Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor

Article abstract of DOI:10.1002/chem.202100059

Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5–10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.

Full text of DOI:10.1002/chem.202100059

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&
Synthetic Methods
Rapid and Mild Lactamization Using Highly Electrophilic
Triphosgene in a Microflow Reactor
Shinichiro Fuse,*[a] Keiji Komuro,[b, c] Yuma Otake,[b, c] Hisashi Masui,[a] and
Hiroyuki Nakamura[b]
Abstract: Lactams are cyclic amides that are indispensable
as drugs and as drug candidates. Conventional lactamization
includes acid-mediated and coupling-agent-mediated ap-
proaches that suffer from narrow substrate scope, much
waste, and/or high cost. Inexpensive, less-wasteful ap-
proaches mediated by highly electrophilic reagents are at-
tractive, but there is an imminent risk of side reactions.
Herein, a methods using highly electrophilic triphosgene in
a microflow reactor that accomplishes rapid (0.5–10 s), mild,
inexpensive, and less-wasteful lactamization are described.
Methods A and B, which use N-methylmorpholine and N-
methylimidazole, respectively, were developed. Various lac-
tams and a cyclic peptide containing acid- and/or heat-labile
functional groups were synthesized in good to high yields
without the need for tedious purification. Undesired reac-
tions were successfully suppressed, and the risk of handling
triphosgene was minimized by the use of microflow technol-
ogy.
Introduction
though these approaches usually use inexpensive reagents,
they require high temperature, extended periods of time, and
acidic conditions; therefore, the substrate scope is limited. Ap-
proaches mediated by coupling agents (e.g., DCC,[16] BOP,[17]
and the Mukaiyama reagent[18]) are used for the synthesis of
functionalized lactams (Scheme 1b). Moderately electrophilic
coupling agents usually are used to avoid undesired reactions
at the amino group in I and racemization. Although these ap-
proaches feature broad substrate scope, they require expen-
Amides are the chemical structure most frequently found in
biologically active compounds reported in medicinal-chemis-
try-related journals from 1976 to 2018.[1] In fact, approximately
40% of bioactive compounds contain the amide structure. The
b- and g-lactam structures rank 15th and 42nd among the 351
ring systems found for marketed drugs,[2] which is why we
stated that cyclic amides are of such importance as drugs and
drug candidates. Lactams can be prepared by iodolactamiza-
tion,[3] Beckmann rearrangement,[4] Schmidt reaction,[5] and Ki-
nugasa reaction.[6] All of these reactions, however, require
harsh conditions and/or are limited in the scope of available
substrates. Lactamization (I!III) is the most frequently used
process in the synthesis of lactams and can be broadly divided
into two groups, as shown in Scheme 1.[7] Approaches mediat-
ed by acids (Ti(OiPr)4,[8] Al2O3,[9] (CF3CH2O)3B,[10] ArB(OH)2,[11]
Bu2SnO,[12] Et3Ga,[13] polyoxometalate,[14] and ZSM-5[15]) are used
for the synthesis of less-functionalized lactams (Scheme 1a). Al-
[a] Prof. Dr. S. Fuse, Dr. H. Masui
Department of Basic Medicinal Sciences
Graduate School of Pharmaceutical Sciences, Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8601 (Japan)
E-mail: fuse@ps.nagoya-u.ac.jp
[b] K. Komuro, Dr. Y. Otake, Prof. Dr. H. Nakamura
Laboratory for Chemistry and Life Science, Institute of Innovative Research
Tokyo Institute of Technology, 4259 Nagatsuta-cho
Midori-ku, Yokohama 226-8503 (Japan)
[c] K. Komuro, Dr. Y. Otake
School of Life Science and Technology, Tokyo Institute of Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503 (Japan)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
Scheme 1. Conventional lactamization approaches (a, b) and the developed
https://doi.org/10.1002/chem.202100059.
microflow lactamization approach (c).
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sive and wasteful coupling agents that sometimes require tedi-
ous purification.
Table 1. Examination of solvents and countercations in 1 in microflow
lactamization.[a]
Continuous-flow synthesis has revolutionized synthetic or-
ganic chemistry over the past several decades.[19] The risk in
handling dangerous compounds can be decreased,[20] and
scale-up can be easily achieved[21] by simply extending the run-
ning time or increasing the number of reactors. Reaction times
(<1 s) and temperatures can be precisely controlled due to
the short diffusion length and rapid heat transfer of microflow
reactors (inner diameter ꢀ1 mm).[22] Many sophisticated meth-
ods for flow synthesis utilize highly active and unstable com-
pounds, and these cannot be achieved by conventional batch
approaches.[23] Therefore, it is important to expand the applica-
tion of microflow approaches to highly active and labile com-
pounds in order to further develop high-yielding, sustainable,
and inexpensive synthetic processes.
Entry
Solvent A
Solvent B
M
Yield[b] [%]
1
2
3
4
5
6
7
8
MeCN
THF
1,4-dioxane
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
THF
1,4-dioxane
hexane
EtOAc
Et2O
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Li
82
76
81
81
82
79
66
28
26
22
7
We have developed synthetic processes using highly active
and unstable compounds that cannot be achieved by conven-
tional batch approaches[24] and reported the mild and rapid
synthesis of linear peptides[24a–d,25] and amino acid N-carboxy
anhydrides (NCAs) with five- and six-membered rings[24e,h]
using highly electrophilic, inexpensive, and less-wasteful tri-
phosgene. During the course of the synthesis of a NCA with
seven-membered ring II from I, we coincidentally obtained g-
lactam III instead of II, probably due to spontaneous ring con-
traction of II (Scheme 1c). In general, the use of highly electro-
philic reagents such as triphosgene is risky in lactamization be-
cause they easily induce an undesired reaction (I!II’) and rac-
emization.[26] If the undesired reactions could be suppressed,
however, it would be an ideal approach. In the present
study we conducted triphosgene-mediated lactamization
(Scheme 1c) that was both rapid (0.5–10 s) and mild. Structur-
ally diverse lactams and a peptide containing acid- and/or
heat-labile functional groups were synthesized in good to high
yields without the need for tedious purification. The aforemen-
tioned undesired reactions were successfully suppressed and
the risk of handling toxic gas was minimized by the use of mi-
croflow technology.
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12
13
14
CH2Cl2
MeCN
MeCN
MeCN
76
84
76
K
Cs
[a] NMI=N-methylimidazole, Cbz=benzyloxycarbonyl, DMF=N,N-di-
methyl formamide, DMSO=dimethyl sulfoxide. [b] Yields were deter-
mined by HPLC-UV analysis.
ganic and aqueous solutions (Table 1, entries 1 and 6–11).
Readily removable MeCN was used as both solvents A and B in
the following studies. Countercations of 1 influenced its solu-
bility and basicity. The use of potassium salts afforded the best
results (Table 1, entries 1 and 12–14).
Organic bases were examined (Table 2). The basicity of the
amines significantly influenced the results. The use of both a
weak base, pyridine (pKaH<7), and strong bases, DMAP, N-
methylpiperidine, and DBU (pKaH>9), resulted in unsatisfacto-
ry yields (ꢀ50%; Table 2, entries 1 and 7–9), whereas the use
of moderately basic amines (7ꢀpKaHꢀ9) afforded higher
yields (Table 2, entries 2, 3, 5, and 6). NMM and N-methylpiperi-
dine have almost the same steric bulkiness, and the obvious
difference in the yields between the two clearly indicates the
importance of basicity in this reaction (Table 2, entry 3 vs.
entry 8). The nucleophilicity of amines is also important in this
reaction. Although N-ethylmorpholine (pKaH=7.7) and NMM
(pKaH=7.4) have similar basicity, the less nucleophilic N-ethyl-
morpholine afforded a lower yield (Table 2, entry 5) than NMM
(Table 2, entry 3). To verify the importance of the microflow
conditions, batch reactions were examined under the same re-
action conditions with the exception of reaction time (10 s),
because it was impossible to perform the batch reaction in
0.5 s (Table 2, entry 4). Although the reaction mixture was vigo-
rously stirred during the experiments, reproducible results
were not observed due to batch-to-batch differences in the
mixing efficiency. Observed yields under batch conditions were
Results and Discussion
Solvents and countercations were examined in the lactamiza-
tion of Cbz-protected ornithine 1 (Table 1). A V-shaped mixer[27]
and a T-shaped mixer were connected with a Teflon tube, and
the reactor was immersed in a water bath (208C). A solution of
the alkali metal salt of 1 and an amine base in solvent A and
water (1:1) was introduced into the first mixer via syringe
pump A. A solution of triphosgene (2) in solvent B was also in-
troduced into the first mixer, via syringe pump B. The carboxyl-
ate was rapidly activated by triphosgene, and this led to lac-
tamization. An aqueous solution of ammonium chloride was
introduced into the second mixer to quench the reaction, and
the resultant mixture containing 3 was poured into ethyl ace-
tate at 08C. Various solvents can be employed as solvent A
(Table 1, entries 1–5). The use of hydrophilic solvents (MeCN
and 1,4-dioxane) as solvent B was important, however, in order
to obtain good results, probably due to the rapid mixing of or-
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Table 2. Examination of bases in microflow lactamization.[a]
Entry
Base (pKaH[c])
Yield[d] [%]
1
2
3
4[b]
5
6
7
8
9
pyridine (5.2)[28]
NMI (7.0)[28]
55
84
Figure 1. 1H NMR spectrum of lactam 3 after phase separation.
Table 3. Study on the lactamization of Cbz-protected lysine 4.
NMM (7.4)[29]
90–92[e] (93[f])
NMM
73–80[e]
N-ethylmorpholine (7.7)[29]
Me2NBn (8.9)[30]
DMAP (9.7)[31]
65
84
40
50
2
N-methylpiperidine (10.1)[30]
DBU (11.5)[32]
[a] NMM: N-methylmorpholine, Bn: benzyl, DMAP: N,N-dimethylaminopyr-
idine, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene. [b] Batch reactions were
performed with vigorous stirring (1000 rpm). Reaction time was 10 s.
[c] The pKa value of the conjugate acid. [d] Yields were determined by
HPLC-UV analysis. [e] Three independent experiments were carried out.
[f] Yield of isolated product.
Entry
Base (pKaH[b]
)
t [s]
T [8C]
Yield[c] [%]
lower than those under flow conditions (Table 2, entry 3 vs.
entry 4). In addition, special care should be taken due to evolu-
tion of large amounts of gas such as HCl, CO2, and phosgene;
therefore, scale-up of the reaction in a batch reactor should be
avoided. On the other hand, microflow experiments were per-
formed safely, and more reproducible results were obtained. It
is noteworthy that no racemization was observed under the
optimized conditions of Table 2, entry 3 (for details, see Sup-
porting Information) although highly electrophilic triphosgene
was used. A plausible reaction mechanism is offered in
Scheme 3.
1
2
3
4
5[a]
NMM (7.4)
NMI (7.0)
NMI
NMI
NMI
0.5
0.5
10
10
10
20
20
20
60
60
35
52
58
61–63[c] (72[d]
61–62[e]
)
[a] Batch reactions were performed with vigorous stirring (1000 rpm). Re-
action time was 10 s. [b] The pKa value of the conjugate acid. [c] Yields
were determined by HPLC-UV analysis. [d] Yields of isolated product.
[e] Three independent experiments were carried out.
The conditions of Table 2, entry 3 (method A) afforded
highly pure lactam 3 with only simple phase-separation purifi-
cation. The observed 1H NMR spectrum of 3 is shown in
Figure 1. Method A was used for a later examination of the
substrate scope.[33]
tion). A plausible reaction mechanism is offered in Scheme 3.
Thus, conditions of Table 3, entry 4 (method B) were also used
for a following examination of the substrate scope.[34]
The substrate scope was examined for developed methods
A and B (Figure 2). Readily cyclizable g-lactams 6–9 as well as
11 and 12 were prepared in high yields by method A. On the
other hand, in the case of N-methylpyrrolidone (10), method B
was preferable, probably due to a slower rate of cyclization,
which was caused by the bulky NMe group. In the case of d-
lactams, interestingly, ornithines 16 and 17 were obtained in
high yields by method A. In the case of 13–15, however, meth-
od B was preferable. Method B was used to prepare e-caprolac-
tam (18) in a good yield. It is noteworthy that acid- and/or
heat-labile tert-butyl ester and the tert-butyloxycarbonyl (Boc)
group tolerated the developed conditions. In all cases, simple
phase separation and/or silica-gel column chromatography af-
forded the highly pure lactams, and tedious purification was
not required.
Next, we examined lactamization of the Cbz-protected lysine
4 (Table 3). Unexpectedly, the optimized conditions (method A)
resulted in a low yield (35%; Table 3, entry 1). We examined or-
ganic bases once again (for details, see Supporting Informa-
tion). As a result, the less-basic (pKaH=7.0) nucleophilic NMI af-
forded the best results for the lactamization of 4 (Table 3,
entry 2). Extension of the reaction time and increase in temper-
ature slightly improved the yield (Table 3, entries 2–4). The
comparative batch conditions afforded similar yields, although
special care should be taken due to the evolution of large
amounts of toxic gas (Table 3, entry 5). No racemization was
observed in the e-lactam formation under the optimized condi-
tions of Table 3, entry 4 (for details, see Supporting Informa-
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Scheme 2. Macrolactamization for the synthesis of protected cilengitide 20.
Labile functional groups are highlighted in yellow. EDC: 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide, Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-
sulfonyl.
Figure 2. Substrate scope of the developed microflow lactamization. Yields
of isolated products are shown. Labile functional groups are highlighted in
yellow.
Method B was applied to the synthesis of a cyclic RGD pep-
tide (protected cilengitide 20[35]).[25,36] Reportedly, macrolactam-
ization of 19b with 10 equiv of EDC·HCl (r.t., overnight) afford-
ed the desired 20b in approximately 38% yield (Scheme 2).[37]
On the other hand, our developed conditions afforded the de-
sired 20a in 72% yield from 19a (for preparation details, see
Supporting Information) in only 10 s, although 20a contains
an acid-labile N-methyl amide structure (Scheme 2).
A plausible reaction mechanism is shown in Scheme 3. We
speculated that highly active electrophiles 21 such as phos-
gene and acyl ammonium or acyl N-methyl imidazolium cation
were generated from the reaction between triphosgene (2)
and various nucleophiles including carboxylates (1 or 4), a
base, and water. The coupling of 1 or 4 with 21 rapidly afford-
ed 22. Then, a proton exchange between 22 and an organic
base occurred. The equilibrium between 22 and 23 prevented
an undesired coupling (22!24). It is conceivable that the use
of moderately basic NMM (pKaH=7.4) or NMI (pKaH=7.0) was
important for controlling the equilibrium (pKa of hydrochloric
salt 23: ca. 10.8[38]). Direct lactamization and/or formation of
NCA 25 and the subsequent ring contraction from 22 afforded
the desired lactams 3 and 5. Although it is unclear why meth-
od A is suitable for 3 and method B for 5, the differences in ba-
sicity and nucleophilicity between NMM (method A) and NMI
(method B) could have influenced the equilibrium between 22
and 23 and/or the reaction pathway (direct lactamization or
NCA formation).
Scheme 3. Plausible reaction mechanism of triphosgene-mediated lactamiza-
tion.
Conclusion
We have described a lactamization process that is rapid (0.5–
10 s), mild, and is accomplished by the use of triphosgene in a
microflow reactor. We developed NMM- (method A) and NMI-
mediated conditions (method B). Various lactams and a cyclic
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layer was washed three times with 1m HCl (1 mL). After the aque-
ous layer was extracted three times with EtOAc (2 mL), the organic
layer was washed with 1m HCl (1 mL), sat. NaHCO3 aq. (1 mL), and
brine (1 mL) at room temperature, dried over MgSO4, filtered, and
evaporated. The reaction mixture was purified by silica-gel column
chromatography (MeOH:CH2Cl2 =1:9). Lactam benzyl (S)-(2-oxoaze-
pan-3-yl)carbamate (5) was obtained as a white solid in 72% yield.
M.p. 119–1228C; IR (neat): 3247, 3091, 2930, 1721, 1668, 1497,
peptide containing acid- and/or heat-labile functional groups
were synthesized in good to high yields. In addition, the de-
sired compounds were obtained without tedious purification.
In lactamization, the use of highly electrophilic reagents is usu-
ally avoided due to high risk of side reactions. These undesired
reactions were successfully avoided, and the risk of handling
toxic gas was minimized by the use of microflow technology.
The developed methodology should be valuable for accelerat-
ing drug development based on various lactams.
1213, 1051, 744 cmÀ1
;
[a]2D5 =À1.3 (c=1.46, MeOH); 1H NMR
(400 MHz, CDCl3): d=7.35–7.27 (m, 5H), 6.70 (brs, 1H), 6.20 (brs,
1H), 5.13–5.06 (m, 2H), 4.33 (dd, J=6.0, 10.1 Hz, 1H), 3.24–3.21 (m,
2H), 2.11–1.98 (m, 2H), 1.83–1.72 (m, 2H), 1.57–1.47 (m, 1H), 1.42–
1.31 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=175.6, 155.6,
Experimental Section
1
136.7, 128.6, 128.1, 128.1, 66.7, 53.7, 42.2, 32.1, 28.9, 28.1 ppm. H
and 13C NMR spectral data were identical to those previously re-
ported.[40]
Typical procedure for synthesis of lactam 3 in a microflow
reactor, method A
A solution of amino acid 1 (0.100m, 0.48 mmol, 1.00 equiv), N-
methylmorpholine (0.650m, 6.50 equiv), 2m KOH (0.100m,
1.00 equiv) in H2O and MeCN (1:1, flow rate: 4.80 mLminÀ1), and a
solution of triphosgene (0.0500m, 1.00 equiv) in MeCN (flow rate:
9.60 mLminÀ1) were introduced into a V-shaped mixer at 208C
with syringe pumps. The resultant mixture was passed through re-
action tube 1 (inner diameter: 0.800 mm, length: 239 mm, volume:
120 mL, reaction time: 0.500 s) at the same temperature. The resul-
tant mixture and 10 wt% NH4Cl aq. (flow rate: 4.80 mLminÀ1) were
introduced into a T-shaped mixer at 208C with the syringe pumps.
The resultant mixture was passed through reaction tube 2 (inner
diameter: 0.800 mm, length: 433 mm, volume: 218 mL, reaction
time: 0.680 s) at the same temperature. After being eluted for ca.
15 s to reach a steady state, the resultant mixture was poured into
EtOAc (5 mL) for 35 s at 08C. The organic layer was washed three
times with 1m HCl (1 mL). After the aqueous layer was extracted
three times with EtOAc (2 mL), the organic layer was washed with
1m HCl (1 mL), sat. NaHCO3 aq. (1 mL), and brine (1 mL) at room
temperature, dried over MgSO4, filtered, and evaporated. The de-
sired lactam benzyl (S)-(2-oxopiperidin-3-yl)carbamate (3) was ob-
tained as a white solid in 93% yield. M.p. 82–848C; [a]2D6 =À17.5
(c=1.11, MeOH); IR (neat): 3303, 3063, 2948, 1714, 1670, 1495,
Pyrrolidin-2-one (6)
Reaction conditions: Method A; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CH2Cl2, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica-gel column chromatography (MeOH:CH2Cl2 =
1:9). Pyrrolidin-2-one was obtained in 88% yield as a colorless oil.
IR (neat): 3249, 2891, 1684, 1464, 1426, 1286 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=6.86 (s, 1H), 3.37 (t, J=7.1 Hz, 2H), 2.27 (t,
J=8.0 Hz, 2H), 2.1 ppm (quint, J=7.6 Hz, 2H); 13C NMR (101 MHz,
CDCl3): d=179.5, 42.4, 30.2, 20.9 ppm. 1H and 13C NMR spectral
data were identical to those previously reported.[41]
2-Azaspiro[4.5]decan-3-one (Gabapentin lactam) (7)
Reaction conditions: Method A; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CHCl3, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica-gel column chromatography (MeOH:CH2Cl2 =
1:9). Gabapentin lactam was obtained in 92% yield as a white
solid. M.p. 84–868C; IR (neat): 3195, 3092, 2924, 2854, 1689, 1446,
1
1300, 1045, 745 cmÀ1; H NMR (400 MHz, CDCl3): d=7.37–7.28 (m,
5H), 6.23 (s, 1H), 5.76 (s, 1H), 5.11 (s, 2H), 4.10 (t, J=5.5 Hz, 1H),
3.32 (d, J=5.0 Hz, 2H), 2.50 (d, J=6.4 Hz, 1H), 1.94–1.86 (m, 2H),
1.67–1.57 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=171.5, 156.5,
1
1380 cmÀ1; H NMR (400 MHz, CDCl3): d=6.87 (s, 1H), 3.11 (s, 2H),
2.13 (s, 2H), 1.52–1.35 ppm (m, 10H); 13C NMR (101 MHz, CDCl3):
d=178.4, 53.8, 43.3, 39.5, 36.9, 25.7, 22.9 ppm; HRMS (ESI) calcd
for [C9H15NO++Na]+: 176.1046, found: 176.1046.
1
136.5, 128.6, 128.2, 66.9, 51.9, 41.9, 27.8, 21.2 ppm. H and 13C NMR
spectral data were identical to those previously reported.[39]
Typical procedure for synthesis of lactam 5 in a microflow
reactor, method B
(S)-N-(Naphthalen-2-yl)-5-oxopyrrolidine-2-carboxamide (8)
A solution of amino acid 4 (0.100m, 0.48 mmol, 1.00 equiv), N-
methylimidazole (0.650m, 6.50 equiv), and 2m KOH (0.100m,
1.00 equiv) in H2O and MeCN (1:1, flow rate: 4.80 mLminÀ1) and a
solution of triphosgene (0.0500m, 1.00 equiv) in MeCN (flow rate:
9.60 mLminÀ1) were introduced into a V-shaped mixer at 608C
with syringe pumps. The resultant mixture was passed through re-
action tube 1 (inner diameter: 0.800 mm, length: 4776 mm,
volume: 2400 mL, reaction time: 10.0 s) at the same temperature.
The resultant mixture and 10 wt% NH4Cl aq. (flow rate:
4.80 mLminÀ1) were introduced into a T-shape mixer at 608C with
syringe pumps. The resultant mixture was passed through reaction
tube 2 (inner diameter: 0.800 mm, length: 433 mm, volume:
218 mL, reaction time: 0.680 s) at the same temperature. After
being eluted for ca. 25 s to reach a steady state, the resultant mix-
ture was poured into EtOAc (5 mL) for 25 s at 08C. The organic
Reaction conditions: Method A; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CH2Cl2, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica gel column chromatography (MeOH:CH2Cl2 =
1:9). (S)-N-(Naphthalen-2-yl)-5-oxopyrrolidine-2-carboxamide was
obtained in 83% yield as a white amorphous solid. [a]2D6 =À11.6
(c=0.72, CHCl3); IR (neat): 3276, 3058, 1693, 1588, 1434, 1257,
1
749 cmÀ1; H NMR (400 MHz, [D6]DMSO): d=10.26 (s, 1H), 8.32 (d,
J=1.4 Hz, 1H), 7.94 (s, 1H), 7.89–7.81 (m, 3H), 7.63 (dd, J=2.1,
8.9 Hz, 1H), 7.49–7.39 (m, 2H), 4.26 (dd, J=4.1, 8.7 Hz, 1H), 2.42–
2.33 (m, 1H), 2.30–2.12 (m, 2H), 2.08–2.01 ppm (m, 1H); 13C NMR
(101 MHz, [D6]DMSO): d=177.5, 171.6, 136.4, 133.4, 129.9, 128.4,
127.5, 127.3, 126.5, 124.7, 120.0, 115.6, 56.5, 29.3, 25.4 ppm; HRMS
(ESI) calcd for [C15H14N2O2+Na]+: 277.0947, found: 277.0948.
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28.4 ppm. 1H and 13C NMR spectral data were identical to those
previously reported.[44]
4-(4-Chlorophenyl)pyrrolidin-2-one (Baclofen lactam) (9)
Reaction conditions: Method A; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CHCl3, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica-gel column chromatography (MeOH:CH2Cl2 =
1:9). Baclofen lactam was obtained in 89% yield as a white solids.
M.p. 115–1188C; IR (neat): 3197, 3094, 2880, 1693, 1491, 1260, 812;
1H NMR (400 MHz, CDCl3): d=7.36–7.14 (m, 5H), 3.79 (t, J=8.9 Hz,
1H), 3.70–3.62 (m, 1H), 3.39 (dd, J=6.9, 9.6 Hz, 1H), 2.74 (dd, J=
8.7, 16.9 Hz, 1H), 2.45 ppm (dd, J=8.5, 16.7 Hz, 1H); 13C NMR
(101 MHz, CDCl3): d=177.9, 140.8, 132.9, 129.0, 128.2, 49.6, 39.7,
38.1 ppm. 1H and 13C NMR spectral data were identical to those
previously reported.[42]
Piperidin-2-one (13)
Reaction conditions: Method A; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CH2Cl2, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica-gel column chromatography (MeOH:CH2Cl2 =
1:9). Piperidin-2-one was obtained in 65% yield as a colorless oil.
Reaction conditions: Method B; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CH2Cl2, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica-gel column chromatography (MeOH:CH2Cl2 =
1:9). Piperidin-2-one was obtained in 93% yield as colorless oil. IR
1-Methylpyrrolidin-2-one (10)
1
(neat): 3232, 2944, 2869, 1663, 1496, 1353 cmÀ1; H NMR (400 MHz,
Reaction conditions: Method A; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CHCl3, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica-gel column chromatography (MeOH:CH2Cl2 =
1:9). 1-Methylpyrrolidin-2-one was obtained in 29% yield as color-
less oil. Reaction conditions: Method B; workup: after removing
the solvent by evaporation, the reaction mixture was dissolved in
THF and CHCl3, the solid was removed by filtration, the solution
was collected, and then the solvent was removed. The reaction
mixture was purified by silica-gel column chromatography
(MeOH:CH2Cl2 =1:9). 1-Methylpyrrolidin-2-one was obtained in
76% yield as a colorless oil. IR (neat): 2923, 1680, 1505, 1300;
1H NMR (400 MHz, CDCl3): d=3.38–3.34 (m, 2H), 2.82 (s, 3H), 2.35
(t, J=8.0 Hz, 2H), 2.04–1.96 ppm (m, 2H); 13C NMR (101 MHz,
CDCl3): d=6.69 (brs, 1H), 3.29 (t, J=5.3 Hz, 2H), 2.33 (t, J=6.2 Hz,
2H), 1.81–1.70 ppm (m, 4H); 13C NMR (101 MHz, CDCl3): d=172.7,
1
42.3, 31.6, 22.3, 20.9 ppm. H and 13C NMR spectral data were iden-
tical to those previously reported.[45]
1,4-Dihydroisoquinolin-3(2H)-one (14)
Reaction conditions: Method A; workup: The organic layer was
washed three times with 1m HCl (1 mL). After the aqueous layer
was extracted three times with EtOAc (2 mL), the organic layer was
washed with 1m HCl (1 mL), sat. NaHCO3 aq. (1 mL), and brine
(1 mL) at room temperature, dried over MgSO4, filtered, and evapo-
rated. 1,4-Dihydroisoquinolin-3(2H)-one was obtained in 77% yield
as white solids. Reaction conditions: Method B; workup: The or-
ganic layer was washed three times with 1m HCl (1 mL). After the
aqueous layer was extracted three times with EtOAc (2 mL), the or-
ganic layer was washed with 1m HCl (1 mL), sat. NaHCO3 aq.
(1 mL), and brine (1 mL) at room temperature, dried over MgSO4,
filtered, and evaporated. The reaction mixture was purified by silica
gel column chromatography (MeOH:CH2Cl2 =1:9). 1,4-Dihydroiso-
quinolin-3(2H)-one was obtained in 95% yield as a white solid.
M.p. 145–1478C; IR (neat): 3191, 3042, 1658, 1497, 1349, 837,
1
CDCl3): d=175.2, 49.5, 30.8, 29.7, 17.8 ppm. H and 13C NMR spec-
tral data were identical to those previously reported.[43]
tert-Butyl (S)-5-oxopyrrolidine-2-carboxylate (11)
Reaction conditions: Method A; workup: The organic layer was
washed three times with 1m HCl (1 mL). After the aqueous layer
was extracted three times with EtOAc (2 mL), the organic layer was
washed with 1m HCl (1 mL), sat. NaHCO3 aq. (1 mL), and brine
(1 mL) at room temperature, dried over MgSO4, filtered, and evapo-
rated. tert-Butyl (S)-5-oxopyrrolidine-2-carboxylate was obtained in
87% yield as a white solid. M.p. 101–1038C; IR (neat): 3236, 2975,
1735, 1690, 1452, 1229; [a]2D6 =À0.6 (c=2.84, CHCl3); 1H NMR
(400 MHz, CDCl3): d=6.58 (brs, 1H), 4.11 (dd, J=5.3, 8.0 Hz, 1H),
2.45–2.25 (m, 3H), 2.18–2.10 (m, 1H), 1.45 ppm (s, 9H); 13C NMR
(101 MHz, CDCl3): d=178.1, 171.2, 82.4, 56.2, 29.5, 28.0, 24.9 ppm;
HRMS (ESI) calcd for [C9H15NO3+Na]+: 208.0944, found: 208.0942.
743 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.51 (brs, 1H), 7.28–7.16
;
(m, 4H), 4.51 (s, 2H), 3.59 ppm (s, 2H); 13C NMR (101 MHz, CDCl3):
1
d=172.3, 131.7, 131.1, 127.8, 127.5, 126.7, 125.4, 45.3, 36.5 ppm. H
and 13C NMR spectral data were identical to those previously re-
ported.[46]
(1S,4S)-2-Azabicyclo[2.2.2]octan-3-one (15)
Reaction conditions: Method A; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CHCl3, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica gel column chromatography (MeOH:CH2Cl2 =
1:9). (1S,4S)-2-Azabicyclo[2.2.2]octan-3-one was obtained in 58%
yield as a white solid. Reaction conditions: Method B; workup:
after removing the solvent by evaporation, the reaction mixture
was dissolved in THF and CHCl3, the solid was removed by filtra-
tion, the solution was collected, and then the solvent was re-
moved. The reaction mixture was purified by silica gel column
chromatography (MeOH:CH2Cl2 =1:9). (1S,4S)-2-Azabicyclo[2.2.2]oc-
tan-3-one was obtained in 89% yield as a white solid. M.p. 135–
1388C; IR (neat): 3181, 3083, 2954, 2871, 1678, 1450, 1273, 1105;
1H NMR (400 MHz, CDCl3): d=7.41 (s, 1H), 3.60 (s, 1H), 2.47 (s, 1H),
1.82–1.57 ppm (m, 8H); 13C NMR (101 MHz, CDCl3): d=178.7, 47.5,
tert-Butyl (S)-(2-oxopyrrolidin-3-yl)carbamate (12)
Reaction conditions: Method A; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CHCl3, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica gel column chromatography (MeOH:CH2Cl2 =
1:9). tert-Butyl (S)-(2-oxopyrrolidin-3-yl)carbamate was obtained in
91% yield as a white solid. M.p. 171–1748C; IR (neat): 3324, 2978,
2931, 1696, 1530, 1294, 1170 cmÀ1; [a]D26 = +3.9 (c=2.05, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.20 (s, 1H), 5.26 (s, 1H), 4.14 (s, 1H),
3.36–3.25 (m, 2H), 2.61 (s, 1H), 2.00–1.87 (m, 1H), 1.40 ppm (s, 9H);
13C NMR (101 MHz, CDCl3): d=176.2, 156.0, 79.9, 51.8, 39.2, 30.2,
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1
37.7, 27.6, 24.0 ppm. H and 13C NMR spectral data were identical
1.00 equiv) in MeCN (flow rate: 9.60 mLminÀ1) were introduced
into a V-shaped mixer at 608C with syringe pumps. The resultant
mixture was passed through reaction tube 1 (inner diameter:
0.800 mm, length: 4776 mm, volume: 2400 mL, reaction time:
10.0 s) at the same temperature. The resultant mixture and 10 wt%
NH4Cl aq. (flow rate: 4.80 mLminÀ1) were introduced into a T-
shaped mixer at 608C with syringe pumps. The resultant mixture
was passed through reaction tube 2 (inner diameter: 0.800 mm,
length: 433 mm, volume: 218 mL, reaction time: 0.680 s) at the
same temperature. After being eluted for ca. 25 s to reach a steady
state, the resultant mixture was poured into EtOAc (20 mL) for 25 s
at 08C. workup: The precipitate was washed with MeCN and col-
lected by decantation. Protected cilengitide 20a was obtained in
72% yield as a white solid. M.p. 189–1928C; IR (neat): 3288, 2929,
1724, 1644, 1535, 1255, 1004, 750 cmÀ1; [a]D26 =À44.3 (c=0.0780,
to those previously reported.[47]
(9H-Fluoren-9-yl)methyl (S)-(2-oxopiperidin-3-yl)carbamate
(16)
Reaction conditions: Method A; workup: after being eluted for ca.
15 s to reach a steady state, the resultant mixture was poured into
EtOAc (20 mL) for 35 s at 08C. The aqueous layer was extracted
three times with EtOAc (3 mL). The organic layer was washed with
NaCl in 1m HCl aq. (3 mL), brine (3 mL), sat. NaHCO3 aq. (3 mL),
and brine (3 mL) at room temperature, dried over MgSO4, filtered,
and evaporated. (9H-Fluoren-9-yl)methyl (S)-(2-oxopiperidin-3-yl)-
carbamate was obtained in 81% yield as a white amorphous solid.
[a]2D5 = +37.9 (c=1.14, CHCl3); IR (neat): 3296, 2947, 1712, 1670,
1
1493, 1247, 758, 741 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.75 (d,
;
DMSO); H NMR (400 MHz, [D6]DMSO): d=9.13 (s, 2H), 8.44 (d, J=
8.3 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.93 (d, J=7.3 Hz, 1H), 7.48–
7.50 (m, 1H), 7.28–7.42 (m, 15H), 7.14–7.24 (m, 5H), 5.22 (d, J=
2.3 Hz, 2H), 5.03–5.11 (m, 4H), 4.93 (td, J=5.8, 8.7 Hz, 1H) 4.56 (m,
1H), 4.33 (d, J=10.9 Hz, 1H), 3.72–3.91 (m, 4H), 3.29 (d, J=3.1 Hz,
1H), 3.01 (dd, J=9.1, 13.2 Hz, 1H), 2.86 (dd, J=7.6, 16.3 Hz, 1H),
2.70–2.77 (m, 4H), 2.57–2.63 (m, 1H), 1.84–1.93 (m, 1H), 1.77 (m,
1H), 1.47–1.58 (m, 3H), 0.73 (d, J=6.5 Hz, 3H) 0.41 ppm (d, J=
6.5 Hz, 3H); 13C NMR (125 MHz, [D6]DMSO): d=171.0, 170.8, 170.0,
169.6, 169.2, 169.1, 162.8, 159.5, 154.9, 137.3, 137.0, 136.0, 135.2,
129.0, 128.4, 128.3, 128.2, 128.2, 128.0, 127.9, 127.7, 127.7, 127.7,
127.6, 126.2, 68.1, 66.0, 65.5, 62.8, 54.2, 50.2, 49.1, 44.3, 43.3, 37.8,
34.5, 30.2, 25.8, 25.6, 19.1, 18.9 ppm; HRMS (ESI) calcd for
[C50H58N8O11+Na]+: 969.4117, found: 969.4118.
J=7.3 Hz, 2H), 7.61 (d, J=5.5 Hz, 2H), 7.39 (t, J=7.3 Hz, 2H), 7.30
(t, J=7.5 Hz, 2H), 6.39 (s, 1H), 5.86 (s, 1H), 4.37 (d, J=5.0 Hz, 2H),
4.23 (t, J=6.9 Hz, 1H), 4.11 (brs, 1H), 3.32 (brs, 2H), 2.51 (brs, 1H),
1.92 (brs, 2H), 1.65 ppm (brs, 1H); 13C NMR (101 MHz, CDCl3): d=
171.6, 156.5, 144.1, 144.0, 141.4, 127.8, 127.2, 125.3, 120.0, 67.1,
51.9, 47.3, 41.8, 27.7, 21.1 ppm; HRMS (ESI) calcd for
[C20H20N2O3+Na]+: 359.1366, found: 359.1370.
tert-Butyl (S)-(2-oxopiperidin-3-yl)carbamate (17)
Reaction conditions: Method A; workup: after being eluted for ca.
15 s to reach a steady state, the resultant mixture was poured into
EtOAc (20 mL) for 35 s at 08C. The aqueous layer was extracted
three times with EtOAc (3 mL). The organic layer was washed with
sat. NaCl-containing 1m HCl aq. (3 mL), brine (3 mL), sat. NaHCO3
aq. (3 mL), and brine (3 mL) at room temperature, dried over
MgSO4, filtered, and evaporated. tert-Butyl (S)-(2-oxopiperidin-3-yl)-
carbamate was obtained in 82% yield as a colorless oil. [a]2D6 =À9.7
(c=0.83, MeOH); IR (neat): 3303, 2975, 1703, 1672, 1493, 1248,
Acknowledgements
This work was supported by a JSPS KAKENHI Grant-in-Aid for
Challenging Research (Exploratory, Grant Number 20K21188).
1
1168 cmÀ1; H NMR (400 MHz, CDCl3): d=6.61 (s, 1H), 5.49 (d, J=
4.6 Hz, 1H), 4.00 (brt, J=5.5 Hz, 1H), 3.31–3.27 (m, 2H), 2.43 (brd,
J=6.9 Hz, 1H), 1.94–1.76 (m, 2H), 1.63–1.53 (m, 1H), 1.42 ppm (s,
9H); 13C NMR (101 MHz, CDCl3): d=172.0, 156.0, 79.7, 51.5, 41.8,
Conflict of interest
1
28.4, 27.9, 21.1 ppm. H and 13C NMR spectral data were identical
to those previously reported.[48]
The authors declare no conflict of interest.
Azepan-2-one (18)
Keywords: amides · lactams · microreactors · peptides ·
synthetic methods
Reaction conditions: Method B; workup: after removing the sol-
vent by evaporation, the reaction mixture was dissolved in THF
and CHCl3, the solid was removed by filtration, the solution was
collected, and then the solvent was removed. The reaction mixture
was purified by silica-gel column chromatography (MeOH:CH2Cl2 =
1:9). Azepan-2-one was obtained in 74% yield as a white solid.
M.p. 67–688C; IR (neat): 3294, 3206, 2927, 1660, 1486, 1417, 1364,
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Reaction conditions: Method B (substrate concentration: 0.0100m);
A
solution of pentapeptide hydrochloride S-13 (0.0100m,
1.00 equiv), N-methylimidazole (0.0650m, 6.50 equiv), and 2m KOH
(0.0200m, 2.00 equiv) in H2O and MeCN (1:1, flow rate:
4.80 mLminÀ1
)
and
a
solution of triphosgene (0.00500m,
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Manuscript received: January 6, 2021
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