Applications of 2-Chloro-3,3,3-trifluoroprop-1-ene (HCFO-1233xf): A Rapid Entry to Various β-Substituted-trifluoromethyl-ethenes

Article abstract of DOI:10.1021/acs.orglett.0c00931

An efficient base-promoted reaction of O-, N-, and S-nucleophiles with 2-chloro-3,3,3-trifluoprop-1-ene (HCFO-1233xf) is described providing access to various β-substituted-trifluoromethyl-ethenes under mild reaction conditions. Mechanistic investigations shed some light on the regio-, chemo-, and stereoselectivities observed. The olefins prepared represent attractive intermediates in chemical discovery: Some applications include their conversion to pyrrolidines via a [3 + 2] dipolar cycloaddition reaction. These weakly basic amines represent novel synthons that could be readily elaborated through a range of reactions.

Full text of DOI:10.1021/acs.orglett.0c00931

pubs.acs.org/OrgLett
Letter
Applications of 2‑Chloro-3,3,3-trifluoroprop-1-ene (HCFO-1233xf):
A Rapid Entry to Various β‑Substituted-trifluoromethyl-ethenes
Daniel Meyer* and Myriem El Qacemi*
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ABSTRACT: An efficient base-promoted reaction of O-, N-, and S-nucleophiles with 2-chloro-3,3,3-trifluoprop-1-ene (HCFO-
1233xf) is described providing access to various β-substituted-trifluoromethyl-ethenes under mild reaction conditions. Mechanistic
investigations shed some light on the regio-, chemo-, and stereoselectivities observed. The olefins prepared represent attractive
intermediates in chemical discovery: some applications include their conversion to pyrrolidines via a [3 + 2] dipolar cycloaddition
reaction. These weakly basic amines represent novel synthons that could be readily elaborated through a range of reactions.
he trifluoromethyl group (−CF3) is a privileged sub-
interested to expand the utility of the inexpensive reagent 2-
chloro-3,3,3-trifluoroprop-1-ene 1, as it could prove an attractive
building block for applications on a technical scale.
1
Tstituent in pharmaceutical and agrochemical research. Its
introduction into organic molecules can significantly alter their
properties such as pKa,2 lipophilicity,3 and conformation,4
thereby influencing their hydrolytic and metabolic stability.5 In
this context, CF3-containing reagents that are inexpensive,
sustainable, and available in bulk quantities are of high interest in
the life sciences.1 The present approach complements existing
trifluoromethylation reaction strategies. However while signifi-
cant advances have been made in recent years, they remain
prohibitive in terms of cost and atom efficiency for large-scale
application.6 In recent years, some low-cost trifluoromethylated
alkenes, such as 2,3,3,3-tetra-fluoropropene (HFO-1234yf) or 2-
chloro-3,3,3-trifluoroprop-1-ene (1, HCFO-1233xf), have
emerged as important compounds or intermediates in the
refrigerant industry due to their low global warming potential
(GWP) and zero or near-zero ozone depletion potential.7
Despite their large-scale production, only a few publications
have reported their conversion into trifluoromethylated fine
chemicals, including reports of oxidative Heck couplings,8 cross-
coupling reactions,9 C−F activation reactions,10 and reactions
with nucleophiles.11 The latter have been reported as base-
promoted reactions that require either a large excess of olefin or
high temperatures. In addition, only a few nucleophiles have
been reported as suitable to access β-substituted-trifluoromethyl
ethenes. While the chemistry of the related 2-bromo-3,3,3-
trifluoroprop-1-ene is more advanced (coupling reactions,12 1,2-
additions,13 cycloadditions,14 reaction with nucleophiles15)
owing to its ease of handling (liquid at room temperature),
the scope of its application to generate β-substituted-
trifluoromethyl-ethenes remains limited. We were therefore
Herein, we report the reaction of O-, S-, and N-nucleophiles
on olefin 1 to afford the corresponding β-trifluoromethyl enol
ethers and vinyl sulfides as well as nitrogen substituted β-
trifluoromethyl-ethenes under mild reaction conditions. Fur-
thermore, [3 + 2] dipolar cycloadditions between these
electron-deficient olefins and N-benzyl azomethine ylide allow
the synthesis of β-trifluoromethyl-substituted pyrrolidines.
These advances highlight the potential of this readily available
fluorinated feedstock in novel and cost-effective fine-chemicals
synthesis.
The optimization of the base-promoted reaction of
nucleophiles with 2-chloro-3,3,3-trifluoroprop-1-ene 1 was
investigated using sulfonamide 2a (Table 1). Employing an
excess of base and nucleophile 2a (2 equiv) in N,N′-
dimethylpropyleneurea (DMPU) gave the bis-substituted
product 5a in 86% yield (entry 1). The use of an excess of 1
(2 equiv) and sodium hydride or potassium tert-butoxide as base
gave mainly the monosubstituted product 4a, which was found
to be an intermediate for the formation of 5a (entries 2−3). The
addition of tert-butyl alcohol as a cosolvent increased the
Received: March 13, 2020
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© XXXX American Chemical Society
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Table 1. Optimization with Sulfonamide 2a and Olefin 1
Scheme 1. Substrate Scope for the Base-Promoted Reaction
with a Range of Nucleophiles
b
19F NMR yield (%)
a
c
d
entry
base (equiv), solvent, temp
3a
4a 5a
6a
1
2
3
4
5
6
7
8
NaH (2.2), DMPU, rt
NaH (1.2), DMPU, rt
t-BuOK (1.2), DMPU, rt
13
2
6
−
50
45
9
8
7
86
23
21
5
4
3
−
−
−
−
−
−
−
−
−
−
2
14
13
12
15
9
16
10
9
7
7
t-BuOK (1.2), DMPU/t-BuOH 6:4, rt
KOH (1.2), DMPU/t-BuOH 6:4, rt
KOH (1.2), DMPU/t-BuOH 6:4, 50 °C
KOH (1.2), DMPU/EtOH 6:4, 50 °C
KOH (1.2), DMPU/i-PrOH 6:4, 50 °C
KOH (1.2), NMP/i-PrOH 6:4, 50 °C
KOH (1.2), DMF/i- PrOH 6:4, 50 °C
KOH (1.2), DMSO/i-PrOH 6:4, 50 °C
KOH (1.2), DMPU/i-PrOH 4:6, 50 °C
KOH (1.5), DMPU/i-PrOH 6:4, 50 °C
KOH (2.0), DMPU/i-PrOH 6:4, 50 °C
48
48
55
69
73
60
69
64
72
73
71
2
−
−
−
3
−
−
−
9
10
11
12
13
14
e
6
a
For reactions at room temperature, 1 was added at −30 °C followed
b
by a slow temperature ramp. 19F NMR yields were calculated with
1,4-bis(trifluoromethyl)benzene as an internal standard. Z/E ratio in
c
a
2.5 equiv of KOH used.
d
all reactions ≥97:3. Compounds 5a were obtained as a mixture of E
e
and Z isomers. Isolated yield (75% yield by 19F NMR) and Z/E ratio
of 97:3.
was obtained with thiopyridine 2p. The reaction with di-
isopropyl malonate gave the corresponding cyclopropyl
derivative 7 in 16% yield, comparable to a previous result
using 2-bromo-3,3,3-trifluoropropene.16
formation of 3a, but also increased the amount of addition
product 6a (entries 4−5). At a higher reaction temperature (50
°C) and using isopropyl alcohol as a cosolvent, the desired
product 3a was obtained in 73% yield (entry 8). Replacing
DMPU by other polar aprotic solvents such as N-methyl-2-
pyrrolidone (NMP), DMF, or DMSO gave 3a in yields of 60−
69% (entries 9−11). Solvents such as THF, dioxane, and
acetonitrile, as well as alternative bases, such as NaOH, Cs2CO3,
K3PO4, DBU, and Triton B, did not increase the yield of 3a (see
Supporting Information). Increasing the amount of isopropyl
alcohol and potassium hydroxide had only a minor impact on
the reaction outcome (entries 12−14).
The scope and limitations of the optimized procedure was
assessed over a broad range of N-, O-, and S-nucleophiles with
olefin 1 (Scheme 1). Di-tert-butyl-iminodicarboxylate 2b was
successfully converted in high (Z)-selectivity to β-trifluor-
omethyl-ethene 3b in 49% yield. N-Vinyl hetereoaromatic
nitrogen compounds 3c−3f were obtained in yields of 60−69%,
albeit with lower Z/E ratios. Noteworthy, in the cases of triazole
2e and pyridinone 2f, the reaction proceeded with good
chemoselectivity and only the regioisomers 3e and 3f were
obtained. Phenols 2g−2j and oxime 2k gave enol ethers 3g−3k
in good yields (58−78%) with excellent Z/E selectivities
(>98:2). Benzyl enol ether 3l was isolated in poor yield, which
may be a result of incomplete deprotonation of the benzyl
alcohol 2l; replacing the base with potassium tert-butoxide did
not increase the yield of 3l. Reactions with benzyl thiols 2m and
2n gave (E)-vinyl sulfides 3m and 3n as main products, in yields
of 78% and 75%, whereas reactions with aromatic thiols 2o, 2p,
and 2q resulted in the formation of (Z)-isomers 3o, 3p, and 3q
in yields of 86−97%. Notably, a good S- vs N- chemoselectivity
To gain a deeper understanding of the origin of selectivity in
these transformations, we undertook a series of preliminary
mechanistic investigations (Scheme 2). In each reaction shown
in Scheme 1, 3,3,3-trifluoroprop-1-yne 8 was detected in small
amounts by 19F NMR, implicating it as a possible intermediate in
the formation of the olefinic products. Previous experimental
studies on nucleophilic additions to trifluoromethylpropyne
derivatives exhibited a strong preference for (Z)-olefin products
(anti-addition).17 This is consistent with ab initio molecular
orbital studies showing preferential trans bending of acetylene in
the transition state for nucleophilic attack.18 This trans bending
forms the vinylic anion with the lone pair anti to the nucleophile.
Owing to the high rotation barrier in simple alkyl or aryl
substituted vinylic anions, protonation leads to an overall anti
addition.19 Indeed, the reaction of various nucleophiles (2a, 2g,
2m, and 2o) with alkyne 8 gave the β-trifluoromethyl
substituted alkenes (3a, 3g, 3m, and 3o) with excellent (Z)-
selectivities (Scheme 2a). These results are consistent with
alkyne 8 being a key intermediate leading for many nucleophiles
to the formation of (Z)-alkenes as the major product (Scheme
1). However, the (E)-selectivity observed with benzyl thiols 2m
and 2n suggests that this particular reaction proceeds either
partially or exclusively through another pathway, or that E/Z
isomerization is particularly favored in 3m and 3n. A possible E/
Z isomerization pathway leading to (E)-3 could result from a
nucleophilic vinylic substitution (SNV)20 with a second
nucleophile 2 on olefin (Z)-3. To support such a mechanism,
vinyl sulfide 3m was treated with thiol 2n under standard
conditions (Scheme 2b). However, only a small amount of
B
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Scheme 2. Mechanistic Studies
Figure 1. Proposed reaction mechanism.
type reaction on compound 4. However, the presence of a protic
solvent has two major impacts on the reaction: it lowers the
nucleophilicity of 2 and provides a proton. In a first pathway
(Path B), the deprotonated form of 2 or potassium hydroxide
triggers the elimination of HCl to form alkyne 8. Nucleophilic
addition of the anionic form of 2 forms the intermediate vinylic
anion B. Since the olefin rotation barrier of this anion is expected
to be high, protonation should lead to a stereospecific anti
addition. Indeed, no (E)-isomers were detected from the
reaction of trifluoroalkyne 8 with various nucleophiles (Scheme
2a). A second nucleophilic addition of the anion of 2 to form
intermediate D was found to be slow and no isomerization was
observed (Scheme 2b). The second pathway starts with a
Michael-type addition of the anion of 2 on olefin 1, which
provides chloroalkane 6 after protonation of E (Path C). A base-
promoted subsequent elimination of hydrochloric acid yields
trifluoromethyl-substituted alkene 3. The stereoselectivity of
this HCl elimination was shown to be substrate dependent
(Scheme 2c). The predominance of each pathway is observed to
be highly dependent on the nucleophile, as shown by the E/Z
ratios in Scheme 1. For reactive and weakly basic nucleophiles
such as 2m and 2n, the chloroalkane 6 formation pathway is
preferred, yielding an increased amount of (E)-3. For the less
reactive and/or more basic nucleophiles like 2a, the alkyne 8
formation pathway is preferred, forming higher amounts of (Z)-
3.
The pyrrolidine moiety can be found in many bioactive
compounds.22 A well-known strategy to access β-substituted
pyrrolidines is a [3 + 2] cycloaddition between electron-
deficient alkenes and azomethine ylides.23 Reaction of olefins of
type I with the nonstabilized azomethine ylide precursor 9 gave
access to N-benzylated pyrrolidines 10 in yields of 64−98%
(Scheme 3).2b,24 In agrochemical research, the basicity of
amines is an important parameter to optimize bioactive
compounds.25 With pKA(H) values for the amino groups of
pyrrolidines 10 ranging from 3.4 to 6.2, significantly lower than
those for 1-benzylpyrrolidine (9.3) and 1-benzyl-3-(trifluoro-
methyl)pyrrolidine (7.2),2b a broad scope of physicochemical
properties are accessible from these simple synthons.
nucleophile exchange and no olefin isomerization was observed
for (E)- and (Z)-3m, thus disfavoring this pathway for the
formation of (E)-3m. The same result was found with enol ether
(Z)-3g and phenol 2h (see Supporting Information). A longer
reaction time for vinyl sulfide 3m with thiol 2n yielded small
amounts of the mixed dithioacetal without olefin isomerization.
These results reflect fast protonation of the intermediate anion
thus hampering the stepwise SNV mechanism. Jiang et al.
described a “Michael-type addition” mechanism for the
nucleophilic additions on 2-bromo-3,3,3-trifluoroprop-1-ene
to afford a bromo-alkane intermediate that eliminates HBr and
gives the observed (Z)-trifluoromethyl products.15c To assess
the viability of such a chloroalkane intermediate in our examples,
we conducted the reaction of 1 with thiol nucleophile 2m using a
substoichiometric amount of potassium hydroxide (0.1 equiv) at
0 °C, which yielded the chloroalkane addition product 6m in
41% yield. Notably, compound 6m was shown to subsequently
convert into 3m with a reproducible Z/E ratio of 1:9 under basic
conditions, implicating 6 as a potential intermediate in the
course of the reaction (Scheme 2c). In contrast, the same
reaction with 6a gave 3a as a 1:1 Z/E mixture. The higher (Z)-
selectivity for 3a compared to the vinyl sulfide 3m fragment has
been described previously and ascribed to some key orbital
interactions.17d,e However, the 1:1 Z/E mixture observed in 3a
derived from 6a is inconsistent with the high (Z)-selectivity
observed in the reaction of 1 with 2a, discrediting 6a as an
intermediate in the formation of 3a under the reaction
conditions shown in Scheme 1.
Based on the above results, we propose the following
mechanism depicted in Figure 1. Product 4 could originate
from intermediate A, itself formed via an SN2′-type reaction
(Path A) favored in polar nonprotic solvents that enhance the
nucleophilicity of 2 and disfavor protonation of the intermediate
carbanion E.21 Similarly, product 5 could be formed by an SN2′-
Pyrrolidinium salts 11 were obtained from pyrrolidines 10 in
gram-scale in very good yield (84−98%) applying two different
debenzylation methods: hydrogenation with palladium on
charcoal or reaction with 1-chloroethyl chloroformate followed
by treatment with methanol (Scheme 4).26 The oxime derivative
C
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Scheme 3. Synthesis of 1-Benzylpyrrolidines
Scheme 5. Derivatization Examples of Some Pyrrolidines
a
I include olefins 1, 3, HFO-1234yf, HFO-1234ze, and 1-(trifluoro-
b
methyl)vinyloxymethylbenzene. cis- and trans-isomers were sepa-
rated by column chromatography.
a
Scheme 4. Synthesis of Pyrrolidinium Salts
We have developed a base promoted addition of various O-,
S-, and N-nucleophiles on 2-chloro-3,3,3-trifluoroprop-1-ene 1.
The resulting β-trifluoromethyl enol ethers and vinyl sulfides as
well as nitrogen substituted β-trifluoromethyl-ethenes were
obtained under mild reaction conditions in good yields and
generally high chemo-, regio-, and stereoselectivities. The β-
substituted-trifluoromethyl ethenes were further transformed
into a variety of pyrrolidines which are of high interest in
chemical discovery. Together, these results highlight the
potential of the low cost and readily available trifluoromethyl-
ethene 1 as a building block in the fine-chemical industry.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00931.
Optimization reactions for the reaction of sulfonamide 2a
and olefin 1, experiments for the mechanistic studies,
synthetic procedures, characterization data, and NMR
spectra of all compounds (PDF)
a
HY are HCl, HBr, or TsOH
AUTHOR INFORMATION
Corresponding Authors
■
cis-11k gave access to alcohol cis-11v by hydrogenation or
hydroxylamine cis-11w by hydrolysis in 76% and 35% yield (67%
based on recovered starting material), respectively.
Myriem El Qacemi − Syngenta Crop Protection Research, Stein,
Switzerland; orcid.org/0000-0001-5894-9292;
Email: Myriem.El_qacemi@syngenta.com
Finally, some preliminary experiments were performed to
study the reactivity of pyrrolidine derivatives 11 (Scheme 5).
Nucleophilic aromatic substitution (SNAr) and reductive
amination of pyrrolidine cis-11d with the pyridine derivatives
12 and 13 gave the corresponding tertiary amines 14 and 15 in
79% and 48% yield, respectively. Reaction of sulfonyl chloride
16 with a small excess of pyrrolidine cis-11b gave exclusively
sulfonamide 17 in excellent yield. The amide coupling with
cyclopropanecarboxylic acid 18 could successfully be achieved
using a combination of N,N,N′,N′-tetramethylchloro-
formamidinium hexafluorophosphate (TCFH) and N-methyl-
imidazole (NMI).27
Daniel Meyer − Syngenta Crop Protection Research, Stein,
Switzerland; Email: Daniel.Meyer@syngenta.com
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00931
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors would like to thank Marina Safeer, Leonard
Hagmann, Katharina Gaus, and Joel Hafliger (all of Syngenta
■
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Guillaume Berthon, Chris Scarborough, Alan Robinson, Alain
De Mesmaeker (all of Syngenta Crop Protection Research), and
̈ ̈
Klaus Muller (ETHZ, Zurich, Switzerland) for their support and
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