Protecting group free, stereocontrolled synthesis of β-halo-enamides

Article abstract of DOI:10.1021/jo202130e

Enamides, dienamides, and enynamides are important building blocks in synthetic, biological, and medicinal chemistry as well as materials science. Despite the extensive breath of their potential utility in synthetic chemistry, there is a lack of simple, high-yielding methods to deliver them efficiently and as single isomers. In this paper, we present a novel, protecting group free, efficient, and stereoselective approach to the generation of β-halo-enamides. The methodology presented provides a robust synthetic platform from which E- or Z-enamides can be generated in good yields and with complete stereocontrol.

Full text of DOI:10.1021/jo202130e

Article
pubs.acs.org/joc
Protecting Group Free, Stereocontrolled Synthesis of β-Halo-
enamides
Adele E. Pasqua,† James J. Crawford,‡ De-Liang Long,†,§ and Rodolfo Marquez*,†,∥
†School of Chemistry, University of Glasgow, Glasgow G12 8QQ, U.K.
‡Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
S
* Supporting Information
ABSTRACT: Enamides, dienamides, and enynamides are important building blocks
in synthetic, biological, and medicinal chemistry as well as materials science. Despite
the extensive breath of their potential utility in synthetic chemistry, there is a lack of
simple, high-yielding methods to deliver them efficiently and as single isomers. In this
paper, we present a novel, protecting group free, efficient, and stereoselective approach
to the generation of β-halo-enamides. The methodology presented provides a robust
synthetic platform from which E- or Z-enamides can be generated in good yields and
with complete stereocontrol.
INTRODUCTION
■
Enamides and dienamides are key intermediates in the
synthesis of a variety of heterocyclic compounds.1 Dienamides
have also been used effectively as both electron-rich and
electron-poor dienes in Diels−Alder reactions. These dien-
amide-based Diels−Alder reactions are regioselective and have
found application in asymmetric cycloadditions.2
Acyclic enamides and dienamides have great synthetic
potential and occur widely in nature. For example, biologically
active natural products and pharmaceutical leads such as the
antibiotic CJ-15,801 1, crocacin A 2, the lituarines 3,
palmerolide A 4, bacillaene 5, the retinoidal dienamide 6, and
ariakemicins A 7 and B 8 all contain enamide or dienamide
functional groups (Figure 1).3
The number of different approaches reported for the
synthesis of enamides and dienamides reflects their importance
and relevance as target units and functional intermediates in
materials, synthetic, and medicinal chemistry.4 The synthetic
methodologies developed thus far enjoy varying degrees of
success, particularly with respect to the yield and control of
double-bond geometries obtained. Indeed, in a number of
cases, there is no control over the geometry of the double bond
generated at all.
Figure 1. Enamide- and dienamide-containing natural products.
A reliable and effective methodology with the ability to
deliver E- and Z-β-halo-enamides stereoselectively could be
envisaged using di-halo-enamides. These are extremely versatile
intermediates, which can provide a viable synthetic platform
from which to generate elaborated enamide and dienamides.5
To date, synthetic approaches toward the synthesis of β-halo-
enamides have offered limited flexibility, being primarily
focused on the synthesis of the E-isomers, largely due to the
availability of starting materials. Access to the corresponding Z-
β-halo-enamides has proven to be challenging, and there are no
stereoselective methods currently available for their synthesis.6,7
As part of this contribution, we now report a novel, flexible,
and reliable approach for the convergent and stereoselective
Received: October 14, 2011
Published: January 19, 2012
© 2012 American Chemical Society
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synthesis of geometrically defined β-halo-enamides, starting
from simple N-formylimides. In turn, this approach provides a
viable synthetic platform from which to generate enamides and
dienamides in good yield and with excellent stereocontrol
(Scheme 1).
Scheme 3. Previous Syntheses of β,β-Dibromo-enamides
under Ramirez Conditions
Scheme 1. Proposed Retrosynthesis of Enamides and β-
Halo-enamides from N-Formylimides
carbonyl (Boc or Piv) or tosyl-protecting group is present on
the formamide.11
We believed that this unexpected and high yielding imide
dibromo-olefination reaction could provide a viable synthetic
alternative for the synthesis of structurally diverse β,β-dibromo-
enamide units. The same bromo-olefination conditions were
applied to a range of N-formylimides with similar success
(Table 1).
RESULTS AND DISCUSSION
■
Our approach hinges on the ability of N-formylimides to
undergo olefination reactions to generate enamides and
dienamides in good yield and without the need for nitrogen
protection. The N-formyl group mimics an aldehyde unit,
which allows for the efficient generation of substrates not
readily available through any other synthetic means.8 In our
initial studies, caprolactam-derived N-formylimide 9 was treated
under Stork−Zhao conditions using (bromomethyl)-
triphenylphosphonium bromide and a variety of bases with
the intention of generating the desired Z-bromoenamide.9
When HMDS bases were employed, despite extensive
experimentation, the desired Z-bromo-enamide was obtained
only in low yields. However, increasing the number of
equivalents of phosphonium salt used, and switching the base
to t-BuOK, resulted in conversion of the N-formylimide 9 into
the unexpected dibromo-enamide product 10b in 93% yield
(Scheme 2).
Table 1. Effect of Imide Substitution on Dibromo-
olefination
Scheme 2. Synthesis of β,β-Dibromo-enamide 10b
Dibromo-enamides are currently accessed through the use of
a Ramirez olefination.5,10 However, the Ramirez conditions are
limited to the dibromo-olefination of formylated tosyl-, Piv-,
and Boc-protected amines and are not applicable to
unprotected and general imide systems (Scheme 3). Indeed,
Lautens and co-workers recently reported that the gem-
dibromination of formamides only proceeds when an N-
a
All reactions were conducted using 1 equiv of N-formylimide, 10
equiv of phosphonium salt, and 10 equiv of base in dry THF (0.33 M)
at rt for 12 h.
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Having obtained encouraging yields and scope for the
synthesis of dibromo-enamides, we investigated whether similar
results could be obtained with using (iodomethyl)-
triphenylphosphonium iodide. Initial iodo-olefination of N-
formyl imide 9 matched the results obtained during the bromo-
olefination and yielded diiodo-enamide 25 in high yield
(Scheme 4). The structure of the diiodo-enamide 25 was
confirmed by crystallographic analysis (Figure 2).12
Table 2. Iodo-olefination of N-Formylimides
Scheme 4. Synthesis of β,β-Diiodo-enamide 25
Figure 2. Crystal structure of diiodo-enamide 25.
To our knowledge, the only other report in the literature for
the synthesis of β,β-diiodo-enamides is that of Ferreira and co-
workers, who reported the generation of β,β-diiodo-enamides
in moderate yield by iodination of amino acid derived enamides
at 80 °C (Scheme 5).13
Application of our same iodo-olefination conditions to the
group of N-formylimides previously used demonstrated that the
iodo-olefination is substrate dependent (Table 2), an
observation noted by the Ferreira group in their enamide
iodination studies.
a
All reactions were conducted using 1 equiv of N-formylimide, 10
equiv of phosphonium salt, and 10 equiv of base in dry THF (0.33 M)
at rt for 12 h.
For instance, iodo-olefination of N-formylimide 13 under the
same conditions yielded the diiodo-enamide 28 together with
traces of the E-iodo-enamide 29. In contrast, the iodo-
olefination of the N-formylimides 11 and 12 resulted
exclusively in the formation of β-iodo-enamides 26 and 27,
respectively, in good yield and with complete E-double bond
selectivity in both instances. Significantly, aromatic N-
formylimides (16, 17) proved inert under the reaction
conditions affording only returned starting materials, whereas
the same substrates generated the dibromo-enamide products
in good yield. Furthermore, the steric environment surrounding
the N-formyl group seems to influence the iodo-olefination
significantly. For example, while the butyramide-derived imide
14 was diiodo-olefinated in moderate yield, the N-methyl
analogue 15 failed to react under the same reaction conditions.
Returning to the dibromo-olefination, it bears mention that
the nature and efficiency of this result are extremely unusual.
Dihalo-olefins are seldom detected as side products during the
olefination of ketones and aldehydes.10 Perhaps the closest and
best studied example is the dibromo-olefination of lactones
reported by Chapleur and co-workers in 2001 (Figure 3).14
Figure 3. Chapleur’s Dibromo-olefination of Lactones.
Mechanistically, the formation of the β,β-dibromo-enamides
using (bromomethyl)triphenylphosphonium bromide could
follow two potentially competing reaction pathways, as
proposed by Chapleur in explaining the lactone dibromo-
olefination.14 Initially, deprotonation of the phosphonium salt
Scheme 5. Ferreira’s Synthesis of β,β-Diiodo-enamides
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yields ylide A, which then reacts with a second equivalent of the
phosphonium salt to generate the dibromo-phosphonium unit
B and methylene ylide C. Deprotonation of the dibromo
phosphonium salt by either ylide C or tert-butoxide then yields
the dibromomethylenetriphenylphosphorane D (Scheme 6).
Scheme 7. Halo-olefination of Pantolactone-Derived N-
Formylimide 32
Scheme 6. Potential Dihalo-olefination Mechanisms
Figure 4. Crystal structures of diiodo-enamide 33 and oxazole 34.
Chapleur concluded that the lactone dibromo-olefination was
taking place through the formation of the dibromomethylene-
triphenylphosphorane D that then reacted with the lactone
starting material to afford the observed dibromo enol ether in a
single step.
These results further support the theory that, at least in the
case of dihalo-enamide formation, a stepwise mechanism is
taking place. In any event, having successfully achieved a high-
yielding, flexible, and reliable synthesis of β,β-dihalo-enamides,
the key steroselective dehalogenations were attempted. We
initially focused our attention on the selective dehalogenation
of the diiodo-enamide units.
We are pleased to report that treatment of the diiodo-
enamides with a Zn−Cu couple proceeded cleanly, generating
the E-β-iodo-enamides 35 and 29 stereoselectively and in good
yield (Table 3). Interestingly, in the case of the pantolactone-
derived iodo-enamide 36, the Z product was the sole isomer
obtained. We believe that the opposite double bond geometry
obtained in iodo-enamide 36 is the result of the electronic
interactions between the tetramethyl dioxirane ring and the
enamide unit affecting the reactive conformation of diiodo-
enamide 33.7
Having access to both the diiodo-enamide 33 and Z-iodo-
enamide 36 provided the opportunity to further probe the
mechanism of the halo-olefination taking place. It was proposed
that if the stepwise mechanistic hypothesis was valid, basic
treatment of iodo-enamide 36 should result in oxazole
formation.
Treatment of Z-iodo-enamide 36 under basic conditions
yielded oxazole 34 together with vinyl enamide 37. On the
other hand, treatment of diiodo-enamide 33 under identical
conditions gave only unreacted starting material (Scheme 9).
These results would further support the theory that the halo-
olefination of N-formylimides initially yields a halo-enamide
intermediate, which can then either undergo a second
halogenation to generate a dihalo-enamide or a deprotona-
tion−cyclization to generate an oxazole (Scheme 10).
Having demonstrated the feasibility of carrying out selective
dehalogenations on diiodo-enamides, it was left to apply the
same methodology to the structurally diverse dibromo-
enamides generated, with the aim of being able to access the
complementary Z-β-bromo-enamide products.
In the case of N-formylimides, we believe that the N-
formylimide reacts with the bromomethylenetriphenylphos-
phorane A to yield a bromo-enamide intermediate 31, which
then undergoes a second bromination to generate the observed
dibromo-enamide. Evidence for a stepwise process was
provided by control experiments in which valeraldehyde
generated the expected monohalogenated olefin when sub-
jected to the same reaction conditions, demonstrating the
enamide nitrogen’s pivotal role during the bromination step.
Further indication that a stepwise pathway is taking place was
provided by the fact that none of the N-formylimides reacted
with the dibromo ylide D generated through Ramirez
olefination conditions.
The high isolated yield of iodo-enamides 25 and 26 supports
the theory that a stepwise process is taking place and that the
rate for the second halogenation step is highly dependent on
the structural nature of the initial halo-enamide intermediate
generated. Alternatively, it could be implied that N-
formylimides with closely related structures have very different
rates of reaction with ylides A or D and that the iodo-enamide
products obtained from the reaction with ylide A are not
intermediates on the pathway for the synthesis of diiodo-
enamides.
Additional evidence for a stepwise process was provided by
treatment of the pantolactone-derived N-formylimide 32 under
the same iodo-olefination conditions. This resulted in the
formation of diiodo-enamide 33 and oxazole 34 (Scheme 7). In
contrast, bromo-olefination of pantolactone-derived N-formy-
limide, 32, gave oxazole 34 in near quantitative yield. The
structures of both the diiodo-enamide and oxazole were
corroborated by crystallographic analysis (Figure 4).15,16
The oxazole is presumably generated through the intra-
molecular cyclization of the iodo-enamide intermediate
obtained in a manner similar to that reported by Ferreira
following treatment of amino acid derived β-iodo-enamides
with base (Scheme 8).13
Initial debromination attempts on dibromo-enamide 18
using the Zn−Cu couple conditions resulted in a 6:1 E:Z
product ratio of β-bromo-enamides 38E/38Z in quantitative
yield (Scheme 11). Although this provides a highly efficient
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Scheme 8. Ferreira’s Formation of Oxazoles from β-Iodo-enamides
Table 3. Selective De-iodination of Diiodo-enamides
approach to the synthesis of E-halo-enamides, it did not provide
us with the complete selectivity observed in the diiodo-enamide
series. However, treatment of dibromo-enamide 18 using
tributyltin hydride/tetrakis(triphenylphosphine)Pd(0) afforded
the highly desirable and elusive Z-β-bromo-enamide 38Z in
excellent yield and with complete diastereoselectivity (Scheme
11).
Faced with such unprecedented efficiency and selectivity for
the synthesis of a Z-bromo-enamide unit, the reproducibility of
the debromination conditions were assessed. We are pleased to
report that, in all cases, the reduction resulted in the desired Z-
bromo enamides 38Z−43 in high yields and with complete
stereocontrol. Table 4 summarizes our two-step process for the
efficient generation of these from the readily available N-
formylimides (Table 4).
CONCLUSIONS
■
In conclusion, we have developed a flexible and stereoselective
synthesis of β-halo-enamides taking advantage of the
unprecedented and high yielding β,β-dihalo-olefination of N-
formylimides. This effective, reproducible, and highly efficient
synthesis of β-halo- and β,β-dihalo-enamides provides a solid
protecting group-free platform from which the full potential of
enamide chemistry can be realized. Furthermore, these results
herein provide evidence that an alternative mechanistic pathway
for dihalo-olefination to that proposed by Chapleur is likely to
be taking place. We are currently carrying out further
experimental and theoretical calculations to shed further light
on the mechanistic aspects of this transformation.
a
All reactions were conducted using 1 equiv of diiodo-enamide, 30
equiv of Zn−Cu couple, and 100 equiv of AcOH at 0 °C for 0.5 h.
Scheme 9. Synthesis of Oxazole 34 from Iodo-enamide 36
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed in oven-dried
glassware under an inert argon atmosphere unless otherwise stated.
Tetrahydrofuran (THF) and toluene were purified through a solvent
purification system. Anhydrous ethyl acetate (EtOAc) and methanol
(MeOH) were obtained commercially. All reagents were used as
received, unless otherwise stated. Solvents were evaporated under
reduced pressure at 40 °C unless otherwise stated. IR spectra were
recorded as thin films on NaCl plates using a Fourier transform
spectrometer. Only significant absorptions (νmax) are reported in
wavenumbers (cm−1). Proton magnetic resonance spectra (1H NMR)
and carbon magnetic resonance spectra (13C NMR) were recorded
respectively at 400 MHz/500 MHz and 100 MHz/125 MHz.
Chemical shifts (δ) are reported in parts per million (ppm) and are
referenced to the residual solvent peak. The order of citation in
parentheses is (1) number of equivalent nuclei (by integration), (2)
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint =
quintet, sext = sextet, sept = septet, m = multiplet, b = broad), (3) and
coupling constant (J) quoted in hertz to the nearest 0.1 Hz. High-
resolution mass spectra were recorded by electrospray (EI) or
chemical ionization (CI) using a mass spectrometer operating at a
Scheme 10. Proposed Stepwise Formation of Dihalo-
enamide and Oxazole Units
Scheme 11. Initial De-bromination Attempts
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Table 4. Stereoselective Synthesis of Z-β-Bromo-enamides
a
The reactions were conducted using 1 equiv of N-formylimide, 10 equiv of phosphonium salt, and 10 equiv of base in dry THF (0.33 M) at rt for
b
12 h. The reactions were conducted using 1 equiv of dibromo-enamide, 1.2 equiv of Bu3SnH, and 0.1 equiv of catalyst in dry EtOAc (16 mM) at rt
for 12 h.
resolution of 15000 full widths at half height. Flash chromatography
was performed using silica gel (40−63 μm) as the stationary phase.
TLC was performed on aluminum sheets precoated with silica (silica
gel 60 F254) unless otherwise stated where aluminum oxide plates
were used. The plates were visualized by the quenching of UV
fluorescence (λmax 254 nm) and/or by staining with potassium
permanganate followed by heating.
organic layers were dried over Na2SO4, filtered, and concentrated
under vacuum to afford a crude brown oil. Purification of the crude
residue by flash column chromatography (silica gel, 80:20 hexane:ethyl
1
acetate) gave 4.8 g (81%) of N-formylimide 17 as a yellow oil: H
NMR (500 MHz; CDCl3) δH 8.90 (1H, s), 7.49−7.40 (5H, m), 3.19
(3H, s); 13C NMR (125 MHz; CDCl3) δC 172.4, 164.3, 133.4, 132.0,
128.8, 128.7, 27.4; IR (neat) νmax 2935, 1722, 1654, 1600, 1413, 1338,
1274, 1043, 1022 cm−1; HRMS (CI+) found (M + H)+ 164.0714,
C9H10NO2 requires 164.0712.
N-Formyl-N-methylpropionamide, 15. A 0 °C solution of N-
methylpropionamide (5.0 g, 57.5 mmol) in dry THF (100 mL) was
treated by the dropwise addition of n-butyllithium (2.5 M in hexanes,
25.3 mL, 63.2 mmol). The resulting mixture was stirred at 0 °C for 1 h
and then treated with a solution of N-formylbenzotriazole (10.15 g,
69.0 mmol) in THF (50 mL). The reaction mixture was then allowed
to warm to room temperature and stirred for a further 12 h. The
mixture was diluted with tert-butyl methyl ether (100 mL) and
quenched with satd aq NaHCO3 (100 mL). The layers were separated,
and the aqueous phase was extracted with diethyl ether (3 × 100 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under vacuum to afford a crude brown oil. Purification of
the crude residue by flash column chromatography (silica gel, 80:20
hexane/ethyl acetate) gave 3.2 g (48%) of N-formylimide 15 as a
yellow oil: 1H NMR (500 MHz; CDCl3) δH 9.14 (1H, s), 2.97 (3H, s),
2.56 (2H, q, J = 7.4 Hz), 1.09 (3H, t, J = 7.4 Hz); 13C NMR (125
MHz; CDCl3) δC 175.1, 162.4, 28.1, 26.3, 8.3; IR (neat) νmax 2985,
1722, 1668, 1452, 1417, 1365, 1265, 1051 cm−1; HRMS (CI+) found
(M + H)+ 116.0707, C5H10NO2 requires 116.0712.
N-Formyl-N-methylbenzamide, 17. A 0 °C solution of N-
methylbenzamide (5.0 g, 37 mmol) in dry THF (100 mL) was treated
by the dropwise addition of n-butyllithium (2.5 M in hexanes, 16.3 mL,
40.7 mmol). The resulting mixture was stirred at 0 °C for 1 h and then
treated with a solution of N-formylbenzotriazole (6.53 g, 44.4 mmol)
in THF (50 mL). The reaction mixture was then allowed to warm to
room temperature and stirred for a further 12 h. The mixture was
diluted with tert-butyl methyl ether (100 mL) and quenched with satd
aq NaHCO3 (100 mL). The layers were separated, and the aqueous
phase was extracted with diethyl ether (3 × 100 mL). The combined
(Bromomethyl)triphenylphosphonium Bromide. A solution
of triphenylphosphine (60 g, 230 mmol) in dry toluene (100 mL) was
treated with the dropwise addition of methylene bromide (21 mL, 300
mmol), and the resulting solution was stirred at 60 °C for 72 h. The
precipitate obtained was filtered, washed with toluene (5 × 100 mL),
and dried under vacuum for 12 h to yield 80.2 g (80%) of
bromomethyl)triphenylphosphonium bromide as a white solid: 1H
NMR (400 MHz; DMSO-d6) δH 7.99−7.93 (6H, m), 7.84−7.79 (3H,
m), 7.73−7.68 (6H, m), 5.88 (2H, d, J = 5.4 Hz); 13C NMR (100
MHz; DMSO-d6) δC 135.6, 135.5, 134.5, 134.4, 130.6, 130.5, 117.5,
116.6, 18.8, 18.3; IR (neat) νmax 3047, 2987, 1589, 1481, 1437, 1340,
1116 cm−1; HRMS (FAB+) found (M − Br)+ 355.0247, C19H17PBr
requires 355.0251; mp 220 °C dec.
General Procedure A for the Dibromo-olefination of N-
Formylimides.
A suspension of (bromomethyl)-
triphenylphosphonium bromide (10 equiv) in anhydrous THF was
treated with potassium tert-butoxide (10 equiv), and the resulting
bright orange suspension was allowed to stir at room temperature until
it turned brown, indicating the ylide formation (6 h). The resulting
brown suspension was then treated dropwise with a solution of N-
formylimide (1.0 equiv) in THF. The resulting mixture was stirred at
room temperature until TLC analysis showed reaction completion (12
h). The reaction mixture was quenched with distilled water (10 mL)
and poured into hexanes (25 mL), and the precipitate formed was
filtered off. The phases were separated, and the aqueous layer was
extracted with diethyl ether (3 × 10 mL). The combined organic layers
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were dried over Na2SO4, filtered, and concentrated under vacuum, and
the crude residue was purified by flash column chromatography.
1-(2,2-Dibromovinyl)azepan-2-one, 10b. Following general
procedure A, (bromomethyl)triphenylphosphonium bromide (2.2 g,
5.0 mmol) in anhydrous THF (10 mL) was deprotonated with
potassium tert-butoxide (0.6 g, 5.0 mmol), and the resulting ylide was
treated with a solution of 2-oxoazepan-1-carbaldehyde 9 (70.5 mg, 0.5
mmol) in THF (5 mL). The crude brown oil was purified by flash
column chromatography (silica gel, 80:20 hexane/ethyl acetate) to
N-(2,2-Dibromovinyl)-N-methylpropionamide, 22. Following
general procedure A, (bromomethyl)triphenylphosphonium bromide
(4.4 g, 10.0 mmol) in anhydrous THF (20 mL) was deprotonated with
potassium tert-butoxide (1.12 g, 10.0 mmol), and the resulting ylide
was treated with a solution of N-formyl-N-methylpropionamide 15
(115 mg, 1.0 mmol) in THF (10 mL). The crude brown oil was
purified by flash column chromatography (silica gel, 80:20 hexane/
ethyl acetate) to afford 310 mg (quant. yield) of dibromo-enamide 22
1
as a yellow oil: H NMR (500 MHz; CDCl3) δH 7.06 (1H, s), 3.01
1
(3H, s), 2.24 (2H, q, J = 7.6 Hz), 1.07 (3H, t, J = 7.4 Hz); 13C NMR
(125 MHz; CDCl3) δC 173.0, 135.5, 94.5, 33.7, 27.8, 9.1; IR (neat)
νmax 2980, 2939, 1666, 1595, 1462, 1373, 1265, 1062 cm−1; HRMS
(CI+) found (M + H)+ 269.9130, C6H10NOBr2 requires 269.9129.
N-(2,2-Dibromovinyl)benzamide, 23. Following general proce-
dure A, (bromomethyl)triphenylphosphonium bromide (4.4 g, 10.0
mmol) in anhydrous THF (20 mL) was deprotonated with potassium
tert-butoxide (1.12 g, 10.0 mmol), and the resulting ylide was treated
with a solution of N-formylbenzamide 16 (149 mg, 1.0 mmol) in THF
(10 mL). The crude brown oil was purified by flash column
chromatography (silica gel, 80:20 hexane:ethyl acetate) to afford 241
afford 139 mg (93%) of dibromo-enamide 10b as a yellow oil: H
NMR (500 MHz; CDCl3) δH 7.41 (1H, s), 3.66 (2H, t, J = 4.7 Hz),
2.58 (2H, t, J = 6.4 Hz), 1.84−1.80 (2H, m), 1.77−1.73 (4H, m); 13C
NMR (125 MHz; CDCl3) δC 175.8, 135.8, 85.2, 50.2, 37.3, 29.9, 29.4,
23.2; IR (neat) νmax 3039, 2928, 1658), 1435, 1392, 1257, 1207, 1188
cm−1; HRMS (CI+) found (M + H)+ 297.9261, C8H12NOBr2 required
297.9265.
1-(2,2-Dibromovinyl)pyrrolidin-2-one, 18. Following general
procedure A, (bromomethyl)triphenylphosphonium bromide (2.2 g,
5.0 mmol) in anhydrous THF (10 mL) was deprotonated with
potassium tert-butoxide (0.6 g, 5.0 mmol), and the resulting ylide was
treated with a solution of 2-oxopyrrolidine-1-carbaldehyde 11 (56.5
mg, 0.5 mmol) in THF (5 mL). The crude brown oil was purified by
flash column chromatography (silica gel, 80:20 hexane/ethyl acetate)
1
mg (79%) of dibromo-enamide 23 as a yellow solid: H NMR (500
MHz; CDCl3) δH 7.85−7.82 (4H, m), 7.59 (1H, tt, J = 6.8, 1.2 Hz
Hz), 7.50 (2H, tm, J = 7.6 Hz); 13C NMR (125 MHz; CDCl3) δC
163.4, 132.9, 132.5, 129.2, 127.8, 127.4, 75.0; IR (neat) νmax 3396,
3066, 1660, 1629, 1504, 1467, 1249, 848 cm−1; HRMS (EI+) found
(M)+ 304.8883, C9H7NOBr2 requires 304.8874; mp 60 °C.
1
to afford 125 mg (94%) of dibromo-enamide 18 as a yellow oil: H
NMR (500 MHz; CDCl3) δH 7.59 (1H, s), 4.01 (2H, t, J = 7.4 Hz),
2.39 (2H, t, J = 8.2 Hz), 2.09 (2H, qn, J = 7.4 Hz); 13C NMR (125
MHz; CDCl3) δC 174.7, 129.6, 74.0, 46.9, 29.9, 18.9; IR (neat) νmax
3039, 2962, 2901, 1697, 1620, 1481, 1373 cm−1; HRMS (CI+) found
(M + H)+ 269.8957, C6H8NOBr2 requires 269.8952.
N-(2,2-Dibromovinyl)-N-methylbenzamide, 24. Following
general procedure A, (bromomethyl)triphenylphosphonium bromide
(4.4 g, 10.0 mmol) in anhydrous THF (20 mL) was deprotonated with
potassium tert-butoxide (1.12 g, 10.0 mmol), and the resulting ylide
was treated with a solution of N-formyl-N-methylbenzamide 17 (163
mg, 1.0 mmol) in THF (10 mL). The crude brown oil was purified by
flash column chromatography (silica gel, 80:20 hexane/ethyl acetate)
to afford 270 mg (85%) of dibromo-enamide 24 as a yellow solid: 1H
NMR (500 MHz; CDCl3) δH 7.52−7.47 (2H, m), 7.46−7.41 (1H, m),
7.40−7.36 (2H, m), 7.09 (1H, bs), 3.26 (3H, s); 13C NMR (125 MHz;
CDCl3) δC 170.5, 136.8, 135.0, 131.0, 128.3, 128.2, 90.0, 34.9; IR
(neat) νmax 3020, 2933, 1716, 1647, 1597, 1346, 1323 cm−1; HRMS
(CI+) found (M)+ 316.9045, C10H9NOBr2 requires 316.9051; mp 80
°C.
2-(2,2,5,5-Tetramethyl-1,3-dioxan-4-yl)oxazole, 34. Following
general procedure A, (bromomethyl)triphenylphosphonium bromide
(2.2 g, 5.0 mmol) in anhydrous THF (10 mL) was deprotonated with
potassium tert-butoxide (0.6 g, 5.0 mmol), and the resulting ylide was
treated with a solution of N-formyl-2,2,5,5-tetramethyl-1,3-dioxane-4-
carboxamide 32 (107.5 mg, 0.5 mmol) in THF (5 mL). The crude
brown oil was purified by flash column chromatography (silica gel,
80:20 hexane:ethyl acetate) to afford 105 mg (99%) of oxazole 34 as a
yellow solid: 1H NMR (400 MHz; CDCl3) δH 7.64 (1H, s), 7.09 (1H,
s), 4.90 (1H, s), 3.78 (1H, d, J = 11.4 Hz), 3.41 (1H, d, J = 11.4 Hz),
1.53 (3H, s), 1.50 (3H, s), 1.06 (3H, s), 0.86 (3H, s); 13C NMR (100
MHz; CDCl3) δC 161.2, 138.9, 127.0, 99.7, 74.8, 71.6, 34.2, 29.5, 21.8,
19.3, 18.7; IR (neat) νmax 3119, 2994, 2969, 1574, 1523, 1459, 1392,
1383, 1370, 1193, 1157 cm−1; HRMS (CI+) found (M + H)+
212.1282, C11H18NO3 requires 212.1287; mp 68−70 °C.
1-(2,2-Dibromovinyl)piperidin-2-one, 19. Following general
procedure A, (bromomethyl)triphenylphosphonium bromide (4.4 g,
10.0 mmol) in anhydrous THF (20 mL) was deprotonated with
potassium tert-butoxide (1.12 g, 10.0 mmol), and the resulting ylide
was treated with a solution of 2-oxopiperidine-1-carbaldehyde 12 (127
mg, 1.0 mmol) in THF (10 mL). The crude brown oil was purified by
flash column chromatography (silica gel, 80:20 hexane/ethyl acetate)
1
to afford 258 mg (91%) of dibromo-enamide 19 as a yellow oil: H
NMR (500 MHz; CDCl3) δH 7.40 (1H, s), 3.64 (2H, t, J = 4.8 Hz),
2.45 (2H, t, J = 6.6 Hz), 1.83 (4H, m); 13C NMR (125 MHz; CDCl3)
δC 169.9, 134.8, 85.9, 48.8, 32.4, 23.1, 20.8; IR (neat) νmax 3047, 2947,
1658, 1612, 1473, 1404, 1260, 1255, 1219, 1157 cm−1; HRMS (CI+)
found (M + H)+ 283.9102, C7H10NOBr2 requires 283.9109.
1-(2,2-Dibromovinyl)azocan-2-one, 20. Following general
procedure A, (bromomethyl)triphenylphosphonium bromide (2.2 g,
5.0 mmol) in anhydrous THF (10 mL) was deprotonated with
potassium tert-butoxide (0.6 g, 5.0 mmol), and the resulting ylide was
treated with a solution of 2-oxoazocan-1-carbaldehyde 13 (77.5 mg,
0.5 mmol) in THF (5 mL). The crude brown oil was purified by flash
column chromatography (silica gel, 80:20 hexane:ethyl acetate) to
afford 140 mg (90%) of dibromo-enamide 20 as a yellow oil: 1H NMR
(500 MHz; CDCl3) δH 7.42 (1H, s), 3.67 (2H, t, J = 5.1 Hz), 2.59
(2H, t, J = 6.4 Hz), 1.85−1.80 (2H, m), 1.78−1.68 (6H, m); 13C NMR
(125 MHz; CDCl3) δC 175.9, 135.8, 77.7, 50.2, 37.3, 29.9, 29.4, 26.3,
23.3; IR (neat) νmax 3039, 2928, 1712, 1658, 1454, 1396, 1361, 1207,
1192 cm−1; HRMS (CI+) found (M + H)+ 311.9413, C9H14NOBr2
required 311.9422.
(Iodomethyl)triphenylphosphonium Iodide. A solution of
triphenylphosphine (30 g, 114.4 mmol) in dry toluene (50 mL) was
treated dropwise with methylene iodide (12 mL, 148.9 mmol). The
reaction mixture was allowed to stir at 60 °C for 72 h, which caused a
white precipitate to form. The suspension was then cooled down to
room temperature, filtered and the white solid residue was washed
several times with toluene (5 × 200 mL). The crude product was dried
under vacuum for 12 h to afford 55 g (91%) of the phosphonium
N-(2,2-Dibromovinyl)butyramide, 21. Following general proce-
dure A, (bromomethyl)triphenylphosphonium bromide (2.2 g, 5.0
mmol) in anhydrous THF (10 mL) was deprotonated with potassium
tert-butoxide (0.6 g, 5.0 mmol), and the resulting ylide was treated
with a solution of N-formylbutyramide 14 (57.5 mg, 0.5 mmol) in
THF (5 mL). The crude brown oil was purified by flash column
chromatography (silica gel, 80:20 hexane/ethyl acetate) to afford 140
1
mg (99%) of dibromo-enamide 21 as a yellow solid: H NMR (500
1
iodide as a pure white solid: H NMR (400 MHz; DMSO-d6) δH
MHz; CDCl3) δH 7.61 (1H, d, J = 11.6 Hz), 7.13 (1H, bs), 2.27 (2H, t,
J = 7.4 Hz), 1.72−1.67 (2H, m), 0.97 (3H, t, J = 7.4 Hz); 13C NMR
(125 MHz; CDCl3) δC 169.5, 127.5, 73.7, 38.3, 18.7, 13.8; IR (neat)
νmax 3053, 2961, 1663, 1631, 1480, 1376, 1268, 1194 cm−1; HRMS
(CI+) found (M + H)+ 271.9110, C6H10ONBr2 required 271.9129;
mp 66 °C.
7.98−7.81 (15H, m), 5.10 (2H, d, J = 8.5 Hz); 13C NMR (100 MHz;
DMSO-d6) δC 136.1, 136.0, 134.8, 134.7, 131.2, 131.0, 119.7, 118.8,
−14.9, −15.4; IR (neat) νmax 2994, 2970, 1575, 1459, 1392, 1383
cm−1; HRMS (FAB+) found (M − I)+ 403.0110, C19H17PI requires
403.0113; mp 235 °C.
2155
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Article
General Procedure B for the Diiodo-olefination of N-
Formylimides. A suspension of (iodomethyl)triphenylphosphonium
iodide (10 equiv) in anhydrous THF was treated with potassium tert-
butoxide (10 equiv), and the resulting bright orange suspension was
allowed to stir at room temperature until it turned brown, indicating
the ylide formation (6 h). The resulting brown suspension was then
treated dropwise with a solution of N-formylimide (1.0 equiv) in THF.
The resulting mixture was stirred at room temperature until TLC
analysis showed reaction completion (12 h). The reaction mixture was
quenched with distilled water (10 mL) and poured into hexanes (25
mL), and the precipitate formed was filtered off. The phases were
separated, and the aqueous layer was extracted with diethyl ether (3 ×
10 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under vacuum, and the crude residue was
purified by flash column chromatography.
1-(2,2-Diiodovinyl)azepan-2-one, 25. Following general proce-
dure B, (iodomethyl)triphenylphosphonium iodide (5.30 g, 10.0
mmol) in anhydrous THF (20 mL) was deprotonated with potassium
tert-butoxide (1.12 g, 10.0 mmol), and the resulting ylide was treated
with a solution of 2-oxoazepane-1-carbaldehyde 9 (141.2 mg, 1.0
mmol) in THF (10 mL). The crude brown oil was purified by flash
column chromatography (silica gel, 80:20 hexane:ethyl acetate) to
afford 390 mg (99%) of diiodo-enamide 25 as a yellow solid: 1H NMR
(400 MHz; CDCl3) δH 7.73 (1H, s), 3.64 (2H, t, J = 4.4 Hz), 2.58−
2.55 (2H, m), 1.83−1.74 (6H, m); 13C NMR (100 MHz; CDCl3) δC
175.4, 147.3, 50.6, 37.4, 31.7, 29.9, 22.8, 14.2; IR (neat) νmax 3010,
2930, 2910, 1646, 1587, 1464., 1443, cm−1; HRMS (CI+) found (M +
H)+ 391.9003, C8H12NOI2 requires 391.9008; mp 75 °C.
24.3, 13.1; IR (neat) νmax 2916, 2852, 1628, 1617, 1588, 1472, 1444
cm−1; HRMS (CI+) found (M + H)+ 405.9169, C9H14NOI2 requires
1
405.9165. (E)-1-(2-Iodovinyl)azocan-2-one, 29: H NMR (400 MHz;
CDCl3) δH 7.95 (1H, d, J = 14.0 Hz), 5.52 (1H, d, J = 14.0 Hz).
N-(2,2-Diiodovinyl)-2,2,5,5-tetramethyl-1,3-dioxane-4-car-
boxamide, 33, and 2-(2,2,5,5-Tetramethyl-1,3-dioxan-4-yl)-
oxazole, 34. Following general procedure B, (iodomethyl)-
triphenylphosphonium iodide (1.20 g, 2.25 mmol) in dry THF (10
mL) was deprotonated with potassium tert-butoxide (0.252 g, 2.25
mmol mmol) and the resulting ylide was treated with a solution of N-
formyl-2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamide 32 (107.5 mg,
0.5 mmol) in THF (5 mL). The crude brown oil was purified by flash
column chromatography (silica gel, 80:20 hexanes: ethyl acetate) to
yield 74 mg (32%) of diiodo-enamide 33 and 17 mg (16%) of oxazole
34 as yellow solids.
N-(2,2-Diiodovinyl)-2,2,5,5-tetramethyl-1,3-dioxane-4-car-
1
boxamide, 33: H NMR (400 MHz; CDCl3) δH 8.34 (1H, bd, J =
10.8 Hz), 7.76 (1H, d, J = 11.4 Hz), 4.14 (1H, s), 3.71 (1H, d, J = 11.7
Hz), 3.32 (1H, d, J = 11.7 Hz), 1.51 (3H, s), 1.45 (3H, s), 1.03 (3H,
s), 1.02 (3H, s); 13C NMR (100 MHz; CDCl3) δC 166.1, 136.4, 99.4,
77.1, 71.4, 33.3, 29.5, 22.9, 18.8,19.1, −6.8; IR (neat) νmax 3351, 2836,
1686, 1612, 1465, 1384, 1379, 1094, 1050 cm−1; HRMS (CI+) found
(M + H)+ 465.9372, C11H18NO3I2 requires 465.9376; mp 135 °C.
1
2-(2,2,5,5-Tetramethyl-1,3-dioxan-4-yl)oxazole, 34: H NMR
(400 MHz; CDCl3) δH 7.64 (1H, s), 7.09 (1H, s), 4.90 (1H, s), 3.78
(1H, d, J = 11.4 Hz), 3.41 (1H, d, J = 11.4 Hz), 1.53 (3H, s), 1.50 (3H,
s), 1.06 (3H, s), 0.86 (3H, s).
General Procedure C for the Dehalogenation of Dihaloena-
mides. The dihaloenamide (1 equiv) was dissolved in an anhydrous
MeOH/THF mixture (1:1), and the resulting solution was cooled to 0
°C. The solution was treated with Zn−Cu couple (30 equiv) and
glacial acetic acid (100 equiv), and the resulting reaction mixture was
stirred at 0 °C until completion by TLC analysis (30 min). The
reaction was quenched with satd aq NaHCO3 (10 mL) and extracted
with diethyl ether (3 × 10 mL). The combined organic phases were
dried over Na2SO4 and concentrated under vacuum.
(E)-1-(2-Iodovinyl)pyrrolidin-2-one, 26. Following general
procedure B, (iodomethyl)triphenylphosphonium iodide (2.65 g, 5.0
mmol) in anhydrous THF (10 mL) was deprotonated with potassium
tert-butoxide (0.6 g, 5.0 mmol), and the resulting ylide was treated
with a solution of 2-oxopyrrolidin-1-carbaldehyde 11 (56.5 mg, 0.5
mmol) in THF (5 mL). The crude brown oil was purified by flash
column chromatography (silica gel, 80:20 hexane/ethyl acetate) to
1
afford 92 mg (78%) of iodo-enamide 26 as a yellow solid: H NMR
(E)-1-(2-Iodovinyl)azepan-2-one, 35E, and (Z)-1-(2-
Iodovinyl)azepan-2-one, 35Z. Following general procedure C, 1-
(2,2-diiodovinyl)azepan-2-one 25 (380 mg, 0.97 mmol) was dissolved
in anhydrous MeOH/THF (1:1, 20 mL total volume) and treated with
Zn−Cu couple (3.7 g, 29.1 mmol) and glacial acetic acid (5.9 mL, 97.0
mmol) to yield 240 mg (94%) of iodo enamides 35E and 35Z (10:1
ratio) as an inseparable mixture. (E)-1-(2-Iodovinyl)azepan-2-one,
35E: 1H NMR (400 MHz; CDCl3) δH 7.84 (1H, d, J = 13.7 Hz), 5.51
(1H, d, J = 14.2 Hz), 3.57−3.52 (2H, m), 2.63−2.58 (2H, m), 1.75−
1.67 (6H, m); 13C NMR (100 MHz, CDCl3) δ: 173.5, 137.3, 55.0,
45.1, 36.9, 29.4, 27.5, 23.4. (Z)-1-(2-Iodovinyl)azepan-2-one, 35Z: 1H
NMR (400 MHz; CDCl3) δH 7.45 (1H, d, J = 6.3 Hz), 5.83 (1H, d, J =
6.9 Hz), 3.76−3.73 (2H, m), 2.63−2.58 (2H, m), 1.75−1.67 (6H, m);
13C NMR (100 MHz, CDCl3) δ: 176.2, 138.6, 66.9,49.5, 37.4, 30.4,
(400 MHz; CDCl3) δH 7.59 (1H, d, J = 15.0 Hz), 5.37 (1H, d, J = 15.0
Hz), 3.51 (2H, t, J = 7.1 Hz), 2.46 (2H, t, J = 7.8 Hz), 2.12 (2H, qn, J
= 7.5 Hz); 13C NMR (100 MHz; CDCl3) δC 172.3, 134.7, 55.0, 44.6,
30.6, 17.4; IR (neat) νmax 3057, 2957, 2917, 2889, 1685, 1607, 1480,
1457, 1263, 1174 cm−1; HRMS (EI) found (M)+ 236.9651, C6H8NOI
requires 236.9655; mp 28 °C.
(E)-1-(2-Iodovinyl)piperidin-2-one, 27. Following general pro-
cedure B, (iodomethyl)triphenylphosphonium iodide (2.65 g, 5.0
mmol) in anhydrous THF (10 mL) was deprotonated with potassium
tert-butoxide (0.6 g, 5.0 mmol), and the resulting ylide was treated
with a solution of 2-oxopiperidin-1-carbaldehyde 12 (63.5 mg,0.5
mmol) in THF (5 mL). The crude brown oil was purified by flash
column chromatography (silica gel, 80:20 hexane/ethyl acetate) to
1
afford 100 mg (80%) of iodo-enamide 27 as a yellow solid: H NMR
29.8, 23.3; IR (neat) νmax 2930, 1658, 1602, 1476, 1389, 1325, 1191
cm−1; HRMS (CI/ISO) found (M + H)+ 266.0042, C8H13NOI
requires 266.0041.
(400 MHz, CDCl3) δ 8.11 (1H, d, J = 14.0 Hz), 5.44 (1H, d, J = 14.0
Hz), 3.41 (2H, t, J = 6.0 Hz), 2.48 (2H, t, J = 6.4 Hz), 1.88−1.81 (2H,
m), 1.79−1.70 (2H, m); 13C NMR (100 MHz, CDCl3) δ 167.8, 137.7,
55.0, 45.0, 32.8, 22.4, 20.6; IR (neat) νmax 2924, 2854, 1651, 1599,
1458, 1404, 1296, 1257 cm−1; HRMS (CI/ISO) found (M + H)+
251.9885, C7H11NOI requires 251.9886; mp 33 °C.
(E)-1-(2-Iodovinyl)azocan-2-one, 29. Following general proce-
dure C, 1-(2,2-diiodovinyl)azocan-2-one 28 (405 mg, 1.0 mmol) was
dissolved in anhydrous MeOH/THF (20 mL total volume) and
treated with Zn−Cu couple (3.81 g, 30.0 mmol) and glacial acetic acid
(6.1 mL, 100.0 mmol) to yield 215 mg (77%) of iodo enamide 29 as
1-(2,2-Diiodovinyl)azocan-2-one, 28, and (E)-1-(2-Iodovinyl)-
azocan-2-one, 29. Following general procedure B, (iodomethyl)-
triphenylphosphonium iodide (5.30 g, 10.0 mmol) in anhydrous THF
(20 mL) was deprotonated with potassium tert-butoxide (1.12 g, 10.0
mmol), and the resulting ylide was treated with a solution of 2-
oxoazocane-1-carbaldehyde 13 (155 mg, 1.0 mmol) in THF (10 mL).
The crude brown oil was purified by flash column chromatography
(silica gel, 80:20 hexanes: ethyl acetate) to yield 386 mg of an
inseparable 13:1 mixture of diiodo-enamide 28 (89%) and E-iodo-
enamide 29 (10%).
1
white solid which did not require any further purification: H NMR
(400 MHz; CDCl3) δH 7.90 (1H, d, J = 13.7 Hz), 5.52 (1H, d, J = 13.6
Hz), 3.75−3.69 (2H,m), 2.61−2.56 (2H, m), 1.88−1.80 (2H, m),
1.74−1.66 (2H, m), 1.60−1.52 (2H, m), 1.50−1.42 (2H, m); 13C
NMR (125 MHz; CDCl3) δC 172.9, 136.1, 55.6, 43.6, 34.3, 29.1, 27.8,
26.3, 24.1; IR (neat) νmax 3083, 2938, 2929, 2915, 1647, 1603, 1484,
1453, 1388, 1312 cm−1; HRMS (CI/ISO) found (M + H)+ 280.0198,
C9H15NOI requires 280.0203; mp 54 °C.
(Z)-N-(2-Iodovinyl)-2,2,5,5-tetramethyl-1,3-dioxane-4-car-
boxamide, 36. Following general procedure C, N-(2,2-diiodovinyl)-
2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamide 33 (160 mg, 0.344
mmol) was dissolved in anhydrous MeOH/THF mixture (10 mL
1-(2,2-Diiodovinyl)azocan-2-one, 28: 1H NMR (400 MHz;
CDCl3) δH 7.56 (1H, s), 3.78 (2H, t, J = 5.6 Hz), 2.53 (2H, t, J = 6.3
Hz), 1.88−1.82 (2H, m), 1.69−1.58 (4H, m), 1.53−1.47 (2H, m); 13C
NMR (100 MHz; CDCl3) δC 175.6, 145.2, 47.0, 34.3, 30.1, 28.8, 26.3,
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The Journal of Organic Chemistry
Article
total volume) and was treated with Zn−Cu couple (1.33 g, 10.32
mmol) and glacial acetic acid (2.1 mL, 34.4 mmol) to yield 80 mg
(71%) of iodo enamide 36 as a yellow solid, which did not require any
further purification: 1H NMR (400 MHz; CDCl3) δH 8.90−8.77 (1H,
m), 7.57 (1H, dd, J = 11.3, 6.5 Hz), 5.72 (1H, d, J = 6.4 Hz), 4.46 (1H,
s), 4.01 (1H, d, J = 11.5 Hz), 3.61 (1H, d, J = 11.5 Hz), 1.83 (3H, s),
1.76 (3H, s), 1.34 (3H, s), 1.33 (3H, s); 13C NMR (100 MHz; CDCl3)
δC 167.5, 129.3, 99.3, 77.2, 71.4, 61.3, 33.2, 29.5, 21.9, 19.0, 18.0; IR
(neat) νmax 2988, 2956, 2872, 1699, 1626, 1464, 1375, 1285, 1235
cm−1; HRMS (EI) found (M)+ 339.0332, C11H18NO3I requires
339.0331; mp 110 °C.
General Procedure D for the Dehalogenation of Dihaloe-
namides. A solution of dihaloenamide (1 equiv) in anhydrous EtOAc
(5 mL) was treated with Pd(PPh3)4 (0.1 equiv) and Bu3SnH (1.2
equiv). The resulting reaction mixture was stirred at room temperature
until completion as indicated by TLC analysis (12 h). The reaction
was diluted with hexane (15 mL), filtered through Celite, and
concentrated under vacuum to afford a crude residue which was
purified by flash column chromatography.
(Z)-1-(2-Bromovinyl)pyrrolidin-2-one, 38. Following general
procedure D, a solution of 1-(2,2-dibromovinyl)pyrrolidin-2-one 18
(90 mg, 0.34 mmol) in anhydrous EtOAc (5 mL) was treated with
Pd(PPh3)4 (39 mg, 0.03 mmol) and Bu3SnH (0.11 mL, 0.40 mmol).
The crude yellow oil was purified by flash column chromatography
(silica gel, 80:20 hexane/ethyl acetate) to afford 56 mg (88%) of
bromo-enamide 38 as a colorless oil: 1H NMR (500 MHz; CDCl3) δH
7.29 (1H, d, J = 7.0 Hz), 5.41 (1H, d, J = 7.0 Hz), 4.14 (2H, t, J = 7.2
Hz), 2.41 (2H, t, J = 7.8 Hz), 2.09 (2H, qn, J = 7.4 Hz); 13C NMR
(125 MHz; CDCl3) δC 175.3, 126.2, 86.6, 47.5, 30.1, 18.8; IR (neat)
νmax 2953, 1703, 1640, 1484, 1381, 1313, 1251 cm−1; HRMS (CI+)
found (M + H)+ 189.9865, C6H9NOBr requires 189.9868.
(Z)-1-(2-Bromovinyl)piperidin-2-one, 39. Following general
procedure D, a solution of 1-(2,2-dibromovinyl)piperidin-2-one 19
(169 mg, 0.60 mmol) in anhydrous EtOAc (32 mL) was treated with
Pd(PPh3)4 (70 mg, 0.06 mmol) and Bu3SnH (0.2 mL, 0.71 mmol).
The crude yellow oil was purified by flash column chromatography
(silica gel, 80:20 hexane/ethyl acetate) to afford 86 mg (70%) of
bromo-enamide 39 as a colorless oil: 1H NMR (400 MHz; CDCl3) δH
7.37 (1H, d, J = 6.5 Hz), 5.74 (1H, d, J = 6.5 Hz), 3.83−3.78 (2H, m),
2.51−2.46 (2H, m), 1.89−1.79 (4H, m); 13C NMR (100 MHz;
CDCl3) δC 170.3, 131.6, 94.8, 48.9, 32.4, 23.1, 20.8; IR (neat) νmax
2953, 2877, 1656, 1626, 1477, 1460, 1427, 1406, 1269, 1172 cm−1;
HRMS (CI+) found (M + H)+ 204.0026, C7H11NOBr requires
204.0024.
C6H11NOBr requires 192.0024; IR (neat) νmax 2961, 1677, 1642,
1239, 1195, 678 cm−1.
2-Propyloxazole: 1H NMR (400 MHz; CDCl3) δH 7.63 (1 H, d, J
= 10.9 Hz), 7.08 (1 H, bs), 2.28 (2H, t, J = 7.6 Hz), 1.72 (2H, sextet, J
= 7.4 Hz), 0.98 (3H, t, J = 7.4 Hz); 13C NMR (100 MHz; CDCl3) δC
131.0, 128.9, 125.4, 29.1, 23.1, 11.1; HRMS (CI+) found (M + H)+
112.0769, C6H10NO requires 112.0762; IR (neat) νmax 2961, 1677,
1642, 1239, 1195, 678 cm−1.
(Z)-N-(2-Bromovinyl)-N-methylpropionamide, 41. Following
general procedure D, a solution of N-(2,2-dibromovinyl)-N-methyl-
propionamide 22 (117 mg, 0.43 mmol) in anhydrous EtOAc (10 mL)
was treated with Pd(PPh3)4 (50 mg, 0.04 mmol) and Bu3SnH (0.14
mL, 0.52 mmol). The crude yellow oil was purified by flash column
chromatography (silica gel, 80:20 hexane/ethylacetate) to afford 60
1
mg (72%) of bromo-enamide 41 as a colorless oil: H NMR (500
MHz; CDCl3) δH 6.95 (1H, bs), 6.00 (1H, bs), 3.16 (3H, s), 2.31−
2.30 (2H, m), 1.15−1.12 (3H, m); 13C NMR (125 MHz; CDCl3) δC
173.6, 133.3, 102.3, 34.0, 27.8, 9.2; IR (neat) νmax 3086, 3063, 2920,
1654, 1624, 1577, 1446, 1346, 1300, 1057 cm−1; HRMS (CI+) found
(M)+ 192.0015, C6H11NOBr requires 192.0024.
(Z)-N-(2-Bromovinyl)-N-methylbenzamide, 42. Following gen-
eral procedure D, a solution of N-(2,2-dibromovinyl)-N-methylbenza-
mide 24 (98 mg, 0.31 mmol) in anhydrous EtOAc (5 mL) was treated
with Pd(PPh3)4 (36 mg, 0.03 mmol) and Bu3SnH (0.1 mL, 0.37
mmol). The crude yellow oil was purified by flash column
chromatography (silica gel, 80:20 hexane/ethyl acetate) to afford 63
mg (86%) of bromo-enamide 42 as a yellow oil: 1H NMR (500 MHz;
CDCl3) δH 7.51−7.49 (2H, m), 7.46−7.43 (1H, m), 7.39−7.37 (2H,
m), 6.96 (1H, bs), 5.73 (1H, d, J = 6.0 Hz), 3.40 (3H, s); 13C NMR
(125 MHz; CDCl3) δC 171.4, 135.4, 134.6, 130.9, 128.4, 97.3, 35.2,
29.8; IR (neat) νmax 3086, 2982, 1666, 1631, 1612, 1462, 1423, 1377,
1276, 1057 cm−1; HRMS (CI+) found (M + H)+ 240.0026,
C10H11NOBr requires 240.0024.
Crystallographic Data Collection and Refinement Details. X-
ray diffraction data of crystals of 25, 33, and 34 were collected at 150
K on an Oxford Diffraction Gemini A Ultra diffractometer equipped
with an Oxford Cryosystems Cryostream low-temperature device, a
graphite-monochromated Enhance Ultra Mo Kα radiation (λ =
0.71073 Å) source and an Atlas CCD detector. Data reduction was
carried out and an analytical numeric absorption correction applied
(based on expressions derived in Clark, R. C.; Reid, J. S. Acta
Crystallogr. 1995, A51, 887−897) using CrysAlisPro software (Oxford
Diffraction Ltd, Version 1.171.33.55, Oxfordshire, UK). The structures
were all solved by direct methods using the program SHELXS97
(SHELX, Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122) and
refined using full-matrix least-squares refinement on F2 (SHELX
Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122) within the
WinGX program suite (Farrugia, L. J. J. Appl. Crystallogr. 1999, 32,
837−838). Full refinement details are given in the Supporting
Information and the CIF. Crystallographic data (excluding structure
factors) have been deposited with the Cambridge Crystallographic
Data Centre (CCDC833481, 833478, and 833480), and copies of
these data can be obtained free of charge via www. ccdc.cam.ac.uk/
data_request/cif.
(Z)-1-(2-Bromovinyl)azepan-2-one, 31Z. Following general
procedure D, a solution of 1-(2,2-dibromovinyl)azepan-2-one 10b
(118 mg, 0.40 mmol) in anhydrous EtOAc (30 mL) was treated with
Pd(PPh3)4 (46 mg, 0.04 mmol) and Bu3SnH (0.13 mL, 0.48 mmol).
The crude yellow oil was purified by flash column chromatography
(silica gel, 80:20 hexane/ethyl acetate) to afford 65 mg (75%) of
1
bromo-enamide 31Z as a colorless oil: H NMR (400 MHz; CDCl3)
δH 7.29 (1H, d, J = 6.3 Hz), 5.73 (1H, d, J = 6.3 Hz), 3.80−3.76 (2H,
m), 2.63−2.61 (2H, m), 1.90−1.81 (2H, m), 1.79−1.71 (4H, m); 13C
NMR (100 MHz; CDCl3) δC 176.4, 132.6, 94.8, 49.4, 37.3, 29.9, 29.3,
23.4; IR (neat) νmax 2929, 2856, 1739, 1666, 1627, 1394, 1332, 1321,
1190 cm−1; HRMS (CI+) found (M + H)+ 218.0181, C8H13NOBr
requires 218.0181.
ASSOCIATED CONTENT
* Supporting Information
■
S
(Z)-N-(2-Bromovinyl)butyramide, 40 and 2-Propyloxazole.
Following general procedure D, a solution of N-(2,2-dibromovinyl)-
butyramide 21 (63 mg, 0.23 mmol) in anhydrous EtOAc (3 mL) was
treated with Pd(PPh3)4 (27 mg, 0.02 mmol) and Bu3SnH (0.10 mL,
0.28 mmol). The crude yellow oil was purified by flash column
chromatography (silica gel, 80:20 hexane/ethyl acetate) to afford 28
mg (63%) of bromo-enamide 40 and 9.6 mg (37%) of 2-propyl-
oxazole as colorless oils.
Characterization data of the described compounds and
intermediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: rudi.marquez@glasgow.ac.uk.
§Author to whom crystallographic data questions should be
addressed.
(Z)-N-(2-Bromovinyl)butyramide, 40: 1H NMR (400 MHz;
CDCl3) δH 7.40 (1H, dd, J = 10.9, 5.9 Hz), 7.32 (1H, bs), 5.47 (1H, d,
J = 5.3 Hz), 2.30 (2H, t, J = 7.3 Hz), 1.71 (2H, sextet, J = 7.4 Hz), 0.99
(3H, t, J = 7.4 Hz); 13C NMR (100 MHz; CDCl3) δC 169.5, 127.5,
88.3, 38.4, 18.8, 13.8; HRMS (CI+) found (M + H)+ 192.0018,
Notes
The authors declare no competing financial interest.
2157
dx.doi.org/10.1021/jo202130e | J. Org. Chem. 2012, 77, 2149−2158

The Journal of Organic Chemistry
Article
∥Ian Sword Reader of Organic Chemistry.
(9) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(10) (a) Bruckner, D. Synlett 2000, 1402. (b) Bruckner, D.
̈
̈
Tetrahedron 2006, 62, 3809.
ACKNOWLEDGMENTS
■
(11) Chai, D. I.; Hoffmeister, L.; Lautens, M. Org. Lett. 2011, 13, 106.
(12) The atomic coordinates for 25 (CCDC deposition no.
CCDC833481) are available upon request from the Cambridge
Crystallographic Centre, University Chemical Laboratory, Lensfield
Road, Cambridge CB2 1EW, United Kingdom. The crystallographic
numbering system differs from that used in the text; therefore, any
request should be accompanied by the full literature citation of this
paper.
(13) (a) Ferreira, P. M. T.; Monteiro, L. S.; Pereira, G. Amino acids
2010, 39, 499. (b) Ferreira, P. M. T.; Monteiro, L. S.; Pereira, G. Eur. J.
Org. Chem. 2008, 4676.
(14) Lakhrissi, Y.; Taillefumier, C.; Chretien, F.; Chapleur, Y.
Tetrahedron Lett. 2001, 42, 7265.
(15) The atomic coordinates for 33 (CCDC deposition no.
CCDC833478) are available upon request from the Cambridge
Crystallographic Centre, University Chemical Laboratory, Lensfield
Road, Cambridge CB2 1EW, United Kingdom. The crystallographic
numbering system differs from that used in the text; therefore, any
request should be accompanied by the full literature citation of this
paper.
(16) The atomic coordinates for 34 (CCDC deposition no.
CCDC833480) are available upon request from the Cambridge
Crystallographic Centre, University Chemical Laboratory, Lensfield
Road, Cambridge CB2 1EW, United Kingdom. The crystallographic
numbering system differs from that used in the text; therefore, any
request should be accompanied by the full literature citation of this
paper.
We thank Dr. Ian Sword for postgraduate support (A.E.P.). We
also thank Dr. Ian Sword and the EPSRC for funding. We
acknowledge Dr. David Norman for useful discussions.
DEDICATION
■
Dedicated to Professor Michael E. Jung on the occasion of his
65th birthday.
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