Synthesis and reactivity of furoquinolines bearing an external methylene-bond: Access to reduced and spirocyclic structures

Article abstract of DOI:10.1039/c1ob05354j

A family of furoquinolines were efficiently obtained through a tandem acetalization/cycloisomerization process catalyzed by (5 mol%) silver imidazolate polymer and triphenylphosphine, and diversity was brought by the use of 7 different alcohol groups. Fro

Full text of DOI:10.1039/c1ob05354j

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PAPER
Synthesis and reactivity of furoquinolines bearing an external
methylene-bond: access to reduced and spirocyclic structures†‡
Xavier Bantreil,a Carine Vaxelaire,b Thomas Godet,b Evelyne Parker,b Carole Sauerb and Philippe Belmont*a,b
Received 7th March 2011, Accepted 30th March 2011
DOI: 10.1039/c1ob05354j
A family of furoquinolines were efficiently obtained through a tandem acetalization/cycloisomerization
process catalyzed by (5 mol%) silver imidazolate polymer and triphenylphosphine, and diversity was
brought by the use of 7 different alcohol groups. From these furoquinolines, 3 examples of reduced
derivatives could be obtained (d.r. up to 94 : 6), 10 different spiroketal derivatives by hetero-Diels–Alder
reaction (d.r. up to 20 : 1), 8 hetero-[5,5]-spirocycles by cycloaddition with dibromoformaldoxime (d.r.
up to 86 : 14) and finally 6 hetero-[5,6]-spirocycles by [4 + 2] cycloaddition with ethyl
3-bromo-2-(hydroxyimino)propanoate (d.r. up to 90 : 10).
Introduction
Furoquinoline alkaloids are natural products mostly extracted
from rutaceous plants (Scheme 1, furo[2,3-b]quinoline) and are of
interest due to their broad biological properties.1 Over the last few
years we have been involved in the synthesis of isomeric structures,
namely furo[3,4-b]quinolines (Scheme 1).
Scheme 2
Scheme 1 Furo[2,3-b]quinoline and furo[3,4-b]quinoline cores.
(IPy2BF4), Asao/Yamamoto’s10 (PdII,11 CuII or CuI, PdII/CuII, AuI
or AuIII) and Mascaren˜as’12 (PdII, W, Pt, Ru) groups.
These heterocycles were first obtained using a base-catalyzed
tandem acetalization/cycloisomerization reaction from quinoline-
carbaldehydes ortho-substituted by alkynyl moieties (Scheme 2,
eq. 1).2 Base catalysis had been developed previously on a pyridine
scaffold by Ohshiro,3 and Abbiati4 reported in parallel to our work
an interesting method on indole cores. Extension of these methods
has been also published5 along with thorough mechanistic studies.6
Due to scope limitation, organometallic conditions were sought
after since various electrophilic inorganic and organometallic
agents are used by several research groups to activate an alkynyl
bond.7 Initially, theses systems (Scheme 2, eq. 2) were studied
by Larock’s8 (I2, ICl, NBS, PhSeBr, p-NO2C6H4SCl), Barluenga’s9
Thus, our original contribution13 has been the use of a range of
silver salts were the p-acidic category (AgOTf, AgPF6, AgSbF6,
AgNO3) yielded the pyranoquinoline cores through a 6-endo-
dig cyclization process and the basic category (AgO, Ag2O,
Ag2CO3) led to the formation of furoquinolines by a 5-exo-dig
cyclization process (Scheme 2, eq. 2). This difference of reactivity
was rationalized based on different mechanistic pathways.13 Our
implication for studying the regioselectivity of such reactions
was crucial since up to that time no general rationale had been
established in the literature. Moreover, an interesting nitrogen-
effect recently disclosed14 led us to develop the use of a silver
imidazolate polymer, as an easy handling and robust silver catalyst,
for the efficient synthesis of a wide range of furoquinoline
structures.
In this paper, we wish to expand the scope of the furoquinoline
family, and furthermore to study the reactivity of their external
methylene unit. Indeed, the reactivity of the enol-ether bond
present in the furo[3,4-b]quinoline scaffold has not been consid-
ered yet for [3 + 2] and [4 + 2] cycloadditions, yielding spirocyclic
structures, or for reduction (Scheme 3). Nevertheless, some
aInstitut Curie and CNRS, UMR 176 CSVB, Institut Curie, 26 rue
d’Ulm, 75248, Paris cedex 05, France. E-mail: Philippe.Belmont@curie.fr;
Fax: +33 (0)1.56.24.66.31; Tel: +33 (0)1.56.24.68.24; Web: http://
umr176.curie.fr/en/group/cohcb
bUniversity of Lyon and CNRS, UMR 5246 ICBMS, 43 Boulevard du 11
Novembre 1918, 69622, Villeurbanne (Lyon), France
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05354j
‡ This paper is dedicated to the memory of Pr. Franc¸ois Tillequin
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Table 1 Furo[3,4-b]quinolines synthesisa
Entry SMc
R1
R2
Yield (%)
Product
1
2
3
4
1
1
1
1
1
1
1
2
2
3
4
Me
CH2OMe
CH2OMe
CH2OMe
CH2OMe
CH2OMe
75
99
99
63
95
79
73
71
85
95
96
6
iPr
7
CH2CH2N(Et)2
(CH2)2OH
allyl
8
9
5
10
11
12
13
14
15
16
6b
7b
8
CH2Ph-p-MeOd CH2OMe
CH2Ph-p-NO2
CH2OMe
H
H
Me
iPr
Me
iPr
9
10
11
CH2OTHP
Scheme 3 Target structures.
interesting cascade15 or sequential reactions16 on exo-methylene
units have recently been published.
12
5
Me
Ph
80
17
These types of double-bonds have already been widely modified
on (tetrahydro)furanes or exo-glycal moieties and the resulting
spirocycles (spiroketals17 or hetero-spirocycles18) obtained are of
interest for their biological relevance and since a number of them
can be found in natural products. Therefore, we wish to present
our work on the reduction of furoquinolines and also the access
to new tetracyclic pharmacophores made of various spirocycles
fused on the quinoline nucleus.
a Reaction conditions: substrate (1 eq), [Ag(Imid)]n (5 mol%), PPh3 (5
mol%), alcohol (0.2 M), rt, 2 h. b Reaction conditions: substrate (1 eq),
[Ag(Imid)]n (5 mol%), PPh3 (5 mol%), alcohol (1 eq), (CH2Cl)2 (0.5 M),
rt, 2 h. c SM: Starting material. d Reaction run at rt, 8 h.
13–17 was efficiently achieved in yields ranging from 71 to 96%.
With methanol as the nucleophile (entries 8, 10, 12, Table 1) the
results were almost the same as for the MOM-substituted alkyne
(entry 1, 75%) except for product 15 which was isolated with 95%
yield. For isopropanol as the nucleophile (entries 9 and 11, Table
1) a good yield was observed for product 14 (85%), which proves
the efficiency of this transformation. Therefore, this reaction is
versatile regarding the nature of the R1 and R2 groups (Table 1)
since the use of functionalized alcohol groups (aminoalcohol, diol,
allyl, benzyl) with a variety of alkynyl-quinoline (R2 = MOM, H,
CH2OTHP, isopropyl or Ph) produce efficiently a family of twelve
furoquinolines 6–17.
Having in hand these furoquinolines we first focused our atten-
tion on the reduction of the external-methylene bond (Scheme 4).
The reduction of furoquinoline 13, under classical conditions (1
atm H2, Pd/C 5 mol%, 7 h), with no alkynyl substituent (R2 =
H) yielded reduced furoquinoline 18 (73%) with a diastereomeric
ratio (d.r.) of 88 : 12. The reduction of the exo-methylene group
of furoquinoline 6, bearing a MOM-substituted alkyne, led to
furoquinoline 19 (71%) with the same d.r. (89 : 11) in favour of the
syn-isomer (racemic mixture).
Results and discussions
In connection with our ongoing studies on silver/gold-catalyzed
cycloisomerization reactions,7f,13a,19 we have recently disclosed the
use of silver imidazolate polymer14 as a new organometallic
catalyst. However only 2-(diethyl)aminoethanol was extensively
studied as the nucleophile. Therefore, we wish to begin this
report with a nice extension of our methodology using a variety
of alcohol groups (R1OH, see Table 1) at room temperature.
Indeed, silver imidazolate and PPh3 (5 mol% each) added in the
appropriate alcohol as the reaction solvent (0.2 M), catalyzed the
tandem acetalization/cycloisomerization reaction on quinoline
derivatives (bearing at position 2 an akynyl substituent and at
position 3 an aldehyde group), leading to furoquinolines bearing
an external methylene-bond. The reaction on MOM-substituted
alkynyl-quinoline (R2 = CH2OMe, Table 1) with simple alkyl-OH
(MeOH,14 iPrOH) is nicely performed with 75% and quantitative
isolated yield, respectively (entries 1 and 2). Only the cis-products
6 and 7 were obtained (entries 1 and 2, Table 1), resulting from a
trans-addition onto the alkynyl bond. Then, using functionalized
alcohol groups such as an aminoalcohol (entry 3), an unprotected
diol (entry 4) or an allyl-alcohol (entry 5) gave furoquinolines 8, 9
and 10 in good to excellent yields (99%, 63% and 95% respectively).
The lower yield observed in the case of the diol (entry 4) can be
explained by a difficult purification of 9, and no traces of dimer
were observed. With 1 equivalent of benzylic alcohols (entries
6 and 7, Table 1) the reaction performed in a 1 M solution of
dichloroethane yielded products 11 (79%) and 12 (73%). Changing
the alkyne substituents R2 to H, CH2OTHP, cyclopropyl or Ph
(entries 8–12, Table 1), with MeOH or iPrOH did not have a real
impact on the reaction outcome and the synthesis of compounds
Scheme 4 Reduced furoquinolines 18–20.
The same ratio was observed using Rh/C, Pt/C or Pd/Al2O3
but the starting material was recovered with Ru/C. In order to
increase the diastereomeric ratio the reduction was then tested on
compound 7 and indeed the presence of the isopropoxy group
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Table 2 Hetero-Diels–Alder reaction productsa
Entry
SMb
R1
R2
Product
Yield (%)
d.r.b
1
2
3
4
5
6
7
8
6
Me
CH2OMe
CH2OMe
CH2OMe
CH2OMe
CH2OMe
CH2OMe
CH2OMe
H
21
22
—
23
24
25
26
27
28
29
30
80
89
nrb
68
73
65
74
76
81
86
75
20 : 1
20 : 1
—
7
iPr
8
9
CH2CH2N(Et)2
(CH2)2OH
allyl
CH2Ph-p-MeO
CH2Ph-p-NO2
Me
iPr
Me
iPr
20 : 1
20 : 1
20 : 1
20 : 1
12 : 1
20 : 1
20 : 1
20 : 1
10
11
12
13
14
15
16
9
10
11
H
CH2OTHP
12
17
Me
Ph
—
nrb
—
a Reaction conditions: substrate (0.2 mmol), ZnCl2 (1 M in Et2O, 0.2 mmol), acrolein (0.6 mmol), toluene–THF (8 : 2, v/v, 0.2 M), 50 ◦C, 8 h. b SM:
Starting material, nr: no reaction, d.r.: diastereomeric ratio.
enhanced the facial selectivity since syn-derivative 20 (73%) was
produced with a d.r. of 94 : 6. In this manner, the diastereomeric
excess was increased from 78 to 88%. Finally, the reduction failed
to happen with substrate 5 bearing a phenyl substituent (R2) and
this even under hydrogen pressure (up to 20 bar) where a complex
mixture was obtained.
We next turned our attention to cycloaddition reactions. At
first, hetero-Diels–Alder reactions with acrolein were performed
onto the electron-rich exocyclic-methylene bond of furoquinolines
6–17 by means of ZnCl2 activation (Table 2).17h,20 Of note, the
use of a mixture of solvents toluene–THF (8 : 2, v/v), was found
compulsory to obtain a homogeneous reaction mixture (THF
solubilising ZnCl2).
Hetero-Diels–Alder products 21–26 (entries 1–2 and 4–7, Table
2) bearing the MOM-substitution were obtained in fair to good
yields (65–89%) but with excellent 20 : 1 diastereomeric ratio. Best
yields were achieved with the methoxy or isopropoxy R1 groups
giving compounds 21 (80%) and 22 (89%). No reaction from
quinoline 8 (entry 3) was seen, probably due to coordination
of ZnCl2 by the diethylaminoethyl R1 group. With the other R1
Table 3 Hetero-[5,5]-sprirocyclic products by a [3 + 2] cycloadditiona
Entry
SMb
R1
R2
Product
Yield (%)
d.r.b
1
2
3
4
5
6
7
8
9
6
Me
CH2OMe
CH2OMe
CH2OMe
CH2OMe
CH2OMe
H
31
32
—
33
34
35
36
37
38
79
96
—
85
79
74
74
78
65
77 : 23
84 : 16
—
58 : 42
77 : 23
77 : 23
84 : 16
79 : 21
86 : 14
7
iPr
8
9
11
13
14
15
16
CH2CH2N(Et)2
(CH2)2OH
CH2Ph-p-MeO
Me
iPr
Me
iPr
H
CH2OTHP
a Reaction conditions: substrate (0.2 mmol), Br2C=NOH (0.6 mmol), Na2CO3 (1.0 mmol), toluene (0.07 M), rt, 16 h. b SM: Starting material, d.r.:
diastereomeric ratio.
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Table 4 Hetero-[5,6]-sprirocyclic products by a [4 + 2] cycloadditiona
Entry
SMb
R1
R2
Product
Yield (%)
d.r.b
1
2
3
4
5
6
6
Me
CH2OMe
CH2OMe
CH2OMe
CH2OMe
H
39
40
41
42
43
44
83
51
20
51
59
63
88 : 12
88 : 12
86 : 14
90 : 10
88 : 12
86 : 14
7
iPr
10
11
13
16
allyl
CH2Ph-p-MeO
Me
iPr
a Reaction conditions: substrate (0.2 mmol), ethyl-3-bromo-2-(hydroxyimino)propanoate (0.6 mmol), slow addition, Na2CO3 (1.0 mmol), (CH2Cl)2 (0.07
M), 50 ◦C, 24 h. b SM: Starting material, d.r.: diastereomeric ratio.
groups (ethylalcohol, allyl, benzyls) the acetal-spiroketal quinoline
products 23–26 (entries 4–7) were synthesized in 65 to 74% yield.
Spiroketal-quinolines 27 and 28 (entries 8–9, Table 2) were formed
in respectively 76 and 81% yield. Interestingly, the diastereomeric
ratio was only 12 : 1 in the case of the methyl R1 substituent (27,
entry 8) whereas it reached a d.r. of 20 : 1 for the isopropyl R1 group
(28, entries 9). Also, furoquinoline 15 and 16 (entries 10 and 11)
were transformed efficiently to spirocycles 29 (86%) and 30 (75%)
with a d.r. of 20 : 1. Noteworthy, as in the case of the reduction
reaction (Scheme 4), with a phenyl R2 group (entry 12, Table 2) no
hetero-Diels–Alder product could be formed, probably due to the
lack of reactivity of the methylene bond engaged in an extended
electronic delocalization.
the d.r. (79 : 21) compared with 77 : 23 d.r. for compound 35
(H group, entry 6, Table 3). In the same manner, compari-
son of the d.r. of compounds 36 and 38 (84 : 16 vs. 86 : 14)
demonstrated that the size of the R2 groups had almost no
influence.
Finally, diversity was also made possible with the forma-
tion of [5,6]-spirocycles by reacting furoquinolines 6–7, 10–
11, 13 and 16 (entries 1–6, Table 4) with ethyl 3-bromo-2-
◦
(hydroxyimino)propanoate (50 C in dichloroethane),22 in basic
conditions. Under these conditions whatever the nature of the
R groups on the starting material was, good diastereoselectivities
were always observed (86 : 14 to 90 : 10). Apart from compound 39
(entry 1, Table 4) which was obtained with a very good 83% yield,
the results were not as good for the other derivatives presumably
due to formation of regioisomers. Indeed, only 51% yield was
Furthermore, reaction of furoquinolines 6–9, 11, and 13–16
with dibromoformaldoxime, in basic conditions required for the
in situ formation of bromonitrile oxide,21 allowed the formation of
8 different hetero-[5,5]-spirocycles by a [3 + 2] room-temperature
process (entries 1–9, Table 3).
i
attained for spirocycles 40 and 42 (R1 = Pr or p-methoxybenzyl,
R2 = MOM, entries 2 and 4, Table 4), 63% for spirocycle 44 bearing
i
the Pr (R1) and cycloPr (R2) groups (entry 6, Table 4) and 59%
Compounds 6–7, 9 and 11 with the MOM-substituent (entries
1–2, 4–5, Table 3) were efficiently converted to the quinoline-
fused [5,5]-spirocycles 31–34 bearing as R1 group a methyl (79%),
isopropyl (96%), ethylalcohol (85%) and p-methoxybenzyl (79%)
with generally good diastereoselectivities ranging from 77 : 23 to
84 : 16. One exception being spirocycle 33, with the ethylalcohol
substituent, that presented almost no facial diastereoselectivity
(58 : 42). Then, reaction of furoquinoline 8, bearing a diethy-
laminoethyl R1 group (entry 3, Table 3), led only to degradation
or unidentified products, compared to the hetero-Diels–Alder
reaction (entry 3, Table 2) where no reaction occurred.
for compound 43 (entry 5, Table 4). A deceiving 20% yield was
noticed for spirocycle 41. The reaction was more sluggish than the
one developed before (Tables 2–3) and the reagent ethyl-3-bromo-
2-(hydroxyimino)propanoate polymerized easily explaining also
the lower yields. Therefore, syringe pump slow addition of ethyl-
3-bromo-2-(hydroxyimino)propanoate helped for getting the best
out of these reactions.
Among these new furo[3,4-b]quinolines 6–17 and spirocyclic
derivatives 21–44, some exhibit interesting biological properties
that will be reported elsewhere in due time.
Compounds 13–14, without substitution on the external
methylene-bond (entries 6–7, Table 3), were similarly transformed
into spirocycles 35–36 (74%) but the size of the R1 group has
an impact on the diastereoselectivity since the 77 : 23 ratio with
the methyl group (35) was increased to a 84 : 16 in the case of
the isopropyl group (36). Also, playing on the steric hindrance of
both R groups was interesting since spirocycle 37 (CH2OTHP
group, entry 8, Table 3) showed a non-significant increase of
Conclusions
In conclusion, we have developed a sequential and efficient
transformation of quinoline derivatives to various furoquinolines
and spirocyclic structures. Scope and limitations of the exo-
methylene bond reactivity have been studied widely since 27 new
structures were obtained in good to excellent yield and with
a good to excellent facial diastereoselectivity. Enantioselectivity
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is under study for the tandem acetalization/cycloisomerization
reaction, therefore opening the way for the access to enantiopure
spirocycles.
acrolein (40 mL, 0.6 mmol) and ZnCl2 (1 M in Et2O, 200 mL,
0.2 mmol). The mixture was then stirred at 50 ◦C for 8 h, allowed
to cool to room temperature and evaporated. The crude product
was purified by flash chromatography on silica gel using mixtures
of pentane and diethyl ether to afford the pure product.
Experimental section
Procedure for [3 + 2] cycloaddition (Table 3)
General considerations
In a sealed tube, to a solution of the appropriate furoquinoline
(0.2 mmol) in toluene (0.07 M, 2.9 mL) were successively added
sodium carbonate (106.0 mg, 1.0 mmol) and dibromoformal-
doxime (121.7 mg, 0.6 mmol). The mixture was then stirred at
room temperature for 16 h and water was added. The mixture was
extracted with ethyl acetate (3 ¥ 5 mL). The combined organic
layers were washed with brine (5 mL) and dried over MgSO4. The
crude product was purified by flash chromatography on silica gel
using mixtures of pentane and diethyl ether to afford the pure
product.
Dichloromethane was distilled on CaH2. THF and toluene were
distilled on sodium/benzophenone. All other reagents and sol-
vents were used without further purification. 1H NMR (300 MHz)
1
and 13C-{ H} NMR (75 MHz) were recorded on a Bruker ACP-
300 spectrometer using the residual peak of chloroform-d as
1
internal standard (7.26 ppm for H NMR and 77.16 ppm for
13C NMR). Chemical shifts are reported in ppm and coupling
constants J in Hertz. Flash chromatography was performed using
40–63 mm silica. Analytical TLC’s were performed on Merck pre-
coated silica 60-F254 plates. IR spectra were recorded on a FTIR
spectrometer. Compounds 6, 7, 8, 9, 11, 13, 15 and 17 were already
described.13a
Procedure for [4 + 2] cycloaddition (Table 4)
To a solution of the appropriate furoquinoline (0.2 mmol) in
dichloroethane (0.1 M, 2.0 mL) was added sodium carbonate
(106.0 mg, 1.0 mmol). The mixture was heated at 50 ◦C and
a solution of ethyl 3-bromo-2-(hydroxyimino)propanoate (126.2
mg, 0.6 mmol) in dichloroethane (0.75 mL) was then added via
syringe pump over 24 h. HClaq 1 M (2.5 mL) was added and
the mixture was extracted with dichloromethane (3 ¥ 5 mL).
The combined organic layers were washed with brine (5 mL)
and dried over MgSO4. The crude product was purified by flash
chromatography on silica gel using mixtures of pentane and diethyl
ether to afford the pure product.
General procedure for silver catalyzed cyclization (Table 1)
To the appropriate quinoline (1 eq), [Ag(Im)]n (5 mol%) and PPh3
(5 mol%) was added the appropriate alcohol (0.2 M). The solution
was stirred at rt for 2 h (TLC monitoring) and evaporated under
vacuum. The crude mixture was purified by flash chromatography
on silica gel using mixtures of pentane and diethyl ether to afford
the pure product.
Procedure for silver catalyzed cyclization using
p-methoxybenzylalcohol and p-nitrobenzylalcohol
To the appropriate quinoline (1 eq), [Ag(Im)]n (5 mol%) and PPh3
(5 mol%) were added dichloroethane (0.5 M) and the appropriate
benzylalcohol (1.0 eq). The solution was stirred at rt for 8 h (TLC
monitoring) and evaporated under vacuum. The crude mixture
was purified by flash chromatography on silica gel using mixtures
of pentane–diethyl ether (gradient 9 : 1 to 7 : 3) to afford the pure
product in 79% yield (for p-methoxybenzylalcohol, respectively
73% for p-nitrobenzylalcohol).
Assignment of the diastereoisomers by NOESY experiments
NOESY experiments were run on a single product for each family
of compounds and assignment was assumed to be correct for
the other products. In the [3 + 2] family, a nOe was observed
in the major isomer between the methyl groups of the iso-propyl
moiety and the CH2 of the newly formed cycle, proving the spatial
arrangement of this isomer (scheme below). In addition, a nOe
was found in the minor isomer between the proton in a of the
iso-propyloxy group and the CH2 of the newly formed cycle.
Procedure for reduction by palladium catalyzed hydrogenation
To a solution of the appropriate furoquinoline (1 eq) in degassed
(argon bubbling for 5 min) methanol (0.06 M) was added Pd/C
(20% in mass). The mixture was stirred under argon bubbling for
5 min and hydrogen was then bubbled for 5 min. The reaction
media was then stirred at room temperature for 4 h under 1 atm
of hydrogen. The mixture was flushed with argon and dissolved
in ethyl acetate. After filtration through a pad of celite, the filtrate
was washed with water (¥3) and brine. The organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The crude
product was purified by preparative TLC or flash chromatography
on silica gel using mixtures of cyclohexane and ethyl acetate to
afford the pure product.
Compound 10 (Table 1, entry 5)
According to the procedure described above, 10 was isolated in
95% yield (yellow solid). 1H NMR (CDCl3, 300 MHz): d (ppm) =
8.20 (s, 1H), 8.13 (d, 1H, J = 8.5 Hz), 7.84 (d, 1H, J = 8.1 Hz), 7.75
(t, 1H, J = 7.1 Hz), 7.54 (t, 1H, J = 7.2 Hz), 6.59 (s, 1H), 6.06–5.95
(m, 1H), 5.95 (t, 1H, J = 7.2 Hz), 5.36 (dd, 1H, J = 1.4, 17.2 Hz),
5.25 (dd, 1H, J = 1.0, 10.4 Hz), 4.42–4.25 (m, 4H), 3.42 (s, 3H).
Procedure for hetero-Diels–Alder reaction with acrolein (Table 2)
In a sealed tube, to a solution of the appropriate furoquinoline
(0.2 mmol) in toluene–THF (0.8/0.2 mL) were successively added
1
13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) = 153.5, 153.0, 150.0,
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133.7, 131.6, 130.7, 129.7, 129.4, 128.6, 127.9, 127.0, 118.2, 103.2,
97.6, 69.2, 66.3, 57.9. HRMS (ESI+) m/z calculated for (MH+):
284.1281. Found: 284.1281. MS (ESI+): 284 (MH+). IR (CH2Cl2):
n 2928, 1726, 1627, 1505, 1264 cm-1.
131.4, 130.2, 129.3 (2C), 128.6, 127.5, 126.5, 104.8, 78.9, 54.8,
22.1. HRMS (ESI+) m/z calculated for (MH+): 216.1015. Found:
∑
216.1019. GC-MS: m/z C13H13NO2 (M+ ) 215. IR (neat): n 2976,
2927, 2826, 1632, 1504, 1306 cm-1.
Compound 12 (Table 1, entry 7)
Compound 19 (Scheme 4)
According to the procedure described above, 12 was isolated in
73% yield (yellow solid). 1H NMR (CDCl3, 300 MHz): d (ppm) =
8.24 (s, 1H), 8.22 (d, 2H, J = 8.8 Hz), 8.17 (d, 1H, J = 8.7 Hz),
7.88 (d, 1H, J = 8.1 Hz), 7.80 (dt, 1H, J = 1.4, 7.1, 8.5 Hz), 7.59
(dt, 1H, J = 1.4, 7.0, 8.0 Hz), 7.55 (d, 2H, J = 8.7 Hz), 6.72 (s,
1H), 6.00 (t, 1H, J = 7.3 Hz), 4.91 (AB system, 2H), 4.37–4.23 (m,
According to the procedure described above, 19 was obtained as
mixture of diastereoisomers 89 : 11 in 71% yield. The major isomer
1
was isolated pure in 45% yield (yellow solid). H NMR (CDCl3,
500 MHz): Major isomer d (ppm) = 8.15 (s, 1H), 8.11 (d, J =
8.7 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.74 (ddd, J = 1.6, 7.0,
8.7 Hz, 1H), 7.54 (ddd, J = 1.1, 7.0, 7.6 Hz, 1H), 6.22 (s, 1H),
5.33 (dd, J = 3.7, 9.0 Hz, 1H), 3.77–3.70 (part of AB system, 1H),
3.69–3.67 (part of AB system, 1H), 3.58 (s, 3H), 3.39 (s, 3H), 2.48–
2.42 (part of AB system, 1H), 2.12–2.04 (part of AB system, 1H).
1
2H), 3.41 (s, 3H). 13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) =
153.1, 152.6, 150.0, 147.5, 144.8, 131.7, 130.9, 129.6, 128.7, 128.6,
128.0, 127.7, 127.2, 123.6, 103.4, 98.0, 68.4, 66.2, 58.0. HRMS
(ESI+) m/z calculated for (MH+): 379.1288. Found: 379.1302. MS
(ESI+): 379 (MH+). IR (CH2Cl2): n 2928, 2824, 1690, 1626, 1608,
1524, 1348 cm-1.
1
Minor isomer d (ppm) (selected peak) = 6.26 (s, 1H). 13C-{ H}
NMR (CDCl3, 125 MHz): Major isomer d (ppm) = 164.4, 149.4,
131.4, 130.2, 129.4, 129.3, 128.6, 127.5, 126.6, 105.0, 79.8, 69.4,
∑
58.8, 55.3, 36.6. HRMS (EI) m/z calculated for (M+ ): 259.1208.
∑
Found: 259.1209. GC-MS: m/z C15H17NO3 (M+ ) 259. IR (neat):
Compound 14 (Table 1, entry 9)
n 2956, 2921, 2883, 2829, 1631, 1580, 1504, 1420 cm-1.
According to the procedure described above, 14 was isolated in
>99% yield (yellow solid). 1H NMR (CDCl3, 300 MHz): d (ppm) =
8.06 (d, 1H, J = 8.5 Hz), 8.00 (s, 1H), 7.69 (d, 1H, J = 8.2 Hz),
7.63 (t, 1H, J = 8.4 Hz), 7.41 (t, 1H, J = 7.5 Hz), 6.45 (s, 1H),
5.30 (d, 1H, J = 1.9 Hz), 4.74 (d, 1H, J = 1.9 Hz), 4.13 (sept, 1H,
J = 6.2 Hz), 1.28 (d, 3H, J = 6.2 Hz), 1.25 (d, 3H, J = 6.2 Hz).
Compound 20 (Scheme 4)
According to the procedure described above, 20 was obtained as
mixture of diastereoisomers 94 : 6 in 75% yield. The major isomer
was isolated pure in 49% yield (yellow solid). H NMR (CDCl3,
1
1
13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) = 157.0, 153.4, 149.7,
300 MHz): Major isomer d (ppm) = 8.11 (s, 1H), 8.09 (d, J =
8.7 Hz, 1H), 7.85 (dd, J = 1.0, 8.1 Hz, 1H), 7.72 (ddd, J = 1.4,
7.0, 8.7 Hz, 1H), 7.52 (ddd, J = 1.0, 7.0, 8.1 Hz, 1H), 6.37 (s,
1H), 5.29 (dd, J = 3.9, 8.9 Hz, 1H), 4.23 (sept, J = 6.2 Hz, 1H),
3.80–3.68 (part of AB system, 1H), 3.67–3.62 (part of AB system,
1H), 3.38 (s, 3H), 2.49–2.38 (part of AB system, 1H), 2.18–2.06
(part of AB system, 1H). Minor isomer d (ppm) (selected peak) =
131.2, 130.3, 129.9, 129.4, 128.3, 127.7, 126.7, 102.4, 83.6, 71.9,
23.5, 22.3. HRMS (ESI+) m/z calculated for (MH+): 242.1176.
Found: 242.1175. MS (ESI+): 242 (MH+). IR (CH2Cl2): n 2975,
1784, 1631, 1605, 1506 cm-1
Compound 16 (Table 1, entry 11)
1
6.40 (s, 1H). 13C-{ H} NMR (CDCl3, 100 MHz): Major isomer
According to the procedure described above, 16 was isolated in
96% yield (yellow solid). 1H NMR (CDCl3, 300 MHz): d (ppm) =
8.10 (s, 1H), 8.04 (d, 1H, J = 8.5 Hz), 7.79 (d, 1H, J = 8.1 Hz), 7.68
(t, 1H, J = 8.3 Hz), 7.47 (t, 1H, J = 7.2 Hz), 6.62 (s, 1H), 5.33 (d,
1H, J = 10.1 Hz), 4.23 (sept, 1H, J = 6.2 Hz), 2.00–1.88 (m, 1H),
1.36 (d, 3H, J = 3.0 Hz), 1.34 (d, 3H, J = 3.0 Hz), 0.91 (dd, 2H, J =
d (ppm) = 164.7, 149.3, 131.2, 130.2, 130.1, 129.3, 128.6, 127.7,
126.5, 102.7, 79.6, 71.0, 69.4, 58.8, 36.7, 23.9, 22.4. HRMS (ESI+)
m/z calculated for (MH+): 288.1591. Found: 288.1594. GC-MS:
∑
m/z C17H21NO3 (M+ ) 287. IR (neat): n 2963, 2918, 2868, 2823,
1630, 1504, 1332 cm-1.
1
2.2, 8.1 Hz), 0.67–0.57 (m, 2H). 13C-{ H} NMR (CDCl3, 75 MHz):
Compound 21 (Table 2, entry 1)
d (ppm) = 153.9, 150.4, 149.8, 131.3, 130.3, 129.8, 129.2, 128.5,
127.6, 126.3, 107.0, 102.6, 71.9, 23.8, 22.6, 8.7, 7.9, 7.7. HRMS
(ESI+) m/z calculated for (MH+): 282.1489. Found: 282.1491. MS
(ESI+): 282 (MH+). IR (CH2Cl2): n 2977, 2930, 1683, 1627, 1506,
1416, 1373 cm-1.
According to the procedure described above, 21 was isolated in
80% yield as a single isomer (white solid). 1H NMR (CDCl3,
300 MHz): d (ppm) = 8.24 (d, 1H, J = 8.5 Hz), 8.20 (s, 1H), 7.88 (d,
1H, J = 8.1 Hz), 7.76 (t, 1H, J = 7.6 Hz), 7.58 (t, 1H, J = 7.4 Hz),
6.43 (d, 1H, J = 7.9 Hz), 6.39 (s, 1H), 5.05 (t, 1H, J = 5.1 Hz),
3.66 (s, 3H), 3.24–3.00 (m, 3H), 3.00 (s, 3H), 2.43–2.34 (m, 1H),
Compound 18 (Scheme 4)
1
2.22–2.12 (m, 1H). 13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) =
According to the procedure described above, 18 was obtained as
159.7, 149.9, 141.4, 131.9, 130.4, 130.1, 129.5, 128.5, 128.3, 127.3,
105.9, 104.5, 101.4, 73.2, 58.4, 56.3, 37.8, 20.9. HRMS (ESI+) m/z
calculated for (MH+): 314.1387. Found: 314.1383. MS (ESI+): 314
(MH+). IR (CH2Cl2): n 2929, 1658, 1630, 1505, 1447, 1397 cm-1.
mixture of diastereoisomers 88 : 12 in 73% yield. The major isomer
1
was isolated pure in 46% yield (yellow oil). H NMR (CDCl3,
300 MHz): Major isomer d (ppm) = 8.13 (s, 1H), 8.11 (d, J =
8.6 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.73 (ddd, J = 1.3, 6.9,
8.6 Hz, 1H), 7.53 (ddd, J = 0.9, 6.9, 8.1 Hz, 1H), 6.21 (s, 1H),
5.31 (q, J = 6.7 Hz, 1H), 3.54 (s, 3H), 1.70 (d, J = 6.7 Hz, 3H).
Compound 22 (Table 2, entry 2)
1
Minor isomer d (ppm) (selected peak) = 6.22 (s, 1H). 13C-{ H}
According to the procedure described above, 22 was isolated in
89% yield as a single isomer (white solid). 1H NMR (CDCl3,
NMR (CDCl3, 75 MHz): Major isomer d (ppm) = 164.5, 149.3,
4836 | Org. Biomol. Chem., 2011, 9, 4831–4841
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300 MHz): d (ppm) = 8.23 (d, 1H, J = 8.4 Hz), 8.17 (s, 1H),
7.88 (d, 1H, J = 8.1 Hz), 7.75 (ddd, 1H, J = 1.3, 6.9, 8.4 Hz),
7.57 (ddd, 1H, J = 1.0, 6.9, 8.0 Hz), 6.58 (s, 1H), 6.43 (dd, 1H,
J = 1.4, 6.2 Hz), 5.04 (dt, 1H, J = 1.9, 5.9 Hz), 4.26 (sept, 1H,
J = 6.2 Hz), 3.28–3.22 (m, 1H), 3.17–3.12 (m, 1H), 3.04–2.96 (m,
1H), 3.03 (s, 3H), 2.43–2.34 (m, 1H), 2.21–2.10 (m, 1H), 1.35 (d,
(ESI+) m/z calculated for (MH+): 420.1805. Found: 420.1817. MS
(ESI+): 420 (MH+). IR (CH2Cl2): n 2926, 1658, 1631, 1607, 1505,
1392 cm-1.
Compound 26 (Table 2, entry 7)
1
6H, J = 6.2 Hz). 13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) =
According to the procedure described above, 26 was isolated in
74% yield as a single isomer (colorless oil that crystallized on
standing). 1H NMR (CDCl3, 300 MHz): d (ppm) = 8.27–8.22 (m,
4 Hz), 7.92 (dd, 1H, J = 0.7, 7.4 Hz), 7.80 (ddd, 1H, J = 1.5, 7.0,
8.4 Hz), 7.65–7.58 (m, 3H), 6.63 (s, 1H), 6.44 (dd, 1H, J = 1.4,
6.2 Hz), 5.07 (dt, 1H, J = 2.0, 6.0 Hz), 5.04 (AB system, 2H), 3.21–
3.02 (m, 3H), 2.98 (s, 3H), 2.43–2.33 (part of AB system, 1H), 2.19–
159.7, 149.9, 141.5, 131.7, 130.2, 130.1, 128.5, 128.3, 127.1, 105.8,
102.5, 101.3, 73.3, 72.2, 58.5, 38.0, 24.0, 22.5, 21.0. HRMS (ESI+)
m/z calculated for (MH+): 342.1700. Found: 342.1697. MS (ESI+):
342 (MH+). IR (CH2Cl2): n 2977, 2927, 1658, 1631, 1506, 1401,
1383 cm-1.
1
2.08 (part of AB system, 1H). 13C-{ H} NMR (CDCl3, 75 MHz):
Compound 23 (Table 2, entry 4)
d (ppm) = 159.5, 150.0, 147.6, 145.0, 141.4, 132.0, 130.7, 130.1,
129.0, 128.6, 128.4, 128.1, 127.5, 123.9, 106.3, 103.3, 101.4, 73.2,
69.4, 58.5, 37.7, 20.9. HRMS (ESI+) m/z calculated for (MH+):
435.1551. Found: 435.1543. MS (ESI+): 435 (MH+). IR (CH2Cl2):
n 3057, 2926, 1658, 1631, 1607, 1524, 1348 cm-1.
According to the procedure described above, 23 was isolated in
68% yield as a single isomer (white solid). 1H NMR (CDCl3,
300 MHz): d (ppm) = 8.24 (s, 1H), 8.23 (d, 1H, J = 8.8 Hz),
7.89 (d, 1H, J = 8.3 Hz), 7.77 (ddd, 1H, J = 1.3, 6.9, 8.4 Hz),
7.59 (ddd, 1H, J = 1.1, 7.0, 8.0 Hz), 6.52 (s, 1H), 6.43–6.39 (m,
1H), 5.04 (dt, 1H, J = 2.1, 5.9 Hz), 4.10–3.94 (m, 2H), 3.85 (t, 2H,
J = 4.3 Hz), 3.21–3.19 (m, 2H), 3.09–2.98 (m, 1H), 3.02 (s, 3H),
Compound 27 (Table 2, entry 8)
1
2.40–2.30 (m, 1H), 2.26–2.15 (m, 1H). 13C-{ H} NMR (CDCl3,
According to the procedure described above, 27 was isolated in
76% yield (white solid). 1H NMR (CDCl3, 300 MHz): d (ppm) =
8.24 (d, 1H, J = 9.6 Hz), 8.23 (s, 1H), 7.92 (d, 1H, J = 8.2 Hz),
7.78 (ddd, 1H, J = 1.2, 7.0, 9.6 Hz), 7.63 (dd, 1H, J = 1.2, 7.0,
8.2 Hz), 6.49 (d, 1H, J = 8.5 Hz), 6.47 (s, 1H), 5.05 (dd, 1H,
J = 4.7, 6.2 Hz), 3.59 (s, 3H), 2.60–2.54 (m, 2H), 2.10 (m, 1H),
75 MHz): d (ppm) = 159.5, 149.9, 141.3, 132.1, 130.5, 130.1, 129.3,
128.6, 128.3, 127.4, 106.0, 104.3, 101.5, 73.0, 72.0, 62.3, 58.6, 37.8,
20.8. HRMS (ESI+) m/z calculated for (MH+): 344.1492. Found:
344.1500. MS (ESI+): 344 (MH+). IR (CH2Cl2): n 2928, 2882, 1658,
1631, 1506, 1397 cm-1.
1
2.05 (m, 1H). 13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) = 160.9,
150.5, 142.2, 132.9, 132.4, 130.8, 130.2, 129.1, 127.7, 105.0, 104.3,
102.2, 55.7, 30.5, 17.0. HRMS (ESI+) m/z calculated for (MH+):
270.1125. Found: 270.1128. MS (ESI+): 270 (MH+). IR (CH2Cl2):
n 2933, 2852, 1654, 1631, 1506, 1399, 1297 cm-1.
Compound 24 (Table 2, entry 5)
According to the procedure described above, 24 was isolated in
73% yield as a single isomer (white solid). 1H NMR (CDCl3,
300 MHz): d (ppm) = 8.25 (d, 1H, J = 8.8 Hz), 8.22 (s, 1H),
7.89 (d, 1H, J = 8.3 Hz), 7.76 (ddd, 1H, J = 1.5, 6.9, 8.4 Hz),
7.59 (ddd, 1H, J = 1.1, 7.0, 8.1 Hz), 6.53 (s, 1H), 6.43 (ddd, 1H,
J = 1.2, 1.3, 6.2 Hz), 6.10–5.97 (m, 1H), 5.39 (dq, 1H, J = 1.6,
17.2 Hz), 5.26 (dq, 1H, J = 1.2, 10.4 Hz), 5.05 (dt, 1H, J = 1.9,
5.9 Hz), 4.53–4.29 (AB system, 2H), 3.26–3.20 (m, 1H), 3.16–3.11
(m, 1H), 3.07–2.97 (m, 1H), 3.01 (s, 3H), 2.44–2.34 (m, 1H), 2.23–
Compound 28 (Table 2, entry 9)
According to the procedure described above, 28 was isolated in
81% yield (white solid). 1H NMR (CDCl3, 300 MHz): d (ppm) =
8.21 (d, 1H, J = 9.0 Hz), 8.19 (s, 1H), 7.88 (d, 1H, J = 8.1 Hz),
7.77 (t, 1H, J = 7.5 Hz), 7.57 (t, 1H, J = 7.5 Hz), 6.58 (s, 1H),
6.47 (d, 1H, J = 5.9 Hz), 5.02 (t, 1H, J = 5.6 Hz), 4.23 (sept,
1H, J = 6.1 Hz), 2.63–2.46 (m, 2H), 2.32–2.06 (m, 2H). 13C-
1
2.11 (m, 1H). 13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) = 159.8,
150.0, 141.4, 134.1, 131.9, 130.4, 130.1, 129.6, 128.5, 128.3, 127.2,
117.8, 106.0, 103.0, 101.4, 73.3, 69.8, 58.5, 38.0, 20.9. HRMS
(ESI+) m/z calculated for (MH+): 340.1543. Found: 340.1551. MS
(ESI+): 340 (MH+). IR (CH2Cl2): n 2926, 2893, 1658, 1631, 1506,
1399 cm-1.
1
{ H} NMR (CDCl3, 75 MHz): d (ppm) = 160.8, 149.7, 142.0,
131.8, 130.3, 130.2, 130.0, 128.5, 128.4, 127.2, 104.7, 102.1, 101.8,
71.7, 30.5, 23.9, 22.6, 16.8. HRMS (ESI+) m/z calculated for
(MNa+): 320.1257. Found: 320.1261. MS (ESI+): 320 (MNa+). IR
(CH2Cl2): n 2975, 2931, 2851, 1654, 1632, 1506, 1400, 1384, 1332,
1294 cm-1.
Compound 25 (Table 2, entry 6)
According to the procedure described above, 25 was isolated in
Compound 29 (Table 2, entry 10)
65% yield as a single isomer (colorless oil that crystallized on
1
standing). H NMR (CDCl3, 300 MHz): d (ppm) = 8.24 (d, 1H,
According to the procedure described above, 29 was isolated in
86% yield (white solid). Presence of 2 diastereoisomers (50 : 50)
due to the presence of a THP group. 1H NMR (CDCl3, 300 MHz):
d (ppm) = 8.24–8.17 (m, 2H), 7.86 (d, 1H, J = 8.1 Hz), 7.74 (ddd,
1H, J = 1.3, 7.1, 8.2 Hz), 7.56 (ddd, 1H, J = 1.1, 7.0, 8.0 Hz), 6.45–
6.38 (m, 2H), 5.04 (dt, 1H, J = 1.9, 5.9 Hz), 4.41 (t, 1H, J = 3.2 Hz,
50%), 4.13 (t, 1H, J = 3.2 Hz, 50%), 3.64 (s, 3H), 3.61–3.15 (m, 4H),
3.03 (sept, 1H, J = 6.1 Hz), 2.42–2.10 (m, 2H), 1.38–0.55 (m, 6H).
J = 8.5 Hz), 8.18 (s, 1H), 7.87 (d, 1H, J = 8.0 Hz), 7.76 (t, 1H, J =
8.1 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.38 (d, 2H, J = 8.5 Hz), 6.92 (d,
2H, J = 8.5 Hz), 6.59 (s, 1H), 6.46 (dd, 1H, J = 1.2, 6.0 Hz), 5.05
(dt, 1H, J = 1.6, 5.8 Hz), 4.88 (AB system, 2H), 3.81 (s, 3H), 3.26–
3.00 (m, 3H), 3.00 (s, 3H), 2.47–2.37 (m, 1H), 2.25–2.15 (m, 1H).
1
13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) = 159.6, 149.9, 141.4,
132.0, 131.9, 130.4, 130.0, 129.9, 129.6, 129.5, 128.5, 128.2, 127.2,
1
114.0, 106.0, 102.7, 101.4, 73.2, 70.7, 58.5, 55.4, 37.9, 20.9. HRMS
13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) = 160.1, 159.8, 149.9,
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141.4, 131.7, 131.6, 130.2, 130.0, 129.6, 129.5, 128.4, 128.4, 128.3,
128.2, 127.2, 127.1, 106.3, 106.1, 104.6, 104.5, 101.4, 101.2, 98.5,
98.1, 67.8, 67.7, 61.6, 61.5, 56.3, 56.2, 38.4, 38.3, 30.4, 30.2, 30.0,
29.8, 25.4, 25.3, 21.0, 20.8, 18.6. HRMS (ESI+) m/z calculated
for (MH+): 384.1805. Found: 384.1798. MS (ESI+): 384 (MH+).
IR (CH2Cl2): n 2941, 2878, 2852, 1658, 1631, 1506, 1398, 1355,
1299 cm-1.
Compound 33 (Table 3, entry 4)
According to the procedure described above, 33 was isolated in
85% yield (white solid). Mixture of diastereoisomers 58 : 42. H
1
NMR (CDCl3, 300 MHz): mixture of isomers d (ppm) = 8.27–
8.26 (m, 2H), 8.18 (d, 1H, J = 8.4 Hz), 7.80–7.75 (m, 1H),
7.60 (t, 1H, J = 7.6 Hz), 6.62 (s, 1H, major isomer), 6.34 (s,
1H, minor isomer), 4.47–4.41 (m, 1H), 4.00–3.69 (m, 6H), 3.20
(s, 3H, major isomer), 3.14 (s, 3H, minor isomer), 2.72 (br s,
1
1H). 13C-{ H} NMR (CDCl3, 75 MHz): Major isomer d (ppm) =
Compound 30 (Table 2, entry 11)
156.3, 149.9, 140.5, 132.4, 131.0, 129.8, 129.2, 128.7, 128.5, 127.9,
114.3, 104.8, 71.6, 66.8, 61.9, 58.9, 56.1. Minor isomer d (ppm) =
156.7, 149.8, 140.0, 132.3, 130.9, 129.8, 128.8, 128.7, 128.4, 127.9,
113.2, 103.7, 70.0, 67.1, 62.0, 58.9, 56.0. HRMS (ESI+) m/z
calculated for (MH+): 409.0394. Found: 409.0388. MS (ESI+): 409
(MH+). IR (CH2Cl2): n 2930, 1725, 1628, 1584, 1507, 1459, 1396,
1298 cm-1.
According to the procedure described above, 30 was isolated in
75% yield as a single isomer (white solid). 1H NMR (CDCl3,
300 MHz): d (ppm) = 8.21 (d, 1H, J = 8.8 Hz), 8.20 (s, 1H),
7.90 (d, 1H, J = 8.1 Hz), 7.75 (ddd, 1H, J = 1.1, 6.9, 8.1 Hz), 7.59
(ddd, 1H, J = 1.0, 7.0, 8.0 Hz), 6.63 (s, 1H), 6.43–6.40 (m, 1H),
5.00 (dt, 1H, J = 2.0, 5.9 Hz), 4.29 (sept, 1H, J = 6.1 Hz), 2.42–2.20
(m, 2H), 1.89–1.79 (m, 1H), 1.84 (ddd, 1H, J = 6.0, 6.0, 9.8 Hz),
1.35 (d, 3H, J = 5.2 Hz), 1.34 (d, 3H, J = 5.2 Hz), 0.79–0.67 (m,
1H), 0.35–0.26 (m, 1H), 0.10–0.02 (m, 1H), (-)0.24– (-)0.35 (m,
Compound 34 (Table 3, entry 5)
1
2H). 13C-{ H} NMR (CDCl3, 75 MHz): d (ppm) = 160.2, 149.6,
According to the procedure described above, 34 was isolated in
79% yield (white solid). Mixture of diastereoisomers 77 : 23. H
141.4, 131.6, 130.6, 130.2, 129.9, 128.5, 128.3, 127.1, 108.1, 102.6,
101.9, 72.1, 43.5, 24.0, 23.6, 22.5, 11.7, 5.2, 2.5. HRMS (ESI+)
m/z calculated for (MH+): 338.1751. Found: 338.1754. MS (ESI+):
338 (MH+). IR (CH2Cl2): n 2976, 2928, 1656, 1632, 1506, 1384,
1294 cm-1.
1
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.20–8.17
(m, 2H), 7.89 (d, 1H, J = 8.1 Hz), 7.78 (dt, 1H, J = 1.0, 7.2,
8.2 Hz), 7.60 (t, 1H, J = 7.1 Hz), 7.36 (d, 2H, J = 8.7 Hz), 6.92
(d, 2H, J = 8.6 Hz), 6.66 (s, 1H, major isomer), 6.38 (s, 1H, minor
isomer), 4.84 (AB system, 2H), 4.40 (dd, 1H, J = 5.5, 6.6 Hz),
3.81 (s, 3H), 3.80–3.77 (m, 2H), 3.19 (s, 3H). 13C-{ H} NMR
1
Compound 31 (Table 3, entry 1)
(CDCl3, 75 MHz): Major isomer d (ppm) = 159.6, 156.4, 149.9,
141.0, 132.2, 130.8, 129.9, 129.5, 129.1, 129.0, 128.6, 128.4, 127.8,
114.5, 114.1, 103.3, 70.6, 66.9, 59.1, 56.7, 55.4. HRMS (ESI+) m/z
calculated for (MH+): 485.0707. Found: 485.0694. MS (ESI+): 485
(MH+). IR (CH2Cl2): n 2930, 1613, 1585, 1514, 1464, 1392, 1342,
1300 cm-1.
According to the procedure described above, 31 was isolated in
1
79% yield (white solid). Mixture of diastereoisomers 77 : 23. H
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.23 (s, 1H),
8.18 (d, 1H, J = 8.5 Hz), 7.90 (d, 1H, J = 8.1 Hz), 7.78 (t,
1H, J = 8.4 Hz), 7.61 (t, 1H, J = 8.0 Hz), 6.50 (s, 1H), 4.38
(t, 1H, J = 6.2 Hz), 3.83–3.71 (m, 2H), 3.64 (s, 3H), 3.22 (s,
3H). Minor isomer (selected signals) d (ppm) = 6.28 (s, 1H),
Compound 35 (Table 3, entry 6)
1
3.50 (s, 3H), 3.14 (s, 3H). 13C-{ H} NMR (CDCl3, 75 MHz):
Major isomer d (ppm) = 156.5, 150.0, 140.8, 132.1, 130.9, 130.0,
129.3, 128.6, 128.5, 127.8, 114.4, 105.3, 66.9, 59.0, 56.6, 56.4.
Minor isomer (selected signals) d (ppm) = 157.0, 150.0, 139.7,
113.1, 104.0, 67.3, 59.0, 56.0, 54.3. HRMS (ESI+) m/z calculated
for (MH+): 379.0288. Found: 379.0286. MS (ESI+): 379 (MH+).
IR (CH2Cl2): n 2932, 2838, 1723, 1628, 1584, 1506, 1448, 1397,
1299 cm-1.
According to the procedure described above, 35 was isolated in
74% yield (white solid). Mixture of diastereoisomers 77 : 23. H
1
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.25 (s, 1H),
8.20 (d, 1H, J = 8.5 Hz), 7.93 (d, 1H, J = 8.1 Hz), 7.81 (ddd, 1H, J =
1.4, 6.9, 8.4 Hz), 7.64 (ddd, 1H, J = 1.1, 6.9, 8.1 Hz), 6.48 (s, 1H),
4.16 (part of AB system, 1H, J = 18.2 Hz), 3.59 (s, 3H), 3.51 (part
of AB system, 1H, J = 18.2 Hz). Minor isomer (selected signals)
d (ppm) = 6.25 (s, 1H), 4.17 (part of AB system, 1H, J = 18.2 Hz),
3.57 (s, 3H), 3.42 (part of AB system, 1H, J = 18.2 Hz). 13C-{ H}
1
Compound 32 (Table 3, entry 2)
NMR (CDCl3, 75 MHz): Major isomer d (ppm) = 156.2, 150.1,
137.7, 132.1, 131.0, 129.9, 129.4, 128.7, 128.4, 128.0, 114.3, 104.9,
56.2, 50.2. HRMS (ESI+) m/z calculated for (MH+): 335.0026.
Found: 335.0028. MS (ESI+): 335 (MH+). IR (CH2Cl2): n 2931,
2854, 1724, 1628, 1582, 1507, 1399, 1336, 1313 cm-1.
According to the procedure described above, 32 was isolated in
1
96% yield (white solid). Mixture of diastereoisomers 84 : 16. H
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.21–8.17 (m,
2H), 7.90 (d, 1H, J = 8.1 Hz), 7.77 (t, 1H, J = 7.5 Hz), 7.60 (t,
1H, J = 7.4 Hz), 6.65 (s, 1H), 4.37 (t, 1H, J = 6.0 Hz), 4.24 (sept,
1H, J = 6.1 Hz), 3.77 (d, 2H, J = 6.1 Hz), 3.24 (s, 3H), 1.36 (t,
6H, J = 5.7 Hz). Minor isomer (selected signals) d (ppm) = 6.34 (s,
Compound 36 (Table 3, entry 7)
1
1H), 3.14 (s, 3H). 13C-{ H} NMR (CDCl3, 75 MHz): Major isomer
According to the procedure described above, 36 was isolated in
74% yield (white solid). Mixture of diastereoisomers 85 : 15. H
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.20 (s, 1H),
8.18 (d, 1H, J = 8.5 Hz), 7.91 (d, 1H, J = 8.1 Hz), 7.79 (t, 1H,
J = 7.1 Hz), 7.62 (t, 1H, J = 7.5 Hz), 6.61 (s, 1H), 4.24 (sept, 1H,
J = 6.2 Hz), 4.16 (part of AB system, 1H, J = 18.2 Hz), 3.48 (part
1
d (ppm) = 156.5, 150.0, 141.0, 132.0, 130.7, 130.1, 129.9, 128.6,
128.5, 127.7, 114.4, 103.4, 72.9, 67.1, 59.0, 56.6, 23.8, 22.5. HRMS
(ESI+) m/z calculated for (MH+): 407.0601. Found: 407.0599. MS
(ESI+): 407 (MH+). IR (CH2Cl2): n 2977, 2929, 1724, 1628, 1583,
1506, 1467, 1385, 1337, 1295 cm-1.
4838 | Org. Biomol. Chem., 2011, 9, 4831–4841
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of AB system, 1H, J = 18.2 Hz), 1.36 (d, 3H, J = 6.1 Hz), 1.33
(d, 3H, J = 6.1 Hz). Minor isomer (selected signals) d (ppm) =
Compound 40 (Table 4, entry 2)
According to the procedure described above, 40 was isolated in
51% yield (white solid). Mixture of diastereoisomers 88 : 12. H
1
6.33 (s, 1H), 3.37 (part of AB system, 1H, J = 18.2 Hz). 13C-{ H}
1
NMR (CDCl3, 75 MHz): Major isomer d (ppm) = 156.3, 150.0,
137.6, 132.0, 131.8, 130.8, 130.3, 129.8, 128.6, 128.5, 127.8, 114.2,
102.9, 72.9, 50.1, 23.7, 22.4. HRMS (ESI+) m/z calculated for
(MNa+): 385.0158. Found: 385.0148. MS (ESI+): 385 (MNa+). IR
(CH2Cl2): n 2977, 2929, 1725, 1630, 1582, 1507, 1405, 1385 cm-1.
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.23–8.19 (m,
2H), 7.91 (dd, 1H, J = 1.0, 8.2 Hz), 7.78 (ddd, 1H, J = 1.4, 7.0,
8.4 Hz), 7.61 (ddd, 1H, J = 1.0, 7.0, 8.0 Hz), 6.58 (s, 1H), 4.38
(q, 2H, J = 7.1 Hz), 4.19 (sept, 1H, J = 6.2 Hz), 3.26–3.05 (m,
4H), 3.11 (s, 3H), 2.43 (AB system, 1H), 1.39 (t, 3H, J = 7.1 Hz),
1.35 (d, 3H, J = 6.1 Hz), 1.33 (d, 3H, J = 6.1 Hz). 13C-{ H}
1
Compound 37 (Table 3, entry 8)
NMR (CDCl3, 75 MHz): Major isomer d (ppm) = 163.3, 157.3,
150.7, 149.9, 131.9, 130.7, 130.6, 130.1, 128.6, 128.5, 127.6, 105.1,
103.1, 72.8, 72.6, 62.3, 58.8, 33.6, 23.9, 22.5, 22.0, 14.3. HRMS
(ESI+) m/z calculated for (MH+): 415.1864. Found: 415.1865. MS
(ESI+): 415 (MH+). IR (CH2Cl2): n 2979, 2929, 1721, 1629, 1506,
1378 cm-1.
According to the procedure described above, 37 was iso-
lated in 78% yield (white solid). Mixture of diastereoisomers
1
40 : 40 : 10 : 10. H NMR (CDCl3, 300 MHz): Major isomers d
(ppm) = 8.25–8.17 (m, 2H), 7.91 (d, 1H, J = 8.1 Hz), 7.81–7.76 (m,
1H), 7.64–7.59 (m, 1H), 6.48 & 6.46 (s, 1H), 4.63 (br s, 1H, 50%),
4.49 (br s, 1H, 50%), 4.48–4.41 (m, 1H), 4.18–4.07 (m, 1H), 3.81–
3.71 (m, 2H), 3.65 & 3.63 (s, 3H), 3.53–3.39 (m, 1H), 1.50–1.06
(m, 6H). Minor isomers (selected signals) d (ppm) = 6.32 & 6.23
Compound 41 (Table 4, entry 3)
According to the procedure described above, 41 was isolated in
20% yield (white solid). Mixture of diastereoisomers 86 : 14. H
1
(s, 1H), 3.50 & 3.49 (s, 3H). 13C-{ H} NMR (CDCl3, 75 MHz):
1
Major isomers d (ppm) = 156.5, 156.4, 149.9, 141.3, 140.8, 132.0,
131.9, 130.9, 129.9, 129.5, 128.6, 128.4, 127.8, 127.7, 114.6, 114.4,
105.5, 105.3, 99.3, 98.8, 62.5, 61.9, 61.6, 56.9, 56.8, 56.7, 56.3,
30.1, 29.8, 25.3, 18.7, 18.6. HRMS (ESI+) m/z calculated for
(MH+): 449.0707. Found: 449.0699. MS (ESI+): 449 (MH+). IR
(CH2Cl2): n 2944, 2854, 1724, 1628, 1584, 1507, 1446, 1398, 1356,
1298 cm-1.
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.24–8.21 (m,
2H), 7.92 (dd, 1H, J = 1.0, 8.3 Hz), 7.79 (ddd, 1H, J = 1.4, 6.9,
8.3 Hz), 7.62 (ddd, 1H, J = 1.0, 7.0, 8.0 Hz), 6.54 (s, 1H), 6.01
(ddt, 1H, J = 6.0, 10.5, 16.5 Hz), 5.38 (dd, 1H, J = 1.5, 17.2 Hz),
5.27 (dd, 1H, J = 1.3, 10.4 Hz), 4.45–4.26 (m, 4H), 3.26–3.04 (m,
4H), 3.09 (s, 3H), 2.51–2.39 (m, 1H), 1.39 (t, 3H, J = 7.1 Hz).
1
13C-{ H} NMR (CDCl3, 75 MHz): Major isomer d (ppm) = 163.2,
157.4, 150.7, 149.9, 133.7, 132.1, 130.7, 130.1, 128.6, 128.4, 127.7,
118.3, 105.2, 103.5, 72.5, 70.1, 62.3, 58.8, 33.6, 21.9, 14.3. HRMS
(ESI+) m/z calculated for (MH+): 413.1707. Found: 413.1704. MS
(ESI+): 413 (MH+). IR (CH2Cl2): n 2985, 2929, 1721, 1628, 1582,
1506, 1399, 1377 cm-1.
Compound 38 (Table 3, entry 9)
According to the procedure described above, 38 was isolated in
1
65% yield (white solid). Mixture of diastereoisomers 86 : 14. H
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.25–8.22
(m, 1H), 8.15 (d, 1H, J = 8.5 Hz), 7.92 (d, 1H, J = 8.2 Hz),
7.78 (t, 1H, J = 8.3 Hz), 7.64–7.59 (m, 1H), 6.69 (s, 1H, major
isomer), 6.40 (s, 1H, minor isomer), 4.24 (sept, 1H, J = 6.2 Hz),
3.35 (d, 1H, J = 10.8 Hz), 1.35 (d, 3H, J = 6.1 Hz), 1.29 (d, 3H,
J = 6.2 Hz), 1.18–1.06 (m, 1H), 0.87–0.70 (m, 1H), 0.51–0.23 (m,
Compound 42 (Table 4, entry 4)
According to the procedure described above, 42 was isolated in
51% yield (white solid). Mixture of diastereoisomers 90 : 10. H
1
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.23–8.19 (m,
2H), 7.89 (dd, 1H, J = 1.0, 8.2 Hz), 7.78 (ddd, 1H, J = 1.4, 7.3,
8.4 Hz), 7.60 (ddd, 1H, J = 1.0, 7.0, 8.0 Hz), 7.35 (d, 2H, J =
8.6 Hz), 6.9 (d, 2H, J = 8.6 Hz), 6.58 (s, 1H), 4.81 (AB system,
2H), 4.39 (q, 2H, J = 7.1 Hz), 3.81 (s, 3H), 3.23–3.04 (m, 4H), 3.07
1
2H). 13C-{ H} NMR (CDCl3, 75 MHz): Major isomer d (ppm) =
156.8, 149.9, 144.8, 132.1, 130.8, 130.7, 129.8, 128.7, 128.6, 127.8,
114.6, 103.2, 72.5, 62.4, 23.7, 22.4, 7.0, 4.7, 2.4. HRMS (ESI+) m/z
calculated for (MH+): 403.0652. Found: 403.0647. MS (ESI+): 403
(MH+). IR (CH2Cl2): n 2977, 2928, 1724, 1628, 1582, 1506, 1403,
1384 cm-1.
(s, 3H), 2.50–2.38 (m, 1H), 1.40 (t, 3H, J = 7.1 Hz). 13C-{ H} NMR
1
(CDCl3, 75 MHz): Major isomer d (ppm) = 163.2, 159.7, 157.3,
150.7, 149.8, 132.1, 130.6, 130.1, 129.2, 128.6, 128.4, 127.6, 114.1,
105.2, 103.2, 72.5, 71.0, 62.3, 58.8, 55.4, 33.7, 22.0, 14.3. HRMS
(ESI+) m/z calculated for (MH+): 493.1969. Found: 493.1970. MS
(ESI+): 493 (MH+). IR (CH2Cl2): n 2983, 2931, 2840, 1721, 1613,
1514, 1299 cm-1.
Compound 39 (Table 4, entry 1)
According to the procedure described above, 39 was isolated in
83% yield. Mixture of diastereoisomers 88 : 12. 1H NMR (CDCl3,
300 MHz): Major isomer d (ppm) = 8.23–8.18 (m, 2H), 7.89 (d, 1H,
J = 7.8 Hz), 7.77 (t, 1H, J = 7.3 Hz), 7.59 (t, 1H, J = 7.6 Hz), 6.39
(s, 1H), 4.36 (q, 2H, J = 7.1 Hz), 3.60 (s, 3H), 3.23–3.04 (m, 4H),
Compound 43 (Table 4, entry 5)
1
3.07 (s, 3H), 2.51–2.39 (m, 1H), 1.37 (t, 3H, J = 7.1 Hz). 13C-{ H}
According to the procedure described above, 43 was isolated in
59% yield (white solid). Mixture of diastereoisomers 88 : 12. H
1
NMR (CDCl3, 75 MHz): Major isomer d (ppm) = 163.1, 157.3,
150.7, 149.8, 132.0, 130.6, 130.0, 129.8, 128.6, 128.3, 127.6, 105.1,
104.9, 72.4, 62.2, 58.7, 56.4, 33.5, 21.9, 14.3. HRMS(ESI+) m/z
calculated for (MNa+): 409.1370. Found: 409.1370. MS (ESI+):
409 (MNa+). IR (CH2Cl2): n 2985, 2932, 1721, 1628, 1506, 1447,
1398 cm-1.
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.25 (s, 1H),
8.19 (d, 1H, J = 8.5 Hz), 7.92 (d, 1H, J = 8.2 Hz), 7.79 (ddd, 1H,
J = 1.4, 7.1, 8.4 Hz), 7.63 (ddd, 1H, J = 1.0, 7.1, 8.1 Hz), 6.48 (s,
1H), 4.38 (q, 2H, J = 7.1 Hz), 3.56 (s, 3H), 3.04–2.96 (part of AB
system, 1H), 2.87–2.64 (part of AB system, 2H), 2.32–2.26 (part of
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1
AB system, 1H), 1.39 (t, 3H, J = 7.1 Hz). 13C-{ H} NMR (CDCl3,
Chem. Commun., 2009, 5075–5087; (p) A. Arcadi, Chem. Rev., 2008,
108, 3266–3325; (q) D. J. Gorin, B. D. Sherry and F. D. Toste, Chem.
Rev., 2008, 108, 3351–3378; (r) M. Alvarez-Corral, M. Munoz-Dorado
and I. Rodriguez-Garcia, Chem. Rev., 2008, 108, 3174–3198; (s) M.
Shibasaki and M. Kanai, Chem. Rev., 2008, 108, 2853–2873; (t) A. S.
K. Hashmi, Chem. Rev., 2007, 107, 3180–3211; (u) V. Michelet, P. Y.
Toullec and J.-P. Geneˆt, Angew. Chem., Int. Ed., 2008, 47, 4268–4315;
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75 MHz): Major isomer d (ppm) = 163.4, 158.5, 150.6, 149.8,
132.2, 130.7, 130.0, 129.8, 128.7, 128.5, 127.7, 104.7, 103.9, 62.3,
55.8, 24.9, 17.9, 14.3. HRMS (ESI+) m/z calculated for (MH+):
343.1288. Found: 343.1288. MS (ESI+): 343 (MH+). IR (CH2Cl2):
n 2983, 2938, 1720, 1628, 1506, 1398, 1378, 1296 cm-1.
Compound 44 (Table 4, entry 6)
According to the procedure described above, 44 was isolated in
63% yield (white solid). Mixture of diastereoisomers 86 : 14. H
8 D. Yue, N. Della Ca and R. C. Larock, Org. Lett., 2004, 6, 1581–1584.
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1
NMR (CDCl3, 300 MHz): Major isomer d (ppm) = 8.25–8.17 (m,
2H), 7.93 (d, 1H, J = 8.2 Hz), 7.79 (t, 1H, J = 7.1 Hz), 7.62 (t, 1H,
J = 7.1 Hz), 6.63 (s, 1H), 4.37 (q, 2H, J = 7.1 Hz), 4.21 (sept, 1H,
J = 6.2 Hz), 3.00–2.89 (part of AB system, 1H), 2.63–2.52 (part
of AB system, 1H), 2.01–1.92 (m, 1H), 1.39 (t, 3H, J = 7.1 Hz),
1.35 (d, 3H, J = 6.2 Hz), 1.31 (d, 3H, J = 6.2 Hz), 0.77–0.65
(m, 1H), 0.43–0.34 (m, 1H), 0.18–0.07 (m, 1H), -0.04–(-)0.18 (m,
11 L.-L. Wei, L.-M. Wei, W.-B. Pan and M.-J. Wu, Synlett, 2004, 1497–
1
2H). Minor isomer d (ppm) (selected peak) = 6.45 (s, 1H). 13C-{ H}
1502.
NMR (CDCl3, 75 MHz): Major isomer d (ppm) = 163.5, 157.9,
150.8, 149.6, 131.8, 131.1, 130.5, 129.9, 128.6, 128.5, 127.5, 107.4,
103.3, 72.7, 62.2, 38.6, 24.2, 23.9, 22.6, 14.3, 11.4, 5.0, 2.3. HRMS
(ESI+) m/z calculated for (MH+): 411.1914. Found: 411.1914. MS
(ESI+): 411 (MH+). IR (CH2Cl2): n 2979, 2928, 1720, 1629, 1608,
1506, 1376, 1299 cm-1.
12 M. Gulias, J. R. Rodriguez, L. Castedo and J. L. Mascaren˜as, Org.
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15 J. Barluenga, J. Calleja, A. Mendoza, F. Rodriguez and F. J. Fananas,
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16 C.-M. Chao, P. Y. Toullec and V. Michelet, Tetrahedron Lett., 2009, 50,
3719–3722.
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Deep thanks are due to INCa and CNRS for an ATIP grant (PB
and XB), the French ministry of Research (TG, EP), the “Ligue
contre le Cancer” (EP), the “Association pour la Recherche sur le
Cancer” (PB) and the “Cluster de Recherche Chimie de la Re´gion
Rhoˆne-Alpes” (PB, EP).
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