Preparation and Conversion of N-Halomethylpyridinium Halides. Comparison with Related Compounds

Article abstract of DOI:10.1021/jo982153z

N-Halomethylpyridinium halides 1a-f (X-CH₂Py⁺X^-, X = Cl, Br) have been synthesized from a three-component reaction mixture containing a thionyl halide 5, formaldehyde (6), and a pyridine 7. The salts 1a-f react readily with a variety of heterocyclic nucleophiles to yield (in general, nonsymmetrical) 1,1-bis(heteroarylium)methyl salts 2ea-hb, (pathway a). The use of trichloroacetaldehyde (9) instead of formaldehyde in this three-component reaction leads to a salt 10 in which one of the CH₂-hydrogens was replaced by the electron-withdrawing CCl₃ substituent. This changes the standard reaction pathway a of 1 in solution toward nucleophiles completely: the chlorinated N-vinylpyridinium salts 11 and 12 were formed after the reaction of 10 with pyridine or triphenylphosphane. These are useful intermediates for the synthesis of new N- and 4-substituted 1,4-dihydropyridines 13-15 as could be demonstrated for compound 11. To explain the reactivity pattern of compounds 1 and 10 and the related structures (MeO-CH₂Py⁺, 16, and Me₃SiO-CH₂Py⁺, 17) we calculated, using ab initio and DFT methods, reaction pathways a and b, both in the gas phase and in solution using ammonia as a model nucleophile. For all of these compounds, pyridine displacement (pathway b) dominates in the gas phase. As an example the energy gap between these two transition states for 1a turns out to be relatively small (11.6 kcal/mol in favor of pathway b, TS2). Solvation effects can therefore stabilize the corresponding transition state TS1 more effectively. In a MeCN solution, TS1 is 1.6 kcal/mol less energetic than TS2.

Full text of DOI:10.1021/jo982153z

J . Org. Chem. 1999, 64, 3113-3121
3113
P r ep a r a tion a n d Con ver sion of N-Ha lom eth ylp yr id in iu m Ha lid es.
Com p a r ison w ith Rela ted Com p ou n d s†
,
‡
‡
‡
‡
‡
Ernst Anders,* Andreas Opitz, Kurt Wermann, Bernd Wiedel, Martin Walther,
§
§
Wolfgang Imhof, and Helmar G o¨ rls
Institut f u¨ r Organische Chemie und Makromolekulare Chemie der Friedrich-Schiller-Universit a¨ t,
Humboldtstrasse 10, and Institut f u¨ r Anorganische und Analytische Chemie der
Friedrich-Schiller-Universit a¨ t, Lessingstrasse 8, D-07743 J ena, Germany
Received October 27, 1998
+
-
N-Halomethylpyridinium halides 1a -f (X-CH
three-component reaction mixture containing a thionyl halide 5, formaldehyde (6), and a pyridine
. The salts 1a -f react readily with a variety of heterocyclic nucleophiles to yield (in general,
2
Py X , X ) Cl, Br) have been synthesized from a
7
nonsymmetrical) 1,1-bis(heteroarylium)methyl salts 2ea -h b, (pathway a). The use of trichloro-
acetaldehyde (9) instead of formaldehyde in this three-component reaction leads to a salt 10 in
which one of the CH -hydrogens was replaced by the electron-withdrawing CCl substituent. This
2 3
changes the standard reaction pathway a of 1 in solution toward nucleophiles completely: the
chlorinated N-vinylpyridinium salts 11 and 12 were formed after the reaction of 10 with pyridine
or triphenylphosphane. These are useful intermediates for the synthesis of new N- and 4-substituted
1
,4-dihydropyridines 13-15 as could be demonstrated for compound 11. To explain the reactivity
+
+
2 3 2
pattern of compounds 1 and 10 and the related structures (MeO-CH Py , 16, and Me SiO-CH Py ,
1
7) we calculated, using ab initio and DFT methods, reaction pathways a and b, both in the gas
phase and in solution using ammonia as a model nucleophile. For all of these compounds, pyridine
displacement (pathway b) dominates in the gas phase. As an example the energy gap between
these two transition states for 1a turns out to be relatively small (11.6 kcal/mol in favor of pathway
b, TS2). Solvation effects can therefore stabilize the corresponding transition state TS1 more
effectively. In a MeCN solution, TS1 is 1.6 kcal/mol less energetic than TS2.
In tr od u ction
Pyridinium salts with an R-halogen atom in the N-
substituent had already been described in the thirties.1
Presumably because of the poor yields obtained in these
first synthetic approaches, they received little further
attention.4
-3
-6
Almost a decade ago, we reported the first preparation
of N-(1-bromo- and chloro-alkyl)heteroarylium salts 1
(Figure 1) by means of a three-component reaction con-
sisting of an N-heteroaromatic compound such as pyri-
dine (or pyridine derivatives such as isoquinoline, etc.),
an aldehyde, and thionyl chloride or bromide.7-9 This very
convenient method has provoked significant interest in
such compounds and has led to many interesting ap-
plications in synthesis.
These salts 1 have been reacted, in many cases in situ,
with a variety of nucleophiles. Systematic investigation
*
Fax: +49 (0)3641/948212; E-mail: c5eran@rz.uni-jena.de.
†
Dedicated to Professor Dr. Dirk Walther (J ena, Germany) on the
th
occasion of his 60 birthday.
‡
Institut f u¨ r Organische Chemie und Makromolekulare Chemie.
Institut f u¨ r Anorganische und Analytische Chemie.
§
(
(
(
(
1) Kr o¨ hnke, F. Chem. Ber. 1933, 66, 1386.
F igu r e 1. Reaction products 2-4 of N-(1-haloalkyl)-pyri-
dinium salts 1, R ) alkyl, aryl.
2) Kr o¨ hnke, F.; B o¨ rner, E. Chem. Ber. 1936, 69, 2006.
3) Kr o¨ hnke, F.; Heffe, W. Chem. Ber. 1937, 70, 864.
4) Almarzoqi, B.; George, A. V.; Isaacs, N. S. Tetrahedron 1986,
4
2, 601.
has yielded many useful products such as novel sulfonato-
pyridinium betaines 2a , phosphonato-pyridinium salts
(
(
5) Olofson, R. A.; Hansen, D. W., J r. Tetrahedron 1971, 27, 4209.
6) Calderon, C. H.; Shi, Y.-F.; Pressman, B. C. Cell. Pharmacol.
2
b, geminal substituted bisonium salts such as the
1
994, 1, 181.
7) Anders, E.; Tropsch, J . G.; Katritzky, A. R.; Rasala, D.; Vanden
Eynde, J .-J . J . Org. Chem. 1989, 54, 4808.
8) Anders, E.; Wermann, K.; Wiedel, B.; Vanden Eynde, J .-J . Liebigs
Ann./ Recueil 1997, 745.
9) Anders, E.; Tropsch, J . G. Bull. Soc. Chim. Belg. 1987, 96, 719.
(
phosphonium/pyridinium species 2c, and the bis(het-
eroarylium) compounds 2d .
Furthermore, one can synthesize five-, six- and seven-
membered ring systems 3a -d , as well as novel imines,
(
(
1
0.1021/jo982153z CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/15/1999

3
114 J . Org. Chem., Vol. 64, No. 9, 1999
Anders et al.
from 1. Recently, these salts 1 have been used as
precursors for the synthesis of other N-(1-alkyl/aryl/
Sch em e 1. N-Ha lom eth ylp yr id in iu m Sa lts 1a -f
fr om a Th ion yl Ha lid e 5, F or m a ld eh yd e (6), a n d a
P yr id in e 7
azolyl)methyl pyridinium salts.7
,8,10-14
Tricyclic (5/6/5)
salts 3e can also be generated from 1.15 In general, all of
these structures can be interpreted to be representatives
of compounds in which the heteroarylium moiety remains
in the molecule after the nucleophilic attack (e.g., 2a -
d , pathway a) or of those in which that moiety was
substituted by a second nucleophile (pathway b). Product
examples of the latter are the heterocycles 3a -e.
Although there are many synthetic applications for the
pyridinium salts 1 (with R ) aryl, alkyl), not much is
known about the parent halides 1 with R ) H. In
addition, nothing is known about the salts 1a -f or other
examples of 1 in which R is a strongly electron-with-
drawing substituent (Figure 1). A general synthesis for
compounds of this type or structural/reactivity studies
have not been reported.
B3LYP/6-31+G* level of theory. The Onsager method,25
as implemented in Gaussian 94, was used to estimate
solvation effects (the dielectric constant of the polar
solvent MeCN (35.9) was employed) at the HF/6-31+G*
level. The HF results were compared with semiempirical
calculations using the AM126 and PM3 parameter set,
as implemented in MOPAC93.28 Solvation effects were
carried out at the semiempirical level using the COSMO
We partially fill this void with this paper, in which we
report a general synthetic method which leads to 1a -f.
We also report the first results of investigations which
explain the structure and reactivity patterns of these new
compounds. It is noteworthy that such R-halogen sub-
stituted N-methylpyridinium salts could be of preparative
interest as starting compounds for the synthesis of a
variety of heterocyclic bisonium methanes. These com-
pounds could possibly be employed as biologically active
27
(
Conducter-like Screening Model) method,29 which is also
available in specially compiled MOPAC93 versions (key-
words: EPS ) 35.9, TS (for transition states), PRECISE,
NSPA ) 0).30 All local minima and transition-state
structures found were verified by calculations of analyti-
cal force constants. These frequencies were also used to
compute the zero-point energies (ZPE).
substances.6
-16
The success of the syntheses reported here depends on
the feasibility of both the nucleophilic substitution path-
ways a and b, Figure 1. They can be controlled by varying
the properties of the heteroarylium moiety, the substitu-
ent R, and to a minor extent, by the nature of the
C-bonded halogen. In this context, the salt 1a appears
to be an especially useful model compound: it is easily
accessible in excellent yields, and its molecular size
allows high-level MO calculations.
Resu lts a n d Discu ssion
1
-Ch lor om eth ylp yr id in iu m Ch lor id e (1a ). The N-
monohalomethyl pyridinium halides 1a -f (Scheme 1)
were synthesized in yields of up to 90% by treating a
mixture of an equimolar amount of 5 (X ) Br, Cl) and
the corresponding pyridine 7a -f with gaseous formal-
Com p u ta tion a l Meth od s. Ab initio and DFT calcula-
tions were performed using the Gaussian 94 suite of
programs.17 Molecular geometries for the species 1a were
optimized at the Hartree-Fock (HF), second-order per-
2 2
dehyde (6) in CH Cl or MeCN at 0 °C. The formaldehyde
was generated externally from paraformaldehyde in a
special apparatus (see the Experimental Section).
Compound 1a was isolated from the reaction mixture
of the three-component reaction and then recrystallized
from methanol/acetone to give large (3 mm/3 mm) color-
turbation (MP2),18 and density functional (B3LYP) levels
of theory using the 6-311+G*1
9-24
basis set. All other
geometries were optimized at the HF/6-31+G* or the
(
10) Maquestiau, A.; Anders, E.; Mayence, A.; Vanden Eynde, J .-J .
Chem. Ber. 1991, 124, 2013.
11) Vanden Eynde, J .-J .; Mayence, A.; Maquestiau, A.; Anders, E.
Synth. Comm. 1992, 22, 3141.
12) Vanden Eynde, J .-J .; Godin, J .; Mayence, A.; Maquestiau, A.;
Anders, E. Synthesis 1993, 867.
13) Vanden Eynde, J .-J .; D′Orazio, P.; Maquestiau, A.; Anders, E.
Tetrahedron 1992, 48, 1263.
14) Vanden Eynde, J .-J .; Mayence, A.; Maquestiau, A.; Anders, E.
Bull. Soc. Chim. Belg. 1992, 101, 801.
15) Anders, E.; Wermann, K.; Wiedel, B.; G u¨ nther, W.; G o¨ rls, H.
Eur. J . Org. Chem. 1998, 2923.
less prisms which were suitable for X-ray analysis
31
(Figure 2).
(
It is notable that pyridine itself does not react at
atmospheric pressure with dichloromethane to form the
(
salt 1a . Under higher pressures, only N,N ′-methylene-
(
4
bis(pyridinium) dichloride was formed. The iodide
(
+ -
2
Cl-CH -Py I (and from that the chloride 1a via anion
(
(24) Clark, T.; Chandrasekhar, J .; Spitznagel, G. W.; Schleyer, P.
v. R. J . Comput. Chem. 1983, 4, 294.
(16) Lukevits, E. Khim. Geterosihl. Soedin. 1995, 6, 723.
(
17) Gaussian 94 (Revision D.1), Frisch, M. J .; Trucks, G. W.;
(25) (a) Wong, M. W.; Frisch, M. J .; Wiberg, K. B. J . Am. Chem.
Soc. 1991, 113, 4776. (b) Wong, M. W.; Wiberg, K. B.; Frisch, M. J . J .
Am. Chem. Soc. 1992, 114, 523. (c) Wong, M. W.; Wiberg, K. B.; Frisch,
M. J . J . Chem. Phys. 1991, 95, 8991.
(26) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902.
(27) (a) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209. (b)
Stewart, J . J . P. J . Comput. Chem. 1989, 10, 221.
(28) Stewart, J . J . P. QCPE 455, Version 93 (HP und PC Version:
Wiedel, B.) 1993.
(29) Klamt, A.; Sch u¨ u¨ rmann, G. J . Chem. Soc., Perkin Trans. 2 1993,
799.
Schlegel, H. B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman,
J . R.; Keith, T. A.; Petersson, G. A.; Montgomery, J . A.; Raghavachari,
K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;
Peng, C. Y.; Ayala, P. Y.; Wong, M. W.; Andres, J . L.; Replogle, E. S.;
Gomperts, R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .;
Baker, J .; Stewart, J . J . P.; Head-Gordon, M.; Gonzalez, C.; Pople, J .
A. Gaussian Inc.: Pittsburgh, PA, 1995.
(18) Møller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618.
(19) McLean, A. D.; Chandler, G. S. J . Chem. Phys. 1980, 72, 5639.
(20) Becke, A. D. Phys. Rev. 1988, 38, 3098.
(
(
(
21) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, 37, 785.
22) Becke, A. D. J . Chem. Phys. 1993, 98, 5648.
23) Perdew, J . P. Phys. Rev. 1986, 33, 8822.
(30) Stewart, J . J . P. MOPAC 93.00 Manual; Fujitsu Limited:
Tokyo, J apan, 1993.

N-Halomethylpyridinium Halides
J . Org. Chem., Vol. 64, No. 9, 1999 3115
reaction energies ∆H
give the corresponding carbenium ion 18 and pyridines
, vide infra and Scheme 3) indicate that these bonds are
R
for a hypothetical dissociation to
7
+
significantly weakened in case of 16 (CR-N 153.5 pm,
+
BO 0.82) and 17 (CR-N 152.3 pm, BO 0.85), as
+
compared with the analogous bond in 1a (CR-N 148.6
+
pm, BO 0.91) and the methylpyridinium cation (CR-N
1
48.6 pm, BO 0.91). The electron withdrawing CCl
3
+
substituent in 10 (CR-N 149.4 pm, BO 0.90) does not,
as expected, cause such an effect. The background of this
bond-lengthening effect can be found in the influence of
the negative hyperconjugation or bond/ no-bond reso-
nance which depends on the extent of the interaction of
F igu r e 2. Crystal structure of 1a . Bond lengths [pm] and
angles [deg]: Cl(1)-C(6) 178.17(11), N-C(1) 135.21(14), C(1)-
C(2) 137.70(16), C(2)-C(3) 138.88(18), C(3)-C(4) 138.86(17),
C(4)-C(5) 137.46(16); C(5)-N-C(1) 121.87(9), C(1)-N-C(6)
+
the oxygen lone pair (n
bond (σ*C-N).
O
) with the antibonding CR-N -σ
35
R ea ct ivit y. The ab initio calculations led us to the
interpretation that the oxygen-substituted compounds 16
and 17 should be much better candidates for nucleophilic
substitution reactions that follow pathway b than the
halo salts belonging to the 1a -f family. The properties
1
19.31(9), N-C(6)-Cl(1) 109.17(8).
exchange) has been synthesized from Cl-CH
2
-I by C. H.
Calderon et al. However, neither spectroscopic or analyti-
cal data nor yield have been published.6
3
of the CCl -substituted cation of 10 should reveal more
similarities with that of 1a than with either 16 or 17.
This interpretation is based on the structural and
electronic properties of the pyridinium cations them-
selves. More reliable results could, however, be obtained
by the calculation of relative activation barriers for the
competing substitution reactions, especially if solvent
effects are included in the calculations. To assess the
reliability of actual methods as applied to the model
systems in solution, we calculated the a and b gas-phase
pathways (HF/6-31+G*//6-31+G*) and their counterparts
in MeCN solution (vide supra) of the cations of 1a , 16,
and 17. We chose ammonia as a standard nucleophile.
The results (Tables 3 and 4) indicate that all three cations
prefer pathway b via TS2 in the gas phase. The activation
barrier for the Cl displacement from 1a is much smaller
1
-Br om om eth ylp yr id in iu m Br om id e (1b). Dibro-
momethane and pyridine have been reacted, giving
exclusively N,N ′-methylene-bis(pyridinium) dibromide.4
The partial formation of 1b was induced by suitable
pressure reactions (solvent-free, molar ratio 2:1). In this
reaction,14 1b was neither isolated nor characterized by
2
spectroscopic or other methods. Attempts to use Br-CH -I
for the synthesis of 1b, although conceivable, have not
been reported. Application of our three-component reac-
tion (thionyl bromide, formaldehyde, and pyridine) to this
problem leads to 1b with an isolated yield of 73%.
Str u ctu r es. The C(6)-N bond length (or CR-N ,
which is the notation used in this paper throughout) in
+
1
a (146.5 pm, Figure 2) appears not to be affected by the
electronic influence of the Cl atom. It is almost identical
(
+11.6 kcal/mol, relative to the alternative route b, Figure
to the corresponding bond length in the N-methylpyri-
dinium cation (146.0 pm)32 and is somewhat shorter than
1) than that for OMe- (16, +72.8 kcal/mol) or OSiMe -
3
substitution (17, +69.2 kcal/mol). The same results are
also found by comparing activation energies based on the
separated reactants (≡0.0 kcal): pyridine substitution via
TS2 requires significantly more energy for 1a (32.8 kcal/
mol) than for either 16 (15.1 kcal/mol) or 17 (14.8 kcal/
mol). The activation barrier of route a which leads to TS1
is much smaller for 1a (+44.4 kcal/mol) as compared with
the values for 16 (+87.9 kcal/mol) and 17 (+83.9 kcal/
mol).
the corresponding bond in either the N-(1-chlorobenzyl)-
3
3
pyridinium chloride 1 (R ) Ph, 150.0 pm ) or the N-(1-
sulfonatoalkyl)pyridinium betaine 2a (R ) 4-MeC
6
4
H ,
3
4
1
49.1 pm ). In contrast to these minor changes, the
CR-Cl bond lengths (178 pm) are almost identical to those
in the haloalkylpyridinium salts 1. Ab initio calculations
on several levels of theory, as well as the inexpensive
semiempirical methods (PM3, AM1), show acceptable
overall agreement with the X-ray structural data (Table
We simulated both of these substitution pathways in
MeCN solution using the Onsager model, Tables 3 and
1
). The dihedral angle Cl-C(6)-N-C(1) (X-ray: 86.97°)
indicates that the cation 1a exhibits only a small devia-
tion from ideal C symmetry.
4
. Pathway a with substitution of Cl now appears to be
s
energetically favored by 1.6 kcal/mol as compared with
the pyridine substitution (pathway b). We then performed
the similar TS1/TS2 calculations (Figure 3) for the OMe
To gain further insight into the structural properties
of such compounds, we extended the calculations to
the cations of 10 (Cl-CH(CCl )-), 16 (MeO-CH -), and 17
3 2
(
3
16) and OSiMe (17) cations. TS1 of both 16 and 17
(Me
3
SiO-CH
2
-) and the methylpyridinium cation of 1 (R
remains significantly disfavored (+66.9 and +46.6 kcal/
mol, respectively), thus indicating that pathway b should
be preferred in MeCN. These findings are in complete
agreement with our experimental observations.
)
X ) H).
+
The calculated CR-N bond lengths (Table 2) of these
pyridinium salts (as well as the bond orders BO and the
Compound 16 has not yet been synthesized. However,
we have a large body of synthetic data for nucleophilic
substitution reactions with derivatives of 17 (synthesized
(
31) Further details of the crystal structure investigations are
available on request from the Cambridge Crystallographic Data Center,
2 Union Road, Cambridge CB2 1EZ, U.K., on quoting the depository
1
number CCDC 104031(1a ), CCDC 104032 (2h a ), CCDC 104033 (12),
and CCDC 104034 (14), the names of the authors, and the journal
citation.
(34) Anders, E.; Duray, S.; Fuchs, R.; Maas, G.; Mayence, A.; Vanden
Eynde, J .-J . Bull. Soc. Chim. Belg. 1997, 106, 383.
(35) Lambert, Ch.; Schleyer, P. v. R. Houben-Weyl Carbanionen-
Polare Organometall-Verbindungen; Georg Thieme Verlag: Stuttgart,
1993; E 19d, p 1-98 and literature cited therein.
(
32) Anders, E.; Tropsch, J . G.; Irmer, E.; Sheldrick, G. M. Chem.
Ber. 1990, 123, 321.
33) Kataeva, O. N.; Litvinov, I. A.; Kataev, V. E.; Vanden Enyde,
J .-J .; Mayence, A.; Anders, E. J . Mol. Struct. 1998, 442, 55.
(

3
116 J . Org. Chem., Vol. 64, No. 9, 1999
Anders et al.
Ta ble 1. Str u ctu r a l Da ta of th e 1-Ch lor om eth ylp yr id in iu m Ca tion of 1a a
C(1)-Cl
[pm]
C(6)-N
[pm]
C(1)-N
[pm]
C(1)-C(2)
C(2)-C(3)
ClC(6)NC(1)
[deg]
method
[pm]
[pm]
PM3
AM1
177.2
174.6
176.4
175.7
178.4
178.1
148.9
146.6
146.9
147.9
148.6
137.7
137.1
134.1
135.5
136.4
139.1
139.9
137.0
138.9
138.8
139.6
140.0
138.8
139.8
140.2
88.5
89.4
RHF/6-311+G*//RHF/6-311+G*
RMP2/6-311+G*//RMP2/6-311+G*
RBP86/6-311+G*//RBP86/6-311+G*
RB3LYP/6-311+G*//RB3LYP/6-311+G*
88.76
89.17
88.69
88.78
86.97
147.9
146.5(14)
135.5
135.2(14)
138.0
137.7(16)
139.5
138.9(18)
X-ray
178.2(11)
a
For numbering, see Figure 2.
+
Ta ble 2. Ca tion s of 1, 1a , 10, 16, a n d 17. Cr-N Bon d
Sch em e 3. Reson a n ce Str u ctu r es a n d
Dissocia tion En er gies of a Hyp oth etica l
Dissocia tion Rea ction
a
Len gth s (BL), Bon d Or d er s (BO), a n d Dissocia tion
b
En er gies (∆HR)
molecule
BL [pm]
BO
∆HR [kcal/mol]
1c
148.6
148.1
149.4
153.5
152.3
0.91
0.91
0.90
0.82
0.85
120.95
87.54
59.58
54.16
44.47
1
0
6
7
a
1
1
1
a
From Natural Populations Analysis (NPA).47
b
RB3LYP/
6
-31+G* results; ∆HR includes a zero-point energy correction with
c
the scaling factor 0.98. The parent 1-methylpyridinium cation,
R ) X ) H, Figure 1.
Sch em e 2. Som e Asp ects of th e Ch em istr y of
N-(1,2,2,2-Tetr a ch lor oeth yl)-p yr id in iu m Ch lor id e
(
10)
the same highly selective alkylation (N4 of 8b is attacked
under formation of 2g) as has been previously observed
8
for N-(1-chlorobenzyl)pyridinium chloride. In general,
the reaction rate decreases if the substituent R in 1
(Figure 1) is replaced by hydrogen when working under
identical conditions. As a typical example, the reaction
with 8b in MeCN is almost complete after 8 h at room
temperature when R ) Ph and X ) Cl. Under the same
experimental conditions, the yield of 2g does not exceed
2
0% but may be increased by heating under reflux (21
h, yield 92%). A substitution of the pyridine moiety under
+
formation of species such as 3 (Nu ) Nu′ ) 8b ) was
neither observed under our standard conditions nor
obtained if either a double molar amount of 8b was used
or the more reactive bromine 1b was used instead of 1a .
This is in contrast with the behavior of the pair of
reactants N-[1-bromo-(4-methylphenyl)methyl]pyridini-
from aliphatic and aromatic aldehydes, pyridine, and
3
6
trimethylsilyl triflate ). All of these results reveal that
the exclusive preference of pathway b is the most
important property of 17 (and presumably of 16 as well).
For the sake of completeness, we include semiempirical
solvation calculations based on the Conductor-like Screen-
ing Model (COSMO) in implanted MOPAC. The results
are promising but seem to overestimate the effect of the
solvent significantly (Table 3).
Exp er im en ta l Ap p lica tion . We found, in agreement
with our calculational results, that a variety of hetero-
cyclic nucleophiles (e.g., 7 and 8) react with 1 to yield
the geminal bis(heteroarylium) salts 2 (Scheme 4). For
example, the chloride 1a reacts with the heterocycles 7c,
9
um bromide /2 × 8b from which the corresponding
structure 3 (the bis[4-(5-amino-1-methyl-1H-1,2,4-tri-
azolium)(4-methylphenyl)] methane) was isolated in 64%
yield.15 This comparison demonstrates that not only
pathway a but also the consecutive second substitution
reaction (pathway b) of the 1-halomethylpyridinium salts
1a and 1b are more complicated as based on the proper-
ties of the aforementioned salts 1 with R ) alkyl, aryl.
This is further supported from the results of the reaction
of 1a /1b with 2 moles of the (ambident) nucleophile 8c,
a thiadiazole. Compound 1 (with R ) alkyl, aryl, X ) Cl,
Br) reacts with 8c via the corresponding structure 3 (Nu
7
g, and 8a to give N-(heteroarylium methyl)pyridinium
dichlorides 2ea , 2eb, and 2fa under mild conditions
room temperature) in excellent yields. In the case of the
ambident triazole 8b and the electrophile 1a , we found
+
) Nu′ ) 8c ) to give tricyclic 5/6/5 structures 3e.
(
However, in the case of 1a /1b, only monosubstitution of
CR-bonded Cl or Br was observed to yield the related
compounds 2h a and 2h b. A geminal bis(thiadiazolium)
salt was not formed. The synthesis of 5/6/5 heterocycle
3e (Figure 1, R ) H) from 1a or 1b therefore appears to
(
36) Anders, E.; Hertlein, K.; Stankowiak, A.; Irmer, E. Synthesis
1
992, 577.

N-Halomethylpyridinium Halides
J . Org. Chem., Vol. 64, No. 9, 1999 3117
Ta ble 3. Tr a n sition Str u ctu r es a n d a b In itioa a n d Sem iem p ir ica l Ga s-P h a se a n d Solva tion Ca lcu la tion s.b,c Alter n a tive
P a th w a ys a via TS1 a n d b via TS2 for Nu cleop h ilic Su bstitu tion Rea ction s. Mod el Nu cleop h ile, NH3
energy (ZPE)e
a
AM1b
gas phase
P M3b
gas phase
structured
TS1(1a )
TS2(1a )
gas phase
in MeCNc
in MeCNc
in MeCNc
-801.119 28 (107.48)
-801.135 38 (105.82)
+11.58
-456.044 63 (134.54)
-456.159 34 (133.57)
+72.84
-824.297 50 (183.64)
-824.405 54 (182.04)
+69.16
-801.144 75 (106.92)
-801.140 42 (105.64)
-1.58
-456.060 55 (134.29)
-456.165 53 (133.20)
+66.85
-824.336 01 (182.77)
-824.408 52 (181.56)
+46.58
229.0
209.4
+19.6
217.6
152.9
+64.7
167.6
82.1
142.7
159.5
-16.8
136.7
104.6
+32.1
92.8
224.7
209.9
+14.8
217.4
165.4
+52.0
153.6
72.8
147.8
159.7
-11.9
142.4
117.0
+25.4
81.6
∆
E TS1(1a )-TS2(1a )d,e
TS1(16)
TS2(16)
∆
E TS1(16)-TS2(16)d,e
TS1(17)
TS2(17)
41.4
+51.4
31.9
+49.7
∆
E TS1(17)-TS2(17)d,e
+85.5
+80.8
a
RHF/6-31+G*//RHF/6-31+G* results, energies in au. b Energies in kcal/mol. c Ab initio, simulating MeCN (Onsager model);
d
semiempirical, COSMO model, MOPAPC 93 keywords NSPA ) 60, EPS ) 35.9, TS, PRECISE. All structures, number of imaginary
frequencies ) 1. For ab initio calculations, relative energies are ZPE-corrected (scaling factor, 0.89). e Zero Point Energy (kcal/mol).
Ta ble 4. Activa tion En er gies for th e Nu cleop h ilic
Rea ction of NH3 w ith th e P yr id in iu m Sa lts 1a , 16, a n d 17,
Alter n a tive P a th w a ys a a n d b
the parent salt 1a . We therefore conclude that the
electron acceptor properties of the CR-bound chlorine and
the incoming heteroarylium moieties are similar.
Regioselectivity. The reaction of 1a with the nucleo-
philes 8b and 8c occurs in all cases at nitrogen ring
atoms which are adjacent to the amino groups (N4 in 8b,
N3 in 8c). This highly selective attack parallels the
activation energya
structure
via TS1
via TS2
+44.42 [+31.62]b
+87.89 [+79.94]
+83.94 [+65.04]
1
6
7
a
+32.84 [+33.20]
+15.05 [+13.09]
+14.78 [+18.47]
1
1
increasing negative charges at the competitive nitrogen
centers in 8b and 8c8
,15
and follows the decreasing
a
In kcal/mol from RHF/6-31+G*//RHF/6-31+G* optimizations.
activation barrier for the alkylation of these nitrogen
centers. These results are comparable to those previously
observed for protonation reactions at either the N4 atom
Separated reactants ≡ 0 kcal/mol. Relative energies are ZPE-
b
corrected (scaling factor, 0.89). Gas-phase calculations [in brack-
ets], simulation of the MeCN solution. Compare Figure 1 and
Table 3.
37,38
39
in 8b
and 2h a was also confirmed by means of NMR and IR
spectroscopy; the characteristic NH singlets are shifted
significantly downfield (δ 9.86 ppm (2g) and 11.76 ppm
2h a )). This proves beyond doubt that primary amino
or the N3 atom in 8c. The formation of 2g
be almost impossible under moderate reaction condi-
tions.15 Only after a reaction time of 50 h at 80 °C was a
minor amount (∼10%) of compound 3e (R ) H), along
2
(
1
with other products, detected in the H NMR of the crude
groups are present and indicates, in agreement with the
IR spectra, the presence of amino triazolium or amino
thiadiazolium units. The structure of 2h a was confirmed
by X-ray analysis (Figure 4). As compared with 1a ,
substitution of the C-bound Cl atom causes a slight
reaction mixture.
More uncomplicated substitution reactions are possible
at room temperature in MeCN between halomethylpy-
1
2
ridinium derivatives such as 1d (R ) CN, R ) H), 1e
1
2
1
2
+
(
R ) H, R ) CN), or 1f (R ) H, R ) CO
-methylimidazole (8a ). This reaction lead to the mixed
2
Me) and
elongation of the CR-N (pyridine) bond length (1a ,
146.5(14); 2h a , 149.4(2) pm).31
1
bisonium compounds 2fa -2fg in excellent yields. Inter-
estingly enough, the 4-cyano substituted salt 1d reacts
We then completed our experimental study on CR
substituent effects by synthesizing and investigating
N-(1,2,2,2-tetrachloroethyl)pyridinium chloride (10). The
synthesis of 10 follows our standard three-component
reaction in which thionyl chloride (5a ), trichloroacetal-
dehyde (9), and pyridine (7a ) were reacted at 0 °C in
MeCN to give this salt in excellent yield (Scheme 2).
3
with some other heterocyclic nucleophiles, for instance
1
7
c and 8c, to yield a complex mixture of products. H
NMR and CI MS spectra of the reaction mixtures show
the simultaneous formation of the substitution products
2
, 3, and 4 from both pathways a and b. Two typical
examples: 1d reacts with 7c to give 2fa and, after
substitution of the 4-cyanyopyridine 7d , a mixture of both
products 3a and 4a (Nu′ ) Nu ) 7c, X ) Cl). Reactants
As might be expected, the CCl group causes significant
1
13
downfield shifts in both the H and C NMR spectra,
thus indicating interesting properties of the central CHCl
group.
8
c and 1d yield the compound mixture 2h a , 3b, and 4b
Nu′ ) Nu ) 8c, X ) Cl). Attempts to isolate these
products have not yet been successful. Although the
(
Compound 10 was then reacted with 1 equiv of the
ambident nucleophile 8b at room temperature. Interest-
ingly enough, neither substitution pathway a nor b were
observed. This salt prefers an alternative route. The
triazole derivative functions as a base and, after the
elimination of HCl, the N-(trichloroethenyl)pyridinium
chloride (11) was isolated. We improved this synthesis
by using pyridine as a base and EtOH as the solvent.
Again, the Cl substitution (pathway a) was not possible.
We tried further nucleophiles which we have previously
successfully applied, e.g., triphenylphosphane, which in
+
4
-cyano group weakens the CR-N bond, the feasibility
of reactions due to pathway b increases only to a minor
extent. The preference of pathway a reactions remains
the dominant property of salts 1a -f.
The new mixed bisonium salts 2 (Scheme 4) were
characterized by NMR spectroscopic methods, massspec-
troscopy, and elemental analyses (see the Experimental
Section). The exchange of the covalently bonded halogen
atom in 1 with the heterocyclic nitrogen nucleophiles 7
and 8 causes downfield chemical shifts of the methylene
1
(37) Barlin, G. B.; Batterham, T. J . J . Chem. Soc. (B) 1967, 516.
signals of about 0.4-0.9 ppm. In addition, the H and
(
(
38) Lynch, D. E.; Smith, G. Acta Crystallogr. 1994, C50, 129.
39) Antolini, L.; Cornia, A.; Fabretti, A. C.; Malavasi, W. J .
1
3
C NMR signals of the pyridinium CH units in the
product salts 2 do not differ significantly from those of
Crystallogr. Spectrosc. Res. 1993, 23, 967.

3
118 J . Org. Chem., Vol. 64, No. 9, 1999
Anders et al.
F igu r e 3. Ab initio (RHF/6-31+G*) transition structures (application of the Onsager method) for pathways a and b of nucleophilic
substitution reactions of pyridinium salts 1 in MeCN using ammonia as a model nucleophile (TS1, pathway a; TS2, pathway b;
see Figure 1).
the case of 1 with R ) Ph substitutes the Cl atom to give
c (cf. ref 7, Figure 1). Surprisingly, the application of
PPh initiated a very effective dehalogenation with
formation of the N-(2,2-dichloroethenyl)pyridinium chlo-
ride (12). The phosphonium/pyridinium dication was not
formed.
ture of 14 (Figure 6) reveals a remarkably short C(vi-
nyl)-N bond length (139.3(5) pm).
+
2
3
It is noteworthy that nucleophilic reactions at the C
atoms in the pyridinium moiety cannot be performed with
“normal” N-substituted pyridinium salts. Activation of
the C4 position needs, in general, very strong electron-
4
0,41
3 2
withdrawing N-substituents, e.g., the CF SO group.
Both of these novel chloroethenyl-pyridinium com-
The trichlorovinyl group fulfills this condition and allows
further related reactions, e.g., with Grignard reagents
and trialkyl phosphites to give the N-(trichlorovinyl)-4-
phenylmethyl- or 4-phoshonato-1,4-dihydropyridines (13)
pounds 11 and 12 were analyzed by spectroscopic means
1
13
(
H and C NMR, IR, MS). The structure of 12 has been
3
1
further confirmed by X-ray analysis (Figure 5).
Interestingly enough, the reaction of 11 with tri-n-
butylphosphane results in the formation of the C4
addition product, i.e., the phosphonium salt 14 (91%). The
isomeric C2-product was not observed. The X-ray struc-
(74% yield) and (15) (80%), respectively. Compound 13
(
40) Anders, E.; Markus, F. Tetrahedron Lett. 1987, 28, 2675.
(41) Anders, E.; Markus, F. Chem. Ber. 1989, 122, 113.

N-Halomethylpyridinium Halides
J . Org. Chem., Vol. 64, No. 9, 1999 3119
F igu r e 6. Crystal structure of 14. Selected bond lengths [pm]
and bond angles [deg]: N(1)-C(6) 1393(5), N(1)-C(1) 139.6-
(
(
5), N(1)-C(5) 140.5(5), C(1)-C(2) 131.8(5), C(2)-C(3) 150.2-
5), C(3)-P(1) 183.3(3), C(6)-C(7) 128.4(7), C(6)-Cl(1) 188.8-
F igu r e 4. Crystal structure of 2h a . Selected bond lengths
(9), C(7)-Cl(3) 171.0(4), C(7)-Cl(2) 173.2(8); C(6)-N(1)-C(1)
119.9(3), N(1)-C(6)-Cl(1) 114.5(4), C(7)-C(6)-N(1) 126.4(5),
C(6)-C(7)-Cl(3) 125.9(4), P(1)-C(3)-H(3) 104(2).
[
1
pm] and bond angles [deg]: N(1)-C(1) 149.4(2), N(2)-C(1)
44.5(2), C(1)-H(1A) 101(2), C(1)-H(1B) 0.95(2); N(1)-C(1)-
H(1A) 108.5(10), N(1)-C(1)-H(1B) 106.4(11), N(2)-C(1)-
H(1A) 108.7(10), N(2)-C(1)-H(1B) 109.9(10), C(6)-N(1)-C(1)
Con clu sion
1
19.07(13), C(7)-N(2)-C(1) 126.63(14), C(2)-N(1)-C(1) 119.28-
(13).
These investigations show that the reactivity pattern
of heteroarylium cations such as 1, 10, 16, and 17 is
determined by the increasing importance of the negative
hyperconjugation due to the n
/σ*C-N+ interaction in the
X
+
X-CR-Py moiety. This effect causes dramatic changes
in the energy gaps between the two transition states TS1
and TS2 in the gas phase. TS1 and TS2 correspond to
the two alternative nucleophilic substitution pathways
a and b. In solution, small energy gaps between TS1 and
TS2 may change their sign and value. Whereas the
substitution of pyridine (pathway b) is the general
pathway in the gas phase, the behavior of 1 changes in
MeCN, with pathway a becoming dominant. The Onsager
method appears to be a useful tool to estimate the relative
energy changes, whereas the semiempirical COSMO
method seems to overestimate solvation effects.
The influence of substituents at the pyridinium ring
may increase or decrease the TS1/TS2 gap. This allows,
to a minor extent, a remote control of the reaction
pathways.
F igu r e 5. Crystal structure of 12. Selected bond lengths [pm]
and bond angles [deg]: C1(1)-C(1) 171.9(2), Cl(2)-C(1) 170.9-
(
2), C(1)-C(2) 131.2(3), C(2)-N(1) 144.4(2), N(1)-C(3) 134.7-
2), N(1)-C(7) 135.0(2); C(2)-C(1)-Cl(2) 126.1(2), C(2)-C(1)-
(
Cl(1) 119.4(2), Cl(2)-C(1)-Cl(1) 114.52(11), C(1)-C(2)-H(2)
1
23(2), C(1)-C(2)-N(1) 122.1(2).
Sch em e 4. Su bstitu tion Rea ction s of
N-Ha lom eth ylp yr id in iu m Sa lts 1a -f w ith
Heter ocyclic Nu cleop h iles 7 a n d 8
Exp er im en ta l Section
Gen er a l Met h od s. Melting points (uncorrected) were
obtaining using a Lindstrom copper block apparatus. Reagents
of commercial quality were purified by common methods.
5
-Amino-1-methyl-1H-1,2,4-triazole was prepared according to
4
4
the literature. NMR spectra were obtained at 250 or 400 MHz
and 62.5 or 100 MHz, for proton and carbon, respectively. For
1
13
H and C NMR, DMSO-d (H δ ) 2.49, C δ ) 39.5) was used
6
as solvent, and TMS was used as internal standard.
Cr ysta l Str u ctu r e An a lysis of 1a , 2h a , 12, a n d 14. Da ta
Collection . The intensity data for the compounds were
collected on a diffractometer using graphite-monochromated
Mo KR radiation. Data were corrected for Lorentz and polar-
ization effects but not for absorption.
Str u ctu r e Solu tion a n d Refin em en t. The structures
4
5
were solved by direct methods (SHELXS ) and refined by full-
2
46
matrix least-squares techniques against Fo (SHELXL-97 ).
The hydrogen atoms were located by difference Fourier
synthesis and refined isotropically. All non-hydrogen atoms
were refined anisotropically.
is very sensitive toward oxygen and should be handled
under N . An alternative formation of an inamine caused
by a dehalogenation comparable to the reaction of poly-
(
43) Ficini, J .; Barbara, C. Bull. Soc. Chim. Fr. 1965, 2787.
2
(44) Barascut, J .-L.; Claramunt, R.-M.; Elguero, J . Bull. Soc. Chim.
Fr. 1973, 1849.
haloenamines with lithium or magnesium alkyl com-
(45) Sheldrick, G. M. Acta Crystallogr. Sect. A 1990, 46, 467-473.
(46) Sheldrick, G. M. SHELXL-97; University of G o¨ ttingen: Ger-
many, 1997.
pounds4
2,43
was not observed.
(
47) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88,
(42) Ficini, J .; Barbara, C. Bull. Soc. Chim. Fr. 1964, 871.
899.

3
120 J . Org. Chem., Vol. 64, No. 9, 1999
Anders et al.
Cr ysta l d a ta for 1a :31 [C
H
ClN] Cl , M
+
-
) 164.03 g mol-1,
1-Ch lor om eth yl-4-cya n op yr id in iu m ch lor id e (1d ): mp
6
7
r
3
1
colorless prism, size 0.40 × 0.38 × 0.36 mm , orthorhombic,
182 °C (dec); IR (KBr) CN inactive; H NMR (DMSO-d
6
) δ 6.82
1
3
space group Pbca, a ) 8.353(2), b ) 10.780(2), c ) 16.262(3)
(s, 2H), 8.86 (d, 2H, J ) 6.8 Hz), 9.85 (d, 2H, J ) 6.7 Hz);
NMR (DMSO-d ) δ 64.4, 114.6, 129.1, 131.6, 146.8; FAB MS
7 6 7 6 2 2
m/z 153 (60) for C H ClN . Anal. Calcd for C H Cl N : C,
C
3
-3
Å, V ) 1464.3(5) Å , T ) -90 °C, Z ) 8, Fcalcd ) 1.488 g cm
,
6
-
1
+
2
µ (Mo KR) ) 7.92 cm , F(000) ) 672, 2538 reflections in h(-
1
3
>
)
2/0), k(-16/0), l(0/24), measured in the range 2.50° e Θ e
1.96°, 2538 independent reflections, 2219 reflections with F
44.47; H, 3.20; Cl 37.51, N 14.82. Found: C, 44.35; H, 3.21;
Cl, 36.80; N, 14.83.
o
2
4σ(F
o
), 111 parameters, R1obs ) 0.027, wR obs ) 0.072, R1all
0.036, wR all ) 0.079, GOOF ) 1.141, largest difference peak
1-Ch lor om eth yl-3-cya n op yr id in iu m ch lor id e (1e): mp
2
-1 1
179 °C (dec); IR (KBr) 2245 cm ; H NMR (DMSO-d
6
) δ 6.79
-
3
and hole 0.457 / -0.232 e Å
.
(s, 2H), 8.50 (t, 1H), 9.27 (d, 1H, J ) 8.2 Hz), 9.81 (d, 1H, J )
3
1
OS]2+2Cl ‚H
-
13
Cr ysta l d a ta for 2h a : [C
9
H
12
N
4
2
O, M
r
)
6.3 Hz), 10.41 (s, 1H); C NMR (DMSO-d
129.0, 148.7, 149.8, 151.0; FAB MS m/z 153 (40) for C
Anal. Calcd for C Cl : C, 44.47; H, 3.20; Cl, 37.51; N,
6
) δ 64.2, 113.1, 113.6,
-
1
3
+
2
2
97.20 g mol , colorless prism, size 0.32 × 0.30 × 0.20 mm ,
monoclinic, space group P2 /c, a ) 11.7095(4), b ) 8.8223(3),
c ) 13.9315(4) Å, â ) 111.243(2)°, V ) 1341.40(8) Å , T ) -90
7 6
H ClN .
1
7
H
6
2 2
N
3
14.82. Found: C, 43.87; H, 3.44; Cl, 37.06; N, 15.03.
-
3
-1
°
)
C, Z ) 4, Fcalcd ) 1.472 g cm , µ (Mo KR) ) 6.3 cm , F(000)
616, 3507 reflections in h(-13/12), k(-9/0), l(-15/15),
measured in the range 2.79° e Θ e 23.27°, 1927 independent
reflections, Rint ) 0.021, 1767 reflections with F > 4σ(F ), 211
parameters, R1obs ) 0.025, wR obs ) 0.078, R1all ) 0.032, wR2all
0.120, GOOF ) 0.946, largest difference peak and hole
.196/-0.231 e Å-3
Cr ysta l d a ta for 12: [C
1-Ch lor om eth yl-3-m eth oxyca r bon ylp yr id in iu m ch lo-
-
1 1
r id e (1f): oil; IR (film) 1738 cm ; H NMR (DMSO-d
(s, 3H), 6.83 (s, 2H), 8.44 (t, 1H), 9.14 (d, 2H, J ) 8.2 Hz), 9.74
(d, 2H, J ) 6.3 Hz), 10.03 (s, 1H); 13C NMR (DMSO-d
) δ 53.6,
64.2, 129.1, 130.2, 146.5, 147.7, 148.6, 161.8; FAB MS m/z 186
6
) δ 3.98
o
o
6
2
+
)
0
(35) for C H ClNO .
8 9 2
.
Gen er a l P r oced u r e for th e Syn th esis of Bis(h eter o-
a r yliu m )m eth a n es 2. A solution of 5 mmol of a nitrogen
nucleophile (7c, 7g, 8a -c in MeCN (10 mL)) was added to a
suspension of 5 mmol of pyridinium salt 1 in MeCN (40 mL).
The mixture was then stirred at room temperature for 15 h.
The precipitate was filtered off and recrystallized from MeOH/
tert-butyl methyl ether.
3
1
+
-
7
6 2 r
H Cl N] Cl , M ) 210.48 g
3
-
1
mol , colorless prism, size 0.39 × 0.32 × 0.28 mm , ortho-
rhombic, space group Pbca, a ) 7.996(2), b ) 12.548(2), c )
3
1
8.035(2) Å, V ) 1809.5(6) Å , T ) -90 °C, Z ) 8, Fcalcd ) 1.545
-
3
-1
g cm , µ (Mo KR) ) 9.45 cm , F(000) ) 848, 1833 reflections
in h(0/9), k(-15/0), l(0/22), measured in the range 2.26° e Θ
e 26.32°, 1833 independent reflections, 1673 reflections with
1-[(4-N ,N -Dim e t h yla m in op yr id in iu m )m e t h yl]p yr i-
d in iu m d ich lor id e (2ea ): 90%; mp 236 °C; IR (KBr) 3372
2
F
o
> 4σ(F
o
), 124 parameters, R1obs ) 0.032, wR obs ) 0.085,
R1all ) 0.043, wR all ) 0.102, GOOF ) 1.106, largest difference
2
-1 1
cm ; H NMR (DMSO-d
6
) δ 3.22 (s, 6H), 7.17 (d, 2H, J ) 7.9
-
3
peak and hole 0.203/-0.426 e Å
.
Hz), 7.21 (s, 2H), 8.28 (t, 2H), 8.74 (t, 1H), 9.05 (d, 2H, J ) 7.8
3
1
+
-
13
Cr ysta l d a ta for 14: [C19
H
32Cl
3
NP] Cl ‚CH
2
Cl
2
, M
r
)
Hz), 9.80 (d, 2H, J ) 6.0 Hz); C NMR (DMSO-d
6
) δ 40.1, 73.2,
-
1
3
5
32.15 g mol , colorless prism, size 0.42 × 0.32 × 0.21 mm ,
108.2, 128.5, 142.1, 145.0, 148.0, 156.6; FAB MS m/z 214 (31)
+
monoclinic, space group C2/c, a ) 24.284(2), b ) 8.352(2), c )
for C13
H
16
N
3
. Anal. Calcd for C13
H
17Cl
2
N
3
2
‚H O: C, 51.33; H,
3
2
8
4
7.685(4) Å, â ) 106.78(1)°, V ) 5376(2) Å , T ) -90 °C, Z )
6.30; Cl, 23.31; N, 13.81. Found: C, 52.02; H, 6.29; Cl, 23.17;
N, 13.56.
-
3
-1
, Fcalcd ) 1.315 g cm , µ (Mo KR) ) 7.07 cm , F(000) ) 2224,
651 reflections in h(-28/27), k(-9/0), l(0/32), measured in the
1-[(4-Met h ylp yr id in iu m )m et h yl]p yr id in iu m d ich lo-
1
range 2.59° e Θ e 24.67°, 4543 independent reflections, Rint
r id e (2eb): 77%; mp 211 °C; H NMR (DMSO-d
6
) δ 2.64 (s,
)
0.013, 3774 reflections with F
o
> 4σ(F
o
), 334 parameters,
3H), 7.57 (s, 2H), 8.14 (d, 2H, J ) 6.5 Hz), 8.30 (t, 2H), 8.76 (t,
2
2
13
R1obs ) 0.061, wR obs ) 0.162, R1all ) 0.075, wR all ) 0.188,
GOOF ) 1.091, largest difference peak and hole 1.088/-0.806
1H), 9.72 (d, 2H, J ) 6.6 Hz), 9.88 (d, 2H, J ) 5.7 Hz);
NMR (DMSO-d ) δ 21.8, 75.0, 128.5, 128.9, 144.8, 145.9, 148.5,
162.5; FAB MS m/z 221 (62) for C12
C
6
-
3
+
2
e Å
.
H
14ClN
, 185 (8) for
O: C, 54.39; H, 5.32;
+
Gen er a l P r oced u r e for th e Syn th esis of N-Mon oh a -
lom et h ylp yr id in iu m Ha lid es 1a -f. To a stirred solution
of 0.1 mol of 5 (X ) Br, Cl) in dichloromethane (150 mL) or
MeCN (150 mL) was added 0.1 mol of 7a -f at 0 °C under
an atmosphere of argon. Gaseous 6 was generated by heating
of paraformaldehyde in a separate flask equipped with a
short wide tube. The formaldehyde was then immediately
introduced into the reaction mixture for a period of 15 min.
The mixture was slightly concentrated, and then the resulting
precipitate was filtered off under vacuum and extracted with
C
12
H
3
N
2
. Anal. Calcd for C12
H
14Cl
2
N
2
‚H
2
Cl, 26.74; N, 10.56. Found: C, 54.14, H, 5.67, Cl, 24.46, N,
10.58.
1-[(1-Meth ylim id a zol-3-yliu m )m eth yl]p yr id in iu m d i-
-1 1
ch lor id e (2fa ): 56%; mp 253 °C; IR (KBr) 3412 cm ; H NMR
(DMSO-d ) δ 3.34 (s, 3H), 7.26 (s, 2H), 7.81 (s, 1H), 8.29 (t,
2H), 8.38 (s, 1H), 8.75 (t, 1H), 9.70 (d, 2H, J ) 5.8 Hz), 9.98 (s,
1H); 13C NMR (DMSO-d
) δ 36.2, 66.9, 122.2, 124.3, 128.3,
138.9, 145.3, 148.1; FAB MS m/z 210 (20) for C10
6
6
+
H
13ClN
3
, 174
O: C, 45.47;
+
(91) for C10
H
12
N
3
. Anal. Calcd for C10
H
13Cl
2
N
3
‚H
2
1
00 mL of acetone/methanol (1:1) at 60 °C. Paraformalde-
H, 5.72; Cl, 26.84; N; 15.91. Found: C, 45.50; H, 5.63; Cl, 26.75;
N, 16.00.
hyde formed again was separated by filtration. The filtrate
was evaporated, and the residue was recrystallized from
MeCN.
-Ch lor om eth ylp yr id in iu m ch lor id e (1a ): mp 172 °C;
H NMR (DMSO-d ) δ 6.74 (s, 2H), 8.30 (t, 2H), 8.79 (t, 1H),
.50 (d, 2H, J ) 6.3 Hz); 13C NMR (DMSO-d
) δ 64.1, 128.7,
45.5, 148.3; FAB MS m/z 128 (100) for C ClN . Anal. Calcd
Cl N: C, 43.93; H, 4.30; Cl, 43.23; N, 8.54. Found: C,
3.80; H, 4.59; Cl, 42.52; N, 8.53.
-Br om om eth ylp yr id in iu m br om id e (1b): mp 215 °C
) δ 6.57 (s, 2H), 8.26 (t, 2H), 8.76 (t,
H), 9.34 (d, 2H, J ) 6.4 Hz); C NMR (DMSO-d ) δ 50.7,
28.8, 145.3, 148.0; CI MS m/z 172 (71) for C
Br N: C, 28.49; H, 2.79; Br, 63.18; N, 5.54.
Found: C, 28.49; H, 2.83; Br, 62.51; N, 5.58.
-Ch lor om eth yl-4-d im eth yla m in op yr id in iu m ch lor id e
1-[(5-Am in o-1-m eth yl-1H-1,2,4-tr ia zol-4-yliu m )m eth yl]-
p yr id in iu m d ich lor id e (2g): 92% (reaction was carried out
at 80 °C, 21 h), mp 255 °C (dec); IR (KBr) 3453, 1684, 1576
1
1
-1 1
6
cm ; H NMR (DMSO-d
6
) δ 3.64 (s, 3H), 7.13 (s, 2H), 8.31 (t,
9
1
6
2H), 8.74 (t, 1H), 9.03 (s, 1H), 9.58 (d, 2H, J ) 5.7 Hz), 9.86 (s,
+
13
6
H
7
2H); C NMR (DMSO-d
147.8, 149.5; CI MS m/z 190 (10) for C
for C : C, 41.24; H, 5.00; Cl, 27.05; N, 26.72. Found:
6
) δ 35.1, 63.6, 128.1, 138.9, 144.7,
+
9 12 5
H N . Anal. Calcd
for C
6
H
7
2
4
9 2 5
H13Cl N
1
C, 41.32; H; 5.04; Cl, 27.04; N, 26.59.
1
(
1
1
dec); H NMR (DMSO-d
6
1-[(2-Am in o-5-m eth yl-1,3,4-th ia d ia zol-3-yliu m )m eth yl]-
p yr id in iu m d ich lor id e (2h a ): 65%, mp 179-182 °C (dec);
1
3
6
+
-1
1
6
H
7
BrN . Anal.
6
IR (ATR) 3449, 3401, 1634 cm ; H NMR (DMSO-d ) δ 2.50
Calcd for C
6
H
7
2
(s, 3H), 7.24 (s, 2H), 8.26 (t, 2H), 8.72 (t, 1H), 9.40 (d, 2H, J )
5.8 Hz), 11.76 (s, 2H); 13C NMR (DMSO-d
) δ 16.1, 68.3, 128.3,
145.2, 148.0, 155.9, 169.6. FAB MS m/z 207 (31) for C
Anal. Calcd for C S: C, 38.72; H, 4.33; Cl, 25.40; N,
6
+
9 11 4
H N S .
1
1
(
(
1c): mp 236 °C (dec); H NMR (DMSO-d
s, 2H), 7.13 (d, 2H, J ) 7.9 Hz), 8.52 (d, 2H, J ) 8.0 Hz); 13
) δ 40.2, 62.4, 108.3, 141.8, 156.5; FAB MS
6
) δ 3.24 (s, 6H), 6.25
9 2 4
H12Cl N
C
20.07; S, 11.48. Found: C, 38.31; H, 4.45; Cl, 24.01; N, 19.34:
S, 11.85.
NMR (DMSO-d
m/z 171 (100) for C
6.40; H, 5.84; Cl, 34.24; N, 13.53. Found: C, 46.20; H, 5.96;
Cl, 33.56; N, 13.31.
6
+
8
H
12ClN
2
. Anal. Calcd for C
8
H
12Cl
2
N
2
: C,
1-[(2-Am in o-5-m eth yl-1,3,4-th ia d ia zol-3-yliu m )m eth yl]-
p yr id in iu m d ibr om id e (2h b): 62%, mp 200-202 °C; IR
4
-
1
1
(ATR) 3447, 3400, 1635 cm ; H NMR (DMSO-d ) δ 2.50 (s,
6

N-Halomethylpyridinium Halides
H), 6.95 (s, 2H), 8.28 (t, 2H), 8.76 (t, 1H), 9.23 (d, 2H, J ) 6.0
J . Org. Chem., Vol. 64, No. 9, 1999 3121
1
1
3
romethane: 68%, mp 165 °C; IR (KBr) 1639 cm- ; H NMR
(DMSO-d ) δ 8.36 (t, 2H), 8.55 (s, 1H), 8.81 (t, 1H), 9.26 (d,
2H, J (H ) 6.0 Hz); C NMR (DMSO-d
145.2, 148.2; CI MS m/z 174 (100) for C
for C Cl N: C, 39.93; H, 2.87; Cl, 50.54; N, 6.65. Found: C,
1
3
Hz), 10.80 (s, 2H); C NMR (DMSO-d
44.98, 148.1, 156.0, 169.7; FAB MS m/z 208 (33) for C
Anal. Calcd for C S: C, 29.37; H, 3.29; Br, 43.42; N,
5.22; S; 8.71. Found: C, 29.38; H, 3.29; Br, 42.83; N, 15.49;
S, 8.75.
-Cyan o-1-[(1-m eth ylim idazol-3-yliu m )m eth yl]pyr idin -
iu m d ich lor id e (2fb): 89%, mp 212-213 °C; IR (KBr) CN
6
) δ 16.2, 68.4, 128.3,
6
+
13
1
9
H
12
N
4
S .
6
) δ 128.0, 128.2, 130.1,
+
9
H
12Br
2
N
4
7 6 2
H Cl N . Anal. Calcd
1
7
H
6
3
39.80; H, 2.88; Cl, 50.14; N, 6.36.
4-P h en ylm et h yl-1-t r ich lor oet h en yl-1,4-d ih yd r op yr i-
d in e (13). To a suspension of 11 (1.23 g, 5 mmol) in diethyl
4
1
inactive; H NMR (DMSO-d
(
6
) δ 3.89 (s, 3H), 7.40 (s, 2H), 7.82
2
ether (10 mL) was added a solution of PhCH MgBr (1.25 molar,
s, 1H), 8.44 (s, 1H), 8.87 (d, 2H, J ) 6.8 Hz), 10.06 (s, 1H),
4 mL) in diethyl ether under argon at -78 °C, and the mixture
was stirred for 1 h. The reaction mixture was allowed to warm
to room temperature in the course of 5 h and then extracted
with 5% aqueous sodium hydrogen carbonate (10 mL). The
1
1
2
0.11 (d, 2H, J ) 6.9 Hz); 13C NMR (DMSO-d
14.6, 122.4, 124.2, 128.8, 131.2, 139.1, 146.9; FAB MS m/z
6
) δ 36.2, 67.1,
+
00 (39) for C11
H N . Anal. Calcd for C11H12Cl N : C, 48.78;
12 4 2 4
H, 4.46; Cl, 26.15; N, 20.66. Found: C, 48.57; H, 4.64; Cl, 25.79;
N, 20.45.
2 4
organic layer was separated, dried (Na SO ), and passed
through a silica gel column. Evaporation of solvent gave 0.82
3
-Cyan o-1-[(1-m eth ylim idazol-3-yliu m )m eth yl]pyr idin -
g (73%) of crystalline 13, which is sensitive to oxygen and was
-
1
iu m d ich lor id e (2fc): 93%, mp 185 °C; IR (KBr) 2250 cm
H NMR (DMSO-d
;
contaminated by 20% benzenemethanol: IR (CCl
1603 cm ; H NMR (CDCl
3
4
) 1680, 1625,
) δ 2.72 (d, 2H, J ) 7.0 Hz), 3.26
(m, 1H), 4.72 (m, 2H), 5.90 (d, 2H, J ) 14.5 Hz), 7.16-7.23
1
-1 1
6
) δ 3.90 (s, 3H), 7.37 (s, 2H), 7.65 (s, 1H),
8
1
d
1
.45 (s, 1H), 8.50 (t, 1H), 9.24 (d, 1H, J ) 8.2 Hz), 10.07 (d,
H, J ) 7.9 Hz), 10.11 (s, 1H), 10.57 (s, 1H); 13C NMR (DMSO-
(m, 5H); C NMR (CDCl ) δ 34.2, 45.8, 106.9, 115.7, 126.1,
13
3
6
) δ 36.2, 66.8, 112.6, 113.6, 122.5, 124.1, 128.6, 139.2, 148.8,
126.7, 128.2, 129.5, 131.7, 138.7; CI MS m/z 300 (98) for C14
H
13
-
+
+
+
+
49.8, 150.8; FAB MS m/z 235 (36) for C11
: C, 48.73; H, 4.46; Cl, 26.15; N, 20.66.
Found: C, 48.23; H, 4.50; Cl, 26.21; N, 20.44.
-Me t h oxyca r b on yl-1-[(1-m e t h ylim id a zol-3-yliu m )-
m eth yl]p yr id in iu m d ich lor id e (2fg): 84%, mp 152 °C; IR
H
12ClN
4
. Anal.
Cl
3
N , 264 (100) for C14
H
12Cl
2
N , 208 (97) for C
7
H
5
Cl
3
N , 129
+
Calcd for C11
H
12Cl
2
N
4
(68) for C
2
Cl
3
.
4-Tr i-n -bu tyl-p h osp h on iu m -1-tr ich lor oeth en yl-1,4-d i-
h yd r op yr id in e Ch lor id e (14). To a suspension of 11 (1.23
g, 5 mmol) in dichloromethane (5 mL) was added tri-n-
butylphosphane (1.01 g, 5 mmol) at 0 °C under an atmosphere
of argon. An intense yellow color developed immediately. The
clear solution was stirred at room temperature for 1 h, followed
by the addition of tert-butyl methyl ether (5 mL). This mixture
was filtered off under vacuum using silica gel. The solution
was evaporated to half of the volume, and 20 mL of tert-butyl
methyl ether was again added. The precipitate was filtered
off and dried in vacuo: 91%, mp 92 °C (dec); IR (KBr) 1606,
3
-
1 1
(
3
(
1
1
KBr) 1728 cm ; H NMR (DMSO-d
H), 7.42 (s, 2H), 7.85 (s, 1H), 8.41 (t, 1H), 8.45 (s, 1H), 9.11
d, 1H, J ) 8.1 Hz), 10.03 (d, 1H, J ) 5.5 Hz), 10.09 (s, 1H),
0.23 (s, 1H); C NMR (DMSO-d
24.2, 128.7, 129.8, 139.0, 147.0, 147.5, 148.5, 161.9; CI MS
6
) δ 3.89 (s, 3H), 3.98 (s,
1
3
6
) δ 36.2, 53.6, 66.9, 122.3,
+
14 3 2 2 3 2
H N O . Anal. Calcd for C12H15Cl N O ‚
m/z 232 (3) for C12
O: C, 44.73; H, 5.32; Cl, 22.01; N, 13.04. Found: C, 44.82;
H, 5.47; Cl, 20.77; N, 12.97.
H
2
-
1 1
N-(1,2,2,2-Tetr a ch lor oeth yl)p yr id in iu m Ch lor id e (10).
To a solution of 5a (36.3 g, 305 mmol) in MeCN (70 mL) was
added 7a (24.1 g, 305 mmol) in MeCN (40 mL) at O °C. To
this mixture was slowly added a solution of trichloroacetal-
dehyde (9) (44.2 g, 300 mmol) in MeCN (40 mL) in a dropwise
manner; the reaction temperature is not to go beyond 5 °C.
The reaction mixture was stirred for 2 h at room temperature.
The precipitate was filtered off by suction and twice washed
1612, 1683 cm ; H NMR (CDCl
2.41 (m, 6H), 4.84 (m, 2H), 5.22 (m, 1H), 6.16 (d, 2H J ) 12.7
Hz); 13C NMR (CDCl
) δ 13.5, 17.1 (d, J ) 43.5 Hz), 24.0, 31.6
(d, J ) 47.0 Hz), 95.8 (d, J ) 5.2 Hz), 118.7, 130.1, 132.0 (d, J
3
) δ 0.91 (t, 9H), 1.51 (m, 12H),
3
3
1
) 6.8 Hz); P NMR (CDCl ) δ 31.1; FAB MS m/z 410 (16) for
3
+
+
C
19
H
32Cl
3
NP , 208 (100) for C
7 5 3 32
H Cl N . Anal. Calcd for C19H -
Cl
4
NP: C, 51.02; H, 7.21; N, 3.13; Cl, 31.71. Found C, 50.61;
H, 7.22; N, 3.11; Cl, 30.64.
with MeCN. Compound 10 can be recrystallized from EtOH:
4-(Di-2-p r op oxy)p h osp h or yl-1-tr ich lor oeth en yl-1,4-d i-
h yd r op yr id in e (15). To a stirred suspension of 11 (1.35 g,
5.5 mmol) in dichloromethane (20 mL) was added tri-2-propyl
phosphite (1.25 g, 6 mmol) at -78 °C under an atmosphere of
argon. After 2 h, the mixture was allowed to warm to room
temperature. The solvent was evaporated in vacuo to dryness,
and the residue was purified by column chromatography (silica
gel 60, 0.063-0.2 mm, EtOAc): 80%, mp 78 °C (dec); IR (ATR)
1
8
0%, mp 223 °C (dec); H NMR (DMSO-d
6
) δ 8.40 (t, 2H), 8.84
1
3
(
d
s, 1H), 8.95 (t, 1H), 9.68 (d, 2H J ) 6.0 Hz); C NMR (DMSO-
6
) δ 82.7, 96.2, 128.6, 145.2, 151.0; CI MS m/z 244 (10) for
+
+
C
7
H
6
Cl
4 7 5 3 7 6
N , 208 (100) for C H Cl N . Anal. Calcd for C H -
Cl
5
N: C, 29.88; H, 2.15, Cl, 62.99, N, 4.98. Found: C, 29.62;
H, 2.35; Cl, 60.78; N, 5.18.
N-(Tr ich lor oeth en yl)p yr id in iu m Ch lor id e (11). Com-
pound 7a (1.58 g, 20 mmol) was added to a suspension of 10
-
1 1
1607, 1623, 1685 cm ; H NMR (CDCl ) δ 1.29 (d, 12H), 3.37
2
3
1
(2.81 g, 10 mmol) in EtOH (10 mL) at room temperature. The
(t, 1H, J (P,H) ) 27.43 Hz), 4.68 (m, 2H), 4.76 (m, 2H, J (P,H)
3 13
mixture was stirred for 20 h at room temperature in the course
of which a yellow solution was formed. The solvent was
removed under reduced pressure, and the residue was treated
with dichloromethane and then refluxed with acetone. The
crystalline material was filtered off and dried in vacuo: 71%,
3
) 10.46 Hz), 5.59 (d, 2H, J (P,H) ) 6.97 Hz); C NMR (CDCl )
δ 24.0, 33.6 (d, J (C,P) ) 149.9 Hz), 70.8 (d, J (C,P) ) 7.55 Hz),
99.4 (d, J (C,P) ) 9.75 Hz), 116.6, 128.7 (d, J (C,P) ) 9.37 Hz),
+
131.1; EI MS m/z 373 (4) for C13
H
19Cl
19Cl
3
3
NO
NO
3
P , 208 (100) for
+
C
7
H
5
Cl
3
N . Anal. Calcd for C13
H
3
P: C, 41.68; H, 5.11;
-
1
1
mp 261 °C (dec); IR (KBr) 1648 cm ; H NMR (DMSO-d
8
6
) δ
N, 3.74; Cl, 28.39. Found: C, 42.18; H, 5.51; N, 3.73; Cl, 27.60.
.50 (t, 2H), 8.99 (t, 1H), 9.66 (d, 2H, J ) 6.5 Hz); 13C NMR
Ack n ow led gm en t. Financial support by the Deut-
sche Forschungsgemeinschaft (Sonderforschungsbereich
(
(
DMSO-d
6
) δ 125.8, 127.0, 129.6, 146.1, 150.6; CI MS m/z 208
+
7 5 3 7 5 4
100) for C H Cl N . Anal. Calcd for C H Cl N: C, 34.58, H,
4
36), the Fonds der Chemischen Industrie, and the
2
5
.07; Cl, 57.58, N 5.76. Found: C, 34.24; H, 2.25; Cl, 57.49; N,
.81.
N-(2,2-Dich lor oeth en yl)p yr id in iu m Ch lor id e (12). To
Th u¨ ringer Ministerium f u¨ r Wissenschaft, Forschung
und Kultur (Erfurt, Germany) is gratefully acknowl-
edged. We thank Dr. J ennie Weston for useful discus-
sions. In addition, we thank the Hewlett-Packard
Company for providing us with CPU time.
a suspension of 10 (8.46 g, 30 mmol) in dichloromethane (90
mL) was added triphenylphosphane (8.65 g, 33 mmol). The
mixture was stirred for 48 h at room temperature, evaporated
to a third of the volume, and then cooled to O °C. The
precipitate was filtered off and washed with cold dichlo-
J O982153Z