N-heterocyclic carbene catalyzed intramolecular acylation of allylic electrophiles

Article abstract of DOI:10.1021/ol501046p

The N-heterocyclic carbene (NHC) catalyzed addition reaction has been well documented recently; however, the NHC-catalyzed substitution reaction especially the S_N2′ type reaction remains a challenge. As one of the most fundamental reaction types in organic chemistry, the S_N2′ reaction catalyzed by NHC would be a powerful tool in organic synthesis. Therefore, the first NHC-catalyzed intramolecular S_N2′ substitution reaction of aldehyde with allylic electrophiles has been developed. A variety of α,β-unsaturated chromanones were obtained under a domino S_N2′ reaction and isomerization. Mechanistic experiments were conducted to confirm the nature of this S_N2′ reaction.

Full text of DOI:10.1021/ol501046p

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene Catalyzed Intramolecular Acylation of Allylic
Electrophiles
Ming Zhao, Hui Yang, Miao-Miao Li, Jie Chen,* and Ling Zhou*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China
S
* Supporting Information
ABSTRACT: The N-heterocyclic carbene (NHC) catalyzed addition
reaction has been well documented recently; however, the NHC-
catalyzed substitution reaction especially the SN2′ type reaction remains a
challenge. As one of the most fundamental reaction types in organic
chemistry, the SN2′ reaction catalyzed by NHC would be a powerful tool
in organic synthesis. Therefore, the first NHC-catalyzed intramolecular SN2′ substitution reaction of aldehyde with allylic
electrophiles has been developed. A variety of α,β-unsaturated chromanones were obtained under a domino SN2′ reaction and
isomerization. Mechanistic experiments were conducted to confirm the nature of this SN2′ reaction.
mpolung reactivity is a valuable synthetic strategy in
organic chemistry because it offers unconventional
substitution reaction.7d It is important and increasingly
challenging to develop new reaction partners, especially new
reaction types to extend the application of the NHC catalysis.
To the best of our knowledge, the NHC-catalyzed reaction of
the acyl anion equivalent with any SN2′ electrophiles has not
been reported.8 Here we wish to report the NHC-catalyzed
intramolecular SN2′ acylation of allylic electrophiles, which
leads to the formation of α,β-unsaturated chromanones after
isomerization (Scheme1, eq 3).
U
methods to traditional bond formations.1 In recent years,
important advances in NHC catalyzed addition reactions have
been achieved in this field,2 such as the benzoin condensation2,3
and the Stetter reaction.2,4 Various electrophiles have been
explored in the NHC-catalyzed addition reactions.2−5 Besides
the NHC-catalyzed addition of the acyl anion equivalent to the
activated Michael acceptor (Scheme1, eq 1),4 the hydro-
Inspired by the NHC-catalyzed addition reactions, we
envisage that the acyl anion equivalent could nucleophilically
attack an allylic electrophile intramolecularly as an SN2′
substitution reaction, and the catalytic cycle would be closed
if a base can deprotonate the addition intermediate to release
an acid HL. The process is similar to the Stetter reaction, but
the enolate protonation step via an intramolecular proton
transfer in the Stetter reaction was replaced by an
intermolecular deprotonation step in this designed reaction.
Accordingly, a good leaving group is expected to be beneficial
to this substitution reaction.
Scheme 1. NHC-Catalyzed Intramolecular Cyclizations
To test this hypothesis, an NHC-catalyzed SN2′ substitution
cyclization of compound 1a bearing an aldehyde group and an
allylic bromide was examined. To our delight, the substitution
cyclization product was obtained. Treatment of 1a with
thiazolium salt 3 in the presence of 2.0 equiv of K2CO3 in
acetonitrile at 80 °C for 5 h resulted in the formation of α,β-
unsaturated chromanone 2a in 28% yield (Table 1, entry 1).
Notably, the desired product 2aa was not observed; the reason
can be ascribed to the isomerization of the α-vinyl ketone
moiety to the more stable α,β-unsaturated ketone with the E-
configuration under the reaction conditions.9 Next we
attempted to optimize the reaction by varying different
parameters systematically. Various bases and solvents were
acylation of unactivated alkenes and alkynes has also been
developed (Scheme1, eq 2).6 However, compared with the
successfully developed NHC-catalyzed addition reactions, the
utilization of NHCs for the nucleophilic substitution reactions
is still lacking; only a few examples using activated alkyl or aryl
halides have been explored.7 In some cases, even a
stoichiometric amount of NHCs is used to realize the
Received: April 10, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501046p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. NHC-Catalyzed Acylation of Allylic Bromides:
Variation of the Aromatic Ring
a
NHC·HX
(x mol %)
t
time
yield
b
entry
base (equiv)
solvent
(°C) (h)
(%)
1
2
3
4
3 (15)
3 (15)
3 (15)
3 (15)
K2CO3 (2.0) CH3CN
K2CO3 (2.0) THF
80
70
60
60
5
5
2
2
28
5
K2CO3 (1.2) 1,4-dioxane
16
15
Cs2CO3
(1.2)
1,4-dioxane
5
3 (15)
3 (15)
3 (15)
3 (15)
3 (15)
3 (15)
3 (10)
4 (15)
5 (15)
6 (15)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (0.3)
DBU (2.0)
DBU (1.1)
DBU (1.2)
DBU (1.2)
DBU (1.2)
CH3CN
60
60
60
25
60
60
60
60
60
60
2
63
76
65
43
14
<5
64
9
6
1,4-dioxane
THF
1.5
2
7
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
3
9
2
10
11
12
13
14
2
1.5
2
2
<5
6
2
a
Reactions were carried out with compound 1a (0.2 mmol), NHC·HX
b
(x mol %), and base (equiv) in solvent (2 mL). Isolated yield.
screened, and we eventually discovered that a DBU (1.2 equiv)
in a 1,4-dioxane system at 60 °C for 1.5 h dramatically
enhanced the yield to 76% (Table 1, entry 6). As expected,
using a substoichiometric amount of DBU (0.3 equiv) gave the
product in low yield (Table 1, entry 9). Surprisingly, excess
DBU (2.0 equiv) resulted in only a trace amount of the product
(Table 1, entry 10), which may be ascribed to the product
being unstable under these basic reaction conditions.10
Attempts to decrease the catalytic loading to 10 mol %
reduced the yield clearly (Table 1, entry 11 vs 6). We have also
investigated other NHCs including compounds 4−6 (Table 1,
entries 12−14), none of which was found to be as effective as
3.11
Having identified the optimized conditions, we examined this
new method in a range of substrates with different substitution
patterns of the aromatic ring (Scheme 2). Overall, a variety of
α,β-unsaturated chromanones were successfully prepared, and
various substituents on the aromatic ring were found to be
tolerable in this process. Substrates with electron-rich
substituents at the 3-position and electron-deficient substitu-
ents at the 4-position of the phenyl ring resulted in the desired
chromanones with good yields (2b, c, e). However, the
electron-rich 4-methoxyl substituted substrate 1d returned a
moderate yield (2d). The negative effects of the electron-rich
substrate 1d on the yield may be attributed to the low reactivity
of the aldehyde with the NHC catalyst. Substrates with various
substituents at the 5-position of the phenyl ring are all well
tolerated (2f−i). The 1-naphthaldehyde substrate also returned
a good yield (2m), and a higher yield was obtained by
decreasing the reaction time (2m, 73%, 0.5 h vs 44%, 1.5 h).
This phenomenon is similar to the case previously observed
a
For the standard reaction conditions, see Table 1, entry 6. Yields
shown are for the isolated products. b Reaction time is 1.0 h. c Reaction
time is 0.5 h.
during optimization of the reaction (Table 1, entry 10),
indicating that this type product is unstable under basic
reaction conditions.10 Additionally, disubstituted substrates
with alkyl and halogen substituents worked well (2j−l).
Furthermore, substrates with a nitrogen or sulfur tether also
returned the desired acylation and isomerization products with
moderate to good yields (2n, o). Satisfactorily, α,β-unsaturated
indanone 2p was obtained in 84% yield under the optimal
conditions. Unfortunately, an aliphatic aldehyde substrate
returned no desired product.12
Besides allylic bromide as an electrophile, other electrophiles
such as allylic chloride and tosylate are all suitable for this
NHC-catalyzed substitution cyclization reaction (Table 2).
Under the optimal conditions, chloro-aldehyde 7 was
examined; however, the desired product 2a was obtained
only in 6% yield (Table 2, entry 1). This may be ascribed to the
leaving ability of chloride not being as good as that of bromide;
then, the reaction temperature was raised to 80 °C, and the
yield was increased to 29%. As a good leaving group, tosylate
substrate 8a here resulted in a comparable yield as bromide
substrate 1a (Table 2, entry 3). Similar results were observed
when other tosylate substrates were employed in this reaction
(Table 2, entries 4−6).
The reaction mechanism may follow our proposal that
involves an SN2′ reaction and isomerization. On the other hand,
B
dx.doi.org/10.1021/ol501046p | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. NHC-Catalyzed Acylation of Allylic Electrophiles:
Variation of the Leaving Groups
Scheme 5. Proposed Catalytic Cycle
a
b
entry
substrate
R1
R2
Cl
product
yield (%)
6
1
2
3
4
5
6
7
H
H
H
2a
2a
2a
2f
2i
c
7
Cl
29
8a
8b
8c
8d
OTs
OTs
OTs
OTs
70
71
81
5-Me
5-Br
3,5-Br2
2l
83
a
b
For the standard reaction conditions, see Table 1, entry 6. Yields
c
shown are for the isolated products. The reaction temperature is 80
°C.
of C and liberation of NHC complete the catalytic cycle
resulting in the formation of compound 2aa. Finally, isomer-
ization of 2aa yields more stable α,β-unsaturated chromanone
2a.
this reaction may follow the other possible pathway: first, the
NHC-catalyzed hydroacylation of alkene to yield a bromo-
intermediate,6 and, second, elimination of HBr under the basic
conditions followed by isomerization to produce the desired
product 2 (Scheme 3). However, the proposed bromo-
intermediate 9 was not detected during the reaction even
when the reaction was conducted at rt (Table 1, entry 8).13
In summary, we have developed the first NHC-catalyzed
intramolecular SN2′ substitution reaction of aldehyde with
allylic electrophiles. Mechanistic studies revealed that this
reaction does not follow the addition−elimination mechanism,
but the SN2′ type reaction. The reaction features good yields
and excellent functional-group tolerance, making it applicable
Scheme 3. Possible Pathway to 2a
to structurally complex compounds and drug discovery.15
A
variety of α,β-unsaturated chromanones were obtained through
a domino SN2′ reaction and isomerization. Further inves-
tigations on other NHC-catalyzed substitution reactions are
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data for all new
compounds; and copies of 1H, 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
To further probe the mechanism, the corresponding bromo-
intermediate 9 was synthesized in three steps from compound
10 (Scheme 4). NHC-catalyzed hydroacylation of 10 according
■
S
Scheme 4. Synthesis of Compound 9 and 12
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chmchenj@nwu.edu.cn.
*E-mail: zhoul@nwu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC-21203148, 21302151), Science and Technology
Department of Shaanxi Province (2013JQ2012), Education
Department of Shaanxi Province (2013JK0644), the New
Teachers’ Fund for Doctor Stations (20126101120010), the
Scientific Research Foundation for the Returned Overseas
Chinese Scholars, Ministry of Education, and the Northwest
University for financial support.
to the Glorius method gave ketone 11 quickly in 26% yield
(none optimized).6a Then, saponification and bromination of
11 yielded 9 (46%) in two steps. Treatment of 9 under the
above-mentioned optimal conditions gave no 2a, but
compound 12 in 92% yield, as a result of an intramolecular
substitution reaction. Thus, the addition−elimination−isomer-
ization mechanism is ruled out, and the reaction mechanism
should follow our proposal that involves an SN2′ substitution
reaction and isomerization.
The proposed catalytic cycle is shown in Scheme 5. First,
addition of carbene catalyst A to aldehyde 1a forms Breslow
intermediate B.14 Next intramolecular nucleophilic attack of the
allylic bromide by the enaminol group via SN2′ type reaction
gives intermediate C. Further deprotonation of hydroxyl group
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