N-Methyl Allylic Amines from Allylic Alcohols by Mitsunobu Substitution Using N-Boc Ethyl Oxamate

Article abstract of DOI:10.1021/acs.joc.1c00918

We report the practical, scalable synthesis of a range of N-methyl allylic amines. Primary and secondary allylic alcohols underwent a regioselective Mitsunobu reaction with readily accessible N-Boc ethyl oxamate to deliver the corresponding N-Boc allylic amines, including in enantiopure form via stereospecific substitution. Subsequent N-methylation and Boc deprotection without chromatography yielded the amine products as hydrochloride salts. This method solves the problem of converting commercially available alcohols into often volatile N-methyl allylic amines, many of which have limited commercial availability.

Full text of DOI:10.1021/acs.joc.1c00918

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N‑Methyl Allylic Amines from Allylic Alcohols by Mitsunobu
Substitution Using N‑Boc Ethyl Oxamate
Branca C. van Veen, Steven M. Wales, and Jonathan Clayden*
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ABSTRACT: We report the practical, scalable synthesis of a range of
N-methyl allylic amines. Primary and secondary allylic alcohols
underwent a regioselective Mitsunobu reaction with readily accessible
N-Boc ethyl oxamate to deliver the corresponding N-Boc allylic
amines, including in enantiopure form via stereospecific substitution.
Subsequent N-methylation and Boc deprotection without chromatog-
raphy yielded the amine products as hydrochloride salts. This method
solves the problem of converting commercially available alcohols into
often volatile N-methyl allylic amines, many of which have limited
commercial availability.
approaches is the most widely recognized, with, for example,
llylic amines are fundamental synthetic building blocks for
Athe construction of many targets including pharmaceut- the Overmann rearrangement allowing allylic amination by
thermal [3,3]-sigmatropic rearrangement of allylic trichlor-
oacetimidates and the Gabriel synthesis being a classic method
to transform allylic halides into allylic amines. Perhaps the
most widely applied method for direct allylic amination is the
transition-metal-catalyzed Tsuji−Trost reaction, which allows
amino substitution of allylic halides, acetates, carbonates, or
the direct amination of allylic alcohols.8 Despite the develop-
ment of various efficient transition metal catalysts, aminations
are typically limited to acidic (sulfonamides, urethanes,
phthalimides) or weakly basic (aryl, propargylic, benzyl)
amines,9 and because these reactions proceed through metal-
π-allyl intermediates, control of regioselectivity is often
challenging and may require careful choice of catalyst.10
In this paper, we present a method that we have found the
most practical for the preparation of N-alkylated allylic amines.
The method we describe is transition-metal-free and scalable
and is, with rare exception, completely regio- and stereo-
specific. Moreover, it allows the direct use of stable allylic
alcohols as starting materials, which are commercially available
in a broad range of substitution patterns.
icals and natural products, including alkaloids and α- and β-
amino acids.1,2 The potential range of transformations that use
allylic amines as starting materials likewise makes their
practical synthesis a significant synthetic goal that underpins
the development of new methodology.
Typical synthetic approaches to allylic amines include
transformations of precursors already containing C−N bonds
(Scheme 1, i) such as the reduction of α,β-unsaturated imine
derivatives or vinyl aziridines,3−5 or C−N bond formation
from nitrogen-free alkene precursors (Scheme 1, ii, iii). The
latter approaches either use unfunctionalized alkenes directly
(ii) or take as their starting point alkenes functionalized with
an allylic C−X bond (iii).1,2,6,7 The last of these direct
Scheme 1. Common Strategies for the Preparation of Allylic
Amines
As part of a project exploring the unusual reactivity of allylic
ureas as agents of intramolecular vinylation,11,12 we required a
supply of structurally diverse N-methylated allylic amines as
starting materials. The operationally simplest approach to these
Received: April 20, 2021
Published: June 8, 2021
https://doi.org/10.1021/acs.joc.1c00918
© 2021 American Chemical Society
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noncommercial compounds involved a classical substitution
reaction in which slow addition of an allyl halide or sulfonate
to an excess of N-methylamine was employed to suppress
double N-allylation. However, in addition to the poor reactivity
observed with secondary allylic electrophiles, the compounds
of most interest to us had low molecular weight, making
isolation of the amines themselves difficult because of their
volatility. This problem can be circumvented by conversion of
the amines into their hydrochloride salts, but this entailed
another challengeseparation of the salts from excess
methylammonium chloride derived from the nucleophile.
A way to circumvent issues of both volatility and amine
separation would be to approach the hydrochloride salts from
N-Boc protected amine precursors. N-Acylated amines may be
formed conveniently from readily available allylic alcohols
using the Mitsunobu reaction,1,13 but with phthalimidethe
most commonly used nitrogen nucleophileundesirable
deprotection conditions are required.14 Alternative nucleo-
philes that require less vigorous deprotection conditions, such
as sulfonyl- and acylcarbamates or imidodicarbonates, may be
used to avoid the phthaloyl deprotection. Nonetheless,
Mitsunobu reactions with these pronucleophiles still yield
potentially volatile free N-allylamine derivatives in depro-
Scheme 2. Synthesis of N-Boc Protected Allylic Amines
under Mitsunobu Conditions
tection.
Berree and co-workers
14
́
have reported a nitrogen
nucleophile for Mitsunobu reactions15 of primary and
secondary alkyl alcohols, N-Boc ethyl oxamate (1, pKa 8.8 in
EtOH/H2O, Scheme 2), that functions as an equivalent of
“BocNH−” and requires only a mild hydrolysis of the oxamate
substitution product to deliver linear and branched primary
amines in their N-Boc protected forms.16−19 For our purposes,
the ability to convert allylic alcohols directly to N-Boc
protected amines without isolation of volatile intermediates
was appealing, but we were surprised to find only two isolated
examples of the Mitsunobu reaction of 1 with allylic
alcohols.14,20 We therefore set out to investigate the
applicability of this reaction to a range of allylic alcohols,
both linear and branched. For this, N-Boc ethyl oxamate (1)
was made on decagram scale following the reported
procedure.14,21
a
b
DEAD was used in place of DIAD. Contains the cis isomer as a
Mitsunobu substitutions (Scheme 2) were initially attemp-
ted with N-Boc ethyl oxamate (1), DEAD, triphenylphosphine,
and each of 3-buten-2-ol and 2-buten-1-ol (crotyl alcohol).
Hydrolysis of the imide with an excess of lithium hydroxide
successfully returned the N-Boc protected amines 2 and 4,
albeit in low yields of 36% and 27% (Scheme 2). Repeating the
reactions with DIAD in the place of DEAD improved these
yields significantly: 63% for 2 and 73% for 4.
These optimized conditions were applied to a further series
of variously substituted allylic primary and secondary alcohols,
and in every case the N-Boc protected allylic amine 2−12 was
obtained (Scheme 2). In most cases the reaction was carried
out on a multigram scale. The reaction tolerated substitution of
the allylic system at the α-, β-, or γ-positions (2−4), giving a
single regioisomer of 2, and was successful with longer chains
(5) and even the rather bulky ring of terpenoid (6). Hexa-2,4-
dien-1-ol reacted with complete regiospecificity to give diene 7.
Likewise, allyl alcohols carrying electron-donating or -with-
drawing functional groups were tolerated, giving the protected
minor impurity carried through from the starting material.
of 2 from 3-buten-2-ol, the Mitsunobu reaction of α-
vinylbenzyl alcohol gave a mixture of 11a and the alternative
allylic regioisomer 11b.
The enantiospecificity of the substitution was confirmed by
the use of enantiopure (S)-1-octen-3-ol (e.r. ≥ 99:1) as a
starting material. The N-Boc amine 12 was formed without
loss of enantiopurity (e.r. ≥ 99:1), demonstrating clean
inversion of configuration.20
To obtain the desired N-methyl allylamines, the substituted
N-Boc allylcarbamates 2−8, 10, 11b, and 12 were N-
methylated using sodium hydride and methyl iodide (Scheme
3). Boc deprotection using an excess of TFA yielded the
corresponding amine·TFA salts as rather intractable sticky oils.
Anion exchange with anhydrous HCl in MeOH converted the
TFA salts to the hydrochloride salts, which were generally
much easier to handle solids. This simple three-step procedure
allowed us to isolate in high yield the hydrochloride salts of a
wide range of N-methyl allylamines without chromatography,
including the salts of rather volatile freebases that had proved
challenging by other methods. Importantly, for the general
́
amines 8 and 9 in excellent yield. Berree and co-workers had
demonstrated that cinnamyl alcohol reacts well with 1;14 we
found that 2-phenyl-2-propen-1-ol is a suitable substrate as
well, giving 10 in good yield. In contrast to the clean formation
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Bellingham and Stanley Ltd. ADP220 polarimeter using a cell with a
path length of 0.25 dm and a concentration (c) in CHCl3 given in g/
100 mL. Melting points were recorded using a Stuart Scientific
apparatus and are reported uncorrected in degrees Celsius (°C).
Infrared (IR) spectra were recorded on a PerkinElmer Spectrum Two
FTIR spectrometer with an attenuated total reflectance (ATR)
attachment; only strong absorbances (νmax) are reported in cm−1.
High-resolution mass spectra (HRMS) were recorded on a Bruker
microOTOF II instrument using electrospray ionization (ESI) and on
a Thermo Scientific Orbitrap Elite using atmospheric-pressure
chemical ionization (APCI). Chiral HPLC was performed on a
Daicel Chiralcel OD-H at room temperature, with a wavelength of
205 nm, an injection volume of 10 μL, and a flow rate of 0.5 mL/min
using a solvent system of i-PrOH/n-hexane (1/99).
Scheme 3. Synthesis of N-Methyl Allylamine Hydrochloride
Salts
Gram-Scale Synthesis of N-Boc Ethyl Oxamate (1). This
compound was prepared following a reported procedure with ethyl
oxamate (2.3 g, 20 mmol, 1 equiv), anhydrous 1,2-DCE (5.6 mL, 0.28
mL/mmol), oxalyl chloride (2.0 mL, 24 mmol, 1.2 equiv), anhydrous
toluene (16 mL, 0.8 mL/mmol), and tert-butyl alcohol (2.2 mL, 23
mmol, 1.15 equiv).21 Purification by flash column chromatography
(20:80 acetone/petroleum ether) gave the product 1 (26.80 g, 123.4
mmol, 70%) as a pale yellow oil. IR (film) vmax 3271, 2983, 2923,
1738, 1708, 1496, 1371, 1307, 1242, 1132, 1018 cm−1. 1H NMR (400
MHz, CDCl3) δ 8.64 (bs, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.51 (s, 9H),
1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.8,
148.6, 84.0, 64.0, 28.0, 14.0. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C9H15NO5Na 240.0842; Found 240.0840. Data are in
agreement with the literature.21
General Procedure for Mitsunobu Reaction Followed by
LiOH Cleavage (2−12). A reported procedure was followed.13,14
A
round-bottom flask containing N-Boc ethyl oxamate 1 (1.1 equiv),
triphenylphosphine (1.1 equiv), the desired allyl alcohol (2.76−21.7
mmol scale, 1 equiv), and anhydrous THF (7.7 mL/mmol) was
cooled to 0 °C. DIAD (1.1 equiv) was added dropwise. The reaction
mixture was stirred at rt for 15−24 h, concentrated under reduced
pressure, and redissolved in THF (3.2 mL/mmol) and H2O (1.25
mL/mmol). LiOH (5 equiv) was added, and the mixture was stirred
at rt for 1.5−3.5 h. After addition of H2O (12 mL/mmol) and EtOAc
(12 mL/mmol), the organic phase was extracted. The aqueous phase
was washed with EtOAc (3× 6 mL/mmol), and then the organic
phases were combined, dried over MgSO4, filtered, and concentrated
in vacuo. Purification by flash column chromatography (1−40%
acetone or 1−32% EtOAc in petroleum ether) gave pure products 2−
12.
General Procedure for N-Methyl-N-Allyl Amine Hydro-
chloride Salt Synthesis (13−22). A round-bottom flask containing
2−8, 10, 11b, 12 (1.23−17.3 mmol scale, 1 equiv), and anhydrous
DMF (1.7 mL/mmol) was cooled to 0 °C. Sodium hydride (2 equiv)
was added slowly under a positive pressure of N2 followed by the
dropwise addition of iodomethane (4 equiv). The reaction mixture
was stirred at rt for 2−4 h and then quenched at 0 °C by the slow
addition of a saturated aqueous solution of NH4Cl (4 mL/mmol).
Et2O (12 mL/mmol) was added, and the aqueous phase was washed
with Et2O (12 mL/mmol, ×3). The combined organic phases were
concentrated under reduced pressure, and the residue was redissolved
in CH2Cl2 (5.3 mL/mmol). TFA (11.1 equiv) was added, and the
mixture was stirred at rt under air for 1−24 h. The reaction mixture
was concentrated under reduced pressure and redissolved in MeOH
(3 mL/mmol). While vigorously stirring, HCl (1.25 M in MeOH,
3.35 equiv) was added rapidly, and after 5 min, hexane was added to
form a separate solvent layer containing residual grease from the
sodium hydride suspension. The methanol layer was separated and
concentrated in vacuo. Trituration with Et2O gave the desired N-
methyl-N-allyl amine hydrochloride salts 13−22.
a
Contains the cis isomer as a minor impurity carried through from the
starting material.
applicability to a range of substrate structures, the reaction
sequence tolerated α-, β-, and γ-substituted allylic systems.
In summary, a range of structurally diverse N-methyl
allylamine derivatives have been synthesized and isolated as
pure hydrochloride salts by a practical, scalable transformation
of commercially available primary and secondary allyl alcohols.
The use of N-Boc ethyl oxamate as a nitrogen nucleophile
which has proven applicability in Mitsunobu reactions but had
been essentially unexplored in combination with allyl
alcoholswas key to the success of this method. We believe
organic chemists will find this method to be of significant
practical value in the preparation of allylic amines and their
derivatives for a variety of applications.
EXPERIMENTAL SECTION
■
General Information. All solvents and reagents were obtained
from commercial suppliers and used as received. All reactions were
carried out under an atmosphere of anhydrous N2 unless otherwise
stated, and all glassware was flame-dried with a Bunsen burner.
Anhydrous solvents were obtained from commercial suppliers or dried
using an Anhydrous Engineering Grubbs-type system (alumina
columns). Thin-layer chromatography (TLC) was carried out on
aluminum-backed silica plates (0.25 mm, Merck, silica gel 60 F254),
and the spots were visualized by UV light (λ = 254 nm) and by
staining with an aqueous basic potassium permanganate (KMnO4)
followed by heating. Normal phase flash column chromatography was
carried out automatically using a Biotage Isolera flash purification
system. NMR spectra were recorded on a Bruker 400 MHz
spectrometer. Chemical shifts (δ) are reported in parts per million
(ppm), and coupling constants (J) are reported in Hertz (Hz). Full
characterization was confirmed by 2D NMR experiments: COSY,
tert-Butyl But-3-en-2-ylcarbamate (2). Reaction performed on
20.0 mmol scale following the general procedure. Flash column
chromatography (2−20% acetone/petroleum ether) gave 2 as a
yellowish solid (2.15 g, 12.6 mmol, 63% yield). MP 34−35 °C. IR
1
(film) vmax 3339, 2977, 2928, 1689, 1514, 1366, 1168, 917 cm−1. H
HSQC and HMBC. Optical rotations ([α]TD) were measured on a
NMR (400 MHz, CDCl3) δ 5.81 (ddd, J = 17.2, 10.4, 5.1 Hz, 1H),
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5.14 (dt, J = 17.2, 1.4 Hz, 1H), 5.05 (dt, J = 10.4, 1.4 Hz, 1H), 4.43
(bs, 1H), 4.21 (bs, 1H), 1.44 (s, 9H), 1.20 (d, J = 6.8 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 155.3, 140.3, 113.7, 79.4, 48.3,
28.6, 20.8. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C9H17NO2Na 194.1151; Found 194.1154. Spectral data agree with
previously reported data.22
C11H19NO2Na 220.1308; Found 220.1305. Spectral data of the
major product (E,E) agree with previously reported data.26
tert-Butyl (E)-(3-(Trimethylsilyl)allyl)carbamate (8). Reaction
performed on 3.84 mmol scale following the modified general
procedure: 1.55 equiv used of 1, PPh3 and DIAD. Flash column
chromatography (5−40% acetone/petroleum ether) gave 8 as a pale-
yellowish oil (0.83 g, 3.62 mmol, 94% yield). IR (film) vmax 3347,
tert-Butyl (2-Methylallyl)carbamate (3). Reaction performed
on 18.6 mmol scale following the general procedure. Flash column
chromatography (5−40% acetone/petroleum ether) gave 3 as a
yellow liquid (2.78 g, 16.2 mmol, 87% yield). IR (film) vmax 3353,
1
2956, 2956, 1694, 1513, 1247, 1171, 851, 836 cm−1. H NMR (400
MHz, CDCl3) δ 6.00 (dt, J = 18.6, 4.8 Hz, 1H), 5.79 (dt, J = 18.6, 1.7
Hz, 1H), 4.60 (bs, 1H), 3.78 (bs, 2H), 1.45 (s, 9H), 0.05 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3) δ 155.9, 142.4, 130.6, 79.5, 45.2,
28.5, −1.2. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C11H23NO2SiNa 252.1390; Found 252.1398. Spectral data agree
with previously reported data.27
tert-Butyl (E)-(4,4,4-Trifluorobut-2-en-1-yl)carbamate (9).
Reaction performed on 6.49 mmol scale following the general
procedure. Flash column chromatography (4−32% ethyl acetate/
petroleum ether) gave 9 as a yellow oil (1.33 g, 5.89 mmol, 91% yield;
corrected for residual solvents present). IR (film) vmax 3345, 2982,
1685, 1269, 1250, 1117 cm−1. 1H NMR (400 MHz, CDCl3) δ 6.41−
6.30 (m, 1H), 5.74 (dtq, J = 15.7, 6.3, 2.0 Hz, 1H), 4.78 (bs, 1H),
3.86 (bs, 2H), 1.44 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
155.7, 137.4 (q, JF = 6.2 Hz), 123.1 (q, JF = 269.0 Hz), 119.0 (q, JF =
34.1 Hz), 80.2, 40.8, 28.4. 19F NMR (377 MHz, CDCl3): δ −64.1 (br
s, 3F). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H14NO2F3Na
248.0869; Found 248.0873.
1
2979, 1696, 1165, 751 cm−1. H NMR (400 MHz, CDCl3) δ 4.84−
4.79 (m, 2H), 4.65 (bs, 1H), 3.65 (d, J = 6.2 Hz, 2H), 1.73−1.71 (m,
3H), 1.44 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.1, 142.8,
110.4, 79.4, 46.4, 28.5, 20.3. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C9H17NO2Na 194.1151; Found 194.1159. Analytical data
agree with previously reported data.23
tert-Butyl But-2-en-1-ylcarbamate (4). Reaction performed on
20.2 mmol scale following the general procedure. Flash column
chromatography (5−40% acetone/petroleum ether) gave 4 as a
yellowish liquid (2.53 g, 14.8 mmol, 73% yield). IR (film) vmax 3348,
2977, 2932, 1692, 1513, 1248, 1168, 965 cm−1. 1H NMR (400 MHz,
CDCl3) (suspected mixture of E:Z in a 0.9:0.1 ratio) δ 5.63−5.50 (m,
1H), 5.48−5.37 (m, 1H), 4.57 (bs, 1H), 3.73 (bs, 0.2H), 3.64 (t, J =
5.9 Hz, 1.8H), 1.66−1.61 (m, 3H), 1.41 (s, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 155.9, 127.7, 127.7, 79.2, 42.6, 28.5, 17.7. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C9H17NO2Na 194.1151;
Found 194.1157. Spectral data agree with previously reported data.24
tert-Butyl (E)-Hex-2-en-1-ylcarbamate (5). Reaction performed
on 20.2 mmol scale following the general procedure. Flash column
chromatography (5−40% acetone/petroleum ether) gave 5 as a
yellowish liquid (3.46 g, 17.4 mmol, 86% yield). IR (film) vmax 3347,
tert-Butyl (2-Phenylallyl)carbamate (10). Reaction performed
on 21.7 mmol scale following the general procedure. Flash column
chromatography (3−24% ethyl acetate/petroleum ether) gave 10 as a
yellow oil (3.91 g, 16.8 mmol, 77% yield). IR (film) vmax 3347, 2977,
1
1693, 1496, 1365, 1246, 1164, 778, 702 cm−1. H NMR (400 MHz,
1
2962, 2930, 1693, 1505, 1248, 1170, 968, 755 cm−1. H NMR (400
CDCl3) δ 7.42 (d, J = 7.1 Hz, 2H), 7.37−7.27 (m, 3H), 5.42 (s, 1H),
5.23 (q, J = 1.4 Hz, 1H), 4.66 (bs, 1H), 4.19 (d, J = 3.7 Hz, 2H), 1.44
(s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.9, 145.1, 138.8,
128.6, 128.0, 126.3, 113.3, 79.6, 44.5, 28.5. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C14H19NO2Na 256.1308; Found 256.1305.
Spectral data agree with previously reported data.28
MHz, CDCl3) δ 5.58 (dtt, J = 15.3, 6.7, 1.3 Hz, 1H), 5.43 (dtt, J =
15.3, 6.0, 1.3 Hz, 1H), 4.51 (bs, 1H), 3.67 (t, J = 6.0 Hz, 2H), 2.01−
1.95 (m, 2H), 1.44 (s, 9H), 1.37 (h, J = 7.4 Hz, 2H), 0.88 (t, J = 7.4
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.9, 133.1, 126.6,
79.3, 42.8, 34.4, 28.5, 22.4, 13.8. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C11H21NO2Na 222.1464; Found 222.1473. Spectral data
agree with previously reported data.25
tert-Butyl (((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-
yl)methyl)carbamate (6). Reaction performed on 10.1 mmol
scale following the general procedure. Flash column chromatography
(1−12% acetone/petroleum ether) gave 6 as a white solid (2.23 g,
8.86 mmol, 88% yield). MP 57−58 °C. IR (film) vmax 3354, 2987,
2914, 1694, 1504, 1365, 1257, 1162 cm−1. 1H NMR (400 MHz,
CDCl3) δ 5.38−5.35 (m, 1H), 4.47 (bs, 1H), 3.61 (bs, 2H), 2.37 (dt,
J = 8.6, 5.6 Hz, 1H), 2.32−2.15 (m, 2H), 2.12−2.02 (m, 2H), 1.44 (s,
9H), 1.27 (s, 3H), 1.14 (d, J = 8.6 Hz, 1H), 0.82 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 156.1, 145.2, 118.2, 79.3, 45.6, 44.1, 41.0,
38.1, 31.7, 31.2, 28.6, 26.3, 21.2. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C15H25NO2Na 274.1778; Found 274.1788.
tert-Butyl (1-Phenylallyl)carbamate (11a). Reaction performed
on 10.2 mmol scale following the general procedure. Flash column
chromatography (2−20% ethyl acetate/petroleum ether) gave 11a as
a white solid (428 mg, 1.83 mmol, 18% yield). MP 65−67 °C. IR
1
(film) vmax 3334, 2978, 1690, 1493, 1366, 1164, 698 cm−1. H NMR
(400 MHz, CDCl3) δ 7.35−7.23 (m, 5H), 5.98 (ddd, J = 17.4, 10.2,
5.4 Hz, 1H), 5.28 (bs, 1H), 5.24−5.17 (m, 2H), 4.96 (bs, 1H), 1.44
(s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.1, 141.2, 138.1,
128.7, 127.5, 127.1, 115.5, 79.7, 56.7, 28.4. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C14H19NO2Na 256.1308; Found 256.1301.
Spectral data agree with previously reported data.29
tert-Butyl Cinnamylcarbamate (11b). Reaction performed on
10.2 mmol scale following the general procedure. Flash column
chromatography (2−20% ethyl acetate/petroleum ether) gave 11b as
a white solid (520 mg, 2.23 mmol, 22% yield). MP 79−80 °C. IR
(film) vmax 3346, 2977, 1690, 1497, 1366, 1248, 1164, 743, 693 cm−1.
1H NMR (400 MHz, CDCl3) δ 7.37−7.27 (m, 4H), 7.25−7.20 (m,
1H), 6.49 (dt, J = 15.8, 1.6 Hz, 1H), 6.18 (dt, J = 15.8, 6.1 Hz, 1H),
4.83 (bs, 1H), 3.90 (bs, 2H), 1.48 (s, 9H). 13C{1H} NMR (101 MHz,
CDCl3) δ 155.9, 136.8, 131.5, 128.7, 127.7, 126.5, 126.5, 79.6, 42.8,
28.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H19NO2Na
256.1308; Found 256.1313. Spectral data agree with previously
reported data.30
tert-Butyl ((2E,4E)-Hexa-2,4-dien-1-yl)carbamate (7). Reac-
tion performed on 15.0 mmol scale following the general procedure.
Flash column chromatography (1−12% ethyl acetate/petroleum
ether) gave 7 as a yellowish solid (2.24 g, 11.4 mmol, 76% yield;
containing traces of isomeric products). MP 47−48 °C. IR (film) vmax
1
3348, 2978, 1694, 1164, 987, 908, 730 cm−1. H NMR (400 MHz,
CDCl3) (suspected mixture of E,E to Z,Z, Z,E, and E,Z in a 0.84:0.16
ratio) δ 6.35 (dd, J = 15.3, 11.1 Hz, 0H), 6.20 (dt, J = 10.2, 3.4 Hz,
0.15H), 6.10−5.86 (m, 2.1H), 5.71 (ddd, J = 16.8, 10.5, 5.4 Hz,
0.05H), 5.56 (dq, J = 13.6, 6.7 Hz, 1.15H), 5.43 (dt, J = 14.2, 6.3 Hz,
1H), 5.37−5.30 (m, 0.05H), 5.11−5.04 (m, 0.2H), 5.03−4.99 (m,
0.05H), 4.98−4.94 (m, 0.1H), 4.81 (bs, 1H), 4.72 (bs, 0.15H), 4.54
(bs, 0.1H), 3.64 (t, J = 6.4 Hz, 2H), 1.80 (d, J = 6.8 Hz, H), 1.65 (d, J
= 6.8 Hz, 3H), 1.60 (d, J = 6.3 Hz, H), 1.35 (s, 10.6H), 1.20−1.16
(m, 0.1H), 1.13 (d, J = 6.9 Hz, 0.3H). 13C{1H} NMR (101 MHz,
CDCl3) (suspected mixture of E,E to Z,Z, Z,E, and E,Z in a 0.84:0.16
ratio) δ 155.7, 155.0, 137.9, 136.3, 135.8, 131.7, 130.7, 130.0, 129. 8,
129.17, 129.0, 127.0, 126.7, 116.8, 114.5, 78.9, 42.2, 29.1, 28.3, 20.7,
17.9, 17.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
tert-Butyl (R)-Oct-1-en-3-ylcarbamate (12). Reaction per-
formed on 2.76 mmol scale following the general procedure. Flash
column chromatography (1−8% acetone/pentane) gave 12 as a
yellow oil (424 mg, 1.86 mmol, 67% yield). [α]2D3= −12 (c = 1.08 in
CHCl3). IR (film) vmax 3343, 2958, 2930, 1690, 1518, 1365, 1246,
1171, 773 cm−1. 1H NMR (400 MHz, CDCl3) δ 5.69 (ddd, J = 16.6,
10.4, 5.7 Hz, 1H), 5.09 (dt, J = 17.2, 1.3 Hz, 1H), 5.01 (dt, J = 10.4,
1.3 Hz, 1H), 4.48 (bs, 1H), 4.02 (bs, 1H), 1.52−1.41 (m, 2H), 1.40
(s, 9H), 1.33−1.19 (m, 6H), 0.83 (t, J = 6.6 Hz, 3H). 13C{1H} NMR
8541
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The Journal of Organic Chemistry
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Note
(101 MHz, CDCl3) δ 155.5, 139.3, 114.2, 79.2, 52.9, 35.2, 31.7, 28.5,
25.4, 22.6, 14.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C13H25NO2Na 250.1777; Found 250.1776. HPLC (OD-H, i-PrOH/
n-hexane = 1/99, flow rate = 0.5 mL/min, λ = 205 nm) tR = 8.79 min
(major), 10.28 min (minor), ≥99:1 er.
MHz, MeOD4) δ 140.6, 134.4, 131.2, 119.5, 51.6, 32.6, 18.2. HRMS
(APCI) m/z: [M + H]+ Calcd for C7H14N 112.1121; Found
112.1116.
N-Methyl-(E)-3-(trimethylsilyl)prop-2-en-1-amine Hydro-
chloride Salt (19). Reaction performed on 3.69 mmol scale
following the general procedure. Yield: 73% (484 mg, 2.69 mmol).
Off-white solid. MP 132−133 °C. IR (film) vmax 3377, 2956, 2494,
2068, 1249, 977, 861, 837, 772 cm−1. 1H NMR (400 MHz, MeOD4)
δ 6.24 (dt, J = 18.7, 1.0 Hz, 1H), 6.15 (dt, J = 18.7, 5.6 Hz, 1H), 3.68
(dd, J = 5.6, 0.7 Hz, 2H), 2.69 (s, 3H), 0.12 (s, 9H). 13C{1H} NMR
(101 MHz, MeOD4) δ 141.0, 136.1, 53.9, 32.9, −1.5. HRMS (APCI)
m/z: [M + H]+ Calcd for C7H18NSi 144.1203; Found 144.1196.
N-Methyl-2-phenylprop-2-en-1-amine Hydrochloride Salt
(20). Reaction performed on 16.6 mmol scale following the general
procedure. Yield: 93% (2.82 g, 15.4 mmol). Greyish solid. MP 115−
117 °C. IR (film) vmax 3382, 2964, 2492, 1463, 973, 778, 766 cm−1.
1H NMR (400 MHz, MeOD4) δ 7.55−7.50 (m, 2H), 7.46−7.36 (m,
tert-Butyl Oct-1-en-3-ylcarbamate ( -12). Reaction performed
on 6.01 mmol scale following the general procedure. Flash column
chromatography (2−20% acetone/pentane) gave -12 as a yellowish
oil (1.05 g, 4.64 mmol, 77% yield). Analytical data agree with 12.
N-Methyl-1-methylallylamine Hydrochloride Salt (13). Re-
action performed on 5.56 mmol scale following the general procedure.
Yield: 81% (545 mg, 4.48 mmol). White solid. MP 101−102 °C. IR
1
(film) vmax 3400, 2958, 2734, 1469, 751 cm−1. H NMR (400 MHz,
MeOD4) δ 5.86 (ddd, J = 17.1, 10.3, 8.2 Hz, 1H), 5.56−5.44 (m,
2H), 3.76 (p, J = 7.0 Hz, 1H), 2.63 (s, 3H), 1.43 (d, J = 6.7 Hz, 3H).
13C{1H} NMR (101 MHz, MeOD4) δ 134.5, 122.7, 59.1, 31.0, 18.0.
HRMS (APCI) m/z: [M + H]+ Calcd for C5H12N 86.0964; Found
86.0961.
3H), 5.72 (s, 1H), 5.53 (t, J = 1.2 Hz, 1H), 4.15 (s, 2H), 2.72 (s, 3H).
13C{1H} NMR (101 MHz, MeOD4) δ 141.4, 138.5, 130.1, 130.0,
N-Methyl-(2-methyl-2-propen-1-amine Hydrochloride Salt
(14). Reaction performed on 15.7 mmol scale following the general
procedure. Yield: 85% (1.62 g, 13.3 mmol); corrected for residual
TFA using 19F NMR with hexafluorobenzene as internal standard.
The following analytical data was obtained with triturated, pure
compound 14: White solid. MP 124−125 °C. IR (film) vmax 3020,
1214, 744, 668 cm−1. 1H NMR (400 MHz, MeOD4) δ 5.20−5.18 (m,
1H), 5.15−5.12 (m, 1H), 3.60 (s, 2H), 2.71 (s, 3H), 1.87 (td, J = 1.0,
0.4 Hz, 3H). 13C{1H} NMR (101 MHz, MeOD4) δ 137.8, 117.9,
55.1, 33.3, 20.7. HRMS (APCI) m/z: [M + H]+ Calcd for C5H12N
86.0964; Found 86.0960.
127.4, 119.8, 53.0, 33.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C10H14N 148.1121; Found 148.1125.
N-Methyl-(E)-3-phenylprop-2-en-1-amine Hydrochloride
Salt (21). Reaction performed on 2.90 mmol scale following the
general procedure. Yield: 81% (0.43 g, 2.34 mmol). Off-white solid.
MP 141−142 °C. IR (film) vmax 3392, 2958, 2751, 2513, 2138, 1449,
1
970, 740, 692 cm−1. H NMR (400 MHz, MeOD4) δ 7.50−7.45 (m,
2H), 7.36−7.25 (m, 3H), 6.88 (d, J = 15.8 Hz, 1H), 6.35 (dt, J = 15.8,
7.1 Hz, 1H), 3.78 (d, J = 7.1 Hz, 2H), 2.70 (s, 3H). 13C{1H} NMR
(101 MHz, MeOD4) δ 139.7, 136.8, 129.7, 129.7, 127.8, 119.3, 51.6,
32.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C10H14N
148.1121; Found 148.1125.
N-Methylbut-2-en-1-amine Hydrochloride Salt (15). Reac-
tion performed on 14.5 mmol scale following the general procedure.
Yield: 72% (1.27 g, 10.4 mmol). Yellowish solid. MP 66−67 °C. IR
N-Methyl-(R)-oct-1-en-3-amine Hydrochloride Salt (22).
Reaction performed on 1.23 mmol scale following the general
1
(film) vmax 3365, 2484, 1220, 971, 775, 771 cm−1. H NMR (400
procedure. Yield: 98% (215 mg, 1.21 mmol). Orange gum. [α]2D3=
+12 (c = 0.96 in CHCl3). IR (film) vmax 3393, 2930, 2720, 1466, 772
cm−1. 1H NMR (400 MHz, MeOD4) δ 5.72 (ddd, J = 16.8, 10.3, 9.1
Hz, 1H), 5.58−5.50 (m, 2H), 3.56 (td, J = 9.6, 4.3 Hz, 1H), 2.62 (s,
3H), 1.87−1.77 (m, 1H), 1.70−1.59 (m, 1H), 1.42−1.28 (m, 6H),
0.91 (t, J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, MeOD4) δ 133.1,
124.8, 64.2, 32.8, 32.3, 31.2, 26.0, 23.4, 14.2. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C9H20N 142.1590; Found 142.1586.
MHz, MeOD4) (suspected mixture of E:Z in a 0.95:0.05 ratio) δ 6.02
(dqt, J = 15.3, 6.6, 1.1 Hz, 1H), 5.57 (dtq, J = 15.3, 7.1, 1.7 Hz, 1H),
3.71−3.67 (m, 0.1H), 3.55 (dt, J = 7.1, 1.1 Hz, 1.9H), 2.68 (s, 0.1H),
2.65 (s, 2.9H), 1.79 (ddt, J = 6.6, 1.7, 1.0 Hz, 2.9H), 1.77−1.75 (m,
0.1H). 13C{1H} NMR (101 MHz, MeOD4) δ 137.5, 121.7, 51.6, 32.5,
18.1. HRMS (APCI) m/z: [M + H]+ Calcd for C5H12N 86.0964;
Found 86.0960.
N-Methyl-(E)-hex-2-en-1-amine Hydrochloride Salt (16).
Reaction performed on 17.3 mmol scale following the general
procedure. Yield: 90% (2.32 g, 15.5 mmol). Off-white solid. MP 107−
N-Methyl-( )-oct-1-en-3-amine Hydrochloride Salt ( -22).
Reaction performed on 3.82 mmol scale following the general
procedure. Yield: 78% (532 mg, 2.99 mmol). Off-white solid. MP 94−
95 °C. Analytical data agree with 22.
1
108 °C. IR (film) vmax 3339, 2472, 2070, 1121, 973, 458 cm−1. H
NMR (400 MHz, MeOD4) δ 6.01 (dtt, J = 15.0, 6.9, 1.2 Hz, 1H),
5.62−5.49 (m, 1H), 3.57 (d, J = 7.1 Hz, 2H), 2.65 (s, 3H), 2.11 (q, J
= 7.1 Hz, 2H), 1.47 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (101 MHz, MeOD4) δ 142.5, 120.7, 51.6, 35.5, 32.5,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00918.
■
sı
22.9, 13.9. HRMS (APCI) m/z: [M + H]+ Calcd for C7H16N
114.1277; Found 114.1272.
N-Methyl-1-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-
ylmethanamine Hydrochloride Salt (17). Reaction performed on
12.5 mmol scale following the general procedure. Yield: 82% (2.07 g,
10.3 mmol). White solid. MP 215−216 °C. IR (film) vmax 3339, 2945,
NMR spectra and HPLC traces for all new compounds
(PDF)
1
2490, 1024, 979 cm−1. H NMR (400 MHz, MeOD4) δ 5.81−5.77
(m, 1H), 3.53 (s, 2H), 2.67 (s, 3H), 2.53 (dt, J = 8.9, 5.6 Hz, 1H),
2.46−2.28 (m, 2H), 2.24 (td, J = 5.6, 1.7 Hz, 1H), 2.15 (ttd, J = 5.6,
2.8, 1.2 Hz, 1H), 1.35 (s, 3H), 1.22 (d, J = 8.9 Hz, 1H), 0.89 (s, 3H).
13C{1H} NMR (101 MHz, MeOD4) δ 140.4, 127.3, 54.5, 45.3, 41.7,
AUTHOR INFORMATION
Corresponding Author
■
Jonathan Clayden − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.; orcid.org/0000-0001-5080-9535;
Email: j.clayden@bristol.ac.uk
39.1, 33.2, 32.5, 32.4, 26.3, 21.4. HRMS (APCI) m/z: [M + H]+
Calcd for C11H20N 166.1590; Found 166.1586.
N-Methyl-(2E,4E)-hexa-2,4-dien-1-amine Hydrochloride Salt
(18). Reaction performed on 10.8 mmol scale following the general
procedure. Yield: 66% (1.05 g, 7.13 mmol; containing traces of
isomeric products); corrected for residual solvent present. Brown
solid. MP 75−76 °C. IR (film) vmax 3396, 2962, 2737, 2182, 1460,
Authors
Branca C. van Veen − School of Chemistry, University of
Bristol, Bristol BS8 1TS, U.K.
Steven M. Wales − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.
1
993 cm−1. H NMR (400 MHz, MeOD4) δ 6.45 (dd, J = 15.2, 10.4
Hz, 1H), 6.14 (ddq, J = 15.0, 10.4, 1.2 Hz, 1H), 5.89 (dq, J = 15.0, 6.7
Hz, 1H), 5.58 (dt, J = 15.2, 7.2 Hz, 1H), 3.62 (d, J = 7.2 Hz, 2H),
2.65 (s, 3H), 1.78 (dd, J = 6.7, 1.2 Hz, 3H). 13C{1H} NMR (101
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00918
8542
https://doi.org/10.1021/acs.joc.1c00918
J. Org. Chem. 2021, 86, 8538−8543

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(20) Pan, Y.; Calvert, K.; Silverman, R. B. Conformationally-
Restricted Vigabatrin Analogs as Irreversible and Reversible Inhibitors
of γ-Aminobutyric Acid Aminotransferase. Bioorg. Med. Chem. 2004,
12, 5719−5725.
(21) Berrée, F.; Bazureau, J. P.; Michelot, G.; Le Cone, M. N-Boc
and N-Cbz Ethyl Oxamates: New Gabriel Reagents. Synth. Commun.
1999, 29, 2685−2693.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the EPSRC through Research Grant
EP/L018527.
(22) Majhail, M. K.; Ylioja, P. M.; Willis, M. C. Direct Synthesis of
Highly Substituted Pyrroles and Dihydropyrroles Using Linear
Selective Hydroacylation Reactions. Chem. - Eur. J. 2016, 22,
7879−7884.
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