An NMR study on a pseudo-intramolecular transacylation reaction of an α-aryl-β-keto ester

Article abstract of DOI:10.1039/c3ra45568h

The pseudo-intramolecular transacylation reaction efficiently proceeds like an intramolecular reaction, even though it is actually an intermolecular reaction. We have obtained valuable insights by monitoring the reaction by ¹H NMR spectroscopy.

Full text of DOI:10.1039/c3ra45568h

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An NMR study on a pseudo-intramolecular
transacylation reaction of an a-aryl-b-keto ester†
Cite this: RSC Adv., 2014, 4, 4889
Sho Hirai, Haruyasu Asahara, Shotaro Hirao, Jun Sawayama, Ryuichi Sugimoto,
*
Kazuhiko Saigo and Nagatoshi Nishiwaki
Received 3rd October 2013
Accepted 13th November 2013
DOI: 10.1039/c3ra45568h
www.rsc.org/advances
The pseudo-intramolecular transacylation reaction efficiently form.5 As a result, the ammonium salt 3 is easily formed upon
proceeds like an intramolecular reaction, even though it is actually an treatment with the amine 2. When a small amount of the amine
intermolecular reaction. We have obtained valuable insights by is liberated under equilibrium, the nucleophilic amine and the
monitoring the reaction by 1H NMR spectroscopy.
electrophilic keto ester locate close to each other. This is
referred to as an intimate pair. The spatial proximity of the
reagents enables an efficient nucleophilic substitution reaction
to proceed, transferring the acyl group from the keto ester 1 to
the amine 2 under mild conditions. The steric congestion
around the reaction site also prevents the approach of other
molecules, which consequently depresses any side reactions.3
Indeed, the efficient progress of the reaction could be easily
The development of a highly efficient reaction which dimin-
ishes both resource waste and energy, is highly desirable from
the viewpoint of green chemistry. In general, an intramolecular
reaction proceeds more efficiently than an intermolecular
reaction because of a higher collision frequency between reac-
tion sites. In other words, an increase in the collision frequency
of reactants results in the improvement of the reaction effi-
ciency, even in an intermolecular process. Indeed, the use of
reaction elds such as micelles and microcapsules, enables
reactions to proceed easily by increasing the opportunity of
reactants to encounter each other.1 Such great success implies
that efficient intermolecular reactions can be achieved if the
collision frequency of the reactants can be increased, even in
the absence of a reaction eld.
1
monitored by H NMR spectroscopy. Just aer the addition of
an equimolar amount of the amine 2 to a solution of the a-aryl-
b-keto ester 1 in CDCl3, the formation of the ammonium eno-
late 3 could be conrmed by the immediate disappearance of
the signal assigned to the enol hydrogen atom. With the
decrease in the signals for the salt, the signals for the trans-
acylated products 4 and 5 increased, without any detectable
formation of by-products, to achieve quantitative conversion.
Recently, we demonstrated a highly effective method called
pseudo-intramolecular reactions.2,3 The reactions proceed
under mild conditions without any reaction elds, additives
and troublesome manipulations. Using this method vicinally
functionalized 1,4-dihydropyridines, 1,2-diazepines, and dia-
zabicyclic compounds have been readily synthesized.2
The transacylation reaction is another example of the
pseudo-intramolecular process (Scheme 1).3a The a-arylation of
a b-keto ester increases the acidity of the hydrogen atom of the
active methylene4 because the aryl group stabilizes its enol
School of Environmental Science and Engineering, Kochi University of Technology,
Tosayamada, Kami, Kochi 782-8502, Japan. E-mail: nishiwaki.nagatoshi@
kochi-tech.ac.jp; Fax: +81 887 57 2520
† Electronic supplementary information (ESI) available: Monitoring the
transacylation reaction by 1H NMR spectroscopy using benzene-d6 as the
solvent and NMR data of compounds 1, 4, and 5. An NMR study of the reaction
of propylamine 2 and an equimolar amount of acetone in benzene-d6. See DOI:
10.1039/c3ra45568h
Scheme 1 A mechanism for the pseudo-intramolecular transacylation
reaction.
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The above features of the pseudo-intramolecular process
The progress of the transacylation reaction was monitored by
enable the chemoselective and regioselective acylation reaction 1H NMR spectroscopy at intervals of several minutes (hours).
to proceed without any modication of the substrate, such as Since no signals were observed other than those for the
the protection of another functionality. Furthermore, this ammonium salt 3, the transacylated product 4 and 2,4-dini-
reaction also enables us to facilely synthesize unsymmetrical trophenylacetate 5, the reaction rate can be discussed on the
malonic acid derivatives by using an a-arylated acetonedi- basis of the conversion of 3. When acetone-d6, methanol-d4, and
carboxylate.3 Hence, the present transacylation reaction is a chloroform-d were used, the reactivities were different from
promising method for synthesising polyfunctionalized each other. This is probably due to the interaction of the solvent
compounds. However, for applying the method to more elabo- with the amine 2, which would arise from an electrophilic
rate syntheses, it is necessary to obtain further insights into the moiety9,10 or a hydroxy group to form a hydrogen bond. Contrary
concept of “the pseudo-intramolecular process”. If the reaction to this, when benzene-d6, THF-d8, and acetonitrile-d3 were used
proceeds in a pseudo-intramolecular process, the reaction order as the solvent, the transacylation reactions proceeded with the
is considered to be close to rst order because the reactants same reaction rate. It is noteworthy that the reaction rates in the
have already encountered each other in the intimate pair. From latter three solvents were almost the same despite their
this viewpoint, we have studied the correlation between the extremely different polarities. This result strongly indicates that
reaction rate and the polarity of the reaction medium/the the transacylation reaction was not affected by the polarity of
concentration of the substrates by monitoring the progress of the solvent, as we hypothesized.
1
the reaction using H NMR spectroscopy. In addition, we have
evaluated the reaction order on the basis of the results.
Next, the effect of the concentration of the reaction mixture
was studied in a similar way by changing the concentration in
Solvation is one of the crucial factors affecting the reactivity of the range from 0.24 to 0.015 M (Fig. 2 and Table 2). Although the
an intermolecular process, because two solvated substrates reaction rate varied depending on the concentration, it became
diminish the collision frequency.6 As a result, the rate of an almost the same in highly diluted solutions. In the case of an
intermolecular process changes depending on the polarity of the intermolecular process, the reaction rate would become
reaction medium. On the other hand, for an intramolecular considerably slower with the dilution of the reaction mixture.
process reaction sites close to each other should be less inu- Thus, the results support the fact that the reaction is a pseudo-
enced by the polarity of the solvent.7 With the characteristics of intramolecular process.
intermolecular and intramolecular processes in mind, we
In order to obtain further insight, the reaction orders n of the
hypothesized that the rate of the pseudo-intramolecular process reactions carried out at different concentrations were calculated
should not be inuenced by the polarity of the solvent even using eqn (1), where k is the rate constant, A is the concentration
though it is actually an intermolecular process. In order to of the ammonium enolate 3, and t is the reaction time.11 The
conrm this hypothesis, we monitored the transacylation reac- calculated value n of each reaction was between rst and second
tion by 1H NMR spectroscopy using six different deuterated order (Table 3). Since the quantitative formation of the
solvents (acetonitrile-d3, THF-d8, benzene-d6, chloroform-d, ammonium salt 3 was conrmed just aer the addition of the
methanol-d4, and acetone-d6) (Fig. 1). The dielectric constants (3r) amine 2 to a solution of the keto ester 1, the higher reaction
and dipole moments (m) of these solvents are shown in Table 1.8 order is caused by the intermolecular reaction between two
intimate pairs, as shown in Fig. 3.
!
1
1
1
ꢀ
¼ kt
(1)
nꢀ1
nꢀ1
n ꢀ 1
½Aꢁ
½Aꢁ
0
These results imply that a rst order reaction and a second
order reaction proceed in the present system. Consequently, the
pseudo-intramolecular process is concluded to be fundamen-
tally a rst order reaction.
In summary, the present transacylation reaction was
monitored by 1H NMR spectroscopy to give the following
Table 1 Rate constants k and relative rate constants krel with the
solvent parameters
Solvent
3r
m/D
k/molꢀ1
krel
Acetonitrile
THF
Benzene
Chloroform
Methanol
Acetone
37.5
7.6
2.3
4.8
32.6
20.7
3.4
1.7
0
1.2
1.7
2.7
5.57 ꢃ 10ꢀ4
5.46 ꢃ 10ꢀ4
5.50 ꢃ 10ꢀ4
1.77 ꢃ 10ꢀ4
1.18 ꢃ 10ꢀ4
5.60 ꢃ 10ꢀ6
1.0
0.99
1.0
0.32
0.21
0.010
Fig. 1 Time/conversion curves for 3 in different solvents: acetonitrile
(black), THF (blue), benzene (red), chloroform (purple), methanol
(green), and acetone (brown). The reactions were conducted at 30 ꢂC
using a 0.06 M solution.
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insights: (1) the reaction rate was not affected by the polarity
of the solvent; (2) the reaction proceeded efficiently even in
highly diluted solvents; and (3) the reaction order was lower
than second order. These results reveal that the trans-
acylation reaction proceeds like an intramolecular process
rather than an intermolecular process. This information will
be helpful for designing highly efficient and environmentally
benign
synthetic
protocols
for
polyfunctionalized
compounds.
Notes and references
1 Reviews: (a) M. Hatano and K. Ishihara, Chem. Commun.,
2012, 48, 4273–4283; (b) V. Ramamurthy and
A. Parthasarathy, Isr. J. Chem., 2011, 51, 817–829; (c)
T. Murase and M. Fujita, Chem. Rec., 2010, 10, 342–347; (d)
M. Yoshizawa, J. K. Klosterman and M. Fujita, Angew.
Chem., Int. Ed., 2009, 48, 3418–3438; (e) T. S. Koblenz,
J. Wassenaar and J. N. Reek, Chem. Soc. Rev., 2008, 37,
247–262; (f) S. Liu and B. C. Gibb, Chem. Commun., 2008,
3709–3716; (g) T. Dwars, E. Paetzold and G. Oehme, Angew.
Chem., Int. Ed., 2005, 44, 7174–7199; (h) M. D. Pluth,
R. G. Bergman and K. N. Raymond, Acc. Chem. Res., 2009,
42, 1650–1659.
Fig. 2 Time/conversion curves for 3 at various concentrations: 0.24
(black), 0.12 (clue), 0.06 (red), 0.03 (purple), 0.025 (green), 0.02
(brown), and 0.015 (orange) M. The reactions were conducted at 30 ꢂC
using benzene-d6 as the solvent.
Table 2 % Conversions of 3 monitored at hourly intervals at 30 ꢂC
using benzene-d6, at differing concentrations of 3
Conversion/%
2 (a) N. Nishiwaki, Heterocycles, 2013, 87, 967–990; (b) S. Hirao,
K. Kobiro, J. Sawayama, K. Saigo and N. Nishiwaki,
Tetrahedron Lett., 2012, 53, 1424–1430; (c) N. Nishiwaki,
S. Hirao, J. Sawayama, K. Saigo and K. Kobiro, Chem.
Commun., 2011, 47, 4938–4940; (d) N. Nishiwaki,
K. Kakutani, M. Tamura and M. Ariga, Chem. Lett., 2009,
38, 680–681.
3 (a) N. Nishiwaki, D. Nishida, T. Ohnishi, F. Hidaka,
S. Shimizu, M. Tamura, K. Hori, Y. Tohda and M. Ariga,
J. Org. Chem., 2003, 68, 8650–8656; (b) Y. Nakaike, N. Taba,
S. Itoh, Y. Tobe, N. Nishiwaki and M. Ariga, Bull. Chem.
Soc. Jpn., 2007, 80, 2413–2417.
Concentration/M
1 h
2 h
3 h
4 h
0.24
0.12
0.06
0.03
0.025
0.02
0.015
96
94
76
54
47
42
38
98
98
85
67
61
55
51
99
99
88
75
68
62
60
100
100
90
80
72
67
65
Table 3 Reaction orders measured for the reactions in benzene-d6
´
4 (a) M. P. Egorov, V. K. Bel'skii, E. S. Petrov, M. I. Terekhova
and I. P. Beletskaya, Journal of Organic Chemistry of the
Concentration/M
Reaction order
´
USSR, 1985, 1855–1862; (b) Z. Bankowska, I. Zadrzna and
0.24
0.12
0.06
0.03
0.015
1.8
1.6
1.6
1.6
1.4
D. Stopa, Pol. J. Chem., 1979, 53, 1563–1569.
5 (a) H. Yamataka and Z. Rappoport, J. Am. Chem. Soc., 2000,
122, 9818–9828; (b) A. Miller, J. Org. Chem., 1976, 41, 3599–
3602.
6 K. C. Westaway and Z. Lai, Can. J. Chem., 1989, 67, 345–349.
7 (a) M. E. Jung and J. Gervay, J. Am. Chem. Soc., 1989, 111,
5469–5470; (b) V. Thavasi, R. Philip, A. Bettens and
L. P. Leong, J. Phys. Chem. A, 2009, 113, 3068–3077.
8 (a) A. R. Hirst and D. K. Smith, Langmuir, 2004, 20, 10851–
10857; (b) P. J. Kinlen, J. Liu, Y. Ding, C. R. Graham and
E. E. Remsen, Macromolecules, 1998, 31, 1735–1744; (c)
K. Clays and A. Persoons, Phys. Rev. Lett., 1991, 66, 2980–
2983.
9 Chloroform is known to form a hydrogen bond with an
amine: (a) G. Pathak and S. Pradhan, Proc. - Indian Acad.
Sci., Chem. Sci., 1987, 99, 413–417; (b) S. Ng, J. Chem. Soc.,
Faraday Trans. 1, 1976, 72, 1101–1104; (c) H. Suhr, J. Mol.
Struct., 1968, 1, 295–303.
Fig. 3 A plausible reaction mechanism between two intimate pairs.
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10 When equimolar amount of acetone was added to a solution
the carbonyl group (see ESI†). In acetone solution, larger
of the propylamine 2 in benzene-d6, small signals were
amount of the adduct should be formed.
observed in the lower eld, which were assigned to the 11 The Third Series of Experimental Chemistry, ed. T. Tachibana,
propylammonium group derived from the addition of 2 to Maruzen, Tokyo, 1975, vol. 14, pp. 2580–2587.
4892 | RSC Adv., 2014, 4, 4889–4892
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