Further Investigation on the Rearrangement Mechanism of Reactions of 1,5-Benzothiazepines with Ethoxycarbonylcarbene1

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CHEM. RES. CHINESE U. 2006, 22( 1 ) , 36-39

Further Investigation on the Rearrangement Mechanism of Reactions of 1 ,5 -Benzothiazepines with Ethoxycarbonylcarbene * WU Chun-zan , HUANG Jia-Xing , ZHANG Qi-han and XU Jia-xi * * Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871 , P. R. China Received May 11 , 2005 The reactions of 2 , 3 -dihydro-1 ,5-benzothiazepines with ethoxycarbonylcarbene undergo complex rearrangements to produce ring-opening and ring contraction products. Previously it was presumed that the different products were formed via different mechanisms depending on the kind of substituents at the 2-position of 1 ,5-benzothiazepines. However, on the basis of the further detailed investigation, it was found that all 1,5-benzothiazepines can undergo the same rearrangement to yield both ring-opening and ring contraction products. Keywords 1,5-Benzothiazepine; Ethoxycarbonylcarbene : Rearrangement ; Ring-contraction ; Ring-opening

Article ID 1005-9040( 2006) -01 -036-04

Introduction During the last decade, our group has investigated a series of cycloaddition reactions of 2,3-dihydro-1 ,5benzothiazepines with a-carbonyl-ketenes"321, nitrile , nitrile i m i n e ~ ' ~,, ~ k] e t e n e ~ ' ~ - ,~ ] and oxides'3341 carbenes"-"] . Normal cycloadducts can be obtained from the reactions of 2 ,3-dihydro-1 ,5-benzothiazepines with a-carbonyl-ketenes , nitrile oxides, nitrile imines and ketenes. However, the reactions of 2,3-dihydro1 ,5-benzothiazepines with carbenes will undergo complex rearrangements. Their reactions with dichlorocarbene produce not only normal cycloadducts , but also cycloaddition and ring-expansion products and other complex rearrangement p r o d ~ c t s ' ,~ while ~ ' ~ ~their reactions with ethoxycarbonylcarbene will undergo complex rearrangements to generate ring-opening or ring contraction products depending on the kind of their 2-position subsituents"" . The rearrangement mechanisms of the reactions of 1 ,5-benzothiazepines with ethoxycarbonylcarbene have been studied and presumed previous1Y [ I . It was presumed that the different types of products could be formed via different mechanisms depending on the kind of the substituents at the 2-position Herein, we describe the of 1,5-benzothia~epines"~~'~~. further investigation on the rearrangement mechanism.

Results and Discussion Mi and Jin"'] found and reported the complex re-

arrangements in the reactions of 2,3-dihydro-1 ,5benzothiazepines with ethoxycarbonylcarbene , and proposed a possible mechanism firstly in 1991. Later Jin and co-workers studied this rearrangement again and found that the different types of products could be formed depending on the kind of the substituents at the 2-position of 1 ,5-benzothiazepines. Thus, they modified their previous mechanism and presumed that 2-methyl-l,5 -benzothiazepines could undergo a ringopening rearrangement"21 , while 2-aryl-l,5-benzothiazepines could undergo a ring contraction rearrange~ n e n t " ~ ] However, . some compositions in the reaction mixture have not been separated and identified yet"41 . This prompted us to further investigate this rearrangement again to get a clear understanding of the mechanism. Firstly we reinvestigated the reaction of 2 , 3-dihydro-2,4-diphenyl-l,5 -benzothiazepine (compound l a ) with ethoxycarbonylcarbene and traced the reaction process with GC-MS. Diethyl fumarate , diethyl maleate, and styrene were easily determined with GC-MS during the reaction process. After very careful separation of the reaction mixture, besides large amounts of diethyl fumarate and diethyl maleate, both the ringcontraction product, compound 2 and the ring-opening product compound 3 a , were obtained in yields of 15% and 26% , respectively ( see Scheme 1 ). For 2 - ( 4-

* Supported partly by the National Natural Science Foundation of China( Nos. 20272002 and 20472005) , Ministry of Education of P. R. China( SRF for ROCS and EYTP) and Peking University( President Grant). * * To whom correspondence should be addressed. E-mail: jxxu@ pku. edu. cn

WU Chun-zan et al.

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chlorophenyl ) -2, 3-dihydro4-phenyl-1 , 5-benzothiazepine( compound l b ) , besides products 2 and 3 b , an N-di-ethoxycarbonylmethylated product compound 4 b was also determined. However, unfortunately, it is difficult to separate products 3 b and 4b. Their structures

were confirmed only at m/z 521 and 607 by mass spectrometry. The results indicate that 2-aryl-1 ,5-benzothiazepines can also produce ring-opening products. This means that the rearrangement seems not depending on the kind of the 2-substituent of 1,5-benzothiazepines.

la: R=Ph Ih: R=4-CIPh lc: R=Me

4

3

2

1

37

4b, 5 %

3a, 26% 3b, 1 6 % 3 c , 21%

2.15% 2,10% 2.4%

with ethoxycarbonylcarbene. Scheme 1 Reactions of 2.4-disubstituted 2,3-dihydro-l,5-benzothiazepines

actions( see scheme 2 ) . Previously, it was presumed that intermediate I could undergo a Stevens rearrangement to afford intermediate II '''] , which could undergo a hydrogen transfer to generate intermediate III ( path A) . Intermediate JI could further cyclize to form intermediate Iv , which could be unstable due to the existence of a strained four-membered ring. It would preferentially undergo a rearrangement to yield product 2 by the loss of a ( substituted) styrene m ~ l e c u l e " ~ ' . After the mechanism being considered carefully again, it can be found that the formation of intermediate IV is not easy due to the existence of a strained four-memebered ring. On the other hand, if the Stevens rearrangement occurrs, its product, intermediate II ,

To further understand the rearrangement, we also conducted the reaction of 2 ,3-dihydro-2-methyl4-( 4methylphenyl) -1 , 5-benzothiazepine ( compound l c ) with ethoxycarbonylcarhene and found that both the ring-opening anti ring contraction products ( compounds 3 c and 2 ) were obtainrd in yields of 21 % and 4% , respectively. Propene could be determined with GC-MS during the reaction process. This result further confirms our conclusion. Because the ring-opening products have also been obtained from the reactions of 2-aryl-2,3-dihydro-l ,5benzothiazepines( compounds l a and l b ) with ethoxycarbonylcarbenr, we should reconsider the previously presumed mechanism for this kind of rearrangement re-

EtOzCCi2

N

-

CHzCOzEt

Path €3

N COzEt

I

Scheme 2

5

Previously presumed rearrangement mechanism for the reactions of 2-phenyl-2,3-dihydro-l,5benzothiazepines with ethoxycarbonylcarbene.

CHEM. RES. CHINESE U.

38

should preferentially cyclize to form product 5 ( path B ) as that obtained in the reactions of 1 , 5-benzothiazepines 1 with dichloro~arbene[~*'~~ because it is easier to form a three-membered ring"6,171than to form a four-membered ring. However, no product 5 was detected in the reaction mixture( Scheme 2 ) . On the basis of the current results, we can now conclude that the reactions of 2,4-disubstituted 2 , 3 dihydro-l,5 -benzothiazepines with ethoxycarbonylcarbene proceed via the same rearrangement mechanism ( shown in Scheme 3 ) . Intermediate 1 more preferentially undergoes a cyclization ( path C ) rather than a Stevens rearrangement to produce intermediate V ,

VOl. 22

which can undergo path D to yield product 2 by the loss of a propene molecule or a ( substituted ) styrene molecule as previously presumed for 2-methyl-2,3-dihydro-l,5-benzothia~epines['~~. Because it is easier to eliminate a styrene molecule than to eliminate a propene molecule due to the stability of styrene, 2-aryl1 , 5-benzothiazepines preferentially afford ring-contraction product 2. Intermediate V can also undergo path E to give rise to product 3, which can further react with ethoxycarbonylcarbene to produce product 4. For 2-methyl-l,5-benzothiazepines,path E is more preferential than path D. That is the reason why they tend to produce ring-opening products 3. EtO&

4

1

I-

1

2 :CHCOzEt

:CHcOzEt

EtOzCdH

A 1 Path E t

I

-

V

qh RZ EtOZ6CH H V

3

PathD -RICH=CHz

~ s ~ c o z E t /

R1

R2


Scheme 3 Mechanism for the reactions of 2,4-disubstituted2,3-dihydro-l,5-benzothiazepines with.ethoxycarbonylcarbene.

In summary, the reactions of 2,4-disubstituted

2,3-dihydro-l , 5 -benzothiazepines with ethoxycarbonylcarbene undergo a rearrangement to yield both ringopening and ring contraction products, of which the yields are dependent on the kind of the 2-substituent of 1,5-benzothiazepines.

Experimental 1 Apparatuses and Materials The melting points were measured on a Yanaco MP-500 melting point apparatus and were uncorrected. The'H NMR spectra were recorded on a Mercury Plus 300( 300 MHz) spectrometer in CDC1, with TMS as the internal standard. The mass spectra were obtained on a VG-ZAB-HS mass spectrometer. The elemental analy-

ses were carried out on an Elementar Vario EL analyzer. The IR spectra were taken on a Brucker Vector 22 FT-IR spectrophotometer in KBr. The GC-MS measurement was performed on an HP5971 GC/MSD system ( 5890 Series I1 GC and 5971 Series Mass Selective Detector). Cyclohexane was heated under reflux over sodium and distilled prior to use.

2 Reaction of 1,5-Benzothiazepines and Ethyl Diazoacetate To a suspension of 1, 5-benzothiazepine ( compound 1, 4 mmol) and freshly made copper powder ( 3 g ) in 30 mL of dried cyclohexane was added dropwise ethyl diazoacetate( 2.74 g , 24 mmol) in 10 mL of

No. 1

WU Chun-zan et al.

dried cyclohexane over 1 h under refluxing, stimng, and the atmosphere of nitrogen. The resulting solution was allowed to reflux under stirring for 6 h. After the filtration and removal of the solvent, the residue was purified on a silica gel column with a mixture of petroleum ether (60-90 “c ) and ethyl acetate ( 20 : l to 5 : 1 , volume ratio) as the eluent to afford products 2 and 3. ( Further purification on another silica gel column is necessary for getting pure products in some ca-

39

( t , J = 7 . 2 Hz, 3 H , CH,). I R ( K B r ) , V / cm-’: 3402( NH) , 1740 ( C = 0 ) , 1721 ( C = 0 ) ; MS ( E I ) , m h : 4 8 7 ( M ” , 2 ) . Elemental anal. ( % ) calc. for C,, H,, NO, S (487.61 ) (found) : C 71.43 (71.66), H 5.99(6.29), N , 2.87(3.01). 2. 3 Ethyl ( E ,E ) -2- ( 2-ethoxycarbonylmethylamino) phenylthio-3-phenyl-2,4-hexadienoate ( Compound 3 c ) Colorless crystals, m. p. 85-86 “c , yield 21 % . In ref. [ 141 : m. p. 85-86 “c.

ses. )

Ethyl 2-ethoxycarbonyl-3-phenyl-4H-lI4-bemothiazine-4-acetate( Compound 2 )

2. 1

Colorless oil, yield 4 % -15%. ’ H NMR ( 300 MHz, CDCl,), 6: 7 . 4 4 - 6 . 5 9 ( m , 9 H , A r H ) , 4.11 ( s , 2 H , CH, C O ) , 4 . 0 6 ( q , J = 7 . 2 Hz, 2 H , OCH,), 3 . 9 0 ( q , J = 7 . 2 Hz, 2 H , OCH,), 1 . 1 4 ( t , 1 ~ 7 . Hz, 2 3 H , C H , ) , 0 . 9 0 ( t , J = 7 . 2 Hz, 3 H , CH,). I R ( K B r ) , v/ cm-’ 1 7 3 8 ( C = O ) , 1719 ( C = O ) . MS ( E I ) , m / z : 383 ( M ’ , 3 9 ) , 338 [ ( M - E t ) ’ , 3 . 0 1 , 310 [ ( M - C O , E t ) ’ , 3 . 0 1 , 296 [ ( M - CH,CO,Et) ’ , 3.01. Elemental anal. ( % ) calc. for C,, H,, NO, S ( 383.46 ) : C 65.78, H 5 . 5 2 , N 3 . 6 5 ; found: C 6 5 . 5 2 ; H 5 . 2 9 ; N3.38. 2 . 2 Ethyl ( E ,E )-2-( 2-ethoxycarbonylmethylamino ) phenylthw-3,5-diphenyl-pentadienoate( Compound 3 a ) Orange crystals, m. p. 205-207 “c , yield 2 6 % . ‘ H NMR( 300 MHz, CDCl,), 6: 8.01-7. 10 ( m , 14H, A r H ) , 4.58(d, J = 1 8 . 4 Hz, I H , C H = ) , 4 . 3 0 ( d , J = 1 8 . 4 Hz, l H , C H = ) , 4 . 2 1 ( d , J = 2 . 7 Hz, 2 H , NCH,), 4. l l ( s , br, l H , N H ) , 4.04 ( 9 , J = 7 . 2 Hz, 2 H , OCH,), 4 . 0 0 ( q , J = 7 . 2 Hz, 2 H , OCH,), 1 . 2 2 ( t , J = 7 . 2 Hz, 3 H , C H , ) , 1.01

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