Interrupted Curtius Rearrangements of Quaternary Proline Derivatives: A Flow Route to Acyclic Ketones and Unsaturated Pyrrolidines

Article abstract of DOI:10.1021/acs.joc.1c01133

Conversion of N-Boc-protected quaternary proline derivatives under thermal Curtius rearrangement conditions was found to afford a series of ring-opened ketone and unsaturated pyrrolidine products instead of the expected carbamate species. The nature of the substituent on the quaternary carbon thereby governs the product outcome due to the stability of a postulated N-acyliminium species. A continuous flow process with in-line scavenging was furthermore developed to streamline this transformation and safely create products on a gram scale.

Full text of DOI:10.1021/acs.joc.1c01133

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Note
Interrupted Curtius Rearrangements of Quaternary Proline
Derivatives: A Flow Route to Acyclic Ketones and Unsaturated
Pyrrolidines
Marcus Baumann,* Thomas S. Moody, Megan Smyth, and Scott Wharry
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ABSTRACT: Conversion of N-Boc-protected quaternary proline derivatives under thermal Curtius rearrangement conditions was
found to afford a series of ring-opened ketone and unsaturated pyrrolidine products instead of the expected carbamate species. The
nature of the substituent on the quaternary carbon thereby governs the product outcome due to the stability of a postulated N-
acyliminium species. A continuous flow process with in-line scavenging was furthermore developed to streamline this transformation
and safely create products on a gram scale.
ince its first reports in the late 19th century, the Curtius
gas, and the potential for run-away phenomena related to the
inherent exothermicity of this reaction sequence. Importantly,
the exploitation of continuous flow processing has enabled
several medicinal chemistry studies7 culminating in the safe
execution of Curtius rearrangements on scales of >40 kg.8
Despite these advances, essentially all studies on the Curtius
rearrangement convert carboxylic acids into amines and amine
derivatives such as carbamates, amides, and ureas (e.g., 3a−d),
thus overlooking opportunities for new directions. To address
this shortcoming, this Note reports the realization of an
interrupted Curtius rearrangement process rendering a set of
new products such as γ-amino ketones and unsaturated
pyrrolidines from Boc-protected proline derivatives.
S
rearrangement1 has established itself as one of the most
versatile transformations to convert ubiquitous carboxylic acids
into valuable amine derivatives.2 Acyl azide species (1a) are
thereby the key intermediates in this process that release
nitrogen upon rearranging into isocyanates that can be trapped
with various nucleophiles (Scheme 1). Mechanistic studies
Scheme 1. Overview of the Curtius Rearrangement
Expanding on prior studies that integrated enzymatic
impurity tagging strategies with flow-based Curtius rearrange-
ment reactions,9 this work evaluated the use of Boc-protected
proline species bearing substitution on the chiral carbon (e.g.,
4). Generation and subsequent trapping of the intermediate
isocyanate 5 were thereby anticipated to afford a selection of
versatile α-amino pyrrolidine species 6 as novel and potentially
useful amine building blocks (Scheme 2).
support a concerted reaction pathway for thermal Curtius
rearrangements, whereas photochemical alternatives proceed
stepwise via nitrene intermediates.3 The popularity of the
thermal Curtius rearrangement is evident from its regular
application in natural product syntheses and drug development
programs.4 Moreover, recent years have witnessed further
developments by harnessing the salient features of continuous
flow5 processing to yield modern variants6 that mitigate safety
concerns due to the use of toxic azides, the release of nitrogen
Special Issue: Enabling Techniques for Organic Syn-
thesis
Received: May 14, 2021
© XXXX The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.joc.1c01133
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A

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Note
Scheme 2. Intended Curtius Rearrangement Application for
N-Boc Proline Derivatives
Scheme 3. Batch Synthesis of Substrates 4 by Lithiation of
N-Boc Proline Methyl Ester 10
Commencing our study, the readily available proline
derivative 4a (R1 = Me)10 was subjected to standard Curtius
rearrangement conditions using DPPA (diphenylphosporyl
azide, 7) as the azide source, triethylamine as the base, and
benzyl alcohol as the trapping agent. Upon heating the reaction
mixture in acetonitrile to reflux, the evolution of nitrogen gas
was observed within minutes, indicating the onset of the
anticipated rearrangement process. However, upon analyzing
To streamline the following evaluation of the reaction scope,
a flow reactor system was exploited to improve the process in
view of safety, reproducibility, and scalability.12 In addition,
toluene was preferred as a solvent in view of its higher boiling
point and lower propensity to introduce water that may
quench the acyl azide or isocyanate intermediate. Alcohols as
nucleophiles were not added as they were found to have little
effect on the reaction outcome (Table 1, entry 7). A simple
flow process was devised and exploited in which streams of the
substrate (4a−g, 1 M, toluene) in the presence of triethyl-
amine as a base (1.0 equiv) and DPPA (7, 0.95 M, toluene,
0.95 equiv) were mixed in a T-piece before entering a heated
flow coil (10 mL, 1/16 in id, PFA, 100 °C) with a residence
time of 20 min (Scheme 4). The reaction mixture passed a
back-pressure regulator (100 psi, Kinesis13) to ensure the
steady release of nitrogen gas before collection in a receiving
flask. A glass column containing a mixture of scavenger resins
(Amberlyst A-21 and Amberlyst A-15;14 2 g each per mmol of
substrate 4a−g) was optionally placed at the end of the
reaction sequence to remove acidic and basic byproducts
(NEt3, substrate, and diphenyl phosphonic acid).
1
the crude reaction mixture by H NMR spectroscopy, not the
anticipated Cbz product (R2 = OBn, 6a), but a new ring-
opened product was observed (entry 1, Table 1). This material
Table 1. Formation of Ketone 9a from N-Boc Proline
Derivative 4a
entry
solvent
MeCN
MeCN
MeCN
MeCN
1,4-dioxane
toluene
MeCN
nucleophile (Nuc)
yield (%)
1
2
3
4
5
6
7
BnOH
EtOH
MeOH
water
BnOH
BnOH
none
85
81
77
75
71
84
81
was subsequently identified as ketone 9a and confirmed by
comparison to literature NMR data.11 As the evolution of
nitrogen gas had indicated the generation of the anticipated
isocyanate species, it was surmised that steric hindrance
around the chiral center may have precluded nucleophilic
attack by the modestly reactive benzyl alcohol. Reactions with
other alcohols such as ethanol, methanol, and water (entries
2−4) resulted in the isolation of the same ketone product as
the sole product in all three cases. Furthermore, alternative
solvents such as toluene and dioxane did not alter the reaction
outcome (entries 5 and 6). This outcome was reproduced even
in the absence of an added alcohol nucleophile (entry 7).
These results prompted consideration of an unprecedented
reaction path that may be governed by the presence of the
pyrrolidine ring as well as the quaternary center.
In view of the synthetic versatility of the 1,4-disubstitution
pattern observed in this unexpected product and the desire to
evaluate the generality of this process, a small selection of N-
Boc-protected proline derivatives were subjected to these
reaction conditions. Pleasingly, their syntheses were readily
accomplished by lithiation of N-Boc proline methyl ester (10,
0.5 M in toluene, 1.0 equiv) with LiHMDS (1.0 M in THF, 1.1
equiv) as a base at −78 °C, followed by trapping the resulting
carbanion with various electrophiles bearing alkyl and benzyl
appendages (Scheme 3). Hydrolysis of the methyl ester (11)
under alkaline conditions rendered the desired carboxylic acid
building blocks 4 in high chemical yields.
The resulting flow study confirmed that the initial substrate
bearing a methyl substituent (4a) smoothly underwent the
rearrangement process rendering methyl ketone 9a in high
chemical yield. Pleasingly, the same result was obtained when
performing this process on a gram scale (Figure 1). Equally,
introducing an ethyl group as a modified alkyl appendage was
well tolerated and gave product 9b in high yield. An interesting
case was observed when subjecting cinnamyl analogue 4f to
the flow rearrangement protocol. As before, the formation of a
gaseous byproduct (e.g., N2) was observed, and analysis of the
1
crude material by H NMR indicated product formation in
high yield; however, during purification by silica flash column
chromatography, this material decomposed. It is surmised that
the delicate skipped keto styryl moiety thereby tautomerized to
a Michael acceptor, thus triggering decomposition by aldol or
cycloaddition pathways. To support this assumption, cinnamyl
ester 11f was converted under transfer hydrogenation
conditions15 into its saturated counterpart, and pleasingly,
the corresponding acid 4g furnished the anticipated ketone
product (9g) in high yield and without any stability concerns.
Furthermore, when subjecting unsubstituted N-Boc proline to
the rearrangement process, decomposition of the labile
aldehyde product (9h) was observed.
In addition, several benzyl-substituted substrates (e.g., 4c−
e) were subjected to the flow protocol to verify if the
analogous ring-opening process would take place. Formation of
a gaseous byproduct was observed as before when employing
B
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Scheme 4. Flow Approach toward Evaluating the Reaction Scope of Interrupted Curtius Rearrangements
Figure 1. Reaction scope rendering acyclic products and unsaturated pyrrolidines.
the previous flow reaction conditions for this interrupted
Curtius rearrangement process. However, when analyzing the
purified reaction products (9c−e) by various NMR techniques,
it was apparent that no ketone product was obtained. As these
products were solids, single crystals were successfully grown for
product 9e, enabling X-ray diffraction experiments to
unambiguously determine the correct connectivity of this
product.16 This clearly indicated the presence of a partially
unsaturated pyrrolidine ring bearing an exocyclic, E-configured
alkene instead of a ring-opened product. Comparison of the
NMR data of the other benzyl-derived products (9c and 9d)
indicated that the same product had formed as an exclusive E-
isomer. Surprisingly relatively few mild and stereoselective
methods for creating such unsaturated pyrrolidine scaffolds are
reported in the literature. As these include examples that
require transition metal catalysts and potentially render
alternative alkene isomers or ring sizes,17 the methodology
presented herein may serve as an attractive alternative.
To account for the observed reaction products, the following
mechanism is proposed (Scheme 5). Activation of the
carboxylic acid functionality with DPPA forms acyl azide 12,
which subsequently undergoes thermal rearrangement to an
isocyanate (5) accompanied by the release of nitrogen gas.
This quaternary isocyanate is assumed to be too hindered to
undergo nucleophilic attack as anticipated in the regular
Curtius rearrangement. In the absence of a strong base, it is
proposed that a unimolecular process in which (iso)cyanate
anion is expelled and cyclic acyliminium18 species 13 is
obtained. This highly electrophilic acyliminium ion then reacts
with adventitious water to give ketones (9a,b,g). In the case of
a neighboring benzylic methylene group, the corresponding
acyliminium appears to tautomerize rapidly by loss of the
benzylic proton giving unsaturated pyrrolidine structures 9c−e
Scheme 5. Proposed Reaction Mechanism Accounting for
Bifurcated Pathway
instead, which appear to be stable under the reaction
conditions.19 It is believed that conjugation of the exocyclic
alkene into the benzene ring for products 9c−e imparts higher
stability toward attack by nucleophiles such as water and thus
accounts for the observed reaction outcome.
In conclusion, a novel reaction pathway for quaternary N-
Boc proline species under thermal Curtius rearrangement
conditions is reported. Fragmentation of the intermediate
isocyanate species thereby renders a proposed N-acyliminium
species, which facilitates ring-opening by adventitious water to
give γ-amino ketone products in the case of small aliphatic
substituents, whereas benzylic appendages render unsaturated
pyrrolidines via tautomerization of this proposed N-acylimi-
nium intermediate. A continuous flow protocol was success-
fully established to enable the safe and scaled exploration of
this transformation. In view of its simplicity, high yields, and
C
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Note
please see copies of 1H and 13C NMR spectra in Supporting
Information. H NMR (500 MHz, CDCl3): δ 7.30−7.21 (m), 7.14
the value of the generated reaction products, this interrupted
Curtius rearrangement method may find future synthetic
applications in both batch and flow mode.
1
(td, J = 6.8, 5.9, 3.2 Hz), 3.77 (d, J = 14.0 Hz), 3.75 (s), 3.57 (d, J =
13.8 Hz), 3.48 (dt, J = 10.5, 7.5 Hz), 3.39 (dt, J = 10.4, 7.2 Hz), 3.05
(d, J = 13.8 Hz), 3.04 (d, J = 13.8 Hz), 2.99 (ddd, J = 10.5, 7.6, 5.3
Hz), 2.88 (ddd, J = 10.4, 7.6, 5.6 Hz), 2.12−1.97 (m), 1.58 (ddt, J =
18.2, 7.4, 5.2 Hz), 1.51 (s), 1.49 (s), 1.00−0.83 (m). 13C{1H} NMR
(126 MHz, CDCl3): δ 175.3, 175.1, 154.1, 153.5, 137.3, 136.9, 130.8,
130.7, 128.2, 128.0, 126.6, 126.4, 80.3, 79.6, 68.3, 68.0, 52.3, 48.2,
39.7, 38.5, 36.6, 35.4, 28.5, 28.4, 22.8, 22.2. IR (neat): ν/cm−1 2975
(m), 2877 (w), 1741 (m), 1694 (s), 1454 (m), 1389 (s), 1366 (m),
1251 (m), 1168 (s), 1119 (m), 1020 (m), 704 (m). HRMS (TOF-
ESI+): calcd for C18H25NO4Na, 342.1676; found, 342.1679 (M +
Na+).
EXPERIMENTAL SECTION
■
Materials and Methods. Unless otherwise stated, all solvents
were purchased from Fisher Scientific and used without further
purification. Substrates and reagents were purchased from Fluo-
rochem or Sigma-Aldrich and used as received.
The heating of reaction mixtures was achieved by using DrySyn
metal heating blocks available from Asynt.
1H NMR spectra were recorded on 300, 400, and 500 MHz
instruments and are reported relative to the residual solvent: CHCl3
(δ 7.26 ppm). 13C{1H} NMR spectra were recorded on the same
instruments (100 and 125 MHz) and are reported relative to CHCl3
(δ 77.16 ppm). 19F NMR were recorded at 282 and 376 MHz. Data
for 1H NMR are reported as follows: chemical shift (δ/ ppm)
(integration, multiplicity, coupling constant (Hz)). Multiplicities are
reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p
= pentet, m = multiplet, br s = broad singlet, app = apparent. Data for
13C{1H} NMR are reported in terms of chemical shift (δ/ppm) and
1-(tert-Butyl) 2-Methyl 2-(4-fluorobenzyl)pyrrolidine-1,2-dicar-
boxylate (11d). Yield: 750 mg (2.3 mmol, 75%). Appearance: clear
oil. Mixtures of Boc-rotamers were observed by NMR spectroscopy;
please see copies of 1H and 13C NMR spectra in Supporting
1
Information. H NMR (500 MHz, CDCl3): δ 7.11−7.06 (m), 6.98−
6.92 (m), 3.74 (s), 3.73 (s), 3.54−3.45 (m), 3.40 (dt, J = 10.6, 7.2
Hz), 3.03 (d, J = 14.2 Hz), 3.01 (d, J = 14.2 Hz), 3.00−2.96 (m), 2.89
(ddd, J = 10.4, 7.4, 5.7 Hz), 2.09−1.98 (m), 1.65−1.55 (m), 1.49 (s),
1.47 (s), 1.05−0.87 (m). 13C{1H} NMR (126 MHz, CDCl3): δ 175.1,
175.0, 161.9 (CF, d, J = 246 Hz), 161.8 (CF, d, J = 246 Hz), 154.2,
153.5, 132.9 (d, J = 4 Hz), 132.6 (d, J = 4 Hz), 132.1 (d, J = 8 Hz),
132.0 (d, J = 8 Hz), 115.1 (d, J = 21 Hz), 114.8 (d, J = 21 Hz), 80.4,
79.7, 68.3, 67.9, 52.3, 52.3, 48.3, 48.2, 38.9, 37.7, 36.5, 35.3, 28.4,
28.4, 22.8, 22.2. IR (neat): ν/cm−1 2976 (m), 2877 (w), 1741 (s),
1693 (s), 1510 (s), 1388 (s), 1251 (m), 1221 (m), 1160 (s), 1131
(m), 1016 (m), 844 (m), 772 (m). HRMS (TOF-ESI+): calcd for
C18H24FNO4Na, 360.1582; found, 360.1585 (M + Na+).
multiplicity (C, CH, CH2, or CH3). COSY and HSQC experiments
were used in the structural assignment.
IR spectra were obtained by use of a Bruker Platinum spectrometer
(neat, ATR sampling) with the intensities of the characteristic signals
being reported as weak (w, <20% of the tallest signal), medium (m,
21−70% of the tallest signal), or strong (s, >71% of the tallest signal).
High-resolution mass spectrometry was performed using the
indicated techniques on a micromass LCT orthogonal time-of-flight
mass spectrometer with leucine-enkephalin (Tyr-Gly-Phe-Leu) as an
internal lock mass. GC−MS was performed on a Waters GCT
Premier Agilent 7898 system (column Macherey−Nagel; Optima 5
MS, length 15 m, diameter 0.25 mm).
1-(tert-Butyl) 2-Methyl 2-(4-(trifluoromethyl)benzyl)pyrrolidine-
1,2-dicarboxylate (11e). Yield: 920 mg (2.4 mmol, 80%).
Appearance: white solid. Melting range: 94−96 °C. Mixtures of
Boc-rotamers were observed by NMR spectroscopy; please see copies
Melting points were recorded on a Stuart SMP10 melting point
apparatus and are uncorrected.
1
1
of H and 13C NMR spectra in Supporting Information. H NMR
(400 MHz, CDCl3): δ 7.48 (dd, J = 8.2, 4.3 Hz), 7.22 (d, J = 7.9 Hz),
3.78 (d, J = 13.8 Hz), 3.71 (s), 3.70 (s), 3.56 (d, J = 13.8 Hz), 3.47
(dt, J = 10.6, 7.3 Hz), 3.37 (dt, J = 10.5, 7.1 Hz), 3.08 (d, J = 13.8
Hz), 3.07 (d, J = 13.8 Hz), 2.95 (ddd, J = 10.5, 7.6, 5.5 Hz), 2.86
(ddd, J = 10.4, 7.4, 5.8 Hz), 2.10−1.94 (m), 1.64−1.54 (m), 1.45 (s),
1.43 (s), 1.01−0.86 (m). 13C{1H} NMR (101 MHz, CDCl3): δ 174.8,
174.7, 154.2, 153.4, 141.5, 141.2, 129.0 (q, J = 32 Hz), 128.8 (q, J =
32 Hz), 125.0 (q, J = 4 Hz), 124.8 (q, J = 4 Hz), 124.3 (CF3, q, J =
273 Hz), 124.2 (CF3, q, J = 273 Hz), 80.5, 79.8, 68.1, 67.8, 52.3, 48.2,
39.7, 38.4, 36.6, 35.3, 28.3, 28.3, 22.7, 22.2.IR (neat): ν/cm−1 2977
(w), 2880 (w), 1742 (m), 1694 (s), 1389 (s), 1324 (s), 1251 (m),
1163 (s), 1123 (s), 1111 (s), 1067 (s), 1019 (m), 851 (m). HRMS
(TOF-ESI+): calcd for C19H24NF3O4Na, 410.1550; found, 410.1551
(M + Na+).
Continuous flow experiments were performed on a Vaportec E-
series system in combination with Omnifit glass columns (6.6 mm id,
150 mm length) filled with scavenging resins (A-15/A-21).
Synthetic Procedures and Spectroscopic Data. Synthesis of
Substituted N-Boc Proline Derivatives 11b−h. For a reaction on 2
mmol scale, to a solution of the N-Boc proline methyl ester (10, 1.0
equiv, 2.0 mmol) in toluene (0.5 M, held at −78 °C) was added a
solution of LiHMDS (1 M, THF, 1.1 equiv, 2.2 mmol) dropwise. The
resulting mixture was allowed to warm to 0 °C within 20 min before
cooling to −78 °C. A solution of alkyl bromide or iodide electrophile
(0.5 M, toluene, 1.0 equiv, 2.0 mmol) was subsequently added
dropwise, and the reaction mixture continued stirring for 12 h,
eventually warming to rt. The reaction mixture was quenched by the
addition of NH4Cl solution (sat. aq) and extracted (DCM/water).
The combined organic layers were dried over anhydrous Na2SO4,
filtered, and evaporated under reduced pressure to give the crude
product. Purification was achieved via silica gel chromatography using
a cyclohexane/ethyl acetate (75:15) eluent system.
1-(tert-Butyl) 2-Methyl 2-cinnamylpyrrolidine-1,2-dicarboxylate
(11f). Yield: 550 mg (1.6 mmol, 81%). Appearance: clear oil. Mixtures
of Boc-rotamers were observed by NMR spectroscopy; please see
1
1
copies of H and 13C NMR spectra in Supporting Information. H
NMR (300 MHz, CDCl3): δ 7.40−7.18 (m), 6.48 (app d, J = 15.7
Hz), 6.27−6.08 (m), 3.76 (s, 3H), 3.73−3.52 (m), 3.48−3.32 (m),
3.26 (dd, J = 14.1, 6.9 Hz), 3.08 (dd, J = 14.3, 6.3 Hz), 2.81 (d, J = 9.1
Hz), 2.76 (d, J = 8.6 Hz), 2.23−2.05 (m), 1.96−1.73 (m), 1.48 (s),
1.46 (s). 13C{1H} NMR (126 MHz, CDCl3): δ 175.1, 174.9, 154.0,
153.6, 137.6, 137.3, 133.9, 133.7, 128.6, 128.5, 127.3, 127.1, 126.3,
126.1, 125.3, 124.9, 80.2, 79.6, 67.9, 67.3, 52.2, 52.2, 48.5, 48.5, 38.9,
37.6, 37.1, 35.9, 28.4, 28.4, 23.2, 22.7. IR (neat): ν/cm−1 2975 (m),
2876 (w), 1741 (s), 1697 (s), 1390 (s), 1249 (m), 1164 (m), 1135
(m), 748 (w), 695 (w). HRMS (TOF-ESI+): calcd for
C20H27NO4Na, 368.1832; found, 368.1835 (M + Na+).
1-(tert-Butyl) 2-Methyl 2-ethylpyrrolidine-1,2-dicarboxylate
(11b).20 Yield: 640 mg (3.6 mmol, 83%). Appearance: clear oil.
Mixtures of Boc-rotamers were observed by NMR spectroscopy;
please see copies of 1H and 13C NMR spectra in Supporting
1
Information. H NMR (400 MHz, CDCl3): δ 3.75−3.69 (m), 3.66
(s), 3.63−3.55 (m), 3.42−3.31 (m), 2.37−2.25 (m), 2.20−2.10 (m),
2.06−1.94 (m), 1.92−1.74 (m), 1.42 (s), 1.37 (s), 0.88−0.80 (m).
13C{1H} NMR (101 MHz, CDCl3): δ 175.6, 175.4, 154.0, 153.8, 79.8,
79.3, 68.3, 67.8, 52.0, 51.9, 48.7, 48.6, 36.9, 35.6, 28.4, 28.3, 27.8,
26.6, 23.2, 22.7, 7.9. IR (neat): ν/cm−1 2974 (m), 2879 (w), 1741
(m), 1693 (s), 1455 (m), 1386 (s), 1234 (m), 1157 (s), 1130 (s),
1075 (m), 1002 (m), 772 (m). HRMS (TOF-ESI+): calcd for
C13H23NO4Na, 280.1519; found, 280.1522 (M + Na+).
1-(tert-Butyl) 2-Methyl 2-benzylpyrrolidine-1,2-dicarboxylate
(11c). Yield: 870 mg (2.7 mmol, 91%). Appearance: clear oil.
Mixtures of Boc-rotamers were observed by NMR spectroscopy;
1-(tert-Butyl) 2-Methyl 2-(3-phenylpropyl)pyrrolidine-1,2-dicar-
boxylate (11g). To a solution of ester 11f (1 mmol, 1.0 equiv) in
EtOAc (10 mL, 0.1 M) were added ammonium formate (5 mmol, 5.0
equiv) and Pd/C (10%, ca. 100 mg). This solution was then heated
under reflux for 5 h when TLC indicated full conversion of the
D
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substrate. After cooling to room temperature, the mixture was filtered
through a pad of Celite, washed with EtOAc (10 mL), and
concentrated in vacuo to give the saturated product 11g (quant.).
Yield: 344 mg (1.0 mmol, 99%). Appearance: clear oil. Mixtures of
Boc-rotamers were observed by NMR spectroscopy; please see copies
(m), 994 (m), 703 (m). HRMS (TOF-ESI+): calcd for C17H24NO4,
306.1700; found, 306.1705 (M + H+).
1-(tert-Butoxycarbonyl)-2-(4-fluorobenzyl)pyrrolidine-2-carbox-
ylic Acid (4d). Yield: 0.5 g (1.5 mmol, 92%). Appearance: waxy white
solid. Mixtures of Boc-rotamers were observed by NMR spectroscopy;
please see copies of 1H and 13C NMR spectra in Supporting
of H and 13C NMR spectra in Supporting Information. H NMR
(500 MHz, CDCl3): δ 7.32−7.24 (m), 7.19 (app dd, J = 8.2, 4.4 Hz),
3.75−3.71 (m), 3.70 (s), 3.69 (s), 3.64−3.56 (m), 3.42−3.30 (m),
2.74−2.56 (m), 2.38 (ddd, J = 14.0, 12.2, 4.8 Hz), 2.20 (td, J = 13.3,
4.4 Hz), 2.13−1.94 (m), 1.94−1.84 (m), 1.79 (tq, J = 12.6, 6.5 Hz),
1.71−1.60 (m), 1.60−1.51 (m), 1.45 (s), 1.33 (s). 13C{1H} NMR
(126 MHz, CDCl3): δ 175.5, 175.3, 154.0, 153.8, 142.6, 142.1, 128.5,
128.4, 128.3, 128.3, 125.8, 125.7, 79.8, 79.4, 67.9, 67.4, 52.1, 52.0,
48.6, 48.5, 37.5, 36.2, 36.1, 34.7, 33.9, 28.4, 28.2, 25.9, 25.4, 23.2,
22.8. IR (neat): ν/cm−1 2974 (m), 2870 (w), 1741 (m), 1697 (s),
1454 (w), 1391 (s), 1366 (m), 1235 (m), 1163 (m), 1132 (m), 700
(w). HRMS (TOF-ESI+): calcd for C20H29NO4Na, 370.1989; found,
370.1994 (M + Na+).
1
1
1
Information. H NMR (500 MHz, CDCl3): δ 7.16−7.09 (m), 7.01−
6.94 (m), 3.67 (d, J = 13.9 Hz), 3.59−3.50 (m), 3.43 (ddd, J = 10.6,
7.5, 5.2 Hz), 3.08 (d, J = 14.0 Hz), 3.05−2.98 (m), 2.94 (dt, J = 10.7,
7.3 Hz), 2.30 (ddd, J = 13.2, 7.2, 5.9 Hz), 2.18 (dt, J = 13.5, 7.7 Hz),
2.11−1.95 (m), 1.73−1.63 (m), 1.53 (s), 1.51 (s), 1.29−1.18 (m),
0.99 (dp, J = 12.1, 7.5 Hz). 13C{1H} NMR (126 MHz, CDCl3): δ
180.8, 178.0, 161.9 (2xd, J = 247 Hz), 155.6, 153.6, 132.3 (2x), 132.0
(m), 115.2 (d, J = 21 Hz), 115.1 (d, J = 21 Hz), 81.0, 81.0, 69.2, 67.9,
48.8, 48.3, 38.6, 37.6, 36.7, 34.9, 28.5, 28.4, 22.5, 22.3. IR (neat): ν/
cm−1 3300−2600 (br), 2977 (m), 2880 (w), 1737 (m), 1696 (s),
1510 (s), 1392 (s), 1368 (s), 1223 (s), 1160 (s), 1140 (m), 996 (m),
840 (m), 771 (m). HRMS (TOF-ESI+): calcd for C17H23FNO4,
324.1611; found, 324.1618 (M + H+).
Synthesis of Acid Products 4a−g. For a reaction on 2 mmol scale,
to a solution of ester intermediate 11 (2 mmol, 1.0 equiv, 2 M, THF/
MeOH, 50:50 vol) was added a solution of NaOH (1 M aqueous, 4
mL, 2.0 equiv). The resulting mixture was heated to reflux until TLC
indicated full consumption of the substrate (ca. 3 h). The resulting
solution was partitioned between EtOAc and water. The aqueous
layer was subsequently acidified by the addition of 1 M HCl (ca. 5
mL) and extracted with DCM, giving the target acid products after
drying of the organic layer over anhydrous Na2SO4, filtration, and
final evaporation under reduced pressure.
1-(tert-Butoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)pyrrolidine-
2-carboxylic Acid (4e). Yield: 0.6 g (1.6 mmol, 95%). Appearance:
waxy solid. Mixtures of Boc-rotamers were observed by NMR
spectroscopy; please see copies of 1H and 13C NMR spectra in
1
Supporting Information. H NMR (400 MHz, CDCl3): δ 7.56−7.52
(m), 7.28−7.24 (m), 3.69 (d, J = 13.7 Hz), 3.62 (d, J = 13.9 Hz), 3.53
(dt, J = 10.5, 7.3 Hz), 3.46−3.39 (m), 3.18 (d, J = 13.6 Hz), 3.08 (d, J
= 13.9 Hz), 3.03−2.91 (m), 2.37 (dt, J = 12.7, 6.6 Hz), 2.24−2.15
(m), 2.08−2.02 (m), 1.98−1.88 (m), 1.73−1.58 (m), 1.52 (s), 1.48
(s), 1.31−1.21 (m), 1.00 (dt, J = 12.5, 7.3 Hz). 13C{1H} NMR (101
MHz, CDCl3): δ 179.9, 176.3, 156.1, 153.5, 140.9, 140.3, 131.0,
130.8, 125.2, 125.1, 125.1, 81.6, 81.1, 49.0, 48.3, 39.4, 38.5, 36.7, 34.7,
28.4, 28.4, 22.4, 22.3, 20.6; some resonances were not observed
clearly. IR (neat): ν/cm−1 3400−2700 (br), 2977 (m), 2882 (w),
1738 (m), 1696 (s), 1392 (s), 1324 (s), 1163 (s), 1124 (s), 1112 (s),
1068 (s), 851 (m). HRMS (TOF-ESI+): calcd for C18H22F3NO4Na,
396.1393; found, 396.1393 (M + Na+).
1-(tert-Butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic Acid
(4a).21 Yield: 2.5 g (10.9 mmol, 91%). Appearance: colorless
crystalline solid. Melting range: 129−131 °C (CHCl3). Mixtures of
Boc-rotamers were observed by NMR spectroscopy; please see copies
1
1
of H and 13C NMR spectra in Supporting Information. H NMR
(500 MHz, CDCl3): δ 11.67 (br s), 3.60−3.39 (m), 2.38−2.30 (m),
2.26−2.22 (m), 1.92 (app tt, J = 10.2, 5.4 Hz), 1.86−1.79 (m), 1.55
(s), 1.48 (s), 1.42 (s), 1.38 (s). 13C{1H} NMR (126 MHz, CDCl3): δ
180.7, 179.0, 154.9, 153.7, 80.4, 80.4, 65.6, 64.8, 48.2, 47.8, 40.3, 39.0,
28.4, 28.3, 23.0, 22.8, 22.7, 22.1. IR (neat): ν/cm−1 3200−2800 (br),
2977 (m), 2884 (m), 1731 (s), 1619 (s), 1446 (m), 1417 (s), 1392
(s), 1366 (s), 1248 (m), 1159 (s), 1138 (s), 1080 (m), 892 (m), 852
(m), 772 (m), 583 (m). HRMS (TOF-ESI+): calcd for C11H20NO4,
230.1387; found, 230.1388 (M + H+).
1-(tert-Butoxycarbonyl)-2-cinnamylpyrrolidine-2-carboxylic Acid
(4f). Yield: 0.6 g (1.8 mmol, 82%). Appearance: clear oil. Mixtures of
Boc-rotamers were observed by NMR spectroscopy; please see copies
1
1
of H and 13C NMR spectra in Supporting Information. H NMR
(300 MHz, CDCl3): δ 7.44−7.21 (m), 6.53 (d, J = 15.7 Hz), 6.04 (dt,
J = 15.5, 7.5 Hz), 3.59−3.48 (m), 3.38−3.28 (m), 3.09 (dd, J = 13.7,
7.9 Hz), 2.88 (dd, J = 13.9, 7.1 Hz), 2.80−2.67 (m), 2.27−2.17 (m),
2.05−1.92 (m), 1.85−1.74 (m), 1.51 (app s). 13C{1H} NMR (126
MHz, CDCl3): δ 180.3, 175.9, 156.5, 153.7, 137.2, 137.2, 134.8,
134.1, 128.6, 127.5, 127.4, 126.2, 126.2, 124.7, 123.3, 81.7, 80.7, 69.6,
67.3, 49.3, 48.5, 38.5, 37.3, 37.2, 34.9, 28.4, 28.4, 22.7, 22.7. IR (neat):
ν/cm−1 3300−2700 (br), 2975 (m), 2879 (w), 1733 (m), 1695 (s),
1390 (s), 1367 (s), 1247 (m), 1164 (s), 998 (m), 969 (m), 734 (s),
694 (s). HRMS (TOF-ESI+): calcd for C19H25NO4Na, 354.1676;
found, 354.1677 (M + Na+).
1-(tert-Butoxycarbonyl)-2-ethylpyrrolidine-2-carboxylic Acid
(4b). Yield: 0.5 g (2.1 mmol, 88%). Appearance: clear oil. Mixtures
of Boc-rotamers were observed by NMR spectroscopy; please see
1
1
copies of H and 13C NMR spectra in Supporting Information. H
NMR (400 MHz, CDCl3): δ 3.73−3.67 (m), 3.54−3.46 (m), 3.37
(dt, J = 10.7, 7.5 Hz), 3.29 (dt, J = 10.3, 8.0 Hz), 2.65−2.48 (m),
2.21−2.03 (m), 2.03−1.85 (m), 1.81−1.71 (m), 1.45 (s), 1.38 (s),
0.84 (app t, J = 7.5 Hz). 13C{1H} NMR (101 MHz, CDCl3): δ 180.9,
175.4, 156.9, 153.9, 81.8, 80.2, 70.8, 67.7, 49.4, 48.6, 36.9, 34.5, 28.3,
28.3, 27.4, 27.1, 22.7, 8.1, 7.7. IR (neat): ν/cm−1 3400−2400 (br),
2974 (m), 2880 (w), 1741 (m), 1698 (s), 1391 (s), 1367 (s), 1161
(s), 931 (m), 858 (m), 773 (m). HRMS (TOF-ESI+): calcd for
C12H21NO4Na, 244.1543; found, 244.1550 (M + Na+).
1-(tert-Butoxycarbonyl)-2-(3-phenylpropyl)pyrrolidine-2-carbox-
ylic Acid (4g). Yield: 0.4 g (1.2 mmol, 88%). Appearance: clear oil.
Mixtures of Boc-rotamers were observed by NMR spectroscopy;
please see copies of 1H and 13C NMR spectra in Supporting
1
Information. H NMR (400 MHz, CDCl3): δ 7.29−7.23 (m), 7.20−
2-Benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic Acid
(4c). Yield: 0.7 g (2.3 mmol, 85%). Appearance: clear oil. Mixtures
of Boc-rotamers were observed by NMR spectroscopy; please see
7.12 (m), 3.75−3.65 (m), 3.54−3.45 (m), 3.37 (dt, J = 10.9, 7.4 Hz),
3.32−3.22 (m), 2.74−2.54 (m), 2.25−1.98 (m), 1.94−1.72 (m),
1.69−1.50 (m,), 1.47 (s), 1.31 (s). 13C{1H} NMR (101 MHz,
CDCl3): δ 180.9, 175.7, 156.7, 153.8, 142.0, 141.9, 128.4, 128.3,
128.3, 125.9, 125.8, 81.8, 80.3, 70.0, 67.3, 49.2, 48.5, 37.5, 36.0, 35.8,
35.2, 34.3, 33.9, 28.4, 28.2, 26.0, 25.3, 22.7, 22.7. IR (neat): ν/cm−1
3250−2600 (br), 2973 (m), 2932 (m), 2873 (w), 1738 (m), 1694
(s), 1453 (m), 1389 (s), 1366 (s), 1244 (m), 1162 (s), 1136 (s), 856
(m), 749 (m), 698 (s). HRMS (TOF-ESI+): calcd for C19H28NO4
334.2013; found, 334.2017 (M + H+).
1
1
copies of H and 13C NMR spectra in Supporting Information. H
NMR (500 MHz, CDCl3): δ 7.31−7.22 (m,), 7.17−7.13 (m), 3.67
(d, J = 13.9 Hz), 3.61 (d, J = 13.8 Hz), 3.51 (dt, J = 10.5, 7.3 Hz),
3.40 (ddd, J = 10.7, 7.5, 5.0 Hz), 3.10 (d, J = 13.7 Hz), 3.03 (d, J =
14.0 Hz), 3.01−2.96 (m), 2.93 (dt, J = 10.7, 7.5 Hz), 2.36 (ddd, J =
13.0, 7.2, 5.6 Hz), 2.21−2.09 (m), 2.01 (ddd, J = 13.0, 8.3, 7.1 Hz),
1.68−1.59 (m), 1.54 (s), 1.52 (s), 1.19 (tdd, J = 12.4, 7.0, 5.3 Hz),
0.93 (dp, J = 12.3, 7.5 Hz). 13C{1H} NMR (126 MHz, CDCl3): δ
180.6, 177.1, 156.1, 153.6, 136.7, 136.2, 130.7, 130.6, 128.3, 128.2,
126.8, 126.7, 81.3, 80.8, 69.8, 68.0, 49.0, 48.3, 39.4, 38.6, 36.7, 34.7,
28.5, 28.4, 22.4, 22.2. IR (neat): ν/cm−1 3300−2700 (br), 2976 (m),
2878 (m), 1737 (m), 1697 (s), 1392 (s), 1368 (m), 1167 (s), 1139
Synthesis of Products 9a−g. For a reaction on a 2 mmol scale, a
solution containing substrate acid 4 (1 M, toluene, 2 mmol, 1.0 equiv)
and NEt3 (2 mml, 1.0 equiv) was prepared and pumped using a
Vaportec E-series flow reactor at a flow rate of 0.25 mL/min. A
E
https://doi.org/10.1021/acs.joc.1c01133
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
second solution containing DPPA (0.95 M, toluene, 1.9 mmol, 0.95
equiv) was pumped at the same flow rate and mixed with the
substrate solution via a T-piece (1/16 in. id). The combined mixture
was then directed into a heated coil reactor (10 mL volume, PFA
tubing, 1/16 in. id) held at 100 °C resulting in a residence time of 20
min. Upon exiting this reactor coil, the mixture passed through a BPR
(100 psi, Kinesis) before entering an Omnifit glass column containing
A-15 and A-21 scavenger resins (mixed bed, ca. 2 equiv each) at an
ambient temperature. The crude mixture was collected in a flask and
evaporated under reduced pressure. Purification was performed via
silica gel chromatography using EtOAc/cyclohexane (10−20%
EtOAc) as an eluent system.
(CH2). 19F-NMR (282 MHz, CDCl3): δ/ppm δ −62.2 (s). IR (neat):
ν/cm−1 2978 (w), 2889 (w), 1706 (m), 1637 (m), 1610 (m), 1386
(m), 1314 (s), 1244 (m), 1159 (s), 1140 (s), 1107 (s), 1066 (s),
1002 (m), 859 (s). HRMS (TOF-ESI+): calcd for C17H20F3NO2Na,
350.1338; found, 350.1338 (M + Na+). Crystal data: CCDC
2083011: C17H20F3NO2; monoclinic, a = 15.3119(2) Å, b =
10.2080(2) Å, c = 21.3592(3) Å, α = 90°, β = 92.8390(10)°, γ =
90°; Z = 8; space group P21/c; T = 100 K; R1 = 0.0872.
tert-Butyl (4-Oxo-7-phenylheptyl)carbamate (9g). Yield: 238 mg
(0.79 mmol, 79%). Appearance: clear oil. 1H NMR (500 MHz,
CDCl3): δ/ppm 7.28 (t, J = 7.7 Hz, 2H), 7.22−7.14 (m, 3H), 4.58 (s,
1H), 3.10 (q, J = 6.7 Hz, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.41 (m, 4H),
1.90 (p, J = 7.4 Hz, 2H), 1.73 (p, J = 7.0 Hz, 2H), 1.43 (s, 9H).
13C{1H} NMR (125 MHz, CDCl3): δ/ppm 210.3 (C), 156.0 (C),
141.5 (C), 128.5 (2CH), 128.4 (2CH), 125.9 (CH), 79.2 (C), 42.0
(CH2), 40.0 (CH2), 39.9 (CH2), 35.1 (CH2), 28.4 (3CH3), 25.2
(CH2), 24.0 (CH2). IR (neat): ν/cm−1 3368 (br, m), 2975 (m), 2931
(m), 1701 (s), 1513 (m), 1453 (m), 1391 (m), 1365 (m), 1248 (m),
1165 (s), 748 (m), 700 (s). HRMS (TOF-ESI+): calcd for
C18H27NO3Na, 328.1883; found, 328.1886 (M + Na+).
A scaled version of this procedure was used starting from acid 4a
(1.55 g, 6.78 mmol) to prepare compound 9a (1.20 g, 5.97 mmol,
88%).
tert-Butyl (4-Oxopentyl)carbamate (9a).11 Yield: 1.20 g (5.97
mmol, 88%). Appearance: colorless oil. 1H NMR (400 MHz, CDCl3):
δ/ppm 4.61 (br s, 1H), 3.08 (q, J = 6.6 Hz, 2H), 2.45 (t, J = 7.1 Hz,
2H), 2.11 (s, 3H), 1.72 (p, J = 7.0 Hz, 2H), 1.40 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3): δ/ppm 208.4 (C), 156.0 (C), 79.1 (C),
40.7 (CH2), 39.9 (CH2), 29.9 (CH3), 28.4 (3CH3), 24.2 (CH2). IR
(neat): ν/cm−1 3365 (br, m), 2976 (m), 2932 (m), 1688 (s), 1517
(m), 1449 (w), 1391 (m), 1365 (s), 1249 (s), 1162 (s). HRMS
(TOF-ESI+): calcd for C10H19NO3Na, 224.1257; found, 224.1259
(M + Na+).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01133.
tert-Butyl (4-Oxohexyl)carbamate (9b). Yield: 289 mg (1.3 mmol,
1
1
Copies of H and 13C NMR spectra (PDF)
84%). Appearance: colorless oil. H NMR (500 MHz, CDCl3): δ/
ppm 4.60 (s, 1H), 3.12 (q, J = 6.6 Hz, 2H), 2.47−2.41 (m, 4H), 1.77
(p, J = 7.0 Hz, 2H), 1.44 (s, 9H), 1.06 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3): δ/ppm 211.2 (C), 156.0 (C), 79.2 (C),
40.1 (CH2), 39.4 (CH2), 36.0 (CH2), 28.4 (3CH3), 24.1 (CH2), 7.8
(CH3). IR (neat): ν/cm−1 3362 (br), 2976 (m), 2936 (m), 1689 (s),
1517 (m), 1454 (m), 1365 (m), 1248 (s), 1165 (s), 1042 (m), 1023
(m), 980 (m), 875 (m), 780 (m). HRMS (TOF-ESI+): calcd for
C11H21NO3Na 238.1414; found, 238.1415 (M + Na+).
Accession Codes
CCDC 2083011 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
tert-Butyl (E)-2-Benzylidenepyrrolidine-1-carboxylate (9c).17a
Yield: 380 mg (1.47 mmol, 88%). Appearance: white solid. Melting
AUTHOR INFORMATION
Corresponding Author
1
■
range: 78−81 °C. H NMR (500 MHz, CDCl3): δ/ppm 7.32−7.28
(m, 2H), 7.26−7.23 (m, 2H), 7.15−7.11 (m, 2H), 3.66 (t, J = 7.0 Hz,
2H), 2.82 (td, J = 7.4, 2.0 Hz, 2H), 1.86 (p, J = 7.2 Hz, 2H), 1.56 (s,
9H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 152.9 (C), 140.9
(C), 139.0 (C), 128.2 (2CH), 128.0 (2CH), 125.0 (CH), 108.3
(CH), 80.6 (C), 48.9 (CH2), 30.6 (CH2), 28.5 (3CH3), 22.1 (CH2).
IR (neat): ν/cm−1 2975 (w), 2883 (w), 1702 (s), 1639 m), 1383 (s),
1323 (s), 1243 (m), 1159 (s), 1136 (s), 1076 (m), 1003 (m), 856
(m), 748 (m), 694 (s). HRMS (TOF-ESI+): calcd for C16H22NO2,
260.1645; found, 260.1647 (M + H+).
Marcus Baumann − School of Chemistry, University College
Dublin, Science Centre South, Belfield D04 N2E2, Ireland;
orcid.org/0000-0002-6996-5893;
Email: marcus.baumann@ucd.ie
Authors
Thomas S. Moody − Department of Technology, Almac
Sciences, Craigavon BT63 5QD, United Kingdom; Arran
Chemical Company, Roscommon N37 DN24, Ireland;
orcid.org/0000-0002-8266-0269
Megan Smyth − Department of Technology, Almac Sciences,
Craigavon BT63 5QD, United Kingdom; orcid.org/0000-
0002-2771-0382
tert-Butyl (E)-2-(4-Fluorobenzylidene)pyrrolidine-1-carboxylate
(9d). Yield: 223 mg (0.81 mmol, 81%). Appearance: white solid.
Melting range: 65−68 °C. 1H NMR (400 MHz, CDCl3): δ/ppm 7.14
(dd, J = 8.7, 5.6 Hz, 2H), 7.06 (br s, 1H), 6.94 (t, J = 8.8 Hz, 2H),
3.62 (t, J = 7.0 Hz, 2H), 2.72 (td, J = 7.4, 2.0 Hz, 2H), 1.82 (p, J = 7.2
Hz, 2H), 1.51 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ/ppm
160.6 (CF, d, J = 243 Hz), 152.8 (C), 140.7 (C), 134.9 (C, d, J = 4
Hz), 129.4 (2CH, d, J = 8 Hz), 114.8 (2CH, d, J = 21 Hz), 107.2
(CH), 80.6 (C), 48.8 (CH2), 30.4 (CH2), 28.4 (3CH3), 22.0 (CH2).
19F-NMR (376 MHz, CDCl3): δ/ppm δ −118 (s). IR (neat): ν/cm−1
Scott Wharry − Department of Technology, Almac Sciences,
Craigavon BT63 5QD, United Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01133
2977 (m), 2934 (w), 1703 (s), 1645 (m), 1507 (s), 1386 (s), 1329
(s), 1228 (m), 1158 (m), 1140 (s), 1002 (m), 860 (m), 768 (m).
HRMS (TOF-ESI+): calcd for C16H20NFO2, 278.1551; found,
278.1552 (M + H+).
Notes
The authors declare no competing financial interest.
tert-Butyl (E)-2-(4-(Trifluoromethyl)benzylidene)pyrrolidine-1-
carboxylate (9e). Yield: 457 mg (1.40 mmol, 85%). Appearance:
white solid. Melting range: 86−88 °C. 1H NMR (500 MHz, CDCl3):
δ/ppm δ 7.51 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.16 (br s,
1H), 3.66 (t, J = 6.9 Hz, 2H), 2.81 (td, J = 7.3, 2.0 Hz, 2H), 1.87 (p, J
= 7.2 Hz, 2H), 1.54 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3): δ/
ppm 152.7 (C), 143.0 (C), 142.8 (C), 128.0 (2CH), 126.6 (C, q, J =
32.3 Hz), 124.9 (2CH, q, J = 3.9 Hz), 124.5 (CF3, q, J = 270 Hz),
107.0 (CH), 81.0 (C), 49.0 (CH2), 30.7 (CH2), 28.3 (3CH3), 22.0
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from Science Foundation
Ireland through the SFI Industry Fellowship Program for the
project entitled “Development of Continuous Biocatalysed
Processes, Continuous Biocatalysed Chemicals (CATCH)”
(19/IFA/7420 to M.B.) as well as the Infrastructure Call 2018
(18/RI/5702) and the European Regional Development Fund
F
https://doi.org/10.1021/acs.joc.1c01133
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
(12/RC2275_P2). We thank Conor Kelly and Helge Mu
Bunz (both UCD, School of Chemistry) for solving the X-ray
structure reported herein.
pubs.acs.org/joc
Note
M. F.; Allanson, N. M.; Blaney, E. L.; Garcia-Irizarry, C. N.; Kohrt, J.
T.; Griffith, D. A.; Dow, R. L. Synthesis of spiropiperidine lactam
acetyl-CoA carboxylase inhibitors. J. Org. Chem. 2012, 77, 10050−
10057. (b) Guetzoyan, L.; Ingham, R. J.; Nikbin, N.; Rossignol, J.;
Wolling, M.; Baumert, M.; Burgess-Brown, N. A.; Strain-Damerell, C.
M.; Shrestha, L.; Brennan, P. E.; Fedorov, O.; Knapp, S.; Ley, S. V.
Machine-assisted synthesis of modulators of the histone reader BRD9
using flow methods of chemistry and frontal affinity chromatography.
MedChemComm 2014, 5, 540−546. (c) Filipponi, P.; Ostacolo, C.;
Novellino, E.; Pellicciari, R.; Gioiello, A. Continuous Flow Synthesis
of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source
of PARP-1 Inhibitors. Org. Process Res. Dev. 2014, 18, 1345−1353.
(8) Marsini, M. A.; Buono, F. G.; Lorenz, J. C.; Yang, B.-S.; Reeves,
J. T.; Sidhu, K.; Sarvestani, M.; Tan, Z.; Zhang, Y.; Li, N.; Lee, H.;
Brazzillo, J.; Nummy, L. J.; Chung, J. C.; Luvaga, I. K.; Narayanan, B.
A.; Wei, X.; Song, J. J.; Roschangar, F.; Yee, N. K.; Senanayake, C. H.
Development of a concise, scalable synthesis of a CCR1 antagonist
utilizing a continuous flow Curtius rearrangement. Green Chem. 2017,
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̈
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The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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https://doi.org/10.1021/acs.joc.1c01133
J. Org. Chem. XXXX, XXX, XXX−XXX