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Radical cyclizatations of α-fluoro-α-iodo and α-iodo esters and amides.
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RADICAL, CYCLIZATIONS OF a-FIUORO-a-IOU0
AND a-IOU0 RSIERS AND AMIDES.1
Francis Barth2 and Counde O-Yang* Syntex Research, 3401 Hillview Ave., Palo Alto, CA 94303 The free radical cyclixation of various unsaturated a-fluom-u-iodo and c&do esters and Abstract: amides is descriu unusual 12ItEmbered dilactones and 18membemd uilactones wete obtained under the standanl atom transfer cyclixation maction conditions. Free radical cyclixations of olefins have been used inmingly membered rings? However, has not been sported.
for the construction of 5- and 6-
to our knowledge, the cyclixation ofradicals bearing a-fluoro substituents
In connection with our interest in the preparation of biologically active fluorinated
molecules, we have explomd the possibility of applying this methodology to the synthesis of a-fluom lactones (la) and lactams (lb) fmm the cormsponding a-fluoro-a-iodo esters (24 and amides (2b).
Since initial attempts to cyclixe (2a) using Bu$nH gave only reduction products, the radical cyclixation reactions were carried out using the atom transfer n~thod.~ Extensive studies by Curran have shown this technique to be particularly useful for the cycliration of stabilized radicals. When a benzene solution of the diiluoro ester (&@j and 0.1 eq. of hexabutylditin was irradiated with a sunlamp, only the starting material was mcovemd. Intemstingly, under the same conditions, the monoiluom ester (3b) produced an unusual 1Zmembemd dilactone (Sb) in 31% yield, with none of the anticipated 5-membered lactone
(W. To our knowledge, the formation of a dilactone of this type through a free radical cyclixation reaction has not been previously reported’
This observation prompted us to investigate the Win” initiated radical
cyclization of various c&do esters and amides, and the results are summart‘red in Table 1. Irradiation of ally1 ester (3c) gave a mixture of products iiom which the expected kuembexed lactone (4c) was isolated in 11% yield along with the dilactone (SC) and uilactone (6c) in 15% and 17% yields, respectively.a In contrast, cyclixation of the dimethylallyl esters (3d) and (3e) proceeded smoothly to give the corresponding lactones (4d) and (4e) in 68% and 62% yields, respectively. On the other hand, the homoallylic ester (3f) gave predolllinanty the dilactone (Sf) (Table 1. entry 8). The proposed pathways leading to the formation of dilactone (SC)and uilactone (SC)am outlined in Schem
1.
1121
1122
x-o, 1:
8: b: 0:
n=l,R-H Y-V-F Y.H,Y’-F Y.V’.H
X-0, d: 0:
n-l,R=CH, Y-v-H Y=H,Y’-F
X-O,
Table1
n=2,R=H Y=Y’.H
X-NCH,n-l,R=H Y-Y’-H Qhi . Y-H,Y’=F
Atom Tramfer Cycl&a!bn of a-lcdo Esfers and Amid&+ PlMucts (% YW)d
Emy 1
Substmte
3b
2
3c
4
6
6
0.05
31*
-
0.006
w
-
Cont. (M)
0.5
11
15
17
4
0.076
19
35
17
5
0.009
64
22
-
3
6
3d
0.076
68
-
-
7
30
0.076
62
-
-
8
91
0.008
7
65
26
9
39
0.076
61
-
-
10
3h
0.076
13’
-
-
a) 0.1 eq. of (SU$~)~ was used for 3b-3f. b) Total 0.3 eq. and 0.5 eq. d (Bu3Sn)p were used for 39 and 3h, respectively. c) All nmtbns were carried auf in refluxln(fbenzene and irrad&tbn times for 3b-3f, 39 and 3h were6h,8hand16h,respc6wly. d) YieWofprocMsaflerpurmbn on silica gel. e) Two diastereomen of 5b in a by~~maloorephy raMof;aMof~Jlatedbychromato9raplly. 9 79%ofthestaltifg
1123
Scheme I Propoeed Pathwayskr
the Formatlenol Dllsdone(So)and Triladone(SC)
‘4c
0
6c
The interndecular additionof the initial radical (7) to the startingolefin (3c) (path b) appaxently competes favorably with a slow radical cyclization (path a), leading to the folmation of the intermediate diiodide (8). The diiodide (8) then proceds to give dikctone (SC)and trihwone (6c) as shown. The slow rate of cyclization to the monolactoneis attributed to the unfavorable s-cis confonnatkm associated with the es&d’and the stabilityof the acarbonyl did The greatly improved yield of (4c) observed for the cyclidon of (3c) under the high dilution condition (8 mM)‘Opresumablyresults from the reduced rate of the intumolecular addition(Table 1, entry 5). Inauhxtion of termid substituentson the olefm in the esters (3d) and (3e) suppressesthe intumolecular addition. leading to the exclusive fomhon of lactoncs (4d) and (4e), respectively. Since the fluorine substituentfurther increasesthestabilityofthe a-cadnmyl radidl, no cyclidon product (4b) is obtained fkomfluoro ester (3b). In contrast to tbc findings obtained for a&lo
esters (3b) and (3c). cyclization of a-iodo amides (3g) and
(3h)~asexpectedmgivethe5-mmbend~(4g)and(4h)in6o9band13%yields, respecti~ely.~~No di- or Hoetam was isolated.13 This dt is consistent with the relatively highcx propdon ofthe squired s-cis conformation in amides.”
1124
Reknces
and Note@
1.
ContributionNo. 7% fmm the Institute of Organic Chemistry.
2.
Syntex Postdoctoral Fellow 1988-1989.
3.
(a) Cmrau, D.P. Syntkis l988.417 and 489. (b) Giese, B. Radicalsin Organic Synthesis: FormationofCarbon-Carbon Bonds, PergamonPress, Oxford, 1986.
4.
Cuuan D.P.; Chang, C.-T.J. Org. Chem. 1989,54,3140.
5.
The requisite a-fluon+a-iodo esters were prepared from CoIIlDlQcially available ethyl bromofluoroacetateand ethyl bnrmodifluaroacetateaaxnding to the following sequence: (i) NaI/acctone,(ii) LiOH/CH~OH&O~ (ii) SO&, (iv) ROH&N/&O. The corresponding amideswere prepa& by aminationof the acid chlorik obtainedas above.
6.
All new compounds wezecharacterized by ‘H NMR and mass spectra. Satisfactory elemental analysis and/or high resolution mass spectra were also obtained.
7.
It should be mentioned that radical cyclization has been utilized for the construction of a diffexent type ofmacnxylic system. porter, N. A. and Chang, V. I-L-T.J. Am. Gem. Sot. 19%7,I@,4976
8.
Atom transfer cyclization of 2-cyclohexenyl k&acetate has been sported by Curran.3 However, nodi-ortrilactoneswemisolated.
9.
Oki, M.; Nakanishi.I-LBull. Chem. Sot. Japan l970,43.2558.
10.
This concentration is umsidembly lower than that of standaxdatom transfer cyclization reacdons (see reference 4).
11.
Chambers.RD. Fluorine in Organic Synthesis,Wiley-Interscience,New York, 1973.
12.
Additionof 3.5 eq. of EtI to the rtactioll of (3h) did not improve the yield of (4b). Jolly, RS.; Livinghouse,T. J. Am. Chem. Sot. l988.110,7536.
13.
Radicalcyclizatkm of N-allyl-N-methylchloroacctamideusing the (n&)&H nxthod has been recently reportad However, the expected lactam was obtained in only 24% yield along with 39% of the reduction product. Sate, T.; Wada, Y.; Nishimoto,M.; Ishibashi,H; and lkeda, IvLJ. Chem. Sot.. Perkin. Trans. I, l989,879.
14.
Stewart,W.E.; Siddall. T.H. III Chem. Rev. l970,70,517.
(Received in USA 22 November 1989)
RADICAL, CYCLIZATIONS OF a-FIUORO-a-IOU0
AND a-IOU0 RSIERS AND AMIDES.1
Francis Barth2 and Counde O-Yang* Syntex Research, 3401 Hillview Ave., Palo Alto, CA 94303 The free radical cyclixation of various unsaturated a-fluom-u-iodo and c&do esters and Abstract: amides is descriu unusual 12ItEmbered dilactones and 18membemd uilactones wete obtained under the standanl atom transfer cyclixation maction conditions. Free radical cyclixations of olefins have been used inmingly membered rings? However, has not been sported.
for the construction of 5- and 6-
to our knowledge, the cyclixation ofradicals bearing a-fluoro substituents
In connection with our interest in the preparation of biologically active fluorinated
molecules, we have explomd the possibility of applying this methodology to the synthesis of a-fluom lactones (la) and lactams (lb) fmm the cormsponding a-fluoro-a-iodo esters (24 and amides (2b).
Since initial attempts to cyclixe (2a) using Bu$nH gave only reduction products, the radical cyclixation reactions were carried out using the atom transfer n~thod.~ Extensive studies by Curran have shown this technique to be particularly useful for the cycliration of stabilized radicals. When a benzene solution of the diiluoro ester (&@j and 0.1 eq. of hexabutylditin was irradiated with a sunlamp, only the starting material was mcovemd. Intemstingly, under the same conditions, the monoiluom ester (3b) produced an unusual 1Zmembemd dilactone (Sb) in 31% yield, with none of the anticipated 5-membered lactone
(W. To our knowledge, the formation of a dilactone of this type through a free radical cyclixation reaction has not been previously reported’
This observation prompted us to investigate the Win” initiated radical
cyclization of various c&do esters and amides, and the results are summart‘red in Table 1. Irradiation of ally1 ester (3c) gave a mixture of products iiom which the expected kuembexed lactone (4c) was isolated in 11% yield along with the dilactone (SC) and uilactone (6c) in 15% and 17% yields, respectively.a In contrast, cyclixation of the dimethylallyl esters (3d) and (3e) proceeded smoothly to give the corresponding lactones (4d) and (4e) in 68% and 62% yields, respectively. On the other hand, the homoallylic ester (3f) gave predolllinanty the dilactone (Sf) (Table 1. entry 8). The proposed pathways leading to the formation of dilactone (SC)and uilactone (SC)am outlined in Schem
1.
1121
1122
x-o, 1:
8: b: 0:
n=l,R-H Y-V-F Y.H,Y’-F Y.V’.H
X-0, d: 0:
n-l,R=CH, Y-v-H Y=H,Y’-F
X-O,
Table1
n=2,R=H Y=Y’.H
X-NCH,n-l,R=H Y-Y’-H Qhi . Y-H,Y’=F
Atom Tramfer Cycl&a!bn of a-lcdo Esfers and Amid&+ PlMucts (% YW)d
Emy 1
Substmte
3b
2
3c
4
6
6
0.05
31*
-
0.006
w
-
Cont. (M)
0.5
11
15
17
4
0.076
19
35
17
5
0.009
64
22
-
3
6
3d
0.076
68
-
-
7
30
0.076
62
-
-
8
91
0.008
7
65
26
9
39
0.076
61
-
-
10
3h
0.076
13’
-
-
a) 0.1 eq. of (SU$~)~ was used for 3b-3f. b) Total 0.3 eq. and 0.5 eq. d (Bu3Sn)p were used for 39 and 3h, respectively. c) All nmtbns were carried auf in refluxln(fbenzene and irrad&tbn times for 3b-3f, 39 and 3h were6h,8hand16h,respc6wly. d) YieWofprocMsaflerpurmbn on silica gel. e) Two diastereomen of 5b in a by~~maloorephy raMof;aMof~Jlatedbychromato9raplly. 9 79%ofthestaltifg
1123
Scheme I Propoeed Pathwayskr
the Formatlenol Dllsdone(So)and Triladone(SC)
‘4c
0
6c
The interndecular additionof the initial radical (7) to the startingolefin (3c) (path b) appaxently competes favorably with a slow radical cyclization (path a), leading to the folmation of the intermediate diiodide (8). The diiodide (8) then proceds to give dikctone (SC)and trihwone (6c) as shown. The slow rate of cyclization to the monolactoneis attributed to the unfavorable s-cis confonnatkm associated with the es&d’and the stabilityof the acarbonyl did The greatly improved yield of (4c) observed for the cyclidon of (3c) under the high dilution condition (8 mM)‘Opresumablyresults from the reduced rate of the intumolecular addition(Table 1, entry 5). Inauhxtion of termid substituentson the olefm in the esters (3d) and (3e) suppressesthe intumolecular addition. leading to the exclusive fomhon of lactoncs (4d) and (4e), respectively. Since the fluorine substituentfurther increasesthestabilityofthe a-cadnmyl radidl, no cyclidon product (4b) is obtained fkomfluoro ester (3b). In contrast to tbc findings obtained for a&lo
esters (3b) and (3c). cyclization of a-iodo amides (3g) and
(3h)~asexpectedmgivethe5-mmbend~(4g)and(4h)in6o9band13%yields, respecti~ely.~~No di- or Hoetam was isolated.13 This dt is consistent with the relatively highcx propdon ofthe squired s-cis conformation in amides.”
1124
Reknces
and Note@
1.
ContributionNo. 7% fmm the Institute of Organic Chemistry.
2.
Syntex Postdoctoral Fellow 1988-1989.
3.
(a) Cmrau, D.P. Syntkis l988.417 and 489. (b) Giese, B. Radicalsin Organic Synthesis: FormationofCarbon-Carbon Bonds, PergamonPress, Oxford, 1986.
4.
Cuuan D.P.; Chang, C.-T.J. Org. Chem. 1989,54,3140.
5.
The requisite a-fluon+a-iodo esters were prepared from CoIIlDlQcially available ethyl bromofluoroacetateand ethyl bnrmodifluaroacetateaaxnding to the following sequence: (i) NaI/acctone,(ii) LiOH/CH~OH&O~ (ii) SO&, (iv) ROH&N/&O. The corresponding amideswere prepa& by aminationof the acid chlorik obtainedas above.
6.
All new compounds wezecharacterized by ‘H NMR and mass spectra. Satisfactory elemental analysis and/or high resolution mass spectra were also obtained.
7.
It should be mentioned that radical cyclization has been utilized for the construction of a diffexent type ofmacnxylic system. porter, N. A. and Chang, V. I-L-T.J. Am. Gem. Sot. 19%7,I@,4976
8.
Atom transfer cyclization of 2-cyclohexenyl k&acetate has been sported by Curran.3 However, nodi-ortrilactoneswemisolated.
9.
Oki, M.; Nakanishi.I-LBull. Chem. Sot. Japan l970,43.2558.
10.
This concentration is umsidembly lower than that of standaxdatom transfer cyclization reacdons (see reference 4).
11.
Chambers.RD. Fluorine in Organic Synthesis,Wiley-Interscience,New York, 1973.
12.
Additionof 3.5 eq. of EtI to the rtactioll of (3h) did not improve the yield of (4b). Jolly, RS.; Livinghouse,T. J. Am. Chem. Sot. l988.110,7536.
13.
Radicalcyclizatkm of N-allyl-N-methylchloroacctamideusing the (n&)&H nxthod has been recently reportad However, the expected lactam was obtained in only 24% yield along with 39% of the reduction product. Sate, T.; Wada, Y.; Nishimoto,M.; Ishibashi,H; and lkeda, IvLJ. Chem. Sot.. Perkin. Trans. I, l989,879.
14.
Stewart,W.E.; Siddall. T.H. III Chem. Rev. l970,70,517.
(Received in USA 22 November 1989)