Halofluorination of N-protected α,β-dehydro-α-amino acid esters—A convenient synthesis of α-fluoro-α-amino acid derivatives

Article abstract of DOI:10.1016/j.jfluchem.2016.06.006

N-protected dehydroamino acid methyl esters have been converted to α-fluoro-β-halo amino acid derivatives under halofluorination reaction conditions. The influences of the nitrogen protecting group of the substrates and of the halonium electrophile on the reaction outcome and the stability of the obtained products have been studied. Furthermore, reduction of the halogen substituent (Cl or Br) under radical conditions provided a possibility for follow-up reactions. Nucleophilic substitution reactions, however, failed.

Full text of DOI:10.1016/j.jfluchem.2016.06.006

Accepted Manuscript
Title: Halofluorination of N-protected ␣,␤-dehydro-␣-amino
acid esters—A convenient synthesis of ␣-fluoro-␣-amino acid
derivatives
¨
Author: Dirk Ulbrich Constantin G. Daniliuc Gunter Haufe
PII:
S0022-1139(16)30151-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.06.006
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Revised date:
Accepted date:
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8-6-2016
9-6-2016
¨
Please cite this article as: Dirk Ulbrich, Constantin G.Daniliuc, Gunter Haufe,
Halofluorination of N-protected ␣,␤-dehydro-␣-amino acid esters—A convenient
synthesis of ␣-fluoro-␣-amino acid derivatives, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.06.006
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Halofluorination of N-protected α,β-dehydro-α-amino acid esters –
a convenient synthesis of α-fluoro-α-amino acid derivatives
Dirk Ulbrich, Constantin G. Daniliuc, Günter Haufe*
Organisch-Chemisches Institut and Cells-in-Motion Cluster of Excellence, Westfälische
Wilhelms-Universität, Münster, Germany.
E-mail: haufe@uni-muenster.de; Fax: 49 251 83 39772; Tel: 49 251 83 33281
Dedicated to Professor Gerhard Erker on the occasion of his 70th birthday
1

Graphical abstract - synopsis
Regioselective halofluorinations of aliphatic and cyclic N-protected α,β-dehydro-α-amino
acid esters lead to α-fluoro-α-amino acid derivatives bearing a reactive β-halogen.
2

Highlights
•
•
Halofluorination reactions of N-protected α,β-dehydro-α-amino acid esters proceed
regioselectively
Most of the formed α-fluoro-β-halo-α-amino acid derivatives are stable until their melting
point
•
•
Reduction of the β-halogen substituent is possible
Nucleophilic substitution reactions of the β-halogen as well as deprotection reactions
failed so far
3

Abstract
N-protected dehydroamino acid methyl esters have been converted to α-fluoro-β-halo amino
acid derivatives under halofluorination reaction conditions. The influences of the nitrogen
protecting group of the substrates and of the halonium electrophile on the reaction outcome
and the stability of the obtained products have been studied. Furthermore, reduction of the
halogen substituent (Cl or Br) under radical conditions provided a possibility for follow-up
reactions. Nucleophilic substitution reactions, however, failed.
Keywords: Amino acids, electrophilic addition, fluorine, halofluorination, regioselectivity.
1. Introduction
Fluoroalkyl groups can exert significant influence on the biochemical properties of molecules,
e.g. their metabolic stability, lipophilicity, acid/base properties or generally their biological
activity [1]. Therefore, development of new methods for the introduction of fluorine into
organic molecules is of continuing interest, especially in the field of medicinal chemistry.
Certain fluorinated amino acids for example are known to be irreversible enzyme inhibitors,
in contrast to their natural analogues [2]. However, α-fluorinated α-amino acid derivatives are
getting comparably little attention in recent research due to their poor availability. Moreover,
among the literature known derivatives [3], only a few compounds contain β-hydrogen atoms
[4] and these are mostly reported to be unstable and could not be isolated [4c,4d] or stored at
room temperature [4b]. Furthermore it is noteworthy that these derivatives have been
synthesized by either using electrophilic [4d], electrochemical [4e] or building block
[4b,4c,4f-h] fluorination methods rather than nucleophilic fluorinating agents like in our case.
Recently, we reported a method to synthesize α,δ-polyfluorinated α-amino acid derivatives
by an oxidative desulfurization-fluorination process [5]. The fact that the obtained products
were stable over several months at ambient temperature under air prompted us to look for
more convenient routs towards α-fluoro-α-amino acid compounds. In this respect, the
halofluorination of dehydroamino acids was one conceivable pathway, even though a good
regioselectivity was at least questionable.
2. Results and discussion
To test the applicability of this approach, we firstly synthesized methyl N-phthaloyl
dehydroalaninate (3), an N,O-protected form of the simplest dehydroamino acid in four steps
with 27% overall yield (Scheme 1). Considering our own [5] as well as other groups’ [3b-
4

e,3k] experiences, we anticipated that a phthaloyl moiety would be one of the most promising
N-protecting groups for the synthesis of stable α-fluorinated α-amino acid derivatives. In this
case, the comparably low electron density at the nitrogen atom makes the loss of fluoride
under formation of an iminium ion less likely.
O
O
1.
PhthN-CO2Et, Na2CO3,
H2O, r.t., 45 min
H2N
PhthN
OH
OH
O
2. MeOH, H2SO4
(43%)
OH
1
2
1.
MsCl, NEt3, CH2Cl2
-20 °C (2 h) Æ r.t., 19 h
O
PhthN
O
2. NEt3, CH2Cl2,
reflux, 1 h
3
(63%)
Scheme 1. Methyl N-phthaloyl dehydroalaninate (3).
Having compound 3 in hand, we subjected it to typical bromo-fluorination conditions (4 equiv
1,3-dibromo-5,5-dimethyl hydantoin (DBH), 6 equiv pyridine polyhydrogenfluoride) and
observed nearly complete conversion of the starting material (GC). The pure product 4 was
isolated in 46% yield after recrystallization (Scheme 2). Later studies have shown that the
reaction proceeds smoothly even with much lower amounts of fluoride source and
electrophile (vide infra).
O
O
DBH, py·9HF
PhthN
PhthN
O
O
F
CH2Cl2, r.t., 23 h
(46%)
Br
3
4
Scheme 2: Methyl 3-bromo-2-fluoro-2-phthalimidopropanoate (3).
To our surprise, the reaction was regioselective, i.e. no β-fluoride was formed according to
19F NMR spectroscopy of the crude product. We reasoned that this was due to the stabilizing
effect of the nitrogen lone pair on a potentially formed α-carbon centered cation. The
bromofluoride 4 is completely stable under ambient conditions even after months of storage.
Besides spectroscopic evidence, the final proof of the constitution of the product was
provided by X-ray diffraction (Fig. 1).
5

Figure 1: X-ray structure of 4 [6].
A common trait of α-fluorinated amino acid derivatives is their reaction with methanol under
ESI mass spectrometry conditions [3k,5]. This has also been observed for our compound, as
the spectrum shows two isotope peaks with m/z = 396.0050/398.0033 that were assigned to
compound 5. However, it was not possible to reproduce this reaction on a preparative scale.
Scheme 3: Possible reaction of 4 with MeOH.
To study the scope of this kind of halofluorination reaction, we first tested the reactivity of
different electrophiles. For this purpose, we reacted different N-halosuccinimides with methyl
N-phthaloyl dehydroalaninate (3). Table 1 shows that all of the investigated halofluorinations
were successful, although with NCS a considerably longer reaction time of 18 days was
needed. The new products 6 and 7 were fully characterized, including X-ray analysis (see
supporting information).
Table 1: Halofluorination of protected dehydroalanine.
Reaction
time [h]
1H NMR*
δ/ppm
13C NMR**
19F NMR
δ/ppm
Yield
[%]
Entry
NXS
Product
δ/ppm
1
2
3
NBS
NIS
3
4
6
7
3.97, 4.97
3.95, 3.97
4.29, 5.10
94.8
95.0
95.2
−126.0
−121.1
−128.5
67
63
44
26.5
NCS
18 days
*CH2X AB signals; **CF signal
In addition to these experiments, it was also tried to use Selectfluor as source of the
electrophile. This however did not lead to the desired α,β-difluorinated product as only the
starting material was re-isolated.
After the synthesis of halofluorides 4, 6 and 7, it was of interest to see what follow-up
reactions would be possible. Unfortunately, substitution of bromine of compound 4 was
neither possible with sulfur (AcSH, PhSH) nor with nitrogen (NaN3) or carbon (commercial
PhMgBr solution) nucleophiles. Attempts to use compound 4 as the starting material for a
6

Grignard reaction by addition of magnesium also failed. The problems were mainly caused by
the ready elimination of hydrogen fluoride under basic conditions, whereas in the absence of
base, no conversion at all was observed. The same observations were made when iodo-
compound 6 was used for the corresponding reactions. Also trials to hydrolyze the ester
function using either acidic or basic conditions were not successful.
Next we attempted to modify compound 4 by a radical reaction. However, initially used
tributyltin hydride did not lead to any conversion. In contrast, employing phenylsilane as
hydride source and AIBN as radical starter according to a method by Jang [7], we were finally
able to convert the bromofluoride to methyl N-phthaloyl α-fluoroalanine (8) (Scheme 4).
Although conversion to the product was practically complete, the yield of pure product was
comparably low as separation from traces of the starting material was possible only by
recrystallization which was connected to erosion of the yield.
O
O
PhSiH3, AIBN
PhthN
O
PhthN
O
F
reflux, 2 h
(20%)
F
Br
4
8
Scheme 4: Methyl N-phthaloyl 2-fluoroalaninate (8).
The α-fluoroalanine derivative 8 [6] was fully characterized and we were also able to grow
crystals suitable for X-ray analysis (Fig. 2).
Figure 2: X-ray structure of 8 [6].
After finding a method to smoothly convert protected dehydroalanine 3 to different
halofluorides, we then thought about additional substrates for this kind of reaction. The first
chosen example was methyl N-phthaloyl-2-aminobut-2-enoate (11), the higher homologue of
compound 3. The synthesis was accomplished with 65% overall yield over four steps starting
from L-threonine (Scheme 5).
7

O
1. MeOH/AcCl,
0 °C reflux, 20 h
O
Æ
H2N
PhthN
OH
O
2. PhthO, NEt3,
PhMe, reflux, 6 h
(100%)
OH
OH
9
10
1. MsCl, NEt3, CH2Cl2,
O
0 °C Æ r.t., 3 h
PhthN
O
2. NEEt3, CH2Cl2,
refflux, 1 h
(65%)
11
Scheme 5: (Z)-Methyl N-phthaloyl but-2-enoate (11).
It is noteworthy that, although the 1H NMR shifts of molecule 11 (δ = 1.84 and δ = 7.41ppm)
differ significantly from the reported values for this Z-isomer (δ = 2.32 and δ = 6.51 ppm [8]),
we were able to confirm the correct configuration by X-ray crystallography [6] (see
supporting information).
As expected, the reaction of 11 with NBS and Olah’s reagent led to formation of
diastereomers 12 and 13 in a ratio of 68:32 (19F NMR) (Scheme 6). Column chromatography
delivered two fractions, one of which contained the diastereomers in a 92:8 and the other one
comprising a 46:54 mixture. From the first fraction we were able to grow single crystals
which according to X-ray analysis were (rel-2R,3R)-configured (Fig. 3) thus hinting at rel-12
[6] being the major diastereomer in this fraction. Compound 13 could not be isolated in pure
form.
O
F
O
O
NBS, py·9HF
PhthN
Br
PhthN
PhthN
O
+
O
O
F
CH2Cl2, r.t., 26 h
(59%)
Br
13
11
12
Scheme 6: Diastereomers of methyl 3-bromo-2-fluoro-2-phthalimidobutanoate (12,13).
Figure 3: X-ray structure of 12 [6].
Subsequently, we tried to react molecules 12 and 13 with different bases to investigate
possibilities to modify the obtained bromofluorides. Unfortunately however, none of the
tested reagents (NEt3, KOtBu, NaH) led to formation of the desired terminal olefin even at
8

elevated temperatures. To our surprise, in most cases no reaction at all took place underlining
the stability of 12 and 13 against bases. The reduction of these compounds to the
corresponding α-fluoro-α-aminobutanoic acid derivatives under Jang’s conditions [7] on the
other hand was successful and delivered product 14 in 72% yield (Scheme 7). The X-ray
crystal structure analysis finally proved its constitution [6] (Fig. 4).
O
O
PhSiH3, AIBN
reflux, 2 h
(72%)
PhthN
PhthN
O
O
F
F
Br
12/13
14
Scheme 7: Methyl 2-fluoro-2-phthalimidobutanoate (14).
Figure 4: X-ray structure of 14 [6].
Additional substrates that were subjected to halofluorination conditions included
dehydrophenylalanine derivative 15 (d.r. 70:30) and dehydroproline 18. While the former one
was synthesized from phenylalanine by protection, radical bromination and subsequent HBr
elimination, the latter one was obtained from proline by esterification, chlorination, N-
protection and HCl elimination [9]. The respective bromofluorination reactions were
successful, although the yields were rather low (Scheme 8).
O
O
O
NBS, py·9HF
PhthN
PhthN
F
PhthN
O
Ph
+
O
Ph
O
F
CH2Cl2, r.t., 24 h
Ph
Br
16a,b
Br
17a,b
(14%, 77:23 dr)
15
CO2Et
CO2Me
N
CO2Et
N
NBS, py·9HF
CO2Me
X
CH2Cl2, r.t., 3 d
Br
18
19a,b: X=F
20a,b: X=OH
Scheme 8: Bromofluorination of compounds 15 and 18.
The protected α-fluoro-β-bromophenylalanines 16 and 17 were obtained in 14% yield with a
diastereomeric ratio (dr) of 77:23 that could be increased to 97:3 by recrystallization.
Unfortunately, due to similar H,F coupling constants and several failed attempts to investigate
the product by X-ray diffraction, it was impossible to determine the relative configuration of
9

the respective diastereomers. The low yield might be explained by the low reactivity of the
double bond because of its participation in a conjugated π-system. Surprisingly, regioisomers
with fluorine in benzylic position were not detected in the crude product mixture.
In case of the α-fluorinated proline derivative, it was difficult to identify the product although
an ESI MS examination delivered the correct mass of bromofluoride 19. The influence of
carbamate rotamers and the likely formed diastereomers caused rather broad and indistinct
proton NMR signals. Furthermore, according to the mass spectrum, at least one side product
(m/z = 313.9634/315.9616, bromine isotope peaks) could not be separated from the desired
product. Even 2D NMR experiments did not allow for a correct assignment of the signals.
Additional measurements to clarify the origin of the broad signals were impossible due to the
short lifetime of the product that hydrolyzed to the α-hydroxy substituted analogue 20 in only
a few hours.
To enhance the stability of α-fluorinated proline derivatives, we chose to synthesize the
corresponding chlorofluorides to make α-fluoro vs. α-hydroxy substitution more difficult
through the stronger electron withdrawing effect of the chlorine substituent that might
stabilize the carbon-fluorine bond. Indeed, this turned out feasible and the desired 21, which
was at least stable for some days, was isolated in 20% yield alongside a fraction containing
the α-hydroxy derivative 22 (12%) (Scheme 9).
CO2Et
CO2Et
CO2Me
NCS, py·9HF
N
N
CO2Me
X
CH2Cl2, r.t., 3 d
Cl
21a,b: X=F (20%)
22a,b
18
: X=OH (12%)
Scheme 9: Chlorofluorination of 18.
Although we faced the same difficulties to interpret the NMR spectra of the chlorofluoride 21
as we did in case of the bromofluoride 19, we were able to gain single crystals of the cis-
diastereomer 21a [6] to prove the assumed structure of the molecule (Fig. 5).
Figure 5: X-ray structure of 21a [6]
.
10

Also, we were able to grow single crystals of one of the diastereomeric chlorohydrins 22. The
X-ray structure of the trans-compound 22b [6] can be found in the supplementary
information. This shows that the halofluorination of dehydro amino acid derivatives is not
limited to N-phthaloyl protected molecules, even though the phthalimide group obviously has
a significant effect on the stability of the products.
Subsequently we also thought investigating the possibility to generate halofluorides of
acyclic, non-phthalimide protected dehydro amino acid derivatives. Nevertheless, from the
experience we gained it seemed necessary to protect the amino function with at least one
electron withdrawing substituent. So we synthesized a variety of dehydroalanine methyl esters
including a valinyl dipeptide 23, N-methylated 24 [6], 25a as well as N-methanesulfonylated
sulfonamides 25b and N-acetylated compounds 26a, 26b [10] (Table 2). Unfortunately,
N-unsubstituted sulfonamides were not accessible by this method due to the reactivity of the
nitrogen atom in presence of methanesulfonyl chloride.
Table 2: Other N-substituted dehydroalanine derivatives.
Compound
23
R1
N-Phth-L-valinyl
SO2Ph
R2
H
Yield [%]
51 (2 steps)
33 (4 steps)
48 (3 steps)
65 (2 steps)
35 (2 steps)
39 (1 step)
24 [6]
25a
Me
Me
Ms
H
SO2-(4-Br-C6H4)
SO2-(4-Br-C6H4)
Ac
25b
26a
26b
Ac
Ac
The reaction of dipeptide 23 with NBS and Olah’s reagent led to cleavage of the peptide
leaving N-phthaloyl valinyl amide (27) the sole isolated product (Scheme 10). A similar
reaction has already been described by Patchornik and Sokolovsky who reacted a
dehydroalanine containing peptide with bromine [11]. While the authors emphasized the
usefulness of this kind of reaction for the targeted cleavage of peptide chains, of course in our
case it proved disadvantageous.
Scheme 10: Attempted bromofluorination of 23.
11

When we subjected sulfonamides 24 and 25a to the usual bromofluorination conditions, we
again observed cleavage of the molecule and the corresponding N-methyl sulfonamides 28
were formed (Scheme 11).
Scheme 11: Attempted bromofluorination of 24 and 25a.
Attempts to shorten the reaction time and lower the temperature for the first time gave us
hints at a possible formation of the desired bromofluoride as an intermediate structure.
Although this product itself was not observed, the ESI MS spectrum showed a peak for the
respective β-bromoalkene 29, which might be formed by HF elimination from the
bromofluoride (Scheme 12).
Scheme 12: Attempted bromofluorination of 24 at 0 °C.
This prompted us to investigate the effect of the electrophile as we have already observed a
stabilizing effect of a chlorine over a bromine substituent before (compare Scheme 9). Indeed,
this was also true for this reaction. According to an ESI MS investigation of the crude
product, chlorofluoride 30 (Scheme 13) was formed in significant amounts in addition to 31.
Unfortunately however, the product was unstable during column chromatography so that we
were not able to isolate it under different conditions.
Scheme 13: Chlorofluorination of 24 at 0 °C.
Initial attempts to synthesize N-unsubstituted sulfonamides led to formation of
N-methylsulfonyl dehydroalanine derivative 25b. This potentially gave us the opportunity to
investigate the effect of a second electron withdrawing group on the nitrogen atom on the
stability of the halofluorinated products. When we tried to perform the reaction of compound
25b with NBS/py⋅9HF, however, we only re-isolated the starting material. This showed that
12

the deactivating effect of two powerful electron withdrawing substituents on nitrogen on the
double bond was obviously too strong (Scheme 14).
Br
Br
O S O O
NBS, py·9HF
O S O O
N
N
S
O
S
O
CH2Cl2, r.t., 3.5 h
O
O
F
O
O
Br
25b
32
Scheme 14: Attempted bromofluorination of 25b.
Our trials to bromofluorinate N-acetylated dehydroalanine also failed as they led to complete
decomposition of the starting materials. All in all we must state that although the reaction
itself seemed to work in most cases, the only stable α-fluoro amino acid derivatives were
those carrying a phthalimide moiety as nitrogen protecting group. Unfortunately, all attempts
to deprotect the amino group failed so far. Basic conditions led to decomposition and under
acidic conditions no reaction was observed.
3. Conclusions
A straightforward synthesis of N-phthalimide protected α-fluorinated α-amino acid esters has
been developed by treating corresponding dehydro amino acid esters with a halonium ion
source (DBH, NBS, NCS or NIS) and pyridine/HF (Olah’s reagent). Furthermore, we
investigated possibilities to modify the functional groups of the obtained molecules and found
that radical reduction of the halogen (I, Br or Cl) was the only option. All attempts to
substitute the halogen by nucleophiles failed. The substrates scope has also been tested by
subjecting different non-phthalimide protected dehydro amino acids to bromofluorination
conditions. At the end, however, it showed that the phthalimide group is crucial for the
desired conversion and the stability of the products, respectively. Though in some reactions of
dehydro amino acid esters bearing only one electron withdrawing group on nitrogen the target
halofluorinated products were formed, but they were highly unstable and could not be isolated
in pure form. Having two electron withdrawing groups on nitrogen on the other hand
seemingly lowers the reactivity of the double bond so much that no reaction at all took place.
4. Experimental
4.1. General information
Column chromatography was performed on Merck silica gel 60 (40–63 µm). NMR spectra
13
were recorded on Bruker AV300 and Bruker DPX300 (1H NMR, 300 MHz, C NMR, 75
19
13
MHz, F NMR, 282 MHz), Bruker AV400 (1H NMR, 400 MHz, C NMR, 101 MHz) and
13

Agilent DD2 600 (1H NMR: 600 MHz, 13C NMR: 151 MHz, 19F NMR: 564 MHz)
spectrometers. TMS (1H), CDCl3 (13C) and CFCl3 (19F) were used as internal standards. Mass
spectra were recorded on Waters-Micromass Triplequad Quattro Micro GC (EI), Waters–
Micromass Quattro LCZ (ESI), and Bruker Daltronics MicroTof (ESI) instruments. All air
and moisture-sensitive reactions were performed under argon atmosphere. Solvents were
purified and dried by literature methods where necessary. Melting points were measured with
Stuart Scientific SMP10 and are uncorrected.
4.2. Methyl N-phthaloyldehydroalaninate (3)
Methyl N-phthaloyl L-serinate (15.500 g, 62.2 mmol) was dissolved in CH2Cl2 (200 mL)
under stirring. NEt3 (9.5 mL, 68.5 mmol, 1.1 equiv) was added and the solution was cooled to
−20 °C. After dropwise addition of mesyl chloride (5.3 mL, 68.5 mmol, 1.1 equiv) the
solution was stirred at this temperature for 2 h and another 19 h at r.t., while it gradually
turned yellow. After that NEt3 (9.5 mL, 68.5 mmol, 1.1 equiv) was added and the solution
heated to reflux for 1 h, causing it to turn orange. The solvent was removed under reduced
pressure and the residue dissolved in CH2Cl2 (80 mL). The solution was washed with water
and sat. aq. NaHCO3 (80 mL each), dried over MgSO4 and the solvent was removed under
reduced pressure. The product was dissolved in hot Et2O/MeOH and by decantation separated
from a brown residue. Storage at 5 °C yielded the product in form of light brown crystals.
Two further fractions could be crystallized from the mother liquor. The product remaining in
the mother liquor was isolated by column chromatography (CyH/EtOAc, 2:1). Yield: 9.078 g
(63%). Mp 109-110 °C (Et2O/MeOH). 1H NMR (300 MHz, CDCl3, 298 K, 298 K): δ 3.82 (s,
2
2
3H, OCH3), 6.01 (d, JH,H = 0.7 Hz, 1H, CHb), 6.70 (d, JH,H = 0.7 Hz, 1H, CHa), 7.74-7.82
13
(m, 2H, CCHCH), 7.90-7.95 (m, 2H, CCH). C NMR (75 MHz, CDCl3, 298 K): δ 53.0 (q,
CH3), 124.1 (d, CCH), 128.2 (CH2), 129.2 (CCO2CH3), 131.9 (s, NCOC), 134.6 (d, CCHCH),
162.9 (s, CO2), 166.5 (s, NCO). MS (EI GC inlet): m/z (%) 231 (73) [M]+, 203 (12), 200 (6)
[C11H6NO3]+, 172 (59) [C10H6NO2]+, 132 (24), 116 (13), 104 (100) [C7H4O]+, 89 (9), 76 (54)
[C6H4]+, 66 (3), 50 (4). HRMS: [M+Na]+ calcd for C12H9NO4Na+: 272.0424; found:
254.0424. The analytical data are consistent with literature data [12].
4.3. Bromofluorination of methyl N-phthaloyldehydroalanate (3) with DBH
To a stirred solution of methyl N-phthaloyldehydroalaninate (3) (304 mg, 1.3 mmol) in
CH2Cl2 (10 mL) were added Olah‘s reagent (1.8 mL, 7.8 mmol, 6 equiv) and portion wise
DBH (1.498 g, 5.2 mmol, 4 equiv). The red solution was continued to stir at r.t. for 23 h. After
14

addition of sat. aq. NaHCO3 until pH = 7-8, the solution was extracted with CH2Cl2
(2 × 25 mL) and the combined organic phases washed with sat. aq. Na2SO3, 1 M aq. HCl and
5% aq. NaHCO3 (30 mL each). The solution was dried over MgSO4 and the solvent
evaporated under reduced pressure. The product was isolated as a light yellow solid by
recrystallization from benzene. To grow single crystals for X-ray crystallography, the
amorphous solid was recrystallized from Et2O. Yield 199 mg (46%). Mp 116-118 °C (PhH).
2
1H NMR (400 MHz, CDCl3, 298 K): δ = 3.97 (s, 3H, OCH3), 4.11 (dd, JH,H = 11.6 Hz,
3JH,F = 29.0 Hz, 1H, CHaBr), 4.97 (dd, 2JH,H = 11.6 Hz, 3JH,F = 7.8 Hz, 1H, CHbBr), 7.79-7.87
13
(m, 2 H, CCHCH), 7.87-7.99 (m, 2H, CCH). C NMR (101 MHz, CDCl3, 298 K): δ = 31.4
(dt, 2JC,F = 30.1 Hz, CH2Br), 53.7 (q, OCH3), 94.8 (ds, 1JC,F = 225.8 Hz, CF), 124.3 (d, CCH),
2
130.9 (s, NCOC), 135.3 (d, CCHCH), 164.6 (ds, JC,F = 31.1 Hz, CO2), 166.2 (ds,
19
3
3JC,F = 2.1 Hz, NCO). F NMR (282 MHz, CDCl3, 298 K): δ = −126.0 (dd, JH,F = 29.0,
7.8 Hz, 1 F). MS (EI GC Inlet): m/z (%) 329/331 (0/0) [M]+, 309/311 (0/0) [M−HF]+, 270/272
(100/98) [C10H6BrFNO2]+, 250/252 (5/5) [C10H5BrNO2]+, 230 (95) [C12H8NO4]+, 151 (25),
123 (10), 104 (40) [C7H4O]+, 95 (38), 76 (60) [C6H4]+. HRMS: [M+Na]+ calcd for
C12H9BrFNO4Na+:
351.9591/353.9571,
found:
351.9589/353.9570;
[M-
F−+MeO−+MeOH+Na]+, calcd for C14H16BrNO6Na+: 396.0053/398.0033, found:
396.0050/398.0033. Elemental Analysis: calcd for C12H9BrFNO4: C 43.66%, H 2.75%, N
4.24%, found C 43.95%, H 2.49%, N 4.32%.
4.4. Bromofluorination of methyl N-phthaloyldehydroalaninate (3) with NBS
Methyl N-phthaloyldehydroalaninate (3) (462 mg, 2.0 mmol) was dissolved in CH2Cl2
(5 mL), Olah‘s reagent (0.92 mL, 4.0 mmol, 2.0 equiv) and NBS (427 mg, 2.4 mmol,
1.2 equiv) were added and the solution stirred at r.t. for 3 h. Afterwards the solution was
neutralized with sat. aq. NaHCO3, extracted with Et2O (3×10 mL) and the combined organic
layers washed with sat. aq. Na2SO3, 1 M aq. HCl and 5% aq. NaHCO3 (20 mL each). After
drying over MgSO4 the solvent was removed under reduced pressure and the product purified
by crystallization from CyH/PhH (6:1). Yield: 440 mg (67%). The analytical data are
consistent with those reported above.
4.5. Iodofluorination of methyl N-phthaloyldehydroalaninate (3) with NIS
15

To a solution of methyl N-phthaloyldehydroalaninate (3) (462 mg, 2.0 mmol) in CH2Cl2
(3 mL) were added Olah’s reagent (0.92 mL, 4.0 mmol, 2.0 equiv) and NIS (585 mg,
2.6 mmol, 1.3 equiv) and the reaction mixture stirred at r.t. for 26.5 h. The reaction was
stopped by addition of sat. aq. Na2SO3 and sat. aq. NaHCO3. To neutralize the mixture, solid
NaHCO3 was added. The solution was extracted with CH2Cl2 (2 × 25 mL) and the combined
organic phases washed with 1 M aq. HCl, 5% aq. NaHCO3 and brine (10 mL each). After
drying over MgSO4 and evaporation of the solvent the product was purified
chromatographically (silica, CyH/EtOAc, 5:1). Recrystallization from MeOH yielded single
crystals which were subjected to X-ray analysis. The elemental analysis was performed after
1
chromatography. Yield: 472 mg (63%). Mp 125 °C (PhH). H NMR (400 MHz, CDCl3, 298
2
3
K): δ = 3.95 (dd, JH,H = 11.4 Hz, JH,F = 29.7 Hz, 1H, CHaI), 3.97 (s, 3H, OCH3), 4.84 (dd,
3
2JH,H = 11.4 Hz, JH,F = 7.3 Hz, 1H, CHbI), 7.80-7.86 (m, 2H, CCHCH), 7.89-7.94 (m, 2H,
13
2
CCH). C NMR (101 MHz, CDCl3, 298 K): δ = 2.9 (dt, JC,F = 30.0 Hz, CH2I), 53.9 (q,
1
OCH3), 95.0 (ds, JC,F = 224.1 Hz, CF), 124.4 (d, CCH), 131.0 (s, NCOC), 135.4 (d,
2
3
19
CCHCH), 165.1 (ds, JC,F = 30.7 Hz, CO2), 166.3 (ds, JC,F = 1.9 Hz, NCO). F NMR (282
3
MHz, CDCl3, 298 K): δ = −121.1 (dd, JH,F = 7.3, 29.7 Hz, 1 F). MS (EI GC Inlet): m/z (%)
377 (0) [M]+, 357 (10) [M−HF]+, 318 (40) [C10H6FINO2]+, 298 (8), 250 (90) [C12H9FNO4]+ ,
230 (100) [C12H8NO4]+, 218 (9), 191 (38), 172 (21), 163 (14), 151 (26), 104 (14) [C7H4O]+,
95 (8), 76 (21) [C6H4]+. HRMS: [M+Na]+, calcd for C12H9FINO4Na+: 399.9453, found:
399.9445; [M−F−+MeO−+MeOH+Na]+, calcd for C14H16INO6Na+: 443.9915, found:
443.9910. Elemental Analysis: calcd for C12H9FINO4 C 38.22%, H 2.41%, N 3.71%, found C
38.16%, H 2.25%, N 3.78%.
4.6. Chlorofluorination of methyl N-phthaloyldehydroalaninate (3) with NCS
To a stirred solution of methyl N-phthaloyldehydroalaninate (3) (1.248 g, 5.4 mmol) in
CH2Cl2 (1 mL) were added Olah’s reagent (6.2 mL, 27.0 mmol, 5.0 equiv) and NCS (2.524 g,
18.9 mmol, 3.5 equiv) and the reaction mixture was stirred at r.t. for 18 d, while the progress
was monitored by GC. After cautious quenching with a mixture of ice, sat. aq. NaHCO3 and
sat. aq. Na2SO3 solid NaHCO3 was added until pH of 8. Shaking with CH2Cl2 (100 mL)
resulted in two phases, which were separated and the aqueous layer extracted with CH2Cl2
(2 × 50 mL). The combined organic layers were washed with 1 M aq. HCl and brine (50 mL
each) and after drying over MgSO4 the solvent was evaporated. Recrystallization from Et2O
yielded the product as colorless crystals that were examined by X-ray. Yield: 685 mg (44%).
1
Mp 134 °C (Et2O). H NMR (300 MHz, CDCl3, 298 K): δ = 3.97 (s, 3H, OCH3), 4.29 (dd,
16

3
2
3
2JH,H = 12.4 Hz, JH,F = 28.1 Hz, 1H, CHaCl), 5.10 (dd, JH,H = 12.4 Hz, JH,F = 8.5 Hz, 1H,
13
CHbCl), 7.79-7.87 (m, 2H, CCHCH), 7.88-7.96 (m, 2H, CCH). C NMR (75 MHz, CDCl3,
298 K): δ = 44.6 (dt, 2JC,F = 29.5 Hz, CH2Cl), 53.8 (q, OCH3), 95.2 (ds, 1JC,F = 226.9 Hz, CF),
124.3 (d, CCH), 130.9 (s, NCOC), 135.3 (d, CCHCH), 164.4 (ds, 2JC,F = 31.3 Hz, CO2), 166.2
3
19
3
(ds, JC,F = 1.7 Hz, NCO). F NMR (282 MHz, CDCl3, 298 K): δ = −128.5 (dd, JH,F = 8.5,
28.1 Hz, 1 F, CF). MS (EI GC Inlet) m/zꢀ(%) 285/287 (0/0) [M]+, 265/267 (3/1) [M−HF]+, 230
(46) [C12H8NO4]+, 226/228 (100/34) [C10H6ClFNO2]+, 206/208 (13/4) [C10H5ClNO2]+, 191
(13) [C10H6FNO2]+, 163 (8), 151 (70), 123 (10), 104 (21) [C7H4O]+, 95 (12), 76 (24) [C6H4]+,
35
50 (4). HRMS: [M+Na]+, calcd for C12H9 ClFNO4Na+: 308.0096, found: 308.0098; [M-
F−+MeO−+MeOH+Na]+, calcd for C14H16ClNO6Na+: 352.0558/354.0529, found:
352.0557/354.0531.
4.7. Reduction of methyl 3-bromo-2-fluoro-2-phthalimidopropanoate (4)
In an argon atmosphere, methyl 3-bromo-2-fluoro-2-phthalimidopropanoate (4) (198 mg,
0.60 mmol) was dissolved in phenylsilane (1.2 mL) and heated to reflux. Over 45 min a
solution of AIBN (30 mg, 0.18 mmol, 0.3 equiv) in 1,4-dioxane (0.3 mL) was added dropwise
by a perfusor. Reaction control was performed via GC. After stirring for 30 min at the same
temperature, another portion of AIBN (30 mg, 0.18 mmol, 0.3 equiv) in 1,4-dioxane (0.3 mL)
was added and the solution again stirred under reflux for 30 min. The mixture was cooled to
r.t. and extracted with CH2Cl2 (10 mL). The organic layer was washed with sat. aq. NaHCO3
and sat. aq. Na2SO3 and dried over MgSO4. Evaporation of the solvent and chromatographic
purification (silica gel, CyH/EtOAc, 2: 1) yielded a colorless substance that was recrystallized
from Et2O to remove traces of the starting material. The obtained crystals were investigated
1
by X-ray analysis. Yield: 30 mg (20%). Mp 109-110 °C (Et2O). H NMR (300 MHz, CDCl3,
3
298 K): δ = 2.28 (d, JH,F = 19.8 Hz, 3H, CH3), 3.90 (s, 3H, OCH3), 7.75-7.84 (m, 2H,
CCHCH), 7.85-7.94 (m, 2H, CCH). 13C NMR (75 MHz, CDCl3, 298 K): δ = 21.8 (dq,
2JC,F = 25.8 Hz, CH3), 53.5 (s, OCH3), 94.7 (ds, 1JC,F = 216.1 Hz, CF), 124.0 (d, CCH), 131.2
3
2
(s, NCOC), 134.9 (d, CCHCH), 166.7 (ds, JC,F = 1.9 Hz, NCO), 167.9 (ds, JC,F = 32.2 Hz,
CO2). 19F NMR (282 MHz, CDCl3, 298 K): δ = −116.8 (q, 3JF,H = 19.8 Hz, 1 F, CF). HRMS:
[M+Na]+,
calcd
for
C12H10FNO4Na+:
274.0486,
found:
274.0495;
[M−F−+MeO−+MeOH+Na]+, calcd for C14H17NO6Na+: 318.0948, found: 318.0957.
4.8. (Z)-Methyl 2-phthalimidobut-2-enoate (11)
17

Methyl N-phthaloyl-L-threoninate (10) (694 mg, 2.6 mmol) and Et3N (0.50 mL, 3.6 mmol,
1.4 equiv) were dissolved in CH2Cl2 (15 mL) and at 0 °C mesyl chloride (0.29 mL, 3.6 mmol,
1.4 equiv) was added under stirring. After stirring at r.t. for 3 h another portion of Et3N
(0.78 mL, 5.2 mmol, 2.0 equiv) was added and the solution was heated to reflux for 2.5 h. The
mixture was acidified with 1 M aq. HCl and extracted with CH2Cl2 (2 × 15mL). The combined
organic phases were washed with water and brine. After drying over MgSO4 and removal of
the solvent, column chromatography (CyH/EtOAc, 2:1) yielded a yellow oil that solidified
after standing overnight to give a yellow solid. Recrystallization from Et2O yielded crystals
1
suitable for X-ray analysis. Yield: 409 mg (65%). Mp 89-90 °C (Et2O). H NMR (400 MHz,
3
CDCl3, 298 K,): δ = 1.84 (d, JH,H = 7.2 Hz, 3H, CH3), 3.77 (s, 3H, OCH3), 7.41 (q,
3JH,H = 7.2 Hz, 1H, CHCH3), 7.74-7.83 (m, 2H, CCHCH), 7.87-7.95 (m, 2H, CCH). 13C NMR
(101 MHz, CDCl3, 298 K): δ = 14.9 (q, CH3), 53.0 (q, OCH3), 123.7 (s, CCO2), 124.3 (d,
CCH), 132.5 (s, NCOC), 134.8 (d, CCHCH), 143.8 (d, CHCH3), 163.5 (s, CO2), 167.1 (s,
NCO). HRMS: [M+Na]+, calcd for C13H11NO4Na+: 268.0580, found: 268.0592;
[M+MeOH+Na]+, calcd for C13H11NO4CH3OHNa+: 300.0842, found: 300.0855. The
analytical data are not consistent with earlier data [8]. Therefore, we verified the structure by
X-ray analysis.
4.9. Bromofluorination of (Z)-methyl 2-phthalimidobut-2-enoate (11) with NBS and Olah’s
reagent
(Z)-Methyl 2-phthalimidobut-2-enoate (11) (200 mg, 0.82 mmol) was dissolved in CH2Cl2
(3 mL) and to the stirred solution were added Olah’s reagent (0.47 mL, 2.05 mmol, 2.5 equiv)
and NBS (292 mg, 1.64 mmol, 2.0 equiv). The clear, colorless solution was stirred at r.t. for
26 h and the reaction then terminated by addition of sat. aq. NaHCO3 and sat. aq. Na2SO3.
The mixture was extracted with CH2Cl2 (3 × 20 mL) and the combined organic layers washed
with 1 M aq. HCl and brine. After drying over MgSO4 and removal of the solvent under
reduced pressure, the product was purified by column chromatography (CyH/EtOAc, 5:1),
which yielded two fractions of white solids. Fraction I contained the product in a
diastereomeric mixture of 92:8 (19F NMR), while the ratio of the other fraction was 46:54.
Recrystallization of the first fraction from Et2O yielded crystals suitable for X-ray analysis.
Yield Fraction I: 89 mg (32%), 12:13 = 92:8, mp 122-123 °C. Fraction II: 75 mg (27%)
12:13 = 46:54, mp 119-126 °C.
4.10. Methyl (rel-2R,3R)-3-bromo-2-fluoro-2-phthalimidobutanoate (12)
18

3
4
1H NMR (600 MHz, CDCl3, 298 K): δ = 1.83 (dd, JH,H = 6.9 Hz, JH,F = 1.0 Hz, 3H,
3
3
CHBrCH3), 3.96 (s, 3H, OCH3), 5.65 (dq, JH,H = 6.9 Hz, JH,F = 11.5 Hz, 1H, CHBr), 7.78-
13
7.86 (m, 2H, CCHCH), 7.87-7.94 (m, 2H, CCH). C NMR (151 MHz, CDCl3, 298 K): δ =
3
2
20.5 (dq, JC,F = 2.5 Hz, CHBrCH3), 42.1 (dd, JC,F = 33.7 Hz, CHBr), 53.4 (q, OCH3), 97.3
1
(ds, JC,F = 222.5 Hz, C-2), 124.15 (d, CCH), 131.02 (s, NCOC), 135.1 (d, CCHCH), 163.71
3
3
(ds, JC,F = 31.3 Hz, CO2), 166.1 (ds, JC,F = 1.7 Hz, NCO). 19F NMR (282 MHz, CDCl3, 298
3
K): δ = −124.0 (d, JH,F = 11.5 Hz, 1F, CF). HRMS: [M+Na]+, calcd for C13H11BrFNO4Na+:
365.9748/367.00728, found: 365.9746/367.9727; [M−F−+MeO−+MeOH+Na]+, calcd for
C15H18BrNO6Na+: 410.210/412.0189, found: 410.0211/412.0189. MS (EI GC Inlet): m/z (%)
343/345 (0/0) [M]+, 284/286 (23/23) [C11H8BrFNO2]+, 264/266 (9/8) [C11H7BrNO2]+, 244
(100) [C13H10NO4]+, 236 (8) [C11H7FNO4]+, 213 (3), 205 (3), 184 (3), 151 (6), 104 (15)
[C7H4O]+, 95 (6), 76 (10) [C6H4]+, 59 (3), 50 (2).
4.11. Methyl (rel-2R,3S)-3-bromo-2-fluoro-2-phthalimidobutanoate (13)*
3
1H NMR (600 MHz, CDCl3, 298 K): δ = 1.90 (d, JH,H = 6.9 Hz, 3H, 4-CH3), 4.00 (s, 3H,
13
5-CH3), 5.65 (m, 1H, 3-CH), 7.78-7.86 (m, 2H, 9/10-CH), 7.87-7.94 (m, 2H, 8/11-CH). C
NMR (151 MHz, CDCl3, 298 K): δ = 21.5 (dq, 3JC,F = 2.5 Hz, C-4), 46.4 (dd, 2JC,F = 29.2 Hz,
1
C-3), 53.4 (q, C-5), 97.0 (ds, JC,F = 226.6 Hz, C-2), 124.22 (d, C-8/11), 131.94 (s, C-7/12),
2
3
19
135.3 (d, C-9/10), 163.74 (ds, JC,F = 29.8 Hz, C-1), 166.3 (ds, JC,F = 1.8 Hz, C-6/13). F
NMR (282 MHz, CDCl3, 298 K): δ = −117.9 (d, 3JH,F = 10.1 Hz, 1F, CF).
*The data were extracted from the spectrum of a 46:54 mixture of diastereomers.
4.12. Bromofluorination of methyl (Z)-2-phthalimido-2-butenoate (11) with DBH and Olah’s
reagent
(Z)-Methyl 2-phthalimidobutenoate (11) (200 mg, 0.82 mmol) was dissolved in CH2Cl2
(4 mL) and the stirred solution was treated with Olah’s reagent (0.47 mL, 2.05 mmol, 2.5
equiv) and DBH (469 mg, 1.64 mmol, 2.0 equiv). The clear, yellow solution was stirred at r.t.
for further 26 h. The workup was done in an analogous fashion as described for the reaction
with NBS and the product purified chromatographically (CyH/EtOAc, 5:1). The
diastereomeric ratio was determined to be 43:57 (19F NMR). Yield: 211 mg (75%)
12:13 = 43:57
The analytical data are consistent with the ones reported above.
19

4.13. Reduction of methyl 3-bromo-2-fluoro-2-phthalimidobutanoate (12/13)
A solution of methyl 3-bromo-2-fluoro-2-phthalimidobutanoate (12/13) (211 mg, 0.61 mmol)
in phenylsilane (1 mL) was heated to reflux under an argon atmosphere and a solution of
AIBN (30 mg, 0.18 mmol, 0.3 equiv) in 1,4-dioxane (0.3 mL) was added over 40 min using a
perfusor. The workup was carried out as described for compound 4 and the product purified
by column chromatography (silica gel, CyH/EtOAc, 2:1). The white solid was recrystallized
1
from Et2O for X-ray crystallography. Yield: 116 mg (72%). Mp 82-89 °C (Et2O). H NMR
3
3
(400 MHz, CDCl3, 298 K): δ = 1.06 (d, JH,H = 7.5 Hz, 3H, CH3), 2.48 (ddq, JH,F = 29.7 Hz,
3
2
3
2JH,H = 14.9 Hz, JH,H = 7.5 Hz, 1H, CFCHa), 3.12 (ddq, JH,H = 14.9 Hz, JH,F = 10.7 Hz,
3JH,H = 7.5 Hz, 1H, CFCHb), 3.91 (s, 3H, OCH3), 7.75-7.84 (m, 2H, CCHCH), 7.85-7.93 (m,
13
3
2H, CCH). C NMR (101 MHz, CDCl3, 298 K): δ = 7.8 (dq, JC,F = 3.6 Hz, CH3), 27.4 (dt,
1
2JC,F = 25.0 Hz, CFCH2), 53.2 (s, OCH3), 97.9 (ds, JC,F = 219.2 Hz, CF), 124.0 (d, CCH),
2
131.2 (s, NCOC), 134.9 (d, CCHCH), 166.7 (ds, JC,F = 32.4 Hz, CO2), 167.8 (ds,
19
3
3JC,F = 2.0 Hz, NCO). F NMR (282 MHz, CDCl3, 298 K): δ = −126.0 (dd, JF,H = 29.7,
10.7 Hz, 1 F, 2-CF). HRMS: [M+Na]+, calcd for C13H12FNO4Na+: 288.0643, found:
288.0644; [M−F−+MeO−+MeOH+Na]+, calcd for C15H19NO6Na+: 332.1105, found: 332.1104.
4.14. Synthesis of methyl N-phthaloyl dehydrophenylalaninate (15)
Methyl N-phthaloyl 3-bromophenylalaninate (17.047 g, 43.9 mmol) was dissolved in CH2Cl2
(100 mL) and treated with NEt3 (7.3 mL, 52.7 mmol, 1.2 equiv) under stirring. The solution
was refluxed for 6 h while the yellow solution gradually turned brown. After cooling to r.t.,
1 M aq. HCl (80 mL) was added, the phases separated and the aqueous phase extracted with
CH2Cl2 (3×50 mL). The combined organic phases were washed with water and sat. aq. NaCl
and dried over MgSO4. The solvent was evaporated in vacuo and the crude product filtered
over silica (CyH/EtOAc, 2:1). The isomers were obtained in a 70:30 ratio. Yield: 12.110 g
(90%). Mp 114-116 °C.
20

1
Isomer I: H NMR (400 MHz, CDCl3, 298 K): δ = 3.71 (s, 3H, OCH3), 7.27-7.35 (m, 3H,
6/8-CH, p-Ph) 7.38-7.43 (m, 2H, o-CH), 7.76-7.84 (m, 2H, CCHCH), 7.87-7.97 (m, 2H,
13
CCH), 8.12 (s, 1H, CHPh). C NMR (101 MHz, CDCl3, 298 K): δ = 52.9 (q, OCH3), 120.0
(s, CCO2), 124.0 (d, CCH), 128.9 (d, m-CH), 129.4 (d, o-CH), 130.6 (d, p-CH), 132.1 (s,
NCOC), 132.3 (s, i-C), 134.5 (d, CCHCH), 143.1 (d, CPh), 163.9 (s, CO2), 166.8 (s, NCO).
HRMS: [M+H]+, calcd for C18H13NO4H+: 308.0917, found: 308.0917. MS (EI GC Inlet):
m/zꢀ(%) 307 (76) [M]+, 279 (37), 248 (43) [C16H10NO2]+, 247 (53), 230 (4) [C7H6ClS]+, 129
(13), 121 (31), 100 (100) [C7H4O]+, 89 (17), 76 (99) [C6H4]+, 50 (23).
Isomer II: 1H NMR (400 MHz, CDCl3, 298 K): δ = 3.83 (s, 3H, OCH3), 7.23 (s, 1H, CPh),
7.36-7.45 (m, 3H, m-CH and p-CH), 7.46-7.50 (m, 2H, o-CH), 7.76-7.84 (m, 2H, CCHCH),
7.87-7.97 (m, 2H, CCH). 13C NMR (101 MHz, CDCl3, 298 K): δ = 52.3 (q, OCH3), 120.7 (s,
CCO2), 123.9 (d, CCH), 128.2 (d, m-CH), 129.35 (d, p-C), 129.41 (d, o-C), 131.7 (s, NCOC),
133.1 (s, i-C), 134.6 (d, CCHCH), 139.8 (d, CPh), 163.7 (s, NCO), 166.7 (s, CO2).
4.15. Bromofluorination of methyl N-phthaloyl dehydrophenylalaninate (15) with NBS and
Olah’s reagent
A stirred solution of methyl N-phthaloyl dehydrophenylalaninate (15) (615 mg, 2.0 mmol) in
CH2Cl2 (8 mL) was treated with Olah’s reagent (0.58 mL, 2.5 mmol, 1.3 equiv) and NBS
(534 mg, 3.0 mmol, 1.5 equiv) and stirring was continued at r.t. for 24 h. After neutralization
with a mixture of ice and sat. aq. NaHCO3 the aqueous phase was extracted with CH2Cl2
(2 × 20 mL) and the combined organic phases washed with 1 M aq. HCl, sat. aq, Na2SO3 and
brine. After that the solution was dried over MgSO4, the solvent removed und reduced
pressure and the product isolated by column chromatography (CyH/EtOAc, 5: 1) as a
colorless solid. The diastereomeric ratio could be improved from 77:23 (19F NMR) to 97:3 by
crystallization from Et2O. Yield: 111 mg (14%), dr 77:23. Mp 159 °C (95:5 mixture).
1
Diastereomer I (16): H NMR (400 MHz, CDCl3, 298 K): δ = 3.82 (s, 3H, OCH3), 6.68 (d,
3JH,F = 12.6 Hz, 1H, CHBr), 7.34-7.38 (m, 3H, m-CH and p-CH), 7.50-7.59 (m, 2H, o-CH),
7.80-7.85 (m, 2H, CCHCH), 7.88-7.95 (m, 2H, CCH). 13C NMR (101 MHz, CDCl3, 298 K): δ
= 48.5 (dd, 2JC,F = 33.3 Hz, CHBr), 53.2 (q, OCH3), 97.0 (ds, 1JC,F = 224.0 Hz, CF), 124.2 (d,
CCH), 128.3 (d, m-CH), 129.4 (d, p-CH), 130.0 (dd, 2JC,F = 1.4 Hz, o-CH), 131.0 (s, NCOC),
2
3
134.0 (s, i-C), 135.2 (d, CCHCH), 163.1 (ds, JC,F = 30.0 Hz, CO2), 166.2 (ds, JC,F = 1.9 Hz,
NCO). 19F NMR (282 MHz, CDCl3, 298 K,): δ = −120.5 (d, 3JF,H = 12.6 Hz, 1 F, CF). HRMS:
[M+Na]+, calcd for C18H13BrFNO4Na+: 427.9904/429.9885, found: 427.9899/429.9879;
[M−F−+MeO−+MeOH+Na]+, calcd for C21H2279BrNO6Na+: 472.0366, found: 472.0361.
21

1
Diastereomer II (17): H NMR (400 MHz, CDCl3, 298 K): δ = 3.50 (s, 3H, OCH3), 6.53 (d,
3JH,F = 23.6 Hz, 1H, CHBr), 7.20-7.26 (m, 3H, m-CH and p-CH), 7.40-7.44 (m, 2H, o-CH),
7.66-7.70 (m, 2H, CCHCH), 7.74-7.79 (m, 2H, CCH). 13C NMR (101 MHz, CDCl3, 298 K): δ
= 50.9 (dd, 2JC,F = 21.6 Hz, CHBr), 53.2 (q, OCH3), 98.5 (ds, 1JC,F = 230.0 Hz, CF), 123.9 (d,
CCH), 128.4 (d, m-CH), 129.6 (d, p-CH), 130.0 (dd, 2JC,F = 1.9 Hz, o-CH), 131.5 (s, NCOC),
2
2
134.4 (d, CCHCH), 135.0 (s, i-C), 164.4 (ds, JC,F = 32.6 Hz, CO2), 165.8 (ds, JC,F = 1.3 Hz,
NCO). 19F NMR (282 MHz, CDCl3, 298 K,): δ = −130.8 (d, 3JF,H = 26.6 Hz, 1 F, CF).
4.16. Synthesis of methyl α,β-dehydro-N-carbethoxyprolinate (18)
In analogy to a procedure by HUY et al. [9] L-proline (4.615 g, 40.0 mmol) was suspended in
methanol (35 mL) and at 0 °C thionyl chloride (3.8 mL, 52.0 mmol, 1.3 equiv) was added
dropwise. After stirring at 0 °C for 30 min the cooling bath was removed and the solution
stirred at r.t. for 22 h. The solvent was removed under reduced pressure and the remaining
slightly yellow oil dried in vacuo. The obtained methyl L-prolinate hydrochloride (6.414 g,
38.7 mmol) was dissolved in CH2Cl2 (130 mL) and treated with Et3N (12.3 mL, 89.0 mmol,
2.3 equiv) and at 0 °C NCS (5.688 g, 42.6 mmol, 1.1 equiv) was added. After stirring at r.t.
for 2 h pyridine (7.2 mL, 89.0 mmol, 2.3 equiv) and at −20°C ethyl chloroformiate (8.1 mL,
85.1 mmol, 2.2 equiv) were added and the mixture stirred at r.t. for 2 d, whereby the solution
first turned orange and then gradually turned dark brown. After that, Et2O (130 mL) and 1 M
aq. HCl (45 mL) were added, the combined organic phases washed with 1 M aq. HCl, sat. aq.
NaHCO3 and brine and then dried over MgSO4. Removal of the solvent and subsequent
chromatography (CyH/EtOAc, 5:1) yielded the product as a yellow oil. Yield: 4.795 g (60%)
3
1H NMR (300 MHz, CDCl3, 298 K): δ = 1.26 (t, JH,H = 7.1 Hz, 3H, CH2CH3), 2.67 (ddd,
3
3JH,H = 9.6, 8.5, 2.9 Hz, 2H, CHCH2), 3.82 (s, 3H, OCH3), 3.97 (dd, JH,H = 9.4, 8.5 Hz, 2H,
NCH2), 4.17 (q, 3JH,H = 7.1 Hz, 2H, OCH2), 5.84 (t, 3JH,H = 2.9 Hz, 1H, CH). HRMS: [M+H]+,
calcd for C9H13NO4H+: 200.0917, found: 200.0928; [M+Na]+, calcd for C9H13NO4Na+:
222.0737, found: 222.0748. MS (EI GC Inlet): m/z (%) 199 (84) [M]+, 168 (13) [C8H10NO3]+,
154 (16) [C7H8NO3]+, 140 (100) [C7H10NO2]+, 127 (64), 126 (46) [C6H8NO2]+, 95 (22), 68
(40), 67 (42), 59 (8).
The analytical data were comparable with those of the dimethyl derivative synthesized by
Huy et al. [9,13].
4.17. Bromofluorination of N-carbethoxy-α,β-dehydroprolinate (18)
22

A solution of methyl N-carbethoxy-α,β-dehydroprolinate (18) (398 mg, 2.0 mmol) in CH2Cl2
(5 mL) was treated with Olah’s reagent (1.2 mL, 5 mmol, 2.5 equiv) and NBS (463 mg,
2.6 mmol, 1.3 equiv) and the solution stirred at r.t. for 3 d. For neutralization, sat. aq.
NaHCO3 and solid NaHCO3 were added. The aqueous phase was extracted with CH2Cl2
(2 × 10 mL) and subsequently the combined organic phases were washed with 1 M aq. HCl,
sat. aq. Na2SO3 and 5% aq. NaHCO3. After drying over MgSO4 the solvent was removed and
the product purified chromatographically (silica gel, CyH/EtOAc, 5:1), giving the product as a
colorless oil.
Due to the formation of diastereomers and the visibility of different rotamers according to 19F
NMR spectroscopy, the measured NMR spectra are very complex, so that the signals could
not be assigned doubtlessly. Furthermore an ESI-MS peak with m/z = 313.9634/315.9616
hinted at one more substance that could not be separated from the product.
Yield: 105 mg (impure) 19a:19b = 46:54. 1H NMR (300 MHz, CDCl3, 298 K): δ = 1.16-1.37
3
(m, 6H, CH2CH3 and CH2CH3*), 2.30-2.64 (m, 4H), 3.55 (tdd, JH,H = 10.4, 6.6 Hz,
4JH,F = 8.6 Hz, 2H, CHBrCHaHb and CHBrCHaHb*), 3.66-3.83 (m, 2H), 3.82-4.01 (m, 4H,
*
3
3
OCH2 and OCH2 ), 4.08-4.30 (m, 4H), 4.41 (ddd, JH,H = 12.5, 7.0 Hz, JH,F = 16.4 Hz, 2H,
19
3
CHBr and CHBr*). F NMR (282 MHz, CDCl3, 298 K): δ = −127.5 (dd, JH,F = 16.4 Hz,
3
4
4JH,F = 8.7 Hz, 1F, CF), −129.6 (dd, JH,F = 16.5 Hz, JH,F = 8.3 Hz, 1F, CF*). HRMS:
[M+Na]+, calcd for C9H13BrFNO4Na+: 319.9904/321.9884, found: 319.9904/321.9884. MS
(EI GC Inlet): m/zꢀ(%) 297/299 (0/0) [M]+, 277/279 (2/2) [M−HF]+, 238/240 (97/100)
[C7H10BrFNO2]+, 224/226 (8/8) [C6H8BrFNO2]+, 166/168 (72/68) [C4H6BrFN]+, 159 (6)
[C7H10FNO2]+, 140 (8) [C7H10NO2]+, 115 (46), 100 (16), 87 (44), 86 (42) [C4H5FN]+, 59 (12).
4.18. Methyl 3-bromo-2-hydroxy-N-carbethoxy-prolinate (20)
HRMS: [M+Na]+, calcd for C9H14BrNO5Na+: 317.9948/319.9928, found: 317.9943/319.9925.
4.19. Chlorofluorination of methyl N-carbethoxy-α,β-dehydroprolinate (18)
In analogy to the respective bromofluorination, methyl α,β-dehydro-N-carbethoxy-prolinate
(18) (801 mg, 4.0 mmol) was reacted with Olah’s reagent (2.3 mL, 10.0 mmol) and NCS
(801 mg, 6.0 mmol, 1.5 equiv). Column chromatography (CyH/EtOAc, 2:1) yielded methyl
N–carbethoxy-3-chloro-2-fluoro-L-prolinate 21 as a colorless oil. Storage in the fridge led to
solidification of the product. Furthermore, a fraction of the byproduct methyl α-hydroxy-
β-chloro-N-carbethoxy-L-prolinate (22) was isolated after chromatography. Recrystallization
from Et2O of both substances yielded single crystals each that were investigated by X-ray
23

diffraction. As mentioned above, the assignment of the signals in the NMR spectra was
1
virtually impossible due to the broad signals in the H spectrum. The fluorinated compound
was very unstable and disintegrated before the melting point was determined.
4.20. Methyl N–carbethoxy-3-chloro-2-fluoro-prolinate (21)
1
Yield: 202 mg (20%) 21a:21b = 46:54. H NMR (600 MHz, CDCl3, 298 K): δ = 1.14-1.32
(m, 6H, CH2CH3 and CH2CH3*), 2.18-2.39 (m, 2H), 2.44-2.51 (m, 2H), 3.52 (tdd,
4
3JH,H = 10.6, 6.6 Hz, JH,F = 8.5 Hz, 2H, CHClCHaHb and CHClCHaHb*), 3.67-3.80 (m, 2H),
3.80-3.93 (m, 4H, OCH2 and OCH2*), 4.07-4.25 (m, 4H), 4.37-4.51 (m, 2H, CHCl and
CHCl*). 19F NMR (564 MHz, CDCl3, 298 K): δ = −132.0 (dd, 3JH,F = 12.1 Hz, 4JH,F = 8.1 Hz,
3
4
1F, CF), −134.1 (dd, JH,F = 12.8 Hz, JH,F = 7.8 Hz, 1F, CF*). HRMS: [M+Na]+, calcd for
C9H13ClFNO4Na+: 276.0409/278.0381, found: 276.0417/278.0385.
4.21. Methyl N–carbethoxy-3-chloro-2-hydroxy-prolinate (22)
1
Yield: 115 mg (12%). Mp 81-90 °C H NMR (300 MHz, CDCl3, 298 K): δ = 1.16-1.36 (m,
*
6H, CH2CH3 and CH2CH3 ), 2.18-2.57 (m), 3.46 (td, JH,H = 10.3, 6.86 Hz), 3.59 (ddd,
JH,H = 10.3, 9.0, 6.6 Hz), 3.66-3.81 (m), 3.85 (s, 3H), 3.88 (s, 3H), 4.04-4.26 (m), 4.27-4.44
(m). HRMS: [M+Na]+, calcd for C9H14ClNO5Na+: 274.0453/276.0424, found:
274.0450/276.0417.
4.22. Synthesis of methyl N-phthaloyl-L-valinyl-L-serinate (33)
N-Phthaloyl-L-valine (3.709 g, 15.0 mmol) and methyl L-serinate hydrochloride (2.334 g,
15.0 mmol) were dissolved in DMF (peptide synthesis grade) (30 mL) and treated with
DIPEA (10.2 mL, 60.0 mmol, 4.0 equiv) under stirring. Furthermore, HOBt (2.757 g,
18.0 mmol, 1.2 equiv), DMAP (0.183 g, 1.5 mmol, 0.1 equiv) and DCC (3.714 g, 18.0 mmol,
1.2 equiv) were added and the solution stirred at r.t. for 18 h, while the formation of a white
precipitate was observed after some minutes. For the workup, EtOAc (80 mL) was added and
the solution washed with 1 M aq. HCl, water (50 mL each) and brine (2×50 mL). The organic
phases were combined, dried over MgSO4 and the solvent removed under reduced pressure.
The obtained yellow oil was dissolved in hot Et2O with a little EtOAc and the solution stored
in the fridge. The product precipitated as a colorless solid. A second fraction of product could
be isolated from the mother liquor. Yield: 2.651 g (51%). Mp 158-161 °C (dec.). [α]2D0 = 29.9
1
3
i
(c = 0.91, CHCl3). H NMR (400 MHz, CDCl3, 298 K): δ = 0.88 (d, JH,H = 6.7 Hz, 3H, Pr-
3
i
3
i
CH3), 1.11 (d, JH,H = 6.7 Hz, 3H, Pr-CH3), 2.94 (dsept, JH,H = 10.5, 6.8 Hz, 1H, Pr-CH),
24

3
3.69 (s, 3H, OCH3), 3.82 (m, 2H, CH2OH), 4.47 (d, JH,H = 10.5 Hz, 1H, PhthNCH), 4.50 (t,
13
3JH,H = 4.3 Hz, 1H, CHCO2Me), 7.82-7.86 (m, 2H, CCHCH), 7.87-7.91 (m, 2H, CCH). C
i
i
i
NMR (101 MHz, CDCl3, 298 K): δ = 19.8 (q, Pr-CH3), 20.5 (q, Pr-CH3), 28.7 (d, Pr-CH),
52.9 (q, OCH3), 56.4 (d, CHCO2Me), 62.6 (t, CH2OH), 62.7 (d, PhthNCH), 124.5 (d, CCH),
132.8 (s, NCOC), 135.8 (d, CCHCH), 169.6 (s, NCOC), 171.4 (s, CHCON), 172.1 (s, CO2).
HRMS: [M+H]+, calcd for C17H20N2O6H+: 349.1394, found: 349.1383; [M+Na]+, calcd for
C17H20N2O6Na+: 371.1214, found: 371.1204.
4.23. Synthesis of methyl N-phthaloyl-L-valinyl dehydroalaninate (23)
Methyl N-phthaloyl-L-valinyl-L-serinate (34) (686 mg, 2.0 mmol) was dissolved in CH2Cl2
(5 mL) under stirring. At 0 °C NEt3 (0.30 mL, 2.2 mmol, 1.1 equiv) and methanesulfonic acid
chloride (0.17 mL, 2.2 mmol, 1.1 equiv) and after stirring at r.t. overnight, further NEt3
(0.60 mL, 4.3 mmol, 2.2 Equiv) was added. After refluxing for 4 h, EtOAc (20 mL) was
added and the solution washed with 1 M aq. HCl and 5% aq. NaHCO3 before drying over
1
MgSO4. Removal of the solvent gave a yellow oil. Yield: 669 mg (100%, crude). H NMR
(300 MHz, CD3OD, 298 K): δ = 0.89 (d, 3JH,H = 6.6 Hz, 3H, iPr-CH3), 1.10 (d, 3JH,H = 6.7 Hz,
i
3
i
3H, Pr-CH3), 2.94 (dsept, JH,H = 10.7, 6.7 Hz, 1H, Pr-CH), 3.81 (s, 3H, OCH3), 4.51 (d,
3JH,H = 10.7 Hz, 1H, PhthNCH), 5.89 (s, 1H, CHaHb), 6.33 (s, 1H, CHaHb), 7.82-7.88 (m, 2H,
CCHCH), 7.88-7.96 (m, 2H, CCH). HRMS: [M+H]+, calcd for C17H18N2O5H+: 331.1288,
found: 331.1290; [M+Na]+, calcd for C17H18N2O5Na+: 353.1108, found: 353.1111;
[M+MeOH+Na]+, calcd for C17H18N2O5CH3OHNa+: 385.1370, found: 385.1372. After a short
while the oil polymerized to a clear, yellow solid. Mp 292 °C (polymer, dec.).
4.24. Reaction of methyl N-phthaloyl-L-valinyl dehydroalaninate (23) with DBH and Olah’s
reagent
N-Phthaloyl-L-valinyl dehydroalaninate (23) (67 mg, 0.20 mmol) was dissolved in CH2Cl2
(5 mL) and treated with Olah’s reagent (0.09 mL, 0.40 mmol, 2.0 equiv) and NBS (46 mg,
0.26 mmol, 1.3 equiv) under stirring. After stirring at r.t. for 18 h, the reaction was stopped by
addition of sat. aq. NaHCO3, which caused the mixture to turn yellow after some minutes. The
mixture was extracted with EtOAc (3×15 mL) and washed with sat. aq. Na2SO3, 1 M aq. HCl
and 5% aq. NaHCO3. The combined organic phases were dried over MgSO4, the solvent
removed by rotary evaporation and the product purified by column chromatography (silica
gel, CyH/EtOAc, 1:1). Yield: 33 mg (65%). 1H-NMR (300 MHz, CDCl3, 298 K): δ = 0.79 (d,
i
3
i
3
3JH,H = 6.6 Hz, 3H, Pr-CH3), 1.06 (d, JH,H = 6.6 Hz, 3H, Pr-CH3), 2.77 (dsept, JH,H = 11.2,
25

6.6 Hz, 1H, iPr-CH), 4.32 (d, 3JH,H = 11.2 Hz, 1H, PhthNCH), 5.84 (br s, 1H, NHa), 6.83 (br s,
1 H, NHb), 7.65-7.73 (m, 2H, CCHCH), 7.76-7.86 (m, 2H, CCH). HRMS: [M+H]+, calcd for
C13H14N2O3H+: 247.1077, found: 247.1085; [M+Na]+, calcd for C13H14N2O3Na+: 269.0897,
found: 269.0903. The spectroscopic data are consistent with literature data [14].
4.25. Reaction of methyl N-methyl N-benzenesulfonyl dehydroalaninate (24) with NCS and
Olah’s reagent
At 0 °C ethyl N-methyl N-benzenesulfonyl dehydroalaninate (24) (268 mg, 1.05 mmol) was
reacted with Olah’s reagent (0.60 mL, 2.61 mmol, 2.5 equiv) and NCS (214 mg, 1.60 mmol,
1.5 equiv). After 3 h the reaction was quenched followed by usual workup. Beside the target
chlorofluoride 30, ESI-MS also hinted at the formation of methyl N-methyl
N-benzenesulfonyl 3-chlorodehydroalaninate (31) and N-methyl benzenesulfonamide (28a).
The chlorofluorinated product, however, was instable on silica gel, so that column
chromatography (CyH/EtOAc, 5:1) exclusively yielded undesired products.
4.26. Methyl N-benzenesulfonyl-N-methyl-3-chloro-2-fluoropropanoate (30)
HRMS: [M+Na]+, calcd for C11H13ClFNO4SNa+: 332.0130/334.0101, found:
332.0144/334.0112.
4.27. Methyl N-benzenesulfonyl-N-methyl-3-chlorodehydroalaninate (31)
1
Yield: 88 mg (29%). H NMR (400 MHz, CDCl3, 298 K): δ = 3.05 (s, 3 H, NCH3), 3.60 (s,
3 H, OCH3), 6.80 (s, 1 H, CHCl), 7.50-7.58 (m, 2 H, m-CH), 7.59-7.67 (m, 1 H, p-CH), 7.77-
13
7.84 (m, 2 H, o-CH). C NMR (101 MHz, CDCl3, 298 K): δ = 37.5 (q, NCH3), 52.2 (q,
OCH3), 127.7 (d, o-CH), 129.0 (d, m-CH), 131.3 (d, CHCl), 132.5 (s, CCHCl), 133.1 (d,
p-CH), 137.5 (s, i-C), 162.2 (s, CO2). HRMS: [M+Na]+, calcd for C11H12ClNO4SNa+:
312.0068/314.0038, found: 312.0070/314.0044.
4.28. N-Methyl benzenesulfonamide (28a)
Yield: 69 mg (38%). 1H NMR (400 MHz, CDCl3, 298 K): δ = 2.57 (s, 1-CH3), 4.80 (br s, 1 H,
NH), 7.40-7.49 (m, 2 H, 4/6-CH), 7.49-7.56 (m, 1 H, 5-CH), 7.70-7.86 (m, 2 H, 3/7-CH). 13C
NMR (101 MHz, CDCl3, 298 K): δ = 127.2 (d, C-3/7), 129.1 (d, C-4/6), 132.7 (d, C-5), 138.7
(s, C-2). HRMS: [M+H]+, calcd for C7H9NO2SH+: 172.0427, found: 172.0427; [M+Na]+,
calcd for C7H9NO2SNa+: 194.0246, found: 194.0246.
4.29. Crystallographic data
26

X-Ray diffraction: Data sets were collected with a Nonius KappaCCD diffractometer.
Programs used: data collection, COLLECT (R. W. W. Hooft, Bruker AXS, 2008, Delft, The
Netherlands); data reduction Denzo-SMN; [15] absorption correction, Denzo; [16] structure
solution SHELXS-97;[17] structure refinement SHELXL-97 [18]. R-values are given for
observed reflections, and wR2 values are given for all reflections.
X-ray crystal structure analysis of 4: formula C12H9BrFNO4, M = 330.11, colourless
crystal, 0.38 × 0.18 × 0.12 mm, a = 7.0681(6), b = 10.0225(8), c = 10.2222(9) Å, α =
113.628(3), β = 108.401(4), γ = 92.309(3)°, V = 617.8(1) Å3, ρcalc = 1.775 gcm-3, μ = 4.782
mm-1, empirical absorption correction (0.264 ≤ T ≤ 0.598), Z = 2, triclinic, space group P1
(No. 2), λ = 1.54178 Å, T = 223(2) K, ω and φ scans, 8484 reflections collected (±h, ±k, ±l),
2105 independent (Rint = 0.039) and 2086 observed reflections [I>2σ(I)], 173 refined
parameters, R = 0.029, wR2 = 0.078, max. (min.) residual electron density 0.32 (-0.35) e.Å-3,
hydrogen atoms were calculated and refined as riding atoms.
X-ray crystal structure analysis of 8: formula C12H10FNO4, M = 251.21, colourless crystal,
0.20 × 0.18 × 0.07 mm, a = 12.7588(3), b = 6.9438(1), c = 13.5859(4) Å, β = 108.896(1) °, V
= 1138.8(1) Å3, ρcalc = 1.465 gcm-3, μ = 0.121 mm-1, empirical absorption correction (0.976 ≤
T ≤ 0.991), Z = 4, monoclinic, space group P21/n (No. 14), λ = 0.71073 Å, T = 223(2) K, ω
and φ scans, 6844 reflections collected (±h, ±k, ±l), 2772 independent (Rint = 0.026) and 2394
observed reflections [I>2σ(I)], 165 refined parameters, R = 0.048, wR2 = 0.121, max. (min.)
residual electron density 0.26 (-0.18) e.Å-3, hydrogen atoms calculated and refined as riding
atoms.
X-ray crystal structure analysis of 13: formula C13H11BrFNO4, M = 344.14, colourless
crystal, 0.20 × 0.16 × 0.10 mm, a = 10.5773(2), b = 6.9082(1), c = 18.3877(4) Å, β =
96.376(1) °, V = 1335.3(1) Å3, ρcalc = 1.712 gcm-3, μ = 3.103 mm-1, empirical absorption
correction (0.575 ≤ T ≤ 0.746), Z = 4, monoclinic, space group P21/c (No. 14), λ = 0.71073 Å,
T = 223(2) K, ω and φ scans, 7839 reflections collected (±h, ±k, ±l), 2660 independent (Rint =
0.025) and 2490 observed reflections [I>2σ(I)], 210 refined parameters, R = 0.028, wR2 =
0.068, max. (min.) residual electron density 0.23 (-0.27) e.Å-3, hydrogen atoms calculated and
refined as riding atoms.
X-ray crystal structure analysis of 14: formula C13H12FNO4, M = 265.24, colourless crystal,
0.34 × 0.14 × 0.09 mm, a = 12.5396(3), b = 6.7943(2), c = 14.8734(4) Å, β = 107.722(1) °, V
= 1207.0(1) Å3, ρcalc = 1.460 gcm-3, μ = 1.015 mm-1, empirical absorption correction (0.721 ≤
T ≤ 0.909), Z = 4, monoclinic, space group P21/n (No. 14), λ = 1.54178 Å, T = 100(2) K, ω
27

and φ scans, 14610 reflections collected (±h, ±k, ±l), 2208 independent (Rint = 0.047) and
1848 observed reflections [I>2σ(I)], 184 refined parameters, R = 0.035, wR2 = 0.091, max.
(min.) residual electron density 0.42 (-0.14) e.Å-3, hydrogen atoms calculated and refined as
riding atoms.
X-ray crystal structure analysis of 21: formula C9H13ClFNO4, M = 253.65, colourless
crystal, 0.30 × 0.20 × 0.10 mm, a = 7.8820(6), b = 7.9464(4), c = 10.4237(8) Å, α =
83.794(3), β = 68.812(6), γ = 75.723(6)°, V = 589.8(1) Å3, ρcalc = 1.428 gcm-3, μ = 0.336 mm-
1, empirical absorption correction (0.905 ≤ T ≤ 0.967), Z = 2, triclinic, space group P1 (No.
2), λ = 0.71073 Å, T = 223(2) K, ω and φ scans, 4696 reflections collected (±h, ±k, ±l), 1985
independent (Rint = 0.040) and 1800 observed reflections [I>2σ(I)], 195 refined parameters, R
= 0.058, wR2 = 0.157, max. (min.) residual electron density 0.35 (-0.34) e.Å-3, hydrogen
atoms were calculated and refined as riding atoms.
Acknowledgements
Financial support of this work by the Cells-in-Motion Cluster of Excellence (EXC 1003 -
CiM) is gratefully acknowledged.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.jfluchem.2016 ...
References
[1]
[2]
[3]
P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications,
Wiley-VCH, Weinheim, 2013.
D. B. Berkowitz, K. R. Karukurichi, R. de la Salud-Bea, D. L. Nelson, C. D. McCune,
J. Fluorine Chem. 129 (2008) 731-742.
a) D. Seyferth, R. A. Woodruff, J. Org. Chem. 38 (1973) 4031-4039; b) Y. Takeuchi,
M. Asahina, A. Murayama, K. Hori, T. Koizumi, J. Org. Chem. 51 (1986) 955-956; c)
Y. Takeuchi, N. Itoh, T. Satoh, T. Koizumi, K. Yamaguchi, J. Org. Chem. 58 (1993)
1912-1820; d) B. Mohar, J. Baudoux, J.-C. Plaquevent, D. Cahard, Angew. Chem. Int.
Ed. 40 (2001) 4214-4216; e) D. S. Reddy, N. Shibata, J. Nagai, S. Nakamura, T. Toru,
S. Kanemasa, Angew. Chem. Int. Ed. 47 (2008) 164-168; f) Y. Takeuchi, M.
Kamezaki, K. Kirihara, G. Haufe, K. W. Laue, Chem. Pharm. Bull. 46 (1998) 1062-
1064; g) Y. Takeuchi, M. Nabetani, K. Takagi, T. Hagi, T. Koizumi, J. Chem. Soc.,
Perkin Trans. 1 (1991) 49-53; h) P. D. Bailey, S. R. Baker, A. N. Boa, J. Clayson, G.
28

M. Rosaira, Tetrahedron Lett. 39 (1998) 7755-7758; i) P. D. Bailey, A. N. Boa, J.
Clayson, Tetrahedron 65 (2009) 1724-1736; j) S. C. Annedi, W. Li, S. Samson, L. P.
Kotra, J. Org. Chem. 68 (2003) 1043-1049; k) P. Hudhomme, G. Duguay, Tetrahedron
46 (1990) 5263-5272.
[4]
a) A. Tarui, N. Kawashima, K. Sato, M. Omote, Y. Miwa, H. Minami, A. Ando,
Tetrahedron Lett. 51 (2010) 2000-2003; b) A. Tarui, N. Kawashima, K. Sato, M.
Omote, A. Ando, Tetrahedron Lett. 51 (2010) 4246-4249; c) S. C. Kim, F. M.
Raushel, J. Enzyme Inhibition 2 (1988) 153-161; d) P. D. Huber, Ph. D. Thesis, ETH
Zürich, 2006; e) D. Baba, T. Fuchigami, Tetrahedron Lett. 43 (2002) 4805-4808; f) J.
Kwiatkowski, Y. Lu, Org. Biomol. Chem. 13 (2015) 2350-2359; g) P.-F. Zheng, Q.
Ouyang, S.-L. Niu, L. Shuai, Y. Yuan, K. Jiang, T.-Y. Liu, Y.-C. Chen, J. Am. Chem.
Soc. 137 (2015) 9390-9399; h) L. Hu, C. Che, Z. Tan, G. Zhu, Chem. Commun. 51
(2015) 16641-16644; i) A. M. Paloyan, L. A. Stepanyan, S. A. Dadayan, A. A.
Hambardzumyan, G. P. Halebyan, A. S. Saghiyan, Appl. Biochem. Micro. 49 (2013)
106-112.
[5]
[6]
D. Ulbrich, C. G. Daniliuc, G. Haufe, Org. Biomol. Chem. 14 (2016) 2755-2767.
CCDC 1451857-1451868 contain the supplementary crystallographic data for this
paper: CCDC 1451857 (4); CCDC 1451858 (6); CCDC 1451859 (7); CCDC 1451860
(8); CCDC 1451867 (10); CCDC 1451861 (11); CCDC 1451862 (13); CCDC
1451863 (14); CCDC 1451864 (21); CCDC 1451865 (22); CCDC 1451866 (24);
CCDC 1451868 (42). These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
D. O. Jang, Synth. Commun. 27 (1997) 1023-1027.
[7]
[8]
[9]
A. G. Brown, T. C. Smale, J. Chem. Soc., Perkin Trans. 1 (1972) 65-68.
P. Huy, J.-M. Neudörfl, H.-G. Schmalz, Org. Lett. 13 (2011) 216-219.
[10] L. A. Adams, V. K. Aggarwal, R. V. Bonnert, B. Bressel, R. J. Cox, J. Shepherd, J. de
Vicente, M. Walter, W. G. Whittingham, C. L. Winn, J. Org. Chem. 68 (2003) 9433-
9440.
[11] A. Patchornik, M. Sokolovsky, J. Am. Chem. Soc. 86 (1964) 1206-1212.
[12] a) Y.-W. Wang, Y. Peng, Acta Cryst. E64 (2008) o296/291-o296/296; b) B. M. K.
Tong, S. Chiba, Org. Lett. 13 (2011) 2948-2951.
[13] J. Häusler, Liebigs Ann. Chem. (1981) 1073-1088.
[14] P. Skowronek, A. Katrusiak, J. Gawronski, Tetrahedron 58 (2002) 10463-10468.
[15] Z. Otwinowski, W. Minor, Methods Enzymol. 276 (1997) 307-326.
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