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Tetrahedron 68 (2012) 705e710

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Tetrahedron

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A systematic study of two complementary protocols allowing the general, mildand efficient deprotection of N-pivaloylindoles

Míriam Ruiz, J. Domingo S�anchez, Pilar L�opez-Alvarado, J. Carlos Men�endez *

Departamento de Química Org�anica y Farmac�eutica, Universidad Complutense, 28040 Madrid, Spain

a r t i c l e i n f o

Article history:Received 30 August 2011Received in revised form 25 October 2011Accepted 27 October 2011Available online 3 November 2011

Keywords:Protecting groupsIndoleChemoselectivityHydride transferHydrolysis

* Corresponding author. E-mail address: josecm@fa

0040-4020/$ e see front matter � 2011 Elsevier Ltd.doi:10.1016/j.tet.2011.10.098

a b s t r a c t

Two mild and general protocols for the high-yielding deprotection of indoles and related fused het-erocyclic systems are described, involving either hydride transfer from LDA or hydrolysis by theDBUewater system. Both methods were shown to tolerate a wide variety of substituents and functionalgroups, but the hydrolytic one proved to be particularly general, being compatible with 2-alkyl sub-stituents, aldehydes, ketones, carboxylic acids, halogens, ethers, amides and esters. Yields were normallyexcellent in both cases, but were usually slightly higher for the reductive method. Taken together, thesetwo protocols provide a general solution to the problem of pivaloyindole deprotection.

� 2011 Elsevier Ltd. All rights reserved.

1. Introduction

Indole is one of the most important heterocycles and is thestructural basis of one of the largest classes of alkaloids, comprisingmore than 4000 natural products. Indole substructures are alsopresent in a huge number of bioactive compounds, including manyestablished drugs. Indeed, indole is considered as a privileged struc-ture1 in drug discovery, since it can properly be described as ‘a singlemolecular framework able to provide ligands for diverse receptors.’2

Indole derivatives are often unstable, specially under acidicconditions. For this reason, protecting groups, specially at nitrogen,are a crucial feature of indole chemistry. Furthermore, N-protectionof indoles allows, and often directs, their lithiation. Due to the highbasicity and nucleophilicity of the indole five-membered ring,protection of the C2eC3 bond is also important in some cases. Themost common protecting groups for the indole nitrogen3 arearylsulfonyl derivatives, carbamates, trialkylsilyl groups (e.g., trii-sopropylsilyl), N,O-acetals (e.g., SEM) and some alkyl groups (e.g.,benzyl). Protection of the indole C2eC3 bond is normally carriedout by its reduction and subsequent re-oxidation4 or by the re-versible addition of 4-methyl-1,2,4-triazoline-3,5-dione to this in-dole bond, although the latter method is not practical as it requiresa very expensive starting material.5

Pivaloyl is potentially an excellent protecting group for indolebecause, besides acting as a nitrogen protection, it also blocks the C-2 position due to steric factors. For instance, a N-pivaloyl group has

rm.ucm.es (J.C. Men�endez).

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been used to direct intramolecular FriedeleCrafts acylations of in-dole-3-propionic acid derivatives to C-4 rather than to the elec-tronically more rich C-2.6 However, reliable removal of the pivaloylis normally difficult to achieve, and this has probably prevented itswidespread use for the protection of indole derivatives.7 Althoughpivaloylindole deprotection has occasionally been achieved by useof alkoxides,8 this method has been studied only in a few specificcases, and the yields found in the literature are variable. For in-stance, treatment of a N-pivaloylcyclohepta[cd]indole derivativewith sodium methoxide gave only 19% yield of the deprotectedderivative,9 although similar conditions had worked well ona closely related cyclohexa[cd]indole system.6 Other nucleophilicreagents that have been used for N-pivaloylindole deprotection aresodium borohydride,10 lithium hydroxide,11 methylamine12 andthiolates, either in solution13 or in polymer support,14 but againthese methods have only been studied for specific cases and thustheir generality has not been established.

In this context, we describe here the development of two mildand efficient methods for N-pivaloylindole deprotection that can beconsidered complementary because they have different scopes andinvolve two different deprotection mechanisms, namely hydridetransfer and hydrolysis.

2. Results and discussion

The work described here was carried out in the context of ourresearch on the synthesis of the tetracyclic core of the oxindolealkaloid N-methylwelwistatin,15,16 which at its initial stages

M. Ruiz et al. / Tetrahedron 68 (2012) 705e710706

involved an attempted allylation at �78 �C of a lithium enolate ofKornfeld’s ketone 1, generated using LDA as base. Interestingly, thisreaction did not afford the expected C-allyl derivative but gaveinstead a mixture of the starting material and small amounts of itsN-depivaloylation product 2, traditionally known as Uhle’s ketone.Forcing conditions (2 equiv LDA, 40 �C) were unable to completethe deprotection and gave 18% of 2 in the best case, although thereaction was difficult to reproduce (Scheme 1). When 4 equiv ofLDAwere employed at 40 �C, only decomposition products could beisolated.

Scheme 1. Reaction between Kornfeld’s ketone and LDA.

This result, although modest, encouraged us to study in moredetail the deprotection of N-pivaloylindoles by LDA.17 The synthesisof the starting materials required for this study was achieved bytreatment of the sodium or lithium anions of corresponding indoleswith pivaloyl chloride, and the results obtained in the LDA depro-tection are shown in the first part of Table 1 (method A). Thesereactions were routinely performed at 40e45 �C for 2 h using2 equiv of LDA, proceeded in excellent yields and were compatiblewith a number of functional groups, including aldehyde (entry 4),ether (entry 9), ester (entries 11 and 14) and carboxylic acid (entry6), although in the latter case there was a significant reduction inyield, probably due to the need to generate a dianion intermediate.These deprotections were quite sensitive to steric hindrance, andthus the starting materials substituted at either C-2 (entry 3) or C-7(entry 12) required much harsher conditions. The limitations of themethod were met in the reaction starting from 2-methylindole,which afforded only a moderate yield (33%) of the desired depro-tection product 4b because of the formation of compound 5 fromlateral lithiation of the methyl substituent assisted by the pivaloyloxygen, followed by intramolecular pivaloyl transfer.

Table 1Comparison of the reaction conditions and yields for the LDA and DBUeH2O-promoted

Entry Product R2 R3 R4 R5 R7 LDA,

Time

1 4a H H H H H 22 4b Me H H H H 23 4c Ph H H H H 2

904 4d H CHO H H H 25 4e H COMe H H H6 4f H (CH2)2CO2H H H H 27 4g H Me H H H 28 4h H H H Br H 29 4i H H H OMe H 210 4j H H H NHPiv H 211 4k H H H CO2Me H 212 4l H H H H Me 2

4013 4m H H Br H H 214 4n H H CO2Me H H 2

a The major product was compound 5, which was isolated in 53% yield.b Decomposition was observed.c This reaction was not attempted due to the side reaction observed during the prepa

The above-mentioned limitations of the LDA-promoted depro-tection were inherent to the use of a lithium base as reagent andprompted us to develop a deprotection method that relied ona different strategy. After some attempts, we discovered an efficientand reliable hydrolytic protocol involving the use of water and DBUin THF. The second and third parts of Table 1 summarize a com-parison of the results obtained using this method at room tem-perature (method B) and under reflux conditions (method C).Generally speaking, the milder room temperature conditions led tohigher yields with the exception of the reactions involving themore hindered substrates such as 2-phenylindole, which could onlybe deprotected under forcing conditions. The hydrolytic methodproved to bemore general than the LDA-promoted one and allowedthe efficient deprotection of compounds containing the sub-stituents that had previously been problematic such as 2-methyl-1-pivaloylindole (entry 2) and 3-acetyl-1-pivaloylindole (entry 5).Interestingly from the point of viewof the generality of themethod,several functional groups were well tolerated, including aldehyde(entry 4), ketone (entry 5), carboxylic acid (entry 6), halogen (en-tries 8 and 13) and ether (entry 9). It is also relevant to note that thedeprotection of pivaloylindoles containing some potentiallyhydrolysis-sensitive functions including amide (entry 10) and ester(entry 11) could be carried out with complete chemoselectivity. Asexpected, the reaction was sensitive to the electron density of theindole ring and was faster for compounds bearing electron-withdrawing substituents (entries 4, 5, 8, 11 and 13).

As shown in Table 2, these deprotection reactionswere extendedto other synthetically and biologically relevant indole-related fusedheterocycles. Thus, the deprotection of N-pivaloylcarbazole 6a was

deprotections of 1-pivaloylindoles

40e45 �C (method A) DBU, THFeH2O

rt (method B) Reflux (method C)

(h) Yield (%) Time (h) Yield (%) Time (h) Yield (%)

100 24 99 3 8833a 74 95 4 6045 96 2 24 339299 12 90 4 0b

c 5 93 1 8378 72 30 6 7499 120 89 24 6586 24 99 3 8292 72 97 18 9987 72 90 18 8793 18 89 3 8555 72 89 24 759383 18 93 3 9493 b b

ration of 4b.

Table 2Comparison of the reaction conditions and yields for the LDA and DBUeH2O-pro-moted deprotections of fused indole systems

Entry Starting compd Method A Method B Method C

140e45 �C, 2 h rt, 24 h Reflux, 3 h93% 91% 82%

2 a rt, 72 h Reflux, 5 h90% 88%

3

40e45 �C, 2 h rt, 24 h Reflux, 7 h18% 98% 87%

a Not attempted due to the poor results obtained with 2-methylindole usingmethod A.

Scheme 3. Mechanism proposed for the hydrolytic deprotections by the watereDBUsystem.

M. Ruiz et al. / Tetrahedron 68 (2012) 705e710 707

performed with similar results by any of the three methods (entry1). On the other hand, LDA was considered unsuitable for thedeprotection of N-pivaloyl-1,2,3,4-tetrahydrocarbazole 6b becauseof the previously mentioned side reaction observed with 2-methylindole, and hence this deprotection was carried out onlyunder the hydrolytic conditions, with excellent yields under bothconditions (entry 2). Finally, the deprotection of Kornfeld’s ketone 1to Uhle’s ketone 2, which had proceeded in a poor 18% yield in thepresence of LDA, was re-examined in the presence of theDBUewater system with excellent results (entry 3), underscoringthe complementary nature of both methods.

Mechanistically, the LDA-promoted deprotection can beexplained via hydride transfer, in a reaction that can be consideredas the nitrogen analogue of the MeerweinePondorffeVerley re-action and that has some precedent in the related reductions of a-halo and a-methoxyketones,18 a-oxoesters19 and bis-(dia-lkylamino)chlorophosphines.20 This is a reversible reaction, drivenby the transfer of negative charge from nitrogen to oxygen.21 In ourcase (Scheme 2), an entropically favoured second step involving theformation of a molecule of pivaldehyde and another of N-lith-ioindole is expected to take place, explaining the chemoselectivityof the deprotection reaction over the reversible reduction of otherfunctional groups (e.g., the aldehyde moiety in indole-3-carbaldehyde, entry 4 of Table 1).

Scheme 2. Plausible mechanistic rationalization of the deprotections with LDA andtheir chemoselectivity.

The hydrolytic deprotection presumably follows the mechanismsummarized in Scheme 3, where DBU deprotonates a molecule ofwater to generate a hydroxide anion, which behaves as a strongnucleophile in the non-solvating reaction medium. After additionof hydroxide to the pivaloyl carbonyl, the resulting tetrahedral in-termediate protonated by the DBU-Hþ species generated in theprevious step evolves to a molecule of pivalic acid and another ofdeprotected indole.

3. Conclusions

In conclusion, we describe two mechanistically complementaryprotocols that allow the mild and high-yielding deprotection ofindoles and related fused heterocyclic systems. Taken together,these methods provide a general solution for the problem of piv-aloyindole deprotection, which is hoped will stimulate the use bythe synthetic community of this very useful group, able to protectboth the N-1 and C-2 positions of indole.

4. Experimental section

4.1. General information

All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS,Scharlau) were of commercial quality and were used as received.Reactions were monitored by TLC on aluminium plates coated withsilica gel with fluorescent indicator (SDS CCM221254). Separationsby flash chromatography were performed on silica gel (SDS 60 ACC40e63 mm). Melting points were measured on a Reichert 723 hotstage microscope and are uncorrected. Infrared spectra wererecorded on a Perkin Elmer Paragon 1000 FTIR spectrophotometerwith all compounds examined as thin films on NaCl disks. NMRspectra were obtained on a Bruker Avance 250 spectrometer op-erating at 250 and 62.9 MHz for 1H and 13C NMR spectra, re-spectively (CAI de Resonancia Magn�etica Nuclear, UniversidadComplutense), with the signal of the residual non-deuterated sol-vent as an internal standard. Combustion elemental analyses weredetermined by the CAI de Microan�alisis Elemental, UniversidadComplutense, using a Leco 932 CHNS microanalyzer. Most startingindoles were commercially available. Compound 26 and 3-methyl-9-1,2,3,4-tetrahydrocarbazole 5b were prepared according to lit-erature methods.

4.2. Synthesis of N-pivaloylindoles. General procedures

Method A (BuLi as base): To a stirred solution of the startingindole in dry THF (5 mL�mmol) under an argon atmosphere at�78 �Cwas added a solution of BuLi 1.6 M in hexane (2 equiv). Afterstirring for 5 min, pivaloyl chloride (1 equiv) was added. The re-actionmixture was stirred for 15 min at�78 �C, followed by 15 minat �50 �C and 15 min at �20 �C. When the reaction finished, asjudged by TLC, it was poured onto saturated aqueous NH4Cl solu-tion (10 mL/mmol) and it was extracted with AcOEt (3�20 mL). The

M. Ruiz et al. / Tetrahedron 68 (2012) 705e710708

combined organic layers were dried over Na2SO4 and evaporated toyield the 1-pivaloylindole derivative.

Method B (NaH as base): To a stirred suspension of NaH (2 equiv)in dry THF (2.5 mL�mmol) was added a solution of indole in dryTHF (2.5 mL�mmol), under an argon atmosphere. After stirring atrt for 5 min, hydrogen evolution ceased and pivaloyl chloride(1 equiv) was added. The reaction mixture was stirred at rt for 1 h.After confirming by TLC the disappearance of the starting indole,the reaction mixture was poured onto saturated aqueous NH4Clsolution (10 mL/mmol), which was extracted with CH2Cl2(3�15 mL). The combined organic layers were dried over Na2SO4and evaporated to yield the 1-pivaloylindole derivative.

4.2.1. 1-Pivaloylindole (3a). Compound 3a was prepared in8.5 mmol scale usingmethod A. Yield: 1.6 g (95%), as white crystals.Mp 70e71 �C (lit.7 68e70 �C). Spectral data were identical to thosefound in the literature.7

4.2.2. 2-Methyl-1-pivaloylindole (3b). Compound 3b was preparedin 7.6 mmol scale using method A. Yield: 1.6 g (97%), as a colourlessoil. IR (NaCl) nmax: 1688 (C]O), 1448.7, 1322.4, 1184.6, 1064.2, 900.1,754.0 cm�1; 1H NMR (CDCl3, 250 MHz) d: 8.57 (dd, J¼7.9 and 0.7 Hz,1H, H-7); 7.54 (br s, 2H, H-2 and H-4); 7.42e7.29 (m, 2H, H-5 and H-6); 2.34 (s, 3H, CH3); 1.55 (s, 9H, C(CH3)3); 13C NMR (CDCl3, 63 MHz)d: 177.1 (CO); 137.5 (C-7a); 130.7 (C-3a); 125.6 (C-4); 123.6 (C-5);123.0 (C-6); 118.8 (C-2); 117.8 (C-7); 117.7 (C-3); 41.5 (C(CH3)3); 29.0(C(CH3)3); 10.2 (CH3). Anal. Calcd for: C14H17NO: C, 78.10; H, 7.96; N,6.51. Found: C, 78.35; H, 7.7; N, 6.57.

4.2.3. 2-Phenyl-1-pivaloylindole (3c). Compound 3c was preparedin 5.1 mmol scale using method B. Yield: 1.14 g (80%), as a yellowoil. Spectral data were identical to those found in the literature.7

4.2.4. 1-Pivaloylindole-3-carbaldehyde (3d). Compound 3d wasprepared in 8.5 mmol scale using method B. Yield: 1.72 g (92%), asa white solid. Mp 105e106 �C. IR (NaCl) nmax: 1674 (C]O) cm�1; 1HNMR (CDCl3, 250 MHz) d: 10.17 (s, 1H, CHO); 8.46 (dd, J¼6.8 and1.8 Hz, 1H, H-7); 8.37 (s,1H, H-2); 8.30 (dd, J¼6.8 and 1.8 Hz, 1H, H-4); 7.48 (td, J¼7.3 and 1.8 Hz,1H, H-6); 7.42 (td, J¼7.3 and 1.4 Hz,1H,H-5); 1.60 (s, 9H, C(CH3)3); 13C NMR (CDCl3, 63 MHz) d: 185.7(CHO); 177.1 (CO); 137.6 (C-7a); 135.5 (C-2); 126.8 (C-5); 125.2 (C-6); 125.0 (C-3a); 121.9 (C-3); 121.5 (C-4); 117.1 (C-7); 40.0 (C(CH3)3);28.6 (C(CH3)3). Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59;N 6.11.Found: C, 73.27; H, 6.68; N, 6.22.

4.2.5. 3-Acetyl-1-pivaloylindole (3e). Compound 3e was preparedin 2.7 mmol scale using method B. Yield: 0.63 g (95%), as a whitesolid. Mp 142e143 �C; IR (NaCl) nmax: 1656 (COCH3) cm�1; 1H NMR(CDCl3, 250 MHz) d: 8.39e8.35 (m, 1H, H-7); 8.26e8.23 (m, 1H, H-4); 8.25 (s, 1H, H-2); 7.33e7.29 (m, 2H, H-5 and H-6); 2.51 (s, 3H,COCH3); 1.49 (s, 9H, C(CH3)3); 13C NMR (CDCl3, 63 MHz) d: 193.6(COCH3); 177.1 (CON); 137.2 (C-7a); 131.4 (C-2);126.1 and 125.0 (C-5and C-6); 126.1 (C-3a); 121.9 (C-4); 121.0 (C-3); 116.8 (C-7); 41.5(C(CH3)3); 28.7 (C(CH3)3); 27.9 (COCH3). Anal. Calcd for C15H17NO2:C, 74.05; H, 7.04; N, 5.76. Found: C, 74.02; H, 7.02; N, 5.86.

4.2.6. 3-(10-Pivaloyl-3-indolyl)propionic acid (3f). Compound 3fwas prepared in 13.2 mmol scale using method A. Yield: 3.5 g(99%), as a white solid. Mp 124e126 �C (lit. 126e127 �C); IR (NaCl)nmax: 1689.5 (CO); 1707 (COOH) cm�1. 1H NMR (CDCl3, 250 MHz)d: 10.7 (br s, 1H, COOH), 8.52 (d, 1H, J¼8.2 Hz, H-70); 7.56 (s, 1H, H-20); 7.49 (d, 1H, J¼10.6 Hz, H-40); 7.36 (d, 1H, J¼7.8 Hz, H-60); 7.19(d, 1H, J¼8.3 Hz, H-50); 3.06 (t, 2H, J¼7.1 Hz, H-2); 3.09 (t, 2H,J¼7.1 Hz, H-3); 1.48 (s, 9H, C(CH3)3); 13C NMR (CDCl3, 63 MHz) d:179.4 (COOH); 177.2 (CO) 137.5 (C-70a); 129.4 (C-30a); 125.8 (C-40);123.8 (C-50); 123.1 (C-60); 120.1 (C-30); 118.6 (C-20); 118.0 (C-70);

41.5 (C(CH3)3); 33.9 (C-2) 29.0 (C(CH3)3); 20.4 (C-3). Anal. Calcdfor C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.04; H, 6.96;N, 5.16.

4.2.7. 3-Methyl-1-pivaloylindole (3g). Compound 3g was preparedin 3.8 mmol scale usingmethod A. Yield: 0.4 g (50%), as a colourlessoil. IR (NaCl) nmax: 1688 (C]O),1448.7, 1322.4, 1184.6, 1064.2, 900.1,754.0 cm�1; 1H NMR (CDCl3, 250 MHz) d: 8.57 (dd, J¼7.9 and 0.7 Hz,1H, H-7); 7.54 (br s, 2H, H-2 and H-4); 7.42e7.29 (m, 2H, H-5 and H-6); 2.34 (s, 3H, CH3); 1.55 (s, 9H, C(CH3)3); 13C NMR (CDCl3, 63 MHz)d: 177.1 (CO); 137.5 (C-7a); 130.7 (C-3a); 125.6 (C-4); 123.6 (C-5);123.0 (C-6); 118.8 (C-2); 117.8 (C-7); 117.7 (C-3); 41.5 (C(CH3)3); 29.0(C(CH3)3); 10.2 (CH3). Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N,6.51. Found: C, 78.35; H, 7.72; N, 6.57.

4.2.8. 5-Bromo-1-pivaloylindole (3h). Compound 3h was preparedin 2.5 mmol scale using method A. Yield: 0.7 g (97%), as pale brownsolid. Mp 134e135 �C; IR (NaCl) nmax: 1698.1 (CO) cm�1; 1H NMR(CDCl3, 250 MHz) d: 8.41 (d, J¼9 Hz,1H, H-7); 7.76 (d, J¼3.85 Hz,1H,H-2); 7.69 (d, J¼2 Hz, 1H, H-4); 7.45 (dd, J¼9 and 2 Hz, 1H, H-6);6.58 (d, J¼3.85 Hz, 1H, H-3); 1.53 (s, 9H, C(CH3)3); 13C NMR (CDCl3,63 MHz) d: 176.9 (CO); 135.3 (C-7a) 131.0 (C-3a); 127.7 (C-6); 126.6(C-2); 123.0 (C-4); 118.6 (C-7); 116.6 (C-5); 107.3 (C-3); 41.2(C(CH3)3); 28.5 (C(CH3)3). Anal. Calcd for C13H14BrNO: C, 55.73; H,5.04; N, 5.00. Found: C, 55.42; H, 5.37; N, 5.28.

4.2.9. 5-Methoxy-1-pivaloylindole (3i). Compound 3iwas preparedin 3.4 mmol scale using method A. Yield: 0.7 g (93%), as a whitesolid. Mp 98e101 �C (lit.7 99e100 �C). Spectral data were identicalto those found in the literature.7

4.2.10. N-(1-Pivaloylindol-5-yl)pivalamide (3j). Compound 3j wasprepared in 3.7 mmol scale using method A. Yield: 1 g (88%), asa pale orange solid. Mp 208e209 �C; IR (NaCl) nmax: 3336 (NH);1661 (2�CO) cm�1; 1H NMR (CDCl3, 250 MHz) d: 8.44 (d, J¼9 Hz,1H, H-7); 8.09 (d, J¼2.1 Hz,1H, H-4); 7.74 (d, J¼3.8 Hz,1H, H-3); 7.47(s, 1H, NH); 7.21 (dd, J¼9 and 2 Hz, 1H, H-6); 6.58 (d, J¼3.8 Hz, 1H,H-2); 1.53 (s, 9H, NCOC(CH3)3); 1.36 (s, 9H, NHCOC(CH3)3). 13C NMR(CDCl3, 63 MHz) d: 176.9 (NCO); 176.6 (NHCO); 133.8 (C-5) 133.4 (C-7a); 129.9 (C-3a); 126.3 (C-3); 117.7 (C-6); 117.4 (C-7); 111.9 (C-4);108.4 (C-2); 41.1 (NCOC(CH3)3); 39.5 (NHCOC(CH3)3); 28.6(NCOC(CH3)3); 27.6 (NHCOC(CH3)3). Anal. Calcd for C18H24N2O2: C,71.97; H, 8.05; N, 9.33. Found: C, 70.20; H, 7.93; N 9.21.

4.2.11. Methyl 1-pivaloylindol-5-ylcarboxylate (3k). Compound 3kwas prepared in 2.8 mmol scale using method A. Yield: 0.67 g(91%), as a pale brown solid. Mp 97e98 �C; IR (NaCl) nmax: 1714(COOCH3); 1653 (NCO) cm�1; 1H NMR (CDCl3, 250 MHz) d: 8.56 (d,J¼8.8 Hz, 1H, H-7); 8.30 (d, J¼1.5 Hz, 1H, H-4); 8.05 (dd, J¼8.9 and1.5 Hz, 1H, H-6); 7.82 (d, J¼3.8 Hz, 1H, H-2); 6.71 (d, J¼3.8 Hz, 1H,H-3); 3.96 (s, 3H, COOCH3); 1.54 (s, 9H, C(CH3)3); 13C NMR (CDCl3,63 MHz) d: 177.2 (CO); 167.9 (COO); 139.3 (C-7a) 129.1 (C-3a);126.8 (C-2); 126.3 (C-6); 125.3 (C-5); 122.7 (C-4); 116.9 (C-7);108.5 (C-3); 52.1 (COOCH3); 41.3 (C(CH3)3); 28.5 (C(CH3)3). Anal.Calcd. C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.02; H,6.71; N, 5.76.

4.2.12. 7-Methyl-1-pivaloylindole (3l). Compound 3l was preparedin 5.3 mmol scale using method A. Yield: 1.06 g (92%), as a whitesolid. Mp 55e56 �C (lit.,22 described as an oil); IR (NaCl) nmax: 1704(NCO) cm�1; 1H NMR (CDCl3, 250 MHz) d: 7.51 (d, J¼3.7 Hz, 1H, H-2); 7.51 (d, J¼7.5 Hz, 1H, H-4); 7.35 (t, J¼7.5 Hz, 1H, H-5); 7.19 (d,J¼7.5 Hz, 1H, H-6); 6.66 (d, J¼3.5 Hz,1H, H-3); 2.41 (s, 3H, CH3);1.59(s, 9H, C(CH3)3); 13C NMR (CDCl3, 63 MHz) d: 178.7 (CO); 136.6 (C-7a*); 130.6 (C-7); 127.1 (C-6); 125.7 (C-2); 125.5 (C-3a); 123.3 (C-5);118.4 (C-4); 107.2 (C-3); 41.9 (C(CH3)3); 28.1 (C(CH3)3); 21.4. (CH3).

M. Ruiz et al. / Tetrahedron 68 (2012) 705e710 709

Anal. Calcd. C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C, 78.04; H,7.66; N, 6.58.

4.2.13. 4-Bromo-1-pivaloylindole (3m). Compound 3m was pre-pared in 2.5 mmol scale using method A. Yield: 0.35 g (50%), asa white solid. Mp 65e66 �C (lit.,22 61e63 �C); IR (NaCl) nmax: 1701.4(CO); 1418 and 1305.4, 1173.6 (CeBr) cm�1; 1H NMR (CDCl3,250 MHz) d: 8.50 (d, J¼8.30 Hz,1H, H-7); 7.82 (d, J¼3.8 Hz,1H, H-2);7.75 (d, J¼7.7 Hz, 1H, H-5); 7.23 (t, J¼8 Hz, 1H, H-6); 6.73 (d,J¼3.8 Hz, 1H, H-3); 1.56 (s, 9H, C(CH3)3); 13C NMR (CDCl3, 63 MHz)d: 178.1 (CO); 138.1 (C-7a); 130.9 (C-3a); 127.4, 127.1 and 126.9 (C-2,C-6 and C-7); 117.2 (C-7); 115.3 (C-4); 108.9 (C-3); 42.3 (C(CH3)3);29.5 (C(CH3)3). Anal. Calcd. C13H14BrNO: C, 55.73; H, 5.04; N, 5.00.Found: C, 55.55; H, 4.96; N, 5.10.

4.2.14. 9-Pivaloylcarbazole (6a). Compound 6a was prepared in2.4 mmol scale usingmethod A. Yield: 0.58 g (98%), as awhite solid.IR (NaCl) nmax: 1691 (NCO) cm�1. Mp 244e245 �C; 1H NMR (CDCl3,250 MHz) d: 7.93 (d, J¼7.5 Hz, 2H, H-4 and H-5); 7.58 (d, J¼7.5 Hz,2H, H-1 and H-8); 7.35 (td, J¼7.5 and 1.3 Hz, 2H, H-2 and H-7); 7.22(td, J¼7.5 and 1.3 Hz, 2H, H-3 and H-6); 1.43 (s, 9H, C(CH3)3); 13CNMR (CDCl3, 63 MHz) d: 184.0 (CO); 139.1 (C-8a and C-8b); 126.3 (C-2 andC-7) 124.6 (C-4a andC-4b); 121.8 (C-3 andC-6); 120.0 (C-4 andC-5); 113.7 (C-1 and C-8); 43.6 (C(CH3)3); 28.3 (C(CH3)3). Anal. Calcd.C17H17NO: C, 81.24; H, 6.92; N, 5.57. Found. C, 77.06; H, 7.40; N, 8.69.

4.2 .15 . 3-Methyl-9-pivaloyl-1,2 ,3 ,4-tetrahydrocarbazole(6b). Compound 6b was prepared in 3.7 mmol scale using methodA. Yield: 0.86 g (85%), as an oil. IR (NaCl) nmax: 1701 (CO) cm�1; 1HNMR (CDCl3, 250 MHz) d: 7.47e7.40 (m, 2H, H-5 and H-8); 7.21 (td,J¼7.2 and 2.1 Hz, 1H, H-6); 7.17 (td, J¼7.2 and 1.6 Hz, 1H, H-7);2.89e2.66 (m, 3H, H-4, 2�H-1); 2.35e2.23 (m, 1H, H-4); 2.03e1.96(m, 2H, H-2 and H-3); 1.65e1.50 (m, 1H, H-2); 1.48 (s, 9H, C(CH3)3);1.18 (d, J¼6.5 Hz, 3H, CH3); 13C NMR (CDCl3, 63 MHz) d: 184.7 (CO);135.7 (C-8a); 135.6 (C-9a); 128.8 (C-4b); 122.0 (C-6); 120.9 (C-7);118.0 (C-5); 114.4 (C-4a); 112.8 (C-8); 43.4 (C(CH3)3); 31.5 (C-2); 29.3(C-4); 28.9 (C-3); 28.3 (C(CH3)3); 23.8 (C-1); 21.6 (CH3). Anal. Calcd.C18H23NO: C, 80.26; H, 8.61; N, 5.20. Found: C, 79.99; H, 8.33; N 5.16.

4.3. General procedures for the deprotection of N-pivaloylindoles

Method A: To 1.6 M solution of butyllithium in hexanes (2 equiv)was added dropwise a stirred solution of diisopropylamine(2 equiv) in dry THF (2 mL�mmol) at 0 �C, under an argon atmo-sphere. Stirring was continued for 10 min at 0 �C, and the solutionof LDA thus prepared was added via cannula to a stirred solution ofthe suitable 1-pivaloyl derivative (1 equiv) in THF (2 mL�mmol),under an argon atmosphere at �78 �C. When addition was com-plete, the reactionmixturewas heated in an oil bath at 40e45 �C for2 h, cooled and poured onto a saturated aqueous NH4Cl solution(30 mL), which was then extracted with CH2Cl2 (3�15 mL). Thecombined organic layers were dried over Na2SO4 and evaporated,and the residuewas chromatographed on silica gel, elutingwith 9:1EtOAcepetroleum ether. Evaporation of the mobile phase yieldedthe deprotected indole, which was identical in all respects to thecommercially available sample employed as starting material forthe protection reaction.

Method B: A mixture of DBU (4 equiv) and water (2 equiv) wasadded to a solution of the suitable 1-pivaloyl derivatives (1 equiv)in THF (3 mL�mmol) and was stirred at rt until the disappearanceof the starting indole. The reaction mixture was eluyed with EtOAc(10 mL) and was washed with a saturated aqueous NH4Cl solution(4 mL�mmol). The aqueous layer was extracted with EtOAc(2�15 mL). The combined organic layers were dried over Na2SO4

and evaporated to afford the corresponding unprotectedcompound.

Method C: DBU (4 equiv) and water (2 equiv) was added to a so-lution of 1-pivaloyl derivatives (1 equiv) in THF (3 mL�mmol) andwas stirred to reflux until the disappearance of the starting indole.The reaction mixture was eluyed with EtOAc (10 mL) and waswashedwith a saturated aqueousNH4Cl solution (4 mL�mmol). Theaqueous layer was extracted with EtOAc (2�15 mL). The combinedorganic layers were dried over Na2SO4 and evaporated to afford thecorresponding unprotected compound.

Indole derivatives thus obtained were commercial compounds,with the exception of compounds 2,13 4j23 and 5. Characterizationdata for the latter are given below.

4.3.1. 1-(1H-indol-2-yl)-3,3-dimethylbutan-2-one (5). Red solid. Mp55 �C; IR (NaCl) nmax: 3367.1 (NH), 1702.6 (CO) cm�1; 1H NMR(CDCl3, 250 MHz) d: 8.93(s, 1H, NH); 7.59 (d, J¼7.5 Hz,1H, H-7); 7.37(d, J¼8.1 Hz, 1H, H-4); 7.23e7.05 (m, 2H, H-5 and H-6); 6.35 (s, 1H,H-2); 4.02 (s, 2H, CH2); 1.27 (s, 9H, C(CH3)3); 13C NMR (CDCl3,63 MHz) d: 213.5 (CO); 136.8 (C); 132.4 (C); 128.5 (C); 121.9 (CH);120.3 (CH); 120.1 (CH); 11.3 (CH); 101.6 (CH); 45.4 (C(CH3)3); 35.9(CH2); 26.5 (C(CH3)3). Anal. Calcd for: C14H17NO: C, 78.10; H, 7.96; N,6.51. Found: C, 78.34; H, 7.80; N, 6.51.

Acknowledgements

We thank MEC (grant CTQ2009-12320-BQU) and UCM (Gruposde Investigaci�on Consolidados, grant GR35/10-A-920234) for fi-nancial support. A predoctoral fellowship from UCM to M.R. is alsogratefully acknowledged.

Supplementary data

Supplementary data associated with this article can be found inthe online version, at doi:10.1016/j.tet.2011.10.098. These data in-clude MOL files and InChiKeys of the most important compoundsdescribed in this article.

References and notes

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