A Facile Synthesis of N -Boc-azocan-5-one

Article abstract of DOI:10.1055/s-0037-1611018

The azacycloalkane 1-azocan-5-one is embedded in the structure of several products of natural origin displaying a variety of bioactivities. Two convenient and straightforward routes were developed to synthesize N -Boc-azocan-5-one from readily available raw materials featuring a ring-closing metathesis (RCM) reaction as the key step.

Full text of DOI:10.1055/s-0037-1611018

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
psp
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en
M. Morales-Chamorro, A. Vázquez
PSP
Synthesis
A Facile Synthesis of N-Boc-azocan-5-one
Maricela Morales-Chamorro
Br
Alfredo Vázquez*
1.
1.
MgBr
Br
BocHN
O
2. Weinreb amide
2.
Facultad de Química, Universidad Nacional Autónoma de México,
Circuito Interior S/N, Ciudad Universitaria 04510, CDMX, México
joseavm@unam.mx
BocN
O
3. RCM
4. H2, Pd/C
3.
MgBr
N
HO
O
Boc
4. RCM
5. H2, Pd/C
60%
70%
N-Boc-azocan-5-one
Received: 15.08.2018
Accepted after revision: 16.09.2018
Published online: 10.10.2018
DOI: 10.1055/s-0037-1611018; Art ID: ss-2018-m0548-psp
OH
O
O
N
OH
OH
O
HN
O
Abstract The azacycloalkane 1-azocan-5-one is embedded in the
structure of several products of natural origin displaying a variety of
bioactivities. Two convenient and straightforward routes were devel-
oped to synthesize N-Boc-azocan-5-one from readily available raw ma-
terials featuring a ring-closing metathesis (RCM) reaction as the key
step.
N
Me
Me
1-azocan-5-one (1)
otonecine (2)
licopladine H (3)
HN
Key words azocanone, nitrogen heterocycles, ring-closing metathe-
sis, synthesis
HO2C
N
N
O
pyrrolizidine (5)
1-Azocan-5-one (1) is a cyclic eight-membered amine
containing a keto group in its structure. This heterocyclic
compound is embedded in the molecular architecture of
some products of natural origin with potential medicinal
applications (Figure 1). For instance, the alkaloid otonecine
(2)1 exhibits remarkable hepatotoxic, and in some cases
carcinogenic properties; the recently discovered lycopla-
dine H (3),2 shows cytotoxicity against murine lymphoma
cells. Another example is actinophyllic acid (4),3 an alkaloid
isolated from the tree Alstonia actinophylla, which has re-
ceived attention for its complex structure and used to treat
cardiovascular disorders.4 1-Azocan-5-one has also been
used as a building block for the synthesis of the lycopodium
alkaloids, sieboldine A and alopecuridine,5 as well as race-
mic and enantioenriched (+)-actinophyllic acid.6–8 More-
over, 1-azocan-5-one (1) can be readily transformed into
pyrrolizidine (5),9 which is present in a wide variety of al-
kaloids. Accordingly, easy access to 1-azocan-5-one would
facilitate the preparation of compounds containing the pyr-
rolizidine motif.
OH
(–)-actinophyllic acid (4)
Figure 1 Examples of some products of natural origin containing the
cyclic amine 1-azocan-5-one (1) in their molecular structures and the
structure of pyrrolizidine (5)
and CC=O.
10,11 Scheme 1 contains the reported syntheses for
1-azocan-5-one (1). In 1955, Leonard10 reported the prepa-
ration of N-Me-1 in 20% yield using a Dieckmann ring clo-
sure approach. Starting from N-benzoylated octahydro-azo-
cine (8), Fonken12 obtained 1 via a microbial hydroxylation,
followed by Jones oxidation after a cumbersome purifica-
tion procedure. No yield is provided for 1. Treatment of
hexahydropyrrolizinium perchlorate (9) with NaOH was
used by Sumoto13 to afford 1 in 63% yield, although the
preparation of 9 might be a problem by itself. Following a
hydroboration–carbon monoxide insertion procedure,
Garst14 prepared a series of N-protected derivatives of 1 in
15–40% yield. A Tiffeneau–Demjanov reaction, followed by
decarboxylation has also been used to prepare 1 in 63%
yield starting from commercially available 11.5 Invoking the
transannular interaction between the N atom and the car-
Despite its deceptively simple structure, the preparation
of the unprotected form of 1 can be troublesome, as a con-
sequence of the known transannular interaction between N
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
M. Morales-Chamorro, A. Vázquez
PSP
Synthesis
Leonard (1955, ref 10): Dieckmann ring closure.
Tu (2011, ref 5): Tiffeneau–Demjanov, followed by decarboxylation.
t-BuOK
xylene
N2CHCOOEt
O
CO2Et
CO2Et
BF3·OEt2
N-Me-1
Et2O, –30 °C
135 °C
20%
N
N-Boc-1
N
Me
41%
Boc
7
11
Maldonado (2013, ref 6). Tedious purification procedure.
Fonken (1968, ref 12): microbial hydroxylation (2 steps).
Yield not reported.
O
1. o-NO2C6H4SO2NH2
2. steps
O
O
1. S. sulfurescens
2. CrO3
Cl
Cl
O
N-Bz-1
HN
ca 25%
N
12
13
Bz
8
Coldham (2014, ref 7): from pyrrolidone and γ-butyrolactone. Harsh reaction conditions.
Sumoto (1975, ref 13): treatment of
hexahydropyrrolizinium perchlorate with NaOH.
1. Na
2. γ-butyrolactone
3. soda lime dry
1. NaOH
2. ClCOOBn
O
ClO4
N-Cbz-1
N
Kugelrohr 80–300 °C
63%
N-Me-1
NH
9
4. aq K3PO4, toluene
CbzCl
14
34%
Garst (1982, ref 14): hydroboration-carbon monoxide
insertion.
This work: ring-closing metathesis followed by hydrogenation.
R
%
1. RCM
2. H2, Pd/C
O
BocN
"CO"
COOMe 20–31
N-R-1
N
Cbz
SO2Ph
15
40
BocN
N-Boc-1
R
15
10
O
Scheme 1 Reported synthesis for N-protected 1-azocan-5-one (1) derivatives and proposed synthesis in this work
bonyl group of 1, Maldonado6 reported the low yielding
synthesis of the cyclic acetal of 1 (ca 25%). More recently, in
2014, Coldham7 was able to obtain N-Boc-1 from pyrroli-
done and γ-butyrolactone in 34% yield, albeit under harsh
reaction conditions. Herein we report two convenient and
straightforward routes to obtain N-Boc-1 starting either
from Boc-γ-aminobutyric acid (16) or N-Boc-pyrrolidine-2-
one (17) and using a ring-closing metathesis (RCM) reac-
tion as the critical step.
Our approach was based on two important consider-
ations. The first was the documented precedent of the tran-
sannular interaction between the N atom and the carbonyl
group of the azocanone.10,11 The second was the search for
simplicity and reproducibility of the procedure. An addi-
tional feature of our proposal is the possibility to perform
further transformations on intermediate 21 (see below
Scheme 3), which would expand the benefits of our proto-
col.
According to the strategy shown in Scheme 2, diene 15
would be prepared from commercially available N-Boc-γ-
aminobutyric acid (16) by N-allylation, followed by ketone
formation via the corresponding Weinreb amide. Similarly,
15 would be prepared by vinyl magnesium bromide addi-
tion onto N-Boc-pyrrolidinone (17), followed by trapping
the resulting intermediate with allyl bromide.
Thus, our work started with the reaction of 16 with allyl
bromide (NaH, THF) to afford the allylated acid15 as the sole
product (Scheme 3). Without further purification, the last
compound was transformed into the Weinreb amide 1816 in
89% yield (two steps). Treatment of 18 with vinylmagne-
sium bromide provided diene 15 in 91% yield (Route A).
With diene 15 available, we conducted exploratory experi-
ments for the RCM17 reaction using second-generation
Grubbs catalyst. When a mixture of diene 15 and the cata-
lyst was refluxed in CH2Cl2, we observed an incomplete re-
action and a low conversion into the desired product. Modi-
fication of the reaction time and temperature did not affect
the conversion of the process.
1. N-allylation
2. Weinreb amide
3. Grignard
BocHN
1. Grignard
2. N-allylation
BocN
The use of p-benzoquinone18 and titanium isopropox-
ide19 as additives to increase the efficiency of the RCM reac-
tion has been reported in the literature. Thus, when we
used the compounds mentioned before as additives for the
conversion of diene 15 into 1, we were delighted to observe
that with Ti(Oi-Pr)4 a total consumption of 15 was achieved,
and enone 26 as the only observable product by TLC and by
O
N
HO
16
O
Boc
17
O
15
Scheme 2 Synthetic strategy for diene 15
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
M. Morales-Chamorro, A. Vázquez
PSP
Synthesis
Route A
Br
1.
2. MeNH(OMe)·HCl
EDC, CH2Cl2, r.t.
BocN
OMe
N
BocN
MgBr
OH
BocHN
Me
THF, 0 °C
91%
89%
O
16
O
O
15
18
PCC
CH2Cl2
80%
Route B
MgBr
NHBoc
NaH, DMF
allyl bromide
NaBH4
MeOH
NHBoc
BocN
THF, 0 °C
O
N
97%
r.t.
98%
0 °C
86% (17 to 22)
Boc
OR
O
OR
19
17
20, R = H
22, R = TBS
23, R = H
94%
89%
21, R = TBS
Scheme 3 Synthesis of intermediate 15. Route A: from N-Boc-GABA 16; Route B: from N-Boc-pyrrolidone 17.
1H NMR of the crude reaction mixture. For characterization
purposes, 26 was isolated and subjected to catalytic hydro-
genation to provide N-Boc-1 in quantitative yield. Further
experiments revealed that performing RCM and hydrogena-
tion without isolation of enone 26 has a detrimental effect
on the reaction yield – 86% of yield for two steps (Scheme
4).
Unfortunately, when the RCM protocol was performed
on 22 (Scheme 4), the desired product 24 was obtained in
only 5% yield, along with isomerized diene 25 (39%) and un-
reacted starting material. Several experiments were con-
ducted to increase the yield of 24 but were unsuccessful.
Deprotection of 22 (BF3·OEt2, 89%) followed by oxidation of
alcohol 23 (PCC, CH2Cl2) fixed this problem and allowed us
to obtain diene 15 in 80% yield (Scheme 3). Transformation
of 22 into 15 without isolation of alcohol 23 proceeded in
71% yield.
It is worth mentioning that enone 26 may undergo con-
jugate addition with different nucleophiles, offering mani-
fold opportunities to increase structural complexity. Addi-
tionally, the presence of the easily removable protective
group on the nitrogen atom facilitates purification of the fi-
nal product and allows the possibility of performing or-
thogonal transformations on this molecule. All the interme-
diates and final product were satisfactorily characterized
(see the Supporting Information).
RCM
Grubbs II
OTBS
BocN
22
+
+
22
BocN
24 (5%)
Ti(Oi-Pr)4
CH2Cl2
25 (39%)
OTBS
RCM
Grubbs II
O
H2, Pd/C
quant
15
N-Boc-1
BocN
Ti(Oi-Pr)4
CH2Cl2
26
97%
Scheme 4 Ring-closing metathesis of 22 and 15
For the second route (Route B, Scheme 3), the addition
of vinylmagnesium bromide to N-Boc-pyrrolidone (17) pro-
vided the corresponding ketone 19 as the only isolated
product in 97% yield. Attempts to allylate 19 using K2CO3 or
NaHCO3 as the base resulted in the unreacted starting ma-
terial. The use of a stronger base such as NaH or t-BuOK fa-
vored the intramolecular attack of the nitrogen anion at the
carbonyl group of the enone moiety, rather than the inter-
molecular allylation process. This inconvenience was solved
reducing enone 19 (NaBH4, MeOH) to give alcohol 20 in 98%
yield. Protection of 20 (TBSCl, imidazole, CH2Cl2) afforded
the TBS protected allylic alcohol 21 in 94% yield. Since the
previously mentioned reactions yielded only the desired
products, we decided to carry out the conversion of 17 into
22 using the corresponding crude products. Thus, 22 was
obtained in 86% isolated yield over four steps.
In conclusion, we have developed two simple and repro-
ducible routes for the preparation of N-Boc-azocan-1-one
starting from inexpensive and readily available raw materi-
als namely 4-(tert-butoxycarbonylamino)butyric acid and
1-(tert-butoxycarbonyl)-2-pyrrolidinone. The first synthet-
ic route provides 1 with a global yield of 70% and the second
one in 60% overall yield. We believe that our synthetic pro-
tocol can be of use for the synthesis of bioactive products
containing the 1-azocan-5-one (1) motif.
Anhydrous solvents were obtained by distillation under inert atmo-
sphere. Column chromatography was performed using 230–400 mesh
silica gel. All reagents were obtained from commercial suppliers and
used without further purification. All compounds were characterized
by ATR 400-4000 ST-IR-spectrophotometer (PerkinElmer), and all
data are expressed in wave numbers (cm–1) and signals are described
according to their intensities as weak (w), medium (m) or strong (s).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
M. Morales-Chamorro, A. Vázquez
PSP
Synthesis
1H and 13C NMR spectra were recorded using a Jeol Eclipse (300MHz),
Bruker Avance III (400 MHz) and Bruker Avance III HD (500 MHz) us-
ing appropriate deuterated solvents. Chemical shifts are in parts per
million (δ, ppm), relative to TMS. Mass spectra were obtained by di-
rect analysis in real time (DART) in a JEOL AccuTOF JMS-T100LC with
TOF mass.
sphere. After the addition was completed, the stirring was continued
at 0 °C for 1 h. Then, the reaction was quenched by the slow addition
of sat. aq NH4Cl (1 mL), diluted with H2O (25 mL), and the organic sol-
vent was evaporated. The aqueous layer was extracted with CH2Cl2 (3
× 25 mL), the combined organic layers were dried (anhyd Na2SO4), and
concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, 20% EtOAc/hexanes) to provide 160 mg of 15
(91%) as a colorless oil.
4-[Allyl(tert-butoxycarbonyl)amino]butanoic Acid (16)
IR (ATR): 2975 (m), 2931 (m), 1684 (s), 1462 (m), 1406 (s), 1365 (s),
Prepared according to a literature method.[15] Purification by column
chromatography (silica gel, gradient 30 to 50% EtOAc/hexanes); 87%
yield as a colorless oil.
1246 (s), 1159 (s), 987 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.36–6.18 (m, 2 H), 5.83–5.73 (m, 2 H),
5.10 (d, J = 12.5 Hz, 2 H), 3.79 (br s, 2 H), 3.22 (s, 2 H), 2.59 (t, J = 7.5
Hz, 2 H), 1.83 (pent, J = 7.0 Hz, 2 H), 1.44 (s, 9 H).
IR (ATR): 3082 (s), 2976 (s), 2932 (s), 1735 (m), 1691 (s), 1665 (s),
1478 (m), 1466 (m), 1410 (s), 1366 (s), 1247 (s), 1158 (s), 1057 (w),
991 (w), 920 (w), 863 (w), 772 (w) cm–1
.
13C NMR (125 MHz, CDCl3). δ = 200.2, 155.7, 136.7, 134.2, 128.2,
1H NMR (400 MHz, CDCl3): δ = 9.91 (br s, 1 H), 5.69–5.76 (m, 1 H),
5.11 (m, 2 H), 3.77 (br s, 2 H), 3.21 (s, 2 H), 2.30 (t, J = 7.5 Hz, 2 H), 1.79
(pent, J = 7.0 Hz, 2 H), 1.41 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 178.5, 155.8, 134.0, 116.7, 80.0, 49.9,
45.7, 31.4, 28.4, 23.4.
116.2, 79.6, 49.7, 45.8, 36.5, 28.5, 22.4.
HRMS (DART): m/z [M + H]+ calcd for C14H24NO3: 254.1756; found:
254.1748.
From Alcohol 23: Pyridinium chlorochromate (0.88 g, 0.41 mmol) was
added to a solution of alcohol 23 (for the preparation of 23, see below;
70 mg, 0.27 mmol) in anhyd CH2Cl2 (2.7 mL) at r.t. The reaction mix-
ture was stirred for 1 h and then filtered on Celite. The solvent was
removed in vacuo and the crude product was purified by column
chromatography (silica gel, 10% EtOAc/hexanes) to give 15 (55 mg,
80%) as a colorless oil. The spectroscopic data are the same as the di-
ene prepared from the Weinreb amide 18 (see above).
HRMS (DART): m/z [M + H]+ calcd for C11H20NO3: 214.1443; found:
214.1441.
[3-(Methoxymethylcarbamoyl)propyl]carbamic Acid tert-Butyl
Ester (18)
A solution of the amino acid 16 (1 g, 4.92 mmol) in anhyd THF (25
mL) was added dropwise to a suspension of 60% NaH (0.984 g, 24.6
mmol) in THF (25 mL) at 0 °C under N2 atmosphere. After stirring the
resultant mixture for 30 min at 0 °C, allyl bromide (1.22 mL, 14.76
mmol) was added dropwise and the stirring continued at r.t. for 14 h.
The reaction mixture was cooled at 0 °C, quenched with H2O, and
washed with hexanes (2 × 50 mL). The aqueous layer was acidified
with aq 1 M HCl until pH 3 and the product extracted with EtOAc (3 ×
75 mL). The organic extracts were combined, dried (anhyd Na2SO4),
and concentrated in vacuo to afford the corresponding acid. Without
further purification, the carboxylic acid, was dissolved in anhyd
CH2Cl2 (43 mL), followed by the sequential addition of Et3N (3.04 mL,
21.78 mmol), DMAP (0.53 g, 4.35 mmol), N,O-dimethylhydroxyl-
amine hydrochloride (1.27 g, 13.02 mmol) and EDC·HCl (0.92 g, 4.80
mmol) at r.t. The resulting mixture was stirred overnight at r.t. under
N2 atmosphere and then diluted with CH2Cl2, and the organic layer
was washed with 5% citric acid, and sat. aq NaHCO3. The organic layer
was dried (anhyd Na2SO4) and evaporated under reduced pressure.
The crude product was purified by column chromatography (silica
gel, 30% EtOAc/hexanes) to give the Weinreb amide 18 (1.25 g, 89%) as
a colorless oil.
N-Boc-1
Second-generation Grubbs catalyst (17 mg, 0.02 mmol) was added to
a solution of diene 15 (102 mg, 0.40 mmol) and Ti(Oi-Pr)4 (24 μL, 0.08
mmol) in anhyd CH2Cl2 (16 mL) under N2 atmosphere. The resulting
mixture was refluxed for 14 h, cooled to r.t. and concentrated to dry-
ness under reduced pressure. The residue was dissolved in MeOH (3.9
mL), and then 10% Pd/C was added and the mixture stirred at r.t. un-
der H2 atmosphere (balloon) for 20 h. The mixture was filtered on
Celite and the solvent evaporated in vacuo. The crude product was
purified by column chromatography (silica gel, gradient 10 to 40%
EtOAc/hexanes) to give N-Boc-1 (79 mg, 86% over two steps) as a col-
orless oil.
IR (ATR): 3473 (s), 2978 (s), 2936 (s), 1741 (s), 1691 (s), 1447 (w),
1415 (m), 1366 (m), 1254 (s), 1162 (s), 1127 (s), 1087 (s), 1019 (s),
862 (w) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.34 (t, 6.0 Hz, 2 H), 3.24 (t, J = 5.6 Hz, 2
H), 2.38–2.33 (m, 4 H), 2.08 (ddd, J = 10.4, 9.2, 6.0 Hz, 4 H), 1.44 (s, 9
H).
13C NMR (100 MHz, CDCl3): δ = 214.0, 155.4, 80.2, 47.4, 46.9, 41.0,
39.3, 28.5, 27.9, 25.9.
HRMS (DART): m/z [M + H]+ calcd for C12H22NO3: 228.1599; found:
228.1602.
IR (ATR): 3505 (w), 2937 (s), 2935 (s), 1687 (s), 1667 (s), 1462 (m),
1408 (s), 1365 (s), 1245 (s), 1162 (s), 995 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.82–5.72 (m, 1 H), 5.13–5.09 (m, 2 H),
3.81 (br s, 2 H), 3.67 (br s, 3 H), 3.24 (br s, 2 H), 3.17 (s, 3 H), 2.41 (t, J =
7.2 Hz, 2 H), 1.83 (pent, J = 7.2 Hz, 2 H), 1.44 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 174.0, 155.7, 134.3, 116.6, 79.6, 61.3,
49.7, 46.1, 32.3, 29.2, 28.5, 23.4.
tert-Butyl (Z)-5-Oxo-3,4,5,8-tetrahydroazocine-1(2H)-carboxylate
(26)
This intermediate 26 formed in the preparation of N-Boc-1 (Scheme
4) was isolated for charaterization. Purification by column chroma-
tography (silica gel, hexanes/EtOAc/CH2Cl2, 4:1:5); 95% yield as a col-
orless oil.
HRMS (DART): m/z [M + H]+ calcd for C14H27N2O4: 287.1970; found:
287.1967.
tert-Butyl Allyl(4-oxohex-5-en-1-yl)carbamate (15)
IR (ATR): 3524 (w), 2974 (s), 2932 (s), 1693 (s), 1404 (s), 1366 (m),
1244 (s), 1152 (s), 1102 (m), 885 (w) cm–1
.
From Weinreb Amide 18: A 1.0 M solution of vinylmagnesium bromide
in THF (0.77 mL) was added dropwise to a solution of Weinreb amide
18 (200 mg, 0.70 mmol) in anhyd THF (7 mL) at 0 °C under N2 atmo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

E
M. Morales-Chamorro, A. Vázquez
PSP
Synthesis
1H NMR (500 MHz, CDCl3): δ (mixture of rotamers) = 5.98–5.92 (m, 1
H), 5.72 (dt, J = 12.0, 2.5 Hz, 1 H), 3.91 (d, J = 19.0 Hz, 2 H), 3.47 (br s, 2
H), 2.45–2.42 (m, 2 H), 2.07 (app pent, J = 6.0 Hz, 2 H), 1.44 (s, 5 H),
1.41 (s, 4 H).
13C NMR (125 MHz, CDCl3): δ (mixture of rotamers) = 208.0, 154.6,
135.4, 135.18, 126.7, 80.7, 80.5, 48.9, 48.6, 47.6, 42.3, 42.0, 28.4, 25.1,
24.4.
IR (ATR): 3371 (s), 3092 (w), 2980 (m), 2950 (m), 1709 (s), 1668 (s),
1532 (s), 1405 (w), 1364 (m), 1271 (s), 1248 (s), 1163 (s), 1006 (w),
980 (m), 1019 (s), 892 (w), 860 (m), 785 (m), 632 (m) cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.33 (dd, J = 17.4, 10.2 Hz, 1 H), 6.20
(dd, J = 17.7, 1.5 Hz, 1 H), 5.81 (dd, J = 10.2, 1.4 Hz, 1 H), 4.67 (br s, 1
H), 3.12 (dd, J = 13.2, 6.6 Hz, 2 H), 2.62 (t, J = 7.2 Hz, 2 H), 1.79 (pent,
J = 6.9 Hz, 2 H), 1.40 (s, 9 H).
HRMS (DART): m/z [M + H]+ calcd for C12H20NO3: 226.1443; found:
13C NMR (75 MHz, CDCl3): δ = 200.4, 156.0, 136.5, 128.3, 79.3, 40.1,
226.1443.
36.8, 28.5, 24.3.
HRMS (DART): m/z [M + H]+ calcd for C11H20NO3: 214.1443; found:
214.1441.
tert-Butyl Allyl{4-[(tert-butyldimethylsilyl)oxy]hex-5-en-1-yl}car-
bamate (22) (17 → 22, Scheme 3)
A 1.0 M solution of vinylmagnesium bromide in THF (11.8 mL, 11.8
mmol) was added dropwise to a solution of the Boc-pyrrolidone (17;
2.0 g, 10.80 mmol) in anhyd THF (108 mL) at 0 °C under N2 atmo-
sphere. The resultant mixture was stirred for 1 h at that temperature
and then quenched by adding sat. aq NH4Cl (1 mL) and diluted with
H2O (50 mL). The organic solvent was evaporated and the aqueous
layer extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were dried (anhyd Na2SO4) and the solvent was evaporated under re-
duced pressure to provide an oil. This was immediately dissolved in
MeOH (46 mL) and the solution cooled to 0 °C, followed by the addi-
tion of NaBH4 (0.89 g, 23.44 mmol). The mixture was stirred at r.t. for
45 min, concentrated in vacuo and the residual aqueous layer extract-
ed with CH2Cl2 (4 × 50 mL). The combined organic layers were dried
(anhyd Na2SO4) and the solvent was evaporated under reduced pres-
sure. The residue thus obtained was used without purification in the
next reaction. The alcohol was dissolved in anhyd CH2Cl2 (52 mL), fol-
lowed by the consecutive addition of imidazole (0.89 g, 1.31 mmol)
and tert-butyldimethylsilyl chloride (0.99 g, 0.65 mmol). The resul-
tant mixture was stirred overnight at r.t. and then diluted with H2O.
The product was extracted with CH2Cl2, the combined CH2Cl2 layers
were dried (anhyd Na2SO4), and the solvent was evaporated. The
crude amine was dissolved in anhyd DMF (14 mL), cooled at 0 °C, and
then 60% NaH, dispersion in mineral oil (1.12 g, 27.90 mmol) was
added in small portions. After stirring the mixture for 5 min at 0 °C,
allyl bromide (2.3 mL, 27.90 mmol) was slowly added to the suspen-
sion and the reaction was maintained to 0 °C for 30 min, and allowed
to warm to r.t. and stirred for 14 h. The reaction was quenched by the
addition of H2O (5 mL) and the product was extracted with hexanes (3
× 50 mL). The combined organic layers were dried (anhyd Na2SO4) and
concentrated in vacuo. Purification by column chromatography (silica
gel, 5% EtOAc/hexanes) provided 22 (3.0 g, 86%) as a colorless oil.
tert-Butyl (4-Hydroxyhex-5-en-1-yl)carbamate (20)
Purification by column chromatography (silica gel, 10% EtOAc/hex-
anes); 98% yield as a colorless oil.
IR (ATR): 3345 (s), 2976 (s), 2931 (s), 1685 (s), 1521 (s), 1453 (w),
1391 (w), 1365 (m), 1272 (m), 1250 (m), 1167 (s), 989 (m), 920 (w)
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 5.84–5.76 (m, 1 H), 5.17 (d, J = 17.2 Hz,
1 H), 5.04 (d, J = 10.4 Hz, 1 H), 4.77 (br s, 1 H), 4.06 (br s, 1 H), 3.09 (br
s, 2 H), 1.50 (br s, 4 H), 1.38 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 156.0, 141.2, 114.6, 79.1, 72.6, 40.4,
34.0, 28.5, 26.0.
HRMS (DART): m/z [M + H]+ calcd for C11H22NO3: 216.1599; found:
216.1592.
tert-Butyl {4-[(tert-Butyldimethylsilyl)oxy]hex-5-en-1-yl}carba-
mate (21)
Purification by column chromatography (silica gel, 20% EtOAc/hex-
anes); 94% yield as pale yellow oil.
IR (ATR): 3352 (s), 2955 (s), 2929 (s), 2857 (s), 1691 (s), 1513 (s), 1472
(m), 1364 (s), 1250 (s), 1171 (s), 1065 (w), 1026 (w), 834 (s), 773 (s),
661 (w) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.77 (ddd, J = 17.2, 10.4, 6.0 Hz, 1 H),
5.14 (dt, J = 17.2, 1.6 Hz, 1 H), 5.03 (dt, J = 10.4, 1.2 Hz, 1 H), 4.55 (br s,
1 H), 3.10 (br s, 2 H), 1.52–1.46 (m, 4 H), 1.44 (s, 9 H), 0.89 (s, 9 H),
0.05 (s, 3 H), 0.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.1, 141.5, 114.1, 79.0, 73.3, 40.5,
35.1, 33.5, 28.4, 25.9 25.5, –4.4, –4.5.
HRMS (DART): m/z [M + H]+ calcd for C17H36NO3Si: 330.2464; found:
330.2460.
IR (ATR): 3080 (w), 2956 (s), 2929 (s), 2857 (s), 1695 (s), 1462 (s),
1408 (s), 1365 (s), 1248 (s), 1170 (s), 1150 (s), 1081 (m), 919 (m), 834
(s), 773 (s) cm–1
.
tert-Butyl Allyl(4-hydroxyhex-5-en-1-yl)carbamate (23)
1H NMR (500 MHz, CDCl3): δ = 5.79–5.72 (m, 2 H), 5.13–5.06 (m, 3 H),
4.99 (d, J = 10.5 Hz, 1 H), 4.06–4.09 (m, 1 H), 3.78 (br s, 2 H), 3.14 (br s,
2 H), 1.59–1.34 (m, 4 H), 1.42 (s, 9 H), 0.87 (s, 9 H), 0.021 (s, 3 H),
0.002 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 155.6, 141.6, 134.5, 116.3, 113.8, 79.4,
73.6, 49.5, 46.6, 35.3, 29.8, 28.5, 26.0, 18.3, 4.3, 4.7.
BF3·OEt2 (0.17 mL, 1.35 mmol) was added dropwise to a solution of 22
(200 mg, 0.54 mmol) in anhyd CH2Cl2 (5.4 mL) under N2 atmosphere
at r.t. The resultant mixture was stirred for 1 h at that temperature
and the reaction was quenched by the addition of H2O (1 mL), diluted
with H2O (50 mL). The product was extracted with CH2Cl2 (3 × 50 mL),
the combined organic layers were dried (anhyd Na2SO4), and the sol-
vent was evaporated under reduced pressure. The residue was puri-
fied by column chromatography (silica gel, 20% EtOAc/hexanes) to
give 23 (122 mg, 89%) as a colorless oil.
HRMS (DART): m/z [M + H]+ calcd for C20H40NO3Si: 370.2770; found:
370.2777.
IR (ATR): 3438 (s), 3080 (w), 2975 (s), 2930 (s), 2870 (w), 1671 (s),
1456 (m), 1410 (s), 1365 (s), 1247 (s), 1163 (s), 991 (m), 916 (m), 872
Characterization of Intermediates 19–21 (Scheme 3)
(w), 772 (w) cm–1
.
tert-Butyl (4-Oxohex-5-en-1-yl)carbamate (19)
Purification by column chromatography (silica gel, 20% EtOAc/hex-
anes); 97% yield as a colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
M. Morales-Chamorro, A. Vázquez
PSP
Synthesis
1H NMR (500 MHz, CDCl3): δ = 5.83 (ddd, J = 17.0, 10.5, 6.0 Hz, 1 H),
5.74–5.6 (m, 1 H), 5.21 (dt, J = 17.2, 1.5 Hz, 1 H), 5.09 (d, J = 11.5 Hz, 3
H), 4.11 (br s, 1 H), 3.77 (br s, 2 H), 3.16 (br s, 2 H), 1.64–1.54 (m, 2 H),
1.50–1.46 (m, 2 H), 1.43 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 155.8, 141.2, 134.4, 116.2, 114.6, 79.6,
72.9, 49.8, 46.4, 34.0, 28.5, 24.2.
(2) (a) Ishiuchi, K.; Kubota, T.; Hayashi, S.; Shibata, T.; Kobayashi, J.
Tetrahedron Lett. 2009, 50, 6534. (b) Sacher, J. R.; Weinreb, S. M.
Org. Lett. 2012, 14, 2172.
(3) Carroll, A. R.; Hyde, E.; Smith, J.; Quinn, R. J.; Guymer, G.;
Forster, P. I. J. Org. Chem. 2005, 70, 1096.
(4) Schatteman, K.; Goossens, F. J.; Leurs, J.; Kasahara, Y.; Scharpe,
S. S.; Hendriks, D. F. Clin. Chem. Lab. Med. 2001, 39, 806.
(5) Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X. Angew.
Chem. Int. Ed. 2011, 50, 3916.
HRMS (DART): m/z [M + H]+ calcd for C14H26NO3: 256.1912; found:
256.1909.
(6) Zaragoza Galicia, I.; Maldonado, L. A. Tetrahedron Lett. 2013, 54,
2180.
(7) Mortimer, D.; Whiting, M.; Harrity, J. P. A.; Jones, S.; Coldham, I.
Tetrahedron Lett. 2014, 55, 1255.
(8) Xue, F.; Xiao, T.; Li, M.; Zhang, K.-F.; He, L.-P.; Qin, Y.; Liu, X.-Y.;
Zhang, D. Tetrahedron 2017, 73, 2109.
Funding Information
Facultad de Química, UNAM. Grant PAIP 5000-9062.
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Acknowledgment
We would like to thank Maricela Gutierrez (USAII-FQ-UNAM) for re-
cording the IR spectra. M. M-C. thanks UNAM-Facultad de Química
PostDoctoral Scholarship Program.
(13) Sumoto, K.; Ibu, N.; Irie, M.; Abe, N.; Miyano, S. Chem. Pharm.
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Supporting Information
Supporting information for this article is available online at
(15) Knipp, R. J.; Estrada, R.; Sethu, P.; Nantz, M. H. Tetrahedron 2014,
70, 3422.
https://doi.org/10.1055/s-0037-1611018.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F