CuCl-catalyzed radical cyclisation of N-α-perchloroacyl-ketene-N,S- acetals: A new way to prepare disubstituted maleic anhydrides

Tetrahedron 68 (2012) 5863e5881

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Tetrahedron

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CuCl-catalyzed radical cyclisation of N-

a

-perchloroacyl-ketene-N,S-acetals: a new

way to prepare disubstituted maleic anhydrides

,

d

Andrea Cornia ^a, Fulvia Felluga ^b, Vincenzo Frenna ^c, Franco Ghelﬁ ^a, Andrew F. Parsons ,

*

,

a

,

e

Mariella Pattarozzi ^a, Fabrizio Roncaglia , Domenico Spinelli

*

a

ꢀ

Dipartimento di Chimica, Universita degli Studi di Modena e Reggio Emilia, Via Campi 183, I-41125 Modena, Italy

Dipartimento di Scienze Chimiche e Farmaceutiche, Universita degli Studi di Trieste, Via L.Giorgeri 1, I-34127 Trieste, Italy

Dipartimento di STEMBIO, Universita degli Studi di Palermo, Viale delle Scienze-Parco D’Orleans II, I-90128 Palermo, Italy

b

c

ꢀ

^dDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK

e

ꢀ

Dipartimento di Chimica “G. Ciamician”, Universita degli Studi di Bologna, Via Selmi 2, I-40126 Bologna, Italy

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 6 March 2012

Received in revised form 20 April 2012

Accepted 26 April 2012

Available online 8 May 2012

The copper-catalyzed radical cyclization (RC) of N-

a

-perchloroacyl cyclic ketene-N,X(X¼O, NR, S)-acetals

was studied. While the RC of N-acyl ketene-N,O-acetals was unsuccessful, the 5-endo cyclization of the

other ketene acetals provided much better results, with the following order of cyclization efﬁciency:

hexa-atomic cyclic ketene-N,NR-acetals<penta-atomic cyclic ketene-N,S-acetals<hexa-atomic cyclic

ketene-N,S-acetals. Invariably the catalytic cycle begins with the formation of a carbamoyl methyl radical.

This leads to a cascade of reactions, including a radical polar crossover step, which ends with the for-

mation of the maleimide nucleus, or precursors of this. Products from the RC of the hexa-atomic cyclic

ketene-N,S-acetals, were efﬁciently transformed into disubstituted maleic anhydrides.

Keywords:

Cyclic ketene-N,S-acetals

a

-Perchloroenamides

Copper(I) chloride

5-endo Radical cyclization

Maleic anhydrides

1. Introduction

The 5-exo- or 5-endo-trig cyclization of N-allyl (B₁) or N-vinyl

(B₀) carbamoyl methyl radicals is a valuable tool for the construc-

tion of

regioselectivity of the cyclization can change and afford also

g

-lactams (Scheme 1).¹However, for N-vinyl radicals B₀, the

b

-

lactams, through an alternative 4-exo-trig attack, which, according

to Baldwin’s rules,²should be favored. Yet in many cases, the 5-endo

radical cyclization (RC) is followed, yielding the ﬁve-membered

ring as the main, or the sole product.³Now it is ascertained that

the course of the reaction is strongly inﬂuenced by the stability of

the cyclic radical intermediates C₀.^3,4Although the exo-C₀adduct is

kinetically favored,⁵in the absence of adjacent radical stabilizing

groups (i.e., Ph, SR) it is converted, through the carbamoyl methyl

radicals B₀, into the more stable endo-C₀adduct.⁶In any case,

a substituent on the amide nitrogen, acting as a cyclization auxil-

iary (AC), is required to force the molecule to adopt a conformation,

whereby the radical center is positioned in close proximity to the

radicophile.⁷

Scheme 1. Cu(I)-catalyzed radical cyclization of N-allyl (n¼1) and N-vinyl (n¼0)

a

-halo-amides (AC¼cyclization auxiliary).

By far the most common method of preparing radicals B is by

homolytic cleavage of the C_a-halogen bond in N-allyl- or N-vinyl-

a-

* Corresponding authors. Tel.: þ39 059 2055049; fax: þ39 059 373543; e-mail

address: franco.ghel ﬁ @unimore.it (F. Ghelﬁ).

halo-amides A_nwith Bu₃SnH, in the presence of radical

a

doi:10.1016/j.tet.2012.04.117

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A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

initiator.^3a,4b,6,8This methodology has been, nowadays, surpassed

by the atom transfer radical cyclization (ATRC), promoted by tran-

sition metals, usually Cu(I)X complexes with polydentate nitrogen

ligands.^1c,3b,4a,7,9In these reactions, the amide radicals B_n, delivered

through halogen abstraction by the cuprous complex, add to the

tethered C]C bond generating the cyclic radicals exo-C_nand/or

endo-C₀, which react further with the redox catalyst in its oxidized

state, returning it to the active reduced form. Practically, these

radicals undergo an irreversible halogen atom transfer from the

Cu(II)X₂complex with formation of the corresponding fully halo-

genated products D and E (Scheme 1, path i). However, the

a-amido

radical endo-C₀, from the 5-endo cyclization of N-vinyl-

a-halo-

amides, can react by an alternative pathway, involving a radical

polar crossover mechanism (RPC) (Scheme 1, path ii),¹⁰due to its

tendency to undergo facile oxidation to the acyliminium ion F,

through a single electron transfer to Cu(II)X₂.¹¹In this case, a nu-

cleophile can be inserted at the C-5 site, through a process akin to

the second step of an S_N1 mechanism (product G), or, if a

drogen is present, the reaction can proceed by an E1-type mecha-

nism affording an unsaturated -lactam (H). For sake of

b-hy-

g

completeness, we cannot omit that the cation F can also be formed

from the ionization of the chloro-lactams E (Scheme 1, path iii).^4a,12

The TMC-ATRC of N-vinyl-a

-halo-amides^4a,11aec,12bis catalyti-

cally less efﬁcient than the analogous reaction with N-allyl-a-halo-

amides,^7,13and requires larger amounts of the Cu(I) complex, typ-

ically 30e100% against 5e10%. We are strongly convinced, that this

discrepancy is a consequence of the release of HCl in the reaction

medium, during the formation of product H.

Scheme 2. Preparation of the 3-ethyl-2-methyl maleic anhydride 5: (i) CuCl (10 mol

%), TMEDA (20 mol %), MeCN, Na₂CO₃, 17 h, 30 ^ꢀC; (ii) silica/sulfuric acid, NaNO₃, SiO₂/

H₂O 3:2, CH₂Cl₂, 40 ^ꢀC, 17 h; (iii) H₂SO₄/AcOH 1:1, 140 ^ꢀC, 65 h.

In our group, the Cu(I)-catalyzed ATRC of N-allyl-a-perchloro-

amides has been extensively studied and used, along with the

CH₃ONa mediated functional rearrangement (FR) of the resulting

chloro-lactams,¹⁴to prepare the 3,4-dialkyl-substituted maleic

anhydride nuclei,¹⁵typical frameworks of valuable natural or syn-

thetic products.¹⁶Since the FR is only viable for the cis-

diastereomer and the stereoselectivity of the ATRC cannot be ex-

actly controlled,⁷the formation of the unwanted trans-isomer leads

to a loss of efﬁciency, which can limit the scope of the method.^15a

Recently, as part of a programme to develop a more versatile

route toward chaetomellic anhydrides and their homologs, we

reported the preparation of 3-ethyl-4-methylmaleic anhydride 5

Scheme 3. Regioselective RC of the a-enamide radical 6.

through the Cu(I)-catalyzed radical cyclization of the N-

a-per-

chloroacyl cyclic ketene-N,S-acetals 1 (Scheme 2).¹⁷

analogous to 2 and 3 were isolated in a lower yield.¹⁷Finally, the

dimer maleimides 2 and 3 were transformed, as described in Scheme

2, into the desired 3-ethyl-4-methylmaleic anhydride 5.¹⁷

The RC of 1 is a clear and effective example of a cascade reaction,

involving a radical polar crossover,²²which represents a novel way

to prepare 3,4-dialkyl-substituted maleic anhydrides.

Following this promising result we decided to investigate the

reactivity of the N-a-perchloroacyl cyclic ketene-N,X-acetals 9e10

(Fig. 1), wherein S is replaced by the heteroatoms O or N. If the new

substrates could give better or analogous performances than those

Notwithstanding the ﬁrst review about ketene acetals was

written by McElvain back in 1949,¹⁸the most comprehensive in-

vestigation of the reactivity of these molecules has been provided

only in the last 15 years, in particular by the work of the Pittman Jr.’s

research group.¹⁹As far as we are aware, just three examples of RC

of N-acyl ketene-N,X-acetals, two cyclic^19g,20a,b, and one acyclic,^20c

were described before our work, but all three of them concerned

the 6-endo-trig cyclization of b-amide radicals.

Interestingly, in the RC of the cyclic ketene acetal 1 the cycli-

zation auxiliary is already included into the structure. Moreover,

the formation of a ﬁve-membered ring was exclusive. This is due to

the greater stability of the radical intermediate 7 compared to 8

(Scheme 3); the semi-occupied orbital of 7 is stabilized by the ad-

jacent nitrogen and sulfur substituents.

Most likely, products 2 and 3 (Scheme 2) arose from oxidation of

the cyclic radical 7, followed by a cascade of ionic transformations.

The addition of carbonate to the reaction mixture was essential to

preserve the effectiveness of the redox catalyst. In fact the process

releases HCl into the reaction mixture, an event, which is known to

disrupt the redox cycle.²¹The RC of the 3-(2,2-dichlorobutanoyl)-2-

ethylidenethiazolidine, a N-a-perchloroacyl cyclic ketene-N,S-acetal

where the heteroatoms N and S are part of a pentatomic cycle, was

also tried. But, compared to 1, it was more unstable and afforded

a

more complex reaction mixture, from which the products

Fig. 1. Archetypal N-2,2-dichlorobutanoyl cyclic ketene-N,X-acetals.

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

5865

observed with 1, the use of malodorous sulfurated reagents could

be avoided. The ketene-N,X-acetals 11e13 (Fig. 1) were also taken

into account to verify if aromatic substrates could be suitable for

the RC process, a crucial step toward the synthesis of the important

diaryl maleic anhydrides.¹⁶All the ketene-N,X-acetals 9e13 were

prepared both with ﬁve-membered (a) and six-membered (b)

rings. In this article we report the results of our study.

2. Results and discussion

2.1. Preparation of substrates 9e13

The procedure we considered for the preparation of the enam-

ides 9e13, as used by Pitmann Jr.,^19,20ainvolved the acylation of the

corresponding imidates, amidines, or thioimidates.^20bed,23

2.1.1. Preparation of ketene-N,O-acetals

9 and 12. 2-Ethyl-4,5-

dihydrooxazole (14a) and 2-ethyl-5,6-dihydro-4H-1,3-oxazine

(14b) (Scheme 4) were prepared, in good yields, using the re-

action between triethyl orthopropionate and the appropriate

aminoalcohol, in the presence of acetic acid at 105 ^ꢀC.²⁴2-

Phenylmethyl-4,5-dihydrooxazole (15a) and 2-phenylmethyl-5,6-

dihydro-4H-1,3-oxazine (15b) were instead secured in satisfactory

yields, starting from phenylacetonitrile (Scheme 4). The best results

were achieved, when the condensation of 3-aminopropanol, or 2-

aminoethanol, and phenylacetonitrile was performed at 130 ^ꢀC in

chlorobenzene, under the catalytic action of anhydrous ZnCl₂

(1e5 mol %) (working under solvent free conditions, we had

problems to isolate 15).²⁵

Fig. 2. Molecular structure of compounds 12a (a), major isomer Ac-10b (b), major

isomer 13b (c), and 11a (polymorph I) (d) from X-ray crystallography. Displacement

ellipsoids are drawn at 50% probability level. Color code: C¼gray, H¼light blue,

Cl¼green, N¼blue, O¼red, S¼yellow.

2.1.2. Preparation of ketene-N,N-acetals. The preparation of the a,a-

dichloro-enamides 10 and 13 requires one more step than the

synthesis of the corresponding ketene-N,X(X¼S, O)-acetals, namely

the protection of the secondary nitrogen atom in the cyclic ami-

dines 16 and 17 (Fig. 3) before acylation. In this way, we can prevent

the generation of unwanted bis-acylated adducts.

Fig. 3. Cyclic amidines.

Scheme 4. Preparation of the oxazolines 14 and dihydro-1,3-oxazine 15.

Unfortunately, the alkyl substitution proved unsuitable, since

the corresponding amidines, on acylation, resulted in polymeriza-

tion, as a consequence of the high nucleophilicity of the vinylic C_b

carbon. Thus we thought to use an electron-withdrawing sub-

stituent, such as the tert-butyloxycarbonyl (Boc) or acetyl (Ac)

group, to reduce the nitrogen nucleophilicity.^19f

The starting amidines H-16 were isolated as acetates 18 in high

yield, by reacting triethyl orthopropionate and the appropriate di-

amine, under acid catalysis (Scheme 6).²⁶Then, the acylation²⁷of

18 with Ac₂O or Boc₂O in anhydrous CH₂Cl₂, using a slight excess of

TEA, gave the adducts R-16, which, being somewhat unstable (but

relatively pure by ¹H NMR), were not puriﬁed and used as such. In

the next step R-16s were smoothly N-acylated, under anhydrous

conditions, by 2,2-dichlorobutanoyl chloride, affording the expec-

ted enamides R-10 in adequate yields (Scheme 6).

The cyclic ketene-N,NR-acetals 10, particularly those with an

hexa-atomic ring, were more resistant to hydrolysis than the cor-

responding ketene-N,O-acetals 9, and were puriﬁed by silica gel

chromatography. In fact Boc-10a and Ac-10a were isolated as in-

separable mixtures together with a small amount of the respective

hydrolyzed adducts (for Boc-10a the ratio was 88:12 and for Ac-10a

it was 78:22). However, we were able to recover clean Boc-10a,

working with chromatographed Boc-16a. Interestingly, the hydro-

lytic byproduct never accompanied the isolation of products de-

rived from R-10bs.

Cyclic imidates 14 and 15 were then N-acylated with 2,2-

dichlorobutanoyl chloride to afford the ketene-N,O-acetals 9 and

12a (Scheme 5). The reaction must be run under rigorously anhy-

drous condition and at room temperature. This was required, be-

cause products 9 and 12a, differently from the corresponding

ketene-N,S-acetals are extremely responsive to acid hydrolysis.

Indeed 9 cannot be puriﬁed by chromatography and, thus, was used

as such in the RC tests. This was instead possible with the enamide

12a, which was isolated, in satisfactory yield, as a mixture with

a little amount of hydrolyzed adduct (84:16). Unfortunately 12b

was so unstable that we were unable to recover it, even as a crude

product. The conﬁguration of 12a, assessed by X-ray crystallogra-

phy, was Z (Fig. 2a); we believe that compounds 9 also have the

same stereochemistry.

The N-a,a-dichloroacyl-ketene-N,S- or N,O-acetals 9b, 11aeb,

Scheme 5. Preparation of the N-2,2-dichlorobutanoyl ketene-N,O-acetals 9 and 12a.

and 12a were obtained as single isomers with Z conﬁguration. As

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A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

puriﬁed by chromatography on silica. Whereas, 13b contained two

separable Z/E diastereomers (ratio 61:39), 13a exhibited only a single

conﬁguration. As indicated by ¹H NMR signal broadening, products 13

are also mixtures of amide rotamers at room temperature. X-ray

crystallography assessed the Z conﬁguration for the major isomer of

13b, revealing also a chair conformation for the 1,3-diazinane ring

(Fig. 2c).

2.1.3. Preparation

of

ketene-N,S-acetals. 2-Phenylmethyl-4,5-

dihydrothiazole (19a) and 2-phenylmethyl-5,6-dihydro-4H-1,3-

thiazine (19b), precursors of enamides 11a and 11b, respectively,

were secured using the same literature procedure as we followed

for preparing the methyl analogs 1 (Scheme 8).³⁰X-ray crystal-

lography assessed a Z conﬁguration for 11a (Fig. 2d), which we also

expected for compound 11b.

Scheme 6. Preparation of the N-2,2-dichlorobutanoyl ketene-N,NR-acetals 10.

suggested by the broadening of the ¹H NMR signals, 9b and 11b are

made up of a mixture of rotamers. In contrast, the enamides 10

were always isolated as mixtures of geometric isomers E/Z, each

containing a mixture of amide rotamers. The ¹H NMR spectrum of

product Ac-10a shows four sets of signals, which correspond to the

two E/Z isomers each one splitting into two amidic rotamers. On the

contrary, the ¹H NMR spectra of the other three amides 10 show

one set of signals for each diastereomer, albeit broadened due to the

presence of rotamers. It was also possible to establish the di-

astereomeric ratio for Boc-10a (74:26 or 91:9, when it was prepared

from chromatographed Boc-16a), for Boc-10b (60:40), and for Ac-

10b (64:36). The Z isomer (the major) of Ac-10b was found to

crystallize out of the mixture from CH₂Cl₂/hexane at 4 ^ꢀC and its

structure was unambiguously determined by X-ray crystallography,

which showed that the 1,3-diazinane ring adopts a chair confor-

mation (Fig. 2b).

The benzyl amidines H-17, on route to the ketene-N,N-acetals 13,

were obtained by reaction of 2-phenylthioacetamide (synthesized

from phenylacetonitrile, adapting the procedure of Shabana)²⁸with

1,2-diaminoethane or 1,3-diaminopropane (Scheme 7).²⁹For these

compounds we considered only the acetylation reaction to protect the

secondary nitrogen. The acylation was accomplished with acetic an-

hydride, as previously described for H-16. The resulting amidines Ac-

17, without puriﬁcation, were reacted with 2,2-dichlorobutanoyl

chloride, providing 13 in satisfactory yields (Scheme 7). Enamides

13 were quite resistant to acid-catalyzed hydrolysis, and so could be

Scheme 8. Synthesis of the N-2,2-dichlorobutanoyl ketene-N,S-acetals 11.

The cyclic thioamide 19a was obtained from the reaction of

phenylacetonitrile with cysteamine hydrochloride. In contrast, 19b

was secured through a two-step process: (i) preparation of N-(3-

hydroxypropyl)-phenylacetamide, from methyl phenylacetate and

3-aminopropanol and (ii) cyclization of the acetamide in the

presence of the Lawesson’s reagent.

The cyclic thioamides 19 were then smoothly acylated using 2,2-

dichlorobutanoyl chloride under anhydrous conditions, to afford

the expected ketene-N,S-acetals 11, which, being stable to acid-

catalyzed hydrolysis, were puriﬁed by chromatography on silica

(Scheme 8). They were isolated as a single Z diastereomer.

2.2. Radical cyclization of substrates 9e13

All the ketene-N,X-acetals 9e13 were generally reacted under

the best experimental conditions observed for the cyclization of

1: namely, reaction of the substrate (2 mmol), CuCl (10e30 mol %),

ligand TMEDA or PMDETA, and K₂CO₃or Na₂CO₃(2 mmol), in an-

hydrous CH₃CN (3 mL), at 30 ^ꢀC for 16 h.¹⁷

2.2.1. Radical cyclization of ketene-N,O-acetals 9 and 12a. Ketene-

N,O-acetals 9 and 12a, despite the several trials, gave no cyclic

products. Uniquely, under the reaction conditions, they were found

to hydrolyse to give the respective ester-amides.

2.2.2. Radical cyclization of ketene-N,NR-acetals R-10 and 13. The

RC of the penta-atomic N-2,2-dichloroacyl-ketene-N,NR-acetals R-

Scheme 7. Synthesis of the N-2,2-dichlorobutanoyl ketene-N,NAc-acetals 13.

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

5867

10a and 13a, gave variable results, as a function of the substituent

(Me or Ph) on the C]C bond, whereas the protecting group

R showed a minor impact on the results (Table 1).

Table 1

RC of N-2,2-diCl-butanoyl ketene-N,NR-acetals R-10a and 13a^a

No. Substrate

Conv.^c(%) R-20a^b,^c(%) R-21^c(%) (ꢁ)-24^c(%)

1

2

3

Boc-10a (dr 91:9)

97

100

11

30

d

49

10

d

Ac-10a^d

d

72(97)^e

13a

a

Reaction conditions: substrate (2 mmol), CuCl (30 mol %), PMDETA (33 mol %),

K₂CO₃(2 mmol), anhydrous CH₃CN (3 mL), 30 ^ꢀC, 16 h.

b

N-(2-(NR-Propionamido)ethyl)-2,2-dichlorobutanamide (R]Ac or Boc).

Determined on isolated material.

This substrate (a mixture of rotamers of E/Z diastereomers) was used together

c

d

Fig. 4. Structures of the two crystallographically independent molecules in compound

24 from X-ray crystallography. Displacement ellipsoids are drawn at 30% probability

level. Same color code as in Fig. 2.

with Ac-20a (78:22).

e

In parentheses, the product yield under the following conditions: CuCl (5 mol %),

TMEDA (10 mol %), Na₂CO₃(2 mmol).

X-ray quality crystals of 24 were grown by slow evaporation of

CH₂Cl₂/n-hexane solutions and structure determination was car-

ried out by X-ray crystallography. The crystal comprises two crys-

tallographically independent molecules with virtually identical

geometry, shown in Fig. 4. The two asymmetric carbons (C2 and C5

in the oxazolidine-4-one moiety) are found to have opposite ab-

solute conﬁgurations. However, the compound crystallizes in cen-

trosymmetric space group P2₁/c and the crystal is a racemic

mixture of the (R,S) and (S,R) enantiomers (Fig. 4).

We presume that the preparation of 24 from 13a starts with the

formation of the carbamoyl methyl radical 25 (Scheme 10). This

radical cyclizes onto the aromatic ring forming the seven-

membered cyclic radical intermediate 26, which, analogously to

the radical adduct 23 (Scheme 9), is converted into the acylimmi-

nium cation 27. This transformation is assisted by restoring the

aromaticity of the phenyl group and by the formation of a reso-

nance-stabilized carbocation. The acyliminium cation 27 is then

quenched by H₂O affording the adducts 28. In this case, however, an

acyclic diamide is not formed (Scheme 9); on the contrary, 28 is

converted into 24, through an intramolecular nucleophilic sub-

stitution reaction of the hydroxyl group with the C_aeCl bond. Since

the substitution is of S_N2 type, the entering O-nucleophile and the

Enamides R-10a afforded complex reaction mixtures, where the

main products were R-20a (from substrate hydrolysis) and the

mono-chloro butanamide R-21. A possible rationalization for the

formation of R-21 is outlined in Scheme 9. The reaction between R-

10a and the Cu(I) complex generates the initial carbamoyl methyl

radical R-22, which, instead of cyclising, abstracts a hydrogen atom

from the terminal methyl group, forming a resonance-stabilized

allylic radical intermediate R-23 (the resonance form shown below

is also stabilised by two adjacent acylamino groups). At this point

the reaction can follow one or both of the two pathways, we have

previously described in Scheme 1, yielding an intermediate acyli-

minium cation, which, after reaction with H₂O, is transformed into

the mono-chloro diamide R-21.

Scheme 9. A plausible mechanism for the formation of R-21.

Formation of R-23 by this mechanism is only possible if, in R-

10a, the methyl appendage, bound to the C_bvinylic site, is in close

proximity to the 2,2-dichlorobutanoyl group. Taking into account

the starting dr of Boc-10a and the signiﬁcant yield of Boc-21, we can

conﬁdently attribute the Z conﬁguration to the major diastereomer

of Boc-10a (giving highest priority to the halogenated substituent);

the same should be true for Ac-10a.

Differently, the enamide 13a, under the same reaction condi-

tions, gave exclusively the tetracyclic epoxy-azepinone 24 (Fig. 4) in

a respectable 72% yield, which even rose to 97%, using 5 mol % of

CuCl/[TMEDA]₂and Na₂CO₃, as base.

Scheme 10. A plausible mechanism for the formation of 24.

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A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

outgoing halide must adopt an anti-periplanar conﬁguration. It is

certainly interesting to clear how this occurs, but currently it is

outside the scope of this study (besides we cannot exclude the al-

ternative/parallel mechanism where the hydrolysis of the CeCl

a to

C]O bond precedes the formation of the acyliminium ion). As for

enamides R-10a, a Z conﬁguration of the C]C bond of 13a is re-

quired for successful transformation into 24; so, we can reasonably

assign the Z conﬁguration to the starting enamide 13a.

In the literature, the intramolecular FriedeleCrafts alkylation of

N-biphenyl-2-chloroacetamides, molecules that are structurally

analogous to 13a, gave dibenzoazepinones, condensed hepta-

atomic ring systems, which were used for the preparation of

g-

secretase inhibitors (for application in the treatment of the Alz-

heimer’s disease).³¹As far we are aware, the efﬁcient transformation

of 13a into (ꢁ)-24 is the ﬁrst example of a 7-ring forming copper-

catalyzed radical cyclization of N-styryl-a-perchloroamides.

The performances of the RC of the six-membered ring N-a,a-

dichloroacyl-ketene-N,NR-acetals R-10b and 13b were, on the

contrary, less inﬂuenced by the Me or Ph substituents on the vinylic

group (Scheme 11 and Table 2). With R-10bdwhere a methyl is

bound to the vinylic componentdwe isolated two main products:

the maleimide R-29 and the succinimide R-30, the latter as a mix-

ture of cis/trans diastereomers. The product yields are not inﬂu-

enced by changing the R protection on the nitrogen atom (Table 2,

No. 1 and 3). However the conversion of Boc-10b, when using

30 mol % of CuCl, was almost complete, whereas that of Ac-10b

showed partial (79%). In this case, the unreacted Ac-10b (21%) was

recovered as the pure Z diastereomer. Interestingly, there was no

evidence that the geometric conﬁguration of the C]C bonds in

10bs had any impact on the products obtained.

Scheme 12. A plausible mechanism for the formation of the maleimide R-29.

Since R-29, under the same conditions of the RC reaction, did not

give the succinimide R-30, the latter should derive directly from the

substrate R-10b, most likely through the mechanism drawn in

Scheme 13. This process implies that the initial reduction of the

starting N-

a,a-dichloroacyl-ketene-N,NR-acetal R-10b gives the

a

-mono-chloroamide 36. Then, substitution of the highly electro-

philic C_aeCl carbon, by the nucleophilic end of the ketene-N,N-

acetal segment, affords the cyclic acyliminium cation intermediate

37. The transformation concludes with a hydrolytic mechanism,

common to the other cases examined, to give R-30.

Scheme 11. RC of N-2,2-diCl-butanoyl ketene-N,NR-acetals R-10b and 13b.

Table 2

RC of N-2,2-diCl-butanoyl ketene-N,NR-acetals R-10b and 13b^a

No.

Substrate

Conv.^b(%)

R-29 or 31^b(%)

R-30^b(%)

1

Boc-10b (dr 60:40)

Ac-10b (Z/E 64:36)

13b (Z/E 57:43)

13b (Z/E 100:0)

13b (Z/E 0:100)

96

22

79

100

57

8

56

59

72

46

13 (dr 74:26)

d

2^c

3

Scheme 13. Possible mechanism for the formation of the succinimide R-30.

7 (dr 86:14)

4

5

6

d

The aromatic substrate 13b, instead, gave exclusively the mal-

eimide product 31 (the mechanism of the process is the same as the

one outlined in Scheme 12). The yield of 31 was higher when

starting from the Z diastereomer than from the E isomer (Table 2,

nos. 5 and 6), although the reason for this is unknown.

a

Reaction conditions: substrate (2 mmol), CuCl (30 mol %), PMDETA (33 mol %),

K₂CO₃(2 mmol), anhydrous CH₃CN (3 mL), 30 ^ꢀC, 16 h.

b

Determined on isolated material.

CuCl (10 mol %), TMEDA (20 mol %), Na₂CO₃(2 mmol).

c

On comparing the results obtained with the pent- and hex-

atomic cyclic ketene-N,NR-acetals, we can note that the radical 5-

endo cyclization was only possible for precursors containing the

larger rings (b). This might be a consequence of a closer proximity

of the radical center and radicophilic C]C in these precursors, or

most likely it is the greater ﬂexibility of the larger ring that can

allow the reacting group to come together.

The maleimide nucleus is likely to be formed according to the

mechanism outlined in Scheme 12. As usual, the catalytic cycle

begins with the formation of the carbamoyl methyl radical 32,

which cyclizes following the expected 5-endo mechanism. The

formation of the cyclic radical intermediate 33, as previously dis-

cussed, can proceed through a classic ATRC and/or via a RPC

pathway. Deprotonation gives intermediate 34, the precursor of the

allylic acyliminium cation 35, which, after quenching with H₂O and

ensuing elimination, is transformed into the maleimide R-29.

2.2.3. Radical cyclization of ketene-N,S-acetals 11. Reaction of the

thioenamide 11a, under typical conditions, afforded a complex re-

action mixture, wherefrom related products, to those we observed

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

5869

in our seminal study of the RC of 3-(2,2-dichlorobutanoyl)-2-

ethylidenethiazolidine,¹⁷were isolated: namely, the disulﬁde di-

mer 38a, the sulﬁde dimer 39a, and the CeC dimer dl-40 (Scheme

14 and Table 3). In addition, two other unisolable products were

detected, to which we assigned the structure meso-40 and 41 (their

yields, determined by ¹H NMR, were always less than 10%).

Scheme 14. RC of N-2,2-diCl-butanoyl ketene-N,S-acetal 11.

Scheme 15. Possible mechanism for the formation of products 38, 39, and 41.

Table 3

RC of N-2,2-diCl-butanoyl ketene-N,S-acetals 11^a

No Sub. CuCl[L]_n^b(mol %) Conv.^c(%) Products^c,d(%)

unsaturated lactam 50 gives dimer 40 through a reductive homo-

coupling process (Scheme 16). This last route is supported by litera-

ture examples.³²Indeed, the capabilityof coppercatalysts to promote

the reductive radical homo-coupling of allyl halides is well known,

and has been exploited to prepare natural compounds such as ter-

penes, bisantraquinones and butenolides.³³

The product 40 has two stereogenic centers, but can also have

a symmetry plane. All the three possible stereomers of 40 were

produced: one achiral (meso-40) and the other two as racemic

mixture (dl-40).

38 39 dl-40 meso-40 41

1^e

2

3

11a

11b

A (30)

B (10)

B (5)

94

100

99

29 29 22

26 48 16

16 51 17

8

5

6

d

6

3

4

d

4

B (5)

100

23 62

d

a

Reaction conditions: substrate (2 mmol), Na₂CO₃(2 mmol), anhydrous CH₃CN

(3 mL), 30 ^ꢀC, 16e17 h.

b

A¼CuCl[PMDETA], B¼CuCl[TMEDA]₂.

c

Determined on isolated material.

d

Determined by ¹H NMR for products 40 and 41.

e

K₂CO₃(2 mmol) was used as base.

The dl isomer was separated from the meso-isomer and from the

side product 41 by crystallization from CH₂Cl₂/n-hexane. Its struc-

ture and conﬁguration were unambiguously determined by X-ray

crystallography (Fig. 5). The two asymmetric carbons in the struc-

ture were found to have the same absolute conﬁguration. However,

since the compound crystallizes in centrosymmetric space group

Pccn, the crystal is a racemic mixture of (R,R) and (S,S) enantiomers.

The lattice comprises three crystallographically independent mol-

ecules, two of which develop around twofold crystal axes and

consequently have rigorous C₂symmetry. The pseudo-twofold

symmetry of the remaining molecule is broken principally by the

conformation of the ethyl substituents. The NeCeCeN torsion

angle involving the quaternary carbon atoms is close to 180^ꢀ, taking

the values 179.7(2), 176.0(2) and 174.28(13) in the three molecules,

respectively.

Products 38a, 39a, and 41, likely, arise from the tandem radical

polar process outlined in Scheme 15, which resembles the one

shown in Scheme 12 for the RC of ketene-N,NR-acetals R-10b and

13b. The process starts with the 5-endo radical cyclization of 42a to

give the cyclic radical 43a. The reaction proceeds with the con-

version of 43a into the transient ketene-N,S-acetal 45a, and its

subsequent hydrolysis, through the hydroxy adduct 47a, gives the

maleimide 48a. This adduct can act as an S-nucleophile and attack

the N-acyliminium ion 46a, derived from 45a, yielding the sulﬁde

dimer 39a, or alternatively, on oxidation, afford the disulﬁde dimer

38a. The side product 41, in turn, can be produced by nucleophilic

attack of the hydroxy function of 47a on 46a.

The CeC dimer 40 might, instead, come from the de-

hydrochlorination of 49, a postulated intermediate dimer, derived

from homo-coupling of radicals 43a. Alternatively, it is also possible

Being in mind our aim to prepare disubstituted maleic anhy-

drides, the formation of the dimer 40, although interesting, consti-

tutes a serious limitation for the RC of the enamide 11a, as 40 cannot

be converted into a maleimide nucleus. Some trials to minimise

that the ATRC

g

-lactam 44a loses HCl, and the resulting D²

5870

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

manipulate (they are resistant to hydrolysis), and because their

transformations are more selective. Thus, analogously to the pre-

vious conversion of the cyclic products of 1 into the 3-ethyl-4-

methyl-2,5-furandione 5, the same transformation was attempted

with 38b and 39b. We, however, encountered insurmountable

problems during the acid hydrolysis of 38. For this reason we

switched to using Argade’s two-step hydrolysis protocol, for the

conversion of the maleimide nucleus into the corresponding maleic

anhydride.³⁵

Scheme 17 summarizes the preparation of the maleic anhydride

52 from the enamide 11b. The N-2,2-dichlorobutanoyl ketene-N,S-

acetal 11b was cyclized in CH₃CN, using the catalyst CuCl/TMEDA.

The dimers 38 and 39 were not isolated, but together they were

subjected to an oxidative treatment to form the C]O group,

masked as an S,S-acetal in 39. The crude products from this step

were then hydrolyzed according to Argade’s method, affording the

expected anhydride 52 in a more than acceptable 52% overall yield.

Scheme 16. Possible mechanism for the formation of products 40.

Scheme 17. Preparation of the 3-ethyl-4-phenyl-2,5-furandione 52: (i) CuCl (5 mol %),

TMEDA (10 mol %), MeCN, Na₂CO₃, 17 h, 30 ^ꢀC; (ii) silica/sulfuric acid, NaNO₃, SiO₂/H₂O

3:2, CH₂Cl₂, 45 ^ꢀC, 40 h; (iii) KOH, CH₃OH/THF, reﬂux 2 h; (iv) HCl (10%), rt.

2.4. Extension of the method

Next we investigated the change of the acyl group bound to the

nitrogen atom of the archetypal 2-ethyliden- or 2-benzyliden-1,3-

thiazinane nuclei. All the starting enamides were prepared, in

satisfactory yields (63e79%), through the typical reaction between

acyl chlorides and 2-ethyl-5,6-dihydro-4H-1,3-thiazine 53³⁰or 2-

benzyl-5,6-dihydro-4H-1,3-thiazine 19 (Scheme 18).

Fig. 5. Structure of one of the three crystallographically independent molecules in

compound dl-40 from X-ray crystallography. Displacement ellipsoids are drawn at 30%

probability level. Same color code as in Fig. 2.

these byproducts were unsuccessful. Thankfully, the RC of the six

members cyclic ketene-N,S-acetal 11b, similarly to the methyl

analogous 1 (Scheme 2), produced more simple reaction mixtures,

essentially composed of dimers 38b and 39b (Table 3, no. 4).

Replacing the methyl group with phenyl makes the catalytic

system more effective and allows efﬁcient conversion with a redox

complex charge of only 5 mol % (Table 3, nos. 3 and 4, Scheme 2). It

is clear from the results observed with the aromatic N or S ketene-

N,X-acetals 13b (Table 2) or 11b (Table 3), that the phenyl sub-

stituent was unable to direct (even partially) the cyclization toward

a 4-exo-trig mode. Probably, the imperfect overlap between the p

Scheme 18. Preparation of N-2,2-dichloroacyl ketene-N,S-acetals 54e57.

We also tried to synthesize the 3-trichloroacetyl-2-(Z)-benzyli-

den-1,3-thiazinane, but owing to its utmost lability, all attempts to

trichloro-acetylate the thiazine 53 were unsuccessful. The

dichloroacetyl chloride was, instead, deliberately not prepared,

because acyl chlorides with hydrogens on the C_aare generally not

efﬁciently converted into N-acyl-ketene-N,X-acetals.^23a,36,37

The structure of enamide 57 was unambiguously determined by

X-ray crystallography. This conﬁrmed the expected Z conﬁguration

(Fig. 6), and this conﬁguration can be safely assigned to the other

enamides (54e56).

orbital of the radical center and the aromatic

p system, reduces the

stability of an intermediate benzyl radical.³⁴As a consequence the

5-endo-trig cyclization mode, giving an intermediate radical co-

operatively stabilized by the acylamino and alkylthio groups, re-

mains favored and it was the only pathway observed.

2.3. Preparation of the 3-ethyl-4-phenylfuran-2,5-dione

Scheme 19 reports the structure of the products isolated from

the RC of the ketene-N,S-acetals 54e57dthe expected disulﬁde (A)

and sulﬁde (B) dimersdwhile Table 4 collects the results of all the

RC of the 3-(2,2-dichloroacyl)-2-(Z)-alkyliden-1,3-thiazinanes. The

combined yields of the two dimers were generally good (>85%),

The previous experiments identiﬁed the six-membered N-acyl

ketene-N,S-acetals as being the best starting material for the RC

reaction, both because they are easy to prepare, purify and

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

5871

Fig. 6. Molecular structure of compound 57 from X-ray crystallography. Displacement

ellipsoids are drawn at 50% probability level. Disorder effects on the carbon atoms of

the 1,3-thiazinane ring are omitted for clarity and only the majority conformer is

shown. Same colour code as in Fig. 2.

Scheme 20. Preparation of the 3,4-disubstituted-2,5-furandiones: (i) CuCl (5 mol %),

TMEDA (10 mol %), MeCN, Na₂CO₃, 17 h, 30 ^ꢀC; (ii) silica/sulfuric acid, NaNO₃, SiO₂/H₂O

3:2, CH₂Cl₂, 45 ^ꢀC, 40 h; (iii) KOH, CH₃OH/THF, reﬂux 2 h; (iv) HCl (10%), rt. In the case

of enamide 1 the datum was gathered from Ref. 17, and the hydrolytic procedure is

different.

apart the one obtained from the trichloroenamide 56 (<60%; Table

4, item 4). Again it was conﬁrmed that the redox complex charge

can be lowered to 5 mol %, when the N-a-perchloroacyl-benzyli-

den-1,3-thiazinanes were reacted (Table 4, nos. 5 and 7).

S)-acetals, substrates that were prepared by acylation of the cor-

responding imidates, amidines, or thioimidates.

While the RC of N-acyl ketene-N,O-acetals was unsuccessful, the

5-endo cyclization of the other ketene acetals provided better results,

with cyclization efﬁciency in the order: hexa-atomic cyclic ketene-

N,NR-acetals<penta-atomic cyclic ketene-N,S-acetals<hexa-atomic

cyclic ketene-N,S-acetals. Invariably the catalytic cycle begins with

the formation of a carbamoyl methyl radical, which leads to a cas-

cade of reactions, including a radical polar crossover step, culmi-

nating in the formation of the maleimide nucleus, or of a direct

precursor (that can be transformed into a maleimide by simple hy-

drolysis). Globally, this is an elegant example of redox economy, in

that the starting material of the RC is subjected to a transformation

equivalent to a refunctionalization by an internal redox reaction.³⁸

The products from the RC of the hexa-atomic cyclic ketene-N,S-

acetals, being secured in higher yields (incidentally the starting

enamides are also relatively easy to prepare) were then trans-

formed into maleic anhydrides. This process bypasses the stereo-

selectivity problem typical of the ATRC-FR method to form maleic

anhydrides.¹⁵The new process is suitable for the synthesis of dia-

lkyl, arylalkyl, or diaryl anhydrides (these last compounds are

otherwise inaccessible with the ATRC-FR method).

Scheme 19. RC of N-2,2-dichloroacyl ketene-N,S-acetals 54e57.

Table 4

RC of N-2,2-diCl-butanoyl ketene-N,S-acetals^a

No.

Sub.

CuCl[TMEDA]₂(mol %)

Conv.^b(%)

Products^b(%)

1

2

3

4

5

6

7

1

10

5

100

2 (14)

58 (19)

60 (15)

62 (26)

38b (23)

64 (45)

64 (7)

3 (80)

59 (73)

61 (83)

63 (29)

39b (62)

65 (53)

65 (92)

54

55

56

11b

57

The penta-atomic N-acyl cyclic ketene-N,NR-acetals were, on

the contrary, unsuitable for the 5-endo RC. However, when a ben-

zylidene substituent was included at the C-2 position of the imi-

dazolidine nucleus, a remarkable and unprecedented 7-ring RC,

involving the aromatic ring, occurred, which produced, in an as-

tonishingly efﬁcient way, the tetracyclic epoxy-azepinone (ꢁ)-24.

10

5

a

Reaction conditions: substrate (2 mmol), Na₂CO₃(2 mmol), anhydrous CH₃CN

(3 mL), 30 ^ꢀC, 16e18 h.

b

Determined on isolated material.

Finally we completed the conversion of the 3-(2,2-

dichloroacyl)-2-(Z)-alkyliden-1,3-thiazinanes into the correspond-

ing maleic anhydrides, without purifying any intermediates, as

outlined in Scheme 20. The desired disubstituted maleic anhy-

drides were isolated in acceptable global yields (>50%), except for

the case of the trichloroacetylenamide 56, which gave, owing to the

less efﬁcient RC, a much reduced global yield of only 24%.

4. Experimental part

4.1. General

Reagents and solvents were standard grade commercial prod-

ucts, purchased from Aldrich, Acros, Fluka, or RdH, and generally

used without further puriﬁcation. CH₃CN and CH₂Cl₂(DCM) were

ꢁ

dried over 3 A sieves (5% w/v). ZnCl₂was dried with trimethyl-

3. Conclusions

chlorosilane, as reported in literature.³⁹Acyl chlorides were pre-

pared by chlorination with Cl₂of acyl chlorides in the presence of

tetrabutylammonium chloride.⁴⁰The 2-ethyl-5,6-dihydro-4H-1,3-

thiazine 53³⁰and silicaesulfuric acid⁴¹were secured following

In this work we have studied the novel copper-catalyzed ring

cyclization (RC) of N-

a

-perchloroacyl cyclic ketene-N,X(X¼O, NR,

5872

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

literature procedures. The silica gels used for gravity or ﬂash

chromatography were, respectively, Silica Gel 60 Merck

0.063e0.2 mm or 0.040e0.063 mm. TLC was performed on silica

coated plates Merck 60 F₂₅₄, using UV light (254 nm), iodine, and

ninhydrin or cerium molybdate solutions to visualize the spots.

¹H NMR spectra were recorded on ‘Bruker DPX 200’, ‘Bruker

Avance 400’ and ‘Varian 500 MHz’. ¹³C NMR was obtained with full

proton decoupling. ¹H NMR and ¹³C NMR signals attribution was

based on Gradient-Enhanced ¹H,¹H-DQF-COSY, ¹H,¹³C-Edited-

HSQC, and ¹H,¹³C-HMBC experiments, run with standard pulses

programmes. IR and MS spectra were recorded, respectively, on

a ‘FTIR Perkin Elmer 1600 Series’ and a ‘HP G1800C GCD System

Series II’ or a ‘LCeMS(n) Ion Trap 6310A Agilent Technologies’. High-

resolution mass spectra (HRMS) were obtained on a ‘Bruker Dal-

tonics microTOF II’ or an ‘Agilent 6520 Accurate-Mass Q-TOF LC/

MS’. Melting point was determined with an ‘Electrothermal Series

IA9100 Digital Melting Point Apparatus’.

reduced pressure. The remaining yellow oil was the product 14b⁴⁶

(7.75 g, 69%), pure enough to be used for subsequent acylation.

4.2.3. Preparation of 2-benzyl-4,5-dihydrooxazole (15a).^25aIn

a three-necked round bottom ﬂask, ﬁtted with an Argon inlet tap,

a condenser, with a CaCl₂tube on the top, and a dropping funnel,

was weighed anhydrous ZnCl₂(5.0 mmol, 0.68 g) and chloroben-

zene (40 mL) was introduced. To the stirred mixture were added,

under argon, phenylacetonitrile (120.0 mmol, 13.9 mL) and, slowly,

a solution of 2-aminoethanol (100.0 mmol, 6.0 mL) in chloroben-

zene (10 mL). The ﬂask was heated at reﬂux with an oil bath,

thermostated at 130 ^ꢀC. After 18 h, the mixture was cooled and the

chlorobenzene distilled off under reduced pressure. The crude

residue was chromatographed on silica gel, eluting with a petro-

leum ether (PE: bp 40e60 ^ꢀC)/diethyl ether (Et₂O) gradient (from

50:50 to 0:100). Product 15a⁴⁷was recovered as a yellow liquid

(5.77 g, 36%). It was pure enough to be used for subsequent

acylation.

Structural determinations on Ac-10b (major diastereomer), 11a,

12a, 13b (major diastereomer), (ꢁ)-24, dl-40, and 57 were carried

out by single-crystal X-ray diffraction at 298(2) K (for (ꢁ)-24, dl-40

and 57) or at 150(2) K (for the remaining compounds) using

4.2.4. Preparation of 2-benzyl-5,6-dihydro-4H-1,3-oxazine (15b).^25a

Following the same procedure used for the preparation of 15a,

a Bruker X8-Apex four-circle diffractometer equipped with Mo K

a

anhydrous 0.68 g),

(100.0 mmol, 11.7 mL), and a solution of 3-aminopropanol

ZnCl₂

(5.0 mmol,

phenylacetonitrile

ꢁ

generator (

l

¼0.71073 A), area detector, and Kryo-Flex cryostat.

Structure solution and reﬁnement (on F_o²) were based on standard

methods.^42e44All nonhydrogen atoms were treated anisotropically,

with the exception of the disordered carbons in the lowest-

occupancy sites of 57. Hydrogen atoms were treated isotropically

(100.0 mmol, 7.6 mL) in chlorobenzene (50 mL) were processed at

130 ^ꢀC (20 h). The cooled reaction mixture was acidiﬁed with HCl_aq

10% (35 mL), washed with DCM (2ꢂ50 mL), treated with NaOH_aq

10% (30 mL), and extracted with DCM (4ꢂ50 mL). The aqueous

phase was further continuously extracted with DCM, overnight. The

organic phases were collected, dried over MgSO₄, ﬁltered, and

evaporated under reduced pressure. Product 15b⁴⁷was recovered

as a yellow liquid (8.93 g, 51%). It was pure enough to be used for

the next acylation.

and either located in

DF maps or set to idealised positions (with

torsion angle reﬁnement for methyl groups in (ꢁ)-24). In the latter

case, their displacement parameters were constrained to be 50%

and 20% larger than those of the parent carbon atom for CH₃and

CH₂/CH groups, respectively. Crystallographic data (excluding

structure factors) for the structures in this paper have been de-

posited with the Cambridge Crystallographic Data Center as sup-

plementary publications nos. CCDC 868795e868802. Copies of the

data can be obtained, free of charge, on application to CCDC, 12

Union Road, Cambridge CB2 1EZ, UK (fax: þ44-(0)1223-336033 or

e-mail: deposit@ccdc.cam.ac.uk).

4.2.5. Preparation of 2-ethylimidazoline acetate (18a).²⁶In a three-

necked round bottom ﬂask, ﬁtted with an argon inlet tap, a con-

denser, mounting a CaCl₂tube, and a dropping funnel, were in-

troduced under Argon, and stirring, CH₃CN (50 mL), ethyl

orthopropionate (53.0 mmol, 10.5 mL), acetic acid (53.0 mmol,

3.1 mL) and, slowly, 1,2-diaminoethane (50.0 mmol, 3.4 mL). A

white precipitate, which hindered the agitation, developed. The

reaction mixture was then heated at reﬂux with an oil bath, ther-

mostated at 85 ^ꢀC (the white precipitate, on heating, solubilized).

After 2 h, it was cooled and the solvent distilled off at reduced

pressure. The crude oil was diluted with DCM and reﬂuxed for some

minutes. The white precipitate of 1,2-ethylendiammonium diac-

etate, in suspension, was ﬁltered off. The ﬁltrate was concentrated

at reduced pressure, giving the product 18a,⁵⁰as a yellow oil

(6.92 g, 88%). It was pure enough to be used for the next acylation.

Products 14a,^29b,4514b,⁴⁶15a,⁴⁷15b,⁴⁷H-17a,^29b,48H-17b,⁴⁹

18a,⁵⁰18b,⁵¹19a,⁵²19b,⁵³52,⁵⁴66,⁵⁵67,⁵⁴68,⁵⁶69,⁵⁷and phenyl-

thioacetamide⁵⁸are known compounds.

4.2. Preparation of cyclic imidates, amidines, and

thioimidates

4.2.1. Preparation of 2-ethyl-4,5-dihydrooxazole (14a).²⁴Ethyl

orthopropionate (50.0 mmol, 9.9 mL), 2-aminoethanol (50.0 mmol,

3.0 mL), and acetic acid (3.0 mmol, 173 mL) were injected, under

Argon, in a Schlenk tube ﬁtted with a pierceable septum (blocked

by a screw cap) and a magnetic stirring bar. The apparatus was then

heated with an oil bath, thermostated at 105 ^ꢀC. After 24 h, the

reaction mixture was cooled. Distillation, under atmospheric

pressure, gave the product 14a,^29b,45as a colorless liquid (3.71 g,

75%), bp 123e126 ^ꢀC.

4.2.6. Preparation of 2-ethyl-1,4,5,6-tetrahydropyrimidine acetate

(18b).²⁶Following the same procedure used for the preparation of

18a, CH₃CN (50 mL), ethyl orthopropionate (41.0 mmol, 8.2 mL),

acetic acid (41.0 mmol, 2.4 mL), and 1,3-diaminopropane

(39.0 mmol, 3.3 mL) were processed at 85 ^ꢀC per 2 h. The solvent

was then distilled off from the reaction mixture, at reduced pres-

sure. The unreacted diamine was separated as the diacetate, after

crystallization in DCM (with few mL of CH₃OH). Product 18b⁵¹was

recovered, after evaporation of the ﬁltrate, under reduced pressure,

as a white solid (6.04 g, 90%). It was pure enough to be used for the

next acylation.

4.2.2. Preparation of 2-ethyl-5,6-dihydro-4H-1,3-oxazine (14b).²⁴

Ethyl orthopropionate (120.0 mmol, 23.9 mL), 2-aminopropanol

(100.0 mmol, 7.6 mL), and acetic acid (6 mmol, 346 mL) were

injected, under Argon, in a Schlenk tube ﬁtted with a pierceable

septum (blocked by a screw cap) and a magnetic stirring bar. The

apparatus was then heated with an oil bath, thermostated at

105 ^ꢀC. After 24 h, the reaction mixture was cooled at 0 ^ꢀC and,

under stirring, HCl_aq10% (30 mL) was added. Then it was washed

with DCM (3ꢂ50 mL), neutralized with NaOH_aq10% (30 mL), and

extracted in continuous with DCM, overnight. The organic phase

was dried over MgSO₄, ﬁltered, and the solvent removed under

4.2.7. Preparation of phenylthioacetamide.²⁸Warning: the original

procedure gave rise to an explosive reaction, using a closed Schlenk;

moreover it always afforded the ester! It was thus modiﬁed as here

reported. In a round bottom ﬂask, ﬁtted with a condenser, phenyl-

acetonitrile (60.0 mmol, 6.9 mL), diethyldithiophosphoric acid 90%

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

5873

(60 mmol, 10.3 mL), and H₂O (60.0 mmol, 1.1 mL) were added in

sequence, under stirring. The reaction mixture was heated with an

oil bath, thermostated at 85e90 ^ꢀC (5 h); during this time it passed

from cloudy gray to clear yellow-orange. The ﬂask was then cooled

and the crude mixture directly chromatographed on silica gel,

eluting with a PE/DCM gradient (from 50:50 to 0:100). The phe-

nylthioacetamide⁵⁸was recovered as a pale yellow ﬂuffy solid,

which was still further puriﬁed by crystallization from DCM/n-

hexane, giving a white crystalline solid (5.50 g, 61%).

was loaded into a round bottom ﬂask, ﬁtted with an argon inlet tap

and a condenser, with a KOH tube on the top (to stop the H₂S re-

leased during the thionation). Afterward, toluene (200 mL) and the

Lawesson’s reagent (46.0 mmol, 18.61 g) were added in sequence,

under argon and vigorous stirring. The suspension was heated at

reﬂux with an oil bath, thermostated at 120 ^ꢀC. After 1.5 h the re-

action mixture was cooled and K₂CO_3aq2 M (150 mL) added. It was

then stirred for further 30 min, at room temperature. The organic

phase was separated, and the aqueous phase extracted with Et₂O

(3ꢂ100 mL). The organic phases were combined and extracted with

HCl_aq10% (3ꢂ100 mL). The acid aqueous phases were combined,

basiﬁed with NaOH_aq5% (400 mL), and extracted with Et₂O

(3ꢂ150 mL). The organic phases were collected, dried over MgSO₄,

and evaporated, under reduced pressure. The product 19b⁵³was

recovered as a bright yellow oil (4.41 g, overall yield 50%)dit was

pure enough to be used for the next acylationd; d_H(200 MHz,

CDCl₃) 1.69 (2H, qn, J 5.8 Hz, CH₂CH₂CH₂), 2.88 (2H, t, J 5.8 Hz, CH₂),

3.60 (2H, s, CH₂Ph), 3.64 (2H, t, J 5.8 Hz, CH₂), 7.10e7.35 (5H, m,

5CHAr); m/z (EI, 70 eV) 190 [70, (MꢃH)^þ], 174 (12), 163 (49), 144

(18), 117 (22), 91 (100), 74 (29%).

4.2.8. Preparation of 2-benzylimidazoline (H-17a).²⁹In a round

bottom ﬂask, ﬁtted with

a condenser, phenylthioacetamide

(17.0 mmol, 2.57 g), anhydrous THF (17 mL), and 1,2-diamino-

ethane (20.4 mmol, 1.4 mL) were added in sequence, under stirring.

The reaction mixture was heated with an oil bath, thermostated at

80 ^ꢀC (16 h); during this time its colour passed from clear yellow to

bright green-yellow. Besides, along the condenser, a patina of

(NH₄)₂S deposited (this salt comes from the reaction between the

gases NH₃and H₂S, evolved during the transformation). The ﬂask

was then cooled. Afterward the solvent was evaporated, under

reduced pressure. The crude reaction mixture was diluted with H₂O

(50 mL) and extracted with DCM (3ꢂ50 mL). The organic phases

were collected, dried over MgSO₄, and ﬁltered. The solvent was

ﬁnally distilled off, under reduced pressure, giving the product H-

17a,^29b,48as a yellow-orange solid (2.69 g, 99%). It was pure enough

to be used for the next acylation.

4.3. Preparation of N-a-perchloroacyl ketene-N,X-acetals

4.3.1. Preparation of 3-(2,2-dichlorobutanoyl)-2-ethylidenoxazolidine

(9a). 2-Ethyl-4,5-dihydrooxazole (14a) (30 mmol, 2.97 g) was

weighed in a Schlenk tube. Anhydrous DCM (30 mL) and triethyl-

amine (TEA) (36 mmol, 5 mL) were then added under argon. The

mixture was cooled at 0 ^ꢀC in a ice-bath and a solution of 2,2-

dichlorobutanoyl chloride (30 mmol, 5.26 g) in anhydrous DCM

(5 mL) was slowly added with a syringe pump (30 min). The re-

action mixture was then stirred at room temperature for 17 h. Af-

terward NaOH_aq5% (30 mL) was added and the product extracted

with DCM (3ꢂ50 mL). The organic phases were collected, dried

over MgSO₄, ﬁltered, and evaporated under reduced pressure.

Crude product 9a was recovered as an orange oil (6.38 g, 89%), and

used immediately as such in the next RC (it cannot be puriﬁed by

chromatography); m/z (EI, 70 eV) 237 (40, M^þ), 202 (100), 126 (16),

111 (22), 103 (81), 98 (72), 75 (34), 70 (25%).

4.2.9. Preparation of 2-benzy1,4,5,6-tetrahydropirymidine (H-

17b).²⁹Following the same procedure used for the preparation of

H-17a, phenylthioacetamide (20.0 mmol, 3.02 g), anhydrous THF

(20 mL), and 1,3-diaminopropane (24.0 mmol, 2.0 mL) were pro-

cessed at 80 ^ꢀC (16 h). The product H-17b⁴⁹was recovered as

a yellowish solid (2.17 g, 62%). It was pure enough to be used for the

next acylation.

4.2.10. Preparation of 2-benzyl-4,5-dihydrothiazole (19a).³⁰In

a Schlenk tube were poured EtOH (50 mL) and then, under argon,

was slowly added Na⁰(120.0 mmol, 2.76 g). Afterward the solution

of EtONa was transferred into a round bottom ﬂask ﬁtted with

a condenser. The ﬂask was placed in an ice-bath. Cysteamine hy-

drochloride (100.0 mmol, 11.36 g), phenylacetonitrile (300.0 mmol,

34.6 mL), and ammonium acetate (60.0 mmol, 4.62 g) were slowly

introduced in sequence, and under stirring. The solution was

heated at reﬂux with an oil bath, thermostated at 85 ^ꢀC (16 h).

Then, the reaction mixture was cooled, concentrated under re-

duced pressure, and diluted with Et₂O (100 mL). The suspension

was washed with brine (2ꢂ50 mL) and the aqueous phases, col-

lected, were extracted with Et₂O (50 mL). The organic phases were

put together, dried over Na₂SO₄, ﬁltered, and concentrated. The

product 19a⁵²was separated from the phenylacetonitrile excess

through distillation under reduced pressure (bp 140 ^ꢀC, 5 mmHg),

and recovered as a colorless liquiddon aging it took a bright yellow

colorationd(12.88 g, 73%); d_H(200 MHz, CDCl₃) 3.25 (2H, t, J 8.4 Hz,

CH₂), 3.83 (2H, br s, CH₂Ph), 4.24 (2H, tt, J 8.4, 1.3 Hz, CH₂),

7.20e7.40 (5H, m, 5CHAr); m/z (EI, 70 eV) 177 [100, M^þ], 149 (67),

117 (38), 91 (54), 60 (82%).

4.3.2. Preparation of 3-(2,2-dichlorobutanoyl)-2-ethyliden-1,3-

oxazinane (9b). Following the same procedure used for the prep-

aration of 9a, 2-ethyl-5,6-dihydro-4H-[1,3]oxazine (14b) (30 mmol,

3.39 g), TEA (36 mmol, 5 mL), and 2,2-dichlorobutanoyl chloride

(30 mmol, 5.26 g), in anhydrous DCM (30þ5 mL), gave crude 9b (it

cannot be puriﬁed by chromatography and was used immediately

as such in the next RC), as a dark orange oil, mixture of rotamers

(6.52 g, 86%); d_H(400 MHz, CDCl₃) 1.15 (3H, br t, J 7.0 Hz, CH₂CH₃),

1.63 (3H, br d, J 6.9 Hz, CH₃CH]), 1.85e2.05 (2H, br m, CH₂), 2.49

(2H, br q, J 7.0 Hz, CH₂CH₃), 3.87 (2H, br s, CH₂), 4.00e4.10 (2H, br m,

CH₂), 5.07 (1H, br s, CH]); d_C(100.62 MHz, CDCl₃) 9.6, 9.8, 25.1,

40.2, 46.4, 67.8, 85.5, 104.7, 144.2, 164.3; m/z (EI, 70 eV) 216 [7,

(MꢃCl)^þ], 180 (2), 140 (100), 112 (52), 84 (54%).

4.3.3. Preparationof3-(2,2-dichlorobutanoyl)-2-benzylidenoxazolidine

(12a). Following the same procedure used for the preparation

of 9a, 2-benzyl-4,5-dihydrooxazole (7a) (23.0 mmol, 3.71 g),

TEA (27.6 mmol, 3.8 mL), and 2,2-dichlorobutanoyl chloride

(23.0 mmol, 4.04 g), were processed in anhydrous DCM (30þ5 mL).

The recovered crude was puriﬁed by ﬂash chromatography on silica

gel, eluting with PE/Et₂O 70:30. Product 12a (3.46 g, 50%) was

isolated, as a yellowish solid with a small amount of unseparable

hydrolyzed adduct (0.70 g, 10%) (12a/hydrolysis adduct¼84:16). A

clean sample of 12a was obtained by crystallization, under argon,

from DCM/hexane at 4 ^ꢀC [HRMS found 300.0555. C₁₄H₁₆Cl₂NO₂

(MþH)^þrequires 300.0553]; R_f(50% PE/Et₂O) 0.55; mp

4.2.11. Preparation of 2-benzyl-5,6-dihydro-4H-1,3-thiazine (19b).³⁰In

ꢁ

a Schlenk tube, where 3 A sieve (3.6 g) were previously weighed in,

3-aminopropanol (80.0 mmol, 6.1 mL) and methyl phenylacetate

(46.0 mmol, 6.6 mL) were added under argon. The stirred solution

was then heated with an oil bath, thermostated at 160 ^ꢀC (16 h).

Afterward the reaction mixture was cooled, diluted with hot MeOH,

and ﬁltered on Celite. The solution, evaporated under reduced

pressure, gave a waxy white solid (10.72 g), containing the N-(3-

hydroxypropyl)-phenylacetamide. All the crude hydroxyamide

103.3e105.7 ^ꢀC; n_max(KBr) 1679 cm^ꢃ1

; d_H(400 MHz, CDCl₃) 1.31

5874

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

(3H, t, J 7.0 Hz, CH₂CH₃), 2.58 (2H, q, J 7.0 Hz, CH₂CH₃), 4.38 (2H, t, J

6.8 Hz, CH₂), 4.53 (2H, t, J 6.8 Hz, CH₂), 6.56 (1H, s, PhCH]), 7.11

(1H, t, J 7.4 Hz, CH_Ar), 7.20e7.40 (2H, m, 2CH_Ar), 7.55 (2H, d, J 7.2 Hz,

2CH_Ar); d_C(100.62 MHz, CDCl₃) 9.5, 38.3, 47.4, 66.2, 86.7, 91.7, 125.1,

128.2, 128.7, 135.9, 147.7, 161.1; m/z (EI, 70 eV) 299 (43, M^þ), 264

(34), 162 (59), 132 (100), 117 (29), 103 (51), 91 (62), 77 (24%).

Selected crystallographic data: C₁₄H₁₅Cl₂NO₂, M¼300.17, mono-

clinic, space group P2₁/c,_ꢀa¼11.0253(4), b¼10.9833(5),

with a solution of acetic anhydride (38.9 mmol, 3.7 mL) in anhy-

drous DCM (2 mL) added with a syringe pump (45 min). The re-

action was worked-up after 19 h. Afterward, following the same

protocol utilized for Boc-16a, the crude 1-acetyl-2-

ethylimidazoline (Ac-16a),⁵⁹recovered (4.95 g) as

a yellow-

orange oil, was reacted with TEA (41 mmol, 5.7 mL) and 2,2-

dichlorobutanoyl chloride (34 mmol, 5.96 g), in anhydrous DCM

(30þ5 mL). After 17 h at room temperature, the reaction mixture

was diluted with H₂O (30 mL) and NaOH_aq5% (10 mL), and

extracted with DCM (3ꢂ30 mL). The crude mixture, obtained from

the collected organic phases, was puriﬁed by ﬂash chromatography

on silica gel, eluting with a PE/Et₂O gradient (from 90:10 to 40:60).

The product Ac-10a was recovered as an orange oil (4.88 g, overall

yield 52%) (mixture of rotamers of diastereomers) [HRMS found

279.0655. C₁₁H₁₇Cl₂N₂O₂(MþH)^þrequires 279.0662]; R_f(10% PE/

Et₂O) 0.33, together with the hydrolysis adduct Ac-20a (1.47 g, 15%)

R_f(10% PE/Et₂O) 0.16 (Ac-10a/Ac-20a¼78:22).

3

ꢁ

c¼11.7154(4) A, ¼105.7931(12) , V¼1365.11(9) A , Z¼4, T¼150(2)

b

K, r_calcd¼1.461 g cm^ꢃ3; reﬂections collected/unique 14,001/3137

(R_int¼0.0220); ﬁnal R indices R₁¼0.0249 [I>2 (I)], wR₂¼0.0713 (all

s

data); data/restraints/parameters¼3137/0/232, GoF¼1.055, re-

ꢁ^ꢃ3

siduals min/max¼ꢃ0.222/0.284 e A

.

4.3.4. Preparation of 3-(2,2-dichlorobutanoyl)-1-(tert-butyloxycarb-

onyl)-2-ethylidenimidazolidine (Boc-10a). A Schlenk tube was con-

nected to an argon line through a CaCl₂trap. Under an inert atmo-

sphere, it was added to a solution of 2-ethylimidazoline acetate (18a)

(29.3 mmol, 4.63 g) in anhydrous DCM (25 mL) and TEA (33.7 mmol,

4.7 mL). The tube was cooled with an ice-bath and a solution of di-

tert-butyl dicarbonate [(Boc)₂O] (33.7 mmol, 7.35 g) in anhydrous

DCM (5 mL) was injected under stirring. When the strong efferves-

cence (due to the released CO₂) subsided, the Schlenk tube (together

the CaCl₂trap) was parted from the Argon line. The mixture was

stirred at room temperature for 14 h, afterward it was diluted with

H₂O (30 mL) and extracted with DCM (3ꢂ30 mL). The organic phases

were collected and washed with NaHCO_3aqsatd (30 mL), dried over

MgSO₄, ﬁltered, and evaporated under reduced pressure. Then, fol-

lowing the same procedure used for the preparation of 9a, the crude

1-(tert-butyloxycarbonyl)-2-ethylimidazoline (Boc-16a), recovered

(6.78 g), as a yellow oil, was solubilized in anhydrous DCM (15 mL)

and reacted with TEA (35.2 mmol, 4.9 mL) and a solution of 2,2-

dichlorobutanoyl chloride (29 mmol, 5.14 g) in anhydrous DCM

(5 mL). The reaction mixture, after stirring for 18 h at room temper-

ature, was diluted with H₂O (25 mL) and extracted with DCM

(3ꢂ25 mL). The organic phases were collected, dried over MgSO₄,

ﬁltered, and concentrated. The crude was puriﬁed by ﬂash chroma-

tography on silica gel, eluting with a PE/Et₂O gradient (from 99:1 to

50:50). The product Boc-10a was recovered as a white-yellowish solid

(4.05 g, overall yield 41%), mixture of two diastereomers (dr 74:26)

[HRMS found 337.1078. C₁₄H₂₃Cl₂N₂O₃(MþH)^þrequires 337.1080]; R_f

(50% PE/Et₂O) 0.60, and of the hydrolysis adduct Boc-20a (Boc-10a/

Boc-20a¼88:12). Boc-20a was also present in other fractions: its

overall yield was 34% (3.54 g). When chromatographed Boc-16a was

used, the yield of Boc-10a increased to 66%, without Boc-20a, and

with a dr¼91:9.

4.3.5.1. 3-(2,2-Dichlorobutanoyl)-1-acetyl-2-ethylidenimidazolidine

(Ac-10a). n_max(ﬁlm) 1699, 1668 cm^ꢃ1

; d_H(400 MHz, CDCl₃) 1.14e1.26

(3H, m, CH₂CH₃), 1.40e1.75 (3H, br m, CH₃CH]), 2.00e2.35 (3H, br m,

CH₃C]O), 2.45e2.60 (2H, m, CH₂CH₃), 3.72 (2H, t, J 6.6 Hz, NCH₂),

4.30 (2H, br s, NCH₂), 5.16 (1H, br s, isomer a CH]), 6.33 (1H, q, J

7.2 Hz, isomer b CH]), 6.43 (1H, br s, isomer c CH]), 6.56 (1H, q, J

7.4 Hz, isomer d CH]); d_C(100.62 MHz, CDCl₃) 9.3, 9.5, 13.8, 14.2, 14.5,

22.7, 24.1, 39.0, 39.4, 43.1, 45.6, 46.3, 46.6, 85.9, 86.5, 102.3 (isomer c

CH]), 104.0 (isomer b CH]), 104.6 (isomer d CH]), 105.1 (isomer

a CH]), 133.2, 134.2, 160.9, 167.3, 168.1; m/z (EI, 70 eV) 278 (5, M^þ),

243 (81), 201 (100), 165 (29%).

4.3.6. Preparation of (Z)-3-(2,2-dichlorobutanoyl)-1-acetyl-2-

benzylidenimidazolidine (13a). Following the procedure used for

preparing Ac-10a, 2-phenylmethylimidazoline (H-17a) (15.85 mmol,

2.54 g) was treated with TEA (19.2 mmol, 2.7 mL) and acetic anhy-

dride (18.2 mmol, 1.72 mL), in anhydrous DCM (16þ3 mLdthe sec-

ond value is referred to the solvent used to dilute the acylating

reagent). Afterward, as described for the preparation of Boc-10a, the

crude 1-acetyl-2-benzylimidazoline (Ac-17a), recovered as a honey-

yellow oil (3.33 g), was reacted with TEA (19.0 mmol, 2.7 mL) and

2,2-dichlorobutanoyl chloride (15.8 mmol, 2.77 g), in anhydrous

DCM (15þ4 mL). The crude mixture, obtained after the usual work-

up, was puriﬁed by ﬂash chromatography on silica gel, eluting with

DCM/Et₂O 90:10. The enamide 13a (2.85 g, overall yield 53%) was

isolated as a white ﬂuffy solid (mixture of rotamers) [HRMS found

363.0645. C₁₆H₁₈Cl₂N₂NaO₂(MþNa)^þrequires 363.0638]; R_f(50%

DCM/Et₂O) 0.53; mp 178e179 ^ꢀC; n_max(KBr) 1689, 1664 cm^ꢃ1

; d_H

(400 MHz, CDCl₃) 0.96 (3H, t, J 7.0 Hz, CH₂CH₃), 2.24 (3H, br s, CH₃C]

O), 2.32 (2H, q, J 7.0 Hz, CH₂CH₃), 3.82 (2H, t, J 6.3 Hz, CH₂), 4.46 (2H,

t, J 6.3 Hz, CH₂), 7.11 (1H, br s, CH_Ar), 7.15e7.30 (4H, m, 4CH_Ar), 7.63

(1H, br s, CH]); d_C(100.62 MHz, CDCl₃) 9.5, 24.7, 39.4, 44.3, 86.1,

106.8, 126.3, 127.4, 128.2, 133.1, 136.8, 160.5, 167.8.

4.3.4.1. 3-(2,2-Dichlorobutanoyl)-1-(tert-butyloxycarbonyl)-2-

ethylidenimidazolidine (Boc-10a). n_max(KBr) 1719, 1692, 1671 cm^ꢃ1

;

d_H(400 MHz, CDCl₃) major diastereomer 1.18 (3H, t, J 7.1 Hz,

CH₂CH₃), 1.46 (3H, d, J 7.2 Hz, CH₃CH]), 1.49 (9H, s, C(CH₃)₃), 2.55

(2H, q, J 7.1 Hz, CH₂CH₃), 3.63 (2H, t, J 6.8 Hz, NCH₂), 4.23 (2H, t, J

6.8 Hz, NCH₂), 5.89 (1H, br s, CH₃CH]), minor diastereomer 1.23

(3H, t, J 7.1 Hz, CH₂CH₃), 1.54 (9H, s, C(CH₃)₃), 1.67 (3H, d, J 7.3 Hz,

CH₃CH]), 2.44 (2H, q, J 7.1 Hz, CH₂CH₃), 3.77 (2H, t, J 6.6, NCH₂),

4.15e4.25 (2H, m, NCH₂), 6.31 (1H, q, J 7.3 Hz, CH₃CH]); d_C

(100.62 MHz, CDCl₃) major diastereomer 9.7, 13.9, 28.3, 40.5, 45.3,

46.8, 81.7, 86.2, 98.7, 133.1, 151.4, 161.2, minor diastereomer 9.6, 14.4,

28.2, 39.7, 44.9, 46.8, 83.9, 87.0, 103.1, 134.3, 152.5, 161.6; m/z (EI,

70 eV) 336 (2, M^þ), 301 (4), 245 (46), 201 (18), 57 (100%).

4.3.7. Preparation of 1-(tert-butyloxycarbonyl)-3-(2,2-dichlorob-

utanoyl)-2-ethyliden-1,3-diazinane (Boc-10b). Following the pro-

cedure used to prepare Ac-10a, 2-ethyl-1,4,5,6-tetrahydropyrimidine

acetate (18b) (28.4 mmol, 4.89 g), was treated with TEA (32.7 mmol,

4.55 mL) and di-tert-butyl dicarbonate (Boc)₂O (32.7 mmol, 7.13 g), in

anhydrous DCM (20þ5 mL). The 1-tert-butoxycarbonyl-2-ethyl-

1,4,5,6-tetrahydropyrimidine (Boc-16b), thus prepared and isolated,

after ﬂash chromatography (eluting with a PE/Et₂O gradient, from

90:10 to 40:60) as a yellow oil (3.62 g, 60%), was reacted with TEA

(20.1 mmol, 2.8 mL) and 2,2-dichlorobutanoyl chloride (17.0 mmol,

2.98 g) in anhydrous DCM (15þ5 mL). The raw Boc-10b, obtained

after the usual work-up, was puriﬁed by ﬂash chromatography on

silica gel, eluting with a PE/Et₂O gradient (from 99:1 to 50:50). The

enamide Boc-10b was recovered as a yellow oil (3.15 g, overall yield

4.3.5. Preparation of 3-(2,2-dichlorobutanoyl)-1-acetyl-2-ethylideni-

midazolidine (Ac-10a). Following the procedure used for preparing

Boc-10a, 1-acetyl-2-ethylimidazoline Ac-16a was prepared by

treating a solution of 2-ethylimidazoline acetate (18a) (33.8 mmol,

5.35 g) and TEA (72.7 mmol, 10.1 mL), in anhydrous DCM (30 mL),

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

5875

32%), mixture of rotamers of diastereomers (dr 60:40) [HRMS found

rotamers) [HRMS found 355.0970]. C₁₇H₂₁Cl₂N₂O₂(MþH)^þrequires

355.0975], R_f(50% PE/Et₂O) 0.11 and as a mixture of the two geo-

metric diastereomers (Z/E 43:57) (0.85 g, overall yield 19%). A clean

sample of Z-13b was obtained by crystallization, under argon, from

DCM/hexane at 4 ^ꢀC, mp 140e141 ^ꢀC.

373.1061. C₁₅H₂₄Cl₂N₂NaO₃(MþNa)^þrequires 373.1056]; R_f(50% PE/

Et₂O) 0.5; n_max(ﬁlm) 1696, 1668 cm^ꢃ1

; d_H(400 MHz, CDCl₃) major

diastereomer 1.12e`1.25 (3H, m, CH₂CH₃), 1,41 (9H, s, C(CH₃)₃),

1.45e1.55 (3H, br m, CH₃CH]), 1.75e1.95 (2H, br m, CH₂), 2.47 (2H, q,

J 7.1 Hz, CH₂CH₃), 3.30e4.30 (4H, br m, 2NCH₂), 5.59 (1H, br q, J 6.4 Hz,

CH]), minor diastereomer 1.12e1.25 (3H, m, CH₂CH₃), 1.42 (9H, s,

C(CH₃)₃), 1.64 (3H, d, J 6.8 Hz, CH₃CH]), 1.75e1.95 (2H, br m, CH₂),

2.47 (2H, q, J 7.1 Hz, CH₂CH₃), 3.30e4.30 (4H, br m, 2NCH₂), 5.67 (1H,

br q, J 6.8 Hz, CH]); d_C(100.62 MHz, CDCl₃) major diastereomer 9.50,

12.4, 24.3, 28.2, 39.6, 44.6, 48.6, 80.4, 85.8, 119.8, 132.4, 153.8, 163.4,

minor diastereomer 9.55, 13.1, 23.6, 28.2, 39.7, 44.6, 49.0, 80.5, 85.9,

122.0, 131.7, 153.8, 163.4.

4.3.9.1. (Z)-1-Acetyl-3-(2,2-dichlorobutanoyl)-2-benzyliden-1,3-

diazinane (Z-13b). n_max(KBr) 1653 cm^ꢃ1

; d_H(400 MHz, CDCl₃) 1.07

(3H, t, J 7.2 Hz, CH₂CH₃), 1.70e2.30 (2H, br m, CH₂), 2.38 (2H, q, J

7.2 Hz, CH₂CH₃), 2.40 (3H, s, CH₃C]O), 3.20 (1H, br s, NCCHH), 3.73

(1H, br s, NCHH), 4.64 (1H, br s, NCHH), 4.95 (1H, br s, NCHH), 6.41

(1H, s, CH]), 7.20e7.40 (5H, m, 5CH_Ar); d_C(100.62 MHz, CDCl₃) 9.5,

22.1, 24.5, 39.4, 43.5, 49.7, 85.4, 125.7, 127.9, 128.6, 132.8, 134.1,

162.5, 169.7. Selected crystallographic data: C₁₇H₂₀Cl₂N₂O₂,

4.3.8. Preparation of 1-acetyl-3-(2,2-dichlorobutanoyl)-2-ethyliden-

1,3-diazinane (Ac-10b). Following the procedure used to prepare Ac-

10a, 2-ethyl-1,4,5,6-tetrahydropyrimidine acetate (18b) (21.7 mmol,

3.74 g) was treated with TEA (47.0 mmol, 6.55 mL) and acetic anhy-

dride (25.4 mmol, 2.4 mL), in anhydrous DCM (20þ2 mL). The crude 1-

acetyl-2-ethyl-1,4,5,6-tetrahydropyrimidine (Ac-16b),⁵⁹thus pre-

pared and isolated as a light yellow oil (2.26 g), was reacted with TEA

(17.6 mmol, 2.45 mL) and 2,2-dichlorobutanoyl chloride (14.7 mmol,

2.58 g) in anhydrous DCM (15þ3 mL). The raw Ac-10b, obtained after

the usual work-up, was puriﬁed by ﬂash chromatography on silica gel,

eluting with a PE/Et₂O gradient (from 99:1 to 10:90). The enamide Ac-

10b (3.43 g, overall yield 54%) was secured as a light brown wax,

mixture of rotamers of diastereomers (Z/E 64:36) [HRMS found

293.0819. C₁₂H₁₉Cl₂N₂O₂(MþH)^þrequires 293.0818]; R_f(50% PE/Et₂O)

M¼355.25, monoclinic, space group P2₁/c, a¼12.4406(3),

3

ꢁ

ꢀ

ꢁ

b¼7.23420(10), c¼19.4493(4) A,

b

¼90.1283(8) , V¼1750.39(6) A ,

Z¼4, T¼150(2) K, r_calcd¼1.348 g cm^ꢃ3; reﬂections collected/unique

30,531/5598 (R_int¼0.0232); ﬁnal R indices R₁¼0.0303 [I>2

s(I)],

wR₂¼0.0873 (all data); data/restraints/parameters¼5598/0/288,

ꢁ^ꢃ3

GoF¼1.053, residuals min/max¼ꢃ0.322/0.347 e A

.

4.3.9.2. (E)-1-Acetyl-3-(2,2-dichlorobutanoyl)-2-benzyliden-1,3-

diazinane (E-13b). n_max(ﬁlm) 1644 cm^ꢃ1

d_H(400 MHz, CDCl₃) 1.31

;

(3H, t, J 7.1 Hz, CH₂CH₃), 1.70e2.00 (1H, m, CHH), 1.94 (3H, s, CH₃C]

O), 2.05e2.25 (1H, m, CHH), 2.56 (2H, q, J 7.1, CH₂CH₃), 3.10e3.35 (1H,

br m, NCHH), 3.65e3.90 (1H, br m, NCHH), 4.74 (1H, br dt, J 12.6,

4.4 Hz, NCHH), 4.91 (1H, brdt, J 13.4, 4.2 Hz, NCHH), 6.54(1H, s, CH]),

7.20e7.50 (5H, m, 5CH_Ar); d_C(100.62 MHz, CDCl₃) 9.3, 21.3, 24.2, 39.2,

42.9, 50.0, 85.5, 126.1, 127.9, 128.6, 128.9, 132.9, 133.1, 163.5, 169.7.

0.14; n_max(ﬁlm) 1693, 1662 cm^ꢃ1

; d_H(400 MHz, CDCl₃) Z isomer 1.21

(3H, t, J 7.2 Hz, CH₂CH₃), 1.55 (3H, d, J 7.0 Hz, CH₃CH]), 1.84 (2H, br s,

CH₂), 2.20 (3H, s, CH₃C]O), 2.45 (2H, q, J 7.2 Hz, CH₂CH₃), 2.70e5.20

(4H, br s, 2NCH₂), 5.55 (1H, q, J 7.0 Hz, CH]), E isomer 1.20 (3H, t, J

7.1 Hz, CH₂CH₃),1.70 (3H, d, J 7.1 Hz, CH₃CH]),1.90e2.10 (2H, m, CH₂),

2.14 (3H, s, CH₃C]O), 2.43 (2H, q, J 7.1 Hz, CH₂CH₃), 2.90 (1H, dt, J

12.2 Hz, 3.3, NCHH), 3.53 (1H, m, NCHH), 4.61 (1H, br d, J 12.2 Hz,

NCHH), 4.85 (1H, br dt, J13.2, 3.6 Hz, NCHH), 5.65 (1H, q, J7.1 Hz, CH]);

d_C(100.62 MHz, CDCl₃) Z isomer 9.5, 12.2, 21.8, 24.5, 39.3, 43.2, 49.5,

4.3.10. Preparation of 3-(2,2-dichlorobutanoyl)-2-(Z)-benzyliden-

thiazolidine (11a). Following the procedure used to acylate Boc-16a,

2-benzyl-4,5-dihydrothiazole (19a) (30.0 mmol, 5.31 g) was treated

with TEA (36.0 mmol, 5.0 mL) and 2,2-dichlorobutanoyl chloride

(30.0 mmol, 5.26 g) in anhydrous DCM (30þ2 mL). The raw material,

obtained after the usual work-up, was puriﬁed by ﬂash chromatog-

raphy on silica gel, eluting with a PE/Et₂O gradient (from 95:5 to

90:10). The enamide 11a was isolated as a white solid (8.81 g, 93%)

[HRMS found 316.0314. C₁₄H₁₆Cl₂NOS (MþH)^þrequires 316.0324]; R_f

85.3, 122.0, 134.8, 162.4, 169.9; E isomer

d

¼9.4, 12.8, 21.3, 24.5, 39.28,

43.1, 50.1, 85.5, 122.9, 134.4, 163.7, 170.0; m/z (EI, 70 eV) 277 [5

(MꢃMe)^þ], 257 (16), 220 (30),177 (75),153 (62),139 (100),111 (69), 43

(36%). Following crystallization, under argon, from DCM/hexane at

4 ^ꢀC, gave a clean sample of the major diastereomer (Z) of Ac-

10b (yellow-orange solid, mp 75e80 ^ꢀC), suitable for single-crystal

X-ray diffraction, was obtained. Selected crystallographic data:

(20% PE/Et₂O) 0.77; mp 78e80 ^ꢀC; n_max(KBr) 1659 cm^ꢃ1

;d_H(400 MHz,

CDCl₃) 1.31 (3H, t, J 7.0 Hz, CH₂CH₃), 2.59 (2H, q, J 7.0 Hz, CH₂CH₃), 3.16

(2H, t, J 6.2 Hz, CH₂), 4.53 (2H, t, J 6.2 Hz, CH₂), 7.15e7.25 (1H, m, CH_Ar),

7.30e7.40 (3H, m, 2CH_ArþCH]), 7.40e7.50 (2H, m, 2CH_Ar); d_C

(100.62 MHz, CDCl₃) 9.6, 29.2, 39.5, 51.8, 87.3,116.2,126.4,128.1,128.3,

135.6, 136.5, 162.7; m/z (EI, 70 eV) 315 (24, M^þ), 280 (30), 244 (6), 176

(100), 148 (40%). A clean sample of 11a, for single-crystal X-ray dif-

fraction, was obtained by crystallization, under argon, from DCM/

hexane at 4 ^ꢀC. The crystallographic analysis at 150(2) K revealed the

occurrence of two packing polymorphs, which crystallize in the same

space group. Selected crystallographic data for polymorph I:

C₁₂H₁₈Cl₂N₂O₂, M¼293.18, monoclinic, space group P2₁/c,

a¼12.2802(3),

b¼8.8798(2),

c¼13.1289(3) A,

b

¼92.1881(8)^ꢀ,

ꢁ

V¼1430.61(6) A , Z¼4, T¼150(2) K, r_calcd¼1.361 g cm^ꢃ3; reﬂections

3

ꢁ

collected/unique 20,181/4549 (R_int¼0.0240); ﬁnal R indices R₁¼0.0286

[I>2s

(I)], wR₂¼0.0830 (all data); data/restraints/parameters¼4549/0/

ꢁ^ꢃ3

235, GoF¼1.047, residuals min/max¼ꢃ0.253/0.316 e A

.

C₁₄H₁₅Cl₂NOS, M¼316.23, monoclinic, space group P2₁/c, a¼6.2101(2),

3

ꢀ

ꢁ

4.3.9. Preparation of 1-acetyl-3-(2,2-dichlorobutanoyl)-2-benzyliden-

1,3-diazinane (13b). Following the procedure used to prepare Ac-

10a, 2-benzyl-1,4,5,6-tetrahydropyrimidine (H-17b) (12.45 mmol,

2.17 g), was treated with TEA (15.0 mmol, 2.1 mL) and acetic anhy-

dride (14.3 mmol, 1.35 mL), in anhydrous DCM (10þ3 mL). The crude

1-acetyl-2-benzyl-1,4,5,6-tetrahydropyrimidine (Ac-17b), thus pre-

pared and isolated as orange oil (2.52 g), was made react with TEA

(14.0 mmol, 2.0 mL) and 2,2-dichlorobutanoyl chloride (11.7 mmol,

2.05 g), in anhydrous DCM (13þ2 mL). The raw material, obtained

after the usual work-up, was puriﬁed by ﬂash chromatography on

silica gel, eluting with a PE/Et₂O gradient (from 99:1 to 50:50). The

enamide 13b was isolated as the E isomer (0.53 g, overall yield 12%),

orange oil (mixture of rotamers) [HRMS found 355.0973.

C₁₇H₂₁Cl₂N₂O₂(MþH)^þrequires 355.0975], R_f(50% PE/Et₂O) 0.22, as

the Z isomer (1.18 g, overall yield 27%), white cream solid (mixture of

b¼25.1112(7), c¼9.4928(3) A,

b

¼94.8705(11) , V¼1474.99(8) A , Z¼4,

T¼150(2) K, r_calcd¼1.424 g cm^ꢃ3; reﬂections collected/unique 15,623/

3592 (R_int¼0.0205); ﬁnal R indices R₁¼0.0308 [I>2 (I)], wR₂¼0.0788

s

(all data); data/restraints/parameters¼3592/0/232, GoF¼1.072, re-

ꢁ^ꢃ3

siduals min/max¼ꢃ0.255/0.284 e A . Selected crystallographic data

for polymorph II: C₁₄H₁₅Cl₂NOS, M¼316.23, monoclinic, space group

ꢁ

P2₁/c, a¼6.0425(4), b¼25.3929(13), c¼9.6370(6) A,

b

¼97.5785(16)^ꢀ,

V¼1465.75(15) A , Z¼4, T¼150(2) K, r_calcd¼1.433 g cm^ꢃ3; reﬂections

3

ꢁ

collected/unique 16,084/3519 (R_int¼0.0212); ﬁnal R indices R₁¼0.0286

[I>2s

(I)], wR₂¼0.0767 (all data); data/restraints/parameters¼3519/0/

ꢁ^ꢃ3

232, GoF¼1.127, residuals min/max¼ꢃ0.239/0.273 e A

.

4.3.11. Preparation of 3-(2,2-dichlorobutanoyl)-2-(Z)-benzyliden-1,3-

thiazinane (11b). Following the procedure used to acylate Boc-16a,

2-benzyl-5,6-dihydro-4H-[1,3]thiazine (19b) (5.0 mmol, 0.96 g)

5876

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

was treated with TEA (10.0 mmol,1.4 mL) and 2,2-dichlorobutanoyl

chloride (7.5 mmol, 1.32 g) in anhydrous DCM (4þ1.5 mL). The

raw material, obtained after the usual work-up, was puriﬁed by

ﬂash chromatography on silica gel, eluting with a PE/Et₂O gradient

(from 99:1 to 90:10). The enamide 11b was isolated as a light yellow

wax (1.49 g, 90%), mixture of rotamers [HRMS found 330.0475.

C₁₅H₁₈Cl₂NOS (MþH)^þrequires 330.0481]; R_f(20% PE/Et₂O) 0.67;

131.9, 132.7, 159.2; m/z (EI, 70 eV) 273 (1, M^þ), 238 (1), 156 (39), 128

(100), 101 (37%).

4.3.15. Preparation of 3-(dichlorophenylacetyl)-2-(Z)-benzyliden-1,3-

thiazinane (57). Following the procedure used to prepare 54, 2-

phenylmethyl-5,6-dihydro-4H-1,3-thiazine (53) (5.0 mmol, 0.956 g),

was reacted with pyridine (12.0 mmol, 0.968 mL) and 2,2-dichloro-2-

phenylacetyl chloride (6.5 mmol, 1.453 g) in anhydrous DCM

(6þ2 mL). The crude reaction product was puriﬁed by ﬂash chro-

matography on silica gel, eluting with a PE/Et₂O gradient (from 100:0

to 70:30). This gave the enamide 57 (1.381 g, 73%) as a white/yel-

lowish solid, mixture of rotamers [HRMS found 378.0492.

C₁₉H₁₈Cl₂NOS (MþH)^þrequires 378.0486]; R_f(70% PE/Et₂O) 0.24, mp

n_max(ﬁlm) 1654 cm^ꢃ1

; d_H(400 MHz, CDCl₃) 1.23 (3H, t, J 7.1 Hz,

CH₂CH₃), 2.17 (2H, quintet, J 6.0 Hz, CH₂), 2.58 (2H, q, J 7.1 Hz,

CH₂CH₃), 2.87 (2H, br t, J 6.0 Hz, CH₂S), 4.07 (2H, br s, CH₂N),

6.98 (1H, br s, CH]), 7.20e7.60 (5H, m, 5CH_Ar); d_C(100.62 MHz,

CDCl₃) 9.7, 25.5, 28.6, 40.3, 49.0, 85.7, 127.8, 128.1, 129.3, 132.4,

134.4, 164.2.

80e82 ^ꢀC; n_max(KBr) 1653 cm^ꢃ1

; d_H(200 MHz, acetone-d₆) 2.05 (2H,

4.3.12. Preparation of 3-(2,2-dichloro-3-methylbutanoyl)-2-ethyliden-

1,3-thiazinane (54). In a round bottom ﬂask, ﬁtted with a dropping

funnel, closed with a CaCl₂tube, 2-ethyl-5,6-dihydro-4H-[1,3]thia-

zine (53) (5.0 mmol, 0.646 g), anhydrous DCM (6 mL), and pyridine

(6.0 mmol, 0.484 mL) were added. The mixture was thermostated at

0 ^ꢀC, and a solution of 2,2-dichloro-3-methylbutanoyl chloride

(5.5 mmol, 1.042 g) in anhydrous DCM (2 mL) was slowly dropped

(30 min) in the ﬂask. The reaction mixture was left under stirring at

25 ^ꢀC for 24 h. Then, it was diluted with NaOH_aq0.5 M (8 mL) and

extracted with DCM (2ꢂ5 mL). The combined organic phases were

concentrated and the crude product was puriﬁed by ﬂash chroma-

tography on silica gel, eluting with a PE/Et₂O gradient (from 100:0 to

90:10). The enamide 54 was isolated as a white solid (1.115 g, 79%),

mixture of rotamers [HRMS found 282.0481. C₁₁H₁₈Cl₂NOS (MþH)^þ

requires 282.0486]; R_f(90% PE/Et₂O) 0.26, mp 66e69 ^ꢀC; n_max(KBr)

br s, CH₂), 2.80 (2H, br t, SCH₂), 3.80 (2H, br s, NCH₂), 6.09 (1H, br s

CH]), 7.05e7.70 (10H, m, 10 CH_Ar); d_C(50.31 MHz, CDCl₃) 25.1, 28.5,

49.2, 88.3, 125.7, 127.9, 128.0, 128.7, 129.3, 129.4, 132.8, 134.0, 140.3,

163.7; m/z (EI, 70 eV) 307 (100), 278 (30), 236 (6), 204 (7), 175 (22),

118 (23), 91 (20%). A clean sample of 57 was obtained by crystalli-

zation from toluene/hexane at 20e25 ^ꢀC. Selected crystallographic

data: C₁₉H₁₇Cl₂NOS, M¼378.30, triclinic, space group P-1,

ꢁ

3

ꢁ

a¼8.9311(2),

b¼9.7317(3),

c¼10.3723(3) A,

a¼89.8913(11),

ꢀ

b

¼88.3043(11),

g

¼76.9034(9) , V¼877.66(4) A , Z¼2, T¼298(2) K,

r_calcd¼1.431 g cm^ꢃ3

;

reﬂections collected/unique 22,324/5124

(R_int¼0.0236); ﬁnal R indices R₁¼0.0384 [I>2 (I)], wR₂¼0.1089 (all

s

data); data/restraints/parameters¼5124/3/290, GoF¼1.105, residuals

ꢁ^ꢃ3

min/max¼ꢃ0.438/0.326 e A . Two carbon atoms in the 1,3-thiazi-

nane rings (C5 and C6) were found disordered over two positions,

with 90:10 relative occupancies. As a consequence, the crystal is

described as a 90:10 mixture of twisted-boat and chair conformers.

1636 cm^ꢃ1

; d_H(200 MHz, CDCl₃) 1.15 (6H, d, J 6.4, CH(CH₃)₂), 1.83

(3H, d, J 7.0 Hz, ]CHCH₃), 2.07 (2H, br m, CH₂), 2.85 (2H, br t, SCH₂),

2.95 (1H, ep, J 6.4, CH(CH₃)₂), 3.98 (2H, br s, NCH₂), 6.09 (1H, br q, J

6.9 Hz, CH]); d_C(50.31 MHz, CDCl₃) 14.4, 18.4, 26.3, 29.4, 41.3, 49.8,

90.9, 130.0, 132.8, 163.9; m/z (EI, 70 eV) 281 (1, M^þ), 246 (37), 156

(100), 128 (71), 101 (50%).

4.4. Radical cyclization of N-a-perchloroacyl ketene-N,X-

acetals

4.4.1. Reaction of 3-(2,2-dichlorobutanoyl)-1-(tert-butyloxycarbonyl)-

2-ethylidenimidazolidine (Boc-10a). CuCl (0.6 mmol, 0.060 g), K₂CO₃

(2 mmol, 0.276 g), and the substrate Boc-10a (2 mmol, 0.675 g, dr

91:9) were weighed into an oven dried Schlenk tube, then anhy-

4.3.13. Preparation of 3-(2,2-dichlorophenylacetyl)-2-ethyliden-1,3-

thiazinane (55). Following the procedure used to prepare 54, 2-

ethyl-5,6-dihydro-4H-1,3-thiazine (53) (5.0 mmol, 0.646 g), was

reacted with pyridine (6.0 mmol, 0.484 mL) and 2,2-dichloro-2-

phenylacetyl chloride (5.5 mmol, 1.229 g) in anhydrous DCM

(6þ2 mL). The crude reaction product was puriﬁed by ﬂash chro-

matography on silica gel, eluting with a PE/Et₂O gradient (from

100:0 to 90:10). This gave the enamide 55 (1.154 g, 73%), as a white/

yellowish solid, mixture of rotamers [HRMS found 316.0333.

C₁₄H₁₆Cl₂NOS (MþH)^þrequires 316.0330]; R_f(90% PE/Et₂O) 0.10,

drous CH₃CN (3 mL) and PMDETA (0.66 mmol, 138 mL) were added

under argon. The mixture was stirred at 30 ^ꢀC and after 16 h diluted

with water and extracted with DCM (3ꢂ20 mL). The combined or-

ganic layers were concentrated under vacuum. Chromatography of

the recovered material on silica gel, eluting with a PE/Et₂O gradient

(from 100:0 to 0:100) gave unreacted Boc-10a (0.020 g, 3%), Boc-20a

(80 mg, 11%) as a pale yellow oil, and the tert-butyl-N-acryloyl-N-[2-

(2-chlorobutanamido)ethyl]carbamate Boc-21 (310 mg, 49%) as

a pale yellow oil [HRMS found 341.1224. C₁₄H₂₃ClN₂NaO₄(MþNa)^þ

requires 341.1239]; R_f(40% PE/Et₂O) 0.25; d_H(400 MHz, CDCl₃) 0.86

(3H, t, J 7.2 Hz, CH₂CH₃), 1.41 (9H, s, C(CH₃)₃), 1.70e1.85 (1H, m,

CHHCH₃), 1.85e2.00 (1H, m, CHHCH₃), 3.35 (2H, q, J 5.7 Hz, NHCH₂),

3.76 (1H, dt, J 14.0, 5.7 Hz, NCHH), 3.80 (1H, dt, J 14.0, 5.7 Hz, NCHH),

4.11 (1H, dd, J 7.6, 4.4 Hz, CHCl), 5.56 (1H, dd, J 10.4, 1.3, ]CHH), 6.16

(1H, dd, J 16.9, 1.3, ]CHH), 6.85 (1H, dd, J 16.9, 10.4 Hz, CH]), 7.09

(1H, br m, NH); d_C(100.62 MHz, CDCl₃) 10.0, 27.6, 28.5, 39.0, 43.0,

61.9, 83.8, 127.8, 130.9, 152.3, 168.96, 168.98; m/z (EI, 70 eV) 226 [16

(MꢃHClꢃ56)^þ], 209 (30), 181 (18), 165 (54), 153 (62), 57 (100%).

mp 92e94 ^ꢀC; n_max(KBr) 1669 cm^ꢃ1

; d_H(200 MHz, acetone-d₆) 1.56

(3H, br d, J 6.4 Hz, ]CHCH₃), 1.86 (2H, br m, CH₂), 2.80 (2H, br t,

SCH₂), 3.60 (2H, br s, NCH₂), 5.30 (1H, br s CH]), 7.38e7.70 (5H, m,

5CH_Ar); d_C(50.31 MHz, CDCl₃) 14.3, 25.8, 29.4, 49.9, 88.1, 125.5,

128.6, 129.4, 131.3, 140.4, 162.9; m/z (EI, 70 eV) 243 (100), 210 (33),

144 (37), 115 (18), 104 (68%).

4.3.14. Preparation of 3-(trichloroacetyl)-2-ethyliden-1,3-thiazinane

(56). Following the protocol used to prepare 54, 2-ethyl-5,6-

dihydro-4H-1,3-thiazine (53) (5.0 mmol, 0.646 g), was reacted

with pyridine (6.0 mmol, 0.484 mL) and trichloroacetyl chloride

(5.5 mmol, 1.000 g) in anhydrous DCM (6þ2 mL). The crude re-

action product was puriﬁed by ﬂash chromatography on silica gel,

eluting with a PE/Et₂O gradient (100:0 to 90:10). This gave the

enamide 56 (0.865 g, 63%), as a orange/brown oil, mixture of

rotamers [HRMS found 273.9635. C₈H₁₁Cl₃NOS (MþH)^þrequires

4.4.2. Reactionof3-(2,2-dichlorobutanoyl)-1-acetyl-2-ethylidenimidaz-

olidine (Ac-10a). CuCl (0.6 mmol, 0.059 g), K₂CO₃(2 mmol, 0.276 g),

and the substrate Ac-10a (2 mmol, 0.565 gdmixture 78:22 with its

hydrolysis adduct Ac-20a) were weighed into an oven dried Schlenk

tube, then anhydrous CH₃CN (3 mL) and PMDETA (0.66 mmol,138 mL)

273,9627]; R_f(95% PE/Et₂O) 0.26; n_max(KBr) 1679 cm^ꢃ1

;

d_H

were added under argon. The mixture was stirred at 30 ^ꢀC and

after 16 h diluted with water and extracted with DCM (3ꢂ20 mL).

The combined organic layers were concentrated under vacuum.

Chromatography of the recovered material on silica gel, eluting with

(200 MHz, acetone-d₆) 1.84 (3H, d, J 7.0 Hz, ]CHCH₃), 2.11 (2H, br

m, CH₂), 2.88 (2H, br t, SCH₂), 3.96 (2H, br s, NCH₂), 6.17 (1H, br q, J

6.8 Hz, CH]); d_C(50.31 MHz, CDCl₃) 14.5, 26.2, 26.6, 51.0, 92.9,

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

5877

a PE/Et₂O gradient (from 90:10 to 40:60) gave Ac-20a (0.178 g, 30%d

after subtraction of the starting Ac-20a) as a yellow oil, and N-(2-(N-

acetylacrylamido)ethyl)-2-chlorobutanamide Ac-21 (0.052 g, 12%) as

a yellow oil [HRMS found 261.0992. C₁₁H₁₈ClN₂O₃[MþH]^þrequires

layers were concentrated under vacuum. Chromatography of the

recovered material on silica gel, eluting with a PE/Et₂O gradient

(from 90:10 to 10:90) gave unreacted Ac-10b (0.129 g, 22%), Ac-29

(0.267 g, 56%), as a yellow oil [HRMS found 239.1392. C₁₂H₁₉N₂O₃

(MþH)^þrequires 239.1390], R_f(10% PE/Et₂O) 0.06, and Ac-30

(0.034 g, 7%), as a yellow-orange oil, mixture of two diastereomers

(dr 86:14) [HRMS found 241.1552. C₁₂H₂₁N₂O₃[MþH]^þrequires

241.1547], R_f(10% PE/Et₂O) 0.04.

261.1000], R_f(33% PE/Et₂O) 0.12; n_max(ﬁlm) 1685 cm^ꢃ1

; d_H(200 MHz,

CDCl₃) 0.99 (3H, t, J 7.3 Hz, CH₂CH₃), 1.80e2.20 (2H, m, CH₂CH₃), 2.43

(3H, s, CH₃C]O), 3.35e3.55 (2H, m, NHCH₂), 3.87 (2H, t, J 6.6 Hz,

NCH₂), 4.23 (1H, dd, J 7.7, 4.5 Hz, CHCl), 5.82 (1H, dd, J 10.3, 1.7 Hz, ]

CHH), 6.41 (1H, dd, J 16.8, 1.7 Hz, ]CHH), 6.78 (1H, dd, J 16.8, 10.3 Hz,

CH]), 7.06 (1H, br s, NH); d_C(50.32 MHz, CDCl₃) 10.2, 26.1, 28.7, 39.1,

43.2, 62.2 (CHCl), 130.0 (CH]), 130.9 (]CH₂), 169.7 (C]O), 173.7 (C]

O); m/z (EI, 70 eV) 260 (5, M^þ), 241 (7),181 (36),169 (24),141 (29),129

(82), 116 (67), 98 (99), 87 (65), 57 (100%).

4.4.4.1. 1-[3-(Acetylamino)propyl]-3-ethyl-4-methyl-2,5-dihydro-

1H-pyrrol-2,5-dione (Ac-29). n_max(ﬁlm) 1709, 1655 cm^ꢃ1

; d_H

(400 MHz, CDCl₃) 1.09 (3H, t, J 7.6 Hz, CH₂CH₃), 1.71 (2H, quintet, J

6.3 Hz, CH₂CH₂CH₂), 1.93 (3H, s, C(4)CH₃), 1.98 (3H, s, CH₃C]O),

2.36 (2H, q, J 7.6 Hz, CH₂CH₃), 3.14 (2H, q, J 6.3, NHCH₂), 3.49 (2H, t, J

6.3 Hz, NCH₂), 6.61 (1H, br s, NH); d_C(100.62 MHz, CDCl₃) 8.4, 12.5,

17.0, 23.0, 28.2 (CH₂), 34.7, 36.2, 136.5, 142.2, 170.5, 172.1, 172.5; m/z

(EI, 70 eV) 238 (53, M^þ), 195 (44), 179 (55), 166 (37), 152 (100), 141

(56), 73 (81), 56 (76%).

4.4.3. Cyclization of 1-(tert-butyloxycarbonyl)-3-(2,2-dichlorobu-

tanoyl)-2-ethyliden-1,3-diazinane

(Boc-10b). CuCl

(0.6 mmol,

0.060 g), K₂CO₃(2 mmol, 0.276 g), and the substrate Boc-10b

(2 mmol, 0.703 g, dr 60:40) were weighed into an oven dried

Schlenk tube, then anhydrous CH₃CN (3 mL) and PMDETA

(0.66 mmol, 138

m

L) were added under argon. The mixture was

4.4.4.2. 1-[3-(Acetylamino)propyl]-3-ethyl-4-methyl-pyrrolidin-

stirred at 30 ^ꢀC and after 16 h diluted with water and extracted with

DCM (3ꢂ20 mL). The combined organic layers were concentrated

under vacuum. Chromatography of the recovered material on silica

gel, eluting with a PE/Et₂O gradient (from 90:10 to 50:50) gave Boc-

29 (0.340 g, 57%), as a pale yellow oil [HRMS found 319.1628.

C₁₅H₂₄N₂NaO₄(MþNa)^þrequires 319.1628], R_f(50% PE/Et₂O) 0.20,

and Boc-30 (0.080 g, 13%), as a pale yellow oil, mixture of two di-

astereomers (dr 74:26) [HRMS found 321.1784. C₁₅H₂₆N₂NaO₄

(MþNa)^þrequires 321.1785], R_f(50% PE/Et₂O) 0.10.

2,5-dione (Ac-30). n_max(ﬁlm) 1700, 1658 cm^ꢃ1

; d_H(400 MHz,

CDCl₃) major isomer 1.03 (3H, t, J 7.4 Hz, CH₂CH₃), 1.22 (3H, d, J

7.7 Hz, C(4)CH₃), 1.50e1.80 (4H, m, CH₂CH₃þCH₂CH₂CH₂), 2.00 (3H,

s, CH₃C]O), 2.73 (1H, q, J 7.6 Hz, C(3)H), 2.95 (1H, quintet, J 7.7 Hz,

C(4)H), 3.14 (2H, br s, NHCH₂), 3.52 (2H, t, J 6.4 Hz, NCH₂), 6.64 (1H,

br s, NH), minor isomer 0.99 (3H, t, J 7.6 Hz, CH₂CH₃), 1.32 (3H, d, J

7.2 Hz, C(4)CH₃), 1.55e1.95 (4H, m, CH₂CH₃þCH₂CH₂CH₂), 2.00 (3H,

s, CH₃C]O), 2.25e2.40 (1H, m, C(3)H), 2.45e2.55 (1H, m, C(4)H),

3.14 (2H, br s, NHCH₂), 3.52 (2H, t, J 6.4 Hz, NCH₂), 6.64 (1H, br s,

NH); d_C(100.62 MHz, CDCl₃) major isomer 11.4, 12.3, 19.7, 23.0, 27.3,

35.4, 36.1, 38.1, 44.9, 170.6, 179.9, 180.9, minor isomer 10.1, 16.3, 23.0,

23.5, 27.3, 35.6, 36.0, 40.3, 49.2, 170.6, 179.4, 180.3; m/z (EI, 70 eV)

major isomer 240 (13, M^þ), 197 (45), 141 (32), 86 (64), 73 (30), 56

(100%), minor isomer 240 (13, M^þ), 197 (42), 149 (71), 141 (30), 86

(61), 73 (28), 56 (100%).

4.4.3.1. 1-[3-(tert-Butyloxycarbonylamino)propyl]-3-ethyl-4-

methyl-2,5-dihydro-1H-pyrrol-2,5-dione

(Boc-29). n_max

(ﬁlm)

1702 cm^ꢃ1

;

d_H(400 MHz, CDCl₃) 1.13 (3H, t, J 7.6, CH₂CH₃), 1.43 (9H,

s, C(CH₃)₃), 1.72 (2H, quintet, J 6.4 Hz, CH₂CH₂CH₂), 1.96 (3H, s, CH₃),

2.40 (2H, q, J 7.6 Hz, CH₂CH₃), 3.06 (2H, br t, J 6.4 Hz, CH₂CH₂CH₂),

3.53 (2H, t,

J 6.4 Hz, CH₂CH₂CH₂), 4.97 (1H, br s, NH); d_C

(100.62 MHz, CDCl₃) 8.5, 12.6, 17.1, 28.4, 28.9, 34.9, 37.5, 79.2, 136.5,

142.2, 155.9, 172.1, 172.5; m/z (EI, 70 eV) 296 (1, M^þ), 240 (17), 223

(26), 195 (27), 180 (34), 167 (19), 152 (69), 141 (98), 57 (100%).

4.4.5. Cyclization of (Z)-3-(2,2-dichlorobutanoyl)-1-acetyl-2-

benzylidenimidazolidine (13a). CuCl (0.1 mmol, 0.010 g), K₂CO₃

(2 mmol, 0.280 g), and the substrate 13a (2 mmol, 0.682 g) were

weighed into an oven dried Schlenk tube, then anhydrous CH₃CN

4.4.3.2. 1-[3-(tert-Butyloxycarbonylamino)propyl]-3-ethyl-4-

(3 mL) and PMDETA (0.11 mmol, 24 mL) were added under argon.

methyl-pyrrolidin-2,5-dione (Boc-30). n_max(ﬁlm) 1699 cm^ꢃ1

;

d_H

The mixture was stirred at 30 ^ꢀC and after 16 h diluted with water

and extracted with DCM (3ꢂ20 mL). The combined organic layers

were concentrated under vacuum. Chromatography of the re-

covered material on silica gel, eluting with a DCM/Et₂O gradient

(from 0:100 to 40:60) gave the 1-acetyl-6,11a-epoxy-6-ethyl-

2,3,11,11a-tetrahydro-1H-benzo[d]imidazo[1,2-a]azepin-5(6H)-one

24 (0.554 g, 97%) as a white ﬂake solid, mixture of rotamers (60:40)

[HRMS found 309.1216. C₁₆H₁₈N₂NaO₃(MþNa)^þrequires 309.1210],

R_f(50% DCM/Et₂O) 0.23; mp 143.6e144.2 ^ꢀC; n_max(KBr) 1732, 1682,

(400 MHz, CDCl₃) major isomer 1.02 (3H, t, J 7.4 Hz, CH₂CH₃), 1.21

(3H, d, J 7.9 Hz, CHCH₃), 1.40 (9H, s, C(CH₃)₃), 1.55e1.80 (4H, m,

CH₂CH₂CH₂þCH₂CH₃), 2.70 (1H, dt, J 7.9, 6.4 Hz, C(3)H), 2.92 (1H,

quintet, J 7.9 Hz, C(4)H), 3.02 (2H, br q, J 6.4 Hz, NHCH₂), 3.52 (2H, t,

J 6.4 Hz, NCH₂), 5.04 (1H, br s, NH), minor isomer 0.98 (3H, t, J 7.4 Hz,

CH₂CH₃), 1.31 (3H, d, J 7.3 Hz, CHCH₃), 1.40 (9H, s, C(CH₃)₃),

1.55e1.80 (3H, m, CH₂CH₂CH₂þCHHCH₃), 1.80e1.95 (1H, m,

CHHCH₃), 2.30 (1H, dt, J 8.3, 5.0 Hz, C(3)H), 2.47 (1H, dq, J 7.3,

5.0 Hz, C(4)H), 3.02 (2H, br q, J 6.4, NHCH₂), 3.52 (2H, t, J 6.4 Hz,

NCH₂), 5.04 (1H, br s, NH); d_C(100.62 MHz, CDCl₃) major isomer

11.4, 12.3, 19.7, 28.0, 28.3, 35.6, 37.2, 38.1, 44.9, 79.1, 155.1 (C]O),

179.7 (C]O), 180.7 (C]O), minor isomer 10.9, 16.3, 23.5, 28.0, 28.3,

35.6, 37.2, 40.2, 49.2, 79.1, 155.1 (C]O), 179.2 (C]O), 180.1 (C]O);

m/z (EI, 70 eV) major isomer 242 [48 (Mꢃ56)^þ], 225 (25), 197 (18),

182 (44), 155 (99), 141 (56), 57 (100%), minor isomer 242 [48

(Mꢃ56)^þ], 225 (24), 197 (20), 182 (48), 155 (100), 141 (56), 57 (99%).

1668 cm^ꢃ1

; d_H(400 MHz, CDCl₃) major rotamer 1.03 (3H, t, J 7.0 Hz,

CH₂CH₃), 2.10e2.40 (2H, m, CH₂CH₃), 2.33 (3H, s, CH₃C]O), 3.07

(1H, d, J 16.4 Hz, CHHPh), 3.20e3.40 (1H, m, CHHCH₂N), 3.80e4.10

(4H, m, CHHPhþCHHCH₂N), 7.10e7.40 (4H, m, 4CH_Ar); minor

rotamer 1.03 (3H, t, J 7.0 Hz, CH₂CH₃), 2.10e2.40 (2H, m, CH₂CH₃),

2.20 (3H, s, CH₃C]O), 2.85 (1H, d, J 16.0 Hz, CHHPh), 3.20e3.40 (1H,

m, CHHCH₂N), 3.80e4.10 (3H, m, CHHCH₂N), 4.69 (1H, d, J 16.0,

CHHPh), 7.10e7.40 (4H, m, 4CH_Ar); d_C(100.62 MHz, CDCl₃) major

rotamer 7.2, 22.6, 23.0, 37.1, 37.5, 47.4, 90.2, 101.7, 124.0, 126.9, 128.4,

129.3, 133.3, 134.5, 169.3, 173.7; minor rotamer 7.2, 23.0, 24.2, 35.2,

39.8, 48.4, 88.8, 103.3, 123.7, 126.3, 128.2, 129.3, 134.3, 169.7, 175.3;

m/z (EI, 70 eV) 286 (5, M^þ), 243 (10), 229 (100), 187 (66), 161 (36),

43 (29%). A sample of 24, suitable for the single-crystal X-ray

diffraction, was obtained by crystallization, under Argon, from

DCM/hexane at 4 ^ꢀC. Selected crystallographic data: C₁₆H₁₈N₂O₃,

M¼286.32, monoclinic, space group P2₁/c, a¼9.3270(3),

4.4.4. Cyclization of 1-acetyl-3-(2,2-dichlorobutanoyl)-2-ethyliden-

1,3-diazinane (Ac-10b). CuCl (0.6 mmol, 0.060 g), K₂CO₃(2 mmol,

0.276 g), and the substrate Ac-10b (2 mmol, 0.586 g, Z/E 64:36)

were weighed into an oven dried Schlenk tube, then anhydrous

CH₃CN (3 mL) and PMDETA (0.66 mmol, 138 mL) were added under

argon. The mixture was stirred at 30 ^ꢀC and after 16 h diluted with

water and extracted with DCM (3ꢂ20 mL). The combined organic

5878

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

3

ꢀ

ꢁ

b¼29.0321(11), c¼10.7640(4) A,

b

¼91.3073(11) , V¼2913.94(18) A ,

(2H, dq, J 14.3, 7.3 Hz, 2CHHCH₃), 2.20 (2H, dq, J 14.3, 7.3 Hz,

2CHHCH₃), 3.35 (2H, q, J 8.4 Hz, 2CHHCH₂), 3.56 (2H, dt, J 8.4,

2.7 Hz, 2CHHCH₂), 3.67 (2H, dt, J 11.5, 8.4 Hz, 2CH₂CHH), 4.16 (2H,

ddd, J 11.5, 8.4, 2.7 Hz, 2CH₂CHH), 7.32e7.48 (10H, m, 10CH_Ar); d_C

(100.62 MHz, CDCl₃) 12.8, 17.7, 38.6, 44.3, 87.7 (2NCS), 127.9, 128.0,

129.1, 132.9, 134.6, 156.2, 173.6; m/z (ESI) 999.0 (2MþNa)^þ, 511.1

(MþNa)^þ, 244.2 (M/2)^þ. Selected crystallographic data:

C₂₈H₂₈N₂O₂S₂, M¼488.64, orthorhombic, space group Pccn,

Z¼8, T¼298(2) K, r_calcd¼1.305 g cm^ꢃ3; reﬂections collected/unique

38,535/8476 (R_int¼0.0257); ﬁnal R indices R₁¼0.0421 [I>2

s(I)],

wR₂¼0.1249 (all data); data/restraints/parameters¼8476/0/383,

ꢁ^ꢃ3

GoF¼1.044, residuals min/max¼ꢃ0.203/0.243 e A

.

4.4.6. Cyclization of 1-acetyl-3-(2,2-dichlorobutanoyl)-2-benzyliden-

1,3-diazinane (13b). CuCl (0.6 mmol, 0.060 g), K₂CO₃(2 mmol,

0.276 g), and the substrate 13b (2 mmol, 0.711 g, Z/E 57:43) were

weighed into an oven dried Schlenk tube, then anhydrous CH₃CN

3

ꢁ

a¼30.2370(7), b¼17.4914(5), c¼18.6559(5) A, V¼9866.9(4) A ,

Z¼16, T¼298(2) K, r_calcd¼1.316 g cm^ꢃ3; reﬂections collected/unique

(3 mL) and PMDETA (0.66 mmol, 138

m

L) were added under argon.

112,644/11,330 (R_int¼0.0405); ﬁnal R indices R₁¼0.0481 [I>2

s(I)],

The mixture was stirred at 30 ^ꢀC and after 16 h diluted with water

and extracted with DCM (3ꢂ20 mL). The combined organic layers

were concentrated under vacuum. Chromatography of the re-

covered material on silica gel, eluting with a PE/Et₂O gradient (from

90:10 to 0:100) gave the 1-(3-acetylamidopropyl)-3-ethyl-4-

phenyl-2,5-dihydro-1H-pyrrol-2,5-dione 31 (0.355 g, 59%), as

a yellow oil [HRMS found 301.1554. C₁₇H₂₁N₂O₃(MþH)^þrequires

wR₂¼0.1372 (all data); data/restraints/parameters 11,330/0/613,

ꢁ^ꢃ3

GoF¼1.020, residuals min/max¼ꢃ0.284/0.313 e A

.

4.4.7.4. meso-(7aR,7⁰aS)-6,6⁰-Diethyl-7,7⁰-diphenyl-2H,2⁰H-

7a,7⁰a-bipyrrolo[2,1-b]-1,3-thiazole-5,5⁰(3H,3⁰H)-dione

(meso-

40). d_H(400 MHz, CDCl₃) 0.81 (6H, t, J 7.2 Hz, 2CH₂CH₃), 1.86 (2H,

dq, 14.1, 7.2 Hz,

14.1, 7.2 Hz, 2ꢂCHHCH₃), 1.97 (2H, dq,

2ꢂCHHCH₃), 3.10e3.25 (4H, m, 2ꢂCH₂CH₂), 3.65e3.85 (2H, m,

J

301.1547]; R_f(95% DCM/MeOH) 0.45; n_max(ﬁlm) 1703, 1652 cm^ꢃ1

;

d_H(400 MHz, CDCl₃) 1.20 (3H, t, J 7.5 Hz, CH₂CH₃), 1.78 (2H, quintet,

J 6.3 Hz, CH₂CH₂CH₂), 1.94 (3H, s, CH₃C]O), 2.55 (2H, q, J 7.5 Hz,

CH₂CH₃), 3.19 (2H, q, J 6.3, CH₂NH), 3.57 (2H, t, J 6.3 Hz, NCH₂), 6.88

(1H, br s, NH), 7.30e7.55 (5H, m, 5CH_Ar); d_C(100.62 MHz, CDCl₃)

12.6, 17.2, 22.6, 27.9, 34.9, 36.0, 128.1, 128.3, 128.8, 129.1, 136.4, 141.4,

170.0, 170.8, 171.2; m/z (EI, 70 eV) 300 (100, M^þ), 258 (7), 241 (70),

228 (40), 214 (19), 203 (46), 129 (54), 115 (63), 73 (99%).

2ꢂCH₂CHH), 4.47 (2H, ddd,

J

11.5, 7.5, 2.3 Hz, 2ꢂCH₂CHH),

6.95e7.70 (10H, m, 10ꢂCH_Ar); d_C(100.62 MHz, CDCl₃) 12.8, 17.4,

36.8, 47.0, 88.6, 127.6, 128.5, 129.7, 132.6, 136.3, 156.2, 175.2; m/z

(ESI) 999.0 (2MþNa)^þ, 511.1 (MþNa)^þ, 244.1 (M/2)^þ.

4.4.7.5. 7a,7a⁰-Oxybis{6-ethyl-7-phenyl-2,3-dihydropyrrolo[2,1-

b]thiazol-5(7aH)-one} (41). d_H(400 MHz, CDCl₃) 1.19 (6H, t, J 7.6 Hz,

2ꢂCH₂CH₃), 2.55e2.70 (4H, m, 2ꢂCH₂CH₃), 2.95e3.05 (4H, m,

2ꢂCH₂), 3.85e3.95 (4H, m, 2ꢂCH₂), 6.95e7.70 (10H, m, 10ꢂCH_Ar);

d_C(100.62 MHz, CDCl₃) (only identiﬁed signals are reported) 13.0,

17.7, 35.9, 37.8, 128.6, 128.9, 129.3, 141.9; m/z (ESI) 1031.4

(2MþNa)^þ, 527.2 (MþNa)^þ.

4.4.7. Cyclization of 3-(2,2-dichlorobutanoyl)-2-(Z)-benzylidenthia-

zolidine (11a). CuCl (0.2 mmol, 0.020 g), Na₂CO₃(2 mmol, 0.212 g),

and the substrate 11a (2 mmol, 0.633 g) were weighed into an oven

dried Schlenk tube, then anhydrous CH₃CN (3 mL) and TMEDA

(0.4 mmol, 58 mL) were added under argon. The mixture was stirred

at 30 ^ꢀC and after 16 h diluted with water and extracted with DCM

(3ꢂ20 mL). The combined organic layers were concentrated under

vacuum. Chromatography of the recovered material on silica gel,

eluting with a PE/Et₂O gradient (from 100:0 to 0:100) gave 38a

(0.135, 26%) as a yellow oil [HRMS found 521.1566. C₂₈H₂₉N₂O₄S₂

(MþH)^þrequires 521.1563], R_f(20% PE/Et₂O) 0.70, 39a (0.242, 48%)

as a yellow oil [HRMS found 522.1878. C₂₈H₃₂N₃O₃S₂(MþNH₄)^þ

requires 522.1880], R_f(20% PE/Et₂O) 0.44, and an unseparable

mixture of dl-40, meso-40, and 41 [68:20:12 (¹H NMR)] as a yellow

foamy solid (0.078 g, 16%; 0.023 g, 5%; 0.015 g, 3%), R_f(20% PE/Et₂O)

0.19. Some dl-40 was separated by crystallization from a solution of

4.4.8. Cyclization of 3-(2,2-dichlorobutanoyl)-2-(Z)-benzyliden-1,3-

thiazinane (11b). CuCl (0.1 mmol, 0.010 g), Na₂CO₃(2 mmol,

0.212 g), and the substrate 11b (2 mmol, 0.661 g) were weighed

into an oven dried Schlenk tube, then anhydrous CH₃CN (3 mL) and

TMEDA (0.2 mmol, 30 mL) were added under argon. The mixture

was stirred at 30 ^ꢀC and after 17 h diluted with water and extracted

with DCM (3ꢂ20 mL). The combined organic layers were concen-

trated under vacuum. Chromatography of the recovered material

on silica gel, eluting with a PE/Et₂O gradient (from 100:0 to 20:80)

gave the dimer 38b (0.127 g, 23%) as a yellow oil [HRMS found

571.1709. C₃₀H₃₂N₂NaO₄S₂(MþNa)^þrequires 571.1696], R_f(20% PE/

Et₂O) 0.67, and the thioacetal 39b (0.331 g, 62%) as a yellow oil

[HRMS found 555.1744. C₃₀H₃₂N₂NaO₃S₂(MþNa)^þrequires

555.1747], R_f(20% PE/Et₂O) 0.45.

DCM/n-hexane, as

a yellow solid [HRMS found 511.1484.

C₂₈H₂₈N₂NaO₂S₂(MþNa)^þrequires 511.1484], mp 175e177 ^ꢀC.

4.4.7.1. 1,1⁰-[2,2⁰-Disulfanediylbis(ethane-2,1-diyl)]bis(3-ethyl-4-

phenyl-1H-pyrrole-2,5-dione) (38a). n_max(ﬁlm) 1699 cm^ꢃ1

;

d_H

4.4.8.1. 1,1⁰-[3,3⁰-Disulfanediylbis(propane-3,1-diyl)]bis(3-ethyl-

(400 MHz, CDCl₃) 1.22 (6H, t, J 7.5 Hz, 2CH₂CH₃), 2.61 (4H, q, J

7.5 Hz, 2CH₂CH₃), 2.99 (4H, t, J 6.8 Hz, 2CH₂), 3.91 (4H, t, J 6.8 Hz,

2CH₂), 7.20e7.60 (10H, m, 10CH_Ar); d_C(100.62 MHz, CDCl₃) 12.9,

17.5, 35.7, 36.9, 128.3, 128.6, 129.1, 129.4, 136.7, 141.7, 170.5, 171.0.

4-phenyl-1H-pyrrole-2,5-dione) (38b). n_max(ﬁlm) 1701 cm^ꢃ1

; d_H

(400 MHz, CDCl₃) 1.23 (6H, t, J 7.4 Hz, 2ꢂCH₂CH₃), 2.04 (4H, quintet,

J 7.1 Hz, 2ꢂCH₂), 2.61 (4H, q, J 7.4 Hz, 2ꢂCH₂CH₃), 2.71 (4H, t, J

7.1 Hz, 2ꢂCH₂), 3.68 (4H, t, J 7.1 Hz, 2ꢂCH₂), 7.35e7.60 (10H, m,

10ꢂCH_Ar); d_C(100.62 MHz, CDCl₃) 13.1, 17.7, 28.1, 36.0, 36.9, 128.6,

128.8, 129.3, 129.5, 136.9, 141.9, 171.0, 171.5.

4.4.7.2. 3-Ethyl-1-[2-(6-ethyl-5-oxo-7-phenyl-2,3,5,7a-tetrahy-

dropyrrolo[2,1-b]thiazol-7a-ylthio)ethyl]-4-phenyl-1H-pyrrole-2,5-

dione (39a). n_max(ﬁlm) 1702 cm^ꢃ1

;

d_H(400 MHz, CDCl₃) 1.20 (3H, t, J

4.4.8.2. 3-Ethyl-1-{3-(7-ethyl-6-oxo-8-phenyl-3,4,6,8a-tetrahy-

dro-2H-pyrrolo[2,1-b]-1,3-thiazin-8a-ylthio)propyl}-4-phenyl-1H-

7.6 Hz, CH₂CH₃), 1.22 (3H, t, J 7.6, CH₂CH₃), 2.35e2.52 (4H, m,

CH₂CH₃þCH₂), 2.58 (2H, q, J 7.6, CH₂CH₃), 3.35e3.52 (2H, m, CH₂),

3.56 (2H, t, J 7.0, CH₂), 3.55e3.66 (1H, m, CHH), 4.34 (1H, ddd, J 11.5,

7.7, 3.5, CHH), 7.30e7.60 (10H, m, 10CH_Ar); d_C(100.62 MHz, CDCl₃)

13.0,13.1,17.6,18.1, 30.8, 37.3, 38.3, 42.2, 85.2,128.2,128.5,128.6,128.7,

129.2, 129.3, 129.5, 131.4, 135.5, 136.7, 141.8, 153.4, 170.4, 170.9, 172.0.

pyrrole-2,5-dione (39b). n_max(ﬁlm) 1704 cm^ꢃ1

; d_H(400 MHz,

CDCl₃) 1.05 (3H, t, J 7.5 Hz, CH₂CH₃), 1.18 (3H, t, J 7.6 Hz, CH₂CH₃),

1.59 (1H, br q, J 13.0, CH₂CH_axHCH₂), 1.76 (2H, quintet, J 6.9 Hz,

CH₂CH₂CH₂), 1.85e2.00 (2H, m, CHHSþCH₂CHH_eqCH₂), 2.00e2.13

(1H, m, CHHS), 2.32 (2H, m, CH₂CH₃), 2.55 (2H, q, J 7.6 Hz, CH₂CH₃),

2.55e2.65 (1H, m, CH_eqHS), 3.13 (1H, dt, J 13.0, 2.4 Hz, CH_axHN),

3.28 (1H, br t, J 13.0 Hz, CHH_axS), 3.40e3.60 (2H, m, CH₂N), 4.33 (1H,

4.4.7.3. (ꢁ)-(7aR,7⁰aR)-6,6⁰-Diethyl-7,7⁰-diphenyl-2H,2⁰H-7a,7⁰a-

bipyrrolo[2,1-b]thiazole-5,5⁰(3H,3⁰H)-dione

(dl-40). n_max

(KBr)

br d,

J

13.0 Hz, CHH_eqN), 7.20e7.60 (10H, m, 10ꢂCH_Ar); d_C

1700 cm^ꢃ1

; d_H(400 MHz, CDCl₃) 0.98 (6H, t, J 7.3 Hz, 2CH₂CH₃), 2.06

(100.62 MHz, CDCl₃) 12.8, 13.2, 17.4, 17.7, 25.3, 26.3, 27.3, 27.8, 35.4,

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

5879

37.0, 74.0 (SCN), 128.0, 128.2, 128.5, 128.7, 128.8, 129.0, 129.2, 131.1,

136.55, 136.60, 141.6, 151.6, 166.7, 170.5, 171.0.

dt, J_gem¼J_aa¼13.5, J_ae¼2.5 Hz, CH_axHS), 3.60 (2H, dt, J 6.9, 2.2 Hz,

acyclic CH₂N), 4.40 (1H, br d, J 13.4 Hz, CH_eqHN), 7.34 (1H, m, CH_Ar),

7.40 (2H, m, CH_Ar), 7.46 (3H, m, CH_Ar), 7.51 (2H, dd, CH_Ar), 7.55 (2H,

dd, CH_Ar); d_C(125 MHz, CDCl₃) 9.9, 11.7, 26.2, 27.1, 28.0, 28.05, 36.0,

37.3, 74.2, 128.2, 128.3, 128.5, 128.9, 129.3, 129.4, 129.5, 130.6, 131.7,

136.6, 137.1, 152.1, 166.5, 170.9, 171.8; m/z (ESI) 543.4 (MþK)^þ, 527.4

(MþNa)^þ, 505.3 (MþH)^þ.

4.4.9. Cyclization of 3-(2,2-dichloro-3-methylbutanoyl)-2-(Z)-ethyl-

iden[1,3]thiazinane (54). Following the procedure used for the cy-

clization of 11b, the enamide 54 (2 mmol, 0.757 g), with a catalyst

load of 10 mol %, gave, after chromatography of the crude extract on

silica gel, eluting with a PE/Et₂O gradient (from 100:0 to 20:80), the

disulﬁde 58 (0.086 g, 19%) as a colorless oil [HRMS found 453.1879.

C₂₂H₃₃N₂O₄S₂(MþH)^þrequires 453.1876], R_f(50% PE/Et₂O) 0.49,

and the thioacetal 59 (0.319 g, 73%) as a yellow oil [HRMS found

437.1937. C₂₂H₃₃N₂O₃S₂(MþH)^þrequires 437.1927], R_f(60% PE/

Et₂O) 0.25.

4.4.11. Cyclization of 3-(trichloroacetyl)-2-(Z)-ethyliden-1,3-

thiazinane (56). Following the procedure used for the cyclization

of 11b, the enamide 56 (2 mmol, 0.757 g), with a catalyst load of

10 mol %, gave, after chromatography of the crude extract on silica

gel, eluting with a PE/Et₂O gradient (from 100:0 to 20:80), the

disulﬁde 62 (0.114 g, 26%) as a white solid [HRMS found 437.0159.

C₁₆H₁₉Cl₂N₂O₄S₂(MþH)^þrequires 437.0158], R_f(50% PE/Et₂O) 0.36,

mp 97e98 ^ꢀC and the thioacetal 63 (0.122 g, 29%) as a yellow solid

[HRMS found 421.0221. C₁₆H₁₉Cl₂N₂O₃S₂(MþH)^þrequires

421.0209], R_f(60% PE/Et₂O) 0.20, mp 127e129 ^ꢀC.

4.4.9.1. 1,1⁰-[3,3⁰-Disulfanediylbis(propane-3,1-diyl)]bis(3-

isopropyl-4-methyl-1H-pyrrole-2,5-dione)

(58). n_max

(ﬁlm)

1702 cm^ꢃ1

;

d_H(200 MHz, CDCl₃) 1.23 (12H, d, J 7.0 Hz, 2ꢂCH(CH₃)₂),

1.95 (4H, quintet, J 7.0 Hz, 2ꢂCH₂CH₂CH₂), 1.98 (6H, s, 2ꢂCH₃), 2.64

(4H, t, J 7.2 Hz, CH₂S), 2.93 (2H, sept, J 7.0 Hz, 2ꢂCH(CH₃)₂), 3.55

(4H, t, J 6.8 Hz, 2ꢂCH₂N); d_C(50 MHz, CDCl₃) 8.6, 20.6, 25.4, 28.2,

36.1, 36.6, 135.4, 145.0, 171.4, 172.2; m/z (EI, 70 eV) 226 (3, 1/2M^þ),

194 (100), 166 (45), 81 (11), 41(9).

4.4.11.1. 1,1⁰-[3,3⁰-Disulfanediylbis(propane-3,1-diyl)]bis(3-

chloro-4-methyl-1H-pyrrole-2,5-dione) (62). n_max(KBr) 1710 cm^ꢃ1

;

d_H(200 MHz, CDCl₃) 1.99 (4H, quintet, J 7.0 Hz, 2ꢂCH₂CH₂CH₂), 2.06

(6H, s, 2ꢂCH₃), 2.67 (4H, t, J 7.2 Hz, 2ꢂCH₂S), 3.65 (4H, t, J 7.0 Hz,

2ꢂCH₂N); d_C(50 MHz, CDCl₃) 9.0, 28.0, 35.9, 37.4, 133.8, 137.7, 165.2,

169.0; m/z (EI, 70 eV) 436 (1, M^þ) (1), 218 (2), 186 (100), 158 (91), 56

(14), 41(12).

4.4.9.2. 3-Isopropyl-1-{3-(7-isopropyl-8-methyl-6-oxo-3,4,6,8a-

tetrahydro-2H-pyrrolo[2,1-b]-1,3-thiazin-8a-ylthio)propyl}-4-

methyl-1H-pyrrole-2,5-dione (59). n_max(ﬁlm) 1768, 1701 cm^ꢃ1

; d_H

(500 MHz, CDCl₃) 1.242, 1.245, 1.250, 1.255 (3H each, 4d, J 7.0 Hz

each, CH(CH₃)₂), 1.62 (1H, m, partially overlapped, CH₂CHH_axCH₂),

1.67 (2H, quintet, J 7.2 Hz, CH₂CH₂CH₂), 1.86 (2H, m, acyclic CH₂S),

1.98 (3H, s, CH₃), 1.99 (m, 1H, CH₂CH_eqHCH₂), 2.07 (3H, s, CH₃), 2.71

(dt, 1H, J_gem13.3 Hz, J_ae¼J_ee¼3.1 Hz, CH_eqHS), 2.89, 2.93 (1H each, 2

sept, J 7.0 Hz each, CH(CH₃)₂), 3.08 (1H, dt, J_aa¼J_gem¼13.4 Hz, J_ae

3.2 Hz, CH_axHN), 3.34 (1H, dt, J_aa¼J_gem¼13.3, J_ae3.1 Hz, CH_axHS),

3.45 (2H, t, J 7.2 Hz, acyclic CH₂N), 4.28 (1H, br d, J 13.4 Hz, CH_eqHN);

d_C(125 MHz, CDCl₃) 8.6, 10.5, 20.5, 20.6, 20.9, 25.35, 25.45, 26.0,

26.8, 27.7, 27.9, 35.5, 37.0, 73.9, 135.5, 137.5, 145.1, 149.2, 167.2, 171.3,

172.1; m/z (ESI) 475.4 (MþK)^þ, 459.5 (MþNa)^þ, 437.4 (MþH)^þ.

4.4.11.2. 3-Chloro-1-{3-(7-chloro-8-methyl-6-oxo-3,4,6,8a-tetra-

hydro-2H-pyrrolo[2,1-b]-1,3-thiazin-8a-ylthio)propyl}-4-methyl-1H-

pyrrole-2,5-dione (63). n_max(KBr) 1756, 1703 cm^ꢃ1

; d_H(500 MHz,

CDCl₃) 1.62 (1H, tq, partially overlapped, CH₂CH_axH CH₂),1.68 (2H, t,

J 7.1 Hz, acyclic CH₂CH₂CH₂), 1.91 (2H, m, J 7.1 Hz, acyclic CH₂S), 2.02

(1H, overlapped m, CH₂CH_eqHCH₂), 2.04 (3H, s, CH₃), 2.10 (3H, s,

CH₃), 2.71 (1H, dt, J_gem13.4, J_ea¼J_ee¼3.4 Hz, CH_eqHS), 3.13 (1H, dt,

J_gem¼J_aa¼13.4, J_ae2.9 Hz, CH_axHN), 3.32 (1H, dt, J_gem¼J_aa¼13.4,

J_ae¼3.4 Hz, CH_axHS), 3.51 (2H, t, J 7.0 Hz, acyclic CH₂N), 4.29 (1H, br

d, J 13.4 Hz, CH_eqHN); d_C(125 MHz, CDCl₃) 9.1, 10.8, 26.0, 26.9, 27.8,

27.9, 36.3, 37.6, 73.7,125.3, 133.8, 137.8,151.6,162.0, 165.1,169.0; m/z

(ESI) 459.2 (MþK)^þ, 443.3 (MþNa)^þ.

4.4.10. Cyclization of 3-(2,2-dichlorophenylacetyl)-2-(Z)-ethyliden-

1,3-thiazinane (55). Following the procedure used for the cycliza-

tion of 11b, the enamide 55 (2 mmol, 0.633 g), with a catalyst load

of 10 mol %, gave, after chromatography of the crude extract on

silica gel, eluting with a PE/Et₂O gradient (from 100:0 to 20:80), the

disulﬁde 60 (0.078 g, 15%) as a thick yellow oil [HRMS found

521.1538. C₂₈H₂₉N₂O₄S₂(MþH)^þrequires 521.1563], R_f(50% PE/

Et₂O) 0.42, and the thioacetal 61 (0.419 g, 83%) as a yellow solid

[HRMS found 505.1600. C₂₈H₂₉N₂O₃S₂(MþH)^þrequires 505.1614],

R_f(50% PE/Et₂O) 0.18, mp 70e71 ^ꢀC.

4.4.12. Cyclization of 3-(2,2-dichlorophenylacetyl)-2-(Z)-benzyliden-

1,3-thiazinane (57). Following the procedure used for the cycliza-

tion of 11b, the enamide 57 (2 mmol, 0.757 g), with a catalyst load

of 10 mol %, gave, after chromatography of the crude extract on

silica gel, eluting with a PE/Et₂O gradient (from 100:0 to 0:100), the

disulﬁde 64 (0.290 g, 45%) as a yellow solid [HRMS found 645.1909.

C₃₈H₃₃N₂O₄S₂(MþH)^þrequires 645.1876], R_f(60% PE/Et₂O) 0.50,

mp 115e117 ^ꢀC, and the thioacetal 65 (0.333 g, 53%) as a bright

yellow solid [HRMS found 629.1939. C₃₈H₃₃N₂O₃S₂(MþH)^þre-

quires 629.1927], R_f(60% PE/Et₂O) 0.15, mp 105e107 ^ꢀC.

4.4.10.1. 1,1⁰-[3,3⁰-Disulfanediylbis(propane-3,1-diyl)]bis(3-

methyl-4-phenyl-1H-pyrrole-2,5-dione) (60). n_max(ﬁlm) 1767,

1701 cm^ꢃ1

;

d_H(500 MHz, CDCl₃) 2.05 (4H, quintet, J 7.0 Hz,

4.4.12.1. 1,1⁰-[3,3⁰-Disulfanediylbis(propane-3,1-diyl)]bis(3,4-

2ꢂCH₂CH₂CH₂), 2.20 (s, 6H, 2ꢂCH₃), 2.71 (4H, t, J 7.0 Hz, 2ꢂCH₂S),

3.69 (4H, t, J 7.0 Hz, 2ꢂCH₂N), 7.44, 7.47 (2 m, 6H, 2ꢂp- and m-

CH_Ar), 7.58 (dd, 4H, 2ꢂo-CH_Ar); d_C(125 MHz, CDCl₃) 9.9, 28.1, 36.0,

36.9, 128.5, 128.9, 129.4, 129.5, 136.5, 137.0, 170.9, 171.8; m/z (ESI)

559.3 (MþK)^þ, 543.4 (MþNa)^þ, 521.4 (MþH)^þ.

diphenyl-1H-pyrrole-2,5-dione) (64). n_max(ﬁlm) 1762, 1700 cm^ꢃ1

;

d_H(500 MHz, CDCl₃) 2.11 (4H, quintet, J 7.0 Hz, 2ꢂCH₂CH₂CH₂), 2.77

(4H, t, J 7.0 Hz, 2ꢂCH₂S), 3.77 (4H, t, J 7.0 Hz, 2ꢂCH₂N), 7.36 (12H, m,

12ꢂCH_Ar), 7.54 (8H, dd, 8ꢂCH_Ar); d_C(125 MHz, CDCl₃) 28.1, 36.0,

37.2, 128.5, 128.6, 129.8, 129.9, 136.1, 170.7; m/z (ESI) 667.4

(MþNa)^þ.

4.4.10.2. 3-Methyl-1-{3-(8-methyl-6-oxo-7-phenyl-3,4,6,8a-tet-

rahydro-2H-pyrrolo[2,1-b]-1,3-thiazin-8a-ylthio)propyl}-4-phenyl-

4.4.12.2. 1-{3-(6-Oxo-7,8-diphenyl-3,4,6,8a-tetrahydro-2H-pyr-

rolo[2,1-b]-1,3-thiazin-8a-ylthio)propyl}-3,4-diphenyl-1H-pyrrole-

1H-pyrrole-2,5-dione (61). n_max(ﬁlm) 1767, 1703 cm^ꢃ1

;

d_H

(500 MHz, CDCl₃) 1.71 (1H, tq, J_aa¼J_gem13.5, J_ae3.7 Hz,

CH₂CH_axHCH₂), 1.79 (2H, quintet, J 7.1 Hz, CH₂CH₂CH₂), 2.03 (2H, t, J

7.1 Hz, acyclic CH₂S), 2.04 (1H, tq, overlapped, CH₂CH_eqHCH₂), 2.17

(3H, s, CH₃), 2.26 (3H, s, CH₃), 2.76 (1H, dt, J_gem13.5, J_ea¼J_ee¼2.5 Hz,

CH_eqHS), 3.20 (1H, dt, J_gem¼J_aa¼13.4, J_ae3.0 Hz, CH_axHN), 3.42 (1H,

2,5-dione (65). n_max(ﬁlm) 1767, 1701 cm^ꢃ1

;

d_H(500 MHz, CDCl₃)

1.76 (1H, qt, J_gem¼J_aa¼13.5, J_ae¼2.7 Hz, CH₂CH_axHCH₂), 1.90 (2H,

quintet,

J

7.2 Hz, CH₂CH₂CH₂), 2.07 (1H, dt, J_gem¼J_aa13.5,

J_ee¼J_ea¼2.7 Hz, CH₂CH_eqHCH₂), 2.13 (1H, dt, J 12.5, 7.2 Hz, acyclic

CHHS), 2.24 (1H, dt, J 12.5, 7.2 Hz, acyclic CHHS), 2.72 (1H, dt, J_gem

5880

A. Cornia et al. / Tetrahedron 68 (2012) 5863e5881

13.5, J_ea¼J_ee¼2.7 Hz, CH_eqHS), 3.30 (1H, dt, J_gem¼J_aa¼13.4, J_ae

2.9 Hz,CH_axHN), 3.42 (1H, dt, J_gem¼J_aa¼13.4, J_ae2.5 Hz, CH_axHS), 3.66

(2H, m, CH₂N), 4.50 (1H, br d, J 13.4 Hz, CH_eqHN), 7.23 (2H, m, CH_Ar),

7.27e7.40 (10H, m, CH_Ar), 7.43 (6H, m, CH_Ar), 7.55 (2H, dd, J 7.9,

1.6 Hz, CH_Ar); d_C(125 MHz, CDCl₃) 25.8, 26.9, 27.7, 28.3, 36.0, 37.6,

74.6, 128.2, 128.35, 128.4, 128.5, 129.2, 129.7, 129.8, 129.85, 129.9,

130.5, 131.5, 132.8, 136.2, 152.6, 166.0, 170.6; m/z (ESI) 651.4

(MþNa)^þ.

eluting with a PE/Et₂O gradient (from 100:0 to 20:80), the maleic

anhydride 68, as a thick beige oil (0.059 g, 20%), spectroscopic data

are in agreement with those reported in the literature.⁵⁶

4.5.5. Preparation of 3,4-diphenylfuran-2,5-dione (69). Following

the procedure used for the preparation of 52, 3-(dichlor-

ophenylacetyl)-2-(Z)-benzyliden[1,3]thiazinane (57) (2 mmol,

0.757 g) gave, after chromatography of the crude product (derived

from the ﬁnal hydrolysis step) on silica gel, eluting with a PE/Et₂O

gradient (from 100:0 to 20:80), the maleic anhydride 69, as a white

solid (0.375 g, 75%), spectroscopic data are in agreement with those

reported in the literature.⁵⁷

4.5. Preparation of disubstituted maleic anhydrides

4.5.1. Preparation of 3-ethyl-4-phenylfuran-2,5-dione (52). In

a Schlenk tube, ﬁtted with a screw cap, a perforable septum and

a stirring bar, were weighed 3-(2,2-dichlorobutanoyl)-2-(Z)-ben-

zyliden-[1,3]thiazinane (11b) (4.5 mmol, 1.485 g), Na₂CO₃

(4.5 mmol, 0.477 g), and CuCl (0.225 mmol, 0.023 g). Anhydrous

Acknowledgements

ꢀ

We thank the Ministero dell’Istruzione, dell’Universita e della

CH₃CN (6.8 mL) and TMEDA (0.45 mmol, 68 mL) were then added

Ricerca (MIUR) for ﬁnancial support (PRIN 20085E2LXC-004,

under argon. The stirred reaction mixture was thermostated at

30 ^ꢀC and, after 16 h, it was diluted with H₂O (20 mL) and extracted

with DCM (3ꢂ20 mL). The organic phases were collected, dried

over MgSO₄, ﬁltered, and evaporated in a Schlenk tube (ﬁtted with

a screw cap and a stirring bar). To the crude product (containing

a 73:27 mixture of the asymmetric and symmetric dimers, 39b and

38b, respectively, which correspond to 1.64 mmol of 39b and

0.61 mmol of 38b, considering a quantitative transformation) were

then added wet SiO₂60%_w/w(0.5 g/mmol of 39b, 0.825 g), NaNO₃

(2 equiv, 3.29 mmol, 0.280 g), silica/sulfuric acid (2 equiv,

3.29 mmol, 0.902 g),⁵⁶and DCM (9 mL). The mixture was stirred at

45 ^ꢀC for 40 h, afterward it was diluted with Et₂O (15 mL) and ﬁl-

tered. The solid was washed three more times with Et₂O (3ꢂ10 mL),

then the combined organic layers were concentrated under vac-

uum. The recovered crude product was diluted with THF/MeOH 1:2

(12 mL) and treated with a solution of KOH (10.5 mmol, 600 mg) in

H₂O. The reaction mixture was reﬂuxed for 2 h, afterward the sol-

vent was evaporated, and the residue acidiﬁed with HCl_aq10%

(7 mL) and extracted with DCM (2ꢂ20 mL). The crude anhydride,

obtained after the usual work-up, was puriﬁed by ﬂash chroma-

tography on silica gel, eluting with a PE/Et₂O gradient (from 100:0

to 20:80). The maleic anhydride 52 was isolated as a yellow oil

(0.47 g, 52%); spectroscopic data are in agreement with those

reported in literature.⁵⁴

20085E2LXC-003).

Supplementary data

Supplementary data associated with this article can be found in

the online version, at doi:10.1016/j.tet.2012.04.117. These data in-

clude MOL ﬁles and InChiKeys of the most important compounds

described in this article.

References and notes

1. (a) Bowman, W. R.; Bridge, C. F.; Brookes, P. J. Chem. Soc., Perkin Trans. 1 2000,

1e14; (b) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.;

€

Trach, F. In Organic Reactions; Paquette, L. A., Ed.; Wiley: NY, USA, 1996; Vol. 48,

pp 301e586; (c) Ghosez, A.; Giese, B.; Zipse, H. Houben-Weil; Georg Thieme:

Stuttgart, 1989; Vol. E19a; 1042e1052; (d) Giese, B.; Kopping, B.; Gobel, T.;

Kopping, B.; Zipse, H. Houben-Weil; Georg Thieme: Stuttgart, 1995; Vol. E21,;

2250e2287.

2. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734e736; (b) Beckwith, A.

L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc., Chem. Commun. 1980, 482e483.

3. For reviews see: (a) Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis 2002, 695e713;

(b) Parsons, A. F. C. R. Acad. Sci. ParisdSer. IIcdChem. 2001, 4, 391e400.

4. (a) Bryans, J. S.; Chessum, N. E. A.; Parsons, A. F.; Ghelﬁ, F. Tetrahedron Lett. 2001,

42, 2901e2905; (b) Ishibashi, H.; Higuchi, M.; Ohba, M.; Ikeda, M. Tetrahedron

Lett. 1998, 39, 75e78.

5. For a different opinion see: Chatgilialoglu, C.; Ferreri, C.; Guerra, M.; Timokhin,

V.; Froudakis, G.; Gimisis, T. J. Am. Chem. Soc. 2002, 124, 10765e10772.

6. Ishibashi, H. Chem. Rec. 2006, 6, 23e31.

7. (a) Bregoli, M.; Felluga, F.; Frenna, V.; Ghelﬁ, F.; Pagnoni, U. M.; Parsons, A. F.;

Petrillo, G.; Spinelli, D. Synthesis 2011, 1267e1278; (b) Ghelﬁ, F.; Bellesia, F.;

Forti, L.; Ghirardini, G.; Grandi, R.; Libertini, E.; Montemaggi, M. C.; Pagnoni, U.

M.; Pinetti, A. Tetrahedron 1999, 55, 5839e5852.

8. (a) Galeazzi, R.; Mobbili, G.; Orena, M. In Targets in Heterocyclic System-

sdChemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Italian Society of

Chemistry: Rome, Italy, 1997; Vol. 1, pp 355e400; (b) Ishibashi, H.; Sato, T.;

Ikeda, M. J. Synth. Org. Chem. Jpn. 1995, 53, 85e94; (c) Curran, D. P. In Com-

prehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,

UK, 1991; Vol. 4,; Chapter 4.2, pp 779e831.

9. (a) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1e11; (b) Nagashima, H.; Itoh, K. J. Synth.

Org. Chem. Jpn. 1995, 53, 298e307.

10. (a) Murphy, J. A. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;

Wiley-VCH: Weinheim, 2001; Vol. 1, pp 298e315; (b) Lampard, C.; Murphy, J.

A.; Lewis, N. J. Chem. Soc., Chem. Commun. 1993, 295e297.

11. (a) Clark, A. J.; Dell, C. P.; McDonagh, J. P. C. R. Acad. Sci. ParisdSer. IIcdChem.

2001, 4, 575e579; (b) Davies, D. T.; Kapur, N.; Parsons, A. F. Tetrahedron Lett.

1999, 40, 8615e8618; (c) Clark, A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.;

McDonagh, J. P. Tetrahedron Lett. 1999, 40, 8619e8623. The radical polar

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RCs of enamides: (d) Clark, A. J.; Dell, C. P.; McDonagh, J. M.; Geden, J.;

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Zard, S. Z. Synlett 1999, 501e503.

4.5.2. Preparation of 3-ethyl-4-isopropylfuran-2,5-dione (66). Follo-

wing the procedure used for the preparation of 52, 3-(2,2-dichloro-

3-methylbutanoyl)-2-ethyliden-[1,3]thiazinane (54) (2 mmol,

0.564 g), with a catalyst load of 10 mol %, gave, after chromatog-

raphy of the crude product (derived from the ﬁnal hydrolysis

step) on silica gel, eluting with a PE/Et₂O gradient (from 100:0 to

20:80), the maleic anhydride 66, as a yellow oil (0.228 g, 74%),

spectroscopic data are in agreement with those reported in the

literature.⁵⁵

4.5.3. Preparation of 3-phenyl-4-methylfuran-2,5-dione (67). Follo-

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ophenylacetyl)-2-ethyliden[1,3]thiazinane (55) (2 mmol, 0.632 g),

with a catalyst load of 10 mol %, gave, after chromatography of the

crude product (derived from the ﬁnal hydrolysis step) on silica gel,

eluting with a PE/Et₂O gradient (from 100:0 to 20:80), the maleic

anhydride 67, as a white solid (0.245 g, 65%), spectroscopic data are

in agreement with those reported in the literature.⁵⁴

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Article Doi

CuCl-catalyzed radical cyclisation of N-α-perchloroacyl-ketene-N,S- acetals: A new way to prepare disubstituted maleic anhydrides

DOI: 10.1016/j.tet.2012.04.117

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