Unexpected dimeric products from the amidomethylation of pentasubstituted benzenes

Article abstract of DOI:10.1016/j.tetlet.2004.03.175

An isomeric series of unexpected diarylmethane products with flexible substituents, isolated from amidomethylation reactions of p-dimethoxybenzene derivatives, was analyzed by X-ray crystallography to reveal novel solid-state structures, two of which have

Full text of DOI:10.1016/j.tetlet.2004.03.175

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4023–4026
Unexpected dimeric products from the amidomethylation of
pentasubstituted benzenesq
David Wiedenfeld,* Mark A. Minton, Vladimir N. Nesterov, David R. Glass
and Crystal L. Montoya
Department of Natural Sciences––Chemistry, New Mexico Highlands University, Las Vegas, NM 87701, USA
Received 24 March 2004; accepted 26 March 2004
Abstract—An isomeric series of unexpected diarylmethane products with flexible substituents, isolated from amidomethylation
reactions of p-dimethoxybenzene derivatives, was analyzed by X-ray crystallography to reveal novel solid-state structures, two of
which have identical elemental cell parameters.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
We have been studying amidomethylation reactions1 of
p-dimethoxybenzene derivatives in order to gain entry
into aminomethylated quinone systems. In two previous
cases, we reacted trimethylhydroquinone dimethyl ether
and also toluhydroquinone dimethyl ether with N-
(hydroxymethyl)trifluoroacetamide in chloroform–tri-
fluoroacetic acid solution.2 The primary product in each
case was the expected trifluoroacetamide adduct. How-
ever, in each case we also isolated a diarylmethane
product that was not expected.
We studied this reaction further with p-dimethoxybenz-
ene derivatives that have a deactivating chlorine group,
namely the three isomers of chlorodimethyl-1,4-di-
methoxybenzene. These three isomeric precursors were
prepared by addition4 of anhydrous hydrogen chloride5
to dimethyl-1,4-benzoquinones (xyloquinones) followed
by O-methylation with dimethyl sulfate under phase
transfer conditions.6
The amidomethylation reactions were carried out as
before2 using N-(hydroxymethyl)trifluoroacetamide in
chloroform–trifluoroacetic acid solution. In contrast to
our early report with systems that did not have the
deactivating chlorine group, only very small amounts of
dimeric products were isolated when the reactions were
carried out under ambient pressure. When we instead
conducted the same reactions at higher temperatures in
sealed tubes, diarylmethane products were formed more
readily in each case (Scheme 1). For example, in the
reaction with 2-chloro-1,4-dimethoxy-3,6-dimethylbenz-
ene approximately 40% of the expected amidomethyl-
ation product, 25% of dimer 1a, and 20% starting
material were recovered (the latter two as a mixture that
could be resolved by differential crystallization) after
silica gel chromatography of the crude reaction mixture;
the reactions of the other two chlorodimethoxydimethyl-
benzene isomers gave similar yields of products.
Only a few earlier reports suggest that a diarylmethane
product would be formed in such a reaction. These all
involved more electron-rich aromatic systems, rather
than substituted benzene derivatives, in amidomethyl-
ation reactions with reagents different than those used
here. In one example, b-naphthol formed an analogous
dinaphthylmethane derivative when reacted with vari-
ous methylenebisamides.3 We have since expanded our
investigation of the diarylmethane forming reaction and
report here a more thorough description of the synthetic
pathway as well as important X-ray data on an isomeric
series of dimeric products.
Keywords: Amidomethylation reactions; Diarylmethanes; X-ray crys-
tallography.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.175
* Corresponding author. Tel.: +1-505-426-2035; fax: +1-505-454-3103;
e-mail: dwiedenfeld@nmhu.edu
The nature of the dimer forming pathway was
probed by reacting a trifluoroacetamide product with N-
(hydroxymethyl)trifluoroacetamide under our reaction
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.175

4024
D. Wiedenfeld et al. / Tetrahedron Letters 45 (2004) 4023–4026
OCH3
OCH3
OCH3
OCH3
CH3
OCH3
OCH3
Cl
CH3
CH3
Cl
Cl
CH3
Cl
H3C
Cl
CF3CONHCH2OH
+
CF3COOH, ∆
H3C
H3C
CH2NHCOCF3
H3C
CH3
OCH3
OCH3
1a
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
CH3
H3C
Cl
H3C
Cl
CH3
H3C
Cl
H3C
CH3
Cl
CF3CONHCH2OH
+
CF3COOH, ∆
CH2NHCOCF3
OCH3
1b
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3C
H3C
Cl
H3C
H3C
Cl
Cl
H3C
H3C
CH3
CH3
CF3CONHCH2OH
+
CF3COOH, ∆
CH2NHCOCF3
OCH3
1c
Scheme 1. Amidomethylation reactions studied. In each case, a mixture of dimeric product, amidomethylation product and starting material was
obtained.
conditions. Only the unchanged trifluoroacetamide was
recovered in this reaction. Thus, we believe that the tri-
fluoroacetamide is the primary product in our dimer
forming sequences and that it can react further with the
starting dimethoxybenzene species. It is likely that the
C–N bond of the trifluoroacetamide can reversibly cleave
under the reaction conditions to form a benzylic cation
type species; such a species could either reform the
trifluoroacetamide or react with a dimethoxybenzene
derivative in an electrophilic aromatic substitution reac-
tion.7 It is also possible that N-(hydroxymethyl)trifluo-
roacetamide reverts to the acetamide and formaldehyde,
which then reacts electrophilically with two molecules of
starting material to produce the observed dimers.
Figure 2. View of dimer 1b with the atom-numbering scheme. The
non-H atoms are shown with thermal ellipsoids drawn at the 50%
probability level. H atoms are drawn as circles of arbitrary small radius
for clarity.
The three dimeric isomers were fully characterized and
their structures investigated by X-ray analysis (Figs. 1–
3). Dimer 1c crystallized in the triclinic space group P-1
and the molecules occupy a general position in the
crystal. In contrast, both compounds 1a and 1b crys-
tallized in the orthorhombic space group Pbcn and these
molecules occupy a special position in the crystal (two-
fold axis passing through the methylene group).
Remarkably, the elemental cells of 1a and 1b have
identical parameters despite the presence of flexible
methoxy groups in each species.
Comparison of results for the three dimeric isomers
Figure 1. View of dimer 1a with the atom-numbering scheme. The
reveals that 1c has a higher density than the other two,
reflecting better packing in this isomer. Examination of
the geometries of the three isomers reveals that the most
non-H atoms are shown with thermal ellipsoids drawn at the 50%
probability level. H atoms are drawn as circles of arbitrary small radius
for clarity.

D. Wiedenfeld et al. / Tetrahedron Letters 45 (2004) 4023–4026
4025
distance is less than the doubled radii of the chlorine
atoms.10 We ascribe the difference in melting points
observed for 1a and 1b (ca. 34° greater for 1a) to the
presence of these contacts in 1a, but not 1b. These
contacts apparently do not distort the geometry of 1a
significantly within the elemental cell, since 1a and 1b
display identical cell parameters.
3. Conclusions
We make the following major conclusions from this
study: (1) unexpected dimeric products are common in
amidomethylation reactions of aromatic species with N-
(hydroxymethyl)trifluoroacetamide, (2) an isomeric ser-
ies of fully substituted aromatic dimers has been fully
characterized and described here, (3) the dimeric prod-
ucts arise from the primary reaction mixture, (4) the rare
phenomenon was observed that two of the isomers, 1a
and 1b, have identical elemental cells, (5) the major
geometrical differences between 1c and the other two
isomers in the solid state are the different dihedral angles
between aryl rings and the different orientations of the
methoxy groups with respect to the aromatic rings.
Figure 3. View of dimer 1c with the atom-numbering scheme. The
non-H atoms are shown with thermal ellipsoids drawn at the 50%
probability level. H atoms are drawn as circles of arbitrary small radius
for clarity.
obviously significant differences in packing appear to be
in the orientations of the methoxy substituents with
respect to the aromatic rings and also in the dihedral
angles between the aromatic rings.
In every case here, the methoxy substituent is almost
perpendicular to the aromatic ring. However, the rela-
tive orientations of the two methoxy groups with respect
to the ring vary in an interesting manner. For the iso-
mers 1a and 1b, the methoxy groups have a syn orien-
tation (Figs. 1 and 2), in concert with the fact that these
molecules have identical elemental cell parameters (iso-
structural). The methoxy group orientations for dimer
1c are striking. In this case, the orientation of the
methoxy substituents with respect to the ring is different
for each aromatic ring; namely, the methoxy groups
have a syn orientation with respect to one ring and anti
with respect to the other (Fig. 3). It is interesting to
mention that in our previous work2 with a similar fully
substituted molecule, which also lies on a twofold axis,
the methoxy groups adopt an anti-orientation about the
aryl ring. In all cases we have examined, the methoxy
group parameters are always in good agreement with
literature data.8
Notes:
Crystallization of the compounds 1a–c from hexanes–
ethyl acetate gave X-ray quality crystals. We did grow
crystals of 1a–c under other conditions (using different
solvents), but obtained identical parameters for each
molecule in each case.
The structures of all isomers were investigated using an
Enraf–Nonius CAD4 diffractometer11 at 295 K. The
structure solution and refinement were usual.12–14
Crystal data for 1a: C21H26Cl2O4, M ¼ 413:32, ortho-
rhombic, space group Pbcn, a ¼ 11:412ð2Þ, b ¼
3
ꢀ
ꢀ
7:623ð2Þ, c ¼ 23:796ð5Þ A, V ¼ 2070:1ð7Þ A , Z ¼ 4,
Dc ¼ 1:326 g cmꢁ3, l(Mo Ka) ¼ 0.337 mmꢁ1, k ¼ 0:71073
ꢀ
A, F ð000Þ ¼ 872, 2hmax ¼ 52°, 3930 reflections mea-
sured, 2028 unique (Rint ¼ 0:067). Final residuals for 131
parameters were R1 ¼ 0:0456 against 1430 reflections
with I > 2rðIÞ and wR2 ¼ 0:1365 for 2028 unique
reflections.
The dihedral angle between the aryl rings in 1c is 101.7
(3)°. In the other isomers, the dihedral angles are sig-
nificantly smaller, namely 79.8 (3)° for 1a and 81.3 (2)°
for 1b.
Crystal data for 1b: C21H26Cl2O4, M ¼ 413:32, ortho-
rhombic, space group Pbcn, a ¼ 11:469ð2Þ, b ¼
3
ꢀ
ꢀ
The values of bond angles around the bridging methyl-
ene group are larger than usual and equal to 117.1 (2)°,
117.2 (2)° and 116.4 (2)°, for 1a–c, respectively. This
constant bond angle is similar to that found in two re-
lated cases.2 Nevertheless, the C–C bond lengths around
the central methylene group are only slightly elongated
compared to the usual value9 in every case.
7:577ð2Þ, c ¼ 23:820ð5Þ A, V ¼ 2070:0ð7Þ A , Z ¼ 4,
Dc ¼ 1:326 g cmꢁ3
,
l(Mo Ka) ¼ 0.337 mmꢁ1
,
k ¼
ꢀ
0:71073 A, F ð000Þ ¼ 872, 2hmax ¼ 54°, 4415 reflections
measured, 2237 unique (Rint ¼ 0:047). Final residuals for
131 parameters were R1 ¼ 0:0551 against 1513 reflec-
tions with I > 2rðIÞ and wR2 ¼ 0:1692 for 2237 unique
reflections.
The crystal packing was standard for each species except
for an intermolecular halogen contact displayed by 1a.
Thus, a very short intermolecular contact Cl1ꢀ ꢀ ꢀCl1 (ꢁx,
Crystal data for 1c: C21H26Cl2O4, M ¼ 413:32, triclinic,
space group P-1, a ¼ 8:807ð2Þ, b ¼ 9:193ð2Þ, c ¼
ꢀ
13:847ð3Þ A, a ¼ 107:17ð3Þ°, b ¼ 105:95ð3Þ°, c ¼
3
ꢁ3
ꢀ
ꢀ
ꢁy, 1 ꢁ z) exists that has a distance of 3.269 (2) A. This
96:02ð3Þ°, V ¼ 1008:6ð4Þ A , Z ¼ 2, Dc ¼ 1:361 g cm
,

4026
D. Wiedenfeld et al. / Tetrahedron Letters 45 (2004) 4023–4026
l(Mo Ka) ¼ 0.346 mmꢁ1, k ¼ 0:71073 A, F ð000Þ ¼ 436,
2hmax ¼ 54°, 4632 reflections measured, 4342 unique
(Rint ¼ 0:034). Final residuals for 252 parameters were
R1 ¼ 0:0612 against 2788 reflections with I > 2rðIÞ and
wR2 ¼ 0:1774 for 4342 unique reflections.
ꢀ
4. For a review of nucleophilic additions to quinones, see
Kutyrev, A. A. Tetrahedron 1991, 47, 8043–8065.
5. Anhydrous HCl can be conveniently prepared by adding
acetyl chloride to dry methanol. Bain, C. D.; Troughton,
E. B.; Tao, Y.-T.; Evall, J.; Whitesides, G. M.; Nuzzo, R.
G. J. Am. Chem. Soc. 1989, 111, 321–335, Supplementary
material.
Supporting information available: Detailed experimental
procedures and NMR data for compounds 1a–c and
their precursors, as well as X-ray crystallographic col-
lection and refinement details and structural data.
Crystal data for 1a–c have been deposited with the
Cambridge Crystallographic Data Center (CCDC
234469-234471).
6. Methylation procedure adapted from El-Kemary, M. A.
Can. J. Appl. Spectrosc. 1996, 41, 81–86; For a general
discussion of optimum conditions for phase transfer
reactions see Foglia, T. A.; Barr, P. A.; Malloy, A. J. J.
Am. Oil Chemists Soc. 1977, 54, 858A–861A.
7. A related alternative mechanism involving the dealkylative
coupling of benzylic ethers to give diarylmethanes has
been described: Rathore, R.; Kochi, J. K. J. Org. Chem.
1995, 60, 7479–7490.
8. Gallagher, J. F.; Hanlon, K.; Howarth, J. Acta Cryst.
2001, C57, 1410–1414.
Acknowledgements
9. Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.;
Orpen, A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2
1987, S1–S19.
10. Rowland, R. S.; Taylor, R. J. Phys. Chem. 1996, 100,
7384–7391.
We thank the N.I.H (D.W., Grant S06 GM008066-31)
for generous financial support.
11. Enraf-Nonius. CAD-4 Software. Version 5.0. Enraf-No-
nius, Delft, The Netherlands, 1989.
References and notes
12. Sheldrick, G. M. Acta Cryst. A 1990, 46, 467–473.
13. Sheldrick, G. M. SHELXTL PLUS. PC Version 5.02.
Program Package for Crystal Structure Solution and
Refinement. Siemens Analytical X-Ray Instruments Inc.,
Karlsruhe, Germany, 1994.
14. Sheldrick, G. M. SHELXL97. Program for the Refinement
of Crystal Structures. University of Goettingen, Germany,
1997.
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H. E. Synthesis 1984, 85–110, 181–212.
2. Wiedenfeld, D. J.; Nesterov, V. N.; Minton, M. A.; Glass,
D. R. Acta Cryst. 2003, C59, o700–o702.
3. Haworth, R. D.; Peacock, D. H.; Smith, W. R.; MacGil-
livray, R. J. Chem. Soc. 1952, 2972–2980.