Chapter 7 Seven-membered rings

437

Chapter 7

Seven-membered rings John B. Bremner Department of of Chemistry, Chemistry, University University of of Wollongong, Wollongong, Wollongong, NSW 2522, AUSTRALIA [email protected] jo hn_b remne r@ uow. edu. au Samosorn Siritron Samosom Department ofChemistry, Department of Chemistry, Faculty ofScience, of Science, Srinakharinwirot University, University, Bangkok 10110, THAiLAND THAILAND [email protected] siritron @swu.ac.th

7.1

INTRODUCTION INTRODUCTION

The chemistry and biological activities of seven-membered heterocyclic systems continued to command significant attention in 2006. In this chapter both fused and non-fused heterocycles are O, and S as the heteroatoms in the seven-membered ring addressed with an emphasis on N, 0, components. Reviews which include some treatment of these heterocyclic derivatives have been published covering ring-closing metathesis of heteroatom substituted dienes <06H(70)70S>, <06H(70)705>, and a review of the pyrrolo[1,2-a]azepine-based pyrrolo[ 1,2-a]azepine-based Stemona alkaloids <06MI99>. A detailed review on synthetic approaches to oxepines has also been published <06T930l>. <06T9301>.

7.2

7.2.1

SEVEN-MEMBERED HETEROATOM SEVEN-MEMBERED SYSTEMS SYSTEMS CONTAINING CONTAINING ONE ONE HETEROATOM

Azepines derivatives Azepines and derivatives

Detailed computational studies have been reported on S-azatropolone 5-azatropolone and IH-azepine-4,S1H-azepine-4,5<06JPC(A)1600>. dione and related isoelectronic homologues and isomers <06JPC(A) 1600>. A novel electrophilic reaction of the 2-methoxyazepinium ion 2, formed in situ from 1 on treatment with TiC1 TiCla,was ,was observed in the presence of benzene to give 3, 4 and 5. The kinetics of 4 (kl, 1<" kz, k3) the isomerisation (k!, kJ ) of the 4H-azepine 3 to 8 via 6 and 7 were also reported <06EJO3803>. <06EJ03803>.

438

J.B. Bremner and S. Samosorn

0

ipro.~OM iprO

Ph Ph

Ph-H

TiCI 4

®~

e TiCI4

N/. OMe

NOMe OMe

b ~

=

2

1

3,43% 3, 43%

0+

QPh

~ ~"~roPh e NOMe

ph.~O Me + Ph N/. OMe

/.

4,49% 4, 49%

~

Pbh

~

/.

/.

~ ONOMe Me

5, 3% 5,3%

~ : O b 1 Ph

-OMe kj

k

I~

OMe

NOMe

OMe OMe

NOMe OMe

7

6

3

"N

P

8

Satake et et al. reported further detailed studies on the chemistry of 2H-azepines 2H-azepines highlighting a propylthio shift on [1,5] sigmatropic hydrogen shift and also an unusual (1,5] [1,5] sigmatropic propylthio measurements were consistent with a heating 9 to afford 10 and 11 respectively; kinetic measurements <06OL5469>. concerted process for the propylthio shift <060L5469>. R R

R R

R R

Q--"-- b

/. pHr ~ ~ ONOMe Me PrS

+

Qspr

A =_ PrS P r S~. ~NOMe O/ .M e +

/.

11 11

10

9

R == t-Bu t-Bu a: R b: Me b: R= R=Me

~~ oNOMe SMP:

Access to the 4,4'-disubstituted 4,4"-disubstituted azepine derivatives 14 was achieved in good yield by ring closing metathesis on the dienes 12 using the Grubbs II catalyst 18; the diene precursors 12 could be made in racemic o~,~'-disubstituted lactone precursors racemic or optically enriched form from a,a'-disubstituted precursors <06S1437>. Removal of of the N-protecting group and reduction of the double bond in 13 by <06S1437>. hydrogenation then resulted in the azepanes 14.

~ -CBz R2~N-CBZ R1

(i)

=

(ii)

-CBz CN-CBZ

R2'" R RI1

,. R~,C N HH R2'" R '~11 14 14

13

12

R11 R Me a: Me b: b: Ph Ph

R22 R H H Me Me

75% 75% 83% 83%

R11 R a: Me Me b: b: Ph Ph

R22 R H H Me Me

100% 100% 90% 90%

Reagents: N"v reflux, reflux, 82°C,S H"2, 50 psi, Reagents: (i), (i), CICH,CH,CI, C1CH2CH2CI,Grubbs Grubbs II Ru cat., cat., N 82 ~ 5 h; (ii), (ii), Pd/C, H psi, AcOH, AcOH, 20°C, 20 ~ overnight. overnight.

439 439

Seven-membered rings

The power of ring closing metathesis for seven-membered ring synthesis continued to be realised as exemplified by the preparation of the tetrahydroazepines 16 (X = CH,) CH2) or 2azepinones 16 (X = CO) from the appropriately substituted precursors 15. Yields were generally good to high (particularly with Grubbs II ruthenium catalyst 18). However, as noted in other reactions of this type, amine functionality (15a, R 1' == Bn, R2= R' = H, X = CH,) CH2) compromised the metathesis process, and a very low yield of 16 was obtained with Grubbs I catalyst 17 and no 1); starting material 15 was reproduct at all with the second generation Grubbs catalyst (Table I); isolated in both cases <06Tl777>. <06T1777>.

R1

RI 11

M~rO

I

(i) (i)

Me

MeO~_~

oO

R2

\R2 R2

16

15

~~9NP--

P(CYh P(CY)3 CI\ I CI-.... RU~

Ru~/ RU~

CI/ I Ph Ci/~u=~ph

CI/ CI/I

P(CYh P(CY)3 17

I

Ph Ph

P(CYh P(CY)3 18

Reagents: Reagents: (i), (i), Grubbs Grubbs I or II cat., cat., DCM, DCM, 40°C. 40 ~

Table 1 I Table Substrate

R 11

R R'2

X

15a 15b

Bn Bn

H H

CH 2 CH, C=O

Grubbs I cat. 16 yield (%) 8 88

Grubbs II cat. 16 yield (%) 0 90

Inclusion of the amide in oxazolidinone functionality can be used to overcome diene statial disposition issues, for example in the conversion of 19 into 20; yields of 20 were generally high (Table 2). Ring opening of the oxazolidine moiety with or without loss of the mandelic acid moiety then afforded the corresponding azepin-2-ones <06TL3625>. <06TL3625>.

TBSO. ~ ~ / / " TBSO~ O"><'N~

o

N~

4RR

PI~

Ph'..~kO0 :: 19

.,-

5 mol% mol% Grubbs Grubbs cat. cat.

CH2CI 2 (abt 10 -2 M)

Reagents: cat. (5 mol %), M). Reagents: (i), (i), Grubbs Grubbs cat. (5 mol %), DCM DCM (ca 10 10.22 M).

TBSO TBSO

Ph,,, Ph'''~O ~/'~

~

#, R

O o 20

440

J.B. Bremner and S. Samosorn

Table Table 2 19 19a 19b 19b

Catalyst 17 18

R H i-Bu

20, Yield (%) 20a, 91 20a,91 20b, 78

Other N-substituted and reduced 2-azepinone derivatives 22 can also be accessed in high precursors 21 using Grubbs II catalyst 18. A yields (Table 3) by ring closing metathesis on the precursors variety of N-heteroaryl substitutent substitutent groups were tolerated in this reaction <06TL3295>. <06TL3295>.

(o •

o

R11 ,R

~H~R' N~~~--R3 BocH

~N0 ~~I~,R 2

Grubbscat. cat. Grubbs

.R2 R2

#

----

R2 22

21 Table 3 Table R' .\~/

R'2 R H

R 33 H

/~..~

H

H

10

88

-I-/-- ~

H

H

10

92

Y)j Iii ~r-Q

-~

rO

R1

BocHN~/~N 'R1 3 I ? R R3

Grubbs II cat. (mol%) 5

Yield (%) 90

-

of the azepinones 24 has been developed based on ring closing A compact synthesis of a-amino enones 23 <06H(67)549>. <06H(67)549>. High yields of products were metathesis reactions of the a-amino R ~ = Me, R' R 2 = Boc). The obtained (for example, 24, R = H, R R'2 = Boc, 90%) from (23, R =H, R' R 2 = (2-Pyr)SO,) (2-Pyr)SO2) was converted into a cathepsin K inhibitor. azepinone derivative 24 (R = H, R'

R~ /~'J"N P

0)

(i)

" O

,

R1

23

RVO ~o

R

, p P

24 24

Reagents: (2.5-5 mol%), Reagents: (i), (i), Grubbs Grubbs II cat. cat. (2.5-5 mol%), DeM, DCM, heat, heat, 12 12 h. h.

Azepanes and azepanones continue to attract attention synthetically because of their incorporation in compounds of biological significance. A new diastereoselective and enantioselective lithiationlithiation - addition methodology has been described to provide access to the (Ar I = p-BrPh, p-BrPh, Ar = p-MeOPh)); p-MeOPh»; these were then converted into 27 via 26, azepine precursors 25 (Ar' via 28 and 29 <06JA2178>. and subsequently to the further substituted azepan-2-ones 30 via <06JA2178>.

441

Seven-membered rings

CH 3

H3C,,,~ 3 Ar

'r):'"

H3C,, ~

H3C~" "':: ,Ar ~ ~.Ar

(i)

(i)

N'Boc "Boc

COzEt CO2Et

,.

H,C"i

3

~.Ar

(ii)

Ar" ~ - "Boc Ar~~ Boc

,. Oj j, -~C H OH3 '

o

o0 / "NH NH

N

I Ar Ar

Ii

25

~H3 .CH3

Ar Ar (ii)

26 Ar

27

(iii) 1(iii)

Ph

.CH3

ArH2C"

Ph Ph

CH3

__

(v) (,j

.CH3 ~H3

A
CH '3 CH

<

0 Ph

(iv) ''V'

o(3// ,~r ~ Ar

oO" ~'~

O" ~

.CH3 CH '

Ar Ar ~ ~ 29 28 Reagents: (i), DCM, 83%; HC! (aq.), Pd(OH)" EtOH, EtOH, benzene, benzene, 96%, Reagents: (i), Me]AI, Me3A1,p-anisidine, p-anisidine, DCM, 83%; (ii), (ii), HC1 (aq.), CHCI" CHC13,86%; 86%; (iii), (iii), H" 1-I2,Pd(OH)2, 96%, dr = 94:6; LOA. b. p-BrC6H4CH2Br, p-BrC 6H,CH,Br, THF, H,O, 62%, 94:6; (iv), (iv), a. a. LDA. THF, 94%, 94%, dr = 98:2; 98:2; (v), (v), CAN, CAN, MeCN, MeCN, I-I20, 62%, dr = >99:1. >99:1. ~ 30

As part of of the development of an efficient synthetic strategy for the synthesis of the little known 3,5- and 3,6-disubstituted 3,6-disubstituted tetrahydro-1H-azepines, tetrahydro-1H-azepines, ring-closing metathesis of the diene 31 to 32 in high yield was reported <06JOM5406>. <06JOM5406>. Boc Boc

Boc Boc

II

II

N

MeO, Meo~'~

(i) (i)

1 ~OTBS OTBS

,

MeoJN Me

!J0

0

31

j

~---OTB$ ~OTBS 32

Reagents: (i), II cat., Reagents: (i), Grubbs Grubbs 11 cat., 2.5 mol%, mol%, 90%. 90%.

The synthesis of the N-protected 7-methylazepine derivative 34 was achieved in 89% yield by a ring-closing metathesis reaction on 33 mediated by Grubbs Grubbs I ruthenium catalyst. This azepine of a number number was an important precursor for the preparation, preparation, via epoxidation of the double bond, of 7-methylazepanone derivatives for evaluation as cathepsin K inhibitors <06JMC1597>. <06JMC 1597>. of 7-methylazepanone

~

Me

NCbz NCbz

~ 33

Me

(i)

NCbz CNCbZ 34

Reagents: (i), Grubbs Grubbs I cat., cat., DCM. Reagents: (i), DCM. A two-carbon two-carbon ring expansion expansion reaction of of 5-membered cyclic enamines gave 6,7-dihydro-1H6,7-dihydro-1Hazepines on reaction with dimethyl acetylenedicarboxylate <06ZN(B)385>. <06ZN(B)385>.

442

J.B. Bremner and S. Samosorn

The synthesis of the D-gulonolactam 36 was based on an intramolecular cyclisation Iring cyclisation/ring enlargement strategy involving reduction of the azido group in 35 followed by intramolecular nucleophilic attack on the lactone moiety to afford 36 in excellent yield <06T7455>.

OH OH

N3v~z O O N'~O

(i) (i)

H Fhl~o

9

Ho-CiL

o• O

Ho HO He

°X

35 Reagents: (i), (i), 10% 10% Pd/C, Pd/C, HCO,NH" HCO2NH4, EtOAc. Reagents: EtOAc.

7.2.2

0/\-

36

Fused azepines azepines and derivatives derivatives

A palladium-catalysed intramolecular hydroamidation (using 39 as the catalyst) with the amido alkyne 37 proceeded regioselectively in the presence of base (KOH or NaOEt) to provide access to the 3-benzazepin-2-one 38. This reaction can also accommodate other alkynes <06TL381l>. <06TL3811 >.

~ N-Me ~-Me

(i)

o

o

NHMe

37

38,82%; 38, 82%; KOH 80%; 80%;NaOEt NaOEt

Reagents: (i), Pd(PPh 3 ),(OAc),239, 39, base, base, DMF, DMF, 60 °e, Reagents: (i), Pd(PPh3)2(OAc) ~ 16 16 h.

C02Me

Me

,Et /CO2Me

40

H"

A

,,,( )~§ B

74% Me02C

~

H 41

,C02M~

'XN.Et

443

Seven-membered rings

Reduced fused azepines (e.g. 40) have been used in a new ring expansion strategy to afford fused hexahydroazoninoindoles (e.g. 41) from reaction with methyl propiolate propiolate in methanol to give the ylide intermediate A which then ring expanded via the methanol stabilised stabilised intermediate intermediate B to give 41 <06Tl239>. <06T1239>. The imidazo-benzazepine imidazo-benzazepine 43 was prepared in moderate yield by a combination combination reaction sequence involving an initial van Leusen reaction to prepare the imidazole 42 followed by a <06TL3225>. microwave-promoted intramolecular intramolecular Heck reaction <06TL3225>.

": C 5:

T01 C I [ ~ S OS02 2T~ CN

~ B r Br

(X [

..-:;;

+ +

H2N ' ' ~ v / ~ H2N~

+

CHO CHO

-~

Ph

~N~

N=!

~ PhjNF

(ii) (ii)

..-:;; B Br

(i)

[":: ..-:;;

42

Ph

N=! N=/

43 Reagents: Pd(OAc)"2, P(o-tolyl)" NEt"3, 125°C, microwave, 66%. Reagents: (i), (i), K,CO" K2CO3, DMF, DMF, 60%; 60%; (ii), (ii), Pd(OAc) P(o-tolyl)3, CH,CN, CH3CN,NEt 125 ~ 1I h, microwave, 66%.

intramolecular nitrone 1,3-dipolar An intramolecular 1,3-dipolar cycloaddition reaction to give 46 from 45 followed by IH-Ireductive N-O bond cleavage afforded a stereoselective synthesis of the tetrahydro 1H-1benzazepines 47; the nitrone precursors 44 were prepared in tum turn by a Claisen rearrangement from an N-allylamine N-allylamine <06SL2275>. <06SL2275>.

(i), (ii)

R2

44

v

,.

R2

-R 1 45

.H R

R (iii)

R..

a R

46 46

R2 R

R1

R1

47 47

R2

b

c

R

R11

R2 2

H CH OH 33 CI Cl

H H H

H H H

R1

Reagents: mol), Na2WO4.2H20 Na,WO,2H,Q (4-6 mol%), to -5 °C, Reagents: (i), (i), 30% 30% H,Q, H202 (3-4 mol), mol%), acetone-H,Q acetone-H20 (9:1vjv), (9:iv/v), 25°C 25 ~ to-5 ~ 40-50 h, then H,Q with CH,Cl,; toluene, reflux, mol), 80% AcOH (excess), then H20 and and extraction extraction with CH2C12;(ii), (ii), toluene, reflux, 3-4 h; (iii), (iii), Zn (6 mol), 80% AcOH (excess), 80-85 80-85 °C, ~ 2-5 h, 25°C then 5% NH.oH solution 25 ~ then 5% NH4OH solution and extraction extraction with with EtOAc. EtOAc.

444

J.B. Bremner and S. Samosorn

Dynamic thermodynamic resolution in a lithiation substitution reaction sequence was used to via 49 and 50, into the chiral provide access to the amino ester 48 which could then be converted, via <060L2667>. substituted 1-benzazepine l-benzazepine derivative 51 <06OL2667>.

0 (i)

(iii) (ii), (iii~

49 49

48 48

°

H2Ph CH 2 Ph

HN•. C & N

~I

,,'Ph ,, ,Ph

"':

"CH2Ph

(iv)

N H~ , , ,

(iv)

"'Ph "Ph

I~

"

,Ph "Ph

//

50 51 Reagents: (i), A1Et 94%" (ii), (ii), n-BuLi; (iii), PhCH PhCH2Br, 79%; (iv), (iv), BH 91%. Reagents: (i), AlEt"3, 94%; n-BuLi; (iii), BH"3, 91 %. 2Br, 79%;

Acid catalysed rearrangement of the tetrahydro I-benzazepine 1-benzazepine sulfonamides 52 gave the 9substituted sulfone derivatives 53 plus, in the case of 52b, 52b, the 7-substituted 7-substituted isomeric derivative <06SC355>. 54 <06SC355>.

"'cO I

O:S=O

"~O

"W "'CO o_-,:o

a ~

52 52

= =

lil

+

.

NO2 12.,, 54

H

54

53 53

= =

a: R 11 = H; R R 22 = H H a: R

= =

= =

a: R 11 = H; H R R 22 = H H a: R

b: R R11 = H; H; R R22 = N0 NO2 b: R R11= H; H; R R22 = N0 NO2 b: b: 2 2 Reagents: (i), S0 at 105 DC for 20 min then pour over ice. Reagents: (i), 98% H H2SO 4 105 ~ for min then pour over ice. 2 4 A compact approach to the 1-phosphonylated 2-benzazepine 56 was achieved based on a ringl-phosphonylated 2-benzazepine closing metathesis reaction on 55 using Grubbs II catalyst catalyst <06SL2771>. <06SL2771>.

445

Seven-membered rings

Ph

~J1

~ t

""

~

'0 06

(i)

(

t ~o/ ~ N ' BN-S n n P(O)(OMe)2 P(O)(OMeh

N

(MeOh(O)P (MeO)2(O)P

55

n

'Sn

56

Reagents: N"v Grubbs Reagents: (i), (i), DCM, DCM, styrene styrene (5 (5 eq.), eq.), ,4 , 4 h, N Grubbs II cat. cat. (10 mol%), mol%), 78%. 78%.

Poly(ethylene glycol) (PEG) was used as a soluble polymeric support in the efficient 2-benzazepine S8 58 via a phosphine-free preparation of the 2-benzazepine phosphine-free palladium-catalysed Heck reaction from S7 57 <06Tl0456>. <06T10456>. COOMe COOMe

(i) (i)

~.~hN~cOOM R

e

C(} @ t

57

""

o

N

-...0

N

ph Ph

'R R

58

R R == PEG-N-(CH2kSi(Meh-CH2CH2S02-~ PEG-N-(CH2)4-Si(Me)2-CH2CH2SO 2~ I

II

Ts T8 Reagents: (i), (i), Pd(OAc) K~CO3, PEG-3400-0H, PEG-3400-OH, 80°C, 80 ~ 12 12 h, 100%. 100%. Reagents: Pd(OAc)"v K,CO" 59 (TT= tris(tetrachlorobenzenediolato)phosphate(V» tris(tetrachlorobenzenediolato)phosphate(V)) and The binaphthyl azepinium salt S9 corresponding corresponding azepine 60 were developed as effective catalysts for the enantioselective enantioselective unfunctionalised alkenes, with enantiomeric excesses up to 87% <06TA2334>. epoxidation epoxidation of unfunctionalised <06TA2334>.

(

..~

TT-

59

7.2.3 7.2.3

60

Oxepines Oxepines and fused derivatives derivatives

oxepin-2-one 61, a mimic of The single crystal X-ray structure of the enantiopure tetrahydro oxepin-2-one steroidal androgens, has been reported <06ZN(B) 111>. Ill>. A new procedure has been described for expoxidation of strained fused the synthesis of substituted furano-fused oxepines based on expoxidation cyclobutenes followed by thermal rearrangement <060L5l83>. <06OL5183>.

446

J.B. Bremner and S. Samosorn

£!pO Me.

.,,,.....~O

Oo~O

o

Me 61

A new and useful route to the 3-benzoxepin-2-one 64 involved coupling of the Fischer 65 to the epoxy phenylacetylene 62 to give 64 (46%) via via 63. An epoxyvinylcarbene carbene 6S complex is proposed for the initiation of the reaction followed by CO insertion and cyclisation <06H(67)233>.

MeO /r

-~7

MeO MeO

40o o

/(~Me

CCc

63

62

(:

64

Cr(CO)s C.r(CO)5

II )l

Reagents: Me Me/~'OMe 65, dioxane, dioxane, reflux, Reagents: OMe 65, reflux, 24 h.

palladium-catalysed ortho-alkylation/intramolecular A tandem palladium-catalysed o r t h o - a l k y l a t i o n / i n t r a m o l e c u l a r Heck reaction coupling 1-benzoxepines 67 from the sequence was used effectively to access in fair yields the tetrahydro I-benzoxepines iodoaryl precursor 66 and the appropriate alkyl bromide. The norbomene plays a relay role in the <06JOC4937> proposed reaction cycle <06JOC4937>

\ 6C)

C o zEt /CO2Et

(i)

I"'" ~

66

o

67

a: a: RR = (CHzhCI, (CH2)3Cl,47% 47% b: b: RR = (CHzhCOOEt, (CH2)3COOEt,45% 45% c: c: RR = (CHzhPh, (CH2)3Ph,45% 45% Reagents: (i), Pd(OAc),2 (10 mo!%), P(2-furyl)3 P(2-furyl)3 (20 mol%), norbornene norbomene (4 Reagents: (i), Pd(OAc) (10 mol%), (20 mol%), (4 eq.), eq.), CS,CO, Cs2CO3(2 (2 eq.), eq.), R(CH2)3Br R(CH2)3Br(6 (6 eq.), eq.), CH,CN, CH3CN, 80°C, 80 ~ 16 16 h.

A new BF -induced stereospecific rearrangement of the epoxy ethers 68 gave the enantiopure BF3-induced 3 tetrahydro 2-benzoxepin-4-ols 69a,b in generally good yields <06JOC1537>. The enantiomerically enriched compounds 69c,d were also produced.

447

Seven-membered rings rings

oO O

~r

-''OcH3 (i)

R.~~ '

OCH3

H O ~ o M e OMe ~

_OMe

g R

68

69 a: R= H a:R=H b: b: RR = CF CF33 c: c: R=CI R=CI d: d: RR = Ph Ph

Reagents: (i), DCM, -78 DC, Reagents: (i), BFJ.OEt, BF3.OEt2(0.3 (0.3 eg.), eq.), DCM,-78 ~ 15 15 min. min.

Ring-closing metathesis has been used effectively to prepare the pyrido[3,2-b]oxepine pyrido[3,2-b]oxepine <06TL6235>. precursor 70 <06TL6235>. derivative 71 in good yield from the pyridyl diene precursor

o

~ CO N

(i)

---=

70 Reagents: (i), toluene, 70 70°C, %. Reagents: (i), Grubbs Grubbs II cat. cat. (10 mol%), mol%), toluene, ~ 16 16 h, 71 71%.

71

The oxepine-fused beta-carboline 73 was synthesized in good yield (71 %) from the diene (71%) precursor 72 using ring-closing metathesis and Grubbs I catalyst <06TL6895>.

~ ~

II~ ~N

b

H

72

(i)

O~

I

._.._.

73

Reagents: mol%), DCM, DCM, rt, ct, 24 Reagents: (i), (i), Grubbs Grubbs I cat. cat. (5 (5 mol%), 24 h.

The synthesis of the fungal natural product ulocladol (from the marine fungus Ulocladium Ulocladium botrytis) was achieved by three routes, including a two-step sequence involving ring enlargement botrytis) of the 6-membered ring lactone in 74 to the 7-membered ring system in ulocladol 77. Treatment of 74 with methanol in the presence of base give 76 (via 75 and the oxy anion A) in 82% yield; <06H(69)217>. hydrogenolysis to remove the benzyl groups then gave 77 in 63% yield <06H(69)217>.

448

J.B. Bremner and S. Samosorn

OH ~OMe

F

~~::: lJyr'

M,O. MeO..~\ y

I

(i)

T "oB.

i

1_

BnO BnO

-

OMe

OMe ~/OM e

OMe

HO

MeO OBn ~eO "U'OBn

MeO .. I'v'eO ,'-'::

OBn OBn 0O

74 74

OH OH

co ~ " ~

OBn

OBno

_

75 HO HO

76

m

BnO BnO

OMe

HO ,,~..~/OMe

(ii) (ii)

OMe

HO MeO MeO

MeO MeO OH O

BnO (~/k~,,,OOe

77 77

A

, Pd/C, AcOEt, 63%. Reagents: (i), Reagents: (i), K,CO K2COJ3,, MeOH, MeOH, reflux, reflux, 82%; 82%; (ii), (ii), H2, 2 Pd/C, AcOEt, 63%.

A palladium-catalysed palladium-catalysed carbometallation-alkyne carbometallation-alkyne cross coupling cascade process has been reported for the stereo- and regio-controlled regio-controlled synthesis of dibenzoxepines dibenzoxepines with substituted substituted exocyclic alkene functionality <060Ll68S>. <06OL 1685>.

7.2.4 Thiepines and fused derivatives A review covering homologation of heterocycles via lithiation-based lithiation-based reductive ring opening, electrophilic substitution, and cyclization includes applications applications to 2,7-dihydro 2,7-dihydro benzothiepine benzothiepine derivatives <06AHC13S>. <06AHC 135>. A neat synthesis of the chiral 10, Il-dibenzo[b,j]thiepine 79 from the chiral precursor 10,11-dibenzo[b,f]thiepine precursor 78 has been described. Cyclisation of the lithiated intermediate was mediated via reaction with sulfur bis(imidazole) 18>. bis(imidazole) <060BC22 <06OBC2218>.

BrO [~OMe

MeO

OMe

(i), (ii) (ii) (i),

Br 78 78

N-0N~"-NIS~N,,% W S'N 0 N Reagents: \d Reagents: (i), (i), t-BuLi; t-BuLi; (ii), (ii), \d

79

449

Seven-membered Seven-membered rings

7.3 7.3.1 7.3.1

SEVEN-MEMBERED SEVEN-MEMBERED SYSTEMS CONTAINING CONTAINING TWO TWO HETEROATOMS HETEROATOMS Diazepines and and fused fused derivatives derivatives Diazepines

Although highly reactive, 2H-azirines are of considerable synthetic interest and serve as a source of the 3-fluoro-4H-l ,3-diazepines 86. Reaction of 80 with difluorocarbene in the presence 3-fluoro-4H- 1,3-diazepines of furfural gave 86, rather than the expected furfural-derived products 83. Rearrangement of the initial 1,3-dipolar intermediate 81 to 84 and then cycloaddition of 84 with 80 are proposed as key steps in the reaction; the intermediate cycloadduct 85 gave 86 on base-induced elimination of HF. Nucleophilic displacement of the fluoro group in 86 provided access to further substituted 1,3-diazepines <06TL639>. 1,3-diazepines

lAr-t"b 11~r..~~r(~!00 Ar O l ~ OC"O . :;-- Ar F

:cF2, [ 80

JHO

~o

81

Ar~___~ ? F2]

84

(i)

0

82

F

--~

0O-..J II J

0 83

:;-0O-..Z/' II

>-F ~N Ar?N~F1 Et3N Ar,(NN' Ar~N~F ArAr~N,. ~y Ar 86. Fj a:a: ArAr = Ph (41%) 85 85 b:ArAr==4-CLC6H s 4(18%) b:

Ph (41%) 4-CIC H4 (18%)

Reagents" (i), (i), CF,Br" CF2Br2,active active Pb, Pb, Bu4NBr, CH2C12,40-43 40-43 DC, ~ 66 h Reagents: Bu 4NBr, furfural, furfural, CH,Cl"

The 1,4-diazepane 87 has been used as a neutral 6-electron ligand for the support of cationic Group 3 metal (Sc,Y) alkyl catalysts <06CC3320>. Me I

N Me 87

Me2

I

Parallel array synthesis was used to access the 3-aryl-tetrahydro-l,2-diazepines 90 (and other related compounds) by cyclisation of the chloro ketones 88 on reaction with hydrazine to give 89 followed by sulfonamide formation; the Si-TrisAmine® Si-TrisAmine | was added at the end as a scavenger to remove any unreacted arylsulfonyl chloride remaining <06MCL3777>.

450 450

J.B. Bremner Bremner and and S. Samosorn

Cl

..s~O o-"

R;

R1

88

R1

89

R1 a: a"

90

R2

3,4-Cl 3,4-CI2 5-Br-2-thienyl 64% z 5-Br-2-thienyl 3-F 4-CI-Ph 82% 4-CI-Ph

b:

Reagents: (i), NH,NH,2(4 eg.), R'SO,C1, PS-DMAP, Reagents: (i), NH2NH eq.), i-PrOH, i-PrOH, 75°C, 75 ~ 16 16 h; (ii), (ii), R2SO2C1, PS-DMAP, DCM, DCM, rt, 16 16 h; (iii), (iii), Si-TrisAmine Si-TrisAmine

In an extension of of previous work on conjugated of the conjugated enamine carbonyl derivatives, reaction of pyrazolone 91 with N,N'-disubstituted N,N-disubstituted hydrazines on heating in an alcohol solvent afforded the hexahydropyrazolo[4,3-d][l,2]diazepine-8-carboxylates 92 in good yields. While the exact hexahydropyrazolo[4,3-d][1,2]diazepine-8-carboxylates mechanism for the formation of 92 is not known, Michael-type addition known, one possibility, namely a Michael-type mechanism of the alcohol to a pre-formed pyrazolo-diazepine, pyrazolo-diazepine, was excluded <06T8l26>. <06T8126>. Ph

~:N

B-

(i)

(i)

"e2NMOOOEt ~

MezN ~ MezN

R 2 0 , , , / ~ ,C~~,Et ~ N RZO'~tX~

H H _COOEt

I

o

COOEt

RLN a 1-N

,

R1N

~

I - ] NN-Ph -Ph

R1

O

0 92 92

91 91

--R-1--R-z- - -

R1

R2

-a-'. a: --,-.,.--------:...,,---=~ Me Me 74%

b: b: c:

Me Me

Et 81% n-Pr 85%

Reagents: reflux. Reagents: (i), (i), R'NHNHR', R'OH, R2OH, reflux.

An elegant two-step solution-phase solution-phase methodology was developed for the synthesis of of the 4 benzodiazepine-2,5-diones (93 ; e.g. R' R ~= PhCH" PhCH 2, R R 5 = Me, 32%). 32%). benzodiazepine-2,5-diones (93; R22 = Me, R R33 = Me, R4 = H, R' The first step was a Ugi four-component reaction followed in the second step by a palladiumpalladiumintramolecular N-arylation reaction. This methodology has considerable scope for mediated intramolecular <06TL3423>. further application in heterocyclic synthesis <06TL3423>.

O R1-NH2 + R 2 L R 3

+ R5-NC

(•

(i), (i), Ugi 4 component reaction reaction

4-

,,/,,~,~COOH R4~B

r

(ii), (ii), [PdJ, [Pd], N-arylation N-arylation

,R1 ....-'~..~/'~ N R2 R 4 ~ R 3

F~5

-O

93

Microwave-promoted Microwave-promoted reactions continue to extend their reach in heterocyclic synthesis. under Regioselective N4-aminoethylation of the 1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one 94 was observed under DMF/K2C0 33 to afford, for example, 96a and 96b 96b in 64% and 67% yield microwave conditions in DMF/K2CO respectively (Table 4). In contrast, the thermal reaction at 80 DC ~ in DMF DMF with K,CO K2CO 3J as base gave the Nl-aminoethylation Nl-aminoethylation products (95a, 65%) These results were 65%) and (95b, 76%). These

451

Seven-membered rings

rationalised using computer-based calculations of the N Nl1 versus N4 alkylation reaction profiles. Microwave irradiation is suggested to facilitate anion production due to a higher change in dipole moment along the deprotonation pathway with a small preference for the N4 anion D over AlB, A/B, although the latter is of lower energy, and fast alkylation then proceeds via E or C <06TL3357>. K+ K +

H

"'" C( N

0 O

N)'''CH3 , ,CH3

/./

NH

Route A A Route

-

~

{

C(N--/(O I

O- K§

N~

, 3 )"'CH

/./

,,C

NH

A

94 94

B

~

+ K2CO3

RCI RCI

CI 1)CI 5- K+ K+ |

,|

R : 1)-

"'" C(

R

0

,

O

N)"'CH3 'CH 3

/./

NH

C

H

O

Route Route B

'OH3

95

H

{C(J~~H'}, ,CH3

O

N [ ~ ~ . ' ~N i~CH3

K+

9

o

L

E

+ K2CO3

'"CI 5-K

l H

0

~ N " 'CH3 96 96

R

Table 4 a b

R (CH,),NCH,CH, (CH3)2NCH2CH2

NCH2CH2

Conditions I(,C0 3,DMF, K2C03, DMF, 80°C, 80 ~ 6 h I(,C0 ,DMF, K2C03, 3 DMF, 80 ~ 7 h 80°C,

Product (%) 95a (65%) 95b (76%)

Conditions K,C0 ,DMF, K2C03, 3 DMF, MW,90s MW, 90 s I(,C0 ,DMF, K2C03, 3 DMF, MW, 90 s MW,90s

Product (%) 96a (64%) 96b (67%)

Reagents and methods for the synthesis of 1,5-benzodiazepine derivatives from 0ophenylenediamine and carbonyl compounds have attracted an unusually high degree of interest in 2006. Illustrative of this, the condensation of two mol tool equivalents of acetone with 0ophenylenediamine 97 was reported <06TL3135> on simple grinding of the components in the presence of an organic acid catalyst at room temperature resulting in 98. The yields of 98 were

452

Bremner and and S. Samosorn Samosorn J.B. Bremner

dependent upon the acid used, but with trimesic acid (5 mol%) a 97% yield of of 98 was obtained obtained dependent grinding for 10 minutes. Picric acid also gave a high yield of of 98 but but use of of this latter acid after grinding should NOT NOT be recommended in view of of the potential potential hazards. Single crystal X-ray data on the of 98 were also reported <06TL3135>. <06TL3135>. trimesic acid and picric acid salts of organic acid

+ v

2(CH3)2CO

~. rt, grinding

"NH2

98

97

1,5-benzodiazepine A range of other catalysts and conditions for similar cyclisations to the 1,5-benzodiazepine <06TL8523>, ultrasound and APPTS <06TL8133>, [BPy]HSO [BPy]HS044 system have included NBS <06TL8523>, <06SC1661>, Mg(C104) Mg(Cl04 ),2 <06SC1645>, <06SCI645>, ZnC12 ZnCl, <06H(68)1017>, <06H(68)1017>, CAN acidic ionic liquid <06SC1661>, <06SLl009>, (NH4)H2PW,2040 (NH4 )H,PW 120 4o <06SC3797>, <06SC3797>, YbC13 YbCl 3 <06SC457>, and solvent-free conditions at <06SL1009>, pH 7 <06SC817>. An intramolecular Pictet-Spengler type cyclisation in the intermediates 100, readily prepared tum from 99, gave the new dihydropyrimido[4,5-b][1,4]benzodiazepines dihydropyrimido[4,5-b][1,4]benzodiazepines 101. in turn 101. Yields were generally good to excellent (101, R' = = H, R' R 2= = Pr, 65%) <06T2563>. a2 CI

CI H R1

CI

H

+H +

R2 R1

-H O CH 3 99

7.3.2 7.3.2

H3C

101

100

Dioxepines, Dioxepines, dithiepines dithiepines and fused derivatives derivatives

In the continuing search for new antimalarial agents, a number of spiroperoxy compounds incorporating a dihydro-2,3-benzodioxepine moiety were designed and synthesised. For example, the spiroperoxy derivative 108 was made from 102 via via oxidation and the Wittig product 103. 103. Deallylation of 103 then gave a mixture of 104, 105 and 106, and finally peroxidation gave 107 and subsequent cyclisation through an intramolecular Michael-type addition reaction afforded 108 <06T7699>.

~ ~ o

~6H 102 0H OH

~CQ: ~.~o

(i), (ii)

-

"::

1-&

OH

103 0H OH 103

-

(iii) (iii)

453 453

Seven-membered rings

~ HO o

I '-':: ~

104

~+~ MeO ,.,

+

+ 4-

0

I GOzEt Et

GOzEt

105

uYt0J ~_'C~ HO. 0

-

(iv)

HO O

U

(v)

0

107

I GOzEt

106

cg 108

GOzEt

GOzEt

(COCI,), DMSO, NEt3; NEt,; (ii), Ph3P=CHCO2Et, Ph,P=CHCO,Et, rt, rI, 12 h, 85% from from 102; (iii), PdC12, PdCI" MeOH, rt, rI, 24 h, then Reagents: (i), (COCI2), rI, 22 h, 71% 71 % from from 103; (v), HNEt HNEt"2, CF3CH2OH, CF,CH,OH, rt, rI, 19 h, 59%. 60 ~cC, 4 h; (iv), UHP, p-TsOH, DME, rt,

Lewis 1,3-dioxepines 109 gave the trisubstituted Lewis acid mediated mediated [1,3] rearrangement rearrangement of of the 1,3-dioxepines trisubstituted tetrahydrofurans 110 110 in high high yields and with with generally high diastereoselectivities. diastereoselectivities. The The Lewis Lewis tetrahydrofurans acids used included included TiCl,(i-PrO), TBSOTf <06CC3119>. <06CC3ll9>. acids used TiC12(i-PrO) 2 and TBSOTf

R2

(i)

,CHO

R2' ' C 2 R 1 109

110

Reagents: (i), Lewis Lewis acid, acid, DCM, DCM, -78 cC. Reagents: ~

7.3.3

Miscellaneous Miscellaneous derivatives derivatives with two heteroatoms heteroatoms

Ring expansion expansion based on the Baeyer-Villiger Baeyer-Villiger reaction continued continued to be a valuable methodology for preparing preparing 1,3-oxazepinones, 1,3-oxazepinones, as exemplified exemplified by the reaction reaction of 111 with m-CPBA m-CPBA giving 112 in high yield; none of the isomeric 1,4-oxazepan-2-one 1,4-oxazepan-2-one derivative was observed consistent consistent with some directive influence influence by the nitrogen <06TL6389>. <06TL6389>.

CfO N I

+s

Ts

111

0

..

m-GPBA m - C P B A,,..._ 89%

(50

O

+s I

Ts

112

454

J.B. Bremner and S. Samosorn

Treatment of 112 with an arylmagnesium bromide, followed by dehydration provided access to the substituted alkenes, e.g., 113a l13a and 113b, l13b, in moderate yields <06TL6389>. <06TL6389>. Ar

0

c)

~N ~ O

(i), (ii)

(i), (ii)

,..

t A Ar r

T8

NH I T8

109

110

\

Ar =Ph, 60% 110 a:a:Ar=Ph, 60%

109

b: Ar = p-MeOC p-MeOC6H4, 6 H4 , 43%

Reagents: ArMgBr; (ii), BF)-OEt,.2. Reagents: (i), (i), ArMgBr; (ii), BF3-OEt

Ring-closing metathesis on the dienes 116 and 117 with Grubbs ruthenium catalyst II 18 afforded the 7-membered precursor 116 was 7-membered ring sulfones 118 and 119 respectively. The diene precursor accessed from reaction of the sulfonyl chloride 115 with 3-buten-I-ol114 3-buten-1-ol 114 <06T9017>. <06T9017>. O2

CI'S~ cl'S"~ 115

115 + + H O . ~

HO~

oo\ \ / /0o

00 %,9

-

(i)

~~ 0 "s

(I)

"

116 116

~1(v) (v) 00 0~ `2

o

(ii), (iii)

(ii), (iii)

-

"

~'(H' ~11-~7~ ~-_ 117

~1(iv) (Iv) 00 0,,9 ~~ " c . a3 o.s.~r~

OCH

118 119 118 119 , 0 °c, Reagents: Et)N, CH,CI (ii), n-BuLi, THF, -78°C; (iii), Mel, 64%; (iv), Grubbs catalyst (5 mol%), Reagents: (i), (i), Et3N, CH2C12, ~ rt; (ii), n-BuLi, THF, -78 ~ (iii), MeI, 64%; (iv), Grubbs catalyst II (5 mol%), 2 , 70°C, 100%. C,H" C6H6,70°C, 70 ~ 60%; 60%; (v), (v), Grubbs Grubbs catalyst catalyst II (5 (5 mol%), mol%), C,H C6H6, 100%. 6 70 ~

The Pd-based methodology described by Ma Ma et et at. al. has scope for the synthesis of fused 1,3oxazepines <06T9002>. <06T9002>. Considerable value would be added to this methodology if it could be 1,3-benzazepine system, perhaps via via alternative methods for adapted to the simpler 1,3-benzazepine carbinolamine carbinolamine precursor precursor generation. A modified four-component Ugi reaction was used to synthesise a variety of heterocyclic ring fused (ring A) 1,4-oxazepine derivatives 123. For example, starting from 120 O-alkylation gave 121 and then 122 after ester hydrolysis; reaction of 122 with amines and isonitriles isonitriles on heating <06TL2659>. Other fused rings A included thiophene and thiazole afforded 123 in low yields <06TL2659>. rings.

Seven-membered rings

G(O'R OH

r 0 O

(i)

O..R

120, R=CH33 Ring A:

~ltN~' N'H

CH 3 CH3

N CH 3

0o

O-'R R

0:}~

o o.,

(ii) (ii)

~O

0 o

Ring A:

455 455

C

(iii) (iii) L

0

O0 121, 121, R=CH R=CH 3, 70% 3 , 70% 122 R=H, 122, R=H, 60% 60%

' 1

R

123,25% 123, 25%

R11 = m-CI-PhCH22 R R2 = = PhCH2 PhCH 2

Reagents: (i), CH3COCH2C1, CH,COCH,CI, I~CO K,CO"3, 18-crown-6, 18-crown-6, CH3CN CH,CN or Nail, NaH, DMF; DMF; (ii), (ii), R'-NH R'-NH"2, R2-NC, R'-NC, MeOH, MeOH, 50 50°C, Reagents: ~ 3-8 h; NaOH, EtOH, EtOH, H20. H20. (iii), 5% NaOH,

example of of a multicomponent multicomponent synthesis, synthesis, dihydrobenz[f][ dihydrobenz[f] [1,4]oxazepin-5-ones were In a further example 1,4]oxazepin-5-ones were prepared in good yields in two two steps steps by combining combining an initial three-component three-component Ugi condensation condensation prepared 3 1 2 with a subsequent subsequent Mitsunobu Mitsunobu cyclisation cyclisation to give (124; (124; e.g. R ' == H, R2= R = i-Pr, R R3== cyclohexyl, cyclohexyl, 65%) <06OBC4236>. <060BC4236>. 65%)

R1

/I O

124

CH-CONHR3 ' R2

l,l-dioxides 126 were prepared in fair yields (e.g. 126, R = The 1,2-benzothiazepine 1,2-benzothiazepine 1,1-dioxides = H, Ar = = p-CIC 6H4 , 52%) by a Heck coupling on the precursors precursors 125, which were obtained in turn tum from an p-C1C6H4, Baylis-Hillman reaction involving the appropriate sulfonamide, aza Baylis-Hillman sulfonamide, aldehyde, and methyl reactants <06TL8591>. <06TL8591>. acrylate reactants

O O

Ar/jj''H

H2N..~O

(i) (i)

Br --'J~'-/~v

o

(ii) (ii)

/ [O[ ~ O ,Ar . .,S..~O~/--R .,~ "

eO

0

H 125

Br

O~// ~S--NS H- NH

cct

R-l.. R ~

'~

126 126

---=

Ar Ar

COOMe COOMe

Reagents: (i), (i), Ti(i-PrO)4' Ti(i-PrO)4, 2-hydroxyquinuc1idine, 2-hydroxyquinuclidine, molecular molecular sieves, sieves, i-PrOH; i-PrOH; (ii), (ii), Pd(OAc)" Pd(OAc)2, P(o-tolyl)" P(o-tolyl)3, NEt" NEt 3, THF, THF, Reagents: 160°C, 160 ~ I1 h, h, microwave microwave

The first observation of the uncommon phenomenon of desmotropy in seven-membered heterocycles was reported for the prototropic annular tautomers 128 and 129. These dihydro-4,1benzothiazepines, which were prepared (via the non-isolated intermediates 130 and 131 from the fused azetidinone 127 on treatment with NaOEt), could be isolated in pure form by column

456

Bremner and S. Samosom J.B. Bremner Samosorn

chromatography. chromatography. However, they equilibrated equilibrated in solution (acidic chloroform) to give a 3:1 ratio of <06TL5665>. 128 and 129, as monitored by NMR NMR spectroscopy <06TL5665>.

O lAN~"~, '

NaOEt, EtOH, ~ S ? c"o~o E t rt, 15min + ~ ..~ S COOEt COOEt CC>COOEt + C(~: ,. ~ -.N~

[ ~ N sS @ 0 ( " ....

NaOEt, EtOH, rt, 15 min

'"CI

127 127

~ /_

H

°

1282 8 0 1

~ S +

1/

129

CI-

..

130 130

131 131

A number of heteroaryl-fused 3-oxo-l,4-thiazepine-5-carboxamides, 3-oxo-l,4-thiazepine-5-carboxamides, for example the indolefused derivatives 133, have been accessed using a modification of of the four-component Ugi condensation. In the case of 133, the starting point was the indolic acid 132. The yields of 133 1 R'== i-Pr, R2= <06JOC2811>. were moderate to good (for example, R R'= EtO-(CH2) EtO-(CH')3'3, 66%) <06JOC281l>. R11 R

" co-

R~2HNOCNyo

CHO

~

I

::/""1 ~ S) ~"%./~N ~ N S

/--COOH (i), (i), (ii) (ii) (COOH

/:/

' sS N ,

- - - -"

,

Me

Me

132 132

133 133

, MeOH, Reagents: MeOH, rt, 10 Reagents: (i), (i), R'NH RINH2, 10 min.; min.; (ii), (ii), R'NC, R2NC,MeOH, MeOH, 50°C, 50 ~ 2-3 h. 2

The unexpected 1,5-benzothiazepine 1,5-benzothiazepine derivatives 135, with an exocyclic substituted double 51%) bond at the 4-position, were obtained in moderate yields (e.g. 135, R = 4-Me, 51 %) on reaction of 134 with the aminothiol 136 in acetic acid. The structure of the products products was confirmed by detailed 1D and 2D NMR experiments <06H(68) 1319>.

"cc cc SH

N°YO

n

~~ H ° 0 H 134 134

/./

NH2

NH 2

136 136

9

[~

AcOH

AcOH

135 135

S~

S

~N ~

R

HO~o~

°

457 457

Seven-membered rings

A further neat example of multicomponent multicomponent reactions in heterocyclic synthesis was reported by al. <06AG(E)7793>. <06AG(E)7793>. They prepared the furan-fused 1,4-thiazepine Ma et at. l,4-thiazepine 140 in good yield using the three components 137, 137, 138, 138, and 139 in the one reaction. A range of other furan-fused analogues with different substituent groups in the thiazepine ring were also synthesised.

°OOil

:r~>

Ph

Sr- Et

Br Et 137 137

::r~PhPh

iO2Me (i) (')

)l

+

,

Ph yS.~Ph

COzMe

[I C

~]~~/~

+

Ph

III

°

N ~ EI~ ~ \C02Me COzMe Me02C

C02Me 139 139 COzMe

138 138

Et ..--: MeOzC

140 140 Reagents: (i), i-Pr,NEt, i-Pr2NEt, DCM, 78%.

7.4

7.4.1

SEVEN·MEMBERED SEVEN-MEMBERED HETEROATOMS HETEROATOMS

SYSTEMS

CONTAINING CONTAINING

THREE

OR

MORE

Systems with N, Sand/or S and/or 0 O

gr

o,,o 0" //0

HN-'S--NH

HN/S'NH

(i)

Y

0')<'0

141 O~<~O /-

141

1l (ii)

142

I (iii)

(ii)

Br

Br

o,,o ~o,/o~

°0° °0° 144 144

°XO 1

R

R

o,,o ~o,/o~

Br

Palladium-catalyzed Palladium-catalyzed amidationreactions reactions amidation MW,15-60 15-60min min MW, deprotection deprotection

0

Z

,0

143 143 R R

o,,o o,/o~

N-'S-N'~

HO OH OH

vOO

145 145

146 146

HO

HO OH OH

HO

Reagents: (i), AgO AgO"2, 2-bromobenzyl bromide, DCM, 100 cC, K,CO], 2-bromobenzyl ~ 60 min, microwave; (ii), K2CO3, bromide,DMF, bromide, DMF, 100 cC, ~ 16 h, 99%; 99%" (iii), K,CO K2COJ3,, benzyl bromide, DMF, 100 CC, ~ I1 h, 98%; (iv), Pd(dba)" Pd(dba)2, Xantphos, CS,CO], Cs2CO3, amide, NMP, dioxane, 160 cC, ~ 15 min, microwave.

458

J.B. Bremner and S. Samosorn

An expeditious route to the cyclic sulfamide sulfamide HIV-l HIV-1 protease protease inhibitors of type 145 and and 146 (tetrahydro-l,2,7-thiadiazepine (tetrahydro-l,2,7-thiadiazepine l,l-dioxide 1,1-dioxide derivatives) from 141 and and 142 palladium-catalysed amidation reactions. These reactions of 144 and were hinges on palladium-catalysed and 143 were microwave promoted promoted and and provided, provided, after removal of the cyclic ketal protecting group, protecting group, moderate to good yields of (145, NHCOCH 22-moderate (145, 57%) and (146,66%) (146, 66%) for example example with R = - NHCOCH 2-naphthyl <06T4671>. A number of [1,2,3]-oxathiazepane [1,2,3]-oxathiazepane 2,2-dioxides have been prepared in good yields by regioselective regioselective nucleophilic ring opening of aziridino[l,2,3]oxathiazinane aziridino[1,2,3]oxathiazinane dioxide precursors <06T11331>. <06Tl1331>. A light-induced ring expansion of the tetrazolo-uracil tetrazolo-uracil147 147 afforded ready access to the ring expanded 5H-l,3,5-triazepine-2,4-dione 5H-1,3,5-triazepine-2,4-dione nucleoside derivative 148 in 80% yield <06JOC1742>.

°O)-NH ~--NH\

N-N N-N

II/ N

) N I [ O 0N 0

o~ Ac AcO

hv >> 290 290 nm nm hv

HN HN

O~N

J

q~

H20' CH CH3CN 3CN H20,

~bAC OAc

0

Ac

ACOJ-{OAC

OAc

147

148

The chiral 1,3,5-triazepane-2,6-dione 1,3,5-triazepane-2,6-dione 149 and its ring fused analogue 150 have been shown to form H-bonded helical molecular tapes with P chirality on self assembly in the solid state. state. With aromatic-aromatic ring interactions resulting in hollow 149, this self assembly proceeds through aromatic-aromatic tubular structures <06CC4069>.

O ° HN/~NH

O ° HN)lNH HN~LNH

HN)lNH

M~lkl-~ cH2Ph ~N~CH2Ph O Me

°

149

~ / ~ cH2Ph ~N~CH2Ph

PhCH20/ PhCH20

°

-" N O 150

Resin bound dipeptides have been used in the parallel synthesis of 3,4,7-trisubstituted 3,4,7-trisubstituted 4,5,8,9tetrahydro-3H-imidazo[1,2-a][1 ,3,5]triazepine-2(7H)-thiones and N-alkyl-4,5,7,8-tetrahydro-3HN-alky1-4,5,7,8-tetrahydro-3Htetrahydro-3H-imidazo[ 1,2-a][ 1,3,5]triazepine-2(7H)-thiones imidazo[I,2-a][1,3,5]triazepin-2-amines imidazo[ 1,2-a][ 1,3,5]triazepin-2-amines by ring construction methodology <06JCOl27>. <06JCO 127>. 1,2-dihydro-3H-1,3,4-benzotriazepines has The single crystal X-ray structures of three new 1,2-dihydro-3H-l,3,4-benzotriazepines been reported <06CHE907>. A compact synthesis of dihydro-l,2,4-benzotriazepin-5-ones has also been described <06M1349>. In connection with studies on antimalarial compounds, simpler mimics of artemisinin based 152, on substituted 1,2,4-trioxepanes were examined. Examples include the 1,2,4-trioxepanes 152, 153 and 154, 154, with the seven-membered seven-membered ring being made by acid catalysed condensation of the appropriate ketone with the hydroxy hydroperoxide 151. 151. Unfortunately the 1,2,5-trioxepanes vitro (up to 1000 were not active as antimalarials in vitro 1000 nM) probably due to their resistance to Fe(II)-mediated degradation <06BMCL6124>. Fe(II)-mediated <06BMCL6124>.

459

Seven-membered rings Seven-membered

a1

a1

o=(

ArS\pOH

ArS___N o ' O ' ~

R2

~OH ~ "OH

(i)

151

R1 a: (CH (CH2) Z)44

R2

152 152 a: 72% b: 76% b:76% c:82% c: 82%

Ar p-CIC6 H44 p-ClC6H p-CIC 6 H4 p-CIC6H4

(CH (CH2) Z)44

jIn)

b: (CH (CH (CH2)5 (CH2)5 Z)5 Z)5 c: Adamantylidene Adamantylidene p-CIC6H4 p-CIC sH4

(ii)

0 o IIII

R1 O

H

..O

(iii)

R2

"~~/~o

"

R2

/'X_,, ~

_

R11

o~O'-L' R2Z o ~~

ArS~/ ~"R Ars~b ~~_/0 153 153

154 a: a : 887% 7% 154 b: 83% b:83% c: 89% c:89%

a: a : 887% 7% b:83% b: 83% c:89% c: 89%

Reagents: ketone, p-toluenesulfonic p-toluenesulfonic acid; Reagents: (i) ketone, acid; (ii) (ii) m-CPBA m-CPBA(1.0 (1.0 eq.), eq.), DCM, DCM, rt, 6 h; h; (iii) (iii) 2,6-lutidine 2,6-1utidine(4.2 (4.2 eq.), eq.), trifluoroacetic trifluoroacetic acid acid anhydride anhydride(3.8 (3.8 eq.), eq.), acetonitrile, acetonitrile,rt.

The chemistry of pentathiepins has been extended to the pyrrolo-fused derivative 155. Reaction of 155 with dimethyl acetylenedicarboxylate (DMAD) and triphenylphosphine at room temperature gave the fused 1,4-dithiin derivative 156 in high yield <060L4529>. <06OL4529>. It is probable that the triphenylphosphine removes three sulfur atoms from 155 to give a dipolar reactive intermediate for a cycloaddition with DMAD DMAD to afford 156.

U) S-S

N

M~ M~

(i)

S-S

Md 155 155

156

Reagents: (i), DMAD, PPPh DCM, rt, , DCM, Reagents: (i), DMAD, P h 3, rt, I1 h, 80%. 80%. J

7.5

SEVEN-MEMBERED SYSTEMS SYSTEMS OF OF PHARMACOLOGICAL PHARMACOLOGICAL SIGNIFICANCE SIGNIFICANCE SEVEN-MEMBERED

Pharmacologically active compounds incorporating 7-membered heterocyclic components continue to flourish. Examples include the designed enhancement of pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione 1,4-benzodiazepine-2,5-dione antagonists 157 of the Hdm2-p53 protein-protein interaction <06MCL33l0>, <06MCL3310>, the synthesis of enantiomerically pure 1,4-benzodiazepine-2,5-diones 1,4-benzodiazepine-2,5-diones and their assessment as Hdm2 antagonists <06BMCL3ll5>, <06BMCL3115>, l,4-benzodiazepines 1,4-benzodiazepines as inhibitors of respiratory syncytial virus <06JMC231l>, <06JMC2311>, benzodiazepinone-based benzodiazepinone-based cysteine protease inhibitors of type 158 as potential antimalarial compounds <06JMC3064>, <06JMC3064>, methyl substituted azepan-3ones as cathepsin K inhibitors <06JMC1597>, <06JMC1597>, novel inhibitors of the epidermal growth factor

460

J.B. Bremner Samosorn Bremner and and S. Samosorn

receptor tyrosine kinase based on pyrimido[ pyrimido[4,5-b]-l,4-benzoxazepines 4,5-b ]-1 ,4-benzoxazepines (and the corresponding fused thiazepines and diazepines) <06BMCL5102>, and xantheno[9,I-cd] xantheno[9,1-cd] azepines as analogues of clavizepine <06JOC3963>. benzo[b]azepin-2-one and -2,5-diones have been assessed as selective dopamine Reduced benzo[b]azepin-2-one D3-receptor antagonists <06BMCL658>, and 2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-ones 2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-ones have moderate herbicidal activity <06JHCI275>. <06JHC1275>. Other compounds of interest include dibenzo[b,j][I,4]oxazepines dibenzo[b,f][1,4]oxazepines for assessing aspects of the histamine H4 receptor site <06JMC4512>, benzodiazepine-based -tum -turn mimetics with moderate affinity for the AT2 receptor and in one case high affinity for the ATl AT1 receptor <06JMC6133>, T-cell selective cytotoxic 1,4-benzodiazepine-2,5-diones <06BMCL2423>, achiral 1,3,4-benzotriazepines 1,3,4-benzotriazepines as selective (over CCKI CCK1 receptors) CCK2 receptor antagonists <06JMC2253>, and 1,51,5benzodiazepines containing a benzophenone moiety as photoaffinity probes for labelling within the membrane-spanning domain of the cholecystokinin receptor <06JMC850>. Further examples include antibody-directed enzyme prodrug therapy (ADEPT) based on pyrrolo[2,1-c][1,4]benzodiazepine pyrrolo[2,I-c][I,4]benzodiazepine prodrugs <06BMCL252>, novel, orally active vasopressin V2 receptor agonists based on 5,Il-dihydropyrido[2,3-b][I,5]benzodiazepines 5,11-dihydropyrido[2,3-b][1,5]benzodiazepines <06BMCL954>, and 5H-1,4-benzodioxepin-3-yl uracil and purine derivatives as anticancer agents <06Tl <06Tl1724>. 1724>. 5H-l,4-benzodioxepin-3-yl Interest continues in the design and pharmacological evaluation of dual functional agents and in 4,1this context molecular docking and QSAR studies have been described on a number of 4, 1benzoxazepinone derivatives as inhibitors of both wild type and mutant (K103N) HIV-I HIV-1 reverse transcriptases <06MI281>. Pyrrolo-l,5-benzoxazepines, which are potent apoptosis inducers in a number of chemotherapy-resistant human cancer cell lines, have been shown to target tubulin and in one case (PBOX-6) was shown not to bind to the vinblastine or colchicine binding sites <06MI60>. A significant advance in selective 5-HTlA 5-HT1A receptor agonists with neuroprotective effects has been detailed <06BMC1978>; <06BMCI978>; these compounds are 1,4-benzoxazepine derivatives. A series of moderately potent thiazepines as inhibitors of interleukin-I interleukin-1 converting enzyme has been described <06BMCL4728>, while a new class of antileukemic agents based on pyrrolo[I,2pyrrolo[1,2b][I,2,5]benzothiazepines b][ 1,2,5]benzothiazepines have been reported <06JMC5840>. Cl

I

Ph~

0

0

HO

ArHNCO2~~-~oN~'~L" N~ O Cl HO2CH2CH2CH2CH2C

O 157

158 158

Using representative 1,3,5-triazepane-2,6-diones, an interesting protein data mining study based on high-throughput docking identified and verified secreted phospholipase A2 as the target for these diones. These diones can be viewed as conformationally restrained dipeptide mimetics <06JMC6768>, and in another significant paper they have been reported as having inhibitory Pyrrolo[2, I-b][ 1,4]benzodiazepine-azepane activity on the liver stage of malaria <06CEJ8498>. Pyrrolo[2,1-b][1,4]benzodiazepine-azepane

461

Seven-membered Seven-membered rings

159) have been synthesised and their DNA-binding conjugates (e.g. 159) DNA-binding properties assessed <06BMCL 1160>. <06BMCLl160>. OH

Me O. /{,. _

HO

MeO 159

7.6

"~~ 0

FUTURE F U T U R E DIRECTIONS DIRECTIONS

The The scope for further developments in the chemistry of of seven-membered heterocyclic systems considerable, particularly particularly with respect to multi-heteroatom component New synthetic is considerable, component systems. New methods are needed for these systems and ring-fused derivatives. The demand for such systems methods is likely to be largely driven by the search for structurally novel drug leads.

7.7

REFERENCES REFERENCES

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462 06BMCL6124 06CC3119 06CC3119 06CC3320 06CC4069 06CC4069

06CEJ8498 06CEJ8498

06CHE907 06EJ03803 06EJO3803 06H(67)233 06H(67)233 06H(67)549 06H(67)549 06H(68) 1017 06H(68)1319 06H(68)1319 06H(69)217 06H(69)217 06H(70)705 06H(70)705 06JA2178 06JA2178 06JC0127 06JCO 127 06JHC 1275 06JHC1275 06JMC850 06JMC1597 06JMC 1597

06JMC2253 06JMC2253

06JMC2311

06JMC3064 06JMC3064

06JMC4512 06JMC4512 06JMC5840

06JMC6133 06JMC6133 06JMC6768 06JMC6768

06JOC1537 06JOC1537 06JOC1742 06JOC 1742 06JOC2811 06JOC3963 06JOC4937 06JOM5406 06JOM5406

J.B. Bremner Brernner and S. Sarnosorn Samosorn

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Seven-membered Seven-membered rings

06JPC(A) 1600 1600 06JPC(A) 06M 1349 06M1349 06MI60 06MI60 06MI99 06MI281 06MI281

06OBC2218 060BC22 I8 06OBC4236 060BC4236 06OL2667 060L2667 06OL4529 060L4529 06OL5183 060L5183 06OL5469 060L5469 06OL 16185 060Ll6185 06S1437 06SC355 06SC457 06SC803 06SC817 06SC 1645 06SCI645 06SC 1661 06SCI661 06SL 1009 06SLl009 06SL2275 06SL2771 06SL277I 06T1777 06T2563 06T4671 06T467I 06T7455 06T7699 06T8126 06T8126 06T9002 06T9017 06T9301 06T10456 06TI0456

06T11331 06TI1331 06T 11724 06T11724 06T12392 06T12392 06TA2334 06TA2334 06TL639 06TL639 06TL2649 06TL2649 06TL3135 06TL3135 06TL3225 06TL3225 06TL3295 06TL3295 06TL3357 06TL3357 06TL3423 06TL3423 06TL3625 06TL3625 06TL3811

463

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