External Oxidant-Dependent Reactivity Switch in Copper-Mediated Intramolecular Carboamination of Alkynes: Access to a Different Class of Fluorescent Ionic Nitrogen-Doped Polycyclic Aromatic Hydrocarbons

Article abstract of DOI:10.1021/acs.joc.9b00120

An interesting case of external oxidant-controlled reactivity switch leading to a divergent set of ionic nitrogen-doped polycyclic aromatic hydrocarbons (N-doped PAHs), is presented here, which is quite unrecognized in copper-mediated reactions. In the current scenario, from the same pyridino-alkyne substrates, the use of the external oxidant PhI(OAc)₂, in combination with Cu(OTf)₂, gave N-doped spiro-PAHs via a dearomative 1,2-carboamination process; whereas, without the use of oxidant, an alkyne/azadiene [4 + 2]-cycloaddition cascade occurred to exclusively afford ionic N-doped PAHs. These newly synthesized N-doped PAHs further exhibit tunable emissions, as well as excellent quantum efficiencies.

Full text of DOI:10.1021/acs.joc.9b00120

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Article
External Oxidant-Dependent Reactivity Switch in Copper-Mediated
Intramolecular Carboamination of Alkynes: Access to a New Class of
Fluorescent Ionic Nitrogen-Doped Polycyclic Aromatic Hydrocarbons
Aslam C. Shaikh, Somsuvra Banerjee, Ravindra D. Mule, Saibal Bera, and Nitin T. Patil
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00120 • Publication Date (Web): 28 Feb 2019
Downloaded from http://pubs.acs.org on February 28, 2019
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External Oxidant-Dependent Reactivity Switch in Copper-Mediated
Intramolecular Carboamination of Alkynes: Access to a New Class of
Fluorescent Ionic Nitrogen-Doped Polycyclic Aromatic Hydrocarbons
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Aslam C. Shaikh,b,d Somsuvra Banerjee,b,d Ravindra D. Mule,b,d Saibal Berac,d and Nitin T.
Patila*
aDepartment of Chemistry, Indian Institute of Science Education and Research (IISER)-Bhopal,
Bhopal – 462 066, India.
bDivision of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune – 411 008, India.
cDivision of Physical and Materials Chemistry, CSIR-National Chemical Laboratory, Dr. Homi
Bhabha Road, Pune – 411 008, India.
dAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad – 201 002, India.
ABSTRACT:
Fluorescent PAHs
R'
Cu(OTf)2
Oxidant
Cu(OTf)2
Oxidant
OTf
O
OTf
N
C
N
N
R'
R''
R'
H
R
R''
activation
R
R''
R
Harder Cu(III) ipso-cyclization
Softer Cu(II)
C
H
Reactivity Switch
An interesting case of external oxidant-controlled reactivity switch leading to a
divergent set of ionic Nitrogen-Doped Polycyclic Aromatic Hydrocarbons (N-doped
PAHs), is presented here which is quite unrecognized in copper mediated reactions. In the
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current scenario, from the same pyridino-alkyne substrates, the use of external oxidant
PhI(OAc)2 in combination with Cu(OTf)2, gave N-doped spiro-PAHs via a dearomative
1,2-carboamination process; whereas, without the use of oxidant, an alkyne/azadiene
[4+2]-cycloaddition cascade occurred to exclusively afford ionic N-doped PAHs. These
newly synthesized N-doped PAHs further exhibit tuneable emissions as well as excellent
quantum efficiencies.
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INRODUCTION
Nitrogen-doped Polycyclic Aromatic Hydrocarbons (N-doped PAHs)1 have garnered
considerable attention owing to their interesting applications in the field of optoelectronics, light
emitting-diodes, supercapacitors and bio-imaging.2,3 It was recently employed as efficient DNA
intercalators as well.4 Consequently, various methods of synthesis have been devised for these
class of compounds. However, available approaches to access N-doped PAHs are confined to
ring-closing metathesis reactions or Rh/Ru catalyzed aromatic C–H activation between
,5
arenes/heteroarenes.1a
Considering their growing importance and multi-purpose
applications, development of newer methods for expedient access to N-doped PAHs is
highly desirable.
For the past decade, metal mediated carboamination reactions of C–C multiple
bonds continue to be one of the most attractive strategies in synthetic organic chemistry
for the incorporation of two distinct functionalities, carbon and nitrogen, across C–C
multiple bonds in a single operation (Scheme 1a).6 For instance, Chemler’s group
pioneered to disclose copper catalyzed/mediated oxidative carboamination reactions to
construct several nitrogen-embedded heterocycles (Scheme 1ba).7 An outstanding
demonstration of external-oxidant-aided Au(I)/Au(III) catalysis strategy has been
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developed by the groups of Toste and Zhang who independently reported carbohetero-
functionalization reaction of alkenes (Scheme 1bb).8 Further, Yang and co-workers
elegantly demonstrated the Pd-catalyzed oxidative carboamination reactions to access
indolines (Scheme 1bc).9 Very recently, in 2017, Liu and co-workers reported a Pd-
catalyzed asymmetric intramolecular oxidative carboamination reaction of alkenes to
access indolines (Scheme 1bd).10
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Based on our previous report on gold-catalyzed oxidative intramolecular 1,2-
amino-oxygenation reaction of alkynes 1 to Pyridinium-Oxazole Diads (PODs) (Scheme
1c, R = OtBu),11 we wondered whether ionic N-doped PAHs could be derived from
substrate of type 1 (Scheme 1c, R = Ar) via 1,2-carboamination of alkynes in the presence
of metal/oxidant conditions. Accordingly, when several metal catalysts/oxidants were
screened (vide infra), an interesting oxidant-dependent reactivity switch was observed
which led to the discovery of two new classes for N-doped PAHs, 2 and 3, starting from
the same substrate 1 through copper-mediated method. The product 2 is a result of
oxidant-unaided carboamination via alkynes/azadienes [4+2]-cycloaddition cascade of 1;
whereas, product 3 is a result of oxidative dearomative carboamination of 1. Of note, part
of this work comprising the Cu(II)-mediated intramolecular [4+2]-cycloaddition cascade
leading to PAHs 2 has been communicated by our group recently.12 Herein, we report full
details of our findings on the dearomative carboamination process leading to ionic N-
doped spiro-PAHs (1→PAHs 3, Scheme 1c) with due comparison to that of ionic N-
doped PAHs 2.13
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a) Catalytic difunctionalization of CC multiple bonds:
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+
C
N
cat M
oxidant
C
N
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9
b) Catalytic intramolecular oxidative carboamination of alkenes:
R'
R' R'
C
ba: cat Cu - Chemler
bb: cat Au - Toste/Zhang
bc: cat Pd - Yang
R'
C
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cat M
N
oxidant
N
H
bd: cat Pd - Liu
R' = H, alkyl, aryl
c) Metal-mediated carboamination of alkynes: Our previous and present work:
OTf
N
MeO
oxidant
[Cu]
cat [Au]
Selectfluor
Our work
(2018)
R'
BF4
R
N
N-doped PAHs (2)
N
O
Our work
(2017)
R = Ar
This
work
R'
1
R = OtBu
R'
PODs
oxidant
O
OTf
N
R'
N-doped spiro-PAHs (3)
Scheme 1. Metal-mediated 1,2-carboamination reactions
RESULTS AND DISCUSSION
We initiated our study by choosing 2-(4-methoxyphenyl)-6-(2-(phenylethynyl)phenyl)
pyridine (1a) as a model substrate (Table 1). Based on the available literature on oxidative gold
catalysis,14 and taking our previous study11 as a reference point, we endeavoured to investigate
the proposed reaction with various gold catalysts in the presence of Selectfluor (oxidant, 1.0
equiv) in CH3CN:MeOH15 (99:1 v/v) at 80 °C. Accordingly, gold catalysts such as Ph3PAuCl,
(C6F5)3PAuCl and JohnPhosAuCl were examined; however, the desired product 3 [X = BF4] was
not observed in any of the cases (entries 1-3). On the contrary, we found that Cu(OTf)2 in
combination with Selectfluor can afford 2 [X = BF4] in 62% yield (entry 4). Several other copper
catalysts were also tested but to no avail; they continued to furnish 2 [X = BF4] in varied yields
(entries 5-8). When other oxidants were tried in combination with Cu(OTf)2, we were
encouraged to observe PAH 3a [X = OTf]; albeit in poor yields (entries 9-11). Without oxidant,
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the reaction yields 2a [X = OTf] (entry 12) in 17% yield; such low yield was expected because
now there’s no entity in the reaction to provide the counter-anion X. Here, it is important to note
that the contrast between entries 9-11 and entry 12 gave an early indication of an oxidant
dependent selectivity of the carboamination reaction. Therefore, we decided to capitalize the
opportunity by searching for two optimum orthogonal reaction conditions leading to PAH 2a or
3a. Not surprisingly, when catalytic loading of Cu(OTf)2 was hiked, the formation of 3a started
to increase (37%, entry 13) and reached a maximum with stoichiometric amount of Cu(OTf)2
(78%, entry 14). On the other hand, use of oxidant PhI(OAc)2 in combination with 1.0 equiv of
Cu(OTf)2 completely switched the reactivity (entries 15-16) and obtained 3a in 94% when 1.5
equiv of oxidant was used (entry 17). We further surmised that the presence of –OTf containing
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Table 1. Optimization studies for catalysts and oxidantsa
X
N
MeO
Ph
cat. M (Z mol%)
oxidant (Y equiv)
2
N
+
CH3CN, 80 °C
12 h
MeO
Ph
X
O
N
1a
Ph
3
Sr.
No.
Yield (%)b
Cat [M] (Z mol%)
(C6F5)3PAuCl (10)
Ph3PAuCl (10)
Oxidant (Y equiv)
Selectflour (1.0)
Selectflour (1.0)
Selectflour (1.0)
Selectflour (1.0)
Selectflour (1.0)
2
3
1
2
3
4
5
--
--
--
--
--
--
--
--
JohnPhosAuCl (10)
Cu(OTf)2 (10)
62c
48
[Cu(OTf)]2·C6H6 (10)
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CuCl2 (10)
Selectflour (1.0)
Selectflour (1.0)
Selectflour (1.0)
Ph2I(OTf) (1.0)
PhI(OAc)2 (1.0)
PhI(CF3CO2)2 (1.0)
--
41
52
57
--
--
--
7
Cu(OAc)2 (10)
Cu(ACN)4BF4 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (50)
Cu(OTf)2 (100)
Cu(OTf)2 (100)
Cu(OTf)2 (100)
Cu(OTf)2 (100)
8
--
9
09d
18d
12d
--
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10
11
12
13
14
15
16
17
--
--
17d
37
78
--
--
--
--
--
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.5)
82
85
94
--
--
aStandard Reaction condition: 0.11 mmol 1a, Z mol% catalyst [M], Y equiv of oxidant, CH3CN (2.0 ml),
80 °C, 12 h. bIsolated yields. cCounter anion X = BF4. dCounter anion X = OTf.
additives would make the reaction catalytic with respect to copper. In this regard, various
additives such as Zn(OTf)2, Sc(OTf)3 and TfOH were examined for both the reactions leading to
2a or 3a (not shown here). However, they were not found to be satisfactory. The structures of
product 2a and 3a were unambiguously confirmed by the X-ray crystallographic analysis (see
Table 2).
Having optimized the reaction conditions, the scope and generality of these two divergent
reactions were studied (Table 2). First, substrates with variation in aryl ring at alkyne-terminus
(1a-1n) were put to test. Initially, it worked well with functional groups such as alkyl and –OMe
under both the conditions (2b-2d and 3b-3d). However, stronger electron donating group such as
–NMe2 was incompatible under the reaction conditions (2e or 3e). With varying substitution
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pattern (ortho, meta, para) on the previously mentioned aryl moiety, both the carboamination
reactions were well tolerated to furnish the corresponding PAHs in good yields (2f-2n and 3f-
3n). Next, screening of substrates bearing bulky aromatics or long-chain/cyclic aliphatics at the
alkyne terminus of the pyridino alkynes (1o-1s) were undertaken. The substrate with sterically
encumbered pyrenyl group results only in desired PAHs 2p (85% yield) but not the
corresponding spiro-PAHs 3p; whereas, 1o, carrying bulky 1-Np aromatic ring, efficiently
afforded both the corresponding PAHs 2o and 3o in 80 and 68% yields, respectively.
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Table 2. Substrate scope of reactiona,b
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Cu(OTf)2
Cu(OTf)2
N
B
A
9
PhI(OAc)2
No PhI(OAc)2
MeO
R'
R
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2a, CCDC 1824190
3a, CCDC 1557530
1a-1af
Scope w.r.t. ring B lacking
4-OMe group
2a, R = H, 78%
2b, R = Me,76%
2c, R = nC5H11, 74%
2d, R = OMe, 48%
2e, R = NMe2, --%c
2f, R = F, 78%
3a, R = H, 94%
3b, R = Me, 88%
3c, R = nC5H11, 78%
3d, R = OMe, 43%
3e, R = NMe2, --%c
3f, R = F, 85%
OTf
O
OTf
N
N
MeO
N
Ar
2g, R = Cl, 75%
Ph
3g, R = Cl, 75%
R
1ag-1am
2h, R = COC4H9, 81%
3h, R = COC4H9, 83%
R
Cu(OTf)2
2i, R = 2-OMe, 57%
2j, R = 3-OMe, 62%
2k, R = 3-Cl, 72%
2l, R = 3,5 di-OMe, 78%
2m, R = 3-Cl, 4-Me, 76%
2n, R = 2-Cl, 5-OMe, 63%
3i, R = 2-OMe, 74%
3j, R = 3-OMe, 82%
3k, R = 3-Cl, 68%
3l, R = 3,5 di-OMe, 76%
3m, R = 3-Cl, 4-Me, 86%
3n, R = 2-Cl, 5-OMe, 72%
OTf
OTf
O
N
N
MeO
OTf
R
N
R
R
R
Ph
2ag, R = H, 60%
2ah, R = OMe, 84%
2o, R = 1-Np,80%
3o, R = 1-Np, 68%
3p, R = 1-Pyrenyl, --%c
3q, R = cHex, 84%
OTf
OTf
2p, R = 1-Pyrenyl, 85%
2q, R = cHex, 72%
2r, R = nBu, 74%
N
O
N
OTf
N
3r, R = nBu, --%c
3s, R = 1-Cyclohexenyl, --%c
MeO
R
R
2s, R = 1-Cyclohexenyl, 58%
Ph
2ai, 65%
3t, R1 = Me, R2 = H, 86%
3u, R1 = F, R2 = H, 65%
3v, R1 = Cl, R2 = H, 56%
3w, R1 = H, R2 = Me, 76%
3x, R1 = H, R2 = Cl, 66%
3y, R1= R2 = F, 62%
OTf
2t, R1 = Me, R2 = H, 70%
2u, R1 = F, R2 = H, 62%
2v, R1 = Cl, R2 = H, 65%
2w, R1 = H, R2 = Me, 60%
2x, R1 = H, R2 = Cl, 64%
2y, R1= R2 = F, 68%
OTf
OTf
O
N
N
N
R1
R1
MeO
Ph
Ph
R2
R2
Ph
MeO
2aj, 76%
OTf
OTf
OTf
O
N
N
3z, R = Me, 62%
3aa, R = OMe, 65%
N
2z, R = Me, 62%
2aa, R = OMe, 74%
R
R
MeO
Ph
Ph
Ph
R
R
N
2ak, 66%
R
2ab, R = iPr, 74%
2ac, R = OMe, 78%
2ad, R = Cl, 58%
3ab, R = iPr, 72%
3ac, R = OMe, 74%
3ad, R = Cl, 76%d
R
OTf
OTf
OTf
N
N
O
O
N
MeO
Ph
Ph
Ph
Ph
2al, 70%
Me
OTf
OTf
Me
OTf
S
OTf
OTf
N
N
O
N
N
MeO
MeO
Me
Ph
Ph
Me Ph
2af, 63%
Ph
2ae, 78%
2am, 65%
3ae, 66%
3af, 82%
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a
Reaction conditions: 0.25 mmol 1, 1.0 equiv Cu(OTf)2 or 1.0 equiv Cu(OTf)2/1.5 equiv PhI(OAc)2,
5
6
b
c
CH3CN (2 mL), 80 °C, 12 h. Isolated yield. Complex reaction mixture was obtained.d CCDC for 2aj -
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1824191 and for 3ad –1557529.
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Further, placement of aliphatic substituents on the alkyne terminus (1q-1s), the desired
PAHs 2q-2s and 3q emerged in good yields except for nBu and cyclohexenyl group which failed
to produce the desired spiro PAHs 3r and 3s. Next, when we focussed on examining the
tolerance of the substituents on ring A, we were pleased to observe that introduction of –F, –Cl,
and –Me substituents to the ring A resulted in the desired PAHs 2t-2x and 3t-3x in 56-86%
yields. Also, both the carboamination reactions permitted di-substitutions at the ring A to furnish
2y-2aa and 3y-3aa in moderate yields.
Next, substrates 1ab-1af were examined under both the optimized reaction conditions to
investigate the tolerance of substituents at ring B. It was observed that the desired PAHs 2ab-2af
and 3ab-3af were obtained in a smooth reaction from 1ab-1af under both catalytic systems
giving the products in good yields (58-82%). At this stage, we wanted to verify whether –OMe
substituent in ring B is essential for the C–H activation pathway leading to PAHs 2. If not, the
substrate scope for the formation of PAHs 2 could be further extended with various substitutions
on ring B. In this attempt, we were able to obtain PAHs 2ag and 2ah in good yields (60 and
84%). Moreover, replacement of phenyl group with 1-Np, 2-Np, 9-phenanthrenyl were well
tolerated in the carboamination reactions to produce the desired PAHs in good yields (2ai-2al).
The fact that heterocyclic moiety 1-benzothiophenyl also allowed the carboamination giving
PAHs 2am in 65% yield, increased the scope of the present carboamination reaction. Scalability
of the methods was tested by employing 1a (2.7 mmol) as a starting material to obtain 2a in 76%
and 3a in 91%.
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Cu(OTf)2 (1.0 equiv)
PhI(OAc)2 (1.5 equiv)
OTf
O
N
(a)
TEMPO (1.2 equiv)
CH3CN, 80 °C, 12 h
7
N
3a, -- %
8
MeO
9
OTf
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1a
N
Cu(OTf)2 (1.0 equiv)
MeO
TEMPO (1.2 equiv)
CH3CN, 80 °C, 12 h
2a, 70%
(b)
OTf
1.0 equiv Cu(OTf)2
O
N
N
BnOR
R = OH, OAc
PhI(OAc)2 (1.5 equiv)
CH3CN, 80 °C, 12 h
BnO
3a. 68%
1an
Scheme 2. Control experiments.
Next, a set of control experiments were performed to gain insight into the mechanism
(Scheme 2). In the presence of radical scavengers such as 2,2,6,6-tetra-methylpiperidine-1-oxyl
(TEMPO), the dearomative carboamination reaction yielding 3a is completely arrested; whereas,
the yield of this reaction 1a→2a is not hampered (Scheme 2a). This implies the involvement of
radical mechanism only in case of dearomative carboamination. In addition, mass spectrometry
detects the formation of BnOH as well as BnOAc in the reaction mixture for 1an which indicates
that such de-alkylation (e.g. debenzylation /demethylation) steps are facile in presence of AcO
and OTf anions (Scheme 2b).
A plausible mechanism based on literature reports and control experiments above is
outlined in Scheme 3. At first, vinyl copper intermediate I is generated after activation of the
alkyne by Cu(OTf)2 which enabled the nucleophilic attack by the pyridyl nitrogen atom in 5-exo-
dig fashion.16 This intermediate would lead to copper(II) intermediate II when C–H bond of
proximal aryl ring in I is activated followed by subsequent removal of TfOH.17 Thereafter,
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reductive elimination would take place to give product 2a. As far as the formation of 3a is
concerned, the instantaneous generation of a highly electrophilic Cu(III) species III is initiated
first from Cu(OTf)2 and PhI(OAc)2.18 Similar to the earlier case, the electrophilic Cu(III)-species
III would trigger syn-aminocupration19 in 1a to form vinyl copper(III) intermediate IV. Next,
instead of regular C–H activation of proximal arene C–H bond, dearomative20 spirocyclization
via the intramolecular ipso-attack of arenes on Cu(III) centre (cf. IV) would lead to six-
membered cyclic copper(III) intermediate V which after reductive elimination would provide 3a.
This is probably due to the inhibition of single electron transfer process between Cu(OTf)2 and
PhI(OAc)2 which generates catalytically active Cu(III)-species III. The bifurcation between the
two distinct mechanisms for the formation of either 2a or 3a from 1a could be accounted for on
the basis of Pearson’s HSAB concept.21 The softer copper Cu(II) center in I is likely to prefer C–
H activation; whereas, the harder Cu(III) center in IV would prefer to act as electrophile for the
ipso attack of aromatic ring.
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C-H
activation
OTf
OTf
N
N
H
Cu
MeO
II
Cu
II
MeO
-TfOH
TfO
Ph
Ph
I
II
1a
Cu(0)
C-H activation
CuII Cu0
Cu(OTf)2
2a
PhI(OAc)2
-OTf
ipso-cyclization
CuII CuIII CuI
3a
III OAc
Cu
AcO
CuIX
III
OTf
1a
O
-MeOAc/
-MeOTf
OTf
OTf
N
N
MeO
III
Cu
III
Cu
X
IV
V
AcO
Ph
Ph
X = OAc/OTf
X = OAc/OTf
X
Scheme 3. A plausible reaction mechanism
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The photophysical properties of both the synthesized PAHs 2 and 3 were studied in
CH2Cl2 solution which exhibited intense fluorescence (Table 3 and 4). For the study of optical
properties pertaining to PAHs 2, preference is given to those containing extended polycyclic core
such as 2ag-aj, 2al. These fluorophores show good photoluminescence capabilities (Φf = 0.06 to
0.88) with the photoluminescence (PL) occuring in the visible region ranging from violet to
orange (λem: 430-619 nm). In particular, the absorption and excitation maxima, the PL maxima
and quantum yields (ϕf), as well as the excited state lifetimes (τƒ) of these compounds in CH2Cl2
solution are listed in Table 3 (for PAHs 2) and 4 (for PAHs 3), whereas the corresponding
absorption and emission spectra are depicted in Figure 1 (for PAHs 2) and 2 (for PAHs 3). The
photoluminescence spectra of fluorophores PAHs 2 show intense peaks between λem: 434-619
nm with Stokes shifts varies between (50-233 nm) which reveals violet-to-red fluorescence
emissions (Table 3 and Figure 1). On the other hand, the photoluminescence spectra of PAHs 3
fluorophores, which are selected on the basis of the presence of a donor/acceptor/bulky
substituent at a certain position, show intense peaks between λem: 430–540 nm with Stokes shifts
varies between (50-137 nm) which reveals violet to yellow fluorescence emissions (Table 4 and
Figure 2). Both of these emissions, of course, depend on the functional group present. For
instance, substituents like methoxy on plain phenyl core in PAHs 2 (2ag and 2aa; Figure 1) and
–OMe, –F on PAHs 3 (3j and 3u; Figure 2) had only modest effects on the fluorescent
properties. When the core phenyl ring was replaced by bulky substituents like 1-napthyl, it had
stronger effect on the fluorescent properties (3o, Figure 2). Extension of the π-conjugated
systems leads to significant bathochromic shifts in emission (2p, 3i-j; Figure 1-2). These
fluorophores have good photoluminescence capabilities with Φf values ranging between 0.06 to
0.86 (for PAHs 2) and 0.10 to 0.80 (for PAHs 3). The life time τƒ values for PAHs 2 are
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consistent with a doublet multiplicity; whereas, the life time τƒ values for PAHs 3 are consistent
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with a singlet multiplicity.
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Table 3. Spectral properties of selected PAHs 2 in CH2Cl2 at RT (10-5 M)
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comp
λabs
(nm)a
388
386
417
385
454
428
346
415
λem
(nm)b
444
619
482
434
507
470
495
490
ΔStoke’s
(nm)c
56
ϕd
τf
(ns)e
6.52
10.48
2.38
0.46
4.89
2.58
4.37
7.52
2a
2p
0.86
0.06
0.38
0.74
0.88
0.54
0.73
0.57
233
65
49
53
42
2aa
2ag
2ah
2ai
2aj
2al
149
75
aThe maximum absorption band is more than 300 nm. Excited at the longest maximum absorption band in
b
c
d
CH2Cl2. Excited wavelength. Stokes shift = λem - λabs. Quinine sulfate and fluorescein was used as the
standard for calculation of quantum yield. eFluorescent lifetime.
(a)
(b)
Figure 1. (a) Absorption spectra of selected PAHs 2 in CH2Cl2 at RT. (b) Emission spectra of
selected PAHs 2 in CH2Cl2 at RT.
Table 4. Photophysical data of selected PAHs 3 in CH2Cl2 at RT
comp
λabs
λem
ΔStoke’s
ϕfd
τf
(nm)a (nm)b
(nm)c
(ns)e
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3a
3b
3g
3d
3h
3u
3aa
3j
393
408
395
444
381
401
436
384
418
426
453
469
460
513
437
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500
521
519
534
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65
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64
137
101
108
0.80
0.74
0.57
0.53
0.10
0.49
0.19
0.24
0.25
0.15
2.1
3.2
2.4
4.0
3.7
2.2
5.9
4.2
7.6
9.7
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3i
3o
aThe maximum absorption bands more than 300 nm; Excited at the longest maximum absorption band in
b
c
d
CH2Cl2. Excited wavelength. Stokes shift = λem - λabs. Quinine sulfate and fluorescein was used as the
standard for calculation of quantum yield. eFluorescent lifetime.
(a)
(b)
Figure 2. (a) Absorption spectra of representative spiro-PAHs 3 in CH2Cl2 at RT. (b) Emission
spectra of representative ionic spiro-PAHs 3 in CH2Cl2 at RT.
CONCLUSION
To conclude, a unique example of divergent reactivity in copper-mediated intramolecular
carboamination reactions of alkynes has been reported. Depending on whether the external
oxidant is employed or not, two different kinds of fluorescent ionic N-doped PAHs were
obtained from the same starting materials. The current phenomenon of oxidant dependent
reactivity switch is quite unfamiliar22 in copper mediated reactions and should be extendable to a
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number of other copper-mediated processes. Also, this establishes the first intramolecular
dearomative carboamination reaction of alkynes utilizing oxidative copper chemistry which is
high-yielding and has broad functional group tolerance. Such a process would allow the direct
preparation of complex “3-dimensional” molecules with a number of functional handles.23 The
presence of inherent three-dimensionality and excellent photophysical properties is supposed to
make them potential candidates for further applications in material science and biology.
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EXPERIMENTAL SECTION
1. General information
Unless otherwise specified, all reactions were carried out in oven dried vials or reaction
vessels with magnetic stirring under argon atmosphere. Screens were performed in 2.5 mL or 5.0
mL glass vials with a PTFE-lined cap, and all other reactions were performed in round-bottom
flasks with rubber septa. All experiments were monitored by analytical thin layer
chromatography (TLC). TLC was performed on pre-coated silica gel plates. After elution, plate
was visualized under UV illumination at 254 nm for UV active materials. Further visualization
was achieved by staining iodine, potassium permanganate solution and charring on a hot plate.
Solvents were removed in vacuo and heated with a water bath at 35 °C. Silica gel finer than 100-
200 mesh was used for flash column chromatography. Columns were packed as slurry of silica
gel in petroleum ether and equilibrated with the appropriate solvent mixture prior to use. The
compounds were loaded neat or as a concentrated solution using the appropriate solvent system.
The elution was assisted by applying pressure with an air pump. Unless otherwise noted,
materials obtained from commercial suppliers were used without further purification.
Tetrahydrofuran was distilled from Na/benzophenone under an atmosphere of dry nitrogen.
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Anhydrous dichloromethane, toluene and acetonitrile were dried by using standard protocol
under nitrogen. Gold and copper catalysts were purchased from Sigma-Aldrich. Deuterated
solvents were used as supplied. Melting points are uncorrected and recorded using digital Büchi
melting point apparatus B-540. NMR spectra were recorded on Bruker AV, 400/500
spectrometers in appropriate solvents using TMS as internal standard or the solvent signals as
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1
secondary standards and the chemical shifts are shown in δ scales. Multiplicities of H NMR
signals are designated as s (singlet), d (doublet), dd (doublet of doublet), dt (doublet of triplet), t
(triplet), quin(quintet), sextet (sxt), br.s. (broad signal), m (multiplet) etc. HRMS (ESI) data were
recorded on an ion trap Thermo Scientific Q-Exactive, Accela 1250 pump. UV-visible
absorption spectra were measured with a Perkin Elmer LAMBDA 950 UV/Vis
Spectrophotometers. Fluorescence spectra were recorded by Photon Technology International,
QuantaMaster™ 400 Spectrofluorometer and absolute quantum yields were determined using a
calibrated integrating sphere system. Time-resolved fluorescence spectra were measured using a
Horiba - Lifetime Fluorescence Spectrofluorometers system equipped with a PLP-10 picosecond
light pulser (LED wavelengths: 470 or 570 nm). Single-crystal data was collected on a Super
Nova Dual source X-ray diffractometer system (Agilent Technologies) equipped with CCD area
detector and graphite-monochromatized (MoKα= 0.71073Å, CuKα= 1.54184Å) radiation.
2
Representative Procedures
2.1
Procedure for the synthesis of starting materials
The synthesis of pyridino-alkynes (1a-z, 1aa-an) are in accordance with methods developed
by our group.12 Please vide ref. 12 for detailed structures of precursors of 1, i.e, bromo-alkynes and
boronic acids.
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2.2
Procedure for copper-promoted intramolecular carboamination of alkynes
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The corresponding synthesis of ionic PAHs 2 and spectral data thereof are reported in our
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previous communication.12
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2.3
Procedure for copper-mediated intramolecular oxidative dearomative
carboamination of alkynes
To a screw-cap vial containing a stir bar were added 2-(4-methoxyphenyl)-6-(2-
(phenylethynyl)phenyl)pyridine (1a) (40 mg, 0.11 mmol, 1.0 equiv), PhI(OAc)2 (54 mg, 0.17
mmol, 1.5 equiv), Cu(OTf)2 (38 mg, 0.11 mmol, 1.0 equiv) and CH3CN (2 mL). The reaction
vial was fitted with a cap, evacuated and back filled with N2 and heated at 80 °C for 12 h. When
the reaction time was completed, the reaction mixture was allowed to cool at ambient
temperature. The mixture was diluted with CH2Cl2 (10 mL) and the combined mixture was
concentrated in vacuo and the resulting residue was purified by column chromatography on silica
(CH2Cl2/MeOH; 95:05) to afford the product 3a in 94% yield.
4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-ium
trifluoromethanesulfonate (3a): Off white solid, 51 mg, 94% yield; mp = 268-270 °C; Rf = 0.30
1
(CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.82 (d, J = 8.0 Hz, 1 H), 8.64 -
8.77 (m, 2 H), 8.35 (d, J = 7.6 Hz, 1 H), 8.20 (d, J = 7.6 Hz, 1 H), 7.91 - 8.04 (m, 2 H), 7.76 -
7.85 (m, 2 H), 7.67 (d, J = 3.4 Hz, 3 H), 6.98 - 7.08 (d, J = 9.9 Hz, 2 H), 6.81 - 6.95 (d, J = 9.9
13
Hz, 2 H); C{1H} NMR (125 MHz, DMSO-d6) δ = 183.9, 146.0, 144.9, 141.3, 140.3, 140.1,
138.1, 135.7, 134.2, 133.3, 132.3, 132.0, 129.9, 129.2, 128.2, 128.1, 125.7, 124.4, 120.1, 119.9,
65.2; 19F NMR (376.5 MHz, DMSO-d6)δ = -77.75; HRMS (ESI) calcd for C25H16ON+ (M -
OTf)+ 346.1226, found 346.1226.
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4-oxo-1'-(p-tolyl)spiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-ium
trifluoromethanesulfonate (3b): Off white solid, 48 mg, 88% yield; mp = 248-250 °C; Rf = 0.30
7
8
9
1
(CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.81 (d, J = 8.0 Hz, 1 H), 8.60 -
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8.73 (m, 2 H), 8.36 (d, J = 7.6 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.88 - 8.05 (m, 2 H), 7.67 -
7.79 (d, J = 7.6 Hz, 2 H), 7.39 - 7.53 (d, J=7.6 Hz, 2 H), 6.95 - 7.08 (d, J = 9.5 Hz, 2 H), 6.79 -
13
6.91 (d, J = 9.5 Hz, 2 H), 2.42 (s, 3 H); C{1H}NMR (125 MHz, DMSO-d6) δ = 183.9, 145.8,
144.5, 142.6, 141.1, 140.7, 140.3, 137.5, 135.5, 134.1, 133.3, 132.1, 130.5, 128.2, 126.5, 125.6,
124.3, 120.1, 119.8, 65.1, 21.2; HRMS (ESI) calcd for C26H18ON+ (M - OTf)+ 360.1383, found
360.1382.
4-oxo-1'-(4-pentylphenyl)spiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3c): Yellowish solid, 41 mg, 78% yield; mp = 202-204 °C; Rf =
1
0.30 (CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.81 (d, J = 8.0 Hz, 1 H),
8.58 - 8.74 (m, 2 H), 8.39 (d, J = 7.2 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H), 7.93 - 8.03 (m, 2 H),
7.69 - 7.80 (t, J = 8.4 Hz, 2 H), 7.44 - 7.55 (t, J = 8.0 Hz, 2 H), 6.97 - 7.06 (t, J = 9.5 Hz, 2 H),
6.80 - 6.90 (d, J = 9.5 Hz, 2 H), 2.68 (t, J = 7.8 Hz, 2 H), 1.63 (quin, J = 7.2 Hz, 2 H), 1.33 (d, J
= 3.1 Hz, 4 H), 0.88 (t, J = 6.7 Hz, 3 H); 13C{1H} NMR (125 MHz, DMSO-d6) δ = 183.9, 147.4,
145.7, 144.5, 141.0, 140.7, 140.4, 137.4, 135.5, 134.0, 133.3, 132.1, 129.8, 128.2, 128.1, 126.7,
125.6, 124.4, 120.0, 119.8, 65.1, 35.1, 30.9, 30.1, 21.9, 13.8; HRMS (ESI) calcd for C30H26ON+
(M - OTf)+ 416.2009, found 416.2006.
1'-(4-methoxyphenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3d): Yellow solid, 24 mg, 43% yield; mp = 198-200 °C; Rf
= 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (400 MHz, DMSO-d6) δ = 8.82 (d, J = 7.9 Hz, 1 H),
8.63 - 8.76 (m, 2 H), 8.35 (d, J = 7.3 Hz, 1 H), 8.20 (d, J = 7.3 Hz, 1 H), 7.93 - 8.05 (m, 2 H),
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7.61 (t, J = 7.9 Hz, 1 H), 7.41 (d, J = 7.3 Hz, 1 H), 7.17 - 7.31 (m, 2 H), 6.97 - 7.09 (d, J = 9.8
Hz, 2 H), 6.81 - 6.93 (d, J = 9.8 Hz, 2 H), 3.80 (s, 3 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
= 183.9, 159.7, 146.0, 145.0, 141.3, 140.2, 139.9, 138.3, 135.8, 134.2, 133.4, 132.4, 131.3,
130.4, 128.1, 125.7, 124.5, 120.6, 120.2, 120.0, 117.6, 113.0, 65.2, 55.3; HRMS (ESI) calcd for
C26H18O2N+ (M - OTf)+ 376.1332, found 376.1331.
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1'-(4-fluorophenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3f): Off white solid, 52 mg, 85% yield; mp = 216-218 °C; Rf =
1
0.30 (CH2Cl2/MeOH = 95/05); H NMR (400 MHz, DMSO-d6) δ = 8.82 (d, J = 7.9 Hz, 1 H),
8.77 - 8.64 (m, 2 H), 8.34 (d, J = 7.3 Hz, 1 H), 8.20 (d, J = 7.9 Hz, 1 H), 8.06 - 7.92 (m, 2 H),
7.88 (t, J = 5.5 Hz, 2 H), 7.53 (t, J = 7.9 Hz, 2 H), 7.10 - 6.96 (d, J = 9.2 Hz, 2 H), 6.93 - 6.78 (d,
13
J = 9.2 Hz, 2 H); C{1H} NMR (100 MHz, DMSO-d6) δ = 183.8, 165.0 - 162.5 (d, J = 252.7
Hz), 145.9, 145.0, 141.3, 139.9, 139.0, 138.1, 135.7, 135.2, 134.3, 133.3, 132.4, 131.0 - 130.9 (d,
J = 9.2 Hz), 128.0, 125.7, 124.5, 120.2 - 120.0 (d, J = 20.4 Hz), 117.4 - 117.2 (d, J = 22.3 Hz),
65.2; HRMS (ESI) calcd for C25H15ONF+ (M - OTf)+ 364.1132, found 364.1130.
1'-(4-chlorophenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3g): Off white solid, 40 mg, 75% yield; mp = 274-276 °C; Rf =
1
0.30 (CH2Cl2/MeOH = 95/05); H NMR (400 MHz, DMSO-d6) δ = 8.82 (d, J = 8.0 Hz, 1 H),
8.73 (t, J = 7.8 Hz, 1 H), 8.69 (d, J = 7.6 Hz, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 8.21 (d, J = 7.6 Hz,
1 H), 8.01 (t, J = 7.6 Hz, 1 H), 7.96 (t, J = 7.4 Hz, 1 H), 7.78 - 7.87 (d, J = 8.4 Hz, 2 H), 7.69 -
7.78 (d, J = 8.4 Hz, 2 H), 6.96 - 7.08 (d, J = 9.9 Hz, 2 H), 6.80 - 6.94 (d, J = 9.9 Hz, 2 H);
13C{1H} NMR (100 MHz, DMSO-d6) δ = 183.8, 146.1, 145.2, 141.4, 139.8, 138.7, 138.5, 136.7,
135.8, 134.4, 133.3, 132.5, 130.2, 130.0, 128.0, 127.9, 125.7, 124.7, 120.2, 120.0, 65.1; HRMS
(ESI) calcd for C25H15ONCl+ (M - OTf)+ 380.0837, found 380.0838.
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4-oxo-1'-(4-pentanoylphenyl)spiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3h): Off white solid, 43 mg, 83% yield; mp = 246-248 °C;
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Rf = 0.30 (CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.83 (d, J = 8.0 Hz, 1
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H), 8.75 (t, J = 8.0 Hz, 1 H), 8.69 (d, J = 7.6 Hz, 1 H), 8.36 (d, J = 7.6 Hz, 1 H), 8.17 - 8.26 (m, 3
H), 7.99 - 8.06 (m, 1 H), 7.88 - 7.99 (m, 3 H), 6.97 - 7.10 (d, J = 9.5 Hz, 2 H), 6.81 - 6.93 (d, J =
9.5 Hz, 2 H), 3.08 (t, J = 7.2 Hz, 2 H), 1.63 (quin, J = 7.3 Hz, 2 H), 1.30 - 1.42 (m, 2 H), 0.92 (t,
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J = 7.2 Hz, 3 H); C{1H} NMR (125 MHz, DMSO-d6) δ = 199.4, 183.8, 146.3, 145.4, 141.5,
139.7, 139.1, 138.7, 138.6, 135.9, 134.4, 133.4, 133.1, 132.7, 129.2, 128.6, 127.9, 125.8, 124.8,
120.3, 120.1, 65.2, 37.8, 25.7, 21.7, 13.8; HRMS (ESI) calcd for C30H24O2N+ (M - OTf)+
430.1802, found 430.1800.
1'-(2-methoxyphenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3i): Yellow solid, 50 mg, 74% yield; mp = 214-216 °C; Rf
= 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.78 (d, J = 7.9 Hz, 1 H),
8.69 (t, J = 7.6 Hz, 1 H), 8.64 (d, J = 7.3 Hz, 1 H), 8.16 (d, J = 7.3 Hz, 1 H), 7.86 - 8.00 (m, 2 H),
7.79 (d, J = 7.3 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.34 (d, J = 8.5 Hz,
1 H), 7.12 (t, J = 7.3 Hz, 1 H), 6.92 - 7.04 (d, J = 9.8 Hz, 2 H), 6.71 - 6.81 (d, J = 9.8 Hz, 2 H),
3.81 (s, 3 H); 13C{1H} NMR (125 MHz, DMSO-d6) δ = 184.1, 157.0, 146.2, 144.7, 141.3, 140.2,
139.3, 135.9, 135.5, 133.6, 133.5, 132.9, 131.8, 129.0, 128.6, 126.3, 125.3, 120.8, 120.2, 120.1,
117.2, 112.5, 66.4, 55.5; HRMS (ESI) calcd for C26H18O2N+ (M - OTf)+ 376.1332, found
376.1332.
1'-(3-methoxyphenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3j): Yellow solid, 56 mg, 82% yield; mp = 216-218 °C; Rf
= 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (400 MHz, DMSO-d6) δ = 8.78 - 8.85 (m, 1 H), 8.62 -
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8.76 (m, 2 H), 8.29 - 8.39 (m, 1 H), 8.21 (d, J = 7.8 Hz, 1 H), 7.93 - 8.04 (m, 2 H), 7.55 - 7.65
(m, 1 H), 7.42 (d, J = 7.3 Hz, 1 H), 7.20 - 7.28 (m, 2 H), 6.97 - 7.09 (m, J = 9.6 Hz, 2 H), 6.87 (s,
1 H), 6.89 (s, 1 H), 3.80 (s, 3 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ = 184.0, 159.7, 146.0,
145.0, 141.3, 140.2, 139.9, 138.3, 135.8, 134.2, 133.4, 132.4, 131.3, 130.4, 128.1, 125.7, 124.5,
120.6, 120.2, 120.0, 117.6, 113.0, 65.2, 55.4; HRMS (ESI) calcd for C26H18O2N+ (M - OTf)+
376.1332, found 376.1330.
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1'-(3-chlorophenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3k): Off white solid, 36 mg, 68% yield; mp = 224-226 °C; Rf =
1
0.30 (CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.83 (d, J = 8.0 Hz, 1 H),
8.76 (t, J = 8.0 Hz, 1 H), 8.69 (d, J = 7.6 Hz, 1 H), 8.25 (t, J = 8.0 Hz, 2 H), 7.92 - 8.05 (m, 2 H),
7.57 - 7.80 (m, 4 H), 6.96 - 7.09 (d, J = 9.5 Hz, 2 H), 6.80 - 6.94 (d, J = 9.9 Hz, 2 H); 13C{1H}
NMR (125 MHz, DMSO-d6) δ = 183.8, 146.2, 145.5, 141.5, 139.6, 139.0, 137.8, 135.9, 134.4,
134.2, 133.5, 132.7, 132.0, 131.6, 131.0, 127.8, 127.2, 127.1, 125.8, 124.5, 120.3, 120.2, 65.3;
HRMS (ESI) calcd for C25H15ONCl+ (M - OTf)+ 380.0837, found 380.0838.
1'-(3,5-dimethoxyphenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-
dien-10'-ium trifluoromethanesulfonate (3l): Yellow solid, 40 mg, 76% yield; mp = 204-206
°C; Rf = 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (400 MHz, DMSO-d6) δ = 8.82 (d, J = 7.9 Hz,
1 H), 8.62 - 8.77 (m, 2 H), 8.35 (d, J = 5.5 Hz, 1 H), 8.21 (d, J = 7.3 Hz, 1 H), 7.95 - 8.03 (m, 2
H), 7.03 (d, J = 9.8 Hz, 2 H), 6.86 - 6.93 (m, 4 H), 6.82 (br.s., 1 H), 3.80 (s, 6 H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ = 184.0, 161.2, 146.0, 145.1, 141.3, 140.2, 139.7, 138.5, 135.8, 134.2,
133.5, 132.4, 130.8, 128.1, 125.8, 124.5, 120.2, 120.1, 106.0, 103.4, 65.3, 55.6; HRMS (ESI)
calcd for C27H20O3N+ (M - OTf)+ 406.1438, found 406.1435.
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1'-(3-chloro-4-methylphenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-
2,5-dien-10'-ium trifluoromethanesulfonate (3m): Off white solid, 45 mg, 86% yield; mp =
236-238 °C; Rf = 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.82 (d, J =
8.0 Hz, 1 H), 8.74 (t, J = 7.8 Hz, 1 H), 8.68 (d, J = 7.6 Hz, 1 H), 8.27 (d, J = 7.6 Hz, 1 H), 8.22
(d, J = 8.0 Hz, 1 H), 7.90 - 8.04 (m, 2 H), 7.73 (s, 1 H), 7.62 - 7.71 (m, 2 H), 6.94 - 7.06 (d, J =
9.9 Hz, 2 H), 6.79 - 6.92 (d, J = 9.9 Hz, 2 H), 2.45 (s, 3 H); 13C{1H} NMR (125 MHz, DMSO-
d6) δ = 183.8, 146.0, 145.2, 141.4, 140.0, 139.8, 138.5, 138.1, 135.8, 134.4, 134.4, 133.4, 132.8,
132.5, 128.4, 127.9, 127.7, 127.0, 125.8, 124.4, 120.3, 120.1, 65.2, 19.8; HRMS (ESI) calcd for
C26H17ONCl+ (M - OTf)+ 394.0993, found 394.0989.
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1'-(2-chloro-5-methoxyphenyl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-
2,5-dien-10'-ium trifluoromethanesulfonate (3n): Yellow solid, 38 mg, 72% yield; mp = 290-
292 °C; Rf = 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.72 - 8.87 (m,
2 H), 8.66 (d, J = 7.3 Hz, 1 H), 8.28 (d, J = 7.3 Hz, 1 H), 7.99 (t, J = 7.6 Hz, 1 H), 7.90 (t, J = 7.6
Hz, 1 H), 7.63 - 7.75 (m, 2 H), 7.24 (dd, J = 9.2, 2.4 Hz, 2 H), 7.03 (d, J = 2.4 Hz, 1 H), 6.91
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(br.s., 2 H), 6.71 (br.s., 1 H), 3.78 (s, 3 H); C{1H} NMR (125 MHz, DMSO-d6) δ = 183.9,
157.7, 146.8, 146.0, 142.0, 140.3, 138.5, 138.1, 136.0, 134.9, 134.1, 133.3, 132.7, 131.6, 127.6,
127.1, 125.7, 125.6, 123.6, 120.8, 120.7, 117.9, 116.2, 67.1, 55.8; HRMS (ESI) calcd for
C26H17O2NCl+ (M - OTf)+ 410.0942, found 410.0945.
1'-(naphthalen-1-yl)-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3o): Yellow solid, 36 mg, 68% yield; mp = 234-236 °C; Rf
= 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (400 MHz, DMSO-d6) δ = 8.89 (d, J = 7.9 Hz, 1 H),
8.81 (t, J = 7.9 Hz, 1 H), 8.68 (d, J = 7.9 Hz, 1 H), 8.30 (d, J = 7.9 Hz, 1 H), 8.22 (d, J = 7.9 Hz,
1 H), 8.16 (t, J = 7.3 Hz, 2 H), 7.92 (t, J = 7.9 Hz, 1 H), 7.62 - 7.76 (m, 4 H), 7.53 (t, J = 7.6 Hz,
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1 H), 7.38 (d, J = 9.2 Hz, 1 H), 6.96 (t, J = 7.9 Hz, 2 H), 6.89 (d, J = 7.9 Hz, 1 H), 6.55 (d, J =
9.8 Hz, 1 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ = 183.9, 146.9, 145.3, 141.8, 140.4, 138.8,
138.4, 137.0, 136.0, 134.8, 134.2, 133.3, 133.0, 132.2, 131.5, 130.1, 129.1, 127.8, 127.7, 127.4,
127.0, 125.6, 125.1, 125.0, 125.0, 124.6, 120.5, 120.4, 67.3; HRMS (ESI) calcd for C29H18ON+
(M - OTf)+ 396.1383, found 396.1383.
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1'-cyclohexyl-4-oxospiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-ium
trifluoromethanesulfonate (3q): Off white solid, 52 mg, 84% yield; mp = 212-214 °C; Rf = 0.30
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(CH2Cl2/MeOH = 95/05); H NMR (400 MHz, DMSO-d6) δ = 8.72 - 8.81 (m, 1 H), 8.58 - 8.71
(m, 2 H), 8.44 (d, J = 7.3 Hz, 1 H), 8.15 (d, J = 7.3 Hz, 1 H), 7.89 - 8.06 (m, 2 H), 6.70 - 6.96 (m,
4 H), 2.30 (br.s., 1 H), 1.81 - 1.89 (m, 5 H), 1.69 - 1.81 (m, 3 H), 1.51 (q, J = 12.4 Hz, 1 H), 1.34
(d, J = 11.6 Hz, 2 H); 13C{1H} NMR (100 MHz, DMSO-d6) δ = 184.1, 149.7, 145.7, 144.3,
141.1, 138.5, 138.1, 135.4, 134.7, 133.1, 131.5, 127.9, 126.3, 125.4, 120.0, 119.9, 66.3, 36.0,
31.3, 25.4, 24.7; HRMS (ESI) calcd for C26H24ON+ (M - OTf)+ 366.1852, found 366.1849.
7'-methyl-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3t): Off white solid, 46 mg, 86% yield; mp = 222-224 °C; Rf =
1
0.30 (CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.75 (d, J = 8.0 Hz, 1 H),
8.70 (t, J = 7.8 Hz, 1 H), 8.52 (s, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H), 7.76 -
7.85 (m, 3 H), 7.61 - 7.71 (m, 3 H), 7.01 - 7.07 (m, J = 9.9 Hz, 2 H), 6.85 (s, 1 H), 6.87 (s, 1 H),
2.62 (s, 3 H); 13C{1H} NMR (125 MHz, DMSO-d6) δ = 183.9, 146.0, 144.8, 143.1, 141.2, 140.3,
139.1, 138.0, 136.0, 134.1, 131.9, 129.9, 129.3, 128.1, 125.8, 125.6, 124.2, 119.9, 119.8, 65.1,
21.5; HRMS (ESI) calcd for C26H18ON+ (M - OTf)+ 360.1383, found 360.1382.
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7'-fluoro-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3u): Off white solid, 35 mg, 65% yield; mp = 216-218 °C; Rf
= 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.80 (d, J = 8.0 Hz, 1 H),
8.76 (t, J = 7.8 Hz, 1 H), 8.68 (dd, J = 8.4, 1.9 Hz, 1 H), 8.38 (dd, J = 8.8, 4.6 Hz, 1 H), 8.26 (d, J
= 7.6 Hz, 1 H), 7.76 - 7.88 (m, 3 H), 7.59 - 7.72 (m, 3 H), 6.97 - 7.07 (d, J = 9.5 Hz, 2 H), 6.80 -
6.92 (d, J = 9.9 Hz, 2 H); 13C{1H} NMR (125 MHz, DMSO-d6) δ = 183.9, 164.6 - 162.6 (d, J =
251.7 Hz), 146.2, 145.0, 140.5, 140.1, 139.9, 137.9 - 137.8 (d, J = 10.5 Hz), 137.2, 134.3, 132.1,
130.0, 129.1, 128.2, 126.7, 126.7, 124.7, 120.8 - 120.7 (d, J = 23.8 Hz), 120.6, 120.5, 113.1 -
112.9 (d, J = 26.7 Hz), 65.1; HRMS (ESI) calcd for C25H15ONF+ (M - OTf)+ 364.1132, found
364.1129.
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7'-chloro-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3v): Off white solid, 30 mg, 56% yield; mp = 262-264 °C; Rf =
1
0.30 (CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.93 (d, J = 1.5 Hz, 1 H),
8.82 (d, J = 8.0 Hz, 1 H), 8.76 (t, J = 7.8 Hz, 1 H), 8.34 (d, J = 8.4 Hz, 1 H), 8.26 (d, J = 8.0 Hz,
1 H), 8.02 (dd, J = 8.6, 1.7 Hz, 1 H), 7.81 (dd, J = 6.1, 3.1 Hz, 2 H), 7.64 - 7.70 (m, 3 H), 7.02
(d, J = 9.9 Hz, 2 H), 6.88 (d, J = 9.9 Hz, 2 H); 13C{1H} NMR (125 MHz, DMSO-d6) δ = 183.8,
146.1, 145.1, 141.0, 140.2, 139.8, 137.2, 136.7, 134.3, 133.1, 132.2, 130.0, 129.0, 128.2, 126.7,
125.8, 125.7, 120.6, 120.6, 65.2; HRMS (ESI) calcd for C25H15OClN+ (M - OTf)+ 380.0837,
found 380.0837.
8'-methyl-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3w): Off white solid, 41 mg, 76% yield; mp = 202-204 °C; Rf
= 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.74 (d, J = 8.0 Hz, 1 H),
8.68 (t, J = 7.8 Hz, 1 H), 8.56 (d, J = 8.0 Hz, 1 H), 8.04 - 8.17 (m, 2 H), 7.75 - 7.87 (m, 3 H),
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H); C{1H} NMR (125 MHz, DMSO-d6) δ = 183.9, 145.9, 144.8, 144.2, 141.4, 140.2, 140.1,
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137.9, 134.1, 133.3, 133.2, 131.9, 129.9, 129.2, 128.4, 128.2, 125.4, 124.5, 119.7, 119.4, 65.2,
21.7; HRMS (ESI) calcd for C26H18ON+ (M - OTf)+ 360.1383, found 360.1382.
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8'-chloro-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3x): Off white solid, 34 mg, 66% yield; mp = 246-248 °C; Rf =
1
0.30 (CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.83 (d, J = 8.0 Hz, 1 H),
8.67 - 8.78 (m, 2 H), 8.17 - 8.29 (m, 2 H), 8.12 (dd, J = 8.4, 1.5 Hz, 1 H), 7.77 - 7.86 (m, 2 H),
7.64 - 7.73 (m, 3 H), 6.96 - 7.06 (d, J = 9.9 Hz, 2 H), 6.81 - 6.92 (d, J = 9.9 Hz, 2 H); 13C{1H}
NMR (125 MHz, DMSO-d6) δ = 183.8, 146.0, 145.0, 142.0, 140.5, 139.7, 138.0, 137.0, 134.4,
134.3, 132.4, 130.1, 129.6, 128.9, 128.3, 127.2, 123.9, 120.3, 120.2, 65.3; HRMS (ESI) calcd for
C25H15ONCl+ (M - OTf)+ 380.0837, found 380.0833.
7',8'-difluoro-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3y): Yellowish solid, 32 mg, 62% yield; mp = 224-226 °C;
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Rf = 0.30 (CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.94 (dd, J = 9.5, 7.2
Hz, 1 H), 8.69 - 8.79 (m, 2 H), 8.39 (dd, J = 9.3, 7.1 Hz, 1 H), 8.24 (dd, J = 6.3, 2.1 Hz, 1 H),
7.82 (dd, J = 6.5, 3.1 Hz, 2 H), 7.64 - 7.73 (m, 3 H), 6.95 - 7.06 (d, J = 9.9 Hz, 2 H), 6.87 (s, 1
H), 6.89 (s, 1 H); 13C{1H} NMR (125 MHz, DMSO-d6) δ = 183.8, 153.4 - 151.3 (dd, J = 254.6
Hz, 14.3 Hz), 152.7 - 150.6 (dd, J = 253.6 Hz, 13.3 Hz), 146.1, 145.1, 141.7, 140.0, 139.7,
136.7, 134.3, 132.7-132.6 (d, J = 10.4 Hz), 132.4, 130.1, 128.8, 128.3, 125.2 - 125.1 (d, J = 9.5
Hz), 121.9, 120.3, 120.1, 115.1 - 115.0 (d, J = 20.9 Hz), 114.1 - 114.0 (d, J = 20.9 Hz), 65.2;
+
HRMS (ESI) calcd for C25H14ONF2 (M - OTf)+ 382.1038, found 382.1038.
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7',9'-dimethyl-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-
dien-10'-ium trifluoromethanesulfonate (3z): Off white solid, 33 mg, 62% yield; mp = 228-
230 °C; Rf = 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.67 - 8.82 (m,
2 H), 8.33 (s, 1 H), 8.21 (d, J = 6.9 Hz, 1 H), 7.48 - 7.64 (m, 4 H), 7.44 (d, J = 6.9 Hz, 2 H), 6.94
- 7.11 (d, J = 9.9 Hz, 2 H), 6.63 - 6.76 (d, J = 9.9 Hz, 2 H), 2.55 (s, 3 H), 1.92 (s, 3 H); 13C{1H}
NMR (125 MHz, DMSO-d6) δ = 183.9, 146.4, 145.3, 142.9, 141.8, 139.4, 139.3, 139.1, 136.3,
135.7, 134.2, 130.5, 129.9, 129.1, 128.0, 125.3, 123.2, 120.0, 119.9, 66.6, 21.2, 20.8; HRMS
(ESI) calcd for C27H20ON+ (M - OTf)+ 374.1539, found 374.1539.
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7',9'-dimethoxy-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-
dien-10'-ium trifluoromethanesulfonate (3aa): Yellow solid, 34 mg, 65% yield; mp = 184-186
°C; Rf = 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.76 (d, J = 8.0 Hz,
1 H), 8.71 (t, J = 7.8 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H), 7.92 (d, J = 1.9 Hz, 1 H), 7.55 (d, J =
7.2 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 2 H), 7.39 - 7.47 (m, 2 H), 7.04 - 7.10 (m, 1 H), 7.02 (d, J = 9.9
Hz, 2 H), 6.77 (d, J = 9.9 Hz, 2 H), 4.03 (s, 3 H), 3.71 (s, 3 H); 13C{1H} NMR (125 MHz,
DMSO-d6) δ = 184.0, 164.6, 157.5, 146.2, 144.7, 141.3, 140.3, 137.9, 136.8, 136.6, 133.9, 130.4,
130.0, 129.5, 127.6, 120.2, 120.0, 110.0, 102.8, 102.6, 65.6, 56.7, 55.8; HRMS (ESI) calcd for
C27H20O3N+ (M - OTf)+ 406.1438, found 406.1438.
3-isopropyl-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3ab): Off white solid, 38 mg, 72% yield; mp = 248-250
°C; Rf = 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.80 (d, J = 8.0 Hz,
1 H), 8.61 - 8.73 (m, 2 H), 8.33 (d, J = 7.6 Hz, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.89 - 8.04 (m, 2
H), 7.77 (d, J = 3.4 Hz, 2 H), 7.51 - 7.70 (m, 3 H), 6.99 (dd, J = 9.7, 2.5 Hz, 1 H), 6.84 (d, J =
9.5 Hz, 1 H), 6.72 - 6.80 (m, 1 H), 3.02 (dt, J = 13.6, 6.7 Hz, 1 H), 1.02 (d, J = 6.9 Hz, 3 H), 0.97
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(d, J = 6.9 Hz, 3 H); 13C{1H} NMR (125 MHz, DMSO-d6) δ = 183.5, 149.9, 146.7, 144.9, 141.2,
140.7, 138.9, 137.8, 135.7, 134.3, 133.3, 132.2, 131.9, 129.8, 129.2, 128.1, 128.1, 125.6, 124.4,
119.9, 119.7, 65.6, 26.6, 21.3, 21.0; HRMS (ESI) calcd for C28H22ON+ (M - OTf)+ 388.1696,
found 388.1696.
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3-methoxy-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3ac): Yellow solid, 39 mg, 74% yield; mp = 230-232 °C;
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Rf = 0.30 (CH2Cl2/MeOH = 95/05); H NMR (500 MHz, DMSO-d6) δ = 8.78 (d, J = 8.0 Hz, 1
H), 8.60 - 8.73 (m, 2 H), 8.30 (d, J = 7.6 Hz, 1 H), 8.19 (d, J = 7.6 Hz, 1 H), 7.90 - 8.03 (m, 2 H),
7.75 - 7.86 (m, 2 H), 7.58 - 7.72 (m, 3 H), 6.98 - 7.05 (m, 1 H), 6.85 (d, J = 9.5 Hz, 1 H), 6.09 (d,
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J = 2.3 Hz, 1 H), 3.57 (s, 3 H); C{1H} NMR (125 MHz, DMSO-d6) δ = 178.9, 154.6, 147.6,
144.9, 141.2, 141.1, 139.5, 137.3, 135.6, 134.4, 133.3, 132.2, 132.0, 129.8, 129.2, 128.1, 125.6,
124.3, 119.9, 119.7, 106.3, 66.3, 55.2; HRMS (ESI) calcd for C26H18O2N+ (M - OTf)+ 376.1332,
found 376.1332.
3-chloro-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-10'-
ium trifluoromethanesulfonate (3ad): Off white solid, 40 mg, 76% yield; mp = 258-260 °C; Rf
= 0.30 (CH2Cl2/MeOH = 95/05); 1H NMR (500 MHz, DMSO-d6) δ = 8.84 (d, J = 8.0 Hz, 1 H),
8.76 (t, J = 8.0 Hz, 1 H), 8.69 (d, J = 7.6 Hz, 1 H), 8.37 (d, J = 7.6 Hz, 1 H), 8.34 (d, J = 8.0 Hz,
1 H), 8.02 (t, J = 7.4 Hz, 1 H), 7.97 (t, J = 7.4 Hz, 1 H), 7.72 - 7.82 (m, 2 H), 7.62 - 7.72 (m, 4
H), 7.36 (d, J = 2.7 Hz, 1 H), 7.11 (dd, J = 9.7, 2.5 Hz, 1 H), 7.02 (d, J = 9.9 Hz, 1 H); 13C{1H}
NMR (125 MHz, DMSO-d6) δ = 177.0, 145.2, 145.0, 141.3, 140.3, 139.3, 138.2, 137.1, 135.8,
135.7, 133.6, 133.4, 132.5, 132.2, 130.1, 128.8, 128.1, 127.9, 125.8, 124.6, 120.4, 66.7; HRMS
(ESI) calcd for C25H15ONCl+ (M - OTf)+ 380.0837, found 380.0838.
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trifluoromethanesulfonate (3ae): Yellowish solid, 35 mg, 66% yield; mp = 236-238 °C; Rf =
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8.70 (d, J = 7.3 Hz, 1 H), 8.65 (t, J = 7.9 Hz, 1 H), 8.35 (d, J = 7.9 Hz, 1 H), 8.22 (d, J = 7.9 Hz,
1 H), 7.90 - 8.07 (m, 3 H), 7.59 - 7.69 (m, 1 H), 7.52 (dd, J = 9.2, 4.9 Hz, 6 H), 7.44 (d, J = 7.9
Hz, 1 H), 7.14 (d, J = 9.8 Hz, 1 H), 7.04 (d, J = 9.8 Hz, 1 H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ = 182.8, 149.4, 145.2, 142.2, 140.2, 138.0, 136.3, 134.1, 133.6, 133.3, 133.2, 132.3, 131.9,
131.8, 130.4, 129.9, 128.9, 128.4, 128.1, 127.4, 127.2, 125.6, 124.5, 120.1, 119.6, 66.5; HRMS
(ESI) calcd for C29H18ON+ (M - OTf)+ 396.1383, found 396.1382.
3,5-dimethyl-4-oxo-1'-phenylspiro[cyclohexane-1,2'-indolizino[3,4,5-ab]isoindole]-2,5-dien-
10'-ium trifluoromethanesulfonate (3af): Off white solid, 43 mg, 82% yield; mp = 234-236 °C;
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H), 8.59 - 8.71 (m, 2 H), 8.34 (d, J = 7.2 Hz, 1 H), 8.13 (d, J = 6.9 Hz, 1 H), 7.90 - 8.04 (m, 2 H),
7.79 (br.s., 2 H), 7.66 (br.s., 3 H), 6.76 (br.s., 2 H), 1.96 (br.s., 7 H); 13C{1H} NMR (125 MHz,
DMSO-d6) δ = 184.9, 147.0, 144.7, 141.1, 140.4, 137.4, 135.7, 133.6, 133.2, 132.2, 132.0, 129.9,
129.3, 128.1, 125.6, 124.4, 119.8, 119.7, 65.5, 16.4; HRMS (ESI) calcd for C27H20ON+ (M - -
OTf)+ 376.1539, found 376.1539.
Gram Scale Synthesis of 3a: In a round bottom flask, equipped with magnetic stir bar, were
added 2-(4-methoxyphenyl)-6-(2-(phenylethynyl)phenyl)pyridine (1a) (1g, 2.7 mmol, 1.0 equiv),
PhI(OAc)2 (1.3g, 4.05 mmol, 1.5 equiv), Cu(OTf)2 (997 mg, 2.7 mmol, 1.0 equiv) and CH3CN
(40 mL) under inert atmosphere. The reaction mixture was heated at 80 °C for 12 h. The mixture
was diluted with CH2Cl2 (10 mL) and the reaction mixture was concentrated in vacuo. The
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3. Control experiments
3.1
Reaction of 1a with TEMPO under standard reaction conditions:
To a stirred solution of 1a (20 mg, 0.055 mmol) in CH3CN (1 ml) was added Cu(OTf)2,
(20 mg, 0.055 mmol) and TEMPO (11 mg, 0.066 mmol) at RT. The resulting mixture was stirred
at 80 °C for 12 h. The mixture was diluted with CH2Cl2 and the reaction mixture was
concentrated in vacuo. The resulting residue was purified by column chromatography on silica
(CH2Cl2/MeOH; 95:05) to afford the product 2a (18 mg) in 70% yield.
To a stirred solution of 1a (20 mg, 0.055 mmol) in CH3CN (1 ml) was added Cu(OTf)2,
(20 mg, 0.055 mmol), TEMPO (11 mg, 0.066 mmol) and PhI(OAc)2 (26 mg, 0.0825 mmol) at
RT. The resulting mixture was stirred at 80 °C for 12 h. In this case, there is no formation of
desired product 3a was observed.
3.2
Reaction of 2-(4-(benzyloxy)phenyl)-6-(2-(phenylethynyl)phenyl)pyridine: To a
stir bar were added 2-(4-(benzyloxy)phenyl)-6-(2-
screw-cap vial containing
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(phenylethynyl)phenyl)pyridine (1an) (40 mg, 0.11 mmol, 1.0 equiv), PhI(OAc)2 (61 mg, 0.17
mmol, 1.5 equiv), Cu(OTf)2 (38 mg, 0.11 mmol, 1.0 equiv) and CH3CN (2 mL). The reaction
vial was fitted with a cap and heated at 80 °C for 12 h. The mixture was diluted with CH2Cl2 (10
mL) and the reaction mixture was concentrated in vacuo. The resulting residue was purified by
column chromatography on silica (CH2Cl2/MeOH; 95:05) to afford the product 3a in 68% yield
along with the detection of BnOH and BnOAc by Mass Spectrometry.
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