Cross-enyne and ring-closing metathesis cascade: A building-block approach suitable for diversity-oriented synthesis of densely functionalized macroheterocycles with amino acid scaffolds

Article abstract of DOI:10.1002/ejoc.200700744

Suitably functionalized glycine derivatives undergo a cross-enyne and ring-closing metathesis cascade to generate macroheterocyclic ring systems in good yield. These macrocycles, prepared on the basis of a fragment coupling strategy, consist of 13-16-membered rings. To this end, 1,5-hexadiene was found to be a promising cross-coupling partner to generate macrocycles by this tandem metathesis sequence. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700744

FULL PAPER
DOI: 10.1002/ejoc.200700744
Cross-Enyne and Ring-Closing Metathesis Cascade: A Building-Block
Approach Suitable for Diversity-Oriented Synthesis of Densely Functionalized
Macroheterocycles with Amino Acid Scaffolds
Sambasivarao Kotha*[a] and Kuldeep Singh[a]
Keywords: Amino acids / Tandem reactions / Metathesis / Heterocycles / Macrocycles / Ring-closing metathesis
Suitably functionalized glycine derivatives undergo a cross-
enyne and ring-closing metathesis cascade to generate
macroheterocyclic ring systems in good yield. These macro-
cycles, prepared on the basis of a fragment coupling strategy,
consist of 13–16-membered rings. To this end, 1,5-hexadiene
was found to be a promising cross-coupling partner to gener-
ate macrocycles by this tandem metathesis sequence.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
The ability to design complex molecules in a simple and
straightforward manner seems to be a long-lasting dream
of chemists. In this regard, nature uses various enzymes to
assemble intricate macrocycles of diverse structural fea-
tures.[1] For example, the biosyntheses of various tricyclic
terpenes involve C5-isoprene units as a starting point.
Macroheterocycles are generally present as core units in
natural products (e.g. epothilone and erythromycin) or cy-
clophane derivatives. Most of these systems, other than nat-
ural products and cyclophanes, were prepared to study aro-
maticity.[2] In general, saturated or unsaturated nonaro-
matic macroheterocycles are relatively rare in the literature.
Recently, diversity-oriented synthesis (DOS)[3] has been ac-
tively pursued with the aim of discovering “drug-like” lead
molecules. Although several diversity-oriented approaches
have been reported for small molecules,[4] they are rare for
macroheterocycles.[5] Therefore, a general and simple strat-
egy for the diversity-oriented synthesis of macrocycles is
highly desirable. Recent work from our group[6] and
others[7] has shown that it is possible to design biologically
relevant diverse skeletons of small molecules starting with
simple starting materials such as β-naphthol by using the
Claisen rearrangement and ring-closing metathesis (RCM)
as the key steps. In this regard, synthetic methodologies that
can deliver skeletal diversity are in great demand. In view
of our continued interest in this area, we sought a simple
and novel approach based on “fragment coupling strategy”
to generate diverse macrocyclic frames starting with amino
acid derivatives by using a cross-enyne metathesis–ring-clos-
ing metathesis cascade (Scheme 1).
Scheme 1.
Metathetic strategies such as RCM, ring-closing enyne
metathesis (RCEM) and cross-enyne metathesis (CEM)
protocols are powerful tools in organic synthesis for C–C
bond formation sequence.[8] Various heterocyclic systems
have been prepared by using different types of metathetic
protocols.[9] To this end, amino acids found extensive use in
the synthesis of heterocycles.[10] Recently, we reported the
synthesis of various N-containing medium-sized heterocy-
cles by using glycine equivalents.[11] Macrocyclic ring for-
mation involves an intramolecular cyclization reaction of a
bifunctional molecule such as 1a; it is not a favourable pro-
cess, and the activation entropy is quite negative. Several
other side reactions that compete with cyclization are inter-
molecular oligomerization (dimerization) and polymeriza-
tion. Under high-dilution conditions one can obtain cy-
clized products. A variety of reagents have been developed
for macrocyclization reactions. In view of these facts, the
synthesis of the macrocyclic system is not a trivial exercise.
In the present study, we identified enyne substrate 1a as a
potential candidate to test our ideas for designing macro-
cycles by a metathesis cascade.[12] Compound 1a can un-
dergo RCEM as well as CEM to generate interesting and
unknown macrocyclic frames. The amino acid building
blocks, such as 1a, are strategically designed to accommo-
date multifunctional groups of diverse structural elements.
In our strategy (Scheme 1), diversity can be generated by
[a] Department of Chemistry, Indian Institute of Technology Bom-
bay,
Mumbai 400076, India
Fax: +91-22-2572-3480
E-mail: srk@chem.iitb.ac.in
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S. Kotha, K. Singh
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(1) varying the length of the chain attached to nitrogen, (2)
varying the length of the chain attached to oxygen, (3) alter-
ing substituents at the α carbon atom, to be precise, by
varying the amino acid (natural, nonnatural, α-amino acid,
β-amino acid, etc.) and (4) changing the alkylation se-
quence at the nitrogen and/or oxygen atoms. Moreover, in-
troduction of diversity is also feasible by using more than
one of the methods stated above. These ideas clearly illus-
trate the potential of this strategy for the generation of vari-
ous macroheterocyclic systems. The additional advantage of
this methodology is that the double bond position in the
newly formed ring can be altered by changing the alkylation
sequence.
Figure 1. Grubbs’ catalysts used in metathesis.
Apart from CEM, the possibility of a one-pot cross-en-
yne metathesis followed by RCM in these systems clearly
opens up a new door for the synthesis of novel macrocycles.
To test this hypothesis, enyne building block 1a was treated
with Grubbs’ 2nd generation catalyst in the presence of 1,5-
hexadiene as a connector. Gratifyingly, the reaction pro-
ceeded smoothly, and the two products were isolated by col-
umn chromatography. NMR spectral analysis of these com-
pounds proved that 2a is a CEM product, whereas 3a is a
CEM–RCM cascade product (Scheme 3). No intramolecu-
lar RCEM products were obtained during this procedure.
To start, tosylglycine 5 was prepared by using a literature
procedure in 87% yield.[13] Later on, esterification of tosyl
derivative 5 was carried out by using a Dean–Stark as-
sembly with propargyl alcohol, 3-butyne-1-ol and allyl
alcohol to yield compounds 6 (86%), 7 (84%) and 8[14]
(99%) (Scheme 2). These compounds were fully charac-
terized by 1H and 13C NMR spectroscopy. Next, N-alkenyl-
ation was achieved by treatment of compound 6 with vari-
ous bromo-alk-1-enes in the presence of K2CO3 in CH3CN
to deliver various enyne substrates. Along similar lines,
compound 7 was treated with allyl bromide to yield 9 in
95% yield. When tosyl derivative 8 was treated with propar-
gyl bromide, building block 10 was obtained in 79% yield.
The presence of a singlet due to α-CH2 at 4.01 ppm, the
absence of an NH proton signal at 5.0 ppm and the pres-
Scheme 3.
1
ence of characteristic olefinic signals in the H NMR spec-
When 2a, obtained from the metathesis, was subjected to
trum supported these structures. All the products were RCM, the formation of 3a was not observed. It seems there
1
characterized by H and 13C NMR spectroscopy as well as are two possible open-chain compounds with different con-
HRMS.
formations (2a and 2aЈ) when 1,5-hexadiene undergoes
intermolecular cross-metathesis with enyne building block
1a. Among these isomers, 2aЈ undergoes intramolecular
ring closer to give 3a, whereas 2a remains intact (Scheme 4).
The formation of an acyclic product (CEM product) sug-
gests that first a CEM and then a RCM pathway is in-
volved. Macrocycle formation is entropically driven due to
the intramolecular nature of the ring closure with 1,5-hexa-
diene.
Along similar lines, enyne substrates 1b–d and 9 were
subjected to the CEM–RCM cascade. Several macrocycles
of varying ring size, from 13–16-membered ring systems
were obtained in good yield (Table 1). The structures of
these products were deduced on the basis of their NMR
spectroscopic and HRMS data. When compound 10 was
subjected to similar reaction conditions, the desired prod-
ucts were isolated in good yield (Table 1, Entry 5). It is well
known that gem dimethyl groups at the α carbon atom of
glycine play a crucial role in conformational aspects of
oligopeptides as a result of the Thorpe–Ingold effect.[16]
Therefore, compound 15 was prepared from α-aminoisobu-
Scheme 2. Reagents and conditions: (i) 1. NaOH, H2O, p-TsCl; 2.
1  HCl; (ii) but-4-yn-1-ol, benzene, p-TsOH; (iii) allyl alcohol,
benzene, p-TsOH; (iv) propargyl alcohol, benzene, p-TsOH; (v)
CH3CN, K2CO3, reflux.
Having enyne building blocks 1a–d, 9 and 10 in hand, we tyric acid (AIB) by esterification with allyl alcohol followed
proceeded to the cross-metathesis protocol of these sub- by N-tosylation. Treatment of tosyl derivative 15 with pro-
strate with 1,5-hexadiene in the presence of Grubbs’ 2nd pargyl bromide in DMF in the presence of K2CO3 gave
generation catalyst (Figure 1). Earlier, Diver and coworkers enyne 16 in 92% yield (Scheme 5). The presence of two ab-
used 1,5-hexadiene to prepare various cyclohexadiene de- sorption bands at 3277 and 2371 cm–1 for the acetylene
rivatives.[15]
moiety indicated the formation of compound 16. Also, the
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Cross-Enyne and Ring-Closing Metathesis Cascade
Scheme 4.
Table 1. List of various macroheterocyclic derivatives prepared by a CEM–RCM metathesis cascade.
appearance of a triplet at δ = 2.22 (t, J = 2.31 Hz) ppm and the characteristic propargyl pattern in the 1H NMR spectra
the absence of an NH signal in the 1H NMR spectrum fur- and the appearance of new signals corresponding to the
ther support the product formation.
alkene moiety suggested the formation of the required
When compound 16 was subjected to the metathesis pro- product. The structures are further supported by their
tocol under similar reaction conditions, the desired prod- HRMS spectroscopic data. In all these cases, formation of
ucts were isolated in good yield (Table 1, Entry 7). The IR the regular RCEM product was not observed. It is known
spectra of these products showed a strong absorption peak that the substrates similar to that of 10 did not undergo
at 1741 cm–1 due to the carbonyl moiety. Disappearance of RCEM.[17]
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S. Kotha, K. Singh
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washed with cold water and dried in air and finally in vacuo. Yield:
20 g, 87%. M.p. 147 °C (ref.[13] 147 °C).
General Procedure for Esterification of 5: To a suspension of 5 in
benzene was added p-toluenesulfonic acid (catalytic amount) and
allyl alcohol (1.2 equiv.), and reaction mixture was heated at reflux
with stirring. The water generated was removed by using a Dean–
Stark trap. After complete consumption of 5 (TLC monitoring,
4 h), benzene was removed, and the obtained semisolid was taken
up in EtOAc and washed with water; the aqueous layer was ex-
tracted with EtOAc (3ϫ25 mL). The combined organic layers were
washed with brine, dried with Na2SO4 and concentrated in vacuo.
The product thus obtained was recrystallized form petroleum ether/
EtOAc, and the product was obtained as white shiny crystals.
Scheme 5.
Prop-2-ynyl 2-(4-methylphenylsulfonamido)acetate (6): To a suspen-
sion of 5 (1.0 g, 4.4 mmol) in benzene (30 mL) was added p-tolu-
enesulfonic acid (10 mg) and propargyl alcohol (0.293 g, 0.3 mL,
5.23 mmol), and the reaction mixture was heated at reflux with
stirring. The water formed during the reaction was removed by
using a Dean–Stark trap. After complete conversion of 5 (TLC
monitoring, 4 h), benzene was remove, and the obtained semisolid
was taken up in EtOAc and washed with water; the aqueous layer
was extracted with EtOAc (3ϫ25 mL). The combined organic layer
was washed with brine, dried with Na2SO4 and concentrated in
vacuo. The product thus obtained was recrystallized form petro-
leum ether/EtOAc to give shiny white crystals. Yield: 1 g, 86%.
In conclusion, novel and unknown macroheterocyclic
rings of varied size (13–16) were prepared by using a CEM–
RCM cascade in good yield. These macrocycles are built
from four building blocks; viz. glycine, propargyl alcohol,
unsaturated alkene and 1,5-hexadiene. 1,5-Hexadiene is
found to be a useful and promising connector for CEM,
and we believe that the presence of 1,5-hexadiene in this
strategy is crucial for the successful assembly of these
macrocycles. Although we focused our strategy on glycine-
and AIB-based amino acid scaffolds in the present study,
this methodology can be extended to other natural and
nonnatural amino acid scaffolds to prepare libraries of
macroheterocyclic compounds.
1
M.p. 99 °C. H NMR (300 MHz, CDCl3): δ = 2.43 (s, 3 H), 2.49
(t, J = 2.6 Hz, 1 H), 3.84 (d, J = 5.5 Hz, 2 H), 4.61 (d, J = 1.6 Hz,2
H), 5.09 (t, J = 5.5 Hz, 1 H), 7.35 (d, J = 8.5 Hz, 2 H), 7.75 (d, J
= 8.5 Hz, 2 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 21.6, 44.1,
53.2, 75.9, 76.6, 127.3, 129.9, 136.1, 144.1, 168.3 ppm. HRMS (Q-
TOF): calcd. for C12H14NO4S [M + H]+ 268.0644; found 268.0643.
Experimental Section
But-3-ynyl 2-(4-Methylphenylsulfonamido)acetate (7): To a suspen-
sion of 5 (1.0 g, 6.54 mmol) in benzene (30 mL) was added p-tolu-
enesulfonic acid (10 mg) and but-3-yn-1-ol (0.55 g,7.85 mmol), and
the reaction mixture was heated at reflux with stirring and water
was removed by using a Dean–Stark trap. After complete conver-
sion of 5 (TLC monitoring, 4.5 h), benzene was remove, and the
obtained semisolid was taken up in EtOAc and washed with water;
the aqueous layer was extracted with EtOAc (3ϫ25 mL). The com-
bined organic layers were washed with brine, dried with Na2SO4
and concentrated in vacuo. The product thus obtained was recrys-
tallized form petroleum ether/EtOAc and obtained as shiny white
crystals. Yield: 1.55 g, 84%. M.p. 78 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.99 (t, J = 2.6 Hz, 1 H), 2.41–2.47 (m, 2 H), 2.44 (s,
3 H), 3.82 (br. s, 2 H), 4.11 (t, J = 6.8 Hz, 2 H), 5.01 (br. s, 1 H),
7.31 (d, J = 8.1 Hz, 2 H), 7.75 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 18.8, 21.5, 44.1, 63.3, 70.3, 79.4,
127.3, 129.8, 143.8, 168.7 ppm. HRMS (Q-TOF): calcd. for
C13H15NNaO4S [M + Na]+ 304.0619; found 304.0626.
General Remarks: Melting points are uncorrected. Analytical thin-
layer chromatography (TLC) was performed on (10ϫ5 cm) glass
plates coated with Acme’s silica gel G or GF 254 (containing 13%
calcium sulfate as a binder). Visualization of the spots on TLC
plates was achieved either by exposure to iodine vapour or UV
light. Flash chromatography was performed by using Acme’s silica
gel (100–200 mesh). Petroleum ether refers to fraction having boil-
ing point 60–80 °C. Yields refer to the chromatographically isolated
yield. Grubbs’ catalysts (1st and 2nd generation) were purchased
from Aldrich Chemical Co. (Milwaukee, WI, USA). All the com-
mercial-grade reagents were used without further purification. In-
frared spectra were recorded with a Nicolet 400 FTIR spectrometer
1
in KBr/CHCl3/CCl4 and the absorptions are reported in cm–1. H
NMR spectra were determined with a Varian 400 MHz spectrome-
ter as CDCl3 solutions. Coupling constants (J values) are given in
Hertz (Hz). Chemical shifts are expressed in parts per million
(ppm) downfield from internal reference tetramethylsilane. The
high-resolution mass measurements were carried out by using a
micromass Q-Tof spectrometer.
Allyl 2-(4-Methylphenylsulfonamido)acetate (8): To a suspension of
5 (3 g, 13 mmol) in benzene (100 mL) was added p-toluenesulfonic
acid (10 mg) and allyl alcohol (0.912 g, 1.1 mL, 15.7 mmol), and
reaction mixture was heated at reflux with stirring. The water was
removed by using a Dean–Stark trap. After complete consumption
of 5 (TLC monitoring, 4 h), benzene was removed, and the remain-
ing semisolid was taken up in EtOAc and washed with water; the
aqueous layer was extracted with EtOAc (3ϫ25 mL). The com-
bined organic layer was washed with brine, dried with Na2SO4 and
concentrated in vacuo. The product thus obtained was recrys-
tallized form petroleum ether/EtOAc and obtained as white shiny
crystals. Yield: 3.5 g, 99%. M.p. 65–67 °C (ref.[13] 59–61 °C). 1H
NMR (400 MHz, CDCl3): δ = 2.46 (s, 3 H), 3.83 (d, J = 5.7 Hz, 2
2-(4-Methylphenylsulfonamido)acetic Acid (5): To partially dis-
solved glycine (4; 7.5 g, 100 mmol) in distilled water (20 mL) was
added a solution of NaOH (2 , 50 mL) followed by the portion-
wise addition of p-toluenesulfonyl chloride (26.7 g, 140 mmol). The
reaction mixture was vigorously stirred and a solution of NaOH
(1 ) was added portionwise to maintain a pH ≈ 9 at 20 °C (ice–
water cooling). After complete consumption of alkali, stirring was
continued at room temperature for an additional 1 h. Unreacted
acid chloride was removed by filtration, and the reaction mixture
was acidified with HCl (5 ) at 0 °C to pH 2; some solid precipi-
tated out. The aqueous solution with solid precipitate was stored in
the refrigerator overnight; the crystals were collected by filtration,
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Cross-Enyne and Ring-Closing Metathesis Cascade
H), 4.55 (d, J = 5.9 Hz, 2 H), 5.12 (br. s, 1 H), 5.25–5.31 (m, 2 H), (m, 2 H), 2.43 (s, 3 H), 2.48 (t, J = 2.4 Hz, 1 H), 3.23 (t, J = 7.6 Hz,
5.78–5.89 (m, 1 H), 7.33 (d, J = 7.68 Hz, 2 H),7.78 (d, J = 7.5 Hz, 2 H), 4.01 (s, 2 H), 4.63 (d, J = 2.4 Hz, 2 H), 4.92–5.07 (m, 2 H),
2 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 21.6, 44.2, 66.4, 5.62–5.75 (m, 1 H), 7.29 (d, J = 8.2 Hz, 2 H), 7.73 (d, J = 8.0 Hz,
119.3, 127.3, 129.8, 131.1, 136.2, 143.9, 168.6 ppm. HRMS (Q-
TOF): calcd. for C12H15NNaO4S [M + Na]+ 292.0619; found
292.0628.
2 H) ppm. 13C NMR (100.6, CDCl3): δ = 21.6, 27.2, 30.6, 48.1,
52.6, 75.5, 76.9, 115.4, 127.5, 129.6, 136.7, 137.3, 143.5, 168.3 ppm.
HRMS (Q-TOF): calcd. for C17H21NNaO4S [M + Na]+ 358.1089;
found 358.1102.
Prop-2-ynyl 2-(N-Allyl-4-methylphenylsulfonamido)acetate (1a): To
a solution of 6 (500 mg, 1.83 mmol) in acetonitrile was added
K2CO3 (776 mg, 5.61 mmol) under an atmosphere of nitrogen.
Then, allyl bromide (272 mg, 0.2 mL, 2.24 mmol) was added slowly
by syringe. The resulting light-brown solution was stirred at 90 °C
for 8 h. Then, the reaction mixture was cooled (0 °C) and diluted
with ethyl acetate. The reaction mixture was filtered over Celite
with the help of a sintered funnel. The combined organic layer was
concentrated in vacuo and then dissolved in ethyl acetate (30 mL).
This solution was washed with water and brine, dried with MgSO4
and concentrated in vacuo to yield an oily product. Purification of
the crude product by column chromatography (SiO2; petroleum
ether/ethyl acetate, 11:1) gave compound 1a (460 mg, 80%) as a
Prop-2-ynyl 2-[N-(Hex-5-enyl)-4-methylphenylsulfonamido]acetate
(1d): To a solution of 6 (500 mg, 1.83 mmol) in acetonitrile was
added K2CO3 (770 mg, 5.57 mmol) under an atmosphere of nitro-
gen. Then, 6-bromohex-1-ene (364 mg, 2.23 mmol) was added
slowly by syringe. The resulting light-brown solution was stirred at
90 °C for 8 h (TLC monitoring) before the reaction was cooled.
The reaction mixture was diluted with ethyl acetate and filtered
over Celite with the help of a sintered funnel. The organic layer was
concentrated in vacuo and then dissolved in ethyl acetate (30 mL),
washed with water and brine, dried (MgSO4) and concentrated in
vacuo to yield an oily product. Purification of the crude product
by column chromatography (SiO2; petroleum ether/ethyl acetate,
12:1) gave compound 1d (500 mg, 76%) as a thick liquid. Yield:
500 mg, 76%. 1H NMR (400 MHz, CDCl3): δ = 1.35–1.45 (m, 2
1
thick liquid. Yield: 460 mg, 80%. H NMR (300 MHz, CDCl3): δ
= 2.43 (s, 3 H), 2.41 (t, J = 2.4 Hz, 1 H), 3.84 (d, J = 6.6 Hz, 2 H),
4.07 (s, 2 H), 4.61 (d, J = 1.2 Hz, 2 H), 5.15–5.21 (m, 2 H), 5.62– H), 1.51–1.76 (m, 2 H), 1.91–2.06 (m, 2 H), 2.42 (s, 3 H), 2.49 (t,
5.75 (m, 1 H), 7.35 (d, J = 8.1 Hz, 2 H), 7.73 (d, J = 8.3 Hz, 2 H) J = 2.6 Hz, 1 H), 3.25 (t, J = 7.4 Hz, 2 H), 4.09 (s, 2 H), 4.63 (d,
ppm. 13C NMR (75.4 MHz, CDCl3): δ = 21.6, 46.8, 50.8, 52.6, J = 2.6 Hz, 2 H), 4.91–5.01 (m, 2 H), 5.68–5.80 (m, 1 H), 7.27 (d,
75.5, 76.9, 120.2, 127.4, 129.7, 132.1, 136.6, 143.7, 168.2 ppm.
HRMS (Q-TOF): calcd. for C15H17NNaO4S [M + Na]+ 330.0776;
found 330.0771.
J = 8.1 Hz, 2 H), 7.73 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 21.6, 25.8, 27.3, 33.2, 47.8, 48.3, 52.6,
75.4, 76.9, 114.9, 127.6, 129.6, 136.8, 138.3, 143.5, 168.4 ppm.
HRMS (Q-TOF): calcd. for C18H24NO4S [M + H]+ 350.1426;
found 350.1434.
Prop-2-ynyl 2-[N-(But-3-enyl)-4-methylphenylsulfonamido]acetate
(1b): To a solution of 6 (100 mg, 0.374 mmol) in acetonitrile was
added K2CO3 (110 mg, 0.8 mmol) under an atmosphere of nitro-
gen. 4-Bromobut-1-ene (64.8 mg, 0.05 mL, 0.48 mmol) was added
slowly by syringe. The resulting light-brown solution was stirred at
90 °C for 8 h (TLC monitoring) before the reaction was cooled.
The reaction mixture was diluted with ethyl acetate and filtered
over Celite with the help of a sintered funnel. The organic layer was
concentrated in vacuo and then dissolved in ethyl acetate (20 mL),
washed with water and brine, dried with Na2SO4 and concentrated
in vacuo to yield an oily product. Purification of the crude product
by column chromatography (SiO2; petroleum ether/ethyl acetate,
11:1) gave compound 1b (490 mg, 74%) as a thick liquid. Yield:
490 mg, 74%. 1H NMR (400 MHz, CDCl3): δ = 2.28–2.37 (m, 2
H), 2.43 (s, 3 H), 2.49 (t, J = 2.4 Hz, 1 H), 3.29–3.63 (m, 2 H), 4.12
But-3-ynyl 2-(N-Allyl-4-methylphenylsulfonamido)acetate (9): To a
solution of 7 (386 mg, 1.37 mmol) in acetonitrile was added K2CO3
(570 mg, 4.12 mmol) under an atmosphere of nitrogen. Allyl bro-
mide (199 mg, 0.2 mL, 1.63 mmol) was added slowly by syringe.
The resulting light-brown solution was stirred at 90 °C for 9 h
(TLC monitoring) before the reaction was cooled. The reaction
mixture was diluted with ethyl acetate and filtered over Celite with
the help of a sintered funnel. The combined organic layer was con-
centrated in vacuo and then dissolved in ethyl acetate (30 mL),
washed with water and brine, dried (MgSO4) and concentrated in
vacuo to yield an oily product. Purification of the crude product
by column chromatography (SiO2; petroleum ether/ethyl acetate,
9:1) gave compound 9 (419 mg, 95%) as a thick liquid. Yield:
(s, 2 H), 4.63 (d, J = 2.7 Hz, 2 H), 5.02–5.09 (m, 2 H), 5.65–5.73 419 mg, 95%. 1H NMR (400 MHz, CDCl3): δ = 2.0 (t, J = 2.6 Hz,
(m, 1 H), 7.29 (d, J = 8.3 Hz, 2 H), 7.72 (d, J = 8.3 Hz, 2 H) ppm. 1 H), 2.43 (s, 3 H), 2.45–2.48 (m, 2 H), 3.91 (d, J = 6.6 Hz, 2 H),
13C NMR (75 MHz, CDCl3): δ = 21.8, 32.7, 47.9, 48.2, 52.9, 75.7,
4.05 (s, 2 H), 4.13 (t, J = 6.8 Hz, 2 H), 5.12–5.22 (m, 2 H), 5.63–
5.74 (m, 1 H), 7.29 (d, J = 8.1 Hz, 2 H), 7.73 (d, J = 8.4 Hz, 2 H)
76.9, 117.6, 127.6, 129.8, 134.6, 136.8, 143.7, 168.4 ppm. HRMS
(Q-TOF): calcd. for C16H20NO4S [M + H]+ 322.1113; found ppm. 13C NMR (75.4 MHz, CDCl3): δ = 18.8, 21.6, 46.5, 50.8,
322.1121.
62.8, 70.2, 79.7, 120.1, 127.4, 129.7, 132.3, 136.8, 143.6, 168.7 ppm.
HRMS (Q-TOF): calcd. for C16H19NNaO4S [M + Na]+ 344.0932;
found 344.0931.
Prop-2-ynyl 2-[N-(Pent-4-enyl)-4-methylphenylsulfonamido]acetate
(1c): To a solution of 6 (500 mg, 1.83 mmol) in acetonitrile was
added K2CO3 (747 mg, 2.3 mmol) under an atmosphere of nitro-
gen. 5-Bromopent-1-ene (332 mg, 2.22 mmol) was added slowly by
syringe. The resulting light-brown solution was stirred at 90 °C for
8 h (TLC monitoring) before the reaction was cooled. The reaction
mixture was diluted with ethyl acetate and filtered over Celite with
the help of a sintered funnel. The organic layer was concentrated
in vacuo and then dissolved in ethyl acetate (30 mL), washed with
water and brine, dried (MgSO4) and concentrated in vacuo to yield
an oily product. Purification of the crude product by column
chromatography (SiO2; petroleum ether/ethyl acetate, 11:1) gave
compound 1c (490 mg, 78%) as a thick liquid. Yield: 490 mg, 78%.
Allyl 2-[4-Methyl-N-(prop-2-ynyl)phenylsulfonamido]acetate (10):
To a solution of 8 (300 mg, 1.114 mmol) in acetonitrile was added
K2CO3 (350 mg, 2.2 mmol) under an atmosphere of nitrogen.
Then, 4-bromo-1-butene (195 mg, 0.015 mL, 1.3 mmol) was added
slowly by syringe. The resulting light-brown solution was stirred at
90 °C for 8 h (TLC monitoring). The reaction mixture was cooled
and diluted with ethyl acetate and then filtered over Celite with the
help of a sintered funnel. The organic layer was concentrated in
vacuo and then dissolved in ethyl acetate (30 mL), washed with
water and brine, dried (Na2SO4) and concentrated in vacuo to yield
an oily product. Purification of the crude product by column
1H NMR (400 MHz, CDCl3): δ = 1.56–1.70 (m, 2 H), 1.98–2.09 chromatography (SiO2; petroleum ether/ethyl acetate, 11:1) gave
Eur. J. Org. Chem. 2007, 5909–5916
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5913

S. Kotha, K. Singh
FULL PAPER
compound 10 (280 mg, 78%) as a thick liquid. Yield: 280 mg, 78%.
General Procedure for CEM–RCM Cascade: To a solution of enyne
1H NMR (400 MHz, CDCl3): δ = 2.15 (t, J = 2.6 Hz, 1 H), 2.43 1 in dry degassed DCM was added 1,5-hexadiene (3 equiv.) fol-
(s, 3 H), 4.15 (s, 2 H), 4.26 (d, J = 2.5 Hz, 2 H), 4.58–4.60 (m, 2
lowed by Grubbs’ 2nd generation catalyst (20 mol-%) at 30 °C. The
H), 5.24–5.34 (m, 2 H), 5.83–5.87 (m, 1 H), 7.30 (d, J = 7.9 Hz, 2 reaction mixture was stirred at 30 °C for 6 h (TLC monitoring) and
H), 7.72 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 21.7, 37.6, 46.9, 66.1, 74.6, 76.5, 119.2, 127.7, 129.8, 131.5,
136.1, 144.1, 168.3 ppm. HRMS (Q-TOF): calcd. for C15H18NO4S
[M + H]+ 308.0957; found 308.0953.
then concentrated in vacuo. Purification of the crude product by
column chromatography (SiO2; petroleum ether/ethyl acetate, 9:1)
affords product 2 as thick liquids. Further elution of the column
gave 3 as a thick liquid.
Allyl 2-Amino-2-methylpropanoate–4-Methylbenzenesulfonic Acid Cross-Enyne Metathesis of Enyne 1a: To a solution of enyne 1a
(14): To a suspension of AIB 13 (5 g, 48.9 mmol) in benzene
(100 mL) was added p-toluenesulfonic acid (11.1 g), and reaction
mixture was heated at reflux with stirring. The water generated was
removed by using a Dean–Stark trap. After complete consumption
of 13 (TLC monitoring, 4 h), benzene was removed. The semisolid
was taken up in EtOAc and was washed with water; the aqueous
layer was extracted with EtOAc (3ϫ25 mL). The combined organic
layer was washed with brine, dried with Na2SO4 and concentrated
in vacuo. The product thus obtained was recrystallized from petro-
leum ether/EtOAc, and the product was obtained as white shiny
(30 mg, 0.098 mmol) in dry degassed DCM was added 1,5-hexa-
diene (0.1 mL) followed by Grubbs’ 2nd generation catalyst 12
(17 mg, 20 mol-%). The reaction mixture was stirred at 30 °C for
8 h (TLC monitoring) and then concentrated in vacuo. Purification
of the crude product by column chromatography (SiO2; petroleum
ether/ethyl acetate, 9:1) afforded product 2a (17 mg, 47%) as a
thick liquid. Further elution of the column gave 3a (13 mg, 38%)
as a thick liquid. Data for 2a: Yield: 17 mg, 47%. 1H NMR
(400 MHz, CDCl3): δ = 2.13–2.26 (m, 4 H), 2.43 (s, 3 H), 3.89 (d,
J = 6.4 Hz, 2 H), 4.06 (s, 2 H), 4.69 (s, 2 H), 4.97–5.20 (m, 6 H),
crystals. Yield: 13.5 g, 87%. M.p. 139–141 °C. 1H NMR (400 MHz, 5.63–5.86 (m, 3 H), 6.06 (d, J = 6.5 Hz, 1 H), 7.29 (d, J = 8.2 Hz,
CDCl3): δ = 1.59 (s, 6 H), 2.37 (s, 3 H), 4.58–4.60 (m, 2 H),5.17–
2 H), 7.73 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (100.6 MHz,
5.30 (m, 2 H), 5.79–5.88 (m, 1 H), 7.14 (d, J = 8.1 Hz, 2 H), 7.78 CDCl3): δ = 21.7, 32.5, 33.4, 47.1, 50.9, 64.9, 115.2, 116.3, 120.1,
(d, J = 8.2 Hz, 2 H), 8.33 (s, 3 H) ppm. 13C NMR (100.5 MHz,
CDCl3): δ = 21.5, 23.7, 57.4, 66.9, 119.1, 126.3, 128.9, 131.4, 140.5,
141.7, 171.4 ppm.
127.6, 129.6, 129.8, 131.1, 132.3, 136.9, 138.0, 139.8, 143.7,
168.8 ppm. HRMS (Q-TOF): calcd. for C21H27NNaO4S [M +
Na]+ 412.1559; found 412.1562. Data for 3a: Yield: 13 mg, 38%.
1H NMR (400 MHz, CDCl3): δ = 2.17–2.22 (m, 4 H), 2.43 (s, 3
H), 3.89 (d, J = 6.4 Hz, 2 H), 4.06 (s, 2 H), 4.47 (s, 2 H), 5.12–5.22
(m, 2 H), 5.63–5.91 (m, 4 H), 7.29 (d, J = 7.8 Hz, 2 H), 7.76 (d, J
= 8.2 Hz, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 21.7,
22.1, 22.2, 47.1, 50.8, 67.5, 120.1, 124.2, 125.9, 127.6, 128.0, 129.8,
130.7, 132.4, 136.9, 143.6, 168.9 ppm. HRMS (Q-TOF): calcd. for
C19H23NNaO4S [M + Na]+ 384.1245; found 384.1256.
Allyl 2-Methyl-2-(4-methylphenylsulfonamido)propanoate (15): To a
cold solution of 14 (5.0 g, 16 mmol) in DCM was slowly added dry
TEA (5.57 g, 57 mmol), and the reaction mixture was stirred at
0 °C. Tosyl chloride (4.0 g, 20 mmol) was added in small portions
over a period of 1 h. Stirring was continued at room temperature
for 12 h. The solvent was removed and the semisolid was taken up
in EtOAc and washed with water. The organic layer was washed
with brine, dried with Na2SO4 and concentrated in vacuo. The
product thus obtained was purified by column chromatography
(SiO2; petroleum ether/ethyl acetate, 19:1) to afford white shiny
Cross-Enyne Metathesis of Enyne 1b: To a solution of enyne 1b
(32 mg, 0.1 mmol) in dry degassed DCM was added 1,5-hexadiene
(0.1 mL) followed by Grubbs’ 2nd generation catalyst 12 (18 mg,
crystals. Yield: 3.9 g, 82%. M.p. 61–62 °C. 1H NMR (400 MHz, 20 mol-%). The reaction mixture was stirred at 30 °C for 8 h (TLC
CDCl3): δ = 1.46 (s, 6 H), 2.42 (s, 3 H), 4.52–4.54 (m, 2 H), 5.24–
monitoring) and then concentrated in vacuo. Purification of the
5.36 (m, 2 H), 5.82–5.90 (m, 1 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.75 crude product by column chromatography (SiO2; petroleum ether/
(d, J = 8.5 Hz, 2 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 21.6,
25.8, 59.1, 66.4, 118.9, 127.2, 129.6, 131.5, 139.4, 143.3, 173.8 ppm.
HRMS (Q-TOF): calcd. for C14H19NNaO4S [M + Na]+ 320.0928;
found 320.0932.
ethyl acetate, 9:1) afforded product 2b (18 mg, 47%) as a thick li-
quid. Further elution of the column gave 3b (12 mg, 34%) as a
thick liquid. Data for 2b: Yield: 18 mg, 47%. 1H NMR (400 MHz,
CDCl3): δ = 2.14–2.19 (m, 4 H), 2.25–2.36 (m, 2 H), 2.41 (s, 3 H),
3.29 (t, J = 7.4 Hz, 2 H), 4.09 (s, 2 H), 4.68 (s, 2 H), 4.96–5.09 (m,
6 H), 5.61–5.82 (m, 3 H), 6.04 (d, J = 16.1 Hz, 1 H), 7.29 (d, J =
8.9 Hz, 2 H), 7.70 (d, J = 8.5 Hz, 2 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 21.7, 32.5, 32.7, 33.5, 47.9, 48.4, 65.0, 115.2, 116.5,
117.5, 127.6, 129.6, 129.7, 131.1, 134.6, 136.9, 138.0, 139.8, 143.6,
168.9 ppm. HRMS (Q-TOF): calcd. for C22H29NNaO4S [M +
Na]+ 426.1715; found 426.1718. Data for 3b: Yield: 12 mg, 34%.
1H NMR (400 MHz, CDCl3): δ = 2.16–2.19 (m, 4 H), 2.25–2.32
(m, 2 H), 2.42 (s, 3 H), 3.30 (t, J = 7.4 Hz, 2 H), 4.10 (s, 2 H), 4.69
(s, 2 H), 4.99–5.06 (m, 2 H), 5.61–5.67 (m, 4 H), 7.28 (d, J = 8.0 Hz,
2 H), 7.71 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 21.7, 32.7, 47.8, 48.1, 48.4, 65.6, 67.2, 117.5, 127.6,
128.3, 128.5, 128.7, 129.8, 131.1, 134.6, 136.9, 143.6, 168.9 ppm.
HRMS (Q-TOF): calcd. for C20H25NNaO4S [M + Na]+ 398.1402;
found 398.1363.
Allyl 2-Methyl-2-[4-methyl-N-(prop-2-ynyl)phenylsulfonamido]pro-
panoate (16): To a solution of 15 (150 mg, 0.5 mmol) in acetonitrile
was added K2CO3 (200 mg, 1.5 mmol) under an atmosphere of ni-
trogen. Then, propargyl bromide (100 mg, 0.8 mmol) was added
slowly by syringe. The resulting light-brown solution was stirred at
90 °C for 8 h (TLC monitoring) before the reaction was cooled and
then quenched by adding ethyl acetate. The reaction mixture was
filtered over Celite with the help of a sintered funnel. The organic
layer was concentrated in vacuo and then dissolved in ethyl acetate
(30 mL), washed with water and brine, dried (MgSO4) and concen-
trated in vacuo to yield an oily product. Purification of the crude
product by column chromatography (SiO2; petroleum ether/ethyl
acetate, 12:1) gave compound 16 (156 mg, 92%) as a thick liquid.
Yield: 156 mg, 92%. 1H NMR (400 MHz, CDCl3): δ = 1.27 (s, 6
H), 2.22 (t, J = 2.3 Hz, 1 H), 2.41 (s, 3 H), 4.03 (d, J = 2.3 Hz, 2
H), 4.66–4.69 (m, 2 H), 5.23–5.39 (m, 2 H), 5.91–6.02 (m, 1 H), Cross-Enyne Metathesis of Enyne 1c: To a solution of enyne 1c
7.27 (d, J = 8.3 Hz, 2 H), 7.88 (d, J = 8.2 Hz, 2 H) pm. 13C NMR
(20 mg, 0.06 mmol) in dry degassed DCM was added 1,5-hexadiene
(100.6 MHz, CDCl3): δ = 21.7, 25.7, 34.5, 63.9, 66.4, 72.9, 80.1, (0.1 mL) followed by Grubbs’ 2nd generation catalyst 12 (12 mg,
118.7, 128.3, 129.6, 132.2, 137.5, 143.9, 174.2 ppm. HRMS (Q-
20 mol-%). The reaction mixture was stirred at 30 °C for 8 h (TLC
monitoring) and then concentrated in vacuo. Purification of the
TOF): calcd. for C17H22NO4S [M + H]+ 336.1270; found 336.1282.
5914
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5909–5916

Cross-Enyne and Ring-Closing Metathesis Cascade
crude product by column chromatography (SiO2; petroleum ether/
ethyl acetate, 9:1) afforded product 2c (9 mg, 40%) as a thick li-
quid. Further elution of the column gave 3c (10 mg, 43%) as a
5.59–5.60 (m, 1 H), 5.77–5.86 (m, 3 H), 7.30 (d, J = 7.9 Hz, 2 H),
7.72 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 21.7, 22.1, 22.4, 46.3, 51.8, 65.8, 118.9, 124.6, 126.3, 127.6, 128.3,
129.7, 130.2, 131.7, 137.0, 143.5, 168.7 ppm. HRMS (Q-TOF):
1
thick liquid. Data for 2c: Yield: 9 mg, 40%. H NMR (400 MHz,
CDCl3): δ = 1.61–1.64 (m, 2 H), 2.0–2.06 (m, 2 H), 2.15–2.20 (m, calcd. for C19H24NO4S [M + H]+ 362.1426; found 362.1435.
4 H), 2.41 (s, 3 H), 3.23 (t, J = 7.3 Hz, 2 H), 4.08 (s, 2 H), 4.75 (s,
Cross-Enyne Metathesis of Enyne 9: To a solution of enyne 9
2 H), 4.95–5.09 (m, 6 H), 5.62–5.85 (m, 3 H), 6.05 (d, J = 16.1 Hz,
1 H), 7.28 (d, J = 9.0 Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 21.6, 27.1, 30.7, 32.4, 33.4, 47.9, 48.2,
64.9, 115.1, 115.5, 116.3, 127.5, 129.5, 129.6, 130.9, 136.8, 137.4,
137.9, 139.7, 143.5, 168.8 ppm. HRMS (Q-TOF): calcd. for
C23H31NNaO4S [M + Na]+ 440.1872; found 440.1867. Data for 3c:
Yield: 10 mg, 43%. 1H NMR (400 MHz, CDCl3): δ = 1.61–1.67
(m, 2 H), 2.0–2.06 (m, 2 H), 2.11–2.21 (m, 4 H), 2.42 (s, 3 H), 3.23
(t, J = 7.8 Hz, 2 H), 4.07 (s, 2 H), 4.47 (s, 2 H), 4.95 (d, J = 1.2 Hz,
1 H), 5.01 (d, J = 1.4 Hz, 1 H), 5.65–5.90 (m, 4 H), 7.28 (d, J =
8.3 Hz, 2 H), 7.72 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.6, 21.9, 22.1, 27.1, 30.7, 47.9, 48.2, 67.5, 115.4,
124.2, 125.9, 127.5, 127.9, 129.6, 130.6, 136.8, 137.4, 143.4,
168.9 ppm. HRMS (Q-TOF): calcd. for C21H27NNaO4S [M +
Na]+ 412.1559; found 412.1570.
(25 mg, 0.078 mmol) in dry degassed DCM was added 1,5-hexa-
diene (0.1 mL) followed by Grubbs’ 2nd generation catalyst 12
(14 mg, 20 mol-%). The reaction mixture was stirred at 30 °C for
8 h (TLC monitoring) and then concentrated in vacuo. Purification
of the crude product by column chromatography (SiO2; petroleum
ether/ethyl acetate, 9:1) afforded product 19 (13 mg, 41%) as a
thick liquid. Further elution of the column gave 20 (11 mg, 37%)
as a thick liquid. Data for 19: Yield: 13 mg, 41%. 1H NMR
(400 MHz, CDCl3): δ = 2.15–2.22 (m, 4 H), 2.42 (s, 3 H), 2.43–
2.47 (m, 2 H), 3.89 (d, J = 6.45 Hz, 2 H), 4.01 (s, 2 H), 4.15 (t, J
= 7.3 Hz, 2 H), 4.86–5.15 (m, 4 H), 5.17–5.20 (m, 2 H), 5.63–5.72
(m, 2 H), 5.76–5.86 (m, 1 H), 6.06 (d, J = 16.1 Hz, 1 H), 7.29 (d,
J = 8.0 Hz, 2 H), 7.43 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 21.7, 31.4, 32.3, 33.6, 47.1, 50.9, 63.9,
115.1, 115.7, 120.0, 127.6, 129.7, 130.1, 132.4, 137.0, 138.1, 141.6,
143.6, 169.0 ppm. HRMS (Q-TOF): calcd. for C22H29NNaO4S [M
+ Na]+ 426.1715; found 426.1708. Data for 20: Yield: 11 mg, 37%.
1H NMR (400 MHz, CDCl3): δ = 2.21–2.38 (m, 4 H), 2.43 (s, 3
H), 2.45–2.49 (m, 2 H), 3.89 (d, J = 6.4 Hz, 2 H), 4.01 (s, 2 H),
4.06 (t, J = 7.42 Hz, 2 H), 5.14–5.19 (m, 2 H), 5.63–5.86 (m, 4 H),
7.29 (d, J = 8.8 Hz, 2 H), 7.73 (d, J = 7.73 Hz, 2 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 21.7, 22.3, 22.4, 34.6, 47.0, 50.8,
64.2, 120.0, 122.8, 127.6, 129.7, 131.9, 132.5, 137.1, 141.6, 143.6,
169 ppm. HRMS (Q-TOF): calcd. for C20H25NNaO4S [M + Na]+
398.1402; found 398.1393.
Cross-Enyne Metathesis of Enyne 1d: To a solution of enyne 1d
(22 mg, 0.063 mmol) in dry degassed DCM was added 1,5-hexa-
diene (0.1 mL) followed by Grubbs’ 2nd generation catalyst 12
(12 mg, 20 mol-%). The reaction mixture was stirred at 30 °C for
8 h (TLC monitoring) and then concentrated in vacuo. Purification
of the crude product by column chromatography (SiO2; petroleum
ether/ethyl acetate, 10:1) afforded product 2d (11 mg, 40%) as a
thick liquid. Further elution of the column gave 3d (9 mg, 35%) as
a thick liquid. Data for 2d: Yield: 11 mg, 40%. 1H NMR
(400 MHz, CDCl3): δ = 1.25–1.56 (m, 2 H), 1.95–2.09 (m, 2 H),
2.15–2.21 (m, 6 H), 2.42 (s, 3 H), 3.23 (t, J = 7.5 Hz, 2 H), 4.08 (s,
2 H), 4.69 (s, 2 H), 4.93–5.10 (m, 6 H), 5.63–5.86 (m, 3 H), 6.06
(d, J = 16.5 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 2 H), 7.72 (d, J = 8.3 Hz,
2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 21.7, 25.8, 27.4,
32.5, 33.5, 45.0, 48.0, 48.3, 64.9, 110.1, 115.2, 116.4, 127.6, 129.6,
129.7, 131.1, 136.9, 138.1, 138.4, 139.8, 143.5, 168.9 ppm. HRMS
(Q-TOF): calcd. for C24H34NO4S [M + H]+ 432.2209; found
432.2216. Data for 3d: Yield: 9 mg, 35%. 1H NMR (400 MHz,
CDCl3): δ = 1.30–1.60 (m, 2 H), 1.90–2.10 (m, 2 H), 2.11–2.25 (m,
6 H), 2.41 (s, 3 H), 3.23 (t, J = 7.2 Hz, 2 H), 4.07 (s, 2 H), 4.68 (s,
2 H), 4.95–5.01 (m, 2 H), 5.65–5.78 (m, 4 H), 7.35 (d, J = 8.2 Hz,
2 H), 7.78 (d, J = 8.0 Hz, 2 H) ppm. HRMS (Q-TOF): calcd. for
C22H29NNaO4S [M + Na]+ 426.1715; found 426.1725.
Cross-Enyne Metathesis of Enyne 16: To a solution of enyne 16
(25 mg, 0.075 mmol) in dry degassed DCM was added 1,5-hexa-
diene (0.1 mL) followed by Grubbs’ 2nd generation catalyst 12
(13 mg, 20 mol-%). The reaction mixture was stirred at 30 °C for
8 h (TLC monitoring) and then concentrated in vacuo. Purification
of the crude product by column chromatography (SiO2; petroleum
ether/ethyl acetate, 10:1) afforded product 21 (11 mg, 35%) as a
thick liquid. Further elution of the column gave 22 (10 mg, 34%)
as a thick liquid. Data for 21: Yield: 11 mg, 35%. 1H NMR
(400 MHz, CDCl3): δ = 1.56 (s, 6 H), 2.13–2.15 (m, 4 H), 2.39 (s,
3 H), 4.03 (s, 2 H), 4.67–4.75 (m, 2 H), 4.80 (s, 1 H), 4.96–5.05 (m,
2 H), 5.13 (d, J = 1.4 Hz, 1 H), 5.26–5.31 (m, 1 H), 5.37–5.43 (m,
1 H), 5.56–5.63 (m, 1 H), 5.74–5.84 (m, 1 H), 5.91–6.08 (m, 2 H),
7.22 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 21.7, 25.5, 32.6, 33.6, 45.4, 64.5, 66.4,
115.2, 115.3, 118.6, 120.5, 129.1, 129.4, 130.6, 132.4, 137.4, 138.1,
141.3, 143.6, 174.6 ppm. HRMS (Q-TOF): calcd. for C23H32NO4S
[M + H]+ 418.2052; found 418.2037. Data for 22: Yield: 10 mg,
Cross-Enyne Metathesis of Enyne 10: To a solution of enyne 10
(112 mg, 0.36 mmol) in dry degassed DCM was added 1,5-hexa-
diene (0.3 mL) followed by Grubbs’ 2nd generation catalyst 12
(36 mg, 12 mol-%). The reaction mixture was stirred at 30 °C for
8 h (TLC monitoring) and then concentrated in vacuo. Purification
of the crude product by column chromatography (SiO2; petroleum
ether/ethyl acetate, 10:1) afforded product 17 (50 mg, 35%) as a
thick liquid. Further elution of the column gave 18 (35 mg, 25%)
as a thick liquid. Data for 17: Yield: 50 mg, 35%. 1H NMR
(400 MHz, CDCl3): δ = 2.04–2.17 (m, 4 H), 2.43 (s, 3 H), 4.02 (s,
2 H), 4.12 (s, 2 H), 4.43–4.45 (m, 2 H), 4.93–5.08 (m, 4 H), 5.19–
5.29 (m, 2 H), 5.73–5.92 (m, 3 H), 6.01 (d, J = 16.1 Hz, 1 H), 7.29
(d, J = 8.8 Hz, 2 H), 7.72 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 21.7, 32.6, 33.4, 46.6, 49.5, 65.8, 115.1,
117.9, 118.9, 127.7, 129.3, 129.7, 131.6, 132.3, 136.8, 138.1, 139.4,
143.6, 168.7 ppm. HRMS (Q-TOF): calcd. for C21H28NO4S [M +
H]+ 390.1739; found 390.1724. Data for 18: Yield: 35 mg, 25%. 1H
1
34%. H NMR (400 MHz, CDCl3): δ = 1.59 (s, 6 H), 1.95–2.1 (m,
4 H), 2.42 (s, 3 H), 3.91 (d, J = 2.4 Hz, 2 H), 4.05 (s, 2 H), 4.71–
4.73 (m, 2 H), 5.28–5.77 (m, 4 H), 7.25 (d, J = 8.1 Hz, 2 H), 7.81
(d,
J = 8.4 Hz, 2 H) ppm. HRMS (Q-TOF): calcd. for
C21H27NNaO4S [M + Na]+ 412.1559; found 412.1552.
Acknowledgments
We thank the DST, New Delhi, IRCC-IIT Bombay, Mumbai (pro-
ject no. 06RPA002) for financial support and SAIF Mumbai for
NMR (400 MHz, CDCl3): δ = 2.09–2.13 (m, 4 H), 2.43 (s, 3 H), recording the spectroscopic data. K. S. thanks the CSIR, New
3.87 (s, 2 H), 4.01 (s, 2 H), 4.46–4.48 (m, 2 H), 5.21–5.29 (m, 2 H), Delhi for the award of a research fellowship.
Eur. J. Org. Chem. 2007, 5909–5916
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5915

S. Kotha, K. Singh
FULL PAPER
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Received: August 11, 2007
Published Online: October 8, 2007
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