SYNTHESIS0039-78 1 437-210X

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2022, 54, 4989–4996
special topic 4989
Aryne Chemistry in Synthesis
Synthesis B. E. Metze et al. Special Topic

Parameterization of Arynophiles: Experimental Investigations to-

wards a Quantitative Understanding of Aryne Trapping Reactions
Bryan E. Metze
(one-pot competition experiment)
Avik Bhattacharjee
Cl
O
Theresa M. McCormick* vs Cl + Cl
O
David R. Stuart* reference
arynophile
arynophile
Department of Chemistry, Portland State University, • "arynophilicity" (A) = log(karynophile/kref) • A-values correlate with other reactivity parameters
1719 SW 10th Ave (room 262), Portland Oregon • >15 arynophiles parameterized by A values • multiple aryne precursors tested
97201, USA
[email protected]
[email protected]

Published as part of the Special Topic

Aryne Chemistry in Synthesis

Corresponding Authors

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Received: 31.03.2022 of the aryne substituent impacts reactivity; 3-substituted
Accepted after revision: 06.05.2022
arynes are more reactive than 4-substituted arynes with
Published online: 06.05.2022
DOI: 10.1055/a-1845-3066; Art ID: ss-2022-f0166-st the same substituent, and reactivity correlates with induc-
tive ′ constants (Scheme 1b).4 More recently, Garg, Mayr
Abstract Arynes are highly reactive intermediates that may be used and co-workers quantified the electrophilicity of benzyne
strategically in synthesis by trapping with arynophilic reagents. Howev-
er, ‘arynophilicity’ of such reagents is almost completely anecdotal and
and other arynes via the diffusion-clock method (Scheme
predicting which ones will be efficient traps is often challenging. Here, 1b).5 Garg and Mayr found that aryne intermediates have
we describe a systematic study to parameterize the arynophilicity of a electrophilicity (E) parameters that range from –1 to ~4.
wide range of reagents known to trap arynes. A relative reactivity scale, These values place benzyne electrophilicity between Vils-
based on one-pot competition experiments, is presented by using furan meier iminium and oxocarbenium cations, and the highly
as a reference arynophile and 3-chlorobenzyne as a the aryne. More
than 15 arynophiles that react in pericyclic reactions, nucleophilic addi-
electrophilic 3-fluorobenzyne is similar in electrophilicity
tion, and -bond insertion reactions are parameterized with aryno- to diarylcarbonium cation (Scheme 1b).6 Additionally, con-
philicity (A) values, and multiple aryne precursors are applicable. sistent between Biehl’s earlier work and Garg’s recent work
is that 3-fluorobenzyne is more reactive (electrophilic)
Key words LFER, aryne, arynophile, percyclic reaction, -bond inser-
than 3-methoxybenzyne. Although Garg and Mayr’s work
tion, nucleophilic addition
permits comparison of nucleophilic arynophiles, there is
little recourse to predict the outcome of reactions with
Arynes play a critical role as intermediates in modern arynophiles that participate in other pathways, e.g., cyc-
organic synthesis and have been implemented in the syn- loaddition, and those whose nucleophilicity parameters
thesis of various natural products and diverse aromatic have not been determined. Additionally, given the high re-
scaffolds.1 The versatility of arynes is attributed to the mul- activity of arynes, and propensity to even react with sol-
titude of reaction pathways in which they participate, i.e., vent, delineating the relative reactivity of arynophiles to
cycloaddition reactions, nucleophilic addition reactions, engage in productive trapping would elevate the use of
formal -bond insertion, and transition-metal-catalyzed these versatile intermediates.
reactions (Scheme 1a).1c Moreover, these general pathways Herein, we describe the development of a relative reac-
can also lead to rearrangements and be integrated into tivity scale for arynophiles that undergo cycloaddition
multi-component coupling reactions.1c The high electro- ([3+2] and [4+2]), nucleophilic addition (aromatic and ali-
philic character of arynes has been well-established theo- phatic amines), and formal -bond insertion (chloroam-
retically2 and experimentally, and in some cases they even ines, ureas) reactions with arynes. In total, 19 arynophiles
react with typically inert solvents.3 Linear free energy rela- are characterized by an arynophilicity (A) parameter, in
tionships (LFER) have been used effectively to characterize which furan is used as a reference arynophile with an A-
the relative reactivity of aryne intermediates (Scheme 1b). value defined as 0 (Scheme 1c). Where possible, the A-val-
For instance, Beihl and co-workers devised a ‘reactivity fac- ues obtained correlate with Mayr nucleophilicity (N) pa-
tor’ scale and correlated it to the polar substituent constant, rameters, but also extend to a large number of non-nucleo-
 (Scheme 1b).4 They found that the proximity and identity philic arynophiles. The A-values obtained in this work are

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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany
 4990

Synthesis B. E. Metze et al. Special Topic

A. Diverse reactivity of aryne intermediates OTs

Ph t-Bu O Me
Cl I 2a (5 equiv)
t-Bu N NaOt-Bu (1.5 equiv)
Cl O
Ph N O cycloaddition + TMP I
reactions O TBME, r.t., 1 h
O
R
Me O
(TMP)
Me 3a
1a 99% yield 99% yield
N nucleophilic
R
HN R addition reactions Scheme 2 Archetypal system for aryne generation and trapping

Me
N
O O
formal σ-bond
MeN
NMe insertion reactions ran as a reference arynophile to assess relative aryophilici-
NMe
R ty.
In the one-pot competition experiments, a large and
B. Relative reactivity of arynes (Roberts, Biehl, Garg, Mayr)
equal excess of furan and an arynophile of interest are add-
Biehl - reactivity factor (ca 1969)
2 2 2 2
ed to the archetypal system (Scheme 3). Product ratios of
Me MeO F
3 3 3
1
3
3b–s/3a are proportional to the ratio of rate constants

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1
<
1 ≅ < 1

F 4 (karynophile/kfuran) and are determined by integration of prod-

(0.11) (0.42) (0.45) (0.79) uct peaks in the crude 1H NMR spectrum.8 The A-parame-
Garg and Mayr - electrophilicity (ca. 2016) ters are calculated from Equation 1 and presented in
MeO F Scheme 3.
E = –1 E = –1 E≅4

0
Me
Me Equation 1 Method used to determine A-values
Cl N O
Me
E = –5.77 E = 2.97 E = 5.47 In addition to the reference arynophile, furan 2a, 18 ad-
C. Relative reactivity of arynophiles (this work) ditional arynophiles 2b–s were parameterized in this work
Cl
(Scheme 3). We focused on three different reaction path-
one-pot competition O
Cl + Cl ways: nucleophilic addition (red), cycloaddition (blue), and
experiment between arynophiles formal -bond insertion (orange) reactions, and each is col-
O
or coded in Scheme 3. The relative reactivity scale that we
t-Bu
Ph N
R' have constructed reflects differences in reactivity for the
HN MeN
O O R NMe three reaction pathways studied and accounts for both elec-
reference
arynophile representative arynophiles of interest tronic and steric effects of the individual arynophiles. Our
analysis reveals that N-nucleophiles 2b–i were the most re-
Scheme 1 Reactivity of arynes
active of the arynophiles we studied. Within, this subset,
cyclic secondary amines 2b–d were the most reactive, and
applied to multiple aryne precursors (diaryliodonium salts for acyclic amines reactivity decreased with increasing ste-
and ortho-(trimethyl)silylphenyl triflates) to demonstrate ric effects of the alkyl substituent in the order 1° > 2° > 3°
the generality of this scale. for 2f, 2g, and 2i, respectively (Scheme 3). Aniline 2h has
A key consideration of our approach to developing a rel- identical A-parameter (A = 0.88) as tert-butyl amine 2i,
ative reactivity scale for arynophiles is a high-yielding whereas N-methylaniline 2e is more reactive (A = 1.10) and
method to generate arynes. We found that 3-chlorophe- acetanilide 2r is much less reactive (A = –0.38), which re-
nyl(2′,4′,6′-trimethoxyphenyl)iodonium tosylate 1a ex- flects the different electronic effects of these aromatic
trudes aryne in high yield when treated with NaOt-Bu (1.5 amine substrates (Scheme 3). Additionally, 2,4,6-trimethyl
equiv) as base in TBME at room temperature, as evidenced aniline 2n is less reactive (A = 0.66) than unsubstituted ani-
by quantitative formation of by-product trimethoxyphenyl line 2h (A = 0.88) as a result of greater steric effects in 2n
iodide (TMP-I; Scheme 2).7 Moreover, in the presence of 5 (Scheme 3).
equivalents of furan 2a, we observed quantitative 1H-NMR Arynophiles that participate in cycloaddition reactions
yield of cycloadduct 3a (Scheme 2). Aryne formation is the include nitrone 2k, pyrroles 2l and 2p, pentamethyl cyclo-
rate-determining step and aryne trapping is the product- pentadiene 2m, and N-benzyl azide 2s (Scheme 3). General-
determining step. Therefore, this is an ideal system for one- ly, these substrates are more reactive than 2a, but broadly
pot competition experiments between arynophiles and fu- have moderate to low A-values (Scheme 3). The most
arynophilic of this subset is nitrone 2k (A = 0.79), which

© 2022. Thieme. All rights reserved. Synthesis 2022, 54, 4989–4996

 4991

Synthesis B. E. Metze et al. Special Topic

2b-s (5 equiv)
OTs 2a (5 equiv)
Cl
I NaOt-Bu (1.5 equiv) O 2a
Cl Cl Cl O
TMP
TBME, r.t., 1 h reference nucleophilic formal σ-bond
via aryne cycloaddition
arynophile addition insertion
1 3b–s 3a

Me
Me
Bn O
Me Me
N H2N
N N Me N
N HN Cl N Me H2N HN HN
Ac Me 2f; A = 1.08
2i; A = 0.88
2s; A = –0.42 2o; A = 0.50 2m; A = 0.69 2j; A = 0.81 2d; A = 1.16 2b; A = 1.45
2r; A = –0.38

A-value O
–0.5 2a; A = 0 0.5 1.0 1.5
O H2N
t-Bu
Me Me Ph N
N N HN
BocN PhN O H2N
HN 2c; A = 1.24
2p; A = 0.18 2l; A = 0.69 2k; A = 0.79 2h; A = 0.88 2g; A = 1.07 Me

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NH2
2q; A = –0.36 2e; A = 1.10
2n; A = 0.66

Scheme 3 Relative reactivity scale of arynophiles (A-value)

participates in a [3+2] cycloaddition with 3-chlorobenzyne. cycloaddition and observed a linear trend with A-values for
However, at the other end of the spectrum is benzyl azide 2a, 2k, 2l, 2p, and 2s (Figure 1b). Pentamethylcyclopentadi-
2s, which has the lowest A-value measured in this study (A ene 2m was an outlier in this trend, possibly due to steric
= –0.42; Scheme 3). Consistent with electronic effects, N- effects of the five methyl groups, which are not well ac-
phenylpyrrole 2l was more arynophilic (A = 0.69) than N- counted for in the HOMOenergy calculation. Collectively,
Boc pyrrole 2p (A = 0.18; Scheme 3). Pentamethylcyclopen- these 10 arynophiles span the range of A-values deter-
tadiene 2m has the same arynophilicity as N-phenylpyrrole
2l (A = 0.69; Scheme 3).
Formal -bond insertion into the C–N bond of ureas 2j
and 2q as well as the Cl–N bond of chloroazepane 2o was
also studied (Scheme 3). The arynophilicity of urea 2j (A =
0.81) is comparable to aniline 2h (A = 0.88) and nitrone 2k
(A = 0.79; Scheme 3). However, urea 2q has one of the low-
est arynophilicities observed in this study (A = –0.36;
Scheme 3). N-Chloroazepane 2o adds a Cl–N bond across 3-
chlorobenzyne derived from 1a. The arynophilicity of 2o (A
= 0.50) is intermediate between urea 2j and 2q, but is sub-
stantially lower than the corresponding N-H azepane 2c (A
= 1.24), likely due to the reduced nucleophilicity of 2o,
which stems from the withdrawing chloro substituent
(Scheme 3).
The A-values obtained here align with other reactivity
parameters and concepts used to describe several of the
compounds studied in this work (Figure 1). For instance, the
A-values obtained for several cyclic and acyclic amines cor-
relate with the nucleophilicity (N) parameters previously
determined by Mayr (2b, 2d, 2f, 2h, 2i; Figure 1a).9 This is
also consistent with the fact that Garg and Mayr used N-pa-
rameters to determine the electrophilicity of several arynes
(Scheme 1b).5 Nucleophilicity parameters are not relevant
or known for arynophiles that react through cycloaddition
reactions or formal -bond insertion.
HOMO-LUMO interactions are often correlated with re-
action rates of cycloaddition reactions.10 As such, we calcu- Figure 1 Correlation of A-values with other reactivity parameters. (a)
lated the HOMOenergy (eV) of the arynophiles that react with Nucleophilicity (N) parameter; (b) HOMOenergy of the arynophile.

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 4992

Synthesis B. E. Metze et al. Special Topic

mined here 2b, A = 1.45 and 2s, A = –0.42 (Scheme 3 and tition experiments with aryne precursor 1d, bearing a fluo-
Figure 1). ro substituent (grey circles, Figure 2). The LFER was also ob-
In order to demonstrate the generality of the A-parame- served in this case, demonstrating that this trend extends
ters derived here, we applied them to other iodonium and to other substituted arynes as well.
non-iodonium aryne precursors. Specifically, we used 1b,
bearing a mesityl iodonium leaving group, and 1c, the ven- Table 1 Comparison of Competition Experiments in TBME and MeCNa
erable Kobayashi-type reagent (Figure 2). As in Scheme 3,
we performed one-pot competition experiments between 2f/j (5 equiv)
Cl 2a (5 equiv) O
the reference arynophile 2a and several representative Cl + Cl
arynophiles that undergo nucleophilic addition (2b and 2f), solvent, r.t., 1 h

cycloaddition (2l and 2p), and -bond insertion (2j) and the
correlation with A-values are shown in Figure 2. Aryne pre-
Aryne precursor/arynophile Solvent log(karynophile/kfuran)
cursors 1b and 1c extrude the same aryne, 3-chloroben-
zyne, as 1a and so competitive trapping with arynophiles 1a/2f TBME 1.08
should follow the same trends. 1a/2f MeCN 0.72
1c/2f MeCN 0.69

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1a/2j TBME 0.81
1a/2j MeCN 0.57
1c/2j MeCN 0.63
a
Conditions for 1a: 1a (0.1 mmol, 1 equiv), 2f/j (0.5 mmol, 5 equiv), 2a
(0.5 mmol, 5 equiv), NaOt-Bu (0.15 mmol, 1.5 equiv), solvent (see table,
0.5 mL), r.t., 1 h. Conditions for 1c: 1c (0.085 mmol, 1 equiv), 2f/j (0.425
mmol, 5 equiv), 2a (0.425 mmol, 5 equiv), CsF (0.425 mmol, 5 equiv),
MeCN (0.41 mL), r.t., 1 h.

In conclusion, we have developed an arynophilicity pa-

rameter (A-value) that describes the relative reactivity in
trapping arynes and includes three different reaction path-
ways. The A-values for arynophiles that act as nucleophiles
correlate with known nucleophilicity parameters. Addition-
ally, the A-values for arynophiles that participate in cyc-
loaddition reactions correlate with HOMOenergy of the
arynophile. Comparison of arynophiles from these groups,
Figure 2 Correlation of A-values with different aryne precursors and from other substrate classes that are not described by
nucleophilicity or HOMOenergy, are now possible as they are
unified by a single A-value scale. The A-values were devel-
However, there are some small distinctions that are oped with diaryliodonium salts as aryne precursors, but are
worth pointing out. When aryne precursor 1b was subject- also compatible with the more common (2-trimethylsi-
ed to competition experiments (Figure 2, orange circles) a lyl)aryl triflate reagents. Further parameterization of other
slope of 1.12 was obtained, indicating that a nearly identi- arynophiles, development of a related scale for arynes, and
cal response was observed as with 1a. However, when use of the A-values in other related reactions are ongoing in
aryne precursor 1c was subjected to competition experi- our laboratory.
ments the linear free-energy relationship was conserved,
but a slope of 0.50 was observed. This difference may be ex-
plained by a change in solvent from TBME for 1a to MeCN Commercially available reagents and solvents were used without fur-
for 1c and a rate enhancement for the reference arynophile ther purification unless otherwise stated. The percentage of active
furan in the more polar solvent.11 To test this hypothesis, oxidant for m-CPBA was determined by iodometric titration prior to
use.12 (3-Chlorophenyl)(2,4,6-trimethoxyphenyl)iodonium tosylate
we used 1a in competition experiments between aryno-
1a,13 (3-chlorophenyl)(mesityl)iodonium tosylate 1b,14 2-chloro-6-
philes 2f and 2j with reference arynophile 2a in MeCN in- (trimethylsilyl)phenyl trifluoromethanesulfonate 1c,15 (3-fluorophe-
stead of TBME as solvent (Table 1). We observed a decrease nyl)(2,4,6-trimethoxyphenyl)iodonium tosylate 1d,13 N-tert-butyl--
in the log(karynophile/kfuran) values for 1a when the competi- phenyl nitrone 2k,16 N-phenylpyrrole 2l,17 chloroazepane 2o,18 N-Boc
tion experiments were conducted in MeCN, consistent with pyrrole 2p,19 and aryne adducts 3a,7 3j,7 3k,7 3o,7 4a,20 4b,21 and 4c22
our hypothesis. Moreover, the log(karynophile/kfuran) values ob- have been previously characterized. Reactions performed above room
tained for 1a in MeCN were very similar to those obtained temperature (ca. 23 °C) were done so in an oil bath or aluminum
block heated externally. Reactions performed below ambient room
for 1c in MeCN (Table 1). Finally, we also performed compe-

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 4993

Synthesis B. E. Metze et al. Special Topic

temperature were done so in an ice, or dry-ice-acetone bath. Crude IR (ATR): 2922, 2851, 1589, 1490, 1233, 1197, 1099, 1001, 752 cm–1.
reaction mixtures were analyzed by 1H NMR spectroscopy or thin- 1
H NMR (CDCl3, 400 MHz):  = 7.09 (t, J = 8.1 Hz, 1 H), 6.63 (t, J = 2.2
layer chromatography (TLC) on Sigma–Aldrich Al Foils Flexible TLC Hz, 1 H), 6.59–6.52 (m, 2 H), 3.43–3.40 (m, 4 H), 1.77 (br, 4 H), 1.55–
plates (silica gel 60 Å F-254) and visualized by UV irradiation, iodine, 1.52 (m, 4 H).
anisaldehyde, or permanganate stain. Crude material was purified by 13
C{H} NMR (CDCl3, 101 MHz):  = 165.8, 162.1, 159.6, 148.3(2),
flash column chromatography on SilicaFlash P60 silica gel. Product
148.3(0), 131.9, 131.7.
distributions for competition experiments were obtained by integra-
tion of peaks known for the analyte molecules, see the Supporting In- HRMS (ESI): m/z [C12H16ClN ++H]+ calcd: 210.1050; found: 210.1042.
formation for competition reaction spectra. 1H and 13C{1H} spectra
were recorded in CDCl3 or DMSO-d6 with tetramethylsilane as an in- 1-(3-Chlorophenyl)piperidine (3d)
ternal standard on a Bruker Avance II 400 MHz or Bruker Avance III Prepared from 1a and piperidine 3d (98 uL, 0.5 mmols, 1 equiv) on a
600 MHz spectrometer; the following notation is used: br – broad, s – 0.5 mmol scale according to general procedure A with the following
singlet, d – doublet, t – triplet, q – quartet, m – multiplet, dd – doublet modifications: the reaction was conducted at 50 °C for 90 min using
of doublets, dt – doublet of triplets, and ddd – doublet of doublet of 1.1 equivalents of NaOtBu (0.0528 g, 0.55 mmol). The product was ob-
doublets. FTIR spectra were recorded on a Thermo Scientific Nicolet tained in an isolated yield of 48% (0.0469 g, 0.37 mmol) as a light-yel-
iS5 Infra-red spectrometer. High-resolution mass spectrometry low oil. Spectral data are consistent with previous reports.24
(HRMS) data were recorded on a Thermo Scientific Q-exactive mass 1
H NMR (CDCl3, 400 MHz):  = 7.13 (t, J = 8.11 Hz, 1 H), 6.88–6.86 (m,
spectrometer by electrospray ionization with an Orbitrap mass-ana-
1 H), 6.79–6.74 (m, 2 H), 3.17–3.14 (m, 4 H), 1.71–1.65 (m, 4 H), 1.60–

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lyzer (ESI-Orbitrap). Melting points were recorded on a Mel-Temp
1.54 (m, 2 H).
(Thermo scientific) and are reported as uncorrected.
13
C{H} NMR (CDCl3, 101 MHz):  = 153.1, 134.8, 129.9, 118.6, 116.0,
General Procedure to Obtain Analytically Pure Samples of Aryne 114.3, 50.1, 25.6, 24.2.
Adducts 3a–s
Iodonium salt 1a (0.5 mmol, 1 equiv) was weighed out in air and add- 3-Chloro-N-methyl-N-phenylaniline (3e)
ed to a 12 mL vial. A magnetic stir bar, TBME (2.5 mL) and arynophile Prepared from 1a and N-methylaniline 2e (0.1071 g, 0.5 mmol, 1
(1–5 equiv) were added sequentially, forming a slurry. NaOtBu equiv) on a 0.5 mmol scale according to the general procedure and
(0.0721 g, 0.75 mmol, 1.5 equiv or as indicated) was weighed out in obtained in an isolated yield of 38% (0.0410 g, 0.19 mmol) as a clear
air and added to the vial with constant stirring in one portion. The liquid. Spectral data are consistent with previous reports.25
vial was sealed with a cap, and the reaction mixture was vigorously 1
H NMR (CDCl3, 400 MHz):  = 7.33 (t, J = 7.9 Hz, 2 H), 7.14–7.06 (m, 4
stirred at room temperature, or as indicated, for one hour. The reac- H), 6.88 (t, J = 2.1 Hz, 1 H), 6.82 (dd, J1 = 7.88, J2 = 1.1 Hz, 1 H), 6.77 (dd,
tion was quenched with ammonium chloride solution (7 mL) and ex- J1 = 8.3, J2 = 2.2 Hz, 1 H), 3.29 (s, 3 H).
tracted with EtOAc (3 × 3 mL). The combined organic phases were 13
C{H} NMR (CDCl3, 101 MHz):  = 150.2, 148.2, 134.8, 129.9, 129.6,
dried with MgSO4. The drying agent was removed by vacuum filtra-
123.5, 123.4, 119.5, 117.4, 115.8, 40.3.
tion, and the crude reaction mixture was concentrated under reduced
pressure using a rotary evaporator. The crude mixture was further
purified by flash chromatography on silica gel using EtOAc or diethyl N-Butyl-3-chloroaniline (3f)
ether in hexanes. Prepared from 1a and N-butylamine 2f (147 L, 1.5 mmol, 3 equiv) on
a 0.5 mmol scale according to the general procedure with the follow-
1-(3-Chlorophenyl)pyrrolidine (3b) ing modifications: 3 equivalents of NaOtBu (1.5 mmol, 0.144 g) was
used. The product was obtained in an isolated yield of 7% (0.0064 g,
Prepared from 1a and pyrrolidine 2b (0.1066 g, 1.5 mmol, 3 equiv) on
0.035 mmol) as a clear liquid.
a 0.5 mmol scale according to the general procedure with the follow-
ing modification: the crude product was purified by filtration Rf = 0.73 (hexanes/EtOAc, 1:0.2).
through a pad of silica and obtained in an isolated yield of 18% IR (ATR): 2956, 2924, 2850, 1598, 1541, 1326, 1279, 1027, 762 cm–1.
(0.0166 g, 0.09 mmol) as a mixture of regioisomers (1:0.1) appearing 1
H NMR (CDCl3, 400 MHz):  = 7.05 (t, J = 8.0 Hz, 1 H), 6.63 (dd, J1 =
as a clear oil. Characterization of the major regioisomer is provided
7.8, J2 = 1.1 Hz, 1 H), 6.56 (t, J = 2.1 Hz, 1 H), 6.45 (dd, J1 = 8.2 J2 = 1.6
below. Spectral data are consistent with previous reports.23
Hz, 1 H), 3.73 (br, 1 H), 3.08 (t, J = 7.2 Hz, 2 H), 1.63–1.56 (m, 3 H),
1
H NMR (CDCl3, 400 MHz):  = 7.10 (t, J = 8.07 Hz, 1 H), 6.60 (dd, J1 = 1.47–1.38 (m, 3 H), 0.96 (t, J = 7.1 Hz, 3 H).
7.83 J2 = 1.2 Hz, 1 H), 6.51 (t, J = 2.2 Hz, 1 H), 6.41 (dd, J1 = 8.4 J2 = 2.3 13
C{H} NMR (CDCl3, 101 MHz):  = 149.6, 135.0, 130.1, 116.8, 112.1,
Hz, 1 H), 3.26–3.23 (m, 4 H), 2.01–1.98 (m, 4 H).
111.0, 43.5, 31.5, 29.7, 20.2, 13.9.
13
C{H} NMR (CDCl3, 101 MHz):  = 148.9, 134.9, 130.0, 115.1, 111.4,
HRMS (ESI): m/z [C10H14ClN + H]+ calcd: 184.0893; found: 184.0889.
109.8, 47.6, 25.5.

3-Chloro-N-cyclohexylaniline (3g)
1-(3-Chlorophenyl)azepane (3c)
Prepared from 1a and cyclohexylamine 2g (171 L, 1.5 mmol, 3
Prepared from 1a and azepane 2c (0.112 mL, 1 mmol, 2 equiv) on a
equiv) on a 0.5 mmol scale according to the general procedure with
0.5 mmol scale according to the general procedure with the following
the following modifications: 3 equivalents of NaOtBu (0.1440 g, 1.5
modifications: 3 equivalents of NaOtBu (0.1440 g, 1.5 mmol) and the
mmol) was used. The product was obtained in an isolated yield of 15%
product was obtained in an isolated yield of 48% (0.0498 g, 0.36
(0.0164 g, 0.08 mmol) as a clear liquid. Spectral data are consistent
mmol) as a clear liquid.
with previous reports.26
Rf = 0.85 (hexanes/EtOAc, 1:0.2).

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Synthesis B. E. Metze et al. Special Topic

1
H NMR (CDCl3, 400 MHz):  = 7.03 (t, J = 8.0 Hz, 1 H), 6.60 (d, J = 7.8 scale and obtained in an isolated yield of 38% (0.0470 g, 0.19 mmol) as
Hz, 1 H), 6.54 (t, J = 2.0 Hz, 1 H), 6.43 (dd, J1 = 8.2, J2 = 2.0 Hz, 1 H), 3.60 a white crystalline solid. This compound was further purified by crys-
(br, 1 H), 3.24–3.19 (m, 1 H), 2.05–2.02 (m, 2 H), 1.76 (dt, J1 = 12.9, J2 = tallization after column chromatography by slow evaporation from
3.8 Hz, 2 H), 1.65 (dt, J = 12.4 Hz, J2 = 3.7 Hz, 2 H), 1.42–1.32 (m, 2 H), hexanes.
1.26–1.20 (m, 1 H), 1.19–1.10 (m, 2 H). Mp 51–53 °C; Rf = 0.91 (hexanes/EtOAc, 1:0.16).
13
C{H} NMR (CDCl3, 101 MHz):  = 148.5, 135.0, 130.2, 116.5, 112.5, IR (ATR): 3057, 2957, 2926, 2903, 2867, 1571, 744 cm–1.
111.4, 51.6, 33.3, 25.8, 24.9. 1
H NMR (CDCl3, 400 MHz):  = 6.92 (dd, J = 5.0, 2.9 Hz, 1 H), 6.85–6.82
(m, 2 H), 2.22 (q, J = 6.4 Hz, 1 H), 1.60 (s, 6 H), 1.49 (d, J = 1.2 Hz, 3 H),
3-Chloro-N-phenylaniline (3h)
1.33 (s, 3 H), 0.81 (d, J = 6.4 Hz, 3 H).
Prepared from 1b and aniline 2h (91.3 L, 1 mmol, 2 equiv) on a 0.5 13
C{H} NMR (CDCl3, 101 MHz):  = 159.4, 150.7, 140.8(1), 140.8(2),
mmol scale according to the general procedure and obtained in an
127.1, 126.0, 125.2, 116.4, 77.0(2) (overlaps with solvent residual
isolated yield of 23% (0.023 g, 0.115 mmol) as a clear liquid. Spectral
peak), 61.3, 58.6, 13.1, 11.8, 11.2, 11.0, 9.3.
data are consistent with previous reports.27
1 HRMS (ESI): m/z [C16H19Cl + H]+ calcd: 247.1248; found: 247.1246.
H NMR (CDCl3, 400 MHz):  = 7.30 (t, J = 7.8 Hz, 2 H), 7.15 (dd, J = 8.4
Hz, 1 H), 7.10 (d, J = 7.8 Hz, 2 H), 7.04 (s, 1 H), 7.00 (t, J = 7.4 Hz, 1 H),
6.90–6.84 (m, 2 H), 5.71 (br, 1 H). N-(3-Chlorophenyl)-2,4,6-trimethylaniline (3n)
13 Prepared from 1a and 2,4,6-trimethylaniline 2n (0.1352 L, 0.5 mmol,
C{H} NMR (CDCl3, 101 MHz):  = 144.8, 141.9, 135.0, 130.3, 129.5,

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1 equiv) on a 0.5 mmol scale according to the general procedure and
122.1, 120.5, 119.0, 116.6, 115.1.
obtained in an isolated yield of 83% (0.1000 g, 0.4150 mmol) as a yel-
low solid. Spectral data are consistent with previous reports.30
N-(tert-Butyl)-3-chloroaniline (3i)
1
H NMR (CDCl3, 400 MHz):  = 7.04 (t, J = 7.0 Hz, 1 H), 6.94 (s, 2 H),
Prepared from 1a and tert-butylamine 2i (0.1097 g, 1.5 mmol, 3
6.69–6.66 (m, 1 H), 6.42 (t, J = 2.1 Hz, 1 H), 6.38–6.35 (m, 1 H), 5.13
equiv) on a 0.5 mmol scale according to general procedure A with the
(br, 1 H), 2.30 (s, 3 H), 2.16 (s, 6 H).
following modifications: 3 equivalents of NaOtBu (0.144 g, 1.5 mmol)
13
was used. The product was obtained in an isolated yield of 72% C{H} NMR (CDCl3, 101 MHz):  = 148.0, 136.1, 136.0, 135.1, 134.6,
(0.0666 g, 0.36 mmol) as a clear liquid. Spectral data are consistent 130.2, 129.3, 117.7, 112.8, 111.4, 20.9, 18.2.
with previous reports.28
1
H NMR (CDCl3, 400 MHz):  = 7.04 (t, J = 8.0 Hz, 1 H), 6.70 (t, J = 2.1 tert-Butyl 5-Chloro-1,4-dihydro-1,4-epiminonaphthalene-9-car-
Hz, 1 H), 6.68 (dd, J1 = 1.9, J2 = 0.8 Hz, 1 H), 6.66 (dd, J1 = 1.9, J2 = 0.8 boxylate (3p)
Hz), 6.57 (dd, J1 = 2.3, J2 = 0.9 Hz, 1 H), 6.55 (dd, J1 = 2.3, J2 = 0.8 Hz, 1 Prepared from 1a and N-Boc-pyrrole 2p (83.5 L, 0.5 mmol, 1 equiv)
H), 3.57 (br, 1 H), 1.34 (s, 9 H). on a 0.5 mmol scale according to the general procedure and obtained
13 in an isolated yield of 74% (0.103 g, 0.37 mmol) as a clear oil.
C{H} NMR (CDCl3, 101 MHz):  = 148.1, 134.5, 129.9, 117.5, 115.9,
114.6, 51.4, 29.9. Rf = 0.63 (hexanes/EtOAc, 1:0.2).
IR (ATR): 2976, 2933, 2828, 1707, 1585, 1327, 1156, 1027, 739 cm–1.
5-Chloro-9-phenyl-1,4-dihydro-1,4-epiminonaphthalene (3l) 1
H NMR (CDCl3, 400 MHz):  = 7.13 (br, 1 H), 7.00 (br, 2 H), 6.93–6.87
Prepared from 1a and N-phenylpyrrole 2l (0.1432 g, 1 mmol, 2 equiv) (m, 2 H), 5.64 (br, 1 H), 5.51 (s, 1 H), 1.37 (s, 9 H).
on a 0.5 mmol scale according to the general procedure and obtained 13
C{H} NMR (CDCl3, 101 MHz):  = 155.0 (br-1C), 150.9 (br-1C), 146.5,
as a mixture of the title compound and trimethoxyphenyl-iodide. The
143.5 (br-1C), 143.0 (br1-C), 141.7 (br), 126.7, 125.6, 119.5–118.9
crude reaction mixture was further purified after column chromatog-
(br)-1C, 81.0, 66.9 (br), 65.6 (br), 28.1.
raphy to 79% (21% TMP-I, 0.0530 g crude mass) by crystallization of
TMP-I from toluene. The impure mixture was obtained as a brown oil. Note: Broad peaks are observed for this compound due to the pres-
ence of Boc-Group rotamers, spectral data are consistent with previ-
Rf = 0.66 (hexanes/EtOAc, 1:0.2).
ous reports of N-Boc-epiminonphthalene type compounds.
IR (ATR): 3059, 3020, 2926, 1581, 1492, 1450, 1296, 1157, 764 cm–1.
HRMS (ESI): m/z [C15H16ClNO2++Na]+ calcd: 300.0762; found:
1
H NMR (CDCl3, 400 MHz):  = 7.17 (t, J = 7.9 Hz, 2 H), 7.11 (dd, J1 = 6.1 300.0753.
Hz, J2 = 1.4 Hz, 1 H), 7.00 (s, 2 H), 6.88–6.81 (m, 5 H), 5.61 (s, 1 H), 5.45
(s, 1 H). 7-Chloro-1,5-dimethyl-2,3,4,5-tetrahydrobenzo[b][1,5]diazocin-
Trimethoxyphenyl iodide impurity;  = 6.14 (s, 2 H), 3.86 (s, 6 H), 3.82 6(1H)-one (3q)
(s, 3 H).29 Prepared from 1a and DMPU 2q (0.187 mL, 1.5 mmol, 3 equiv) ac-
13
C{H} NMR (CDCl3, 101 MHz):  = 150.8, 146.7, 146.4, 142.4, 141.4, cording to the general procedure on a 0.5 mmol scale with the follow-
128.9, 128.0, 126.7, 125.5, 121.1, 119.8, 117.9, 70.2, 67.6. ing modifications: The reaction was performed using LiHMDS (1 M in
toluene, 0.5 mL, 1 equiv) as base and toluene (2 mL) as the reaction
Trimethoxyphenyl iodide impurity;  = 162.1, 159.8, 91.2, 66.7, 56.4,
solvent. The reaction was allowed to stir for 40 min. The product was
55.5.
obtained in an isolated yield of 59% (0.0704 g, 0.30 mmol) as a white
HRMS (ESI): m/z [C16H12ClN ++Na]+ calcd: 254.0737 Found; 254.0726. solid. Spectral data are consistent with previous reports.25
1
H NMR (CDCl3, 400 MHz):  = 7.08 (t, J = 8.2 Hz, 1 H), 6.78 (dd, J = 7.8,
5-Chloro-1,2,3,4,9-pentamethyl-1,4-dihydro-1,4-methanonaph-
0.7 Hz, 1 H), 6.58 (d, J = 8.6 Hz, 1 H), 3.64–3.56 (m, 2 H), 3.19–3.16 (m,
thalene (3m)
1 H), 3.02–3.00 (m, overlaps with singlet at 2.99 and 3.03, 1 H), 3.03
Prepared from 1a and pentamethylcyclopentadiene 2m (0.243 mL, (s, 3 H), 2.99 (s, 3 H), 1.88–1.78 (m, 2 H).
1.5 mmol, 3 equiv) according to the general procedure on a 0.5 mmol

© 2022. Thieme. All rights reserved. Synthesis 2022, 54, 4989–4996

 4995

Synthesis B. E. Metze et al. Special Topic

13
C{H} NMR (CDCl3, 101 MHz):  = 170.9, 149.1, 133.3, 129.8, 121.6, Note: Broad peaks are observed for this compound due to the pres-
118.7, 112.7, 48.8, 48.0, 42.2, 33.6, 26.72. ence of Boc-group rotamers, spectral data is consistent with previous
reports of N-Boc-epiminonaphthlalene type compounds.
N-(3-Chlorophenyl)-N-phenylacetamide (3r) HRMS (ESI): m/z [C15H16FNO2+Na]+ calcd: 284.1063; found: 284.1052.
Prepared from 1a and acetanilide (0.1351 g, 1 mmol, 2 equiv) on a 0.5
mmol scale according to the general procedure and obtained in an General Procedure for Competition Experiments to Determine A-
isolated yield of 21% (0.0256 g, 0.105 mmol) as a brown oil. Spectral Values
data are consistent with previous reports.31 A 3 mL vial containing a magnetic stir bar was charged with aryno-
1
H NMR (CDCl3, 400 MHz):  = 7.52–7.12 (m, 9 H), 2.06 (s, 3 H). phile 2b–s (0.5 mmol, 5 equiv), TBME (0.5 mL) and furan 2a (36 L,
13
C{H} NMR (CDCl3, 101 MHz):  = 170.4, 129.8, 128.4, 126.4, 23.9. 0.5 mmol, 5 equiv). The aryne precursor 1a–c (0.1 mmol, 1 equiv) was
weighed out in air and added to the vial. NaOtBu (0.0144 g, 0.15
1-Benzyl-4-chloro-1H-benzo[d][1,2,3]triazole (3s)
mmol, 1.5 equiv) was weighed out in air and added to the vial with
Prepared from 1a and benzylazide 2s (0.5 mmol, 68 L, 1 equiv) ac- vigorous stirring in one portion. The vial was sealed with a cap, and
cording to the general procedure on a 0.5 mmol scale for 1 hour with the reaction mixture was allowed to stir at room temperature for 1
the following modification: the reaction was conducted at 0 °C. The hour. The reaction was quenched with ammonium chloride solution
product was obtained in an isolated yield of 59% (0.0714 g, 0.295 (2 mL) and extracted with EtOAc (3 × 1 mL). The combined organic
mmol) as an off-white solid. Spectral data are consistent with previ- phases were filtered through a Pasteur pipette containing a cotton
ous reports.15

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plug and MgSO4, drying agent into a 20 mL scintillation vial. The sol-
1
H NMR (CDCl3, 400 MHz):  = 7.37–7.30 (m, 5 H), 7.28–7.23 (m, 3 H), vent is then removed by rotary evaporation. CDCl3 with tetramethyl-
5.86 (s, 2 H). silane as an internal standard (1 mL) was added to the vial, and the
13 NMR sample was prepared. The spectral data was acquired with a
C{H} NMR (CDCl3, 101 MHz):  = 144.1, 134.3, 134.1, 129.1, 128.7,
Bruker Avance II 400 MHz spectrometer with a D1 relaxation time of
127.9, 127.6, 125.5, 123.8, 108.5, 52.69.
30 seconds. Select arynophile competition reactions were run in trip-
licate, and the computed A values represent an average, with standard
6-Fluoro-1,4-dimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaze- deviation reported as ± values.
pin-5-one (4a)
Prepared from 1d and DMI 2j (0.166 mL, 1.5 mmol, 3 equiv) on a 0.5 Procedure for Competition Experiments with Kobayashi Reagents
mmol scale according to the general procedure and obtained in an
A 3 mL vial containing a magnetic stir bar was charged with 1c (0.085
isolated yield of 43% (0.045 g, 0.215 mmol) as a white solid.
mmol, 0.02828 g), MeCN (0.41 mL), the arynophile (0.425 mmol, 5
Mp 110–114 °C; Rf = 0.09 (hexanes/acetone, 1:0.2). equiv), and furan (31 L, 0.425 mmol, 5 equiv). CsF (0.06455 g, 0.425
IR (ATR): 3063, 2995, 2883, 2820, 1641, 1607, 1457, 1172, 803 cm–1. mmol, 5 equiv) was weighed out in air and quickly added to the vial
1 with vigorous stirring in one portion. The vial was sealed with a cap,
H NMR (CDCl3, 400 MHz):  = 7.31–7.25 (m, 1 H), 6.72 (t, J = 8.6 Hz, 1
and the reaction mixture was allowed to stir at room temperature for
H), 6.66 (d, J = 8.4 Hz), 3.45 (t, J = 5.7 Hz, 2 H), 3.24 (t, J = 5.7, 2 H), 3.19
4 hours. The reaction mixture was filtered through a small plug of sil-
(s, 3 H), 2.80 (s, 2 H).
ica with 10 mL EtOAc as the eluent. The solvent was then removed by
19
F{1H} NMR (CDCl3, 376 MHz):  = –113.06. rotary evaporation. CDCl3 with tetramethylsilane as an internal stan-
13
C{H} NMR (CDCl3, 101 MHz):  = 165.8, 160.9 (d, JC–F = 252.1 Hz), dard (1 mL) was added to the vial, and the NMR sample was prepared.
148.3 (d, JC–F = 5.4 Hz), 131.8 (d, JC–F = 10.9 Hz), 117.6 (d, JC–F = 14.0 The spectral data was acquired with a Bruker Avance II 400 MHz
Hz), 113.3 (d, JC–F = 2.9 Hz), 109.5 (d, JC–F = 22.2 Hz), 57.4, 47.7, 40.3, spectrometer with a D1 relaxation time of 30 seconds.
33.6.
HRMS (ESI): m/z [C11H13FN2O+H]+ calcd: 209.1085; found: 209.1088.
Conflict of Interest
tert-Butyl 5-Fluoro-1,4-dihydro-1,4-epiminonaphthalene-9-car- The authors declare no conflict of interest.
boxylate (4b)
Prepared from 1d and N-Boc-pyrrole 2p (83.5 uL, 0.5 mmols, 1 equiv)
on a 0.5 mmol scale according to the general procedure and obtained Funding Information
in an isolated yield of 37% (0.0492 g, 0.185 mmol) as a clear oil.
This work was supported in part by the National Science Foundation
Rf = 0.61 (hexanes/EtOAc, 1:0.2).
(NSF, CHE #1856705). The NSF provided instrument funding for the
–1
IR (ATR): 3063, 2995, 2883, 2820, 1641, 1607, 1457, 1172, 803 cm . BioAnalytical Mass Spectrometry Facility at PSU (MRI #1828753).NationlScieFoundati(185670)NationlScienFoundatio(182753)
1
H NMR (CDCl3, 400 MHz):  = 7.07 (br d, J = 6.4 Hz, 1 H), 7.00 (br, 1
H), 6.97–6.92 (m, 1 H), 6.68 (t, J = 8.4 Hz, 1 H), 5.73 (br, 1 H), 5.51 (br, 1
H), 1.38 (s, 9 H). Acknowledgment
19 1
F{ H} NMR (CDCl3, 376 MHz):  = –120.55, –121.69. We acknowledge Portland State University.
13
C{H} NMR (CDCl3, 101 MHz):  = 154.8, 152.0 (d, J = 4.5 Hz), 143.5–
141.8 (br), 133.0 (d, J = 20.3 Hz), 127.3 (d, J = 6.2 Hz), 117.2 (br), 113.6
(d, J = 21.7 Hz), 80.92, 66.4 (br), 63.4 (br), 28.1. Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1845-3066. SuportingIformatinSuportingIformatin

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 4996

Synthesis B. E. Metze et al. Special Topic

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© 2022. Thieme. All rights reserved. Synthesis 2022, 54, 4989–4996