Diastereoselective synthesis of cis-fused pyrano[4,5-c]pyrrole derivatives via microwave-accelerated intramolecular Knoevenagal hetero Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetasy.2010.10.025

The synthesis of enantiomerically pure pyrano[4,5-c]pyrroles has been accomplished by the intramolecular hetero Diels-Alder reaction of enantiomerically pure N-allyltetheredalkenyl aldehydes with various 1,3-diones. The reaction led to the formation of ci

Full text of DOI:10.1016/j.tetasy.2010.10.025

Tetrahedron: Asymmetry 21 (2010) 2726–2732
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective synthesis of cis-fused pyrano[4,5-c]pyrrole derivatives
via microwave-accelerated intramolecular Knoevenagal hetero
Diels–Alder reaction
⇑
Mathesan Jayagobi, Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of enantiomerically pure pyrano[4,5-c]pyrroles has been accomplished by the intramolec-
ular hetero Diels–Alder reaction of enantiomerically pure N-allyltetheredalkenyl aldehydes with various
1,3-diones. The reaction led to the formation of cis-fused enantiomerically pure pyrano[4,5-c]pyrroles in
excellent yield under mild conditions and the products were characterized by spectroscopic data.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 October 2010
Accepted 26 October 2010
Available online 20 November 2010
1. Introduction
their benzopyrans analogues but there is no literature available
on pyranopyrrole derivatives.9a–g
One of the more important objectives in organic synthesis is the
development of highly efficient synthetic procedures towards
complex molecules. The hetero-Diels–Alder reaction represents
one of the more effective methods for the synthesis of heterocyclic
compounds, especially for natural product synthesis.1,2 In recent
years, intramolecular hetero-Diels–Alder (IMHDA) reactions have
been widely used in organic synthesis, because of their economical
and stereocontrolled nature.3 These reactions allow the formation
of two or more rings in a single operation, avoiding sequential
chemical transformations. Amongst these reactions, hetero
Diels–Alder reactions provide a means for the synthesis of pyran
moieties,4 since many natural products, such as carbohydrates,
talaromycins, milbemycins, avermectins, pheromones and iridoids,
contain a pyran skeleton5a–e and possess interesting biological
activities with potential medical applications,6a,6b This wide range
of interesting activities and properties has prompted studies into
the development of a convenient and efficient methodology for
synthesizing polyheterocycles with pyranopyrrole moieties. The
domino hetero-Diels–Alder reaction is one of the most important
methods for the construction of heterocyclic compounds.7a–h Here-
in we propose to utilise the hetero Diels–Alder reaction as a tool for
the diastereoselective construction of pyranopyrroles, which are
structurally related to natural products. Symmetrical 1,3-diones
have been subjected to intramolecular cycloaddition reaction as
heterodienes for the synthesis of complex polycyclic heterocycles.8
A number of reports are available for the synthesis of pyrans and
Over the course of our investigation directed towards the syn-
thesis of pyrrole derivatives, we herein report a new diastereose-
lective route for the synthesis of pyranopyrrole derivatives based
on the tandem Knoevenagel IMHDA reaction. Domino hetero
Diels–Alder reactions have been well exploited by Tietze for the
synthesis of polycyclic compounds.10a,b Herein we have used a chi-
ral N-alkenyl aldehyde11 for the first time in an intramolecular het-
ero Diels–Alder reaction for the synthesis of enantiomerically pure
pyranopyrrole derivatives in a stereoselective manner.
2. Results and discussion
2.1. Synthesis of enantiopure alkenyl aldehyde
Phenyl alaninol 1 upon treatment with p-toluenesulfonyl chlo-
ride under phase transfer catalyst conditions gave N-sulphonyl
alaninol 2 in good yield12 (Scheme 1). Compound 2 was character-
ized by spectroscopic data.
The N-sulfonyl chiral alcohol 2 was then subjected to N-prenyl-
ation using prenyl bromide with anhydrous potassium carbonate
in dry acetone solvent to obtain the N-prenyl alcohol 3a in good
yield. The structure of chiral N-prenyl-N-tosyl alcohol 3a was
established on the basis of its spectroscopic data. The alkenyl alco-
hol was oxidized quantitatively to the alkenyl aldehyde, (S)-2-(N-
allyl-N-tosylamino)-3-phenylpropanal by stirring the suspension
of 3a with 2-iodoxybenzoic acid in DMSO with for 4 h (Scheme 2).
The structure of alkenyl aldehyde 4a was confirmed on the basis of
spectroscopic data. The same methodology was followed for the
synthesis of the alkenyl aldehyde, (S)-2-(N-cinnamyl-N-tosylami-
no)-3-phenylpropanal 4b in quantitative yield by using cinnamyl
⇑
Corresponding author. Tel.: +91 44 22202811; fax: +91 4422300488.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.025

M. Jayagobi, R. Raghunathan / Tetrahedron: Asymmetry 21 (2010) 2726–2732
2727
H
H
N
H
OH
OH
OH
(ii)
(i)
NH2
NH
R2
Ts
Ts
2
1
3a-b
R1
(iii)
O
H
N
H
R2
Ts
4a-b
R1
R1 = H, CH3
R2 = CH3, Ph
Scheme 1. Regents and conditions: (i) TBAB, 10% NaOH/benzene, tosyl chloride 2, 0 °C to rt; 8 h, 90%; (ii) prenyl bromide/cinnamyl bromide, K2CO3/acetone, 12 h, 90%; (iii)
iodoxybenzoic acid, DMSO, 4 h, 98%.
R1
R
O
Ha
O
H
N
O
Diverse
Conditions
N
Ts
N
H
N
O
N
O
R1
Hb
O
Ts
H
N
O
R
4a R = R1 = CH3
4b R = H; R1= Ph
6a R = R1 = CH3
6b R = H; R1 = Ph
5
Scheme 2. Reaction conditions: Method A: toluene, reflux; Method B: toluene, MW.
bromide (Scheme 2). The structure of alkenyl aldehyde 4b was
confirmed on the basis of the spectroscopic data.12
The structure of the product was assigned on the basis of spectro-
scopic studies. Similarly, the reaction of 4b with barbituric acid 5
(Scheme 2) was carried out under the optimized reaction
conditions to give the product 6b and the results are summarized
in Table 1, The structures of the products were confirmed by
spectroscopic techniques.
Thus, starting from a chiral substrate (S)-phenyl alanine, strate-
gically positioned chiral alkenyl aldehydes 4a–b were synthesized.
Dienes generated from the reaction of aldehydes 4a–b with various
1,3-diones, were trapped by the dienophile to yield a variety of
enantiomerically pure pyrano[4,5-c]pyrroles.
The 1H NMR spectrum of compound 6b exhibited a distorted
doublet of triplets at d 2.00 (dt, 1Ha, J = 3.00, 6.00, 12.00 Hz) and
one doublet at d 2.70 (d, 1H, J = 6.0 Hz). The N–CH2 protons of
the pyrrolidine ring were observed as multiplets in the range
3.02–3.12 (2H), two doublet of doublets at d 3.32 (dd, 1H, J = 6.0,
12.0 Hz) and a doublet of doublets at d 3.50 (dd, 1H, J = 9.0,
9.0 Hz). One triplet at d 4.33 (t, 1H, J = 3.00 Hz) appeared for –
NCH proton. Particularly diagnostic were the Ha and Hb protons
situated at the ring junctions showing doublets of triplets at d
2.00 (J = 6.0, 12.0 Hz) and d 2.70 (J = 6.0), respectively. Furthermore
2.2. Synthesis of enantiopure pyrano[4,5-c]pyrroles
An equimolar mixture of (S)-2-(N-(3-methylbut-2-enyl)-N-
tosylamino)-3-phenylpropanal 4a and barbituric acid 5 in presence
of EDDA when refluxed, in toluene furnished a [4+2] cycloadduct,
cis-[4bR,5S,7aR]-2-benzyl-1,3,8,8-tetramethyl-6-tosylpyrrolo[3,4-
c]pyrano[5,6-b]pyrimidine-2,4-dione 6a. The cis-isomer was found
to be the major product with an overall yield of 64% (Scheme 2).
Table 1
Reaction times and yields of the products in domino reactions of 4a–b with 5 under various conditions
Entry
Aldehydes
1,3-Diones
Conditions
Time
Products
Yield (%)
Method A
Method B
6 h
2 min
8a
8a
64
80
O
O
H
N
N
H
H
1
O
O
N
O
O
Ts
5
O
Method A
Method B
6 h
2 min
8b
8b
67
80
O
H
N
N
2
Ph
N
Ts
H
5
Reaction conditions: Method A: toluene, reflux; Method B: toluene, MW.

2728
M. Jayagobi, R. Raghunathan / Tetrahedron: Asymmetry 21 (2010) 2726–2732
the cis-annulation of the pyrrolo-pyrano rings was determined by
the small value of the coupling constant (6.0 Hz).
The stereochemistry observed is also consistent with this observa-
tion. Although two different transition states A and B are possible
(Fig. 2), transition state B would be less favourable due to elec-
tronic repulsions between the lone pair on the oxygen atom at
the carbonyl group and the aromatic ring of the phenyl substituent.
The off-resonance decoupled 13C NMR spectrum also confirmed
the proposed structure for 6b (vide experimental). The mass spec-
trum of compound 6b showed the molecular ion peak at m/z 369.1
(M+) and the compound gave satisfactory elemental analysis.
Moreover, the structure of compound 6b was unambiguously
established by its single crystal X-ray diffraction analysis
(Fig. 1).13 The structure of the cis-product was determined on the
basis of detailed 2D NMR studies.
3. Conclusion
In conclusion, the chiral alkenyl aldehyde synthesized from
(S)-phenyl alanine was successfully subjected to an intramolecular
domino Knoevenagal hetero Diels–Alder reaction with various 1,3-
diones to give chiral pyrano[4,5-c]pyrroles. The cycloaddition
reactions were found to be stereoselective and gave cis-fused
cycloadducts. We have accomplished the synthesis of novel poly-
cyclic heterocyclic ring systems containing pyrano fused pyrimi-
dine, indanone, cyclohexanone and dioxinone derivatives under
mild condition enroute to diverse set of natural products. We have
shown that use of microwave irradiation improved the yield of the
products.
4. Experimental
4.1. General
All melting points are uncorrected. IR spectra were recorded on
a SHIMADZU IR-8300 series FT-IR spectrophotometer. 1H NMR and
13C NMR spectra were recorded on BRUKER 300 MHz instruments
in CDCl3 solvent with TMS as standard. Mass spectra were recorded
on JEOL-DX303 HF mass spectrometer. Elemental analysis was car-
ried out on a Perkin–Elmer CHNS 2400 instrument. Single crystal
X-ray diffraction analysis was performed on Bruker SMART APEX
CCD area-detecter diffractometer and Bruker SMART APEXII CCD
area-detector diffractometer. A microwave synthesizer Chem Dis-
cover benchmate microwave 300 W, P = 100, T = 110 °C, 20 MHz)
was used for all the reactions.
Column chromatography was performed on silica gel (ACME,
100–200 mesh). Routine monitoring of the reaction was done using
thin layer chromatogram developed on glass plates coated with sil-
ica gel-G (ACME) of 25 mm thickness and visualized with iodine.
Figure 1. ORTEP diagram of 6b.
In an attempt to improve the reaction yields we carried out the
reaction under microwave conditions.14a–f We observed that the
reaction in toluene under microwave irradiation gave a better yield
of the product 6a (80%) and was found to be totally stereoselective
to give only one diastereomer. Encouraged by these findings, we
expanded the scope of the hetero-Diels–Alder reaction by reacting
4b with barbituric acid 5 (Scheme 2) under microwave conditions
and we observed there was an improvement in the yield of the
product 6b; the results are summarized in Table 1.
4.2. Synthesis of (S)-3-phenyl-2-(tosylamino)propan-1-ol 2
The compound was prepared as per the procedure reported by
us previously.12
4.3. Synthesis of compound 3b
4.3.1. Synthesis of (S)-2-(N-(3-methyl but-2-enyl)-N-
Having optimized the reaction conditions for the stereoselective
synthesis of pyrano[4,5-c]pyrrole derivatives, we conducted
the intramolecular Knoevenagel hetero-Diels–Alder reaction by
employing various symmetrical diones, dimedones, dioxinones
and indane-1,3-diones with aldehydes 4a and 4b (Schemes 2 and
3). The results are summarized in Table 2. The intramolecular
Knoevenagel hetero-Diels–Alder reaction of 4a and 4b with
indane-1,3-dione in refluxing toluene was completed in 6 h
(Scheme 3). As observed previously, we readily isolated the ex-
pected cis pyrano[4,5-c]pyrrole derivatives in good yield by chang-
ing from toluene/reflux conditions to microwave irradiation
(Scheme 4).
The intramolecular cycloaddition of the heterodiene occurred
with complete facial selectivity providing the pyranopyrrole deriv-
atives with high diastereoselectivity. The stereochemistry ob-
served can be explained by considering that the dienophile
approaches the diene in an exo mode with respect to the diene.
tosylamino)-3-phenylparopan-1-ol (3a) and (S)-2-(N-cinnamyl-
N-tosylamino)-3-phenylparopan-1-ol 3b
To a solution of 20 mmol of (S)-3-phenyl-2-(tosylamino)pro-
pan-1-ol in dry acetone (100 mL) under a nitrogen atmosphere
were added potassium carbonate (60 mmol) and prenyl/cinnamyl
bromide (20 mmol) in 50 mL of dry acetone. The mixture was stir-
red for 8–10 h and after completion of the reaction, the solid was
filtered off. The residue was washed several times with acetone
and the filtrate was concentrated in vacuo and extracted with
dichloromethane (100 mL) and water (100 mL). The organic extract
was washed with brine solution and concentrated under reduced
pressure. The crude product was subjected to column chromatog-
raphy with a hexane–ethylacetate mixture (9:1) to obtain pure
N-allylated (S)-3-phenyl-2-(tosylamino)propan-1-ol, 3a. Colour-
less oil, 80% (5.52 g); ½a D34
ꢀ
¼ ꢁ30:0 (c 1, CHCl3); IR (KBr): 1330,
1169, 1600 and 3546 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d 1.68
(s, 6H), 2.39 (s, 3H), 2.17 (br s, 1H, OH), 2.65–2.78 (m, 2H),

M. Jayagobi, R. Raghunathan / Tetrahedron: Asymmetry 21 (2010) 2726–2732
2729
R1
O
R
O
Ha
H
N
X
X
Diverse
H
Ts
N
Conditions
O
O
X
R1
Hb
O
Ts
H
X
R
4a R = R1 = CH3
4b R = H; R1= Ph
9a X= CH2 ; R = R1 = CH3
7 X = CH2
8 X = O
9b X = O; R = R1 = CH3
9c X = CH2; R = H; R1= Ph
9d X = O; R = H; R1 = Ph
Scheme 3. Reaction conditions: Method A: toluene, reflux; Method B: toluene, MW.
Table 2
Reaction time and yields of the products in domino reactions of 4a–b with various symmetrical 1,3-diones under various conditions
Entry
Aldehydes
1,3-Diones
Conditions
Time
Products
Yield (%)
Method A
Method B
6 h
2 min
8a
8a
63
75
O
O
H
N
H
1
O
O
O
Ts
7
Method A
Method B
6 h
2 min
8b
8b
72
84
H
N
H
O
Ph
Ts
7
H
Method A
Method B
6 h
2 min
8a
8a
64
80
O
O
H
N
O
O
O
H
O
O
O
O
Ts
Ts
8
Method A
Method B
6 h
2 min
8a
8a
64
80
H
N
O
O
H
2
Ph
8
H
Method A
Method B
8 h
2.5 min
8a
8a
58
68
O
O
H
N
H
Ts
O
O
10
10
Method A
Method B
8 h
2.5 min
8a
8a
63
72
H
N
H
Ph
Ts
O
H
Reaction conditions: Method A: toluene, reflux; Method B: toluene, MW.
O
O
R
R1
Ha
O
H
O
Diverse
Conditions
H
Ts N
N
R1
Hb
H
Ts
R
O
4a R = R1 = CH3
11a R = R1 = CH3
11b R = H; R1 = Ph
10
4b R = H; R1= Ph
Scheme 4. Reaction conditions: Method A: toluene, reflux; Method B: toluene, MW.
3.54–3.67 (m, 2H), 3.86 (d, 2H, J = 6.0 Hz), 4.03–4.13 (m, 1H), 5.16
(dd, 1H, J = 3.0, 9.0 Hz), 7.03–7.61 (m, 9H, ArH); 13C NMR (CDCl3,
75 MHz): 15.83, 19.44, 23.10, 34.32, 40.52, 59.65, 60.62, 119.54,
124.49, 125.16, 126.51, 126.97, 127.49, 133.37, 135.80, 135.91
and 141.09 ppm; MS m/z: 373.90 (M+). Anal. Calcd for C21H27NO3S:
C, 67.53; H, 7.29; N, 3.75%;Found: C, 67.64; H, 7.38; N, 3.69.

2730
M. Jayagobi, R. Raghunathan / Tetrahedron: Asymmetry 21 (2010) 2726–2732
300 MHz): d 2.40 (s, 3H), 2.82 (dd, 1H, J = 9.0, 12.0 Hz); 3.41 (dd, 1H,
Me
N
O
H
Me
N
J = 6.0, 12.0 Hz), 3.84 (dd, 1H, J = 9.0, 15.0 Hz), 3.97 (dd, 1H, J = 9.0,
15.0 Hz), 4.52 (dd, 1H, J = 6.0, 6.0 Hz), 5.94–5.98 (m, 1H), 6.34 (d,
1H, J = 15.0 Hz), 7.06–7.56 (m, 14H, ArH, 9.70 (s, CHO); 13C NMR
(CDCl3, 100 MHz): d 21.50, 0.90, 33.47, 48.6, 67.45, 124.05, 126.58,
126.73, 127.44, 128.26, 128.64, 128.67, 129.11, 129.75, 135.21,
135.77, 137.20, 143.73 and 198.73 ppm; MS m/z: 419.19 (M+). Anal.
Calcd for C25H25NO3S: C, 71.57; H, 6.01; N, 3.34. Found: C, 71.69; H,
5.08; N, 3.42.
H
O
H
Ph
Ts
NMe
Ph
Ts
N
NMe
N
O
O
Ph
H
H
Ph
B
A
Figure 2.
4.5. Synthesis of enantiopure cis-fused pyrano[4,5-c]pyrroles
Method A: To a refluxing solution of 1,3-diones (1 mmol) in
10 mL of dry toluene, the aldehyde 4a/4b (1 mmol) was added
and the reaction mixture was refluxed until the disappearance of
the starting material as evidenced by thin layer chromatography.
After the completion of the reaction as evidenced by TLC, the reac-
tion mixture was concentrated under reduced pressure. The resi-
due was extracted with dichloromethane (2 ꢂ 20 mL) and water
(2 ꢂ 20 mL). The organic layer was washed with brine solution
(2 ꢂ 20 mL), dried over anhydrous sodium sulfate and concen-
trated in vacuo. The residue was then subjected to column chroma-
tography (silica gel, 100–200 mesh) with hexane–ethylacetate
(7.5:2.5) to obtain the cycloadducts.
Method B: A solution of 1,3-diones (1 mmol) and the corre-
sponding aldehyde (1 mmol) in dry toluene (2 ml) without base
was irradiated under microwaves (MODEL = Chem Discover bench
mate microwave, 300 W, P = 100, T = 110 °C, 20 MHz) until the thin
layer chromatography showed the disappearance of the starting
material. The reaction mixture was concentrated under reduced
pressure, after which the residue was extracted with dichloro-
methane (2 ꢂ 20 mL) and water (2 ꢂ 20 mL). The organic layer
was washed with brine solution (2 ꢂ 20 mL), dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was then
subjected to column chromatography (silica gel, 100–200 mesh)
with hexane–ethylacetate (7.5:2.5) to give the cycloadducts.
Following the general procedure (Methods A and B), the reac-
tions of 1,3-diones (1 mmol) with various chiral alkenyl aldehydes
afforded chiral pyrrolo[3,4-c]pyrano derivatives.
4.3.2. (S)-2-(N-Cinnamyl-N-tosylamino)-3-phenylparopan-1-ol
3b
Colourless solid, 80% (5.52 g); ½a D34
ꢀ
¼ ꢁ30:0 (c 1, CHCl3); mp:
1H NMR
89–91 °C; IR (KBr): 1330, 1169, 1600 and 3546 cmꢁ1
;
(CDCl3, 300 MHz): d 2.21 (br s, 1H, OH), 2.35 (s, 3H), 2.76 (dq,
2H, J = 6.0, 12.0 Hz), 3.58–3.74 (m, 2H), 3.97–4.21 (m, 3H), 6.05–
6.15 (m, 1H), 6.52 (d, 1H, J = 15.0 Hz), 7.01–7.60 (m, 14H, ArH);
13C NMR (CDCl3, 75 MHz): d 21.49, 36.51, 46.98, 61.90, 62.69,
126.53, 126.61, 127.36, 127.94, 128.30, 128.62, 129.10, 129.64,
132.94, 136.29, 137.78, 137.85 and 143.34 ppm; MS m/z: 421.72
(M+). Anal. Calcd for C25H27NO3S: C, 71.23; H, 6.46; N, 3.32. Found:
C, 71.32; H, 6.55; N, 3.24.
4.4. Synthesis of compound 4a
4.4.1. Synthesis of (S)-2-(N-(3-methyl but-2-enyl)-N-
tosylamino)-3-phenyl propanal 4a
Toa stirred solution of2-iodoxybenzoicacid(2.94 g, 0.010 mmol),
dissolved in dimethyl sulfoxide (10 mL), was added 2.07 g
(0.006 mmol) of (S)-2-(N-allyl-N-tosylamino)-3-phenylpropan-1-ol
5. After 2 h of vigorous stirring, the reaction mixture was diluted with
water and the precipitate formed was filtered and washed with ethyl
acetate (2 ꢂ 20 mL). The organic layer was dried over anhydrous so-
dium sulfate and the solvent was distilled off at reduced pressure to
obtaina browncolouredcrudeproduct. Thiswassubjectedtocolumn
chromatography (silica gel, 100–200 mesh) using hexane–ethyl ace-
tate mixture (9:1) to obtain pure (S)-2-(N-(3-methyl but-2-enyl)-N-
tosylamino)-3-phenylpropanal 4a. Yellow oil, 90% (1.86 g);
4.5.1. (4bR,5S,7aR)-cis-5-Benzyl-1,3,8,8-tetramethyl-6-tosyl-
pyrrolo[3,4-c]pyrano [5,6-b]primidin-2,4-dione 6a
½
a 3D4
ꢀ
¼ ꢁ14:8 (c 1, CHCl3); IR (KBr): 1335, 1161 and 1735 cmꢁ1
;
1H
White solid, 64% (0.320 g); ½a D34
ꢀ
¼ þ18:4 (c 1, CHCl3); mp: 202–
NMR (CDCl3, 300 MHz): d 1.44 (s, 3H), 1.55 (s, 3H), 2.30 (s, 3H), 2.60
(dd, 1H, J = 6.0, 15.0 Hz), 3.68 (d, 2H, J = 6.0 Hz), 4.35 (dd, 1H, J = 6.0,
6.0 Hz), 3.95 (dd, 1H, J = 6.0, 9.0 Hz), 6.95–7.41 (m, 9H, ArH), 9.56
(s, 1H, CHO); 13C NMR (CDCl3, 75 MHz): d 16.89, 20.45, 24.68,
31.84, 42.77, 66.12, 118.29, 125.55, 126.23, 127.57, 127.99, 128.63,
136.21, 136.44, 137.75, 142.44 and 197.86 ppm; MS m/z: 371.47
(M+). Anal. Calcd for C21H25NO3S: C, 67.89; H, 6.78; N, 3.77. Found:
C, 67.93; H, 6.87; N, 3.65.
204 °C; IR (KBr): 1695, 1647, 1342, 1159 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d 0.85 (s, 3H), 1.08 (dt, Ha, J = 6.0, 12.0 Hz), 1.21 (s, 3H),
2.29 (t, 1H, J = 12.0 Hz), 2.40 (s, 3H), 2.53 (dd, 1H, J = 9.0, 12.0 Hz),
3.21 (s, 3H), 3.33 (s, 3H), 3.47 (dd, 1H, J = 3.0, 12.0 Hz), 4.01 (dd,
J = 3.0, 12.0 Hz), 4.17 (td, 1H, J = 3.0, 6.0 Hz), 7.19–7.74 (m, 9H,
ArH); 13C NMR (CDCl3, 75 MHz): 19.35, 20.23, 26.63, 27.02, 27.80,
34.49, 38.22, 47.33, 47.87, 62.22, 81.49, 86.56, 124.85, 125.97,
126.49, 126.52, 130.30, 133.88, 136.42, 142.27, 149.48, 154.46 and
160.37 ppm; MS m/z: 509.18 (M+). Anal. Calcd for C27H31N3O5S: C,
63.03; H, 6.13; N, 8.25. Found: C, 63.17; H, 6.18; N, 8.31.
4.4.2. Synthesis of (S)-2-(N-cinnamyl-N-tosylamino)-3-
phenylpropanal 4b
To a stirred solution of 2-iodoxybenzoic acid (2.94 g, 0.010 mmol),
dissolved in dimethylsulfoxide (10 mL) was added 2.07 g
(0.006 mmol) of (S)-2-(N-cinnamyl-N-tosylamino)-3-phenylpropan-
1-ol. After 2 h of vigorous stirring, the reaction mixture was diluted
with water and the precipitate formed was filtered and washed with
ethyl acetate (20 mL). The filtrate was then extracted with ethyl ace-
tate (2 ꢂ 20 mL). The organic layer was dried over anhydrous sodium
sulfate and the solvent was distilled off at reduced pressure to give a
brown coloured crude product. This was subjected to column chro-
matography (silica gel, 100–200 mesh) using a hexane–ethyl acetate
mixture (9:1) to give pure (S)-2-(N-cinnamyl-N-tosylamino)-3-phe-
4.5.2. (4bR,5S,7aR)-cis-5-Benzyl-1,3-dimethyl-8-phenyl-6-tosyl-
pyrrolo[3,4-c]pyrano [5,6-b]primidin-2,4-dione 6b
White solid, 68% (0.370 g); ½a D34
¼ þ4:4 (c 1, CHCl3); mp: 174–
ꢀ
176 °C; IR (KBr): 1695, 1628, 1340 and 1163 cmꢁ1; 1H NMR (CDCl3,
300 MHz): d 2.00 (distorted, dt, 6.0, 12.0 Hz), 2.40 (s, 3H), 2.70 (d,
1H, J = 6.0 Hz), 3.02–3.12 (m, 2H), 3.19 (s, 3H), 3.21 (s, 3H), 3.32
(dd, 1H, J = 6.0, 12.0 Hz), 3.50 (dd, 1H, J = 9.0, 9.0 Hz), 4.33 (t, 1H,
J = 3.0 Hz), 5.12 (d, 1H, J = 3.0 Hz), 6.75–7.64 (m, 14H, ArH); 13C
NMR (CDCl3, 75 MHz): 21.64, 27.70, 28.28, 34.67, 42.11, 49.52,
64.38, 87.05, 124.90, 126.89, 127.41, 128.44, 128.62, 128.85,
128.87, 130.45, 133.54, 136.26, 137.63, 143.93, 150.24, 153.75
and 162.18 ppm; MS m/z: 557.12 (M+). Anal. Calcd for
nylpropanal 4b. Yellow solid, 90% (1.86 g); ½a D34
¼ ꢁ5:0 (c 1, CHCl3);
ꢀ
mp: 94–96 °C; IR (KBr): 1335, 1161 and 1735 cmꢁ1; 1H NMR (CDCl3,

M. Jayagobi, R. Raghunathan / Tetrahedron: Asymmetry 21 (2010) 2726–2732
2731
C31H31N3O5S: C, 66.77; H, 5.60; N, 7.54. Found: C, 66.87; H, 5.49; N,
7.48.
300 MHz): d 0.85 (s, 3H), 1.08 (dt, 1Ha, J = 6.0, 12.0 Hz), 1.20 (s,
3H), 2.30 (t, 1H, J = 12.0 Hz), 2.52 (dd, 1H, J = 9.0, 12.0 Hz), 3.40
(dd, 1H, J = 6.0, 12.0 Hz), 3.56 (dd, 1H, J = 6.0, 12.0 Hz), 3.89 (dd,
1H, J = 3.0, 12.0 Hz), 4.10 (td, J = 3.0, 6.0 Hz), 7.16–7.74 (m, 13H,
ArH); 13C NMR (CDCl3, 75 MHz): 20.26, 26.86, 28.47, 76.14,
104.32, 125.02, 125.54, 126.81, 127.98, 128.46, 128.52, 130.31,
131.16, 131.18, 134.92, 135.71, 135.82, 141.69, 169.36 and
190.62 ppm; MS m/z: 499.80 (M+). Anal. Calcd for C30H29NO4S: C,
72.12; H, 5.85; N, 2.80. Found: C, 72.26; H, 5.79; N, 2.73.
4.5.3. (1bR,2S,4aR)-cis-2-Benzyl-5,5,8,8-tetramethyl-3-tosyl
pyrrolo[3,4-c]pyrano [5,6-b] cyclohexan-1-one (9a)
White solid, 63% (0.306 g); ½a D34
ꢀ
¼ þ32:2 (c 1, CHCl3); mp: 163–
165 °C; IR (KBr): 1619, 1342 and 1166 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d 0.72 (s, 3H), 0.78 (dt, Ha, J = 6.0, 12.0 Hz), 0.90 (s,
3H), 1.96–2.21 (m, 5H), 3.28 (t, 1H, J = 12.0 Hz), 2.39 (s, 3H), 3.39
(dd, 1H, J = 6.0, 12.0 Hz), 3.53 (dd, 1H, J = 3.0, 6.0, 12.0 Hz), 3.88
(d, 1H, J = 3.0, 9.0 Hz), 4.09 (td, 1H, J = 3.0, 6.0 Hz), 7.15–.73 (m,
9H, ArH); 13C NMR (CDCl3, 75 MHz): 20.47, 21.49, 26.61, 28.46,
29.16, 31.68, 36.01, 40.15, 42.92, 48.77, 49.53, 51.17, 63.53,
79.53, 111.26, 126.10, 127.34, 127.79, 129.64, 131.59, 135.40,
138.13, 143.42, 169.63 and 196.35 ppm; MS m/z: 495.79 (M+).
Anal. Calcd for C29H35NO4S: C, 70.36; H, 7.15; N, 2.84. Found: C,
70.48; H, 7.21; N, 2.79.
4.5.8. (1bR,4S,4aR)-cis-2-Benzyl-5-phenyl-3-tosyl-pyrrolo[3,4-
c]pyrano[5,6-b]indan-1-one (11b)
Yellow solid, 58% (0.315 g); ½a D34
ꢀ
¼ þ19:0 (c 1, CHCl3); mp: 211–
213 °C; IR (KBr): 1612, 1343 and 1158 cmꢁ1
;
1H NMR (CDCl3,
300 MHz):
d 1.97 (s, 3H), 2.14–2.23 (m, 1H), 254 (d, 1H,
J = 6.0 Hz), 3.02 (t, 1H, J = 9.0 Hz), 3.08 (dd, 1H, J = 3.0, 12.0 Hz),
3.55 (dd, 1H, J = 6.0, 9.0 Hz), 4.40–4.43 (m, 1H), 5.22 (d, 1H,
J = 3.0 Hz), 6.86–7.59 (m, 18H, ArH); 13C NMR (CDCl3, 75 MHz):
19.77, 31.38, 37.44, 40.32, 47.6, 61.55, 76.13, 104.35, 115.96,
119.21, 123.12, 125.00, 125.56, 126.63, 126.70, 127.00, 127.63,
128.46, 128.51, 130.30, 131.12, 131.19, 134.79, 135.75, 135.85,
170.16 and 190.64 ppm; MS m/z: 547.03 (M+). Anal. Calcd for
C34H29NO4S: C, 74.56; H, 5.34; N, 2.56. Found: C, 74.63; H, 5.31;
N, 2.62.
4.5.4. (1bR,4S,4aR)-cis-4-Benzyl-8,8-dimethyl-5-phenyl-3-tosyl
pyrrolo[3,4-c]pyrano [5,6-b] cyclohexan-1-one (9b)
White solid, 70% (0.372 g); ½a D34
ꢀ
¼ ꢁ0:2 (c 1, CHCl3); mp: 186–
188 °C; IR (KBr): 1629, 1341 and 1159 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d 0.83 (s, 3H), 0.85 (s, 3H), 1.93–2.07 (m, 5H), 2.43 (s,
3H), 2.64 (dd, 1Ha, J = 3.0, 6.0 Hz), 3.02–3.10 (m, 1H, Hb), 3.29–
3.38 (m, 2H), 3.97 (td, 1H, J = 3.0, 6.0 Hz), 4.84 (d, 1H, J = 3.0 Hz),
6.86–7.72 (m 14H, ArH); 13C NMR (CDCl3, 75 MHz): d 21.53,
26.93, 29.46, 32.25, 34.33, 38.19, 41.13, 42.48, 49.68, 50.89,
64.71, 75.02, 110.63. 125.53, 126.51, 127.77, 128.14, 128.47,
129.67, 130.82, 134.65, 137.69, 138.10, 143.08, 168.36 and
197.64 ppm; MS m/z: 541.62 (M+). Anal. Calcd for C33H35NO4S: C,
73.17; H, 6.51; N, 2.59. Found: C, 73.28; H, 6.49; N, 2.64.
Acknowledgements
M.J. and R.R. thank UGC New Delhi for financial support. We are
grateful to Dr. K. K. Balasubramanian, Shasun Chemicals Ltd for the
Microwave Synthesizer facility.
References
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C, 65.28; H, 6.32; N, 2.79.
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¼ þ4:7 (c 1, CHCl3); mp:
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300 MHz): d 0.83 (s, 3H), 0.85 (s, 3H), 1.54 (s, 6H), 1.93–2.07 (m,
2H), 2.43 (s, 3H), 2.64 (dd, 1Ha, J = 3.0, 6.0 Hz), 3.02–3.10 (m, 1H,
Hb), 3.29–3.38 (m, 2H), 3.97 (td, 1H, J = 3.0, 6.0 Hz), 4.84 (d, 1H,
J = 3.0 Hz), 6.86–7.72 (m, 14H, ArH); 13C NMR (CDCl3, 75 MHz): d
21.53, 24.34, 26.90, 29.54, 32.21, 34.33, 38.21, 41.15, 42.50 49.68,
50.86, 64.69, 75.02, 110.63, 125.53, 126.51, 127.77, 128.14,
128.47, 129.67, 130.80, 134.65, 137.69, 138.10, 143.08, 154.19
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C, 68.24; H, 5.73; N, 2.57. Found: C, 68.34; H, 5.81; N, 2.64.
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p
White solid, 68% (0.335 g); ½a D28
ꢀ
¼ þ6:6 (c 1, CHCl3); mp: 201–
203 °C; IR (KBr): 1619, 1339 and 1169 cmꢁ1
;
1H NMR (CDCl3,

2732
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