Picolinoxy group, a new leaving group for anti SN2 selective allylic substitution with Aryl Anions Based on Grignard Reagents

Article abstract of DOI:10.1021/ol800300x

The picolinoxy group was found to be an extremely powerful leaving group for allylic substitution with aryl nucleophiles derived from ArMgBr and CuBr?Me₂S. The substitution proceeds with anti S_N2 pathway and with high chirality transfer. The electron-withdrawing effect of the pyridyl group and chelation to MgBr₂ are likely the origin of success. Results suggesting these effects were obtained.

Full text of DOI:10.1021/ol800300x

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1719-1722
Picolinoxy Group, a New Leaving Group
for anti SN2′ Selective Allylic
Substitution with Aryl Anions Based on
Grignard Reagents
Yohei Kiyotsuka, Hukum P. Acharya, Yuji Katayama, Tomonori Hyodo, and
Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
Box B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received February 10, 2008
ABSTRACT
The picolinoxy group was found to be an extremely powerful leaving group for allylic substitution with aryl nucleophiles derived from ArMgBr
and CuBr•Me2S. The substitution proceeds with anti SN2′ pathway and with high chirality transfer. The electron-withdrawing effect of the
pyridyl group and chelation to MgBr2 are likely the origin of success. Results suggesting these effects were obtained.
Copper-promoted allylic substitution of optically enriched
secondary allylic alcohol derivatives with hard nucleo-
philes is a potentially useful method for construction of
an asymmetric C-C bond.1 Since the R and γ positions of
the allylic moiety are susceptible, regio-(R vs γ) and stereose-
lections should be highly controlled. Furthermore, stoichio-
metric use of reagent and low cost for obtaining the leaving
group are desirable. Thus far, good to excellent levels of
the selectivities have been attained with the following leaving
group/reagent systems: C6F5CO2-,2 2,6-F2C6H3CO2- (in one
occasion),2f and o-(Ph)2P(dO)C6H4CO2-(o-DPPB oxide
group)3 with R2Zn/CuCN·2LiCl; (RO)2P(O)O-4 with R2Zn/
CuCN·2LiCl; MsO in γ-mesyloxy-R,ꢀ-unsaturated esters5
with R2Cu(CN)Li2·BF3 or RCu(CN)Li·BF3; o-(Ph)2PC6H4CO2-
(3) (a) Breit, B.; Demel, P.; Studte, C. Angew. Chem., Int. Ed. 2004,
43, 3786–3789. (b) Breit, B.; Demel, P.; Grauer, D.; Studte, C. Chem. Asian
J. 2006, 1, 586–597.
(4) (a) Yanagisawa, A.; Nomura, N.; Noritake, Y.; Yamamoto, H.
Synthesis 1991, 1130–1136. (b) Torneiro, M.; Fall, Y.; Castedo, L.; Mourino,
A. J. Org. Chem. 1997, 62, 6344–6352. (c) Calaza, M. I.; Hupe, E.; Knochel,
P. Org. Lett. 2003, 5, 1059–1061. (d) Piarulli, U.; Daubos, P.; Claverie,
C.; Roux, M.; Gennari, C. Angew. Chem., Int. Ed. 2003, 42, 234–236. (e)
Soorukram, D.; Knochel, P. Org. Lett. 2004, 6, 2409–2411. (f) Belelie,
J. L.; Chong, J. M. J. Org. Chem. 2001, 66, 5552–5555. (g) Whitehead,
A.; McParland, J. P.; Hanson, P. R. Org. Lett. 2006, 8, 5025–5028. (h)
Niida, A.; Tanigaki, H.; Inokuchi, E.; Sasaki, Y.; Oishi, S.; Ohno, H.;
Tamamura, H.; Wang, Z.; Peiper, S. C.; Kitaura, K.; Otaka, A.; Fujii, N. J.
Org. Chem. 2006, 71, 3942–3951.
(1) (a) Negishi, E.; Liu, F. In Metal-Catalyzed Cross-coupling Reactions;
Diederich, F., Stang P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998;
Chapter 1. (b) Negishi, E. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2002; Vol. 1. (c)
Kar, A.; Argade, N. P. Synthesis 2005, 2995–3022. (d) Krause, N.; Gerold,
A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186–204.
(2) (a) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.;
Knochel, P. Org. Lett. 2003, 5, 2111–2114. (b) Calaza, M. I.; Yang, X.;
Soorukram, D.; Knochel, P. Org. Lett. 2004, 6, 529–531. (c) Leuser, H.;
Perrone, S.; Liron, F.; Kneisel, F. F.; Knochel, P. Angew. Chem., Int. Ed.
2005, 44, 4627–4631. (d) Soorukram, D.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 3686–3689. (e) Soorukram, D.; Knochel, P. Org. Lett. 2007,
9, 1021–1023. (f) Perrone, S.; Knochel, P. Org. Lett. 2007, 9, 1041–1044.
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10.1021/ol800300x CCC: $40.75
Published on Web 04/09/2008
2008 American Chemical Society

(o-DPPB group)6 with RMgX/CuBr·Me2S, etc.7 Among these
leaving groups, the o-DPPB group meets the requirement
for the reagent stoichiometry, and thus the stereoselective
synthesis of certain polyketides of deoxy-type and tocopherol
has been concisely attained.8–10 However, the o-DPPB group
is quite expensive, while the other leaving groups generally
require a large quantity of the reagents.
Scheme 1
.
Expected Activations of the Picolinoxy Group in the
Allylic Substitution
It should be noted that these reaction systems have been
developed for alkyl reagents (sp3-C reagents). Unfortunately,
application of the systems to aryl and alkenyl reagents (sp2-C
reagents) has been unsuccessful4b,11 except for certain types
of reactive or sterically biased substrates.2a,f,12–14 The lower
nucleophilicity of the sp2-C reagents is responsible for the
unsuccessful results. Recently, the regioselectivity in the
reaction of a racemic allylic o-DPPB ester with copper
reagents derived from PhMgBr and CH2dC(Me)MgBr was
improved (use of CH2Cl2 in place of Et2O or slow addition),6b
but the scope of substrates to be covered by the improved
conditions and the chirality transfer (C/T, (% ee of product)/
(% ee of substrate) × 100) thereof are uncertain.
describe successful results of this idea with aryl reagents of
an ArMgBr/CuX type.
A phenyl reagent derived from PhMgBr (2 equiv) and
CuBr·Me2S (1 equiv) was first submitted to the allylic
substitution with the racemic allylic picolinate 1a that was
selected as a typical substrate (eq 1).
To overcome the above limitation associated with the sp2-C
reagents, we directed our attention to the picolinoxy group
(2-pyridyl-CO2-),15 for which we expected two types of
activations (Scheme 1). One is electrostatic activation by the
electron-withdrawing pyridyl group as the C6F5 group in the
C6F5CO2 moiety. The other is dynamic activation induced
by chelating the carbonyl oxygen and the pyridyl nitrogen
to a metal cation (M+) as illustrated in 3, Scheme 1. In
addition, picolinic acid is quite inexpensive.16 Herein, we
(6) (a) Breit, B.; Demel, P. AdV. Synth. Catal. 2001, 343, 429–432. (b)
Demel, P.; Keller, M.; Breit, B. Chem. Eur. J. 2006, 12, 6669–6683.
(7) Other studies: (a) Gallina, C.; Ciattini, P. G. J. Am. Chem. Soc. 1979,
101, 1035–1036. (b) Trost, B. M.; Klun, T. P. J. Org. Chem. 1980, 45,
4256–4257. (c) Goering, H. L.; Tseng, C. C. J. Org. Chem. 1985, 50, 1597–
1599. (d) Persson, E. S. M.; Bäckvall, J.-E. Acta Chem. Scand. 1995, 49,
899–906. (e) Smitrovich, J. H.; Woerpel, K. A. J. Am. Chem. Soc. 1998,
120, 12998–12999.
(1)
(8) (a) Breit, B.; Herber, C. Angew. Chem., Int. Ed. 2004, 43, 3790–
3792. (b) Herber, C.; Breit, B. Chem. Eur. J. 2006, 12, 6684–6691
.
(9) (a) Herber, C.; Breit, B. Angew. Chem., Int. Ed. 2005, 44, 5267–
5269. (b) Herber, C.; Breit, B. Eur. J. Org. Chem. 2007, 3512–3519
(10) Rein, C.; Demel, P.; Outten, R. A.; Netscher, T.; Breit, B. Angew.
Chem., Int. Ed. 2007, 46, 8670–8673
.
The reaction at 0 °C in THF completed within 1 h to
afford the desired SN2′ product 2a with high regioselectivity
.
(11) (a) Fujii, N.; Habashita, H.; Shigemori, N.; Otaka, A.; Ibuka, T.;
Tanaka, M.; Yamamoto, Y. Tetrahedron Lett. 1991, 32, 4969–4972. (b)
Habashita, H.; Kawasaki, T.; Takemoto, Y.; Fujii, N.; Ibuka, T. J. Org.
Chem. 1998, 63, 2392–2396. (c) Borthwick, S.; Dohle, W.; Hirst, P. R.;
(99:1) over the SN2 product 417 by H NMR spectroscopy
1
(Table 1, entry 2); in contrast, the trans isomer of 1a showed
low regioselectivity.18 The free alcohol 5 was not detected.
Even with 1.2 equiv of PhMgBr the reaction was completed
(entry 4).19 In contrast to 1a, isonicotinate 6 underwent
incomplete reaction even at somewhat higher temperatures
(0 °C to rt) (entry 10), while no reaction took place with
benzoate 7 (entry 11). The high reactivity observed for the
picolinoxy group could be understandable by the dual effect
we have postulated in the above paragraph.
Booker-Milburn, K. I. Tetrahedron Lett. 2006, 47, 7205–7208
.
(12) (a) Yamazaki, T.; Umetani, H.; Kitazume, T. Tetrahedron Lett.
1997, 38, 6705–6708. (b) Spino, C.; Beaulieu, C. J. Am. Chem. Soc. 1998,
120, 11832–11833. (c) Belelie, J. L.; Chong, J. M. J. Org. Chem. 2002,
67, 3000–3006
(13) In contrast to the o-DPPB ester, the o-DPPB oxide ester3b requires
2 equiv of Ph2Zn/Cu(CN)·2LiCl, which is equal to 4 equiv of the Ph anion
.
.
(14) Another solution is PPh2 directed nickel-catalyzed substitution of
allylic ethers possessing the PPh2 ligand in substrates. However, removal
of the PPh2 group in the products is the another problem of this approach:
Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. J. Am. Chem. Soc. 1995,
117 , 727–7274.
Reagents with different Ph/Cu ratios of 2:0.5 and 2:2
provided similarly high reactivity and regioselectivity (entries
(15) (a) On the other hand, allylic substitution of 2-alkenyl-1-ol
derivatives with a pyridyloxy group as a leaving group was reported to
show similar reactivity and regioselectivity to the corresponding acetates:
Tominaga, S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto, S. Tetrahedron Lett.
2004, 45, 5585–5588. (b) Okamoto, S.; Tominaga, S.; Saino, N.; Kase, K.;
Shimoda, K. J. Organomet. Chem. 2005, 690, 6001–6007.
(17) Authentic 4 possessing the trans olefin in it was synthesized
unambiguously (see entry 8 of Table 2 for the enantiomerically enriched
version of 4 as (S)-2e).
(16) Relative prices (Aldrich) of the major leaving groups as compared
with picolinic acid (28 $/mol): C6F5CO2H 43 times; o-(Ph)2PC6H4CO2H
330 times; (Ph)2P()O)C6H4CO2H available by oxidation of (Ph)2PC6H4-
CO2H; (EtO)2P(O)Cl 4 times; cf. DCC 2.1 times.
(18) A mixture of 2a and 4 in a 60:40 ratio was obtained from the trans
isomer of 1a.
(19) Two equivalents of ArMgBr were used in most cases to avoid any
technical error.
1720
Org. Lett., Vol. 10, No. 9, 2008

Table 1. Exploration of Leaving Groups and Reagents in an Allylic Substitution
entry
substrate
reagent (equiv)
temp (°C)
time (h)
ratio of 2a/4/5/1aa
Yield [%]b,c
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
6
PhMgBr (2)/CuBr·Me2S (0.5)
PhMgBr (2)/CuBr·Me2S (1)
PhMgBr (2)/CuBr·Me2S (2)
PhMgBr (1.2)/CuBr·Me2S (0.5)
PhMgBr (2)/CuCN (0.5)d
Ph2Zn·2LiBr (3)/CuBr·Me2S (1.5)
Ph2Zn·2LiBr (3)/CuCN·2LiCl (1.5)
Ph2Zn·2MgBr2 (2)/CuBr·Me2S (1)
Ph2Zn·2MgBr2 (2)/CuCN·2LiCl (1)
PhMgBr (2)/CuBr·Me2S (1)
PhMgBr (2)/CuBr·Me2S (1)
PhMgBr (2)/CuBr·Me2S (2)
PhMgBr (3)/CuBr·Me2S (1)
0
0
0
0
1
1
1.5
1
1
4
99:1:0:0
99:1:0:0
98:2:0:0
98:0:1:1
96:0:2:2
31:0:46:23
25:0:60:15
99:1:0:0
84:1:5:10
46:0:0:54
0:0:0:100
60:0:40:0
99f:1:0:0
85
91
84
92
0
88
-15 to 0
-15 to 0
-15 to 0
-15 to 0
0 to rt
0 to rt
0 to rt
0e
ND
ND
91
ND
ND
-
4
1
1.5
13
20
18
3
10
11
12
13
a
7
8
9
ND
90
Zero (0) is given in the case the product signal(s) was not detected by H NMR spectroscopy. b Isolated yield of 2a (and 4, if produced). c ND: not
1
determined. d Other CuX (X ) Cl, Br, I) showed similar results to CuCN. e Almost no reaction took place at -50 to -30 °C for 4 h. f An olefinic impurity
was seen in the H NMR spectrum.
1
Table 2. Allylic Substitution of Enantiomerically Enriched Allylic Picolinates
a Absolute configurations of 2a, 2d, and 2e were determined unambiguously, while that of the products 2b, 2c, and 2f were determined by analogy.
b
Regioselectivities of >98:2 were determined by H NMR spectroscopy. c Chirality transfers were determined by chiral HPLC of the derivatives.
1
1, 3). The independence of the results from the Ph/Cu
composition (entries 1-3) is unusual in the allylic substitu-
tion. From the synthetic point of view, the independence is
welcome since the precise measurement of the source
reagents is no longer necessary. Other copper salts (CuCl,
CuBr, CuI, CuCN) were equally effective (entry 5 for
CuCN). However, except for CuCN, the other reagents
derived with CuX (X ) Cl, Br, I) showed slightly decreased
reactivity when reactions were carried out at lower temper-
atures (ca. 10% recovery of 1a) (data not shown).
(M ) Li, MgBr) and ZnBr2 (therefore one more step of
the transmetalation is required) were briefly examined.
Surprisingly, Ph2Zn derived from PhLi and ZnBr2 with
CuBr·Me2S and that with CuCN·2LiCl (Knochel
reagent)2a,c–f,4c,d,20 were ill-suited to 1a (entries 6, 7). On
the other hand, Ph2Zn derived from PhMgBr with CuBr·Me2S
(entry 8) afforded the SN2′ product 2a efficiently. These
results suggest that the metal cation to be chelated effectively
Although we have attained full success using PhMgBr
as a reagent source, phenylzinc reagents derived from PhM
(20) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390–2392
.
Org. Lett., Vol. 10, No. 9, 2008
1721

to the picolinoxy group is MgBr2produced in situ from
PhMgBr and CuBr·Me2S.
efficiency as (S)-1a (entries 7 and 8).23 These results clearly
indicate that anti SN2′ selectivity and the reactivity are not
affected by any methylene substituents at the R and γ
positions. An additional result supporting this conclusion is
presented in entry 9.
In summary, we have developed anti SN2′ selective allylic
substitution for the aryl reagents, for the first time, using
the picolinoxy group as the powerful leaving group. The
reaction proceeded with the efficient chirality transfer (C/
T). Additionally, picolinic acid/DCC and RMgBr/CuBr·Me2S
are inexpensive, while both enantiomers of the starting allylic
alcohols are easily available by asymmetric reactions and
from natural sources (condensation using DCC and the
Mitsunobu inversion). The concept of the chelation-induced
activation of the picolinoxy leaving group seems applicable
to other types of coupling reactions. We are continuing
investigation along this line.
To compare reactivity of the picolinoxy group with the
others, pentafluorobenzoate 8 and phosphonate 9 were sub-
mitted to reaction with PhMgBr/CuBr·Me2S (entries 12 and
13). The former produced alcohol 5 competitively and the
latter provided a mixture of 2a and an olefinic isomer
(footnote f). On the other hand, an attempted mesylation gave
a mixture of products.
We then studied the reaction course and the chirality
transfer (C/T) using (S)-1a of 90% ee, which was prepared
through the Sharpless asymmetric epoxidation21 (see Sup-
porting Information). The anti SN2′ pathway with the Ph/Cu
reagent of 2:0.5 ratio was proven by establishing the absolute
configuration of the product 2a as R (Table 2, entries 1–3).22
Unexpectedly, the C/T for the reaction at 0 °C was
unacceptable (entry 1). However, we were pleased to attain
high level of C/T (98%) at -60 to -40 °C (entry 3, cf. entry
2). High efficiency was also recorded with the Ph/Cu reagent
of 2:1 ratio (entry 4).
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture, Japan and in part by a
Grant-in-Aid for Young Scientists from JSPS. The authors
thank Ms. M. Ishikawa of Center for Advanced Materials
Analysis, Technical Department, Tokyo Institute of Technol-
ogy, for HRMS analysis.
To clarify the range of substrates the present reaction
system covers, the following reactions were examined. The
substituent (Me and MeO groups) at the ortho position of
the phenyl ring neither retarded the reaction nor lowered the
C/T (entries 5 and 6). Substrates (S)-1b and (S)-1c produced
(R)-2d and (S)-2e, respectively, with the almost same
Supporting Information Available: Experimental pro-
cedures and spectral data of compounds described herein.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
(22) Transformed into the known compound i (S configuration):
[R]25D-13 (c 0.12, CHCl3); cf. lit. [R]23 +14.6 (c 0.12, CHCl3) for the
D
(R)-enantiomer. Maruoka, K.; Ooi, T.; Nagahara, S.; Yamamoto, H.
Tetrahedron 1991, 47, 6983–6998.
OL800300X
(23) The absolute configurations of (R)-2d and (S)-2e in Table 2 were
determined by transformation into the known compounds (see Supporting
Information). Other products of the allylic substitution were assigned by
analogy.
1722
Org. Lett., Vol. 10, No. 9, 2008