Hydrogen-Bond-Promoted Friedel-Crafts Reaction of Secondary Propargylic Fluorides: Preparation of 1-Alkyl-1-aryl-2-alkynes

Article abstract of DOI:10.1055/s-0036-1589057

We report that aromatic propargylation is achievable with secondary propargylic fluorides, thus affording 1-alkyl-1-aryl-2-alkynes. In the present case, hydrogen bonding is responsible for the activation of the C-F bond. A large excess of arene nucleophil

Full text of DOI:10.1055/s-0036-1589057

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© Georg Thieme Verlag Stuttgart · New York
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J.-D. Hamel et al.
Letter
Synlett
Hydrogen-Bond-Promoted Friedel–Crafts Reaction of Secondary
Propargylic Fluorides: Preparation of 1-Alkyl-1-aryl-2-alkynes
Jean-Denys Hamel
activation of the C–F bond through hydrogen bonding
Meggan Beaudoin
Mélissa Cloutier
ArH
F
Ar
Jean-François Paquin*
cat. TFA
HFIP
15 examples
up to 97%
R2
R2
R1
R1 = Ph, TMS or t-Bu
2 = alkyl, etc.
R1
CCVC, PROTEO, Département de chimie, Université Laval,
1045 Avenue de la Médecine, Québec, QC G1V 0A6, Canada
jean-francois.paquin@chm.ulaval.ca
1-alkyl-1-aryl-2-alkynes
R
Dedicated to Prof. Victor Snieckus on the occasion of his
80th birthday
Received: 20.04.2017
Accepted after revision: 29.05.2017
Published online: 06.07.2017
or metal-allenylidene intermediates. Likewise, propargylic
allylation was shown to be an appropriate strategy (Scheme
1, c).12–15 The asymmetric Negishi cross-coupling of propar-
gylic halides and carbonates with arylzinc reagents also al-
lowed the preparation of enantioenriched 1-alkyl-1-aryl-2-
alkynes (Scheme 1, d).16 Finally, aryl sulfoxides underwent
DOI: 10.1055/s-0036-1589057; Art ID: st-2017-r0278-l
Abstract We report that aromatic propargylation is achievable with
secondary propargylic fluorides, thus affording 1-alkyl-1-aryl-2-alkynes.
In the present case, hydrogen bonding is responsible for the activation
of the C–F bond. A large excess of arene nucleophile is shown to be nec-
essary to achieve good yields.
Previous work
a)
OH
Ar
ArH
L.A. or B.A.
Key words alkynes, arenes, C–F bond activation, Friedel–Crafts reac-
tion, HFIP, hydrogen bond, propargylation, propargylic fluoride
R
R
CO2(CO)6
CO2(CO)6
b)
c)
OR1
R
Ar
R
ArH
[Sc], [Ru], [Bi]
Alkynes are very valuable in both organic and medicinal
chemistry,1 one of the reasons being that they can easily be
transformed into new highly desirable functionalities.
While they are well-known substrates for hydrogenation2
and hydroboration3 reactions, for example, their reactivity
goes far beyond that. This is notably shown by the advent of
gold-catalyzed nucleophilic additions,4 Sonogashira cross-
coupling reactions,5 alkyne click chemistry,6 and alkyne
metathesis.7
Among motifs featuring a carbon–carbon triple bond,
an intriguing case is that of 1-alkyl-1-aryl-2-alkynes, as it
highlights a central carbon atom bonded to four substitu-
ents of differing formal hybridizations (H = s; alkynyl = sp;
aryl = sp2; alkyl = sp3). Noteworthy, while not of wide use
yet in medicinal chemistry, this motif has recently found
applications in the development of dihydrofolate reductase
inhibitors.8 However, to this day, only a few methods allow
the preparation of 1-alkyl-1-aryl-2-alkynes, most of them
relying on propargylic substitution reactions. As part of a
Nicholas reaction, Co2(CO6)-complexed propargylic alcohols
were reacted with aromatic nucleophiles in presence of an
acid (Scheme 1, a),9 while aromatic propargylation with
propargylic alcohols10 and acetates11 was carried out under
transition-metal catalysis (Scheme 1, b) via either cationic
R1 = H, Ac
Ar
R
X
Ar
R
OR1
R1 = H, Ac
X = Br, [B], OH, [Si]
d)
e)
X
R
Ar
ArZnEt
[Ni]
*
R
R
R
X = Br, Cl, OCO2R1
TMS
R
MeS
PhS(O)Me
Tf2O
This work
f)
F
Ar
ArH
HBD
R
Scheme 1 Known methodologies for the preparation of 1-alkyl-1-aryl-
2-alkynes via propargylic substitution reactions and present work. R =
alkyl chain; L.A. = Lewis acid; B.A. = Brønsted acid; * = enantioenriched
stereocenter; HBD = hydrogen-bond donor.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
J.-D. Hamel et al.
Letter
Synlett
ortho propargylation with propargylic silanes via an inter-
rupted Pummerer–allenyl thio-Claisen rearrangement se-
quence (Scheme 1, e).17 Overall, compared to their allylic
and benzylic counterparts, propargylic substitution reac-
tions are much less developed,18 and propargylic10c,19 and
Meyer–Schuster19b,20 rearrangements are processes that
sometimes compete.
ture to 0 °C had little effect on side-product formation, but
resulted in improved ortho/para selectivity (Table 1, entry
3), whereas running the reaction at –30 °C slowed it down
to the point where full conversion had not occurred after 18
hours (Table 1, entry 4). As ortho/para selectivity was not
the main concern of this study, we arbitrarily chose to run
subsequent reactions at room temperature as shorter in-
duction periods were preferred. Using CH2Cl2 (Table 1, en-
try 5) and CHCl3 (Table 1, entry 6) as 1:1 mixtures with
HFIP as solvent resulted in similar yields with slightly im-
proved ortho/para selectivity. Increasing the CH2Cl2/HFIP
ratio to 4:1 (Table 1, entry 7) and 10:1 (Table 1, entry 8) re-
sulted in better yields, the latter giving rise to a 74% yield
(ortho/para = 1:9.2). However, the longer induction period
associated with the smaller amount of HFIP had to be coun-
terbalanced with longer reaction times. When decreasing
further the amount of HFIP to a 20:1 ratio (Table 1, entry 9)
or by simply omitting it (Table 1, entry 10), lower yields and
ortho/para selectivities were obtained. Keeping the 10:1
CH2Cl2/HFIP mixture as the solvent, but lowering the tem-
Our group has a longstanding interest in the activation
of the C–F bond by means of hydrogen bonding.21,22 This has
led us to the development of the Friedel–Crafts reaction of
benzylic fluorides using 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) as the activator, which allowed the preparation of di-
arylmethanes.21c This system was shown to be autocatalytic
through the formation of HF, which is a strong hydrogen-
bond donor (HBD). Recently, we have shown that addition
of trifluoroacetic acid (TFA) to the reaction mixture results
in the shortening of the induction period associated with
the formation of the first HF molecules.21e We were now in-
terested in applying these findings about the Friedel–Crafts
reaction to other activated organic fluorides. Propargylic
fluorides appeared to be ideal substrates (Scheme 1, f), as
while the chemistry of the carbon–carbon triple bond is
well known,23 to our knowledge no example of C–F bond
activation onto this motif has ever been reported. Herein,
we thus describe the use of propargylic fluorides in a hy-
drogen-bond-promoted aromatic propargylation reaction.
Propargylic monofluorides were synthesized by means
of nucleophilic addition of acetylides to aldehydes to form
propargylic alcohols, followed by deoxofluorination with
N,N-dimethylaminosulfur trifluoride (Me-DAST) (Scheme
2).23a,24 Through this methodology, a series of (α-al-
kyl)propargylic fluorides was obtained, as well as a
bis(propargylic) fluoride and a primary fluoride.25
Table 1 Optimization of the Friedel–Crafts Reaction of Propargylic
Fluoride 1 with Toluene
Me
toluene
TFA (cat.)
F
Ph
Ph
1
2
Entry Toluene TFA
(equiv) (mol%)
Solvent
Temp Time Yield (%)a
(°C)
(h)
71b
25
25
25
25
25
25
25
25
25
25
25
25
25
5
5
5
5
5
5
5
5
5
5
5
0
5
0
toluene/HFIP (3:1)
HFIP
r.t.
r.t.
0
1
74 (1:10)
31 (1:13)
39 (1:20)
35c(1:19)
36 (1:12)
40 (1:13)
59 (1:9.0)
74 (1:9.2)
61 (1:7.6)
54 (1:8.0)
57 (1:12)
65 (1:8.7)
54 (1:9.0)
0
F
1
2
1) R2CHO
2) Me-DAST
M
R2
1
1
R1
R1
3
HFIP
M = Li, MgBr
R1 = alkyl, aryl, H, TMS
R2 = alkyl, alkynyl, H
4
HFIP
–30
18
1
5
CH2Cl2/HFIP (1:1)
CHCl3/HFIP (1:1)
CH2Cl2/HFIP (4:1)
CH2Cl2/HFIP (10:1)
CH2Cl2/HFIP (20:1)
CH2Cl2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
Scheme 2 Two-step preparation of propargylic fluorides from
6
1
acetylides
7
18
18
18
18
18
18
1
8
Secondary propargylic fluoride 1 was selected as the
model substrate for the optimization of the Friedel–Crafts
reaction with toluene as the nucleophile (Table 1). For the
initial experiment, a 3:1 mixture of toluene and HFIP was
chosen as the solvent, and TFA was added in catalytic
amount. After one hour at room temperature, this resulted
in the formation of 1-alkyl-1-aryl-2-alkyne 2 in 74% yield
as an inseparable 1:10 mixture of ortho/para isomers (Table
1, entry 1). We next sought to reduce the amount of arene
nucleophile. The use of 25 equivalents of toluene while
keeping HFIP as the solvent resulted in a decrease of the
yield down to 31% (Table 1, entry 2). Lowering the tempera-
9
10
11
12
13
14
CH2Cl2/HFIP (10:1)
CH2Cl2/HFIP (10:1)
CH2Cl2/HFIP (10:1)
CH2Cl2/HFIP (10:1)
r.t.
r.t.
r.t.
1
a Product isolated as an inseparable mixture of ortho/para isomers. The or-
tho/para ratio is given in parentheses and was determined by 1H NMR analy-
sis by comparing integrations for propargylic protons.
b Corresponds to the amount of toluene in the solvent mixture at a concen-
tration of propargylic fluoride of 0.1 M.
c Incomplete conversion (ca. 90% as estimated by 1H NMR analysis).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
J.-D. Hamel et al.
Letter
Synlett
perature to 0 °C, resulted in a lower 54% yield, albeit with
greater ortho/para selectivity (Table 1, entry 11). Lastly, we
wanted to assess the beneficial or detrimental effect of TFA
on yields and also its ability to accelerate the reaction. Per-
forming the reaction at room temperature in absence of TFA
resulted in a somewhat lower yield of 65% with similar or-
tho/para selectivity (Table 1, entry 12). The effect on the in-
duction period was shown by stopping the reaction after
one hour.
Indeed, while the reaction with TFA afforded 2 in 54%
yield (Table 1, entry 13), no conversion was observed in the
absence of TFA (Table 1, entry 14). In view of all the data,
the reaction conditions outlined in entry 8 (arene: 25
equiv; TFA: 5 mol%; CH2Cl2/HFIP (10:1), r.t., 18 h) were de-
termined as the optimal ones.
With the optimized conditions in hand, the scope of the
transformation was studied (Scheme 3). A selection of
arenes of varying electronic properties reacted well with
secondary propargylic fluorides featuring a nonterminal
acetylenic unit to form 1-alkyl-1-aryl-2-alkynes 3–13 in
mostly good yields. Weaker nucleophiles such as benzene
and fluorobenzene generally had to be used as co-solvents
to overcome their lesser nucleophilicity. Even so, the reac-
tion between 1 and benzene led to a poor 14% yield of 6, as
attack onto the phenyl of another propargylic fluoride was
predominant. A bispropargylic fluoride was also shown to
be a suitable substrate, as exemplified by the formation of
14 in 52% yield. When a primary propargylic fluoride was
treated under the same reaction conditions with p-xylene
as the nucleophile, the starting material remained intact,
and, even when the reaction was heated up to 60 °C in HFIP,
15 was never observed. Similarly, when the reaction was
carried out with a terminal propargylic fluoride (R1 = H), no
conversion into 16 was observed, even at elevated tempera-
tures. However, under similar reaction conditions, a TMS-
protected propargylic fluoride (R1 = TMS, 17) reacted with
p-xylene so that 18 was formed, albeit with partial fluoride-
induced TMS deprotection to the terminal acetylene. Sub-
sequent treatment with TBAF completed the deprotection
so that 16 was obtained in 79% yield over two steps
(Scheme 4).
The fact that a primary propargylic fluoride did not re-
act supports the claim that the reaction presumably goes
through the intermediacy of a carbocation, as is the case for
benzylic fluorides.21a Indeed, the developing primary carbo-
cation is presumably too high in energy for the C–F bond to
F
ArH (25 equiv)
TFA (5 mol%)
Ar
R2
R2
CH2Cl2/HFIP (10:1)
r.t., 18 h
R1
R1
5
t-Bu
Ph
Me
OMe
Me
OMe
Me
Me
Me
Me
Me
Me
3
65%
4
5
8
78%
9
10
59%b
73% (o/p = 1:18)
85% (o/p = 1:3.6)
78% (o/p = 1:1.3)
F
S
6
7
11
54%
12
13
14%a
60%a (o/p = 1:45)
97% (α/β = 2.0:1)
79% (α/β = 2.4:1)
Me
Me
Me
Me
Me
Me
H
9
t-Bu
t-Bu
C8H17
H
16
0%c,e
14
52%
15
0%c,d,e
Scheme 3 Scope of the hydrogen-bond-promoted Friedel–Crafts reaction of propargylic fluorides. The yields given are for isolated products, and the
ratio of isomers is given in parentheses with the major isomer shown. a The reaction was carried out using arene/HFIP (3:1) as the solvent. b The reaction
was carried out using CH2Cl2/HFIP (3:1) as the solvent. c The reaction was carried out at 60 °C. d The reaction was carried out using HFIP as the solvent. e
No conversion.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
J.-D. Hamel et al.
Letter
Synlett
was too reactive27 and 2 was formed in 5% yield albeit full
conversion of the starting material, with what appear as
elimination and polymerization side reactions prevailing
over the desired reactivity.
Me
F
Me
TFA (5 mol%)
9
9
p-xylene/HFIP (3:1)
TMS
TMS
60 °C, 18 h
18
16
17
Me
TBAF
THF
r.t., 2 h
X
toluene (25 equiv)
TFA (5 mol%)
79% (over 2 steps)
CH2Cl2/HFIP (10:1)
Ph
Ph
r.t., 18 h
19 (X = OH)
20 (X = Cl)
21 (X = OTs)
2
Scheme 4 Friedel–Crafts reaction of TMS-protected propargylic fluo-
ride 17
0% (from 19 and 20)
5%a (from 21; o/p = 1:4.0)
Scheme 6 Reactivity of other propargylic substrates. a Estimated by 1H
break, which would account for the lack of reactivity under
the reaction conditions. Also in analogy with benzylic fluo-
rides, TFA, the best HBD initially in the system, would cata-
lyze the abstraction of the first fluoride. Electrophilic aro-
matic substitution would follow, ultimately generating the
desired 1-alkyl-1-aryl-2-alkyne and HF. This HF, a better
HBD than TFA, would in turn catalyze the Friedel–Crafts re-
action at an even faster rate, making the transformation au-
tocatalytic (Scheme 5).
NMR analysis using 1,4-dimethoxybenzene as an internal standard.
To summarize this work, we have demonstrated that the
C–F bond of secondary propargylic fluorides can be activat-
ed by means of hydrogen bonding.28 The resulting carboca-
tionic intermediate was trapped with arene nucleophiles to
form 1-alkyl-1-aryl-2-alkynes in what is essentially a
Friedel–Crafts-type propargylation reaction. A large excess
of arene nucleophile is, however, necessary to control the
reactivity.
F
R2
Acknowledgment
R1
HBD
This work was supported by the Natural Sciences and Engineering Re-
search Council of Canada (NSERC), The Fonds de recherche du Québec
– Nature et technologies (FRQNT) and Université Laval. J.D.H. thanks
the NSERC for a Vanier Canada Graduate Scholarship
F
HBD
+
R2
HF
R1
Supporting Information
Supporting information for this article is available online at
HBD
F–
https://doi.org/10.1055/s-0036-1589057.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
+
R2
H+
R1
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HBD = TFA, HFIP, HF
Scheme 5 Proposed mechanism; HBD = hydrogen bond donor
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
J.-D. Hamel et al.
Letter
Synlett
(25) All our efforts towards the preparation of an (α-aryl)propargylic
fluoride failed as spontaneous decomposition kept occurring
upon purification. Since decomposition only occurred after
purification, a sample of crude (α-aryl)propargylic fluoride was
directly engaged in a Friedel–Crafts reaction. However, decom-
position still prevailed over the desired reactivity when using
CH2Cl2/HFIP (30:1) as the solvent.
(26) At this point, the reasons for the absence of reaction with
alcohol 20 are not understood. Our current hypothesis is that
20 is involved in a strong hydrogen-bond network, as an alcohol
is capable, at the same time, of accepting and donating hydro-
gen bonds, with HFIP and/or TFA, which would overall protect it
from further reaction. For examples of hydrogen bonded com-
plexes with HFIP, see: (a) Berrien, J.-F.; Ourévitch, M.; Morgant,
G.; Ghermani, N. E.; Crousse, B.; Bonnet-Delpon, D. J. Fluorine.
Chem. 2007, 128, 839. (b) Berkessel, A.; Adrio, J. A.; Hüttenhain,
D.; Neudörfl, J. M. J. Am. Chem. Soc. 2006, 128, 8421. (c) Further
experiments were performed and no reaction was observed
when running the reaction at r.t. or 40 °C using either 5 or 50
mol% of TFA. At best, a low conversion (ca. 13%) to the trifluoro-
acetate of 20 was observed under more forcing conditions (i.e.,
TFA (50 mol%), DCE/HFIP (9 :1), 70 °C, 18 h).
(28) Representative Procedure for the Friedel–Crafts Reaction of
Propargylic Fluorides – Synthesis of 1-Methyl-4-(1-phenyl-
hex-1-yn-3-yl)benzene (2)
A solution of TFA (8.7 μL, 0.114 mmol) in CH2Cl2 (13 mL) was
prepared. 3-(Fluorohex-1-ynyl)benzene (1, 40 mg, 0.227 mmol)
was then charged in a vial and dissolved in this TFA/CH2Cl2 solu-
tion (1.3 mL, resulting in 5 mol% of TFA). Toluene (0.60 mL, 5.68
mmol) was added, followed by HFIP (0.13 mL). The resulting
solution was stirred at r.t. for 18 h. The reaction was quenched
with sat. NaHCO3 and stirred until no more gas evolved. It was
then extracted with CH2Cl2 (3×). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The desired
product (41.5 mg, 74%, o/p = 1:9.2) was isolated as a colorless oil
by flash chromatography using hexanes. IR (ATR, ZnSe): ν =
2957, 2925, 2871, 1686, 1599, 1450, 1281, 812, 754, 689 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.57 (d, 0.11 H, minor, J = 7.7 Hz)
7.44–7.42 (m, 2 H), 7.31–7.24 (m, 4.89 H), 7.14 (d, 2 H, J = 7.8
Hz), 4.04 (dd, 0.11 H, minor, J = 9.1, 5.1 Hz), 3.81 (dd, 0.89 H,
major, J = 8.4, 6.1 Hz), 2.39 (s, 0.32 H), 2.34 (s, 2.68 H), 1.85–1.72
(m, 2 H), 1.59–1.44 (m, 2 H), 0.99–0.93 (m, 3 H). 13C NMR (126
MHz, CDCl3): δ = 139.5, 136.3, 131.8, 130.6 (minor), 129.3,
128.3, 127.8, 127.7 (minor), 127.5, 126.7 (minor), 126.4
(minor), 124.0, 92.1, 83.1, 41.0, 39.4 (minor), 38.0, 34.7 (minor),
29.9 (minor), 21.2, 21.1 (minor), 20.8, 19.4 (minor), 14.0; ESI-
HRMS: m/z calcd for C19H21[M + H]+: 249.1638; found: 249.1634
(27) Compound 21 principally led to side reactions even under reac-
tion conditions where HFIP was omitted, affording 2 in 29%
NMR yield (o/p = 1:7.7). It should also be mentioned that 21 was
also subject to rapid decomposition during column chromatog-
raphy or during evaporation postpurification.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F