Chapter 9
Studies Toward the Syntheses of Functionalized, Fluorinated Allyl Alcohols P. V. Ramachandran, M. Venkat Ram Reddy, and Michael T. Rudd
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H . C. Brown and R. B. Wetherill Laboratories of Chemistry, Purdue University, West Lafayette, IN 47907-1393
This chapter reviews our study of Morita-Baylis-Hillman (MBH) and vinylmetalation reactions for the synthesis of achiral and chiral, functionalized, fluorinated allyl alcohols. Vinylmetalation of fluoro -carbonyls with aluminum and copper reagents for the synthesis of unsubstituted, and β-substituted fluorinated allyl alcohols is summarized. An exploratory study of terpenyl alcohols as chiral auxiliaries in these reactions is also discussed.
Carbon-carbon bond forming reactions constitute the core of organic synthesis, and novel, efficient methods are always desirable. One such reaction that has attracted much attention in recent days is the Morita-Baylis-Hillman (MBH) reaction; the reaction of activated olefins with reactive carbonyls or imines in the presence of a catalytic amount of trialkyl(aryl)phosphine or amine (i-3). Of all the amines tested, 1,4diazabicyclo[2.2.2]octane (Dabco) has been found to be superior (Scheme 1). This reaction, which provides multifunctional molecules has been accommodated in certain undergraduate curriculum (4), and does not demand any sophisticated techniques or instrumentation.
X = O, NR"
E W G = CHO, C N , COOMe, C O C H , S 0 P h , etc. 3
2
Scheme 1. General scheme for M B H reaction Various electron-withdrawing groups, such as aldehyde, nitrite, esters, ketones, sulfones, etc. have been utilized to activate the vinyl moiety. The generally accepted mechanism (i) shown in Scheme 2 involves the Michael addition of die amine catalyst to the alkene, followed by an aldol type addition to the carbonyl or imine compound. Subsequent elimination releases the catalyst, and the cycle continues.
© 2000 American Chemical Society
In Asymmetric Fluoroorganic Chemistry; Ramachandran, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
117
118
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Scheme 2. Mechanism for M B H reaction The product allyl alcohols have been employed in the synthesis of various biologically active compounds, such as the anti-tumor agent Sarkomycin ester (5) and a-methylene-y-butyrolactones (6). These lactones constitute 10% of all natural products, including medicinals for cardio-vascular diseases (7). In materials chemistry, the Morita-Baylis-Hillman products have been applied to prepare novel side chains of liquid crystal polymers (8). There are several drawbacks for this otherwise simple reaction. One of the shortcomings is its impractical slow rate, often requiring two or more weeks for completion. Also, the yields are inconsistent. In addition, the reaction is not applicable to β-substituted alkenes and is limited to only a few classes of activated ketones, such as α-keto esters (9,10), perfluoroalkyl ketones (11), and non-enolizable 1,2-diketones (12). For example, only 7% conversion occurs when acetone is reacted with w-butyl acrylate at 120 °C in 4-6 d and aralkyl ketones fail to react even under high pressure (2). A convenient alternative to the M B H reaction which avoids the slow rate is the vinylmetalation reaction (13-15). 1,2-Addition of a vinyl group to carbonyl compounds and imines via a vinylmetal intermediate is known as the vinylmetalation reaction. This methodology allows the reactions of ketones, β-substituted, and β,βdisubstituted olefins also to be included in the scheme. We carried out a systematic study of both M B H and vinylmetalation reactions for the syntheses of functionalized, fluorine-containing allyl alcohols from fluoro-aldehydes and -ketones. We have also explored the asymmetric version of these reactions. This review discusses our successes and failures, with pointers for the future. Morita-Baylis-Hillman Reaction of Fluoro-carbonyls M B H Reaction of Fluorinated Benzaldehydes. Although M B H reaction with benzaldehyde and several of its substituted derivatives has been studied (/), the reactions of the corresponding fluorinated benzaldehydes are not known. We studied the effect of fluorine subsitution of benzaldehydes in M B H reaction by reacting ethyl acrylate, acrylonitrile, acrolein and methyl vinyl ketone with several fluorinated benzaldehydes. The reactions of mono (2-, 3'-, and 4'-), di-(2',3 -,2',4'-, 2',5'-, 2',6'-, 3',4'-, 3',5*-), and 2 ,3',4',5',6 -pentafluorobenzaldehydes were complete within 4 d and the product allylic alcohols were obtained in good yields (Scheme 3). ,
,
,
M B H Reaction of Perfluoro-aliphatic Aldehydes. Fluoral is known to polymerize in the presence of amines (Scheme 4) (16). However, we tested whether the polymerization is favored in the presence of activated olefins.
In Asymmetric Fluoroorganic Chemistry; Ramachandran, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
119 )H EWG 10%Dabco
/
EWG
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rt,4d
EWG EWG EWG EWG
F = C 0 E t : 72% = CN:78% = CHO: 50% = COMe: 73% 2
Scheme 3. M B H reaction of pentafluorobenzaldehyde Ο
Η
Π
R N
Τ
3
H
CF CHO
Ψ
3
CF
1x3-
3
C
F
etc.
CF
3
3
Scheme 4. Polymerization of fluoral Ethyl acrylate provided -20% yield of the product along with the polymer (Scheme 5). Polymerization is faster than the reaction with acrylonitrile ( i 7). Two of die reactive olefins, acrolein and methyl vinyl ketone provided 50-70% yields of the product allyl alcohols (Scheme 6). Indeed, the reaction of these reactive olefins and aldehydes was complete in THF at -25 °C within 1 h (Reddy, M . V . R.; Rudd, M . T., unpublished results).
Π
/
R p ^ H
RF
+
C
°
0
E
t
II
10%Dabco ,24h
rt
'
V
,COOEt
R F ^ Y
— Γ*Τ3 ρ c r c - ^ 3 » ^ 3 7
··
20%
R
Scheme 5. M R H reaction of perfluoro-aldehydes with ethyl acrylate O
O
OH
Ο
10% Dabco R
R - CF , C F , C F F
3
2
5
3
7
R
=
H
M
e
THF,-25°C,lh
R
'
Τ
R
R = H : 50-70% R = Me: 65-70%
Scheme 6. M B H reaction of perfluoro-aldehydes We observed similar results with two other perfluoroalkyl aldehydes, 2,2,3,3,3-pentafluoropropionaldehyde, and 2,2,3,3,4,4,4-heptafluorobutyraldehyde.
In Asymmetric Fluoroorganic Chemistry; Ramachandran, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
120 M B H Reaction of Aromatic Trifluoromethyl Ketones. The M B H reaction of hexafluoroacetone and the corresponding N-benzoyl imine is known (Scheme 7) (10). We were engaged in the reaction of perfluoroalkyl alkyl and aryl ketones due to our interest in asymmetric synthesis of fluoroalkyl allylic alcohols. ° Π F C
CF
3
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^ rT II
+
3
E
W
G i
n
^ OH 10%Dabeo^ F < L I THF, rt, 3 h F C Tf^
