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

563

Sodium cyanoborohydride NaBH3CN in methanol is the reagent of choice for the reductive alkylation of ammonia, primary aliphatic and aromatic amines and secondary aliphatic amines with aldehydes and relatively unhindered ketones (equation 53).

	+		H
C O + HN			C N	(53)
	C N

HO−

Carbonyl compounds include isobutyraldehyde, phenyl isopropyl ketone, glyoxylic acid and pyruvic acid. Diaryl ketones do not react154. Modifications of the method consist in the use of a borohydride exchange-resin155, of sodium triacetoxyborohydride NaBH(OAc)3156 or in treating a mixture of a ketone and an amine with an equivalent of titanium(IV) chloride and Hunig’s¨ base (ethyldiisopropylamine) in dichloromethane, followed by a methanolic solution of sodium cyanoborohydride157. The borane pridine complex158 and hydrogen telluride159 are excellent replacements for sodium cyanoborohydride.

N-Alkylarylamines are produced from primary aromatic amines, ketones (acetone, butan-2-one, pentan-3-one, cyclohexanone, cycloheptanone etc.) and zinc dust in warm aqueous acetic acid. Methyl acetoacetate and aniline yield methyl 3-anilinobutanoate, MeO2CCH2CH(NHPh)Me160. The methylation of numerous primary and secondary aliphatic amines by means of paraformaldehyde in the presence of titanium(IV) isopropoxide and sodium borohydride has been reported161. When a suspension of an aromatic primary amine ArNH2 (Ar D Ph, 4-MeC6H4, 4-FC6H4, 3-O2NC6H4 etc) and sodium borohydride in THF is added to 3M sulphuric acid and 40% aqueous formaldehyde in THF, the N,N-dimethylated compound ArNMe2 is formed readily162. Very good yields of N-alkylarylamines 160 are obtained by treating a mixture of an aldehyde or ketone 158 (R1 D Me, Ph etc.; R2 D H or Me), dilute sulphuric acid and THF with a solution of an aromatic amine 159 (Ar D Ph, 2-MeC6H4, 2-, 3- or 4-O2NC6H4 etc.) in THF and then adding sodium borohydride163.

R1
C O	+ H2 NAr		R1R2 CHNHAr
R2
(158)	(159)	(160)

Phenyl hydrogen selenide, generated from diphenyl diselenide and sodium borohydride in ethanol, promotes the N-benzylation of cyclohex-2-enylamine (equation 54)164.

	NH2		NHCH2 Ph
	+ PhCHO	+ 2[Η ]	(54)
		− H2 O

Conditions for the optimization of the Leuckart reaction have been established. Thus heating a mixture of acetophenone, formamide and water for 6 h at 205 °C, followed by the addition of 6M hydrochloric acid, gave a 86% yield of 1-phenylethylamine (equation 55a)165.

PhCOMe + HCONH2 PhCH NH2

(55a)

Me

564	G. V. Boyd

Phenylphosphinic acid and dialkyl sulphoxides are alternatives for, respectively, the reducing agent (formic acid) and the alkylating agent (an aldehyde) used for the N-alkylation of secondary aliphatic amines (the Eschweiler Clarke procedure) (equation 55b)166.

R1R2NH C PhHPO2H C R3SO ! R1R2NR3

55b

Reductive amination of aromatic aldehydes to give benzylamines is accomplished by heating the aldehyde and tritylamine with molecular sieves, followed by the addition of sodium cyanoborohydride. Catalytic hydrogenolysis of the products with palladium on charcoal yields the benzylamines (equation 56)167.

Ph3CNH2 C ArCHO ! Ph3CNHCH2Ar ! H2NCH2Ar

56

The reductive amination of hexane-2,5-dione and heptane-2,6-dione with ammonia and primary amines RNH2 (R D PhCH2, Ph2CH, PhMeCH, Ph, 4-MeOC6H4, 2-ClC6H4 and 2,6-Me2C6H3) under the influence of sodium cyanoborohydride or sodium triacetoxyborohydride has been studied. The reactions yield respectively pyrrolidines and piperidines as mixtures of cis- and trans-isomers; no cyclic products were obtained when 2-chloroaniline of 2,6-dimethylaniline were employed (equation 57)168.

Me	O	O	Me	Me	N	Me
					R

(57)

Me O O Me	Me	N	Me
		R

A one-pot procedure for the preparation of 1,2-diamines 161 (NR12 D NMe2, NEt2 or piperidin-1-yl; R2 D Ph, Ar or 2-furyl) has been described: the lithium amide LiNR12 is added to an aldehyde R2CHO and the mixture is treated successively with an equivalent of titanium(IV) chloride and a low-valent titanium reagent prepared by reducing titanium(IV) chloride with magnesium. The products are obtained in 23 81% yields as mixtures of DLand meso-isomers169.

C2[H]

2R12NH C 2R2CHO ! R12NCHR2CHR2NR12

2H2O

(161)

12. By means of organoboron compounds

Hydroboration of alkenes generates organoboranes, which react with sodium azide in the presence of an aqueous acid to give primary amines (equation 58). Thus 1-nonene

12. Advances in the chemistry of amino and nitro compounds

565

yields nonylamine and cyclohexene cyclohexylamine170.

				R					R		R
						−
R3 B + HN3		R		B			NH			B N	H2 NR
							N2 +
									R		H
				R

58

An analogous reaction is the conversion of olefins into primary amines by the consecutive action of BH3. THF and trimethylsilyl azide171. The observation172 that organoboranes and chloramine give primary amines is the basis of an amine synthesis in which olefins are treated with the complex BH3 Ð THF, followed by aqueous ammonia and aqueous sodium hypochlorite173. Imines are reduced by the chiral dioxaborolidine 162 to yield optically active amines. 1-Imino-1-phenylpropane, for instance, affords 1- phenylpropylamine in 73% enantiomeric excess (equation 59)174.

MeOMe2 C	CMe2 OMe
O	O
	B
	H
	(162)
Ph	Ph
NH	H C NH2	(59)
Et	Et

N-Borylimines 163 (R1 D Et, Pr, Ph, 2-MeC6H4 etc), formed from cyanides R1CN and the BH3 Ð THF complex, react with organometallic compounds R2M (R D Bu, Pr, Ph etc.) to yield primary amines (equation 60)175.

					R1		R1
					N	R2	C NH2	(60)
					H	BH2	H
					(163)
	Secondary amines have been prepared from organoboron compounds R13B, R12 BCl
	1BCl		(R1	D	Et, Bu, i-Bu, s-Bu, 3-hexyl, cyclopentyl etc.) by treatment with azides
or2 R		22
R	N3	(R	D Bu, i-Bu, s-Bu, cyclohexyl, Ph etc.) and aqueous work-up. It is suggested

that the reactions proceed by way of anionotropic rearrangements (equation 61)176.

R1							R1
		−	N		R2		B N		HNR1R2	(61)
B								R2
			N2+

566	G. V. Boyd
N3 (CH2 )nN3	+ RBCl2		RNH(CH2 )nNHR
n = 2− 4
(164)	(165)		(166)

The procedure has been extended to the synthesis of N,N0-substituted diamines 166 from the diazides 164 and dichloroboranes 165177. Primary amines protected by the t- butoxycarbonyl group are obtained by the action of trialkylboranes R3B (R D Bu, s-Bu, C8H17 or cyclohexyl) on the lithium or potassium salt of t-butyl N-(tosyloxy)carbamate (equation 62)178.

−

CO2 But

+ R3 B

CO2 But

TosO

N

R

N

+

M

(62)

H

N-Chloroalkylamines R1NHCl (R1 D Me, Bu, C7H15, etc.), generated from primary amines and sodium hypochlorite, react with the alkyldimethylboranes R2BMe2 (R2 D

C6H13, cyclopentyl or cyclohexyl) to give the secondary amines R1R2NH in 50 68% yields179.

The action of diborane on the 2-vinylaziridines 167 (R D H or Me) results exclusively in the (Z)-olefins 168180.

Ph			Me			H2 N	Me
H2 C					Me		C
				B2 H6		C C	R
	N		R
					H		Ph
	H
	(167)					(168)

The Mannich reaction of secondary amines with paraformaldehyde and vinylboronic acids gives excellent yields of pure (E)-allylamines, e.g. equation 63181.

	HO	Ph
O	N + (CH2 O)n +	B
	HO

(63)

H

O N CH2 C Ph

H

A synthesis of ˇ-aminoacetylenes is exemplified by equation 64. The alkynylborane 170, generated by the action of boron trifluoride diethyl etherate on the lithium compound

12. Advances in the chemistry of amino and nitro compounds

567

169, reacts with 3-benzyltetrahydro-1,3-oxazine to yield 171182.

Me3 SiC CLi Me3 SiC CBF2

(169)(170)

+NCH2 Ph

O

	CH2 Ph	(64)
	N
CH2	CH2 C	CSiMe3
CH2

CH2 OH

(171)

13. Synthesis of olefinic and acetylenic amines

Syntheses of primary allylic amines have been reviewed183. The regiochemistry of the reaction of iron carbonyl complexes with nucleophiles such as morpholine has been investigated. The ( 3-crotyl) FeC (CO)4 BF4 complexes 172 (R1 D H; R2 D Me or R1 D Me; R2 D H) undergo preferential attack at the less substituted allyl terminus to yield allylic amines 173. The ( 2-crotyl acetate) Fe(CO)4 complex 174, on the other hand, does not react with morpholine184.

O

R1			R1	N
+ HN	O
R2 Fe+(CO)4				R2
BF4−
(172)				(173)
Me		OAc

H

Fe(CO)4

(174)

568	G. V. Boyd

-Allylpalladium complexes react with primary or secondary amines to give allylamines (equation 65)185, but ammonia is inert186.

+HN

(65)

Pd	N

For the synthesis of primary allylic amines, an allyl acetate, e.g. 175, is treated with the benzhydrylamine 176 (Ar D 4-MeOC6H4) in the presence of a catalytic amount of (Ph3P)4Pd and the product 177 is cleaved to the amine 178 with 88% formic acid186.

Pri(CH2 )3	OAc
	+		H2 NCHAr2
	(175)		(176)
Pri(CH2 )3	NHCHAr2			Pri(CH2 )3	NH2
(177)					(178)

Protected primary allylic amines are prepared from allyl halides and di-t-butyl imidodicarbonate 179 in the presence of lithium iodide, followed by the selective removal of one of the protecting groups by means of trifluoroacetic acid, e.g. equation 66187.

		CO2 But
Cl	CO2 But	N
+	HN	CO2 But
	CO2 But	(66)
	(179)
		NHCO2 But

Protected allylic amines R1R2CDCHCH2N(CO2But )2 (R1 D H or Me; R2 D H, Me, Pr or Ph) are also obtained from the corresponding allylic acetates and the reagent 179 under Pd(0) catalysis188. Allylic alcohols (CH2DCHCH2OH, MeCHDCHCH2OH and CH2DCHCHMeOH) react with aromatic amines ArNH2 (Ar D Ph, 4-MeC6H4 or 2- BrC6H4) in the presence of catalytic amounts of mercury(II) tetrafluoroborate to yield the corresponding N-allylarylamines189. The reaction of but-2-enyl chloride (180) with amines (aniline, diethylamine and diphenylamine), catalysed by copper(II) perchlorate

12. Advances in the chemistry of amino and nitro compounds

569

and metallic copper, leads to a mixture of unrearranged and rearranged allylic amines (equation 67)190.

Me	Cl + HN	Me	N	+ Me		(67)
(180)				N
Secondary allylic amines 184 have been prepared from aldehydes 181 (R1					D	H, Me
2						3
or Ph; R	D Me, Et or H) by the following sequence: treatment with an amine R NH2

(R3 D i-Pr, t-Bu, cyclohexyl or PhCH2) yields an imine 182, which is chlorinated by N- chlorosuccinimide. Dehydrochlorination of the resulting chloro compound with potassium t-butoxide gives an allylic imine 183, which is reduced to the product by means of methanolic sodium borohydride191.

		H
CHO
R1	R1	NR3		R1	NR3
R2	R2			Cl	R2
(181)	(182)
	H			H
R1	NR3	R1

	R2	NHR3
		R2
	(183)	(184)

The chiral oxirane derivative 185 (R D 4-BrC6H4CH2) and vinylmagnesium bromide yield the allylic amine 186; allylmagnesium bromide reacts in an analogous fashion192.

		Me
	H	C H				H	CH	CH2
RO	C N	Ph			RO	C			Me
							N	C	H
O						O	H	Ph
	(185)						(186)
The bismuth-	or tantalum-promoted			allylation of		aldimines 187		(R1	D Ph or

PhCHDCHCH2; R2 D Me, Ph or PhCH2) with allyl bromide in the systems Bi/Bu4NC Br /MeCN or Ta/Bu4NC Br /MeCN yields the amines 188193.

570				G. V. Boyd
							R1
R1 CH		NR2 + CH2		CHCH2 Br			CH NHR2
						CH2	CHCH2
(187)							(188)

Homoallylic amines result from the reaction of aldimines, previously activated by boron trifluoride etherate, with allylic bromides in the presence of chromium(II) chloride, e.g. equation 68194.

					NHR2
R1CH		NR2 + Br	CO2 Me	R1CH	CO2 Me

(68)

Another general synthesis of homoallylamines is the conversion of the trifluoroacetate of a primary or secondary amine into the corresponding immonium salt by the action of aqueous formaldehyde, followed by successive treatment with allyltributylstannane and dilute hydrochloric acid; e.g. equations 69 and 70 (TFA D CF3 CO2)195.

+

+

PhCH2 NH3 TFA−

PhCH2 NH

CH2 TFA−

PhCH2 N(CH2 CH2 CH

CH2 )

(69)

+

−

+

−

(70)

Et2 NH2 TFA

Et2 N

CH2 TFA

Et2 NCH2 CH2 CH

CH2

The preparation of vicinal diallyldiamines is illustrated by the following sequence: condensation of glyoxal with benzhydrylamine yields the diimine 189, which is converted into 190 by the action of allylmagnesium chloride. The diphenylmethyl groups are then removed reductively by treatment with triethylsilane196.

OHC		CHO + 2Ph2 CHNH2		H	NCHPh2
				Ph2 CHN	H
					(189)

HN	NH	H2 N	NH2
CHPh2	CHPh2
(190)

Acetylenes 191 (R1 D C5H11, Me3Si or MeS; R2 D C5H11 or C10H21) react with tantalum(V) chloride and zinc to form tantalum complexes. Addition of the imine

12. Advances in the chemistry of amino and nitro compounds

571

C8H17CMeDNMgI, produced from octyl cyanide and methylmagnesium iodide, affords adducts of unspecified structure, which are decomposed to the amines 192 by aqueous sodium hydroxide197.

				R1	R2			R1	R2
R1C		CR2				adduct		H	Me
(191)					Ta				C8 H17
									NH2
					Ln	L = ligand			(192)

Conjugated arylalkenes undergo allylic amination on treatment with N-phenylhydro- xylamine under the influence of iron phthalocyanin, e.g. equation 71. The yields from aliphatic olefins are very poor: 1-octene gives only 3% of the amine 193198.

PhCMe CH2 + PhNHOH PhC(=CH2 )CH2 NHPh

NHPh

CH2

Me

+	PhNHOH
+	PhNHOH

(71)

CH2

NHPh

+ PhNHOH

NHPh

(193)

In the presence of the dioxomolybdenum complex MoO2 (dipic) (HMPA) (dipic D pyridine-2,6-dicarboxylate, HMPA D hexamethylphosphoramide), 2-methylhex-2-ene and phenylhydroxylamine produce the amine 194 in 52% yield; other alkenes react analogously199.

Bis(4-toluenesulphonyl)selenodiimide (TosNDSeDNTos), prepared from Chloramine T and metallic selenium, reacts with olefins by insertion at the more substituted allylic

572	G. V. Boyd

+ PhNHOH

NHPh

(194)

carbon atom to yield N-tosyl-allylamines, e.g. equation 72200.

BuCH2 CH		CH2		BuCHCH		CH2

(72)

NHTos

N-Sulphinyl-4-toluenesulphonamide (TosNDSDO) and pyridine yield bis(4-toluenesul- phonyl)sulphodiimide, which reacts analogously with olefins, e.g. equation 73201.

NHTos

S

NTos

TosN S NTos +

(73)

NHTos

S

NTos

NHTos

H2 O

Mixtures of allylic tosylamines are produced from alkenes and tosyliminoiodobenzene (PhIDNTos), generated in situ from iodobenzene and 4-toluenesulphonamide under the influence of manganese tetraphenylporphyrin, e.g. equation 74202.

					+	NHTos
		NHTos
						NHTos
						+
Phosphorylated allenes 195 (R1						74
	D H or	Me) are a source of secondary (E)-allylamines.
		R	2		2	D t-Bu or 4-MeC6H4 and the
The allenes are treated with an amine				NH2 (R
products, which exist as equilibrium mixtures of					enamines 196 and imines 197, are

olefinated by successive reaction with methyllithium and an aldehyde R3CHO (R D i- Bu, 4-MeC6H4, PhCH2CH2 etc). Reduction with sodium borohydride finally yields the