Aryne cycloaddition with 3-oxidopyridinium species

Article abstract of DOI:10.1039/c2ob26519b

The [3 + 2] cycloaddition of arynes with 3-oxidopyridinium species is examined using the Kobayashi benzyne precursor. The reaction affords a bicyclo[3.2.1] skeleton under mild conditions. A [7 + 2] cycloaddition mode with a subsequent pyridine ring-opening event has also been observed.

Full text of DOI:10.1039/c2ob26519b

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Organic &
Biomolecular
Chemistry
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Volume 10 | Number 45 | 7 December 2012 | Pages 8929–9100
ISSN 1477-0520
PAPER
Feng Shi et al.
Aryne cycloaddition with 3-oxidopyridinium species

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PAPER
Aryne cycloaddition with 3-oxidopyridinium species†
Hailong Ren, Chunrui Wu, Xiuxiu Ding, Xiaoge Chen and Feng Shi*
Received 2nd August 2012, Accepted 28th August 2012
DOI: 10.1039/c2ob26519b
The [3 + 2] cycloaddition of arynes with 3-oxidopyridinium species is examined using the Kobayashi
benzyne precursor. The reaction affords a bicyclo[3.2.1] skeleton under mild conditions. A [7 + 2]
cycloaddition mode with a subsequent pyridine ring-opening event has also been observed.
Introduction
The 3-oxidopyridinium species (Fig. 1, 1) is well known as a
latent dipole1 with several possible modes of cycloaddition
arising from different resonance structures thereof. For instance,
olefin and alkyne cycloaddition typically takes place in a [3 + 2]
(sometimes called [5 + 2] in literature) mode with a 2,6-peri-
selectivity engaging resonance structure A or B.2 In contrast,
ketene cycloaddition typically engages resonance structure C or
D in a [7 + 2] mode with a 2,O- or O,4-periselectivity.3 Diene
cycloaddition, on the other hand, typically engages resonance
structure E or F with a 2,4-periselectivity in a [5 + 4] mode.4
The FMO analysis of these cycloadditions has been carried out
to account for these observations.5
Among these reactions, the olefin and alkyne cycloaddition
has found the greatest application in synthetic chemistry, as wit-
Fig. 1 3-Oxidopyridinium species: resonance structures and cyclo-
addition modes.
nessed by a number of elegant total syntheses employing this
cycloaddition as a strategic step.6 The closely related cyclo-
addition employing arynes as a 2e dipolarophile, however, has
not been much studied. In the 1970’s, Katritzky and co-workers
briefly visited this reaction7 using diazotized anthranilic acid as
the benzyne precursor, and found that N-phenyl-3-oxidopyridi-
nium afforded a bicyclo[3.2.1] scaffold 2 (eqn (1)) in low yield.
In sharp contrast, the N-methyl variant over-reacted with a
second equivalent of benzyne affording a bicyclo[4.3.1] scaffold
(eqn (2)). The incorporation of a second benzyne was presum-
ably triggered by the more electron-releasing nature of the
methyl group as well as the forcing conditions employed in the
diazotized anthranilic acid decomposition. About two decades
later, Carroll and co-workers used this aryne cycloaddition strat-
egy to synthesize MK801,8 a channel-blocking antagonist of the
NMDA receptor complex, using the Kobayashi benzyne
precursor9 and a 4-oxidoisoquinolinium species (eqn (3)).
Clearly, the Kobayashi precursor allowed for milder reaction
conditions and a better yield. Yet unfortunately, both studies
above targeted a very limited number of substrates and to date,
no follow-up studies have been performed to systematically
examine the reaction or to expand the scope.10
ð1Þ
Key Laboratory of Natural Medicine and Immuno-Engineering of
Henan Province, Henan University, Jinming Campus, Kaifeng, Henan
475004, PR China. E-mail: fshi@henu.edu.cn;
Fax: +86-378-286-4665; Tel: +86-378-286-4665
ð2Þ
†Electronic supplementary information (ESI) available: Procedures and
characterization data for the substrates, and full NMR spectra for the pro-
ducts. See DOI: 10.1039/c2ob26519b
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Table 1 Reaction optimizationa
prolonged stirring. Even at 16–18 °C, clogging of CsF was com-
monly observed if the CsF used was not a fine powder. Under
these conditions, 1a was still incompletely converted, but char-
ging additional 3a or CsF did not improve the yield.
Scope of 3-oxidopyridinium species
With the optimal reaction conditions in hand, we moved forward
to screen additional substrates (Table 2). Substitution at the pyri-
dine ring was tolerated at 2, 5, or 6-positions (entries 1–3). Sub-
stitution at the nitrogen was also broadly tolerated. Other than
the benzyl group, primary (entries 4 and 5), secondary (entry 6),
and tertiary (entry 7) alkyl groups were all tolerated. It is note-
worthy that over-phenylation of 1e with benzyne, as described in
eqn (2), was diminished under our conditions. Aryl groups
(entries 8–10) and heteroaryl groups (entries 11 and 12) were
also compatible, and electronic or steric factors posed no big
influence on yield. Additionally, functionalized substitutions
were also tested. While the N-MOM pyridinium species 1n
(entry 13) and the N-ethoxycarbonylmethyl variant (not shown)
both afforded complex mixtures, the alcohol-containing 1o,
despite its poor solubility in MeCN, was successfully employed
(entry 14) where the benzylic hydroxyl group remained intact.12
Entry
3a/equiv
F−/equiv
Conditions
Yieldb/%
1
2
3
4
5
6
7
8
1.1
1.1
1.1
1.3
1.3
1.3
1.3
1.3
CsF/1.5
CsF/1.5
CsF/1.5
TBAF/1.5
CsF/1.5
CsF/2.6
CsF/2.6
CsF/1.5
MeCN, 80 °C, 12 h
THF, 70 °C, 12 h
Dioxane, 100 °C, 12 h
THF, 25 °C, 12 h
MeCN, 25 °C, 48 h
MeCN, 25 °C, 12 h
MeCN, ∼17 °C, 18 h
MeCN, ∼17 °C, 18 h
33
Trace
0
38
59
62
78
65
a Reactions were carried out on an approximately 0.2 mmol scale in
5 mL of solvent. Compound 1a was obtained as a monohydrate.
b Isolated yields.
ð3Þ
Scope of arynes and the observation of the [7 + 2] cycloaddition
mode
With our continuing interest in aryne cycloaddition chemi-
stry,11 we wished to revisit this cycloaddition reaction using the
Kobayashi aryne precursor in the hope to cover more substrates,
expand the reaction scope, examine detailed substitution
compatibility, and seek other possible periselectivities in the
cycloaddition. At a minimum, we wished to develop reaction
conditions to afford 2 universally regardless of the N-substi-
tution. Herein we report our results.
Our next effort was directed to examine different aryne precur-
sors (Table 3). First, the symmetrical 4,5-dimethoxybenzyne
derived from 3b afforded 2p smoothly in good yield (entry 1),
despite being slow. The unsymmetrical 4-methoxybenzyne
derived from 3c afforded two regioisomeric products 2q and 2q′
in approximately equal amounts (entry 2). However, when the
benzyne is equipped with a 3-methoxy group, the reaction
started to deviate from the expected [3 + 2] pathway. Thus, when
the 3-methoxybenzyne derived from 3d was employed, in
addition to the desired two regioisomeric products 2r and 2r′,13
a third product with a benzofuran core (4a) was observed in sig-
nificant quantity (entry 3). A similar outcome was observed for
the 3,5-dimethoxybenzyne derived from 3e (entry 4). This trend
was followed for other 3-oxidopyridinium species, as 4a was
always observed regardless of the N-substitution (entries 5 and
6), and it seemed difficult to correlate the yield of 4a with the
nature of the N-substitution as well.
These apparently unexpected results raised several questions.
First, for benzynes derived from 3d and 3e, almost all nucleophi-
lic addition and dipolar cycloaddition reactions have been
demonstrated to be regioselective where the nucleophile or the
nucleophilic end of the dipole attacks distal to the methoxyl
group.14 So why then was such a regioselectivity not realized in
our reaction (assuming that resonance structure A is more domi-
nant than B, cf. Fig. 1)? Secondly, how was 4 formed, and what
role did the 3-methoxy group play in this transformation?
Results and discussion
Reaction optimization
Our journey began with N-benzyl-3-oxidopyridinium 1a and the
parent benzyne precursor 3a (Table 1). Running the reaction in
refluxing MeCN using CsF as the fluoride source with 1.1 equiv
of 3a gave the desired product 2a in 33% yield (entry 1). Repla-
cing MeCN with THF or dioxane resulted in complete failure
(entries 2 and 3). Since 1a was poorly converted in all cases, we
increased 3a to 1.3 equiv. for the following studies. With this
change, running the reaction in THF with TBAF as the fluoride
source afforded 38% yield (entry 4). A higher yield of 59%
could be obtained using CsF in MeCN at room temperature, but
the reaction proceeded much more slowly. Increasing CsF to 2.6
equiv could shorten the reaction time but the yield remained
moderate (entry 6). Somewhat unexpectedly, by simply lowering
the temperature by another 7–8 °C (from ∼25 °C to about
16–18 °C), the yield increased to 78% (entry 7). This is the first
time in aryne chemistry that we have observed such a significant
temperature dependency. Nonetheless, it is NOT suggested to
further lower the temperature, as the solubility of CsF is
decreased and the reaction affords low conversion after
Although we are not prepared to answer the first question in
this report, we need to mention that similar observations are
known. Thus ethyl vinyl ether reacted with 1 to afford the same
regioisomer as methacrylaldehyde.4a FMO analysis supported15
that shifting from electron-poor olefins to electron-rich olefins,
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Table 2 Scope of 3-oxidopyridinium speciesa
Entry 1 (R1, R2)
Time/h Product
20
Yieldb/% Entry R1, R2
Time/h
18
Product
Yieldb/%
48
1
1b
55
8
1ic
R1 = Bn
R2 = 2-Me
R1 = 4-MeC6H4
R2 = H
2
1c
18
76
9
1jc
16
<63e
R1 = Bn
R2 = 5-Cl
R1 = 4-ClC6H4
R2 = H
3
4
5
1dc
18
14
37
67
39
46
10
11
12
1kc
5
49
62
58
R1 = Bn
R2 = 6-Me
R1 = 2-(MeO)C6H4
R2 = H
1ec
1ld
20
18
R1 = Me
R2 = H
R1 = 2-pyridyl
R2 = H
1f
1mc
R1 = c-PrCH2
R2 = H
R1 = 3-pyridyl
R2 = H
6
7
1gc
12
20
66
57
13
14
1nc
20
Complex mixture
R1 = Cy
R2 = H
R1 = MOM
R2 = H
1hc
1oc
20
54
R1 = t-Bu
R2 = H
R1 = Bn
R2 = 6-CH2OH
a All reactions were carried out in an approximately 0.2 mmol scale. Reaction time was individually optimized and prolonged reaction led to lowered
yields. b Isolated yield. c Prepared as a monohydrate. d Prepared as an HBr salt. One additional equiv of CsF was used to neutralize the HBr. e We are
unable to completely purify this compound. The 13C NMR is clean, but 1H NMR shows ∼95 mol% purity, with an extra signal at 9.72 ppm (0.05 H).
The impurity may correspond to product type 4 (vide infra) but was not isolable.
the major contribution to the reaction accordingly shifted from
LUMO(1) interaction. Although we do not know whether a
the HOMO(1)–LUMO(olefin) interaction to the HOMO(olefin)–
similar explanation is valid in our case for 3-methoxybenzyne,
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Table 3 Scope of arynesa
Entry
1
1
3
Time/h
68
Desired product
Yieldb/%
66
Unexpected product
Yieldb/%
1a
—
—
2
3
1a
1a
18
20
51 (1.3 : 1)c
—
—
19 + 19
23
4
5
6
1a
1g
1h
20
20
20
18 + 20
20 + 15
20 + 22
11
27
12
3d
3d
4a
4a
a All reactions were carried out in an approximately 0.2 mmol scale. Reaction time was individually optimized and prolonged reaction led to lowered
yields. All substrates were prepared as monohydrates. b Isolated yield. c Since the two products were inseparable and NMR signals are seriously
overlapping, no attempts were made to identify the major isomer.
we consider that a detailed and professional FMO analysis might
bring the eventual clue to the question.
periselectivity can be explained by a large coefficient of O in the
HOMO of 1.5 It is noteworthy that Katritzky and co-workers
have observed similar events. For example, cycloaddition of 1
with phenylacetylene gave rise to exclusive [3 + 2] adducts,
while when moving to the more electron-negative dimethyl
acetylenedicarboxylate (DMAD), the formation of the [7 + 2]
adducts increased significantly in certain 3-oxidopyridinium
species.16 Additionally, the more electrophilic ketene undergoes
the [7 + 2] cycloaddition in contrast to the [3 + 2] cycloaddition
for typical alkenes.3 Thus shifting from the traditional [3 + 2]
The second question can be explained in Scheme 1. Taking
the reaction between 1a and 3d as an example, the two desired
products can be obtained from the expected [3 + 2] cyclo-
addition pathways involving resonance structures A and B,
respectively (the arrow-pushing for 2r′ might appear arbitrary
before a detailed FMO analysis is done). Formation of 4a,
however, must come from a [7 + 2] cycloaddition mode in a 2,
O-periselectivity involving resonance structure C. This shift in
8978 | Org. Biomol. Chem., 2012, 10, 8975–8984
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Table 4 Reaction of 3-amidopyridinium speciesa
Entry 5 (R, X)
3
Time/h Product
Yieldb/%
22
1
5a
3a 18
R = Bn
X = Ts
2
3
5b
3a 20
3a 16
4c
19
18
R = c-PrCH2
X = Ts
5c
R = Bn
X = Boc
4
5a
3d 22
19
30
5c
3a
5
4c
Scheme 1 Mechanistic paths for reactions involving 3-meth-
oxybenzyne.
a Reactions were carried out on an approximately 0.2 mmol scale in
5 mL of solvent. Except for the last entry, 5 were obtained as HBr salts.
b Isolated yields. c Reaction performed with 2.5 equiv of 3a and 3.5
equiv of CsF.
mode to the [7 + 2] mode seems to be caused by electronic per-
turbation of the FMO’s, particularly those of the dipolarophile.
Thus, the role that the 3-methoxy group plays should possibly
lie in its electron-withdrawing nature (on the σ-skeleton), which
may polarize the “third” bond of the aryne, leading to a redistri-
bution of the coefficients of the HOMO and LUMO. Accord-
ingly, benzynes generated from 3b and 3c do not have enough
electronic perturbation, as the methoxy groups are not proximal
enough to cause the polarization. However, we do not have a
reasonable explanation as to why the parent benzyne does not
undergo the [7 + 2] cycloaddition, given the large coefficient of
O in the HOMO.
Nonetheless, as shown in Scheme 1, this [7 + 2] cycloaddition
breaks the aromaticity of the pyridine ring, and triggers a ring-
opening event through the retro 6π-electrocyclization process,17
affording a benzofuran core with an α,β-unsaturated imine side
chain. Under the reaction conditions, hydrolysis and E–Z isomer-
ization took place to afford 4a as the final product.
This hypothesis proved only partially correct. While we have
found that reaction of 5 with 3a indeed led to the formation of
indole 4 as the only isolable product, we were unable to optimize
the yields to a synthetically useful level (Table 4). Thus, the
3-tosylimidopyridinium species 5a and 5b afforded only 20%
yields of the indole 4c (entries 1 and 2). The Boc variant 5c also
afforded a same yield (entry 3). Now the reaction became no
longer sensitive to the nature of benzyne, as use of either 3a or
3d afforded the same outcome and similar yields (entry 4).
Considering that the substitution on the pyridine nitrogen was
completely irrelevant to the final products, we next attempted to
use 3-tosylamidopyridine directly in the reaction. Here an excess
of benzyne was charged and an N-phenyl-3-tosylimidopyridi-
nium species was expected to be generated in situ. However,
even under these conditions, the yield remained modest (entry
5). Given these results, examining the substitution on the pyri-
dine did not seem to make much sense and thus was not
attempted.
Reaction of 3-amidopyridinium species
These results above triggered our attention to examining the
closely related 3-amidopyridinium species (5, Table 4). For
reasons we do not understand well, nitrogen nucleophiles are
more “arynophilic” than the corresponding oxygen nucleo-
philes.12 Thus, by replacing the oxyanion with the isoelectronic
nitrogen anion, we hoped to increase the [7 + 2] cycloaddition
product 4.
Manipulations of the product
As stated before, the bicyclo[3.2.1] scaffold has been actively
manipulated, mainly through reductions, in the early literature,
particularly during the total syntheses of natural and unnatural
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products.6,8,18 Thus, we sought other possibilities in the manipu-
lation of the [3 + 2] adducts.
Representative procedures for reactions of 3-oxidopyridinium
species with arynes (Tables 2 and 3, outlined for compound 2a)
The Michael acceptor moiety of 2 could be utilized in a
Baylis–Hillman reaction. Reaction of 2a with formaldehyde
afforded 60% yield of the adduct 6 (eqn (4)).19 This transform-
ation not only increases the functionality of 2, but also comp-
lements its scope, since 4-substituted 3-oxidopyridinium species
are difficult to access. The electron-deficient olefin moiety could
be exploited in a further dipolar cycloaddition event. Thus reac-
tion of 2a with ethyl diazoacetate fused another 5-membered
ring to the bicyclo[3.2.1] scaffold (eqn (5)). Disappointingly, all
attempts to oxidatively cleave the olefin were unsuccessful in our
hands.
To a 10 mL round-bottom flask equipped with a stir bar was
added 1a (as monohydrate, 37 mg, 0.182 mmol) followed by 3a
(71 mg, ∼0.24 mmol, 1.3 equiv). MeCN (5 mL) was added and
the mixture was briefly stirred before addition of CsF (72 mg,
0.47 mmol, 2.6 equiv). The mixture was stirred in a 17 °C bath
for 18 h before being diluted with EtOAc and water. Layers were
separated and the aqueous layer was extracted with EtOAc twice.
The combined organic phases were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (petroleum ether–EtOAc) to
1
afford 37 mg of 2a as a light-yellow oil. H NMR (300 MHz,
CDCl3) δ 7.48–7.44 (m, 1 H), 7.35–7.26 (m, 7 H), 7.22–7.19
(m, 2 H), 5.55 (dd, J = 9.7, 1.4 Hz, 1 H), 4.44–4.39 (m, 2 H),
3.75 (s, 2 H); 13C NMR (75 MHz, CDCl3) δ 194.6, 151.0,
145.8, 138.5, 137.3, 129.0, 128.5, 127.6, 127.5, 127.2, 125.9,
ð4Þ
ð5Þ
123.1, 123.0, 76.7, 64.6, 56.0; IR (KBr) 1685, 1454 cm−1
;
HRMS (ESI) calcd for C18H16NO (M + H) 262.1226, found
262.1225.
Characterization data for other products 2 and 4 (Tables 2
and 3)
Product 2b. The general procedure was applied to 39.8 mg of
1b, 75 mg of 3a, and 77 mg of CsF to afford 30.3 mg of 2b as a
yellow solid, mp 97–98 °C; 1H NMR (400 MHz, CDCl3) δ
7.40–7.27 (m, 6 H), 7.24–7.14 (m, 3 H), 7.03 (dd, J = 9.7,
4.9 Hz, 1 H), 5.64 (d, J = 9.6 Hz, 1 H), 4.34 (d, J = 4.9 Hz,
1 H), 3.91 (s, 2 H), 1.67 (s, 3 H); 13C NMR (100 MHz, CDCl3)
δ 196.8, 147.9, 146.0, 143.2, 138.1, 128.9, 128.5, 127.4, 127.3,
126.9, 123.9, 123.6, 121.6, 76.5, 61.5, 49.9, 14.8; IR (KBr)
1680, 1454 cm−1; HRMS (ESI) calcd for C19H18NO (M + H)
276.1383, found 276.1384.
Conclusions
In summary, the Kobayashi aryne precursor proves suitable in
the [3 + 2] cycloaddition with 3-oxidopyridinium species. Under
mild conditions, the reaction can afford the bicyclo[3.2.1] scaf-
fold in moderate to good yields irrespective of the N-substi-
tution. Interestingly, benzynes with a 3-methoxy group can
trigger a [7 + 2] cycloaddition mode unprecedented for benzyne
reaction, leading to a benzofuran derivative. The analogous
3-amidopyridinium species underwent the [7 + 2] cycloaddition
as the only productive path leading to the formation of indoles in
low yields. The analogous aryne cycloaddition with 3-oxido-
pyrylium species is under active investigation in our group.
Product 2c. The general procedure was applied to 44 mg of
1c, 75 mg of 3a, and 77 mg of CsF to afford 45 mg of 2c as a
1
yellow solid, mp 114–116 °C; H NMR (300 MHz, CDCl3) δ
7.46–7.31 (m, 7 H), 7.26–7.21 (m, 2 H), 5.72 (t, J = 1.2 Hz,
1 H), 4.47 (d, J = 0.6 Hz, 1 H), 4.43 (d, J = 0.7 Hz, 1 H), 3.93
(s, 2 H); 13C NMR (75 MHz, CDCl3) δ 192.4, 157.0, 144.2,
138.8, 136.6, 129.1, 128.6, 127.84, 127.75 (overlap), 125.0,
Experimental section
122.3, 120.8, 74.2, 70.6, 54.3; IR (KBr) 1686, 1589 cm−1
;
General information
HRMS (ESI) calcd for C18H15NO35Cl (M + H) 296.0837, found
296.0834.
All materials supplied from commercial sources were used as
received unless otherwise noted. MeCN and THF were distilled
over CaH2 and Na–benzophenone, respectively. Silica gel for
column chromatography was supplied as 300–400 mesh from
Haiyang Chemicals (Qingdao, China, which gives a different
retardation compared with silica gel typically used in the western
countries). CsF was stored in a desiccator and only the powders
Product 2d. The general procedure was applied to 43.4 mg of
1d (as monohydrate), 75 mg of 3a, and 77 mg of CsF to afford
1
37 mg of 2d as a light yellow oil; H NMR (400 MHz, CDCl3)
δ 7.37–7.27 (m, 6 H), 7.25–7.20 (m, 2 H), 7.15 (ddd, J = 7.1,
6.5, 2.3 Hz, 1 H), 6.90 (d, J = 9.8 Hz, 1 H), 5.54 (dd, J = 9.8,
1.6 Hz, 1 H), 4.25 (d, J = 1.5 Hz, 1 H), 3.89 and 3.93 (ABq, J =
13.1 Hz, 2 H), 1.74 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
195.8, 152.0, 149.8, 138.9, 137.7, 129.1, 128.4, 127.5, 127.3,
126.9, 124.7, 122.3, 120.6, 73.4, 67.1, 50.5, 18.6; IR (KBr)
1691, 1454 cm−1; HRMS (ESI) calcd for C19H18NO (M + H)
276.1383, found 276.1377.
were used. All melting points are uncorrected. The H and 13C
1
NMR spectra were referenced to the residual solvent signals
(7.26 ppm for H and 77.0 ppm for 13C in CDCl3, 4.79 ppm for
1
1H and uncorrected for 13C in D2O, 2.50 ppm for 1H and
39.52 ppm for 13C in DMSO-d6).
Preparation of the substrates is listed in the ESI.†
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32.5 mg of 2j as a yellow solid, mp 115–116 °C; 1H NMR
(400 MHz, CDCl3) δ 7.55–7.51 (m, 1 H), 7.38–7.35 (m, 1 H),
7.28–7.25 (m, 2 H), 7.25–7.23 (m, 2 H), 7.22–7.21 (m, 1 H),
6.83–6.78 (m, 2 H), 5.45–5.40 (m, 2 H), 5.24 (d, J = 1.3 Hz,
1 H); 13C NMR (100 MHz, CDCl3) δ 192.8, 149.6, 145.1, 144.7,
138.0, 129.5, 127.9, 127.4, 125.3, 124.7, 124.1, 121.5, 117.6,
73.3, 62.1; IR (KBr) 1687, 1495, 1336 cm−1; HRMS (ESI)
calcd for C17H1335ClNO (M + H) 282.0680, found 282.0685.
Product 2e. The general procedure was applied to 32.7 mg of
1e (0.257 mmol) (as monohydrate), 102 mg of 3a (1.33 equiv),
and 104 mg of CsF (2.65 equiv) to afford 18.5 mg of 2e as a
1
light green solid, mp 50–51 °C; H NMR (400 MHz, CDCl3) δ
7.47–7.44 (m, 1 H), 7.36–7.30 (m, 2 H), 7.20–7.16 (m, 2 H),
5.51 (dd, J = 9.7, 1.1 Hz, 1 H), 4.37 (d, J = 5.6 Hz, 1 H), 4.31
(s, 1 H), 2.45 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 194.5,
151.4, 145.4, 138.0, 127.7, 127.2, 126.1, 123.1, 122.6, 78.8,
67.3, 39.9; IR (KBr) 1690, 1456 cm−1; HRMS (ESI) calcd for
C12H12NO (M + H) 186.0913, found 186.0911.
Product 2k. The general procedure was applied to 40.2 mg of
1k (as monohydrate), 71 mg of 3a, and 72 mg of CsF to afford
25 mg of 2k as a green solid, mp 181–184 °C; 1H NMR
(400 MHz, CDCl3) δ 7.54–7.49 (m, 1 H), 7.37–7.33 (m, 1 H),
7.25 (dd, J = 9.8, 5.1 Hz, 1 H), 7.22–7.16 (m, 2 H), 6.99 (ddd, J
= 8.1, 7.4, 1.5 Hz, 1 H), 6.92–6.83 (m, 2 H), 6.75 (dd, J = 7.8,
1.5 Hz, 1 H), 5.62 (d, J = 5.1 Hz, 1 H), 5.51 (dd, J = 9.7,
1.5 Hz, 1 H), 5.24 (s, 1 H), 3.91 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 194.9, 151.5, 149.9, 146.1, 138.5, 135.2, 127.6, 127.0,
124.7, 123.2, 122.9, 121.7, 121.0, 119.1, 111.5, 74.2, 62.6, 55.5;
IR (KBr) 1693, 1502, 1244 cm−1; HRMS (ESI) calcd for
C18H16NO2 (M + H) 278.1176, found 278.1180.
Product 2f. The general procedure was applied to 33.4 mg of
1f, 83 mg of 3a, and 85 mg of CsF to afford 23.1 mg of 2f as a
1
brown oil; H NMR (400 MHz, CDCl3) δ 7.46–7.42 (m, 1 H),
7.31–7.27 (m, 2 H), 7.20–7.14 (m, 2 H), 5.52 (dd, J = 9.7,
1.4 Hz, 1 H), 4.68 (d, J = 5.5 Hz, 1 H), 4.58 (s, 1 H), 2.57 and
2.45 (d of ABq, JAB = 12.3 Hz, 3J = 6.5 Hz, 2 H), 1.01–0.89 (m,
1 H), 0.56–0.50 (m, 2 H), 0.09–0.00 (m, 2 H); 13C NMR
(100 MHz, CDCl3) δ 194.9, 150.5, 145.8, 138.5, 127.5, 127.1,
125.7, 123.0, 122.7, 76.5, 64.6, 56.2, 9.3, 3.6, 3.4; IR (KBr)
1685, 1456 cm−1; HRMS (ESI) calcd for C15H16NO (M + H)
226.1226, found 226.1221.
Product 2l. The general procedure was applied to 50.4 mg of
1l (as HBr salt), 75 mg of 3a, and 106 mg of CsF to afford
30.6 mg of 2l as a yellow solid, mp 151–152 °C; 1H NMR
(400 MHz, CDCl3) δ 8.26–8.24 (m, 1 H), 7.56–7.51 (m, 2 H),
7.39–7.35 (m, 2 H), 7.26–7.19 (m, 2 H), 6.78–6.73 (m, 2 H),
5.82 (d, J = 4.6 Hz, 1 H), 5.48 (d, J = 1.4 Hz, 1 H), 5.36 (dd, J
= 9.7, 1.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 192.9,
157.2, 151.6, 148.5, 145.0, 138.2, 137.7, 127.8, 127.2, 124.5,
123.4, 121.5, 115.5, 109.9, 72.2, 60.8; IR (KBr) 1699, 1473,
1434 cm−1; HRMS (ESI) calcd for C16H13N2O (M + H)
249.1022, found 249.1018.
Product 2g. The general procedure was applied to 39 mg of
1g (as monohydrate), 75 mg of 3a, and 77 mg of CsF to afford
33.5 mg of 2g as a yellow solid, mp 106–107 °C; 1H NMR
(300 MHz, CDCl3) δ 7.44–7.40 (m, 1 H), 7.30–7.27 (m, 1 H),
7.22–7.14 (m, 2 H), 7.11 (dd, J = 9.8, 5.0 Hz, 1 H), 5.56 (dd, J
= 9.7, 1.5 Hz, 1 H), 4.76 (d, J = 5.0 Hz, 1 H), 4.66 (d, J =
1.3 Hz, 1 H), 2.76–2.65 (m, 1 H), 2.07–1.93 (m, 1 H),
1.91–1.70 (m, 3 H), 1.67–1.51 (m, 1 H), 1.35–1.08 (m, 5 H);
13C NMR (75 MHz, CDCl3) δ 195.4, 147.5, 146.5, 139.3,
127.4, 126.8, 124.8, 123.7, 121.7, 72.9, 60.6, 55.0, 31.3, 30.8,
25.7, 24.6, 24.5; IR (KBr) 1684, 1122, 756 cm−1; HRMS (ESI)
calcd for C17H20NO (M + H) 254.1539, found 254.1534.
Product 2m. The general procedure was applied to 38 mg of
1m (as monohydrate), 75 mg of 3a, and 77 mg of CsF to afford
Product 2h. The general procedure was applied to 30.9 mg of
1h (as monohydrate), 71 mg of 3a, and 72 mg of CsF to afford
23.8 mg of 2h as an orange solid, mp 87–89 °C; 1H NMR
(400 MHz, CDCl3) δ 7.48 (dd, J = 9.5, 5.9 Hz, 1 H), 7.41–7.37
(m, 1 H), 7.23–7.20 (m, 1 H), 7.14–7.11 (m, 2 H), 5.40 (dd, J =
9.5, 1.2 Hz, 1 H), 4.82 (d, J = 6.0 Hz, 1 H), 4.77 (s, 1 H), 0.97
(s, 9 H); 13C NMR (100 MHz, CDCl3) δ 195.2, 154.3, 147.7,
140.3, 127.4, 126.9, 124.3, 122.1, 121.1, 73.3, 61.7, 54.5, 28.1;
IR (KBr) 1687, 1456, 1365, 1222, 754 cm−1; HRMS (ESI)
calcd for C15H18NO (M + H) 228.1383, found 228.1383.
1
28.8 mg of 2m as a yellow solid, mp 125–127 °C; H NMR
(300 MHz, CDCl3) δ 8.30 (dd, J = 2.7, 0.8 Hz, 1 H), 8.15 (dd, J
= 4.2, 1.7 Hz, 1 H), 7.57–7.53 (m, 1 H), 7.40–7.36 (m, 1 H),
7.31 (dd, J = 9.8, 4.5 Hz, 1 H), 7.28–7.22 (m, 2 H), 7.21–7.14
(m, 2 H), 5.49 (d, J = 4.5 Hz, 1 H), 5.43 (dd, J = 9.8, 1.6 Hz,
1 H), 5.30 (d, J = 1.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
δ 192.4, 149.5, 144.8, 142.2, 141.5, 138.6, 137.6, 128.0, 127.4,
124.7, 124.1, 123.8, 123.2, 121.5, 73.0, 61.4; IR (KBr) 1689,
1483, 1334 cm−1; HRMS (ESI) calcd for C16H13N2O (M + H)
249.1022, found 249.1020.
Product 2i. The general procedure was applied to 37 mg of 1i
(as monohydrate), 71 mg of 3a, and 72 mg of CsF to afford
23 mg of 2i as a yellow solid, mp 164–167 °C; 1H NMR
(400 MHz, CDCl3) δ 7.56–7.52 (m, 1 H), 7.38–7.34 (m, 1 H),
7.26–7.21 (m, 3 H), 7.09 (d, J = 8.1 Hz, 2 H), 6.83–6.77 (m,
2 H), 5.46–5.41 (m, 2 H), 5.25 (d, J = 1.4 Hz, 1 H), 2.27
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 193.4, 149.7, 145.5,
143.8, 138.5, 130.1, 129.7, 127.8, 127.2, 124.7, 124.1, 121.5,
Product 2o. The general procedure was applied to 43 mg of
1o (as monohydrate), 71 mg of 3a, and 72 mg of CsF to afford
29.2 mg of 2o as an orange solid, mp 93–95 °C; 1H NMR
(400 MHz, CDCl3) δ 7.37–7.21 (m, 8 H), 7.17 (td, J = 7.4,
1.2 Hz, 1 H), 6.80 (d, J = 9.9 Hz, 1 H), 5.65 (dd, J = 9.9,
1.6 Hz, 1 H), 4.36 (d, J = 1.1 Hz, 1 H), 4.28 (left side of a d of
ABq, JAB = 11.8 Hz, JAX = 6.0 Hz, 1 H), 4.09 (right of a d of
ABq, JAB = 11.8 Hz, JBX = 0 Hz, 1 H), 4.09 and 3.83 (ABq, J =
13.3 Hz, 2 H), 2.26 (d, J = 4.7 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 195.7, 146.6, 145.7, 138.8, 137.0, 129.0, 128.7, 127.7,
127.6, 127.3, 124.6, 123.6, 120.9, 73.4, 70.6, 58.9, 50.0; IR
(KBr) 3632–3024 (br), 1684 cm−1; HRMS (ESI) calcd for
C19H18NO2 (M + H) 292.1332, found 292.1335.
116.6, 73.4, 62.2, 20.4; IR (KBr) 1688, 1676, 1512, 1460 cm−1
;
HRMS (ESI) calcd for C18H16NO (M + H) 262.1226, found
262.1227.
Product 2j. The general procedure was applied to 41 mg of 1j
(as monohydrate), 71 mg of 3a, and 72 mg of CsF to afford
This journal is © The Royal Society of Chemistry 2012
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104.5, 103.5, 55.6; IR (KBr) 1688 cm−1; HRMS (ESI) calcd for
C12H11O3 (M + H) 203.0703, found 203.0701.
Product 2p. The general procedure was applied to 40.6 mg of
1a (as monohydrate), 90 mg of 3b, and 77 mg of CsF to afford
42.5 mg of 2p as a brown solid, mp 102–104 °C; 1H NMR
(400 MHz, CDCl3) δ 7.34–7.27 (m, 6 H), 7.03 (s, 1 H), 6.90 (s,
1 H), 5.52 (dd, J = 9.7, 1.3 Hz, 1 H), 4.35–4.31 (m, 2 H), 3.88
(s, 3 H), 3.86 (s, 3 H), 3.74 (s, 2 H); 13C NMR (100 MHz,
CDCl3) δ 194.8, 151.5, 148.2, 148.0, 138.5, 137.3, 130.0, 128.9,
128.4, 127.4, 122.8, 109.7, 107.2, 76.7, 64.8, 56.2, 56.1
(overlap); IR (KBr) 1685, 1493, 1298 cm−1; HRMS (ESI) calcd
for C20H20NO3 (M + H) 322.1438, found 322.1431.
Product 2s and 2s′. The general procedure was applied to
40.6 mg of 1a (as monohydrate), 89.5 mg of 3e, and 77 mg of
CsF to afford 11.3 mg of 2s as a brown oil and 12.8 mg of 2s′ as
a yellow oil.
Data for 2s. 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 9.7,
5.5 Hz, 1 H), 7.34–7.27 (m, 5 H), 6.65 (d, J = 1.8 Hz, 1 H), 6.32
(d, J = 1.9 Hz, 1 H), 5.53 (dd, J = 9.6, 1.4 Hz, 1 H), 4.54 (d, J =
5.5 Hz, 1 H), 4.34 (s, 1 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.75 and
Product 2q and 2q′. The general procedure was applied to
40.6 mg of 1a (as monohydrate), 82 mg of 3c, and 77 mg of
CsF to afford 29.4 mg of 2q and 2q′ as an inseparable mixture
3.69 (ABq, J = 13.0 Hz, 2 H), an impurity shows up at 3.74; 13
C
NMR (100 MHz, CDCl3) δ 195.0, 161.1, 155.9, 152.0, 141.6,
137.4, 129.0, 128.5, 127.4, 125.3, 122.8, 103.3, 97.9, 77.4,
1
as a brown oil. H NMR (400 MHz, CDCl3) δ 7.37–7.23 (m,
62.0, 56.4, 55.7, 55.4; IR (KBr) 1689, 1603, 1435, 1206 cm−1
;
6 H from isomer A + 7 H from isomer B), 7.19 (d, J = 8.0 Hz, 1
H from isomer A), 7.04 (d, J = 2.2 Hz, 1 H from isomer A),
6.89 (d, J = 2.2 Hz, 1 H from isomer B), 6.72–6.67 (m, 1 H
from isomer A + 1 H from isomer B), 5.58–5.52 (m, 1 H from
isomer A + 1 H from isomer B), 4.37–4.33 (m, 2 H from isomer
A + 2 H from isomer B), 3.80 (s, 3 H from isomer B), 3.79 (s, 3
H from isomer A), 3.73 (s, 2 H from isomer A + 2 H from
isomer B); 13C NMR (100 MHz, CDCl3) δ 194.7, 194.6, 159.5,
159.2, 151.7, 150.6, 147.9, 140.5, 137.6, 137.4, 129.8, 129.0,
128.5, 127.5, 126.6, 123.5, 123.4, 122.7, 112.7, 112.2, 111.0,
110.6, 76.9, 76.0, 64.6, 64.1, 56.2, 56.1, 55.5; IR (KBr) 1690,
1477, 1284, 1255, 1234 cm−1; HRMS (ESI) calcd for
C19H18NO2 (M + H) 292.1332, found 292.1336.
HRMS (ESI) calcd for C20H20NO3 (M + H) 322.1438, found
322.1442.
Data for 2s′. 1H NMR (400 MHz, CDCl3) δ 7.34–7.27 (m,
5 H), 7.23 (dd, J = 9.7, 5.6 Hz, 1 H), 6.53 (d, J = 1.8 Hz, 1 H),
6.30 (d, J = 1.9 Hz, 1 H), 5.57 (dd, J = 9.7, 1.5 Hz, 1 H), 4.55
(s, 1 H), 4.28 (d, J = 5.6 Hz, 1 H), 3.81 (s, 6 H), 3.76 and 3.66
(ABq, J = 13.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 193.7,
161.6, 158.6, 150.2, 149.4, 137.5, 129.0, 128.5, 127.4, 123.7,
115.9, 101.9, 97.0, 73.6, 65.0, 56.3, 55.7, 55.6; IR (KBr) 1686,
1602, 1261, 1028 cm−1; HRMS (ESI) calcd for C20H20NO3
(M + H) 322.1438, found 322.1440.
Product 4b. (5.1 mg) was obtained as a side-product from the
above reaction as a green solid, mp 143–146 °C; 1H NMR
(400 MHz, CDCl3) δ 9.66 (d, J = 7.9 Hz, 1 H), 7.26 (d, J =
15.5 Hz, 1 H), 7.09 (s, 1 H), 6.68 (dd, J = 15.5, 7.9 Hz, 1 H),
6.62 (dd, J = 1.7, 0.8 Hz, 1 H), 6.30 (d, J = 1.8 Hz, 1 H), 3.91
(s, 3 H), 3.87 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 192.7,
161.8, 158.1, 154.3, 149.9, 137.9, 126.3, 113.3, 111.4, 94.9,
87.9, 55.8, 55.6; IR (KBr) 1663, 1501, 1262, 1111 cm−1; HRMS
(ESI) calcd for C14H15O4 (M + H) 247.0925, found 247.0924.
Product 2r, 2r′ and 4a. The general procedure was applied to
40.6 mg of 1a (as monohydrate), 82 mg of 3d, and 77 mg of
CsF to afford 11.3 mg of 2r as a yellow oil and 11.0 mg of 2r′
as a yellow oil.
Data for 2r. 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 9.7,
5.6 Hz, 1 H), 7.36–7.29 (m, 5 H), 7.20 (dd, J = 8.1, 7.4 Hz,
1 H), 7.08 (d, J = 7.2 Hz, 1 H), 6.79 (d, J = 8.2 Hz, 1 H), 5.56
(dd, J = 9.6, 1.4 Hz, 1 H), 4.64 (d, J = 5.5 Hz, 1 H), 4.42 (s,
1 H), 3.85 (s, 3 H), 3.74 and 3.70 (ABq, J = 12.9 Hz, 2 H); 13C
NMR (100 MHz, CDCl3) δ 194.8, 155.3, 151.2, 140.4, 137.3,
133.0, 129.1, 129.0, 128.5, 127.4, 123.2, 118.2, 110.6, 77.1,
Product 2t and 2t′. The general procedure was applied to
39 mg of 1g (as monohydrate), 82 mg of 3d, and 77 mg of CsF
to afford 11.5 mg of 2t as a brown solid and 8.4 mg of 2t′ as a
yellow solid.
62.2, 56.2, 55.3; IR (KBr) 1686, 1604, 1479, 1267 cm−1
;
HRMS (ESI) calcd for C19H18NO2 (M + H) 292.1332, found
292.1327.
1
Data for 2t. mp 99–101 °C; H NMR (400 MHz, CDCl3) δ
7.18 (dd, J = 9.7, 4.9 Hz, 1 H), 7.13 (dd, J = 8.2, 7.3 Hz, 1 H),
7.04 (d, J = 7.2 Hz, 1 H), 6.73 (d, J = 8.2 Hz, 1 H), 5.56 (dd, J
= 9.7, 1.5 Hz, 1 H), 4.93 (d, J = 4.9 Hz, 1 H), 4.65 (d, J =
1.4 Hz, 1 H), 3.83 (s, 3 H), 2.74–2.59 (m, 1 H), 2.06–1.91 (m,
1 H), 1.91–1.68 (m, 3 H), 1.66–1.55 (m, 1 H), 1.33–1.07 (m,
5 H); 13C NMR (100 MHz, CDCl3) δ 195.7, 153.8, 147.7, 141.3,
134.0, 128.6, 123.8, 117.3, 110.4, 73.4, 57.7, 55.4, 55.1, 31.3,
30.8, 25.8, 24.7, 24.6; IR (KBr) 1695, 1483, 1277 cm−1; HRMS
(ESI) calcd for C18H22NO2 (M + H) 284.1645, found 284.1640.
Data for 2r′. 1H NMR (400 MHz, CDCl3) δ 7.35–7.17 (m,
7 H), 6.93 (d, J = 7.2 Hz, 1 H), 6.76 (d, J = 8.3 Hz, 1 H), 5.57
(d, J = 9.6 Hz, 1 H), 4.65 (s, 1 H), 4.38 (d, J = 5.6 Hz, 1 H),
3.84 (s, 3 H), 3.92 and 3.57 (ABq, J = 12.9 Hz, 2 H); 13C NMR
(100 MHz, CDCl3) δ 193.9, 158.0, 150.5, 148.1, 137.4, 129.8,
129.0, 128.5, 127.4, 124.3, 123.3, 115.6, 110.6, 74.0, 64.9, 56.2,
55.6; IR (KBr) 1686, 1479, 1068 cm−1; HRMS (ESI) calcd for
C19H18NO2 (M + H) 292.1332, found 292.1328.
1
Product 4a. (9.1 mg) was obtained as a side-product from the
above reaction as light-yellow needles: mp 132–134 °C; 1H
NMR (400 MHz, CDCl3) δ 9.69 (d, J = 7.9 Hz, 1 H), 7.33 (t, J
= 8.2 Hz, 1 H), 7.32 (d, J = 15.6 Hz, 1 H), 7.17 (s, 1 H), 7.12
(d, J = 8.4 Hz, 1 H), 6.77 (dd, J = 15.6, 7.9 Hz, 1 H), 6.67 (d, J
= 8.0 Hz, 1 H), 3.95 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
192.8, 157.1, 154.1, 150.6, 137.9, 128.2, 127.7, 119.1, 110.8,
Data for 2t′. mp 71–73 °C; H NMR (400 MHz, CDCl3) δ
7.15 (dd, J = 8.3, 7.3 Hz, 1 H), 7.09 (dd, J = 9.8, 5.0 Hz, 1 H),
6.92 (d, J = 7.2 Hz, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 5.57 (dd, J
= 9.7, 1.5 Hz, 1 H), 4.85 (d, J = 1.5 Hz, 1 H), 4.72 (d, J =
5.0 Hz, 1 H), 3.83 (s, 3 H), 2.73–2.61 (m, 1 H), 2.07–1.96 (m,
1 H) 1.90–1.71 (m, 3 H), 1.66–1.55 (m, 1 H), 1.33–1.09 (m,
5 H); 13C NMR (100 MHz, CDCl3) δ 194.7, 156.7, 148.8,
8982 | Org. Biomol. Chem., 2012, 10, 8975–8984
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147.0, 129.5, 125.5, 123.9, 114.5, 110.3, 69.8, 60.9, 55.6, 55.0,
31.3, 30.8, 25.8, 24.7, 24.6; IR (KBr): 1686, 1483, 1273 cm−1
HRMS (ESI) calcd for C18H22NO2 (M + H) 284.1645, found
284.1640.
10.2 mg of pure 4d); 1H NMR (400 MHz, CDCl3) δ 9.72 (d, J =
7.9 Hz, 1 H), 8.29 (d, J = 15.9 Hz, 1 H), 8.10 (dd, J = 8.5,
0.7 Hz, 1 H), 7.59 (d, J = 7.7 Hz, 1 H), 7.38 (ddd, J = 8.5, 6.6,
1.0 Hz, 1 H), 7.30–7.23 (m, 1 H), 7.10 (s, 1 H), 6.68 (dd, J =
15.9, 7.9 Hz, 1 H), 1.73 (s, 9 H); 13C NMR (100 MHz, CDCl3)
δ 193.4, 150.3, 143.8, 137.8, 135.8, 129.3, 128.6, 126.3, 123.6,
121.6, 116.0, 111.8, 85.3, 28.2; IR (KBr) 1732, 1681, 1370,
1328 cm−1; HRMS (ESI) calcd for C17H20NO3 (M + H)
286.1438, found 286.1443.
;
Product 2u and 2u′. The general procedure was applied to
33.8 mg of 1h (as monohydrate), 82 mg of 3d, and 77 mg of
CsF to afford 10.1 mg of 2u as a green solid and 11.4 mg of 2u′
as a green solid.
1
Data for 2u. mp 124–125 °C; H NMR (400 MHz, CDCl3) δ
Product 4e. The general procedure was applied to 83.6 mg of
5a (as an HBr salt) and 82 mg of 3d to afford 13.8 mg of 4e as
an orange solid: mp 199–202 °C; 1H NMR (400 MHz, CDCl3) δ
9.76 (d, J = 7.9 Hz, 1 H), 8.31 (dd, J = 15.8, 0.6 Hz, 1 H), 7.81
(d, J = 8.5 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.32 (dd, J =
14.8, 6.4 Hz, 1 H), 7.24 (s, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 6.67
(d, J = 8.0 Hz, 1 H), 6.65 (dd, J = 16.0, 7.9 Hz, 1 H), 3.90 (s,
3 H), 2.32 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 193.2,
153.5, 145.4, 141.5, 139.7, 134.8, 134.4, 129.9, 129.8, 128.1,
126.5, 120.2, 111.2, 108.0, 104.3, 55.5, 21.6; IR (KBr) 1680,
1372, 1106 cm−1; HRMS (ESI) calcd for C19H18NO4S (M + H)
356.0951, found 356.0955.
7.56 (dd, J = 9.5, 5.9 Hz, 1 H), 7.11 (dd, J = 8.1, 7.3 Hz, 1 H),
7.01 (d, J = 7.2 Hz, 1 H), 6.69 (d, J = 8.1 Hz, 1 H), 5.40 (dd, J
= 9.5, 1.2 Hz, 1 H), 4.97 (dd, J = 5.8, 0.8 Hz, 1 H), 4.77 (s,
1 H), 3.83 (s, 3 H), 0.97 (s, 9 H); 13C NMR (100 MHz, CDCl3)
δ 195.5, 154.2, 153.7, 142.6, 135.1, 128.9, 122.3, 116.8, 110.2,
73.8, 58.9, 55.3, 54.5, 28.1; IR (KBr) 1685, 1479, 1265 cm−1
;
HRMS (ESI) calcd for C16H20NO2 (M + H) 258.1489, found
258.1485.
Data for 2u′. mp 165–166 °C; 1H NMR (400 MHz, CDCl3) δ
7.46 (dd, J = 9.5, 5.9 Hz, 1 H), 7.12 (dd, J = 8.1, 7.4 Hz, 1 H),
6.86 (d, J = 7.2 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H), 5.41 (d, J =
9.5 Hz, 1 H), 4.95 (s, 1 H), 4.77 (d, J = 6.0 Hz, 1 H), 3.83 (s,
3 H), 0.97 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 194.4,
156.6, 153.6, 150.3, 129.6, 126.4, 122.4, 113.8, 110.2, 70.2,
62.1, 55.6, 54.5, 28.1; IR (KBr) 1686, 1477, 1265 cm−1; HRMS
(ESI) calcd for C16H20NO2 (M + H) 258.1489, found 258.1485.
Manipulations of 2a
Compound 6. A mixture of 2a (51.6 mg, 0.2 mmol), formal-
dehyde (36 wt% in water, 30 μL, 0.4 mmol), and DMAP
(∼2.5 mg, 0.02 mmol), in 1 mL of THF was stirred for 20 h at
room temperature. After being acidified by dropwise addition of
1.5 M HCl, the reaction mixture was extracted with DCM, and
the combined extracts were washed successively with NaHCO3
and brine before being dried over Na2SO4 and concentrated. The
residue was purified by column chromatography (petroleum
Representative procedures for reactions of 3-amidopyridinium
species with arynes (Table 4, outlined for compound 4c)
To a 10 mL round-bottom flask equipped with a stir bar was
added 5a (as an HBr salt, 83.6 mg, 0.2 mmol) followed by 3a
(75 mg, 0.25 mmol, 1.25 equiv). MeCN (5 mL) was added and
the mixture was briefly stirred before addition of CsF (91 mg,
0.6 mmol). The mixture was stirred in a 50 °C bath for 18 h
before being diluted with EtOAc and water. The layers were sep-
arated and the aqueous layer was extracted with EtOAc twice.
The combined organic phases were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (petroleum ether–EtOAc) to
1
ether–EtOAc) to afford 34.8 mg of 6 as a brown oil. H NMR
(400 MHz, CDCl3) δ 7.47–7.44 (m, 1 H), 7.35–7.27 (m, 6 H),
7.23–7.17 (m, 3 H), 4.45 (d, J = 5.9 Hz, 1 H), 4.40 (s, 1 H),
4.15 and 4.07 (d of ABq, JAB = 14.2 Hz, 3J = 1.2 Hz, 2 H), 3.69
(s, 2 H), 2.46–2.16 (brs, 1 H); 13C NMR (100 MHz, CDCl3) δ
195.2, 146.0, 145.8, 138.1, 137.1, 132.4, 129.1, 128.5, 127.8,
127.5, 127.2, 126.0, 123.2, 76.3, 64.8, 60.1, 56.2; IR (KBr)
3533–3167 (br), 1685, 1456, 727 cm−1; HRMS (ESI) calcd for
C19H18NO2 (M + H) 292.1332, found 292.1330.
1
afford 14.6 mg of 4c as a brown glass; H NMR (400 MHz,
CDCl3) δ 9.78 (d, J = 7.9 Hz, 1 H), 8.33 (d, J = 15.9 Hz, 1 H),
8.23 (dd, J = 8.5, 0.7 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.53
(d, J = 7.8 Hz, 1 H), 7.41 (ddd, J = 8.5, 7.3, 1.3 Hz, 1 H),
7.31–7.27 (m, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.10 (s, 1 H),
6.66 (dd, J = 15.9, 7.9 Hz, 1 H), 2.32 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 193.2, 145.4, 141.4, 138.5, 135.8, 134.8,
130.4, 129.9, 129.2, 126.9, 126.5, 124.6, 121.9, 115.4, 113.8,
21.6; IR (KBr) 1675, 1372, 1120 cm−1; HRMS (ESI) calcd for
C18H26NO3S (M + H) 326.0845, found 326.0849.
Compound 7. To a solution of 2a (52.1 mg, 0.2 mmol) in
0.5 mL of Et2O was added ethyl diazoacetate (42 μL, 0.4 mmol,
caution!), and the solution was stirred at room temperature for 3
days. The excess ethyl diazoacetate was destroyed by addition of
HOAc. The mixture was diluted with EtOAc and water. Layers
were separated and the aqueous layer was extracted with EtOAc
twice. The combined organic phases were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography (petroleum ether–
1
EtOAc) to afford 51 mg of 7 as a light-yellow oil. H NMR
(400 MHz, CDCl3) δ 7.50 (d, J = 6.9 Hz, 1 H), 7.42–7.36 (m,
2 H), 7.36–7.19 (m, 9 H), 6.75 (s, 1 H), 4.89 (d, J = 1.6 Hz,
1 H), 4.27 (s, 1 H), 4.14–4.04 (m, 2 H), 3.84 (d, J = 11.1 Hz,
1 H), 3.67 and 3.60 (ABq, J = 13.0 Hz, 2 H), 3.57 (dd, J = 11.1,
1.9 Hz, 2 H), 1.28 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 198.6, 161.8, 144.1, 137.6, 137.0, 129.4, 128.8, 128.5
Characterization data for other products 4 (Table 4)
Product 4d. The general procedure was applied to 72.8 mg of
5c (as an HBr salt) and 75 mg of 3a to afford 11.2 mg of 4d as a
brown oil (contaminated by petroleum ether residue, H NMR
1
ratio 1 : 0.15 (product to PE, as dodecane), corresponding to
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8975–8984 | 8983

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6 (a) K. M. Peese and D. Y. Gin, J. Am. Chem. Soc., 2006, 128, 8734;
(b) K. M. Peese and D. Y. Gin, Org. Lett., 2005, 7, 3323; (c) V. C. Pham
and J. L. Charlton, J. Org. Chem., 1995, 60, 8051; (d) K. M. Peese and
D. Y. Gin, Chem.–Eur. J., 2008, 14, 1654; (e) M. J. Sung, H. I. Lee,
Y. Chong and J. K. Cha, Org. Lett., 1999, 1, 2017; (f) L. Zeng, T. Peng,
H. Zeng, Y. Le and J. Su, J. Org. Chem., 1992, 57, 3528; (g) H. I. Lee,
M. J. Sung, H. B. Lee and J. K. Cha, Heterocycles, 2004, 62, 407.
7 (a) N. Dennis, A. R. Katritzky and S. K. Parton, J. Chem. Soc., Perkin
Trans. 1, 1976, 2285; (b) N. Dennis, A. R. Katritzky and S. K. Parton,
J. Chem. Soc., Chem. Commun., 1972, 1237; (c) N. Dennis,
A. R. Katritzky and M. Ramaiah, J. Chem. Soc., Perkin Trans. 1, 1975,
1506; (d) ref. 2a.
(overlap), 128.4, 127.4, 124.8, 123.8, 73.7, 63.7, 63.4, 61.0,
57.0, 51.7, 14.0; IR (KBr) 1729, 1692, 1112 cm−1; HRMS (ESI)
calcd for C22H22N3O3 (M + H) 376.1656, found 376.1660.
Acknowledgements
This project was financially supported by the National Natural
Science Foundation of China (no. 21002021) and Chinese
Ministry of Education (the Scientific Research Foundation for
the Returned Overseas Chinese Scholars). We also thank
Dr Jiang Zhou (Peking University) and Prof. Zheng Duan
(Zhengzhou University) for their help in the spectroscopic
analysis.
8 K. P. Constable, B. E. Blough and F. I. Carroll, Chem. Commun., 1996,
717.
9 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983, 1211.
10 The reaction of 3-oxidopyridinium species with Kobayashi benzyne pre-
cursor was utilized in a patent application, see: A. W. Konradi, X. M. Ye,
S. Bowers, A. W. Garofalo, D. L. Aubele, D. Dressen, R. Ng, G. Probst,
C. M. Semko, M. Sun, A. P. Truong and M. S. Dappen, US Patent Appl.,
2010/0081680 A1.
11 (a) C. Wu, Y. Fang, R. C. Larock and F. Shi, Org. Lett., 2010, 12, 2234;
(b) J. Zhao, C. Wu, P. Li, W. Ai, H. Chen, C. Wang, R. C. Larock and
F. Shi, J. Org. Chem., 2011, 76, 6837; (c) P. Li, J. Zhao, C. Wu,
R. C. Larock and F. Shi, Org. Lett., 2011, 13, 3340; (d) Y. Fang, C. Wu,
R. C. Larock and F. Shi, J. Org. Chem., 2011, 76, 8840; (e) J. Zhao,
P. Li, C. Wu, H. Chen, W. Ai, R. Sun, H. Ren, R. C. Larock and F. Shi,
Org. Biomol. Chem., 2012, 10, 1922.
Notes and references
1 For a comprehensive review, see: A. R. Katritzky and N. Dennis, Chem.
Rev., 1989, 89, 827.
2 For selected references, see: (a) N. Dennis, A. R. Katritzky, T. Matsuo
and S. K. Parton, J. Chem. Soc., Perkin Trans. 1, 1974, 746;
(b) A. R. Katritzky, A. Boonyarakvanich and N. Dennis, J. Chem. Soc.,
Perkin Trans. 1, 1980, 343; (c) J. Banerji, N. Dennis, J. Frank,
A. R. Katritzky and T. Matsuo, J. Chem. Soc., Perkin Trans. 1, 1976,
2334; (d) N. Dennis, A. R. Katritzky, S. K. Parton, Y. Nomura,
Y. Takahashi and Y. Takeuchi, J. Chem. Soc., Perkin Trans. 1, 1976,
2289; (e) N. Dennis, A. R. Katritzky and R. Rittner, J. Chem. Soc.,
Perkin Trans. 1, 1976, 2329; (f) A. R. Katritzky, J. Banerji, N. Dennis,
J. Ellison, G. J. Sabongi and E.-U. Wurthwein, J. Chem. Soc., Perkin
Trans. 1, 1979, 2528; (g) A. R. Katritzky, J. Banerji,
A. Boonyarakvanich, A. T. Cutler, N. Dennis, S. Q. A. Rizvi,
G. J. Sabongi and H. Wilde, J. Chem. Soc., Perkin Trans. 1, 1979, 399;
(h) A. R. Katritzky and N. E. Grzeskowiak, J. Chem. Res. (S), 1981, 208.
3 (a) N. Dennis, A. R. Katritzky and G. J. Sabounji, Tetrahedron Lett.,
1976, 17, 2959; (b) A. R. Katritzky, A. T. Cutler, N. Dennis,
G. J. Sabongi, S. Rahimi-Rastgoo, G. W. Fischer and I. J. Fletcher,
J. Chem. Soc., Perkin Trans. 1, 1980, 1176.
12 Arynes are reactive with benzylic alcohols: Z. Liu and R. C. Larock,
J. Org. Chem., 2006, 71, 3198.
13 Compounds 2r and 2r′ were differentiated by an NOESY experiment.
See the ESI.† Other compounds were assigned based on analogy.
14 (a) R. Sanz, Org. Prep. Proced. Int., 2008, 40, 215; (b) P. M. Tadross,
C. D. Gilmore, P. Bugga, S. C. Virgil and B. M. Stoltz, Org. Lett., 2010,
12, 1224.
15 N. Dennis, A. R. Katritzky and Y. Takeuchi, Angew. Chem., Int. Ed.
Engl., 1976, 15, 1 and references therein.
16 (a) G. Ferguson, K. J. Fisher, B. E. Ibrahim, C. Y. Ishag, G. M. Iskandev,
A. R. Katritzky and M. Parvez, J. Chem. Soc., Chem. Commun., 1983,
1216; (b) C. Y. Ishag, K. J. Fisher, B. E. Ibrahirn, G. M. Iskander and
A. R. Katritzky, J. Chem. Soc., Perkin Trans. 1, 1988, 917.
17 For an excellent review of this process and its application in synthesis,
see: C. D. Vanderwal, J. Org. Chem., 2011, 76, 9555.
18 (a) M. Sawa, Y. Imaeda, J. Hiratake, R. Fujii, R. Umeshita, M. Watanabe,
H. Kondo and J. Oda, Bioorg. Med. Chem. Lett., 1998, 8, 647;
(b) X. Pei, T. H. Gupta, B. Badio, W. L. Padgett and J. W. Daly, J. Med.
Chem., 1998, 41, 2047.
4 (a) N. Dennis, B. Ibrahim and A. R. Katritzky, J. Chem. Soc., Perkin
Trans. 1, 1976, 2307; (b) N. Dennis, A. R. Katritzky, G. J. Sabounji and
L. Turker, J. Chem. Soc., Perkin Trans. 1, 1977, 1930; (c) ref. 2e.
5 A. R. Katritzky, N. Dennis, M. Chaillet, C. Larrieu and M. E. Mouhtadi,
J. Chem. Soc., Perkin Trans. 1, 1979, 408.
19 F. Rezgui and M. M. El Gaied, Tetrahedron Lett., 1998, 39, 5965.
8984 | Org. Biomol. Chem., 2012, 10, 8975–8984
This journal is © The Royal Society of Chemistry 2012