Enantioselective organocatalytic asymmetric allylic alkylation. Bis(phenylsulfonyl)methane addition to MBH carbonates

Article abstract of DOI:10.1039/c1ob06308a

The highly enantioselective asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates with bis(phenylsulfonyl)methane is presented. The reaction is simply catalyzed by cinchona alkaloid derivatives affording the final alkylated products in good yields and enantioselectivities. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06308a

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Enantioselective organocatalytic asymmetric allylic alkylation.
Bis(phenylsulfonyl)methane addition to MBH carbonates†
Xavier Companyo´,a Guillem Valero,a Victor Ceban,a Teresa Calvet,b Merce´ Font-Bard´ıa,b Albert Moyano*a and
Ramon Rios*a,c
Received 2nd August 2011, Accepted 13th September 2011
DOI: 10.1039/c1ob06308a
The highly enantioselective asymmetric allylic alkylation
of Morita–Baylis–Hillman carbonates with bis(phenyls-
ulfonyl)methane is presented. The reaction is simply catalyzed
by cinchona alkaloid derivatives affording the final alkylated
products in good yields and enantioselectivities.
In recent years, one of the major goals for organic chemists has
been the synthesis of asymmetric C–C bonds. Allylic substitution
has emerged as one of the most powerful methods for the
enantioselective synthesis of C–C bonds.1
Scheme 1 Pioneering works with MBH derivatives.
In 1977, Trost and co-workers reported the first example of
an enantioselective catalyzed allylic substitution with a stabilized
kinetic resolution of MBH carbonates using different nucleophiles
nucleophile.2 Since then, much study has been carried out on the
was developed by Lu and coworkers.5 Remarkably, in this work,
asymmetric potential of allylic alkylations. One of the outcomes
the authors reported the reaction of an MBH carbonate with
of this research was the development of new methods based
dimethyl malonate. Despite the low enantioselectivity of the
on transition metal catalysts; these methods turned asymmetric
reaction, Lu and co-workers established for the first time, the
allylic alkylation (AAA) into a powerful tool for the synthesis
possibility of using carbon nucleophiles for an organocatalytic
allylic alkylation (Scheme 1, eq. 2).
Two years later, Hiemstra and co-workers reported the syn-
thesis of adjacent quaternary and tertiary stereocenters via the
of asymmetric C–C bonds. Most of these methods use Pd as
the metal catalyst, but transition metals complexes of Ir, Rh,
or Cu have also been used to give excellent results. Despite
these successes, it was not until 2002 that the organocatalytic
organocatalytic allylic alkylation of MBH carbonates using b-
version of this important reaction was developed by Kim and
isocupreidine as catalyst.6 Since these initials reports, several
co-workers, who reported the use of cinchona alkaloid derivatives
research groups have developed similar reactions for synthesizing
for the hydrolysis of Morita–Baylis–Hillman (MBH) acetates with
the C–C bond. For example, Y.-C. Chen and co-workers reported
sodium bicarbonate.3 (Scheme 1, eq. 1) Since then, the allylic
the use of a,a-dicyanoalkenes as a suitable nucleophile for this
alkylation of MBH adducts catalyzed by a metal-free organic
Lewis-base has attracted considerable attention from the organic
reaction, affording the final allylic derivatives in excellent yields
and enantioselectivities.7 Soon after, the same research group
chemistry community.
reported the alkylation of oxindoles8 and the allylic alkylation
Following the pioneering report of Kim, Krische reported in
of MBH carbonates catalyzed by cinchona alkaloid derivatives
2004, that Cl-OMe-BIPHEP promotes the amination of MBH
acetates with phthalimides.4 In the same year, the first dynamic
with very good results.9
However, in all these methods, the added fragment contains new
functional groups. As a result, none of these methods is suitable
aDepartment de Qu´ımica Orga`nica, Universitat de Barcelona, Mart´ı
Franque´s 1-11, 08028 Barcelona, Spain. E-mail: amoyano@
for adding simple aliphatic chains.
i
In recent years, our research group has developed several
methods for the formal alkylation of enals10 and oxazolones11
using bis(phenylsulfone) derivatives as the synthetic equivalent
of an alkyl group, as disulfone moieties can be easily removed
(Scheme 2).12
Based on previous reports and our experience with organo-
catalysis,13 we formulated an easy entry to chiral allyl methyl
derivatives via the nucleophilic addition of bis(phenylsulfonyl)
methane to MBH carbonates.
ub.edu, rios.ramon@icrea.cat; Web: http://www.runam.host22.com;
Tel: +34934021257
bUnitat de Difraccio´ de RX, Centre Cient´ıfic i Tecnolo`gic de la Universitat de
Barcelona (CCiTUB), Universitat de Barcelona, Sole´ i Sabar´ıs 1-3, 08028
Barcelona, Spain
cICREA, Passeig Lluis Companys 23, 08010 Barcelona, Spain
† Electronic supplementary information (ESI) available: NMR data
and HPLC traces. CCDC reference number 844907. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob06308a
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Table 2 Scope of the reactiona,b,c
Scheme 2 Use of sulfones as alkyl equivalent developed in our research
group.
In our preliminary experiments, we investigated the reaction
of MBH carbonate 1a with bis(phenylsulfonyl)methane 2a in the
presence of different organic chiral Brønsted bases. As it is depicted
in Table 1, b-isocupreidine (b-ICPD, entry 1; Table 1) was the most
active catalyst, causing full conversion of the expected product in
14 h but with low enantioselectivity. Cinchona or quinine, did not
give better results in terms of yield or enantioselectivity (entries
2–3; Table 1). On the opposite hand, Sharpless ligands catalyze the
reaction smoothly but with higher enantioselectivities (entries 6–9;
Table 1). Dichloromethane, MTBE, AcOEt or MeOH are suitable
solvents to run the reaction in, but afford the final compound
in lower conversions and/or lower enantioselectivities. Finally,
increasing the concentration of the reactant 1a to 0.5 M, using
(DHQD)2AQN as the catalyst in toluene at room temperature re-
sulted in the best conditions, affording 3a in a 57% conversion and
94% ee after 14 h (entry 16, Table 1). Further screening of different
solvents or additives did not improve the results (see ESI†).
Once we determined the optimum conditions, we proceeded to
study the scope of the reaction in terms of MBH carbonate. The
reaction under the optimized conditions afforded the final allylic
compounds in high to excellent yields and enantioselectivities. The
reaction was found to tolerate halogen atoms on the aromatic
moiety, including 2-Br or 4-F, affording the final compounds
in 83% and 94% yield and 91% and 94% enantioselective ex-
cess, respectively (entries 2 and 3; Table 2). When an electron
Table 1 Conditions screeninga
a In a small flask, 1a–k (1.2 equiv), 2a (1 equiv.) and (DHQD)2AQN (10
mol%) were added in 0.5 mL toluene. b Isolated yield. c Determined by
chiral HPLC. d Using sulfone 2b as nucleophile.
Entry Catalyst
Solvent Conc. Conv. (14 h)b eec
1
2
3
4
5
6
7
8
b-ICPD (I)
Toluene 0.1 M 100%
Toluene 0.1 M 70%
Toluene 0.1 M traces
26%
13%
n.d.
Quinine (II)
donating group (4-MeO) was present on the aromatic moiety,
the reaction produced the compound 3d with 89% yield and
the enantioselectivity increased to 99% (entry 4; Table 2). The
use of naphthyl derivatives afforded the final products with
excellent yields and enantioselectivities. In particular, when 1-
naphthyl derivatives were used, the reaction produced an almost
enantiopure final product (entry 5; Table 2). The reaction tolerated
different substituents on the aryl ring, including Cl, CN, and even
CF3, without any decrease in the yields or enantioselectivities
(entries 7–9; Table 2). We also studied the use of different ester
substituents in order to examine the effect of the bulkiness of the
ester moiety in terms of yield and stereoselectivity. As shown in
Table 2, entries 10 and 11, when the steric hindrance of the ester
moiety increases, a slight decrease in enantioselectivity is observed.
Surprisingly, when cyclic 1,3-benzodithiole-1,1,3,3-tetraoxide 2b,
Cinchonine (II)
(DHQD)2PHAL (IV) Toluene 0.1 M 20%
64%
-65%
95%
-48%
94%
-81%
86%
97%
98%
94%
70%
94%
94%
(DHQ)2PHAL (V)
(DHQD)2AQN (VI)
(DHQ)2AQN (VII)
Toluene 0.1 M 15%
Toluene 0.1 M 36%
Toluene 0.1 M 33%
(DHQD)2PYR (VIII) Toluene 0.1 M 63%
9
(DHQD)2PYR (IX)
(DHQD)2AQN (VI)
(DHQD)2AQN (VI)
(DHQD)2AQN (VI)
(DHQD)2AQN (VI)
(DHQD)2AQN (VI)
(DHQD)2AQN (VI)
(DHQD)2AQN (VI)
Toluene 0.1 M 5%
CH2Cl2 0.1 M 56%
MeOH 0.1 M 10%
TBME 0.1 M 13%
AcOEt 0.1 M 79%
10
11
12
13
14
15
16
DMF
0.1 M 16%
Toluene 0.25 M 37%
Toluene 0.5 M 57%
a In a small flask, 1a (1.2 equiv), 2a (1 equiv.) and catalyst (10 mol%) were
added in 0.5 mL toluene. b Determined by 1H NMR of the crude reaction.
c Determined by chiral HPLC
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which was previously reported by Palomo and co-workers,10d is
used, the reaction produces the final product in higher yields and
lower enantioselectivities (entry12; Table 2).
To perform the synthesis of fluoro methyl derivatives, we
studied the addition of fluoromethylenebissulfone derivatives
to the MBH carbonates. Unfortunately, the addition of fluo-
romethylenebissulfones 4a and 4b15 requires long reaction times
and produces the desired fluoro derivatives in lower yields and
enantioselectivities than the previously reported methylenbissul-
fones. Therefore, a suitable synthetic pathway for the synthesis of
fluoro derivatives would probably require two simple steps, first
addition of bis(phenylsulfonyl)methane to the MBH carbonate
and subsequently fluorination (Scheme 3).
Scheme 5 Derivatization of compound 3m.
The absolute configuration of compound 3a was ascertained
by a single crystal X-ray analysis (Fig. 1).14 The X-ray crystal
structure unambiguously shows that the enantiomer obtained
from the (DHQD)2AQN has the (R) configuration.
Scheme 3 Synthesis of fluoromethyl derivatives.
Next, we decided to study the applicability of the reaction by
derivatization of compounds 3. The reduction of the double bond
was achieved by treatment of compounds 3 with Pd over H2,
affording the hydrogenated compounds in excellent yields and
moderate to good diastereoselectivities (Scheme 4).
Fig. 1 ORTEP diagram for 3a.
To understand the mechanism of the reaction, we performed
several experiments to study the behavior of the starting ma-
terials and the products during the reaction. We checked the
enantioselectivity of the starting material and the final products
at different stages to understand a plausible mechanism pathway.
As shown in Fig. 2, the enantioselectivity of the final compound
is independent of the reaction conversion. This data indicates a
common diastereopure intermediate in the reaction. However, the
starting material increased the enantiopurity with conversion. This
behavior indicates a kinetic resolution of the MBH-carbonate
With this information we suggest the mechanism illustrated in
Scheme 6. First substrate 1a undergoes a conjugate addition,
followed by elimination of the OBoc group leading to the
formation of CO2 and tert-butoxide anion, whichprovides Michael
acceptor A. This step is responsible for the observed kinetic
resolution of the MBH carbonates. Next, the nucleophile attacks
from Re face (the Si face of the MBH adduct is blocked by the
catalyst) the intermediate B to afford the final product.
Scheme 4 Hydrogenation of compounds 3.
Moreover, we have shown the applicability of this reaction to
the synthesis of highly complex structures like 7m by simple cross
metathesis in good yields (Scheme 5).
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4 C.-W. Cho, J.-R. Kong and M. J. Krische, Org. Lett., 2004, 6, 1337–
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5 Y. Du, X. Han and X. Lu, Tetrahedron Lett., 2004, 45, 4967–
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J., 2009, 15, 11095–11099; (b) A. N. Alba, X. Companyo, A. Moyano
and R. Rios, Chem.–Eur. J., 2009, 15, 7035–7038For similar reactions
see also: (c) J. L. Garcia Ruano, V. Marcos and J. Aleman, Chem.
Fig. 2 Kinetic resolution of 1a.16
´
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Vera, M. Oiarbide and C. Palomo, Chem.–Eur. J., 2009, 15, 11954–
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Valero, X. Companyo, A. Moyano and R. Rios, New J. Chem., 2010,
34, 1816–1820.
12 For reviews on the use of sulfones in organocatalysis see: (a) A.
N. R. Alba, X. Companyo and R. Rios, Chem. Soc. Rev., 2010,
39, 2018–2033; (b) M. Nielsen, C. B. Jacobsen, N. Holub, M. W.
Paixao and K. A. Jorgensen, Angew. Chem., Int. Ed., 2010, 49, 2668–
2679.
13 For a non exhaustive list of our previous works in organocatalysis, see:
(a) G. Valero, A.-N. Balaguer, A. Moyano and R. Rios, Tetrahedron
Lett., 2008, 49, 6559–6562; (b) X. Companyo´, G. Valero, L. Crovetto,
A. Moyano and R. Rios, Chem.–Eur. J., 2009, 15, 6564–6568; (c) X.
Companyo´, M. Hejnova´, M. Kamlar, J. Vesely, A. Moyano and R.
Rios, Tetrahedron Lett., 2009, 50, 5021–5024; (d) X. Companyo´, A.-N.
Scheme 6 Proposed SN2¢-SN2¢ mechanism.
Balaguer, F. Ca´rdenas, A. Moyano and R. Rios, Eur. J. Org. Chem.,
2009, 3075–3080; (e) A.-N. R. Alba, X. Companyo´, G. Valero, A.
Moyano and R. Rios, Chem.–Eur. J., 2010, 16, 5354–5361; (f) A.-N.
Balaguer, X. Companyo´, T. Calvet, M. Font-Bard´ıa, A. Moyano and
R. Rios, Eur. J. Org. Chem., 2009, 199–203; (g) G. Valero, A.-N. R.
Alba, X. Companyo´, N. Bravo, A. Moyano and R. Rios, Synlett, 2010,
1883–1908; (h) A.-N. R. Alba, G. Valero, T. Calvet, M. Font-Bardia,
A. Moyano and R. Rios, Chem.–Eur. J., 2010, 16, 9884–9889; (i) X.
Companyo´, A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moyano and R.
Rios, Chem. Commun., 2010, 46, 6953–6955; (j) G. Valero, J. Schimer, I.
Cisarova, J. Vesely, A. Moyano and R. Rios, Tetrahedron Lett., 2009, 50,
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and R. Rios, Eur. J. Org. Chem., 2011, 2053–2056; (l) A. Zea, A.-N. R.
Alba, G. Valero, T. Calbet, M. Font-Bard´ıa, A. Mazzanti, A. Moyano
and R. Rios, Eur. J. Org. Chem., 2011, 1318–1325.
Moreover, we conducted a reaction using only 0.5 equivalents of
2a, affording after column chromatography the unreacted starting
material in 24% yield and 99% ee (Scheme 7).17
Scheme 7 Kinetic resolution of BOC carbonates.
14 CCDC 844907 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
15 For a pioneering report on the use of compound 4b see: (a) T. Furukawa,
Y. Goto, J. Kawazoe, E. Tokunaga, S. Nakamura, Y. Yang, H. Du, A.
Kakehi, M. Shiro and N. Shibata, Angew. Chem., Int. Ed., 2010, 49,
1642–1647; for an exhaustive review on organocatalytic synthesis of
fluorocompounds: G. Valero, X. Companyo´ and R. Rios, Chem.–Eur.
J., 2011, 17, 2018–2037.
Conclusions
To summarize, we have described a practical, inexpensive,
and powerful method as an organocatalytic alternative for
organometallic allylic substitution. We have achieved an asym-
metric bis(phenylsulfonyl)methane addition to MBH carbonates
with excellent yields and enantioselectivities. Moreover, we showed
the broad applicability of this method not only for synthesizing
derivatives but also for removing the bis sulfone moiety to give
access to a formal allylic methylation.18
16 Experimental procedure: In a small vial, 1a (1.2 equiv.), 2a (1 equiv.)
and catalyst VII (0.2 equiv.) were added in toluene. The reaction was
monitored by 1H-NMR and HPLC.
17 The absolute configuration of compound 1a was determined by
chemical correlation with reference 6.
Notes and references
18 During the final writing of this manuscript, several research groups have
reported similar reactions: (a) W. Yang, X. Wei, Y. Pan, R. Lee, B. Zhu,
H. Liu, L. Yan, K.-W. Huang, Z. Jiang and C.-H. Tan, Chem.–Eur. J.,
2011, 17, 8066; (b) L. Jiang, Q. Lei, X. Huang, H.-L. Cui, L. Zhou and
Y.-C. Chen, Chem. Eur. J., 2011, 17, 8066–8070; (c) T. Furukawa, T.
Nishimine, E. Tokunaga, K. Hasegawa, M. Shiro and N. Shibata, Org.
Lett., 2011, 13, 3972–3975.
1 For an excellent review on asymmetric transition metal-catalyzed allylic
alkylations see: B. M. Trost and D. L. Van Vranken, Chem. Rev., 1996,
96, 395–422.
2 B. M. Trost and P. E. Strege, J. Am. Chem. Soc., 1977, 99, 1650–1652.
3 J.-N. Kim, H.-J. Lee and J.-H. Gong, Tetrahedron Lett., 2002, 43, 9141–
9146.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7986–7989 | 7989
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