New efficient RCM-mediated synthesis of pyrrolidine derivatives

Article abstract of DOI:10.1080/00397910802109240

Fast and effective ring-closing olefin metathesis (RCM) of diallyamine derivatives of coumarin, quinolone, pyridine, and substituted benzene, using first-generation RCM ruthenium-based catalyst, leads to corresponding pyrrolidine derivatives in 70-95% yie

Full text of DOI:10.1080/00397910802109240

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New Efficient RCM-Mediated
Synthesis of Pyrrolidine
Derivatives
Krishna C. Majumdar a , Santanu Chakravorty a
Abu Taher a
&
a Department of Chemistry , University of Kalyani ,
Kalyani, India
Published online: 09 Sep 2008.
To cite this article: Krishna C. Majumdar , Santanu Chakravorty & Abu Taher
(2008) New Efficient RCM-Mediated Synthesis of Pyrrolidine Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:18, 3159-3169
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Synthetic Communications1, 38: 3159–3169, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802109240
New Efficient RCM-Mediated Synthesis of
Pyrrolidine Derivatives
Krishna C. Majumdar, Santanu Chakravorty, and Abu Taher
Department of Chemistry, University of Kalyani, Kalyani, India
Abstract: Fast and effective ring-closing olefin metathesis (RCM) of diallyamine
derivatives of coumarin, quinolone, pyridine, and substituted benzene, using first-
generation RCM ruthenium-based catalyst, leads to corresponding pyrrolidine
derivatives in 70–95% yields under very mild conditions.
Keywords: Diallylamine derivatives, pyrrolidine, ring-closing metathesis
INTRODUCTION
Ring-closing metathesis (RCM) has emerged as one of the most powerful
tools for the construction of carbo- and heterocyclic compounds, as
demonstrated by the numerous total syntheses of complex molecules
and natural products that include this versatile technique as the key syn-
thetic step.[1] Consequently, the RCM of olefinic ethers, esters thioethers,
allylic phosphanes, and allyl phosphonamides has been well established
using various catalytic systems.[2] Very few examples are known where
less basic N,N-diallyl amine derivative[3] or Lewis acid–assisted[4] RCM
gave pyrrolidine derivatives. In view of the wide range of biological
activities, pyrrolidine derivatives have received much attention. For
example, pyrrolidine-3-carboxylate has been utilized as a b-turn motif
in GP II b=III an antagonist.[5] Some of these derivatives have been
proven to be neurotransmitters.[6] They can also be incorporated as a
3,4-dehydro-isoproline-peptidomimetic scaffold to be used as inter-
mediates to construct alkaloid natural products and drug candidates.[7]
On the other hand, coumarin, quinolone, and pyridine are structural
Received January 4, 2008.
Address correspondence to Krishna C. Majumdar, Department of Chemistry,
University of Kalyani, Kalyani 741235, India. E-mail: kcm_ku@yahoo.co.in
3159

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K. C. Majumdar, S. Chakravorty, and A. Taher
subunits in numerous natural products that exhibit a wide range of biologi-
cal activities such as antibacterial, antifungal, anti-allergic, and DNA-gyrase
inhibition.[8] In connection with our studies, directed toward the syntheses of
heterocycles using metathesis,[9] we became interested in accessing hitherto
unreported pyrrolidine derivatives containing coumarin, quinolone, pyri-
dine, substituted benzene, and naphthalene moiety using Grubbs 1 catalyst.
RESULTS AND DISCUSSION
The requisite precursor N,N-diallylamine may be accessed by allylation
of the amine. Direct allylation of the amines gives only mono-allylated
product in moderate yields under prolonged refluxing condition. Further-
more, 2-aminopyridine on direct allylation gives only the pyridinum salt.
So, we have chosen a four-step process to prepare the precursors 1a–f as
depicted in (Scheme 1). All the corresponding amines were first converted
ꢀ
into their N-tosyl derivatives by heating at 70–80 C with tosylchloride
and pyridine for about 3–4 h. The N-tosyl derivatives were then subjected
to allylation with allylbromide (1.2 equiv) in refluxing dry acetone in
the presence of anhydrous K2CO3 to afford N-allyl-N-tosyl derivative
of the corresponding amines. The reaction takes place within 3–4 h, and
the yield of the product is quantitative. Detosylation of N-allyl-N-tosyl
derivatives were carried out with a mixture of acetic acid and sulfuric acid
(3:1), by heating on a water bath for about 3–4 h. Monoallyl derivatives
Scheme 1. Reagents and conditions: (i) TsCl, pyridine, heat 3–4 h; (ii) allyl
bromide, anhy. K2CO3, dry acetone, reflux, 3–4 h; (iii) AcOH, H2SO4 (3:1), heat,
3–4 h; (iv) allyl bromide, anhy. K2CO3, reflux, 12–24 h.

Pyrrolidine Synthesis
3161
of the corresponding amines on refluxing with allylbromide (1.2 equiv)
and anhydrous K2CO3 in dry acetone for about 12–24 h afforded
compounds 1a–f in good yields (Table 1).
Precursor molecules 1a–f were then subjected to RCM condition
(catalyst 1, CH2Cl2) at room temperature as depicted in (Scheme 2).
This led to the corresponding pyrrolidine derivatives 2a–d in good to
excellent yields within a very short time (Table 1). Unfortunately, all
attempts to prepare the corresponding pyrrolidine derivative of 1e under
the same condition were unsuccessful, the starting material was recov-
ered. The problem associated with pyridine nitrogen and the compati-
bility of the olefin metathesis catalyst has been reported many times.
Perhaps the pyridine nitrogen interferes with the catalytic cycle by coor-
dinating with ruthenium.[10]
To circumvent this problem, we have blocked the nitrogen function-
ality by the formation of pyridinium salt with 4-toluenesulfonic acid so
that it cannot interfere with the ruthenium. Pyridinium salt on treatment
with Grubbs catalyst for 30 min followed by a basic workup gave the
desired pyrrolidine derivative 2e in good yield. The hydrogenated product
of 2e has been reported in poor yield by cycloaddition of ethylene with
2H-pyrrole-1(5H)-carbonitrile under high pressure and moderate tem-
perature in the presence of cobaltocene catalyst.[11] However, this can
be achieved very easily by hydrogenation of 2e. On the other hand, under
the same set of conditions as describe for 1a–d, compound 1f gives 2f,
the usual pyrrolidine derivative, and unusual pyrrole derivative 2g. The
pyrrole formation can be explained through an RCM followed by in situ
oxidation. Amines with an electron-withdrawing group on the nitrogen
atom did not dehydrogenate to the pyrrole but to the expected pyrroli-
dine derivative, so it is clear that oxidation is dependent upon nitrogen
basicity.
In conclusion, we have successfully extended the RCM to the
synthesis of coumarin, quinolone, pyridine, substituted benzene, and
naphthalene-containing pyrrolidine derivatives. The process is quite
general and afforded good to excellent yields of the desired product.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
IR spectra were recorded on a Perkin-Elmar L 120–000A spectrometer
(cmax in cmꢁ1) using samples as neat liquids, and solid samples were
1
recorded in KBr disks. H NMR (400-MHz) spectra were recorded on a
Bruker DPX-400 spectrometer in CDCl3 (chemical shift in d) with TMS
as internal standard. Silica gel [(60–120, 230–400 mesh), Spectrochem,

3162

3163

3164
K. C. Majumdar, S. Chakravorty, and A. Taher
Scheme 2. Reagents and conditions: catalyst 1 (5 mol%), dry CH2Cl2.
India] was used for chromatographic separation. Silica gel G [E-Merck
(India)] was used for thin-layer chromatography ꢀ(TLC). Petroleum ether
refers to the fraction boiling between 60 and 80 C.
General Procedure for the Preparation of Diallyl Derivatives 1a–f
A mixture of corresponding monoallyl derivative of amines 1a–e
(2 mmol), allylbromide (2.4 mmol), and anhydrous K2CO3 (1 g) in dry
acetone (75 mL) was refluxed for 12–24 h. The reaction mixture was
cooled and filtered, and the solvent was removed. The residual mass
was extracted with CH2Cl2 (3 ꢂ 20 mL). The CH2Cl2 extract was washed
with water (3 ꢂ 15 mL) and dried(Na2SO4). The solvent was removed,
and the residual mass was purified by column chromatography over silica
gel using petroleum ether–ethylacetate as elutent.
Data
6-(Diallylamino)-2H-chromen-2-one (1a): Yellowish oil, yield 95%. IR
1
(KBr): vmax ¼ 1721, 1568 cmꢁ1; H NMR (400 MHz, CDCl3): dH ¼ 7.58
(d, 1H, J ¼ 9.5 Hz), 7.15 (d, 1H, J ¼ 9.2 Hz), 6.87 (dd, 1H, J ¼ 9.1 Hz,
J ¼ 3.0 Hz), 6.62 (d, 1H, J ¼ 3.0 Hz), 6.34 (d, 1H, J ¼ 9.6 Hz), 5.82–
5.88 (m, 2H), 5.14–5.18 (m, 4H), 3.92–3.93 (m, 4H) ppm; MS
(m=z) ¼ 241 (Mþ ). Anal. calcd. for C15H15NO2; C, 74.67; H, 6.27; N,
5.81%. Found: C, 74.93; H, 6.13; N, 5.82%.
7-(Diallylamino)-4-methyl-2H-chroman-2-one (1b): Yellowish oil;
yield 90%. IR (KBr): dmax ¼ 1716, 1605 cmꢁ1; 1H NMR (400 MHz,
CDCl3): dH ¼ 7.35 (d, 1H, J ¼ 8.9 Hz), 6.57 (dd, 1H, J ¼ 8.9 Hz,
J ¼ 2.6 Hz), 6.53 (d, 1H, J ¼ 2.5 Hz), 5.95 (d, 1H, J ¼ 0.7 Hz), 5.78–
5.87 (m, 2H), 5.13–5.20 (m, 4H), 3.96–3.98 (m, 4H), 2.32 (d, 3H,
J ¼ 0.7 Hz) ppm; MS (m=z) ¼ 255 (Mþ ). Anal. calcd. for C16H17NO2;
C, 75.27; H, 6.71; N, 5.49%. Found: C, 75.30; H, 6.69; N, 5.60%.
6-(Diallylamino)-1-methylquinolin-2(1H)-one (1c): Yellow viscous liquid;
yield 90%. IR (KBr): vmax ¼ 1650, 1440 cmꢁ1; 1H NMR (400 MHz, CDCl3):

Pyrrolidine Synthesis
3165
dH ¼ 7.55 (d, 1H, J ¼ 9.4 Hz), 7.45 (d, 1H, J ¼ 9.3 Hz), 7.28 (dd, 1H,
J ¼ 9.3Hz, J ¼ 2.9Hz), 6.73 (d, 1H, J ¼ 2.9 Hz), 6.63 (d, 1H, J ¼ 9.4 Hz),
Hz), 5.82–5.90 (m, 2H), 5.16–5.20 (m, 4H), 3.94–3.95 (m, 4H), 3.66 (s, 3H)
ppm. MS (m=z) ¼ 254 (Mþ ). Anal. calcd. for C16H18N2O; C, 75.56; H,
7.13; N, 11.01%. Found: C, 75.35; H, 7.01; N, 11.08%.
3-(Diallylamino)phenyl 4-methylbenzenesulfonate (1d): Yellow liquid;
yield 85%, IR (KBr) vmax ¼ 1632, 1615 cmꢁ1; 1H NMR (400 MHz,
CDCl3): dH ¼ 7.71 (d, 2H, J ¼ 8.2 Hz), 7.27 (d, 2H, J ¼ 8.0 Hz), 7.00
(t, 1H, J ¼ 8.1 Hz), 6.50–6.54 (m, 1H), 6.24–6.26 (m, 2H), 5.80–5.81
(m, 2H), 5.12–5.15 (m, 4H), 4.05–4.07 (m, 4H), 2.42 (s, 3H) ppm. MS
(m=z) ¼ 343(Mþ ). Anal. calcd. for C19H21NO3S: C, 66.45; H, 6.16; N,
4.08%. Found: C, 66.69; H, 6.13; N, 4.05%.
N, N-Diallylpyridin-2-amine (1e): Yellow liquid; yield 70%. IR (KBr):
vmax ¼ 2850, 1600 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH ¼ 8.13 (m,
1H), 7.38–7.42 (m, 1H), 6.50–6.53 (m, 1H), 6.44 (d, 1H, J ¼ 8.6 Hz),
5.80–5.89 (m, 2H), 5.11–5.15 (m, 4H), 4.09–4.10 (m, 4H) ppm. MS
(m=z) ¼ 174 (Mþ ). Anal. calcd. for C11H14N2: C, 75.82; H, 8.10; N,
16.08%. Found: C, 75.77; H, 8.33; N, 16.26%.
N, N-Diallylnaphthalen-2-amine (1f): Yellow liquid; yield 80%. IR
1
(KBr): vmax ¼ 2855, 1600 cmꢁ1; H NMR (400 MHz, CDCl3): dH ¼ 7.65
(d, 1H, J ¼ 8.9 Hz), 7.60 (d, 1H, J ¼ 8.2 Hz), 7.55 (d, 1H, J ¼ 8.2 Hz),
7.30–7.33 (m, 1H), 7.10–7.15 (m, 1H), 6.90 (dd, 1H, J ¼ 8.9 Hz,
J ¼ 2.1 Hz), 6.69 (d, 1H, J ¼ 2.1 Hz), 5.75–5.82 (m, 2H), 5.13–5.17 (m,
4H), 3.98–4.05 (m, 4H), ppm. MS (m=z) ¼ 223 (Mþ ). Anal. calcd. for
C16H17N: C, 86.05; H, 7.67; N, 6.27%. Found: C, 85.96; H, 7.74; N,
6.23%.
General Procedure for Ring-Closing Metathesis of
Diallyl Derivatives 1a–f
The ruthenium catalyst 1 (5 mol%) (and a catalytic amount 4-methylben-
zenesulfonic acid for 1e only) in dichloromethane (1 mL) was added
under a nitrogen atmosphere to a solution of corresponding diallyl
derivative (0.2 mmol) in dry dichloromethane (1.5 mL). The reaction mix-
ture was stirred for 20–30 min (12 h for 1e). The solvent was evaporated,
and the residue was purified by flash chromatography over silica gel
using petroleumether–ethylacetate as elutent.
Data
6-(2H-Pyrrol-1(5H)-yl)-2H-chromen-2-one (2a): Yellowish solid; yield 95%;
ꢀ
1
mp 156–158 C. IR (KBr): vmax ¼ 1714, 1569 cmꢁ1; H NMR (400 MHz,

3166
K. C. Majumdar, S. Chakravorty, and A. Taher
CDCl3): dH ¼ 7.62 (d, 1H, J ¼ 9.5 Hz), 7.22 (d, 1H, J ¼ 9.2 Hz), 6.71 (dd,
1H, J ¼ 9.0, J ¼ 2.9 Hz), 6.44 (d, 1H, J ¼ 2.8Hz), 6.37 (d, 1H, J ¼ 9.5 Hz),
Hz), 5.97 (s, 2H), 4.12 (s, 4H) ppm. 13C NMR (125 MHz, CDCl3):
dc ¼ 156.4, 140.6, 139.1, 138.6, 121.3, 114.5, 112.5, 111.8, 110.5, 102.1,
49.7ppm; HRMS: m=z calcd. for C13H11NO2 [M þ H]þ : 214.0859; found:
214.0863. Anal. calcd. for C13H11NO2; C, 73.23; H, 5.20; N, 6.57%. Found:
C, 73.47; H, 5.13; N, 6.71%.
4-Methyl-7-(2H-pyrrol-1(5H)-yl)-2H-chromen-2-one
(2b):
Light
yellow solid; yield 90%, mp 156–158 ꢀC. IR (KBr) vmax ¼ 1703,
1
1605 cmꢁ1; H NMR (400 MHz, CDCl3): dH ¼ 7.40 (d, 1H, J ¼ 8.8 Hz),
6.44 (dd, 1H, J ¼ 8.8 Hz, J ¼ 2.4 Hz), 6.35 (d, 1H, J ¼ 2.4 Hz), 5.96 (s,
2H), 5.95 (d, 1H, J ¼ 0.9 Hz), 4.16 (s, 4H), 2.34 (d, 3H, J ¼ 0.9 Hz)
ppm; MS (m=z) ¼ 227 (Mþ ). Anal. calcd. for C14H13NO2: C, 73.99; H,
5.77; N, 6.16%. Found: C, 73.87; H, 5.73; N, 6.05%.
1-Methyl-6H-(2H-pyrrol-1(5H)-yl)quinolin-2(1H)-one (2c): Yellow
solid; yield 85%; mp 94–96 ꢀC. IR (KBr) vmax ¼ 1651, 1446 cmꢁ1;
1H NMR (400 MHz, CDCl3): dH ¼ 7.57 (d, 1H J ¼ 9.4 Hz),
7.26 (d, 1H, J ¼ 9.0 Hz), 6.83 (dd, 1H, J ¼ 9.1 Hz, J ¼ 2.7 Hz), 6.66
(d, 1H, J ¼ 9.4 Hz), 6.57 (d, 1H, J ¼ 2.6 Hz), 5.98 (s, 2H), 4.14
(s, 4H), 3.69 (s, 3H) ppm; MS (m=z) ¼ 226 (Mþ ). Anal. calcd. for
C14H14N2O: C, 74.31; H, 6.24; N, 12.38%. Found: C, 74.34; H, 6.07;
N, 12.21%.
3-(2H-Pyrrol-1(5H)-yl)phenyl 4-methylbenzenesulfonate (2d): White
ꢀ
1
solid; yield 95%; mp 78–80 C. IR (KBr) vmax ¼ 1630, 1610 cmꢁ1; H
NMR (400 MHz, CDCl3): dH ¼ 7.73 (d, 2H, J ¼ 8.2 Hz), 7.28 (d, 2H,
J ¼ 8.0 Hz), 7.04 (t, 1H, J ¼ 8.1 Hz), 6.34 (dd, 1H, J ¼ 8.2, J ¼ 1.9 Hz),
6.18 (dd, 1H, J ¼ 8.0 Hz, J ¼ 1.7 Hz), 6.14–6.15 (m, 1H), 5.90 (s, 2H),
3.99 (s, 4H), 2.43 (s, 3H) ppm.13C NMR (125 MHz, CDCl3):
dc ¼ 146.0, 143.0, 140.0, 127.8, 124.9, 124.6, 123.5, 121.1, 104.8, 103.7,
99.9, 49.4, 16.6 ppm; MS (m=z) ¼ 315 (Mþ ). Anal. calcd. for
C17H17NO3S: C, 64.74; H, 5.43; N, 4.44%. Found: C, 64.86; H, 5.52;
N, 4.36%.
2-(2H-Pyrrol-1(5H)-yl)pyridine (2e): Yellow liquid; yield 70%. IR
(KBr) vmax ¼ 2851, 1598 cmꢁ1; 1H NMR (400 MHz, CDCl3): dH
¼
8.15–8.17 (m, 1H), 7.42–7.47 (m, 1H), 6.52–6.55 (m, 1H), 6.32 (d, 1H,
J ¼ 8.4 Hz), 5.94 (s, 2H), 4.24 (s, 4H) ppm; MS (m=z) ¼ 146 (Mþ ). Anal.
calcd. for C9H10N2: C, 73.94; H, 6.89; N, 19.16%. Found: C, 73.75; H,
6.90; N, 19.28%.
1-(Napthalen-2-yl)-2,5dihydro-1H-pyrrole (2f): Yellow viscous liquid;
yield 30%. IR (KBr) vmax ¼ 2850, 1600 cmꢁ1; 1H NMR (400 MHz,
CDCl3): dH ¼ 7.70 (d, 1H, J ¼ 8.96 Hz), 7.66 (d, 1H, J ¼ 8.16 Hz), 7.62
(d, 1H, J ¼ 8.28 Hz), 7.32–7.36 (m, 1H), 7.13–7.17 (m, 1H), 6.93 (dd,
1H, J ¼ 8.92 Hz, 2.0 Hz), 6.71 (d, 1H, J ¼ 2.0 Hz), 5.99 (s, 2H), 4.22

Pyrrolidine Synthesis
3167
(s, 4H), ppm; MS (m=z) ¼ 195 (Mþ ). Anal. calcd. for C14H13N; C, 86.12;
H, 6.71; N, 7.17%. Found: C, 86.25; H, 6.80; N, 7.25.
1-(Napthalen-2-yl)-1H-pyrrole (2g): Yellow viscous liquid; yield 60%.
1
IR (KBr) vmax ¼ 2853, 1598 cmꢁ1; H NMR (400 MHz, CDCl3): dH
¼
7.89 (d, 1H, J ¼ 8.8 Hz), 7.83 (d, 2H, J ¼ 8.16 Hz), 7.78 (d, 1H, J ¼
2.0 Hz), 7.57 (dd, 1H, J ¼ 8.8 Hz, 2.0 Hz), 7.41–7.53 (m, 2H), 7.22 (s,
2H), 6.40 (s, 2H) ppm; MS (m=z) ¼ 193 (Mþ ). Anal. calcd. for
C14H11N; C, 87.01; H, 5.74; N, 7.25%. Found: C, 87.15; H, 5.79; N,
7.20%.
ACKNOWLEDGMENTS
We thank the CSIR (New Delhi) for financial assistance. Two of us (S.C. and
A.T.) are thankful to the CSIR (New Delhi) for their fellowship. We also
thank the DST (New Delhi) for providing UV-vis and IR spectrometers
under the Department of Science and Technology–Fund for Improvement
of S & T Infrastructure in Universities and Higher Education program.
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