Vilsmeier formylation of tert-anilines: Dibenzo[b,f][1,5]diazocines and quinazolinium salts via the 't-amino effect'

Article abstract of DOI:10.1039/a708799c

The attempted Vilsmeier ortho-formylation of p-substituted N,N-dimethylanilines 1 with N-formyl-N-alkylarylamides 2 unexpectedly gives dibenzo[b,f][1,5]diazocines 5 in 26-74% yield. This reaction proceeds by Vilsmeier formylation ortho to the dimethylamino group of 1 followed by hydride migration from the N-methyl group to the newly formed iminium =CH group, followed by intramolecular cyclisation, a new example of the 't-amino effect'. Similar formylation of cyclic tert-anilines such as 4-tolyl-pyrrolidines 6a,e,g, -piperidines 6b,f,h, -perhydroazepines 6c,i and -morpholine 6d, however, shows a different chemistry giving diformylated enamines 7 as the major products (12-60%). A small amount of diazocines 8 (1-13%) with a substituted benzyl at the nitrogen and N-formylated diazocines 9 are also isolated in some cases. When N-formyl-1,2,3,4-tetrahydroquinoline is used as the Vilsmeier reagent, normal formylation is observed, while use of aliphatic Vilsmeier reagents such as DMF and W-formylmorpholine give quinazolinium salts 16 and 17, also by way of the 't-amino effect'. The key feature in these formylations is the hydride transfer from the α-position of a tertiary amine to an unsaturated ortho-substituent CH=NR₂⁺, the 't-amino effect'.

Full text of DOI:10.1039/a708799c

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Vilsmeier formylation of tert-anilines: dibenzo[b,f ][1,5]diazocines
1
and quinazolinium salts via the ‘t-amino effect’
Ying Cheng, Otto Meth-Cohn* and David Taylor
Department of Chemistry, University of Sunderland, Sunderland, UK SR1 3SD
The attempted Vilsmeier ortho-formylation of p-substituted N,N-dimethylanilines 1 with N-formyl-N-
alkylarylamides 2 unexpectedly gives dibenzo[b,f ][1,5]diazocines 5 in 26–74% yield. This reaction proceeds
by Vilsmeier formylation ortho to the dimethylamino group of 1 followed by hydride migration from the
N-methyl group to the newly formed iminium ᎐CH group, followed by intramolecular cyclisation, a new
᎐
example of the ‘t-amino effect’. Similar formylation of cyclic tert-anilines such as 4-tolyl-pyrrolidines
6
a,e,g, -piperidines 6b,f,h, -perhydroazepines 6c,i and -morpholine 6d, however, shows a different
chemistry giving diformylated enamines 7 as the major products (12–60%). A small amount of diazocines 8
1–13%) with a substituted benzyl at the nitrogen and N-formylated diazocines 9 are also isolated in some
(
cases. When N-formyl-1,2,3,4-tetrahydroquinoline is used as the Vilsmeier reagent, normal formylation is
observed, while use of aliphatic Vilsmeier reagents such as DMF and N-formylmorpholine give
quinazolinium salts 16 and 17, also by way of the ‘t-amino effect’. The key feature in these formylations is؉
the hydride transfer from the á-position of a tertiary amine to an unsaturated ortho-substituent CH᎐NR ,
᎐
2
the ‘t-amino effect’.
Me
Introduction
Me
N
Me
N
N
Y
Although the first example of the Vilsmeier formylation
involved the para-formylation of dimethylaniline, very little
work has been reported on the corresponding ortho-formyl-
Me
+
CHO
2
POCl3
X
Y
X
8
0 °C, 4 h
N
3
ation of 4-substituted tert-anilines. Thus while 4-acetyl- and
Me
4
4
-(β-styryl)-dimethylanilines give low yields of the 2-aldehyde,
1
2
5
4
-tolylbis(2-cyanoethyl)amine is reported to give a high yield of
5
the expected aldehyde. Similarly, while 4-tolyl-N,N-dibenzyl-
aminesortho-formylateeffectively,N-(4-tolyl)-N-(2-cyanoethyl)-
benzylamines undergo a novel 2-formylation and consequent
Me
Me
6
+
debenzylation reaction under similar conditions. 3-Dialkyl-
N
N
aminothiophenes and 2-morpholinobenzo[b]thiophenes are
1,5-sigmatropic shift
H
reported to formylate efficiently in the 2- and 3-position respect-
X
X
7
ively. We have undertaken a study of the 2-formylation of
N
+
N
4
-substituted tert-anilines. The results were surprisingly diverse,
Me
Me
depending upon the nature of the Vilsmeier reagent (dialkyl-
formamides, alkylformanilides and some heterocyclic form-
amides gave different results) and of the tert-aniline (dimethyl-
anilines behaved differently to other tert-anilines).
Y
Y
3
4
Scheme 1
a
1
–5
X
Y
Yield of 5 (%)
Results and discussion
a
b
c
d
e
f
Me
Me
Me
Me
Cl
MeO
Me
H
Cl
Cl
44
74
52
57
49
26
Formylation of 4-substituted dimethylanilines with N-methyl-
formanilides
The interaction of 4-substituted N,N-dimethylanilines 1 with
b
N-methylformanilides 2 in POCl did not give the expected
3
MeO
Cl
ortho-formylated products but resulted in the formation of
dibenzo[b,f ][1,5]diazocines 5 generally in fair yield (Scheme 1).
We explain this remarkable transformation as follows: the
a
b
Isolated yield. Y = CHO.
Vilsmeier reagent derived from 2 and POCl attacks at the
formylation of the initially formed diazocine 5c (Y = H). This
simple one-pot method for the construction of pharmaceutic-
ally attractive diazocines is a major improvement on existing
methodology, particularly in that unsymmetrically substituted
3
position ortho to the dimethylamino group of the anilines 1
forming iminium ion 3. A 1,5-sigmatropic shift of hydride from
the α-position of a tertiary amine to the unsaturated iminium
group gives a new iminium intermediate 4 (this step is an
9
derivatives are easily accessible. Furthermore this reaction
8
example of the now well established ‘t-amino effect’ ) which
extends the scope of the t-amino effect which until now has
been used only for the generation of five- and six-membered
rings.
undergoes an electrophilic cyclisation by attacking the adjacent
activated aromatic ring to yield diazocines 5 (Scheme 1). N,N-
Dimethylanisidine 1f gave a lower yield (26%) of diazocine 5f
probably due to the inductive deactivation of the site of
formylation. With the parent N-methylformanilide 2c, a further
formylated diazocine 5c (Y = CHO) was obtained, due to
1
The very broad, almost invisible methylene signals in the H
NMR spectrum of the diazocines 5 at probe temperature at 4.0
and 4.7 ppm indicate a slow conformational flexion of the
eight-membered ring. These peaks sharpen on heating to 80 ЊC
J. Chem. Soc., Perkin Trans. 1, 1998
1257

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Table 1 Reaction of cyclic tert-anilines 6 with formanilides 2 in POCl3
and -morpholine 6d were formylated under the same conditions
the enamino aldehydes 7 were obtained as the major products
instead of the expected diazocines 5Ј (Scheme 2). More interest-
ingly, a diazocine 8 bearing a substituted benzyl group was
Yield (%)
Entry
X
Y
R
t/h
7
8
9
1
2
3
4
5
6
7
8
9
—
—
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
F
F
Cl
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
7
24
7
24
7
24
15
24
7
36
49
12
34
54
58
31
60
10
6
9
1
6
3
9
5
4
4
3
—
—
—
—
—
—
X
CH2
N
Y
CH2
(CH2)2
(CH2)
2
2
Me
N
O
—
CH2
—
CH2
11
—
13
—
—
—
Me
15
40
35
5′
Y
1
1
1
0
1
2
6
6
4
Et
Et
(CH2)2
60 (Y = CHO)
N
N+ PF6–
Et
X
R
Me
N
N
N
CHO
Et
+
Me
Y
Y
6
2
1
0a, Y = F; 10b, Y = Cl
8
0–85 °C POCl3
found in most cases, albeit in low yield (1–13%). An N-formyl-
ated dibenzo[b,f ][1,5]diazocine 9 was also isolated in very poor
yield in some cases (Table 1). It is worth noting that the iminium
salt precursors 10a,b of the aldehydes 7 were stable and easily
extracted with dichloromethane and could even be chromato-
graphed on silica. They were surprisingly resistant to hydrolysis
but gave the corresponding aldehyde 7 in high yield after 1–2
hours in warm sodium hydroxide. In order to put the structures
beyond doubt, the crystal and molecular structure of 8b was
determined by X-ray crystallography. The chemical yields of
the enamino aldehydes 7 were improved significantly by use of
prolonged reaction times (Entries 2, 4, 6 and 8 in Table 1). Five-
and seven-membered tert-anilines tended to give higher yields
of enamino aldehyde 7 than their six-membered analogues
X
X
N
Me
N
CHO
OHC
+
Me
N
Y
N
R
Y
N
Me
11
Y
7
8
+
OHC
N
Y
(
Entries 1–6). In a manner similar to the formation of 5c,
Y
N
an enamino aldehyde derivative 7i was obtained, resulting
from a second formylation of the aniline ring. The diazocines 8
were isolated in low yields which decreased as reaction time
increased.
Me
9
Scheme 2
We explain the origin of these products as follows. Vilsmeier
formylation of the cyclic tert-anilines 6 yields the iminium salt
3Ј which undergoes hydride migration with the formation of
new iminium intermediate 11. In contrast to the cases of the
dimethylanilines discussed above, iminium ion 11 is stabilised
by a rapid loss of a proton from the β-position of the
ring rather than by intramolecular cyclisation. The resulting
cyclic enamine 12, being highly reactive towards the Vilsmeier
reagent, forms the iminium salt 10. This newly generated
iminium ion 10 contains a tert-aniline moiety which is also sus-
ceptible to ortho-formylation and, via intermediates 13 and 14,
gives rise to the diazocine 8 (Scheme 3) on work-up; in a similar
manner hydrolysis of the isolable salts 10 with alkali afforded
aldehyde 7. The N-formylated diazocine 9 was formed most
probably from diazocine 8 by formylative N-debenzylation.
The key feature of all of the reactions of the tert-anilines
2
,6–9
X
Y
R
a
b
c
d
e
f
g
h
i
—
Cl
Cl
Cl
Cl
F
F
F
Me
Me
Me
Me
Me
Me
Et
CH2
(CH2)2
O
—
CH2
—
CH2
(CH2)2
Cl
H(CHO)
Et
Me
to give one singlet and resolve into two AB pairs of doublets
with ~16 Hz coupling on cooling the solution to Ϫ40 ЊC. Ollis
and co-workers have examined the temperature NMR of
simple dibenzodiazocines thoroughly and showed that the boat-
like conformation was preferred at low temperatures while at
10
with N-alkylformanilides in POCl
is the 1,5-sigmatropic trans-
3
fer of hydride from the α-position of a tertiary amine to an
unsaturated ortho-substituent, in these cases the iminium
moiety. This is a new example of the ‘t-amino effect’.
6
0 ЊC flipping between boat and chair conformations was
observed.
Formylation of other 4-substituted tert-anilines with N-
methylformanilides
A quite different chemistry was encountered when the reaction
was extended to the cyclic tert-anilines. Thus when 4-tolyl-
pyrrolidines 6a,e,g, -piperidines 6b,f,h, -perhydroazepines 6c,i
Formylation of 4-substituted dimethylanilines with N-formylated
heterocycles
When N-formyltetrahydroquinoline (NFTHQ) was used as the
Vilsmeier reagent to formylate N,N-dimethyl-p-toluidine, sur-
prisingly no diazocine formed but the reaction stopped at the
1
258
J. Chem. Soc., Perkin Trans. 1, 1998

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X
X
X
+
N
N
N
N
H
POCl3
Me
Me
6
+ 2
Me
N
+
N
R
R
R
Y
Y
Y
3
′
11
12
2
, POCl3
Y
Y
Y
X
Cl–
N+
Me
X
Cl–
N
X
N
N
W–
N+
Me
N
N+
R
Me
Me
N+
N
2, POCl3
Me
N
R
H
Y
Y
Y
N
+
Me
Me
1
0
Y
Y
1
1
0a, R = Et, X = –, Y = F, W = PF6–
0b, R = Et, X = –, Y = Cl, W = PF6
1
4
13
–
X
N
Me
X
N
N
CHO
OHC
N
Y
Me
R
Y
N
Me
Y
8
7
Scheme 3
ortho-formylationstep,togive2-formyl-4-methyl-N,N-dimethyl-
aniline 15 in 56% yield (Scheme 4). To our surprise the analo-
gous attempted formylation utilising N-formylindoline was
totally without effect, even after raising the reaction tempera-
ture to 100 ЊC for 3 hours. It would seem that the iminium salt
intermediate derived from the bulkier reagent, N-formyltetra-
hydroquinoline lies out-of-plane with respect to the dimethyl-
aniline ring, thus not allowing the concerted sigmatropic
H-shift to take place. The almost planar Vilsmeier reagent
derived from N-formylindoline appears to be incapable of
approaching the more sterically crowded ortho-position of the
phatic amine appendage (Scheme 4). A similar product 17 was
derived from N-formylmorpholine and 4-methyl-N,N-dimethyl-
aniline in 49% yield. Bulky formamides such as diisopropyl-
formamide were ineffective in this process. These quinazolinium
salts are the presumed intermediate in the already noted
debenzylation of a 4-substituted N-benzyl-N-alkylaniline,
where the ortho-dimethylaminomethylated derivative was
isolated as the final product.
6
Experimental
4
-methyl-N,N-dimethylaniline. We have found that this reagent
Melting points, which are uncorrected, were determined using a
Reichert Kofler hot-stage apparatus. Infrared spectra were
obtained on a Unicam Research Series 1 FTIR instrument as
KBr discs or liquid films. NMR spectra were recorded in CDCl3
12
is a powerful formylating agent in other applications.
Formylation of 4-substituted dimethylanilines with N-formylated
aliphatic secondary amines
solution with SiMe as internal standard on JEOL 270 and
4
Finally we have studied briefly the effect of Vilsmeier reagents
derived from simple aliphatic N,N-disubstituted formamides on
Varian Unity 200 spectrometers. Chemical shifts are reported
in ppm while the coupling constant J values are in Hz. Mass
spectra were measured on a Kratos MS8ORF mass spectro-
meter and microanalyses were carried out at Newcastle
University, UK and at the Institute of Chemistry, Academia
Sinica, Beijing. Thin layer chromatography (TLC) was per-
formed with Merck silica 60F254 plates and Janssen silica (35–70
µm) was used for flash chromatography. Light petroleum refers
to that of bp 60–80 ЊC.
4
-substituted dimethylanilines. Using DMF and POCl with 4-
3
methyl-N,N-dimethylaniline, a ready reaction ensued which was
1
monitored by H NMR spectroscopy. In the event, a quinazo-
linium salt 16 was formed in 31% yield, isolated by precipitation
Ϫ
of its PF6 salt. This compound is derived by ortho-formylation
followed by the usual ‘t-amino effect’ transfer of hydride,
whereupon the new iminium salt cyclises onto the basic ali-
J. Chem. Soc., Perkin Trans. 1, 1998
1259

View Article Online
NMe2
CHO
CH ), 2.81 (3H, s, CH ), 4.22 (4H, broad s, CH ) and 6.74–7.15
3 3 2
(
6H, m, aromatic H); δC 20.3, 39.1, 39.2, 58.1, 58.2, 115.5,
1
1
1
16.1, 122.1, 126.5, 127.2, 127.6, 128.5, 128.6, 130.8, 131.9,
48.1 and 149.1; m/z (EI) 286 (M , 100%), 271 (95), 166 (70),
46 (92), 134 (95) and 132 (90).
ϩ
1
5
5
,6,11,12-Tetrahydro-2,8-dichloro-5,11-trimethyldibenzo[b,f ]-
POCl3 NFTHQ
[1,5]diazocine 5e. Mp 195.5–198 ЊC (Found: C, 62.5; H, 5.0;
N, 9.05. C H N Cl requires C, 62.55; H, 5.25; N, 9.1%);
1
6
16
2
2
Ϫ1
νmax/cm 2868, 1592 and 1498; δ 2.79 (6H, s, CH ), 4.21 (4H,
H
3
NMe2
s, CH ) and 6.75–7.15 (6H, m, aromatic H); δ 39.1, 58.0, 116.7,
2
C
1
3
22.7, 127.9, 128.1, 130.9 and 149.0; m/z (EI) 308 (M ϩ 2, 70),
06 (M , 95%), 166 (99) and 154 (100).
ϩ
5
,6,11,12-Tetrahydro-2-chloro-8-methoxy-5,11-dimethyl-
dibenzo[b,f ][1,5]diazocine 5f. Mp 158.5–160 ЊC (Found: C, 67.3;
POCl3
DMF
H, 6.25; N, 9.4. C H N ClO requires C, 67.4; H, 6.3; N,
17
19
2
Ϫ1
9
2
6
1
.25%); νmax/cm 2861, 1591 and 1499; δH 2.79 (3H, s, CH ),
3
O
NCHO
.83 (3H, s, CH ) 3.77 (3H, s, OCH ), 4.22 (4H, s, CH ) and
3
3
2
.70–7.13 (6H, m, aromatic H); δ 39.0, 39.3, 39.7, 55.7, 58.4,
C
12.8, 116.3, 116.4, 117.2, 117.4, 122.6, 127.6, 127.8, 128.7,
ϩ
N
N
130.8, 149.2 and 152.3; m/z (EI) 302 (M , 100%).
N
N+
+
PF6–
Reaction of cyclic tert-anilines 6 with N-alkylformanilides 2
Using the same procedure as for the preparation of diazocines
O
PF6–
5
, cyclic tert-anilines 6 (10 mmol) were reacted with N-alkyl-
3
1
1
6
17
formanilides 2 (30 mmol) in POCl (10 cm ) until H NMR
3
spectroscopy indicated completion of reaction (Table 1). The
cooled reaction mixture was poured into ice–water (ca. 100 g)
and worked up following one of two methods.
Scheme 4
General procedure for the preparation of dibenzo[b,f ][1,5]-
diazocines 5
Method A. NH PF (10 mmol) was added to the aqueous
4
6
In a dry flask, the N-methylformanilide 2 (11 mmol) was mixed
solution and the mixture was stirred vigorously for 10 minutes.
3
3
with POCl (10 cm ) and the mixture was warmed at 70 ЊC for
Extraction with dichloromethane (3 × 50 cm ) gave, after dry-
3
about 10 minutes. The resulting red solution then cooled in an
ice bath, and to it was added tert-anilines 1 (10 mmol) slowly
under nitrogen. The deep red mixture was kept stirring at 70–
ing over Na SO and removal of the solvent, a residue which
2
4
was subjected to column chromatography using ethyl acetate
and light petroleum (3:1) as eluent to give iminium salt 10 as
follows.
8
0 ЊC for 4 h. After cooling to room temperature, the reaction
mixture was poured into ice–water (ca. 100 g), basified with
10a. (40%) Mp 198–200 ЊC (Found: C, 57.4; H, 5.4; N, 6.9.
Ϫ1
aqueous NaOH (20%) and extracted with dichloromethane
C H N F P requires C, 57.5; H, 5.3; N, 6.9%); νmax/cm 1631,
29
32
3
8
3
(
4 × 50 cm ). The organic phase was dried over MgSO and
1562, 1504 and 838; δH 1.04 (3H, t, J 7.0, CH ), 1.25 (3H, t,
4
3
filtered quickly through a silica pad. The product precipitated
after removal of most of the solvent, and recrystallisation from
ethyl acetate gave the diazocine 5 as colourless prisms as
follows.
J 7.3, CH ), 2.35 (3H, s, CH ), 2.84 (2H, t, J 8.9, ᎐CCH ), 3.25
3
3
2
ϩ
(2H, q, J 7.0, NCH CH ), 3.79 (2H, q, J 7.3, N CH CH ), 3.88
2
3
2
3
(2H, t, J 8.9, NCH CH ), 4.29 (2H s, NCH Ar), 6.67–7.20
2
2
2
(11H, m, aromatic H), 7.86 (1H, s, N᎐CH᎐C), and 7.90 (1H, s,
ϩ
5
,6,11,12-Tetrahydro-2-methoxy-5,8,11-trimethyldibenzo[b,f ]-
N ᎐CH); δ 29.3, 29.6, 29.9, 30.3, 30.4, 30.6, 30.9, 31.2, 40.3,
C
[
9
2
1,5]diazocine 5a. Mp 141.5–143 ЊC (Found: C, 76.7; H, 8.1; N,
.9. C H N O requires C, 76.6; H, 7.85; N, 9.9%); νmax/cm
18 22 2
43.2, 50.2, 55.1, 74.9, 80.3, 87.8, 145.3, 145.6, 145.8, 145.9,
146.3, 147.3, 155.6, 159.2, 159.9, 160.7, 163.9, 165.5, 169.8 and
183.2; m/z (electrospray) 460 (M , 100%).
Ϫ1
ϩ
850, 1600, 1500 and 1480; δH 2.27 (3H, s, CH ), 2.78 (3H, s,
3
CH ) 2.82 (3H, s, CH ), 3.77 (3H, s, CH ), 4.20 (4H, s, CH ) and
10b. (41%) Mp 197–199 ЊC (Found: C, 54.4; H, 4.9; N, 6.5.
3
3
3
2
Ϫ1
6
1
1
.71–7.01 (6H, m, aromatic H); δ 20.4, 39.5, 39.9, 55.6, 55.7,
C H N Cl F P requires C, 54.6; H, 5.05; N, 6.6%); νmax/cm
C
29 32
3
2
3
12.5, 115.6, 117.1, 117.2, 117.3, 127.5, 127.7, 128.4, 129.5,
1629, 1594, 1554 and 836; δ 1.05 (3H, t, J 6.8, CH ), 1.23 (3H,
H
3
ϩ
31.9, 145.2, 148.6 and 152.2; m/z (EI) 282 (M , 100%) and 266
t, J 7.3, CH ), 2.34 (3H, s, CH ), 2.85 (2H, t, J 8.9, ᎐CCH ), 3.26
3 3 2
ϩ
(
55).
,6,11,12-Tetrahydro-2,5,8,11-tetramethyldibenzo[b,f ][1,5]-
diazocine 5b. Mp 152–153.5 ЊC (Found: C, 81.1; H, 8.7; N,
(2H, q, J 7.3, NCH CH ), 3.78 (2H, q, J 7.3, N CH CH ), 3.88
2 3 2 3
5
(2H, t, J 8.9, NCH CH ), 4.34 (2H, s, NCH Ar), 6.68 (2H, dd,
2
2
2
J 8.4, aromatic H), 7.06–7.19 (7H, m, aromatic H), 7.44 (2H,
dd, J 8.4, aromatic H), 7.83 (1H, s, N᎐CH᎐C) and 7.86 (1H, s,
Ϫ1
1
2
4
3
0.55. C H N requires C, 81.2; H, 8.3; N, 10.5%); νmax/cm
18 22 2
ϩ
᎐
ϩ
870, 1500 and 1480; δH 2.27 (6H, s, CH ), 2.80 (6H, s, CH ),
N ᎐CH); m/z (electrospray) 492 (M , 100%).
3
3
.22 (4H, s, CH ) and 6.76–7.00 (6H, m, aromatic H); δ 20.4,
Method B. The aqueous phase was basified with aqueous
2
C
9.4, 58.6, 115.4, 127.0, 127.3, 128.4, 131.9, 145.2 and 148.5.
,6,11,12-Tetrahydro-2-formyl-5,8,11-trimethyldibenzo[b,f ]-
1,5]diazocine 5c (Y ؍ CHO). Mp 226–228 ЊC (Found: C, 76.8;
H, 7.2; N, 9.8. C H N O requires C, 77.1; H, 7.2; N, 10.0%);
NaOH (20%) in an ice-bath and then extracted with dichloro-
3
5
methane (3 × 50 cm ). After removal of the solvent the residue
[
was hydrolysed in aqueous NaOH (20%) at ca. 50–60 ЊC for 1 h,
the mixture cooled, and extracted with dichloromethane
18
20
2
Ϫ1
3
νmax/cm 1660 and 1590; δH 2.29 (3H, s, CH ), 2.78 (3H, s,
(3 × 50 cm ) and dried (MgSO ). After removal of the solvent
3
4
CH ), 2.94 (3H, s, CH ), 4.40 (4H, broad s, 2CH ), 6.76–6.70
the residue was purified by column chromatography eluting
with light petroleum containing gradually increasing amounts
of ethyl acetate and finally pure ethyl acetate to give the follow-
ing products.
3
3
2
(
6H, m, aromatic H) and 9.78 (1H, s, CHO); δ 38.3, 38.4, 40.8,
C
5
1
1
7.2, 57.6, 113.1, 114.3, 123.8, 125.0, 125.3, 126.1, 128.5, 130.6,
31.8, 132.9, 147.0, 154.5 and 189.4; m/z (EI) 280 (M , 100%),
46 (61) and 132 (69).
ϩ
7a. Mp 123–125 ЊC (Found: C, 70.5; H, 6.15; N, 8.2.
Ϫ1
5
,6,11,12-Tetrahydro-2-chloro-5,8,11-trimethyldibenzo[b,f ]-
C H N ClO requires C, 70.6; H, 6.2; N, 8.2%); νmax/cm 2856,
20
21
2
[
1,5]diazocine 5d. Mp 152.5–153.5 ЊC (Found: C, 71.3; H, 6.7;
2790, 1621, 1598 and 1573; δH 2.30 (3H, s, CH ), 2.97 (3H, s,
3
Ϫ1
N, 9.8. C H N Cl requires C, 71.2; H, 6.7; N, 9.8%); νmax/cm
CH ), 2.97 (2H, t, J 10, ᎐CCH ), 3.95 (2H, t, J 10, NCH ), 4.41
17
19
2
3
2
2
2
947, 2867, 1510 and 1497; δH 2.28 (3H, s, CH ), 2.80 (3H, s,
(2H, s, NCH Ar), 6.60–7.21 (8H, aromatic H and N᎐CH᎐C)
3
2
᎐ ᎐
1
260
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
and 9.37 (1H, s, CHO); δ 21.1, 25.3, 38.6, 55.3, 113.8, 120.2,
CHO); δ 21.2, 25.0, 39.2, 52.6, 55.0, 58.3, 115.5, 118.7, 119.9,
C
C
1
1
22.2, 124.5, 128.9, 129.0, 129.2, 133.0, 137.2, 138.0, 148.2,
56.4 and 182.9; m/z (EI) 340 (M , 18%), 199 (90), 172 (100)
122.8, 123.6, 124.4, 127.9, 128.3, 129.5, 131.0, 131.2, 131.4,
136.4, 138.6, 148.7, 148.8, 156.5 and 183.0; m/z (EI) 491 (M ,
ϩ
ϩ
and 170 (70).
b. Oil (Found: 354.1485. C H N ClO requires 354.1499);
5%), 291 (40), 201 (100) and 172 (30).
7
8b. Mp 137–139 ЊC (Found: 505.1685. C H N Cl O
21
23
2
29 29
3
2
Ϫ1
Ϫ1
νmax/cm 2850, 2711, 1648, 1596 and 1500; δH 1.98 (2H, quin-
tet, J 6.2, CH CH CH ), 2.31 (3H, s, CH ), 2.40 (2H, t, J 6.2,
requires 505.1688); νmax/cm 2867, 1614, 1590 and 1502; δH
1.78 (2H, quintet, J 5.7, CH CH CH ), 2.28 (2H, t, J 5.7,
2
2
2
3
2
2
2
CH CH C᎐), 2.98 (3H, s, CH ), 3.52 (2H, t, J 6.2, NCH ), 4.39
᎐CCH ), 2.34 (3H, s, CH ), 2.84 (3H, s, CH ), 3.30 (2H, t, J 5.7,
2
2
3
2
᎐
2
3
3
(
2H, s, NCH Ar), 6.60–7.20 (8H, m, aromatic H and N᎐CH᎐C)
NCH ), 4.28 (2H, s, NCH Ar), 4.34 (2H, s, NCH Ar), 4.40 (2H,
2 2 2
2
ϩ
and 8.99 (1H, s, CHO); m/z (EI) 354 (M , 10%), 214 (100) and
85 (85).
c. Oil (Found: 368.1668. C H N ClO requires 368.1655);
s, NCH Ar), 6.50–7.20 (10H, m, aromatic H and N᎐CH᎐C)
2
1
and 8.86 (1H, s, CHO); δ 17.8, 20.8, 21.2, 38.9, 50.6, 51.9, 55.1,
C
7
58.0, 113.7, 115.9, 119.4, 122.9, 124.4, 126.2, 126.9, 128.1,
128.2, 129.2, 129.8, 130.0, 131.0, 131.3, 133.6, 137.6, 142.8,
22
25
2
Ϫ1
νmax/cm 2857, 2707, 1652, 1598 and 1498; δH 1.65 (2H, m,
CH CH CH ), 1.95 (2H, m, CH CH CH ), 2.30 (3H, s, CH ),
ϩ
148.8, 149.1, 153.5 and 187.8; m/z (EI) 505 (M , 3%), 293 (70),
2
2
2
2
2
2
3
2
.56 (2H, t, J 6.5, CH ), 2.98 (3H, s, CH ), 3.64 (2H, t, J 5.7,
291 (100), 215 (90), 214 (80) and 184 (60).
2
3
NCH ), 4.42 (2H, s, NCH Ar), 6.60–7.20 (8H, m, aromatic H
8c. Mp 245–247 ЊC (Found: 519.1871. C H N Cl O requires
2
2
30 31
3
2
ϩ
Ϫ1
and N᎐CH᎐C) and 8.95 (1H, s, CHO); m/z (EI) 368 (M , 18%),
519.1844); νmax/cm 2863, 2790, 1673, 1614, 1592 and 1500; δH
1.75 (4H, m, CH CH CH CH ), 2.30 (3H, s, CH ), 2.47 (2H, t,
᎐
2
28 (100) and 198 (60).
d. Oil (Found: 356.1285. C H N ClO requires 356.1292);
2
2
2
2
3
7
J 5.9, ᎐CCH ), 2.85 (3H, s, CH ), 3.46 (2H, t, J 5.1, NCH ), 4.17
20
21
2
2
2
3
2
Ϫ1
νmax/cm 2881, 2825, 1733, 1660, 1617 and 1500; δ 2.23 (3H, s,
(2H, s, NCH Ar), 4.20 (2H, s, NCH Ar), 4.29 (2H, s, NCH Ar),
2 2 2
H
CH ), 2.89 (3H, s, CH ), 3.56 (2H, t, J 4.3, NCH ), 4.13 (2H, t,
6.51 (1H, s, N᎐CH᎐C), 6.70–7.10 (9H, m, aromatic H) and 8.87
3
3
2
᎐
J 4.3, OCH ), 4.33 (2H, s, NCH Ar), 6.51–7.09 (8H, m,
(1H, s, CHO); δ 21.3, 23.2, 26.2, 28.6, 38.9, 51.5, 55.9, 57.8,
2
2
C
aromatic H and N᎐CH᎐C) and 8.60 (1H, s, CHO); m/z (EI) 356
60.3, 115.6, 117.5, 119.0, 122.6, 123.9, 126.2, 128.0, 128.1,
128.4, 128.6, 129.1, 129.4, 130.9, 131.3, 137.6, 145.2, 158.9,
161.8 and 190.8; m/z (EI) 519 (M , 2%), 293 (65), 291 (100), 229
᎐
ϩ
(
M , 40%), 216 (100), 158 (80) and 143 (80).
e. Mp 115–117 ЊC (Found: C, 74.15; H, 6.52; N, 8.51. C -
ϩ
7
20
Ϫ1
H N FO requires C, 74.04; H, 6.53; N, 8.64%); νmax/cm 3036,
(90) and 228 (65).
2
1
2
2
935, 2884, 2789, 1621 and 1572; δ 2.31 (3H, s, CH ), 2.91 (3H,
8d. Mp 212–214 ЊC (Found: C, 65.7; H, 5.2; N, 8.1. C H -
H
3
28 27
Ϫ1
s, CH ), 2.95 (2H, t, J 10.8 ᎐CCH ), 3.95 (2H, t, J 10.8, NCH ),
N Cl O requires C, 66.25; H, 5.4; N, 8.2%); νmax/cm 2883,
3
2
2
3
2
2
4
.34 (2H, s, NCH Ar), 6.65–7.22 (8H, m, aromatic H and
1616 and 1598; δ 2.34 (3H, s, CH ), 2.83 (3H, s, CH ), 3.38 (2H,
2
H 3 3
N᎐CH᎐C) and 9.35 (1H, s, CHO); δ 21.0, 25.1, 39.0, 54.4, 55.2,
t, J 4.3, NCH CH ), 3.99 (2H, t, J 4.3, OCH ), 4.15 (2H, s,
2 2 2
᎐
C
1
1
14.3, 114.4, 115.3, 115.6, 119.9, 124.2, 128.9, 129.7, 133.0,
NCH Ar), 4.22 (2H, s, NCH Ar), 4.24 (2H, s, NCH Ar), 6.27
2
2
2
36.9, 137.9, 146.4, 146.5, 154.1, 156.5, 157.7 and 182.7; m/z
(1H, s, N᎐CH᎐C), 6.59–7.14 (9H, m, aromatic H) and 8.57 (1H,
ϩ
ϩ
(
EI) 324 (M , 28%), 172 (100) and 105 (90).
s, CHO); m/z (EI) 507 (M , 70%), 291 (100) and 217 (60).
7
f. Oil (Found: 338.1802 C H N FO requires 338.1794);
8f. Mp 212–214 ЊC (Found: C, 73.55; H, 6.05; N, 8.8.
21
23
2
Ϫ1
Ϫ1
νmax/cm 2850, 2715, 1675, 1648, 1598 and 1511; δH 1.99 (2H,
quintet, J 6.2, CH CH CH ), 2.32 (3H, s, CH ), 2.39 (2H, t,
J 6.2, CH ), 2.93 (3H, s, CH ), 3.50 (2H, t, J 6.2, NCH ), 4.34
C H N F O requires C, 73.5; H, 6.2; N, 8.9%); νmax/cm 2854,
29
29
3
2
2809, 1646, 1598, 1577 and 1500; δH 1.74 (2H, quintet, J 5.7,
CH CH CH ), 2.27 (2H, t, J 6.5, ᎐CCH ), 2.34 (3H, s, CH ),
2
2
2
3
2
3
2
2
2
2
2
3
(
2H, s, NCH Ar), 6.60–7.20 (8H, m, aromatic H and N᎐CH᎐C)
2.83 (3H, s, CH ), 3.23 (2H, t, J 5.7, NCH ), 4.12 (2H, s,
NCH Ar), 4.16 (2H, s, NCH Ar), 4.21 (2H, s, NCH Ar), 6.30–
2 2 2
2
3
2
ϩ
and 8.97 (1H, s, CHO); m/z (EI) 338 (M , 15%), 214 (100) and
84 (80).
g. Mp 128–130 ЊC (Found: C, 74.0; H, 6.95; N, 8.1. C H -
1
7.25 (10H, m, aromatic H and N᎐CH᎐C) and 8.85 (1H, s,
᎐
7
2
CHO); δC 17.7, 20.7, 21.2, 39.3, 50.3, 52.5, 55.0, 58.4, 113.1,
114.2, 114.3, 114.5, 114.6, 115.8, 115.9, 117.1, 117.4, 117.6,
117.9, 120.5, 120.6, 126.2, 129.0, 130.3, 133.8, 137.6, 142.6,
21
23
Ϫ1
N FO requires C, 74.5; H, 6.85; N, 8.3%); νmax/cm 2867, 2784,
1
J 10, ᎐CCH ), 2.31 (3H, s, CH ), 3.38 (2H, q, J 7.0, CH CH ),
631, 1573 and 1511; δH 1.15 (3H, t, J 7.0, CH ), 2.97 (2H, t,
3
ϩ
153.8 and 187.8; m/z (EI) 473 (M , 5%), 259 (100), 215 (49) and
᎐
2
3
2
3
3
.97 (2H, t, J 10, NCH ), 4.34 (2H, s, NCH Ar), 6.59–7.09 (7H,
214 (50).
2
2
m, aromatic H), 7.25 (1H, s, N᎐CH᎐C) and 9.35 (1H, s, CHO);
δC 11.7, 21.1, 25.1, 45.6, 51.5, 55.1, 114.6, 114.8, 115.3, 115.5,
9a. Mp 249–251 ЊC (Found: C, 59.5; H, 4.3; N, 8.7.
᎐
Ϫ1
C H N Cl O requires C, 60.0; H, 4.4; N, 8.75%); νmax/cm
16
14
2
2
1
1
15.8, 119.9, 124.2, 128.8, 129.5, 133.2, 136.9, 137.8, 144.9,
56.7, 182.8; m/z (EI) 338 (M , 9%), 201 (100) and 172 (80).
2863, 2798 and 1673; δ 2.83 (3H, s, CH ), 4.18 (2H, s, CH ) 4.71
H 3 2
ϩ
(2H, s, CH ), 6.87–7.35 (6H, m, aromatic H) and 8.32 (1H, s,
2
7
h. Oil (Found: 368.1665. C H N ClO requires 368.1656);
CHO); δC 38.0, 38.3, 38.6, 38.9, 39.2, 39.5, 39.8, 48.3, 57.0,
116.8, 125.1, 126.8, 127.2, 129.0, 130.5 and 160.4; m/z (EI) 322
(70), 320 (M , 100%) and 166 (80).
22
25
2
Ϫ1
νmax/cm 2861, 2709, 1649, 1616 and 1594; δ 1.19 (3H, t, J 7.3,
CH ), 2.00 (2H, quintet, J 5.7, CH CH CH ), 2.32 (3H, s, CH ),
H
ϩ
3
2
2
2
3
2
.42 (2H, t, J 6.2, ᎐CCH ), 3.43 (2H, q, J 7.3, NCH CH ), 3.55
᎐
2
2
3
(
(
2H, t, J 5.7, NCH CH ), 4.37 (2H, s, NCH Ar), 6.25–7.15
Formylation of N,N-dimethyl-p-toluidine utilising N-formyl-
1,2,3,4-tetrahydroquinoline and N-formylindoline
N,N-Dimethyl-p-toluidine (1.35 g, 10 mmol) and N-formyl-
2
2
2
m, 8H, alkenic and aromatic H) and 9.00 (s, 1H, CHO);
ϩ
m/z (EI) 368 (M , 9%), 214 (100) and 184 (80).
i. Oil (Found: C, 75.56; H, 7.28; N, 7.68. C H N O
3
7
1,2,3,4-tetrahydroquinoline (3.02 g, 20 mmol) in POCl (5 cm )
23
26
2
2
3
Ϫ1
requires C, 76.20; H, 7.23; N, 7.73%); νmax/cm 2854, 2726,
664, 1592 and 1527; δ 1.88 (2H, m, CH CH CH ), 1.97 (2H,
were heated at 80 ЊC for 3 h after which the mixture was poured
onto ice and basified with aqueous sodium hydroxide (5 ) and
1
H
2
2
2
m, CH CH CH ), 2.18 (3H, s, CH ), 2.57 (2H, t, J 5.7, ᎐CCH ),
warmed on a water bath for 30 min. The cooled mixture was
2
2
2
3
2
3
3
.16 (3H, s, CH ), 3.69 (2H, t, J 5.4, NCH CH ), 4.59 (2H, s,
extracted with dichloromethane (3 × 50 cm ), dried (MgSO )
3
2
2
4
NCH Ar), 6.69–7.75 (8H, m, aromatic and N᎐CH᎐C), 8.98
and evaporated and the resulting red oil subjected to flash
chromatography using petroleum–ethyl acetate (50:50) as
2
ϩ
(
1H, s, CHO) and 9.75 (1H, s, CHO); m/z (EI) 362 (M , 9%)
and 228 (100).
a. Mp 217–219 ЊC (Found: C, 68.4; H, 5.1; N, 8.3. C H -
eluent. The first band (R 0.16) gave 2-formyl-4,N,N-trimethyl-
f
8
aniline 15 as a pale yellow solid (0.91 g, 56%), mp 71 ЊC (Found:
28
27
Ϫ1
Ϫ1
N Cl O requires C, 68.4; H, 5.5; N, 8.55%); νmax/cm 2859,
m/z 163.0995. C H NO requires m/z 163.0997); νmax/cm
3
2
10 13
2
763, 1623, 1567 and 1598; δH 2.36 (3H, s, CH ) 2.79 (2H, t,
1671; δ 2.79 (3H, s, CH ), 3.62 (6H, s, 2 × NCH ), 7.88 (1H, dd,
3
H
3
3
J 9.7, ᎐CCH ), 2.83 (3H, s, CH ), 3.76 (2H, t, J 9.7, NCH ), 4.20
J 1.6 and 8.1, H-5), 8.10 (1H, J 1.6, H-3), 8.14 (1H, J 8.1, H-6)
and 10.12 (1H, s, CHO).
᎐
2
3
2
(
2H, s, NCH Ar), 4.22 (2H, s, NCH Ar), 4.27 (2H, s, NCH Ar),
2
2
2
6
.50–7.20 (10H, m, aromatic H and N᎐CH᎐C) and 9.16 (1H, s,
A similar reaction with N-formylindoline in place of
᎐
J. Chem. Soc., Perkin Trans. 1, 1998
1261

View Article Online
formyltetrahydroquinoline resulted in unchanged dimethyl-p-
toluidine, even after prolonged heating at 100 ЊC.
Acknowledgements
We are grateful to SmithKline Beecham for financial sup-
port that made this work possible and we thank Dr Brian
Warrington of SB for his interest and help.
Formylation of p-substituted tert-anilines using aliphatic
formamides
N,N-Dimethyl-p-toluidine (1.35 g, 10 mmol) and the form-
3
amide (10 mmol) in POCl (5 cm ) were heated at 80 ЊC for 3 h
References
3
after which the reaction mixture was poured onto ice and
ammonium hexafluorophosphate (1.63 g, 10 mmol) was added.
If no precipitate formed, the solution was basified with sodium
carbonate and extracted with ethyl acetate (3 × 40 cm ) and the
extract dried (MgSO ) and evaporated to give the salt as
1
Preliminary communications: O. Meth-Cohn and D. L. Taylor,
J. Chem. Soc., Chem. Commun., 1995, 1463; Y. Cheng and O. Meth-
Cohn, Tetrahedron Lett., 1996, 37, 2679.
2 A. Vilsmeier and A. Haack, Chem. Ber., 1927, 60B, 119.
3 Z. Arnold and A. Holy, Collect. Czech. Chem. Commun., 1963, 28,
3
4
8
69.
follows.
4
5
6
7
T. Eszenyi and A. Timar, Syn. Commun., 1990, 20, 3219.
From dimethylformamide was obtained 1,2,3,4-tetrahydro-
,3,3,6-tetramethylquinazolinium hexafluorophosphate 16 (1.04
g, 31%) as a pale brown solid by extraction. Recrystallisation
from acetonitrile and ethyl acetate gave the product as pale buff
needles, mp 223 ЊC (Found: C, 43.0; H, 5.7; N, 8.3. C H -
A. P. Shawcross and A. P. Stanforth, Tetrahedron, 1988, 44, 1461.
A. P. Shawcross and A. P. Stanforth, Tetrahedron, 1989, 45, 7063.
H. Hartmann and S. Scheithauer, J. Prakt. Chem., 1969, 311, 827.
1
8 O. Meth-Cohn, Adv. Heterocycl. Chem., 1996, 65, 1 and references
therein.
12
19
Ϫ1
9
H. D. Perlmutter, Adv. Heterocycl. Chem., 1989, 46, 1.
0 R. Crossley, A. P. Downing, M. Nogradi, A. Braga de Oliviera,
W. D. Ollis and I. O. Sutherland, J. Chem. Soc., Perkin Trans. 1,
F N P requires C, 42.9; H, 5.7; N, 8.3%); νmax/cm 838 (PF );
δ 2.26 (3H, s, CH ) 3.23 (3H, s, CH ), 3.35 (6H, s, 2 × NCH ),
6
2
6
1
H
3
3
3
4
6
.77 (2H, s, CH ), 4.84 (2H, s, CH ), 6.92 (1H, d, J 8.6, H-8),
2
2
1
973, 205.
.96 (1H, br s, H-5) and 7.17 (1H, br d, J 8.6, H-7).
From N-formylmorpholine was isolated by precipitation
1
1 To be published elsewhere; thanks to Drs D. Eggleston and
C. Haltewanger of SB for the X-ray crystallography.
morpholinium-4-spiro-3Ј-1Ј,2Ј,3Ј,4Ј-tetrahydro-1Ј,6Ј-dimethyl-
quinazolinium hexafluorophosphate 17 as pale yellow needles
from acetonitrile and ethyl acetate, mp 192–193 ЊC (Found: C,
12 O. Meth-Cohn and D. L. Taylor, unpublished observations.
4
7
4.5; H, 5.55; N, 7.3. C H F N OP requires C, 44.4; H, 5.6; N,
14 21 6 2
Ϫ1
.4%); νmax/cm 838 (PF ); δH 2.25 (3H, s, CH ), 3.24 (3H, s,
6
3
CH ), 3.67 (4H, m, NCH CH ), 4.18 (4H, t, J 5.0, OCH ) 4.97
Paper 7/08799C
Received 8th December 1997
Accepted 26th January 1998
3
2
2
2
ϩ
ϩ
(
2H, s, NCH N ), 5.07 (2H, s, N CH Ar), 6.90 (1H, d, J 8.4,
2
2
H-8Ј), 7.00 (1H, br s, H-5Ј) and 7.16 (1H, dd, J 1.4, 8.4, H-7Ј).
1
262
J. Chem. Soc., Perkin Trans. 1, 1998