An efficient electrophilic N-amination utilizing in situ generated
chloramine under phase transfer conditions
Apurba Bhattacharya,a,*Nitin C.Patel,a Robert Erik Plata,a Michael Peddicord,b Qingmei Ye,b Luca Parlanti,b Venkatapuram A.Palaniswamy b and John A.Grosso b
a
Department of Chemistry,Texas A&M University-Kingsville,Kingsville,TX 78363,United States
b
Bristol-Myers Squibb Company,Process Research and Development Department,PO Box 191,New Brunswick,
NJ 08903-0191,United States
Received 22December 2005;accepted 18May 2006
Available online 13June 2006
Abstract—An efficient,one-pot,phase transfer N-amination technology was developed.The protocol utilizes chloramine,an inex-pensive and safe electrophilic aminating agent potentially viable for commercial manufacturing.Ó2006Elsevier Ltd.All rights reserved.
As part of our ongoing industry-university collaborative research program established between Texas A&M Uni-versity-Kingsville and Bristol-Myers Squibb Co.,we needed an expeditious entry into a diverse spectrum of N-aminated pyrroles.1Although a number of electro-philic amination methodologies are well known,their utility is often limited by poor yields,prohibitive costs,and serious safety issues,making them unsuitable for large scale application.2An alternative N-amination of pyrroles and indoles utilizing chloramine (NH 2Cl)was recently reported by researchers at Bristol-Myers Squibb.3This N-amination protocol involves initial gen-eration of NH 2Cl from aqueous NH 4OH,NH 4Cl and bleach,followed by extraction of NH 2Cl with methyl tert -butyl ether (MTBE)from the aqueous mixture.The chloramine solution is dried with anhydrous CaCl 2and then reacted in a separate vessel with the pyrrole an-ion generated from NaH in DMF,to produce the corre-sponding N-aminated pyrroles.While this technology was invaluable during our early development efforts and provided us with multi-gram supplies of N-amino-pyrroles,we sought improvements that would allow for greater safety,efficiency and operational simplicity.In the above procedure,because of the high solu
bility of chloramine in water and its limited solubility in MTBE (0.09M),large solvent volumes are required for efficient,extractive removal of chloramine from the
aqueous reaction mixture.4This reduces the overall reaction throughput.In addition,chloramine is not suf-ficiently stable for storage.On standing,chloramine dis-proportionates to NHCl 2and NCl 3,a shock-sensitive compound constituting a potential safety concern.5Devising a technology where chloramine would be instantaneously consumed as soon as it is generated could potentially circumvent these problems by avoiding any undesirable accumulation during the process.Based on this premise,we devised a cost effective and practical one-pot,two phase (H 2O–MTBE)N-amination proto-col.The process can be accomplished in good yields and efficiency and offers significant advantages over the existing technologies in terms of throughput,safety,and operational simplicity.
In the optimal procedure,chloramine is generated in the aqueous layer through oxidation of ammonia by NaOCl.At the same time,the substrate is deprotonated in the organic phase with the aid of a small amount of Aliquat-336(methyltrioctylammonium chloride)and promptly reacts with the small portion of chloramine present in the organic layer,affording the desired N–NH 2derivative in high yield.An excess of base (aq NaOH)is necessary to efficiently achieve the pyrrole deprotonation.After reaction completion,the organic layer is separated and can be utilized directly in the next step without further pu
rification (Scheme 1).
This process avoids accumulation of unreacted chlor-amine at any given time,thereby rendering this approach
0040-4039/$-see front matter Ó2006Elsevier Ltd.All rights reserved.doi:10.let.2006.05.102
*Corresponding author.Tel.:+13615932664;fax:+13615933597;e-mail:
kfab002@tamuk.edu
Tetrahedron Letters 47(2006)
5341–5343
safe and viable for on-scale implementation.As opposed to the previously published chloramine N-amination protocol,this new procedure does not require the prepa-ration of the pyrrole anion under anhydrous conditions in a separate vessel or the drying of the diluted organic chloramine solution after the extractions.The low solu-bility of chloramine in organic solvents is no longer a limiting factor to the reaction throughput.The presence of the quaternary ammonium salt,Aliquat-336,is imper-ative;reactions conducted without Aliquat-336showed only trace amounts of the desired N-aminated product under otherwise identical conditions.Attempts to re-place Aliquat-336with several other surface active poly-ethylene glycol(PEG)type phase transfer agents such as Triton-X,were unsuccessful.6These conditions were also successfully applied to prepare a series of N-aminated heterocycles(pyrroles and indoles)in consistently high yield(Table1).A typical experimental procedure is as follows:aqueous sodium hypochlorite (58.76ml of ca.9%solution)was added over a period of20min,at room temperature,to a vigorously stirred mixture of3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester(2g,8.9mmol)in MTBE(24ml,ammo-nium chloride(2.9g,53.2mmol),Aliquat-336(0.1g), aqueous NaOH(25.6ml of28.4%solution)and aqueous NH4OH(8.28ml of28%solution).The resulting reac-tion mixture was stirred at room temperature for an additional2–4h at the end of which time the complete disappearance of starting material and formation of product is observed by capillary GC and HPLC.The upper product-rich organic layer was separated from the spent aqueous layer and washed
with aqueous Na2S2O3(40ml).The organic layer was then dried over anhydrous Na2SO4and evaporated in vacuo to produce 2.01g of1-amino-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester(94%yield).
In summary,we have demonstrated an efficient,one-pot,phase transfer catalyzed N-amination process utiliz-ing chloramine as an inexpensive electrophilic aminating agent which proved to be superior to the existing tech-nologies.This protocol is practical and safe and is potentially viable for on-scale manufacturing.Studies aimed at extending the scope of this technology are in progress in our laboratories.
Acknowledgements
Financial support provided by Bristol-Myers Squibb Company,the Petroleum Research Fund(PRF),The National Institute of Health(NIH)and The Welch Foundation is gratefully acknowledged.
References and notes
1.The program was aimed at giving BS/MS level students
exposure to pharmaceutical process R&D in an academic setting.Chem.Eng.News2001,41.
Table  1.Phase transfer catalyzed electrophilic N-amination of heterocycles with chloramine7
Entry Substrate N-Aminated substrate Yield(%)
1
N
H
OEt
O
EtO
CH3
N
O
OEt
O
EtO
CH3
2
94
2
N
H
OEt
O
EtO
H
N
O
OEt
O
reaction between pvp and aminoEtO
H
2
92
3
N
H
OEt
O
EtO
N
O
OEt
O
EtO
2
96
4
N
H
OEt
O
EtO
Ph
N
O
OEt
O
EtO
Ph
2
94
5
N
H O
OEt
O
EtO
N
O
OEt
O
EtO
2
90
6
2
93
7
2
91
5342  A.Bhattacharya et al./Tetrahedron Letters47(2006)5341–5343
2.For O-(2,4-dinitrophenyl)hydroxylamine see:(a)Salem-
nick,G.;Nir,Z.Tetrahedron1972,28,3833;A detonation has been reported while using this reagent.See:Radha-krishna,A.S.;Loudon,G.M.;Miller,M.J.J.Org.Chem.
1979,44,4836;For safety studies of substituted(nitro-phenyl)hydroxylamines see:Boyles,D.C.;Curran,T.T.;
Parlett,R.V.Org.Proc.Res.Dev.2002,6,230;(b) Sheradsky,T.Tetrahedron Lett.1968,16,1909;For a review on electrophilic amination see:(c)Tamura,Y.;
Minamikawa,J.;Ikeda,M.Synthesis1977,1.
3.Hynes,J.,Jr.;Doubleday,W.W.;Dyckman,  A.J.;
Godfrey,J.D.,Jr.;Grosso,J.A.;Kiau,S.;Leftheris,K.
J.Org.Chem.2004,69,1368,and references cited therein.
4.The concentration of NH2Cl was determined by iodometric
titration.
5.Goehring,R.R.In Encyclopedia of Reagents for Organic
Synthesis;Paquette,L.A.,Ed.;Wiley:New York,1995;
Vol.2,pp1052–1053.
6.Bhattacharya,A.;Purohit,V.;Rinaldi,F.Org.Proc.Res.
Dev.2003,7,254.
7.NMR data for all the compounds synthesized are consistent
with their expected structures,as for instance:1-Amino-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester(entry
1):1H NMR(400-MHz,DMSO-d6):d1.26(t,J=7.3,3H),
1.32(t,J=7.3,3H),
2.47(s,3H),4.18(q,J=7.3,2H),4.28
(q,J=7.3,2H),6.41(s,2H,NH2),7.43(s,1H);13C NMR (100-MHz,DMSO-d6):d11.9,14.4,14.5,59.4,60.2,110.4, 119.9,128.4,130.9,161.5,163.7;HRMS(ESI+)calcd for (M+H+)C11H17N2O4241.1188,found241.1189.1-Amino-1H-pyrrole-2,4-dicarboxylic acid diethyl ester(entry2):1H NMR(400-MHz,DMSO-d6):d1.24(t,J=7.3,3H),1.27 (t,J=7.3,3H),4.16(q,J=7.3,2H),4.22(q,J=7.3,2H),
6.50(s,2H,NH2),
7.01(s,1H),7.50(s,1H);13C NMR
(100-MHz,DMSO-d6):d15.0,15.1,60.4,60.9,112.4,115.8, 122.1,131.5,161.0,163.7;HRMS(ESI+)calcd for(M+H+) C10H15N2O4227.1032,found227.1034.1-Amino-3-ethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester(entry3):1H NMR(400-MHz,DMSO-d
6
):d1.06(t,J=7.3,3H), 1.23(t,J=7.3,3H),1.29(t,J=7.3,3H),2.96(q,J=7.3, 2H),4.15(q,J=7.3,2H),4.25(q,J=7.3,2H),6.39(s,2H, NH2),7.40(s,1H);13C NMR(100-MHz,DMSO-d6):d 14.9,15.1,16.4,19.3,59.9,60.8,110.2,119.9,131.5,135.6, 161.8,164.0;HRMS(ESI+)calcd for(M+H+)C12H19N2O4 255.1345,found255.1336.
1-Amino-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester(entry4):):1H NMR(400-MHz,DMSO-d6):d0.85 (t,J=7.3,3H),1.03(t,J=7.3,3H),3.95(q,J=7.3,2H), 3.99(q,J=7.3,2H),6.50(s,2H,NH2),7.29(m,5H),7.55 (s,1H);13C NMR(100-MHz,DMSO-d6):d11.8,12.3,57.5, 58.2,108.3,124.9,125.2,128.4,128.9,133.0,159.1,161.7; HRMS(ESI+)calcd for(M+H+)C16H19N2O4303.1331, found303.1345.1-Amino-3-propyl-1H-pyrrole-2,4-dicarb-oxylic acid diethyl ester(entry5):1H NMR(400-MHz, DMSO-d6):d0.89(t,J=7.3,3H),1.25(t,J=7.1,3H), 1.31(t,J=7.1,3H),1.48(m,2H),2.95(t,J=7.8,2H), 4.16(q,J=7.1,2H),4.26(q,J=7.1,2H),6.43(s,2H, NH2),7.43(s,1H);13C NMR(100-MHz,DMSO-d6):d 14.2,14.3,14.5,24.5,27.4,59.4,60.2,109.9,119.6,131.0, 132.3,161.4,163.6;HRMS(ESI+)calcd for(M+H+) C13H21N2O4269.1501,found269.1488.1-Amino-5-chloro-1H-indole-2-carboxylic acid ethyl ester(entry6):1H NMR (400-MHz,DMSO-d6):d  1.35(t,J=7.3,3H),  4.36(q, J=7.3,2H),6.09(s,2H,NH2),7.11,(s,1H)7.32(dd, J=9.2,2.2,1H),7.60(d,J=9.2,1H),7.71(d,J=2.2, 1H);13C NMR(100-MHz,DMSO-d6):d14.5,60.8,106.3, 113.0,121.3,123.7,125.1,125.2,128.2,137.7,161.2;HRMS (ESI+)calcd for(M+H+)C11H12ClN2O2239.0587,found 239.0581.1-Amino-1H-indole-2-carboxylic acid ethyl ester (entry7):1H NMR(400-MHz,CD3OD):d1.41(t,J=7.3, 3H),4.39(q,J=7.3,2H),7.09(apparent t,J=8.1,1H), 7.14(s,1H),7.30(apparent t,J=8.1,1H),7.60(two overlapping d,J=9.9,2H);13C NMR(100-MHz, CD3OD):d15.1,62.1,108.9,112.2,122.0,123.6,124.9, 126.5,128.3,141.1,163.9;HRMS(ESI+)calcd for(M+H+) C11H13N2O2205.0977,found205.0974.
A.Bhattacharya et al./Tetrahedron Letters47(2006)5341–53435343

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