SN2-Selective allylic substitution of chiral γ-aryl substituted allylic picolinates with alkynylcopper reagents

Article abstract of DOI:10.1016/j.tetlet.2010.08.051

Substitution of γ-aryl secondary allylic picolinates with alkynyl copper reagents was studied. The copper reagent, prepared from TMSCCMgBr and CuBr·Me₂S in 2:1, was subjected to substitution of the picolinate derived from (E)-3-phenyl-1-methyl-2-propenyl alcohol at 0 °C for 1 h in THF to produce a mixture of α-and γ-products and the alcohol in 67:20:13, while the reagent in 3 or 4:1 ratio gave the α-product with 90-91% selectivity. On the contrary, reaction in CH₂Cl ₂-THF (6-8:1) at 0 °C for 1 h furnished the α-product with 99% regioselectivity. The effect of CH₂Cl₂ was also demonstrated with eight more examples. Furthermore, 99% inversion was determined by transformation to the literature compound and by chiral HPLC.

Full text of DOI:10.1016/j.tetlet.2010.08.051

Tetrahedron Letters 51 (2010) 5592–5595
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
SN2-Selective allylic substitution of chiral c-aryl substituted allylic
picolinates with alkynylcopper reagents
⇑
Qian Wang, Yuichi Kobayashi
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2010
Revised 11 August 2010
Accepted 18 August 2010
Available online 21 August 2010
Substitution of c-aryl secondary allylic picolinates with alkynyl copper reagents was studied. The copper
reagent, prepared from TMSC„CMgBr and CuBrꢀMe2S in 2:1, was subjected to substitution of the picoli-
nate derived from (E)-3-phenyl-1-methyl-2-propenyl alcohol at 0 °C for 1 h in THF to produce a mixture
of
a- and c-products and the alcohol in 67:20:13, while the reagent in 3 or 4:1 ratio gave the a-product
with 90–91% selectivity. On the contrary, reaction in CH2Cl2–THF (6–8:1) at 0 °C for 1 h furnished the
a
-
product with 99% regioselectivity. The effect of CH2Cl2 was also demonstrated with eight more examples.
Furthermore, 99% inversion was determined by transformation to the literature compound and by chiral
HPLC.
Keywords:
Allylic substitution
Picolinate
Ó 2010 Elsevier Ltd. All rights reserved.
Acetylene
Solvent effect
CH2Cl2
c
-Aryl secondary allylic esters have been substrates for allylic
the regio- and product-selectivities we have examined were some-
what lower than those for the -alkyl allylic picolinates. Fortunately,
we found that several solvents increase the regioselectivity and
substitution because the conjugation between the aryl and the
allylic olefin moieties gives an opportunity to study the influence
of the conjugation on the regio- and stereoselectivities.1 In the
substitution using alkyl and aryl copper reagents, either of the
c
stereoselectivity to high levels. Herein, we report these findings.
previous work
a
and c
carbons has been subjected to the reaction,2,3 and the inver-
R3
OCO-Py
R3MgBr
sion is the major stereochemical course for the reaction at the
a car-
R1
R1
R2
bon,4 though the stereoselectivity has been varied depending on the
organocopper species, steric factor, and other reaction conditions.
Quite recently, the selectivity with alkyl copper reagents was
improved by us to high levels.5
ð1Þ
R2
Cu Br2·Me2S
γ
1
2 (γ-product)
R3 = alkyl, alkenyl, aryl, heteroaryl, alkynyl
Recently, we have established substitution of secondary c-alkyl
R2
present work
allylic esters with organocopper reagents using picolinates as allylic
esters to furnish anti SN2’ products with high levels of regio- and
stereoselectivities (the latter being assessed by chirality transfer)6
(Eq. (1)).7 The method is compatible with a wide variety of alkyl,
alkenyl, aryl, and heteroaryl copper reagents. Furthermore, we suc-
ceeded in picolinate-allylation with alkynyl copper reagents,8 which
are probably among the least nucleophilic reagents on the basis of
the reactivity for 1,4-addition to conjugated enones. Apparently,
the high potency of the picolinoxy group as the leaving group com-
pensates the low nucleophilicity of the alkynyl reagents. With these
R2
MgBr (4)
γ
OCO-Py
ð2Þ
Ar
R1
Ar
R1
α
Cu Br2·Me2S
3
5 (α-product)
In relation to the present investigation, Chen and Deng dis-
closed a nickel-catalyzed substitution of a -aryl secondary allylic
carbonate with alkynyl borates to produce the
-products.9 De-
spite the high regioselectivity, chiral induction of the reaction with
a chiral nickel catalyst was 13% ee, whereas stereoselectivity using
any optically active carbonate was not investigated.
Initially, two types of copper reagents with the established
compositions were investigated. In brief, magnesium reagent 4A
(R2 = TMS), freshly prepared from TMSC„CH and i-PrMgBr in
THF (rt, 2 h), was added to an ice-cold suspension of CuBrꢀMe2S
in THF in a 1:1 ratio of 4A/Cu, and the mixture was stirred at
c
a
findings in mind, we focused our attention to substitution of
c-aryl
allylic picolinates with alkynyl copper reagents (Eq. (2)). Although
a
regioselectionand inversion of thestereochemistryatthe acarbon
were expected on the basis of the results by us5 and other groups,4
⇑
Corresponding author. Tel./fax: +81 45 924 5789.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.051

Q. Wang, Y. Kobayashi / Tetrahedron Letters 51 (2010) 5592–5595
5593
0 °C for 30 min to produce TMSC„CCuꢀMgBr2, which was sub-
jected to reaction of 3A at 0 °C in THF. The reaction was completed
(Ar = p-FC6H4) furnished 5d regioselectively (entry 5). Alkynyl cop-
per reagent with the p-MeC6H5 group, which was prepared from
4B and CuBrꢀMe2 as a typical example of substituted acetylenes,
afforded 5e, 5f, and 5g in reactions with 3A, 3B, and 3C, respectively
(entries7–9). The efficiency for the reaction of 3A in CH2Cl2–THFwas
higher than that observed in THF (entry 6). High regioselectivities
were also found in entries 10 and 11. Thus, we attained high levels
of regio- and product-selectivity with the copper reagents derived
from R2C„CMgBr (4) and CuBrꢀMe2S in the 3–4:1 ratios in
CH2Cl2–THF. Furthermore, these results indicate that the selectivity
is irrespective of the electronic nature of Ar in the picolinates and of
R2 in the alkynyl reagents.
For the determination of stereoselectivity and the stereochem-
ical outcome of the reaction, (R)-3A, -3B, and -3D were synthesized
from alcohol 7 (99% ee) as shown in Scheme 1.13 In brief, the Sono-
gashira coupling of 7 with PhI under the standard conditions gave
8 in good yield. The acetylene part of 8 was reduced to trans olefin
and the hydroxyl group was esterified with Py-CO2H using DCC to
afford (R)-3A in 68% yield from 7. Enantiomeric excess (ee) of (R)-
3A was 99% by chiral HPLC analysis (Chiralcel OD-H, hexane/i-
PrOH = 96:4, 0.3 mL/min, rt, tR/min = 65.7 (R-isomer), 72.9 (S-iso-
mer)). Similarly, alcohol 7 was converted to (R)-3B (87% ee) and
(R)-3D (92% ee).
within 1 h, but afforded a mixture of
a and c products (5a and 6a)
and alcohol (Table 1, entry 1). Next examined was
7
(TMSC„C)2CuMgBrꢀMgBr2, which produced the mixture in a simi-
lar ratio (entry 2). The observed regioselectivity indicates that
regioselection by the Ph group is slightly predominant over the
a
c
selection inherent in the
c-alkyl picolinates. We then studied re-
agents derived from 4A/Cu in other ratios of 3:1 and 4:1, both of
which showed higher
tries 3 and 4).
a regio- and product-selectivities for 5a (en-
Although the improved regio- and product-selectivities are
probably in good levels (entries 3 and 4), we continued investiga-
tion to attain higher selectivity, which was realized by using a
mixed solvent of CH2Cl2 and THF.10,11 Thus, a THF solution of 4A
(3–4 equiv) was added to a suspension of CuBrꢀMe2S (1 equiv) in
CH2Cl2 at 0 °C and, after 30 min, picolinate 3A was added to the
mixture. The reaction in CH2Cl2–THF (6–8:1) was completed with-
in 1 h at 0 °C to afford
a-product 5a with high selectivity and in
85% isolated yield (entry 5). Use of (CH2Cl)2, PhCl, and hexane as
solvents was also effective, giving 5a with high selectivity (entries
6, 9, and 11), whereas the selectivity obtained from the reaction in
EtBr was comparable to that recorded in THF (entry 10 vs entry 3).
Reactions examined in CHCl3 and in CCl4 produced alcohol 7 (en-
tries 7 and 8). Other copper sources such as CuBr and CuCN were
also effective (entries 13 and 15 vs entries 12 and 14). In conclu-
sion, we succeeded in the production of 5a with >96% selectivity
in entries 5, 6, 9, 11, 13, and 15. On the basis of these results and
an additional result12 as well as handling, we decided to apply
the protocol using CuBrꢀMe2S in CH2Cl2–THF to other substrates/
alkynyl copper reagents and the results are described in the next
paragraphs.
Picolinate 3B (Ar = p-MeC6H4) upon reaction with 4A-based
copper reagent (4A/CuBrꢀMe2S = 3:1) in CH2Cl2–THF gave 5b with
higher efficiency in yield and selectivity than that in THF (Table 2,
entry 2 vs entry 1). Picolinate 3C with the long pentyl group
participated in the reaction uneventfully, producing the expected
product 5c efficiently (entry 4 vs entry 3). Similarly, picolinate 3D
Substitution of (R)-3A with the 4A-based copper reagent in
CH2Cl2–THF was repeated to elucidate 99% inversion (inv.) on the
basis of the observed ee of (R)-3A and (S)-5a (Scheme 2), whereas
the (S) configuration was determined unambiguously by compar-
ing the specific rotation of the derived hydrocarbon 11 (Scheme
3)14 with that reported,15 thus indicating the inversion mode of
reaction at the
a carbon. For the other products shown in Scheme
2 the same (S) configuration was assigned by analogy. Reaction of
(R)-3A with 4B delivered (S)-5e with 99% inv. In contrast, reaction
of (R)-3B and copper reagents 4A–C furnished (S)-5b, -5f, and -5h,
respectively, but with varying % inv. On the other hand, (R)-3D was
a good substrate for reaction with 4A and 4C producing (S)-5d and
-5i, respectively, with high % inv. These results indicate that (1)
TMS acetylenic copper is an excellent reagent for attaining high
regio- and stereoselectivity; (2) electron-donating Ar group tends
Table 1
Optimization of reaction conditions for the reaction shown belowa
TMS
TMS
TMS
CuBr2·Me2S
MgBr (4A)
OH
OCO-Py
+
+
Ph
Ph
Ph
Ph
solvent
0 ºC, 1 h
3A
5a
6a
7
Entry
Solvent
Equiv of 2a
Cu salt (equiv)
5a:6a:7:3Ab
Yield of 5a + 6ac
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
THF
THF
THF
THF
CH2Cl2–THF
(CH2Cl)2–THF
CHCl3–THF
CCl4–THF
PhCl–THF
EtBr–THF
Hexane–THF
THF
2
2
3
4
3
3
3
3
3
3
3
3
3
3
3
CuBrꢀMe2S (2)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBrꢀMe2S (1)
CuBr (1)
63:16:21:0
67:20:13:0
90:4:6:0
91:4:5:0
99:1:0:0
99:1:0:0
0:0:100:0
0:0:100:0
98:1:1:0
90:2:8:0
96:2:2:0
69:3:23:5
99:1:0:0
63:2:30:5
97:3:0:0
nd
nd
85
84
85
84
d
—
—
d
86
80
82
nd
84
nd
86
CH2Cl2–THF
THF
CH2Cl2–THF
CuBr (1)
CuCN (1)
CuCN (1)
a
b
c
Reactions were carried out at 0 °C for 1 h in THF or in a mixed solvent with THF.
Determined by 1H NMR spectroscopy.
nd: not determined.
d
Unidentified products were coproduced.

5594
Q. Wang, Y. Kobayashi / Tetrahedron Letters 51 (2010) 5592–5595
Table 2
Generality of the reactiona
Entry
Picolinate
Alkynyl-MgBr
Solvent
Major product
5:6:alcoholb
Yield of 5 + 6
1
2
3
4
5
6
7
8
9
3B
3B
3C
3C
3D
3A
3A
3B
3C
3B
3D
4A
4A
4A
4A
4A
4B
4B
4B
4B
4C
4C
THF
CH2Cl2–THF
THF
5b
5b
5c
5c
5d
5e
5e
5f
91:9:0
97:3:0
90:4:6
99:1:0
96:4:0
94:2:4
97:3:0
92:8:0
94:4:2
90:4:6
91:4:5
82
87
85
94
94
80
84
86
91
82
82
CH2Cl2–THF
CH2Cl2–THF
THF
CH2Cl2–THF
CH2Cl2–THF
CH2Cl2–THF
CH2Cl2–THF
CH2Cl2–THF
5g
5h
5i
10
11
a
Reactions were carried out with copper reagents derived from 4A, 4B, or 4C (3–4 equiv) and CuBrꢀMe2S (1 equiv) at 0 °C for 1 h in CH2Cl2–
THF or in THF.
b
Determined by 1H NMR spectroscopy.
OH
OH
ArI (1.3 equiv), t-BuNH2 (10 equiv)
R2
CuI (cat.), Pd(PPh3)4 (cat.)
rt, 14 h
Ar
8, Ar = Ph
9, Ar = p-MeC6H4
10, Ar = p-FC6H4
R2
MgBr
(4A, 4B)
7
(R)-3A
Ph
Cu Br2·Me2S
OCO-Py
1) LiAlH4, THF
(S)-5a, R2 = TMS
Ar
99% inv. (99% inv.)
2) Py-CO2H, DCC
DMAP, CH2Cl2
(R)-3A, Ar = Ph,
(S)-5e, R2 = p-MeC6H4
99% ee, 68% yield
(R)-3B, Ar = p-MeC6H4
87% ee, 85% yield
99% inv.
R2
(R)-3D, Ar = p-FC6H4
92% ee, 85% yield
4A, 4B, 4C
(R)-3B
Scheme 1. Synthesis of optically active picolinates.
Cu Br2·Me2S
p-MeC6H4
(S)-5b, R2 = TMS
to lower the stereoselectivity;16 (3) electron-withdrawing Ar group
does not affect the inversion.
97% inv. (91% inv.)
(S)-5f, R2 = p-MeC6H4
89% inv. (80% inv.)
OCO-Py
(S)-5h, R2 = p-FC6H4
R2
MgBr
85% inv.
Ar
R1
3A, Ar = Ph, R1 = Me
4A, R2 = TMS
R2
3B, Ar = p-MeC6H4, R1 = Me
3C, Ar = Ph, R1 = C5H11
3D, Ar = p-FC6H4, R1 = Me
4B, R2 = p-MeC6H4
4C, R2 = p-FC6H4
4A, 4C
(R)-3D
Cu Br2·Me2S
p-FC6H4
(S)-5d, R2 = TMS
R2
R2
99% inv.
(S)-5i, R2 = p-FC6H4
96% inv.
R1
Ar
R1
Ar
Scheme 2. Chirality transfer of the reaction and the supposed absolute configu-
ration. % Inv. = % inversion. Inv. shown in parenthesis was determined in THF.
6
5
b, Ar = p-MeC6H4, R1 = Me, R2 = TMS
c, Ar = Ph, R1 = C5H11, R2 = TMS
for 5 and 6:
d, Ar = p-FC6H4, R1 = Me, R2 = TMS
e, Ar = Ph, R1 = Me, R2 = p-MeC6H4
f, Ar = p-MeC6H4, R1 = Me, R2 = p-MeC6H4
g, Ar = Ph, R1 = C5H11, R2 = p-MeC6H4
h, Ar = p-MeC6H4, R1 = Me, R2 = p-FC6H4
i, Ar = p-FC6H4, R1 = Me, R2 = p-FC6H4
TMS
1) Bu4NF, AcOH
Ph
Ph
2) H2, RhCl(PPh3)3 (cat.)
3) H2, Pd/C
(S)-5a
11
c 0.24, heptane)
[α]24D —13 (
[α]20D +15.4 (c 0.05, heptane)
for the (S)-isomer
In conclusion, we have described the unusual effect of CH2Cl2 on
the regio- and stereoselectivities for substitution of -aryl allylic
picolinates with alkynyl copper reagents. The reaction proceeded
c
Scheme 3. Transformation of (S)-5a to the enantiomer of the known compound.

Q. Wang, Y. Kobayashi / Tetrahedron Letters 51 (2010) 5592–5595
5595
Kobayashi, Y. Org. Lett. 2009, 11, 1103–1106; (e) Kiyotsuka, Y.; Kobayashi, Y.
Tetrahedron 2010, 66, 676–684.
8. Kiyotsuka, Y.; Kobayashi, Y. J. Org. Chem. 2009, 74, 7489–7495.
9. Chen, H.; Deng, M.-Z. J. Organomet. Chem. 2000, 603, 189–193.
10. The mixed solvent with low concentration of THF might be responsible for
stronger coordination of the picolinoxy group to MgBr2 than that in THF, thus
at the
a carbon exclusively with high inversion, except in a few
cases, thus expanding a scope of allylic substrates for installing
the alkynyl group.17
Acknowledgment
promoting the reaction at the
11. In contrast to the present study,
a
carbon.
selectivity has been increased in CH2Cl2 and
c
toluene: (a) Persson, E. S. M.; Van Klaveren, M.; Grove, D. M.; Bäckvall, J. E.; Van
Koten, G. Chem. Eur. J. 1995, 1, 351–359; (b) Alexakis, A.; Malan, C.; Lea, L.;
Benhaim, C.; Fournioux, X. Synlett 2001, 927–930; (c) Belelie, J. L.; Chong, J. M. J.
Org. Chem. 2002, 67, 3000–3006.
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan.
12. CuX-based reagents (X = Br, CN) gave low selectivity in reactions of other
combination of substrate/reagents.
13. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
8738–8739.
14. Hydrogenation by using 10%Pd/C in solvents such as EtOAc suffered from a
partial racemization.
15. Davis, D. D.; Ansari, G. G. J. Org. Chem. 1970, 35, 4285–4287.
16. The electron-donating methyl substituent in p-MeC6H4 probably assists partial
racemization during the substitution reaction.
References and notes
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Argade, N. P. Synthesis 2005, 2995–3022; (c) Negishi, E.; Liu, F. In Metal-
catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998. Chapter 1.
2. (a) Goering, H. L.; Kantner, S. S. J. Org. Chem. 1981, 46, 2144–2148; (b) Goering,
H. L.; Seitz, E. P., Jr.; Tseng, C. C. J. Org. Chem. 1981, 46, 5304–5308; and
references cited therein.
17. Representative procedure: To an ice-cold suspension of CuBrꢀMe2S (38.6 mg,
0.188 mmol) in THF (1 mL) was added TMSC„CMgBr (1.32 mL, 0.57 M in THF,
0.752 mmol) dropwise. The resulting mixture was stirred at 0 °C for 30 min
and picolinate 3A (99% ee by chiral HPLC, 47.6 mg, 0.188 mmol) in THF (1 mL)
was added dropwise. After 1 h at 0 °C, saturated NH4Cl was added to the
solution and the resulting mixture was extracted with EtOAc three times. The
combined extracts were dried over MgSO4 and concentrated to afford an oil,
which was purified by chromatography on silica gel with hexane/EtOAc to
3. Cf. substitution of
c-aryl primary allylic esters and halides: (a) Okamoto, S.;
Tominaga, S.; Saino, N.; Kase, K.; Shimoda, K. J. Organomet. Chem. 2005, 690,
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6. Defined as ‘(% ee of product/% ee of substrate) ꢁ 100’.
afford
a
-product 5a (35.4 mg, 83%): 1H NMR (300 MHz, CDCl3) d 0.19 (s, 9H),
1.35 (d, J = 7 Hz, 3H), 3.28–3.41 (m, 1H), 6.15 (dd, J = 15, 6 Hz, 1H), 6.60 (d,
J = 15 Hz, 1H), 7.19–7.42 (m, 5H); 13C NMR (75 Hz, CDCl3, APT in parenthesis) d
0.3 (+), 21.8 (+), 30.0 (+), 86.6 (ꢂ), 108.7 (ꢂ), 126.4 (+), 127.4 (+), 128.6 (+),
129.6 (+), 131.0 (+), 137.2 (ꢂ). The stereochemical outcome (98% ee, 99%
inversion) was determined by chiral HPLC analysis: Chiralcel OJ-H, 25 °C,
hexane/i-PrOH = 99.1:0.1, 0.3 mL/min, tR/min = 20.4 (S-isomer, major), 24.2 (R-
isomer, minor).
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2008, 10, 1719–1722; (b) Kiyotsuka, Y.; Kobayashi, Y. Tetrahedron Lett. 2008,
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