Synthesis of polycyclic tertiary carbinamines by samarium diiodide mediated cyclizations of indolyl sulfinyl imines

Article abstract of DOI:10.1002/anie.201408324

Samarium diiodide mediated cyclizations of N-acylated indole derivatives bearing sulfinyl imine moieties afforded polycyclic tertiary carbinamines with moderate to excellent diastereoselectivities. Lithium bromide and water turned out to be the best additives to achieve these transformations in good yields. Using enantiopure sulfinyl imines the outcome strongly depends on the reactivity of the indole moiety. Whereas with unactivated indole derivatives desulfinylation and formation of racemic products was observed, indoles bearing electron-withdrawing substituents at C-3 afforded the polycyclic products with intact N-sulfinyl groups and with excellent diastereoselectivity, finally allowing the preparation of enantiopure tertiary carbinamines. The mechanisms of these processes are discussed.

Full text of DOI:10.1002/anie.201408324

Angewandte
Chemie
DOI: 10.1002/anie.201408324
Polycyclic Amines
Synthesis of Polycyclic Tertiary Carbinamines by Samarium Diiodide
Mediated Cyclizations of Indolyl Sulfinyl Imines**
Chintada Nageswara Rao, Dieter Lentz, and Hans-Ulrich Reissig*
Dedicated to Professor Johann Mulzer on the occasion of his 70th birthday
Abstract: Samarium diiodide mediated cyclizations of N-
acylated indole derivatives bearing sulfinyl imine moieties
afforded polycyclic tertiary carbinamines with moderate to
excellent diastereoselectivities. Lithium bromide and water
turned out to be the best additives to achieve these trans-
formations in good yields. Using enantiopure sulfinyl imines
the outcome strongly depends on the reactivity of the indole
moiety. Whereas with unactivated indole derivatives desulfi-
nylation and formation of racemic products was observed,
indoles bearing electron-withdrawing substituents at C-3
afforded the polycyclic products with intact N-sulfinyl groups
and with excellent diastereoselectivity, finally allowing the
preparation of enantiopure tertiary carbinamines. The mech-
anisms of these processes are discussed.
S
amarium diiodide mediated reactions find wide application
in organic synthesis.[1] Many selective and unique trans-
formations are possible[2] and quite a number of natural-
product syntheses witnesses the usefulness of this electron-
transfer reagent.[3] Our group discovered and explored
samarium-ketyl/aryl cyclizations that convert simple or com-
plex (hetero)aryl ketones, such as 1, into dearomatized
products 2 with excellent diastereoselectivity (Scheme 1).[4]
The method proved to be particularly useful in reactions of N-
acylated or N-alkylated indolyl ketones of type 3 or 5 that
provided tricyclic compounds 4 and 6, respectively.[5] This
approach to functionalized indoline derivatives could be
further extended to cascade reactions employing precursors
such as 7. This compound was smoothly converted into
tetracyclic compound 8 that is an ideal intermediate of one of
the shortest syntheses of the alkaloid strychnine reported to
date.[6] Whereas the cyclizations of ketones were investigated
in detail, demonstrating scope and limitations, the related
imine derivatives have not been studied so far.[7,8] With the
objective of developing an enantioselective synthesis of cyclic
Scheme 1. Samarium diiodide mediated cyclizations of g-arylketones 1,
N-acylated and N-alkylated indole derivatives 3, 5, and 7 leading to bi-
and tricyclic tertiary alcohols 2, 4, 6, or to tetracyclic strychnine
precursor 8.
products similar to 8 we started to study samarium diiodide
promoted reactions of indole-derived sulfinyl imines deriva-
tives.[9] We selected indoles because of their excellent
behavior in the ketone cyclizations and because of our
interest in the expected indolinyl-substituted tertiary carbin-
amines[10] that are of relevance for the synthesis of natural
products or their analogues.
We started our investigations with the sulfinyl imine 10
that is easily available by Ti(OEt)4-promoted condensation of
N-acylated indole derivative 3 with racemic tert-butylsulfin-
amide 9.[11] Treatment of compound 10 with 2.4 equivalents of
SmI2 under standard conditions used for ketone cyclizations
in the presence of hexamethyl phosphoramide (HMPA)[12]
and tert-butanol provided the expected cyclization product 11
only in around 5% yield and mainly led to decomposition
(Scheme 2). We therefore examined alternative conditions
and finally found that the cyclization proceeds in excellent
yield within 5 min if SmI2 (6 equiv) was employed in the
presence of lithium bromide (72 equiv) and water (72 equiv)
as additives.[8,13,14] The two diastereomers 11a and 11b were
isolated in a 67:33 ratio in 90% yield. The cyclization also
occurs with slightly diminished yields when only LiBr (67%
yield) or only H2O (60% yield) were used as additives. Under
all conditions examined the primary amines were isolated and
not the expected the N-sulfinylated amines. The two diaste-
[*] Dr. C. N. Rao, Prof. Dr. D. Lentz, Prof. Dr. H.-U. Reissig
Institut fꢀr Chemie und Biochemie
Freie Universitꢁt Berlin
Takustrasse 3, 14195 Berlin (Germany)
E-mail: hans.reissig@chemie.fu-berlin.de
[**] This work was supported by the Alexander von Humboldt
Foundation (fellowship for C.N.R.), the Deutsche Forschungsge-
meinschaft, and Bayer HealthCare. We also thank Dr. R. Zimmer for
his assistance during preparation of the manuscript.
Supporting information for this article (experimental details,
compound characterization of all new compounds, and additional
information) is available on the WWW under http://dx.doi.org/10.
1002/anie.201408324.
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furnished the cyclization products 11a and 11b, but
as suspected both isomers were racemic as shown by
their conversion to Mosher amides (see Supporting
À
Information). This result indicates that the N S
bond is very likely cleaved before the cyclization
occurs and hence the chiral auxiliary has no
À
influence on the C C bond forming step.
Gratifyingly, the reaction of indole derivative 15
(Scheme 5) bearing an electron-withdrawing group
at C-3 exhibits a different behavior. The majority of
the cyclization products still bear the N-sulfinyl
group and compound 16 was formed as a single
diastereomer. As racemic by-products the desulfi-
nylated compounds 17a and 17b were formed. The
constitution and configuration of the tricyclic prod-
uct 16 was established by an X-ray crystal-structure
Scheme 2. Reagents and conditions: a) 9=(rac)-tert-butylsulfinamide, Ti(OEt)4,
THF, reflux, 36 h; b) SmI2 (2.4 equiv), HMPA (10 equiv), tBuOH (10 equiv), THF,
room temperature, 7 h, ca. 5% (d.r. ca. 75:25); c) SmI2 (6.0 equiv), LiBr
(72 equiv), H2O (72 equiv), THF, room temperature, <5 min, 90% (d.r. =67:33);
d) Ac2O, Et3N, DMAP, CH2Cl2, room temperature, 16 h.
reomers 11a and 11b were separated and N-acylated with
acetic acid anhydride to afford compounds 12a and 12b. The
constitution and relative configuration of 12a was determined
by an X-ray crystal-structure analysis (see Supporting Infor-
mation).[15] This result unequivocally demonstrates that
starting from the sulfinyl imines the slightly favored diaste-
reomer 11a shows a trans-relationship of the amino group and
the bridgehead hydrogen whilst for ketone cyclizations the
opposite relative configuration was observed exclusively (see
transformation 3 to 4 in Scheme 1).
The cyclization of the homologous N-sulfinyl imine 13
under the conditions described above furnished the expected
products 14a and 14b with a newly generated seven-
membered ring in good yield and low diastereoselectivity
(Scheme 3). The configurations are assigned in analogy to 11
since the NMR spectroscopic data are similar.
Scheme 5. Reagents and conditions: a) SmI2, LiBr, H2O, THF, 10–
128C, syringe-pump addition to 15 for 30 min; b) 1n HCl, MeOH,
room temperature, 20 h. Molecular structure (ORTEP)[16] of compound
16 (thermal ellipsoid at 50% probability).
analysis.[15,16] Compound 16 was smoothly desulfinylated by
treatment with 1n hydrochloric acid to give (R,S,S)-17a in
excellent yield.
The homologous sulfinyl imine 18 (Scheme 6) afforded
the tricyclic indoline derivative 19 in higher yield as a single
diastereomer (configuration proposed in analogy to 16)
demonstrating that precursors of type 15 and 18 allow the
preparation of tricyclic amines in high enantiopurity (e.r. >
97:3). In contrast, imino ester 20 furnished two desulfinylated
spiro compounds 21a and 21b (77% yield, d.r. 68:32). Since
the two products did not show any optical rotation we assume
that they are racemic. The two examples in Scheme 6 reveal
that a subtle influence of the structure of precursors decides
the outcome of these reductive cyclizations.
Scheme 3. Reagents and conditions: a) SmI2, LiBr, H2O, THF, room
temperature, 30 min.
The observed desulfinylation made us skeptical whether
an enantiopure sulfur auxiliary will have any influence on the
cyclization. The N-sulfinyl imine (R)-10 (Scheme 4), gener-
ated from compound 3 and (R)-tert-butylsulfinamide (R)-9,
Altogether, the examples of Schemes 2–6 demonstrate
that the cyclizations of sulfinyl imines with the indole moiety
proceed smoothly providing tertiary carbinamines with good
yields and varying diastereoselectivities. Two competing
mechanisms are apparently operating depending on the
substitution pattern of the indole unit. Without an electron-
withdrawing group, a desulfinylation reaction occurs at the
imine unit that provides a species undergoing the intra-
Scheme 4. Reagents and conditions: a) SmI2, LiBr, H2O, THF, room
temperature, <5 min.
2
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If, on the other hand, an electron-withdrawing group
activates the indole derivative, an electron transfer to this
moiety is more likely.[19] The generated radical anion 26
(Scheme 8) subsequently adds to the imine still bearing the
chiral auxiliary to provide intermediate 27.[20] A second
electron transfer and subsequent protonation affords product
16. High diastereoselectivity is observed in this case and the
Scheme 6. Reagents and conditions: a) SmI2, LiBr, H2O, THF, 10–
128C, syringe-pump addition to 18 for 30 min; b) SmI2, LiBr, H2O,
THF, 188C, syringe-pump addition to 20 for 45 min.
molecular addition to C-2 of the indole derivative. Hence the
chiral sulfur auxiliary has no influence on the stereochemical
outcome of this step (see example presented in Scheme 4).
That the N-desulfinylation very likely occurs at the imine
stage and not after the cyclization is also shown by the
stability of N-sulfinyl amines, such as 16 or 19, under the
reaction conditions despite of an excess of samarium diiodide.
A possible mechanism for this pathway is depicted in
Scheme 7 involving formation of an azaketyl intermediate
22.[17] This species adds to the indole unit to deliver 23 that
after a further electron transfer and protonation affords
cyclization product 11. Since the cyclization of 22 to 23
proceeds only with a 2:1 diastereoselectivity, a discussion of
this aspect seems not to be appropriate at the moment. To our
knowledge the desulfinylation of N-sulfinyl imines has not
been reported to date.[18] The feasibility of this process was
demonstrated by the smooth transformation of cyclohexa-
none-derived ketimine 24 into amine 25.
Scheme 8. Proposed “indole-first” mechanism for the cyclization of
activated indole derivatives and samarium diiodide promoted reduc-
tion of indole 28 to 29: reagents and conditions: a) SmI2, LiBr, H2O,
THF, room temperature, 10 min; (in addition, 4% of the compound
with reduced N-acetyl group of 28 was isolated, see Supporting
Information).
configuration at the carbon atom adjacent to the amino group
can be explained by the models suggested for the additions of
nucleophiles to tert-butylsulfinyl imines. In general, nucleo-
philes preferentially attack the Si-face of ketimines which
have an R-configured sulfur auxiliary.[21] The plausibility of
a fast electron transfer to activated indoles is demonstrated by
the immediate reduction of model compound 28 to indoline
29 under the reaction conditions.[22]
In conclusion, our results present two seemingly similar
cyclization processes leading to tertiary carbinamines in good
yield and moderate to excellent diastereoselectivity. A closer
look reveals mechanistic differences and only activated indole
derivatives allow the preparation of enantiopure compounds.
Nevertheless, the procedures described allow an entry to
interesting molecular skeletons incorporating indoline moi-
eties not available by other methods. A new samarium
diiodide promoted desulfination of sulfinyl imines was
discovered during this investigation.
Received: August 18, 2014
Revised: November 6, 2014
Published online: && &&, &&&&
Scheme 7. Proposed “imine-first mechanism” for the cyclization of
unactivated indole derivatives and samarium diiodide promoted reduc-
tion of N-sulfinyl imine 24 to 25; reagents and conditions: a) SmI2,
LiBr, H2O, THF, room temperature, <1 min.
À
Keywords: amines · C C coupling · cyclization · indoles ·
.
radical reactions · samarium diiodide
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can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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lation comes into play.
4
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Polycyclic Amines
C. N. Rao, D. Lentz,
H.-U. Reissig*
&&& — &&&
Synthesis of Polycyclic Tertiary
Carbinamines by Samarium Diiodide
Mediated Cyclizations of Indolyl Sulfinyl
Imines
Two ways to three rings: Indolyl sulfinyl
imines undergo smooth SmI2-mediated
cyclizations and provide polycyclic terti-
ary carbinamines in good yield. N-Sulfinyl
imines with unactivated indole units (X=
H) undergo an N-desulfinylation—a pre-
viously unknown reaction—and then the
cyclization. In contrast, activated indoles
(X=CO2R) undergo cyclization with
intact N-sulfinyl imine moiety leading to
the formation of enantiomerically pure
tricyclic products.
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