Synthesis of Tetrahydroisoquinolines by Visible-Light-Mediated 6- exo -trig Cyclization of α-Aminoalkyl Radicals

Article abstract of DOI:10.1055/s-0039-1690006

Starting from the respective tertiary α-silylmethyl amines, the intramolecular cyclization of α-aminoalkyl radicals to Michael acceptors produced tetrahydroisoquinolines. The reaction conditions included the use of 5 molpercent of an iridium photoredox catalyst, dimethylformamide as the solvent, and equimolar amounts of water and cesium carbonate as the additives. 13 substrates were synthesized from ortho -alkylbenzaldehydes in a three-step procedure involving a carbonyl condensation, a radical bromination, and a substitution by a secondary α-silylmethyl amine. After optimization of the photocyclization, the reaction delivered tetrahydroisoquinolines in moderate to high yields (41-83percent). A facial diastereoselectivity (dr ? 80:20) was observed with chiral substrates and a crystal structure provided evidence for the relative configuration of the major diastereoisomer. A catalytic cycle with direct electron transfer to the photoexcited metal catalyst is proposed.

Full text of DOI:10.1055/s-0039-1690006

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
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M. Grübel et al.
Letter
Synlett
Synthesis of Tetrahydroisoquinolines by Visible-Light-Mediated
6-exo-trig Cyclization of α-Aminoalkyl Radicals
Michael Grübel
hn (l = 455 nm)
[Ir{dF(CF3)ppy}2(tbbpy)]PF6
H2O/Cs2CO3
EWG
EWG
Christian Jandl
Thorsten Bach*
TMS
R2
0
0
0
0-0
0
0
2-1
3
4
2-
0
2
0
2
DMF, 14 h, r.t.
N
N
X
X
R2
Department Chemie and Catalysis Research Center (CRC),
Technische Universität München, 85747 Garching, Germany
thorsten.bach@ch.tum.de
13 examples, 41–83%
R1
R1
X = H, Cl, MeO; R1 = H, Me; R2 = alkyl, benzyl; EWG = CN, COR, COOR
Received: 14.05.2019
Accepted after revision: 01.07.2019
Published online: 17.07.2019
intramolecular fashion.5 Typically, the α-aminoalkyl radical
is generated from α-silylmethyl amines employing ultravio-
let irradiation or visible light with different sensitizers,
such as anthraquinone,8 benzophenones,9 1,4-dicyano-
naphthalenes,5d,f or 9,10-dicyanoanthracene5c,e to induce
the SET.
In recent years, several protocols have been reported for
the generation of α-aminoalkyl radicals by photoredox-ac-
tive iridium or ruthenium polypyridyl complexes. Visible
light irradiation induces an electron transfer from the
amine to the photoexcited transition-metal complex. Sub-
sequent formation of an α-aminoalkyl radical allows for a
conjugate addition to a double bond, which results – if per-
formed intramolecularly – in a cyclization (Scheme 1).10,11,12
DOI: 10.1055/s-0039-1690006; Art ID: st-2019-r0271-l
Abstract Starting from the respective tertiary α-silylmethyl amines,
the intramolecular cyclization of α-aminoalkyl radicals to Michael ac-
ceptors produced tetrahydroisoquinolines. The reaction conditions in-
cluded the use of 5 mol% of an iridium photoredox catalyst, dimethyl-
formamide as the solvent, and equimolar amounts of water and cesium
carbonate as the additives. 13 substrates were synthesized from ortho-
alkylbenzaldehydes in a three-step procedure involving a carbonyl con-
densation, a radical bromination, and a substitution by a secondary α-
silylmethyl amine. After optimization of the photocyclization, the reac-
tion delivered tetrahydroisoquinolines in moderate to high yields (41–
83%). A facial diastereoselectivity (dr ≅ 80:20) was observed with chiral
substrates and a crystal structure provided evidence for the relative
configuration of the major diastereoisomer. A catalytic cycle with direct
electron transfer to the photoexcited metal catalyst is proposed.
EWG
EWG
EWG
Ir or Ru cat.
visible light
Key words catalysis, cyclization, electron transfer, iridium, photo-
chemistry, radical reaction
TMS
R
N
N
N
R
R
Photoinduced single-electron oxidation of amines pro-
vides access to nucleophilic α-aminoalkyl radicals which
can act as reactive intermediates.1 Besides the generation of
α-aminoalkyl radicals by single-electron transfer (SET) and
subsequent deprotonation,2 the radicals can be produced by
oxidative decarboxylation of α-amino acid derivatives,3 by
hydrogen atom transfer,4 or by oxidative desilylation of α-
silylalkyl amines.5 The silyl group renders the formation of
α-aminoalkyl radicals regioselective6 and avoids overoxida-
tion of the α-aminoalkyl radicals to the corresponding
iminium ions.7
Several research groups reported the utilization of the
trimethylsilyl (TMS) group as a suitable electrophilic leav-
ing group in photosensitized electron-transfer reactions.
Frequently, a consecutive reaction is the addition of the
photochemically generated α-aminoalkyl radical to elec-
tron-deficient alkenes (Michael acceptors) in an inter- or
EWG
EWG
TMS
O
N
R
N
R
X
X
R
X
R
R
1
2
3
Scheme 1 Generation of α-aminoalkyl radicals through a SET and con-
secutive addition to a Michael system in an intramolecular fashion (top)
and its application to the synthesis of tetrahydroisoquinolines 1 (bottom)
Herein, we present a visible-light-mediated cyclization
reaction to tetrahydroisoquinolines 1 (THIQs) that relies on
a conjugate addition of SET-generated α-aminoalkyl radi-
cals to Michael acceptors and is catalyzed by an iridium
polypyridyl complex. THIQs are usually synthesized from a
β-arylethylamine and an aldehyde or ketone following the
Pictet–Spengler protocol.13 Although photoredox-based
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Grübel et al.
Letter
Synlett
methods have been established in recent years to further
modify the THIQ core structure10b,14–17 there is not yet a
method to access this skeleton by photoredox catalysis.
The synthesis of the respective starting materials 2 for
the photoreactions required in all cases the corresponding
ortho-alkyl-substituted benzaldehydes 3. Aldehyde sub-
strates with substituents at the phenyl skeleton (X = OMe,
Cl) and R1 = CH3 were prepared by a halogen-metal ex-
change and subsequent formylation with N,N-dimethylfor-
mamide (DMF).18 In the next synthetic step, the electron-
withdrawing groups (EWG) were introduced by either an
aldol condensation (nitriles, ketones) or a Wittig reaction
(methyl and ethyl ester). For compounds 2a and 2b it was
also possible to commence the synthesis with the respec-
tive cinnamates 4 (EWG = CO2Me, CO2Et). A literature pro-
cedure was adapted to introduce the sulfone by addition of
thiophenol to 1-ethynyltoluene and subsequent oxidia-
tion.19 The radical bromination at the benzylic position of
substrates 4 was performed by using N-bromosuccinimide
(NBS) in chloroform and dibenzoylperoxide (DBP) as radical
initiator. A nucleophilic substitution of bromides 5 by sec-
ondary α-silylmethyl amines in acetone with K2CO3 con-
cluded the synthesis (Table 1). The corresponding amines
for substrates 2g, 2m were synthesized as previously re-
ported.20 All substrates exhibit oxidation potentials be-
tween Eox (2+•/2) = +0.75 V and +0.95 V vs. SCE [for further
details, see the Supporting Information (SI)].
Our investigation of the intramolecular cyclization com-
menced with model substrate 2a, which was irradiated in
the presence of 5 mol% [Ir{dF(CF3)ppy}2(tbbpy)]PF6 [Ir(dF)]
[E1/2(IrIII*/IrII) = +1.21 V vs. SCE]21 as a photocatalyst. After ir-
radiation for 14 hours in DMF at 25 °C with a blue LED (30
W, λ = 455 nm), 29% of the desired product was obtained
(Table 2, entry 1).
Table 2 Optimization Studies for the Intramolecular Photocyclization
of 2a to Tetrahydroisoquinoline 1a
O
O
Ir(dF)
CF3
F
OEt
OEt
Bn
hν (λ = 455 nm)
N
Ir
TMS
N
N
14 h, Ir(dF)
F
F3C
PF6
N
N
solvent
additive, concn
N
F
Bn
2a
1a
F
Entry Ir cat. (mol%) Solvent
Concn (mM) Additivea
Yield (%)b
1
2
5
5
5
5
5
5
5
5
5
2
5
–
5
5
5
DMF
MeCN
CH2Cl2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
50
50
50
25
100
50
50
50
50
50
50
50
50
50
50
–
29
7
–
Table 1 Synthesis of Amine Substrates 2 Starting from ortho-Alkyl-
Substituted Styrenes 4 by Bromination (4→5) and Nucleophilic Substi-
tution (5→2)
3
–
12
17
22
28
40
32
52
23
0
4
–
EWG
5
–
O
6
AcOH
H2O
aldol or
Wittig reaction
7
X
X
NBS
DBP
(CHCl3)
EWG
R1
R1
3
4
8
H2O/LiBF4
5.0 equiv K2CO3
9
H2O/Cs2CO3
H2O/Cs2CO3
H2O/Cs2CO3
H2O/Cs2CO3
H2O/Cs2CO3
H2O/Cs2CO3
H2O/Cs2CO3
EWG
TMS
TMS
N
R2
1.2 equiv
(acetone)
10
11c
12d
13e
14f
15g
H
Br
N
X
X
R1
R1 R2
0
2
5
0
Substrate
X
R1
R2
EWG
Yield (%) Yield (%)
28
55
4→5
5→2
2a
2b
2c
2d
2e
2f
H
H
Ph
CO2Et
70
80
57
69
36
34
80
72
85
81
75
76
80
72
90
56
58
72
71
90
95
33
a Addition of additive in stoichometric amounts.
H
H
H
Cl
H
Ph
CO2Me
COMe
CN
b Yield of isolated product after chromatographic purification.
c No light.
H
Ph
d No photocatalyst (71% recovered starting material).
e Ru(bpy)3(PF6)2 as photocatalyst.
H
Ph
f [Ir(dF(CF3)ppy)2(bpy)]PF6 as photocatalyst.
g Irradiation of photoproduct 1a under optimized conditions.
H
Ph
CO2Me
CO2Me
CO2Me
COMe
CO2Me
CN
OMe
H
H
Ph
2g
2h
2i
H
isobutyl
Ph
Variation of the solvent led to decomposition of the
starting material and a low product yield (entries 2–3). En-
tries 4 and 5 show that a change in the substrate concentra-
tion did not improve the yield. The addition of Brønsted
acid has been reported to accelerate the rate-determining
carbon–carbon bond formation step10b but use of acetic
acid as proton source did not alter the reaction outcome
(entry 6). However, the addition of water in stoichiometric
H
Me
Me
Me
H
H
Ph
2j
H
Ph
quant
2k
2l
H
Ph
COPh
SO2Ph
CO2Me
29
54
80
H
H
Ph
2m
H
H
Ph-CF3
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
M. Grübel et al.
Letter
Synlett
amounts had a positive effect, improving the yield to 40%
(entry 7). From a screening of several Lewis acids and inor-
ganic bases (for further additive screening, see the SI), cesi-
um carbonate evolved as the most beneficial additive in-
creasing the yield up to 52% at a conversion of 83% (entry 9).
Lowering the catalyst loading only decreased the yield (en-
try 10). Control experiments (entry 11 and 12) validated
the necessity of light and catalyst in the reaction. Only 71%
of starting material and no product could be re-isolated af-
ter irradiation of a sample without a catalyst, which
demonstrates the limited stability of the starting material.
Neither Ru(bpy)2(PF6)2 nor a different iridium catalyst
[Ir{dF(CF3)ppy}2(bpy)]PF6 proved to be a suitable catalyst in
the cyclization reaction (entry 13 and 14). The excited state
potential of Ru(bpy)2(PF6)2 [E1/2 (RuII*/RuI) = +0.80 V vs. SCE]22
might be too low to oxidize the tertiary amine. Eventually,
we checked the stability of the photoproduct under the op-
timized conditions and observed decomposition during ir-
radiation (entry 15). With an oxidation potential of Eox
(1a+•/1a) = +1.15 vs. SCE, the photoproduct could potential-
ly still be oxidized by the excited state of the iridium cata-
lyst, resulting in decomposition as previously described.23
No reaction was observed with an amine substrate without
a trimethylsilyl group in the α position (see the SI).
hν (λ = 455 nm)
1.0 equiv H2O
1.0 equiv Cs2CO3
5 mol% [Ir(dF)]
EWG
TMS
EWG
N
N
X
X
(DMF), 14 h, 25 °C
R1 R2
R1 R2
2
1
O
O
O
N
CN
N
OEt
OMe
N
N
1a 52%
1b 62%
69% conv.
1c 52%
1d 41%
53% conv.
83% conv.
77% conv.
O
O
O
OMe
OMe
OMe
N
N
N
O
Cl
1e 66%
1f 58%
69% conv.
1g 41%
85% conv.
85% conv.
O
O
CN
N
OMe
N
N
1h 57%
72% conv.
d.r. = 80:20
1i 83%
95% conv.
d.r. = 82:18
1j 43%
50% conv.
d.r. = 73:27
O
O
In the next set of experiments, we examined the sub-
strate scope of this transformation under the optimized re-
action conditions (Table 2, entry 9).24 As shown in Scheme 2
the reaction seems to be fairly general and applicable to a
range of substrates with moderate to high yields (41–83%).
By changing the EWG from the model substrate 2a to a me-
thoxycarbonyl substituent (2b) the yield increased to 62%
but the conversion dropped to 69%. With a stronger EWG
such as cyano or sulfonyl the yields decreased to 41% (1d)
and 36% (1l) and in both cases the conversion was only
around 50% (53% for 1d, 51% for 1l). With acetyl or benzoyl
as EWG, products 1c and 1k were isolated in 52% and 55%
yield, respectively, at a conversion of 77% for 1c and 88% for
1k. Variation of the substituents at the aryl core resulted in
a yield of 66% for 1e with a weakly deactivating chloro sub-
stituent and 58% for 1f with a strongly activating methoxy
group attached to the phenyl ring. In both reactions, the
starting material was not fully converted to the products
(85% and 69% conversion). Different substituents at the
amine moiety such as a 4-trifluoromethylbenzyl group 1m
(59%) or an aliphatic isobutyl group 1g (41% yield) were
also tolerated with conversions of 78% and 85%, respective-
ly. Acetyl- (2h), methoxycarbonyl- (2i), and cyano-substi-
tuted (2j, E/Z = 73:27) substrates with a methyl group at the
1-position of the THIQ core successfully afforded the de-
sired products 1h–j in 57, 83, and 43% yield. The conversion
in the three reactions was 72%, 95%, and 50%, respectively.
THIQs 1h–j were isolated as a mixture of diastereomeric
products, which could be separated by column chromatog-
raphy. In all three cases, the formation of a major diastereo-
SO2Ph
N
OMe
Ph
N
N
1k 55%
1l 36%
51% conv.
1m 59%
88% conv.
78% conv.
CF3
Scheme 2 Intramolecular photocatalytic cyclization of α-silylated
amines 2 to products 1 under optimized reaction conditions. Yields are
given for isolated products and are not based on the conversion.
isomer was observed (dr ≅ 80:20). The assignment of the
relative configuration of product 1i was accomplished after
a palladium-catalyzed debenzylation of the tertiary amine
(Scheme 3). The crystal structure of the corresponding am-
monium salt 6 revealed for the major diastereoisomer a cis
configuration of the substituents in positions C1 and C4.
Comparing the 1H NMR spectra for products 1i showed that
the shift of the signal for the proton in position C1 is dis-
tinctly different for the major (3.75 ppm) and minor (4.10
ppm) diastereoisomer. The same chemical shift difference
was also observed for products 1h and 1j suggesting that in
all diastereomeric mixtures the major product displays a cis
configuration of the substituents in positions C1 and C4.
The diastereoselectivity can be rationalized by assuming
that the conformation of the cyclization precursor is gov-
erned by 1,3-allylic strain.25 Accordingly, the hydrogen
atom at the stereogenic center that is located in the plane of
the aryl group, minimizes the steric strain between the Mi-
chael system and substituents in ortho position. The conju-
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
M. Grübel et al.
Letter
Synlett
gate addition of the α-aminoalkyl radical 7i presumably
proceeds from the bottom face generating the major prod-
uct with a cis configuration (Scheme 4). Scheme 4 describes
a reasonable mechanistic scenario for the photocatalytic
cyclization of 2i to THIQ 1i as representative product. The
first step involves a reductive quench of the photoexcited
iridium complex by the amine producing a radical cation,
which loses the TMS group generating the α-aminoalkyl
radical.
radical. All substrates show relatively high redox potentials
compared to other α-silylmethyl anilines.26 The photocy-
clization occurs in moderate to high yields and offers a yet
unexplored entry to biologically relevant tetrahydroiso-
quinolines.
Acknowledgment
This project was supported by the Deutsche Forschungsgemeinschaft
(DFG). M.G. acknowledges the TUM graduate school for financial sup-
port and Prof. Corinna Hess for valuable discussions.
O
H2 (1 atm)
30 mol% Pd/C
O
H
Supporting Information
1i
Cl
4
(MeOH/HCl)
NH2
1
Supporting information for this article is available online at
88%
6
https://doi.org/10.1055/s-0039-1690006.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
Scheme 3 Palladium-catalyzed deprotection of the N-benzyl group and
confirmation of the relative configuration of the major diastereoisomer
by X-ray crystal structure analysis.
Primary Data
for this article are available online at https://doi.org/10.1055/s-0039-
1690006 and can be cited using the following DOI: 10.4125/pd0105th. Pri
m
ary
D
ataPri
m
ary
D
ata
1
0
.
4
1
2
5/p
d
0
1
0
5th
.
2
0
1
8-08-1
4
Z
a
h
l
e
n
1
C
h
e
m
i
stry
CO2Me
CO2Me
TMS
H
References and Notes
H
N
−"TMS"
Bn
N
(1) Reviews: (a) Nakajima, K.; Miyake, Y.; Nishibayashi, Y. Acc.
Chem. Res. 2016, 49, 1946. (b) Renaud, P.; Giroud, L. Synthesis
1996, 913. (c) Pandey, G. Synlett 1992, 546. (d) Yoon, U. C.;
Mariano, P. S. Acc. Chem. Res. 1992, 25, 233.
H
2i
7i
Bn
[IrIII(dF)]*
(2) (a) Pienta, N. J.; McKimmey, J. E. J. Am. Chem. Soc. 1982, 104,
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Chem. Soc. 2012, 134, 3338.
[IrII(dF)]
1i
[IrIII(dF)]
H+
O
(3) (a) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2014, 136, 10886. (b) Fan, L.; Jia, J.; Lefebvre, H. Q.; Rueping,
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Choi, J.; Fu, G. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2016, 138,
1832.
CO2Me
OEt
Bn
H
H
N
N
Bn
9i
8i
(4) Ashley, M. A.; Yamauchi, C.; Chu, J. C. K.; Otsuka, S.; Yorimitsu,
H.; Rovis, T. Angew. Chem. Int. Ed. 2019, 58, 4002.
Scheme 4 Mechanistic scenario for the catalytic cycle in the photo-
chemical transformation of 2j to the THIQ 1i and model for an 1,3-allyl-
ic strain stereocontrol
(5) (a) Yoon, U. C.; Kim, J. U.; Hasegawa, E.; Mariano, P. S. J. Am.
Chem. Soc. 1987, 109, 4421. (b) Hasegawa, E.; Xu, W.; Mariano,
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Intramolecular addition of the radical to the double
bond closes the ring in a 6-exo-trig fashion. The catalytic
cycle is completed by oxidation of the photocatalyst and the
formation of enolate 9i, which gets trapped by a TMS source
or is directly hydrolyzed. Intermediate 9i can also be
formed from 8i by simultaneous oxidation of amine 2i
(chain process).
In summary, we have described a new intramolecular 6-
exo-trig photocyclization to tetrahydroisoquinolines in-
duced by visible-light-mediated photoredox catalysis with
an iridium complex. A three-step synthesis route has been
developed to access a variety of substrates incorporating
the α-silylmethyl amine. The latter entity proved to be es-
sential for the generation of the nucleophilic α-aminoalkyl
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

E
M. Grübel et al.
Letter
Synlett
(9) (a) de Alvarenga, E. S.; Mann, J. J. Chem. Soc., Perkin Trans. 1
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(0.05 equiv) were dissolved in dry DMF (ca. 2 mL/0.1 mmol sub-
strate). The yellow mixture was degassed by repeating a freeze-
pump-thaw cycle (3×) and irradiated for 14 h with 30 W blue
LED lamps (λ = 455 nm) at r.t. whilst continuously stirring
under an argon atmosphere. After 14 h, water (ca. 5 mL/0.1
mmol) was added. The layers were separated and the aqueous
layer was extracted with diethyl ether (3× ca. 6 mL/0.1 mmol).
The combined organic layers were washed with brine and dried
with Na2SO4. After filtration, residual solvent was removed
under reduced pressure. The crude product was purified by
column chromatography to obtain the photoproduct.
Representative NMR data (1a): 1H NMR (500 MHz, CDCl3): δ =
7.40–7.34 (m, 2 H, 2× meta-CPh-H), 7.34–7.28 (m, 2 H, 2× ortho-
C
Ph-H), 7.27–7.21 (m, 1 H, para-CPh-H), 7.17–7.07 (m, 3 H, H-6,
H-7, H-8), 7.00–6.94 (m, 1 H, H-5), 4.13–3.99 (m, 2 H, CH2CH3),
3.80 (d, 2J = 14.9 Hz, 1 H, CHH-1), 3.71 (d, 2J = 13.1 Hz, 1 H, Ph-
CHH), 3.58 (d, 2J = 13.1 Hz, 1 H, Ph-CHH), 3.42 (d, 2J = 14.9 Hz, 1
H, CHH-1), 3.38–3.31 (m, 1 H, H-4), 2.88 (dd, 2J = 16.0 Hz, 3J = 9.7
Hz, 1 H, CHHCO2Et), 2.80 (ddd, 3J = 11.7 Hz, 4J = 3.2, 1.3 Hz, 1 H,
CHH-3), 2.61–2.58 (m, 2 H, CHH-3, CHHCO2Et), 1.20 (t, 3J = 7.1
Hz, 3 H, CH2CH3). 13C NMR (101 MHz, CDCl3): δ = 172.9 (s,
CO2Et), 138.7 (s, CH2-CPh), 137.6 (s, C-4a), 135.3 (s, C-8a), 129.1
(d, meta-CHPh), 128.4 (d, C-8), 128.4 (d, ortho-CHPh), 127.2 (d,
para-CHPh), 126.7 (d, C-6*), 126.5 (d, C-7*), 126.2 (d, C-5), 62.8
(t, CH2-CPh), 60.4 (t, CH2CH3), 56.5 (t, C-1), 54.7 (t, C-3), 41.2 (t,
CH2CO2Et), 35.8 (d, C-4), 14.3 (q, CH2CH3). * Assignment is inter-
convertible. Major diastereoisomer (1i): 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.36 (m, 2 H, 2× meta-CPh-H), 7.33–7.29 (m, 2
H, 2× ortho-CPh-H), 7.27−7.22 (m, 1 H, para-CPh-H), 7.22–7.13
(m, 4 H, H-5, H-6, H-7, H-8), 4.10 (d, 2J = 13.6 Hz, 1 H, Ph-CHH),
3.75 (q, 3J = 6.3 Hz, 1 H, H-1), 3.55 (s, 3 H, CO2CH3), 3.40 (d, 2J =
13.6 Hz, 1 H, Ph-CHH), 3.26 (dq, 3J = 9.0 Hz, 3J = 5.0 Hz, 1 H, H-4),
2.90–2.80 (m, 2 H, CHH-3, CHHCO2CH3), 2.66 (dd, 2J = 16.0 Hz, 3J
= 5.0 Hz, 1 H, CHHCO2CH3), 2.62–2.56 (m, 1 H, CHH-3), 1.53 (d, 3J
= 6.3 Hz, 3 H, CH3). 13C NMR (101 MHz, CDCl3): δ = 173.2 (s, CO),
140.4 (s, C-8a), 139.6 (s, CH2-CPh), 137.7 (s, C-4a), 128.9 (d,
meta-CHPh), 128.3 (d, ortho-CHPh), 128.1 (d, C-8*), 127.3 (d, C-
5*), 127.0 (d, para-CHPh), 126.4 (d, C-6**), 126.1 (d, C-7**), 58.9
(t, CH2-CPh), 57.8 (d, C-1), 51.5 (q, CO2CH3), 50.9 (t, C-3), 39.9 (t,
CH2CO2H3), 35.1 (d, C-4), 21.9 (q, CH3). */** Assignments are
interconvertible. Minor diastereoisomer (1i): 1H NMR (400
MHz, CDCl3): δ = 7.39–7.35 (m, 2 H, 2× meta-CPh-H), 7.33–7.28
(m, 2 H, 2× ortho-CPh-H), 7.27–7.22 (m, 1 H, para-CPh-H), 7.17–
7.09 (m, 3 H, H-6, H-7, H-8), 7.06–7.00 (m, 1 H, H-5), 4.10 (q, 3J =
6.6 Hz, 1 H, H-1), 3.83 (d, 2J = 13.1 Hz, 1 H, Ph-CHH), 3.63 (d, 2J =
13.1 Hz, 1 H, Ph-CHH), 3.52 (s, 3 H, CO2CH3), 3.23–3.17 (m, 1 H,
H-4), 3.00 (d, 2J = 10.6 Hz, 1 H, CHH-3), 2.88 (dd, 2J = 16.2 Hz, 3J =
10.1 Hz, 1 H, CHHCO2CH3), 2.55–2.45 (m, 2 H, CHH-3, CHH-
CO2CH3), 1.28 (d, 3J = 6.6 Hz, 3 H, CH3). 13C NMR (101 MHz,
CDCl3): δ = 173.5 (s, CO), 141.4 (s, C-8a), 139.4 (s, CH2-CPh),
137.5 (s, C-4a), 129.2 (d, meta-CHPh), 128.8 (d, C-8), 128.3 (d,
ortho-CHPh), 127.4 (d, para-CHPh), 127.0 (d, C-5), 126.4 (d, C-6*),
126.2 (d, C-7*), 58.4 (t, CH2-CPh), 56.0 (d, C-1), 51.5 (q, CO2CH3),
45.8 (t, C-3), 41.1 (t, CH2CO2CH3), 35.9 (d, C-4), 14.8 (q, CH3). *
Assignment is interconvertible.
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Substrate (1.00 equiv), Cs2CO3 (1.00 equiv), H2O (1.00 equiv),
and photoredox catalyst [Ir{dF(CF3)ppy}(dtbpy)]PF6 [Ir(dF)]
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E