Observations on the reductive ring opening reactions of alkylidenecyclopropyl ketones promoted by lithium in liquid ammonia

Article abstract of DOI:10.1016/j.tetlet.2006.09.124

The regio- and stereochemical outcome of the reductive ring opening reactions of alkylidenecyclopropyl ketones is a function of substrate structure.

Full text of DOI:10.1016/j.tetlet.2006.09.124

Tetrahedron Letters 47 (2006) 8789–8791
Observations on the reductive ring opening reactions
of alkylidenecyclopropyl ketones promoted
by lithium in liquid ammonia
William B. Motherwell* and Sheena Zuberi
University College London, Chemistry Department, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, UK
Received 30 May 2006; revised 12 September 2006; accepted 21 September 2006
Available online 20 October 2006
Abstract—The regio- and stereochemical outcome of the reductive ring opening reactions of alkylidenecyclopropyl ketones is a func-
tion of substrate structure.
Ó 2006 Elsevier Ltd. All rights reserved.
Whilst the cyclopropylcarbinyl homoallylic radical rear-
rangement has unquestionably served in a wide variety
of useful synthetic sequences,1 ring opening reactions
of alkylidenecyclopropane congeners have, by way of
contrast, received little attention. For this reason, we
therefore elected to examine the sequential single elec-
tron transfer induced reduction of some alkylidenecyclo-
propyl ketones (1) as outlined in a general form in
Scheme 1.
simple cyclopropane would favour C1–C3 cleavage
and hence the formation of a single regioisomeric eno-
late dianion intermediate 2. Such an outcome would also
of course be ultimately preferred in terms of allylic sta-
bilisation. From a stereochemical standpoint, however,
as illustrated in Figure 1 for the important case of for-
mation of a tetrasubstituted enolate, it was of interest
to note that the outcome would be dependent on the
preferential collapse of either the cisoid or transoid
conformer of the reactive intermediate. Figure 1 also
As implied in Scheme 1, we anticipated that the inclu-
sion of the additional sp2 centre at C-2 in 1 with its con-
sequential weakening of the C1–C3 bond relative to a
H
H
3
1
3
1
2
2
H
H
R1
R2
O
R2
O
R1
2
O
O
+1e
M
3
R1
R1
R3
R3
1
cisoid
+1e
transoid
+1e
R2
R2
1
+1e
ring opening
R1
O
3
O
3
R1
2
O
2
transoid gauche
+1e
cisoid gauche
+1e
R3
R1 R2
O
R2
O
2
R1
R1
R2
Z-enolate"
Scheme 1.
"
"E-enolate"
*
Corresponding author. Tel.: +44 (0)20 7679 7533; fax: +44 (0)20
7679 7524; e-mail: w.b.motherwell@ucl.ac.uk
Figure 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.124

8790
W. B. Motherwell, S. Zuberi / Tetrahedron Letters 47 (2006) 8789–8791
opening sequence. In the first instance, as a consequence
(i), (ii), (iii)
O
OH
O
of our own studies in developing tandem radical ring
opening reactions of bicyclic cyclopropyl ketones using
samarium diiodide,2 we elected to examine the use of
this powerful reducing agent. To our surprise, however,
under a range of conditions, complex reaction mixtures
were produced. For this reason, we then chose to use the
more traditional combination of lithium in liquid
ammonia as reductant. The preliminary results for a ser-
ies of reactions involving the dropwise addition of a
solution of the alkylidene cyclopropyl ketone in ether
to a solution of lithium in liquid ammonia followed by
protic work-up with ammonium chloride are shown in
Table 1 and revealed several features of interest.
(iv), (v)
(vi), (vii)
O
O
H
R
Scheme 2. Reagents and conditions: (i) dihydropyran, HCl 48 h 70%;
(ii) nBuLi, CH3CHCl2, Et2O, À35 °C (iii) KOtBu, DMSO, 70 °C, 18 h,
43%; (iv) TsOH, MeOH, 70%; (v) PDC, CH2Cl2, rt, 20 h, 95%; (vi)
RMgX, Et2O, 0 °C, R = nC12H25, 50%; R = cyclohexyl, 20%; R = Ph,
41%; (vii) PDC, pyridinium trifluoroacetate, CH2Cl2, rt, R = nC12H25
,
93%, R = cyclohexyl, 92%, R = Ph, 80%.
Thus, whilst the anticipated cleavage of the weaker
C1–C3 distal bond was observed for all cases studied,
subsequent product evolution is clearly dependent on
substrate structure. In particular, whilst the examples
shown in entries 1 and 2 yielded the expected b–c unsat-
urated ketones, over-reduction to give alcohols can be
noted in entries 3–5. This latter phenomenon has been
observed previously both by Dauben3 and by Norin4
in the lithium ammonia reduction of cyclopropyl
ketones and was assumed to arise via further rapid
reduction and protonation steps during work-up. For
those substrates which possess additional alkyl substitu-
ents on the alkylidenecyclopropane ring (entries 4 and
5), it was of interest to note that regiospecific proton-
ation of the allylic anion fragment leading to the more
substituted alkene had occurred. In terms of stereoselec-
tive trisubstituted alkene formation however, only a
emphasises the intriguing situation that the stereoelec-
tronic requirements for an effective enolate formation
through correct orbital alignment of the C1–C3 bond
would lead in the first instance, to an ‘allylic’ intermedi-
ate, which does not benefit from overlap with the
orthogonal p—cloud of the alkylidene cyclopropane.
With the above thoughts in mind, a number of simple
monocyclic alkylidene cyclopropyl ketones were pre-
pared by the straightforward sequence illustrated in
Scheme 2. More highly substituted derivatives were
readily accessible in similar fashion from the appropri-
ately substituted isomer of the starting allylic alcohol.
With a selection of appropriate ketones in hand, our
attention was then directed towards the reductive ring
Table 1.
Entry
Substrate
Product(s)
Yield (%)
78
O
O
1
(CH2)11CH3
(CH2)11CH3
O
O
O
O
2
3
63
48
OH
OH
4
41
41
(CH2)8CH3
O
(CH2)8CH3
(CH2)8CH3
OH
O
5
(CH2)11CH3
59
(CH2)11CH3
H3CH2C
(E:Z; 2.8:1)

W. B. Motherwell, S. Zuberi / Tetrahedron Letters 47 (2006) 8789–8791
8791
0.4%
1.0%
O
OAc
H
H
(i) Li, NH3, Et2O
H
(i) Li, NH3, Et2O
(ii) NH4Cl
(ii) Ac2O
H
H
0 oC RT(18 h)
O
O
2.3%
H
1.3%
35%
OH
OH
O
Scheme 3.
+
+
modest preference for formation of the E isomer was
noted. From a mechanistic perspective, the ring opening
reaction of the benzoyl substituted alkylidene cyclopro-
pane (entry 3) is certainly the most intriguing, especially
since it is known that dissolving metal reduction of the
related benzoyl cyclopropane leads only to benzyl cyclo-
propane without any evidence for the ring opened prod-
uct.5 This latter observation has also been supported by
detailed kinetic measurements which indicate that, at the
one electron reduction level, the equilibrium between the
ketyl radical anion and the open form lies strongly in
favour of the former.6 For the case of an alkylidenecy-
clopropane, however, irrespective of whether ring open-
ing occurs after the delivery of one or two electrons to
the carbonyl group, essentially irreversible ring opening
is clearly favoured, not only on kinetic grounds by the
greater release of strain, but also in thermodynamic
terms by the formation of an allylic intermediate. The
isolation of the tetrasubstituted allylic alcohol rather
than the homoallylic alcohol is also surprising, and at
this stage, no clear mechanistic rationale can be
advanced for the timing of this isomerisation sequence.
15%
12%
24%
Scheme 4.
propyl ketones proceeds via distal cleavage and hence
offers a novel regio- and stereoselective route to thermo-
dynamic enolates.
By way of contrast, stereoelectronic factors can domi-
nate the ring opening in a fused bicyclic system, albeit
that the degree of regioselectivity is less than in the case
of their cyclopropyl congeners.
Acknowledgement
We are grateful to the EPSRC for the provision of a
studentship (to S.Z.).
References and notes
Given that the immediate precursor, prior to protic
work-up, should be the thermodynamic lithium enolate
of a conjugated ketone, it was of interest to examine the
stereochemical outcome of the ring opening sequence,
especially in terms of the more problematic case of tetra-
substituted enolate geometry. The results for a prelimin-
ary experiment involving trapping with acetic anhydride
are shown in Scheme 3, and the isolation of the E enol
acetate, as confirmed by the NOE measurements shown,
is indicative of ring opening via the transoid gauche
conformer.
1. Far recent overviews of the synthetic utility of the cyclo-
propyl carbonyl radical ring opening reaction see inter alia:
(a) Zard, S. Z. Radical Reactions in Organic Synthesis;
Oxford University Press, 2003, Chapter 3, 3.3; (b) Gansa¨uer,
A.; Pierobon, M. In Radicals in Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, New York,
Chichester, Brisbane, Singapore, Toronto, 2001; Vol. 2,
Chapter 3.3.
2. (a) Batey, R. A.; Harling, J. D.; Motherwell, W. B.
Tetrahedron 1996, 52, 11421–11444; (b) Batey, R. A.;
Motherwell, W. B. Tetrahedron Lett. 1991, 32, 6211–6214.
3. (a) Dauben, W. G.; Schutte, L.; Wolf, R. E.; Deviny, E. J.
J. Org. Chem. 1969, 34, 2512–2517; (b) Dauben, W. G.;
Wolf, R. E. J. Org. Chem. 1970, 35, 374–379.
4. Norin, T. Acta Chem. Scand. 1965, 19, 1289–1292.
5. Hall, S. S.; Sha, C.-K. Chem. Ind. 1976, 216–217.
6. (a) Tanko, J. M.; Drumright, R. E. J. Am. Chem. Soc. 1992,
114, 1844–1854; (b) Tanko, J. M.; Drumright, R. E.;
Kamrudin Suleman, N.; Brammer, L. E., Jr. J. Am. Chem.
Soc. 1994, 116, 1785–1791; (c) Millard, B.; Forrest, D.;
Ingold, K. U. J. Am. Chem. Soc. 1976, 98, 7024–7026; (d)
Beckwith, A. L. J.; Moad, G. J. Chem. Soc., Perkin Trans. 2
1980, 1473–1482.
7. For stereoelectronic considerations in cyclopropyl carbinyl
radical ring opening of bicyclic systems see inter alia: (a)
Motherwell, W. B.; Harling, J. D. J. Chem. Soc., Chem.
Commun. 1988, 1380–1382; (b) Batey, R. A.; Grice, P.;
Harling, J. D.; Motherwell, W. B.; Rzepa, H. S. J. Chem.
Soc., Chem. Commun. 1992, 942–944.
Finally, albeit that cleavage of the distal bond is over-
whelmingly favoured both on kinetic and thermo-
dynamic grounds, it was of especial interest, as implied
in Scheme 4, to study the behaviour of a simple bicyclic
system in which the dictates of stereoelectronic control
could override these factors and favour production of
the higher energy vinylic intermediate via proximal bond
cleavage.7 The results for the ring opening of 7-methyl-
enebicyclo[4.1.0]heptan-2-one are shown in Scheme 4
and reveal a 3:1 preference in favour of the six-
membered ring products.
In summary, the foregoing examples have hopefully
provided some indication that the reductive ring open-
ing of suitably constituted monocyclic alkylidenecyclo-