Water-soluble chiral ruthenium(II) phenyloxazoline complex: Reusable and highly enantioselective catalyst for intramolecular cyclopropanation reactions

Article abstract of DOI:10.1002/adsc.201200508

The intramolecular cyclopropanation of various trans-allylic diazoacetates and alkenyl diazoketones has been achieved with excellent enantioselectivities of up to 98% ee and in quantitative yields by using a water-soluble ruthenium(II)/hydroxymethyl(phenyl)oxazoline catalyst in a water/ether biphasic medium. The catalyst could be reused at least five times.

Full text of DOI:10.1002/adsc.201200508

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DOI: 10.1002/adsc.201200508
Water-Soluble Chiral Ruthenium(II) Phenyloxazoline Complex:
Reusable and Highly Enantioselective Catalyst for Intramolecular
Cyclopropanation Reactions
Abdel-Moneim Abu-Elfotoh,a,b Diem Phuong Thi Nguyen,a Soda Chanthamath,a
Kesiny Phomkeona,a Kazutaka Shibatomi,a and Seiji Iwasaa,*
a
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1, Tempaku-cho, Toyohashi,
Aichi 441-8580, Japan
Fax : (+81)-532-44-6817; e-mail: iwasa@ens.tut.ac.jp
Chemistry Department, Rabigh-College, King Abdelaziz University, Kingdom of Saudia Arabia
b
Received: June 8, 2012; Revised: October 24, 2012; Published online: December 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200508.
Abstract: The intramolecular cyclopropanation of
various trans-allylic diazoacetates and alkenyl diaz-
oketones has been achieved with excellent enantio-
selectivities of up to 98% ee and in quantitative
yields by using a water-soluble ruthenium(II)/
forded excellent diastereo- and enantioselectivity
(99:1 trans/cis and 97% ee, respectively) in the case of
intermolecular cyclopropanation of terminal olefins
with diazoacetate in a biphasic toluene/water system,
only low enantioselectivity (52% ee) was obtained by
using the Ru complex of 2 as a catalyst in the intra-
molecular cyclopropanation of trans-cinnamyl diazo-
hydroxymethyl
G
a
water/ether biphasic medium. The catalyst could be
reused at least five times.
AHCTUNGTREGaNNUN cetate. The reusability of the water-soluble Ru com-
plex of 1 suffered from a dramatic decrease in reactiv-
ity from 62% yield to 13% yield and in enantioselec-
tivity from 97% ee to 42% ee in intermolecular cyclo-
propanation.
Keywords: asymmetric synthesis; biphasic medium;
cyclopropanation; ruthenium; water-soluble catalyst
Very recently, we reported the efficient use of
a
novel macroporous polymer-supported chiral
Ru(II)-Pheox catalyst in inter- and intramolecular cy-
The intramolecular cyclopropanation reaction is one clopropanation reactions.[6] Despite the high reactivi-
of the most useful synthetic methodologies for con- ty, enantioselectivity and reusability of the macropo-
structing bicyclic structures containing fused cyclopro- rous catalyst, the challenge still remains to develop
pane ring as natural product precursors.[1] Since the a robust, highly enantioselective and reusable catalyst,
first report in 1961 of the catalytic intramolecular cy- which has the ability to dissolve in water. Especially,
ACHTUNGTRENNUNG
clization with an unsaturated diazo ketone,[2] different water is a desirable solvent for catalysis with respect
catalytic systems have been used for intramolecular to environmental concerns, safety, and costs.[7] During
cyclopropanations.[3] Despite the high reactivity and our ongoing research, we found that our novel
enantioselectivity displayed by the previously report- Ru(II)-hydroxymethylACTHNUTRGNE(NUG phenyl)oxazoline [Ru(II)-hm-
ed catalysts, only a few catalytic reactions could be Pheox] complex 7 has ability to dissolve in water and
performed in aqueous media, which is desirable for is completely undissolved in diethyl ether. Interesting-
green chemistry.[4] Our research group has developed ly, we found that the Ru(II)-hm-Pheox complex 7
efficient water-soluble RuACTHUNTGRNEUNG(pybox) catalysts of 1 and 2 could effectively catalyze the intramolecular cyclopro-
for asymmetric inter- and intramolecular cyclopropa- panation of trans-cinnamyl diazoacetate in a water/
nation reactions.[5] Although the Ru complex of 1 af- ether biphasic system to furnish a 99% yield of cyclo-
propane-fused g-lactone system with 97% ee. Encour-
aged by this preliminary result, we prepared a variety
of functionalized Ru(II)-Pheox complexes (3–6)[8] and
evaluated their catalytic activities in the intramolecu-
lar cyclopropanation of trans-cinnamyl diazoacetate
as shown in Table 1. It was observed that catalysts 3
to 7 afforded very similar enantioselectivities, but
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Abdel-Moneim Abu-Elfotoh et al.
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Table 1. Intramolecular cyclopropanation catalyzed by vari-
ous Ru(II)-Pheox catalysts in a biphasic medium.[a]
Figure 1. A comparison of the solubilities of catalysts 3 and
7 in water by using test tube as vessel.
A comparison between the solubilities of catalysts 3
and 7 in water is shown in Figure 1. Notably, when we
replaced the hydroxymethyl group by the methoxy
group, a 69% yield was obtained in 5 h (Table 1,
entry 3). However, the use of other polar groups like
chloromethyl or chloro as substituent could not in-
crease the yield to more than 72% (Table 1, entries 2
and 4). Thus, an Ru(II)-Pheox catalyst functionalized
with polar protic groups is the best choice for the effi-
cient intramolecular cyclopropanation of trans-allylic
diazoacetates in a water/ether biphasic medium. The
effect of the functional group on the solubility and
the reactivity of the ruthenium catalysts can easily be
understand from the proposed mechanism shown in
Scheme 1.
[a]
Reaction conditions: to a solution of Ru(II)-Pheox com-
plex (0.005 mmol, 5 mol%) in H2O (3.0 mL) was added
a
solution of trans-cinnamyl diazoacetate in Et2O
(0.1 mmol in 3.0 mL, ca. 0.033M) at room temperature
and the absolute configuration was determined by com-
parison with the reported specific rotation values (ref.[3j]).
Yield of isolated product.
Determined by GLC using chiral b-Dex 225.
Performed with 1.0 mmol of trans-cinnamyl diazoacetate
in 30 mL of Et2O (ca. 0.033M).
[b]
[c]
[d]
with different yields and in different times. The
Ru(II)-hm-Pheox catalyst 7 was found to be the most
effective (Table 1, entry 5) and we can attribute this
to its ability to form strong hydrogen bonding with
water, which makes it easily soluble and highly effec-
tive. Indeed, the solubility is very important in this
case, since only the soluble molecules will migrate to
the interface and react with the carbene source (allyl-
ic diazoacetate). To test the practicality of the current
catalytic system, the reaction on a 1-mmol scale of
trans-cinnamyl diazoacetate in 30 mL of Et2O was car-
ried out and we found that the cyclopropanation reac-
tion was able to afford bicylic product 9a with little
effect on the yield and reaction time (Table 1,
entry 6). Additionally, the catalyst could be recovered
in 83% in this scale by extaction with CH3CN.
The difference in the solubility is the main reason
for the variations of the yields. For example, Ru(II)-
Pheox catalyst 3 was slightly soluble in water and af-
forded only a 44% yield of the product in one day
(Table 1, entry 1).
Scheme 1. Plausible mechanism for the intramolecular cyclo-
propanation of trans-cinnamyl diazoacetate catalyzed by 7
in a water/ether medium.
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Water-Soluble Chiral Ruthenium(II) Phenyloxazoline Complex: Reusable and Highly Enantioselective Catalyst
Table 2. Asymmetric intramolecular cyclopropanation of
The effect of the catalyst 7 loading on the intramo-
lecular cyclopropanation of trans-cinnamyl diazoace-
tate in water/ether biphasic medium was also investi-
gated. It was possible to reduce the catalyst loading
from 5 to 1 mol% without detrimental effects on the
yield and enantioselectivity, but a longer reaction
time was required (from 1.5 h to 4 h). By using ruthe-
nium catalyst 7 and under the optimized reaction con-
ditions, a broad palette of trans-allylic diazoacetates
8a–8g, which were derived from the corresponding al-
lylic alcohols using the Fukuyama method,[9] were in-
vestigated as shown in Table 2 (entries 1–15). Excel-
lent reactivities and enantioselectivities were obtained
in all of the cases. Interestingly, the water-soluble cat-
alyst 7 could effectively promote the intramolecular
cyclopropanation of both substituted and non-substi-
tuted trans-cinnamyl diazoacetates (Table 2, entries 1–
7) and alkyl trans-allylic diazoacetates with short
(Table 2, entries 8, 14) and long (Table 2, entries 11,
13) chains. Furthermore, the reusability of the water-
soluble catalyst 7 was checked by separating the
ether-phase and washing the aqueous-phase with
ether until no product remains adherent to the aque-
ous-phase. A new amount of trans-allylic diazoacetate
dissolved in ether was added and vigorously stirred
for 1~3 h. It is noteworthy that catalyst 7 could be
reused at least five times without any significant de-
crease in reactivity or enantioselectivity in the intra-
molecular cyclopropanation of trans-cinnamyl diazo-
various trans-allylic diazo compounds catalyzed by 7.[a]
ACHTUNGTRENNUNGacetate as shown in Table 2 entries 1–5. Additionally,
catalyst 7 had the ability to be reused from two to
three times with the other substrates (Table 2, en-
tries 8–10, 11and 12, and 14 and 15).
Inspired by the results above, the intramolecular cy-
clopropanations of alkenyl diazo ketone 8h and trans-
allylic diazoacetamides 8i–8j were also investigated
under the same reaction conditions (Table 2, en-
tries 16–18). Although the catalytic system was not
suitable for the cyclization of trans-allylic diazo-
ACHTUNGTRENNUNGacetamides, the reaction of alkenyl diazo ketone pro-
ceeded smoothly to afford the corresponding cyclo-
propane ring fused ketone product 9h in high yield
with excellent enantioselectivity (98% ee).
To explore further insights, the intermolecular cy-
clopropanation of styrene with EDA catalyzed by 7 in
a water/ether biphasic medium was also checked. Al-
though high trans-selectivity (97% ee) was obtained,
only 30% yield of the cyclopropanation product was
isolated. The reason for this low yield may came from
the partial solubility of EDA in the water-phase and
[10]
À
the possibility of the O H insertion reaction.
[a]
Reaction conditions: to a solution of Ru(II)-hm-Pheox
In conclusion, we have developed an efficient
water-soluble Ru(II)-hm-Pheox catalyst 7. The water-
soluble catalyst 7 delivered excellent reactivities with
up to 99% yield and enantioselectivitis up to 98% ee
in the intramolecular cyclopropanation of trans-allylic
diazoacetates and alkenyl diazo ketone in a water/
complex 7 (0.005 mmol, 5 mol%) in H2O (3.0 mL) was
added a solution of trans-allylic diazo compound in Et2O
(0.1 mmol in 3.0 mL, ca. 0.033M) at room temperature
and the mixture stirred for 1–3 h.
Yield of isolated product.
Determined by GLC or HPLC, see the Supporting Infor-
[b]
[c]
mation.
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Abdel-Moneim Abu-Elfotoh et al.
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York, 1997; b) M. P. Doyle, M. N. Protopopova, Tetra-
hedron 1998, 54, 7919–7946; c) W. A. Donaldson, Tetra-
hedron 2001, 57, 8589–8627; d) A. Reichelt, S. F.
Martin, Acc. Chem. Res. 2006, 39, 433–442; e) H.
Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette,
Chem. Rev. 2003, 103, 977–1050; for a specific example,
see: f) S. M. Berberich, R. J. Cherney, J. Colucci, C.
Courillon, L. S. Geraci, T. A. Kirkland, M. A. Marx,
M. F. Schneider, S. F. Martin, Tetrahedron 2003, 59,
6819–6832.
ether biphasic medium. The functionality of the
ruthenium catalyst with a polar protic group is impor-
tant to furnish high yields. The easy separation of the
ether phase, which contains the cyclopropane product,
allows the simple reuse of the catalyst in the water
phase at least five times without significant decrease
in reactivity or enantioselectivity. To the best of our
knowledge, this is the first report of a reusable water-
soluble catalyst in the intramolecular cyclopropana-
tion reaction. We are currently applying this catalyst
for other carbon-carbon bond forming reactions in
aqueous medium.
[2] G. Stork, J. Ficini, J. Am. Chem. Soc. 1961, 83, 4678.
[3] For transition metal catalysts, see: a) M. P. Doyle, R. E.
Austin, A. S. Bailey, M. P. Dwyer, A. B. Dyatkin, A. V.
Kalinin, M. M. Y. Kwan, S. Liras, C. J. Oalmann, R. J.
Pieters, M. N. Protopopova, C. E. Raab, G. H. P. Roos,
Q.-L. Zhou, S. F. Martin, J. Am. Chem. Soc. 1995, 117,
5763–5775; b) S.-B. Park, K. Murata, H. Matsumoto, H.
Nishiyama, Tetrahedron: Asymmetry 1995, 6, 2487–
2494; c) T. G. Gant, M. C. Noe, E. J. Corey, Tetrahedron
Lett. 1995, 36, 8745–8748; d) D.-J. Cho, S.-J. Jeon, H.-S.
Kim, C.-S. Cho, S.-C. Shim, T.-J. Kim, Tetrahedron:
Asymmetry 1999, 10, 3833–3848; e) M. P. Doyle, W. Hu,
B. Chapman, A. B. Marnett, C. S. Peterson, J. P. Vitale,
S. A. Stanley, J. Am. Chem. Soc. 2000, 122, 5718–5728;
f) M. P. Doyle, S. B. Davies, W. Hu, Org. Lett. 2000, 2,
1145–1147; g) T. Uchida, B. Saha, T. Katsuki, Tetrahe-
dron Lett. 2001, 42, 2521–2524; h) C.-M. Che, J.-S.
Huang, F.-W. Lee, Y. Li, T.-S. Lai, H.-L. Kwong, P.-F.
Teng, W.-S. Lee, W.-C. Lo, S.-M. Peng, Z.-Y. Zhou, J.
Am. Chem. Soc. 2001, 123, 4119–4129; i) J.-L. Zhang,
C.-M. Che, Org. Lett. 2002, 4, 1911–1914; j) B. Saha, T.
Uchida, T. Katsuki, Tetrahedron: Asymmetry 2003, 14,
823–836; k) B. K. Langlotz, H. Wadepohl, L. H. Gade,
Angew. Chem. 2008, 120, 4748–4752; Angew. Chem.
Int. Ed. 2008, 47, 4670–4674; l) Z.-J. Xu, R. Fang, C.
Zhao, J.-S. Huang, G.-Y. Li, N. Zhu, C.-M. Che, J. Am.
Chem. Soc. 2009, 131, 4405–4417; m) C.-M. Ho, J.-L.
Zhang, C.-Y. Zhou, O.-Y. Chan, J. J. Yan, F.-Y. Zhang,
J.-S. Huang, C.-M. Che, J. Am. Chem. Soc. 2010, 132,
1886–1894; n) C. Escudero, J. Pꢂrez-Prieto, S.-E. Stiri-
ba, Inorg. Chim. Acta 2006, 359, 1974–1978; for organo-
catalysts, see: o) N. Bremeyer, S. C. Smith, S. V. Ley,
M. J. Gaunt, Angew. Chem. 2004, 116, 2735–2738;
Angew. Chem. Int. Ed. 2004, 43, 2681–2684; p) C. C. C.
Johansson, N. Bremeyer, S. V. Ley, D. R. Owen, S. C.
Smith, M. J. Gaunt, Angew. Chem. 2006, 118, 6170–
6175; Angew. Chem. Int. Ed. 2006, 45, 6024–6028; for
the stoichiometric process, see: q) D. M. Hodgson,
Y. K. Chung, J.-M. Paris, J. Am. Chem. Soc. 2004, 126,
8664–8665.
Experimental Section
General Remarks
All reactions were performed under the normal air atmos-
phere. CH2Cl2 dehydrated was purchased from Kanto
Chemical Co., Inc. Et2O dehydrated was purchased from
Wako Pure Chemical Industries Co., Ltd. Reactions were
monitored by TLC, glass plates pre-coated with silica gel –
Merck 60 F254, layer thickness 0.2 mm. All the starting mate-
rials (trans-allylic diazoacetates) were prepared using the
Fukuyama method.[8] Flash column chromatography was
performed over Merck silica gel (Art. No. 7734).
Typical Procedure for Intramolecular Cyclopropan-
ation Catalyzed by Ru(II)-hm-Pheox Complex 7
To a solution of Ru(II)-hm-Pheox complex 7 (0.005 mmol,
5.0 mol%) in H2O (3.0 mL) was added a solution of trans-al-
lylic diazo compound in Et2O (0.1 mmol in 3.0 mL, ca.
0.033M) at room temperature. The biphasic medium was
stirred vigorously for 1–3 h. After the starting material had
completely reacted, the product was collected by separation
of the ether phase. The water phase, which contains the cat-
alyst, was washed three times with ether (3ꢁ 5.0 mL). The
collected product in the ether-phase was dried over anhy-
drous Na2SO4 and condensed under reduced pressure. The
crude product was purified by column chromatography on
silica gel (n-hexane/EtOAc=10:1) to afford the correspond-
ing bicyclic product. The remaining water-soluble catalyst
was reused for the next cycle. The enantiomeric excesses of
products were determined by HPLC or GC analysis.
Acknowledgements
[4] For examples of cyclopropanation reactions in water
with achiral catalysts, see: a) A. G. M. Barrett, D. C.
Braddock, I. Lenoir, H. Tone, J. Org. Chem. 2001, 66,
8260–8263; b) see also ref.[3m]; c) see also ref.[3q]; con-
versely a few catalytic systems have been developed to
perform enantioselective intermolecular cyclopropana-
tion reactions, for a review, see: d) T. Ikeno, A. Nishi-
zuka, M. Sato, T. Yamada, Synlett 2001, 406–408;
e) R. P. Wurz, A. B. Charette, Org. Lett. 2002, 4, 4531–
4533; f) F. Estevan, J. Lloret, M. Sanau, M. A. Ubeda,
Organometallics 2006, 25, 4977–4984; g) I. Nicolas, P.
This work was supported by a Grant-in Aid for Scientific Re-
search (C) (No. 20550137) from Japan Society for the Pro-
motion of Science.
References
[1] Reviews: a) M. P. Doyle, M. A. McKervey, T. Ye,
Modern Catalytic Methods for Organic Synthesis with
Diazo Compounds, John Wiely & Sons, Inc., New
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Adv. Synth. Catal. 2012, 354, 3435 – 3439

Water-Soluble Chiral Ruthenium(II) Phenyloxazoline Complex: Reusable and Highly Enantioselective Catalyst
Le Maux, G. Simonneaux, Tetrahedron Lett. 2008, 49,
5793–5795.
[5] a) S. Iwasa, F. Takezawa, Y. Tuchiya, H. Nishiyama,
Chem. Commun. 2001, 59–60; b) S. Iwasa, S. Tsushima,
K. Nishiyama, Y. Tsuchiya, F. Takezawa, H. Nishiyama,
Tetrahedron: Asymmetry 2003, 14, 855–865.
[6] A.-M. Abu-Elfotoh, K. Phomkeona, K. Shibatomi, S.
Iwasa, Angew. Chem. 2010, 122, 8617–8621; Angew.
Chem. Int. Ed. 2010, 49, 8439–8443.
[7] Organic Reactions in Water: Principles, Strategies and
Applications, (Ed.: U. M. Lindstrçm), Blackwell,
Oxford, 2007.
[8] For the preparation of Ru(II)-Pheox complexes 4, 5
and 6, see the Supporting Information.
[9] T. Toma, J. Shimokawa, T. Fukuyama, Org. Lett. 2007,
9, 3195–3197.
[10] A. B. Charette, R. P. Wurz, T. Ollevier, Helv. Chim.
Acta 2002, 85, 4468–4484.
Adv. Synth. Catal. 2012, 354, 3435 – 3439
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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