Highly stereoselective synthesis of tertiary propargylic centers and their isomerization to enantiomerically enriched allenes

Article abstract of DOI:10.1002/chem.201201607

Center of attention: A new approach for the synthesis of enantiomerically enriched allenes by isomerization of 2-p-tolylsulfinylphenyl propargylic derivatives is presented, which in turn are prepared by reaction of sulfinylated lithium benzylcarbanions with arylsulfonylacetylenes (see scheme). The high control of stereoselectivity in both steps is exerted by the sulfinyl group. Copyright

Full text of DOI:10.1002/chem.201201607

COMMUNICATION
DOI: 10.1002/chem.201201607
Highly Stereoselective Synthesis of Tertiary Propargylic Centers and Their
Isomerization to Enantiomerically Enriched Allenes
Josꢀ Luis Garcꢁa Ruano,* Leyre Marzo, Vanesa Marcos, Cuauhtꢀmoc Alvarado, and
Josꢀ Alemꢂn*[a]
Allenes are important compounds that exhibit axial chir-
ality[1] and are present in a large number of medicinal and
natural products.[2] One of the most frequently used methods
for obtaining racemic allenes involves the isomerization of
propargylic centers.[3] However, it is surprising that this
method has rarely been used for preparing enantiomerically
pure compounds, probably due to the rather poor results ob-
tained in its application. Thus, the few examples reported
for the synthesis of allenols using chiral auxiliaries are mini-
mally successful,[4] and only moderate enantiomeric excess
(ee) has been achieved with organocatalytic methods.[5] Very
recently Yoshida et al. reported one of the best procedures
for the synthesis of allenols (74 to 92% ee), which is based
on the method previously published by Hoppe and co-work-
ers.[6] It consists of the carbolithiation of 2-OCb (OCONiPr2)
conjugated enynes in the presence of stoichiometric (À)-
sparteine, followed by addition of the resulting propargylic
anions to electrophiles to give the corresponding allene de-
rivatives (Scheme 1a). The key to the success of this nice
transformation seems to be related to the chemical and con-
figurational stability of the propargylic lithium carbanion by
association with the OCb group and the (À)-sparteine,
which is used in stoichiometric amounts. These results sug-
gest that the main difficulty for obtaining enantiomerically
enriched allenes by isomerization of compounds with chiral
propargylic centers of a defined configuration is due to the
configurational stabilization of the propargylic carbanion in-
termediates.
In recent years, we have reported that an ortho-sulfinyl
group is able to provide a high configurational stabilization
to differently substituted benzylic anions, allowing them to
react with various electrophiles in an almost completely ste-
reoselective manner.[7] From these results we hypothesized
that ortho-sulfinyl benzylcarbanions containing acetylenic
moieties joined to the benzyl carbon would be able to
evolve in a highly stereoselective manner into enantiomeri-
cally enriched allenes due to the configurational stabiliza-
tion provided by the sulfinyl group (Scheme 1b). To confirm
this hypothesis, it was necessary to prepare the propargylic
precursors shown in Scheme 1. The results obtained in these
two fields, synthesis of alkynes and their isomerization into
trisubstituted allenes,[8] are presented herein.
The preparation of enantiomerically pure tertiary propar-
gylic centers can be achieved by the nucleophilic addition of
acetylenic residues to proper electrophiles such as enones,[9]
enals,[10] nitroalkenes,[11] Meldrumꢀs acid derivatives,[12] and
thioamides.[13] In all these cases, the acetylenic moiety is sup-
ported by the reagent acting as nucleophile, and the electro-
phile contains an electron-withdrawing group (EWG) to
allow the conjugate addition (Scheme 2a). As the acidity of
the a protons to these groups could interfere with the ab-
straction of the propargylic protons required for the isomeri-
zation to the allene, the resulting compounds from these
routes are not appropriated for our study.
Scheme 1. Approaches used in the synthesis of enantioenriched allenes.
[a] Prof. J. L. Garcꢁa Ruano, L. Marzo, Dr. V. Marcos, Dr. C. Alvarado,
Dr. J. Alemꢂn
Departamento de Quꢁmica Orgꢂnica (Mꢃdulo-1)
Universidad Autꢃnoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
Fax : (+34)914973966
E-mail: joseluis.garcia.ruano@uam.es
jose.aleman@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201607.
Scheme 2. Asymmetric synthesis of propargylic centers.
Chem. Eur. J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Our group has recently published that arylsulfonylacety-
ported by the fact that tert-butyl derivative 2h, lacking
acidic protons, gave the addition product 3Ah in 60% yield
(Table 1, entry 8), despite the large size of the tBu group.
The reaction with 2i was analogously successful (entry 9),
with an 84% yield for 3Ai under the standard conditions.
Finally, we studied the influence of R1 on the reaction, ob-
taining similar yields with different alkyl groups (1B–E) and
with complete diastereoselectivity (only one diastereoisomer
was detected by NMR spectroscopy). The structure and ab-
solute configuration (SS, 3R) of 3Aa were unequivocally es-
tablished by using X-ray analysis (Figure 1).[15] This assign-
ment was then extended to all the alkynyl derivatives 3.
2
À
lenes, such as 2, can act as alkynylating reagents of Csp
H
3
À
and Csp H bonds due to their unexpected electrophilic be-
havior when they react with aryllithiums at the a carbon, re-
sulting in the formation of alkynes by elimination of
À [14]
ArSO2 . As this reaction seemed to be efficient for creat-
3
À
ing C
(sp ) C(sp) bonds, we wondered if it would be also
successful in enantioselective generation of propargylic cen-
ters starting from configurationally stabilized carbanions,
such as the 2-p-tolylsulfinyl benzylalkyl carbanions derived
from 1. These reactions would provide enantiomerically en-
riched alkynyl derivatives 3, lacking of the EWG groups,
and therefore suitable for the isomerization studies
(Scheme 2b).
Reaction of enantiomerically pure 1A (0.4 mmol,
98% ee) with sulfone 2a in the presence of LDA at À788C
(see the Supporting Information for screening details, Table
S-1) and final protonation with NH4Cl at À788C, yielded
the alkynyl derivative 3Aa in 64% yield as a single diaste-
reomer (diastereomeric ratio (d.r.) >98:2 by NMR spectros-
copy and 98% ee by HPLC). When the reaction was carried
out on larger scales (2.0 mmol), 3Aa was obtained with sim-
ilar yield and complete diastereoselectivity (compare en-
tries 1 and 2, Table 1). Next, we investigated the scope of
this reaction with different arylsulfonylalkynes (2a–i) and
different sulfoxides (1A–E; Table 1). The reaction was suc-
cessful for electrophiles containing electron-donating (p-
MeO, p-Me, Table 1, entries 3 and 4) and electron-withdraw-
ing (p-F, entry 5) groups on the aryl aromatic ring of the
alkyne, including those with ortho substitution (o-Cl,
entry 6). Reactions of acetylenes containing an alkyl chain
were unsuccessful, affording only the starting material
(Table 1, entry 7), likely due to competitive deprotonation
of the propargylic position. This explanation is further sup-
Figure 1. X-ray ORTEP of compound 3Aa.
The main conclusion deduced from these results is that
the alkynylation reaction of b-substituted electrophilic sul-
fone (2) with 2-p-tolylsulfinyl benzylcarbanions derived
from 1 proceeds with complete stereochemical control, thus
providing a new entry for the synthesis of compounds with
enantiomerically pure benzyl propargylic centers.[16] It is
worth noting that the alkyne moiety shows umpolung reac-
tivity; it is usually employed as nucleophile,[9–13] however in
this case it acts as an electrophile.
The stereochemical results obtained in these reactions can
be explained as follows. According to theoretical calcula-
tions,[17] the sulfinylated benzylcarbanion should adopt the
structure B (Scheme 3), stabilized by a hydrogen bond
formed with the aminic nitrogen of the iPr2NH, whose nitro-
gen acts as ligand of the lithium cation. This would result in
the stereoselective deprotonation of compounds 1 (they
mainly adopt the A conformation, because the A’ conforma-
tion is relatively destabilized by steric reasons) with the
LDA used as base, which is previously associated to the sul-
finyl oxygen (Scheme 3). The approach of the electrophile
to the lower face of B (the upper face would be hindered by
the amine) would result in the formation of the diastereoiso-
Table 1. Reactions of the sulfoxides 1A–E with alkynes 2a–i.[a]
Entry
R1
R2
Yield [%] (product)
d.r.[b]
1
2
3
4
5
6
7
8
Me-1A
Me-1A
Me-1A
Me-1A
Me-1A
Me-1A
Me-1A
Me-1A
Me-1A
Et-1B
C6H5-2a
C6H5-2a
64 (3Aa)
60 (3Aa)[c]
57 (3Ab)
63 (3Ac)
49 (3Ad)
72 (3Ae)
>98:2
>98:2
95:5
>98:2
>98:2
>98:2
–
92:8
92:8
>98:2
>98:2
>98:2
>98:2
p-MeOC6H4-2b
p-MeC6H4-2c
p-FC6H4-2d
o-ClC6H4-2e
Et-2 f
tBu-2h
TIPS-2i
C6H5-2a
C6H5-2a
[d]
–
60 (3Ah)
9
84
52 (3Ba)
65(3Ca)
(3Ai)
10
11
12
13
nBu-1C
allyl-1D
benzyl-1E
ACHTUNGTRENNUNG
C6H5-2a
C6H5-2a
58 (3 Da)
68 (3Ea)
[a] All reactions were performed on a 0.4 mmol scale. [b] Diastereomeric
ratio determined by 1H NMR spectroscopy. [c] Reaction carried out at
2.0 mmol scale. [d] Recovered starting material.
&
2
&
www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Stereoselective Synthesis of Tertiary Propargylic Centers
COMMUNICATION
achieved when the reaction was performed on higher scales
(starting from 1.15 mmol of 3Aa, Table 2, entry 2). Other al-
kynyl derivatives 3 exhibit a similar behavior under these
conditions, to afford 4 in good yields and stereoselectivities
(Table 2). In most cases, the diastereomeric ratio was higher
than 90:10, even in cases with alkyl groups different to Me
at the benzylic position (entries 9–12). It is worth noting
that the negative influence exerted by steric effects, which
decreases the reactivity of the substrates with bulkiest
groups (a lower conversion was shown for 3Ah (Table 2,
entry 7) and no reaction for 3Ai (entry 8)) and the stereose-
lectivity (entry 7). Strong EDG, such as OMe (Table 2,
entry 3), also decrease the stereoselectivity.
Finally, we carried out a one-pot procedure for the direct
preparation of allenes 4 from 2-p-tolylsulfinyl benzylcarban-
ions derived from 1 (Scheme 4), avoiding isolation of the
alkyne intermediates. Treatment of 1A and 1D with LDA
(2.4 equiv) at À988C in the presence of 2a, followed by ad-
dition of H2O at the same temperature afforded the allenes
4Aa and 4Da, respectively, in good yields and diastereo-
meric ratios. Similar results were obtained by reaction of
1A with 2c, yielding 4Ac. In all these cases, the stereoselec-
tivity was identical to that obtained in Table 2 and the yields
clearly higher than those obtained in two steps from
1 (Tables 1 and 2).
Scheme 3. Stereochemical proposal for explaining alkynylation reactions.
mers 3, with R configuration at the benzylic carbon. In case
that deprotonation was not highly stereoselective, thus yield-
ing B and B’, their equilibration (with B favored by steric
reasons) could also explain the stereochemical results.[18]
Having obtained compounds 3, we studied their isomeri-
zation to chiral allenes 4 by deprotonation with lithium
bases at the benzyllic position (Table 2). We studied the in-
fluence of the base (NaHDMS, LiHDMS, LDA), tempera-
ture (RT to À988C), and solvent (THF, Et2O, CH2Cl2, tolu-
ene). The best stereochemical results for 3Aa were obtained
by using LDA as the base in THF at À988C, and H2O as the
proton source (see the Supporting Information for screening
details, Table S-2). Under these conditions, optically en-
riched allene 4Aa was obtained in good yield (71%) and
d.r.=95:5 (entry 1, Table 2). Almost identical results were
Scheme 4. One-pot synthesis of allenes 4.
Table 2. Isomerization of alkynes 3 into allenes 4.[a]
These results indicate that the regioselectivity of the pro-
tonation seems to be completely dependent on the reaction
conditions. According to our previous DFT calculations,[17]
ortho-sulfinylated benzyl carbanions are strongly stabilized
by forming a hydrogen bond with iPr2NH after the abstrac-
tion of the proton (Scheme 4). Starting from compounds 3,
and taking into account the lower size of the alkynyl group
with respect to R1, the presumably most stable structure of
the benzylic carbanion is C (Scheme 5). Due to conjugation,
propargylic carbanions are species with two basic centers,
Ent
R1/R2-Starting Material
Yield [%] (product)
d.r.[b]
95:5
95:5
81:19
90:10
93:7
>98:2
75:25
n.r.[e]
94:6
1
2
3
4
5
6
7
8
Me/C6H5-3Aa
Me/C6H5-3Aa
71 (4Aa)
67 (4Aa)[c]
70 (4Ab)
75 (4Ac)
83 (4Ad)
72 (4Ae)
45 (4Ah)[d]
–
48 (4Ba)
58 (4Ca)
69 (4Da)
77 (4Ea)
Me/p-MeOC6H5-3Ab
Me/p-MeC6H5-3Ac
Me/p-FC6H5-3Ad
Me/o-ClC6H5-3Ae
Me/tBu-3Ah
Me/TIPS-3Ai
Et/C6H5-3Ba
nBu/C6H5-3Ca
allyl/C6H5-3Da
benzyl/C6H5-3Ea
the propargylic CACTHNUTRGNEUNG
(sp3) and the alkynylic Cb(sp), which are
both susceptible to protonation. To explain the formation of
the alkynyl derivatives with NH4Cl (indicating protonation
9
10
11
12
95:5
90:10
95:5
is taking place on the propargylic CACTHNUTRGNEUNG
(sp3)), we postulate that
this acid protonates the nitrogen of the amine, which indi-
rectly produces the protonation at propargylic carbon with
complete retention of the configuration of the carbanion[19]
(Scheme 5). This is supported by the results obtained with
ND4Cl, which did not produce deuterated alkynes. The
lower acidity of the water makes difficult the protonation at
[a] All reactions were performed on a 0.12 mmol scale starting from sulf-
oxides with the indicated diastereoselectivity in Table 1. [b] Diastereo-
meric ratio determined by 1H NMR spectroscopy. [c] Reaction carried
out at 1.15 mmol scale. [d] Conversion measured by H NMR spectrosco-
py because this compound was unstable under flash chromatography.
1
[e] n.r.=No reaction.
Chem. Eur. J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

J. L. Garcꢁa Ruano, J. Alemꢂn et al.
In conclusion, we have pre-
sented a new conceptually dif-
ferent approach for the synthe-
sis of enantiomerically enriched
propargylic centers, involving
the incorporation of alkynyl
moieties into electrophilic re-
agents. Our method involves
the reaction of ortho-sulfinylat-
ed benzyllithiums with b-substi-
tuted sulfonylacetylenes. In ad-
dition, the obtained propargylic
substrates can be stereospecifi-
cally isomerized into allenes,
due to the chemical and config-
urational stabilization exerted
by the sulfinyl group on the
propargylic benzylcarbanion.
Scheme 5. Tentative mechanism for the formation of allenes 4.
the nitrogen,[20] and the reaction course is different. In this
case, the incorporation of the proton must take place at the
favored Cb, thus affording allenes. The high stereoselectivity
observed in this reaction must be explained taking into ac-
count the desymmetrization of the two p bonds forming the
triple bond produced by the conjugation with the carbanion.
Only the p bond adopting a parallel orientation with respect
to the orbital containing the lone electron pair (which has
a defined orientation) will be electron-rich and therefore
susceptible to protonation. The favored approach of the
H2O will take place to the lower face, thus avoiding steric
interactions with the amine blocking the upper face, result-
ing in the stereoselective formation of allenes 4 with the
configuration (aR). This explanation is also supported by
the incorporation of deuterium to C3 observed when D2O is
used as reagent. This fact, as well as the high stereoselectiv-
ity observed, would be difficult to explain by assuming the
formation of a free carbanion. The different protonation site
for H2O (Cb at triple bond) and NH4Cl (propargylic carbon)
would also explain that the large size of the substituents at
triple bond, like tBu and TIPS, only affects negatively the
reactivity of the process yielding allenes (entries 7 and 8,
Table 2).[21]
Removal of the sulfinyl group of compounds 3 and 4 can
be easily performed by reaction of these substrates with
tBuLi (Scheme 6) without erosion in the optical purity of
the resulting alkynes and allenes. Allenes 5Aa and 5Ca
were obtained in almost quantitative yields from 4Aa and
4Ca, respectively, whereas alkynes 6Aa and 6Ba resulted in
reactions from 3Aa and 3Ba, respectively (Scheme 6). The
absolute configuration (SS, aR) of 4Ca was established by
chemical correlation and comparison of optical rotation of
5Ca, which is a compound of known configuration[22] (see
the Supporting Information for more details). This assign-
ment was then extended to all the allene derivatives 4.
Scheme 6. Desulfinylation reactions of allenes (4) and alkynes (3).
Acknowledgements
Financial support from the Spanish Government (CTQ-2009-12168) and
CAM (“programa AVANCAT CS2009/PPQ-1634”) is gratefully acknowl-
edged. J.A. thanks the MICINN for “Ramon y Cajal” contracts, C.A.
thanks the “Consejo Nacional de Ciencia y Tecnologꢁa de Mꢅxico” for
a postdoctoral fellowship and L.M. thanks the Ministerio de Educaciꢃn y
Ciencia for a predoctoral fellowship.
Keywords: allenes
· anti-michael addition · propargylic
centers · sulfonylacetylenes · sulfoxides
[1] a) B. S. Burton, H. Von Pechman, Ber. Dtsch. Chem. Ges. 1887, 20,
145; b) The Chemistry of Ketenes, allenes and related compounds,
(Ed.: I. Patai), Wiley, New York, 1980; c) The chemistry of allenes
(Ed.: S. R. Landor), Academic Press, London, 1984; d) A. Hoff-
mann-Rçder, N. Krause, Angew. Chem. 2004, 116, 1216; Angew.
Chem. Int. Ed. 2004, 43, 1196; e) S. Ma, Chem. Rev. 2005, 105, 2829;
f) Special Volume in Cumulenes and Allenes, Vol. 44 (Eds.: N.
Krause), Houben-Weyl-Georg Thieme Verlag KG, Stuttgart, 2008;
g) For recent reviews, see: S. Yu, S. Ma, Chem. Commun. 2011, 47,
5384; h) B. Alcaide, P. Almendros, T. M. del Campo, E. Soriano, J.
Marco-Contelles, Top. Curr. Chem. 2011, 302. Computational mech-
&
4
&
www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Stereoselective Synthesis of Tertiary Propargylic Centers
COMMUNICATION
anisms of Au- and Pt-catalyzed reactions: i) N. Krause, C. Winter,
Chem. Rev. 2011, 111, 1994; j) F. Lꢃpez, J. L. Mascarenas, Chem.
Eur. J. 2011, 17, 418; k) S. Yu, S. Ma, Angew. Chem. Int. Ed. 2012,
51, 3074; l) N. Krause, Nachr. Chem. 2012, 60, 118; m) Q.-Y. Zhao,
Z. Lian, Y. Wei, M. Shi, Chem. Commun. 2012, 48, 1724.
shi, Org. Lett. 2009, 11, 3222; f) T. Nishimura, T. Sawano, K. Ou, T.
Hayashi, Chem. Commun. 2011, 47, 10142.
[10] T. Nishimura, T. Sawano, T. Hayashi, Angew. Chem. 2009, 121, 8201;
Angew. Chem. Int. Ed. 2009, 48, 8057.
[11] T. Nishimura, T. Sawano, S. Tokuji, T. Hayashi, Chem. Commun.
2010, 46, 6837.
[2] a) N. Krause, A. Hoffmann-Rçder, in Modern Allene Chemistry, Ch.
19, Vol. 2: Allenic Natural Product and Pharmaceuticals. (Eds.: N.
Krause, A. S. K. Hashmi), Wiley-VCH, 2004; b) K. M. Brummond,
H. Chen, in Modern Allene Chemistry, Ch. 18, Vol. 2: Allenes in
Natural Product Synthesis (Eds:. N. Krause, A. S. K. Hashmi),
Wiley-VCH, 2004; c) For allenes in b-lactams, see: B. Alcaide, P. Al-
mendros, Chem. Rec. 2011, 11, 311; For recent papers in the synthe-
sis of natural and bioactive products, see, for example: d) M. Shimi-
zu, M. Higashi, Y. Takeda, M. Murai, G. Jiang, Y. Asai, Y. Nakao,
E. Shirakawa, T. Hiyama, Future Med. Chem. 2009, 1, 921; e) K.
Miyashita, H. Maeda, T. Okada, M. Abe, M. Hosokawa, Agro Food
Inustry Hi Tech 2010, 21, 24; f) Y. Zhang, Y. Wu, Org. Biomol.
Chem. 2010, 8, 4744; g) M. Woerly, A. H. Cherney, E. K. Davis,
M. D. Burke, J. Am. Chem. Soc. 2010, 132, 6941; h) Y.-J. Jian, Y.
Wu, Org. Biomol. Chem. 2010, 8, 811; i) T. Kajikawa, S. Okumura,
T. Iwashita, D. Kosumi, H. Hashimoto, S. Katsumura, Org. Lett.
2012, 14, 808.
[3] For a concise chapter in the synthesis of allenes by this synthetic ap-
proach, see: A. S. K. Hashmi, in Modern Allene Chemistry, Ch. 1,
Vol. 1: Synthesis of allenes by Isomerization Reactions (Eds.: N.
Krause, A. S. K. Hashmi), Wiley-VCH, 2004.
[4] The use of chiral auxiliaries has provided a good solution for the
synthesis of optically enriched allenols by isomerization of propar-
gylic alcohols, but only moderate d.r.ꢀs have been achieved. For the
use of carbohydrates as chiral auxiliaries (up to 50% d.r.), see: A.
Hausherr, B. Orschel, S. Scherer, H. U. Reissig, Synthesis 2001, 1377.
Better drꢀs were reported by using a camphor-derived auxiliary, see:
P. E. Harrington, T. Murai, C. Chu, M. A. Tius, J. Am. Chem. Soc.
2002, 124, 10091.
[12] a) T. F. Knçpfel, P. Zarotti, T. Ichikawa, E. M. Carreira, J. Am.
Chem. Soc. 2005, 127, 9682; b) E. Fillion, A. K I. Zorzitto, J. Am.
Chem. Soc. 2009, 131, 14608; c) S. Cui, S. D. Walker, J. C. S. Woo,
C. J. Borths, H. Mukherjee, M. J. Chen, M. M. Faul, J. Am. Chem.
Soc. 2010, 132, 436.
[13] a) R. Yazaki, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2010,
132, 10275; b) R. Yazaki, N. Kumagai, M. Shibasaki, Org. Lett. 2011,
13, 952.
[14] a) J. L. Garcꢁa Ruano, J. Alemꢂn, L. Marzo, C. Alvarado, M. Torto-
sa, S. Dꢁaz-Tendero, S. Fraile, Angew. Chem. Int. Ed. 2012, 51, 2712;
b) J. L. Garcꢁa Ruano, J. Alemꢂn, L. Marzo, C. Alvarado, M. Torto-
sa, S. Dꢁaz-Tendero, S. Fraile, Chem. Eur. J. 2012, 18, 8245.
[15] CCDC-790355ACHTNUTGRNEUNG(3Aa) contains the supplementary crystallographic
data for this paper (also see the Supporting Information for details).
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[16] Other approaches have been used for preparing these compounds.
See: a) J. Caeiro, J. P. Sestelo, L. A. Sarandeses, Chem. Eur. J. 2008,
14, 741; b) A. J. Oelke, J. Sun, G. C. Fu, J. Am. Chem. Soc. 2012,
134, 2966; c) For a review in the preparation of propargylic centers,
see: C.-H. Ding, Chem. Rev. 2011, 111, 1914.
[17] a) Y. Arroyo, A. Meana, M. A. Sanz-Tejedor, I. Alonso, J. L. Gar-
cꢁa Ruano, Chem. Eur. J. 2010, 16, 9874; see also b) J. L. Garcꢁa-
Ruano, J. Alemꢂn, I. Alonso, A. Parra, V. Marcos, J. Aguirre, Chem.
Eur. J. 2007, 13, 6169.
[18] Results obtained in the reaction of the 2-p-tolylsulfinyltoluene 2F
with sulfinylacetylene 2A, in the presence of LDA, were surprising.
We did not observe the formation of the expected alkyne, but a mix-
ture (1:3) of the olefins resulting in the Michael and anti-Michael
additions of the carbanion to the triple bond were observed. On the
other hand, the fact that the “anti-Michael product” did not evolve
into the alkynyl derivative would be explaining by assuming the
quick transformation of the primary olefinic anion into the allenyl
carbanion, stabilized by the sulfinyl group.
[5] a) T. L. Jacobs, D. Dankner, J. Org. Chem. 1957, 22, 1424 (with bru-
cine and quinine combined with Al2O3); b) U. Mçdlhammer, H.
Hopf, Angew. Chem. 1975, 87, 492; Angew. Chem. Int. Ed. Engl.
1975, 14, 501 (with stoichiometric sodium mentholate); c) M. Oku,
S. Arai, K. Katayama, T. Shioiri, Synlett 2000, 493 (with PTC cataly-
sis).
[6] a) Y. Tomida, A. Nagaki, J. Yoshida, J. Am. Chem. Soc. 2011, 133,
3744; the same strategy had been previously used by Hoppe for pre-
paring enantioenriched allenols, see: b) M. Dreller, D. Dyrbusch, D.
Hoppe, Synlett 1991, 397; c) C. Schultz-Fademrecht, B. Wibbeling,
D. Frçhlich, D. Hoppe, Org. Lett. 2001, 3, 1221.
[7] For a general reference see: a) J. L. Garcꢁa Ruano, J. Alemꢂn, M. B.
Cid, M. A. Fernandez IbꢂÇez, M. C. Maestro, M. R. Martꢁn, A. M.
Martꢁn Castro, in Organosulfur Chemistry in Asymmetric Synthesis
(Ed.: T. Toru, C. Bolm), Wiley-VCH, 2009, pp. 55–161. For selected
references: for alkyl ortho-sulfinylbenzyl carbanions see: b) J. L.
Garcꢁa Ruano, J. Alemꢂn, M. T. Aranda, M. J. Arꢅvalo, A. Padwa,
Org. Lett. 2005, 7, 19; c) S. Fustero, M. Sꢂnchez-Rosellꢃ, C. Bꢂez, C.
del Pozo, J. L. Garcꢁa Ruano, J. Alemꢂn, L. Marzo, A. Parra, Amino
Acids 2011, 41, 559; d) J. L. Garcꢁa Ruano, C. Schopping, C. Alvara-
do, J. Alemꢂn, Chem. Eur. J. 2010, 16, 8968; For halogenated ortho-
sulfinylbenzyl carbanions see: e) J. L. Garcꢁa Ruano, A. Parra, I.
Alonso, S. Fustero, C. del Pozo, Y. Arroyo, M. A. Sanz-Tejedor,
Chem. Eur. J. 2011, 17, 6142.
[19] This proposal is also in agreement with the fact that all the trials to
epimerize the benzylic center of enantiomerically pure 3Aa have
been unsuccessful because the processes of deprotonation and pro-
tonation are both stereoselective, obtaining, in all cases, the original
configuration.
[20] Additionally, the retention of configuration at the benzylic center
observed in the transformation (see Scheme 5) supports that proto-
nation takes place on the nitrogen atom.
[8] Only good selectivities can be achieved by using an strong EWG,
see: a) H. Liu, D. Leow, K. Huang, C. Tan, J. Am. Chem. Soc. 2009,
131, 7217; b) T. Inokuma, M. Furukawa, T. Uno, Y. Suzuki, K. Yosh-
ida, Y. Yano, K. Matsuzaki, Y. Takemoto, Chem. Eur. J. 2011, 17,
10470.
[9] a) J. M. Chong, L. Shen, N. J. Talyor, J. Am. Chem. Soc. 2000, 122,
1822; b) T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2005, 127, 3244;
c) O. V. larionov, E. J. Corey, Org. Lett. 2010, 12, 300; d) M. Tissot,
A. Pꢅrez-Hernꢂndez, D. Mꢆller, M. Mauduit, A. Alexakis, Org.
Lett. 2011, 13, 1524; e) T. Nishimura, S. Tokuji, T. Sawano, T. Haya-
[21] The lower stereoselectivity observed in the reaction of the tBu
alkyne (entry 7, Table 2) could be attributed to steric effects, which
could difficult the stabilization of the anion by association. This
effect, but to a lesser extent, is also observed in the alkyne forma-
tion (entries 8 and 9, Table 1) in which the stereoselectivity control
is not complete for substrates 2h and 2i (d.r. 92:8).
[22] A. Jansen, N. Krause, Inorg. Chim. Acta 2006, 359, 1761.
Received: May 8, 2012
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

J. L. Garcꢁa Ruano, J. Alemꢂn et al.
Synthetic Methods
J. L. Garcꢀa Ruano,* L. Marzo,
V. Marcos, C. Alvarado,
J. Alemꢁn* .................... &&&& — &&&&
Highly Stereoselective Synthesis of
Tertiary Propargylic Centers and Their
Isomerization to Enantiomerically
Enriched Allenes
Center of attention: A new approach
for the synthesis of enantiomerically
enriched allenes by isomerization of 2-
p-tolylsulfinylphenyl propargylic deriv-
atives is presented, which in turn are
prepared by reaction of sulfinylated
lithium benzylcarbanions with arylsul-
fonylacetylenes (see scheme). The high
control of stereoselectivity in both
steps is exerted by the sulfinyl group.
&
6
&
www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!