Synthesis and reactivity of highly nucleophilic pyridines

Article abstract of DOI:10.1021/ol1029589

3,4,5-Triamino-substituted pyridines are avid for electrophiles but are still willing to give them back. In these compounds three amino groups conjoin their forces into the heterocyclic nitrogen, making it a powerful Lewis base. A short and efficient synt

Full text of DOI:10.1021/ol1029589

ORGANIC
LETTERS
2011
Vol. 13, No. 3
530-533
Synthesis and Reactivity of Highly
Nucleophilic Pyridines
Nicolas De Rycke,† Guillaume Berionni,‡ Franc¸ois Couty,† Herbert Mayr,‡
Regis Goumont,† and Olivier R. P. David*,†
UniVerSud Paris, Institut LaVoisier, UniVersite´ de Versailles St. Quentin-en-YVelines,
UMR 8180, 45 aVenue des Etats-Unis, 78035, Versailles, France, and
Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Department Chemie, Butenandtstr.
5-13, 81377 Mu¨nchen, Germany
odaVid@chimie.uVsq.fr
Received December 7, 2010
ABSTRACT
3,4,5-Triamino-substituted pyridines are avid for electrophiles but are still willing to give them back. In these compounds three amino groups
conjoin their forces into the heterocyclic nitrogen, making it a powerful Lewis base. A short and efficient synthesis is described, and the
origin of its unique activity in nucleophilic organocatalysis is rationalized by kinetics and thermodynamic quantifications.
4-Dimethylaminopyridine (DMAP) 1 is a classical nucleo-
philic organocatalyst which was initially employed as an
acylation catalyst.1,2 Chiral derivatives have later been
developed to promote diverse enantioselective transforma-
tions.3 By embedding the dimethylamino group of DMAP
in a tricyclic framework, it is possible to improve the catalytic
activity of DMAP.4
(3) For reviews on chiral DMAPs: (a) Spivey, A. C.; Maddaford, A.;
Redgrave, A. Org. Prep. Proc. Int. 2000, 32, 331–365. (b) France, S.;
Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003, 103, 2985–3012.
(c) Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420. (d) Fu, G. C. Acc. Chem.
Res. 2004, 37, 542–547. (e) Fu, G. C. Acc. Chem. Res. 2006, 39, 853–860.
(f) Wurz, R. P. Chem. ReV. 2007, 107, 5570–5595. (g) Marion, N. M.; Fu,
G. C. Applications of Aza- and Phosphaferrocenes and Related Compounds
in Asymmetric Catalysis. Chiral Ferrocenes in Asymmetric Catalysis; Dai,
L.-X., Hou, X.-L., Eds.; Wiley-VCH: New York, 2010; Chapter 11. For
recent primary literature: (h) Spivey, A. C.; Leese, D. P.; Zhu, F.; Daveya,
S. G.; Jarvest, R. L. Tetrahedron 2004, 60, 4513–4525. (i) Spivey, A. C.;
Arseniyadis, S.; Fekner, T.; Maddaford, A.; Leese, D. P. Tetrahedron 2006,
62, 295–301. (j) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va,
P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925–934. (k) Dochnahl, M.;
Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 2391–2393. (l) Duffey, T. A.;
Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14–15.
† Universite´ de Versailles St. Quentin-en-Yvelines.
‡ Ludwig-Maximilians-Universita¨t Mu¨nchen.
(1) (a) Steglich, W.; Ho¨fle, G. Angew. Chem., Int. Ed. Engl. 1969, 8,
981. (b) Ho¨fle, G.; Steglich, W. Synthesis 1972, 619–621. (c) Litvinenko,
L. M.; Kirichenko, A. I. Dokl. Akad. Nauk SSSR Ser. Khim. 1967, 176,
97–100
.
(2) (a) Ho¨fle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569–583. (b) Scriven, E. F. V. Chem. Soc. ReV. 1983, 12,
129–161. (c) Hassner, A. In Encyclopedia of Reagents for Organic Synthesis,
Vol. 3; Paquette, L. A., Ed.; Wiley: Chichester, 1995; pp 2022-2024. (d)
Murugan, R.; Scriven, E. F. V. Aldrichimica Acta 2003, 36, 21–27. (e)
Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1998, 31, 494–501. (f) Steglich,
W.; Ho¨fle, G. Tetrahedron Lett. 1970, 54, 4727–4730. (g) Hassner, A.;
Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34, 2069–2076
.
10.1021/ol1029589  2011 American Chemical Society
Published on Web 12/27/2010

More recently, this strategy was combined with the
introduction of additional amino moieties at the 3- and
5-positions, which further increases electron density in
the pyridine ring.5 In the context of our research, we
became interested in the work of Han’s group on triami-
nopyridine catalysts derived from 2 (see Scheme 1).5b
Scheme 2. Four-Step Synthesis of Unsubstituted superDMAP 2
Scheme 1. Han’s Synthesis of Key Intermediate 2
nitration of 4-pyridone8 and subsequent chlorination.9,10
Nucleophilic aromatic substitution of 4 with bis-(2-chloro-
ethyl)-amine 5 yielded 93% of 6. Catalytic hydrogenation
using palladium on charcoal under an atmospheric pressure
of hydrogen, in the presence of potassium carbonate, gave
2 as the sole product after simple filtration in essentially
quantitative yield.
With multigram quantities of compound 2 in hand, we
prepared a small library of diversely substituted super-
DMAPs; see Scheme 3. Dimethyl- and diethyl- derivatives
These compounds display very good catalytic activity and
are able to promote the acetylation of very hindered and
deactivated alcohols for which DMAP is inefficient. These
improved catalytic activities were found to correlate with
calculated acyl-transfer enthalpies. We now report on an
efficient access and modification of these compounds and
characterize their nucleophilic reactivities by the benzhy-
drylium method employing three-parameter eq 16 where
E and N parameters measure the strength of the electro-
phile and the nucleophile, respectively, while the s
parameter characterizes the sensitivity of the nucleophile
on variation of the electrophile.
Scheme 3. superDMAP Derivatives 2 and 2-R
log k(20 °C) ) s(N + E)
(1)
Key intermediate 2 was initially prepared by Han5b in four
steps from 3,4,5-triaminopyridine 3, the latter being prepared
in three steps from 4-aminopyridine7 as depicted in Scheme 1.
Our new preparation of key compound 2, depicted in
Scheme 2, takes advantage of the facile SNAr reaction of
secondary amines with pyridine 4 prepared by double
(4) For a review on DMAP derivatives potency: (a) Spivey, A. C.;
Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436–5441. For primary
literature: (b) Heinrich, M. R.; Klisa, H. S.; Mayr, H.; Steglich, W.; Zipse,
H. Angew. Chem., Int. Ed. 2003, 42, 4826–4828. (c) Singh, S.; Das, G.;
Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 1983–1986. (d) Wong,
K. T.; Ku, S. Y.; Yen, F. W. Tetrahedron Lett. 2007, 48, 5051–5054.
(5) (a) Held, I.; Xu, S. J.; Zipse, H. Synthesis 2007, 8, 1185–1196. (b)
Singh, S.; Das, G.; Singh, O. V.; Han, H. Org. Lett. 2007, 9, 401–404. (c)
Held, I.; Larionov, E.; Bozler, C.; Wagner, F.; Zipse, H. Synthesis 2009,
2267–2277.
2-Me and 2-Et were prepared by reductive amination as
previously described by Han, although a modified procedure
for the purification step increased the yield to 89% for 2-Me
and 97% for 2-Et. As reductive amination was unsuccessful
with benzaldehyde, we switched to a two-step procedure
involving acylation and amide reduction to prepare the dibenzyl
derivative 2-Bn. Double benzoylation with benzoyl chloride in
(6) General reviews: (a) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem.
Res. 2003, 36, 66–77. (b) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl.
1994, 33, 938–957. (c) Mayr, H.; Patz, M.; Gotta, M. F.; Ofial, A. R. Pure
Appl. Chem. 1998, 70, 1993–2000. (d) Mayr, H.; Ofial, A. R. In Carbocation
Chemistry; Olah, G. A., Prakash, G. K. S., Eds.; Wiley: Hoboken, NJ, 2004;
Chapter 13, pp 331-358. (e) Mayr, H.; Ofial, A. R. Pure Appl. Chem.
2005, 77, 1807–1821. (f) Lucius, R.; Loos, R.; Mayr, H. Angew. Chem.,
Int. Ed. 2002, 41, 91–95. (g) Baidya, M.; Kobayashi, S.; Brotzel, F.;
Schmidhammer, U.; Riedle, E.; Mayr, H. Angew. Chem., Int. Ed. 2007, 46,
6176–6179. (g) Nucleophilicities of arenes: (h) Mayr, H.; Bartl, J.; Hagen,
G. Angew. Chem., Int. Ed. Engl. 1992, 31, 1613–1615.
(8) Diehl, R.; Walworth, B. Patent US3826643 1974/07/30, American
Cyanamid Co.
(9) Okafor, C. O. J. Org. Chem. 1967, 32, 2006–2007
.
(7) Graboyes, H.; Day, A. R. J. Am. Chem. Soc. 1957, 79, 6421–6426.
(10) Petrow, V. A.; Rewald, E. L. J. Chem. Soc. 1945, 313–315.
Org. Lett., Vol. 13, No. 3, 2011
531

Table 1. Benzhydrylium Ions 13a-f Used As Reference
Electrophiles in This Work
Figure 1. Plots of log k versus E for the reactions of DMAP
derivatives 2-R with benzhydrylium ions 13a-f.
Table 2. Second-Order Rate Constants for Reactions of DMAP
Derivatives 2-R and DMAP 1, with Benzhydrylium
Tetrafluoroborates 13a-f in Acetonitrile at 20 °C
derivative
Ar2CH+
k [M-1 s-1
]
N/s
pyridine gave 2-Bz in 89% yield, which was reduced with the
borane-DMS complex to yield 82% of 2-Bn. The diacetylated
compound 2-Ac was prepared using acetic anhydride in pyridine
and was isolated in 84% yield.
In order to compare the nucleophilic reactivities of these
substituted pyridines 2-R with those of other pyridines, we
have measured the rates of their reactions with benzhydry-
lium ions 13a-f (see Scheme 4 and Table 1) in acetonitrile.
2-Me
13b
13c
13d
13e
13b
13c
13d
13e
13c
13d
13e
13f
13a
13b
13c
13d
13a
13b
13c
13d
4.46 × 105
1.51 × 105
3.99 × 104
1.63 × 104
7.93 × 105
3.21 × 105
7.05 × 104
2.75 × 104
5.52 × 105
1.42 × 105
5.43 × 104
2.48 × 104
9.82 × 105
1.25 × 105
5.81 × 104
1.00 × 104
5.45 × 105
6.75 × 104
2.47 × 104
3.69 × 103
4.46 × 105
16.65/0.58
16.81/0.60
2-Et
2-Bn
2-Ac
17.69/0.57
Scheme 4
.
Reaction of superDMAP 2-R with Benzhydrylium
Ions 13
15.39/0.60
14.19/0.67
2-Bz
DMAP1
14.95/0.6811
The decay of the benzhydrylium ion absorbances was
followed photometrically after combining benzhydrylium
tetrafluoroborates 13a-f with variable excesses of DMAPs
in a stopped-flow apparatus. Plots of pseudo-first-order rate
constants kobs versus the concentration were linear in all
reactions studied (see Supporting Information), with the
second-order rate constants k2 (Table 2) being the slopes of
the correlation lines. Plots of log k2 versus the electrophilicity
parameter E of benzhydrylium ions (Figure 1) are linear as
required by eq 1.
specific parameter s, respectively, which are listed in the
fourth column of Table 2. As the catalytic activities of tertiary
amines depend not only on their nucleophilicities but also
on their Lewis basicities,12 we have also measured some
equilibrium constants (K) which are listed in Table 3. As
benzhydrylium ions are colored and the resulting adducts
are colorless, the equilibrium constants for the reaction
depicted in Scheme 4 could be determined by UV-vis
(11) Brotzel, F.; Kempf, B.; Singer, T.; Zipse, H.; Mayr, H. Chem.sEur.
J. 2007, 13, 336–345.
From the slopes and the intercepts on the abscissa, we
have derived the nucleophilicity N and the nucleophile-
(12) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560–1638.
532
Org. Lett., Vol. 13, No. 3, 2011

demonstrated by Han et al.5b for the first two of these
compounds. In Figure 1 and Table 3 one can see that the
nucleophilic reactivities increase from DMAP over 2-Me and
2-Et to 2-Bn, which reacts 10 times faster than DMAP and
is thus the most nucleophilic pyridine reported to date. As
the increase of nucleophilicity is combined with a weaker
increase in Lewis basicity, one can calculate that the
pyridines 2-Et and 2-Bn are not only much better nucleo-
philes than DMAP but also, at the same time, somewhat
better nucleofuges. The unprecedented catalytic activity of
these derivatives is presently elucidated.
Table 3. Equilibrium Constants K [M-1] in Acetonitrile at 20°C
for DMAP 1 and 2-R Ordered According to N values, with k2
and k-2
[Ar2CH.DMAP+]
[Ar2CH+][DMAP]
(A - A0)
A[DMAP]
K )
)
)
(A - A0)
(A - A0)
ε d
A [DMAP] -
{
}
0
The straightforward access to this new class of pyridines
and the surprising observation that the nucleophilicity of
pyridines 2-Me and 2-Et developed by Han et al. can further
be augmented by variation of the alkyl side chain (Figure 2)
reaction with 13d
k2
reaction with 13e
k2
K
k-2
K
k-2
2-Bz 3.69 × 103 1.07 × 104 0.34
1.34 × 103 7.89 × 102 1.7
2-Ac 1.00 × 104 6.40 × 103 1.56
3.66 × 103 4.30 × 102 8.5
1
1.29 × 104 5.60 × 105 0.023 5.30 × 103 2.60 × 104 0.20
2-Et 7.05 × 104 9.10 × 105 0.077 2.75 × 104 8.08 × 104 0.34
2-Bn 1.42 × 105 1.47 × 106 0.096 5.43 × 104 1.89 × 105 0.28
spectroscopy. They can be expressed by the initial absorbance
of benzhydrylium ions (A0) and its final absorbance (A) after
the addition of DMAP derivatives, as shown in the following
equation.6g
Table 3, which compares rate and equilibrium constants
of two reaction series, shows that the substituents in pyridine
have significantly different effects on rate and equilibrium
constants. The trend that 13d is approximately 2.5 times more
electrophilic (k), but 8-21 times more Lewis acidic (K), than
13e has previously been observed in reactions of these
benzhydrylium ions with other nucleophiles13 and shall not
be discussed here. Table 3 values also show that the acetyl
substituted compound 2-Ac has a similar nucleophilicity (N)
as DMAP while its Lewis basicity (K) is 102 times smaller.
This difference is due to the much higher (102 times) leaving
group ability of 2-Ac compared with that of DMAP. A
similar effect is observed in the comparison of 2-Bz with
DMAP: 2-Bz is 3-4 times less nucleophilic and 30-50
times less Lewis basic than DMAP. Thus, 2-Ac and 2-Bz
may be suitable catalysts in processes requiring nucleophiles
comparable to DMAP but having a much better leaving
group ability.
Figure 2. Nucleophilicity scale for compounds 1 and 2-R.
stimulates further activities to generate tailor-made DMAP
derivatives suitable for variable catalytic processes.
Acknowledgment. We would like to acknowledge the
technical expertise of Dr. Elyane Kizilian (Universite´ de
Versailles St Quentin-en-Yvelines) in kinetics measurements.
We thank Dr. Armin Ofial (Ludwig-Maximilians-Universita¨t
Mu¨nchen) for data accuracy checking and Dr. Sami Lakhdar
(Ludwig-Maximilians-Universita¨t Mu¨nchen) for fruitful dis-
cussions.
Supporting Information Available: Full experimental
description, copies of proton and carbon NMR spectra, rate
constants and equilibrium constants measurements. This
material is available free of charge via the Internet at
http://pubs.acs.org.
At present, the N-alkyl substituted compounds 2-Me, 2-Et,
and 2-Bn have greater practical relevance, as already
(13) Schaller, H. F.; Tishkov, A. A.; Feng, X.; Mayr, H. J. Am. Chem.
Soc. 2008, 130, 3012–3022.
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