Iron-catalyzed aminolysis of β-carbonyl 1,3-dithianes: Synthesis of stereodefined β-enaminones and 3,4-disubstituted pyrazoles

Article abstract of DOI:10.1021/ol200246x

A novel iron-catalyzed aminolysis of β-carbonyl 1,3-dithianes with various amines including ammonia, primary and secondary amines, as well as hydrazine hydrate has been developed, leading to the synthesis of stereodefined β-enaminones and 3,4-disubstitute

Full text of DOI:10.1021/ol200246x

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1722–1725
Iron-Catalyzed Aminolysis of β-Carbonyl
1,3-Dithianes: Synthesis of Stereodefined
β-Enaminones and 3,4-Disubstituted
Pyrazoles
Yeming Wang,† Xihe Bi,*,†,‡ Wei-Qi Li,§ Dehua Li,† Qian Zhang,† Qun Liu,† and
Brim Stevy Ondon†
Department of Chemistry, Northeast Normal University, Changchun 130024, China,
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China, and Physical Department, Harbin Institute of Technology,
Harbin 150001, China
bixh507@nenu.edu.cn
Received January 26, 2011
ABSTRACT
A novel iron-catalyzed aminolysis of β-carbonyl 1,3-dithianes with various amines including ammonia, primary and secondary amines, as well as
hydrazine hydrate has been developed, leading to the synthesis of stereodefined β-enaminones and 3,4-disubstituted pyrazoles in good to high
yields.
As a masked 1,3-dicarbonyl system, β-carbonyl 1,3-
dithianes are easily prepared through the conjugate addi-
tion of dithiols to ynones, ynoates, and ynals1 or by the
reduction of R-oxo ketene-(S,S)-acetals using metal reduc-
tion systems such as Zn/HOAc, and Mg/Methanol.2
Although β-carbonyl 1,3-dithianes are readily available,
exploration of their synthetic utility isstill rare. Ley and co-
workers have done excellent pioneering work in this
direction.3 They developed an elegant methodology
converting β-carbonyl 1,3-dithiane units to functionalized
oxygen-containing heterocycles, useful in the synthesis of
natural products such as lyngbouilloside, callipeltoside
A,3b and fragments of the spongistatins.3c,d Recently, we
reported a copper-promoted aminolysis of β-carbonyl 1,3-
dithianes with amines, providing a new access to β-
enaminones,4 a class of important compounds known as
versatile synthetic building blocks and therapeutic
pharmacophores.5,6 However, this methodology was
hampered by some striking shortcomings which in-
cluded the use of substoichiometric cupric salts and poor
† Northeast Normal University.
‡ Nankai University.
§ Harbin Institute of Technology.
(4) Kang, J.; Liang, F.; Sun, S.-G.; Liu, Q.; Bi, X. Org. Lett. 2006, 8,
2547.
(1) (a) Sneddon, H. F.; van den Heuvel, A.; Hirsch, A. K. H.; Booth,
R. A.; Shaw, D. M.; Gaunt, M. J.; Ley, S. V. J. Org. Chem. 2006, 71,
2715. (b) Xu, C.; Bartley, J. K.; Enache, D. I.; Knight, D. W.; Lunn, M.;
Lok, M.; Hutchings, G. J. Tetrahedron Lett. 2008, 49, 2454.
(2) (a) Choi, E. B.; Youn, I. K.; Pak, C. S. Synthesis 1988, 792. (b)
Mellor, J. M.; Schofield, R.; Korn, S. R. Tetrahedron 1997, 53, 1711.
(3) (a) Gaunt, M. J.; Sneddon, H. F.; Hewitt, P. R.; Orsini, P.; Hook,
D. F.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 15. (b) Sneddon, H. F.;
Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5, 1147. (c) Gaunt, M. J.; Hook,
D. F.; Tanner, H. R.; Ley, S. V. Org. Lett. 2003, 5, 4815. (d) Gaunt, M. J.;
Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook, D. F.; Ley, S. V. Org.
Lett. 2003, 5, 4819. (e) For a review, see: Ley, S. V. Tetrahedron 2010, 66,
6270.
(5) For reviews on β-enaminones, see: (a) Stanovnik, B.; Svete, J.
Chem. Rev. 2004, 104, 2433. (b) Elassara, A.-Z. A.; El-Khair, A. A.
Tetrahedron 2003, 59, 8463. (c) Greenhill, J. V. Chem. Soc. Rev. 1977, 6,
277. (d) Eddingtona, N. D.; Coxa, D. S.; Robertsb, R. R.; Stablesc, J. P.;
Powelld, C. B.; Scotte, K. R. Curr. Med. Chem. 2000, 7, 417.
(6) Recent examples on the synthetic utility of β-enaminones, see: (a)
Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed.
2009, 48, 8078. (b) Wan, J.-P.; Pan, Y.-J. Chem. Commun. 2009, 2768. (c)
Ilangovan, A.; Kumar, R. G. Chem.;Eur. J. 2010, 16, 2938. (d) Saito,
A.; Konishi, T.; Hanzawa, Y. Org. Lett. 2010, 12, 372. (e) Chen, Y.; Ju,
T.; Wang, J.; Yu, W.; Du, Y.; Zhao, K. Synlett 2010, 231. (f) Lu, J.; Cai,
X.; Hecht, S. M. Org. Lett. 2010, 12, 5189.
r
10.1021/ol200246x
Published on Web 03/08/2011
2011 American Chemical Society

stereoselectivity of produced β-enaminones. To address
these issues and achieve a catalytic process, after many
attempts we found that the nontoxic and cheaper iron salts
could efficiently catalyze the aminolysis of β-carbonyl 1,3-
dithianes. Herein we wish to report the research details.
Initially, the survey on reaction parameters including
iron catalysts, temperature, and solvents was performed
using the reaction of β-carbonyl 1,3-dithiane 1a with
ammonia as a model reaction. This choice was based on
the consideration that although β-enaminones bearing an
unprotectedamino group assyntheticbuildingblocks were
much more attractive, only a few synthetic methods are
available,9 necessitating a search for a simple and practical
protocol for their synthesis. Some key results of the con-
dition screening are summarized in Table 1. The reaction
of 1a with ammonia smoothly proceeded at room tem-
perature in DMF, affording the desired product 2a in 90%
yield;oncethereaction temperaturewasincreasedto 60°C,
the reaction time was dramatically reduced to 0.6 h, yet in a
similarly high yield (entries 1 and 2). Other tested iron salts
such as FeBr3 and Fe(ClO4)3 all efficiently catalyzed this
transformation and gave 2a in good yields (entries 3 and 4).
In comparison, the solvent types significantly influenced
target yields. For example, the weakly polar, aprotic
solvents such as THF and DCE gave poor yields of 2a
(33 and 25%, respectively) even within an extended reac-
tion time, and most substrate 1a was recovered (entries 5
and 6). EtOH as solvent resulted in a complete conversion
but with a moderate yield of 2a (entry7). Consequently, the
conditions in entry 2 were the best, and they were chosen
for furtherinvestigation. Noticeably, the formation of2ain
the above experiments was completely stereoselective, and
only the (Z)-isomer was detected by 1H NMR analysis of
crude product mixture.
Table 1. Optimization of Iron Salt-Catalyzed Aminolysis of
β-Carbonyl 1,3-Dithiane 1a with Ammoniaa
entry
Fe source
solvent temp (°C) time (h) yieldb (%)
1
2
3
4
5
6
7
FeCl3
FeCl3
FeBr3
DMF
DMF
DMF
25
60
60
60
60
60
60
9
90
91
90
81
33
25
67
0.6
1
Fe(ClO4)3 DMF
1.5
5
FeCl3
FeCl3
FeCl3
THF
DCE
EtOH
5
5
a Reactions were performed with β-carbonyl 1,3-dithiane 1a (1.0
mmol), ammonia (5.0 mmol), and [Fe] (10 mol %) in solvent (1 mL).
b Isolated yields.
In the past few years, the study of the iron-catalyzed
reactions has received great attention,7 because compared
with precious metal catalysts such as Pt, Rh, Ru, Pd, Au,
and Ag, etc., iron is cheaper, nontoxic, and above all
abundant on earth. In our continued efforts to exploit iron
salts as catalyst in organic reactions, we previously have
realized iron-catalyzed intramolecular aromatic C-H al-
kenylation of arenes with nonactivated ketones and the
synthesis of polysubstituted pyrroles via [4Cþ1N] cycliza-
tion of 4-acetylenic ketones with primary amines.8 We thus
became interested in investigating iron-catalyzed amino-
lysis of β-carbonyl 1,3-dithianes. In this paper, we dis-
closed that the iron salts acted as efficient catalyst for the
aminolysis of β-carbonyl 1,3-dithianes, featuring in a wide
variety of applicable substrates and excellent stereoselec-
tivity. When using hydrazine hydrate instead of amines,
the pharmaceutically relevant 3,4-disubstituted pyrazoles
were prepared in high yields.
Scheme 1. Synthesis of β-Enaminones 2 with an Unprotected
Amino Groupa-c
(7) For reviews on iron-catalyzed reactions, see: (a) Iron Catalysis in
Organic Chemistry: Reactions and Applications; Plietker, B., Ed.; Wiley-
VCH: Weinheim, 2008. (b) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2010,
111, 1293. (c) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
104, 6217.
(8) (a) Wang, Y.; Li, W.-Q.; Che, G.; Bi, X.; Liao, P.; Zhang, Q.; Liu,
Q. Chem. Commun. 2010, 46, 6843. (b) Wang, Y.; Bi, X.; Li, D.; Liao, P.;
Wang, Y.; Yang, J.; Zhang, Q.; Liu, Q. Chem. Commun. 2011, 47, 809.
(9) For example, see: (a) Seko, S.; Tani, N. Tetrahedron Lett. 1998,
39, 8117. (b) Luo, B. H.; Guan, H. P.; Hu, C. M. Synlett 1997, 1261. (c)
Haight, A. R.; Stuk, T. L.; Menzia, J. A.; Robbins, T. A. Tetrahedron
Lett. 1997, 38, 4191. (d) Lue, P.; Greenhill, J. V. Adv. Heterocycl. Chem.
1997, 67, 215. (e) Dominguez, E.; Ibeas, E.; de Maigorta, E. M.; Palacios,
J. K.; SanMartin, R. J. Org. Chem. 1996, 61, 5435. (f) Hegde, S. G.;
Jones, C. R. J. Heterocycl. Chem. 1993, 30, 1501. (g) Elnagdi, M. H.;
Fahmy, S. M.; Hafez, E. A.; Elmoghayer, M. R. H.; Amer, S. A. R.
J. Heterocycl. Chem. 1979, 16, 1109.
a Reactions were performed with β-carbonyl 1,3-dithianes (1.0 mmol),
ammonia (5.0 mmol), and FeCl3 (10 mol %) in DMF (2 mL) at 60 °C.
b Isolated yields.
c The isomer ratio of 2 was determined by 1H NMR analysis of the
crude product mixture, and the configuration was assigned by NOE
experiment.
With the optimal conditions in hand (Table 1, entry 2),
we sought to study the reaction scope for substrate applic-
ability. As summarized in Scheme 1, β-enaminones 2 with
an unprotected amino group were prepared in short
reaction times (0.5-2.0 h) and with good to high yields (75
Org. Lett., Vol. 13, No. 7, 2011
1723

- 93%). In addition to the formation of acyclic, symmetric
β-enaminones2band 2c, the cyclic β-enaminones 2dand 2e
were also prepared in good yields. For the β-enaminones
2f-i produced from unsymmetric substrates, the stereo-
chemistry was worthy noting. Except for 2h with an E/Z
ratio of 1/1, the formation of β-enaminones 2f and 2g was
completely (Z)-selective (E/Z = 0/100); as opposed to
enaminone 2i with the (E)-configuration being the major
product (E/Z = 6/1). These results demonstrated that the
iron-catalyzed aminolysis of β-carbonyl 1,3-dithiane with
ammonia represented an efficient and stereoselective ap-
proach to β-enaminones bearing a free amino group.
with an electron-donating or electron-withdrawing group
smoothly proceeded and gave β-enaminones 3j-l in good
yields. In addition to primary amines, the secondary amines
such as dimethylamine and piperidine also proved to be
suitable partners (3m and 3n). Further, variations on the R1
and R2 groups on substrate 1were tested, and to our dismay,
no observable influence on the reaction efficiency was
observed (3o-r). It seems the double carbonyl groups are
essential for the aminolysis reaction because no reaction
took place using the substrate (R1 = Ph, R2 = H) to react
with benzylamine. Analysis of the stereochemistry of pro-
ducts 3a-p showed that in most cases the (E)-isomer was
dominant (the ratio of E/Z up to 25), except for 3n.
Scheme 2. Synthesis of N-Protected β-Enaminones 3a-c
Scheme 3. Synthesis of 3,4-Disubstituted Pyrazoles 4a,b
a Reactions were performed with β-carbonyl 1,3-dithianes (1.0 mmol),
hydrazine hydrate (2.5 mmol), and FeCl3 (10 mol %) in DMF (1 mL) at
60 °C.
b Isolated yields.
The wide scope of substrates and excellent stereoselec-
tivity authenticated this iron-catalyzed aminolysis of β-
carbonyl 1,3-dithianes to be a general and stereoselective
approach to β-enaminones. Noticeably, β-enaminones 2
and 3 structurally contained double carbonyl at R-position
and one hydrogen at β-position; such β-enaminones have
been found to modulate R7 nAChRs and the effect of γ-
aminobutyric acid (GABA) on the GABA receptor
complex.10 We therefore developed a straightforward ap-
proach to this kind of β-enaminones.
a Reactions were performed with β-carbonyl 1,3-dithianes (1.0 mmol),
amines (2.0 mmol), and FeCl3 (10 mol %) in DMF (1 mL) at 60 °C.
b Isolated yields.
c The isomer ratio of 3 was determined by 1H NMR analysis of the
crude product mixture, and the configuration was assigned by NOE
experiment.
(10) (a) Hogenkamp, D. J.; Johnstone, T. B. C.; Gee, K. W. U.S. Pat.
Appl. Publ. 2008/0064748 A1, 2008. (b) Hogenkamp, D. J.; Johnstone,
T. B. C.; Gee, K. W. U.S. Pat. Appl. Publ. 2006/0293329 A1, 2006.
(11) Seltzman, H. H. Drug Dev. Res. 2009, 70, 601.
Next, the iron-catalyzed reaction between β-carbonyl 1,3-
dithianes and primary/secondary amines was carried out
aiming to prepare N-protected β-enaminones. As shown in
Scheme 2, a range of aliphatic primary amines, even includ-
ing the sterically hindered tert-butylamine, could be used
and afforded the corresponding β-enaminones 3a-i in
moderate to high yields. Noticeably, a variety of functional
groups were tolerant in this process, including alkyl, aryl,
hydroxyl, ester, acetal, alkenyl, and alkynyl groups. Also,
the aminolysis reaction involving aromatic primary amines
(12) (a) Lin, R.; Chiu, G.; Yu, Y.; Connolly, P. J.; Li, S.; Lu, Y.;
Adams, M.; Fuentes-Pesquera, A. R.; Emanuel, S. L.; Greenberger,
L. M. Bioorg. Med. Chem. Lett. 2007, 17, 4557. (b) Franchini, M. C.;
Bonini, B. F.; Camaggi, C. M.; Gentili, D.; Pession, A.; Rani, M.;
Strocchi, E. Eur. J. Med. Chem. 2010, 45, 2024. (c) Dzhuraev, A. D.;
Makhsumov, A. G.; Zakirov, U. B.; Nikbaev, A. T. Pharm. Chem. J.
1987, 21, 718. (d) Berdini,V.; O’Brien, M. A.; Carr, M. G.; Early, T. R.;
Gill, A. L.; Trewartha, G.; Woolford, A. J.-A.; Woodhead, A. J.; Wyatt,
P. G. U.S. Pat. Appl. Publ. 2008/0200509 A1, 2008. (e) Berdini,V.;
O'Brien, M. A.; Carr, M. G.; Early, T. R.; Gill, A. L.; Trewartha, G.; Woolford,
A. J.-A.; Woodhead, A. J.; Wyatt, P. G. U.S. Pat. Appl. Publ. 7825140 B2,
2010. (f) Gill, A. L.; Carr, M. G.; O'Brien, M. A.; Wyatt, P. G.; Berdini, V.
U.S. Pat. Appl. Publ. 2008/0004270 A1, 2008.
1724
Org. Lett., Vol. 13, No. 7, 2011

Further, synthetic access to the pyrazoles was achieved
by using hydrazine hydrate instead of amines in the iron-
catalyzed aminolysis of β-carbonyl 1,3-dithianes. Pyra-
zoles serve as important core structures in many pharma-
ceuticals and pharmaceutical leads with a wide range of
biological activities,11in particular, the 3,4-disubstituted
pyrazoles known as anticancer and anti-inflammatory
agents.12 As shown in Scheme 3, the 3,4-disubstituted
pyrazoles 4a-e were made in excellent yields (81-91%).
This provided a new route to the medicinally important
pyrazole derivatives.13
possible catalytic route as depicted in Scheme 4.14 The
Fe(III) first coordinated to the carbonyl and sulfur atoms
in 1,3-dithioacetal moiety, forming the intermediate (i).
Subsequently, one C-S bond cleaved to gave intermediate
(ii) either through β-elimination reaction using the amine
as a base to extract the R-hydrogen or via a Fe(III)-
catalyzed retro-thio-Michael addition without the aid of
amine asa base. Finally, the amine displaced the remaining
alkylthio group via an 1,4-addition-elimination approach
to furnish β-enaminones 2 and 3, accompanying the gen-
eration of Fe(III) catalyst, during which time the steros-
electivity of products was influenced by the type of amines
as well as the R2 substituent.
In conclusion, a novel iron-catalyzed aminolysis of β-
carbonyl 1,3-dithianes with various amines has been
developed, leading to the synthesis of stereodefined β-
enaminones and 3,4-disubstituted pyrazoles. This cata-
lytic procedure is striking in terms of the wide range of
applicable substrates, mild reaction conditions, and
excellent stereoselectivity. Further studies in combina-
tion with theoretical calculation to elucidate the reason
for the stereoselectivity and application of this metho-
dology to synthesize other interesting heterocycles are
underway.
Scheme 4. Plausible Catalytic Mechanism
Acknowledgment. This work was supported by NSFC
(20902010), the State Key Laboratory of Bio-organic and
Natural Products Chemistry, Key Laboratory of Natural
ResourcesofChangbaiMountain& FunctionalMolecules
(Yanbian University), Jilin Provincial Natural Science
Foundation (20101537), and Science Foundation for Young
Teachers of Northeast Normal University (09QNJJ013).
Many thanks for the reviewer’s suggestion on the reaction
mechanism.
Although the mechanistic details of this transformation
are not clear at the moment, we tentatively proposed a
(13) For reviews on pyrazoles synthesis, see: (a) Science of Synthesis;
Stanovnik, B., Svete, J. D., Eds.; Thieme: Stuttgart, 2002; Vol. 12, pp 22-81,
84-91. (b) Elguero, J. In Comprenhensive Heterocyclic Chemistry II;
Shinkai, I., Ed.; Elsevier, Oxford, 1996; Vol. 3, pp 3-75. Recent examples,
see: (c) Okitsu, T.; Sato, K.; Wada, A. Org. Lett. 2010, 12, 3506. (d)
Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131,
3042.
(14) For a recent report on Lewis acid-catalyzed the cleavage of C-S
bond of dithioacetals, see: Tobisu, M.; Ito, S.; Kitajima, A.; Chatani, N.
Org. Lett. 2008, 10, 5223.
Supporting Information Available. Experimental pro-
1
cedures; H/13C NMR and NOE spectroscopic data for
compounds 2-4. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
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