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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
4 Mechanism Problems from Reactions Give Expected Products108
Stirring was continued over a period of 30 min. A solution of 10% NaOH (ca. 1 mL)
was added and the mixture was extracted with ether. The combined ether layers
were dried over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The resulting crude material was purified by flash chromatography on
silica gel.
3-Benzyl-5-methyl-3-azabicyclo[3.1.0]hept-1-ylamine (4):
1
HNMR (CDCl
3
,
250 MHz) δ: 0.25 (m, 1H), 1.10 (m, 4H), 1.50 (s, 2H), 2.20 (d, J = 8.4 Hz, 1H), 2.25
(d, J = 8.4 Hz, 1H), 2.90 (d, J = 8.3 Hz, 1H), 3.05 (d, J = 8.3 Hz, 1H), 3.55 (s, 2H),
7.25–7.40 (m, 5H);
13
CNMR (CDCl
3
, 250 MHz) δ: 14.2, 20.6, 26.1, 43.0, 59.2, 60.6,
68.8, 126.7, 128.0, 128.5, 139.1; MS (EI) m/z (%): 202 (M
+•
, 13), 147 (2), 120 (4),
111 (14), 91(100).
*Comments on the
1
H NMR data: The date presented in the literature seems wrong.
R
1
O
O
+
MgX
2
1. Ti(OiPr)
4
(5–10%)
2. H
3
O
+
OH
Kulinkovich reaction
de Meijere variation
N
O
+
MgX
>2
N
Szymoniak variation
CN
+
MgX
R
2
R
2
R
1
R
1
R
4
R
3
R
2
1. Ti(OiPr)
4
(>1 eq.)
2. H
3
O
+
1. Ti(OiPr)
4
2. BF
3
-OEt
2
3. H
3
O
+
R
1
R
2
NH
2
R
1
R
2
R
1
R
3
R
2
R
4
NaCN
+
HCHO
Boc
2
O
O CN
Boc
1 (72%)
EtMgBr (2.2 eq.)
Ti(OiPr)
4
(0.2 eq.)
Et
2
O, 0 °C, 1 h
NHBoc
HO
2 (58%)
N
O
H
N
FO
O
H
2
N
Anlotinib
N
O
H
N
F
O
HO
Steps
67%
N
CN
N
NH
2
1. Ti(OiPr)
4
, Et
2
O
cyclohexylmagnesium chloride
2. Et
2
O-BF
3
3
4
4.3 Formation of Cyclic Alkane and Derivatives 109
The Mechanism
The Grignard reagent as a nucleophile attacks the titanium isopropoxide to give
the dicyclohexyltitanium diisopropoxide (A). After one molecule of cyclohexane is
eliminated, the cyclohexene-titanium complex (B) is formed. Then alkene exchange
with the C═C bond of the nitrile yields the complex (C), which in turn reacts with
the nitrile in the intramolecular reaction to afford the cyclopropylamine product.
Problem 23: Formation of Cyclopropane by Dialkylation of Active Methylene
(1R,2S)-1-Amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is a key building
block in the synthesis of potent inhibitors of the hepatitis C virus NS3 protease such
as BILN 2061.
Chemists from Boehringer Ingelheim developed a scalable process that deliv-
ered derivatives of this unusual amino acid in >99% ee [66]. In an initial study,
they carried out a reaction between ethyl (E)-2-(benzylideneamino) acetate (1) and
(E)-1,4-dibromobut-2-ene (2) under the conditions shown below. A mixture of 3 and
N
O
S
N
NH
N
H
N
O
O
NH
O
O
OMe
H
BILN2061
(HCV NS3 inhibitor)
H
2
N
H
Methyl (1R,2S)-1-amino-2-
vinylcyclopropane-1-carboxylate
Steps
CO
2
Me
CO
2
H
4 Mechanism Problems from Reactions Give Expected Products110
4 (3:1) was detected in the reaction mixture. After the acid-base aqueous workup,
the amino ester 5 was obtained in 45% yield.
Could you please provide a mechanism for the formation of 3 and 4? Why
compound 5 was the only product obtained after the acid-base aqueous workup?
Experimental Procedure (from J. Org. Chem., 2005, 70, 5869)
General Procedure for the Dialkylation of Imine 1: Optimization Studies
Using Hydroxide Bases and Phase Transfer Catalysis (Table 1). The follow-
ing procedure using KOH is representative. Powdered KOH (0.336 g, 6.00 mmol,
3 equiv) was added to a stirred mixture of imine 1 (0.574 g, 3.00 mmol, 1.5 equiv),
trans-1,4-dibromo-2-butene (0.428 g, 2.0 mmol, 1 equiv), toluene (10 mL), and tri-
ethylbenzylammonium chloride (0.068 g, 0.3 mmol, 0.15 equiv). The mixture was
stirred for 18 h at room temperature. An aliquot (2 mL) was then diluted with
tert-butylmethyl ether (TBME, 5 mL) and washed with saturated aqueous NaHCO
3
(2 mL). The organic portion was dried (MgSO
4
), concentrated under reduced
pressure, and analyzed by
1
HNMR in CDCl
3
(see below for complete assignments)
to determine the ratio of the desired vinyl-ACCA imine intermediate 3 (δ 2.27, q =
1H or δ 2.00, dd = 1H or 1.70, dd = 1H) and side product 4 (δ 6.04–5.95, m = 2 olefinic
Hs). In this case, a 3:1 ratio of 3 to 4 was obtained. Similar procedures were used
for other hydroxide bases, replacing KOH with NaOH, CsOH•H
2
O, LiOH•H
2
O, or
tetramethylammonium hydroxide.
Isolation and Characterization of 7-Phenyl-6,7-dihydro-1H-azepine-2-
carboxylic Acid Ethyl Ester 4. Imine 1 (5.737 g, 30.0 mmol, 1.5 equiv) was alkyl-
ated with trans-1,4-dibromo-2-butene (4.278 g, 20.0 mmol, 1 equiv) and KOtBu
(6.172 g, 55 mmol, 2.75 equiv) in THF (100 mL) using the general procedure
described above. Following acidic cleavage of the imine, the organic phase con-
taining benzaldehyde and 4 was separated from the aqueous phase containing
vinyl-ACCA-OEt 3. The solution was washed with 1 N HCl (50 mL) and brine
(50 mL) and dried over Na
2
SO
4
. After removal of volatiles under vacuum at 60 °C to
remove benzaldehyde, the residual oil was purified by flash chromatography using
0–5% EtOAc in hexane as an eluent. Dihydroazepine 4 was obtained as a colorless
oil (0.300 g), which slowly turned orange on prolonged exposure to air: TLC R
f
)
Ph N CO
2
Et
+
Br
Br
KOH, toluene
PhCH
2
Et
3
N
+
Cl
–
rt, 18 h
Ph
N
+
NH
Ph
CO
2
Et
(+/–)-3 (+/–)-4
Ratio 3 : 4 = 3 : 1
1. H
3
+
O
2.
(+/–)-5
1
2
CO
2
Et
HO
–
CO
2
Et
H
2
N
4.3 Formation of Cyclic Alkane and Derivatives 111
0.55 (10% EtOAchexane);
1
HNMR (400 MHz, CDCl
3
) δ 7.39–7.33 (m, 2H), 7.32–7.24
(m, 3H), 6.04–5.96 (m, 2H), 5.93–5.84 (m, 1H), 5.22 (broad s, 1H), 4.23 (q, J = 7.0 Hz,
2H), 4.15 (broad d, J = 7.4 Hz, 1H), 2.88–2.78 (m, 1H, part of AB), 2.68 (broad dd,
J = 17.4 and 7.4 Hz, 1H, part of AB), 1.31 (t, J = 7.1 Hz, 3H);
13
CNMR (100 MHz,
CDCl
3
) δ 165.7, 144.0, 135.4, 131.4, 128.8, 127.5, 126.6, 124.7, 103.2, 61.6, 58.2, 42.7,
14.1; HRMS (FAB) m/z C
15
H
18
NO
2
(MH
+
) calcd 244.1338, found 244.1338.
Crude imine 3 had the following spectral characteristics:
1
HNMR (400 MHz,
CDCl
3
) δ 8.36 (s, 1H), 7.60 (m, 2H), 7.42 (m, 3H), 5.83–5.72 (m, 1H), 5.27 (broad d,
J = 17.0 Hz, 1H), 5.13 (dd, J = 10.2 and 1 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 2.27 (dd,
J = 8.8 and 8.6 Hz, 1H), 2.00 (dd, J = 7.8 and 5.5 Hz, 1H), 1.70 (dd, J = 9.4, 5.5 Hz,
1H), 1.30 (t, J = 7.1 Hz, 3H).
Intermediate Vinyl-ACCA-OEt (Racemic-5):
1
HNMR (400 MHz, CDCl
3
)
δ 5.71 (ddd, J = 19.4, 10.2, 9.2 Hz, 1H), 5.21 (ddd, J = 17.2 and 1.9, 0.6 Hz, 1H), 5.03
(dd, J = 10.5 and 1.9 Hz, 1H), 4.21–4.14 (m, 2H), 2.5 (broad s, 2H), 2.05–1.98 (m, 1H),
1.55 (dd, J = 7.6, 4.8 Hz, 1H), 1.32 (dd, J = 9.2, 4.8 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H).
The Mechanism
The first step is a normal alkylation of the imine ester 1 with dibromide 2 under basic
condition. The second alkylation should give a mixture of cis-(4a) and trans-(3).
The cis-4a could cyclize to the seven-membered product 4 via aza-Cope rearrange-
ment [67]. However, the trans-(3) would not cyclize by this rearrangement. Under
the acidic aqueous workup, compound 3 will hydrolyze to the amine 5a as the salt
form, which is soluble in aqueous phase. Whereas the product 4 and the by-product,
benzaldehyde, will remain in organic phase.
Problem 24: A Tandem Cyclopropanation Ring-Expansion Reaction
Saridegib, also known as IPI-926 (2), is a novel, semisynthetic analog of cyclopamine
(1, a natural product), with potent activity on the Hedgehog pathway, significant
antitumor activity, and attractive pharmaceutical properties [68, 69]. The key step
for this semisynthesis is the cyclopropanation ring-expansion from 3 to 4. Please
suggest a mechanism for the reactions.
Ph N
Br
Br
OEt
O
H
HO
–
Ph N
OEt
Br
Ph N
OEt
O
H
Ph N
OEt
N
Ph
4a
Aza-Cope
rearrangement
[3,3]-sigma tropic
rearrangement
N
Ph
CO
2
Et
H
[1,3]-H shift
NH
Ph
1
+
N
3
Ph
Acidic aq.
workup
5a, in aq. phase
PhCHO
In organic
phase
4, in organic phase
Basified
EtO
2
C
5
Br
KOH
KBr
KBr
O
–
HO
–
CO
2
Et
NH
2
EtO
2
C
NH
2.
HCI
EtO
2
C
CO
2
Et
O
–
4 Mechanism Problems from Reactions Give Expected Products112
Experimental Procedure (from Org. Process Res. Dev., 2016, 20, 786)
Compound 4. Equipment: Reaction Vessel A 2500 L (for diethylzinc solution and
reaction) is an appropriately sized, cryogenic capable jacketed reactor equipped
with a temperature control unit, a nitrogen/vacuum port, a charge port, an overhead
stirrer, and condenser. Reagent Vessel B (for bis(2,6-dimethylphenyl)phosphoric
acid [BDMPP] solution) is an appropriately sized jacketed reactor equipped with a
temperature control unit, a nitrogen/vacuum port, a charge port, an overhead stir-
rer, and condenser. Reagent Vessel C (for starting material compound 3 solution) is
an appropriately sized jacketed reactor equipped with a temperature control unit, a
nitrogen/vacuum port, a charge port, an overhead stirrer, and condenser. Reagent
Vessel D (for methanesulfonic acid solution) is an appropriately sized jacketed
reactor equipped with a temperature control unit, a nitrogen/vacuum port, a charge
port, an overhead stirrer, and condenser. Reaction setup: Vessel B is charged with
BDMPP (45.46 kg, 1.39 wt, 3.10 equiv), then sealed and pressurized with nitrogen to
1.7 bar. The pressure is released, and a vacuum to 0.3 bar is pulled. This step is
repeated twice; then the reactor is backfilled with nitrogen to 1 bar. Using residual
vacuum and utilizing anhydrous techniques, charge anhydrous DCM (400 L,
13 volumes) to Vessel B. The batch is agitated at 20 ± 5 °C until all the solid has dis-
solved. Vessel B is sealed and pressurized with nitrogen to 1.7 bar. The pressure is
released to a minimum of 0.3 bar and held for ≥5 min; then nitrogen is backfilled to
1 bar. This step is repeated three more times. The diethylzinc cylinder is connected
to the transfer manifold and purged accordingly (see Supporting Information). The
charge manifold is connected to Vessel A via a transfer line employing Swagelok
fittings, and also to a cylinder of anhydrous DCM, and a nitrogen source. A nitrogen
sweep (25 psi) is applied through the charge manifold, transfer line, and reaction
O
NH
HO
H
H
H
H
A
D
E
F
1 (cyclopamine)
N
H
H
A
2 (IPI-926)
O
H
H
H
H
H
H
S
O
O
D
E
F
Cl
–
O
NCbz
CbzO
H
H
H
H
A
D
E
F
3
CbzO
H
A
4
O
NCbz
H
H
H
D
E
F
55–80%
1. Et
2
Zn
(ArO)
2
P(O)OH,
CH
2
I
2
, DCM, 27 °C
2. MsOH, –45 °C
P
O
OO
OH
(ArO)
2
P(O)OH =
N
+
4.3 Formation of Cyclic Alkane and Derivatives 113
Vessel A for a minimum of 12 h. Using residual vacuum and utilizing anhydrous
techniques, anhydrous DCM (500 L, 15 volumes) is charged to Vessel A, which is
then sealed and pressurized with nitrogen to 1.7 bar. The pressure is released, and a
vacuum is pulled to 0.3 bar. This step is repeated twice, then finished with nitrogen
backfill to 1 bar. The batch is agitated under nitrogen, then cooled to 10 ± 5 °C.
Using low pressure nitrogen, diethylzinc (18.03 kg, 0.55 wt, 3.05 equiv) is charged
into Vessel A. The manifold and transfer line are rinsed with anhydrous DCM three
times; the rinses (30 L) are directed into the reaction (Vessel A). After each rinse the
lines are flushed with nitrogen for ≥2 min. The phosphate solution is slowly trans-
ferred from Vessel B into the reaction (Vessel A), while maintaining the temperature
≤5 °C under nitrogen. This transfer typically takes 4 h and must not exceed 7 h.
Diiodomethane is charged (39.75 kg, 1.22 wt, 3.10 equiv) to the reaction (Vessel A),
while maintaining the temperature ≤10 ± 5 °C. Vessel C is charged with compound
3b (32.55 kg, 1 wt, 1.0 equiv), then pressurized with nitrogen to 1.7 bar. The pressure
is released and a vacuum is pulled to 0.3 bar. This step is repeated twice, then fin-
ished with a nitrogen backfill to 1 bar. Using residual vacuum and utilizing anhy-
drous techniques, anhydrous DCM is charged (65 L, 2 volumes) to Vessel C, and the
material is agitated at 20 ± 5 °C until it dissolves. The DC solution of compound 3b
is transferred from Vessel C into the reaction (Vessel A), while maintaining the tem-
perature ≤10 ± 5 °C with stirring. Using residual vacuum and utilizing anhydrous
techniques, Vessel C is rinsed with anhydrous DCM (32 L, 1.33 wt, 1 volume). Once
the transfer is complete, the batch is warmed to 7.5 ± 2.5 °C and held with a nitrogen
purge to the scrubber for 1 h in order to allow dissolved ethane to vent off. The batch
is then warmed to 30 ± 5 °C while monitoring the internal pressure monitored every
5 °C. If the reactor pressure increases by 1 bar above atmospheric pressure, suspend
the warm up, and vent the reactor with a nitrogen purge to the scrubber over 1 h.
The batch is agitated at 30 ± 5 °C for ≥4 h. After the reaction is found to be complete,
the batch is cooled to 60 ± 5 °C. Ring-expansion: Using residual vacuum, meth-
anesulfonic acid (13.9 kg, 0.424 wt, 3.0 equiv) is charged to Vessel D. Using residual
vacuum and utilizing anhydrous techniques, anhydrous DCM (55.6 kg, 1.72 wt,
1.3 volumes) is charged to Vessel D. When the batch in Vessel A reaches ≤55 °C,
the methanesulfonic acid solution in Vessel D is transferred to the batch (Vessel A),
while maintaining the temperature at ≤50 °C. Using residual vacuum and uti-
lizing anhydrous techniques, anhydrous DCM is transferred (11.7 kg, 0.36 wt, 0.27
volumes) to Vessel D, then the rinse is transferred to the batch (Vessel A). Quench:
Once the ring-expansion reaction is complete, morpholine (42.1 kg, 1.28 wt,
1.29 volumes, 10 equiv) is charged to the batch (Vessel A), while maintaining the
temperature at ≤35 °C. The batch (Vessel A) is then warmed to 20 °C and held for
≥1 h. The batch is washed with an aqueous solution of 2N hydrochloric acid (336 kg,
10.3 wt, 10 volumes, 13.6 equiv) for ≥60 min at 2025 °C. The agitation is stopped,
and the organic layer (bottom layer) is separated from the aqueous layer (top layer).
The organic layer is transferred back into the reactor (Vessel A), and the washing
step with 2N hydrochloric acid (336 kg, 10.3 wt, 10 volumes, 13.6 equiv) is repeated
for ≥15 min at 2025 °C. The organic layer is washed with an aqueous solution of
4 Mechanism Problems from Reactions Give Expected Products114
4.8 wt % sodium carbonate (338 kg, 10.5 wt, 10 volumes, 3.2 equiv) for ≥15 min at
2025 °C. The agitation is stopped, and the organic layer (bottom layer) is separated
from the aqueous layer (top layer). The organic layer is transferred back into the
reactor (Vessel A). The batch is washed with an aqueous solution of 4.8 wt % sodium
sulfite (339.4 kg, 10.5 wt, 10 volumes, 2.7 equiv) for ≥15 min at 2025 °C. The agita-
tion is stopped, and the organic layer (bottom layer) is separated from the aqueous
layer (top layer). The organic layer is transferred back into the reactor (Vessel A).
The batch is washed with purified water (326 kg, 10.5 wt, 10 volumes, 5.9 equiv) for
≥15 min at 2025 °C. The agitation is stopped, and the organic layer (bottom layer)
is separated from the aqueous layer (top layer). The organic layer is polished, fil-
tered, and transferred into a 630-L reactor. The filtrate is distilled under vacuum to
2 ± 0.25 volumes, while maintaining the batch temperature at ≤35 °C during the
distillation. To the concentrated filtrate is charged 2-propanol (97.7 kg, 3.0 wt,
3.82 volumes), and the batch is agitated at 20 ± 5 °C until the solution is homoge-
neous. Methanol (49.0 kg, 1.5 wt, 1.90 volumes) is then charged into the batch over
≥10 min at 20 ±5 °C. The mixture is agitated for 30 ± 5 min at 20 ± 5 °C to initiate
nucleation. Then, more methanol (179.2 kg, 5.5 wt, 6.95 volumes) is charged over 45
± 15 min at 20 ± 5 °C. The batch is agitated at 20 ±5 °C for ≥4 h, then at 0 ± 5 °C for
≥4 h. The solid is filtered off over a 30 µm nylon filter cloth and deliquored with
nitrogen. The solid is washed with methanol (130.4 kg, 4 wt, 5.1 volumes), soaked
for ≥10 min, then deliquored with nitrogen. The solid is washed with heptane
(130 kg, 4 wt, 5.8 volumes), soaked for ≥10 min, then deliquored with nitrogen. The
solid is dried with nitrogen for ≥4 h; then warm nitrogen (40 °C) for ≥12 h while
periodically stirring the filter cake. The solid is dried under vacuum at 40 °C for ≥8 h
while periodically stirring the filter cake. This procedure delivered 18.326.7 kg of
4 (N = 7 on 33 kg scale, range 5580% yield). Mp = 148 °C;
1
HNMR (400 MHz,
pyridine-d
5
) δ 7.637.50 (m, 4H), 7.477.30 (m, 6H), 5.485.32 (m, 5H), 4.93 (s,
3H), 4.69 (tt, J = 11.3, 4.7 Hz, 1H), 3.95 (dd, J = 12.8, 4.3 Hz, 1H), 3.64 (td, J = 10.8,
4.1 Hz, 1H), 3.24 (dd, J = 10.1 and 6.1 Hz, 1H), 2.88 (m, 1H), 2.702.56 (m, 2H), 2.52
(d, J = 14.1 Hz, 1H), 2.42 (td, J = 12.4, 2.9 Hz, 1H), 2.23 (dtd, J = 14.5, 6.7, 6.1, and
3.2 Hz, 2H), 2.161.92 (m, 5H), 1.901.53 (m, 7H), 1.471.28 (m, 2H), 1.261.00
(m, 6H), 0.900.77 (m, 6H);
13
CNMR (101 MHz, pyridine-d
5
) δ 158.20, 155.46,
141.67, 140.71, 138.10, 136.94, 129.43, 129.41, 129.20, 129.10, 129.02, 128.91, 124.58,
82.42, 78.53, 75.70, 69.87, 67.72, 63.06, 53.29, 52.75, 50.67, 50.46, 46.86, 44.37, 38.42,
38.38, 38.34, 38.14, 37.37, 32.42, 31.16, 29.37, 29.28, 28.24, 24.55, 19.81, 18.95, 11.18;
LRMS: m/z = 694.7 [M + H]
+
; HPLC purity (Method D) range of 95.697.2 a/a %.
The Mechanism
The first reaction is a Simmons-Smith reaction [70] to give the cyclopro-
pane A. At acidic conditions, under the participation of the neighbor THF, the
bicyclo[4.1.0]heptane rearranges to cycloheptane 4.
4.3 Formation of Cyclic Alkane and Derivatives 115
4.3.2 Cyclobutane
Problem 25: Synthesis of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one
Mirogabalin besylate was developed by Daiichi Sankyo and was first approved in
Japan for the treatment of peripheral neuropathic pain (PNP), including diabetic
PNP and postherpetic neuralgia. In a patent application [71], as shown below,
chemists from Daiichi Sankyo described a synthesis of the key intermediate,
3-ethylbicyclo[3.2.0]hept-3-en-6-one 5.
Please provide mechanisms for the reactions of 2 to 3 and 4 to 5.
Experimental Procedure (from patent US2014/0094623, 2014, A1)
2-Ethylpent-4-enal (3). 1,1-Bis(allyloxy)butane (102.15 g, 0.60 mol) was dissolved
in N,N-dimethylacetamide (306 mL) under a nitrogen atmosphere. To the solution,
acetic anhydride (170 mL, 1.80 mol) and maleic acid (3.48 g, 0.03 mol) were added,
and the mixture was stirred. The reaction was warmed to 120 to 125 °C, stirred at
this temperature for 24 h, and then cooled to 10 °C or lower. To this reaction mixture,
Simmons–Smith
cyclopropanation
O
N
CbzO
H
H
H
H
A
Cbz
A
HO
N
H
Cbz
H
HO
N
H
Cbz
H
HO
N
H
Cbz
H
CbzO
H
A
4
O
N
H
H
H
D
E
F
Cbz
O
N
CbzO
H
H
H
H
A
D
E
F
3
Cbz
Zn
P
O
O
OAr
OAr
H
L
=
Zn
L
EtH
I
I
CH
2
I
2
EtI
I Zn
L
I
Zn
L
L
Zn
I
+
H
O
HO
1
MgSO
4
, p-TsOH
15–25 °C, 91%
O
O
H
2
OH
OO
HO
Ac
2
O, DMA
125 °C, 87%
H
O
3
HO OH
O O
Morpholine, Py
MeCN, PhCH
3
, 80 °C
CO
2
H
4
Ac
2
O, TEA, DMA
115 -117 °C
62%, 2 steps
O
5
Steps
Mirogabalin besylate
H
H
NH
2
. PhSO
3
H
HO
2
C
4 Mechanism Problems from Reactions Give Expected Products116
toluene (410 mL) and water (410 mL) were added, and a 25% aqueous sodium
hydroxide solution (586 mL) was slowly added with stirring to separate an organic
layer. The aqueous layer was subjected to extraction with toluene (210 mL), and the
extract was combined with the organic layer and then washed with water (102 mL)
and 20% saline (102 mL) in this order. The organic layer was filtered to remove
insoluble matter. Then, the obtained product was used in the next step without
being concentrated or purified. The solution of the crude product thus obtained was
analyzed by gas chromatography and consequently contained 2-ethylpent-4-enal
(58.44 g, yield: 87%).
1
HNMR (400 MHz, CDCl
3
) d 0.93 (t, 3H, J = 7.4 Hz), 1.53–1.61
(m, 1H), 1.64–1.73 (m, 1H), 2.21–2.34 (m, 2H), 2.37–2.44 (m, 1H), 5.04–5.11 (m, 2H),
5.75 (ddt, 1H, J = 10.0, 17.2, and 7.0 Hz), 9.62 (d, 1H, J = 2.0 Hz).
3-Ethylbicyclo[3.2.0]hept-3-en-6-one (5). (2E)-4-Ethylhepta-2,6-dienoic
acid (100.57 g) obtained by the method described above was dissolved in
N,N-dimethylacetamide (255 mL) under a nitrogen atmosphere. To the solution,
acetic anhydride (108 mL, 1.14 mol) and triethylamine (79 mL, 0.57 mol) were
added. The reaction mixture was warmed and stirred at 115 to 117 °C for 5 hours.
The reaction mixture was cooled to room temperature, and n-hexane (510 mL) and
water (714 mL) were added thereto to separate an organic layer. The aqueous layer
was subjected to two extractions with hexane (each with 255 mL), and all organic
layers were combined and then washed with a 5% aqueous sodium bicarbonate
solution (102 mL) and water (102 mL) in this order. The obtained organic layer
was concentrated under reduced pressure, and the residue was distilled (90–100 °C,
approximately 25 mmHg) to obtain the title compound (50.92 g, colorless oil sub-
stance) (overall yield from 1,1-bis(allyloxy)butane: 62%).
1
HNMR (400 MHz, CDCl
3
)
δ 1.07 (t, 3H, J = 7.4 Hz), 2.14 (q, 2H, J = 7.4 Hz), 2.28–2.34 (m, 1H), 2.75–2.86
(m, 1H), 2.21–2.34 (m, 1H), 3.16–3.25 (m, 1H), 4.16–4.22 (m, 1H), 5.20–5.24 (m, 1H).
The Mechanism
The acid-catalyzed elimination of allylic alcohol from 2 gives vinyl allyl ether A and
then a Claisen rearrangement leads to the aldehyde 3.
Reaction of the acid 4 with Ac
2
O provides the mixed anhydride B. In the presence
of TEA, one molecule of acetic acid is eliminated to form a mixture of cis and trans
𝛼, β-unsaturated ketenes C. The cis isomer undergoes an intramolecular [2 + 2]
cycloaddition to produce the product (5). In the conventional method, the ketene
intermediate C was produced from corresponding acid chloride and the yield of the
cycloaddition was lower (≤50%) [72].
Another possible mechanism is that the mixed anhydride B undergoes an intra-
molecular synergistic cyclization to yield the product 5. This mechanism explains
the yield of the product is higher than the conventional method [72].
O
O
OH
OO
HO
Ac
2
O, DMA
125 °C
H
O
H
+
H
O
H
O
HO
Claisen
rearrangement
2
3
A
O
+
4.3 Formation of Cyclic Alkane and Derivatives 117
4.3.3 Cyclopentane
Problem 26: Preparation of cis-2-(Methoxycarbonyl)cyclopentane-1-
carboxylic Acid
Compound 3 is a diacyl glycerolacyl transferase-1 inhibitor with potential appli-
cation for treatment of obesity and dyslipidemia [73]. In a synthesis of 3, chemists
from Abbott Laboratories employed (±)-2-(methoxycarbonyl)cyclopentane-1-
carboxylic acid (2) as a starting material [73]. The synthesis of 2 was described in
a patent application starting from ethyl 2-oxocyclohexane-1-carboxylate (1) by the
reaction sequence as shown below [74].
Please explain the mechanism for the formation of 2 from 1.
Experimental Procedure (from WO2013/095275 A1)
(1,2-Cis)-cyclopentane-1,2-dicarboxylic acid (BB2-a). Br
2
(112.8 g, 705.6 mmol)
was added dropwise at 0 °C to a solution of ethyl 2-oxocyclohexane carboxylate
(120 g, 705.6 mmol) in chloroform (360 mL). The resulting reaction mixture was
stirred at room temperature overnight, then washed with NaHCO
3
(2 × 200 mL)
and brine (2 × 100 mL). The organic layer was dried over Na
2
SO
4
and concentrated
O
5
CO
2
H
AcOH
O
O O
H
4
Et
3
N
B
AcOH
C O
+
Cis-C
C O
Trans-C
[2+2]
Ac
2
O
H
+
O
5
CO
2
H
Ac
2
O
AcOH
O
O O
H
H
+
AcOH
4
Et
3
N
B
O
CO
2
Et
1. Br
2
, CHCl
3
2. KOH
3. Ac
2
O
4. MeOH
55%
HO
2
C
CO
2
Me
(+/–)-2
1
Steps
O
N
H
N
H
O
Ph
3
CO
2
Me