Synthetic studies towards N-substituted 3-vinyl-4-piperidineacetic acid derivatives

Article abstract of DOI:10.24820/ark.5550190.p010.905

The synthesis and full characterization of two new (E)-2-butenyl)-5-amino-2-pentenoates, (Z)-4-[N-(3-buten-1-yl)benzamido]-2-buten-1-ol, and (Z)-1-chloro-4-[N-(3-buten-l-yl)benzamido]-2-butene are reported. These were designed as substrates for a projected thermal ene cyclization leading to the N-substituted 3-vinyl-4-piperidineacetic acid scaffold. Although conditions for this ene-cyclization have not yet been uncovered, the ease of preparation of these ene-cyclization substrates gives promise for their future use.

Full text of DOI:10.24820/ark.5550190.p010.905

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Synthetic studies towards N-substituted 3-vinyl-4-piperidineacetic acid
derivatives
David A. Johnson and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
ggribble@dartmouth.edu
Received 02-08-2019
Accepted 03-08-2019
Published on line 03-29-2019
Abstract
The synthesis and full characterization of two new (E)-2-butenyl)-5-amino-2-pentenoates, (Z)-4-[N-(3-buten-
1-yl)benzamido]-2-buten-1-ol, and (Z)-1-chloro-4-[N-(3-buten-l-yl)benzamido]-2-butene are reported. These
were designed as substrates for a projected thermal ene cyclization leading to the N-substituted 3-vinyl-4-
piperidineacetic acid scaffold. Although conditions for this ene-cyclization have not yet been uncovered, the
ease of preparation of these ene-cyclization substrates gives promise for their future use.
BOC
H
H
N
N
N
O
CO2Bn
CO2Bn
Keywords: 2-Piperidone, 3-vinyl-4-piperidineacetic acid, 1,7-dienes, ene-cyclization
DOI: https://doi.org/10.24820/ark.5550190.p010.905
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Introduction
The intramolecular thermal ene reaction of 1,6-dienes in which the “enophile” is attached to an olefinic
terminus (“ene”) has been used extensively in the preparation of vinylcyclopentane derivatives, including
natural products, in a regio- and stereoselective manner.1-3 Although the formation of six-membered ring
compounds by the analogous cyclization of 1,7-dienes (1 to 2) is less stereoselective and proceeds in lower
yield,1-3 good yields of cyclic products have been obtained from 1,7-dienes containing carbonyl-activated
enophile or ene components.4-7
X
Y
X
Y
heat
R1
R1
X = CH2, CHMe2, NAc, NMe
Y = H2, O
R2
R1 = Me, H
R2
R2 = H, CO2Me
2
1
Figure 1. Formation of six-membered rings from 1,7-dienes.
Given the aforementioned precedent, we imagined that the thermal intramolecular ene cyclization of the
carbonyl-activated indole diene 3 would be a viable synthetic route to highly substituted 2-(2-piperidinyl)-
indoles 4. These latter intermediates are of interest in a Friedel–Crafts-type cyclization approach to the
Corynanthe and sarpagine alkaloid ring systems. Thus, in the cyclization step we envisioned formation of the
piperidine C-4, C-5 bond with concomitant generation of the C-5 vinyl substituent. Assuming kinetic
stereoselection, we presumed that the bulky N-protected 2-indolyl substituent would occupy a pseudo-
equatorial position in the developing chair transition states thus providing the desired cis-diaxial disposition of
C-2–H and C-4–H present in these alkaloids. Moreover, even though four diastereomeric piperidines are
theoretically possible, only the two alternative chair-chair transition states giving rise to cis and trans esters 4a
and 4b, might be expected to predominate. Also, a pseudoequatorial orientation of the E-enophile might favor
formation of product 4b.
Figure 2. Ene cyclization of diene 3 forming 2-(2-indolyl)piperidines 4a,b.
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Results and Discussion
Since the ene cyclization of activated 1,6- and 1,7-dienes that lack a methyl substituent at the terminus of the
ene unit (e.g., 3) can be capricious,8-10 we examined the cyclization of a model 1,7-dienyl system first. Model
diene 5 was particularly intriguing since deprotection of the product(s) would give meroquinene (6a, cis-3-
ethenyl-4-piperidineacetic acid), a key intermediate in several total syntheses11,12 of Cinchona alkaloids,
and/or the unnatural trans-diastereomer 6b, which was used to forge the D and E rings of the heteroyohimbe
alkaloid ajmalicine.13
Figure 3. Proposed ene cyclization of diene 5 forming meroquinene (6a) and/or 3-epi-meroquinene (6b).
The synthesis of diene 5 was accomplished in five steps from 2-piperidone (7) (Scheme 1). Aqueous
barium hydroxide hydrolysis14 of 7 and liberation of the amino acid from its barium salt with carbon dioxide
afforded 5-aminopentanoic acid (8) in 95% yield. Treatment of 8 in a 1,4-dioxane-water (1:1) mixture
containing 2.5 equivalents of triethylamine with BOC-ON ([2-(tert-butoxycarbonyloxyimino)-2-
phenylacetonitrile]15 provided the crystalline t-BOC amino acid 9 in 75% yield. Esterification of acid 9 with
benzyl bromide and triethylamine in refluxing chloroform16 provided the benzyl ester 10 in 62% yield.
Alkylation of 10 with trans-crotyl chloride17 and sodium hydride in HMPA (0 °C
r.t., 8 h) furnished the
to
monoolefin 11 but in only 25% yield. Since benzyl alcohol was also isolated from the reaction mixture (23%
yield), the low yield of 11 can be attributed to the initially generated anion undergoing an intramolecular
condensation to give the UV transparent imide 12 (not isolated). Deprotonation of ester 11 in THF at –78 °C
with one equivalent of LDA followed by reaction of the enolate with phenylselenenyl chloride provided the
selenide intermediate which was converted into the α,β-unsaturated ester 5 (40% yield) via selenoxide
formation/elimination with sodium periodate in methanol/water at room temperature.18 The trans (E)-
1
stereochemistry of the newly formed double bond was readily apparent from inspection of the 300 MHz H
NMR spectrum of 5 in CDCl3. The C-3 proton appears as a doublet of triplets centered at δ 6.96 which overlap
to form a 1:2:2:2:1 pentet; the C-3 proton in 5 is trans-coupled to the C-2 proton (J 16 Hz) and is also split by
the “geminal” C-4 methylene protons (J 7 Hz). The other vinyl proton of this ABX spin system, the C-2 proton,
appeared as a sharp doublet (J 16 Hz) centered at δ 5.88. These coupling constants and chemical shifts are
characteristic of an α,β-unsaturated ester with trans-geometry;19 the calculated chemical shifts for the C-2 and
C-3 protons are δ 5.86 (δ 5.88 observed) and δ 5.87 (δ 6.96 observed), respectively.19,20
We examined both the thermal ene reaction3 as well as Lewis acid-induced cyclization4-7,10 of the diene
ester 5. However, no reaction was observed in refluxing toluene (110 °C), and heating a 2% solution of 5 in o-
xylene (145 °C) led to its slow decomposition as evidenced by the formation of benzyl alcohol by TLC. When
neat 5 was heated under argon at 205 °C for several hours, complete decomposition was observed. Following
Oppolzer's work10 on the Lewis acid-promoted ene cyclization of 1,6-diene esters, we treated 5 with two
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equivalents of diethylaluminum chloride in dry dichloromethane at –78 °C. Unfortunately, the anticipated ene-
cyclization of 5 did not occur. When three quivalents of Et2AlCl were employed (–78 °C, 3 h), cleavage of the
benzyl ester group resulted.
H
N
H
O
NH2
N
Ba(OH)2
95%
BOC-ON
75%
BnBr
Et3N
62%
BOC
CO2H
CO2H
7
8
9
BOC
N
BOC
H
N
N
1. LDA
1. NaH, HMPA
BOC
2. PhSeCl
3. NaIO4
2.
CO2Bn
Cl
25%
CO2Bn
CO2Bn
11
10
40%
5
H3C
H3C
H3C
BOC
O
CN
N
O
O
BOC-ON
=
N
O
Bn = CH2Ph; Bz = COPh, throughout
12
Scheme 1. Preparation of the diene 5.
We turned our attention to the synthesis of diene 13 by a route similar to that used in the preparation of
5, reasoning that the methyl ester and N-benzoyl protective groups would be more stable to the projected
cyclization conditions and, in the event of the successful ene cyclization, would provide known diastereomeric
piperidines 14a and 14b21 (Scheme 2). To circumvent the apparent intramolecular condensation reaction
observed in the alkylation of 10, we examined the alkylation of the dianion of acid amide 15. N-Benzoyl 5-
aminopentanoic acid (15) was commercially available and also could be conveniently prepared from 8 with
benzoyl chloride in 1N aqueous sodium hydroxide at 0 °C (41%). Satisfyingly, treatment of a mixture of amino
acid 15 and trans-crotyl chloride in dry DMF at –5 °C with excess sodium hydride furnished the desired amide
16 in 65% yield (~100% based on recovered starting material). Diazomethane methylation of 16 in ether at
0 °C gave the methyl ester 17 in 94% analytically pure yield. Unlike the colorless solution that was obtained by
deprotonation of 11 with LDA, similar treatment of ester 17 with LDA at low temperature produced a dark
purple solution which decolorized on quenching with phenyl-selenenyl chloride. Sodium periodate treatment
of the crude reaction mixture led to a mixture of several very polar products, which were not identified. The
known susceptibility of tertiary benzamides to nucleophilic attack22 suggests that intramolecular condensation
of the generated anion on the amide moiety had taken place. We anticipated that this difficulty could be
circumvented by N-alkylation of the trans-α,β-unsaturated ester 18. We would not have expected
intramolecular attack on the ester carbonyl as this requires placing a trans-double bond in a six-membered
ring transition state.
Although 18 has been prepared in several steps by two different routes from phthalimide,23 we envisioned
that it would be possible to introduce the double bond in one step from the dianion of ester 19 via successive
selenation of the enolate, oxidation and selenoxide elimination. As anticipated, treatment of ester 19, which
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was readily prepared from 15 with diazomethane in ether-methanol (99% yield), with two equivalents of LDA
at –78 °C in THF followed by the oxidative selenation protocol provided the desired enoate 18 in 74% yield.
Because ester 18 was not easily separable from starting material 19 by chromatographic means, we found it
convenient to isolate the intermediate α-phenylselenenyl derivative prior to oxidation and selenoxide
1
elimination. In the 300 MHz H NMR spectrum of 18 in CDCl3, the C-1 vinyl protons appear as a doublet of
narrow multiplets centered at δ 5.89, trans-coupled to the C-3 proton (J 16.5 Hz), and the C-2 vinyl proton
appeared as a doublet of triplets centered at δ 6.93 split by C-3H and by the geminal methylene protons (Jgem
6.7 Hz). Unfortunately, alkylation of 18 with sodium hydride and crotyl chloride HMPA at 0 °C, irrespective of
the order of addition of reactants or concentration, consistently gave one major product (25% isolated yield in
one case) which was assigned the structure 20 on the basis of elemental analysis and spectroscopic data. The
1
300 MHz H NMR spectrum of 20 in CDCl3 exhibited very complex aromatic and aliphatic regions. A triplet
centered at δ 6.85 was assigned to the single vinyl proton coupled to the geminal methylene protons (Jgem 6.9
Hz). The E-configuration depicted (vinyl proton cis to the ester group) follows from a comparison with the vinyl
chemical shifts of E- and Z-methyl 2-methyl-2-butenoates19 which resonate at δ 6.73 and δ 5.98, respectively
(vide supra), and the C-3 vinyl proton of E-enoates 18 (δ 6.93) and 5 (δ 6.96). Broad exchangeable triplets
centered at δ 7.55 and δ 7.13 were ascribed to the two amide protons in 20. Other salient features included
two methyl esters signals at δ 3.61 and δ 3.57 and two “haystack” multiples, each integrating for one proton,
centered at δ 2.10 and δ 1.85. These latter signals, the only ones present above δ 2.5, were attributed to the
methylene protons attached to the chiral center at C-3 of the heptenoate backbone. The 13C NMR of 20
exhibited a total of 22 carbon signals: 4 in the range δ 174–166 (amide and ester carbonyl carbons), 10
aromatic/olefinic and 8 aliphatic signals. The MS and IR spectra are also consistent with structure 20.
Scheme 2. Projected synthesis of diene 13, and formation of dimer 20.
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The dimeric by-product 20 may arise via intramolecular Michael attack of the generated amide anion from
18 on the enoate, followed by conjugate addition of the formed enolate on a second molecule of starting
material to give intermediate dihydro-1,3-oxazine 21. Base-catalyzed fragmentation of the oxazine ring or
elimination on acidic work-up would give 20. Danheiser24 reported the formation of dihydro-1,3-oxazine by-
products 22 from the titanium tetrachloride-catalyzed [2+3] cyclization of alicyclic N-acylimmonium ions and
allenylsilanes, presumably via a related process involving amide capture of a vinyl cation intermediate.
Scheme 3. Suggested route to dimer 20 from 18.
We examined the “hydrogen bond-assisted” N-alkylation25 of 18 with crotyl chloride using potassium
fluoride on alumina. Ando26 has reported that secondary amides and lactams can be smoothly N-alkylated
with benzyl chloride in acetonitrile in the presence of KF-alumina. However, in the case of 18 no reaction was
observed. Similarly, attempts to N-alkylate 18 under SN1 conditions27 with silver trifluoroacetate at 100 °C
produced no reaction. Therefore, we pursued a different synthetic route to the dienoate 13 (Scheme 4). Our
plan was to construct the dienoate double bond in the last step from aldehyde 23 via a Horner–Wadsworth–
Emmons reaction.28 Accordingly, the commercially available bromide 24 was converted into the azide 25 with
sodium azide under phase transfer conditions (PTC) and the crude azide was subjected to Staudinger
conditions29 to provide the amino acetal 26 in 65% overall yield from 24. Acylation of 26 with benzoyl chloride
and triethylamine in methylene chloride at 0 °C delivered the benzamide 27 (87% yield), which was alkylated
with crotyl chloride and sodium hydride in DMF to provide amide acetal 28 in high yield. Acidic hydrolysis30 of
28 in AcOH-THF-H2O (2:2:1) at reflux provided the desired aldehyde 23 but in only 28% yield; also isolated
were starting material 28 (14%) and elimination by-product 29 (25%). Treatment of 23 with the sodium salt of
methyl diethylphosphonoacetate, generated with sodium hydride in dimethoxyethane (DME) at 0 °C,31
1
provided the desired dienoate 13 in 78% yield. Inspection of the 300 MHz H NMR of 13 (in CDCl3) revealed,
inter alia, the expected low field multiplet centered at δ 6.97 for the C-3 vinyl proton and a doublet centered
1
at δ 5.91 for the trans-coupled C-1 vinyl protons (J 15.6 Hz), thus corresponding nicely to the H NMR
spectrum of diene 5.
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H
Br
N3
NH2
O
N
Bz
NaN3
Ph3P
65%
BzCl
87%
1. NaH, DMF
2.
O
O
O
O
O
O
O
PTC
Cl
~100%
24
26
25
27
92%
Bz
N
Bz
N
Bz
N
Bz
H3O+
28%
Horner
78%
HN
H
O
O
O
CO2Me
28
29
23
13
Scheme 4. Synthesis of diene 13.
Thus far, our attempts to effect the ene cyclization of 13 to 14 under thermal and Lewis acid conditions
analogous to those employed for 5 have been unsuccessful. Thermolysis of 13 under argon at 300 °C leads to
extensive decomposition. Lower temperatures (220 °C, 250 °C) and longer reaction times produced very little
reaction although the formation of several very minor products was observed by TLC. Similarly, attempts to
cyclize 13 in methylene chloride, even at reflux, with excess diethylaluminum chloride, resulted in no reaction.
Interestingly, treatment of 13 with excess Et2AlCl in the absence of solvent at room temperature gave an
1
unidentified substance, which does not appear by H NMR and IR spectroscopy to be the desired ene product
or the product of an intramolecular hetero-Diels–Alder reaction.32 While our cyclization studies have been
limited by the available supply of 13, it is clear that the monoactivated 1,7-diene 13 is less reactive than
anticipated.
In comparison to the intramolecular thermal ene reaction, intramolecular ene reactions involving the
transfer of metal atoms have been effected under extraordinarily mild conditions (0°–80 °C, Et2O) and in very
good yield.33-37 The formal ene addition of allylic Grignard reagents and allylic organolithium compounds to
olefins and subsequent trapping of the cyclized organometallic intermediate with various electrophiles has led
to the preparation of 1,3-disubstituted cyclopentane and cyclohexane derivatives in a regio- and stereo-
selective manner (vide infra).38,39 We envisioned that the metallo-ene synthesis of the N-benzoyl derivative of
meroquinene (6a) and its trans isomer 6b could serve as a model study for the synthesis of the pivotal 2-(2-
piperidinyl)indole intermediates that we required in our Corynanthe/sarpagine studies. We thought that the
relative cis configuration about the C-3, C-4 bond of meroquinene (6a) might be achieved in a regioselective
thermal cyclization of the Z-allylic Grignard (ene unit) 30 as shown retrosynthetically in Figure 4. Model
considerations show that a chair-boat transition state results in the steric congestion of allylic and olefinic
protons thus favoring formation of the cis-substituted piperidine 31 via the relatively unstrained chair-chair
transition state B.
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R
N
R
N
H
N
MgX
CO2H
6a
MgX
31
30
Figure 4. Possible route to meroquinene 6a by intramolecular organometallic transfer reaction.
A suitable precursor to the Z-allylic Grignard 30 appeared to be the tetrahydropyranyl (THP) ether 32,
which was derivable from 4-benzamido-1-butene (33) and allylic chloride 35 (Scheme 5). Despite Brown’s
report40 on the smooth reduction of allyl cyanide to 3-butenylamine (36) with aluminum hydride, we obtained
very low yields (8–12%) of 36 by this procedure. Amine 36 could, however, be conveniently prepared from 3-
butenyl alcohol in two steps. Thus, 3-butenyl alcohol (34) was converted into the N-alkylphthalimide 37 in 85%
yield via a Mitsunobu reaction with triphenylphosphine and diethyl azodicarboxylate (DEAD). Imide 37 was
subsequently treated with hydrazine hydrate in ethanol to give 36 in 54% distilled yield. 3-Butenylamine (36)
was then converted to 4-benzamido-1-butene (33)41 in 84% yield with benzoyl chloride in 10% aqueous
sodium hydroxide. The synthesis of the requisite THP-protected chloride 35 was accomplished in two steps
from 2-butene-1,4-diol. Following the report of Thuy and Maitte,42 38 was prepared in 49% yield by refluxing a
benzene solution of 2-butene-1,4-diol and dihydropyran (DHP) in the presence of active montmorillonite. The
alcohol 38 was readily transformed into allylic chloride (35) using methanesulfonyl chloride and a mixture of
lithium chloride and S-collidine in DMF at 0 °C.43,44 Reaction of amide 33 with 1.5 equivalents of sodium
hydride in dry THF and alkylation of the resulting sodium salt with allylic chloride 35 at 55 °C for several hours
furnished a mixture of amide product 32 and starting material 33 which appeared as one spot by TLC.
Separation was achieved by THP-ether deprotection in AcOH-THF-H2O (4:2:1) at 45–50 °C for four hours.45
Flash chromatography of the resulting mixture afforded the desired dienol 39 in 47% yield (from 33).
O
H
N
NH
OH
NH NH
BzCl
NaOH
84%
2
2
2
Mitsunobu
85%
Bz
N
54%
O
33
36
34
37
Bz
N
OTHP
OTHP
OH
OH
MsCl
LiCl
O
1. NaH, THF
2. 35
cat
OR
Cl
OH
49%
80%
32, R = THP
39, R = H (47%)
35
38
Scheme 5. Synthesis of the dienol 39.
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Compound 39 was transformed into the allylic chloride 40 using methanesulfonyl chloride and a mixture
of lithium chloride and S-collidine in DMF at 0 °C (Scheme 6). The unstable allylic chloride 40 was purified by
rapid filtration through silica gel to give analytically pure 40 in 73% yield. Conversion of 40 into the
corresponding Grignard reagent 41 with magnesium turnings was accomplished by entrainment with 1,2-
dibromoethane in THF at 60 °C. However, quenching the reaction at 0 °C with carbon dioxide led to the
isolation of decomposition product 33 and not to the desired piperidine 42. Presumably, the benzamide 33
arises from vinylogous β-elimination of Grignard 41 and concomitant formation of butadiene. In future work
this latter complication may be circumvented by replacing the Grignard species 41 with a bis-metallo species
such as 43.
Bz
N
Bz
N
Bz
N
CO
2
X
MgCl
90%
CO H
2
39, X = OH
40, X = Cl
41
42
heat
MgX
H
N
N
Bz
MgX
43
33
Scheme 6. Formation of the dienyl Grignard 41 and its fragmentation.
Conclusions
We have described the syntheses of several new dienes (i.e., 5, 13, 39 and 40) preparatory for an ene
cyclization leading to the N-substituted 3-vinyl-4-piperidineacetic acid scaffold, which is embedded in
numerous alkaloids. Although conditions for the ene-cyclization have yet to be found, the relative ease of
preparation of these cyclization diene substrates presages the opportunity for their future use.
Experimental Section
General. Melting points were determined in open capillaries (except for compound 25 which was determined
in an evacuated capillary tube) with either a Mel-Temp Laboratory Devices apparatus or a Buchi 510 apparatus
and are uncorrected. Elemental analyses were performed by Atlantic Microlabs, Atlanta, GA, or Micanal,
Tucson, AZ. Infrared spectra were recorded on a Perkin-Elmer 599 instrument. 1H NMR (60 MHz) spectra were
1
obtained on a Perkin-Elmer R-24 or EM-360A spectrometer. 13C NMR and 300 MHz H NMR spectra were
recorded on a Varian XL-300 multinuclear Fourier transform NMR. Mass spectra were obtained at the NSF
regional instrumentation facility at Johns Hopkins University School of Medicine and on a Finnigan 4023
GC/MS system. UV spectra were recorded on a Unicam SP-800A spectrophotometer. Analytical and
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preparative TLC employed silica gel (Merck silica gel 60 F-254). TLC spots were visualized with 254 nm UV light
and/or with an appropriate reagent: ketones, 2,4-dinitrophenylhydrazine (0.4% in 2 N HCl); acids, bromocresol
green (0.3% in 80% methanol, 0.5% 30% NaOH); N-H indoles, ceric ammonium sulfate (3% in 10% H2SO4);
aliphatic compounds, phosphomolybdic acid (5% in ethanol). Tetrahydrofuran (THF) was distilled from
Na/benzophenone; other solvents were rigorously dried according to published procedures. Alkyllithium
reagents were standardized by titration against 2,5-dimethoxybenzyl alcohol or diphenylacetic acid. All
reagents were purchased from Aldrich Chemical Company unless otherwise indicated.
5-Aminopentanoic acid (8). A mixture of 2-piperidone (7) (5.0 g, 0.050 mol; Fluka) and barium hydroxide
octahydrate (17.5 g, 0.055 mol) in H2O (75 mL) was heated to reflux for 48 h. The cooled reaction mixture was
treated with gaseous carbon dioxide until neutral to litmus. The precipitated barium carbonate was collected
and triturated with hot H2O (2 × 50 mL). The filtrate and triturates were combined and concentrated in vacuo
to give 5.6 g (95%) of 8 as a colorless solid which was dried at 60 °C (0.5 mmHg): mp 152–154 °C. This material
is also commercially available from Aldrich: mp 158–161 °C.
N-(t-Butoxycarbonyl)-5-aminopentanoic acid (9). To a solution of 5-aminopentanoic acid (8, 2.17 g, 0.0185
mol) and triethylamine (4.7 g, 0.046 mol) in 1:1 dioxane-H2O (50 mL) at 25 °C was added 2-(t-butoxycarbonyl-
oxyimino)-2-phenylacetonitrile (BOC-ON; 5.0 g, 0.020 mol) over 5 min. The resulting reaction mixture was
stirred at room temperature for 12 h, diluted with ethyl acetate (75 mL) and H2O (75 mL) and the layers were
separated. The aqueous phase was washed with ethyl acetate (15 mL), acidified to pH 2.85 with solid citric
acid, and extracted with ethyl acetate (2 × 75 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo to give 3.0 g (75%) of 9 as a light yellow oil which crystallized on standing: mp 43–46 °C
(lit.46 mp 45–52 °C); 13C NMR (CDCl3) δ 178.5, 156.2, 78.7, 40.0, 33.5, 29.2, 28.3, 21.7.
Benzyl N-(t-butoxycarbonyl)-5-aminopentanoate (10). A solution of acid 9 (2.80 g, 0.0129 mol) in dry CHCl3
(20 mL) at 0 °C was treated with triethylamine (1.30 g, 0.0129 mol), followed by benzyl bromide (2.27 g,
0.0129 mol), warmed to room temperature overnight and then treated with additional benzyl bromide (0.45
g, 2.6 mmol) along with triethylamine (0.26 g, 2.6 mmol). The resulting reaction mixture was heated at 35 °C
for 8 h, diluted with CHCl3 (50 mL) and washed twice with 20 mL portions of H2O, 5% aqueous NaHCO3, and
brine, dried (MgSO4) and concentrated in vacuo to give 2.46 g (62%) of 10 as a light yellow oil which was pure
by TLC: IR (neat) νmax 3370 (m), 2980 (m), 2940 (m), 2870 (m), 1740 (s), 1720 (s), 1520 (m), 1460 (m), 1400 (m),
1
1375 (m), 1260 (m), 1170 (s), 1015 (w), 875 (w), 755 (m), 745 (m), 705 (m) cm-1; H NMR (CDCl3) δ 9.0 (br s,
1H), 7.33 (s, 5H), 5.12 (s, 2H), 3.11 (m, 2H), 2.38 (m, 2H), 1.78–1.12 (m, 4H), 1.43 (s, 9H); 13C NMR (CDCl3) δ
172.9, 155.8, 128.2, 128.0, 127.8, 65.9, 53.3, 39.8, 33.6, 29.2, 28.2, 21.8; MS m/e (relative intensity) 251 (M+-
(Me)2C=CH2, 1), 236 (1), 206 (1), 146 (6), 116 (10), 115 (2), 100 (2), 92 (9), 91 (100), 89 (13), 77 (9), 78 (2), 76
(2), 65 (9), 57 (10), 51 (10), 50 (4).
Benzyl N-(t-butoxycarbonyl)-N-((E)-2-butenyl)-5-aminopentanoate (11). Dry sodium hydride (0.16 g, 0.0067
mol) was added to a solution of ester 10 (1.47 g, 0.00478 mol) and freshly distilled trans-crotyl chloride (0.56
g, 0.0062 mol) in HMPA (20 mL) at 0 °C, and the resulting gray suspension was stirred at 0 °C for 2 h and then
allowed to warm slowly to 20 °C over 8 h. The reaction mixture was poured into ice cold brine (100 mL) and
extracted with ether (3 x 75 mL). The combined ethereal layers were washed with brine (5 x 100 mL), dried
(MgSO4) and concentrated in vacuo to give an oil. Column chromatography over silica gel with 6:1 (v/v)
hexanes-Et2O afforded 0.43 g (25%) of 11 as a colorless oil. IR (neat) νmax 2980 (m), 2940 (m), 1745 (s), 1700
(s), 1450 (m), 1420 (m), 1370 (m), 1245 (m), 1170 (s), 1095 (m), 975 (m), 880 (w), 740 (m) cm-1; 1H NMR (CDCl3)
δ 7.3 (s, 3H), 5.65–4.85 (m, 2H), 5.08 (s, 2H), 3.70 (m, 2H), 3.15 (t, J 6.5 Hz, 2H), 2.38 (m, 2H), 1.8–1.5 (m, 7H),
1.43 (s, 9H); 13C NMR (CDCl3) δ 173.1, 155.3, 135.9, 128.4, 128.3, 128.2, 128.1, 126.9, 79.1, 66.0, 48.8, 45.5,
33.8, 28.3, 22.1, 17.5; MS m/e (relative intensity) 305 (M+ – Me2C=CH2, 2), 261 (18), 260 (13), 246 (6), 206 (7),
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170 (45), 91 (84), 84 (100), 70 (63), 57 (62), 55 (65), 41 (51). Anal. Calcd for C21H31NO4: C, 69.77; H, 8.65; N,
3.88. Found: C, 69.95; H, 8.65; N, 3.86%.
Benzyl (E)-N-(t-butoxycarbonyl)-N-((E)-2-butenyl)-5-amino-2-pentenoate (5). To a solution of diisopropyl-
amine (0.11 g, 0.79 mmol) in THF (10 mL) under nitrogen at –78 °C was added dropwise over 10 min n-
butyllithium (1.05 M in hexane, 0.72 mL, 0.76 mmol). After 20 min, the LDA was treated dropwise over 15 min
with a solution of 11 (0.24 g, 0.66 mol) in THF (3 mL). The slightly turbid solution was stirred at –78 °C for 45
min and then treated dropwise with a solution of phenylselenenyl chloride (0.15 g, 0.76 mmol) in THF (2 mL)
over 5 min. The resulting light yellow solution was allowed to warm to –15 °C over 5 h and then a solution of
sodium periodate (0.43 g, 0.20 mmol) in 1:1 methanol-H2O (10 mL) was added and the reaction was allowed
to warm to room temperature overnight. The reaction mixture was partitioned between ether (50 mL) and
cold saturated aqueous NaHCO3 and the layers separated. The aqueous phase was extracted with Et2O (25 mL)
and the combined ethereal layers were washed with brine (2 x 15 mL), dried (MgSO4) and concentrated in
vacuo to give a light yellow oil. Column chromatography over silica gel (20 g) with 6.5:1 (v/v) ether-hexane
afforded 0.095 g (40%) of 5 as a colorless oil; IR (neat) νmax 2980 (m), 2930 (m), 1730 (s), 1700 (s), 1460 (m),
1420 (m), 1370 (m), 1270 (m), 1250 (m), 1170 (s), 1130 (m), 1095 (m), 1025 (w), 975 (w), 700 (m) cm-1; 300
1
MHz H NMR (CDCl3) δ 7.36 (s, 5H), 6.96 (dt, J 16 Hz, J 7 Hz, 1H), 5.88 (d, J 16 Hz, 1H), 5.65–5.20 (m, 2H), 5.16
(s, 2H), 3.74 (m, 2H), 3.28 (m, 2H), 2.40 (m, 2H), 1.68 (d, J 7 Hz, 3H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 166.0,
155.2, 146.6, 136.0, 128.5, 128.4, 128.4, 128.1, 126.8, 122.5, 79.6, 66.1, 49.0, 44.8, 28.4, 28.3, 17.6; MS m/e
(relative intensity) 303 (M+ – Me2C=CH2, 1), 261 (1), 260 (1), 218 (4), 184 (13), 128 (30), 91 (80), 84 (99), 57
(100). Anal. Calcd for C21H29NO4: C, 70.17; H, 8.13; N, 3.90. Found: C, 70.22; H, 8.16; N, 3.91%.
N-Benzoyl-5-aminopentanoic acid (15). Amide 15 was prepared in 41% yield from 8 and benzoyl chloride
according to the procedure of Hurd47: mp 91.5–94 °C (lit.47 mp 93–94 °C). This material is also commercially
available from Sigma.
N-Benzyl-N-((E)-2-butenyl)-5-aminopentanoic acid (16). To a solution of 15 (2.45 g, 0.0111 mol) and trans-
crotyl chloride (1.20 g, 0.0133 mol) in dry DMF (20 mL) at –5 °C was added sodium hydride powder (0.67 g,
0.028 mol) over 10 min. The resulting suspension was stirred at –5 °C for 40 min and then allowed to warm to
room temperature overnight. The reaction mixture was heated to ~40 °C for 5 h, treated with additional crotyl
chloride (0.20 g, 2.2 mmol) and heated at 40 °C for an additional 2.6 h. The reaction mixture was cooled to 0
°C, quenched carefully with H2O (10 mL) and then poured into 5% aqueous HCl (100 mL) and extracted with
ether (2 x 100 mL). The combined ethereal layers were washed with brine (2 x 50 mL), dried (Na2SO4) and
concentrated in vacuo to give 2.6 g of crude 16 as a viscous light yellow oil. Attempts to crystallize 16 from
ether-pentane instead provided 2.0 g (65%) of 16 as a colorless oil which was pure by TLC. Flash
chromatography with hexane-EtOAc-AcOH (3:1:0.1) afforded the analytical sample: IR (neat) νmax 3680–2380
(m), 2950 (s), 2870 (m), 1740 (s), 1605 (s), 1580 (s), 1510 (m), 1470 (s), 1440 (s), 1385 (m), 1220 (m), 1255 (m),
1185 (m), 1080 (m), 1035 (m), 975 (s), 795 (m) cm-1; 1H NMR (CDCl3) δ 10.91 (br s, 1H), 7.45 (s, 5H), 5.8–5.2 (m,
2H), 3.91 (m, 2H), 3.48 (m, 2H), 2.38 (m, 2H), 1.9–1.4 (m, 7H); 13C NMR (CDCl3) δ 178.2, 171.9, 136.2, 129.3,
128.3, 128.2, 126.4, 125.7, 51.1, 43.9, 33.6, 26.4, 21.9, 17.6; MS: m/e (relative intensity) 275 (M+, 3), 246 (4),
202 (2), 188 (3), 174 (3), 170 (24), 134 (4), 124 (4), 106 (11), 105 (100), 77 (37), 55 (11), 51 (6), 41 (3), 39 (3).
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.62; H, 7.73; N, 5.03%.
Methyl N-benzoyl-N-((E)-2-butenyl)-5-aminopentanoate (17). A –5 °C solution of diazomethane in ether (125
mL), generated from 1-methyl-3-nitro-1-nitrosoguanidine (2.2 g, 8.015 mol) and 5N NaOH (20 mL), was slowly
poured into a solution of 16 (1.34 g, 4.87 mmol) in ether at 0 °C until a yellow color persisted. Acetic acid (1
mL) was added and the resulting colorless solution was washed with 5% aqueous NaOH (2 x 50 mL), brine (2 x
100 mL), dried (MgSO4) and concentrated in vacuo to give 1.32 g (94%) of analytically pure 17 as a colorless oil:
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IR (neat) νmax 2950 (m), 2865 (m), 1740 (s), 1635 (s), 1425 (3), 1380 (m), 1360 (m), 1315 (m), 1300 (m), 1250
1
(m), 1200 (m), 1175 (m), 1150 (m), 1110–1070 (m), 930 (m), 970 (s), 790 (m), 705 (s) cm-1; H NMR (CDCl3) δ
7.46 (s, 5H), 5.8–5.2 (m, 2H), 3.90 (m, 2H), 3.70 (s, 3H), 3.45 (m, 2H), 2.33 (m, 2H), 1.9–1.3 (m, 7H); 13C NMR
(CDCl3) δ 173.6, 171.3, 136.6, 129.0, 128.9, 128.15, 128.1, 126.2, 125.9, 51.2, 50.8, 43.6, 33.4, 26.4, 22.0, 17.5;
MS: m/e (relative intensity) 2890 (M+, 2), 260 (2), 234 (1), 202 (1), 188 (2), 185 (3), 184 (23), 174 (2), 134 (2),
115 (2), 106 (8), 105 (100), 77 (25), 59 (2), 55 (9), 51 (4), 41 (2). Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N,
4.84. Found: C, 70.48; H, 8.06; N, 4.80%.
Methyl N-benzoyl-5-aminopentanoate (19). Application of the same diazomethane procedure that was used
to prepare 17 (from 16) to the preparation of ester 19 from 15 (1.00 g, 4.52 mmol) afforded 1.05 g (99%) of 19
as a colorless oil which crystallized on standing: mp 43–45.5 °C (lit.48 mp 40–41 °C); IR (neat) νmax 3300 (s),
1
2930 (s), 1740 (s), 1640 (s), 1585 (m), 1540 (s), 1495 (m), 1440 (m), 1310 (s), 1175 (s) cm-1; H NMR (CDCl3) δ
8.03–7.73 (m, 2H), 7.60–7.30 (m, 2H), 7.05 (br s, 1H), 3.68 (s, 3H), 3.48 (m, 2H), 2.36 (m, 2H), 1.83–1.47 (m,
4H); 13C NMR δ 173.7, 167.4, 134.4, 131.0, 128.2, 126.7, 51.4, 39.4, 33.4, 28.8, 22.0.
Methyl (E)-N-benzoyl-5-amino-2-pentanoate (18). To a solution of LDA prepared from diisopropylamine (2.17
g, 0.0214 mmol) and n-butyllithium (0.99 M in hexane; 21.6 mL, 0.0214 mol) in THF (100 mL) at –78 °C was
added dropwise over 15 min a solution of 19 (2.09 g, 8.91 mmol) in THF (25 mL). The solution was stirred at –
78 °C for 45 min and the resulting densely turbid mixture was treated dropwise over 15 min with a solution of
phenylselenenyl chloride (2.09 g, 0.0107 mol) in THF (20 mL). The resulting light yellow solution was stirred at
–78 °C for 30 min, quenched with methanol (1 mL), and allowed to warm to room temperature overnight. The
mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with ether (3 x 75 mL). The
combined ethereal extracts were dried (MgSO4) and concentrated in vacuo to give a mixture of selenide and
starting material by TLC. Flash chromatography with EtOAc-hexane (1:2) furnished 2.62 g (75%) of the selenide
as a colorless oil (MS m/e (relative intensity)) 391 (M+1, 1), 359 (6), 234 (6), 174 (5), 157 (6), 146 (5), 105 (100),
77 (46) followed by 0.31 g (15%) of recovered starting material 19. A solution of the selenide (2.20 g, 5.64
mmol) in THF (100 mL) at –5 °C was treated dropwise over 30 min with a solution of sodium periodate (3.62 g,
0.17 mol) in MeOH-H2O (1:1, 10 mL). The resulting mixture was allowed to warm to room temperature over 5
h and then was cooled to –5 °C and treated with pyridine (0.5 mL). After stirring 1 h at room temperature the
resulting suspension was partitioned between ether (200 mL) and H2O-brine (1:1, 200 mL) and the layers were
separated. The aqueous phase was extracted with ether (2 x 100 mL) and the combined organic layers were
washed with 2% aqueous HCl (2 x 10 mL), H2O (25 mL), brine (2 x 50 mL), dried (MgSO4) and concentrated in
vacuo to give 1.28 g (98%, 74% overall from 19) of 18 as light yellow flakes: mp 84–88 °C (lit.23 mp 86–87 °C);
IR (KBr) νmax 3270 (s), 1720 (s), 1655 (s), 1625 (s), 1530 (s), 1435 (m), 1325 (s), 1290 (s), 1270 (s), 1210 (s), 1170
1
(s), 975 (m), 870 (m), 800 (m), 710 (s), 690 (s) cm-1; 300 MHz H NMR (CDCl3) δ 7.80–7.72 (m, 2H), 7.51–7.33
(m, 3H), 6.98 (br s, 1H), 6.93 (δ of t, J 15.9 Hz, J 6.8 Hz, 1H), 5.89 (δ of t, J 15.9 Hz, J 1.5 Hz, 1H), 3.55 (m, 2H),
2.52 (m, 2H); 13C NMR (CDCl3) δ 167.7, 166.6, 145.6, 134.2, 131.3, 128.3, 126.8, 122.7, 51.4, 38.3, 32.1; MS:
m/e (relative intensity) 233 (M+, 1), 135 (2), 134 (23), 128 (2), 106 (8), 105 (100), 77 (28), 51 (3).
Attempted N-alkylation of 18: Self-condensation of 18 to give methyl (E)-N-benzoyl-3-benzamidoethyl-4-
carbomethoxy-5-amino-3-heptenoate (20). To a solution of 18 (0.307 g, 1.32 mmol) in HMPA (3 mL) at 0 °C
under argon was added dropwise over 5 min a suspension of dry sodium hydride (0.035 g, 1.4 mmol) in HMPA
(1 mL). The resulting reaction mixture was stirred at 0 °C for 15 min, and then treated dropwise with trans-
crotyl chloride (0.15 g, 1.7 mmol). After stirring at 0 °C for 2 h, the reaction mixture was poured into saturated
aqueous NH4Cl (75 mL) and extracted with ether (3 x 50 mL). The combined ethereal extracts were washed
with brine (2 x 25 mL), dried (Na2SO4) and concentrated in vacuo to give an oil. Flash chromatography with
EtOAc-hexane (3:2) afforded 0.155 g (25%) of 20 as a colorless oil. Crystallization from ether-pet ether
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furnished the analytical sample as extremely hygroscopic, fluffy crystals: mp 44–47 °C; IR (neat) νmax 3300 (s),
3055 (m), 2940 (s), 2920 (s), 1730 (s), 1700 (s), 1660–1620 (s), 1600 (s), 1575 (s), 1555 (s), 1540 (s), 1530 (s),
1520 (s), 1490 (s), 1430 (s), 1360 (s), 1420–1230 (s), 1200 (s), 1155 (s), 1120 (s), 1080 (s), 1020 (m), 800 (m) cm-
1; 300 MHz 1H NMR (CDCl3) δ 7.91–7.76 (m, 4H), 7.55 (br t, J 5.0 Hz, 1H), 7.49–7.29 (m, 6H), 7.13 (br t, J 5.5 Hz,
1H), 6.85 (t, J 6.9 Hz, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.47–3.22 (m, 4H), 2.85–2.53 (m, 5H), 2.19–2.02 (m, 1H),
1.93–1.77 (m, 1H); 13C NMR (CDCl3) δ 173.3, 167.9, 167.7, 166.7, 143.0, 134.2, 134.15, 133.3, 131.3, 131.2,
128.3, 128.2, 127.1, 126.9, 51.5, 51.3, 39.3, 38.0, 37.8, 32.6, 32.2, 28.2; MS: m/e (relative intensity) 466 (M+,
1), 393 (1), 333 (2), 313 (1), 301 (2), 252 (1), 240 (1), 210 (1), 197 (2), 180 (1), 165 (1), 150 (1), 149 (1), 136 (10),
122 (12), 106 (8), 105 (100), 103 (4), 77 (45), 51 (16). Anal. Calcd for C26H30N2O6·1/4 H2O: C, 66.29; H, 6.53; N,
5.95. Found: C, 66.25; H, 6.56; N, 5.87%.
2-(2-Aminomethyl)-1,3-dioxolane (26). Amine 26 was prepared in two steps in 65% overall yield from 2-(2-
bromoethyl)-1,3-dioxolane (24) according to a known method:49 bp 83–84 °C/25 mmHg (lit.50 bp 70–75 °C/18
mmHg).
2-(2-Benzamidoethyl)-1,3-dioxolane (27). To a solution of 26 (3.80 g, 0.0325 mol) and triethylamine (4.1 g,
0.041 mol) in dry CH2Cl2 (75 mL) at –10 °C was added dropwise over 45 min a solution of benzoyl chloride (5.5
g, 0.039 mol) in CH2Cl2 (20 mL). The resulting turbid solution was warmed to room temperature over 4 h and
poured into saturated aqueous NaHCO3 (100 mL). The layers were separated and the organic phase was
washed with 10% aqueous NaOH (3 x 50 mL), 2N aqueous HCl (2 x 50 mL), brine (2 x 100 mL), dried (K2CO3)
and concentrated in vacuo to give a viscous oil. Flash chromatography with ether-hexane (1:1 to 2:1, gradient
elution) furnished 6.23 g (87%) of analytically pure 27 as a colorless oil: IR (neat) νmax 3330 (s), 2960 (m), 2885
(s), 1645 (s), 1585 (m), 1545 (s), 1495 (m), 1315 (m), 1300 (m), 1140 (s), 1090 (m), 1030 (m), 945 (m), 715 (s),
1
700 (s) cm-1; H NMR (CDCl3) δ 8.1–7.0 (m, 6H), 5.06 (t, J 4.5 Hz, 1H), 3.97 (m, 4H), 3.66 (m, 2H), 2.03 (m, 2H);
13C NMR (CDCl3) δ 166.9, 134.2, 130.8, 128.0, 126.5, 103.2, 64.6, 35.0, 32.4; MS: m/e (relative intensity) 221
(M+, 1), 178 (13), 149 (12), 148 (12), 134 (5), 116 (17), 106 (8), 105 (97), 104 (6), 99 (6), 87 (16), 77 (43), 73
(100), 51 (8), 45 (28). Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.10; H, 6.83; N, 6.21%.
2-(N-Benzoyl-N-((E)-2-butenyl)-2-aminoethyl)-1,3-dioxolane (28). To a solution of 27 (2.64 g, 0.0119 mol) in
dry DMF (20 mL) at –5 °C was added sodium hydride powder (0.370 g, 0.0155 mol) over a 10 min period. The
resulting solution was 28 at –5 °C for 45 min, treated dropwise over 10 min with the trans-crotyl chloride (1.29
g, 0.0143 mol) and allowed to warm to room temperature over 12 h. The reaction mixture was diluted with
H2O (200 mL) and extracted with ether (3 x 75 mL). The combined ethereal extracts were washed with brine-
H2O (1:1, 4 x 100 mL), dried (K2CO3) and concentrated in vacuo to give 3.0 g (92%) of 28 as a light yellow oil
which was pure by TLC. Kugelrohr distillation provided the analytical sample as a colorless oil: bp 250 °C (bath
temp)/0.4 mmHg; IR (neat) νmax 2940 (m), 2880 (m), 1635 (s), 1465 (m), 1445 (m), 1425 (m), 1375 (m), 1260
(m), 1245 (m), 1130 (m), 1085 (m), 1020 (m), 965 (m), 940 (m), 895 (m), 790 (m), 700 (m) cm-1; 1H NMR (CDCl3)
δ 7.45 (s, 5H), 5.9–5.2 (m, 2H), 4.92 (m, 1H), 3.92 (m, 4H), 3.35 (m, 2H), 2.28–1.85 (m, 2H), 1.72 (d, J 5 Hz, 3H);
13C NMR (CDCl3) δ 171.2, 136.4, 129.0, 128.8, 128.0, 126.2, 102.6, 64.6, 51.1, 39.9, 31.5, 17.6; MS: m/e
(relative intensity) 275 (M+, 1), 232 (2), 202 (4), 188 (3), 174 (9), 170 (4), 106 (8), 105 (100), 99 (7), 87 (10), 82
(10), 77 (25), 73 (17), 55 (9), 45 (6). Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.62; H,
7.73; N, 5.03%.
N-Benzoyl-N-(3-oxo-1-propyl)-(E)-1-amino-2-butene (23) and N-benzoyl-(E)-1-amino-2-butene (29). A
solution of 28 (2.20 g, 7.99 mmol) in a 2:2:1 (v/v) mixture of AcOH-THF-H2O (30 mL) was heated at 70 °C for 12
h, then diluted with ether (200 mL) and washed with saturated aqueous NaHCO3 (3 x 50 mL). The ethereal
layer was dried (Na2SO4) and concentrated in vacuo to give an oil. Flash chromatography with EtOAc-hexane
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(1:4) afforded 0.35 g (25%) of by-product 29, followed by 0.30 g (14%) of starting material 28 and 0.52 g (28%)
of aldehyde 23 as a hygroscopic colorless oil which rapidly decomposed on standing.
Aldehyde 23: IR (neat) νmax 3410 (m), 2970 (m), 2920 (m), 2720 (w), 1730 (s), 1635 (s), 1470 (m), 1450 (m),
1430 (m), 1380 (m), 1070 (m), 975 (m), 795 (m), 710 (m) cm-1; 1H NMR (CDCl3) δ 9.95 (s, 1H), 7.48 (s, 5H), 5.8–
5.2 (m, 2H), 3.80 (t, J 7 Hz, 2H), 2.85 (t of d, J 6 Hz, J 2 Hz, 2H), 1.75 (d, J 7 Hz, 3H); MS m/e (relative intensity)
231 (M+, 1), 202 (3), 146 (3), 126 (12), 106 (8), 105 (100), 82 (4), 78 (3), 77 (42), 70 (5), 56 (4), 55 (8), 51 (5).
Amide 29: colorless oil; IR (neat) νmax 3300 (s), 3060 (m), 3020 (m), 2910 (m), 1640 (s), 1605 (m), 1540 (s), 1490
1
(m), 1450 (m), 1430 (m), 1310 (s), 970 (s), 805 (m), 715 (s) cm-1; H NMR (CDCl3) δ 8.0–7.7 (m, 2H), 7.65–7.30
(m, 2H), 6.7 (br s, 1H), 5.8–5.2 (m, 2H), 4.03 (t, J 6 Hz, 2H), 1.75 (d, J 4 Hz, 3H); 13C NMR (CDCl3) δ 167.1, 134.2,
131.0, 128.1, 127.9, 126.8, 126.6, 41.8, 17.6; MS: m/e (relative intensity) 175 (M+, 8), 146 (11), 106 (8), 105
(100), 104 (5), 78 (4), 77 (43), 70 (16), 55 (3), 51 (7).
Methyl (E)-N-benzoyl-N-((E)-2-butenyl)-5-amino-2-pentenoate (13). To a slurry of sodium hydride powder
(0.044 g, 1.8 mmol) in dry dimethoxyethane (DME) (4 mL) at 0 °C was added methyl diethyl phosphonoacetate
(0.350 g, 1.66 mmol). After stirring for 1 h at room temperature, the resulting solution was cooled to –5 °C,
treated dropwise with a solution of 23 (0.385 g, 1.66 mmol) in DME (4 mL), and allowed to warm slowly to
room temperature over 6 h. The reaction mixture was poured into H2O (50 mL) and extracted with ether (3 x
40 mL). The combined ethereal extracts were washed with brine (2 x 20 mL), dried (MgSO4) and concentrated
in vacuo to give a colorless oil. Column chromatography over silica gel with hexane-EtOAc (5:1) afforded 0.195
g (78%) of 13 as an analytically pure colorless oil: IR (neat) νmax 2950 (m), 2920 (m), 1730 (s), 1640 (s), 1610
1
(m), 1585 (m), 1505 (m), 1185 (m), 1150 (m), 1045 (m), 975 (m), 860 (m), 795 (m) cm-1; 300 MHz H NMR δ
7.37 (s, 5H), 7.06–6.87 (m, 1H), 5.91 (d, J 15.6 Hz, 1H), 5.85–5.25 (m, 2H), 3.72 (br s, 5H), 3.57 (br t, J 7 Hz, 2H),
2.57 (m, 2H), 1.72 (d, J 5.5 Hz, 3H); 13C NMR (CDCl3) δ 71.3, 166.3, 145.6, 136.1, 129.1, 128.1, 126.2, 126.6,
125.1, 122.4, 51.5, 51.3, 43.1, 30.1, 17.6; MS: m/e (relative intensity) 287 (M+, 1), 286 (1), 272 (1), 256 (1), 228
(1), 189 (2), 188 (15), 182 (3), 174 (3), 134 (3), 106 (8), 105 (100), 77 (16), 55 (4). Anal. Calcd for C17H21NO3: C,
71.05; H, 7.37; N, 4.87. Found: C, 70.72; H, 7.57; N, 5.10%.
4-Benzamido-1-butene (33). Amide 33 was prepared in 84% yield from 36 according to the method of
Davies:41 IR (neat) νmax 3330 (s), 3085 (m), 2990 (m), 2945 (m), 1650 (s), 1610 (m), 1585 (m), 1550 (s), 1500
1
(m), 1315 (s), 925 (m) cm-1; H NMR (CDCl3) δ 7.95–7.0 (m, 5H), 6.55 (broad s, 1H), 6.25–5.47 (m, 1H), 5.45–
4.85 (m, 2H), 3.49 (q, JH-N-C-H JH-C-C-H 6 Hz, 2H), 2.60–2.10 (m, 2H); MS: m/e (relative intensity) 175 (M+, 12), 134
(38), 105 (100), 77 (53), 51 (10), 39 (3).
(Z)-4-((Tetrahydro-2H-pyran-2-yl)oxy)-2-butene-1-ol (38)42.. A mixture of 2-butene-1,4-diol (17.6 g, 0.20 mol),
dihydropyran (8.4 g, 0.10 mmol) and montmorillonite (0.2 g) in benzene (25 mL) was heated to 80 °C for 12 h.
The reaction mixture was dried (Na2CO3) and concentrated in vacuo to give an oil which was distilled through a
Vigreaux column (10 cm) to afford a colorless liquid (bp 104–106 °C, 10 mmHg; lit.,42 bp 102–106 °C, 10
1
mmHg) which was a mixture of 2-butene-1,4-diol and THF-ether 38 by TLC and H NMR analysis. Flash
chromatography over silica gel with 1:2 (v/v) Et2O-hexane furnished 7.3 g (42%) of 38 as a colorless oil: IR
(neat) νmax 3660–3080 (s), 3030 (m), 3000–2860 (s), 1470 (m), 1460 (m), 1455 (m), 1390 (m), 1355 (m), 1325
(m), 1265 (m), 1205 (s), 1185 (m), 1160 (m), 1150–930 (s), 905 (s), 870 (s), 815 (s) cm-1; 1H NMR (CDCl3) δ 5.75
(m, 2H), 4.66 (m, 1H), 4.4–3.3 (m, 6H), 3.1 (t, 1H), 2.1–1.4 (m, 6H).
(Z)-4-((Tetrahydro-2H-pyran-2-yl)oxy)-1-chloro-2-butene (35).43,44 To a mixture of alcohol 38 (0.5 g, 2.9 mmol)
and s-collidine (0.39 g, 3.2 mmol) at 25 °C was added a solution of lithium chloride (0.123 g, 3.2 mmol) in dry
DMF (1.5 mL). The resulting suspension was cooled to 0 °C and treated dropwise over 5 min with mesyl
chloride (0.37 g, 3.2 mmol). The mixture was stirred at 0 °C for 1 h and then allowed to warm to room
temperature over 2 h. The light yellow reaction mixture was then poured into ice-H2O (25 mL) and extracted
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with cold pentane-Et2O (1:1, v/v; 3 x 25 mL). The combined organic extracts were washed with saturated
Cu(NO2)2 (3 x 10 mL), dried (Na2SO4) and concentrated in vacuo at 25 °C bath temperature to afford 0.44 g
(80%) of 35 as a light yellow oil (pure by TLC) that decomposed on standing: IR (neat) νmax 3040 (w), 1950 (s),
2870 (m), 2860 (m), 1450 (m), 1440 (m), 1370 (s), 1025 (s), 965 (m), 900 (m), 865 (m), 810 (m), 750 (m) cm-1;
1H NMR (CDCl3) δ 5.70 (m, 2H), 4.6 (m, 1H), 4.35–3.25 (m, 6H), 2.2–1.3 (m, 6H).
(Z)-4-[N-(3-buten-1-yl)benzamido]-2-buten-1-ol (39). To a solution of amide 33 (0.32 g, 1.5 mmol) and allylic
chloride 35 (0.37 g, 1.95 mmol) in THF (20 mL) at 0 °C under nitrogen was added dry sodium hydride (0.052 g,
2.1 mmol). The resulting suspension was stirred at –5 °C for 1 h and allowed to warm to ambient temperature
overnight (10 h). The reaction mixture was then cooled to 0 °C and treated with additional sodium hydride
(0.026 g, 1.05 mmol). The mixture was stirred at 0 °C for 1 h, allowed to warm to 25 °C over 1 h, and then
heated to 50 °C for 20 h. The reaction mixture was poured over ice (50 g) and extracted with CH2Cl2 (4 x 50
mL). The combined CH2Cl2 extracts were washed with brine (2 x 25 mL), aqueous 5% Na2CO3 (2 x 25 mL), dried
(MgSO4-Na2SO4) and concentrated in vacuo to afford a light yellow oil. Flash chromatography over silica gel
(25 g) with 1:1 (v/v) ether-hexane furnished a mixture (0.34 g) of starting material 33 and 32 (Rf 0.19 Et2O-
hexane, 1:1) by 1H NMR and IR spectroscopy. A solution of this mixture (0.3 g) in AcOH-THF-H2O (4:2:1, 10 mL)
was heated at 45–50 °C for 6 h. The reaction mixture was diluted with Et2O (100 mL) and extracted with
saturated aqueous NaHCO3 (2 x 25 mL). The base washes were extracted with Et2O (2 x 25 mL) and the
combined ethereal extracts were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to give
an oil. Flash chromatography over silica gel with EtOAc-hexane (2:1, v/v) afforded 0.15 g of 33 followed by
0.095 g (43%) of 39 as a colorless oil. Alcohol 39: IR (neat) νmax 3600–3020 (s), 3080 (w), 3030 (2), 2990 (2),
2940 (m), 1625 (s), 1585 (w), 1500 (w), 1470 (m), 1450 (m), 1430 (s), 1270 (m), 1030 (m), 920 (m), 790 (m), 735
1
(m), 705 (m) cm-1; H NMR (CDCl3) δ 7.33 (s, 5H), 6.2–4.6 (m, 2H), 4.3–2.8 (m, 7H), 2.6–1.9 (m, 2H); MS: m/e
(relative intensity) 204 (M+-CH2C=CH2), 149 (40), 121 (12), 105 (100), 100 (30), 82 (21), 77 (46), 69 (16), 71 (15),
63 (8), 57 (22), 55 (24), 44 (14), 40 (24). Anal. Calcd for C15H19NO2·1/8 H2O: C, 72.77; H, 7.84; N, 5.66. Found: C,
72.73; H, 7.94; N, 5.64%.
(Z)-1-Chloro-4-[N-(3-buten-l-yl)benzamido]-2-butene (40). To a solution of 39 (0.2 g, 0.82 mmol) in s-collidine
(0.104 g, 0.86 mmol) at 25 °C was added a solution of lithium chloride (0035 g, 0.82 mmol) in dry DMF (0.75
mL). The resulting suspension was cooled to 0 °C and treated dropwise over 3 min with mesyl chloride (0.099
g, 0.86 mmol). The mixture was stirred at 0 °C for 1 h and then allowed to warm to room temperature over 1
h. The light yellow reaction mixture was poured into ice-H2O (25 g) and extracted with cold pentane-ether
(1:1, v/v; 3 x 25 mL). The combined organic extracts were washed with saturated Cu(NO2)2 (2 x 25 mL), brine (2
x 25 mL), dried (MgSO4-NaSO4) and concentrated in vacuo at 25 °C bath temperature to afford 0.22 g (100%)
of 40 as a colorless oil that darkened on standing. Rapid, suction filtration through a pad of silica gel with cold
Et2O-pentane (7:3) provided 0.16 g (73%) of 40 as an analytically pure oil. IR (neat) νmax 3070 (m), 3040 (m),
2970 (m), 2940 (s), 2880 (m), 1650 (s), 1500 (m), 1450 (s), 1425 (s), 1320 (m), 1300 (m), 1260 (m), 1080 (m),
1010 (m), 995 (m), 925 (m), 795 (m), 730 (m), 710 (s) cm-1; 1H NMR (CDCl3) δ 7.39 (s, 5H), 6.2–4.8 (m, 2H), 4.5–
3.1 (m, 7H), 2.6–1.8 (m, 2H); MS: m/e (relative intensity) 222 (M+-CH2CH=CH2, 5), 149 (4), 105 (100), 77 (32).
Anal. Calcd for C25H18ClNO: C, 68.30; H, 6.88; N, 5.31. Found: C, 68.21; H, 6.91; N, 5.26%.
Attempted synthesis of 1-benzoyl-3-vinyl-4-piperidine acetic acid (42a,b): Decomposition of 41 to 4-
benzamido-1-butene (33). A solution of chloride 40 (0.10 g, 0.38 mmol) in THF (4 mL) was added dropwise
over 1 h to magnesium turnings (0.020 g, 0.82 mmol) in THF (3 mL) under nitrogen at –70 °C. During the
addition the internal reaction temperature rose to –20 °C. The cooling bath was removed and the mixture was
allowed to warm to room temperature over 30 min. A few iodine crystals were then added and the resulting
dark red mixture was heated at 45 °C for 15 h. Additional magnesium turnings (0.20 g, 0.82 mmol) and 1,2-
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dibromoethane (0.065 g, 0.35 mmol) were added and the reaction mixture was heated at 60 °C for 12 h.
Excess carbon dioxide (g) was then introduced into the solution at 0 °C for 10 min and the mixture was poured
into saturated aqueous ammonium chloride (20 mL) and extracted with ether (3 x 20 mL). The combined
ethereal extracts were washed with water (20 mL), brine (20 mL) and dried (Na2SO4). Concentration in vacuo
1
afforded 0.065 g (90%) of 33 as a light yellow oil which was identical by TLC, IR, and H NMR to an authentic
sample.
Acknowledgements
We thank Dartmouth College for support of this work.
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