Investigation of the carboxylate position during the acylation reaction catalyzed by biaryl DMAP derivatives with an internal carboxylate

Article abstract of DOI:10.1002/anie.201300665

Location of the carboxylate ion: A series of biaryl DMAP catalysts with an internal carboxylate was prepared, and the catalytic activities of the derivatives were evaluated to determine the carboxylate position that most accelerated the DMAP-catalyzed acylation. The carboxylate ion proximal to the pyridine ring in a face-to-face geometry was found to act as an effective general base for the acylation reaction. Copyright

Full text of DOI:10.1002/anie.201300665

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DOI: 10.1002/anie.201300665
Counteranion Control
Investigation of the Carboxylate Position during the Acylation
Reaction Catalyzed by Biaryl DMAP Derivatives with an Internal
Carboxylate**
Reiko Nishino, Takumi Furuta,* Keizo Kan, Makoto Sato, Masahiro Yamanaka,
Takahiro Sasamori, Norihiro Tokitoh, and Takeo Kawabata*
The 4-dimethylaminopyridine (DMAP) (1)-catalyzed acyla-
tion of an alcohol with acid anhydrides 2 is one of the most
fundamental and widely used organic transformation for the
synthesis of esters.[1] The currently accepted mechanism
underlying the catalytic cycle in the presence of an auxiliary
base (B:) is depicted in Scheme 1.[2] The first key step of this
irreversible nucleophilic attack of alcohol 5 on the carbonyl
group of the acylpyridinium ion via the transition state TS-I. It
has been proposed that the rate-determining step of the
catalytic cycle is the second key step. Therefore, the efficiency
of the DMAP-catalyzed acylation depends not only on the
concentration of the acylpyridinium salt, but also on the
kinetics of the second step via TS-I.
In the rate-determining TS-I, it has been postulated that
the carboxylate ion 4 of the acylpyridinium salt plays a crucial
role as a general base catalyst in the deprotonation of the
alcohol hydroxy group.[3,4] Steglich and Hçfle found that the
acylation of a tertiary alcohol with acetic anhydride pro-
ceeded faster than acylation by acetyl chloride in the presence
of excess DMAP.[3a] Kattnig and Albert also found that the
acylation of 1- and 2-propanol with acetic anhydride in the
presence of catalytic amounts of DMAP proceeded faster
than that with acetyl chloride in the presence of K2CO3 as the
auxiliary base.[5] These results supported that the acetate,
which was more basic than chloride, functioned better as
a general base to accelerate the nucleophilic attack of the
alcohol on the acylpyridinium ion. Wakselman observed that
the acetylation of tBuOH proceeded only in the presence of
the N-acetyl-dimethylaminopyridinium salt with acetate as
the counteranion, and the reaction did not proceed if acetate
Scheme 1. Catalytic cycle of the DMAP-catalyzed acylation with acid
anhydride.
À
[6]
cycle is the establishment of equilibrium between DMAP and
its acylpyridinium salt composed of the acylpyridinium ion 3
and its counteranion, carboxylate 4. The second key step is the
were substituted for other counteranions, such as BF4 .
Apart from improving the reaction efficiency, we found
that a carboxylate ion also affected the regiochemical out-
come of the acylation of glucose derivative 6 in the presence
of a DMAP-related nucleophilic catalyst 7 (Scheme 2).[7]
Although the acylation of 6 with isobutyric anhydride
proceeded at the secondary C4 OH group with high
regioselectivity to yield 8, this regioselectivity was dramati-
cally reduced upon substitution with isobutyryl chloride,
[*] R. Nishino, Dr. T. Furuta, Dr. K. Kan, Dr. T. Sasamori,
Prof. Dr. N. Tokitoh, Prof. Dr. T. Kawabata
Institute for Chemical Research, Kyoto University
Uji, Kyoto 611-0011(Japan)
E-mail: furuta@fos.kuicr.kyoto-u.ac.jp
kawabata@scl.kyoto-u.ac.jp
Dr. M. Sato, Prof. Dr. M. Yamanaka
Department of Chemistry and Research Center for Smart Molecules,
Rikkyo University
3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501 (Japan)
[**] We are grateful to Prof. Hendrik Zipse (Ludwig-Maximilians-
Universitꢀt Mꢁnchen) for valuable discussion on theoretical
aspects for catalyst performance. This work was supported by
a Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysts” and
a Grant-in-Aid for Scientific Research (C) from the Ministry of
Education, Culture, Sports, Science and Technology (Japan).
DMAP=4-dimethylaminopyridine.
Scheme 2. Regioselectivities of the acylation reactions of 6 with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300665.
isobutyric anhydride or isobutyryl chloride in the presence of catalyst
7.
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giving the acylate 9 at the primary C6 alcohol as the major
product, along with significant amounts of the diacylates.
Kattnig and Albert also observed that the regioselectivity
depended on the acylating agents in the presence of DMAP.[5]
The acylation of 6 with acetyl chloride or acetic anhydride has
been reported to predominantly give C6 acetate or C3
acetate, respectively. Burke also found that regioselectivity
of acylation of amphotericin B was influenced by the elec-
tronic nature of the carboxylate ion.[8]
more, the precise positioning of the carboxylate was expected
to be verified by the well-defined rigid catalyst structure.[13]
Catalyst 11a, in which the carboxylate group was linked
by a naphthyl spacer, was synthesized as shown in Scheme 4.
Recently, the carboxylate ion was also found to act as
a pivotal counteranion in asymmetric acylation reactions by
virtue of its interaction with chiral thiourea.[9] These results
indicated that the carboxylate ion played a crucial role not
only in the reactivity, but also in the regio- and stereoselec-
tivity of the acylation reaction.
Scheme 4. Preparation of catalyst 11a: a) [Pd(PPh3)4], K3PO4, DMF,
1208C, 12 h, 70%; b) diisobutylaluminum hydride, toluene, À788C to
À458C, 1 h, 82%; c) NaClO2, H2SO4, 2-methyl-2-butene, CH3CN, H2O,
08C, 2 h, 55%; d) nBu4NOH, MeOH, RT, 12 h.
Recently, Glatthaar, Schreiner, et al. investigated the
structures and the dynamics of acetylpyridinium salts by X-
ray, spectroscopic, and computational experiments.[10] Based
on the results, carboxylate ion 4 interacting with pyridinium
Suzuki–Miyaura cross-coupling between 13 and aryl iodide
14[14] gave 15. After the transformation of the CN group in 15
to carboxylic acid 16, carboxylate catalyst 11a was obtained as
a tetrabutylammonium salt by treatment of an equivalent
amount of tetrabutylammonium hydroxide.
X-ray analysis of 16 indicated that the carboxyl group was
positioned proximal to the pyridine ring in a face-to-face
geometry with a distance of 2.9 ꢀ between the pyridine C3
and the carbonyl carbon (Figure 1).
À
C2 H and acetyl H via hydrogen-bonding was proposed as
a general base to guide the alcohol towards the carbonyl
group of 3. Zipse and co-workers proposed a model of the TS-
I on the basis of results obtained in a computational study.[11]
They proposed that the carboxylate ion 4, positioned
proximal to the acylpyridinium ion 3 by a hydrogen-bonding
À
interaction with the C2 H of the pyridinium moiety, acted as
a general base; however, experimental evidence supporting
the position of the carboxylate, which acts as a general base in
TS-I, has not been obtained to date. Determination of the
carboxylate position, which affects both reactivity and
regioselectivity, would be valuable for a mechanistic under-
standing as well as for the rational design of DMAP-related
nucleophilic catalysts.[12] This context prompted us to exper-
imentally investigate the positioning of the carboxylate ion.
The carboxylate position during DMAP-catalyzed acyla-
tion was investigated by designing the relative positions of an
ion pair comprising 3 and 4 in TS-I by preparing a series of
biaryl DMAP catalysts 10a–12a in the tetrabutyl ammonium
salt forms (Scheme 3).
Figure 1. X-ray analysis of 16 (ellipsoids set at 60% probability).
C gray, O red, N blue; hydrogen atoms are omitted for clarity. a) View
through the carboxyl group to the pyridine moiety. b) Distance between
the carbonyl carbon and the C3 position of the pyridine ring.
The catalytic activities of the catalyst 10a
and the corresponding methyl ester 10b were
investigated in a kinetic study. The acetylation
of cyclohexanol was carried out in the pres-
ence of 5 mol% catalyst under pseudo first-
order conditions employing 10 equivalent
amounts of acetic anhydride and Et3N in
CDCl3 (Figure 2a). The conversion was moni-
Scheme 3. a) DMAP derivatives having an internal carboxylate group. b) Representation of
the transition state (TS-II) involving the internal carboxylate group.
1
tored by H NMR spectroscopy. Compounds
10a and 10b yielded indistinguishable rate
constants (k10a = 1.2 ꢁ 10À2 minÀ1, k10b = 1.2 ꢁ
In these catalysts, the internal carboxylate was connected
at different distances from and in different geometries
relative to the pyridine moiety by a rigid aryl spacer
(Scheme 3a). Appropriate positioning of the carboxylate
with respect to the acylpyridinium ion was expected to
increase the acylation rate by activation of the alcohol by the
internal carboxylate group in TS-II (Scheme 3b). Further-
10À2 minÀ1; k10a/k10b = 1.0; Figure 2b). Therefore, the internal
carboxylate in 10a negligibly affected the acylation efficiency.
The catalytic activities of 10a and 10b were lower than the
activity of DMAP (kDMAP = 1.3 ꢁ 10À1 minÀ1, k10a/kDMAP
=
0.094). We also tested the catalytic activity of 10c,[15] which
did not include substituents on the ring. The activity of 10c
(k10c = 9.6 ꢁ 10À3 minÀ1) was lower than the activity of DMAP
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Instead, the low activities reflected the intrinsic properties
of the C3-substituted DMAP derivative. This clearly indi-
cated that a carboxylate at the peri position in 11a enhanced
the activity of the intrinsically low-potency DMAP deriva-
tives that included a naphthyl skeleton.
Next, we evaluated the catalytic activities of 12a
(Scheme 3) and 12b (Scheme 5), in which the carboxylate
groups were linked to the naphthyl ring through an alkene
Scheme 5. Structures of 12b, 17a, and 17b.
Figure 2. a) Acetylation of cyclohexanol under pseudo first-order con-
ditions: 0.05m substrate concentration. b) Kinetic profiles of the
acetylation of cyclohexanol, catalyzed by 10a–10c and DMAP.
spacer. The activities of the catalysts were similar (k12a = 5.4 ꢁ
10À3 minÀ1, k12b = 8.1 ꢁ 10À3 minÀ1; k12a/k12b = 0.7; see the Sup-
porting Information). Thus, a carboxylate group tethered by
a two-carbon spacer to the naphthyl ring did not accelerate
the reaction, even though 11a, with a carboxylate group
and comparable with the activities of the catalysts 10a and
10b. This result suggested that the activity of a catalyst with
a phenyl substituent at the C3 position of the pyridine ring
was intrinsically lower than the activity of DMAP.
linked directly to the naphthyl ring, was highly active (k11a
/
k
12a = 25). This indicated that only a carboxylate positioned
In sharp contrast to the results obtained using catalysts
10a and 10b, catalyst 11a, with a carboxylate group at the peri
position of the naphthyl ring, showed a higher catalytic
activity than the corresponding methyl ester 11b (k11a = 1.3 ꢁ
10À1 minÀ1, k11b = 1.0 ꢁ 10À2 minÀ1; k11a/k11b = 13) or 11c[15]
appropriately, as found in 11a, could accelerate the acylation
reaction.
Catalyst 17a (Scheme 5), possessing an alkyl spacer, was
prepared, and its catalytic activity was measured. No signifi-
cant differences between the activities of 17a (k17a = 4.8 ꢁ
without an internal carboxyl group (k11c = 1.4 ꢁ 10À2 minÀ1
;
10À3 minÀ1) and the corresponding methyl ester 17b (k17b
=
k11a/k11c = 9.6), under the conditions employed for Figure 2
5.9 ꢁ 10À3 minÀ1, k17a/k17b = 0.8) were observed (see the Sup-
porting Information). This indicated that a carboxylate ion
connected by a flexible two-carbon spacer did not affect the
acylation efficiency. The activities of 17a and 17b were lower
(Figure 3a).[16] Although the activities of the catalysts 11b and
11c were lower than the activity of DMAP (k11b/kDMAP
=
0.077, k11c/kDMAP = 0.10),[17] the activity of 11a approached
that of DMAP (k11a/kDMAP = 1.0). Given that 11b, 11c, and
10c showed comparable activities (Figure 3a, k10c = 9.6 ꢁ
10À3 minÀ1), the relatively low activities of 11b and 11c does
not appear to have arisen from the steric effects of the
carboxymethyl group at the peri position and/or the naphthyl
ring itself.
than the activity of DMAP (k17a/kDMAP = 0.036, k17b/kDMAP
=
0.045). Therefore, the catalytic activities of catalysts with
a substituent at the C3 position of the pyridine ring were
generally low,[18] except for 11a.
The relative catalytic activities on acetylation of all
catalysts with respect to the simple biphenyl catalyst 10c are
summarized in Figure 4. This diagram clearly shows that the
activity of 11a was particularly high. The carboxylate position
Figure 3. a) Kinetic profiles of the acetylation of cyclohexanol catalyzed
by 11a–11c under the identical conditions employed for Figure 2. The
kinetic activities of 10c and DMAP, shown in Figure 2, are also
included. b) Structures of 11b and 11c.
Figure 4. Relative catalytic activities of the catalysts and DMAP with
respect to the biphenyl catalyst 10c on the cyclohexanol acetylation.
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that enhanced the acylation rate most efficiently was deter-
mined to be as shown in 11a.
The effects of the acylating agent were further inves-
tigated in the presence of benzoic anhydride (Figure 5a). The
benzoylation rate of cyclohexanol was evaluated in the
the relative acetylation rates (k11a/kDMAP = 1.0), may arise
from the deceleration of the DMAP (1)-catalyzed benzoyla-
tion reaction. This observation supported the notion that the
higher acylation rate by 11a arose from general base catalysis
of the internal carboxylate, as expected in the TS-II (Sche-
me 3b).
4-Pyrrolidinopyridine (PPY) has been known to be
a more potent nucleophilic catalyst than DMAP.[19] The
benzoylation activity of 11a approached the activity of PPY
(kPPY = 1.8 ꢁ 10À1 hÀ1, k11a/kPPY = 1.1; Figure 5b). The high
activity of 11a indicated that the catalytic potential of
DMAP-type nucleophilic catalysts may be controlled by the
positioning of the counteranion.
The most stable structures of the N-acetylpyridinium salts
derived from 10a–12a and 17a at the B3LYP/6-31G* level are
shown in Figure 6 (ac-10a–ac-12a and ac-17a).[20] In each of
Figure 5. a) Benzoylation of cyclohexanol under pseudo first-order
conditions using 10 equivalents of Bz2O at the substrate concentration
of 0.05m. b) Kinetic profiles of the cyclohexanol benzoylation, cata-
lyzed by 11a–11c, DMAP, or PPY. c) Structures of the acylpyridinium
salts generated from benzoic anhydride and DMAP or 11a.
presence of 5 mol% of the catalysts 11a–11c or DMAP
under pseudo first-order conditions employing 10 equivalents
of benzoic anhydride (Figure 5a). The relative activity of 11a
with respect to 11b or 11c increased beyond the acetylation
activity given in Figure 3.
The relative benzoylation rate constants employing 11a
(k11a = 2.0 ꢁ 10À1 hÀ1) versus 11b (k11b = 7.2 ꢁ 10À3 hÀ1), and
11a versus 11c (k11c = 1.5 ꢁ 10À2 hÀ1) were found to be 28 and
14, respectively, both of which were larger than the relative
Figure 6. 3D structures of ac-10a–ac-12a, ac-17a, ac-10a-TS, and ac-
11a-TS optimized at the B3LYP/6-31G* level (C gray, O red, N blue).
Distances between the atoms are in ꢂ. Hydrogen atoms are partially
omitted for clarity. Relative energy differences [kcalmolÀ1] between TS
and N-acetylpiridinium salt–MeOH complex (RC is depicted in the
Supporting Information) are shown in parentheses. Relative energy
differences [kcalmolÀ1] between TS and RC in the catalyst moiety (10a
and 11a) at the B3LYP/6-31+G* level are shown in italics.
acetylation rates reported in Figure 3 (k11a/k11b = 13, k11a/k11c
=
9.6).
The benzoylation activity of 11a was 2.5 times greater
than the activity of DMAP (kDMAP = 8.2 ꢁ 10À2 hÀ1, k11a
DMAP = 2.5), although the acetylation activities of 11a and
the structures, the anionic carboxylate groups are oriented
parallel to the N-acylpyridinium moiety to interact with both
the positive NMe2 group[21] and the acetyl group by the
electrostatic interaction. Focusing on the conformational
space of the reactive site, the shorter distance between the
carboxylate group and the reacting carbonyl carbon of the
acylpyridinium ion is found in ac-11a (3.445 ꢀ). The distance
between C3 of the pyridinium moiety and the carbonyl carbon
in ac-11a was 2.757 ꢀ, which is comparable to the distance
(2.9 ꢀ) observed in the crystal structure of 16 (Figure 1). To
verify the ideal linker structure in the highly active 11a, the
activation energies and the transition structures with MeOH
as a model alcohol were compared between 10a and 11a,
which contain relatively similar and rigid linker structure but
exhibit much different activity. In agreement with the
experimental catalyst activities, the activation energy is
higher in ac10a-TS (10.6 kcalmolÀ1) than ac-11a-TS (8.1 kcal
/
k
DMAP were almost identical. The superior activity of 11a
was further established by substituting the acylating agent
(Ac2O) with Bz2O. In the benzoylation reaction, the counter-
anion of N-benzoylpyridinium ion 3’ derived from DMAP
was benzoate 4’ (Figure 5c), which was a less-effective (lower
basicity) general base than the acetate ion. The DMAP-
catalyzed benzoylation reaction could, therefore, be decel-
erated by reducing the reactivity of the acylpyridinuim salt in
TS-I by the less basic external base 4’ (Scheme 1). On the
other hand, the activity of the acylpyridinium ion 11a’ derived
from 11a was not influenced by the external benzoate 4’
because the internal carboxylate preferentially acted as
a general base. Therefore, the larger relative benzoylation
rates of 11a versus DMAP (k11a/kDMAP = 2.5), as compared to
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molÀ1). This energy difference could be explained by the
energies required to deform N-acetylpiridinium salt–MeOH
complexes (RC) into the corresponding transition states (ac-
10a-TS and ac-11a-TS). The deformation energies estimated
at the B3LYP/6-31 + G* level single point energy calculations
of the catalyst unit (10a, 11a) between RC and TS is higher in
ac-10a-TS (6.4 kcalmolÀ1) than ac-11a-TS (1.8 kcalmolÀ1; for
details, see the Supporting Information). This indicates that
the larger structural deformation during the deprotonation of
the alcohol hydroxy group is required in ac-10a-TS rather
than ac-11a-TS. In conclusion, a carboxylate group positioned
in close proximity to the pyridine ring in a face-to-face
geometry was found to act as an effective general base to
accelerate the acylation reaction.
In summary, we determined the position of the carbox-
ylate ion that accelerates the DMAP-catalyzed acylation by
preparing a series of DMAP derivatives with an internal
carboxylate. The ability to accelerate the acylation reaction
by introducing an internal carboxylate group offers new
possibilities for the design of further potent nucleophilic
catalysts. Applications to asymmetric acylation by virtue of
the axial chirality of 11a and related carboxylate catalysts are
under investigation.[22]
Am. Chem. Soc. 2010, 132, 13624; c) E. G. Klauber, N. Mittal,
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[11] E. Larionov, F. Achrainer, J. Humin, H. Zipse, ChemCatChem
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[12] For reviews of DMAP-related nucleophilic catalysts, see:
a) E. F. V. Scriven, Chem. Soc. Rev. 1983, 12, 129; b) R. P.
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[13] DMAP derivatives possessing a carboxylate linked to an N,N-
dimethylamino moiety via a flexible alkyl chain were prepared
by Mizutani and Yoshida for the regioselective acylation of
a glucose derivative 6; see: T. Kurahashi, T. Mizutani, J. Yoshida,
Tetrahedron 2002, 58, 8669.
[14] P. C. Gros, A. Doudouh, C. Woltermann, Chem. Commun. 2006,
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[15] A. C. Spivey, T. Fekner, S. E. Spey, H. Adams, J. Org. Chem.
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[16] 11a yielded a higher activity relative to 11c in the presence of
5 mol% catalyst with two equivalents of Ac2O. In this experi-
ment, the acetylation of cyclohexanol was monitored until full
conversion (see the Supporting Information).
[17] The low activity of 11c was consistent with the results obtained
in the acetylation of 1-methylcyclohexanol by Spivey and co-
workers, see Ref. [15].
Received: January 25, 2013
Revised: March 18, 2013
[18] This may arise from the unfavorable equiliblium formation of
acylpyridinium ion owing to less delocalization of positive
charge by nitrogen lone pair caused by steric repulsion between
the substituent at C3 position of pyridine and the dimethylamino
group; see Ref. [3b]. Potent DMAP-type catalysts were devel-
oped by securing overlap between the nitrogen lone pair and the
pyridine p*-orbital; see: a) M. R. Heinrich, H. S. Klisa, H. Mayr,
W. Steglich, H. Zipse, Angew. Chem. 2003, 115, 4975; Angew.
Chem. Int. Ed. 2003, 42, 4826; b) S. Singh, G. Das, O. V. Singh, H.
Han, Org. Lett. 2007, 9, 401; c) N. D. Rycke, G. Berionni, F.
Couty, H. Mayr, R. Goumont, O. R. P. David, Org. Lett. 2011, 13,
530.
Published online: May 6, 2013
Keywords: acylation · base catalysis · counteranions · ion pairs ·
.
organocatalysis
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Figure 6.
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