Atom- and step-economical preparation of reduced knoevenagel adducts using CO as a deoxygenative agent

Article abstract of DOI:10.1021/ol502424t

A highly efficient one-step Rh-catalyzed preparation of reduced Knoevenagel adducts of various aldehydes and ketones with active methylene compounds has been developed. The protocol does not require an external hydrogen source and employs carbon monoxide

Full text of DOI:10.1021/ol502424t

Letter
pubs.acs.org/OrgLett
Atom- and Step-Economical Preparation of Reduced Knoevenagel
Adducts Using CO as a Deoxygenative Agent
Pavel N. Kolesnikov, Dmitry L. Usanov,† Evgeniya A. Barablina, Victor I. Maleev, and Denis Chusov*
A.N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, 119991, Vavilova St. 28, Moscow,
Russian Federation
S
* Supporting Information
ABSTRACT: A highly efficient one-step Rh-catalyzed prep-
aration of reduced Knoevenagel adducts of various aldehydes
and ketones with active methylene compounds has been
developed. The protocol does not require an external
hydrogen source and employs carbon monoxide as a
deoxygenative agent. The use of malonic acid or cyanoaceta-
mide enabled efficient formal deoxygenative addition of methyl
acetate or acetonitrile to aldehydes. The developed method-
ology was applied to the synthesis of the precursors of
biomedically important compounds.
n light of growing environmental concerns, the concepts of
atom,1 step,2 and redox3 economies, introduced by Trost,
protocol equivalent of the Knoevenagel condensation/reduc-
tion sequence.15
We recently reported a novel method of Rh-catalyzed
reductive amination, which does not require an external
hydrogen source: instead, carbon monoxide can be efficiently
employed as the deoxygenative agent (Scheme 1).16 Since
I
Wender, and Baran respectively, are becoming increasingly
influential on the design of novel chemical methodologies.4 The
atom economical approach seeks to maximize the incorporation
of the reagents into the final product with concomitant
minimization of side product formation. Whereas development
of atom economical chemical methods has received consid-
erable attention,5,6 atom economical redox processes remain
understudied.7 Quite a few indispensable laboratory synthetic
procedures, e.g. reduction with complex hydride agents, can
hardly be used on the industrial scale due to the formation of
substantial amounts of chemical waste. Certain redox trans-
formations, e.g. hydrogenation of double bonds, seem to be
almost perfectly atom economical at first glance. However,
most hydrogen is industrially produced via steam reforming of
natural gas;8 the conventional technology involves a sequence
of three high-temperature catalytic processes (conducted at
190−800 °C) followed by separation of the resulting gaseous
products.9 In order to accurately assess the economical and
environmental profile of a given process, one should therefore
consider the entire synthetic sequence starting from the natural
sources.10 Undoubtedly, development of novel atom-econom-
ical redox processes while keeping in mind a greater picture of
environmental impact therefore represents an important goal
for contemporary chemical methodology.
Scheme 1. Use of Carbon Monoxide As a Deoxygenative
Agent for the Formation of C−N and C−C Bonds
carbon monoxide is formed in multiton quantities as a side
product of steel production,17 implementation thereof as a
reagent in potentially scalable processes of high synthetic value
is in compliance with the commitment to recycling and waste
management optimization. In fact, purified carbon monoxide is
employed in industrial processes of great importance (e.g., 75%
of the worldwide production of acetic acid comes from the
reaction of CO with methanol).18 The use of CO in chemical
synthesis is also becoming increasingly popular in the academic
community.19 Inspired by our success with the deoxygenative
Knoevenagel condensation is one of the essential C−C bond
forming reactions which is widely employed as a useful
synthetic tool for the construction of α,β-unsaturated carbonyl
compounds.11 Notably, some reported synthetic strategies
involve α,β-reduction immediately following the condensa-
tion,12 which includes a number of industrially important
processes, such as preparation of top-selling drugs pregabalin13
and pioglitazone.14 In this context, from the standpoint of step
economy, it would be highly desirable to design a one-step
Received: August 15, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502424t | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formation of a C−N bond, we decided to attempt
implementation of CO as a reductant in deoxygenative C−C
bond formation. Thus, herein we report the development of an
atom-economical rhodium-catalyzed deoxygenative coupling of
active methylene compounds with aldehydes and ketones,
which results in efficient preparation of reduced Knoevenagel
adducts.
We began our studies with the model reaction between ethyl
cyanoacetate and para-methoxybenzaldehyde (Table 1).
Table 1. Catalyst and Solvent Optimization for the
Preparation of Reduced Knoevenagel Adducts
a
entry
catalyst
Pd(OAc)2
solvent
THF
yield (%)
b
1
trace
trace
trace
trace
trace
trace
trace
19
b
2
PdCl2
THF
b
3
Pd(dppf)Cl2
CpRu(PPh3)Cl2
[Pt(NH3)4Cl2](NO3)2
[(cod)IrCl]2
CpRh(CO)I2
[(cod)RhCl]2
[Rh(CO)2Cl]2
Rh2(OAc)4
THF
b
4
THF
b
5
THF
6
THF
b
7
THF
8
THF
9
THF
21
10
11
12
13
14
15
16
17
18
19
THF
36
Rh2(OAc)4
dioxane
Et2O
4
Rh2(OAc)4
12
Rh2(OAc)4
toluene
MeCN
CH2Cl2
solvent free
water
35
Rh2(OAc)4
48
Rh2(OAc)4
13
Rh2(OAc)4
19
Rh2(OAc)4
13
Rh2(OAc)4
ethanol
methanol
50
c
Rh2(OAc)4
64
Figure 1. Investigation of the substrate scope for the Rh-catalyzed
a
b
Yields were determined by NMR with internal standard. 2 mol % of
preparation of reduced Knoevenagel adducts with CO as a
c
a
the catalyst was used. Predominantly the product of transesterification
(methyl ester).
deoxygenative agent. 0.4−1 mmol scale; 1:1 ratio of reactants, 1
mol % Rh2(OAc)4, methanol, 50 bar of CO, 110−140 °C, 22−44 h.
Yields were determined by NMR with an internal standard. Isolated
b
c
yields are shown in parentheses. Ethanol was used as a solvent.
d
Initially, a number of platinum group metal complexes were
screened, among which rhodium(II) acetate showed the most
promising catalytic activity (Table 1, entries 1−10); other
rhodium complexes demonstrated inferior performance. We
then tested a variety of reaction media (including solvent-free
conditions; Table 1, entries 11−19); conducting the reaction in
methanol furnished the product in 64% yield (predominantly
transesterified). With these results in hand, we decided to test
the optimized conditions (catalysis by rhodium(II) acetate in
alcohols) for a representative range of substrates (Figure 1).
Good-to-excellent yields were observed for both electron-
rich and -deficient aromatic aldehydes with various substitution
patterns (1a−1n). The benzyloxy moiety was shown to be
stable under reaction conditions; product 1n was isolated in
60% yield. Aliphatic aldehydes efficiently furnished products
1o−1r without any substantial competition from aldol
condensation. The methodology could be successfully
expanded to ketones, as exemplified by preparation of the
cyclopentanone and cyclohexanone derivatives 1s and 1t
respectively.
Isopropanol was used as a solvent. 20 mmol scale: 99% NMR yield,
e
94% isolated yield. Malonic acid was used as the active methylene
component. f 1 equiv of water was added. Cyanoacetamide was used as
the active methylene component.
Thus, methyl ester 1u could be prepared in 51% yield from 1-
naphthaldehyde by the use of malonic acid in methanol.
Alternatively, formal deoxygenative addition of acetonitrile to
aldehydes was successfully accomplished when cyanoacetamide
was employed as the active methylene component in the
presence of water: nitriles 1v and 1w were isolated in 50% and
64% yield, respectively.
Based on our previous mechanistic studies on reductive
amination,16 a plausible mechanism for this catalytic process
can be speculated (Scheme 2). The catalytic cycle might involve
oxidative insertion of the rhodium carbonyl species into the C−
OH bond of the intermediate alcohol followed by intra-
molecular hydroxylation of the CO ligand; a rhodium hydride
species formed after decarboxylation would then undergo
reductive elimination to yield the reduced Knoevenagel adduct
and reform the active catalytic species. Further investigation of
Altering the active methylene counterpart enabled one-step
preparation of other types of synthetically useful products.
B
dx.doi.org/10.1021/ol502424t | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrogen source and employs carbon monoxide as a
deoxygenative agent, which renders our methodology more
atom economical in comparison to the existing synthetic
alternatives. A wide range of aromatic and aliphatic aldehydes as
well as ketones furnish the corresponding adducts with
cyanoacetic esters in high yield; the use of malonic acid or
cyanoacetamide as the active methylene counterpart enables
efficient formal deoxygenative addition of methyl acetate and
acetonitrile to aldehydes. The synthetic utility of the developed
methodology was exemplified by the synthesis of precursors of
biomedically important compounds, such as peptidic human
renin inhibitors and pregabalin.
Scheme 2. Putative Mechanistic Scheme for the Developed
Catalytic Process
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and full spectroscopic data
for all new compounds are included. This material is available
free of charge via the Internet at http://pubs.acs.org.
the mechanistic details is currently underway in our group and
is expected to be reported in due course.
We exemplified the practical significance of the developed
methodology by implementation thereof into the synthesis of
pharmaceutically important compounds. Pregabalin 2 is one of
the leading anticonvulsant and neuropathic pain relieving drugs
with 2013 sales exceeding $4.5 billion (Pfizer Inc.).20 The
manufacturing process involves synthetic intermediate 1p
prepared via a Knoevenagel condensation/catalytic hydro-
genation sequence;21 in contrast, our protocol allowed a single-
step multigram preparation of compound 1p in 94% yield after
distillation (Scheme 3). The catalyst remained active after at
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Chusov@ineos.ac.ru; Denis.chusov@gmail.com.
Present Address
†Harvard University, Department of Chemistry and Chemical
Biology, 12 Oxford Street, Cambridge, MA 02138 (USA).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Dedicated to Professor Yuri N. Belokon (Nesmeyanov
Institute, Moscow) on the occasion of his 76th birthday.
■
Scheme 3. Application of the Developed Methodology to the
Synthesis of Precursors of Biomedically Important
Compounds
REFERENCES
(1) Trost, B. M. Science 1991, 254, 1471−1477.
(2) (a) Wender, P. A.; Croatt, M. P.; Witulski, B. Tetrahedron 2006,
62, 7505−7511. (b) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow,
T. H. Acc. Chem. Res. 2008, 41, 40−49. (c) Wender, P. A. Tetrahedron
2013, 69, 7529−7550.
■
(3) (a) Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.;
Llamas, T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
17938−17954. (b) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew.
Chem., Int. Ed. 2009, 48, 2854−2867.
(4) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev.
2009, 38, 3010−3021.
(5) For reviews see: (a) Trost, B. M. Angew. Chem., Int. Ed. Engl.
1995, 34, 259−281. (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695−
705.
(6) For selected reviews on specific atom-economical trans-
formations, see: (a) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T.
Angew. Chem., Int. Ed. 2005, 44, 6630−6666. (b) Iida, H.; Krische, M.
J. Top. Curr. Chem. 2007, 279, 77−104. (c) Fustero, S.; San
́
chez-
Rosello, M.; del Pozo, C. Pure Appl. Chem. 2010, 82, 669−677.
́
(d) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600−1632.
(e) Kumagai, N. Chem. Pharm. Bull. 2011, 59, 1−22. (f) Hilt, G. Eur. J.
Org. Chem. 2012, 4441−4451. (g) Marson, C. M. Chem. Soc. Rev.
2012, 41, 7712−7722. (h) Kotha, S.; Goyal, D.; Chavan, A. S. J. Org.
Chem. 2013, 78, 12288−12313. (i) Sebren, L. J.; Devery, J. J.;
Stephenson, C. R. J. ACS Catal. 2013, 4, 703−716. (j) Peng, B.;
Maulide, N. Chem.Eur. J. 2013, 19, 13274−13287. (k) Xie, J.; Jin,
H.; Xu, P.; Zhu, C. Tetrahedron Lett. 2014, 55, 36−48.
least three reaction cycles carried out in the same autoclave
without intermediate isolation of the product; each cycle led to
full conversion. Likewise, the developed protocol could be
successfully applied to the synthesis of a precursor of human
renin inhibitory peptides22 (Scheme 3 and Figure 1).
In summary, we have developed a highly efficient method-
ology for one-step preparation of reduced Knoevenagel adducts
from a variety of aldehydes/ketones and active methylene
compounds. The reaction does not require an external
(7) For some successful developments of atom-economical redox
processes, see: (a) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873−
3876. (b) Lofberg, C.; Grigg, R.; Whittaker, M. A.; Keep, A.; Derrick,
̈
A. J. Org. Chem. 2006, 71, 8023−8027. (c) Zeitler, K. Org. Lett. 2006,
C
dx.doi.org/10.1021/ol502424t | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
8, 637−640. (d) Haak, E. Eur. J. Org. Chem. 2008, 5, 788−792.
(e) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008, 130,
11970−11978. (f) Trost, B. M.; Maulide, N.; Livingston, R. C. J. Am.
Chem. Soc. 2008, 130, 16502−16503. (g) Zeitler, K.; Rose, C. A. J. Org.
Chem. 2009, 74, 1759−1762. (h) Trost, B. M.; Gutierrez, A. C.;
Livingston, R. C. Org. Lett. 2009, 11, 2539−2542. (i) Goto, A.; Naka,
H.; Noyori, R.; Saito, S. Chem.Asian. J. 2011, 6, 1740−1743.
(j) Lumbroso, A.; Koschker, P.; Vautravers, N. R.; Breit, B. J. Am.
Chem. Soc. 2011, 133, 2386−2389. (k) Trost, B. M.; Breder, A.;
O’Keefe, B. M.; Rao, M.; Franz, A. W. J. Am. Chem. Soc. 2011, 133,
4766−4769. (l) Trost, B. M.; Breder, A. Org. Lett. 2011, 13, 398−401.
(m) Trost, B. M.; Lumb, J.-P.; Azzarelli, J. M. J. Am. Chem. Soc. 2011,
133, 740−743. (n) Jonek, A.; Berger, S.; Haak, E. Chem.Eur. J. 2012,
18, 15504−15511. (o) Li, Y.; Zhang, X.-S.; Chen, K.; He, K.-H.; Pan,
F.; Li, B.-J.; Shi, Z.-J. Org. Lett. 2012, 14, 636−639. (p) Lumbroso, A.;
Abermil, N.; Breit, B. Chem. Sci. 2012, 3, 789−793. (q) Nguyen, T. B.;
Ermolenko, L.; Al-Mourabit, A. J. Am. Chem. Soc. 2012, 135, 118−121.
(r) Thies, N.; Hrib, C. G.; Haak, E. Chem.Eur. J. 2012, 18, 6302−
6308. (s) Trost, B. M.; Breder, A.; Kai, B. Org. Lett. 2012, 14, 1708−
1711. (t) Kang, B.; Fu, Z.; Hong, S. H. J. Am. Chem. Soc. 2013, 135,
11704−11707. (u) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Org.
Lett. 2013, 15, 4218−4221. (v) Nguyen, T. B.; Retailleau, P.; Al-
Mourabit, A. Org. Lett. 2013, 15, 5238−5241. (w) Thies, N.; Gerlach,
M.; Haak, E. Eur. J. Org. Chem. 2013, 32, 7354−7365. (x) Muralirajan,
K.; Cheng, C.-H. Adv. Synth. Catal. 2014, 356, 1571−1576. (y) Nakai,
K.; Yoshida, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2014,
136, 7797−7800. (z) Roudier, M.; Constantieux, T.; Quintard, A.;
Rodriguez, J. Org. Lett. 2014, 16, 2802−2805. (aa) Talbot, E. P. A.;
Richardson, M.; McKenna, J. M.; Toste, F. D. Adv. Synth. Catal. 2014,
356, 687−691. (ab) Peng, B.; Huang, X.; Xie, L.-G.; Maulide, N.
Angew. Chem., Int. Ed. 2014, 53, 8718−8721.
10589−10594. (g) Schranck, J.; Wu, X.-F; Tlili, A.; Neumann, H.;
Beller, M. Chem.Eur. J. 2013, 19, 12959−12964. For the use of CO
as a component of syngas, see: (h) Pospech, J.; Fleischer, I.; Franke,
R.; Buchholz, S.; Beller, M. Angew. Chem., Int. Ed. 2013, 52, 2852−
2872.
(20) Pfizer Inc.; 2013 Financial Report.
(21) (a) Roy, B. N.; Singh, G. P.; Lathi, P.; Agrawal, M.; Mitra, R.;
Rupnawar, M. D. Process for Synthesis of (S)−Pregabalin.
WO2012059797, 2012. (b) Burell, A. J. M; Martinez, C. A.;
McDaid, P. O.; O’Neill, P. M.; Wong, J. W. Process for the
Preparation of (S)-3-Cyano-5-Methylhexanoic Acid Derivatives Adn of
Pregabalin, WO2012025861, 2012.
(22) Harada, H.; Iizuka, K.; Kamijo, T.; Akahane, K.; Yamamoto, R.;
Nakano, Y.; Tsubaki, A.; Kubota, T.; Shimaoka, I.; Umeyama, H.; Kiso,
Y. Chem. Pharm. Bull. 1990, 38, 3042−3047.
(8) Yurum, Y. Hydrogen Energy System; Kluwer Academic Publishers:
̈
̈
Dordrecht, Netherlands, 1994; p 16.
(9) Romm, J. J. The Hype about Hydrogen; Island Press: Washington,
DC, 2004; p 72.
(10) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437−1451.
(11) (a) Tietze, L. F.; Beifuss, U. In Comprehensive Organic Synthesis,
Vol. 2; Trost, B. M., Fleming, I., Eds.; Pergamon Press, Oxford, 1991;
p 341. (b) Ebitani K. In Comprehensive Organic Synthesis II, Vol. 2;
Knochel, P., Molander, G. A., Eds.; Amsterdam, 2014; p 571.
(12) For selected examples see: (a) Couladouros, E. A.; Pitsinos, E.
N.; Moutsos, V. I.; Sarakinos, G. Chem.Eur. J. 2005, 11, 406−421.
(b) Coleman, R. S.; Campbell, E. L.; Carper, D. J. Org. Lett. 2009, 11,
2133−2136. (c) Hong, S.; Lee, M.; Jung, M.; Park, Y.; Kim, M.-H.;
Park, H.-G. Tetrahedron Lett. 2012, 53, 4209−4211.
(13) Debarge, S.; McDaid, P.; O’Neill, P.; Frahill, J.; Wong, J. W.;
Carr, D.; Burell, A.; Davies, S.; Karmilowicz, M.; Steflik, J. Org. Process
Res. Dev. 2014, 18, 109−121.
(14) Madivada, L. R.; Anumala, R. R.; Gilla, G.; Alla, S.; Charagondla,
K.; Kagga, M.; Bhattacharya, A.; Bandichhor, R. Org. Process Res. Dev.
2009, 13, 1190−1194.
(15) For a mild method involving Hantzsch ester as a reductant, see:
Ramachary, D. B.; Kishor, M.; Reddy, Y. V. Eur. J. Org. Chem. 2008,
975−993. (b) Ramachary, D. B.; Venkaiah, C.; Reddy, Y. V. Org.
Biomol. Chem. 2014, 12, 5400−5406. (c) Ramachary, D. B.; Kishor, M.
Org. Biomol. Chem. 2010, 8, 2859−2867.
(16) Chusov, D.; List, B. Angew. Chem., Int. Ed. 2014, 53, 5199−
5201.
(17) Bhardwaj, B. P. Steel and Iron Handbook; NPCS: Delhi, 2014.
(18) Cheung, H.; Tanke, R. S.; Torrence, G. P. Acetic Acid, Ullmann’s
Encyclopedia of Industrial Chemistry; Wiley-VCH: 2005.
(19) (a) Ragaini, F.; Cenini, S.; Gallo, E.; Caselli, A.; Fantauzzi, S.
Curr. Org. Chem. 2006, 10, 1479−1510. (b) Wu, X.-F.; Neumann, H.;
Beller, M. Angew. Chem., Int. Ed. 2010, 49, 5284−5288. (c) Klein, H.;
Jackstell, R.; Netscher, T.; Bonrath, W.; Beller, M. ChemCatChem
2011, 3, 1273−1276. (d) Fang, X.; Jackstell, R.; Beller, M. Angew.
Chem., Int. Ed. 2013, 52, 14089−14093. (e) Wu, X.-F; Neumann, H.;
Beller, M. ChemSusChem 2013, 6, 229−241. (f) Fleischer, I.; Wu, L.;
Profir, I.; Jackstell, R.; Franke, R.; Beller, M. Chem.Eur. J. 2013, 19,
D
dx.doi.org/10.1021/ol502424t | Org. Lett. XXXX, XXX, XXX−XXX