Phosphine-catalyzed β′-umpolung addition of nucleophiles to activated α-alkyl allenes

Article abstract of DOI:10.1021/ol200697m

Highly functionalized alkenes can be prepared through phosphine-catalyzed β′-umpolung additions of nucleophiles (carbon-, oxygen-, nitrogen-, and sulfur-centered) to activated α-disubstituted allenes, providing many potentially useful synthetic intermediates in good to excellent yields, often with high levels of stereoselectivity for the product olefin geometry. Various substitution patterns around the allene are compatible with the process, showcasing the synthetic utility of allenes under the conditions of nucleophilic phosphine catalysis.

Full text of DOI:10.1021/ol200697m

ORGANIC
LETTERS
Phosphine-Catalyzed β0-Umpolung
Addition of Nucleophiles to Activated
r-Alkyl Allenes
2011
Vol. 13, No. 10
2586–2589
Tioga J. Martin, Venus G. Vakhshori, Yang S. Tran, and Ohyun Kwon*
Department of Chemistry and Biochemistry, University of California, Los Angeles, 607
Charles E. Young Drive East, Los Angeles, California 90095-1569, United States
ohyun@chem.ucla.edu
Received March 15, 2011
ABSTRACT
Highly functionalized alkenes can be prepared through phosphine-catalyzed β0-umpolung additions of nucleophiles (carbon-, oxygen-, nitrogen-,
and sulfur-centered) to activated r-disubstituted allenes, providing many potentially useful synthetic intermediates in good to excellent yields,
often with high levels of stereoselectivity for the product olefin geometry. Various substitution patterns around the allene are compatible with the
process, showcasing the synthetic utility of allenes under the conditions of nucleophilic phosphine catalysis.
Nucleophilic phosphine catalysis is firmly established as
a reliable platform for a variety of transformations
involving activated allenes as starting materials.1 Within
this field, γ-umpolung addition of nucleophiles to activated
allenes and acetylenes allows the formation of a myriad of
substrates. Since the first report by Trost,2 there has been
increasing interest in phosphine-catalyzed γ-umpolung ad-
ditions of pronucleophiles to electron-deficient alkynes and
allenes (Scheme 1; eq 1).3 Combining the mechanistic in-
sights gained from studies of the γ-umpolung additions and
nucleophilic phosphine-catalyzed reactions of R-substituted
allenoates developed in our laboratory4 and by others,5 we
envisaged the possibility of a β0-umpolung addition to R-
alkyl allenoates (Scheme 1; eq 2). This process facilitates
functionalization of the seemingly unactivated β0-CꢀH
bond, allowing the generation of unique, highly versatile
olefinic products. The observed activation of the β0-carbon
atom of R-alkyl allenoates stems from the equilibrium
(1) For reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res.
2001, 34, 535. (b) Valentine, D. H.; Hillhouse, J. H. Synthesis 2003, 317.
(c) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (d)
Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985. (e) Nair, V.;
Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem.
Res. 2006, 39, 520. (f) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int.
Ed. 2008, 47, 1560. (g) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev.
2008, 37, 1140. (h) Kwong, C. K.-W.; Fu, M. Y.; Lam, C. S.-L.; Toy,
P. H. Synthesis 2008, 2307. (i) Aroyan, C. E.; Dermenci, A.; Miller, S. J.
Tetrahedron 2009, 65, 4069. (j) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev.
2009, 38, 3102. (k) Marinetti, A.; Voituriez, A. Synlett 2010, 174. (l)
Beata, K. Cent. Eur. J. Chem. 2010, 1147.
(2) (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167. (b)
Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819. (c) Trost, B.
M.; Drake, G. R. J. Org. Chem. 1997, 62, 5670. Albeit not in catalytic
form, Cristau first demonstrated the γ-umpolung addition of nucleo-
philes to activated allenes; see: (d) Cristau, H.-J.; Viala, J.; Christol, H.
Tetrahedron Lett. 1982, 23, 1569. (e) Cristau, H.-J.; Viala, J.; Christol, H.
Bull. Chim. Soc. Fr. 1985, 5, 980. (f) Cristau, H. J.; Fonte, M.; Torreilles,
E. Synthesis 1989, 301.
(3) (a) Zhang, C.; Lu, X. Synlett 1995, 645. (b) Chen, Z.; Zhu, G.;
Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Org. Chem. 1998, 63, 5631. (c)
Alvarez-Ibarra, C.; Csaky, A. G.; Oliva, C. G. Tetrahedron Lett. 1999,
40, 8465. (d) Alvarez-Ibarra, C.; Csaky, A. G.; Oliva, C. G. J. Org.
Chem. 2000, 65, 3544. (e) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677. (f)
Pakulski, Z.; Demchuk, O. M.; Frelek, J.; Luboradzki, R.; Pietrusiewicz,
K. M. Eur. J. Org. Chem. 2004, 3913. (g) Virieux, D.; Guillouzic, A.-F.;
Cristau, H.-J. Tetrahedron 2006, 62, 3710. (h) Chung, Y. K.; Fu, G. C.
Angew. Chem., Int. Ed. 2009, 48, 2225. (i) Smith, S. W.; Fu, G. C. J. Am.
Chem. Soc. 2009, 131, 14231. (j) Guan, X.-Y.; Wei, Y.; Shi, M. Org. Lett.
2010, 12, 5024. (k) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc.
2010, 132, 2550.
(4) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4716. (b) Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289. (c) Castellano,
S.; Fiji, H. D. G.; Kinderman, S. S.; Watanabe, M.; de Leon, P.;
Tamanoi, F.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 5843. (d) Tran,
Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632. (e) Lu, K.; Kwon,
O. Org. Synth. 2009, 86, 212. (f) Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem.
Soc. 2009, 131, 6318. (g) Khong, S. N.; Tran, Y. S.; Kwon, O. Tetra-
hedron 2010, 66, 4760.
(5) (a) Zhao, G.-L.; Shi, M. Org. Biomol. Chem. 2005, 3, 3686. (b)
Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (c) Wang, T.;
Ye, S. Org. Lett. 2010, 12, 4168.
r
10.1021/ol200697m
Published on Web 04/14/2011
2011 American Chemical Society

between the β-phosphonium dienolate and the vinylogous
ylide (see the mechanistic discussion below).4d,f,g
Table 1. Addition of Phenols to Activated Allenesa
Scheme 1. γ-Addition and β0-Umpolung Addition of Allenes
yield
(%)b
entry
R1
R2
E
1
E/Zc
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
1a
1b
1c
1d
1e
1f
>99
97
92
69
72
62
78
73
90
89
95
96
91
66
E only
E only
E only
E only
E only
E only
E only
E only
E only
4:1
2
4-Me
4-OMe
4-I
3
We began our studies by treating ethyl R-methyl alleno-
ate with a variety of substituted phenols and catalytic PPh3
inbenzene underreflux(Table 1). Thereactionwithphenol
proceeded smoothly to produce the β0-umpolung adduct
1a in quantitative yield as a single geometrical isomer
(entry 1). To our delight, we detected no γ-umpolung
addition product. Notably, unlike the requirements of
the γ-umpolung addition, no basic or acidic/basic addi-
tives were needed for the β0-umpolung reaction,2,3 which
provided an expedient route to the allylphenyl ether 1a, a
known intermediate in the functionalized coumarin
synthesis.6 We also obtained high yields from reactions
of phenols bearing electron-donating methyl or methoxy
substituents (entries 2 and 3). The allylaryl ethers 1dꢀ1h
derived from phenols with electron-withdrawing substitu-
ents were, however, isolated in diminished yields (entries
4ꢀ8), the result of a competitive fragmentation, producing
ethyl 2-methylenebut-3-enoate, which underwent known
dimerization through a DielsꢀAlder reaction.7 The pre-
sence of carboxylic ester and protected amino groups on
the phenols was tolerated well (entries 9 and 10). Intrigu-
ingly, a phenol featuring a Boc-protected amino substitu-
ent produced a mixture of E and Z isomers (entry 10).
Ortho and meta substitutions on the phenol ring were also
well tolerated (entries 11ꢀ13), although we observed a
slight decrease in stereoselectivity in the case of o-cresol
(entry 12). Extreme steric hindrance around the phenolic
nucleophile diminished the reaction efficiency. For in-
stance, 2,6-dimethylphenol provided a relatively low yield
(entry 14) and 2,6-di-tert-butylphenol gave no reaction
(entry 15).
4
5
4-Br
6
4-Cl
7
4-F
1g
1h
1i
8
4-CF3
4-CO2Et
4-NHBoc
3-Me
2-Me
2-I
9
10
11
12
13
14
1j
1k
1l
E only
20:1
1m
1n
E only
E only
2,6-di-
Me
15
2,6-di-t-
Bu
H
CO2Et
1o
0
N/A
16
17
18
4-OMe
4-CF3
4-CF3
Ph
Ph
Ph
CO2Et
CO2Et
CN
1p
1q
1r
89
97
88
Z only
Z only
Z only
a Reactions were performed using 1.1 equiv of allene. b Isolated yield.
c Determined through 1H NMR spectroscopic analysis.
entry 8, 73%). Allenonitrile also worked well as the
electrophile: the arylallyl ether 1r was obtained in excellent
yield (entry 18).8
Because our initial investigations with phenol pronu-
cleophiles were highly successful, we expanded our ex-
ploration of the β0-umpolung additions to amine-based
pronucleophiles (Table 2). N-Phenyl-p-toluenesulfona-
mide gave its expected product in excellent yield, albeit as
a 2.5:1 mixture of E and Z olefins (entry 1). N-Benzyl-p-
toluenesulfonamide and tert-butyl N-tosylcarbamate pro-
nucleophiles were also viable substrates (entries 2 and 3).
p-Toluenesulfonamide itselfresultedinlower productyield
and selectivity, favoring the Z-olefin geometry (entry 4).
The use of tert-butyl N-phenylcarbamate resulted in no
reaction product, due to the diminished acidity of the
pronucleophile (entry 5).3g The allylic amine product
derived from phthalimide was obtained in 71% yield as a
single E isomer (entry 6). p-Toluenesulfonohydrazine
gave its β-amino acid product in moderate yield (entry 7).
N-Tosyl-protected ethyl phenylalanine was also a suitable
pronucleophile, producing the amide 2h in excellent yield
(entry 8). Employing protected amines provides access to
R-substituted β-amino esters, which have great utility in
Further substitution at the β0-position of the allene
produced Z-olefins, presumably because of steric clash
between the methyl and alkyl groups (entries 16ꢀ18).
Furthermore, the β0-substitution protected the arylallyl
ether 1q from undergoing fragmentation to produce the
diene,7 providing 1q in 97% isolated yield (entry 17; cf.
(6) Drewes, S. E.; Emslie, N. D.; Karodia, N.; Loizou, G. Synth.
Commun. 1990, 20, 1437.
(7) For entry 8, the DielsꢀAlder adduct was isolated in 25% yield.
For other entries, this adduct was observed in the 1H NMR spectraof the
crude products. The characteristics of the isolated adduct matched those
reported in the literature; see: Mandai, T.; Yokoyama, H.; Miki, T.;
Fukuda, H.; Kobata, H.; Kawada, M.; Otera, J. Chem. Lett. 1980, 1057.
(8) Compound 1r contains the phenoxy phenyl propylamine skeleton
found in a number of pharmaceuticals (e.g., the antidepressant
fluoxetine); see: (a) Wong, D. T.; Horng, J. S.; Bymaster, F. P.; Hauser,
K. L.; Molloy, B. B. Life Sciences 1974, 15, 471. (b) Wong, D. T.; Perry,
K. W.; Bymaster, F. P. Nat. Rev. Drug Discovery 2005, 4, 764.
(9) For reviews, see: (a) Seebach, D.; Matthews, J. L. Chem. Commun.
1997, 21, 2015. (b) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206. (c)
Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity 2004, 1,
1111.
Org. Lett., Vol. 13, No. 10, 2011
2587

Table 2. Addition of Amines to R-Methyl Allenoatea
Table 3. Addition of Carboxylic Acids to Allenoatesa
a Reactions were performed using 1.1 equiv of the allenoate. b Iso-
lated yield. c Determined through 1H NMR spectroscopic analysis.
a Reactions were performed using 1.1 equiv of allenoate. b Isolated
yield. c Determined through 1H NMR spectroscopic analysis.
β-peptide chemistry;9 in addition, R-methylene-β-alanine
is a naturally occurring herbicidal amino acid.10
addition at the R-carbon atom (Table 4). We obtained the
resulting dienes as mixtures of E and Z R,β-unsaturated
enoates, with the β,γ-olefin unit from the cyanoacetate
existing exclusively in E form. Although we obtained these
products in relatively modest yields, the alkylcyanoacetate
pronucleophiles provided access to highly functionalized all-
carbon diene substrates.
Carboxylic acids also turned out to be excellent pronu-
cleophiles for this β0-umpolung reaction and worked well
with a variety of diversely substituted allenoates (Table 3).
With ethyl R-methyl allenoate, both acetic acid and ben-
zoic acid provided their corresponding acylated allylic
alcohols in excellent yields, as E isomers exclusively
(entries 1 and 2).11 Complementary to the N-terminus
addition of phenylalanine (Table 2, entry 8), the C-termi-
nus addition of N-tert-butoxycarbonyl phenylalanine was
just as efficient (Table 3, entry 3). The mild and neutral
conditions ensured that no epimerization occurred during
the reaction.12 Benzoic acid reacted as anticipated with the
γ-methyl-substituted allenoate (entry 4), but the exces-
sively large γ-tert-butyl substituent inhibited the reaction
(entry 5). Ethyl R-(5-hexenyl)allenoate was compatible
with the transformation (entry 6). In accordance with
our observations regarding phenol pronucleophiles, the
R-benzyl allenoate produced the Z-olefinic enoate in ex-
cellent yield (entry 7). Diethyl 2-vinylidenesuccinate also
proved to be a viable substrate for the β0-addition of
benzoic acid, producing a mixture of its two olefinic
isomers in excellent yield (entry 8).
We further expanded the reaction scope to consider car-
bon-centered pronucleophiles. The reaction of malononitrile
with ethyl R-methyl allenoate gave a Z-configured olefin
product, which structurally resembles a mixed Rauhutꢀ
Currier adduct (4, eq 3), in 86% yield.1i Although dimethyl
malonate and ethyl cyanoacetate did not undergo corre-
sponding β0-umpolung additions, R-alkylcyanoacetates
did.13 The actual pronucleophiles employed were alkylidene-
cyanoacetates, which underwent γ-deprotonation and
Table 4. Addition of Cyanoacetates to Activated Allenesa
entry
R1
R2
5
yield (%)b
E/Zc
1
2
3
n-Bu
Me
H
5a
5b
5c
57
42
79
1:5
H
1:5
1:2d
Me
Me
a Reactions were performed using 1.1 equiv of the allenoate. b Iso-
lated yield. c Determined through 1H NMR spectroscopic analysis.
d Isomers were separated and characterized; details provided in the
Supporting Information.
Furfuryl alcohol, oxime, and thiol functionalities were
compatible with the β0-umpolung addition (Table 5).
While most aliphatic alcohols did not participate in the
umpolung reaction, due to their high values of pKa,14 the
relatively low pKa offurfuryl alcohol (9.55) made ita prime
candidate for the β0-addition reaction (entry 1). Oximes
and thiols also possess suitable values of pKa for this
transformation. Indeed, (E)-benzaldehyde oxime (pKa
(10) Isaac, B. G.; Ayer, S. W.; Stonard, R. J. J. Antibiot. 1991, 44, 795.
(11) (E)-Ethyl 2-acetoxy-2-butenoate (3a) is an intermediate for the
synthesis of mikanecic acid; see: Edwards, J. D.; Matsumoto, T.; Hase,
T. J. Org. Chem. 1967, 32, 244.
(12) No epimerization occurred during the reaction, as verified
through HPLC analysis; see the Supporting Information for details.
(13) Lu has reported that tributylphosphine facilitates γ-umpolung
addition of dimethyl malonate to ethyl R-methyl allenoate; see ref 3a.
(14) Lu has reported that benzyl alcohol functions as a γ-umpolung
donor when reacted with allenoates; see ref 3a.
2588
Org. Lett., Vol. 13, No. 10, 2011

As mentioned previously, many of these substrates are
synthetically useful. For example, we performed a further
transformation of the allylphenyl ether 1a. Upon heating in
diethylaniline under reflux, the allylaryl ether 1a underwent a
facile Claisen rearrangement, lactonization, and isomeriza-
tion cascade to produce 3,4-dimethylcoumarin (13, eq 4).19
Table 5. Addition of Pronucleophiles to Ethyl R-Methylalle-
noatea
entry
NuH
product
yield (%)b
E/Zc
1
2
3
furfuryl alcohol
(E)-benzaldehyde oxime
PhSH
6
7
8
88
77
65
1:1
4:1
5:1
This paper reports the first examples of β0-umpolung
additions of nucleophiles(carbon-, oxygen-, nitrogen-, and
sulfur-centered) to activated allenes, producing many use-
ful synthetic intermediates in good to excellent yields, often
with high levels of selectivity for the olefin geometry.
Whereas activated R-monosubstituted allenes undergo
the well-established γ-umpolung addition, activated
R-disubstituted allenes undergo β0-umpolung addition ex-
clusively, underlining the synthetic utility of this versatile
class of molecules. As a showcase of the power of this
reported reaction, we performed a one-step cascade pro-
cess from an allylphenyl ether intermediate to a coumarin
product. We are currently exploring applications of this
methodology to other syntheses of small molecules.
a Reactions were performed using 1.1 equiv of allenoate. b Isolated
yield. c Determined through 1H NMR spectroscopic analysis.
11.3) and benzenethiol (pKa 7) underwent the reaction
smoothly (entries 2 and 3). O-Allyl oximes are useful
synthetic precursors for allylation of activated methylene
compounds15 and [2,3]-sigmatropic N,O rearrange-
ments.16 When treated with palladium(II), oxime O-allyl
ether undergoesformal[2,3]-sigmatropicrearrangement to
form N-allyl nitrone, which can then be engaged in a
dipolar cycloaddition reaction in situ.17 O-Allyl oximes
have also been converted in one step into pyrroles under
iridium catalysis.18
Scheme 2 presents a plausible mechanism for this
reaction. Phosphine addition to the allenoate gives the
phosphonium dienolate 9. A well-established equili-
brium between the phosphonium enolate 9 and the
vinylogous phosphorus ylide 10 is facilitated through
proton transfer steps.4d,f,g Deprotonation of the pronu-
cleophile by the ylide 11 forms the phosphonium enoate
electrophile 12. Conjugate addition of the anionic nu-
cleophile to the enoate and subsequent β-elimination of
the phosphine yield the observed β0-umpolung addition
product.
Acknowledgment. Financial support was provided by
the NIH (R01GM071779 and P41GM081282).
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This information is available free of charge via the Inter-
net at http://pubs.acs.org.
(15) Suzuki, O.; Hashiguchi, Y.; Inoue, S.; Sato, K. Chem. Lett. 1988,
291.
(16) Davies, S. G.; Fox, J. F.; Jones, S.; Price, A. J.; Sanz, M. A.;
Sellers, T. G. R.; Smith, A. D.; Teixeira, F. C. J. Chem. Soc., Perkin
Trans. 1 2002, 1757.
(17) Oikawa, M.; Takeda, Y.; Naito, S.; Hashizume, D.; Koshino,
H.; Sasaki, M. Tetrahedron Lett. 2007, 48, 4255.
(18) Wang, H.-Y.; Mueller, D. S.; Sachwani, R. M.; Londino, H. N.;
Anderson, L. L. Org. Lett. 2010, 12, 2290.
Scheme 2. Mechanism of the β0-Umpolung Addition
(19) For the synthesis of 3,4-dimethylcoumarin, see: (a) Dittmer,
D. C.; Li, Q.; Avilov, D. V. J. Org. Chem. 2005, 70, 4682. (b) Chatterjee,
A. K.; Toste, F. D.; Goldberg, S. D.; Grubbs, R. H. Pure Appl. Chem.
2003, 75, 421. (c) Fuerstner, A.; Jumbam, D. N.; Shi, N. Z. Naturforsch.,
B: Chem. Sci. 1995, 50, 326. (d) Patil, V. O.; Kelkar, S. L.; Wadia, M. S.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1987, 26B, 674. (e)
Mali, R. S.; Tilve, S. G.; Patil, K. S.; Nagarajan, G. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1985, 24B, 1271. (f) Falsone, G.;
Spur, B.; Wingen, H. P. Arch. Pharm. (Weinheim, Ger.) 1983, 316, 763. (g)
Motoyoshiya, J.;Teranishi, A.;Mikoshiba, R.; Yamamoto, I.;Gotoh, H.;
Enda, J.; Ohshiro, Y.; Agawa, T. J. Org. Chem. 1980, 45, 5385.
Org. Lett., Vol. 13, No. 10, 2011
2589