Organic reaction mechanisms. 1998 / 13

13 Addition Reactions: Polar Addition

429

Ar

SAr

S

+ ArSe+ −OTf

+

(48)

Nu

1. Br2

OH

2. TfOH

....

(ArSe)2

...

.

Se

+

H

Ph

H

H

(49)

SCHEME 8

(CF3CO)2O

Me2S

Me2SO

Me2S+

OSO2CF3

Me2S+

S+Me2

(50)

Me2S+

R

Me2S+

S+Me2

R

Ar

Ar

+SMe2

(51)

(52)

Me2S+

S+Me2

+

S+Me2

(53)

Me2S

(54)

SCHEME 9

The first example of an acyclic S−S dication (50) has been prepared by acylation of DMSO with trifuoroacetyl anhydride followed by reaction with Me2S (Scheme 9). The S−S dication (50) has been shown to add across a double bond in an anti fashion: (50) + (51) → (52). Conjugated dienes undergo 1,4-addition: (53) → (54).33

In a related study, the reactions of a bicyclic dithioether dication (58) (generated from 1,4-dithiane 1-oxide) with alkenes and alkynes has been found to proceed as conjugate addition of two sulfonium groups, giving rise to derivatives of dithioniabicyclo[2.2.2]octane (56) and (57), respectively (Scheme 10). The reaction is sensitive to electronic and steric factors and appears invariably to proceed with retention of the relative arrangement of substituents at the double bond of the original alkene (58).34

430

Organic Reaction Mechanisms 1998

R

+

R2

S+

Ar

R

S

R1

R2

S+

S+

+

S+

S

R1

Ar

(56)

(55)

(57)

Ar

S+

S+

Ar

S+ S+

(58)

R

R

SCHEME 10

Additions of Hydrogen Halides and Other Acids

Ab initio calculations and density functional theory studies of the gas-phase addition of HF to CH2=CH2 have revealed the possibility of forming trimolecular (two HF and one ethylene) and dimolecular (one HF and one ethylene) complexes and transitionstate structures and of the catalytic effect of the second molecule of the reagent. An energetically favourable pathway was selected on the basis of the computed potentialenergy surface for these two reactions.35

The addition of 0.1 M quaternary ammonium halide to a solution of 20% trifluoroacetic acid in methylene chloride has been reported to cause a large rate increase in the addition of HX to simple alkenes,36 alkynes,37 and allenes.37 The proposed mechanism involves a halide-assisted protonation of the alkene, which produces a carbocation intermediate sandwiched between the attacking halide ion and the trifluoroacetate ion. At higher concentrations of halide ion, the proton-donating ability of the solution decreases, slowing the reaction and increasing the efficiency of cation capture by the halide ion. This leads to a greater proportion of unrearranged halide product. At the highest concentration of the halide ion, cation rearrangement is virtually eliminated.36,37

The acid-catalysed transannular cyclization of 8–10-membered γ ,δ-unsaturated cyclic sulfides (59) or (60) yields cis-fused bicyclic sulfonium salts (61) independently of the geometry of the double bond. The rate varies linearly with the acidity function −(H0)I with a slope of 1. The rate variations span a range of about 106, the maximum rate difference being observed for the (E/Z)-thiacyclooct-4-ene pair. The data are consistent with the classical interpretation of the intramolecular reactivity in terms of internal strain of the substrate and/or of the transition state.38

( )n or	( )n	H+		( )n
			S+
S	S
(59)	(60)	(61)

13 Addition Reactions: Polar Addition

431

Me

Me

R′O

R

Si

hn

R′OH

Si

CH

Me

Si

CH3

−C2H4

2

R

R

(62)

(63)

(64)

The reactivitiest

of a series of substituted 1-methylsilenes RMeSi=CH2 (63; R = H,

Me, Et, Bu , vinyl, ethynyl, Ph, Me3Si,

and Me3SiCH2) in hydrocarbon solvents

have been investigated by far-UV (193 nm) laser flash photolysis techniques, using the corresponding 1-methylsilacyclobutane derivatives (62) as silene precursors. Each of these silacyclobutanes yields ethylene and the corresponding silene (63), which can be trapped as the alkoxysilane (64) cleanly upon 193 or 214 nm photolysis in solution in the presence of aliphatic alcohols. UV absorption spectra and absolute rate constants for reaction of the silenes with MeOH, EtOH, and But OH have been determined in hexane solution at 23 ◦C. The rate constants vary from 3 × 107 M−1 s−1 (for reaction of 1-methyl-1-trimethylsilylsilene with But OH) to 1 × 1010 M−1 s−1 (for reaction of 1-ethynyl-1-methylsilene with MeOH). In several cases, rate constants have been determined for addition of the deuteriated alcohols, and for addition of methanol over the range 0–55 ◦C. Invariably, small primary deuterium kinetic isotope effects and negative Arrhenius activation energies were observed. These characteristics are consistent with a mechanism involving reversible formation of a silene–alcohol complex which collapses to alkoxysilane by unimolecular proton transfer from oxygen to carbon. Silene reactivity proved to increase with increasing resonance electrondonating and inductive electron-withdrawing ability of the substituents at silicon and is significantly affected by steric effects. The authors suggested that this is due to a combination of effects on both the degree of electrophilicity at silicon (affecting the rate constants for the formation and reversion of the complex) and nucleophilicity at carbon (affecting the partitioning of the complex between product and free reactants). Two 1-methyl-1-alkoxysilacyclobutanes were also investigated, but proved to be inert to 193 nm photolysis.39

Absolute rate constants for the reactions of a series of 1,1-diarylsilenes (65a–c) with MeOH, But OH, and AcOH in MeCN at 23 ◦C have been determined using nanosecond laser flash photolysis techniques. The reaction has been found to exhibit small positive Hammett ρ values, consistent with a mechanism involving initial, reversible nucleophilic attack at Si to form a σ -bonded complex that collapses via rate-limiting proton transfer. Deuterium kinetic isotope effects and Arrhenius parameters have been determined for the reaction of (65b) and (65c) with MeOH and compared with those for the parent compound (65a). Proton transfer within the complex is dominated by entropic factor, resulting in negative activation energies. A comparison of the Arrhenius activation energies for the reactions of AcOH with (65a) (Ea = +1.9 ± 0.3 kcal mol−1) and the more reactive (65c) (Ea = +3.6 ± 0.5 kcal mol−1) suggests that carboxylic acids also add by a stepwise mechanism, but with formation of the complex being rate determining.40

432						Organic Reaction Mechanisms 1998
X						X
								OH
		Si		CH2				Si		CH3

X X

(65a) X = H

(65b) X = Me

(65c) X = CF3

Additions of Electrophilic Carbon

A detailed mechanistic study of acid-catalysed monocyclization of 5,6-unsaturated epoxides, such as (66), has now provided compelling evidence for a pathway in which the oxirane C−O cleavage and the C−C bond formation are concerted.41 These experimental results are now further supported by theoretical evidence for a concerted mechanism of the oxirane cleavage and A-ring formation in epoxysqualene cyclisation, obtained at the RHF/6–31G and B3LYP/6–31 + G levels.42 The chemical pathway thus parallels the mechanism of the enzymatic cyclization43 that plays a role in the biosynthesis of isoprenoids.

			H+A−		+	−H+
					A−
H+ O				HO			HO
(66)	(67)					(68)

Additions Initiated by Metals and Metal Ions as Electrophiles

In the hydroboration of terminal alkenes, carrying a ketone or aldehyde group, with a variety of borane reagents, dicyclohexylborane has been identified as the most efficient reagent. Analogous hydroboration of alkynyl ketones and alkynyl aldehydes with dicyclohexylborane yields the corresponding olefinic carbonyl compounds after protonation, or dicarbonyl compounds after oxidation.44

The investigation of factors affecting facial selectivity in the hydroboration of steroidal5-alkenes revealed the facial (α vs β) stereoselectivities of hydroboration of androst- 5-enes (69) and B-norandrost-5-enes (70) do not parallel the difference between the calculated force-field energies for α- and β-cyclobutane models (71)–(74). This finding appears to suggest that the facial selectivity is not determined by the four-centre transition state but by the relative ease of formation of the initial π -complex.45

13 Addition Reactions: Polar Addition

433

AcO

(69)

(71)

(72)

AcO

(70)

(73)

(74)

The hydroboration of 3α-, 3β-, 6α-, and 6β-methoxyandrost-4-enes (75)–(78) has been shown to proceed predominantly trans to the MeO group, which parallels the behaviour of the corresponding alcohols. With 6-OMe derivatives (77) and (78), a small amount of Markovnikov hydration, giving 5-alcohols, has been observed.46

Epoxidation, osmylation, and bromination of 5β-androst-3-enes (79) have been found to take place from the β-face; in the last reaction, diequatorial dibromide and bromohydrin accompany the axial addition products.47

Palladacycles, such as (80), derived from tri(1-naphthyl)phosphine, proved to be very active catalysts for Heck reactions to produce (81) (ArX = PhI, 4-MeCOC6H4Br,

MeO

	OMe	H
(75) a-MeO	(77) a-MeO	(79)
(76) b-MeOH	(78) b-MeOH

Ph2P

Br

Pd

Pd

Br

Y

Y

ArX +

(80)

Ar

(80)

(81)

434 Organic Reaction Mechanisms 1998

4-NCC6H4Br; Y = Ph, CO2Me). Mechanisms based on a Pd(II)–Pd(IV) cycle were proposed and a new, very efficient method of separating the product from the catalyst

has been devised, which involves treatment with cyanide ion.48
Hydrosilylation of o-allylstyrene (82) with trichlorosilane	in the presence	of
0.3 mol% of a palladium catalyst bearing triphenylphosphine	has been found	to

produce a mixture of indane (83) and the open-chain products (84) and (85) (Scheme 11). The reaction of styrene with trichlorosilane gave a quantitative yield of 1-phenyl-1-(trichlorosilyl)ethane whereas allylbenzene did not give silylation products under the same reaction conditions. These results show that the hydropalladation process is operative in the hydrosilylation of styrene derivatives with trichlorosilane catalysed by palladium–phosphine complexes.49

			H
Cl3SiH			Pd[Si]Ln
Ph3P, [Pd]

Pd[Si]Ln

Pd[Si]Ln

	SiCl3
			SiMe3		SiCl3
(83)
(84)				(85)
	SCHEME 11

Miscellaneous Electrophilic Additions

Addition of perfluoroalkyl iodides to allyl chloride unexpectedly afforded polyfluorinated alkenes RFCH2CH=CH2 aside from the expected adduct RFCH2CH(I)CH2Cl. The ratio of these two products increased with increasing molar ratio of the reagents and temperature. A mechanistic rationale has been offered.50

A kinetic and product analysis study of the reactions of the three isomeric phenylazopyridines (86)–(88) (PAPys) in aqueous sulfuric acid media (30–97 wt% H2SO4) has been reported. The γ -isomer (86) afforded a mixture of the hydroxylated product 4-(4-hydroxyphenylazo)pyridine, the reduction products 4-aminophenol and

13 Addition Reactions: Polar Addition

435

Ph

N

Ph

N

Ph

N

N

N

N

N

N

N

(86)

(87)

(88)

4-aminopyridine, and a small amount of a dimerized product. β-Isomer (87) proved to be unreactive, but α-isomer (88) gave 2-(4-hydroxyphenylazo)pyridine, 4-amino- phenol, and 2-aminopyridine products. This reactivity pattern, resulting in an oxidized azo compound and two reduced amines, is similar to that found in the disproportionation of di-para-substituted hydrazinobenzenes observed in benzidine rearrangement studies. Consequently, it has been proposed that the corresponding [N -(4- hydroxyphenylhydrazino)] pyridines were formed as reaction intermediates in the present system, which was confirmed by showing that [N -4-(4-hydroxyphenylhydr- azino)]pyridine synthesized independently gave the same products as (86) under the same conditions. The kinetic study has demonstrated that the γ -isomer (86) reacted faster than the α-isomer (88) at all the acid concentrations investigated. Rate maxima were observed, at ca 72 wt% H2SO4 for (86) and ca 86 wt% H2SO4 for (88). To facilitate the kinetic analysis, values of pKBH2 2+ for the protonation of the substrates and the possible hydroxy products at the azo group were determined, using the excess acidity method; the first protonation occurs on the pyridine nitrogen. An excess acidity analysis of the observed pseudo-first-order rate constants as a function of acidity indicate an A2 mechanism, with the diprotonated substrate and either one HSO4− ion or one H2O molecule in the activated complex. The proposed mechanism thus involves nucleophilic attack of HSO4− or H2O at an aryl carbon of the diprotonated substrate in the slow step, resulting in an intermediate hydrazo species which gives the observed products in a subsequent fast step (cf. benzidine rearrangement).51

Nucleophilic Additions

Additions to Multiple Bonds Conjugated with C=O

High pressure vs thermal activation in the conjugate addition of amines has been examined as part of an effort to develop a new access to spirocyclamines. The reactions of methyl or ethyl 4-t-butylcyclohexylidene bromoacetates (89) with amines turned out to afford various products depending on the experimental conditions and the nature of the amine. When the starting ester (89) was treated with benzylamine in refluxing methanol, ester (90a) and the corresponding amide (90b) were isolated as the main products. By contrast, the same reaction, carried out at room temperature and under high pressure, led to a diastereoisomeric mixture of the spiroaziridine derivative (92) and (93) in good yield and high stereoselectivity.52

Microwave irradiation has been reported to accelerate the Michael addition of primary and cyclic secondary amines to esters of α,β-unsaturated α-unsubstituted carboxylic acids to produce β-amino acids.53

436				Organic Reaction Mechanisms 1998
		CO2Me		CO2Me
But			PhCH2NH2
				But
		Br		Br
				HNCH2Ph
(89)
			(91)

COX

CO2Me

But

Ph

N

NHCH2Ph

N

(90a) X = OMe

But

But

CO2Me

(90b) X = NHCH2Ph

Ph

(92)

(93)

CO2Me

CO2Me

CO2R

OH

O

O

(94)

(95)

(96) R = Me

(97) R = H

CO2Me

CO2Me

CO2Me

NH

AcONH4

O

AcONH4

NH

NaBH3CN

NaBH3CN

(E)

(Z)

(99)

(98)

(100)

SCHEME 12

Intramolecular Michael addition of N - and O-centred nucleophiles to tethered acrylates has been elucidated and the role of double-bond geometry in controlling the diastereoselectivity of cyclizations assessed. Thus, the oxyanion derived from hydroxyacrylate (E)-(94) has been found to undergo readily an intramolecular Michael addition to give the trans-2,6-disubstituted tetrahydropyran (95) as the major product. By contrast, the oxyanion obtained from (Z)-(94) cyclizes to afford the cis-2,6-disubstituted tetrahydropyran (96). This chemistry has been extended to the enantioselective synthesis of (+)-(96), an intermediate in the synthesis of acid (+)-(97), a constituent of the glandular secretion from the civet cat (Viverra civetta). Similarly, the corresponding (E)- and (Z)-ketones (98) undergo a one-pot reductive amination, followed by a diastereoselective Michael-type cyclization to produce cis- and trans-piperidines (99) and (100), respectively. Chair-like transition-state structures have been proposed to account for the diastereoselectivities observed in these cyclizations.54

13 Addition Reactions: Polar Addition

437

A kinetic study of the reaction of benzylidene Meldrum’s acid (101) with a series of thiolate and alkoxide ions RX− (X = S or O) in DMSO–water (1:1, v/v) at 20 ◦C has been reported. The reactions lead to adducts of the type (102), which can be viewed as a model for the intermediate of a nucleophilic vinylic substitution on substrates such as PhC(LG)=C(CO2)2CMe2(LG = leaving group). The kinetic measurements allowed the determination of rate and equilibrium constants for these processes with RS− = n-BuS−, HOCH2CH2S−, MeO2CCH2CH2S−, and MeO2CCH2S− and RO− = HO−, MeO− (only rate constant of breakdown of adduct), HCCCH2O−, and CF3CH2O−. The results show that there are major differences between the alkoxide and thiolate ions with respect to their thermodynamic and kinetic affinities to (101). They arise mainly from differences in the polarizability and solvation between the sulfur and the oxygen bases. Similar differences in the reactions of thiolate ions with α-nitrostilbenes have also been discussed.55

	O						Ph		O
Ph		O							O
		+ RX−				H		C −
		O				RX			O
	O								O
	(101)								(102)

An efficient asymmetric Michael addition of thiols to cycloalkenones (103) (56–90% ee) and an effective asymmetric protonation in Michael additions of thiols to non-cyclic enones (104) (75–90% ee), catalysed by LaNa3• tris(binaphthoxide) (105) and SmNa3• tris(binaphthoxide) (106) complexes, respectively, has been reported.56

Both diastereoisomers of β-homothreonine derivatives (109) and their 2-deuteriated analogues have been synthesized by 1,4-addition of homochiral lithium amides (107) as nitrogen nucleophiles to γ -alkoxyenoates (108) (Scheme 13). The product distribution of the 1,4-addition depends strongly on the nature of the substrate (110) vs

O

O

R2SH

SR2

Na

O

*

La L

O

( )n R1

( )n

O

R1

*

M

Na

(103)

O

O

O

O

Na

O

*

(105) M = La

R2SH

R3

R3

SR2

(106) M = Sm

La/Sm L

R4

R4

(104)

438	Organic Reaction Mechanisms 1998

(111). The configuration can in one case be controlled by the reagent irrespective of the substrate stereochemistry; in other cases the topicity of the addition is complementary to the published results.57

R	3	Li		R2O
		NSiMe3	+
		Ph		R1
		(107)		(108)
		Nu
		H		Me CO2Me

H

H

OR2

(110) (non-chelation)

R2O

						R1
									CO2But
CO2But						R3			NH
								Ph
								(109)
			Nu
			....
			.
				OR2
H								CO2Me
						H H
Me

(111) (chelation)

SCHEME 13

Suitably protected amino acids (112) (cysteine, serine, and lysine) have been added via the side-chain heteroatom (S, O, and N, respectively) to conjugated alkynones, alkynoic ester and alkynoic amide (113). The expected heterosubstituted vinyl product (114) was formed in each case, mainly as the E-isomer.58 In an accompanying paper,59 this type of addition was applied to the derivatives of fluorescein, 7-hydroxycoumarin, Sudan 1, and dansyl chloride with linker arms containing a conjugated terminal alkyne.

				O			O
R1XH	+
						R1X			R2
				R2
(112)	(113)						(114)

Chiral, Lewis acidic bisoxazoline complexes of Mg(II) have been employed as catalysts in asymmetric Michael addition of O-benzylhydroxylamine to unsaturated amides, (115) → (116). The enantioselectivity (67–90% ee) was rationalized by transition state (117). This approach constitutes a promising methodology for the synthesis of β-amino acids.60

Regiospecific, uncatalysed hydrophosphination of typical Michael acceptors, such as methyl acrylate, has been reported to proceed readily with alkenylan alkynylphosphine oxides, e.g. R(Pri )P(H)O. Good stereoselectivity was observed when a chiral electrophile was used. The reaction is believed to proceed owing to the strong