Organocatalysis in water at room temperature with in-flask catalyst recycling

Article abstract of DOI:10.1021/ol203242r

A new designer surfactant is described containing a covalently bound organocatalyst, proline. This species is water-soluble and, via spontaneous nanomicelle formation, catalyzes aldol reactions on water-soluble or -insoluble substrates in water as the onl

Full text of DOI:10.1021/ol203242r

ORGANIC
LETTERS
2012
Vol. 14, No. 1
422–425
Organocatalysis in Water at Room
Temperature with In-Flask Catalyst
Recycling
Bruce H. Lipshutz* and Subir Ghorai
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
California 93106, United States
*lipshutz@chem.ucsb.edu
Received December 5, 2011
ABSTRACT
A new designer surfactant is described containing a covalently bound organocatalyst, proline. This species is water-soluble and, via spontaneous
nanomicelle formation, catalyzes aldol reactions on water-soluble or -insoluble substrates in water as the only medium. Recycling the catalyst is
trivial, as the amphiphile/catalyst remains in the aqueous phase in the flask.
Although organocatalysis dates back to 1971,1 it is only
over the past decade during which remarkable progress
has been made.2,3 An impressive number of reaction types
can now be effected using this transition-metal-free ap-
proach, and applications abound. Reviews on this subject
in 2010 alone are plentiful.4 Included among the new
directions in organocatalysis being pursued are tandem or
“organocascade” reactions that combine multiple reac-
tion partners leading to significant increases in molecular
complexity in a one-pot sequence.5 Notwithstanding
these advances, the vast majority of reactions that utilize
organocatalysis rely on relatively few catalyst turnovers;
typically, g10% catalyst is needed to achieve reasonable
reaction rates and ultimately, isolated yields. Under such
circumstances the implications are clear: a considerable
amount of organic material is lost upon workup. While
economics may not enter into consideration, e.g., using
an inexpensive commercially available catalyst such as
proline, many second-generation catalysts require several
steps to prepare.4a,6 Moreover, the waste component due
(1) (a) Hajos, Z. G.; Parrish, D. R. DE 2102623, 1971. (b) Eder, U.;
Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496–497. (c)
Deer, U.; Sauer, G.; Wiechert, R. DE 2014757, 1971. (d) Hajos, Z. G.;
Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
(2) Special issues dealing with asymmetric organocatalysis: (a) Acc.
Chem. Res. 2004, 37, 487ꢀ621 (Eds.: Houk, K. N., List, B.). (b)
Tetrahedron 2006, 62, 255-502. (Eds.: Kocovsky, P., Malkov, A. V.).
(c) Chem. Rev. 2007, 107, 5413ꢀ5883 (Ed.: List, B.).
(3) Reviews: (a) Moisan, L.; Dalko, P. I. Angew. Chem., Int. Ed. 2001,
40, 3840–3864. (b) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–
2495. (c) List, B. Chem. Commun. 2006, 819–824. (d) Doyel, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743. (e) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569. (f)
Barbas, C. F. Angew. Chem., Int. Ed. 2008, 47, 42–47. (g) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660. (h) Bella, M.;
Gasperi, T. Synthesis 2009, 1583–1614.
(4) (a) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–
ꢀ
1632. (b) Nunez, M. G.; Garcia, P.; Moro, R. F.; Diez, D. Tetrahedron
2010, 66, 2089–2109. (c) Johnston, J. N. J. Am. Chem. Soc. 2011, 133,
2330.
(5) (a) Tietze, L. F.; Brasche, G.; Gerke, K. Domino Reactions in
Organic Chemistry; Wiley-VCH: Weinheim, Germany, 2007. (b) Brandau,
S.; Maerten, E.; Jorgensen, K. A. J. Am. Chem. Soc. 2006, 128, 14986–
14991. (c) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett.
2006, 8, 2217–2220. (d) Enders, D.; Huettl, M. R. M.; Grondal, C.;
Raabe, G. Nature 2006, 441, 861–863. (e) Carlone, A.; Cabreea, S.;
Marigo, M.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1101–
1104. (f) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew.
(6) (a) Zlotin, S. G.; Kucherenko, A. S.; Beletskaya, I. P. Russ. Chem.
Rev. 2009, 78, 737–784. (b) Sakthivel, K.; Notz, W.; Bui, T; Barbas, C. F.
J. Am. Chem. Soc. 2001, 123, 5260–5267. (c) Tang, Z.; Yang, Z. H.;
Chen, X. H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. J. Am.
Chem. Soc. 2005, 127, 9285–9289. (d) Samanta, S.; Liu, J. Y.; Dodda, R.;
Zhao, C. G. Org. Lett. 2005, 7, 5321–5323. (e) Guillena, G.; Hita, M. C.;
€
ꢀ
Chem., Int. Ed. 2007, 46, 4922–4925. (g) Enders, D.; Huttl, M. R. M.;
Najera, C. Tetrahedron: Asymmetry 2006, 17, 1493–1497. (f) Gandhi, S.;
Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem., Int. Ed. 2007, 46, 467–
469. (h) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 15051–15053.
Singh, V. K. J. Org. Chem. 2008, 73, 9411–9416. (g) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 958–961.
r
10.1021/ol203242r
Published on Web 12/19/2011
2011 American Chemical Society

Scheme 1. Synthesis of PQS-Proline (2)
Figure 1. PQS attached proline catalyst for reactions in water.
to catalyst loss upon workup is necessarily large, detract-
ing from even those processes amenable to use in water as
solvent.7 Those run in organic media where most sub-
strates of interest find solubility are even less environmen-
tally friendly. Not surprisingly, therefore, recent efforts
that address catalyst recycling have come to light.8 Those
reported to date follow a similar pattern, i.e., attachment
to a solid support, thereby requiring catalyst separa-
tion from a reaction mixture and, oftentimes, reactiva-
tion. Ideally, no such manipulation would be needed; i.e.,
in-flask processing should prevail, where the catalyst re-
mains in the reaction vessel.9 Use of water in place of
organic solvent(s) would add a considerable element of
“greenness” as well. In this communication we describe a
newly designed organocatalyst-containing system that
provides a solution to all of these issues: organocatalysis
involving water-soluble or insoluble substrates, done in water
at room temperature, with in-flask catalyst recycling.
follows the outline shown in Scheme 1. Protected proline
derivative 311 was used to open succinic anhydride to
arrive at acid 4 in close to quantitative yield. Esterifi-
cation of coenzyme Q10-derived PQS (1) led to ester 5
(96%), which underwent global hydrogenation to remove
(1) the benzyl ester, (2) the Cbz residue, and (3) all 10
olefins present in the 50-carbon side chain found in the
reduced form of CoQ10, ubiquinol. Compound 2 thus
functions inmultiplecapacities it: (a) servesasthesourceof
the organocatalyst, in this case, proline; (b) provides the
reaction solvent in the form of the 50 carbon hydrocarbon
chain; (c) forms a water-soluble nanoparticle that, due to
the MPEG-2000 component, remains in water upon in-flask
extraction of the product. Dissolution of PQS-proline (2)
in pure water results in formation of 79 nm micelles, as
determined by Dynamic Light Scattering (DLS),12 within
which homogeneous organocatalysis can occur.
For comparison purposes, the aldol reaction between
cyclohexanone and p-nitrobenzaldehyde was chosen for
initial study (Table 1). This particular pair of reactants is
described in the literature with considerable frequency for
related studies in organocatalysis.13 The closest analogy
to PQS-proline 2 is Barbas’ micelle-forming proline deri-
vative 6C,7b which shows considerable promise for use in
industrial settings.7c Catalysts screened for this aldol re-
action included not only PQS-proline but also the analo-
gous mixed diester derivative 6A14 of 4-hydroxyproline,
As a “proof-of principle” case, 4-hydroxyproline was
selected to represent the potential of the new technology
developed. Covalent attachment to the water-soluble micelle-
forming species “PQS” (1)10 via its OH group was antici-
pated to arrive at species 2 (Figure 1). The synthesis of 2
(7) (a) Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687–6703. (b)
Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F;
Barbas, C. F. J. Am. Chem. Soc. 2006, 128, 734–735. In this work, the
authors state “Furthermore, crude aldol products were easily isolated by
removal of water using centrifugal separation”, suggesting that the
catalyst remains in the aqueous phase and may be recyclable, although
catalyst reuse is not described. (c) Mase, N.; Watanabe, K.; Yoda, H.;
Takabe, K.; Tanaka, F; Barbas, C. F. J. Am. Chem. Soc. 2006, 128,
4966–4967. For a review, see: Mase, N.; Barbas, C. F. Org. Biomol.
Chem. 2010, 8, 4043–4050. (d) Mase, N.; Noshiro, N.; Mokuya, A.;
Takabe, K. Adv. Synth. Catal. 2009, 351, 2791–2796. (e) Hayashi, Y.;
Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 5527–5529. (f) Lei, M.; Shi, L.; Li, G.; Chen, S.;
Fang, W.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron 2007, 63, 7892–7898. (g)
Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed.
2006, 45, 8100–8102. (h) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45,
8103–8104. (i) Huang, J.; Zhang, X.; Armstrong, D. W. Angew. Chem.,
Int. Ed. 2007, 46, 9073–9077.
ꢁ
(8) (a) Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericas, M. A.
(11) Barrett, A. G. M.; Pilipauskas, D. J. Org. Chem. 1991, 56, 2787–
2800.
Org. Lett. 2008, 10, 337–340. (b) Yan, J.; Wang, L. Synthesis 2008, 2065–
2072. (c) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006,
8, 4417–4420. (d) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc.
Rev. 2008, 37, 1666ꢀ1688 and references therein.
(12) Borkovec, M. Measuring particle size by light scattering. Hand-
book of Applied Surface and Colloid Chemistry; John Wiley & Sons Ltd.:
Chichester, U.K., 2002; pp 357ꢀ370.
(9) Sheldon, R. A.; Arends, I. W. C. E.; Hanefeld, U. Green Chem-
istry and Catalysis; Wiley-VCH: Weinheim, Germany, 2007.
(10) (a) Lipshutz, B. H.; Ghorai, S. Org. Lett. 2009, 11, 705–708. (b)
Lipshutz, B. H.; Ghorai, S. Tetrahedron 2010, 66, 1057–1063. (c) Moser,
R.; Ghorai, S.; Lipshutz, B. H. Unpublished.
ꢀ
(13) (a) Hernandez, J. G.; Juaristi, E. J. Org. Chem. 2011, 76, 1464–
ꢀ
ꢀ
ꢀ
1467. (b) Pedrosa, R.; Andres, J. M.; Manzano, R.; Roman, D.; Tellez,
S. Org. Biomol. Chem. 2011, 9, 935–940. (c) Ricci, A.; Bernardi, L.;
Gioia, C.; Vierucci, S.; Robitzer, M.; Quignard, F. Chem. Commun.
2010, 6288–6290.
Org. Lett., Vol. 14, No. 1, 2012
423

Table 1. Comparisons between Organocatalysts in an Aldol
Reaction, in Water at rt
Table 2. Representative PQS-Proline (2)-Catalyzed Reactionsa
a Combined yield of isolated diastereomers. b Determined by 1H
NMR of the crude product. c Determined by chiral-phase HPLC ana-
lysis for anti-product.
designed to test the importance of the micelle-forming
CoQ10 platform and proline itself. As illustrated in
Table 1, only PQS-proline (2) afforded the aldol product
to any significant extent, the reaction being run in water at
room temperature. With less ketone present (2.5 equiv),
the extent of conversion was lower andthe yield, therefore,
dropped to 80%.
Several additional examples of aldol reactions occur-
ring within, and mediated by, PQS-proline can be found
in Table 2. Catalyst loading (10 mol %) was chosen as a
compromise between maximizing the amount of 2 used
(since none is lost), and the overall viscosity of the
aqueous medium (typically hosting large excesses of
ketone). While proline works well insofar as ee’s are con-
cerned in several cases, the goal in this study was not to
maximize levels of stereoinduction. Rather, both the dr’s
and ee’s resulting from various ketone/aldehyde com-
binations are all as expected based on proline as the
catalyst.15 In several cases, far better ee’s can be realized
using known alternative catalysts that could replace pro-
line bonded to the PQS backbone.16 Another feature
worthy of note, given that catalysis is presumably taking
place within the lipophilic core of 2 (and not in water), is
that water-insoluble educts, in fact, are the preferred
(14) See Supporting Information for preparation.
ꢁ
(15) (a) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653–
4655. (b) Kristensen, T. E.; Vestli, K.; Fredriksen, K. A.; Hansen, F. K.;
Hansen, T. Org. Lett. 2009, 11, 2968–2971. (c) Lombardo, M.; Easwar,
S.; Marco, A. D.; Pasi, F.; Trombini, C. Org. Biomol. Chem. 2008, 6,
4224–4229. See also refs 7b and 8a.
(16) (a) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa, H. Angew.
Chem., Int. Ed. 2008, 47, 2082–2084. (b) Hayashi, Y.; Samanta, S.; Itoh,
T.; Ishikawa, H. Org. Lett. 2008, 10, 5581–5583. (c) Marigo, M.;
Wabnitz, T. C.; Fielenbach, D.; Jorgensen, K. A. Angew. Chem., Int.
Ed. 2005, 44, 794–797. (d) Zheng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem.
Soc. 2010, 132, 50–51.
a The reactions were performed with aldehyde (0.1 mmol), ketone
(0.5 mmol), and catalyst 2 (0.01 mmol) at rt. b Combined yield of iso-
lated diastereomers. c Determined by 1H NMR of the crude product.
d Determined by chiral-phase HPLC analysis for anti-product.
424
Org. Lett., Vol. 14, No. 1, 2012

Table 3. In-Flask Recycling of Catalyst 2
Scheme 2. In-Flask Recycling of Catalyst 2 in Different Asym-
metric Aldol Reactions
run
yielda (%)
anti/synb
eec (%)
1
2
3
4
94
94
93
91
92:8
94:9
91:9
90:10
96
96
96
96
a Combined yield of isolated diastereomers. b Determined by 1H
NMR of the crude product. c Determined by chiral-phase HPLC
analysis for anti-product.
sed of amphiphile 2. Reintroduction of starting materials
begins the first recycle. Table 3 documents, through three
recycles, that the yield, diastereomeric ratio, and ee of the
process are essentially invariant.
The option to add educts differing in constitution at
any point exists as well. For example, as illustrated in
Scheme 2, following an initial PQS-proline-catalyzed
aldol reaction between aldehyde 7c and ketone 8c giving
product 9c, addition of aldehyde 7d and ketone 8d to the
same pot containing 2 now leads to aldol 9d.
substrates. Thus, substituted cyclohexanones (entries 4, 5,
7, and 8) readily participate at ambient temperatures.
Key to the value of 2 as a model for organocatalytic
processes is its inherent potential for in-flask recycling.10
Thus, upon completion of the aldol event, introduction
of a single organic solvent (e.g., EtOAc) allows in-flask
extraction of the product. Removal of the EtOAc layer is
followed by product purification and potential solvent
recovery, while the residual aqueous layer in the reaction
flask retains the proline-containing nanomicelles compo-
In summary, a new surfactant has been designed with
the principles of green chemistry in mind to address the
high levels of catalyst loading typically associated with
organocatalysis. Proline, as a model catalyst, has been
attached to a nanomicelle-forming amphiphile derived
from the dietary supplement CoQ10. In water this species
self-aggregates into nanoreactors in which catalysis takes
place at room temperature. Given the covalent linkage of
the catalyst (that can be varied) and the high solubility in
water of the amphiphile to which it is attached, typical
extractive workup is avoided, and in-flask recycling of the
catalyst is easily performed.17
(17) Representative procedure (Table 2, entry 6). 3-Cyanobenzalde-
hyde 7f (13 mg, 0.10 mmol), cyclohexanone (52 μL, 0.50 mmol), and
catalyst 2 (33 mg, 0.01 mmol) were sequentially added into a Teflon-
coated stir-bar-containing glass vial at rt. Water (0.25 mL) was added,
and the resulting solution was allowed to stir at rt for 30 h. The
homogeneous reaction mixture was then diluted with EtOAc (1 mL)
and filtered through a bed of silica gel layered over Celite, and the bed
was further washed (3 ꢁ 4 mL) with EtOAc to collect all of the aldol
product material. The volatiles were removed in vacuo to afford the
crude product which was subsequently purified by flash chromatogra-
phy on silica gel (eluting with 20% EtOAc/hexanes) to afford the
product as a white solid (18 mg, 80%). Enantiomeric excess: 97%,
determined by HPLC (Daicel Chiralpak AD, iPrOH/hexane = 10:90), λ =
273 nm, flow rate 0.5 mL/min, tRmajor = 46.92 min, tRminor = 60.28 min;
anti isomer (2S,10R)-9f: [R]20 = þ28.0 (c = 0.30, CHCl3); mp
D
69ꢀ72 °C; IR (thin film): 3498, 2941, 2864, 2229, 1704, 1483, 1449, 1434,
1
1311, 1229, 1130, 1042, 805 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.64
Acknowledgment. Financial support provided by the
NIH (GM 86485) is warmly acknowledged with thanks.
(t, J = 1.2 Hz, 1H), 7.60 (dt, J = 7.6, 1.2 Hz, 1H), 7.57 (dt, J = 7.6, 1.2
Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 4.82 (dd, J = 8.4, 2.8 Hz, 1H), 4.08
(d, J = 2.8 Hz, 1H), 2.61ꢀ2.54 (m, 1H), 2.53ꢀ2.48 (m, 1H), 2.41ꢀ2.33 (m,
1H), 2.15ꢀ2.09 (m, 1H), 1.85ꢀ1.80(m, 1H), 1.67(qt, J= 12.8, 4.0 Hz, 1H),
1.59ꢀ1.51 (m, 2H), 1.35 (qd, J = 12.8, 4.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 215.1, 142.8, 131.7, 130.9, 129.4, 118.9, 112.7, 74.2, 57.3, 42.8,
30.9, 27.8, 24.9; MS (ESI): m/z 252 (M þ Na); HRMS (ESI) calcd for
C14H15NO2Na [M þ Na]þ = 252.1000, found 252.0993.
Supporting Information Available. Experimental proce-
dures and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
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