A facile synthesis of novel acyclo-C-nucleoside analogues from L-rhamnose via variants of Bohlmann-Rahtz reaction

Article abstract of DOI:10.1055/s-0030-1258038

Synthesis of a series of novel acyclo-C-nucleoside analogues bearing substituted pyridines, dihydro-6H-quinolin-5-ones, dihydro-5H-cyclopentapyridin- 5-one, tetrahydrocyclohepta[b] pyr-idine-5-one, and azafluorinone has been achieved in very good yields, through CeCl₃·7H ₂O-NaI-catalyzed one-pot condensation of a variant of the Bohlmann-Rahtz reaction using β-enaminones derived from l-rhamnose, acyclic and cyclic 1,3-dicarbonyls, and ammonium acetate. Ready availability of reactive β-enaminones, use of a cerium catalyst, and shorter reaction times are the advantages of this protocol over previous methodology. A plausible mechanism invoking cerium-catalyzed sequential Michael addition-cyclode- hydration-elimination reactions is also presented. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258038

LETTER
2251
A Facile Synthesis of Novel Acyclo-C-Nucleoside Analogues from L-Rhamnose
via Variants of Bohlmann–Rahtz Reaction
Synthesisof
N
r
ovel
A
c
i
C
n
i
nalog
v
ues as Kantevari,* Siddamal Reddy Putapatri
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500007, India
E-mail: kantevari@yahoo.com; E-mail: kantevari@gmail.com
Received 9 June 2010
Incisive work by Bagley5 has unveiled a remarkable vari-
Abstract: Synthesis of a series of novel acyclo-C-nucleoside ana-
logues bearing substituted pyridines, dihydro-6H-quinolin-5-ones,
dihydro-5H-cyclopentapyridin-5-one, tetrahydrocyclohepta[b] pyr-
idine-5-one, and azafluorinone has been achieved in very good
ant of the classical Bohlmann–Rahtz synthesis,6 wherein
an alkynone and 3-amino alkenoate combine in refluxing
solvent to afford substituted pyridines in good yields. This
yields, through CeCl3·7H2O-NaI-catalyzed one-pot condensation of chemistry could deliver libraries of pyridine analogues, if
a variant of the Bohlmann–Rahtz reaction using b-enaminones de-
rived from L-rhamnose, acyclic and cyclic 1,3-dicarbonyls, and am-
monium acetate. Ready availability of reactive b-enaminones, use
of a cerium catalyst, and shorter reaction times are the advantages
of this protocol over previous methodology. A plausible mechanism
invoking cerium-catalyzed sequential Michael addition–cyclode-
hydration–elimination reactions is also presented.
it were to prove serviceable with variants of alkynones
and 3-aminoalkenoates.7 From our research8 as well as
others,9 it is clear that b-enaminones could serve as polar-
ized variants of alkynones in the synthesis of 2,3,6-trisub-
stituted pyridines. In order to obtain a suitable sugar-
containing enaminone building block, the readily avail-
able deoxymonosaccharide, L-rhamnose (6-deoxyman-
nose) was taken as the starting substrate.
Key words: Bohlmann–Rahtz reaction, acyclo-C-nucleosides,
CeCl3·7H2O-NaI, one-pot condensation, b-enaminone, L-rhamnose,
heterocycles
Among lanthanide-based catalysts, cerium(III) chloride
has emerged as a cheap, efficient, and green reagent (it
shows the same toxicity level as sodium chloride) able to
catalyze selective transformations and cyclizations.10 In
most cases, the activity of CeCl3 can be increased in com-
bination with NaI.10 The successful use of cerium(III) in
reactions using 1,3-dicarbonyl substrates11 prompted us to
investigate its applicability in the one-pot condensation of
b-enaminones derived from L-rhamnose with 1,3-dicarbo-
nyl compounds and ammonium acetate.
Acyclo-C-nucleosides with an open-chain sugar moiety
attached to a heterocycle through a C–C bond have gained
considerable attention in recent years due to their broad
spectrum of biological activity.1 Notable among them are
the natural bengazoles and synthetic carbohybrids linked
to imidazoles, pyrazoles, benzimidazoles, piperidines, in-
dolizidines, and nitrones (Figure 1), which have been
shown to possess significant pharmacological activity.2,3
We envisaged that fusing acyclic polyol units to a pyri-
dine core would create a series of acyclo-C-nucleosides
with similar properties.4
In this paper we report an efficient CeCl3·7H2O-NaI cata-
lyzed one-pot synthesis of acyclo-C-nucleoside analogues
bearing 2,3,6-trisubstituted pyridines 6a–f,i, dihydro-6H-
quinolin-5-ones 6j,l,o, dihydro-5H-cyclo pentapyridin-5-
one 6k, tetrahydrocyclohepta[b]pyridine-5-one 6m, and
azafluorinone 6n. The one-pot condensation of (E)-3-
(dimethylamino)-1-[(4S,4¢S,5R)-2,2,2¢,2¢-tetramethyl-4,4¢-
bi(1,3-dioxolan)-5-yl]-2-propenone 4 (here after referred
to as enaminone 4) derived from L-rhamnose, with acyclic
and cyclic 1,3-diketones 5a–p and ammonium acetate in
the presence of CeCl3·7H2O-NaI catalyst resulted in the ti-
tle compounds with high regioselectivity.
HO
OH OBn
HO
HO
BnO
N
N
N
N
O
R
N
OBn
OH
N
RO
bengazoles
O
OH
HO
OBn
HO
R2
R1
HO
OH
OH
As a starting point of the study, 1-[(4S,4¢S,5R)-2,2,2¢,2¢-
tetramethyl-4,4¢-bi(1,3-dioxolan)-5-yl)ethanone (3) re-
quired for the preparation of enaminone 4 was synthesized
by improving the literature method12 starting from L-
rhamnose (Scheme 1). L-Rhamnitol (1) obtained after
NaBH4 reduction, was protected by reacting with 2,2-
dimethoxypropane. Swern oxidation of 2 gave methyl ke-
tone 3 in excellent yield. Finally, the required building
block 4 was obtained in 88% yield after refluxing 3 with
dimethylformamide dimethylacetal (DMF-DMA) in xy-
lene.
OH
O
O
OH
OBn
N
HO
HN
N
N
R3
N
NH
OR
Ph
Figure 1 Representatives of natural and synthetic acyclo-C-nucleo-
sides
SYNLETT 2010, No. 15, pp 2251–2256
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258038; Art ID: D13610ST
© Georg Thieme Verlag Stuttgart · New York

2252
S. Kantevari, S. R. Putapatri
LETTER
OH
Here it is also noteworthy that tetrabutylammonium bro-
mide (TBAB) and K5CoW12O40·3H2O catalysts also gave
product 6l in comparable yields (84% and 76%, respec-
tively; Table 1, entries 9 and 18) but the procedure re-
quired longer reaction times and the latter catalyst
required special preparation.
dimethoxy-
propane,
acetone
OH
OH
OHC
HO
NaBH4
MeOH, r.t.
0.5 h, 98%
p-TSA, r.t.
6 h, 85%
HO
OH
OH
HO
HO
L-rhamnose
1
Encouraged by these results, the general scope of the
reaction was further investigated with various acyclic 1,3-
diketones 5a–i (Figure 2) under the optimized protocol.
All the reactions except with 5g and 5h proceeded
Me
O
Me
O
O
N
O
O
O
O
O
CH2Cl2, (COCl)2
DMF–DMA
xylene
reflux
DMSO, 3 h
OH
O
O
O
–78 °C, 90%
O
O
Table 1 Evaluation of Potential Catalystsa
7 h, 88%
O
Me
Me
2
3
4
O
O
N
O
O
O
O
O
O
O
NH4OAc
catalyst
Scheme 1 Synthesis of b-enaminone 4
+
5l
i-PrOH, reflux
O
N
O
O
O
O
4
6l
R1
R2
n
5a R1 = Me, R2 = OMe
5b R1= Me, R2 = OEt
5c R1 = Me, R2 = Ot-Bu
5d R1 = Me, R2 = Me
5e R1 = Pr, R2 = OEt
5f R1 = CH2Cl, R2 = OEt
5g R1 = CF3, R2 = OEt
5h R1 = Ph, R2 = CF3
5k n = 1
5l n = 2
5m n = 3
Entry
1
Catalyst (mol%)
AcOH (solvent)
HClO4-SiO2 (20)
Co(OAc)2·4H2O (20)
CeCl3·7H2O (20)
FeCl3·H2O (20)
Time (h) Yield (%)b
24
12
12
24
24
12
12
12
24
24
24
24
24
24
24
24
24
5
sluggish
5
O
2
3
18
55
15
12
15
10
84
18
12
18
16
12
10
18
9
O
5n
4
O
O
5
O
NO2
6
Zn(ClO4)2·4H2O (20)
SnCl2·2H2O (20)
CoCl2 (20)
O
O
7
5i
5j
5o
8
O
OH
O
O
O
9
TBAB (20)
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
Mg(ClO4)2 (20)
O
O
O
O
5p
5q
5r
5s
La(CF3SO3)3 (5)
In(CF3SO3)3 (5)
Sc(CF3SO3)3 (5)
Cu(CF3SO3)3 (5)
Yb(CF3SO3)3 (5)
Montmorillonite-K10 (20)
Na2WO4·2H2O (20)
K5CoW12O40·3H2O (5)
K5CoW12O40·3H2O (10)
anhyd CeCl3 (20)
CeCl3·7H2O-NaI (20)
NaI (20)
Figure 2 Acyclic and cyclic 1,3-dicarbonyl compounds examined
With the desired sugar building block 4 to hand, various
catalysts and reaction conditions were screened to effect
the desired reaction (Table 1). Initial efforts using AcOH
as solvent9f in the condensation of enaminone 4 with
cyclohexane-1,3-dione 5l and ammonium acetate led to a
mixture of products. After a series of experiments, the
condensation of enaminone 4 with cyclohexane-1,3-dione
5l and ammonium acetate was successful using
CeCl3·7H2O-NaI (20.0 mol%) in refluxing 2-propanol for
3 hours (Table 1, entry 21) to afford quinolinone 6l in very
good yield (88%). From our results it appears that the wa-
ter associated with cerium(III) salt plays a role in the abil-
ity of the CeCl3·7H2O-NaI to promote the condensation of
enaminone 4 with 1,3-cyclohexanedione. When we at-
tempted reaction in the presence of NaI without using
CeCl3·7H2O starting material was quantitatively recov-
ered (Table 1, entry 22). It was also noted that, in the ab-
sence of NaI, the procedure with CeCl3·7H2O required 24
hours to give product 6l in 55% yield (Table 1, entry 4).
76
61
ca. 3
88
0
5
24
3
24
a All the reactions were performed with 4 (1.0 mmol), 5l (1.2 mmol),
and NH4OAc (2.0 mmol). The progress of the reaction was monitored
by TLC.
b Isolated yield.
Synlett 2010, No. 15, 2251–2256 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Acyclo-C-Nucleoside Analogues
2253
smoothly to give the corresponding trisubstituted pyr-
O
O
O
O
O
O
idines 6a–f,i in good to excellent yields (Table 2). All the
O
O
1
O
O
products obtained were fully characterized by IR, H
NMR, 13C NMR, ESI-MS, and HRMS analysis.
N
n
N
In the case of fluorinated acyclic 1,3-diketones 5g and 5h,
the reaction was sluggish and did not give the desired
product. In both these cases, purification of reaction mix-
ture through silica gel column chromatography led to the
recovery of starting substrate 4 in quantitative yield.
6j (3.5 h, 86%)
6k n = 1 (8 h, 32%)
6l n = 2 (3 h, 88%)
6m n = 3 (6 h, 53%)
In an extension, we further tested the protocol with vari-
ous cyclic 1,3-diketones 5j–s (Figure 3). Most of the reac-
tions proceeded well and acyclo-C-nucleoside analogues
bearing dihydro-6H-quinolin-5-ones 6j,l,o, dihydro-5H-
cyclopentapyridin-5-one 6k, tetrahydrocyclohepta[b]pyr-
idine-5-one 6m, and azafluorinone 6n were isolated in
moderate to very good yields. With 5o, the condensation
reaction proceeded regioselectively to give 6o as the sole
product, the regioselectivity of methyl substituents in 6o
being assessed by 1H-13C HMBC spectroscopic analysis.
O
O
O
O
O
O
O
N
N
O
O
O
6n (2.5 h, 64%)
6o (4 h, 78%)
Figure 3 Synthesis of acyclo-C-nucleosides analogues bearing di-
hydro-6H-quinolin-5-ones 6j,l,o, dihydro-5H-cyclopenta pyridin-5-
one 6k, tetrahydrocyclohepta [b]pyridine-5-one 6m, and azafluorinone
6n.
Table 2 Synthesis of Trisubstituted Pyridines 6a–i
were fully characterized by IR, 1H NMR, 13C NMR, ESI-
MS, and HRMS analysis.
Me
Me
O
O
N
O
O
O
Under the reaction conditions, Meldrum’s acid 5p
(Scheme 2) behaved as a masked ketone, generating ace-
tone which condensed with ammonia and then reacted
with 4 in the pyridine forming process to give 6-substitut-
ed picoline 6p in 35% yield. Use of ammonium formate or
ammonium carbonate instead of ammonium acetate did
not alter the product or yield and increasing the equiva-
lents of Meldrum’s acid (2.5 equiv) was necessary to en-
sure maximum consumption of starting material 4 (75%
yield).
O
O
O
NH4OAc
4
O
O
CeCl3⋅7H2O-NaI
R2
+
i-PrOH, reflux
O
O
N
R1
R1
R2
5a–i
6a–i
Entry 1,3-Dicarbonyl
Time (h) Product Yield (%)
O
O
O
O
5
R1
R2
O
O
O
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
Me
Me
Me
Me
Pr
OMe
OEt
Ot-Bu
Me
3.0
3.5
3.0
3.0
4.0
3.5
6a
6b
6c
6d
6e
6f
82
80
76
82
72
65
<1
<1
32
Me
N
Me
O
O
N
O
O
O
O
a
+
O
O
O
O
O
5p
OEt
OEt
OEt
OCF3
O
O
4
CH2Cl
CF3
Ph
N
12
6g
6h
6i
12
8
6p
a
Scheme 2 Formation of picoline analogue 6p. Reagents and condi-
tions: (a) NH4OAc, CeCl3·7H2O-NaI, i-PrOH, reflux.
Ph
NO2
a NO2 replaces COR2 moiety.
At this stage of investigation the exact mechanism of this
reaction is not clear; although a plausible cerium-activat-
ed reaction sequence for the formation of 6 is presented
here (Scheme 3). Based on the above results, and litera-
ture precedent on cerium-catalyzed chemical transforma-
tions,12 both CeCl3·7H2O and NaI are required in the
The low yield obtained with 1,3-cyclopentadione 5k
(Figure 3) may be due to the steric strain arising in the re-
action. Reaction with olefinic 1,3-dicarbonyl compounds
5q–s failed to give the desired products. All products 6j–o
Synlett 2010, No. 15, 2251–2256 © Thieme Stuttgart · New York

2254
S. Kantevari, S. R. Putapatri
LETTER
Me
Me
O
O
N
O
O
O
Me
NH
CeCl3⋅7H2O
NaI
O
O
O
Me
O
O
R2
4
CeCl3I–Na+⋅nH2O
N
R1
6
Ce(III)
Me
Me
Me
Me
N+
O
O
N
N
OH
O
O
O
O
O
O
R2
I–Na+
Ce(III)Cl3
R1
O
Me
Me
R1
R2
R2
O
O
N
O
O
O
NH2
••
O
H2O
Ce(III)
Me
Me
R1
+
O
O
N
O
NH4OAc
H2N
O
O
Ce(III)Cl3⋅I–Na+
R2
R1
R2
••
N
R1
O
O
H
O
(III)
Ce
Scheme 3 CeCl3·7H2O-NaI-catalyzed plausible reaction sequence for the formation of acyclo-C-nucleoside analogues 6
catalytic process. Although the enhanced catalytic activity rivative 7l thus obtained was fully characterized by NMR
exerted by NaI with CeCl3·7H2O is still obscure, it is be- spectroscopy and mass spectrometric analysis.
lieved to be due to the formation of an activated complex
In conclusion, we have described an efficient method for
the synthesis of a series of acyclo-C-nucleoside analogues
bearing 2,3,6-trisubstituted pyridines 6a–f,i, dihydro-6H-
quinolin-5-ones 6j,l,o, dihydro-5H-cyclopentapyridin-5-
one 6k, tetrahydrocyclohepta[b]pyridine-5-one 6m, and
azafluorinone 6n. CeCl3·7H2O-NaI-catalyzed one-pot
condensation of b-enaminone 4 with acyclic and cyclic
1,3-dicarbonyls 5a–p and ammonium acetate proceeded
CeCl3I–Na+·nH2O. Another unexplained aspect is the role
of water as anhydrous CeCl3 is found to be inactive.
Mechanistically similar to the Bohlmann–Rahtz reaction
the condensation is postulated proceed through a cerium-
activated process12 initially with the formation of enamin-
one from the corresponding 1,3-dicarbonyl compound
and then Michael addition to the activated enaminone 4.
The intermediate thus formed can undergo cyclodehydra-
efficiently to give the target products in very good yields.
tion, followed by elimination of dimethylamine13 leading
Low toxicity and ready availability of reagents and start-
ing materials, shorter reaction times at comparatively low
to product 6.
To test the applicability to generate a library of novel wa- temperatures are advantages of this protocol. The present
ter soluble acyclo-C-nucleoside derivatives, 6l was suc- procedure is also readily amenable to parallel synthesis
cessfully deprotected with BF3·OEt2 in dichloroethane and the generation of new acyclo-C-nucleoside libraries
and methanol (Scheme 4). The acyclo-C-nucleoside de- and deprotection of ketal 6l with BF3·OEt2 afforded water-
soluble analogue 7l. The complete library generation of
these novel acyclo-C-nucleosides and associated biologi-
cal evaluations will be reported in due course.
O
O
O
OH
O
OH
BF3⋅OEt2
(2S,3S,4S,5R)-Hexane-1,2,3,4,5-pentanol (1)
DCE, MeOH
r.t., 4 h
To a solution of L-rhamnose (5.0 g, 30 mmol) in MeOH (25 mL)
NaBH4 (0.9 g, 25 mmol) was added in portions for 0.5 h. After vig-
orous stirring for another 0.5 h, the reaction mixture was neutralized
with Dowex IR-120 H+ resin (ca. 6.0 g) to remove the sodium salts.
The solid resin was filtered and the MeOH solution was concentrat-
N
N
O
HO
O
HO
6l
7l
Scheme 4 Deprotection of 6l
Synlett 2010, No. 15, 2251–2256 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Acyclo-C-Nucleoside Analogues
2255
ed under vacuum to give L-rhamnitol (1, 4.96 g, 98%) as a viscous
oil that was used in the next step without further purification.
mmol), 1,3-cyclohexanedione (5l, 0.13 g, 1.2 mmol), NH4OAc
(0.15 g, 2.0 mmol) in i-PrOH (5 mL) were added CeCl3·7H2O (75
mg, 0.2 mmol) and NaI (30 mg, 0.2 mmol) and the mixture refluxed
for 3 h (monitored by TLC). The reaction mixture was cooled to r.t.,
and the solid precipitate was filtered and washed with cold i-PrOH.
The combined solvents were evaporated, and the crude residue was
subjected to column chromatography (silica gel; hexane–EtOAc =
85:15) to obtain 2-[(4R,4¢S,5S)-2,2,2¢,2¢-tetramethyl-4,4¢-bi(1,3-di-
oxolan)-5-yl]-7,8-dihydroquinolin-(6H)-one (6l, 0.306 g, 88%) as
pale yellow oil. [a]D –7.4 (c 1.0, CHCl3). H NMR (300 MHz,
CDCl3): d = 8.24 (d, J = 8.1 Hz, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 4.87
(d, J = 6.8 Hz, 1 H),4.26–4.37 (m, 2 H), 4.06–4.1 (dd, J = 2.8 Hz, 2
H), 3.12 (t, J = 6.2 Hz, 2 H), 2.66 (t, J = 6.0 Hz, 2 H), 2.14–2.24 (m,
2 H), 1.50 (s, 3 H) 1.44 (s, 3 H), 1.31 (s, 3 H), 1.24 (s, 3 H). 13C
NMR (75 MHz, CDCl3): d = 197.71, 163.19, 163.26, 135.55,
127.16, 119.98, 110.8, 109.5, 81.4, 81.0, 76.2, 66.0, 38.5, 32.4,
27.1, 26.9, 26.2, 25.2, 21.8. IR (neat): 2985, 2928, 1691, 1585,
1376, 1216, 1158, 1069 cm–1. ESI-MS: m/z 348 [M + H]+. ESI-
HRMS: m/z calcd for C19H25NO5Na: 370.1630 [M + Na]+; found:
370.1649.
(R)-1-[(4S,4¢S,5S)-2,2,2¢,2¢-Tetramethyl-4,4¢-bi(1,3-dioxolan)-5-
yl]ethanol (2)
To a solution of L-rhamnitol (1, 4.81 g, 29.0 mmol) in anhyd ace-
tone (80 mL), 2,2-dimethoxypropane (7.54 mL, 72 mmol) and
PTSA (0.4 g) were added under nitrogen and stirred at r.t. for 6 h.
Triethylamine (2.0 mL) was added, and the reaction mixture was
concentrated under vacuum to dryness. The residue obtained was
purified by column chromatography (silica gel; hexane–EtOAc =
95:5) to afford (R)-1-[(4S,4¢S,5S)-2,2,2¢,2¢-tetramethyl-4,4¢-bi(1,3-
25
1
1
dioxolan)-5-yl]ethanol (2, 6.05 g) in 85% yield. H NMR (300
MHz, CDCl3): d = 4.15 (q, J = 6.0 Hz, 1 H), 3.93–4.05 (m, 2 H),
3.56–3.73 (m, 3 H), 3.25 (br s, 1 H), 1.43 (s, 3 H), 1.35 (s, 6 H), 1.33
(s, 3 H), 1.23 (d, J = 6.0 Hz, 3 H). The spectral data are in agreement
with literature values.12
1-[(4S,4¢S,5R)-2,2,2,2¢-Tetramethyl-4,4¢-bi(1,3-dioxolan)-5-
yl]ethanone (3)
To a cooled (–78 °C) solution of DMSO (4.3 mL, 60.9 mmol) in an-
hyd CH2Cl2 (20 mL) was added oxaloyl chloride (3.43 mL, 40.6
mmol) over 5 min under nitrogen. A solution of 1,2:3,4-di-O-iso-
propylidene-L-rhamnitol (2, 5.0 g, 20.3 mmol) in anhyd CH2Cl2 (15
mL) was added dropwise over 10 min, and the mixture was stirred
at –78 °C for 1 h. Triethylamine (8.55 mL, 60.9 mmol) was intro-
duced to the solution, the mixture was stirred at –78 °C for 20 min,
allowed to warm up to r.t., H2O (50 mL) was added, and the product
was extracted with CH2Cl2 (6 × 25 mL). The organic phase was
washed with brine solution and dried over anhyd Na2SO4. After re-
moval of the solvent, the residue was purified by column chroma-
tography (silica gel; hexane–EtOAc = 97:3) to give 1-[(4S,4¢S,5R)-
2,2,2¢,2¢-tetramethyl-4,4¢-bi(1,3-dioxolan)-5-yl]ethanone (3, 4.46 g,
90%) as a colorless liquid: [a]D25 –0.7 (c 1.0, CHCl3); lit. [a]D20 –0.1
(c 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): d = 4.26 (d, J = 5.1 Hz,
1 H), 4.05–4.16 (m, 2 H), 3.91 (dd, J = 3.9, 4.5 Hz, 2 H), 2.28 (s, 3
H), 1.43 (s, 3 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.32 (s, 3 H). 13C NMR
(125 MHz, CDCl3): d = 207.0, 111.0, 109.5, 82.9, 77.8, 76.2, 66.3,
26.7, 26.4, 26.1, 25.9, 24.8. IR (neat): 2936, 1724, 1373, 1252,
1215, 1073 cm–1. ESI-MS: m/z = 245 [M + H]+, 267 [M + Na]+. ESI-
HRMS: m/z calcd for C12H20O5Na: 267.1208 [M + Na]+; found:
267.1212.
6,6-Dimethyl-2-[(4R,4¢S,5S)-2,2,2¢,2¢-tetramethyl-4,4¢-bi(1,3-di-
oxolan)-5-yl]-7,8-dihydroquinolin-5(6H)-one (6o)
Yield 78%; [a]D25 –5.5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 8.26 (d, J = 8.1 Hz, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 4.87 (d,
J = 6.6 Hz, 1 H),4.26–4.37 (m, 2 H), 4.07 (d, J = 5.4 Hz, 2 H),3.13
(t, 6.4 Hz, 2 H), 2.02 (t, 6.4 Hz, 2 H), 1.50 (s, 3 H) 1.45 (s, 3 H), 1.30
(s, 3 H),1.25 (s, 3 H), 1.22 (s, 6 H). 13C NMR (75 MHz, CDCl3):
d = 202.2, 163.0, 162.1, 136.4, 126.0, 120.0, 110.8, 109.5, 81.4,
81.0, 76.3, 66.0, 41.4, 35.2, 29.6, 28.8, 27.1, 26.9, 26.2, 25.2, 24.0.
IR (neat): 2925, 2856, 1687, 1585, 1377, 1220, 1157, 1071 cm–1.
ESI-MS: m/z = 376 [M + H]+. ESI-HRMS: m/z calcd for
C21H29NO5Na: 398.1943 [M + Na]+; found: 398.1928.
Typical Procedure for the Deprotection of 6l
To a solution of compound 6l (0.25 g, 0.72 mmol) in DCE–MeOH
(1:1, 4 mL), BF3·OEt2 (0.6 mL, 2.6 mmol) was added and the mimx-
ture stirred at 25 °C. After 4 h, Na2CO3 (0.5 g) was added, the solid
residue was filtered and washed with MeOH. The organic solution
was concentrated, and the crude residue was purified by column
chromatography (silica gel, EtOAc–MeOH = 96:4) to give 2-
[(1S,2R,3S)-1,2,3,4-tetrahydroxybutyl]-7,8-dihydroquinolin-5(6H)-
25
one (7l, 0.17g) in 91% yield; mp 103–106 °C. [a]D –14.3 (c 1.0,
(E)-3-(Dimethylamino)-1-[(4S,4¢S,5R)-2,2,2¢,2¢-tetramethyl-
4,4¢-bi(1,3-dioxolan)-5-yl]-2-propenone (4)
MeOH). 1H NMR (300 MHz, D2O): d = 8.33 (d, J = 8.3 Hz, 1 H),
7.60 (d, J = 8.3 Hz, 1 H), 5.07 (d, J = 2.0 Hz, 1 H), 3.79–3.89 (m, 3
H), 3.67 (dd, J = 6.0 Hz, 1 H), 3.12 (t, J = 6.0 Hz, 2 H), 2.74 (t, J =
5.8 Hz, 2 H), 2.154–2.242 (m, 2 H). 13C NMR (75 MHz, DMSO-
d6): d = 198.5, 168.8, 162.9, 134.7, 126.3, 120.3, 74.3, 72.8, 71.7,
63.8, 38.4, 32.2, 21.9. IR (KBr): 3348, 2946, 1699, 1587, 1384,
1095, 1046 cm–1. ESI-MS: m/z = 268 [M + H]+. ESI-HRMS: m/z
calcd for C13H18NO5 [M + H]+: 268.1184; found: 268.1179.
To a solution of 3 (2.0 g, 8.19 mmol) in xylene (25 mL) was added
under nitrogen N,N-dimethylformamide dimethylacetal (3.4 mL,
24.5 mmol) and the mixture refluxed for 7 h (monitored by TLC).
The xylene was distilled off, and the crude residue was purified by
column chromatography (silica gel; hexane–EtOAc = 3:7) to yield
(E)-3-(dimethylamino)-1-[(4S,4¢S,5R)-2,2,2¢,2¢-tetramethyl-4,4¢-
bi(1,3-dioxolan)-5-yl]-2-propenone (4) as pale brown oil, 2.16 g
25
1
(88%). [a]D –27.5 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3):
d = 7.62 (d, J = 12.8 Hz, 1 H), 5.42 (d, J = 12.8 Hz, 1 H), 4.10–4.28
(m, 3 H), 3.95–4.08 (m, 2 H), 3.13 (s, 3 H), 2.87 (s, 3 H), 1.47 (s, 3
H), 1.42 (s, 3 H), 1.36 (s, 3 H), 1.35 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 194.8, 154.0, 110.5, 109.4, 91.2, 81.5, 78.7, 76.3, 65.6,
44.9, 37.1, 27.1, 26.30, 26.3, 25.2. IR (neat): 2986, 2933, 1651,
1572, 1424, 1370, 1215, 1068. cm–1. ESI-MS: m/z = 300 [M + H]+,
322 [M + Na]+. ESI-HRMS: m/z calcd for C15H25NO5Na: 322.1630
[M + Na]+; found: 322.1643.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
1
spectral data and copies of H NMR, 13C NMR, and HRMS of all
novel products 3, 4, 6a–f, 6i–p,7l.
Acknowledgement
The authors are grateful to Dr. J. S. Yadav, Director, IICT and Dr.
V. V. N. Reddy, Head, Organic Chemistry Division-II, IICT,
Hyderabad for their continuous support, encouragement and finan-
cial assistance throughout the MLP projects. S.R.P. is grateful to
CSIR for a fellowship (JRF).
General Procedure for the Synthesis of 2-[(4R,4¢S,5S)-2,2,2¢,2¢-
Tetramethyl-4,4¢-bi(1,3-dioxolan)-5-yl]-7,8-dihydroquinolin-
5(6H)-one (6l)
To a mixture of (E)-3-(dimethylamino)-1-[(4S,4¢S,5R)-2,2,2¢,2¢-
tetramethyl-4,4¢-bi(1,3-dioxolan)-5-yl]-2-propenone (4, 0.3 g, 1.0
Synlett 2010, No. 15, 2251–2256 © Thieme Stuttgart · New York

2256
S. Kantevari, S. R. Putapatri
LETTER
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Synlett 2010, No. 15, 2251–2256 © Thieme Stuttgart · New York

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