Oxazolinyl-Assisted Ru(II)-Catalyzed C-H Allylation with Allyl Alcohols and Synthesis of 4-Methyleneisochroman-1-ones

Article abstract of DOI:10.1021/acs.joc.9b01536

We report herein a ruthenium-catalyzed, oxazoline-directed strategy for C-H allylation of aryl oxazolines using allylic alcohols as the coupling partner. The present transformation unravels the unusual reactivity of allylic alcohols in the synthesis of 4-

Full text of DOI:10.1021/acs.joc.9b01536

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Article
Oxazolinyl-Assisted Ru(II)-Catalyzed C-H Allylation with Allyl
Alcohols and Synthesis of 4-methyleneisochroman-1-ones.
Diksha Singh, Gangam Srikanth Kumar, and Manmohan Kapur
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01536 • Publication Date (Web): 16 Aug 2019
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-
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Oxazolinyl Assisted Ru(II) Catalyzed C-H Allylation with
Allyl Alcohols and Synthesis of 4-methyleneisochroman-1-
ones.
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Diksha Singh#, Gangam Srikanth Kumar# and Manmohan Kapur*
# Both authors contributed equally.
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal
Bypass Road, Bhauri, Bhopal 462066, MP, India
E-mail: mk@iiserb.ac.in
Abstract:
We report herein a ruthenium-catalyzed, oxazoline-directed strategy for C-H allylation of aryl
oxazolines using allylic alcohols as the coupling partner. The present transformation unravels the
unusual reactivity of allylic alcohols in the synthesis of 4-methyleneisochroman-1-ones and C-H
allylated products. A complete switch in the product selectivity was observed with substrate
control and tuning the reaction conditions. The approach employs allyl alcohols as an efficient
alternative to preactivated allylating agents to access diverse products in a highly selective
manner.
Introduction:
The development of efficient, selective, and sustainable C-H functionalization strategies has
gained tremendous importance in the recent years, as they continue to provide solutions to
challenging synthetic problems in organic chemistry.1 In particular, the development of divergent
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methods which utilize versatile coupling partners in C-H functionalization and are capable of
following two distinct reactive pathways has evolved as a unique approach to access diverse
products.2 In this regard, the use of allyl alcohols as coupling partners in C-H functionalization
transformations has emerged as a powerful tool for the construction of C-C bonds due to their
unique reactivity, availability and stability.3 Allyl alcohols have often been employed as
alternatives to α,β-unsaturated carbonyl compounds and other pre-activated allylating agents,
however, their direct utilization as allylating agents was less explored until recent times. This
could be attributed to the reason that allyl alcohols often tend to follow the β-hydride
elimination pathway preferentially over the β-hydroxide elimination pathway. The directed C-H
functionalization of arenes with allyl alcohols to obtain C-H alkylated products has received
much attention in recent years.4,5 In this context, tuning the reactivity of the allyl alcohols in
transition metal-catalyzed directed C-H functionalizations, to undergo selectively either
b-hydride elimination or b-hydroxide elimination, itself represents a remarkable challenge.
Owing to the importance of the allyl moiety in organic synthesis in the construction of complex
molecules, the development of selective C-H functionalization methods for construction of the
allylated arenes is of critical importance. In recent years, transition metal-catalyzed C-H
allylation of arenes with numerous preactivated allyl surrogates such as allylic acetates, allylic
halides, allylic carbonates, allyl phosphates and allyl amines has attracted a lot of interest.6-10
However, the use of pre-activated allylating agents is in a way not step-economical and at times
harsh reaction conditions such as high temperatures, stoichiometric amounts of oxidants need to
be employed.6-8 In this regard, Kanai and co-workers first reported a unique cobalt(III)-catalyzed
dehydrative C–H allylation of indoles with allyl alcohols.11 In 2016, our group demonstrated the
use of the allylic alcohols in the ruthenium-catalyzed C-H allylation of indoles.12 The research
groups of Sundararaju, Gooßen and Ji have also reported efficient C-H allylation strategies for
the synthesis of allyl arenes with allyl alcohols.13 Despite these advances, the development of
sustainable approaches for C-H allylation of arenes via efficient catalytic systems that can
enable the b-hydroxide elimination still remains a highly desirable target.
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The utilization of the oxazolinyl group as a unique directing group in C-H functionalizations has
emerged as an important approach because of the prevalence of the oxazoline moiety in natural
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products and biologically active compounds.14 This is due to their ubiquitous availability as well
as their unique reactivity of undergoing cascade cyclizations to access nitrogen heterocycles.15, 16
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Scheme 1: Transition Metal-Catalyzed direct C-H Allylation transformations
Recently, we have successfully developed a three-component cascade cyclization for the
synthesis of isoquinolinones via a step-efficient ruthenium-catalyzed, oxazolinlyl-mediated C-H
functionalization involving a metal-carbene migratory insertion.17 To the best of our knowledge,
the ruthenium-catalyzed direct C-H allylation of aryl oxazolines with the use of allyl alcohols as
allylating agents has never been reported. In continuation to our previous explorations involving
the reactivity of allyl alcohols in C-H functionalization of arenes,18 we have successfully
developed a highly selective, ruthenium-catalyzed ortho-C-H allylation of aryloxazolines by
employing allyl alcohols as coupling partners, under mild reaction conditions (Scheme 1).
Results and Discussion:
We began our optimization studies by probing numerous conditions for the oxazolinyl-assisted
Ru(II)-catalyzed C-H allylation by choosing 2-(o-tolyl)-4,5-dihydrooxazole (1a) and 1-
phenylprop-2-en-1-ol (2a) as the benchmark substrates for the transformation (Table 1). To our
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delight, in preliminary experiments, a very simple catalytic system comprising of [RuCl2(p-
cym)]2, AgSbF6, and Cu(OAc)2.H2O delivered the desired C-H allylated product in 15% yield
(Table 1, entry 1). The solvent was found to be a critical parameter for the selective formation of
C-H allylation product and systematic screening of solvents revealed that TFE was the solvent
of choice for the transformation (Table 1, entries 4-9).
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Table 1. Optimization studies for C-H allylation:a
Entry
1
catalyst/acetate source/additive/solvent/temp/time
[RuCl2(p-cym)]2/Cu(OAc)2 (2 equiv)/AgSbF6/DCE/85 °C/12h
[RuCl2(p-cym)]2/Cu(OTf)2(2 equiv)/AgSbF6/DCE/85 °C/12 h
[RuCl2(p-cym)]2/nBu4NOAc (2 equiv)/AgSbF6/DCE/85 °C/12 h
[RuCl2(p-cym)]2/Cu(OAc)2 (2 equiv)/AgSbF6/dioxane/85 °C/12 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/AgSbF6/t-BuOH/60 oC/6 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/AgSbF6/MeOH/60 oC/6 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/AgSbF6/toluene/85oC/6 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/AgSbF6/THF/60 oC/6 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O (2.0 equiv)/AgSbF6/TFE/80 oC/6 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O (0.25 equiv)/AgSbF6/TFE/60 oC/6 h
RuCl2(p-cym)]2/Cu(OAc)2.H2O (0.5 equiv)/AgSbF6/TFE/60 oC/6 h
[RuCl2(p-cym)]2/CsOAc (0.5 equiv)/AgSbF6/TFE/60 oC/6 h
[RuCl2(p-cym)]2/AgOAc (1 equiv)/TFE/60 oC/6 h
Yield 3a (%)
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81
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86 (E:Z = 12:1)
74 (E:Z = 2.7:1)
51 (E:Z = 2:1)
[RuCl2(p-cym)]2/KOAc (0.5 equiv)/AgSbF6/TFE/60 oC/6 h
[RuCl2(p-cym)]2/NaOAc (0.5 equiv)/AgSbF6/TFE/60 oC/6 h
[RuCl2(p-cym)]2/NaOAc (0.5 equiv)/TFE/60 oC/6 h
[RuCl2(p-cym)]2/AgSbF6/TFE/60 oC/6 h
63 (E:Z = 2:1)
74 (E:Z = 8:1)
81 (E:Z = 2:1)
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[RuCl2(p-cym)]2/TFE/60 oC/16 h
[RuCl2(p-cym)]2/K3PO4/TFE/60 oC/16 h
Cu(OAc)2.H2O/AgSbF6/TFE/60 oC/6 h
aUnless otherwise mentioned, all reactions were performed with 1 (0.3 mmol), 2 (0.45 mmol), catalyst (0.015
mmol), Cu(OAc)2.H2O (0.15 mmol) and AgSbF6 (0.06 mmol) in 1.5 mL solvent.
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Lowering the reaction temperature as well as the loading of Cu(OAc)2.H2O resulted in a better
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yield (Table 1, entries
9-11). Scanning other acetate sources only afforded poor
diastereoselectivity (E:Z ratios), and the best results were obtained with Cu(OAc)2.H2O (Table
entries 11-16). The presence of the Cu(OAc)2.H2O and AgSbF6 plays a crucial role in the E:Z
selectivity (Table 1 entries 11-16). As expected, control reactions carried out in the absence of
the Ru-catalyst did not yield the desired product (Table 1, entry 20).
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With the optimized conditions in hand, we sought to explore the versatility of the transformation.
The reaction displayed good functional group tolerance and a good substrate scope concerning
oxazolines as well as allylic alcohols.
Scheme 2. Substrate scope for C-H allylation:a
aUnless otherwise mentioned all reactions were performed with 1 (0.3 mmol), 2 (0.45 mmol), [RuCl2(p-cym)]2
(0.015 mmol), Cu(OAc)2.H2O (0.15 mmol) and AgSbF6 (0.06 mmol) in 1.5 mL solvent. All yields are isolated
yields. E:Z ratios were calculated based on integration of isomeric signals in 1H NMR of the crude reaction mixture.
c
d
bReaction performed on 1 mmol scale. 1.0 equiv of phenylprop-2-en-1-ol was used. diallylated product was also
observed along with desired product (See Supporting Information (SI) for details). eyield based on recovered starting
material.
Several allylic alcohols, with varied substitution at the carbinol carbon afforded the allylated
products displaying almost exclusive γ-selectivity (3a-3h, Scheme 2). In most of the cases, the
stereochemistry of the resulting olefin was E. In the case of but-3-en-2-ol and pent-1-en-3-ol as
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coupling partners, poor diastereomeric selectivity was observed (3g, 3h, Scheme 2). Steric
factors are well tolerated in the transformation and ortho-Me, -Cl, -F and -Br substituted aryl
oxazolines were found to be suitable substrates for the transformation (3a-3k, Scheme 2). The
reaction worked with oxazolines containing electron-donating as well as electron-withdrawing
substituents (Scheme 2). However, the reaction displayed an electronic bias; oxazolines bearing
electron-withdrawing substituents were found to possess relatively decreased reactivity (3a vs 3i,
3j, Scheme 2). The reaction of 2-(2-fluorophenyl)-4,5-dihydrooxazole under standard reaction
conditions afforded the desired product (3j) in 55% yield. Unfortunately for us, the synthesis of
methyl 2-(4,5-dihydrooxazol-2-yl)benzoate was unsuccessful in our hands and therefore the
substrate scope with an ester substituent could not be tested. Importantly, the desired products
were obtained in good yields in the reaction of 2-(naphthalen-1-yl)-4,5-dihydrooxazole (3k, 3l,
Scheme 2). The reaction of 5,5-dimethyl-2-(o-tolyl)-4,5-dihydrooxazole afforded the desired
C-H allylated product in 73% yield (3m, Scheme 2). The oxazolines bearing meta- and para-
substituents provided a mixture of di- and monoallylated products under standard reaction
conditions (see the Supporting Information (SI) for details).The reduction in the equivalents of
the allylic alcohol led to the selective formation of the mono- allylated products (3o, 3p, Scheme
2), however the reaction of the 2-(4-methoxyphenyl)-4,5-dihydrooxazole resulted in the
formation of mixture of mono- and di-allylated products (see the Supporting Information (SI)
for details). The reaction of 2-(m-tolyl)-4,5-dihydrooxazole resulted in the C-H allylation at the
sterically less-hindered site to afford the product (3o, Scheme 2).
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During the optimization studies, we had observed that the reaction of prop-2-en-1-ol with the
oxazolines afforded the C-H allylated products along with a trace amount of 4-
methyleneisochroman-1-one as the side product. This intriguing nature of annulation to obtain
the 4-methyleneisochroman-1-ones, prompted us to probe various conditions for the
transformation for the expedient synthesis of 4-methyleneisochroman-1-ones. To the best of our
knowledge, the synthesis of the methyleneisochroman-1-one from oxazolines and allylic
alcohols has never been reported. We chose 2-(p-tolyl)-4,5-dihydrooxazole and prop-2-en-1-ol as
standard substrates for the optimization of the annulation of oxazolines with allyl alcohols (Table
2). In an early trial, the catalytic system comprising of [RuCl2(p-cym)]2, AgSbF6, and
Cu(OAc)2.H2O yielded the desired product in 23% yield (Table 2, entry 2). The choice of the
solvent was again found to be a critical parameter in the transformation. Among the various
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solvents screened for the transformation, MeOH was found to be the optimal solvent for the best
conversion (Table 2, entries 3-12). Substituting the silver salt with KOAc resulted in a good
increment in the yield (Table 2, entry 6).
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Table 2. Optimization studies:a
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Entry
1
catalyst/acetate source/additive/solvent/temp/time
[RuCl2(p-cym)]2/K3PO4/DCE/100 oC/12 h
Yield of 4a (%)
0
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[RuCl2(p-cym)]2/Cu(OAc)2.H2O/AgSbF6/DCE/100 oC/16 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/AgSbF6/DMF/100 oC/16 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/KOAc/DCE: H2O (1:1)/85 oC/16 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/KOAc/H2O/85 oC/16 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/KOAc/MeOH/85 oC/16 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/KOAc/t-BuOH/85 oC/16 h
[RuCl2(p-cym)]/Cu(OAc)2.H2O/KOAc/toluene/85 oC/16 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/KOAc/dioxane/85 oC/16 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/KOAc/THF/85 oC/16 h
[RuCl2(p-cym)]2/Cu(OAc)2.H2O/KOAc/DMSO/85 oC/16 h
[RuCl2(p-cym)]2/O2balloon/KOAc/MeOH/85 oC/16 h
[RuCl2(p-cym)]2/AgOAc/KOAc/MeOH/85 oC/16 h
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[RuCl2(p-cym)]2/Cu(OAc)2.H2O/AcOH/KOAc/MeOH/85 oC/16 h
[RuCl2(p-cym)]/Cu(OAc)2.H2O (1 equiv)/KOAc/MeOH/85 oC/16 h
[RuCl2(p-cym)]2/KOAc/MeOH/85 oC/18 h
35
30
5
Cu(OAc)2.H2O/KOAc/MeOH/85 oC/16 h
0
aUnless otherwise mentioned, all reactions were performed with 1 (0.3 mmol), 2 (0.45 mmol), catalyst (0.015
mmol), Cu(OAc)2.H2O (0.6 mmol) and additive (0.3 mmol) in 2 mL solvent.
Among the various oxidants scanned, the best results were obtained with Cu(OAc)2.H2O and
poor conversions were observed in the absence of the Cu(OAc)2.H2O (Table 2, entries 13-17). A
control reaction, carried out without the ruthenium catalyst, did not yield the desired product
(Table 2, entry 18). The distinct selectivity in the formation of the C-H allylated products and 4-
methyleneisochroman-1-ones was observed with substrate control and tuning the reaction
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conditions (Table 1 and Table 2). In C-H allylation reaction, the use of AgSbF6 and Cu(OAc)2
leads to the generation of cationic ruthenium complex [Ru(OH)p-cymene][SbF6] whereas in the
synthesis of 4-methyleneisochroman-1-ones the use of KOAc and Cu(OAc)2 generates a
covalent system [(p-cymene)Ru(OAc)2] as the active catalyst.
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With the optimized reaction conditions, we explored the substrate scope for this transformation
(Scheme 3).
Scheme 3. Substrate scope:a
aUnless otherwise mentioned, all reactions were performed with 1 (0.3 mmol), 2 (0.45 mmol), catalyst (0.015
mmol), Cu(OAc)2.H2O (0.6 mmol) and additive (0.3 mmol) in 2 mL solvent.bReaction performed on 1 mmol scale.
The substrate scope with respect to oxazolines also displayed a distinct electronic-bias and it was
observed that the electron-withdrawing substituents greatly hampered the reactivity of the
oxazolines (Scheme 3). However, the reaction worked fairly well for most of the electron-rich
-
oxazolines (Scheme 3, 4a 4d, 4f, 4h). X-ray crystallographic analysis of 4h unambiguously
confirmed the structure of the product (Scheme 3). The reaction of 2-(m-tolyl)-4,5-
dihydrooxazole resulted in the formation of the desired product (Scheme 3, 4g) at the less
sterically hindered position. The reaction with other allylic alcohols such as 1-phenylprop-2-en-
1-ol and crotyl alcohol did not afford the desired product.
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To understand the versatile reactivity of Ru(II)-catalyzed C-H allylation in a better manner and
to gain more insights into the mechanism of this transformation, a series of studies were
conducted (Scheme 4). To check the reversibility of C-H ruthenation step, studies were
performed in the presence as well as absence of the allylic alcohol with D2O under standard
conditions.
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Scheme 4: Mechanistic studies:
In the absence of the coupling partner, the transformation resulted in approximately 23%
deuterium incorporation in the starting material at the ortho-position (Scheme 4a). In the
presence of the coupling partner, desired product formation was observed in 77% yield (Scheme
4b). Similarly, the reaction of 2-(p-tolyl)-4,5-dihydrooxazole and 2a (1 equiv) with D2O under
standard conditions resulted in 21% deuterium incorporation in the product along with the 25 %
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deuterium incorporation in the recovered starting material (Scheme 4c). This significant amount
of deuterium incorporation in the recovered starting material indicates that the formation of the
ruthenacycle is a reversible transformation (Scheme 4b). To check whether the cleavage of
C(sp2)−H was involved in the rate-determining step, kinetic isotope effect studies were carried
out. The value of kinetic isotope effect was found to be approximately 1.0 thereby indicating that
the C-H bond cleavage is unlikely to be the rate-limiting step (Scheme 4d). It is possible that
either the migratory insertion or the b-hydroxide elimination could be the rate-limiting step in the
transformation. A control reaction carried out using 1-phenylbut-3-en-2-d-2-ol (2a’) with 1a
resulted in 91% deuterium incorporation in the resulting product, indicating a high g-selectivity
of the transformation (Scheme 4e).
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Based on our previous work and the literature reports,11-13 a plausible reaction pathway for the
C-H allylation is proposed (Scheme 5). The reaction initiates with the generation of the cationic
Ru(II) catalyst, followed by the coordination of the metal to the oxazolinyl nitrogen. Subsequent
C-H activation at the proximal C-2 position results in the formation of the ruthenacycle A.
Intermediate B results from the insertion of the allyl alcohol via carboruthenation. This
organometallic intermediate undergoes a selective b-hydroxide elimination to afford the desired
product. In the C-H allyation transformation, Cu(OAc)2 acts as acetate source in the
transformation. Oxidant-free Ru(II)-catalyzed C-H allylation reactions have been reported in the
literature in which the regeneration of the catalyst proceeds via a protonolysis of the Ru(OH)
intermediate (Scheme 5).13a, 13d-13e The oxophilicity of the metal and solvent stabilization could
be the major factors for the selective b-hydroxide elimination. The lack of formation of a p-allyl
intermediate is probably the reason for the g-selectivity observed in the reaction. To obtain
additional proofs on the formation of the ruthenacycle, MS studies were performed (Scheme 5)
and the ruthenacycle A was detected in ESI-HRMS, thereby lending credence to the proposed
pathway.
The plausible reaction mechanism for the synthesis of the 4-methyleneisochroman-1-ones is
depicted in Scheme 6. The postulated reaction mechanism begins with a nucleophilic attack of
the allylic alcohol onto the oxazoline moiety, followed by a subsequent C-H activation to lead to
the formation of the intermediate H (Scheme 6-I). This intermediate H undergoes a migratory
insertion with alkene of allylic alcohol to result in intermediate (I), which undergoes a b-hydride
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elimination to deliver the intermediate E.This is then followed by a hydrolysis of intermediate E
to afford 4-methyleneisochroman-1-one as the product (Scheme 6-I).
Scheme 5: Plausible reaction mechanism for C-H allylation:
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It is also possible that another plausible reaction pathway involving an initial C-H activation and
followed by a migratory insertion of the allylic alcohol with the opposite regioselectivity could
lead to formation of the desired product (Scheme 6-II). The proposed reaction mechanism
begins with an initial C-H activation step followed by the insertion of the allylic alcohol with the
opposite regioselectivity to provide intermediate C. The subsequent b-hydride elimination
delivers the intermediate D. This is then followed by a cyclization of allylic alcohol onto the
oxazolinyl moiety and a hydrolysis to deliver the isochromanone product. The Cu(OAc)2.H2O
serves as an oxidant in both the reaction plausible mechanisms to complete catalytic cycle by the
regeneration of the active catalyst. In C-H allylation transformation, Cu(OAc)2.H2O most likely
acts as the acetate source in the transformation. This was supported by the observation that the
reaction worked with the other acetate sources like NaOAc, CsOAc, etc., as well (Table 1,
entries 10-16) and the sub-stoichiometric amounts of Cu(OAc)2.H2O delivers the final product.
The C-H activation step is likely to be a concerted deprotonation/metalation in which -OAc acts
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as the base. In the synthesis of the 4-methyleneisochroman-1-ones, Cu(OAc)2.H2O acts as
oxidant. This is supported by the observation that the absence of the Cu(OAc)2.H2O did not lead
to the formation of the product (Table 2, entry 10).
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Scheme 6. Plausible mechanism for the synthesis of the 4-methyleneisochroman-1-ones:
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In summary, we have successfully developed a new ruthenium-catalyzed C-H allylation of aryl
oxazolines using allylic alcohols as a coupling partner.The transformation displays a broad
substrate scope with excellent g-selectivity and moderate yields under mild reaction conditions.
We have also successfully disclosed the unprecedented reactivity of allylic alcohols in the
synthesis of 4-methyleneisochroman-1-one as the products. The current approach represents the
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first example of a Ru(II)-catalyzed synthesis of 4-methyleneisochroman-1-one and allylated
arenes from oxazolines and allyl alcohols.
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Experimental Section:
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(1) General Methods:
All commercially available compounds were used as such without any purification. Unless
otherwise noted, all reactions were performed in oven-dried glassware. All reactions were run
under argon or nitrogen atmosphere. All heating reactions were carried out using an oil bath. All
solvents used in the reactions were purified before use. Column chromatography was performed
with freshly distilled solvents. Dry tetrahydrofuran and toluene were distilled from sodium and
benzophenone, whereas dry dichloromethane, dichloroethane and triethylamine were distilled
from CaH2. Petroleum ether with a boiling range of 40–60 °C was used. Melting points are
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uncorrected. H, and C NMR: Recorded at 295 K in CDCl3; chemical shifts are calibrated to
the residual proton and carbon resonance of the solvent: CDCl3 (1H δ 7.24; 13C δ 77.0). LC-
HRMS: Analysed using Electron spray ionization (ESI) or Atmospheric pressure chemical
ionization (APCI). GC-HRMS: Performed on GC-QToF (with Electron Impact (EI), 70eV). GC-
LRMS: Performed on GC-MS (EI, 70 eV) with single quadrupole. FT-IR: Recorded as thin films
between KBr plates.
(2) General procedure for the synthesis of oxazolines (1a-1j):20
To a solution of corresponding aldehyde (5 mmol) in tert-butyl alcohol (25 mL), aminoethanol
(5.5 mmol) was added. The reaction mixture was stirred for 30 min at room temperature under
argon atmosphere, then K2CO3 (15 mmol) and I2 (10 mmol) were added to the reaction mixture
and stirred at 70 oC. After 18 h, the reaction mixture was quenched with saturated Na2S2O3 until
the iodine-colour almost disappeared and the mixture was then extracted with EtOAc. Upon
drying over anhydrous Na2SO4, the solvent was removed under reduced pressure and the
resulting residue was purified by silica gel flash column chromatography.
2.1. 2-(o-tolyl)-4,5-dihydrooxazole (1a):
Yield: 61% (491 mg); Physical appearance: Yellow oil; TLC Rf 0.4 (9:1, Petroleum
ether:EtOAc). Spectral data matched well with those reported in the literature.16d
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2.2. 2-(p-tolyl)-4,5-dihydrooxazole (1b):
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Yield: 65% (524 mg); Physical appearance: Off-white solid; TLC Rf 0.4 (3:1, Petroleum
ether:EtOAc). Spectral data matched well with those reported in the literature.20
2.3. 2-phenyl-4,5-dihydrooxazole (1c):
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Yield: 68% (472 mg); Physical appearance: Yellow oil; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.20
2.4. 2-(4-methoxyphenyl)-4,5-dihydrooxazole (1d):
Yield: 70% (620 mg); Physical appearance: Off-white solid; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.20
2.5. 2-(4-bromophenyl)-4,5-dihydrooxazole (1e):
Yield: 67% (753 mg); Physical appearance: Off-white solid; TLC Rf 0.4 (3:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.20
2.6. 2-(naphthalen-1-yl)-4,5-dihydrooxazole (1f):
Yield: 67% (660 mg); Physical appearance: Off-white solid; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.20
2.7. 2-(3,4-dimethoxyphenyl)-4,5-dihydrooxazole (1g):
Yield: 55% (570 mg); Physical appearance: Off-white solid; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.21
2.8. 2-(3,4-dimethylphenyl)-4,5-dihydrooxazole (1h):
Yield: 64% (560 mg); Physical appearance: Persian-red solid; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.22
2.9. 2-(4-isopropylphenyl)-4,5-dihydrooxazole (1i):
Yield: 67% (634 mg); Physical appearance: Off-white gel; TLC Rf 0.4 (9:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.20
2.10.5,5-dimethyl-2-(o-tolyl)-4,5-dihydrooxazole (1j):
Yield: 72% (630 mg); Physical appearance: Brown gel; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H),
7.23 (t, J = 7.6 Hz, 2H), 3.82 (s, 2H), 2.60 (s, 3H), 1.51 (s, 6H); 13C{H} NMR (126 MHz,
CDCl3): δ 163.9, 138.5, 131.1, 130.3, 129.7, 127.9, 125.5, 83.2, 67.3, 27.4, 21.5; IR (KBr, cm-1):
2979, 2869, 1643, 1493, 1368, 1050, 963, 780; ESI-HRMS: Calculated for C12H15NO [M+H]+
190.1226, found 190.1216.
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(3) General procedure for the synthesis of oxazolines (1k 1n):
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Step 1. To a solution of the benzoic acid (1 equiv) in dry DCM (0.3 M) at 0 C, oxalyl chloride
(3 equiv) and DMF (few drops) were added. The reaction mixture was allowed to warm to room
temperature and stirred for 3 hours under an argon atmosphere before removing the solvent
under reduced pressure. The crude product was employed immediately in the next step.
Step 2. To the solution of amino ethanol (1 equiv) in methanol (0.25 M), K2CO3 (1.1 equiv) was
added and the mixture was cooled to 0 oC. Then, benzoyl chloride (1.1 equiv) was added and the
mixture was stirred for 15 hours at room temperature. The solvent was distilled off under
reduced pressure and the reaction mixture was diluted with DCM. This was washed with brine
and the organic extract was dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude product (N-(2-hydroxyethyl)benzamide) was employed in the next
step without the further purification.
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Step 3. To a solution of DDQ (1.5 equiv) in DCM (0.2 M), PPh3 (1.5 equiv) was added and the
mixture was stirred at room temperature under argon atmosphere for 5 minutes. This was
followed by the addition of N-(2-hydroxyethyl)benzamide (1 equiv) and the reaction mixture was
stirred for 20 minutes. The color of the mixture turned yellow and precipitation occurred. The
reaction mixture was washed with NaOH solution (5%) and the separated aqueous layer was
extracted with DCM and the organic layer was washed with brine and the organic extract was
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude
product was purified by a silica gel flash column chromatography to afford the desired product.
3.1. 2-(m-tolyl)-4,5-dihydrooxazole (1k):
Yield: 70% (338 mg); Physical appearance: Yellow oil; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.16d
3.2. 2-(2-chlorophenyl)-4,5-dihydrooxazole (1l):
Yield: 70% (380 mg); Physical appearance: Yellow oil; TLC Rf 0.4 (9:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.23
3.3. 2-(2-bromophenyl)-4,5-dihydrooxazole (1m):
Yield: 70% (472 mg); Physical appearance: Pale-yellow clear viscous liquid; TLC Rf 0.4 (9:1,
Petroleum ether:EtOAc). Spectral data obtained matched well with those reported in the
literature.24a
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3.4. 2-(2-fluorophenyl)-4,5-dihydrooxazole (1n):
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Yield: 61% (302 mg); Physical appearance: Pale-yellow clear viscous liquid; TLC Rf 0.4 (4:1,
Petroleum ether:EtOAc). Spectral data obtained matched well with those reported in the
literature.24b
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(4) Procedure for the synthesis of 2-(2-methylphenyl-6-d)-4,5-dihydrooxazole:18c,25
Step 1. In a pressure tube equipped with a stir bar, the benzoic acid (100 mg, 0.73 mmol) was
dissolved in D2O (1.5 mL) under N2 atmosphere. The reaction mixture was degassed for 5-10
min followed by the addition of [RuCl2(p-cym)]2 (9 mg, 0.015 mmol), and K2CO3 (100 mg, 0.73
mmol). The tube was fitted with a Teflon screw cap under an argon flow, and the reaction
mixture was heated to 85 oC and allowed to stir for 12 h. Upon cooling to room temperature, the
reaction mixture was washed with NaHCO3 and then acidified with 1M HCl, and extracted with
DCM, and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure
(crude yield, 88%). Further, the product (2-methylbenzoic-6-d acid) was employed in the
synthesis of 2-(2-methylphenyl-6-d)-4,5-dihydrooxazole by using the same procedure as the
general procedure 3.
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4.1. 2-(2-methylphenyl-6-d)-4,5-dihydrooxazole (1a’):
Yield: 85% (85 mg); Physical appearance: Yellow oil; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc); 1H NMR (500 MHz, CDCl3): δ 7.34 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 8.4 Hz, 2H),
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4.39 – 4.33 (m, 2H), 4.09 (t, J = 9.4 Hz, 2H), 2.61 (s, 3H); C{H} NMR (126 MHz, CDCl3): δ
165.0, 138.7, 131.2, 130.5, 129.5 (t), 127.1, 125.4, 66.8, 55.4, 21.8; IR (KBr, cm-1): 2971, 2878,
1643, 1467, 1350, 1046, 946, 773; ESI-HRMS: Calculated for C10H11DNO [M+H]+ 163.0976,
found 163.0971.
(5) General procedure for the synthesis of the 1-phenyl-prop-2-en-1-ol (2):26, 27
To a solution of the aldehyde (5.0 mmol) in dry THF (0.5 M), vinyl magnesium bromide (10.0
mmol, 1.0 M in THF) was added dropwise at 0 °C. After 15 min, the reaction was allowed to
warm to r.t. and stirred for additional 3 h. Then the reaction was quenched by adding saturated
NH4Cl aq. and the reaction mixture was extracted with Et2O. The combined organic extracts
were washed with brine, dried over anhydrous NaSO4, filtered, concentrated and purified by
silica gel flash chromatography (EtOAc/petroleum ether as eluent) to give the allylic alcohol.
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5.1. 1-phenylprop-2-en-1-ol (2a):
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Yield: 72% (482 mg); Physical appearance: Pale-yellow clear liquid; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.26
5.2. 1-(p-tolyl)prop-2-en-1-ol (2b):
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Yield: 67% (496 mg); Physical appearance: Pale-yellow oil; TLC Rf 0.4 (9:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.27
5.3. 1-(4-chlorophenyl)prop-2-en-1-ol (2c):
Yield: 55% (462 mg); Physical appearance: Pale-yellow oil; TLC Rf 0.4 (9:1, Petroleum
ether:EtOAc). Spectral data obtained matched well with those reported in the literature.27
5.4. 1-(4-fluorophenyl)prop-2-en-1-ol (2d):
Yield: 50% (380 mg); Physical appearance: Pale-yellow oil; TLC Rf 0.4 (9:1, Petroleum
ether:EtOAc). Spectral data matched well with those reported in the literature.26
5.5. 1-(3-methoxyphenyl)prop-2-en-1-ol (2e):
Yield: 61% (500 mg); Physical appearance: Yellow oil; TLC Rf 0.4 (4:1, Petroleum
ether:EtOAc). Spectral data obtained were in good agreement with those reported in the
literature.26
(6) General procedure for the ruthenium-catalyzed C-H allylation of oxazoline with allyl
alcohols:
In a pressure tube equipped with a stir bar, the aryl oxazoline (0.3 mmol) and allylic alcohol
(0.45 mmol) were dissolved in TFE (1.5 mL). The reaction mixture was degassed for 5-10 min
followed by the addition of [RuCl2(p-cym)]2 (0.015 mmol), Cu(OAc)2.H2O (0.15 mmol), and
AgSbF6 (0.06 mmol). The tube was fitted with a Teflon screw cap under an argon flow, and the
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reaction mixture was heated to 60 C and allowed to stir for 6-10 h. Upon cooling to room
temperature, the reaction mixture was diluted with ethyl acetate and concentrated under reduced
pressure. The crude product was purified by a silica gel flash column chromatography to afford
the desired product.
6.1. 2-(2-cinnamyl-6-methylphenyl)-4,5-dihydrooxazole (3a):
Yield: 86% (71 mg) 80% (210 mg, 1 mmol scale); Physical appearance: Yellow oil; TLC Rf 0.3
(9:1, Petroleum ether:EtOAc); 1H NMR (400 MHz, DMSO-d6): δ 7.37 (d, J = 7.4 Hz, 2H), 7.30
(t, J = 7.0 Hz, 3H), 7.24 – 7.12 (m, 3H), 6.45 (d, J = 15.8 Hz, 1H), 6.31 (dt, J = 15.8, 6.8 Hz,
1H), 4.34 (t, J = 9.4 Hz, 2H), 3.99 (t, J = 9.4 Hz, 2H), 3.53 (d, J = 6.8 Hz, 2H), 2.26 (s, 3H);
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13C{H} NMR (126 MHz, DMSO-d6): δ 168.0, 144.1, 142.3, 141.9, 135.8, 134.7, 134.4, 134.1,
133.8, 133.1, 132.4, 132.0, 131.1, 72.1, 60.1, 41.9, 24.5; IR (KBr, cm-1): 2928,1660,1449,1352,
1253, 1049, 765; ESI-HRMS: Calculated for C19H20NO [M+H]+ 278.1539, found 278.1526.
6.2. (E)-2-(2-methyl-6-(3-(p-tolyl)allyl)phenyl)-4,5-dihydrooxazole (3b):
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Yield: 65% (57 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum ether:EtOAc);
1H NMR (400 MHz, CDCl3): δ 7.29 – 7.23 (m, 4H), 7.12 (t, J = 8.7 Hz, 4H), 6.43 (d, J = 15.8
Hz, 1H), 6.26 (dt, J = 15.7, 6.8 Hz, 1H), 4.37 (t, J = 9.5 Hz, 2H), 4.09 (t, J = 9.6 Hz, 2H), 3.61
(d, J = 6.8 Hz, 2H), 2.37 (s, 3H), 2.34 (s, 3H); 13C{H} NMR (126 MHz, CDCl3): δ 164.6, 139.4,
137.3, 136.8, 134.8, 130.9, 129.6, 129.2, 128.9, 128.0, 127.9, 126.9, 126.0, 67.2, 55.3, 37.4, 21.2,
19.7; IR (KBr, cm-1): 2922,1661, 1348, 1252, 1164, 1045, 764; ESI-HRMS: Calculated for
C20H22NO [M+H]+ 292.1696, found 292.1683.
6.3. (E)-2-(2-(3-(3-methoxyphenyl)allyl)-6-methylphenyl)-4,5-dihydrooxazole (3c):
Yield: 70% (60 mg); Physical appearance: Yellow gel; TLC Rf 0.3 (9:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.28 – 7.18 (m, 2H), 7.11 (t, J = 7.2 Hz, 2H), 6.95
(d, J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.78 (dd, J = 8.0, 2.4 Hz, 1H), 6.45 (d, J = 15.6, 1H), 6.37 –
6.25 (m, 1H), 4.37 (t, J = 9.2 Hz, 2H), 4.09 (t, J = 9.2 Hz, 2H), 3.81 (s, 3H), 3.62 (d, J = 6.6 Hz,
2H), 2.35 (s, 3H); 13C{H} NMR (100 MHz, CDCl3): δ 159.8, 139.1, 138.9, 137.4, 130.9, 129.6,
129.5, 129.3, 129.2, 128.8, 128.1, 127.0, 118.8, 112.8, 111.3, 67.3, 55.2, 55.3, 37.3, 19.7; IR
(KBr, cm-1): 2926,1560,1408,1333, 1258, 1049, 755; ESI-HRMS: Calculated for C20H22NO2
[M+H]+ 308.1645, found 308.1627.
6.4. (E)-2-(2-(3-(4-chlorophenyl)allyl)-6-methylphenyl)-4,5-dihydrooxazole (3d):
Yield: 74% (72 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum ether:EtOAc);
1H NMR (400 MHz, CDCl3): δ 7.30 – 7.20 (m, 5H), 7.11 (d, J = 7.6 Hz, 2H), 6.38 (d, J = 15.8
Hz, 1H), 6.29 (dd, J = 15.8, 6.4 Hz, 1H), 4.36 (t, J = 9.6 Hz, 2H), 4.08 (t, J = 9.6 Hz, 2H), 3.60
(d, J = 6.4 Hz, 2H), 2.36 (s, 3H); 13C{H} NMR (100 MHz, CDCl3): δ 164.5, 138.9, 137.4, 136.0,
132.6, 129.8, 129.7, 129.6, 128.8, 128.6, 128.2, 127.3, 126.9, 67.2, 55.2, 37.3, 19.7; IR (KBr,
cm-1): 2924,1651, 1594, 1489, 1260, 1091, 749; ESI-HRMS: Calculated for C19H19ClNO
[M+H]+ 312.1150, found 312.1145.
6.5. (E)-2-(2-(3-(4-fluorophenyl)allyl)-6-methylphenyl)-4,5-dihydrooxazole (3e):
Yield: 62% (55 mg); Physical appearance: brownish-yellow oil; TLC Rf 0.3 (9:1, Petroleum
ether:Acetone); 1H NMR(400 MHz, CDCl3): δ 7.35 – 7.24 (m, 3H), 7.16 – 7.10 (m, 2H), 7.03 –
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6.96 (m, 2H), 6.41 (d, J = 15.8 Hz, 1H), 6.28 – 6.19 (m, 1H), 4.38 (t, J = 9.4 Hz, 2H), 4.10 (t, J =
9.4 Hz, 2H), 3.60 (d, J = 6.8 Hz, 2H), 2.37 (s, 3H); 13C{H} NMR (100 MHz, CDCl3): δ 162.0 (J
= 246.0 Hz), 138.3 (J = 171.1 Hz), 133.7 (J = 3.3 Hz), 129.8, 129.6, 128.8, 128.8 (J = 2.2 Hz),
128.2, 127.6, 127.5, 126.9, 115.5, 115.2, 67.2, 55.3, 37.3, 19.7; 19F NMR (376 MHz, CDCl3): δ
-115.0; IR (KBr, cm-1): 2924, 1659, 1508, 1275, 1157, 937, 750; ESI-HRMS: Calculated for
C19H19FNO [M+H]+ 296.1445, found 296.1473.
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6.6. 2-(2-allyl-6-methylphenyl)-4,5-dihydrooxazole (3f):
Yield: 61% (39 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
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ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.34 – 7.18 (m, 1H), 7.08 (d, J = 7.4 Hz, 2H),
6.03 – 5.83 (m, 1H), 5.09 – 5.00 (m, 2H), 4.40 (t, J = 9.4 Hz, 2H), 4.09 (t, J = 9.4 Hz, 2H), 3.44
(d, J = 6.6 Hz, 2H), 2.34 (s, 3H); 13C{H} NMR (100 MHz, CDCl3): δ 164.5, 139.1, 137.3, 137.2,
129.5, 128.7, 127.9, 126.7, 115.7, 67.1, 55.2, 38.1, 19.7; IR (KBr, cm-1): 2925, 1662, 1464,
1348, 1251, 1045, 770; ESI-HRMS: Calculated for C13H16NO [M+H]+ 202.1226, found
202.1203.
6.7. 2-(2-(but-2-en-1-yl)-6-methylphenyl)-4,5-dihydrooxazole (E:Z: 1.1:1) (3g):
Yield: 58% (38 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
ether:EtOAc); 1H NMR (500 MHz, CDCl3): δ 7.28 – 7.20 (m, 2H), 7.12 – 7.06 (m, 4H), 5.65 –
5.42 (m, 4H), 4.52 – 4.31 (m, 4H), 4.20 – 4.00 (m, 4H), 3.46 (d, J = 6.4 Hz, 2H), 3.38 (d, J = 6.2
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Hz, 2H), 2.35 (s, 6H), 1.75 – 1.63 (m, 6H); C{H} NMR (126 MHz, CDCl3): δ 164.7, 164.6,
140.2, 140.1, 137.2, 137.1, 129.7, 129.5, 129.5, 128.9, 128.7, 128.6, 127.7, 127.7, 126.6, 126.4,
126.3, 124.7, 67.2, 67.1, 55.3, 55.2, 36.9, 31.0, 19.7, 18.0, 12.9; IR (KBr, cm-1): 2925, 1662,
1464, 1348, 1251, 1045, 770; ESI-HRMS: Calculated for C14H18NO [M+H]+ 216.1383, found
216.1376.
6.8. 2-(2-methyl-6-(pent-2-en-1-yl)phenyl)-4,5-dihydrooxazole (E:Z: 1.2:1) (3h):
Yield: 55% (42 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.23 (m, 3H), 7.11 – 7.02 (m, 4H), 5.59 – 5.42 (m,
4H), 4.49 – 4.34 (m, 4H), 4.09 (t, J = 9.4 Hz, 4H), 3.52 – 3.31 (m, 4H), 2.33 (s, 6H), 2.22 – 1.97
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(m, 4H), 1.08 – 0.92 (m, 6H); C{H} NMR (126 MHz, CDCl3): δ 164.7, 164.6, 140.2, 140.1,
137.2, 137.1, 133.6, 132.5, 129.6, 129.5, 128.7, 128.6, 127.7, 127.6, 127.5, 127.3, 126.6, 126.4,
67.2, 67.1, 55.3, 36.9, 31.2, 25.6, 20.6, 19.7, 14.3, 13.8; IR (KBr, cm-1): 2962, 1661, 1463, 1098,
971, 765; ESI-HRMS: Calculated for C15H20NO [M+H]+ 230.1539, found 230.1527.
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6.9. 2-(2-chloro-6-cinnamylphenyl)-4,5-dihydrooxazole (3i):
o
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Yield: 59% (52 mg); Physical appearance: Yellow solid; M.p. 70 - 76 C; TLC Rf 0.3 (9:1,
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Petroleum ether:EtOAc); H NMR(400 MHz, CDCl3): δ 7.36 (d, J = 7.5 Hz, 2H), 7.33 – 7.27
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(m, 4H), 7.21 (d, J = 6.2 Hz, 2H), 6.46 (d, J = 15.8 Hz, 1H), 6.33 – 6.22 (m, 1H), 4.40 (t, J = 9.5
Hz, 2H), 4.11 (t, J = 9.5 Hz, 2H), 3.62 (d, J = 6.6 Hz, 2H);13C{H} NMR (100 MHz, CDCl3): δ
162.5, 141.6, 137.2, 133.7, 131.7, 130.7, 128.8, 128.5, 127.9, 127.8, 127.5, 127.3, 126.2, 67.7,
55.3, 37.3; IR (KBr, cm-1): 2918, 1590, 1437, 1261, 1042, 749; ESI-HRMS: Calculated for
C18H17ClNO [M+H]+ 298.0993, found 298.0971.
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6.102-(2-cinnamyl-6-fluorophenyl)-4,5-dihydrooxazole(3j):
Yield: 55% (44 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum ether:
Acetone); 1H NMR (400 MHz, CDCl3): δ 7.40 – 7.27 (m, 6H), 7.27 – 7.20 (m, 1H), 7.12 (d, J =
7.6 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 6.30 (dd, J = 15.8, 6.6 Hz, 1H),
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4.41 (t, J = 9.6 Hz, 2H), 4.11 (t, J = 9.6 Hz, 2H), 3.71 (d, J = 6.6 Hz, 2H); C{H} NMR (100
MHz, CDCl3): δ 161.1 (J = 250.6 Hz), 160.6, 142.1, 137.3, 131.62, 131.32 (J = 9.0 Hz), 128.5,
128.0, 127.3, 126.1, 125.3 (J = 3.2 Hz), 117.3 (J = 15.2 Hz), 113.7 (J = 21.6 Hz), 67.5, 55.3,
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36.9; F NMR (376 MHz, CDCl3) δ -113.2; IR (KBr, cm-1): 2905, 1666, 1578, 1463, 1253,
1088, 969, 744; ESI-HRMS: Calculated for C18H17FNO [M+H]+ 282.1289 found 282.1310.
6.11. (E)-2-(2-bromo-6-(3-(4-fluorophenyl)allyl)phenyl)-4,5-dihydrooxazole (3k):
Yield: 52% (56 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
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ether:Acetone); H NMR (400 MHz, CDCl3): δ 7.51 (dd, J = 6.6, 2.5 Hz, 1H), 7.35 – 7.28 (m,
3H), 7.25 – 7.20 (m, 1H), 7.03 – 6.96 (m, 2H), 6.42 (d, J = 15.8 Hz, 1H), 6.21 (dt, J = 15.8, 6.8
Hz, 1H), 4.46 – 4.38 (t, J = 9.6 Hz, 2H), 4.12 (t, J = 9.6 Hz, 2H), 3.64 – 3.58 (d, J = 6.8 Hz, 2H);
13C{H} NMR (126 MHz, CDCl3): δ 162.2 (J = 246.4 Hz), 141.6, 133.4 (J = 3.4 Hz), 131.0,
130.8, 130.5,128.4, 127.8, 127.7, 127.7, 127.6 (J = 8.0 Hz), 122.8, 115.4 (J = 21.6 Hz), 67.7,
55.4, 37.4; 19F NMR (376 MHz, CDCl3): δ -115.0; IR (KBr, cm-1): 258, 1651, 1507, 1260,
1227, 1042, 764; ESI-HRMS: Calculated for C18H16BrFNO [M+H]+ 360.0394, found 360.0409.
6.12. 2-(2-cinnamylnaphthalen-1-yl)-4,5-dihydrooxazole (3l):
Yield: 73% (68 mg); Physical appearance: Brown gel; TLC Rf 0.3 (9:1, Petroleum
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ether:Acetone); H NMR(400 MHz, CDCl3): δ 7.96 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 13.7, 8.2
Hz, 2H), 7.56 – 7.43 (m, 3H), 7.38 (d, J = 7.5 Hz, 2H), 7.33 – 7.27 (m, 2H), 7.22 (t, J = 7.3 Hz,
1H), 6.53 (d, J = 15.8 Hz, 1H), 6.40 (dt, J = 15.8, 6.6 Hz, 1H), 4.54 (t, J = 9.6 Hz, 2H), 4.26 (t, J
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= 9.6 Hz, 2H), 3.80 (d, J = 6.6 Hz, 2H); 13C{H} NMR (100 MHz, CDCl3): δ 164.1, 137.5, 137.4,
132.1, 131.8, 131.3, 130.1, 128.8, 128.5, 128.0, 127.6, 127.2, 126.9, 126.2, 125.7, 125.4, 125.1,
67.4, 55.6, 37.7; IR (KBr, cm-1): 2931, 1656, 1531, 1318, 1208, 1010, 756; ESI-HRMS:
Calculated for C22H20NO [M+H]+ 314.1539, found 314.1537.
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6.13. (E)-2-(2-(3-(3-methoxyphenyl)allyl)naphthalen-1-yl)-4,5-dihydrooxazole (3m):
Yield: 65% (67 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
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ether:Acetone); H NMR(400 MHz, CDCl3): δ 7.96 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 13.8, 8.2
Hz, 2H), 7.50 (m, 3H), 7.22 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.91 (s, 1H), 6.78 (dd, J
= 8.2, 2.3 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H), 6.39 (dt, J = 15.8, 6.6 Hz, 1H), 4.54 (t, J = 9.6 Hz,
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2H), 4.26 (t, J = 9.6 Hz, 2H), 3.81 (s, 3H), 3.79 (s,2H); C{H} NMR (126 MHz, CDCl3): δ
164.0, 159.8, 138.9, 137.5, 132.1, 131.8, 131.2, 130.1, 129.5, 129.1, 128.0, 127.6, 126.9, 125.7,
125.4, 125.1, 118.9, 113.0, 111.3, 67.5, 55.5, 37.7, 29.7; IR (KBr, cm-1): 2920, 2850, 2358,
1727, 1614, 1496, 1278, 1031, 790; ESI-HRMS: Calculated for C23H22NO2 [M+H]+ 344.1645,
found 344.1622.
6.14. 2-(2-cinnamyl-6-methylphenyl)-5,5-dimethyl-4,5-dihydrooxazole (3n):
Yield: 73% (68 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
ether:Acetone); 1H NMR(400 MHz, CDCl3): δ 7.39 – 7.34 (m, 2H), 7.33 – 7.27 (m, 3H), 7.25 –
7.18 (m, 1H), 7.16 – 7.07 (m, 2H), 6.46 (d, J = 15.8 Hz, 1H), 6.36 (dt, J = 15.8, 6.4 Hz, 1H), 3.85
(s, 2H), 3.64 (d, J = 6.4 Hz, 2H), 2.39 (s, 3H), 1.51 (s, 6H); 13C{H} NMR (100 MHz, CDCl3): δ
163.0, 139.1, 137.5, 137.2, 131.1, 129.5, 129.2, 129.8, 128.5, 128.1, 127.0, 126.9, 126.2, 83.7,
67.3, 36.9, 27.6, 19.7; IR (KBr, cm-1): 2924, 1708, 1597, 1377, 1275, 1054, 764; ESI-HRMS:
Calculated for C21H24NO [M+H]+ 306.1852, found 306.1826.
6.15. 2-(2-cinnamyl-5-methylphenyl)-4,5-dihydrooxazole (3o):
Yield: 40% (34 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
ether:Acetone); 1H NMR(400 MHz, CDCl3): δ 7.66 (s, 1H), 7.37 (d, J = 7.0 Hz, 2H), 7.30 (t, J =
6.9 Hz, 2H), 7.24 – 7.18 (m, 3H), 6.47 – 6.33 (m, 2H), 4.41 (t, J = 9.6 Hz, 2H), 4.09 (t, J = 9.6
Hz, 2H), 3.92 (d, J = 5.8 Hz, 2H), 2.37 (s, 3H); 13C{H} NMR (126 MHz, CDCl3): δ 165.1,
137.8, 137.4, 135.8, 131.6, 130.7, 130.6, 130.5, 129.7, 128.5, 126.9, 126.1, 67.1, 55.3, 37.2,
20.9; IR (KBr, cm-1): 2910, 1675, 1551, 1368, 1150, 775; ESI-HRMS: Calculated for
C19H20NO [M+H]+ 278.1539, found 278.1537.
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6.16. 2-(2-cinnamyl-4-methylphenyl)-4,5-dihydrooxazole (3p):
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Yield: 35% (30 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
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ether:Acetone); H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.8 Hz, 1H), 7.41 – 7.30 (m, 4H),
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7.25 – 7.18 (m, 1H), 7.16 – 7.06 (m, 2H), 6.51 – 6.31 (m, 2H), 4.48 – 4.27 (m, 2H), 4.10 (t, J =
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9.4 Hz, 2H), 3.94 (d, J = 5.9 Hz, 2H), 2.37 (s, 3H); C{H} NMR (126 MHz, CDCl3): δ 166.8,
141.0, 140.4, 133.4, 137.7, 131.2, 130.8, 130.1, 129.6, 128.5, 126.9, 126.3, 126.1, 124.2, 66.9,
55.2, 37.6, 21.4; IR (KBr, cm-1): 2917, 1597, 1399, 1274, 1044, 749; APCI-HRMS: Calculated
for C19H20NO [M+H]+ 278.1539, found 278.1545.
6.18. 2-(2-cinnamyl-4-methoxyphenyl)-4,5-dihydrooxazole (3q):
Yield: 28% (25 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum ether:EtOAc);
1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.8 Hz, 1H), 7.38 – 7.30 (m, 4H), 7.25 – 7.18 (m,
1H), 6.86 (d, J = 2.6 Hz, 1H), 6.80 (dd, J = 8.8, 2.6 Hz, 1H), 6.50 – 6.34 (m, 2H), 4.38 (t, J = 9.4
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Hz, 2H), 4.08 (d, J = 9.4 Hz, 2H), 4.01 – 3.96 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H); C{H} NMR
(100 MHz, CDCl3): δ 164.5, 161.3, 142.8, 137.7, 131.9, 131.0, 129.2, 128.4, 126.9, 126.1, 119.5,
116.0, 111.2, 66.7, 55.3, 55.2, 37.8; IR (KBr, cm-1): 2929, 1719, 1604, 1496, 1151, 1031, 744;
ESI-HRMS: Calculated for C19H20NO2 [M+H]+ 294.1489, found 294.1497.
6.9(E)-2-(2-methyl-6-(3-phenylallyl-3-d)phenyl)-4,5-dihydrooxazole(3a’):
Yield: 85% (69 mg); Physical appearance: Yellow oil; TLC Rf 0.3 (9:1, Petroleum
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ether:Acetone); H NMR (400 MHz, CDCl3): δ 7.44 – 7.19 (m, 6H), 7.13 (t, J = 8.2 Hz, 2H),
6.33 (t, J = 6.4 Hz, 1H), 4.38 (t, J = 9.6 Hz, 2H), 4.10 (t, J = 9.6 Hz, 2H), 3.63 (d, J = 6.4 Hz,
2H), 2.38 (s, 3H); 13C{H} NMR (126 MHz, CDCl3): δ 139.2, 137.5, 137.4, 129.6, 128.9, 128.9,
128.8, 128.5, 128.3, 128.1, 127.1, 126.9, 126.1, 67.2, 55.3, 37.3, 19.7; IR (KBr, cm-1): 2931,
1723, 1643,1316, 1236, 1053, 780; ESI-HRMS: Calculated for C19H19DNO [M+H]+ 279.1602,
found 279.1595.
(7) General procedure for the ruthenium-catalyzed synthesis of isochromanones:
In a pressure tube equipped with a stir bar, the oxazoline (0.3 mmol) and allylic alcohol (0.45
mmol) were dissolved in 1.5 mL of MeOH. The reaction mixture was degassed for 5-10 min
followed by the addition of [RuCl2(p-cym)]2 (0.015 mmol), Cu(OAc)2.H2O (0.45 mmol), and
KOAc (0.3 mmol). The tube was fitted with a Teflon screw cap under an argon flow, and the
o
reaction mixture was heated to 85 C and allowed to stir for 12 - 16 h. Upon cooling to room
temperature, the reaction mixture was diluted with ethyl acetate and washed with brine and the
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organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by a silica gel flash column chromatography to yield
the desired product.
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7.1. 6-methyl-4-methyleneisochroman-1-one (4a):
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o
Yield: 60% (36 mg); Physical appearance: Yellow solid; M.p. 114 - 116 C; TLC Rf 0.3 (9:1,
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Petroleum ether:EtOAc); H NMR (500 MHz, CDCl3): δ 8.05 (d, J = 8.0 Hz, 1H), 7.45 – 7.40
(m, 1H), 7.34 – 7.30 (m, 1H), 5.74 (d, J = 1.0 Hz, 1H), 5.41 (t, J = 1.4 Hz, 1H), 5.00 (t, J = 1.2
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Hz, 2H), 2.48 (s, 3H); C{H} NMR (126 MHz, CDCl3): δ 164.7, 144.9, 136.8, 135.4, 130.6,
130.4, 123.6, 121.1, 113.3, 71.4, 21.9; IR (KBr, cm-1): 2919, 1642, 1271, 1120, 950, 748; ESI-
HRMS: Calculated for C11H11O2 [M+H]+ 175.0754, found 175.0746.
7.2. 6-methoxy-4-methyleneisochroman-1-one (4b):
o
Yield: 55% (32 mg); Physical appearance: Off-white solid; M.p. 60 - 62 C; TLC Rf 0.3 (9:1,
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Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 8.6 Hz, 1H), 7.01 – 6.92
(m, 2H), 5.67 (s, 1H), 5.36 (s, 1H), 4.93 (s, 2H), 3.87 (s, 3H); 13C{H} NMR (126 MHz, CDCl3):
δ 164.5, 164.0, 138.9, 135.5, 132.9, 116.5, 115.7, 113.7, 107.4, 71.2, 55.7; IR (KBr, cm-1): 2918,
1714, 1601, 1316, 1250, 1070, 765; ESI-HRMS: Calculated for C11H11O3 [M+H]+ 191.0703,
found 191.0684.
7.3.4-methyleneisochroman-1-one (4c):
Yield: 43% (21 mg) 40% (64 mg, 1 mmol scale); Physical appearance: Yellow oil; TLC Rf 0.3
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(9:1, Petroleum ether:EtOAc); H NMR(400 MHz, CDCl3): δ 8.11 (d, J = 7.8 Hz, 1H), 7.62 –
13
7.55 (m, 2H), 7.49 – 7.42 (m, 1H), 5.70 (s, 1H), 5.38 (s, 1H), 4.97 (s, 2H); C{H} NMR (126
MHz, CDCl3): δ 164.5, 136.9, 135.2, 133.9, 130.5, 129.4, 123.7, 123.3, 113.7, 71.3; IR (KBr,
cm-1): 2361, 1719, 1275, 1094, 764; ESI-HRMS: Calculated for C10H9O2 [M+H]+ 161.0597,
found 161.0593.
7.4. 6-isopropyl-4-methyleneisochroman-1-one (4d):
Yield: 40% (25 mg); Physical appearance: Pale-yellow gel; TLC Rf 0.3 (9:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.35 – 7.28
(m, 1H), 5.70 (s, 1H), 5.36 (s, 1H), 4.95 (s, 2H), 3.04 – 2.89 (m, 1H), 1.26 (d, J = 7.0 Hz, 6H);
13C{H} NMR (100 MHz, CDCl3): δ 164.6, 155.6, 137.0, 135.6, 130.7, 127.9, 121.5, 121.0,
113.2, 71.4, 34.5, 29.7, 23.6; IR (KBr, cm-1): 2918, 1678, 1285, 1122, 955, 745; ESI-HRMS:
Calculated for C13H15O2 [M+H]+ 203.1067, found 203.1040.
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7.5. 6-bromo-4-methyleneisochroman-1-one (4e):
o
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Yield: 12% (10 mg); Physical appearance: White solid; M.p. 102 - 104 C; TLC Rf 0.3 (9:1,
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Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.4 Hz, 1H), 7.72 (d, J =
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1.8 Hz, 1H), 7.58 (dd, J = 8.4, 1.8 Hz, 1H), 5.72 (s, 1H), 5.44 (s, 1H), 4.96 (s, 2H); 13C{H} NMR
(126 MHz, CDCl3): δ 163.8, 138.4, 134.1, 132.7, 132.2, 129.2, 126.4, 122.5, 115.0, 71.2; IR
(KBr, cm-1): 2359, 1728, 1589, 1262, 1118, 1085; ESI-HRMS: Calculated for C10H8BrO2
[M+H]+ 240. 9682 and 238.9702, found 240.9663 and 238.9682.
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7.6. 6,7-dimethyl-4-methyleneisochroman-1-one (4f):
Yield: 61% (34mg); Physical appearance: Yellow gel; TLC Rf 0.3 (9:1, Petroleum ether:EtOAc);
1H NMR (400 MHz, CDCl3): δ 7.91 (s, 1H), 7.38 (s, 1H), 5.68 (s, 1H), 5.34 (s, 1H), 4.98 (s,
13
2H), 2.38 (s, 3H), 2.34 (s, 3H); C{H} NMR (126 MHz, CDCl3): δ 164.9, 143.8, 138.6, 135.3,
134.6, 131.1, 124.2, 121.2, 112.2, 71.5, 20.3, 19.6; IR (KBr, cm-1): 2917, 1716, 1613, 1317,
1164, 1046, 751; ESI-HRMS: Calculated for C12H13O2 [M+H]+ 189.0910, found 189.0897.
7.7. 7-methyl-4-methyleneisochroman-1-one (4g):
Yield: 58% (46 mg); Physical appearance: Yellow gel; TLC Rf 0.3 (9:1, Petroleum
ether:Acetone); 1H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.44 (d, J
13
= 8.0 Hz, 1H), 5.69 (s, 1H), 5.36 (s, 1H), 4.99 (s, 2H), 2.43 (s, 3H); C{H} NMR (126 MHz,
CDCl3): δ 164.8, 139.7, 135.1, 134.9, 134.3, 130.6, 123.4, 123.2, 112.6, 71.4, 21.2; IR (KBr,
cm-1): 2920, 1727, 1614, 1418, 1278, 1031, 790; ESI-HRMS: Calculated for C11H10O2Na
[M+Na]+ 197.0573, found 197.0562.
7.8. 6,7-dimethoxy-4-methyleneisochroman-1-one (4h):
o
Yield: 47% (32 mg); Physical appearance: White solid; M.p. 110 - 116 C; TLC Rf 0.3 (9:1,
Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 6.94 (s, 1H), 5.56 (s, 1H),
13
5.28 (s, 1H), 4.93 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H); C{H} NMR(126 MHz, CDCl3): δ 164.6,
154.0, 150.2, 135.2, 131.4, 116.5, 111.7, 111.4, 104.7, 71.5, 56.25, 56.2; IR (KBr, cm-1): 2918,
1726, 1615, 1316, 1248, 1092, 760; ESI-HRMS: Calculated for C12H13O4 [M+H]+ 221.0808,
found 221.0819.
AUTHOR INFORMATION
Corresponding Author
mk@iiserb.ac.in
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ORCID
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Diksha Singh: 0000-0002-2416-2536
Gangam Srikanth Kumar: 0000-0002-6052-9913
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Manmohan Kapur: 0000-0003-2592-6726
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Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the Internet at http://pubs.acs.org.
Copies of 1H and 13C spectra for all new compounds (PDF) and X-ray crystallographic data of 3i
and 4h.
ACKNOWLEDGMENTS
Funding from SERB-India (EMR/2016/004298) and CSIR-India (02(0361)/19/EMR-II is
gratefully acknowledged. GS thanks CSIR-India for a Research Fellowship. DS thanks IISERB
for a Fellowship. We also thank Director IISERB for funding and infrastructural facilities. We
thank the Reviewers for their suggestions, especially pertaining to the mechanism depicted in
Scheme 6.
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