Base-promoted transformation of 2-C(O)R-1,8-bis(dimethylamino)naphthalenes into benzo[g]indole derivatives

Article abstract of DOI:10.1016/j.mencom.2015.05.007

1,8-Bis(dimethylamino)naphthalenes bearing 2-positioned trifluoroacetyl or ethoxycarbonyl group on treatment with 2-lithio-1,8-bis-dimethylamino)naphthalene undergo base-promoted transformation into benzo[g]indole derivatives in small to moderate yield, representing previously unknown mode of the pyrrole ring closure which proceeds via deprotonation of the NMe group.

Full text of DOI:10.1016/j.mencom.2015.05.007

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 182–184
Base-promoted transformation of 2-C(O)R-1,8-bis(dimethylamino)-
naphthalenes into benzo[g]indole derivatives
a
b
a
a
Svetlana G. Kachalkina, Gennady S. Borodkin,* Alexander F. Pozharskii,* Alexander S. Antonov,
b
b
a
c
a
Inna G. Borodkina, Yuri F. Maltsev, Ekaterina A. Filatova, Aleksander Filarowski and Valery A. Ozeryanskii
a
Department of Organic Chemistry, Southern Federal University, 344090 Rostov-on-Don, Russian Federation.
Fax: +7 863 297 5146; e-mail: apozharskii@sfedu.ru
Institute of Physical and Organic Chemistry, Southern Federal University, 344090 Rostov-on-Don, Russian
b
Federation. E-mail: nmr@ipoc.sfedu.ru
Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland
c
DOI: 10.1016/j.mencom.2015.05.007
1
,8-Bis(dimethylamino)naphthalenes bearing 2-positioned trifluoroacetyl or ethoxycarbonyl group on treatment with 2-lithio-1,8-bis-
(dimethylamino)naphthalene undergo base-promoted transformation into benzo[g]indole derivatives in small to moderate yield,
representing previously unknown mode of the pyrrole ring closure which proceeds via deprotonation of the NMe group.
Unlike the widely known abnormally high basicity (pK 12.1,
Me N
NMe2
a
2
1,2
H O) of 1,8-bis(dimethylamino)naphthalene (1, ‘proton sponge’
Li
2
or DMAN), a question of the CH-acidity of its NMe groups
2
until recent time has remained untouched except for a brief
mention in ref. 3. A natural feeling is that acidic ionization of the
methyl groups in diamine 1 should be quite unprofitable due to
the destabilization of anion 3 caused by the neighboring of three
4
(CF CO) O
3
2
Et2O, –20 °C
NMe2
(
1.5 equiv.)
4
unshared electron pairs. Nevertheless, in the present work we
Me
CH2–
report that under certain conditions NMe groups in DMAN-type
Me N
Me N
N
2
2
2
compounds can manifest acidic character which in some cases
may be synthetically useful. Lithium derivative of DMAN 4
C(O)CF3
CF3
4
C
O
(Scheme 1) was the crucial reagent.
5
6
Me
N
MeCH2– Me
Me
N
Me
Me
Me
N
Me
Me
N
– OH–
H
+
Me
Me
N
N
Me2N
NMe2
Me
1
2
H+
+ H+
–
C(O)CF3
Me2N
N
3
9
CF3
8
7
3
1
2
4
C(O)CF3
6
5
Primarily, our goal was to obtain previously unknown 2-tri-
fluoroacetyl-1,8-bis(dimethylamino)naphthalene 5 (Scheme 1).
7
1
8
+
+
For this purpose we treated 2-lithio-1,8-bis(dimethylamino)-
oligomer
mixture
Me
5
naphthalene 4 with 1.2–2.0 equiv. of trifluoroacetic anhydride
2
Me N
N
†
(
TFAA) in dry diethyl ether at –20°C (Scheme 1, procedure 1).
R1
Unexpectedly, the desired monoketone 5 was not formed.
Instead, four different products 7–10 were isolated (along with
parent 1 and red oligomers). The benzo[g]indole derivatives 8
R2
1
2
9
R = CF3, R = C(O)CF3
†
Procedure 1: reaction between 4 and TFAA. BuLi solution (1.6 m in
1
2
1
0 R = R = H
hexane, 2.1 ml, 3.4 mmol) was added under argon to a cooled to –20°C
solution of 2-bromo-1,8-bis(dimethylamino)naphthalene (1 g, 3.4 mmol)
6
Scheme 1
in dry Et O (25 ml). The mixture was kept at –20°C for 30 min and then
2
TFAA (9.2 ml, 5.1 mmol) in dry Et O (20 ml) was added dropwise. After
and 9 (each in 5–7% yield) were of special interest. The product
ratio and even their type considerably depended on the amount
of TFAA used. With excess of TFAA (Table 1, runs 1–3), the
starting 1, diketone 7 and benzo[g]indole 8 prevailed in the
reaction mixture. In contrast, on lowering TFAA (runs 4 and 5),
2
a minute the red solid precipitated from which the solvent was decanted
and the solid was triturated with 30 ml of H O–CHCl (1:1). Both layers
2
3
were decanted from the less soluble oligomeric mixture and separated. The
chloroform solution was then evaporated to a small volume and using
TLC (Al O , CHCl –hexane, 1:1) diketone 7 (20 mg) was isolated as red
2
3
3
primarily illusive monoketone 5 and indole 10 with missed 3-CF3
group dominated among the reaction products.
orange crystals. The Et O solution was evaporated to dryness and four
2
fractions were collected by TLC from the residue: colorless (R = 0.8),
f
yellow (R = 0.7), orange (R = 0.4) and colorless (R = 0.2) representing
We believe that the formation of benzo[g]indoles most likely
f
f
f
compounds 8, 9, 7 and 1, respectively.
originates from the acidic ionization of the C–H bond in the
©
2015 Mendeleev Communications. Published by ELSEVIER B.V.
–
182 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2015, 25, 182–184
Table 1 Trifluoroacetylation of 4 on variation of 4:TFAA ratio.
group with the following protodetrifluoroacetylation. To test this
hypothesis we subjected compound 8 to the action of TFAA in
Product yield (%)a
4
ratio
:TFFA
Et O (Scheme 2). Five ketones 9, 11–14 were isolated in 48, 8,
2
Run
6
, 13, and 6% yields, respectively, along with 19% of the starting
1
5
7
8
9
10
material (procedures S1, S2, Online Supplementary Materials).
The formation of diketones 12 and 14 as well as monoketone
1
2
3
4
5
1:2
20
15
28
–b
–b
–
14
35
14
6
24
7
2
6
2
–
–
–
1:1.5
1:1
–
–
1
3 has clearly confirmed our assumption. Simultaneously, this
–
10
14
14
–
experiment has demonstrated that the benzene ring carrying the
1:0.5
1:0.25
25
50
3
NMe group in 8 is activated towards electrophile much stronger
2
3
21
than that fused with the pyrrole ring. The structures of all obtained
a
benzo[g]indoles were supported by mass- and multinuclear
( H, C and N) NMR spectra. Shortly, the most informative
Preparative yields of all compounds isolated by TLC; all yields were cal-
culated relatively to reactant taken in a smaller amount: DMAN 1 in runs
–3 and TFAA in runs 4 and 5. The yield is not indicated because much
1
13
15
b
1
for the elucidation of benzo[g]indole structures was the disap-
DMAN 1 (after protonation of 4) was obtained due to excess 4.
1
pearance in their H NMR spectra of a signal of 1-NMe group at
2
d 2.4–3.0 ppm instead of which a characteristic singlet of the
pyrrole NMe group arose at d 3.7–4.0 ppm. Compounds 10, 13
1
-NMe group of initially formed 5 under the action of highly
2
5
basic 4. Thereupon, equilibrium amounts of aminomethyl carb-
anion 6 undergo nucleophilic cyclization at COCF group to
and 14 with missed CF group could be easily identified by the
3
1
presence in their H NMR spectra of two doublets at 6.6–7.2 ppm
3
produce benzo[g]indole 8 (see Scheme 1); the trifluoroacetylation
of 8 then gives ketone 9. Obviously, the formation of compound
with the typical of pyrroles J value of about 3 Hz.
0
Me
1
0 looks especially intriguing. Since the CF should be a poor
3
Me2N
N
leaving group, we assumed that its elimination occurs as a
R1
R2
two-step process involving ipso-substitution of CF by COCF
3
3
(CF CO) O (1.05 equiv.)
3
2
8
Et2O, argon,
20 °C to room
teperature, 4.5 h
7
For 7: orange crystals, yield 0.48 g (35%), mp 178–179°C (lit., 180–
82°C); spectral properties are consistent with the authentic sample.
Procedure 2: reaction between 5 and 2-lithio-1,8-bis(dimethylamino)-
–
1
C(O)CF3
naphthalene 4. A solution of 5 (88 mg, 0.284 mmol) in dry Et O (6 ml)
was added portionwise at –20°C and under argon atmosphere to a solu-
1
2
2
9
R = H, R = CF3
1
2
1
1
1
1
1 R = C(O)CF3, R = CF3
tion of 4 in dry Et O (10 ml) obtained as indicated above from 2-bromo-
1
2
2
2 R = H, R = C(O)CF3
1
,8-bis(dimethylamino)naphthalene (166 mg, 0.568 mmol, 10 ml of Et O).
2
1
2
3 R = R = H
A pale-orange reaction mixture was kept for 42 h at –20°C and then
treated with water (20 ml). The organic layer was separated and the
1
2
4 R = C(O)CF3, R = H
aqueous one was extracted with Et O (5×5 ml). The combined organic
Scheme 2
2
extracts were evaporated to dryness and then subjected to column chro-
matography (37.6×1.7 cm) with Al O (V), using light petroleum as an
2
3
We also succeeded in rather effective preparation of mono-
ketone 5 via protolytic deacetylation (procedure S3) of more
accessible diketone 7. It was also found that treatment of ketone
with lithium derivative 4 gave benzo[g]indole alcohol 15 in
eluent. A yellowish fraction with R = 0.7 containing a mixture of com-
8
f
pounds 8 and 10 (mixture 1) was collected. A subsequent elution was
conducted with Et O–light petroleum mixture (1:2) to obtain sequentially
2
5
5
the yellow and orange fractions. The former (mixture 2) contained 2,2'-bi-
2% yield together with dinaphthylmethanol derivative 16 (28%)
naphthyl alcohol 16 (R = 0.8) and proton sponge 1 while the latter
f
(
(
(
mixture 3) contained initial ketone 5 (R = 0.6) and indole alcohol 15
and trace amounts of indoles 8 and 10; considerable quantity of
DMAN 1 was also isolated as a result of protolysis of 4 (Scheme 3,
procedure 2).Alcohol 15 is rather stable to dehydration, however,
can be aromatized on treatment with SiO or Al O to afford
f
R = 0.4). All three mixtures were evaporated to dryness. Mixture 1
f
1
3 mg) was not separated; according to the H NMR spectrum, it con-
tained indoles 8 and 10 along with an unidentified component in a 4:2:1
proportion, respectively. Mixture 2 was chromatographed on a column
2
2
3
‡
compound 8 (procedure S4).
(
27×1.8 cm) with Al O (V) using dichloromethane as an eluent. Color-
2 3
In case of 2,4-diketone 7, the reaction with 4 proceeds in more
less fractions of 16 (R = 0.4) and 1 (R = 0.1) were collected. Similar
separation of mixture 3 with ethyl acetate–light petroleum (1:10) as an
eluent gave ketone 5 (R = 0.7) and indole alcohol 15 (R = 0.5). After
f
f
complex fashion (Scheme 4). Here, 2-COCF group is again
3
engaged in the pyrrole cyclization (17®18) whereas its 4-COCF3
f
f
evaporation to dryness, the isolated compounds were obtained in the
following total yields: 15, 46 mg (52%); 16, 42 mg (28%); 8, 2 mg (2%);
Me
1
0, 1 mg (1%); 1, 62 mg; 5, 1 mg.
Procedure 3: reaction between 21 and 2-lithio-1,8-bis(dimethylamino)-
Me N
N
2
OH
CF3
CF3CO2H
4
naphthalene 4. A solution of compound 21 (500 mg, 1.75 mmol) in dry
Et O (9 ml) was added dropwise to a solution of 4 in dry Et O (25 ml)
7
5
+
2
2
prepared as described above from 2-bromo-1,8-bis(dimethylamino)-
naphthalene (1.024 g, 3.5 mmol) under argon atmosphere at –20°C. The
bright yellow mixture was kept at –20°C for 72 h and then treated with
water (30 ml). The organic layer was separated and the water layer was
1
5
Me
Me
Me2N
H
N
O Me2N
NMe2
extracted with Et O (5×5 ml). The combined organic layers were evaporated
2
F3C
+ 8 + 10 + 1
to dryness and chromatographed by TLC (Al O , Et O–light petroleum,
2
3
2
1
:1). Two fractions with R = 0.6 and 0.3 were collected. The first fraction
f
1
6
(
(
67 mg, 8%) represented ketone 22, orange crystals, mp 171–172°C
heptane). The second fraction (212 mg, 28%) contained practically pure
Scheme 3
indole 23, beige crystals, mp 204–205°C (decomp., MeCN).
If the reaction mixture was kept for 72 h at room temperature, ketone
2 became the major product (217 mg, 27%) and minor quantities of
‡
2
Alcohol 16 demonstrates dynamic behavior, equilibrating between two
indole 23 (130 mg, 17%) were isolated.
For characteristics of compounds obtained, see Online Supplementary
Materials.
equivalent hydrogen bonded structures. The switching process can be
frozen at –60 to –55°C against –90°C for the analogue of 16 with the
phenyl group instead of CF3.9
–
183 –

Mendeleev Commun., 2015, 25, 182–184
Me
CH2–
Me
and nucleophilic addition of 4 to the carbonyl group of 25. The
structure of 22 was proved by spectral data and X-ray diffraction
4
Me2N
N
Me2N
N
CF3
O
(
2 equiv.)
OH
(Figure S4).
7
Et2O,
To our knowledge,10 such a pyrrole ring closure has not been
CF3
–
20 °C
reported previously. The combination of several factors can be
responsible for this process in proton sponges: (1) the presence
of rather strong ortho-electron-withdrawing group which acidifies
C(O)CF3
C(O)CF3
1
7
18
the 1-NMe group; for example, we have found that 2-benzoyl-
2
Me
1
,8-bis(dimethylamino)naphthalene does not react similarly,
(2) the exceptionally high proton affinity of naphthyllithium 4,
3) the enhanced nucleophilicity of the aminomethyl anion of
Me
Me2N
N
OH
Me2N
N
(
CF3
CF3
type 6, (4) the assistance of lithium cation to the nucleophilic
addition through its coordination with the carbonyl oxygen atom;
the larger preference of the O®Li coordination over N®Li in
aminomethyl anion 6 was evidenced by the results of DFT
calculations (see Online Supplementary Materials), and (5) the
favorable orientation of the ionized NMe and carbonyl groups.
The importance of stereochemical factor is confirmed by X-ray
study of ketones 5 and 7 (Figure S2). As seen, the anion moiety
4
+
1
F3C
O
Me
Me
H
O
H
N
CF3
N
Me2N
Me
Me
NMe2
1
9
20
–
NCH should attack the appropriate carbonyl group having the
2
Scheme 4
most optimal orientation. The fact that the distance between the
carbonyl carbon atom and the 1-NMe group in monoketone 5
1
1
counterpart reacts with 2-lithio derivative 4 to produce
dinaphthylmethanol 19 in 43% yield (procedure S5). It should
be pointed out that alcohols of this type apparently constitute
the main contents of the above mentioned red oligomer mixture.
In particular, it is supported by the presence of several peaks
(2.91 Å) is shorter than that in diketone 7 (2.96 Å) can explain
why 5 is cyclized easier than 7.
To improve the yields of benzo[g]indoles as rather potent
biologically active compounds and to spread the scope of the
above reactions to other substrates, further studies are now in
progress.
1
between 12.6–12.8 ppm in the H NMR spectrum of the latter,
5
which are characteristic of the chelated tertiary hydroxyl group.
In addition, in one case we isolated from such a mixture small
amount of crystals of compound 20, whose structure was con-
firmed by X-ray diffraction study (Figure S3).
The X-ray diffraction experiments were performed by Z. A.
Starikova. This work was supported by the RF Ministry of
Education and Science (grant no. 4.967.2014/K).
The reaction proceeded somewhat differently when lithium
derivative 4 reacted with 2-ethoxycarbonyl one 21 (Scheme 5,
procedure 3). We anticipated to obtain previously unknown
ketone 22. In fact, we isolated it along with benzo[g]indole deri-
vative 23, the ratio of the two products being strongly dependent
on the reaction temperature. At 25°C, compounds 22 and 23
were obtained in 27 and 17% yield, respectively, whereas at
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2015.05.007.
References
1
(a) R. W. Alder, P. S. Bowman, W. R. S. Steele and D. R. Winterman,
J. Chem. Soc., Chem. Commun., 1968, 723; (b) F. Hibbert, J. Chem.
Soc., Perkin Trans. 2, 1974, 1862.
A. F. Pozharskii and V. A. Ozeryanskii, in The Chemistry of Anilines,
ed. Z. Rappoport, J. Wiley & Sons, Chichester, 2007, part 2, ch.17, p. 931.
A. F. Pozharskii, V. A. Ozeryanskii and V. V. Kuz’menko, Russ. J. Org.
Chem., 1996, 32, 66 (Zh. Org. Khim., 1996, 32, 76).
–
20°C they were formed in the reversed proportion: 8 and 28%.
Since benzo[g]indole 23 cannot be obtained on treatment of
authentic ketone 22 with 4, we suggest that 23 is actually formed
through the acidic ionization of the NMe group in ester 21,
followed by subsequent cyclization into pyrrolinone (24®25)
2
3
4
5
A. R. Katritzky and M. Qi, Tetrahedron, 1998, 54, 2647.
Me2N
Me2N
Me2N
NMe2 O
Me N
NMe2 O Me N
NMe2
2
2
A. F. Pozharskii, A. V. Degtyarev, O. V. Ryabtsova, V. A. Ozeryanskii,
M. E. Kletskii, Z. A. Starikova, L. Sobczyk and A. Filarowski, J. Org.
Chem., 2007, 72, 3006.
N. J. Farrer, R. McDonald and J. S. McIndoe, Dalton Trans., 2006, 4570.
A. F. Pozharskii, N. G. Tregub, N. V. Vistorobskii, E. Yu. Romanova,
Z. A. Starikova and A. I. Yanovsky, Russ. Chem. Bull., 1999, 48, 1299
OEt
4
Et2O,
20 °C
6
7
–
2
2
2
1
+
Me
4
(
Izv. Akad. Nauk, Ser. Khim., 1999, 1311).
Me2N
N
Me N
NMe2
2
8 E. Okada, H. Mioken, T. Tomoda,Y. Shimizu, M. Medebielle, N. Ota and
H. Takeuchi, Book of Abstracts. Congress of Heterocyclic Chemistry
(Japan), 2003, vol. 33, p. 186.
Me
CH2–
N
OEt
O
9
A. F. Pozharskii, A. V. Degtyarev, V. A. Ozeryanskii, O. V. Ryabtsova,
Z. A. Starikova and G. S. Borodkin, J. Org. Chem., 2010, 75, 4706.
2
3
1
0 (a) R. J. Sundberg, in Comprehensive Heterocyclic Chemistry, eds. A. R.
Katritzky and C. W. Rees, Elsevier, Oxford, 1984, vol. 4, p. 313;
2
4
(
b) R. J. Sundberg, in Comprehensive Heterocyclic Chemistry II, eds.
–
EtO–
N
A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Pergamon, Oxford,
1996, vol. 2, p. 119; (c) J. Bergman and T. Janosik, in Comprehensive
Heterocyclic Chemistry III, eds. A. R. Katritzky, C. A. Ramsden, E. F. V.
Scriven and R. J. K. Taylor, Elsevier, Oxford, 2008, vol. 3, p. 269.
Me2N
NMe2
Me
Li
O
11 L. Z. Boiko,V. I. Sorokin, E.A. Filatova, Z.A. Starikova,V.A. Ozeryanskii
and A. F. Pozharskii, J. Mol. Struct., 2011, 1005, 12.
–
LiOH
2
5
Scheme 5
Received: 24th November 2014; Com. 14/4509
–
184 –