LETTER
Stereoselectivity in Amidyl Radical Cyclisations: Alkyl Mode Cyclisations
445
With the desired precursors 6a-f in hand attention was in the cis isomers appear further downfield than those of
turned to their cyclisation reactions. It was hoped that the the corresponding trans isomers. The previously un-
steric nature of the nitrogen substituent (R) might play a known major compound 7e was also assigned as trans
role in determining the stereochemical outcome of the cy- based upon this effect and by comparison of an authentic
clisations. Hence, to a 0.15mmol/ml solution of the sub- sample prepared by acylation of a commercially available
strate in toluene was added, via a syringe pump over 8 hrs, 2:1 cis:trans mixture of 2,5-dimethyl pyrrolidine (Ald-
1
9
Bu SnH (1.1eq) and AIBN (10mol%), (the final concen- rich) .
3
tration of substrate was 0.075mmol/ml). After work-up
The formation of the trans compounds as the major prod-
and chromatography the cyclised diastereomeric com-
pounds 7a-f and 8a-f were isolated in addition to varying
ratios of the reduced compound 9a-f (ratio of products
ucts is in line with the well established “Beckwith Model”
suggesting that cyclisation proceeds via a chair-like tran-
sition state. Semi-empirical MO calculations using the
1
were determined from the 250 MHz or 400 MHz H NMR
20
AM1 approximation, as implemented in version 6 of
spectrum of the crude samples).
21
MOPAC indicated that for the unsubstituted radical 11
the chair-like transition state was lower in energy than the
-
1
boat-like transition state (DE = 2.5 kJ mol ). In addition
Me
N
Me
N
Bu3SnH, AIBN,
toluene, 110°C,
syringe pump, 8 hrs
both semi-empirical (AM1) and higher level ab initio cal-
culations (DFT ) indicated that the transition state for cy-
clisation of 6a to 7a was lower in energy than that to 8a
DE= 2.1 (AM1) and 7.0 kJ mol (DFT) respectively). In-
terestingly the diastereoselectivity of the reactions are sig-
nificantly better than for related amidyl radical
cyclisations proceeding in the acyl mode (de = 10-23%)10
O
O
O
22
HN
6a-f
R
R
R
Me
a-f
Me
Me
9a-f
-1
(
7
8a-f
Scheme 4
and for the cyclisation of the 2-methyl-5-hexenyl carbon
Although conversions were good and NMR yields of the radical 12 (de=30%)5 and the corresponding N-methyl-
-7
23
cyclised products were high (60-70%) the isolated yields 5-pentenaminium radical 13 (de=34%) . The steric na-
of the cyclised products after chromatography were low ture of the N-substituent of the amidyl radicals seems to
1
5
(
7a/8a = 38%, 7e/8e = 52% , 7f/8f = 46%). This was a have little controlling effect on the stereoselectivity of the
consequence of the repeated chromatography required to process with both 6a and 6e undergoing cyclisation with
1
6
remove the final traces of tin residues from the mixtures . similar selectivities (de 54% and 58% respectively). The
In addition to the cyclised and reduced compounds 7-9e slightly higher selectivity in the cyclisation of 6f suggests
produced in the cyclisation of 6e a trace amount (3%) of a that the electronic nature of the N-substituent may play an
further product 10 was detected as a 1/1 mixture of dias- important role in controlling the outcome of the reaction,
tereomers. The formation of 10 may arise via a hetero however how this electronic effect influences the stereo-
[
3,3] sigmatropic rearrangment of the enol form of the selectivity is less certain. Further experiments in combina-
1
7
starting material 6e (see Fig. 1) .
tion with molecular modelling are currently underway to
probe further the electronic influences of this process and
will be reported at a later date.
Me
OH
Ph
Me
O
Ph
N
O
Ph
OBz
O
N
O
H
Me
N
Me
HN
10
Me
Me
Figure 1
12
13
11
The cyclisation reactions failed with a bulky (2° or 3°
alkyl) N-substituted group with either reduction products References and notes
9
b,d or unreacted starting material 6c being isolated.
(
1) Fossey, J.; Lefort, D.; Sorba, J.; Free Radicals in Organic Syn-
thesis. Wiley: Chichester, 1995.
2) Curran, D.P.; Comprehensive Organic Synthesis, Pergamon
Press: Oxford, 1991, Vol 4, 716-779.
These results are consistent with the large amounts of re-
duction products reported with bulky alkyl N-substituents
in the related acyl mode amidyl radical cyclisations e.g of
(
1
0
1
. This is presumably due to the increased steric bulk at
(3) Curran, D.P.; Synthesis 1988, 417.
(
4) Giese, B.; Radicals in Organic Synthesis: Formation of Car-
bon-Carbon Bonds, Pergamon Press, Oxford, 1986.
5) Beckwith, A.L.J.; Schiesser, CH. Tetrahedron 1985, 45, 3925.
6) Beckwith, A.L.J.; Easton, C.J.; Lawrence, T.; Serelis, A.K.;
Aust. J. Chem. 1983, 545.
nitrogen which retards the relative rates of these respec-
tive cyclisations allowing for competitive trapping by
Bu SnH prior to cyclisation. The major cyclised diastere-
omers 7a and 7f were determined to be trans by compari-
son of their spectroscopic data with authentic samples of
(
(
3
(
7) Beckwith, A.L.J.; Phillipou, G.; Serelis, A.K.; Tetrahedron
Lett. 1981, 22, 2811.
1
8
13
cis and trans products . The C NMR methyl resonances
Synlett 1999, No. 4, 444–446 ISSN 0936-5214 © Thieme Stuttgart · New York
Clark, Andrew J.
