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Contribution

Development of New Iodocyclization and Radical Cycloaddition Reaction

Lecturer Osamu Kitagawa

Professor Takeo Taguchi

Laboratory of Synthetic Organic Chemistry, School of PharmacyTokyo University of Pharmacy and Life Science

1. Introduction

Alicyclic and N-heterocyclic compounds are basic struc-tures that are often found in natural products, medical andagricultural drugs as well as other functional materials.Given their importance, there are already many reportsregarding the synthetic methods of these cyclic compounds,such as the cyclization reactions. The importance of newcyclization reactions lies in the novelty and exhibition ofhigh-selectivity, as well as the possibility of easy procure-ment and synthesis of cyclization precursors. It is difficultto say if any of these reports about cyclization reaction meetall of these criteria.

As new cyclization reactions, we have recentlys u c c e e d e d i n d e v e l o p i n g a n i o d o c y c l i z a t i o n(halocyclization) reaction mediated by metallic reagentsand a radical [3+2] cycloaddition reaction using theiodoalkylated three-membered ring compounds obtainedby our iodocyclization reaction (Scheme 1, Formulas 2 and3). These reactions can be conducted using precursorswhich can be readily synthesized in short steps to givecarbocyclic and N-heterocyclic compounds with high regio-and stereo-selectivity. In this article we describe thesereactions which we have been working on for the last 10years or so.

Halocyclization is a reaction whereby the intramolecu-lar nucleophilic species (or group) attacks the carbon-carbon double bond activated by electrophilic halogenat-ing reagents to give cyclic compounds. This is widely usedfor syn thes iz ing he terocyc l i c compounds andfunctionalization of alkenes.1) The first report onhalocyclization reactions dates back to about 100 yearsago;2) however, there is almost no difference regarding thereagents and the reaction conditions used in modern timesfrom those reported 100 years ago. The old and new

NuH

NuH

X2

MLn, I2

X2

MLn, I2NuH

R

Nu Nu

R

I2

NuH

NuI

Nu MLn-1

Et3B

Nu

RI

-HX

Nu

NuX

R

NuI

(Conventional halocyclization)

(Our halocyclization)

NuH = COOH, OH, NHR X2 = I2, Br2, NIS, NBS

MLn = metallic reagent"activation of nucleophile""control of selectivity"

( )n ( )n ( )n

( )n( )n( )n

(Radical [3+2] cycloaddtion with iodoalkylated three-membered ring compounds)

(1)

(2)

(3)

Scheme 1. Halocyclization and radical [3+2] cycloaddition.

methods simply involve adding the halogenating reagentsto the substrate or simultaneously adding a base such asNaHCO3 in order to trap the generated hydrogen halide(Scheme 1, Formula 1).

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On the other hand, metallic reagents are nowindispensable reagents for developing new syntheticreactions and manifesting selectivity. However, there havebeen few report in which metallic reagents were effectivelyused for halocyclization. This is caused by the fact thathalogenating reagents react readily with most metallicreagents. We have focused our attention on the fact thatiodine can stably coexist with some metallic reagents, whichresulted in the successful development of an iodocyclizationreaction possessing excellent selectivity, hitherto unknown.This is achieved by performing an iodocyclization reactionin the presence of a certain type of metallic reagent(Scheme 1, Formula 2).3) We also found that iodomethylcyclopropane and iodoaziridine derivatives, obtained bythese reactions, can act as excellent precursors forhomoallyl radicals and azahomoallyl radicals respectively.Thus we have succeeded in developing iodine atomtransfer type [3+2] cycloaddition reactions with variousalkenes (Scheme 1, Formula 3). The details of thesereactions are discussed below.

2. Iodocarbocyclization Reaction

As typ i f ied by ha lo lac ton iza t ion and ha lo-aminocyclization, in the halocyclozation reactions theintramolecular nucleophiles generally consist of heteroatoms such as oxygen and nitrogen atoms (Scheme 1,Formula 1). In contrast, the so-called ‘halocarbocyclizationreaction’ which involves carbon nucleophile, especiallycarbanion, were not known. When carbanions are involved,as indicated in Scheme 2, the direct halogenation of thecarbanion (Path b) precedes the halocarbocyclization (Patha); therefore, halocarbocyclizations are difficult to realize.In fact, even when a soft carbanion, such as 4-pentenyl-malonate anion (prepared from 4-pentenylmalonate 1a andpotassium hydride) was used, no iodocarbocyclizationproduct was obtained at all from the reaction with NIS andonly α-iodomalonate was formed (Scheme 2).4)

2.1. Iodocarbocyclization Reaction of Alkenylated Malonates

We have found that, when a reaction between4-pentenylmalonate 1a and iodine is conducted in thepresence of titanium alkoxide and copper oxide (II), α-iodomalonate is not generated while iodocarbocyclizationproduct 2a is obtained in a high yield (83%) (Scheme 2).5)

This reaction proceeds via the titanium enolate, as shownin Scheme 3. In the absence of titanium alkoxide nocyclized product 2a was formed. When copper oxide (II)was not added, the yield of 2a slightly decreased to 74%.These results indicate that the key to success in thisreaction is the use of a weak base such as titanium alkoxide,while using a strong base would lead an α-iodinationreaction.

This reaction proceeds with complete regioselectivity(5-exo-cyclization) and high stereospecificity (trans-addition). Thus, when (E)- and (Z)-4-hexenylmalonate 1band 1c were used, the bicyclic lactones 3b and 3c havingthree consecutive chiral centers were fomed in a highlystereospecific manner through substitution reaction of theprimarily formed secondary iodide with ester carbonyl group(Scheme 3). Furthermore, malonate (1d) also reacted withcomplete selectivity to produce the bicylic compound 2dhaving mode to give adjacent two quaternary carbons(Scheme 3). In addition, the cyclization reaction ofallylmalonate 1e also proceeded with complete 3-exo-iodomethylcyclopropane 2e in high yield (Scheme 3).6)

Scheme 2. Halocarbocyclization and direct halogenation.

RR'

CO2Me

CO2Me

I

X2X2

X2

CO2Me

CO2Me

RR'

RR'

XR

R'

CO2Me

CO2Me

I

RR'

X

( )n

( )n

( )n

( )n

path a

path b

(major)

(minor)

1) KH2) NIS

1) Ti(Oi-Pr)4 CuO2) I2

2a (83%) 1a (90%)

( )n

CO2Me

CO2Me

R2 R1

CO2Me

CO2Me

HI

R2

R1

CO2Me

CO2Me

CH2Cl2, rt

MeI

O

MeO2C

HR1

R2

O

I2

CH2Cl2, rt

CO2Me

CO2Me

CH2Cl2, rt

OTi(Oi-Pr)n

O

MeO

R2

R1OMe

IMeO2C

CO2Me

H

I CO2MeCO2Me

Ti(Oi-Pr)4I2, CuO

1b (R1 = Me, R2 = H)1c (R1 = H, R2 = Me)

3b (96%, 3b/3c = 16)3c (96%, 3b/3c = 1/48)

Ti(Oi-Pr)4, I2

2d (77%)

5-exo-cyclizationtrans-addition

1d

Ti(Oi-Pr)4I2, CuO

1e2e (96%)

Scheme 3. Ti(OR)4-mediated iodocarbocyclization ofvarious alkenylated malonates.

2.2. Catalytic Asymmetric Iodocarbocyclization Reaction

Based on the consideration of titanium enolate inter-mediate in the present reaction, we examined theenantioselective iodocarbocyclization reaction mediated bya variety of chiral titanium reagents. We considered that ifchiral titanium enolate intermediate is generated, the

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enantiofacial differentiation of the alkene moiety would berealized at the cyclization step. Consequently, in the pres-ence of Ti(TADDOLate)2 complex the iodocarbocyclizationof various alkenylated malonates 1a, 1f and 1g proceededhighly enantioselectively to give the products 2a, 2f and2g, respectively.7) If 2,6-dimethoxypyridine (DMP) is addedas the hydrogen iodide scavenger, a high enantioselectivity(>96% ee) was demonstrated even when a catalytic amount(20 mol%) of Ti(TADDOLate)2 complex was used (Scheme4).8) Without DMP, Ti(TADDOLate)2 complex is decom-posed by hydrogen iodide generated as the reactionproceeds, resulting in a drastic decrease in both chemicalyield and optical purity of the product. These are the firstexamples of catalytic asymmetric reaction in the field ofhalocyclization reaction.

This catalytic asymmetric iodocarbocyclization reac-tion is also applicable to the enantiotopic group selectivereaction. For instance, when the iodocarbocyclization ofbisalkenylmalonate 1h is performed under the aboveconditions, only one of the prochiral alkenes in malonate1h reacted giving rise to the trisubstituted cyclopentanederivative 2h with an extremely high enantio excess (99%ee) (Scheme 4). The cyclized product 2h can be convertedto boschnialactone, an iridoid natural product, in high yield,via the path indicated in Scheme 4.

2.3. Iodocarbocyclization Reaction of Various AlkenylatedActive Methines

The above-mentioned iodocarbocyclization reaction isapplicable only to alkenylated malonate. No products weregenerated in the case of iodocarbocyclization of 4-pentenyl-2-phosphonoacetate 1i and sulfonyl acetate 1j in thepresence of titanium alkoxide and iodine. It seems that thisis because the titanium enolates of 1i and 1j were notgenerated under the above-mentioned conditions. We havefound that when titanium tetrachloride and triethylamineare used, the titanium enolate is effectively generated froma variety of alkenylated active methine compounds 1i-1l ,a n d t h a t b y s u b s e q u e n t l y a d d i n g i o d i n e ,iodocarbocyclization products 2i-2l are obtained in goodyield (Scheme 5).9)

XCO2Me

CO2Me

CO2Me

CO2Me

O

O

O

OTi

Me

Me

Ph Ph

Ph Ph

O

O

HO H

H

O

O

H

H

O

H

H

O

NMeO OMe

I2

H

H

OBnOBn

CO2Me

CO2MeI

X

OTiO

MeO

OMe

O

OHO

O

∆

O

MeO2C

H

O

XCO2Me

CO2Me

I

Ti(TADDOLate)2 (0.2 eq)I2 (4 eq), DMP (2 eq)

"chiral Ti-enolate"

2a (87%, 98% ee)2f (76%, 98% ee)2g (60%, 96% ee)

Ti(TADDOLate)2 (0.2 eq)I2 (4 eq), DMP (2 eq)

CH2Cl2-THF (4:1), -78 °C

3h 80% (99% ee)

2

Ti(TADDOLate)2 DMP (HI scavenger)

1) 1N NaOH2) ∆, xylene

1) LiAlH42) NaH, BnBr

(96 %) (98%)

1) BH3/THF2) Jones Oxi3) H2/Pd-C

(75%)

1) TsCl, Py2) NaI, Zn

(65%)

(+)-boschnialactone

CH2Cl2-THF (4:1), -78 °C

(Enantiofacial selective reaction)

1a X = CH21f X = CMe21g X = O

(Enantiotopic group selective reaction and its application to synthesis of boschnialactone)

1h 2h

4 5

6

Scheme 4. Catalytic asymmetric iodocarbocyclizationwith chiral titanium alkoxide.

X

CO2Me

I2

CO2Et

P(O)(OEt)2

CH2Cl2, rt

CH2Cl2, rt

X TiCl3

O

OMe

I

P(O)(OEt)2EtO2C

I

CO2Me

X

I

P(O)(OEt)2EtO2C

I

CO2Me

X

1) TiCl4, Et3N2) I2

+

2i (78%, 12/1)2j (81%, 8.6/1)2k (92%, 1.4/1)

1) TiCl4, Et3N2) I2

2l (78%, 2/1)

1i X = P(O)(OEt)21j X = PhSO2 1k X = CN

1l

+

Scheme 5. TiCl4-mediated iodocarbocyclization ofvarious alkenylated active methine compounds.

Interestingly, when the iodocarbocyclization reactionwas applied to alkynyled malonate 1m , inversed stereo-selectivity was observed depending on the titanium reagentused.9) When 1m was reacted with titanium alkoxide andiodine, (E)-2m was obtained with high selectivity (E/Z =28) through the iodocarbocyclization reaction (trans-addition). When 1m was reacted with titanium tetrachlo-ride, triethylamine, and iodine, the reaction proceededthrough an intramolecular carbotitanation of the thetitanium enolate to the alkyne (cis-addition) to generate the(Z)-vinyl titanium intermediates which on subsequentlyiodination gives (Z)-2m with complete stereoselectivity(Scheme 6).

Therefore, when titanium tetrachloride is used, thealkyne bond would be activated by the strong Lewis acidityof the titanium atom of trichlorotitanium enolate intermedi-ates to promote carbotitanation prior to the iodo-carbocyclization.

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Scheme 6. Iodocarbocyclization and intermolecularcarbotitanation of alkynylated malonates.

Furthermore, we examined iodocarbocyclization ofdifluoroalkenylated malonates and obtained satisfactoryresults by using tin tetrachloride and triethylamine.10) Whicha 5-endo cyclization product 2n was obtained fromreaction of 4,4-difluoro-3-butenylmalonate 1n, and a 5-exocyclization product 2o was obtained as the principalcomponent from reaction of 5,5-difluoro-4-pentenylmalonate 1o (Scheme 7), which was similar to the reactiono f t h e n o n - f l u o r i n a t e d s u b s t r a t e 1 a . T h eiodocarbocyclization reaction of 3-butenylmalonate, a non-fluorinated counter part of 1n, was examined undervarious conditions; however, no cyclized product could beisolated. Therefore, it is evident that the endo-cyclizationselectivity of 1n is caused by the effect of the fluorinesubstituent.

3. Iodoaminocyclization Reaction

The iodoaminocyclization reaction has already beenreported11) and thus it is not necessarily a novel reaction,though some issues still remain to be solved. For instance,N- or O-cyclization is possible with the substrates havingan ambident nucleophilic centers such as amide,carbamate, and urea. In these cases, N-cyclization has notbeen prevalent. Furthermore, haloaminocyclization to formthe three-membered aziridine ring, i.e., haloaziridinationreaction, has never been reported. We have succeeded indeveloping a method for N-selective cyclization of ambidentnucleophiles including the haloaziridination reaction.

3.1. N-Selective Iodoaminocyclization Reaction ofAlkenylted Amide, Carbamate, and Urea Derivatives

It is well known, that in the halocyclization reactions ofalkenylated amide, carbamate, and urea derivatives, O-cyclization is preferred to N-cyclization. This is readilyunderstood in terms of the HSAB theory as shown inScheme 8. We have found that the iodocyclizationreaction of an ambident nucleophile proceeds with acomplete N-cyclization selectivity when mediated by alithium reagent.12) For instance, the iodocyclizationreaction of N-allylurea 7a gave only O-cyclized product 8a'under normal conditions using sodium bicarbonate(I2-NaHCO3), while a reaction using n-BuLi or LiAl(Ot-Bu)4gave N-cyclization product 8a with almost completeselectivity (Scheme 8). Although the effect of lithiumreagents on the N-cyclization selectivity have not beenclear, we have shown that this selectivity was greatly influ-enced by the metallic reagent used. When sodium hydridewas used, a mixture of N-cyclization product 8a and O-cyclization product 8a' was obtained.

CO2Me

CO2Me

CH2Cl2, rt

CH2Cl2, rt

I2

CO2Me

CO2Me

TiCl3

OTi(Oi-Pr)n

O

MeO

OMe

CO2Me

CO2Me

I

CO2Me

CO2Me

I

Ti(Oi-Pr)4, I2

1) TiCl4, Et3N2) I2

cis-addition

E-2m (84%, E/Z = 28)

Z-2m (79%, Z only)

trans-addition

1m

CO2Me

CO2Me

CH2Cl2, rt

IF

F

MeO2CCO2Me MeO2C

CO2Me

CF2I

1n (n=1)

1o (n=2)

( )n

1) SnCl4, Et3N2) I2 or

2n (5-endo, 70%)2o (5-exo, 58%)

F F

Scheme 7. Iodocarbocyclization of difluoroalkenylatedmalonates.

As shown above, the iodocarbocyclization reactiondeveloped by us is applicable to various alkenylated andalkynylated active methine compounds. The reactionproceeds with complete regioselectivity and with highstereoselectivity. Furthermore, the cyclization precursor (1)can be synthesized in a short steps in a satisfactory yield,by means of an alkylation reaction of active methylenecompounds.

Y

OX

NR

NH

NHCO2Et

O

n-BuLi

NaH

NaHCO3

LiAl(Ot-Bu)4

X2 Y

NHR

O

NH

NCO2EtI

O NH

OI

NCO2Et

Y

NRX

O( )n ( )n( )n

N-cyclizationO-cyclization

hardnucleophile

softnucleophile

hardelectrophile

(major) (minor)

1) Additive2) I2

+

(N-cyclization) (O-cyclization)

0% 77%

7a Additive 8a 8a'

45% 21%

88% trace

88% 0%

Scheme 8. Halocyclization of ambident nucleophile.

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An iodoaminocyclization reaction that uses a lithiumreagent is applicable to various alkenylated urea,carbamate, and amide derivatives 7a-7f and in all cases,N-cyclized products 8 were exclusively obtained in satis-factory yield and with complete selectivity (Scheme 9).Furthermore, this reaction is applicable not only to formfive-membered ring cpmpounds, but also to form six-membered rings, as in the cases of 7b and 7e (n=2).Fukuyama et al. recently reported that this reaction is alsouseful for the construction of the nitrogen-containing qua-ternary center.13)

The cyclization substrates for this reaction, alkenylatedurea, carbamate, and amide derivatives 7, can be readilysynthesized by reactions of commercially available N-alkoxycarbonylisocyanates with alkenyl alcohols,alkenylamines, and alkenylmagnesium reagents.

NHTsR1

R2

R3 1) t-BuOK (1 equiv)2) I2 (3 equiv)

NHTs t-BuOK (1 equiv) I2 (3 equiv)

NTs

I

K

I2

N

Ts

R1

R2

R3 TsNR1

I

R3

R2

109toluene

9b (R1 = R2 = H, R3 = Me)9c (R1 = R2 =Me, R3 = H)9d (R1 = Me, R2 = R3 = H)9e (R1 = R3 = H, R2 = Me)

"3-exo-cyclization""trans-addition"

10b (90%)10c (74%)10d (80%)10e (88%)

toluene( )n

9f (n = 1), 9g (n = 2)

10f (n = 1, 92%)10g (n = 2, 63%)( )n

Scheme 11. Iodoaziridination of various N-allyltosylamides.

Y

NHCO2R

O Y

NCO2RI

O( )n

1) LiAl(Ot-Bu)4 2) I2

7

toluene, 0 °C

8

Y = O, NR, CH2R = Et, Bn, t-Bun = 1, 2

(62-88 %)"complete N-selectivity"

( )n

7b (Y = NH, R = Et, n = 2)7c (Y = O, R = Et, n = 1)7d (Y = O, R = t-Bu, n = 1)7e (Y = O, R = Et, n =2)7f (Y = CH2, R = Et, n = 1)

8b (86%)8c (85%)8d (68%)8e (73%)8f (69%)

NHTsTsN

I9a

I2, NBS or NISno reaction

1)Additive2) I2 10a

Additiven-BuLiNaHt-BuOK

Yield53%81%94%

Scheme 9. Regio-controlled iodoaminocyclization ofambident nucleophile mediated by lithium reagent.

3.2. Iodoaziridination Reaction of N-AllyltosylamideDerivatives

For the three-membered ring-forming reaction usinghalocyclization, there is one report on halo epoxidationreaction of allyl alcohol derivative.14) However, only limitedsubstrates gave the products in satisfactory yield. Asdescribed above, we found that in the iodocarbocyclizationreaction of allylated active methine compounds 1e and 1l ,the iodomethylcyclopropane derivatives 2e and 2l wereobtained in good yield (Schemes 3 and 5). This resultindicates that a three-membered ring-forming reactionusing halocyclization would be feasible. With this in mind,we examined the three-membered haloaminocyclization re-actions (haloaziridination reactions), which had not beenpreviously reported.

As shown in Scheme 10, with N-allyltosylamide 9aoccured no reaction when just treating with the halogenat-ing reagent. On the other hand, we found thatiodomethylaziridine 10a was obtained in satisfactory yieldwhen this reaction was run in the presence of an alkalimetal reagent and iodine.15) For the metallic reagent,t-BuOK was the most effective, giving 10a in 94% yield.

Scheme 10. Additive effect in iodoaziridination reaction.

Iodoaziridination reaction using t-BuOK and iodine wasapplied to various N-allyltosylamide derivatives 9a-9e, togive the products 10a-10e in satisfactory yield. The reac-tions proceeded with complete regioselectivity (3-exo-cyclization) and stereoselectivity (trans-addition). Moreover,reactions of N-cycloalkenyltosylamide such as 9f and 9galso proceeded in satisfactory yield to afford the bicycliciodoaziridine 10f and 10g.

Next, we would like to report radical [3+2] cycloaddi-tion reaction using iodoalkylated three-membered ring com-pounds 2e and 10, which were synthesized in the mannerdescribed above.

4. Radical [3+2] Cycloaddition Reaction UsingIodomethylcyclopropane Derivatives

The radical [3+2] cycloaddition reaction of homoallylradicals with alkenes, is useful for the one-step synthesisof cyclopentane compounds, and many reports dealing thisreaction have been appeared (Scheme 12).16) The usualhomoallyl radical is a nucleophilic radical, which reacts withelectron-deficient alkenes such as α,β-unsaturated carbo-nyl compounds (Scheme 12). In contrast, allyl substituted

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EE

I

E1

E

EI

II

E2

E2

E

ER

E

E

R

EE

E

EI

II

I

"nucleophilic radical"

"electrophilic radical"

"electron-defficient alkenes"

"simple alkenes"

E1 = E2 = electronwithdrawing group

(Known allylated active methine radical precursors)

(Possible side reaction in the reaction with I or II)

or

(E = CO2R, CN)

EE

EE

I

RR

E E

EE

R

E E

I

E

ER

2e (E = CO2Me)

radicalinitiator

11

active methine radicals are known as electrophilic homoallylradicals, and these are synthetically very useful becausethey can react with enol ether and simple alkyl substitutedalkenes. Meanwhile, the vinylcyclopropane derivative Ι17)and iodomalonate ΙΙ18), the precursors of the allylatedactive methine radicals so far reported, possess analkene part and therefore, the generated allyl activatedmethine radical possibly attacks the alkene group of otherradical precursor molecule, which is an undesired sidereaction (Scheme 12). In order to avoid these sidereactions, a large excess amount of alkene must be usedor an alkene with high reactivity must be used. However,these are not always definite solutions.

Scheme 12. [3+2] Cycloaddition with homoallyl radicalspecies.

We considered that iodomethylcyclopropane-1,1-dicarboxylate 2e, which can readily be synthesized by theabove-mentioned iodocarbocyclization of allylmalonate 1e(Scheme 3), could be an efficient allylated active methineradical precursor. We anticipated that when 2e is treatedwith a radical initiator, the allylmalonate radical would begenerated through regioselective cleavage of thecyclopropylmethyl radical. The resulting allyl radical isexpected to undergo an iodine atom transfer [3+2] cyclo-addition reaction with an alkene (Scheme 13). In thismanner, 2e was assumed to be an allylated active methineradical precursors with alkene moiety protected.

Scheme 13. Radical iodine atom transfer [3+2] cyclo-addition with iodomethylcyclopropane.

The rad ica l cyc loadd i t ion reac t ions o f theiodomethylcyclopropane 2e with a variety of alkenesprovided satisfactory results (Scheme 14).19) For instance,when the reaction between 2e and silylenol ether wasconducted using triethylborane as a radical initiator, weobtained the iodine atom transfer cycloaddition product 11ain high yield (79%). On the other hand, the reaction withalkyl-substituted alkene such as 1-hexene required thepresence of Yb(OTf)3 in addition to triethylborane; withoutYb(OTf)3 , the yield dropped significantly to 22%. It wasconsidered that Yb(OTf)3 enhances the electrophilicity ofthe allylmalonate radical and promotes the reaction byforming a chelated complex with the malonate carbonylgroup. This reaction is applicable to a variety of alkenes. Itis worth noting that even a 1,2-disubstituted alkene, whichis generally unreactive by conventional methods becauseof the low reactivity can undergo the cycloaddition reactionin a satisfactory yield. For instance, bicyclo[3.3.0]octanederivative 11d was obtained in a yield of 70% from thereaction with cyclopentene (Scheme 14). Furthermore, ata low temperature (0 °C and below), higher stereoselectivitywas observed in the reactions with alkyl-substitutedalkenes, when compared with that by conventionalmethods.

EE

I

R1 R2Et3BAdditive

CH2=CHOTMS

Yb(OTf)3

Yb(OTf)3

R2

E E

IR1

2e (E = CO2Me) 11

+CH2Cl2, 0 °C

Alkenes Products 11 Yield

(2 eq)

11a (R1= OH, R2= H)

cis/transAdditive

1/1.8 79%

1-hexene 11b (R1=H, R2=n-Bu) 8.8 22%

1-hexene 11b (R1=H, R2=n-Bu) 11.2 82%

methylenecyclohexane 11c (R

1=R2= -(CH2)5-) 88%

Et3BYb(OTf)3

EE

I

2e11d (E=CO2Me)

+CH2Cl2, 0 °C

(5 eq)

H

H

70% (single stereoisomer)

Scheme 14. Radical [3+2] cycloaddition of 2e withvarious alkenes.

A cascade reactions could be performed when thecycloaddition reaction of 2e is conducted with 1,4-dienederivative. This involves three separate carbon-carbon bondformation, that is, the initial [3+2] cycloaddition reaction isfollowed by a 5-exo cyclization, which produces the bicyclo[3.3.0]octane derivative 11 in one step (Scheme 15).20)

A complete regioselectivity was observed in the reaction of2e with an unsymmetrical 1,4-diene derivative (R≠H).For instance, in the reaction with 1,4-hexadiene (R=Me),the initial reaction by the allylmalonate radical occurredexclusively at the most reactive 1-alkene position.

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Products derived from the initial attack of the active methineradical at the 1,2-disubstituted alkene moiety were notdetected. Consequently, we established that radicalcycloaddition using 2e provides a useful one-step syntheticmethod not only for cyclopentane ring formation but alsofor bicyclo[3.3.0]octane ring formation.

5. Radical [3+2] Cycloaddition Reaction UsingIodoaziridine Derivatives

Next, we would like to describe the radical [3+2]cycloaddition reaction using the iodoaziridine derivative 10(Scheme 17). This reaction is similar to the reactions usingiodoalkylcyclopropanes. The [3+2] cycloaddition reactionof azahomoallyl radicals (2-alkenylamine radical) withalkenes, provides a one-step synthetic route to pyrrolidinederivatives. In contrast to a number of examples withhomoallyl radicals, only one report by Newcomb et al. hasdescribed such a reaction (Scheme 16),21) in which thereremained various issues, such as:

1) A large excess of alkene (100 equiv) was required, andthe yield was only 50-59%.

2) Only three examples using enol ether derivatives, asole structural variant, were shown and thus, theapplication and limitation of the reaction remainunclear.

3) A Brønsted acid was required in order to generate anallylamminium radical, which is more reactive species.

Most of the reactions between nitrogen radicals andalkenes, are limited to intramolecular 5-exo cyclization,which is due to entropy effects.22) Only a few examplesregarding intermolecular versions were reported becausethe reactivity of the nitrogen radical is known to besignificantly lower than that of the carbon radical. Further-more, efficient nitrogen radical precursors have not beendeveloped.

EE

I

REt3BYb(OTf)3

R

E

E

H

H

I DBU

R

E

E

H

H

EE

R

2e (E = CO2Me)

CH2Cl2, 0 °C+

11e (R=H) 78%, 11f (R=Me) 75%

Scheme 16. [3+2] Cycloaddition with azahomoallylradical species.

N

S

O

O

NR

OEt

NR

NR H

OEt

NR

H3C OEt

"homoallyl radical" "azahomoallyl radical"

"electrophilic""less reactive"

"nucleophilic"

t-BuSHH+, hν

Newcomb et al (1990)

+

R=C7H15, (56%)(100 eq)

Scheme 17. Radical iodine atom transfer [3+2] cyclo-addition with iodoaziridine.

TsN

I

TsN

R

NR Ts

NTs

R

NR R'

TsN

NTs

RI

TsN

RN

R'

H

Rradicalinitiator

12

(less reactive) (more reactive)(more reactive)

10a

Scheme 15. Radical cascade cycloaddit ion ofiodomethylcyclopropane with 1,4-dienes.

We anticipated that iodoaziridine derivatives would beefficient azahomoallyl radical precursors. Furthermore,these precursors could be readily synthesized by the above-mentioned iodocarbocyclization of N-allyltosylamidederivatives. When iodoaziridine 10a is treated withtriethylborane, the allylamidyl radical should be generatedthrough regioselective cleavage of the initially generatedaziridinylmethyl radical. The subsequent [3+2] cycloaddi-tion reaction might proceed in the presence of alkenes togive the pyrrolidine derivatives. The nitrogen radical is anelectrophilic radical (Scheme 16) whose reactivity is knownto improve as the electron density is decreased (Scheme17). Therefore, the tosylamidyl radical generated from 10awas also expected to possess higher reactivity towardalkenes than the usual aminyl radical.

First, we examined reactions between iodoaziridine 10aand various alkenes (Scheme 18). Reactions with enol etherand ketene acetal were conducted in the presence oftriethylborane, and both resulted in cycloaddition products12a-12c in high yield (62-71%).23,24) As initially anticipated,the reactivity of N-allyl(tosyl)amidyl radical generated fromthis reaction was relatively high and the reactionsproceeded effectively, even in the presence of only two-equivalent of alkenes. Next, we examined the reaction with

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alkyl-substituted alkenes, which produced lower yields,compared to enol ether derivative (Scheme 18). Asmentioned above, the nitrogen radical is an electrophilicradical, and therefore, its reactivity with an alkene isdecreased as the electron density of the alkene declines.This was the case in the reaction of 10a with 1-hexenewhere the yield was only 34% (12e). The stereoselectivityin reactions of allylamidyl radical and alkenes wasgenerally low, and this issue remains to be solved.

Scheme 18. Radical [3+2] cycloaddition of 10a withvarious alkenes.

TsN

IR1 R2 Et3B

CH2=CHOTMS

CH2=C(Me)OMe

CH2=C-O(CH2)4O-

NTs

R2I

R1

12

+C6H6, rt

Alkenes Products 12 Yield

(2 eq)

12a (R1= OH, R2= H)

cis/trans

1.3 66%

12b (R1=Me, R2=OMe) 1/1.7 71%

1-hexene 12e (R1=H, R2=n-Bu) 2.1 34%

methylenecyclohexane

12d (R1=R2= -(CH2)5-) 56%

10a

12c (R1=R2= -O(CH2)4O-) 62%a

asingle stereoisomer

Scheme 19. Radical [3+2] cycloaddition with bicycliciodoaziridines.

NTs

I

OOEt3B

TsN

O O

TsN

H

HI OO

10f (n=1)10g (n=2)

( )n+

(2 eq)

C6H6, rt( )n

( )n

12f (64%)12g (59%)

"complete stereoselectivity"

(+)-10g (n=2, 94%ee) (+)-12g (61%, 93%ee)

6. Conclusion

As described above, we have succeeded in develop-ing new iodocyclization reactions mediated by metallicreagents. Furthermore, we have succeeded in developinga [3+2] cycloaddition reaction using the iodoaziridine asthe radical precursor. The reactions proceed with highregioselectivity and stereoselectivity using readilysynthesized precursors. Therefore, these are usefulsynthetic method of carbocyclic compounds and nitrogenheterocyclic compounds.

This research was enabled by the efforts made by ourco-researchers appeared in the References section belowand we would like to express our sincere gratitude to them.We would also like to thank the Ministry of Education forfunding this research and for the Japan Society for thePromotion of Science for supporting our research.

References

1) For reviews in relation to halocyclization: a) P. A.Bartlett, In Asymmetric Synthesis, Ed. J. D. Morrison,Academic Press, Orland, 1984, Vol. 3, p411. b) G.Cardillo, M. Orena, Tetrahedron, 46, 3321 (1990). c)K. E. Harding, T. H. Tiner, In Comprehensive OrganicSynthesis, Eds. B. M. Trost, I. Fleming, pergamonPress, New York, 1991, Vol. 4, p363.

2) M. J. Bougalt, Compt. Rend., 139, 864 (1904).3) For a review: a) O. Kitagawa, T. Taguchi, Synlett, 1191

(1999).4) D. P. Curran, C. Chang, J. Org. Chem., 54, 3140 (1989).5) a) O. Kitagawa, T. Inoue, T. Taguchi, Tetrahedron Lett.,

33, 2167 (1992). b) O. Kitagawa, T. Inoue, K. Hirano,T. Taguchi, J. Org. Chem., 58, 3106 (1993). c) T. Inoue,O. Kitagawa, Y. Oda, T. Taguchi, J. Org. Chem., 61,8256 (1996).

6) T. Inoue, O. Kitagawa, O. Ochiai, T. Taguchi,Tetrahedron: Asymmetry, 6, 691 (1995).

7) T. Inoue, O. Kitagawa, S. Kurumizawa, O. Ochiai, T.Taguchi, Tetrahedron Lett., 36, 1479 (1995).

8) T. Inoue, O. Kitagawa, A. Saito, T. Taguchi, J. Org.Chem., 62, 7384 (1997).

9) O. Kitagawa, T. Suzuki, T. Inoue, Y. Watanabe, T.Taguchi, J. Org. Chem., 63, 9470 (1998).

10) A. Saito, M. Okada, Y. Nakamura, O. Kitagawa, H.Horikawa, T. Taguchi, J. Fluorine Chem., 123, 75(2003).

11) a) A. J. Biloski, R. D. Wood, B. Ganem, J. Am. Chem.Soc., 104, 3233 (1982). b) M. Hirama, M. Iwashita, Y.Yamazaki, S. Ito, Tetrahedron Lett., 25, 4963 (1984).c) S. Knapp, A. Levorse, J. Org. Chem., 53, 4006(1988).

12) M. Fujita, O. Kitagawa, T. Suzuki, T. Taguchi, J. Org.Chem., 62, 7330 (1997).

13) T. Itoh, M. Watanabe, T. Fukuyama, Synlett, 1323(2002).

On the other hand, a reaction between a bicycliciodoaziridine 10f (n=1), 10g (n=2), and a ketene acetalproceeded with almost complete stereoselectivity and gavethe bicyclic pyrrolidine derivatives 12f and 12g (Scheme19). Since the octahydro-indole ring system is a basicstructure that is often found in bioactive natural alkaloids,we examined asymmetric synthesis of 12g. We conducteda reaction of the optically active iodoaziridine (+)-10g (94%ee) with the ketene acetal, which proceeded withoutracemization to yield (+)-12g with 93% ee. We arecurrently examining the synthesis of octahydro-indolenatural products using optically active (+)-12g .

10

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14) R. D. Evans, J. W. Magee, J. H. Schauble, Synthesis,862 (1988).

15) O. Kitagawa, T. Suzuki, T. Taguchi, J. Org. Chem., 63,4842 (1998).

16) For reviews: a) P. Dowd, W. Zhang, Chem. Rev., 93,2091 (1993). b) A. J. McCarroll, J. C. Walton, J. Chem.Soc., Perkin Trans. 1, 3215 (2001). c) T. R. Rheault,M. P. Sibi, Synthesis, 803 (2003).

17) a) K. S. Feldman, A. L. Romanelli, R. E. Jr. Ruckel, R.F. Miller, J. Am. Chem. Soc., 110, 3300 (1988). b) K.Miura, K. Fugami, K. Oshima, K. Uchimoto,TetrahedronLett., 29, 5135 (1988).

18) a) D. P. Curran, M. Chen, E. Spletzer, C. Seong, C.Chang, J. Am. Chem. Soc., 111, 8872 (1989). b) B. B.Snider, B. O. Buckman, Tetrahedron, 45, 6969 (1989).

19) O. Kitagawa, Y. Yamada, H. Fujiwara, T. Taguchi, J.Org. Chem., 67, 922 (2002).

20) O. Kitagawa, Y. Yamada, A. Sugawara, T. Taguchi, Org.Lett., 4, 1011 (2002).

About the Authors:

Osamu Kitagawa , Lecturerat School of Pharmacy, Tokyo University of Pharmacy and Life Science

[Personal History]1984 Graduated from Tokyo University of Pharmacy and Life Science.1989 Completed a Ph.D. at Tokyo University of Pharmacy and Life Science and assumed a position as anassistant lecturer at the same university.1993-1994 Post-Doctoral Researcher at University of Kansas.1995 Assumed current position.

[Expertise]Synthetic organic chemistry.

Takeo Taguchi , Professorat School of Pharmacy, Tokyo University of Pharmacy and Life Science

[Personal History]1969 Graduated from Department of Chemistry, Faculty of Science, Tokyo Institute of Technology.1974 Completed a Ph.D. at Tokyo Institute of Technology and assumed a position as an assistant lecturerat the same university.1976 Lecturer at the School of Pharmacy, Tokyo University of Pharmacy and Life Science1981 Post-Doctoral Researcher at UCLA.1989 Assumed current position.

[Expertise]Synthetic organic chemistry, organic fluorine chemistry.

21) M. Newcomb, M. U. Kumar, Tetrahedron Lett., 31, 1675(1990).

22) For reviews in relation to nitrogen centered radicals:a) L. Stella, Angew. Chem. Int. Ed. Engl., 22, 337(1983). b) J. L. Esker, M. Newcomb, In Advances inHeterocyclic Chemistry; Ed. A. R. Katritzky, AcademicPress: San Diego, 1993, Vol. 58, pp 1-45. c) A. G.Fallis, I. M. Brinza, Tetrahadron, 53, 17543 (1997).

23) a) O. Kitagawa, Y. Yamada, H. Fujiwara, T. Taguchi,Angew. Chem. Int. Ed., 40, 3865 (2001). b) O.Kitagawa, S. Miyaji, Y. Yamada, H. Fujiwara, T. Taguchi,J. Org. Chem., 68, 3184 (2003).

24) At around the same time, a similar addition-cyclizationreaction, which uses azahomoallyl radical, wasreported by Oshima et al.T. Tsuritani, H. Shinokubo, K. Oshima, Org. Lett., 3,2709 (2001).

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DPA ETHYL ESTER

D2964 DPA Ethyl Ester ( = Ethyl all cis -7,10,13,16,19-Docosapentaenoate) (1) 100mg

S0483 Seal Oil (2) 100ml

INTRAMOLECULAR ACYLATING REAGENT

D2883 Diphosphoryl Chloride (1) 25g

There has been much research focused on EPA and DHA and the biological activities of ω-3 polyunsaturated fatty acid (PUFA) are now under great scrutiny. This is particularly so, since a relationshipbetween thrombosis disorders has been linked with EPA. Currently, PUFA is under vigorous R&D studies,and it has already been utilized in EPA preparation for the treatments of hyperlipemia and other adverseconditions such as ulcer, gout and chills related to arteriosclerosis obliterans.

On the other hand, the research progress on DPA, which is also classified as ω-3 PUFA, has beendelayed because it is present in very small quantities. However, the potency of DPA stimulation ofEndorhelial cell migration is much higher and it is reported that it has 100 times greater activity than EPA,and for this reason it is now coming to the fore.1) Furthermore, DPA demonstrates the possibilities ofantithrombotic2) and antiangiogenesis3) activity. Of all the important findings, its antiangiogenesis activityis expected to be effective in cancer treatment and for this reason DPA is attracting much of the attentionsthese days.

1 is DPA ethyl ester which has been highly purified using the original technology developed atTokyo Kasei Kogyo, Co., Ltd. It is suitable for use in the experiments at cellular levels. The seal oil is thebest source of DPA, which comes in the form of glycerides along with other natural oils, and it is used forbioactivity tests of DPA in animal studies.

References1) T. Kanayasu-Toyoda, I. Morita, S. Murota, Prostaglandins, Leukot. Essent. Fatty Acids, 54, 319 (1996).2) S. Akiba, T. Murata, K. Kitatani, T. Sato, Biol. Pharm. Bull., 23, 1293 (2000).3) M. Tsuji, I. Morita, S. Murota, Kekkan (Japanese J. Circlation Resarch), 25(1), 5 (2002).

1

EPA : 7%DHA : 9%DPA : 4%

Composition of the main ω-3 poly unsaturated fatty acid (PUFA) of Seal Oil.

COOEt

Cl P O

Cl

P

O

Cl

Cl

1HOC

O

CCl2PO O

O

Y. 90%

HOPCl2

43

OO

O+

2

El-Sayrafi and co-workers have reported on an intramolecular acylation reactions using diphosphorylchloride 1. Diphosphoryl chloride (1) reacts with carboxylic acid 2 to give cyclic ketones 4 via the mixedacid anhydride 3. This reaction proceeds under mild conditions and within short period of time, and it givecyclic ketones in high yields. Also, 1 is used for phosphorylation, and has been used in various fields as areaction reagent.

Reference1) Intramolecular acylation of aryl- and aroyl-aliphatic acids

S. El-Sayrafi, S. Rayyan, Molecules, 6, 279 (2001).

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USEFUL REAGENTS for PRIMARY and SECONDARY AMINE SYNTHESIS

A1632 N-Allyloxycarbonyl-2-nitrobenzenesulfonamide (1a) 5gB2303 N-(tert -Butoxycarbonyl)-2-nitrobenzenesulfonamide (1b) 5g, 1gC1757 N-Carbobenzoxy-2-nitrobenzenesulfonamide (1c) 5g

USEFUL CHIRAL BUILDING BLOCK

A1620 (R)-3-(Acetylthio)isobutyryl Chloride (1) 25g

Fukuyama and co-workers have recently demonstrated the amination of alkyl halides and alcoholsusing the N-substituted sulfonamide 1.1a) Smooth reactions of 1 occur with alkyl halides under basicconditions and alcohols under Mitsunobu conditions to provide o-nitrobenzenesulfonyl (o-Ns) amines 2.The various o-Ns amines (Alloc, Boc, Cbz) 2 obtained from these reactions can be deprotected, under theappropriate conditions, to afford the monoprotected amines 3 and 4. Furthermore, 3 can be converted tothe primary amine 5 in high yields via a second deprotection. Compound 4 can be converted to the second-ary amine 6 in high yields by repeating the alkylation and deprotection process.1b)

References1) Synthetic utility of N-carboalkoxy-2-nitrobenzenesulfonamides

a) T. Fukuyama, M. Cheung, T. Kan, Synlett, 1999, 1301.b) T. Kan, A. Fujiwara, H. Kobayashi, T. Fukuyama, Tetrahedron, 58, 6267 (2002).

R1NHY R1NH2

R1NHR2

12

3

4

5

6

Y =

a)

RS

i) c)

ii) RS

b)

b)

b) Whena) R1X, K2CO3, DMF

R1OH, DEAD, PPh3

c) R2X, K2CO3, DMF

R2OH, DEAD, PPh3

SO2NHY

NO2NO2

O2SN

R1

Y

SO2NHR1

NO2

-

-

1a Pd(Ph3)4, pyrrolidine1b TFA1c BCl3

Alloc 1aBoc 1bCbz 1c

or or

1

Me S

O

Cl

O

Me

NOH

OOHS

Me

Captopril

(R)-3-(Acetylthio)isobutyryl Chloride (1) was introduced into prolines followed by deacetylationto give Captopril. Captopril is an effective inhibitor of the angiotensin converting enzyme (ACE), which isutilized in the treatments of hypertension. Recently, there have been many other studies where 1 has beenintroduced into amino acids and nitrogen-containing heterocycles to make new products with improvedmedicinal effects.

References1) Synthesis of angiotensin converting inhibitors

a) J. L. Stanton, N. Gruenfeld, J. E. Babiarz, M. H. Ackerman, R. C. Friedmann, A. M. Yuan, W. Macchia, J. Med. Chem.,26, 1267 (1983).b) A. J. G. Baxter, R. D. Carr, S. C. Eyley, L. Fraser-Rae, C. Hallam, S. T. Harper, P. A. Hurved, S. J. King, P. Meghani,J. Med. Chem., 35, 3718 (1992).c) S. Hanessian, U. Reinhold, M. Saulnier, S. Claridge, Bioorg. Med. Chem. Lett., 8, 2123 (1998).

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CHIRAL GUANIDINE

D2898 (4R,5R)-1,3-Dimethyl-4,5-diphenyl-2-[( S)-1-benzyl-2-hydroxyethyl- imino]imidazolidine (1a) 100mg

D2899 (4S,5S)-1,3-Dimethyl-4,5-diphenyl-2-[( R)-1-benzyl-2-hydroxyethyl- imino]imidazolidine (1b) 100mg

C1752 (4R,5R)-2-Chloro-1,3-dimethyl-4,5-diphenyl-1-imidazolinium Chloride (2a) 100mg

C1753 (4S,5S)-2-Chloro-1,3-dimethyl-4,5-diphenyl-1-imidazolinium Chloride (2b) 100mg

The chiral auxiliary 1, developed by Ishikawa and co-workers, is a monocyclic chiral guanidine.The chiral guanidines have been used in various studies of asymmetric synthesis.1) For example, in theMichael reaction of iminoacetic acid derivatives with methyl vinyl ketone in THF, 1b was used as catalystto prepare 3a with high enantioselectivity. When ethyl acrylate was used as Michael acceptor, the reactionproduced 3b without any solvent. The reason for the high enantioselectivity, as proposed by Ishikawa andhis group, is the presence of a transition state where the chiral guanidine derivative and the iminoaceticacid derivatives are bound together at 3-points by either hydrogen bonding or aromatic-aromaticinteraction.2) Efforts to synthesize various chiral guanidine compounds from reactions betweenimidazolinium compound 2 and chiral amines are being made continuously in the quest to develop novelchiral auxiliaries.3)

References1) Modified guanidines as chiral auxiliaries

T. Ishikawa, T. Isobe, Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem., Japan), 61, 58 (2003).2) Asymmetric Michael reaction

T. Ishikawa, Y. Araki, T. Kumamoto, H. Seki, K. Fukuda, T. Isobe, Chem. Commun., 2001, 245.3) Preparation of monocyclic guanidines

T. Isobe, K. Fukuda, T. Ishikawa, Tetrahedron: Asymmetry, 9, 1729 (1998).

1b

20 °C

3

2b

1b (0.2 eq.)

transition state

Ph N CO2tBu

Ph

+ X

N

NPh

Ph

N

Me

Me

OH

Ph

NN MeMe

Ph Ph

Cl

Ph N CO2tBu

Ph X

Cl

run

1

2

X

3a COMe3b CO2Et

Solv.

THF

–

Y (%)

90

85

ee (%)

96

97

C

O

H

OC

ButO

N

H

N

N

NC

H

C

Me

H

Me

CH2 CHX

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number 121

POLYMER SUPPORTED HYPERVALENT IODINE REAGENT

P1415 Poly[4-(diacetoxyiodo)styrene] (1) 1g

ANIONIC PYRAZOLYLBORATE LIGANDS

P1439 Potassium Bis(1-pyrazolyl)borohydride (1) 5g, 1g

P1440 Potassium Tris(1-pyrazolyl)borohydride (2) 5g, 1g

P1441 Potassium Tris(3,5-dimethylpyrazol-1-yl)borohydride (3) 5g

Poly[4-(diacetoxyiodo)styrene] (1) is a useful and convenient oxidizing agent. For example, Togoand his co-workers successfully oxidized primary and secondary alcohols to the corresponding aldehydesand ketones, respectively, in the presence of TEMPO under mild conditions.

After undergoing the oxidation reaction, the reduced poly(4-iodostyrene) can be recovered simplyand quantitatively by filtration. It can then be regenerated by oxidation with peracetic acid and reused.1 is expected to be a benign oxidizing reagent.

References1) Polymer-supported hypervalent iodine reagent

a) H. Togo, K. Sakuratani, Kagaku To Kogyo (Tokyo), 55, 1018 (2002).b) H. Togo, K. Sakuratani, Synlett, 2002, 1966.c) Tokyo Kasei Kogyo Co., Ltd., JP Patent 2003-113131.

I

OAc

OAc

1OH

R R'

, TEMPO

MeCN, r.t.

O

R R'

Product t (h) Y (%)

benzaldehyde 4 83

acetophenone 4 94

KNN

B

R

R

3

HKN

NB

2

H

H2: R = H3: R = CH3

1

The poly(pyrazolyl)borohydrides 1, 2 and 3 are the anionic pyrazolylborate ligands which formstable complexes with transition metal ions.1) In particular, 1 forms tetrahedral or square planar complexeswith divalent metal ions. The complexes are soluble in organic solvents, and therefore 1 is used for theextraction of divalent metal ions.2) 2 and 3 are utilized as tridentate ligands for homogeneous metalcomplex catalyst which are used for regioselective hydrogenation of quinoline3a) and reduction of unactivatedketones.3b)

References1) Reviews

S. Trofimenko, Chem. Rev., 93, 943 (1993).2) Solvent extraction of metals with potassium-dihydro-bispyrazolyl-borate

R. Shukla, G. N. Rao, Talanta, 57, 633 (2002).3) Pyrazolyl borate ligand and transition metal complexes as a catalyst

a) Y. Alvarado, M. Busolo, F. López-Linares, J. Mol. Catal. A: Chem., 142, 163 (1999).b) C. Vicente, G. B. Shul’pin, B. Moreno, S. Sabo-Etienne, B. Chaudret, J. Mol. Catal. A: Chem., 98, L5 (1995).

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