Carbon Nucleophiles in the Mitsunobu Reaction. Mono- and Dialkylation of Bis(2,2,2-trifluoroethyl) Malonates

Article abstract of DOI:10.1021/ol0266626

(Matrix Presented) Simple dialkyl malonate esters, for example diethyl malonate, exhibit relatively limited scope as carbon nucleophiles in the Mitsunobu dehydrative alkylation reaction. In contrast, bis(2,2,2-trifluoroethyl) malonate readily undergoes dehydrative alkylation with primary alcohols, and using only a slight excess of malonate gives monoalkylated product in good yield. Some secondary alcohols can also be employed, and bis(2,2,2-trifluoroethyl) malonates can be used in a second dehydrative alkylation to give dialkylated products in good to excellent yield.

Full text of DOI:10.1021/ol0266626

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3843-3845
Carbon Nucleophiles in the Mitsunobu
Reaction. Mono- and Dialkylation of
Bis(2,2,2-trifluoroethyl) Malonates
James M. Takacs,* Zhenrong Xu, Xun-tian Jiang, Alexei P. Leonov, and
Gregory C. Theriot
Department of Chemistry, UniVersity of Nebraska-Lincoln,
Lincoln, Nebraska 68588-0304
jtakacs1@unl.edu
Received August 2, 2002
ABSTRACT
Simple dialkyl malonate esters, for example diethyl malonate, exhibit relatively limited scope as carbon nucleophiles in the Mitsunobu dehydrative
alkylation reaction. In contrast, bis(2,2,2-trifluoroethyl) malonate readily undergoes dehydrative alkylation with primary alcohols, and using
only a slight excess of malonate gives monoalkylated product in good yield. Some secondary alcohols can also be employed, and bis(2,2,2-
trifluoroethyl) malonates can be used in a second dehydrative alkylation to give dialkylated products in good to excellent yield.
The Mitsunobu reaction is a versatile method for the coupling
of an alcohol (R1OH) with a pronucleophile (H-Nu) to form
the dehydrative alkylation product (R1-Nu) (Scheme 1).1 The
limited due to the relatively low acidity of most carbon acids.
For example, simple malonic esters such as diethyl malonate
are not efficient nucleophiles for the Mitsunobu condensa-
tion,5 especially under the original conditions employing
diethyl diazodicarboxylate (DEAD) and triphenylphosphine.
The lack of reactivity exhibited by malonates is attributed
to their relatively weak acidity; the pKa of diethyl malonate
in water is 13.3.6 To expand the utility of carbon nucleo-
philes, two general improvements have been sought: the
development of more acidic carbon nucleophiles, and the
development of alternative coupling reagents. Considerable
progress has been made in the latter approach, and a number
of reaction protocols now prove more effective than the
original recipe7,8 and/or are tuned for specialty applications.9
Some of the newer procedures are reported to be useful
for the alkylation of diethyl malonate,8,10 but more com-
monly, more acidic active methylene compounds or related
Scheme 1
reaction typically employs a triaryl- or trialkylphosphine and
an azodicarboxylate as stoichiometric reagents to activate
the coupling components and has been extensively studied
with regard to its mechanism2 and widely used, particularly
with heteroatom pronucleophiles, in organic synthesis.1,3 The
Mitsunobu reaction requires a relatively acidic pronucleo-
phile,4 and its utility in carbon-carbon bond formation is
(3) (a) Simon, C.; Hosztafi, S.; Makleit, S. J. Heterocycl. Chem. 1997,
34, 349-365. (b) Wisniewski, K.; Koldziejczyk, A. S.; Falkiewicz, B. J.
Pept. Sci. 1998, 4, 1-14.
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Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67, 1751-1753.
(c) Watanabe, T.; Gridnev, I. D.; Imamoto, T. Chirality 2000, 12, 346-
351. (d) Eberson, L.; Persson, O.; Svensson, J. O. Acta Chem. Scand. 1998,
52, 1293-1300. (e) Shull, B. K.; Sakai, T.; Nichols, J. B.; Koreeda, M. J.
Org. Chem. 1997, 62, 8294-8303.
(4) Koppel, I.; Koppel, J.; Degerbeck, F.; Grehn, L.; Ragnarsson, U. J.
Org. Chem. 1991, 56, 7172-7174.
(5) Wada, M.; Mitsunobu, O. Tetrahedron Lett. 1972, 1279-1282.
(6) Pearson, R. G.; Dillon, R. L. J. Am. Chem. Soc. 1953, 75, 2439-
2443.
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2521. (b) Zaragoza, F.; Stephensen, H. Tetrahedron 2001, 57, 5451-5454.
(c) Steinreiber, A.; Stadler, A.; Mayer, S. F.; Faber, K.; Kappe, C. O.
Tetrahedron Lett. 2001, 42, 6283-6286. (d) Ito, S.; Tsunoda, T. Pure Appl.
10.1021/ol0266626 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/09/2002

derivatives and synthetic equivalents are employed.11 For
example, Shing reported the C-alkylation of Meldrum’s acid
under Mitsunobu conditions.12 Its alkylation works using a
limited range of alcohols, principally, primary allylic or
arylmethyl alcohols, and only dialkylated products are
obtained. Attempts to selectively monoalkylate failed. The
problem of dialkylation is inherent in such reactions and is
seen even in polymer-bound applications, where the reacting
partners are constrained.13
conditions and fluorous-based separations.16 The reaction of
1 was examined under three sets of frequently used Mit-
sunobu conditions (Table 1).
Table 1. The Monoalkylation of Bis(2,2,2-trifluoroethyl)
Malonate (1) under Three Common Mitsunobu Conditions
We were encouraged that, while not suitable for our use,
Meldrum’s acid derivatives were at least sufficiently reactive
to participate in the Mitsunobu reaction. We reasoned that
by appropriate choice of the ester substituent another
malonate derivative with suitable acidity could be found. We
carried out the reaction of diphenyl malonate with allyl
alcohol and obtained a mixture of O- and C-alkylation
products, with the former predominating by about 2:1. The
problem of regiocontrol in the Mitsunobu reaction of
ambident nucleophiles is inherent to such substrates.4,14
We next investigated the reaction of bis(2,2,2-trifluoro-
ethyl) malonate (1), a compound that has been described in
both the open and patent literature for other purposes.15
Fluorine-containing compounds have been used in Mitsunobu
reactions, most frequently as substituents in the alcohol
component or in the development of fluorous reaction
entry
R1OH
methoda
product
yield (%)
1
2
3
4
5
Ph(CH2)3OH
Ph(CH2)3OH
Ph(CH2)3OH
PhCH2OH
A
B
C
A
B
2a
2a
2a
2b
2b
40
84
82
41
63b
PhCH2OH
a Reaction conditions: A mixture of 1 (1.1 equiv), alcohol (1.0 equiv),
phosphine (1.5 equiv), and azo compound (1.5 equiv) in dry toluene at
room temperature. Methods: (A) DEAD-Ph3P; (B) ADDP-Ph3P; and (C)
ADDP-Bu3P. b Bis(2,2,2-trifluoroethyl) dibenzylmalonate was isolated in
27% yield.
Under the original Mitsunobu DEAD-Ph3P conditions,
dehydrative coupling with a simple primary alcohol test
substrate, 3-phenyl-1-propanol, gives the desired C-alkylated
product 2a in 40% yield (Table 1, entry 1). However, using
the 1,1′-(azodicarbonyl)dipiperidine (ADDP)-Ph3P or ADDP-
Bu3P reagents,8 the monoalkylated product 2a was obtained
in greater than 80% yield (Table 1, entries 2 and 3,
respectively). Benzyl alcohol behaves similarly, although the
combination of a more reactive alcohol and the more reactive
ADDP reagent gives a significant amount of the dialkylated
product (27%) in addition to the major monoalkylated
product 2b (63%).
Having identified bis(2,2,2-trifluoroethyl) malonate (1) as
a malonate derivative suitable for use in the ADDP-Ph3P
promoted Mitsunobu reaction, and finding that it reacts via
C-alkylation and can be selectively monoalkylated, other
aspects probing the scope of reaction were investigated. The
starting materials, products, and data obtained are sum-
marized in Table 2. With a limiting amount of allyl alcohol,
the reaction proceeds much like that of benzyl alcohol; the
monoalkylated product 2c is obtained in 60% yield (entry
1). Using an excess of the alcohol and coupling components,
malonate 1 can be efficiently dialkylated. For example, in
the presence of excess allyl alcohol, the dialkylated malonate
3a was formed in 92% yield (entry 2). Similarly, starting
with the monoalkylated malonate 2a, dehydrative alkylation
Chem. 1999, 71, 1053-1057. (e) Kiankarimi, M.; Lowe, R.; McCarthy, J.
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1994, 35, 5081-5082.
(8) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34,
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(9) For example: (a) Ryoo, S.-J.; Kim, J.; Kim, J.-S.; Lee, Y.-S. J. Comb.
Chem. 2002, 4, 187-190. (b) Li, Z.; Zhou, Z.; Wang, L.; Zhou, Q.; Tang,
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A. B.; Janes, M. K.; Boezio, A. A. J. Org. Chem. 2001, 66, 2178-2180.
(e) Ding, S.; Gray, N. S.; Ding, Q.; Schultz, P. G. J. Org. Chem. 2001, 66,
8273-8276. (f) Viirre, R. D.; Hudson, R. H. E. Org. Lett. 2001, 3, 3931-
3934. (g) Winum, J. Y.; Barragan, V.; Montero, J. L. Tetrahedron Lett.
2001, 42, 601-603.
(10) Tsunoda, T.; Nagaku, M.; Nagino, C.; Kawamura, Y.; Ozaki, F.;
Hioki, H.; Ito, S. Tetrahedron Lett. 1995, 36, 2531-2534.
(11) (a) Macor, J. E.; Wehner, J. M. Tetrahedron Lett. 1991, 32, 7195-
7198. (b) Yu, J. R.; Cho, H. S.; Falck, J. R. J. Org. Chem. 1993, 58, 5892-
5894. (c) Lai, J. Y.; Yu, J. R.; Hawkins, R. D.; Falck, J. R. Tetrahedron
Lett. 1995, 36, 5691-5694. (d) Yu, J. R.; Lai, J. Y.; Falck, J. R. Synlett
1995, 1127-1128. (e) Tsunoda, T.; Nagino, C.; Oguri, M.; Ito, S.
Tetrahedron Lett. 1996, 37, 2459-2462. (f) Cravotto, G.; Glovenzana, G.
B.; Sisti, M.; Palmisano, G. Tetrahedron 1996, 52, 13007-13016. (g)
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1999, 40, 7359-7362. (h) Uemoto, K.; Kawahito, A.; Matsushita, N.;
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(12) Shing, T. K. M.; Li, L. H.; Narkunan, K. J. Org. Chem. 1997, 62,
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3844
Org. Lett., Vol. 4, No. 22, 2002

Table 2. Dehydrative Mono- and Dialkylations of Bis(2,2,2-trifluoroethyl) Malonates 1 and 2a
entry
NuH
alcohol
H2CdCHCH2OH
H2CdCHCH2OH
H2CdCHCH2OH
(E)-PhCHdCHCH2OH
(E)-(n-Bu)3SnCHdCHCH2OH
H3CCHdCHCH(CH3)OHe
(HCtC)CH(CH3)OH
H2CdCHCH2CH(CH3)OH
(E) H3C(CH2)2CHdCHCH2OH
prod
R1
R2
yield (%)
1b
2c
3
4d
5
6
7
8
9f
1
1
2a
1
2l
1
1
1
1
2c
3a
3b
2d
3c
2ee
2f
2 g
2h
2i
2je
2k
3d
2l
3e
3f
H2CdCHCH2
H2CdCHCH2
PhCH2CH2CH2
H
60
92
96
76
86
54
23
trace
35
15
52
58
89
56
75
75
63
H2CdCHCH2
H2CdCHCH2
(E)-PhCHdCHCH2
H2CdCHCHdCH(CH2)2
H3CCHdCHC(CH3)H
(HCtC)CH(CH3)
H2CdCHCH2C(CH3)H
H3C(CH2)2CHdCHCH2
H3C(CH2)2CHCHdCH2
H2CdCHCHdCHCH2
H3C
H
(n-Bu)3SnCHdCHCH2
H
H
H
H
H
H
H
10d
11d
12
1
1
2a
1
1
(CH2dCH)2C(H)OH
H3COH
H2CdCH(CH2)3OH
H2CdCHCHdCH(CH2)2OH
H2CdCHCHdCH(CH2)2OH
H2CdCHCHdCH(CH2)3OH
H2CdCHCHdCH(CH2)3OH
PhCH2CH2CH2
H2CdCH(CH2)3
13
H2CdCHCHdCH(CH2)2
H2CdCHCHdCH(CH2)2
H2CdCHCHdCH(CH2)2
H2CdCHCHdCH(CH2)3
H
14c
15
H2CdCHCHdCH(CH2)2
H2CdCHCHdCH(CH2)3
H2CdCHCHdCH(CH2)3
2l
1
16c
3g
a Reaction conditions (unless otherwise noted): A mixture of alcohol (1 equiv), 1 or 2 (1.1 equiv), Ph3P (1.5 equiv), and ADDP (1.5 equiv) in dry toluene
at room temperature. The course of the reaction is followed by TLC. b A small amount of dialkylated product 3a was also obtained. c 1 (1.0 equiv), alcohol
(2.5 equiv), Ph3P (3.5 equiv), and ADDP (3.75 equiv) in dry toluene at room temperature. d This reaction was run at 0 °C; when run at room temperature,
the yield was lower. e Predominantly E. f An inseparable 2.4:1 mixture of 2h:2i is obtained in 50% yield.
with allyl alcohol affords the dialkylated malonate ester 3b
in high yield (96%, entry 3).
and the extent of regioselectivity depends on the nature of
the alkene substituent. For example, cinnamyl alcohol (entry
4) and a vinyl tin derivative (entry 5) react with high
regioselectivity for the SN2 pathway, while trans-2-hexen-
1-ol affords a 2.4:1 mixture that favors the SN2 mode (entry
9). In contrast, divinyl alcohol reacts almost exclusively via
the SN2′ mode to afford the conjugated diene, 2j (entry 10).
2,4-Hexadien-1-ol (Scheme 2) reacts with 1 in good yield
(70% of monoalkylated product), but affords an unfavorable
mixture of regioisomeric products 4, 5, and 6. Entries 11-
16 in Table 2 further illustrate the use of primary alcohols
as Mitsunobu electrophiles for mono- or double-dehydrative
alkylation.
Scheme 2
In summary, the alkylations of bis(2,2,2-trifluoroethyl)
malonates under typical Mitsunobu conditions provide mono-
or dialkylated products in good to excellent yield and
establish these malonates as convenient, practical carbon
nucleophiles for the Mitsunobu dehydrative alkylation method.
Acknowledgment. Support from the NIH under grant
GM34927 is gratefully acknowledged. We would like to
thank Dr. Dipanjan Nag for helpful discussions on NMR.
The NMR spectrometers used for these studies were pur-
chased with shared instrument grant funds (NIH SIG-1-510-
RR-06307 and NSF CHE-0091975).
A secondary allylic alcohol, 3-penten-2-ol, gives mono-
alkylated product (i.e., 2e) in yield comparable to that
achieved with allyl alcohol (54%, entry 6). In contrast, a
secondary propargylic alcohol affords a modest yield of
product (23%, entry 7), and a simple unactivated secondary
alcohol, 4-penten-2-ol, gives only a trace of alkylated product
2g under these reaction conditions (entry 8).
Supporting Information Available: Spectral data for
compounds 1-4 as well as representative procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Returning to the discussion of primary allylic alcohols,
higher homologues can substitute in an SN2 or SN2′ fashion,
OL0266626
Org. Lett., Vol. 4, No. 22, 2002
3845