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

583

The reaction of tertiary aromatic amines with butyl nitrite has been investigated in detail. The main products arise from N-dealkylation/N-nitrosation, e.g. equation 91270.

Me

Me

+

+BuO

−

+

Ph

N

NO

PhNMe2

+ ΒuONO −BuO−

Ph

N

NO −BuOH

−CH2

Me

−NO

(91)

Ph

Me

Ph

Me

Me

−

+

BuONO

N

N

+HO

Ph

N

−BuOH

−CH2 O

H

CH2

NO

3. Alkylation, arylation, etc.

Primary

amines

RNH2

(R

D

i

-Pr,

i

-Bu,

t

-Bu

or

cyclohexyl)

react

with

the

carbamate

271

EtO2CNDCCl2

to

yield

the

carbodiimides EtO2CNDCDNR

. A

new

method of preparing imines is to add a carbonyl compound (2,6-dimethylcyclohexanone, 2-tetralone, 2-decalone etc.) to a preformed complex of a primary amine (t- butylamine, cyclohexylamine, benzylamine or 1-phenylethylamine) and titanium(IV) chloride suspended in hexane or octane272. Primary amines R1NH2 (R1 D t-Bu, N C, Tos or phthalimido) react with nitroso compounds R2NO (R2 D t-Bu, pyrrolidin-1-yl, Ph

or 2-MeCC6H4) in the presence of the hypervalent iodine compound PhI (OAc)2 to give
+	273	. Lithium salts of hindered secondary
unsymmetrical azoxy compounds R1NDN(O )R2

amines [diisopropylamine, bis(trimethylsilyl)amine and 2,2,6,6-tetramethylpiperidine] are obtained by ultrasonic irradiation of lithium metal and the amine in THF in the presence of isoprene as an electron carrier274.

Monoalkylation of optically active 1-phenylethylamine with benzyl bromide in N,N- dimethylpropyleneurea (249a) at 100 °C in the presence of sodium carbonate gives the enantiomerically pure N-benzyl derivative. Isopropyl iodide and neopentyl iodide behave analogously275.

			O
	NMe	Ph	OCCF3
			Te
				R1R2 NH	NR1R2	(91a)
N	O		O
Me

(249a)

The reaction of allyltrimethylsilane with benzenetellurinyl trifluoroacetate, followed by a primary or secondary amine (octylamine, aniline, piperidine, etc.) and boron trifluoride

etherate, yields the corresponding allylamine (equation 91a)276. N-Allylarylamines are

+

formed in excellent yields from allyldialkyltelluronium bromides CH2DCHCH2TeR2Br and arylamines277. N-Phenylation of primary amines (aniline, p-nitroaniline etc.) and of secondary amines (diethylamine, N-butylethylamine etc.) is achieved by treatment

584 G. V. Boyd

with triphenylbismuth diacylates Ph3Bi(OR)2 (R D Ac, OCCF3 or Tos) in the presence of copper powder278. Similarly, aryllead triacetates ArPb(OAc)3 monoarylate aliphatic, aromatic and heteroaromatic amines under copper(II) acetate catalysis279. The Ullmann synthesis of triarylamines (equation 92) from diphenylamine and aryl iodides IC6H4R (R D 2-, 3- or 4-Me, 2-, 3- or 4-Cl, 3- or 4-OMe) proceeds efficiently in refluxing o- dichlorobenzene in the presence of copper, potassium carbonate and 18-crown-6 under phase-transfer conditions280.

Ph2NH	C	IC6H4R	!	Ph2NC6H4R	92
			HI

Primary and secondary amines (aniline, t-butylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine and morpholine) are N-phenylated in good yields by adding the amine to a suspension of lithium in THF, followed by bromobenzene281. Aminostannanes, generated in situ by transamination of tributyl(diethylamino)tin with primary or secondary amines, undergo palladium-catalysed reactions with aryl bromides to yield arylated amines. Thus successive reaction of benzylmethylamine with the tin compound and ethyl 4-bromobenzoate in the presence of PdCl2[P(2-MeC6H4)3] gave 88% of 4- EtO2CC6H4NMeCH2Ph282. Diphenylamine-2-carboxylic acids 250 are obtained when

arylamines ArNH2 (Ar D Ph, 4-MeC6H4, 4-MeOC6H4, 4-H2NC6H4, 3-ClC6H4, 3- O2NC6H4 or 4-HO3SC6H4) are heated with 2-chlorobenzoic acid in water in the presence of copper powder283.

HO2 C

ArNH

(250)

Trimethylsilyl trichloroacetate is a useful reagent for the N-trimethylsilylation of amines284. The combined action of primary aliphatic or aromatic amines and trimethylsilyl cyanide on aliphatic or aromatic aldehydes yields ˛-amino nitriles (equation 93)285,286.

		OSiMe3			NHR2
R1CHO + Me3 SiCN				+ Ν Η 2R2		(93)
		R1CH			R1CH
				−Η ΟSiMe3
		CN			CN

The ˛-arylamino nitriles 251, obtained from primary aromatic amines, trimethylsilyl cyanide and acetone in the presence of zinc chloride, react with methyllithium to give N-t-butylarylamines 252287. N,N-Bis(trimethylsilyl)amines 253 (R D allyl, benzyl, 3- phenylpropyl etc.) are formed in 50 88% yields by the action of chlorotrimethylsilane on primary amines in the presence of a catalytic amount of titanium(IV) chloride288.

	CMeLi
ArNHCMe2CN	!		ArNHCMe3	RN(SiMe3)2
(251)		LiCN	(252)	(253)

Trichlorosilane reacts with secondary amines (diethylamine, pyrrolidine, piperidine, morpholine and 1-methylpiperazine) to give the corresponding tris(dialkylamino)silanes HSi(NR2)3289.

12. Advances in the chemistry of amino and nitro compounds

585

Aromatic Mannich reactions have been reviewed290. Recent examples are the formation of 254 from p-cresol, paraformaldehyde and 1-methylpiperazine and of 255 from salicylaldehyde, aqueous formalin and 1-methylpiperazine291.

Me		Me
		NMe
+ (CH2 O)n + HN	NMe	N
		CH2
OH		OH
		(254)
CH2	N	NMe

OCH

CH2 N

NMe

OH

(255)

˛-Oxoketene dithiacetals 256 (Ar1 D Ph, 4-MeC6H4, 4-MeOC6H4 or 4-ClC6H4) condense with primary aromatic amines Ar2NH2 (Ar2 D Ph, 2- or 4-ClC6H4 or 4-MeC6H4) under the influence of boron trifluoride etherate to give S,N-acetals 257 in yields of up to 98%292.

SMe		NHAr2
Ar1COCH C		Ar1COCH C
SMe		SMe
(256)	(257)

The reaction of ˛,ˇ-epoxy sulphoxides with aliphatic or aromatic amines affords ˛- amino ketones, e.g. equation 94293.

O
Ph S	H	(94)
	Ph + HN
H13 C6		H13 C6 C CHPh N
	O	O

The joint action of primary or secondary amines (aniline, allylamine, benzylamine, butylmethylamine, N-methylglycine methyl ester etc.) and copper bis(acetylacetonate) on the thiophen ylide 258 leads to dimethyl aminomalonates 259 by a carbene insertion reaction294.

	586			G. V. Boyd
		Cl
			−	CO2 Me	CO2 Me
	R1R2 NH +	S+			R1R2 N CH
			C
				CO2 Me	CO2 Me
		Cl
		(258)			(259)

Treatment of secondary amines, e.g. dibenzylamine, with the complex 260, followed by oxidative removal of the iron carbonyl group, yields methyl 4-dialkylamino enoates 261295.

Me		CO2 Me		Me	CO2 Me
	Fe+(CO)4	BF4 −			NR2
(260)					(261)

Aliphatic ˛,˛0-dibromo ketones, such as 2,4-dibromopentan-3-one (262), react with primary amines RNH2 (R D Me, Et, Pr, i-Pr or t-Bu) to give mixtures of imines 263 and lesser amounts of diimines 264. 1,3-Dibromo-1-phenylpropan-2-one yields only the amide 265, the product of a Favorskii rearrangement. The nature of the products from aliphatic amines and cyclic ˛,˛0-dibromo ketones depends on ring size: the cyclohexanone derivative 266 gave Favorskii amides 267 (R D Pr, i-Pr or t-Bu), while trans-2,5- dibromocyclopentanone afforded the enamines 268 (R D i-Pr or t-Bu) (equation 95)296.

NR

NR

RNH2

MeCHBr CCHBrMe

Me CH2 C

C Me +

Me CH2 C

CMe

O

O

NR

(262)

(263)

(264)

O

PhCHBrCCH2 Br

RNH2

Ph

(95)

NHR

O

(265)

O

Br

Br

Me

Me

C NHR

O

Me

Me

(266)

(267)

12. Advances in the chemistry of amino and nitro compounds		587
O	O

Br	Br	NHR
			(95 continued)
		(268)

A mixture of enamines 270 and 271 and Favorskii products 272 and 273 is produced by the action of morpholine on the dibromotetrahydropyran-4-one 269297.

							O	O
	O
					O
Br		Br				N		N
		+ HN	O
							+
									O
Me	O	Me		Me
					O	Me
	(269)				(270)		Me	O	Me
								(271)
			O					O
		+	C	N	O	+ Br		C N	O
		Me	O	Me		Me	O	Me
			(272)				(273)

4. Amination of olefins

Reactions of amines with alkenes have been reviewed298,299. Alkali metal amides are active homogeneous catalysts for the amination of olefins. Thus diethylamine and ethylene yield triethylamine when heated at 70 90 °C at 6 10 atm in the presence of lithium diethylamide and N,N,N0,N0 -tetramethylethylenediamine. Solutions of caesium amide promote the addition of ammonia to ethylene at 100 °C and 110 atm to give mixtures of mono-, diand triethylamines300. The iridium(I)-catalysed addition of aniline to norbornene affords the anilinonorbornane 274301. Treatment of norbornene with aniline

H2 N

NHPh

H H

(274)

(275)

588	G. V. Boyd

and a catalyst generated from PhNHLi and [Rh(PEt3)2Cl]2 produces a mixture of the product 275 of ‘hydroarylation’ and minor amounts of 274302.

The addition of morpholine to 2,3-dihydrofuran in the presence of palladium(II) thiocyanateÐbis(triphenylphosphine) yields 2-(morpholin-4-yl)tetrahydrofuran (276)303. Irradiation of mixtures of 2-(2-methylpropenyl)phenol (277) and alkylamines yields adducts, e.g. 278 with isopropylamine304.

O	O	N
		O
	(276)
	OH	OH
	Me	Me
	Me	Me
		NHPri
	(277)	(278)

Chiral amino alcohols react with achiral nitroalkenes such as 1-nitrocyclohexene almost stereospecifically to give optically active products, e.g. equation 96305.

	NO2
	CH2 OH
	N
+	NO2	(96)

N	CH2 OH
H

The action of piperazine on dilute solutions of fullerene C60 in toluene leads to a ‘monoadduct’, together with a mixture of regioisomeric ‘diadducts’. The reactions take place at bonds joining six-membered rings and are accompanied by loss of hydrogen306.

5. Formation of enamines

Cyanoacetaldehyde, freshly prepared by the ozonization of allyl cyanide or (E)-1,4-dicyanobut-2-ene, reacts with primary aromatic amines to give the ˇ- cyanoenamines 279307.

CNCH2CHO C H2NAr ! NCCHDCHNHAr

(279)

12. Advances in the chemistry of amino and nitro compounds

589

ˇ-Cyanoenamines are also obtained when mixtures of ortho esters, secondary amines and cyanoacetic acid are heated in a pressure bottle, e.g. equation 97308.

OEt	CO2 H
Me2 NH + ΗC OEt + H2 C		−3EtOH	Me2 NCH		CHCN (97)
		−CO2
OEt
	CN

The Pd(PPh3)4-catalysed reaction of perfluoroalkyl iodides with tertiary aliphatic amines gives enamines in 40 50% yields, e.g. equation 98309.

F3CCF2CF2CF2I C CH3CH2NEt2 ! F3CCF2CF2CF2CHDCHNEt2

98

The cis-enamino ketone 281 is formed stereoselectively by the reaction of benzylamine with the (trimethylsilyl)ethynyl ketone 280310.

							H	H
PhCC					CSiMe3 + H2 NCH2 Ph			C C
							PhC	NHCH2 Ph
O								O
(280)								(281)

Irradiation of mixtures of 1,3-diketones and aliphatic or aromatic primary or secondary amines absorbed over montmorillonite clay or silica in a microwave oven affords enamino ketones, e.g. equation 99311.

O	O		NBu2 O
	+ Βu2 NH		Me	(99)
Me	Me		Me

3-Dimethylamino-1-butyne (282) undergoes a base-catalysed isomerization to 2- dimethylamino-1,3-butadiene (283)312.

NMe2

NMe2

HC CCHCH3 H2 C CHC CH2

(282)

(283)

Secondary propargylic amines 284 (R D Pr, t-Bu, C5H11, C6H13 or C7H15) rearrange to the enamines 285 and thence to the imines 286 in the presence of potassium t-butoxide313.

HC CCH2NHR ! H2CDCDCHNHR ! H2CDCHCHDNR

(284) (285) (286)

Allylamines 287 (R1 D H or Me; R2 D H, Me or Ph) form the rearranged adducts 288 with dimethyl acetylenedicarboxylate314.

The reaction of S-methyl O-ethyl dithiocarbonate with methyl ketones 289 (R1 D Me, i-Pr or Ph) in toluene in the presence of sodamide gives thioxo esters, which exist in the

590				G. V. Boyd
Me2 NCHR1CR2		CH2 + ΜeO2 CC				Me2 N	CHR1 CR2 CH2
				CCO2 Me			C C
(287)						MeO2 C	CO2 Me
							(288)

enol form 290. Addition of primary amines R2NH2 (R2 D Et, Pr or cyclohexyl) and formic acid yields the ˛-oxoketene O,N-acetals 291. In the absence of formic acid the acetals are accompanied by about equal amounts of the enamino esters 292 (equation 100)315.

O

MeS COEt

O

OH

S

R1CCH3

R1C

CH2 C

OEt

R1C

CHC

OEt

−HSMe

S

S

(289)

R2 NH2

(290)

(100)

O

NHR2

HNR2

S

R1CCH C

R1C

CH

OEt

OEt

(291)

(292)

6. Formation of amides etc.

The absolute

configuration

of primary

amines containing

the chiral

centre

at the

˛-position has been correlated with the relative 1H shifts (upfield or downfield) observed in the NMR spectra of the amides formed with (S)-O-methylmandelic acid, PhCH(OMe)CO2H316.

The reaction of tertiary amines such as trimethylamine or triethylamine, with acetyl or benzoyl chloride, followed by anion exchange with sodium tetraphenylborate gives stable

+		317
crystalline non-hydroscopic acylammonium salts, e.g. PhCONMe3 BPh4		.
	˚
Heating carboxylic acids and primary amines and activated 4 A molecular sieves
under argon affords high yields of amides318. The conversion	of primary aliphatic

or aromatic amines into amides by reaction with carboxylic acids in lukewarm benzene under triphenylstibine oxide/tetraphosphosphorus decasulphide catalysis has been reported319. Benzoic acid reacts with aniline in hot pyridine in the presence of polyphosphoric acid trimethylsilyl ester to give benzanilide. In the absence of pyridine, N,N0-diphenylbenzamidine, PhC(NHPh)DNPh, is formed. A number of analogous amidines were prepared from carboxylic acids, primary amines and polyphosphoric acid trimethylsilyl ester320. Copper(I) chloride promotes the reaction of cyanides RCN with dimethylamine to yield the amidines RC(DNH)NMe2321. The formation of N,N0- disubstituted amidines R1C(DNR2)NHR2 from R1CN and primary aliphatic or aromatic amines is catalysed by lanthanide(III) ions322.

N,N-Disubstituted thioformamides, R1R2NCHDS, are obtained from primary or secondary amines and dimethylthioformamide at 110 °C. Aromatic amines do not react for electronic reasons nor does N-methylcyclohexylamine because of steric hindrance323. Decomposition of carbon disulphide in a high-voltage discharge gives CS, which reacts

12. Advances in the chemistry of amino and nitro compounds

591

with amines [t-BuNH2, PhNH2, PhCH2NH2, Bu2NH, (i-Pr)2NH, MePhNH and Ph2NH] to yield thioformamides (equation 101)324.

R1R2NH C CS ! R1R2NCHDS

101

The formation of thioamides from amines (methylamine, dimethylamine and morpholine) and dithioester sulphines, prepared from dithio esters and peracids, is thought to proceed via the intermediates shown in equation 102325.

				O
	S			S		R2 R3 N	S OH
					HNR2 R3
R1			R1	C		R1	S Me
	SMe			SMe

(102)

R2 R3 N

S

R1

The reaction of thioaldehydes, generated from phosphonium ylides and sulphur with secondary amines such as dimethylamine, leads to thioamides. If the thioaldehydes possess a ˛-hydrogen atom enamines are produced (equation 103)326.

+S8

H

+2HNR2 2

NR2

2

2

+S8

NR 2

R1CH

PPh3

R1C

R1CH

R1C

−Η 2S

S

2

2

−HNR2

2

S

NR

(103)

H

PhCH2 C

+HNR2 2

PhCH

CHNR2 2

−Η2S

S

Diisopropenyl oxalate results from the addition of oxalic acid to propyne. The ester condenses with all types of amines under ruthenium catalysis to yield the corresponding ester amides or oxamides, depending on the amounts of amines used (equation 104)327.

CONR1R2

+HNR1R2

CO2 H

CO2 CMe

CH2

+2MeC

CH

CO2 CMe

CH2

(104)

CO2 H

CO2 CMe

CH2

CONR1R2

+2HNR1R2

CONR1R2

The reaction of ˇ-keto esters with primary or secondary amines in the presence of a trace of 4-(dimethylamino)pyridine affords keto amides in good yields. Thus methyl acetoacetate and p-toluidine gave MeCOCH2CONHC6H4Me328. Several selective acylation reactions of amines have been described. Amines are converted into formamides

592	G. V. Boyd

by cyanomethyl formate, HCO2CH2CN, under mild neutral conditions. Ethanolamine undergoes solely N-formylation329. All types of amines are acylated by vinyl esters RCO2CHDCH2 (R D Me, C15H31 or Ph) to form amides; hydroxyl groups are not affected330. N-Methoxydiacetamide, MeONAc2, effects the chemoselective acetylation of primary amines in the presence of alcohols or secondary amines331. Similarly, N-(diethylcarbamoyl)-N-methoxyformamide, Et2NCON(OMe)CHO, is a selective formylating agent for primary amines; hydroxyl and secondary amino groups are inert. Thus PhCH(OH)CH2NH2 gave 93% of PhCH(OH)CH2NHCHO and PhCH2NHCH2CH2NH2 gave 94% of PhCH2NHCH2CH2NHCHO332. Acetone oxime esters Me2CDNOCOR1 (R1 D Me, Pr or CHDCHMe) and primary or secondary amines afford good yields of acylated amines R1CONR2R3 even in the presence of hydroxyl functions333.

Transamidation reactions of unactivated amides are exemplified by the formation of N-acetylbenzylamine from acetamide and benzylamine in the presence of aluminium trichloride. Primary amines gave higher yields than secondary amines in these reactions. Activated amides, e.g. MeCONMeCOBut and PhCONMeTos, give good yields of, respectively, N-acetyl and N-benzoyl derivatives with both primary and secondary amines under mild conditions334. Diazoacetylations of all types of amines with succinimidyl diazoacetate 293 have been reported. The reagent, a stable crystalline solid, is prepared by the action of N-hydroxysuccinimide on glyoxylic acid tosylhydrazone in the presence of dicyclohexylcarbodiimide (equation 105)335.

	O	O
		O	R1R2 NH	O
	N OH + HO2 CCH NNHTos
		N OCCHN2		R1R2 NCCHN2

O	(105)
	O

(293)

Candida antarctica lipase in hexane catalyses the conversion of primary amines RNH2 (R D Bu, C8H17, C10H21, C12H25 and PhCH2) into the (R)-amines 294 by ethyl (S)-2- methylbutanoate336.

Me CO2 Et	Me CONHR
Et	Et

(294)

The enzyme also effects the aminolysis of non-activated diesters with diamines, e.g. equation 106337.

MeO2 C(CH2 )3 CO2 Me + H2 N(CH2 )2 NH2

(106)

MeO2 C(CH2 )3 CONH(CH2 )2 NHCO(CH2 )3 CO2 Me

The lactams 295 (n D 1,2,3 or 4) are cleaved to the amides 296 on treatment with secondary amines in the presence of aluminium trichloride338.

N-Cyanodiethylamine and sulphur trioxide yield the 1,5,2,6,3,7-dioxadithiadiazocine 2,2,6,6-tetroxide 297, which reacts with aliphatic secondary amines to furnish the sulphonamides 298339.