Ru(ii)-catalyzed allenylation and sequential annulation of: N -tosylbenzamides with propargyl alcohols

Article abstract of DOI:10.1039/d1cc01768c

We hereby report Ru(ii)-catalyzed C(sp2)-H allenylation of N-tosylbenzamides to access multi-substituted allenylamides. Furthermore, the allenylamides were converted to the corresponding isoquinolone derivatives via base mediated annulation. The current protocol features low catalyst loading, mild reaction conditions, high functional group compatibility and desired scalability. The unique functionality of the afforded allenes allowed further transformations to expand the practicality of the protocol. This journal is

Full text of DOI:10.1039/d1cc01768c

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Ru(II)-catalyzed allenylation and sequential
annulation of N-tosylbenzamides with propargyl
alcohols†
Cite this: Chem. Commun., 2021,
57, 6280
Received 2nd April 2021,
Accepted 25th May 2021
Shreemoyee Kumar,
Akshay M. Nair
and Chandra M. R. Volla
*
DOI: 10.1039/d1cc01768c
rsc.li/chemcomm
We hereby report Ru(II)-catalyzed C(sp2)–H allenylation of N-tosylben-
On the other hand, propargyl alcohols owing to their feed-
zamides to access multi-substituted allenylamides. Furthermore, the stock availability have received significant attention as coupling
allenylamides were converted to the corresponding isoquinolone deri- partners in C–H functionalization reactions.7 The presence of
vatives via base mediated annulation. The current protocol features low three carbon centers, which react differently depending upon
catalyst loading, mild reaction conditions, high functional group com- the nature of the metal and the directing group, give rise to
patibility and desired scalability. The unique functionality of the afforded their multifarious reactivity leading to 1,1-annulations, 1,
allenes allowed further transformations to expand the practicality of the 2-annulations, 1,3-annulations or allenylations (Scheme 1a).
protocol.
Intriguingly, C–H allenylation with propargyl alcohols has
emerged as a valuable tool to access functionalized allenes,
The past decade has witnessed a revolution in the field which have huge synthetic potential.8,9 At the same time, the
of transition-metal catalysed C–H activation, offering new dis- superior reactivity of allenes adds a challenge in the presence of
connections in retrosynthetic analysis for accessing active
pharmaceutical ingredients, natural products and functional
materials.1 The selective conversion of unreactive C–H bonds to
C–C and C–X bonds has become an efficient alternative to
traditional cross coupling reactions. In general, a vast majority
of these C–H functionalizations rely on the use of rare and
expensive Pd(II),2 Rh(III)3 and Ir(III)4 complexes which often
hamper their practicality. Subsequently, the desire to explore
the catalytic potential of readily available inexpensive transition
metals has led to the emergence of ruthenium complexes as
viable catalysts for C–H functionalizations.5 In particular, the
emanation of [RuCl2(p-cymene)]2 as an inexpensive alternative
to Ir(III) and Rh(III) complexes has contributed enormously
towards the development of economical and resourceful cata-
lytic systems. The ability of this catalyst to chelate with weakly
coordinating directing groups has translated to novel reaction
outcomes.6 Additionally, facile formation of a cyclometalated
ruthenacycle via C–H activation along with its superior air and
moisture stability has translated to the near versatility of this
catalyst.
Department of Chemistry, Indian Institute of Technology Bombay, Powai,
Mumbai-400076, India. E-mail: Chandra.volla@chem.iitb.ac.in
† Electronic supplementary information (ESI) available: Synthetic procedues and
full characterization details of all the products (3a–3ag, 4a–4j, 5–7), spectroscopic
data, NMR spectra, kinetic studies etc. CCDC 2072388. For ESI and crystal-
Scheme 1 Overview of the work.
lographic data in CIF or other electronic format see DOI: 10.1039/d1cc01768c
6280 | Chem. Commun., 2021, 57, 6280–6283
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Table 1 Screening the directing groups and reaction optimization
nucleophilic directing groups to culminate the reaction at the
allenylation stage, avoiding the subsequent nucleophilic
addition.10 In this regard, Ma, in a landmark report, documen-
ted a Rh(III)-catalyzed C–H allenylation of amides using
propargyl alcohols employing mild reaction conditions
(Scheme 1b-left)9a averting the subsequent 1,1 annulation
(Scheme 1b-right).10a
A vast majority of C–H activation reactions with propargyl
alcohols rely on the use of expensive Rh catalysts,7a while in
comparison only a handful of reports exist based on Ru
complexes.11 Glorius in an elegant work documented the
synthesis of iso-chromanones via cascade C–H activation, alle-
nylation and annulation of benzoic acids under Ru(II) catalysis
(Scheme 1c-right).12 Independently, Ma reported Ru(II)-
catalyzed ortho-C–H activation, and allenylation of benzoic
acids with propargylic alcohols to furnish allenoic acids, using
mild conditions to avert the subsequent annulation as reported
by Glorius (Scheme 1c-left).13 Only a single report exists on C–H
allenylation of benzamides under Ru catalysis by Ackermann
et al. employing silyl allenes as coupling partners.6e Consider-
ing our interest in Ru(II)-catalyzed C–H activations,14 we envi-
Entry Variation from standard conditions
Yieldsa (%)
1
2
3
4
5
6
7
8
9
NaOPiv as base
None
Na2CO3, NaHCO3, KOAc or CsOAc as base
Without Ru(II) catalyst
Without KPF6
45 (41)
82 (81)
o67
Traces
Traces
Toulene, MeCN, DCM or 1,4-dioxane as solvent o62
Reaction at 60 1C
Reaction at 90 1C
30 mol% of NaOAc
63
70
39
sioned developing
a Ru(II)-catalyzed C–H allenylation of
benzamide derivatives using propargyl alcohols. Additionally,
the obtained allenylamides could be subjected to subsequent
annulation to access valuable nitrogen containing heterocycles.
Consequently, we hereby report a [RuCl2(p-cymene)]2 catalyzed
a
NMR yields calculated using 1,3,5-trimethoxybenzene as internal
standard. Isolated yields in parentheses.
ortho-C–H allenylation and sequential K2CO3 mediated 1, product (entries 4 and 5). Other solvents like toluene, MeCN,
2-annulation of N-tosylbenzamides with propargyl alcohols to DCM or 1,4-dioxane instead of DCE were found to be delete-
access diversely substituted allenylamides and isoquinolones rious (entry 6). Decreasing or increasing the temperature of the
(Scheme 1d).
reaction leads to diminished yields of the allenylated product
The nature of the protecting group on the amide group is 3a (entries 7 and 8). The use of a sub-stoichiometric quantity of
quite detrimental for coordination with the metal and the the base also leads to diminished yields (entry 9).
subsequent cyclometalation. Hence, we initiated our studies
With the optimized conditions in hand, we proceeded to
by exploring a suitable protecting group for deliberating a probe the substrate scope of the allenylation protocol. The
Ru(II)-catalyzed C–H allenylation (Table 1a). No product for- reactivity with an array of substituted N-tosylbenzamides 1
mation was observed when N-methoxybenzamide was reacted was studied with alkyne 2a (Table 2). Delectably, electron-
with propargyl alcohol 2a using [RuCl2(p-cymene)]2 (5 mol%) in donating (Me, OMe, OBn) as well as electron-withdrawing
DCE. Further studies with different protecting groups like (CF3, F, Cl and Ph) groups were well tolerated at the para
–OPiv, –Ac and –Me also failed to deliver the envisioned position of the benzamide, furnishing the corresponding
allenylation. At this juncture, we postulated that a protecting allenes 3b–3h in good yields. 2,4-Dimethylbenzamide afforded
group that could make the amide more acidic would facilitate the corresponding allene 3i in 72% yield. Substitutions at the
the process of carboruthenation. Furthermore, the low nucleo- ortho-position of the benzamide furnished the products 3j–3o
philicity of the amide nitrogen would impede the subsequent in good yields of up to 79%. The structure of C-2 allenylated
undesired nucleophilic addition onto the allene. Consequently, benzamide was confirmed by performing single crystal X-ray
we screened the reactivity of N-tosylbenzamide and were diffraction studies of 3l. While 2-thiophene carboxamide
delighted to observe the formation of allenylamide 3a in 41% yielded the product 3p in 32% yield, 2-pyridyl carboxamide
yield. Motivated by these initial results, we then proceeded to failed to provide the corresponding product 3q probably due to
optimize the reaction. After the rigorous screening of various the chelation with the metal catalyst and rendering the catalytic
reaction parameters, we arrived at the following optimized complex inactive. Next, the scope of various substituted pro-
conditions (Table 1b): 1a (1 equiv.) with 2a (1 equiv.) in the pargyl alcohols was probed with benzamide 1a. Diverse sub-
presence of 5 mol% [RuCl2(p-cymene)]2, 30 mol% KPF6 and stitutions on the phenyl ring of the propargylic alcohol were
1 equiv. NaOAc in DCE at 70 1C for 10 h delivered 82% of the well tolerated to afford the corresponding allenes 3r–3w in good
allene 3a (entry 2). Other bases like Na2CO3, NaHCO3, KOAc yields (61–82%). Naphthyl and 2-thiophenyl substituted pro-
and CsOAc were found to be inferior (entry 3). The reaction pargyl alcohols were also found to be suitable for providing 3x
does not proceed in the absence of either the catalyst or the and 3y in 75% and 58% yields, respectively. Diversification of
additive KPF6 indicating their key role in the formation of the the aliphatic groups on the carbon 3 of the allene was
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Table 2 Scope of C-2 allenylationa
Table 3 Base mediated annulationa
a
Reaction conditions: 3 (0.15 mmol), K2CO3 (0.075 mmol), toluene
(0.75 mL), 50 1C for 12 h.
having substituents at various positions were obtained in moderate
to good yields 64–75%.
Subsequently, we carried out further functionalizations to
probe the synthetic utility of C-2 allenylated benzamide 3a
(Scheme 2). Allene 3a on catalytic hydrogenation delivered the
alkane derivative 5 in 52%. Allenoic acid 6 was obtained in 65%
yield under base mediated hydrolysis. Interestingly, when the
allenylated product 3a was treated with N-iodosuccinimide,15
a
chemoselective iodocarbocyclization was observed resulting in
the formation of the substituted 2-iodoindene 7 in 73% yield.
An intermolecular competition experiment between electro-
nically variant p-substituted benzamides 1c and 1d with pro-
pargyl alcohol 2a (Scheme 3a) was carried out and no notable
preference was observed for the formation of 3c or 3d. This
indicated that C–H activation might proceed via concerted-
metalation-deprotonation pathway. A substantial amount of
deuterium incorporation (35%) was observed at the ortho-
position of benzamide 1a when subjected to standard condi-
tions with MeOH-d4 in the absence of 2a (Scheme 3b). This
indicates that alkyne insertion is preceded by reversible coor-
dination and C–H activation. Kinetic isotopic studies
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), [RuCl2(p-cymene)]2
(5 mol%), KPF6 (30 mol%), NaOAc (0.2 mmol), DCE (1 mL), 70 1C for
10 h. Reaction performed with 1.0 g of 1a.
b
compatible as the corresponding products 3z–3ad were
obtained in good yields 68–78%. To our delight, the current
protocol also allowed for the late stage modification of natural
products like R-(À)-carvone, raspberry ketone and ethisterone
to the corresponding allene derivatives 3ae-3ag in good yields.
Additionally, when 1 g of the amide 1a was reacted with 0.838 g
of alkyne 2a under our standard conditions, 1.29 g of the allene
3a was obtained in 66% yield.
Delectably, allenes 3 could be effortlessly converted into the
corresponding isoquinolone derivatives 4 under basic conditions
leading to formal 1,2-annulation products (Table 3). Allene 3a on
treatment with 0.5 equiv. of K2CO3 in toluene furnished 4a in 73%
yield. With these results in hand, we probed the scope of this
transformation employing allenylamides 3 bearing diverse substitu-
ents on both the amide fragment as well as on the allene moiety.
A variety of structurally diversely functionalized isoquinolones 4b–4j,
Scheme 2 Synthetic utility of 3a.
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Notes and references
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(Scheme 3c) depict a mild kH/kD ratio of 2.3 indicating that C–H
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Based on the above experimental observations and preceding
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Supporting Information). The nitrogen atom of benzamide 1
coordinates with ruthenium catalyst I and undergoes ortho-
metalation to form a five-membered ruthenacycle intermediate
II, which coordinates with the propargyl alcohol 2 to generate
intermediate III. A subsequent regioselective migratory insertion
of the alkyne onto the Ru–carbon bond of III gives seven-
membered metallacycle intermediate IV. b-Hydroxy elimination
from intermediate IV then affords the ortho-allenylated benza-
mide 3a and the ruthenium hydroxy species which undergoes
water elimination regenerating the active catalyst I.
In summary, we have successfully demonstrated C–H bond
allenylation of benzamides with propargyl alcohols using a
readily available ruthenium catalyst. Furthermore, the afforded
allenylamides could be conveniently converted to the corres-
ponding isoquinolone derivatives under basic conditions. In
addition, the high functional group tolerance, scalability and
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mechanistic insights emphasized the application of such types
of catalytic transformations. The formation of water as the sole
byproduct adds to the value of the protocol from a sustain-
ability point of view.
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This activity is supported by SERB, India (CRG/2019/
005059). S. K. thanks University Grants Commission (U.G.C.)
for the fellowship.
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Conflicts of interest
There are no conflicts to declare.
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