Tropylium-promoted Ritter reactions

Article abstract of DOI:10.1039/d1cc02947a

The Ritter reaction used to be one of the most powerful synthetic tools to functionalize alcohols and nitriles, providing valuableN-alkyl amide products. However, this reaction has not been frequently used in modern organic synthesis due to its employment of strongly acidic and harsh reaction conditions, which often lead to complicated side reactions. Herein, we report the development of a new method using salts of the tropylium ion to promote the Ritter reaction. This method works well on a range of alcohol and nitrile substrates, giving the corresponding products in good to excellent yields. This reaction protocol is amenable to microwave and continuous flow reactors, offering an attractive opportunity for further applications in organic synthesis.

Full text of DOI:10.1039/d1cc02947a

ChemComm
View Article Online
View Journal
COMMUNICATION
Tropylium-promoted Ritter reactions†
Son H. Doan, Mohanad A. Hussein and Thanh Vinh Nguyen
*
Cite this: DOI: 10.1039/d1cc02947a
Received 4th June 2021,
Accepted 9th August 2021
DOI: 10.1039/d1cc02947a
rsc.li/chemcomm
The Ritter reaction used to be one of the most powerful synthetic promote the metal-free acetalization6 and retro-Claisen
tools to functionalize alcohols and nitriles, providing valuable reactions7 of carbonyl compounds as well as the prenylation
N-alkyl amide products. However, this reaction has not been fre- reaction of phenols.8 Tropylium salts are environmentally
quently used in modern organic synthesis due to its employment of benign, mildly acidic and soluble in organic solvents,4,9 allow-
strongly acidic and harsh reaction conditions, which often lead to ing the reactions that they catalyze to be highly amenable to
complicated side reactions. Herein, we report the development of a modern synthetic techniques, such as microwave irradiation or
new method using salts of the tropylium ion to promote the Ritter continuous flow methods.6–8
reaction. This method works well on a range of alcohol and nitrile
We started our investigation by looking at the catalytic
substrates, giving the corresponding products in good to excellent activity of a range of Brønsted and Lewis acid catalysts in the
yields. This reaction protocol is amenable to microwave and con- reaction between 1-phenylethanol (2a) and acetonitrile (3a).
tinuous flow reactors, offering an attractive opportunity for further Tropylium tetrafluoroborate (1) gave superior reaction out-
applications in organic synthesis.
comes to tritylium salts,10 another family of Lewis acidic
organic carbocations, and the super strong triflic Brønsted
Most industrial synthetic processes developed more than 25 acid11 or other commonly used acid catalysts such as TFA,
years ago are robust methods that work efficiently with broad pTSA, HBF4, HCl, AgBF4 and AlCl3 (as listed in entry 12,
reaction scopes.1 Up to that point, however, waste minimiza- Table 1). We subsequently proceeded further to optimize the
tion and environmental footprints were only vague or unknown reaction conditions including the reaction time, tropylium
concepts.1 Therefore, many of these processes need to be catalyst loading, temperature and heating method, as well as
re-optimized, improved or replaced completely to meet the the stoichiometry of the water additive.12 The optimal condi-
current standards of production sustainability. Among these tions are outlined in Table 1, using 10 mol% 1 and two
traditional methods, the Ritter reaction used to be considered equivalents of water at 150 1C under microwave (MW) irradia-
to be the most powerful tool to combine alcohols and nitriles, tion for one hour.
readily available synthetic precursors, to access valuable N-alkyl
Lower catalyst loadings or shorter reaction times were
amide products.2 However, this reaction has not been fre- detrimental to the reaction efficiency (entries 1–4, Table 1).
quently used in modern organic synthesis due to its employ- Conventional heating or lower reaction temperatures led to
ment of strongly acidic and harsh reaction conditions, which decreases in the product yield (entries 5–9). The reactions with
often lead to complicated side reactions.2b,3 Herein, we report one equivalent of water or without the water additive still
the development of a new method using salts of the tropylium worked in high yields, however they were slightly less effective
ion to promote the Ritter reaction. This method works well with than the optimal conditions (entries 9 and 10). Finally, we did
a range of alcohol and nitrile substrates, giving the corres- further control experiments with previously screened acid
ponding products in good to excellent yields. Our inspiration to catalysts under otherwise optimal conditions, and they indeed
use the tropylium ion4 as a catalyst for the Ritter reaction came led to lower product yields and more complicated reaction
from our earlier works in this area,5 where we used it to mixtures, especially with TfOH, HBF4 and AgBF4, than our
tropylium-promoted conditions (entry 12, Table 1). This can
be attributed to the mild acidity of the tropylium ion, which
reduced the issues of other side competing processes such as
School of Chemistry, University of New South Wales, Sydney, Australia.
E-mail: t.v.nguyen@unsw.edu.au
elimination, oligomerization or polymerization reactions, in
comparison to the other acid catalysts.2b
† Electronic supplementary information (ESI) available: Experimental details,
analytical data and NMR spectra are provided. See DOI: 10.1039/d1cc02947a
This journal is © The Royal Society of Chemistry 2021
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Optimization of the tropylium-catalyzed reaction between 2a
and 3aa
Entry
Variation from the optimal conditions
Yield of 4ab (%)
1
2
No catalyst
30 min
Trace
68
3
4
5
6
7
8
1 mol% catalyst 1
5 mol% catalyst 1a
100 1C (conventional heating)
120 1C (conventional heating)
150 1C (conventional heating)
100 1C (MW)
78
86
40
63
89
49
9
120 1C (MW)
No water
1 equiv. of water
Variation of catalyst (10 mol%)
71
82
89
10
11
12c
See below
a
Reaction conditions: 2 mmol 2a in MeCN, 3a (5 mL) and catalyst 1 in a
pressurized reaction vial at the indicated temperature for the indicated
c
time.12 b Yield of the isolated 4a. All catalysts are anhydrous.
We then applied these optimal conditions to carry out
tropylium-promoted reactions with a range of alcohol and
nitrile substrates. Primary and tertiary alcohols are not good
substrates for the Ritter reaction2b so our work mainly
focused on secondary alcohols. Our synthetic protocol
worked smoothly for the combination of eight different
alcohols and 13 different nitriles to give a diverse library of
Scheme 1 Substrate scope of the tropylium-promoted Ritter reaction.
amide products (4a–z and 4aa–cc, Scheme 1, top) in good to yield. Interestingly, the reaction with malononitrile only
excellent yields. A good range of functional groups were selectively produced the monoamide 4e as the major pro-
tolerated in this reaction protocol, including halide (4h and duct, even if an excess amount of alcohol was used.
4x), carbonyl (4i, 4o and 4y), C–C multiple bond (4j) and
We also expanded the applicability of our method by inves-
acetal groups (4dd and ee). However, highly labile groups, tigating the installation of fluorine-bearing amide functional
such as epoxide, were not compatible with the reaction groups via tropylium-promoted Ritter reactions. Fluorine-
conditions. Nitrile substrates containing N-heterocyclic sys- containing moieties are important features of many valuable
tems, such as pyridine or indole rings, also survived our synthetic precursors and biologically-relevant organic
reaction conditions, giving the corresponding products 4k structures.14 Gratifyingly, we were able to access a family of
and 4l in moderate yields. The lower efficiency with these N- these products (6a–e, Scheme 1, bottom) in good to high yields
heterocyclic systems can be rationalized by the fact that the using fluoroacetonitrile 5 as the Ritter reaction nucleophile. To
tropylium ion is known to coordinate well with Lewis-basic facilitate the stirring of the reaction mixture without using an
nitrogen centres,6,9e,13 hence rendering the catalysts less excess amount of the less readily available compound 5, a non-
effective. Deuterated acetonitrile could be used to afford reactive co-solvent such as 1,2-dichloroethane (DCE) was
the CD3-containing amide 4aD in an almost quantitative required for the reaction (Scheme 1, bottom).
Chem. Commun.
This journal is © The Royal Society of Chemistry 2021

View Article Online
ChemComm
Communication
Scheme 3 Tropylium-promoted Ritter reactions in flow.
facilitate the Ritter reaction on 12. Products 13a and b were
obtained in high yields from this procedure, which is the
first report of a carbocation-catalyzed Piancatelli–Ritter
reaction sequence.16 A full investigation into the synthetic
application of this reaction sequence to convert biomass-
Scheme 2 Further applications of the tropylium-promoted Ritter
reaction.
We subsequently explored the scope of the intramolecular derived compounds into valuable organic architectures is
Ritter reaction, using similar reaction setups, for the installa- currently on-going in our laboratory and will be reported in
tion of the fluorine-containing amide group. Thus, a selected due course.
number of g-cyano alcohols 7 were subjected to microwave
In another demonstration of the applicability of our Ritter
irradiation in the presence of 10 mol% tropylium catalyst 1 and reaction in organic synthesis, we carried out a range of large-
one equivalent of the water additive. These intramolecular scale syntheses of selected amides in a continuous flow setup
Ritter amination reactions worked smoothly to give a range of (Scheme 3). Chemistry in flow is highly attractive to organic
lactams and fused bicyclic lactams in good to high yields chemists due to its practicality and environmentally benign
(8a–f, Scheme 2, top). On the other hand, when an amino nature.17 Our tropylium catalytic system is considered to be
alcohol such as 9 was used as the substrate, cyclization reac- more promising to facilitate chemical transformations in
tions occurred to produce quinazoline derivatives (10a and b, flow6–8 than the other potential acid catalysts for this Ritter
Scheme 2, middle). Presumably, these chemical transforma- reaction (cf. entry 12, Table 1) in that (i) the catalytic reaction
tions proceeded via the normal Ritter reaction followed by a system is homogeneous, which simplifies the requirements for
cyclizing condensation reaction between the existing amino the flow setup, (ii) the tropylium catalyst can be easily removed
group and the newly generated carbonyl moiety to afford from the reaction mixture and products with simple purifica-
quinazoline products.
tion techniques such as liquid–liquid extraction and filtration
From 1-phenyl furfuryl alcohol (11), which was produced and (iii) tropylium is only mildly acidic, making it highly
in one step from the Grignard reaction of biomass-derived compatible with the reaction pump, tubing and reactor. The
furfural with phenylmagnesium bromide, we could apply a last point is particularly useful for economical flow setups, as
modified procedure of our tropylium-promoted Ritter reac- strongly acid-resistant flow equipment is normally highly
tion to access the 4-amido cyclopentenone products 13a and priced. Thus, we were able to use a simple one pump one tube
b (Scheme 2, bottom). The reaction went through a two-step reactor system to implement the tropylium-promoted Ritter
one-pot process. Firstly, furfuryl alcohol 11 was treated with reaction to produce eight amides on 20–100 mmol scales with
water under microwave irradiation for two minutes, which only 1 mol% tropylium catalyst loading (Scheme 3). The reac-
converted it to 4-hydroxycyclopentenone 12 via a Piancatelli- tion conditions mimicked the microwave irradiated batch
type rearrangement.15 The tropylium catalyst 1 and nitrile 3 setups, giving our target products in comparable or even
were then added to the reaction vessel and the whole mixture higher yields. All of these syntheses produced technically pure
underwent further microwave irradiation for one hour to (490% pure) solutions of amides after a simple liquid–liquid
This journal is © The Royal Society of Chemistry 2021
Chem. Commun.

View Article Online
Communication
ChemComm
support. SHD thanks UNSW for sponsoring his UIPA PhD
scholarship.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 (a) R. A. Sheldon, Green Chem., 2007, 9, 1273–1283; (b) R. A. Sheldon,
Chem. Commun., 2008, 3352–3365; (c) R. A. Sheldon, Green Chem.,
2016, 18, 3180–3183; (d) H. C. Erythropel, J. B. Zimmerman, T. M. de
Winter, L. Petitjean, F. Melnikov, C. H. Lam, A. W. Lounsbury,
´
K. E. Mellor, N. Z. Jankovic, Q. Tu, L. N. Pincus, M. M. Falinski,
W. Shi, P. Coish, D. L. Plata and P. T. Anastas, Green Chem., 2018, 20,
1929–1961.
2 (a) J. J. Ritter and J. Kalish, Org. Synth., 1964, 44, 44; (b) G. Mohammadi
Ziarani, F. Soltani Hasankiadeh and F. Mohajer, ChemistrySelect, 2020,
5, 14349–14379.
3 (a) K. Kiyokawa, T. Watanabe, L. Fra, T. Kojima and S. Minakata, J. Org.
´
Chem., 2017, 82, 11711–11720; (b) T. Duhamel, M. D. Martınez,
˜
I. K. Sideri and K. Muniz, ACS Catal., 2019, 9, 7741–7745; (c) C. Liu
and F. Yang, Eur. J. Org. Chem., 2019, 6867–6870; (d) M. Ueno,
R. Kusaka, S. D. Ohmura and N. Miyoshi, Eur. J. Org. Chem., 2019,
1796–1800; (e) S. M. Sutar, H. M. Savanur, R. G. Kalkhambkar,
G. L. Borosky, G. Aridoss and K. K. Laali, Tetrahedron Lett., 2020,
61, 152553.
Scheme 4 Proposed mechanism for the tropylium-promoted Ritter
reaction.
4 D. J. M. Lyons, R. D. Crocker, M. Blu¨mel and T. V. Nguyen, Angew.
Chem., Int. Ed., 2017, 56, 1466–1484.
5 (a) G. Oss, J. Ho and V. Nguyen Thanh, Eur. J. Org. Chem., 2018,
3974–3981; (b) U. P. N. Tran, G. Oss, D. P. Pace, J. Ho and T. V. Nguyen,
Chem. Sci., 2018, 9, 5145–5151; (c) C. Empel, T. V. Nguyen and
R. M. Koenigs, Org. Lett., 2021, 23, 548–553.
6 D. J. M. Lyons, R. D. Crocker, D. Enders and T. V. Nguyen, Green
Chem., 2017, 3993–3996.
7 M. A. Hussein, V. T. Huynh, R. Hommelsheim, R. M. Koenigs and
T. V. Nguyen, Chem. Commun., 2018, 54, 12970–12973.
8 K. Omoregbee, K. N. H. Luc, A. H. Dinh and T. V. Nguyen, J. Flow
Chem., 2020, 10, 161–166.
9 (a) T. V. Nguyen and A. Bekensir, Org. Lett., 2014, 16, 1720–1723;
(b) T. V. Nguyen and M. Hall, Tetrahedron Lett., 2014, 55, 6895–6898;
(c) T. V. Nguyen and D. J. M. Lyons, Chem. Commun., 2015, 51,
3131–3134; (d) D. Lyons, R. Crocker and V. Nguyen Thanh, Chem. –
Eur. J., 2018, 24, 10959–10965; (e) G. Oss, S. D. de Vos, K. N. H. Luc,
J. B. Harper and T. V. Nguyen, J. Org. Chem., 2018, 83, 1000–1010;
( f ) M. A. Hussein, U. P. N. Tran, V. T. Huynh, J. Ho, M. Bhadbhade,
H. Mayr and T. V. Nguyen, Angew. Chem., Int. Ed., 2020, 59,
1455–1459.
extraction step. Further experimental details for the Ritter
reaction in continuous flow can be found in page S7 of
the ESI.†12
While elucidating the mechanistic details of this reaction
was not the main focus of this work, based on our previous
work in this area,5–8 we postulated that tropylium ion acts as a
Lewis acid catalyst in this reaction to promote the nucleophilic
attack of nitrile 3 on the alcohol 2. The tropylium ion 1 is
capable of coordinating with the oxygen centre of the alcohol 1,
rendering the adjacent carbon electron-deficient to allow for
the nucleophilic substitution reaction with the nitrogen centre
of the nitrile substrate (Scheme 4) via the SN1 or SN2 pathways.
A subsequent hydrolysis reaction converts the iminium inter-
mediate 15 into the amide product 4. It is also possible that the
tropylium ion can coordinate with the alcohol hydroxyl group
´
or water in the reaction medium and enhance their Brønsted 10 V. R. Naidu, S. Ni and J. Franzen, ChemCatChem, 2015, 7, 1896–1905.
11 M. A. Hussein, A. H. Dinh, V. T. Huynh and T. V. Nguyen, Chem.
Commun., 2020, 56, 8691–8694.
12 See the ESI† for further details.
acidity (18) such that they can in turn catalyze the reaction in a
hidden Brønsted acid pathway. However, given the low effi-
ciency of the control study with HBF4 and other Brønsted acid 13 J. M. Allen and T. H. Lambert, J. Am. Chem. Soc., 2011, 133, 1260–1262.
14 (a) D. O’Hagan, Chem. Soc. Rev., 2008, 37, 308–319; (b) S. Purser,
catalysts (entry 12, Table 1), we believe that such a pathway,
although it cannot be ruled out, might not be the only activa-
P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008,
37, 320–330; (c) L. Yang, W.-X. Fan, E. Lin, D.-H. Tan, Q. Li and
tion mechanism to promote this reaction.
In conclusion, we have developed a new method using
tropylium salts to promote the Ritter reactions of a range of
H. Wang, Chem. Commun., 2018, 54, 5907–5910; (d) G. Tarantino
and C. Hammond, Green Chem., 2020, 22, 5195–5209.
15 G. Piancatelli, A. Scettri and S. Barbadoro, Tetrahedron Lett., 1976,
17, 3555–3558.
alcohol and nitrile substrates, giving the corresponding amide 16 (a) G. K. Veits, D. R. Wenz and J. Read de Alaniz, Angew. Chem., Int.
Ed., 2010, 49, 9484–9487; (b) C. Piutti and F. Quartieri, Molecules,
2013, 18, 12290–12312; (c) D. Lebœuf, L. Marin, B. Michelet,
A. Perez-Luna, R. Guillot, E. Schulz and V. Gandon, Chem. – Eur.
products in good to excellent yields. This reaction protocol is
amenable to microwave and continuous flow reaction condi-
tions, paving the way for its future applications in organic
synthesis.
The authors acknowledge the Australian Research Council
(grants FT180100260 and DP200100063) for the financial
J., 2016, 22, 16165–16171.
17 (a) L. Rogers and K. F. Jensen, Green Chem., 2019, 21, 3481–3498;
(b) C. De Risi, O. Bortolini, A. Brandolese, G. Di Carmine, D. Ragno
and A. Massi, React. Chem. Eng., 2020, 5, 1017–1052; (c) A. I. Alfano,
M. Brindisi and H. Lange, Green Chem., 2021, 23, 2233–2292.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2021