Carbenoid reactions of 2-halomethyl-4,6-dimethyl-s-triazines

Article abstract of DOI:10.1021/jo0111412

Reactions of lithium, sodium, and potassium salts of 2,4,6-trimethyl-s-triazine (1) with 2-halomethyl-4,6-dimethyl-s-triazine (2) (X = Cl, Br) in glyme have been studied and found to give 1,2-bis(4,6-dimethyl-s-triazin-2-yl)ethane (3), 1,2-bis(4,6-dimethy

Full text of DOI:10.1021/jo0111412

J . Org. Chem. 2002, 67, 3051-3056
3051
Ca r ben oid Rea ction s of 2-Ha lom eth yl-4,6-d im eth yl-s-tr ia zin es
Craig L. Stephens, H. LeRoy Nyquist,* and Kenneth I. Hardcastle†
Department of Chemistry, California State University, Northridge, California 91330-8262
leroy.nyquist@csun.edu
Received December 12, 2001
Reactions of lithium, sodium, and potassium salts of 2,4,6-trimethyl-s-triazine (1) with 2-halomethyl-
4
,6-dimethyl-s-triazine (2) (X ) Cl, Br) in glyme have been studied and found to give 1,2-bis(4,6-
dimethyl-s-triazin-2-yl)ethane (3), 1,2-bis(4,6-dimethyl-s-triazin-2-yl)ethene (5), 1,2,3-tris(4,6-
dimethyl-s-triazin-2-yl)cyclopropane (6), 1,2,3-tris(4,6-dimethyl-s-triazin-2-yl)propane (7), and
1
,2,3,4-tetrakis(4,6-dimethyl-s-triazin-2-yl)butane (8). It is proposed that product 3 is formed
primarily via an S 2 reaction, whereas the remaining products are formed primarily via carbenoid
N
reactions that are enumerated.
In tr od u ction
Resu lts a n d Discu ssion
In view of the successful synthesis of a number of
The reaction of 1a with 2b in ether gave only a trace
amount of product 3, whereas when glyme was used as
the solvent, the reaction of 1a and 1c with 2b gave
moderate amounts of 3. In addition to 3, we report four
other new and interesting products: 1,2-bis(4,6-dimethyl-
s-triazin-2-yl)ethene (5), 1,2,3-tris(4,6-dimethyl-s-triazin-
2-yl)cyclopropane (6), 1,2,3-tris(4,6-dimethyl-s-triazin-2-
yl)propane (7), and 1,2,3,4-tetrakis(4,6-dimethyl-s-triazin-
2-yl)butane (8). All of the above products were identified
1
heterocyclophanes involving the pyridine ring and the
2
pyrrole ring, it was challenging to consider the possibil-
ity of synthesizing a heterocyclophane that contained two
s-triazine rings connected via two or three ethylene
bridges, the latter being [2
] (2,4,6)-s-triazinophane (4)3
3
analogous to [2
3
](1,3,5)cyclophane.4
The initial plan, as represented by Scheme 1, was to
react the 2,4,6-trimethyl-s-triazinyl anion of 1 with the
1
13
2
-halomethyl-4,6-dimethyl-s-triazine (2) via an S
N
2 reac-
by H and C NMR and elemental analyses, as well as
tion to form alkane 3 containing the first ethylene bridge
between the two s-triazine rings. Possible conversion of
compound 3 to the desired heterocyclophane 4 was to be
achieved by one of the following routes. (1) The mono-
bromination of the dianion from 3 should enable an
N 2
intramolecular S 2 reaction to form the [2 ](2,4)-s-tri-
azinophane, and repeating the reactions on the dianion
of the latter should give 4. (2) The dianion of 3 could be
dibrominated to give the 4,4′-dibromomethyl derivative
of 3, and the latter, upon treatment with n-butyllithium,1b
should give the [2
sequence of reactions on the [2
should give 4. (3) The reaction with sodium sulfide of the
,4′,6,6′-tetrabromomethyl derivative formed from 3 should
2
](2,4)-s-triazinophane. Repeating the
2
](2,4)-s-triazinophane
4
give the trithia-s-triazinophane, and the transformation
of the latter into 4, or its corresponding diene, could be
achieved by a number of possible routes.4,5
N
During our attempts at the synthesis of 3 by the S 2
reaction of 1 with 2, we became aware of the predomi-
nance of their carbenoid reactions and the resulting
products that we now report.
†
Current address: Department of Chemistry, Emory University,
X-ray diffraction studies (excluding compound 3). X-ray
diffraction data showed alkene 5 to be the trans isomer
and that the arrangement of the 4,6-dimethyl-s-triazine
Atlanta, GA 30322-2210.
6
(
1) (a) Martel, H. J . J .-B.; Rasumussen, M. Tetrahedron Lett. 1971,
4
1, 3843-3846. (b) Baker, W.; Buggle, K. M.; McOmie, J . F. W.;
Watkins, D. A. M. J . Chem. Soc. 1958, 3594-3603. (c) Bruhin, J .;
J enny, W. Tetrahedron Lett. 1973, 15, 1215-1218.
(
2) Haley, J . F., J r.; Keehn, P. M. Tetrahedron Lett. 1975, 21, 1675-
(6) Thermal ellipsoid figures and crystallographic data are available
in Supporting Information. Atomic coordinates for the following
compounds have been deposited with the Cambridge Crystallographic
Data Centre: numbers CCDC 177 880 (5), CCDC 177 881 (6), CCDC
177 882 (7), CCDC 177 883 (meso-8), and CCDC 177 884 (racemate
8). The coordinates can be obtained upon request from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, U.K.
1
3
678.
(
3) T u¨ rker, L. J . Mol. Struct. (THEOCHEM) 2000, 530, 131-136.
(
4) Boekelheide, V.; Hollins, R. A. J . Am. Chem. Soc. 1970, 92, 3512-
513.
5) (a) Boekelheide, V. In Cyclophanes I; V o¨ gtle, F., Ed.; Springer-
(
Verlag: New York, 1983; pp 87-143. (b) Meyers, C. Y.; Malte, A. M.;
Matthews, W. S. J . Am. Chem. Soc. 1969, 91, 7510-7512.
1
0.1021/jo0111412 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/02/2002

3
052 J . Org. Chem., Vol. 67, No. 9, 2002
Stephens et al.
Sch em e 1
the latter simply enabled each species to regenerate the
other. It is generally recognized that R-elimination on
haloalkanes by an organolithium gives rise to a carbenoid
7
,8d,9
species in most cases rather than a free carbene
or
an isolable carbene.10 Reported evidence also indicates
that the carbenoid species formed by the use of potassium
tert-butoxide for R-elimination becomes the free carbene
only in the presence of 18-crown-6-ether.11 Therefore, we
assumed in this investigation that the use of a sodium
or a potassium base for R-metalation in the absence of a
crown ether would also yield predominantly carbenoid
species and that the presence of glyme as a solvent
undoubtedly assisted in the stabilization of the carbenoid
Ta ble 1. Yield s of P r od u cts fr om Rea ction s of 1 w ith 2
8
c,12
species as is reported for tetrahydrofuran
ether.
and ethyl
relative yields of products
absolute
7b,9a
reactants
(mol %)a
yield
b
In interpreting the behavior of a carbenoid species such
as 9, it is advantageous to consider it as encompassing a
spectrum of species that may be represented by a
nucleophilic species (9a ), an amphophilic or ambiphilic
species (9b), and an electrophilic species (9c) depending
entry
1
2
T (°C)
25 15
-60 17
3
5
6
7
8
(mol %)
1
2
3
1a 2a
1a 2a
1a 2a
1a 2b
1a 2b
1b 2a
1b 2a
1b 2b
1b 2b
1c 2a
1c 2a
1c 2b
1c 2b
1c 2b
68
65
56
17
18
23
36
29
24
45 ( 4e
c
25 21
d
4
25 44 ( 4 8 ( 2
33 ( 0 16 ( 2
5
6
7
-60 50
25 12
-60
25
-60 12
25
26
6
11
7
82
89
10
7 56
38
34
f
39 ( 5e
36
49
75
66 ( 2e
8
8 ( 6 59 ( 17 26 ( 9 7 ( 7
9
73
16
100
100
1
1
1
1
1
0
1
2
3
4
-60
f
25 38 ( 7 9 ( 9
-60 27
37 ( 5 16 ( 3
14
22
19
16
40 34
75
c
25 62
a
Based upon single runs unless noted otherwise. Precision
b
within 4%. Based upon total moles of triazine ring in each
product (3, 1 mol; 5, 2 mol; 6 and 7, 3 mol; 8, 4 mol) compared to
the total moles of 2. Uncorrected for any recovered 2 (less than
c
d
5
%). Rapid addition (10 s vs 25 min). Average of two runs.
e
Based upon a single run. f Average of four runs.
rings about the cyclopropane in compound 6 was two up
and one down. The structures of 7, the meso form of 8,
upon the degree of bond making or breaking between the
6
8c,9a,12b,13
carbon, the halogen, and the metal.
These species
which itself
8
c,14
and the (2S,3S)-enantiomer of racemate 8 were also
may also give rise to 9d , the free carbene,
6
13c,d,15
determined by X-ray diffraction studies. From the above
may be amphophilic.
The electron-withdrawing
products, it became apparent that the predominant
reaction was not the desired substitution reaction but
rather the formation of carbenoid species whose reactions
led to compounds 5-8, as well as possibly some alkane
(9) (a) Friedman, L.; Honour, R. J .; Berger, J . G. J . Am. Chem. Soc.
970, 92, 4640-4645. (b) Closs, G. L.; Closs, L. E. Angew. Chem., Int.
1
Ed. Engl. 1962, 1, 334-335.
(10) (a) Arduengo, A J ., III. Acc. Chem. Res. 1999, 32, 913-921. (b)
3
. The relative and absolute yields of the products are
Tomioka, H.; Watanabe, T.; Hirai, K.; Furukawa, K.; Takui, T.; Itoh,
K. J . Am. Chem. Soc., 1995, 117, 6376-6377. (c) Sol e´ , S.; Gornitzka,
H.; Schoeller, W. W.; Bourissou, D.; Bertrand, G. Science 2001, 292,
1901-1903.
reported in Table 1.
In considering the possible routes for the formation of
the above products, the attractive routes, in general,
(11) (a) Moss, R. A.; Pilkiewicz, F. G. J . Am. Chem. Soc. 1974, 96,
5
3
632-5633. (b) Patrick, T. B.; Schmidt, D. J . J . Org. Chem. 1977, 42,
7
appear to involve a carbene complex or carbenoid species
354-3356. (c) Moss, R. A.; Mallon, C. B.; Ho, C.-T. J . Am. Chem. Soc.,
formed by the anion 1 reacting with 2 in the role of a
base (R-metalation) to give carbenoid species represented
by 9. Although R-metalation is generally found to be
1977, 99, 4105-4110.
(
12) (a) Hoeg, D. F.; Lusk, D. I. J . Organomet. Chem. 1966, 5, 1-12.
b) Hoeg, D. F.; Lusk, D. I.; Crumbliss, A. L. J . Am. Chem. Soc. 1965,
7, 4147-4155. (c) K o¨ brich, G.; Merkle, H. R. Chem. Ber. 1966, 99,
1782-1792. (d) K o¨ brich, G.; Merkle, H. R.; Trapp, H. Tetrahedron Lett.
965, 15, 969-972.
13) (a) Siegel, H.; Hiltbrunner, K.; Seebach, D. Angew. Chem., Int.
(
8
8
slower than metal-halogen exchange, in this study,
1
(
(
7) (a) Kirmse, W. Angew. Chem., Int. Ed. Engl. 1965, 4, 1-10.
b) Closs, G. L.; Moss, R. A. J . Am. Chem. Soc. 1964, 86, 4042-
053.
8) (a) March, J . Advanced Organic Chemistry: Reactions, Mecha-
nisms, and Structure, 3rd ed.; Wiley-Interscience: New York, 1985; p
5
1
5
Ed. Engl. 1979, 18, 785-786. (b) K o¨ brich, G.; Flory, K.; Fischer, R. H.
Chem. Ber. 1966, 99, 1793-1804. (c) Moss, R. A. Acc. Chem. Res. 1980,
13, 58-64. (d) Moss, R. A.; Shen, S.; Hadel, L. M.; Kmiecik-Ławrynow-
icz, G.; Włostowska, J .; Krogh-J espersen, K. J . Am. Chem. Soc. 1987,
109, 4341-4349. (e) Moss, R. A.; Fedorynski, M.; Shieh, W.-C. J . Am.
Chem. Soc. 1979, 101, 4736-4738. (f) Topolski, M.; Walborsky, H. M.
J . Org. Chem. 1994, 59, 5506-5510. (g) Maercker, A. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1023-1025. (h) Braun, M. Angew. Chem., Int.
Ed. Engl. 1998, 37, 430-451.
(
4
(
61. (b) Zhil’tsov, S. F.; Druzhkov, O. N. Russ. Chem. Rev. 1971, 40,
26-141. (c) K o¨ brich, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 41-
2. (d) Nefedov, O. M.; D′yachenko, A. I.; Prokof′ev, A. K. Russ. Chem.
Rev. 1977, 46, 941-966.

2
-Halomethyl-4,6-dimethyl-s-triazines
J . Org. Chem., Vol. 67, No. 9, 2002 3053
influence of the triazine ring16 would enhance the re-
moval of the R-hydrogen, stabilize species 9a and de-
crease its nucleophilicity, but it would destabilize species
reacting with 2b (Table 1, entries 8 and 9). However, in
the other cases, compound 5, or its precursor 10, may
have served as a precursor to other products, principally
compound 6, and possibly 7 and 8. The formation of 5 by
the dimerization of two free carbenes is possible, but
under the conditions of this investigation, this route is
rather unlikely.8
The reaction of sodium hydride with 2b gave results
qualitatively consistent with those of 1b with 2b except
that essentially no alkane 3 was formed due to the
absence of 1b in the former reaction.
1
7
9
c and increase its electrophilicity. However, it is
conceivable that species 9c could be stabilized either by
the intramolecular association of the unshared pair of
electrons on the neighboring nitrogen with the electron-
deficient carbon as has been postulated for the carbo-
methoxycarbene18 or by the intermolecular formation of
an ylide, which has been shown to form between carbenes
c,22
1
9
and heteroatoms. Due to the heterogeneity of the
reaction,9
a,20
temperature dependence, and less signifi-
F or m a tion of Com p ou n d 6. Most reported cyclopro-
panation reactions have involved an external alkene
added during or after the formation of the carbene or
carbenoid species.23 However, few cases have been re-
ported in which the alkenes generated from the parent
carbene or carbenoid species continue to undergo reaction
with the remaining carbene or carbenoid species, as in
this study, to give cyclopropane products.2 Thus, in this
investigation, compound 6 is most probably formed by a
one-step addition reaction of the electrophilic carbenoid
species 9c with alkene 5. It is interesting to note that
the chlorocompound 2a , in contrast to the bromocom-
pound 2b, gave much higher yields of the cyclopropane
product 6, indicating that 2a favors, within each of the
three different metal carbenoids, the more electrophilic
carbenoid species 9c (Table 1, entries 1-3 vs 4 and 5; 6
and 7 vs 8 and 9; 10 and 11 vs 12-14). This result is
2
cant variables such as the concentration and the rate of
addition, some variation in the reproducibility of the
yields became apparent. Also, in considering the yield of
a given product, one has to do so relative to the competi-
tive formation of the other products.
F or m a tion of Com p ou n d 3. As seen from Table 1
1a,c
(entries 4 and 5 vs 1-3; 8 and 9 vs 6 and 7; and 12-14
vs 10 and 11), alkane 3 was formed in a greater yield in
the case of 1 reacting with the bromocompound 2b than
with the chlorocompound 2a . This would support the
formation of 3 primarily via an S
N
2 reaction. It is also
possible that alkane 3 could arise via a carbenoid species
inserting into either the carbon-metal bond of 18
c,13f
to
give an organometallic precursor of 3 or the carbon-
hydrogen bond of 2,4,6-trimethyl-s-triazine (formed con-
currently with R-metalation). However, evidence for the
latter insertion is not supported in the literature.7
F or m a tion of Com p ou n d 5. Numerous alkenes have
a,9a,14
contrary to the trend cited in the literature for CBr and
2
4
CCl as true carbenes and for bromomethyllithium and
2
chloromethyllithium as carbenoids9 but is supported by
a
been reported as products resulting from possible car-
benoid or carbene formations in solution.1
2c,21
Alkene 5
the report that the fluorenylidenechloromethyllithium
carbenoid is less stable (more reactive) than the corre-
sponding bromocarbenoid.8 However, an alternative
route, consistent with the trend reported in the literature,
would be a stepwise addition reaction in which the
nucleophilic carbenoid species 9a would attack the
electron-poor alkene 5 in a Michael-type reaction to give
an anion (stabilized by the adjacent triazine ring), which
then would undergo ring closure by displacing the halide
to form compound 6. Although significant differences
exist between alkene 5 and simpler alkenes, evidence to
distinguish between the above two mechanisms might
be obtained by examining the stereospecificity of the
reaction of carbenoid 9 with simple alkenes. It is note-
worthy that the reaction of 1b with 2b (entry 8) gave a
high yield of alkene 5 at 25 °C with a low conversion of
5 to cyclopropane 6, whereas 1c with 2b (entry 12) gave
little alkene as a result of most of it presumably being
converted to 6 and 7. Thus, the sodium carbenoid appears
to favor the nucleophilic species 9a , whereas the potas-
sium carbenoid favors the electrophilic species 9c and
could arise as a result of the reaction of the nucleophilic
species 9a reacting with the electrophilic species 9c or
with the amphophilic species 9b or 9d , followed by
c
elimination of a molecule of MX (dimerizing R-elimina-
tion).8
c,12c
Compound 5 could also arise by the nucleophilic
N
attack of 9a on 2 (S 2 reaction) to give intermediate 10
from which the elements of hydrogen halide could be
eliminated under the basic conditions of the reaction.12a
The comparable reaction of benzyl chloride with phenyl-
lithium has been reported to give the phenyl analogue
of species 10.1 It is noteworthy that compound 5 was
isolated in a significant yield only in the case of 1b
2a
(
14) Skell, P. S.; Cholod, M. S. J . Am. Chem. Soc. 1969, 91, 6035-
038.
15) (a) Moss, R. A.; Ge, C.-S.; Włostowska, J .; J ang, E. G.; J efferson,
(21) (a) Corey, E. J .; Carey, F. A.; Winter, R. A. E. J . Am. Chem.
Soc. 1965, 87, 934-935. (b) DeMore, W. B.; Pritchard, H. O.; Davidson,
N. J . Am. Chem. Soc. 1959, 81, 5874-5879. (c) Grundmann, C. Ann.
1938, 536, 29-36. (d) Munro, D. P.; Sharp, J . T. J . Chem. Soc., Perkins
Trans. 1 1984, 849-858. (e) Nazran, A. S.; Griller, D. J . Chem. Soc.,
Chem. Commun. 1983, 850-851. (f) K o¨ rbrich, G.; Goyert, W. Tetra-
hedron 1968, 24, 4327-4342.
(22) (a) Cheung, L. M.; Sundberg, K. R.; Ruedenberg, K. J . Am.
Chem. Soc. 1978, 100, 8024-8025. (b) Hoffmann, R.; Gleiter, R.;
Mallory, F. B. J . Am. Chem. Soc. 1970, 92, 1460-1466. (c) Alder, R.
W.; Blake, M. E. Chem. Commun. 1997, 1513-1514.
(23) (a) March, J . Advanced Organic Chemistry, 3rd ed.; Wiley-
Interscience: New York, 1985; pp 768-774. (b) Kirmse, W. Carbene
Chemistry, 2nd ed.; Blomquist, A. T., Wasserman, H., Eds.; Academic
Press: New York, 1971; Vol. 1, Chapter 8.
(24) Skell, P. S.; Cholod, M. S. J . Am. Chem. Soc. 1969, 91, 7131-
7137.
6
(
E. A.; Fan, H. Tetrahedron Lett. 1995, 36, 3083-3086. (b) Brahms, D.
L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585-1632.
(
(
(
16) Nyquist, H. L.; Wolfe, B. J . Org. Chem. 1974, 39, 2591-2595.
17) Regitz, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 725-728.
18) Noyori, R.; Yamakawa, M. Tetrahedron Lett. 1980, 21, 2851-
2
854.
(19) (a) Wang, J .-L.; Toscano, J . P.; Platz, M. S.; Nikolaev, V.; Popik,
V. J . Am. Chem. Soc. 1995, 117, 5477-5483. (b) Zaragoza, F.
Tetrahedron 1997, 53, 3425-3439. (c) Padwa, A.; Hornbuckle, S. F.
Chem. Rev. 1991, 91, 263-309. (d) J ackson, J . E.; Platz, M. S. In
Advances in Carbene Chemistry; Brinker, U. H., Ed.; J AI Press:
Stamford, CT, 1994; Vol. 1, pp 89-160.
(
20) K o¨ brich, G.; B u¨ ttner, H.; Wagner, E. Angew. Chem., Int. Ed.
Engl. 1970, 9, 169-170.

3
054 J . Org. Chem., Vol. 67, No. 9, 2002
Stephens et al.
9
1
d . This trend is also evident in the reactions of 1b and
c with 2a (Table 1, entries 6 and 10).
F or m a tion of Com p ou n d 7. The formation of com-
Exp er im en ta l Section
1
Melting points and boiling points are uncorrected. H and
C NMR spectra were recorded at 200 and 50 MHz, respec-
13
pound 7 appears to have proceeded most feasibly via the
reaction of species 1 with the alkene 5 (Michael-type
tively. Proton and carbon chemical shifts were referenced to
residual solvent protons and the solvent, respectively. Elemen-
tal analyses were performed by Desert Analytics, Tucson, AZ.
Unless otherwise noted, materials were obtained from com-
mercial suppliers and used without further purification. Ether
and glyme were distilled prior to use from sodium benzo-
phenone ketyl and lithium aluminum hydride, respectively.
reaction)25 or with species 10 (S
2 reaction). These
N
reactions would lead to a lower yield of 5 and higher
yields of 6 and 7, which was found experimentally (Table
1
, entries 1-3 and 12-14). Carbenoid precursors to
alkane 3 could conceivably react with carbenoid 9 or
compound 2 (S 2 reaction) to give 7, but these two
2
,4,6-Trimethyl-s-triazine was prepared by the method of
27
N
Schaefer and Peters. Compound 2a was prepared by the
method of Campaigne and Tullar using NCS.28
alternative reactions are not consistently supported by
the experimental results.
P r ep a r a tion of 2-Br om om eth yl-4,6-d im eth yl-s-tr ia zin e
2
9
1
(2b). The general procedure of Glaze was followed. n-
Butyllithium in hexane (1.6 M, 0.160 mol) was added dropwise
under argon to a stirred solution (-78 °C ) of 2,4,6-trimethyl-
s-triazine (18.74 g, 0.152 mol) in ether (750 mL). The bright-
yellow suspension was allowed to warm to room temperature
and then transferred (80 min) under argon to a stirred solution
(0 °C) of bromine (8.7 mL, 0.17 mol) in pentane (400 mL). The
flask was covered with foil and allowed to warm to room
temperature overnight. The cream-colored mixture was cooled
0 °C); ice water (25 mL) was added dropwise, and the phases
were separated. The aqueous phase was extracted with ether
150 mL); the organic phase was extracted with ice water (10
mL), and the combined organic phases were dried (MgSO ) in
the dark. The solution was filtered and evaporated under
reduced pressure to give a red-orange liquid, which was
distilled to afford 19.8 g (64%) of 2b: bp 60-68 °C (0.15 Torr)
lit. 93-95 °C (10 Torr)).
Rea ction of 1c w ith 2b. Isola tion of 3 a n d 5. A 35 wt %
dispersion of KH in mineral oil (802 mg KH, 20.0 mmol) was
washed under argon with dry benzene (3 × 4 mL) and covered
with glyme (50 mL). To the stirred suspension was added a
solution of 2,4,6-trimethyl-s-triazine (2.43 g, 19.7 mmol) in
glyme (20 mL). The slurry was stirred at room temperature
until all the hydride had reacted (2 h or longer) to give a red-
orange mixture. The slurry was then transferred (18 min)
under argon to a magnetically stirred solution of 2b (3.89 g,
The H NMR spectrum of compound 7 indicated that
the two hydrogens of the methylene groups are dia-
stereotopic due to the presence of the middle prochiral
carbon. Presumably, a significant contribution to the
nonequivalence of these methylene hydrogens arises from
an unequal population of the conformers of 7 at room
temperature.26
F or m a tion of Com p ou n d 8. Both the meso and the
racemic forms of 8 were isolated and identified. The
formation of a significant amount of 8 was unique to the
reaction of 1c with 2b at -60 °C, and data at the higher
temperature would indicate that 8 was formed at the
expense of compounds 3 and 6, and not of 7 (Table 1,
entry 13 vs 12 and 14). This observation would enable
one to conclude that the majority of the tetramer 8 was
not formed by the trimer 7, or its precursors, reacting
with a monomer but rather from the reaction of two
dimeric precursors to compounds 3 and 5.
It is of interest to compare the above reactions and
their products to the reported results of the reaction of
benzyl chloride with n-butyllithium (R-metalation) in
different solvents and at different temperatures. In this
latter study only compounds analogous to compounds 3
and 5 were reported in addition to a derivative of a
compound analogous to intermediate 10. No correspond-
ing cyclopropane, trimer, or tetramer was reported.
(
(
4
3
0
(
1
2a
1
9.2 mmol) in glyme (70 mL) at room temperature. The
reaction mixture was stirred for approximately 15 h; the brick-
red slurry was filtered, and the filtrate was evaporated under
reduced pressure to give 4.30 g of a viscous red residue. A
portion (0.76 g) of the above viscous residue was eluted on
neutral alumina (17.3 g) with 50% ether/pentane to give 0.12
g of solid, which was separated into approximately equal
amounts of compound 3 and compound 6 by the sublimation
of 3. Resublimation of 3 gave an analytical sample: mp (sealed)
Con clu sion
Reactions of lithium, sodium, and potassium salts of
,4,6-trimethyl-s-triazinyl anion (1) with 2-halomethyl-
,6-dimethyl-s-triazine (2) (X ) Cl, Br) in glyme have
2
4
-
1 1
1
47-149 °C; IR (KBr) 2960, 2920, 1515, 1380 cm ; H NMR
13
(CDCl
3
) δ 2.54 (s, 12H), 3.33 (s, 4H); C NMR (CDCl
3
) δ 25.8,
been examined semiquantitatively, and the following new
compounds have been characterized: 1,2-bis(4,6-di-
methyl-s-triazin-2-yl)ethane (3), 1,2-bis(4,6-dimethyl-s-
triazin-2-yl)ethene (5), 1,2,3-tris(4,6-dimethyl-s-triazin-
3
5.5, 176.1, 177.9. Anal. Calcd for C12 (244.30): C, 59.00;
16 6
H N
H, 6.60; N, 34.40. Found: C, 58.97; H, 6.57; N, 34.30.
In a comparable run, the above viscous residue yielded light-
orange crystals with time. Some of the crystals were removed,
washed with pentane and water, dissolved in CH
dried (MgSO ). The resulting solution was filtered and evapo-
2 2
Cl , and
2
-yl)cyclopropane (6), 1,2,3-tris(4,6-dimethyl-s-triazin-2-
yl)propane (7), and 1,2,3,4-tetrakis(4,6-dimethyl-s-triazin-
-yl)butane (8). It is proposed that product 3 is formed
primarily via an S 2 reaction, whereas the remaining
4
rated to afford a solid that was recrystallized from absolute
ethanol (2×) and from dichloromethane/ether (2×) to give an
analytical sample of 5: mp (sealed) 229-230 °C; IR (KBr)
2
N
products are formed primarily via carbenoid reactions.
To the best of our knowledge, this is the first reported
study of carbenoid reactions facilitated by the s-triazine
ring.
-1 1
2
970, 1500, 1425, 1375, 970 cm ; H NMR (CDCl
3
) δ 2.63 (s,
1
3
12H), 7.99 (s, 2H); C NMR (CDCl ) δ 25.8, 138.8, 170.0, 176.8.
3
Anal. Calcd for C12
14 6
H N (242.28): C, 59.49; H, 5.82; N, 34.69.
Found: C, 59.47; H, 5.59; N, 34.45.
Rea ction of 1c w ith 2a . Isola tion of 6. A 35 wt %
dispersion of KH in mineral oil (736 mg KH, 18.4 mmol) was
(25) (a) March, J . Advanced Organic Chemistry, 3rd ed.; Wiley-
Interscience: New York, 1985; pp 664-665. (b) Grovenstein, E., J r.;
Wentworth, G. J . Am. Chem. Soc. 1967, 89, 1852-1862. (c) Welch, J .
G.; Magid, R. M. J . Am. Chem. Soc. 1967, 89, 5300-5301. (d)
Mulvaney, J . E.; Gardlund, Z. G. J . Org. Chem. 1965, 30, 917-920.
(27) Schaefer, F. C.; Peters, G. A. J . Org. Chem. 1961, 26, 2778-
2784.
(28) Campaigne, E.; Tullar, B. F. Organic Syntheses; Rabjohn, N.,
Ed.; J ohn Wiley & Sons: New York, 1963, Collect. Vol. IV, pp 921-
923.
(29) Glaze, W. H.; Selman, C. M.; Ball, A. L., J r.; Bray, L. E. J . Org.
Chem. 1969, 34, 641-644.
(30) Schaefer, F. C.; Ross, J . H. J . Org. Chem. 1964, 29, 1527-1537.
(
e) Parham, W. E.; Motter, R. F. J . Am. Chem. Soc. 1959, 81, 2146-
148.
26) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric
Identification of Organic Compounds, 4th ed; Wiley & Sons: New York,
981; p 207.
2
(
1

2
-Halomethyl-4,6-dimethyl-s-triazines
J . Org. Chem., Vol. 67, No. 9, 2002 3055
washed under argon with dry benzene (4 × 3 mL) and covered
with glyme (50 mL). To the stirred suspension was added a
solution of 2,4,6-trimethyl-s-triazine (2.10 g, 17.1 mmol) in
glyme (10 mL). The slurry was stirred until all the hydride
had reacted (2 h or longer) to give an orange-rust mixture.
The slurry was transferred (25 min) under argon to a stirred
solution of 2a (2.69 g, 17.1 mmol) in glyme (115 mL) at room
temperature. The dark reaction mixture was stirred for
approximately 15 h and filtered through Celite, and the major
amount of solvent was removed under reduced pressure to
yield a red-black residue. A portion (0.67 g) of the residue was
eluted on neutral alumina (1 × 19 cm) to afford 0.10 g of crude
The above reaction was repeated using 2,4,6-trimethyl-s-
triazine (2.02 g, 16.4 mmol), tert-butyllithium in pentane (1.7
M, 16.3 mmol), and 2b (3.31 g, 16.4 mmol). However, in this
case, the solution of 2b was cooled in a dry ice/acetone bath
before the addition of the slurry. The resulting mixture was
maintained below -60 °C (internal) for 6-8 h before being
warmed to room temperature. After 4 days, the reaction
mixture was filtered through Celite; the filtercake was washed
with CH
2
Cl
2
(3 × 25 mL), and the filtrates were combined. A
portion (75 mL) of the filtrates was removed and worked up
as described for the reaction of 1a with 2a .
Rea ction of 1b w ith 2a . 2,4,6-Trimethyl-s-triazine (2.14
g, 17.4 mmol), dissolved in glyme (20 mL), was added under
argon to a magnetically stirred suspension of dry (95%) sodium
hydride (417 mg NaH, 17.4 mmol) in glyme (50 mL) with
gentle heating. The mixture was heated (79 °C) for 7 days and
cooled to room temperature, and the deep-red slurry was
transferred (25 min) under argon to a stirred solution of 2a
(2.74 g, 17.4 mmol) in glyme (70 mL) at room temperature.
After 6 days, the reaction mixture was filtered through Celite;
6
. The crude 6 was recrystallized (3×) from pentane to give a
pure sample of 6 for X-ray diffraction and elemental analysis:
-1 1
mp 99-100 °C; IR (KBr) 2960, 1510, 1420, 1375 cm ; H NMR
CDCl
(
3
3
3
) δ 2.43 (s, 12H), 2.57 (s, 6H), 3.54 (d, J ) 5.7 Hz, 2H),
.81 (t, J ) 5.7 Hz, 1H); 13C NMR (CDCl
) δ 25.5, 25.7, 33.4,
7.1, 174.0, 175.6, 175.9, 176.3. Anal. Calcd for C18
3
21 9
H N
(
363.43): C, 59.49; H, 5.82; N, 34.69. Found: C, 59.67; H, 5.76;
N, 34.89.
Rea ction of 1a w ith 2a . tert-Butyllithium in pentane (1.7
the filtercake was washed with CH
2
Cl
2
(4 × 25 mL), and the
filtrates were combined. A portion (75 mL) of the filtrates was
removed and worked up as described for the reaction of 1a
with 2a .
M, 17.0 mmol) was added dropwise under argon to a stirred
solution (-78 °C) of 2,4,6-trimethyl-s-triazine (2.09 g, 17.0
mmol) in glyme (40 mL). The bright-yellow slurry was allowed
to warm to room temperature overnight and then transferred
The above reaction was repeated using 2,4,6-trimethyl-s-
triazine (2.07 g, 16.8 mmol), dry (95%) sodium hydride (406
mg NaH, 16.9 mmol), and 2a (2.66 g, 16.9 mmol). However,
in this case, the solution of 2a was cooled in a dry ice/acetone
bath before the addition of the slurry. The resulting mixture
was maintained below -60 °C (internal) for 6-8 h before being
warmed to room temperature. After 3 days, the reaction
mixture was filtered through Celite; the filtercake was washed
(22 min) under argon to a stirred solution of 2a (2.69 g, 17.0
mmol) in glyme (70 mL) at room temperature. After 7 days,
the reaction mixture was filtered through Celite; the filtercake
was washed with CH
combined. A portion (100 mL) of the filtrates was evaporated,
and the residue was dried under vacuum to a constant mass
2
Cl
2
(5 × 25 mL), and the filtrates were
(
1.03 g). The residue was dissolved in CH
extracted with cold, saturated NH
Cl (4 × 5 mL), dried
MgSO ), filtered, and evaporated to afford a residue that was
dried under vacuum to a constant mass (0.49 g). The residue
was then dissolved in a measured amount of CH Cl to give a
2 2
Cl (45 mL),
with CH
2
Cl
2
(2 × 25 mL), and the filtrates were combined. A
4
portion (75 mL) of the filtrates was removed and worked up
as described for the reaction of 1a with 2a .
(
4
Rea ction of 1b w ith 2b. 2,4,6-Trimethyl-s-triazine (2.03
g, 16.5 mmol), dissolved in glyme (20 mL) was added under
argon to a stirred suspension of dry (95%) sodium hydride (375
mg NaH, 15.6 mmol) in glyme (50 mL). The slurry was heated
2
2
solution with an approximate concentration of 10 mg/mL.
Three aliquots (2 mL) were removed, dried under vacuum, and
dissolved in CDCl for quantitative GC and NMR analyses
3
(81 °C) for 7 days, cooled to room temperature, and transferred
using bibenzyl as an internal reference.
(20 min) under argon to a stirred solution of 2b (3.31 g, 16.4
The above reaction was repeated using 2,4,6-trimethyl-s-
triazine (1.96 g, 15.9 mmol), tert-butyllithium in pentane (1.7
M, 15.7 mmol), and 2a (2.48 g, 15.8 mmol). However, in this
case, the solution of 2a was cooled in a dry ice/acetone bath
before the addition of the slurry. The resulting mixture was
then maintained below -60 °C (internal) for 6-8 h before
being warmed to room temperature. After 2 days, the reaction
mixture was filtered through Celite; the filtercake was washed
mmol) in glyme (70 mL) at room temperature. After 2 days,
the reaction mixture was filtered through Celite; the filtercake
was washed with CH
2
Cl
2
(5 × 25 mL), and the filtrates were
combined. A portion (100 mL) of the filtrates was removed and
worked up as described for the reaction of 1a with 2a .
The above reaction was repeated using 2,4,6-trimethyl-s-
triazine (2.01 g, 16.3 mmol), dry (95%) sodium hydride (399
mg NaH, 16.6 mmol), and 2b (3.31 g, 16.4 mmol). However,
in this case, the solution of 2b was cooled in a dry ice/acetone
bath before the addition of the slurry. The resulting mixture
was maintained below -60 °C (internal) for 6-8 h before being
warmed to room temperature. After 2 days, the reaction
mixture was filtered through Celite; the filtercake was washed
with CH
2
Cl
2
(4 × 25 mL), and the filtrates were combined. A
portion (100 mL) of the filtrates was removed and worked up
as described for the reaction of 1a with 2a .
The above original reaction was repeated using 2,4,6-
trimethyl-s-triazine (1.91 g, 15.5 mmol), tert-butyllithium in
pentane (1.7 M, 15.6 mmol), and 2a (2.44 g, 15.5 mmol).
However, in this case, the slurry was added rapidly (10 s) to
the solution of 2a at room temperature. After 3 days, the
reaction mixture was filtered through Celite; the filtercake was
with CH
2
Cl
2
(5 × 25 mL), and the filtrates were combined. A
portion (100 mL) of the filtrates was removed and worked up
as described for the reaction of 1a with 2a .
Rea ction of 1c w ith 2a . A 35 wt % dispersion of KH in
mineral oil (710 mg KH, 17.7 mmol) was washed under argon
with dry benzene (5 × 4 mL) and then covered with glyme (50
mL). To the stirred suspension was added a solution of 2,4,6-
trimethyl-s-triazine (2.26 g, 18.4 mmol) in glyme (20 mL). After
2 days, the rust-colored slurry was transferred (40 min) under
argon to a stirred solution of 2a (2.79 g, 17.7 mmol) in glyme
(70 mL) at room temperature. After 2 days, the reaction
mixture was filtered through Celite; the filtercake was washed
washed with CH
combined. A portion (100 mL) of the filtrates was removed and
2
Cl
2
(4 × 25 mL), and the filtrates were
worked up as described for the reaction of 1a with 2a .
Rea ction of 1a w ith 2b. tert-Butyllithium in pentane (1.7
M, 16.5 mmol) was added dropwise to a stirred solution (-78
°
C) of 2,4,6-trimethyl-s-triazine (2.03 g, 16.5 mmol) in glyme
(40 mL) under argon. The suspension was allowed to warm to
room temperature. After 2 days, the bright-yellow slurry was
transferred (31 min) under argon to a stirred solution of 2b
with CH
2
Cl
2
(3 × 25 mL), and the filtrates were combined. A
(3.33 g, 16.5 mmol) in glyme (70 mL) at room temperature.
portion (75 mL) of the filtrates was removed and worked up
as described for the reaction of 1a with 2a .
After 3 days, the reaction mixture appeared to be homoge-
neous. A portion of the solution (50 mL) was evaporated to
afford a residue that was dried under vacuum to a constant
The above reaction was repeated using 2,4,6-trimethyl-s-
triazine (1.99 g, 16.1 mmol), potassium hydride (647 mg KH,
16.1 mmol), and 2a (2.57 g, 16.3 mmol). However, in this case,
the solution of 2a was cooled in a dry ice/acetone bath before
the addition of the slurry. The resulting mixture was main-
tained below -60 °C (internal) for 6-8 h before being warmed
mass. To the residue was added CH
suspension was filtered through Celite, and the filtercake was
washed with CH Cl
(2 × 10 mL). The filtrates were combined
and worked up as described for the reaction of 1a with 2a .
2 2
Cl (50 mL); the resulting
2
2

3
056 J . Org. Chem., Vol. 67, No. 9, 2002
Stephens et al.
mass (1.05 g). The residue was dissolved in CH Cl (20 mL),
to room temperature. After 3 days, the reaction mixture was
filtered through Celite; the filtercake was washed with CH Cl
2
2
2
2
and 10 mL of the solution was removed and worked up as
described for the reaction of 1a with 2a . The remaining
solution was evaporated to a minimum volume and eluted on
neutral alumina (21.2 g) with ether. Selected fractions were
combined and recrystallized from dichloromethane/ethanol
(2×) to obtain a sample of 8 for elemental analysis: mp 198-
(
4 × 25 mL), and the filtrates were combined. A portion (100
mL) of the filtrates was removed and worked up as described
for the reaction of 1a with 2a .
Rea ction of 1c w ith 2b. Isola tion of 7. A 35 wt %
dispersion of KH in mineral oil (644 mg, KH, 16.1 mmol) was
washed under argon with dry benzene (4 × 4 mL) and then
covered with glyme (50 mL). To the stirred suspension was
added a solution of 2,4,6-trimethyl-s-triazine (2.05 g, 16.6
mmol) in glyme (20 mL). After 2 days, the rust-colored slurry
was transferred (20 min) under argon to a stirred solution of
-
1
200 °C; IR (KBr) 2980, 2940, 1540, 1440 cm . Anal. Calcd for
24 30
C H N12 (486.62): C, 59.24; H, 6.21; N, 34.55. Found: C,
59.26; H, 5.96; N, 34.43.
The crystals of 8 were visually separated into the racemic
1
and meso forms. meso-8: mp 174-175 °C; H NMR (CDCl ) δ
3
2
b (3.35 g, 16.6 mmol) in glyme (70 mL) at room temperature.
After 2 days, the reaction mixture was filtered through Celite;
the filtercake was washed with CH Cl
2.43 (s, 12H), 2.48 (s, 12H), 3.14 (dd, J ) 3.9, 16.5 Hz, 2H),
3.57 (dd, J ) 9.6, 16.5 Hz, 2H), 4.17 (m, 2H); 13C NMR (CDCl )
3
2
2
(5 × 25 mL), and the
δ 25.6 , 25.7 , 39.3, 49.1, 175.8, 177.0, 178.7. Racemic 8: mp
6
3
1
filtrates were combined. A portion (125 mL) of the filtrates
was removed and worked up as described for the reaction of
1
203-205 °C; H NMR (CDCl ) δ 2.43 (s, 12H), 2.47 (s, 12H),
3
3.30 (dd, J ) 4.1, 16.5 Hz, 2H), 3.73 (dd, J ) 9.6, 16.5 Hz,
2H), 4.32 (m, 2H); 13C NMR (CDCl ) δ 25.6 , 25.7 , 37.3, 48.1,
a with 2a .
3
9
5
A portion of the above solution (15 mL) was removed and
175.8, 177.3, 178.8.
evaporated to afford a residue (0.25 g) that was eluted on
neutral alumina (1 × 21 cm) with 2% methanol/ether. Selected
fractions were combined and distilled in a Kugelrohr distilla-
Rea ction of Na H w ith 2b. An 80 wt % dispersion of NaH
213 mg NaH, 8.90 mmol) was washed with dry benzene (4 ×
(
5
mL) and then covered with glyme (50 mL). To the stirred
tion apparatus to afford 14 mg of 7: bp 162 °C (0.3 Torr); mp
suspension, under argon, was added (20 s) a solution of 2b
1.81 g, 8.95 mmol) in glyme (20 mL). After 5 days, the mixture
1
2
3
48-153 °C; IR (neat) 2920, 1525 cm-1; H NMR (CDCl
1
3
) δ
(
.48 (s, 12H), 2.50 (s, 6H), 3.18 (dd, J ) 6.5, 15.4 Hz, 2H),
was filtered through Celite, and the filtrate was evaporated
to yield 1.11 g of yellow-orange solid. A small amount of the
solid was washed with water to give a white solid. The water
1
3
.47 (dd, J ) 7.7, 15.4 Hz, 2H), 4.20 (m, 1H); C NMR (CDCl
, 25.7 , 41.9, 43.9, 175.9 , 175.9 , 176.9, 179.8. Anal.
Calcd for C18 (365.44): C, 59.16; H, 6.34; N, 34.50.
3
)
δ 25.6
7
1
6
9
23 9
H N
was removed via pipet, and the solid was dissolved in CH
25 mL), dried (MgSO
4
2
Cl
), and filtered through Celite. A portion
1 mL) of the resulting solution was evaporated under vacuum
and analyzed via
2
Found: C, 58.95; H, 6.11; N, 34.36.
The above reaction was repeated using 2,4,6-trimethyl-s-
triazine (1.97 g, 16.0 mmol), potassium hydride (645 mg KH,
(
(
to afford a solid that was dissolved in CDCl
3
1
6.1 mmol), and 2b (3.23 g, 16.0 mmol). However, in this case,
the potassium salt was added rapidly (10 s) to the solution of
b at room temperature. After 3 days, the reaction mixture
was filtered through Celite; the filtercake was washed with
CH Cl
(4 × 25 mL), and the filtrates were combined. A portion
100 mL) of the filtrates was removed and worked up as
1
H NMR. Relative mol %: 3, 2; 5, 61; 6, 37.
2
Ack n ow led gm en t. We are pleased to acknowledge
the financial support provided by the California State
University, Northridge, including a Research Fellowship
(C.L.S.) from the Center for Cancer and Developmental
Biology. The authors also acknowledge an X-ray instru-
mentation grant from NIH (S10-RR13673).
2
2
(
described for the reaction of 1a with 2a .
Isola tion of 8. The above reaction was repeated using 2,4,6-
trimethyl-s-triazine (1.96 g, 15.9 mmol), potassium hydride
(638 mg KH, 15.9 mmol), and 2b (3.22 g, 15.9 mmol). However,
in this case, the solution of 2b was cooled in a dry ice/acetone
bath before the addition of the slurry. The resulting mixture
was maintained below -60 °C (internal) for 6-8 h before being
warmed to room temperature. After 1 day, the reaction
mixture was filtered through Celite; the filtercake was washed
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 3, 5-7 ( H only), meso-8, racemate 8, a mixture
of meso- and racemate 8, and a mixture of 7 and 8, and
crystallographic data and thermal ellipsoid figures for com-
pounds 5-7, meso-8, and racemate 8. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
1
with CH
2
Cl
2
(5 × 25 mL), and the filtrates were combined. A
portion (100 mL) of the filtrates was removed and evaporated
to afford a residue that was dried under vacuum to a constant
J O0111412