Carbon to Trifluoromethyl Group - American Chemical Society

Chapter 18

Functional Group Transformations at a-Carbon to Trifluoromethyl Group

Downloaded by UNIV OF ARIZONA on December 24, 2012 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch018

Toshimasa Katagiri and Kenji Uneyama Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushimanaka 3-1-1, Okayama 700-8530, Japan

This account summarizes the building methods of chiral αcarbon to trifluoromethyl group and further substitutions on that carbon. The preparations of the chiral trifluoromethylated compounds are relatively well studied. Meanwhile, the stereospecific substitutions on the α-carbon to trifluoromethyl group should be developed to increase the versatility of synthetic strategies.

1. Introduction The importance of optically active fluoro-organic compounds in the fields of medicinal chemistry, agrochemicals, and material science is well known [/]. The poor availability of optically activefluoro-organicstarting materials, which stems from a lack of natural fluoro-organics, has made the preparations of optically active fluoro-organics only via synthetic methodologies [2]. The unique reactivity of suchfluoro-organicsmakes the construction of the desired structure challenging. Therefore, a smart strategy and an effective device have been needed to achieve this goal. Thus, a stereocontrolled preparation of fluoroorganics has been of interest not only to biochemists and medicinal chemists, but also to synthetic organic chemists. Among tie second-row elements, nucleus of the fluorine atom has biggest positive charge next to neon atom. Thus, the electrons surrounding the fluorine atom are attracted near by the nucleus, due to lack of the shielding effects by 318

© 2005 American Chemical Society

In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

319 inner sphere electrons. This strongest electron withdrawing effect of the fluorine atom characterizes properties and reactivities of the fluoro-organics. It is well known that the orbital energy level of fluorine 2p is ca. 5 eV lower than that of hydrogen Is [3], Thus, both the bonding and the antibonding orbitals generated by the interaction of parent organic SOMO andfluorine2p (right hand side) are always lower than those generated with hydrogen Is (left hand side), as illustrated in Scheme 1. Atomic and molecular


orbital energy level ^

R-H H

l

5

MOs

K-SOMO R-F

antibonding

M

O

s

antibonding

Scheme 1. Molecular orbital energy diagram forfluorinatedcompounds This MO energy level diagram explains some properties of fluoro-organics also. One may find the eneigy level of bonding (occupied) orbital resembles to that of fluorine 2p. Thus, the wave fonction of the bonding orbital resembles to that of fluorine 2p. That is, the electrons in this orbital are attracted around the fluorine atom. Moreover, the lower level of the bonding orbital suggests smaller fluctuation of electrons, due to strong interaction by nuclei of the molecule. In other words, the fluoro-organic has smaller electric polarizabilities and refractive index; thus, causes a smaller van der Waals interactions [4]. The o ofthe fluorine atom is 0.34 and σ is 0.06, thus σι (inductive effect) is 0.50 while o (resonance effect) is -0.44 [5]. That is, the fluorine atom itself is an electron withdrawing group from inductive point of view, while electron donating group from resonance. Meanwhile, trifluoromethyl group is a pure electron withdrawing group. The a of the trifluoromethyl group is 0.43 and σ is 0.54; thus the σι of the group is 0.41 and OR is 0.14 [J]. Trifluoromethyl group withdraws electrons anyway, which makes the surroundings of the group electron deficient and makes the trifluoromethyl group itself negatively charged. Of course, the extent of the negative charge on the trifluoromethyl group is depending on the residual moieties; some MO calculation estimated it to be 0.1 eV [6]. One may consider that the trifluoro methyl group is a concentrated negative charge, thus hinders access of m

ρ

R

m


ρ

320

negatively charged nucleophiles [7]. The effect of the trifluoromethyl group to the reactivity is such simple, but strong.

2. Construction of trifluoromethylated chiral carbon center The most popular structures of optically activefluoro-organics,3-substitutedl,l,l-trifluoro-2-propanol, 1 [8] and 2-amino-3-substituted-l,l l-trifluoropropane, 2 [9], are shown in Scheme 2. The merit forthe utilization of 1 and 2 is not only limited in their easy preparations but also their possible optical purification via recrystallizations.


9

Scheme 2

Q

F C^ : 3

^

H

R

F C^ :

R

3

R

R

2.1 Trifluoromethylated carbinols Higher than 96% ee (2% impurity) is required for optically pure materials, and >99.6% ee (02% impurity) is required for pharmaceuticals. Thus, the optically active fluoro-organics with moderate enantiomeric excess cannot be used practically as they are. They need some methods for optical purifications. It is very fortunate that the β-fluorinated alcohols have higher melting points than non-fluorinated alcohols; melting point of 2,2,2-trifluoroethanol (-44 °C) is 86 °C higher than that of ethanol (-130 °C) and that of l,l,l,3,3,3-hexafluoro-2propanol (-4 °C) is 85 °C higher than that of 2-propanol (-90 °C) [70]. This would be due to higher acidities of fluorinated alcohols. Optical purification of 3-piperidyH,l,l-trifluoro-2-propanol an amino alcohol with intramolecular hydrogen bond acceptor, was reported [77]. The hydrogen bondings of 3,3,3trifluorolactates recognize their chirality even in the liquid state [72]. The structure of the hydrogen bonding systems in the crystal had been studied by Xray crystallographic analyses [73]. Thus, some fluoro-alcohols with moderate optical purities may be purified in almost optically pure form via reciystallizations [14-17]. 9

2.1.1 Biochemical resolution of racemates (Scheme 3). Lipase acylation [75-20] as well as deacylation [20-27] resolves optically active α-trifluoromethylated carbinols 1. Deacylation of the ester seems much effective than acylation [20]. Even optically active teri-alcohols have been prepared by the process [23b,26\. Scheme 3 OH

XR F3C

' OAc lipase

OH

• Λ acylation F3C

R

OAc

OAc

* P3C ΛR

F C^R 3

lipase

OAc

deacylation F C ^ R 3

OH +

FgC^R


321

2.1.2 Stereocontrolled reductions (Scheme 4). Stereocontrolled reduction of trifluoromethylated ketones would be the most popular preparative method for 3-substituted-l,l,l-trifluoro-2-propanols [28]. Scheme 4

_ Ο

Λ 1 1

H


F3C

ÇH

reduction*

^ R

: F3C

OH

or R

ϊ F C^R 3

Noteworthy is that enantioselective reduction of trifluoroacetophenones seems more difficult than that of trifluoroacetones. This would be due to similarity between the electrostatic structure of negatively charged trifluoromethyl group and that of negatively charged π-system of aromatic rings (Scheme 5) [ unit has been attributed to iie strong electron wfthdrawing effect as well as the steric hindrance of the trifluoromethyl group. The former effect strengthens and shortens the C-0 bond. The steric hindrance of the group is much larger than that of the methyl group and has sometimes been compared with the isopropyl and/or tert~buty\ groups [111,112], The origin of the steric hindrance is the electrostatic repulsion of the negatively charged trifluoromethyl group to the negatively charged nucteophiles; thus the group would be repulsed by a greater distance than ftat results from the van der Waals repulsion. We believed that the Coulombic repulsion effect would be suppressed in an intramolecular substitution, because a nucleophile would be readily put near the reaction center. In fact, we succeeded in preparing optically active aziridine [113], and cyclopropanes [114] νια the intramolecular nucleophilic substitutions of the hydroxy group in the CF -CH(OH)- unit. Until 1995, a few nucleophilic substitutions of the hydroxy group of the CF CH(OH> unit had been reported [115-121], However, the S 2-type reactions without participation of the neighboring heteroatom or π-conjugations had been a very few [115,117,118]. We had made a study on the halogenations of 3-isopropyloxy-l,l l-trifluoro2-propanol 3 to chlorinated product 4 with a series of reagents (Scheme 16). Our trials, as well as previous reports, found that only PPh /CCl was effective [118,122], After the cautious separation from startmg fluoro-alcohol 3, the product 4 was submitted to hydrolysis under a basic condition. A trace (ca. 3%) amount of fluoro-afcohol 3 was isolated and chiral G C analysis of the product was identified to be the starting fluoro-alcohol 3 with 75% ee (S), Thus, the halogenation with PPh /CCl would be enantiospecific process with inversion of configuration.


3

3

3

N

5

3

3

Scheme 16

Q

χ

-gBRr

3 75% ee 4

2

F a C

4

F 3 C

A^O*r

3 75%ee

4

SOjjCi^Py Δ: no reaction PCI3/CH2CI2 Δ: no reaction PCl5/CH CI Δ: no reaction (PhO) P, BnBr/CH CI Δ: no reaction 2

OH

Λ

-flgf—

A/O-iPr

refs 118,122

PPh /CCI Δ: 4,40% HCI/H S0 Δ: no reaction HCI/AcOH Δ: no reaction SOCI^Py Δ: no reaction 3

4

H

A^Pr

F 3 (

4

Ph PCI, Et N Δ: no reaction Ph3pCI /CH CI Δ: no reaction 2

3

2

2

2

2

3

2

2

Contrary to the reaction of hydroxyether 3, reactions of hydroxysulfides 5 withPPh CyCH CN or PPh /CCl produced two different halo sulfides, 6 and 7, depending on the reagents and conditions (Scheme 17) [123]; the reaction with PPh Cl /CH CN mainly produced rearranged halo sulfide 7, while the reaction with PPh /CCl gave a directly substituted halo sulfide 6. When the 3

3

3

2

3

4

3

3

4


327 latter reagent was used in a more polar solvent, such as CH3CN, the main product of the reaction became the rearranged 7 (Scheme 17). S

C

h

e

m

e

1

?

OH F a C

ÇI

r e a g e n t s

^\/S-Ph

conditions

5

S

3

7

6

3

3

3

α

*ψ ο^^ 3

reagent, conditions PPh Ci /CH CN,A,22h PPh / CCI4, Δ, 2.5 h PPh , CCI4 / CH CN, Δ, 24 h 2

P h

3

ref 123

3

S-Ph

F c'"\^ "

3

6 : 7 yield 10:90(92%) 60 :40 (64%) 23 :77 (77%)

Scheme 18 O


F

3

H

PPhaClg/CHgCN

C ^ ^ 5

S

R

o1>Phf CI

orPPha^CU ref123

C

-A^SR

3

S 2

ψ

N

substitutionpgC"^

80

6

8 L Ph P«0 3

FC 3

Θ ...JRiR^CJn'ng opening reaction~ F C

f

R

CI

3

7

Both compounds would be produced via common intermediate 8 in Scheme 18. The halo sulfide 6 would be produced via direct SN2 through the action of the counter chloride ion of mteimediate 8, while fte halo sulfide 7 would be produced via intramolecular S 2 through the action of the sulfur atom to give an episulfonium 9, followed by a successive ring-opening reaction at the lesshindered methylene position by counter chloride ion. The solvent effect would play an important role in determining the reaction course as shown in Scheme 18. When the solvent is less polar, the ion pair should be "contact." Thus, the counter chloride ion would be located close to the reaction center; it would be near enough to undertake the direct S 2 to give 6. In the case of more polar solvent, on the other hand, the ion pair would be somewhat "separated." Thus> the intramolecular S 2 would be initially preferable at producing electronically unstable episulfonium 9, which would then ring-opened by counter anion, to give 7. The total transformation of 4 to either 6 or 7 involves a stereospecific inversion at the trifluoromethylated carbon atom. Here, we can propose that the key item for nucleophilic substitution atacarbon to trifluoromethyl group is "how to put the nucleophile near by the reaction center". On this basis, an intramolecular reaction would be the most simple and reliable way to put a nucleophile near by the reaction center. N

N

N

3.1.1 Intramolecular strategy Appels condition with enantiomerically pure aminoalcohol 10 with PPh Cl /CH CN produced a corresponding iV-benzyl-2-trifluoromethylaziridine 11 in good yield (Scheme 19) [773]. The stereochemistry of the aziridine was confirmed to be (R); the reaction also completed with perfect inversion of configuration. With a similar manner, JV-tosyl-2-trifluoromethyl aziridine was produced [124]. These aziridine can be a general precursor for β,β,βtrifluoroamines. Ring opening reaction of the aziridine has been reported, elsewhere Γ 7251 3

2

3


328 Scheme 19 F

9

H

H

C ^ % n

3

10

Scheme 20

0 H

B n

M

Ph,PCI„ EfaN, F a C

85% isolate yield 96% NMR yield ref 113

-

O-Bn

81%, (90% ee)

B r

48%,(83%ee)

OMe

A substitution of chlorine by fluorine under a strong oxidative condition also underwent with inversion of absolute configuration, but with some racemization (Scheme 28) [735]. Scheme 28

F HC'°X

C F 3

2

ci Ή (R)-98.5% ee

BrF Bri

3

ref 133

F HC'°X

C F 3

2

H F (S)-91.7%ee

f

3.1.3 S 2 strategy. An SN2' type reaction of γ-trifluoromethylated allyklcohols gave tert-carbon framework with complete chirality transfer (Scheme 29) [134]. The reaction N


331 could be an alternative method for stereospecific preparation of optically active trifluoromethylated carbon without heteroatom substituents. Scheme 29 ÇF

3

Ο OMe

ref134a

OH 73%, >98% de

H

° ? B r K ) ^ ^ ^

F

a

1)AcCl.Fv 2)ÊuMgBr, CuCN, ÎMS-CI

54% ee

ref 134b


3

^

82% ee

x

n

93%, 54% ee

O-Ms F C

g o

O-Bz "R

F ref 135

3

C ^ ^ R

87%, 84% ee

The starting compound was produced from trifluoroacetylenes but would be prepared from optically pure α-trifhioromethylated allylalcohols via an S 2' substitution [755], N

3.1.4 Scope and remained problems on enantiospecific S 2 strategy Among the nucleophilic substitutions at α-carbon of trifluoromethyl group, intramolecular nucleophilic substitution seems to work, somewhat. However, sever limitation is that the products have been limitai to the three-membered ring compounds. Production of five membered ring compounds became tough due to the higher degree of freedom of longer methylene chain. Present scope of the stereospecific intermolecular substitution is still narrow. Trifluoromethylated carbinols have experienced heteroatom substitutions with the aid of CsF salt, but no carbanion substitutions, yet. Neighboring group participation by oxygen enabled substitutions by carbanions, but causes some epimerizations. N

3.2 Substitution of protons by electrophiles: trifluoromethylated carbanion chemistry. A carbanion with sp carbon cento- can hold its chirality in the course of some additions to electrophiles. Moreover, trifluoromethyl group is a strong electron withdrawing group, thus it should stabilize the carbanion at α-carbon. Therefore, the α-trifluoromethylated carbanions from optical active trifluoromethylated compounds could be good synthetic units which posses both trifluoromethyl group and chirality. However, there have been a few reports on such sp carbanion species [136,137]. This present situation is due to unstable nature of such carbanion, it spontaneously gives off a fluorine atom as a fluoride to produce difluoroolefins [lb,2]. To suppress this unwanted side reaction, many trifluoromethylated carbanions have been prepared as conjugate enol form with sp carbanion center [137,138], where they have no chance for stereospecific reaction at that carbon. One of the possible access to the stereoehemically stable carbanion is to utilize a ring fused carbanion, in particular, a carbanion on a small ring such as cyclopropanes, oxiranes, and aziridines. In actual, only the 3

3

2


332 Scheme 30 Η

Carbon to Trifluoromethyl Group - American Chemical Society

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