Lithiation of pivaloylamino derivatives of dibenzofuran and 9-methylcarbazole

Article abstract of DOI:10.1071/CH01017

2-, 3- and 4-Pivaloylamino derivatives of dibenzofuran [compounds (5), (4) and (6), respectively] and analogous 3-, 2- and 1-substituted derivatives of 9-methylcarbazole [compounds (8), (7) and (9), respectively] were subjected to lithiation at 0°C and subsequent reaction with dimethylformamide. Aldehyde formation took place at positions α to δ to the heteroatom as follows: α for (4) and (7); δ for (5); δ and β (3 : 1) for (8); and α′ (6). No formylation occurred with (9).

Full text of DOI:10.1071/CH01017

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Aust. J. Chem. 2001, 54, 177–180
Lithiation of Pivaloylamino Derivatives of
Dibenzofuran and 9-Methylcarbazole
Leslie W. DeadyA,B and Robert M. D. SetteA
A
Chemistry Department, La Trobe University, Vic. 3086.
Author to whom correspondence should be addressed.
B
2
3
-, 3- and 4-Pivaloylamino derivatives of dibenzofuran [compounds (5), (4) and (6), respectively] and analogous
-, 2- and 1-substituted derivatives of 9-methylcarbazole [compounds (8), (7) and (9), respectively] were subjected
to lithiation at 0°C and subsequent reaction with dimethylformamide. Aldehyde formation took place at positions
α to δ to the heteroatom as follows: α for (4) and (7); δ for (5); δ and β (3 : 1) for (8); and α′ for (6). No formylation
occurred with (9).
Manuscript received: 2 March 2001.
Final version: 4 May 2001.
C
H0 01 7
L
.W De ad y,R .M .D .S et
e
L. W. Deady
andR. M. D. Sette Li thia tio no Df eri vat ive so fD ibe nzo fu ran an d9 -M eth ylc arb azo le
Introduction
As part of a continuing investigation of testing derivatives of
polycyclic heterocycles for anticancer activity, we wished to
[
1]
[2]
prepare analogues of (1) and (2), with X = O or NR, in
which the positions of the pyrido and side chain containing
rings are reversed.
various 4-substituted products.[4] A recent example is
formation of the 4-carbaldehyde derivative by reaction with
N,N-dimethylformamide and subsequent hydrolysis.[ Since
the aldehyde function could be useful in further synthesis,
this reaction was chosen for the present study. While free
amino groups are inappropriate for lithiation, the pivaloyl-
amino group was shown to be a good modification of
anilines for ortho-directed lithiation and subsequent reaction
with electrophiles (including the dimethylformamide (DMF)
5]
A possible approach would be to construct the pyrido ring
from known amino-dibenzofurans and -carbazoles. An
additional pertinent substituent ortho to the amino group
would be useful for this annulation, e.g. (3a), or as
forerunner of derivatives for biological testing (3b) (Fig. 1).
[
6]
reaction). We therefore wished to see how the position of
substitution in dibenzofuran would be modified by the
presence of a pivaloylamino group at various ring positions.
The same questions would be posed for analogous pival-
oylamino derivatives of 9-methylcarbazole. Simple 9-alkyl
derivatives of carbazole are less reactive to ring-carbon lithi-
[
7]
ation than dibenzofuran, though useful 1-substitution was
found by lithiation of 9-(dialkylamino)methyl derivatives.[
8]
Results and Discussion
Fig. 1. Possible approach to the construction of a pyrido ring from
substituted aminodibenzofurans and aminocarbazoles.
Dibenzofuran-2-, -3-and-4-aminesand 9-methylcarbazol-1-,
-
2- and -3-amines were prepared by literature procedures,
Directed ortho-metallation is a useful synthetic tool[3] but
the products from electrophilic substitution of lithiated
aminodibenzofurans and carbazoles were not known, which
therefore prompted the present study.
some with modifications (see Experimental). For comparison
purposes, all compounds were lithiated under the same
conditions. Tetrahydrofuran was found to be superior to
diethyl ether as solvent in earlier lithiations of dibenzofuran
[9]
and 9-ethylcarbazole.
The previous lithiation of N-
Dibenzofuran has long been known to lithiate at the
pivaloylanilines also used n-butyllithium in tetrahydrofuran,
4
-position and reaction with electrophiles is a useful route to
©
CSIRO 2001
10.1071/CH01017
0004-9425/01/030177

178
L. W. Deady and R. M. D. Sette
and so lithiation at 0°C and subsequent reaction with DMF
was carried out by this literature procedure.[
singlets for H α and H δ in (15) were characteristic. In the
dibenzofuran analogue, only the product of δ-substitution
(12) was evident in the crude mixture.
6]
As illustrated above, the systematic numbering of
dibenzofuran and carbazole are different, which is confusing
when comparing the same ring positions. Systematic
numbering is used in the Experimental section but in this
discussion the ring positions will be referred to by α, β, γ, δ
as shown in Scheme 1.
It is interesting that the β-aldehyde should be formed to
this extent in the carbazole example since, in the other case
where this position was supposedly activated, i.e. compound
(9) (Scheme 3), no aldehyde was found and (9) showed the
lack of reactivity previously noted for simple 9-substituted
[
7]
carbazoles. This low reactivity of the β-position was also
noted in the O analogue (6) but here, because of the greater
heteroatom activation, a ready reaction occurred in the
α-position of the other ring to give (16) which was isolated
1
in 67% yield. A correlation spectroscopy (COSY) H NMR
experiment showed that each of the two aromatic triplet
signals was coupled to a different pair of the four doublet
signals, a result consistent only with this substitution pattern.
A small amount of a second aldehyde was present in the
1
crude product but too few H NMR signals were
distinguishable for it to be identified.
Where the effect of the heteroatom and pivaloylamino
group were reinforcing (Scheme 1, compounds (4) and (7)),
the expected α-products (10) and (11), respectively, were the
only aldehydes detected and these were isolated in ca. 65%
1
yields. Throughout this study, H nuclear magnetic
resonance (NMR) spectra provided unequivocal evidence for
the assigned structures. Thus, for (10) and (11), the singlet
for H α evident in the precursors was absent.
This study has showed an interesting interplay of effects
from the heteroatom and pivaloylamino substituent in
directing electrophilic substitution in these dibenzofuran and
carbazole derivatives. Viable syntheses of precursors to
ortho-amino aldehydes for further construction of tetracyclic
systems have been established from (4), (5) and (7)
The pivaloylamino group was activating enough to
compete with the heteroatom in some situations. Thus, for
compounds with a γ-pivaloylamino substituent (Scheme 2,
compounds (5) and (8)), substitution ortho to the
pivaloylamino group was seen, rather than the α-product.
Here though, an appreciable difference was noted between
the analogous N and O substrates. For the former, a 3 : 1
mixture of the isomers (13) and (15) was found. These had a
substantial difference in chemical shift for the CHO signal in
(
separation of isomeric products from (8) is problematic on
a preparative scale), while the dissimilar α,α′-substitution in
6) may also have future synthetic utility.
(
Experimental
1
the H NMR spectrum (11.3 and 10.0 ppm, respectively).
NMR spectra were recorded in CDCl unless stated otherwise, on a
3
1
Partial separation was achieved by chromatography and the
Bruker AM-300 spectrometer operating at 300.13 ( H) and 75.47 MHz
C). H NMR signals are for single protons unless otherwise
13
1
(
indicated. Standard PENDANT (polarization enhancement during
attached nucleus testing) experiments were used to identify proton-
bound carbons in 13C NMR spectra. Microanalyses were carried out at
the Campbell Microanalytical Laboratory, University of Otago, New
Zealand.
Dibenzofuran-2-amine [10]
[
10]
The title compound was prepared as reported from 2-bromodibenzo-
[
11] 1
furan.
H NMR δ 3.75, br s, NH ; 6.81, dd, J 8.6, 2.3 Hz; 7.22, d, J
2
2
8
1
1
.3 Hz; 7.27, t, J 7.3 Hz; 7.35, d, J 8.6 Hz; 7.39, t, J 7.3 Hz; 7.50, d, J
1
3
.1 Hz; 7.85, d, J 7.6 Hz. C NMR δ 105.9, CH; 111.6, CH; 111.9, CH;
15.7, CH; 120.5, CH; 122.2, CH; 124.3, C; 124.8, C; 126.9, CH;
42.0, C; 150.3, C; 156.7, C.
Dibenzofuran-4-amine
The title compound was prepared as reported[12] (1H NMR δ 4.0, br s,
NH ; 6.81, d, J 7.7 Hz; 7.14, t, J 7.7 Hz; 7.32, t, J 7.3 Hz; 7.36, d, J 7.9
2
1
3
Hz; 7.43, t, J 7.4 Hz; 7.55, d, J 8.1 Hz; 7.91, d, J 7.6 Hz. C NMR δ
1
1
10.4, CH; 111.6, CH; 112.9, CH; 120.9, CH; 122.6, CH; 123.4, CH;
24.5, C; 124.7, C; 126.8, CH; 131.9, C; 144.8, C; 155.9, C).

Lithiation of Derivatives of Dibenzofuran and 9-Methylcarbazole
179
3
-Nitrodibenzofuran
A literature method was modified.[13] A mixture of fuming nitric acid
8 mL, 190 mmol) in glacial acetic acid (12 mL) was added dropwise
9-Methylcarbazol-3-amine
9-Methyl-3-nitrocarbazole was reduced as for the synthesis of
dibenzofuran-3-amine above to give the title amine as a white solid
(93%), m.p. 164–167°C (lit. 173–174°C) H NMR δ 3.78, s, CH ;
6.91, dd, J 8.5, 2.0 Hz; 7.15, t, J 7.6 Hz; 7.20, d, J 8.9 Hz; 7.32, d, J 8.1
Hz; 7.39–7.45, m, 2H; 7.98, d, J 7.8 Hz. C NMR δ 29.0, CH ; 106.2,
(
[
20]
1
over 5 min to a solution of dibenzofuran (20 g, 119 mmol) in glacial
acetic acid (40 mL) at 90°C. The solution was heated for 10 min, during
which time a heavy yellow precipitate separated. This mixture of nitro
products (23.9 g) was filtered off, washed thoroughly with water and
extracted with hot ethanol (2×150 mL). The insoluble off-white powder
was recrystallized from acetic acid to give the product (17.1 g, 67%),
3
1
3
3
CH; 108.3, CH; 108.9, CH; 115.5, CH; 118.0, CH; 120.2, CH; 122.3,
C; 123.4, C; 125.5, CH; 135.6, C; 138.9, C; 141.4, C.
melting point (m.p.) 180–181°C (lit.[14] 181–182°C). H NMR δ 7.42,
t, J 6.9 Hz; 7.58, t, J 7.5 Hz; 7.63, d, J 8.0 Hz; 8.00, d, J 7.6 Hz; 8.02, d,
J 8.5 Hz; 8.26, dd, J 8.5, 1.8 Hz; 8.42, d, J 1.8 Hz, H 4. C NMR δ
1
9-Methylcarbazol-1-amine
-Nitrocarbazole was N-methylated[17] in 98% yield ( H NMR δ 3.84,
1
1
1
3
s, CH ; 7.24, t; 7.32, dt, J 7.9, 1.0 Hz; 7.49, d, J 8.2 Hz; 7.57, dt, J 7.1,
3
1
1
07.9, CH; 112.2, CH; 118.4, CH; 120.5, CH; 121.7, CH; 122.4, C;
23.7, CH; 129.5, CH; 130.1, C; 146.7, C; 155.0, C; 158.2, C.
1
.1 Hz; 7.99, dd, J 8.0, 0.8 Hz; 8.09, d, J 7.7 Hz; 8.29, dd, J 7.8, 1.1 Hz)
and this intermediate was reduced as for the synthesis of dibenzofuran-
1
3
4
-amine above to give the title amine (85%) as a red oil. H NMR δ
Dibenzofuran-3-amine
.17, s, CH ; 6.76, dd, J 7.5, 0.7 Hz; 7.01, t, J 7.6 Hz; 7.18, t, J 7.7 Hz;
3
The following represents a convenient alternative to previous reduction
conditions. A mixture of 3-nitrodibenzofuran (10 g), hydrazine mono-
hydrate (30 mL), 10% Pd–C (0.4 g) in ethanol (200 mL) was refluxed
for 2 h, then filtered through a bed of Celite and the ethanol was re-
moved under reduced pressure. The residual solid was taken up in ether
7.34, d, 8.3 Hz; 7.44, t, 7.1 Hz; 7.61, dd, J 7.9, 0.75 Hz; 8.02, d, J 7.8
1
3
Hz. C NMR δ 32.0, NCH ; 108.6, CH; 112.5, CH; 114.9, CH; 118.8,
3
CH; 119.8, CH; 120.1, CH; 123.1, C; 124.7, C; 125. 6, CH; 131.3, C;
131.9, C; 141.8, C.
(
40 mL), washed with water (2 × 20 mL), dried (MgSO ) and the ether
4
General Procedure for the Preparation of Pivaloylamino
Derivatives
was removed under reduced pressure to leave the amine (7.5 g, 87%) as
a pale pink solid, m.p. 93°C (from ethanol/water; lit.[ 94°C). H NMR
15]
1
Freshly distilled pivaloyl chloride (0.85 g, 7.1 mmol) was added
dropwise, with stirring, to a solution of the amino compound (5.5 mmol)
and triethylamine (1.05 g, 10.4 mmol) in dry dichloromethane (60 mL),
and the solution was stirred for a further 16 h. Ether (150 mL) was added
and the solution was washed with 10% sodium bicarbonate (2 × 20 mL),
water (2 × 20 mL), 10% hydrochloric acid (2 × 20 mL), and water
δ 3.68, br s, NH ; 6.67, dd, J 8.2, 2.0 Hz; 6.83, d, J 2.0 Hz; 7.24–7.33,
2
1
3
m, 2H; 7.46, d, J 7.2 Hz; 7.67, d, J 8.2 Hz; 7.74, dd, J 7.4, 1.5 Hz.
C
NMR δ 97.4, CH; 111.1, CH; 111.2, CH; 115.6, C; 119.3, CH; 121.2,
CH; 122.5, CH; 124.8, C; 125.1, CH; 146.7, C; 155.9, C; 157.9, C.
9-Methylcarbazol-2-amine
[
16]
deacetylated[16] and N-methy-
(2 × 20 mL), then dried (MgSO ) and the solvent was removed. The
residual solid was recrystallized from light petroleum (b.p. 100–130°C).
4
9
-Acetylcarbazole was nitrated,
[
17]
lated to give 9-methyl-2-nitrocarbazole. This was reduced as for the
synthesis of dibenzofuran-3-amine above. Minor impurities from the
nitration reaction were carried through to this stage and the amine was
obtained as a red oil sufficiently pure for use in the amidation reaction.
H NMR δ 3.73, s, CH ; 6.59, dd, J 6.1, 1.5 Hz; 6.63, d, J 1.5 Hz; 7.16,
In this way, the following compounds were prepared.
N-(Dibenzofuran-3-yl)-2,2-dimethylpropionamide (4)
1
This was obtained as a white solid (89%), m.p. 161°C (Found: C, 76.4;
3
1
H, 6.7; N, 5.4. C H NO requires C, 76.4; H, 6.4; N, 5.2%). H NMR
t; 7.28–7.36, m, 2H; 7.83, d, J 8.0 Hz; 7.92, d, J 7.7 Hz.
17 17
2
δ 1.35, s, C(CH ) ; 7.25–7.33, m, 2H; 7.40, dt, J 7.2, 1.3 Hz; 7.50, br s,
3
3
1
3
1
-Nitrocarbazole and 3-Nitrocarbazole
NH; 7.53, d, J 8.1 Hz; 7.81–7.87, m, 2H; 8.08, d, J 1.5 Hz. C NMR δ
7.6, (CH ) ; 39.7, C; 103.6, CH; 111.6, CH; 114.9, CH; 120.1, CH;
2
3
3
This preparation resulted in major modifications to a reported
[
18]
120.3, C; 120.5, CH; 122.7, CH; 124.0, C; 126.5, CH; 137.4, C; 156.6,
C; 156.7, C; 176.5, C.
procedure. Concentrated nitric acid (0.40 mL, 6.3 mmol) was added,
dropwise over 2 min, to a suspension of carbazole (1 g, 6.0 mmol) in
glacial acetic acid (8 mL) at 60°C. The mixture was heated for a further
0 min (during which time all the solid disappeared), and then allowed
to cool for 1.5 h. The solid which separated was then filtered off to give
,6-dinitrocarbazole (0.30 g, 19%) as a light brown solid, m.p. >310°C
from dimethyl sulfoxide; lit. 383–385°C). H NMR δ [(CD ) SO]
.73, d, J 9.0 Hz; 8.36, dd, J 8.9, 2.3 Hz; 9.44, d, J 2.3 Hz; 12.65, br s, NH.
The filtrate from the above reaction mixture was poured onto ice/
water and a mixture of 1- and 3-nitrocarbazoles separated as a yellow
solid, which was filtered off (0.90 g, 71%). Soxhlet extraction with
carbon tetrachloride (150 mL) was carried out for 16 h, and the cooled
solution gave 3-nitrocarbazole (0.40 g, 31%) as a yellow solid, m.p.
N-(Dibenzofuran-2-yl)-2,2-dimethylpropionamide (5)
1
This was obtained as a cream solid (99%), m.p. 185–186°C (Found: C,
1
7
6.1; H, 6.5; N, 5.6. C H NO requires C, 76.4; H, 6.4; N, 5.2%). H
3
(
7
17 17
2
1
5
1
NMR δ 1.31, s, C(CH ) ; 7.31, t, J 7.5 Hz; 7.35, dd, J 8.6, 2.2 Hz; 7.41–
3 3
3
2
1
3
7
.46, m, 3H; 7.52, t, J 8.1 Hz; 7.91, d, J 7.5 Hz; 8.37, d, J 2.2 Hz. C
NMR δ 27.6, (CH ) ; 39.5, C; 111.5, CH; 111.6, CH; 112.8, CH; 120.0,
3 3
CH; 120.8, CH; 122.7, CH; 124.2, C; 124.6, C; 127.3, CH; 133.2, C;
1
52.9, C; 156.7, C; 176.7, C.
N-(Dibenzofuran-4-yl)-2,2-dimethylpropionamide (6)
[
19]
1
2
08–210°C (lit. 215–216°C). H NMR δ 7.30–7.36, m; 7.49, d, J 7.9
This was obtained as a white solid (94%), m.p. 109°C (Found: C, 76.3;
1
Hz; 7.49–7.52, m, 2H; 8.13, d, J 7.9 Hz; 8.34, dd, J 8.9, 1.9 Hz; 8.50, br
s, NH; 9.00, d, J 1.9 Hz. The filtrate was concentrated to ca. 50 mL,
filtered and the filtrate was evaporated to dryness under reduced
pressure to give 1-nitrocarbazole (0.20 g, 16%) as a yellow solid, ca.
H, 6.5; N, 5.5. C H NO requires C, 76.4; H, 6.4; N, 5.2%). H NMR
1
7
17
2
δ 1.42, s, C(CH ) ; 7.31, t, J 7.9 Hz; 7.36, t, J 7.5 Hz; 7.46, t, J 7.3 Hz;
3
3
7.58, d, J 8.2 Hz; 7.65, d, J 7.7 Hz; 7.93, d, J 7.5 Hz; 8.01, br s, NH;
1
3
8.40, d, J 8.0 Hz. C NMR δ 27.6, (CH ) ; 39.9, C; 111.6, CH; 115.4,
3
3
[
19]
1
9
0% pure, m.p. 170–174°C (lit. 188–189°C). H NMR δ 7.26–7.58,
CH; 117.8, CH; 120.9, CH; 123.1, CH; 123.4, CH; 123.9, C; 124.1, C;
124.5, C; 127.1, CH; 145.6, C; 155.6, C; 176.7, C.
m, 4H; 8.10, d, J 8.0 Hz; 8.27–8.36, m, 2H; 10.00, br s, NH.
9-Methyl-3-nitrocarbazole
N-(9-Methylcarbazol-2-yl)-2,2-dimethylpropionamide (7)
[
17]
3
-Nitrocarbazole was N-methylated
to give the product (97%) as a
This was obtained as a white solid (63%), m.p. 205°C (formed needles
>170°C) (Found: C, 77.3; H, 7.4; N, 10.0. C H N O requires C, 77.1;
[
19]
1
yellow solid, m.p. 168°C (lit. 173–174°C). H NMR δ 3.90, s, CH ;
.31–7.41, m, 2H; 7.46, d, J 8.2 Hz; 7.57, dt, J 8.2, 1.1 Hz; 8.14, d, J 7.8
Hz; 8.38, dd, J 9.1, 2.2 Hz; 8.99, d, J 2.2 Hz. C NMR δ 29.5, CH3;
08.0, CH; 109.4, CH; 117.2, CH; 120.8, C; 120.9, CH; 121.6, CH;
22.5, C; 122.7, C; 127.4, CH; 140.6, C; 142.1, C; 143.9, C.
3
18 20
2
1
7
H, 7.2; N, 10.0%). H NMR δ 1.36, s, C(CH ) ; 3.82, s, NCH ; 6.91, dd,
3 3 3
1
3
J 8.3, 1.8 Hz; 7.20, t, J 6.8 Hz; 7.35–7.45, m, 2H; 7.55, br s, NH; 7.96,
1
3
1
1
d, J 8.3 Hz; 8.00, d, J 7.7 Hz; 8.21, d, J 1.8 Hz. C NMR δ 27.6, (CH ) ;
3 3
29.1, NCH ; 39.7, C; 100.1, CH; 108.3, CH; 111.2, CH; 118.9, CH;
3

180
L. W. Deady and R. M. D. Sette
1
19.1, C; 119.7, CH; 120.3, CH; 122.6, C; 125.1, CH; 136.2, C; 141.4,
N
-
(
(
4-Formyl-9-methylcarbazol-3-yl
)
-2
-2,
,
2-dimethylpropionamide(13) and
2-dimethylpropionamide (15)
C; 141.6, C; 176.7, C.
N-
2-Formyl-9-methylcarbazol-3-yl
)
The crude product contained a 3 : 1 isomeric mixture of (13) and (15)
respectively. Column chromatography (silica gel; dichloromethane)
gave partial separation of the isomers. Most product was obtained as a
clean mixture of the two (52%), as a bright yellow solid, m.p. 156–
N-(9-Methylcarbazol-3-yl)-2,2-dimethylpropionamide (8)
This was obtained as a grey/brown solid (84%), m.p. 189°C (Found: C,
1
7
7.0; H, 7.4; N, 9.9. C H N O requires C, 77.1; H, 7.2; N, 10.0%). H
18
20
2
1
58°C [from light petroleum (b.p. 100–130°C)] (Found: C, 73.8; H, 6.6;
NMR δ 1.36, s, C(CH ) ; 3.81, s, NCH ; 7.19, t, J 7.2 Hz; 7.30, d, J 8.7
3
3
3
N, 9.2. C H N O requires C, 74.0; H, 6.5; N, 9.1%), along with small
Hz; 7.35, d, J 8.1 Hz; 7.42–7.49, m, 2H; 8.04, d, J 7.8 Hz; 8.35, d, J 1.9
19 20
2
2
1
3
samples of the individual compounds (both of which have an intense
Hz. C NMR δ 27.7, (CH ) ; 29.1, NCH ; 39.4, C; 108.3, CH; 108.4,
3
3
3
yellow fluorescence in solution).
CH; 112.7, CH; 118.7, CH; 119.4, CH; 120.5, CH; 122.6, C; 122.8, C;
25.8, CH; 129.9, C; 138.2, C; 141.4, C; 176.5, C.
1
Isomer (13) was obtained as a yellow solid (R 0.46), m.p. 190°C. H
1
F
NMR δ 1.40, s, C(CH ) ; 3.88, s, NCH ; 7.25, t; 7.46, d, J 8.1 Hz; 7.53, t,
3
3
3
J 7.4 Hz; 7.66, d, J 9.2 Hz; 8.15, d, J 8.1 Hz; 8.97, d, J 9.2 Hz; 11.29, s,
N-(9-Methylcarbazol-1-yl)-2,2-dimethylpropionamide (9)
1
3
CHO; 11.77, br s, NH. C NMR δ 27.7, (CH ) ; 29.1, NCH ; 40.4, C;
3
3
3
This was obtained as a grey solid (70%), m.p. 183°C (formed needles
109.5, CH; 116.2, CH; 117.1, C; 118.1, CH; 119.6, CH; 120.7, C; 123.2,
C; 124.4, CH;126.8,CH; 135.6, C; 136.9, C; 141.9, C;178.4,C;193.0,C.
>
165°C) (Found: C, 77.1; H, 7.3; N, 9.9. C H N O requires C, 77.1;
18 20 2
1
H, 7.2; N, 10.0%). H NMR δ 1.39, s, C(CH ) ; 3.93, s, NCH ; 7.12–
Isomer (15) was obtained as a yellow solid (R 0.54), m.p. 185–
3
3
3
F
1
7
0
1
1
.23, m, 2H; 7.32, d, J 8.2 Hz; 7.42–7.48, t and br s, 2H; 7.98, dd, J 7.5,
186°C. H NMR δ 1.41, s, C(CH ) ; 3.79, s, NCH ; 7.22, t, J 7.5 Hz;
3
3
3
1
3
.8 Hz; 8.04, d, J 7.7 Hz. C NMR δ 27.7, (CH ) ; 31.0, CH ; 39.2, C;
7.33, d, J 8.2 Hz; 7.50–7.53, s and t, 2H; 8.12, d, J 7.9 Hz; 9.51, s; 9.98,
3
3
3
1
3
08.6, CH; 119.0, CH; 119.3, CH; 120.1, CH; 120.5, C; 122.6, C;
25.4, C; 125.7, CH; 126.0, CH; 136.5, C; 141.7, C; 178.3, C.
s; 11.43, br s, NH. C NMR δ 27.7, (CH ) ; 29.1, NCH ; 40.3, C;
3 3 3
108.8, CH; 111.3, CH; 116.3, CH; 119.6, CH; 120.5, C; 122.0, CH;
28.2, CH; 128.5, C; 133.5, C; 136.0, C; 143.4, C; 178.3, C; 195.0, C.
1
General Procedure for the Lithiation of Pivalamides
n-Butyllithium in hexanes (2.5 M, 5 mL, 8.2 mmol) was added, with
stirring, to a solution of the amide (0.6 mmol) in dry tetrahydrofuran
N-(6-Formyldibenzofuran-4-yl)-2,2-dimethylpropionamide (16)
Column chromatography (silica; dichloromethane) gave the title
(
12 mL) at 0°C under an atmosphere of nitrogen (an immediate colour
aldehyde (67%; R 0.3) as a white solid, m.p. 137–139°C [from light
F
change occurred). Stirring was continued at 0°C for 1 h, then N,N-
dimethylformamide (6 mL, 81.6 mmol) was added and the solution was
stirred for a further 2 h (during which time it returned to its original
colour). Diethyl ether (50 mL) was added and the organic layer was
washed with water (2×50 mL) and brine (1×50 mL), then dried
petroleum (b.p. 100–130°C)] (Found: C, 73.3; H, 5.9; N, 4.7.
1
C H NO requires C, 73.2; H, 5.8; N, 4.7%). H NMR δ 1.42, s,
1
8
17
3
C(CH ) ; 7.37, t, J 7.9 Hz; 7.49, t, J 7.5 Hz; 7.67, d, J 7.8 Hz; 7.94, d, J
3
3
7
.7 Hz; 8.09, br s, NH; 8.17, d, J 7.3 Hz; 8.42, d, J 8.0 Hz; 10.56, s,
13
CHO. C NMR δ 27.6, (CH ) ; 40.0, C; 115.6, CH; 118.9, CH; 121.3,
3
3
(
MgSO ) and the solvent was removed to leave a semi-solid.
4
C; 122.7, C; 123.4, CH; 124.1, C; 124.3, CH; 126.3, C; 126.9, CH;
27.8, CH; 146.2, C; 155.1, C; 176.9, C; 187.9, C.
The following compounds were obtained in this way.
1
N-(4-Formyldibenzofuran-3-yl)-2,2-dimethylpropionamide (10)
Acknowledgment
Column chromatography (silica; dichloromethane) gave the title
This work was supported by an Australian Research Council
Small Grant.
aldehyde (67%; R 0.7) as a yellow solid, m.p. 157–158°C [from light
F
petroleum (b.p. 100–130°C)] (Found: C, 73.4; H, 5.8; N, 4.9.
1
C H NO requires C, 73.2; H, 5.8; N, 4.7%). H NMR δ 1.35, s,
1
8
17
3
References
C(CH ) ; 7.38, t, J 7.4 Hz; 7.46, t, J 7.3 Hz; 7.59, d, J 7.3 Hz; 7.90, d, J
3
3
7
.6 Hz; 8.10, d, J 8.8 Hz; 8.80, d, J 8.8 Hz; 10.80, s, CHO; 11.66, br s,
[
1] L. W. Deady, A. J. Kaye, G. J. Finlay, B. C. Baguley, W. A. Denny,
J. Med. Chem. 1997, 40, 2040.
2] X. Bu, L. W. Deady, W. A. Denny, Aust. J. Chem. 2000, 53, 143.
3] V. Snieckus, Chem. Rev. 1990, 90, 879.
1
3
NH. C NMR δ 27.5, (CH ) ; 40.5, C; 107.7, C; 111.6, CH; 114.6, CH;
3
3
1
1
19.2, C; 120.3, CH; 123.1, C; 123.7, CH; 127.0, CH; 128.6, CH;
40.7, C; 156.2, C; 158.6, C; 178.6, C; 190.7, C.
[
[
[
4] M. V. Sargent, P. O. Stransky, Adv. Heterocycl. Chem. 1984, 35,
N-(1-Formyl-9-methylcarbazol-2-yl)-2,2-dimethylpropionamide (11)
1, and references therein.
[
[
[
5] F. Jean, O. Melnyk, A. Tartar, Tetrahedron Lett. 1995, 36, 7657.
6] W. Fuhrer, H. W. Gschwend, J. Org. Chem. 1979, 44, 1133.
7] H. Gilman, C. G. Stuckwisch, A. R. Kendall, J. Am. Chem. Soc.
Column chromatography (silica; dichloromethane) gave the title
aldehyde (65%) as a cream solid, m.p. 230°C (formed needles >200°C)
(
Found: C, 74.0; H, 6.7; N, 9.2. C H N O requires C, 74.0; H, 6.5; N,
19 20 2 2
1
1
941, 63, 1758; H. Gilman, C. G. Stuckwisch, J. Am. Chem. Soc.
943, 65, 1729.
1
9
7
8
.1%). H NMR δ 1.40, s, C(CH ) ; 4.07, s, NCH ; 7.30, t, J 7.4 Hz;
3 3 3
.40, d, J 8.1 Hz; 7.47, t, J 7.4 Hz; 8.00, d, J 7.7 Hz; 8.21, d, J 8.7 Hz;
[8] A. R. Katritzky, G. W. Rewcastle, L. M. Vazquez de Miguel,
1
3
.69, d, J 8.1 Hz; 10.85, s, CHO; 12.06, br s, NH. C NMR δ 27.6,
J. Org. Chem. 1988, 53, 794.
(
CH ) ; 30.8, NCH ; 40.6, C; 108.5, C; 109.2, CH; 111.4, CH; 119.6,
3 3 3
[
9] H. Gilman, S. Gray, J. Org. Chem. 1958, 23, 1476.
10] H. Gilman, G. E. Brown, W. G. Bywater, W. H. Kirkpatrick,
J. Am. Chem. Soc. 1934, 56, 2473.
CH; 120.2, C; 120.8, CH; 122.7, C; 125.9, CH; 128.5, CH; 141.3, C;
42.2, C; 143.1, C; 178.6, C; 190.7, C.
[
1
[
[
[
11] E.S.Hand,S.C.Johnson,D.C.Baker,J. Org. Chem. 1997,62,1348.
12] E. V. Brown, R. L. Coleman, Org. Prep. Proced. Int. 1973, 5, 125.
13] V. G. Poludnenko, V. I. Enya, Khim. Prom-st., Ser.: Reakt. Osobo
Chist. Veshchestva 1981, 25 (Chem. Abstr. 1982, 96, 68737h).
14] S. Yamashiro, Bull. Chem. Soc. Jpn 1941, 16, 61.
N-(1-Formyldibenzofuran-2-yl)-2,2-dimethylpropionamide (12)
Column chromatography (silica; dichloromethane) gave the aldehyde
(
54%; R 0.6) as a yellow solid, m.p. 152°C [from light petroleum (b.p.
F
[
1
7
7
8
00–130°C)] (Found: C, 73.4; H, 5.9; N, 4.8. C H NO requires C,
18 17 3
1
[15] W. Borsche, W. Bothe, Ber. Dtsch. Chem. Ges. 1908, 41, 1940.
16] J. B. Kyziol, A. Domanski, Org. Prep. Proced. Int. 1981, 13, 419.
[17] E. Sawicki, J. Am. Chem. Soc. 1953, 75, 4106.
3.2; H, 5.8; N, 4.7%). H NMR δ 1.39, s, C(CH ) ; 7.38, t, J 7.5 Hz;
3
3
[
.55, t, J 7.2 Hz; 7.63, d, J 8.3 Hz; 7.79, d, J 9.2 Hz; 8.04, d, J 7.9 Hz;
1
3
.97, d, J 9.2 Hz; 11.09, s, CHO; 11.71, br s, NH. C NMR δ 27.6,
[
[
18] P. Ziersch, Ber. Dtsch Chem. Ges. 1909, 42, 3797.
19] J. Kyziol, Z. Daszkiewicz, J. Hetper, Org. Mass Spectrom. 1987,
(
CH ) ; 40.0, C; 115.6, CH; 118.9, CH; 121.3, C; 122.7, C; 123.4, CH;
3 3
124.1, C; 124.3, CH; 126.3, C; 126.9, CH; 127.8, CH; 146.2, C; 155.1,
2
2, 39.
C; 176.9, C; 187.9, C.
[
20] E. Sawicki, J. Am. Chem. Soc. 1954, 76, 664.