A mild method for the replacement of a hydroxyl group by halogen: 3. the dichotomous behavior of α-haloenamines towards allylic and propargylic alcohols

Tetrahedron 89 (2021) 132148

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Tetrahedron

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A mild method for the replacement of a hydroxyl group by halogen: 3.

the dichotomous behavior of

propargylic alcohols

a-haloenamines towards allylic and

,

c

,

d

,

1

a, b, *

François Munyemana ^{a 1}, Luc Patiny ^a, Leon Ghosez

ꢀ

^aUCLouvain, Place L. Pasteur, 1, B-1348, Louvain-la-Neuve, Belgium

^bEuropean Institute of Chemistry and Biology (IECB), Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248 2, Rue Robert Escarpit, FR-33607, Pessac,

France

^cDepartment of Chemistry, Eduardo Mondlane University, Av. Julius Nyerere Nr, 3453, PO Box 257, Maputo, Mozambique

d

ꢁ

Zakodium Sarl, Route d’Echandens 6b, 1027, Lonay, Switzerland

a r t i c l e i n f o

a b s t r a c t

Article history:

A study of the deoxyhalogenation of allylic and propargylic alcohols with tetramethyl-a-halo-enamines

Received 11 February 2021

Received in revised form

31 March 2021

Accepted 2 April 2021

Available online 16 April 2021

is reported. Primary allylic and primary and secondary propargylic alcohols gave the corresponding

halides in high yields. Secondary allylic and propargylic alcohols yielded the corresponding secondary

halides but the reaction also produced some rearranged primary halides (I > Br > Cl). The reactions with

tertiary allylic and tertiary propargylic alcohols gave several products and was therefore of little synthetic

value. However, the addition of triethylamine to the reaction mixture or the use of lithium alkoxide

instead of alcohol brought about a major change of the course of the reaction which led to amides

carrying an allyl or an allenyl group at C₂. This was shown to result from a Claisen-Eschenmoser rear-

To Stephen Martin, an outstanding scientist

and a dedicated editor of Tetrahedron, with

thanks for his continuous friendship.

rangement of an intermediate

a

-allyloxy- or propargyloxy-enamine.

Keywords:

a

-Halo-enamines

Deoxyhalogenation

Allylation

Allenylation

Claisen-eschenmoser rearrangement

1. Introduction

of alcohols and oxyacids but they often require strong acid condi-

tions and lack sustainability (production of large amounts of waste,

poor atom economy, toxic reagents) [2,3]. Also, the synthesis of

more complex organohalides often pose chemoselectivity prob-

lems which are not properly handled by many existing methods.

Halogenated organic compounds constitute a large and ever-

increasing group of environmental chemicals [1]. Natural organic

halides are widespread especially in marine organisms but man-

made organohalides are even more abundant being produced in

multi-tons quantities for a wide variety of industrial applications.

Also, organic halides have been extensively used as reagents and

solvents in organic synthesis [2]. Hydroxyl-containing compounds

have been identiﬁed as an attractive and practical source of orga-

nohalides since they are plentiful and often cheap chemicals. There

are presently many practical procedures for the deoxyhalogenation

Several years ago, we discovered that

a-halo-enamines [4]

performed the deoxyhalogenation of carboxylic acids and alcohols

under very mild conditions [5]. These early results attracted the

attention of several research groups who reported additional suc-

cessful examples of deoxyhalogenaton reactions using

enamine reagents [2g,h, 4]. -Chloroenamine 2a is commercially

available and large amounts of -chloro- and bromoenamines 2a,b

a-halo-

a

and 3a,b can be readily prepared (Scheme 1) by the reaction of

tertiary amides 1a,b with OPCl₃or OPBr₃followed by addition of

triethylamine [8]. They are bench-stable reagents which can be

* Corresponding author. UCLouvain, Place L. Pasteur, 1, B-1348 Louvain-la-Neuve,

Belgium.

puriﬁed by distillation. The corresponding a-iodo-enamines 4a,b

were prepared from 2a and 2b by halide exchange with an alkali

iodide [9]. Two detailed accounts of this practical

E-mail addresses: l.ghosez@iecb.u-bordeaux.fr, leon.ghosez@uclouvain.be

(L. Ghosez).

1

These co-authors contributed equally.

https://doi.org/10.1016/j.tet.2021.132148

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

inversion of conﬁguration [7].

Allylic and propargylic halides are extremely useful synthetic

building blocks and therefore a great deal of effort has gone into the

development of practical synthesis of these classes of organo-

halides [1]. Here again the deoxyhalogenation of the corresponding

allylic and propargylic alcohols attracted the attention of many

research groups as a practical source of the allylic and propargylic

halides [1d,10,11]. The interaction of the double or triple bond with

the neighboring functional group in allylic and propargylic systems

raises however regio- and stereochemical problems not encoun-

tered with saturated alcohols.

In this report we describe the details of our studies on the

deoxyhalogenation reactions of allylic and propargylic alcohols

Scheme 1. Synthesis of the haloenamine reagents.

using

a-halo-enamines 2a, 3a and 4a. We will also show that

adding a base to the reaction mixture dramatically modiﬁed the

course of the reaction leading to an interesting variant of the

Eschenmoser-Claisen (amide Claisen) reaction which allowed the

allylation or allenylation of 2,2⁰-disubstituted amides under mild

conditions.

deoxyhalogenation method [6,7] have been published recently. The

discovery that both -bromo- or -iodo-enamines 3a,b and 4a,b

could be formed in situ from 2a,b in the deoxy-bromination or

iodination reactions further increased the practicality of the

method [7]. All a-halo-enamines 2e4 had to be kept away from

a

moisture. However small amounts of hydrolysis products (tertiary

amides 1a,b) in the reagents were found to be harmless to the

deoxyhalogenation reaction which anyway produced one equiva-

lent of these amides as co-products.

2. Results and discussion

2.1. Deoxyhalogenations of allylic alcohols

The deoxyhalogenation reaction was shown to take place via a

keteniminium halide 5 in equilibrium with the

a-halo-enamine

Scheme 3 is another illustration of the usefulness of TMXE as

deoxyhalogenation reagents: their reactions with a series of pri-

mary allylic alcohols took indeed place in a few minutes at room

temperature to give exclusively the primary allylic halides in high

yields. The co-product of the reaction was the tertiary amide 1a

which, if desired [6,7], can be recovered by distillatin and recycled

(Scheme 2, X ¼ Cl, Br, I) [6,7]. Addition of an alcohol or a carboxylic

acid to this highly electrophilic iminium salt generated oxy-

iminium halides 6 or 7 which can be regarded as an activated

form of the hydroxyl-containing substrates. Nucleophilic attack of

the halide ion on these intermediates gave the corresponding acyl

or alkyl halides and regenerated amides 1a or 1b which were the

starting materials for the synthesis of reagents 2, 3 and 4. Thus the

reaction showed a high atom-economy. Reaction conditions were

very mild and yields were high. This allowed successful deoxy-

halogenation reactions of alcohols or carboxylic acids carrying

sensitive functional groups. Furthermore both the reactivity and

selectivity of these deoxyhalogenation reactions could be ﬁnely

tuned by increasing the size of the nitrogen substituents. Remark-

as starting material for the synthesis of the

reactions took place without isomerization of the oleﬁnic double

bond even with a (Z)-oleﬁn as in 8d. Thus, the -halo-enamine

a-halo-enamines. All

a

reagents TMXE compared very favorably with the best reagents

(e.g.: Ph₃P/CCl₄, Ph₃P/(Cl₃C)₂CO, Ph₃P/I₂) [2,1 1] available for the

deoxyhalogenation of primary allylic alcohols: aside from the high

yields and total regioselectivity, one should mention the mild

conditions and the high atom economy. The method was applied to

the synthesis of the chlorides 8a-f, bromides 9a-c and the more

reactive iodides 10a-d.

ably the bulkier a-halo-enamines 2b, 3b, 4b were found to be both

more selective [6] and more reactive [7] than 2a, 3a, 4a carrying

methyl groups on nitrogen. The substitution step took place with

Deoxyhalogenations of secondary allylic alcohols with TMCE,

TMBE and TMIE also occurred under mild conditions and gave high

yields of the corresponding halides (Scheme 4). However, the re-

actions were less regioselective yielding mixtures of secondary and

primary halides. The regioselectivity decreased in the order

TMCE > TMBE > TMIE. Deoxychlorinations gave a high yield of the

secondary chlorides 11a-c. Deoxybrominations were somewhat

less regioselective but still gave the secondary bromides 12a,b as

major products. Deoxyiodination reactions gave almost equimolar

mixtures of secondary 13a,b and primary allylic iodides 10a and

10e. The formation of an allylic carbocation from the reactive imi-

nium salt 14 could be rejected on the basis of the formation of

distinct halides from (E)-but-2-en-1-ol (8a, 9a and 10a, Scheme 3)

and from but-3-en-2-ol (11a þ 8a,12a þ 9a and 13a þ 10a) (Scheme

4). Thus, the formation of the secondary halides must result from a

S_N2 reaction (route a). A competing S_N2⁰reaction could account for

the formation of the primary halide (route b). Increasing the size of

the nucleophilic halide expectedly favored route b at the expense of

route a. Interestingly, we also observed that the amount of primary

halide slowly increased when the reaction mixture was left for 2

days at room temperature: the 3:1 mixture of bromides 12a:9a

then became a 1:1 mixture. The equimolecular mixture of sec-

ondary and primary iodides 13a:10a became a 1:6 mixture after 2

days at room temperature. This slow equilibrium between

Scheme 2. Deoxyhalogenation of carboxylic acids and alcohols.

2

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

Scheme 3. Deoxyhalogenations of primary allylic alcohols.

secondary and primary allylic halides could result from the pres-

ence of a stoichiometric amount of amide 1a as co-product of the

deoxyhalogenation reaction. The heterolytic cleavage of the CeBr

or CeI bonds could be more favorable as a result of the higher

polarity of the mixture and a possible stabilization of cationic

species by amide 1a acting as a Lewis base. The take-home message

is that best yields of secondary halides will be obtained if the

deoxyhalogenation reaction is stopped as soon as completed.

The deoxyhalogenation of tertiary allylic alcohols usually yiel-

ded complex mixtures resulting from the presence of rearranged

and elimination products [1d,10,11]. Thus, TMCE and 2-methylbut-

3-en-2-ol yielded a mixture of three products (Scheme 5). The

rearranged chloride 8b was the major product of the reaction. We

also observed almost equimolecular amounts of unrearranged

tertiary chloride 15 and isoprene. Elimination of hydrogen halide

became thus signiﬁcant in this weakly basic reaction mixture. Thus,

in spite of the very mild conditions of the reaction, TMCE did not

perform better towards tertiary allylic alcohols than most other

deoxychlorination reagents. The reaction of 2-methylbut-3-en-2-ol

with TMIE was more interesting although no tertiary iodide was

formed. The reaction gave a 41% of primary iodide 10b and two

have resulted from a cyclization of either amide 18 or intermediate

17a. To test this mechanistic scheme, we reacted TMCE with 2-

methylbut-3-en-2-ol in the presence of triethylamine (Scheme 6).

This was expected to favor the formation of intermediate 17a at the

expenses of the substitution product 10b. The Claisen rearrange-

ment was very fast and amide 18a was formed in 85% yield. The

cyclization of amide 18a took place readily in an aqueous solution

of HI. Iminium salt 19 was obtained in 78% yield. It was readily

hydrolyzed to the corresponding lactone under basic conditions.

2.2. -Allylation of 2-disubstituted amides

We were both intrigued and interested by the Claisen-

Eschenmoser rearrangement of intermediate 17. This compound

appeared to rearrange as soon as formed even at room tempera-

ture. This was all the more surprising since the rearrangement

involved the creation of a quaternary carbon atom. Thus, if the

competing substitution pathways from 16 could be suppressed, the

reaction of a

b-disubstituted-a-chloro-enamine with an allylic

alcohol in the presence of a base could be an attractive variant of

the Claisen-Eschenmoser route for the synthesis of amides carrying

unexpected products. These were shown to be the

a-allylated

a quaternary a-carbon atom (Scheme 7). However, the reaction of

amide 18a and the cyclic iminium salt 19. We had shown in our

early studies that the key step of the deoxyhalogenation reaction

was the formation of an alkoxy-iminium halide 16. The reaction

mixture being slightly basic, the loose ion pair 16 could be in

equilibrium with 17 which underwent an amide acetal Claisen

rearrangement (Eschenmoser-Claisen rearrangement) to yield the

TMCE in dichloromethane with a variety of allylic alcohols in the

presence of triethylamine (conditions A) still yielded allylic chlo-

rides as major products. Low yields of allylic amides 18 were ob-

tained except with the tertiary alcohol 2-methylbut-3-en-2-ol

which gave a high yield of 18a. It was thus necessary to decrease the

concentration of chloride ion in the solution by using a solvent

which would not dissolve triethylamine hydrochloride.

a

-allylated amide 18 [4d,12,13]. The third reaction product 19 must

3

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

Scheme 4. Deoxyhalogenation of secondary allylic alcohols. Reactions in CDCl₃. Yields measured by ¹H NMR (internal standard) except for 11c (reaction in CH₂Cl₂, yields after

distillation).

Scheme 6. Independent syntheses of 18a and 19.

the major product was isoprenyl chloride. This resulted from steric

hindrance caused by the formation of two vicinal quaternary car-

bon atoms. The formation of the chloride could be reduced by using

the corresponding isoprenyl alkoxide (conditions C or D). The cor-

responding allylic amide 18e was then obtained in 66% (C) and 75%

Scheme 5. Reaction of TMCE and TMIE with 2-methylbut-3-en-2-ol.

(D) yields. Similarly the reaction with cyclohex-2-en-1-ol in

dichloromethane in the presence of triethylamine (conditions A)

only gave 3-chlorocyclohex-1-ene. However, the desired amide 18f

Rewardingly the reaction in cyclohexane (conditions B) gave better

could be isolated in 59% yield when the reaction was run in

yields of allylated amides 18b,c,d but the reactions were much

dimethoxyethane at 100 ^ꢀC with the preformed lithium cyclo-

slower probably as a result of the heterogeneity of the reaction

hexenolate (conditions D). Reactions were not optimized in terms

mixture. We had also shown that intermediate tetramethyl kete-

of time and temperature.

niminium salt 5a formed much more slowly in solvents like ben-

zene or cyclohexane than in dichloromethane [3]. Not surprisingly

isoprenyl alcohol only gave a 18% yield of the desired amide 18e and

We expanded this study to

prepared in good yields by the published procedure [7]. Routes C

a-chloroenamine 2c which was

4

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

Scheme 7. -Allylation of 2-disubstituted tertiary amides via the corresponding

BuLi/hexane þ alcohol þ cyclohexane d: n-BuLi/hexane þ alcohol þ dimethoxyethane. Yields of amides are for puriﬁed products.

a

-chloro-enamines. Conditions: a: alcohol þ Et₃N þ CH₂Cl₂; b: alcohol þ Et₃N þ cyclohexane; c: n-

sigmatropic rearrangement (Scheme 8). Generation of the lithium

alkoxide prior to the addition of TMCE (conditions C) resulted in the

formation of 18g in 45% yield but the reaction required 72 h. Similar

observations were made for the reaction of (Z)- and (E)-hex-2-en-

1-ol with 2c. The allylation reaction with (Z)-hex-2-en-1-ol

required the use of the corresponding lithium alkoxide (condi-

tions C). The results described in Scheme 7 for the reaction of TMCE

2a with isoprenol and cyclohex-2-en-1-ol to yield 18a and 18f are

further illustrations of this inhibiting effect.

In contrast with the reported examples of Eschenmoser- or

Ficini-Claisen rearrangements [4d,12,13], the N,O-ketene acetals

intermediates 17a-f and 20a-c derived from

c carry two substituents at the oleﬁnic -carbon atom. The steric

interaction between an oleﬁn -substituent (eg: Me in 2a,b) and a

nitrogen substituent causes a twist around the CeN bond which

reduces the interaction of the nitrogen lone pair with the orbital

and induces an interaction with the orbital. This had been shown

to be responsible for both the low nucleophilicity and the enhanced

electrophilicity of these -chloro-enamines. It should therefore be

expected that this effect should also show up in the rearrangement

of N,O-ketene acetals generated from these tetrasubstituted

a-chloro-enamines 2a-

b

p

s

a

Scheme 8. Reactions of (Z) and (E) allylic alcohols.

a-

chloro-enamines. It was indeed found that the replacement of two

methyl by two i-propyl groups on nitrogen slowed down the for-

mation of the Eschenmoser-Claisen product (Scheme 9). As shown,

the Me/i-Pr interaction should bring the amine group of the N,O

ketene acetal out of conjugation with the C]C bond. Thus, in

contrast with what had been observed for the deoxyhalogenation

reactions of alcools, increasing the size of the nitrogen substituents

was detrimental on the Eschenmoser-Claisen rearrangement of

and D gave moderate yields of the Eschenmoser-Claisen products

21a-c. As expected, a substituent cis to the allylic group was shown

to slow down the [3.3] rearrangement (Scheme 8): the reaction of

(E)-hex-2-en-1-ol with TMCE in the presence of triethylamine in

cyclohexane (conditions B) at 60 ^ꢀC yielded 42% of 18g whereas the

corresponding (Z) isomer merely led to a 15% yield. In this case

nucleophilic substitution by a chloride ion competed favorably with

the rearrangement as a result of strong steric interactions between

Me and i-Pr groups in the s-cis conformation required for the

these

We also examined the reaction of allylic alcohols with an

chloro-enamine 2d carrying two different substituents at C-2

b-substituted N,O-ketene acetals.

a-

5

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

Scheme 9. Inﬂuence of the size of the amine group.

Scheme 11. Mechanistic hypothesis for the allylation reaction.

2.3. Deoxyhalogenations of primary and secondary propargylic

alcohols

A mild, non-acidic and sustainable route towards propargylic

halides would also be welcome, in particular for the iodides which

are difﬁcult to obtain with a high degree of purity as a result of their

easy isomerization to the corresponding iodoallenes [15]. The re-

action of TMXE 2a-c (X ¼ Cl, Br, I) with primary and secondary

propargylic alcohols 26 for 1 h at room temperature gave high

yields of the corresponding propargylic halides 27a-f and N,N-

dimethylisobutyramide 1a (Scheme 12). Under these mild condi-

tions, we observed no allenic halide in the mixtures except for the

secondary propargylic iodides 27e and 27f which were contami-

nated by 6% of the corresponding allenic iodides. Decreasing re-

action times should probably suppress the formation of this small

amount of allenic iodides. We found indeed that the isomerization

was catalyzed by amide 1a which was the coproduct of the deox-

yhalogenation reaction: the deoxyiodination of oct-1-yn-3-ol 26

(R ¼ C₅H₁₁) yielded a 15:1 mixture of propargylic 27f and allenic 28

iodides (conditions a). Under these conditions, only one equivalent

of amide 1a was present at the end of the reaction. Reﬂuxing the

Scheme 10. Diastereoselectivity of the allylation reaction.

(Scheme 10). Compound 2d was prepared as a mixture of (E) and (Z)

isomers in 65% yield from the treatment of amide 1d with OPCl₃

followed by HCl elimination with Et₃N. The reaction with the allylic

alcohols was performed under conditions B to yield 55%e77% of

allylated amides as a mixture of diastereoisomers 23a,b,c and

24a,b,c. Compound 23c could be puriﬁed by recrystallisation in

acetone/water. Analysis of the crystals by X-ray diffraction ﬁrmly

established the relative conﬁgurations of the two diastereoisomeric

centers [14]. We believe that the poor diastereoselectivity mainly

resulted from the formation of a mixture of (E) and (Z) ketene ac-

etals (Scheme 1 1). Both (E) and (Z) isomers of 2d should give the

same keteniminium chloride intermediate which meant that the

conﬁguration of the a-chloro-enamine 2d should have no impor-

tance on the stereochemistry of the substitution reaction yielding

the N,O-ketene acetal intermediate. The stereoselectivity should

rather be the result of the relative rates of addition to the diaste-

reoisomeric faces of the iminium salt. It thus appeared that there

was a slight preference for an addition of the alcohol to the a face

(cis to the methyl group).

A chair transition state for the

Eschenmoser-Claisen rearrangement would account for the selec-

tive formation of either 23a-c or 24a-c from the (Z) or (E)-N,O-

ketene acetals 25.

We believe that this “variation” of the Eschenmoser-Claisen

rearrangement reaction has some synthetic value: it allows the b-

allylation of 2-disubstituted tertiary amides and thus the creation

of a quaternary carbon atom under rather mild conditions. The

limitation of the method results from the poor diastereoselectivity

encountered with amides carrying two different groups at C-2.

Scheme 12. Deoxy-halogenations of propargylic alcohols. (Yields determined by ¹H

NMR using an internal standard).

6

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

increase concentration of iodide ion resulting from the better sol-

ubility of triphenylphosphite methiodide in this solvent. Iodide ion

would then add to the activated triple bond to generate an

iodoallene. This explanation did indeed not hold here since there

were no iodide ions in the starting materials. Iodide ions can only

be produced by a nucleophilic attack of amide 1a on the propargyl

iodide to yield an oxyiminium salt 29 which would then undergo a

S_N2’ reaction to yield the allenic iodide 28.

These observations showed that both propargyl and allenyl io-

dides could be readily obtained from the reaction of TMIE 4a and a

secondary propargylic alcohol (see Scheme 13).

Scheme 13. Isomerization of propargylic iodide 27f to allenic iodide 28.

2.4. Reaction of a-haloenamine 2a with a tertiary propargylic

alcohol 30a

CHCl₃solution for 19 h led to the almost quantitative trans-

formation of propargylic iodide 27f into the isomeric allenic iodide

28 (conditions b). We also showed that propargyl iodide 27f iso-

merized much more slowly in the absence of amide 1a (conditions

c). This agreed with the early observations that propargyl iodides

readily isomerized to allenic iodides in the presence of triphenyl-

phosphite methiodide in DMF but remained unchanged when DMF

was replaced by dichloromethane [15d]. However, our observations

did not support the mechanism proposed by the authors who

claimed that the rate enhancement in DMF resulted from an

The reaction of 2-methylbut-3-yn-2-ol 30a with TMCE 2a gave

low yields of deoxychlorination product 31 and chloroallene 32

(Scheme 14). The major product 33 resulted from an elimination of

HCl. Interestingly we also observed an amide product 34 resulting

from

a

[3.3] rearrangement of an intermediate

a-

propargyloxyenamine.

The reaction of TMIE 4a with alcohol 30a was less complex but

more intriguing (Scheme 15). No deoxyiodination product was

formed. The major product was amide 39 (51%) which can be

regarded as an isoprenylation product of amide 1a. The minor

product 40 (27%) was even more surprising: the dihydropyridone

ring must indeed have been the result of a cyclization involving the

amide nitrogen and a cationic center on the side-chain. It also

supposed the formation of methyl iodide which was indeed

observed by ¹H NMR (d_CH3¼ 2.16 ppm) in the crude reaction

mixture. A possible mechanism would involve a nucleophilic attack

of alcohol 30a on the keteniminium iodide in equilibrium with

TMIE 4a to generate an oxonium salt 35 which should be easily

converted into the more stable ammonium iodide 36. Deprotona-

tion would generate the ketene N,O-acetal 37 which would un-

dergo a fast [3.3] sigmatropic shift to 34a. Protonation of 34a by the

acidic ammonium 36 (or oxonium 35) iodide would lead to a

cationic intermediate 38. The cyclization reaction occurred on the

amide nitrogen rather than on the more nucleophilic oxygen atom.

This was very surprising since we had shown earlier (Scheme 5)

Scheme 14. Reactions of TMCE with 2-methylbut-3-yn-2-ol 30a.

Scheme 15. Reactions of TMIE with 2-methylbut-3-yn-2-ol 30a.

7

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

deoxychlorination products were observed except for 34d which

carries a substituent in place of hydrogen on the allenic carbon

atom next to the quaternary carbon atom. These results perfectly

complement earlier studies of similar [3.3] sigmatropic rearrange-

ments yielding allenic ketones, aldehydes and amides [14]. Since

disubstituted -chloroenamines are readily available from the

corresponding amides, this method offers an attractive route to-

wards -allenic amides carrying a quaternary carbon atom at C₂.

b-

a

b

Scheme 16. Isomerization of 34a.

3. Conclusions

that the cyclization of a rather similar cationic intermediate

occurred on the amide oxygen. We have no explanation for this

difference. However it is not unprecedented: a similar example of a

AgBF₄catalyzed cyclization of an allenic amide involving a primary

nitrogen atom has been reported [16]. Loss of a methyl group by

nucleophilic attack of an iodide ion on a methyl substituent carried

by the amide nitrogen would drive the equilibrium toward the

observed dihydropyridone 40. The hypothesis of Brønsted acid

catalyzed isomerization of 34a was further conﬁrmed as shown in

Scheme 16.

A ﬁrst conclusion is that the above results signiﬁcantly broaden

the scope of the deoxyhalogenation method of alcohols with TMXE

and DIXE reagents. The method had already been shown to be

chemo- and stereoselective and it also occurred with high atom

economy and sustainability. Now we showed that it could be suc-

cessfully applied to the deoxyhalogenation of primary and sec-

ondary allylic and propargylic alcohols into the corresponding

halides in excellent yields and under mild and neutral conditions.

The deoxyhalogenation of secondary allylic alcohols gave only

small amounts of rearranged halides with TMCE and TMBE. The

iodination reagent TMIE gave higher amounts of rearranged io-

dides. We also found that the isomerization of propargylic iodide

was catalyzed by the presence of the N,N-dimethylisobutyramide

in the reaction mixture. Thus it was possible to obtain either a

propargylic or an allenic iodide depending on the reaction time. As

pointed out in the introduction allylic, propargylic and allenyl ha-

lides are very useful synthetic intermediates. An additional

advantage of the deoxyhalogenation method with TMXE and DIXE

is that the tertiary amide coproduct of the reaction is rather inert: in

many instances, it will thus be possible to use these halides in situ.

A second interesting fall-out of our studies came from the failure

of the method for tertiary allylic and propargylic alcohols. The

2.5. -Allenylation of 2-disubstituted amides

The formation of a dienylated amide 39 from a tertiary prop-

argylic alcohol and TMIE 4a could probably ﬁnd synthetic appli-

cations but we did not further explore this pathway. We rather

explored the scope of the transformation of

2a,c,e into -allenyl-amides 34 (Scheme 1 7). -Chloroenamine 2e

characterized by an isoprenyl carbon skeleton was prepared by the

published procedure [6b]. Treatment of the -chloroenamines

a-chloroenamines

a

2a,c,e with a tertiary or a secondary propargylic alcohol 30 in the

presence of triethylamine or with the corresponding alkoxide

rewardingly led to

a-allenic amides 34a-g in good yields. No

major products of these reactions resulted from

a Claisen-

Eschenmoser rearrangement of an intermediate N,O-ketene

acetal. These intermediates could be generated more efﬁciently

from the reaction of allylic and propargylic alcohols under basic

conditions. Under these conditions, no or very little deoxyhaloge-

nation product was observed. Rewardingly this unplanned spin-off

from these studies led to the discovery of a mild and a practical

method for allylation, propargylation and allenylation of a-disub-

stituted amides under mild conditions with simultaneous creation

of a quaternary carbon atom. This further illustrated the impor-

tance of a-chloroenamines as activated derivatives of amides.

4. Experimental section

4.1. General

All reactions were carried out in oven or ﬂame-dried glassware

under argon atmosphere using freshly dried solvents. Distillations

of products were performed using a 10 cm Vigreux column or a

Büchi Kugelrohr GKR-50 apparatus. Solvents were distilled under

argon or under reduced pressure. Chlorinated solvents (chloroform,

dichloromethane, carbon tetrachloride) were dried over P₄O₁₀then

distilled. Cyclohexane was dried over CaH₂and distilled. Triethyl-

amine was dried over solid KOH or CaH₂and distilled. Alcohols

were dried over Mg/I₂then distilled. Dimethoxyethane was

distilled over sodium/benzophenone. Commercial reagents were

reagent grade and used without further puriﬁcation. ¹H NMR

spectra were recorded at 60 MHz (Varian T 60), 200 MHz (Varian

Gemini-200 and VXR-200), 300 MHz (Bruker Avance 300) and

500 MHz (Bruker AM 500). ¹³C NMR spectra were recorded at 50, 75

and 125 MHz. Infra-red spectra were recorded on a PerkinElmer

Scheme 17. Reaction of a-chloroenamines 2a,c,e with propargylic alcohols under basic

conditions.

8

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

681 spectrometer.¹H and ¹³C chemical shifts are expressed in part

per million (ppm) with respect to tetramethylsilane as internal

standard. Mass spectra were recorded on Varian Mat 44 and Fin-

nigan Mat-TSQ 70 using electronic impact at 70 eV, chemical

ionization (100 eV, acetone or mixture of nitrogen oxide and

methane) or FAB (70 eV). Flash chromatography was performed

using silica gel 60 (230e400 Mesh). Thin layer chromatography was

performed using silicagel 60 F254. GLCs were performed using

Varian Aerograph 1400 (detector FID, nitrogen) or Carlo Erba

Fractovap (detector FID, nitrogen) on either a SE30 column or a

capillary column type 3700 (length 30 m, polydimethylsiloxane).

HPLCs were performed using Waters 600 pump and Waters 486 UV

variable wavelength detector. Elemental analyses were performed

in Dr Bieler University of Vienna and Dr Stones laboratories. The

4.3.6. 1-Iodo-3-methylbut-2-ene 10b

3-methylbut-2-en-1-ol 0.41 ml (0.35 g, 4 mmol); 1 g (4.4 mmol)

TMIE 4a, 0.5 h, 98.5% (¹H NMR). No transposed iodide was observed

(¹H NMR and GLC).

4.3.7. Trans-1-chlorohex-2-ene 8c

Trans-hex-2-en-1-ol 0.80 ml (0.68 g, 6.8 mmol); 1 g (7.5 mmol)

TMCE 2a, 1 h. Trans-1-chlorohex-2-ene was puriﬁed by horizontal

distillation (temperature maintained at 50 ^ꢀC under 13 mm Hg).

Yield: 0.7 g (87%). ¹H NMR (200 MHz, CDCl₃):

d (ppm): 5.78 (dt,

J_1trans¼ 15 Hz, J₂¼ 7.2 Hz), 1H), 5.60 (dtt, J_1trans¼ 15 Hz, J₂¼ 6.8 Hz,

J₃¼ 3Hz, 1H), 4.03 (d, J ¼ 6.8 Hz, 2H), 2.04 (q, J ¼ 7.2 Hz, 2H), 1.41

(sext, J ¼ 7.2 Hz, 2H), 0.90 (t, J ¼ 7.2 Hz, 3H).

known

a

-chloro-, -bromo-, and -iodo-enamines 2a, 2c, 2d, 3a, 4a

4.3.8. Cis-1-chlorohex-2-ene 8d

were prepared from the corresponding amides following the pro-

cedures previously described [8b,9].

Cis-hex-2-en-1-ol 0.76 ml (0.64 g, 6.4 mmol); 0.95 g (7 mmol)

TMCE 2a, 1 h. Cis-1-chlorohex-2-ene was puriﬁed by horizontal

distillation (temperature maintained at 50 ^ꢀC under 13 mm Hg).

Yield: 0.65 g (86%). In ¹H NMR (200 MHz, CDCl₃), the chemical

shifts of the oleﬁnic protons overlapped; so C₆D₆was used instead

4.2. General procedure for the reaction of

allylic and propargylic alcohols

a-haloenamines with

of CDCl₃. ¹H NMR (200 MHz, C₆D₆):

d

(ppm): 5.45 (dt, J_1cis¼ 10.8 Hz,

J₂¼ 7.3 Hz, 1H), 5.31 (dt, J_1cis¼ 10.8 Hz, J₂¼ 7.3 Hz, 1H), 3.72 (d,

J ¼ 7.3 Hz, 2 H),1.75 (q, J ¼ 7.3 Hz, 2H),1.15 (sext, J ¼ 7.3 Hz, 2H), 0.73

(t, J ¼ 7.3 Hz, 3H).

Reactions were performed in an oven- or ﬂame-dried three-

neck round-bottomed ﬂask under dry argon and with magnetic

stirring. The ﬂask was equipped with a septum and a refrigerator

isolated from moisture by an oil trap. A solution of alcohol in CDCl₃

or CH₂Cl₂was syringed in through the septum and cooled down at

4.3.9. Geranyl chloride 8e

^ꢀC. A solution of

a-haloenamine (1.1 equiv.) was then syringed

Geraniol 0.59 ml (0.52 g, 3.4 mmol); 0.5 g (3.7 mmol) TMCE 2a;

0

0.5 h, 95% (¹H NMR). ¹H NMR (200 MHz, CDCl₃):

d (ppm): 5.45 (tm,

into the ﬂask and the mixture was left at room temperature. The

reaction was followed by ¹H NMR. Yields were determined after

removal of the solvent either by ¹H NMR using an added standard

(usually benzene or toluene) or by GLC. In some cases, the halides

were puriﬁed by distillation or ﬂash chromatography. The isolated

yields were always very close to those measured by NMR or GLC.

Most of the halogenation products obtained in this study were known

compounds: their spectroscopic properties have been shown to be

identical to those reported in the literature Therefore, no data or

only ¹H NMR are reported for these molecules.

J ¼ 8 Hz,1H), 5.08 (m,1H), 4.10 (d, J ¼ 8 Hz, 2H), 2.07 (m, 4H),1.72 (s,

3H), 1.68 (s, 3H), 1.60 (s, 3H).

4.3.10. Geranyl bromide 9c

Geraniol 0.89 ml (0.79 g, 5.1 mmol); 1 g (5.6 mmol) TMBE 3a,

0.5 h, 95% (¹H NMR). ¹H NMR (200 MHz, CDCl₃):

d (ppm): 5.53 (t,

J ¼ 8.4 Hz, 1H), 5.07 (m, 1H), 4.03 (d, J ¼ 8.4 Hz, 2H), 2.07 (m, 4H),

1.73 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H).

4.3.11. Geranyl iodide 10c

Geraniol 0.70 ml (0.62 g, 4 mmol); 1 g (4.4 mmol) TMIE 4a, 0.5 h,

4.3. Deoxyhalogenations of allylic alcohols

99% (¹H NMR). ¹H NMR (200 MHz, CDCl₃):

d (ppm): 5.53 (tm,

J ¼ 8.8 Hz, 1H), 5.06 (tm, 1H), 3.94 (d, J ¼ 8.8 Hz, 2H), 1.9e2.2 (m,

4.3.1. Trans-crotyl chloride 8a

4H), 1.68 (s, 3H), 1.64 (s, 3H), 1.60 (s, 3H).

Trans-crotyl alcohol 0.60 ml (0.51 g, 7 mmol); 1 g (7.5 mmol)

TMCE 2a; 0.5 h, 99% (¹H NMR). No transposed chloride was

observed (¹H NMR and GLC).

4.3.12. Farnesyl chloride 8f

Farnesol 0.85 ml (0.75 g, 3.4 mmol); 0.5 g (3.7 mmol) TMCE 2a;

0.5 h, 95% (¹H NMR). ¹H NMR (200 MHz, CDCl₃):

d (ppm): 5.44 (t,

4.3.2. Trans-crotyl bromide 9a

J ¼ 7.9 Hz, 1H), 5.09 (m, 2H), 4.10 (d, J ¼ 7.9 Hz, 2H), 4.07 (d,

J ¼ 7.9 Hz), 2.2e1.9 (m, 8H),1.77 (s, 3H), 1.72 (s, 3H),1.68 (s, 3H),1.60

(s, 3H).

Trans-crotyl alcohol 0.44 ml (0.37 g, 5.1 mmol); 1 g (5.6 mmol)

TMBE 3a; 0.5 h, 98% (¹H NMR). No transposed bromide was

observed by ¹H NMR and GLC.

4.3.13. Farnesyl iodide 10d

4.3.3. Trans-crotyl iodide 10a

Farnesol 1.01 ml (0.90 g, 4 mmol); 1 g (4.4 mmol) TMIE 4a, 0.5 h,

98% (¹H NMR). ¹H NMR (200 MHz, CDCl₃):

d (ppm): 5.54 (tm,

Trans-crotyl alcohol 0.35 ml (0.30 g, 4 mmol); 1 g (44 mmol)

TMIE 4a; 0.5h, 99% (¹H NMR). No transposed iodide was observed

(¹H NMR and GLC).

J ¼ 8.8 Hz, 1H), 5.2e5.0 (m, 2H), 3.94 (d, J ¼ 8.8 Hz, 2H), 2.2e1.9 (m,

8H), 1,69 (s, 6H), 1.60 (s, 6H).

4.3.4. 1-Chloro-3-methylbut-2-ene 8b

4.3.14. Reaction of but-3-en-2-ol with TMCE 2a

3-methylbut-2-en-1-ol 0.70 ml (0.59 g, 6.8 mmol);

1 g

But-3-en-2-ol 0.59 ml (0.49 g, 6.8 mmol); 1 g (7.5 mmol) TMCE

2a; 0.5 h. A 84/10 mixture of 3-chlorobut-1-ene 11a/1-chlorobut-2-

ene 8a (rearranged chloride) was obtained as shown by ¹H NMR.

(7.5 mmol) TMCE 2a; 0.5 h, 99% (¹H NMR). No transposed chloride

was observed (¹H NMR and GLC).

4.3.5. 1-Bromo-3-methylbut-2-ene 9b

4.3.15. Reaction of but-3-en-2-ol with TMBE 3a

3-methylbut-2-en-1-ol 0.52 ml (0.44 g, 5 mmol); 1 g (5.6 mmol)

TMBE 3a; 0.5 h, 95% (¹H NMR). No transposed bromide was

observed (¹H NMR and GLC).

But-3-en-2-ol 0.44 ml (0.366 g, 5.1 mmol); 1 g (5.6 mmol) TMBE

3a; 0.5 h. A 71/28 mixture of 3-bromobut-1-ene 12a/1-bromobut-

2-ene 9a (rearranged bromide) was obtained as shown by ¹H NMR.

9

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

4.3.16. Reaction of but-3-en-2-ol with TMIE 4a

4.4. General procedures and conditions for the reaction of a-

But-3-en-2-ol 0.35 ml (0.29 g, 4 mmol); 1 g (4.4 mmol) TMIE 4a;

0.5 h. A 53/45 mixture of 3-iodobut-1-ene 13a/1-iodo-but-2-ene

10a (rearranged iodide) was obtained as shown by ¹H NMR.

When the reaction mixture (containing both iodides and the amide

1a) was left at room temperature for 3 days, the rearranged product

10a became the major product: the ratio 13a:10a became 14/86.

chloroenamines with allylic and propargylic alcohols under basic

conditions

Procedure 1(P-1). The alcohol was added dropwise at 0 ^ꢀC to a

solution of a-chloroenamine and triethylamine. A white precipitate

of triethylamine hydrochloride was immediately formed. ¹H NMR

analysis of a sample of the solution showed the presence of the N,O-

ketene acetal 17a-f. The heterogeneous mixture was stirred until

complete disappearance of the N,O-ketene acetal. The mixture was

then ﬁltered and the solvent was evaporated under reduced pres-

sure. The crude product was puriﬁed by ﬂash-chromatography on

silica gel.

4.3.17. Reaction of 3-methylbut-3-en-2-ol with TMCE 2a

3-Methylbut-3-en-2-ol 0.59 g (6.8 mmol); 1 g (7.5 mmol) TMCE

2a; 0.5 h. A mixture of 3-chloro-2-methylbut-1-ene 11b (80%) and

1-chloro-2-methylbut-2-ene 8g (19%) was obtained as shown by ¹H

NMR.

Procedure 2 (P-2). n-Butyllithium was added dropwise at 0 ^ꢀC

to the solution of the allylic alcohol in a three-necked ﬂask. The a-

4.3.18. Reaction of 3-methylbut-3-en-2-ol with TMBE 3a

chloroenamine was added after 10 min and the resulting mixture

was stirred until complete disappearance of the N,O-ketene acetal.

The mixture was then ﬁltered and the solvent was evaporated

under reduced pressure. The crude product was puriﬁed by ﬂash

chromatography on silica gel.

3-Methylbut-3-en-2-ol 0.44 g (5.1 mmol); 1g (5.6 mmol) TMBE

3a; 0.5 h. A mixture of 3-bromo-2-methylbut-1-ene 12b (71%) and

1-bromo-2-methylbut-2-ene 9d (24%) was obtained as shown by

¹H NMR. When the reaction mixture (containing both bromides

and the amide 1a) was left at room temperature for 2 days, more

rearranged product was observed: the ratio 12b:9d became 45:55.

Procedure 3 (P-3). The alcohol was added dropwise at 0 ^ꢀC to a

solution of a-chloroenamine and triethylamine. A white precipitate

of triethylamine hydrochloride was immediately formed. The

mixture was ﬁltered through a fritted plate into another reaction

ﬂask. The solution was stirred until complete disappearance of the

N,O-ketene acetal. After evaporation of the solvent under reduced

pressure, the crude product was puriﬁed by ﬂash-chromatography

on silica gel.

4.3.19. Reaction of 3-methylbut-3-en-2-ol with TMIE 4a

3-Methylbut-3-en-2-ol 0.35 g (4 mmol); 1 g (4.4 mmol) TMIE

4a; 0.5 h. A mixture of 3-iodo-2-methylbut-1-ene 13b (40%) and 1-

iodo-2-methylbut-2-ene 10e (53%) was obtained as shown by ¹H

NMR. When the mixture containing the two iodides and the amide

1a was left at room temperature for 12h, the ratio secondary iodide

13b/primary iodide 10e became 8/92.

Conditions.

A: alcohol þ Et₃N þ CH₂Cl₂; B: alcohol þ Et₃N þ cyclohexane; C:

n-BuLi/hexane

hexane þ alcohol þ dimethoxyethane.

þ

alcohol

þ

cyclohexane; D: n-BuLi/

4.3.20. 3-Chlorocyclohex-1-ene 11c

Cyclohex-2-en-1-ol 0.33 g (3.4 mmol); 0.5 g (3.7 mmol) TMCE

2a in CH₂Cl₂; 3h. 3-chlorocyclohex-1-ene 11c was obtained quan-

titatively. Horizontal distillation at 50 ^ꢀC/13 mm Hg gave 0.32 g

4.5. Allylations of -chloroenamines with allylic alcohols

a

(81%) pure 11c. ¹H NMR (200 MHz, CDCl₃):

d (ppm): 5.84 (m, 2H),

4.61 (m, 1H), 2.15e1.55 (m, 6H).¹³C NMR (50 MHz, CDCl₃):

d (ppm):

4.5.1. N,N,2,2,5-pentamethylhex-4-enamide 18a

P-1, B: 1.48 ml (1.22 g, 14.14 mmol) of 2-methylbut-3-en-2-ol,

2 ml (1.89 g, 14.14 mmol) of TMCE, 4 ml (2.90 g, 28.70 mmol) of

triethylamine, 25 ml of cyclohexane; 12 h r.t.; ﬂash chromatog-

raphy (ethyl acetate/cyclohexane: 1/4); yield: 2.20 g (85%); color-

less liquid; ¹H NMR (CDCl₃, 200 MHz): 5.06 (t, J ¼ 7.2 Hz, 1H, ¼CH);

3.04 (s, 6 H, N(CH₃)₂); 2.32 (d, J ¼ 7.2 Hz, 2 H, CH₂); 1.70 (d,

J ¼ 1.3 Hz, 3 H, ¼CCH₃); 1.61 (s, 3 H, ¼CCH₃); 1.25 (s, 6 H,

CH₂C(CH₃)₂); ¹³C NMR (CDCl₃, 50 MHz): 176.4 (S, C]O); 133.2

131.05; 127.87; 55.25; 32.22; 24.48; 18.19.

4.3.21. Reaction of 2-methylbut-3-en-2-ol with TMCE 2a

2-Methylbut-3-en-2-ol 0.71 ml (0.59 g, 6.8 mmol);

1 g

(7.5 mmol) TMCE 2a; 1.5 h. A mixture of 3-chloro-3-methylbut-1-

ene 14 (25%), 1-chloro-3-methylbut-2-ene 8b (46%) and isoprene

(30%) was obtained (yields determined by ¹H NMR in the presence

of an internal standard). Monitoring the reaction at room temper-

ature by ¹H NMR revealed that the percentage of rearranged

chloride increased over time. After 15 h, the relative percentages

(S, ¼C(CH₃)₂); 120.0 (D sept,

J

¼ 151, 5.6, ¼CH); 42.5 (S,

CH₂C(CH₃)₂); 38.4 (T, J ¼ 116, CH₂); 37.9 (Q, J ¼ 137, N(CH₃)₂); 26.0

(Qq, J ¼ 127, 4.6, ¼C(CH₃)); 25.6 (Q, J ¼ 125, ¼C(CH₃)); 17.6 (Q,

J ¼ 125, CH₂C(CH₃)₂); MS: 184 ([M^þH]^þ); 183 ([M]^þꢁ); 168

were:

3-chloro-3-methylbut-1-ene

14

(18%)/1-chloro-3-

methylbut-2-ene 8b (51%)/isoprene (31%).

([M

ꢂ

CH₃]^þ); 140 ([M-N(CH₃)₂]^þ); 72 ([CON(CH₃)₂]^þ); 69

([CH₂CH]C(CH₃)₂]^þ); IR (CH₂Cl₂): 3054w; 1620s; Anal. calc. for

₁₁H₂₁NO (183.29): H 11.54, C 72.08, N 7.64; found: H 11.60, C 72.10,

4.3.22. Reaction of 2-methylbut-3-en-2-ol with TMIE 4a

2-Methylbut-3-en-2-ol 0.35 g (4 mmol); 1 g (4.4 mmol) TMIE 4a,

r.t. 3 h, led to a mixture of 1-iodo-3-methylbut-2-ene 10b (41%), a-

C

N 7.77.

allylated amide 18a (37%) and cyclic iminium salt 19 (22%) (relative

percentage determined by ¹H NMR). No 3-iodo-3-methylbut-1-

ene; nor isoprene. When the addition was made at.

4.5.2. Cyclization of 18a into cyclic iminium salt 19

Aqueous HI (57%, 0.79 ml) was syringed into a solution of 1 g a-

0 ^ꢀC and the temperature allowed to gradually increase to room

temperature, the cyclic iminium salt 19 became the major product.

1-Iodo-3-methylbut-2-ene 10b was puriﬁed by distillation. The

residue was dissolved in CCl₄and then ﬁltered. The ﬁltrate con-

allylated amide 18a in 5 ml CH₂Cl₂. The mixture was stirred over-

night at r.t. Evaporation of the solvent, extraction with CH₂Cl_2,

drying of the organic phases on Na₂SO₄, ﬁltration and evaporation

of the solvent gave 1.33 g (78%) of cyclic iminium salt 19. ¹H NMR

tained

a

-allylated amide 18a and N,N-dimethylisobutyramide 1a.

(200 MHz, CDCl₃):

d

(ppm) ¼ 3.66 (s, 3H), 3.41 (s, 3H), 2.01 (m, 4H),

They were puriﬁed by ﬂash chromatography on silica gel (cyclo-

hexane/ethylacetate: 8/2). The solid residue was the iminium salt

19 which could be readily hydrolyzed with 0.1 N aqueous KOH (see

4.5.3.).

1.67 (s, 6H),1.66 (s, 6H). ¹³C NMR (50 MHz, CDCl₃):

d

(ppm) ¼ 179.11,

91.95, 42.74, 35.19. 34.19. 30.16, 28.70, 25.99. Mass (C.I., acetone):

184 ([M ꢂ 127]^þ, [C₁₁H₂₂NO]^þ, 100%); IR (CH₂Cl₂): 1620 cm^ꢂ1(OC]

N^þ(CH₃)₂).

10

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

4.5.3. Hydrolysis of iminium salt 19

A solution of 1.33 g of cyclic iminium salt 19 in 10 ml CH₂Cl₂was

reﬂuxed with 10 ml of aqueous 0.1 N KOH for 2 h. After decantation,

(D, J ¼ 124 Hz, CHCH₃); 38.5 (Qq, J ¼ 138 Hz, 3.7, N(CH₃)₂); 23.7 (Q

quint, J ¼ 127 Hz, CCH₃); 22.6 (Q quint, J ¼ 127 Hz, CCH₃); 15.2 (Q,

J ¼ 126 Hz, CHCH₃); MS: 170 ([MþH]^þ); 169 ([M]^þꢁ); 154

([M ꢂ CH₃]^þ); 113 ([(CH₃)₂NCOC(CH₃)₂eH]^þꢁ); 72 ([CON(CH₃)₂]^þ);

55 ([CH₃CHCH]CH₂]^þ); IR (CH₂Cl₂): 3078w; 3052 m; 1620s;

1002 m; 920s; Anal. calc. for C₁₀H₁₉NO (169.26): C 70.95, H 11.31, N

8.27; found: C 71.01, H 11.35, N 8.33.

the organic phase was dried over MgSO₄. The d-lactone was puri-

ﬁed by ﬂash chromatography on silica gel (cyclohexane/ethyl ace-

tate: 8/2). Rf ¼ 0.4. Yield: 75%. White solid m.p.: 78e79 ^ꢀC; ¹H NMR

(200 MHz, CDCl₃):

d

(ppm) ¼ 1.80 (m, 4H), 1.40 (s, 6H), 1.29 (s, 6H).

¹³C NMR (50 MHz, CDCl₃):

d (ppm): 177.54, 82.35, 36.84, 31.77,

31.27, 28.73, 27.44. Mass (E.I.): 157([MþH]^þ, 37%), 141 ([M ꢂ CH₃]^þ,

CO₂]^þ.

,

47%), 56([(CH₃)₂CCH₂]^þ.,100%),

4.5.7. N,N,2,2,3,3-hexamethylpent-4-enamide 18e

16%), 112([M

ꢂ

43([(CH₃)₂CH]^þ,46%). IR (CH₂Cl₂): 1715 cm^ꢂ1(COO). Anal. calc. for

C₉H₁₆O₂(156) C: 69.195, H: 10.323; Found: C: 68.53, H: 10.49.

P-2, C: 1.60 ml (1.36 g, 15.75 mmol) of 3-methylbut-2-en-1-ol,

2 ml (1.89 g, 14.14 mmol) of TMCE, 6 ml (15 mmol) of n-BuLi 2.5 M

in hexane, 25 ml of cyclohexane; 12h, 60 ^ꢀC; ﬂash chromatography

(ethyl acetate/cyclohexane: 1/4); yield: 1.71 g (66%).

4.5.4. N,N,2,2-tetramethylhex-4-enamide 18b

P-2, D: 0.72 ml (0.61 g, 7.07 mmol) of 3-methylbut-2-en-1-ol,

1 ml (0.945 g, 7.07 mmol) of TMCE, 3.4 ml (8.47 mmol) of 2.5 M n-

BuLi in hexane, 15 ml of DME; 12h, 100 ^ꢀC; ﬂash chromatography

(petroleum ether/ether: 2/1); yield: 0.97 g (75%); colorless liquid;

¹H NMR (CDCl₃, 200 MHz): 5.90 (dd, J ¼ 17.9 Hz, 10.3 Hz, 1 H, ¼CH);

4.95e5.05 (m, 2 H, ¼CH₂); 3.01 (s, 6H, N(CH₃)₂); 1.26 (s, 6 H,

CC(CH₃)₂); 1.07 (s, 6 H, CHC(CH₃)₂); ¹³C NMR (CDCl₃, 50 MHz): 176.1

(S, C]O); 145.7 (D, J ¼ 151 Hz, ¼CH); 111.9 (T, J ¼ 156 Hz, ¼CH₂);

48.5 (S, CC(CH₃)₂); 42.0 (S, CHC(CH₃)₂); 38.1 (Qq, J ¼ 138 Hz, 3.5 Hz,

N(CH₃)₂); 24.5 (Qq, J ¼ 127 Hz, 5.0 Hz, CC(CH₃)₂); 22.6 (Q quint,

J ¼ 126 Hz, 4.5 Hz, CHC(CH₃)₂); MS: 184 ([M^þH]^þ); 183 ([M]^þꢁ); 168

([M ꢂ CH₃]^þ); 114 ([M-CH2¼CHC(CH₃)₂]^þ); 72 ([CON(CH₃)₂]^þ); IR

(CH₂Cl₂): 3054w; 1607s; 1013w; 919w; Anal. calc. for C₁₁H₂₁NO

(183.29): C 72.08, H 11.54, N 7.64, O 8.72; found: C 72.10, H 11.61, N

7.68, O 8.61.

P-1, A: 1.23 ml (1.02 g, 14.14 mmol) of but-3-en-2-ol, 2 ml

(1.89 g, 14.14 mmol) of TMCE, 4 ml (2.90 g, 28.70 mmol) of trie-

thylamine, 25 ml of dichloromethane, 10 h, r.t.; ﬂash chromatog-

raphy (ethyl acetate/cyclohexane: 1/4); yield: 1.20 g (50%).

P-1, B: 1.23 ml (1.02 g, 14.14 mmol) of but-3-en-2-ol, 2 ml

(1.89 g, 14.14 mmol) of TMCE, 4 ml (2.90 g, 28.70 mmol) of trie-

thylamine, 25 ml of cyclohexane; 24h, r.t.; ﬂash chromatography

(ethyl acetate/cyclohexane: 1/4); yield: 1.74 g (74%); colorless

liquid; IR (CH₂Cl₂): 3050w; 3027 m; 1620s; 969 m; ¹H NMR (CDCl₃,

200 MHz): 5.51 (dq, J ¼ 15.0 Hz, 5.7 Hz, 1 H, ¼CHCH₃); 5.41 (dt,

J ¼ 15.0 Hz, 5.7 Hz, 1 H, ¼CHCH₂); 3.04 (s, 6H, N(CH₃)₂); 2.30 (d,

J ¼ 5.7 Hz, 2 H, CH₂); 1.65 (d, J ¼ 5.7 Hz, 3 H, ¼CHCH₃); 1.24 (s, 6 H,

C(CH₃)₂); ¹³C NMR (CDCl₃, 50 MHz): 177.0 (S, C]O); 128.2 (D,

J ¼ 151 Hz, ¼CH); 127.4 (D, J ¼ 152 Hz, ¼CH); 43.8 (T, J ¼ 128 Hz,

CH₂); 42.5 (S, C(CH₃)₂); 38.3 (Q, J ¼ 138 Hz, N(CH₃)₂); 26.3 (Q,

J ¼ 128 Hz, CHCH₃); 18.1 (Qt, J ¼ 126 Hz, 5.7 Hz, C(CH₃)₂); MS: 170

([MþH]^þ); 169 ([M]^þꢁ); 154 ([M ꢂ CH₃]^þ); 126 ([M-N(CH₃)₂þH]^þꢁ);

97 ([CH₃CH]CHCH₂C(CH₃)₂]^þ); 72 ([CON(CH₃)₂]^þ); Anal. calc. for

4.5.8. 2-(Cyclohex-2-enyl)-N,N,2-trimethylpropanamide 18f

P-2, D: 0.7 ml (0.7 g, 7.07 mmol) of cyclohex-2-en-1-ol, 1 ml

(0.945 g, 7.07 mmol) of TMCE, 3.4 ml (8.5 mmol) of 2.5 M n-BuLi in

hexane, 15 ml of DME; 12h, 100 ^ꢀC; ﬂash chromatography (petro-

leum ether/ether: 3/2); yield: 0.82 g (59%); ¹H NMR (CDCl₃,

300 MHz): 5.76 (m, 1 H, ¼CH); 5.48 (d quint, J ¼ 6.6 Hz.

1.9, 1H, ¼CH); 3.05 (s, 6 H, N(CH₃)₂); 2.68 (m, 1 H, CHCH₂);

2.00e1.30 (m, 6 H, CH₂CH₂CH₂); 1.25 (s, 3 H, CCH₃); 1.17 (s, 3 H,

CCH₃); ¹³C NMR (CDCl₃, 75 MHz): 176.9 (S, C]O); 128.7 (D,

J ¼ 156 Hz, ¼CH); 127.7 (D, J ¼ 155 Hz, ¼CH); 45.4 (S, C(CH₃)₂); 41.8

(D, J ¼ 125 Hz, CHCH₂); 38.5 (Q, J ¼ 137 Hz, N(CH₃)₂); 25.1; 24.5;

23.4; 22.9 (T, J ¼ 128 Hz, CH₂); 22.6 (T, J ¼ 129 Hz, CH₂); MS: 196 (39,

[M^þH]^þ); 195 (100, [M]^þꢁ); 180 (83, [M ꢂ CH₃]^þ); 123 (57, [M-

CON(CH₃)₂]^þ); 122 (96, [MeCON(CH₃)₂e1]^þꢁ); IR: 1624s; Anal. calc.

for C₁₂H₂₁NO (195.30): C 73.79, H 10.83, N 7.17; found: C 73.61, H

11.09, N 7.01.

C

₁₀H₁₉NO (169.26): C 70.95, H 11.31, N 8.27; found: C 71.01, H 11.35,

N 8.31.

4.5.5. N,N,2,2-tetramethylpent-4-enamide 18c

P-1, A: 0.96 ml (0.82 g, 14.14 mmol) of allyl alcohol, 2 ml (1.89g,

14.14 mmol) of TMCE, 4 ml (2.90 g, 28.70 mmol) of triethylamine,

25 ml of dichloromethane; 48 h, r.t.; ﬂash chromatography (eth-

ylacetate/cyclohexane: 1/4); yield: 0.40 g (18%).

P-1, B: 0.96 ml (0.82 g, 14.14 mmol) of allyl alcohol, 2 ml (1.89 g,

14.14 mmol) of TMCE, 4 ml (2.90 g, 28.70 mmol) of triethylamine,

25 ml of cyclohexane; 24 h, r.t.; ﬂash chromatography (ethyl ace-

tate/cyclohexane: 1/4); yield: 1.71 g.

(78%); RN 16487-57-3; colorless liquid; ¹H NMR (CDCl₃,

200 MHz): 5.72 (m, 1 H, ¼CH); 5.12e4.96 (m, 2 H, ¼CH₂); 3.04 (s,

6H, N(CH₃)₂); 2.38 (d, J ¼ 6.7 Hz, 2 H, CH₂); 1.27 (s, 6 H, C(CH₃)₂); ¹³

C

NMR (CDCl₃, 50 MHz): 175.8 (S, C]O); 134.3 (Dt, J ¼ 153 Hz,

6.0 Hz, ¼CH); 116.8 (T, J ¼ 155 Hz, ¼CH₂); 44.5 (T, J ¼ 127 Hz, CH₂);

41.6 (S, C(CH₃)₂); 37.7 (Qq, J ¼ 137 Hz, 3.4 Hz, N(CH₃)₂); 25.7 (Q sext,

J ¼ 127 Hz, C(CH₃)₂); MS: 156 ([M^þH]^þ); 155 ([M]^þꢁ); 140 ([M-

CH3]^þ); 84 ([M-CON(CH₃)₂^þH]^þꢁ); 72 ([CON(CH₃)₂]^þ); IR (CH₂Cl₂):

3077w; 3049w; 1620s; 998 m; 921 m; Anal. calc. for C₉H₁₇NO

(155.24): C 69.63, H 11.03, N 9.02; found: C 69.65, H 11.05, N 9.00.

4.5.9. N,N,3-trimethyl-2,2-pentamethylenepent-4-enamide 21a

P-1, B: 0.61 ml (0.52 g, 7.17 mmol) of crotyl alcohol, 1.02 g

(5.88 mmol) of a-chloroenamine 2c 1.6 ml (1.19 g; 11.76 mmol) of

triethylamine, 20 ml of cyclohexane; 72h, 60 ^ꢀC; ﬂash chromatog-

raphy (petroleum ether/ether: 2/1); yield: 575 mg (47%); colorless

liquid; bp.: 100 ^ꢀC (0.2 torr); ¹H NMR (CDCl₃, 200 b MHz): 5.76 (ddd,

J ¼ 16.67 Hz, 10.44, 8.42, 1 H, ¼CH); 5.05e4.90 (m, 2 H, ¼CH₂); 3.07

(s, 6H, N(CH₃)₂); 2.35 (m, 1 H, CHCH₃); 2.30e2.10 (m, 2 H,

CH₂CCH₂); 1.70e1.00 (m, 8 H, (CH₂)₄); 0.97 (d, J ¼ 7.0 Hz, 3 H,

CHCH₃); ¹³C NMR (CDCl₃, 50 MHz): 174.0 (S, C]O); 139.7 (D,

J ¼ 152 Hz, ¼CH); 114.5 (Td, J ¼ 155 Hz, 5.8 Hz, ¼CH₂); 51.1 (S,

CH₂CCH₂); 43.6 (D, CHCH₃); 38.2 (Q, J ¼ 148, N(CH₃)₂); 32.3 (T,

CH₂); 30.8 (T, CH₂); 25.9 (T, CH₂); 23.1 (T, CH₂); 14.7 (Q, J ¼ 126 Hz,

CHCH₃); MS: 210 (16, [MþH]^þ); 209 (38, [M]^þꢁ); 194 (12,

[M ꢂ CH₃]^þ); 154 (100, [(CH₃)₂NCOC₆H₁₀]^þ); IR (neat): 1620s; Anal.

calc. for C₁₃H₂₃NO (209.33): C 74.59, H 11.07, N 6.69; found: C 74.52,

H 10.98, N 6.85.

4.5.6. N,N,2,2,3-pentamethylpent-4-enamide 18d

P-1, B: 1.19 ml (1.02 g, 14.14 mmol) of crotyl alcohol, 2 ml (1.89 g,

14.14 mmol) of TMCE, 4 ml (2.90 g, 28.70 mmol) of triethylamine,

25 ml of cyclohexane; 6h, 60 ^ꢀC; ﬂash chromatography (ethyl ac-

etate/cyclohexane: 1/4); yield: 1.80 g (76%); colorless liquid; ¹H

NMR (CDCl₃, 200 MHz): 5.72 (m, 1 H, ¼CH); 5.08e4.94 (m,

2 H, ¼CH₂); 3.06 (s, 6H, N(CH₃)₂); 2.69 (quint, J ¼ 7.0 Hz, 1 H,

CHCH₃); 1.20 (s, 3 H, CCH₃); 1.18 (s, 3 H, CCH₃); 0.97 (d, J ¼ 6.8 Hz,

3 H, CHCH₃); ¹³C NMR (CDCl₃, 50 MHz): 177.2 (S, C]O); 140.3 (D,

J ¼ 151 Hz, ¼CH); 115.5 (T, J ¼ 156 Hz, ¼CH₂); 45.8 (S, C(CH₃)₂); 43.5

11

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

4.5.10. N,N-dimethyl-2,2-pentamethylene-3-phenyl-pent-4-

enamide 21b

P-1, B: 1.86 ml (1.95 g, 14.5 mmol) of cinnamyl alcohol, 2.07 g

(11.9 mmol) of a-chloroenamine 2c, 3.3 ml (2.41 g; 23.8 mmol) of

([M]^þꢁ); 182 ([M

ꢂ

CH₃]^þ); 154 ([M-N(CH₃)₂þH]^þꢁ); 114

([MeCON(CH₃)₂eH]^þꢁ); 83 ([CH₃CH₂CH₂CHCH]CH₂]^þ); 72

([CON(CH₃)₂]^þ); IR (CH₂Cl₂): 3077w; 3051w; 1619s; 1002w; 920 m;

Anal. calc. for C₁₂H₂₃NO (197.32): C 73.04, H 11.74, N 7.09; found: C

73.08, H 11.80, N 7.13.

triethylamine, 20 ml of cyclohexane; 72h, 60 ^ꢀC; ﬂash chromatog-

raphy (petroleum ether/ether: 2/1); yield: 2.11 g (65%); colorless

liquid; ¹H NMR (CDCl₃, 300 MHz): 7.30e7.10 (m, 5 H, Ph); 6.36 (dt,

J ¼ 16.8 Hz, 10.1 Hz, 1 H, ¼CH); 5.15e5.00 (m, 2 H, ¼CH₂); 3.45 (d,

J ¼ 10.2 Hz, 1H, CHPh); 2.72 (s br, 6 H, N(CH₃)₂); 2.40e2.30 (m, 2 H,

CCH₂); 1.00e1.70 (m, 8 H, (CH₂)₄); ¹³C NMR (CDCl₃, 75 MHz): 172.6

(S, C]O); 139.6 (Sq, J ¼ 6.5 Hz, C); 136.2 (D, J ¼ 152 Hz, ¼CH); 127.8

(Dq, J ¼ 157 Hz, 6.1 Hz, C_ar); 126.6 (Dd, J ¼ 159 Hz, 7.3 Hz, C_ar); 125.3

(Dt, J ¼ 160 Hz, 7.3 Hz, C_ar); 115.3 (Td, J ¼ 156 Hz, 6.2 Hz, ¼CH₂); 57.3

(D, J ¼ 128 Hz, CHPh); 52.1 (S, CH₂CCH₂); 37.0 (Q large, J ¼ 137 Hz,

N(CH₃)₂); 33.7 (T, J ¼ 127 Hz, CH₂); 32.7 (T large, J ¼ 124 Hz, CH₂);

24.9 (T, J ¼ 126 Hz, CH₂); 22.54 (T, J ~126 Hz, CH₂); 22.49 (T,

J~126 Hz, CH₂); MS: 271 (7, [M]^þꢁ); 270 (10, [M ꢂ H]^þ); 154 (100,

[M-PhCHCHCH₂]^þ); 117 (29, [PhCHCHCH₂]^þ); HR-MS: 271.1936

(M^þ, C₁₈H₂₅NO^þ; calc. 271.1939). IR (neat): 3050 m; 3020 m;

2920 m; 1610s.

4.5.13. N,N-dimethyl-2,2-pentamethylene-3-propylpent-4-enamide

21d

P-1, B from (E)-hex-2-en-1-ol: 1.49 ml (1.27 g, 12.6 mmol) of

trans-hex-2-en-1-ol, 1.8 g (10.4 mmol) of

2.9 ml (2.1 g; 20.8 mmol) of triethylamine, 20 ml of cyclohexane;

72 h, 60 ^ꢀC; ﬂash chromatography (petroleum ether/ether: 2/1);

yield: 1.31 g (53%).

P-1, B from (Z)-hex-2-en-1-ol: 1.70 ml (1.44 g, 14.3 mmol) of cis-

hex-2-en-1-ol, 2.04 g (11.8 mmol) of

(17.5 mmol) of n-BuLi 2.5 M in hexane, 20 ml of cyclohexane; 72 h,

60 ^ꢀC; ﬂash chromatography (petroleum ether/ether: 2/1); yield:

1.41 g (51%); colorless liquid; IR (neat): 1620s; ¹H NMR (CDCl₃,

200 MHz): 5.58 (dt, J ¼ 16.9 Hz, ~9.8 Hz, 1H, ¼CH); 5.08 (dd,

J ¼ 10.3 Hz, 2.2 Hz, 1 H, ¼CH E-isomer); 4.94 (dd, J ¼ 16.9 Hz, 2.1 Hz,

1 H, ¼CH Z-isomer); 3.07 (s, 6 H, N(CH3)2); 2.00e2.20 (m, 3H,

CHCCH₂); 1.70e1.00 (m, 12 H, (CH₂)₄þ (CH₂)₂); 0.84 (t, J ¼ 6.9 Hz,

3 H, CH₂CH₃); ¹³C NMR (CDCl₃, 50 MHz): 174.5 (S, C]O); 138.7 (D,

J ¼ 150 Hz, ¼CH); 116.6 (T, J ¼ 155 Hz, ¼CH₂); 51.7 (S, CH₂CCH₂);

50.3 (D, CHCH₂);

a-chloroenamine 2c,

a-chloroenamine 2c, 7 ml

4.5.11. N,N,3,3-tetramethyl-2,2-pentamethylene-pent-4-enamide

21c

P-1, B: 1.43 ml (1.21 g, 14.1 mmol) of 3-methylbut-2-en-1-ol,

1.38 g (7.9 mmol) of a-chloroenamine 2c, 7 ml (17.5 mmol) of n-

BuLi 2.5 M in hexane, 20 ml of cyclohexane; 72h, 60 ^ꢀC; ﬂash

chromatography (petroleum ether/ether: 2/1); yield: 0.90 g (51%);

white solid; bp.: 110 ^ꢀC (0.2 torr); mp.: 75.5e75.9 ^ꢀC; IR (neat):

1595s; 1365 m; 1H NMR (CDCl3, 300 MHz): 5.88 (dd, J ¼ 17.4 Hz,

9.9 Hz, 1 H, ¼CH); 5.04e4.92 (m, 2 H, ¼CH₂); 3.07 (s br, 6H,

N(CH₃)₂); 2.50e2.40 (m, 2 H, CCH₂); 1.70e1.60 (m, 2 H.

38.5 (Qq, J ¼ 138 Hz, 3.6 Hz, N(CH₃)₂); 32.9 (T, CH₂); 31.2 (T,

CH₂); 30.8 (T, CH₂); 26.1 (T, CH₂); 23.5 (T, CH₂); 23.4 (T, CH₂); 20.7 (T,

CH₂); 13.6 (Q, J ~125 Hz, CH₃CH₂); MS: 238 (11, [MþH]^þ); 237 (44,

[M]^þꢁ); 222 (13, [M ꢂ CH₃]^þ); 194 (26, [M ꢂ Pr]^þ); 154 (100,

[(CH₃)₂NCOC₆H₁₀]^þ); Anal. calc. for C₁₅H₂₇NO (237.38): C 75.89, H

11.46, N 5.9; found: C 76.37, H 11.37, N 6.14.

CCH₂); 1.30e1.15 (m, 6 H, (CH₂)₃); 1.05 (s, 6 H, C(CH₃)₂); ¹³C NMR

(CDCl₃, 75 MHz): 173.5 (S, C]O); 145.9 (D, J ¼ 151 Hz, ¼CH); 111.8

(T, J ¼ 156, ¼CH₂); 55.2 (S, CCH₂); 42.3 (S, C(CH₃)₂); 39.0 (Q, J ¼ 136,

N(CH₃)₂); 32.5 (T br, CH₂CCH₂); 26.3 (T, C(CH₂CH₂)₂); 24.1 (T,

C(CH₂)₂CH₂); 23.3 (Q, C(CH₃)₂); MS: 224 (3, [MþH]^þ); 223 (11,

[M]^þꢁ); 208 (3, [M ꢂ CH₃]^þ); 155 (35, [M-C(CH₃)₂CHCH^þ₂H]^þꢁ); 154

(100, [M-C(CH₃)₂CHCH₂]^þ); 151 (16, [M-(CH₃)₂NCO]^þꢁ); 72 (51,

[(CH₃)₂NCO]^þ); 69 (53, [C(CH₃)₂CH₂CH]^þ); Anal. calc. for C₁₄H₂₅NO

(223.35): C 75.28, H 11.28, N 6.27; found: C 75.20, H 11.15, N 6.46.

4.5.14. 2,2-dimethyl-3-phenyl-N,N-diisopropyl-pent-4-enamide 22

P-1, B: 2.10 ml (2.19 g, 16.3 mmol, 1.22 eq.) of cinnamyl alcohol,

2.54 g (13.4 mmol, 1 eq) of a-chloroenamine 2b, 4.10 ml (2.98 g,

29.4 mmol, 2.2 eq) triethylamine in cyclohexane (20 ml); 120 h, r.t.;

ﬂash chromatography (petroleum ether/ether 4/1) then horizontal

distillation (0.5 Torr, oven t^ꢀC: 155 ^ꢀC); yield: 1.65 g (43%). ¹H NMR

2

3

(CDCl₃, 200 MHz): 7.25e7.15 (m, 5 H); 6.26 (ddd, J_4-5Z¼ 16.8, J_4-

¼ 10.2, ³J_4-3¼ 8.5 Hz, 1 H); 5.0e5.2 (m, 2H, E þ Z), 4.52 (m, 1 H),

5E

3

3.78 (d, J_3-4¼ 8.6 Hz, 1 H), 3.3 (m, 1 H), 1.21 (s) and 1.12(s) and

4.5.12. N,N,2,2-tetramethyl-3-propylpent-4-enamide 18g

P-1, B from (E)-hex-2-en-1-ol: 1.67 ml (1.42 g, 14.14 mmol) of

trans-hex-2-en-1-ol, 2 ml (1.89 g, 14.14 mmol) of TMCE, 4 ml

(2.90 g, 28.70 mmol) of triethylamine, 25 ml of cyclohexane; 8h,

60 ^ꢀC; ﬂash chromatography (ethylacetate/cyclohexane: 1/4);

yield: 1.16 g (42%).

P-1, B from (Z)-hex-2-en-1-ol: 1.67 ml (1.42 g, 14.14 mmol) of

cis-hex-2-en-1-ol, 2 ml (1.89 g, 14.14 mmol) of TMCE, 4 ml (2.90 g,

28.70 mmol) of triethylamine, 25 ml of cyclohexane; 12h, 60 ^ꢀC; not

puriﬁed; by GC IBA: 82/18.

1.45e1.10 (m, 18 H of methyl groups); ¹³C NMR (CDCl₃, 75 MHz):

174.3 (S, C]O), 140.6 (S,.1C_ar), 137.7 (D, ¹J ¼ 154.5 Hz, HC ¼ ), 129.4

(Dq, ¹J ¼ 126.7 Hz, ²J ¼ 6.2 Hz) 127.6 (Dd, ¹J ¼ 159.2 Hz, ²J ¼ 7.2 Hz)

and 126.3 (Dt, ¹J ¼ 160.6 Hz, ²J ¼ 6.8 Hz) for 3 Car, 116.8 (Td

¹J ¼ 156.2 Hz, ²J ¼ 6.0 Hz ¼ CH₂), 55.0 (D, ¹Je130 Hz CH), 48.1 (D,

¹Je135 Hz, CH), 46.8 (S, quaternary C), 46.7 (D, ¹Je126 Hz, CH), 24.4

(Q, ¹J ¼ 127.3 Hz, CH₃) and 20.4 (Q, ¹J ¼ 126.6 Hz, CH₃); MS: 287 (14

[M]^þꢁ); 286 (38 [M ꢂ H]^þ); 245 (17 [M-iPr þ H]^þ); 244 (100 [M-

iPr]^þ);

170

(16

[M-CH₂CHCHPh]^þ);

159

(30

[C(CH₃)₂CHPhCHCH₂]^þ); 128 (14 [iPr₂NCO]^þ); 117 (59

[CH₂CHCHCH₂]^þ); Anal. calc. for C₁₉H₂₉NO (287.44):, C 79.39, H

10.16, N 4.87; found: C 79.57, H 10.00, N 4.73.

P-2, C from (Z)-hex-2-en-1-ol: 1.84 ml (1.56 g, 15.75 mmol) of

cis-hex-2-en-1-ol, 2 ml (1.89 g, 14.14 mmol) of TMCE, 6 ml

(15 mmol) of n-BuLi 2.5 M in hexane, 25 ml of cyclohexane; ﬂash

chromatography (ethylacetate/cyclohexane: 1/4); 72h, 60 ^ꢀC; yield:

1.26 g (45%); colorless liquid.

4.5.15. (2R*,3S*)-N,N,2,3-tetramethyl-2-phenylpent-4-enamide

23a and (2R*,3R*)-N,N,2,3-tetramethyl-2-phenylpent-4-enamide

24a

¹H NMR (CDCl₃, 200 MHz): 5.60 (m, 1 H, ¼CH); 4.95e5.15 (m,

2 H, ¼CH₂); 3.05 (s, 6H, N(CH₃)₂); 2.41 (td, J ¼ 9.4 Hz, 4.0 Hz, 1 H,

P-1, B: 0.59 ml (0.49 g, 6.86 mmol) of crotyl alcohol, 1.1 g

CH₂CH); 1.20 (s,

6

H, C(CH₃)₂); 1.50e1.00 (m, 10 H,

(5.62 mmol) of a-chloroenamine 2d, 1.57 ml (1.14 g; 11.2 mmol) of

CH₂CH₂þ C(CH₃)₂); 0.86 (t, J ¼ 6.8 Hz, 3 H, CH₂CH₃); ¹³C NMR

(CDCl₃, 50 MHz): 176.8 (S, C]O); 138.7 (D, J ¼ 150 Hz, ¼CH); 117.0

(T, J ¼ 154 Hz, ¼CH₂); 50.2 (D, J ¼ 128 Hz, CH₂CH); 45.9 (S, C(CH₃)₂);

38.4 (Qq, J ¼ 137 Hz, 3.7 Hz, N(CH₃)₂); 31.7 (T, CHCH₂); 24.1 (Q,

J ¼ 127 Hz, CCH₃); 22.8 (Q, J ¼ 132 Hz, CCH₃); 21.0 (T, J ¼ 128 Hz,

CH₂CH₃); 14.0 (Q, J ¼ 123 Hz, CH₂CH₃); MS: 198 ([MþH]^þ); 197

triethylamine, 20 ml of cyclohexane; 72 h, 60 ^ꢀC; ﬂash chroma-

tography (petroleum ether/ether: 2/1); yield: 0.85 g (65%) of a

diastereoisomeric mixture; diastereoisomeric ratio (glc) 23a/24a:

2.6.

Analysis of the diastereoisomeric mixture: ¹H NMR (CDCl₃,

200 MHz): 7.40e7.10 (m, 5aþ5 b H, Ph); 5.06 (ddd, J ¼ 16.7, 10.6, 8.2,

12

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

1aþ1 b H, ¼CH); 5.10e4.80 (m, 2aþ2 b H, ¼CH₂); 2.20e3.10 (m,

7aþ7 b H, N(CH₃)₂þCHCH₃); 1.55 (s, 3a H, CCH₃); 1.52 (s, 3b H,

CCH₃); 1.09 (d, J ¼ 6.6 Hz, 3a H, CHCH₃); 0.84 (d, J ¼ 6.7 Hz, 3b H,

CHCH₃); ¹³C NMR (CDCl₃, 50 MHz): 174.1 (S, b, C]O); 173.9 (S, a,

C]O); 142.6 (S, a, C_ar); 141.0 (S, b, C_ar); 140.4 (D, J ¼ 152, b, ¼CH);

140.2 (D, a, ¼CH); 127.34 (Dd, J ¼ 160 Hz, 7.0, a, CH); 127.26 (Dd,

J ¼ 159, 7.0, b, CHarom); 125.7 (D, J ¼ 156, b, C_arH); 125.4 (D, a,

C_arH); 125.4 (D, b, C_arH); 125.2 (D, a, C_arH); 113.8 (T, J ¼ 154 Hz,

b, ¼CH₂); 113.7 (T, a, ¼CH₂); 51.6 (S, a, CCH₃); 51.4 (S, b, CCH₃); 45.7

(D, J ¼ 129 Hz, a, CHCH₃); 44.5 (D, J ¼ 132 Hz, b, CHCH₃); 36.7 (Q,

J ¼ 138 Hz, N(CH₃)₂); 19.6 (Qd, J ¼ 128 Hz, 3.4, b, CH₃); 18.0 (Q,

J ¼ 128 Hz, a, CH₃); 15.8 (Qt, J ¼ 126 Hz, 3.5 Hz, b, CH₃); 15.4 (Qt,

J ¼ 126 Hz, 3.7 Hz, a, CH₃); MS: 231 (63, [M]^þꢁ); 216 (44,

4.5.17. N,N,2-trimethyl-2,3-diphenylpent-4-enamide 23c and 24c

P-1, B: 0.76 ml (0.79 g, 5.9 mmol) of cinnamyl alcohol, 0.95 g

(4.85 mmol) of a-chloroenamine 2d, 1.35 ml (0.98 g; 9.71 mmol) of

triethylamine, 20 ml of cyclohexane; 72 h, 60 ^ꢀC; yield: 1.10 g (77%);

diastereoisomeric ratio by ¹H NMR 23c/24c: 3.8. Flash chroma-

tography (petroleum ether/ether: 4/1) gave 23c (purity > 99%) and

24c (purity 87%).

(2R*,3S*)-23c colorless solid; ¹H NMR (CDCl₃, 200 MHz):

7.20e6.70 (m, 10 H, Ph); 6.23 (ddd, J ¼ 17.0 Hz, 10.3 Hz, 8.3 Hz,

1 H, ¼CH); 5.10 (ddd, J ¼ 10.4 Hz, 2.0 Hz, 1.0 Hz, 1 H, ¼CH(E)); 5.02

(ddd, J ¼ 17.0 Hz, 1.8 Hz, 1.0 Hz, 1 H, ¼CH(Z)); 4.30 (d, J ¼ 8.4, 1 H,

CHPh); 2.20e3.00 (m, 6 H, N(CH₃)₂); 1.71 (s, 3 H, CCH₃); ¹³C NMR

(CDCl₃, 50 MHz): 175.0 (S, C]O); 141.7 (S, C_ar); 141.3.

[M

ꢂ

CH₃]^þ); 176 (72, [M-CH₂CHCHCH₃]^þ); 159 (15, [M-

(S, C_ar)); 139.1 (D, J ¼ 154 Hz, ¼CH); 130.5 (D, J ~155 Hz, C_ar);

127.7 (D, J~155 Hz, HC_ar)); 126.8 (D, J~155 Hz, HC_ar)); 126.6 (D,

J~155 Hz, HC_ar)); 126.2 (D, J ¼ 160 Hz, HC_ar)); 125.5 (D, J ¼ 160 Hz,

HC_ar); 116.3 (Td, J ¼ 156 Hz, 5.7 Hz, ¼CH₂); 58.4 (D, J ¼ 130 Hz,

CHPh); 53.9 (S, CCH₃); 37.9 (Q br, J~140 Hz, N(CH₃)₂); 19.6 (Qd,

J ¼ 127 Hz, 3.4 Hz, CCH₃); MS: 294 (6, [MþH]^þ); 293 (42, [M]^þꢁ);

278 (3, [M ꢂ CH₃]^þ); 176 (63, [M-CH₂CHCHPh]^þ); 148 (100,

[(CH₃)₂NC(CH₃)Ph]^þ); HR-MS: 293.1773 (M^þ, C₂₀H₂₃NO^þ; calc.

293.1779).

CO(CH₃)₂]^þ); 148 (100, [(CH₃)₂NC(CH₃)Ph]^þ); IR (neat): 3050 m;

1630s; 1595 m; 1575 m; Anal. calc. for C₁₅H₂₁NO (231.33): C 77.87, H

9.14, N 6.05; found: C 77.98, H 9.25, N 6.33.

4.5.16. N,N,2-trimethyl-2-phenyl-3-propylpent-4-enamide 23b and

24b

P-1, B: 0.77 ml (0.65 g, 6.5 mmol) of (E)-hex-2-en-1-ol, 1.05 g

(5.37 mmol) of a-chloroenamine 2d, 1.50 ml (1.09 g; 10.7 mmol) of

triethylamine, 20 ml of cyclohexane; 72 h, r.t.; ﬂash chromatog-

raphy (petroleum ether/ether: 4/1); yield: 0.77 g (55%); diaste-

reoisomeric ratio (glc): 23b/24b: 2.3. Puriﬁcation by ﬂash

chromatography (petroleum ether/ether: 4/1).

(2R*,3R*)-24c: ¹H NMR (CDCl₃, 200 MHz): 7.34e6.68 (m, 10 H,

Ph); 6.17 (ddd, J ¼ 17.6 Hz, 9.6 Hz, 8.2 Hz, 1 H, ¼CH); 5.07e4.96 (m,

2 H, ¼CH₂); 4.27 (d, J ¼ 8.1 Hz, 1H, CHPh); 3.00e2.20 (m, 6 H,

N(CH₃)₂); 1.47 (s, 3 H, CCH₃); ¹³C NMR (CDCl₃, 50 MHz): 175.1;

140.8; 140.7; 139.7; 130.6; 127.72; 127.7; 127.2; 126.6; 126.2; 116.5;

58.4; 53.9; 37.8; 22.5.

P-2, C: 0.74 ml (0.62 g, 6.23 mmol) of (Z)-hex-2-en-1-ol, 1.0 g

(5.11 mmol) of a-chloroenamine 2d, 2.45 ml (6.13 mmol) of nBuLi

4.6. Deoxygenation of propargylic alcohols 26 into 3-halo-prop-1-

yne 27

2.5 M in hexane, 20 ml of cyclohexane; 72 h, 60 ^ꢀC; ﬂash chroma-

tography (petroleum ether/ether: 4/1); yield: 770 mg (39%); dia-

stereoisomeric ratio (glc): 23b/24b: 2.0.

4.6.1. 3-Chloroprop-1-yne 27a

(2R*,3S*)-isomer 23b: ¹H NMR (CDCl₃, 200 MHz): 7.00e7.40 (m,

5 H, Ph); 5.45 (ddd, J ¼ 17.0, 10.2, 9.3, 1 H, ¼CH); 4.80 (dd,

J ¼ 10.2 Hz, 2.2 Hz,1 H, ¼CH(E)); 4.67 (dd, J ¼ 17.0, 2.2,1 H, ¼CH(Z));

2.20e3.00 (m, 7 H, N(CH₃)₂þCHCH₂); 1.59 (s, CHCH₃); 1.70e1.00

(m, 7 H, CHCH₃þCH₂CH₂); 0.85 (t, J ¼ 7.1 Hz, 3 H, CH₂CH₃); ¹³C NMR

(CDCl₃, 50 MHz): 175.1 (S, C]O); 143.9 (S, C_ar); 138.9 (D,

J ¼ 150 Hz, ¼CH); 128.1 (Dd, J ¼ 159 Hz, 7.3 Hz, C_ar); 126.0 (D,

J ¼ 160 Hz, C_ar); 125.8 (D, J ¼ 157 Hz, c); 116.2 (Td, J ¼ 155 Hz,

6 Hz, ¼CH2); 53.9 (D, J ¼ ~130 Hz, CHCH₂); 52.8 (S, CCH₃); 37.6 (Q

br, J ¼ 137 Hz, N(CH₃)₂); 32.8 (T, J ¼ 126 Hz, CHCH₂); 21.0 (T, J ~125,

CH₂CH₃); 19.6 (Q, J ¼ 127 Hz, CCH₃); 13.9 (Q, J ¼ 123 Hz, CH₂CH₃);

Prop-2-yn-1-ol 0.40 ml (0.38 g, 6.8 mmol); 1 g (7.5 mmol) TMCE

2a; 1 h, 99% (¹HNMR). No chloroallene was detected.

4.6.2. 3-Chlorobut-1-yne 27b

But-3-yn-2-ol 0.53 ml (6.8 mmol); 1 g (7.5 mmol) TMCE 2a, 1 h,

98% (¹H NMR). Under these conditions, no chloroallene was

detected. However, the propargylic chloride slowly isomerized into

chloroallene over time in the reaction mixture. After 4 days, the

proportions between the 2 chlorides were: 3-chlorobut-1-yne/1-

chlorobuta-1,2-diene: 93/7.

MS: 259 (31, [M]^þꢁ); 244 (13, [M

ꢂ

CH₃]^þ); 177 (37, [M-

PrCHCHCH₂þH]^þꢁ); 176 (100, [M-PrCHCHCH₂]^þ); 148 (89,

4.6.3. 3-Bromobut-1-yne 27c

[(CH₃)₂NC(CH₃)Ph þ H]^þꢁ); IR (CH₂Cl₂): 1620s; Anal. calc. for

But-3-yn-2-ol 0.4 ml (5.1 mmol); 1 g (5.6 mmol) TMBE 3a; 1 h,

95% (¹H NMR). No bromoallene detected under these conditions.

However, the propargyl bromide slowly converted into bro-

moallene over time in the reaction mixture. After 4 days, the ratio

was: 3-bromobut-1-yne/1-bromobuta-1,2-diene: 4/1.

C

₁₇H₂₅NO (259.39): C 78.71, H 9.71, N 5.39; found: C 78.70, H 9.87, N

5.05.

(2R*,3R*)-isomer 24b:white solid; mp.: 63.5e64 ^ꢀC; ¹H NMR

(CDCl₃, 200 MHz): 7.40e7.15 (m, 5 H, Ph); 5.30 (ddd, J ¼ 16.7 Hz,

10.0 Hz, 5.3 Hz, 1 H, ¼CH); 5.06 (dd, J ¼ 10.3 Hz, 2.7 Hz, 1 H, ¼CHE);

4.98 (dd, J ¼ 16.6 Hz, 2.7 Hz, 1 H, ¼CH(Z)); 3.00e2.20 (m, 7 H,

4.6.4. 3-Iodoprop-1-yne 27d

N(CH₃)₂þCHCH₂); 1.54 (s, CCH₃); 1.80e1.10 (m,

7

H,

Prop-2-yn-1-ol 0.24 ml (0.23 g, 4 mmol); 1 g (4.4 mmol) TMIE

4a; 1 h, 93% (¹H NMR). Under these conditions, no rearranged

product was detected. However, after four days at room tempera-

ture, the crude reaction mixture was shown to contain a 1:3

mixture of 1-iodopropa-1,2-diene and 3-iodo-1-propyne (72%). The

spectral properties were identical with those of authentic samples:

CH₂CH₂þCCH₃); 0.85 (t, J ¼ 7.1 Hz, 3 H, CH₂CH₃); ¹³C NMR (CDCl₃,

50 MHz): 174.9 (S, C]O); 141.4 (S, C_ar)); 138.6 (D, J ¼ 155 Hz, ¼CH);

127.6 (Dd, J ¼ 159 Hz, 7.0, C_ar)); 126.4 (Dt, J ¼ 156, 6.5, CHarom);

125.8 (Dt, J ¼ 160 Hz, 7.0, C_ar)); 116.5 (T, J ¼ 158 Hz, ¼CH₂); 52.3 (S,

CCH₃); 51.2 (D, J~130 Hz, CHCH₂); 37.5 (Q br, J ~140 Hz, N(CH₃)₂);

32.7 (T, J ¼ 125 Hz, CHCH₂); 22.1 (Qd, J ¼ 128 Hz, 2.9 Hz, CCH₃); 20.4

(T, J ¼ 122 Hz, CH₂CH₃); 13.6 (Q, J ¼ 123 Hz, CH₂CH₃); MS: 259 (45,

[M]^þꢁ); 244 (13, [M ꢂ CH₃]^þ); 177 (36, [M-PrCHCHCH₂þH]^þꢁ); 176

(100, [M-PrCHCHCH₂]^þ); 148 (87, [(CH₃)₂NC(CH₃)Ph]^þ); IR

(CH₂Cl₂): 1620s; Anal. calc. for C₁₇H₂₅NO (259.39): C 78.71, H 9.71, N

5.39; found: C 78.67, H 9.84, N 5.12.

for 3-iodo-1-propyne 27d: ¹H NMR (200 MHz, CDCl₃):

d (ppm):

3.64 (d, J ¼ 2.5 Hz, 2H), 2.43 (t, J ¼ 2.5 Hz, 1). IR(CH₂Cl₂): 3320 cm^ꢂ1

(HeC^C), 2130 cm^ꢂ1(C^C); for 1-iodopropa-1,2-diene: ¹H NMR

(200 MHZ, CDCl₃):

d

(ppm): 5.71 (t, J ¼ 6.2Hz, 1H), 4.62 (d,

J

¼

6.2 Hz, 2H). IR (CH₂Cl₂): 1950 cm^ꢂ1(C]C]C),

860 cm^ꢂ1(H₂C ¼ ).

13

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

4.6.5. 3-Iodo-1-butyne 27e

2 ml (1.89 g, 14.14 mmol) of TMCE, 4 ml (2.90 g; 28.70 mmol) of

triethylamine, 25 ml of cyclohexane; 12h, r.t.; ﬂash chromatog-

raphy (ethyl acetate/cyclohexane: 1/4); yield: 1.87 g (73%); color-

less liquid; ¹H NMR (CDCl₃, 200 MHz): 5.18 (sept, J ¼ 2.8 Hz,

1H, ¼CH); 3.05 (s br, 6 H, N(CH₃)₂); 1.70 (d, J ¼ 2.8 Hz,

6 H, ¼C(CH₃)₂); 1.29 (s, 6 H, C(CH₃)₂); ¹³C NMR (CDCl₃, 50 MHz):

But-3-yn-2-ol 0.32 ml (4 mmol); 1 g (4.4 mmol) TMIE 4a; 1 h. A

mixture of 3-iodo-1-butyne 27e (92%) and 1-iodobuta-1,2-diene

(6%) was obtained (yields determined by ¹H NMR). After 4 days at

r.t. the crude reaction mixture only contained 1-iodobuta-1,2-diene

(90%). The spectral properties were identical with those of

authentic samples: for 3-iodobut-1-yne 27e, ¹H NMR (200 MHz,

199.1 (S, ¼C

¼ ); 175.3 (S, C]O); 98.3 (S, ¼C); 96.3 (D,

CDCl₃):

d

(ppm): 4.59 (qd, J₁¼ 7 Hz, J₂¼ 2.5 Hz, 1H), 2.67 (d,

J ¼ 165 Hz, ¼CH); 42.2 (S, C(CH₃)₂); 37.4 (Q, J ¼ 138 Hz, N(CH₃)₂);

26.5 (Q, J ¼ 128 Hz, C(CH₃)₂); 19.5 (Q, J ¼ 128 Hz, ¼C(CH₃)₂); MS:

181 ([M]^þꢁ); 166 ([M ꢂ CH₃]^þ); 151 ([MeCH₃eCH₃]^þ); 138 ([M-

N(CH₃)₂þH]^þꢁ); 109 ([M-CON(CH₃)₂]^þ); 72 ([CON(CH₃)₂]^þ); 67

([(CH₃)₂C]C]CH]^þ); IR (CH₂Cl₂): 3048w; 1967w; 1626s; Anal.

calc. for C₁₁H₁₉NO (181.27): H 10.56, C 72.88, N 7.72; found: H 10.60,

C 72.91, N 7.75.

J ¼ 2,5 Hz, 1H), 2.07 (d, J ¼ 7Hz, 3H); for 1-

iodobuta-1,2-diene, ¹H NMR (200 MHz, CDCl₃):

d (ppm); 5.59

(m, 1H), 5.01 (m, 1H), 1.72 (dd, J₁¼ 7.4 Hz, J₂¼ 2.6 Hz, 3H).

4.6.6. 3-Iodooct-1-yne 27f

Oct-1-yn-3-ol 0.59 ml (0.51 g, 4 mmol); 1 g (4.4 mmol)TMIE 4a;

1 h. A mixture of 3-iodo-1-octyne 27f (91%) and 1-iodoocta-1,2-

diene (6%) was obtained (yields determined by ¹H NMR). After

12 h at r.t., the crude mixture (which also contained N,N-

dimethylisobutyramide) contained a 15:1 mixture of 3-iodooct-1-

yne/1-iodoocta-1,2-diene. After 19 h in reﬂuxing chloroform,

isomerization into 1-iodoocta-1,2-diene was almost completed

(1:13.3). N,N-dimethylisobutyramide 1a was separated from the

iodide mixture by ﬂash chromatography on silica gel (cyclohexane/

ethyl acetate: 2/1). In the absence of 1a, the isomerization was very

slow: after 4 days at r.t., the mixture of the 2 iodides remained

unchanged (74% of propargylic iodide þ 26% of iodoallene). How-

ever, after 24 h in reﬂuxing chloroform, the ratio 3-iodooct-1-yne/

1-iodoocta-1,2-diene became 1/3. The spectral properties were

identical with those of authentic samples.

4.7.2. N,N,2,2-tetramethylhexa-3,4-dienamide 34b

P-1, B: 1.11 ml (0.99 g, 14.14 mmol) of rac-but-3-yn-2-ol, 2 ml

(1.89 g, 14.14 mmol) of TMCE, 4 ml (2.90 g; 28.70 mmol) of trie-

thylamine, 25 ml of cyclohexane; 12 h, r.t.; ﬂash chromatography

(ethyl acetate/cyclohexane: 1/4); yield: 1.82 g (77%); colorless

liquid; ¹H NMR (CDCl₃, 200 MHz): 5.35e5.15 (m, 2H, HC]C]CH);

3.04 (s br, 6 H, N(CH₃)₂); 1.67 (dd, J ¼ 6.7 Hz, 4.4 Hz, 3 H, CHCH₃);

1.42 (s, 3 H, CCH₃); 1.41 (s, 3 H, CCH₃); ¹³C NMR (CDCl₃, 50 MHz):

201.9 (S, ¼C ¼ ); 174.7 (S, C]O); 97.6 (D, J ¼ 162 Hz, ¼CHC); 88.5 (D

quint, J ¼ 162 Hz, 3 Hz, 7.0 Hz, ¼CHCH₃); 41.8 (S, C(CH₃)₂); 37.4 (Q,

J ¼ 139 Hz, N(CH₃)₂); 26.6 (Q, J ¼ 128 Hz, CCH₃); 26.3 (Q, J ¼ 128 Hz,

CCH₃); 13.5 (Q, J ¼ 129 Hz, CHCH₃); MS: 168 ([MþH]^þ); 167 ([M]^þꢁ);

152 ([M ꢂ CH₃]^þ); 137 ([M ꢂ CH₃eCH₃]^þ); 124 ([M-N(CH₃)₂þH]^þꢁ);

95 ([M-CON(CH₃)₂]^þ); 72 ([CON(CH₃)₂]^þ); 53 ([CH₃C]C]CH]^þ); IR

(CH₂Cl₂): 3049w; 1965w; 1626s; Anal. calc. for C₁₀H₁₇NO (167.25):

H 10.24, C 71.81, N 8.37; found: H 10.29, C 71.90, N 8.40.

For 3-iodo-1-octyne 27f: ¹H NMR (200 MHz, CDCl₃):

4.48 (td, J₁¼ 6.9 Hz, J₂¼ 2.5 Hz, 1H), 2.61 (d, J ¼ 2.5 Hz, 1H), 1.95 (m,

2H), 1.2e1.6 (m, 6H), 0.9 (t, J ¼ 6.6 Hz, 3H). IR (CH₂Cl₂): 3300 cm^ꢂ1

(HeC^C), 2100 cm^ꢂ1(C^C); 1-iodoocta-1,2-diene 28: ¹H NMR

d (ppm):

(200 MHz, CDCl₃):

d

(ppm): 5.66 (dt, J₁¼ 5.8 Hz, J₂¼ 2.4 Hz, 1H),

4.7.3. N,N,2,2-tetramethylpenta-3,4-dienamide 34c

5.09 (td, J₁¼ 6.9 Hz, J₂¼ 5.8 Hz, 1H), 2.11 (m, 2H), 1.2e1.6 (m, 6H),

P-1, A: 0.82 ml (0.79 g, 14.14 mmol) of propargyl alcohol, 2 ml

(1.89 g, 14.14 mmol) of TMCE, 4 ml (2.90 g; 28.70 mmol) of trie-

thylamine, 25 ml of dichloromethane; 36h, r.t.; ﬂash chromatog-

0.9 (t, J ¼ 6.6 Hz, 3H).¹³C NMR (50 MHz, CDCl₃):

d (ppm): 205.61,

96.45, 35.45, 31.09, 27.92, 26.76, 22.28, 13.86. IR (CH₂Cl₂):

1945 cm^ꢂ1(C]C]C).

raphy (ethyl acetate/cyclohexane: 1/4); yield: 1.67 g (77%);

colorless liquid; ¹H NMR (CDCl₃, 200 MHz): 5.36 (t, J ¼ 6.7 Hz,

1 H, ¼CH); 4.86 (d, J ¼ 6.7 Hz, 2 H, ¼CH₂); 3.03 (s br, 6H, N(CH₃)₂);

1.34 (s, 6 H, C(CH₃)₂); ¹³C NMR (CDCl₃, 50 MHz): 205.8 (S, ¼C ¼ );

174.5 (S, C]O); 97.3 (D, J ¼ 164 Hz, ¼CH); 77.5 (Td, J ¼ 167 Hz,

8.1 Hz, ¼CH₂); 41.2 (S, C(CH₃)₂); 37.5 (Q, J ¼ 138 Hz, N(CH₃)₂); 26.2

(Q, J ¼ 128 Hz, C(CH₃)₂); MS: 154 ([MþH]^þ); 153 ([M]^þꢁ); 152

([M ꢂ H]^þ); 138 ([M ꢂ CH₃]^þ); 110 ([M-N(CH₃)₂þH]^þꢁ); 81 ([M-

CON(CH₃)₂]^þ); 72 ([CON(CH₃)₂]^þ); IR (CH₂Cl₂): 3055 m; 1956 m;

1626s; Anal. calc. for C₉H₁₅NO (153.22): H 9.86, C 70.54, N 9.14;

found: H 9.92, C 70.65, N 9.21.

4.6.7. Reaction of 2-methylbut-3-yn-2-ol with TMCE 2a

2-Methylbut-3-yn-2-ol 0.33 ml (0.29 g, 3.4 mmol); 0.5 g

(3.7 mmol) TMCE 2a;

2

h, r.t. In addition to N,N-

dimethylisobutyramide, the reaction mixture contained: 3-

chloro-3-methylbut-1-yne 31 (20%), 1-chloro-3-methylbuta-1,2-

diene 32 (2.3%), 2-methylbut-1-en-3-yne 33 and allenic amide

34a. Yields were determined by ¹H NMR in presence of an internal

standard. The spectral properties were identical with those of

authentic samples. 31: ¹H NMR (200 MHz, CDCl₃):

d

(ppm): 2.64 (s,

1H), 1.86 (s, 6H), 32: ¹H NMR (200 MHz, CDCl₃):

d (ppm): 5.9 (sept,

J ¼ 2 Hz, 1H), 1.81 (d, J ¼ 2 Hz, 6H). 33: ¹H NMR (200 MHz, CDCl₃):

4.7.4. N,N,2,2,3-pentamethylpenta-3,4-dienamide 34d

d

(ppm): 5.39 (m,1H), 5.29 (m, 1H), 2.88 (m, 1H), 1.90 (dd, J₁¼1.5Hz,

P-1, B: 1.06 ml (0.99 g, 14.14 mmol) of but-2-yn-1-ol, 2 ml

(1.89 g, 14.14 mmol) of TMCE, 4 ml (2.90 g; 28.70 mmol) of trie-

thylamine, 25 ml of cyclohexane; 12h, r.t.; ﬂash chromatography

(ethyl acetate/cyclohexane: 1/4); yield: 1.33 g (56%).

J₂¼ 1Hz, 3H).

4.6.8. Reaction of 2-methylbut-3-yn-2-ol with TMIE 4a

2-Methylbut-3-yn-2-ol 0.39 ml (0.34 g, 4 mmol); 1 g (4.4 mmol)

TMIE 4a; 3 h. Neither propargylic iodide nor iodoallene observed. In

addition to N,N-dimethylisobutyramide, the mixture contained

dienylated amide 39 and dihydropyridone 40 which were sepa-

rated by ﬂash chromatography (cyclohexane/ethyl acetate: 8/2).

Yield: 39: 0.37 g (51%); 40: 0.18 g (27%) (see 4.8. for spectral data).

P-2, C 1.06 ml (0.99 g, 14.14 mmol) of but-2-yn-1-ol, 2 ml (1.89 g,

14.14 mmol) of TMCE, 6 ml (15 mmol) of n-BuLi 2.5 M in hexane,

25 ml of cyclohexane; 12h, 60 ^ꢀC; ﬂash chromatography (ethyl

acetate/cyclohexane: 1/4); yield: 1.63 g (69%); colorless liquid; ¹H

NMR (CDCl₃, 200 MHz): 4.76 (q, J ¼ 3.1 Hz, 2 H, ¼CH₂); 3.10 (s br,

3 H, NCH₃); 3.06 (s br, 3 H, NCH₃); 1.66 (t, J ¼ 3.1 Hz, 3 H, ¼CCH₃);

1.32 (s, 6 H, C(CH₃)₂); ¹³C NMR (CDCl₃, 50 MHz): 205.3 (S, ¼C ¼ );

175.2 (S, C]O); 104.8 (S, ¼C); 76.7 (T, J ¼ 168 Hz, ¼CH₂); 44.8 (S,

C(CH₃)₂); 37.5 (Q, J ¼ 140 Hz, N(CH₃)₂); 26.0 (Qq, J ¼ 129 Hz, 4.7 Hz,

C(CH₃)₂); 15.5 (Q, J ¼ 129 Hz, ¼C(CH₃)₂); MS: 168 ([MþH]^þ); 167

4.7. Reactions of

a-chloroenamines with propargyl alcohols in the

presence of a base

4.7.1. N,N,2,2,5-pentamethylhexa-3,4-dienamide 34a

([M]^þꢁ); 166 ([M

ꢂ

H]^þ); 152 ([M

ꢂ

CH₃]^þ); 124

P-1, B: 1.37 ml (1.19 g, 14.14 mmol) of 2-methylbut-3-yn-2-ol,

([MeN(CH₃)₂eH]^þꢁ); 95 ([M-CON(CH₃)₂]^þ); 72 ([CON(CH₃)₂]^þ); IR

14

F. Munyemana, L. Patiny and L. Ghosez

Tetrahedron 89 (2021) 132148

(CH₂Cl₂): 3050w; 1956w; 1626s; Anal. calc. for C₁₀H₁₇NO (167.25):

H 10.24, C 71.81, N 8.37; found: H 10.31, C 71.90, N 8.43.

([(CH₃)₂NCO]^þ); 67 ([H₂C]C(CH₃) CH]CH]^þ).

Dihydropyridone 40: ¹H NMR (C₆D₆, 200 MHz): 5.23 (d,

J_cis¼ 10.08 Hz,1H, HeC ¼ ); 5.05 (d, J_cis¼ 10.08 Hz, HeC ¼ ); 2.76 (s,

3H, NeCH₃); 1.31 (s, 6H, CH₃), 0.90 (s, 6H, CH₃); ¹³C NMR (CDCl₃,

50 MHz): 174.32 (S, C]O); 130.67 (Dxm, ¹J ¼ 160.6 Hz, CH ¼ ),

129.53 (Dxm, ¹J ¼ 161.7, HC ¼ ); 58.05 (Sxm, CeN); 37.48 (Sxm,

4.7.5. Synthesis of allenyl amide 34e

P-1, A: addition of 0.67 ml (0.58 g, 6.9 mmol) 2-methylbut-3-yn-

2-ol to a solution of

a-chloroenamine 2e (1 g, 6.87 mmol) and

triethylamine (1.92 ml, 1.39 g, 13.7 mmol) in 4 ml CH₂Cl₂at r.t.;

overnight at r.t.; ﬁltration, evaporation of the solvent and ﬂash

chromatography (ethyl acetate/cyclohexane: 1/4); yield: 1.113 g

(84%); ¹H NMR (CDCl₃, 200 MHz): 6.08 (dxd, J_cis¼ 10.7 Hz,

J_trans¼ 17.5 Hz, 1H, vinyl H); 5.21 (sept, ⁵J ¼ 2.9 Hz, 1H, allenyl H);

5.09 (d, J_cis¼ 10.7 Hz, 1H, vinyl H) 5.05 (d, J_trans¼ 17.5 Hz, 1H, vinyl

H) 2.97 (s, 6H, H₃CeN); 1.70 (d, ⁵J ¼ 2.9, 6H, H₃CeC ¼ ); 1.37 (s, 3H,

H₃C); ¹³C NMR (CDCl₃, 50 MHz): 200.02, 173.48, 141.50, 112.92,

98.72, 93.90, 49.04, 38.59, 36.58, 28.21, 19.82, 19.73; MS: 194

([MþH]^þ); 193 ([M]^þꢁ); 178 ([M ꢂ CH₃]^þ); 166, 121, 105, 72

([CON(CH₃)₂]^þ).

C

_quat.); 28.11 (Qxm, ¹J ¼ 128.6 Hz, CH₃); 27.82 (Qxm, ¹J ¼ 128.0 Hz,

CH₃); 27.82 (Qxm, ¹J ¼ 138.4 Hz, CH₃); MS: 168 ([MþH]^þ); 152

([M ꢂ CH₃]^þ), 137 ([M-2CH₃]^þ), 124 ([MeCH₃eCO]^þ).

Declaration of competing interest

The authors declare that they have no known competing

ﬁnancial interests or personal relationships that could have

appeared to inﬂuence the work reported in this paper.

Ackowledgments

4.7.6. Synthesis of allenyl amide 34f

P-1, A: addition of a dichloromethane (2.5 ml) solution of

0,854 g (6.87 mmol) 1-ethynylcyclohexan-1-ol into a solution of a-

We warmly thank the following organisations for their generous

support to our work: the General Agency for Cooperation and

Development (AGCD, Belgium), UCLouvain, the National Founda-

tion for Scientiﬁc Research (FNRS. Belgium), the Institute for Sci-

entiﬁc Research in Industry and Agriculture (IRSIA, Belgium), the

Rwanda Government. We would like to thank Prof. E. de Hoffmann

and Prof. Flammang (University of Mons-Hainaut) for the mass

spectra, A. Dekoker and Van Tran Trieu for their technical assistance

and the late Drs. A-M. Hesbain-Frisque and R. Touillaux for their

help in NMR spectroscopy.

chloroenamine 2e (1 g, 6.87 mmol) and triethylamine (1.92 ml,

1.39 g, 13.7 mmol) in 2.5 ml CH₂Cl₂at r.t.; overnight at r.t.; ﬁltration,

evaporation of the solvent and ﬂash chromatography (ethyl ace-

tate/cyclohexane: 1/4); yield: 1.377 g (86%); ¹H NMR (CDCl₃,

200 MHz): 6.09 (dxd, J_cis¼ 10.7 Hz, J_trans¼ 17.5 Hz, 1H, vinyl H);

5.20 (quint, ⁵J ¼ 2, 1H, allenyl H); 5.09 (d, J_cis¼ 10.7, 1H, vinyl H);

5.05 (d, J_trans¼ 17.5, 1H, vinyl H); 2.96 (s, 6H, H₃CeN); 2.10 (m, 4H,

allylic CH₂); 1.56 (m, 6H, CH₂); 1.38 (s, 3H, CH₃); ¹³C NMR (CDCl₃,

50 MHz): 196.82 (¼C ¼ ); 173.64 (CO); 141.76, 113, 93.81, 49.32,

39.49, 31, 28.43, 27.16, 25.76; MS: 234 ([MþH]^þ); 233 ([M]^þꢁ); 218

([M ꢂ CH₃]^þ); 206, 161, 72 ([CON(CH₃)₂]^þ); IR (CH₂Cl₂): 1965 (C]

C]C), 1630 (NeC]O).

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Article Doi

A mild method for the replacement of a hydroxyl group by halogen: 3. the dichotomous behavior of α-haloenamines towards allylic and propargylic alcohols

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