An efficient procedure for the deprotection of N-pivaloylindoles, carbazoles and β-carbolines with LDA

Article abstract of DOI:10.1055/s-2004-836060

Treatment of variously substituted indoles with 2 equivalents of LDA at 40-45 °C led to their fast and efficient deprotection. This method was also extended to N-pivaloylcarbazoles and β-carbolines.

Full text of DOI:10.1055/s-2004-836060

LETTER
107
An Efficient Procedure for the Deprotection of N-Pivaloylindoles, Carbazoles
and b-Carbolines with LDA
Deprotectionof
N
a
-
Pivaloylin
r
doles
w
m
ith LDA en Avendaño, J. Domingo Sánchez, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
E-mail: josecm@farm.ucm.es
Received 27 September 2004
worked very well on a closely related cyclohexa[cd]in-
Abstract: Treatment of variously substituted indoles with 2 equiv-
dole system.5
alents of LDA at 40–45 °C led to their fast and efficient deprotec-
tion. This method was also extended to N-pivaloylcarbazoles and b-
carbolines.
Due to the potential advantages of the pivaloyl groups as
an indole protection, a general deprotection method of
Key words: protecting groups, pivalamides, lithium bases, indoles, pivalolyindoles is desirable, and we report here our find-
carbazoles
ings on the use of LDA to achieve this transformation.
During the course of our studies on the synthesis of
compounds related to the natural multi-drug resistance
The use of suitable protecting groups is a crucial issue in
indole chemistry because of the poor stability of indole
under a variety of conditions, especially acidic ones, and
also because N-protection allows, and often directs, the
inhibitor N-methylwelwitindolinone C isothiocyanate
(welwistatin, compound 1)6–8 we examined the alkylation
of tricyclic ketone 2a3,5 with allyl bromide in the presence
of LDA as a base at –78 °C, and the only observed product
lithiation of the heterocyclic nucleus. Due to the high
(together with unreacted starting material) was compound
basicity and nucleophilicity of the indole five-membered
ring, protection of the C2-3 bond can also be desirable in
2b, from depivaloylation of 2a (Figure 1).
some cases.
Cl
O
H2C
H3C
The most commonly employed indole N-protecting
groups are arylsufonyl derivatives (e.g. tosyl), carbamates
(e.g. Boc), trialkylsilyl groups (e.g. triisopropylsilyl),
N,O-acetals (e.g. SEM) and some alkyl groups (e.g. ben-
zyl).1 Protection of the indole C2-3 bond is normally car-
ried out by its reduction and subsequent re-oxidation.2a,b
Although more efficient methods based on the reversible
addition of 4-methyl-1,2,4-triazoline-3,5-dione to the in-
dole C2-3 bond are known, they require the use of a very
expensive starting material.2c
H
CH3
D
O
SCN
CH3
H
C
N
O
A
B
R
N
2a
2b
R = Piv
R = H
CH3
1
Figure 1
The above observation led us to consider the possibility of
employing LDA for the deprotection of pivaloylindoles.
After some experimentation, we found that treatment of
pivaloylindole itself with two equivalents of LDA in THF
at 40–45 °C for two hours led to its quantitative deprotec-
tion. In order to verify the generality of the method, sev-
eral variously substituted pivaloylindole derivatives were
prepared by generation of the anion of the suitable indole
derivative by treatment with sodium hydride, followed by
addition of pivaloyl chloride.9 The results obtained in the
reaction of these compounds with LDA under the same
conditions developed for the model are summarized in
Scheme 1 and Table 1.10
Pivaloyl would be a very interesting protecting group for
indole because, due to the steric hindrance that it imposes,
it protects both the N-1 and C-2 positions. For instance, it
has been used to direct intramolecular Friedel–Crafts acy-
lations of indole-3-propionic acid derivatives to C-4 rath-
er than to the electronically more favorable C-2.3
However, pivaloyl is notoriously difficult to remove, and
this factor has probably prevented its widespread use for
indole derivatives. Although its deprotection has occa-
sionally been achieved by use of alkoxides, the generality
of this method has not been established because it has
been studied only in a few specific cases, and the yields
found in the literature are very variable. For instance,
treatment of a N-pivaloylcyclohepta[cd]indole derivative
with sodium methoxide gave only 19% yield of the depro-
tected derivative,4 although similar conditions had
R4
R4
R5
R5
R3
R3
LDA, THF,
40–45 °C
R2
R2
N
N
H
4
R7
R7
Pv
3
SYNLETT 2005, No. 1, pp 0107–0110
0
5.
0
1.
2
0
0
5
Advanced online publication: 07.12.2004
DOI: 10.1055/s-2004-836060; Art ID: D29804ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Deprotection of N-pivaloylindoles with LDA

108
C. Avendaño et al.
LETTER
Table 1 Deprotection of N-Pivaloylindoles with LDA
Entry
1
R2
H
R3
R4
R5
R7
H
Reaction time (h) Product
Yield (%)
100
99
H
H
H
2
2
4a
4b
4c
4d
4d
4e
4f
2
H
CH3
H
H
H
3
H
CHO
H
H
H
2
99
4
H
H
H
H
CH3
CH3
H
2
55
5
H
H
H
H
40
2
93
6
H
H
CO2C2H5
H
89
7
H
H
H
H
H
H
H
H
CO2C2H5
H
2
93
8
H
H
OCH3
H
2
4g
4h
4i
92
9
H
CH2CH2CO2H
H
H
H
H
H
2
78
10
11
12
C6H5
C6H5
CH3
H
H
H
H
2
45
H
90
2
4i
92
H
4j
33
As shown there, the reactions carried out on a number of can be explained by assisted metallation of the methyl
indoles substituted at the 3-, 4-, 5- and 7-positions (entries side chain of the starting material to give the lithio deriv-
2–10) proceeded in excellent yields. A variety of func- ative 5 followed by intramolecular transfer of the pivaloyl
tional groups like aldehyde (entry 3), ester (entries 6 and group (Scheme 2). Intermolecular pivaloyl transfer could
7) and ether (entry 8) were tolerated without any notice- also in principle account for the isolation of 6 in this ex-
able decomposition, and a carboxylic group in a side chain periment, but this mechanism can be excluded because it
at C-3 caused only a slight decrease in yield (entry 9), in should lead to similar yields for compounds 4i and 6.
spite of its reactivity towards LDA. On the other hand, and Intermediates 5 can be considered as related to the 1-Boc-
because of steric interference, 2-substituted and 7-substi- 2-lithioindole species formed in the lithiation of N-Boc-
tuted indoles were less reactive and thus the reactions indoles where lithium is also coordinated to oxygen,
starting from 7-methyl-1-pivaloylindole (entries 4 and 5) although forming a five-membered ring.11
and 2-phenyl-1-pivaloylindole (entries 10 and 11) re-
After this study of the deprotection of pivaloylindoles, we
quired 40 hours and 90 hours to achieve completion, re-
briefly examined the possibility of extending this method-
spectively, although the yields were again excellent. In the
ology to more complex heterocyclic systems containing
indole subunits, among which we chose carbazole and b-
carboline because of their widespread natural occurrence
case of 2-methyl-1-pivaloylindole (entry 12), deprotec-
tion to 4i proceeded in low yield (33%) because in this
case it was accompanied by an interesting side reaction
and their relevant biological properties. As shown in
leading to 2-(pivaloylmethyl)indole (compound 6) as the
Table 2, treatment of N-pivaloylcarbazole 7 with LDA
under our standard conditions led to its deprotection in
major observed product (53% yield). The isolation of 6
93% yield to carbazole 8 (entry 1). A more complex N-
pivaloylated carbazole system containing a fused 2-pyri-
done ring and fluoro and methoxy substituents (com-
pound 9) was also efficiently deprotected to compound 10
(entry 2). Finally, the method was also succesfully applied
to N-pivaloyl-b-carboline (compound 11, entry 3), which
gave b-carboline 12 in 80% yield using our standard
reaction conditions.
H2O
LDA
CH3
CH3
CH3
N
N
H
N
Li
H3C
H3C
O
4i (33%)
CH3
LDA
Regarding the mechanism of the deprotection, direct
nucleophillic displacement by LDA seems unlikely. Al-
though LDA has been employed as a nucleophile for the
demethylation of alkyl aryl ethers,12 the experimental con-
ditions were considerably harsher than ours (sealed tube,
185 °C) and steric hindrance on the substrate was much
smaller than in our case. Another argument against a nu-
cleophillic attack by LDA is our inability to isolate the
H2O
N
H
N
CH3
CH3
CH3
Li
O
H3C
H3C
O
CH3
6 (53%)
5
Scheme 2
Synlett 2005, No. 1, 107–110 © Thieme Stuttgart · New York

LETTER
Deprotection of N-Pivaloylindoles with LDA
109
Table 2 Deprotection of N-Pivaloylcarbazoles and b-Carbolines
In conclusion, we have developed an efficient protocol
that allows the deprotection of a variety of N-pivaloylin-
doles and can also be extended to N-pivaloylcarbazoles
and N-pivaloyl-b-carbolines, generally in high to excel-
lent yields. This finding should facilitate the future use of
pivaloyl as a protecting group in indole chemistry, taking
advantage of the possibility that this group offers of
simultaneously protecting the N-1 and C-2 positions of
indole.
Entry Starting compound
Product
Yield
(%)
1
93
N
N
Piv
H
7
8
2
79
O
O
H3C
H3C
N
N
Acknowledgment
CH3
OCH3
CH3
OCH3
We thank CICYT for financial support of this research through
grants SAF 2000-0130 and SAF 2003-03141.
F
F
N
N
H
Piv
10
9
References
3
80
(1) (a) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg
Thieme Verlag: Stuttgart, 2004. (b) Greene, T. W.; Wuts, P.
G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley-Interscience: New York / Weinheim, 1999, 615–631.
(2) (a) He, F.; Snider, B. B. Synlett 1997, 483. (b) Yokoyama,
F.; Sugiyama, H.; Aoyama, T.; Shiori, T. Synthesis 2004,
1476. (c) Baran, P. S.; Guerrero, C. A.; Corey, E. J. Org.
Lett. 2003, 5, 1999.
N
N
N
H
N
Piv
11
12
other expected reaction product, namely N,N-diisopro-
pylpivalamide, from the reaction medium. Carbonyl re-
duction by hydride transfer from LDA has been described
in a number of cases involving a-halo and a-methoxyke-
tones,13 a-oxoesters14 and bis-(dialkylamino)chlorophos-
phines.15 These results were explained in terms of a
nitrogen analogue of the Meerwein–Pondorff–Verley re-
duction, as shown in Scheme 3 for the case of our sub-
strates. This is a reversible reaction, driven by the transfer
of negative charge from nitrogen to oxygen. Attempts to
characterize imine 13 thus generated by GC-MS have
been unsuccesful.15 In our case, an entropically favored
second step would also take place, where the tetrahedral
intermediate generated in the reduction would evolve to a
molecule of pivaldehyde and another of N-lithioindole.
The existence of this thermodynamically favored second
step can explain the chemoselectivity of the deprotection
reaction over the reduction of other potentially sensitive
functional groups (e.g. the aldehyde group in indole-3-
carbaldehyde, entry 3 of Table 1).
(3) Teranishi, K.; Hayashi, S.; Nakatsuka, S.; Goto, T.
Tetrahedron Lett. 1994, 35, 8173.
(4) Horwell, D. C.; McKiernan, M. J.; Osborne, S. Tetrahedron
Lett. 1998, 39, 8729.
(5) Teranishi, K.; Hayashi, S.; Nakatsuka, S.; Goto, T. Synthesis
1995, 506.
(6) (a) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J.
B.; Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T.
A. J. Am. Chem. Soc. 1994, 116, 9935. (b) Smith, C. D.;
Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.; Moore, R.
E. Mol. Pharmacol. 1995, 47, 241.
(7) For a review of synthetic work on welwitindolinones and
related areas, see: Avendaño, C.; Menéndez, J. C. Curr. Org.
Synth. 2004, 1, 65.
(8) For selected reviews on MDR modulators, see: (a) Wiese,
M.; Pajeva, I. K. Curr. Med. Chem. 2001, 8, 685.
(b) Teodori, E.; Dei, S.; Scapecchi, S.; Gualtieri, F. Il
Farmaco 2002, 57, 385. (c) Avendaño, C.; Menéndez, J. C.
Curr. Med. Chem. 2002, 9, 159. (d) Robert, J.; Jarry, C. J.
Med. Chem. 2003, 46, 4805. (e) Avendaño, C.; Menéndez,
J. C. Med. Chem. Rev. Online 2004, 1, 419.
(9) Representative Procedure for the N-Pivaloylation:
To a stirred suspension of NaH (409 mg, 17.08 mmol) in dry
THF (20 mL) was added a solution of indole-3-carbaldehyde
(1.230 g, 8.54 mmol) in dry THF (20 mL), under an argon
atmosphere. After stirring at r.t. for 5 min, hydrogen
evolution ceased and the solution became reddish yellow in
color. Pivaloyl chloride (1.05 mL, 1.03 g, 8.54 mmol) was
added and the reaction mixture was stirred at r.t. for 1 h.
After confirming by TLC the disappearance of the starting
indole, the reaction mixture was poured onto a sat. aq NH4Cl
solution (30 mL), which was then extracted with CH2Cl2
(5 × 30 mL). The combined organic layers were dried over
Na2SO4 and evaporated to yield 1-pivaloylindole-3-
carbaldehyde as a pale orange solid (1.79 g, 92%). Mp 93–
95 °C. IR: 1711, 1678, 1551, 1400 cm–1. 1H NMR (250
MHz, CDCl3): d = 10.32 (s, 1 H, CHO), 8.46 (d, 1 H, J = 7.8
Hz, H-7), 8.34 (s, 1 H, H-2), 8.28 (d, 1 H, J = 8.1 Hz, H-4),
7.47–7.40 (m, 2 H, H-5 and H-6), 1.58 [(s, 9 H, C(CH3)3]
ppm. 13C NMR (63 MHz, CDCl3): d = 185.8 (CHO), 177.2
CH3
R
CH3
CH3
H3C
N
13
N
O
CH3
H
Li
tBu
CH3
CH3
+
N
R
CH3
N
tBu
H
OLi
R
H
+
tBu
O
N
Li
Scheme 3
Synlett 2005, No. 1, 107–110 © Thieme Stuttgart · New York

110
C. Avendaño et al.
LETTER
(CO-t-Bu), 135.5 (C-7), 126.8 (C-4), 126.4 (C-7a), 125.3 (C-
2), 123.0 (C-3a), 122.0 (C-3), 121.6 (C-6), 117.6 (C-5), 38.6
[C(CH3)3], 28.43 [C(CH3)3] ppm. Anal. Calcd for
C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.04; H,
6.86; N, 6.03.
petroleum ether, yielding indole-3-carbaldehyde (627 mg,
99%), which was identical in all respects to the
commercially available sample employed as starting
material for the protection reaction.
(11) (a) Zhao, S.; Gan, T.; Yu, P.; Cook, J. M. Tetrahedron Lett.
1998, 39, 7009. (b) Zhao, S.; Smith, K. S.; Deveau, A. M.;
Dieckhaus, C. M.; Johnson, M. A.; Macdonald, T. L.; Cook,
J. M. J. Med. Chem. 2002, 45, 1559. (c) Selvi, S.; Pu, S.-C.;
Cheng, Y.-M.; Fang, J.-M.; Chou, P. T. J. Org. Chem. 2004,
69, 6674.
(12) Hwu, J. R.; Wong, F. F.; Huang, J. J.; Tsay, S. C. J. Org.
Chem. 1997, 62, 4097.
(13) (a) Kowalski, C.; Creary, X.; Rollin, A. J.; Burke, M. C. J.
Org. Chem. 1978, 43, 2601. (b) De Kimpe, N.; Palamareva,
M.; Schamp, N. J. Org. Chem. 1985, 50, 2993.
(10) Representative Procedure for the Deprotection:
A 1.6 M solution of butyllithium in hexanes (5.45 mL, 8.72
mmol) was added dropwise to a stirred solution of
diisopropylamine (880 mg, 8.72 mmol) in dry THF (20 mL),
at 0 °C, under an argon atmosphere. Stirring was continued
for 10 min at 0 °C, and the solution of LDA thus prepared
was added via cannula to a stirred solution of 1-pivaloyl-
indole-3-carbaldehyde (1 g, 4.36 mmol) in dry THF (20
mL), under an argon atmosphere at –78 °C. When the
addition was complete, the reaction mixture was heated in an
oil bath at 40–45 °C for 2 h, cooled and poured onto a sat. aq
NH4Cl solution (30 mL), which was then extracted with
CH2Cl2 (5 × 30 mL). The combined organic layers were
dried over Na2SO4 and evaporated, and the residue was
chromatographed on silica gel, eluting with 9:1 EtOAc–
(14) Hoare, J. H.; Yates, P. J. Org. Chem. 1983, 48, 3333.
(15) Baceiredo, A.; Bertrand, G.; Dyer, P. W.; Fawcett, J.; Griep-
Raming, N.; Guerret, O.; Hanton, M. J.; Russell, D. R.;
Williamson, A. M. New J. Chem. 2001, 25, 591.
Synlett 2005, No. 1, 107–110 © Thieme Stuttgart · New York