Dearomatization-bis-alkylation of aromatic and heteroaromatic diesters promoted by Me3SnLi via a Stanna-Brook rearrangement

Article abstract of DOI:10.1021/ol053130r

Reaction of Me₃SnLi with aromatic and heteroaromatic diesters proceeds through a fast stanna-Brook rearrangement that generates an stable bis-enolate which can be regioselectively alkylated and cyclized, in one step, to bicyclic compounds conta

Full text of DOI:10.1021/ol053130r

ORGANIC
LETTERS
2006
Vol. 8, No. 5
951-954
Dearomatization−Bis-alkylation of
Aromatic and Heteroaromatic Diesters
Promoted by Me3SnLi via a
Stanna−Brook Rearrangement
Pablo Monje, Paula Gran˜a, M. Rita Paleo, and F. Javier Sardina*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de Santiago
de Compostela, 15782 Santiago de Compostela, Spain
qojskd@usc.es
Received December 26, 2005
ABSTRACT
Reaction of Me3SnLi with aromatic and heteroaromatic diesters proceeds through a fast stanna-Brook rearrangement that generates an stable
bis-enolate which can be regioselectively alkylated and cyclized, in one step, to bicyclic compounds containing 6,5-, 6,6-, and 6,7-fused ring
systems.
Trialkylstannyllithium reagents (R3SnLi) have found numer-
ous applications in organic synthesis.1 They are easily
prepared and react as nucleophiles to give stannanes of high
synthetic value2,3 upon reaction with carbonyl compounds,
R,â-unsaturated carbonyl compounds, alkyl or aryl chlorides,
benzotriazoles, or epoxides. In contrast, only a few examples
of the addition of anionic tin nucleophiles to carboxylic acid
derivatives have been reported,4 although direct acylation
of R3SnLi with thioesters, or with esters in the presence of
BF3‚OEt2, has allowed the preparation of acylstannanes in
moderate yields.5 We have recently reported6 that R3SnLi
reagents add to carboxylic acid derivatives (esters, amides,
and Weinreb amides) to give an R-alkoxystannyl adduct that
suffers a stanna-Brook rearrangement where the stannyl
group migrates from carbon to oxygen to give a carbanion,
which then evolves differently depending on the structure
of the substrate.
In this paper, we report a novel dearomatization-alkyl-
ation procedure resulting from the addition of trimethyl-
stannyllithium to aromatic and heteroaromatic diesters, a
process that does not occur by nucleophilic addition to the
electron-deficient aromatic ring but instead by 1,2-addition
to one of the carboxylic ester groups followed by Sn-Brook
rearrangement of the initial stannyl adduct to give an stable
bis-enolate. This bis-enolate can be alkylated with bis-
electrophiles to provide bicyclic compounds containing 6,5-,
(1) (a) Davies, A. G. Organotin Chemistry, 2nd ed.; Wiley-VCH:
Weinheim, 2004. (b) Sato, T. Synthesis 1990, 259.
(2) Marshall, J. A. Organometallics in Synthesis: A Manual, 2nd ed.;
Schlosser, M., Ed.; Wiley: Chichester, 2002.
(3) (a) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481. (b) Still, W. C.;
Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201.
(5) Capperucci, A.; Degl’Innocenti, A.; Faggi, C.; Reginato, G.; Ricci,
A.; Dembech, P.; Seconi, G. J. Org. Chem. 1989, 54, 2966.
(6) Paleo, M. R.; Calaza, M. I.; Gran˜a, P.; Sardina, F. J. Org. Lett. 2004,
6, 1061.
(4) Wyatt, P. B. Sci. Synth. 2003, 5, 423.
10.1021/ol053130r CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/10/2006

6,6-, and 6,7-fused ring systems in one step. Dearomatization
of aromatic rings has been achieved by Birch reduction7,8 or
by nucleophilic addition to an electron-deficient arene that
possesses groups which are either not electrophilic9 or whose
reactivity at the carbonyl group has been blocked by using
hindered derivatives10 or Lewis acids.11
Addition of excess Me3SnLi (300 mol %) to phthalate 1
in THF gave, after quenching with pH 7.0 buffer, a mixture
of dienes 2 and 3. When the reaction was quenched with
1
iPrOH, only 2 was observed in the H NMR of the crude
product (80% isolated yield). A very clean reaction was also
observed when AcOH was used as the quench: 3 was the
only product present in the reaction mixture (isolated in 65%
yield as a 2.2:1 mixture of stereoisomers). Diene 3 proved
to be quite unstable on standing and during chromatography,
and it slowly underwent isomerization to the more stable
isomer 2.
Scheme 1. Dearomatization Reactions of Aromatic Diesters
Figure 1. Mechanism for the partial reduction reaction and
representative NMR data for intermediate bisenolate 10. All
chemical shifts in ppm.
one of the carboxylate groups of 1 should give the stannyl
alkoxyde 7, which would then suffer a rapid Sn-Brook
rearrangement to formally give R-oxy-carbanion 8 which is,
actually, enolate 9. This rearrangement should be fast due
to the very stable nature of the resulting enolate. Nucleophilic
displacement at tin by Me3SnLi (second equivalent) in
intermediate 9 would give the lithium bis-enolate 10 and
hexamethyldistannane. Bis-enolate 10 would then undergo
kinetically (AcOH or TFA) or thermodynamically (iPrOH)
controlled protonation to provide the observed reaction
products, dienes 2 or 3, respectively.13
The effect of the ester group (Me, Et, Bu, iPr, tBu) was
investigated, and it was found that the isopropyl group
showed cleaner reactions. Regarding the amount of Me3SnLi,
at least 200 mol % is necessary for complete conversion as
starting material was recovered when the reactions were
performed using 100 or 150 mol % of Me3SnLi. The use of
300 or 500 mol % did not lead to higher yields.12
A similar behavior was observed when terephthalate 4 was
used as a substrate. Treatment of 4 with Me3SnLi at -78
°C for 1 h followed by quenching with TFA allowed the
isolation of the unconjugated diene 5 in 81% yield. The R,â-
unsaturated diester 6 was formed when the reaction was
quenched with iPrOH.
The presence of dilithium bis-enolate 10 as an intermediate
in this reaction was substantiated by analysis of the 1H, 13C,
and 119Sn NMR spectra of several reaction mixtures. When
a mixture of MeLi (250 mol %) and Me6Sn2 (250 mol %) in
THF-d8 was treated with diester 1 (100 mol %) at -78 °C
and the subsequent reaction followed by NMR, we observed
the complete disappearance of starting material and the
appearance of a new product which showed signals consistent
with the structure of bis-enolate 10 (Figure 1).
The presence of only four signals in the 1H NMR spectrum
and of six signals in the 13C NMR spectrum of the reaction
mixture before quenching in THF-d8, taken together with
the upfield chemical shifts displayed by H-5 and H-6, and
by C-4 and C-5, strongly suggest the formation of a
symmetric bis-enolate intermediate, such as 10. The 119Sn
NMR spectrum showed only two signals that can be assigned
To explain these results, we propose the mechanism
depicted in Figure 1. Addition of 100 mol % of Me3SnLi to
(7) Schultz, A. G. Chem. Commun. 1999, 1263.
(8) Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1.
(9) (a) Comins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett. 2002, 4,
1611. (b) Clayden, J.; Kenworthy, M. N. Org. Lett. 2002, 4, 787. (c)
Kolotuchin, S. V.; Meyers, A. I. J. Org. Chem. 2000, 65, 3018.
(10) (a) Clayden, J.; Foricher, Y. J. Y.; Lam, H. K. Chem. Commun.
2002, 2138. (b) Clayden, J.; Foricher, Y. J. Y.; Lam, H. K. Eur. J. Org.
Chem. 2002, 3558.
(11) Maruoka, K.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117,
9091.
(12) For convenience, 250 mol % of Me3SnLi (obtained by reaction of
Me6Sn2 with MeLi at 0 °C for 15 min) was used in most of the experiments.
(13) Leading references on lithium bis-enolates in synthesis: (a) Bilyard,
K. G.; Garratt, P. J.; Hunter, R.; Lete, E. J. Org. Chem. 1982, 47, 4731. (b)
Langer, P.; Freiberg, W. Chem. ReV. 2004, 104, 4125 and references therein.
952
Org. Lett., Vol. 8, No. 5, 2006

to Me4Sn (δ 0 ppm) and Me6Sn2 ( δ -112 ppm), no other
stannyl-containing product, such as a stannyl enolate like 9,
is present in the reaction mixture14 which is supportive of
the proposed mechanism. The corresponding bisenolate
intermediates were also observed in the reactions of diesters
4 and 23 with Me3SnLi (vide infra).
Since the proposed intermediate bis-enolates should be
powerful nucleophiles we decided to study their reaction with
bis-electrophiles, in the hope of developing straightforward
access to highly functionalized bicyclic systems of great
synthetic potential. Thus, treatment of diester 1 with Me3SnLi
in THF at -78 °C for 1 h, followed by addition of 1,3-
diiodopropane or 1,3-propanediol di-p-toluensulfonate (300
mol %) afforded hydrindane diene 14 in 99% and 90%
yields, respectively (see Scheme 2). When 1,4-diiodobutane
yield. All bicyclic compounds were obtained with complete
stereoselectivity, as only one stereoisomer was detected in
the crude reaction mixtures. The products were shown to be
the cis-fused stereoisomers by reduction of hydrindane 14
and decalin 15 to the corresponding diols (excess LiAlH4 in
THF at 0 °C) and X-ray diffraction analysis of these
compounds (see the Supporting Information). The close
similarities of the NMR chemical shifts of compounds 14-
16 lead us to believe that the stereochemistry of the ring
junction in the 6,7-fused system 16 is also cis.
The bis-enolate derived from the reaction of p-diester 4
with Me3SnLi proved to be less reactive than its ortho
analogue, and starting material was often recovered from the
reaction mixture. Thus reaction of terephthalate 4 with the
tin nucleophile, followed by 1,3-diiodopropane provided
hydrindane 18 as a 2:1 nonseparable mixture with starting
ester 4. NMR analysis of the reaction showed the complete
consumption of starting material before the addition of the
electrophile, and the reformation of the starting ester and
cyclopropane, along with the expected alkylation product
18, afterward. These observations indicate that 1,3-diiodo-
propane acts partially as an iodinating agent and not only as
a C-electrophile. When 1,3-dibromopropane was used as
electrophile the desired bicycle 18 was isolated in 89% yield.
No bicyclic products were isolated when excess 1,4-
diiodobutane or 1,5-diiodopentane were used as electrophiles,
the products being dialkylated compounds incorporating two
molecules of the electrophile. The cis-fused nature of
hydrindane 18 was tentatively established by NOE studies.
Scheme 2. Dearomatizing Anionic Cyclizations of Aromatic
Di- and Triesters
A cursory exploration of the effects of the presence of
further substituents on the starting ester on the outcome of
the dearomatization-cyclization sequence was carried out.
The presence of alkyl substituents on the ring does not appear
to adversely affect the process, since methyl-substituted
phthalate 12 provided the expected bicycle 19 (isolated in
60% yield) when reacted with Me3SnLi and 1,3-diiodo-
propane.
The incorporation of a third ester group into the aromatic
ring of the substrate allowed us to explore the regioselectivity
of the reaction. Thus, when triester 13 was submitted to the
usual reaction conditions using 1,3-diiodopropane and 1,4-
diiodobutane as electrophiles, the only products formed were
those arising from the alkylation of the ortho-diester system,
hydrindan 20 and decalin 21, which were isolated in excellent
yields.
was used as electrophile, unsaturated decalin 15 was obtained
in 85% yield. The ring-forming dialkylation of bis-enolate
10 with 1,5-diiodopentane to build a seven-membered ring
was not as straightforward as the previous examples, and
the main product obtained under the usual conditions was
diene 11 (E ) (CH2)5I, Figure 1), which had incorporated
two molecules of electrophile. A successful way of con-
structing the seven-membered ring was found, nevertheless.
Thus, treatment of the reaction intermediate with only 100
mol % of 1,5-diiodopentane at -78 °C for 3 h, followed by
warming up to 35 °C, afforded 16 in 71% yield. When using
a functionalized bis-electrophile such as cis-1,4-dichloro-2-
butene, the corresponding bicycle 17 was isolated in 60%
This dearomatization-bisalkylation methodology was then
applied to electron-deficient pyridines 22 and 23, obtained
from the corresponding commercially available diacids
(iPrOH, DCC, DMAP, 70%). As can be seen from the data
presented in Scheme 3, fused 6,5-, 6,6-, and 6,7-ring systems
(24-29) were prepared in one step and isolated in high yields
by reaction of Me3SnLi with diesters 22 or 23 followed by
addition of the appropriate diiodoalkane. Treatment of 2,3-
disubstituted pyridine 22 with Me3SnLi followed by 1,3-
diiodopropane afforded a mixture of regioisomers 24 and
the nitrogen analogue to 14 in approximately 1:1 ratio, this
ratio increased to 9.3:1 when the harder electrophile 1,3-
dibromopentane was used, and indolizidine 24 was thus
(14) It has been described that a mixture of Me3SnLi and Me3SnSnMe3
shows a single 119Sn NMR signal at a position depending on the ratio of
the two compounds, as a result of rapid exchange through nucleophillic
attack of tin on tin: Kobayashi, K.; Kawanisi, M.; Kozima, S.; Hitomi, T.;
Iwamura, H.; Sugawara, T. J. Organomet. Chem. 1981, 217, 315. Me4Sn
is formed as a side product of the generation of Me3SnLi.
Org. Lett., Vol. 8, No. 5, 2006
953

tion of 27-29 had already been accomplished15 by partial
reduction of electron deficient pyridine 23 by using Birch
or sodium naphthalenide, followed by quenching with
chloroiodoalkanes and then cyclization in the presence of
DBU in a two-steps sequence.
Scheme 3. Dearomatizing Anionic Cyclizations of
Heteroaromatic Diesters
We are currently extending this methodology to different
aromatic and heteroaromatic systems and investigating the
viability of the asymmetric version of this dearomatization-
cyclization process.
Acknowledgment. Financial support from the MCYT and
MECD (Spain, Grant No. BQU2002-01368 and fellowships
to P.M. and P.G.) and the Xunta de Galicia (Grant No.
PGIDIT03PXIC20910PN) are gratefully acknowledged.
Supporting Information Available: Complete experi-
mental procedures, spectroscopic and analytical data of all
new compounds, and ORTEP projections of diols 30 and
31. This material is available free of charge via the Internet
at http://pubs.acs.org.
isolated in 86% yield. Only the indolizidine isomer was
detected in the reactions with 1,4-diiodobutane (25, 86%)
and 1,5-diiodopentane (26, 81%). It is surprising that the
cyclization to give the seven-membered ring occurs now
uneventfully to give the bicyclo 6,7-ring system in very good
yield.
OL053130R
The same set of reactions was performed starting from
2,5-disubstituted pyridine 23 (see Scheme 3) to prepare
compounds 27-29 in good to excellent yields. The prepara-
(15) (a) Donohoe, T. J.; McRiner, A. J.; Sheldrake, P. Org. Lett. 2000,
2, 3861. (b) Donohoe, T. J.; McRiner, A. J.; Helliwell, M.; Sheldrake, P. J.
Chem. Soc., Perkin Trans. 1 2001, 1435.
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Org. Lett., Vol. 8, No. 5, 2006