Domino cyclocondensation of arylaldehydes with 2-acetylpyridine

Article abstract of DOI:10.1016/j.tet.2012.09.048

A novel synthetic route for the preparation of cyclohexane skeleton 3 was developed via the one-pot domino Claisen-Schmidt condensation reaction/Michael addition/double aldol reaction of 1 equiv of functionalized arylaldehyde 1 with 3 equiv of 2-acetylpyridine (2a).

Full text of DOI:10.1016/j.tet.2012.09.048

Tetrahedron 68 (2012) 9616e9623
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Domino cyclocondensation of arylaldehydes with 2-acetylpyridine
*
Meng-Yang Chang , Ming-Hao Wu
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2012
Received in revised form 7 September 2012
Accepted 11 September 2012
Available online 16 September 2012
A novel synthetic route for the preparation of cyclohexane skeleton 3 was developed via the one-pot
domino ClaiseneSchmidt condensation reaction/Michael addition/double aldol reaction of 1 equiv of
functionalized arylaldehyde 1 with 3 equiv of 2-acetylpyridine (2a).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Condensation
Arylaldehyde
2-Acetylpyridine
Cyclohexane
1. Introduction
O
O
Ar
Ar
chalcone / α-enolate = 2 / 1
Ar'
Ar
Ar' Ar
HO
Ar'
Ar
O
The formation of cyclohexane motif has been well-developed
via a stepwise Michael addition of an enolate with a conjugated
enone/cyclodehydration of the resulting adduct sequence or Mi-
chael-aldol reaction/dehydration of ketol sequence under the in-
fluence of catalysts.1 It has been widely used as a useful building
block in the construction of a variety of pharmacophores and/or
natural products.2,3 Extensive synthetic efforts have been reported
for substituted six-membered carbocycles, in which an annulation
route from acyclic functionalized precursors constitutes a tandem
strategy.4 Normally, the base-mediated ClaiseneSchmidt conden-
sation of acetophenone and benzaldehyde with a mole ratio of 1:1
affords chalcone derivative (benzylidene acetophenone).5 How-
Ar
O
CO Et
2
CN
HO
O
Ar'
(ref 6f)
Ar'
(ref 6e)
O
Ar
Ar'
Ar'
Ar
Ar'
O
O
NC
CO Et
2
Ar
(ref 6g)
HO Ar
O
Scheme 1. Domino Robinson annulations.
ever, when the chalcone are conducted with aryl
a-enolate in
a molar ratio of 2/1 under alkaline alcoholic condition, the di-
versified six-membered carbocyclic frameworks form via a com-
mon method from the double conjugate addition of chalcone with
next. As shown in Scheme 2, the formation of chalcone or 1,5-
diketone was involved in the reaction of 2 and 1a with a ratio of
1:1 or 2:1 under the alkaline methanolic condition. It is noteworthy
that when the ratio of 3/1 (2a/1a) is adopted in an attempt to
provide cyclohexanes via one-pot facile tandem ClaiseneSchmidt
condensation/Michael addition/double aldol reaction, no products
with the skeleton of chalcone or 1,5-diketone were isolated.
a
-carbanion of ketone and subsequent aldol reaction (Robinson
annulations), as shown in Scheme 1.6
In continuation of our recent investigation of the tandem aldol
condensation/Michael addition for the preparation of poly-
oxygenated rigid and cyclic benzannulated molecules (e.g., benzo
[g]indazoles, azahomoisotwistanes),7 a facile stereochemical route
for synthesizing the novel framework of cyclohexane was studied
2. Results and discussion
In an attempt to develop a practical synthetic method of cy-
clohexane skeleton, we investigated the base-mediated cyclo-
condensation reaction of substituted arylaldehyde 1 with freshly
distilled 2-acetylpyridine (2a). We found that by using NaOH in
* Corresponding author. Tel.: þ886 7 3121101x2220; e-mail addresses: mychang@
kmu.edu.tw, mychang624@yahoo.com.tw (M.-Y. Chang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.048

M.-Y. Chang, M.-H. Wu / Tetrahedron 68 (2012) 9616e9623
9617
MeO
O
chalcone
(2/1a = 1/1)
(aldol)
(ref 7a)
MeO
Ar
1
O
Ar
1
Me
Ar
1
2
O
O
NaOH
(2/1a = 2/1) MeO
1,5-diketone
+
(aldol/Michael)
(ref 7b)
MeOH
O
MeO
Ar
1
MeO
MeO
O
H
Ar
OH
Ar
1
(2a/1a = 3/1)
cyclohexane
(aldol/Michael/
double aldol)
1a
1
(this work)
MeO
MeO
Scheme 2. Reactions of 2 with 1a.
2/1a = mole ratio
Ar
1
HO
2a, Ar = 2-pyridine
1
MeOH at reflux temperature, the intermediates of chalcone and 1,5-
diketone smoothly proceeded the condensation to directly give six-
membered carbocycle 3a in decent yield. Herein, we report the
details of our findings. Condensation reaction of 1a (1.0 equiv) with
2a (3.0 equiv) established four stereochemical centers to produce
3a in 78% yield. The synthetic route is shown in Scheme 3.
Fig. 2. X-ray structure of 3a.
Michael
addition
Claisen-Schmidt
condensation
N
O
O
NaOH, 2a
2a
O
MeO
MeO
MeO
MeO
1a
MeOH
N
N
aldol
aldol
reaction
N
reaction
N
O
O
O
N
OH
2a
MeO
MeO
MeO
MeO
N
HO
HO
N
N
3a
Scheme 3. Synthetic route for 3a.
Fig. 3. X-ray structure of 3r.
To prepare 5-arylcyclohexane-1,2-diols 3 bearing different R1eR4
substituted aryl group, electron-donating or electron-withdrawing
groups substituted arylaldehydes were employed to react with
3 equivof2aunder the catalysis ofNaOH inMeOH (Table 1). As shown
in entries 1e15, four stereocenters of skeleton 3 are constructed in
one-pot cyclocondensation and possessing excellent stereo- and
regio-selectivity. However, 3p with electron-withdrawing group was
yielded in trace amounts (entry 16). As shown in Table 1, some het-
erocyclic arylaldehydes 1qev also reacted with 2a to produce het-
erocyclic rings substituted cyclohexane-1,2-diols 3qev, albeit the
indolylandpyrrolylsubstitutedcyclohexane-1,2-diols3uand3vwere
isolated in low yields (entries 17e22). To deserve to be mentioned, all
of four 2-pyridinyl groups of 3s were oriented to equatorial position.
Basically, 3qes should be the potential chelators for some metal ions.
So far, there is still no distinct and exact example to describe the base-
promoted straightforward synthesis of skeleton 3 via a domino
cyclocondensation reaction.9,10
The formation of the adduct 3a was confirmed through spectral
analysis, as shown in Fig. 1. The 1H NMR spectrum of 3a exhibited
one singlet at
doublet of triplet of H2 (
appeared as one doublet of doublet of H3equatorial
triplet of H3axial 2.53). The other CH2 protons of C5 position
appeared as one doublet of doublet of H5equatorial 3.10) and one
doublet of doublet of H5axial 2.00). Furthermore, 3a was de-
d
5.46 for C1 proton. Another CH proton appeared as
4.36). The CH2 protons of C3 position
2.05) and one
d
(d
(d
(d
(d
termined by the single-crystal X-ray crystallography. Structures 3a
and 3r are shown in Figs. 2 and 3.8
Ar = 2-pyridine 2.05, dd,
4.36, dt,
J = 2.8, 12.0 Hz
1
J = 2.8, 12.8 Hz
3.10, dd,
J = 0.8, 15.2 Hz
OH
H
2
OH
H
3
OMe
OMe
Ar
1
O
H
5
Furthermore, while changing the 2-pyridinyl group of 2-
acetylpyridine 2a to another aromatic group, methyl arylketones
2bee (Ar1¼b, Ph; c, 4-MeOePh; d, 2-furan; e, 2-thiophene) reacted
with substrate 1a (1a/2bee¼1:3) to produce 1,5-diketone skeleton 4
with acceptable yields (4a, 88%; 4b, 85%; 4c, 65%; 4d, 70%) under the
above mentioned conditions (see Scheme 4). When the equivalents of
H
3
Ar
1
Ar
1
H
5
H
1
2.00, dd,
J = 2.8, 15.2 Hz
2.53, t,
J = 12.8 Hz
5.46, d,
J = 12.0 Hz
Fig. 1. Selected 1H NMR parameters of 3a.

9618
M.-Y. Chang, M.-H. Wu / Tetrahedron 68 (2012) 9616e9623
Table 1
regio- and stereoselective formation of four contiguous chiral centers
for the cyclocondensation.
Reaction of 1aeu with 2aa,b,c
N
How is 3a produced? As shown in Scheme 5, the initial event
may be considered as the formation of a symmetrical 1,5-diketone
from the ClaiseneSchmidt condensation (1 equiv of 2a) and Mi-
chael reaction (2 equiv of 2a) of 2a and 1a.9b,c The proposed in-
termediate I may exhibit a possible Na-chelated between one
carbonyl group of 1,5-diketone and the enolate of 2a (3 equiv of 2a).
After the first aldol reaction of intermediate I, intermediate II is
afforded from the intramolecular proton exchange and followed by
the second aldol reaction via the cascade-type ring-closure on the
intermediate II. The six-membered ring is generated and the car-
bocycles skeleton is established. After selective protonation of in-
termediate II, 3a is yielded.
O
OH
R
4
R
4
O
H
R
N
3
R
3
R
R
1
3a ~ 3p
2
HO
R
R
N
2
1
2a (3.0 equiv)
1a ~ 1p
N
O
NaOH, MeOH
reflux, 5 h
O
OH
R
H
R
N
1q ~ 1u
HO
N
3q ~ 3u
Entry
1 (R1, R2, R3, R4/R)
3, Yield
1
2
3
4
5
6
7
8
1a (R1¼Allyl, R2¼R3¼OMe, R4¼H)
1b (R1¼H, R2, R3¼OCH2O, R4¼H)
1c (R1¼H, R2¼R3¼R4¼OMe)
78%
65%
68%
72%
74%
77%
77%
73%
68%
75%
70%
69%
80%
82%
83%
< 10%
71%
70%
65%
60%
32%
< 8%
Na
O
H
Claisen-Schmidt
condensation,
O
OMe
OMe
2a
1d (R1¼R3¼R4¼H, R2¼OMe)
O
+
1e (R1¼H, R2¼OMe, R3¼OBn, R4¼H)
1f (R1¼H, R2¼OBn, R3¼OMe, R4¼H)
1g (R1¼R2¼R3¼OMe, R4¼H)
N
Michael addition
1a
then aldol reaction
N
N
I
1h (R1¼H, R2¼OMe, R3¼OAllyl, R4¼H)
1i (R1¼H, R2¼OMe, R3¼OH, R4¼H)
1j (R1¼H, R2¼OPropagyl, R3¼OMe, R4¼H)
1k (R1¼Allyl, R2¼OAllyl, R3¼OMe, R4¼H)
1l (R1¼R2¼R4¼H, R3¼OMe)
1m (R1¼R2¼R3¼R4¼H)
9
proton exchange
then aldol reaction
10
11
12
13
14
15
16
17
18
19
20
21
22
H
O
H
O
OMe
protonation
O
3a
1n (R1¼R2¼R4¼H, R3¼Ph)
1o (R1¼Me, R2¼R3¼R4¼H)
1p (R1¼R2¼R4¼H, R3¼CN)
1q (R¼2-Furan)
N
OMe
N
N
II
1r (R¼2-Thiophene)
Scheme 5. A possible mechanism of 3a.
1s (R¼2-Pyridine)
1t (R¼4-Pyridine)
1u (R¼3-Indole)
1v (R¼2-Pyrrole)
In another way, different base (e.g., LiOH, NaOH, KOH, Ba(OH)2)
or alcoholic solvent (MeOH, EtOH) could be employed for the one-
pot reaction of 1a with 2a under the above condition (see Table 2).
For the synthesis of 3a, the similar yields were obtained with five
different reaction conditions.
a
The reactions were run on a 0.5 mmol scale with 1.
The results were determined by 1H NMR analysis.
The provided yields was based on the skeleton 1.
b
c
O
Ar
1
O
O
Ar
2b~2d,
1
MeO
MeO
Table 2
1a
Reaction of 1a with 2aa,b
NaOH, MeOH
Ar
1
Entry
Reagents (equiv), solvent, temp
Yieldb
1
2
3
4
5
LiOH (4.0), MeOH, reflux
LiOH (4.0), EtOH, reflux
NaOH (4.0), EtOH, reflux
KOH (4.0), MeOH, reflux
Ba(OH)2 (4.0), MeOH, reflux
72%
70%
76%
75%
66%
4a, Ar = Ph (88%)
1
4b, Ar = 4-MeOPh (85%)
1
4c, Ar = 2-furan (65%)
1
4d, Ar = 2-thiophene (70%)
1
a
The reactions were run on a 0.5 mmol scale with 1a.
Scheme 4. Synthesis of 4.
b
The product was >95% pure as determined by 1H NMR analysis.
reactants 2 were increased to 8.0 equiv, products 4 with the similar
yields were provided and no isolation of products 3 was observed.
However, attempts to obtainproducts 3 were unsuccessful within the
reaction time of 40 h for the reaction of 1a with 2b under a number of
conditions. The possible mechanism should be the nitrogen lone-pair
of pyridine ring of 2a providing the better electronic effect (for car-
bonyl group) to accelerate the double aldol reaction of 1,5-diketone
than 2bee. Also, the reaction of 1a with 2-furfural (2d, oxygen
atom) or 2-thiophene (2e, sulfur atom) could not trigger the forma-
tion of products 3. Based on the phenomenon, we envisioned that the
nitrogen atoms of the pyridine rings on the structural skeleton of 1,5-
diketone should form the possible chelated intermediate for the next
double aldol reaction,9b,c and it should be the key factor affecting the
To broaden the synthetic application, 2-acetylthiazole (2f) with
the similar skeleton of 2-acetylpyridine (2a) had also been demon-
strated for the facile one-pot methodology, as shown in Scheme 6. In
particular, 5a or 5b was provided from the one-pot domino reaction
of 1a or 1b with 2f with 72% or 65% yield. We have successfully
presented the facile and efficient synthetic methodology for skele-
ton 5 with tetra-aryl benzene moiety, which involved NaOH-
mediated one-pot tandem combination of ClaiseneSchmidt con-
densation reaction, Michael addition and double aldol reaction,
followed by sequential dehydration and oxidative dehydrogenation.
To the best of our knowledge, there are no literature reports con-
sidering the preparation of skeleton 5, with a novel dendritic ben-
zenoid structural framework.

M.-Y. Chang, M.-H. Wu / Tetrahedron 68 (2012) 9616e9623
9619
1H), 7.46 (dt, J¼2.0, 7.6 Hz, 1H), 7.39 (dt, J¼2.0, 7.6 Hz, 1H), 7.35 (t,
J¼8.8 Hz, 2H), 7.18 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 7.12 (ddd, J¼1.2, 4.8,
7.6 Hz, 1H), 6.85 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 6.65 (br s, 1H), 6.50 (d,
J¼8.4 Hz, 1H), 6.17 (s, 1H), 6.05e6.96 (m, 1H), 5.46 (d, J¼12.0 Hz,
1H), 5.06e5.00 (m, 2H), 4.36 (dt, J¼2.8, 12.0 Hz, 1H), 3.66 (s, 3H),
3.65 (s, 3H), 3.56e3.45 (m, 2H), 3.10 (dd, J¼0.8, 15.2 Hz, 1H), 2.53 (t,
J¼12.8 Hz, 1H), 2.05 (dd, J¼2.8, 12.8 Hz, 1H), 2.00 (dd, J¼2.8, 15.2 Hz,
S
O
S
N
S
O
R
N
N
S
2f (3.0 equiv)
R
3
1a ~ 1b
NaOH, MeOH
reflux, 5 h
R
2
1
N
1H); 13C NMR (100 MHz, CDCl3):
d 204.43, 164.91, 162.89, 153.90,
5a, R = R = MeO, R = allyl (72%)
2
1
3
1
150.80, 147.89, 147.79, 147.74, 146.66, 137.08, 136.71, 136.26, 136.23,
133.98, 132.19, 126.01, 123.47, 121.85, 121.80, 121.78, 120.04, 119.40,
115.39, 110.04, 78.97, 75.86, 60.60, 55.43, 54.52, 46.85, 46.67, 33.88,
29.97; Anal. Calcd for C33H33N3O5: C, 71.85; H, 6.03; N, 7.62. Found:
C, 72.12; H, 6.34; N, 7.90. Single-crystal X-ray diagram: crystal of
compound 3a was grown by slow diffusion of EtOAc into a solution
of compound 3a in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the triclinic crystal system, space group Pꢂ1,
5b, R = H, R / R = OCH O (65%)
2
3
2
Scheme 6. Reaction of 1aeb with 2f.
3. Conclusion
In summary, we have successfully presented a synthetic meth-
odology for the skeleton of cyclohexanes 3 by the treatment of
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼10.3140(3) A, b¼11.3462(3) A, c¼13.1298(4) A, V¼1384.42(7) A ,
Z¼2, Dcalcd¼1.323 g/cm3, F(000)¼584, 2
q
range 1.60e26.40ꢁ, R in-
functionalized arylbenzaldehydes
1 with 2-acetylpyridine 2a,
dices (all data) R1¼0.0446, wR2¼0.0976.
which involved a base-mediated ClaiseneSchmidt condensation,
a Michael reaction followed by a double aldol reaction. The novel
strategy showed that the reaction condition provides an excellent
stereochemical control of chiral centers on the carbocyclic skeleton
3 and dendritic benzenoid skeleton 5.
4.2.2. (6-Benzo[1,3]dioxol-5-yl-2,4-dihydroxy-2,4-di-pyridin-2-yl-
cyclohexyl)-pyridin-2-yl-methanone (3b). Yield 65% (161 mg); vis-
cous gum; HRMS (ESI, Mþþ1) calcd for C29H26N3O5 496.1873, found
496.1882; 1H NMR (400 MHz, CDCl3):
d
8.50 (ddd, J¼0.8, 1.6, 4.8 Hz,
1H), 8.47 (ddd, J¼0.8, 1.6, 4.8 Hz, 1H), 8.25 (ddd, J¼0.8, 1.6, 4.8 Hz,
1H), 7.75 (dt, J¼0.8, 8.0 Hz, 1H), 7.65 (dt, J¼2.0, 7.6 Hz, 1H), 7.56 (dt,
J¼0.8, 8.0 Hz, 1H), 7.46 (dt, J¼1.6, 7.6 Hz, 1H), 7.43e7.36 (m, 3H), 7.17
(ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 7.11 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H),
6.88e6.81 (m, 2H), 6.72 (dd, J¼1.6, 8.0 Hz, 1H), 6.43 (d, J¼7.6 Hz,
1H), 5.70e5.68 (m, 2H), 5.38 (d, J¼12.4 Hz, 1H), 4.01 (dt, J¼3.2,
12.4 Hz, 1H), 3.07 (d, J¼14.4 Hz, 1H), 2.65 (t, J¼13.2 Hz, 1H), 2.05 (dt,
J¼2.8, 13.2 Hz, 1H), 2.10e2.05 (m, 1H), 1.99 (dd, J¼2.4, 14.4 Hz, 1H);
4. Experimental section
4.1. General
All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous MgSO4 before concentration in vacuo. Melting points
were determined with a SMP3 melting apparatus. 1H and 13C NMR
spectra were recorded on a Varian INOVA-400 spectrometer oper-
13C NMR (100 MHz, CDCl3):
d 204.61, 164.91, 162.62, 153.46, 148.04,
147.92, 147.80, 147.03, 136.66, 136.25, 136.21, 136.18, 126.13, 121.81,
121.78, 121.75, 121.27, 120.00, 119.25, 113.86, 108.72, 107.64, 100.44,
78.83, 75.73, 54.27, 46.55, 46.39, 39.79.
ating at 200/400 and at 100 MHz, respectively. Chemical shifts (d)
are reported in parts per million (ppm) and the coupling constants
(J) are given in hertz. High resolution mass spectra (HRMS) were
measured with a mass spectrometer Finnigan/Thermo Quest MAT
95XL. X-ray crystal structures were obtained with an Enraf-Nonius
FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were
carried out with Heraeus Vario III-NCSH, Heraeus CHNeOSeRapid
Analyzer or Elementar Vario EL III.
4.2.3. [2,4-Dihydroxy-2,4-di-pyridin-2-yl-6-(3,4,5-trimethoxy-phe-
nyl)-cyclohexyl]-pyridin-2-yl-methanone (3c). Yield 68% (184 mg);
viscous gum; HRMS (ESI, Mþþ1) calcd for C31H32N3O6 542.2291,
found 542.2288; 1H NMR (400 MHz, CDCl3):
d
8.39 (ddd, J¼0.8, 1.6,
4.8 Hz, 1H), 8.34 (ddd, J¼0.8, 1.6, 4.8 Hz, 1H), 8.12 (ddd, J¼0.8, 1.6,
4.8 Hz, 1H), 7.65 (d, J¼7.6 Hz, 1H), 7.56 (dt, J¼1.6, 8.0 Hz, 1H), 7.46 (d,
J¼8.0 Hz, 1H), 7.34 (dt, J¼1.6, 7.6 Hz, 1H), 7.30e7.25 (m, 2H), 7.06
(ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 7.01 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 6.72
(ddd, J¼1.6, 4.8, 7.6 Hz, 1H), 6.45 (s, 2H), 6.32 (br s, 1H), 6.12 (br s,
1H), 5.42 (d, J¼12.0 Hz,1H), 3.95 (dt, J¼3.2,12.0 Hz,1H), 3.56 (s, 6H),
3.49 (s, 3H), 2.96 (d, J¼14.4 Hz, 1H), 2.52 (t, J¼13.2 Hz, 1H), 2.02 (dt,
J¼2.8, 13.2 Hz, 1H), 1.89 (dd, J¼2.4, 14.4 Hz, 1H); 13C NMR (100 MHz,
4.2. A representative synthetic procedure of skeleton 3 is as
follows
NaOH (160 mg, 4.0 mmol) was added to a solution of skeleton 1
(0.5 mmol) in MeOH (15 mL) at rt. Then skeleton 2 (1.5 mmol) was
added to the reaction mixture. The reaction mixture was stirred at
reflux for 6 h. The reaction mixture was cooled to rt. HCl(aq) (0.5 N,
5 mL) was added to the reaction mixture and the solvent was
concentrated. The residue was diluted with water (10 mL) and the
mixture was extracted with EtOAc (3ꢀ20 mL). The combined or-
ganic layers were washed with brine, dried, filtered, and evapo-
rated to afford crude product. Purification on silica gel (hexanes/
EtOAc¼10/1e6/1) afforded skeleton 3, 4 or 5.
CDCl3):
d
204.33, 164.73, 162.19, 153.68, 152.62 (2ꢀ), 147.88, 147.74,
147.46, 138.36, 136.79, 136.29, 136.21, 135.91, 126.25, 121.89, 121.86,
121.75, 120.17, 119.31, 104.90 (2ꢀ), 78.63, 75.76, 60.49, 55.78 (2ꢀ),
53.16, 47.02, 46.48, 40.42.
4.2.4. [2,4-Dihydroxy-6-(3-methoxy-phenyl)-2,4-di-pyridin-2-yl-cy-
clohexyl]-pyridin-2-yl-methanone (3d). Yield 72% (173 mg); viscous
gum; HRMS (ESI, Mþþ1) calcd for C29H28N3O4 482.2080, found
482.2087; 1H NMR (400 MHz, CDCl3):
d
8.52 (dd, J¼0.8, 4.8 Hz, 1H),
8.46 (dd, J¼0.8, 4.8 Hz, 1H), 8.27 (dd, J¼0.8, 4.8 Hz, 1H), 7.77 (d,
J¼8.0 Hz,1H), 7.68 (dt, J¼1.6, 7.6 Hz,1H), 7.47e7.39 (m, 3H), 7.20e7.10
(m, 2H), 6.93e6.90 (m, 4H), 6.86 (ddd, J¼0.8, 4.8, 7.6 Hz,1H), 6.63 (br
s, 1H), 6.48 (ddd, J¼0.8, 4.8, 8.0 Hz, 1H), 6.26 (br s, 1H), 5.48 (d,
J¼12.0 Hz, 1H), 4.10 (dt, J¼3.2, 12.0 Hz, 1H), 3.63 (s, 3H), 3.12 (d,
J¼14.4 Hz, 1H), 2.69 (t, J¼13.2 Hz, 1H), 2.13 (dt, J¼3.2, 13.2 Hz, 1H),
4.2.1. [6-(2-Allyl-3,4-dimethoxy-phenyl)-2,4-dihydroxy-2,4-di-pyr-
idin-2-yl-cyclohexyl]-pyridin-2-yl-methanone
(3a). Yield
78%
(215 mg); colorless solid; mp¼146e147 ꢁC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C33H34N3O5
552.2499, found 552.2508; 1H NMR (400 MHz, CDCl3):
d 8.50 (ddd,
J¼1.6, 2.4, 4.4 Hz, 2H), 8.31 (ddd, J¼0.8, 2.0, 4.8 Hz, 1H), 7.74 (dt,
2.03 (dd, J¼2.4, 14.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 204.35,
J¼1.2, 8.0 Hz, 1H), 7.67 (dt, J¼2.0, 7.6 Hz, 1H), 7.58 (dt, J¼1.2, 2.0 Hz,
164.92, 162.57, 159.21, 153.60, 147.95, 147.78, 147.60, 144.00, 136.73,

9620
M.-Y. Chang, M.-H. Wu / Tetrahedron 68 (2012) 9616e9623
136.28, 136.19, 128.96, 126.16, 121.85, 121.82 (2ꢀ), 120.69, 120.17,
121.83, 121.78, 120.41, 120.12, 119.37, 117.62, 113.01, 111.47, 78.91,
75.87, 69.69, 55.69, 53.94, 46.84, 46.45, 39.85.
119.33, 112.90, 112.74, 78.76, 75.76, 54.99, 53.89, 46.63, 46.45, 40.18.
4.2.5. [6-(4-Benzyloxy-3-methoxy-phenyl)-2,4-dihydroxy-2,4-di-
pyridin-2-yl-cyclohexyl]-pyridin-2-yl-methanone (3e). Yield 74%
(217 mg); viscous gum; HRMS (ESI, Mþþ1) calcd for C36H34N3O5
4.2.9. [2,4-Dihydroxy-6-(4-hydroxy-3-methoxy-phenyl)-2,4-di-pyr-
idin-2-yl-cyclohexyl]-pyridin-2-yl-methanone
(3i). Yield
68%
(169 mg); colorless solid; mp >230 ꢁC (recrystallized from hexanes
and EtOAc); HRMS (ESI, Mþþ1) calcd for C29H28N3O5 498.2029, found
588.2499, found 588.2504; 1H NMR (400 MHz, CDCl3):
d 8.53 (dd,
J¼1.6, 5.6 Hz, 1H), 8.46 (dd, J¼1.6, 5.6 Hz, 1H), 8.28 (dd, J¼1.6,
4.8 Hz, 1H), 7.78 (d, J¼8.0 Hz, 1H), 7.69 (dt, J¼1.6, 8.0 Hz, 1H), 7.60
(dt, J¼1.6, 8.0 Hz, 1H), 7.48e7.28 (m, 8H), 7.19e7.11 (m, 2H), 7.04
(d, J¼1.6 Hz, 1H), 6.88e6.85 (m, 2H), 6.57 (d, J¼8.4 Hz, 1H), 6.55 (br
s, 1H), 6.25 (br s, 1H), 5.47 (d, J¼12.0 Hz, 1H), 4.98 (d, J¼11.6 Hz,
1H), 4.89 (d, J¼11.6 Hz, 1H), 4.04 (dt, J¼3.2, 12.0 Hz, 1H), 3.67 (s,
3H), 3.10 (d, J¼14.4 Hz, 1H), 2.66 (t, J¼13.2 Hz, 1H), 2.10 (dt, J¼2.8,
13.2 Hz, 1H), 2.03 (dd, J¼2.4, 14.4 Hz, 1H); 13C NMR (100 MHz,
498.2032; 1H NMR (400 MHz, CDCl3):
d
8.53 (d, J¼4.0 Hz,1H), 8.48 (d,
J¼4.4 Hz, 1H), 8.28 (dd, J¼4.0 Hz, 1H), 7.80 (d, J¼7.6 Hz, 1H), 7.71 (dt,
J¼1.6, 7.6 Hz, 1H), 7.56 (d, J¼8.0 Hz, 1H), 7.54e7.37 (m, 2H), 7.20 (dd,
J¼4.4, 7.6 Hz,1H), 7.14 (ddd, J¼4.4, 7.6 Hz,1H), 6.89e6.84 (m, 2H), 6.76
(d, J¼8.4 Hz,1H), 6.56 (d, J¼8.4 Hz,1H), 6.26 (s,1H), 5.46 (d, J¼12.0 Hz,
1H), 5.36 (br s,1H), 4.40 (d, J¼5.6 Hz,1H), 4.04 (dt, J¼4.8,10.4 Hz,1H),
3.74 (s, 3H), 3.10 (d, J¼14.0 Hz, 1H), 2.66 (t, J¼13.2 Hz, 1H), 2.11 (dt,
J¼3.2,13.2Hz,1H),2.02(dd,J¼2.4,14.0Hz,1H),1.73(brs,1H);13CNMR
CDCl3):
d
204.77, 165.01, 162.69, 153.61, 148.99, 147.98, 147.80,
(100 MHz, CDCl3): d 204.74, 165.05, 162.69, 153.64, 148.66, 148.00,
147.65, 137.12, 136.75, 136.32, 136.24, 135.04, 132.28, 128.38 (2ꢀ),
127.70, 127.49 (2ꢀ), 126.22, 121.88, 121.82, 121.14, 120.12, 119.61,
119.34, 113.95, 113.81, 111.60, 78.92, 70.80, 55.88, 54.05, 46.79,
46.47, 39.74.
147.76, 147.66, 143.85, 136.79, 136.35, 136.32, 134.41, 126.23, 121.92,
121.89, 121.85, 120.13, 120.13, 119.40, 113.85, 110.73, 78.90, 75.89,
55.78, 54.19, 46.98, 46.47, 39.88. Single-crystal X-ray diagram: crystal
of compound 3i was grown by slow diffusion of EtOAc into a solution
of compound 3i in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group P 1 21/n 1,
4.2.6. [6-(3-Benzyloxy-4-methoxy-phenyl)-2,4-dihydroxy-2,4-di-
pyridin-2-yl-cyclohexyl]-pyridin-2-yl-methanone (3f). Yield 77%
(226 mg); colorless solid; mp¼174e176 ꢁC (recrystallized from
hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for C36H34N3O5
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼10.9658(3) A, b¼19.6631(6) A, c¼12.0754(3) A, V¼2506.74(12) A ,
Z¼4, Dcalcd¼1.318 g/cm3, F(000)¼1048, 2
q
range 2.04e26.40ꢁ, R in-
dices (all data) R1¼0.0561, wR2¼0.0996.
588.2499, found 588.2509; 1H NMR (400 MHz, CDCl3):
d 8.53 (ddd,
J¼0.8, 1.6, 4.8 Hz, 1H), 8.46 (ddd, J¼0.8, 1.6, 4.8 Hz, 1H), 8.28 (ddd,
J¼0.8, 1.6, 4.8 Hz, 1H), 7.91 (dt, J¼1.2, 8.0 Hz, 1H), 7.75 (dt, J¼1.6,
7.6 Hz, 1H), 7.69 (dt, J¼1.6, 7.6 Hz, 1H), 7.60 (dt, J¼0.8, 8.0 Hz, 1H),
7.50e7.37 (m, 5H), 7.31e7.28 (m, 4H), 7.20e7.11 (m, 3H), 6.92 (br d,
J¼2.0 Hz, 1H), 6.56 (d, J¼8.4 Hz, 1H), 6.25 (br s, 1H), 5.47 (d,
J¼12.0 Hz, 1H), 4.94 (s, 2H), 4.05 (dt, J¼3.2, 12.0 Hz, 1H), 3.74 (s, 3H),
3.10 (d, J¼14.4 Hz, 1H), 2.67 (t, J¼13.2 Hz, 1H), 2.11 (dt, J¼3.2,
13.2 Hz, 1H), 2.03 (dd, J¼2.4, 14.4 Hz, 1H).
4.2.10. [2,4-Dihydroxy-6-(4-methoxy-3-prop-2-ynyloxy-phenyl)-
2,4-di-pyridin-2-yl-cyclohexyl]-pyridin-2-yl-methanone (3j). Yield
75% (201 mg); viscous gum; HRMS (ESI, Mþþ1) calcd for
C32H30N3O5 536.2186, found 536.2198; 1H NMR (400 MHz, CDCl3):
d
8.50 (ddd, J¼0.8, 2.4, 4.8 Hz, 1H), 8.46 (ddd, J¼0.8, 2.4, 4.8 Hz, 1H),
8.25 (ddd, J¼0.8, 2.4, 4.8 Hz, 1H), 7.76 (d, J¼7.6 Hz, 1H), 7.67 (dt,
J¼1.6, 7.6 Hz, 1H), 7.58 (d, J¼8.0 Hz, 1H), 7.47e7.38 (m, 3H), 7.17
(ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 7.12 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 6.97 (br
d, J¼1.6 Hz, 1H), 6.91 (dd, J¼2.0, 8.4 Hz, 1H), 6.85 (ddd, J¼1.2, 4.8,
7.6 Hz, 1H), 6.57 (br s, 1H), 6.55 (d, J¼8.4 Hz, 1H), 6.24 (s, 1H), 5.43
(d, J¼12.0 Hz, 1H), 4.57 (d, J¼2.4 Hz, 2H), 4.05 (d, J¼3.2, 12.4 Hz, 1H),
3.65 (s, 3H), 3.08 (d, J¼14.4 Hz, 1H), 2.65 (t, J¼13.6 Hz, 1H), 2.43 (t,
J¼2.4 Hz, 1H), 2.10 (dt, J¼3.2, 13.6 Hz, 1H), 2.01 (dd, J¼2.4, 14.4 Hz,
4.2.7. [2,4-Dihydroxy-2,4-di-pyridin-2-yl-6-(2,3,4-trimethoxy-phe-
nyl)-cyclohexyl]-pyridin-2-yl-methanone (3g). Yield 77% (208 mg);
viscous gum; HRMS (ESI, Mþþ1) calcd for C31H32N3O6 542.2291,
found 542.2296; 1H NMR (400 MHz, CDCl3):
d
8.48 (ddd, J¼0.8, 1.6,
4.8 Hz, 2H), 8.29 (ddd, J¼0.8, 1.6, 4.8 Hz, 1H), 7.73 (dt, J¼7.6 Hz, 1H),
7.64 (dt, J¼1.6, 7.6 Hz,1H), 7.56 (dt, J¼0.8, 8.8 Hz,1H), 7.46 (dt, J¼1.6,
7.6 Hz, 1H), 7.41e7.34 (m, 4H), 7.17e7.11 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H),
7.10 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 6.84 (ddd, J¼0.8, 4.8, 7.6 Hz, 1H),
6.34 (d, J¼8.8 Hz, 1H), 6.28 (br s, 1H), 5.37 (d, J¼12.4 Hz, 1H), 4.53 (s,
1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.09 (d, J¼14.0 Hz, 1H),
2.12 (br s, 1H), 2.09e1.97 (m, 2H); 13C NMR (100 MHz, CDCl3):
1H); 13C NMR (100 MHz, CDCl3):
d 204.47, 164.90, 162.55, 153.55,
147.93, 147.88, 147.78, 147.57, 147.48, 146.21, 136.71, 136.27, 136.22,
134.93, 126.19, 121.85, 121.79 (2ꢀ), 120.08, 119.28, 114.16, 111.37,
78.79, 78.43, 75.79, 75.56, 56.59, 55.67, 54.12, 46.64, 46.64, 39.58.
4.2.11. [6-(2-Allyl-3-allyloxy-4-methoxy-phenyl)-2,4-dihydroxy-2,4-
di-pyridin-2-yl-cyclohexyl]-pyridin-2-yl-methanone (3k). Yield 70%
(202 mg); colorless solid; mp¼130e132 ꢁC (recrystallized from hex-
anes and EtOAc); HRMS (ESI, Mþþ1) calcd for C35H36N3O5 578.2655,
d
204.41, 164.98, 163.04, 153.80, 148.89, 147.89, 147.75, 147.72,
136.66, 136.31, 136.23, 132.28, 128.38 (2ꢀ), 127.70, 127.49 (2ꢀ),
126.03, 121.90, 120.00, 119.36, 107.04, 78.90, 75.76, 61.05, 60.46,
55.75, 54.29, 46.48, 46.39, 31.44.
found 578.2661; 1H NMR (400 MHz, CDCl3):
d
8.49 (dd, J¼1.6, 4.4 Hz,
2H), 8.30 (dd, J¼1.6, 4.8 Hz, 1H), 7.74 (dt, J¼1.2, 8.0 Hz, 1H), 7.66 (dt,
J¼1.6, 7.6 Hz,1H), 7.57 (dt, J¼1.6, 7.6 Hz,1H), 7.39 (dt, J¼1.6, 7.6 Hz, 1H),
7.37e7.35 (m, 1H), 7.36 (t, J¼8.8 Hz, 1H), 7.17 (ddd, J¼1.2, 4.8, 7.6 Hz,
1H), 7.12 (ddd, J¼1.2, 4.8, 7.6 Hz,1H), 6.85 (ddd, J¼1.2, 4.8, 7.6 Hz,1H),
6.68 (br s, 1H), 6.49 (d, J¼8.4 Hz, 1H), 6.17 (s, 1H), 6.05e6.94 (m, 2H),
5.45 (d, J¼12.0 Hz, 1H), 5.29 (dq, J¼1.6, 17.2 Hz, 1H), 5.14 (dq, J¼1.6,
10.4 Hz, 1H), 5.03 (s, 1H), 5.00 (dd, J¼1.6, 8.8 Hz, 1H), 4.38e4.24 (m,
3H), 3.64 (s, 3H), 3.57e3.44 (m, 2H), 3.10 (dd, J¼0.8,14.0 Hz,1H), 2.54
(t, J¼13.6 Hz, 1H), 2.07e1.98 (m, 3H); 13C NMR (100 MHz, CDCl3):
4.2.8. [6-(4-Allyloxy-3-methoxy-phenyl)-2,4-dihydroxy-2,4-di-pyr-
idin-2-yl-cyclohexyl]-pyridin-2-yl-methanone
(3h). Yield
73%
(196 mg); viscous gum; HRMS (ESI, Mþþ1) calcd for C32H32N3O5
538.2342, found 538.2348; 1H NMR (400 MHz, CDCl3):
d 8.52 (dd,
J¼1.6, 4.8 Hz,1H), 8.47 (dd, J¼1.6, 4.8 Hz,1H), 8.27 (dd, J¼1.6, 4.8 Hz,
1H), 7.78 (d, J¼8.0 Hz, 1H), 7.69 (dt, J¼1.6, 8.0 Hz, 1H), 7.60 (d,
J¼8.0 Hz, 1H), 7.52e7.35 (m, 4H), 7.20 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H),
7.15 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 6.93e6.85 (m, 2H), 6.78 (dd, J¼2.0,
8.4 Hz, 1H), 6.54 (d, J¼8.4 Hz, 1H), 6.25 (s, 1H), 5.99e6.90 (m, 1H),
5.48 (d, J¼12.4 Hz, 1H), 5.25 (dq, J¼1.6, 17.2 Hz, 1H), 5.17 (dq, J¼1.6,
10.4 Hz,1H), 4.40 (d, J¼5.6 Hz, 2H), 4.05 (dt, J¼4.8, 10.4 Hz, 1H), 3.72
(s, 3H), 3.10 (d, J¼14.4 Hz,1H), 2.67 (t, J¼13.6 Hz, 1H), 2.10 (dt, J¼2.0,
12.8 Hz, 1H), 2.03 (dd, J¼2.0, 14.4 Hz, 1H); 13C NMR (100 MHz,
d
204.45, 164.92, 162.89, 153.80, 150.82, 147.89, 147.72, 145.51, 136.97,
136.68, 136.27, 136.22, 134.44, 133.87, 132.27, 127.70, 126.01, 123.57,
121.82, 121.76, 120.16, 119.98, 119.38, 116.65, 115.31, 109.96, 78.97,
75.84, 73.55, 55.42, 54.53, 46.81, 46.63, 33.88, 30.12.
4.2.12. [2,4-Dihydroxy-6-(4-methoxy-phenyl)-2,4-di-pyridin-2-yl-
cyclohexyl]-pyridin-2-yl-methanone (3l). Yield 69% (166 mg); col-
orless solid; mp¼113e115 ꢁC (recrystallized from hexanes and
CDCl3):
d 204.38, 165.02, 162.64, 153.58, 148.79, 147.98, 147.80,
147.63, 146.19, 136.76, 136.33, 136.26, 135.41, 133.39, 126.26, 121.88,

M.-Y. Chang, M.-H. Wu / Tetrahedron 68 (2012) 9616e9623
9621
EtOAc); HRMS (ESI, Mþþ1) calcd for C29H28N3O4 482.2080, found
127.07, 126.00, 125.86, 125.66, 121.77, 121.74, 121.60, 120.00, 119.22,
78.63, 75.67, 54.12, 46.45, 46.00, 34.13, 19.38.
482.2084; 1H NMR (400 MHz, CDCl3):
d
8.51 (dd, J¼0.8, 4.8 Hz, 1H),
8.46 (d, J¼4.8 Hz, 1H), 8.28 (d, J¼4.8 Hz, 1H), 7.76 (d, J¼8.0 Hz, 1H),
7.67 (dt, J¼1.6, 7.6 Hz, 1H), 7.58 (d, J¼8.0 Hz, 1H), 7.47e7.38 (m, 3H),
7.21 (d, J¼7.6 Hz, 2H), 7.17 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 7.12 (ddd,
J¼1.2, 4.8, 7.6 Hz, 1H), 6.85 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 6.66 (br s,
1H), 6.61 (d, J¼7.6 Hz, 2H), 6.26 (s, 1H), 5.40 (d, J¼12.4 Hz, 1H), 4.04
(dt, J¼3.6, 12.8 Hz, 1H), 3.59 (s, 3H), 3.10 (d, J¼14.4 Hz, 1H), 2.68 (t,
J¼13.2 Hz, 1H), 2.08 (dt, J¼2.4, 13.2 Hz, 1H), 2.01 (dd, J¼2.0, 14.4 Hz,
4.2.16. (6-Furan-2-yl-2,4-dihydroxy-2,4-di-pyridin-2-yl-cyclohexyl)-
pyridin-2-yl-methanone (3q). Yield 71% (157 mg); viscous gum;
HRMS (ESI, Mþþ1)calcd forC26H24N3O4 442.1767, found 442.1773;1H
NMR (400 MHz, CDCl3):
d
8.51 (dd, J¼1.6, 4.8 Hz, 1H), 8.46 (dd, J¼1.6,
4.8 Hz,1H), 8.24 (dd, J¼1.6, 5.6 Hz,1H), 7.76 (dd, J¼1.2, 8.0 Hz,1H), 7.67
(dt, J¼1.6, 7.2 Hz, 1H), 7.64e7.51 (m, 3H), 7.42 (dt, J¼1.6, 7.2 Hz, 1H),
7.21 (ddd, J¼1.6, 4.8, 7.2 Hz, 1H), 7.13 (ddd, J¼1.6, 4.8, 7.2 Hz,1H), 6.96
(d, J¼2.0 Hz,1H), 6.86 (ddd, J¼1.2, 4.8, 7.2 Hz,1H), 6.50 (br s,1H), 6.18
(s, 1H), 5.96e5.91 (m, 2H), 5.39 (d, J¼12.0 Hz, 1H), 4.19 (dt, J¼3.6,
12.0 Hz, 1H), 2.99 (d, J¼14.4 Hz, 1H), 2.78 (t, J¼13.6 Hz, 1H), 2.19 (dt,
J¼2.4, 13.6 Hz, 1H), 2.00 (dd, J¼2.4, 14.4 Hz, 1H); 13C NMR (100 MHz,
1H); 13C NMR (100 MHz, CDCl3):
d 204.80, 165.07, 162.82, 157.89,
153.51, 147.98, 147.79, 147.69, 136.67, 136.27, 136.21, 134.38, 129.20
(2ꢀ), 126.13, 121.86, 121.82, 121.75, 120.15, 119.30, 113.33 (2ꢀ),
78.91, 75.82, 54.99, 54.57, 46.61, 46.42, 39.27.
4.2.13. (2,4-Dihydroxy-6-phenyl-2,4-di-pyridin-2-yl-cyclohexyl)-
pyridin-2-yl-methanone (3m). Yield 80% (180 mg); colorless solid;
mp¼178e179 ꢁC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C28H26N3O3 452.1974, found 452.1981; 1H
CDCl3): d 204.81, 164.83, 162.67, 155.95,153.30,148.07, 148.01, 147.66,
140.75, 136.70, 136.32, 136.25, 126.17, 121.88, 121.82, 121.80, 120.09,
119.34, 109.69, 105.63, 78.84, 75.37, 52.45, 46.47, 43.06, 33.66.
NMR (400 MHz, CDCl3):
d
8.51 (dd, J¼0.8, 4.8 Hz, 1H), 8.44 (dd,
4.2.17. (2,4-Dihydroxy-2,4-di-pyridin-2-yl-6-thiophen-2-yl-cyclo-
hexyl)-pyridin-2-yl-methanone (3r). Yield 70% (160 mg); colorless
solid; mp¼183e185 ꢁC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C26H24N3O3S 458.1538, found 458.1545; 1H NMR
J¼0.8, 4.8 Hz, 1H), 8.28 (dd, J¼1.2, 4.0 Hz, 1H), 7.77 (dt, J¼0.8, 8.0 Hz,
1H), 7.66 (dt, J¼2.0, 8.0 Hz, 1H), 7.59 (dt, J¼1.2, 8.0 Hz, 1H),
7.44e7.35 (m, 3H), 7.30 (d, J¼8.4 Hz, 2H), 7.16e7.10 (m, 2H), 7.00 (t,
J¼7.6 Hz, 2H), 6.91 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 6.85 (ddd, J¼0.8, 4.8,
7.6 Hz, 1H), 6.64 (br s, 1H), 6.33 (s, 1H), 5.46 (d, J¼12.4 Hz, 1H), 4.09
(dt, J¼3.6, 12.4 Hz, 1H), 3.12 (d, J¼14.0 Hz, 1H), 2.72 (t, J¼13.2 Hz,
1H), 2.11 (dt, J¼2.8, 14.0 Hz, 1H), 2.03 (dd, J¼2.8, 14.4 Hz, 1H); 13C
(400 MHz, CDCl3):
d
8.52 (ddd, J¼0.8, 1.6, 4.8 Hz, 1H), 8.44 (dt, J¼1.2,
4.8 Hz, 1H), 8.26 (ddd, J¼0.8, 1.6, 4.8 Hz, 1H), 7.76 (dt, J¼0.8, 8.0 Hz, 1H),
7.68 (dt, J¼1.6, 7.6 Hz, 1H), 7.56 (dt, J¼0.8, 8.0 Hz,1H), 7.50e7.48 (m, 2H),
7.40 (dt, J¼1.6, 7.2 Hz, 1H), 7.19e7.12 (m, 2H), 6.87e6.83 (m, 3H), 6.60
(dd, J¼3.6, 5.2 Hz,1H), 6.58 (br s,1H), 6.22 (s,1H), 5.38 (d, J¼11.6 Hz,1H),
4.45 (dt, J¼3.6, 12.0 Hz, 1H), 3.10 (dd, J¼0.8, 14.4 Hz, 1H), 2.73 (t,
J¼13.2 Hz,1H), 2.60 (ddd, J¼2.4, 3.2,13.6 Hz,1H), 2.00 (dd, J¼2.4,14.4 Hz,
NMR (100 MHz, CDCl3):
d 204.61, 165.99, 162.72, 153.48, 147.95,
147.78, 147.65, 142.22, 136.67, 136.26, 136.16, 128.22 (2ꢀ), 127.92
(2ꢀ), 126.26, 126.12, 121.82, 121.79, 121.76, 120.03, 119.29, 78.85,
75.74, 54.18, 46.41 (2ꢀ), 40.09.
1H); 13C NMR (100 MHz, CDCl3):
d 203.84,164.66,162.32,153.43,147.98,
147.88,147.59, 146.22,136.75,136.27, 136.21,126.16 (2ꢀ), 124.76,123.01,
121.89, 121.87, 121.82, 120.11, 119.31, 78.67, 75.63, 55.50, 47.40, 46.35,
35.17. Single-crystal X-ray diagram: crystal of compound 3r was grown
by slow diffusion of EtOAc into a solution of compound 3r in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the triclinic crystal
4.2.14. (6-Biphenyl-4-yl-2,4-dihydroxy-2,4-di-pyridin-2-yl-cyclo-
hexyl)-pyridin-2-yl-methanone (3n). Yield 82% (216 mg); colorless
solid; mp¼225e227 ꢁC (recrystallized from hexanes and EtOAc);
HRMS (ESI, Mþþ1) calcd for C34H30N3O3 528.2287, found 528.2297;
1H NMR (400 MHz, CDCl3):
d
8.54 (dd, J¼0.8, 4.8 Hz, 1H), 8.47 (dd,
system, space group Pꢂ1, a¼6.0683(9) A, b¼10.2258(14) A,
3
ꢀ ꢀ
ꢀ
ꢀ
J¼0.8, 4.8 Hz, 1H), 8.30 (dd, J¼1.2, 4.0 Hz, 1H), 7.79 (dt, J¼0.8, 8.0 Hz,
1H), 7.69 (dt, J¼2.0, 8.0 Hz, 1H), 7.62 (d, J¼8.0 Hz, 1H), 7.48e7.16 (m,
12H), 7.17e7.10 (m, 2H), 6.88 (ddd, J¼1.2, 4.8, 7.6 Hz, 1H), 6.62 (br s,
1H), 6.29 (s, 1H), 5.52 (d, J¼12.0 Hz, 1H), 4.16 (dt, J¼3.2, 12.4 Hz, 1H),
3.15 (d, J¼14.4 Hz, 1H), 2.77 (t, J¼13.6 Hz, 1H), 2.17 (dt, J¼2.4,
13.6 Hz, 1H), 2.06 (dd, J¼2.4, 14.4 Hz, 1H); 13C NMR (100 MHz,
c¼19.178(3) A, V¼1130.2(3) A , Z¼2, Dcalcd¼1.344 g/cm3, F(000)¼480,
2q
range 1.08e26.50ꢁ, R indices (all data) R1¼0.1088, wR2¼0.2818.
4.2.18. (2,4-Dihydroxy-2,4,6-tri-pyridin-2-yl-cyclohexyl)-pyridin-2-
yl-methanone (3s). Yield 65% (147 mg); colorless solid;
mp¼165e167 ꢁC(recrystallized from hexanesandEtOAc);HRMS(ESI,
Mþþ1) calcd for C27H25N4O3 453.1927, found 453.1933; 1H NMR
CDCl3):
d 204.83, 164.99, 162.76, 153.58, 148.01, 147.88, 147.70,
141.49, 140.86, 139.08, 136.74, 136.32, 136.19, 128.68 (2ꢀ), 128.52
(2ꢀ), 127.17, 126.96, 126.79 (2ꢀ), 126.70 (2ꢀ), 126.13, 121.88 (2ꢀ),
120.13, 119.35, 78.94, 75.80, 54.09, 46.51, 46.43, 39.84. Single-
crystal X-ray diagram: crystal of compound 3n was grown by
slow diffusion of EtOAc into a solution of compound 3n in CH2Cl2 to
(400 MHz, CDCl3):
d
8.48 (dd, J¼1.6, 4.8 Hz,1H), 8.36 (dt, J¼1.2, 4.8 Hz,
1H), 8.20e8.19 (m, 2H), 7.75 (dt, J¼1.2, 8.0 Hz, 1H), 7.65 (dt, J¼1.6,
7.6 Hz, 1H), 7.57 (dt, J¼1.2, 8.0 Hz, 1H), 7.50e7.42 (m, 2H), 7.40e7.33
(m, 2H), 7.27e7.25 (m,1H), 7.12e7.09 (m, 2H), 6.89e6.79(m, 2H), 6.44
(br s, 1H), 6.19 (s, 1H), 5.50 (d, J¼12.0 Hz, 1H), 4.35 (dt, J¼3.2, 12.0 Hz,
1H), 3.12 (d,J¼14.4 Hz,1H), 2.84 (t, J¼13.2 Hz,1H), 2.17(ddd,J¼2.4, 3.2,
13.2 Hz,1H), 2.00 (dd, J¼2.4,14.4 Hz,1H); 13C NMR (100 MHz, CDCl3):
yield colorless prisms. The compound crystallizes in the monoclinic
ꢀ
crystal system, space group
C
1
2/c 1, a¼19.4402(11) A,
3
ꢀ
ꢀ
ꢀ
b¼10.4392(7) A, c¼27.0384(18) A, V¼5320.7(6) A , Z¼8,
d
204.05, 164.88, 162.28, 161.90, 153.83, 148.61, 147.94 (2ꢀ), 147.35,
Dcalcd¼1.317 g/cm3, F(000)¼2224, 2
q
range 2.16e26.52ꢁ, R indices
136.66, 136.14, 136.01, 135.96, 125.74, 123.01, 121.78 (2ꢀ), 121.20,
(all data) R1¼0.0780, wR2¼0.1539.
120.43, 119.34, 78.40, 75.56, 53.20, 46.47, 44.44, 41.85.
4.2.15. (2,4-Dihydroxy-2,4-di-pyridin-2-yl-6-o-tolyl-cyclohexyl)-
pyridin-2-yl-methanone (3o). Yield 83% (193 mg); colorless solid;
mp¼174e175 ꢁC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C29H28N3O3 466.2131, found 466.2123; 1H
4.2.19. (2,4-Dihydroxy-6-pyridin-4-yl-2,4-di-pyridin-2-yl-cyclo-
hexyl)-pyridin-2-yl-methanone (3t). Yield 60% (136 mg); colorless
solid; mp¼95e97 ꢁC (recrystallized from hexanes and EtOAc);
HRMS (ESI, Mþþ1) calcd for C27H25N4O3 453.1927, found 453.1935;
NMR (400 MHz, CDCl3):
d
8.49 (dd, J¼0.8, 4.8 Hz, 1H), 8.44 (dd,
1H NMR (400 MHz, CDCl3):
d
8.52 (dd, J¼1.6, 4.8 Hz, 1H), 8.43 (dt,
J¼0.8, 4.8 Hz, 1H), 8.29 (dd, J¼1.2, 4.0 Hz, 1H), 7.73 (d, J¼8.0 Hz, 1H),
7.65 (dt, J¼2.0, 7.6 Hz, 1H), 7.56 (dt, J¼1.2, 8.0 Hz, 2H), 7.41e7.32 (m,
3H), 7.14e7.08 (m, 2H), 6.91e6.80 (m, 4H), 6.74 (br s, 1H), 6.29 (s,
1H), 5.50 (d, J¼12.0 Hz, 1H), 4.46 (dt, J¼3.6, 12.4 Hz, 1H), 3.16 (d,
J¼14.4 Hz, 1H), 2.54 (t, J¼13.2 Hz, 1H), 2.35 (s, 3H), 2.05e1.99 (m,
J¼1.2, 4.8 Hz, 1H), 8.25 (d, J¼6.0 Hz, 2H), 8.24 (dd, J¼1.6, 4.8 Hz, 1H),
7.74 (dt, J¼1.2, 8.0 Hz, 1H), 7.64 (dt, J¼1.6, 7.6 Hz, 1H), 7.56 (dt, J¼1.2,
8.0 Hz, 1H), 7.48e7.38 (m, 3H), 7.29 (d, J¼6.0 Hz, 2H), 7.18e7.15 (m,
2H), 6.83 (ddd, J¼1.2, 4.8, 7.2 Hz, 1H), 6.41 (br s, 1H), 6.21 (s, 1H),
5.52 (d, J¼12.4 Hz, 1H), 4.13 (dt, J¼3.6, 12.4 Hz, 1H), 3.10 (d,
J¼14.4 Hz, 1H), 2.68 (t, J¼13.2 Hz, 1H), 2.07 (ddd, J¼2.4, 3.2, 13.2 Hz,
1H), 2.01 (dd, J¼2.4, 14.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
2H); 13C NMR (100 MHz, CDCl3):
d 203.87, 164.71, 162.50, 153.58,
147.82, 147.69, 147.55, 140.61, 136.68, 136.21, 136.13, 135.66, 129.87,

9622
M.-Y. Chang, M.-H. Wu / Tetrahedron 68 (2012) 9616e9623
d
203.60, 164.50, 162.00, 153.37, 151.78, 149.42 (2ꢀ), 148.01, 148.00,
Mþþ1) calcd for C24H25O4S2 441.1194, found 441.1202; 1H NMR
147.53, 136.88, 136.40, 136.33, 126.46, 123.59 (2ꢀ), 122.00 (2ꢀ),
(400 MHz, CDCl3):
d
7.77 (dd, J¼1.2, 4.0 Hz, 2H), 7.59 (dd, J¼1.2,
121.69, 120.22, 119.34, 78.49, 75.46, 52.84, 46.49, 45.60, 39.50.
4.8 Hz, 2H), 7.09 (d, J¼4.0, 4.8 Hz, 2H), 7.05 (d, J¼8.8 Hz, 1H), 6.78
(dd, J¼8.8 Hz, 1H), 5.95e5.85 (m, 1H), 4.88e4.82 (m, 2H), 4.26e4.19
(m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.52 (dt, J¼1.6, 5.6 Hz, 2H), 3.39
(dd, J¼7.6, 16.0 Hz, 2H), 3.15 (dd, J¼6.8, 16.0 Hz, 2H); 13C NMR
4.2.20. [2,4-Dihydroxy-6-(1H-indol-3-yl)-2,4-di-pyridin-2-yl-cyclo-
hexyl]-pyridin-2-yl-methanone (3u). Yield 32% (78 mg); colorless
solid; mp¼202e204 ꢁC (recrystallized from hexanes and EtOAc);
HRMS (ESI, Mþþ1) calcd for C30H27N4O3 491.2083, found 491.2088; 1H
(100 MHz, CDCl3):
d
191.52 (2ꢀ), 151.09, 147.09, 144.16, 137.19 (2ꢀ),
134.68, 133.57 (2ꢀ), 132.16 (2ꢀ), 131.79, 128.03 (2ꢀ), 121.77, 114.93,
110.44, 60.65, 55.44, 45.45 (2ꢀ), 32.37, 29.93; Anal. Calcd for
C24H24O4S2: C, 65.43; H, 5.49. Found: C, 65.63; H, 5.69.
NMR (400 MHz, CDCl3):
d
9.43 (br s, 1H), 8.41 (ddd, J¼0.8, 1.6, 4.8 Hz,
1H), 8.32 (dt, J¼1.2, 4.8 Hz, 1H), 8.09 (br d, J¼4.4 Hz, 1H), 7.72 (br d,
J¼7.2 Hz, 1H), 7.59 (dt, J¼0.8, 8.0 Hz, 1H), 7.53 (d, J¼2.0 Hz, 1H),
7.43e7.36 (m, 4H), 7.19e7.17 (m, 1H), 7.07e6.99 (m, 4H), 6.85e6.82 (m,
2H), 6.67 (br s, 1H), 6.45 (s, 1H), 5.60 (d, J¼12.4 Hz, 1H), 4.53 (dt, J¼3.6,
12.0 Hz, 1H), 2.93 (d, J¼14.4 Hz, 1H), 2.27e2.13 (m, 2H), 1.92 (dd, J¼2.4,
4.2.25. (20-Allyl-30,40-dimethoxy-4,5-bis-thiazol-2-yl-biphenyl-2-yl)-
thiazol-2-yl-methanone (5a). Yield 72% (191 mg); yellowish solid;
mp¼88e90 ꢁC (recrystallized from hexanes and EtOAc); HRMS (ESI,
Mþþ1) calcd for C27H22N3O3S3 532.0823, found 532.0832; 1H NMR
14.4 Hz, 1H); 13CNMR(100MHz,CDCl3):
d204.17,164.01,163.25,153.93,
147.58 (2ꢀ), 147.36, 137.09, 136.41, 136.26, 136.04, 126.90, 125.78,
122.42, 121.78, 121.76, 121.67, 121.61, 120.25, 119.38, 119.19, 118.86,
118.33, 111.04, 78.65, 75.24, 54.15, 47.01, 46.06, 30.16.
(400 MHz, CDCl3):
d
8.52 (d, J¼1.2 Hz, 1H), 7.93 (d, J¼3.2 Hz, 1H),
7.90 (br d, J¼1.2 Hz, 1H), 7.74 (d, J¼3.2 Hz, 1H), 7.58e7.56 (m, 1H),
7.46 (br d, J¼2.8 Hz,1H), 7.41 (d, J¼3.6 Hz,1H), 7.25 (d, J¼2.8 Hz,1H),
6.75 (br s, 2H), 5.96e5.89 (m, 1H), 4.96 (dq, J¼1.6, 10.4 Hz, 1H), 4.81
(dq, J¼1.6, 17.2 Hz, 1H), 3.92 (d, J¼12.4 Hz, 2H), 3.81 (br s, 6H).
4.2.21. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1,5-diphenylpentane-1,5-
dione (4a). Yield 88% (188 mg); colorless solid; mp¼99e100 ꢁC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C28H29O4 429.2066, found 429.2070; 1H NMR (400 MHz, CDCl3):
4.2.26. (2-Benzo[1,3]dioxol-5-yl-4,5-bis-thiazol-2-yl-phenyl)-thia-
zol-2-yl-methanone (5b). Yield 65% (154 mg); viscous gum; HRMS
(ESI, Mþþ1) calcd for C23H14N3O3S3 476.0197, found 476.0201; 1H
d
7.97e7.94 (m, 4H), 7.57e7.52 (m, 2H), 7.46e7.42 (m, 4H), 7.04 (d,
J¼8.4 Hz, 1H), 6.79 (d, J¼8.4 Hz, 1H), 5.90e5.81 (m, 1H), 4.86e4.80
(m, 2H), 4.27e4.20 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.49e3.43 (m,
4H), 3.21 (dd, J¼6.4, 16.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
NMR (400 MHz, CDCl3):
d
8.42 (d, J¼1.6 Hz, 1H), 8.01 (d, J¼1.6 Hz,
1H), 7.94 (d, J¼3.2 Hz, 1H), 7.75 (dd, J¼0.4, 2.8 Hz, 1H), 7.57 (d,
J¼3.2 Hz, 1H), 7.52 (d, J¼3.2 Hz, 1H), 7.43 (d, J¼3.2 Hz, 1H), 7.25 (dd,
J¼0.4, 4.0 Hz, 1H), 6.81 (d, J¼1.6 Hz, 1H), 6.76 (dd, J¼1.6, 8.0 Hz, 1H),
6.69 (d, J¼8.0 Hz, 1H), 5.92 (s, 2H); 13C NMR (100 MHz, CDCl3):
d
198.93 (2ꢀ), 151.08, 147.13, 137.28, 136.86 (2ꢀ), 135.33, 133.02
(2ꢀ), 131.94, 128.53 (4ꢀ), 128.16 (4ꢀ), 121.86, 114.93, 110.44, 60.75,
55.53, 45.20 (2ꢀ), 31.72, 30.01; Anal. Calcd for C28H28O4: C, 78.48;
H, 6.59. Found: C, 78.76; H, 6.90. Single-crystal X-ray diagram:
crystal of compound 4a was grown by slow diffusion of EtOAc into
a solution of compound 4a in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the monoclinic crystal system, space
d
188.95, 168.78, 166.26, 165.30, 147.37, 147.29, 144.46, 144.12,
143.46,142.50,137.26,134.83,132.75,132.68,129.59,125.54,125.48,
123.07, 119.97, 119.92, 109.79, 108.02, 101.11.
Acknowledgements
ꢀ
ꢀ
ꢀ
group P 1 21/c 1, a¼19.4340(8) A, b¼10.8561(4) A, c¼11.2370(4) A,
V¼2282.43(15) A , Z¼4, Dcalcd¼1.247 g/cm3, F(000)¼912, 2
q
range
3
ꢀ
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-037-
006-MY3).
1.09e26.40ꢁ, R indices (all data) R1¼0.0584, wR2¼0.1056.
4.2.22. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1,5-bis(4-methoxy-phenyl)
pentane-1,5-dione (4b). Yield 85% (207 mg); viscous oil; HRMS (ESI,
Mþþ1) calcd for C30H33O6 489.2277, found 489.2275; 1H NMR
Supplementary data
(400 MHz, CDCl3):
d
7.94 (d, J¼8.8 Hz, 4H), 7.05 (d, J¼8.4 Hz, 1H),
Scanned photocopies of 1H NMR of new compounds, and crys-
tallographic data of compounds 3a, 3i, 3n, and 3r were supported.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.09.048.
6.91 (d, J¼8.8 Hz, 4H), 6.79 (d, J¼8.4 Hz, 1H), 5.91e5.81 (m, 1H),
4.85e4.80 (m, 2H), 4.22e4.17 (m, 1H), 3.85 (s, 6H), 3.80 (s, 3H), 3.75
(s, 3H), 3.47 (d, J¼4.4 Hz, 2H), 3.40 (dd, J¼7.2, 16.4 Hz, 2H), 3.13 (dd,
J¼6.8, 16.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
197.49 (2ꢀ),
References and notes
163.37 (2ꢀ), 150.98, 137.32, 147.10, 137.32, 135.51, 131.87, 130.46
(4ꢀ), 130.01, 121.91, 114.89, 113.62 (4ꢀ), 110.44, 60.72, 55.51, 55.41
(2ꢀ), 44.96 (2ꢀ), 32.18, 30.00; Anal. Calcd for C30H32O6: C, 73.75; H,
6.60. Found: C, 73.89; H, 6.78.
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4.2.23. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1,5-di-furan-2-yl-pentane-
1,5-dione (4c). Yield 65% (133 mg); viscous oil; HRMS (ESI, Mþþ1)
calcd for C24H25O6 409.1651, found 409.1655; 1H NMR (400 MHz,
CDCl3):
d
7.52 (dd, J¼0.4,1.6 Hz, 2H), 7.18 (dd, J¼0.4, 3.6 Hz, 2H), 7.01
(d, J¼8.4 Hz, 1H), 6.76 (d, J¼8.4 Hz, 1H), 6.48 (dd, J¼1.6, 3.6 Hz, 2H),
5.98e5.88 (m, 1H), 4.91e4.80 (m, 2H), 4.21e4.14 (m, 1H), 3.80 (s,
3H), 3.75 (s, 3H), 3.57 (dt, J¼1.6, 6.0 Hz, 2H), 3.23 (dd, J¼7.6, 16.0 Hz,
2H), 3.10 (dd, J¼6.8, 16.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
187.59 (2ꢀ),152.58,151.10,147.14,146.25 (2ꢀ),137.25 (2ꢀ),134.89,
131.90, 121.72, 117.28 (2ꢀ), 114.92, 112.14 (2ꢀ), 110.47, 60.70, 55.50,
44.66 (2ꢀ), 31.63, 29.98.
4.2.24. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1,5-di-thiophen-2-yl-pen-
tane-1,5-dione (4d). Yield 70% (154 mg); colorless solid;
mp¼87e88 ꢁC (recrystallized from hexanes and EtOAc); HRMS (ESI,
6. (a) Raval, A. A.; Shah, N. M. J. Org. Chem. 1975, 22, 305; (b) Michael, A.; Ross, J. J.
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M.-Y. Chang, M.-H. Wu / Tetrahedron 68 (2012) 9616e9623
9623
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deposit@ccdc.cam.ac.uk).
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8. CCDC 887899 (3a), 892795 (3i), 893107 (3n), and 894066 (3r) contain the
supplementary crystallographic data for this paper. This data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the