One-Pot Synthesis of α-Amino Acids through Carboxylation of Ammonium Ylides with CO2 Followed by Alkyl Migration

Article abstract of DOI:10.1021/acs.joc.6b00837

A simple, yet powerful protocol for α-amino acid synthesis using carbon dioxide (CO₂) was developed. α-Amino silanes could undergo four successive reactions (formation of ammonium salt, carboxylation, esterification, and 2,3- or 1,2-Stevens rearrangement) in the presence of allylic or benzylic halides under a CO₂ atmosphere (1 atm). It is noteworthy that carboxylation at the position adjacent to a nitrogen atom proceeded via an ammonium ylide intermediate under mild conditions.

Full text of DOI:10.1021/acs.joc.6b00837

Note
pubs.acs.org/joc
One-Pot Synthesis of α‑Amino Acids through Carboxylation of
Ammonium Ylides with CO2 Followed by Alkyl Migration
Tsuyoshi Mita,* Masumi Sugawara, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: A simple, yet powerful protocol for α-amino
acid synthesis using carbon dioxide (CO2) was developed. α-
Amino silanes could undergo four successive reactions
(formation of ammonium salt, carboxylation, esterification,
and 2,3- or 1,2-Stevens rearrangement) in the presence of
allylic or benzylic halides under a CO2 atmosphere (1 atm). It
is noteworthy that carboxylation at the position adjacent to a
nitrogen atom proceeded via an ammonium ylide intermediate
under mild conditions.
n α-amino carbanion is a synthetically useful intermediate
for preparing α-substituted amino compounds such as
A
amino acids, amino alcohols, and diamines. Since the α-
hydrogen of amine derivatives is not acidic enough, the
generation of an α-amino carbanion necessitated highly basic
conditions in classical organic chemistry: (1) deprotonation of
α-hydrogen of amine derivatives with a powerful base such as
n-, s-, or t-BuLi;1 (2) transmetalation of α-amino stannanes with
organolithium (Sn−Li exchange);1 and (3) reductive gener-
ation from imine equivalents with alkali metals or SmI2.2 In the
former two cases, a chelating carbonyl group for a lithium
cation (Boc, oxazolidinone, etc.) was introduced on the
nitrogen atom to assist the event. In contrast, α-amino
carbanions can also be accessed by treatment of α-amino
silanes with a fluoride ion.3 These desilylative methods require
neither toxic stannane reagents nor strong reductants. More-
over, carbanion formation can proceed under almost neutral
conditions. Therefore, the desilylative substitution would have
great potential for the synthesis of a variety of amine
compounds.
Figure 1. Our new strategy for carboxylation.
shown that ammonium ylide can be generated even without the
assistance of the carbonyl group and charge delocalization by π-
conjugation. In 1979, Vedejs and co-workers developed a
method for the generation of ammonium ylides using tertiary
amines with TMSCH2OTf followed by treatment of CsF.6a
This method has advantages over the use of organolithium
reagents7 including (1) regioselective generation of ylides from
the corresponding ammonium salts and (2) high functional
group tolerability under mild conditions. There were several
reports with regard to intramolecular rearrangements6 and ring
expansion reactions.8 However, reactions of ammonium ylides
generated in this manner with carbonyl compounds have been
limited, and only the reaction with aldehydes was reported.9 If
this species can react with CO2 selectively with suppression of
rearrangement/ring expansion, the framework of an α-amino
acid would be created.
Our synthetic plan for α-alkylated α-amino acids is shown in
Scheme 1. α-Amino silane, which is prepared from an amine
and TMSCH2Cl, is alkylated with an allylic halide to form an
ammonium salt. A fluoride ion such as CsF would then
promote the formation of ammonium ylide followed by
carboxylation with CO2, affording ammonium carboxylate. It
would undergo 2,3-allylic rearrangement (2,3-Stevens rear-
rangement10,11) in the presence of an appropriate base after
We have already developed desilylative carboxylation of α-
amino silanes with CO2,4 an abundant, inexpensive, and
relatively nontoxic C1 source,5 to synthesize α-amino acids.
Taking advantage of the accessibility of N-Boc-α-amino silanes
from N-Boc-imines by silylation, we also developed a novel
one-pot procedure for the synthesis of α-amino acids from
imine precursors, α-amino sulfones. However, this carbox-
ylation with CO2 limitedly proceeded at the benzylic and allylic
positions, so that only phenyl and alkenyl glycine derivatives
were able to be prepared (Figure 1A). Thereby, we next turned
our attention to how to prepare α-alkylated amino acids. In
order to realize fast and quantitative generation of an α-
carbanion without an α-substituent for delocalizing the
resultant anion, we considered employing ammonium ylide
derived from a silylmethyltrialkylammonium salt (Figure 1B).
Desilylative formation of ammonium ylide and its applications
have been widely studied by several research groups, and it was
Received: April 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00837
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
consumed even without CsF, but intermediate A depicted in
Scheme 3 was obtained quantitatively (entry 7). This result
suggested that the iodide ion of TBAI was not involved in
silane activation. The addition of a catalytic amount of TBAI or
a stoichiometric amount of tetrabutylammonium bromide
(TBAB) instead of TBAI was not effective (entries 8 and 9).
According to these results, TBAI is thought to be a
stoichiometric iodide source to form β-methallyl iodide in
situ, rather than either a silane activator or a phase transfer
catalyst. Furthermore, the combination with TBAI actually
worked well for less reactive β-methallyl chloride and tosylate
(entries 10 vs 11 and entries 12 vs 13).
Scheme 1. Plan for the Synthesis of α-Alkylated α-Amino
Acids
With the optimal conditions in hand, we then investigated
the substrate scope for allylic halides (Figure 2). The use of β-
substituted and nonsubstituted allylic halides gave 4a−c in
good yields. The reaction with allyl bromide was readily
scalable, and the product 4c was obtained with 2.2 g (10
mmol). α-Amino acids 4d and 4e were obtained in high yields
with 1:1 dr from γ-monosubstituted allylic chloride and
bromide. γ-Disubstituted and fully substituted allylic bromides
were also applicable, affording 4f−h in good yields. The
different substitution pattern between the ester moieties and
the α-alkyl groups in 4d−h indicated that α-alkylation should
occur via 2,3-Stevens rearrangement. Moreover, benzylic
halides were also active in this one-pot carboxylation. When
benzyl bromide and benzyl chlorides with an electron-donating
substituent at the para-position were employed, 1,2-Stevens
rearrangement products 4i−k were selectively obtained in
moderate yields. In contrast, when p-bromobenzyl bromide was
used, the migration pattern was changed to 2,3-allylic
rearrangement (Sommelet−Hauser rearrangement10,11), afford-
ing 4l as a major product.11a Furthermore, one-pot reactions
with 1-naphthylmethyl chloride and 2-naphthylmethyl bromide
also selectively promoted Sommelet−Hauser rearrangement to
afford 4m and 4n in good yields. Sommelet−Hauser rearrange-
ment is comprised of 2,3-allylic rearrangement and the
following rearomatization. Depending on substrate structures,
however, an isotoluene intermediate was sometimes obtained
ahead of rearomatization as a stable product.6c,12 Sato and co-
workers demonstrated that rearomatization of the isotoluene
intermediate was facilitated by DBU.6e According to their
report, after completion of the reactions of p-bromobenzyl
bromide and 2-naphthylmethyl bromide, the resulting mixtures
were treated with 5 equiv of DBU to afford the products 4l and
4n in 52% and 57% yield, respectively.
To obtain information about the reaction course, we first
conducted carboxylation in the absence of allylic halide
(Scheme 2a). The substrate was completely recovered at
room temperature. Even when the reaction was conducted at a
high temperature (150 °C, in NMP), 5 was obtained only in
26% yield after esterification. This result clearly indicated that
the formation of ammonium ylide was inevitable for
carboxylation with CO2. Next, potential intermediates (A, B,
and C) in this one-pot reaction were prepared and subjected to
the reaction conditions (Schemes 2b−d). In all cases, α-amino
acid 4a was obtained in yields comparable to that of the one-
pot reaction (83% yield). Furthermore, 2,3-Stevens rearrange-
ment of B did not proceed in the absence of allylic halide,
suggesting that esterification is indispensable for the following
base-induced alkyl migration (Scheme 2e).
esterification with allylic halide. If the base-induced 2,3-allylic
rearrangements of ammonium ester can be mediated by the
fluoride as well, all steps would be carried out in a single flask as
a one-pot operation.
To determine the feasibility of the planned one-pot α-amino
acid synthesis, α-amino silane 1 was treated with β-methallyl
iodide (2.2 equiv) and CsF (5 equiv) in DMF at 0 °C for 24 h
under CO2 (1 atm: balloon). The desired one-pot reaction
actually proceeded to afford the corresponding α-amino ester
4a in 60% yield (Table 1, entry 1). The use of β-methallyl
Table 1. Condition Screening
a
entry
temp (°C)
X
additive
yield (%)
1
2
3
4
5
0
0
0
0
0
0
0
0
0
rt
rt
rt
rt
I (2aa)
−
−
NaI
60
Br (2ab)
40
Br
0
Br
KI
34
Br
TBAI
TBAI
TBAI
TBAI
TBAB
−
73 (66)
(83)
0
b
6
Br
c
7
d
Br
8
Br
46
9
Br
32
10
11
12
13
Cl (2ac)
Cl
0
TBAI
43
OTs (2ad)
−
TBAI
32
OTs
70
a
Yields were determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as an internal standard. Isolated yields are given
b
c
d
in parentheses. Conducted in 5 mmol scale. Without CsF. 20 mol
% of TBAI was added.
bromide instead of the iodide decreased the yield to some
extent (entry 2). We then attempted in situ generation of the
reactive β-methallyl iodide by adding an iodide salt. Although
the yields did not improve with alkali metal iodides (entries 3
and 4), tetrabutylammonium iodide (TBAI) greatly accelerated
the reaction, affording the desired product in 73% yield (entry
5). A larger-scale synthesis (5 mmol) improved the yield to
83% (entry 6). To confirm the role of TBAI, several reaction
conditions were investigated. The substrate 1 was completely
Based on the above experimental data, we propose a
reasonable reaction mechanism for the one-pot α-amino acid
synthesis from α-amino silane and CO2 (Scheme 3). The
B
DOI: 10.1021/acs.joc.6b00837
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The Journal of Organic Chemistry
Note
Figure 2. Substrate scope for α-amino acid synthesis (0.2 mmol scale). Isolated yields are shown unless otherwise noted. a Conducted in 5 mmol
c
1
scale. b Without TBAI. Conducted in 10 mmol scale for 4c. d Determined by H NMR. Isolated yield was 38%.
Scheme 2. Mechanistic Studies
Scheme 3. Proposed Reaction Pathway
reaction is initiated by the formation of ammonium salt A from
α-amino silane 1 and allylic halide followed by fluoride-
mediated silane activation to generate ammonium ylide 3.
Carboxylation then takes place to give zwitterionic ammonium
carboxylate B, which is esterified by an excess amount of allylic
halide to form ammonium ester C. Finally, base-promoted 2,3-
Stevens rearrangement of C occurs to afford the target α-amino
acid 4. In this reaction sequence, CsF functions as both a silane
activator and a base to promote the formation of ammonium
ylides (the former: unstable ylide 3 to react with CO2; the
latter: stable ylide to undergo allylic rearrangement). TBAI
C
DOI: 10.1021/acs.joc.6b00837
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Note
by silica gel column chromatography (hexane/AcOEt, 5/1 to 2/1) to
afford α-amino silane 1 (2.0 g, 8.7 mmol, 87% yield) as a colorless oil.
8-((Trimethylsilyl)methyl)-1,4-dioxa-8-azaspiro[4.5]decane (1). IR
(neat): 2953, 2881, 2796, 1363, 1303, 1248, 1140, 1092, 1041, 850
should accelerate both the formation of ammonium salt and
esterification by halide exchange with less reactive allylic
compounds (Cl, Br, and OTs). Notably, four successive
reactions proceeded in a single flask as a one-pot operation.
Considering the synthetic utility of the products, the removal
of the protecting group was demonstrated (Scheme 4). Carreira
1
cm−1; H NMR (500 MHz, CDCl3) δ = 3.91 (s, 4H), 2.52−2.36 (m,
4H), 1.91 (s, 2H), 1.74−1.63 (m, 4H), 0.03 (s, 9H) ppm; 13C NMR
(125 MHz, CDCl3) δ = 106.9, 64.1, 55.2, 50.3, 35.0, −1.3 ppm;
HRMS (EI) m/z calcd for C11H23O2NSi [M]+: 229.1498. Found:
229.1491.
Scheme 4. Removal of the Protecting Group
Supply of Allylic and Benzylic Halides. Allylic halides 2aa,14
2b,15 2g,16 and 2h17 were prepared according to the reported methods.
Allylic tosylate 2ad was prepared from 3-chloro-2-methylpropene
using the reported method.18 The NMR data for 2ad were identical to
those for the reported product.19 Other allylic/benzylic halides are
commercially available.
General Procedure of One-Pot Synthesis of α-Amino Acids.
A test tube was charged with CsF (151.9 mg, 1.0 mmol, 5 equiv),
which was dried with a heat gun for 2 min under vacuum (<5 mmHg
at ca. 400 °C). After the displacement with CO2 gas, TBAI (162.5 mg,
0.44 mmol, 2.2 equiv) was added followed by α-amino silane 1 (45.9
mg, 0.20 mmol) in DMF (1 mL, 0.2 M). After the reaction mixture
was cooled to 0 °C, 3-bromo-2-methyl-1-propene 2ab (45 μL, 0.44
mmol, 2.2 equiv) was added and the solution was stirred for 24 h at
the same temperature. The reaction was quenched by the addition of
water. The product was extracted with AcOEt three times, washed
with water followed by brine and then dried over Na2SO4. The solvent
was evaporated under reduced pressure. The yield was determined by
1H NMR at this stage using 1,3,5-trimethoxybenzene (δ = 6.1 ppm in
CDCl3, 3H) as an internal standard (73%). The crude product was
purified by silica gel column chromatography (hexane/AcOEt, 5/1 to
2/1) to afford 4a (40.8 mg, 131.9 mmol, 66% yield) as a colorless oil.
2-Methylallyl 4-Methyl-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-
pent-4-enoate (4a). Colorless oil (5 mmol scale in 0.4 M DMF,
1.29 g, 4.16 mmol, 83% yield); IR (neat): 3078, 2958, 2881, 1733,
1651, 1442, 1162, 1092, 1039, 910 cm−1; 1H NMR (500 MHz,
CDCl3) δ = 5.00 (s, 1H), 4.93 (s, 1H), 4.77 (s, 1H), 4.73 (s, 1H), 4.51
(s, 2H), 3.93 (s, 4H), 3.48 (dd, J = 9.3, 5.9 Hz, 1H), 2.80−2.71 (m,
2H), 2.70−2.62 (m, 2H), 2.54 (dd, J = 14.2, 9.3 Hz, 1H), 2.35 (dd, J =
14.2, 5.9 Hz, 1H), 1.78−1.64 (m, 10H) ppm; 13C NMR (125 MHz,
CDCl3) δ = 171.3, 141.9, 139.8, 113.3, 112.6, 107.2, 67.4, 65.9, 64.2,
47.5, 37.7, 35.4, 22.4, 19.6 ppm; HRMS (EI) m/z calcd for
C17H27O4N [M]+: 309.1940. Found: 309.1937.
and co-workers reported the removal of 4-piperidone by using
aminomethylated polystyrene resin to afford the corresponding
primary amine.13 According to their report, we then
investigated deprotection of the piperidone acetal moiety of
compounds 4c (R1 = allyl) and 4j (R1 = p-methylbenzyl).
Acidic hydrolysis of acetal moieties gave 6c and 6j in nearly
quantitative yields. Saponification of the ester was conducted
followed by heating with the basic resin in the presence of
NH4Cl in EtOH. The transfer alkylation cleanly proceeded, and
the unprotected α-amino acids 7c and 7j were obtained in 91%
and 85% yields, respectively, in two steps after purification
using acidic ion-exchange column chromatography (Dowex
50W-X2).
In summary, we have developed a simple but powerful
method for α-amino acid synthesis with CO2. The reaction
cascade consists of four consecutive transformations (formation
of ammonium salt, carboxylation, esterification, and alkyl
migration). Various substituted allylic halides and benzylic
halides can be used to afford α-alkylated α-amino acid
derivatives.
2-Phenylallyl 4-Phenyl-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-
pent-4-enoate (4b). Colorless oil (0.2 mmol scale, 53.7 mg, 123.9
μmol, 62% yield); IR (neat): 3056, 2956, 1732, 1634, 1496, 1316,
1
1161, 1089, 909, 778 cm−1; H NMR (500 MHz, CDCl3) δ = 7.43−
7.38 (m, 2H), 7.36−7.22 (m, 8H), 5.53 (s, 1H), 5.34 (s, 1H), 5.19 (s,
1H), 5.04 (s, 1H), 4.99 (d, J = 13.8 Hz, 1H), 4.93 (d, J = 13.8 Hz, 1H),
3.92 (s, 4H), 3.32 (dd, J = 9.1, 6.1 Hz, 1H), 2.92 (dd, J = 14.3, 9.1 Hz,
1H), 2.83 (dd, J = 14.3, 6.1 Hz, 1H), 2.72−2.62 (m, 2H), 2.61−2.48
(m, 2H), 1.70−1.50 (m, 4H) ppm; 13C NMR (125 MHz, CDCl3) δ =
171.2, 145.1, 142.5, 140.7, 138.0, 128.4, 127.9, 127.4, 126.3, 126.1,
115.6, 115.0, 107.1, 66.0, 65.4, 64.1, 47.4, 35.5, 35.2 ppm; HRMS (EI)
m/z calcd for C27H31O4N [M]+: 433.2253. Found: 433.2244.
EXPERIMENTAL SECTION
■
General. NMR spectra were recorded on 500 MHz (1H) and 125
MHz (13C) instruments. Chemical shifts were reported in the scale
relative to CHCl3 (7.26 ppm), C6D6 (7.16 ppm), acetone-d6 (2.05
ppm), and D2O (4.79 ppm) for 1H NMR and to CDCl3 (77.00 ppm),
C6D6 (128.06 ppm), and acetone-d6 (206.26 ppm) for 13C NMR as
internal references. For D2O, chemical shifts were reported in the scale
relative to CH3OH (49.50 ppm) for 13C NMR as an external standard.
High-resolution mass spectra were obtained with EI-HRMS (TOF)
and ESI-HRMS (orbitrap) instruments. Column chromatography was
performed with neutral silica gel (40−50 μm). In general, all
manipulations were performed under an argon atmosphere unless
otherwise stated. Dry DMF was purified under argon using a solvent
purification system.
Allyl 2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)pent-4-enoate (4c).
Yellow oil (10 mmol of allyl bromide 2c were used in 0.4 M DMF,
2.24 g, 8.0 mmol, 80% yield); IR (neat): 3079, 2956, 2833, 1732, 1643,
1
1364, 1166, 1088, 1039, 914 cm−1; H NMR (500 MHz, CDCl3) δ =
5.97−5.87 (m, 1H), 5.83−5.72 (m, 1H), 5.33 (d, J = 16.9 Hz, 1H),
5.23 (d, J = 10.3 Hz, 1H), 5.09 (d, J = 16.9 Hz, 1H), 5.04 (d, J = 10.3
Hz, 1H), 4.61 (d, J = 5.5 Hz, 1H), 3.93 (s, 4H), 3.31 (dd, J = 8.5, 6.5
Hz, 1H), 2.77−2.70 (m, 2H), 2.68−2.61 (m, 2H), 2.57−2.48 (m, 1H),
2.46−2.37 (m, 1H), 1.78−1.65 (m, 4H) ppm; 13C NMR (125 MHz,
CDCl3) δ = 171.1, 134.3, 132.2, 118.3, 117.2, 107.1, 67.2, 64.8, 64.1,
47.6, 35.3, 33.9 ppm; HRMS (EI) m/z calcd for C12H18O4N [M-
(CH2CHCH2)]+: 240.1236. Found: 240.1236.
Synthesis of α-Amino Silane 1. In a round-bottom flask, 1,4-
dioxa-8-azaspiro[4.5]decane (1.3 mL, 10 mmol), chloromethyl-
trimethylsilane (1.7 mL, 11 mmol, 1.1 equiv), potassium carbonate
(1.5 g, 11 mmol, 1.1 equiv), and potassium iodide (3.0 g, 18 mmol, 1.8
equiv) in DMF (10 mL, 1.0 M) were stirred for 5 h at 80 °C. Water
was added to quench the reaction. The product was extracted with
AcOEt three times, and the combined organic layer was washed with
water followed by brine and then dried over Na2SO4. After the solvent
was removed under reduced pressure, the crude product was purified
(E)-But-2-en-1-yl 3-Methyl-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-
yl)pent-4-enoate (4d). Colorless oil (0.2 mmol scale, 51.3 mg,
165.8 μmol, 83% yield with 1:1 dr); IR (neat): 3078, 2959, 2880, 1729,
1456, 1340, 1224, 1146, 1088, 966 cm−1; 1H NMR (diastereomixture:
D
DOI: 10.1021/acs.joc.6b00837
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Note
1
500 MHz, CDCl3) δ = 5.86−5.71 (m, 3H), 5.65−5.50 (m, 3H), 5.06−
4.92 (m, 4H), 4.53 (d, J = 7.0 Hz, 2H), 4.48 (d, J = 7.0 Hz, 2H), 3.92
(s, 4H), 3.90 (s, 4H), 2.96 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz,
1H), 2.74−2.58 (m, 6H), 2.57−2.47 (m, 4H), 1.76−1.56 (m, 14H),
1.03 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H) ppm; 13C NMR
(diastereomixture: 125 MHz, CDCl3) δ = 170.6, 170.5, 141.0, 140.3,
131.4, 131.1, 125.3, 125.2, 115.6, 113.7, 107.32, 107.30, 72.5, 72.1,
64.6, 64.4, 64.11, 64.09, 47.3, 37.2, 36.6, 35.4, 17.74, 17.71, 17.4, 16.7
ppm; HRMS (EI) m/z calcd for C13H20O4N [M-(CH2CH
CHCH3)]+: 254.1392. Found: 254.1395.
1144, 1038, 911, 734 cm−1; H NMR (500 MHz, CDCl3) δ = 7.32−
7.14 (m, 10H), 5.08 (d, J = 12.0 Hz, 1H), 5.04 (d, J = 12.0 Hz, 1H),
3.95 (s, 4H), 3.55 (dd, J = 9.6, 5.7 Hz, 1H), 3.10 (dd, J = 13.4, 9.6 Hz,
1H), 2.97 (dd, J = 13.4, 5.7 Hz, 1H), 2.88−2.80 (m, 2H), 2.75−2.66
(m, 2H), 1.81−1.65 (m, 4H) ppm; 13C NMR (125 MHz, CDCl3) δ =
171.1, 138.0, 135.7, 129.2, 128.4, 128.3, 128.1, 126.3, 107.1, 69.4, 65.9,
64.2, 47.8, 35.8, 35.3 ppm; HRMS (EI) m/z calcd for C16H20O4N [M-
(CH2C6H5)]+: 290.1392. Found: 290.1391.
4-Methylbenzyl 2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)-3-(p-
tolyl)propanoate (4j). Colorless oil (5 mmol scale in 0.4 M DMF,
1.21 g, 2.95 mmol, 59% yield); IR (neat): 2956, 2881, 1732, 1517,
1159, 1088, 1040, 912, 805, 734 cm−1; 1H NMR (500 MHz, CDCl3) δ
= 7.13−7.01 (m, 8H), 5.03 (d, J = 12.0 Hz, 1H), 4.98 (d, J = 12.0 Hz,
1H), 3.95 (s, 4H), 3.50 (dd, J = 9.9, 5.8 Hz, 1H), 3.04 (dd, J = 13.2,
9.9 Hz, 1H), 2.92 (dd, J = 13.2, 5.8 Hz, 1H), 2.85−2.76 (m, 2H),
2.74−2.65 (m, 2H), 2.35 (s, 3H), 2.31 (s, 3H), 1.80−1.63 (m, 4H)
ppm; 13C NMR (125 MHz, CDCl3) δ = 171.3, 137.8, 135.7, 134.9,
132.7, 129.04, 129.03, 128.9, 128.3, 107.1, 69.5, 65.8, 64.1, 47.8, 35.4,
35.3, 21.2, 21.0 ppm; HRMS (EI) m/z calcd for C17H22O4N [M-
(CH2C6H4CH3)]+: 304.1549. Found: 304.1541.
Cinnamyl 3-Phenyl-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pent-
4-enoate (4e). White solids (0.2 mmol scale, 81.4 mg, 187.8 μmol,
94% yield with 1:1 dr); mp 98−100 °C; IR (neat): 3027, 2955, 2835,
1727, 1494, 1341, 1220, 1156, 1087, 917 cm−1
;
1H NMR
(diastereomixture: 500 MHz, C6D6) δ = 7.25 (d, J = 7.0 Hz, 2H),
7.21 (d, J = 7.0 Hz, 2H), 7.14−6.97 (m, 16H), 6.44 (d, J = 15.8 Hz,
1H), 6.29−6.11 (m, 3H), 6.01−5.91 (m, 1H), 5.80 (dt, J = 15.8, 6.3
Hz, 1H), 5.20 (d, J = 17.0 Hz, 1H), 5.05 (d, J = 10.3 Hz, 1H), 5.01 (d,
J = 10.3 Hz, 1H), 4.97 (d, J = 17.0 Hz, 1H), 4.73−4.63 (m, 2H), 4.37
(d, J = 6.0 Hz, 2H), 4.06−3.98 (m, 2H), 3.74 (d, J = 3.8 Hz, 1H), 3.72
(d, J = 3.8 Hz, 1H), 3.50 (s, 4H), 3.40 (s, 4H), 3.13−3.03 (m, 2H),
3.02−2.92 (m, 2H), 2.86−2.77 (m, 2H), 2.76−2.67 (m, 2H), 1.92−
1.65 (m, 4H), 1.61−1.51 (m, 2H), 1.49−1.39 (m, 2H) ppm; 13C
NMR (diastereomixture: 125 MHz, C6D6) δ = 169.9, 169.2, 141.5,
141.2, 139.7, 139.4, 136.9, 134.3, 133.8, 129.1, 128.82, 128.79, 128.57,
128.49, 128.3, 128.01, 127.97, 127.1, 127.02, 126.6, 124.0, 123.9,
116.7, 115.7, 107.6, 107.4, 72.3, 71.3, 64.7, 64.4, 64.2, 64.1, 50.0, 49.4,
48.0, 36.1, 35.8 ppm; HRMS (EI) m/z calcd for C18H22O4N [M-
(CH2CHCHC6H5)]+: 316.1549. Found: 316.1547.
4-Methoxybenzyl 3-(4-Methoxyphenyl)-2-(1,4-dioxa-8-azaspiro-
[4.5]decan-8-yl)propanoate (4k). White solids (0.2 mmol scale,
48.6 mg, 110.1 μmol, 55% yield); mp 62−64 °C; IR (neat): 2957,
2836, 1730, 1613, 1515, 1249, 1145, 1088, 1037, 912 cm−1; H NMR
1
(500 MHz, acetone-d6) δ = 7.18 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.0
Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 5.03 (d, J
= 13.0 Hz, 1H), 4.98 (d, J = 13.0 Hz, 1H), 3.89 (s, 4H), 3.79 (s, 3H),
3.76 (s, 3H), 3.54−3.39 (m, 1H), 2.98 (dd, J = 13.0, 9.5 Hz, 1H),
2.89−2.74 (m, 3H), 2.68−2.54 (m, 2H), 1.70−1.53 (m, 4H) ppm; 13C
NMR (125 MHz, acetone-d6) δ = 171.7, 160.6, 159.3, 131.3, 131.2,
130.9, 129.3, 114.7, 114.5, 107.7, 70.3, 66.0, 64.8, 55.7, 55.5, 48.5, 36.4,
35.6 ppm; HRMS (EI) m/z calcd for C17H22O5N [M-
(CH2C6H4OCH3)]+: 320.1498. Found: 320.1496.
3-Methylbut-2-en-1-yl 3,3-Dimethyl-2-(1,4-dioxa-8-azaspiro[4.5]-
decan-8-yl)pent-4-enoate (4f). Colorless oil (0.2 mmol scale, 54.8
mg, 162.4 μmol, 81% yield); IR (neat): 2957, 2877, 1732, 1442, 1363,
1
1214, 1138, 1084, 1040, 912 cm−1; H NMR (500 MHz, CDCl3) δ =
6.11 (dd, J = 17.1, 11.8 Hz, 1H), 5.40−5.34 (m, 1H), 5.00 (d, J = 17.7
Hz, 1H), 4.96 (d, J = 11.8 Hz, 1H), 4.63−4.54 (m, 2H), 3.92 (s, 4H),
2.98 (s, 1H), 2.96−2.88 (m, 2H), 2.51−2.42 (m, 2H), 1.75 (s, 3H),
1.73−1.62 (m, 7H), 1.13 (s, 3H), 1.06 (s, 3H) ppm; 13C NMR (125
MHz, CDCl3) δ = 170.3, 145.2, 138.9, 118.8, 111.9, 107.1, 75.5, 64.1,
60.4, 50.3, 40.4, 35.6, 25.6, 25.4, 23.6, 18.0 ppm; HRMS (EI) m/z
calcd for C14H22O4N [M-(CH2CHC(CH3)2]+: 268.1549. Found:
268.1551.
4-Bromobenzyl 2-(5-Bromo-2-methylphenyl)-2-(1,4-dioxa-8-
azaspiro[4.5]decan-8-yl)acetate (4l). After 24 h, CO2 was released
and then DBU (149 μL, 1.0 mmol, 5 equiv) was added. The reaction
mixture was stirred at 0 °C for 5 h. The yield of the product 4l was
determined by 1H NMR using 1,3,5-trimethoxybenzene (δ = 6.1 ppm
in CDCl3, 3H) as an internal standard (52%) after the extraction. The
crude mixture was purified by GPC to afford 4l. Colorless amorphous
solid (0.2 mmol scale, 40.8 mg, 75.7 μmol, 38% yield); IR (neat):
1
2957, 2880, 2823, 1741, 1488, 1368, 1217, 1144, 1091, 754 cm−1; H
3,3-Diphenylallyl 3,3-Diphenyl-2-(1,4-dioxa-8-azaspiro[4.5]-
decan-8-yl)pent-4-enoate (4g). Yellow amorphous solid (0.2 mmol
scale, 84.5 mg, 144.3 μmol, 72% yield); IR (neat): 3021, 2955, 2830,
NMR (500 MHz, CDCl3) δ = 7.64 (s, 1H), 7.42 (d, J = 8.3 Hz, 2H),
7.30 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.3 Hz,
1H), 5.06 (s, 2H), 4.28 (s, 1H), 3.93 (s, 4H), 2.58−2.50 (m, 4H), 2.32
(s, 3H), 1.76−1.68 (m, 4H) ppm; 13C NMR (125 MHz, CDCl3) δ =
170.8, 136.7, 136.2, 134.5, 132.2, 131.6, 131.03, 130.99, 129.6, 122.3,
120.0, 107.0, 69.2, 64.2, 48.9, 34.8, 19.2 ppm; HRMS (EI) m/z calcd
for C16H19BrO4N [M-(CH2C6H4Br)]+: 368.0498. Found: 368.0499.
Naphthalen-1-ylmethyl 2-(1-Methylnaphthalen-2-yl)-2-(1,4-
dioxa-8-azaspiro[4.5]decan-8-yl)acetate (4m). White amorphous
soild (0.2 mmol scale, 44.8 mg, 93.0 μmol, 47% yield); IR (neat):
1
1734, 1495, 1444, 1219, 1149, 1079, 756 cm−1; H NMR (500 MHz,
acetone-d6) δ = 7.46−7.11 (m, 21H), 5.98 (t, J = 7.0 Hz, 1H), 5.33 (d,
J = 10.8 Hz, 1H), 4.59 (d, J = 17.8 Hz, 1H), 4.52 (dd, J = 12.5, 7.0 Hz,
1H), 4.44 (dd, J = 12.5, 7.0 Hz, 1H), 3.89 (s, 4H), 2.98−2.88 (m, 2H),
2.64−2.47 (m, 2H), 1.71−1.56 (m, 4H) ppm; 13C NMR (125 MHz,
acetone-d6) δ = 168.8, 146.9, 146.1, 145.9, 143.8, 142.5, 139.7, 130.9,
130.6, 130.2, 129.4, 129.2, 128.83, 128.80, 128.61, 128.57, 128.1,
127.4, 127.0, 123.7, 118.1, 107.4, 77.4, 64.9, 62.4, 58.3, 51.7, 36.6 ppm;
1
2958, 2881, 1741, 1511, 1367, 1229, 1144, 1095, 947, 755 cm−1; H
+
MS (ESI) m/z calcd for C39H39O4NNa [M + Na] : 608.29. Found:
608.28; HRMS (EI) m/z calcd for C39H39O4N [M]+: 585.2879.
Found: 585.2869.
NMR (500 MHz, acetone-d6) δ = 8.05 (d, J = 8.0 Hz, 1H), 7.88−7.81
(m, 3H), 7.77−7.68 (m, 3H), 7.56−7.49 (m, 2H), 7.44 (d, J = 7.0 Hz,
1H), 7.41 (dd, J = 8.0, 7.0 Hz, 1H), 7.35 (dd, J = 8.0, 7.0 Hz, 1H), 7.21
(dd, J = 8.0, 7.0 Hz, 1H), 5.56 (d, J = 12.8 Hz, 1H), 5.53 (d, J = 12.8
Hz, 1H), 4.68 (s, 1H), 3.86 (s, 4H), 2.66 (s, 3H), 2.64−2.50 (m, 4H),
1.68−1.55 (m, 4H) ppm; 13C NMR (125 MHz, acetone-d6) δ = 172.0,
134.7, 134.3, 134.2, 133.9, 133.2, 132.6, 132.5, 130.1, 129.4, 129.3,
128.2, 127.24, 127.20, 127.02, 127.00, 126.79, 126.75, 126.1, 125.4,
124.5, 107.6, 70.9, 65.5, 64.9, 49.7, 36.0, 14.6 ppm; HRMS (EI) m/z
calcd for C20H22O4N [M-(CH2C10H7)]+: 340.1549. Found: 340.1544.
Naphthalen-2-ylmethyl 2-(2-Methylnaphthalen-1-yl)-2-(1,4-
dioxa-8-azaspiro[4.5]decan-8-yl)acetate (4n). After 24 h, CO2 was
released and then DBU (149 μL, 1.0 mmol, 5 equiv) was added. The
reaction mixture was stirred at rt for 5 h. White solids (0.2 mmol scale,
55.3 mg, 114.8 μmol, 55% yield); mp 125−127 °C; IR (neat): 3051,
2,3-Dimethylbut-2-en-1-yl 3,3,4-Trimethyl-2-(1,4-dioxa-8-
azaspiro[4.5]decan-8-yl)pent-4-enoate (4h). White solids (0.2
mmol scale, 49.3 mg, 134.9 μmol, 67% yield); mp 52−54 °C; IR
(neat): 2957, 2926, 2881, 1733, 1634, 1451, 1363, 1121, 1082, 912
1
cm−1; H NMR (500 MHz, CDCl3) δ = 4.78 (s, 1H), 4.77 (s, 1H),
4.57 (d, J = 11.8 Hz, 1H), 4.54 (d, J = 11.8 Hz, 1H), 3.91 (s, 4H), 3.26
(s, 1H), 2.98−2.87 (m, 2H), 2.58−2.45 (m, 2H), 1.79−1.60 (m, 16H),
1.17 (s, 3H), 1.15 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ =
170.8, 151.1, 131.8, 122.8, 110.8, 107.1, 73.5, 64.9, 64.1, 50.7, 43.0,
35.7, 25.4, 22.8, 20.9, 20.4, 20.3, 17.2 ppm; HRMS (EI) m/z calcd for
C15H24O4N [M-(CH2C(CH3)C(CH3)2]+: 282.1705. Found:
282.1706.
Benzyl 3-Phenyl-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-
propanoate (4i). Colorless oil (0.2 mmol scale, 46.3 mg, 121.4
μmol, 61% yield); IR (neat): 2957, 2882, 1731, 1604, 1455, 1215,
1
2958, 2816, 1746, 1508, 1366, 1144, 1096, 815, 752 cm−1; H NMR
(500 MHz, acetone-d6) δ = 9.18 (d, J = 10.0 Hz, 1H), 7.87−7.77 (m,
E
DOI: 10.1021/acs.joc.6b00837
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3H), 7.69 (d, J = 9.0 Hz, 1H), 7.61−7.54 (m, 1H), 7.48−7.37 (m,
5H), 7.33 (s, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.27 (d, J = 13.3 Hz, 1H),
5.12 (d, J = 13.3 Hz, 1H), 5.02 (s, 1H), 3.88 (s, 4H), 2.85−2.65 (m,
5H), 2.45−2.35 (m, 2H), 1.73−1.59 (m, 4H) ppm; 13C NMR (125
MHz, CDCl3) δ = 171.8, 137.2, 134.2, 134.1, 133.9, 133.6, 130.9,
130.6, 129.6, 129.0, 128.9, 128.8, 128.5, 127.4, 127.1, 127.0, 126.7,
126.6, 126.1, 125.8, 107.6, 69.6, 66.5, 64.9, 50.3, 36.1, 22.0 ppm;
HRMS (EI) m/z calcd for C20H22O4N [M-(CH2C10H7)]+: 340.1549.
Found: 340.1540.
Carboxylation of α-Amino Silane 1. A test tube was charged
with CsF (152 mg, 1.0 mmol, 5 equiv), which was dried with a heat
gun for 2 min under vacuum (<5 mmHg at ca. 400 °C). After the
displacement with CO2 gas, α-amino silane 1 (45.9 mg, 0.20 mmol) in
NMP (2 mL, 0.1 M) was added. After the reaction mixture was heated
to 150 °C, the solution was stirred for 24 h at the same temperature.
CO2 was released, and then hexyl iodide (35 mL, 0.24 mmol, 1.2
equiv) was added followed by Cs2CO3 (65.2 mg, 0.20 mmol, 1.0
equiv); the reaction mixture was stirred for 1 h at 50 °C. The reaction
was quenched by the addition of water. The product was extracted
with AcOEt three times, and the combined organic layers were washed
with water followed by brine and then dried over Na2SO4. The solvent
was evaporated under reduced pressure. The yield was determined by
1H NMR at this stage using 1,3,5-trimethoxybenzene (δ = 6.1 ppm in
CDCl3, 3H) as an internal standard (26% of 5 and 33% of recovered
substrate). The crude product was purified by silica gel column
chromatography (hexane/AcOEt, 5/1 to 1/1) to afford 5 (15.5 mg,
54.3 μmol, 27% yield) as a colorless oil.
Hexyl 2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)acetate (5). IR
(neat): 2957, 2931, 2251, 1744, 1468, 1187, 1098, 1040, 914, 732
cm−1; 1H NMR (500 MHz, CDCl3) δ = 4.10 (t, J = 6.8 Hz, 2H), 3.93
(s, 4H), 3.21 (s, 2H), 2.69−2.58 (m, 4H), 1.82−1.74 (m, 4H), 1.62
(tt, J = 7.0, 6.8 Hz, 2H), 1.37−1.22 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ = 170.6, 106.7, 64.7, 64.2, 59.2,
51.4, 34.7, 31.4, 28.5, 25.5, 22.5, 13.9 ppm; HRMS (ESI) m/z calcd for
C15H28O4N [M + H]+: 286.2013. Found: 286.2010.
Removal of Protecting Groups. Ester 4c (56.3 mg, 0.20 mmol)
in 10% H2SO4 aq./THF (3/1, 2.4 mL, 0.08 M) was stirred at 60 °C.
After 15 h, the reaction mixture was cooled to 0 °C and then
neutralized by 3 M NaOH aq. The product was extracted with AcOEt
three times, washed with brine, and dried over Na2SO4. The solvent
was evaporated under reduced pressure to afford 6c (46.2 mg, 194.7
μmol, 97% yield) as a colorless oil. The product was used for the next
reaction without further purification.
Ester 6c (108.4 mg, 0.46 mmol) was dissolved in THF/H2O (1/1,
4.6 mL, 0.1 M) and treated by LiOH·H2O (38.6 mg, 0.92 mmol, 2
equiv) at 0 °C. The reaction mixture was allowed to warm to room
temperature. After stirring for 23 h, LiOH·H2O (38.6 mg, 0.92 mmol,
2 equiv) was added. After stirring for an additional 5 h. The reaction
mixture was acidified by 3 M HCl, and solvent was removed under
reduced pressure.
The crude product was dissolved in EtOH (4.6 mL, 0.1 M) and
transferred to a sealed tube. Aminomethylated polystyrene resin (PS-
NH2, 2.1 mmol/g) (328.6 mg, 0.69 mmol, 1.5 equiv) and NH4Cl
(29.5 mg, 0.55 mmol, 1.2 equiv) were added to the mixture. The test
tube was sealed and then heated at 100 °C. After 24 h, the reaction
mixture was filtered through a Celite pad and washed with EtOH and
3 M HCl. After neutralization to pH 7 using 3 M NaOH aq. followed
by concentration under reduced pressure, the crude product was
loaded on a cationic ion exchange column chromatography instrument
(Dowex 50W-X2, 50−100 mesh, H+ form). After the column was
washed with water, ammonia solution (28% w/w) was introduced into
the column. Ninhydrin-active fractions were collected, and the water
was removed under high vacuum to afford free α-amino acid 7c (48.4
mg, 420.4 μmol, 91% yield in two steps) as yellow solids.
2-Aminopent-4-enoic Acid (7c). Mp 245−247 °C; IR (neat): 2932,
1
2856, 1588, 1455, 1404, 1333, 1164, 1106, 913, 706 cm−1; H NMR
(500 MHz, D2O) δ = 5.82−5.71 (m, 1H), 5.27 (d, J = 17.0 Hz, 1H),
5.25 (d, J = 10.0 Hz, 1H), 3.80 (dd, J = 6.3, 5.3 Hz, 1H), 2.70−2.55
(m, 2H) ppm; 13C NMR (125 MHz, D2O) δ = 174.8, 132.0, 121.2,
54.7, 35.5 ppm; HRMS (ESI) m/z calcd for C5H10O2N [M + H]+:
116.0706. Found: 116.0707.
Ester 6j (146.2 mg, 0.40 mmol) was dissolved in THF/H2O (1/1,
4.0 mL, 0.1 M) and treated by LiOH·H2O (67.1 mg, 1.6 mmol, 4
equiv) at 0 °C. The reaction mixture was allowed to warm to room
temperature. After stirring for 14 h, the reaction mixture was acidified
by 3 M HCl, and solvent was removed under reduced pressure.
The crude product was dissolved in EtOH (4.0 mL, 0.1 M) and
transferred to a sealed tube. Aminomethylated polystyrene resin (PS-
NH2, 2.1 mmol/g) (285.7 mg, 0.60 mmol, 1.5 equiv) and NH4Cl
(26.2 mg, 0.48 mmol, 1.2 equiv) were added to the mixture. The test
tube was sealed and then heated at 100 °C. After 24 h, the reaction
mixture was filtered through a Celite pad and washed with EtOH and
3 M HCl. After neutralization to pH 7 using 3 M NaOH aq. followed
by concentration under reduced pressure, the crude product was
loaded on a cationic ion exchange column chromatography instrument
(Dowex 50W-X2, 50−100 mesh, H+ form). After the column was
washed with water, ammonia solution (28% w/w) was introduced into
the column. Ninhydrin-active fractions were collected, and the water
was removed under high vacuum to afford free α-amino acid 7j (61.1
mg, 340.9 μmol, 85% yield) as yellow solids.
Allyl 2-(4-Oxopiperidin-1-yl)pent-4-enoate (6c). IR (neat): 3079,
1
2962, 2823, 1717, 1645, 1417, 1345, 1173, 988, 919 cm−1; H NMR
(500 MHz, CDCl3) δ = 5.95−5.75 (m, 2H), 5.32 (d, J = 17.0 Hz, 1H),
5.24 (d, J = 10.5 Hz, 1H), 5.12 (d, J = 17.0 Hz, 1H), 5.07 (d, J = 10.5
Hz, 1H), 4.64−4.55 (m, 2H), 3.46 (t, J = 7.8 Hz, 1H), 3.03−2.95 (m,
2H), 2.90−2.82 (m, 2H), 2.61−2.52 (m, 1H), 2.50−2.35 (m, 5H)
ppm; 13C NMR (125 MHz, CDCl3) δ = 208.8, 170.9, 134.1, 131.9,
118.8, 117.4, 66.6, 65.1, 49.0, 41.9, 34.0 ppm; HRMS (EI) m/z calcd
for C10H14O3N [M-(CH2CHCH2)]+: 196.0974. Found: 196.0971.
Ester 4j (409.6 mg, 1.0 mmol) in 10% H2SO4 aq./THF (3/1, 24.8
mL, 0.04 M) was stirred at 60 °C. After 10 h, the reaction mixture was
cooled to 0 °C and then neutralized by 3 M NaOH aq. The product
was extracted with AcOEt three times, washed with brine, and dried
over Na2SO4. The solvent was evaporated under reduced pressure to
afford 6j (344.4 mg, 942.3 μmol, 94% yield) as white solids. The
product was used for the next reaction without further purification.
4-Methylbenzyl 2-(4-Oxopiperidin-1-yl)-3-(p-tolyl)propanoate
(6j). Mp 98−99 °C; IR (neat): 2959, 2823, 1733, 1518, 1441, 1218,
1160, 1059, 1000, 755 cm−1; 1H NMR (500 MHz, CDCl3) δ = 7.14−
7.05 (m, 8H), 5.01 (s, 2H), 3.63 (dd, J = 8.8, 6.9 Hz, 1H), 3.08 (dd, J
= 13.4, 8.8 Hz, 1H), 3.05−2.98 (m, 2H), 2.94 (dd, J = 13.4, 6.9 Hz,
1H), 2.89−2.81 (m, 2H), 2.46−2.33 (m, 7H), 2.32 (s, 3H) ppm; 13C
NMR (125 MHz, CDCl3) δ = 208.8, 171.1, 138.2, 136.0, 134.6, 132.5,
129.2, 129.1, 129.0, 128.5, 68.9, 66.2, 49.3, 41.9, 35.6, 21.2, 21.0 ppm;
HRMS (EI) m/z calcd for C15H18O3N [M-(CH2C6H4CH3)]+:
260.1287. Found: 260.1282.
2-Amino-3-(p-tolyl)propanoic Acid (7j). Mp 227−229 °C; IR
(neat): 1583, 1504, 1411, 1308, 1156, 1106, 856, 804, 761, 676 cm−1;
1H NMR (500 MHz, D2O) δ = 7.25 (d, J = 8.0 Hz, 2H), 7.20 (d, J =
8.0 Hz, 2H), 3.95 (dd, J = 7.9, 5.0 Hz, 1H), 3.23 (dd, J = 14.9, 5.0 Hz,
1H), 3.07 (dd, J = 14.9, 7.9 Hz, 1H), 2.32 (s, 3H) ppm; 13C NMR
(125 MHz, D2O) δ = 174.7, 138.5, 132.6, 130.4, 130.0, 56.7, 36.6, 20.8
ppm; HRMS (EI) m/z calcd for C10H13O2N [M]+: 179.0946. Found:
179.0944.
Synthesis of Ammonium Salt Intermediates. Intermediate A
was prepared by the following procedure. α-Amino silane 1 (688.2 mg,
3 mmol) and 3-bromo-2-methyl-1-propene (914 μL, 9 mmol, 3.0
equiv) in MeCN (3 mL, 1.0 M) were stirred for 12 h at room
temperature. After the solvent was removed under reduced pressure,
the desired ammonium salt A was obtained (839.0 mg, 2.3 mmol, 77%
yield) as a yellow amorphous solid.
F
DOI: 10.1021/acs.joc.6b00837
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
8-(2-Methylallyl)-8-((trimethylsilyl)methyl)-1,4-dioxa-8-azaspiro-
[4.5]decan-8-ium Bromide (A). IR (neat): 3393, 2954, 2895, 1637,
1457, 1255, 1169, 1119, 1034, 856 cm−1; 1H NMR (500 MHz, D2O) δ
= 5.61 (s, 1H), 5.37 (s, 1H), 4.10−4.04 (m, 4H), 4.02 (s, 2H), 3.66−
3.57 (m, 2H), 3.50−3.42 (m, 2H), 3.19 (s, 2H), 2.22−2.09 (m, 4H),
2.00 (s, 3H), 0.30 (s, 9H) ppm; 13C NMR (125 MHz, D2O) δ = 133.9,
128.4, 104.5, 69.4, 65.32, 65.29, 60.0, 54.2, 30.0, 24.3, −0.8 ppm;
HRMS (ESI) m/z calcd for C15H30O2NSi [M-Br]+: 284.2040. Found:
284.2035.
Intermediate B was prepared by the following procedure. In a
round-bottom flask, 1,4-dioxa-8-azaspiro[4.5]decane (1.9 mL, 15
mmol), 3-chloro-2-methyl-propene (1.6 mL, 16.5 mmol, 1.1 equiv),
potassium carbonate (2.3 g, 16.5 mmol, 1.1 equiv), and potassium
iodide (4.5 g, 27 mmol, 1.8 equiv) in DMF (15 mL, 1.0 M) were
stirred for 17 h at 80 °C. Water was added to quench the reaction. The
product was extracted with AcOEt three times, and the combined
organic layer was washed with water followed by brine and then dried
over Na2SO4. After evaporation of the solvent, the crude product 8
was used for the next reaction without further purification.
Amine 11 and 3-bromo-2-methyl-propene (5 mL, 50 mmol, 5
equiv) in MeCN (10 mL, 1.0 M) were stirred for 20 h at room
temperature. After evaporation, the crude product was dissolved in
water and washed with AcOEt. The water layer was evaporated
followed by trituration with hexane. The solids were filtered and
washed with hexane and AcOEt to afford C (561.1 mg, 1.44 mmol,
14% yield in two steps) as yellow solids.
8-(2-Methylallyl)-8-(2-((2-methylallyl)oxy)-2-oxoethyl)-1,4-dioxa-
8-azaspiro[4.5]decan-8-ium Bromide (C). Mp 169−171 °C; IR
(neat): 3420, 2968, 1747, 1646, 1445, 1383, 1191, 1088, 945, 752
1
cm−1; H NMR (500 MHz, CD3OD) δ = 5.57 (s, 1H), 5.36 (s, 1H),
5.06 (s, 1H), 5.02 (s, 1H), 4.70 (s, 2H), 4.53 (s, 2H), 4.34 (s, 2H),
4.03 (s, 4H), 3.99−3.90 (m, 2H), 3.82−3.71 (m, 2H), 2.22−2.06 (m,
4H), 2.00 (s, 3H), 1.80 (s, 3H) ppm; 13C NMR (125 MHz, CD3OD)
δ = 116.2, 140.4, 134.8, 128.8, 115.1, 104.5, 70.6, 67.4, 66.0, 65.9, 60.5,
56.3, 30.8, 23.8, 19.6 ppm; HRMS (ESI) m/z calcd for C17H28O4N
[M-Br]+: 310.2013. Found: 310.2011.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00837.
1H and 13C NMR spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: tmita@pharm.hokudai.ac.jp.
*E-mail: biyo@pharm.hokudai.ac.jp.
■
Amine 8 and methylbromoacetate (4.1 mL, 45 mmol, 3.0 equiv) in
MeCN (15 mL, 1.0 M) were stirred for 13 h at 60 °C. The solids were
washed with hexane to afford 9 (3.4 g, 9.7 mmol, 65% in two steps) as
white solids.
Ammonium salt 9 (1.05 g, 3.0 mmol) dissolved in water was passed
through an ion-exchange chromatography column (Amberlite IRA-
402(OH)). The solvent was removed under reduced pressure to afford
B (808.4 mg, quant.) as colorless solids.
2-(8-(2-Methylallyl)-1,4-dioxa-8-azaspiro[4.5]decan-8-ium-8-yl)-
acetate (B). Mp 196−198 °C; IR (neat): 3445, 2974, 1635, 1456,
1384, 1217, 1169, 1118, 944, 751 cm−1; 1H NMR (500 MHz, DMSO-
d6) δ = 5.43 (s, 1H), 5.29 (s, 1H), 4.32 (s, 2H), 3.93 (s, 4H), 3.90−
3.80 (m, 2H), 3.55 (s, 2H), 3.48−3.38 (m, 2H), 2.02−1.85 (m, 7H)
ppm; 13C NMR (125 MHz, DMSO-d6) δ = 163.9, 134.4, 126.2, 103.8,
64.2, 64.0, 63.3, 58.1, 56.5, 29.1, 23.6 ppm; HRMS (ESI) m/z calcd for
C13H21O4NNa [M + Na]+: 278.1363. Found: 278.1361.
Intermediate C was prepared by the following procedure. In a
round-bottom flask, 1,4-dioxa-8-azaspiro[4.5]decane (1.3 mL, 10
mmol), α-chloroacetate 1020 (1.6 g, 1.1 equiv), potassium carbonate
(1.5 g, 11 mmol, 1.1 equiv), and potassium iodide (3.0 g, 18 mmol, 1.8
equiv) in DMF (10 mL, 1.0 M) were stirred for 14 h at 80 °C. Water
was added to quench the reaction. The product was extracted with
AcOEt three times, and the combined organic layer was washed with
water followed by brine and then dried over Na2SO4. After
evaporation of the solvent, the crude product 11 was used for the
next reaction without further purification.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by Grants-in-Aid for
Scientific Research (C) (No. 26410108), Grants-in-Aid for
Scientific Research (B) (No. 26293001) from JSPS, and also by
ACT-C, JST. M.S. thanks JSPS for a fellowship (No.
13J02099).
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