Coinage metals-catalyzed cascade reactions of aryl alkynylaziridines: Silver(I)-single vs gold(I)-double cyclizations

Article

pubs.acs.org/joc

Coinage Metals-Catalyzed Cascade Reactions of Aryl

Alkynylaziridines: Silver(I)-Single vs Gold(I)-Double Cyclizations

Nicolas Kern, Aurelien Blanc,* Solene Miaskiewicz, Michelle Robinette, Jean-Marc Weibel,

́

̀

and Patrick Pale*

Laboratoire de Synthes

Blaise Pascal, 67070 Strasbourg, France

̀

e et Rea

́

ctivite

́

́ ́

Organiques UMR 7177 associe au CNRS, Institut de Chimie, Universite de Strasbourg, 4 rue

S

* Supporting Information

ABSTRACT: Alkynylaziridines carrying an aryl group could

be eﬃciently converted into aminoallenylidene isochromans,

isoquinolines, or tetrahydronaphtalenes with silver(I) salts and

into 1-azaspiro[4.5]decane derivatives with gold(I) complexes.

Mechanistic investigations revealed that both Ag- and Au-

catalyzed reactions involved a Friedel−Crafts type intra-

molecular reaction leading to an allene and that Au also

rapidly promoted a second intramolecular cyclization of the

aminoallene intermediate to the corresponding spiro deriva-

tive. Stereochemical investigations suggested an anti-SN₂′-type

pathway for the ﬁrst cyclization leading to a stereodeﬁned

allene, which could then be cyclized to the corresponding stereodeﬁned spiro product. These results highlight the duality

between oxo- or azaphilicity and alkynophilicity of Ag and Au as well as their complementarity in terms of reactivity.

same structure oﬀers the possibility of silver or gold cations to

act as both π and σ Lewis acid, leading to new reactions. Thus,

during the past four years, we have demonstrated that

alkynyloxiranes or alkynylaziridines could lead to various

interesting motifs (Scheme 1). Furans could be generated

from alkynyl epoxides by treatment with either Ag(I) or Au(I)

in the presence of an alcohol as cocatalyst.⁹Mechanistic studies

revealed a cascade pathway, through an alcohol addition-

cyclization-elimination process initiated by the σ Lewis acidity

of gold or silver catalysts. The introduction at the propargylic

position of an acyl group led to acyloxylated divinyl ketones,

which are ideal candidates for a subsequent Nazarov reaction.¹⁰

In this rearrangement, the ambivalent nature of coinage cations

has been emphasized by recent theoretical mechanistic

studies.¹¹Performed in the presence of an external nucleophile,

such as alcohol or thiol, these starting materials rearranged to

substituted furans or pyrroles.¹²Switching to a diﬀerent internal

nucleophile, we very recently found that alkynyl aziridines

bearing a benzyl group at the propargylic position were

eﬃciently converted into 1-azaspiro[4.5]decane derivatives

through most probably two successive cyclizations via amino-

allene intermediates.¹³

INTRODUCTION

■

As metal, silver and gold have been known since ancient times

and used for jewelry and ornaments and as coinage metals, with

a special fascination for gold due to its bright-yellow color.

From a chemical point of view, their historical use was far more

recent, with a special emphasis on silver(I).¹In the past decade,

a fast reversal of tendency was noticed, especially in organic

chemistry due to the (re)discovery of the strong relativistic

eﬀects²associated with gold conferring to its cations, gold(I)

and (III), both π and σ Lewis acidities. Indeed, it has been

shown at the beginning of the 21st century that gold salts

exhibit higher catalytic activity, faster reaction rate and better

yields under milder reaction conditions than silver salts.³More

remarkably, gold salts also oﬀer new reactivities such as

rearrangements,²C−H activations,⁴cycloisomerizations⁵and,

more recently, oxidative cross coupling reactions.⁶

The major drawback of gold salts compared to silver salts is

unquestionably their prices, but sometimes, the strong catalytic

activities of gold complexes could also be detrimental leading to

unwanted byproduct. This high reactivity can be ascribed to the

strong π and σ Lewis acidities of gold cations. Silver(I) also

possesses these properties although to a lower extent.⁷This

silver dual ability, that is, carbophilicity and oxo- or azaphilicity,

has been demonstrated in the literature but not always

recognized as such.⁸In contrast, the recent developments in

gold organic chemistry were essentially based on alkyne, allene

or alkene activation.

In the present contribution, we report the extension of the

latter gold(I)-catalyzed double cyclization cascade to new

substrates and we also provide further insights into the

mechanism allowing conﬁrmation of it. Furthermore, we were

able to stop the cascade at the ﬁrst cyclization step using softer

In our laboratory, we are interested in revealing such duality

and exploiting it, especially in cascade reactions. Indeed, the

presence of an alkyne and at least one heteroatom within the

Received: February 14, 2012

Published: April 3, 2012

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elimination in the presence of phosphorus oxychloride. For all

the enynes Ca-t, the ﬁnal aziridination was best achieved using

the reaction conditions described by Andersson,¹⁵aﬀording the

2-(aryloxyprop-1-ynyl)aziridines 1a−u with good to low yields

depending on the substrate nature.

Scheme 1. Gold(I) or Silver(I)-Catalyzed Cascades Initiated

by Intra- or Intermolecular Nucleophilic Addition on

Alkynyl Epoxides or Aziridines

Gold-Catalyzed Double Cyclizations. As previously

reported,¹³a rapid screening of simple gold complexes and

salts revealed that the Gagosz’s catalyst¹⁶in dichloromethane at

room temperature was the most eﬀective in rearranging 2-(3-

benzyloxyprop-1-ynyl)-2-methyl-N-tosylaziridine 1a (Table 1,

entry 1) to the azaspiro[4.5] product 2a in 70% yield. Other

counterions, such as BF₄, OTf⁻and SbF₆, led to lower yields

−

(entries 2−4). Whatever the catalyst, two side products could

1

be detected in H NMR spectra of the crude mixtures, that is,

the transient aminoallene intermediate 3a, only detected as

trace¹⁷(see Stereochemical Aspects and Mechanism section)

and the pyrrole compound 4a, observed in variable amounts

(Table 1). The formation of the latter could be ascribed to the

presence of water⁹contained in the silver salts used to in situ

activate the precatalyst (Ph₃PAuCl). The already active and

stable triphenylphosphinogold(I) triﬂimidate complex pre-

vented the formation of 4a by avoiding the chloride abstraction

step with Ag salts (entry 1). To further optimize this

rearrangement, gold(I) complexes, either with ligands of

various size and electronic density or dinuclear, were prepared

and evaluated as catalysts. The less electron donating phosphite

complex 5 still eﬃciently catalyzed the reaction but gave slightly

lower yield than the Gagosz catalyst (entry 5 vs 1; Figure 1).

The family of bulky dialkylbiarylphosphine gold(I) complexes

6a−e, known to be very eﬃcient for various gold-catalyzed

reactions,¹⁸was then examined. The rearrangement still

occurred but more or less eﬃciently depending on the catalyst

bulkiness (entries 6−10). Using the bulkiest catalysts 6a−c (R¹

= tBu), reaction completion required 2 h at reﬂux instead of 1 h

at room temperature (entries 6−8 vs 1). Moderate yields of 2a

were thus achieved, with the concomitant formation of pyrrole

4a and various unidentiﬁed byproduct. Decreasing steric

hindrance by replacing tert-butyl with cyclohexyl substituents

restored the catalyst activity. Indeed, a complete conversion was

obtained in less than 1 h at room temperature (entries 9 and

10). For these catalysts, the hexaﬂuoroantimonate counterion

gave better results than the triﬂimidate, 6d and 6e furnishing

the spiro[isochroman-4,2′-pyrrolines] in respectively 57 and

silver(I) salts. This led to a new synthesis of aminoallenes,

which we also exemplify here.

RESULTS AND DISCUSSION

■

Substrate Preparation. Aryloxylated alkynylaziridines 1a−

u (see Table 2 for the nature of R₁, R₂, R₃, R₄and R₅) were

obtained in 3 or 4 steps using diﬀerent strategies (Scheme 2).

For compounds oxygenated at the propargylic position, the

condensation of lithiated commercially available enynes¹⁴with

aldehydes or ketones aﬀorded enynols A in excellent yields (see

Experimental Section for the nature of R₁, R₂, R₃and R₄).

Ethers and malonates derivatives Ca,c−e,g,h,l,o−u were

prepared under classical conditions using the appropriate

benzyl chloride or bromide derivatives, with yields routinely

higher than 80% from A or D. Alternatively, the benzyl-

protected propargylic alcohols B (see Experimental Section for

the nature of R₃, R₄and R₅) were engaged in Sonogashira

reactions with iodo or bromoalkenes, giving the enyne ethers

Cf,m,n in good to moderate yields mostly due to the formation

of homocoupling byproduct. Enynes Ci and Cj were prepared

by addition of the lithiated 3-benzyloxyprop-1-yne to

respectively cycloheptanone and cyclooctanone, followed by

Scheme 2. Preparation of the Arylalkynyl Aziridine 1a−u

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been screened (Table 2). Switching from tosyl to nosyl

aziridine to oﬀer a more labile protecting group led to a slight

decrease in yield together with a slightly longer reaction time

(entry 1 vs 2). Such eﬀects can easily be rationalized by the

decrease in nitrogen nucleophilicity due to this modiﬁcation.

Steric hindrance at the propargylic position across the aziridine

part was assessed with compounds 1c−e (entries 3−6). The

introduction of a single substituent (1c) led to the formation of

2 diastereoisomers in 1/1 ratio. Both reacted but with a

dramatically reduced reaction time (from 1 to 16 h; entry 3 vs

1). However, the yield was improved in this case (77 vs 70%,

entry 3 vs 1). This observation and reaction monitoring

suggested that hindrance at the propargylic position slowed

down the second cyclization. This hypothesis was conﬁrmed by

the rearrangement of compounds 1d and 1e. With such starting

materials, the ﬁrst cyclization proceeded but far more slowly

(entries 4, 6 vs 1) due to the creation of neopentylic positions.

The latter inhibited the next step and only the aminoallenes 3d

and 3e were isolated, with respectively 60 and 74% despite the

prolonged contact time (entries 4 and 6). Nevertheless,

switching to the Echavarren catalyst 6e allowed to go further

and in the case of 1d, the azaspiro product 2d could be formed

in high yield although with a long reaction time (entry 5).²⁰

The latter results highlighted the complementarity between the

Gagosz and Echavarren catalyst 6e, while revealing the higher

reactivity of the latter.

Table 1. Screening of Reaction Conditions for the Gold(I)-

Catalyzed Transformation of Alkynylaziridine 1a

b

catalyst

time

(h)

yield

a

entry

1

(5 mol %)

conditions

CH₂Cl₂,

2a (%) 3a (%) 4a (%)

PPh₃AuNTf₂

1

70

0 °C→r.t.

2

PPh₃AuCl/

AgOTf

CH₂Cl₂,

1

46

60

62

67

56

54

58

57

70

55

56

11

6

0 °C→r.t.

3

PPh₃AuCl/

AgBF₄

CH₂Cl₂,

0 °C→r.t.

CH₂Cl₂,

0 °C→r.t.

CH₂Cl₂,

0 °C→r.t.

CH₂Cl₂,

r.t.→rfx

1

4

PPh₃AuCl/

AgSbF₆

1

3

5

1

trace

6

6a

6b

6c

6d

6e

7

2

9

7

CH₂Cl₂,

r.t.→rfx

2

trace

10

6

8

CH₂Cl₂,

r.t.→rfx

CH₂Cl₂,

r.t.

2

9

0.75

0.5

15

1

10

11

12

CH₂Cl₂,

r.t.

trace

34

6

Substitutions at the aziridine part did not have such strong

inﬂuence (entries 9−12), except in the case of the gem-

disubstituted aziridine 1f. Introduction of large substituent at

the gem-position of aziridine indeed led to poor yield under

standard conditions (entry 7 vs 1), as expected from a possible

transition state for the ﬁrst cyclization in which such substituent

would hamper Au coordination (see the mechanistic section).

Once again, the use of 6e signiﬁcantly increased the isolated

amount of azaspiro 2f (entry 8 vs 7).

CH₂Cl₂,

r.t.

c

8

CH₂Cl₂,

0 °C→r.t.

trace

a

b

Reactions run under argon, C = 0.1 mol/L. Estimated yield on the

c

¹H NMR of the crude mixture; 2.5 mol % of catalyst was used (5 mol

% in gold).

Trisubstituted aziridines eﬃciently furnished the double-

cyclization products in good to high yields under standard

conditions, but as mixtures of diastereoisomers with variable

ratios (entries 9−12). The relative stereochemistry of the

corresponding spiro products was established by NOE NMR

experiments (2g and 2j) or from X-ray Diﬀraction (2h).

Interestingly, the cis aziridine 1g mostly gave the trans product

(entry 9),²¹while the bicyclic aziridines 1h−j mostly gave the

cis products, although in diﬀerent ratios, from 1:1 to 5:1

(entries 10−12). These trends strongly suggested a common

but stereocontrolled process (see the Stereochemical and

Mechanistic section). It is noteworthy that mono- and cis or

trans-disubstituted alkynylaziridines could not be compared as

substrates due to problems in their syntheses, notably at the

ﬁnal aziridination step.

The introduction of diﬀerent linkers between the alkynylazir-

idine and aryl parts of the substrate (Z = NTs, CH₂,

C(CO₂Et)₂instead of O) did not impair the cyclization

cascade and aﬀorded the expected 1-azaspiro[4.5]decane

derivatives in good yields (entries 13−15). It is worth

mentioning the signiﬁcant improvement brought by a gem-

dicarboxylate motif, probably due to Thorpe-Ingold eﬀect

(entry 14 vs 13 and 15). However, the reduction of the

aliphatic chain from 3 to 2 carbons exclusively yielded the

pyrrole 4n instead of the expected azaspiro[4.4]nonane

derivative (entry 16 vs 15).

Figure 1. Structure of the gold catalysts screened.

70%. The stable and silver-free gold(I) triazolate complex¹⁹

7

proved to be far less reactive, requiring long reaction time

(entry 11). Under these conditions, the spiro compound 2a was

obtained in moderate yield, together with a signiﬁcant amount

of pyrrole. Although as reactive as the most eﬃcient catalysts,

the dinuclear gold-complex 8 did not give any advantage (entry

12).

From the optimization studies, two catalysts, PPh₃AuNTf₂

and 6e, appeared to be the most eﬀective for the cyclo-

isomerization reaction. Due to its handling convenience, the

Gagosz catalyst was chosen for studying the scope of this

rearrangement (Table 2), this choice also allowed to compare

with our preliminary results.¹³

To explore the scope and limitations of the present

cycloisomerization, various substrates exhibiting variations in

nitrogen substitution, in substituents and in aryl group nature

as well as in the linker between the aryl and alkynyl parts have

Eﬀects of aromatic substitution were then investigated with

compounds 1o−r carrying either one electron donating or one

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Table 2. Scope of the Gold(I)-Catalyzed Transformation of Various Aryl Alkynylaziridines

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Table 2. continued

a

b

c

d

Reaction run with 5 mol % of 6e. Catalyst 6e failed to give the azaspiro compound. Only the major isomer was represented. 35% of pyrrole was

e

1

observed on the H NMR of the crude mixture; Performed at reﬂux.

electron-withdrawing group (1o,q R⁵= OMe and 1p,r R⁵= Cl,

respectively) (entries 17−20). As expected, a strong eﬀect was

observed with such substituents at the meta position (entries

17−18). For the methoxy compound 1o, a fast reaction was

observed giving the corresponding spiro compound 2o with an

excellent yield of 80% and a good regioselectivity in favor of the

less strain product 2o (entries 17). With the deactivated chloro

substrate 1p, the azaspiro derivative 2p was obtained in poor

yield and low regioselectivity, together with a signiﬁcant

amount of unstable pyrrole (entries 18). To avoid the

formation of regioisomers, para substituted arylalkynylazir-

idines were prepared and examined. Not so surprisingly, with

reaction kinetic drastically decreased for both substrates and

even under reﬂux, 5 h were required to reach full conversion

(entries 19 and 20). Interestingly, when the 1- or 2-naphtyl

group was introduced into the substrate, a single spiro product

was produced with high yields (entries 21 and 22). The 1-

naphtyl derivative 1s was rapidly and very eﬃciently rearranged,

while the 2-naphtyl 1t required longer time and gave the spiro

2t with a slightly lower yield.

tion of alkynylaziridines. To validate this hypothesis, and to

isolate some of these intermediates, we explored the reactivity

of silver salts toward alkynylaziridines. Since silver salts and

complexes are usually less active as catalysts than their gold

analogs, we expected to slow the cascade process and produce

more eﬃciently this intermediate.

Our model compound 1a was thus submitted to various

silver salts (Table 3). The most electrophilic of them, silver

hexaﬂuoroantimonate, led to degradation at room temperature

(entry 1). However, other salts gave at room temperature the

same transformation as gold catalysts, but in very slow reactions

(24 h vs 1 h; Table 3, entries 2−4 vs Table 1, entries 1−4).

During this reaction, both the spiro compound and the

intermediate were observed but the latter was produced earlier

and slowly disappeared. Rewardingly, stopping the reaction

catalyzed by silver triﬂimide after just one hour at −20 °C

allowed to exclusively form the allene 3a in 55% yield (entry 5).

Spectroscopic analysis conﬁrmed the expected allenylidenyl

isochroman 3a structure of this compound. Other silver salts

also gave the allene 3a but with the concomitant formation of

pyrrole 4a, probably due to the presence of water as

contaminant in these Ag salts, more hygroscopic than the

triﬂimide (entries 5−7). Using AgSbF₆as catalyst only gave the

pyrrole 4a, although in modest yield (entry 8).

Silver-Catalyzed Single Cyclization. Monitoring the

evolution of these gold−catalyzed reactions revealed the

appearance and disappearance of an intermediate product,

which could be isolated in a few cases (entries 4 and 6, Table

2). The latters revealed an allenic structure, suggesting the

transient allene formation in each Au-catalyzed cycloisomeriza-

The allenylidenyl isochroman 3a motif is so far unreported in

the literature and thus, the present new Ag-catalyzed cyclization

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Substituting the oxygen atom by nitrogen improved rate and

yield (entry 11 vs 1), aﬀording the allenylidenyl tetrahydroi-

soquinoline 3k. The introduction of a carbodiester moiety in 1l

had a beneﬁcial impact on the reaction, which became faster

and gave higher yield. The analog but simpler 1m did not

beneﬁciate from this improvement, suggesting the key role of

the Thorpe-Ingold eﬀect brought by the gem-diester motif

(entry 13 vs 12).

As expected, the meta-methoxy substituted 1o proved very

reactive, even at low temperature and provided the allenes 3o in

the same 5.6/1 ratio as the one obtained in gold-catalyzed

reaction but with several unidentiﬁed byproduct (entry 14). In

contrast, and as expected, the meta-chloro analog 1p did not

readily react and even at reﬂux, only small amount of the allene

3p could be observed among unidentiﬁed byproduct (entry

15). A mixture of regioisomeric cyclization products was

formed with a ratio close to 1. As for the Au-catalyzed cascade,

the corresponding para-substituted analogs produced lower

amounts of aminoallenes, but signiﬁcant amounts of pyrroles

(entries 16 and 17).

As for the Au-catalyzed cascade, aromatic groups other than

phenyl could also be involved in this silver-catalyzed rearrange-

ment. Naphtyl derivatives 1s−t indeed gave the corresponding

allenes in good yields (entries 18 and 19). Whatever the

naphtyl connectivity, the reactions were faster and the allenes

3s−t were obtained as single regioisomers.

As showed, the present Ag-catalyzed cyclization thus

provided a convenient access to various new types of

compounds, that is, allenylidenyl isochroman, isoquinoline²²

or tetrahydronaphtalene.

Table 3. Screening of Reaction Conditions for the Silver(I)-

Catalyzed Transformation of Alkynylaziridine 1a

yield

2a

(%)

yield

3a

(%)

yield

4a

(%)

catalyst (5

mol %)

time

(h)

a

entry

conditions

b

1

2

3

4

5

6

7

8

AgSbF₆

AgNTf₂

AgOTf

AgBF₄

CH₂Cl₂, 0 °C→r.t.

CH₂Cl₂, −20 °C

24

1

-

54

trace

12

-

48

trace

-

41

9

AgNTf₂

AgOTf

AgBF₄

trace

55

1

54

10

c

1

52

4

AgSbF₆

3

trace

b

trace

34

a

Reactions run under argon, C = 0.1 mol/L. Degradation occurs

c

leading to unidentiﬁed byproduct. Calculated yield from the ¹H NMR

spectrum of the crude mixture.

could open the way to the synthesis of this new family of

compounds. To substantiate such idea, this Ag-promoted

rearrangement was further investigated. Its scope was thus

explored with the substrates 1a−t (Table 4).

As observed for the gold-catalyzed double cyclization, the

presence of a more electron-withdrawing group at the aziridine

nitrogen favored the ﬁrst opening-cyclization step and

disfavored the following cyclization, due to the formation of a

less nucleophilic amine. A nosyl group indeed signiﬁcantly

increased the allene yield compared to a tosyl group (entry 2 vs

1).

Mechanism and Stereochemical Aspects. Both set of

results showed that the above-described Au- and Ag-catalyzed

cycloisomerizations most probably proceeded through the same

mechanism.

To conﬁrm this hypothesis and to clearly identify the

intermediate compound in the Au-catalyzed cascade, the

reaction of the aziridine 1a was run in a NMR tube at −70

°C in the presence of PPh₃AuNTf₂and the evolution of 1a was

monitored by NMR upon warming (see Figure 2 in Supporting

Information). After only 10 min at −70 °C, the characteristic

protons of 1a (red arrows on spectrum a) had already

disappeared (spectrum b). After an additional 10 min and

warming to −40 °C, total conversion was reached and the

intermediate was clearly the major product (spectrum c). The

latter could be unambiguously attributed to the allene 3a by

comparison with a sample of 3a obtained by the silver-catalyzed

rearrangement (see Table 4, entry 1). Between −40 and −20

°C, no evolution was noticed, but warming the mixture above

−20 °C slowly promoted further transformation and new peaks

emerged from the baseline (spectrum e). Warming up to 0 °C

clearly showed that this evolution occurred in favor of the spiro

compound 2a (spectrum f). The presence of a vinylic proton

(green arrow in spectrum j) and of three AB systems (blue, red

and orange arrows in spectrum j) was indeed typical of this

azaspiro structure. Finally, after 2 h at 0 °C, the consumption of

3a was completed and the product 2a was cleanly produced

(spectrum j).

As already observed with Au catalysts, hindering the

cyclization site could slow down the hydroamination step.

Aziridines of increasing substitution at the propargylic position

indeed gave the corresponding allene with increasing yields

(entries 3−5). No signiﬁcant diﬀerence was observed with a

single substituent (entry 3 vs 1), but with two simple methyl

groups, the apparition of the spiro compound resulting from

the second cyclization was markedly delayed and the allene 3d

was thus isolated with higher yield (entry 4 vs 1). A cyclic

substituent was even more eﬃcient (entry 5 vs 4 vs 1). The

presence of a bulky group (TBS) spatially closed to

coordination sites slowed down the rate and gave lower yield

(entry 6) but did not alter the reaction when remote from the

coordination sites (entry 7). Bicyclic aziridines furnished the

corresponding allene in good to high yields depending on the

ring size (entries 8−10). Surprisingly, it was necessary to

perform the reaction at higher temperature for the

azabicycloheptane and -octane systems (entries 9−10 vs 1).

Interestingly, the Ag-cyclization of aziridines 1c,1g−j gave

diastereomeric mixtures of allenes 3c, 3g−j in unequal

amounts, suggesting a stepwise formation although a non-

equivalent consumption of allenes in the subsequent cyclization

step cannot be ruled out (entries 7−8 and 10 vs 9). These

diastereoisomeric ratios were identical to those obtained in the

Au-catalyzed cascade reaction.

To get more insight into the mechanism, we focused on

reactions providing mixture of diastereoisomers. In some cases,

the same starting aziridine was converted by the Au- or Ag-

cycloisomerization into the corresponding 1-azaspiro[4.5]-

decane or aminoallene derivatives as mixture of diaster-

eoisomers (Table 2, entries 9−12 and Table 4, entries 7−

As for the gold-catalyzed reaction, variation of the connecting

(Z in Table 4) part between the alkyne function and aryl parts

in the starting materials aﬀorded other allenylidene derivatives

(entries 11−15).

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Table 4. Scope of Silver(I)-Catalyzed Aminoallene Formation

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Table 4. continued

a

b

c

d

Spiro derivatives 2 were also detected in some cases. Performed at −60 °C. Performed at reﬂux. NMR yields; degradation occurs leading to

e

unidentiﬁed byproduct. Pyrroles were also isolated with 10% and 34% yields for respectively entriy 14 and 15.

Scheme 3. Evidences for the Stereochemical Course of the Gold(I) and Silver(I) Rearrangements of 1h

10). Depending on the starting materials, variable ratios were

observed but with a perfect correlation between the allene and

the spiro products. For example, from the racemic aziridine 1h,

the silver-mediated process gave the allene 3h with a 3 to 1 dr

and the gold-catalyzed reaction gave the azaspiro compound 2h

with an identical ratio (Scheme 3). This correlation was clearly

substantiated by the NMR monitoring results and suggested

that the stereochemical outcome at the allene stage was further

transferred into the spiro structure.

To check this assumption, the major diastereoisomer of 3h

(3h-maj) was isolated from the mixture of diastereoisomers

and resubmitted to the gold-catalyzed cyclization conditions. As

suspected, this single allene diastereoisomer gave a single spiro

diastereoisomer, which corresponded to the major isomer (2h-

maj) observed in the direct reaction from 1h (Scheme 3).

Furthermore, we were able to crystallize both compounds (2h-

maj and 3h-maj) and thus, the relative conﬁgurations of each

could be assigned from their respective X-ray diﬀraction

patterns (see Supporting Information).²³

These data conﬁrmed the two-steps sequence of the Au-

catalyzed reaction initiated by an intramolecular Friedel−Crafts

type reaction²⁴and followed by hydroamination²⁵of the

aminoallene transient intermediate. They also conﬁrmed that

the stereochemical course of the whole cascade was determined

at the ﬁrst step.

To get further insights into this key step, common to the Au-

and Ag-catalyzed cycloisomerizations, we prepared the

perdeuterated compound 1u and monitored the deuterium

labeling into the products (Scheme 4). In Friedel−Crafts type

Scheme 4. Deuterium Distribution in Product 2u from

Labeled Compound 1u

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reaction, a proton/deuterium should be lost, but the latter

should be then involved into protodemetalation²⁶during Ag- or

Au-mediated reactions (Scheme 5). In the Ag-catalyzed

CONCLUSION

■

In the present work, we demonstrated the stereoselective

formation of aminoallenylidene isochromans, isoquinolines or

tetrahydronaphtalenes with silver(I) salts as catalyst and of 1-

azaspiro[4.5]decane derivatives with gold(I) complexes as

catalysts from alkynylaziridines carrying an aryl group.

Mechanistic investigations showed that both Ag- and Au-

catalyzed reactions involved a Friedel−Crafts type intra-

molecular reaction leading to an allene and that Au also

rapidly promoted the further cyclization of the aminoallene

intermediate to the corresponding spiro derivative. Stereo-

chemical investigations suggested an anti-SN₂′-type pathway for

the ﬁrst cyclization leading to a stereodeﬁned allene, which

could then be cyclized to the corresponding stereodeﬁned spiro

product.

Scheme 5. Mechanism and Stereochemistry for the Ag(I) or

Au(I)-Catalyzed Cascade Reaction of Arylalkynyl Aziridine

These results highlight the duality between oxo- or

azaphilicity and alkynophilicity of silver and gold catalysts and

their complementarity in term of reactivity.

EXPERIMENTAL SECTION

■

General Information. Proton (¹H NMR) and carbon (¹³C NMR)

nuclear magnetic resonance spectra were recorded on 300, 400, or 500

MHz instruments. Chemical shifts are given in part per million (ppm)

on the delta scale. Solvent peaks were used as reference values, with

1

CDCl₃at 7.26 ppm for H NMR and 77.23 ppm for ¹³C NMR. Data

are presented as followed: chemical shift, multiplicity (s = singlet, d =

doublet, t = triplet, q = quartet, quint = quintet, m = multiplet),

integration and coupling constants (J in Hz). Assignments were

determined on the basis of either unambiguous chemical shifts or

coupling patterns, and of COSY, HMQC, HMBC, ROESY experi-

ments when required. Infrared spectra were recorded neat. Wave-

lengths of maximum absorbance (ν_max) are quoted in wave numbers

(cm⁻¹). Mass spectra were recorded by ElectroSpray Ionization (ESI).

The parent ions [M + H]⁺, [M + Na]⁺or [M + Li]⁺are quoted.

Analytical Thin Layer Chromatographies (TLC) were carried out on

silica gel 60 F₂₅₄plates with visualization by ultraviolet, potassium

permanganate or Ceric Ammonium Molybdate (CAM) dip. Flash

column chromatography was carried out using silica gel 60 (40−63

μm) and the procedure included the subsequent evaporation of

solvents in vacuo. Reagents and solvents were puriﬁed using standard

means. Dichloromethane (CH₂Cl₂) and acetonitrile (CH₃CN) were

distilled from CaH₂under an argon atmosphere; THF was distilled

from sodium metal/benzophenone. AuCl (Premion grade, 99.99%),

AuCl₃(99.9%) and NaAuCl₄.2H₂O (Premion grade, 99.99%) were

purchased from Alfa Aesar whereas AgSbF₆(98%), AgOTf (99%),

AgBF₄(99%), Ag₂CO₃(99%+) and AgCl (99.9%) were purchased

from STREM Chemicals. AgNTf₂was prepared from commercially

available HNTf₂and Ag₂CO₃.²⁹All phosphinegold(I) chloride

precatalysts were prepared by reduction of NaAuCl₄with

thiodiethanol and subsequent addition of the appropriate phosphine.³⁰

Silver-free preactivated catalysts were prepared either from the

corresponding phosphinegold chloride and AgSbF₆in acetonitrile³¹

or AgNTf₂in CH₂Cl₂and ﬁltration over a short pad of silica gel.¹⁶All

other chemicals were used as received. All other extractive procedures

were performed using technical solvents and all aqueous solutions

used were saturated.

reaction, this proton/deuterium would end up at the sulfonyl

amine group and being thus quite labile, it should be mostly

lost due to workup, while in the Au-catalyzed reaction, it could

be transferred, at least in part, into the pyrroline moiety. This

was actually the case. Deuterium labeling was indeed found at

the expected vinylic position of the pyrroline ring in the Au-

catalyzed reaction (Scheme 4).

All these results clearly established the two-step mechanism,

with an intramolecular Friedel−Crafts type reaction and a

hydroamination of the intermediate allene (Scheme 5).

For both coinage-metal-catalyzed rearrangements, the stereo-

chemical outcomes showed that an anti-addition pathway

(SN₂′)²⁷mostly occurred at the ﬁrst intramolecular Friedel−

Crafts step (Scheme 5). This pathway allowed to rationalize the

stereochemical relationship between the allenes 3 and the spiro

derivatives 2, since a Friedel−Crafts cyclization more or less

concerted with an anti-opening of the aziridine part would led

to an allene of deﬁned stereochemistry, which could only

cyclize further to a single spiro product. The cis/trans

relationships observed from the aziridine to the spiro

compounds (see Table 2, entries 9 vs 10−12 and comments)

could also be understood through this SN₂′ pathway. It also

explained the production of diastereoisomers starting from the

cis aziridine 1g and from the bicyclic aziridines 1h−j.

General Procedure 1 for the Gold-catalyzed Conversion of

Alkynylaziridines to 1-Azaspiro[4,5]decane Derivatives. To a

solution cooled at 0 °C of alkynylaziridine (0.1 mmol) in CH₂Cl₂(1

mL) was added Ph₃PAuNTf₂(0.005 mmol). The resulting mixture

was allowed to warm at room temperature. Monitored by thin-layer

chromatography, the reaction was stirred until complete conversion of

both the starting material and allene intermediate. After concentration

of the reaction mixture, the crude residue was puriﬁed by ﬂash

chromatography (Cyclohexane/EtOAc).

Depending on steric hindrance (for 1g R¹in Scheme 5), on

cis

the ring size and strain due to conformations²⁸(for 1h−j R¹

,

trans

R¹−R²= −(CH₂)₃₋₅− in Scheme 5), the anti-conformation

leading to the Wheland intermediate of the Friedel−Crafts

cyclization might be diﬃcult to achieve and nonconcerted

pathways could become competitive.

4′-Methyl-1′-tosyl-1′,5′-dihydrospiro[isochroman-4,2′-pyrrole]

(2a). Prepared following the general procedure 1 in 70% yield (35 mg)

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from 50 mg of 1a. Colorless oil; R_f= 0.18 (Cyclohexane/EtOAc 20%);

= 13.4 Hz), 4.35 (d, 1H, J_ab= 13.4 Hz), 4.62 (d, 1H, J_ab= 11.0 Hz),

4.74 (d, 1H, J_ab=14.7 Hz), 4.93 (d, 1H, J_ab= 14.7 Hz), 5.70−5.77 (m,

1H), 6.89−6.96 (m, 1H), 6.97−7.04 (m, 2H), 7.16−7.27 (m, 1H),

7.19 (d, 2H, J = 8.3 Hz), 7.48 (d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ −5.3, 18.3, 21.5, 25.8, 55.7, 60.1, 68.8, 72.7, 73.2, 124.0,

126.9, 127.3, 127.5, 127.7, 129.0, 129.2, 134.7, 135.8, 136.1, 137.3,

143.1; HR-MS 508.194 (C₂₆H₃₅NO₄SSi + Na calcd 508.195).

5′-((tert-Butyldimethylsilyloxy)methyl)-4′-methyl-1′-tosyl-1′,5′-

dihydrospiro[isochroman-4,2′-pyrrole] (2g). Prepared following the

general procedure 1 in 74% yield (74 mg, dr 2:1) from 100 mg of

alkynylaziridine 1g. Mixture of diastereoisomers: colorless oil; IR

IR (neat) ν

2924, 2849, 1448, 1337, 1157, 1092, 814, 760, 710,

max

1

698, 577, 543; H NMR (300 MHz, CDCl₃) δ 1.75 (dd, 3 H, J = 1.4

Hz), 2.40 (s, 3 H), 3.91 (d, 1 H, J_ab= 10.8 Hz), 4.14 (d, 1 H, J_ab= 13.1

Hz), 4.25 (d, 1 H, J_ab= 13.0 Hz), 4.61 (d, 1 H, J_ab= 10.8 Hz), 4.72 (d,

1 H, J_ab= 14.4 Hz), 4.91 (d, 1 H, J_ab= 14.4 Hz), 5.54−5.59 (m, 1 H),

6.90−7.09 (m, 3 H), 7.15 (dd, 1 H, J = 7.2, 1.5 Hz), 7.19 (d, 2 H, J =

8.3 Hz), 7.49 (d, 2 H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ

14.0, 21.5, 58.8, 68.7, 72.9, 73.4, 123.9, 126.8, 127.1, 127.4, 127.6,

129.2, 129.7, 131.4, 134.6, 136.6, 137.3, 143.0; HR-MS 362.144

(C₂₀H₂₁NO₃S+Li, calcd 362.140).

(neat) ν

2959, 2929, 2851, 1686, 1592, 1328, 1303, 1253, 1224,

4′-Methyl-1′-(4-nitrophenylsulfonyl)-1′,5′-dihydrospiro-

[isochroman-4,2′-pyrrole] (2b). Prepared following the general

procedure 1 in 60% yield (30 mg) from 50 mg of 1b. Pale-yellow

solid: mp =164−165 °C; R_f= 0.24 (Cyclohexane/EtOAc 20%); IR

(neat) ν _max3103, 2918, 2851, 1529, 1347, 1158, 1090, 948, 852, 738,

max

1159, 1087, 1026, 1006, 966; HR-MS 522.210 (C₂₇H₃₇NO₄SSi + Na

calcd 522.210). Major diastereoisomer (2′S*,5′S*): Colorless oil; R_f=

0.40 (Cyclohexane/EtOAc 20%); 1H NMR (300 MHz, CDCl₃) δ 0.02

(s, 3 H), 0.06 (s, 3 H), 0.89 (s, 9 H), 1.75 (s, 3 H), 2.38 (s, 3 H), 3.83

(dd, 1 H, J_ab= 10.7, 1.9 Hz), 4.00 (dd, 1 H, J_ab= 11.0, 2.0 Hz), 4.01 (d,

1 H, J = 11.2 Hz), 4.49−4.57 (m, 1 H), 4.52 (d, 1 H, J = 11.2 Hz),

4.69 (d, 1 H, J_ab= 14.5 Hz), 4.91 (d, 1 H, J_ab= 10.5 Hz), 5.43−5.52

(m, 1 H), 6.75 (d, 1 H, J = 7.9 Hz), 6.90 (t, 1 H, J = 7.4 Hz), 7.00 (d, 1

H, J = 7.6 Hz), 7.11 (d, 2 H, J = 7.9 Hz), 7.14 (t, 1 H, J = 7.4 Hz), 7.33

(d, 2 H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ −5.71, −5.38,

13.7, 18.3, 21.4, 25.9, 62.2, 68.6, 71.5, 71.9, 74.6, 124.0, 126.3, 127.0,

127.6, 128.5, 128.9, 129.5, 133.8, 135.1, 135.9, 138.7, 142.6. Minor

diastereoisomer (2′S*,5′R*): Colorless oil; R_f= 0.32 (Cyclohexane/

EtOAc 20%); ¹H NMR (300 MHz, CDCl₃) δ 0.10 (s, 3 H), 0.11 (s, 3

H), 0.92 (s, 9 H), 1.73 (s, 3 H), 2.36 (s, 3 H), 3.73 (d, 1 H, J = 10.5

Hz), 4.00 (dd, 1 H, J = 11.1, 2.0 Hz), 4.35 (dd, 1 H, J = 11.0, 3.3 Hz),

4.44 (m, 1 H), 4.70 (d, 1 H, J_ab= 14.7 Hz), 4.76 (d, 1 H, J = 10.7 Hz),

4.83 (d, 1 H, J_ab= 14.5 Hz), 5.60 (s, 1 H), 6.87 (dd, 1 H, J = 7.2, 0.7

Hz), 7.06−7.14 (m, 4 H), 7.56 (d, 2 H, J = 8.4 Hz), 7.86 (dd, 1 H, J =

8.8, 1.2 Hz); ¹³C NMR (75 MHz, CDCl₃) δ −5.52, −5.35, 13.8, 18.4,

21.5, 25.9, 62.6, 68.7, 70.9, 72.0, 73.2, 123.3, 126.7, 127.0, 127.8, 128.6,

129.1, 130.0, 133.2, 133.8, 137.5, 138.1, 142.9.

1

688, 608, 554, 459; H NMR (300 MHz, CDCl₃) δ 1.76−1.84 (m, 3

H), 3.91 (d, 1 H, J_ab= 11.3 Hz), 4.29 (s, 2 H), 4.51 (d, 1 H, J_ab= 11.3

Hz), 4.71 (d, 1 H, J_ab= 14.7 Hz), 4.92 (d, 1 H, J_ab= 14.7 Hz), 5.45−

5.53 (m, 1 H), 6.74 (d, 1 H, J = 7.4 Hz), 6.92 (t, 1 H, J = 7.4 Hz), 7.02

(d, 1 H, J = 7.4 Hz), 7.18 (dt, 1 H, J = 1.0 Hz, 7.4 Hz), 7.69 (d, 2 H, J

= 8.8 Hz), 8.18 (d, 2 H, J = 8.8 Hz); ¹³C NMR (75 MHz, CDCl₃) δ

13.9, 59.2, 68.6, 72.8, 73.4, 123.8, 124.2, 126.6, 126.8, 127.7, 129.0,

132.1, 135.1, 135.3, 145.6, 149.7; HR-MS 409.080 (C₁₉H₁₈N₂O₅S+Na,

calcd 409.083).

3-Hexyl-4′-methyl-1′-tosyl-1′,5′-dihydrospiro[isochroman-4,2′-

pyrrole] (2c). Prepared following the general procedure 1 in 77% yield

(77 mg, dr 1:1) from 100 mg of 1c. Mixture of diastereoisomers: IR

(neat) ν

2959, 2848, 1447, 1335, 1156, 1094, 763, 720, 669, 579,

max

545; HR-MS 462.204 (C₂₆H₃₃NO₃S+Na calcd 462.208). Diaster-

1

eoisomer 1: Colorless oil; R_f= 0.48 (Cyclohexane/EtOAc 20%); H

NMR (300 MHz, CDCl₃) δ 0.88 (t, 3 H, J = 6.9 Hz), 1.10−1.38 (m, 8

H), 1.56 (s, 2 H), 1.76 (d, 3 H, J = 1.3 Hz), 2.41 (s, 3 H), 4.11 (d, 1 H,

J_ab= 13.0 Hz), 4.30 (d, 1 H, J_ab= 13.0 Hz), 4.39 (dd, 1 H, J = 8.9 Hz,

2.5 Hz), 4.77 (d, 1 H, J_ab= 14.4 Hz), 4.94 (d, 1 H, J_ab= 14.4 Hz), 5.39

(q, 1 H, J = 1.5 Hz), 6.99−7.03 (m, 3 H), 7.12−7.20 (m, 1 H), 7.22

(d, 2 H, J = 8.3 Hz), 7.52 (d, 2 H, J = 8.3 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ 14.0, 14.1, 21.5, 22.7, 26.4, 29.6, 30.5, 31.2, 59.2, 69.2, 80.5,

123.6, 126.7, 126.9, 127.2, 127.6, 127.7, 129.3, 131.2, 134.5, 137.6,

138.4, 143.0. Diastereoisomer 2: Colorless oil; R_f= 0.45 (Cyclo-

hexane/EtOAc 20%); ¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, 3 H, J =

6.8 Hz), 1.10−1.37 (m, 8 H), 1.56 (s, 2 H), 1.84 (d, 3 H, J = 1.3 Hz),

1-Tosyl-1,4,5,6,7,7a-hexahydrospiro[indole-2,4′-isochroman]

(2h). Prepared following the general procedure 1 in 68% yield (34 mg,

dr 3/1) from 50 mg of 1h. Mixture of diastereoisomers: colorless solid;

IR (neat) ν _max2855, 2840, 1337, 1096, 1029, 949, 757, 666, 578, 544;

HR-MS 418.145 (C₂₃H₂₅NO₃S + Na calcd 418.145); Major

diastereoisomer (2S*,7aR*): mp = 90 °C; R_f= 0.38 (Cyclohexane/

1

EtOAc 20%); H NMR (300 MHz, CDCl₃) δ 1.19−1.38 (m, 3 H),

1.79−1.82 (m, 2H), 1.96−2.07 (m, 1 H), 2.39 (s, 3 H), 2.39−2.46 (m,

1 H), 2.53−2.57 (m, 1 H), 3.99 (dd, 1 H, J = 10.8, 1.0 Hz), 4.31−4.37

(m, 1 H), 4.64 (d, 1 H, J = 10.8 Hz), 4.70 (d, 1 H, J_ab= 14.4 Hz), 4.92

(d, 1 H, J_ab= 14.4 Hz), 5.36−5.42 (m, 1 H), 6.71 (dd, 1 H, J = 7.4, 1.0

Hz), 6.91 (dt, 1 H, J = 1.0 Hz, 7.4 Hz), 6.99 (d, 1 H, J = 7.4 Hz),

7.11−7.14 (m, 3 H), 7.34 (d, 2 H, J = 8.3 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ 21.5, 23.9, 26.6, 28.3, 37.6, 67.3, 68.8, 72.7, 75.4, 124.0,

124.9, 126.5, 127.0, 127.6, 128.2, 129.0, 135.3, 135.7, 138.4, 138.5,

142.8. Minor diastereoisomer (2S*,7aS*): R_f= 0.38 (Cyclohexane/

EtOAc 20%); ¹H NMR (300 MHz, C₆D₆) δ 0.71−1.96 (m, 7 H), 1.83

(s, 3 H), 2.78−2.87 (m, 1 H), 3.90 (d, 1 H, J = 10.4 Hz), 4.16 (dd, 1

2.35 (s, 3 H), 3.43 (dd, 1 H, J = 9.5 Hz, 2.2 Hz), 4.13 (d, 1 H, J_ab

=

13.4 Hz), 4.28 (d, 1 H, J_ab= 13.4 Hz), 4.73 (d, 1 H, J_ab= 15.4 Hz),

5.00−5.07 (m, 1 H), 5.05 (d, 1 H, J_ab= 15.4 Hz), 6.84 (d, 1 H, J = 7.3

Hz), 6.95 (t, 1 H, J = 7.1 Hz), 7.14−7.23 (m, 1 H), 7.21 (t, 2 H, J = 6.2

Hz), 7.26 (d, 2 H, J = 8.1 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.0,

14.1, 21.4, 22.7, 26.4, 29.2, 29.4, 31.9, 60.2, 68.1, 74.5, 81.5, 123.7,

126.2, 127.1, 127.6, 128.7, 128.9, 134.2, 135.6, 135.9, 137.8, 142.2.

3,3,4′-Trimethyl-1′-tosyl-1′,5′-dihydrospiro[isochroman-4,2′-pyr-

role] (2d). Prepared following the general procedure 1 in 70% yield

(35 mg) from 50 mg of 1d using catalyst 6e instead of Ph₃PAuNTf₂.

Colorless oil; R_f= 0.21 (Cyclohexane/EtOAc 20%); IR (neat) ν

H, J = 11.0, 4.7 Hz), 4.56 (d, 1 H, J_ab= 14.8 Hz), 4.76 (d, 1 H, J_ab

=

max

2983, 2921, 2844, 1447, 1343, 1156, 1093, 1039, 907, 814, 726, 686,

532, 543; ¹H NMR (300 MHz, CDCl₃) δ 1.17 (s, 3 H), 1.21 (s, 3 H),

1.65 (s, 3 H), 2.35 (s, 3 H), 4.07 (d, 1 H, J_ab= 13.8 Hz), 4.21 (d, 1 H,

J_ab= 13.8 Hz), 4.86 (d, 1 H, J_ab= 15.6 Hz), 5.04 (d, 1 H, J_ab= 15.6

Hz), 5.14 (q, 1 H, J = 1.6 Hz), 6.92−6.97 (m, 1H), 6.98−7.06 (m,

2H), 7.06 (d, 2H, J = 8.6 Hz), 7.16 (d, 2H, J = 8.6 Hz), 7.21−7.29 (m,

1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.2, 21.4, 21.7, 24.0, 30.2, 30.9,

59.8, 62.9, 123.2, 126.0, 126.2, 127.6, 127.7, 128.7, 129.1, 132.5, 136.3,

136.4, 137.7, 142.2; HR-MS 406.143 (C₂₂H₂₅NO₃S + Na, calcd

406.145).

4′-(((tert-Butyldimethylsilyl)oxy)methyl)-1′-tosyl-1′,5′-

dihydrospiro[isochroman-4,2′-pyrrole] (2f). Prepared following the

general procedure 5 in 60% yield (30 mg) from 50 mg of 1f. Colorless

oil; R_f= 0.27 (Cyclohexane/EtOAc 20%); IR (neat) ν _max2954, 2927,

2855, 1462, 1338, 1253, 1158, 1094, 835, 777, 731, 667, 598, 545; ¹H

NMR (300 MHz, CDCl₃) δ 0.03 (s, 3H), 0.04 (s, 3H), 0.87 (s, 9H),

2.40 (s, 3H), 3.94 (d, 1H, J_ab= 11.0 Hz), 4.23 (s, 2H), 4.24 (d, 1H, J_ab

14.8 Hz), 5.03 (d, 1 H, J = 10.4 Hz), 5.31−5.37 (m, 1 H), 6.59−6.68

(m, 3 H), 6.77 (d, 1 H, J = 7.9 Hz), 6.92 (dt, 1 H, J = 3.8, 1.5 Hz), 7.02

(t, 1 H, J = 7.1 Hz), 7.66 (d, 2 H, J = 8.4 Hz); ¹³C NMR (75 MHz, C

C₆D₆) δ 21.3, 24.1, 26.6, 27.4, 38.6, 67.0, 69.2, 73.7, 76.0, 124.2, 126.3,

127.2, 127.3, 128.3, 128.5129.5, 135.1, 138.0, 138.5, 140.0, 142.6.

1-Tosyl-4,5,6,7,8,8a-hexahydro-1H-spiro[cyclohepta[b]pyrrole-

2,4′-isochroman] (2i). Prepared following the general procedure 1 in

66% yield (33 mg) from 50 mg of 1i. Reaction was complete after 3 h

stirring at room temperature. Two diastereoisomers: dr 1:1; pale-

yellow oil; R_f= 0.24 (Cyclohexane/EtOAc 20%); IR (neat) ν _max2920,

1

2846, 1451, 1333, 1154, 1091, 759, 663, 575, 546; H NMR (300

MHz, CDCl₃) δ 1.47−1.59 (m, 7H), 1.67−2.09 (m, 7H), 2.34−2.14

(m, 6H), 2.30−2.38 (m, 1H), 2.38 (s, 3H), 2.39 (s, 3H), 2.60−2.71

(m, 1H), 3.71 (d, 1H, J_ab= 10.6 Hz), 4.00 (d, 1H, J_ab= 11.1 Hz),

4.54−4.48 (m, 1H), 4.55 (d, 1H, J_ab= 11.1 Hz), 4.65−4.59 (m, 1H),

4.70 (d, 1H, J_ab= 14.6 Hz), 4.72 (d, 1H, J_ab= 10.3 Hz), 4.73 (d, 1H,

J_ab= 14.6 Hz), 4.84 (d, 1H, J_ab= 14.6 Hz), 4.92 (d, 1H, J_ab= 14.6 Hz),

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5.49 (dd, 1H, J = 7.0 Hz, 3.5 Hz), 5.53 (dd, 1H, J = 7.0 Hz, 3.5 Hz),

6.68−6.73 (m, 1H), 6.89−6.93 (m, 2H), 6.97−7.01 (m, 1H), 7.10−

7.21 (m, 7H), 7.29 (d, 2H, J = 8.3 Hz), 7.43−7.49 (m, 1H), 7.61 (d,

2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.4, 24.7, 25.3, 26.7,

27.8, 27.9, 28.0, 29.7, 29.8, 30.2, 35.3, 35.7, 68.6, 68.7, 70.3, 70.4, 72.3,

72.6, 72.8, 75.3, 123.6, 124.0, 126.4, 127.0, 127.2, 127.5, 127.6, 127.8,

128.0, 128.3, 128.9, 129.2, 133.6, 135.3, 135.6, 137.7, 138.2, 138.5,

141.0, 141.6, 142.7, 142.9; HR-MS 432.156 (C₂₄H₂₇NO₃S + Na calcd

432.160).

yield (32.5 mg) from 50 mg of 1o. 5-Methoxy-4′-methyl-1′-tosyl-1′,5′-

dihydrospiro[isochroman-4,2′-pyrrole] was also formed in 15% yield,

and could not be separated from 2o. Major regioisomer: Pale-yellow

oil; R_f= 0.20 (Cyclohexane/EtOAc 20%); IR (neat) ν _max2930, 2855,

1710, 1500, 1335, 1248, 1154, 1094, 964, 813, 708, 660, 545; ¹H NMR

(300 MHz, CDCl₃) δ 1.75 (s, 3H), 2.40 (s, 3H), 3.77 (s, 3H), 3.88 (d,

1H, J_ab= 11.0 Hz), 4.12 (d, 1H, J_ab= 12.9 Hz), 4.23 (d, 1H, J_ab= 12.9

Hz), 4.56 (d, 1H, J_ab= 11.0 Hz), 4.68 (d, 1H, J_ab= 14.8 Hz), 4.88 (d,

1H, J_ab= 14.8 Hz), 5.50 (ddd, 1H, J = 1.7 Hz, 1.7 Hz, 1.7 Hz), 6.50 (d,

1H; J = 2.6 Hz), 6.57 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.83 (d, 1H, J = 8.6

Hz), 7.19 (d, 2H, J = 8.2 Hz), 7.49 (d, 2H, J = 8.2 Hz); ¹³C NMR (75

MHz, CDCl₃) δ 14.0, 21.5, 30.2, 55.3, 58.7, 68.9, 72.5, 73.5, 108.2,

113.3, 127.5, 129.0, 129.2, 129.6, 131.3, 136.1, 137.5, 143.0, 158.6;

HR-MS 408.124 (C₂₁H₂₃NO₄S + Na calcd 408.124).

(2R*,9aS*)-1-Tosyl-1,4,5,6,7,8,9,9a-octahydrospiro[cycloocta[b]-

pyrrole-2,4′-isochroman] (2j). Prepared following the general

procedure 1 in 77% yield (38.5 mg) from 50 mg of 1j. Reaction

was complete after 5 h stirring at room temperature: 2

diastereoisomers; dr 5:1; yellow oil; R_f= 0.37 (Cyclohexane/EtOAc

30%); IR (neat) ν _max2925, 2855, 1737, 1446, 1333, 1156, 1090, 662,

Diethyl 7-Methoxy-4′-methyl-1′-tosyl-1′,5′-dihydro-2H-spiro-

[naphthalene-1,2′-pyrrole]-3,3(4H)-dicarboxylate (2q). Prepared

following the general procedure 1 in 61% yield (30.5 mg) from 50

mg of 1q. TLC monitoring showed completion of the reaction after 5

h heating at 40 °C. Colorless solid: mp = 120 °C (d); R_f= 0.32

1

582, 546; Major diastereomer: H NMR (300 MHz, CDCl₃) δ 1.46−

1.54 (m, 2H), 1.62−1.76 (m, 4H), 1.86−2.03 (m, 2H), 2.16−2.38 (m,

2H), 2.39 (s, 3H), 2.40−2.49 (m, 1H), 3.72 (d, 1H, J_ab= 10.1 Hz),

4.41−4.47 (m, 1H), 4.73 (d, 1H, J_ab= 10.1 Hz), 4.76 (d, 1H, J_ab= 14.9

Hz), 4.90 (d, 1H, J_ab= 14.9 Hz), 5.59 (s, 1H), 6.93−6.98 (m, 1H),

7.12−7.21 (m, 2H), 7.22 (d, 2H, J = 8.4 Hz), 7.57−7.60 (m, 1H), 7.64

(d, 2H, J = 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.5, 23.6, 25.3,

25.6, 29.2, 29.5, 29.8, 30.2, 68.8, 68.8, 72.6, 72.8, 123.8, 127.0, 127.0,

127.1, 127.8, 129.1, 129.3, 133.7, 138.0, 140.5, 143.1 ; HR-MS 446.176

(C₂₅H₂₉NO₃S + Na calcd 446.176).

(Cyclohexane/EtOAc 30%); IR (neat) ν

2984, 2920, 1728, 1502,

max

1

1463, 1234, 1150, 1091, 666; H NMR (300 MHz, CDCl₃) δ 1.06 (t,

3H, J = 7.0 Hz), 1.29 (t, 3H, J = 7.0 Hz), 1.73−1.81 (m, 3H), 2.34 (s,

3H), 2.87 (dd, 1H, J_ab= 14.4 Hz, 2.5 Hz), 3.30 (dd, 1H, J_ab= 15.0 Hz,

2.5 Hz), 3.38 (s, 3H), 3.39 (d, 1H, J_ab= 14.4 Hz), 3.45 (d, 1H, J_ab

=

15.0 Hz), 3.95−4.09 (m, 2H + 1H), 4.13−4.34 (m, 2H + 1H), 5.50−

5.54 (m, 1H), 5.93 (d, 1H, J = 2.5 Hz), 6.66 (dd, 1H, J = 8.5 Hz, 2.5

Hz), 7.01 (d, 2H, J = 8.3 Hz), 7.01−7.09 (m, 1H), 7.06 (d, 2H, J = 8.3

Hz); ¹³C NMR (75 MHz, CDCl₃) δ 13.8, 13.9, 14.1, 21.4, 30.2, 34.1,

41.8, 54.4, 56.0, 57.8, 61.2, 61.7, 74.5, 113.5, 113.8, 127.0, 127.8, 128.8,

129.7, 130.3, 132.0, 136.4, 136.8, 157.9, 170.7, 170.9; HR-MS 550.185

(C₂₈H₃₃NO₇S + Na calcd 550.187).

Diethyl 7-Chloro-4′-methyl-1′-tosyl-1′,5′-dihydro-2H-spiro-

[naphthalene-1,2′-pyrrole]-3,3(4H)-dicarboxylate (2r). Prepared fol-

lowing the general procedure 1 in 48% yield (34 mg) from 70 mg of

1r. Reaction was complete after 5 h heating at 40 °C. Colorless solid:

4′-Methyl-1′,2-ditosyl-1′,2,3,5′-tetrahydro-1H-spiro[isoquinoline-

4,2′-pyrrole] (2k). Prepared following the general procedure 1 in 68%

yield (34 mg) from 50 mg of 1k. White solid: mp =115 °C (d); Rf =

0.43 (Cyclohexane/EtOAc 30%); IR (neat) ν

3040−2880, 1597,

max

1460, 1332, 1155, 1094, 1056, 899, 811, 765, 730, 701, 543; ¹H NMR

(300 MHz, CDCl₃) δ 1.76 (s, 3H), 2.43 (s, 3H), 2.46 (s, 3H), 3.61 (d,

1H, J_ab= 10.6 Hz), 3.82 (d, 1H, J_ab= 14.6 Hz), 3.89 (dd, 1H, J_ab= 10.6

Hz, 1.8 Hz), 4.17 (d, 1H, J_ab= 13.1 Hz), 4.25 (d, 1H, J_ab= 13.1 Hz),

4.64 (dd, 1H, J_ab=14.3 Hz, 1.9 Hz), 5.70 (q, 1H, J = 1.8 Hz), 6.87−

6.94 (m, 1H), 6.99−7.08 (m, 2H), 7.15 (ddd, 1H, J =7.2 Hz, 8.3 Hz,

1.0 Hz), 7.21 (d, 2H, J =8.3 Hz), 7.37 (d, 2H, J = 8.3 Hz), 7.39 (d, 2H,

J = 8.3 Hz), 7.70 (d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ

14.0, 21.6, 21.6, 48.6, 53.2, 58.8, 74.7, 126.0, 127.2, 127.4, 127.4, 127.6,

127.7, 129.3, 129.8, 129.9, 131.1, 131.3, 132.8, 137.1, 137.3, 143.3,

144.1; HR-MS 531.137 (C₂₇H₂₈N₂O₂S + Na calcd 531.139).

mp = 186 °C (d); R_f= 0.42 (Cyclohexane/EtOAc 30%); IR (neat) ν

1

2939, 1726, 1485, 1340, 1262, 1156, 1094, 670, 668, 584, 543; H

max

NMR (300 MHz, CDCl₃) δ 1.07 (t, 3H, J = 7.0 Hz), 1.29 (t, 3H, J =

7.0 Hz), 1.79 (s, 3H), 2.37 (s, 3H), 3.32 (dd, 1H, J_ab= 15.4 Hz, 2.5

Hz), 3.41 (d, 1H, J_ab= 14.4 Hz), 3.45 (d, 1H, J_ab= 15.4 Hz), 3.96−

4.08 (m, 2H + 1H), 4.19−4.29 (m, 2H + 1H), 5.41−5.49 (m, 1H),

6.31−6.38 (m, 1H), 7.03−7.10 (m, 6H); ¹³C NMR (75 MHz, CDCl₃)

δ 13.9, 14.1, 21.5, 30.2, 34.4, 41.7, 55.7, 57.8, 61.4, 61.9, 73.9, 126.6,

127.9, 128.8, 129,1, 130.1, 131.2, 131.5, 132.3, 134.3, 136.5, 137.4,

143.0, 170.4, 170.6; HR-MS 554.137 (C₂₇H₃₀ClNO₆S + Na calcd

554.137).

Diethyl 4′-Methyl-1′-tosyl-1′,5′-dihydro-2H-spiro[naphthalene-

1,2′-pyrrole]-3,3(4H)-dicarboxylate (2l). Prepared following the

general procedure 1 in 74% yield (37 mg) from 50 mg of 1l. Reaction

was complete within 30 min. Colorless oil; R_f= 0.22 (Cyclohexane/

EtOAc 20%); IR (neat) ν _max1730, 1451, 1259, 1153, 1091, 666, 580,

544; ¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, 3H, J = 7.1 Hz), 1.29 (t,

3H, J = 7.1 Hz), 1.77 (d, 3H, J = 1.5 Hz), 2.34 (s, 3H), 2.87 (dd, 1H,

J_ab=14.1 Hz, 2.5 Hz), 3.36 (dd, 1H, J_ab= 15.3 Hz, 2.5 Hz), 3.44 (d,

1H, J_ab= 14.1 Hz), 3.51 (d, 1H, J_ab= 15.3 Hz), 4.02 (t, 2H, J = 7.1

Hz), 4.02 (d, 1H, J_ab= 13.3 Hz), 4.18 (d, 1H, J_ab= 13.3 Hz), 4.24 (q,

2H, J = 7.1 Hz), 5.48 (q, 1H, J = 1.5 Hz), 6.60 (d, 1H), 6.72−6.84 (m,

1H), 7.03 (d, 2H, J = 8.1 Hz), 7.12 (d, 2H, J = 8.1 Hz), 7.12 (m, 2H);

¹³C NMR (75 MHz, CDCl₃) δ 13.9, 14.1, 21.4, 30.9, 34.9, 41.6, 55.7,

58.0, 61.2, 61.8, 74.5, 126.6, 127.1, 127.6, 128.5, 128.7, 129.0, 130.3,

131.8, 135.3, 136.0, 136.9, 142.4, 170.7, 170.8; HR-MS 520.177

(C₂₇H₃₁NO₆S + Na calcd 520.176).

4′-Methyl-1′-tosyl-1′,3,4,5′-tetrahydro-2H-spiro[naphthalene-

1,2′-pyrrole] (2m). Prepared following the general procedure 1 in 72%

yield (36 mg) from 50 mg of 1m. Colorless oil; R_f= 0.40

4′-Methyl-1′-tosyl-1,1′,3,5′-tetrahydrospiro[benzo[h]-

isochromene-4,2′-pyrrole] (2s). Prepared following the general

procedure 1 in 82% yield (41 mg) from 50 mg of 1s. Pale-yellow

crystals: mp = 165 °C; R_f= 0.23 (Cyclohexane/EtOAc 20%); IR

(neat) ν _max2930, 2846, 1588, 1336, 1154, 1096, 1068, 811, 667, 565,

1

542; H NMR (300 MHz, CDCl₃) δ 1.80 (s, 3H), 2.38 (s, 3H), 3.97

(d, 1H, J_ab= 10.7 Hz), 4.21 (ddt, 1H, J_ab= 13.1 Hz, 0.8 Hz, 1.0 Hz),

4.35 (ddt, 1H, J_ab= 13.1 Hz, 0.8 Hz, 1.0 Hz), 4.69 (d, 1H, J_ab= 10.7

Hz), 5.28 (s, 2H), 5.59 (d, 1H), 7.10 (d, 1H, J = 8.6 Hz), 7.14 (d, 2H,

J = 8.2 Hz), 7.45−7.56 (m, 3H), 7.51 (d, 2H, J = 8.2 Hz), 7.66−7.71

(m, 1H), 7.77−7.81 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.0,

21.5, 59.0, 66.7, 72.5, 73.2, 122.2, 124.7, 125.9, 126.5, 127.1, 127.4,

128.6, 128.8, 129.1, 129.2, 129.4, 132.2, 132.3, 133.9, 137.3, 143.1;

HR-MS 428.128 (C₂₄H₂₃NO₃S + Na calcd 428.129).

(Cyclohexane/EtOAc 20%); IR (neat) ν

3158, 2923, 1330, 1151,

max

1

1093, 1046, 765, 688, 659, 582, 540; H NMR (300 MHz, CDCl₃) δ

1.71 (s, 3H), 1.60−1.78 (m, 1H), 2.38 (s, 3H), 2.64−2.80 (m, 1H),

2.88−3.06 (m, 2H), 4.12−4.21 (m, 2H), 5.47 (q, 1H, J = 1.7 Hz),

6.82−6.97 (m, 2H), 7.01−7.13 (m, 2H), 7.15 (d, 2H, J = 8.3 Hz), 7.46

(d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.0, 21.5, 22.1,

29.7, 30.2, 36.6, 58.5, 76.3, 125.9, 126.8, 127.4, 128.3, 128.5, 128.7,

129.1, 129.6, 131.5, 137.3, 137.8, 139.3, 142.6; HR-MS 376.132

(C₂₁H₂₃NO₂S + Na calcd 376.134).

4′-Methyl-1′-tosyl-1′,2,4,5′-tetrahydrospiro[benzo[f]-

isochromene-1,2′-pyrrole] (2t). Prepared following the general

procedure 1 in 78% yield (39 mg) from 50 mg of 1t. Colorless oil;

R_f= 0.32 (Cyclohexane/EtOAc 20%); IR (neat) ν

1529, 1344, 1156, 1093, 808, 730, 706, 688, 666, 582, 544; H NMR

(300 MHz, CDCl₃) δ 1.84 (s, 3 H), 2.27 (s, 3 H), 3.93 (d, 1 H, J_ab

2926, 2844,

max

1

=

11.3 Hz), 4.27 (d, 1 H, J_ab= 13.8 Hz), 4.47 (d, 1 H, J_ab= 13.8 Hz),

4.60 (d, 1 H, J_ab= 11.3 Hz), 4.85 (d, 1 H, J_ab= 15.2 Hz), 5.11 (d, 1 H,

J_ab= 15.2 Hz), 5.63 (q, 1 H, J = 1.7 Hz), 6.82 (d, 2 H, J = 8.2 Hz), 6.97

(ddd, 1 H, J = 7.1 Hz, 8.3 Hz, 1.5 Hz), 7.07−7.13 (m, 3H), 7.27 (ddd,

7-Methoxy-4′-methyl-1′-tosyl-1′,5′-dihydrospiro[isochroman-

4,2′-pyrrole] (2o). Prepared following the general procedure 1 in 65%

4333

dx.doi.org/10.1021/jo300294r | J. Org. Chem. 2012, 77, 4323−4341

The Journal of Organic Chemistry

Article

1 H, 7.1 Hz, 8.3 Hz, 1.5 Hz), 7.39 (d, 1 H, J = 8.7 Hz), 7.68−7.81 (m,

2 H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 21.5, 60.0, 69.8, 72.4, 75.7,

122.5, 124.2, 124.5, 125.6, 127.0, 128.5, 128.6, 128.7, 128.8, 129.6,

131.7, 132.8, 133.1, 134.7, 136.3, 142.5; HR-MS 428.126

(C₂₄H₂₃NO₃S + Na, calcd 428.129).

General Procedure 2 for the Silver-Catalyzed Preparation of

Aminoallenes. To a solution cooled at −20 °C of alkynylaziridine

(0.1 mmol) in CH₂Cl₂(1 mL) was added AgNTf₂(0.005 mmol).

Monitored by thin-layer chromatography, the reaction was stirred until

conversion of the starting material to the corresponding allene (of

lower R_f) then, the reaction mixture was ﬁltered throughout a pad of

silica gel and rinsed with CH₂Cl₂. After concentration of the reaction

mixture, the crude residue was puriﬁed by ﬂash chromatography

(Cyclohexane/EtOAc).

Hz), 4.77 (s, 2 H), 7.00−7.05 (m, 1 H), 7.09−7.23 (m, 2 H), 7.20−

7.30 (m, 1 H), 7.26 (d, 2 H, J = 8.3 Hz), 7.72 (d, 2 H, J = 8.3 Hz); ¹³C

NMR (75 MHz, CDCl₃) δ 16.8, 21.5, 23.6, 37.2, 37.6, 45.9, 63.1, 83.8,

102.9, 108.7, 124.4, 126.8, 127.0, 127.1, 129.8, 133.4, 136.6, 143.5,

195.5; HR-MS 432.157 (C₂₄H₂₇NO₃S + Na, calcd 432.160).

N-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-(isochroman-4-

ylidene)allyl)-4-methylbenzenesulfonamide (3f). Prepared following

the general procedure 2 in 44% yield (22 mg) from 50 mg of 1f.

Colorless oil; R_f= 0.21 (Cyclohexane/EtOAc 20%); IR (neat) ν

max

3286, 2927, 2855, 1329, 1252, 1157, 1090, 834, 777, 732, 663, 548; ¹H

NMR (300 MHz, CDCl₃) δ 0.03 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H),

2.41 (s, 3H), 3.76 (d, 2H, J = 5.8 Hz), 4.24 (d, 2H, J = 5.1 Hz), 4.41

(s, 2H), 4.77 (s, 2H), 4.85 (t, 1H, J = 11.6 Hz), 7.00−7.05 (m, 1H),

7.14−7.20 (m, 2H), 7.28 (d, 2H, J = 8.2 Hz), 7.31−7.38 (m, 1H), 7.74

(d, 2H, J = 8.2 Hz); ¹³C NMR (75 MHz, CDCl₃) δ −5.4, −5.3, 18.2,

21.6, 25.4, 25.8, 43.1, 63.1, 67.4, 68.7, 102.1, 106.7, 124.7, 126.5, 127.2,

127.2, 127.6, 127.9, 129.7, 133.9, 136.8, 143.5, 194.8; HR-MS 508.195

(C₂₆H₃₅NO₄SSi + Na calcd 508.195).

N-(3-(Isochroman-4-ylidene)-2-methylallyl)-4-methylbenzenesul-

fonamide (3a). Prepared following the general procedure 2 in 55%

yield (22 mg) from 40 mg of 1a. Colorless oil; R_f= 0.22

(Cyclohexane/EtOAc 20%); IR (neat) ν

3254, 2911, 2837, 1329,

max

1

1158, 1088, 811, 762; H NMR (300 MHz, CDCl₃) δ 1.79 (s, 3 H),

2.41 (s, 3 H), 3.60 (d, 2 H, J = 6.0 Hz), 4.40 (d, 2 H, J = 1.9 Hz),

4.55−4.61 (m, 1 H), 4.76 (s, 2 H), 6.99−7.04 (m, 1 H), 7.14−7.19

(m, 2 H), 7.22−7.34 (m, 3 H), 7.72 (d, 2 H, J = 8.4 Hz); ¹³C NMR

(75 MHz, CDCl₃) δ 18.8, 21.6, 45.8, 67.7, 88.7, 101.1, 102.8, 124.7,

126.3, 127.0, 127.1, 127.3, 128.5, 129.8, 133.9, 136.7, 143.5, 195; HR-

MS 378.111 (C₂₀H₂₁NO₃S + Na, calcd 378.113).

N-(1-(tert-Butyldimethylsilyloxy)-4-(isochroman-4-ylidene)-3-

methylbut-3-en-2-yl)-4-methylbenzenesulfonamide (3g). Prepared

following the general procedure 2 in 60% yield (60 mg, dr 2:1) from

100 mg of 1g. Colorless oil; Mixture of diastereoisomers: R_f= 0.38

(Cyclohexane/EtOAc 20%); IR (neat) ν

3284, 2953, 2928, 2857,

max

1460, 1402, 1331, 1254, 1159, 1089, 1031, 1005, 906, 835, 727; MS

(ESI) m/z (%) 1021 (100, 2M^+·+ Na), 522 (95, M^+·+ Na); HR-MS

522.210 (C₂₇H₃₇NO₄SSi + Na calcd 522.211). Major diastereoisomer

(2S*,4S*): ¹H NMR (300 MHz, CDCl₃) δ −0.01 (s, 6 H), 0.85 (s, 9

H), 1.80 (s, 3 H), 2.43 (s, 3 H), 3.57−3.87 (m, 3 H), 4.47 (s, 2 H),

4.76 (s, 2 H), 5.00 (d, 1 H, J = 7.3 Hz), 7.00−7.06 (m, 1 H), 7.14−

7.35 (m, 5 H), 7.72 (d, 2 H, J = 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃)

δ −5.64, −5.61, 16.3, 18.2, 21.5, 25.8, 57.4, 64.4, 67.7, 68.7, 100.2,

104.7, 124.5, 126.4, 126.9, 127.0, 127.1, 128.6, 129.6, 133.7, 137.4,

143.3, 196.5. Minor diastereoisomer (2R*,4S*): ¹H NMR (300 MHz,

CDCl₃) δ 0.01 (s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 1.82 (s, 3 H), 2.43

(s, 3 H), 3.57−3.87 (m, 3 H), 4.30 (d, 1 H, J_ab= 13.0 Hz), 4.35 (d, 1

H, J_ab= 13.0 Hz), 4.76 (s, 2 H), 4.92 (d, 1 H, J = 7.1 Hz), 7.00−7.06

(m, 1 H), 7.14−7.35 (m, 5 H), 7.73 (d, 2 H, J = 8.4 Hz); ¹³C NMR

(75 MHz, CDCl₃) δ −5.56, −5.52, 16.3, 18.3, 21.4, 25.9, 57.4, 64.4,

67.5, 68.7, 100.7, 105.0, 124.5, 126.6, 126.9, 127.0, 127.1, 128.5, 129.6,

133.7, 137.4, 143.3, 196.2.

N-(3-(Isochroman-4-ylidene)-2-methylallyl)-4-nitrobenzenesulfo-

namide (3b). Prepared following the general procedure 2 in 68% yield

(17 mg) from 25 mg of 1b. Yellow powder: mp = 51−52 °C; R_f= 0.13

(Cyclohexane/EtOAc 20%). IR (neat) ν

3273, 2922, 2851, 1526,

max

1346, 1157, 1091, 734, 608; ¹H NMR (300 MHz, CDCl₃) δ 1.79 (s, 3

H), 3.60−3.80 (m, 2 H), 4.39 (s, 2 H), 4.74 (s, 2 H), 5.03 (t, 1 H, J =

5.7 Hz), 7.00 (d, 1 H, J = 6.9 Hz), 7.11−7.19 (m, 2 H), 7.29 (t, 1 H, J

= 8.2 Hz), 7.97 (d, 2 H, J = 8.9 Hz), 8.19 (d, 2 H, J = 8.9 Hz); ¹³C

NMR (75 MHz, CDCl₃) δ 16.9, 45.7, 67.7, 68.7, 101.6, 102.8, 124.3,

124.8, 126.2, 126.4, 127.0, 127.6, 128.1, 129.7, 133.9, 145.9, 194.8;

HR-MS 409.080 (C₁₉H₁₈N₂O₅S + Na, calcd 409.083).

N-(3-(3-Hexylisochroman-4-ylidene)-2-methylallyl)-4-methylben-

zenesulfonamide (3c). Prepared following the general procedure 2 in

50% yield (15 mg, dr 1:1) from 30 mg of 1c. Mixture of inseparable

diastereoisomers: White crystalline powder: R_f= 0.26 (Cyclohexane/

EtOAc 20%); IR (neat) ν _max3262, 2926, 2851, 1327, 1160, 1089, 813,

660, 548; ¹H NMR (300 MHz, CDCl₃) δ 0.83−0.91 (m, 3 H), 1.14−

1.36 (m, 8 H), 1.55−1.70 (m, 2 H), 1.72−1.85 (m, 3 H), 2.35−2.48

(m, 3 H), 3.55−3.63 (m, 2 H), 4.18−4.27 (m, 1 H), 4.47−4.54 (m, 1

H), 4.71−4.84 (m, 2 H), 7.00−7.04 (m, 1 H), 7.14−7.36 (m, 5 H),

7.68−7.76 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 16.6, 16.9,

21.6, 22.6, 25.4, 25.8, 29.3, 29.4, 30.2, 31.9, 33.5, 33.8, 45.6, 46.0, 67.6,

67.8, 75.5, 75.6, 102.2, 103.2, 106.0, 124.5, 124.6, 127.0, 127.1, 128.9,

129.8, 134.0, 136.7, 143.5, 195.4, 195.8; HR-MS 462.204

(C₂₆H₃₃NO₃S + Na, calcd 462.207).

N-(2-(Isochroman-4-ylidenemethylene)cyclohexyl)-4-methylben-

zenesulfonamide (3h). Prepared following the general procedure 2 in

71% yield (35.5 mg, dr 3:1) from 50 mg of 1h. IR (neat) ν

3158,

max

2925, 2851, 1444, 1314, 1152, 1097, 926, 810, 758, 734, 656, 545; HR-

MS 418.141 (C₂₃H₂₅NO₃S + Na, calcd 418.145); Major diaster-

eoisomer (2S*,R*): colorless crystalline powder: mp = 153 °C; R_f=

0.19 (Cyclohexane/EtOAc 20%); ¹H NMR (300 MHz, CDCl₃) δ

1.30−1.53 (m, 2 H), 1.69−1.88 (m, 2 H), 1.96−2.12 (m, 1 H), 2.19−

2.33 (m, 1 H), 2.35−2.45 (m, 1 H), 2.40 (s, 3 H), 3.64−3.72 (m, 1 H),

4.46 (d, 2 H, J = 2.1 Hz), 4.75−4.88 (m, 1 H), 4.79 (s, 2 H), 6.95 (d, 1

H, J = 7.4 Hz), 7.02 (d, 1 H, J = 7.6 Hz), 7.08 (d, 1 H, J = 7.6 Hz),

7.14 (d, 2 H, J = 8.3 Hz), 7.19 (d, 1 H, J = 7.4 Hz), 7.63 (d, 2 H, J =

8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.6, 24.4, 26.8, 31.1, 36.8,

53.0, 68.2, 68.7, 102.4, 110.7, 124.6, 126.4, 126.8, 126.9, 127.3, 128.6,

129.6, 133.9, 137.6, 143.0, 190.5. Minor diastereoisomer (2R*,R*):

white crystalline powder: mp = 114 °C; R_f= 0.24 (Cyclohexane/

N-(3-(3,3-Dimethylisochroman-4-ylidene)-2-methylallyl)-4-meth-

ylbenzenesulfonamide (3d). Prepared following the general proce-

dure 2 in 64% yield (32 mg) or following the general procedure 1 in

61% yield (30.5 mg) from 50 mg of 1d. Colorless oil; R_f= 0.20

(Cyclohexane/EtOAc 20%); IR (neat) ν

3280, 2977, 2930, 2851,

max

1706, 1324, 1153, 1085, 815, 662, 542; ¹H NMR (300 MHz, CDCl₃) δ

1.39 (s, 6 H), 1.83 (s, 3 H), 2.40 (s, 3 H), 3.59 (dd, 2 H, J = 6.0 Hz,

2.1 Hz), 4.40 (t, 1 H, J = 6.0 Hz), 4.80 (s, 2 H), 7.00−7.10 (m, 1H),

7.12−7.28 (m, 3 H), 7.28 (d, 2 H, J = 8.1 Hz), 7.72 (d, 2 H, J = 8.1

Hz); ¹³C NMR (75 MHz, CDCl₃) δ 16.8, 21.5, 26.8, 27.0, 45.8, 62.6,

73.0, 103.1, 110.1, 124.4, 126.9, 127.1, 128.1, 129.8, 133.2, 136.7,

143.6, 195.4; HR-MS 390.173 (C₂₂H₂₅NO₃S + Li, calcd 390.171).

4-Methyl-N-(2-methyl-3-(spiro[cyclopentane-1,3′-isochroman]-

4′-ylidene)allyl)benzenesulfonamide (3e). Prepared following either

the general procedure 1 or the general procedure 2 in 74% yield (37

mg) from 50 mg of 1e. Orange crystalline powder: mp = 136−137 °C;

1

EtOAc 20%). H NMR (300 MHz, CDCl₃) δ 1.14−1.97 (m, 6 H),

2.25−2.37 (m, 2 H), 2.43 (s, 3 H), 3.60−3.77 (m, 1 H), 4.13 (d, 1 H,

J_ab= 12.7 Hz), 4.25 (d, 1 H, J_ab= 12.7 Hz), 4.63 (d, 1 H, J = 7.6 Hz),

4.78 (d, 2 H, J = 3.0 Hz), 7.00−7.07 (m, 1 H), 7.11−7.25 (m, 2 H),

7.28−7.45 (m, 1 H), 7.30 (d, 2 H, J = 8.1 Hz), 7.73 (d, 2 H, J = 8.1

Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.5, 25.0, 27.2, 31.6, 37.6, 53.3,

67.5, 68.7, 102.7, 111.3, 124.9, 125.7, 127.0, 127.3, 127.5, 128.6, 129.7,

134.0, 137.9, 143.3, 190.1.

N-(2-((3,4-Dihydronaphthalen-1(2H)-ylidene)methylene)-

cycloheptyl)-4-methylbenzenesulfonamide (3i). Prepared following

the general procedure 2 in 59% total yield (29.5 mg) from 50 mg of 1i,

after 4 h stirring at room temperature. Two diastereoisomers: dr 1:1.

R_f= 0.27 (Cyclohexane/EtOAc 20%); IR (neat) ν

3288, 2955,

max

2859, 1326, 1156, 1079, 812, 762, 726, 661, 546; ¹H NMR (300 MHz,

CDCl₃) δ 1.60−1.78 (m, 6 H), 1.82 (s, 3 H), 1.90−2.11 (m, 2 H),

2.41 (s, 3 H), 3.60 (dd, 2 H, J = 5.9 Hz, 2.0 Hz), 4.57 (t, 1 H, J = 5.9

Pale-yellow oil; IR (neat) ν

3271, 2915, 2846, 1710, 1446, 1327,

max

1156, 1090, 729, 663, 547. Diastereoisomer 1: R_f= 0.33 (Cyclo-

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1

hexane/EtOAc 30%); H NMR (300 MHz, CDCl₃) δ 1.60−1.69 (m,

7.16−7.25 (m, 1H), 7.26 (d, 2H, J = 8.3 Hz), 7.72 (d, 2H, J = 8.3 Hz);

¹³C NMR (75 MHz, CDCl₃) δ 16.9, 21.6, 23.1, 29.0, 30.0, 45.7, 99.5,

6H), 1.77−1.84 (m, 1H), 2.02−2.15 (m, 2H), 2.31−2.38 (m, 1H),

2.41 (s, 3H), 3.89−3.97 (m, 1H), 4.15 (d, 1H, J = 12.9 Hz), 4.25 (d,

1H, J = 12.9 Hz), 4.64 (broad d, 1H, J = 7.3 Hz), 4.76 (s, 2H), 7.02−

7.05 (m, 1H), 7.18−7.21 (m, 2H), 7.26 (d, 2H, J = 8.3 Hz), 7.35−7.38

(m, 1H), 7.71 (d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ

21.6, 24.7, 28.5, 29.3, 30.6, 37.2, 55.4, 67.5, 68.7, 102.1, 113.3, 124.8,

125.8, 127.1, 127.3, 127.5, 128.6, 129.6, 133.9, 137.6, 143.3, 195.1;

HR-MS 432.159 (C₂₄H₂₇NO₃S + Na calcd 432.160). Diastereoisomer

2: R_f= 0.30 (Cyclohexane/EtOAc 30%); ¹H NMR (300 MHz,

CDCl₃) δ 1.56−1.70 (m, 6H), 1.75−1.84 (m, 1H), 1.96−2.23 (m,

2H), 2.25−2.33 (m, 1H), 2.34 (s, 3H), 3.95−4.01 (m, 1H), 4.41 (s,

2H), 4.68 (d, 1H, J = 7.0 Hz), 4.77 (s, 2H), 7.00−7.19 (m, 6H), 7.13

(d, 2H, J = 8.2 Hz), 7.65 (d, 2H, J = 8.2 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ 21.5, 24.5, 28.9, 29.6, 30.1, 30.2, 36.7, 55.3, 67.9, 68.7, 101.4,

113.0, 124.7, 126.2, 127.0, 127.2, 128.5, 129.6, 133.9, 137.4, 143.1,

195.9; HR-MS 432.159 (C₂₄H₂₇NO₃S + Na calcd 432.160).

105.5, 126.0, 126.8, 127.0, 127.1, 129.3, 129.7, 131.4, 136.8, 136.9,

143.4, 197.2; HR-MS 376.133 (C₂₁H₂₃NO₂S + Na calcd 376.134).

Diethyl 6-methoxy-4-(2-methyl-3-(4-methylphenylsulfonamido)-

prop-1-en-1-ylidene)-3,4-dihydronaphthalene-2,2(1H)-dicarboxy-

late (3q). Prepared following the general procedure 2 in 50% yield (25

mg) from 50 mg of 1q, after 15 min stirring at −20 °C. Colorless oil;

R_f= 0.21 (Cyclohexane/EtOAc 30%); IR (neat) ν

1728, 1613, 1485, 1226, 1157, 1092, 1043, 663, 548; H NMR (300

3276, 2979,

max

1

MHz, CDCl₃) δ 1.15 (t, 3H, J = 7.1 Hz), 1.25 (t, 3H, J = 7.1 Hz), 1.75

(s, 3H), 2.38 (s, 3H), 2.81 (d, 1H, J_ab= 14.4 Hz), 3.03 (dd, 1H, J_ab

=

14.4 Hz, 1.4 Hz), 3.25−3.34 (m, 2H), 3.49 (dd, 1H, J_ab= 15.1 Hz, 3.5

Hz), 3.63 (dd, 1H, J_ab= 15.1 Hz, 6.9 Hz), 3.71 (s, 3H), 4.12−4.26 (m,

4H), 5.32 (dd, 1H, J = 7.0 Hz, 3.5 Hz), 6.67−6.76 (m, 2H), 7.04 (d,

1H, J = 8.4 Hz), 7.16 (d, 2H, J = 8.2 Hz), 7.66 (d, 2H, J = 8.2 Hz); ¹³C

NMR (75 MHz, CDCl₃) δ 14.0, 14.1, 16.7, 21.5, 34.5, 45.5, 54.0, 55.2,

61.8, 62.1, 100.8, 103.3, 110.9, 114.3, 125.2, 127.1, 128.8, 129.5, 130.0,

131.0, 137.0, 142.9, 158.2, 170.8, 170.8, 198.0; HR-MS 550.188

(C₂₈H₃₃NO₇S + Na calcd 550.187).

N-(2-((3,4-Dihydronaphthalen-1(2H)-ylidene)methylene)-

cyclooctyl)-4-methylbenzenesulfonamide (3j). Prepared following

the general procedure 2 in 52% yield (26 mg) from 50 mg of 1j, after

2h20 reﬂuxing in dichloromethane. Two diastereoisomers: dr 5:1; pale

yellow oil; Rf = 0.32 (Cyclohexane/EtOAc 30%); IR (neat) ν

3271, 2920, 2851, 1694, 1446, 1328, 1155, 1091, 729, 665, 548. Major

Diethyl 6-Chloro-4-(2-methyl-3-(4-methylphenylsulfonamido)-

prop-1-en-1-ylidene)-3,4-dihydronaphthalene-2,2(1H)-dicarboxy-

late (3r). Prepared following the general procedure 2 in 32% yield (16

mg) from 50 mg of 1r, after 15 min stirring at −20 °C. Colorless oil;

max

1

diastereoisomer: H NMR (300 MHz, CDCl₃) δ 1.59−1.75 (m, 9H),

Rf = 0.31 (Cyclohexane/EtOAc 30%); IR (neat) ν

3291, 2994,

1.99−2.04 (m, 2H), 2.29−2.38 (m, 1H), 2.41 (s, 3H), 3.89−3.93 (m,

1H), 4.23 (d, 1H, J = 12.9 Hz), 4.25 (d, 1H, J = 12.9 Hz), 4.63 (broad

d, 1H, J = 7.5 Hz), 4.77 (d, 2H, J = 2.3 Hz), 7.01−7.04 (m, 1H), 7.16−

7.20 (d, 2H, J = 8.3 Hz), 7.24−7.28 (m, 2H), 7.36−7.39 (m, 1H), 7.73

(d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.6, 23.2, 26.2,

28.3, 30.2, 30.6, 34.1, 43.5, 55.2, 67.6, 68.7, 102.1, 113.0, 124.8, 126.5,

127.1, 127.2, 127.4, 129.7, 134.0, 137.8, 143.3, 195.9; HR-MS 446.176

(C₂₅H₂₉NO₃S + Na calcd 446.176).

max

1

2920, 1728, 1584, 1463, 1158, 1091, 730, 663, 549; H NMR (300

MHz, CDCl₃) δ 1.16 (t, 3H, J = 7.0 Hz), 1.26 (t, 3H, J = 7.0 Hz), 1.76

(m, 3H), 2.40 (s, 3H), 2.81 (d, 1H, J = 14.3 Hz), 3.04 (dd, 1H, J =

14.4 Hz, 1.4 Hz), 3.27−3.36 (m, 2H), 3.51 (dd, 1H, J = 15.0 Hz, 3.5

Hz), 3.64 (dd, 1H, J = 15.0 Hz, 7.0 Hz), 4.13−4.28 (m, 4H), 5.26 (dd,

1H, J = 7.0 Hz, 3.5 Hz), 7.03−7.13 (m, 3H), 7.19 (s, 2H, J = 8.3 Hz),

7.64 (s, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.0, 14.1,

16.7, 21.6, 34.3, 34.6, 45.4, 53.6, 62.0, 62.3, 101.5, 102.3, 126.4, 127.2,

127.8, 129.7, 130.5, 131.3, 132.0, 132.5, 136.9, 143.2, 170.5, 170.6,

198.2; HR-MS 554.136 (C₂₇H₃₀ClNO₆S + Na calcd 554.137).

N-(3-(1H-Benzo[h]isochromen-4(3H)-ylidene)-2-methylallyl)-4-

methylbenzenesulfonamide (3s). Prepared following the general

procedure 2 in 66% yield (33 mg) from 50 mg of 1s. Colorless

4-Methyl-N-(2-methyl-3-(2-tosyl-2,3-dihydroisoquinolin-4(1H)-

ylidene)allyl)benzenesulfonamide (3k). Prepared following the

general procedure 2 in 70% yield (35 mg) from 50 mg of 1k.

Colorless solid: mp = 80 °C; Rf = 0.22 (Cyclohexane/EtOAc 30%); IR

3291 (broad), 2910, 1597, 1327, 1155, 1088, 909, 758,

728, 659, 546; H NMR (300 MHz, CDCl₃) δ 1.76 (s, 3H), 2.38 (s,

3H), 2.39 (s, 3H), 3.56 (dd, 2H, J = 1.3 Hz, 5.7 Hz), 3.93 (d, 1H, J_ab

14.0 Hz), 4.02 (d, 1H, J_ab= 14.0 Hz), 4.31 (d, 1H, J_ab= 15.3 Hz), 4.38

(d, 1H, J_ab= 15.3 Hz), 4.52 (t, 1H, J = 6.3 Hz), 6.98−7.06 (m, 1H),

7.08−7.13 (m, 2H), 7.20 (d, 2H, J = 8.3 Hz), 7.26 (d, 2H, J =8.3 Hz),

7.23−7.33 (m, 1H), 7.61 (d, 2H, J = 8.3 Hz), 7.70 (d, 2H, J =8.3 Hz);

¹³C NMR (75 MHz, CDCl₃) δ 16.6, 21.5, 21.6, 45.8, 47.1, 48.4, 99.9,

103.2, 126.5, 127.1, 127.2, 127.6, 127.8, 128.8, 128.9, 129.6, 129.7,

129.8, 130.9, 133.8, 143.6, 143.8, 196.9; HR-MS 531.136

(C₂₇H₂₈N₂O₄S₂+ Na calcd 531.138).

(neat) ν

max

1

crystals: mp = 147 °C; R_f= 0.12 (Cyclohexane/EtOAc 20%); IR

=

1

(neat) ν

3251, 1417, 1329, 1158, 1085, 814, 744, 669, 555; H

max

NMR (300 MHz, CDCl₃) δ 1.84 (s, 3H), 2.33 (s, 3H), 3.63 (t, 2H, J =

5.4 Hz), 4.45 (d, 1H, J = 1.6 Hz), 4.84 (t, 1H, J = 6.0 Hz), 5.21 (d, 2H,

J = 2.2 Hz), 7.20 (d, 2H, J = 8.3 Hz), 7.34 (d, 1H, J = 8.6 Hz), 7.44−

7.54 (m, 2H), 7.63 (d, 1H, J = 8.6 Hz), 7.64−7.69 (m, 1H), 7.84−7.78

(m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 16.9, 21.5, 45.9, 66.4, 67.1,

101.8, 102.8, 121.9, 124.1, 125.9, 126.0, 126.6, 127.1, 127.2, 128.8,

129.4, 129.7, 129.0, 132.5, 136.8, 143.4, 196.0; HR-MS 428.128

(C₂₄H₂₃NO₃S + Na calcd 428.129).

N-(3-(2,4-Dihydro-1H-benzo[f]isochromen-1-ylidene)-2-methyl-

allyl)-4-methylbenzenesulfonamide (3t). Prepared following the

general procedure 2 in 56% yield (28 mg) from 50 mg of 1t.

Bright-orange crystals: mp = 99 °C; R_f= 0.18 (Cyclohexane/EtOAc

Diethyl 4-(2-Methyl-3-(4-methylphenylsulfonamido)prop-1-en-1-

ylidene)-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (3l). Pre-

pared following the general procedure 2 in 69% yield (34.5 mg)

from 50 mg of 1l, after 50 min stirring at −20 °C. Colorless solid: mp

= 83 °C; R_f= 0.16 (Cyclohexane/EtOAc 20%); IR (neat) ν _max3261,

1

20%); IR (neat) ν

3251, 2911, 2834, 1314, 1158, 1081, 810, 662,

2979, 1720, 1575, 1472, 1159, 1091, 662, 551; H NMR (300 MHz,

max

550; ¹H NMR (300 MHz, CDCl₃) δ 1.92 (s, 3 H), 2.34 (s, 3 H), 3.64

(dd, 2 H, J = 6.0 Hz, 2.2 Hz), 4.44 (d, 2 H, J = 2.2 Hz), 4.63 (t, 1 H, J

= 6.0 Hz), 4.96 (s, 2 H), 7.05−7.18 (m, 3 H), 7.35−7.50 (m, 2 H),

7.60−7.72 (m, 2 H), 7.72 (d, 1 H, J = 8.4 Hz), 7.78−7.86 (m, 1 H),

8.30−8.40 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ 17.2, 21.5, 46.1,

69.1, 70.1, 98.8, 122.7, 123.9, 125.5, 126.7, 127.0, 128.4, 128.9, 129.6,

130.8, 132.0, 133.1, 136.6, 143.4, 199.7; HR-MS 428.126

(C₂₄H₂₃NO₃S + Na, calcd 428.129).

CDCl₃) δ 1.13 (t, 3H, J = 7.1 Hz), 1.26 (t, 3H, J = 7.1 Hz), 1.76 (s,

3H), 2.40 (s, 3H), 2.84 (d, 1H, J = 14.3 Hz), 3.05 (dd, 1H, J = 14.3

Hz, 1.5 Hz), 3.33−3.40 (m, 2H), 3.48 (dd, 1H, J = 15.0 Hz, 3.5 Hz),

3.64 (dd, 1H, J = 14.9 Hz, 7.1 Hz), 4..10−4.30 (m, 4H), 5.25 (dd, 1H,

J = 3.5 Hz, 7.0 Hz), 7.05−7.22 (m, 4H), 7.18 (d, 2H, J = 8.3 Hz), 7.68

(d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.0, 14.1, 16.8,

21.5, 34.5, 35.2, 45.6, 53.8, 61.9, 62.1, 100.6, 103.1, 126.7, 126.8, 127.1,

127.5, 129.1, 129.6, 130.1, 132.7, 137.2, 143.1, 170.87 170.8, 198.0;

HR-MS 520.171 (C₂₇H₃₁NO₆S + Na calcd 520.176).

N-(3-(3,4-Dihydronaphthalen-1(2H)-ylidene)-2-methylallyl)-4-

methylbenzenesulfonamide (3m). Prepared following the general

procedure 2 in 69% yield (34.5 mg) from 50 mg of 1m, after 45 min

stirring at −20 °C. Colorless oil; R_f= 0.25 (Cyclohexane/EtOAc

20%); IR (neat) ν _max3273, 2924, 1597, 1450, 1323, 1155, 1091, 812,

759, 661, 549; ¹H NMR (300 MHz, CDCl₃) δ 1.76 (s, 3H), 1.80−1.92

(m, 2H), 2.40 (m, 2H), 2.37−2.46 (s, 3H), 2.80 (t, 2H, J = 6.1 Hz),

3.57 (d, 2H, J = 5.6 Hz), 4.47 (t, 1H, J = 5.6 Hz), 7.00−7.14 (m, 3H),

General Procedure 3 for Preparation of Enynyl Alcohol. To a

cooled solution of n-BuLi (1.6 M in hexanes, 10.5 mmol) in THF (20

mL) at −78 °C and under argon was added dropwise the

corresponding enyne (10 mmol). The resulting reaction mixture was

stirred at the same temperature for 30 min, then a ketone or an

aldehyde (11 mmol) was added at −78 °C. The reaction mixture was

then allowed to reach room temperature and was further stirred until

reaction completion as monitored by TLC. The mixture was quenched

with aqueous NH₄Cl (5 mL) and extracted twice with Et₂O (20 mL).

4335

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The combined organic extracts were dried over MgSO₄. After ﬁltration

and evaporation, the crude product was puriﬁed by ﬂash

chromatography (Cyclohexane/EtOAc) to aﬀord the title compound.

4-Methylpent-4-en-2-yn-1-ol (A1). Prepared following the general

procedure 3 in 99% yield (1.89 g) from 1.32 g of 2-methylbut-1-en-3-

yne and 696 mg of p-formaldehyde. Pale-yellow oil; R_f= 0.23

1 H), 2.06−2.10 (m, 4 H), 4.37 (s, 2 H), 6.10 (quint, 1 H, J = 1.8 Hz);

¹³C NMR (75 MHz, CDCl₃) δ 21.4, 22.2, 25.5, 29.0, 51.5, 84.5, 87.4,

120.0, 135.4.

General Procedure 4 for Preparation of Enynyl Benzyl

Ether/Enynyl Benzyl Malonate. To a solution at 0 °C of enynyl

alcohol or enynyl malonate (8 mmol) in THF (20 mL) were added N-

tetrabutylammonium iodide (0.8 mmol) and sodium hydride by

portions (8.8 mmol) at 0 °C. The solution was stirred under argon for

20 min. The appropriate benzyl or methyl naphtyl halide (8.8 mmol)

was then added at 0 °C. The mixture was then warmed to room

temperature and stirred overnight. The mixture was quenched with

saturated NH₄Cl (5 mL). THF was removed under vacuo and the

aqueous layer was extracted twice with Et₂O (20 mL). The combined

organic extracts were dried over Na₂SO₄. After ﬁltration and

evaporation, the crude product was puriﬁed by ﬂash chromatography

to aﬀord the title compound.

(Cyclohexane/EtOAc 20%); IR (neat) ν

3300, 2925, 2210, 1613,

max

1435, 1289, 1070, 999, 896; ¹H NMR (300 MHz, CDCl₃) δ 1.75 (t, 1

H, J = 5.7 Hz, −OH), 1.88 (dd, 3 H, J = 1.3 Hz, 1.3 Hz), 4.38 (d, 2 H,

J = 5.2 Hz), 5.23 (quint, 1 H, J = 1.7 Hz,), 5.30 (s, 1 H); ¹³C NMR (75

MHz, CDCl₃) δ 23.3, 51.4, 86.3, 86.8, 122.3, 126.2.

2-Methylundec-1-en-3-yn-5-ol (A2). Prepared following the

general procedure 3 in 73% yield (1.29 g) from 0.661 g of 2-

methylbut-1-en-3-yne and 1.232 g of heptanal. Pale-yellow oil; R_f=

0.21 (Cyclohexane/EtOAc 20%); IR (neat) ν_max3334, 3097, 2954,

2924, 2857, 2223, 1614, 1455, 1434, 1373, 1337, 1335, 1286, 1182,

1041, 1009, 893, 725; ¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, 3 H, J =

6.9 Hz), 1.28−1.58 (m, 10 H), 1.68−1.80 (m, 2 H), 1.90 (s, 3 H), 4.50

(t, 1 H, J = 6.4 Hz), 5.24 (s, 1 H), 5.30 (s, 1 H); ¹³C NMR (75 MHz,

CDCl₃) δ 14.0, 22.5, 23.4, 25.1, 28.9, 31.7, 37.8, 62.8, 85.9, 89.3, 122.0,

126.3.

5-Benzyloxy-2-methylpent-1-en-3-yne (Ca). Prepared following

the general procedure 4 in 94% yield (1.65 g) from 900 mg of A1.

Colorless liquid; R_f= 0.57 (Cyclohexane/EtOAc 20%); IR (neat) ν _max

1

2962, 1724, 1454, 1259, 1070, 1010, 795, 698; H NMR (300 MHz,

CDCl₃) δ 1.91 (dd, 3 H, J = 1.3 Hz, 1.3 Hz), 4.29 (s, 2 H), 4.61 (s, 2

H), 5.26 (s, 1 H), 5.33 (s, 1 H), 7.26−7.62 (m, 5H); ¹³C NMR (75

MHz, CDCl₃) δ 23.4, 57.8, 71.6, 76.6, 122.0, 127.9, 128.1, 128.4,

128.8, 129.0, 137.5.

2,5-Dimethylhex-5-en-3-yn-2-ol (A3). Prepared following the

general procedure 3 in 85% yield (1.63 g) from 1.32 g of 2-

methylbut-1-en-3-yne and 696 mg of p-formaldehyde. Pale-yellow oil;

R_f= 0.25 (Cyclohexane/EtOAc 20%); IR (neat) ν_max3305, 2925,

5-Benzyloxy-2-methylundec-1-en-3-yne (Cc). Prepared following

the general procedure 4 in 99% yield (1.93 g) from 1.29 g of A2.

Colorless liquid; R_f= 0.63 (Cyclohexane/EtOAc 20%); IR (neat) ν _max

2923, 2856, 1454, 1065, 895, 733, 696; ¹H NMR (300 MHz, CDCl₃) δ

0.89 (t, 3 H, J = 6.6 Hz), 1.24−1.43 (m, 6 H), 1.46−1.53 (m, 2 H),

1.71−1.82 (m, 2 H), 1.93 (dd, 3 H, J = 1.3 Hz, 1.3 Hz), 4.21 (t, 1 H, J

= 6.5 Hz), 4.33 (d, 1 H, J_AB= 11.6 Hz), 4.66 (d, 1 H, J_AB= 11.6 Hz),

5.23 (quint, 1 H, J = 1.4 Hz), 5.32 (s, 1 H), 7.26−7.41 (m, 5 H); ¹³C

NMR (75 MHz, CDCl₃) δ 14.1, 22.6, 23.6, 25.4, 29.0, 31.8, 35.8, 69.1,

70.5, 87.1, 87.5, 121.9, 126.5, 127.6, 128.0, 128.3, 138.2.

1

2210, 1611, 1440, 1289, 1073, 1001; H NMR (300 MHz, CDCl₃) δ

1.51 (s, 6 H), 1.85 (s, 3 H), 2.32 (s, 1 H, −OH), 5.15−5.21 (m, 1 H),

5.24 (s, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ 23.4, 31.4, 65.3, 83.1,

92.8, 121.7, 126.3.

1-(3-Methylbut-3-en-1-ynyl)cyclopentanol (A4). Prepared follow-

ing the general procedure 3 in 56% yield (586 mg) from 462 mg of 2-

methylbut-1-en-3-yne and 647 mg of cyclopentanone. Pale-yellow oil;

R_f= 0.34 (Cyclohexane/EtOAc 20%); IR (neat) ν_max3340, 2961,

2214, 1614, 1205, 994, 892; ¹H NMR (300 MHz, CDCl₃) δ 1.72−1.80

(m, 4 H), 1.84−1.91 (m, 4 H), 1.91−1.99 (m, 4 H), 5.20 (quint, 1 H, J

= 1.7 Hz), 5.24−5.27 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ 23.5,

23.6, 42.5, 74.8, 84.3, 91.9, 121.7, 126.5.

5-Benzyloxy-2,2-dimethylpent-1-en-3-yne (Cd). Prepared follow-

ing the general procedure 4 in 88% yield (1.52 g) from 1 g of A3.

Colorless liquid; R_f= 0.55 (Cyclohexane/EtOAc 20%); IR (neat) ν _max

(Z)-1-tert-Butyldimethylsilyloxy-3-methylpent-2-en-4-yne. tert-

Butyldimethylsilyl chloride (1.56 g, 11 mmol) was added to a solution

of distilled (Z)-3-methylpent-2-en-4-yn-1-ol (1 g, 10 mmol) and

imidazole (817 mg, 12 mmol) in dry CH₂Cl₂(20 mL). The mixture

was stirred at room temperature for 16 h. The reaction was quenched

by addition of water (10 mL). The aqueous layer was extracted twice

with CH₂Cl₂(10 mL). The combined organic layers were washed with

brine and dried over Na₂SO₄. After ﬁltration and evaporation, the

crude mixture was ﬁltered through a pad of silica gel with cyclohexane

to aﬀord 1.80 g of the title compound (85%, 8.5 mmol) as a colorless

oil. R_f= 0.75 (Cyclohexane/EtOAc 15%); IR (neat) ν_max2954, 2929,

2857, 1471, 1463, 1361, 1253, 1104, 1058, 1004, 938, 832, 776 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 0.07 (s, 6 H), 0.90 (s, 9 H), 1.87 (s, 3

H), 3.13 (s, 1 H), 4.36 (d, 2 H, J = 6.3 Hz), 5.85 (t, 1 H, J = 6.3 Hz);

¹³C NMR (75 MHz, CDCl₃) δ −5.1, 18.3, 22.8, 26.0, 62.1, 81.8, 82.0,

1

2984, 2924, 2851, 1590, 1453, 1377, 1292, 1150, 832, 732, 695; H

NMR (300 MHz, CDCl₃) δ 1.56 (s, 6 H), 1.89 (dd, 3 H, J = 1.3 Hz,

1.3 Hz), 4.63 (s, 2 H), 5.20−5.24 (m, 1 H), 5.25−5.29 (m, 1 H),

7.14−7.64 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 23.6, 29.0, 66.6,

71.0, 72.2, 85.7, 90.6, 121.8, 127.4, 127.8, 128.4, 139.3.

1-Benzyloxy-1-(3-methylbut-3-en-1-ynyl)-cyclopentane (Ce). Pre-

pared following the general procedure 4 in 91% yield (830 mg) from

571 mg of A4. Colorless liquid; R_f= 0.64 (Cyclohexane/EtOAc 20%);

IR (neat) ν _max2955, 2870, 1613, 1495, 1453, 1372, 1291, 1201, 1084,

1051, 1027, 894, 731, 694; ¹H NMR (300 MHz, CDCl₃) δ 0.71−1.85

(m, 4 H), 1.90 (s, 3 H), 1.89−2.00 (m, 2 H), 2.07−2.18 (m, 2 H), 4.60

(s, 2 H), 5.22 (quint, 1 H, J = 1.7 Hz), 5.26−5.30 (m, 1 H), 7.22−7.42

(m, 5 H); ¹³C NMR (75 MHz, CDCl₃) δ 23.4, 23.6, 39.7, 67.0, 80.9,

86.3, 90.0, 121.5, 126.8, 127.3, 127.7, 129.3, 139.2.

(Z)-6-(Benzyloxy)-1-(tert-butyl)dimethylsilyloxy-3-methylhex-2-

en-4-yne (Cg). Prepared following the general procedure 4 in 99%

yield (1.50 g) from 1.10 g of A5. Colorless oil; R_f= 0.70

117.7, 138.6.

(Z)-6-(tert-Butyldimethylsilyloxy)-4-methylhex-4-en-2-yn-1-ol

(A5). Prepared following the general procedure 3 in 63% yield (1.25 g)

from 1.75 g of (Z)-1-tert-Butyldimethylsilyloxy-3-methylpent-2-en-4-

yne and 262 mg of p-formaldehyde. Pale-yellow oil; R_f= 0.44

(Cyclohexane/EtOAc 25%); IR (neat) ν_max3343, 2953, 2856, 1471,

1462, 1379, 1360, 1253, 1198, 1110, 1065, 1034, 1002, 938, 832, 812,

774; ¹H NMR (300 MHz, CDCl₃) δ 0.08 (s, 6 H), 0.90 (s, 9 H), 1.78

(broad, 1 H, −OH), 1.85 (s, 3 H), 4.34 (dd, 2 H, J = 6.4, 1.2 Hz), 4.41

(d, 2 H, J = 4.7 Hz), 5.79 (dt, 1 H, J = 6.4, 1.5 Hz); ¹³C NMR (75

MHz, CDCl₃) δ −5.1, 18.3, 23.0, 26.0, 51.5, 62.1, 84.0, 91.9, 118.2,

137.2.

3-(Cyclohex-1-enyl)prop-2-yn-1-ol (A6). Prepared following the

general procedure 3 in 72% yield (2.03 g) from 2.1 g of 1-

ethynylcyclohexene and 732 mg of p-formaldehyde. Pale-yellow oil; R_f

= 0.20 (Cyclohexane/EtOAc 20%); IR (neat) ν _max3317, 3026, 2926,

2857, 2834, 2218, 1631, 1434, 1346, 1270, 1206, 1135, 1017, 975, 918,

844, 799; ¹H NMR (300 MHz, CDCl₃) δ 1.54−1.61 (m, 4 H), 1.74 (s,

(Cyclohexane/EtOAc 20%); IR (neat) ν

2952, 2928, 2884, 2855,

max

1

1471, 1452, 1352, 1253, 1084, 1066, 1028, 1004, 938, 833, 775; H

NMR (300 MHz, CDCl₃) δ 0.09 (s, 6 H), 0.91 (s, 9 H), 1.89 (s, 3 H),

4.34 (s, 2 H), 4.39 (d, 2 H, J = 6.5 Hz), 4.63 (s, 2 H), 5.82 (t, 1 H, J =

6.4 Hz), 7.30−7.37 (m, 5 H); ¹³C NMR (75 MHz, CDCl₃) δ −5.0,

18.4, 23.0, 26.0, 57.8, 62.3, 71.5, 84.9, 89.8, 118.2, 127.9, 128.1, 128.4,

137.3, 137.5.

[1-(3-Benzyloxy)prop-1-ynyl]cyclohex-1-ene (Ch). Prepared fol-

lowing the general procedure 4 in 77% yield (1.69 g) from 1.32 g of

A6. Colorless liquid; R_f= 0.53 (Cyclohexane/EtOAc 20%); IR (neat)

1

ν

2927, 2853, 1453, 1348, 1205, 1070, 918, 734, 696; H NMR

max

(300 MHz, CDCl₃) δ 1.55−1.68 (m, 4 H), 2.05−2.18 (m, 4 H), 4.30

(s, 2 H), 4.62 (s, 2 H), 6.15 (quint, 1 H, J = 2.0 Hz), 7.26−7.39 (m, 5

H); ¹³C NMR (75 MHz, CDCl₃) δ 21.5, 22.3, 25.6, 29.2, 58.0, 71.4,

82.5, 88.6, 120.5, 127.8, 128.1, 128.4, 135.4, 138.0.

4336

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1

1-Methoxy-3-(((4-methylpent-4-en-2-yn-1-yl)oxy)methyl)-

benzene (Co). Prepared following the general procedure 4 in 86%

yield (465 mg) from 240 mg of A1 and 484 mg of 3-methoxybenzyl

chloride. Pale-yellow oil ; R_f= 0.34 (Pentane/Et₂O 5%); IR (neat) ν

_max2944, 2837, 1586, 1489, 1455, 1351, 1263, 1154, 1084, 1050, 898,

3394, 2920, 2851, 1512, 1445, 1351, 1068, 981, 905, 732, 696; H

NMR (300 MHz, CDCl₃) δ 1.45−1.52 (m, 3H), 1.58−1.70 (m, 8H),

1.88−1.98 (m, 4H), 4.22 (s, 2H), 4.60 (s, 2H), 7.27−7.40 (m, 5H);

¹³C NMR (75 MHz, CDCl₃) δ 22.1, 24.4, 27.9, 38.1, 57.4, 71.3, 71.4,

78.9, 91.3, 127.8, 128.1, 128.4, 137.5.

Step 2: To a solution of propargylic alcohol (2 mmol) in pyridine

(10 mL) was added dropwise phosphorus oxychloride at 0 °C, while

stirring under argon. After 20 min, the ice bath was removed and the

mixture was allowed to stir at room temperature for 6 h. The reaction

was quenched by slow addition of water (10 mL) at 0 °C, then the

whole mixture was extracted with EtOAc (2× 10 mL). The organic

layer was washed with 1N HCl (20 mL), water (20 mL) and brine (20

mL), dried over MgSO₄, then ﬁltered and concentrated under reduced

pressure. The residue was then puriﬁed by ﬂash chromatography

(Cyclohexane/EtOAc) to aﬀord the title compound.

780, 692; ¹H NMR (300 MHz, CDCl₃) δ 1.91 (m, 3H), 3.81 (s, 3H),

4.29 (s, 2H), 4.59 (s, 2H), 5.25 (dq, 1H, J = 1.6 Hz, 1.6 Hz), 5.33 (s,

1H), 6.82−6.87 (m, 1H), 6,92−6.96 (m, 2H), 7.23−7.29 (m, 1H); ¹³C

NMR (75 MHz, CDCl₃) δ 23.4., 55.3, 57.8, 71.5, 84.0, 87.7, 113.3,

113.6, 120.3, 122.3, 126.3, 129.5, 139.1, 159.8.

1-Chloro-3-(((4-methylpent-4-en-2-yn-1-yl)oxy)methyl)benzene

(Cp). Prepared following the general procedure 4 in 91% yield (840

mg) from 400 mg of A1 and 1.057 g of 3-chlorobenzyl bromide.

Colorless oil; R_f= 0.60 (Pentane/Et₂O 5%); IR (neat) ν

2850,

max

1

1575, 1431, 1350, 1289; 1204, 1079, 896, 778, 681; H NMR (300

MHz, CDCl₃) δ 1.91 (s, 3H), 4.31 (s, 2H), 4.58 (s, 2H), 5.24−5.29

(m, 1H), 5.30−5.35 (s, 1H), 7.20−7.25 (m, 1H), 7.27−7.32 (m, 2H),

7.35−7.39 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 23.4, 58.1, 70.8,

83.7, 88.0, 126.0, 126.2, 127.9, 128.0, 129.7, 134.4, 139.7.

1-(3-(Benzyloxy)prop-1-yn-1-yl)cyclohept-1-ene (Ci). Prepared in

62% yield (284 mg) from 500 mg of 1-(3-(benzyloxy)prop-1-yn-1-

yl)cycloheptanol. Yellow oil; R_f= 0.54 (Cyclohexane/EtOAc 20%); IR

1

(neat) ν

2926, 1715, 1620, 1452, 1069, 736, 697; H NMR (300

max

(5-Methylhex-5-en-3-yn-1-yl)benzene (Cs). Prepared following the

general procedure 4 in 89% yield (1.260 g) from 577 mg of A1 and

1165 mg of 1-chloromethylnaphtalene. Colorless oil; R_f= 0.56

MHz, CDCl₃) δ 1.45−1.69 (m, 4H), 1.70−1.80 (m, 2H), 2.14−2.28

(m, 2H), 2.32−2.36 (m, 2H), 4.29 (s, 2H), 4.61 (s, 2H), 6.32 (t, 1H, J

= 6.5 Hz), 7.21−7.40 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 26.5,

26.6, 29.2, 32.1, 34.2, 58.1, 71.5, 82.2, 90.0, 126.3, 127.8, 128.1, 128.4,

137.7, 140.5.

(E)-1-(3-(Benzyloxy)prop-1-yn-1-yl)cyclooct-1-ene (Cj). Prepared

in 79% yield (662 mg) from 500 mg of 1-(3-(benzyloxy)prop-1-yn-1-

yl)cyclooctanol. This compound was found to be very unstable, and

was readily used for the next aziridination step leading to 1j without

further puriﬁcation. Yellow oil; R_f= 0.54 (Cyclohexane/EtOAc 20%);

¹H NMR (300 MHz, CDCl₃) δ 1.46−1.56 (m, 5H), 1.62−1.71 (m,

(Cyclohexane/EtOAc 20%); IR (neat) ν

2851, 1610, 1520, 1354,

max

1288, 1088, 895, 791, 774; ¹H NMR (300 MHz, CDCl₃) δ 1.95 (t, 3H,

J = 1.4 Hz), 4.35 (s, 2H), 5.07 (s, 2H), 5.28 (quint, 1H, J = 1.4 Hz),

5.36 (s, 1H), 7.44 (dd, 1H, J = 7.3 Hz, 8.0 Hz), 7.49−7.58 (m, 3H),

7.82−7.89 (m, 2H), 8.20 (d, 1H, J = 8.3 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ 23.4, 57.9, 69.9, 84.2, 87.9, 122.3, 124.1, 125.2, 126.3, 126.4,

127.1, 128.5, 128.9, 131.9, 133.0, 133.8.

5-(Naphth-2-yl)methyloxy-2-methylpent-1-en-3-yne (Ct). Pre-

pared following the general procedure 4 in 99% yield (1.060 g)

from 439 mg of A1. Colorless liquid; R_f= 0.56 (Cyclohexane/EtOAc

20%); IR (neat) ν _max3040, 2929, 2856, 1083, 894, 814, 749, 474; ¹H

NMR (300 MHz, CDCl₃) δ 1.94 (dd, 3 H, J = 1.3 Hz, 1.3 Hz), 4.35 (s,

2 H), 4.80 (s, 2 H), 5.28 (quint, 1 H, J = 1.3 Hz), 5.36 (s, 1 H), 7.49

(d, 1 H, J = 9.5 Hz), 7.42−7.55 (m, 2 H), 7.84 (s, 1 H), 7.82−7.87 (m,

2 H), 7.85 (d, 1 H, J = 9.5 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 23.5,

57.9, 71.7, 84.1, 87.8, 122.4, 126.0, 126.1, 126.5, 127.0, 127.7, 127.9,

128.2, 128.8, 133.1, 133.3, 135.0.

3H), 2.14−2.22 (m, 2H), 2.29−2.35 (m, 2H), 4.29 (s, 2H), 4.61 (s,

2H), 6.12 (t, 1H, J = 8.4 Hz), 7.23−7.40 (m, 5H).

Enynyl Benzyl Malonates were all prepared by alkylation of the

following precursor D. Diethyl 2-(4-methylpent-4-en-2-yn-1-yl)-

malonate (D). Prepared following the general procedure 5 for

Sonogashira-type coupling (see below) in 74% yield (1255 mg)

from 1.400 g of diethyl 2-(prop-2-yn-1-yl)malonate.³⁴Yellow

oil; R_f= 0.44 (Cyclohexane/EtOAc 20%); IR (neat) ν _max2974,

1

1731, 1596, 1412, 1375, 1231, 1151, 1032; H NMR (300

d₇-5-Benzyloxy-2-methylpent-1-en-3-yne (Cu). Prepared following

the general procedure 4 in 84% yield (1.12 g) from 660 mg of A1 and

1.465 g of d₇-benzyl bromide.³²Colorless oil; R_f= 0.39 (Pentane/Et₂O

MHz, CDCl₃) δ 1.28 (t, 6H, J = 7.1 Hz), 1.83 (s, 3H), 2.89 (d,

2H, J = 7.7 Hz), 3.56 (t, 1H, J = 7.7 Hz), 4.22 (q, 4H, J = 7.1

Hz), 5.15 (quint, 1H, J = 1.6 Hz), 5.18−5.21 (m, 1H); ¹³C

NMR (75 MHz, CDCl₃) 14.1, 19.3, 23.5, 51.5, 61.7, 83.7, 84.4,

121.3, 126.7, 168.0; HR-MS 261.112 (C₁₃H₁₈O₄+ Na calcd

261.110).

Diethyl 2-benzyl-2-(4-methylpent-4-en-2-yn-1-yl)malonate (Cl).

Prepared following the general procedure 4 in 85% yield (286 mg)

from 245 mg of D. Colorless oil; R_f= 0.50 (Cyclohexane/EtOAc

20%); IR (neat) ν _max2984, 1733, 1571, 1470, 1275, 1179, 1085, 1058,

701; ¹H NMR (300 MHz, CDCl₃) δ 11.26 (t, 6H, J = 7.1 Hz), 1.86−

1.92 (m, 3H), 2.78 (s, 2H), 3.40 (s, 2H), 4.21 (q, 4H, J = 7.0 Hz), 5.20

(qt, 1H, J = 1.6 Hz), 5.24−5.30 (m, 1H), 7.35−7.15 (m, 5H); ¹³C

NMR (75 MHz, CDCl₃) δ 14.1, 23.0, 23.7, 37.5, 58.5, 61.7, 83.8, 85.5,

121.8, 126.8, 127.1, 128.4, 129.9, 135.8, 169.8; HR-MS 351.157

(C₂₀H₂₄O₄+ Na calcd 351.157).

5%); IR (neat) ν

2845, 1613, 1356, 1289, 1206, 1181, 1095, 898,

max

1

539; H NMR (300 MHz, CDCl₃) δ 11.93 (s, 3H), 4.30 (s, 2H),

5.24−5.31 (m, 1H), 5.32−5.39 (m, 1H); ¹³C NMR (75 MHz, CDCl₃)

δ 23.4, 57.7, 70.6 (m), 84.1, 87.7, 122.3, 126.3, 127.4 (m), 127.6 (m),

127.8 (m), 137.5.

Ethers Ci and Cj Were Prepared in Two Steps. Step 1: To a

solution at −78 °C under argon of n-BuLi (1.6 M in hexanes, 5.25

mmol) in THF (10 mL) was added ((prop-2-yn-1-yloxy)methyl)-

benzene³³(5 mmol). The resulting reaction mixture was stirred at the

same temperature for 30 min, and the ketone (5.5 mmol) was then

added at −78 °C. The reaction mixture was then allowed to reach

room temperature and was stirred further until completion of reaction

as monitored by TLC. The mixture was quenched with aqueous

NH₄Cl (5 mL) and extracted twice with Et₂O (20 mL). The combined

organic layers were dried over MgSO₄. After ﬁltration and evaporation,

the crude product was puriﬁed by ﬂash chromatography (Cyclo-

hexane/EtOAc) to aﬀord the title compound.

Diethyl 2-(4-Methoxybenzyl)-2-(4-methylpent-4-en-2-yn-1-yl)-

malonate (Cq). Prepared following the general procedure 4 in 91%

yield (600 mg) from 438 mg of D. Colorless oil; R_f= 0.43

(Cyclohexane/EtOAc 20%); IR (neat) ν

2979, 1733, 1587, 1512,

max

1

1-(3-(Benzyloxy)prop-1-yn-1-yl)cycloheptanol. Prepared in 84%

yield (1.180 g) from 800 mg of ((prop-2-yn-1-yloxy)methyl)benzene.

1277, 1248, 1176, 1036, 842; H NMR (300 MHz, CDCl₃) δ 1.27 (t,

6H, J = 7.1 Hz), 1.87−1.92 (m, 3H), 2.77 (s, 2H), 3.33 (s, 2H), 3.77

(s, 3H), 4.21 (q, 4H, J = 7.0 Hz), 5.17−5.21 (m, 1H), 5.23−5.29 (m,

1H), 6.80 (d, 2H, J_AB= 8.5 Hz), 7.08 (d, 2H, J_AB= 8.5 Hz); ¹³C NMR

(75 MHz, CDCl₃) δ 14.1, 22.9, 23.7, 36.6, 55.2, 58.5, 61.7, 83.9, 85.5,

113.8, 121.4, 126.8, 127.7, 130.9, 158.7, 169.9; HR-MS 381.165

(C₂₁H₂₆NO₅+ Na calcd 381.167).

Colorless oil; R_f= 0.42 (Cyclohexane/EtOAc 30%); IR (neat) ν

3394, 2925, 2854, 1640, 1454, 1349, 1068, 1026, 736, 696; H NMR

max

1

(300 MHz, CDCl₃) δ 1.50−1.75 (m, 8H), 1.81−1.92 (m, 2H), 1.87 (s,

1H), 2.01−2.06 (m, 2H), 4.23 (s, 2H), 4.60 (s, 2H), 7.26−7.37 (m,

5H); ¹³C NMR (75 MHz, CDCl₃) δ 22.7, 28.5, 43.6, 58.1, 72.0, 72.3,

79.6, 91.9, 128.3, 128.6, 128.9, 138.0.

1-(3-(Benzyloxy)prop-1-yn-1-yl)cyclooctanol. Prepared in 80%

yield (1.184 g) from 800 mg of ((prop-2-yn-1-yloxy)methyl)benzene.

Diethyl 2-(4-Chlorobenzyl)-2-(4-methylpent-4-en-2-yn-1-yl)-

malonate (Cr). Prepared following the general procedure 4 in 82%

yield (547 mg) from 438 mg of D. Colorless oil; R_f= 0.56

Colorless oil; R_f= 0.39 (Cyclohexane/EtOAc 20%); IR (neat) ν

(Cyclohexane/EtOAc 20%); IR (neat) ν

2979, 1733, 1586, 1496,

max

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The Journal of Organic Chemistry

Article

1268, 1177, 1041, 848; ¹H NMR (300 MHz, CDCl₃) δ 1.26 (t, 6H, J =

7.0 Hz), 1.87−1.91 (m, 3H), 2.76 (s, 2H), 3.35 (s, 2H), 4.21 (q, 4H, J

2-(3-(Benzyloxy)prop-1-ynyl)-2-methyl-1-tosylaziridine (1a). Pre-

pared following the general procedure 6 in 48% yield (455 mg) from

500 mg of Ca. Pale-yellow oil; R_f= 0.24 (Cyclohexane/EtOAc 20%);

IR (neat) ν _max3040−2860, 2240, 1598, 1450, 1325, 1159, 1087, 1068,

868, 694, 571; ¹H NMR (300 MHz, CDCl₃) δ 1.63 (s, 3 H), 2.43 (s, 3

H), 2.45 (s, 1 H), 2.92 (s, 1 H), 4.20 (s, 2 H), 4.63 (s, 2 H), 7.23−7.38

(m, 7 H), 7.86 (d, 2 H, J = 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ

21.6, 23.7, 38.0, 41.8, 57.2, 71.6, 80.8, 83.2, 127.8, 128.3, 128.4, 129.6,

131.3, 136.7, 137.4, 144.3; HR-MS 378.109 (C₂₀H₂₁NO₃S + Na calcd

378.113).

= 7.0 Hz), 5.20−5.23 (m, 1H), 5.24−5.29 (m, 1H), 7.10 (d, 2H, J_AB

=

8.4 Hz), 7.24 (d, 2H, J_AB= 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ

14.1, 23.0, 23.6, 36.8, 58.3, 61.8, 83.5, 85.7, 121.5, 126.6, 128.5, 131.3,

133.1, 134.3, 169.6; HR-MS 385.119 (C₂₀H₂₃ClO₄+ Na calcd

385.118).

General Procedure 5 for the Coupling of Alkynes with Vinyl

Halides. To a solution of the alkyne (4 mmol) in dry and degassed

THF (10 mL) were added copper(I) iodide (6 mol %) and

Pd(PPh₃)₂Cl₂(3 mol %) while stirring under argon. Diisopropylamine

(16 mmol) and the vinyl halide (5 mmol) were then added, and the

solution was heated at 50 °C until completion as monitored by TLC.

Volatile compounds were then removed in vacuo. The residue was

dissolved in Et₂O (15 mL) and washed with 1N HCl (20 mL), water

(2× 20 mL) and brine (20 mL). The organic layer was then dried over

MgSO₄. After ﬁltration and evaporation, the crude product was

puriﬁed by ﬂash chromatography (cyclohexane/EtOAc) to aﬀord the

title compound.

2-(3-(Benzyloxy)prop-1-ynyl)-2-methyl-1-(4-nitrophenylsulfonyl)-

aziridine (1b). Prepared following the general procedure 6 in 36%

yield (260 mg) from 366 mg of Ca. Pale-yellow oil; R_f= 0.22

(Cyclohexane/EtOAc 20%); IR (neat) ν

2925, 2851, 1530, 1346,

max

1165, 1087, 1010, 854, 791, 740, 686; ¹H NMR (300 MHz, CDCl₃) δ

1.67 (s, 3 H), 2.53 (s, 1 H), 3.00 (s, 1 H), 4.20 (s, 2 H), 4.62 (s, 2 H),

7.25−7.38 (m, 5 H), 8.17 (d, 2 H, J = 8.6 Hz), 8.35 (d, 2 H, J = 8.6

Hz); ¹³C NMR (75 MHz, CDCl₃) δ 23.8, 30.9, 42.6, 57.1, 71.7, 81.6,

82.4, 124.2, 128.0, 128.3, 128.5, 129.2, 137.2, 145.1, 150.5; HR-MS

409.080 (C₁₉H₁₈N₂O₅S + Na calcd 409.083).

((5-(Benzyloxy)-2-methylenepent-3-yn-1-yl)oxy)(tert-butyl)-

dimethylsilane (Cf). Prepared following the general procedure 5 in

76% yield (1.320 g) from 800 mg of ((prop-2-yn-1-yloxy)methyl)-

benzene and 2120 mg of tert-butyl((2-iodoallyl)oxy)dimethylsilane.³⁵

2-(3-(Benzyloxy)non-1-ynyl)-2-methyl-1-tosylaziridine (1c). Pre-

pared following the general procedure 6 in 48% yield (311 mg, dr 1:1)

from 400 mg of Cc. Mixture of diastereoisomers: pale-yellow oil; R_f=

Colorless oil; R_f= 0.44 (Pentane/Et₂O 5%); IR (neat) ν

2954,

max

0.34 (Cyclohexane/EtOAc 20%); IR (neat) ν

2959, 2927, 2855,

max

1

2935, 2855, 1455, 1252, 1093, 834, 777, 736, 696; H NMR (300

MHz, CDCl₃) δ 0.09 (s, 6H), 0.92 (s, 9H), 4.16 (t, 2H, J = 1.7 Hz),

4.30 (s, 2H), 4.61 (s, 2H), 5.49 (dt, 1H, J = 1.7, 1.7 Hz), 5.62 (dt, 1H,

J = 1.7, 1.7 Hz), 7.28−7.36 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ

−5.3, 18.4, 25.9, 57.8, 65.0, 71.7, 84.6, 86.1, 119.9, 127.9, 128.1, 128.5,

130.4, 139.5.

1465, 1328, 1160, 1088, 814, 732, 693, 549; H NMR (300 MHz,

CDCl₃) δ 0.87 (t, 3 H, J = 6.4 Hz), 1.20−1.32 (m, 6 H), 1.39−1.48

(m, 2 H), 1.63 (s, 3 H), 1.66−1.80 (m, 2 H), 2.43 (s, 3 H), 2.44 (s, 1

H), 2.93 (s, 1 H), 4.10 (t, 1 H, J = 6.6 Hz), 4.53 (d, 1 H, J_ab= 11.6

Hz), 4.79 (dd, 1 H, J_ab= 11.6 Hz, 6.4 Hz), 7.31 (d, 2 H, J = 11.6 Hz),

7.22−7.44 (m, 5 H), 7.87 (d, 2 H, J = 8.3 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ 14.1, 21.6, 22.6, 24.0, 25.2, 29.0, 31.7, 35.5, 38.1, 41.8, 68.6,

70.6, 82.4, 84.3, 127.6, 127.8, 128.1, 128.4, 129.6, 136.8, 138.1, 144.3;

HR-MS 462.204 (C₂₆H₃₃NO₃S + Na calcd 462.207).

N-Benzyl-N-tosyl-4-methylpent-4-en-2-yn-1-amine (Ck). Prepared

following the general procedure 5 in 76% yield (783 mg) from 913 mg

of N-benzyl-N-tosylprop-2-yn-1-amine.^22bOrange solid: mp = 48 °C;

R_f= 0.52 (Cyclohexane/EtOAc 30%); IR (neat) ν

3010−2870,

max

2-(3-(Benzyloxy)-3-methylbut-1-ynyl)-2-methyl-1-tosylaziridine

(1d). Prepared following the general procedure 6 in 44% yield (552

mg) from 647 mg of Cd. Pale-yellow oil; R_f= 0.27 (Cyclohexane/

1590, 1385, 1325, 1164, 1120, 1091, 895, 815, 769, 730, 699, 654, 571;

¹H NMR (300 MHz, CDCl₃) δ 1.63 (dd, 3H, J = 1.3 Hz, 1.3 Hz), 2.41

(s, 3H), 4.03 (s, 2H), 4.32 (s, 2H), 4.94−5.00 (m, 1H), 5.09−5.14 (m,

1H, J = 1.6 Hz), 7.30 (d, 2H, J = 8.3 Hz), 7.27−7.40 (m, 5H), 7.78 (d,

2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.9, 23.5, 36.8, 50.4,

81.0, 87.6, 122.5, 126.3, 128.3, 128.5, 129.1, 129.2, 129.9, 135.5, 136.4,

143.9.

EtOAc 20%); IR (neat) ν

2983, 2930, 2861, 1724, 1453, 1328,

max

1158, 1087, 1059, 814, 664, 550; ¹H NMR (300 MHz, CDCl₃) δ 1.55

(s, 6 H), 1.61 (s, 3 H), 2.42 (s, 3 H), 2.43 (s, 1 H), 2.91 (s, 1 H), 4.64

(s, 2 H), 7.21−7.42 (m, 7 H), 7.86 (d, 2 H, J = 8.2 Hz); ¹³C NMR (75

MHz, CDCl₃) δ 21.7, 24.0, 28.7, 38.1, 41.9, 66.7, 70.6, 81.2, 87.0,

127.3, 127.8, 127.9, 128.3, 129.6, 137.0, 139.2, 144.3; HR-MS 390.173

(C₂₂H₂₅NO₃S + Li calcd 390.171).

7-Phenyl-2-methylhept-1-en-3-yne (Cm). Prepared following the

general procedure 5 in 88% yield (900 mg) from 800 mg of

commercially available 5-phenyl-1-pentyne and 925 mg of 2-

bromopropene. Orange oil; R_f= 0.60 (Cyclohexane/EtOAc 20%);

IR (neat) ν _max2940, 1604, 1495, 1453, 890, 742, 697; ¹H NMR (300

MHz, CDCl₃) δ 1.70 (s, 3H), 1.81−1.91 (m, 2H), 2.32 (t, 2H, J = 7.1

Hz), 2.74 (t, 2H, J = 7.5 Hz), 5.16 (s, 1H), 5.23 (s, 1H), 7.17−7.25

(m, 3H), 7.25−7.33 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 18.7,

23.9, 30.3, 34.8, 82.4, 88.9, 120.5, 125.9, 127.3, 128.4, 128.5, 141.7.

(5-Methylhex-5-en-3-yn-1-yl)benzene (Cn). Prepared following the

general procedure 5 in 78% yield (517 mg) from 500 mg of

commercially available 4-phenyl-1-butyne and 581 mg of 2-

2-((1-(Benzyloxy)cyclopentyl)ethynyl)-2-methyl-1-tosylaziridine

(1e). Prepared following the general procedure 6 in 45% yield (311

mg) from 400 mg of Ce. Pale-yellow oil; R_f= 0.37 (Cyclohexane/

EtOAc 20%); IR (neat) ν

2976, 2947, 2848, 1595, 1446, 1381,

max

1324, 1085, 1061, 1022, 923, 902, 817, 732, 693; ¹H NMR (300 MHz,

CDCl₃) δ 1.60 (s, 3 H), 1.66−1.83 (m, 4 H), 1.88−2.16 (m, 4 H),

2.42 (s, 1 H), 2.43 (s, 3 H), 2.93 (s, 1 H), 4.61 (s, 2 H), 7.21−7.39 (m,

5 H), 7.31 (d, 2 H, J = 8.3 Hz), 7.86 (d, 2 H, J = 8.3 Hz); ¹³C NMR

(75 MHz, CDCl₃) δ 21.6, 23.4, 24.1, 38.2, 39.4, 41.9, 67.2, 80.6, 81.6,

86.6, 126.2, 127.3, 127.7, 127.8, 129.6, 136.9, 139.1, 144.2; HR-MS

432.163 (C₂₄H₂₇NO₃S + Na, calcd 432.160).

bromopropene. Yellow oil; R_f= 0.61 (Cyclohexane/EtOAc 20%); IR

1

(neat) ν

2940, 1572, 1453, 1277, 892, 748, 695, 499; H NMR

2-(3-(Benzyloxy)prop-1-yn-1-yl)-2-(((tert-butyldimethylsilyl)oxy)-

methyl)-1-tosylaziridine (1f). Prepared following the general

procedure 6 in 34% yield (315 mg) from 600 mg of Cf. Pale-yellow

oil; R_f= 0.27 (Cyclohexane/EtOAc 20%); IR (neat) ν _max2927, 2855,

1329, 1252, 1161, 1087, 835, 779, 732, 696, 548; ¹H NMR (300 MHz,

CDCl₃) δ −0.05 (s, 3H), −0.01 (s, 3H), 0.78 (s, 9H), 2.38 (s, 3H),

2.54 (s, 1H), 2.91 (s, 1H), 3.77 (s, 2H), 4.19 (s, 2H), 4.61 (s, 2H),

7.25 (d, 2H, J = 8.1 Hz), 7.21−7.39 (m, 5H), 7.81 (d, 2H, J = 8.1 Hz);

¹³C NMR (75 MHz, CDCl₃) δ −5.4, −5.3, 18.3, 21.6, 25.7, 37.2, 41.5,

57.2, 65.1, 71.4, 80.0, 83.5, 127.8, 128.0, 128.3, 128.4, 129.5, 136.4,

137.4, 144.3; HR-MS 508.195 (C₂₆H₃₅NO₄SSi + Na calcd 508.195).

2-(3-(Benzyloxy)prop-1-ynyl)-3-((tert-butyldimethylsilyloxy)-

methyl)-2-methyl-1-tosylaziridine (1g). Prepared following the

general procedure 6, in 17% yield (250 mg) from 700 mg of Cg.

max

(300 MHz, CDCl₃) δ 1.86 (t, 3H, J = 1.1 Hz), 2.58 (t, 2H, J = 7.4 Hz),

2.86 (t, 2H, J = 7.4 Hz), 5.14 (dq, 1H, J = 1.7 Hz), 5.20 (s, 1H), 7.18−

7.33 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 21.2, 23.4, 34.8, 82.2,

88.1, 120.1, 125.9, 126.8, 127.9, 128.1, 140.3.

General Procedure 6 for Aziridination of Enyne.^15aTo a

solution of enyne ether (2 mmol) in acetonitrile (10 mL) were added

[Cu(MeCN)₄]ClO₄(0.1 mmol) and 4 Å molecular sieves (500 mg).

TsN = IPh (or NsN = IPh in the case of 1b, 2.2 mmol) was added by

portions under argon over 3 h, the reaction was then monitored by

thin-layer chromatography and stopped before complete conversion of

the starting material (ca. 2 h for TsN = IPh, 5 h for NsN = IPh) to

avoid degradation. The solution was ﬁltrated, concentrated in vacuo

and the crude residue was puriﬁed by ﬂash chromatography

(Cyclohexane/EtOAc) to aﬀord the title compound. Starting material

could also be recovered.

Colorless oil; R_f= 0.5 (Cyclohexane/EtOAc 20%); IR (neat) ν

max

2952, 2928, 2883, 2856, 1680, 1455, 1357, 1328, 1303, 1253, 1224,

4338

dx.doi.org/10.1021/jo300294r | J. Org. Chem. 2012, 77, 4323−4341

The Journal of Organic Chemistry

Article

1

1159, 1087, 1026, 1006, 966, 897, 833, 777; H NMR (300 MHz,

CDCl₃) δ −0.04 (s, 3 H), −0.01 (s, 3 H), 0.83 (s, 9 H), 1.99 (s, 3 H),

2.42 (s, 3 H), 3.17 (dd, 1 H, J = 6.3, 5.3 Hz), 3.59 (dd, 1 H, J = 11.2,

6.5 Hz), 3.81 (dd, 1 H, J = 11.2, 5.3 Hz), 4.17 (s, 2 H), 4.55 (s, 2 H),

7.30−7.37 (m, 7 H), 7.86 (d, 2 H, J = 8.2 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ −5.61, 18.1, 20.3, 21.5, 43.8, 52.4, 57.2, 62.3, 71.6, 79.4,

83.5, 127.5, 127.9, 128.0, 128.4, 129.4, 137.1, 137.5, 144.0; HR-MS

522.210 (C₂₇H₃₇NO₄SSi + Na calcd 522.209).

NMR (300 MHz, CDCl₃) δ 1.63 (s, 3H), 1.78−1.89 (m, 2H), 2.22 (t,

2H, J = 7.0 Hz), 2.43 (s, 3H), 2.44 (s, 1H), 2.74 (t, 2H, J = 7.0 Hz),

2.87 (s, 1H), 7.22 (m, 5H), 7.31 (d, 2H, J = 8.3 Hz), 7.86 (d, 2H, J =

8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 18.3, 21.6, 24.2, 30.0, 34.7,

35.0, 42.0, 77.3, 85.3, 125.9, 127.8, 128.4, 128.6, 129.5, 137.0, 141.6,

144.1; HR-MS 376.132 (C₂₁H₂₃NO₂S + Na calcd 376.134).

2-Methyl-2-(4-phenylbut-1-yn-1-yl)-1-tosylaziridine (1n). Pre-

pared following the general procedure 6 in 59% yield (537 mg)

from 455 mg of Cn. Pale-yellow oil; R_f= 0.33 (Cyclohexane/EtOAc

1-(3-(Benzyloxy)prop-1-ynyl)-7-tosyl-7-azabicyclo[4.1.0]heptane

(1h). Prepared following the general procedure 6 in 57% yield (498

mg) from 500 mg of Ch. Pale-yellow oil; R_f= 0.34 (Cyclohexane/

EtOAc 20%); IR (neat) ν _max2937, 2855, 1325, 1154, 1089, 958, 916,

20%); IR (neat) ν

2930, 1587, 1324, 1157, 1088, 813, 749, 699,

max

662, 548 ; ¹H NMR (300 MHz, CDCl₃) δ 1.60 (s, 3H), 2.43 (s, 1H),

2.44 (s, 3H), 2.50 (t, 2H, J = 7.6 Hz), 2.81 (s, 1H), 2.84 (t, 2H, J = 7.6

Hz), 7.20−7.24 (m, 2H), 7.26−7.33 (m, 3H), 7.32 (d, 2H, J = 8.3 Hz),

7.85 (d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.1, 21.6,

23.9, 34.7, 38.9, 41.9, 77.7, 84.8, 126.3, 127.8, 128.4, 128.5, 129.5,

136.9, 140.5, 144.1; HR-MS 362.119 (C₂₀H₂₁NO₂S + Na calcd

362.119).

1

810, 696, 672, 527; H NMR (300 MHz, CDCl₃) δ 1.10−1.41 (m, 4

H), 1.59−1.70 (m, 1 H), 1.84−1.97 (m, 2 H), 2.10−2.22 (m, 1 H),

2.42 (s, 3 H), 3.36 (dd, 1 H, J = 5.2 Hz, 1.1 Hz), 4.22 (s, 2 H); 4.64 (s,

2 H), 7.23−7.41 (m, 7 H), 7.65 (d, 2 H, J = 8.4 Hz); ¹³C NMR (75

MHz, CDCl₃) δ 19.1, 19.2, 21.6, 22.6, 31.3, 40.4, 46.8, 57.3, 71.5, 81.7,

83.4, 127.7, 127.8, 128.0, 128.4, 129.5, 137.2, 137.5, 143.9; HR-MS

418.141 (C₂₃H₂₅NO₃S + Na calcd 418.145).

2-(3-((3-Methoxybenzyl)oxy)prop-1-yn-1-yl)-2-methyl-1-tosyla-

ziridine (1o). Prepared following the general procedure 6 in 34% yield

(150 mg) from 250 mg of Co. Pale-yellow oil; R_f= 0.19

1-(3-(Benzyloxy)prop-1-yn-1-yl)-8-tosyl-8-azabicyclo[5.1.0]-

octane (1i). Prepared following the general procedure 6 in 30% yield

(140 mg) from 280 mg of Ci. Yellow oil; R_f= 0.24 (Cyclohexane/

(Cyclohexane/EtOAc 20%); IR (neat) ν

2935, 2836, 1596, 1489,

max

1

1454, 1324, 1264, 1158, 1086, 868, 785, 692, 549 ; H NMR (300

MHz, CDCl₃) δ 1.65 (s, 3H), 2.43 (s, 3H), 2.46 (s, 1H), 2.81 (s, 1H),

3.80 (s, 3H), 4.20 (s, 2H), 4.60 (s, 2H), 6.82−6.86 (m, 1H), 6.92−

6.99 (m, 2H), 7.26 (t, 1H, J = 8.0 Hz), 7.31 (d, 2H, J = 8.2 Hz), 7.86

(d, 2H, J = 8.2 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.7, 23.7, 38.1,

41.8, 55.3, 57.2, 71.5, 80.8, 83.2, 113.4, 113.8, 120.5, 127.8, 129.5,

129.6, 136.7, 137.0, 144.3, 159.8; HR-MS 408.124 (C₂₁H₂₃NO₄S + Na

calcd 408.124).

EtOAc 20%); IR (neat) ν

2925, 2851, 1585, 1471, 1326, 1158,

max

1

1088, 725, 699 ; H NMR (300 MHz, CDCl₃) δ 1.33−1.49 (m, 4H),

1.50−1.69 (m, 3H), 1.89−2.00 (m, 2H), 2.09−2.17 (m, 1H), 2.42 (s,

3H), 3.33 (dd, 1H, J = 7.4 Hz, 3.7 Hz), 4.23 (s, 2H), 4.65 (s, 2H), 7.29

(d, 2H, J = 7.9 Hz), 7.31−7.42 (m, 5H), 7.85 (d, 2H, J = 7.9 Hz); ¹³C

NMR (75 MHz, CDCl₃) δ 21.7, 25.0, 25.1, 28.4, 31.2, 36.2, 45.7, 51.4,

57.3, 71.4, 81.3, 87.0, 127.7, 127.8, 128.3, 128.4, 129.5, 137.2, 137.6,

143.9; HR-MS 432.161 (C₂₄H₂₇NO₃S + Na calcd 432.160).

1-(3-(Benzyloxy)prop-1-yn-1-yl)-9-tosyl-9-azabicyclo[6.1.0]-

nonane (1j). Prepared following the general procedure 6 in 37% yield

(248 mg) from 400 mg of Cj. Yellow oil; R_f= 0.37 (Cyclohexane/

EtOAc 30%); IR (neat) ν _max2925, 2841, 1471, 1324, 1155, 1089, 934,

2-(3-((3-Chlorobenzyl)oxy)prop-1-yn-1-yl)-2-methyl-1-tosylaziri-

dine (1p). Prepared following the general procedure 6 in 50% yield

(350 mg) from 400 mg of Cp. Pale-yellow oil; R_f= 0.27

(Cyclohexane/EtOAc 20%); IR (neat) ν

2851, 1597, 1325, 1159,

max

1

1085, 869, 783, 892, 549 ; H NMR (300 MHz, CDCl₃) δ 1.63 (s,

3H), 2.42 (s, 3H), 2.44 (s, 1H), 2.91 (s, 1H), 4.22 (s, 2H), 4.60 (s,

2H), 7.24−7.28 (m, 3H), 7.31 (d, 2H, J = 8.3 Hz), 7.38 (s, 1H), 7.83

(d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.6, 23.7, 37.9,

41.8, 57.5, 70.7, 80.5, 83.5, 126.2, 127.8, 127.9, 128.2, 129.6, 129.7,

134.3, 136.7, 139.6, 144.3; HR-MS 412.073 (C₂₀H₂₀ClNO₃S + Na

calcd 412.074).

1

714, 699, 565 ; H NMR (300 MHz, CDCl₃) δ 1.20−1.78 (m, 10H),

2.03 (ddt, 1H, J = 13.9 Hz, 3.5 Hz, 3.4 Hz), 2.17 (dt, 1H, J = 13.8 Hz,

3.3 Hz), 2.42 (s, 3H), 3.13 (dd, 1H, J = 11.3 Hz, 3.7 Hz), 4.25 (s, 2H),

4.66 (s, 2H), 7.28 (d, 2H, J = 8.3 Hz), 7.26−7.44 (m, 5H), 7.85 (d,

2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.8, 25.7, 26.0, 26.1,

26.1, 26.2, 32.3, 44.8, 51.6, 57.5, 71.6, 82.5, 82.7, 127.9, 128.0, 128.6,

128.6, 129.7, 137.1, 137.2, 144.2; HR-MS 446.172 (C₂₅H₂₉NO₃S + Na

calcd 446.176).

Diethyl 2-(4-methoxybenzyl)-2-(3-(2-methyl-1-tosylaziridin-2-yl)-

prop-2-yn-1-yl)malonate (1q). Prepared following the general

procedure 6 in 53% yield (308 mg) from 397 mg of Cq. Colorless

oil; R_f= 0.35 (Cyclohexane/EtOAc 30%); IR (neat) ν _max2979, 1731,

2-(N-Benzyl-N-tosyl-3-aminoprop-1-ynyl)-2-methyl-1-tosylaziri-

dine (1k). Prepared following the general procedure 6 in 52% yield

(390 mg) from 500 mg of (Ck). White solid: mp = 103−104 °C; R_f=

1

1584, 1506, 1335, 1249, 1160, 1032, 814, 633; H NMR (300 MHz,

0.42 (Cyclohexane/EtOAc 30%); IR (neat) ν

3080−2925, 1605,

CDCl₃) δ 1.26 (t, 6H, J = 7.1 Hz), 1.59−1.66 (m, 3H), 2.42 (s, 1H),

2.43 (s, 3H), 2.71 (s, 2H), 2.88 (s, 1H), 3.34 (s, 2H), 3.76 (s, 3H),

4.11−4.29 (m, 4H), 6.79 (d, 2H, J = 8.6 Hz), 7.11 (d, 2H, J = 8.6 Hz),

7.32 (d, 2H, J = 8.4 Hz), 7.86 (d, 2H, J = 8.4 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ 14.1, 21.6, 22.4, 24.1, 36.5, 38.3, 41.9, 55.2, 58.3, 61.7, 80.5,

80.9, 113.8, 127.6, 127.7, 129.6, 131.0, 136.9, 144.2, 158.6, 169.7; HR-

MS 550.186 (C₂₈H₃₃NO₇S + Na calcd 550.187).

max

1

1457, 1325, 1156, 1094, 899, 815, 766, 693, 665, 535; H NMR (300

MHz, CDCl₃) δ 1.37 (s, 3H), 2.24 (s, 1H), 2.42 (s + s, 3H + 3H), 2.50

(s, 1H), 3.91 (d, 1H, J_ab= 18.7 Hz), 4.03 (d, 1H, J_ab= 18.7 Hz), 4.37

(d, 1H, J_ab= 13.7 Hz), 4.46 (d, 1H, J_ab= 13.7 Hz), 7.25−7.37 (m, 7H),

7.39−7.45 (m, 1H), 7.44 (m, 1H), 7.79 (d, 2H, J = 8.3 Hz), 7.81 (d,

2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 21.5, 21.6, 23.4, 35.8,

37.4, 41.6, 49.9, 77.7, 82.5, 127.6, 127.8, 127.9, 128.6, 129.0, 129.5,

129.5, 135.1, 136.3, 136.7, 143.3, 144.4; HR-MS 531.137

(C₂₇H₂₈N₂O₂S + Na calcd 531.139).

Diethyl 2-(4-chlorobenzyl)-2-(3-(2-methyl-1-tosylaziridin-2-yl)-

prop-2-yn-1-yl)malonate (1r). Prepared following the general

procedure 6 in 70% yield (554 mg) from 542 mg of Cr. Colorless

oil; R_f= 0.39 (Cyclohexane/EtOAc 30%); IR (neat) ν _max2979, 1732,

Diethyl 2-benzyl-2-(3-(2-methyl-1-tosylaziridin-2-yl)prop-2-yn-1-

yl)malonate (1l). Prepared following the general procedure 6 in 52%

yield (212 mg) from 270 mg of Cl. Colorless oil; R_f= 0.24

1

1579, 1480, 1327, 1160, 1091, 1015, 815, 670 ; H NMR (300 MHz,

CDCl₃) δ 1.26 (t, 6H, J = 7.1 Hz), 1.62 (s, 3H), 2.40 (s, 1H), 2.43 (s,

3H), 2.71 (s, 2H), 2.90 (s, 1H), 3.39 (s, 2H), 4.11−4.29 (m, 4H), 7.16

(d, 2H, J = 8.5 Hz), 7.23 (d, 2H, J = 8.5 Hz), 7.32 (d, 2H, J = 8.3 Hz),

7.85 (d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.0, 21.6,

22.5, 24.3, 36.7, 38.1, 42.0, 58.2, 61.8, 77.5, 80.7, 127.7, 128.5, 129.6,

131.5, 133.0, 134.2, 136.9, 144.2, 169.4; HR-MS 554.139

(C₂₇H₃₀ClNO₆S + Na calcd 554.137).

2-Methyl-2-(3-(naphthalen-1-ylmethoxy)prop-1-yn-1-yl)-1-tosy-

laziridine (1s). Prepared following the general procedure 6 in 32%

yield (284 mg) from 520 mg of Cs. Colorless oil; R_f= 0.24

(Cyclohexane/EtOAc 20%); IR (neat) ν

2976, 1731, 1473, 1176,

max

1338, 1277, 1176, 1040, 665, 585; ¹H NMR (300 MHz, CDCl₃) δ 1.26

(t, 3H, J = 7.1 Hz), 1.61−1.68 (m, 3H), 2.43 (s, 1H), 2.43 (s, 3H),

2.72 (s, 2H), 2.88 (s, 1H), 3.40 (s, 2H), 4.21 (q, 4H, J = 7.0 Hz),

7.16−7.25 (m, 5H), 7.32 (d, 2H, J = 8.3 Hz), 7.86 (d, 2H, J = 8.3 Hz);

¹³C NMR (75 MHz, CDCl₃) δ 14.1, 21.6, 22.5, 24.1, 37.4, 38.3, 41.9,

58.3, 61.7, 80.6, 80.8, 127.1, 127.8, 128.4, 129.6, 130.0, 135.7, 137.0,

144.2, 169.7; HR-MS 520.175 (C₂₇H₃₁NO₆S + Na calcd 520.176).

2-Methyl-2-(5-phenylpent-1-ynyl)-1-tosylaziridine (1m). Prepared

following the general procedure 6 in 44% yield (337 mg) from 400 mg

(Cyclohexane/EtOAc 20%); IR (neat) ν

1564, 1472, 1323, 1156,

max

of Cm. Pale-yellow oil; R_f= 0.30 (Cyclohexane/EtOAc 20%); IR

1054, 1017, 866, 821, 782, 690, 640, 546 ; ¹H NMR (300 MHz,

1

(neat) ν

2928, 1598, 1325, 1559, 1089, 909, 814, 730, 730; H

CDCl₃) δ 1.67 (s, 3H), 2.41 (s, 3H), 2.47 (s, 1H), 2.94 (s, 1H), 4.25

max

4339

dx.doi.org/10.1021/jo300294r | J. Org. Chem. 2012, 77, 4323−4341

The Journal of Organic Chemistry

Article

(s, 2H), 5.08 (s, 2H), 7.30 (d, 2H, J = 8.3 Hz), 7.40−7.60 (m, 4H),

7.81−7.89 (m, 2H), 7.87 (d, 2H, J = 8.3 Hz), 8.15−8.21 (m, 1H); ¹³C

NMR (75 MHz, CDCl₃) δ 21.6, 23.7, 38.1, 41.8, 57.3, 70.0, 81.0, 83.4,

124.3, 125.2, 125.8, 126.3, 127.4, 127.9, 128.5, 128.9, 129.6, 132.0,

132.9, 133.8, 136.7, 144.3; HR-MS 428.130 (C₂₄H₂₃NO₃S + Na calcd

428.129).

2-Methyl-2-(3-naphthalen-2-ylmethoxy)prop-1-ynyl)-1-tosylaziri-

dine (1t). Prepared following the general procedure 6 in 51% yield

(444 mg) from 500 mg of Ct. Pale-yellow oil; R_f= 0.32 (Cyclohexane/

4416. (b) Sengupta, S.; Shi, X. ChemCatChem 2010, 2, 609−619.

(c) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232−5241.

(d) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075−6089.

(e) Muzart, J. Tetrahedron 2008, 64, 5815−5849. (f) Li, Z.; Brouwer,

C.; He, C. Chem. Rev. 2008, 108, 3239−3265. (g) Arcadi, A. Chem.

Rev. 2008, 108, 3266−3325. (h) Gorin, D. J.; Sherry, B. D.; Toste, F.

D. Chem. Rev. 2008, 108, 3351−3378.

(4) Boorman, T. C.; Larrosa, I. Chem. Soc. Rev. 2011, 40, 1910−1925.

(5) (a) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108,

3326−3350. (b) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew.

Chem., Int. Ed. 2008, 47, 4268−4315.

EtOAc 20%); IR (neat) ν

3075, 2993, 2941, 2853, 2232, 1585,

max

1325, 1160, 1086, 909, 868, 813, 728, 691; ¹H NMR (300 MHz,

CDCl₃) δ 1.66 (s, 3 H), 2.42 (s, 3 H), 2.46 (s, 1 H), 2.93 (s, 1 H), 4.25

(s, 2 H), 4.80 (s, 2 H), 7.31 (d, 2 H, J = 8.3 Hz), 7.41−7.53 (m, 3 H),

7.80−7.94 (m, 6 H); ¹³C NMR (75 MHz, CDCl₃) δ 21.6, 23.7, 38.1,

41.8, 57.2, 71.6, 80.7, 83.3, 126.0, 126.1, 126.2, 127.3, 127.6, 127.8,

128.0, 128.2, 129.6, 133.1, 133.3, 134.9, 136.7, 144.4; HR-MS 428.124

(C₂₄H₂₇NO₃S + Na, calcd 428.129).

(6) Hopkinson, M. N.; Gee, A. D.; Gouverneur, V. Chem.Eur. J.

2011, 17, 8248−8262.

(7) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817−7831.

(8) For selected reviews on silver chemistry, see: (a) Weibel, J.-M.;

Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149−3173. (b) Alvarez-

Corral, M.; Munoz-Dorado, M.; Rodriguez-Garcia, I. Chem. Rev. 2008,

108, 3174−3198.

d₇-2-(3-(Benzyloxy)prop-1-ynyl)-2-methyl-1-tosylaziridine (1u).

Prepared following the general procedure 6 in 56% yield (1.12 g)

from 660 mg of Cu. Pale-yellow oil; R_f= 0.23 (Cyclohexane/EtOAc

(9) (a) Blanc, A.; Tenbrink, K.; Weibel, J.-M.; Pale, P. J. Org. Chem.

2009, 74, 4360−4363. (b) Blanc, A.; Tenbrink, K.; Weibel, J.-M.; Pale,

P. J. Org. Chem. 2009, 74, 5342−5348.

20%); IR (neat) ν

3273, 2925, 1597, 1324, 1157, 1089, 814, 662,

max

1

545; H NMR (300 MHz, CDCl₃) δ 1.65 (s, 3H), 2.43 (s, 3H), 2.46

(s, 1H), 2.92 (s, 1H), 4.20 (s, 2H), 7.30 (d, 2H, J = 8.3 Hz), 7.87 (d,

2H, J = 8.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 22.1, 24.1, 38.5, 42.2,

57.6, 71.2 (m), 81.3, 83.6, 128.0 (m), 128.3, 128.3 (m), 128.7 (m),

130.0, 137.1, 137.5, 144.8; HR-MS 385.156 (C₂₀H₁₄D₇NO₃S + Na,

calcd 385.157).

(10) Cordonnier, M.-C.; Blanc, A.; Pale, P. Org. Lett. 2008, 10,

1569−1572.

́

(11) Perez, A. G.; Lopez, C. S.; Marco-Contelles, J.; Faza, O. N.;

Soriano, E.; De Lera, A. R. J. Org. Chem. 2009, 74, 2982−2991.

(12) Blanc, A.; Alix, A.; Weibel, J.-M.; Pale, P. Eur. J. Org. Chem.

2010, 1644−1647.

4-Methyl-2-phenethyl-1-tosyl-1H-pyrrole (4n). Prepared using the

same conditions as in the general procedure 1 in 68% yield (34 mg)

from 50 mg of 1n (using catalyst 6 instead of Ph₃PAuNTf₂). Colorless

oil; R_f= 0.48 (Cyclohexane/EtOAc 30%); IR (neat) ν _max2925, 1733,

(13) Kern, N.; Blanc, A.; Weibel, J.-M.; Pale, P. Chem. Commun.

2011, 47, 6665−6667.

(14) Except for compound 1f, for which the corresponding

commercially available enyne was ﬁrst TBS-protected.

(15) (a) Sodergren, M. J.; Alonso, D. A.; Bedekar, A. V.; Andersson,

P. G. Tetrahedron Lett. 1997, 38, 6897−6900. (b) Evans, D. A.; Faul,

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2742−2753.

1

1564, 1462, 1169, 1094, 812, 699, 665, 585; H NMR (300 MHz,

CDCl₃) δ 2.01 (d, 3H, J = 1.2 Hz), 2.39 (s, 3H), 2.85−2.97 (m, 4H),

5.87 (d, 1H, J = 1.2 Hz), 6.99−7.09 (m, 1H), 7.15−7.31 (m, 3H), 7.26

(d, 2H, J = 8.3 Hz), 7.63 (d, 2H, J = 8.3 Hz); ¹³C NMR (75 MHz,

CDCl₃) δ 11.4, 21.2, 28.9, 35.1, 114.6, 119.0, 121.7, 125.6, 126.2,

127.9, 127.9, 129.5, 134.7, 136.3, 140.9, 144.1; HR-MS 362.118

(C₂₀H₂₁NO₂S + Na calcd 362.119).

(16) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133−

4136.

(17) It is noteworthy that the allene 3a could be detected by TLC

ASSOCIATED CONTENT

■

S

during the course of the reaction.

* Supporting Information

¹H and ¹³C NMR spectra of all compounds and crystallographic

data of 2h-maj. This material is available free of charge via the

Internet at http://pubs.acs.org.

(18) Amijs, C. H. M.; Lop

P.; Ferrer, C.; Echavarren, A. M. J. Org. Chem. 2008, 73, 5342−5348.

(19) Hashmi, A. S. K.; Lothschutz, C. ChemCatChem 2010, 2, 133−

́ ́ ́

ez-Carrillo, V.; Raducan, M.; Perez-Galan,

̈

134.

(20) As the Gagosz catalyst, 6e failed to give the spiro compound

from 1e.

(21) cis and trans in spiro compounds referred here to the

dihydropyrrole ring.

AUTHOR INFORMATION

Corresponding Author

*ablanc@unistra.fr; ppale@unistra.fr

■

(22) (a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004,

104, 3341−3370. (b) Huang, W.; Shen, Q.; Wang, J.; Zhou, X. J. Org.

Chem. 2008, 73, 1586−1589.

Notes

The authors declare no competing ﬁnancial interest.

(23) Cristallographic data of 3h-maj (CCDC 816973) have been

already reported in reference 13.

ACKNOWLEDGMENTS

■

We gratefully acknowledge the CNRS and the French Ministry

of Research for ﬁnancial support. N.K. thanks the French

Ministry of Research for a PhD fellowship; M.R. thanks the

REU exchange program for supporting her stay at the

University of Strasbourg.

(24) For examples of gold and silver-catalyzed Friedel−Crafts type

reactions on aziridines, see: (a) Sun, X.; Sun, W. W.; Fan, R.; Wu, J.

Adv. Synth. Catal. 2007, 349, 2151−2155. (b) Bera, M.; Roy, S.

Tetrahedron Lett. 2007, 48, 7144−7146.

(25) For gold-catalyzed hydroamination of allenes, see: (a) Morita,

N.; Krause, N. Org. Lett. 2004, 6, 4121−4123. (b) Morita, N.; Krause,

N. Eur. J. Org. Chem. 2006, 4634−4641. (c) Zhang, Z.; Liu, C.; Kinder,

R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006,

128, 9066−9073. (d) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste,

F. D. J. Am. Chem. Soc. 2007, 129, 2452−2453. (e) Wang, Z. J.;

Benitez, D.; Tkatchouk, E.; Goddard, W. A., III; Toste, F. D. J. Am.

Chem. Soc. 2010, 132, 13064−13071.

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Coinage metals-catalyzed cascade reactions of aryl alkynylaziridines: Silver(I)-single vs gold(I)-double cyclizations

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