Some unusual reactivities in the SmI2-mediated reductive coupling of acrylamides and acrylates with imides

Article abstract of DOI:10.1016/j.tet.2009.10.089

A serendipitous discovery of some intra-molecular enolate addition reactions following a SmI₂-mediated reductive cross-coupling between imides and electron-deficient olefins leading to some novel compounds was investigated to determine the generality of the protocol and the possible mechanistic pathways involved. This provided a Z-selective synthesis of γ-ketoenediamides in good yields, albeit as of now the substrate scope remains limited. It was also shown that the seemingly similar acrylate substrates can behave differently compared to the corresponding acrylamides in their SmI₂-mediated reductive cross-coupling reaction with imides, and it was argued that these diverging reactivities are dominated by the ability of the acrylates to coordinate the samarium metal centre.

Full text of DOI:10.1016/j.tet.2009.10.089

Tetrahedron 65 (2009) 10908–10916
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Some unusual reactivities in the SmI2-mediated reductive coupling of acrylamides
and acrylates with imides
*
Rolf H. Taaning, Karl B. Lindsay, Troels Skrydstrup
Center for Insoluble Protein Structures, Department of Chemistry and Interdisciplinary Nanoscience Center, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
A serendipitous discovery of some intra-molecular enolate addition reactions following a SmI2-mediated
reductive cross-coupling between imides and electron-deficient olefins leading to some novel com-
pounds was investigated to determine the generality of the protocol and the possible mechanistic
Received 10 September 2009
Received in revised form 13 October 2009
Accepted 26 October 2009
pathways involved. This provided a Z-selective synthesis of g-ketoenediamides in good yields, albeit as of
Available online 1 November 2009
now the substrate scope remains limited. It was also shown that the seemingly similar acrylate
substrates can behave differently compared to the corresponding acrylamides in their SmI2-mediated
reductive cross-coupling reaction with imides, and it was argued that these diverging reactivities are
dominated by the ability of the acrylates to coordinate the samarium metal centre.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
In this paper, we seek to highlight some recent unusual
reactivities observed in the course of our studies on SmI2-mediated
SmI2-mediated carbonyl–olefin couplings hold an increasingly
important position in the growing family of C–C bond forming
reactions mediated by SmI2.1 The outcome of such coupling re-
actions depends strongly on the relative reactivity of the coupling
partners towards SmI2 as has been elegantly demonstrated in an
example by the group of Procter, in which a carbonyl–olefin cou-
pling can proceed either through a ‘carbonyl first’ or an ‘alkene first’
mechanism.2 Most carbonyl–olefin couplings are carried out in the
presence of a proton donor.3,8f,g Little is known about the role of
proton donors in the initial mechanistic steps in the carbonyl–
olefin coupling, however, substantial effort has been made by the
laboratories of Flowers,4 Hoz5 and Hilmersson6 to understand the
role of proton donors in carbonyl reductions mediated by SmI2.
carbonyl–olefin couplings between imides and electron-deficient
alkenes, namely the reactivity of arising samarium enolates
towards intra-molecular acyl substitution and aldol-condensation
type reactions and the notable reactivity difference between
seemingly similar coupling partners, acrylamides and acrylates.
2. Results and discussion
Recently, we published a novel application of N-acyl succini-
mides as acyl transfer reagents in the SmI2-mediated reductive
cross-coupling reactions (RCCRs) between electron-deficient ole-
fins and imides.10 It was proposed that the acyl transfer followed
a mechanism similar to the coupling reactions with N-acyl oxazo-
lidinones.10 Hence, reductive coupling through a chelated transi-
tion state resulted in the formation of enolate intermediate 1
(Scheme 1). Subsequent protonation by H2O afforded hemiaminal
2, which collapses to the ketone during workup. The N-acyl succi-
nimides were utilised to provide evidence for the influence of C–N
bond rotation on the outcome of aforementioned reactions.
During the course of these studies, we isolated an interesting
byproduct 6 in a 15% yield upon the reaction of N-acetyl succini-
mide 3 with N-tert-butylacrylamide 4 (Scheme 2). The double
enamide motif in 6 was supported by the presence of four olefinic
carbons in the 13C NMR spectrum, two of which were shifted
upfield (106.6 and 100.9 ppm). Significantly, only one olefinic
proton was identified by 1H NMR and was observed as a quartet
with a coupling constant of J¼1.2 Hz, indicative of an allylic cou-
pling to a methyl. Moreover, the identification of two amides, one
Imides,
ticularly good alternative carbonyl coupling partners in carbonyl–
olefin couplings, and Flowers9 has revealed that
-keto amides and
b-keto amides and b
-keto esters7,8 have shown to be par-
b
esters are reduced 6 and 2 orders of magnitude faster, respectively,
than the equivalent alkyl ketone. Moreover, the resulting hemi-
aminal obtained from addition to an imide carbonyl will be
stabilised by the bidentate coordination of samarium preventing
hemiaminal collapse, and hence preventing over-reduction of the
resulting ketone. In our hands, imides have proven to be excellent
acyl equivalents in carbonyl–olefin couplings, and have demon-
strated their utility in a variety of applications.8
* Corresponding author.
E-mail address: ts@chem.au.dk (T. Skrydstrup).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.089

R.H. Taaning et al. / Tetrahedron 65 (2009) 10908–10916
10909
SmIII
Table 1
O
NHt-Bu
O
Influence of the proton donor ability on the SmI2-mediated reductive coupling of
O
N-acetyl succinimide13 (1.5 equiv) and tert-butylacrylamide (1 equiv)
O
SmI2
O
NHt-Bu
N
N
O
O
H
N
O
SmI2, Additive
THF,-78°C
O
O
N
5
6
7
SmI2
O
O
3
4
SmIII
O
SmIII
OH
SmIII
O
HO
O
Entry
Additive
Yielda of 5
Yielda of 6
Yielda of 7
NH -Bu
t
NHt-Bu
O
Proton Donor
1
2
3
4
TEA/H2O
TFE
H2O
MeOH
t-BuOH
None
None
None
Major
Major
75%
Trace
Trace
15%
d
d
N
N
d
1
2
d
O
O
d
d
5
18%
Trace
11%
Trace
12%
d
37%
36%
49%
58%
H3O+
O
6
7b
8c
10%
d
O
a
Isolated yields after column chromatography.
The order of addition is reversed, i.e., the substrates were added as a solution in
b
NHt-Bu
NH
THF to a stirring cold solution of SmI2 in THF.
O
c
N-Acetyl succinimide (1 equiv) and 1.5 equiv of acrylamide. Yield is based on the
O
N-acetyl succinimide. The order of addition as for entry 7.
Scheme 1.
mixture resulted in suppression of the formation of 6 (Table 1,
entries 1 and 2). MeOH produced a range of unidentified products,
while the addition of t-BuOH and the exclusion of the proton donor
to our surprise resulted in a new product 7 in a modest yield of 37%
(Table 1, entries 5 and 6, and Scheme 2).11
Transformation of 7 into 6 could be achieved with catalytic
amounts of either p-TsOH or TFA in dichloromethane in a 50% and
75% yield, respectively (Scheme 2) suggesting that 7 does not derive
from an alternative reaction path, but rather 7 is an intermediate in
the formation of 6. Although, intra-molecular enamide formation
seems remarkable given the sterically congested nature of the tert-
butyl amide, this kind of transformation has been reported
secondary and one tertiary by 1H and 13C NMR spectroscopy helped
to substantiate the proposed structure 6. Intrigued by its structure,
we therefore set out to identify reaction conditions, which could
favour its formation in higher yields, as well as to understand its
mechanism of formation. It was expected that 6 would most likely
involve the enolate addition to one of the ring carbonyls succeeding
the reductive coupling of the substrates.
O
H
O
N
N
O
previously proceeding under mild acidic conditions with
g-keto
O
4
3
amides.12 Reversing the order of addition, by adding a THF solution
of the substrates to a pre-cooled solution of freshly formed SmI2,
resulted in an increased yield of 7 to 49%. Finally, a 58% yield of 7
was achieved based on N-acetyl succinimide by using an excess of
acrylamide (Table 1, entries 7 and 8). Gratifyingly, the reaction
between the intermediate reactive enolate and a second equivalent
of N-acetyl succinimide was suppressed resulting in a di-acetylated
acrylamide (13, Scheme 5), which was observed as a byproduct
(w3%) in the reactions described in entries 6 and 7 of Table 1.
While the reaction appears to be tolerant to increase in the bulk
of the N-acyl moiety as was also observed by us in previous studies
for the RCCR utilising N-acyl oxazolidinones, in this transformation
N-pivaloyl succinimide provides none of the desired enamide
product. Surprisingly, both N-pivaloyl succinimide and N-tert-
butylacrylamide were recovered unreacted in the absence of water.
This suggests that the RCCR between N-acyl succinimides and
acrylamides without water progresses through a different mecha-
nism, as opposed to the RCCR between N-acyl oxazolidinones and
acrylamides, where the acrylamide is reduced independently of the
N-acyl oxazolidinone in the presence of water. Alternatively, the
coupling reaction between imides and acrylamides in general may
not progress through any intermediates of acrylamide reduction,
but rather in direct competition. For example, the reaction may
occur by way of a concerted reductive C–C bond formation.
1. SmI2
2. H2O
SmI2, H2O
THF, -78°C
THF, -78°C
O
O
H
N
H
N
O
O
O
5 75 %
5 10 %
O
NH
NH
O
O
O
N
HN
TFA
7 49 %
6 15 %
75 %
Scheme 2.
Both the collapse of the hemiaminal formed upon reaction onto
the acyl carbonyl and the premature protonation of an intermediate
enolate to produce the g-keto amide 5 were expected to be strongly
influenced by the nature of the proton donor, and we therefore
conducted a small screening of proton donors in an attempt to
promote the formation of 6 (Table 1). Not surprisingly, the more
acidic proton donor trifluoroethanol (TFE) and the TEA/H2O
It was observed that yields increased with the bulk of the N-acyl
moiety (Scheme 3), going from R¼Me (58%) to R¼Et (79%) to R¼i-Pr
(99%). This could be attributed to either the stability of the resulting
ketone and/or the effectiveness of hemiaminal collapse.
Compounds
8 and 9 were obtained as two stereoisomers,
easily separable by column chromatography, Z/E¼15:1 and Z/
E¼5.7:1, respectively. A crystal structure was acquired for the major

10910
R.H. Taaning et al. / Tetrahedron 65 (2009) 10908–10916
Z-isomer of 9 (Fig. 1), the preference for which clearly is a result of
the formation of an intra-molecular hydrogen bond (NH–O,
2.018 Å). To our surprise, N-pivaloyl succinimide provided none of
the enamide product 10, and both coupling precursors were
recovered unreacted in the absence of water. This suggests that the
reductive coupling reaction between N-acyl succinimides and
acrylamides without water progresses through a different mecha-
nism, as opposed to the coupling reaction with N-acyl oxaz-
olidinones.
(13%) with n-butylacrylamide as a coupling partner. The application
of acrylates does show some promise and provided 11 in a 14 and
20% yield for R¼Me and R¼i-Pr, respectively, as a mixture of E/Z-
stereoisomers (Scheme 4).
O
NH
O
O
R
Ot-Bu
SmI2
O
N
O
THF, -78°C
O
R
O
R = Me: 14 %
Ot -Bu
R = i-Pr: 20 %
O
11
mixture of E/Z-
H
N
O
R
R = Me, Et,
stereoisomers
N
i-Pr, t-Bu
Scheme 4.
O
O
A mechanistic proposal for the reaction is depicted in Scheme 5.
It is expected that the formation of 7 proceeds via a C–C bond
1. SmI2
THF,-78°C
O
2. H2
formation between the N-acyl carbonyl and the
intermediate acrylamide derived radical anion, followed by
reduction of the resulting stabilised -radical 12 to the corre-
b-carbon of the
a
O
sponding amide enolate 1 and succeeding addition to the ring
carbonyl of the succinimide unit.
R = Me
R = Et
7 58 %
NH
O
8 79 % (Z/E = 15:1)
9 99 % (Z/E = 5.7:1)
10 not detected
R = i-Pr
R = t-Bu
O
O
O
R
O
OSmIII
NHt-Bu
SmI2
HN
N
N
O
O
12
NHt-Bu
O
Scheme 3.
O
SmI2
O
1
OSmIII
ROH
O
N
O
O
NHt-Bu
NHt-Bu
O
SmIIIO
5
O
O
13
NHt-Bu
O
O
OSmIII
N
H+
-2H2O
14
SmIII
N
O
15
O
NHt-Bu
-H2O H+
O
NHt-Bu
Figure 1. X-ray crystal structure of compound 9 (Z-isomer).
H+
-H2O
O
Unfortunately, the utility of the reaction is somewhat limited by
the poor stability of the N-acyl succinimides making the synthesis
and purification of the starting materials a difficult task. Also, it
appears that there exists a delicate balance between the successful
O
N
H
N
H
O
O
O
H+
-H2O
Nt -Bu
reduction of the intermediate a-radical followed by enolate addi-
tion to the ring carbonyl and a variety of intermolecular side
reactions (e.g., radical or anionic addition reactions), possibly also
with resulting polymerisation processes. Preliminary studies sug-
gest that simple variations of the N-acyl moiety is tolerated
(Scheme 3), yet small changes to the electron-deficient olefin, such
as changing from tert-butyl to n-butylacrylamide or from second-
ary to tertiary amide results in substantial decomposition/poly-
merisation under the reaction conditions. The di-acetylated
acrylamide (13, Scheme 5) was isolated as a significant byproduct
7
NHt-Bu
6
Scheme 5.
The resulting double hemiaminal 14 should then readily elimi-
nate one molecule of H2O and ringopen to produce the -ketoe-
namide 7. At first, we assigned 6 to the bicyclic pyrrole structure 15,
g
however, at a later stage it was acknowledged that the same

R.H. Taaning et al. / Tetrahedron 65 (2009) 10908–10916
10911
spectroscopic data could be assigned to the dienamide structure 6.
Extensive efforts to crystallise the compound has so far failed, albeit
the most likely structure is 6, as the 1H NMR spectrum suggests the
presence of an amide proton participating in a hydrogen bond
(10.3 ppm in deuterated acetonitrile), being only possible for the
structure 6.
reminiscent of the results obtained by Evans et al. upon hydrolysis
of sterically congested N-acyl oxazolidinones with LiOH, preferring
attack on the ring carbonyl, as opposed to LiOOH, which prefers
attack on the acyl carbonyl.15
When the N-acyl oxazolidinone 17 was reacted with di-n-
butylacrylamide, to our surprise, a third compound 24 was formed
as the major product in a 58% yield (Scheme 6c), possibly arising
from an enolate intermediate similar to 1 (Scheme 5) proposed for
the N-acyl succinimide olefin couplings. Enolate addition to the
endo-cyclic carbonyl group would be followed by ring opening,
providing a primary alkoxide, which is rapidly protonated by H2O.
Two other products were isolated from the reaction mixture, being
the expected coupling product 22 (21% yield), as well as compound
23 (15% yield), the latter of which arises from attack of the reduced
acrylamide at the oxazolidinone carbonyl group, as observed for
the acrylates (Scheme 5a). Because the products 22 and 24 are
derived from the addition to the acyl carbonyl group and 23 orig-
inates from the addition to the endo-cyclic carbonyl group, this
signifies that in the SmI2-mediated RCCR, tertiary acrylamides
exhibit properties intermediate to those of the secondary
acrylamides and acrylates.
In the course of our studies on this type of SmI2-mediated RCCRs
we have observed that even small changes to the electron-deficient
alkene can have a profound effect on the reactions. This effect has
manifested itself in more than one way, e.g., ease of reduction,
regioselectivity in the C–C bond forming step, reactivity of the
intermediate enolate and product stability. An example of the di-
verging reaction pathways experienced for acrylamides and acry-
lates in SmI2-mediated coupling of N-acyl oxazolidinones and
electron-deficient olefins is outlined in Scheme 6. Curiously, when
the N-acyl oxazolidinones 16 and 17 were reacted with n-butyl
acrylate, we isolated products 18 and 19 in a 37% and 41% yield,
respectively, as the sole coupling products (Scheme 6a), bearing
witness to a cross-coupling between the oxazolidin-2-one carbonyl
group and the olefin with concomitant ring opening. Contrary to
this, their reaction with tert-butylacrylamide provides the expected
g
-keto amides 20 and 21 in a 65% and 62% yield, respectively
The divergence in regioselectivity between acrylamides and
acrylates can also be observed in their reaction with N-pivaloyl
pyrrolidin-2-one. It was found that tert-butylacrylamide preferred
addition to the acyl carbonyl group, affording 26 and 28 in a 72%
and 15% yield (5:1 ratio), respectively. Whereas n-octyl acrylate was
essentially unselective giving a 1:1 mixture of 25 and 27 derived
from addition to the acyl carbonyl in a 38% yield and the ring car-
bonyl in a 41% yield, respectively (Scheme 7). This regioselectivity is
in contrast to that reported by Namy,16 in which selectivity for
reaction at the ring carbonyl of N-acyl lactams was observed in
their reductive coupling with ketones.
(Scheme 6b).14 The divergence in regioselectivity observed is
R
(a)
Ph
O
O
O
O
N
O
SmI2 (3 equiv)
H2O (6 equiv)
Ph
R
O
N
H
On-Bu
16 R = Me
17 R = Ph
O
THF,-78°C
R = Me
R = Ph
18 37 %
19 41 %
On-Bu
O
O
O
X
SmI2 (3 equiv)
H2O (6 equiv)
N
O
X = On-octyl 25 38 %
X = NHt-butyl 26 72 %
R
(b)
O
Ph
O
O
O
THF,-78°C
X
O
N
SmI2(3 equiv)
H2O (6 equiv)
O
O
X
Ph
R
NHt-Bu
16 R = Me
17 R = Ph
O
N
H
O
THF,-78°C
O
X = On-octyl 27 41 %
X = NHt-butyl 28 15 %
R = Me
R = Ph
20 65 %
21
62 %
NHt-Bu
25 or 26
27 or 28
O
X = On-octyl
X = NHt-butyl
1
5
:
:
1
1
Ph
(c)
Ph
O
Scheme 7.
SmI2 (3 equiv)
O
O
N
O
O
17
O
H2 (6 equiv)
Ph
Ph
Nn-Bu2
In an attempt to pinpoint the determining factors for the
observed reactivity differences between acrylamides and acrylates,
we conducted a few competition experiments. A 1:1 ratio of N-tert-
butylacrylamide and n-octyl acrylate was subjected to the dropwise
addition of an excess of SmI2 at ꢀ78 ꢁC in the absence of an imide
coupling partner (Scheme 8). This resulted in a 2:1 mixture of
compounds 30 (60%) and 29 (30%), and a 70% yield of recovered
acrylamide. This result can be explained by one of two possible
scenarios. Either the acrylates are initially more reactive towards
reduction by SmI2 (corroborating rates of reduction obtained in
collaboration with Flowers et al.14) or the two alkenes are reduced
at similar rates by the lanthanide reagent, and the radical anions
produced react preferentially with acrylates. This latter point could
be expected when considering the relative rates for the addition of
THF,-78°C
O
Nn-Bu2
22 21 %
O
O
Ph
Ph
O
N
H
N -Bu
n
2
O
23 15 %
OH
O
NH
O
24 58 %
Ph
Ph
O
carbon-centred radicals to acrylates and acrylamides (1.2–1.9ꢂ108
N -Bu
n
2
17
and 3.2–5.4ꢂ107 Mꢀ1 sꢀ1, respectively) reported by Wojnarovits.
´
We have also previously noted that under the same reaction
Scheme 6.

10912
R.H. Taaning et al. / Tetrahedron 65 (2009) 10908–10916
conditions, acrylates alone are more prone to dimerisation,
whereas acrylamides are preferentially reduced to the corre-
sponding propionic amide,14 signifying that acrylates are better
acceptors (anionic or radical) than acrylamides given that a radical
dimerisation pathway can be excluded.18
and the results of Fleming21 on hydrodimerisation of acrylates.
Inanaga reported diastereoselective hydrodimerisation of
a
N,N-dibenzyl crotonamide to achieve the corresponding DL-3,4-
dimethyladipiamide, exclusively.20a Inanaga20b and Kim19 later
reported enantioselective versions with the same diastereoslective
outcome. Both Kim and Inanaga rationalised that the diaster-
eoselectivity arises by a tight coordination of the two reacting
acrylamides to the same samarium centre, as depicted in Scheme
10. Inanaga also noted that the hydrodimerisation of acrylamides
O
NHt-Bu
NHt-Bu
n-OctO
SmI2 (4 equiv)
O
O
H2O (8 equiv)
THF,-78°C
29 30% (based on
(0.28mmol)
Oct
slowed significantly with increasing bulk in the b-position in good
acrylate)
accordance with the proposed transition state, resulting in com-
peting reduction of the C]C bond.20b Fleming, however, succes-
sively reported a meso-selective hydrodimerisation of both cis- and
trans-acrylic esters, most likely arising from a transition state,
whereby only one acrylate is coordinated to the samarium centre
and the incoming olefin positions itself so as to minimise
O
O
n-
On-Oct
n-OctO
O
O
(0.25mmol)
30 60 % (based on
acrylate)
interactions between the two bulky
b
-substituents (Scheme 10).21
And recovered acrylamide 70%
Scheme 8.
NR2
NR2
OR
O
O
H
O
H
R'
R'
R'
When the same two alkenes were reacted with a limiting
amount of N-pivaloyl oxazolidinone, 53% of the N-acyl oxazolidi-
Sm(Lx-2)I2
Sm(Lx)I2
Sm(Lx-1)I2
H
R'
O
H
O
OR
none reacted to produce the
the
g
-keto amide 26, and 24% to produce
NR2
OR
g
-keto ester 25 (Scheme 9a).
O
Fleming
Inanaga
O
(a)
SmI2 (4 equiv)
H2O (8 equiv)
NHt-Bu
NHt-Bu
On-Oct
NHt-Bu
NHn-Bu
O
R'
R'
R'
THF, -78°C
O
(1 equiv)
CONR2
CONR2
CO2R
CO2R
26 53%
R'
On-Oct
O
O
Scheme 10.
O
O
N
O
(1 equiv)
Reacting a 1:1 mixture of tert-butylacrylamide and n-butyla-
crylamide with a limiting amount of N-pivaloyl oxazolidinone re-
sults in the formation of the -keto amide 26 in a 19% yield and the
-keto amide 31 in a 53% yield (Scheme 9b). Again, it can be pro-
posed that the aptitude for the olefin to coordinate samarium is
decisive. With the tert-butyl group being a better electron donating
group than n-butyl in terms of inductive effects, one could argue
that tert-butylacrylamide should provide the more Lewis basic
carbonyl. However, it is not hard to imagine that the bulk of the
tert-butyl group will interfere significantly with the coordination
sphere of samarium, hence with the result that the n-butylacryl-
amide becomes the better ligand.
O
(1 equiv)
25 24%
g
g
O
(b)
SmI2 (4 equiv)
H2O (8 equiv)
NHt-Bu
O
O
THF, -78°C
(1 equiv)
26 19%
NHn-Bu
O
O
O
O
N
O
(1 equiv)
O
(1 equiv)
31 53%
Scheme 9.
3. Conclusion
This result is difficult to explain with either of the hypotheses
A SmI2-mediated reductive cross-coupling reaction between
N-acyl succinimides and N-tert-butylacrylamide has provided an
entry into some novel enediamide22 and dienediamide structures
by way of two consecutive C–C bond formations followed by de-
hydration to generate the enediamide core. Although at present the
bicyclic pyrrole 15 structure has been ruled out, it seems plausible
that careful manipulation of 7–9 could provide an entry into these
compounds. Alternatively, optimisation of the protocol to facilitate
the use of either N,N-dialkyl acrylamides or acrylates should allow
for the possible formation of the bicyclic pyrrole. On the basis of the
observed differences in reactivity for the acrylamide and acrylate
coupling partners investigated, we propose that the relative rate of
reductive cross-coupling with imides could be governed by the
strength of coordination to the samarium metal and follow the
trend; n-butylacrylamide>tert-butylacrylamide>n-octyl acrylate.
Also, it is postulated that reduction and dimerisation of acrylamides
and acrylates are in direct competition with cross-coupling be-
tween imides and acrylamides/acrylates. The two pathways may
stated above and therefore the explanation for the higher reactivity
of acrylamides towards N-acyl oxazolidinones must be sought
elsewhere. An obvious possibility is that the N-acyl oxazolidinone
plays a central role in the selection between acrylates and acryl-
amides. This can be envisioned in two ways. (1) Reduction of the
N-acyl oxazolidinone precedes addition to the olefin, whereby the
radical addition steps become decisive for the selectivity. However,
in collaboration with the Flowers group, we previously rejected this
pathway.14 A cyclopropyl probe on the acyl carbonyl provided
coupling products with an intact cyclopropane ring suggesting that
a ketyl-radical is not formed. (2) After bidentate coordination of the
N-acyl oxazolidinone to SmI2 the more Lewis basic of the two
olefins can be expected to coordinate preferentially and thereby
react fastest, effectively circumventing their individual reduction
potentials. Whereas the first can be ruled out by our previous
work,14 the second coincides surprisingly well with the combined
results of Kim19 and Inanaga20 on hydrodimerisation of acrylamides

R.H. Taaning et al. / Tetrahedron 65 (2009) 10908–10916
10913
not share intermediates, such as a distinct radical anion or allyl
radical species. This could be the case if the cross-coupling between
imides and acrylamides/acrylates proceeded through a concerted
mechanism, whereas, e.g., acrylamide reduction naturally must
proceed through a distinct radical anion or allyl radical species.
These hypotheses are currently under investigation.
1 mol %) was added to the mixture and left stirring for 21 h. TLC
analysis revealed a poor conversion to the less polar UV-active
compound 4, and more TFA in dichloromethane was added
(0.05 mL, 0.1 M, 4 mol %). After 3 h complete conversion was ob-
served by TLC, the molecular sieves were filtered off and washed
with dichloromethane (20 mL). Subsequently the organics were
washed with a 1:1 mixture of satd aq NaHCO3 and H2O (10 mL),
brine, dried over Na2SO4, filtered and evaporated in vacuo. The
resulting crude oil was subjected to column chromatography (in-
creasing polarity from 10% to 50% EtOAc in pentane as the eluant) to
achieve the title compound 4 (22.3 mg, 0.0952 mmol, 75%) as
a weakly yellow solid. Despite numerous attempts, recrystallisation
of the compound failed in our hands and often led to de-
4. Experimental section
4.1. General methods
Unless otherwise noted all reactions were carried out under an
inert atmosphere. Solvents were dried according to standard pro-
cedures, reactions were monitored by thin-layer chromatography
(TLC) analysis. All other chemicals were used as received from the
appropriate suppliers. Flash chromatography was carried out on
silica gel 60 (230–400 mesh). SmI2 was prepared according to
a literature method.23
composition. 1H NMR (400 MHz, CD3CN)
5.47 (br q, J¼1.2 Hz, 1H), 2.96–2.91 (m, 2H), 2.49–2.44 (m, 2H), 2.25
(br s, 3H), 1.57 (s, 9H). 13C NMR (100 MHz, CD3CN)
(ppm) 178.9,
d (ppm) 10.34 (br s, 1H),
d
170.6, 150.5, 139.3, 106.6, 100.9, 58.3, 30.2 (3C), 28.4, 25.6, 20.0. MS
(ES) C13H18N2O2 [MþNaþ]; calculated: 257.1, found: 257.1.
The 1H NMR spectra were recorded at 400 MHz and 13C NMR
spectra were recorded at 100 MHz. The chemical shifts are reported
4.3. General procedure for the SmI2-mediated reductive
coupling of acrylamides or acrylates with N-acyl succinimides
with no additive
in parts per million downfield to TMS (
d
¼0) and referenced using
the residual CHCl3 resonance (
d
¼7.26) or CHD2CN centre peak
resonance (
d
¼1.94) for 1H NMR and the central CDCl3 resonance
(d
¼77.16) or CD3CN centre peak resonance (
d
¼1.39) for 13C NMR. 1H
SmI2 in THF (1.00 mmol, 2.3 equiv) under an atmosphere of argon
was cooled to ꢀ78 ꢁC. Then N-acyl succinimide (0.436 mmol,1 equiv)
and N-tert-butylacrylamide (0.502 mmol, 1.15 equiv) as a solution in
THF (5 mL) were added to the stirring solution and kept at ꢀ78 ꢁC for
2 h. Quenching of excess SmI2 was achieved with O2 with concomi-
tantchangeincolourfromdarkbluetoyellow, followedbyadditionof
H2O (3 mL) and heating to room temperature. Next satd aq Na2S2O3
(40 mL), EtOAc (20 mL) and HCl (1 M, 8 mL) were added sequentially.
Extraction of the aqueous phase with EtOAc (3ꢂ20 mL) followed by
washing of the collected organic phases with brine, drying over
Na2SO4, filtration and evaporation in vacuo resulted in a heteroge-
neous mixture of oil and solid. The pure product(s) were obtained by
column chromatography using the stated solvent system.
NMR spectra are reported as follows (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, quin¼quintet, sext¼sextet, sept¼septet,
oct¼octet, br¼broad; coupling constant(s) in Hz; integration).
4.2. Experimental procedures
4.2.1. N-Propionyl succinimide13. Succinimide (5.00 g, 50.5 mmol)
inpyridine (30 mL) under an atmosphere of argonwas cooled to 0 ꢁC
and propionic anhydride (13 mL,101 mmol) was added. Thereaction
mixture was allowed to reach room temperature and left stirring for
two days, after which TLC analysis showed complete conversion to
a less polar compound. Solvent was removed in vacuo (65 ꢁC) and
co-evaporated with toluene and dichloromethane to remove pyri-
dine. The resulting crude oil was subjected to column chromatog-
raphy with massive decomposition tosuccinimide as a consequence,
therefore the remaining N-propionyl succinimide was recrystallised
from EtOAc/heptanes to give the title compound (1.57 g, 10.1 mmol,
4.3.1. (Z)-N-tert-Butyl-4-oxo-2-(5-oxopyrrolidin-2-ylidene)pentana-
mide (7). The title compound was prepared according to the
general method above using N-acetyl succinimide (33.1 mg,
0.220 mmol) and N-tert-butylacrylamide (32.6 mg, 0.256 mmol).
Purification by column chromatography (increasing polarity from
30% to 100% EtOAc in pentane) afforded the title compound 7
(32.1 mg, 0.127 mmol, 58%) as a weakly yellow solid. 1H NMR
20%) as colourless crystals. 1H NMR (400 MHz, CDCl3)
d (ppm) 2.89
(q, J¼7.2 Hz, 2H), 2.78 (s, 4H), 1.18 (t, J¼7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d (ppm) 174.5 (2C), 173.7, 32.4, 28.5 (2C), 7.7.
(400 MHz, CD3CN)
d (ppm) 10.92 (br s, 1H), 5.90 (br s, 1H), 3.25 (s,
4.2.2. N-iso-Butyroyl succinimide13. Succinimide (5.00 g, 50.5 mmol)
in pyridine (30 mL) under an atmosphere of argon was cooled to
0 ꢁC and iso-butyroyl chloride (8.0 mL, 76 mmol) was added. The
reaction mixture was allowed to reach room temperature over
30 min, after which TLC analysis showed complete conversion to
a less polar compound. Pyridinium chloride formed in the reaction
was removed by filtration and the solvent was removed in vacuo
(65 ꢁC) and co-evaporated with toluene and dichloromethane to
remove pyridine. The resulting heterogeneous mixture was taken
up in EtOAc and washed once with H2O, once with brine, dried over
Na2SO4 followed by evaporation to dryness. Recrystallisation from
EtOAc/heptanes gave the title compound (6.76 g, 40.0 mmol, 79%)
2H), 2.82–2.78 (m, 2H), 2.42–2.38 (m, 2H), 2.15 (s, 3H), 1.31 (s, 9H).
13C NMR (100 MHz, CD3CN)
d (ppm) 208.0, 177.3, 167.8, 152.0, 97.9,
51.6, 43.3, 29.4, 28.9 (3C), 28.0, 25.9. HRMS C13H20N2O3 [MþNaþ]
calculated: 275.1366, found: 275.1368.
4.3.2. (Z)-N-tert-Butyl-4-oxo-2-(5-oxopyrrolidin-2-ylidene)hex-
anamide (8). The title compound was prepared according to the
general method above using N-propionyl succinimide (68.0 mg,
0.443 mmol) and N-tert-butylacrylamide (65.3 mg, 0.551 mmol).
Purification by column chromatography (increasing polarity from
40% to 100% EtOAc in pentane) afforded two pure stereoisomers: 8
(Z-isomer) (87.5 mg, 0.329 mmol, 74%) as a colourless solid and 8
(E-isomer) (6.0 mg, 0.023 mmol, 5%) as a colourless solid. Com-
as colourless crystals. 1H NMR (400 MHz, CDCl3)
d (ppm) 3.31 (sept,
J¼7.2 Hz, 1H), 2.77 (s, 4H), 1.15 (d, J¼7.2 Hz, 6H). 13C NMR (100 MHz,
pound 8 (Z-isomer): 1H NMR (400 MHz, CD3CN)
d (ppm) 10.90 (br s,
CDCl3)
d
(ppm) 177.3, 174.6 (2C), 36.9, 28.6 (2C), 17.9 (2C).
1H), 6.00 (br s,1H), 3.24 (s, 2H), 2.82–2.78 (m, 2H), 2.53 (q, J¼7.2 Hz,
2H), 2.41–2.38 (m, 2H), 1.31 (s, 9H), 0.98 (t, J¼7.2 Hz, 3H). 13C NMR
4.2.3. N-tert-Butyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrrolizine-7-
carboxamide (6) from 7. To compound 5 (32.0 mg, 0.127 mmol)
dissolved in dichloromethane (13 mL) under an atmosphere of
argon at room temperature was added activated 4 Å molecular
sieves. Then a solution of TFA in dichloromethane (0.13 mL, 0.01 M,
(100 MHz, CD3CN) d (ppm) 211.2, 178.7, 169.5, 154.1, 98.7, 52.0, 41.9,
35.9, 29.0 (3C), 28.6, 26.5, 8.1. HRMS C14H22N2O3 [MþNaþ] calcu-
lated: 289.1523, found: 289.1523. Compound 8 (E-isomer): 1H NMR
(400 MHz, CD3CN)
2H), 3.05–3.01 (m, 2H), 2.51 (q, J¼7.2 Hz, 2H), 2.42–2.38 (m, 2H),
d (ppm) 8.08 (br s, 1H), 5.94 (br s, 1H), 3.25 (s,

10914
R.H. Taaning et al. / Tetrahedron 65 (2009) 10908–10916
1.31 (s, 9H), 0.98 (t, J¼7.2 Hz, 3H). HRMS C14H22N2O3 [MþNaþ]
30.5, 29.0, 28.9, 26.9, 19.0, 13.6. HRMS C25H31NO5 [MþNaþ] calcu-
calculated: 289.1523, found: 289.1517.
lated: 448.2100, found: 448.2113.
4.3.3. (Z)-N-tert-Butyl-5-methyl-4-oxo-2-(5-oxopyrrolidin-2-ylide-
ne)hexanamide (9). The title compound was prepared according to
the general method above using N-iso-butyroyl succinimide
(73.8 mg, 0.436 mmol) and N-tert-butylacrylamide (63.8 mg,
0.502 mmol). Purification by column chromatography (increasing
polarity from 60% to 100% EtOAc in pentane) afforded the two pure
stereoisomers: 9 (Z-isomer) (93.2 mg, 0.332 mmol, 76%) as col-
ourless crystals and 9 (E-isomer) (16.4 mg, 0.058 mmol, 13%) as
a colourless solid. Compound 9 (Z-isomer): 1H NMR (400 MHz,
4.3.6. N,N-Di-n-butylacrylamide. Di-n-butylamine (1.00 g, 7.737
mmol) and triethylamine (1.95 mL, 14.00 mmol) were dissolved in
CH2Cl2 (20 mL) and then the mixture was cooled to 0 ꢁC. Acryloyl
chloride (0.63 mL, 700 mg, 7.737 mmol) was added dropwise, the
mixture was stirred at 0 ꢁC for 2 h and then at room temperature for
18 h. The mixture was poured into water (50 mL) and extracted with
CH2Cl2 (3ꢂ20 mL). The combined organic portions were dried
(MgSO4), filtered and evaporated in vacuo. The pure product was
obtained by column chromatography (increasing polarity from 5% to
35% EtOAc in pentane as eluant), which gave the title compound
(1.118 g, 6.10 mmol,79%)asacolourlessoil.1HNMR(400 MHz, CDCl3)
CD3CN)
2.72 (m, 3H), 2.42–2.36 (m, 2H), 1.31 (s, 9H), 1.07 (d, J¼6.8 Hz, 6H).
13C NMR (100 MHz, CD3CN)
(ppm) 214.2, 178.6, 169.5, 154.0, 98.6,
d (ppm) 10.88 (br s, 1H), 5.82 (br s, 1H), 3.33 (s, 2H), 2.83–
d
d
(ppm) 6.50 (dd, J¼16.4, 10.4 Hz, 1H), 6.47 (dd, J¼16.4, 2.0 Hz, 1H),
52.0, 40.6, 40.5, 29.0 (3C), 28.6, 26.5, 18.8. HRMS C15H24N2O3
5.60 (dd, J¼10.4, 2.0 Hz, 1H), 3.33 (t, J¼7.6 Hz, 2H), 3.25 (t, J¼7.6 Hz,
2H),1.56–1.45 (m, 4H),1.28 (app. hex, J¼7.2 Hz, 4H), 0.90 (t, J¼7.2 Hz,
[MþNaþ] calculated: 303.1679, found: 303.1686. Compound 9 (E-
isomer): 1H NMR (400 MHz, CD3CN)
d
(ppm) 8.06 (br s, 1H), 5.84 (br
3H), 0.88 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d (ppm) 165.8,
s, 1H), 3.33 (s, 2H), 3.05–2.99 (m, 2H), 2.72 (sept, J¼7.2 Hz, 1H),
2.43–2.37 (m, 2H), 1.30 (s, 9H), 1.06 (d, J¼7.2 Hz, 6H). HRMS
C15H24N2O3 [MþNaþ] calculated: 303.1679, found: 303.1683.
127.9 (2C),127.4 (2C), 47.9, 46.4, 31.8, 29.9, 20.3, 20.0,13.9,13.8. HRMS
C11H21NO [MþNaþ] calculated: 206.1521, found: 206.1518.
4.4. Experimental procedure for Scheme 6c
4.3.4. n-Butyl 2-(2-methyl-2-phenylpropionylamino)ethyl succinate
(18)14. N-Acyl oxazolidinone 16 (109 mg, 0.467 mmol) was dis-
N-Acyl oxazolidinone 17 (97 mg, 0.33 mmol) and N,N-di-n-
butylacrylamide (46 mg, 0.25 mmol) were dissolved in THF (5 mL)
and then water (36 mg, 2.00 mmol) was added. The mixture was
cooled to ꢀ78 ꢁC under a strict argon atmosphere before a solution
of SmI2 (10 mL, 1.00 mmol, 0.1 M in THF) was added dropwise over
5 min. The mixture was stirred at ꢀ78 ꢁC for 18 h, and then the flask
was flushed with oxygen to quench excess SmI2. It was poured into
satd aq Na2S2O3 (40 mL) and extracted with EtOAc (3ꢂ20 mL). The
combined organic portions were dried (MgSO4), filtered and
evaporated in vacuo. The pure products were obtained by column
chromatography (increasing polarity from 5% to 50% EtOAc in
pentane, and then 2% to 10% MeOH in DCM as eluant), which gave
the products 22 (21 mg, 0.053 mmol, 21%), 23 (18 mg, 0.037 mmol,
15%), 24 (69 mg, 0.144 mmol, 58%) and recovered N-acyl oxazoli-
dinone 17 (21 mg, 0.071 mmol, 23%).
solved in THF (7.5 mL), then water (54
mL, 3.00 mmol) and n-butyl
acrylate (216 L, 1.50 mmol) were added. The mixture was cooled
m
to ꢀ78 ꢁC and then SmI2 in THF (0.1 M, 15 mL, 1.50 mmol) was
added dropwise over 10 min. The mixture was stirred at ꢀ78 ꢁC
for 18 h and then the flask was flushed with O2. Satd aq NH4Cl
(5 mL) was added, and then the mixture poured into 0.5 M HCl
(40 mL) and extracted with EtOAc (3ꢂ15 mL). The combined or-
ganic portions were washed with satd aq Na2S2O5 (30 mL), dried
(MgSO4) filtered and evaporated in vacuo. The pure product was
obtained by column chromatography (increasing polarity from 5%
to 30% diethyl ether in 1:1 DCM/pentane as eluant), which gave
the title compound 18 (62 mg, 0.171 mmol, 36.5%) as a colourless
oil, and recovered 16 (15 mg, 0.063 mmol, 13.8%). 1H NMR
(400 MHz, CDCl3)
d
(ppm) 7.36–7.20 (m, 5H), 5.60 (br t, J¼5.2 Hz,
1H), 4.08 (t, J¼5.2 Hz, 2H), 4.03 (t, J¼6.8 Hz, 2H), 3.40 (q, J¼5.2 Hz,
2H), 2.49 (AA0BB0 system, 4H), 1.57 (pent, J¼7.2 Hz, 2H), 1.54 (s,
6H), 1.34 (hex, J¼7.6 Hz, 2H), 0.91 (t, J¼7.6 Hz, 3H). 13C NMR
4.4.1. N,N-Di-n-butyl-4-oxo-5,5-diphenylhexanamide (22). 1H NMR
(400 MHz, CDCl3)
d
(ppm) 7.34–7.17 (m, 10H), 3.27 (t, J¼7.6 Hz, 2H),
(100 MHz, CDCl3)
d
(ppm) 177.5, 172.3, 172.1, 145.0, 128.5 (2C),
3.21 (t, J¼7.6 Hz, 2H), 2.82 (t, J¼6.8 Hz, 2H), 2.47 (t, J¼6.8 Hz, 2H),
1.94 (s, 3H), 1.57–1.42 (m, 4H), 1.36–1.22 (m, 4H), 0.93 (t, J¼7.6 Hz,
126.3 (2C), 64.6, 63.1, 46.8, 38.6, 30.5, 29.0, 28.9, 26.8 (2C), 19.0,
13.6. HRMS C20H29NO5 [MþNaþ] calculated: 386.1944, found:
386.1943.
3H), 0.90 (t, J¼7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d (ppm) 221.2,
171.2, 144.1 (2C), 128.5 (4C), 128.4 (4C), 126.9 (2C), 61.9, 47.8, 46.1,
35.2, 31.2, 30.0, 27.6, 26.6, 20.4, 20.2, 14.0, 13.9. HRMS C26H35NO2
[MþNaþ] calculated: 416.2565, found: 416.2558.
4.3.5. n-Butyl 2-(2,2-diphenylpropanamido)ethyl succinate (19)14. N-
Acyl oxazolidinone 17 (138 mg, 0.467 mmol) was dissolved in THF
(7.5 mL), then water (54
m
L, 3.00 mmol) and n-butyl acrylate (216
m
L,
4.4.2. 2-(2,2-Diphenylpropanamido)ethyl 4-(di-n-butylamino)-4-oxo-
1.50 mmol) were added. The mixture was cooled to ꢀ78 ꢁC and then
SmI2 in THF (0.1 M, 15 mL, 1.50 mmol) was added dropwise over
10 min. The mixture was stirred at ꢀ78 ꢁC for 18 h and then the flask
was flushed with O2. Satd aq NH4Cl (5 mL) was added, and then the
mixture poured into 0.5 M HCl (40 mL) and extracted with EtOAc
(3ꢂ15 mL). The combined organic portions were washed with satd
aq Na2S2O5 (30 mL), dried (MgSO4), filtered and evaporated in vacuo.
The pure product was obtained by column chromatography (in-
creasing polarity from 5% to 20% diethyl ether in 1:1 pentane/DCM as
eluant), which gave the title compound 19 (115 mg, 0.270 mmol,
57.8%) as a colourless oil and recovered 17 (57 mg, 0.193 mmol,
butanoate (23). 1H NMR (400 MHz, CDCl3)
d (ppm) 7.34–7.20 (m,
10H), 6.00 (br t, J¼4.8 Hz, 1H), 4.15 (t, J¼4.8 Hz, 2H), 3.51 (q,
J¼4.8 Hz, 2H), 3.27–3.17 (m, 4H), 2.53 (AA0BB0 system, 4H), 1.99 (s,
3H), 1.58–1.49 (m, 2H), 1.49–1.40 (m, 2H), 1.37–1.20 (m, 4H), 0.95 (t,
J¼7.6 Hz, 3H), 0.89 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
(ppm) 175.4, 173.3, 170.0, 145.1 (2C), 128.5 (4C), 128.3 (4C), 127.0
(2C), 63.1, 57.1, 47.7, 45.9, 39.0, 31.1, 30.0, 29.5, 28.2, 27.1, 20.4, 20.3,
14.0, 13.9. HRMS C29H40N2O4 [MþNaþ] calculated: 503.2886,
found: 503.2892.
4.4.3. N1,N1-Di-n-butyl-N3-(2-hydroxyethyl)-2-(2-oxo-3,3-diphe-
41.3%) as colourless solids. 1H NMR (400 MHz, CDCl3)
d
(ppm) 7.35–
nylbutyl)malonamide (24). 1H NMR (400 MHz, CDCl3)
d (ppm) 7.34–
7.20 (m, 10H), 5.82 (br t, J¼5.6 Hz, 1H), 4.14 (t, J¼5.6 Hz, 2H), 4.05 (t,
J¼6.8 Hz, 2H), 3.51 (q, J¼5.6 Hz, 2H), 2.51 (AA0BB0 system, 4H),1.99 (s,
3H), 1.59 (pent, J¼7.2 Hz, 2H), 1.35 (hex, J¼7.6 Hz, 2H), 0.93 (t,
7.20 (m, 6H), 7.17–7.09 (m, 4H), 7.00 (t, J¼6.0 Hz, 1H), 3.86 (dd,
J¼10.0, 3.2 Hz, 1H), 3.61 (ddd, J¼15.6, 10.0, 5.2 Hz, 1H), 3.55 (t,
J¼5.6 Hz, 2H), 3.46 (dt, J¼13.6, 7.2, 1H), 3.35 (dd, J¼18.4, 10.8 Hz,
1H), 3.33–3.15 (m, 4H), 2.89 (br s, 1H), 2.84 (dd, J¼18.4, 3.2 Hz, 1H)
1.89 (s, 3H), 1.70–1.45 (m, 4H), 1.37–1.23 (m, 4H), 0.93 (t, J¼7.2 Hz,
J¼7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d (ppm) 175.2, 172.1, 172.0,
144.8 (2C), 128.4 (4C), 128.0 (4C), 126.9 (2C), 64.6, 63.1, 56.9, 38.8,

R.H. Taaning et al. / Tetrahedron 65 (2009) 10908–10916
10915
3H), 0.91 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
(ppm) 209.4,
added before the solution was cooled to ꢀ78 ꢁC. A 0.1 M solution of
SmI2 (10 mL, 1.00 mmol) was added dropwise over 5 min, and then
the solution was stirred at ꢀ78 ꢁC for 18 h. Excess SmI2 was
quenched by flushing the flask with O2, and then the mixture was
poured into aqueous Na2S2O3 (40 mL) and extracted with EtOAc
(3ꢂ20 mL). The combined organic portions were dried (MgSO4),
filtered and evaporated in vacuo. The pure products were obtained
by column chromatography (increasing polarity from 5% to 30%
EtOAc in pentane as eluant), which gave di-n-octyl adipate 30
(28 mg, 0.0756 mmol, 60%), recovered tert-butylacrylamide
(25 mg, 0.197 mmol, 70%), and the hetero dimer 29 (24 mg,
0.0766 mmol, 31%).
170.6, 170.5, 143.6, 143.5, 128.4 (2C), 128.4 (2C), 128.3 (2C), 128.3
(2C),127.9 (2C), 61.9, 61.4, 48.6, 46.9, 46.3, 42.5, 42.1, 31.2, 29.6, 26.5,
20.1, 20.1, 13.9, 13.8. HRMS C29H40N2O4 [MþNaþ] calculated:
503.2886, found: 503.2881.
4.4.4. 1-Pivaloylpyrrolidin-2-one. 2-Pyrrolidinone
(0.454 mL,
5.87 mmol) was dissolved in THF (20 mL) and the solution was
cooled to 0 ꢁC. n-BuLi (3.5 mL, 5.88 mmol) was added dropwise and
the solution was stirred at 0 ꢁC for 30 min, before pivaloyl chloride
(1.1 mL, 8.81 mmol) was added. The mixture was stirred at room
temperature for 1 h, and then poured into aqueous NaHCO3 (40 mL)
and extracted with EtOAc (3ꢂ20 mL). The combined organic por-
tions were dried (MgSO4), filtered and evaporated in vacuo. The
pure product was obtained by column chromatography (6% EtOAc
in pentane as eluant), which gave the title compound (917 mg,
5.42 mmol, 92%) as a colourless oil. 1H NMR (400 MHz, CDCl3)
4.4.8. n-Octyl 6-(tert-butylamino)-6-oxohexanoate (29). 1H NMR
(400 MHz, CDCl3)
d
(ppm) 5.31 (br s, 1H), 4.04 (t, J¼6.8 Hz, 2H),
2.35–2.26 (m, 2H), 2.12–2.05 (m, 2H),1.66–1.55 (m, 6H),1.33 (s, 9H),
1.36–1.20 (m, 10H), 0.87 (t, J¼6.4 Hz, 3H). 13C NMR (100 MHz,
d
(ppm) 3.78 (t, J¼7.6 Hz, 2H), 2.55 (t, J¼7.6 Hz, 2H), 1.99 (pent.,
CDCl3) d (ppm) 173.6,171.8, 64.5, 51.1, 37.2, 34.0, 31.7, 29.2, 29.1, 28.8
J¼7.6 Hz, 2H), 1.29 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
(ppm) 180.2,
(3C), 28.6, 25.9, 25.1, 24.4, 22.6, 14.0. HRMS C18H35NO3 [MþNaþ]
173.6, 48.5, 41.6 (3C), 34.5, 26.1, 17.8. HRMS C9H15NO2 [MþNaþ]
calculated: 336.2515, found: 336.2509.
calculated: 192.1000, found: 192.0990.
4.4.9. Di-n-octyl adipate (30). 1H NMR (400 MHz, CDCl3)
d (ppm)
4.4.5. n-Octyl 4-oxo-7-pivalamidoheptanoate (27). 1-Pivaloylpyr-
4.05 (t, J¼6.9 Hz, 4H), 2.36–2.28 (m, 4H), 1.69–1.58 (m, 8H), 1.35–
rolidin-2-one (75 mg, 0.44 mmol), n-octyl acrylate (92
mL,
1.22 (m, 20H), 0.95–0.88 (m, 6H). 13C NMR (100 MHz, CDCl3)
0.44 mmol) and water (64 L, 3.55 mmol) were dissolved in THF
m
d (ppm) 173.6 (2C), 64.7 (2C), 34.1 (2C), 31.9 (2C), 29.4 (2C), 29.3
(5 mL) and then the solution was cooled to ꢀ78 ꢁC. A 0.1 M solution
of SmI2 (17.7 mL, 1.77 mmol) was added dropwise over 30 min, and
then the mixture was stirred at ꢀ78 ꢁC for 22 h. Excess SmI2 was
quenched by flushing the flask with O2, and then the mixture
poured into aqueous Na2S2O3 (30 mL) and extracted with EtOAc
(3ꢂ15 mL). The combined organic portions were dried (MgSO4),
filtered and evaporated in vacuo. The pure product was obtained by
column chromatography (increasing polarity from 1% to 3% MeOH
as eluant), which gave the title compound 27 (64 mg, 0.18 mmol,
(2C), 28.8 (2C), 26.1 (2C), 24.6 (2C), 22.8 (2C), 14.2 (2C). HRMS
C22H42O4 [MþNaþ] calculated: 393.2981, found: 393.2991.
4.5. X-ray crystallographic data for 9 (Z-isomer)
The crystal structure illustration is produced with thermal-mo-
tion probability ellipsoids, using ORTEP-III.24 CCDC 743683 9
(Z-isomer) contains the supplementarycrystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223
336033.
41%) as a colourless oil. 1H NMR (400 MHz, CDCl3)
d (ppm) 5.99 (br
s, 1H), 4.01 (t, J¼6.8 Hz, 2H), 3.19 (td, J¼6.7, 5.7 Hz, 2H), 2.67 (t,
J¼6.7 Hz, 2H), 2.57 (t, J¼6.3 Hz, 2H), 2.52 (t, J¼6.3 Hz, 2H), 1.78
(pent., J¼6.7 Hz, 2H), 1.58 (pent., J¼6.8 Hz, 2H), 1.30–1.20 (m, 10H),
1.46 (s, 9H), 0.85 (t, J¼6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
(ppm) 209.3, 178.9, 173.1, 65.1, 40.4, 39.3, 38.8, 37.3, 32.0, 29.4,
Acknowledgements
29.3, 28.8, 28.3, 27.8, 26.1, 23.3, 22.8, 14.3. HRMS C20H37NO4
[MþNaþ] calculated: 378.2620, found: 378.2605.
We are deeply appreciative of generous financial support from
the Danish National Research Foundation, the Lundbeck Founda-
tion, the Carlsberg Foundation, the iNANO and OChem Graduate
Schools and the University of Aarhus. The authors are grateful to
Dr. Jacob Overgaard for the X-ray crystallographic analysis.
4.4.6. N-tert-Butyl-4-oxo-7-pivalamidoheptanamide
aloylpyrrolidin-2-one (75 mg, 0.44 mmol), N-tert-butylacrylamide
(56 mg, 0.44 mmol) and water (64 L, 3.55 mmol) were dissolved
(28). 1-Piv-
m
in THF (5 mL) and then the solution was cooled to ꢀ78 ꢁC. A 0.1 M
solution of SmI2 (17.7 mL, 1.77 mmol) was added dropwise over
30 min, and then the mixture was stirred at ꢀ78 ꢁC for 22 h. Excess
SmI2 was quenched by flushing the flask with O2, and then the
mixture poured into aqueous Na2S2O3 (30 mL) and extracted with
EtOAc (3ꢂ15 mL). The combined organic portions were dried
(MgSO4), filtered and evaporated in vacuo. The pure product was
obtained by column chromatography (increasing polarity from 1%
to 3% MeOH as eluant), which gave the title compound 28 (68 mg,
0.066 mmol, 15%) as a colourless oil. 1H NMR (400 MHz, CDCl3)
References and notes
1. For reviews on the application of SmI2 in organic synthesis, see: (a) Soderquist,
J. A. Aldrichimica Acta 1991, 24, 15–23; (b) Molander, G. A. Chem. Rev. 1992, 92,
29–68; (c) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307–338; (d)
Skrydstrup, T. Angew. Chem., Int. Ed. 1997, 36, 345–347; (e) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321–3354; (f) Nomura, R.; Endo, T. Chem.dEur.
J. 1998, 4, 1605–1610; (g) Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745–777; (h)
Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727–2751; (i) Agarwal, S.; Greiner,
A. J. Chem. Soc., Perkin Trans. 1 2002, 2033–2042; (j) Kagan, H. B. Tetrahedron
2003, 59, 10351–10372; (k) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev.
2004, 104, 3371–3403; (l) Concello´ n, J. M.; Rodrı´guez-Solla, H. Chem. Soc. Rev.
2004, 33, 599–609; (m) Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32,
607–637.
2. (a) Johnston, D. J.; Couche´, E.; Edmonds, D. J.; Muir, K. W.; Procter, D. J. Org.
Biomol. Chem. 2003, 1, 328–337; (b) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org.
Lett. 2003, 5, 4811–4814.
3. For some recent examples of the utilisation of carbonyl–olefin couplings em-
ploying proton donor additives: (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew.
Chem., Int. Ed. 2006, 45, 7086–7090; (b) Kan, T.; Hosokawa, S.; Nara, S.; Tamiya,
H.; Shirahama, H.; Matsuda, F. J. Org. Chem. 2004, 69, 8956–8958; (c) Huang,
L.-L.; Xu, M.-H.; Lin, G.-Q. J. Org. Chem. 2005, 70, 529–532; (d) Molander, G. A.;
d
(ppm) 6.15 (br s, 1H), 5.25 (s, 1H), 3.19 (q, J¼6.6 Hz, 2H), 2.66 (t,
J¼6.5 Hz, 2H), 2.52 (t, J¼6.6 Hz, 2H), 2.38 (t, J¼6.5 Hz, 2H), 1.77
(pent., J¼6.6 Hz, 2H), 1.15 (s, 9H), 1.05 (s, 9H). 13C NMR (100 MHz,
CDCl3)
d (ppm) 210.4, 178.9, 171.2, 51.4, 40.2, 38.9, 38.8, 37.7, 31.2,
28.9, 27.8, 23.3. HRMS C16H30N2O3 [MþNaþ] calculated: 321.2154,
found: 321.2153.
4.4.7. Experimental procedure for Scheme 8. tert-Butylacrylamide
(36 mg, 0.281 mmol) and n-octyl acrylate (46 mg, 0.25 mmol) were
´
Czako, B.; Rheam, M. J. Org. Chem. 2007, 72, 1755–1764; (e) Helm, M. D.;
dissolved in THF (2.5 mL) and then water (36
mL, 2.00 mmol) was
Sucunza, D.; Da Silva, M.; Helliwell, M.; Procter, D. J. Tetrahedron Lett. 2009,

10916
R.H. Taaning et al. / Tetrahedron 65 (2009) 10908–10916
50, 3224–3226; (f) Saadi, J.; Lentz, D.; Reissig, H.-U. Org. Lett. 2009, 11, 3334–
3337.
9. Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2002, 124, 6357–6361.
10. Taaning, R. H.; Lindsay, K. B.; Schiøtt, B.; Daasbjerg, K.; Skrydstrup, T. J. Am.
Chem. Soc. 2009, 131, 10253–10262.
11. (a) Namy, J.-L.; Farcas, S. Tetrahedron Lett. 2001, 42, 879–881; (b) Ha, D.-C.; Yun,
C.-S.; Lee, Y. J. Org. Chem. 2000, 65, 621–623; (c) Ha, D.-C.; Yun, C.-S.; Yu, E.
Tetrahedron Lett. 1996, 37, 2577–2580.
12. Padwa, A.; Rashatasakhon, P.; Rose, M. J. Org. Chem. 2003, 68, 5139–5146.
13. Synthesised according to literature procedures. (a) Heller, G.; Jacobsohn, P. Ber.
1921, 54, 1107–1117; (b) McAlees, A. J.; McCrindle, R. J. Chem. Soc. C 1969, 2425–
2435.
14. Hansen, A. M.; Lindsay, K. B.; Antharjanam, P. K. S.; Karaffa, J.; Daasbjerg, K.;
Flowers, R. A., II; Skrydstrup, T. J. Am. Chem. Soc. 2006, 128, 9616–9617.
15. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141–6144.
16. Farcas, S.; Namy, J.-.L. Tetrahedron Lett. 2000, 41, 7299–7302.
17. Wojna´rovits, L.; Taka´cs, E.; Emmi, S. S. Chem. Phys. 2006, 327, 335–343.
18. A dropwise addition of SmI2-solution to the substrates, combined with a titra-
tion like reaction ensures a constantly low concentration of radical anion.
19. Jung, D. Y.; Kim, Y. H. Synlett 2005, 3019–3032.
4. (a) Flowers, R. A., II. Synlett 2008, 1427–1439; (b) Teprovich, J. A., Jr.; Balili, M.
N.; Pintauer, T.; Flowers, R. A., II. Angew. Chem., Int. Ed. 2007, 46, 8160–8163;
(c) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2005, 127, 18093–18099;
(d) Prasad, E.; Knettle, B. W.; Flowers, R. A., II. J. Am. Chem. Soc. 2004, 126,
6891–6894; (e) Chopade, P. R.; Davis, T. A.; Prasad, E.; Flowers, R. A., II. Org.
Lett. 2004, 6, 2685–2688; (f) Chopade, P. R.; Prasad, E.; Flowers, R. A., II. J.
Am. Chem. Soc. 2004, 126, 44–45.
5. (a) Farran, H.; Hoz, S. Org. Lett. 2008, 10, 865–867; (b) Tarnopolsky, A.; Hoz, S.
Org. Biomol. Chem. 2007, 5, 3801–3804; (c) Tarnopolsky, A.; Hoz, S. J. Am. Chem.
Soc. 2007, 129, 3402–3407; (d) Hoz, S.; Yacovan, A.; Bilkis, I. J. Am. Chem. Soc.
1996, 118, 261–262.
6. (a) Dahlen, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 17, 3393–3403;
(b) Dahlen, A.; Hilmersson, G. Tetrahedron Lett. 2001, 42, 5565–5569.
b-Keto amides and esters in carbonyl–olefin couplings: (a) Molander, G. A.;
Kenny, C. J. Am. Chem. Soc. 1989, 111, 8236–8246; (b) Molander, G. A.; Kenny, C. J.
Org. Chem. 1991, 56, 1439–1445.
7.
8. (a) Hansen, A. M.; Lindsay, K. B.; Sudhadevi Antharjanam, P. K.; Karaffa, J.;
Daasbjerg, K.; Flowers, R. A., II; Skrydstrup, T. J. Am. Chem. Soc. 2006, 128, 9616–
9617; (b) Jensen, C. M.; Lindsay, K. B.; Taaning, R. H.; Karaffa, J.; Hansen, A. M.;
Skrydstrup, T. J. Am. Chem. Soc. 2005, 127, 6544–6545; (c) Karaffa, J.; Lindsay, K.
B.; Skrydstrup, T. J. Org. Chem. 2006, 71, 8219–8226; (d) Ebran, J.-P.; Jensen, C.
M.; Johannesen, S. A.; Karaffa, J.; Taaning, R. H.; Skrydstrup, T. Org. Biomol.
Chem. 2006, 3553–3564; (e) Lindsay, B. K.; Ferrando, F.; Christensen, K. L.;
Overgaard, J.; Roca, T.; Bennasar, M.-L.; Skrydstrup, T. J. Org. Chem. 2007, 72,
4181–4188; (f) Mittag, T.; Christensen, K. L.; Lindsay, K. B.; Nielsen, N. C.;
Skrydstrup, T. J. Org. Chem. 2008, 73, 1088–1092; (g) Taaning, R. H.; Thim, L.;
Karaffa, J.; Campana, A. G.; Hansen, A. M.; Skrydstrup, T. Tetrahedron 2008, 64,
11884–11895.
20. (a) Inanaga, J.; Handa, Y.; Tabuchi, T.; Otsubo, K.; Yamaguchi, M.; Hanamoto, T.
Tetrahedron Lett. 1991, 32, 6557–6558; (b) Kikukawa, T.; Hanamoto, T.; Inanaga,
J. Tetrahedron Lett. 1999, 40, 7497–7500.
21. Fleming, I.; Ghosh, S. K. J. Chem. Soc., Chem. Commun. 1992, 1775–1777.
22. Enediamide and enamide esters have been reported as practical entries into
pyrimidones. (a) Jeong, J. U.; Chen, X.; Rahman, A.; Yamashita, D. S.; Luengo, J. I.
Org. Lett. 2004, 6, 1013–1016; (b) Shcherbakova, I.; Huang, G.; Geoffroy, O. J.;
Nair, S. K.; Swierczek, K.; Balandrin, M. F.; Fox, J.; Heaton, W. L.; Conklin, R. L.
Bioorg. Med. Chem. Lett. 2005, 15, 2537–2540.
23. Samarium(II) diiodide was prepared according to a literature procedure Girard,
P.; Namy, J.-L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693–2698.
24. Farrugia, L. J. J. Appl. Cryst. 1997, 30, 565.