Formation of chiral C(sp3)-C(sp) bond by allylic substitution of secondary allylic picolinates and alkynyl copper reagents

Article abstract of DOI:10.1021/jo901728b

(Chemical Equation Presented) To establish allylic substitution of secondary allylic alcohol derivatives with alkynyl copper reagents, allylic esters bearing the (2-pyridine)CO₂-, (2-pyrazine)CO₂-, (EtO)₂PO₂-, C₆F₅CO₂-, o-(Ph₂P)-C₆H₄CO₂-, MeOCO ₂-, or. AcO- group were examined. First, picolinate (R ¹=Me, R²=CH₂OPMB) was subjected to reaction with (TMS-C≡C)₂CuLi 3 LiBr at 0 °C. Although no substitution took place, MgBr₂ (3 equiv) was found to promote the reaction to produce the anti S_N2′ product in 93% yield with 94% regioselectivity and 99% chirality transfer. In contrast, substitution of the other esters with the copper reagent in the presence of MgBr₂ were less reactive ((2-pyrazine)CO₂-) or marginally reactive (other cases). Generality of the substitution using picolinates was established with five picolinates (R¹=Me, Ph(CH₂)₂, PMBO(CH ₂)₃; R²=Me, CH₂OPMB, CH ₂OTBS, C₅H₁₁, c-C₆H₁₁) and seven alkynyl copper reagents (R³=TMS, Ph, p-TBSOC ₆H₄, p- and o-MeOC₆H₄, p-MeC ₆H₄, p-FC₆H₄), furnishing anti S_N2′ products in 61-93% yields with high regioselectivity (usually >90%) and high chirality transfer (usually >95%). In addition, transformation of the products was briefly studied. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901728b

pubs.acs.org/joc
Formation of Chiral C(sp3)-C(sp) Bond by Allylic Substitution of
Secondary Allylic Picolinates and Alkynyl Copper Reagents
Yohei Kiyotsuka and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, B52, Nagatsuta-cho 4259,
Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received August 9, 2009
To establish allylic substitution of secondary allylic alcohol derivatives with alkynyl copper reagents,
allylic esters bearing the (2-pyridine)CO2-, (2-pyrazine)CO2-, (EtO)2PO2-, C6F5CO2-, o-(Ph2P)-
C6H4CO2-, MeOCO2-, or AcO- group were examined. First, picolinate (R1=Me, R2=CH2OPMB)
was subjected to reaction with (TMS-CtC)2CuLi LiBr at 0 °C. Although no substitution took place,
3
MgBr2 (3 equiv) was found to promote the reaction to produce the anti SN20 product in 93% yield
with 94% regioselectivity and 99% chirality transfer. In contrast, substitution of the other esters with
the copper reagent in the presence of MgBr2 were less reactive ((2-pyrazine)CO2-) or marginally
reactive (other cases). Generality of the substitution using picolinates was established with five
picolinates (R1=Me, Ph(CH2)2, PMBO(CH2)3; R2=Me, CH2OPMB, CH2OTBS, C5H11, c-C6H11)
and seven alkynyl copper reagents (R3=TMS, Ph, p-TBSOC6H4, p- and o-MeOC6H4, p-MeC6H4,
p-FC6H4), furnishing anti SN20 products in 61-93% yields with high regioselectivity (usually >90%)
and high chirality transfer (usually >95%). In addition, transformation of the products was briefly
studied.
Introduction
of sp2-C copper reagents to afford 2 highly efficiently
(Scheme 1).3 We then switched our attention to allylic
substitution with alkynyl (sp-C) copper reagents. Generally,
the sp-C copper reagents are poor nucleophiles for 1,4-
addition to enones,4 though methods to accomplish the
addition have been published.5 Probably for the same rea-
son, allylic substitution with sp-C reagents was reported
once using racemic secondary allylic bromides,6 which are
generally more reactive than allylic esters. However, the
Allylic substitution of secondary allylic alcohol derivatives
with organocopper reagents is an attractive method of
forming a C-C bond on chiral carbons.1 Although good
leaving groups to attain high levels of regioselectivity and
chirality transfer have been established for alkyl (sp3-C)
copper reagents, less reactive aryl and alkenyl (sp2-C) copper
reagents generally give lower efficiencies except for the case
where substrates are activated or sterically biased.2 To over-
come this limitation, we have introduced the picolinates 1,
which undergo anti SN20 displacement with a broad range
(3) (a) Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.; Hyodo, T.; Kobayashi,
Y. Org. Lett. 2008, 10, 1719–1722. (b) Kiyotsuka, Y.; Kobayashi, Y. Tetrahedron
Lett. 2008, 49, 7256–7259. (c) Kiyotsuka, Y.; Katayama, Y.; Acharya, H. P.;
Hyodo, T.; Kobayashi, Y. J. Org. Chem. 2009, 74, 1939–1951.
(1) (a) Negishi, E.; Liu, F. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 1. (b) Kar,
A.; Argade, N. P. Synthesis 2005, 2995–3022.
(2) (a) Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. J. Am. Chem. Soc.
1995, 117, 7273–7274. (b) Yamazaki, T.; Umetani, H.; Kitazume, T. Tetra-
hedron Lett. 1997, 38, 6705–6708. (c) Spino, C.; Beaulieu, C. J. Am. Chem.
Soc. 1998, 120, 11832–11833. (d) Belelie, J. L.; Chong, J. M. J. Org. Chem.
2002, 67, 3000–3006. (e) Perrone, S.; Knochel, P. Org. Lett. 2007, 9, 1041–
1044.
(4) (a) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210–7211.
(b) House, H. O.; Umen, M. J. J. Org. Chem. 1973, 38, 3893–3901. (c) Corey,
E. J.; Floyd, D.; Lipshutz, B. H. J. Org. Chem. 1978, 43, 3418–3420.
(5) (a) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244–3245.
€
(b) Knopfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem.
Soc. 2005, 127, 9682–9683. (c) Pellegrinet, S. C.; Goodman, J. M. J. Am.
Chem. Soc. 2006, 128, 3116–3117.
(6) Matveeva, E. D.; Yerin, A. S.; Kurts, A. L. Russ. J. Org. Chem. 2000,
36, 15721576; Zh. Org. Khim. 2000, 36, 1619-1623.
DOI: 10.1021/jo901728b
r
Published on Web 09/02/2009
J. Org. Chem. 2009, 74, 7489–7495 7489
2009 American Chemical Society

Kiyotsuka and Kobayashi
SCHEME 2. Synthesis of Allylic Estersa
JOCArticle
SCHEME 1. Allylic Substitution: Previous Results and Present
Purpose
regioselectivity in the report is uncertain. Furthermore, the
method suffers from low regioselectivity in the preparation
of the bromides and seems difficult to apply to optically
active bromides. On the other hand, substitution of 1-halo-2-
alkenes and 3-halo-1-alkenes takes place at the primary
carbon.6,7 To establish the substitution at secondary car-
bons, we examined the reaction of picolinate rac-1a and
other esters 4-9 (Figure 1) with (TMS-CtC)2CuLi LiBr.8,9
3
FIGURE 1. Substrates for the present investigation.
Although no esters underwent the substitution, rac-1a was
found to be activated by MgBr2 to produce 3a with high
levels of regio- and stereoselectivities. Herein, we present the
results obtained with picolinates (R)-1a and (S)-1b-1e.
Results and Discussion
Preparation of Allylic Esters. Optically active allylic pico-
linates (R)-1a and (S)-1b-1e were prepared by methods
delineated in Scheme 2. The optically active propargylic
alcohol 10, kindly gifted from a company, was converted
to the TBDPS ether 11, which was transformed to the most
(7) (a) Jeffery, T. Tetrahedron Lett. 1989, 30, 2225–2228. (b) Mignani, G.;
Chevalier, C.; Grass, F.; Allmang, G.; Morel, D. Tetrahedron Lett. 1990, 31,
5161–5164. and references therein.
(8) Asymmetric formation of C(sp3)-C(sp) bond by using substitution at
propargylic carbon: (a) Inada, Y.; Nishibayashi, Y.; Uemura, S. Angew.
Chem., Int. Ed. 2005, 44, 7715–7717. (b) Smith, S. W.; Fu, G. C. J. Am. Chem.
Soc. 2008, 130, 12645–12647. (c) Idem Angew. Chem., Int. Ed. 2008, 47, 9334–
9336. (d) Rubenbauer, P.; Herdtweck, E.; Strassner, T.; Bach, T. Angew.
Chem., Int. Ed. 2008, 47, 10106–10109.
(9) Other reactions to create racemic C(sp3)-C(sp) bonds: (a) Shirakura,
M.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 5410–5411. (b) Idem Org.
Lett. 2009, 11, 523–526. (c) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem.
Soc. 2005, 127, 13510–13511.
aRu cat. = Ru[(S,S)-TsDPEN](p-cymene)
7490 J. Org. Chem. Vol. 74, No. 19, 2009

Kiyotsuka and Kobayashi
JOCArticle
TABLE 1. Preliminary Study Using Racemic Substratesa
entry
substrate
L
additivea
yield
rac-3a:32b
1
2
3
4
5
6
7
8
rac-1a
rac-1a
rac-1a
(2-Py)CO2
(2-Py)CO2
(2-Py)CO2
(2-pyrazine)CO2
(2-pyrazine)CO2
(EtO)2P(O)O
(EtO)2P(O)O
(EtO)2P(O)O
C6F5CO2
C6F5CO2
C6F5CO2
o-(Ph2P)C6H4CO2
o-(Ph2P)C6H4CO2
o-(Ph2P)C6H4CO2
MeOCO2
0c
88
MgBr2
ZnBr2
94:6
0c
4
4
5
5
5
6
6
6
7
7
7
8
8
9
9
0c
MgBr2
51d
nre
12f
nre
nre
nre
nre
0h
92:8
ndg
MgBr2
ZnBr2
9
10
11
12
13
14
15
16
17
18
MgBr2
ZnBr2
MgBr2
ZnBr2
0h
0h
nre
nre
nre
nre
MeOCO2
AcO
AcO
MgBr2
MgBr2
aThree equivalents. bDetermined by 1H NMR spectroscopy. cAlcohol 30 was obtained. dUnidentified products were coproduced. eNo reaction after
18 h at rt. fAllylic bromides 33a and 33b were produced in 88% NMR yield (Jolefinic-H = 15 Hz). gNot determined. hThe corresponding phosphine oxide
was produced.
frequently examined substrate (R)-1a with 98% ee according
to the method published by us.3c Previously, (S)-1b and -1c
were prepared in ca. 90% ee through the Yadav’s transfor-
mation10 of the epoxy chlorides to propargylic alcohol 15.3c
In the present investigation, we used the asymmetric hydro-
gen transfer reaction developed by Noyori11 to deliver (S)-1b
and -1c with higher ee of 98% and 94%, respectively.
Similarly, asymmetric reduction of ketones 22 and 25 furn-
ished (S)-1d and -1e with 93% and 99% ee, respectively. The
overall yields of (S)-1c-1e were 30-33%.
For preliminary investigation, racemic picolinate rac-1a
and 4 were prepared by applying the above method to the
racemic alcohol rac-12 (Scheme 3). In contrast, Lindlar
reduction of rac-12 to the cis alcohol 30 followed by ester-
ification delivered 5-9 in good yields.12
from TMS-CtCLi (31) (2 equiv) and CuBr Me2S
3
(1 equiv) (Table 1). Unfortunately, these substrates underwent
nucleophilic attack to the carbonyl group (entries 1 and 4).
Substitution was also examined using esters 5-7 possess-
ing leaving groups that are suited to sp2-C and/or sp3-C
reagents13-15 and esters 8 and 9 with the standard leaving
groups. No reaction took place with 5, 6, 8, and 9 (entries 6, 9,
15, 17), while 7 was changed to the corresponding phos-
phine oxide16 (entry 12). We then envisioned participation(s)
of MgBr2 and ZnBr2 in the reaction, as a Lewis acid to activate
the leaving groups and/or as a source to generate
[R2Cu]-MBrþ (M=Mg, Zn), which was expected to be more
reactive than lithium cuprate on the analogy of the substitution
with sp3- and sp2-C reagents.17 In practice, MgBr2
(3 equiv) was found to assist the substitution of picolinate
Preliminary Study of Allylic Substitution Using Racemic
Substrates. Initially, substitution was investigated in THF at
0 °C using racemic picolinate rac-1a and a related substrate 4
rac-1a (1 equiv) and (TMS-CtC)2CuLi LiBr (1 equiv), fur-
3
nishing rac-3a in 88% yield with 94% regioselectivity over its
regioisomer rac-32 after 1 h at 0 °C (entry 2).18 Use of lower
with (TMS-CtC)2CuLi LiBr, which had been prepared
3
(14) Pentafluorobenzoates: (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) See ref 2e.
(15) o-Diphenylphosphinobenzoates: (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. (c) Breit, B.; Herber, C. Angew. Chem., Int. Ed. 2004, 43,
3790–3792. (d) Herber, C.; Breit, B. Chem.;Eur. J. 2006, 12, 6684–6691.
(e) Herber, C.; Breit, B. Angew. Chem., Int. Ed. 2005, 44, 5267–5269.
(16) Nieto, S.; Metola, P.; Lynch, V. M.; Anslyn, E. V. Organometallics
2008, 27, 3608–3610.
(10) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990,
46, 7033–7046.
(11) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738–8739.
(12) Attempted Lindlar reduction of the phosphate of rac-12 produced
deoxygenated compound, while the carbonate and the acetate of rac-12
produced saturated compounds.
(13) Phosphates: (a) Yanagisawa, A.; Nomura, N.; Noritake, Y.; Yama-
moto, 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) L.
Belelie, J.; 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.
(17) For example: (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. See also refs 2a, 3, and 14a.
(18) Attempted reaction in the presence of MgBr2 without CuBr Me2S
3
afforded alcohol 30.
J. Org. Chem. Vol. 74, No. 19, 2009 7491

Kiyotsuka and Kobayashi
SCHEME 3. Synthesis of Racemic Allylic Esters
JOCArticle
temperatures of -20 and -60 °C merely retarded the reaction
without improving the regioselectivity. Pyrazinecarboxylate 4
was activated by MgBr2 as well, but to somewhat low extent,
producing rac-3a in 51% yield with unidentified products
(entry 5), whereas substitution of phosphate 5 was marginally
promoted by MgBr2 at 0 °C for 1 h, and further reaction at
room temperature for 18 h produced rac-3a in 12% yield and
a regioisomeric mixture of allylic bromides 33a/33b (1:1)19 in
88% yield (entry 7). No other substrates6-9 were activated by
MgBr2 (entries 10, 13, 16, 18). In contrast to the above results,
ZnBr2 (3 equiv) did not promote substitution of picolinate rac-
1a and other substrates 5-7with (TMS-CtC)2CuLi LiBr at 0
3
°C for 1 h, and further reactions at room temperatures resulted
in production of alcohol 30 from rac-1a, recovery of 5 and 6,
oxidation of 7, respectively (entries 3, 8, 11, and 14).
efficiency is attained without precise measurement of
CuBr Me2S for preparation of the copper reagent.
3
Alkynyl copper reagents derived from lithium acetylide 31
and other copper salts (CuCl, CuBr, CuI, CuCN) in the 2:1
ratio produced (S)-3a as well (Table 3). However, the
efficiency in terms of product selectivity over bromides 3a
and 3b, isolated yield, and/or CT was slightly lower than that
Next, substitution of trans allylic picolinate 34 with (TMS-
CtC)2CuLi LiBr was investigated in the presence of MgBr2
3
to afford a mixture of rac-3a and the regioisomer 35 (eq 1).
Another copper reagent, TMS-CtCCu LiBr, also produced
a mixture of the regioisomers.
obtained with 31 and CuBr Me2S. On the basis of these
results we used CuBr Me2S as a copper source in the
following reactions.
3
3
3
The above substitution was applied to a range of allylic
picolinates and other alkynyl coppers to assess reactivity,
regioselectivity, and CT (Table 4).22 Various methylene
units and/or CH2OR group attached to the allylic moiety
did not interfere with the MgBr2-promoted substitution
with (TMS-CtC)2CuLi LiBr, producing anti SN20 pro-
3
ducts (R)-3b-d21 efficiently from (S)-1b-d (entries 1-3).
In contrast, a more bulky c-hexyl group at the olefinic
carbon of (S)-1e reduced efficiency in selectivity and yield
(entry 4). An additional entry is the reaction of racemic
picolinate 1m23 to produce 35, which is the regioisomer of
rac-3a (eq 2).
In addition to the different regioselectivities observed
above with rac-1a (cis isomer) and 34 (trans isomer), we note
that the cis geometry of rac-1a is retained in the regioisomer
32 (SN2-type product), whereas the SN2-type product in the
previous substitution of picolinates with Ph2CuMgBr (sp2-C
copper reagent) is the trans olefin.3 Presently, we are trying to
find results to support these differences.
Substitution Using Optically Active Picolinates. The opti-
mal reaction conditions were applied to (R)-1a (98% ee),
Phenylacetylenic copper, (Ph-CtC)2CuLi LiBr, pre-
3
pared from Ph-CtCLi (36, 2 equiv) and CuBr Me2S
which attained near perfect chirality transfer (99% CT20
)
3
(1 equiv), was found to be less reactive than (TMS-CtC)2-
CuLi LiBr, and 18% of picolinate (R)-1a was recovered
with (TMS-CtC)2CuLi LiBr, giving anti SN20 product
3
(S)-3a21 and the regioisomer 32 in 94:6 and in 93%
combined yield (Table 2, entry 2). Copper reagents con-
sisting of lithium acetylide 31 and CuBr Me2S in other
3
after 1 h at 0 °C. This problem was operationally solved with
(22) Signals corresponding to the regioisomers of the products shown in
Table 4 are assigned by analogy to those for 32 (mostly δ 1.3 (d) for CH3, 4.1
(s) for CH2OPMB, 5.5-5.6 (m) for CHdCH).
3
ratios of 1:1 and 4:1 showed reactivity and selectivity compar-
able to those of the above 2:1 reagent (entries 1 and 3). These
results implies an operational advantage of that the high
(23) Prepared by the following method:
(19) Bromination of rac-1a with CuBr Me2S (0.5 equiv) and MgBr2
3
(3 equiv) at rt proceeded slowly to afford, after 18 h, trans allylic bromides
33a and 33b in a 2:3 ratio by 1H NMR spectroscopy (Jolefinic-H=15 Hz).
(20) CT, defined as (% ee of product/% ee of substrate) ꢀ 100, was
determined by chiral HPLC.
(21) Acetylenes (S)-3a and (R)-3b were transformed to the known com-
pounds, respectively, and their [R]D values were compared to determine their
absolute configurations. See the Experimental Section for the former and the
Supporting Information for the latter. Other products were assigned by
analogy.
7492 J. Org. Chem. Vol. 74, No. 19, 2009

Kiyotsuka and Kobayashi
JOCArticle
a
TABLE 2. Reaction of (R)-1a with 31/CuBr Me2S/MgBr2
3
entry
31/CuBr Me2S/MgBr2, equiv
ratiob of (S)-3a:32:30:(R)-1a
yield, %c
CT, %d
3
1
2
3
2/2/3
2/1/3
2/0.5/3
93:7:0:0
94:6:0:0
91:5:4:0
86
93
81
99
99
nde
aIn the absence of MgBr2, reactions in entries 1-3 gave alcohol 30 in 13%, 23%, and 45% yields, respectively. bDetermined by 1H NMR spectroscopy.
cIsolated yield of (S)-3a and 32. dDetermined by chiral HPLC analysis. eNot determined.
TABLE 3. Effect of CuX on Substitutiona
SCHEME 4. Transformations of (S)-3a
entry
CuX
ratio of (S)-3a:32:30:(R)-1a
yield, %b
CT, %c
1
2
3
4
CuBr
CuCl
CuI
93:7:0:0
86:6:0:8
94:6:0:0
81:6:6:7
74d
57d
83
96
95
91
nde
CuCN
nde
aReactions of (R)-1a with copper reagents derived from 31 (2 equiv)
and CuX (1 equiv) were examined in the presence of MgBr2 (3 equiv) at
0 °C for 1 h. bIsolated yield of (S)-3a and 32. cDetermined by chiral
d
e
HPLC analysis. Allylic bromides 33a and 33b were coproduced. nd:
not determined.
the use of 1.5 times more reagent to afford (S)-3f in 70% yield
with selectivity comparable to that obtained with (TMS-CtC-
)2CuLi LiBr (entry 5). Similarly, (Ar-CtC)2CuLi LiBr
3
3
(Ar=p-TBSOC6H4, p-MeOC6H4, o-MeOC6H4, p-MeC6H4,
p-FC6H4) derived from lithium acetylides 37-41 produced
(S)-3g-k in good yields with high selectivity (entries 6-10). It
should be noted that electron-withdrawing and -donating
factors on the aromatic ring did not affect the reactivity nor
selectivity of the present reaction.24
Transformation of Products. Use of the products in various
ways was investigated briefly. As delineated in Scheme 4,
removal of the TMS group from (S)-3a with Bu4NF and
AcOH (1:1) in THF produced acetylene (S)-42 in 95%
yield.25 Sonogashira reaction of (S)-42 with iodides 43 and
45 under the standard conditions afforded (S)-44 and -3f in
68% and 94% yields, respectively. Although the latter
product is synthesized directly by the present substitution
using PhCtCH (Table 4, entry 5), the Sonogashira route
would be useful for aryl and alkenyl iodides bearing a
carbonyl group(s) as is seen in the synthesis of (S)-47 from
acetylene (S)-42 and iodide 46. Copper-catalyzed 1,3-dipo-
lar reaction26 of (S)-42 with azide 48 afforded triazole
(S)-49 in high yield. On the other hand, copper-catalyzed
reaction27 withp-NH(Ac)C6H4SO2N3 (50) followed by further
reaction with EtOH afforded imidate (R)-51 in 81% yield.28
(24) Presently, reaction of racemic picolinate rac-1a with (t-BuCtC)2-
CuLi LiBr afforded SN20 product v in moderate yield.
3
(27) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127,
16046–16047.
(28) A similar reaction of rac-42 with azide 50 in aqueous t-BuOH gave
amide vi in 47% yield.
(25) Similarly, (R)-3b was converted to acetylene alcohol, which was
further transformed to the known compound for determination of the
absolute structure of (R)-3b as described in Supporting Information. On
the other hand, reaction with Bu4NF gave a mixture of products.
(26) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599.
J. Org. Chem. Vol. 74, No. 19, 2009 7493

Kiyotsuka and Kobayashi
JOCArticle
TABLE 4. Substitution of Picolinates with Alkynyl Copper Reagentsa
aReactions in entries 1-4 were carried out with 31 (2 equiv), CuBr Me2S (1 equiv), and MgBr2 (3 equiv) in THF at 0 °C for 1 h. Reactions in entries
3
5-10 were carried out with Ar-CtCLi (3 equiv), CuBr Me2S (1.5 equiv), and MgBr2 (4 equiv) in THF at 0 °C for 1 h. bIn percent. cCombined yield of the
3
regioisomers. dDetermined by 1H NMR spectroscopy. eDetermined by chiral HPLC analysis. fHPLC signals on several chiral columns were separated
incompletely.
Conclusions
(1 mL) was added to it dropwise. The mixture was stirred at 0 °C
for 1 h and diluted with EtOAc and saturated NH4Cl with
vigorous stirring. The layers were separated, and the aqueous
layer was extracted with EtOAc twice. The combined extracts
were washed with brine, dried over MgSO4, and concentrated to
give a residue, which was purified by chromatography on silica
gel (hexane/EtOAc) to afford a 94:6 mixture of (S)-3a and 3229
We have attained allylic substitution with alkynyl copper
reagents using picolinates 1 as allylic esters in the presence of
MgBr2 to produce the anti SN20 products in 61-93% yields
with high regioselectivity (usually >90%) and high chirality
transfer (usually >95%). The picolinates were prepared
by several methods as shown in Scheme 2 using Lindlar
hydrogenation to construct the requisite cis olefins, which
are also prepared by Wittig reaction.3 Thus, the present
substitution offers a convenient and efficient method for
construction of enantiomerically enriched C(sp)-C(sp3)
bond. In addition, transformation of the products was
briefly studied.
(29.5 mg, 93%, 94% regioselectivity): [R]26 þ57.8 (c 0.816,
D
1
CHCl3); IR (neat) 2172, 1514, 1250, 843 cm-1; H NMR (300
MHz, CDCl3) δ 0.17 (s, 9 H), 1.71 (ddd, J=7, 2, 2 Hz, 3 H),
3.28-3.39 (m, 1 H), 3.42 (dd, J=9, 7 Hz, 1 H), 3.51 (dd, J=9,
6 Hz, 1 H), 3.80 (s, 3 H), 4.51 (s, 2 H), 5.43 (ddq, J=15, 6, 2 Hz,
1 H), 5.78 (ddq, J=15, 2, 7 Hz, 1 H), 6.88 (d, J=9 Hz, 2 H), 7.27
(d, J=9 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 0.23 (-), 17.9
(-), 36.4 (-), 55.3 (-), 72.7 (þ), 72.9 (þ), 87.7 (þ), 105.6 (þ),
113.8 (-), 127.3 (-), 127.7 (-), 129.3 (-), 130.4 (þ), 159.2 (þ);
HRMS (FAB) calcd for C18H26O2SiNa [(M þ Na)þ] 325.1600,
found 325.1598. The enantiomeric information (97% ee, 99%
CT) was determined by chiral HPLC analysis: Chiralcel AS-H;
hexane/i-PrOH = 98/2, 0.2 mL/min, rt; tR (min) = 27.6 (R),
38.9 (S).
Experimental Section
General Procedure of Allylic Substitution. (Table 2, entry 2)
To an ice-cold solution of trimethylsilylacetylene (0.032 mL,
0.231 mmol) in THF (0.4 mL) was added BuLi (0.13 mL, 1.60 M
in hexane, 0.208 mmol) dropwise. After 30 min at 0 °C, a
solution of MgBr2 (1.60 mL, 0.20 M in THF, 0.320 mmol)
(29) The substitution was repeated several times to collect enough
quantity of the minor isomer for 1H NMR spectroscopy, by which the
structure 32 including cis olefin (Jolefinic-H =11 Hz) was determined. See
Supporting Information.
and CuBr Me2S (21.6 mg, 0.105 mmol) was added to the
solution. The resulting mixture was stirred at 0 °C for 30 min,
and a solution of (R)-1a (34.1 mg, 0.105 mmol, 98% ee) in THF
3
7494 J. Org. Chem. Vol. 74, No. 19, 2009

Kiyotsuka and Kobayashi
JOCArticle
Determination of the Absolute Configuration of (S)-3a.
CHCl3)) was opposite to that of the (S)-enantiomer30 ([R]25
D
-12.8 (c 1.0, CHCl3)), thus confirming the (R) chirality for 54.
(R)-1-[(2-Ethylpentyloxy)methyl]-4-methoxybenzene (53) from 52.
To a solution of 52 (17.4 mg, 0.0743 mmol) in EtOAc (1 mL)
was added 10% Pd/C (8 mg). The mixture was stirred at rt for
1 h under H2 atmosphere and filtered through a pad of
Celite. The filtrate was concentrated to give a residue, which
was purified by chromatography on silica gel (hexane/
EtOAc) to afford 53 (12.2 mg, 69%): [R]28 -7.2 (c 0.166,
D
CHCl3); IR (neat) 1612, 1513, 1248, 1094, 1038 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 0.86 (t, J=8 Hz, 3 H), 0.86 (t, J=
8 Hz, 3 H), 1.18-1.64 (m, 7 H), 3.31 (d, J = 6 Hz, 2 H),
3.81 (s, 3 H), 4.42 (s, 2 H), 6.88 (d, J=9 Hz, 2 H), 7.26 (d, J=9
Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 11.1 (-), 14.6 (-),
20.1 (þ), 24.0 (þ), 33.3 (þ), 39.6 (-), 55.4 (-), 72.7 (þ), 73.0
(þ), 113.8 (-), 129.2 (-), 131.1 (þ), 159.1 (þ). Chiralcel
OB-H; hexane/i-PrOH = 96/4, 0.4 mL/min, 40 °C; tR (min) =
27.8 (S), 34.9 (R).
(S,E)-1-[(2-Ethynylpent-3-enyloxy)methyl]-4-methoxybenzene ((S)-
42). To an ice-cold solution of (S)-3a (101 mg, 0.334 mmol)
in THF (0.5 mL) was added a solution of Bu4NF (0.67 mL,
1.0 M in THF, 0.67 mmol) and AcOH (0.038 mL, 0.664 mmol) in
THF (0.5 mL). The resulting solution was stirred at rt over-
night and diluted with EtOAc and saturated NH4Cl. The
layers were separated, and the aqueous layer was extracted
with EtOAc twice. The combined extracts were washed with
brine, dried over MgSO4, and concentrated to give a residue,
which was purified by chromatography on silica gel (hexane/
(R,E)-1-[(2-Ethylpent-3-enyloxy)methyl]-4-methoxybenzene (52).
To a suspension of CuBr Me2S (23.8 mg, 0.116 mmol) in
3
THF (3 mL) was added EtMgBr (0.23 mL, 1.00 M in THF,
0.23 mmol) slowly at -60 °C. After 30 min at -60 °C,
a solution of (R)-1a (37.7 mg, 0.116 mmol, 98% ee) in THF
(1 mL) was added to the mixture dropwise. The mixture was
allowed to warm to -50 °C for 1 h and was diluted with
EtOAc and saturated NH4Cl with vigorous stirring. The
layers were separated, and the aqueous layer was extracted
with EtOAc twice. The combined extracts were washed with
brine, dried over MgSO4, and concentrated to give a residue,
which was purified by chromatography on silica gel (hexane/
EtOAc) to afford (S)-42 (73.0 mg, 95%): [R]27 þ54.2
D
(c 0.542, CHCl3); IR (neat) 3292, 1612, 1513, 1249, 1100,
1036 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.70 (ddd, J=6, 2,
2 Hz, 3 H), 2.23 (d, J=2 Hz, 1 H), 3.26-3.37 (m, 1 H), 3.43
(dd, J=9, 7 Hz, 1 H), 3.50 (dd, J=9, 7 Hz, 1 H), 3.81 (s, 3 H),
4.51 (s, 2 H), 5.43 (ddq, J=15, 6, 2 Hz, 1 H), 5.81 (ddq, J=15,
EtOAc) to afford 52 (23.4 mg, 86%): [R]25 -6.4 (c 0.346,
D
CHCl3); IR (neat) 1612, 1513, 1248, 1096, 1038 cm-1 1H
;
2, 6 Hz, 1 H), 6.88 (d, J=9 Hz, 2 H), 7.27 (d, J=9 Hz, 2 H); 13
C
NMR (300 MHz, CDCl3) δ 0.84 (t, J=8 Hz, 3 H), 1.12-1.38
(m, 1 H), 1.46-1.63 (m, 1 H), 1.67 (dd, J = 6, 2 Hz, 3 H),
2.11-2.25 (m, 1 H), 3.30 (dd, J=9, 7 Hz, 1 H), 3.33 (dd, J=9,
7 Hz, 1 H), 3.80 (s, 3 H), 4.43 (s, 2 H), 5.23 (ddq, J=15, 8, 2
Hz, 1 H), 5.48 (ddq, J=15, 1, 6 Hz, 1 H), 6.87 (d, J=9 Hz, 2
H), 7.25 (d, J=9 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 11.5
(-), 18.2 (-), 24.6 (þ), 44.6 (-), 55.3 (-), 72.6 (þ), 73.8 (þ),
113.7 (-), 126.2 (-), 129.2 (-), 130.9 (þ), 132.6 (-), 159.1
(þ); HRMS (FAB) calcd for C15H22O2Na [(M þ Na)þ]
257.1517, found 257.1522. The enantiomeric information
(98% ee, 100% CT) was determined by chiral HPLC: Chir-
alcel OB-H; hexane/i-PrOH = 98/2, 0.2 mL/min, 40 °C;
NMR (75 MHz, CDCl3) δ 17.9 (-), 35.2 (-), 55.3 (-), 71.3
(þ), 72.7 (þ), 72.8 (þ), 83.5 (þ), 113.8 (-), 126.9 (-), 128.1
(-), 129.4 (-), 130.2 (þ), 159.3 (þ); HRMS (FAB) calcd for
C
15H18O2 (Mþ) 230.1307, found 230.1308.
(R)-1-[(2-Ethylpentyloxy)methyl]-4-methoxybenzene (53) from
(S)-42. To a solution of (S)-42 (26.3 mg, 0.114 mmol) in
benzene (1 mL) was added RhCl(PPh3)3 (21 mg, 0.0227
mmol).31 The solution was stirred at rt for 20 h under H2
atmosphere, and filtered through a pad of Celite. The filtrate
was concentrated to give a residue, which was purified by
chromatography on silica gel (hexane/EtOAc) to afford 53
(19.4 mg, 72%). Retention time for 53 was identical with that
derived from 52.
t
R (min)=67.3 (R), 73.8 (S).
(R)-2-(4-Methoxybenzyloxymethyl)butan-1-ol (54). A stream
of O3 in O2 was gently bubbled into a solution of 52 (25.7 mg,
0.110 mmol) in MeOH at -78 °C for 5 min. Excess O3 remaining
in the solution was purged by bubbling argon at -78 °C, and
NaBH4 (41 mg, 1.08 mmol) was added. After 1 h at -78 °C,
saturated NH4Cl was added to the solution, and the resulting
mixture was extracted with EtOAc three times. The combined
extracts were washed with brine, dried over MgSO4, and con-
centrated to obtain a residue, which was purified by chroma-
tography on silica gel (hexane/EtOAc) to give 54 (19.6 mg,
79%). The 1H NMR spectrum of 54 was identical with the data
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture, Japan.
Supporting Information Available: Experimental proce-
dures for the preparation of allylic picolinates, determi-
nation of the absolute configuration of (R)-3b, and spec-
tral data of compounds described herein. This material
is available free of charge via the Internet at http://pubs.
acs.org.
reported.30 The specific rotation of 54 ([R]27 þ13 (c 0.238,
D
(31) Hydrogenation of (S)-42 with 10% Pd/C in EtOAc resulted in partial
racemization.
(30) Yadav, J. S.; Nanda, S. Tetrahedron: Asymmetry 2001, 12, 3223–
3234.
J. Org. Chem. Vol. 74, No. 19, 2009 7495