Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0533 626

	12. Advances in the chemistry of amino and nitro compounds										573
allylamines (equation 75)203.
		OPh				O		OPh
						NHR2
O P							P
R1CH C CH		OPh				R1CH2 C CH		OPh
(195)					(196)						(75)
	O	OPh									H
NR2						NR2		H		NHR2
	P
		OPh						C
R1CH2 CCH2						R1CH2 C	C	R3		R1CH2 CH	R3
(197)							H				H

The silylated tin compound 199, obtained from tributyltin hydride and N- bis(trimethylsilyl)propargylamine (198) in the presence of a trace of AIBN (2,20 -azobisisobutyronitrile), is a versatile reagent for the preparation of allylic amines. Treatment with aryl bromides ArBr (Ar D Ph, 4-MeOC6H4, 4-O2NC6H4 etc.) under Pd(PPh3)4 catalysis yields the silylated amines 200, which are hydrolysed by acids to the free amines 201. 199 is converted into the lithium compound 202, which is transformed into 203 by aqueous ammonium chloride and into 204 by the action of alkyl halides RX (R D Me, Et or allyl) (equation 76)204.

Ar

			SiMe3			Ar
		CH2 N				CH2 NH2
			SiMe3
		(200)			(201)
			A rBr
	SiMe3		Bu3 Sn
Bu3 SnH + HC CCH2 N						SiMe3
(198)	SiMe3				CH2 N
					(76)
						SiMe3
			BuLi		(199)
Li
			SiMe3			SiMe3
		CH2 N				CH2 N
R	RX		SiMe3			SiMe3
		(202)			(203)

SiMe3

CH2 N

SiMe3

(204)

574	G. V. Boyd

Silylated primary allylic amines, e.g. CH2DCHCH2N(SiMe3)2, are produced from allylic chlorides and the mixed reagent AgI/LiN(SiMe3)2205. The formation of allylic amines from olefins by the ene reaction is shown in equation 77. The ene adducts 205 from bis(2,2,2-trichloroethyl) azodicarboxylate are converted into 206 by zinc dust in acetone/acetic acid206.

		CO2 CH2 CCl3			CO2 CH2 CCl
	+	N			N
H		N			NH
	CCl3 CH2 O2 C			CCl3 CH2 O2 C

(77)

(205)

NH2

(206)

O-Methanesulphonyloximes of ˛,ˇ-unsaturated ketones yield allylic amines on reduction with lithium aluminium hydride (equation 78)207.

R1C DNO3SMe CHDCHR2 ! R1 CH(NH2)CHDCHR2

78

Protected primary allylic amines 210 are obtained208 as mixtures of (E)- and (Z)-isomers

by the combined action of an aldehyde RCHO (R D C6H11, Ph, 4-MeOC6H4, 4-CNC6H4, PhCHDCH etc.) and triphenylphosphine on the aziridine 207 by way of an equilibrium

mixture of the betaines 208 and 209.

Me	Ph3 P+	Me	Ph3 P+	Me
			−
N		N −	HN
CO2 But		CO2 But		CO2 But
(207)		(208)	(209)
			RCHO
			R
			Me
			H HN
			CO2 But

(210)

12. Advances in the chemistry of amino and nitro compounds

575

The conversion of allylic selenides into allylic amines is illustrated for the ester 211, which forms the protected amine 212 by reaction with sodium t-butyl N-chlorocarbamate. The reaction involves a [2,3] sigmatropic rearrangement (equation 79)209.

Ph		−			Ph	NCO2 But
	Se					Se
		CINCO2 But Na+
Me	CO2 Me				Me		CO2 Me
	(211)							(79)
		PhSe	CO2 Bu		t		CO	But
							2
			N				HN
	Me		CO2 Me			Me	CO2 Me
							(212)

Tributylvinylphosphonium bromide forms the betaine 213 with sodium phthalimide. Addition of aldehydes RCHO (ketones are inert) gives almost exclusively the (E)- allylphthalimides 214, which form the corresponding allylamines by cleavage with hydrazine210.

O		O
+	−	−	+
CH2 CHPBu3 Br
N −		NCH2 CH	PBu3
Na+
O		O
		(213)
		RCHO
		O	H
			C
		NCH2 C	R
		H
		O
		(214)

Copper(I) bromide catalyses the reaction of primary and secondary amines R1R2NH (R1 D H, R2 D i-Pr, Bu, t-Bu, Ph, Ar, PhCH2; NR1R2 D NEt2 or piperidin-1-yl) with the allenes R3R4CDCDCHBr (R3 D H or Me; R4 D Me, Et or t-Bu) to give propargylamines R3R4C(NR1R2) C CH211. Propargyl acetates and phosphates are aminated by primary

576	G. V. Boyd

and secondary amines under the influence of copper(I) chloride to yield the corresponding propargylamines212. A one-pot synthesis of N-propargylarylamines RC CCH2NHAr (R D H, C6H13, Ph, Et2NCH2, CH2DCMe) is by the addition of butyllithium to a mixture of the acetylene RC CH and a methoxymethylarylamine ArNHCH2OMe. The imine ArNDCH2 is generated and reacts with the lithium compound RC CLi to form the product213. Primary N-alkynylamines are obtained from the silylated imine 215 and allenic organomagnesium, zinc or aluminium compounds 216214.

PhCHDNSiMe3 C CHRDCDCHM ! PhCH (NH2) CHRC CH

(215)(216)

N-Propargylpiperidines 218 (Ar D Ph, 4-MeOC6H4 or 2-thienyl) are produced from the aminals 217 and phenylacetylene under the influence of copper(I) chloride215.

N CHAr N	+ HC		CPh		N CHAr C CPh
(217)				(218)

The chiral aldehyde 219 reacts with dimethyl diazophosphonate (220) to yield the protected propargylamine 221 of high optical purity216.

	CH2 Ph		O	CH2 Ph
			OMe
		+	N2 CHP
But O2 CNH	CHO		OMe	But O2 CNH
				H
	(219)		(220)	(221)

˛-Allenic amines 223 are produced from the propargylsilanes 222 (R1 D H or Me; R2 D H, Me or SiMe3), paraformaldehyde and secondary amines (Et2NH, Bu2NH, piperidine or morpholine) in the presence of trifluoroacetic acid217.

Me3SiCHR1C CR2	C (CH2O)n C R32NH ! R1CHDCDCR2CH2NR32
(222)	(223)

The protected propargylamines 224 (R D H, CH2CO2Me or CH2CH2CO2Me) react with aqueous formaldehyde under copper(I) bromide catalysis to yield the allene derivatives 225. Deprotection with ethereal hydrogen chloride affords the free amines218.

							CH2				CH2
		CH				H	C			H	C
H	C				H		C		H		C
	C		CH2	O		C				C
But O2 CN					But O2 CN				H2 N		R
	R						R
H					H
	(224)					(225)

12. Advances in the chemistry of amino and nitro compounds

577

High yields of ˇ-substituted allenic primary amines 227 are obtained by the CuBrÐMe2S- or NiCl2 Ð Ph2PCH2CH2CH2PPh2-catalysed reaction of the acetylene derivative 226 with aryl Grignard compounds and subsequent deprotection by flash chromatography219.

SiMe3							SiMe3
	A rMgBr
MeOCH2 C CCH2 N		H2 C C CArCH2 N
SiMe3							SiMe3
(226)
		H2 C		C			CArCH2 NH2
	(227)

14. By miscellaneous methods

Hydrogenation of enamines in the presence of a chiral titanocene catalyst yields optically active amines in more than 90% enantiomeric excess, e.g. equation 80220.

Ph	CH2	Ph	CH3
	N	N	(80)

˛-Enamino ketones 229 are produced by the action of sodium azide on ˛-bromo ketones 228 (R1 D Me or Ph; R2 D CF3 or CO2 Et) as shown in equation 81221.

O

OH

O−

CH R2

NaN3

CH2 R

2

2

R1C

CHCH2 R2

R1C

C

R1C

C

+

+

Br

−N

N2

HN N2

(228)

− N2

(81)

O

CHR

2

R1C

C

NH2

(229)

A simple synthesis of ˛

-amino

ketones and esters 231 (R1

D

EtO or Ph; R2

D

H

3

4

or CO2Et; R

D Me or CH2CO2Et; R

D PhCH2 or CH2CO2Et) proceeds from diazo

ketones and esters, respectively, tertiary amines and copper powder. The intermediate

578	G. V. Boyd

ylides 230, formed by carbenoid insertion reactions, undergo a [1,2] sigmatropic shift to give the products (equation 82)222.

O						O	R2		O	R2
						−
R1CCR2 + MeNR3 R4									R1C	C
						R1 CC
						N +				R4	(82)
		N2					R4			N
					Me				Me	R3
						R3
					(230)					(231)

A new carbon nitrogen bond formation reaction involves the fixation of molecular nitrogen. A mixture of titanium(III) or titanium(IV) chloride and magnesium in THF under nitrogen is treated with carbon dioxide to give the complex [3THF Ð Mg2 Cl2O Ð TiNCO]. Addition of 2-methylcyclohexane-1,3-dione and bromobenzene and a catalytic amount of Pd (PPh3)4 affords a mixture of the vinylamines 232 and 233 (equation 83)223.

O	O		O
	Me	Me	Me
	+ PhBr + complex	+	(83)
	O	NHPh	NH2
	(232)		(233)

B. Reactions of Amino Compounds

1. Oxidation and dehydrogenation

Anilines are converted into nitrosoarenes ArNO by the action of hydrogen peroxide in the presence of [Mo(O)(O2)2(H2O) (HMPA)]224, whereas catalysis of the reaction by titanium silicate and zeolites results in the formation of azoxybenzenes ArN (O)DNAr225. Azo compounds ArNDNAr are formed in 42 99% yields by the phase-transfer assisted potassium permanganate oxidation of primary aromatic amines in aqueous benzene containing a little tetrabutylammonium bromide226. The reaction of arylamines with chromyl chloride gives solid adducts which, on hydrolysis, yield mixtures of azo compounds, p-benzoquinone and p-benzoquinone anils 234227.

NAr
	Me
	Me	O	+
	O		N
O			O−
(234)	(235)		(236)

12. Advances in the chemistry of amino and nitro compounds

579

Oxidation of primary amines RNH2 with dimethyldioxirane (235), generated from acetone and ‘oxone’, 2KHSO5ÐKHSO4ÐK2SO2, affords the corresponding nitro compounds RNO2228,229. Fluorine reacts with wet acetonitrile to produce an oxidizing agent which converts all types of primary aromatic amines into nitro compounds. Thus p-nitroaniline yields p-dinitrobenzene and m-hydroxyaniline gives m-nitrophenol230. Primary aliphatic amines, e.g. C12H21NH2, cyclohexylamine and PhCH2NH2, react analogously231. Nitrones, e.g. 236 from piperidine, are obtained by the sodium tungstatecatalysed oxidation of secondary amines with hydrogen peroxide232. Oxidation of secondary amines with dimethyldioxirane gives hydroxylamines or nitrones in up to 99% yields233. Cyclic secondary amines such as pyrrolidine, piperidine, morpholine and indoline afford hydroxamic acids by the action of dimethyldioxirane in acetone, e.g. equation 84234.

O

(84)

N N

H

OH

The reaction of cyclohexylamine with dimethyldioxirane has been examined in detail. The main products are cyclohexanone oxime and dimeric nitrosocyclohexane 237; these are accompanied by a little nitrocyclohexane235. Nitrones 239 (R D Et, Bu or C6H13) are formed in 74 85% yields in the oxidation of secondary amines 238 with hydrogen peroxide under selenium dioxide catalysis236. Piperidine yields the nitrone 236 in this reaction236. A biphasic system of ethyl acetate and water containing sodium perborate (NaBO3), sodium hydrogen carbonate and N, N0-diacetylethylenediamine oxidizes primary aliphatic amines RNH2 to dimeric nitrosoalkanes (RNO)2237. The reaction of 3-phenyl-2-phenylsulphonyloxaziridine (240) with various amines more basic than pyridine has been investigated. Primary amines RNH2 (R D t-Bu, cyclohexyl, PhCH2 and 1-adamantyl) yield nitroso compounds RNO as mixtures of monomers and dimers, secondary amines yield mixtures of hydroxylamines and nitrones, e.g. 242 and 243 from dibenzylamine (241), and tertiary amines (triethylamine, N-methylpiperidine and quinuclidine) yield the corresponding N-oxides238.

+

+

+

N

N

RCH2 HNCH2 R

RCH2 N

CHR

O−

O−

O−

(237)

(238)

(239)

Ph

NSO2 Ph

PhCH2 NCH2 Ph

PhCH2

NCH2 Ph

+

PhCH2 N

CHPh

H

O

OH

−

O

(240)

(241)

(242)

(243)

Primary amines RNH2, where R is a primary alkyl group

such as Pr, benzyl or

allyl, are oxidized to

O-benzoylhydroxamic acids RNHOBz

by

benzoyl peroxide239.

580	G. V. Boyd

Oximes result from the reactions of primary aliphatic amines possessing ˛-hydrogen atoms with hydrogen peroxide in the presence of the ten-membered ring zeolites TS-1 or TS-2. Thus isopropylamine yields acetone oxime and benzylamine gives benzaldehyde oxime240. Addition of hydrogen peroxide to a solution of a copper(II) salt in slightly acidic water gives an insoluble copper derivative CuO2H, which oxidizes benzylamine to benzaldehyde241. High yields of ketones result when primary amines possessing ˛-hydrogen atoms are treated with sodium hypochlorite in ethyl acetate/water under phase-transfer catalysis with tetrabutylammonium bromide. Cyclohexylamine gives cyclohexanone, benzhydrylamine benzophenone and 1-phenylethylamine acetophenone. The reactions proceed by way of N-chloroimines (equation 85)242.

										R1
				R1R2				H2	O
R1R2 CHNH2		R1R2 CHNCl2			C		NCl			CO (85)
			−HCl							R2

Similarly, tetrakis(pyridino)cobalt(II) dichromate [pyridine4 Co (HCrO4)2] smoothly oxidizes amines to carbonyl compounds243. The lithium or zinc salts of N-

trimethylsilylamines R1R2CHNHSiMe3	are	converted		into	carbonyl	compounds
R1R2CDO in good yields by reaction	with	air for 5		45 min	at low	temperatures.

Other oxygen-sensitive functions, such as thioether or tertiary amino groups, are not affected244. Primary amines are oxidized to carbonyl compounds by iodosylbenzene (PhIO) in the presence of Ru(PPh3)2Cl2 and molecular sieves, e.g. PhCH2NH2 ! PhCHO and Ph2CHNH2 ! Ph2CO. Secondary amines give imines, e.g. PhCH2NHPh ! PhCHDNPh and PhCHDCHCH2NHPh ! PhCHDCHCHDNPh245. Other methods for the conversion of secondary amines R1R2CHNHR3 into imines R1R2CDNR3 are by oxidation with t-butyl hydroperoxide in the presence of Ru (PPh3)3Cl2246, with Ni(II) sulphate potassium persulphate247, with a reagent prepared from copper(II) bromide and lithium t-butoxide248 and with 4-methylmorpholine N-oxide in acetonitrile in the presence of tetrapropylammonium perrhenate and 4 A˚ molecular sieves249.

The oxidative deamination of primary and secondary amines is accomplished efficiently by treatment with 3-trifluoromethylbenzenesulphonyl peroxide (ArSO2)2O2 (Ar D 3-F3CC6H4) in ethyl acetate, followed by powered potassium hydroxide at 78 °C and finally water (equation 86).

Ar

OSO2

									H2 O
R1R2 CHNHR3		R1R2 CHNR3			R1R2	C		NR3		R1R2 CO + H2 NR3
				− HO3 SA r					(86)

Benzylamine gave benzaldehyde, hexylamine hexanal, octylamine octanal, 2- octylamine octan-2-one, cyclohexylamine cyclohexanone and dibenzylamine gave benzophenone250. Copper(I) chloride in pyridine in an atmosphere of oxygen converts primary amines into cyanides, e.g. benzylamine gave benzonitrile and 2-(3,4-dimethoxypheny)ethylamine gave 3,4-dimethoxyphenylacetonitrile. The

secondary amine 244 gave the aldehyde	245	in this reaction251. An improvement
of the procedure resulting in yields	of	better		than 95% is to conduct
˚			252	. Other methods for carrying out
the oxidation in the presence of 4 A molecular sieves

12. Advances in the chemistry of amino and nitro compounds				581
MeO		MeO
PhCH2 O	CH2 NHMe	PhCH2 O	CHO
	(244)		(245)

the oxidation of primary amines to cyanides are by using 4% aqueous sodium hypochlorite in the presence of hexadecyltrimethylammonium bromide253, potassium persulphate in the presence of nickel(II) sulphate254, silver(II) picolinate255 or with N-bromosuccinimide to give an N,N-dibromide, which is decomposed by adding trimethylamine (equation 87).

RCH2NH2	!	RCH2NBr2	!	RCN	87
			2HBr

1,6-Diaminohexane gives 60% of adiponitrile in this reaction256.

The photooxidation of tertiary methylamines sensitized by electron acceptors such as 9,10-dicyanoanthracene in the presence of lithium perchlorate results in demethylation; thus tropinone yields nortropinone257. Photoinduced cyanation of tertiary amines with oxygen, a sensitizer and trimethylsilyl cyanide results in ˛-cyano nitriles (equation 88)258.

R1R2NCH2R3 !		+		CHR3		Me3SiCN	R1R2NCH(CN)R3
		[R1R2N	D		]	!		88
	H

The cyanides 246, obtained from aldehydes R1CHO (R1 D alkyl, Ph or PhCHDCH), amines HNR2R3 (aniline or morpholine etc.) and potassium cyanide undergo autoxidation in the presence of potassium t-butoxide to give amides (equation 89)259.

R1CHOCHNR2R3CKCN ! R1CH(CN)NR2R3 ! R1CONR2R3

89

(246)

2. Dealkylation

Dealkylations

of amines

by means

of

acyl

chlorides

have been reviewed

(equation 90)260.

R

O

R

O

R

N+

C

R1

NCOR1

(90)

R

N +

R

ClCR1

− RCl

R

Cl−

R

R

Phenyl carbonochloridate (phenyl chloroformate) effects the dealkylation of tertiary amines: N,N-dimethylaniline yields methyl chloride and the amide 247, and quinuclidine yields the piperidine derivative 248261.

However, the resulting amides are difficult to hydrolyse. A more efficient dealkylating agent is 2,2,2-trichloroethyl carbonochloridate ClC(O)OCH2CCl3. It readily decomposes

582	G. V. Boyd

CH2 CH2 Cl

O				O					N
				Ph
Me2 NPh + ClCOPh − MeCl			+	NCOPh
					N				C
				Me				O	OPh
				(247)					(248)

tertiary amines to give carbamates 249 which are easily cleaved to secondary amines by zinc in methanol or in acetic acid262.

O
R2 NCOCH2 CCl3				R2 NH
(249)

Other useful reagents are vinyl carbonochloridate ClC(O)OCHDCH2263 and ˛- chloroethyl carbonochloridate ClC(O)OCHClCH3, which is unsurpassed in effectiveness. The resulting carbamates R2NCO2CHClCH3 are decomposed to secondary amines in hot methanol264. Tertiary N-methylamines RArNMe (R D Me, Et, MeO2CCH2CH2 or CH2DCHCH2CH2) are demethylated by the ruthenium-catalysed reaction with t-butyl hydroperoxide to give RArNCH2OOBut , which are hydrolysed to RArNH Ð HCl by dilute hydrochloric acid. The procedure is chemoselective, N-alkyl groups other than methyl not being affected265. The debenzylation of N-benzyl tertiary amines PhCH2NR1R2 with ethyl carbonochloridate gives carbamates R1R2NCO2Et, which are converted into the secondary

amines R1 2	BI	Ð	Et NPh266	. A method for the
R NH by the action of the boron complex1	23		2
selective N-demethylation of tertiary methylamines R	R NMe is ruthenium(III)-catalysed

oxidation with methanolic hydrogen peroxide to yield R1R2NCH2OMe, followed by removal of the methoxymethyl group with dilute hydrochloric acid267. para-Substituted N,N-dimethylanilines 4-RC6H4NMe2 (R D Me, MeO or Cl) react with oxygen and acetic anhydride in the presence of copper(I) chloride or cobalt(II) chloride to give the demethylated products 4-RC6H4NMeAc268. The combined action of trifluoroacetic anhydride and triethylamine on some unsaturated tertiary N-(2,4-dimethoxybenzyl)amines

leads to the selective cleavage of the benzyl			nitrogen bond (equation 90a)269.
	Me
MeO	CH2 NCH2 CH		CHC CBut

(90a)

OMe

Me

CF3 CONCH2 CH CHC CBut