Rh(III)-Catalyzed [3 + 2] Spirocyclization of 2 H-Imidazoles with 1,3-Diynes for the Synthesis of Spiro-[imidazole-indene] Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c02805

An effective strategy to synthesize spirocyclic compounds, [imidazole-4,1′-indene], has been efficaciously developed relied on Rh(III)-catalyzed [3 + 2] spirocyclization of 2H-imidazoles and 1,3-diynes with excellent chemselectivity and regioselectivity.

Full text of DOI:10.1021/acs.orglett.0c02805

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Letter
Rh(III)-Catalyzed [3 + 2] Spirocyclization of 2H‑Imidazoles with 1,3-
Diynes for the Synthesis of Spiro-[imidazole-indene] Derivatives
Yi Luo, Hao Liu, Jing Zhang, Man Liu, and Lin Dong*
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ABSTRACT: An effective strategy to synthesize spirocyclic compounds,
[imidazole-4,1′-indene], has been efficaciously developed relied on Rh(III)-
catalyzed [3 + 2] spirocyclization of 2H-imidazoles and 1,3-diynes with
excellent chemselectivity and regioselectivity. This protocol shows a
straightforward way to construct the versatile spirocyclic compounds with
wide functional group compatibility, high atom economy, and diverse
functionalization of products.
pirocyclic frameworks, bearing spiro[imidazolidine-4,1′-
Scheme 1. Metal-Catalyzed C−H Activation by 1,3-Diynes
S
indene], lie in many bioactive molecules and pharmaceut-
icals, which are widely concerned by synthetic and medical
chemistry (see Figure 1).1 There are versatile efforts dedicated
Figure 1. Representative compounds.
to the synthesis of spirocyclic compounds.2 However, tradi-
tional methods are ordinarily involved in multistep processes
with a demand of complicated catalytic systems as well.
Accordingly, there remains a great need to search for a
desirable approach to synthesize complex spiro compounds.
C−H bond functionalization catalyzed by transition metals has
been served as a well-established measure to build spirocyclic
products in recent years.3
Since the Glaser coupling reaction appeared, 1,3-diynes have
been extensively utilized as a raw material to assemble complex
aromatic or heterocyclic compounds.4 After that, many
attempts for the elaboration of this motif have been presented.5
Despite its importance, reported examples sparingly underwent
broadly applicable C−H functionalization strategy,6 because it
is very difficult to control the chemselectivity and regiose-
lectivity of two alkyne bonds. Very recently, Glorius
demonstrated a selective alkenylation pathway to get 1,3-
enyne molecules catalyzed by Mn(I) (see eq 1 in Scheme 1),7
and most of the C−H activation reactions that involve diynes
went through a [4 + 2] annulation process to produce six-
membered ring structures (see eq 2 in Scheme 1).6 There is
our growing interest in developing the 2H-imidazole unit.
Herein, we report a new [3 + 2] annulation reaction that
involves C−H functionalization strategy catalyzed by Rh(III)
to build multifunctional spirocyclic [imidazole-4,1′-indene]
derivatives from 1,3-diynes (see eq 3 in Scheme 1). Notably,
we only obtained isoquinoline scaffolds with 2H-imidazoles as
directing groups,8 which had heretofore seldom been
investigated in C−H functionalization (see eq 4 in Scheme 1).9
We initiated our explorations by applying the 2H-imidazole
motif (1a) with 1,3-diynes (2a) under diverse conditions for
envisioned C−H activation (see Table 1). Delightfully,
Received: August 21, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02805
© XXXX American Chemical Society
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A

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Letter
a
Next, the applicability of 2H-imidazoles was explored
(Scheme 2). A great array of 2H-imidazoles containing
Table 1. Optimization of Reaction Conditions
a
Scheme 2. Substrate Scope of 2H-Imidazoles
b
entry
additive/equiv
Cu(OTf)2/2
AgOAc/2
Cu(OAc)2/2
Cu(acac)2/2
solvent
yield (%)
1
2
3
4
5
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
PhCl
TFE
DME
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
21
47
58
67
69
45
61
57
34
50
49
56
55
54
20
49
95
79
75
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2/AgSbF6/0.3
Mn(OAc)3·2H2O/2/AcOH/1
Mn(OAc)3·2H2O/2/1-AdCOOH/1
Mn(OAc)3·2H2O/2/PivOH/1
Mn(OAc)3·2H2O/2/NaOAc/1
Mn(OAc)3·2H2O/2/Na2CO3/1
Mn(OAc)3·2H2O/2/KPF6/1
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/0.3
−
c
6
d
7
8
9
10
11
12
13
14
15
16
a
Reaction conditions: 1 (0.1 mmol), 2a (2.0 equiv), [Cp*Rh-
(MeCN)3(SbF6)2] (5 mol %), Mn(OAc)3·2H2O (2.0 equiv), DCE (1
mL) at 100 °C for 12 h, under air, isolated yield.
e
17
e
18
19
e
e f
g
,
substituents with different electrical characteristics were
smoothly transformed with 2a. 2H-imidazoles with substitu-
ents in the para-position of aryl group were all afforded, giving
products (3ba−3fa) in excellent yields (91%−98%). In
addition, the meta-substituted substituents provided the
corresponding products (3ga−3ia) still in excellent yields
with excellent regioselectivity (90%−95%). However, ortho-
substituted 2H-imidazole generated the compound 3ja in 36%
yield, probably because of the steric hindrance. Notably, the n-
butyl substituent did not decrease the reaction efficiency at all,
affording the corresponding 3ka in 97% yield. Moreover, the
substrates bearing cyclohexyl or cyclopropyl groups also
exhibited superior reactivity, delivering spiro compounds (3la
and 3ma) in great yields (95% and 72%, respectively).
Gratifyingly, using 3-phenylquinoxalinyl propionate as a
substrate to react with 2a, the novel spirocyclic product 3na
could be obtained in 88% yield.
Subsequently, the applicability of reaction regarding a great
variety of 1,3-diynes was tested (Scheme 3). Various
substituted diaryl 1,3-diynes showed high reactivity in the
protocol, producing envisioned compounds (3ab−3af) in
good to great yields (81%−92%). It is noted that TMS-
substituted 1,3-diyne 2g worked smoothly, generating a
desirable product 3ag in 85% yield, which could further
transform to diverse useful products. Alkyl-substituted 1,3-
diynes 2h was also a suitable reactant. Next, we proceeded to
probe the generality of this method with multifarious
unsymmetrical 1,3-diynes. Excitedly, the asymmetrical sub-
strates 2i−2k, containing TMS, t-butyl, and tertiary hydroxy
groups, afforded compounds in moderate to great yields
(64%−94%) with excellent chemselectivity and regioselectiv-
ity, which implied that the steric effect affects the reaction
selectivity. Meanwhile, asymmetrical substrates bearing a
primary alcohol structure providing the single isomers 3al
and 3am in 55% and 77% yields, respectively. Similarly, the
presence of unbiased diynes containing secondary hydroxyl
20
21
22
23
24
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2
Mn(OAc)3·2H2O/2
nd
nd
nd
nd
e h
g
,
e i
g
,
e j
g
,
k
72
a
Unless otherwise stated, reaction conditions are as follows: 1a (0.05
mmol), 2a (1.0 equiv), [Cp*Rh(MeCN)3(SbF6)2] (5 mol %), solvent
b
c
(0.5 mL) at 100 °C for 12 h, under air. Isolated yield. Ar
d
e
f
atmosphere. [Cp*RhCl2]2 (5 mol %). 2a (2.0 equiv). [Ru(p-
g
h
cymene)Cl2]2 (5 mol %). Not determined. [Cp*IrCl2]2 (5 mol %).
i
j
k
Cp*Co(CO)I2 (5 mol %). Without [Cp*Rh(MeCN)3(SbF6)2]. 1a
(1.0 mmol), 2a (2.0 equiv), DCE (10 mL).
unprecedented spiro product 3aa was detected in 21% yield by
employing a catalytic amount of [Cp*Rh(MeCN)3(SbF6)2]
and Cu(OTf)2 as an additive at 100 °C in DCE (Table 1, entry
1), which was verified by X-ray analysis.10 Among various
additives screened, Mn(OAc)3·2H2O obviously enhanced the
efficiency of catalytic system, affording the product in 69%
yield (Table 1, entries 2−5). The yield of reaction was reduced
to 45% in argon atmosphere (Table 1, entry 6). [Cp*RhCl2]2
as the catalyst also showed good activity (Table 1, entry 7). In
addition, the introduction of acid or base had no improvement
on the reaction (Table 1, entries 8−13). During further solvent
screening, dichloroethane (DCE) was proven to be the best
(Table 1, entries 14−16). It is pleasing that the yield of 3aa
was increased to 95%, when the amount of 1,3-diynes was
increased to 2.0 equiv (Table 1, entry 17). Reducing the
amount of Mn(III) gave rise to poor reactivity, while the [3 +
2] reaction could still occur in the absence of Mn(OAc)3·
2H2O (Table 1, entries 18 and 19). However, other metal
catalysts exhibited negative activity (Table 1, entries 20−22).
While without [Cp*Rh(MeCN)3(SbF6)2], no reaction oc-
curred (Table 1, entry 23). Moreover, this reaction could be
smoothly scaled up, giving 3aa in 72% yield (Table 1, entry
24).
B
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a
Scheme 3. Substrate Scope of 1,3-Diynes
Scheme 4. Synthetic Applications
Scheme 5. Preliminary Mechanistic Investigation
a
Reaction conditions: 1a (0.1 mmol), 2 (2.0 equiv), [Cp*Rh-
(MeCN)3(SbF6)2] (5 mol %), Mn(OAc)3·2H2O (2.0 equiv), DCE (1
b
mL) at 100 °C for 12 h, under air, isolated yield. Mn(OAc)3·2H2O
(0.3 equiv), 1-AdCOOH (2.0 equiv), 1,4-dioxane (1 mL).
group was well-tolerated, leading to the single product 3an in
71% yields via the same regioselectivity. Notably, triynes 2o
was also very suitable for this coupling system. However, when
using electron-withdrawing 1,3-diynes (2p−2q) as a substrate,
none of reaction can proceed, which indicated that electron-
poor substrates were not applicable to this reaction. Similarly,
we have tried to use 2r as a coupling partner, while still no
desired product was observed. We suppose that 1,3-diynes
used as substrates proceed smoothly, because 1,3-diynes are
electron-rich structural units with large conjugation compared
to other alkynes, which is easier to chelate with the metal for
subsequent migration and insert the C−Rh bond in the cycle
of catalysis.
To illustrate the diversity of spirocyclic indenes, representa-
tive transformations were completed under the reported
conditions in Scheme 4. Compounds 3ai and 3am can be
respectively transformed to desilylation products 4ai and 4am
with K2CO3 (eq 5 in Scheme 4). Different removing methods
generated bis- or monodesilylation products 4ag and 5 in
excellent yields (eqs 6 and 7 in Scheme 4). Treatment 5 with
TMSN3 under different conditions to afford alkenyl azide 6 or
triazole 7 (eqs 7 and 8 in Scheme 4). 3aa could be converted
to amide compound 8 (eq 9 in Scheme 4).
To probe the reaction mechanism, competition reactions
underwent between 2a and 2g with 2H-imidazole 1a under
reaction conditions, which showed aromatic substituents
showed better reactivity (Scheme 5, eq 10). 80% Deuterium
was discovered at the both ortho-positions of 2H-imidazole 1a
without 2a. Remarkably, the experiment gave a methyl group
with obvious deuterium (Scheme 5, eq 11). 9 could be formed
under standard conditions, which indicated that the methyl site
is reactive (Scheme 5, eq 12). Finally, a kinetic isotope
experiment was performed,11 thus implying that the cleavage
process of the C−H bond is fast and not a rate-limiting step
(Scheme 5, eqs 13 and 14).
According to experimental results and known reports,3a,b,8a
a
reasonable catalytic cycle has been presented in Scheme 6.
First, RhIII species coordinates with the N-atom of 2H-
imidazole 1a to afford a five-membered rhodacycle I.
C
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Letter
Center for Drug Precision Industrial Technology, West China
School of Pharmacy, Sichuan University, Chengdu 610041,
China
Scheme 6. Plausible Mechanism
Man Liu − Key Laboratory of Drug-Targeting and Drug Delivery
System of the Education Ministry, Sichuan Research Center for
Drug Precision Industrial Technology, West China School of
Pharmacy, Sichuan University, Chengdu 610041, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02805
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Subsequently, 1,3-diynes 2a coordinates with rhodacyclic
intermediate I, then the migratory insertion of diynes yields
intermediate II. Finally, key intermediate III may be formed
via Grignard-type migration, producing the final product 3aa
via proto-demetalation.
Generally, we accomplished a new highly chemselectivity
and regioselectivity approach to synthesize spiro[imidazole-
4,1′-indene] derivatives through rhodium-catalyzed [3 + 2]
spirocyclization reactions of 2H-imidazoles and 1,3-diynes.
Various complex multifunctional spirocyclic derivatives were
constructed using this efficient and atom-economy strategy,
which could further transform to the more-useful molecules.
We thank the financial support from the NSFC (No.
21572138), Key Laboratory of Drug-Targeting and Drug
Delivery System of the Education Ministry, Sichuan Research
Center for Drug Precision Industrial Technology. We also
thank the Analytical & Testing Center of Sichuan University
for X-ray crystallography and Daibing Luo for performing the
analysis.
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02805.
Synthetic procedures, analysis of new molecules, data of
X-ray analysis, and NMR spectrum of products (PDF)
Accession Codes
CCDC 2006938 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Lin Dong − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Education Ministry, Sichuan Research
Center for Drug Precision Industrial Technology, West China
School of Pharmacy, Sichuan University, Chengdu 610041,
China; orcid.org/0000-0002-8004-821X; Email: dongl@
scu.edu.cn
Authors
Yi Luo − Key Laboratory of Drug-Targeting and Drug Delivery
System of the Education Ministry, Sichuan Research Center for
Drug Precision Industrial Technology, West China School of
Pharmacy, Sichuan University, Chengdu 610041, China
Hao Liu − Key Laboratory of Drug-Targeting and Drug Delivery
System of the Education Ministry, Sichuan Research Center for
Drug Precision Industrial Technology, West China School of
Pharmacy, Sichuan University, Chengdu 610041, China
Jing Zhang − Key Laboratory of Drug-Targeting and Drug
Delivery System of the Education Ministry, Sichuan Research
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diynes: (a) Kathiravan, S.; Nicholls, I. A. Org. Lett. 2017, 19, 4758−
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(10) Crystallographic data for 3aa: CCDC 2006938, C28H24N2, M =
̅
388.49 g/mol, space group P1, unit cell: a = 10.4080(6) Å, b =
10.6994(6) Å, c = 21.3995(14) Å, α = 77.444(5)°, β = 83.211(5)°, γ
= 71.757(5)°, temperature = 293.15 K. calcd density = 1.170 g/cm3.
(11) For more information, please see the Supporting Information.
E
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