1,4-Dichloro- and 1,4-dibromo-2-butenes as substrates for Cu-catalyzed asymmetric allylic substitution

Article abstract of DOI:10.1002/anie.200604963

(Chemical Equation Presented) Cu at the AAA meeting: Difunctionalized allylic substrates can undergo Cu-catalyzed asymmetric allylic alkylation (AAA) reactions with high enantioselectivities. The products have a functional group that remains for further t

Full text of DOI:10.1002/anie.200604963

Angewandte
Chemie
DOI: 10.1002/anie.200604963
Asymmetric Catalysis
1,4-Dichloro- and 1,4-Dibromo-2-butenes as Substrates for Cu-
Catalyzed Asymmetric Allylic Substitution**
Caroline A. Falciola and Alexandre Alexakis*
In recent years, the transition-metal-catalyzed asymmetric
nucleophilic transformations and deliver new products with
allylic alkylation (AAA) has become an effective method for
the preservation of the optical purity of the starting material.
We initially investigated the influence of the cis and trans
geometry of the allylic substrate on the stereochemical
outcome of the reaction. Other research groups have reported
that a cis isomer yields a product with significant loss of
enantioselectivity because of steric or other energetically
competitive interactions between the catalyst and the sub-
strate.[10] Two exceptions to this observation were reported by
Okamoto and co-workers[11] in the addition of Grignard
reagents to various allylic silylated ethers using chiral
diaminocarbene catalysts,[12] and by Gennari and co-workers
in the desymmetrization of meso cyclic allylic bisphos-
phates.[13]
[1,2]
À
the formation of enantiomerically enriched C C bonds.
Complementary to the widely studied Pd-catalyzed version,
investigations of the Cu-mediated reaction have shown that,
with the use of hard nucleophiles such as organozinc[3] or
organomagnesium reagents,[4] good to excellent control of
chemo-, regio-, and enantioselectivity is achievable.[5]
Over the past years, our research group has developed the
Cu-catalyzed addition of Grignard reagents promoted by
phosphoramidite chiral ligands to allylic chlorides with
excellent stereocontrol, both on disubstituted derivatives[6,7]
and more recently on trisubstituted substrates.[7]
Table 1 summarizes the comparative results for the
asymmetric addition of cyclohexylmagnesium chloride to
the trans and cis isomers of 1,4-dichloro-2-butene (1 and 2,
Table 1: Addition of cyclohexylmagnesium chloride to trans and cis 1,4-
dichlorobutenes, 1 and 2.
To broaden the scope of our methodology, we sought
simple difunctionalized substrates that would offer the high-
est synthetic versatility. Ideally, such a substrate should be
commercially available at low cost and offer the possibility to
use the resulting product both as an electrophile or as a
potential nucleophile.
We focus herein on difunctionalized allylic substrates, the
1,4-bishalo-2-butenes, which are small, simple, and commer-
cially available. These allylic substrates are known to undergo
clean SN2’ reactions to give racemic products using various
cuprate reagents[8] and under the Cu-catalyzed addition of
Grignard reagents.[9] We anticipated that the enantiomerically
enriched products that result from the asymmetric Cu-
catalyzed g-substitution reaction would provide interesting
chiral synthons because of their remaining tunable function-
alities. Thus, besides the well-known transformations of the
double bond (for example, oxidative cleavage, hydroboration,
metathesis), the residual halide could undergo electrophilic or
Entry[a]
Substr.
L*
Conv.
[%][b]
3a/4a[c]
ee
[%][d]
1
2
3
4
5
6
7
8
9
1
2
1
2
1
2
1
2
1
1
2
1
2
1
2
L1
L2
L3
L4
L5
>99 (98)
87
>99
95
>99
86
>99
86
>99 (89)
>99
92
>99
91
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
75(S)
31(S)
52(R)
8(R)
54(S)
37(S)
38(R)
24(S)
74(R)
77(R)
44(R)
62(R)
39(R)
52(R)
49(S)
10[e]
11
12
13
14
15
L6
L7
[*] C. A. Falciola, Prof. Dr. A. Alexakis
DØpartment de Chimie Organique
UniversitØ de Gen›ve
>99
93
30 quai E. Ansermet, 1211 Gen›ve 4 (Switzerland)
Fax: (+41)22-379-3215
E-mail: alexandre.alexakis@chiorg.unige.ch
[a] Conditions: 1 or 2 (1 mmol), CuTC (1 mol%), L* (1.1 mol%) in
CH2Cl2 (2 mL) at À788C with addition of cHexMgCl in Et2O (1.2 equiv)
over 1 h. [b] Conversion determined by GC-MS (in parentheses: yield of
isolated product after purification by column chromatography on silica
gel). [c] Ratio determined by GC-MS and 1H NMR spectroscopy.
[d] Values of enantiomeric excess (and configuration in parentheses) of
3a determined by GC on a chiral stationary phase. [e] 3 mol% of CuTC
and 3.3 mol% of L*.
[**] The authors thank the Swiss National Research Foundation
(200020-105368) and COST action D24/003/01 (OFES contract
C02.0027) for financial support, as well as BASF for the generous
gift of chiral amines and Solvias for the taniaphos ligand.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
respectively), promoted by a small range of biphenol-[14] and
g adducts regiospecifically and providing compounds 3 to 10
in moderate to high enantioselectivity (Table 2 and 3). It
should be pointed out that we used the commercially available
substrates 1 and 5 directly without prior purification.
binaphtol-based[6b,15] phosphoramidite ligands (Scheme 1).
Table 2: Asymmetric CuTC-catalyzed allylic alkylation of 1 with RMgBr
(Scheme 2, L*=L1–L9).
Entry
Product
L*
Conv
[%][a]
g/a[b]
ee
[%][c]
1
2
6a
6a
7a
7a
7a
8a
8a
8a
9a
9a
L1
L4
L1
ent-L4
L9
L1
ent-L4
L9
L1
ent-L4
>99 (98)
>99
>99 (55)
>99
>99
>99 (80)
>99
35
>99 (88)
>99
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
78(R)
57(S)[18]
85(À)
81(À)
10(+)
85(À)
79(À)
32(+)
85(À)
85(À)
3[d]
4[d]
5[d]
6
7
8
9
10
[a] Conversion determined by GC-MS (in parentheses, yield of isolated
product after purification by column chromatography on silica gel).
[b] Ratio determined by GC-MS and 1H NMR spectroscopy. [c] Values of
enantiomeric excess (and configuration or optical rotation in parenthe-
ses) determined by GC on a chiral stationary phase. [d] 3 mol% of CuTC
and 3.3 mol% of L*.
Scheme 1. Chiral ligands used in the AAA reaction.
The best outcome for the allylic alkylation of cis-2 was
achieved using ligand L7 (1 mol%), in which an ee value of
49% in product (S)-3a was attained (Table 1, entry 15). On
the other hand, when the trans-1 was treated by slow addition
of cyclohexylmagnesium chloride (cHexMgCl, 1.1 equiv) in a
reaction catalyzed by copper(I) thiophene carboxylate
(CuTC, 1 mol%) and chiral ligand L5 (1.1 mol%), the
product (R)-3a was obtained in 89% yield and 74% ee
(Table 1, entry 9). This was later improved to 77% ee by
increasing the catalyst loading of CuTC/L5 to 3 mol%, which
was found to be optimal (Table 1, entry 10). The clear
conclusions of these results are that higher enantioselectiv-
ities are achieved with the trans isomer than with the cis, and
that there is complete regiocontrol towards the g adduct in
both cases (Scheme 2).[16]
Good enantioselectivities of upto 85% ee were achieved
in the allylic substitution of substrate 1 using saturated
primary Grignard reagents and with both ligands L1 and L4,
to give products 7a–9a (Table 2, entries 3, 6, 9, and 10).
Another bidentate ferrocenyl-based ligand, taniaphos L9,[17]
was also tested with allylic substrate 1 and only poor
enantiomeric excesses of 10% and 32% for products 7a
and 8a, respectively, were achieved (Table 2, entries 5 and 8).
The bulkier phenethylmagnesium reagent gave adduct (R)-6a
in the presence of the chiral ligand L1 with 78% ee (Table 2,
entry 1).
Likewise, allylic substitutions were performed on the
corresponding commercially available trans-dibromo sub-
strate 5. According to previous results, addition of cyclo-
hexylmagnesium chloride to the difunctionalized substrate 5
afforded a moderate asymmetric outcome of 63% ee for 3b
with L2 (Table 3, entry 2).[19] We were delighted to observe
that under similar conditions, using a catalyst loading as low
as 1 mol% of CuTC and chiral ligand, chiral homoallylic
bromide adducts with enantioselectivities as high as 92% ee
could be achieved for the addition of the functionalized
Grignard reagent, (4-tert-butoxybutyl)magnesium bromide,
with ent-L4 to provide compound (À)-8b (Table 3, entry 10).
Again, ee values higher than 86% could not be reached using
ligand L9 (Table 3, entry 11). Moreover, the terpenic bromo-
citronellene (À)-9b was obtained with the best selectivity of
this series in 94% ee using a CuTC/L4 loading of 3 mol%
(Table 3, entry 13). Overall, the dibromo substrates gave
similar or better results in terms of their enantioselectivity
than the dichloro derivatives when the two phosphoramidite
ligands L1 and L4 were used.
Scheme 2. Enantioselective CuTC-catalyzed allylic alkylation of 1 and 5
with various Grignard reagents.
Next, to confirm these preliminary results, other Grignard
reagents were added to the trans isomers of the difunction-
alized allylic substrates, trans-1,4-dichloro-2-butene (1) and
trans-1,4-dibromo-2-butene (5, Scheme 2), which afforded the
For the sake of comparison, the AAA reaction was tested
using traditional procedures for the diorganozinc reagents as
shown in Scheme 3.[3,20] Although the reaction was found to
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Table 3: Asymmetric CuTC-catalyzed allylic alkylation of 5 with RMgBr
(Scheme 2, L*=L1–L9).
Entry
Product
L*
Conv. [%][a]
g/a[b]
ee [%][c]
1
3b
3b
3b
6b
6b
6b
7b
7b
8b
8b
8b
9b
9b
10b
10b
L1
L2
ent-L3
L1
L2
ent-L4
L1
ent-L4
L1
ent-L4
L9
L1
88
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
23(S)
63(R)
54(R)
83(À)
76(+)
67(À)
86(À)
87(À)
88(À)
92(À)
86(+)
89(À)
94(À)
85(À)
84(À)
2[d]
3
>99 (99)
>99 (83)
>99 (94)
>99
>99
>99
>99 (80)
>99
>99 (77)
>99
4
5
6
7
8
9
10
11
12[d]
13[d]
14
15
75
ent-L4
L1
ent-L4
93 (70)
>99 (79)
>99
[a–d] See Table 2.
Scheme 5. Electrophilic derivatization of chiral homoallylic bromides.
DMF=N,N-dimethylformamide.
Scheme 3. Asymmetric allylic alkylation of 5 with a dibutylzinc reagent
and a range of Cu catalysts. Tf=trifluoromethanesulfonyl.
of allylmagnesium bromide with no loss of enantioselectivity
(Scheme 4). Previous findings from our research group[6]
showed that product 11 can undergo clean ring-closing
metathesis with no loss in enantiomeric excess.[21] Conversely,
adduct (+)-7b with 80% ee was derivatized through the
addition of benzenethiolate with a good yield of 75% to
afford compound 13, which was further oxidized to give the
chiral sulfone (+)-14 to assess the optical purity of 82% ee.
Similar products were obtained through electrophilic
means when the remaining halide moiety was transformed
into an organometallic species (Scheme 5). The formation of a
Grignard reagent from (+)-3b with 51% ee and subsequent
addition of allyl bromide led to compound 11 with complete
retention of the chiral information. A sample of the organo-
magnesium intermediate was hydrolyzed to give but-3-en-2-
ylcyclohexane (15) and consequently we could assign the
absolute stereochemistry by correlation with previous stud-
ies.[6a,20b,22] It should be mentioned that the racemic bromide
10b has already been transformed into a Grignard reagent
and used for the synthesis of analogues of keto-dipeptides.[9]
An analogous organolithium reagent was prepared from the
corresponding iodide 16 (from a Finkelstein reaction of the
chiral bromide (+)-7b) by treatment with tert-butyllithium at
À788C.[23] This reagent was later treated with diphenyldi-
thiane to afford the sulfane 13, and further chiral sulfone
(+)-14 in 82% ee. The similar treatment of bromide (+)-7b
with tert-butyllithium followed by a dimethylformamide
quench afforded the chiral aldehyde 17 with retention of
the enantiomeric excess.[24]
be regiospecific using these conditions, the reactivity was
much lower, with incomplete conversions after one day, and
the enantioselectivity was found to be much lower than when
using Grignard reagents (Table 3, entries 7 and 8).
To illustrate the synthetic utility of this methodology, the
chiral monohalides were easily derivatized through nucleo-
philic (Scheme 4) or electrophilic (Scheme 5) pathways. The
brominated cyclohexyl adduct, 1-bromobut-3-en-2-ylcyclo-
hexane ((+)-3b) with 51% ee, was transformed into the
hepta-1,6-dien-3-ylcyclohexane (11) in 64% yield by addition
Scheme 4. Nucleophilic derivatization of chiral homoallylic bromides.
HMPA=hexamethyl phosphoramide.
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www.angewandte.org
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Communications
[9] C. Jennings-White, R. G. Almquist, Tetrahedron Lett. 1982, 23,
2533.
[10] a) K. E. Murphy, A. H. Hoveyda, Org. Lett. 2005, 7, 1255; b) B.
Breit, D. Breuninger, Synthesis 2005, 147.
[11] S. Tominaga, Y. Oi, T. Kato, D. K. An, S. Okamoto, Tetrahedron
Lett. 2004, 45, 5585.
[12] A. Alexakis, C. L. Winn, F. Guillen, J. Pytkowicz, S. Roland, P.
Mangeney, Adv. Synth. Catal. 2003, 345, 345.
[13] U. Piarulli, P. Daubos, C. Claverie, M. Roux, C. Gennari, Angew.
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Benhaim, Synlett 2001, 1375; b) A. Alexakis, D. Polet, S. Rosset,
S. March, J. Org. Chem. 2004, 69, 5660.
In conclusion, we have succeeded in demonstrating the
value of this allylic substitution methodology by forming
highly tunable chiral synthons, starting from commercially
available difunctionalized substrates, trans-1,4-bishalo-2-
butenes. Both the dichloro and dibromo allylic substrates
gave good enantioselectivities and excellent regioselectivities.
Values for the enantiomeric excess of 85% and 94%,
respectively for dichloro and dibromo substrates were
obtained as exclusive g adducts in both cases.
Received: December 7, 2006
Published online: March 9, 2007
[15] B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M.
De Vries, Angew. Chem. 1997, 109, 2733; Angew. Chem. Int. Ed.
Engl. 1997, 36, 2620.
[16] The enantioselectivity and the geometry of the olefin were
followed during the addition of the organomagnesium reagent to
the cis-2 substrate, and no isomerization was observed during the
course of the reaction.
[17] F. López, A. W. Van Zijl, A. J. Minnaard, B. L. Feringa, Chem.
Commun. 2006, 409.
[18] The absolute stereochemistry was determined by the optical
rotation of the known alcohol, (S)-2-methyl-4-phenylbutan-1-ol.
Keywords: alkylation · allylic compounds · asymmetric catalysis ·
copper· nucleophilic substitution
.
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[24] Chiral homoallylic chlorides also underwent transformations
with retention of ee value, either through Grignard reaction or
through prior formation of the iodide, although they were less
reactive.
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