自由基在有機合成上的運用(IV)

行政院國家科學委員會專題研究計畫成果報告

自由基在有機合成上的運用(IV)

The Applications of Fr ee Radical Reactions in Or ganic Synthesis

計畫編號：NSC 87-2113-M-002-022

執行期限：86 年 8 月 1 日至 87 年 7 月 31 日

主持人：蔡蘊明 國立臺灣大學化學系

α -Stannyl bromides and xanthates are prepared. Reactions of these compounds with tributyltin hydride generate α-stannyl radicals. Intramolecular cyclizations of these radicals with formyl group afford γ -stannyl alkoxy radicals which undergo 1,3-stannyl shift from carbon to oxygen.

Keywor ds: α-stannyl radicals, 1,3-stannyl shift

二、緣由與目的

Intramolecular radical addition to carbonyl to give cyclic alcohol is a potentially useful reaction.1 However, this type of cyclizations (eq 1) is reversible, and the reverse reactions are generally faster than the cyclizations.2 _{In the cases of}

acylgermanes,3 acylsilanes,1 thioesters and selenoesters,4 intramolecular radical additions to the carbonyl moiety in these compounds are followed by irreversible processes. Therefore, these cyclizations can be stopped at the cyclization side.5 _Herein,

we wish to report the intramolecular

cyclization of formyl group with α-stannyl radical6 _{(eq 2). In this cyclization, a}

heretofore unprecedented homolytic 1,3-stannyl shift from carbon to oxygen7–10

serves as the driving force.

O H O H O H O H HO SnBu3 SnBu3 SnBu3 S S H O H O SnBu3 Br shift n (2) 1,3-Sn 1b n = 4 1a n = 3 n 1) Bu₃SnLi, THF 78o C 2a (56%) 2b (42%) 2) CBr4, PPh3 CH₂Cl₂, 0oC 3) CAN, 15o_C CH₃CN/H₂O (3) (1) 三、研究報告內容

As shown in eq 3, aldehydes 111 were coupled with tributyltin lithium,12 and the resulting α-stannyl alcohols were converted to α-stannyl bromide by using carbon tetrabromide and triphenylphosphine.13

The dithiane moiety was then deprotected14 to give aldehydes 2 in mild yields over three steps. Treatment of aldehyde 2a with tributyltin hydride15 _{(Scheme 1) followed}

by quenching the reaction with benzoyl chloride gave us the benzoate derivative of cyclohexanol 3 in 57% yield. Uncyclized reduction product aldehyde 4 was also isolated in 12% along with trace amount of

benzoate 5. The benzoate 5 was

presumably derived from over-reduction of aldehyde 4 by tributyltin hydride followed by

benzoate formation.

This cyclization reaction occurred through the formation of α-stannyl radical 6 first. This radical then cyclized with the formyl group to generate the γ-stannyl alkoxy radical 7. Because the carbonyl radical cyclizations are in general reversible,2 it is likely that the alkoxy radical and stannyl group may have a chance to adopt a syn-relationship as shown in 7. Alkoxy radical

7 presumably underwent 1,3-stannyl shift

from carbon to oxygen to generate radical 8. It is known that O-Sn bond is stronger than C-Sn bond by about 25 kcal/mol.16 _This

big difference provides a strong

thermodynamic driving force to trap the alkoxy radical 7. Abstraction of hydrogen from tributyltin hydride by radical 8 gave stannyl ether 9. Oxygen atom in stannyl ethers is known to be quite nucleophilic.17

Therefore, we directly added benzoyl chloride to the reaction mixture at the end of the cyclization reaction followed by heating and obtained benzoate 3.

OCOPh H O SnBu₃ OCOPh SnBu₃ H O SnBu₃ O SnBu₃ O SnBu3 O SnBu3 9 Bu3Sn 1,3-stannyl shift 4 + 4 (trace) 2a + 3 4 5 (57%) (12%) Bu3SnH PhCOCl 6 7 8 Scheme 1 1) Bu3SnH (1.3 equiv) AIBN (cat) PhH, 80oC 2) PhCOCl Et3N

When aldehyde 2a (Scheme 2) was treated with allyltributyltin (4 equiv) in the presence of hexabutylditin (0.2 equiv) and photolyzed with long wavelength UV light for initiation18 (12 h), we were able to isolated alcohol 1019 in 35% yield. Although this intermolecular process is not

very efficient, yet the reaction provided evidence that radical 8 was formed indeed.

OH OSnBu3 SnBu3 Bu3Sn-SnBu3(0.2 equiv) hν, PhH, 12 h Scheme 2 2a CH2=CHCH2SnBu3(4 equiv) 10 (35%) Bu₃Sn 8 + Bu₃Sn

In the case of 6-exo cyclization (eq 4), aldehyde 2b reacted with tributyltin hydride15 _{and gave 27% of cyclohexanol (11),}

29% of uncyclized product aldehyde 12, and 9% of over-reduction product alcohol 13. The problem of this reaction was revealed by

the reaction of aldehyde 2b with

allyltributyltin (eq 5). In addition to alcohol

1420 _{(10%), we isolated 50% of aldehyde 15}

which contains an allyl group at the α -position of the carbonyl group. This result indicated that after the generation of the α -stannyl radical from aldehyde 2b, a 1,5-hydrogen transfer21 occurred to give an α -carbonyl radical. The α-carbonyl radical was then trapped by allyltributyltin to give aldehyde 15. H O SnBu3 OH SnBu3 OH H SnBu₃ O OH SnBu3 (4) 4 + 2b (2 equiv) 14 (10%) _(50%)15 (5) (Bu3Sn)2 (0.1 equiv) hν, 8 h 5 + + 11 12 5 13 (27%) (29%) 2b PhH 80oC, 6 h (9%) Bu₃SnH (1.3 equiv) AIBN (cat)

This stannyl shift promoted carbonyl radical cyclization reaction can be employed in a tandem cyclization mode. As shown in Scheme 3, we prepared diester 17 via alkylation of dimethyl malonate with

bromide 1622 _{and 4-bromo-1-butene.}

cyanide23 gave ester 18. Reduction of ester

18 followed by Swern oxidation24 _{of the}

resulting alcohol afforded aldehyde 19. The aldehyde 19 was S S Br S S E E S S E S S CHO S S O SnBu₃ S H₃CS H O O SnBu₃ S H₃CS H O O SnBu3 S H₃CS TMS 19 (79%) Scheme 3 16 17 (86%) E = CO₂Me i, ii iii 18 (88%) 21 (70%)

Reagents and conditions: i, CH2(CO2Me)2, NaH, DMF, 80oC.

ii, NaH, DMF; BrCH2CH2CH=CH2. iii, NaCN, DMF, 120oC. iv,

LAH, THF. v, Swern oxidation. vi, Bu3SnLi, THF; CS2,; MeI.

vii, MeI (15 equiv), acetone/H2O.

22

vii iv, v

20 (80%)

vi

treated with tributyltin lithium, and the resulting oxide was trapped with carbon disulfide and methyl iodide to give xanthate

20. The dithiane moiety in xanthate 20 was

hydrolyzed with excess methyl iodide in wet acetone25 _{under reflux to obtain aldehyde 21.}

In a similar process we also prepared aldehyde 22. When we tried to convert aldehyde 19 to the corresponding α-stannyl bromide using the sequence shown in eq 3, low yield of the bromide was obtained. Therefore, the xanthate was used instead for our study.

The reaction of aldehyde 21 with tributyltin hydride15 (eq 6) gave monocyclic aldehyde 23 in 33% yield. This aldehyde

H O Bu₃Sn CH₃ OH Bu₃Sn CH₃ H H HO H H HO 23 (33%) 24 (5%) + (6) 25 (29%) 26 (4%) + 21 Bu₃SnH (1.3 equiv) AIBN (cat) PhH, 80oC 4 h +

was derived from the addition of α-stannyl radical to the olefin first. An alcohol 24 (5%) was also obtained. This material was presumably derived from reduction of aldehyde 23 by tributyltin hydride. Bicyclic alcohol 25 was isolated in 29% yield. Small amount of bicyclic alcohol 26 was also present in about 4% yield. To determine the stereochemistry of alcohols 25 and 26, we treated the cyclization crude product with benzoyl chloride. The benzoates derived from alcohols 25 and 26 thus obtained are identical to that reported by Wilcox et al.26

There appeared to be other stereoisomers of alcohol 25 and 26 present; however, the amount was very small and we were not able to identify these minor isomers. Bicyclic alcohols 25 and 26 were tandem cyclization products derived from addition of α-stannyl radical 27 (Scheme 4) to formyl group first. The cyclization presumably prefers to adopt a chair transition state27 _{with large groups}

located at equatorial position as shown in 27. This led to the formation of alkoxy radical 28 with a predominant trans-1,3-relationship. A stannyl shift of 28 gave radical 29 which cyclized with the olefin with the known endo-selectivity28 _{to give bicyclic alcohol 25}

as the major isomer.

O H H H SnBu₃ O H H H SnBu3 OSnBu₃ H H Scheme 4 27 1 2 3 28 29

Because the total yields of monocyclic products 23 and 24 are close to that of

bicyclic alcohols 25 and 26, the addition rates of α-stannyl radical to olefin and formyl group appeared to be similar. With this information available, it is possible to attenuate the tandem system to favor the bicyclic product. For example, it is known that 5-exo cyclization of 5-hexynyl radical is slower than the corresponding 5-hexenyl radical cyclization by about ten fold.29

Therefore, for aldehyde 22, one would expect the carbonyl cyclization to be faster than the alkyne cyclization. As shown in eq 7, the cyclization of aldehyde 22 gave four isomeric bicyclic alcohols 30 and 31 in a combined yields of 68%.30 _{Monocyclic alcohol 32}

was isolated in 10% yield. The rates of carbonyl addition product versus alkyne addition product was improved to about 7/1.

H H HO H H HO X Y X Y Bu₃Sn TMS HO 22 Bu3SnH (1.3 equiv) AIBN (cat) PhH, 80oC 4 h + (7) E-31 (13%) X = H, Y = TMS E-30 (32%) X = H, Y = TMS Z-30 (17%) X = TMS, Y = H Z-31 (6%) X = TMS, Y = H + 32 (10%)

In conclusion, a 1,3-stannyl shift promoted cyclization of α-stannyl radical with formyl group was developed. This process is successful for 5-exo cyclization; however, the corresponding 6-exo cyclization has serious competition of 1,5-hydrogen transfer. The 5-exo cyclization of α-stannyl radical with formyl group has similar rate as that with terminal olefin. This information will be useful in the design of tandem cyclizations. In the tandem cyclizations, the α-bromostannane moiety serves as a novel gem-diyl equivalent.31

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