Hydroxylamine-O-Sulfonic Acid (HOSA) as a Redox-Neutral Directing Group: Rhodium Catalyzed, Additive Free, One-Pot Synthesis of Isoquinolines from Arylketones

Article abstract of DOI:10.1002/ejoc.201901825

A new application of hydroxylamine-O-sulfonic acid (HOSA) has been discovered whereby aromatic ketones react with HOSA and alkynes to form isoquinolines in the presence of a Rh^III catalyst. This C–H/N–O annulation methodology gives excellent yields even without any silver additive, acid/base or metal oxidant. This is the first report wherein a directing group is simultaneously forming in situ, acting as acid additive, and also as an internal oxidant.

Full text of DOI:10.1002/ejoc.201901825

A Journal of
Accepted Article
Title: Hydroxylamine-O-Sulfonic Acid (HOSA) as a Redox–Neutral
Directing Group: Rhodium Catalyzed, Additive Free, One-Pot
Synthesis of Isoquinolines from Arylketones
Authors: Pragati Biswal, Bedadyuti Vedvyas Pati, Rajesh Chebolu, Asit
Ghosh, and Ponneri Chandrababu Ravikumar
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901825
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901825
Supported by

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
Hydroxylamine-O-Sulfonic Acid (HOSA) as a Redox–Neutral
Directing Group: Rhodium Catalyzed, Additive Free, One-Pot
Synthesis of Isoquinolines from Arylketones
Pragati Biswal,a Bedadyuti Vedvyas Pati,a Rajesh Chebolu,a Asit Ghosh,a and P. C. Ravikumar*a
[a] Pragati Biswal, Bedadyuti Vedvyas Pati, Rajesh Chebolu, Asit Ghosh, and Dr. P. C. Ravikumar, School of Chemical Sciences, National Institute of Science
Education and Research (NISER) Bhubaneswar, HBNI, Jatani, Khurda, 752050, Odisha, India.
E-mail: pcr@niser.ac.in; Home Page: https://www.niser.ac.in/users/pcr#profile-main.
Abstract:
A
new application of hydroxylamine-O-sulfonic acid
positive cooperativities either as a ligand for the cyclometalated
intermediate or by making active catalyst within the reaction
condition.[8] Therefore, discovery of a directing group is highly
needed which can simultaneously act as in situ traceless
directing group, substitute for acid additive as well as internal
oxidant whereby solving all the three issues viz. (1) step
economy (2) use of acid additive and (3) use of heavy metal
oxidant.[9]
(HOSA) has been discovered whereby aromatic ketones react with
HOSA and alkynes to form isoquinolines in the presence of a Rh(III)
catalyst. This C-H/N-O annulation methodology gives excellent
yields even without any silver additive, acid/base or metal oxidant.
This is the first report wherein a directing group is simultaneously
forming in situ, acting as acid additive, and also as an internal
oxidant.
Introduction
Compared with traditional methods, transition metal-catalyzed
C-H bond activation with subsequent functionalization
represents
a more direct strategy for the synthesis of
pharmaceutically important heterocycles, including quinolines
and isoquinolines.[1] C-H bond activation has advantages in
terms of more concise synthetic routes. Nevertheless, some
drawbacks may be encountered, including the use of
stoichiometric heavy metal oxidants, covalently attached
directing groups which must later be removed and use of acid or
base additives.[2] Hence, there is a need to develop more
general and straightforward methods of C-H bond activation in
heterocycle synthesis.
Discovering a new directing group, which can serve as an
effective ligand and in some cases, oxidant, but also balance the
required reactivity with selectivity, is a challenging task.[3] The
Fagnou[4] and Glorius[5] groups have made considerable
progress in the development of redox-neutral directing groups
(no use of heavy metal oxidant) for the oxidative C-H/N-O
annulation of alkynes using Cp*Rh(III) complexes to access
isoquinoline/isoquinolone derivatives. Glorius, Sundararaju,
Chiba, Jeganmohan and several other groups independently
have explored different types of redox neutral directing groups
towards the construction of azaheterocycles.[6] However they still
needed to use extra acid/base additive and one extra step
required to install the directing group. In recent years,
developing an in situ/transient directing group is gaining
prominence due to step economy. Yu and other groups have
explored this in situ/transient directing group concept in the
Pd(II)-catalyzed C-H functionalization by using amino acids as
directing group, however they still needed to use extra acid
additive and metal oxidant.[7] Invariably for C-H functionalization
reactions involving transient directing groups, acid additives
were commonly used to drive the substrate-directing group
binding equilibrium.[7] In C-H activation reactions it has been
observed that, additional acid or base additives are showing
Scheme 1. Comparison with previous work.
Hydroxylamine-O-sulfonic acid (HOSA) may correspond to
either an electrophilic (NH2+ synthon) or a nucleophilic (NH2-
synthon) reagent depending on the substrates and reaction
conditions adopted.[10] Recently, HOSA has been used as C-H
aminating agent for naphthalenes and silyl enol ethers in the
presence of transition metal catalyst (Scheme 1, a-b).[10f, g]
Intrigued by the experimental and computational studies by
Chen group on the importance of neutral and anionic bidentate
ligands as well as weakly coordinating directing groups[11] and
above-mentioned challenges, we hypothesized that HOSA might
act as a new redox-neutral directing group for C-H activation.
Most importantly inherent mild acidity of HOSA might help for in
situ imination and C-H activation (Scheme 1, c).
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization studies.[a],[b]
[a] Reaction conditions: 1a (0.10 mmol), 2a (0.13 mmol), HOSA (0.11 mmol), Cp*Rh (3 mol %), additive (1 equiv), solvent (0.12 M), temp (°C), 10 h. L = CH3CN.
[b] See the supporting information for details. [c] NMR yields using 1, 3, 5-trimethoxybenzene as an internal standard. [d] No reaction.
[a]
Scheme 2. Comparison with reported redox-neutral directing groups.
[a]Reaction conditions: 1a (0.10 mmol), 2a (0.13 mmol), directing group (0.11 mmol),
Cp*Rh (3 mol %), MeOH (0.12 M), 70 °C, 10 h. nd = not detected.
Hexafluoroisopropanol and toluene were screened as solvents
under the same conditions, but in neither case was any reaction
observed (Table 1, entries 2-3). Then we changed various other
weak bases such as NaOAc, LiOAc, CsOAc. The use of CsOAc
improved the yield up to 61% (Table 1, entry 6). Various other
catalysts such as [Cp*CoI2], Co(acac)2, Co(acac)3, and [RuCl2(p-
cymene)]2 failed to produce the desired annulated product
(Table 1, entries 7-10). We presumed that, the use of a reactive
Results and Discussion
To test our hypothesis, acetophenone and diphenylacetylene
were taken as the model substrate and coupling partner
respectively. To our delight, when acetophenone and
diphenylacetylene were treated with HOSA (1.1 equiv) in the
presence of 3 mol % of [Cp*RhCl2]2 and 1 equivalent of KOAc,
afforded the desired isoquinoline in 30% yield (Table 1, entry 1).
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
cationic Rh-catalyst such as [Cp*Rh(CH3CN)3][SbF6]2 might
enhance the yield. Interestingly, this cationic Rh (III) catalyst
afforded the product in 80% yield (Table 1, entry 11). To know
the influence of extra additive in product yield, we performed a
reaction in the absence any additive. Gratifyingly, a considerable
improvement of yield was noticed under additive free condition
(Table 1, entry 12). For further improvement of product yield, we
screened the reaction at different temperatures ranging from
60 °C to 80 °C (Table 1, entries 13-15) and achieved excellent
yield of 92% at 70 °C. We tested this one-pot protocol using
other redox-neutral directing groups which showed inferior
results as compared to HOSA (Scheme 2).
With this optimized conditions in hand,
a variety of
electronically different acetophenones were tested using
diphenylacetylene as the coupling partner (Scheme 3). Except
for ortho-substituted examples (3ma, 3na and 3oa), most
acetophenones gave the isoquinolines in high yield. The poor
yields were recorded with ortho-substituted acetophenones may
Scheme 3. Substrate and coupling parterner scope for one-pot synthesis of isoquinolines.[a], [b] [a] Reaction conditions: 1a (0.10 mmol), 2a (0.13 mmol), HOSA
(0.11 mmol), [Cp*Rh (MeCN)3][SbF6]2 (3 mol %), MeOH (0.12 M), 70 °C, 10-20 h. [b] Isolated yields. [c] Isolated yield obtained from 1.00 mmol scale.
be due to steric hindrance near to the reaction site. Notably, 1r,
in which the alkoxy substituent is the part of a dioxolane ring
produced the desired product 3ra in 71% yield. The cyclic alkoxy
group may be acting as a secondary directing group.[12] The
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
structure of 3ra was confirmed by single crystal X-ray
analysis.[13] With non-coordinating meta-substituents (m-Br and
m-CH3) the annulated products 3ja and 3ka were formed
exclusively, positioning the meta-substituent as far as possible
away from the alkyne substituents in the final product. Curiously,
with an acetophenone containing the Lewis basic (m-OMe)
group, a mixture of annulated products 3la and 3l’a were
obtained in a 1.4:1 ratio, favouring the formation of isoquinoline
with unfavourable peri interactions between the methoxy group
of the acetophenone and a phenyl substituent of the alkyne.
Although the product 3la suffers from greater steric hindrance
than 3l’a in the intermediate pincer complex, the methoxy group
may act as an additional donor ligand, stabilizing the Rh-
complex and favouring the activation of the adjacent C-H bond.
Halo-substituted acetophenones (1d, 1e, 1f, 1g and 1j) were
also compatible with the reaction conditions, producing good to
excellent yield of their respective annulated products (3da, 3ea,
3fa, 3ja and 3ga). Interestingly, the acetophenone 1q bearing
free hydroxyl group also worked efficiently giving 3qa in 71%
yield. Indeed, the optimized conditions worked well with
heteroarylmethylketone 3p giving 3pa in good yield. Moreover,
we also have performed the 1.00 mmol scale reaction applying
the same general procedure with acetophenone 1a which
resulted 87% yield of 3aa.
In addition, the scope of this methodology was evaluated with
benzophenones (Scheme 3, 3sa-3va). Both symmetrical and
unsymmetrical benzophenones afforded good yields of
triarylisoquinolines. Especially, in the case of the 4-
nitrophenylbenzophenone 3v, annulation occurred only at the
electron-rich phenyl ring of benzophenone, rather than the
electron-deficient para-nitrophenyl, to give 3va in 70% yield.
To extend the generality of this developed protocol, we further
tested the reaction using different alkynes (Scheme 4, 3ab-3aj).
Dialkylalkynes (3ab and 3ac), alkyl-aryl alkynes (3ad, 3ae, 3af,
3ag and 3ah) and diarylalkynes (3ai and 3aj) all gave good
yields. It is noteworthy that, in the case of alkyl-aryl alkynes,
formation of a single regioisomer was observed where, the aryl
ring is oriented towards the heteroatom of isoquinoline.[14]
Formation of the selective regioisomeric product can be
rationalized with the stabilization of the intermediate III (Scheme
6) by the phenyl ring through π-interaction with the metal orbitals.
Notably,
terminal
alkynes
(trimethylsilylacetylene,
phenylacetylene) failed to produce the expected annulated
products, possibly due to reaction with Cp*Rh(III) catalyst to
produce
dimeric
alkynes.[15]
Interestingly
silylalkynes
(bis(trimethylsilyl)acetylene, trimethylsilyl phenylacetylene) also
failed. We presumed that, there may be protodesilylation
pathway operating under the influence of acidic HOSA, which
then produces terminal alkynes.
Scheme 4. Coupling parterner scope for one-pot synthesis of isoquinolines.[a], [b] [a] Reaction conditions: 1a (0.10 mmol), 2a (0.13 mmol), HOSA (0.11 mmol),
[Cp*Rh (MeCN)3][SbF6]2 (3 mol %), MeOH (0.12 M), 70 °C, 10-20 h. [b] Isolated yields.
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
Scheme 5. Competitive and mechanistic studies.
Competitive studies were carried out using a range of
acetophenones and alkynes (Scheme 5, a-c) to elucidate how
electronic effects influence the reactivity. First, an intermolecular
competitive annulation reaction (Scheme 5, a) was performed
between acetophenones 1c (para-electron donating group), and
1h (para-electron withdrawing group), which produced annulated
products 3ca and 3ha in a ratio of 6.2:1. This experiment clearly
indicated that cyclometallation-deprotonation is faster in
electron-rich acetophenone 1c.
In order to better understand the catalytic activity of Cp*Rh2+,
few kinetic experiments were conducted (Scheme 4, d-e).
Initially, the standard condition was employed on 1a with and
without the use of the alkyne 2a in 10 equiv of methanol-D4,
which showed no ortho-deuteriation on 3aa and 1a respectively
(Scheme 5, d, details are in supporting information). These
results reveal that the C-H activation step is irreversible.
Moreover, we observed the Kinetic Isotope Effect (KIE) for the
intra and intermolecular kinetic experiments to be 3.5 and 5.2
respectively (Scheme 5, e, and also see supporting information),
suggesting that the initial C-H activation step may be the rate
limiting step.[16]
Next, an intramolecular competitive Rh-insertion study was
performed
between
sp3-(cyclohexyl)
and
sp2-(para-
methoxyphenyl) C-H bonds, using ketone 1w. Again, the
experiment was conclusive, with 1w undergoing exclusive sp2 C-
H activation to give 3wa in 64% yield (Scheme 5, b). In an
intermolecular competition between diphenylalkyne 2a and
diethylalkyne 2b, comparable reactivity was observed between
the two alkynes, that gave their respective annulated products
3aa and 3ab in 1.22:1.00 ratio (Scheme 5, c).
Based on these experimental observations and literature
[11c-d]
precedents,[6h],
we proposed a 5-stage catalytic cycle
(Scheme
6).
Initially,
the
cationic
active
catalyst,
[Cp*Rh(MeCN)3][SbF6]2 undergoes cyclometallation with the in
situ generated ketoxime 1a’ to form a five-membered rhodacycle
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
I, which after π-complexation with the alkyne 2a gives
intermediate II. Next, alkyne insertion occurs to afford the seven-
membered rhodacycle III, which undergoes subsequent
reductive elimination and N-O oxidative insertion to give IV. The
last step of the catalytic cycle involves regeneration of active
catalyst and formation of the desired annulated product 3aa
along with the by-product H2SO4. We presume that the acid
generated in the final step reacts immediately with the product
3aa and forms isoquinolinium salt. Proton NMR of the crude
Scheme 6. Proposed catalytic cycle.
All 1H NMR experiments were reported in parts per million (ppm), and
were measured relative to the signals for residual chloroform (7.26 ppm)
in the deuterated solvent. All 13C NMR spectra were reported in ppm
relative to CDCl3 (77.36 ppm).[17] Chemical shift multiplicities have
represented as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m),
doublet of doublet (dd), doublet of triplet (dt), triplet of doublet (td). All
crude NMR analysis were performed by using 1,3,5-trimthoxybenzene as
the internal standard. X-ray crystallography was recorded at SCS, NISER,
mixture (filtering over celite pad) showed down field shift of
methyl group signal in 3aa, suggesting the formation of
isoquinolinium salt in the crude mixture.
Conclusion
JATNI,
BHUBANESWAR,
India.
[D]5-acetophenone,[6f]
[D]1-
In summary, this is the first time HOSA has ever been used as
a redox-neutral directing group for the synthesis of isoquinolines
through C-H/N-O annulation from alkynes and the transient
ketoxime. Moreover, it is simultaneously acting as an internal
oxidant, in situ generated traceless directing group. Owing to
these multiple advantages of this reagent, we believe that this
reagent has much potential which can be use in various metal-
catalyzed transformations.
[18]
acetophenone[6f] and [Cp*Rh(CH3CN)3][SbF6]2
were prepared by
following the literature procedure.
Representative Procedure for the Annulation Reaction.
To an oven dried 25 mL schlenk tube, charged with a magnetic stirring
bar, arylketone (0.1 mmol, 1 equiv), dry MeOH (0.12 M, 0.8 mL),
hydroxylamine-O-Sulfonic
acid
(0.11
mmol,
1.1
equiv),
[Cp*Rh(CH3CN)3][SbF6]2 (0.003 mmol, 0.03 equiv) and alkyne (0.13
mmol, 1.3 equiv) were added under nitrogen atmosphere sequentially.
The reaction mixture was allowed to stir (~500 rpm) at 70 °C in a pre-
heated aluminium block. Reaction was monitored by TLC. After
completion of the reaction (10-20 h), reaction mixture was transferred in
to a 50 mL round bottom flask. The reaction vial was washed for two
times with ethyl acetate/methanol. The solvent was removed under
reduced pressure to get crude mixture and was extracted with ethyl
acetate (3×10 mL) and saturated NaHCO3. After brine wash, the organic
layer was dried over anhydrous Na2SO4 and then purified through
column chromatography by using 230-400 mesh silica, giving the product
(3aa).
Experimental Section
Acetophenone/benzophenone derivatives were bought from Sigma
Aldrich, Alfa-Aesar, Avra, TCI and Spectrochem and used without any
further purification. For column chromatography, silica gel (100–200 /
230-400 mesh) from Acme Co. was used. A gradient elution using
distilled hexane and ethyl acetate was performed, based on Merck
aluminium TLC sheets. All isolated compounds were characterized by 1H
NMR, 13C NMR spectroscopy and HRMS. Copies of the 1H NMR, 13C
NMR can be found in the Supporting Information. Nuclear Magnetic
Resonance spectra were recorded on a Bruker 400 MHz and 700 MHz
instrument.
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
1-Methyl-3,4-diphenylisoquinoline (3aa).[6f] White solid (24 mg, 89%
yield); Rf=0.4 (in 10% EtOAc/Hexane); m.p. 155-157 °C; 1H NMR (400
MHz, CDCl3): δ 8.22-8.20 (m, 1H), 7.68-7.66 (m, 1H), 7.61-7.59 (m, 2H),
7.38-7.32 (m, 5H), 7.24-7.17 (m, 5H), 3.09 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 158.1, 149.8, 141.3, 137.9, 136.3, 131.7, 130.6, 130.2, 129.5,
128.5, 127.9, 127.5, 127.3, 126.9, 126.6, 126.5, 125.9, 23.0; HRMS (ESI)
m/z: calcd for C22H18N [M+H]+ 296.1439; found, 296.1439.
23.1; HRMS (ESI) m/z: calcd for C23H17F3N [M+H]+ 364.1308; found,
364.1305.
6-Nitro-1-methyl-3,4-diphenylisoquinoline (3ia).[6f] Yellow solid (17 mg,
51% yield); Rf=0.4 (in 10% EtOAc/Hexane); m.p. 173-176 °C; 1H NMR
(400 MHz, CDCl3): δ δ 8.59 (s, 1H), 8.37-8.31 (m, 2H), 7.41-7.37 (m, 5H),
7.23-7.22 (m, 5H), 3.14 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.4,
151.9, 148.6, 140.2, 136.3, 136.2, 131.5, 130.8, 130.5, 129.1, 128.4,
128.15, 128.1, 128.0, 123.1, 120.3, 23.2; HRMS (ESI) m/z: calcd for
C22H17N2O2 [M+H]+ is 341.1285; found, 341.1293.
1,6-Dimethyl-3,4-diphenylisoquinoline (3ba).[6f] White solid (29 mg,
94% yield); Rf=0.4 (in 10% EtOAc/Hexane); m.p.168-170 °C; 1H NMR
(400 MHz, CDCl3): δ 8.10 (d, J = 9.2 Hz, 1H), 7.44-7.43 (m, 2H), 7.36-
7.34 (m, 5H), 7.23-7.16 (m, 5H), 3.06 (s, 3H), 2.44 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 157.7, 149.8, 141.4, 140.6, 138.0, 136.6, 131.8, 130.6,
129.1, 129.1, 128.5, 127.9, 127.4, 127.2, 125.8, 125.4, 124.9, 22.9, 22.5;
HRMS (ESI) m/z: calcd for C23H20N [M+H]+ 310.1596; found, 310.1595.
7-Bromo-1-methyl-3,4-diphenylisoquinoline (3ja).[6f] White solid (28
mg, 74% yield); Rf=0.55 (in 10% EtOAc/Hexane); m.p. 132-135 °C; 1H
NMR (400 MHz, CDCl3): δ 8.62 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 9.0 Hz,
1.7 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.28-7.25 (m, 5H), 7.12-7.09 (m,
5H), 3.09 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.1, 150.2, 140.9,
137.3, 135.0, 133.6, 131.6, 130.5, 129.4, 128.7, 128.6, 128.2, 127.7,
127.6, 127.5, 120.8, 23.0; HRMS (ESI) m/z: calcd for C22H17BrN [M+H]+
374.0544; found, 374.0545.
6-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ca).[6f]
White solid
(32 mg, 98% yield); m.p. 183-184 °C; Rf=0.6 (in 20% EtOAc/Hexane); 1H
NMR (400 MHz, CDCl3): δ 8.1 (d, J = 9.2 Hz, 1H), 7.36-7.3 (m, 5H), 7.23-
7.17 (m, 6H), 6.91 (d, J = 2.8 Hz, 1H), 3.73 (s, 3H), 3.03 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 160.8, 157.3, 150.4, 141.5, 138.3, 138.1,
131.6, 130.5, 128.6, 127.9, 127.7, 127.4, 127.2, 122.2, 119.0, 104.7,
55.5, 22.9; HRMS (ESI) m/z: calcd for C23H20NO [M+H]+ 326.1545; found,
326.1545.
1,7-Dimethyl-3,4-diphenylisoquinoline (3ka).[6f] White solid (28 mg,
90% yield); Rf=0.4 (in 10% EtOAc/Hexane); m.p. 132-134 °C; 1H NMR
(400 MHz, CDCl3): δ 7.89 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.35 (dd, J =
4.8 Hz, 0.5 Hz, 1H), 7.28-7.22 (m, 5H), 7.14-7.07 (m, 5H), 2.99 (s, 3H),
2.50 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.4, 148.8, 141.1, 138.0,
136.9, 134.6, 132.6, 131.7, 130.6, 129.6, 128.5, 127.9, 127.4, 127.2,
126.7, 126.5, 124.9, 22.9, 22.2; HRMS (ESI) m/z: calcd for C23H20N
[M+H]+ 310.1590; found, 310.1583.
6-Fluoro-1-methyl-3,4-diphenylisoquinoline (3da).[6f] White solid (20
mg, 64% yield); Rf=0.6 (in 10% EtOAc/Hexane); m.p. 140-142 °; 1H NMR
(400 MHz, CDCl3): δ 8.20 (dd, J = 9.2 Hz, 5.6 Hz, 1H), 7.39-7.32 (m, 6H),
7.29-7.26 (m, 1H), 7.23-7.20 (m, 5H), 3.07 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 164.8, 162.3, 157.8, 150.7, 140.9, 138.4 (d, J = 9.6 Hz), 137.4,
131.5, 130.5, 129.3 (d, J = 5.2 Hz), 128.9 (d, J = 9.5 Hz), 128.7, 128.0,
127.7, 127.5, 123.7, 117.0 (d, J = 25.0 Hz), 110.2 (d, J = 22.1 Hz), 23.1;
HRMS (ESI) m/z: calcd for C22H17FN [M+H]+ 314.1345; found, 314.1347.
5-Methoxy-1-methyl-3,4-diphenylisoquinoline (3la).[6a]
White solid
(17 mg, 53% yield); Rf=0.6 (in 20% EtOAc/Hexane); m.p. 151-153 °C; 1H
NMR (400 MHz, CDCl3): δ 7.8 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H),
7.25 (d, J = 6.8 Hz, 2H), 7.19-7.12 (m, 8H), 6.97 (d, J = 7.6 Hz, 1H), 3.4
(s, 3H), 3.06 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.4, 157.2, 151.4,
141.9, 141.7, 130.7, 130.6, 128.2, 128.1, 127.8, 127.6, 127.4, 126.8,
125.9, 118.4, 110.4, 55.8, 23.7; HRMS (ESI) m/z: calcd for C23H20NO
[M+H]+ 326.1545; found, 326.1518.
6-Chloro-1-methyl-3,4-diphenylisoquinoline (3ea).[6f] White solid (28
mg, 85% yield); Rf=0.5 (in 10% EtOAc/Hexane); m.p. 179-181 °C; 1H
NMR (400 MHz, CDCl3): δ 8.14 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 2.0 Hz,
1H), 7.53 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.38-7.34 (m, 5H), 7.22-7.17 (m,
5H), 3.06 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.0, 150.9, 140.9,
137.5, 137.2, 136.7, 131.6, 130.5, 128.8, 128.7, 128.0, 127.8, 127.78,
127.7, 127.5, 125.5, 124.7, 23.0; HRMS (ESI) m/z: calcd for C22H17ClN
[M+H]+ 330.1044; found, 314.1037.
7-Methoxy-1-methyl-3,4-diphenylisoquinoline (3l’a).[6a]
White solid
(12 mg, 40% yield); Rf=0.5 (in 20% EtOAc/Hexane); m.p. 116-118 °C; 1H
NMR (400 MHz, CDCl3): δ 7.58 (d, J = 9.2 Hz, 1H), 7.4 (d, J = 2.4 Hz,
1H), 7.37-7.33 (m, 5H), 7.24-7.15 (m, 6H), 3.99 (s, 3H), 3.04 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 158.2, 156.3, 148.1, 148.06, 141.3, 138.0,
131.7, 130.6, 129.5, 128.5, 128.4, 127.9, 127.7, 127.4, 127.1, 122.6,
103.8, 55.8, 23.2; HRMS (ESI) m/z: calcd for C23H20NO [M+H]+
326.1545; found, 326.1548.
6-Bromo-1-methyl-3,4-diphenylisoquinoline (3fa).[6f] White solid (36
mg, 96% yield);.m.p.183-185 °C. Rf=0.4 (in 10% EtOAc/Hexane); 1H
NMR (400 MHz, CDCl3): δ 8.06 (d, J = 4.8 Hz, 1H), 7.8 (s, 1H), 7.66 (dd,
J = 5.2 Hz, 2.0 Hz, 1H), 7.37-7.34 (m, 5H), 7.21-7.18 (m, 5H), 3.06 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 158.1, 150.9, 140.9, 137.7, 137.1,
131.6, 130.5, 130.3, 128.74, 128.7, 128.6, 128.0, 127.8, 127.6, 127.5,
125.4, 124.9, 23.0; HRMS (ESI) m/z: calcd for C22H17BrN [M+H]+
374.0544; found, 374.0552.
1,8-Dimethyl-3,4-diphenylisoquinoline (3ma). It was prepared
according to the general procedure by taking the corresponding ketone in
0.2 mmol scale. White solid (6 mg, 10% yield); Rf=0.6 (in 10%
EtOAc/Hexane); m.p. 121-123 °C; 1H NMR (400 MHz, CDCl3): δ 7.49 (d,
J = 7.2 Hz, 1H), 7.38-7.30 (m, 7H), 7.20-7.10 (m, 5H), 3.24 (s, 3H), 3.0 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 158.0, 148.9, 141.2, 138.6, 138.4,
136.3, 131.8, 130.52, 130.5, 129.8, 129.5, 128.5, 127.9, 127.5, 127.4,
127.3, 125.4, 30.0, 26.3; HRMS (ESI) m/z: calcd for C23H20N [M+H]+
310.1590; found, 310.1582.
6-Iodo-1-methyl-3,4-diphenylisoquinoline (3ga). White solid (39 mg,
93% yield); Rf=0.5 (in 10% EtOAc/Hexane); m.p. 189-191 °C; 1H NMR
(400 MHz, CDCl3): δ 8.04 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.85 (d, J =
8.8 Hz, 1H), 7.36-7.33 (m, 6H), 7.21-7.18 (m, 5H), 3.04 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 158.2, 150.8, 140.9, 137.8, 137.1, 135.7, 135.4,
131.6, 130.5, 128.7, 128.3, 128.0, 127.8, 127.5, 127.3, 125.2, 98.0, 23.9.
HRMS (ESI) m/z: calcd for C22H17IN [M+H]+ 422.0400; found, 422.0405.
8-Methoxy-1-methyl-3,4-diphenylisoquinoline (3na).[6a] White solid (7
mg, 20% yield); Rf=0.5 (in 10% EtOAc/Hexane); m.p. 149-151 °C; 1H
NMR (400 MHz, CDCl3): δ 7.44 (t, J = 8.0 Hz, 1H), 7.37-7.3 (m, 5H),
6-(Trifluoromethyl)-1-methyl-3,4-diphenylisoquinoline (3ha).[6f] White
solid (35 mg, 96% yield); Rf=0.6 (in 10% EtOAc/Hexane); m.p.114-
116 °C; 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 8.8 Hz, 1H), 7.99 (s,
1H), 7.77 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.39-7.37 (m, 5H), 7.24-7.21 (m,
5H), 3.12 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.2, 151.2, 140.7,
136.8, 135.8, 132.0, 131.7, 131.6, 130.6, 130.1, 128.8, 128.1, 128.0,
127.7, 127.3, 127.2, 124.2 (q, J = 4.5 Hz), 122.8, 122.5 (q, J = 2.8 Hz),
7.22-7.16 (m, 6H), 6.90 (d, J = 7.6 Hz, 1H), 4.02 (s, 3H), 3.22 (s, 3H); 13
C
NMR (100 MHz, CDCl3): δ 158.5, 157.8, 149.8, 141.3, 139.2, 138.5,
131.8, 130.5, 130.4, 128.7, 128.5, 127.9, 127.3, 127.2, 119.4, 118.7,
106.7, 55.9, 29.6; HRMS (ESI) m/z: calcd for C23H20NO [M+H]+ is
326.1539; found, 326.1541.
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
7-Methyl-4,5-diphenylthieno[2,3-c]pyridine (3pa).[6e] White solid (21
mg, 71% yield); Rf=0.6 (in 10% EtOAc/Hexane); m.p. 153-155 °C; 1H
NMR (400 MHz, CDCl3): δ 7.53 (d, J = 5.4 Hz, 1H), 7.29-7.26 (m, 5H),
7.17-7.11 (m, 6H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 151.7,
151.2, 146.1, 140.6, 138.5, 134.6, 131.4, 130.9, 130.7, 128.6, 128.6,
128.1, 127.5, 127.46, 124.6, 23.9; HRMS (ESI) m/z: calcd for C20H16NS
[M+H]+ 302.0998; found, 302.0996.
Hz, 1H), 7.5 (t, J = 7.2 Hz, 1H), 3.05 (q, J = 7.2 Hz, 2H), 2.97 (q, J = 7.2
Hz, 2H), 2.92 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3): δ 156.1, 152.8, 135.5, 129.9, 127.6, 126.5,
126.4, 125.6, 123.7, 28.8, 22.6, 21.0, 15.6, 15.3. HRMS (ESI) m/z: calcd
for C14H18N [M+H]+ 200.1439; found, 200.1440.
1-Methyl-dipropylisoquinoline (3ac).[6e] Colourless liquid (19 mg, 83%
yield); Rf=0.6 (in 10% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3): δ
8.08 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.65 (td, J = 8.0 Hz, 1.2
Hz, 1H), 7.5 (td, J = 8.0 Hz, 0.8 Hz, 1H), 2.98 (t, J = 7.6 Hz, 2H), 2.93-
2.89 (m, 5H), 1.80 (sext, J = 8 Hz, 2H), 1.67 (sext, J = 8.0 Hz, 2H), 1.09
(t, J = 7.2 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
155.9, 151.9, 135.8, 129.8, 126.6, 126.4, 126.3, 125.6, 123.9, 37.7, 30.1,
24.5, 24.2, 22.6, 14.9, 14.7; HRMS (ESI) m/z: calcd for C16H22N [M+H]+
228.1747; found, 228.1745.
1,7-Dimethyl-3,4-diphenylisoquinolin-6-ol (3qa). White solid (23 mg,
71% yield); Rf=0.70 (in 30% EtOAc/Hexane); m.p. 157-159 °C; 1H NMR
(400 MHz, CDCl3 + DMSO-d6): δ 9.1 (br, 1H), 7.90 (s, 1H), 7.29-7.25 (m,
4H), 7.23-7.18 (m, 3H), 7.1-7.16 (m, 3H), 6.90 (s, 1H), 2.96 (s, 3H), 2.43
(s, 3H); 13C NMR (175 MHz, CDCl3 + DMSO- d6): δ 158.3, 156.4, 149.0,
141.5, 138.8, 137.1, 131.7, 130.5, 128.7, 128.3, 128.0, 127.7, 127.3,
126.9, 121.7, 107.2, 22.6, 17.2; IR (neat): 3439, 3054, 2989, 2924, 2855,
2305, 1613, 1554, 1516, 1384, 1263, 1165, 898, 741,700 cm-1; HRMS
(ESI) m/z: calcd for C23H20NO [M+H]+ 326.1539; found, 326.1534.
1-Methyl-3-ethyl-4-phenylisoquinoline (3ad).[6e] White solid (21 mg,
83% yield); Rf= 0.5 (in 10% EtOAc/Hexane); m.p; 122-123 °C; 1H NMR
(400 MHz, CDCl3): δ 8.18 (d, J = 7.6 Hz, 1H), 8.90 (d, J = 8.8 Hz, 1H),
7.75 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H),
7.47 (t, J = 7.2 Hz, 2H), 7.4 (t, J = 7.2 Hz, 1H), 3.03-2.98 (m, 5H), 1.27 (t,
J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 157.9, 153.0, 138.2,
136.5, 130.7, 130.0, 129.1, 128.8, 127.7, 126.2, 126.1, 125.8, 125.7,
29.3, 22.8, 15.3; HRMS (ESI) m/z: calcd for C18H18N [M+H]+ 248.1424;
found, 248.1427.
6-Methyl-8,9-diphenyl-[1,3]dioxolo[4,5-f]isoquinoline (3ra).[6f] White
solid (25 mg, 74% yield); Rf=0.2 (in 10% EtOAc/Hexane); m.p. 248-
249 °C; 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.7 Hz, 1H), 7.21-7.07
(m, 11H), 7.23 (s, 2H), 2.92 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.1,
150.2, 148.2, 142.1, 140.7, 138.6, 131.5, 130.6, 127.8, 127.4, 127.3,
127.2, 125.3, 123.5, 122.8, 121.4, 111.3, 101.8, 23.5; HRMS (ESI) m/z:
calcd for C23H18NO2 [M+H]+ 340.1338; found, 340.1340. It was
crystallized from dichloromethane.
1,4-Dimethyl-3-phenylisoquinoline (3ae).[6f] Pale yellow solid (29 mg,
75% yield); Rf=0.48 (in 10% EtOAc/Hexane); m.p. 100-103 °C; 1H NMR
(400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H),
7.75 (t, J = 7.6 Hz, 1H), 7.61-7.58 (m, 3H), 7.48 (t, J = 7.6 Hz, 2H), 7.40
(t, J = 7.6 Hz, 1H), 3.00 (s, 3H), 2.61 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 156.2, 151.0, 142.0, 136.6, 130.2, 128.4, 127.7, 126.6, 126.5,
126.4, 124.4, 122.5, 22.8, 15.7; HRMS (ESI) m/z: calcd for C17H18N
[M+H]+ 234.1277; found, 234.1289.
1,3,4-Triphenylisoquinoline (3sa).[6g] White solid (23 mg, 64% yield);
Rf=0.58 (in 10% EtOAc/Hexane); m.p. 181-183 °C; 1H NMR (400 MHz,
CDCl3): δ 8.18 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 6.8 Hz, 2H), 7.72 (d, J =
8.4 Hz, 1H), 7.61-7.49 (m, 5H), 7.43-7.29 (m, 7H), 7.19-7.15 (m, 3H); 13
C
NMR (100 MHz, CDCl3): δ 160.1, 150.0, 141.2, 140.1, 137.9, 137.3,
131.7, 130.8, 130.5, 130.3, 130.1, 128.9, 128.6, 127.9, 127.6, 127.3,
126.9, 126.3, 125.7; HRMS (ESI) m/z: calcd for C27H20N [M+H]+
358.1596; found, 358.1598.
4-Butyl-1-methyl-3-phenylisoquinoline (3af). Oily liquid (28 mg, 83%
yield); Rf=0.35 (in 10% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3): δ
8.17 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H),
7.61 (t, J = 8.0 Hz, 3H), 7.52-7.44 (m, 4H), 7.40 (t, J = 7.2 Hz, 1H), 2.98-
2.95 (m, 5H), 1.65-1.59 (m, 2H), 1.36-1.31 (m, 2H), 0.85 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 156.1, 151.2, 142.1, 135.7, 130.1,
129.7, 128.4, 127.8, 127.7, 127.0, 126.6, 126.5, 124.6, 33.7, 28.6, 23.3,
22.8, 14.1; IR (neat): 3424, 3067, 3026, 2956, 2926, 2869, 2359, 1723,
1614, 1563, 1503, 1463, 1439, 1391, 1333, 1274, 1155, 1101, 1072,
1029, 853, 792, 758, 701, 616 cm-1; HRMS (ESI) m/z: calcd for C20H22N
[M+H]+ 276.1747; found, 276.1743.
6-Methyl-3,4-diphenyl-1-(p-tolyl)isoquinoline (3ta).[19] White solid (33
mg, 85% yield); Rf=0.55 (in 20% DCM/Hexane); m.p. 171-173 °C; 1H
NMR (400 MHz, CDCl3): δ 8.14 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 7.75 (dd, J =
8.4 Hz, 1.2 Hz, 1H), 7.5 (s, 1H), 7.46-7.31 (m, 10H), 7.20-7.18 (m, 3H),
2.49 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.8, 150.1,
141.4, 140.5, 138.6, 138.1, 137.5, 137.4, 131.7, 130.8, 130.5, 129.4,
129.3, 129.0, 128.6, 127.8, 127.8, 127.5, 127.2, 125.1, 124.2, 22.4, 21.7.
HRMS (ESI) m/z: calcd for C29H24N [M+H]+ 386.1909; found, 386.1918.
6-Methoxy-1-(4-methoxyphenyl)-3,4-diphenylisoquinoline
(3ua).[6g]
White solid (30 mg, 72% yield); Rf=0.43 (in 10% EtOAc/Hexane); m.p.
1
174-176 °C; H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 9.2 Hz, 1H), 7.67
1-Methyl-4-pentyl-3-phenylisoquinoline (3ag). Oily liquid (29 mg, 85%
yield); Rf=0.4 (in 10% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3): δ
8.17 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 8.4 Hz, 1H),
7.59 (t, J = 8 Hz, 3H), 7.52-7.45 (m, 4H), 7.39 (t, J = 7.2 Hz, 1H), 2.98-
2.94 (m, 5H), 1.69-1.61 (m, 2H), 1.34-1.21 (m, 4H), 0.85 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 156.1, 151.2, 142.2, 135.7, 130.1,
129.6, 128.4, 127.8, 127.7, 127.0, 126.6, 126.5, 124.5, 32.4, 31.2, 28.8,
22.8, 22.6, 14.3; IR (neat): 3424, 3067, 2955, 2926,2868, 1726, 1614,
1563, 1503, 1440, 1391, 1333, 1266, 1122, 1072, 1050, 1029, 982, 962,
869, 805, 789, 758, 736, 701, 618, 592 cm-1; HRMS (ESI) m/z: calcd for
C21H24N [M+H]+ 290.1903; found, 290.1899.
(d, J = 8.4 Hz, 2H), 7.33-7.19 (m, 7H), 7.11-7.03 (m, 4H), 6.98 (d, J = 8.4
Hz, 2H), 6.87 (d, J = 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 160.8,
160.3, 159.1, 150.6, 141.5, 139.4, 138.3, 132.8, 131.8, 131.6, 130.7,
129.8, 129.0, 128.7, 127.8, 127.5, 127.2, 121.5, 119.1, 114.1, 104.5,
55.7, 55.5; HRMS (ESI) m/z: calcd for C29H24NO2 [M+H]+ is 418.1807;
found, 418.1812.
1-(4-Nitrophenyl)-3,4-diphenylisoquinoline (3va). Pale yellow solid (32
mg, 80% yield); Rf=0.5 (in 60% DCM/Hexane); m.p. 179-181 °C; 1H NMR
(400 MHz, CDCl3): δ 8.34 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 8.3 Hz, 1H),
7.94 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 15.0 Hz, 1H),
7.49 (t, J = 15.0 Hz, 1H), 7.34-7.31 (m, 5H), 7.23-7.21 (m, 2H), 7.13-7.11
(m, 3H); 13C NMR (100 MHz, CDCl3): δ 157.5, 150.3, 148.3, 146.4, 140.7,
137.4, 137.4, 131.6, 131.5, 131.3, 130.7, 130.7, 128.8, 128.0, 127.9,
127.7, 127.6, 126.8, 126.8, 125.5, 123.9; HRMS (ESI) m/z calcd for
C27H19N2O2 [M+H]+ 403.1447; found, 403.1431.
4-Hexyl-1-methyl-3-phenylisoquinoline (3ah). Oily liquid (26 mg, 87%
yield); Rf=0.4 (in 10% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3): δ
8.16 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H),
7.58 (t, J = 7.6 Hz, 1H), 7.51-7.36 (m, 5H), 2.97-2.93 (m, 5H), 1.67-1.59
(m, 2H), 1.34-1.18 (m, 6H), 0.86-0.82 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 155.7, 150.9, 141.8, 135.3, 129.7, 129.3, 128.1, 127.4, 127.3,
126.6, 126.2, 126.1, 124.2, 31.3, 31.2, 29.5, 28.5, 22.5, 22.4, 14.0;
HRMS (ESI) m/z: calcd for C22H26N [M+H]+ 304.2050; found, 304.2060.
1-Methyl-diethylisoquinoline (3ab). White solid (15 mg, 75% yield);
Rf=0.4 (in 10% EtOAc/Hexane); m.p. 57-59 °C; 1H NMR (400 MHz,
CDCl3): δ 8.08 (d, J = 4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.2
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
1-Methyl-3,4-di-p-tolylisoquinoline (3ai).[6f] Pale yellow solid (31 mg,
80% yield); Rf=0.5 (in 10% EtOAc/Hexane); m.p. 151-154 °C; 1H NMR
(400 MHz, CDCl3): δ 8.19-8.17 (m, 1H), 7.68-7.66 (m, 1H), 7.78-7.55 (m,
2H), 7.3 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 7.12 (d, J = 8.0 Hz,
2H), 7.02 (d, J = 7.6 Hz, 2H), 3.07 (s, 3H), 2.40 (s, 3H), 2.29 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 157.7, 149.7, 138.6, 136.9, 136.8, 136.6,
135.0, 131.5, 130.5, 130.0, 129.3, 129.2, 128.7, 126.6, 126.4, 125.8,
23.0, 21.6, 21.5; HRMS (ESI) m/z: calcd for C24H22N [M+H]+ 324.1747;
found, 324.1761.
[5]
[6]
Selected examples: a) H. Wang, C. Grohmann, C. Nimphius, F.
Glorius, J. Am. Chem. Soc. 2012, 134, 19592–19595; b) Z. Shi, M.
Boultadakis-Arapinis, D. C. Koester, F. Glorius, Chem. Commun. 2014,
50, 2650; c) D. Zhao, F. Lied, F. Glorius, Chem. Sci. 2014, 5, 2869.
Selected examples: a) P. C. Too, Y.-F. Wang, S. Chiba, Org. Lett. 2010,
12, 5688–5691; b) R. K. Chinnagolla, S. Pimparkar, M. Jeganmohan,
Org. Lett. 2012, 14, 3032–3035; c) Z. Shi, M. Boultadakis-Arapinis, D.
C. Koester, F. Glorius, Chem. Commun. 2014, 50, 2650; d) D. Zhao, F.
Lied, F. Glorius, Chem. Sci. 2014, 5, 2869; e) M. Sen, D. Kalsi, B.
Sundaraju, Chem. Eur. J. 2015, 21, 15529–15533; f) H. Wang, J.
Koeller, W. Liu, L. Ackermann, Chem. Eur. J. 2015, 21, 15525–15528;
g) A. B. Pawar, D. Agarwal, D. M. Lade, J. Org. Chem. 2016, 81,
11409–11415; h) X.-C. Li, C. Du, H. Zhang, J.-L. Niu, M.-P. Song, Org.
Lett. 2019, 21, 2863–2866 and references cited therein.
3,4-Bis(4-fluorophenyl)-1-methylisoquinoline (3aj).[6f]
Pale yellow
solid (28 mg, 72% yield); m.p. 143-145 °C; Rf=0.55 (in 10%
EtOAc/Hexane); 1H NMR (400 MHz, CDCl3): δ 8.22-8.20 (m, 1H), 7.62-
7.61 (m, 3H), 7.35-7.31 (m, 2H), 7.20-7.17 (m, 2H), 7.10 (t, J = 8.8 Hz,
2H), 6.91 (t, J = 8.8 Hz, 2H), 3.10 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
163.6 (d, J = 8.0 Hz), 161.1 (d, J = 7.7 Hz), 158.4, 148.9, 137.2 (d, J =
3.3 Hz), 137.3, 133.6 (d, J = 3.5 Hz), 133.2 (d, J = 7.9 Hz), 132.3 (d, J =
8.1 Hz), 130.5, 128.4, 127.1, 126.5, 126.2, 126.0, 115.8 (d, J = 21.0 Hz),
115.0 (d, J = 21.0 Hz), 23.0; HRMS (ESI) m/z: calcd for C22H16F2N
[M+H]+ 332,1245; found, 333.1244.
[7]
[8]
a) H. Park, P. Verma, K. Hong, J.-Q. Yu, Nat. Chem. 2018, 10, 755–
762; b) Z. Guan, S. Chen, Y. Huang, H. Yao, Org. Lett. 2019, 21, 3959–
3962.
a) S.-C. Chuang, P. Gandeepan, C.-H. Cheng, Org. Lett. 2013, 15,
5750–5753; b) C.-Z. Luo, P. Gandeepan, Y.-C. Wu, C.-H. Tsai, C.-H.
Cheng, ACS Catal. 2015, 5, 4837–4841; c) J. Váňa, J. Bartáček, J.
Hanusek, J. Roithová, M. Sedlák, J. Org. Chem. 2019, 84, 12746–
12754.
1-Cyclohexyl-6-methoxy-3,4-diphenylisoquinoline (3wa). Colurless
oily liquid (32 mg, 64% yield); Rf=0.45 (in 5% EtOAc/Hexane); 1H NMR
(700 MHz, CDCl3): δ 8.20 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 6.3 Hz, 2H),
7.36 (t, J = 7.0 Hz, 2H), 7.33 (t, J = 7.0 Hz, 1H), 7.23 (d, J = 7.0 Hz, 2H),
7.20-7.16 (m, 4H), 6.93 (d, J = 2.1 Hz, 1H), 3.7 (s, 3H), 3.58-3.55 (m, 1H),
2.05 (d, J = 12.6 Hz, 2H), 2.00-1.94 (m, 4H), 1.82 (d, J = 12.6 Hz, 1H),
1.56 (q, J = 13.3 Hz, 3H); 13C NMR (175 MHz, CDCl3): δ 164.2, 160.4,
149.7, 141.8, 138.9, 138.7, 131.7, 130.9, 128.7, 128.0, 127.7, 127.4,
127.1, 126.8, 120.9, 118.7, 105.1, 55.5, 42.2, 32.8, 27.3, 26.6; IR (neat):
3427, 2925, 2852, 1617, 1574, 1502, 1410, 1373, 1264, 1235, 1030, 738,
700 cm-1; HRMS (ESI) m/z: calcd for C28H28NO [M+H]+ 394.2171: found,
394.2153.
[9]
A Scifinder search (key word such as additive free, redox-neutral and
transient directing group, C-H activation) did not retrieve any report
regarding additive free redox neutral traceless directing group.
[10] Selected examples: a) R. G. Wallace, J. M. Barker, M. L. Wood,
Synthesis, 1990, 1990, 1143–1144; b) L. E. Evans, M. D. Cheeseman,
K. Jones, Org. Lett. 2012, 14, 3546–3549; c) A. E. Strom, J. F. Hartwig,
J. Org. Chem. 2013, 78, 8909 –891; d) S. Voth, J. W. Hollett, J. A.
McCubbin, J. Org. Chem. 2015, 80, 2545; e) Z. Ma, Z. Zhou, L. Kürti,
Angew. Chem. 2017, 129, 10018; Angew. Chem. Int. Ed. 2017, 56,
9886–9890; f) Z. Zhou, Q.-Q. Cheng, L. Kürti, J. Am. Chem. Soc. 2019,
141, 2242–2246; g) S. Munnuri, R. R. Anugu, J. R. Falck, Org. Lett.
2019, 21, 1926–1929; h) J.-C. Yi, Z.-J. Wu, S.-L. You, Eur. J. Org.
Chem. 2019, 2019, 5736–5739; i) S. Munnuri, S. Verma, D. Chandra, R.
R. Anugu, J. R. Falck, J. L. Jat, Synthesis 2019, 51, 3709–3714.
[11] Selected examples: a) Y. Tan, J. F. Hartwig, J. Am. Chem. Soc. 2010,
132, 3676–3677; b) L. Xu, Q. Zhu, G. Huang, B. Cheng, Y. Xia, J. Org.
Chem. 2012, 77, 3017–3024; c) H. Tang, B. Zhou, X.-R. Huang, C.
Wang, J. Yao, H. Chen, ACS Catal. 2014, 4, 649–656; d) H. Tang, X.-R.
Huang, J. Yao and H. Chen, J. Org. Chem. 2015, 80, 4672–4682.
[12] B. Punji, W. Song, G. A. Shevchenko, L. Ackermann, Chem. Eur. J.
2013, 19, 10605–10610.
Acknowledgements
We are thankful to SERB (EMRII/2017/001475) for funding. P.B
& A.G. thank DAE, B.V.P. thanks DST-INSPIRE, R.C. thanks
CSIR for financial support. Arindam and Shreenibasa NISER, for
solving single crystal data. We are also thankful to Dr. Ian
Beadham, Kingston University, London for his help in improving
this manuscript.
[13] CCDC 1911600 contains supplementary crystallographic data for the
compound 3ra.
[14] a) H. Wang, J. Koeller, W. Liu, L. Ackermann, Chem. Eur. J. 2015, 21,
15525–15528; b) L. Ackermann, A. V. Lygin, N. Hofmann, Angew.
Chem. 2011, 123, 6503–6506; Angew. Chem. Int. Ed. 2011, 50, 6379–
638; c) H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto, N. Chatani, J. Am.
Chem. Soc. 2011, 133, 14952.
Keywords: Hydroxylamine-O-sulfonic acid; Isoquinoline; Redox-
neutral; Rhodium catalysis; C-H activation.
[15] C.-C. Lee, Y.-C. Lin, Y.-H. Liu, Y. Wang, Organometallics, 2005, 24,
136–143.
References
[16] E. M. Simmons, J. F. Hartwig, Angew. Chem. 2012, 124, 3120; Angew.
Chem. Int. Ed. 2012, 51, 3066–3072.
[1]
a) L. McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40,
1885; b) K. Godula, D. Sames, Science, 2006, 312, 67–72; c) J.
Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem. 2012, 124,
9092–9142; Angew. Chem. Int. Ed. 2012, 51, 8960–9009; d) R. He, Z.-
T. Huang, Q.-Y. Zheng, C. Wang, Tetrahedron Lett. 2014, 55, 5705–
5713.
[17] H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997, 62, 7512–
7515.
[18] C. White, S. J. Thompson, P. M. Maitlis, J. Chem. Soc. Dalt. Trans.
1977, 1654–1661.
[19] L. Qiu, D. Huang, G. Xu, Z. Dai, J. Sun, Org. Lett. 2015, 17, 1810–
1813.
[2] T. Gensch, M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc.
Rev. 2016, 45, 2900–2936.
[3] a) D. A. Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem. Res.
2012, 45, 814–825; b) G. Rouquet, N. Chatani, Angew. Chem. 2013,
125, 11942–11959; Angew. Chem. Int. Ed. 2013, 52, 11726–11743; c)
R.-Y. Zhu, M. E. Farmer, Y.-Q. Chen, J.-Q. Yu, Angew. Chem. 2016,
128, 10734; Angew. Chem. Int. Ed. 2016, 55, 10578–10599.
[4] a) N. Guimond, C. Gouliaras, K. Fagnou, J. Am. Chem. Soc. 2010, 132,
6908–6909; b) N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem.
Soc. 2011, 133, 6449–6457.
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901825
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Key topic: C-H Activation
A new reactivity of hydroxylamine-O-sulfonic acid (HOSA) has been demonstrated as redox-neutral directing group for rhodium-
catalyzed one-pot synthesis of diverse isoquinolines. This protocol reveals the utility of HOSA as a dircting group for the addditive
free C-H/N-O annulations. Moreover the in situ cleavage of the directing group reduces one step making it as a step-economical
process.
10
This article is protected by copyright. All rights reserved.