Reactions of HDDA Benzynes with C,N-Diarylimines (ArCH=NAr')

Article abstract of DOI:10.1002/ejoc.201901855

o-Benzynes can be utilized to construct heterocyclic motifs using various nucleophilic and cycloaddition trapping reactions. Acridines have been synthesized by capture of C,N-diarylimines with benzynes generated by classical methods (i.e., from ortho-elimination of precursor arene compounds), although in poor yields. We report here that these imines can be trapped by benzynes generated by the hexadehydro-Diels–Alder (HDDA) reaction in an efficient manner to produce 1,4-dihydroacridine products. These dihydroacridines were subsequently aromatized using MnO₂ to provide structurally complex acridines.

Full text of DOI:10.1002/ejoc.201901855

DOI: 10.1002/ejoc.201901855
Full Paper
Acridines
Reactions of HDDA Benzynes with C,N-Diarylimines (ArCH=NAr′)
Sahil Arora,[a][‡] Dorian S. Sneddon,[a][‡] and Thomas R. Hoye*[a]
Abstract: o-Benzynes can be utilized to construct heterocyclic trapped by benzynes generated by the hexadehydro-Diels–
motifs using various nucleophilic and cycloaddition trapping Alder (HDDA) reaction in an efficient manner to produce 1,4-
reactions. Acridines have been synthesized by capture of C,N- dihydroacridine products. These dihydroacridines were subse-
diarylimines with benzynes generated by classical methods (i.e., quently aromatized using MnO2 to provide structurally complex
from ortho-elimination of precursor arene compounds), al- acridines.
though in poor yields. We report here that these imines can be
Introduction
Yoshida and co-workers[4] demonstrated the ability to access
benzoxazinones 5b via trapping of the 1,3-zwitterion by carbon
dioxide using imines in which the carbon-bound group is an
alkyl moiety. In 2015 Hwu et al.[5] showed the diastereoselective
formation of imidazolidines 5a and other N-heterocycles via
trapping of the intermediate 1,3-dipole 3e, formed via intra-
molecular proton transfer within 3a. Finally, in 2017 researchers
in the Tian laboratory[6] showed that 3a may be trapped by
protic carbon nucleophiles in a three-component fashion to
form products of the type 5c.
In 2017 H. Yoshida and co-workers[7] showed that trapping
of the aza-ortho-quinone methide intermediate 3c to form 2:1
imine:benzyne adducts 4c was possible when benzyne was
used in molar excess. This mode of reactivity prevails when the
aryl moieties are more highly substituted, presumably slowing
the electrocyclization of 3c to 3d.
o-Benzynes and related arynes have been used as versatile in-
termediates for construction of various aromatic heterocycles.[1]
In a few instances, six-membered nitrogen-containing heterocy-
cles of the acridine family have been produced, at least to small
extents, by trapping of a classically generated aryne (i.e., one
formed by way of an ortho-elimination of a precursor aromatic
compound) by an imine. The previously observed reaction
pathways may be roughly placed into two categories: a) a net
[2+2] process by way of an initial, transient zwitterion
(Scheme 1a); b) initial [4+2] cycloaddition between the benzyne
(acting as a dienophile) and the N-aryl imine moiety (acting as
the diene) (Scheme 1b).
The initial reports of reactivity between o-benzynes and C,N-
diaryl imines came from the laboratories of M. Yoshida[2] (1975)
and Storr[3] (1984), which independently reported the reaction
of N-benzylideneaniline [2, R1 = R2 = Ph (= 2a)] with o-benzyne
(1) generated from benzenediazonium-2-carboxylate. In both
studies the dihydrophenanthridine 7a was isolated (8 % or 6 %
yield) and in the latter the dihydroacridine 4b (5 %) was also
obtained. These were rationalized as arising from competitive
[2+2]- vs. [4+2]-cycloaddition of o-benzyne with 2a via interme-
diates 3b (through 3d) or 6a and 6b, respectively. The major
isolated product in both of these original studies (18 % and
16 %, respectively) was the diamine 4a.
Finally, in addition to M. Yoshida and Storr's initial isolation
of phenanthridine adducts, other groups have sought to exploit
the [4+2] pathway to access this class of product more effi-
ciently. In 2006 Wang et al.[8] showed that benzyne could be
used in a 3-component process to access phenanthridines 7c
with high efficiency using an electron-poor benzaldehyde and
an electron-rich aniline. Similarly, in 2016 researchers in the He
group[9] were able to isolate 7b in a three-component process
using Kobayashi[10] arynes, an aldehyde ester, and an aniline.
In 2015 Coquerel and co-workers[11] reported the formation of
isoquinolines 7d derived from an imine containing a nitrogen-
bound pyrazole moiety, and, through a computational study,
suggested that an electron-rich aromatic group bound to the
imine nitrogen favors [4+2] cycloaddition over a [2+2] pathway.
More recently, additional modes of reactivity between o-ben-
zynes and imines have been studied. Some have focused on
trapping of the presumed 1,3-zwitterion 3a, which arises via
imine nitrogen attack on the electrophilic benzyne. In 2006 H.
To summarize, reported examples of benzynes reacting with
imines to give acridine-like products have shown low selectivity
and efficiency. Given the interest in acridine compounds more
broadly as well as the fact that hexadehydro-Diels–Alder
(HDDA)-derived benzynes[12] often lead to outcomes comple-
mentary to those from classical benzynes, we have explored
the reactions of several polyyne substrates with various imine
trapping agents and report the results of those studies here.
[a] Department of Chemistry, University of Minnesota
207 Pleasant St. SE, Minneapolis, MN 55455 USA
E-mail: hoye@umn.edu
http://www1.chem.umn.edu/groups/hoye/
[‡] equal contributors
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901855.
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Scheme 1. Previous studies of reactions of benzynes with imines in either (a) a net [2+2] pathway or (b) a [4+2] pathway.
Results and Discussion
We first examined (Scheme 2) the reaction between the HDDA
benzyne 9, generated by warming triyne 8, with N-benzylidene-
aniline (2a). This resulted in formation of the dihydroacridine
11 in a remarkably clean reaction, which contrasts significantly
with the lower efficiencies of previous reactions giving rise to
dihydroacridines (cf. Scheme 1a). Compound 11 was subse-
quently oxidized with MnO2 to afford the acridine derivative
12a in 68 % yield.
To demonstrate generality of this reaction with different
types of electronically modified aryl substituents in the imines,
we explored the reactions between benzyne 9 and imines 2b–
2g (Table 1). For each entry, only the acridine product that re-
sults from subsequent MnO2 oxidation of the intermediate di-
hydroacridine is shown (see Supporting Information for charac-
terization of the dihydro-intermediates SI-1–SI-6). The reaction
showed relatively broad tolerance of electronic perturbation of
the aryl substituent on both the carbon and nitrogen atoms
composing the imine. That is, imines 2b–g all provided the cor-
responding dihydroacridines and, then, the acridines 12b–g
(Table 1). Only in the instance of the most electron-poor imine
Scheme 2. Reaction of the HDDA-generated benzyne 9 proceeds nearly ex-
clusively to the 1,4-dihydroacridine 11, presumably via the [2+2]-benzazeti-
dine 10. Compound 11 was subsequently oxidized to acridine 12a.
2f, was the yield of the initial dihydroacridine low. This is con- acridine derivative 14 (Scheme 3). This suggests that additional
sistent with the view that the initial event in the engagement analogs with yet more extended conjugation can also be ac-
of benzyne with imine is nucleophilic attack by the nitrogen cessed.
atom to generate the zwitterion 3a (Scheme 1a).
Amidines are amino-substituted analogs of imines. N,N-Di-
As a final example, this with a different type of imine, the 1- methyl-N′-phenylamidine (15) efficiently engaged the benzyne
naphthyl derivative 13 gave the more highly annulated benzo- 9 (Scheme 4). It gave rise directly to the acridine derivative 17a,
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Table 1. Reactions of triyne 8 with several C,N-diaryl imines.
Scheme 4. Reaction of amidine 15 with aryne 9 generated from triyne 8.
yield along with the oxidized acridine 21a (19 %), presumably
from air oxidation. Reaction of 19b and 2a produced the ex-
pected indolinoquinoline 21b in 51 % yield over two steps. The
formation of a single benzyne (i.e., 22b; see dashed lines in
19b) from this unsymmetrical tetrayne precursor was first ob-
served[14] by Lee and co-workers (and on many subsequent oc-
casions) and is consistent with a computational study[15] that
addressed exactly that point. To summarize, the reactions of
both 19a/b with 2a proceeded via the corresponding benzaze-
tidine 23a/b and azo-quinonemethide species 24a/b en route
to the 1,4-dihydroacridines 20a/b.
[a] Yield of the 1,4-dihydroacridine from the HDDA reaction; b yield of the
acridine adduct following MnO2 treatment.
Scheme 3. Reaction of triyne 8 with imine 13. ayield of the 1,4-dihydroacri-
dine from the HDDA reaction. byield of the acridine adduct following MnO2
treatment.
which has no substituent at C9 of the acridine. However, this
reaction was accompanied by the formation of a similar amount
of the dimethylamine-trapped benzyne product 17b. Presuma-
bly the dihydroacridine 16, arising from a [2+2] pathway di-
rectly analogous to that depicted for 8 to 11 (Scheme 2), under-
went an elimination event under the reaction conditions to pro-
duce 17a. That process can be envisioned to proceed by a di-
rect (and possibly unimolecular) loss of dimethylamine, which,
once released, then competitively trapped benzyne 9 (red ar-
rows). Alternatively, a second copy of 9 could engage the terti-
ary aliphatic amine in intermediate 16 to give the 1,3-zwitter-
ion[13] 18 (shown in a truncated form for simplicity), which
could then collapse directly to one molecule each of 17a and
17b. Although of limited preparative value, this trapping reac-
tion with an amidine provides interesting mechanistic insights.
To establish that the reaction is not limited to benzyne 9, we
have trapped the HDDA benzynes derived from the precursor
tetraynes 19a and 19b with N-benzylideneaniline (2a)
(Scheme 5). The symmetrical tetrayne, which previously has
been shown to react with various nucleophiles to give a pair of
Scheme 5. Reactions of tetraynes 19a/b with imine 2a to give acridines
21a/b.
Conclusions
constitutional isomers with relatively little preference, produced In summary, these results establish that trapping of thermally
only the single regioisomeric isoindoline derivative 20a in 42 % generated, polycyclic benzyne derivatives with C,N-diaryl
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chloroethane was added (0.05
M
) and the resulting solution was
imines leads to dihydroacridine derivatives, which can be fur-
ther and readily oxidized to their acridine analogs. These reac-
tions proceed considerably more efficiently than those reported
earlier for imine trapping of benzyne itself (from benzenediazo-
nium-2-carboxylate thermolysis). In no case have we observed
products arising from initial [4+2] cycloaddition, as has been
seen in previous studies.[2,3,8,9,11] This work represents another
instance in which the arynes generated through the HDDA-cy-
cloisomerization reaction, which are produced in a purely ther-
mal environment, has allowed for the formation of the trapping
products in a much cleaner,[16] if not unique,[17] manner.
placed in an oil bath maintained at 90 °C and allowed to react
overnight. Subsequently, the solvent was removed under reduced
pressure, and the crude material was purified using MPLC with the
elution solvent mixture indicated for each compound.
B. General Procedure for Oxidation of 1,4-Dihydroacridines to
Their Respective Acridines: A scintillation vial or a culture tube
was charged with a stir bar and the respective 1,4-dihydroacridine
(1 equiv.). Chloroform or dichloromethane (0.005
M) was added,
along with MnO2 (ca. 10–20 equiv.). The resulting slurry was allowed
to stir at ambient temperature until the reaction was observed to be
complete by TLC analysis. The reaction mixture was filtered through
Celite® and the filtrate was concentrated in vacuo.
C. General Procedure for One-pot Synthesis of Acridines from
HDDA-Generated Benzynes and Imines: The HDDA polyyne pre-
cursor (1 equiv.) and the imine (1–3 equiv.) were added to a screw-
Experimental Section
General Experimental Protocols: 13C and 1H NMR spectra were
recorded on a Bruker HD-500, AV-500, AV-400, or AX-400 spectrom-
eter. Proton chemical shifts are referenced to TMS (δ = 0.00 ppm)
in CDCl3 solutions and to the residual CHD5 (δ = 7.16 ppm) in
[D6]benzene solutions. A non-first order multiplet, doublet, or dou-
blet of doublets in a 1H NMR spectrum is denoted as a “nfom”,
“nfod”, or “nfodd”, respectively. For the latter two, the coupling con-
stant is listed as an apparent value (Japp), because the spacing be-
tween the two major lines for the population of molecules having
magnetically equivalent protons (ca. 50 %) is actually the value of
Jo + Jp. Resonances are reported in the following format: chemical
shift (ppm) [multiplicity, coupling constant (s) (in Hz), integral value
(to the nearest integer), and assignment of the substructural envi-
ronment within the structure]. First-order coupling constants were
cap culture tube. 1,2-Dichloroethane was added (0.05
M), and the
resulting solution was placed in an oil bath maintained at 90 °C
and allowed to react overnight. MnO2 (ca. 10–20 equiv.) and a stir
bar were added. The slurry was then stirred at ambient temperature
until the reaction was observed to be complete by TLC. The reaction
mixture was filtered through Celite® and the filtrate was concen-
trated in vacuo.
10,11-Dimethoxy-6-methyl-13-phenyl-7-(trimethylsilyl)-5,13-di-
hydro-8H-indeno[1,2-a]acridin-8-one (11): Following general pro-
cedure A, 1-[4,5-dimethoxy-2-(penta-1,3-diyn-1-yl)phenyl]-3-(tri-
methylsilyl)prop-2-yn-1-one (8, 0.024 g, 0.074 mmol, 1 equiv.), (E)-
N,1-diphenylmethanimine (2a, 0.015 g, 0.083 mmol, 1.1 equiv.), and
dichloroethane (2 mL) were used to prepare the 1,4-dihydroacridine
11. Purification of the crude product by MPLC (2:1 hexanes/EtOAc)
yielded 11 (0.038 g, 0.076 mmol, 98 %) as an orange crystalline
solid. 1H NMR (500 MHz, CDCl3): δ = 7.45 (d, J = 7.8, 1.4 Hz, 1H, H1),
7.29 (nfod, Japp = 7.5 Hz, 2H, ArHo), 7.22 (nfodd, Japp = 7.7, 7.7 Hz,
2H, PhHm), 7.126 (ddd, J = 7.4, 7.4, 1.5 Hz, 1H, H3), 7.125 (tt, J = 7.4,
1.5 Hz, 1H, ArHp), 7.10 (s, 1H, H9), 7.09 (s, 1H, H12), 6.95 (dd, J = 7.4,
7.4, 1.1 Hz, 1H, H2), 6.81 (dd, J = 7.9, 1.3 Hz, 1H, H4), 6.48 (s, 1H,
NH), 5.77 (s, 1H, H13), 3.90 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 2.45 (s,
3H, ArCH3), and 0.46 (s, 9H, Si(CH3)3). 13C NMR (126 MHz, CDCl3):
193.6, 153.0, 149.0, 144.7, 143.1, 142.6, 141.2, 137.6, 137.5, 133.8,
129.1, 128.70, 128.67, 127.8, 127.1, 127.0, 125.3, 123.9, 122.3, 118.8,
115.2, 107.8, 106.7, 56.6, 56.2, 44.7, 18.2, and 3.2. HRMS (ESI-TOF):
analyzed using methods we have published elsewhere.[18,19]The 13
C
NMR chemical shifts are taken from the “1D” spectrum where possi-
ble, although some were deduced from HMBC correlations. Carbon
chemical shifts are referenced to δ = 77.16 ppm in CDCl3 solutions
and to δ = 128.06 for C6D6 solutions. Infrared spectra were recorded
using a Bruker Alpha II Spectrometer. Samples were prepared as
thin films on a diamond window in the attenuated total reflectance
(ATR) mode. Absorption maxima are given in cm–1. The high-resolu-
tion mass spectrometry (HRMS) measurements were made in the
ESI mode using a Thermo Orbitrap Velos instrument (mass accuracy
of ≤ 3 ppm). An external calibrant was used (PierceTM LTQ) and the
samples were directly injected into the ion source. Medium pressure
liquid chromatography (MPLC) was often used to purify newly syn-
thesized materials. Hand-packed silica gel columns (normal-phase,
25–200 psi, 20–40 μm, 60 Å pore size, Teledyne RediSep Rf Gold®)
were used. The apparatus consisted of a Waters HPLC pump (model
510), a Gilson (111 UV) detector, and a Waters (R401) differential
refractive index detector. Preparative flash chromatography was
performed on columns packed with Agela silica gel (230–
400 mesh). Thin layer chromatography (TLC) was performed on sil-
ica-gel coated, plastic-backed plates that were visualized by UV light
and/or by a solution of potassium permanganate and heating. The
indicated reaction temperature refers to the temperature of the ex-
ternal cooling or heating bath. HDDA reactions, including those
performed at temperatures higher than the boiling point of the
reaction solvent, were done in a screw-top culture tube that was
capped with an inert, Teflon®-lined closure. Polyyne substrates 8,[20]
19a,[21] and 19b[21] were synthesized according to reported meth-
ods. N-Benzylideneaniline (2a) was prepared according to a re-
ported procedure.[22]
Calcd for
C
32H32NO3Si+ [M + H+]+ requires 506.2146, found
506.2150. IR (neat): ν = 3440, 3390, 3059, 3001, 2924, 2853, 2359,
˜
2342, 2069, 2034, 1976, 1961, 1944, 1694, 1605, 1577, 1546, 1489,
1465, 1432, 1416, 1375, 1343, 1324, 1299, 1283, 1259, 1245, 1215,
1173, 1158, 1091, 1045, 1027, 991, 936, 873, 854, 797, 771, 751, 727,
699, 676, 645, 630, 613, 599, 575, 519, 493, 449, and 408 cm–1. mp:
249–250 °C.
10,11-Dimethoxy-6-methyl-13-phenyl-7-(trimethylsilyl)-8H-in-
deno[1,2-a]acridin-8-one (12a): Following general procedure C, 1-
[4,5-dimethoxy-2-(penta-1,3-diyn-1-yl)phenyl]-3-(trimethyl-
silyl)prop-2-yn-1-one (8, 0.010 g, 0.030 mmol, 1 equiv.), (E)-N,1-di-
phenylmethanimine (2a, 0.007 g, 0.038 mmol, 1.3 equiv.), MnO2
(excess), and dichloroethane (2 mL) were used to prepare acridine
12a. Purification of the crude product yielded acridine 12a (0.011 g,
1
0.022 mmol, 71 %) as a purple crystalline solid. H NMR (500 MHz,
CDCl3): δ = 8.26 (d, J = 8.6 Hz, 1H, H4), 8.14 (d, J = 8.9 Hz, 1H, H1),
7.78 (nfod, Japp = 7.2 Hz, 2H, PhHo), 7.77 (br dd, J = 8.8, 6.8 Hz, 1H,
H3), 7.56 (nfodd, Japp = 7.5, 7.5 Hz, 2H, PhHm), 7.53 (tt, J = 6.9, 1.7 Hz,
1H, PhHp), 7.48 (br dd, J = 8.6, 6.6 Hz, 1H, H2), 7.04 (s, 1H, H9), 5.64
(s, 1H, H12), 3.83 (s, 3H, C10OCH3), 3.51 (s, 3H, C11OCH3), 3.06 (s,
1H, ArCH3), and 0.51 (s, 9H, Si(CH3)3). 13C NMR (126 MHz, CDCl3):
A. General Procedure for Trapping of HDDA-Generated Arynes
with Imines: The polyyne precursor (1 equiv.) and the imine (1–
3 equiv.) were combined in a screw-capped culture tube. 1,2-Di-
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195.4, 153.0, 150.6, 149.0, 148.0, 146.9, 145.1, 143.0, 140.1, 138.6,
137.3, 136.1, 132.8, 130.9, 130.3, 129.5, 129.0, 126.7, 126.5, 125.2,
125.0, 120.8, 109.3, 106.5, 56.7, 56.1, 20.7, and 2.7. HRMS (ESI-TOF):
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˜
2041, 2023, 1984, 1758, 1709, 1595, 1579, 1498, 1463, 1442, 1418,
1405, 1376, 1336, 1285, 1250, 1224, 1180, 1144, 1109, 1059, 1026,
1012, 972, 896, 842, 816, 799, 764, 734, 702, 671, 642, 619, 604, 568,
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1
new compounds, and copies of H and 13C NMR spectra as well as
selected 2D NMR spectra.
Acknowledgments
The U.S. Department of Health and Human Services, National
Institutes of General Medical Sciences (R35 GM127097) sup-
ported this research. Some NMR spectroscopic data were ob-
tained using an instrument funded through the NIH Shared
Instrumentation Grant program (S10OD011952). Mass spec-
trometry was performed in the Analytical Biochemistry Shared
Resource of the Masonic Cancer Center at the University of
Minnesota, funded in part by a Cancer Center Support Grant
(CA-77598).
Keywords: HDDA-benzynes · Benzazetidines · Azoquinone
methides · Dihydroacridines · Acridines
[1] a) A. V. Dubrovskiy, N. A. Markina, R. C. Larock, Org. Biomol. Chem. 2013,
11, 191–218; b) D. Peña, D. Pérez, E. Guitián, Heterocycles 2007, 74, 89–
100.
Received: December 17, 2019
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Acridines
S. Arora, D. S. Sneddon,
T. R. Hoye* ............................................ 1–6
Reactions of HDDA Benzynes with
C,N-Diarylimines (ArCH=NAr′)
Benzynes generated by the hexadehy- undergo electrocyclic ring-opening
dro-Diels–Alder (HDDA) reaction are and -closing (and rearomatization) to
shown to capture C,N-diarylimines to give the dihydroacridines. These were
produce 1,4-dihydroacridine products. easily oxidized with MnO2 to provide
The reaction is thought to proceed via structurally complex acridines.
benzazetidine intermediates that then
DOI: 10.1002/ejoc.201901855
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
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