An unusual synthesis of Troeger's bases using DMSO/HCl as formaldehyde equivalent

Article abstract of DOI:10.1055/s-2005-861868

The reactions between anilines and DMSO/HCl produce Troeger's bases in moderate yield. The Troeger's bases bearing an electron-withdrawing group can also be synthesized through this procedure. In this reaction, DMSO/HCl acts as formaldehyde equivalent. Ge

Full text of DOI:10.1055/s-2005-861868

1
228
SHORT PAPER
An Unusual Synthesis of Tröger’s Bases Using DMSO/HCl as Formaldehyde
Equivalent
a
a
a
a
b
A
Z
n
U
nusual Syn
h
thesis of Tr
o
a
Shanghai Key Lab of Chemistry Biology, Institute of Pesticides and Pharmaceuticals, East China University of Science and Technology,
P.O. Box 544,130, Meilong Road Shanghai 200237, P. R. China
b
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, P. R. China
Fax +86(21)64252603; E-mail: lizhong@ecust.edu.cn
Received 3 December 2004
groups was preventing the formation of Tröger’s base.15,16
However, -CN, -NO , -COOR, and -CF , are very useful
functional groups, which can be further elaborated to ex-
pand their application. Therefore, it is important to find
and develop the synthesis of symmetrical Tröger’s base
analogs bearing a strong electron-withdrawing group di-
rectly from substituted anilines.
Abstract: The reactions between anilines and DMSO/HCl produce
Tröger’s bases in moderate yield. The Tröger’s bases bearing an
electron-withdrawing group can also be synthesized through this
procedure. In this reaction, DMSO/HCl acts as formaldehyde
equivalent.
2
3
Key words: Tröger’s bases, DMSO/HCl, formaldehyde equivalent
In order to explore the synthesis of Tröger’s base analogs
bearing an electron-withdrawing group, Wilcox had re-
2
,8-Dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]di-
azocine Tröger’s base (1) was first isolated by Tröger in ported the synthesis of unsymmetrical Tröger’s base ana-
1
1
887, and was structurally characterized in 1935 as the logues bearing -NO on one aromatic ring, but the
2
product of the reaction between p-toluidine and formalde- procedure has to start from substituted 2-amino-benzyl-
2
5
hyde in acidic aqueous solution. In recent years, Tröger’s amines. Via double bromine–lithium exchange reaction
base and its analogs have been describeded as ‘fascinating of Tröger’s base, Wärnmark reported a procedure to ob-
3
,4
molecules’ due to their particular structures. The rigid tain some Tröger’s base analogs bearing -COOH and
H,12H-5,11-methanodibenzo [b,f][1,5]diazocine skele- -CHO substituents in moderate yield, but the same proce-
6
ton has recently gained additional prominence by serving dure only produced impure dicyano-substituted com-
as a molecular framework. The two aromatic rings, ori- pound.6 Kobayashi had reported the synthesis and
ented at a right angles, delimit a V-structure which makes functionalization of thiophene congeners of Tröger’s
5–7
7
this substrate suitable for the recognition of specific base. Goswami obtained the ethyl ester compound from
shapes or conformation of substrates. This unique geome- ethyl p-aminobenzoate and hexamethylenetetramine in
9
try has been exploited for the design of recognition of 23% yield, and Mederski reported the efficient procedure
8
9
DNA sequences, and dicarboxylic acids. Furthermore, to synthesize nitro functionalized Tröger’s base directly
their applications were also reported in novel molecular from diglycolic acid in 56% yield.17
replication system, chiral solvating agents, and chiral
molecular tweezers.
1
0
11
Herein, we report an unusual synthesis of Tröger’s bases
via the reaction of substituted anilines with DMSO and
anhydrous HCl (g), in which DMSO acts as a formalde-
hyde equivalent under the conditions. Interestingly, this
procedure could also yield 2,8-dicyano-6H,12H-5,11-
methanodibenzo [b,f][1,5] diazocine directly from 4-cy-
ano-aniline.
1
2
N
CH3
CH3
N
Figure 1 Tröger’s base (1)
From our understanding, DMSO/HCl (g) was normally
1
8
used for thiomethylation of phenols and in some cases,
One limitation to its usefulness, in this regard, has been
the inability to prepare the ring systems with a wide vari-
19
DMSO/HCl (37% aqueous) or DMSO/HBr (40% aque-
ous)20 respectively acted as chlorination or bromination
reagents. In a previous report on the synthesis of Tröger’s
base, DMSO was presumed to act as a formaldehyde
equivalent, however, only under drastic conditions of
185-190 °C.4
1
3
ety of functional groups on the aromatic rings. Common
synthetic procedures involve reaction with aqueous form-
aldehyde and a strong acid in a protic solvent. However,
this method does not work well with many substrates, pre-
1
4
sumably due to solubility problems. In addition, the ac-
cumulated evidence supported the conclusion that the
deactivation of the aromatic ring by electron-withdrawing
In our research upon chlorination of substituted anilines
with DMSO/HCl (g), we observed that, besides chlorinat-
ed products, analogs of Tröger’s base (1) were obtained in
very low yield. After optimization, this reaction can give
moderate yields of Tröger’s bases. For the substituted
anilines containing electron-donating or weak electron-
SYNTHESIS 2005, No. 8, pp 1228–1230
x
x
.
x
x
.2
0
0
5
Advanced online publication: 10.03.2005
DOI: 10.1055/s-2005-861868; Art ID: F18004SS
Georg Thieme Verlag Stuttgart · New York
©

SHORT PAPER
An Unusual Synthesis of Tröger’s Bases
1229
withdrawing groups, such as p-toluidine, p-anisidine, p- In summary, we introduce here an efficient and conve-
chloroaniline, p-fluoroaniline, 2,4-dimethylaniline, and nient method for the preparation of Tröger’s base analogs
so on, all the reactions were carried out at room tempera- from substituted anilines and DMSO/HCl(g). This proce-
ture to give moderate yields (45–60%). For the anilines dure could also produce di-cyano, di-trifluoromethyl, and
bearing electron-withdrawing groups (-NO , -CN, and di-2,4-difluoro, three novel Tröger’s base compounds.
2
-
COOC H ), the reaction needed to be performed at Under these reaction, conditions DMSO appears to be a
2 5
8
0 °C, and the corresponding Tröger’s bases were ob- formaldehyde equivalent.
tained in 23%, 21%, and 37% yield, respectively. It has
been known for some time that the fluorine atom can lead
to unexpected biological activity arising due to the special
properties of the fluorine atom, such as the high electro-
negativity of fluorine and high carbon–fluorine bond en-
O
S
OH
S
-
H2O
H+
S
2
2
1
ergy. We tried to synthesis Tröger’s bases bearing -CF
3
H2
N
H
N
NH2
NH2
S
-MeSH
and -2,4-F, the yields were 20% and 17%, respectively
Scheme 1, Table 1).
(
3
4
5
N
S
4
6
7
R
8
DMSO/HCl (g)
AcOH
3
H
N
H
N
H
N
+
S
R
NH2
13
-H
N
H
2
9
R
N
1
1
10
12
1
1a–l
5
6
Scheme 1 Synthesis of Tröger’s base from aniline and DMSO/HCl
g)
(
-H
-MeSH
N
N
NH
Table 1 Synthesis of Tröger’s Base Analogs from Anilines and
DMSO/HCl
N
H
8
7
Analog R
Mp (°C)
128–129
173–174
143–144
130–131
134–136
116–117
110–112
258–259
152–153
248–249
130–131
135–136
Mp (°C, Lit.) Yield (%)
S
-MeSH
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
4-CH3
127–12815
172–1732
140–14122
127–12823
131–13224
112–11322
104–10615
258–26017
126–1289
–
55
60
45
53
58
61
57
23
37
21
20
17
N
N
NH
N
4-OCH3
9
4-Cl
H
S
10
N
-H
4-OC H5
2
N
4-F
1
g
h
i
2,4-Dimethyl
4-NO2
Scheme 2 Plausible mechanism of the reaction between anilines
and DMSO/HCl
4-COOC H5
2
All chemicals or reagents were purchased from standard commer-
cial suppliers. Melting points were determined on XT4-100X melt-
ing point apparatus and were uncorrected. Infrared spectra were
measured on a Nicolet FT-IR-20SX instrument using a pressed KBr
j
4-CN
4-CF3
2,4-F
k
l
–
–
1
–
pellet, scanning from 625–4000 cm . High resolution mass spectra
1
were obtained on MicroMass GCT CA 055 spectrometer. H NMR
spectra were obtained on a Bruker-AC 500 (500 MHz) spectrometer
We believe the mechanism to be similar to that of the
using CDCl as the solvent and were reported in ppm (d) downfield
3
Pummerer rearrangement, a plausible mechanism for the from TMS (internal reference). The analyses for elemental compo-
reaction is proposed as shown in Scheme 2. First, DMSO/ sition were undertaken with an Italy MOD-1106 analyzer.
HCl forms sulfonium intermediate 2, which reacts with
Tröger’s Base Derivatives; General Procedure
DMSO (5 mL) was added to the appropriate aniline (0.005 mol) so-
lution in HOAc (5 mL) in a 50-mL three-neck flask. Then, anhyd
HCl (g) was continuously passed through the mixture. An exother-
aniline to form diaminomethane 5 via the iminium inter-
mediate 4. Then, the diaminomethane compound 5 reacts
with sulfonium intermediate 2 again to generate iminium
intermediate 7, which undergoes intramolecular cycliza-
mic reaction ensued, which made the mixture very warm, and the
tion to form compound 8. In the same way, compound 8 color gradually turned to dark red. After the starting material was
reacts with the sulfonium intermediate 2 to give Tröger’s consumed as indicated by TLC, the mixture was quenched with ice
water (20 mL), and neutralized with sat. aq Na CO . The mixture
base 1 as the final product.
2
3
Synthesis 2005, No. 8, 1228–1230 © Thieme Stuttgart · New York

1
230
Z. Li et al.
SHORT PAPER
was extracted with CH Cl (2 × 20 mL). The combined extracts
1l
2
2
were washed successively with water (10 mL) and brine (10 mL),
and dried over Na SO . After concentration, the residue was chro-
Yield: 125 mg (17%); white crystals; mp 135–136 °C.
2
4
IR (KBr): 3058, 2905, 2859, 1633, 1597, 1482, 1316, 1118, 930,
matographed on silica gel (EtOAc–hexane) to give target com-
pounds 1a–l. The procedure for the synthesis of 1h,l is similar to
that mentioned above, except for the fact, that the mixtures had to
be heated to 80 °C prior to passing anhyd HCl through them.
–1
8
52, 710 cm .
1
H NMR (500 MHz, CDCl ): d = 4.12 (d, 2 H, H-6,12endo, J = 17.3
3
Hz), 4.29 (s, 2 H, H-4), 4.58 (d, 2 H, H-6,12exo, J = 17.3 Hz), 6.52
(
d, 2H, H-1, J = 8.2 Hz), 6.72 (m, 2 H, H-3).
Compounds 1a–g was confirmed by mp, GC-MS, and spectral data
1
5
HRMS (EI): m/z calcd for C H N F , 294.0780; found, 294.0751.
obtained were compared with those from the literature.
15 10
2 4
1
h
Acknowledgment
Yield: 180 mg (23%); yellow crystals; mp 258–259 °C.
This work was supported by Minister of Science and Technology
(2003CB114405, 2004AA235070) and Shanghai Education Com-
mittee. The authors gratefully have heart-felt thanks for Dr. Akihiko
Ouchi for his valuable discussions. (Research Institute for Green
Technology, National Institute of Advanced Industrial Science and
Technology, Tsukuba, Ibaraki 305-8565, Japan)
IR (KBr): 2960, 2926, 1610, 1570, 1510, 1480, 1340, 1310, 1210,
–1
1
090, 950 cm .
1
H NMR (500 MHz, CDCl ): d = 4.32 (d, 2 H, H-6,12endo, J = 15.7
3
Hz), 4.34 (s, 2 H, H-13), 4.83 (d, 2 H, H-6,12exo, J = 17.1 Hz), 7.27
(d, 2 H, H-4, J = 8.5 Hz), 7.89 (d, 2 H, H-1, J = 1.9 Hz), 8.06 (dd, 2
H, H-3, J = 8.9, 2.3 Hz).
HRMS (EI): m/z calcd for C H N O , 312.0859; found, 312.0869;
1
5
12
4
4
References
Anal. Calcd for C H N O : C, 57.69; H, 3.87; N, 17.94. Found: C,
1
5
12
4
4
5
7.55; H, 3.62; N, 18.22.
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(
2) Spielman, M. A. J. Am. Chem. Soc. 1935, 57, 583.
1
i
(3) Kubo, Y.; Ohno, T.; Yamanaka, J.; Tokita, S.; Iida, T.;
Yield: 338 mg (37%); white crystals; mp 152–153 °C.
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(
(
4) Becker, D. P.; Finnegan, P. M.; Collins, P. M. Tetrahedron
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IR (KBr): 2983, 2952, 1710, 1607, 1566, 1489, 1283, 1186, 1104,
–
1
9
03, 841, 770 cm .
1
H NMR (500 MHz, CDCl ): d = 1.33 (t, 6 H, CH , J = 7.1 Hz),
3
3
678.
4
.25 (d, 2 H, H-6,12endo, J = 16.9 Hz), 4.31 (q, 4 H, OCH , J = 7.2
2
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Hz), 4.33 (s, 2 H, H-4), 4.75 (d, 2 H, H-6,12exo, J = 16.6 Hz), 7.17
d, 2 H, H-4, J = 8.4 Hz), 7.64 (s, 2 H, H-1), 7.84 (dd, 2 H, H-3,
6008.
(
(7) Kobayashi, T.; Moriwaki, T.; Tsubakiyama, M.; Yoshida, S.
J = 8.5, 1.3 Hz).
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HRMS (EI): m/z calcd for C H N O , 366.1580; found, 366.1540.
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65, 1907.
2
1
22
2
4
1
j
Yield: 143 mg (21%); white crystals; mp 248–249 °C.
(
10) Bag, B. G.; Kiedrowski, G. Angew. Chem. Int. Ed. 1999, 38,
IR (KBr): 3065, 3029, 2958, 2223, 1607, 1489, 1442, 1211, 1098,
3713.
–
1
9
49, 893, 841, 772 cm .
(
11) Samuel, H. W.; Qi, J. Z. J. Org. Chem. 1991, 56, 485.
1
H NMR (500 MHz, CDCl ): d = 4.21 (d, 2 H, H-6,12endo, J = 16.8
3
(12) Pardo, C.; Sesmilo, E.; Gutierrez-Puebla, E.; Angeles, M. J.
Org. Chem. 2001, 66, 1607.
(
Hz), 4.29 (s, 2 H, H-13), 4.73 (d, 2 H, H-6,12exo, J = 16.7 Hz), 7.21
(d, 2 H, H-4, J = 8.4 Hz), 7.24 (s, 2 H, H-1), 7.46 (dd, 2 H, H-3,
13) Webb, T. H.; Wilcox, C. S. J. Org. Chem. 1990, 55, 363.
J = 8.5, 1.5 Hz).
(14) Bag, B. G.; Maitra, U. Synth. Commun. 1995, 25, 1849.
(
(
(
(
15) Sucholeiki, I.; Lynch, V.; Phan, L.; Wilcox, C. S. J. Org.
HRMS (EI): m/z calcd for C H N , 272.1062; found, 272.1054.
1
7
12
4
Chem. 1988, 53, 98.
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Abstr. 1989, 113, 114730.
1
k
Yield: 178 mg (20%), white crystals; mp 130–131 °C.
IR (KBr): 2962, 2917, 1628, 1586, 1503, 1332, 1306, 1152, 1123,
–1
8
74, 835 cm .
1
H NMR (500 MHz, CDCl ): d = 4.24 (d, 2 H, H-6,12endo
,
3
J = 16.8Hz), 4.32 (s, 2 H, H-13), 4.76 (d, 2 H, H-6,12exo, J = 16.8
Hz), 7.20 (s, 2 H, H-1), 7.24 (d, 2 H, H-4, J = 8.4 Hz), 7.43 (d, 2 H,
H-3, J = 8.4 Hz).
(19) Majetich, G. J. Org. Chem. 1997, 4321.
(20) Srivastava, S. K. Chem. Commun. 1996, 2679.
(21) Welch, J. T. Tetrahedron 1987, 43, 3123.
(
(
(
22) Jensen, J.; Wäernmark, K. Synthesis 2001, 1873.
23) Partridge, C. J. Chem. Soc. 1955, 991.
24) Miller, W. J. Am. Chem. Soc. 1941, 63, 832.
HRMS (EI): m/z calcd for C H N F , 358.0905; found, 358.0881.
1
7
12
2 6
Synthesis 2005, No. 8, 1228–1230 © Thieme Stuttgart · New York