Page 287 - Arrow Pushing in Inorganic Chemistry A Logical Approach to the Chemistry of the Main Group Elements

7.5 ELECTROPHILIC FLUORINATING AGENTS: N-FLUORO COMPOUNDS 267

REVIEW PROBLEM 7.7

(a) Draw a mechanism for reaction 7.37
(b) Why does reaction 7.39 proceed without the need for prior enolate formation?
(c) Suggest a radical mechanism for enolate fluorination based on single-electron
transfers.

Given the importance of fluorination in drug design, chiral N-fluoro reagents were
also sought after and developed. The first such reagents to be developed were the
N-fluorocamphorsultams (a sultam is a cyclic sulfonamide):

R

R
N
F
S H
O 2
R = H, Cl, OMe

These, however, led to products with modest enantiomeric excesses (% major enan-
tiomer − % minor enantiomer). Subsequently, a variety of chiral N-fluoro reagents were
obtained via the interaction of cinchona alkaloid derivatives (the substrates in the reaction
below) and Selectfluor, as shown below:

−
BF 4
+
H N H N
2
2
R O Selectfluor-(BF 4 ) 2 R O
H CH CN, 20 °C H F
3
R 1 R 1
1
R = H, OMe
2
R O = HO, ether, ester
N N
(7.41)
These reagents generally lead to good to excellent enantiomeric excesses. Their down-
side, however, is that they are too expensive for general use. Most current research on
enantioselective, electrophilic fluorination relies on the less expensive achiral reagents
shown in Figure 7.1, in conjunction with standard organic or metal-based, chiral
catalysts.