Me
Me
NBoc
Me
Me
NH2
H
H
D
D
(1) TiCl3 (71%)
(2) hν (74%)
TiCl3 / aq. MeOH
(86%)
NBoc
OH
NBoc
OH
Cr*
Cr*
Cr*
H
3a 3 M HCl
3b propene oxide
10a
91% ee
11
89% ee
6a
99% ee
7
(100%)
99% ee
Scheme 3
hν, air
(89%)
5a by ButLi deprotonation–electrophilic quench sequences.2
Reaction of 9a and 9b with HN(OH)C(O)OBut gave the novel
complexes 10a and 10b in 79 and 48% yield, 88 and 80% ee
respectively (Table 1, entries 4 and 5). Thus steric hindrance
around the tertiary carbocation generated in the conversion of
9b to 10b appears to reduce the rate of nucleophilic attack by
HN(OH)C(O)OBut allowing significant rotation around the
ipso carbon–benzylic carbon bond to occur and hence some loss
of enantiomeric purity. Finally, the deuterated product 10a was
converted into the labelled amine 11 in good overall yield and
without loss of enantiomeric purity (Scheme 3).¶
A
Me
NH2
Me
H
H
(Boc)2O, Et3N
NBoc
H
(88%)
B
8
29
[α]D +58
From route A:
29
[α]D +62
From route B:
The authors thank the EPSRC for a studentship (E. R.), and
The Accademia Nazionale dei Lincei/The Royal Society for
funding a study visit (D. A.) under the auspices of the European
Science Exchange Programme.
Scheme 2
protonation of 5a at 240 °C with HBF4·OMe2 followed by
addition of commercially available tert-butyl N-hydroxycarba-
mate [HN(OH)C(O)OBut] gave the nitrogen substitution prod-
uct 6a in 85% yield. Moreover the ee of the novel† complex 6a
was measured by chiral HPLC‡ and found to be 99% (Table 1,
entry 1).
The absolute configuration of the nitrogen substitution
product 6a was determined by chemical correlation. Reduction
of the nitrogen–oxygen bond using TiCl3 in aqueous MeOH6
proceeded smoothly to give the novel complex 7 without loss of
stereochemistry (Scheme 2).§ Oxidative removal of the tri-
carbonylchromium(0) unit from 7 gave carbamate 8, the optical
rotation of which was essentially identical to a sample prepared
from authentic (R)-a-methylbenzylamine. Thus the absolute
configuration of 6a is R and the conversion of 5a to 6a proceeds
with retention of configuration, presumably via a chromium
stabilised carbocation.
In order to probe the effect on the nitrogen substitution
reaction of increasing steric hindrance around the benzylic
position, complexes 5b7 (R1 = H, R2 = Et) and 5c7 (R1 = H,
R2 = Pri) were prepared and reacted with HN(OH)C(O)OBut.
The reactions led to the novel products 6b and 6c in 53 and 43%
yield and 96 and 91% ee respectively (Table 1, entries 2 and 3).
Thus increasing steric hindrance leads to notable yield reduc-
tions and a small but significant stereochemical leakage. These
effects are attributed to a reduced rate of addition of the nitrogen
nucleophile to the intermediate carbocation, the increased
lifetime of the latter leading to byproducts and rotation about the
ipso carbon–benzylic carbon bond.
Notes and references
† The novel complexes 6a–c, 7, 9b, 10a and 10b all gave satisfactory
spectroscopic (IR, 1H NMR, 13C NMR and low resolution MS) and
microanalytical or high resolution MS data.
‡ Racemic products for HPLC analysis were generated by addition of
HN(OH)C(O)OBut to ether substrates produced by ButLi deprotonation–
electrophilic quench of the tricarbonylchromium(0) complex of benzyl
methyl ether.
§ The ee of 7 was measured by Boc removal, replacement with Z and HPLC
analysis (Chiralcel OD-H)
¶ The ee of 11 was measured by derivatisation with 3,5-dinitrobenzoyl
chloride and HPLC analysis (Phenomenex - Phase 3014).
1 E. L. M. Cowton, S. E. Gibson (née Thomas), M. J. Schneider and M. H.
Smith, Chem. Commun., 1996, 839.
2 S. E. Gibson (née Thomas), P. C. V. Potter and M. H. Smith, Chem.
Commun., 1996, 2757.
3 S. G. Davies and T. D. McCarthy, in Comprehensive Organometallic
Chemistry II, ed. E.W. Abel, F. G. A. Stone and G. Wilkinson, Pergamon,
Oxford, 1995, vol. 12, p. 1048.
4 S. Top, B. Caro and G. Jaouen, Tetrahedron Lett., 1978, 787.
5 S. Top and G. Jaouen, J. Org. Chem., 1981, 46, 78.
6 A. Dondoni, S. Franco, F. Merchan, P. Merino and T. Tejero, Synlett,
1993, 78; S.-I. Murahashi and Y. Kodera, Tetrahedron Lett., 1985, 26,
4633.
7 The racemic complexes have been reported previously: J. Blagg, S. G.
Davies, N. J. Holman, C. A. Laughton and B. E. Mobbs, J. Chem. Soc.,
Perkin Trans. 1, 1986, 1581.
Subsequently, in order to test whether a,a-disubstituted
benzylic ethers may be used as substrates in the reaction,
complex 9a2 and the novel complex 9b were synthesised from
Communication 8/06832A
2572
Chem. Commun., 1998, 2571–2572