Practical synthesis of ethyl 3-fluoro-1-pyrrole-2-carboxylate: A key fragment of a potent drug candidate against hepatitis b virus

Article abstract of DOI:10.1021/acs.oprd.9b00382

We report herein the development of two efficient synthetic routes for the preparation of a key fragment required for the synthesis of potent drug candidates of Hepatitis B virus. The ethyl 3-fluoro-1-H-pyrrole-2-carboxylate scaffold was synthesized from readily available starting materials in good overall yields. The scalability of one of the developed routes was demonstrated and afforded the desired target in good yield and excellent purity (99%).

Full text of DOI:10.1021/acs.oprd.9b00382

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Communication
Practical Synthesis of Ethyl 3-Fluoro-1-Pyrrole-2-Carboxylate: a
Key Fragment of a potent drug candidate against Hepatitis B virus.
Adeline René, Maxime Quilan, Yicheng Deng, Yang Cheng, Christopher Allan
Teleha, Pierre Raboisson, Jean -François Bonfanti, Jerome Fortin, André
B. Charette, Xavier Pannecoucke, Thomas Poisson, and Philippe Jubault
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00382 • Publication Date (Web): 26 Sep 2019
Downloaded from pubs.acs.org on September 28, 2019
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Practical Synthesis of Ethyl 3-Fluoro-1-Pyrrole-2-
Carboxylate: a Key Fragment of a potent drug
candidate against Hepatitis B virus.
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Adeline René,a,† Maxime Quilan,a,† Yicheng Deng,b Yang Cheng,b Christopher A.
Teleha,c Pierre Raboisson,d,‡ Jean-François Bonfanti,e Jérôme Fortin,e André. B.
Charette,f Xavier Pannecoucke,a Thomas Poisson,a,g* and Philippe Jubault a*
a
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000
Rouen, France.
b
AcceleDev R&D Co., Ltd, Building J4, No. 15 Wanshou Road, Pukou Economy
Development Zone, Nanjing City, China 211800.
c
Janssen Research & Development, Small Molecule Pharmaceutical Development,
Janssen Pharmaceutical Companies of Johnson & Johnson, 1400 McKean Road, Spring
House, PA 19477, USA.
d Janssen Research & Development, Medicinal Chemistry Infectious Diseases, Beerse,
Belgium.
e
Janssen Research & Development, Medicinal Chemistry Infectious Diseases, Centre
de Recherche Janssen Cilag, Campus de Maigremont, BP 615, 27106 Val de Reuil
Cedex, France.
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f Centre in Green Chemistry and Catalysis, Faculty of Arts and Sciences Department of
Chemistry, Université de Montréal, PO Box 6128, Station Downtown Montréal, Québec,
H3C3J7, Canada.
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g Institut Universitaire de France, 1 rue Descartes, 75231 Paris, France.
TOC:
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ABSTRACT
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We report herein the development of two efficient synthetic routes for the preparation of
a key fragment required for the synthesis of potent drug candidates of Hepatitis B virus.
The ethyl 3-fluoro-1-H-pyrrole-2-carboxylate scaffold was synthesized from readily
available starting materials in good overall yields. The scalability of one of the developed
routes was demonstrated and afforded the desired target in good yield and excellent
purity (99%).
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Keywords: Fluorinated molecules, academic-industrial collaboration, heterocycles,
pyrrole
INTRODUCTION
Hepatitis B virus (HBV) has developed into major disease all over the world. Recent
estimates suggest that 5% of the world population are infected with the HBV and 25% of
these individuals with develop chronic hepatitis, cirrhosis, and hepatocellular carcinoma
during the course of their lifetime.1 Although vaccines are currently available, the
treatment of infected patient relied on the use of a limited number of treatments.
Compounds of formula A were recently found as inhibitors of HBV, with promising
properties as a pre-clinical candidates (Figure 1).2
Figure 1. Structure of A and Key Fragment 1.
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Retrosynthetic analysis shows that compounds of formula A are constructed from ethyl
3-fluoro-pyrrole-2-carboxylate 1. However, this fragment is scarcely available from
commercial suppliers, or at a high cost, and its synthesis is not described in the literature;
rather a single report described this compound as a side product.3 Therefore, due to the
need of A in a large quantity for pre-clinical studies, the development of a practical,
efficient and reliable route to synthesize 1 was critical for the production of A. Herein, we
report our efforts to synthesize this important building block. At the outset of the project,
many retrosynthetic pathways were suggested and these were ultimately triaged down to
three approaches, which were prioritized and evaluated at the laboratory scale (Scheme
1).
Scheme 1. Selected Retrosynthetic Approaches.
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Route A
Br
OR
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8
OR
O
N
H
N
O
R
2
9
Route B
F
F
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O
O
OR
N
OH
O
N
R
N
R
O
F
R
4
F
3
1
Route C
F
O
F
O
O
OR
OR
Cl.H3N
N
H
N
H
OR
OR
O
O
5
6
The first synthetic approach selected by the team relied on a halogen exchange strategy
with the 3-bromopyrrole derivatives 2 (Route A). The intermediate organometallic species
could then be trapped with an electrophilic source of fluorine,4a,b or submitted to a Pd-
catalyzed Br-to-F although “five-membered heteroaryl halides remain challenging
substrates for this methodology” according to the authors.4c This 3-bromo-pyrrole 2 could
be itself obtained from a proline derivative after a one-pot bromination/oxidation
sequence, as described by Banwell and co-workers.5 A second approach to access 1,
relied on an organometallic addition on fluoro-pyrrolidinone 3 (route B). A subsequent
oxidation into the corresponding pyrrole followed by further trivial functional group
manipulation to build up the ester function should give access to 1. Note that 3, could be
readily synthesized from the fluorovinyl amide 4 thanks to a RCM reaction, itself
synthesized from commercially available fluoroacrylic acid.6 Finally, a third route was
designed (route C). The fluoropyrrole 1 could be obtained from the 3,3-difluoroproline
derivative 5, itself synthesized from the 3-oxoproline 6.
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RESULTS AND DISCUSSION
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In this report, we described our synthetic effort to access 1 through these three different
synthetic routes. The scalability for the synthesis of 1 is also described.
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Evaluation of route A. We first investigated the route A to build up the key fluoro-pyrrole
1 starting from the readily available proline ethyl ester (Scheme 2).
Scheme 2. Synthetic Approach to 1a Through Route A.
Boc2O (1.5 equiv)
Br
OEt
Et3N (1.5 equiv)
OEt
NBS (3.5 equiv)
OEt
N
H
N
N
O
O
DCM, 0 °C to rt, 16 h
85%
CCl4, 85 °C
49%
Boc
O
Boc
7
2
Br
F
1. Grignard reagent formation
2. NFSI
OEt
OEt
N
N
O
O
Boc
Boc
2
1a
We first started the synthesis with proline ethyl ester, which was submitted to a N-Boc
protection under standard conditions, giving 7 in a decent 85% yield. Then, the N-Boc-
protected amino ester 7 was reacted with an excess of NBS (3.5 equiv) to furnish the
corresponding 3-bromo-N-Boc-pyrrole-2-carboxylate 2 in 49% yield, according to the
procedure described by Banwell and co-workers.5 Various attempts to generate the
Grignard reagent from 2 followed by a trapping with NFSI were performed.4Unfortunately,
none of the tested conditions gave detectable amount of product. Similarly, the Pd-
catalyzed Br-to-F exchange did not afford the product in an acceptable amount. Hence,
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these disappointing results prompted us to attempt other synthetic approaches to access
the desired backbone.
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Evaluation of route B. Due to the inefficiency of route A, we started the evaluation of
synthetic approach B based on the key formation of pyrrolidinone 3 (Scheme 3).
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Scheme 3. Synthesis of Fluorinated Pyrrolidinone 3.
F
O
O
HATU, Et3N
HG II (2 mol%)
H
N
OH
N
O
N
Bn
toluene, 100 °C
97% (1.5 g scale)
DMF, rt
91%
F
F
Bn
Bn
8
3
The synthesis of 3 started with the formation of the fluorinated amide 8. Commercially
available 2-fluoro-acrylic acid was reacted with N-benzyl-allylamine in the presence of
HATU in DMF using Et3N as the base. The corresponding tertiary amide 8 was isolated
in 91% yield. Then, the challenging RCM reaction was attempted. Using the HG II catalyst
in toluene under diluted conditions, the RCM reaction furnished the desired pyrrolidinone
3 in an excellent 97% yield. Note that the reaction could be readily scale up to 1.5 g,
without loss of efficiency. The introduction of various precursors of the ester or acid motifs
in an addition/oxidation sequence was also evaluated (Table 1).
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Table 1. Addition/oxidation Sequence on Pyrrolidinone 3.
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F
F
R-M
O
R
N
N
Et2O, 0 °C, 1 h
Bn
Bn
3
9a-f
Entry
1
R-M
Product
9a-f
9a
Isolated Yield
(%)
F
nBuLi
33
nBu
N
Bn
F
2
3
4
5
MeLi
9b
9c
9d
9e
24
Me
N
Bn
F
73
MgBr
N
Bn
< 20a
NR
F
S
Li
S
S
N
S
Bn
N
F
Li
O
N
N
O
Bn
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F
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9f
NR
5
OPiv
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8
N
Bn
a NMR Yield determined by 19F NMR. NR = no reaction.
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First, to ascertain the feasibility of the process, nBuLi was used as a test nucleophile in
the reaction with compound 3 (entry 1). Pleasingly, the addition/oxidation sequence
proceeded smoothly, giving 9a in a moderate 33% yield. MeLi proved to be less efficient
and the 2-methylpyrrole 9b was isolated in a moderate 24% yield (entry 2). On the other
hand, vinyl magnesium bromide was used and the corresponding 2-vinylpyrrole 9c was
isolated in a very good 73% yield (entry 3). Finally, the addition of the lithiated dithiane7
gave the corresponding product 9d in lower yield (< 20% 19F NMR yield, entry 4), while
neither the addition of the lithiated oxazoline nor the Grignard reagent derived from
(Pivaloyloxy)methyl iodide8 occurred (entries 5 and 6). Although the useful synthons
leading to the desired ester functionality at the C2 position of the pyrrole ring limited the
number of nucleophiles surveyed. It appeared that sp2-nucleophiles worked better for this
addition than those of an sp3 nature, with the low yielding dihydrooxazoline as an outlier
to this trend.
With these results in hand, we attempted to modify the residue at the 2-position of the
pyrrole ring to build up either the ester or the acid derivatives.
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Scheme 4. Functional Group Manipulations to Access 1c.
a Determined by 19F NMR.
We first started our investigation using 2-methylpyrrole 9b. The oxidation of the methyl
group into the corresponding aldehyde 10 was achieved using the conditions described
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by Chiba,9 albeit in a moderate 37% yield (Scheme 4, eq. 1), which hampered the
scalability of the reaction sequence. Then, we turned our attention to the 2-vinyl-pyrrole
9c. To our delight, a dihydroxylation/oxidation sequence led to the corresponding
aldehyde 10 in a good 86% yield (Scheme 4, eq. 2). Application of the Corey’s
conditions,10 to convert the aldehyde into the corresponding methyl ester, did not afford
the desired ester 1b (Scheme 4, eq. 3). Hence, we envisioned the oxidation of the
aldehyde in 10 into the corresponding acid by the use of KMnO4 in a H2O/acetone mixture.
We were gratified with the result, which gave the acid 1c in 65% yield (Scheme 4, eq. 4).
The same two steps sequence starting from 9c yielded 1c in 42% yield without the need
for a purification of the intermediate (Scheme 4, eq. 5).
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Evaluation of route C. Alternative route C starting from 3-oxoproline 6.
Scheme
5.
Synthesis
of
1d
According
to
Route
C.
F
F
F
O
F
F
MnO2, Et3N
condition A, 70%
condition B, 69%
HCl 4N in dioxane
OEt
OEt
OEt
OEt
N
N
N
N
rt, 4 h
quantitative
THF, 80 °C, 16 h
30%
O
H
H
O
O
O
Boc
H
Boc
Cl
6
13
14
1d
MnO2, Et3N
THF, 80 °C, 16h
F
OEt
O
N
Boc
1a
Conditions A: DAST (5 equiv), DCM, rt, 16 h, 70%. Conditions B: Xtalfluor-E (6 equiv),
Et3N.HF (4 equiv), 20 °C, 30h, then then 30 °C 1h, 69%.
In parallel to the development of route B, the alternative route C starting from 3-oxoproline
6 was studied (Scheme 5). First, the conversion of ethyl N-Boc-3-oxoproline ester 6 into
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the corresponding 3,3-difluoro proline ethyl ester 13 was performed in an excellent 70%
yield. Note that due to its high toxicity and its explosive character, DAST was replaced by
the safer Xtalfluor-E11 at the cost of a slight decrease of the reaction yield. Indeed, using
6 equivalents of Xtalfluor-E, 13 can be obtained in 69% yield. Attempts to convert 9 into
the corresponding pyrrole remained unsuccessful. Alternatively, we sought that the N-
Boc protecting group might hamper the oxidation of the pyrrolidine ring into pyrrole. A
typical deprotection of the Boc protecting group under acidic conditions (HCl 4M in 1,4-
dioxane) gave quantitatively the hydrochloride salt 14. An oxidation using MnO2 in the
presence of Et3N was tested. To our delight, the corresponding pyrrole 1d was isolated
in a moderate 30%, demonstrating the feasibility of the approach. Variable yields were
found when this reaction was repeated, and we traced this back to the quality of MnO2
used in the reaction. The best results were obtained when freshly prepared MnO2 was
used for this oxidation step.12 In order to optimize the last step, other oxidants, bases, as
well as the reaction parameters (solvent, stoichiometry) were screened (table 2).
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Table 2. Optimization of the Formation of 10 from 11.a
F
F
F
[O] (x equiv), Base (1.2 equiv)
Solvent, 80 °C, 16 h
OEt
Cl
OEt
N
N
H
O
H
H
O
14
1d
Entry
[O]
x
8
0
8
Base
Et3N
Et3N
-
Solvent
THF
Yield (%)
30
1
2
3
MnO2
MnO2
MnO2
THF
NR
THF
< 5
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5b
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DDQ
DDQ
4
4
8
8
8
8
8
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
THF
THF
traces
Traces
29
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
2-Me-THF
1,4-dioxane
EtOH
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9
DCM
30
10
11
acetone
88 (68)c
65
acetone
Technical
grade
12
13
14
15
16
MnO2
MnO2
MnO2
MnO2
MnO2
8
8
2
4
6
DIEA
NaHCO3
Et3N
acetone
acetone
acetone
acetone
acetone
24
18
0
Et3N
12
65
Et3N
a Reaction were carried out on a 0.1 or 0.2 mmol scale. b Reaction was carried out at 20
°C. c reaction was carried out on a 1.2 mmol scale.
First, we demonstrated that the concomitant use of MnO2 and Et3N was crucial to access
pyrrole 1d (entries 2 and 3). Then, DDQ was also tested to replace MnO2, however
whatever the temperature (20 °C or 85 °C) no desired product was observed (entries 4
and 5). To improve the reaction yield, various solvents were tested. 2-Methyl-THF, 1,4-
dioxane and EtOH did not improve the reaction yield, furnishing 1d in less than 30% yield
(entries 7, 8 and 9). The use of dry acetone as a solvent allowed a significant increase of
the reaction yield to 88% (entry 10). Note that even technical grade acetone can be used
giving 1d in 65% yield (entry 11). Other bases were tested like DIEA or NaHCO3 and did
not improve the reaction yield. Finally, in order to decrease the amount of MnO2 the
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stoichiometry of the reaction was studied (entries 14, 15 and 16). We found that 8
equivalents of MnO2 was the optimum amount to get the desired pyrrole 1d in a
satisfactory yield.
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With these optimized reaction oxidation conditions, the three steps sequence was
validated, furnishing the fluoropyrrole 1d, in 57% over three steps from 6 (Scheme 6).
Scheme 6. Validation of the Three Step Sequence to Access 1d.
F
F
O
F
F
F
MnO2, Et3N
DAST (5 equiv)
HCl 4N in dioxane
OEt
Cl
OEt
OEt
OEt
N
N
N
H
N
DCM, rt, 16 h
84%
rt, 4 h
quantitative
Acetone, 80 °C, 16 h
68%
O
H
H
O
O
O
Boc
Boc
6
13
14
1d
, 57% over 3 steps
Recognizing the compatibility of the fluoropyrollidine to the oxidation conditions, we
sought an alternative entry from commercially available N-Boc-3-hydroxyproline 15, a
readily available starting material (Scheme 7).
Scheme 7. Attempts with N-Boc-3-Hydroxyproline 15.
OH
OH
NaHCO3, MeI
OH
OMe
OMe
N
N
DMF, 50 °C, 16 h
80%
O
O
Boc
15
Boc
16
OH
F
F
MnO2, Et3N
DAST
OEt
OMe
OEt
N
N
N
N
DCM, 25 °C, 16 h
32% (unoptimized)
THF, 80 °C, 16 h
O
O
O
O
Boc
Boc
Boc
Boc
16
17
1a
< 20%
not observed
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After an esterification reaction under standard conditions (MeI, NaHCO3, DMF, 50 °C),
the corresponding methyl ester 16 was readily converted into the fluorinated derivative
17 according to a deoxofluorination reaction with DAST® in a moderate 32% yield.
Various attempts to convert the latter into the 3-fluoropyrrole 17 were performed.
Unfortunately, no trace of the desired product was observed and only decomposition of
the starting material into unidentified products was noticed. Note that when the previously
developed conditions (Table 2, entry 1) were used, only dihydropyrrole was observed in
the reaction media in low amount (< 20%). The observation of the fluoride elimination
suggests that the mechanism for our successful oxidation occurs stepwise with initial
formation of a vinyl fluoride, which is further oxidized to the pyrrole. This result led us to
give up this approach starting from methyl ester 16.
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Scalability of route C.13 In order to ascertain a robustness of our route C, the synthesis
of ethyl 3-oxoproline ester 6 was investigated for scalability to multi-gram amounts.
Although, 6 was commercially available its price led us to design an economic approach
to construct this scaffold starting from glycine ethyl ester and ethyl acrylate (Scheme 8).
Scheme 8. Large scale synthesis of 6.
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O
H
N
NaOH aq., rt
64% (348 g)
O
OEt
OEt
NH2
EtO
EtO
O
O
18
7
8
9
Boc2O, NaOH
DCM, rt
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89% 230 g
O
O
Boc
N
tBuOK, toluene
OEt
OEt
EtO
N
0 °C to rt
39% (150 g)
O
O
Boc
6
19
First, ethyl glycine ester was reacted with ethyl acrylate in the presence of aqueous
NaOH, giving 18 in 64% yield after distillation (348 g, 99% GC purity). Then, a Boc
protection of the secondary amine 18 was carried out, giving 19 in 89% isolated yield (230
g, 92% GC purity). Finally, a Dieckmann condensation14 was performed in the presence
of tBuOK in toluene to afford 3-oxo-proline 6 in 39% yield when performed on a 150 g
scale (93% purity). Note that despite all our efforts, the purification of 6 through a
chromatography on silica gel could not be avoided.
Then, a purification free sequence from 6 to access fluoropyrrole 1d was designed
(Scheme 9).
Scheme 9. Scalability of route C.
F
MnO2 (1 equiv)
Et3N (1.2 equiv)
F
O
F
F
F
DAST (2.7 equiv)
HCl 4N in dioxane
OEt
Cl
OEt
OEt
OEt
N
N
N
H
N
DCM, rt, 87%
(20 g scale, 82% purity)
rt, 4 h
102% crude yield
acetone, 65 °C
38%
O
H
H
O
O
O
Boc
Boc
(18.9 g scale, 85% purity)
(14 g scale, 99% purity)
6
13
14
1d
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The difluorination reaction using DAST was achieved in an excellent 87% yield using 2.7
equivalents of DAST. The product 13 was obtained with 82% HPLC purity and used
without further purification in the next step. Unfortunately, the replacement of DAST by
Xtalfluor-E on a similar scale did not provide a satisfactory result and was not considered
further for the large-scale production of 13. The removal of the N-Boc protecting group
was achieved in excellent yield (102% crude yield) and the compound 14 was pure
enough to be taken directly into the next step in the synthesis (85% purity), without further
purification. The final step, ie. the oxidation reaction of 14 into the pyrrole 1d, was
performed on a 14g scale using 1 equivalent of MnO2 and the desired target 1d was
isolated in 38% yield.
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CONCLUSION
In summary, we reported herein our effort to develop a practical synthesis of A, a key
fragment required for the synthesis of potent drug candidates of Hepatitis B virus. To
achieve this goal, three synthetic pathways were explored in detail to determine whether
they could provide efficient access to the key 3-fluoropyrrole-2-carboxylate scaffold 1.
Two of the proposed synthetic routes were successful validated and gave efficient access
to this key fragment. Moreover, route C was performed on a large scale and demonstrated
its potential to be used as part of a scale-up campaign to produce this important motif.
EXPERIMENTAL SECTION
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All air and/or water sensitive reactions were conducted in oven-dried glassware under
argon. The nuclear magnetic resonance spectra were recorded on a Bruker DXC 300
instrument. Data are reported as follows: chemical shifts (δ), multiplicity (recorded as s
singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constants and integration.
CFCl3 has been used as internal fluorinated reference. High-resolution mass spectra
(HRMS) were recorded on Waters LCT Premier, IR spectra were recorded on a
PerkinElmer Spectrum 100. THF was distilled from sodium-benzophenone. DCM was
distilled from CaH2. Thin-layer chromatography (TLC) were performed on Merck 60F-250
silica gel plates.
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1-tert-Butyl 2-methyl pyrrolidine-1,2-dicarboxylate (7). To a mixture of proline
methyl ester (100 mg, 0.60 mmol, 1 equiv) in DCM (5 mL), Boc2O (196 mg, 0.90 mmol,
1.5 equiv) and Et3N (0.12 mL, 0.90 mmol, 1.5 equiv) were added at 0 °C and the mixture
was allowed to room temperature and stirred overnight. H2O was added to the solution
and the organic layer was extracted with DCM, washed with brine, dried over MgSO4,
filtered and concentrated. Purification by flash chromatography (SiO2) 100% PE to 90:10
PE/EtOAc gave 117 mg of the clean product 7. Yield: 85%. 1H NMR (300 MHz, CDCl3) δ
(ppm) 4.37 – 4.16 (m, 1H), 3.72 (s, 3H), 3.62 – 3.30 (m, 2H), 2.32 – 2.06 (m, 1H), 2.03 –
1.78 (m, 3H), 1.46&1.40 (s, rotamers, 9H). Data are in agreement with the literature.15
1-tert-Butyl 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylate (2). NBS (317 mg, 1.80
mmol, 3.5 equiv) was added to a solution of 7 (117 mg, 0.50 mmol, 1 equiv) in CCl4 (57
mL). The resulting suspension was heated at 85 °C for 2 h. The mixture was cooled to 0
°C, succinimide was filtered and CCl4 was removed under vacuum to give 74 mg of the
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clean product 2. Yield: 49%. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.22 (d, J = 3.3 Hz, 1H),
6.24 (d, J = 3.3 Hz, 1H), 3.90 (s, 3H), 1.56 (s, 9H).
7
8
9
N-allyl-N-benzyl-2-fluoroacrylamide (8). To a solution of 2-fluoroacrylic acid (100 mg,
1.11 mmol) in DMF (10 mL) were added HATU (435 mg, 1 equiv), Et3N (309.4 µL, 2 equiv)
and N-benzyl-allylamine (163.5 mg, 1 equiv). The pH has to be about 8 to 9. The mixture
was stirred for 16 h at room temperature. EtOAc was added (20 mL) and the organic layer
was successively washed with a solution of KHSO4 (1 M, 3 x 20 mL), H2O (20 mL), a
saturated solution of NaHCO3 (3 x 20 mL) and brine (20 mL). The organic layer was dried
over MgSO4 and the solvent was removed under vacuum. The crude product was purified
by flash chromatography (SiO2) 100% PE to 80:20 PE/EtOAc to give 221 mg of the
expected compound 8. Yield: 91%. Rf = 0.4, 80:20 PE/EtOAc. 1H NMR (300 MHz, CDCl3)
δ (ppm) 7.26-7.35 (m, 5H), 5.72-5.85 (m, 1H), 5.11-5.44 (m, 4H), 4.6 (s, 2H), 3.90 (s, 2H).
19F NMR (282 MHz, CDCl3) δ (ppm) -104.85 (d, J = 14.1 Hz, rotamers); -105.54 (d, J
=11.3 Hz, rotamers). Data are in agreement with the literature.16
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1-benzyl-3-fluoro-1,5-dihydro-2H-pyrrol-2-one (3). To a solution of 8 (1.71 g, 7.80
mmol) in dry and degassed toluene (340 mL) was added HG II catalyst (2 mol%, 98 mg).
The mixture was stirred at 100 °C for 45 min. The solvent was removed under vacuum
and the crude product was purified by flash chromatography (SiO2) 100% PE to 70:30
PE/EtOAc to give 1.45 g of the expected compound 3. Yield: 97%. Rf = 0.8, 80:20,
PE/EtOAc. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.23-7.37 (m, 5H), 6.25 (s, 1H), 4.64 (s,
2H), 3.74 (dd, 2H, J = 3.0 and 6.0 Hz). 19F NMR (282 MHz, CDCl3) δ (ppm) -136.77. Data
are in agreement with the literature.16
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General procedure for the addition of organometallic species to 3. To a solution of
3 (10 mg, 0.052 mmol) in dry Et2O (0.03 M) was added R-Li (1 equiv) or R-MgBr (1.5
equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Then, the reaction was
quenched with H2O (2 mL). The aqueous layer was extracted with Et2O (3 x 10 mL). The
combined organic layers were washed with brine and dried over MgSO4. The solvent was
removed under vacuum and the crude product was purified by flash chromatography
(SiO2) 100% PE to 90:10 PE/EtOAc to give the expected compound 9.
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1-benzyl-2-butyl-3-fluoro-1H-pyrrole (9a). Yield: 33%. 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.23-7.34 (m, 3H), 6.99 (d, J = 9.0 Hz, 2H); 6.31-6.34 (m, 1H), 5.91 (d, J = 6.0 Hz,
2H); 4.95 (s, 2H), 2.45 (t, J = 6.0 Hz, 2H); 1.24-1.55 (m, 4H); 0.84 (t, J = 6.0 Hz, 3H). 19F
NMR (282 MHz, CDCl3) δ (ppm) -167.97 (d, J = 2.83 Hz). Data are in agreement with the
literature.17
1-benzyl-3-fluoro-2-methyl-1H-pyrrole (9b). Yield: 24%. 1H NMR (300 MHz, CDCl3)
δ (ppm) 7.20-7.31 (m, 3H), 6.95 (d, J = 9.0 Hz, 2H); 6.32-6.35 (m, 1H), 5.88 (d, J = 3.0
Hz, 1H); 4.90 (s, 2H), 2.00 (s, 2H). 19F NMR (282 MHz, CDCl3) δ (ppm) -168.86 (d, J =
5.66 Hz)
1
1-benzyl-3-fluoro-2-vinyl-1H-pyrrole (9c). Yield: 73%. H NMR (300 MHz, CDCl3) δ
(ppm) 7.29-7.35 (m, 3H), 7.02 (d, J = 6.0 Hz, 2H); 6.30-6.42 (m, 2H), 5.95 (d, J = 3.0 Hz,
1H); 5.54 (d, J = 18.0 Hz, 2H), 5.09 (d, J = 12.0 Hz, 2H), 5.05 (s, 2H). 19F NMR (282 MHz,
CDCl3) δ (ppm) -158.78 (d, J = 5.66 Hz).
1-benzyl-3-fluoro-1H-pyrrole-2-carbaldehyde (10). 2,6-Lutidine (0.180 mL, 4 equiv),
potassium osmate dehydrate (2.6 mg, 2 mol%) and NaIO4 (166 mg, 2 equiv) were added
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sequentially to a solution of 9c (0.388 mmol, 78 mg) in dioxane/H2O (5 mL, 40:15) and
stirred at room temperature until all the starting material had been consumed (monitored
by TLC). H2O (5 mL) and CH2Cl2 (5 mL) were added, layers separated and the aqueous
layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed
sequentially with aqueous HCl (1M, 20 mL) and aqueous NaOH (1M, 20 mL), dried over
MgSO4 and concentrated under vacuum. The crude product was purified by flash
chromatography (SiO2) 100% PE to 95:5 PE/EtOAc to give the expected compound 10.
Yield: 86%. Rf = 0.8, 90:10 PE/EtOAc. 1H NMR (300 MHz, CDCl3) δ (ppm) 9.64 (s, 1H),
7.24-7.30 (m, 3H), 7.12 (d, J = 6.0 HZ, 2H), 6.70-6.73 (m, 1H), 5.87 (d, J = 3.0 Hz, 1H),
5.40 (s, 2H). 19F NMR (282 MHz, CDCl3) δ (ppm) -152.03.
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1-benzyl-3-fluoro-1H-pyrrole-2-carboxylic acid (1c). KMnO4 (256 mg, 2 equiv) in
acetone/H2O (1:1; 19 mL) was added dropwise to a stirred solution of aldehyde 10 (192
mg, 0.810 mmol) in acetone (9.5 mL). After stirring at room temperature for 16 h, acetone
was removed under vacuum and the aqueous solution was acidified with aqueous HCl (4
M) to pH = 2, followed by the addition of aqueous 10% NaHSO3 (3 mL). The mixture was
extracted with EtOAc and the combined organic extracts were washed with H2O, brine,
dried over MgSO4 and then concentrated. The expected compound 1c was obtained by
1
precipitation in cold Et2O. Yield: 65%. Rf = 0.3, 80:20 PE/EtOAc. H NMR (300 MHz,
MeOH-d4) δ (ppm) 7.21-7.27 (m, 3H), 7.06-7.08 (m, 2H), 6.91 (d, J = 3.0 Hz, 1H), 5.95
19
(d, J = 3 Hz, 1H), 5.46 (s, 2H). F NMR (282 MHz, MeOH-d4) δ (ppm) -143.05 (d, J =
2.83 Hz). 13C NMR (75 MHz, MeOH-d4) δ (ppm) 162.44 (d, JC-F = 3.75 Hz), 158.95,
155.53, 139.25, 128.95, 127.86, 127.19, 126.71 (d, JC-F = 6.0 Hz), 108.06 (d, JC-F = 17.2
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Hz), 96.75 (JC-F = 15.7 Hz), 52.89. HRMS calculated for C12H9NO2F : 218.0615, found
5
6
218.0617.
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1-tert-Butyl 2-ethyl 3,3-difluoropyrrolidine-1,2-dicarboxylate (13). DASTTM (1.30
mL, 9.70 mmol, 5 equiv) was added to a solution of 6 (500 mg; 1.94 mmol, 1 equiv) in
DCM (10 mL). The resulting mixture was stirred at room temperature for 16 h. Ice was
added to the solution and the mixture was stirred for an additional 2 h. Then, the aqueous
layer was extracted with DCM (3 times) and the combined organic layers were washed
with brine, dried over MgSO4, filtered and concentrated. Purification by flash
chromatography (SiO2) 100% PE to 90:10 PE/EtOAc gave 374 mg of the clean product
13. Yield: 70%. Rf = 0.7, 90/10 PE/EtOAc (ninhydrin). 1H NMR (300 MHz, CDCl3) δ (ppm)
4.45 (dd, J = 24.3 and 17.3 Hz, 1H), 4.25 (dd, J = 14.2 and 7.1 Hz, 2H), 3.83 – 3.46 (m,
2H), 2.59 – 2.25 (m, 2H), 1.46&1.41 (s, rotamers, 9H), 1.30 (t, J = 7.1 Hz, 3H). 19F NMR
(282 MHz, CDCl3) δ (ppm) -94.43 and -95.08 (m, conformers), -106.95 and -108.37 (m,
conformers).
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Ethyl 3,3-difluoropyrrolidine-2-carboxylate hydrochloride (14). A solution of 13
(304 mg, 1.10 mmol, 1 equiv) in HCl 4N (1,4-dioxane solution, 2.5 mL) was stirred at room
temperature for 18 h. The solvent was evaporated and the remaining HCl was co-
evaporated with cyclohexane (4 times) to give 258 mg of the clean product 14. Yield:
quantitative. 1H NMR (300 MHz, CDCl3) δ (ppm) 4.77 (s, 1H), 4.37 (dd, J = 10.7 and 6.8
Hz, 2H), 3.82 – 3.59 (m, 2H), 1.35 (t, J = 6.6 Hz, 3H). 19F NMR (282 MHz, CDCl3) δ (ppm)
-99.91 – -100.14 (m), -100.14 – -100.63 (m).
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Ethyl 3-fluoro-1H-pyrrole-2-carboxylate (1d). In a two-necked flask under argon
equipped with a condenser, 14 (25 mg, 1.10 mmol, 1 equiv) was diluted in dry acetone
(2.5 mL). Then, Et3N (1.2 eq, 0.02 mL, 0.14 mmol) and freshly prepared MnO2 (8 eq, 78
mg, 0.90 mmol) were added and the resulting mixture was stirred at 80 °C for 4 h. After
cooling the reaction to room temperature, the solution was filtered over a pad of celite®.
Solvent was removed under vacuum and the crude product was purified by flash
chromatography (SiO2) 100% PE to 90:10 PE/EtOAc to give 16mg of the expected
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compound 1d. Yield: 88%. Rf = 0.45, 80/20 PE/EtOAc. H NMR (300 MHz, CDCl3) δ
(ppm) 8.99 (s, 1H), 6.73 (dd, J = 7.4 and 3.6 Hz, 1H), 5.99 (t, J = 2.9 Hz, 1H), 4.35 (q, J
= 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 19F NMR (282 MHz, CDCl3) δ (ppm) -150.11 (d, J
= 4.3 Hz). 13C NMR (75 MHz, CDCl3) δ (ppm) 160.36 (d, JC-F = 3.6 Hz), 156.01, 152.61,
120.22 (d, JC-F = 7.1 Hz), 98.64 (d, JC-F = 16.1 Hz), 60.55, 14.42. HRMS: calculated for
C7H8NO2NaF [M+Na]+ 180.0437, found 180.0436.
Preparation of MnO2. KMnO4 (1.975 g, 12.5 mmol) in 100 mL of EtOH/H2O (1:1) and
Mn(OAc)2 (3.252 g, 18.8 mmol) in 100 mL of EtOH/H2O (1:1) were dripped alternatively
into a EtOH/H2O solution (100 mL) with stirring. After addition a black precipitate was
formed. Then, the solid is filtered, washed with H2O (100 mL) and washed with anhydrous
ethanol (100 mL). The black precipitate was dried at 100 °C under vacuum to afford MnO2
as a black thin powder.
1-tert-Butyl 2-methyl 3-hydroxypyrrolidine-1,2-dicarboxylate (16). To a solution of
15 (100 mg, 0.43 mmol, 1 equiv) in DMF (4 mL), NaHCO3 (54 mg, 0.64 mmol, 1.5 equiv)
and MeI (183 mg, 1.90 mmol, 3 equiv) were added and the mixture was stirred at 50 °C
overnight. Then, EtOAc and water were added. The organic layer was extracted with
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EtOAc (3 times), washed with H2O (3 times) and brine, dried over MgSO4, filtered and
concentrated. Purification by flash chromatography (SiO2) 9:1 to 1:1 PE/EtOAc, gave 69
mg of the product 16. Yield: 67%. Rf = 0.5, 60/40 PE/EtOAc (ninhydrine). 1H NMR (300
MHz, CDCl3) δ (ppm) 4.44 (s, 1H), 4.23 (d, J = 35.5 Hz, 1H), 3.74 (s, 3H), 3.62 (s, 2H),
2.10 (s, 2H), 1.47 and 1.41 (rotamers, s, 9H). Data are in agreement with the literature.18
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1-tert-Butyl 2-ethyl 3-fluoropyrrolidine-1,2-dicarboxylate (17). DASTTM (0.17 mL,
1.30 mmol, 5 equiv) was added to a solution of 16 (64 mg, 0.27 mmol, 1 equiv) in DCM
(5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was
quenched with ice and stirred for an additional 1 h. Then, the organic layer was extracted
with EtOAc (3 times), washed with brine and concentrated. Purification by flash
chromatography (SiO2) 100% PE to 85:15 PE/EtOAc gave 21 mg of the product 17. Yield:
28%. Rf = 0.25, 8/2 PE/EtOAc (ninhydrine). 1H NMR (300 MHz, CDCl3) δ (ppm) 5.35 (d,
J = 53.0 Hz, 1H), 4.66 – 4.32 (m, 1H), 3.85 – 3.68 (m, 3H), 3.61 (dt, J = 17.0 and 9.8 Hz,
2H), 2.38 – 1.88 (m, 2H), 1.41 and 1.36 (s, rotamers, 9H). 19F NMR (282 MHz, CDCl3) δ
(ppm) -186.06 – -186.65 (m), -186.69 – -187.22 (m). Data are in agreement with the
literature.19
Large scale synthesis of 6. To a solution of t-BuOK (83.3 g, 0.742 mol, 1.5 equiv) in
toluene (1500 mL) at 0 °C was added a solution of 19 (150 g, 0.495 mol) in toluene (375
mL), while maintaining the temperature around 0 - 5 °C. The resulting solution then stirred
for 0.5 h (reaction was monitored to confirm the completion). Then, AcOH (59 mL) was
added followed by an aqueous solution of NaH2PO4. The layers were separated and the
aquous layer was extracted with toluene (1700 mL). The combined organic layers was
washed with a Na2HPO4/ NaH2PO4 buffer solution (pH = 7, 2 x 1500 mL), then washed
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with a Na2CO3/NaHCO3 solution (pH = 9.5, 4 x 1500 mL), brine (1500 mL) and dried over
MgSO4 and concentrated. The residue was then purified by flash chromatography (SiO2,
PE/EtOAc 100:0 to 60:40) to yield 6 (39%, 93.2% purity).
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Large scale synthesis of 13. To a reaction flask under nitrogen atmosphere containing
6 (20 g, 77.7 mmol, 1 equiv) was added DCM (160 mL). The reaction mixture was stirred
at room temperature until complete dissolution. Then the reaction mixture was cooled to
0-5 °C and DAST was added dropwised (25.069 g, 155 mmol 2 equiv.). The reaction
mixture was allowed to reach to room temperature and stirred for 18 h. Then, 0.5 equiv
of DAST (39 mmol, 6.260 g) was added and the reaction was stirred for an additional 20
h. To reach completion, 0.2 equiv of DAST (15 mmol, 2.506 g) was added and the reaction
mixture was stirred for an additional 50 h. Then, water was added (40 mL) and the
resulting mixture was stirred ro 3 h. Then, the aqueous layer was extracted with DCM (2
x 30 mL). the combined organic layers were washed with brine, dried over MgSO4 and
concentrated. The residu was dissolved in a 1:1 mixture of MTBE:PE (160 mL). Silica gel
was added (6 g) and the mixture was filtered. The solution was then concentrated to afford
13 in 87% yield (18.9 g, 85% purity), which was used in the next step without further
purification.
Large scale synthesis of 14. To a reaction flask under nitrogen containing 13 (18.9 g,
67.7 mmol, 1 equiv), was added in HCl 4N (1,4-dioxane solution, 160 mL) was stirred at
room temperature for 18 h. The solvent was evaporated and the remaining HCl dioxane
solution was co-evaporated with cyclohexane (3 x 40 mL) to give 14 as a clean product
in a quantitative yield.
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Large scale synthesis of 1d. To To a reaction flask under nitrogen containing 14 (14 g,
64.9 mmol, 1 equiv), 200 mL of acetone and Et3N (9.78 mL, 70.1 mmol, 1.08 equiv) were
added. Then, freshly prepared MnO2 (40 g, 460 mmol, 7.1 equiv) was added. The reaction
was then stirred at 60-65 °C for 20 h. Then, the crude was dissolved in EtOAc (100 mL)
and washed with water (30 mL). Then, PE (100 mL) was added and the organic layer was
washed with HCl (aqueous 36%, 3 x 20 mL), NaHCO3 (aqueous saturated, 2 x 40 mL),
brine (40 mL), dried over MgSO4 and concentrated. To the residue was added a
PE:EtOAc mixture (97.5:2.5, ca. 40 mL). The resulting solution was cooled to 0-5 °C for
2 h. Then, the resulting solid was filtered and washed with cold PE to afford 1d.
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ASSOCIATED CONTENT
Supporting Information.
The following files are available free of charge.
1H, 13C and 19F NMR spectra of compounds 1c, 1d, 2, 3, 7 , 8, 9a, 9b, 9c, 10, 13, 14, 16
and 17 (PDF)
AUTHOR INFORMATION
Corresponding Author
* thomas.poisson@insa-rouen.fr ; * philippe.jubault@insa-rouen.fr
Present Addresses
† Novalix, Boulevard Sébastien Brant, Bioparc, 67405 Illkirch Cedex.
‡ Aligos bvba, Leuven, Belgium
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The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
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Funding Sources
This work was supported by Janssen Research & Development.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
X.P., T.P. and P.J. thank INSA Rouen, Rouen University, CNRS, EFRD, Labex SynOrg
(ANR-11-LABX-0029) and Région Normandie (Crunch Network) for funding. T.P. thanks
the “Institut Universitaire de France” (IUF) for support. The coauthors also wish to thank
Mr. Kaijian Ge, Mr. Cheng Zhang, Mr. Wenye Zhou, Mr. Qi Wang, Mrs Ting Lu and Mrs.
Xiaohong Geng (AcceleDev R&D Co) for their technical contributions to this manuscript.
ABBREVIATIONS
DABCO, 1,4-Diazabicyclo[2.2.2]octane; DAST, Diethylaminosulfur trifluoride; DDQ, 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone; DIEA, Diisopropylethylamine; HATU, N-
[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-
methylmethanaminium hexafluorophosphate N-oxide; HBV, Hepatitis B Virus; HG II,
Hoveyda-Grubbs
2nd
generation;
NBS,
N-Bromosuccinimide;
NFSI,
N-
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Fluorobenzenesulfonimide; RCM, Ring Closing Metathesis; TLC, thin layer
chromatography.
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8
9
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