Bronsted base catalyzed [2,3]-Wittig/phospha-Brook tandem rearrangement sequence

Article abstract of DOI:10.1021/ol402144q

A Bronsted base catalyzed rearrangement reaction of 2-allyloxy-2-phosphonoacetate derivatives was developed. This reaction proceeded via a [2,3]-Wittig rearrangement followed by a phospha-Brook rearrangement. This is the first example of a catalytic [2,3]-Wittig rearrangement initiated by a Bronsted base.

Full text of DOI:10.1021/ol402144q

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4568–4571
Brønsted Base Catalyzed [2,3]-Wittig/
Phospha-Brook Tandem Rearrangement
Sequence
Azusa Kondoh† and Masahiro Terada*,†,‡
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku,
Sendai 980-8578, Japan, and Research and Analytical Center for Giant Molecules,
Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
mterada@m.tohoku.ac.jp
Received July 29, 2013
ABSTRACT
A Brønsted base catalyzed rearrangement reaction of 2-allyloxy-2-phosphonoacetate derivatives was developed. This reaction proceeded via a
[2,3]-Wittig rearrangement followed by a phospha-Brook rearrangement. This is the first example of a catalytic [2,3]-Wittig rearrangement initiated
by a Brønsted base.
The [2,3]-Wittig rearrangement is a useful tool in syn-
thetic organic chemistry, especially for the total synthesis
of natural products and the preparation of bioactive
compounds.1 The conventional initiation of this rearran-
gement is accomplished through generation of R-allyloxy
carbanions by deprotonation using a stoichiometric
amount of strong Brønsted bases, such as nBuLi and
NaH, followed by [2,3] sigmatropic rearrangement to
provide homoallyl alkoxides. Many reaction systems in
[2,3]-Wittig rearrangement have been studied thoroughly.
Among the systems investigated, catalytic rearrangements
have stimulated intensive interest because they allow a
reaction without the use of a stoichiometric amount of a
strong Brønsted base. To develop a catalytic rearrange-
ment, methods using a Lewis base2 as well as a Lewis acid
catalyst3 have been reported. However, these catalytic
methods require preformed silyl enol ethers of R-allyloxy
esters or ketones.4 Recently, a direct rearrangement with-
out preparation of a preformed enolate equivalent was
reported using a secondary amine catalyst.5 Although this
direct catalysis can be performed under mild reaction
conditions, the substrates are inherently limited to R-
allyloxy ketones because of participation of the enamine
intermediate generated from the ketone and secondary
amine catalyst. No direct rearrangements using Brønsted
base catalysis have been reported to date. In this context,
we designed a tandem rearrangement sequence to develop
a novel catalytic [2,3]-Wittig rearrangement initiated
by Brønsted bases. In our proposed system, a [2,3]-
Wittig rearrangement is combined with a phosphonateꢀ
phosphate rearrangement, so-called phospha-Brook rear-
rangement,6,7 using substrates containing a phosphono
† Department of Chemistry.
‡ Research and Analytical Center for Giant Molecules.
(1) For reviews, see: (a) Nakai, T.; Mikami, K. Org. React. 1994, 46,
105. (b) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885. (c) Mikami, K.;
Nakai, T. Synthesis 1991, 594. (d) Marshall, J. A. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 3, Chapter 3. (e) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl.
1979, 18, 563. (f) Nakai, T.; Tomooka, K. Pure Appl. Chem. 1997, 69,
595.
(4) Lewis acid catalyzed [2,3]-rearrangement of propargyloxy enols
was reported; see: Moniz, G. A.; Wood, J. L. J. Am. Chem. Soc. 2001,
123, 5095.
(5) McNally, A.; Evans, B.; Gaunt, M. J. Angew. Chem., Int. Ed.
2006, 45, 2116.
(6) For early studies, see: (a) Fitch, S. J.; Moedritzer, K. J. Am. Chem.
Soc. 1962, 84, 1876. (b) Hall, L. A. R.; Stephenes, C. W.; Drysdals, J. J. J.
Am. Chem. Soc. 1957, 79, 1768. (c) Barthel, W. F.; Alexander, B. H.;
Giang, P. A.; Hall, S. A. J. Am. Chem. Soc. 1955, 77, 2424. (d) Mattson,
A. M.; Spillane, J. T.; Pearce, G. W. J. Agric. Food Chem. 1955, 3, 319. (e)
Lorenz, W.; Henglbin, A.; Schrader, G. J. Am. Chem. Soc. 1955, 77,
2554.
(2) Sato, Y.; Fujisawa, H.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
2006, 79, 1275.
(3) Mikami, K.; Takahashi, O.; Tabei, T.; Nakai, T. Tetrahedron
Lett. 1986, 27, 4511.
r
10.1021/ol402144q
Published on Web 08/27/2013
2013 American Chemical Society

group R to an allyloxy group. The proposed reaction is
shown in Scheme 1. At first, deprotonation by a Brønsted
base followed by [2,3]-Wittig rearrangement provides alk-
oxide C. Conventional [2,3]-Wittig rearrangement is ter-
minated at this point; for the designed substrate, 1,2-
rearrangement of the phosphono group from carbon to
oxygen, i.e., phospha-Brook rearrangement, occurs to
generate carbanion D. Finally, carbanion D is protonated
by the conjugated acid of the Brønsted base or substrate A
to afford the product along with regeneration of the
Brønsted base or carbanion B. The key step for the
catalytic reaction is the last step of the catalytic cycle,
which involves regeneration of the Brønsted base or R-
allyloxy carbanion. For conventional [2,3]-Wittig rearran-
gement, this step is difficult because the acidity of the
proton R to the allyloxy group of the substrate is lower
than that of the hydroxy proton of the product. In
contrast, the newly designed reaction system maintains
the acidity of the substrate that is relatively high compared
to that of the product because of the influence of an
electron-withdrawing phosphono group. As a conse-
quence, protonation of carbanion D to regenerate a
Brønsted base or carbanion B can occur and reaction
should proceed catalytically. This report describes the
tandem rearrangement of phosphonoacetate derivatives
containing an allyloxy group in the presence of a catalytic
amount of a Brønsted base.
Table 1. Screening of Reaction Conditionsa
entry
base (mol %)
solvent
DMF
temp
yield (%)b
1
tBuOK (10)
LHMDS (10)
Cs2CO3 (10)
P4-tBu (10)
P2-tBu (10)
P1-tBu (20)
TBD (20)
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
rt
89 (86)
81
2
DMF
3
DMF
(86)
82 (81)
88 (85)
32
4
DMF
5
DMF
6
DMF
7
DMF
34
8
DBU (20)
DMF
14
9
tBuOK (10)
P2-tBu (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
DMF
(93)
(86)
(86)
75
10
11
12
13
14
15
DMF
rt
DMSO
THF
rt
rt
1,4-dioxane
toluene
tBuOH
rt
52
rt
0
rt
0
a Reaction conditions: 1a (0.10 mmol), base (0.010ꢀ0.020 mmol),
solvent (1.0 mL), 90 °C or rt, 12 h. b NMR yields of 2a. CHBr3 was used
as an internal standard. Isolated yields are in parentheses.
Scheme 1. Proposed Catalytic System
inorganic bases as well as organic bases (entries 2ꢀ8).
Among them, inorganic bases, such as LHMDS and
Cs2CO3, and phosphazene bases P2-tBu and P4-tBu,
which are organosuperbases, provided 2a in good yield.
With these bases, tBuOK and P2-tBu, the reaction pro-
ceeded smoothly even at room temperature (entries 9 and 10).
Next, the effect of solvents was investigated with tBuOK
at room temperature (entries 11ꢀ15). The result indicated
that aprotic polar solvents such as DMF and DMSO
proved to be the solvents of choice (entries 9 and 11),
whereas ethereal solvents were less effective (entries 12
and 13). The use of toluene and tBuOH did not provide
any product, and 1a was completely recovered (entries 14
and 15).
With the optimized conditions in hand, the scope of the
substrates was investigated (Scheme 2).8 Substrates posses-
sing a variety of substitution patterns involving an allyloxy
group were subjected to the reaction conditions. Reactions
of 1b and 1c, which have a trans-1,2-disubstituted alkene
moiety, proceeded to provide the corresponding products
2b and 2c, respectively, in good yield with moderate
diastereoselectivity. The cis-alkene 1d gave a result similar
to that of trans-alkene 1c. A methallyloxy-substituted 1e
also underwent the reaction to afford 2e in good yield.
Next, the substrates containing substituents at the allylic
To ascertain the viability of the proposed tandem re-
arrangement, we attempted the reaction of ethyl 2-ally-
loxy-2-diethylphosphonoacetate (1a) as the primary
substrate. An initial experiment was performed using 10
mol % of tBuOK in DMF at 90 °C for 12 h. Delightfully,
the envisioned tandem rearrangement proceeded catalyti-
cally to afford 2a in 89% NMR yield and 86% isolated
yield (Table 1, entry 1). This preliminary result prompted
us to a further screening of Brønsted bases, including
(7) For selected examples, see: (a) Bausch, C. C.; Johnson, J. S. Adv.
€
:
ꢀ
Synth. Catal. 2005, 347, 1207. (b) Demir, A. S.; Reis, O.; Igdir, A. C-.;
:
€
Esiringu, I.; Eymur, S. J. Org. Chem. 2005, 70, 10584. (c) Demir, A. S.;
€
Reis, B.; Reis, O.; Eymur, S.; Gollu, M.; Tural, S.; Saglam, G. J. Org.
€
€ €
€
€
€ €
Chem. 2007, 72, 7439. (d) Demir, A. S.; Esiringu, I.; Gollu, M.; Reis, O.
J. Org. Chem. 2009, 74, 2197. (e) El Kaım, L.; Gaultier, L.; Grimaud, L.;
Dos Santos, A. Synlett 2005, 2335. (f) Hayashi, M.; Nakamura, S.
Angew. Chem., Int. Ed. 2011, 50, 2249. (g) Corbett, M. T.; Uraguchi, D.;
Ooi, T.; Johnson, J. S. Angew. Chem., Int. Ed. 2012, 51, 4685.
(8) The reaction was conducted at 90 °C because the reaction of the
substrates possessing substituent(s) on the allyloxy moiety was very slow
at room temperature.
Org. Lett., Vol. 15, No. 17, 2013
4569

underwent the reaction smoothly as with 1a (eq 1). The
substrate 1o, which had a diphenylphosphono group
instead of diethylphosphono group, also reacted to pro-
vide the corresponding product 2o in high yield. In con-
trast, the reaction of N,N-dialkylacetamide analog 1p and
acetophenone analog 1q did not afford the desired pro-
ducts (Figure 1). The reaction of an acetonitrile analog 1r
provided a complex mixture of products.
Scheme 2. Substrate Scopea
Figure 1. Unsuitable substrates for the reaction.
Additional investigation of this reaction involved appli-
cation to ring contraction (Scheme 3).9 The 11- and 12-
membered substrates 4a and 4b were synthesized by ring-
closing metathesis of dienes 3a and 3b, respectively.10 The
substrates obtained then were subjected to the reaction
conditions. Both substrates underwent the reaction to
provide the corresponding 7- and 8-membered lactones
5a and 5b, respectively, with good diastereoselectivity.
Interestingly, in the reaction of 4a, the trans isomer was
obtained as the major diastereomer, while 4b afforded the
cis isomer as the major diastereomer.11 These major isomers
were easily isolated using silica gel column chromatography.
Scheme 3. Application to Ring Contractions
a Reaction conditions: 1 (0.20 mmol), tBuOK (0.020 mmol), DMF
(2.0 mL), 90 °C, 12 h. Ratios of diastereomers were determined by H
NMR analysis of a crude mixture.
1
position were investigated. Monosubstituted 1f and 1g as
well as disubstituted 1h underwent the reaction smoothly
to afford the corresponding products in high yields. Note
that the reaction of 1f and 1g proceeded with perfect E
selectivity. Two substituents at the alkene terminus did not
compromise the reaction, and 2i was produced in good
yield. The reaction of 1j occurred in an entirely stereo-
selective manner to provide the corresponding stereode-
fined trisubstituted alkene 2j. Finally, the substrates with a
substituent at each allylic position and alkene terminus
were examined. For 1k and 1l, the reaction proceeded in
good yield with perfect E selectivity and moderate diaster-
eoselectivity. In contrast, 1m provided the corresponding
product 2m, which has a cyclic Z alkene moiety, as a 1:1
diastereomixture along with a small amount of isomer 2m0.
The use of phosphonoacetate is essential for this reaction
(eq 1, Figure 1). The other acetate such as benzyl acetate 1n
(9) Takahashi, T.; Nemoto, H.; Kanda, Y.; Tsuji, J.; Fujise, Y. J.
Org. Chem. 1986, 51, 4315.
€
€
(10) Furstner, A.; Guth, O.; Duffels, A.; Seidel, G.; Liebl, M.; Gabor,
B.; Mynott, R. Chem.;Eur. J. 2001, 7, 4811.
4570
Org. Lett., Vol. 15, No. 17, 2013

The reduction of 2b and 2c with LiAlH4 provided the
corresponding diols 7a and 7b, respectively, in good yields.
Nucleophilic substitution occurred by treating 2a with
dodecanethiol in the presence of cesium carbonate, where
a diethoxyphosphoryloxy group served as a leaving group.
Finally, allylation of the R position of an ester was
conducted to yield a product containing a tetrasubstituted
carbon.
Scheme 4. Transformation of 2
In conclusion, a novel catalytic [2,3]-Wittig rearrange-
ment was developed by utilizing phospha-Brook rearran-
gement, which is the first example of direct rearrangement
under Brønsted base catalysis. This operationally simple
reaction is applicable to substrates containing substitutions
on an allyloxy moiety and can provide building blocks
that are easily modified in a variety of ways. Further
investigation of this methodology, including development
of an enantioselective rearrangement, is now in progress.
Acknowledgment. This work was partially supported
by a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Orga-
nocatalysts” from MEXT, Japan and a Grant-in-Aid for
Scientific Research from the JSPS.
The products of this reaction possess a diethoxypho-
sphoryloxy group, which can function as a handle for
further manipulation. Based on this functionality, several
transformations were performed (Scheme 4). For example,
treatment of 2f with sodium ethoxide in ethanol provid-
ed the corresponding hydroxy ester 6 in good yield.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(11) Relative configurations of the major isomers of 5a and 5b were
determined by NOE analysis. See Supporting Information for details.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
4571