Friedel-Crafts alkylation reaction with fluorinated alcohols as hydrogen-bond donors and solvents

Article abstract of DOI:10.1039/c8ra01397g

An effective and clean FC alkylation of indoles and electron-rich arenes with β-nitroalkenes in HFIP was reported. The desired products are formed rapidly in excellent yields under mild conditions without the need for any additional catalysts or reagents. Further, this methodology can be applied to one-pot synthesis of biologically active tryptamine derivatives.

Full text of DOI:10.1039/c8ra01397g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Friedel–Crafts alkylation reaction with fluorinated
alcohols as hydrogen-bond donors and solvents†
Cite this: RSC Adv., 2018, 8, 10314
*
Ren-Jin Tang, Thierry Milcent and Benoit Crousse
Received 13th February 2018
Accepted 5th March 2018
An effective and clean FC alkylation of indoles and electron-rich arenes with b-nitroalkenes in HFIP was
reported. The desired products are formed rapidly in excellent yields under mild conditions without the
need for any additional catalysts or reagents. Further, this methodology can be applied to one-pot
synthesis of biologically active tryptamine derivatives.
DOI: 10.1039/c8ra01397g
rsc.li/rsc-advances
Friedel–Cras (FC) alkylation is one of the most important acidity, and hydrogen-bond donation HBD (or H-bond acidity)
methods for C–C bond formation in organic chemistry.1 The FC are increased, whereas nucleophilicity and hydrogen-bond
alkylation between indoles and b-nitroalkenes is of particular acceptance HBA (or H-bond basicity) are signicantly
interest due to the versatility by which the nitro group can be depleted.6 Furthermore, the HBD was strongly connected to the
transformed into other functional groups.2 Numerous conformation along the C–O bond. Moreover, it was suggested
researchers have developed new conditions and effective cata- that aggregation of HFIP as dimers or trimers could also
lysts in the past decades.3 Among them, H-bond donor (HBD) enhance this property.7 Few FC alkylations have been studied
catalysts have become a focus of an increasing amount of solely in HFIP in last years. In 2010, Qu and co-workers
research.4 Signicant advances have been made in the area of described the intra- and intermolecular FC alkylations of
homogeneous HBD catalysts by using urea or thiourea,4a 2- electron-rich arenes with epoxides promoted by uorinated
aminopyridinium ions4b boronate ureas,4e and silanediol.4d,4f alcohols.8 Recently, FC alkylations of arenes with benzyl halides
However, the strong hydrogen-bonding nature of the HBD in HFIP have been developed by Paquin et al.9 and Khaled et al.
catalysts drives a detrimental self-association or aggregation, (Scheme 1a). More recently, HFIP promoting intramolecular
thus reducing or enhancing catalytic activity.5
and intermolecular Friedel–Cras acylation have been reported
Triuoroethanol (TFE) and hexauoro-2-propanol (HFIP), by Jeffrey Aube and co-workers (Scheme 1b).10
exhibit unique features in organic synthesis. Indeed, the pres-
ence of the strong electron-withdrawing triuoromethyl group
inuences several key parameters: ionizing power, Brønsted
Table 1 Optimization of conditions for the FC alkylationa
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
HFIP
2
4
16
24
6
6
6
0.75
8
16
2
99 (96)c
97
89
45
93
85
24
99
90
DCM/HFIP (3 : 1)
DCM/HFIP (6.7 : 1)
DCM/HFIP (17.2 : 1)
H2O/HFIP (3 : 1)
Toluene/HFIP (3 : 1)
THF/HFIP (3 : 1)
(CF3)3COH (PFTB)
CF3CH2OH (TFE)
EtOH
Scheme 1 Examples of FC alkylation promoted by HFIP.
9
10
Trace
99
11d
HFIP
a
´
Faculty of Pharmacy, UMR 8076, BioCIS, Univ. Paris-Sud, CNRS, Universite
Conditions: 1a (0.6 mmol, 1.2 equiv.) and 2a (0.5 mmol) was dissolved in
solvent (0.25 M) and stirred at r.t. for a specied period unless otherwise
noted. b NMR yields using mesitylene as internal standard. c Isolated yield
in parentheses. d The reaction was performed in the dark.
ˆ
Paris-Saclay, 92290, Chatenay-Malabry, France. E-mail: benoit.crousse@u-psud.fr
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra01397g
10314 | RSC Adv., 2018, 8, 10314–10317
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
In our interest for the use of uorous medium in organic hydrogen bond between HFIP and THF which inhibits the reac-
synthesis,11 and in the pursuit of more efficient catalytic tion6b With other uorinated alcohols, peruoro-2-methylpropan-
systems, we found that uorinated alcohols promoted the FC 2-ol (PFTB) was more efficient than the triuoroethanol (TFE)
alkylation between indoles and b-nitroalkenes.
(entries 10 and 11). In contrast, in EtOH, only traces of product
The FC alkylation between indole (1a) and b-nitroalkene (2a) were observed (entry 12). When performed the reaction in the
was used as model system to optimize the reaction conditions dark had no effect on the yield (entry 13), which suggested HFIP
(Table 1). We rst examined the reaction in pure HFIP solvent and promoted FC alkylation is not a photochemical pathway.12
the reaction mixture was stirred at r.t. for 2 h. The product 3aa was
Under the optimized conditions (Table 1, entry 1), the
isolated in 96% yield (entry 1). When HFIP was used as additive substrate scope and limitation for this FC alkylation between
with other solvents (entries 2–7), good to moderate yields of 3aa various indoles and b-nitroalkenes were explored. As shown by
were obtained. In DCM, the addition of HFIP from 2.0 to 9.5 the results in Table 2, all the aryl-b-nitroalkene analogs tested
equiv. (entries 4–6) decreased product yield and reaction rate. (2a–2q) reacted with indoles (1a–1h) to produce the corre-
Good results were obtained when added 9.5 equiv. HFIP in water sponding products in excellent yields in HFIP, no matter the
and toluene (entries 5 and 6). With THF the reaction was presence of substituents with electron withdrawing or electron
completely unfavourable (entry 7), probably because of the donating groups in various positions. A variety of functional
groups such as methoxy (3ab–3ad), ethoxy (3ae), N,N-dimethy-
lamino (3af), halides (3ah–3aj), nitrile (3ak) and nitro (3al) were
tolerated. The aliphatic nitroalkenes were successfully trans-
Table 2 Scope of FC alkylation between indoles and b-nitroalkenesa
formed into the desired products (3am–3ao) in good yields aer
8 h under the mild conditions. Trans-2-(2-nitrovinyl)-thiophene
Table 3 Scope of FC alkylation between arenes and b-nitroalkenesa
a
a
Conditions: 1a–1h (0.6 mmol, 1.2 equiv.) and 2a–2q (0.5 mmol) was
Conditions: 4a–4i (0.6 mmol, 1.2 equiv.) and 2a (0.5 mmol) was
dissolved in HFIP (0.25 M) and stirred at r.t. for a specied period dissolved in HFIP (0.25 M) and stirred at r.t. for a specied period
b
b
unless otherwise noted. Isolated yields. Solvent: CH2Cl2/HFIP (1 : 1). unless otherwise noted. Isolated yields. Major product is shown.
c
c
Major product is shown.
aza Michael adduct was formed.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 10314–10317 | 10315

View Article Online
RSC Advances
Paper
was also applicable in this reaction providing the product 3ap in
92% yield. Less reactive substrate N-tosyl imine showed good
reactivity, giving 3aq in 86% yield aer 16 h. This study expands
upon our scope of imines with similarly satisfying results. Then
various indoles and pyrrole with aryl b-nitroalkene were tested.
Reactions of functionalized indoles (1b–h) reacted with b-
nitroalkene smoothly in HFIP to lead to the corresponding
products in excellent yields. Treatment of the pyrrole (1i) with b-
nitroalkene afforded a mixture of mono- and bis-substituted
products in 77/23 ratio in 85% yield.
Aer development of FC alkylation of indoles and pyrrole, we
focused on the FC alkylation of arene derivatives. To the best of
our knowledge, there are few reports on the FC alkylation of
arenes with b-nitroalkene in the literature.3f,13
We tested N,N-dimethyl aniline with b-nitroalkene 2a in
HFIP at room temperature. To our delight, the corresponding
product 5a was obtained aer 16 h in 94% yield. Other tertiary
anilines such as N,N-diethyl aniline (4b), N-phenylpyrrolidine
(4c) and N-methyl-N-phenylaniline (4d) were also efficient in
these conditions to afford regioselectively only the para-alky-
lated products. Triphenylamine (4e) showed no reactivity under
the same conditions, probably because of the lower electron
density at the phenyl ring. Interestingly, the reaction also
worked with secondary anilines (4f–4j) in a moderate yield
without the presence of the aza Michael product. In contrast to
the primary aniline (4k), the major product was the aza-Michael
adduct. Besides, the electron-rich arene, 1,3,5-trimethox-
ybenzene (4l) reacted with b-nitroalkene to afford the corre-
sponding alkylated product in good yield (87%) (Table 3).
Then following to these effective and mild conditions, we
investigated the one-pot combination FC alkylation/NO2
Scheme 2 Proposed mechanism for the FC alkylation.
Scheme 3 Gram scale reaction.
reduction. Interestingly, the one-pot synthesis of tryptamines
has not been reported previously. In preliminary experiments
aer completion of the rst step, stoichiometric amounts of
zinc powder or granular were added. Unfortunately, despite the
slight acidity of HFIP, the reduction of the nitro group was not
observed at room temperature and at reux. On the other hand,
when HCl (2 N) was added, the corresponding tryptamine was
formed successfully aer 2 h in reux. Thus, different reactions
have been performed and reported in Table 4. Indoles and
benzene, thiophene and cyclohexane b-nitroalkenes were
tolerated (6a–d). Additionally, reaction with electron-rich arenes
such as N,N-dimethylaniline, 1,3,5-trimethoxybenzene succeed
to lead to the corresponding products 6e–f in good yields.
Based on the literature6e,10,14 and our studies,11a,15 a plausible
H-bond activation mechanism was proposed in Scheme 2. First
HFIP activated the nitro group through hydrogen bond and
following by the nucleophilic attack of the indole. The gener-
ated intermediate 7 underwent to the subsequent hydrogen
transfer to afford the expected product 3aa.
Table 4 One-pot FC alkylation and reduction of nitro groupa
To further explore the synthetic utility of this system, a gram-
scale reaction was also evaluated (Scheme 3). The FC alkylation
of 1a (12 mmol, 1.40 g) with 2a (10.0 mmol, 1.49 g) was per-
formed in 20 mL HFIP for 2 h. The desired product 3aa was
obtained in 92% yield (2.45 g) and 18 mL of HFIP was recovered
aer distillation directly from the reaction.
Conclusions
a
Conditions: 0.6 mmol of indoles or arenes (1.2 equiv.), 0.5 mmol of b-
nitroalkenes in 2 mL HFIP for the rst step 2.0 mmol of Zn (4.0 equiv.)
and 2.5 mL 2 N HCl (10 equiv.) were added for the second step. Isolated
yields.
In conclusion, we have developed an effective and clean FC
alkylation between b-nitroalkenes and arenes in HFIP. The
10316 | RSC Adv., 2018, 8, 10314–10317
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
desired products formed smoothly in short times at ambient
temperature without any additional catalysts or reagents.
Further, this methodology can be applied to one-pot synthesis
of biologically active tryptamine derivatives. Besides, because of
4 (a) A. Ricci, R. P. Herrera and G. Dessole, Synlett, 2004, 2004,
2374; (b) N. Takenaka, R. S. Sarangthem and S. K. Seerla, org.
Lett., 2007, 9, 2819; (c) J. Cai, P. Wu and Y. Wan, Synlett, 2008,
2008, 1193; (d) A. G. Shafer, J. M. Wieting and A. E. Mattson,
Org. Lett., 2011, 13, 5228; (e) S. S. So, J. A. Burkett and
A. E. Mattson, Org. Lett., 2011, 13, 716; (f) N. T. Tran,
S. O. Wilson and A. K. Franz, org. Lett., 2012, 14, 186.
5 (a) M. C. Etter, Z. Urbakzyk-Lipkowska, S. M. Zia-Ebrahimi
and T. W. Panunto, J. Am. Chem. Soc., 1990, 112, 8415; (b)
C. M. McGuirk, C. L. Stern and C. A. Mirkin, J. Am. Chem.
Soc., 2014, 136, 4689.
ꢀ
low boiling point (b.p. ¼ 59 C) and low viscosity, HFIP can be
easy recovered and reused.
Experimental section
A general experimental procedure is described as follows:
To a stirred solution of indole 1a (70.2 mg, 0.6 mmol, 1.2
equiv.) in HFIP (2 mL) was added b-nitroalkene 2a (74.5 mg,
0.5 mmol, 1.0 equiv.) under air. The reaction mixture was stir-
red at room temperature for 2 h. Aer, the reaction mixture was
evaporated under reduced pressure and the crude product was
puried by column chromatography on silica gel using
cyclohexane/ethyl acetate (10/1) as the eluent afforded a white
solid 3aa (128 mg, 96% yield).
6 (a) C. Reichardt, Chem. Rev., 1994, 94, 231; (b) A. Berkessel,
J. A. Adrio, D. H. ttenhain and J. M. Neudo, J. Am. Chem.
¨
Soc., 2006, 128, 8421; (c) A. Borner, I. Shuklov and
N. Dubrovina, Synthesis, 2007, 2007, 2925; (d) C. Laurence,
J. Legros, P. Nicolet, D. Vuluga, A. Chantzis and
D. Jacquemin, J. Phys. Chem. B, 2014, 118, 7594; (e)
S. Gennen, M. Alves, R. Mereau, T. Tassaing, B. Gilbert,
C. Detrembleur, C. Jerome and B. Grignard, ChemSusChem,
2015, 8, 1845; (f) S. Khaksar, J. Fluorine Chem., 2015, 172,
51; (g) C. Laurence, J. Legros, A. Chantzis, A. Planchat and
D. Jacquemin, J. Phys. Chem. B, 2015, 119, 3174.
Conflicts of interest
The authors declare no competing nancial interest.
7 (a) A. Berkessel, J. A. Adrio, D. Huttenhain and
J. M. Neudor, J. Am. Chem. Soc., 2006, 128, 8421; (b)
J. Mars, M. Mezger, A. Wiebe, S. R. Waldvogel and
B. Kirchner, ACS Catal., 2017, 7, 1846.
8 G. X. Li and J. Qu, Chem. Commun., 2010, 46, 2653.
9 (a) P. A. Champagne, Y. Benhassine, J. Desroches and
J. F. Paquin, Angew Chem Int Ed Engl, 2014, 53, 13835; (b)
N. Weisner and M. G. Khaledi, Green Chem., 2016, 18, 681.
10 (a) H. F. Motiwala, R. H. Vekariya and J. Aube, Org. Lett.,
2015, 17, 5484; (b) R. H. Vekariya and J. Aube, Org. Lett.,
2016, 18, 3534.
Acknowledgements
Central Glass Co. Ltd. is gratefully acknowledged for kindly
providing HFIP. R.-J. T. thanks the China Scholarship Council
for a doctoral fellowship.
References
1 (a) C. Friedel and J. M. Cras, J. Chem. Soc., 1877, 32, 725; (b)
M. Bandini, A. Melloni and A. Umani-Ronchi, Angew. Chem.,
Int. Ed., 2004, 43, 550; (c) T. B. Poulsen and K. A. Jørgensen,
Chem. Rev., 2008, 108, 2903; (d) S.-L. You, Q. Cai and M. Zeng,
Chem. Soc. Rev., 2009, 38, 2190; (e) V. Terrasson, R. Marcia de
Figueiredo and J. M. Campagne, Eur. J. Org. Chem., 2010,
2635; (f) M. Rueping and B. J. Nachtsheim, Beilstein J. Org.
Chem., 2010, 6, 6; (g) R. R. Naredla and D. A. Klumpp,
Chem. Rev., 2013, 113, 6905.
11 (a) K. De, J. Legros, B. Crousse and D. Bonnet-Delpon, J. Org.
Chem., 2009, 74, 6260; (b) C. Venkateswarlu, P. V. Balaji,
`
K. De, B. Crousse, B. Figadere and J. Legros, J. Fluorine
Chem., 2013, 152, 94; (c) A. Fedotova, B. Crousse,
I. Chataigner, J. Maddaluno, A. Y. Rulev and J. Legros, J.
Org. Chem., 2015, 80, 10375.
12 S. Yadav, M. Srivastava, P. Rai, B. P. Tripathi, A. Mishra,
J. Singh and J. Singh, New J. Chem., 2016, 40, 9694.
13 (a) N. Takenaka, R. S. Sarangthem and S. K. Seerla, org. lett.,
2007, 9, 2819; (b) A. Z. Halimehjani, M. V. Farvardin,
H. P. Zanussi, M. A. Ranjbari and M. Fattahi, J. Mol. Catal.
A: Chem., 2014, 381, 21; (c) X.-W. Dong, T. Liu, Y.-Z. Hu,
X.-Y. Liu and C.-M. Che, Chem. Commun., 2013, 49, 7681.
14 M. O. Ratnikov, V. V. Tumanov and W. A. Smit, Angew.
Chem., Int. Ed., 2008, 47, 9739.
15 (a) K. De, J. Legros, B. Crousse and D. Bonnet-Delpon,
Tetrahedron, 2008, 64, 10497; (b) A. Di Salvo, M. David,
B. Crousse and D. Bonnet-Delpon, Adv. Synth. Catal., 2006,
348, 118; (c) R.-J. Tang, T. Milcent and B. Crousse, Eur. J.
Org. Chem., 2017, 4753; (d) R.-J. Tang, T. Milcent and
B. Crousse, J. Org. Chem., 2018, 83, 930.
2 S. Lancianesi, A. Palmieri and M. Petrini, Chem. Rev., 2014,
114, 7108.
3 (a) I. Komoto and S. Kobayashi, Org. Lett., 2002, 4, 1115; (b)
Z.-P. Zhan, R.-F. Yang and K. Lang, Tetrahedron Lett., 2005,
46, 3859; (c) H. Firouzabadi, N. Iranpoor and F. Nowrouzi,
Chem. Commun., 2005, 789; (d) R. Ballini, R. R. Clemente,
A. Palmieri and M. Petrini, Adv. Synth. Catal., 2006, 348,
191; (e) L.-T. An, J.-P. Zou, L.-L. Zhang and Y. Zhang,
Tetrahedron Lett., 2007, 48, 4297; (f) N. T. Tran,
S. O. Wilson and A. K. Franz, org. lett., 2012, 14, 186; (g)
P. M. Habib, V. Kavala, C.-W. Kuo and C.-F. Yao,
Tetrahedron Lett., 2008, 49, 7005; (h) L. Liang, Q. Liu,
J. Zhang, F. Wang and Y. Yuan, Res. Chem. Intermed., 2012,
39, 1957; (i) M. De Rosa and A. Soriente, Tetrahedron, 2010,
66, 2981.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 10314–10317 | 10317