Reinvestigation of synthesis of halo-substituted 3-phenyl-1-(2-pyridyl)-2-propen-1-ones (azachalcones). A tandem reaction for formation of penta-substituted cyclohexanols

Article abstract of DOI:10.1016/j.tet.2017.06.033

A systematic study of the synthesis of halo-substituted azachalcones was conducted. During the reaction course, we obtained not only the target azachalcones, but also penta-substituted cyclohexanols, which are seldom reported in the literatures. The forma

Full text of DOI:10.1016/j.tet.2017.06.033

Accepted Manuscript
Reinvestigation of synthesis of halo-substituted 3-phenyl-1-(2-pyridyl)-2-propen-1-
ones (azachalcones). A tandem reaction for formation of penta-substituted
cyclohexanols
Chia-Wai Li, Tzu-Hsuan Shen, Tzenge-Lien Shih
PII:
S0040-4020(17)30666-X
10.1016/j.tet.2017.06.033
TET 28798
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 February 2017
Revised Date: 15 June 2017
Accepted Date: 19 June 2017
Please cite this article as: Li C-W, Shen T-H, Shih T-L, Reinvestigation of synthesis of halo-substituted
3-phenyl-1-(2-pyridyl)-2-propen-1-ones (azachalcones). A tandem reaction for formation of penta-
substituted cyclohexanols, Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.033.
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Reinvestigation of synthesis of halo-substituted 3-
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phenyl-1-(2-pyridyl)-2-propen-1-ones (azachalcones).
A tandem reaction for formation of penta-substituted
cyclohexanols
Chia-Wai Li, Tzu-Hsuan Shen and Tzenge-Lien Shih*
Department of Chemistry, Tamkang University, 25137 Tamsui Dist., New Taipei City, Taiwan, Republic of China

1
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Tetrahedron
journal homepage: www.elsevier.com
Reinvestigation of synthesis of halo-substituted 3-phenyl-1-(2-pyridyl)-2-propen-
1-ones (azachalcones). A tandem reaction for formation of penta-substituted
cyclohexanols
Chia-Wai Li, Tzu-Hsuan Shen and Tzenge-Lien Shih*
Department of Chemistry, Tamkang University, 25137 Tamsui Dist., New Taipei City, Taiwan, Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A systematic study of the synthesis of halo-substituted azachalcones was conducted. During the
reaction course, we obtained not only the target azachalcones, but also penta-substituted
cyclohexanols, which are seldom reported in the literatures. The formation of penta-substituted
cyclohexanols was dependent on equivalents of base used and reaction time. Their formation
followed a tandem reaction: Claisen-Schmidt condensation, three Michael reactions, retro-aldol
reaction, and intramolecular aldol cyclization.
Available online
Keywords:
azachalcone, chalcone, Claisen-Schmidt
condensation, Michael reaction, retro-aldol reaction,
tandem reaction.
biological properties similar to those of chalcones.6 Further, they
have been used in studies of asymmetric Diels-Alder reactions.7
1. Introduction
Chalcones are precursors in the synthesis of flavonoids and
are found pervasively in natural plants. They exhibit a wide
variety of biological activity such as antibacterial1, antifungal1b,
antimalarial2, antioxidant3, antitumor4 and antiinflammatory5
properties. Chalcones possess a 1,3-diphenyl-2E-propene-1-one
framework (Figure 1). The most common and widely used
strategy in synthesis of chalcones or their analogues is Claisen-
Schmidt condensation.
The target azachalcones synthesized in this article are from 2-
acetylpyridine with a series of halobenzaldehydes under Claisen-
Schmidt condensation. We obtained not only the target
azachalcones but also unexpected products. These unexpected
products were later confirmed to be unusual penta-substituted
cyclohexanols by NMR experiments or X-ray analysis. There
have been very few reports that mention these cyclohexanol
derivatives.8 In order to clarify their formation, herein we
reinvestigate their syntheses and discuss their formation
mechanism.
Another non-naturally occurring chalcone-like family is the
azachalcones in which annular carbons in either the A or B ring
are replaced by nitrogen atom(s) (Figure 1). Azachalcones exhibit
Figure 1 Representative structures of chalcone and C-2 azachalcone
O
OH
2
O
2
2'
B
2'
B
N
A
3'
4'
3'
4'
A
Azachaclone
Chaclone

2
Tetrahedron
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2. Results and discussion
penta-substituted cyclohexanol 4a was well-resolved by NMR
spectroscopy. Normally, an equatorial hydrogen is more
deshielding than a gemenial axial hydrogen in cyclohexane.
However, the opposite result was observed for H5a and H5e of 4a
(Figure 2), which was probably due to the equatorial hydrogen
being in a shielding position on an aromatic ring. Also, the
NOESY spectrum observed between H3 and H5a was as indicated
in Figure 2. The structure of compound 4a was further confirmed
by X-ray crystallography12 (Figure 3). We conclude from Table 1
that higher concentrations of base and shorter reaction times
produced the target azachalcones at moderate yields (entries
3, 5, 7). Once the reaction time was extended to 4-5h, the yields
of isolated azachalcones dropped dramatically, and the penta-
substituted 4a-c were isolated as major products (Table 1, entries
6, 8).
We synthesized a series of B-ring halo-substituted chalcones
for evaluation of their biological activity.9 The synthesis of
azachalcones using Claisen-Schmidt condensation6a,7d,e,8,10,11
(Scheme 1) can be carried out either under catalytic conditions8,11
or in the presence of a slightly excess amount of base (1−3
equivalent of NaOH or KOH).6a,10 Either MeOH or EtOH was
used as a solvent. Reaction temperature was kept either at 0 to 10
oC for 2−5h7d,e,10d,e or at room temperature overnight.6a,10b,c Some
reports describe procedures but without providing yields6a,10
﹔
others describe procedure whereby the expected azachalcones are
obtained at moderate10f to high yields.7d,e,11
We tried to replicate the above-mentioned conditions using
stoichiometric amounts of base﹔however, we were not able to
obtain the expected azachalcones at as high yields as described.
Only moderate to low yields were obtained. We therefore
carefully surveyed the amounts of base used in the reaction.
Initially, the mixture concentration was 0.35M based on 1 in
EtOH and an aqueous 8M KOH solution (1 equivalent) was used
as a base (Table 1, entry 1). Reaction completed within an hour
and compounds 3a-c were obtained at moderate to low yields.
We observed longer reaction times to result in much lower yields
of 3a-c (Table 1, entry 2). When two equivalents of base were
used, not only chalcone 3a but also an unexpected penta-
substituted cyclohexanol 4a were obtained (Table 1, entry 3). A
structure similar to that of 4a has been reported as a side product
at a low yield (8%) or as a major product during the preparation
of 4'-p-Tolyl-2,2':6',2”-terpyridine.8a However, neither detailed
mechanisms nor procedures have been explicitly described. This
A plausible mechanism for the formation 4a is depicted in
Figure 4. Its formation involved tandem Claisen-Schmidt
condensation, three Michael reactions (3a−7), a retro-aldol
reaction (8) and an intramolecular aldol reaction (9).
During the prolonged reaction course, we observed gradually
increasing amounts of a polar mixture once the target chalcones
were formed (Table 1, vide infra Tables 2 and 3). This polar
mixture was purified by column chromatography to isolate 4a-h
along with a complex mixture that could not be identified. The
unidentified complex mixture was assumed to be a combination
of incomplete Michael reaction and uncyclized products which
resulted in the low yields of 3a-i as well as 4a-h. We do not
exclude the possibility of the formation of 4’a-i8a (Figure 2),
however, we were not able to isolate any of these compounds.
Scheme 1. Synthesis of azachaclones 3a-i and penta-substituted cyclohexanols 4a-h.
Table 1. Synthesis of 4’-haloazachaclones 3a-c and penta-substituted cyclohexanols 4a-c
Entry
KOH (eq)
3a:4a (%)
Time
3b:4b (%)
Time
3c:4c (%)
Time
1
2
3
4
5
6
7
8
1
1
2
2
4
4
6
6
51:0a
35:0
57:1a
22:3
50:9a
9:9
30 min
4 h
35:0a
19:0
43:2a
21:5
44:4a
0:13
41:4a
0:11
45 min
5 h
32:0a
1 h
5 h
12:0
35 min
4 h
40 min
5 h
15:6a
4:12
15:3a
75 min
5 h
15 min
4 h
20 min
5 h
45 min
5 h
0:23
54:4a
15 min
4 h
15 min
5 h
37:20a
0:18
15 min
5 h
0:6
a
Isolated yields all based on the complete consumption of 1.

3
Figure 2 Stereochemistry confirmation by NOESY
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Figure 3 Structure of 4a obtained by X-ray diffraction analysis
* Table Correlating NMR and X-ray carbon numbers
NMR C1 C2 C3 C4 C5 C6
X-ray =C(2) =C(1) =C(6) =C(5) =C(4) =C(3)
The same conditions were applied to synthesis of 3’-
haloazachalcones (Table 2). With one equivalent of base and
relatively short times, compounds 3d-f were obtained at
moderate to low yields (entry 1). No penta-substituted
cyclohexanols were obtained with longer reaction times except 4f
(entry 2). When two or more equivalents of base were used,
yields of 3d-f decreased and 4d-f increased with longer reaction
times (entry 3−8). The results show a similar to that trend in
Table 1.
We also studied the 2’-haloazachalcones’ synthesis (Table 3).
Our observations were consistent with the trends shown in Tables
1 and 2. Yields of 4g and 4h increased under extended reaction
times with 2, 4, and 6 equivalents base used (entries 4, 6, 8). No
penta-substituted cyclohexanol derivative 4i was formed from
condensation between 1 and 2i even when six equivalents of base
were used, probably owing to the larger atom size of bromine in
the vicinity of the reaction center restricting cyclization.

4
Tetrahedron
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Figure 4 Plausible mechanism for formation, for example, of penta-substituted cyclohexanol 4a
Table 2. Synthesis of 3’-haloazachalcones 3d-f and penta-substituted cyclohexanols 4d-f
Entry
KOH (eq)
3d:4d (%)
Time
3e:4e (%)
Time
3f:4f (%)
Time
1
2
3
4
5
6
7
8
1
1
2
2
4
4
6
6
28:0a
12:0
25:2a
0:13
37:5a
0:16
17:4a
0:9
100 min
8 h
46:0a
30 min
3 h
46:0a
24:10
52:0a
0:18
20 min
5 h
43:0
1 h
44:0a
36:6
27:2a
21:14
36:1a
10:10
45 min
3 h
40 min
5 h
7 h
20 min
6 h
20 min
3 h
48:2a
10 min
5 h
0:30
20 min
6 h
30 min
3 h
44:1a
0:26
5 min
5 h
a
Isolated yields all based on the complete consumption of 1
Table 3. Synthesis of 2’-haloazachaclones 3g-i and penta-substituted cyclohexanols 4g,h
Entry
KOH (eq)
3g:4g (%)
Time
3h:4h (%)
Time
3i:4i (%)
Time
1
2
3
4
5
6
7
8
1
1
2
2
4
4
6
6
35:0a
45 min
8 h
56:0a
1 h
8 h
41:0a
63:0
51:0a
62:0
54:0a
65:0
50:0a
44:0
20 min
5 h
26:0
38:0
43:6a
21:21
28:4a
19:12
45:4a
15:14
45 min
8 h
58:4a
20:20
42:5a
0:31
50 min
8 h
20 min
5 h
25 min
5 h
15 min
8 h
15 min
5 h
10 min
5 h
47:2a
20 min
8 h
10 min
5 h
0:20
a
Isolated yields all based on the complete consumption of 1.

5
In order to test whether the inductive effect might influence the
but in low yields (6−11%) and its structure was confirmed by x-
ACCEPTED MANUSCRIPT
ray crystallography (Figure 5).13 Apparently penta-substituted
cyclohexanols 4a-h and 12 were inevitable formation under
slightly excess basic conditions but were always in low yields. It
is also noticed that halo-substituted azachalcones 3a-i were
proceeded subsequent Michael reaction faster than that of 11 thus
led to low yields of 3a-i. This might be due to the inductive effect
of halo substituent in increasing the electron deficiency of β-
carbon for accelerating Michael reaction.
formation of penta-substituted cycloheanol, we replaced the para-
halo substituents in B ring with an electron-donating group
(OMe, 10) and reacted under the same conditions as in Scheme 1
(Scheme 2). Compound 11 was received in high yields (87−94%)
once compound 1 was completely reacted (Table 4, entries 1, 4,
7, and 10). Unlike the results in Tables 1−3, the extended reaction
time (4−8 h) did not reduce too much amount of 11, which
received in moderate yields (Table 4, entries 2, 3, 5, 6, 8, 9, 11
and 12). The penta-substituted cyclohexanol 12 was also obtained
Scheme 2. Synthesis of azachaclone 11 and penta-substituted cyclohexanol 12.
Table 4. Synthesis of 4’-methoxyazachaclone 11 and penta-substituted cyclohexanol 12
Entry
1
KOH (eq)
11:12 (%)
Time
10 min
1
94:0a
2
3
4
5
6
7
8
1
1
83:6
68:9
89:0a
4 h
8 h
2
3 min
4 h
2
64:7
2
62:9
94:0a
8 h
4
2 min
4 h
4
79:10
9
4
6
6
6
64:11
8 h
1 min
4 h
8 h
10
11
12
87:0a
64:10
64:11
a
Isolated yields all based on the complete consumption of 1.
Conclusion
Little attention has been paid to the formation of penta-
substituted cyclohexanols during the synthesis of azachalcones
via Claisen-Schmidt condensation under stoichiometric
conditions or in the presence of a slightly excess amount of base.
In our systematic studies, the more equivalents of base and
prolonged reaction times might be needed to obtain the
distinctive structures 4a-h and 12. We also observed that yields
of 4a-h and 12 were not improved even after reaction stirring for
24h. It is clear that compounds 4a-h were obtained from a
tandem reaction of 3a-i once they were formed that ultimately led
to low yields of 3a-i. This same mechanism as in Figure 4 also
occurred during the course in synthesis of 11 and 12. The
differences between Scheme 1 and Scheme 2 were the substituted
groups in B ring as well as the yields of 3a-i and 11. We believe
that more equivalents of base induced this tandem reaction,
resulting in products 4a-h and 12 which may have been neglected
in reports of synthesis of azachalcones owing to their low yields.
These products are distinctive because we do not obtain penta-
substituted cyclohexanols when we synthesize chalcones. Thus
the nitrogen atom at 2-position of A ring must play an important

6
Tetrahedron
directing role of formation of cyclized adducts. This is the first
time that the mechanism of formation of these unique structures
ACCEPTED MANUSCRIPT
4a-h and 12 has been clearly demonstrated.
Figure 5 Structure of 12 obtained by X-ray diffraction analysis
Conflict of interest
recorded on a Bruker 600 spectrometer. Chemical shifts were
reported in ppm and referenced to the residue of solvent: (CDCl3:
7.26 ppm for 1H; 77.0 ppm for 13C). Melting points were
determined on a Fargo MP-2D apparatus and not corrected.
HRMS were recorded on a Finnigan MAT-95S instrument. The
IR spectra were recorded
The authors declare no conflict of interest.
Acknowledgement
on Bruker Tensor 27 in KBr.
We gratefully acknowledge the Ministry of Science and
Technology (MOST 104−2113−M−032−002) and Tamkang
University for supporting this work. We thank Professor Chung-
Hung Hsieh for his assistance on X-ray crystallography.
4.1 General procedure of Claisen-Schmidt condensation
To a stirred solution of 2-acetylpyridine (0.100 mL, 0.108
g, 0.890 mmol), for example, in EtOH (2.5 mL) was added
aqueous 8M KOH (1 to 6 equivalent). This mixture was stirred at
3. Experimental
o
0 C for 10 min, followed by addition of the corresponding
aldehyde (1.5 equivalent) dropwise at the same temperature. The
mixture was gradually warmed up to room temperature until 2-
acetylpyridine was completely consumed according to TLC
All chemicals were purchased from either Alfa or Aldrich
1
and used without purification except where otherwise stated. H
NMR (600 MHz) and 13C NMR (150 MHz) spectra were

7
NMR (150 MHz, CDCl ) δ 189.3, 163.1 (1J = 244.5 Hz),
analysis. At the end of the reaction time, the mixture was
ACCEPTED MANUSCRIPT
3
C-F
153.9, 148.9, 143.1, 137.4 (3JC-F = 7.5 Hz), 137.0, 130.3 (4JC-F
=
quenched by 2N HCl, diluted with H2O and extracted with
CH2Cl2. Method A: The organic layer was dried over MgSO4
and purified by flash column chromatography.
6.0 Hz), 127.0, 124.8, 123.0, 122.2, 117.3 (2JC-F = 21.0 Hz),
114.8 (2JC-F = 21.0 Hz). HRMS (ESI) calculated for C14H10FNO
[M]+ 227.0746. Found: 227.0745.
Method B: An alternative method for purification of 4a-h
and 12: The above-mentioned CH2Cl2 layer was dried over
MgSO4 and concentrated. To this mixture was added 95% EtOH
and this mixture was sonicated for a few minutes until the
solution turned from clear to turbid. The mixture was filtrated
and the solid washed with 95% EtOH. The resulting sticky solid
was collected and dissolved in EtOAc then sonicated for a few
minutes until a white solid formed. The solid was collected to
give pure 4a-h without column chromatography. Slightly lower
yields of 4a-h were obtained to compare with purification by
column chromatography.
4.6 (E)-3-(3-Chlorophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
(3e). Purification: same as for 3a. Mp 89−91 oC (lit.10e 92−93 oC).
A pale yellow solid. IR (cm-1) 3098, 1691, 1628, 1535, 1459,
1
1416, 1353, 1058, 793. H NMR (600 MHz, CDCl3) δ 8.75 (d, J
= 7.9 Hz,1H), 8.30 (d, J = 16.0 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H),
7.88 (t, J = 7.6 Hz, 1H), 7.85 (d, J = 16.0 Hz, 1H), 7.72 (s, 1H),
7.57 (d, J = 7.3 Hz, 1H), 7.50 (dd, J = 7.4, 7.4 Hz, 1H), 7.37 (d, J
= 8.4 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H). 13C NMR (150 MHz,
CDCl3) δ 189.2, 153.9, 148.9, 142.9, 137.1, 137.0, 134.9, 130.3,
130.1, 128.2, 127.1, 127.0, 123.0, 122.2. HRMS (ESI) calculated
for C14H10ClNO [M]+ 243.0451. Found: 243.0452.
4.2 (E)-3-(4-Fluorophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
(3a). Purification by flash column chromatography (230−400
mesh SiO2, CH2Cl2:Hexanes = 1:3, Rf = 0.3) provided compound
4.7 (E)-3-(3-Bromophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
(3f). Purification: same as for 3a. Mp 88−92 oC (lit.10e 84−86 oC).
A white solid. IR (cm-1) 3075, 1691, 1634, 1532, 1349, 1263,
o
o
3a as a white solid. Mp 90−92 C (lit.10e 84−86 C). The eluent
was changed (EtOAc:Hexanes
=
1:4) to produce 4a
solid which was
(EtOAc:Hexanes=1:4, Rf 0.25) as
=
a
1
1005, 783. H NMR (600 MHz, CDCl3) δ 8.75 (d, J = 5.1 Hz,
recrystallized from EtOAc/Hexanes. The solid was filtrated and
washed with hexanes and CH2Cl2 to give 4a as a white crystalline
solid. IR (cm-1) 3082, 1687, 1638, 1522, 1422, 1346, 1247, 1038,
1H), 8.29 (d, J = 16.1 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H),
7.90−7.86 (m, 2H), 7.83 (d, J = 16.1 Hz, 1H), 7.62 (d, J =7.7 Hz,
1H), 7.53−7.48 (m, 2H), 7.28 (t, J = 7.9 Hz, 1H). 13C NMR (150
MHz, CDCl3) δ 189.1, 153.9, 148.9, 142.9, 137.3 (X2), 137.1,
133.2, 131.2, 130.3, 127.6, 127.1, 123.0, 122.2. HRMS (ESI)
calculated for C14H10BrNO [M]+ 286.9946. Found: 286.9946.
1
803. For (3a): H NMR (600 MHz, CDCl3) δ 8.73 (ddd, J = 4.7,
1.7, 1.0 Hz, 1H), 8.23 (d, J = 16.0 Hz, 1H), 8.18 (ddd, J = 5.3,
2.0, 1.0 Hz, 1H), 8.04−7.85 (m, 2H), 7.75−7.70 (m, 2H),
7.50−7.47 (m, 1H), 7.10 (t, J = 11.5 Hz, 2H). 13C NMR (150
MHz, CDCl3) δ 189.2, 164.1 (1JC-F = 251.0 Hz), 154.1, 148.8,
143.4 (X2), 137.1, 131.3 (4JC-F = 3.0 Hz), 130.7 (3JC-F = 9.0 Hz,
X2), 126.9, 122.9, 120.6, 116.0 (2JC-F = 22.5 Hz). HRMS (ESI)
calculated for C14H10FNO [M]+ 227.0746. Found: 227.0744.
4.8 (E)-3-(2-Fluorophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
(3g). Purification: same as for 3a. Mp 65−66 oC (lit.10e 72−74 oC).
A pale yellow-green solid. IR (cm-1) 3079, 1697, 1638, 1502,
1
1353, 1008, 783. H NMR (600 MHz, CDCl3) δ 8.73 (d, J = 4.3,
0.6 Hz, 1H), 8.36 (d, J = 16.2 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H),
8.09 (d, J = 16.2 Hz, 1H), 7.86 (dt, J = 9.5, 1.7 Hz, 1H), 7.78 (d,
J = 9.2, 1.7 Hz, 1H), 7.48 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H),
7.39−7.34 (m, 1H), 7.17 (td, J = 15.1, 0.8 Hz, 1H), 7.10 (ddd, J =
10.5, 8.3, 1.0 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 189.4,
161.8, 154.0, 148.8, 137.0, 136.9, 131.9 (3JC-F = 9.0 Hz), 129.2,
126.9 124.3 (4JC-F = 3.0 Hz), 123.3, 123.1 (2JC-F = 21.0 Hz), 123.0
(2JC-F = 15.0 Hz), 116.1 (2JC-F = 21.0 Hz). HRMS (ESI) calculated
for C14H10FNO [M]+ 227.0746. Found: 227.0745.
4.3 (E)-3-(4-Chlorophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
o
(3b). Purification: same as for 3a. Mp 92−94 C (lit.10e 100−102
oC). A white solid. IR (cm-1) 3025, 1687, 1631, 1515, 1356,
1
1038, 806. H NMR (600 MHz, CDCl3) δ 8.74 (s, 1H), 8.29 (d, J
= 16.2 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.89 (td, J = 7.7, 1.7
Hz, 1H), 7.88 (d, J = 16.2 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.50
(ddd, J = 7.3, 4.6, 0.9 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H). 13C
NMR (150 MHz, CDCl3) δ 189.2, 154.0, 148.8, 143.2, 137.1,
136.4, 133.7, 129.9 (X2), 129.1 (X2), 127.0, 123.0, 121.4.
HRMS (ESI) calculated for C14H10ClNO [M]+ 243.0451. Found:
243.0449
4.9 (E)-3-(2-Chlorophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
(3h). Purification: same as for 3a. Mp 98−99 oC (lit.10e 92−96 oC)
(decomposed). A white solid. IR (cm-1) 3102, 1687, 1631, 1512,
4.4 (E)-3-(4-Bromophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
1
o
(3c). Purification: same as for 3a. Mp 99−100 C (lit.10e 97−99
1346, 1310, 1008, 763. H NMR (600 MHz, CDCl3) δ 8.73 (d, J
oC). A white solid. IR (cm-1) 3102, 1687, 1631, 1595, 1515,
= 4.3 Hz, 1H), 8.35 (d, J = 16.0 Hz, 1H), 8.28 (d, J = 16.0 Hz,
1H), 8.19 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.6, 1.6 Hz, 1H), 7.87
(t, J = 7.7 Hz, 1H), 7.48 (td, J = 6.0, 4.8 Hz, 1H), 7.43 (d, J = 7.8
Hz, 1H), 7.34−7.28 (m, 2H). 13C NMR (150 MHz, CDCl3) δ
189.2, 154.0, 148.9, 143.0, 137.1, 135.8, 133.4, 131.2, 130.2,
128.1, 127.0 (X2), 123.3, 123.0. HRMS (ESI) calculated for
C14H10ClNO 243.0451. Found: 243.0449.
1
1346, 1308, 803. H NMR (600 MHz, CDCl3) δ 8.73 (d, J = 4.4
Hz, 1H), 8.29 (d, J = 16.1 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.88
(td, J = 7.7, 1.4 Hz, 1H), 7.85 (d, J = 16.1 Hz, 1H), 7.58 (d, J =
8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.49 (ddd, J = 7.3, 4.8, 1.0
Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 189.2, 154.0, 148.8,
143.2, 137.1, 134.1, 132.1 (X2), 130.1 (X2), 127.0, 124.8, 123.0,
121.4. HRMS (ESI) calculated for C14H10BrNO [M]+ 286.9946.
Found: 286.9945.
4.10 (E)-3-(2-Bromophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
o
(3i). Purification: same as for 3a. Mp 109−110 C (lit.10e 95−97
oC). A white solid. IR (cm-1) 3098, 1687, 1631, 1475, 1349,
4.5 (E)-3-(3-Fluorophenyl)-1-(pyridin-2-yl)prop-2-en-1-one
1
o
(3d). Purification: same as for 3a. Mp 74−77 C (lit.10e 72−74
1038, 763. H NMR (600 MHz, CDCl3) δ 8.72 (dd, J = 4.7, 0.5
oC). A pale yellow solid. IR (cm-1) 3092, 1687, 1641, 1499, 1459,
Hz, 1H), 8.30 (d, J = 16.0 Hz, 1H), 8.23 (d, J = 16.0 Hz, 1H),
8.19 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.86 (dd, J =
7.8, 1.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47 (td, J = 6.6, 0.7
Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.23 (td, J = 7.9, 1.6 Hz, 1H).
13C NMR (150 MHz, CDCl3) δ 189.0, 154.0, 148.8, 142.8, 137.0,
1
1041, 793. H NMR (600 MHz, CDCl3) δ 8.74 (d, J = 4.5 Hz,
1H), 8.29 (d, J = 16.0 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H),
7.89−7.86 (m, 2H), 7.51−7.47 (m, 2H), 7.43 (d, J = 9.8 Hz, 1H),
7.38 (dd, J = 13.7, 7.9 Hz, 1H), 7.10 (td, J = 8.2, 1.9 Hz, 1H). 13C

8
Tetrahedron
o
ylmethanone) (4d). Mp 229−233 C. A white solid. IR (cm-1)
135.1, 133.4, 131.3, 128.2, 127.6, 127.0, 126.2, 123.5, 123.0.
ACCEPTED MANUSCRIPT
HRMS (ESI) calculated for C14H10BrNO [M]+ 286.9946. Found:
286.9946.
1
3168, 1714, 1658, 1552, 1422, 1177, 710. H NMR (600 MHz,
CDCl3) δ 8.48 (dd, J = 4.8, 4.8 Hz, 1H), 8.20 (d, J = 4.6 Hz, 1H),
8.15 (dt, J = 4.7, 1.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.66 (d, J
= 8.8 Hz, 1H), 7.51 (td, J = 7.7, 1.3 Hz, 1H), 7.46 (td, J = 7.7, 1.8
Hz, 1H), 7.43 (td, J = 7.3, 1.7 Hz, 1H), 7.39 (dt, J = 7.7, 1.1 Hz,
1H), 7.15 (ddd, J = 7.1, 4.7, 1.4 Hz, 1H), 7.08−7.04 (m, 4H),
7.00−6.94 (m, 2H), 6.87 (dd, J = 7.1, 5.1 Hz, 1H), 6.77 (dt, J =
14.0, 6.2 Hz, 1H), 6.59 (td, J = 8.3, 2.2 Hz, 1H), 6.39 (td, J = 8.5,
2.7 Hz, 1H), 6.25 (d, J = 12.4 Hz, 1H), 5.80 (br s, 1H), 5.56 (t, J
= 5.0 Hz, 1H), 4.47 (dd, J = 12.4, 5.0 Hz, 1H), 4.18 (dt, J = 13.0,
4.0 Hz, 1H), 3.51 (t, J = 13.0 Hz, 1H), 1.99 (dd, J = 13.0, 3.3 Hz,
4.11 (±)-((1S,2S,3R,4S,6S)-2,6-Bis(4-fluorophenyl)-4-hydroxy-
4-(pyridin-2-yl)cyclohexane-1,3-diyl)-bis(pyridin-2-
ylmethanone) (4a). Mp 249−253 C. A white solid. IR (cm-1)
o
3105, 1707, 1667, 1525, 1495, 1253, 1194. 1H NMR (600 MHz,
CDCl3) δ 8.48 (d, J = 4.3 Hz, 1H), 8.21 (d, J = 4.3 Hz, 1H), 8.15
(d, J = 4.3 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.8 Hz,
1H), 7.52−7.46 (m, 2H), 7.44 (td, J = 7.6, 1.6 Hz, 1H), 7.40 (d, J
= 7.7 Hz, 1H), 7.26−7.15 (m, 5H), 7.10−7.07 (m, 1H), 6.87 (td, J
= 7.4, 0.7 Hz, 1H), 6.70 (t, J = 8.7 Hz, 2H), 6.49 (t, J = 7.5 Hz,
2H), 6.26 (d, J = 12.5 Hz, 1H), 5.77 (s, -OH), 5.51 (t, J = 5.0 Hz,
1H), 4.44 (dd, J = 12.5, 5.0 Hz, 1H), 4.16 (dt, J = 12.7, 4.0 Hz,
1H), 3.50 (t, J = 13.0 Hz, 1H), 1.97 (dd, J = 13.0, 3.2 Hz,
1H). 13C NMR (150 MHz, CDCl3) δ 205.4, 203.4, 162.5, 161.2
(1JC-F = 242.8 Hz), 161.1 (1JC-F = 242.5 Hz), 154.1, 152.9, 148.0
1H). 13C NMR (150 MHz, CDCl3) δ 204.9, 203.1, 162.4 (1JC-F
=
243.7 Hz), 162.2 (1JC-F = 243.7 Hz), 162.1, 154.0, 153.9, 148.1,
148.0, 144.6 (3JC-F = 7.0 Hz), 143.2 (3JC-F = 7.0 Hz), 136.3, 136.0,
135.9, 129.2 (3JC-F = 8.0 Hz), 129.1 (3JC-F = 8.0 Hz), 126.0 (X2),
124.3, 123.6 (X2), 122.0, 121.6, 121.2, 121.0, 115.5 (2JC-F = 21.6
Hz), 114.7 (2JC-F = 21.4 Hz), 113.0, 112.9, 75.6, 48.4, 47.6, 45.1,
40.9, 38.0. HRMS (ESI) calculated for C35H28F2N3O3 [M+H]+
576.2099. Found: 576.2100.
(X2), 147.0, 137.8, 136.4, 136.2, 136.1, 136.0, 130.0 (X2, 3JC-F
=
3
7.8 Hz), 129.2 (X2, JC-F = 7.8 Hz), 126.1, 126.0, 121.9, 121.7,
121.1, 120.9, 114.5 (X2, 2JC-F = 20.4 Hz), 114.4 (X2, JC-F = 20.4
2
Hz), 75.8, 48.7, 48.2, 44.7, 40.5, 38.2. HRMS (ESI) calculated
4.15
(±)-((1S,2S,3R,4S,6S)-2,6-Bis(3-chlorophenyl)-4-
for C35H28F2N3O3 [M+H]+ 576.2100. Found: 576.2095.
hydroxy-4-(pyridin-2-yl)cyclohexane-1,3-diyl)-bis(pyridin-2-
ylmethanone) (4e). Mp 174−178 C. A white solid. IR (cm-1)
o
1
4.12
(±)-((1S,2S,3R,4S,6S)-2,6-Bis(4-chlorophenyl)-4-
3125, 1711, 1644, 1449, 1005, 803. H NMR (600 MHz, CDCl3)
hydroxy-4-(pyridin-2-yl)cyclohexane-1,3-diyl)-bis(pyridin-2-
δ 8.52 (d, J = 4.5 Hz, 1H), 8.23 (d, J = 4.5 Hz, 1H), 8.18 (dd, J =
4.6, 0.7 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.9 Hz,
1H), 7.53 (td, J = 7.7, 1.3 Hz, 1H), 7.50 (td, J = 7.8, 1.6 Hz, 1H),
7.45 (td, J = 7.5, 1.6 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.33 (s,
1H), 7.24 (s, 1H), 7.18 (dd, J = 6.2, 1.2 Hz, 1H), 7.16 (d, J = 8.8
Hz, 1H), 7. 13 (s, 1H), 7.08 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 6.96
(t, J = 7.8 Hz, 1H), 6.89 (t, J = 7.5 Hz, 2H), 6.73 (t, J = 7.9 Hz,
1H), 6.69 (d, J = 8.2 Hz, 1H), 6.26 (d, J = 12.4 Hz, 1H), 5.73 (s,
1H), 5.55 (t, J = 5.0 Hz, 1H), 4.43 (dd, J = 12.4, 5.0 Hz, 1H),
4.16 (dt, J = 13.0, 4.1 Hz, 1H), 3.49 (t, J = 13.0 Hz, 1H), 1.99
(dd, J = 13.0, 3.3 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 204.8,
203.4, 162.3, 154.0, 148.1, 148.0, 147.0, 144.1, 142.5, 136.3,
136.1, 136.0, 133.7, 133.5, 129.1 (X2), 129.0, 128.9 (X2), 128.1,
126.7, 126.3, 126.1, 126.0 (X2), 122.0, 121.6, 121.2, 121.1, 75.7,
48.2, 47.6, 45.2, 40.9, 37.9. HRMS (ESI) calculated for
C35H2835Cl35ClN3O3 [M+H]+ 608.1508. Found: 608.1510.
C35H2835Cl37ClN3O3 [M+H]+ 610.1479. Found: 610.1498.
o
ylmethanone) (4b). Mp 245−248 C. A white solid. IR (cm-1)
1
3168, 1711, 1664, 1608, 1502, 1452, 1025, 763. H NMR (600
MHz, CDCl3) δ 8.47 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 4.8 Hz,
1H), 8.15 (d, J = 4.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.63 (d, J
= 7.8 Hz, 1H), 7.51 (dd, 7.7, 1.6 Hz, 1H),7.50 (dd, J = 7.7, 1.6
Hz, 1H), 7.44 (td, J = 7.7, 1.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H),
7.23 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.17−7.14 (m,
1H), 7.10 (ddd, J = 7.3, 4.7, 0.8 Hz, 1H), 6.98 (d, J = 8.4 Hz,
2H), 6.87 (dd, J = 6.9, 4.9 Hz, 1H), 6.77 (d, J = 8.5 Hz, 2H), 6.24
(d, J = 12.5 Hz, 1H), 5.75 (s, 1H), 5.52 (t, J = 5.0 Hz, 1H), 4.44
(dd, J = 12.5, 5.0 Hz, 1H), 4.15 (dt, J = 13.0, 4.0 Hz, 1H), 3.49 (t,
J = 13.1 Hz, 1H), 1.95 (dd, J = 13.1, 3.6 Hz, 1H). 13C NMR (150
MHz, CDCl3) δ 205.1, 203.1, 162.3, 154.0, 153.8, 148.07, 148.02,
147.0, 140.6, 139.2, 136.2, 136.1, 131.9, 129.9, 129.2 (X2),
127.9 (X2), 127.8 (X2), 126.12, 126.05, 121.9, 121.7, 121.1,
121.0, 75.6, 48.5, 47.9, 44.8, 40.6, 38.0. HRMS (ESI) calculated
for C35H27Cl2N3O3 [M]+ 607.1429. Found: 607.1428.
4.16
(±)-((1S,2S,3R,4S,6S)-2,6-Bis(3-bromrophenyl)-4-
hydroxy-4-(pyridin-2-yl)cyclohexane-1,3-diyl)-bis(pyridin-2-
4.13
(±)-((1S,2S,3R,4S,6S)-2,6-Bis(4-bromrophenyl)-4-
o
ylmethanone) (4f). Mp 155−158 C. A white solid. IR (cm-1)
hydroxy-4-(pyridin-2-yl)cyclohexane-1,3-diyl)-bis(pyridin-2-
1
ylmethanone) (4c). Mp 242−246 C. A white solid. IR (cm-1)
o
3108, 1707, 1641, 1528, 1449, 1012, 803. H NMR (600 MHz,
3198, 1707, 1658, 1512, 1452, 846, 760. 1H NMR (600 MHz,
CDCl3) δ 8.60 (d, J = 4.2 Hz, 1H), 8.33 (d, J = 4.0 Hz, 1H), 8.28
(d, J = 4.2 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.7 Hz,
1H), 7.65−7.60 (m, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.7
Hz, 1H), 7.30−7.28 (d, J = 8.5 Hz, 3H), 7.27−7.23 (m, 5H), 7.05
(t, J = 8.4, 2H), 7.0 (t, J = 7.0 Hz, 1H), 6.37 (d, J = 12.5 Hz, 1H),
5.92 (s, −OH, 1H), 5.65 (dd, J = 12.9, 2.6 Hz, 1H), 4.56 (dd, J =
12.4, 4.9 Hz, 1H), 4.29−4.25 (m, 1H), 3.62 (t, J = 12.9 Hz, 1H),
2.08 (dd, J = 12.9, 2.6 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ
205.6, 203.1, 162.2, 154.0, 153.8, 148.10, 148.03, 147.0, 141.1,
139.8, 136.2, 136.1, 130.86, 130.73, 130.3, 129.6, 126.12,
126.07, 121.9, 121.7, 121.2, 121.03, 119.98, 75.6, 48.5, 47.8,
44.9, 40.7, 38.0. HRMS (ESI) calculated for C35H2879Br79BrN3O3
[M+H]+ 696.0497. Found: 696.0499. C35H2879Br81BrN3O3
[M+H]+ 698.0477. Found: 696.0482.
CDCl3) δ 8.52 (dd, J = 2.5, 2.2 Hz, 1H), 8.22 (t, J = 2.9 Hz, 1H),
8.18 (t, J = 0.7 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.67 (dd, J =
7.9, 0.8 Hz, 1H), 7.53−7.49 (m, 3H), 7.45−7.42 (m, 1H),
7.41−7.37 (m, 2H), 7.20 (t, J = 8.8 Hz, 1H), 7.18−7.15 (m, 1H),
7.09−7.06 (m, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.88 (td, J = 7.9, 2.4
Hz, 2H), 6.83 (d, J = 7.9 Hz, 1H), 6.66 (td, J = 7.9, 2.3 Hz, 1H),
6.26 (d, J = 12.0 Hz, 1H), 5.71 (br s, 1H), 5.45 (t, J = 5.0 Hz,
1H), 5.28 (t, J = 1.4 Hz, 1H), 4.41 (dd, J = 12.4, 5.0 Hz, 1H),
4.15 (dt, J = 13.0, 3.9 Hz, 1H), 3.47 (t, J = 13.0 Hz, 1H), 1.98
(dd, J = 13.0, 3.1 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 204.7,
203.4, 162.3, 153.9, 148.1, 148.0, 147.0, 144.4, 142.8, 136.3,
136.0, 135.9, 131.9, 131.0, 129.4, 129.23, 129.21, 129.18, 127.1,
126.5, 126.1, 121.98, 121.95, 121.8, 121.6, 121.07, 121.05, 75.7,
48.0, 47.5, 45.1, 40.8, 37.9. HRMS (ESI) calculated for
C35H2879Br79BrN3O3 [M+H]+ 696.0497. Found: 696.0494.
C35H2879Br81BrN3O3 [M+H]+ 698.0477. Found: 696.0474.
4.14 (±)-((1S,2S,3R,4S,6S)-2,6-Bis(3-fluorophenyl)-4-hydroxy-
4-(pyridin-2-yl)cyclohexane-1,3-diyl)-bis(pyridin-2-

9
4.17 (±)-((1S,2S,3R,4S,6S)-2,6-Bis(2-fluorophenyl)-4-hydroxy-
Hz, 1H), 4.38 (dd, J = 12.3, 4.6 Hz, 1H), 4.13−4.10 (m, 1H),
ACCEPTED MANUSCRIPT
4-(pyridin-2-yl)cyclohexane-1,3-diyl)-bis(pyridin-2-
3.59 (s, 3H), 3.50 (t, J = 13.0 Hz, 1H), 3.46 (s, 3H), 1.96 (d, J =
12.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 205.7, 203.7,
162.9, 157.7, 157.6, 154.2, 154.1, 147.9 (X2), 146.9, 136.2,
136.0, 135.7, 134.4, 132.9, 129.5 (X2), 128.7 (X2), 125.9, 125.7,
121.8, 121.7, 121.2, 121.0, 113.2 (X2), 113.0 (X2), 75.9, 55.0,
54.8, 49.1, 48.6, 44.7, 40.5, 38.4. HRMS (ESI) calculated for
C37H34N3O5 [M+H]+ 600.2498. Found: 600.2498.
o
ylmethanone) (4g). Mp 236−243 C. A white solid. IR (cm-1)
1
3118, 1711, 1671, 1512, 1479, 1349, 1257, 780. H NMR (600
MHz, CDCl3) δ 8.49 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 4.4 Hz,
1H), 8.16 (d, J = 4.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.57 (d, J
= 8.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H),
7.42−7.38 (m, 2H), 7.30−7.24 (m, 1H), 7.17 (t, J = 5.3 Hz, 1H),
7.05 (t, J = 7.3 Hz, 1H), 7.00 (dd, J = 6.3, 4.9 Hz, 1H), 6.87 (dd,
J = 7.1, 4.7 Hz, 2H), 6.80 (t, J = 9.5 Hz, 1H), 6.74−6.69 (m, 3H),
6.45−6.41 (m, 1H), 6.27 (d, J = 12.6 Hz, 1H), 5.83 (s, 1H), 5.67
(t, J = 4.9 Hz, 1H), 4.89 (dd, J = 12.7, 4.7 Hz, 1H), 4.58 (dd, J =
9.5, 3.8 Hz, 1H), 3.58 (t, J = 13.0 Hz, 1H), 1.90 (dd, J = 13.0, 2.9
Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 205.1, 203.1, 162.7,
Supplementary data
Supplementary data (1H and 13C NMR data) for all of the
compounds associated with this article can be found in the online
version.
161.7 (1JC-F = 245.0 Hz), 161.0 (1JC-F = 245.0 Hz), 154.1 (3JC-F
=
References and note:
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8.4 Hz), 148.2, 148.0, 147.1, 136.2, 136.1, 135.7, 129.2, 129.1,
129.0, 127.9, 127.8, 127.6, 127.5 (3JC-F = 7.0 Hz), 126.0, 125.8,
123.1, 123.0, 121.8, 121.7, 121.0, 120.7, 114.8 (2JC-F = 22.4 Hz),
114.7 (2JC-F = 22.4 Hz), 75.8, 48.8, 44.3, 37.3, 37.0, 33.8. HRMS
(ESI) calculated for C35H28F2N3O3 [M+H]+ 576.2100. Found:
576.2102.
4.18
(±)-((1S,2S,3R,4S,6S)-2,6-Bis(2-chlorophenyl)-4-
hydroxy-4-(pyridin-2-yl)cyclohexane-1,3-diyl)-bis(pyridin-2-
ylmethanone) (4h). IR (cm-1) 3171, 1707, 1658, 1492, 1452,
o
1
1018, 770. Mp 263−266 C. A white solid. H NMR (600 MHz,
CDCl3) δ 8.51 (d, J = 3.8 Hz, 1H), 8.29 (s, 1H), 8.16 (d, J = 3.9
Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.53 (d, J = 7.8
Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.36
(d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 2.1 Hz,
2H), 7.07 (d, J = 7.9 Hz, 1H), 7.04 (t, J = 3.9 Hz, 1H), 6.99 (dd, J
= 6.6, 5.1 Hz, 1H), 6.92 (br s, 1H), 6.84 (t, J = 3.7 Hz, 2H), 6.67
(t, J = 7.4 Hz, 1H), 6.57 (t, J = 7.5 Hz, 1H), 6.27 (d, J = 11.7 Hz,
1H), 6.05 (br s, 1H), 5.89 (t, J = 4.2 Hz, 1H), 5.01 (dd, J = 12.3,
3.8 Hz, 1H), 4.69 (d, J = 13.1 Hz, 1H), 3.61 (t, J = 13.0 Hz, 1H),
1.91 (d, J = 12.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 205.0,
202.9, 162.8, 154.2, 154.1, 148.4, 147.9, 147.0, 139.3, 138.0,
136.4, 136.2, 135.6, 135.3, 135.0, 129.3, 129.2 (X2), 128.9,
127.7, 127.2, 126.1, 126.0, 125.9, 125.7, 121.9, 121.8, 121.1,
120.7, 75.9, 49.8, 42.5, 41.2, 37.8, 37.6. HRMS (ESI) calculated
for C35H2835Cl35ClN3O3 [M+H]+ 608.1508. Found: 608.1503.
C35H2835Cl37ClN3O3 [M+H]+ 610.1479. Found: 610.1486.
7. (a) Lu, Y.; Zhou, Y.; Lin, L.; Zheng, H.; Fu, K.; Liu, X.;
Feng, X. Chem. Commun. 2016, 52, 8255−8258. (b)
Himiyama, T.; Sauer, D. F.; Onoda, A.; Spaniol, T. P.;
Okuda, J.; Hayashi, T. J. Inorg. Biochem. 2016, 158, 55–61.
(c) Boersma, A. J.; Klijn, J. E.; Feringa, B. L.; Roelfes, G. J.
Am. Chem. Soc. 2008, 130, 11783–11790. (d) Mubofu, E. B.;
Engberts, J. B. F. N. J. Phys. Org. Chem. 2004, 17, 180–186.
(e) Otto, S.; Bertoncin, F.; Engberts, J. B. F. N. J. Am. Chem.
Soc. 1996, 118, 7702−7707.
4.18
(E)-3-(4-Methoxyphenyl)-1-(pyridin-2-yl)prop-2-en-1-
o o
one (11). Method B. Mp 83−88 C (lit.14a 126 C; lit.14b 81−82
oC). A white solid. IR (cm-1) 3026, 1681, 1631, 1525, 1495,
1320, 1277, 1058, 806. H NMR (600 MHz, CDCl3) δ 8.74 (d, J
1
= 3.8 Hz, 1H), 8.18 (d, J = 16.0 Hz, 1H), 8.17 (d, J = 8.6 Hz,
1H), 7.92 (d, J = 16.0 Hz, 1H), 7.87 (t, J = 6.4 Hz, 1H), 7.69 (d, J
= 8.6 Hz , 2H), 7.47 (dd, J = 6.7, 6.2 Hz, 1H), 6.93 (d, J = 8.5
Hz, 2H), 3.85 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 189.3,
161.8, 154.4, 148.7, 144.8, 137.1, 130.7 (X2), 128.0, 126.7,
122.9, 118.5, 114.3 (X2), 55.4. HRMS (ESI) calculated for
C15H14NO2 [M+H]+ 240.1025. Found: 240.1027.
8. (a) Chamchoumis, C.; Potvin, P. G. J. Chem. Res. (S), 1998,
180−181. (b) Constable, E. C.; Harverson, P.; Smith, D. R.;
Whall, L. A. Tetrahedron 1994, 50, 7799−7806.
4.19 ((1S,2S,3R,4S,6S)-4-hydroxy-2,6-bis(4-methoxyphenyl)-
4-(pyridin-2-yl)cyclohexane-1,3-diyl)bis(pyridin-2-
9. Unpublished results.
10. (a) Fosso, M. Y.; LeVine 3rd, H.; Green, K. D.; Tsodikov, O.
V.; Garneau-Tsodikova, S. Org. Biomol. Chem. 2015, 13,
9418–9426. (b) Lone, I. H.; Khan, K. Z.; Fozdar, B. I. Med.
Chem. Res. 2014, 23, 363–369. (c) Bhat, K. I.; Kumar, A.;
Nisar, M.; Kumar, P. Med. Chem. Res. 2014, 23, 3458–3467.
(d) Franco, F.; Cometto, C.; Vallana, F. F.; Sordello, F.; Priola,
E.; Minero, C.; Nervi, C.; Gobetto, R. Chem. Commun. 2014,
50, 14670−14673. (e) Mamolo, M. G.; Zampieri, D.;
Falagiani, V.; Vio, L.; Banfi, E. Il Farmaco 2001, 56, 593–
o
ylmethanone) (12). Method B. Mp 223−227 C. A white solid.
1
IR (cm-1) 3178, 1707, 1661, 1525, 1495, 1267, 1214. H NMR
(600 MHz, CDCl3) δ 8.47 (d, J = 3.8 Hz, 1H), 8.22 (s, 1H), 8.13
(d, J = 2.3 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz,
1H), 7.51 (t, J = 7.0 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.41 (d, J
= 8.0 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.17−7.13 (m, 5H), 7.02
(t, J = 7.0 Hz, 1H), 6.87 (t, J = 5.6 Hz, 1H), 6.54 (d, J = 8.5 Hz,
2H), 6.23 (d, J = 12.3 Hz, 1H), 5.81 (br s, 1H), 5.48 (t, J = 4.6

10
Tetrahedron
ACCEPTED MANUSCRIPT
599. (f) Marvel, C. S.; Colman, L. E. Jr.; Scott, G. P. J. Org.
Chem. 1955, 20, 1785−1792.
14. (a) Prasad, Y. R.; Kumar, P. P.; Kumar, P. R.; Rao, A. S. E-
Journal of Chemistry. 2008, 5, 144−148. (b) Annigeri, A.
C.; Siddappa, S. Indian. J. Chem. 1963, 1, 484−486.
11. Ciupa, A.; Mahon, M. F.; De Bank, P. A.; Caggiano, L. Org.
Biomol. Chem. 2012, 10, 8753−8757.
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12. The ccdc number for 4a is 1533553.
13. The ccdc number for 12 is 1555308.