Thereaction of phenyldimethylsilyllithium with N-phenylpyrrolidone

Article abstract of DOI:10.1039/b210445h

Phenyldimethylsilyllithium reacts with N-phenylpyrrolidone 5 to give the known tetracyclic amines [2,3,3a,3b,4,5,6,11b-octahydro-3aα,3bα,11bα-1-phenyl-1H- dipyrrolo(1,2a:3′,2′c)quinoline and its 3bβ isomer] 6 and 7.

Full text of DOI:10.1039/b210445h

The reaction of phenyldimethylsilyllithium with N-phenylpyrrolidone
Marina Buswell and Ian Fleming*
Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW. E-mail: if10000@cam.ac.uk; Fax: 44
1223 336362; Tel: 44 1223 336372
Received (in Cambridge, UK) 29th October 2002, Accepted 9th December 2002
First published as an Advance Article on the web 17th December 2002
Phenyldimethylsilyllithium reacts with N-phenylpyrroli-
Some of the literature procedures are based on reduction of
the lactam 5, notably that using lithium aluminium hydride.4,8
Others are based on the oxidation of the corresponding
pyrrolidine, using such reagents as diethyl azodicarboxylate,6
ozone,6 irradiation with gamma rays7 and tert-butoxy radicals.7
The key step in the mechanism suggested in the literature4,6 is
a Diels–Alder reaction (Scheme 3) between the iminium ion 8
and the enamine 9, both of which have oxidation states between
that of the pyrrolidone and that of the pyrrolidine. The major
isomer 6 corresponds to the endo product, which was the basis
for the earlier assignment of relative configuration.
Given the ease and the variety of ways with which the
products 6 and 7 can be formed, they must represent a deep hole
on the energy surface, or at any rate there must be a deep valley
leading to them.10 Nevertheless, the mechanism in Scheme 3
did not seem to be compatible in detail with our reaction
conditions. In particular, we could not see how the iminium ion
could be formed in aprotic conditions, and then survive long
enough to react with the enamine in a solution containing an
excess of the powerful nucleophile, phenyldimethylsilyllithium.
We therefore varied the reaction conditions and the stoichio-
metry, searching for evidence of intermediates that might help
us to a better understanding. Without going into detail, we
isolated more or less of each of the compounds 10–14 illustrated
in Scheme 4 with the highest yield for each, one of them 1111
quite high, and that a plausible intermediate, since it reacted
with the silyllithium reagent to give the same mixture of
products 6 and 7.
done
5
to give the known tetracyclic amines
[2,3,3a,3b,4,5,6,11b-octahydro-3aa,3ba,11ba-1-phenyl-1H-
dipyrrolo(1,2a+3A,2Ac)quinoline and its 3bb isomer] 6 and
7.
Whereas phenyldimethylsilyllithium reacts with N,N-dialkyl-
amides to give a variety of unexpected products,1 we find that
the reaction with the N-phenylamide 1 is more straightforward
(Scheme 1): the tetrahedral intermediate 2 breaks down by
expulsion of the N-methylanilide ion before any of the more
surprising events takes place. The acylsilane 3 so formed is
attacked by another equivalent of the silyllithium reagent to
give the known disilyl alcohol 4.2 We had a similar experience
with N,N-dialkylthioamides, except that the corresponding
thioacylsilanes enolised, instead of being attacked by a second
equivalent.3
We reasoned that if the nucleofugal amide ion were tied to the
rest of the molecule, it might return in the sense 3 ? 2, and
allow one or more of the Brook-rearrangement and carbene-
based reactions that we had seen earlier take place. Accord-
ingly, we treated N-phenylpyrrolidone 5 with the silyllithium
reagent, and obtained as the major products the two tetracyclic
amines 6 and 7 (Scheme 2). Clearly we had succeeded in
tapping into another remarkable sequence of reactions.
These two compounds are well known,4–9 and our products
were identical with authentic samples prepared by one of the
literature procedures.4 The relative stereochemistry, although
correctly assigned,4 had not been proved. We obtained X-ray
crystal structures† for both compounds, which confirm their
structures, and prove that the major product, with the higher
melting point, has the 3ba stereochemistry 6 relative to 3aa and
11ba.
In all of these reactions, we always obtained a large amount,
up to 42%, of unchanged pyrrolidone 5. This was clearly present
in the reaction mixture as its enolate, since it gave the C-
Scheme 3
Scheme 1 Reagents and conditions: i, 2.4 equiv. PhMe2SiLi, 278 °C; ii,
NaHCO3, H2O.
Scheme 2 Reagents and conditions: i, 2.4 equiv. PhMe2SiLi, 278 °C; ii,
warm to –20 °C; iii, NaHCO3, H2O.
Scheme 4 Reagents and conditions: i, PhMe2SiLi, THF, various conditions;
ii, NaHCO3, H2O.
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methylated product when we quenched with methyl iodide.
Although the silyllithium reagent is usually a better nucleophile
than a base, it is hardly surprising that it deprotonated some of
the starting material, and that some of the resultant enolate
survived until the workup.
The a-silylamine 10 is the normal product for a reaction
taking place between a tertiary amide and two or more
equivalents of the silyllithium reagent.1 Its formation suggests
that, at least in part, the reaction is taking the pathway involving
Brook rearrangement, and the formation of a carbene or
carbenoid 15. The formation of the lactam 11 can be explained
if the carbene 15, in addition to reacting with the silyllithium
reagent to give the a-silylamine 10, reacts with the enolate 16 to
give the anion 17 (Scheme 5).
The only problem with this suggestion was that we had been
unable in our earlier work1 to trap a carbene intermediate using
an enolate ion—the Brook-rearranging nucleophile intervened,
giving an enediamine. However, that work had used ketone-
derived and ester-derived enolates, and so we carried out the
model reaction between our usual amide 19 and the enolate ion
16 (Scheme 6). This time we were able to isolate the product 20,
although not in high yield. Presumably the more nucleophilic
enolate derived from a lactam was able to compete with the
Brook-rearranging nucleophile.
details any further, since this is far from being a general
reaction. With the corresponding b-lactam, ring opening was
the only detectable pathway, and with the corresponding
piperidone 22 (Scheme 7), the yield of the analogous tetracyclic
products 23 was low, a product 24 analogous to the intermediate
11 barely recognisable, and the major product was the ketone
25, derived by hydrolysis of the enediamine.
The anion 17, by proton loss and gain, can rearrange to the
enolate 18. Elimination of the anilide group, and other
straightforward steps, can account for the formation of the
products 11–14. It can equally account for the formation of the
tetracyclic amines 6 and 7, if the lactam 11 forms another
carbene with the silyllithium reagent. The steps between the
enolate 18 and the byproducts 13 and 14 supply the protons,
which are needed only in catalytic amounts, to give the lactam
11 from the lithium reagent 17 and the enolate 18.
The final intermediate before the quench must be an
organolithium reagent, but we have been unsuccessful in
pinning down its details. The work-up with methyl iodide
mentioned above did not give us recognisable methylation
products derived from the organolithium reagent, merely giving
us a much lower yield of the products 5 and 6 themselves. In one
run, we did isolate in 43% yield the C-methyl derivative 21
derived from the enolate 18, together with the product from C-
methylation of the starting lactam 5.
Scheme 7 Reagents and conditions: i, PhMe2SiLi, THF, 278 °C, warm to
220 °C; ii, NaHCO3, H2O.
We thank the EPSRC for a maintenance award (M. B.) and
for support in purchasing the Nonius CCD diffractometer, Dr J.
E. Davies for determining the X-ray structures, and Dr Matthew
Russell for the experiment in Scheme 6.
Notes and references
† CCDC 199968 and 199969. See http://www.rsc.org/suppdata/cc/b2/
b210445h/ for crystallographic data in CIF or other electronic format.
We have only established the outline of a possible mecha-
nism. Our mechanism cannot be involved in the earlier
preparations of the tetracyclic amines 6 and 7, although they
were formed, in 30 and 7% yield, respectively, when we treated
the lactam 11 with lithium aluminium hydride, indicating that it
could be an intermediate in that case. We have not pursued the
1 I. Fleming, U. Ghosh, S. R. Mack and B. P. Clark, Chem. Commun.,
1998, 711; I. Fleming, S. R. Mack and B. P. Clark, Chem. Commun.,
1998, 713; I. Fleming, S. R. Mack and B. P. Clark, Chem. Commun.,
1998, 715; I. Fleming and M. G. Russell, Chem. Commun., 2003, 198;
I. Fleming, E. Marangon, C. Roni, M. G. Russell and S. T. Chamudis,
Chem. Commun., 2003, 200.
2 I. Fleming and U. Ghosh, J. Chem. Soc., Perkin Trans. 1, 1994, 257.
3 M. Buswell and I. Fleming, ARKIVOC, 2002, 2002(vii), 46.
4 G. A. Swan and J. D. Wilcock, J. Chem. Soc., Perkin Trans. 1, 1974,
885.
5 G. D. Khandelwal, G. A. Swan and R. B. Roy, J. Chem. Soc., Perkin
Trans. 1, 1974, 891.
6 G. H. Kerr, O. Meth-Cohn, E. B. Mullock and H. Suschitzky, J. Chem.
Soc., Perkin Trans. 1, 1974, 1614.
7 S. Minakata, Y. Ohshima, A. Takemiya, I. Ryu, M. Komatsu and Y.
Ohshiro, Chem. Lett., 1997, 311.
8 The first preparation, as pointed out in ref. 4, is probably: G. Wittig and
H. Sommer, Liebigs Ann. Chem., 1955, 594, 1.
9 Some related reactions: J. B. P. A. Wijnberg, J. J. J. de Boer and W. N.
Speckamp, Recl. Trav. Chim. Pays-Bas, 1978, 97, 227; D. Anastasiou,
E. M. Campi, H. Chaouk, G. D. Fallon, W. R. Jackson, Q. J. McCubbin
and A. E. Trnacek, Aust. J. Chem., 1994, 47, 1043; M. Hadden and P. J.
Stevenson, Tetrahedron Lett., 1999, 40, 1215; R. A. Batey, D. A.
Powell, A. Acton and A. J. Lough, Tetrahedron Lett., 2001, 42, 7935
and references therein.
Scheme 5
10 We predict that treatment with samarium iodide will almost certainly
provide yet another route.
11 A mixture of diastereoisomers, the major crystalline, and known: A. K.
Bocz, Chem. Ber., 1966, 99, 1923, as also is the aldol product 12: H.
Eilingsfeld, M. Seefelder and H. Weidinger, Angew. Chem., 1960, 72,
836; K. H. Büchel, A. K. Bocz and F. Korte, Chem. Ber., 1966, 99,
724.
Scheme 6 Reagents and conditions: i, PhMe2SiLi, THF, 278 °C; ii, 16,
THF, 278 °C, derived from 5 with LDA, then ? 220 °C, 1 h; iii, NaHCO3,
H2O.
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