Selective Zincation of 1,2-Dicyanobenzene and Related Benzonitriles in Continuous Flow Using in Situ Trapping Metalations

Article abstract of DOI:10.1055/s-0036-1588837

A mild and general metalation procedure for the functionalization of 1,2-dicyanobenzene and related polyfunctionalized benzonitriles using a commercially available continuous flow setup is reported. The addition of TMPLi (TMP = 2,2,6,6-tetramethylpiperidy

Full text of DOI:10.1055/s-0036-1588837

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© Georg Thieme Verlag Stuttgart · New York
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M. Ketels et al.
Letter
Synlett
Selective Zincation of 1,2-Dicyanobenzene and Related Benzoni-
triles in Continuous Flow Using In Situ Trapping Metalations
Marthe Ketels ‡
Dorothée S. Ziegler‡
0 °C, 20 s
1.5 mL/min
TMPLi
(1.5 equiv)
CN
CN
workup
Paul Knochel*
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0
0
0
0-
0
0
1
7-
9
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3
4-
3
3
2
CN
Department of Chemistry, Ludwig-Maximilians-Universität
München, Butenandtstr. 5-13, Haus F, 81377 München, Germany
paul.knochel@cup.uni-muenchen.de
‡ These authors contributed equally.
E+
E
1.5 mL/min
CN
16 examples
up to 88% yield
CN
+ ZnCl2 (0.5 equiv)
Dedicated to Professor Victor Snieckus on the occasion of his 80th
birthday and in recognition of his pioneer contributions in organo-
metallic chemistry
CN
Zn2
Received: 10.04.2017
Accepted after revision: 26.04.2017
Published online: 06.06.2017
ation of the arene followed by transmetalation with the
metal salt to afford an ortho-zincated intermediate and pro-
vides after iodolysis the desired 3-iodo derivative (3a) in
80% yield. Further experiments showed that the generation
of the lithium species and in situ trapping with ZnCl2 re-
quires a temperature of –78 °C in batch and cannot be
scaled-up without further optimization (Scheme 1).
DOI: 10.1055/s-0036-1588837; Art ID: st-2017-r0246-l
Abstract A mild and general metalation procedure for the functional-
ization of 1,2-dicyanobenzene and related polyfunctionalized benzoni-
triles using a commercially available continuous flow setup is reported.
The addition of TMPLi (TMP = 2,2,6,6-tetramethylpiperidyl) to a mix-
ture of an aromatic substrate with a metallic salt such as ZnCl2 under
appropriate conditions (0 °C, 20 s) leads to fast in situ lithiation of the
arene followed by transmetalation with ZnCl2 to afford the correspond-
ing functionalized arylzinc compound that were trapped with various
electrophiles in high yields. The reaction scope of these in situ trapping
metalations in flow is broader and needs less equivalents of the base
and the metal salt than the corresponding batch procedure.
1) ZnCl2 (2.0 equiv)
2) TMPLi (2.0 equiv)
CN
CN
3) I2 (4.0 equiv)
CN
THF, –78 °C up to r.t.
CN
overnight
I
1a
3a: 80% yield
Scheme 1 Batch conditions for the functionalization of 1,2-dicyano-
benzene (1a)
Key words continuous flow, in situ trapping metalation, TMPLi, ZnCl2,
1,2-dicyanobenzene
We reported that in situ trapping metalations can be
performed at mild conditions using a continuous flow set
up.7 In this procedure, the substrate, here 1,2-dicyanoben-
zene (1a) is mixed with ZnCl2 (0.5 equiv) in THF and this
solution is mixed in continuous flow with a THF solution of
TMPLi (ca. 0.6 M). Such a mixing is done at 0 °C (and not
cryogenic temperatures like for the batch procedure) and
requires only 20 seconds reaction time.
Herein, we wish to report the successful use of this set-
up to prepare a range of functionalized 1,2-dicyanoben-
zenes of type 3 as well as some related polyfunctionalized
benzonitriles of type 4. Thus, the treatment of a mixture of
1,2-dicyanobenzene (1a; 1.0 equiv) and ZnCl2 (0.5 equiv)
with TMPLi (1.5 equiv) under flow conditions8 (1.5 mL/min,
0 °C, 20 s) led to a regioselective lithiation of 1a, giving after
transmetalation with ZnCl2 the corresponding diarylzinc
reagent (2a), which was quenched with iodine, providing 3-
iodo-1,2-dicyanobenzene (3a) in 88% yield9 (Scheme 2).
The metalation of polyfunctionalized aromatics and
heterocycles pioneered among others by Victor Snieckus1 is
a key reaction of the expedited functionalization of these
unsaturated building blocks for pharmaceutical, agrochem-
ical and material science applications.2 Of special impor-
tance is the functionalization of 1,2-dicyanobenzenes since
derivatives of such scaffolds may be used for heterocyclic
syntheses and for the elaboration of phthalocyanines with
potential applications as solar cells.3
Recently, we have shown that the performance of the so
called in situ trapping metalations4 for polyfunctionalized
aromatics can be advantageous since the produced lithium
intermediate is immediately trapped with metallic salt such
as MgCl2·2LiCl, ZnCl2,CuCN·2LiCl or LaCl3·2LiCl.5 Preliminary
experiments with 1,2-dicyanobenzene (1a) have shown
that the addition of TMPLi6 (THF, 1.2 equiv) to a mixture of
1a with the metal salt ZnCl2 at –78 °C first leads to the lithi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
M. Ketels et al.
Letter
Synlett
0 °C, 20 s
1.5 mL/min
1.5 mL/min
TMPLi
(1.5 equiv)
CN
CN
I
workup
CN
I2
3a: 88% yield
CN
CN
1a
CN
Zn
+ ZnCl2 (0.5 equiv)
2
2a
Scheme 2 Continuous flow setup for in situ trapping metalations of 1,2-dicyanobenzene (1a) using TMPLi in the presence of the metal salt ZnCl2
Table 1 Functionalized 1,2-Dicyanobenzenes of Type 3 Obtained via
an In Situ Trapping Procedure in Continuous Flow Using ZnCl2 and Sub-
sequent Trapping with an Electrophile (E+) in Batch
Entry
Electrophile (E+)a
Product: yieldb
CN
CN
I
Entry
Electrophile (E+)a
Product: yieldb
7
OMe
CN
CN
OMe
3h: 87%e
Br
1
CN
CN
I
3b: 81%c
8
CO2Et
CN
CN
CO2Et
3i: 82%e
CO2Et
Br
2
3
a Amount of E+ used was 1.1 equiv.
CO2Et
b Yield of isolated, analytically pure product.
3c: 76%c
c Obtained in the presence of 10 mol% CuCN·2LiCl at 0 °C in 2 h.
d Obtained after transmetalation with 1.1 equiv of CuCN·2LiCl at 0 °C in 2 h.
e Obtained using 2 mol% of Pd(OAc)2 and 4 mol% of SPhos at r.t., overnight.
CN
CN
O
O
Cl
This in situ generation of a zincated dicyanobenzene
such as 2a can be used to perform reactions with various
classes of organic electrophiles. Thus, collecting the flow
stream in a flask containing an allylic bromide such as 2-
bromocyclohexene or ethyl 2-(bromomethyl)acrylate and
10 mol% CuCN·2LiCl10 on a ca. half mmol scale gives the al-
lylated products 3b and 3c in 81% and 76% yield, respective-
ly (entries 1 and 2 of Table 1). A scale-up of this procedure is
easily possible and is described below.
Cl
Cl
3d: 57%d
CN
CN
O
O
4
Cl
Cl
Cl
Cl
Similarly, copper-mediated acylations with 3-chloro-
benzoyl chloride or 3,5-dichlorobenzoyl chloride afforded
the functionalized 1,2-dicyanobenzene derivatives (3d and
3e) in 57% and 74% yield, respectively (Table 1, entries 3 and
4). The ketones (3f and 3g) were obtained in 76–78% yield
when the zincated intermediate 2a was transmetalated to
the corresponding copper derivative using CuCN·2LiCl10 and
acylated with cyclopropanecarbonyl chloride or thiophene-
2-carbonyl chloride (Table 1, entries 5 and 6). The zinc in-
termediate 2a underwent various Negishi cross-couplings11
with 4-iodoanisole, ethyl 4-iodobenzoate or 4-iodo-1,2-di-
methylbenzene using 2 mol% Pd(OAc)2 and 4 mol% SPhos,12
leading to the desired products 3h and 3i in 82 and 87%
yield (Table 1, entries 7 and 8).
Cl
3e: 74%d
CN
CN
O
O
5
6
Cl
3f: 78%d
CN
CN
O
COCl
S
S
3g: 76%d
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
M. Ketels et al.
Letter
Synlett
The scale-up of these in situ trapping metalations in
flow is readily performed and does not require further opti-
mization. It is realized simply by extending the collection
time of the metalated species in batch. Thus, the flow meta-
lation of 1,2-dicyanobenzene (1a) was performed on a 8-
mmol scale for the Negishi cross-coupling11 with 2-iodo-
1,2-dimethylbenzene (2 mol% Pd(OAc)2, 4 mol% SPhos;12
Scheme 3) leading to the biphenyl (3j) in 77% yield (Scheme
3). In addition a 10-mmol scale-up for the reaction of the
zincated 1,2-dicyanobenzene with iodine led to 3a in 87%
yield.
Furthermore, the in situ trapping metalation procedure
was extended for the zincation of 1,3-dicyanobenzene (1b)
and 3-methoxybenzonitrile (1c; Table 2). Thus, the treat-
ment of a mixture of 1,3-dicyanobenzene (1b; 1.0 equiv)
and ZnCl2 (0.5 equiv) with TMPLi (1.5 equiv) under flow
conditions (2.5 mL/min, –78 °C, 45 s) led to a regioselective
lithiation of 1b in position 2, giving after transmetalation
with ZnCl2 the corresponding diarylzinc reagent (2b),
which was quenched with iodine, providing the desired
product 4a in 79% yield (entry 1 of Table 2). A copper-cata-
lyzed allylation with 3-bromocyclohex-1-ene provided the
2-allylated 1,3-dicyanobenzene (4b) in 88% yield (Table 2,
entry 2). Pd-catalyzed Negishi cross-coupling11 (2 mol%
Pd(OAc)2 and 4 mol% SPhos12) with 4-iodoanisole furnished
the arylated 1,3-dicyanobenzene (4c) in 70% yield (Table 2,
entry 3).
Similiary, 3-methoxybenzonitrile (1c) was regioselec-
tively lithiated and transmetalated to the zinc species (2c)
in continuous flow (2.0 mL/min, 0 °C, 45 s), and iodinated,
allylated and cross-coupled, leading to the expected prod-
ucts 4d–f in 58–82% yield (Table 2, entries 4–6).13
The iodinated dicyanobenzene (3a) can be further mod-
ified to extend the variety of precursors for phthalocya-
nines. Thus, an iodine–magnesium exchange reaction
(Scheme 4) in continuous flow (0.75 mL/min, r.t., 20 s) was
realized by the reaction of 3a with i-PrMgCl·LiCl (0.9
equiv).14 Subsequent quenching with 1,2-bis(chlorodimeth-
ylsilyl)ethane (0.6 equiv) produces the desired product 5,
which could act as an interesting precursor for the synthe-
sis of bridged phthalocyanines,15 in 60% yield while in batch
only 30% was isolated (Scheme 4).
In summary, we have developed a general methodology
for the functionalization of 1,2-dicyanobenzene and related
polyfunctionalized benzonitriles using
a commercially
available continuous flow setup. The flow metalations of
the lithiated substrates involving an in situ trapping with
the metallic salt ZnCl2 proceeded under convenient condi-
tions (0 °C, 20 s). The resulting Zn organometallic species
0 °C, 20 s
1.5 mL/min
1.5 mL/min
TMPLi
(1.5 equiv)
CN
workup
CN
CN
Pd(OAc)2 (2 mol%)
SPhos (4 mol%)
CN
1a
Me
I
+ ZnCl2 (0.5 equiv)
Me
3j
77% yield (8 mmol scale)
76% yield (0.37 mmol scale)
Me
Me
(1.1 equiv)
Scheme 3 An 8-mmol scale-up for the in situ trapping metalation of 1,2-dicyanobenzene
CN
CN
0.75 mL/min
0.75 mL/min
r.t., 30 s
.
i-PrMgCl⋅LiCl
(0.9 equiv)
Si
workup
Cl
CN
CN
Si
NC
Si
Si
Cl
I
(0.6 equiv)
NC
3a
5: 60% yield (flow conditions)
30% yield (batch conditions)
Scheme 4 Iodine–magnesium exchange by the reaction of 3a with i-PrMgCl·LiCl.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
M. Ketels et al.
Letter
Synlett
Table 2 Related Functionalized Benzonitriles of Type 4 Obtained via an In Situ Trapping Procedure in Continuous Flow Using ZnCl2 and Subsequent
Trapping with an Electrophile (E+) in Batch
1b: –78 °C, 36 s
1c: 0 °C, 45 s
2–2.5 mL/min
TMPLi
(1.5 equiv)
R1
E
workup
R1
CN
E+
4a–f
2–2.5 mL/min
CN
R1
+ ZnCl2 (0.5 equiv)
Zn
2b: R1 = CN
2c: R1 = OMe
1b: R1 = CN
1c: R1 = OMe
2
CN
Entry
1
Educt
Electrophile (E+)a
Product/Yieldb
CN
I
1b
1b
I2
CN
4a: 79%
CN
Br
2
3
CN
4b: 88%c,d
OMe
CN
I
1b
OMe
CN
4c: 70%d,e
OMe
I
4
5
1c
1c
I2
CN
4d: 82%
OMe
CO2Et
CO2Et
Br
CN
4e: 58%c,d
OMe
OMe
I
6
1c
OMe
CN
4f: 80%d,e
a Amount of E+ used was 1.1 equiv.
b Yield of the isolated, analytically pure product.
c Obtained in the presence of 10 mol% CuCN·2LiCl at 0 °C in 2 h.
d Amount of E+ used was 0.8 equiv.
e Obtained using 2 mol% of Pd(OAc)2 and 4 mol% of SPhos at r.t., overnight.
were trapped with various classes of electrophiles in high
yields. Also a simple scale-up without further optimization
of the reaction conditions was possible. The reaction scope
of the in situ trapping metalations in flow is broader and
needs less equivalents of the base and the metal salt than
that of the batch procedures. Further extensions of these in
situ trapping metalations are currently underway in our
laboratories.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
M. Ketels et al.
Letter
Synlett
Acknowledgment
R.; Ketels, M.; Knochel, P. Org. Lett. 2016, 18, 828. (d) Petersen, T.
P.; Becker, M. R.; Knochel, P. Angew. Chem. Int. Ed. 2014, 53,
7933.
We thank the BASF SE (Ludwigshafen) and Albermarle (Germany) for
the generous gift of chemicals and the DIP (German-Israeli Project
Cooperation) for financial support. M.K. thanks the Foundation of
German Business for a scholarship.
(8) Flow reactions were performed with commercially available
equipment from Uniqsis Ltd (FlowSyn; http://www.uniqsis.com).
(9) Using the same stoichiometry in a batch reaction leads to a
lower conversion and poorer yields are obtained.
(10) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
Supporting Information
(11) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(12) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(13) General Procedure for the In situ Trapping Metalation of 1,2-
Dicyanobenzene in Flow followed by the Reaction with an
Electrophile in Batch: The flow system (FlowSyn, Uniqsis) was
dried by flushing it with anhyd THF (flow rate of all pumps:
1.00 mL/min, run-time: 30 min). Injection loop A (1.0 mL) was
loaded with TMPLi (0.60–0.66 M in anhyd THF; 1.5 equiv) and
injection loop B (1.0 mL) was loaded with the reactant solution
(0.40–0.43 M in anhyd THF containing 0.5 equiv ZnCl2 additive).
The solutions were simultaneously injected into separate THF
streams (pump A and B, flow rates: 1.50 mL/min), which passed
a pre-cooling loop (1 mL, residence time: 40 s, 0 °C) respec-
tively, before they were mixed in a coiled reactor (1 mL; resi-
dence time: 20 s, 0 °C). The combined streams were collected in
a flame-dried, argon flushed 25-mL flask equipped with a mag-
netic stirrer and a septum containing the electrophile (1.1
equiv) dissolved in anhyd THF (1 mL). Then, the reaction
mixture was further stirred for the indicated time at the indi-
cated temperature.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588837.
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References and Notes
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(b) Fuentes, M. A.; Kennedy, A. R.; Mulvey, R. E.; Parkinson, J. A.;
Rantanen, T.; Robertson, S. D.; Snieckus, V. Chem. Eur. J. 2015,
21, 14812. (c) Zhao, Y.; Snieckus, V. J. Am. Chem. Soc. 2014, 136,
11224. (d) Schneider, C.; David, E.; Toutov, A. A.; Snieckus, V.
Angew. Chem. Int. Ed. 2012, 11, 2722. (e) Chauder, B. A.; Kalinin,
A. V.; Snieckus, V. Synthesis 2001, 140. (f) Beaulieu, F.; Snieckus,
V. Synthesis 1991, 112. (g) Snieckus, V. Chem. Rev. 1990, 90, 879.
(h) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306.
(i) Snieckus, V. Heterocycles 1980, 14, 1649. (j) Watanabe, M.;
Snieckus, V. J. Am. Chem. Soc. 1980, 102, 1457.
(2) (a) Nicolaou, K. C.; Chen, J. S.; Edmonds, D. J.; Estrada, A. A.
Angew. Chem. Int. Ed. 2009, 48, 660. (b) Chinchilla, R.; Nájera, C.;
Yus, M. Tetrahedron 2005, 61, 3139. (c) Nicolaou, K. C.;
Sorensen, E. J. In Classics in Total Synthesis; Wiley-VCH: Wein-
heim, 1996. (d) Nafe, J.; Knochel, P. Synthesis 2016, 48, 103.
(e) Nicolaou, K. C.; Snyder, S. A. In Classics in Total Synthesis II;
Wiley-VCH: Weinheim, 2003. (f) Lima, F.; Kabeshov, M. A.; Tran,
D. N.; Battilocchio, C.; Sedelmeier, J.; Sedelmeier, G.; Schenkel,
B.; Ley, S. V. Angew. Chem. Int. Ed. 2016, 55, 14085. (g) Kim, J. Y.;
Lee, K.; Coates, N. E.; Moses, D.; Nguyen, T.-Q.; Dante, M.;
Heeger, A. J. Science 2007, 317, 222. (h) Kohei, M.; Schwaerzer,
K.; Karaghiosoff, K.; Knochel, P. Synthesis 2016, 48, 3141.
(i) Clarke, T.; Ballantyne, A.; Jamieson, F.; Brabec, C.; Nelson, J.;
Durrant, J. Chem. Commun. 2009, 89. (j) Bellan, B.; Kuzmina, O.
M.; Vetsova, V. A.; Knochel, P. Synthesis 2017, 49, 188.
4′-Methoxy-[1,1′-biphenyl]-2,3-dicarbonitrile (3h): Accord-
ing to the typical procedure, injection loops A and B were
loaded with solutions of 1,2-dicyanobenzene (1a; 0.44 M con-
taining 0.5 equiv ZnCl2, 1 mL) and TMPLi (0.66 M, 1 mL), respec-
tively. After injection and in situ trapping metalation the com-
bined streams were collected in a flask containing 4-iodoanisol
(113 mg, 0.49 mmol, 1.1 equiv), Pd(OAc)2 (2.0 mg, 2 mol%) and
SPhos (7.2 mg, 4 mol%) dissolved in THF (1 mL) at r.t. The reac-
tion mixture was stirred overnight before it was quenched with
sat. NH4Cl (15 mL). The aq. layer was extracted with EtOAc (3 ×
15 mL), the combined organic fractions were dried over anhyd
Mg2SO4, filtrated and the solvent was removed in vacuo. Purifi-
cation by flash column chromatography (silica gel; i-hexane–
EtOAc, 9:1) afforded 3h as a pale brown solid (89 mg, 0.38
mmol, 87%; mp 200.3–201.5 °C). IR (Diamond-ATR, neat): 2225,
1608, 1580, 1523, 1514, 1460, 1442, 1308, 1298, 1249, 1178,
1117, 1082, 1026, 991, 861, 840, 820, 802, 783, 769, 743, 725,
(3) (a) Tejerina, L.; Martínez-Díaz, M. V.; Nazeeruddin, M. K.;
Torres, T. Chem. Eur. J. 2016, 22, 4369. (b) Yamamoto, S.; Zhang,
A.; Stillmann, M. J.; Kobayashi, N.; Kimura, M. Chem. Eur. J. 2016,
22, 18760. (c) Xu, H.; Chan, W.-K.; Ng, D. K. P. Synthesis 2009,
1791. (d) Senge, M. O.; Sergeeva, N. N. In The Chemistry of
Organozinc Compounds; Rappoport, Z.; Marek, I., Eds.; John
Wiley & Sons., Ltd: Chichester, 2006, 395.
(4) Frischmuth, A.; Fernández, M.; Barl, N. M.; Achrainer, F.; Zipse,
H.; Berionni, G.; Mayr, H.; Karaghiosoff, K.; Knochel, P. Angew.
Chem. Int. Ed. 2014, 53, 7928.
683 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.72–7.76 (m, 3 H),
.
7.49–7.55 (m, 2 H), 7.02–7.06 (m, 2 H), 3.88 (s, 3 H). 13C NMR
(101 MHz, CDCl3): δ = 161.0, 147.2, 134.1, 133.0, 131.7, 130.2,
128.8, 117.5, 115.9, 115.7, 114.7, 114.2, 55.6. MS (EI, 70 eV): m/z
(%) = 235 (18), 234 (100), 219 (6), 191 (28), 165 (10), 164 (10),
138 (5), 43 (6). HRMS (EI): m/z [M] calcd for C15H10N2O:
234.0793; found: 234.0783.
(5) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed. 2006,
45, 497.
(6) (a) Uzelac, M.; Kennedy, A. R.; Hevia, E.; Mulvey, R. E. Angew.
Chem. Int. Ed. 2016, 55, 13147. (b) Kissel, C. L.; Rickborn, B.
J. Org. Chem. 1972, 37, 2060. (c) Rathke, M. W.; Kow, R. J. Am.
Chem. Soc. 1972, 49, 6854. (d) Olofson, R. A.; Dougherty, C. M.
J. Am. Chem. Soc. 1973, 95, 581. (e) Olofson, R. A.; Dougherty, C.
M. J. Am. Chem. Soc. 1973, 95, 582.
(7) (a) Ketels, M.; Konrad, D. B.; Karaghiosoff, K.; Trauner, D.;
Knochel, P. Org. Lett. 2017, 19, 1666. (b) Becker, M. R.; Knochel,
P. Angew. Chem. Int. Ed. 2015, 54, 1. (c) Ganiek, M. A.; Becker, M.
Ethyl 2-(2,3-Dicyanobenzyl)acrylate (3c): According to the
typical procedure, injection loops A and B were loaded with
solutions of 1,2-dicyanobenzene (1a; 0.42 M containing 0.5
equiv ZnCl2, 1 mL) and TMPLi (0.63 M, 1 mL), respectively. After
injection and in situ trapping metalation the combined streams
were collected in a flask containing ethyl 2-(bromomethyl)acry-
late (89 mg, 0.46 mmol, 1.1 equiv) and CuCN·2LiCl solution
(0.04 mL, 10 mol%) dissolved in THF (1 mL) at 0 °C. The reaction
mixture was stirred for further 2 h at 0 °C before it was
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
M. Ketels et al.
Letter
Synlett
quenched with sat. NH4Cl (15 mL). The aq. layer was extracted
with EtOAc (3 × 15 mL), the combined organic fractions were
dried over anhyd Mg2SO4, filtrated and the solvent was removed
in vacuo. Purification by flash column chromatography (silica
gel; i-hexane–EtOAc, 9:1) afforded 3c as a colorless liquid (77
mg; 0.32 mmol; 76%). IR (Diamond-ATR, neat): 3085, 2984,
2930, 2854, 2362, 2236, 1711, 1632, 1586, 1465, 1447, 1408,
1369, 1329, 1300, 1255, 1200, 1175, 1139, 1096, 1024, 959, 858,
MHz, CDCl3): δ = 165.8, 145.0, 137.0, 134.5, 132.9, 131.7, 128.8,
116.5, 116.1, 115.7, 114.7, 61.3, 37.0, 14.1. MS (EI, 70 eV): m/z
(%) = 212 (37), 195 (20), 194 (12), 168 (14), 167 (31), 166 (100),
165 (12), 141 (13), 140 (21). HRMS (EI): m/z [M] calcd for
C
14H12N2O2: 240.0899; found: 240.0883.
(14) (a) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem. Int. Ed.
2006, 45, 159. (b) i-PrMgCl·LiCl in THF is available from Alber-
male (Frankfurt/Höchst, Germany).
(15) (a) Leznoff, C. C.; Dre, D. M. Can. J. Chem. 1996, 74, 307.
(b) Drew, M.; Leznoff, C. C. Synlett 1994, 623.
809, 792, 753, 733, 715 cm–1
.
1H NMR (400 MHz, CDCl3): δ =
7.62–7.69 (m, 3 H), 6.57 (s, 1 H), 5.72 (s, 1 H), 4.13–4.18 (q, J = 8
Hz, 2 H) 3.9 (s, 2 H), 1.22–1.26 (t, J = 8 Hz, 3 H). 13C NMR (101
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F