Reusable and highly enantioselective water-soluble Ru(II)-Amm-Pheox catalyst for intramolecular cyclopropanation of diazo compounds

Article abstract of DOI:10.3762/bjoc.15.31

A reusable and highly enantioselective catalyst for the intramolecular cyclopropanation of various diazo ester and Weinreb amide derivatives was developed. The reactions catalyzed by a water-soluble Ru(II)-Amm-Pheox catalyst proceeded smoothly at room temperature, affording the corresponding bicyclic cyclopropane ring-fused lactones and lactams in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). After screening of various catalysts, the Ru(II)-Amm-Pheox complex having an ammonium group proved to be crucial for the intramolecular cyclopropanation reaction in a water/ether biphasic medium. The water-soluble catalyst could be reused at least six times with little loss in yield and enantioselectivity.

Full text of DOI:10.3762/bjoc.15.31

Reusable and highly enantioselective water-soluble
Ru(II)-Amm-Pheox catalyst for intramolecular
cyclopropanation of diazo compounds
Hamada S. A. Mandour*1, Yoko Nakagawa2, Masaya Tone2, Hayato Inoue2,
Nansalmaa Otog2, Ikuhide Fujisawa2, Soda Chanthamath2 and Seiji Iwasa*2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 357–363.
1Department of Chemistry, Faculty of Science, Tanta University,
Tanta 31527, Egypt and 2Department of Environmental and Life
Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka,
Tempaku-Cho, Toyohashi 441-8580, Japan
doi:10.3762/bjoc.15.31
Received: 07 November 2018
Accepted: 16 January 2019
Published: 06 February 2019
Email:
Hamada S. A. Mandour* - hamada.mandour@science.tanta.edu.eg;
Seiji Iwasa* - iwasa@ens.tut.ac.jp
This article is part of the thematic issue "Cyclopropanes and
cyclopropenes: synthesis and applications".
* Corresponding author
Guest Editor: M. Tortosa
Keywords:
© 2019 Mandour et al.; licensee Beilstein-Institut.
License and terms: see end of document.
asymmetric synthesis; carbene transfer; cyclopropanation; diazoester;
intramolecular diazoamide; Ru(II)-Pheox; water-soluble catalyst;
Weinreb amide
Abstract
A reusable and highly enantioselective catalyst for the intramolecular cyclopropanation of various diazo ester and Weinreb amide
derivatives was developed. The reactions catalyzed by a water-soluble Ru(II)-Amm-Pheox catalyst proceeded smoothly at room
temperature, affording the corresponding bicyclic cyclopropane ring-fused lactones and lactams in high yields (up to 99%) with
excellent enantioselectivities (up to 99% ee). After screening of various catalysts, the Ru(II)-Amm-Pheox complex having an am-
monium group proved to be crucial for the intramolecular cyclopropanation reaction in a water/ether biphasic medium. The water-
soluble catalyst could be reused at least six times with little loss in yield and enantioselectivity.
Introduction
Water-soluble transition metal complexes have been attracting research [14-21]. Nevertheless, only a few catalytic cyclo-
increasing interest for catalytic applications because of their propanation reactions were carried out in aqueous media
many advantages such as simple product separation, low cost, [22-28]. In our previous work, we developed Ru(II)-Pheox cata-
safety, and environmentally friendly processing [1-13]. Thus, lysts for the intramolecular cyclopropanation of trans-allylic
the study of organic reactions in water is an important area of diazoacetates in a biphasic medium [29-31]. During the course
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Beilstein J. Org. Chem. 2019, 15, 357–363.
Results and Discussion
Asymmetric cyclopropanation using various
of our continuous study on the development of a series of
Ru(II)-Pheox catalysts, we found the introduction of an ammo-
nium group on the aromatic ring connected with Ru gave high
solubility in the water phase compared to a normal Ru(II)-
Pheox complex as shown below (Figure 1) [32,33].
diazo compounds with Ru(II)-Amm-Pheox
Several diazoacetates and diazoacetamides were tested for
asymmetric intramolecular cyclopropanation reactions using
Ru(II)-Amm-Pheox catalyst (cat. 2) in H2O/ether biphasic medi-
um as shown in Table 1. A diazo compound derived from allyl
diazoacetate could be cyclopropanated affording the corre-
sponding lactone with low yield and good enantioselectivity
(Table 1, entry 1).
Then, Ru(II)-Amm-Pheox (cat. 2) was found to be soluble in
water but not in diethyl ether. This fact prompted us to explore
the asymmetric intramolecular cyclopropanation of a variety of
diazo compounds such as diazoacetates and diazoacetamides in
a biphasic medium. Diazoacetates were tested in our catalytic
system because they are widely used for intramolecular cyclo- In case of the diazo compound derived from cinnamyl diazoace-
propanation reactions and also the resulted lactones are widely tate the corresponding lactone was obtained in high yield with
distributed in nature and have excellent biological activity, in- high enantioselectivity (Table 1, entry 2). A spirocyclopropana-
cluding strong antibiotic, antihelmetic, antifungal, antitumor, tion product and a functionalized cyclopropane were obtained
antiviral and anti-inflammatory, which make them interesting with high enantioselectivities (Table 1, entries 3 and 4).
lead structures for new drugs [34]. That is why a great deal of N-Benzyl-diazoacetamide underwent the asymmetric cyclo-
attention has been paid to the synthesis of the lactone ring propanation reaction affording the corresponding lactam in
[35,36]. Diazoacetamides, in particular, diazo Weireb amides moderate yield and moderate enantioselectivity (Table 1, entry
were tested in our catalytic system because the resulting cyclo- 5). Interestingly, Ru(II)-Amm-Pheox complex (cat. 2) catalyzes
propane products can be easily converted into the correspond- the asymmetric intramolecular cyclopropanation of diazo
ing aldehydes, ketones, and alcohols [37-48].
Weinreb amide (N-cinnamyl-2-diazo-N-methoxyacetamide) in a
Figure 1: A comparison of the solubility of Ru(II)-Pheox (cat. 1) and Ru(II)-Amm-Pheox (cat. 2).
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Beilstein J. Org. Chem. 2019, 15, 357–363.
affording chiral cyclopropylamide 2f in 97% yield with a high
Table 1: Asymmetric intramolecular cyclopropanation using various
substrates.a
enantioselectivity of 96% in 5 h (Table 2, entry 5) [49].
Table 2: Catalyst screening.a
entry
1
product
yield [%]b ee [%]c
entry
catalyst
X mol [%] yield [%]b
ee [%]c
2a
2b
18
93
88
93
1
2
3
4
5
6
7
8
cat. 1
cat. 2
cat. 2
cat. 2
cat. 3
cat. 4
cat. 5
cat. 6
3
3
2
1
3
5
5
5
53
99
99
99
97
41
37
61
91
99
99
99
96
95
88
96
2
3
4
5
6
2c
2d
2e
2f
56
38
50
99
97
96
43
99
aReaction conditions: (3 mol %) of the catalyst was dissolved in water
(1 mL) and a solution of diazo compound 1f in ether was added. The
reaction was stirred until the reaction was finished at room tempera-
ture. bIsolated yield. cDetermined by chiral HPLC analysis.
Next, the intramolecular cyclization of trans-allylic diazo
Weinreb amide 1f catalyzed by Ru(II)-Amm-Pheox (cat. 2) was
examined in various solvents, as shown in Table S1 (Support-
ing Information File 1). Notably, the catalytic reaction
proceeded in a variety of solvents, including aromatic, aliphatic,
polar, non-polar, and halogenated solvents (Table S1, entries
1–8). In non-polar solvents (Table S1, entries 1−4), in which
aReaction conditions: 3 mol % of the catalyst was dissolved in water
(1 mL) and a solution of the diazo compound in ether (1 mL) was
added. The reaction was stirred until the reaction was finished at room
temperature. bIsolated yield. cDetermined by chiral HPLC analysis.
water/ether mixture, giving the corresponding lactam in high Ru(II)-Amm-Pheox (cat. 2) was poorly soluble, low yields and
yield with high enantioselectivity (99% yield, 99% ee, Table 1, moderate enantioselectivities were obtained. On the other hand,
entry 6). These results encouraged us to explore the asym- the reaction in halogenated solvents proceeded in moderate
metric intramolecular cyclopropanation of diazo Weinreb yields with high enantioselectivities (Table S1, entries 5−7).
amides in a biphasic medium.
Among the solvents examined, water/diethyl ether was identi-
Asymmetric cyclopropanation using diazo
Weinreb amide with Ru(II)-Amm-Pheox
fied as the solvent system of choice because it afforded the
desired product in the highest yield and enantioselectivity at
Ru(II)-Pheox (cat. 1) was slightly soluble in water, and room temperature.
afforded only a 53% yield of product in 5 h (Table 2, entry 1).
On the other hand, hydroxymethyl Ru(II)-Pheox (cat. 3), which With the optimal conditions in hand, various trans-allylic diazo
is completely soluble in water, catalyzed the cyclization of 1f Weinreb amide derivatives, prepared from the corresponding
359

Beilstein J. Org. Chem. 2019, 15, 357–363.
allylic alcohols by the Fukuyama method [50] were investigat- the intramolecular cyclopropanation in this catalytic system,
ed as shown in Scheme 1. The catalytic system was applicable providing the corresponding product in high yield with moder-
to a wide variety of substrates, which reacted smoothly to give ate enantioselectivity (Scheme 1, 2q). Similar results were ob-
the corresponding bicyclic products. For example, diazo tained with trans-allylic diazo Weinreb amide derivatives bear-
Weinreb amide derivatives bearing electron-donating or elec- ing aliphatic substituents (Scheme 1, 2r and 2s). As shown in
tron-withdrawing groups at the ortho, meta, or para positions Figure S1 (Supporting Information File 1), the absolute config-
could be converted to the corresponding bicyclic products in uration of product 2g was determined to be (1S,5R,6R) by
excellent yields (up to 99%) and enantioselectivities (up to single-crystal X-ray diffraction analysis (Supporting Informa-
98% ee, Scheme 1, 2g−m).
tion File 1) [51]. Since the stereoselectivity of products depends
on the cis/trans geometry of the reactants, other stereoisomers
A diazo compound with two chlorine substituents on the aro- such as the (1S,5R,6S) product was not formed in this catalytic
matic ring also underwent the cyclopropanation reaction cyclopropanation. During the reaction process, no other stereo-
affording the desired bicyclic compound in high yield and enan- isomers were obtained.
tioselectivity (Scheme 1, 2o). Remarkably, the derivative
featuring the bulky naphthyl group instead of the phenyl Next, the reusability of water-soluble catalyst cat. 2 was exam-
group was also well tolerated and afforded the corresponding ined. After separation of the ether layer, the aqueous phase was
bicyclic product in excellent yield with high enantioselectivity extracted with diethyl ether several times until no product
(Scheme 1, 2p).
remained. A new solution of trans-allylic diazo Weinreb amide
1f in ether was added, and the mixture was stirred until comple-
Even the sterically demanding trisubstituted olefin-based allyl tion of the reaction. Interestingly, Ru(II)-Amm-Pheox catalyst
diazo Weinreb amide was found to be an effective substrate for (cat. 2) could be reused at least six times with little loss of reac-
Scheme 1: Intramolecular cyclopropanation of various trans-allylic diazo Weinreb amide derivatives catalyzed. Reaction conditions: to a solution of
Ru(II)-Amm-Pheox (cat. 2, 3 mol %) in water (1 mL) was added a solution of trans-allylic diazo Weinreb amide derivatives 1f–s and the reaction mix-
ture was stirred at room temperature for 1–5 h.
360

Beilstein J. Org. Chem. 2019, 15, 357–363.
tivity and enantioselectivity (Table 3). It is expected that the de- (Scheme 2, reaction 1) [52]. We then investigated the arylation
creasing activity depended on the catalyst leakage during the of chiral cyclopropylamide 2f with Grignard reagent PhMgBr
work-up.
(Scheme 2, reaction 2). Only 37% of cyclopropyl ketone 4 were
observed at room temperature with unaltered enantioselectivity
(98% ee).
Table 3: Reusability of Ru(II)-Amm-Pheox (cat. 2).a
Conclusion
In conclusion, we have developed an efficient water-soluble
Ru(II)-Amm-Pheox (cat. 2) for the intramolecular cyclopropan-
ation of trans-allylic diazo Weinreb amide derivatives. The
water-soluble catalyst provided excellent yields of the bicyclic
products (up to 99%) with excellent enantioselectivities (up to
99% ee). The easy separation of the ether layer containing the
cyclopropane product allowed for simple reuse of the catalyst in
the water phase for at least six times with little loss of reactivi-
ty and enantioselectivity.
entry
run
time [h]
yield [%]b
ee [%]c
1
2
3
4
5
6
1
2
3
4
5
6
50 min
2
99
97
95
94
96
93
99
99
97
95
92
90
16
24
24
Supporting Information
36
aReaction conditions: After the use of the catalyst in the first run, the
ether layer was separated and the aqueous layer was washed 3 times
with ether. A new amount of trans-allylic diazo Weinreb amide 1f dis-
solved in Et2O (2.0 mL) was added and the reaction mixture was
stirred until the end of the reaction. bIsolated yield. cDetermined by
chiral HPLC analysis.
Supporting Information File 1
Full experimental details and analytical data (reaction
method, 1H NMR, 13C NMR, HPLC, X-ray analysis).
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-31-S1.pdf]
Synthetic transformations of 2d and 2f
Acknowledgements
In order to demonstrate the advantages of products, further syn-
thetic transformations of the cyclopropane products were inves-
tigated. A ring opening and direct amidation of the chiral cyclo-
propane-fused γ-lacton 2d using DIBAL-H with benzylamine
afforded the desired product 3 in 44% yield with 95% ee
This work was supported by a Grant-in-Aid for Scientific
Research (B) (No. 26288087) from Japan Society for the
Promotion of Science. The data in this paper are partially taken
from Dr. Mandour’s Ph.D. thesis (Toyohashi University of
Technology, 2017).
Scheme 2: Synthetic transformation of cyclopropane products 2d and 2f.
361

Beilstein J. Org. Chem. 2019, 15, 357–363.
26.Wurz, R. P.; Charette, A. B. Org. Lett. 2002, 4, 4531–4533.
ORCID® iDs
Hamada S. A. Mandour - https://orcid.org/0000-0001-9189-676X
doi:10.1021/ol0270879
27.Estevan, F.; Lloret, J.; Sanaú, M.; Úbeda, M. A. Organometallics 2006,
25, 4977–4984. doi:10.1021/om060484t
Yoko Nakagawa - https://orcid.org/0000-0001-8189-5552
28.Nicolas, I.; Le Maux, P.; Simonneaux, G. Tetrahedron Lett. 2008, 49,
5793–5795. doi:10.1016/j.tetlet.2008.07.133
References
29.Abu-Elfotoh, A.-M.; Nguyen, D. P. T.; Chanthamath, S.;
Phomkeona, K.; Shibatomi, K.; Iwasa, S. Adv. Synth. Catal. 2012, 354,
3435–3439. doi:10.1002/adsc.201200508
1. Koelle, U. Coord. Chem. Rev. 1994, 135–136, 623–650.
doi:10.1016/0010-8545(94)80079-0
2. Schaper, L.-A.; Hock, S. J.; Herrmann, W. A.; Kühn, F. E.
Angew. Chem., Int. Ed. 2013, 52, 270–289.
30.Chanthamath, S.; Iwasa, S. Acc. Chem. Res. 2016, 49, 2080–2090.
doi:10.1021/acs.accounts.6b00070
doi:10.1002/anie.201205119
31.Nakagawa, Y.; Nakayama, N.; Goto, H.; Fujisawa, I.; Chanthamath, S.;
Shibatomi, K.; Iwasa, S. Chirality 2019, 31, 52–61.
doi:10.1002/chir.23033
3. Martins, L. M. D. R. S.; Pombeiro, A. J. L. Eur. J. Inorg. Chem. 2016,
2236–2252. doi:10.1002/ejic.201600053
4. Breno, K. L.; Ahmed, T. J.; Pluth, M. D.; Balzarek, C.; Tyler, D. R.
Coord. Chem. Rev. 2006, 250, 1141–1151.
32.Chanthamath, S.; Mandour, H. S. A.; Tong, T. M. T.; Shibatomi, K.;
Iwasa, S. Chem. Commun. 2016, 52, 7814–7817.
doi:10.1039/c6cc02498j
doi:10.1016/j.ccr.2005.12.001
5. Sheldon, R. A. J. Mol. Catal. A: Chem. 1996, 107, 75–83.
doi:10.1016/1381-1169(95)00229-4
33.Mandour, H. S. A.; Chanthamath, S.; Shibatomi, K.; Iwasa, S.
Adv. Synth. Catal. 2017, 359, 1742–1746.
6. Darensbourg, D. J.; Joo, F.; Kannisto, M.; Katho, A.; Reibenspies, J. H.
Organometallics 1992, 11, 1990–1993. doi:10.1021/om00042a006
7. Silbestri, G. F.; Flores, J. C.; de Jesús, E. Organometallics 2012, 31,
3355–3360. doi:10.1021/om300148q
doi:10.1002/adsc.201601345
34.Seitz, M.; Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285–292.
doi:10.1016/j.cbpa.2005.03.005
35.Collins, I. J. Chem. Soc., Perkin Trans. 1 1999, 1377–1396.
doi:10.1039/a808137i
8. Mohr, F.; Sanz, S.; Tiekink, E. R. T.; Laguna, M. Organometallics 2006,
25, 3084–3087. doi:10.1021/om0602456
36.El Ali, B.; Alper, H. Synlett 2000, 161–171. doi:10.1055/s-2000-6477
37.Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
doi:10.1016/s0040-4039(01)91316-4
9. Saoud, M.; Romerosa, A.; Peruzzini, M. Organometallics 2000, 19,
4005–4007. doi:10.1021/om000507i
10.Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022.
doi:10.1002/1521-3773(20020617)41:12<2008::aid-anie2008>3.0.co;2-
4
38.Vanderwal, C. D.; Vosburg, D. A.; Sorensen, E. J. Org. Lett. 2001, 3,
4307–4310. doi:10.1021/ol016994v
39.Jeong, I. H.; Jeon, S. L.; Min, Y. K.; Kim, B. T. Tetrahedron Lett. 2002,
43, 7171–7174. doi:10.1016/s0040-4039(02)01679-9
40.Taillier, C.; Bellosta, V.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6,
2145–2147. doi:10.1021/ol049434f
11.Samec, J. S. M.; Bäckvall, J.-E.; Andersson, P. G.; Brandt, P.
Chem. Soc. Rev. 2006, 35, 237–248. doi:10.1039/b515269k
12.Lindström, U. M., Ed. Organic Reactions, in Water: Principles,
Strategies and Applications; Blackwell Publishing Ltd.: Oxford, UK,
2007.
41.Labeeuw, O.; Phansavath, P.; Genêt, J.-P. Tetrahedron Lett. 2004, 45,
7107–7110. doi:10.1016/j.tetlet.2004.07.106
13.Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68–82.
doi:10.1039/b507207g
42.Hisler, K.; Tripoli, R.; Murphy, J. A. Tetrahedron Lett. 2006, 47,
6293–6295. doi:10.1016/j.tetlet.2006.06.118
14.Grieco, P. A., Ed. Organic Synthesis in Water; Blackie: London, 1998.
15.Li, C. J. Chem. Rev. 1993, 93, 2023–2035. doi:10.1021/cr00022a004
16.Lindström, U. M. Chem. Rev. 2002, 102, 2751–2772.
doi:10.1021/cr010122p
43.Friel, D. K.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008,
130, 9942–9951. doi:10.1021/ja802935w
44.Yang, F.; Ackermann, L. Org. Lett. 2013, 15, 718–720.
doi:10.1021/ol303520h
17.Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816–7817.
doi:10.1021/ja00546a048
45.Baker, D. B.; Gallagher, P. T.; Donohoe, T. J. Tetrahedron 2013, 69,
3690–3697. doi:10.1016/j.tet.2013.03.009
18.Breslow, R.; Maitra, U.; Rideout, D. Tetrahedron Lett. 1983, 24,
1901–1904. doi:10.1016/s0040-4039(00)81801-8
19.Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239–1240.
doi:10.1016/s0040-4039(01)80122-2
46.Harikrishna, K.; Rakshit, A.; Aidhen, I. S. Eur. J. Org. Chem. 2013,
4918–4932. doi:10.1002/ejoc.201300622
47.Bailey, C. L.; Clary, J. W.; Tansakul, C.; Klabunde, L.; Anderson, C. L.;
Joh, A. Y.; Lill, A. T.; Peer, N.; Braslau, R.; Singaram, B.
Tetrahedron Lett. 2015, 56, 706–709. doi:10.1016/j.tetlet.2014.12.066
48.Mamuye, A. D.; Castoldi, L.; Azzena, U.; Holzer, W.; Pace, V.
Org. Biomol. Chem. 2015, 13, 1969–1973. doi:10.1039/c4ob02398f
49.This part is partially taken from Dr. Mandour’s Ph.D. theses (Toyohashi
University of Technology, 2017).
20.Grieco, P. A.; Garner, P.; He, Z.-m. Tetrahedron Lett. 1983, 24,
1897–1900. doi:10.1016/s0040-4039(00)81800-6
21.Grieco, P. A.; Yoshida, K.; Garner, P. J. Org. Chem. 1983, 48,
3137–3139. doi:10.1021/jo00166a051
22.Barrett, A. G. M.; Braddock, D. C.; Lenoir, I.; Tone, H. J. Org. Chem.
2001, 66, 8260–8263. doi:10.1021/jo0108111
50.Toma, T.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2007, 9,
3195–3197. doi:10.1021/ol701432k
23.Ho, C.-M.; Zhang, J.-L.; Zhou, C.-Y.; Chan, O.-Y.; Yan, J. J.;
Zhang, F.-Y.; Huang, J.-S.; Che, C.-M. J. Am. Chem. Soc. 2010, 132,
1886–1894. doi:10.1021/ja9077254
51.Crystallographic data have been deposited in the Cambridge
Crystallographic Data Center with the deposition number CCDC
1528321. A copy of the data can be obtained, free of charge, on
application to the Director, CCDC, 12 Union Road, Cambridge
CB21EZ, U.K. (fax, + 44(0)-1233-336033; e-mail, deposit@ccdc.cam.
ac.uk).
24.Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am. Chem. Soc. 2004,
126, 8664–8665. doi:10.1021/ja047346k
25.Ikeno, T.; Nishizuka, A.; Sato, M.; Yamada, T. Synlett 2001, 406–408.
doi:10.1055/s-2001-11416
362

Beilstein J. Org. Chem. 2019, 15, 357–363.
52.Zheng, B.; Hou, S.; Li, Z.; Guo, H.; Zhong, J.; Wang, M.
Tetrahedron: Asymmetry 2009, 20, 2125–2129.
doi:10.1016/j.tetasy.2009.07.050
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