39.5, 38.2, 37.6, 37.5, 37.5, 37.4,
1
tography. H NMR (400 MHz, CDCl3) of major epimer (full spectrum
with all peaks): δ = 7.05 (m, 2 H), 6.91 (s, 1 H), 6.89–6.78 (complex,
3 H), 4.23 (m, 1 H), 3.77 (s, 3 H), 3.02–2.89 (complex, 4 H), 2.48 (m,
1 H), 2.52–2.00 (complex, 5 H), 1.88 (m, 1 H), 1.64–1.38 (complex, 6
37.1, 32.9, 32.7, 30.8, 28.1, 24.9, 24.5, 23.4, 22.9, 22.8, 20.9, 19.9,
H), 0.88 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3) of major epimer 19.7, 19.6, 16.3 ppm. H NMR (400 MHz, CDCl3) of minor isomer 3s
1
(full spectrum with all peaks): δ = 220.7, 168.0, 158.9, 149.71, 137.5,
136.4, 132.8, 128.4, 125.22, 123.2, 116.94, 114.51, 55.3, 50.43, 47.92,
44.0, 33.99, 38.13, 37.6, 35.9, 31.5, 29.2, 26.4, 25.9, 21.62, 13.87 ppm.
1H NMR (400 MHz, CDCl3) of minor epimer (diagnostic peaks only):
δ = 3.78 (s, 3 H), 0.87 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3) of
minor epimer (diagnostic peaks only): δ = 220.7, 168.1, 149.70,
137.4, 136.2, 132.7, 128.5, 125.27, 123.3, 116.89, 114.49, 50.44, 47.95,
44.2, 40.01, 38.11, 37.7, 29.3, 26.3, 25.8, 21.61, 13.89 ppm. IR (solu-
(diagnostic peaks only): δ = 6.74 (s, 1 H), 4.35 (m, 1 H), 2.01 (s, 3 H)
ppm. IR (solution): ν = 3005, 1762 cm–1. HRMS (ESI): m/z calcd. for
˜
C
37H54O4 [M + H]+ 563.4095; found 563.4094.
3-[5-(tert-Butyl)-2-hydroxyphenyl]-N,N-diethyl-3-(4-methoxy-
phenyl)propanamide (5): Following the general procedure, a solu-
tion of 4-(tert-butyl)phenol (45 mg, 0.30 mmol, 1.0 equiv.) and (E)-
N,N-diethyl-3-(4-methoxyphenyl)acrylamide 4 (70 mg, 0.30 mmol,
1.0 equiv.) in HFIP (1.0 mL) was treated with acetyl chloride (10.7 μL,
0.15 mmol, 0.50 equiv.) for 56 h at 44 °C. Reaction mixture was
concentrated and a solution of the resulting residue in DCM was
loaded on a silica gel in a sample cartridge. Purification on a Combi-
flash purification system using a 12 g of silica flash column (0–
100 % EtOAc/hexanes over 15 min) afforded 5 as yellowish liquid
(49 mg, 43 %). 1H NMR (400 MHz, CDCl3): δ = 8.73 (br. s, 1 H), 7.23–
7.18 (m, 2 H), 7.05 (dd, J = 8.4, 2.5 Hz, 1 H), 6.89 (d, J = 2.5 Hz, 1 H),
6.87–6.81 (m, 3 H), 4.96 (t, J = 6.9 Hz, 1 H), 3.79 (s, 3 H), 3.48–3.20
(m, 4 H), 3.10 (d, J = 6.9 Hz, 2 H), 1.15 (s, 9 H), 1.12–0.97 (m, 6 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 172.2, 158.0, 152.1, 143.0,
136.6, 131.6, 129.1, 125.6, 124.3, 117.7, 113.8, 55.3, 42.3, 41.1, 39.8,
tion): ν = 1763, 1735 cm–1. HRMS (ESI): m/z calcd. for C28H30O4 [M
˜
+ H]+ 431.2217; found 431.2205.
6-Allyl-8-methoxy-4-(4-methoxyphenyl)chroman-2-one (3q):
Following the general procedure, a solution of 4-allyl-2-methoxy-
phenol (49 mg, 0.30 mmol, 1.0 equiv.) and 4-methoxycinnamic acid
(53 mg, 0.300 mmol, 1.0 equiv.) in HFIP (1.0 mL) was treated with
acetyl chloride (2.1 μL, 0.03 mmol, 0.10 equiv.) for 1 h at room temp.
Reaction mixture was concentrated and a solution of the resulting
residue in DCM was loaded on a silica gel in a sample cartridge.
Purification on a Combiflash purification system using a 12 g of
silica flash column (0–100 % EtOAc/hexanes over 15 min) afforded
3q as yellowish liquid (41 mg, 42 %). 1H NMR (400 MHz, CDCl3): δ =
7.14–7.00 (m, 2 H), 6.83–6.76 (m, 3 H), 6.63 (s, 1 H), 5.88 (ddt, J =
16.6, 10.2, 6.3 Hz, 1 H), 5.08–4.84 (m, 2 H), 4.65 (X part of ABX
system, m, 1 H), 3.83 (s, 3 H), 3.76 (s, 3 H), 3.44–3.20 (m, 2 H), 2.96
(A part of ABX system, JAB = 16.0, JAX = 8.5 Hz, 1 H), 2.92 (B part of
ABX system, JAB = 16.0, JBX = 7.2 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 177.8, 158.1, 145.1, 144.0, 137.5, 135.5, 134.4, 129.3,
128.8, 115.9, 114.0, 113.4, 112.7, 56.0, 55.3, 41.3, 40.8, 36.8 ppm. IR
38.2, 34.1, 31.6, 14.1, 13.0 ppm. IR (solution): ν = 3005, 1622 cm–1
.
˜
HRMS (ESI): m/z calcd. for C24H33NO3 [M + H]+ 384.2533; found
384.2526.
Acknowledgments
We acknowledge financial support of this work by the National
Cancer Institute (CA19178). We thank the University of North
Carolina's Department of Chemistry Mass Spectrometry Core
Laboratory, especially Brandie M. Ehrmann, for assistance with
mass spectrometry analysis.
(solution): ν = 1710 cm–1. HRMS (ESI): m/z calcd. for C20H20O4 [M +
˜
H]+ 325.1434; ion corresponding to [M + H]+ was not observed
under ESI conditions.
(8R)-1-(4-Methoxyphenyl)-6,8-dimethyl-8-[(4R,8R)-4,8,12-tri-
methyltridecyl]-1,8,9,10-tetrahydropyrano[3,2-f]chromen-
3(2H)-one (3r): Following the general procedure, a solution of (R)-
2,8-dimethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-ol
(100 mg, 0.248 mmol, 1.0 equiv.) and 4-methoxycinnamic acid
(44 mg, 0.248 mmol, 1.0 equiv.) in HFIP (0.83 mL) was treated with
acetyl chloride (1.8 μL, 0.025 mmol, 0.10 equiv.) for 1 h at room
temp. Reaction mixture was concentrated and a solution of the
resulting residue in DCM was loaded on a silica gel in a sample
cartridge. Purification on a Combiflash purification system using a
12 g of silica flash column (0–100 % EtOAc/hexanes over 15 min)
afforded a 2.8:1 mixture of constitutional isomers containing 3r as
yellowish liquid (83 mg) and 3s as yellowish liquid (29 mg), total
yield of 112 mg (80 %). Ratio of the constitutional isomers were
determined by integration in 1H NMR spectroscopy. The constitu-
tional structure of the major isomer 3r was confirmed by 1D and
2D NOESY studies, but the configuration of the newly formed
stereogenic center was not established. The minor isomer is most
likely an epimer at the newly-formed benzylic stereocenter in 3r,
although we cannot rule out the possibility of it being a constitu-
tional isomer. Small quantities of the major isomer 3r was isolated
for characterization purposes, otherwise the mixture of the isomers
co-eluted under the conditions of normal phase column chroma-
Keywords: Hydroarylation · Homogeneous catalysis ·
Dihydrocoumarins · Hydrogen bonds · Natural products
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Received: September 7, 2017
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Hydroarylation
HFIP facilitates the mild catalytic
hydroarylation of phenols to provide
dihydrocoumarins using sub-stoichio-
metric amounts of acetyl chloride as
catalyst.
S. Roy, H. F. Motiwala, K. M. Koshlap,
J. Aubé* .............................................. 1–11
Hexafluoroisopropanol and Acetyl
Chloride Promoted Catalytic Hydro-
arylation with Phenols
DOI: 10.1002/ejoc.201701256
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