Research Article Iodine-Mediated Neutral and …downloads.hindawi.com/journals/jchem/2013/916960.pdfResearch Article Iodine-Mediated Neutral and Selective N -Boc Deprotection G.PavanKumar,

Hindawi Publishing CorporationJournal of ChemistryVolume 2013 Article ID 916960 5 pageshttpdxdoiorg1011552013916960

Research ArticleIodine-Mediated Neutral and Selective N-Boc Deprotection

G Pavan Kumar1 D Rambabu2 M V Basaveswara Rao3 and Manojit Pal2

1 Department of Chemistry Acharya Nagarjuna University Guntur Andhra Pradesh 522510 India2Dr Reddyrsquos Institute of Life Science University of Hyderabad Campus Hyderabad 500046 India3 Department of Chemistry Krishna University Machilipatnam Andhra Pradesh 521001 India

Correspondence should be addressed to Manojit Pal manojitpalrediffmailcom

Received 6 May 2013 Accepted 17 June 2013

Academic Editor Hakan Arslan

Copyright copy 2013 G Pavan Kumar et alThis is an open access article distributed under theCreativeCommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A simple efficient and alternative method has been developed for theN-Boc deprotection of structurally diverse protected aminesSelective removal of N-Boc groups was achieved with excellent yields under a solvent-free condition or in a solvent using iodineas a catalyst The methodology involving the first use of iodine for N-Boc deprotection of protected amines represents an effectiveand useful alternative to the previously reported methods

1 Introduction

Amine is one of the commonly used functionalities in syn-thetic organic chemistry and its protection in the form ofan N-tert-butoxycarbonyl (N-Boc) derivative has become aregular strategy in the synthesis of complex natural productspeptides or small organic molecules [1] The key advantagesof Boc group include its ease of installation and stabilitytowards various nucleophiles including strong basic con-ditions in a number of chemical transformations [2ndash4]Traditional methods for Boc-protection involve the reactionof amines with di-tert-butyl dicarbonate (Boc)

2O in the

presence of 4-(NN-dimethylamino) pyridine (DMAP) [5] orinorganic bases [6] Several strategies have been developedfor the N-Boc deprotection earlier A variety of reagentshave been employed to effect this transformation includingstrong acids Lewis acids and neutral conditions assistedby microware Thus N-Boc deprotection has been carriedout successfully using mild acidic conditions [7] such as tri-fluoroacetic acid (TFA) HCl H

2SO4 aqueous phosphoric

acid [8] or Lewis acids such as BF3sdotOEt2 TMSI TMSOTf

TiCl4 SnCl

4 AlCl

3 Sn(OTf)

2 and ZnBr

2[9] The use of

montmorillonite K10 clay catalyst [10] and silica gel [11] orthermolytic conditions at high temperature [12 13] have alsoshown to work Cleavage of the Boc group can be achievedin some cases under basic conditions where the amine isactivated such as pyrroles [14ndash16] Microware-assisted N-Boc deprotection under mild conditions using K

3PO4sdotH2O

in CH3OH has been reported [17] A catalyst-free N-Boc

deprotection has been reported in subcritical water underpressure [18] Recently severalN-Boc derivatives of aromaticamines and amino acids were deprotected in boiling water[19] While many of these methods are quite elegant andeffective a few number of them however suffer from draw-backs such as (i) longer reaction time (ii) high temperature(iii) low yield of products and (iv) the use of expensivecatalysts Moreover preparation of some of the catalystsrequires cumbersome procedures As an inexpensive andreadily available reagent iodine has attracted considerableinterest due to its less hazardous nature and efficiency invarious organic transformations [20] Herein we report ourpreliminary results of newly found iodine-mediated N-Bocdeprotection of various protected amines under a mild andsolvent-free condition

2 Experimental

21 GeneralMethod for N-BocDeprotection of 1 Amixture ofN-Boc protected amine 1 (10mmol) and iodine (008mmol)was grinded in a mortar for the time indicated in Table 2After completion of the reaction (indicated by TLC) themixture was diluted with CH

2Cl2(10mL) and washed with

saturated aqueous solution of sodium thiosulphate (2times 5mL)and then with saturated aqueous solution of NaCl (2 times5mL) The organic layer was collected dried over anhydrousNa2SO4 and filtered and concentrated under low vacuum

2 Journal of Chemistry

Table 1 Effect of solvents on iodine-mediated de-N-tert-butoxy-carbonylation of N-Boc-aniline (1a)a

HN

O

O

I2rt solvent

NH2

1a 2a

Entry Solvent Time Yieldb ()1 DCM 5h 942 CH3CN 6h 923 Benzene 9 h 884 Toluene 12 h 825 No solvent 30min 98aAll the reactions were carried out using the tert-butyl phenylcarbamate (1a10mmol) and iodine (008mmol) at room temperaturebIsolated yield

The residuewas purified by column chromatography to affordthe pure products 2andasho

3 Results and Discussion

In our initial study tert-butyl phenylcarbamate (1a) wasreacted with 8mol of iodine at room temperature in arange of organic solvents separately Results of this studyare summarized in Table 1 A number of solvents suchas DCM CH

3CN benzene and toluene were examined

(Table 1 entries 1ndash4) when the deprotected aniline (2a) wasisolated in good yield

While the duration of the reaction was 5ndash12 h in all thesecases in the absence of a solvent the reaction was completedwithin 30min affording the desired product in 98 yield(Table 1 entry 5)These observations encouraged us to exam-ine the generality and scope of this method Accordinglya variety of aliphatic and aromatic N-tert butylcarbamates(2) were treated with iodine under a solvent free conditionwhen the corresponding amine (1) was isolated in good yield(Table 2) A variety of aryl (entries 1ndash9 Table 2) heteroaryl(entries 11ndash14 Table 2) and aliphatic amines (entries 10 and15 Table 2) were deprotected following this methodologyWe have also examined all these reactions in DCM andthe desired amines were isolated in good yields (Table 2)Notably the present iodine-mediated N-Boc deprotectionwas found to be a slower process than the iodine-mediatedN-Boc protection [21] perhaps due to the higher stability ofthe N-tert butylcarbamate moiety of 2 than the ndashOCOOtBugroup of Boc

2O towards elemental iodine

A plausible mechanism for iodine catalyzed N-depro-tection of 1 is presented in Scheme 2The reaction seemed toproceed via activation of the carbonyl oxygen of 1 by iodineleading to E-1 which underwent the sequential cleavageof several bonds such as CndashH CndashO and CndashN bond Theinteraction of molecular iodine with carbonyl oxygen hasbeen described in the literature earlier [21 22] For example

N

O

O

21

rt 30ndash240 min(no solvent)

R

R998400

NR

R998400

HI2

Scheme 1 Iodine-mediated N-Boc deprotection of amines undersolvent-free conditions

1I2 X

X

HN

HN

O

O

O

O

CH3

CH3

CH3

CH3

I+

I+

Iminus

Iminus

HCH2

H3C

I2 + CO2

2

E-1

+ CH2=C(CH3)2

Scheme 2 Proposed mechanism for iodine catalyzedN-Boc depro-tection of 1

nucleophilic addition of indole to a carbonyl compound wascatalyzed efficiently by molecular iodine [23] It was sug-gested that a halogen bond [defined as intermolecular non-covalent interaction between halogen atom and electron-donor atom such as O or N (similar to hydrogen bond)] [24]between the carbonyl oxygen and iodine molecule plays akey role in the catalytic effect of iodine observed in thesereactions [25] Nevertheless the cleavage of CndashH of the tBugroup perhaps was facilitated by the iodine coordinated withthe carbonyl oxygen As a result the catalyst iodine wasregenerated along with the extrusion of carbon dioxide and2-methylpropene affording the desired amine 2

4 Conclusions

In conclusion we have developed a simple efficient andalternativemethod for theN-Boc deprotection of structurallydiverse protected amines The selective removal of N-Bocgroups was achieved with excellent yields under a solventfree condition using iodine as a catalyst To the best of ourknowledge this is the first example of N-Boc deprotection ofprotected amines catalyzed by elemental iodine The presentdeprotection methodology has potential to become an effec-tive and useful alternative to the previously reportedmethodsand may find applications in protecting group chemistry

Acknowledgments

The authors thank the management of Acharya NagarjunaUniversity andDr Reddyrsquos Institute of Life Science for contin-uous encouragement and support

Journal of Chemistry 3

Table 2 Iodine-mediated deprotection of N-tert butylcarbamates (1) (Scheme 1)

Entry N-tert butylcarbamates (1) Time (min) Producta (2) Yieldb () Yieldc () DCM solvent

1

NHBoc

1a 30

NH2

2a 98 94

2 1b

NHBoc

F50

NH2

2bF

90 82

3 1c

NHBoc

Cl90

NH2

2cCl

92 80

4 1d

NHBoc

Br120

NH2

2dBr

90 80

5 1e

NHBoc

CH3

90

NH2

2eCH3

82 80

6 1f

NHBoc

OH120

NH2

2fOH

90 85

7

NHBoc

1g

OH

H3C150

NH2

2g

OH

H3C86 80


Table 2 Continued


8

NHBoc

1hOCH3

60

NH2

2hOCH3

92 85

9

NHBoc

1iNO2

120

NH2

2iNO2

90 85

10

NHBoc

1j 90

NH2

2j 82 78

11

NBoc

1k 100

NH

2k 85 80

12

NBoc

1l

CHO

150

NH

2l

CHO

82 76

13

NBoc

1m

O

180

NH

2m

O

80 72

14

NBoc

1n

COOEt

240

NH

2n

COOEt

86 80

15

NBoc1o

O

120

NH2o

O

84 78aAll the reactions were carried out using the N-tert butylcarbamate 1 (10mmol) and iodine (008mmol) at room temperature

bIsolated yieldcAll the reactions were carried out using DCM (5mL) at room temperature for 5-6 h

References[1] G Sartori R Ballini F Bigi G Bosica R Maggi and P Righi

ldquoProtection (and deprotection) of functional groups in organicsynthesis by heterogeneous catalysisrdquo Chemical Reviews vol104 no 1 pp 199ndash250 2004

[2] E Gross and JMeienhoferThePeptides vol 3 Academic PressNew York NY USA 1981

[3] P J Kocienski Protecting Groups vol 185 chapter 6 Thieme-Stuttgart 1994

[4] G Theodoridis ldquoNitrogen protecting groups recent develop-ments and new applicationsrdquo Tetrahedron vol 56 no 16 pp2339ndash2358 2000

[5] Y Basel andAHassner ldquoDi-tert-butyl dicarbonate and 4-(dim-ethylamino)pyridine revisited Their reactions with amines


and alcoholsrdquo Journal of Organic Chemistry vol 65 no 20 pp6368ndash6380 2000

[6] S T Handy J J Sabatini Y Zhang and I Vulfova ldquoProtectionof poorly nucleophilic pyrrolesrdquoTetrahedron Letters vol 45 no26 pp 5057ndash5060 2004

[7] P G M Wuts and T W Greene Greenersquos Protective Group inOrganic Synthesis JohnWily and Sons NewYork NY USA 4thedition 2007

[8] B Li R Bemish R A Buzon et al ldquoAqueous phosphoric acid asa mild reagent for deprotection of the t-butoxycarbonyl grouprdquoTetrahedron Letters vol 44 no 44 pp 8113ndash8115 2003

[9] D S Bose K K Kumar and A V N Reddy ldquoA new protocolfor selective deprotection of N-tert-butoxycarbonyl protectivegroup (t-Boc) with Sn(OTf)

2rdquo Synthetic Communications vol

33 no 3 pp 445ndash450 2003[10] N S Shaikh A S Gajare V H Deshpande and A V Bedekar

ldquoAmild procedure for the clay catalyzed selective removal of thetert- butoxycarbonyl protecting group from aromatic aminesrdquoTetrahedron Letters vol 41 no 3 pp 385ndash387 2000

[11] T Apelqvist and D Wensbo ldquoSelective removal of the N-Bocprotective group using silica gel at low pressurerdquo TetrahedronLetters vol 37 no 9 pp 1471ndash1472 1996

[12] V H Rawal R J Jones and M P Cava ldquoPhotocyclizationstrategy for the synthesis of antitumor agent CC-1065 synthesisof dideoxy PDE-I and PDE-II Synthesis of thiophene and furananalogues of dideoxy PDE-I and PDE-IIrdquo Journal of OrganicChemistry vol 52 no 1 pp 19ndash28 1987

[13] K Nadia B Malika K Nawel B MedYazid R Zine and N-EAouf ldquoSimple and efficient cleavage reaction of the Boc groupin heterocyclic compoundsrdquo Journal of Heterocyclic Chemistryvol 41 no 1 pp 57ndash60 2004

[14] I Hasan E R Marinelli L-C C Lin F W Fowler and AB Levy ldquoSynthesis and reactions of N-protected 2-lithiatedpyrroles and indoles The tert-butoxycarbonyl substituent as aprotecting grouprdquo Journal of Organic Chemistry vol 46 no 1pp 157ndash164 1981

[15] S El Kazzouli J Koubachi S Berteina-Raboin A Mouaddiband G Guillaumet ldquoAmild and selective method for the N-Bocdeprotection by sodium carbonaterdquo Tetrahedron Letters vol 47no 48 pp 8575ndash8577 2006

[16] N J Tom W M Simon H N Frost and M EwingldquoDeprotection of a primary Boc group under basic conditionsrdquoTetrahedron Letters vol 45 no 5 pp 905ndash906 2004

[17] S R Dandepally and A L Williams ldquoMicrowave-assistedN-Boc deprotection under mild basic conditions usingK3PO4sdotH2O in MeOHrdquo Tetrahedron Letters vol 50 no 9 pp

1071ndash1074 2009[18] GWang C Li J Li and X S Jia ldquoCatalyst-free water-mediated

N-Boc deprotectionrdquo Tetrahedron Letters vol 50 no 13 pp1438ndash1440 2009

[19] JWang Y-L Liang and J Qu ldquoBoiling water-catalyzed neutraland selective N-Boc deprotectionrdquo Chemical Communicationsno 34 pp 5144ndash5146 2009

[20] J S Yadav B V Subba Reddy K Premalatha and T SwamyldquoFirst example of the activation of polymethylhydrosiloxanewith molecular iodine a facile synthesis of 36-dihydropyranderivativesrdquo Tetrahedron Letters vol 46 no 15 pp 2687ndash26902005

[21] R Varala S Nuvula and S R Adapa ldquoMolecular iodine-cata-lyzed facile procedure for N-Boc protection of aminesrdquo Journalof Organic Chemistry vol 71 no 21 pp 8283ndash8286 2006

[22] Y-H Wang L Li and X-S Chen ldquoTheoretical studies on theiodine-catalyzed nucleophilic addition of acetone with five-membered heterocyclesrdquo Chemical Research in Chinese Univer-sities vol 24 no 4 pp 520ndash524 2008

[23] B P Bandgar and K A Shaikh ldquoMolecular iodine-catalyzedefficient and highly rapid synthesis of bis(indolyl)methanesunder mild conditionsrdquo Tetrahedron Letters vol 44 no 9 pp1959ndash1961 2003

[24] A C Legon ldquoPrereactive complexes of dihalogens XY withLewis bases B in the gas phase a systematic case for the halogenanalogue Bsdot sdot sdotXY of the hydrogen bond Bsdot sdot sdotHXrdquo AngewandteChemie vol 38 no 18 pp 2686ndash2714 1999

[25] G R Desiraju and R L Harlow ldquoCyano-halogen interactionsand their role in the crystal structures of the 4-halobenzoni-trilesrdquo Journal of the American Chemical Society vol 111 no 17pp 6757ndash6764 1989

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


Table 1 Effect of solvents on iodine-mediated de-N-tert-butoxy-carbonylation of N-Boc-aniline (1a)a

HN

O

O

I2rt solvent

NH2

1a 2a

Entry Solvent Time Yieldb ()1 DCM 5h 942 CH3CN 6h 923 Benzene 9 h 884 Toluene 12 h 825 No solvent 30min 98aAll the reactions were carried out using the tert-butyl phenylcarbamate (1a10mmol) and iodine (008mmol) at room temperaturebIsolated yield

The residuewas purified by column chromatography to affordthe pure products 2andasho

3 Results and Discussion

In our initial study tert-butyl phenylcarbamate (1a) wasreacted with 8mol of iodine at room temperature in arange of organic solvents separately Results of this studyare summarized in Table 1 A number of solvents suchas DCM CH

3CN benzene and toluene were examined

(Table 1 entries 1ndash4) when the deprotected aniline (2a) wasisolated in good yield

While the duration of the reaction was 5ndash12 h in all thesecases in the absence of a solvent the reaction was completedwithin 30min affording the desired product in 98 yield(Table 1 entry 5)These observations encouraged us to exam-ine the generality and scope of this method Accordinglya variety of aliphatic and aromatic N-tert butylcarbamates(2) were treated with iodine under a solvent free conditionwhen the corresponding amine (1) was isolated in good yield(Table 2) A variety of aryl (entries 1ndash9 Table 2) heteroaryl(entries 11ndash14 Table 2) and aliphatic amines (entries 10 and15 Table 2) were deprotected following this methodologyWe have also examined all these reactions in DCM andthe desired amines were isolated in good yields (Table 2)Notably the present iodine-mediated N-Boc deprotectionwas found to be a slower process than the iodine-mediatedN-Boc protection [21] perhaps due to the higher stability ofthe N-tert butylcarbamate moiety of 2 than the ndashOCOOtBugroup of Boc

2O towards elemental iodine

A plausible mechanism for iodine catalyzed N-depro-tection of 1 is presented in Scheme 2The reaction seemed toproceed via activation of the carbonyl oxygen of 1 by iodineleading to E-1 which underwent the sequential cleavageof several bonds such as CndashH CndashO and CndashN bond Theinteraction of molecular iodine with carbonyl oxygen hasbeen described in the literature earlier [21 22] For example

N

O

O

21

rt 30ndash240 min(no solvent)

R

R998400

NR

R998400

HI2

Scheme 1 Iodine-mediated N-Boc deprotection of amines undersolvent-free conditions

1I2 X

X

HN

HN

O

O

O

O

CH3

CH3

CH3

CH3

I+

I+

Iminus

Iminus

HCH2

H3C

I2 + CO2

2

E-1

+ CH2=C(CH3)2

Scheme 2 Proposed mechanism for iodine catalyzedN-Boc depro-tection of 1

nucleophilic addition of indole to a carbonyl compound wascatalyzed efficiently by molecular iodine [23] It was sug-gested that a halogen bond [defined as intermolecular non-covalent interaction between halogen atom and electron-donor atom such as O or N (similar to hydrogen bond)] [24]between the carbonyl oxygen and iodine molecule plays akey role in the catalytic effect of iodine observed in thesereactions [25] Nevertheless the cleavage of CndashH of the tBugroup perhaps was facilitated by the iodine coordinated withthe carbonyl oxygen As a result the catalyst iodine wasregenerated along with the extrusion of carbon dioxide and2-methylpropene affording the desired amine 2

4 Conclusions

In conclusion we have developed a simple efficient andalternativemethod for theN-Boc deprotection of structurallydiverse protected amines The selective removal of N-Bocgroups was achieved with excellent yields under a solventfree condition using iodine as a catalyst To the best of ourknowledge this is the first example of N-Boc deprotection ofprotected amines catalyzed by elemental iodine The presentdeprotection methodology has potential to become an effec-tive and useful alternative to the previously reportedmethodsand may find applications in protecting group chemistry

Acknowledgments

The authors thank the management of Acharya NagarjunaUniversity andDr Reddyrsquos Institute of Life Science for contin-uous encouragement and support




1

NHBoc

1a 30

NH2

2a 98 94

2 1b

NHBoc

F50

NH2

2bF

90 82

3 1c

NHBoc

Cl90

NH2

2cCl

92 80

4 1d

NHBoc

Br120

NH2

2dBr

90 80

5 1e

NHBoc

CH3

90

NH2

2eCH3

82 80

6 1f

NHBoc

OH120

NH2

2fOH

90 85

7

NHBoc

1g

OH

H3C150

NH2

2g

OH

H3C86 80


Table 2 Continued


8

NHBoc

1hOCH3

60

NH2

2hOCH3

92 85

9

NHBoc

1iNO2

120

NH2

2iNO2

90 85

10

NHBoc

1j 90

NH2

2j 82 78

11

NBoc

1k 100

NH

2k 85 80

12

NBoc

1l

CHO

150

NH

2l

CHO

82 76

13

NBoc

1m

O

180

NH

2m

O

80 72

14

NBoc

1n

COOEt

240

NH

2n

COOEt

86 80

15

NBoc1o

O

120

NH2o

O











































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




1

NHBoc

1a 30

NH2

2a 98 94

2 1b

NHBoc

F50

NH2

2bF

90 82

3 1c

NHBoc

Cl90

NH2

2cCl

92 80

4 1d

NHBoc

Br120

NH2

2dBr

90 80

5 1e

NHBoc

CH3

90

NH2

2eCH3

82 80

6 1f

NHBoc

OH120

NH2

2fOH

90 85

7

NHBoc

1g

OH

H3C150

NH2

2g

OH

H3C86 80


Table 2 Continued


8

NHBoc

1hOCH3

60

NH2

2hOCH3

92 85

9

NHBoc

1iNO2

120

NH2

2iNO2

90 85

10

NHBoc

1j 90

NH2

2j 82 78

11

NBoc

1k 100

NH

2k 85 80

12

NBoc

1l

CHO

150

NH

2l

CHO

82 76

13

NBoc

1m

O

180

NH

2m

O

80 72

14

NBoc

1n

COOEt

240

NH

2n

COOEt

86 80

15

NBoc1o

O

120

NH2o

O











































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table 2 Continued


8

NHBoc

1hOCH3

60

NH2

2hOCH3

92 85

9

NHBoc

1iNO2

120

NH2

2iNO2

90 85

10

NHBoc

1j 90

NH2

2j 82 78

11

NBoc

1k 100

NH

2k 85 80

12

NBoc

1l

CHO

150

NH

2l

CHO

82 76

13

NBoc

1m

O

180

NH

2m

O

80 72

14

NBoc

1n

COOEt

240

NH

2n

COOEt

86 80

15

NBoc1o

O

120

NH2o

O











































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Research Article Iodine-Mediated Neutral and …downloads.hindawi.com/journals/jchem/2013/916960.pdfResearch Article Iodine-Mediated Neutral and Selective N -Boc Deprotection G.PavanKumar,