KOBut/DMSO-Mediated α-C-H Vinylation of N-Benzyl Ketimines with Acetylene Gas: Stereoselective Synthesis of (E, Z)-2-Azadienes

Article abstract of DOI:10.1021/acs.orglett.0c00564

Several imines, readily derived from aryl methyl ketones and benzylamines, react with acetylene gas in KOBu^t/DMSO system to afford 2-azadienes stereoselectively. This new C-C bond constructing reaction involves, instead of the expected ethynyla

Full text of DOI:10.1021/acs.orglett.0c00564

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Letter
t
KOBu /DMSO-Mediated α‑C−H Vinylation of N‑Benzyl Ketimines
with Acetylene Gas: Stereoselective Synthesis of (E,Z)‑2-Azadienes
Ivan A. Bidusenko, Elena Yu. Schmidt, Nadezhda I. Protsuk, Igor A. Ushakov, Alexander V. Vashchenko,
Andrei V. Afonin, and Boris A. Trofimov*
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ABSTRACT: Several imines, readily derived from aryl methyl
t
ketones and benzylamines, react with acetylene gas in KOBu /
DMSO system to afford 2-azadienes stereoselectively. This new
C−C bond constructing reaction involves, instead of the expected
ethynylation of the CN bond, the addition of azaallyl anions to
the triple bond of acetylene.
3
2
3
he C−C bond forming reactions are cornerstones of
Scheme 1. Transition-Metal-free Csp −Csp and Csp −Csp
T
organic chemistry that occupy an important place in its
Bond-Forming Reactions of Acetylenes in Basic Media
1
toolkit. In light of growing eco-concerns, research efforts are
especially focused on those C−C bond constructing processes
that are atom-economic and proceed under nature-mimicking
conditions (physiological temperatures, atmospheric pressure)
using no heavy metals and toxic solvents. These requirements,
2
also coined as a pot-, atom-, step-economy (PASE) paradigm,
well meet the framework of acetylene chemistry. Indeed,
acetylene has high and multilateral reactivity. It is industrially
manufactured from oil, gas, and coal as well as from calcium
carbide, which is now becoming a renewable feedstock (it can
3
be produced from cellulose/lignin). The dual chemistry of
acetylene (both electrophilic and nucleophilic reactant) is
4
especially pronounced in basic media (pK ∼ 30−32), where
a
Scheme 2. Reaction of Ketimine 1a with Acetylene Gas in
acetylene deprotonation, activity of the reacting nucleophiles,
and complexing of the triple bond with alkali metal cations are
t
the KOBu /DMSO System
5
specifically enhanced.
Recently, two transition metal-free involving acetylene
3
2
3
Csp −Csp and Csp −Csp bond-forming reactions occurring
in the basic media have been discovered, namely α-C−H
vinylation of ketones (Scheme 1, A), where acetylenes behave
6
as electrophiles, and the addition of deprotonated acetylenes as
7
Consequently, we studied this reaction in detail to improve
nucleophiles to the CN bond (Scheme 1, B).
2
2
yield of the products and to understand the new Csp −Csp
bond-construction process. This communication is a concise
summary and analysis of the results obtained.
As a reference for the investigation, the reaction of imine 1a
with acetylene (Scheme 2) was chosen. In Table 1, the selected
In continuation of this research, we have attempted to
extend the latter reaction (Scheme 1, B) to a class of CN
bond containing compounds such as Schiff bases derived from
8
aromatic (heteroaromatic) ketones and benzylamines. How-
ever, under the optimum conditions reported for imine
alkynylation, instead of the addition of acetylene to the C
N bond of ketimine 1a, we detected the formation of 2-
azadiene 2a in 34% yield (Scheme 2). This likely results from a
Received: February 13, 2020
8
b
higher acidity of the N-benzyl ketimines (pKa ∼ 24)
compared to acetylene. Along this line, transition-metal-free
chemo- and regioselective cross-coupling of azaallyls with vinyl
9
bromides has been recently published.
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00564
A
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representative experimental data illustrating the effect of the
reaction conditions on the yield of azadiene 2a is presented.
Scheme 3. Competitive C−H Vinylation of Ketimine 1a
Table 1. Effects of the Reaction Conditions on the Yield of
a
2
-Azadiene 2a
1a/KOBut
b
T (°C)
time (min)
yield of 2a (%)
c
entry
Table 3, 2r′) was isolated in 3% yield and was fully
characterized.
1
2
3
4
5
6
7
8
1:1
1:1
1:1
1:1
1:0.5
1:0.5
1:0.2
1:0.2
1:1.2
1:1
25
40
40
40
40
40
40
40
40
40
20
40
40
60
60
30
15
30
120
120
180
30
30
30
8
68
72
56
66
55
56
43
56
48
71
traces
14
After optimizing the conditions for the formation of 2a, it
was applied to an array of substituted N-benzyl ketimines. For
the convenience of the substituent effect evaluation, we divided
the ketimine series into two sets: one derived from various
ketones with an amine counterpart fixed as benzylamine
(Table 2) and the second having the varying amine moiety
with the fixed ketone counterpart as acetophenone (Table 3).
As follows from Table 2, the reaction proceeded well with
several N-benzyl ketimines obtained from aryl alkyl ketones
including heteroaromatic ones affording products 2a−m in
good yields. Reaction of the imine 1n obtained from
cyclohexanone did not take place at all.
9
d
10
11
12
13
e
f
1:1
1:1
1:1
30
30
g
a
t
A similar trend was observed in the formation of vinylation
products 2 from the benzylic counterpart of ketimines 1
Conditions: 1a (5 mmol, 1.046 g), KOBu (5 mmol), DMSO (50
mL), acetylene (flow rate ∼15 cm /min). Molar ratio. Isolated yield
after column chromatography (SiO , n-hexane/Et O = 20:1).
3
b
c
(Table 3). In the case when the α-CH group was linked to an
2
2
2
d
e
f
t
DMSO (20 mL). Acetylene under pressure ∼2 atm. NaOBu (5
aromatic or heteroaromatic substituent, the vinylation
occurred, while with a fully aliphatic substituent at the nitrogen
atom (ketimine 1t) no reaction was observed. The azaallyl
anion cannot be stabilized by charge distribution, and hence,
the intermediate anionic species were not nucleophilic enough
to add to acetylene.
g
mmol). KOH·0.5H O (5 mmol).
2
The reactions were carried out under atmospheric pressure
a flow reactor) by bubbling of acetylene gas from a
commercially available standard cylinder through a stirred
solution of ketimine 1a in the KOBu /DMSO system. The
reaction was monitored by H NMR spectroscopy. Immedi-
ately after mixing of ketimine 1a with KOBu /DMSO solution,
the reaction mixture turned reddish-purple, which indicated
the deprotonation of the substrate to generate semistabilized
azaallyl anions that is typical for N-benzyl ketimines. In the
course of the process, the color of the reaction mixture faded
and became light brown. The optimized conditions providing
(
t
The structure and stereochemistry (E,Z configuration) of 2-
1
1
azadienes 2 have been established by NMR spectroscopy ( H,
1
3
15
t
C, N), including 2D techniques (NOESY, COSY, HSQC,
HMBC), and was also confirmed by single-crystal X-ray
analysis of 2k (Figure 1).
8b
7
2% yield of 2a can be specified as follows: atmospheric
t
pressure, equimolar ratio of 1a and KOBu , 40 °C, 30 min
(
(
2
entry 3). Performing the reaction at slightly excessive pressure
∼2 atm, closed reactor, 20 °C, 30 min) secured 71% yield of
t
a (entry 11). Notably, in the NaOBu /DMSO system, only
Figure 1. X-ray structure of 2k (from ethanol; CCDC 1968359)
traces of 2a were observed (entry 12), indicating a crucial role
of the alkali metal cation in the reaction. Another characteristic
of the process was the need for significant dilution (5 mmol of
The reaction represents a base-mediated stereoselective α-
C−H vinylation of N-benzyl ketimines with acetylene gas
(Scheme 4, with example of 1a). Consequently, the key step of
the reaction is the addition of the deprotonated substrates
1
a in 50 mL of DMSO). This indicated the importance of the
t
dissociation of KOBu and prevention of possible interaction of
azaallyl anions with nondeprotonated starting ketimines.
Carrying the reaction at a higher concentration of 1a (5
mmol in 20 mL of DMSO) resulted in lowering the yield of 2a
to 48% (entry 10), although the productivity per unit volume
became three to four times larger. When the base loading was
reduced to 0.5 equiv, the yield of 2a decreased by only 6%
(
semistabilized azaallyl anions A) to the triple bond. Such
anions are usually depicted as a three-atom system with the
delocalized negative charge. Actually, the electron density
delocalization is here extended over the adjacent aromatic or
Scheme 4. Tentative Mechanism of C−H Vinylation of
Ketimines 1 with Acetylene
(
entry 5). As evident from Table 1, the reaction could be
conducted on a gram scale.
1
Analysis of the H NMR spectrum of the crude product
indicated the formation of the 2a′, an isomer of 2a, which can
be formed by the addition of more hindered site of the 2-
azaallyl anion to acetylene. The azaallyl anions are known to
8b
have the negative charge at the both ends (Scheme 3).
Although isomer 2a′ was present in the crude product in
∼
13%, it was difficult to isolate probably due to its hydrolysis
on silica gel column. However, in one case, the isomer (see
B
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Table 2. Effect of the Ketone Counterpart Structure of
Ketimines 1 on the Yield of Vinylation Products 2
Table 3. Effect of the Benzylamine Counterpart Structure of
Ketimines 1 on the Yield of Vinylation Products 2
a
a
a
b
Reactions were carried out under conditions as in Table 2. Isolated
yield.
heteroromatic substituent that additionally stabilizes these
anionic systems. This increases the concentration of anions A
in the reaction mixture, thereby making the α-C−H vinylation
possible.
An interesting feature of the reaction is the E,Z stereo-
chemistry of the azadiene product. Formation of the azadiene
can be explained by the following. The intermediate A
obtained from 1a reacts with acetylene to form the vinyl
carbanion B, which leads to the formation of the 2-aza-1,4-
diene C. The latter prototropically isomerizes, still retaining in
the coordination sphere of the K+ that warrants the Z
orientation of the forming Me group to finally afford
conjugated (E,Z) 2-aza-1,3-diene 2a and recover the base.
This mechanism was supported by the following experi-
1
3
t
ments: (i) In the C NMR spectrum of 1a/KOBu /DMSO
system, the carbon atom signals of azaallyl anion [CN−
−
CH] were almost equivalent (107.8 and 104.7 ppm,
1
3
correspondingly) as compared to the C NMR spectrum of
neutral ketimine 1a (164.0 and 54.0 ppm, correspondingly),
see the SI for details. (ii) The determining effect of alkali metal
a
t
Conditions: 1 (5 mmol), KOBu (5 mmol), DMSO (50 mL),
3
b
acetylene (flow rate ∼15 cm /min). Isolated yield.
C
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Letter
cation nature on the reaction course (no reaction with
Notes
t
+
NaOBu ) implies the specific coordination of K with the
reacting species. The latter was additionally confirmed by the
especially positive role of high dilution of the reaction mixture
The authors declare no competing financial interest.
Please be aware of potential safety hazards associated with the
use of a KOBu /DMSO system at increased temperatures.
t
12
+
t
−
that rendered a better separation of the K /Bu O ion pair.
(
iii) The competitive α-C−H vinylation (in a smaller degree)
ACKNOWLEDGMENTS
We thank the Baikal Analytical Centre of collective use for the
equipment.
■
of ketone site of azaallyl system. (iv) The treatment of the
reaction mixture with D O did not lead to incorporation of
deuterium in the target product.
2
In summary, we have developed a transition-metal-free
REFERENCES
2
2
■
Csp −Csp bond construction reaction comprising the
(
2
1) For recent reviews, see: (a) Rao, B.; Kinjo, R. Chem. - Asian J.
addition of azaallyl anions to acetylene. The methodology
018, 13, 1279−1292. (b) Heravi, M. M.; Ghanbarian, M.;
2
meets pot-, atom-, step-economy (PASE) paradigm require-
Ghalavand, N.; Nazari, N. Curr. Org. Chem. 2018, 22, 1420−1457.
ments. Apart from a contribution to fundamental organic
chemistry, this reaction offers a convenient and operationally
simple stereoselective synthesis of 2-azadienes, important
(
c) Santos, A. S.; Mortinho, A. C.; Marques, M. M. B. Molecules 2018,
23, 2673. (d) Akhtar, R.; Zahoor, A. F.; Parveen, B.; Suleman, M.
Synth. Commun. 2019, 49, 167−192. (e) Hyatt, I. F. D.; Dave, L.;
David, N.; Kaur, K.; Medard, M.; Mowdawalla, C. Org. Biomol. Chem.
1
0
building blocks for creating molecular complexity and
11
2
(
9
019, 17, 7822−7848.
2) (a) Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem. 2007,
, 438−440. (b) Xiang, H.; Chen, Y.; He, Q.; Xie, Y.; Yang, C. RSC
Adv. 2013, 3, 5807−5810.
3) (a) Lehmann, J. Nature 2007, 447, 143−144. (b) Li, G.; Liu, Q.;
Liu, Z.; Zhang, Z. C.; Li, C.; Wu, W. Angew. Chem., Int. Ed. 2010, 49,
480−8483.
4) (a) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem.
diversity of medicinal and biological importance.
ASSOCIATED CONTENT
sı Supporting Information
■
*
(
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00564.
8
(
1
Experimental procedures, compound characterizations,
NMR spectra, and crystallographic data (PDF)
980, 45, 3295−3299. (b) Yuan, Y.; Thome, I.; Kim, S. H.; Chen, D.;
Beyer, A.; Bonnamour, J.; Zuidema, E.; Chang, S.; Bolm, C. Adv.
Synth. Catal. 2010, 352, 2892−2898.
Accession Codes
(
5) Trofimov, B. A.; Schmidt, E. Yu. Acc. Chem. Res. 2018, 51,
CCDC 1968359 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
1
117−1130.
(6) Trofimov, B. A.; Schmidt, E. Yu.; Zorina, N. V.; Ivanova, E. V.;
Ushakov, I. A. J. Org. Chem. 2012, 77, 6880−6886.
(7) (a) Bidusenko, I. A.; Schmidt, E. Yu.; Ushakov, I. A.; Trofimov,
B. A. Eur. J. Org. Chem. 2018, 2018, 4845−4849. (b) Schmidt, E. Yu.;
Bidusenko, I. A.; Protsuk, N. I.; Demyanov, Y. V.; Ushakov, I. A.;
Trofimov, B. A. Eur. J. Org. Chem. 2019, 2019, 5875−5881.
(
8) For recent examples, see: (a) Wu, Y.; Hu, L.; Li, Z.; Deng, L.
AUTHOR INFORMATION
Corresponding Author
■
Nature 2015, 523, 445−450. (b) Tang, S.; Zhang, X.; Sun, J.; Niu, D.;
Chruma, J. Chem. Rev. 2018, 118, 10393−10457.
(
9) Li, M.; Gutierrez, O.; Berritt, S.; Pascual-Escudero, A.;
̧ lc i̧ men, A.; Yang, X.; Adrio, J.; Huang, G.; Nakamaru-Ogiso, E.;
Boris A. Trofimov − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences
Yesi
Kozlowski, M. C.; Walsh, P. J. Nat. Chem. 2017, 9, 997−1004.
10) For recent reviews, see: (a) Jayakumar, S.; Ishar, M. P. S.;
6
64033 Irkutsk, Russia; orcid.org/0000-0002-0430-3215;
(
Email: boris_trofimov@irioch.irk.ru
Mahajan, M. P. Tetrahedron 2002, 58, 379−471. (b) Monbaliu, J.-C.
M.; Masschelein, K. G. R.; Stevens, C. V. Chem. Soc. Rev. 2011, 40,
Authors
4
(
708−4739.
Ivan A. Bidusenko − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences
11) For examples, see: (a) Nicolaou, K. C.; Nevalainen, M.; Safina,
B. S.; Zak, M.; Bulat, S. Angew. Chem., Int. Ed. 2002, 41, 1941−1945.
(b) Moody, C. J.; Hughes, R. A.; Thompson, S. P.; Alcaraz, L. Chem.
Commun. 2002, 1760−1761. (c) Stocking, E. M.; Williams, R. M.
Angew. Chem., Int. Ed. 2003, 42, 3078−3115. (d) Nicolaou, K. C.;
Safina, B. S.; Zak, M.; Lee, S. H.; Nevalainen, M.; Bella, M.; Estrada,
A. A.; Funke, C.; Zecri, F. J.; Bulat, S. J. Am. Chem. Soc. 2005, 127,
6
64033 Irkutsk, Russia; orcid.org/0000-0003-0783-6233
Elena Yu. Schmidt − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences
6
64033 Irkutsk, Russia
Nadezhda I. Protsuk − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences
1
1159−11175. (e) Shao, X.; Li, K.; Malcolmson, S. J. J. Am. Chem.
Soc. 2018, 140, 7083−7087. (f) Li, K.; Shao, X.; Tseng, L.;
6
64033 Irkutsk, Russia
Malcolmson, S. J. J. Am. Chem. Soc. 2018, 140, 598−601.
Igor A. Ushakov − A. E. Favorsky Irkutsk Institute of Chemistry,
Siberian Branch, Russian Academy of Sciences 664033 Irkutsk,
Russia
Alexander V. Vashchenko − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences
(
g) Malcolmson, S. J.; Li, K.; Shao, X. Synlett 2019, 30, 1253−1268.
(
12) (a) Lam, T. T.; Vickery, T.; Tuma, L. J. Therm. Anal. Calorim.
2006, 85, 25−30. (b) Wang, Z.; Richter, S. M.; Gates, B. D.; Grieme,
T. A. Org. Process Res. Dev. 2012, 16, 1994−2000. (c) Wang, Z.;
Richter, S. M.; Bellettini, J. R.; Pu, Y.-M.; Hill, D. R. Org. Process Res.
Dev. 2014, 18, 1836−1842. (d) Yang, Q.; Sheng, M.; Henkelis, J. J.;
Tu, S.; Wiensch, E.; Zhang, H.; Zhang, Y.; Tucker, C.; Ejeh, D. E. Org.
Process Res. Dev. 2019, 23, 2210−2217.
6
64033 Irkutsk, Russia
Andrei V. Afonin − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences
6
64033 Irkutsk, Russia; orcid.org/0000-0001-7916-2421
Complete contact information is available at:
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