Synthesis of 5-hydroxy-Δ1-pyrrolines from aryl isoalkyl ketoximes and acetylene in a tuned superbase medium

Article abstract of DOI:10.1016/j.tetlet.2016.06.025

The reaction between aryl isoalkyl ketoximes and acetylene under atmospheric pressure was applied to the synthesis of 5-hydroxy-Δ¹-pyrrolines, containing aromatic substituents at the carbon–nitrogen double bond, in moderate yields. A crucial fa

Full text of DOI:10.1016/j.tetlet.2016.06.025

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 5-hydroxy-D
1-pyrrolines from aryl isoalkyl ketoximes
and acetylene in a tuned superbase medium
⇑
Dmitrii A. Shabalin, Marina Yu. Dvorko, Elena Yu. Schmidt, Nadezhda I. Protsuk, Boris A. Trofimov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St., Irkutsk 664033, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction between aryl isoalkyl ketoximes and acetylene under atmospheric pressure was applied to
the synthesis of 5-hydroxy-
1-pyrrolines, containing aromatic substituents at the carbon–nitrogen dou-
ble bond, in moderate yields. A crucial factor for the synthesis is the accurate tuning of the system basic-
ity to prevent further dehydration of the target compounds to 3H-pyrroles.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 30 April 2016
Revised 24 May 2016
Accepted 6 June 2016
Available online xxxx
D
Keywords:
Hydroxypyrroline
3,4-Dihydro-2H-pyrrol-2-ol
Ketoxime
Acetylene
Superbase
Introduction
It is common knowledge that ketoximes having methyl and
methylene substituents at the
a-position to the oxime functional
D
1-Pyrrolines are of interest due to their abundance in natural
products1 and living organisms.2 Furthermore, a number of unnat-
group react with acetylene in a KOH/DMSO system to give 1H-pyr-
roles (Trofimov’s reaction16) via dehydration of the intermediate 5-
hydroxypyrrolines, which can occur without acetylene. However,
when using ketoximes with only one C–H bond adjacent to the
oxime functional group, further vinylation of the hydroxy group
with acetylene in pyrrolines E (Scheme 1) has been proven to be
an imperative step in the assembly of the 3H-pyrrole core.17
It is assumed that 5-hydroxypyrolines could be chemoselec-
tively obtained (i.e., undesirable dehydration could be hindered)
provided that the basicity of the MOH (M = Na, K)/DMSO superbase
systems could be tuned to suppress their vinylation without signif-
icant hindrance of the preceding reaction steps.
ural
D
1-pyrrolines have been used as synthons for new drugs3 and
intermediates in the synthesis of biologically active compounds,4
light-driven switches,5 and boranil fluorophores.6
Despite the advances in methods to synthesize the
D
1-pyrroline
scaffold (e.g., by intramolecular cyclizations of bifunctional com-
pounds and multi-component cyclizations,7 1,3-dipolar cycloaddi-
tions,8 photo- and thermo-induced9,10 reactions), the synthesis of
hydroxy-substituted pyrrolines, particularly 5-hydroxy-D
1-pyrro-
lines (3,4-dihydro-2H-pyrrol-2-ols) with aromatic substituents, is
much less developed. To date, only three preparative methods for
their synthesis have been reported. The first based on the reaction
between 1,4-diketones and liquid ammonia was put into practice
by Sammes and co-workers11 and was shown to be reliable in
recent work.12 Two other methods have been published recently,
though they give access exclusively to condensed 5-hydroxypyrro-
lines13 or 5-hydroxypyrroline-3,3-dicarbonitriles.14 Other relevant
examples are also known.15 Among these is the reaction of iso-
propyl phenyl ketoxime with acetylene in the presence of NaOH
in DMSO to afford 3,3-dimethyl-2-phenyl-5-hydroxypyrroline in
26% yield.15e
Although only one representative of the hydroxypyrroline
series, namely 3,3-dimethyl-2-phenyl-5-hydroxypyrroline, as an
intermediate in the synthesis of 3H-pyrrole has been occasionally
reported,15e,17,18 the feasibility of
a
general synthesis of
5-hydroxypyrrolines from aryl(hetaryl) isoalkyl ketoximes and
acetylene remained obscure. Our previous investigations
provided a deeper insight17 into the mechanism of 3H-pyrrole syn-
thesis and allowed us to propose that these intermediates could be
isolated as major products provided that the subsequent vinylation
of the hydroxy group could be suppressed. Indeed, as shown
herein, this goal is achievable by tuning the catalytic system so that
the catalyst becomes inactive during the vinylation stage.
Due to the straightforward preparation of aromatic or
heteroaromatic ketoximes with isoalkyl groups via acylation, this
⇑
Corresponding author. Tel.: +7 395 242 1411; fax: +7 395 241 9346.
E-mail address: boris_trofimov@irioch.irk.ru (B.A. Trofimov).
http://dx.doi.org/10.1016/j.tetlet.2016.06.025
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shabalin, D. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.025

2
D. A. Shabalin et al. / Tetrahedron Letters xxx (2016) xxx–xxx
R2
R2
O
R2
O
Me
Me
Me
N
R2 R3
HC CH
MOH/DMSO
Me
Ph
Me
Ph
Ph
Me
R1
R1
R1
HN
R1
Ph
1a
R3
R3
N
R3
1,3-H
[3,3]
HC CH
Me
OH
OH
O
N
N
N
N
HN
O
Me
OH
D
A
B
C
4a
1a
2a
R3
R3
R3
Scheme 2. Reaction of ketoxime 1a with 5-hydroxypyrroline 2a during the work-
up process.
R2
R1
R2
R1
R2
R1
HC CH
OH
O
-
N
N
OH
N
E
F
It should be noted that in the crude reaction mixture, along
with expected products 5-hydroxypyroline 2a and 3H-pyrrole 3a,
by-products such as 5-hydroxypyrroline ester 4a and 4,4-
dimethyl-5-phenyl-1-vinyl-2-pyrrolidinone were also observed
(earlier described18b). The former results from the reaction of the
starting ketoxime 1a with 5-hydroxypyrroline 2a (Scheme 2),
and is probably formed during the work-up procedure since
ether 4a was not detected by 1H NMR of the reaction mixture.
To demonstrate the generality of this methodology aryl(hetaryl)
isoalkyl ketoximes 1a–g were tested in the reaction with acetylene
under optimum conditions (0.5 mol KOHÁ0.5H2O, 1 mol ketoxime,
2 wt % of water to DMSO, 90 °C, 4 h, Table 2).
Scheme 1. 3H-Pyrrole synthesis from aryl(hetaryl) isoalkyl ketoximes and
acetylene.
methodology has the potential to become the first general route to
5-hydroxypyrrolines with aromatic and heteroaromatic sub-
stituents at the carbon–nitrogen double bond.
Results and discussion
As can be seen from Table 2, the one-pot synthesis of 5-hydrox-
ypyrrolines was effective for various aryl (1a–f) substituted ketox-
imes providing the corresponding products in moderate yields. The
reaction of 2-furylisopropyl ketoxime 1g with acetylene proved to
be more sensitive to base and hence this reaction needed to be fur-
ther optimized. Under the standard conditions (0.5 equiv of
KOHÁ0.5H2O), mainly O-vinyl ketoxime 5g was formed in 12% yield
(Scheme 3), whereas at a higher base content (1.0 equiv of
KOHÁ0.5H2O), the crude reaction mixture represented an equimo-
lar mixture of 5-hydroxypyrroline 2g, starting ketoxime 1g and
3H-pyrrole 3g, from which the desired product 2g was not easily
isolated.
The synthesized compounds represent a potential useful family
of building blocks, which owing to their hydroxy functional group
may be widely employed for the design of diverse conjugated
arene-pyrroline ensembles. This would require systematic investi-
gation of the hydroxy functional group reactivity, which was not
examined. Although it was reported17 that 3,3-dimethyl-2-phe-
nyl-5-hydroxypyrroline reacted with acetylene to give 3H-pyrrole,
this transformation was mainly related to the mechanism of 3H-
pyrrole formation. Another example is the formation of 2-phe-
nyl-3,3-dimethylpyrroline18a and 4,4-dimethyl-5-phenyl-1-vinyl-
To prove this assumption, the reaction between isopropyl phe-
nyl ketoxime 1a and acetylene under atmospheric pressure was
investigated as a model. The following variables were tested: type
of superbase system, ketoxime: base molar ratio, water content,
temperature, and time (Table 1).
Initial screening of the reaction conditions was carried out using
the following parameters: 0.5 mol KOHÁ0.5H2O, dry DMSO, 90 °C,
4 h. Under these conditions, mainly 3H-pyrrole 3a was observed
(entry 2). Decreasing the molar equivalents of base led to almost
full prevention of ketoxime 1a vinylation (entry 1). Subsequently
increasing the water content in the reaction mixture completely
suppressed 3H-pyrrole 3a formation at acceptable conversions of
ketoxime 1a to the desired 5-hydroxypyrroline 2a (entries 3 and
4). Longer reaction times or higher reaction temperatures facili-
tated both vinylation of ketoxime 1a and dehydration of 5-hydrox-
ypyrroline 2a (via vinylation of 2a, entries 5 and 7, respectively).
The amount of 5-hydroxypyrroline 2a in the crude reaction mixture
was increased by changing the nature of the base (NaOH instead of
KOH, entry 9) but due to the significant quantity of 3H-pyrrole 3a
which complicates the isolation of 2a, the isolated yield of the for-
mer was lower compared to that in entry 4. The same was observed
when 1 wt % of water to DMSO was used (entry 3).
Table 1
Screening of reaction conditions for the selective synthesis of 5-hydroxypyrroline 2a
Me
Me
Me
Me
Me
N
HC CH
MOH/DMSO
Me
Ph
Me
Ph
Me
Ph
Ph
Me
Ph
N
+
+
OH
O
N
N
N
OH
Me
1a
2a
3a
4a
Entry
MOH, mol per 1 mol of ketoxime 1a
Water content (wt % to DMSO)
Temperature (°C)
Time (h)
Ratio of 1a:2a:3a:4aa
1
2
3
4
5
6
7
8
9
10
KOHÁ0.5H2O, 0.25
KOHÁ0.5H2O, 0.5
KOHÁ0.5H2O, 0.5
KOHÁ0.5H2O, 0.5
KOHÁ0.5H2O, 0.5
KOHÁ0.5H2O, 0.5
KOHÁ0.5H2O, 0.5
NaOH, 1.0
0
0
1
2
2
2
2
0
2
3
90
90
90
90
90
80
100
90
90
90
4
4
4
4
6
4
4
4
4
4
92:2:0:6
12:12:58:7b
15:52 (23)c:29:4
39:51 (44):0:10
9:45 (11):32:10b
65:22:0:13
16:30:40:6b
21:31:40:6b
NaOH, 1.0
NaOH, 1.0
25:58 (32):12:5
55:29:5:11
a
b
c
According to 1H NMR data of the crude product.
4,4-Dimethyl-5-phenyl-1-vinyl-2-pyrrolidinone was detected.
In brackets isolated yield of 5-hydroxypyrroline 2a.
Please cite this article in press as: Shabalin, D. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.025

D. A. Shabalin et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 2
One-pot synthesis of 5-hydroxypyrrolines 2a–g from ketoximes 1a–g and acetylenea
Conclusions
D
1-pyrrolines,
R2
R3
In conclusion, we have shown that 5-hydroxy-
KOH (0.5 equiv)
2 wt% H2O, DMSO
R2
R1
R1
R3
bearing aromatic substituents at the carbon–nitrogen double bond,
can be synthesized in moderate yields by the straightforward reac-
tion of the corresponding aryl isoalkyl ketoximes and acetylene in
the presence of an appropriately tuned superbase KOH/DMSO sys-
tem. Further investigations of the reaction scope and application of
the compounds obtained as a pyrroline synthon are under way in
our laboratory.
HC CH
+
OH
N
90 °C, 4 h
N
OH
1a-g
2a-g
Entry Ketoxime 1
5-Hydroxypyrroline 2
Isolated yield
(%)
Me
Me
Me
Me
Acknowledgements
1
2
44
35
OH
N
N
The spectral data were obtained using the instrument park of
Baikal Analytical Center.
OH
2a
1a
Supplementary data
N
OH
N
OH
N
Supplementary data (synthetic procedure, characterization
data, 1H and 13C NMR spectra of new products) associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2016.06.025.
1b
2b
Me
Me
Me
Me
Me
Me
OH
OH
3
4
31
29
N
Me
OH
2c
References and notes
1c
1. (a) Tsukamoto, D.; Shibano, M.; Okamoto, R.; Kusanot, G. Chem. Pharm. Bull.
2001, 49, 492–496; (b) Kleinsasser, N. H.; Wallner, B. C.; Harréus, U. A.;
Zwickenpflug, W.; Richter, E. Toxicology 2003, 192, 171–177; (c) Adams, A.; De
Kimpe, N. Chem. Rev. 2006, 106, 2299–2319.
N
N
Me
2. (a) Kadish, K. M.; Smith, K. M.; Guilard, R. In The Porphyrin Handbook; Academic
OH
Press: San Diego, 2003; Vol. Vols. 11–20,; (b) Jones,
T H.; Zottig, V. E.;
2d
1d
Robertson, H. G.; Snelling, R. R. J. Chem. Ecol. 2003, 29, 2721–2727; (c) Clark, V.
C.; Raxworthy, C. J.; Rakotomalala, V.; Sierwald, P.; Fisher, B. L. Proc. Natl. Acad.
Sci. U.S.A. 2005, 102, 11617–11622.
Me
Me
Me
Me
Me
Me
3. Dannhardt, G.; Kiefer, W. Arch. Pharm. Pharm. Med. Chem. 2001, 334, 183–188.
4. (a) Snider, B. B.; Neubert, B. J. Org. Lett. 2005, 7, 2715–2718; (b) Lygo, B.; Kirton,
E. H. M.; Lumley, C. Org. Biomol. Chem. 2008, 6, 3085–3090; (c) Davis, F. A.;
Theddu, N.; Edupuganti, R. Org. Lett. 2010, 12, 4118–4121.
5. Sampedro, D.; Migani, A.; Pepi, A.; Busi, E.; Basosi, R.; Latterini, L.; Elisei, F.; Fusi,
S.; Ponticelli, F.; Zanirato, V.; Olivucci, M. J. Am. Chem. Soc. 2004, 126, 9349–
9359.
OH
N
5
31
Me
2e
Me
Me
N
OH
1e
6. Cardona, F.; Rocha, J.; Silva, A. M. S.; Guieu, S. Dyes Pigments 2014, 111, 16–20.
7. (a) Shvekhgeimer, M.-G. A. Chem. Heterocycl. Compds. 2003, 39, 405–448; (b)
Singh, P. N. D.; Klima, R. F.; Muthukrishnan, S.; Murthy, R. S.;
Sankaranarayanan, J.; Stahlecker, H. M.; Patel, B.; Gudmundsdóttir, A. D.
Tetrahedron Lett. 2005, 46, 4213–4217; (c) Asghari, S.; Qandalee, M. Synth.
Commun. 2010, 40, 2172–2177; (d) Elamparuthi, E.; Sarathkumar, S.; Girija, S.;
Anbazhagan, V. Tetrahedron Lett. 2014, 55, 3992–3995.
8. (a) Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. Rev. 2004, 104, 2353–
2399; (b) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126, 12776–12777;
(c) Pandit, P.; Chatterjee, N.; Maiti, D. K. Chem. Commun. 2011, 1285–1287; (d)
Cui, B.; Ren, J.; Wang, Z. J. Org. Chem. 2014, 79, 790–796.
Me
OH
6
7
38
N
Me
N
Me
OH
2f
1f
Me
Me
Me
Me
O
O
See text
OH
N
N
OH
9. Soldevilla, A.; Sampedro, D.; Campos, P. J.; Rodríguez, M. A. J. Org. Chem. 2005,
70, 6976–6979.
2g
1g
10. Campos, P. J.; Soldevilla, A.; Sampedro, D.; Rodríguez, M. A. Tetrahedron Lett.
2002, 43, 8811–8813.
11. (a) Chiu, P.-K.; Lui, K.-H.; Maini, P. N.; Sammes, M. P. J. Chem. Soc., Chem.
Commun. 1987, 109–110; (b) Chiu, P.-K.; Sammes, M. P. Tetrahedron 1988, 44,
3531–3538; (c) Lui, K.-H.; Sammes, M. P. J. Chem. Soc., Perkin Trans. 1 1990,
457–468.
a
Conditions: ketoxime 1 (12.50 mmol), KOHÁ0.5H2O (0.406 g, 6.25 mmol), DMSO
(50 mL), water (1.1 mL), acetylene under atmospheric pressure, 90 °C, 4 h.
12. (a) Pflantz, R.; Tielmann, P.; Rössle, M.; Hoenke, C.; Christoffers, J. Eur. J. Org.
Chem. 2007, 3227–3238; (b) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2011, 13,
1622–1625.
13. Rostovskii, N. V.; Sakharov, P. A.; Novikov, M. S.; Khlebnikov, A. F.; Starova, G. L.
Org. Lett. 2015, 17, 4148–4151.
Me
Me
Me
Me
KOH (0.5 equiv)
2 wt% H2O, DMSO
O
O
HC CH
+
N
N
90 °C, 4 h
OH
O
14. Alizadeh, A.; Moafi, L. Helv. Chim. Acta 2016, 99, 306–309.
15. (a) Saiki, H.; Mukai, T. Chem. Lett. 1981, 10, 1561–1564; (b) Andersen, S. H.;
Sharma, K. K.; Torssell, K. B. G. Tetrahedron 1983, 39, 2241–2245; (c) Schmitt,
G.; Nasser, B.; An, N. D.; Laude, B.; Roche, M. Can. J. Chem. 1990, 68, 863–868;
(d) Shimizu, H.; Hamada, K.; Ozawa, M.; Kataoka, T.; Hori, M.; Kobayashi, K.;
Tada, Y. Tetrahedron Lett. 1991, 32, 4359–4362; (e) Korostova, S. E.;
Shevchenko, S. G.; Sigalov, M. V. Chem. Heterocycl. Compd. 1991, 27, 1101–
1104; (f) Zimmer, R.; Hoffmann, M.; Reissig, H.-U. Chem. Ber. 1992, 125, 2243–
2248; (g) Depature, M.; Grimaldi, J.; Hatem, J. Eur. J. Org. Chem. 2001, 941–946;
(h) Murphy, J. A.; Mahesh, M.; McPheators, G.; Anand, R. V.; McGuire, T. M.;
Carling, R.; Kennedy, A. R. Org. Lett. 2007, 9, 3233–3236; (i) Cai, X.-C.; Snider, B.
B. J. Org. Chem. 2013, 78, 12161–12175.
1g
5g (12%)
Scheme 3. Reaction of 2-furylisopropyl ketoxime 1g with acetylene under standard
conditions.
2-pyrrolidinone18b which was proposed to originate from the
intermediate 3,3-dimethyl-2-phenyl-5-hydroxypyrroline without
robust evidence.
Please cite this article in press as: Shabalin, D. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.025

4
D. A. Shabalin et al. / Tetrahedron Letters xxx (2016) xxx–xxx
16. (a) Trofimov, B. A.; Mikhaleva, A. I.; Schmidt, E. Yu.; Sobenina, L. N. Adv.
Heterocycl. Chem. 2010, 99, 209–254; (b) Li, J. J. Name Reactions in Heterocyclic
Chemistry II; J. Wiley & Sons: Hoboken, NJ, 2011; (c) Trofimov, B. A.; Mikhaleva,
A. I.; Schmidt, E. Yu.; Sobenina, L. N. Chemistry of Pyrroles; CRC Press: Florida,
2014.
N. M.; Mikhaleva, A. I.; Trofimov, B. A. Tetrahedron 2015, 71, 3273–
3281.
18. (a) Korostova, S. E.; Shevchenko, S. G.; Shcherbakov, V. V. Zh. Org. Khim. 1993,
29. 1639-1639; (b) Shabalin, D. A.; Glotova, T. E.; Schmidt, E. Yu.; Ushakov, I. A.;
Mikhaleva, A. I.; Trofimov, B. A. Mendeleev Commun. 2014, 24, 100–101.
17. Shabalin, D. A.; Dvorko, M. Yu.; Schmidt, E. Yu.; Ushakov, I. A.; Protsuk,
N. I.; Kobychev, V. B.; Soshnikov, D. Yu.; Trofimov, A. B.; Vitkovskaya,
Please cite this article in press as: Shabalin, D. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.025