Ruthenium catalyzed synthesis of enaminones

Article abstract of DOI:10.1021/ol202812d

The Grubbs first-generation catalyst has been found to be an effective catalyst for the synthesis of enaminones by coupling thioamides with α-diazodicarbonyl compounds. The reaction is successful in converting primary, secondary, and tertiary thioamides into their corresponding enaminones. The reaction is also suitable for the synthesis of chiral enaminones.

Full text of DOI:10.1021/ol202812d

ORGANIC
LETTERS
2012
Vol. 14, No. 2
440–443
Ruthenium Catalyzed Synthesis of
Enaminones
Naga Durgarao Koduri, Halee Scott, Bethany Hileman, Justin D. Cox, Michael Coffin,
Lindsay Glicksberg, and Syed R. Hussaini*
Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall,
800 South Tucker Drive, Tulsa, Oklahoma 74101, United States
syed-hussaini@utulsa.edu
Received October 19, 2011
ABSTRACT
The Grubbs first-generation catalyst has been found to be an effective catalyst for the synthesis of enaminones by coupling thioamides with
R-diazodicarbonyl compounds. The reaction is successful in converting primary, secondary, and tertiary thioamides into their corresponding
enaminones. The reaction is also suitable for the synthesis of chiral enaminones.
Enaminones have long been used as synthetic intermedi-
ates in organic synthesis. One reason for their widespread
application istheirversatile reactivity, asboth electrophiles
and nucleophiles. Due to their value, a number of methods
have been developed for the preparation of enaminones.1
The Eschenmoser coupling reaction provides the un-
ambiguous formation of a particular enaminone. The re-
action couples an R-halocarbonyl compound with a sec-
ondary or tertiary thioamide (Scheme 1). It is tolerant of
various functional groups and base-sensitive stereocenters.
As such, it has been widely used in the synthesis of natural
products2 and other bioactive compounds.3
However, the Eschenmoser reaction has limitations. Pri-
mary thioamides are not acceptable substrates because of
their ready conversion to nitriles;3 the reactions often require
a long duration of time;2c,4 and the coupling of secondary
thioamides and R-monocarbonyl compounds is not typical.
It fails to undergo sulfide contraction under mildly basic
conditions and provides thioethers without the aid of addi-
tives. The reaction between piperidinethione and electron-
donating monoesters does not provide enaminoesters, and
instead thiazolidones are obtained.2e,f,5 Therefore, there is a
need todevelop a method that can solve these issues. Inthis
paper, we would like to report our efforts which have been
successful in overcoming some of the above-mentioned
restrictions.
(1) (a) Elassar, A. -Z. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463.
(b) Negri, G.; Kascheres, C.; Kascheres, A. J. J. Heterocycl. Chem. 2004,
41, 461. (c) Elliott, M. C.; Wood, J. L.; Wordingham, S. V. Trends
Heterocycl. Chem. 2005, 10, 73. (d) Ferraz, H. M. C.; Goncalo, E. R. S.
Quim. Nova 2007, 30, 957.
(2) (a) Shiosaki, K. Comprehensive Organic Synthesis; Trost, B. M.,
Flemming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 2, Chapter
3.7, pp 865À892. (b) Smith, D. C.; Fuchs, P. L. J. Org. Chem. 1995, 60,
2692. (c) Campbell, J. A.; Rapoport, H. J. Org. Chem. 1996, 61, 6313. (d)
Butters, M.; Davies, C. D.; Elliott, M. C.; -Cousins, J. H.; Kariuki,
B. M.; Ooi, L. -L.; Wood, J. L.; Wordingham, S. V. Org. Biomol. Chem.
2009, 7, 5001. (e) Neto, B. A. D.; Lapis, A. A. M.; Bernd, A. B.;
Russowsky, D. Tetrahedron 2009, 65, 2484. (f) Pettersson, B.; Hasimbe-
govic, V.; Bergman, J. J. Org. Chem. 2011, 76, 1554.
The reactions and the applications of R-diazocarbonyl
compounds in the presence of transition metals are a rapidly
growing area in organic synthesis.6 Still, the use of such
(4) (a) Bachi, M. D.; Breiman, R.; Meshulam, H. J. Org. Chem. 1983,
48, 1439. (b) Hussaini, S. R.; Moloney, M. G. Org. Biomol. Chem. 2006,
4, 2600.
(5) Hussaini, S. R.; Hammond, G. B. ARKIVOC 2008, xiii, 129.
(6) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577.
(3) (a) Edafiogho, I. O.; Kombian, S. B.; Ananthalakshmi, K. V. V;
Salama, N. N.; Eddington, N. D.; Wilson, T. L.; Alexander, M. S.;
Jackson, P. L.; Hanson, C. D.; Scott, K. R. J. Pharm. Sci. 2007, 96, 2509.
(b) Chandan, N.; Moloney, M. G. Org. Biomol. Chem. 2008, 6, 3664.
r
10.1021/ol202812d
Published on Web 12/29/2011
2011 American Chemical Society

Table 1. Optimization of Ru Catalyzed Eschenmoser Type
Condensationa
Scheme 1. Eschenmoser Coupling Reaction of R-Halocarbonyl
Compounds
metal carbenes, instead of halo compounds, is less known in
the Eschenmoser type condensation. Copper7 and rhodium
metals have been tried in this transformation, and rhodium
has been successful in producing the enaminoesters in the
intramolecular reaction of tert-thioamides.8 The ruthenium
catalyzed condensation of R-diazocarbonyl compounds
with thioamides has not previously been reported. Here,
we describe the first successful use of ruthenium as the cat-
alyst for the transformation of thioamides into enaminones.
In an olefin metathesis reaction, Grubbs catalysts gen-
erate ruthenium carbenoids.9 Since diazo compounds are
generally more reactive than alkenes, we hypothesized that
the formation of dicarbonyl ruthenacarbenes may also be
possible by the reaction of R-diazodicarbonyl compounds
with the Grubbs catalysts.10 These dicarbonyl carbenoids
are expected to be very electrophilic and highly reactive.11
As such, like the rhodium carbenoids,8 these ruthenium
carbenoids should also be able to carry out the Eschenmo-
ser type condensation reaction with thioamides.
2
catalyst
(mol %)
yield
(%)
entry
(equiv)
catalyst
solvent
DCE
1
2
3
4
5
6
7
8
1.3
1.3
2.5
1.3
1.3
1.3
1.3
1.3
À
4
5
5
4
5
5
4
À
10b
3b
c
1.3
2.0
1.0
1.0
2
CH2Cl2
toluene
benzene
benzene
THFc
73d
74d
73d
63d
71d
77d
1.7
1.3
DCE
benzene
a Reaction conditions: Heated for 26 h in a sealed tube immersed in a
120 °C oil bath. b Percentage conversion relative to 1 as determined by
the 1H NMR. c Refluxed for 26 h in a sealed tube. d Isolated yield.
lowered to 1.3 without substantially compromising the
yield (entries 4, 5 vs 8).
To test the hypothesis, the condensation of thiolactam 1
and ethyl diazomalonate 2a was carried out. This condensa-
tion was chosen because enaminoester 3 is one of the best
yielding compounds in the Eschenmoser coupling reaction.4b
Table 1 shows the results. The background reaction had a
low yield (entry 1). Both the Grubbs first-generation 4 and
HoveydaÀGrubbs second-generation 5 catalysts were suc-
cessful in enacting the transformation, and using benzene
as a solvent provided the best yield (entries 2À8). Also, it
was discovered that the amount of catalyst could be
lowered to 1.0 mol % and the equivalents of 2a can be
It was found that reproducible yields could be obtained
when the reaction was performed in a pressure vessel that
was heated in a 120 °C oil bath. Catalyst 5 was expected to
be more stable at higher temperatures and12 is also re-
ported to be more suited for the generation of carbenoids
with electron-withdrawing groups.13 However, we did not
observe much difference in the reactivity of 4 and 5 in this
reaction (entries 4, 5). As 4 is more economical than 5, we
selected 4 for all of the subsequent transformations. The
reaction generally required less time (26 h) than the re-
ported uncatalyzed version (48 h).4b
In order to showcase the scope of this transformation,
thioamides 6 were prepared (Table 2). Except for phenyl-
(piperidine-1-yl)methanethione 6e, all thiocarbonyl deriv-
atives were synthesized in good yields (70À100%) by
treating the respective amides with Lawesson’s reagent at
room temperature using CH2Cl2 as a solvent.14 In addi-
tion to good yields, these conditions allow easy purifica-
tion of the thiocarbonyl derivatives and only a single
(7) Bartels, G.; Hinze, R. -P.; Wullbrandt, D. Liebigs Ann. Chem.
1980, 168.
(8) (a) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263. (b)
Padwa, A.; Kinder, F. R.; Zhi, L. Synlett 1991, 287. (c) Padwa, A.;
Kinder, F. R.; Nadler, W. R.; Zhi, L. Heterocycles 1993, 35, 367. (d)
Kim, G.; -Moyer, M. Y. C.; Danishefsky, S. J.; Schulte, G. K. J. Am.
Chem. Soc. 1993, 115, 30.
(9) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(10) Hodgson, D. M.; Angrish, D. Chem.;Eur. J. 2007, 13, 3470.
(11) (a) Demonceau, A.; Noels, A. F.; Saive, E.; Hubert, A. J. J. Mol.
Catal. 1992, 76, 123. (b) France, M. B.; Paciello, R. A.; Grubbs, R. H.
Macromolecules 1993, 26, 4739. (c) Ulman, M.; Belderrain, T. R.;
Grubbs, R. H. Tetrahedron Lett. 2000, 41, 4689. (d) Davies, H. M. L.;
Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
(12) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(13) (a) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Chem.
Commun. 2001, 430. (b) Randl, S.; Cannon, S. J.; Blechert, S. Chem.
Commun. 2001, 1796.
(14) Hussaini, S. R.; Moloney, M. G. Tetrahedron Lett. 2004, 45,
1125.
Org. Lett., Vol. 14, No. 2, 2012
441

The coupling of 2 with thioamides 6 was then examined.
The reaction was successful for primary (entry 1), secondary
(entries 3, 5, 6, and 8À13), and tertiary thioamides (entries 7
and 14) and provided low (entry 7) to high yields (entry 3) of
the enaminones. However, it was necessary to use 5 mol %
of the catalyst 4 to obtain consistently higher yields for
all of the substrates (entry 3 vs 11). Both acyclically
(entries 1 and 14) and cyclically (entries 3 and 5À13)
positioned thiocarbonyl groups can be converted into enamin-
ones. Steric hindrance was detrimental to this condensation
(entries 7 and 15), as an incomplete conversion (entry 7) or no
conversion (entry 15) of thioamides into enaminones was
observed with increasing steric hindrance. Thioamide 6e,
substituted with a group capableof resonance contribution,
was able to perform the transformation despite the steric
hindrance (entry 14). This is probably due to the increased
nucleophilicity of the S atom in 6e due to the resonance
contribution of the phenyl ring. The same effect can also
better stabilize the reaction intermediate 14 vide infra.
Table 2 also shows that R-diazodiketones (entries 10 and
12), R-diazodiesters(entries 1, 3, 5À7, 9, 11, 13, and 14) and
R-diazodicarbonylmonoesters (entry 8) are all viable cou-
pling partners. In the case of unsymmetrically substituted
diazo compounds, only the more stable E diastereomer
was obtained (entry 8). The stereochemistry of the com-
pound was determined by the 1H NMR.17 It was necessary
to change the amount of diazo compounds (entries 8, 10,
and 12) and the reaction times (entry 9) in certain cases to
obtain reasonable yields. Still, 2-diazo-3-oxo-3-phenylpro-
panoate 2b was not a suitable coupling partner under the
reaction conditions and complete decomposition of the
starting materials was observed (entries 2 and 4). These
trends are probably due to the differences in the reactivity
and the stability of the diazo compounds. In addition,
dimerization of carbenoids may also be responsible for
the depletion of the diazo compounds.11d However, no such
dimerized products could be isolated in the above reactions.
Scheme 2 shows a proposed mechanism for this trans-
formation. WespeculatethatR-diazocarbonylcompounds
attack 4, generating the 14 electron Ru(II) complex 12,
liberating N2 and the enone. The additional attack of
R-diazocarbonyl on 12 provides ruthenacarbene 13.10 Many
ruthenacarbenes, including 4, have been prepared by such
a reaction of diazo compounds on 12.18 The nucleophilic
attack of thioamide on 13 provides a metal complex-
associated thiocarbonyl ylide 14 and a free ylide 15.6 Ylide
14 dissociates to regenerate 12 while 15 cyclizes to produce
an episulfide 16. Finally, expulsion of sulfur from 16 gives
the observed eneaminones.2a,8 The proposed species 12 is a
Ru(II) complex. As such, other more economical Ru(II)
sources may also be able to catalyze this reaction. Indeed,
Table 2. Scope of the Ruthenium Catalyzed Synthesis of
Enaminonesa
a Reaction conditions: 2 (1.3 equiv), 4 (5 mol %), benzene, heated for
26 h in a sealed tube immersed in a 120 °C oil bath. b 1.3 equiv of 4 was
used. c 2 equiv of 2 were used. d Heated for 36 h. e An equivalent of 2 was
added at the beginning, after 8 and 16 h. The reaction was heated for 24 h
in total.
(15) Buswell, M.; Fleming, I. ARKIVOC 2002, vii, 46.
(16) Kapanda, C. N.; Muccioli, G. G.; Labar, G.; Draoui, N.;
Lambert, D. M.; Poupaert, J. H. Med. Chem. Res. 2009, 18, 243.
ꢀ ꢀ
(17) (a) Brunerie, P; Celerier, J.-P.; Petit, H.; Lhommet, G.
J. Heterocycl. Chem. 1986, 23, 1183. (b) Fernandes, M. A.; Michael,
J. P.; Perry, C. B. Acta Crystallogr., Sect. E: Struct. Rep. Online 2007,
E63, o2380.
(18) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
chromatographic step was necessary for the isolation
of pure thioamides.14,15 Compound 6e was obtained
by the WillgerodtÀKindler reaction with 97% yield.16
442
Org. Lett., Vol. 14, No. 2, 2012

some Ru(II) complexes have been used in the generation of
ruthenium carbenoids that are similar to 12.11b,19 We are
currently investigating the feasibility of such commercially
available Ru(II) complexes, and the results of the study will
be disclosed in due course.
Scheme 3. Thioimine Formation with Monoester Carbenea
Scheme 2. Proposed Mechanism for the Ru-Catalyzed Synthesis
of Enaminones
a Reaction conditions: 17 (1.3 equiv), 4 (5 mol %), benzene, heated for
26 h in a sealed tube immersed in a 120 °C oil bath. 1 was recovered in
27% yield. Diethyl fumarate was also detected in semipure form.
In summary, we have shown that catalysts 4and 5can cat-
alyze the condensation of thioamides and R-diazocarbonyl
compounds. Primary, secondary, and tertiary thioamides
can be converted into enaminones. Chiral and achiral, and
cyclic and acyclic thioamides can undergo this reaction.
Also, both catalysts 4 and 5 are more economical than
Rh2(OAc)4 which has been previously used for this type of
coupling reaction.8,21 Therefore, this report is expected to
broaden the scope of such condensation reactions. In addi-
tion, the carbenoid 13 and the ylide 15 proposed in the
mechanism (Scheme 2) have great potential in the fields of
olefin metathesis10,11b,11c,13b,19b,19d,22 and in the chemistry of
sulfur ylides respectively.8a,23 Presently, efforts are under-
way to show such applications.
Acknowledgment. Financial support was provided by
the University of Tulsa new faculty Lab-startup funds.
H.S. and B.H., The University of Tulsa, would like to thank
both the CSURP and TURC scholarship funds from the
Univeristy of Tulsa. S.R.H., The University of Tulsa, is
grateful for the ACS Organic Division’s sponsored travel
award. We thank K. P. Roberts and J. Holland, The Uni-
versity of Tulsa, for their help with the spectrometric mea-
surements. This material is based upon work supported
by the National Science Foundation Chemistry Research
Instrumentation and Facilities program under Grant
No. CHE-1048784.
Some evidence for the proposed mechanism comes from
the fact that the reaction of ethyl diazoacetate 17 with 1 pro-
duces the iminothioether 18 (Scheme 3). The reaction does
not go through the episulfide contraction step (15 f 16)
(Scheme 2) possibly because, in the case of the monoester, the
anion on 15 is less stabilized as the pKa of monoesters com-
pared to diesters is higher.20,4b As such, proton transfer from
the nitrogen atom of 14 or 15 takes place and 18 is obtained.
In the case of R-diazocarbonyl compounds (Tables 1 and 2)
no such thioether was isolated. Further work is underway to
better understand the mechanism of this reaction.
Supporting Information Available. General experimen-
tal procedures and spectroscopic data for all the isolated
compounds (except 1 and 2b). This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Current Aldrich prices: 4, 1G $108; 5, 500 mg $233; Rh2(OAc)4,
250 mg $333.5.
(19) (a) Demonceau, A.; Lemoine, C. A.; Noels, A. F. Tetrahedron
Lett. 1995, 36, 8419. (b) Baratta, W.; Zotto, A. D.; Rigo, P. Organome-
tallics 1999, 18, 5091. (c) Baratta, W.; Zotto, A. D.; Rigo, P. Chem.
Commun. 1997, 2163. (d) Zotto, A. D.; Baratta, W.; Verardo, G.; Rigo,
P. Eur. J. Org. Chem. 2000, 2795.
(20) Bahaji, E. H.; Bastide, P.; Bastide, J.; Rubat, C.; Tronche, P.
Eur. J. Med. Chem. 1988, 23, 193.
(22) (a) Lee, H. M.; Bianchini, C.; Jia, G.; Barbaro, P. Organome-
tallics 1999, 18, 1961. (b) Hansen, J. H.; Parr, B. T.; Pelphrey, P.; Jin, Q.;
Autschbach, J.; Davies, H. M. L. Angew. Chem., Int. Ed. 2011, 50, 2544.
(23) (a) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072. (b) Lakeev, S. N.;
Maydanova, I. O.; Galin, F. Z.; Tolstikov, G. A. Russ. Chem. Rev. 2001,
70, 655.
Org. Lett., Vol. 14, No. 2, 2012
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