Regioselection in the synthesis of 4-benzyltetral-1-ones and the new 4-arylbenzosuber-1-ones

Article abstract of DOI:10.1016/j.tet.2021.132034

The intramolecular Friedel-Crafts acylation of 4,5-diarylpentanoic acids has the possibility to cyclise to either a 6-membered ring to give 4-benzyltetral-1-one or a 7-membered ring to give 4-arylbenzosuber-1-one. Of these, only the former compound class has previously been reported. The impact of the substituents positioning on the outcome of the cyclisation has been investigated. The complete formation of either the tetralone or the benzosuberone regioisomer was possible under the same reaction conditions, dependent upon the ring activation and/or deactivation of the chosen substituents. Selected bromo or methoxy substituents could be used as auxiliaries, included in precursors to afford the desired regioisomer and then subsequently removed.

Full text of DOI:10.1016/j.tet.2021.132034

Tetrahedron 85 (2021) 132034
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselection in the synthesis of 4-benzyltetral-1-ones and the new
4-arylbenzosuber-1-ones
Daniel Truong, Brittany L. Howard, Philip E. Thompson*
Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, 3052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular Friedel-Crafts acylation of 4,5-diarylpentanoic acids has the possibility to cyclise to
either a 6-membered ring to give 4-benzyltetral-1-one or a 7-membered ring to give 4-arylbenzosuber-
1-one. Of these, only the former compound class has previously been reported. The impact of the sub-
stituents positioning on the outcome of the cyclisation has been investigated. The complete formation of
either the tetralone or the benzosuberone regioisomer was possible under the same reaction conditions,
dependent upon the ring activation and/or deactivation of the chosen substituents. Selected bromo or
methoxy substituents could be used as auxiliaries, included in precursors to afford the desired
regioisomer and then subsequently removed.
Received 16 December 2020
Received in revised form
7 February 2021
Accepted 15 February 2021
Available online 22 February 2021
Keywords:
Tetralone
Benzosuberone
Regioselectivity
Cyclisation
© 2021 Elsevier Ltd. All rights reserved.
Friedel-Crafts acylation
1. Introduction
regioisomer, as is the case for the synthesis of the natural product,
sequirin D [10]. 4,5-Bis-p-methoxyphenylpentanoic acid (7) un-
The tetralone and benzosuberone classes of benz-fused cyclo-
alkanes have a long history as core scaffolds and intermediates in
synthetic organic chemistry. The 1-tetralones have been shown to
be a multipurpose core [1e4], appearing as intermediates for the
preparation of pharmaceuticals (eg. sertraline [5] (1)) and are also
found in natural products (eg. vismione B [6] (2)) (Fig. 1). Similarly,
1-benzosuberones have been incorporated in a range of biologically
active compounds [7] (eg. 3 and 4) and natural products (eg. the-
aflavin [8] (5)).
derwent an intramolecular Friedel-Crafts acylation to form a 4-
benzyltetral-1-one (8) in the presence of polyphosphoric acid
(Scheme 1) [10]. There were no indications of a second benzosu-
berone regioisomer. The potential formation of the 4-
arylbenzosuber-1-one regioisomer (10) was noted by Hatam
et al., however, none was observed [9]. Recently, Feixas et al. also
described the synthesis of 4-benzyltetral-1-ones from a range of
4,5-diarylpentanoic acids with polyphosphoric acid [12]. There was
no report of the competing benzosuberone formation.
One of the most important methods to prepare such compounds
is the intramolecular Friedel-Crafts cyclisation, which serves as a
useful and facile reaction to access cyclic aryl ketones [1]. The
cyclisation reaction of carboxylic acids can be catalysed by
hydrogen fluoride [9] or by heating in an excess of polyphosphoric
acid [10]. Aluminium chloride is another suitable acid catalyst for
the cyclisation of acid chlorides [11].
The Friedel-Crafts cyclisation of 4,5-diarylpentanoic acids pre-
sent an interesting case as there is the potential for regioisomeric
tetralone and benzosuberone products to be formed. Previously
this has been shown to favour the formation of the tetralone
In fact, the synthesis of 4-arylbenzosuber-1-one has not yet
been reported, while each of the other arylbenzosuber-1-one
regioisomers (aryl group in the 2-, 3- and 5-positions) have been
described [13e15]. We posited that 4-arylbenzosuber-1-one could
be a useful intermediate for potential pharmaceutical agents
[7,16e18]. For example, rimegepant (6), which has recently been
approved as a treatment for migraines [19], bears a comparable
substitution pattern that could be structurally mimicked by 4-
arylbenzosuber-1-one. We hypothesised that the regioselectivity
of the cyclisation reaction could be controlled by the inclusion of
substituents, A or B, on the aromatic rings allowing access to 4-
arylbenzosuber-1-one (11) (Scheme 2). The cyclisation is pro-
posed to progress through a Wheland intermediate and so, stabi-
lisation or destabilisation of the competing cations should alter the
product balance. As such, we investigated the influence of ring
* Corresponding author.
E-mail address: philip.thompson@monash.edu (P.E. Thompson).
https://doi.org/10.1016/j.tet.2021.132034
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
Fig. 1. Example of tetralone and benzosuberone based compounds.
Scheme 1. Synthesis of sequirin D (9) [10].
Scheme 2. Retrosynthesis of substituted 4-arylbenzosuber-1-ones (11).
activators, such as electron donating groups (methoxy), and ring
deactivators, such as electron withdrawing groups (halogens,
nitro). Here we report on the outcomes of this study as well as the
further manipulation of the substituents to yield the first synthesis
of the parent compound of the class.
Firstly, the preparation of the precursor deoxybenzoins 15 was
conveniently achieved under palladium-catalysed conditions
described by Das et al. using 2-(3,5-dimethyl-1H-pyrazol-1-yl)
pyridine as the ligand [20]. Alternatively, 1,2-deoxybenzoin 15H
was prepared by Friedel-Crafts acylation of dimethoxybenzene and
phenylacetyl chloride. Michael addition between the deoxy-
benzoins and ethyl acrylate was followed by direct saponification in
one pot to yield the carboxylic acids 16. In some cases, the inter-
mediate ester was isolated (16E, 16H, 16L and 16M) and then
hydrolysed. The ketone group was reduced using triethylsilane and
trifluoroacetic acid according to Kursanov et al. [21] The products
(17) from this reaction were sufficiently pure to be progressed to
2. Results and discussion
To access the precursor 4,5-diarylpentanoic acids (17),
substituted deoxybenzoins (15) were elaborated in a sequence of
Michael addition with ethyl acrylate, followed by ester hydrolysis
and then ketone reduction (Scheme 3).
2

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
Scheme 3. General synthesis of 17. i, 2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine, Pd(OAc)2, H2O:TfOH (3:1), 60 ꢀC, 3.5 h; ii, ethyl acrylate, t-BuOK, t-BuOH, room temp., 1 h; iii, 1 M aq.
NaOH, 60 ꢀC, 1 h; iv, triethylsilane, trifluoroacetic acid, room temp., 16 h.
Table 1
the next reaction without further purification (see Table 1).
Yields of 15BeO, 16A-O and 17A-O.
With the key precursors 17 in hand, the Friedel-Crafts cyclisa-
tion was performed by treatment with polyphosphoric acid at 80 ꢀC
for 4 h (Scheme 4). 1H NMR was used to determine the identity of
the regioisomers, tetralone 18 or benzosuberone 19 and the inte-
gration of discrete signals was used to assess the regioisomer ratios
(Supplementary data). The outcome of the cyclisations are sum-
marised in Table 2. Products which contained a mixture of
regioisomers were resolved by column chromatography with the
exception of 18H and 19H.
The resulting product mixtures ranged from exclusive tetralone
formation to exclusive benzosuberone formation. Cyclisation of 17A
yielded only the tetralone regioisomer (18A) as expected, with no
evidence of benzosuberone formation. The inclusion of the bromo
substituent at R1 (17B) or a methoxy substituent at either R2 (17C)
or R4 (17D) similarly resulted in specific formation of tetralone
regioisomers, 18B, 18C and 18D respectively.
For compounds 17E and 17F, the benzosuberone regioisomer
(19E and 19F) was observed, albeit as the minor product of the
cyclisation. It would appear that the electron withdrawing prop-
erties of these halogens caused the 4-phenyl ring to be less reactive
during cyclisation, which allowed some of the benzosuberone
regioisomer to be produced. The slightly higher ratio observed with
17F may be due to the ortho-fluoro substituent hindering reaction
further. Interestingly, a different outcome was observed when a
methoxy group was present at R1 (17G) compared to when it was at
R2 (17C). In both cases, the methoxy group would be expected to
activate the 5-phenyl ring, however, only the methoxy group at R1
(17G) yielded a regioisomeric mixture, favouring benzosuberone
(19G). This signalled the directing property of the methoxy group.
For 17G, the methoxy group at R1 is able to stabilise the Wheland
intermediate required to form the benzosuberone. Acylation only
occurred in the para-position with the ortho-position likely to be
sterically hindered. On the other hand, for 17C the intermediate to
form the benzosuberone could not be stabilised and no
R1
R2
R3 R4
R5
15 (Yield %)a 16 (Yield %)a 17 (Yield %)b
A
B
C
D
Ec
F
H
Br
H
H
H
H
H
OMe
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
e
61
71
91
85
25
82
80
54
92
35
72
38
25
52
80
69
41
75
87
66
79
99
96
67
98
80
54
69
65
19
33
40
OMe 69
Br
H
H
H
H
F
40
85
77
53
80
65
79
H
H
H
H
G
OMe
H
H
F
H
H
H
Hc,d OMe OMe
I
J
OMe OMe
OMe OMe
OMe OMe
OMe OMe
H
H
H
H
H
H
H
H
H
H
H
NO2
K
Br
Lc
NO2 54
OMe 60
Br
H
Mc OMe OMe
N
O
OMe
H
H
H
79
66
a
b
c
Yields were determined after purification.
Yields of the crude product.
The ester was isolated before hydrolysis (see General procedure III and IV). The
yield of 16 is over the two steps.
d
A Friedel-Crafts acylation was utilised for the preparation of 15H.
benzosuberone formation was observed. The lack of influence by
the methoxy group at R2 was further demonstrated with the cyc-
lisation of 17H resulting in the same ratio as 17G.
The results from 17E to 17H demonstrated that the regiose-
lectivity could be altered with just one of the phenyl rings being
substituted. The next step was to combine these features to see if
the regiospecific formation of the benzosuberone regioisomer
would be possible under the same conditions. We particularly
focused on the 3,4-dimethoxy substitution from 17H, as the cate-
chol ether group is frequently associated with bioactive molecules
[22,23]. In addition, the 1H NMR profile characterised by two aro-
matic singlets would be a ready indicator for the benzosuberone
regioisomer. Remarkably, only the benzosuberone regioisomer was
Scheme 4. Cyclisation of 17. i, polyphosphoric acid, 80 ꢀC, 4 h.
3

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
Table 2
17A-O cyclisation regioselectivity and their yields.
R1
R2
R3
R4
R5
Ratio of 18:19a
18 (Yield %)b
19 (Yield %)b
A
B
C
D
E
H
Br
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
OMe
H
H
H
H
H
H
H
F
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
OMe
Br
H
H
H
100:0
100:0
100:0
100:0
85:15
80:20
30:70
30:70
0:100
0:100
0:100
0:100
0:100
0:100
0:100
40
59
67
19
53
48
7
10
0
0
0
0
0
0
8
Fc
G
Hc
I
H
H
11
24
24
59
75
56
89
39
53
44
OMe
OMe
OMe
OMe
OMe
OMe
H
H
F
J
K
L
M
N
O
Br
NO2
OMe
Br
H
0
0
0
0
H
0
a
Regioisomer ratios were determined by 1H NMR of the crude mixture.
Yields were determined after purification.
The yields of 18 and 19 were calculated based on the ratio as the regioisomers were not fully separated.
b
c
obtained in each case. The combination of appropriate ring acti-
vation on the 5-phenyl ring in conjunction with the decreased
reactivity of the 4-phenyl ring from electron withdrawing groups
excluded tetralone formation (17I-L). As observed with 17G and
17H, the absence of the methoxy group at R2 for 17N had the same
result as 17K.
The 4-methoxy substituent on the 4-phenyl ring (17M) also
resulted in the complete formation of the benzosuberone
regioisomer (19M). To form the tetralone, cyclisation occurs in the
position meta to the methoxy group on the 4-phenyl ring. The
inability to resonance stabilise the carbocation intermediate during
the electrophilic aromatic substitution may have limited the for-
mation of the tetralone, similar to the result difference between 17C
and 17G.
In a second route, 19N was subjected to demethylation in the
presence of aluminium chloride (Scheme 6). While the demethy-
lation was successful, it was accompanied by an unexpected but
desirable debromination to give 20.
N-Phenyl-bis(tri-
fluoromethanesulfonimide) was then used to successfully convert
the phenol to a triflate group. Lastly, a palladium-catalysed reduc-
tion was used to yield 4-phenylbenzosuber-1-one (19A). The
overall yield from 17N to 19A was 16%, a four-fold improvement
upon synthesis from 17E.
The successful synthesis of 19A by these methods show that a
variety of substituted 4-arylbenzosuber-1-ones might be achieved
by employing regioselection auxiliaries to drive the outcome of the
Friedel-Crafts cyclisation.
The last analogue listed (17O) demonstrates that the original
regioselectivity can be completely reversed with a single substit-
uent that heavily disfavours reaction with the 4-phenyl ring. As the
nitro substituent is an electron withdrawing group, acylation is not
favoured in the ortho or para positions, thus this significantly dis-
favoured tetralone formation. Collectively, these results show that
the regioselectivity can be influenced towards the formation of the
benzosuberone by inclusion of the appropriate substituents on
either ring.
Finally, we speculated that the directing groups could be
removed to access the parent benzosuberone 19A, which was
otherwise inaccessible from this synthetic route. The halogen and
ether substituents in products 19E and 19N presented as groups
that could be removed by a variety of chemical transformations.
Firstly, the successful separation of 19E from 18E followed by a
debromination of 19E with hydrogen gas in the presence of palla-
dium on carbon yielded 4-phenylbenzosuber-1-one (19A) (Scheme
5). However, with 19E only being 15% of the cyclisation product
crude mixture, this route was relatively inefficient.
3. Conclusions
We were able to establish the requirements for the formation of
either the 4-benzyltetral-1-one or 4-arylbenzosuber-1-one from
4,5-diarylpentanoic acids. The underpinning reactions are well
established and the regiochemical outcomes are logical according
to conventional mechanistic arguments, but it demonstrated the
power of regiochemical directing groups in generating novel mol-
ecules. Interestingly, the prior work of Feixas et al. described a se-
ries of 4-benzyltetral-1-one compound with varying substitutions
Scheme 6. Alternative synthesis of 19A. i, AlCl3, toluene, reflux, 2 h, 53%; ii, N-phenyl-
bis(trifluoromethanesulfonimide), N,N-diisopropylethylamine, dichloromethane, room
temp., 2 h; iii, PPh3, Pd(OAc)2, formic acid, triethylamine, dimethylformamide, 65 ꢀC,
12 h, 58% over two steps.
Scheme 5. First-time synthesis of 19A. i, H2, Pd/C, methanol, room temp., 2 h, 40%.
4

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
[12]. While not addressed in that work, our results would suggest
that competing benzosuberone formation would be unlikely in
most cases, and at best a minor side product as there are no groups
to favour the cyclisation with the 5-phenyl ring. The ring activating
and deactivating properties of aromatic substituents can be easily
controlled to give the desired ring closure and the ability to remove
or alter certain substituents allows them to act as auxiliaries for
regioselective syntheses. This then allows further manipulation of
the scaffold to allow for more elaborate substitutions such as those
represented in Fig. 1. Our demonstration of the synthetic access to
4-arylbenzosuber-1-one opens up an avenue to a range of com-
pounds of pharmaceutical relevance.
(3 ꢁ 30 mL). The organic extracts were combined, washed with
brine (100 mL), dried over MgSO4 and concentrated in vacuo. The
residue was then purified by column chromatography to yield the
product.
4.2.2. General procedure II for the synthesis of carboxylic acid
analogues (16A-D, F, G, IeK, N and O)
To a solution of potassium tert-butoxide (1.50 equiv.) in tert-
butanol (15 mL), was added the deoxybenzoin (15) (1 mmol, 1.00
equiv.). The reaction mixture was then added ethyl acrylate (2.10
equiv.) in a drop-wise manner. The reaction mixture was stirred at
room temperature for 1 h. After consumption of the deoxybenzoin,
the solution was added 1 M aq. NaOH (5 mL) and stirred at 60 ꢀC for
1 h. The mixture was cooled and concentrated in vacuo. The crude
material was diluted in water (30 mL) and washed with ethyl ac-
etate (30 mL). The aqueous layer was made acidic with 1 M HCl to
pH ~2. It was then extracted with ethyl acetate (3 ꢁ 30 mL). The
organic extracts were combined, washed with brine (100 mL), dried
over MgSO4 and concentrated in vacuo. The residue was then pu-
rified by column chromatography to yield the product.
4. Experimental section
4.1. General information
All reagents were purchased and used without further purifi-
cation. Silica gel was used for column chromatography purification.
1H NMR and 13C NMR spectra were collected on a Bruker Advance
III Nanobay 400 MHz spectrometer (1H at 400 MHz and 13C at
100 MHz). All spectra were processed using MestReNova 11.0
software. The chemical shifts of 1H and 13C are reported in parts per
million (ppm) and were measured relative to the expected chem-
ical shifts of the NMR solvents; CDCl3, 7.26 (77.16 for 13C NMR) and
CD3OD, 3.31 (49.00 for 13C NMR). The format used to report the
spectra was as followed: chemical shift (multiplicity, coupling
constant (if applicable), integration). Multiplicity was defined as:
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, sd ¼ singlet of
doublets, dd ¼ doublet of doublets, dt ¼ doublet of triplets,
tt ¼ triplet of triplets and m ¼ multiplet. Apparent splitting was
abbreviated as app. and a broad resonance was abbreviated as br.
Coupling constants were reported as J in Hertz (Hz).
4.2.3. General procedure III for the synthesis of ester analogues
(16E, H, L and M)
To a solution of the deoxybenzoin (15) (1 mmol, 1.00 equiv.) in
tetrahydrofuran (15 mL), was added ethyl acrylate (2.10 equiv.). The
mixture was cooled to 0 ꢀC, then added a slurry of potassium tert-
butoxide (0.10 equiv.) in THF. The reaction mixture was warmed to
room temperature and stirred for 2 h. The reaction mixture was
concentrated in vacuo. The crude material was taken up into ethyl
acetate (30 mL) and water (30 mL). The organic phase was sepa-
rated and the aqueous phase was extracted again with ethyl acetate
(2 ꢁ 30 mL). The combined organic extract was washed with brine
(100 mL), dried over MgSO4 and concentrated in vacuo to give a
crude product. The residue was carried forward to General pro-
cedure IV without further purification.
All analytical HPLC analyses were done on an Agilent 1260 In-
finity Analytical HPLC coupled with a 1260 Degasser: G1322A, 1260
Binary Pump: G1312B, 1260 HiP ALS autosampler: G1367E, 1260
TCC: G1316A and 1260 DAD detector: G4212B. The column used
was a Zorbax Eclipse Plus C18 Rapid Resolution 4.6 ꢁ 100 mm 3.5-
4.2.4. General procedure IV for the hydrolysis of ester analogues
(16E, H, L and M)
micron. The sample injection volume was 2
mL which was run in
The intermediate ester (1 mmol, 1.00 equiv.), from General
procedure III, was dissolved in a mixture of 1,4-dioxane and 1 M
aq. NaOH (1:1, 15 mL) and stirred at 60 ꢀC for 1.5 h. The reaction
mixture was cooled and 1,4-dioxane was removed in vacuo. The
residue was diluted with water (30 mL) and washed with ethyl
acetate (30 mL). The aqueous phase was made acidic with 1 M HCl
to pH ~2 and was extracted with ethyl acetate (3 ꢁ 30 mL). The
organic extracts were combined, washed with brine (100 mL), dried
over MgSO4 and concentrated in vacuo. The residue was then pu-
rified using column chromatography to give the product.
0.1% TFA in acetonitrile at a gradient of 5e100% over 10 min with a
flow rate of 1 mL/min. Detection methods were with 214 nm and
254 nm.
All HRMS analyses were done on an Agilent 6224 TOF LC/MS
Mass Spectrometer coupled to an Agilent 1290 Infinity (Agilent,
Palo Alto, CA). All data were acquired and reference mass corrected
via a dual-spray electrospray ionization (ESI) source. Each scan or
data point on the Total Ion Chromatogram (TIC) is an average of
13,700 transients, producing a spectrum every second. Mass
spectra were created by averaging the scans across each peak and
background subtracted against the first 10 s of the TIC. Acquisition
was performed using the Agilent Mass Hunter Fata Acquisition
software version B.05.00 Build 5.0.5042.2 and analysis was per-
formed using Mass Hunter Qualitative Analysis version B.05.00
Build 5.0.519.13.
4.2.5. General procedure V for the reduction of the ketone (17A-O)
To a solution of the carboxylic acid (16) (1 mmol, 1.00 equiv.) in
trifluoroacetic acid (15 mL), was added triethylsilane (2.20 equiv.)
in a drop-wise manner under nitrogen. The reaction mixture was
stirred at room temperature for 16 h. The reaction mixture was
made basic with 1 M aq. NaOH to pH ~9 and washed with diethyl
ether (30 mL). The aqueous layer was then made acidic with 1 M
HCl to pH ~4 and extracted with diethyl ether (3 ꢁ 30 mL). The
organic extracts were combined, washed with brine (100 mL), dried
over MgSO4 and concentrated in vacuo to give the crude product.
The residue was carried forward to General procedure VI without
further purification.
4.2. Synthesis and characterisation
4.2.1. General procedure I for the synthesis of deoxybenzoin
analogues (15B-G, IeO)
To a solution of phenylacetonitrile (14) (1 mmol, 1.00 equiv.) and
boronic acid (13) (1.20 equiv.), in water and triflic acid (3:1, 12 mL),
was added 2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (0.05 equiv.)
and Pd(OAc)2 (0.05 equiv.). This reaction mixture was stirred at
60 ꢀC for 3.5 h. The mixture was cooled to room temperature,
neutralised with sat. aq. NaHCO3 and extracted with diethyl ether
4.2.6. General procedure VI for the intramolecular Friedel-Crafts
acylation (18A-H & 19E-O)
To 17 (1 mmol, 1.00 equiv.), was added polyphosphoric acid
5

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
(15 mL) and stirred at 80 ꢀC for 4 h. The reaction mixture was
diluted with water (40 mL) and extracted with diethyl ether
(3 ꢁ 50 mL). The organic extracts were combined, washed with sat.
aq. NaHCO3 (150 mL), brine (150 mL), dried over MgSO4 and
concentrated in vacuo. The residue was then purified by column
chromatography to yield the product.
4.2.14. 1-(3,4-Dimethoxyphenyl)-2-(2-fluorophenyl)ethan-1-one
(15I)
General procedure I e White powder (163 mg, 80% yield).;
Rf ¼ 0.32 (20% ethyl acetate in petroleum ether). 1H NMR
(400 MHz, CDCl3)
d
7.69 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.57 (d, J ¼ 2.1 Hz,
1H), 7.28e7.22 (m, 2H), 7.12e7.05 (m, 2H), 6.91 (d, J ¼ 8.4 Hz, 1H),
4.28 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H).; 13C NMR (100 MHz, CDCl3)
4.2.7. 1-(3-Bromophenyl)-2-phenylethan-1-one (15B) [24]
General procedure I e Clear liquid (87 mg, 33% yield).; Rf ¼ 0.31
(10% diethyl ether in petroleum ether).; 1H NMR (400 MHz, CDCl3)
d 195.2 (C), 162.2 (C), 159.8 (C), 153.6 (C), 149.2 (C), 131.6 (d,
J ¼ 4.2 Hz, CH), 129.7 (C), 128.9 (d, J ¼ 8.1 Hz, CH), 124.3 (d,
J ¼ 3.7 Hz, CH), 123.3 (CH), 115.5 (d, J ¼ 22.1 Hz, CH), 110.7 (CH),
110.2 (CH), 56.2 (CH3), 56.1 (CH3), 38.3 (d, J ¼ 2.3 Hz, CH2).;
Analytical HPLC: tR ¼ 5.75 min, > 95% purity (214 and 254 nm).;
HRMS: (ESIþ) calc. m/z for [C16H15FO3 þ H]þ 275.1078, found
275.1077.
d
8.14 (t, J ¼ 1.8 Hz, 1H), 7.92 (ddd, J ¼ 7.8, 1.7, 1.0 Hz, 1H), 7.68 (ddd,
J ¼ 7.9, 2.0,1.0 Hz,1H), 7.36e7.32 (m, 3H), 7.29e7.24 (m, 3H), 4.26 (s,
2H).
4.2.8. 1-(4-Methoxyphenyl)-2-phenylethan-1-one (15C) [25]
General procedure I e Yellow gum (155 mg, 40% yield).;
Rf ¼ 0.25 (30% diethyl ether in petroleum ether).; 1H NMR
4.2.15. 1-(3,4-Dimethoxyphenyl)-2-(4-fluorophenyl)ethan-1-one
(15J) [30]
(400 MHz, CDCl3)
d
8.00 (d, J ¼ 8.9 Hz, 2H), 7.34e7.30 (m, 2H),
General procedure I e Orange powder (157 mg, 65% yield).;
Rf ¼ 0.18 (20% ethyl acetate in petroleum ether).; 1H NMR
7.28e7.21 (m,3H), 6.93 (d, J ¼ 8.9 Hz, 2H), 4.23 (s, 1H), 3.86 (s, 2H).
(400 MHz, CDCl3)
1H), 7.23 (dd, J ¼ 8.7, 5.3 Hz, 2H), 7.01 (t, J ¼ 8.7 Hz, 2H), 6.89 (d,
J ¼ 8.4 Hz, 1H), 4.21 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H).
d
7.64 (dd, J ¼ 8.4, 2.0 Hz, 1H), 7.55 (d, J ¼ 2.0 Hz,
4.2.9. 2-(4-Methoxyphenyl)-1-phenylethan-1-one (15D) [26]
General procedure I e White powder (106 mg, 69% yield).;
Rf ¼ 0.20 (5% ethyl acetate in petroleum ether).; 1H NMR (400 MHz,
CDCl3)
d 8.02e8.00 (m, 2H), 7.57e7.53 (m, 1H), 7.48e7.43 (m, 2H),
4.2.16. 2-(4-Bromophenyl)-1-(3,4-dimethoxyphenyl)ethan-1-one
(15K)
7.18 (d, J ¼ 8.8 Hz, 2H), 6.87 (d, J ¼ 8.7 Hz, 2H), 4.23 (s, 2H), 3.79 (s,
3H).
General procedure I e White powder (136 mg, 79% yield).;
Rf ¼ 0.18 (20% ethyl acetate in petroleum ether).; 1H NMR
4.2.10. 2-(4-Bromophenyl)-1-phenylethan-1-one (15E) [27]
General procedure I e White powder (84 mg, 40% yield).;
Rf ¼ 0.26 (5% diethyl ether in petroleum ether).; 1H NMR (400 MHz,
(400 MHz, CDCl3)
d
7.63 (dd, J ¼ 8.4, 2.0 Hz, 1H), 7.54 (d, J ¼ 2.0 Hz,
1H), 7.44 (d, J ¼ 8.4 Hz, 2H), 7.14 (d, J ¼ 8.5 Hz, 2H), 6.88 (d,
J ¼ 8.4 Hz, 1H), 4.19 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H).; 13C NMR
CDCl3)
d 8.01e7.98 (m, 2H), 7.60e7.56 (m, 1H), 7.50e7.44 (m, 4H),
(100 MHz, CDCl3)
d 195.8 (C), 153.7 (C), 149.3 (C), 134.1 (C), 131.9
7.14 (d, J ¼ 8.5 Hz, 2H), 4.25 (s, 2H).
(CH), 131.3 (CH), 129.7 (C), 123.5 (CH), 121.0 (C), 110.7 (CH), 110.2
(CH), 56.2 (CH3), 56.1 (CH3), 44.6 (CH2). Analytical HPLC:
4.2.11. 2-(2-Fluorophenyl)-1-phenylethan-1-one (15F) [28]
General procedure I e White powder (185 mg, 78% yield).;
Rf ¼ 0.25 (5% diethyl ether in petroleum ether).; 1H NMR (400 MHz,
tR ¼ 6.54 min, > 90% purity (214 and 254 nm).; HRMS: (ESIþ) calc.
79
m/z for [C
H
BrO3 þ H]þ 335.0277, found 335.0277.
16 15
CDCl3)
d 8.06e8.03 (m, 2H), 7.61e7.56 (m, 1H), 7.51e7.46 (m, 2H),
4.2.17. 1-(3,4-Dimethoxyphenyl)-2-(4-nitrophenyl)ethan-1-one
(15L) [31]
7.30e7.22 (m, 2H), 7.13e7.06 (m, 2H), 4.33 (s, 2H).
General procedure I e White powder (121 mg, 54% yield).;
4.2.12. 1-(3-Methoxyphenyl)-2-phenylethan-1-one (15G) [29]
General procedure I e Clear liquid (149 mg, 77% yield).;
Rf ¼ 0.45 (10% diethyl ether in petroleum ether).; 1H NMR
Rf ¼ 0.15 (30% ethyl acetate in petroleum ether).; 1H NMR
(400 MHz, CDCl3)
1H), 7.55 (d, J ¼ 2.0 Hz, 1H), 7.44 (d, J ¼ 8.8 Hz, 2H), 6.91 (d,
J ¼ 8.4 Hz, 1H), 4.37 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H).
d
8.20 (d, J ¼ 8.8 Hz, 2H), 7.65 (dd, J ¼ 8.4, 2.1 Hz,
(400 MHz, CDCl3)
d
7.61 (ddd, J ¼ 7.7, 1.6, 1.0 Hz, 1H), 7.53 (dd,
J ¼ 2.7, 1.6 Hz, 1H), 7.39e7.31 (m, 3H), 7.28e7.23 (m, 3H), 7.10 (ddd,
J ¼ 8.2, 2.7, 1.0 Hz, 1H), 4.27 (s, 2H), 3.84 (s, 3H).
4.2.18. 1-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)ethan-1-one
(15M) [30]
4.2.13. 1-(3,4-Dimethoxyphenyl)-2-phenylethan-1-one (15H) [30]
To a solution of phenylacetic acid (300 mg, 2.20 mmol) in
dichloromethane (7 mL), was added oxalyl chloride (186 mg,
General procedure I e White powder (117 mg, 60% yield).;
Rf ¼ 0.29 (1% ethyl acetate in dichloromethane).; 1H NMR
126
1 h. The reaction mixture was cooled to room temperature and was
added 1,2-dimethoxybenzene (203 mg, 188 L, 1.47 mmol) and
m
L, 1.47 mmol). The reaction mixture was stirred at 60 ꢀC for
(400 MHz, CDCl3)
d
7.65 (dd, J ¼ 8.4, 2.0 Hz, 1H), 7.55 (d, J ¼ 2.0 Hz,
1H), 7.19 (d, J ¼ 8.7 Hz, 2H), 6.89e6.85 (m, 3H), 4.18 (s, 2H), 3.94 (s,
3H), 3.91 (s, 3H), 3.78 (s, 3H).
m
aluminium chloride (294 mg, 2.20 mmol) gradually. The reaction
mixture was then stirred at 60 ꢀC for 4 h. The reaction mixture was
cooled, poured into ice water and acidified with 1 M HCl to pH ~4.
The organic phase was separated and the aqueous phase was
extracted with dichloromethane (2 ꢁ 20 mL). The combined
organic extract was washed with water (30 mL), dried over MgSO4
and concentrated in vacuo. The residue was then purified by column
chromatography (20% diethyl ether in petroleum ether) to give the
title product as a fluffy white powder (200 mg, 53% yield). Rf ¼ 0.13
(20% diethyl ether in petroleum ether).; 1H NMR (400 MHz, CDCl3)
4.2.19. 2-(4-Bromophenyl)-1-(3-methoxyphenyl)ethan-1-one
(15N)
General procedure I e White powder (370 mg, 79% yield).;
Rf ¼ 0.18 (10% diethyl ether in petroleum ether).; 1H NMR
(400 MHz, CDCl3)
d
7.58 (ddd, J ¼ 7.6, 1.6, 0.9 Hz, 1H), 7.51 (dd,
J ¼ 2.6, 1.6 Hz, 1H), 7.45 (d, J ¼ 8.4 Hz, 2H), 7.38 (t, J ¼ 7.9 Hz, 1H),
7.15e7.10 (m, 3H), 4.22 (s, 2H), 3.85 (s, 3H).; 13C NMR (100 MHz,
CDCl3)
d 197.0 (C), 160.0 (C), 137.9 (C), 133.6 (C), 131.9 (CH), 131.4
(CH), 129.8 (CH), 121.3 (CH), 121.1 (C), 119.9 (CH), 113.0 (CH), 55.6
d
7.66 (dd, J ¼ 8.4, 2.0 Hz, 1H), 7.56 (d, J ¼ 2.0 Hz, 1H), 7.34e7.28 (m,
(CH3), 45.0 (CH2).; Analytical HPLC: tR ¼ 6.13 min, > 96% purity
79
4H), 7.25e7.22 (m, 1H), 6.88 (d, J ¼ 8.4 Hz, 1H), 4.24 (s, 2H), 3.94 (s,
(214 and 254 nm).; HRMS: (ESIþ) calc. m/z for [C
H
BrO2 þ H]þ
15 13
3H), 3.91 (s, 3H).
305.0172, found 305.0166.
6

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
79
4.2.20. 2-(3-Nitrophenyl)-1-phenylethan-1-one (15O) [32]
General procedure I e Yellow oil (195 mg, 66% yield).; Rf ¼ 0.28
(30% diethyl ether in petroleum ether).; 1H NMR (400 MHz, CDCl3)
m/z for [C H
17 15
BrO3 þ H]þ 347.0277, found 347.0271.
4.2.26. 4-(2-Fluorophenyl)-5-oxo-5-phenylpentanoic acid (16F)
General procedure II e White powder (207 mg, 82% yield).;
Rf ¼ 0.21 (10% ethyl acetate in petroleum ether þ 1% acetic acid).;
d
8.17e8.14 (m, 2H), 8.04e8.01 (m, 2H), 7.64e7.59 (m, 2H),
7.54e7.49 (m, 3H), 4.42 (s, 2H).
1H NMR (400 MHz, CDCl3)
d 7.98e7.95 (m, 2H), 7.52e7.48 (m, 1H),
4.2.21. 5-Oxo-4,5-diphenylpentanoic acid (16A) [33]
7.42e7.38 (m, 2H), 7.23e7.19 (m, 2H), 7.10e7.04 (m, 2H), 5.05 (dd,
J ¼ 7.9, 6.5 Hz,1H), 2.53e2.43 (m, 1H), 2.42e2.33 (m, 2H), 2.22e2.14
General procedure II e After the aqueous layer was made acidic
with 1 M HCl to pH ~ 2, a yellow precipitate was collected by vac-
uum filtration and recrystallised from ethanol to give the title
compound as a white powder (833 mg, 61% yield).; Rf ¼ 0.41 (20%
ethyl acetate in petroleum ether þ 1% acetic acid). 1H NMR
(m, 1H).; 13C NMR (100 MHz, CDCl3)
d 198.7 (C), 179.0 (C), 160.2 (d,
J ¼ 245.0 Hz, C), 136.2 (C), 133.4 (CH), 129.3 (d, J ¼ 8.2 Hz, CH), 129.1
(d, J ¼ 3.5 Hz, CH), 128.8 (CH), 128.7 (CH), 125.8 (d, J ¼ 15.1 Hz, C),
125.0 (d, J ¼ 3.6 Hz, CH), 115.9 (d, J ¼ 22.7 Hz, CH), 43.9 (CH), 31.5
(CH2), 27.6 (CH2).; Analytical HPLC: tR ¼ 5.68 min, > 95% purity
(214 and 254 nm).; HRMS: (ESIþ) calc. m/z for [C17H15FO3 þ H]þ
287.1078, found 287.1076.
(400 MHz, CDCl3)
d 10.45 (br. s, 1H), 7.96e7.94 (m, 2H), 7.50e7.45
(m, 1H), 7.40e7.36 (m, 2H), 7.32e7.28 (m, 4H), 7.25e7.19 (m, 1H),
4.67 (t, J ¼ 7.3 Hz, 1H), 2.51e2.43 (m, 1H), 2.38e2.34 (m, 2H),
2.23e2.14 (m, 1H).
4.2.27. 5-(3-Methoxyphenyl)-5-oxo-4-phenylpentanoic acid (16G)
General procedure II e White powder (75 mg, 80% yield).;
Rf ¼ 0.26 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
4.2.22. 5-(3-Bromophenyl)-5-oxo-4-phenylpentanoic acid (16B)
General procedure II e White powder (72 mg, 71% yield).;
Rf ¼ 0.26 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
1H NMR (400 MHz, CDCl3)
d
7.53 (ddd, J ¼ 7.7, 1.6, 0.9 Hz, 1H), 7.48
1H NMR (400 MHz, CDCl3)
d
8.07 (t, J ¼ 1.8 Hz,1H), 7.84 (ddd, J ¼ 7.8,
(dd, J ¼ 2.7, 1.6 Hz, 1H), 7.32e7.27 (m, 5H), 7.24e7.19 (m, 1H), 7.02
(ddd, J ¼ 8.2, 2.7, 0.9 Hz, 1H), 4.65 (t, J ¼ 7.3 Hz, 1H), 3.80 (s, 3H),
2.51e2.42 (m, 1H), 2.37e2.34 (m, 2H), 2.22e2.14 (m, 1H).; 13C NMR
1.7, 1.0 Hz, 1H), 7.60 (ddd, J ¼ 8.0, 2.0, 1.0 Hz, 1H), 7.34e7.29 (m, 2H),
7.27e7.21 (m, 4H), 4.61 (t, J ¼ 7.3 Hz, 1H), 2.49e2.41 (m, 1H),
2.37e2.34 (m, 2H), 2.22e2.13 (m, 1H).; 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3) d 199.1 (C), 179.1 (C), 159.9 (C), 138.8 (C), 138.0 (C),
d
197.9 (C), 178.6 (C), 138.4 (C), 138.2 (C), 136.0 (CH), 131.9 (CH),
129.7 (CH), 129.3 (CH), 128.4 (CH), 127.5 (CH), 121.5 (CH), 119.7 (CH),
113.2 (CH), 55.5 (CH3), 52.7 (CH), 31.6 (CH2), 28.6 (CH2).; Analytical
HPLC: tR ¼ 5.55 min, > 95% purity (214 and 254 nm).; HRMS: (ESIþ)
calc. m/z for [C18H18O4 þ H]þ 299.1278, found 299.1286.
130.2 (CH), 129.4 (CH), 128.4 (CH), 127.8 (CH), 127.4 (CH), 123.1 (C),
52.7 (CH), 31.3 (CH2), 28.5 (CH2).; Analytical HPLC: tR ¼ 6.07 min, >
95% purity (214 and 254 nm).; HRMS: (ESIþ) calc. m/z for
79
[C
H
BrO3 þ H]þ 347.0277, found 347.0268.
17 15
4.2.28. 5-(3,4-Dimethoxyphenyl)-5-oxo-4-phenylpentanoic acid
(16H)
4.2.23. 5-(4-Methoxyphenyl)-5-oxo-4-phenylpentanoic acid (16C)
General procedure II e Yellow oil (120 mg, 91% yield).;
Rf ¼ 0.23 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
General procedure III and IV e Fluffy white powder (123 mg,
54% yield over two steps).; Rf ¼ 0.10 (20% ethyl acetate in petroleum
1H NMR (400 MHz, CDCl3)
d
7.94 (d, J ¼ 9.0 Hz, 2H), 7.33e7.28 (m,
ether þ 1% acetic acid).; 1H NMR (400 MHz, CDCl3)
d 7.60 (dd,
4H), 7.23e7.18 (m, 1H), 6.85 (d, J ¼ 8.9 Hz, 2H), 4.62 (t, J ¼ 7.3 Hz,
J ¼ 8.5, 2.0 Hz, 1H), 7.53 (d, J ¼ 2.0 Hz, 1H), 7.30e7.28 (m, 4H),
7.24e7.19 (m, 1H), 6.80 (d, J ¼ 8.5 Hz, 1H), 4.64 (t, J ¼ 7.3 Hz, 1H),
3.89 (s, 3H), 3.88 (s, 3H), 2.51e2.42 (m, 1H), 2.38e2.34 (m, 2H),
1H), 3.81 (s, 3H), 2.50e2.41 (m, 1H), 2.37e2.33 (m, 1H), 2.21e2.12
(m, 1H).; 13C NMR (100 MHz, CDCl3)
d 197.8 (C), 179.1 (C), 163.5 (C),
139.3 (C), 131.2 (CH), 129.6 (C), 129.2 (CH), 128.3 (CH), 127.4 (CH),
113.9 (CH), 55.6 (CH3), 52.1 (CH), 31.6 (CH2), 28.6 (CH2).; Analytical
HPLC: tR ¼ 5.07 min, > 98% purity (214 and 254 nm).; HRMS: (ESIþ)
calc. m/z for [C18H18O4 þ H]þ 299.1278, found 299.1287.
2.22e2.13 (m, 1H).; 13C NMR (100 MHz, CDCl3)
d 197.8 (C), 178.8 (C),
153.3 (C), 149.1(C), 139.4 (C), 129.7 (C), 129.2 (CH), 128.3 (CH), 127.4
(CH), 123.6 (CH), 111.1 (CH), 110.1 (CH), 56.2 (CH3), 56.0 (CH3), 52.1
(CH), 31.5 (CH2), 28.7 (CH2). Analytical HPLC: tR ¼ 5.45 min, > 99%
purity (214 and 254 nm).; HRMS: (ESIþ) calc. m/z for
[C19H20O5 þ H]þ 329.1384, found 329.1393.
4.2.24. 4-(4-Methoxyphenyl)-5-oxo-5-phenylpentanoic acid (16D)
General procedure II e White powder (67 mg, 85% yield).;
Rf ¼ 0.15 (10% ethyl acetate in petroleum ether þ 1% acetic acid).;
4.2.29. 5-(3,4-Dimethoxyphenyl)-4-(2-fluorophenyl)-5-
oxopentanoic acid (16I)
1H NMR (400 MHz, CDCl3)
d 7.95e7.93 (m, 2H), 7.50e7.45 (m, 1H),
7.40e7.35 (m, 2H), 7.20 (d, J ¼ 8.7 Hz, 2H), 6.83 (d, J ¼ 8.8 Hz, 2H),
General procedure II e Clear oil (58 mg, 92% yield).; Rf ¼ 0.11
4.61 (dd, J ¼ 7.8, 6.6 Hz, 1H), 3.75 (s, 3H), 2.45e2.33 (m, 3H),
(20% ethyl acetate in petroleum ether þ 1% acetic acid).; 1H NMR
2.20e2.12 (m,1H).; 13C NMR (100 MHz, CDCl3)
d
199.5 (C),159.0 (C),
(400 MHz, CDCl3)
d
7.62 (dd, J ¼ 8.5, 2.1 Hz, 1H), 7.54 (d, J ¼ 2.0 Hz,
136.7 (C), 133.1 (CH), 130.7 (C), 129.5 (CH), 128.9 (CH), 128.7 (CH),
114.7 (CH), 55.4 (CH3), 51.6 (CH), 31.4 (CH2), 28.6 (CH2). Carboxyl
carbon not observed.; Analytical HPLC: tR ¼ 5.42 min, > 90% purity
(214 and 254 nm).; HRMS: (ESIþ) calc. m/z for [C18H18O4 þ H]þ
299.1278, found 299.1284.
1H), 7.25e7.17 (m, 2H), 7.09e7.04 (m, 2H), 6.83 (d, J ¼ 8.5 Hz, 1H),
5.01 (dd, J ¼ 7.8, 6.6 Hz, 1H), 3.89 (app. br. s, 6H), 2.50e2.42 (m, 1H),
2.41e2.30 (m, 2H), 2.21e2.14 (m, 1H).; 13C NMR (100 MHz, CDCl3)
d
197.2 (d, J ¼ 1.6 Hz, C),178.7 (C), 160.1 (d, J ¼ 244.6 Hz, C),153.5 (C),
149.1 (C), 129.2 (C), 129.2 (d, J ¼ 8.2 Hz, CH), 129.0 (d, J ¼ 3.5 Hz, CH),
126.3 (d, J ¼ 15.0 Hz, C), 125.1 (d, J ¼ 3.5 Hz, CH),123.3 (CH), 115.8 (d,
J ¼ 22.7 Hz, CH), 110.9 (CH), 110.3 (CH), 56.2 (CH3), 56.0 (CH3), 43.3
(d, J ¼ 2.0 Hz, CH), 31.5 (CH2), 27.8 (CH2).; Analytical HPLC:
tR ¼ 5.31 min, > 95% purity (214 and 254 nm).; HRMS: (ESIþ) calc.
m/z for [C19H19FO5 þ H]þ 347.1289, found 347.1304.
4.2.25. 4-(4-Bromophenyl)-5-oxo-5-phenylpentanoic acid (16E)
General procedure III and IV e Clear oil (33 mg, 25% yield over
two steps).; Rf ¼ 0.20 (10% ethyl acetate in petroleum ether þ 1%
acetic acid).; 1H NMR (400 MHz, CDCl3)
d 7.93e7.91 (m, 2H),
7.52e7.48 (m, 1H), 7.45e7.38 (m, 4H), 7.17 (d, J ¼ 8.5 Hz, 2H), 4.66 (t,
J ¼ 7.3 Hz, 1H), 2.49e2.40 (m, 1H), 2.37e2.33 (m, 2H), 2.19e2.12 (m,
4.2.30. 5-(3,4-Dimethoxyphenyl)-4-(4-fluorophenyl)-5-
oxopentanoic acid (16J)
1H).; 13C NMR (100 MHz, CDCl3)
d 198.9 (C), 178.2 (C) 137.8 (C),
136.4 (C), 133.4 (CH), 132.4 (CH), 130.2 (CH), 128.9 (CH), 128.8 (CH),
121.6 (C), 51.7 (CH), 31.3 (CH2), 28.5 (CH2).; Analytical HPLC:
tR ¼ 6.34 min, > 95% purity (214 and 254 nm).; HRMS: (ESIþ) calc.
General procedure II e Clear oil (23 mg, 35% yield).; Rf ¼ 0.16
(20% ethyl acetate in petroleum ether þ 1% acetic acid). 1H NMR
(400 MHz, CDCl3)
d
7.57 (dd, J ¼ 8.4, 2.0 Hz, 1H), 7.52 (d, J ¼ 2.0 Hz,
7

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
1H), 7.28e7.25 (m, 2H), 6.99 (t, J ¼ 8.7 Hz, 2H), 6.81 (d, J ¼ 8.5 Hz,
1H), 4.65 (t, J ¼ 7.3 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.49e2.40 (m,
1H), 2.37e2.33 (m, 2H), 2.18e2.12 (m, 1H). 13C NMR (100 MHz,
tR ¼ 5.72 min, > 96% purity (214 and 254 nm).; HRMS: (ESIþ) calc.
79
m/z for [C
H
BrO4 þ H]þ 377.0383, found 377.0377.
18 17
CDCl3)
d
197.7 (C), 179.0 (C), 162.1 (d, J ¼ 246.2 Hz, C), 153.4 (C),
4.2.35. 4-(3-Nitrophenyl)-5-oxo-5-phenylpentanoic acid (16O)
General procedure II e Yellow oil (196 mg, 80% yield).; Rf ¼ 0.18
(40% diethyl ether in petroleum ether þ 1% acetic acid).; 1H NMR
149.2 (C), 135.0 (d, J ¼ 3.2 Hz, C), 129.82 (d, J ¼ 8.0 Hz, CH), 129.4 (C),
123.6 (CH), 116.1 (d, J ¼ 21.4 Hz, CH), 110.9 (CH), 110.1 (CH), 56.2
(CH3), 56.0 (CH3), 51.0 (CH), 31.5 (CH2), 28.7 (CH2).; Analytical
HPLC: tR ¼ 5.58 min, > 99% purity (214 and 254 nm).; HRMS: (ESIþ)
calc. m/z for [C19H19FO5 þ H]þ 347.1289, found 347.1300.
(400 MHz, CDCl3)
d
8.21 (t, J ¼ 2.0 Hz, 1H), 8.11 (ddd, J ¼ 8.2, 2.3,
1.0 Hz,1H), 7.97e7.95 (m, 2H), 7.67 (dt, J ¼ 7.8, 1.3 Hz,1H), 7.56e7.48
(m, 2H), 7.46e7.41 (m, 2H), 4.88 (t, J ¼ 7.4 Hz, 1H), 2.59e2.50 (m,
1H), 2.39 (t, J ¼ 7.0 Hz, 2H), 2.24e2.16 (m, 1H).; 13C NMR (100 MHz,
4.2.31. 4-(4-Bromophenyl)-5-(3,4-dimethoxyphenyl)-5-
oxopentanoic acid (16K)
CDCl3) d 198.3 (C), 177.7 (C), 148.8 (C), 140.8 (C), 136.1 (C), 134.5
(CH), 133.8 (CH), 130.2 (CH), 129.0 (CH), 128.9 (CH), 123.6 (CH),
122.7 (CH), 51.6 (CH), 31.2 (CH2), 28.7 (CH2).; Analytical HPLC:
tR ¼ 5.17 min, > 98% purity (214 and 254 nm).; HRMS: (ESIþ) calc.
m/z for [C17H15NO5 þ H]þ 314.1023, found 314.1021.
General procedure II e Yellow oil (184 mg, 72% yield).; Rf ¼ 0.13
(20% ethyl acetate in petroleum ether þ 1% acetic acid).; 1H NMR
(400 MHz, CD3OD)
d
8.17 (d, J ¼ 8.8 Hz, 2H), 7.71 (dd, J ¼ 8.5, 2.1 Hz,
1H), 7.59 (d, J ¼ 8.8 Hz, 2H), 7.55 (d, J ¼ 2.1 Hz, 1H), 6.97 (d,
J ¼ 8.5 Hz, 1H), 4.99 (t, J ¼ 7.3 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H),
2.49e2.40 (m, 1H), 2.30e2.25 (m, 2H), 2.16e2.07 (m, 1H).; 13C NMR
(100 MHz, CD3OD)
(C), 148.5 (C), 130.6 (CH), 130.5 (C), 125.0 (CH), 124.9 (CH), 112.2
(CH), 111.7 (CH), 56.5 (CH3), 56.4 (CH3), 52.5 (CH), 32.5 (CH2), 30.1
4.2.36. 4,5-Diphenylpentanoic acid (17A) [34]
General procedure V e Clear oil (121 mg, 69% crude yield).;
Rf ¼ 0.49 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
d 198.9 (C), 176.6 (C), 155.4 (C), 150.6 (C), 148.5
1H NMR (400 MHz, CDCl3)
d 7.28e7.25 (m, 2H), 7.22e7.18 (m, 3H),
7.16e7.13 (m, 1H), 7.12e7.10 (m, 2H), 7.04e7.02 (m, 2H), 2.95e2.80
(m, 3H), 2.18e2.13 (m, 2H), 2.09e2.03 (m, 1H), 1.95e1.86 (m, 1H).
(CH2).; Analytical HPLC: tR ¼ 6.06 min, > 99% purity (214 and
BrO5 þ H]þ 407.0489,
79
254 nm).; HRMS: (ESIþ) calc. m/z for [C
H
19 19
found 407.0491.
4.2.37. 5-(3-Bromophenyl)-4-phenylpentanoic acid (17B)
General procedure V e Clear oil (20 mg, 41% crude yield).;
Rf ¼ 0.29 (10% ethyl acetate in petroleum ether þ 1% acetic acid).;
4.2.32. 5-(3,4-Dimethoxyphenyl)-4-(4-nitrophenyl)-5-
oxopentanoic acid (16L)
1H NMR (400 MHz, CDCl3)
d 7.30e7.26 (m, 3H), 7.22e7.18 (m, 2H),
General procedure III and IV e Yellow oil (33 mg, 38% yield
over two steps).; Rf ¼ 0.23 (40% ethyl acetate in petroleum
7.10e7.07 (m, 2H), 7.05e7.03 (m, 1H), 6.92 (dt, J ¼ 7.7, 1.3 Hz, 1H),
2.88e2.79 (m, 3H), 2.20e2.15 (m, 2H), 2.11e2.01 (m, 1H), 1.96e1.87
(m, 1H).
ether þ 1% acetic acid).; 1H NMR (400 MHz, CDCl3)
d 8.17 (d,
J ¼ 8.8 Hz, 2H), 7.56 (dd, J ¼ 8.5, 2.0 Hz, 1H), 7.52e7.49 (m, 3H), 6.83
(d, J ¼ 8.5 Hz, 1H), 4.83 (t, J ¼ 7.3 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H),
2.56e2.48 (m, 1H), 2.38 (t, J ¼ 6.9 Hz, 2H), 2.21e2.13 (m, 1H).; 13C
4.2.38. 5-(4-Methoxyphenyl)-4-phenylpentanoic acid (17C)
General procedure V e Yellow gum (129 mg, 75% crude yield).;
Rf ¼ 0.38 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
NMR (100 MHz, CDCl3)
d 196.6 (C), 177.7 (C), 154.0 (C), 149.5 (C),
147.4 (C), 146.7 (C), 129.3 (CH), 129.2 (C), 124.4 (CH), 123.6 (CH),
110.9 (CH), 110.2 (CH), 56.3 (CH3), 56.1 (CH3), 51.4 (CH), 31.3 (CH2),
28.7 (CH2).; Analytical HPLC: tR ¼ 5.54 min, > 92% purity (214 and
254 nm).; HRMS: (ESIþ) calc. m/z for [C19H19NO7 þ H]þ 374.1234,
found 374.1237.
1H NMR (400 MHz, CDCl3)
d 7.29e7.24 (m, 2H), 7.20e7.16 (m, 1H),
7.11e7.09 (m, 2H), 6.93 (d, J ¼ 8.6 Hz, 2H), 6.74 (d, J ¼ 8.7 Hz, 2H),
3.76 (s, 3H), 2.87e2.77 (m, 3H), 2.18e2.13 (m, 2H), 2.09e2.00 (m,
1H), 1.94e1.84 (m, 1H).
4.2.39. 4-(4-Methoxyphenyl)-5-phenylpentanoic acid (17D)
General procedure V e Clear oil (39 mg, 87% crude yield).;
Rf ¼ 0.30 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
4.2.33. 5-(3,4-Dimethoxyphenyl)-4-(4-methoxyphenyl)-5-
oxopentanoic acid (16M)
General procedure III and IV e Yellow oil (20 mg, 25% yield
over two steps).; Rf ¼ 0.10 (20% ethyl acetate in petroleum
1H NMR (400 MHz, CDCl3)
d 7.22e7.18 (m, 2H), 7.16e7.12 (m, 1H),
7.03e7.00 (m, 4H), 6.80 (d, J ¼ 8.7 Hz, 2H), 3.78 (s, 3H), 2.88e2.86
(m, 2H), 2.83e2.77 (m, 1H), 2.18e2.08 (m, 2H), 2.09e1.99 (m, 1H),
1.91e1.81 (m, 1H).
ether þ 1% acetic acid). 1H NMR (400 MHz, CDCl3)
7.59 (dd, J ¼ 8.5,
d
1.9 Hz, 1H), 7.52 (d, J ¼ 1.9 Hz, 1H), 7.19 (d, J ¼ 8.7 Hz, 2H), 6.83e6.78
(m, 3H), 4.58 (t, J ¼ 7.2 Hz, 1H), 3.88 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H),
2.46e2.32 (m, 3H), 2.19e2.09 (m, 1H).; 13C NMR (100 MHz, CDCl3)
4.2.40. 4-(4-Bromophenyl)-5-phenylpentanoic acid (17E)
d
198.1 (C), 179.1 (C), 158.9 (C), 153.3 (C), 149.1 (C), 131.3 (C), 129.7
General procedure V e Clear oil (21 mg, 66% crude yield).;
Rf ¼ 0.54 (30% ethyl acetate in petroleum ether þ 1% acetic acid).;
(C), 129.3 (CH), 123.6 (CH), 114.6 (CH), 111.1 (CH), 110.1 (CH), 56.2
(CH3), 56.0 (CH3), 55.4 (CH3), 51.2 (CH), 31.6 (CH2), 28.7 (CH2).;
Analytical HPLC: tR ¼ 4.85 min, > 99% purity (214 and 254 nm).;
HRMS: (ESIþ) calc. m/z for [C20H22O6 þ H]þ 359.1489, found
359.1499.
1H NMR (400 MHz, CDCl3)
d
7.38 (d, J ¼ 8.4 Hz, 2H), 7.22e7.14 (m,
3H), 7.01e6.94 (m, 4H), 2.93e2.79 (m, 3H), 2.21e2.02 (m, 3H),
1.93e1.84 (m, 1H).
4.2.41. 4-(2-Fluorophenyl)-5-phenylpentanoic acid (17F)
4.2.34. 4-(4-Bromophenyl)-5-(3-methoxyphenyl)-5-oxopentanoic
acid (16N)
General procedure V e Clear oil (150 mg, 79% crude yield).;
Rf ¼ 0.36 (10% ethyl acetate in petroleum ether þ 1% acetic acid).;
General procedure II e Clear oil (238 mg, 52% yield).; Rf ¼ 0.20
1H NMR (400 MHz, CDCl3)
d 7.23e7.18 (m, 2H), 7.17e7.11 (m, 3H),
(40% diethyl ether in petroleum ether þ 1% acetic acid).; 1H NMR
7.08e7.03 (m, 3H), 6.99e6.94 (m,1H), 3.29e3.21 (m,1H), 2.96e2.93
(m, 1H), 2.21e2.17 (m, 2H), 2.12e1.92 (m, 3H).
(400 MHz, CDCl3)
d
7.49 (ddd, J ¼ 7.7, 1.6, 0.9 Hz, 1H), 7.46e7.41 (m,
3H), 7.29 (t, J ¼ 8.0 Hz, 1H), 7.17 (d, J ¼ 8.5 Hz, 1H), 7.04 (ddd, J ¼ 8.2,
2.7, 0.9 Hz, 1H), 4.63 (t, J ¼ 7.3 Hz, 1H), 3.81 (s, 3H), 2.48e2.40 (m,
1H), 2.36e2.33 (m, 2H), 2.18e2.13 (m, 1H).; 13C NMR (100 MHz,
4.2.42. 5-(3-Methoxyphenyl)-4-phenylpentanoic acid (17G)
General procedure V e Clear oil (68 mg, 99% crude yield).;
Rf ¼ 0.31 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
CDCl3)
d 198.7, 179.1, 159.9, 137.8, 137.7, 132.4, 130.1, 129.7, 121.6,
121.4, 119.8, 113.2, 55.5, 51.9, 31.5, 28.5.; Analytical HPLC:
1H NMR (400 MHz, CDCl3)
d 7.29e7.25 (m, 2H), 7.21e7.16 (m, 1H),
8

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
7.14e7.10 (m, 3H), 6.69 (ddd, J ¼ 8.3, 2.6, 1.0 Hz, 1H), 6.65 (dt, J ¼ 7.7,
1.2 Hz, 1H), 6.54 (dd, J ¼ 2.6, 1.6 Hz, 1H), 3.71 (s, 3H), 2.91e2.82 (m,
3H), 2.18e2.02 (m, 3H), 1.95e1.88 (m, 1H).
(m, 3H), 2.19e2.15 (m, 2H), 2.12e2.03 (m, 1H), 1.93e1.85 (m, 1H).
4.2.50. 4-(3-Nitrophenyl)-5-phenylpentanoic acid (17O)
General procedure V e Clear oil (36 mg, 19% crude yield).;
Rf ¼ 0.30 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
4.2.43. 5-(3,4-Dimethoxyphenyl)-4-phenylpentanoic acid (17H)
General procedure V e Orange oil (46 mg, 96% crude yield).;
Rf ¼ 0.26 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
1H NMR (400 MHz, CDCl3)
d
8.05 (ddd, J ¼ 7.6, 2.3, 1.7 Hz, 1H), 7.98
(t, J ¼ 1.9 Hz, 1H), 7.44e7.37 (m, 2H), 7.22e7.12 (m, 3H), 7.00e6.98
(m, 2H), 3.07e2.98 (m, 2H), 2.92e2.86 (m, 1H), 2.22e2.12 (m, 3H),
2.05e1.94 (m, 1H).
1H NMR (400 MHz, CDCl3)
d 7.29e7.25 (m, 2H), 7.21e7.16 (m, 1H),
7.11e7.09 (m, 2H), 6.72 (d, J ¼ 8.2 Hz, 1H), 6.60 (dd, J ¼ 8.1, 2.0 Hz,
1H), 6.41 (d, J ¼ 1.9 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 2.90e2.76 (m,
3H), 2.27e2.16 (m, 2H), 2.13e2.03 (m, 1H), 1.98e1.89 (m, 1H).
4.2.51. 4-Benzyl-3,4-dihydronaphthalen-1(2H)-one (18A) [34]
General procedure VI e Clear oil (11 mg, 40% yield).; Rf ¼ 0.66
(20% ethyl acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
4.2.44. 5-(3,4-Dimethoxyphenyl)-4-(2-fluorophenyl)pentanoic acid
(17I)
d
8.06 (dd, J ¼ 7.8, 1.4 Hz, 1H), 7.47 (td, J ¼ 7.5, 1.5 Hz, 1H), 7.34e7.31
General procedure V e Yellow oil (32 mg, 67% crude yield).;
Rf ¼ 0.45 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
(m, 3H), 7.27e7.23 (m, 1H), 7.21e7.17 (m, 3H), 3.27e3.21 (m, 1H),
3.12 (dd, J ¼ 13.6, 6.0 Hz, 1H), 2.90e2.86 (m, 1H), 2.84e2.79 (m, 1H),
2.58 (dt, J ¼ 17.8, 4.9 Hz, 1H), 2.20e2.11 (m, 1H), 1.99e1.92 (m, 1H).
1H NMR (400 MHz, CDCl3)
d
7.19e7.03 (m, 3H), 6.97 (ddd, J ¼ 10.6,
8.1, 1.3 Hz, 1H), 6.71 (d, J ¼ 8.2 Hz, 1H), 6.62 (dd, J ¼ 8.1, 2.0 Hz, 1H),
6.48 (d, J ¼ 2.0 Hz, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.22 (ddt, J ¼ 12.0,
7.4, 3.7 Hz, 1H), 2.89 (d, J ¼ 7.5 Hz, 2H), 2.24e2.20 (m, 2H),
2.13e2.05 (m, 1H), 2.02e1.92 (m, 1H).
4.2.52. 4-(3-Bromobenzyl)-3,4-dihydronaphthalen-1(2H)-one
(18B)
General procedure VI e Yellow oil (11 mg, 59% yield).; Rf ¼ 0.45
(10% ethyl acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
d
4.2.45. 5-(3,4-Dimethoxyphenyl)-4-(4-fluorophenyl)pentanoic acid
(17J)
8.06 (dd, J ¼ 7.8, 1.5 Hz, 1H), 7.48 (td, J ¼ 7.5, 1.5 Hz, 1H), 7.40e7.33
General procedure V e Clear oil (27 mg, 98% crude yield).;
Rf ¼ 0.34 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
(m, 3H), 7.20e7.15 (m, 2H), 7.09e7.07 (m, 1H), 3.25e3.19 (m, 1H),
3.09 (dd, J ¼ 13.7, 6.1 Hz, 1H), 2.86e2.76 (m, 2H), 2.60 (dt, J ¼ 17.8,
5.0 Hz, 1H), 2.22e2.13 (m, 1H), 1.98e1.91 (m, 1H).; 13C NMR
1H NMR (400 MHz, CDCl3)
J ¼ 8.7 Hz, 2H), 6.71 (d, J ¼ 8.2 Hz, 1H), 6.55 (dd, J ¼ 8.1, 2.0 Hz, 1H),
6.41 (d, J ¼ 1.9 Hz, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.86e2.78 (m, 3H),
2.20e2.17 (m, 2H), 2.12e2.04 (m, 1H), 1.94e1.88 (m, 1H).
d
7.04 (dd, J ¼ 8.7, 5.4 Hz, 2H), 6.95 (t,
(100 MHz, CDCl3)
d 198.0 (C), 146.9 (C), 142.2 (C), 133.7 (CH), 132.1
(CH), 132.1 (C), 130.2 (CH), 129.8 (CH), 128.5 (CH), 127.9 (CH), 127.6
(CH), 127.2 (CH), 122.8 (C), 41.0 (CH2), 40.0 (CH), 34.8 (CH2), 26.3
(CH2).; Analytical HPLC: tR ¼ 6.92 min, > 95% purity (214 and
79
BrO þ H]þ 315.0379,
4.2.46. 4-(4-Bromophenyl)-5-(3,4-dimethoxyphenyl)pentanoic
acid (17K)
254 nm).; HRMS: (ESIþ) calc. m/z for [C
H
17 15
found 315.0375.
General procedure V e Orange oil (33 mg, 80% crude yield).;
Rf ¼ 0.32 (20% ethyl acetate in petroleum ether þ 1% acetic acid).;
4.2.53. 4-(4-Methoxybenzyl)-3,4-dihydronaphthalen-1(2H)-one
(18C)
1H NMR (400 MHz, CDCl3)
J ¼ 8.4 Hz, 2H), 6.71 (d, J ¼ 8.2 Hz, 1H), 6.55 (dd, J ¼ 8.1, 2.0 Hz, 1H),
6.40 (d, J ¼ 2.0 Hz, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.86e2.78 (m, 3H),
2.22e2.18 (m, 2H), 2.12e2.05 (m, 1H), 1.95e1.87 (m, 1H).
d
7.39 (d, J ¼ 8.4 Hz, 2H), 6.96 (d,
General procedure VI e White powder (80 mg, 67% yield).;
Rf ¼ 0.36 (15% ethyl acetate in petroleum ether).; 1H NMR
(400 MHz, CDCl3)
d
8.06 (dt, J ¼ 7.8, 1.5 Hz, 1H), 7.46 (td, J ¼ 7.5,
1.5 Hz, 1H), 7.33 (td, J ¼ 7.5, 1.2 Hz, 1H), 7.19e7.17 (m, 1H), 7.08 (d,
J ¼ 8.6 Hz, 2H), 6.86 (d, J ¼ 8.6 Hz, 2H), 3.81 (s, 3H), 3.18 (dq, J ¼ 9.8,
4.7 Hz, 1H), 3.06 (dd, J ¼ 13.8, 6.1 Hz, 1H), 2.86e2.77 (m, 2H), 2.57
(dt, J ¼ 17.8, 4.9 Hz, 1H), 2.16 (ddt, J ¼ 13.6, 12.1, 4.7 Hz, 1H), 1.95 (dq,
4.2.47. 5-(3,4-Dimethoxyphenyl)-4-(4-nitrophenyl)pentanoic acid
(17L)
General procedure V e Yellow gum (26 mg, 54% crude yield).;
Rf ¼ 0.23 (40% ethyl acetate in petroleum ether þ 1% acetic acid).;
J ¼ 13.7, 4.9 Hz, 1H).; 13C NMR (100 MHz, CDCl3)
d 198.4 (C), 158.3
1H NMR (400 MHz, CDCl3)
d
8.13 (d, J ¼ 8.8 Hz, 2H), 7.26e7.24 (m,
(C), 147.6 (C), 133.6 (CH), 132.1 (C), 131.9 (C), 130.1 (CH), 128.6 (CH),
127.5 (CH), 127.0 (CH), 114.1 (CH), 55.4 (CH3), 40.5 (CH2), 40.3 (CH),
34.8 (CH2), 26.2 (CH2).; Analytical HPLC: tR ¼ 5.89 min, > 98%
purity (214 and 254 nm).; HRMS: (ESIþ) calc. m/z for
[C18H18O2 þ H]þ 267.1380, found 267.1376.
2H), 6.69 (d, J ¼ 8.2 Hz, 1H), 6.50 (dd, J ¼ 8.1, 2.0 Hz, 1H), 6.46 (d,
J ¼ 2.0 Hz,1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.03e2.91 (m, 2H), 2.82 (dd,
J ¼ 13.3, 8.2 Hz, 1H), 2.22e2.13 (m, 3H), 2.01e1.93 (m, 1H).
4.2.48. 5-(3,4-Dimethoxyphenyl)-4-(4-methoxyphenyl)pentanoic
acid (17M)
General procedure V e Clear oil (13 mg, 69% crude yield).;
Rf ¼ 0.68 (30% ethyl acetate in petroleum ether þ 1% acetic acid).;
4.2.54. 4-Benzyl-7-methoxy-3,4-dihydronaphthalen-1(2H)-one
(18D)
1H NMR (400 MHz, CDCl3)
d
7.00 (d, J ¼ 8.7 Hz, 2H), 6.81 (d,
General procedure VI e Yellow oil (5 mg, 19% yield).; Rf ¼ 0.65
J ¼ 8.7 Hz, 2H), 6.71 (d, J ¼ 8.2 Hz, 1H), 6.58 (dd, J ¼ 8.1, 1.9 Hz, 1H),
6.43 (d, J ¼ 1.9 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.73 (s, 3H),
2.82e2.76 (m, 3H), 2.21e2.03 (m, 3H), 1.92e1.83 (m, 1H).
(20% ethyl acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
d
7.54 (d, J ¼ 2.8 Hz, 1H), 7.34e7.29 (m, 2H), 7.26e7.22 (m, 1H),
7.18e7.15 (m, 2H), 7.10 (d, J ¼ 8.5 Hz, 1H), 7.04 (dd, J ¼ 8.5, 2.8 Hz,
1H), 3.85 (s, 3H), 3.20e3.15 (m, 1H), 3.10 (dd, J ¼ 13.5, 6.0 Hz, 1H),
2.86e2.76 (m, 2H), 2.56 (dt, J ¼ 17.8, 5.0 Hz, 1H), 2.18e2.09 (m, 1H),
4.2.49. 4-(4-Bromophenyl)-5-(3-methoxyphenyl)pentanoic acid
(17N)
1.97e1.90 (m, 1H).; 13C NMR (100 MHz, CDCl3)
d 198.3 (C), 140.2 (C),
General procedure V e Yellow oil (150 mg, 65% crude yield).;
Rf ¼ 0.31 (25% ethyl acetate in petroleum ether þ 1% acetic acid).;
140.0 (C), 129.8 (CH), 129.2 (CH), 128.7 (CH), 126.5 (CH), 121.9 (CH),
109.4 (CH), 55.7 (CH3), 41.5 (CH2), 39.4 (CH), 34.8 (CH2), 26.5 (CH2).
Two quaternary carbons not observed.; Analytical HPLC:
tR ¼ 6.62 min, > 95% purity (214 and 254 nm).; HRMS: (ESIþ) calc.
m/z for [C18H18O2 þ H]þ 267.1380, found 267.1384.
1H NMR (400 MHz, CDCl3)
d
7.38 (d, J ¼ 8.4 Hz, 2H), 7.15e7.09 (m,
1H), 6.98 (d, J ¼ 8.4 Hz, 2H), 6.70 (ddd, J ¼ 8.2, 2.6, 0.9 Hz, 1H), 6.60
(dt, J ¼ 7.5, 1.3 Hz, 1H), 6.53 (t, J ¼ 2.1 Hz,1H), 3.72 (s, 3H), 2.88e2.82
9

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
4.2.55. 4-Benzyl-7-bromo-3,4-dihydronaphthalen-1(2H)-one (18E)
& 8-(4-bromophenyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-
one (19E) (85:15)
2H), 6.71e6.70 (m, 1H), 3.79 (s, 3H), 3.27e3.18 (m, 1H), 3.10 (dd,
J ¼ 13.6, 6.0 Hz,1H), 2.86e2.77 (m, 2H), 2.58 (dt, J ¼ 17.8, 5.0 Hz,1H),
2.21e2.12 (m, 1H), 1.98e1.92 (m, 1H).; 13C NMR (100 MHz, CDCl3)
4.2.55.1. General procedure VI. Isolated 18E: Clear oil (40 mg, 53%
d 198.3 (C), 159.9 (C), 147.5 (C), 141.5 (C), 133.6 (CH), 132.1 (C), 129.7
yield).; Rf ¼ 0.38 (5% ethyl acetate in petroleum ether).; 1H NMR
(CH), 128.5 (CH), 127.5 (CH), 127.1 (CH), 121.6 (CH), 115.0 (CH), 111.7
(CH), 55.3 (CH3), 41.4 (CH2), 40.0 (CH), 34.9 (CH2), 26.2 (CH2).;
Analytical HPLC: tR ¼ 6.44 min, > 90% purity (214 and 254 nm).;
HRMS: (ESIþ) calc. m/z for [C18H18O2 þ H]þ 267.1380, found
267.1391.
(400 MHz, CDCl3)
d
8.18 (d, J ¼ 2.2 Hz, 1H), 7.55 (dd, J ¼ 8.2, 2.3 Hz,
1H), 7.34e7.30 (m, 2H), 7.27e7.25 (m, 1H), 7.16e7.14 (m, 2H), 7.02
(d, J ¼ 8.3 Hz, 1H), 3.22e3.16 (m, 1H), 3.07 (dd, J ¼ 13.6, 6.4 Hz, 1H),
2.89e2.76 (m, 2H), 2.58 (dt, J ¼ 17.9, 4.9 Hz, 1H), 2.20e2.11 (m, 1H),
1.97 (dq, J ¼ 14.1, 5.0 Hz, 1H).; 13C NMR (100 MHz, CDCl3)
d
196.8
Isolated 19G: White solid (9 mg, 24% yield).; Rf ¼ 0.26 (10% ethyl
(C), 146.0 (C), 139.3 (C), 136.1 (CH), 133.4 (C), 130.4 (CH), 130.3 (CH),
129.0 (CH), 128.6 (CH), 126.6 (CH), 121.1 (C), 41.1 (CH2), 39.6 (CH),
34.4 (CH2), 26.1 (CH2).; Analytical HPLC: tR ¼ 7.49 min, > 99%
acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
d 7.86 (d,
J ¼ 8.6 Hz, 1H), 7.33e7.28 (m, 2H), 7.25e7.21 (m, 1H), 7.18e7.15 (m,
2H), 6.86 (dd, J ¼ 8.7, 2.6 Hz,1H), 6.60 (d, J ¼ 2.5 Hz,1H), 3.82 (s, 3H),
3.24e3.15 (m, 3H), 2.97 (ddd, J ¼ 16.7, 9.8, 3.2 Hz, 1H), 2.74 (ddd,
J ¼ 16.7, 8.4, 2.7 Hz, 1H), 2.22e2.14 (m, 1H), 2.01e1.92 (m, 1H).; 13C
purity (214 and 254 nm).; HRMS: (APCIþ) calc. m/z for
79
[C
H
17 15
BrO þ H]þ 315.0379, found 315.0378.
Isolated 19E: Yellow oil (6 mg, 8% yield).; Rf ¼ 0.22 (5% ethyl
NMR (100 MHz, CDCl3) d 203.8 (C), 162.8 (C), 146.2 (C), 142.6 (C),
acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
d
7.79 (dd,
131.5 (C), 131.5 (CH), 128.7 (CH), 127.3 (CH), 126.7 (CH), 116.0 (CH),
112.3 (CH), 55.5 (CH3), 42.9 (CH), 40.4 (CH2), 40.2 (CH2), 29.1 (CH2).;
Analytical HPLC: tR ¼ 6.44 min, > 80% purity (214 and 254 nm).;
HRMS: (ESIþ) calc. m/z for [C18H18O2 þ H]þ 267.1380, found
267.1388.
J ¼ 7.6, 1.6 Hz, 1H), 7.45e7.34 (m, 4H), 7.06 (dd, J ¼ 7.5, 0.7 Hz, 1H),
7.01 (d, J ¼ 8.4 Hz, 2H), 3.27e3.16 (m, 2H), 3.09 (dd, J ¼ 13.7, 5.9 Hz,
1H), 2.95 (ddd, J ¼ 17.1, 9.1, 3.0 Hz,1H), 2.75 (ddd, J ¼ 17.1, 9.1, 2.8 Hz,
1H), 2.21e2.12 (m, 1H), 1.95e1.86 (m, 1H).; 13C NMR (100 MHz,
CDCl3)
d 205.5 (C), 144.9 (C), 139.0 (C), 138.8 (C), 132.5 (CH), 131.8
(CH), 130.8 (CH), 129.1 (CH), 128.9 (CH), 127.3 (CH), 120.4 (C), 42.4
(CH), 40.3 (CH2), 39.6 (CH2), 28.9 (CH2).; Analytical HPLC:
4.2.58. 4-(3,4-Dimethoxybenzyl)-3,4-dihydronaphthalen-1(2H)-
one (18H) & 2,3-dimethoxy-8-phenyl-6,7,8,9-tetrahydro-5H-benzo
[7]annulen-5-one (19H) (30:70)
4.2.58.1. General procedure VI. Mixture of 18H and 19H: Yellow oil
(7:3, 16 mg, 34% yield).; Rf ¼ 0.36 (20% ethyl acetate in petroleum
ether).
tR ¼ 7.33 min, > 99% purity (214 and 254 nm). HRMS: (ESIþ) calc. m/
79
z for [C
H
BrO þ H]þ 315.0379, found 315.0365.
17 15
4.2.56. 4-Benzyl-5-fluoro-3,4-dihydronaphthalen-1(2H)-one (18F)
& 8-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-
one (19F) (80:20)
18H: 1H NMR (400 MHz, CDCl3)
d
8.06 (dd, J ¼ 7.8, 1.5 Hz, 1H),
7.47e7.43 (m, 1H), 7.33e7.28 (m, 1H), 7.16e7.14 (m, 1H), 6.82 (d,
J ¼ 8.1 Hz, 1H), 6.71 (dd, J ¼ 7.6, 1.5 Hz, 1H), 6.61 (d, J ¼ 1.9 Hz, 1H),
3.88 (s, 3H), 3.83 (s, 3H), 3.25e3.12 (m, 1H), 3.07e2.95 (m, 1H),
2.86e2.73 (m, 2H), 2.59 (dt, J ¼ 9.4, 4.9 Hz, 1H), 2.23e2.17 (m, 1H),
2.01e1.93 (m, 1H).
4.2.56.1. General procedure VI. Isolated 18F: Clear oil (32 mg, 21%
yield).; Rf ¼ 0.66 (25% ethyl acetate in petroleum ether).; 1H NMR
(400 MHz, CDCl3)
d
7.87 (dd, J ¼ 7.7, 1.4 Hz, 1H), 7.37e7.31 (m, 3H),
7.30e7.19 (m, 4H), 3.56e3.53 (m, 1H), 3.09 (dd, J ¼ 13.7, 4.5 Hz, 1H),
2.90e2.79 (m, 2H), 2.59 (ddd, J ¼ 17.9, 4.0, 2.8 Hz,1H), 2.12e1.96 (m,
19H: 1H NMR (400 MHz, CDCl3)
d 7.44 (s, 1H), 7.32e7.28 (m, 2H),
2H).; 13C NMR (100 MHz, CDCl3)
d
197.3 (C), 160.2 (d, J ¼ 246 Hz, C),
7.25e7.20 (m, 1H), 7.16e7.13 (m, 2H), 6.54 (s, 1H), 3.94 (s, 3H), 3.86
(s, 3H), 3.24e3.12 (m, 3H), 2.98 (ddd, J ¼ 16.5, 9.7, 3.2 Hz, 1H), 2.76
(ddd, J ¼ 16.5, 8.5, 2.7 Hz, 1H), 2.23e2.15 (m, 1H), 2.01e1.90 (m, 1H).
139.8 (C), 134.9 (C), 133.7 (C), 129.1 (CH), 128.7 (CH), 127.9 (d,
J ¼ 8.2 Hz, CH), 126.7 (CH), 123.1 (d, J ¼ 3.4 Hz, CH), 120.4 (d,
J ¼ 22.3 Hz, CH), 39.0 (CH2), 33.4 (CH2), 33.2 (CH), 23.9 (CH2).;
Analytical HPLC: tR ¼ 6.75 min, > 95% purity (214 and 254 nm).;
HRMS: (ESIþ) calc. m/z for [C17H15FO þ H]þ 255.1180, found
255.1180.
4.2.59. 8-(2-Fluorophenyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5H-
benzo[7]annulen-5-one (19I)
General procedure VI e Clear oil (23 mg, 59% yield).; Rf ¼ 0.24
Isolated 19F: Clear oil (6 mg, 4% yield).; Rf ¼ 0.58 (25% ethyl
(20% ethyl acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
d
7.80 (dd,
d 7.44 (s, 1H), 7.23e7.17 (m, 1H), 7.10e7.02 (m, 3H), 6.54 (s, 1H), 3.93
J ¼ 7.6,1.6 Hz,1H), 7.42 (td, J ¼ 7.4,1.6 Hz,1H), 7.35 (td. J ¼ 7.5,1.4 Hz,
1H), 7.24e7.19 (m, 1H), 7.11e7.03 (m, 4H), 3.60e3.53 (m, 1H),
3.22e3.20 (m, 2H), 2.99 (ddd, J ¼ 16.8, 9.7, 3.3 Hz, 1H), 2.79 (ddd,
J ¼ 16.8, 8.4, 2.9 Hz, 1H), 2.20e2.12 (m, 1H), 2.04e1.95 (m, 1H).; 13C
(s, 3H), 3.86 (s, 3H), 3.57e3.50 (m, 1H), 3.23e3.12 (m, 2H), 3.00
(ddd, J ¼ 16.3, 10.1, 3.4 Hz, 1H), 2.78 (ddd, J ¼ 16.3, 8.0, 2.8 Hz, 1H),
2.20e2.12 (m, 1H), 2.01e1.92 (m, 1H).; 13C NMR (100 MHz, CDCl3)
d
203.2 (C), 160.4 (d, J ¼ 245.2 Hz, C), 152.3 (C), 147.9 (C), 135.0 (C),
NMR (100 MHz, CDCl3)
d
205.5 (C),160.5 (d, J ¼ 245 Hz, C),139.7 (C),
132.7 (d, J ¼ 14.5 Hz, C), 130.7 (C), 128.2 (d, J ¼ 4.7 Hz, CH), 128.0 (d,
J ¼ 8.4 Hz, CH), 124.2 (d, J ¼ 3.4 Hz, CH), 115.7 (d, J ¼ 22.9 Hz, CH),
113.2 (CH), 111.5 (CH), 56.2 (CH3), 56.4 (CH3), 40.5 (CH2), 38.8 (CH2),
35.6 (d, J ¼ 2.0 Hz, CH), 27.5 (CH2).; Analytical HPLC: tR ¼ 6.25 min,
> 95% purity (214 and 254 nm).; HRMS: (ESIþ) calc. m/z for
[C19H19FO3 þ H]þ 315.1391, found 315.1403.
138.8 (C), 132.6 (d, J ¼ 14.3 Hz, C), 132.4 (CH), 130.7 (CH), 128.9 (CH),
128.1 (d, J ¼ 2.3 Hz, CH), 128.0 (d, J ¼ 1.3 Hz, CH), 127.2 (CH), 124.2
(d, J ¼ 3.6 Hz, CH), 115.7 (d, J ¼ 22.8 Hz, CH), 40.4 (CH2), 38.7 (d,
J ¼ 1.3 Hz, CH2), 35.5 (d, J ¼ 2.1 Hz, CH), 27.6 (CH2).; Analytical
HPLC: tR ¼ 6.55 min, > 70% purity (214 and 254 nm). HRMS: (ESIþ)
calc. m/z for [C17H15FO þ H]þ 255.1180, found 255.1185.
Co-eluted mixture of 18F and 19F: Clear oil (4:1, 52 mg, 34%
yield).
4.2.60. 8-(4-Fluorophenyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5H-
benzo[7]annulen-5-one (19J)
General procedure VI e White gum (14 mg, 75% yield).;
4.2.57. 4-(3-Methoxybenzyl)-3,4-dihydronaphthalen-1(2H)-one
(18G) & 2-methoxy-8-phenyl-6,7,8,9-tetrahydro-5H-benzo[7]
annulen-5-one (19G) (30:70)
Rf ¼ 0.15 (20% ethyl acetate in petroleum ether).; 1H NMR
(400 MHz, CDCl3)
d
7.43 (s, 1H), 7.08 (dd, J ¼ 8.7, 5.4 Hz, 2H), 6.97 (t,
J ¼ 8.7 Hz, 2H), 6.51 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.24e3.16 (m,
2H), 3.08e3.02 (m, 1H), 2.96 (ddd, J ¼ 16.6, 9.4, 3.1 Hz, 1H), 2.75
(ddd, J ¼ 16.6, 8.9, 2.6 Hz, 1H), 2.22e2.13 (m, 1H), 1.93e1.84 (m,
4.2.57.1. General procedure VI. Isolated 18G: Clear oil (3 mg, 7%
yield).; Rf ¼ 0.34 (10% ethyl acetate in petroleum ether).; 1H NMR
(400 MHz, CDCl3)
1.5 Hz, 1H), 7.36e7.33 (m, 1H), 7.24e7.20 (m, 2H), 6.81e6.77 (m,
d
8.06 (dd, J ¼ 7.9, 1.5 Hz, 1H), 7.47 (td, J ¼ 7.5,
1H).; 13C NMR (100 MHz, CDCl3)
C), 152.3 (C), 147.9 (C), 141.9 (d, J ¼ 3.2 Hz, C), 134.4 (C), 130.7 (C),
d
203.5 (C), 161.6 (d, J ¼ 244.6 Hz,
10

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
128.7 (d, J ¼ 7.8 Hz, CH), 115.4 (d, J ¼ 21.1 Hz, CH), 113.4 (CH), 111.5
(CH), 56.2 (CH3), 56.2 (CH3), 42.4 (CH), 40.5 (CH2), 40.0 (CH2), 29.1
(CH2).; Analytical HPLC: tR ¼ 6.49 min, > 99% purity (214 and
254 nm).; HRMS: (ESIþ) calc. m/z for [C19H19FO3 þ H]þ 315.1391,
found 315.1394.
4.2.65. 8-(3-Nitrophenyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-
5-one (19O)
General procedure VI e Yellow oil (14 mg, 44% yield).; Rf ¼ 0.18
(15% ethyl acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
d
8.12e8.09 (m, 1H), 8.04e8.03 (m, 1H), 7.82 (dd, J ¼ 7.7, 1.5 Hz, 1H),
7.50e7.43 (m, 3H), 7.39 (td, J ¼ 7.5, 1.4 Hz, 1H), 7.07e7.05 (m, 1H),
3.40e3.30 (m, 2H), 3.18e3.13 (m, 1H), 2.99 (ddd, J ¼ 17.1, 9.0, 3.0 Hz,
1H), 2.80 (ddd, J ¼ 17.1, 9.3, 2.8 Hz, 1H), 2.28e2.20 (m, 1H), 1.97 (dtd,
4.2.61. 8-(4-Bromophenyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5H-
benzo[7]annulen-5-one (19K)
General procedure VI e White powder (16 mg, 56% yield).;
J ¼ 14.4, 9.4, 3.0 Hz, 1H).; 13C NMR (100 MHz, CDCl3)
d 205.0 (C),
Rf ¼ 0.23 (20% ethyl acetate in petroleum ether).; 1H NMR
147.9 (C), 138.7 (C), 138.3 (C), 133.6 (CH), 132.7 (CH), 130.7 (CH),
129.7 (CH), 129.1 (CH), 127.6 (CH), 122.3 (CH), 121.9 (CH), 42.6 (CH),
40.2 (CH2), 39.3 (CH2), 28.8 (CH2). One quaternary carbon not
observed.; Analytical HPLC: tR ¼ 5.78 min, > 95% purity (214 and
254 nm).; HRMS: (ESIþ) calc. m/z for [C17H15NO3 þ H]þ 282.1125,
found 282.1124.
(400 MHz, CDCl3)
d
7.43 (s, 1H), 7.40 (d, J ¼ 8.5 Hz, 2H), 7.00 (d,
J ¼ 8.4 Hz, 2H), 6.51 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.24e3.13 (m,
2H), 3.05 (dd, J ¼ 13.9, 5.9 Hz, 1H), 2.95 (ddd, J ¼ 16.6, 9.4, 3.0 Hz,
1H), 2.75 (ddd, J ¼ 16.6, 8.9, 2.6 Hz, 1H), 2.17 (dddd, J ¼ 16.8, 9.6, 7.1,
2.6 Hz, 1H), 1.92e1.83 (m, 1H).; 13C NMR (100 MHz, CDCl3)
d 203.3
(C), 152.3 (C), 148.0 (C), 145.2 (C), 134.2 (C), 131.7 (CH), 130.7 (C),
129.1 (CH), 120.4 (C), 113.4 (CH), 111.5 (CH), 56.3 (CH3), 56.2 (CH3),
42.6 (CH), 40.5 (CH2), 39.7 (CH2), 28.9 (CH2).; Analytical HPLC:
4.2.66. 2-Hydroxy-8-phenyl-6,7,8,9-tetrahydro-5H-benzo[7]
annulen-5-one (20)
tR ¼ 6.99 min, > 99% purity (214 and 254 nm).; HRMS: (ESIþ) calc.
To
tetrahydro-5H-benzo[7]annulen-5-one (19N) (40 mg, 116
in toluene (6 mL), was added AlCl3 (70 mg, 525 mol). The reaction
a
solution of 8-(4-bromophenyl)-2-methoxy-6,7,8,9-
79
m/z for [C
H
BrO3 þ H]þ 375.0590, found 375.0595.
mmol)
19 19
m
4.2.62. 2,3-Dimethoxy-8-(4-nitrophenyl)-6,7,8,9-tetrahydro-5H-
benzo[7]annulen-5-one (19L)
mixture was stirred at reflux for 2 h. It was then poured into ice
water (15 mL) and was made acidic with 1 M HCl to pH ~ 2. The
organic phase was collected and washed with brine. The aqueous
phase was further extracted with dichloromethane (2 ꢁ 15 mL). The
two dichloromethane extracts were combined and washed with
brine. The toluene and dichloromethane extracts were combined,
dried over MgSO4 and concentrated in vacuo. The residue was then
purified by column chromatography (25% ethyl acetate in petro-
leum ether) to give the title compound as a brown oil (16 mg, 53%
yield). Rf ¼ 0.21 (25% ethyl acetate in petroleum ether).; 1H NMR
General procedure VI e Beige powder (10 mg, 89% yield).;
Rf ¼ 0.23 (30% ethyl acetate in petroleum ether).; 1H NMR
(400 MHz, CDCl3)
d
8.15 (d, J ¼ 8.8 Hz, 2H), 7.45 (s, 1H), 7.30 (d,
J ¼ 8.7 Hz, 2H), 6.50 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.37e3.26 (m,
2H), 3.09 (dd, J ¼ 14.5, 6.2 Hz, 1H), 2.99 (ddd, J ¼ 16.6, 9.4, 3.0 Hz,
1H), 2.79 (ddd, J ¼ 16.6, 8.9, 2.6 Hz, 1H), 2.27e2.19 (m, 1H),
1.97e1.88 (m, 1H).; 13C NMR (100 MHz, CDCl3)
d 202.8 (C), 153.7 (C),
152.5 (C), 148.2 (C), 146.9 (C), 133.5 (C), 130.7 (C), 128.2 (CH), 124.0
(CH), 113.3 (CH), 111.7 (CH), 56.3 (CH3), 56.2 (CH3), 43.1 (CH), 40.4
(CH2), 39.4 (CH2), 28.7 (CH2).; Analytical HPLC: tR ¼ 6.27 min, >
99% purity (214 and 254 nm).; HRMS: (ESIþ) calc. m/z for
[C19H19NO5 þ H]þ 342.1336, found 342.1337.
(400 MHz, CDCl3)
d
7.81 (d, J ¼ 8.5 Hz, 1H), 7.32e7.28 (m, 2H),
7.24e7.20 (m, 1H), 7.17e7.15 (m, 2H), 6.81 (dd, J ¼ 8.5, 2.5 Hz, 1H),
6.68 (br.s, 1H), 6.58 (d, J ¼ 2.5 Hz, 1H), 3.23e3.09 (m, 3H), 2.97 (ddd,
J ¼ 16.7, 9.8, 3.1 Hz, 1H), 2.74 (ddd, J ¼ 16.8, 8.5, 2.7 Hz, 1H), 2.17
(dddd, J ¼ 14.4, 9.6, 6.8, 2.7 Hz, 1H), 2.00e1.91 (m, 1H).; 13C NMR
4.2.63. 2,3-Dimethoxy-8-(4-methoxyphenyl)-6,7,8,9-tetrahydro-
5H-benzo[7]annulen-5-one (19M)
(100 MHz, CDCl3) d 204.9 (C), 160.0 (C), 146.0 (C), 143.3 (C), 131.9
(CH), 131.1 (C), 128.7 (CH), 127.2 (CH), 126.7 (CH), 117.5 (CH), 114.3
(CH), 42.8 (CH), 40.4 (CH2), 40.0 (CH2), 29.1 (CH2).; Analytical
HPLC: tR ¼ 5.18 min, > 95% purity (214 and 254 nm).; HRMS: (ESIþ)
calc. m/z for [C17H16O2 þ H]þ 253.1223, found 253.1229.
General procedure VI e White gum (5 mg, 39% yield).; Rf ¼ 0.58
(30% ethyl acetate in petroleum ether).; 1H NMR (400 MHz, CDCl3)
d
7.43 (s, 1H), 7.06 (d, J ¼ 8.7 Hz, 2H), 6.83 (d, J ¼ 8.8 Hz, 2H), 6.53 (s,
1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.79 (s, 3H, 3.22e3.05 (m, 3H), 2.96
(ddd, J ¼ 16.6, 9.5, 3.0 Hz, 1H), 2.74 (ddd, J ¼ 16.6, 8.7, 2.6 Hz, 1H),
2.16 (dddd, J ¼ 16.8, 9.6, 7.1, 2.6 Hz,1H), 1.94e1.85 (m, 1H).; 13C NMR
4.2.67. 8-(4-Bromophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]
annulen-2-yl trifluoromethanesulfonate (21)
(100 MHz, CDCl3)
d
203.8 (C), 158.3 (C), 138.4 (C), 134.9 (C), 130.8
To
tetrahydro-5H-benzo[7]annulen-5-one (20) (15 mg, 59
dichloromethane (4 mL), was added diisopropylethylamine (21 mg,
28 L, 178 mol) and N-phenyl-bis(trifluoromethanesulfonimide)
(21 mg, 59 mol). The reaction mixture stirred at room temperature
a
solution of 8-(4-bromophenyl)-2-hydroxy-6,7,8,9-
(C), 128.2 (CH), 114.0 (CH), 113.5 (CH), 111.5 (CH), 56.2 (CH3), 56.2
(CH3), 55.4 (CH3), 42.3 (CH), 40.6 (CH2), 40.2 (CH2), 29.2 (CH2). Two
quaternary carbons not observed.; Analytical HPLC: tR ¼ 6.33 min,
> 99% purity (214 and 254 nm).; HRMS: (ESIþ) calc. m/z for
[C20H22O4 þ H]þ 327.1591, found 327.1575.
mmol) in
m
m
m
for 2 h. It was then washed with sat. aq. NaHCO3 (10 mL). The
organic phase was collected and the aqueous phase was further
extracted with dichloromethane (2 ꢁ 10 mL). The organic extracts
were combined, washed with brine, dried over MgSO4 and
concentrated in vacuo to give a brown oil (63 mg). The residue was
carried forward without further purification. Rf ¼ 0.59 (25% ethyl
acetate in petroleum ether).
4.2.64. 8-(4-Bromophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-
benzo[7]annulen-5-one (19N)
General procedure VI e Clear oil (157 mg, 52% yield).; Rf ¼ 0.35
(40% diethyl ether in petroleum ether). 1H NMR (400 MHz, CDCl3)
d
7.85 (d, J ¼ 8.7 Hz, 1H), 7.42 (d, J ¼ 8.5 Hz, 2H), 7.02 (d, J ¼ 8.4 Hz,
2H), 6.86 (dd, J ¼ 8.7, 2.6 Hz,1H), 6.56 (d, J ¼ 2.4 Hz,1H), 3.82 (s, 3H),
3.24e3.15 (m, 2H), 3.11e3.05 (m, 1H), 2.93 (ddd, J ¼ 16.9, 9.4, 3.0 Hz,
1H), 2.73 (ddd, J ¼ 16.9, 8.9, 2.6 Hz, 1H), 2.16 (dddd, J ¼ 14.4, 9.5, 6.8,
4.2.68. 8-Phenyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one
(19A)
2.6 Hz, 1H), 1.94e1.85 (m, 1H).; 13C NMR (100 MHz, CDCl3)
d
203.6
Method 1: A two-neck round bottom flask was charged with a
(C), 162.9 (C), 145.0 (C), 141.9 (C), 131.8 (CH), 131.6 (CH), 131.5 (C),
129.0 (CH), 120.4 (C), 116.1 (CH), 112.4 (CH), 55.6 (CH3), 42.4 (CH),
40.3 (CH2), 40.0 (CH2), 28.9 (CH2).; Analytical HPLC: tR ¼ 6.43 min,
magnetic stir bar and Pd/C 10% w/w (7 mg, 63 mmol). To the flask
was added dichloromethane until all Pd/C was fully immersed. The
flask was evacuated and back-filled with nitrogen. To the flask was
> 96% purity (214 and 254 nm).; HRMS: (ESIþ) calc. m/z for
added
a
solution of 8-(4-bromophenyl)-6,7,8,9-tetrahydro-5H-
mol) in methanol (5 mL).
79
[C
H
BrO2 þ H]þ 345.0485, found 345.0486.
benzo[7]annulen-5-one (19E) (20 mg, 63 m
18 17
11

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
Chem. Biol. Drug Des. 86 (2015) 895e904.
[4] G.R. Dwivedi, H.C. Upadhyay, D.K. Yadav, V. Singh, S.K. Srivastava, F. Khan,
N.S. Darmwal, M.P. Darokar, 4-Hydroxy- -Tetralone and its derivative as drug
The flask was evacuated and back-filled with nitrogen. The
evacuation-back-fill sequence was repeated for an additional 2
times. The flask was then filled with hydrogen. The flask was
evacuated and back-filled with hydrogen for an additional 2 times
and the reaction mixture was stirred vigorously at room tempera-
ture for 2 h. The flask was then evacuated and back-filled with ni-
trogen and the reaction mixture filtered through a pad of Celite,
washed with dichloromethane. The filtrate was then concentrated
in vacuo and the resulting residue was purified by flash column
chromatography (5% ethyl acetate in petroleum ether) to give the
title compound as a clear oil (6 mg, 40% yield).
a
resistance reversal agents in multi drug resistant Escherichia coli, Chem. Biol.
Drug Des. 83 (2014) 482e492.
ꢀ
ꢀ
[5] K. Vukics, T. Fodor, J. Fischer, I. Fellegvari, S. Levai, Improved industrial syn-
thesis of antidepressant, Sertraline. Org. Process Res. Dev. 6 (2002) 82e85.
[6] A.A. Hussein, B. Bozzi, M. Correa, T.L. Capson, T.A. Kursar, P.D. Coley, P.N. Solis,
M.P. Gupta, Bioactive constituents from three vismia species, J. Nat. Prod. 66
(2003) 858e860.
[7] H. Behbehani, K.M. Dawood, T.A. Farghaly, Biological evaluation of benzosu-
berones, Expert Opin. Ther. Pat. 28 (2018) 5e29.
[8] S. Prasad, J. Kaur, P. Roy, N. Kalra, Y. Shukla, Theaflavins induce G2/M arrest by
modulating expression of p21waf1/cip1, cdc25C and cyclin
B in human
prostate carcinoma PC-3 cells, Life Sci. 81 (2007) 1323e1331.
Method 2: To a solution of 8-(4-bromophenyl)-5-oxo-6,7,8,9-
tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate
(21) (60 mg) in DMF (4 mL), was added triphenylphosphine
[9] N.A.R. Hatam, D.A. Whiting, Synthesis, conformation, and chirality of di-O-
methylsequirin D, a biogenetically novel metabolite of Sequoia sempervirens,
J. Chem. Soc., Perkin Trans. 1 (1982) 461e465.
[10] M.P. Reddy, G.S.K. Rao, Synthesis of 5-p-hydroxybenzyl-5,6-dihydro-2-
naphthol, ( )-sequirin D, J. Chem. Soc., Perkin Trans. 1 (1981) 2662e2665.
[11] G. Baddeley, D. Voss, The mechanism of FriedeleCrafts acylation, J. Chem. Soc.
(1954) 418e422.
(0.7 mg, 2.6
mmol), palladium acetate (1.2 mg, 5.2
mmol), formic acid
(4.8 mg, 4 L,104
m
mmol) and triethylamine (16 mg, 22
m
L,156 mol).
m
The reaction mixture was stirred at 65 ꢀC for 12 h. It was then
diluted with water (10 mL) and ethyl acetate (10 mL). The organic
phase was separated and the aqueous phase was further extracted
(2 ꢁ 10 mL). The organic extracts were combined, washed with
brine, dried over MgSO4 and concentrated in vacuo. The residue was
then purified by column chromatography (5% ethyl acetate in pe-
troleum ether) to give the title compound as a clear oil (8.2 mg, 58%
yield over two steps).
ꢀ
[12] J. Feixas, J.-M. Jimenez, N. Godessart, C. Puig, L.d. Soca, M.a.I. Crespo, Naph-
thalene derivatives: a new series of selective cyclooxygenase-2 inhibitors,
Biorg. Med. Chem. Lett. 11 (2001) 2687e2690.
[13] K. Hino, Y. Nagai, H. Uno, Agents acting on the central nervous system. Syn-
thesis
of
3-Phenyl-2-piperazinyl-1-benzazocines,
3-Substituted-2-
piperazinyl-1-benzazepines and related compounds, Chem. Pharm. Bull.
(Tokyo) 36 (1988) 2386e2400.
[14] E.V. Beletskiy, C. Sudheer, C.J. Douglas, Cooperative catalysis approach to
intramolecular hydroacylation, J. Org. Chem. 77 (2012) 5884e5893.
[15] W.G. Kofron, US Patent, Process for Preparation of Diphenyl Alkanoic Acids,
vol. 3, 1968, p. 412, 146.
Rf ¼ 0.18 (5% ethyl acetate in petroleum ether).; 1H NMR
ꢀ
ꢀ
(400 MHz, CDCl3)
d
7.80 (dd, J ¼ 7.6, 1.5 Hz, 1H), 7.42 (td, J ¼ 7.4,
[16] K. Monostory, V. Tamasi, L. Vereczkey, P. Perjesi, A study on CYP1A inhibitory
action of E-2-(40-methoxybenzylidene)-1-benzosuberone and some related
chalcones and cyclic chalcone analogues, Toxicology 184 (2003) 203e210.
[17] T.A. Farghaly, N.A. Abdel Hafez, E.A. Ragab, H.M. Awad, M.M. Abdalla, Syn-
thesis, anti-HCV, antioxidant, and peroxynitrite inhibitory activity of fused
benzosuberone derivatives, Eur. J. Med. Chem. 45 (2010) 492e500.
[18] I.T. Forbes, D.G. Cooper, E.K. Dodds, S.E. Douglas, A.D. Gribble, R.J. Ife,
A.P. Lightfoot, M. Meeson, L.P. Campbell, T. Coleman, G.J. Riley, D.R. Thomas,
Identification of a novel series of selective 5-HT7 receptor antagonists, Bioorg.
Med. Chem. Lett 13 (2003) 1055e1058.
1.6 Hz,1H), 7.36 (td, J ¼ 7.5, 1.3 Hz,1H), 7.34e7.29 (m, 2H), 7.25e7.21
(m, 1H), 7.17e7.14 (m, 2H), 7.09 (dd, J ¼ 7.4, 0.7 Hz, 1H), 3.27e3.16
(m, 3H), 2.98 (ddd, J ¼ 16.8, 9.4, 3.2 Hz, 1H), 2.77 (ddd, J ¼ 16.9, 8.8,
2.9 Hz, 1H), 2.23e2.14 (m, 1H), 2.02e1.93 (m, 1H).; 13C NMR
(100 MHz, CDCl3)
d 205.8 (C), 146.1 (C), 139.7 (C), 138.8 (C), 132.4
(CH), 130.8 (CH), 128.8 (CH), 128.7 (CH), 127.3 (CH), 127.2 (CH), 126.7
(CH), 43.0 (CH), 40.5 (CH2), 39.8 (CH2), 29.2 (CH2).; Analytical
HPLC: tR ¼ 6.71 min, > 99% purity (214 and 254 nm).; HRMS:
(APCIþ) calc. m/z for [C17H16O þ H]þ 237.1274, found 237.1267.
[19] G. Luo, L. Chen, C.M. Conway, R. Denton, D. Keavy, L. Signor, W. Kostich,
K.A. Lentz, K.S. Santone, R. Schartman, M. Browning, G. Tong, J.G. Houston,
G.M. Dubowchik, J.E. Macor, Discovery of (5S,6S,9R)-5-Amino-6-(2,3-
difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-
2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-
927711): an oral calcitonin gene-related peptide (CGRP) antagonist in clinical
trials for treating migraine, J. Med. Chem. 55 (2012) 10644e10651.
[20] T. Das, A. Chakraborty, A. Sarkar, Palladium catalyzed addition of arylboronic
acid or indole to nitriles: synthesis of aryl ketones, Tetrahedron Lett. 55 (2014)
7198e7202.
Notes
The authors declare no competing financial interests.
Declaration of competing interest
[21] D.N. Kursanov, Z.N. Parnes, G.I. Bassova, N.M. Loim, V.I. Zdanovich, Ionic hy-
drogenation of the ethylene bond and the double bond of the carbonyl group,
Tetrahedron 23 (1967) 2235e2242.
[22] C.K. Rhee, J.H. Kim, B.-C. Sub, M.X. Xiang, Y.S. Youn, W.Y. Bang, E. Kim,
J.K. Shin, Y. Lee, Synthesis and biological studies of catechol ether type de-
rivatives as potential phosphodiesterase (PDE) IV inhibitors, Arch Pharm. Res.
(Seoul) 22 (1999) 202.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[23] R.T. Cameron, R.G. Coleman, J.P. Day, K.C. Yalla, M.D. Houslay, D.R. Adams,
B.K. Shoichet, G.S. Baillie, Chemical informatics uncovers a new role for
moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4), Biochem.
Pharmacol. 85 (2013) 1297e1305.
[24] Y. Ding, W. Zhang, H. Li, Y. Meng, T. Zhang, Q.-Y. Chen, C. Zhu, Metal-free
synthesis of ketones by visible-light induced aerobic oxidative radical addi-
tion of aryl hydrazines to alkenes, Green Chem. 19 (2017) 2941e2944.
[25] B. Landers, C. Berini, C. Wang, O. Navarro, N-heterocyclic carbene)-Pd-
catalyzed anaerobic oxidation of secondary alcohols and domino
OxidationꢂArylation reactions, J. Org. Chem. 76 (2011) 1390e1397.
[26] C.M. Zinser, K.G. Warren, F. Nahra, A. Al-Majid, A. Barakat, M.S. Islam,
S.P. Nolan, C.S.J. Cazin, Palladate precatalysts for the formation of CeN and
CeC bonds, Organometallics 38 (2019) 2812e2817.
Acknowledgements
Daniel Truong is a recipient of an RTP scholarship from the
Australian Government. Brittany Howard was a recipient of an
Australian Post-graduate Award.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2021.132034.
[27] F. Hu, J. Yang, Y. Xia, C. Ma, H. Xia, Y. Zhang, J. Wang, Catalyst-free cross-
coupling of N-tosylhydrazones with chromium(0) Fischer carbene com-
plexes:
1450e1456.
a
new approach to diarylethanone, Org. Chem. Front.
2
(2015)
References
[28] I. Astarloa, R. SanMartin, M.T. Herrero, E. Domínguez, Aqueous
a-arylation of
mono- and diarylethanone enolates at low catalyst loading, Adv. Synth. Catal.
360 (2018) 1711e1718.
[29] K. Huang, G. Li, W.-P. Huang, D.-G. Yu, Z.-J. Shi, Arylation of a-pivaloxyl ke-
tones with arylboronic reagents via Ni-catalyzed sp3 CeO activation, Chem.
Commun. 47 (2011) 7224e7226.
[30] C.-K. Chan, Y.-C. Chen, Y.-L. Chen, M.-Y. Chang, Synthesis of substituted phe-
nanthrofurans, Tetrahedron 71 (2015) 9187e9195.
[1] H. Heaney, 3.3 The intramolecular aromatic FriedeleCrafts reaction, in:
B.M. Trost, I. Fleming (Eds.), Comprehensive Organic Synthesis, Pergamon,
Oxford, 1991, pp. 753e768.
[2] R.D. Robson, H.R. Kaplan, The cardiovascular pharmacology of bunolol, a new
beta adrenergic blocking agent, J. Pharmacol. Exp. Therapeut. 175 (1970) 157.
[3] L.J. Legoabe, A. Petzer, J.P. Petzer, The synthesis and evaluation of C7-
substituted
a-tetralone derivatives as inhibitors of monoamine oxidase,
12

D. Truong, B.L. Howard and P.E. Thompson
Tetrahedron 85 (2021) 132034
[31] I. Moreno, I. Tellitu, E. Domínguez, R. SanMartín, A simple route to new
phenanthro- and phenanthroid-fused thiazoles by a PIFA-mediated (Hetero)
biaryl coupling reaction, Eur. J. Org Chem. 2002 (2002) 2126e2135.
[32] M. Bu, T.F. Niu, C. Cai, Visible-light-mediated oxidative arylation of vinyl-
arenes under aerobic conditions, Catal. Sci. Technol. 5 (2015) 830e834.
[33] M. Brown, R. Kumar, J. Rehbein, T. Wirth, Enantioselective oxidative
rearrangements with chiral hypervalent iodine reagents, Chem. Eur J. 22
(2016) 4030e4035.
[34] C. Tyllick, M.F. El-Zohry, M. Li, R.M. Roberts, Cyclialkylation studies. 1. A
practical synthetic approach to the 2,3:6,7-dibenzobicyclo[3.2.2]nona-2,6-
diene system, J. Org. Chem. 56 (1991) 2938e2940.
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