A scalable process to the key intermediate of cilazapril, (S)-1-benzyloxycarbonylhexahydropyridazine-3-carboxylic acid, through a novel cascade course

Article abstract of DOI:10.1021/op400155u

A novel and efficient manufacturing technology is disclosed in the present work for the preparation of (S)-1-benzyloxycarbonylhexahydropyridazine-3- carboxylic acid, which is a key intermediate of cilazapril. The whole process includes only three steps; the first two steps were conducted in one pot, followed by a novel selective removal of a Cbz group in a cascade course.

Full text of DOI:10.1021/op400155u

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Full Paper
A Scalable Process to the Key Intermediate of Cilazapril:
(S)-1-Benzyloxycarbonylhexahydropyridazine-3-
carboxylic acid, Through a Novel Cascade Course
Yu Chen, Yuwei Lu, Qing Zou, Huansheng Chen, and Dawei Ma
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op400155u • Publication Date (Web): 29 Jul 2013
Downloaded from http://pubs.acs.org on August 3, 2013
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A Scalable Process to the Key Intermediate of
Cilazapril: (S)ꢀ1ꢀ
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Benzyloxycarbonylhexahydropyridazineꢀ3ꢀ
carboxylic acid, Through a Novel Cascade Course
Yu Chen,* Yuwei Lu, Qing Zou, Huansheng Chen, Dawei Ma
Shanghai AoBo Bio-pharmaceutical Technology Co., Ltd.,
No.1011, Halei Road, Zhangjiang High-Tech Park, Shanghai 201203, P.R.
China
ABSTRACT: A novel and efficient manufacturing technology is disclosed in the present work
for the preparation of (S)ꢀ1ꢀbenzyloxycarbonylhexahydropyridazineꢀ3ꢀcarboxylic acid, which is a
key intermediate of cilazapril. The whole process includes only three steps; the first two steps
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were conducted in one pot, followed by a novel selective removal of Cbz group in a cascade
course.
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Introduction
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(S)ꢀHexahydropyridazineꢀ3ꢀcarboxylic acid1 (1, Figure 1), an architecturally novel cyclic αꢀ
hydrazino acid, has been found to be an important component in a large of peptide natural
substances, such as monamycins,2 azinothricin,3 aurantimycins,4 polyoxypeptins5, etc.
Compound 1 shows appreciable biological activity, and appears to interfere with γꢀaminoꢀbutyric
acid (GABA) uptake.6 Among (S)ꢀhexahydropyridazineꢀ3ꢀcarboxylic acid derivatives, (S)ꢀ1ꢀ
benzyloxycarbonylhexahydropyridazineꢀ3ꢀcarboxylic acid (2, Figure 1), a key intermediate of
antihypertensive drug cilazapril,7 is the most attractive.
Figure 1. (S)ꢀHexahydropyridazineꢀ3ꢀcarboxylic acid derivatives.
However, it’s still a challenge to construct this chiral sixꢀmembered nitrogen containing
heterocyclic compound 2. To the best of our knowledge, all methods reported by other groups for
the synthesis of 2 are through removal of both substituent groups on two nitrogen atoms of (S)ꢀ1,
2ꢀdiꢀ(benzyloxycarbonyl)hexahydropyridazineꢀ3ꢀcarboxylic acid (3, Figure 1), followed by the
rebuilding of Cbz group on one of the nitrogen atoms far away from carboxyl group. These
methods suffer from the drawbacks such as long route, tedious operation as well as the use of
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expensive regents (Scheme 1).8 Herein, we report a novel scalable approach to (S)ꢀ1ꢀ
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benzyloxycarbonylhexahydropyridazineꢀ3ꢀcarboxylic acid 2.
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Scheme 1. Known methods reported by other groups
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Results and Discussion
During the exploration of cilazapril, our group developed a novel synthetic method to 2, which
could be directly constructed by selective removal of one Cbz group on nitrogen atom adjacent to
carboxyl group of 3 (Scheme 2).9 However, 2 could be only synthesized in a very small scale
(grams scale) in the early stage by using this method.
Scheme 2. Formation of 2 through selective removal of one Cbz group of 3
After careful optimization and deep exploration, we realized the synthesis of 2 in Kg scale. The
whole process, as shown in Scheme 3, includes only three steps starting from the asymmetric αꢀ
hydrazination of bromoaldehyde 4.10 Only intermediate hydrazine acid 6 was isolated in the
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whole course. Specially, selective removal of one Cbz group in a cascade course simplifies the
operation, consequently brings more benefits to the industrial development.
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Scheme 3. The whole process for the synthesis of 2
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First, hydrazine aldehyde 5 was formed through prolineꢀinduced asymmetric αꢀhydrazination of
4 with DBAD (dibenzyl azodicarboxylate), which was commercially available or could be
prepared easily according to the known method.11 Since this asymmetric αꢀhydrazination was
first reported by another group,12 we just made simple modifications to the process. It was found
that one of the key points was the amount of bromoaldehyde 4 because of its instability under
these conditions even at −10 °C. The details are shown in Table 1. For example, when 1.3 equiv
of 4 was used, the yield was only 57% without any 4 detected after reaction. Instead, several
impurities appeared (Table 1, entry 1). The yield was improved with the increased amount of
aldehyde. 1.8 equiv was found to be the best for yield of 5. However, the yield was not helped
when the amount of 4 increased further (Table 1, entries 2−4). According to the literature,12
higher temperature resulted in poor yield. Nevertheless, we found it unnecessary to conduct the
reaction under lower temperature, such as −10 °C, which on the contrary led to a very slow
reaction (Table 1, entry 5). In addition to CH3CN, DCM was found to be another good solvent
(Table 1, entry 6).
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Table 1. Asymmetric α-hydrazinationa
5
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9
yield of 5
entry
4 (equiv)
solvent
temp (°C)
time (h)
(%)b
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1.3
1.5
1.8
2.0
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1.8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
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aAll reactions were carried out with DBAD (0.01 mol), 4 and Dꢀproline (10 mol% related to
the amount of 4) in solvent. bIsolated yield. c>99% ee%. The enantiomeric excess was determined
for 6 after direct oxidation of 5 without separation, because 5 was liable to be racemized.
The next step was to convert 5 to its acid 6. When KMnO4 was first used as the oxidant, the yield
was good in small scale. Unfortunately, the yield decreased to less than 50% when scaled up.
What made it even worse is that separation of the product was quite hard because large amounts
of black materials formed during oxidation. After screening, NaClO2 showed a good
performance, not only for the reaction, but also for the separation. Strikingly, the transformation
from DBAD to 6 could be completed in a oneꢀpot course without separation of 5, which was
liable to be racemized.[13] If the reaction was performed in that way, it should be monitored by
TLC or HPLC. For a typical reaction, 0.75 equiv of NaClO2 with respect to aldehyde 4 is
sufficient for a complete oxidation. When the reaction was carried out in oneꢀpot, DCM had an
advantage over CH3CN, due to much easier separation from aqueous mixture. After simple
purification, 6 was obtained in good yield as well as high enantiomeric excess from DBAD
(Scheme 4).
Scheme 4. Formation of 6 from the reaction of DBAD with 4 in one-pot
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The ringꢀclosing reaction of 6 to 2 was unexpected but interesting. In the initial explorations,
either δꢀlactone 7 or the mixture of 7 and 3 was produced. As can be seen from table 2 and
Scheme 5, when an organic base such as Et3N, DMAP or an inorganic base such as Na2CO3 or
NaH was used at 25 °C, δꢀlactone 7 was the only product (Table 2, entries 1−4). Lower
temperature decelerated the attack of carboxyl group on bromide, causing the formation of 3 as
minor product, when at least 2 equiv of NaH was employed (Table 2, entries 5−6). But 1 equiv of
NaH still generated 7 completely at 0 °C (Table 2, entry 7). In contrast to NaH, other bases like
Et3N, DMAP or Na2CO3 gave nothing at 0 °C with the starting material recovered (Table 2,
entries 8−10). It seemed that the further freduction in temperature made the reaction proceed
quite slowly even in the presence of NaH (Table 2, entry 11). It was surprising that 2 was
unexpectedly observed, when the mixture of 3 and 7 stood with the temperature rising from 0 °C
to 25 °C before quenching (Table 2, entry 12).
Scheme 5. Ring-closing reaction of compound 6
Table 2. Ring-closing reaction of compound 6a
yield (%)b
entry
1
base
solvent
DCM
temp (°C)
25
time (h)
24
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Et3N, 2 equiv
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DMAP, 2 equiv
Na2CO3, 2 equiv
NaH, 2 equiv
NaH, 2 equiv
NaH, 3 equiv
NaH, 1 equiv
Et3N, 2 equiv
DMAP, 2 equiv
Na2CO3, 2 equiv
NaH, 2 equiv
NaH, 2 equiv
DCM
DMF
DMF
DMF
DMF
DMF
DCM
DCM
DMF
DMF
DMF
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aAll reactions were carried out with 6 (0.01 mol) and base in solvent. Isolated yield. cThe
b
d
reaction was quenched with HCl aq also at 0 °C. The reaction was stirred at 0 °C for 12 h, was
then warmed to 25 °C on standing. eThe reaction time at 0 °C.
The direct formation of 2 from the reaction attracted our great attention, and compelled us to
study it. We found that this transformation actually included two successive stages. In the first
stage, 9[14] (anion of 3) was formed at lower temperature (0 °C). When temperature rose at next
stage, the transformation of 9 to 2 occurred (25 °C). A possible mechanism is postulated in
Scheme 6. The removal of hydrogen proceeded in the presence of at least 2 equiv of base to yield
dianion 8 from 6 at 0 °C. After the attack of nitrogen anion on bromide, intermediate 9 was
formed. At higher temperature such as 25 °C, 9 was then subjected to ringꢀclosing reaction to
form bicyclicꢀring anhydride 10,[15, 16] which was transformed to 2 through either an acid or base
mediated hydrolysisꢀdecarboxylation cascade course. It was obvious that temperature and the
kind of base were the crucial factors for this cascade reaction.
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Scheme 6. Postulated mechanism
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Knowing the above information, we then turned our attention to other bases. The results arelisted
in table 3 and Scheme 7. The reaction proceeded slowly in the presence of alkoxides such as
NaOtBu, NaOEt, and only δꢀlactone 7 was obtained with a trace of 3 detected by TLC (Table 2,
entries 1−2). Surprisingly, NaOH exhibited perfect activity for the formation of 3 exclusively,
and the yield of 3 was doubled to 92% when the reaction time was extended (Table 2, entries
3−4). As long as 3 was wellꢀformed, the formation of 2 was quite easy. The selective removal of
the Cbz group took place spontaneously at increasing temperature (Table 2, entry 5). In addition,
KOH in THF was a good option (Table 2, entries 6−7).
Scheme 7. Condition screen for the formation 2 from 6
Table 3. Condition screen for the formation 2 from 6a
entry
conditiona
yield (%)b
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−
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Stage 1: NaOtBu (2 equiv), DMF, 0 °C, 24 hc
Stage 1: NaOEt (2 equiv), DMF, 0 °C, 24 hc
Stage 1: NaOH (2 equiv), DMF, 0 °C, 12 hc
Stage 1: NaOH (2 equiv), DMF, 0 °C, 24 hc
Stage 1: NaOH (2 equiv), DMF, 0 °C, 24 h
Stage 2: 3 h, 25 °C
−
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−
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trace
trace
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Stage 1: NaOH (2 equiv), THF, 0 °C, 24 h
Stage 2: 3 h, 25 °C
Stage 1: KOH (2 equiv), THF, 0 °C, 24 h
Stage 2: 3 h, 25 °C
aAll reactions were carried out with 6 (0.01 mol) and base in solvent. Isolated yield. cThe
b
reaction was not proceeded to stage 2.
CONCLUSION
A novel and efficient manufacturing technology was developed for the preparation of (S)ꢀ1ꢀ
benzyloxycarbonylhexahydropyridazineꢀ3ꢀcarboxylic acid 2, which is a key intermediate of
antihypertensive drug cilazapril. Compound 2 was finally obtained in 75% overall yield with
99% purity and >99%ee after three steps. In the final step, a novel selective removal of Cbz
group took place in a cascade course.
EXPERIMENTAL SECTION
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General. Melting points were recorded on an RYꢀ1 melting point apparatus and are uncorrected.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a Bruker Avance 400
spectrometer in CDCl3 or DMSOꢀd6 using tetramethylsilane (TMS) as internal standards. J
values are given in hertz. Mass spectra were recorded on a Finnigan MATꢀ95/711 spectrometer.
Elemental analysis was performed on an MODꢀ1106 instrument. Optical resolutions were
determined on a Jasco Pꢀ1020 polarimeter. HPLC analysis was performed by a standard method
on an Intersil ODSꢀ3 C18 column, 250 mm × 4.6 mm (5 ꢀm); λ = 210 nm; mobile phase: A
(CH3CN) and B (0.2% H3PO4), 60:40 v/v. Enantiomeric excess was determined by HPLC using
CHIRALCEL OJꢀH column, 250 mm × 4.6 mm (5 ꢀm); λ = 210 nm; mobile phase: A (hexane)
and B (iꢀPrOH), 80:20 v/v. The HPLC analysis data are reported in area % and are not adjusted
to weight %.
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(S)-5-Bromo-2-N, N’-di-(benzyloxycarbonyl)hydrazino-1-pentanoic acid (6). To a stirred
solution of 4 (1.49 kg, 9.0 mol) in DCM (12 L) was added DꢀProline (103.5 g, 0.9 mol) and
DBAD (1.49 kg, 5.0 mol) at 0 °C. DBAD disappeared after the mixture was stirred for 12 h at
that temperature. Then NH2SO3H (873.0 g, 9.0 mol) was added in portion to the above mixture at
0 °C, followed by the slow addition of 80% NaClO2 (763.6 g, 6.75 mol) in H2O (6 L) with
control of the temperature less than 0 °C. The reaction was finished after the addition of NaClO2
solution. Then the mixture was quenched by addition of saturated Na2SO3 solution until the
potassium iodideꢀstarch test paper showed that no oxidant existed. Solid was removed after the
mixture was stirred for 1 h at 25 °C. The aqueous layer was extracted with DCM (2 × 3 L) after
separation. The combined organic layer was concentrated after washed with brine (10 L). Solid
precipitate when solvent was concentrated to 10% of the total volume. This solid was dried at 50
°C under vacuum after filtration to afford 6 (2.11 kg, 88% from DBAD) as an offꢀwhite solid
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with 98.5% purity by HPLC (retention time: 30.2 min), and >99%ee (retention time: 22.5 min for
(S) and 18.7 min for (R)). Mp: 114−115 oC. 1H NMR (DMSOꢀd6, 400 MHz): δ = 1.73−2.06 (br,
m, 4H), 3.48 (br, s, 2H), 4.60 (br, s, 1H), 5.11−5.16 (br, s, 4H), 7.25−7.40 (br, m, 10H),
9.06−9.58 (br, s, 1H); 13C NMR (DMSOꢀd6, 100 MHz): δ = 27.3, 27.5, 29.5, 35.1, 60.2, 61.2,
66.7, 67.7, 67.9, 127.6, 127.9, 128.1, 128.3, 128.4, 128.8, 136.6, 136.9, 155.9, 156.2, 157.2,
171.8; ESIꢀMS (m/z) 477, 479 [M − H]‾.
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(S)-1-Benzyloxycarbonylhexahydropyridazine-3-carboxylic acid (2). The mixture of NaOH
(352.0 g, 8.8 mol) with 6 (2.11 kg, 4.4 mol) in THF (15 L) was stirred for 24 h at 0 °C, followed
by keeping stirring at 25 °C for another 3 h. To this mixture was added successively 1N NaOH
aq (4.4 L) and sat NaHCO3 aq (5 L). The organic layer was separated and extracted with sat
NaHCO3 aq (2 × 5 L), then discarded. The combined aqueous layer was washed with hexane (2 ×
5 L), was then acidified with 37% HCl aq. to pH=4~5. The precipitated solid was collected and
slurried with EtOAc (3 L) for 3 h. This solid was dried at 50 °C under vacuum to afford 2 (982.9
g, 85%) as a white solid with 99% purity by HPLC (retention time: 15.4 min), and >99%ee
(retention time: 20.9 min for (S) and 17.7 min for (R)). Mp: 166−167 °C (lit. mp 168−169).8c
[α]D = −35.4 (T = 20 oC, c = 1 g/100 mL, MeOH), (lit. [α]D = −35.0)8c 1H NMR (DMSOꢀd6, 400
MHz): δ = 1.51−1.55 (br, m, 2H), 1.68−1.70 (br, m, 1H), 1.87−1.91 (br, m, 1H), 3.06 (br, s, 1H),
3.37 (dd, J = 9.6 Hz, 2.8 Hz, 1H), 3.82 (d, J = 12.8 Hz, 1H), 5.09 (dd, J = 15.2 Hz, 12.4 Hz, 2H),
7.30−7.38 (m, 5H), 12.75 (br, s, 1H); 13C NMR (DMSOꢀd6, 100 MHz): δ = 23.4, 27.6, 44.5, 58.3,
66.8, 128.0, 128.3, 128.8, 137.4, 155.6, 173.2; ESIꢀMS (m/z) 265 [M + H]+; Anal. Calcd for
C13H16N2O4: C, 59.08; H, 6.10; N, 10.60. Found: C, 59.20; H, 6.18; N, 10.53.
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(S)-5-Bromo-2-N, N’-(dibenzyloxycarbonyl)hydrazino-1-pentanal (5).
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To a stirred solution of 4 (2.97 g, 0.018 mol) in CH3CN (24 mL) was added DꢀProline (0.21 g,
0.0018 mol) and DBAD (2.98 g, 0.01 mol) at 0 °C. DBAD disappeared after the mixture was
stirred for 12 h at that temperature. The mixture was then concentrated to afford an oil, which
was purified via silica gel column chromatography using EtOAc/hexane (1:4) as eluent to yield
4.26 g (92%) of 5 as an offꢀwhite solid. Mp: 84−85 °C. 1H NMR (CDCl3, 400 MHz): δ =
1.65−2.20 (br, m, 4H), 3.35−3.50 (br, m, 2H), 4.50−4.80 (br, m, 1H), 5.11−5.16 (br, s, 4H),
6.68−6.82 (br, s, 1H), 7.25−7.35 (br, m, 10H), 9.50−9.60 (br, s, 1H); 13C NMR (CDCl3, 100
MHz): δ = 24.3, 24.9, 28.9, 33.5, 33.9, 66.6, 67.7, 68.0, 68.7, 69.1, 127.8, 128.2, 128.7, 135.1,
135.4, 156.3, 156.9, 198.5, 199.0; ESIꢀMS (m/z) 461, 463 [M − H]‾.
(S)-1, 2-Di-(benzyloxycarbonyl)hexahydropyridazine-3-carboxylic acid (3). To a solution of
6 (4.79 g, 0.01 mol) in DMF (40 mL) was added NaOH (0.80 g, 0.02 mol) at 0 °C. The mixture
was stirred for 24 h at 0 °C, then quenched by 1 N HCl aq (30 mL) at 0 °C. The aqueous layer
was removed after extracted with EtOAc (2 × 80 mL). The combined organic layer was dried
with anhydrous Na2SO4, then concentrated to afford an oil after filtration. The product was
purified via silica gel column chromatography using EtOAc/hexane (1:2) as eluent to yield 3.83 g
(96%) of 3 as an oil. 1H NMR (CDCl3, 400 MHz): δ = 1.56−2.21 (br, m, 4H), 2.90−3.20 (br, m,
1H), 4.00−4.25 (br, m, 1H), 5.05−5.29 (br, m, 5H), 7.25−7.40 (br, m, 10H); 13C NMR (CDCl3,
100 MHz): δ = 20.0, 20.3, 23.9, 24.6, 43.7, 44.7, 55.7, 56.9, 68.0, 68.7, 69.1, 127.7, 127.9, 128.2,
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128.4, 128.5, 128.6, 128.7, 135.2, 135.5, 136.1, 155.2, 155.6, 156.6, 171.4, 172.8; ESIꢀMS (m/z)
399 [M + H]+.
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(S)-3-N, N’-di-(benzyloxycarbonyl)hydrazinyltetrahydro-2H-pyran-2-one (7). The mixture
of 6 (4.79 g, 0.01 mol) and Et3N (2.02 g, 0.02 mol) was stirred in DCM (30 mL) for 24 h at 25
°C. After the reaction was finished, the mixture was concentrated, and then purified via silica gel
column chromatography using EtOAc/hexane (1:8) as eluent to yield 3.30 g (83%) of 7 as an offꢀ
white solid. Mp: 93−94 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.95−2.45 (br, m, 4H), 4.20−5.20
(br, m, 7H), 6.60−6.95 (br, s, 1H), 7.20ꢀ7.35 (br, m, 10H); 13C NMR (CDCl3, 100 MHz): δ =
21.8, 22.0, 22.6, 23.6, 57.2, 58.6, 67.8, 68.6, 69.0, 127.6, 128.1, 128.2, 128.4, 128.6, 135.5, 155.8,
156.2, 156.8, 169.9, 170.4; ESIꢀMS (m/z) 399 [M + H]+; Anal. Calcd for C21H22N2O6: C, 63.31;
H, 5.57; N, 7.03. Found: C, 63.41; H, 5.51; N, 7.14.
ASSOCIATED CONTENT
Supporting Information.
1H and 13C NMR spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: chenykk@hotmail.com. Tel: +86(21)51320130. Fax: +86(21)51320368.
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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We thank Dr. Wei Zhu, Dr. Xiaoan Xie and Dr. Qiliang Yuan for their support and discussion.
We are also grateful for the paperꢀediting from Miss Jessica Jialu Chen, Miss Annie Jing Hu and
Dr Jiong Zou as well as for the cooperation from the colleagues of analytic department.
REFERENCES
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7. Attwood, M. R.; Hassall, C. H.; Krohn, A.; Lawton, G.; Redshaw, S. J. Chem. Soc. Perkin
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Bhatia, G. S.; Collins, T. C.; Jogiya, N. Tetrahedron. 1996, 52, 1047. (c) Coats, R. A.; Lee, S.;
Davis, K. A.; Patel, K. M.; Rhoads, E. K.; Howard, M. H. J. Org. Chem. 2004, 69, 1734. (d)
Schmidt, U.; Braun, C.; Sutoris, H. Synthesis. 1996, 223. (e) Adams, C. E.; Aguilar, D.;
Hertel, S.; Knight, W. H.; Paterson, J. Syn. Commun. 1988, 18, 2225. (f) Aoyagi, Y.; Saitoh,
Y.; Ueno, T.; Horiguchi, M.; Takeya, K. J. Org. Chem. 2003, 68, 6899. (g) Brieden, W.;
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9. Ma, D.; Yuan, Q.; Xie, X.; Fan, Q.; Chen, Y.; Zhu, W. C. N. patent 102250014, 2011; CAN
156:11146.
10. Compound 4 was synthesized according to the known method. Please see: (a) Chong, M.;
Heuft, M. A.; Rabbat, P. J. Org. Chem. 2000, 65, 5837. (b) Shu, L.; Wang, P.; Radinov, R.;
Dominique, R.; Wright, J.; Alabanza, L. M.; Dong, Y. Org. Process. Res. Dev. 2013, 17, 114.
11. DABD could be commercially purchased or easily prepared according to the known method.
Please see: (a) Little, R. D.; Venegas, M. G. Org. Syn., Coll. 1990, 7, 56. (b) Mellor, J. M.;
Pathirana, R. N. J. Chem. Soc. Perkin Trans. 1. 1984, 753. (c) Starr, J. T.; Rai, G. S.; Dang,
H.; McNelis, B. J. Syn. Commun. 1997, 27, 3197.
12. Henmi, Y.; Makino, K.; Yoshitomi, Y.; Hara, O.; Hamada, Y. Tetrahedron: Asymmetry.
2004, 15, 3477.
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13. >99% ee% was obtained for crude 6, if the reaction was carried out in oneꢀpot without
separation of 5. However, 6 was found to be completely racemized (0%ee and [α]D = 0),
when the separated 5, either by column chromatography or by recrystallization, was used
under the same oxidation condition.
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14. Compound 3 could be transformed to compound 2 in 95% yield in THF using NaOH as base
at ambient temperature, which meant that 3 (or 9) was one of the intermediate from 6 to 2.
15. Compound 10 was synthesized according to literature listed in reference 16. To 3 (200 mg,
0.5 mmol) was added a solution of oxalyl chloride (318 mg, 2.5 mmol) in benzene (5 mL) at
25 oC. The reaction mixture was stirred for 18 h at that temperature, and then concentrated in
vacuo to afford the 10 as a colorless oil mixed with BnCl. 1H NMR (CDCl3, 400 MHz): δ =
1.65−2.23 (br, m, 4H), 3.02−3.33 (br, m, 1H), 4.07−4.21 (br, m, 2H), 4.52 (s, CH2 of BnCl),
5.14 (br, s, 2H), 7.12−7.29 (br, m, 5H, mixed with ArꢀH of BnCl). ESIꢀMS (m/z) 265 [M －
CO2 + H3O]+. With 10 in hand, we then mixed the solution of 10 in THF with water under
either acidic or basic condition. As expected, 2 was formed smoothly almost quantitatively.
16. Oelke, A. J.; Antonietti, F.; Bertone, L.; Cranwell, P. B.; France, D. J.; Goss, R. J. M.;
Hofmann, T.; Knauer, S.; Moss, S. J.; Skelton, P. C.; Turner, R. M.; Wuitschik, G.; Ley, S. V.
Chem. Eur. J. 2011, 17, 4183.
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