Regiocontrolled set promoted photocyclisation of 2-alkyl-1-piperidine and pyrrolidine propanols: Stereoselective synthesis of cis-α,α′-dialkyl piperidines and pyrrolidines via tetrahydro-1,3-oxazines

Article abstract of DOI:10.1016/S0040-4039(00)93451-8

Photocyclisation of amino alcohols (1a-c) to (4a-c) via insitu generated iminium cation by photoinduced SET reaction and their utility in the stereoselective synthesis of cis-α-α′-dialkyl piperidines and pyrrolidines is described.

Full text of DOI:10.1016/S0040-4039(00)93451-8

"l'ettahedron Letters, Vol.32, No.38, pp 5147-5150, 1991
Printed in Great Britain
0040-4039/91 $3.00 + .00
Pergamon Press ple
REGIOCONTROLLED SET PROMOTED PHOTOCYCLISATION OF
2-ALKYL-1-PIPERIDINE AND PYRROLIDINE PROPANOLS: STEREOSELECTIVE SYNTHESIS
OF CIS-¢z,cx'-DIALKYL PIPERIDINES AND PYRROLIDINES VIA TETRAHYDRO-1,3-OXAZINES
Ganesh Pandey*, P. Yella Reddy, and U.T. Bhalerao
Organic Division II, Indian Institute of Chemical Technology#
Hyderabad 500007, India
Abstract: Photocyclisation of amino alcohols ( l a-c) to (4a-c) via insitu generated iminium cation by
photoinduced SET reaction and their utility in the stereoselective synthesis of cis-o,-tx'-diallcyl piperi-
dines and pyrrolidines is described.
Ion radicals serve as key intermediates in a variety of SET initiated photochemical reactions. A
number of recent studies have focussed on the synthetic and mechanistic problems related to the chemis-
try of amine cation radicals1,2. The rates of ct-deprotonation 1 and pKa values3 of amine cation radicals
have been measured. Lewis et all., in their study of SET promoted tertiary amine photoadditions to stil-
hene, have reported that rate of ct-deprotonation appears to be govemed by stereoelectronic/steric fac-
tors. Our continuing efforts on the development of SET initiated photoreactions of amine-DCN (1,4-
dicyanonapthalene) systems4, have provided us with an opportunity to investigate the consequences of
SET promoted photoreactions from amino alcohols la-c, particularly to probe the ct-deprotonation site
by generating and studying the insitu intramolecular cyclisation of respective iminium cations from
corresponding la-c+" and to explore the synthetic potentials of this study. We are plea.~ed to disclose the
results of these studies in this communication.
2-Methyl-l-piperdine propanol (la) underwent SET initiated intramolecular photocyclisation to
yield 4a (major, 95%) and 5b (minor, 5%)5 in over all 92% yield by irradiating in the presence of DCN
using methyl viologen (MV++) as electron relay6. Absence of other regioisomer with ring closed at the
more substituted a-carbon was ensured by IH NMR and GC analysis. This cyclisation clearly shows
that there is complete regioselectivity for ring closure towards the less substituted o~-carbon of piperi-
dine moiety, confirming the faster rate of tx-deprotonation to generate least substituted a-amino radical
and subsequent iminium cation from la +'. Chlorine dioxide (C102) mediated cyclisation of la, known
to occur via an electron abstraction route, is reported to show greater, but not complete preference for
ring closure towards the less substituted (ratio 6: l) carbon atom7. This marked difference suggests that
the basicity of the oxidising agent/radical anion is also an important factor along with the stereoelectron-
ic factors in determining the deprotonation site from tertiary amine radical cation, as postulated by
Lewis lc and Wagner8. Furthermore, the cyclisation gives diastereoselective molecule 4a where two
Respectfully dedicated to Professor K.N. Mehrotra, B.H.U., Varanasi, on the occasion of his 60th birth-
day.
5147

5148
substituents adopt equitorial orientation. The cis-stereochemistry of 4a is likely to emerge due to prefer-
ential front side attack of - OH group to iminium cation 3. The assignments of 4a and 5a stereochemis-
try is based on the comparison of 9H proton chemical shifts as reported in literature9. The signal for 9H
in 4a appears at 5 4.01 whereas for 5a at 5 4.11. The ring closure at the less substituted o~-carbon from
other amino alcohols lb and lc (SCHEME-I) shows the generality of the reaction. These cyclisations
are different from the Hg(OAc)2 oxidative Cyclisation of the same amines 10, where ring closure is
dominated at the more substituted tx-carbon of piperidine and pyrrolidine moiety.
H
. . ~ H
btN*/MV'" /,..-~.,~. _--..~,.. "~N/~R l----- o ~ / - " . + Or"N~"-"a
,
c. c.
g
{CH2)]OH
I
2)3OH
(
'
"L
°"1
l a - c
2
3
/.,a
16 : 1
SQ
lo
b
c
n ,
n ,
2
2
R
R
R
•
He
4a
/,b
4r
°
So
=
,,
•
92%
90%
ISe",'.
• n - B u
. n - B u
*
.
Sb
n • 1
Sc
S c h e m e - l
In a typical cyclisation reaction a solution of la-c (10 mM), DCN (1.12 raM) and MV ++
(0.31 mM) in moist acetonitrile was irradiated through pyrex f'dtemd light ( > 280 nm, all light absorbed
by DCN) using 450-W Hanovia medium pressure lamp for 2-3h without removing dissolved air. After
irradiation and removal of solvent, the MV++ was quantitatively recovered by triturating and decanting
the reaction mixture with benzene. Chromotography of the benzene portion of the reaction mixture over
neutral alumina (activity grade/]I, using n-pentane ether 4:1 as eluent) gave tetrahydro-1,3-oxazine 4a-c
and 5a-c. DCN was recovered as such (98%).
To explain the catalytic role of MV ++ in this study, a plausible schematic Electron transfer steps
axe shown as below:
la- c
DCN
IIV
02
H202+OH
Procl~ts . , " - - { l a - c i ~/
~'~'OCN /
~ l ' t Y'~''"
" ' ~ 0 2
/
~
H20
S c h e m e - II
From the respective reduction potentials of ground state 0 2 (O2/O2"'=-0.78 eV)11 and MV++

5149
(MV++/MV+'=-0.45 eV) 12 it is probable that the anion radical of DCN (DCN/DCN-'=-I.28 eV) 10
transfers its electron preferentially to MV++ to produce MV+- and ground state DCN which participates
in further electron abstraction process from amino radical. The characteristic blue colour of MV+'
during irradiation suggests this step. The MV+" is subsequently oxidized rapidly by atmospheric oxygen
possibly, producing 0 2" which in aqueous solution dismutates via hydrogen peroxide 13. The above
argument is supported from the observation of reaction neither in the inert atmosphere nor in dry aceto-
nitrile.
Our results indicate that this novel cyclisation strategy (la-c to 4a-c) is potentially useful
reaction and we envisaged to utilize 4a-c as precursor for the synthesis of o~-~'-dialkyl piperidines and
pyrrolidines by their nucleophilic opening along the lines reported earlier 14. Due to wide distribution
and significant biological activity 13 associated with these alkaloids, a number of synthetic routes have
appeared over the years 16. To this end 4b (2 raM) was reacted with n-butyl magnesium bromide
(3 raM) in ether at -20°C and usual workup and chromatographic purification gave 6b in 95% yield
(SCHEME I]/).
4a - c
H9C"~'~''I~'''R
( CH2)3 -OH
6 a - c
H
I,,,.,. Ph
8a -c
7Q-c
a. n-C6HgHgBr/ether, . 20"C
;
b . ( i ) ~-chloroethylchlorotormate /(CH2CI)2
/
reflux, lh , lii) HeOH retlux,lh
/
; c. benzylbromide / CH3CN/K2CO3/reflux ,12h
S c h e m e - III
The compound 6b was characterised by IH NMR, 13C NMR and mass spectral data. The cis-
stereochemistry of 6b was suggested by observing C2symmetry in the 13C NMR spectra17. This was
further conftrmed by characteristic singlet for benzylic protons in IH N1VIR of 8b, obtained after benzy-
lating the 7b18. The dealkylation of 6b to 7b was achieved by following the Olofson et al., procedure19.
Similar reaction of other oxazines (4a and 4c) gave corresponding cis-(x-ct'-dialkylpiperidine (6a) and
pyrrolidine (6c) respectively. Further study is in progress.
ACKNOWLEDGEMENT: We are thankful to Dr A V Rama Rao, Director, HCT, for encouragement.
One of us (P.Y. Reddy) thartks CSIR, New Delhi, for financial support.

5150
References:
#11CT Communication n0.2772
1.
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therein.
5.
6.
The ratio of diastereomers was determined by capillary GC (methyl silicone, 50 mrs) and pure
isomers were isolated by column chromatography.
The reaction also underwent smoothly without MV++ as reported earlier (ref. 4b) but reaction
rate was dramatically enhanced in the presence of MV++.
7.
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Chen, C-K., Hortmann, A.G., Marzabadi, M.R., J. Am. Chem. Soc., 110, 4829 (1988).
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16.
17.
For earlier synthetic routes see a) Wasserman, H.H., Rodriques, K., Kucharczyk, R.,
Tetrahedron Letters, 30, 6077 (1989); b) Tufariello, J.J., Puglis, J.M., Tetrahedron Letters, 27,
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and references cited in all above.
1H NMR, 200 MHz of 6b (CDCL3, 5 ppm): 3.75 (t, J=5.6 Hz, 2H), 2.70 (t, J=6.6 Hz 2H), 2.50
(M 2H), 1.62-1.74 (M, 6H), 1.56 (M, 3H), 1.11-1.32 (M, 12H), 0.82 (t, J=6.8 6H); 13C NMR of
6b (CDCI3, 5 ppm): 62.00, 61.10, 43.32, 26.81, 25.10, 24.82, 23.34, 21.52, 21.00, 17.10,.
Hill, R.K.,Chan, T-H., Tetrahedron, 21, 2015 (1965).
18.
19.
Olofson, R.A., Martz, T.J., J. Org. Chem., 49, 2081 (1984).
(Received in UK 26 June 1991)