Dynamic covalent chemistry of the Nicholas ether-exchange reaction

Article abstract of DOI:10.1021/ol900095d

The Nicholas ether-exchange reaction was found to be reversible and can be used to synthesize complex molecules in dynamic covalent chemistry (DCC). The Nicholas ether-exchange reaction is used to prepare 20-Crown-6 ether in the presence of potassium salt

Full text of DOI:10.1021/ol900095d

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1313-1316
Dynamic Covalent Chemistry of the
Nicholas Ether-Exchange Reaction
Nobuhiro Kihara* and Kazuyuki Kidoba
Department of Chemistry, Faculty of Science, Kanagawa UniVersity, Tsuchiya,
Hiratsuka 259-1293, Japan
kihara@kanagawa-u.ac.jp
Received January 16, 2009
ABSTRACT
The Nicholas ether-exchange reaction was found to be reversible and can be used to synthesize complex molecules in dynamic covalent
chemistry (DCC). The Nicholas ether-exchange reaction is used to prepare 20-Crown-6 ether in the presence of potassium salt at low temperature.
Dynamic covalent chemistry (DCC) is a method used to
obtain a thermodynamically stable product by a reversible
Scheme 1. Nicholas Reaction
chemical reaction under equilibrium conditions.1 It is a
powerful method to construct macrocycles and self-as-
semblies because any errors that occur while constructing
covalent bonds in complex molecules can be revised during
equilibrium.ReactionsusedforDCCarecurrentlylimitedsonly
the ester-exchange, olefin metathesis, disulfide-exchange, and
imine-exchange reactions are well studied. Therefore, new
DCC reactions are strongly desired.
Our investigation focused on the Nicholas reaction: SN1-
type reaction at the propargyl position of the alkyne-cobalt
carbonyl complex (Scheme 1).2 Since the cobalt carbonyl
moiety strongly stabilizes the R cation, the ether group at
the R to the alkyne-cobalt carbonyl complex can be a
leaving group in the presence of strong acid. Therefore, we
expected that etherification under the Nicholas reaction
condition is reversible, and the ether-exchange reaction
occurs as the equilibrium. Although etherification using the
Nicholas reaction has been reported,3 the reversibility of the
reaction has not been studied extensively. To the best of our
knowledge, there were some examples of the isomerization
of the cobalt-propargyl ether complex,3b,4 although there
(1) (a) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.;
Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898–952. (b) Lehn, J.-M.
Prog. Polym. Sci. 2005, 30, 814–831. (c) Takata, T. Polym. J. 2006, 1,
1–20. (d) Meyer, C. D.; Joiner, C. S.; Stoddart, J. F. Chem. Soc. ReV. 2007,
36, 1705–1723.
(3) (a) Quintal, M. M.; Closser, K. D.; Shea, K. M. Org. Lett. 2004, 6,
4949–4952. (b) Ortega, N.; Martı´n, T.; Martín, V. S. Org. Lett. 2006, 8,
871–873. (c) Hope-Weeks, L. J.; Mays, M. J.; Solan, G. A. Eur. J. Inorg.
Chem. 2007, 310, 1–3114.
(2) (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214. (b) Teobald,
B. J. Tetrahedron 2002, 58, 4133–4170.
(4) Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J. Am. Chem. Soc.
1987, 109, 5749–5759.
10.1021/ol900095d CCC: $40.75
Published on Web 02/17/2009
2009 American Chemical Society

was no example of intermolecular ether exchange by the
Nicholas reaction. In this paper, we report the DCC of the
Nicholas ether-exchange reaction and the synthesis of crown
ether as an application of this reaction.5
Table 1. Etherification by the Nicholas Ether-Exchange
Reaction
To study the equilibrium nature of the Nicholas ether-
exchange reaction, a mixture of two alkyne complexes (1a
and 1b) was treated with trifluoromethanesulfonic acid
(TfOH) (Scheme 2). After the oxidative treatment of the
Scheme 2. Nicholas Ether-Exchange Reaction
yield/%
run
1
E
acida
concn/M additiveb
2
3
1
2
3
4
5
6
7
8
a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
TfOH
TfOH
TfOH
TFA
MsOH
TMSOTf
Et2AlCl
ZnCl2
AgOTf
BF3OEt2
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
1
none
34
47
40
0
21
21
19
0
a
a
a
a
a
a
a
a
a
c
MS4A
MS5A
MS5A
MS4A
MS4A
MS4A
MS4A
MS4A
MS4A
none
none
none
none
MS3A
MS4A
trace trace
0
0
0
0
0
0
0
15
1
10
33
9
0
10
11
37
34
0
mixture with cerium(IV) diammonium nitrate (CAN) to
remove the cobalt carbonyl moiety,6 the products were
isolated. Along with 3 that was formed from 1b, the ether-
exchange product 2a was obtained. Therefore, the ether-
exchange reaction between reactants 1a and 1b occurred
under the Nicholas reaction condition. When the reaction
was carried out for 24 h, the asymmetrical ether (2a) was
isolated with 42% yield. Since the theoretical yield of 2a at
equilibrium is 50%, this indicates that the Nicholas ether-
exchange reaction is reversible and can be used for DCC.
Given that the Nicholas ether-exchange reaction is revers-
ible, quantitative etherification is possible when the byproduct
of the ether-exchange reaction is removed from the reaction
system. Thus, the reaction of 1 with 2 equiv of alcohol 4
was carried out in CH2Cl2 at room temperature for 24 h to
investigate the effect of the leaving groups (X and E) in the
ether-exchange reaction (Table 1). The monosubstituted
product 2 and the bis-substituted product 3 were isolated after
CAN treatment. When the reaction was carried out with
reactant 1a in the presence of molecular sieves as the
methanol absorbent, the yield of ether slightly improved (runs
1-3). This result prompted examination of various acid
catalysts for etherification (runs 4-10). Although TMSOTf
and BF3OEt2 were as effective as TfOH, a better acid catalyst
than TfOH was not found. Therefore, the effect of the leaving
group in 1 (X) was examined (runs 11-14). When 1d (X )
OTs) and 1e (X ) Cl) were used, 2 was not observed,
although the yield of desired ether 3 was low. When 1f (X
) OH) was used, the yield of 3 drastically increased, and
12 dc
13 ec
0
14
15
16
17
18
19
20
21
22
23
24
25
f
f
f
f
f
f
c
g
c
g
f
trace 52
62
trace 62
8
MgSO4 37
16
7
CaCl2
none
none
none
none
none
none
none
4
TMS
TMS
TMS
TMS
TMS
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
trace 74
41
0
33
0
ND
ND
31
69
30
83
49
17
1
0.01
0.01
TBDMS TMSOTf
TBDMS TMSOTf
g
a 20 mol % for 1. b 500 mg for 0.25 mmol of 1. c Cobalt complex was
prepared in situ and used without purification.
only a trace of 2f was observed. Since the deactivation of
TfOH by the produced water was of concern, the addition
of dehydrating material was examined (runs 15-18). While
molecular sieves only slightly increased the yield of 3,
MgSO4 or CaCl2 prevented the etherification reaction. When
TMS ether was used instead of alcohol in the presence of
TMSOTf, 3 was obtained in good yield (run 19).7 The best
result was obtained when the reaction was carried out with
1g (X ) OTMS) at a high concentration condition (run 23).
The TBDMS ether was not effective (runs 24 and 25). Thus,
etherification was effectively carried out when siloxane was
the counterpart of the ether.
Since DCC is particularly effective for the construction
of macrocycles, the synthesis of crown ether 6 was inves-
(5) Trityl ether has also been used for DCC: (a) Harrison, I. T. J. Chem.
Soc., Chem. Commun. 1972, 231–232. (b) Furusho, Y.; Oku, T.; Rajkumar,
G. A.; Takata, T. Chem. Lett. 2004, 33, 52–53.
(7) Yokozawa, T.; Nishimori, M.; Endo, T. Macromol. Chem. Phys.
1996, 197, 1361–1371.
(6) Seyferth, D.; Wehman, A. J. Am. Chem. Soc. 1970, 92, 5520.
1314
Org. Lett., Vol. 11, No. 6, 2009

tigated using reactant 1g and disilyl ether 5 as shown in
Scheme 3. When macrocyclization was carried out under the
Table 2. Template Effect in the Preparation of Crown Ether
Scheme 3. Macrocyclization
run templatea concn/M
temp
time/h yield/%
1
2
3
4
5
6
7
8
none
KOTf
none
0.01
0.01
1
1
1
1
1
1
1
rt
rt
rt
rt
24
24
24
24
24
48
24
3-24
3-24
3-24
3-24
50
49
13
25
39
65
14
66
35
36
30
KOTf
KOTf
KOTf
none
KOTf
NaOTf
RbOTf
CsOTf
-40 °C
-40 °C
-40 °C
rt to -40 °C
rt to -40 °C
rt to -40 °C
rt to -40 °C
9
10
11
1
1
a 100 mol % for 5.
since the complexation of 6 with potassium ion lowered the
potential of 6, and complexation is more favored as the
concentration increases. Therefore, the reaction was carried out
at a low temperature to improve complexation. The yield
substantially increased at -40 °C, although the reaction
proceeded slowly (runs 5 and 6). Since no yield improvement
of 6 was observed in the absence of KOTf (run 7), it became
obvious that the temperature effect originated from the stronger
complexation at a lower temperature. The template effect acts
more effectively under the condition in which the complexation
is favored: lower temperature and high concentration condition.
To facilitate the equilibrium process, the reaction was first
carried out at ambient temperature, and the system was then
cooled to shift the equilibrium. Since the Nicholas ether-
exchange reaction is DCC, a high yield of 6 was achieved in a
best conditions mentioned above, [1 + 1] macrocyclic crown
ether 6 was obtained, although the main product was polymer
7. When the concentration was reduced to 0.01 M, the yield
of 6 increased because macrocyclization is thermodynami-
cally favored under the lower concentration. Although the
reaction was carried out for 24 h, the system reached
equilibrium within 3 h. It should be noted that a Friedel-Crafts
type alkylation of the electron-rich aromatic ring was not
observed, indicating the stability of the R cation of the cobalt
carbonyl complex and the high chemoselectivity of the
Nicholas ether-exchange reaction.
Scheme 4
.
Modification of the Cobalt Moiety in the Crown
Ether
Since the Nicholas ether-exchange reaction is DCC, a
remacrocyclization of polymer 7 to form 6 was expected.
When the polymer was treated with TMSOTf, 6 was obtained
in 12% yield. TfOH was the better acid catalyst for
remacrocyclization of 7 than TMSOTf, and 6 was obtained
in 22% yield. The yield of 6 was lower than that of direct
macrocyclization because the terminal silyl groups of 7 were
mostly hydrolyzed during the workup.
To increase the yield of crown ether, the use of the template
effect was investigated (Table 2). When KOTf was used as the
template, the yield of 6 improved under the high concentration
conditions, although no change was observed under the low
concentration conditions (runs 1-4). Although macrocyclization
is not thermodynamically favored under the concentrated
conditions, the template effect altered the effect of concentration
Org. Lett., Vol. 11, No. 6, 2009
1315

short reaction period (run 8). Further, other alkali metal salts
used as the template were examined, although a smaller template
effect was observed (runs 9-11).
In summary, it was demonstrated that the Nicholas ether-
exchange reaction is reversible and can be used for DCC.
Cross-etherification was successfully achieved when siloxane
was the leaving molecule. As an application of the Nicholas
ether-exchange reaction, the synthesis of crown ether was
successfully carried out in the presence of potassium salt as
the template. Investigations of further applications of the
Nicholas ether-exchange reaction for constructing various
supramolecules are currently in progress.
To demonstrate product 6 as the functional crown ether,
the deprotection of the cobalt carbonyl moiety was investi-
gated. When 6 was treated with 400 mol % of CAN, crown
ether bearing triple bond 8 was obtained in high yield
(Scheme 4). The use of excess CAN resulted in the oxidation
of the aromatic ring. It is expected that crown ether 8 can
be further functionalized by the reaction of the triple bond.
As the application of 8, crown ether 9 bearing a vinyl iodide
moiety was easily prepared,8 which is a versatile reactant
for the transition metal complex-catalyzed coupling reaction.
Supporting Information Available: Experimental pro-
cedures and characterization data for key compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Paterson, I.; Fessner, K.; Finlay, M. R. V.; Jacobs, M. F. Tetrahedron
Lett. 1996, 37, 8803–8806.
OL900095D
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Org. Lett., Vol. 11, No. 6, 2009