Complete regio- and stereoselectivity control in the halohydroxylation of non-activated allenes mediated by a remote sulfinyl group

Full text of DOI:10.1002/anie.200900448

Angewandte
Chemie
DOI: 10.1002/anie.200900448
Asymmetric Synthesis
Complete Regio- and Stereoselectivity Control in the
Halohydroxylation of Non-activated Allenes Mediated by a Remote
Sulfinyl Group**
Josꢀ Luis Garcꢁa Ruano,* Vanesa Marcos, and Josꢀ Alemꢂn*
Dedicated to Professor Josep Font Cierco on the occasion of his 70th birthday
Allenes have recently gained much attention as versatile
building blocks. The allene motif is present in a large number
of medicinal and natural products.[1] One of the most used
methods for the synthesis of optically pure allenes involves
the highly stereoselective addition of organocopper reagents
to optically pure propargylic derivatives.[1] The main limita-
tion of this procedure centers around the availability of the
alcohols used as starting materials. We have recently reported
that reactions of copper/ortho-sulfinyl benzyl carbanions with
racemic propargyl derivatives allow the synthesis of optically
pure g-sulfinyl allenes with central and/or axial chirality.[2]
The influence of the remote sulfinyl group on the stereo-
chemical outcome of these reactions is reflected in the
complete kinetic resolution that it is observed (Scheme 1).
stereoselectivity in allenic system is not an easy task, unless,
a chiral center is directly connected to the reactive double
bond.[5] On the basis of this prior knowledge, we envisioned
that allenes 1 (Scheme 1) could be appropriate substrates for
the remote control of both regio- and stereoselectivity of
reactions taking place on the nonpolarized allenic systems—
the ability of the sulfinyl group to participate in anchimeric
assistant is the controlling factor.[6] The anchimeric assistance
that is provided by a sulfinyl group has been successfully
exploited by Ma et al. in the conversion of allenyl sulfoxides
into allylic alcohols by halohydroxylation.[7] However, the
complete regioselectivity observed in these reactions occur-
red as a consequence of the well-known influence of the
electron-withdrawing group, like sulfinyl, which was directly
bonded to the allene moiety. It is also known that control of
stereoselectivity, which is also complete when starting from
allenes with axial chirality, is exclusively dependent on the
configuration of the chiral axis, regardless of the configuration
at the sulfinyl group. Thus, the synthesis of optically pure
secondary allylic alcohols is only possible when starting from
enantiopure sulfinyl allenes. In turn, these allenes are
obtained from enantiopure propargyllic alcohols; this
approach is not synthetically useful because of the limited
availability of the starting substrates. Herein, we report the
ability of a remote sulfinyl groups to control both the regio-
and stereoselectivity in the halohydroxylation of scarcely
polarized allenes 1. We also highlight several synthetic uses
for the resulting halohydrines, which are used as chiral
synthons.
We first studied the reaction of allene 1a with different
halogen sources (Table 1). The use of bromine as a reagent
afforded a complex mixture of diastereoisomers, regioisom-
ers, and other by-products (Table 1, entries 1 and 2). These
results were improved with NBS, which only gave 2a as a
86:14 mixture of stereoisomers in 84% yield with complete
control of the regioselectivity (Table 1, entry 3).[8] The
addition of LiOAc had a negative influence on the reaction
and gave 2a/3a as a 60:40 mixture of regioisomers (Table 1,
entry 4). The use of either NIS/H2O or NIS in the presence of
LiOAc provided similar results to when NBS was employed
(70–74% de; Table 1, entries 5 and 6). Whereas, the use of I2/
H2O resulted in a completely diastereoselective reaction, and
exclusively afforded one diastereoisomer of 4a in moderate
yield (Table 1, entry 7), which was substantially improved by
addition of LiOAc (Table 1, entry 8). Thus, the treatment of
1a with I2/LiOAc/H2O occurs in a completely regioselective
Scheme 1. Synthesis of optically pure sulfinylated allenes. Tol=p-tolyl,
LDA=lithium diisopropylamide, X=halogen or methanesulfonate
group.
The lack of regioselectivity control is one of the main
problems encountered when trying to functionalize allenes.
Normally, mixtures of regioisomers are obtained unless the
C C C system is polarized by strongly electron-donating[3] or
= =
electron-withdrawing groups.[4] Moreover, control of the
[*] Prof. Dr. J. L. G. Ruano, V. Marcos, Dr. J. Alemꢀn
Departamento de Quꢁmica Orgꢀnica (C-I)
Universidad Autꢂnoma de Madrid
Cantoblanco, 28049-Madrid (Spain)
Fax: (+34)91-497-466
E-mail: joseluis.garcia.ruano@uam.es
jose.aleman@uam.es
[**] Financial support of this work by the Ministerio de Educaciꢂn y
Ciencia (CTQ2006-06741/BQU) is gratefully acknowledged. The
Ministerio de Ciencia e Innovaciꢂn is thanked for a predoctoral
fellowship (V.M.) and a Juan de la Cierva contract (J.A.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900448.
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3155

Communications
group[9] regardless of the nature of the R group (Table 2,
entries 2–5). Bromohydroxylation of allenes 1b,d was also
completely regioselective and highly stereoselectivity, and
with slightly better results than those observed for 1a
(compare Table 2, entries 7–8 with entry 6), and provided
compounds 2 with up to 95:5 d.r. This selectivity indicates that
substituents at C1 have a positive influence on the stereose-
lectivity of the reaction. The yield obtained under the various
reaction conditions shown in Table 2 ranged between 62%
and 95%.
Table 1: Screening of reaction conditions for the addition of halogens to
g-sulfinylallenes.[a]
Entry Electrophile (E+)
2a/3a
4a/5a
Yield [%][b] d.r.[c]
The absolute configuration of the halohydrin derivatives
obtained in these reactions as major or exclusive products,
was unequivocally established by X-ray diffraction studies
4e[10] (see the ORTEP plot in the Supporting Information).
This study also revealed that the configuration at the sulfinyl
group of 4e is R, which is opposite to the configuration of 1e,
thus indicating that halohydroxylation takes place with
inversion of configuration at the sulfur atom. A plausible
mechanism explaining the stereochemical outcome is indi-
cated in Scheme 2. The halonium intermediate I, which is
generated in the first step of these reactions, is attacked by the
oxygen atom of the sulfinyl group, thus providing the cyclic
alkoxysulfonium species II. Intermediate II is then opened by
attack of water on the sulfur atom, thereby inverting its
configuration. To provide additional proof to support the
mechanism proposed in Scheme 2, the reaction of 1a with I2/
MeOH (instead water) also afford iodohydrin 4a as the
exclusive product. This result confirms that it is not the
solvent but is instead the sulfinyl oxygen atom which opens
the iodosulfonium intermediate.[9] According to Ma et al.,[3f]
the ability of the LiOAc to neutralize strong acids could be
responsible for the improved yield and d.r. value when the
reactions are carried out in the presence of I2/H2O (see
Table 1).[11]
[d]
1
2
3
4
5
6
7
8
Br2/H2O
Br2/LiOAc/H2O
NBS/H2O
NBS/LiOAc/H2O
NIS/H2O
NIS/LiOAc/H2O
I2/H2O
–
–
–
–
–
–
–
–
[d]
–
–
>98:2
40:60
84[e]
86:14
n.d.
85:15
87:13
>98:2
>98:2
71[e]
–
–
–
–
>98:2
n.d.
>98:2 70[e]
>98:2 40
>98:2 83
I2/LiOAc/H2O
[a] Reaction conditions: 1a (0.2 mmol), the corresponding electrophile
(0.5 mmol), CH3CN (4.0 mL) and H2O (0.2 mL) at 08C. [b] Yield of
isolated product. [c] Diastereomeric ratio of epimers at the hydroxylated
carbon atom in 2a or 4a. [d] A complex reaction mixture. [e] Combined
yield. NBS=N-bromosuccinimide, n.d.=not determined, NIS=N-
iodosuccinimide.
and stereoselective manner, only yielding 4a in 83% yield
(Table 1, entry 8). In summary, the reaction conditions out-
lined in entries 3 and 8 of Table 1 are the most convenient for
achieving bromohydroxylation and iodohydroxylation of 1a,
respectively.
To investigate the scope of these reactions, we studied the
behavior of 1,1-disubstituted allenes (only having the sulfinyl
group as the chiral element) under the best reaction
conditions (Table 1, entries 3 and 8). The results are shown
in Table 2. Iodohydroxylation of 1b–e gave 4b–e as the only
products, thus indicating that both the stereoselectivity and
regioselectivity are completely controlled by the sulfinyl
Finally, we have also studied the reaction of allenes 1 f and
1g, which have two chiral centers, with I2/H2O. Allene 1 f gave
a 40:60 mixture of regioisomers 4 f (de > 98%) and 5 f,
whereas 1g exhibited similar behavior to that of the
compounds described in Table 1 and only yielded optically
pure 4g (Scheme 3). These results suggest that regiochemis-
try—but not stereochemistry—could be altered by the
presence of substituents at the benzylic position, however,
further studies will be necessary to confirm this assumption.
Table 2: Scope of the halohydroxylation of g-sulfinylallenes.[a]
Entry
Allene
R
X
Product
Yield [%][a]
d.r. [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1a
1b
1d
H
Me
Et
nPent
Ph
H
I
I
I
I
4a
4b
4c
4d
4e
2a
2b
2d
83
80
84
62
75
84[c]
99
95
>98:2
>98:2
>98:2
>98:2
>98:2
88:12
93:7
I
Br
Br
Br
Me
nPent
95:5
[a] Combined yield after chromatographic purification. [b] Determined by
1H NMR spectroscopy. [c] Reaction performed at À108C.
Scheme 2. Stereochemical course for the halohydroxylation of 1a–1e.
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Keywords: allenes · asymmetric synthesis · halohydroxylation ·
.
sulfoxides
[1] a) Modern Allene Chemistry (Eds.: N. Krause, A. S. K. Hashmi),
Wiley-VCH, Weinheim, 2004; b) S. Ma, Chem. Rev. 2005, 105,
2829; c) Cumulenes and Allenes: Synthesis from Other Allenes in
Science of Synthesis, Vol. 44 (Ed.: N. Krause), Georg Thieme
(Houben-Weyl), Stuttgart, 2008.
Scheme 3. Reaction of 1 f and 1g.
[2] J. L. Garcꢀa Ruano, V. Marcos, J. Alemꢁn, Angew. Chem. 2008,
120, 6942; Angew. Chem. Int. Ed. 2008, 47, 6836.
[3] For representative examples with electron-withdrawing groups
(EWG), see: a) K. Natsias, H. Hopf, Tetrahedron Lett. 1982, 23,
3673; b) S. Ma, Q. Wei, H. Wang, Org. Lett. 2000, 2, 3893;
c) chapter 7 of Ref. [1c]; d) for a review, see: S. Ma, Pure Appl.
Chem. 2007, 79, 261; for sulfones as EWG, see: e) H. Zhou, C.
Fu, S. Ma, Tetrahedron 2007, 63, 7612; f) for racemic
sulfoxides, see: Ref. [3b].
The halohydrin derivatives obtained were easily desulfi-
nylated and could be targets of high synthetic potential.[12]
This potential has been illustrated for some compounds (4) in
reactions that yielded allylic and propargylic alcohols, or
Baylis–Hillman products (Scheme 4). Desulfinylation of 4a
[4] For representative examples with electron-donating
groups (EDG), see: a) H. Monenschein, G. Sourkouni-
Argirusi, K. M. Schubothe, T. OꢂHare, A. Kirsching,
Org. Lett. 1999, 1, 2101; b) P. Renaud, F. Beaufils, L.
Feray, K. Schenk, Angew. Chem. 2003, 115, 4362;
Angew. Chem. Int. Ed. 2003, 42, 4230; c) chapter 8 of
Ref. [1c].
[5] For example, see: Z. Gu, Y. Deng, W. Shu, S. Ma, Adv.
Synth. Catal. 2007, 349, 1653.
[6] For examples on the anchimeric assistant of sulfinyl
groups, see: a) J. L. Garcꢀa Ruano, A. M. Castro, J. H.
Rodrꢀguez, Tetrahedron Lett. 1996, 37, 4569; b) J. L.
Garcꢀa Ruano, A. Esteban Gamboa, L. Gonzꢁlez Gu-
tiꢃrrez, A. M. Martꢀn Castro, J. H. Rodrꢀguez Ramos,
F. Yuste, Org. Lett. 2000, 2, 733; c) S. Raghavan, R.
Reddy, K. Tony, C. N. Kumar, A. K. Varma, A. Nangia,
Scheme 4. The use of the iodohydrins as precursors for various synthetic targets.
Ar=2-(p-tolylsulfinyl), DMF=N,N-dimethylformamide, HMDS=1,1,1,3,3,3-hexa-
methyldisilazane, THF=tetrahydrofuran.
J. Org. Chem. 2002, 67, 5838; d) S. Raghavan, C. N.
Kumar, K. A. Tony, K. Reddy, K. R. Kumar, Tetrahe-
dron Lett. 2004, 45, 7231.
[7] S. Ma, H. Ren, Q. Wie, J. Am. Chem. Soc. 2003, 125,
4817.
[8] This result was slightly improved when the reaction was
performed at À108C (12 h; d.r. 88:12) instead of 08C (2 h;
d.r. 86:14).
using tBuLi took place with concomitant deiodination and
afforded alcohol 6. Meanwhile, Raney nickel (Raney-Ni) was
also used to reduce the double bond and gave 7a and 7b with
good yields. Deiodination of 4a was carried out with Bu3SnH
and the allylic alcohol 8 was obtained. The iodine/magnesium
exchange and subsequent treatment with ethyl cyanoacetate
yielded the Baylis–Hillman-type product 9a. This reaction
also efficiently gave the tertiary alcohol 9b, which is not easily
accessible by other methods.[13] In both cases, almost quanti-
tative yields and d.r. values higher than 98:2 were obtained.
Finally, iodohydrins 4 can also be used to access propargylic
alcohols. Thus, dehydrohalogenation of 4a with NaHMDS in
DMF,[14] led to optically pure propargylic alcohol 10[15] in high
yield (95%) and with a diastereomeric ratio up to 98:2.
In conclusion, we have demonstrated that both regiose-
lectivity and stereoselectivity of the halohydroxylation of
non-activated allenes 1a–1g are completely controlled by a
remote sulfinyl group, and thereby takes advantage of its
ability to participate in anchimeric assistance. The resulting
secondary or tertiary allylic alcohols are excellent chiral
targets used for the preparation of optically pure propargylic
alcohols and Baylis–Hillman-type products.
[9] Iodohydroxylation of the sulfone obtained by oxidation of 1a
with iodine in water gave the opposite regioselectivity to 1a. This
outcome can be attributed to inductive effects, which decrease
the electronic density of the double bond next to the sulfony-
lated ring. This behavior suggests a significant role played by the
sulfinyl group of 1a in controlling the regioselectivity.
[10] CCDC 705625 (4e) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[11] The lower yield obtained in reactions with NBS/H2O/LiOAc
(see Table 1) could be attributed to the decomposition of NBS in
the presence of LiOAc. However, we do not have an explanation
for the negative influence of LiOAc on the regioselectivity of
this reaction.
[12] For examples, see: a) R. Ostwald, P.-Y. Chavant, H. Stadtmꢄller,
P. Knochel, J. Org. Chem. 1994, 59, 4143; b) D. Zhang, J. M.
Ready, J. Am. Chem. Soc. 2007, 129, 12088.
[13] For a recent review, see: V. Singh, S. Batra, Tetrahedron 2008, 64,
4511.
[14] R. W. Friesen, C. Vanderwal, J. Org. Chem. 1996, 61, 9103.
[15] For the asymmetric addition of alkynyl derivatives to carbonyl
groups, see: M. Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853.
Received: January 23, 2009
Revised: February 2, 2009
Published online: March 25, 2009
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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