Br?nsted acid promoted imino-ene reactions

Article abstract of DOI:10.1016/j.tetlet.2008.05.075

A series of all-carbon olefins react with glyoxylate derived imines in the presence of a phosphonic acid through an ene reaction. The isolation of the α-aminoester products is a clear indication that Br?nsted acids efficiently promote the imino-ene reacti

Full text of DOI:10.1016/j.tetlet.2008.05.075

Tetrahedron Letters 49 (2008) 4636–4639
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Brønsted acid promoted imino-ene reactions
*
Lindsey H. Oliver, Lauren A. Puls, Suzanne L. Tobey
Department of Chemistry, Wake Forest University, Salem 4, Winston-Salem, NC 27109, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of all-carbon olefins react with glyoxylate derived imines in the presence of a phosphonic acid
Received 5 April 2008
Revised 13 May 2008
Accepted 14 May 2008
Available online 20 May 2008
through an ene reaction. The isolation of the
acids efficiently promote the imino-ene reaction with hydrocarbon nucleophiles to deliver functionalized
-aminoesters in good yield. The reaction scope and preliminary mechanistic investigations are
discussed.
a-aminoester products is a clear indication that Brønsted
a
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Ene reaction
Phosphonic acid
Hydrogen bonding
The imino-ene reaction (Eq. 1) provides an elegant entry into
the generation of homoallylic amines through the formation of a
new carbon–carbon bond between an all-carbon alkene (ene) and
an imine (enophile).1
masked amino
NHPg
CO2Et
acid
R
diversity through
different alkyl and
aryl groups
Purposeful selection of the ene and enophile components will
lead to products containing an olefin and a masked amino acid,
both of which endow the substrates with synthetic utility
(Fig. 1). A defining advantage of the imino-ene reaction is the ready
access to naturally available olefins (ene components) which can
permit rapid and cheap access to a series of imino-ene products.
The potential of the imino-ene reaction is realized by the Brønsted
acid promoted reaction reported herein. The single-step method
complements the Lewis acid chemistry as it allows access to amine
substrates that are often found to be limiting cases in the tradi-
tional Lewis acid catalysis methods.
Figure 1. Imino-ene products that feature useful functional groups. Pg = protecting
group.
effective for imine activation, it can preclude reactions from occur-
ring. Imino-ene reactions facilitated by Lewis acids require addi-
tives to interrupt the chelation6 or necessitate the use of
fluorinated solvents4 for the reaction to occur to an appreciable ex-
tent. The limits of Lewis acid catalysis provide an opportunity to
pursue milder imine activation modes. In particular, we chose to
effect a hydrogen-bond interaction for activation of the imine.8,9
The results below show that Brønsted acid activation of the imine,
presumably through hydrogen bonding, is an effective method for
promoting the imino-ene reaction. The average hydrogen-bond
strength between a donor and an acceptor in organic media (1–
8 kcal/mol)10 can be sufficiently activating for reaction to occur
NHR
NR
Lewis acid
H
ð1Þ
ene
enophile
The enantioselective Lewis acid catalyzed carbonyl-ene reac-
tions are well documented in the literature.2,3 The analogous Lewis
acid catalyzed imino-ene reactions are also reported to proceed in
good yields and high enantioselectivities,4–7 but the scope of the
reaction is limited. The limitation results from significant interac-
tions between a Lewis acid, such as copper, and the starting imine
(Fig. 2) or the resulting product amine. Though the interaction is
although it is significantly weaker than
interaction.
a metal–nitrogen
Recent literature highlights the use of Brønsted acids as hydro-
gen-bonding catalysts for activating carbonyl and imine moieties
for nucleophilic attack.11–15 Our preliminary experiments showed
that thiourea-,16,17 urea-, and guanidinium-containing18–20 com-
pounds were ineffective for the imino-ene reaction; however,
phosphonic acids were found to be suitable Brønsted acids for
the imino-ene chemistry. Phosphonic acids are reported as
* Corresponding author. Tel.: +1 336 758 5513; fax: +1 336 758 4656.
E-mail address: tobeysl@wfu.edu (S. L. Tobey).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.075

L. H. Oliver et al. / Tetrahedron Letters 49 (2008) 4636–4639
4637
The scope of the imino-ene reaction with respect to the ene
component was investigated by using the optimized reaction con-
ditions (Table 1, entry 1). Traditional ene reactants are electron-
rich 1,1-disubstituted olefins and all those used for this research
*
*
X
X
*
M
H
H
PgN
PgN
PgN
react with N-tosyl-a-iminoester 2 under the Brønsted acid condi-
O
tions. Both the -methylstyrene and cyclopentenyl substrates pro-
a
O
O
ceed in good yield (Table 2, entries 1 and 3), and the cyclohexenyl
substrates both react to give products in moderate yield (Table 2,
entries 4 and 5). The acyclic and 1-substituted olefins (Table 2, en-
tries 6 and 7) are typically poorer ene substrates and the same
trend is reflected with our Brønsted acid promoted imino-ene reac-
tion. Alternatively we used diethyl phosphoramidate for some of
the above reactions and we noted that reproducible yields of
product could be obtained in the presence of 2 mol % of the
Brønsted acid, indicating somewhat increased reactivity relative
OEt
OEt
OEt
A
B
Figure 2. (A) Traditional Lewis acid activation the
alternative activation though hydrogen bonds. This can occur via
interaction or a bifurcated interaction. X = heteroatom: Pg = protecting group.
a
-imino ester. (B) Proposed
single
a
catalysts for reactions involving imine-type substrates,21–27 includ-
ing the aza-ene reaction.28,29 Unlike the reported aza-ene reaction
that employs enamines as the ene component, the imino-ene reac-
tion reported herein is the first example of a Brønsted acid-pro-
moted reaction employing unactivated, all-carbon, olefin
containing nucleophiles.30 The reactions proceed in moderate to
good yield and do not require air-free techniques.
Table 2
Scope of the imino-ene reactiona
Entry
Ene
Product
Yieldsb (%)
90 (42)
NHTs
CO2Et
Optimization of the reaction conditions for the reaction of
methylstyrene (1) and N-tosyl- -iminoester 2 included screening
a-
a
1
3a
other organic acids, solvents, and reactant ratios (Table 1). This
imino-ene reaction proceeds in high yield (90%) in the presence
of one equivalent of the phosphonic acid (diethyl phosphate) in
CH2Cl2 at room temperature (Table 1, entry 1). The increased yield
over that of the thermal reaction (42%) (Table 1, entry 2) supports
the assertion that the Brønsted acid has a significant role in pro-
moting the reaction. Toluene or THF as the solvent-resulted in little
to no yield of the product, thereby identifying dichloromethane as
the most suitable medium for the reaction. Noteworthy is the fact
that acids such as acetic acid, phosphoric acid, and p-toluenesul-
fonic acid (Table 1, entries 3–5) are ineffective in promoting the
imino-ene reaction, thereby confirming the unique role of diethyl
phosphate for the highlighted imino-ene reaction.
NHTs
CO2Et
2c
62
91
3a
NHTs
CO2Et
3d
3b
NHTs
CO2Et
4
45 (24)
Table 1
Optimization of reaction conditions for the imino-ene reactiona
3c
NHTs
CO2Et
NTs
CO2Et
conditions
NHTs
+
CO2Et
5
6
39e
1
2
3a
3d
Entry
Additive (equiv)b
Imine (equiv)
Solvent
Yield 3a (%)
NHTs
1
2
Diethyl phosphate (1)
0
2
2
CH2Cl2
CH2Cl2
90
42
EtO2C
Organic
Acid
25e (25)
3
4
5
AcOH (0.5)
H3PO4 (0.5)
p-tolSO2H (0.5)
1
1
1
CH2Cl2
CH2Cl2
CH2Cl2
29
27
7
3e
Solvent
6
7
Diethyl phosphate (0.5)
Diethyl phosphate (0.5)
1
1
Toluene
THF
—
18
CO2Et
NHTs
7
Trace
Reactants
8
9
Diethyl phosphate (1)
Diethyl phosphate (0.5)
1
2
CH2Cl2
CH2Cl2
61
68
3f
a
All reactions run on a 0.5 mmol scale (1 M) with respect to the alkene at room
temperature for 48 h unless otherwise noted.
a
All reactions run on a 0.5 mmol scale (1 M) with respect to 1, except entry 7,
which was run on a 1 mmol scale (2 M). All reactions run at room temperature for
48 h.
b
Yield reported in parentheses are of the isolated product when using diethyl
phosphoramidate.
c
b
Reaction run for 12 h.
The commercially available diethyl phosphate can be purchased as 100% pure
d
Reported yield is not significantly increased relative to thermal reaction.
or as a mixture that contains 25% phosphoric acid. Both produce the same results
when used in the imino-ene reaction.
The dr = 5:1 as determined by 1H NMR spectroscopy.
e

4638
L. H. Oliver et al. / Tetrahedron Letters 49 (2008) 4636–4639
to the conditions employing one equivalent of the phosphonic acid.
The yields reported herein for an intermolecular imino-ene reac-
tion are significant in light of the fact that (a) the ene component
is an all-carbon nucleophile and (b) the proposed mode of activa-
tion is a hydrogen bond.
tosylsulfonamide to 2 (Eq. 2). The fate of the imine in the presence
of diethyl phosphate suggests that the potential for multiple reac-
tion pathways makes it necessary to use two equivalents of the
imine for the imino-ene reaction to deliver and optimum yield of
the a
-aminoester products.34
Throughout the optimization of the reaction conditions there
were two observations that warranted additional investigation:
(1) the optimal conditions required one equivalent of diethylphos-
phate and two equivalents of imine substrate 2, and (2) the yield of
the isolated product after a 12 h reaction time was moderate (e.g.
Table 2, entry 2), but an additional 36 h was required to increase
the yield by an additional 30%. To better understand the roles of
the components of the reaction we used 1H NMR titrations. Ini-
tially, we sought to identify and quantify the interaction between
diethyl phosphate and 2, however we were unable to rigorously
identify the presence of a H-bond between the two compounds.31
A shift in the OH peak of diethyl phosphate was observed in d-
CH2Cl2 as incremental amounts of imine 2 were added to the
diethyl phosphate solution (note that concentration of the phos-
phonic acid solution concentration was kept constant). The titra-
tion data indicates that imine 2 and diethyl phosphate do not
form a clean 1:1 complex (see the Supplementary data). A shift
in the OH proton was also observed for an experiment in which
the diethyl phosphate concentration was incrementally decreased.
A plot of the dilution experiment data shows a saturation curve
rather than a linear relationship between the OH peak shift and
the concentration (see the Supplementary data). Together the data
suggest the possibility of diethyl phosphate existing in an aggre-
gate state under the reaction conditions.32,33 Potentially, the two
equivalents of imine are needed to interrupt the aggregate state
to facilitate the imino-ene reaction.
EtO
O
OH
Ts
NH2
P
N
O
NHTs
OEt
S
O
O
EtO
OEt
OEt
TsHN
O
O
O
addition
product
2
ethyl glyoxylate N-tosylsulfon-
amide
ð2Þ
In summary, we have shown that Brønsted acids are effective in
promoting an imino-ene reaction in which the ene component is a
simple, unactivated olefin. The reaction is proposed to proceed by
phosphonic acid activation of the imine to attack by the olefin. We
also presented some initial 1H NMR studies that were designed to
probe the role of the phosphonic acid, and they suggest that the
aggregation state of the acid and the potential for the imine to
yield byproducts through other reaction pathways lead to a com-
plex reaction system. The success of the reaction and the prelimin-
ary look at physical aspects of the reaction will effectively permit
the design of more efficient reaction conditions and catalysts.
Investigations into the enantioselective imino-ene reaction will
be reported in due course.
Acknowledgment
Additionally, 1H NMR spectroscopy was used to observe a 1:1
mixture of the 2 and diethyl phosphate over a 5 h period to probe
any potential reactions that occur in the absence of the ene compo-
nent. The phosphonic acid indeed appears to promote a hydrolysis
reaction of imine 2 as evidenced by the disappearance of the imine
peak (d = 8.17) and the in-growth of an aldehyde-containing com-
pound (d = 9.35) and a sulfonamide-containing compound. The dis-
appearance of the imine peak and the newly formed aldehyde peak
plotted against time is shown in Figure 3. The rate of the disap-
pearance of the imine peak (t1/2 = 2 h) is faster than the in-growth
of the aldehyde peak, indicating the potential for more than just a
simple hydrolysis reaction. 1H NMR evidence and careful isolation
and characterization of the components of the reaction mixture
confirmed that the imine substrate was reacting in the presence
of diethyl phosphate to give three products: ethylglyoxylate, N-
tosylsulfonamide, and a product derived from the addition of N-
We gratefully acknowledge financial support from the Herman
Frasch Foundation (RG0786) and Wake Forest University.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.075.
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