General, robust, and stereocomplementary preparation of β-ketoester enol tosylates as cross-coupling partners utilizing TsCl-N-methylimidazole agents

Article abstract of DOI:10.1021/ol800480d

(Chemical Equation Presented) We have developed a general, robust, and cost-effective method for the (E)- or (Z)-stereocomplementary enol tosylation of β-ketoesters using TsCl-N-methylimidazole (NMI)-Et₃N or LiOH. TsCl coupled with NMI formed a

Full text of DOI:10.1021/ol800480d

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2131-2134
General, Robust, and
Stereocomplementary Preparation of
ꢀ-Ketoester Enol Tosylates as
Cross-Coupling Partners Utilizing
TsCl-N-Methylimidazole Agents
Hidefumi Nakatsuji, Kanako Ueno, Tomonori Misaki, and Yoo Tanabe*
Department of Chemistry, School of Science and Technology, Kwansei Gakuin
UniVersity, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
tanabe@kwansei.ac.jp
Received March 3, 2008
ABSTRACT
We have developed a general, robust, and cost-effective method for the (E)- or (Z)-stereocomplementary enol tosylation of ꢀ-ketoesters using
TsCl-N-methylimidazole (NMI)-Et3N or LiOH. TsCl coupled with NMI formed a highly reactive N-sulfonylammonium intermediate. Stereocongested
secondary alcohols were smoothly sulfonylated using Ts(Ms)Cl-NMI-Et3N. ꢀ-Ketoesters underwent (E)-selective tosylation using TsCl-NMI-Et3N
and (Z)-selective tosylation using TsCl-NMI-LiOH (total of 23 examples; 60%-99% yield). Stereoretentive Negishi and Sonogashira couplings
using enol tosylates proceeded successfully to give trisubstituted r,ꢀ-unsaturated esters.
Tosylation and mesylation of alcohols are well-recognized
fundamental processes in various fields of organic synthesis.1
In our continuing study of mild, practical, and cost-effective
condensation reactions, we reported four pyridine-free
methods that utilized TsCl and a sterically uncongested amine
system.2 This protocol was applied in natural product
synthesis and process chemistry, for example, vinblastine,3
fluorescent amino acid derivatives,4 and flumioxadine.5 We
present herein highly efficient (E)- and (Z)-stereocomple-
mentary enol tosylations of ꢀ-ketoesters utilizing TsCl-N-
methylimidazole (NMI)-Et3N or LiOH (Scheme 1).
NMI is an efficient promoter of the condensation reactions,
O-, N-, and S-acylations, esterification, amide formation, and
thioesterification,6 as well as C-acylation (crossed Ti-Claisen
condensation).7
(1) Smith, M. T.; March, J. AdVanced Organic Chemistry, 5th ed.; Wiley:
New York, 2001; p 576.
With this information taken into account, the fundamental
tosylation reactivity was monitored using 3-octanol with a
TsCl-NMI-Et3N (most available tertiary amine) reagent
(2) (a) Tanabe, Y.; Yamamoto, H.; Yoshida, Y.; Miyawaki, T.; Utsumi,
N Bull. Chem. Soc. Jpn. 1995, 68, 297. (K2CO3-cat. Et3N-cat. Me3N·HCl).
(b) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, T. Tetrahedron,
1999, 55, 2183. (Et3N-cat. Me3N·HCl). (c) Yoshida, Y.; Shimonishi, K.;
Sakakura, Y.; Okada, S.; Aso, N.; Tanabe, Y. Synthesis 1999, 1633.
[(Me2N(CH2)nNMe2)]. (d) Morita, J; Nakatsuji, H.; Misaki, T.; Tanabe, Y.
Green Chem. 2005, 7, 711. [cat. BnNMe2 (BuNMe2)/H2O/pH ∼10].
(3) (a) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama,
T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137. (b)
Miyazaki, T.; Yokoshima, S.; Simizu, S.; Osada, H.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2007, 9, 4737.
(4) Hudgins, R. P.; Huang, F.; Gramlich, G.; Nau, W. M. J. Am. Chem.
Soc. 2002, 124, 556.
(5) Yoshida, R.; Sakai, M.; Sato, R.; Haga, T.; Nagano, E.; Oshio, H.;
Kamoshita, K. Proceedings of the Brighton Crop Protection
Conference-Weeds; BCPC: Hampshire, U.K., 1991; p 69.
(6) Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. AdV. Synth.
Catal. 2003, 345, 1209.
10.1021/ol800480d CCC: $40.75
Published on Web 05/09/2008
2008 American Chemical Society

be the most powerful and fastest method among the reported
amine-promoted sulfonylations (entry 11).
A plausible mechanism for this observation is as follows
(Scheme 2). The NMI reagent captures TsCl to form a highly
Scheme 1. Tosylations of Alcohols and ꢀ-Ketoesters Using a
TsCl-N-Methylimidazole (NMI)-Et3N or LiOH System
Scheme 2
.
Plausible Mechanism for NMI-Promoted
Sulfonylation of Alcohol
(Table 1). The combination of NMI and Et3N exhibited a
remarkable synergistic effect (entries 1-4).8 In contrast, the
Table 1. Powerful Sulfonylation of Alcohols
reactive N-sulfonylammonium intermediate, which in turn
condenses with an alcohol to produce a tosylate assisted by
Et3N, while releasing Et3N·HCl. Careful 1H NMR (300 MHz)
monitoring of a mixture of TsCl and NMI in CD3CN
rationally supported the present hypothesis; the generation
of a N-sulfonylammonium intermediate was unambiguously
detected.9 The apparent downfield chemical shift of NMI
moieties in the intermediate is related to the higher sulfo-
nylation reactivity of the present system in accordance with
a relevant discussion.8a This successful result prompted us
to investigate stereoselective enol tosylation of ꢀ-ketoesters.
(E)- or (Z)-Stereofixed enol sulfonates are recognized as
useful cross-coupling partners. Enol triflates are generally
used for this purpose,10 but they have two drawbacks
particularly for process chemistry: instability and high cost.
Despite its high demand, there have been few investigation
of enol tosylation. Recently, the Merck process group
disclosed a notable stereocomplementary tosylation method
for a sole specific γ-amino-ꢀ-ketoester using Ts2O and Et3N
or LDA.11 They rationally point out the advantage over enol
triflates with regard to stability and benchtop handling
procedures, etc. Expensive reagents (Ts2O and LDA) and
low temperature (-50 °C) for 3 h were, however, required.12
Our initial investigation was guided by the tosylation of
methyl acetoacetate using TsCl-NMI-Et3N or other bases
(Table 2). The use of Et3N successfully promoted the (E)-
selective tosylation (entry 1), which is consistent with the
reported reaction using Ts2O and Et3N.11
a Chlorobenzene(C6H5Cl)wasusedinsteadoftoluene.b Et3N-Me3N·HCl2a
was used instead of NMI-Et3N.
use of DMAP, a super acylation catalyst, instead of Et3N
resulted in no reaction (entry 5). Stereocongested secondary
alcohols, such as l-menthol, methyl mandelate, and 3,3-
dimethyl-2-butanol, underwent the present reaction to give
the desired tosylates (entries 7, 9, 11). Relevant mesylations
also proceeded more smoothly (entries 8, 10, 12). This might
t
Lithium reagents (nBuLi, LDA, LiHMDS, BuOLi) pro-
moted the (Z)-selective tosylation (entries 3-5, 8), whereas
the use of KHMDS and NaHMDS decreased the selectivity
(entries 6 and 7). More practical and robust LiOH exhibited
(7) (a) Misaki, T.; Nagase, R.; Matsumoto, K.; Tanabe, Y. J. Am. Chem.
Soc. 2005, 127, 2854. (b) Iida, A.; Nakazawa, S.; Okabayashi, T.; Horii,
A.; Misaki, T.; Tanabe, Y. Org. Lett. 2006, 8, 5215. (c) Iida, A.; Nakazawa,
S.; Nakatsuji, H.; Misaki, T.; Tanabe, Y. Chem. Lett. 2007, 36, 48. We
have been pointing out that NMI is superior to DMAP for acylation reactions
with regard to reactivity, cost, and toxicity [NMI (rat LD50, oral, 1130 mg/
kg) and DMAP (56 mg/kg)]
(8) This observation resembles the precedent reports of esterification
and amide formations promoted by combined bases NMI and TMEDA. (a)
Nakatsuji, H.; Morita, J.; Misaki, T.; Tanabe, Y AdV. Synth. Catal. 2006,
348, 2057. (b) Nakatsuji, H.; Morimoto, M.; Misaki, T.; Tanabe, Y.
Tetrahedron 2007, 50, 12071.
(9) NMI [δ 3.63 (s, 3H), 6.89 (s, 1H), 6.95 (s, 1H), 7.38 (s, 1H)] and A
[δ 2.39 (s, 3H), 3.93 (s, 3H), 7.46-7.48(m, 2H), 7.70. (s, 1H), 8.02 (s,
1H), 8.12-8.15 (m, 2H), 11.05 (s, 1H)]. A chart was described in ESI.
(10) For a recent example Hansen, A. L.; Skrydstrup, T. J. Org. Chem.
2005, 70, 5997.
(11) Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies, I. W. Org.
Lett. 2005, 7, 215.
(12) Klapars, A.; Campos, K. R.; Chen, C-y.; Volante, R. P. Org. Lett.
2005, 7, 1185. TsCl is ca. 1/10 more inexpensive than Ts2O. It was
commented that the use of TsCl caused R-chlorination as a side reaction.
2132
Org. Lett., Vol. 10, No. 11, 2008

conditions than for the corresponding Suzuki-Miyaura
coupling.10
Table 2. Tosylation of Methyl Acetoacetate Using
TsCl-NMI-Bases
Table 3. Enol Tosylation of ꢀ-Keto Esters by
TsCl-NMI-Bases
entry
base
Et3N
temp / °C
20-25
solvent yield / %a E / Za
1
C6H5Cl
92
98/2
2
3
tracea
80
nBuLi
-50 to -45 THF
3/97
8/92
4
LDA
70
5
6
7
8
LiHMDS
KHMDS
NaHMDS
tBuOLi
Li2CO3
LiCl
39
23
69
68
10/90
35/65
39/61
7/93
0 f 20-25 C6H5Cl
9
NR
NR
86
10
11
12
LiOH
4/96
traceb
a Determined by 1H NMR of the crude products. b In the absence of
NMI.
markedly higher reactivity and (Z)-selectivity (entry 11). The
absence of NMI resulted in no reaction (entries 2 and 12).
The proposed mechanism is illustrated in Scheme 3. In
Method A using Et3N, the reaction does not proceed via
chelation to give (E)-products, whereas in Method B using
LiOH, the reaction proceeds via a Li-chelation pathway to
give (Z)-products.
Scheme 3
.
Proposed Mechanism of the Stereoselective Enol
Tosylation
Table 3 lists the substrate-generality of the present enol
tosylation. The salient features are as follows: (i) All
substrates examined produced good to excellent results in
yield and (E)- and (Z)-stereoselectivity. (ii) Double bonds,
ω-chloro, and methyl ester functionalities were tolerated
(entries 9-14). (iii) Sterically congested ꢀ-ketoesters and
R-substituted ꢀ-ketoesters could also be applied (entries
15-23).
To demonstrate the present method, we focused our
attention on the stereoretentive cross-coupling of enol
tosylates. Table 4 lists the Negishi cross-coupling13 of various
enol tosylates. The present reaction proceeded under milder
a General Procedure. [Method A] TsCl (1.50 mmol) in chlorobenzene
(1.0 mL) was added to a stirred solution of a ꢀ-ketoester (1.00 mmol),
NMI (1.50 mmol), and Et3N (1.5 mmol) in C6H5Cl (1.0 mL) at 20-25 °C
and the mixture was stirred for 1 h. Water was added to the stirred mixture,
which was extracted with EtOAc. The organic phase was washed with 1
M HCl and brine, dried (Na2SO4), and concentrated. The obtained crude
product was purified by SiO2column chromatography (hexane-AcOEt )
20:1-5:1) to give the desired product. [Method B] TsCl (1.50 mmol) in
chlorobenzene (1.0 mL) was added to the stirred solution of a ꢀ-ketoester
(1.00 mmol), NMI (1.50 mmol), and LiOH (1.5 mmol) in C6H5Cl (1.0 mL)
at 0-5 °C under an Ar atomosphere, and the mixture was stirred at 20-25
°C for 1 h. Similar workup as for Method A gave the desired products.
b
Determined by H NMR of the crude products. c In CH2Cl2. d TMEDA
1
was used instead of Et3N.
(13) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
1821.
Org. Lett., Vol. 10, No. 11, 2008
2133

Table 4. Stereoretentive Negishi Coupling of Enol Tosylates
Table 5. Stereoretentive Sonogashira Coupling of Enol
Tosylates
a
i
An alkyne (1.50 mmol) in THF (0.5 mL) and Pr2NH (1.0 mL) was
added to a stirred solution of (E)- or (Z)-enol tosylate (1.00 mmol), CuI
(0.15 mmol), and Pd((PPh3)4 (0.05 mmol) in THF (1.0 mL) at 20 - 25 °C
b
i
under an Ar atomosphere. iPr2NEt was used instead of Pr2NH.
a R3MgBr (1.20 mmol) in THF (1.0 mL) was added to a stirred solution
of ZnCl2 (1.20 mmol) in THF (1.0 mL) at 0-5 °C under an Ar atomosphere,
and the mixture was stirred for 30 min. To the mixture was successively
added an (E)- or (Z)-enol tosylate (1.00 mmol) in THF (1.0 mL) and
Pd(PPh3)2Cl2 (0.01 mmnol), followed by stirring at 20-25 °C for 1 h.
b Pd(PPh3)4 was used instead of Pd(PPh3)2Cl2. c 15 h.
TsCl-NMI-Et3N or LiOH. Cross-coupling reactions (Negishi
and Sonogashira) were successfully performed to give
stereoretentive trisubstituted R,ꢀ-unsaturated esters. The
present method provides a new avenue for practical and
stereocontrolled preparation of trisubstituted olefins.
Table 5 lists the application to the Sonogashira coupling.14
The reaction using (E)-substrates proceeded within 2 h using
Pd(PPh3)2Cl2 catalyst, whereas (Z)-substrates required 14 h
using Pd(PPh3)4catalyst.
All reactions examined (Tables 4 and 5) were successfully
performed in good to excellent yield with nearly complete
stereoretention.
Acknowledgment. This research was partially supported
by Grant-in-Aids for Scientific Research on Basic Areas (B)
18350056, Priority Areas (A) 17035087 and 18037068, and
Exploratory Research 17655045 from MEXT. This Letter
is dedicated to Professor Ryoji Noyori on the occasion of
his 70th birthday.
In conclusion, we developed a general, robust, and (E)-
and (Z)-enol tosylation of ꢀ-ketoesters promoted by
Supporting Information Available: Experimental pro-
cedure and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467.
OL800480D
2134
Org. Lett., Vol. 10, No. 11, 2008