Synthesis and RCM reactions using a recyclable grubbs-hoveyda metathesis catalyst activated by a light fluorous tag

Article abstract of DOI:10.1021/jo101140w

A recyclable Grubbs-Hoveyda second-generation catalyst activated by a light fluorous tag was prepared. The modified light fluorous catalyst exhibited higher catalytic activity than the parent or the previously reported light fluorous variant for RCM react

Full text of DOI:10.1021/jo101140w

pubs.acs.org/joc
the catalytic activity of light fluorous RCM catalysts by
Synthesis and RCM Reactions Using a Recyclable
Grubbs-Hoveyda Metathesis Catalyst Activated
by a Light Fluorous Tag
tuning the ligand structure.5 Grela et al. reported that
electron-withdrawing groups on the aromatic ring of the
ligand increased the catalytic activity6 of Grubbs-Hoveyda
catalysts.7 This observation has been verified by others,8 and
we planned to incorporate this design feature into our cata-
lyst in the hopes of increasing activity. It was envisioned that
a light fluorous tag directly attached to the aromatic ring of
the ligand will serve as both an electron-withdrawing group
and a handle for FSPE. Thus Grubbs-Hoveyda catalyst 2a
with no ethylene spacer between the aromatic ring and the
fluorous tag was prepared. Concurrently catalyst 2b was
prepared based on Blechert’s report that increased steric
hindrance ortho to the isopropoxy group on the ligand en-
hanced reactionrates for metathesis reactions.9 (See Figure1).
Masato Matsugi,* Yuki Kobayashi, Naoki Suzumura,
Yuki Tsuchiya, and Takayuki Shioiri
Faculty of Agriculture, Meijo University, 1-501
Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
matsugi@meijo-u.ac.jp
Received June 25, 2010
FIGURE 1. Grubbs-Hoveyda catalyst (GH 2nd) and light fluo-
rous Grubbs-Hoveyda catalysts.
A recyclable Grubbs-Hoveyda second-generation catalyst
activated by a light fluorous tag was prepared. The modified
light fluorous catalyst exhibited higher catalytic activity
than the parent or the previously reported light fluorous
variant for RCM reactions and could be routinely recov-
ered. The light fluorous tag incorporated in the catalyst
served as both an activator as well as a handle for separation
and recovery with fluorous solid-phase extraction.
The synthesis of catalysts 2a and 2b is shown in Scheme 1.
The direct perfluoroalkylation10 of 3a and 3b under mildly
basic conditions with V-70 L (2,20-azobis-(2,4-dimethyl-4-
methoxyvaleronitrile)11 provided mono perfluoroalkylated
compounds 4a12 and 4b in 36 and 12% yields respectively.
Isopropyl ether formation, followed by Wittig olefination
provided ligand precursor 5a-b in 78 and 75% yield respec-
tively over the two steps. Trans-metathesis13 with standard
second-generation Grubbs catalyst provided the modified
light fluorous Grubbs-Hoveyda catalyst 2a and 2b as dark-
green crystals (2a:mp182.0-183.0 °C; 2b: mp 158.0-159.0 °C).
These two catalysts required no special storage or handling and
Olefin metathesis is among the most powerful and popular
methods for carbon-carbon bond formation today,1 and an
assortment of environmentally sustainable metathesis cata-
lysts are now available.2 We have reported that a light
fluorous Grubbs-Hoveyda second-generation metathesis
catalyst 1b is readily recovered from reaction mixtures by
fluorous solid phase extraction3 (FSPE) and can be routinely
reused.4 Although 1b shows similar catalytic activity to the
original Grubbs-Hoveyda second-generation catalyst 1a
for RCM reactions, we have been interested in improving
1
were stable to air and in solution for several months. (see H
NMR spectra in the Supporting Information).
(6) (a) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int.
Ed. 2002, 41, 4038. (b) Zaja, M.; Connon, S. J.; Dunne, A. M.; Rivard, M.;
Buschmann, N.; Jiricek, J.; Blechert, S. Tetrahedron 2003, 59, 6545.
(7) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H.
J. Am. Chem. Soc. 1999, 121, 791.
(8) (a) Vinokurov, N.; Garabatos-Perera, J. R.; Zhao-Karger, Z.;
€
A.; Gulajski, L.; Mennecke, K.; Meyer, A.; Busch, T.; Grela, K. Synlett 2008,
2692. (c) Borre, E.; Caijo, F.; Rix, D.; Crevisy, C.; Mauduit, M. Chim. Oggi
2008, 26, 89.
(1) (a) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim,
Germany, 2003. (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(c) Furstner, A. Alkene Metathesis in Organic Synthesis; Springer: New York,
1998.
Wiebcke, M.; Butenschon, H. Organometallics 2008, 27, 1878. (b) Kirschning,
(2) (a) Samojzowicz, C.; Bieniek, C.; Grela, K. Chem. Rev. 2009, 109,
3708. (b) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit, M.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 6786.
(9) (a) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 794.
(b) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 2403.
(10) Matsugi, M.; Hasegawa, M.; Hasebe, S.; Takai, S.; Suyama, R.;
Wakita, Y.; Kudo, K.; Imamura, H.; Hayashi, T.; Haga, S. Tetrahedron Lett.
2008, 49, 4189.
(11) Kita, Y.; Gotanda, K.; Murata, K.; Suemura, M.; Sano, A.;
Yamaguchi, T.; Oka, M.; Matsugi, M. Org. Process Res. Dev. 1998, 2, 250.
(12) Pozzi, G.; Cavazzini, M.; Cinato, F.; Montanari, F.; Quici, S. Eur. J.
Org. Chem. 1999, 1947.
(3) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837.
(4) Matsugi, M.; Curran, D. P. J. Org. Chem. 2005, 70, 1636.
(5) Examples: (a) Kuhn, K. M.; Bourg, J.; Chung, C. K.; Virgil, S. C.;
Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 5313. (b) Vorfalt, T.;
Leuthaeusser, S.; Plenio, H. Angew. Chem., Int. Ed. 2009, 48, 5191. (c) Grisi,
F.; Mariconda, A.; Costabile, C.; Bertolasi, V.; Longo, P. Organometallics
2009, 28, 4988. (d) Berlin, J. M.; Campbell, K.; Ritter, T.; Funk, T. W.;
Chlenov, A.; Grubbs, R. H. Org. Lett. 2007, 9, 1339.
(13) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
DOI: 10.1021/jo101140w
r
Published on Web 10/18/2010
J. Org. Chem. 2010, 75, 7905–7908 7905
2010 American Chemical Society

Matsugi et al.
JOCNote
SCHEME 1. Synthesisa of the Modified Light Fluorous
Grubbs-Hoveyda Catalyst 2a and 2b
aReagents and conditions: (a) 1.0 equiv V-70 L, 1.5 equiv C8F17I, 8.0
equiv Cs2CO3, DMF, rt, 4a: 36%, 4b: 12%. (b) 5.0 equiv iPrI, 8.0 equiv
K2CO3, DMF, 70 °C. (c) 4.0 equiv [Ph3PCH3]Br, 8.0 equiv NHMDS,
THF, -78 °C, 5a: 78%, 5b: 75% (2 steps). (d) 1.0 equiv Grubbs second-
generation catalyst, 1.1 equiv CuCl, CH2Cl2, rt, 2a: 66%, 2b: 58%.
FIGURE 3. Comparison ofcatalytic activityfor RCMof8in CDCl3.
TABLE 1. Reuse of Modified f-GH Catalyst 2a in the RCM of Diethyl
2,2-Diallylmalonate
cycles
1
2
3
4a
5
RCM product (%)
recovered catalyst (%)
aThe reaction was conducted for 1.5 h.
95
97
100
100
95
91
96
95
82
100
FIGURE 2. Comparison ofcatalyticactivityforRCMof6inCDCl3.
The relative turnover rates of catalysts 1a, 2a, and 2b were
determined by comparing the RCM reaction rates of these
catalysts in the conversion of N,N-diallyl-p-toluenesulfon-
amide 6 to N-p-tosyl-2,5-dihydro-1H-pyrrole 7. The reac-
tions were conducted with CDCl3 as solvent to allow for
NMR monitoring of reaction aliquots. Three reactions, each
with catalyst 1a, 2a, and 2b respectively, were set up under
identical conditions with identical catalyst loadings. At given
time points the % conversion of the reaction was determined
by recording 1H NMR spectra of reaction mixtures and
calculating the relative integrals of the corresponding methy-
lene protons of product 7. A plot of % conversion versus
time is shown in Figure 2. It is apparent that 2b has the
highest activity among the three catalysts because it reaches
100% conversion after 50 min, whereas it takes catalysts 2a
and 1b 80 and 130 min, respectively, to reach the same con-
version in the RCM reaction of 6. After the reaction, the
RCM product 7 was isolated in almost quantitative yield
using either 2a or 2b. Furthermore, we compared the cata-
lytic activity between 1a and 2b using other bulky substrate
diethyl 2-allyl-2-(2-methylallyl)malonate, 8.14 As a result, 2b
showed a higher catalytic activity than 1a in this case, too
(Figure 3).15 Although the catalytic activity of 2a was lower
than known activated catalyst,6a 2b showed similar activity
in the RCM reaction of 8.
The purification and recycling features of 2a were exam-
ined using diethyl 2,2-diallylmalonate 10 as the substrate
1
(Table 1).16 The recovered catalyst exhibited a H NMR
spectrum similar to that of fresh catalyst and was used directly
in the second cycle with appropriate adjustments of all other
components to maintain the same 5 mol % catalyst ratio.
This process was repeated through five cycles. The 1H NMR
spectra of product 11 in each case was clean, and resonnaces
corresponding to the free ligand resonances could not be
observed in all cases by 1H and 19F NMR. The yield of the
product was high (95-100%) in each iteration, while the
yield of the recovered catalyst ranged from 91% to 100%. At
the end of the fifth cycle, about 84% of the original catalyst
was recovered. Although the recovered catalyst was no
1
longer pristine by H NMR, we expect that it was still active
because the 1H NMR was similar to that of the catalyst after the
fourth cycle. If desired, it could be repurified by chromatography
or recrystallization prior to reuse. Unfortunately, catalyst 2b
could not be recovered and reused because it was not stable
to the FSPE protocol. We assume that the coordination
ability of the ligand was lower than that of 2a for the aqueous
conditions in the presence of fluorous silica gel.
(14) Doran, W. J.; Shonle, H. A. J. Am. Chem. Soc. 2000, 122, 8168.
(15) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos,
G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318.
(16) Taber, D. F.; Frankowski, K. J. J. Org. Chem. 2003, 68, 6047.
7906 J. Org. Chem. Vol. 75, No. 22, 2010

Matsugi et al.
JOCNote
In summary, we have prepared two modified Grubbs-
Hoveyda second-generation catalysts (2a and 2b) activated
by a light fluorous tag. Although, catalyst 2b was not
recoverable by FSPE, 2b exhibited higher catalytic activity
than 1a and 2a. Catalyst 2a on the other hand could be
routinely recovered using FSPE in each iteration, and it
was reused up to five times with minimal loss in reactivity.
We have shown that the fluorous tag serves two purposes:
(1) to provide a purification handle through FSPE and (2)
to improve the catalytic activity through the electron-
withdrawing nature of the perfluoroalkyl chain. At pres-
ent, we believe that catalyst 2a is one of the most effective
light fluorous Grubbs-Hoveyda catalyst available to
date.
layer was concentrated in vacuo, and the residue was purified by
column chromatography over silica gel, eluting with AcOEt/
hexane, 1:10 to give 5a (78 mg, 78%).
1-Isopropoxy-4-perfluorooctyl-2-vinylbenzene (5a): yellow oil;
1H NMR (270 MHz, CDCl3) δ 7.65 (d, J = 2.1 Hz, 1H), 7.40
(dd, J = 8.9, 2.4 Hz, 1H), 6.97-7.08 (m, 1H), 6.94 (d, J = 8.3,
1H), 5.79 (dd, J = 17.8, 1.1 Hz, 1H), 5.33 (dd, J = 17.3, 1.1 Hz,
1H), 4.59-4.68 (m, 1H), 1.38 (d, J = 2.9 Hz, 6H); 19F NMR
(466 MHz, CDCl3) δ -126.0 (2F), -122.6 (2F), -121.8 (2F),
-121.7 (4F), -121.2 (2F), -109.7 (2F), -80.7 (3F); 13C NMR
(67.8 MHz, CDCl3) δ 157.8, 131.1, 128.0, 127.4, 125.5 (t, J = 6.6
Hz), 120.6, 115.7, 112.9, 105-121 (m, C8F17), 71.0, 22.1; EI-MS
m/z: 580 (Mþ), 538, 169; HRMS (EI) m/z calcd for C19H13F17O
580.0695, found 580.0711.
3-Fluoro-1-isopropoxy-4-perfluorooctyl-2-vinylbenzene (5b):
1
yellow oil; H NMR (270 MHz, CDCl3) δ 7.49 (s, 1H), 7.21
(dd, J = 11.3, 2.2 Hz, 1H), 6.97-7.08 (m, 1H), 5.81 (dd, J =
17.8, 0.8 Hz, 1H), 5.41 (d, J = 11.3 Hz, 1H), 4.50-4.63 (m, 1H),
1.34 (d, J = 5.7 Hz, 6H); 19F NMR (466 MHz, CDCl3) δ -126.8
(1F), -126.0 (2F), -122.6 (2F), -121.8 (2F), -121.6 (4F),
-121.2 (2F), -110.1 (2F), -80.7 (3F); 13C NMR (67.8 MHz,
CDCl3) δ 157.4, 153.8, 146.2, 134.3, 130.4, 123.7, 120.2 (t, J =
6.7 Hz), 117.2, 105-120 (m, C8F17), 77.2, 22.6; EI-MS m/z: 598
(Mþ), 556, 187; HRMS (EI) m/z calcd for C19H12F18O 598.0601,
found 598.0582.
Experimental Section
General Procedure for Perfluoroalkylation. To a solution of
salicylaldehyde (300 mg, 2.46 mmol) and perfluorooctyl iodide
(2.01 g, 3.68 mmol) in DMF (16 mL) was added V-70 L (758 mg,
2.46 mmol) and cesium carbonate (6.41 g, 19.7 mmol) at room
temperature. The mixture was stirred for 20 h at ambient
temperature. After the addition of aq HCl (1.0 M), the reaction
mixture was extracted with diethyl ether. The organic layer was
concentrated, and the three regioisomers of perfluoroctylated
compounds (ortho, para, and ortho/para dialkylated) were puri-
fied by column chromatography over silica gel eluting with
AcOEt/hexane, 1:20 to furnish 4a in 36% yield.
Modified light fluorous metathesis catalyst (2a): green crystals;
1
mp 182.0-183.0 °C: H NMR (270 MHz, CDCl3) δ 16.38 (s,
1H), 7.69-7.72 (m, 1H), 7.08-7.13 (m, 5H), 6.90 (d, J = 8.6 Hz,
1H), 4.90-4.99 (m, 1H), 4.21 (s, 4H), 2.47 (s, 12H), 2.39 (s, 6H),
1.29 (d, J = 6.2 Hz, 6H); 19F NMR (466 MHz, CDCl3) δ -125.9
(2F), -122.5 (2F), -121.7 (2F), -121.4 (4F), -121.0 (2F),
-109.3 (2F), -80.6 (3F); 13C NMR (67.8 MHz, CDCl3) δ
293.5, 209.6, 154.4, 144.7, 139.1, 129.4, 127.4, 123.1, 121.2 (t,
J = 6.0 Hz), 119.2, 115.5, 113.0, 107-123 (m, C8F17), 76.4, 51.5,
29.7, 21.1, 19.4; IR: 2924, 1592, 1487, 1240, 1202, 1146, 1115,
661 cm-1; HRMS (FAB) m/z calcd for C39H39Cl2F17N2ORu
1046.1211, found 1046.1224.
2,20-Azobis(2,4-dimethyl-4-methoxyvaleronitrile). This is com-
mercially available, and the abbreviation in brackets [V-70] is its
trade name. This compound is a mixture of diastereomeric isomers
whose melting points are 58 and 107 °C and should be stored below
-10 °C to prevent any decomposition. V-70 L is the isomer, with
the lower melting point. The typical procedure to separate the
diastereomers is described below: V-70 (5.0 g) in Et2O (25 mL) was
stirred at 10 °C for 30 min to precipitate the V-70H (1.8 g; no V-70
L was observed by 1H NMR). Subsequently, the filtrate was cooled
to -10 °C for 2 days to give crystallized V-70 L (0.7 g; 100% by 1H
Modified light fluorous metathesis catalyst (2b): green crystals;
1
mp 158.0-159.0 °C: H NMR (270 MHz, CDCl3) δ 16.31 (s,
1H), 7.47 (d, J = 11.6 Hz, 1H), 7.07 (s, 4H), 6.92 (s, 1H), 5.39-
5.45 (m, 1H), 4.21 (s, 4H), 2.47 (s, 12H), 2.39 (s, 6H), 1.26 (s, 6H);
19F NMR (466 MHz, CDCl3) δ -130.2 (1F), -125.9 (2F),
-122.5 (2F), -121.7 (4F), -121.3 (2F), -121.1 (2F), -109.5
(2F), -80.6 (3F); 13C NMR (67.8 MHz, CDCl3) δ 292.2, 208.4,
153.3, 149.7, 148.1, 140.4, 139.2, 129.5, 124.3, 117.2 (t, J = 6.3
Hz), 115.3, 107-124 (m, C8F17), 82.2, 77.3, 51.5, 29.7, 22.0, 20.8;
IR: 2924, 1487, 1324, 1240, 1196, 1145, 1104, 668 cm-1; HRMS
(FAB) m/z calcd for C39H38Cl2F18N2ORu 1064.1117, found
1064.0961.
1
NMR); V-70 L: mp ∼58 °C (dec); H NMR (CDCl3) δ 3.21 (s,
6H), 2.42 (d, J = 11 Hz, 2H), 2.26 (d, J = 11 Hz, 2H), 1.64 (s,
12H), 1.29 (s, 12H).
2-Hydroxy-5-perfluorooctylbenzaldehyde (4a):12 white crys-
1
tals; mp 73.0-74.0 °C; H NMR (270 MHz, CDCl3) δ 11.85
(s, 1H), 9.96 (s, 1H), 7.79 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H); 19
F
NMR (466 MHz, CDCl3) δ -126.0 (2F), -122.6 (2F), -121.8
(2F), -121.7 (2F), -121.5 (2F), -121.3 (2F), -108.9 (2F),
-80.6 (3F).
1-Tosyl-2,5-dihydro-1H-pyrrole13 (7): white crystals; mp
3-Fluoro-2-hydroxy-5-perfluorooctylbenzaldehyde (4b): pale-
yellow crystals; mp 64.0-65.0 °C: 1H NMR (270 MHz, acetone-
1
124.5-125.5 °C: H NMR (270 MHz, CDCl3) δ 7.72 (d, J =
d6) δ 10.16 (s, 1H), 7.88 (s, 1H), 7.69 (d, 1H, J = 10.8 Hz); 19
F
7.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 5.65 (s, 2H), 4.12 (s, 4H),
2.43 (s, 3H).
NMR (466 MHz, CDCl3) δ -132.8 (1F), -126.0 (2F), -122.6
(2F), -121.7 (2F), -121.5 (4F), -121.0 (2F), -110.0 (2F),
-80.6 (3F); 13C NMR (67.8 MHz, CDCl3) δ 195.6, 153.0,
152.8, 149.2, 127.5 (t, J = 6.6 Hz), 121.9, 120.7, 106-121 (m,
C8F17); EI-MS m/z: 558 (Mþ), 189; HRMS (EI) m/z calcd for
C15H4F18O2 557.9924, found 557.9915.
General Procedure for Wittig Reaction. To a solution of
methyltriphenylphosphoniumbromide (245 mg, 0.68 mmol) in
anhydrous THF (8 mL) was added sodium bis(trimethylsilyl)-
amide (252 mg, 1.37 mmol) under nitrogen at -78 °C and stirred
for 30 min. Then the reaction temperature rose to -10 °C and
was stirred for further 30 min. A solution of 2-isopropoxy-5-
perfluorooctylbenzaldehyde (100 mg, 0.17 mmol) in anhydrous
THF (5 mL) was then added and stirring continued for 2 h at
room temperature. After the addition of aq HCl (1.0 M), the
reaction mixture was extracted with diethyl ether. The organic
Diethyl 3-methylcyclopent-3-ene-1,1-dicarboxylate14 (9): pale-
yellow oil; 1H NMR (270 MHz, CDCl3) δ 5.18 (m, 1H), 4.19 (q,
J = 7.3 Hz, 4H), 2.96 (m, 2H), 2.90 (s, 2H), 1.71 (s, 3H), 1.25 (t,
J = 7.3 Hz, 6H).
Diethyl cyclopent-3-ene-1,1-dicarboxylate15 (11): colorless oil;
1H NMR (270 MHz, CDCl3) δ 5.61 (s, 2H), 4.19 (d, J = 7.6 Hz,
4H), 3.00 (s, 4H), 1.25 (t, J = 7.6 Hz, 6H).
General Procedure for RCM and FSPE. Diethyl 2,2-diallyl-
malonate 10 (375 mg, 1.56 mmol) and 2a (81.8 mg, 0.078 mmol,
0.050 equiv) were dissolved in dichloromethane (31 mL, 0.05 M)
under a nitrogen atmosphere, and the mixture was stirred for
1 h at room temperature. After removal of the volatile compo-
nents by rotary evaporation, the brownish mixture was sub-
mitted to separation by FSPE. A short column was packed
with fluorous silica gel (2.4 g) using aq 80% MeOH as the
J. Org. Chem. Vol. 75, No. 22, 2010 7907

Matsugi et al.
JOCNote
solvent. The crude reaction mixture was then loaded onto this
column and eluted with 9.6 mL of aq 80% MeOH followed by
12 mL of THF. The evaporation of the 80% MeOH fraction
and the THF fraction by vacuum centrifuge gave RCM
product 11 in 95% yield (314 mg) and catalyst 2a in 97% yield
(79.7 mg).
Grant-in-aid for Scientific Research (C), 20580115, and the
fund for Agriomics project. We thank Prof. Shuji Akai, Uni-
versity of Shizuoka, for the elemental analysis. We also thank
The Uehara Memorial Foundation for funding this work.
Supporting Information Available: Copies of 1H NMR of 2a
with the passage of time, and 1H NMR, 19F NMR, 13C NMR
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was partially supported
by the Ministry of Education, Science, Sports and Culture,
7908 J. Org. Chem. Vol. 75, No. 22, 2010