Microwave enabled external carboxymethyl substituents in the ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(03)00083-2

The ring-closing metathesis of diolefin substrates containing an external carboxymethyl substituent is presented. The reaction is enabled through microwave irradiation allowing greatly enhanced yields and conversion rates. The reaction results in the formation of carboxymethyl substituted dihydropyrroles, dihydrofurans, and cyclopentenes. In certain cases, pyrroles are formed through further in situ oxidation.

Full text of DOI:10.1016/S0040-4039(03)00083-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1783–1786
Microwave enabled external carboxymethyl substituents in the
ring-closing metathesis
Cangming Yang, William V. Murray and Lawrence J. Wilson*
Johnson & Johnson Pharmaceutical Research & Development LLC, 920 Route 202, PO Box 300, Raritan, NJ 08869, USA
Received 30 December 2002; accepted 8 January 2003
Abstract—The ring-closing metathesis of diolefin substrates containing an external carboxymethyl substituent is presented. The
reaction is enabled through microwave irradiation allowing greatly enhanced yields and conversion rates. The reaction results in
the formation of carboxymethyl substituted dihydropyrroles, dihydrofurans, and cyclopentenes. In certain cases, pyrroles are
formed through further in situ oxidation. © 2003 Elsevier Science Ltd. All rights reserved.
The olefin metathesis reaction resulting in ring forma-
tion (ring-closing metathesis or RCM) has become an
important and powerful reaction within the field of
synthetic organic chemistry.1 The ruthenium catalysts
developed by Grubbs (1 and 2, Scheme 1)2 have been
utilized for RCM based ring formation as a key step in
numerous natural product synthesis.3 The reaction is
very general in the formation of many ring sizes and
types,4 with notable exceptions in the eight member
ring size cases.5,6 In addition, it is fairly general to
functionality that is internal to the new ring system
being formed. However, the reaction does show limita-
tions to external substituents.6 So far, only substituents
with little or no steric or electronic bias are compatible
(i.e. Me or Et). External groups with an electronic bias
(CO2Me, OMe, CN, Br) result in little to no yield of the
RCM product.6,7 Adding additional substitution exter-
nal to the newly formed double bond would allow the
formation of an activated system enabling further
unique functionalization.
As part of a drug discovery program, we became
interested in exploring the carboxymethyl substituent
via 2-substituted methacrylate systems (Scheme 2).
Although the only report of this system in the ring-clos-
ing metathesis resulted in a low conversion (ꢀ5%), we
extrapolated that we could realize our goal to access
this system by applying microwave irradiation to raise
the yield and apply this reaction to other systems.8
Investigations into the conditions suitable for ring clos-
ing metathesis reactions of these substrates under
microwave irradiation were initiated. The N-p-toluene-
sulfonyl substrate (4a, Table 1) with the added car-
boxymethyl substituent was investigated under a variety
of conditions. Treatment with Grubbs type I catalyst
(1) resulted in only a trace of the desired dehydropyrro-
lidine product (5a). Switching to the Grubbs type II
catalyst (2) gave slightly better results, and at room
temperature the reaction proceeded to about 40% con-
version even after prolonged exposure. Heating to
50°C, resulted in conversion to about 75% after 5 h, but
proceeded no further. We then investigated irradiation
in the microwave, which gave more promising results.9
Irradiation for 5 min at 50°C gave 85% conversion, and
at 150°C for 5 min gave 97% conversion. Further
beneficial effects of the microwave can be seen in
comparison reaction times and conversions. In condi-
Scheme 1.
Scheme 2.
* Corresponding author. Tel.: 908-429-1981; fax: 908-203-8109;
e-mail: lwilson3@prdus.jnj.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00083-2

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C. Yang et al. / Tetrahedron Letters 44 (2003) 1783–1786
Table 1. Conversion of 4a to 5a with 3% of 2 in 1,2-
goal of obtaining product yields after purification. The
N-p-tosylsulfonamide substrate (4a) gave 82% of the
dehydropyrrolidine (5a).11,12 The diallyl malonate sub-
strate 4b followed suit and gave a 100% conversion and
56% isolated yield of the cyclopentene ester 5b when
exposed to the same conditions. The lower isolated
yield is due presumably to product volatility. We were
gratified to see this conversion, since Grubbs reported
that this substrate gave ꢀ5% conversion when using
the type I catalyst (1).6 Finally, the reaction translated
to the dihydrofuran system 5c with bisolefin 4c in 82%
isolated yield under slightly lower temperature
(100°C).12,13
DCE9–11
Conditions (0.025 M in
4a)
Temperature
(°C)
% Conversion
(time)a
rt
rt
24
24
6 (5 min)
30 (6 h)
We next considered several nitrogen substrates which
would give dehydropyrrolidines with different groups
on nitrogen.12,13 This type of substrate could be incor-
porated as a 3,4-dehydro-isoproline peptidomimetic
scaffold or be utilized as an intermediate to construct
alkaloid natural products.14,15 We were also interested
in determining if the basicity would effect the RCM in
these systems. We discovered that the reaction was
successful, but were surprised to find that we isolated
the pyrrole products (6a,b) along with the expected
dehydropyrrolidines. The N-phenyl substrate translated
cleanly in a similar fashion to the N-tosyl result (entry
1) resulting in a 70% yield of the dehydropyrrolidine 5d.
The methallyl-acrylate substrate 4e was exposed to
these conditions and we were intrigued to find that not
only did the reaction provide a successful RCM reac-
tion resulting in a tetrasubstituted olefin product 5e
(16%), but also the corresponding 2,3,5-trisubstituted
pyrrole 6a (48%) as the major product.13 The pyrrole
formation can be explained through an RCM followed
by an in situ oxidation. The final example, the N-(S-a-
methylbenzyl) substrate 4f gave the pyrrole product 6b
exclusively in 76% isolated yield.13 When comparing
substrates (4a to 4d to 4f), it is clear this oxidation is
dependent upon the nitrogen basicity.
rt
24
50
50
50
50
150
37 (20 h)
62 (5 min)
75 (20 min)
75 (5 h)
85 (5 min)
97 (5 min)
Thermal
Thermal
Thermal
mwave, 0–10 W, 1 psi
mwave, 60–80 W, 60 psi
a % Conversions determined by 1H NMR analysis of the crude
reaction mixture.
tions not involving microwave heating, conversion
reaches a maximum after several hours, presumably due
to lower catalyst turnover or catalyst decomposition.
At room temperature the maximum conversion is 37%
and at 50°C it is 75%, compared to 85 and 97% after 5
min using the microwave. These results clearly show
that microwave heating results in further conversions in
shorter time either overcoming catalyst decomposition
or increasing catalyst turnover.
With evidence that we were observing a rate accelera-
tion and increase in catalyst efficiency for this ring
closure via microwave irradiation we investigated the
substrate variability (Scheme 3, Table 29–13). We began
our study by preparing carboxymethyl containing sub-
strates based on known analogous bisolefin compounds
which give successful ring closing metathesis reactions.
We focused on the various five member ring cases.1,4,6
Alkylations with methyl-2-(bromomethyl) acrylate were
carried out with a variety of allylated substrates (3a–f,
Scheme 3) with carbon, oxygen, and nitrogen nucle-
ophiles in the presence of cesium carbonate or sodium
hydride as base. Analogs were prepared that were pre-
cursors to dihydropyrrole (4d–f), dihydrofuran (4c),
and cyclopentene (4b) systems. We ran reactions at
either 100 or 150°C, with a catalyst amount of 3, 6, or
12 mol%, and irradiation times of 5 or 10 min with the
In conclusion, we have provided an example of the
microwave accelerated ring-closing metathesis reaction
with an external carboxymethyl substituent forming
products with an activated olefin. In the case of five-
membered rings, dehydropyrrolidines, dihydrofuran,
cyclopentene, and pyrrole substrates are formed in
good yields. The microwave allows shorter conversion
times and higher conversion rates. Also, to our knowl-
edge, this is the first reported pyrrole formation utilizing
the RCM. Further progress in these areas will be the
subject of future reports.
Scheme 3.

C. Yang et al. / Tetrahedron Letters 44 (2003) 1783–1786
1785
Table 2.
Acknowledgements
2. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29.
3. Recent examples: (+)-Laurencin: Crimmins, M. T.; Choy,
A. L. J. Am. Chem. Soc. 1999, 121, 5653–5660; Sarain A:
Irie, O.; Samizu, K.; Henry, J. R.; Weinreb, S. M. J. Org.
Chem. 1999, 64, 587–595; (−)-Fumagillol: Boiteau, J. G.;
Van de Weghe, P.; Eustache, J. Org. Lett. 2001, 3,
2737–2740; Octalactin A: Buszek, K. R.; Sato, N.; Jeong,
Y. Tetrahedron Lett. 2002, 43, 181–184; Amphidinolide
A: Maleczka, R. E.; Terrell, L. R.; Geng, F.; Ward, J. S.
Org. Lett. 2002, 4, 2841–2844; (−)-Pinolidoxin: Liu, D.;
Kozmin, S. A. Org. Lett. 2002, 4, 3005–3007.
The authors wish to thank Amy Maden for assistance
with all spectral acquisitions and interpretations, and
Dr. Bharat Lagu for editorial contributions.
References
1. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450.

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C. Yang et al. / Tetrahedron Letters 44 (2003) 1783–1786
4. Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
tions. The reaction conversion was monitored and ana-
lyzed by LC/MS. The solvent was removed by rotary
evaporator, and the crude product was purified by flash
chromatography (hexane/ethyl acetate=9/1 for entries 1
and 2; hexane/ethyl acetate=20/1 for entries 4 and 6;
hexane/ethyl acetate=100/1 for entry 5; methylene chlo-
ride for entry 3).
Soc. 1993, 115, 9856–9857.
5. Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.;
Hoveyda, A. H. J. Am. Chem. Soc. 1996, 118, 4291–4298.
6. Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62,
7310–7318.
7. Basu, K.; Cabral, J. A.; Paquette, L. A. Tetrahedron Lett.
2002, 43, 5453–5456.
13. 13C NMR-DEPT and mass spectral data for all new
products in Table 2. Dehydro analogs: 5a: 13C NMR-
DEPT (75 MHz, CDCl3): 21.91 (CH3), 52.34 (CH3), 53.9
(CH2), 55.85 (CH2), 127.85 (CH), 130.32 (CH), 136.47
(CH); MS (ESI): 585 (2M+23), 304 (M+23), 282 (M+H);
5c: 13C NMR-DEPT (75 MHz, CDCl3): 52.23 (CH3),
74.77 (CH2), 88.93 (CH), 126.75 (CH), 128.71 (CH),
129.11 (CH), 140.9 (CH); MS (ESI): 205 (M+H); 5d: 13C
NMR-DEPT (75 MHz, CDCl3): 52.19 (CH3), 53.83
(CH2), 55.67 (CH2), 111.55 (CH), 116.73 (CH), 129.8
(CH), 138.08 (CH); MS (ESI): 204 (M+H); 5e: 13C NMR-
DEPT (75 MHz, CDCl3): 12.02 (CH3), 52.54 (CH3),
55.53 (CH2), 60.94 (CH2), 111.46 (CH), 116.52 (CH),
120.94 (CH), 129.75 (CH); MS (ESI): 218 (M+H).
Pyrroles: 6a: 13C NMR-DEPT (75 MHz, CDCl3): 12.10
(CH3), 51.20 (CH3), 119.42 (CH), 120.94 (CH), 125.23
(CH), 126.86 (CH), 130.07 (CH); MS (ESI): 238 (M+23),
216 (M+H); 6b: 13C NMR-DEPT (75 MHz, CDCl3): 22.3
(CH3), 51.38 (CH3/CH), 57.36 (CH3/CH), 110.44 (CH),
121.23 (CH), 125.06 (CH), 126.33 (CH), 128.3 (CH),
129.22 (CH); MS (ESI): 481 (2M+23), 230 (M+H).
14. To our knowledge, this system has not been prepared or
reported. The pyrrolidine-3-carboxylate has been utilized
as a b-turn motif in a GPIIb/IIIa antagonist, see: Hoek-
stra, W. J.; Maryanoff, B. E.; Damiano, B. P.; Andrade-
Gordon, P.; Cohen, J. H.; Costanzo, M. J.; Haertlein, B.
J.; Hecker, L. R.; Hulshizer, B. L.; Kauffman, J. A.;
Keane, P.; McComsey, D. F.; Mitchell, J. A.; Scott, L.;
Shah, R. D.; Yabut, S. C. J. Med. Chem. 1999, 42,
5254–5265.
8. Mayo, K. G.; Nearhoof, E. H.; Kiddle, J. J. Org. Lett.
2002, 4, 1567–1570.
9. All microwave reactions were performed in the CEM
Discover™ unit produced by the CEM Corporation,
Mathews, N.C. Settings and readings for power (W), time
of irradiation, and pressure were taken from the instru-
ment. Reactions were performed in an 8 mL sealed vessel
equipped with a Teflon stir flea. The vessels were sealed
with septa and aluminum crimp provided by the vendor.
1
10. All new RCM products gave satisfactory H NMR, MS,
and 13C NMR/DEPT spectra consistent with the struc-
tural assignments.
11. Procedure for the ring-closing metathesis of 4a to give 5a.
Substrate 4a (31 mg, 0.1 mmol) was dissolved in 4 mL of
1,2-dichloroethane in a pressure tube containing a mag-
netic stir bar. Grubb’s II catalyst (2) (2.6 mg, 0.003
mmol) was then added into the pressure tube. The pres-
sure tube was then sealed and heated to 150°C (60–80 W,
60 psi) for 10 min. The solvent was removed by rotary
evaporator, and the crude product was purified by flash
chromatography (hexane/ethyl acetate=9/1) to provide
5a as a white solid (23 mg, 82% yield). Physical data for
5a: 13C NMR-DEPT (75 MHz, CDCl3): 21.91 (CH3),
52.34 (CH3), 53.9 (CH2), 55.85 (CH2), 127.85 (CH),
130.32 (CH), 136.47 (CH); MS (ESI): 585 (2M+23), 304
(M+23), 282 (M+H).
12. General procedure for microwave-assisted RCM prod-
ucts in Table 2. Substrate (4a–f) was dissolved in 4 mL of
1,2-dichloroethane in a pressure tube containing a mag-
netic stir bar to yield solutions with a concentration
between 0.025 and 0.05 M. The catalyst (2) was then
weighed into the pressure tube. The pressure tube was
then sealed and heated under selected microwave condi-
15. The 1,2-dehydro variant has been utilized in an
intramolecular Diels–Alder approach to the galanthan
ring system, see: Morgans, D. J.; Stork, G. Tetrahedron
Lett. 1979, 20, 1959–1962.