Enhancing the Catalytic Activity of 4-(Dialkylamino)pyridines by Conformational Fixation

Article abstract of DOI:10.1002/anie.200352289

Six times more active than DMAP (1), the tricyclic DMAP analogue 2 catalyzes the acetylation of a tertiary alcohol with acetic anhydride. The experimental results can be rationalized by quantum chemical calculations.

Full text of DOI:10.1002/anie.200352289

Communications
Powerful Acylation Catalyst
Enhancing the Catalytic Activity of 4-
(Dialkylamino)pyridines by Conformational
Fixation**
Markus R. Heinrich, Heike Sabine Klisa, Herbert Mayr,
Wolfgang Steglich,* and Hendrik Zipse
Dedicated to Professor Heinrich Nöth
on the occasion of his 75th birthday
4-(Dimethylamino)pyridine (DMAP, 1) was introduced to
synthetic chemistry as a powerful nucleophilic group-transfer
catalyst more than three decades ago[1,2] and has become a
standard
reagent[3]
for
acylation,
esterification,[4]
macrolactonization,[5] and silylation reactions,[6] to mention
only a few applications. DMAP has since served as a basis for
several research groups for the development of chiral
acylation catalysts.[7] Herein we report on the enhanced
[*] Prof. Dr. W. Steglich, Dr. M. R. Heinrich, H. S. Klisa, Prof. Dr. H. Mayr,
Prof. Dr. H. Zipse
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, 81377 München (Germany)
Fax: (+49)89-2180-77756
E-mail: wos@cup.uni-muenchen.de
[**] We thank Sabine Voss for valuable experimental support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4826
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200352289
Angew. Chem. Int. Ed. 2003, 42, 4826 –4828

Angewandte
Chemie
catalytic activity of 4-(dialkylamino)pyr-
idines in which the 4-amino group is
conformationally fixed in a ring fused to
number of DMAP derivatives at the B3LYP/6-311 + G(d,p)//
B3LYP/6-31G(d) level of theory,[12] whereby more negative
values indicate better stabilization of the acetyl group relative
to pyridine (Table 1). As expected, a strongly negative
the pyridine ring.
Previous work showed that 4-pyrro-
lidinopyridine (PPY, 2)[3a,8,9] is a more
Table 1: Calculated reaction enthalpies DHrxn for the acetyl-transfer
reaction (1) and experimental half-lives t1/2 for the reference reaction (2).
effective acylation catalyst than DMAP.
Evidently the catalytic activity depends
on the stabilization of the N-acyl pyridinium ion by inter-
action with the lone pair of electrons of the 4-amino group.[10]
Therefore, an increase in this interaction should lead to
enhanced catalytic performance.
DMAP (1)
PPY (2)
6
7
DHrxn [kJmolÀ1
t1/2 [min]
]
À82.1
À93.1
À96.0
À108.9
151
69
63
26
Studies on 4,4’-bis(dialkylamino)benzhydryl cations
showed a dramatic increase in stabilization when the nitrogen
atom was part of a conformationally fixed ring system. This is
illustrated by the series of benzhydryl cations 3–5 (Scheme 1),
reaction enthalpy was calculated for DMAP, which confirms
the special properties of this compound from the viewpoint of
the stability of the acyl intermediate. Reaction enthalpies
more negative by 11–14 kJmolÀ1 were predicted for the singly
annulated DMAP analogue 6 and PPY (2). Annulation of an
additional six-membered ring as in 7 lowers the reaction
enthalpy by 27 kJmolÀ1. These results suggest that the DMAP
derivative 7 may be a significantly better acyl-transfer catalyst
than DMAP itself or even 2.
The known pyridonaphthyridine derivative 7[13] was
prepared from 1,6-naphthyridine in four steps according to
a literature procedure.[13b] The bicyclic analogue 6 was
synthesized by reaction of the ortho-lithiated derivative of
4-(tert-butoxycarbonylamino)pyridine[7e] with 1-chloro-3-
iodopropane and reduction of the resulting tert-butoxycar-
bonyl (Boc) derivative[14] with diisobutylaluminum hydride.[15]
To test the catalytic activity of the 4-aminopyridines 1 , 2,
6, and 7, the acetylation of 1-ethynylcyclohexanol (8) with
acetic anhydride in the presence of triethylamine as the
auxiliary base was studied in CDCl3 at 208C [standard
reaction, Eq. (2)].[3a] The reaction was monitored by
Scheme 1. Relative reactivities of benzhydryl cations derived from the
rate constants of their reactions with p nucleophiles (208C).[11]
in which the bisjulolidinyl derivative 5 is about 300 times less
electrophilic than the simple bis(dimethylamino) derivative
3.[11] We reasoned that conformational fixation combined with
the inductive electron-donating effect of an alkyl group in the
meta position might have a similar effect on the correspond-
ing (4-dialkylamino)pyridines and cause an increase in
electron density at the pyridine nitrogen atom, thus resulting
in stabilization of the N-acyl pyridinium ion derivative. We
used the 4-(dialkylamino)pyridines 6 and 7 for this study.
1H NMR spectroscopy under the conditions described,
based on the increase in the intensity of the CH3CO signals.
The results are illustrated in Figure 1 and summarized in
Table 1.
The results indicate that the incorporation of the 4-amino
group in one single six-membered ring (as in 6) leads to an
enhancement of the catalytic activity similar to that observed
for 2 relative to 1. Compound 7, in which the amino group is
incorporated in two six-membered rings, exhibits a substantial
increase in activity and appears to be about six times more
active than DMAP (1). It even outperforms PPY (2), until
now the best catalyst known for this transformation, by a
factor of 2.5. The acylation of the sterically hindered alcohol 8
was complete within 2 to 3 h under the catalysis of 7, whereas
the DMAP- or PPY-catalyzed reactions were far from
completion after the same amount of time (Figure 1).[16]
In conclusion, we have shown that it is possible to develop
nucleophilic acylation catalysts that are superior to the
The expected enhanced stability of the N-acyl intermedi-
ates derived from the DMAP analogues 6 and 7 can be
verified through theoretical evaluation of the reaction
enthalpies for the acetyl-transfer reaction shown in Equa-
tion (1). Reaction enthalpies at 298 K were calculated for a
Angew. Chem. Int. Ed. 2003, 42, 4826 –4828
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4827

Communications
9443, and references therein; f) A. C. Spivey, T. Fekner, S. E.
Spey, J. Org. Chem. 2000, 65, 3154 – 3159; g) A. C. Spivey, A.
Maddaford, T. Fekner, A. J. Redgrave, C. S. Frampton, J. Chem.
Soc. Perkin Trans. 1 2000, 3460 – 3468; h) G. C. Fu, Acc. Chem.
Res. 2000, 33, 412 – 420, and references therein; i) A. C. Spivey,
A. Maddaford, T. Fekner, D. P. Leese, A. J. Redgrave, C. S.
Frampton, J. Chem. Soc. Perkin Trans. 1 2001, 1785 – 1794; j) G.
Priem, B. Pelotier, S. J. F. Macdonald, M. S. Anson, I. B. Camp-
bell, J. Org. Chem. 2003, 68, 3844 – 3848; k) S. France, D. J.
Guerin, S. J. Miller, T. Lectka, Chem. Rev. 2003, 103, 2985 – 3012.
[8]W. Steglich, G. Höfle, Tetrahedron Lett. 1970, 54, 4727 – 4730.
[9]A. Hassner, L. R. Krepski, V. Alexanian, Tetrahedron 1978, 34,
2069 – 2076.
[10]Compare the analogous effects in the enamine series: a) S.
Hünig, H. Hoch, Fortschr. Chem. Forsch. 1970, 14, 235 – 293;
b) B. Kempf, N. Hampel, A. R. Ofial, H. Mayr, Chem. Eur. J.
2003, 9, 2209 – 2218.
[11]a) H. Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang, B. Janker,
B. Kempf, R. Loos, A. R. Ofial, G. Remennikov, H. Schimmel, J.
Am. Chem. Soc. 2001, 123, 9500 – 9512; b) H. Mayr, B. Kempf,
A. R. Ofial, Acc. Chem. Res. 2003, 36, 66 – 77.
Figure 1. Acetylation of 8 (c=0.2 molLÀ1) with Ac2O (c=0.4 molLÀ1
)
in the presence of NEt3 (c=0.6 molLÀ1) and various (4-dialkylamino)-
pyridine catalysts (c=0.02 molLÀ1) in CDCl3 at 208C.
[12]All structures were first optimized at the Becke3LYP/6-31G(d)
level of theory. Zero-point vibrational energies and thermo-
chemical corrections to enthalpies at 298 K were calculated
based on the rigid-rotor/harmonic-oscillator model at the same
level of theory. Single-point energies were then calculated at the
Becke3LYP/6-311 + G(d,p) level of theory. Combination of the
Becke3LYP/6-311 + G(d,p) total energies with the previously
calculated thermochemical data yielded the enthalpies termed
“B3LYP/6-311 + G(d,p)//B3LYP/6-31G(d)” in the text. Boltz-
mann averaging of enthalpies was performed for those systems
that display more than one low-energy conformation. All
calculations were performed with the Gaussian 98 (Rev. A.7)
package.[17] Energy data and structural parameters for pyridine,
the pyridine bases 1 , 2, 6, and 7, and their N-acetyl derivatives
are given in the Supporting Information.
[13]a) K. Tsuda, S. Saeki, S. Imura, S. Okuda, Y. Sato, H. Mishima, J.
Org. Chem. 1956, 21, 1481 – 1486; b) T. Sakomoto, N. Miura, Y.
Kondo, H. Yamanaka, Chem. Pharm. Bull. 1986, 34, 2018 – 2023.
[14]J. N. Reed, J. Rotchford, D. Strickland, Tetrahedron Lett. 1988,
29, 5725 – 5728.
[15]The synthesis of 6 and the spectroscopic data of compounds 6
and 7 are described in the Supporting Information.
[16]The importance of the auxiliary base is illustrated by the fact that
the half-life for the acetylation of 8 under the catalysis of 7 is
increased from 151 to 465 min if pyridine is used instead of
triethylamine.
[17]Gaussian 98 (Revision A.7), M. J. Frisch, G. W. Trucks, H. B.
Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G.
Zakrzewski, J. A. Montgomery, R. E. Stratmann, J. C. Burant, S.
Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin, M. C. Strain,
O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B.
Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Ochterski, G. A.
Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick,
A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski, J.
V. Ortiz, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M.
Challacombe, P. M. W. Gill, B. G. Johnson, W. Chen, M. W.
Wong, J. L. Andres, M. Head-Gordon, E. S. Replogle, J. A.
Pople, Gaussian, Inc., Pittsburgh, PA, 1998.
familiar DMAP. Compounds such as 7 are of potential value
for acylations that proceed in low yields because of undesired
side reactions when the less active catalysts 1 or 2 are used.
Moreover, the annulated derivative 7 provides a rigid, highly
reactive scaffold upon which new generations of chiral
DMAP derivatives can be built.
Received: July 2, 2003 [Z52289]
Keywords: ab initio calculations · acylation ·
.
dimethylaminopyridine · kinetics
[1]a) W. Steglich, G. Höfle, Angew. Chem. 1969, 81, 1001; Angew.
Chem. Int. Ed. Engl. 1969, 8, 981; b) G. Höfle, W. Steglich,
Synthesis 1972, 619 – 621.
[2]For kinetic evidence for the high catalytic activity of DMAP in
the benzoylation of aryl amines, see: L. M. Litvinenko, A. I.
Kirichenko, Dokl. Akad. Nauk SSSR Ser. Khim. 1967, 176, 97 –
100.
[3]For reviews, see: a) G. Höfle, W. Steglich, H. Vorbrüggen,
Angew. Chem. 1978, 90, 602 – 615; Angew. Chem. Int. Ed. Engl.
1978, 17, 569 – 583; b) E. F. V. Scriven, Chem. Soc. Rev. 1983, 12,
129 – 161; c) A. Hassner in Encyclopedia of Reagents for Organic
Synthesis, Vol. 3 (Ed.: L. A. Paquette), Wiley, Chichester, 1995,
pp. 2022 – 2024.
[4]a) B. Neises, W. Steglich, Angew. Chem. 1978, 90, 556 – 557;
Angew. Chem. Int. Ed. Engl. 1978, 17, 552; b) A. Hassner, V.
Alexanian, Tetrahedron Lett. 1978, 4475 – 4478.
[5]a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi,
Bull. Chem. Soc. Jpn. 1979, 52, 1989 – 1993; b) E. P. Boden, G. E.
Keck, J. Org. Chem. 1985, 50, 2394 – 2395.
[6]S. K. Chaudhary, O. Hernandez, Tetrahedron Lett. 1979, 99 – 102.
[7]a) E. Vedejs, X. Chen, J. Am. Chem. Soc. 1996, 118, 1809 – 1810;
b) J. C. Ruble, G. C. Fu, J. Org. Chem. 1996, 61, 7230 – 7231; c) T.
Kawabata, M. Nagato, K. Takasu, K. Fuji, J. Am. Chem. Soc.
1997, 119, 3169 – 3170; d) B. Tao, J. C. Ruble, D. A. Hoic, G. C.
Fu, J. Am. Chem. Soc. 1999, 121, 5091 – 5092; e) A. C. Spivey, T.
Fekner, S. E. Spey, H. Adams, J. Org. Chem. 1999, 64, 9430 –
4828
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 4826 –4828