Scope and Optimization of the Double Knorr Cyclization: Synthesis of Novel Symmetrical and Unsymmetrical Tricyclic 1,8-Diazaanthraquinones

Article abstract of DOI:10.1055/s-0036-1589134

The Knorr cyclization of β-ketoanilides to form 2-quinolones in the presence of acid is well documented chemistry. Double Knorr cyclization is rare, with very few examples appearing in the literature to date. The double Knorr methodology can provide access to tricyclic 1,8-diazaanthraquinones, a scaffold seen in the diazaquinomycin family. The optimized synthesis of diazaquinomycin A and structural analogues thereof via double Knorr cyclization of di-β-ketoanilide precursor substrates is reported. The scope and generality of the double Knorr cyclization were investigated along with an optimization study. The double Knorr cyclization was found to be sensitive to steric bulk on precursor substrates. In addition, the presence of a 5-hydroxy group on the 1,3-di-β-ketoanilide facilitated the double Knorr cyclization, possibly due to its stabilizing effect on the carbocation intermediates formed during the reaction.

Full text of DOI:10.1055/s-0036-1589134

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–M
paper
A
en
A. M. Prior, D. Sun
Paper
Synthesis
Scope and Optimization of the Double Knorr Cyclization:
Synthesis of Novel Symmetrical and Unsymmetrical Tricyclic
1,8-Diazaanthraquinones
Allan M. Prior
Dianqing Sun*
assess alternative cores
in the double Knorr reaction
OH
optimize
reaction
conditions
R2
O
R4
Department of Pharmaceutical Sciences, The Daniel K.
Inouye College of Pharmacy, University of Hawaii at Hilo,
34 Rainbow Drive, Hilo, Hawaii 96720, USA
dianqing@hawaii.edu
10 examples
R1
O
R3
O
O
O
O
O
up to 96% isolated yield
R1, R3 = H, Me, Et
R2, R4 = Me, Pr
R2
N
N
R4
H
H
N
H
N
H
R1
OH
R3
O
explore other b-keto side
chain substitution
diazaquinomycins
(symmetrical & unsymmetrical)
Received: 13.09.2017
Accepted after revision: 19.10.2017
Published online: 20.11.2017
against common drug-resistant strains of M. tuberculosis
with MIC values in the range of 0.06–0.27 μg/mL.4
DOI: 10.1055/s-0036-1589134; Art ID: ss-2017-m0594-op
n
O
Abstract The Knorr cyclization of β-ketoanilides to form 2-quinolones
in the presence of acid is well documented chemistry. Double Knorr cy-
clization is rare, with very few examples appearing in the literature to
date. The double Knorr methodology can provide access to tricyclic 1,8-
diazaanthraquinones, a scaffold seen in the diazaquinomycin family.
The optimized synthesis of diazaquinomycin A and structural analogues
thereof via double Knorr cyclization of di-β-ketoanilide precursor sub-
strates is reported. The scope and generality of the double Knorr cy-
clization were investigated along with an optimization study. The dou-
ble Knorr cyclization was found to be sensitive to steric bulk on
precursor substrates. In addition, the presence of a 5-hydroxy group on
the 1,3-di-β-ketoanilide facilitated the double Knorr cyclization, possi-
bly due to its stabilizing effect on the carbocation intermediates formed
during the reaction.
O
5
4
6
3
10
9
O
N
N
O
O
8 N
N 1
O
H
H
H
H
O
O
diazaquinomycin H (n = 5), MIC = 0.04 µg/mL
diazaquinomycin J (n = 6), MIC = 0.07 µg/mL
M. tuberculosis (H37Rv)
diazaquinomycin A
MIC = 0.10 µg/mL
Figure 1 Diazaquinomycins A, H, and J show excellent anti-TB activity
The remarkable anti-TB activities reported for di-
azaquinomycins A, H, and J along with low cytotoxicity pro-
file prompted us to establish a robust and modular synthet-
ic route that will be used to efficiently construct a com-
pound library of symmetrical and unsymmetrical
diazaquinomycin analogues. The synthetic route should al-
low for structural variations on the 3, 4, 5, and 6 positions
of the diazaquinomycin scaffold, facilitating future struc-
ture-activity relationship (SAR) studies. Although synthetic
routes to access analogous compounds are known,5–9 we
became particularly interested in exploring and expanding
upon an uncommon route that utilizes a double Knorr cy-
clization as the key ring forming step, pioneered by Kelly et
al.5 Knorr cyclization to form 2-quinolones from β-ketoani-
lides in the presence of acid is well documented chemistry;
however, double Knorr cyclization remains underexplored.
To the best of our knowledge, only one example of a suc-
cessful double Knorr cyclization has appeared in the litera-
ture to date and is shown in Scheme 1.5
Key words diazaquinomycin A, double Knorr methodology, cycliza-
tion, di-β-ketoanilide, 1,8-diazaanthraquinone
In 2015, the World Health Organization reported more
than 10 million new cases of tuberculosis (TB) and approxi-
mately 1.8 million deaths worldwide, predominantly in de-
veloping countries.1 Tuberculosis is a bacterial infection
caused by Mycobacterium tuberculosis (M. tuberculosis) and
is spread from person to person through the air.1 The occur-
rence of cases of multidrug-resistant tuberculosis (MDR-TB)
and extensively drug-resistant TB (XDR-TB) is of growing
concern, highlighting the importance and clinical need for
continued anti-TB drug discovery efforts.2,3
A recent report showed diazaquinomycins A, H, and J
(Figure 1) to be potent and selective antibacterial agents
against M. tuberculosis (MIC range 0.04–0.10 μg/mL) and
exhibited no cell cytotoxicity against Vero cells (ATCC CRL-
1586) at 28 μM, the highest concentration tested.4 Striking-
ly, diazaquinomycin A retained excellent anti-TB activity
In this example, the symmetrical di-β-ketoanilide 1d
having a 2,5-dihydroquinone core underwent double Knorr
cyclization in hot sulfuric acid, open to air, providing di-
azaquinomycin A (2d) in excellent yield.5 Notably, this ele-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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A. M. Prior, D. Sun
Paper
Synthesis
OH
5
O
O
O
O
O
O
H2SO4, air
N
1
N
2
110 °C, 95%
H
H
O
N
N
O
OH
H
H
1d
diazaquinomycin A (2d)
Scheme 1 Double Knorr cyclization to form diazaquinomycin A5
gant chemistry has not yet been successfully expanded
upon to access structural derivatives of diazaquinomycin A.
Also as mentioned by Kelly et al., an attempted double
Knorr cyclization of a variant of substrate 1d was reported
in 1973; however, this reaction failed despite trying various
reaction conditions.10
More recently, preliminary studies in published Ph.D.
theses suggested that the double Knorr methodology
reported by Kelly et al. could not be extended to other
substrates.11,12 Despite these unsuccessful reports, we
remained optimistic that double Knorr cyclization method-
ology can be used to access other diazaquinomycin deriva-
tives.
In this work, we expand the double Knorr methodology
to construct symmetrical and unsymmetrical analogues of
diazaquinomycin A. We also probe the double Knorr reac-
tion to gauge its tolerance to changes in steric bulk in the
di-β-ketoanilide side chains, optimize the reaction condi-
tions, and investigate what impact alternative cores (other
cations. Commercially available 1,4-diacetoxybenzene (3)
was nitrated using 70% nitric acid to provide the dinitro de-
rivative 4 in 42% yield.13 The acetyl group was removed by
refluxing 4 in methanol and hydrochloric acid to give the
phenol 5 in quantitative yield.14 The phenolic groups of 5
were protected using chloromethylmethyl ether (MOM-Cl)
and diisopropylethylamine (DIPEA) in tetrahydrofuran, af-
fording pure di-O-MOM protected product 6 in quantitative
yield.5 Compound 6 was found to gradually decompose (loss
of a MOM group) in methanol (as seen by HPLC monitoring)
but was stable in ethyl acetate (see Table S1 in Supporting
Information). The reduction of the nitro groups in 6 was
therefore performed using palladium/carbon and hydrogen
in ethyl acetate. This provided diamine 7 in quantitative
yield after filtration of the reaction mixture through Celite
and evaporation of the filtrate. The symmetrical di-β-ke-
toanilides 9a–i were obtained in good to excellent yields by
heating diamine 7 in excess β-keto ester 8a–i followed by
flash column chromatography.5 A literature O-MOM depro-
tection procedure [1 M HCl/THF/acetone (1:1:1) at 65 °C]5
was employed to deprotect our series of di-β-ketoanilides
9a–i and provide the corresponding di-β-ketoanilide hydro-
quinones 1a–i in good to excellent yields.
than 2,5-hydroquinone) have on the double Knorr cyclization
.
To start, a series of symmetrical di-β-ketoanilides 1a–i
having a 2,5-dihydroquinone core were synthesized accord-
ing to Scheme 2 by following the Kelly route5 with modifi-
OMOM
OAc
OH
OAc
i
ii
iii
O2N
NO2
O2N
NO2
42%
quant.
quant.
O2N
NO2
OMOM
OAc
OH
OH
3
4
5
6
R2
O
O
OR
R2
OMOM
R1
R1
R2
OR
v,
O
O
R1
iv
quant.
O
N
H
N
H
O
8a R = Me, R1 = H, R2 = Me
H2N
NH2
8b R = Me, R1 = H, R2 = n-Pr
8c R = Et, R1 = Me, R2 = Me
8d R = Me, R1 = Me, R2 = n-Pr
8e R = Et, R1 = Et, R2 = Me
8f R = Et, R1 = H, R2 = i-Pr
8g R = Et, R1 = i-Pr, R2 = Me
8h R = Et, R1 = H, R2 = c-Pr
8i R = Et, R1 = CH2Ph, R2 = Me
OR
vi
OMOM
1a–i
(R = H)
9a–i
(R = MOM)
7
44–quant.
Scheme 2 Synthesis of symmetrical di-β-ketoanilides 1a–i. Reagents and conditions: (i) 70% HNO3, 20 °C, 2 h; (ii) HCl/MeOH, reflux, 2 h; (iii) MOM-Cl,
DIPEA, THF, 25 °C, 18 h; (iv) 10% Pd/C, 1.4 bar H2, EtOAc, 45 °C, 18 h; (v) neat, 130–200 °C, 1–5 h, 39–74% yield; (vi) 1 M HCl/THF/acetone (v/v/v, 1:1:1),
65 °C, 1 h.
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A. M. Prior, D. Sun
Paper
Synthesis
The symmetrical di-MOM protected di-β-ketoanilides
9c–e, g, and i were predicted to form as a mixture of stereo-
isomers since the corresponding β-keto esters used (8c–e,
g, and i) were racemic. As expected, two enantiomers (R,R
and S,S) and one meso compound (R,S = S,R) were formed in
each case with a stereoisomeric ratio of 1:1:2, respectively.
1
This was confirmed using H NMR spectroscopy and chiral
HPLC. In all these cases, the diastereotopic methylene pro-
tons of the O-MOM protecting group appeared as two dou-
blets for the enantiomeric pair and a singlet for the meso
1
isomer in their H NMR spectra when CDCl3 was used as a
1
solvent. Interestingly, when the H NMR spectrum was re-
corded in DMSO-d6, the signals associated with these meth-
ylene protons coalesced into one singlet.
As noted previously,15 this observed signal coalescence
in DMSO-d6 is most likely caused by solvent dependent ef-
fect, in which DMSO-d6 is involved in the interconversion
process of these diastereotopic methylene protons. Taking
9d (Figure 2, A) as an example, its 1H NMR spectra (recorded
in CDCl3 and DMSO-d6) and chiral HPLC chromatogram are
shown in Figure 2 (B and C), respectively. In CDCl3 the dia-
stereotopic methylene protons resonate as two doublets at
4.94 and 5.09 ppm (enantiomeric pair) as well as a singlet
at 5.02 ppm (meso form), however, in DMSO-d6 the same
methylene protons appear as one singlet (4.91 ppm). A dis-
1
crepancy was found when comparing our H NMR data for
9d with published data for the same compound.5 Specifical-
ly, the literature 1H NMR data for 9d (recorded in CDCl3) did
not report the singlet that we observed at 5.02 ppm. To clar-
ify this discrepancy, we contacted and consulted with Prof.
T. Ross Kelly who suggested that one of the diastereomeric
forms (meso) might have been lost during their column pu-
rification and/or recrystallization process (personal com-
munication).
It is known that Knorr cyclization generally requires
heating in the presence of strong acids.16,17 The first and
only report of a successful double Knorr cyclization was
carried out at 110 °C in concentrated sulfuric acid.5 The
symmetrical di-β-ketoanilide 2,5-hydroquinone substrates
1a–i were therefore subjected to these reported cyclization
conditions (110 °C in sulfuric acid) to gauge their suitability
as double Knorr substrates. In each case the reaction prog-
ress was monitored by HPLC and the results are shown in
Table 1.
The double Knorr cyclization of unhindered substrates
1a–e proceeded smoothly to give 1,8-diazaanthraquinones
2a–e in good to excellent yields (Table 1, entries 1–5). Isola-
tion of pure 1,8-diazaanthraquinones 2a–e was achieved by
precipitation in ice-water followed by centrifugation, re-
moval of supernatant, and washing the solids with addi-
tional cold water until the pH of supernatant became neu-
tral. This method proved easier than filtration procedure
because in our hands the 1,8-diazaanthraquinones formed
fine suspensions in water that easily passed through the fil-
Figure 2 A: Structure of 9d highlighting diastereotopic methylene pro-
tons of interest; B: Magnified regions of 1H NMR spectra (recorded at
400 MHz) of 9d in CDCl3 and DMSO-d6, respectively; C: Chiral HPLC
chromatogram of 9d, showing the meso form (50%) and two enantio-
mers (25% each). Chiral HPLC was performed using an analytical HPLC
(Shimadzu LC-20A series) equipped with a Lux 5 μm Amylose-1 column
(150 mm × 4.6 mm, Phenomenex) and flow rate of 1 mL/min. Mobile
phase conditions: hexane/EtOH/TFA (65:35:0.1, v/v/v) (isocratic elu-
tion), UV detection at 254 nm and 220 nm.
ter paper during filtration. Overall, the sterically hindered
di-β-ketoanilides 1f–i were found to be poor substrates for
the double Knorr cyclization (entries 6–9). When α-carbon-
yl substitution on the β-ketoanilide side chain is changed to
bulkier isopropyl (i-Pr), cyclopropyl (c-Pr), or benzyl
groups, the double Knorr cyclization pathway is not favor-
able. Instead, a complex mixture of products formed, with
single Knorr cyclization and acid-mediated amide hydroly-
sis reaction pathways dominating, an observation that is
consistent with literature reports.5,10
Next, to further explore the scope of the double Knorr
methodology and potentially improve the cyclization of ste-
rically hindered di-β-ketoanilides, an optimization study
was performed by varying the solvent/reagent and tem-
perature. The results are shown in Table 2. At 110 °C, the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

D
A. M. Prior, D. Sun
Paper
Synthesis
double Knorr cyclization was complete after 1 minute in
sulfuric or triflic acid (Table 2, entries 1 and 5). Traces of
unidentified by-products were formed at 110 °C resulting
in an 88% and 82% yield of 2d, respectively. It was found that
lowering the temperature to 50 °C resulted in less by-prod-
uct formation, allowing for higher yields for 2d in both sul-
furic acid (94%) and triflic acid (>99%) (entries 2 and 6). In-
terestingly, the double Knorr cyclization occurred smoothly
even at ambient temperature (25 °C), giving quantitative
conversions of 1d into 2d (entries 4 and 7). At room tem-
perature, the double Knorr cyclization proceeded faster in
triflic acid and was complete after 50 minutes compared to
4 hours in sulfuric acid (Table 2, entry 4 vs entry 7). Our ob-
servation that triflic acid was a superior solvent for Knorr
cyclization is in agreement with literature findings.16
Table 1 Symmetrical Double Knorr Cyclization of 1a–i to 2a–i
R2
OH
R2
R2
O
R2
R1
R1
R1
O
R1
O
H2SO4
O
O
110 °C, 30 min
O
N
H
N
H
O
N
H
N
H
OH
O
A thermally induced double Knorr cyclization was also
attempted using diphenyl ether as solvent. At 110 °C, no re-
action took place with only starting material recovered, as
seen by HPLC analysis on the reaction mixture (Table 2, en-
try 8). When the temperature was raised to 210 °C, the
starting material was consumed within 30 minutes and the
double Knorr product 2d was formed in 26% yield along
with a single Knorr cyclized, but side chain hydrolyzed, by-
product (74%). Attempts were made to cyclize the sterically
hindered substrate 1g into 2g using milder conditions such
as triflic acid at 25 or 50 °C. In both cases, HPLC reaction
monitoring showed that starting material 1g was rapidly
consumed; however, double cyclized product 2g could not
be obtained in the reaction mixture comprised of predomi-
nantly hydrolyzed and monocyclized by-products. More-
over, decreasing the reaction concentration by 50-fold in an
effort to favor an intramolecular cyclization process did not
improve the reaction outcome.
1a–i
2a–i
Entry
Product
R1
R2
Yield
(%)a
Retention time
(min)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
H
H
Me
69 (67)
5.32
6.23
5.78
6.77
6.25
6.17
6.86
–
n-Pr
Me
86 (70)
92 (75)
88 (74)
81 (61)
13
Me
Me
Et
n-Pr
Me
H
i-Pr
Me
2g
2h
2i
i-Pr
H
7
c-Pr
Me
0
CH2Ph
0
–
a Yield observed by HPLC (254 nm), numbers in parentheses indicate isolat-
ed yield.
To expand the scope of the double Knorr substrates, we
envisioned that this methodology can be extended to access
unsymmetrical 1,8-diazaanthraquinones by simply em-
ploying unsymmetrical di-β-ketoanilide 2,5-hydroquinone
substrates in the double Knorr reaction. To validate this, un-
symmetrical substrates 1j,k were synthesized according to
Scheme 3. The mono-β-ketoanilide 7a was obtained by cou-
pling 7 with 2-methyl-3-oxohexanoic acid (0.7 equiv) using
EDC in 25% yield after flash chromatography to remove re-
maining diamine 7 and traces of di-β-ketoanilide 9d. The
unsymmetrical di-β-ketoanilides 9j,k were obtained using
EDC coupling with corresponding β-keto acids 8j or 8k in
86% and 78% yield, respectively. Removal of MOM protect-
ing groups using 1 M HCl/THF/acetone (1:1:1, v/v/v) at
65 °C furnished 1j,k in moderate to good yields. As expect-
ed, the unsymmetrical di-β-ketoanilide hydroquinones 1j,k
were smoothly converted into 1,8-diazaanthraquinones
2j,k in excellent yields using the optimized double Knorr
cyclization conditions (Table 3, entries 1 and 2).
Table 2 Survey of Double Knorr Cyclization Reaction Conditions (1d to
2d)
OH
O
O
O
O
N
N
O
O
N
N
H
O
H
H
H
OH
O
1d
2d
Entry
Solvent/reagent
Temp
(°C)
Time
(min)
Yield
(%)a
1
2
3
4
5
6
7
8
9
H2SO4
H2SO4
H2SO4
H2SO4
TfOH
TfOH
TfOH
Ph2O
110
50
1
25
50
240
1
88
94
25
73
25
>99
82
110
50
25
50
30
30
>99 (95)
>99
NRb
26
Lastly, we investigated what impact the central core
structure had on the double Knorr cyclization. Specifically,
we wanted to probe the importance of the 2- and 5-hy-
droxy groups. The monohydroxy di-β-ketoanilides 10 and
11 were synthesized (Schemes S1 and S2; Supporting
25
110
210
Ph2O
a Yield observed by HPLC (254 nm), number in parentheses indicates isolat-
ed yield.
b NR: No reaction.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

E
A. M. Prior, D. Sun
Paper
Synthesis
cyclization. Although starting material 11 was consumed
during the reaction, a complex final reaction mixture re-
sulted, which contained mostly hydrolyzed by-product 11a
(59%) along with monocyclized and hydrolyzed by-product
11b (15%). These results were intriguing and highlighted
the importance of the 5-hydroxy group on the 1,3-di-β-ke-
toanilide substrates in the double Knorr reaction. We be-
lieve that the meta positioning of the 5-hydroxy moiety rel-
ative to the 1,3-anilide groups in 1d and 10 contributes to
the stabilization (via resonance) of carbocation intermedi-
ates formed during this transformation, allowing the dou-
ble Knorr cyclization to take place. A simplified mechanism
that starts from two possible proposed monocyclized inter-
mediates 17 and 18 is illustrated in Scheme 5. If the reac-
tion proceeds from 17, the lack of substitutions on both C-6
and C-8 positions accounts for the formation of linear re-
gioisomer 10a (path in green) and angular isomer 10b (path
OMOM
OMOM
O
O
ii,
HO
O
i
R1
H2N
NH2
OMOM
H2N
N
O
H
8j, R1 = H
8k, R1 = Me
OMOM
7
7a
OMOM
OH
R1
R1
O
O
iii
O
O
O
N
H
N
O
O
N
H
N
O
H
H
OH
1j,k
OMOM
9j,k
Scheme 3 Synthesis of unsymmetrical di-β-ketoanilides 1j,k. Reagents
and conditions: (i) 2-methyl-3-oxohexanoic acid, EDC·HCl, DMAP, CH2Cl2,
r.t., 30 min, 25%; (ii) 8j or 8k, EDC·HCl, DMAP, CH2Cl2, r.t., 30 min, 9j
(86%) or 9k (78%); (iii) 1 M HCl/THF/acetone (1:1:1, v/v/v), 65 °C, 1 h; 1j
(78%) or 1k (57%).
Table 3 Unsymmetrical Double Knorr Cyclization of 1j,k to 2j,k
Information) and tested as double Knorr cyclization sub-
strates (Scheme 4).
OH
O
R1
R1
O
TfOH
Interestingly, 10 having a 5-hydroxy group successfully
cyclized to form two inseparable regioisomeric tricyclic
double Knorr products in triflic acid (25 °C) in 83% com-
bined yield. The linear isomer 10a and angular isomer 10b
were formed in 2:3 ratio, respectively, and their structures
O
O
50 °C, 25 min
O
N
H
N
H
O
N
N
O
H
H
OH
1j,k
O
2j,k
1
were validated using H NMR and HRMS (see Supporting
Entry
Product
R1
Yield (%)a
Retention time (min)
Information). In sulfuric acid (110 °C), 10a and 10b were
1
2
2j
H
96
94
6.06
6.28
formed in a 91% combined yield but in a 1:4 ratio, respec-
2k
Me
1
tively, based on H NMR analysis. Surprisingly, 11 having a
a Isolated yield.
2-hydroxy group (Scheme 4) did not undergo double Knorr
OH
5
O
O
O
O
O
TfOH
N
N
1
2
O
N
H
O
N
O
H
H
50 °C
H
OH
1d
2d (95%)
OH
OH
5
OH
O
O
O
O
HN
N
H
O
TfOH
25 °C
+
N
N
O
H
H
O
N
N
O
H
H
10
10a (33%)
10b (50%)
O
O
O
O
TfOH
50 °C
H2N
NH2
+
N
N
O
N
NH2
2
H
H
H
OH
OH
OH
11b (15%)
11a (59%)
11
Scheme 4 Assessment of di-β-ketoanilides 10 and 11 in the double Knorr reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

F
A. M. Prior, D. Sun
Paper
Synthesis
in red, Scheme 5), respectively. However, if the reaction
proceeds from 18, only the angular isomer 10b can be
formed. Our proposed mechanisms also offer a potential
explanation why 10b was the major product and 10a was
minor under our examined reaction conditions.
timization study and it was found that the double Knorr cy-
clization is sensitive to increased steric bulk on precursor
substrates. The unhindered di-β-ketoanilides 1a–e success-
fully cyclized to give 1,8-diazaanthraquinones 2a–e in ex-
cellent yields. In addition, the unsymmetrical di-β-ketoani-
lides 1j,k similarly cyclized to provide unsymmetrical 1,8-
diazaanthraquinones 2j,k in excellent isolated yields. An
optimization study using 1d as a model substrate showed
that the double Knorr cyclization can occur smoothly in tri-
flic acid at 50 °C to give 2d in excellent isolated yield (95%)
after 25 minutes. Moreover, the double Knorr reaction pro-
ceeded faster in triflic acid compared to sulfuric acid. An as-
sessment of alternative cores validated the importance of
the 5-hydroxy group that resides meta to the 1,3-β-ketoani-
lide groups. The di-β-ketoanilides 1d and 10 both have a 5-
hydroxy moiety and were the only cores in our substrate li-
brary to undergo double Knorr cyclization in sulfuric or tri-
flic acid. It is also hypothesized that the 5-hydroxy group of
1,3-β-ketoanilides plays a stabilizing role in carbocation in-
termediates, enabling double Knorr cyclization reaction.
Synthesis and antituberculosis evaluation of unsymmetri-
cal diazaquinomycins H and J as well as an expanded series
of diazaquinomycin derivatives are ongoing, and will be re-
ported in due course.
Additional di-β-ketoanilides 12–16 (Figure 3) were also
synthesized according to Schemes S3–S7 (see Supporting
Information) and similarly screened as double Knorr cy-
clization substrates. Unfortunately, none of these di-β-ke-
toanilides underwent double Knorr cyclization despite try-
ing a variety of reaction conditions. Instead, complex mix-
tures containing predominantly hydrolysis and single
Knorr-cyclized products were formed (vide supra). It
should be noted, in the case of 16, our finding also support-
ed previous experimental data by Kelly et al., demonstrat-
ing the double Knorr cyclization occurred first, followed by
oxidation from tricyclic 9,10-dihydroquinone to 9,10-qui-
none.5
In summary, we have demonstrated that the double
Knorr cyclization of di-β-ketoanilide hydroquinones was an
efficient synthetic route to access symmetrical and unsym-
metrical tricyclic 1,8-diazaanthraquinone analogues of the
diazaquinomycin family. The scope and generality of the
double Knorr cyclization was investigated along with an op-
OH
OH
HO
HO
OH
linear isomer
path
O
N
N
H
O
O
N
N
H
O
O
N
N
O
H
H
H
H
OH
5
O
OH
O
OH
10a
H
6
O
+
– H+
O
N
N
O
H
1
H
H
8
OH
7
OH
OH
O
– H2O
HO
HO
H
17
6
angular isomer
path
O
1
HN
N
O
HN
N
O
O
N
N
H
O
O
N
N
H
O
H
H
H
– H+
H
O
O
O
OH
O
OH
– H2O
18
10b
Scheme 5 Proposed mechanism and resonance structures of carbocation intermediates accounting for the stabilizing role of the 5-hydroxy group of
1,3-di-β-ketoanilide in double Knorr cyclization
O
OH
H
H
N
N
R
R
R
R
R
R
R
R
R
R
N
N
N
N
N
N
N
N
H
H
H
H
H
H
H
H
O
OH
OH
16
12
15
13
14
O
O
R =
Figure 3 Di-β-ketoanilide cores failed to undergo double Knorr cyclization
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

G
A. M. Prior, D. Sun
Paper
Synthesis
N,N′-(2,5-Dihydroxy-1,3-phenylene)bis(2-methyl-3-oxobutan-
amide) (1c)
Solvents and reagents were purchased from Sigma-Aldrich, Acros, or
Fisher Scientific, and used without further purification. Reactions
were monitored either by TLC or by analytical HPLC employing a
Shimadzu LC-20A series high-performance liquid chromatography
(HPLC) system. 1H and 13C NMR spectra were recorded on a Bruker
Avance III HD-400 (ultrashield) spectrometer (400 MHz and 100 MHz,
respectively). All chemical shifts are given as δ value (ppm) and cou-
pling constants, J, are reported in hertz (Hz). NMR solvent peaks were
referenced as follows: (1H NMR) CDCl3: 7.27 ppm, DMSO-d6: 2.50
ppm; (13C NMR) CDCl3: 77.23 ppm, DMSO-d6: 39.51 ppm. High-reso-
lution mass spectroscopy data was obtained using an Agilent 6530 Q-
TOF LC/MS. Low-resolution mass spectroscopy data was obtained us-
ing an Agilent 6120 single quad MS using direct injection. H2 for hy-
drogenation reactions was generated on site using a domnick hunter
NITROX UHP-60H hydrogen generator, USA. Melting points were de-
termined in open capillary tube using a Büchi B-540 melting point
apparatus. Compounds were purified by flash chromatography on sil-
ica gel using a Biotage Isolera One system. The purity of compounds
was determined by analytical HPLC (Shimadzu LC-20A series) using a
Gemini, 3 μm, C18, 110 Å column (50 mm × 4.6 mm, Phenomenex)
and flow rate of 1 mL/min. Gradient conditions: solvent A (0.1% TFA in
H2O) and solvent B (MeCN): 0–2.0 min 100% A, 2.0–7.0 min 0–100% B
(linear gradient), 7.0–8.0 min 100% B, UV detection at 254 nm and
220 nm.
Yield: 36 mg (61%) (0.18 mmol scale); sticky light brown solid as a
mixture of enantiomers (R,R and S,S) and meso form (S,R = R,S) after
flash column chromatography (hexane/EtOAc 9:1 to 1:1, v/v); mp
122–124 °C (dec.); Rf = 0.11 (hexane/EtOAc, 1:1).
HPLC purity: 99.5% (254 nm), 98.9% (220 nm); tR = 5.48 min.
1H NMR (400 MHz, CDCl3): δ = 9.12 (br s, 2 H), 8.70 (br s, 1 H), 7.08 (s,
2 H), 3.64 (q, J = 7.21 Hz, 2 H), 2.29 (s, 6 H), 1.48 (d, J = 7.21 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 207.3, 170.0, 150.2, 132.2, 127.4,
105.6, 54.9, 29.0, 15.2.
HRMS (ESI): m/z [M + H]+ calcd for C16H21N2O6+: 337.1394; found:
337.1398; m/z [M + Na]+ calcd for C16H20N2O6Na+: 359.1214; found:
359.1214.
N,N′-(2,5-Dihydroxy-1,3-phenylene)bis(2-methyl-3-oxohexan-
amide) (1d)
Yield: 209 mg (85%) (0.53 mmol scale); viscous light brown oil as a
mixture of enantiomers (R,R and S,S) and meso form (S,R = R,S) after
flash column chromatography (hexane/EtOAc 9:1 to 1:1, v/v); Rf =
0.24 (hexane/EtOAc, 1:1).
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.44 min.
1H NMR (400 MHz, CDCl3): δ = 9.21 (s, 2 H), 9.20 (s, 2 H), 8.78 (br s, 2 H),
7.19 (s, 4 H), 3.64 (q, J = 7.31 Hz, 4 H), 2.60 (t, J = 7.14 Hz, 8 H), 1.58–
1.70 (m, 8 H), 1.52 (d, J = 7.09 Hz, 12 H), 0.92 (t, J = 7.35 Hz, 12 H).
Removal of MOM Protecting Groups; N,N′-(2,5-Dihydroxy-1,3-
phenylene)bis(3-oxobutanamide) (1a); Typical Procedure
13C NMR (100 MHz, CDCl3): δ = 209.98, 209.96, 169.9, 150.5, 131.9,
127.5, 105.2, 54.2, 44.0, 17.0, 16.20, 16.16, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O6+: 393.2020; found:
393.2014; m/z [M + Na]+ calcd for C20H28N2O6Na+: 415.1840; found:
415.1835.
Compound 9a (115 mg, 0.29 mmol) was dissolved in 1 M HCl/THF/ac-
etone (1:1:1, 40 mL) and stirred at 65 °C for 1 h. Once the reaction
was complete (seen by TLC analysis), the reaction was diluted with
EtOAc (200 mL) and washed with H2O (2 × 100 mL). The organic layer
was dried (anhyd Na2SO4), filtered, and concentrated to give 1a (89
mg, 0.29 mmol, quant.) as a light brown solid that was used directly
without further purification; mp 174–176 °C; Rf = 0.31 (hexane/EtOAc,
1:4).
N,N′-(2,5-Dihydroxy-1,3-phenylene)bis(2-ethyl-3-oxobutan-
amide) (1e)
HPLC purity: 92.4% (254 nm), 95.7% (220 nm); tR = 4.99 min.
1H NMR (400 MHz, DMSO-d6): δ = 9.77 (s, 2 H), 9.01 (s, 1 H), 8.73 (s, 1
H), 6.99 (s, 2 H), 3.67 (s, 4 H), 2.19 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 203.1, 166.0, 149.9, 131.1, 127.9,
Yield: 70 mg (62%) (0.19 mmol scale); viscous light brown oil as a
mixture of enantiomers (R,R and S,S) and meso form (S,R = R,S) after
flash column chromatography (hexane/EtOAc 9:1 to 1:1, v/v); Rf =
0.19 (hexane/EtOAc, 1:1).
104.8, 51.5, 30.2.
HPLC purity: 99.6% (254 nm), 98.0% (220 nm); tR = 5.93 min.
HRMS (ESI): m/z [M + H]+ calcd for C14H17N2O6+: 309.1081; found:
309.1074; m/z [M + Na]+ calcd for C14H16N2O6Na+: 331.0901; found:
331.0890.
1H NMR (400 MHz, CDCl3): δ = 9.25 (s, 2 H), 8.72 (br s, 1 H), 8.28 (br s,
1 H), 7.21 (s, 2 H), 3.55 (t, J = 7.09 Hz, 2 H), 2.33 (s, 6 H), 1.91–2.12 (m,
4 H), 1.00 (t, J = 7.58 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 207.60, 207.58, 168.9, 150.6, 131.9,
127.5, 105.3, 62.2, 30.2, 25.0, 24.9, 11.8.
N,N′-(2,5-Dihydroxy-1,3-phenylene)bis(3-oxohexanamide) (1b)
Yield: 45 mg (82%) (0.12 mmol scale); viscous light brown oil after
flash column chromatography (hexane/EtOAc 9:1 to 1:1, v/v); Rf =
0.19 (hexane/EtOAc, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O6+: 365.1707; found:
365.1711; m/z [M + Na]+ calcd for C18H24N2O6Na+: 387.1527; found:
387.1529.
HPLC purity: 97.2% (254 nm), 97.2% (220 nm); tR = 6.08 min.
1H NMR (400 MHz, DMSO-d6): δ = 9.78 (s, 2 H), 9.01 (br s, 1 H), 8.74 (s,
1 H), 6.98 (s, 2 H), 3.65 (s, 4 H), 2.52 (t, J = 7.18 Hz, 4 H), 1.45–1.56 (m,
4 H), 0.86 (t, J = 7.34 Hz, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 205.0, 166.0, 149.9, 131.1, 127.9,
104.7, 50.8, 44.1, 16.4, 13.5.
N,N′-(2,5-Dihydroxy-1,3-phenylene)bis(4-methyl-3-oxopentan-
amide) (1f)
Yield: 16 mg (44%) (0.044 mmol scale); white solid after flash column
chromatography (hexane/EtOAc 9:1 to 1:1, v/v); mp 159–160 °C; Rf =
0.24 (hexane/EtOAc, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O6+: 365.1707; found:
365.1710; m/z [M + Na]+ calcd for C18H24N2O6Na+: 387.1527; found:
387.1529.
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.02 min.
1H NMR (400 MHz, DMSO-d6): δ = 9.79 (br s, 2 H), 9.02 (s, 1 H), 8.77 (s,
1 H), 6.98 (s, 2 H), 3.75 (s, 4 H), 2.67–2.81 (m, 2 H), 1.05 (d, J = 7.02 Hz,
12 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

H
A. M. Prior, D. Sun
Paper
Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 208.6, 166.2, 149.9, 131.0, 127.9,
N-[2,5-Dihydroxy-3-(3-oxobutanamido)phenyl]2-methyl-3-oxo-
104.7, 48.8, 40.3, 17.8.
hexanamide (1j)
HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O6+: 365.1707; found:
365.1712; m/z [M + Na]+ calcd for C18H24N2O6Na+: 387.1527; found:
387.1531.
Yield: 50 mg (78%) (0.18 mmol scale); viscous light brown oil as a pair
of enantiomers after flash column chromatography (hexane/EtOAc
9:1 to 1:1, v/v); Rf = 0.13 (hexane/EtOAc, 1:1).
HPLC purity: 97.2% (254 nm), 97.2% (220 nm); tR = 5.79 min.
N,N′-(2,5-Dihydroxy-1,3-phenylene)bis(2-acetyl-3-methylbutan-
amide) (1g)
1H NMR (400 MHz, CDCl3): δ = 9.70 (s, 1 H), 9.17 (s, 1 H), 7.12 (d, J =
2.93 Hz, 1 H), 7.05 (d, J = 2.93 Hz, 1 H), 3.63 (s, 2 H), 3.63 (q, J = 7.27
Hz, 1 H), 2.59 (t, J = 7.25 Hz, 2 H), 2.28 (s, 3 H), 1.55–1.66 (m, 2 H),
1.48 (d, J = 7.09 Hz, 3 H), 0.90 (t, J = 7.46 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 209.7, 204.6, 170.0, 165.8, 150.2,
132.1, 127.6, 127.3, 105.5, 54.4, 49.5, 43.8, 31.1, 17.0, 15.6, 13.7.
Yield: 50 mg (87%) (0.13 mmol scale); sticky off-white solid as a mix-
ture of enantiomers (R,R and S,S) and meso form (S,R = R,S) after flash
column chromatography (hexane/EtOAc 9:1 to 1:1, v/v); mp 62–
64 °C; Rf = 0.22 (hexane/EtOAc, 1:1).
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.35 min.
HRMS (ESI): m/z [M + H]+ calcd for C17H23N2O6+: 351.1551; found:
351.1545; m/z [M + Na]+ calcd for C17H22N2O6Na+: 373.1370; found:
373.1364.
1H NMR (400 MHz, CDCl3): δ = 9.14 (s, 2 H), 9.14 (s, 2 H), 8.65 (s, 1 H),
8.63 (s, 1 H), 8.46 (br s, 2 H), 7.24 (s, 4 H), 3.39 (d, J = 9.29 Hz, 4 H),
2.35–2.44 (m, 4 H), 2.35 (s, 12 H), 1.05 (d, J = 7.03 Hz, 12 H), 1.03 (d, J
= 7.03 Hz, 12 H).
N-[2,5-Dihydroxy-3-(2-methyl-3-oxobutanamido)phenyl]-2-
methyl-3-oxohexanamide (1k)
13C NMR (100 MHz, CDCl3): δ = 208.33, 208.31, 168.1, 150.73, 150.71,
131.9, 127.6, 127.5, 105.1, 68.8, 32.6, 31.88, 31.86, 21.1, 20.5.
Yield: 31 mg (57%) (0.15 mmol scale); viscous light brown oil as a
mixture of two pairs of enantiomers (R,R; S,S and S,R; R,S) after flash
column chromatography (hexane/EtOAc 9:1 to 1:1, v/v); Rf = 0.19
(hexane/EtOAc, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O6+: 393.2020; found:
393.2018; m/z [M + Na]+ calcd for C20H28N2O6Na+: 415.1840; found:
415.1837.
HPLC purity: 97.7% (254 nm), 97.1% (220 nm); tR = 6.01 min.
N,N′-(2,5-Dihydroxy-1,3-phenylene)bis(3-cyclopropyl-3-oxopro-
panamide) (1h)
1H NMR (400 MHz, CDCl3): δ = 9.20 (s, 1 H), 9.12 (s, 1 H), 8.76 (br s, 1
H), 7.14 (s, 2 H), 3.64 (q, J = 7.09 Hz, 2 H), 2.60 (t, J = 7.09 Hz, 2 H), 2.32
(s, 3 H), 1.57–1.69 (m, 2 H), 1.52 (d, J = 7.18 Hz, 3 H), 1.51 (d, J = 7.18
Hz, 3 H), 0.91 (t, J = 7.46 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 209.9, 207.3, 170.0, 169.8, 150.4,
132.0, 127.5, 105.4, 105.3, 54.9, 54.2, 43.9, 29.1, 17.0, 16.01, 15.99,
15.42, 15.39, 13.7.
Yield: 104 mg (quant.) (0.29 mmol scale); light red-brown solid was
used directly without further purification; mp 126–128 °C (dec.); Rf =
0.23 (hexane/EtOAc, 1:1).
HPLC purity: 98.4% (254 nm), 98.7% (220 nm); tR = 5.67 min.
1H NMR (400 MHz, DMSO-d6): δ = 9.84 (s, 2 H), 9.02 (br s, 1 H), 8.76 (s,
HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O6+: 365.1707; found:
365.1712; m/z [M + Na]+ calcd for C18H24N2O6Na+: 387.1527; found:
387.1528.
1 H), 6.99 (s, 2 H), 3.79 (s, 4 H), 2.08–2.17 (m, 2 H), 0.88–0.97 (m, 8 H).
13C NMR (100 MHz, DMSO-d6): δ = 204.8, 165.8, 149.9, 131.0, 127.9,
104.7, 51.0, 20.6, 10.7.
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2O6+: 361.1394; found:
361.1393; m/z [M + Na]+ calcd for C18H20N2O6Na+: 383.1214; found:
383.1217.
Symmetrical Double Knorr Cyclization; 4,5-Dimethyl-1H,8H-1,8-
diazaanthracene-2,7,9,10-tetraone (2a); Typical Procedure
H2SO4 (2 mL) was added to a 5 mL round-bottom flask containing 1a
(45 mg, 0.15 mmol), which was then placed in a preheated oil bath at
110 °C. The solution was stirred at 110 °C for 5 min open to air. The
reaction was confirmed complete using HPLC analysis. The reaction
mixture was poured onto ice and diluted to 20 mL using cold H2O. The
solid precipitate was collected by centrifugation. The supernatant
was carefully decanted and the solid was washed with cold H2O (2 ×
10 mL) using the centrifugation method. The solid was dried under
vacuum to afford 2a (26 mg, 0.10 mmol, 67%) as a brown solid; mp
>300 °C (dec.); Rf = 0.52 (CH2Cl2/MeOH, 9:1).
N,N′-(2,5-Dihydroxy-1,3-phenylene)bis(2-benzyl-3-oxobutan-
amide) (1i)
Yield: 50 mg (73%) (0.10 mmol scale); viscous light brown oil as a
mixture of enantiomers (R,R and S,S) and meso form (S,R = R,S) after
flash column chromatography (hexane/EtOAc 9:1 to 1:1, v/v); Rf =
0.34 (hexane/EtOAc, 1:1).
HPLC purity: 99.3% (254 nm), 98.6% (220 nm); tR = 6.73 min.
1H NMR (400 MHz, CDCl3): δ = 8.99 (s, 2 H), 8.99 (s, 2 H), 8.58 (br s, 2
H), 7.16–7.30 (m, 20 H), 7.04 (s, 4 H), 3.88 (t, J = 7.46 Hz, 4 H), 3.19–
3.32 (m, 8 H), 2.16 (s, 12 H).
13C NMR (100 MHz, CDCl3): δ = 206.5, 168.3, 150.3, 137.2, 132.1,
129.0, 128.9, 127.3, 105.5, 62.9, 37.1, 30.61, 30.60.
HRMS (ESI): m/z [M + H]+ calcd for C28H29N2O6+: 489.2020; found:
489.2028; m/z [M + Na]+ calcd for C28H28N2O6Na+: 511.1840; found:
511.1854.
HPLC purity: 98.8% (254 nm), 95.6% (220 nm); tR = 5.32 min.
1H NMR (400 MHz, CDCl3/2% CF3CO2D): δ = 7.13 (s, 2 H), 2.83 (s, 6 H).
13C NMR (100 MHz, CDCl3/2% CF3CO2D): δ = 179.9, 172.6, 163.7, 158.1,
136.6, 127.8, 119.2, 23.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H11N2O4+: 271.0713; found:
271.0708.
4,5-Dipropyl-1H,8H-1,8-diazaanthracene-2,7,9,10-tetraone (2b)
Yield: 15 mg (70%) (0.066 mmol scale); orange solid; mp 290 °C
(dec.); Rf = 0.50 (CH2Cl2/MeOH, 9:1).
HPLC purity: 98.8% (254 nm), 97.3% (220 nm); tR = 6.23 min.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

I
A. M. Prior, D. Sun
Paper
Synthesis
1H NMR (400 MHz, CDCl3/2% CF3CO2D): δ = 7.11 (s, 2 H), 3.13–3.22 (m,
4 H), 1.62–1.75 (m, 4 H), 1.11 (t, J = 7.34 Hz, 6 H).
13C NMR (100 MHz, CDCl3/2% CF3CO2D): δ = 179.9, 172.8, 163.8, 161.4,
HPLC purity: 98.7% (254 nm), 97.3% (220 nm); tR = 6.06 min.
1H NMR (400 MHz, CDCl3/2% CF3CO2D): δ = 7.10 (s, 1 H), 3.13–3.22 (m,
2 H), 2.82 (s, 3 H), 2.38 (s, 3 H), 1.55–1.70 (m, 2 H), 1.17 (t, J = 7.34 Hz,
3 H).
136.8, 127.3, 118.6, 37.0, 23.2, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O4+: 327.1339; found:
327.1340.
13C NMR (100 MHz, CDCl3/2% CF3CO2D): δ = 180.6, 172.8, 163.9, 163.5,
157.7, 156.0, 138.0, 136.3, 134.4, 127.8, 119.3, 118.9, 32.9, 23.1, 22.7,
14.5, 13.0.
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2O4+: 313.1183; found:
3,4,5,6-Tetramethyl-1H,8H-1,8-diazaanthracene-2,7,9,10-tetra-
one (2c)
313.1176.
Yield: 20 mg (75%) (0.089 mmol scale); red solid; mp >300 °C (dec.);
Rf = 0.47 (CH2Cl2/MeOH, 9:1).
3,5,6-Trimethyl-4-propyl-1H,8H-1,8-diazaanthracene-2,7,9,10-
tetraone (2k)
HPLC purity: 100.0% (254 nm), 100.0% (220 nm): tR = 5.78 min.
1H NMR (400 MHz, CDCl3/2% CF3CO2D): δ = 2.75 (s, 6 H), 2.36 (s, 6 H).
13C NMR (100 MHz, CDCl3/2% CF3CO2D): δ = 181.7, 172.5, 163.0, 152.0,
151.9, 137.5, 133.7, 120.14, 120.11, 18.6, 13.43, 13.40.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O4+: 299.1026; found:
Prepared from 1k following the procedure for 2j; yield: 23.5 mg (94%)
(0.077 mmol scale); red solid; mp >300 °C (dec); Rf = 0.51 (CH2-
Cl2/MeOH, 9:1).
HPLC purity: 99.5% (254 nm), 100.0% (220 nm); tR = 6.28 min.
1H NMR (400 MHz, CDCl3/2% CF3CO2D): δ = 3.08–3.16 (m, 2 H), 2.73 (s,
3 H), 2.35 (s, 6 H), 1.56–1.68 (m, 2 H), 1.15 (t, J = 7.34 Hz, 3 H).
299.1031.
13C NMR (100 MHz, CDCl3/2% CF3CO2D): δ = 181.6, 172.7, 155.3, 151.1,
137.6, 137.4, 134.0, 133.5, 119.9, 119.1, 32.8, 22.8, 18.7, 14.6, 13.5,
13.0.
3,6-Dimethyl-4,5-dipropyl-1H,8H-1,8-diazaanthracene-2,7,9,10-
tetraone (2d)
Yield: 17 mg (95%) (0.051 mmol scale); red solid; mp 295 °C (dec);
Rf = 0.48 (CH2Cl2/MeOH, 9:1).
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O4+: 327.1339; found:
327.1334.
HPLC purity: 100.0% (254 nm), 97.6% (220 nm); tR = 6.77 min.
1H NMR (400 MHz, CDCl3/2% CF3CO2D): δ = 3.06–3.14 (m, 4 H), 2.33 (s,
6 H), 1.54–1.66 (m, 4 H), 1.14 (t, J = 7.21 Hz, 6 H).
13C NMR (100 MHz, CDCl3/2% CF3CO2D): δ = 181.7, 172.8, 163.1, 154.2,
137.4, 134.0, 118.8, 32.7, 22.8, 14.7, 13.1.
HRMS (ESI): m/z [M + H]+ calcd for C20H23N2O4+: 355.1652; found:
4-Hydroxy-3,5-dinitrophenyl Acetate (4)13
The current procedure was adapted from Nissen et al.13 with modifi-
cation. 1,4-Diacetoxybenzene (2; 5.0 g, 25.7 mmol) was added por-
tionwise to 70% HNO3 at 0 °C. The reaction vessel was capped and al-
lowed to warm to 20 °C followed by stirring at 20 °C for 2 h. The solu-
tion was poured onto ice and filtered. The solid was washed with cold
H2O (100 mL) and air dried to afford 4 (2.61 g, 10.8 mmol, 42%) as a
yellow solid; mp 94 °C (Lit.13 mp 94 °C); Rf = 0.18 (hexane/EtOAc, 1:1).
355.1666.
The spectroscopic data of 2d are consistent with those of natural di-
azaquinomycin A.18,19
1H NMR (400 MHz, CDCl3): δ = 11.35 (s, 1 H), 8.16 (s, 2 H), 2.37 (s, 3 H).
MS (ESI): m/z [M + H]+ calcd for C8H7N2O7+: 243.0; found: 243.0; m/z
3,6-Diethyl-4,5-dimethyl-1H,8H-1,8-diazaanthracene-2,7,9,10-
tetraone (2e)
[M + Na]+ calcd for C8H6N2O7Na+: 265.0; found: 265.0.
Yield: 26 mg (61%) (0.13 mmol scale); red solid; mp >300 °C (dec.);
2,6-Dinitrobenzene-1,4-diol (5)14
Rf = 0.50 (CH2Cl2/MeOH, 9:1).
The current procedure was adapted from Burger et al.14 with modifi-
cation. Concd HCl (1.0 mL) was added to a solution of 4 (2.0 g, 8.3
mmol) in MeOH (200 mL) and the solution was refluxed at 65 °C for 2
h. The solvent was removed using a rotary evaporator to give a solid
that was recrystallized from toluene to afford 5 (1.65 g, 8.3 mmol,
quant.) as an orange solid; mp 132–134 °C (Lit.14 mp 132–136 °C); Rf =
0.80 (EtOAc, 100%).
HPLC purity: 97.3% (254 nm), 98.4% (220 nm); tR = 6.25 min.
1H NMR (400 MHz, CDCl3/2% CF3CO2D): δ = 2.84 (q, J = 7.58 Hz, 4 H),
2.74 (s, 6 H), 1.17 (t, J = 7.58 Hz, 6 H).
13C NMR (100 MHz, CDCl3/2% CF3CO2D): δ = 182.0, 172.6, 162.7, 150.2,
143.0, 133.7, 119.6, 20.8, 18.0, 12.3.
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O4+: 327.1339; found:
327.1339.
1H NMR (400 MHz, DMSO-d6): δ = 10.85 (br s, 1 H), 10.51 (br s, 1 H),
7.61 (s, 2 H).
Unsymmetrical Double Knorr Cyclization; 3,5-Dimethyl-4-propyl-
1H,8H-1,8-diazaanthracene-2,7,9,10-tetraone (2j); Typical Opti-
mized Procedure
MS (ESI): m/z [M + H]+ calcd for C6H5N2O6+: 201.0; found: 201.0; [M +
Na]+ calcd for C6H4N2O6Na+: 223.0; found: 223.0.
Triflic acid (2 mL) was added to a 5 mL round-bottom flask containing
1j (30 mg, 0.086 mmol), which was then placed in a preheated oil
bath at 50 °C. The solution was stirred at 50 °C for 25 min open to air.
The reaction was confirmed complete using HPLC analysis. The reac-
tion mixture was poured onto ice and diluted to 15 mL using ice cold
H2O. The solid precipitate was collected by centrifugation. The super-
natant was carefully decanted and the solid was washed with ice cold
H2O (2 × 10 mL) using the centrifugation method. The solid was dried
under vacuum to afford 2j (26 mg, 0.083 mmol, 96%) as a red solid;
mp >300 °C (dec); Rf = 0.53 (CH2Cl2/MeOH, 9:1).
2,5-Bis(methoxymethoxy)-1,3-dinitrobenzene (6)5
The current procedure was adapted from Kelly et al.5 with modifica-
tion. To a solution 5 (1.18 g, 5.9 mmol) in anhyd THF at 0 °C was add-
ed DIPEA (3.1 mL, 18.1 mmol) followed by MOM-Cl (1.7 mL, 22.1
mmol). The solution was allowed to warm to r.t. and stirred for 3 h.
The reaction mixture was diluted with EtOAc (200 mL) and washed
with deionized H2O (2 × 200 mL). The organic layer was dried (anhyd
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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A. M. Prior, D. Sun
Paper
Synthesis
Na2SO4), filtered, and concentrated to give 6 (1.7 g, 5.9 mmol, quant.)
as a yellow oil that was used directly without further purification; Rf =
0.86 (hexane/EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): δ = 7.68 (s, 2 H), 5.24 (s, 2 H), 5.14 (s, 2 H),
1H NMR (400 MHz, CDCl3): δ = 9.38 (s, 2 H), 7.80 (s, 2 H), 5.15 (s, 2 H),
5.07 (s, 2 H), 3.65 (s, 3 H), 3.58 (s, 4 H), 3.47 (s, 3 H), 2.34 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 204.2, 163.6, 154.2, 132.4, 131.8,
105.0, 101.3, 95.0, 58.4, 56.4, 51.3, 31.2.
3.50 (s, 3 H), 3.49 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.0, 146.6, 138.4, 116.6, 103.1, 95.3,
58.4, 56.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O8+: 397.1605; found:
397.1610; m/z [M + Na]+ calcd for C18H24N2O8Na+: 419.1425; found:
419.1424.
MS (ESI): m/z [M + Na]+ calcd for C10H12N2O8Na+: 311.0; found: 311.0.
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(3-oxohexan-
amide) (9b)
2,5-Bis(methoxymethoxy)benzene-1,3-diamine (7)
A solution of 7 (100 mg, 0.44 mmol) in methyl 3-oxohexanoate (8b; 1.2
mL) was refluxed at 190 °C for 1.5 h. The reaction was cooled to r.t. and
the crude product was purified by flash chromatography (silica gel,
hexane/EtOAc 9:1 to 1:1, v/v), affording 9b (75 mg, 0.17 mmol, 39%) as
a light brown solid; mp 97–98 °C; Rf = 0.33 (hexane/EtOAc, 1:1).
To a suspension of 10% Pd/C (120 mg) in EtOAc (35 mL) was added 6
(600 mg, 2.10 mmol). The reaction vessel was purged with H2 (g) and
the contents were stirred at 45 °C for 18 h at 1.4 bar H2 (g). The reaction
mixture was filtered through Celite and the filtrate was concentrated to
yield 7 (0.50 g, 2.1 mmol, quant.) as a brown oil that was used directly
without further purification; Rf = 0.32 (hexane/EtOAc, 1:1).
HPLC purity: 97.0% (254 nm), 95.4% (220 nm); tR = 6.58 min.
HPLC purity: 99.0% (254 nm), 98.8% (220 nm); tR = 4.64 min.
1H NMR (400 MHz, CDCl3): δ = 5.94 (s, 2 H), 5.06 (s, 2 H), 4.98 (s, 2 H),
3.60 (s, 3 H), 3.46 (s, 3 H), 3.37–3.70 (br s, 4 H).
13C NMR (100 MHz, CDCl3): δ = 155.2, 140.8, 128.8, 99.7, 95.0, 94.8,
1H NMR (400 MHz, CDCl3): δ = 9.40 (s, 2 H), 7.80 (s, 2 H), 5.15 (s, 2 H),
5.08 (s, 2 H), 3.67 (s, 3 H), 3.55 (s, 4 H), 3.47 (s, 3 H), 2.58 (t, J = 7.15
Hz, 4 H), 1.61–1.71 (m, 4 H), 0.95 (t, J = 7.34 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 206.5, 163.7, 154.2, 132.5, 131.9,
105.0, 101.4, 95.0, 58.4, 56.4, 50.6, 46.0, 17.1, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C22H33N2O8+: 453.2231; found:
453.2227; m/z [M + Na]+ calcd for C22H32N2O8Na+: 475.2051; found:
475.2040.
57.7, 56.1.
MS (ESI): m/z [M + H]+ calcd for C10H17N2O4+: 229.1; found: 229.1.
N-[3-Amino-2,5-bis(methoxymethoxy)phenyl]-2-methyl-3-oxo-
hexanamide (7a)
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(2-methyl-3-
EDC·HCl (589 mg, 3.07 mmol) was added to a stirred solution of 7 (1.0
g, 4.38 mmol), 2-methyl-3-oxohexanoic acid (442 mg, 3.07 mmol),
and DMAP (107 mg, 0.88 mmol) in CH2Cl2 (30 mL). The solution was
stirred at r.t. for 30 min. The reaction mixture was diluted with CH2Cl2
(200 mL) and the organic layer was washed with H2O (2 × 100 mL).
The organic layer was dried (anhyd Na2SO4), filtered, and concentrat-
ed to yield an oil that was purified by flash chromatography (NH-
functionalized silica gel, hexane/EtOAc 9:1 to 5:2, v/v), affording 7a
(270 mg, 0.76 mmol, 25%) as a light brown oil as a pair of enantio-
mers; Rf = 0.35 (hexane/EtOAc, 1:1).
oxobutanamide) (9c)
A solution of 7 (100 mg, 0.44 mmol) in ethyl 2-methyl-3-oxobuta-
noate (8c; 2.0 mL) was stirred at 130 °C for 5 h. The reaction was
cooled to r.t. and purified by flash chromatography (silica gel, hex-
ane/EtOAc 9:1 to 1:1, v/v), affording 9c (86 mg, 0.20 mmol, 46%) as an
off-white solid as a mixture of enantiomers (R,R and S,S) and meso
form (S,R = R,S); mp 108–109 °C; Rf = 0.25 (hexane/EtOAc, 1:1).
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.03 min.
1H NMR (400 MHz, CDCl3): δ = 8.90 (br. s, 4 H), 7.81 (s, 4 H), 5.16 (s, 4
H), 5.05 (d, J = 5.87 Hz, 1 H), 5.01 (s, 2 H), 4.97 (d, J = 5.87 Hz, 1 H),
3.67 (s, 6 H), 3.55 (q, J = 7.21 Hz, 4 H), 3.47 (s, 6 H), 2.31 (s, 12 H), 1.51
(d, J = 7.21 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 207.5, 167.5, 154.3, 132.4, 131.8,
104.8, 101.5, 95.0, 58.3, 56.4, 56.3, 28.9, 15.0.
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O8+: 425.1918; found:
425.1916; m/z [M + Na]+ calcd for C20H28N2O8Na+: 447.1738; found:
447.1733.
HPLC purity: 97.0% (254 nm), 94.0% (220 nm); tR = 6.17 min.
1H NMR (400 MHz, CDCl3): δ = 8.79 (br s, 1 H), 7.47 (d, J = 2.69 Hz, 1
H), 6.23 (d, J = 2.69 Hz, 1 H), 5.11 (s, 2 H), 5.01 (d, J = 5.62 Hz, 1 H),
4.96 (d, J = 5.62 Hz, 1 H), 3.92 (br s, 2 H), 3.63 (s, 3 H), 3.55 (q, J = 7.34
Hz, 1 H), 3.46 (s, 3 H), 2.51–2.66 (m, 2 H), 1.57–1.67 (m, 2 H), 1.48 (d, J
= 7.34 Hz, 3 H), 0.91 (t, J = 7.34 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 209.3, 167.6, 154.7, 140.3, 132.4,
130.3, 100.4, 100.0, 99.1, 94.9, 58.0, 56.3, 56.1, 43.6, 17.1, 15.0, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H27N2O6+: 355.1864; found:
355.1853; m/z [M + Na]+ calcd for C17H26N2O6Na+: 377.1683; found:
377.1671.
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(2-methyl-3-
oxohexanamide) (9d)
A solution of 7 (400 mg, 1.75 mmol) in methyl 2-methyl-3-oxohexa-
noate (8d; 6.0 mL) was stirred at 210 °C for 1 h. The reaction mixture
was cooled to r.t. and the crude product was purified by flash chroma-
tography (silica gel, hexane/EtOAc 9:1 to 3:2, v/v), affording 9d (625
mg, 1.30 mmol, 74%) as an off-white solid as a mixture of enantio-
mers (R,R and S,S) and meso form (S,R = R,S); mp 67–68 °C; Rf = 0.39
(hexane/EtOAc, 1:1).
Di-β-ketoanilides 9a–k
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(3-oxobutan-
amide) (9a)
A solution of 2,5-bis(methoxymethoxy)benzene-1,3-diamine (7; 150
mg, 0.66 mmol) in methyl acetoacetate (8a; 2.0 mL) was refluxed at
170 °C for 3 h. The reaction was cooled to r.t. and the crude product
was purified by flash chromatography (silica gel, hexane/EtOAc 9:1 to
2:3, v/v), affording 9a (126 mg, 0.32 mmol, 48%) as an off-white solid;
mp 89–90 °C; Rf = 0.38 (hexane/EtOAc, 1:1).
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.95 min.
1H NMR (400 MHz, CDCl3): δ = 8.91 (br s, 4 H), 7.80 (s, 4 H), 5.15 (s, 4 H),
5.08 (d, J = 5.87 Hz, 1 H), 5.01 (s, 2 H), 4.94 (d, J = 5.87 Hz, 1 H), 3.67 (s, 6
H), 3.53–3.60 (m, 4 H), 3.47 (s, 6 H), 2.56–2.61 (m, 8 H), 1.57–1.68 (m, 8
H), 1.49 (d, J = 7.34 Hz, 12 H), 0.92 (t, J = 7.34 Hz, 12 H).
HPLC purity: 99.3% (254 nm), 99.8% (220 nm); tR = 5.63 min.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

K
A. M. Prior, D. Sun
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Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 9.63 (s, 4 H), 7.39 (s, 4 H), 5.10 (s, 4
H), 4.91 (s, 4 H), 3.85 (q, J = 7.09 Hz, 4 H), 3.49 (s, 6 H), 3.36 (s, 6 H),
2.51–2.56 (m, 8 H), 1.43–1.55 (m, 8 H), 1.23 (d, J = 6.85 Hz, 12 H), 0.83
(t, J = 7.46 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 209.71, 209.69, 167.7, 154.3, 132.4,
131.9, 104.7, 101.4, 95.0, 58.4, 56.4, 55.8, 43.7, 43.6, 17.1, 15.3, 13.7.
HPLC purity: 95.0% (254 nm), 94.9% (220 nm); tR = 6.85 min.
1H NMR (400 MHz, CDCl3): δ = 8.87 (br s, 2 H), 8.85 (br s, 2 H), 7.80 (s,
2 H), 7.79 (s, 2 H), 5.18 (d, J = 5.75 Hz, 1 H), 5.15 (s, 4 H), 4.99 (s, 2 H),
4.80 (d, J = 5.75 Hz, 1 H), 3.70 (s, 3 H), 3.69 (s, 3 H), 3.47 (s, 6 H), 3.24
(d, J = 9.66 Hz, 2 H), 3.22 (d, J = 9.66 Hz, 2 H), 2.35–2.48 (m, 4 H), 2.32 (s,
6 H), 2.31 (s, 6 H), 1.03 (d, J = 6.60 Hz, 12 H), 0.99 (d, J = 6.60 Hz, 12 H).
HRMS (ESI): m/z [M + H]+ calcd for C24H37N2O8+: 481.2544; found:
481.2538; m/z [M + Na]+ calcd for C24H36N2O8Na+: 503.2364; found:
503.2357.
13C NMR (100 MHz, CDCl3): δ = 208.1, 207.9, 166.12, 166.09, 154.3,
154.2, 132.3, 132.2, 131.9, 131.8, 104.6, 104.4, 101.5, 101.4, 95.0,
70.97, 70.89, 58.5, 58.4, 56.4, 31.7, 31.6, 31.3, 31.0, 21.02, 20.98, 20.7.
HRMS (ESI): m/z [M + H]+ calcd for C24H37N2O8+: 481.2544; found:
481.2533; m/z [M + Na]+ calcd for C24H36N2O8Na+: 503.2364; found:
503.2353.
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(2-ethyl-3-
oxobutanamide) (9e)
A solution of 7 (120 mg, 0.53 mmol) in ethyl 2-ethyl-3-oxobutanoate
(8e; 2.0 mL) was stirred at 130 °C for 5 h. The reaction mixture was
cooled to r.t. and the crude product was purified by flash chromatog-
raphy (silica gel, hexane/EtOAc 9:1 to 3:2, v/v), affording 9e (165 mg,
0.37 mmol, 69%) as a white solid as a mixture of enantiomers (R,R and
S,S) and meso form (S,R = R,S); mp 122–123 °C; Rf = 0.33 (hexane/EtOAc,
1:1).
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(3-cyclopropyl-
3-oxopropanamide) (9h)
A solution of 7 (150 mg, 0.66 mmol) in ethyl 3-cyclopropyl-3-oxopro-
panoate (8h; 2.0 mL) was stirred at 160 °C for 1 h. The reaction mix-
ture was cooled to r.t. and the crude product was purified by flash
chromatography (silica gel, hexane/EtOAc 9:1 to 1:1, v/v), affording
9h (210 mg, 0.47 mmol, 71%) as a white solid; mp 123–124 °C; Rf =
0.38 (hexane/EtOAc, 1:1).
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.47 min.
1H NMR (400 MHz, CDCl3): δ = 8.93 (s, 2 H), 8.93 (s, 2 H), 7.81 (s, 4 H),
5.15 (s, 4 H), 5.12 (d, J = 5.87 Hz, 1 H), 5.01 (s, 2 H), 4.90 (d, J = 5.87 Hz,
1 H), 3.68 (s, 3 H), 3.67 (s, 3 H), 3.47 (s, 6 H), 3.39–3.45 (m, 4 H), 2.30
(s, 12 H), 1.93–2.04 (m, 8 H), 1.00 (t, J = 7.46 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 207.5, 207.4, 166.8, 154.3, 132.4,
132.3, 131.83, 131.82, 104.7, 104.6, 101.5, 101.4, 95.0, 64.12, 64.09,
58.4, 56.4, 29.9, 29.8, 24.4, 24.3, 12.1, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C22H33N2O8+: 453.2231; found:
453.2226; m/z [M + Na]+ calcd for C22H32N2O8Na+: 475.2051; found:
475.2041.
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.21 min.
1H NMR (400 MHz, CDCl3): δ = 9.54 (s, 2 H), 7.81 (s, 2 H), 5.15 (s, 2 H),
5.02 (s, 2 H), 3.69 (s, 4 H), 3.61 (s, 3 H), 3.46 (s, 3 H), 2.01–2.13 (m, 2
H), 1.13–1.20 (m, 4 H), 0.98–1.07 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 206.5, 163.9, 154.1, 132.4, 131.9,
105.0, 101.3, 95.0, 58.4, 56.4, 50.7, 21.9, 12.4.
HRMS (ESI): m/z [M + H]+ calcd for C22H29N2O8+: 449.1918; found:
449.1917; m/z [M + Na]+ calcd for C22H28N2O8Na+: 471.1738; found:
471.1732.
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(4-methyl-3-
oxopentanamide) (9f)
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(2-benzyl-3-
oxobutanamide) (9i)
A solution of 7 (110 mg, 0.48 mmol) in ethyl 4-methyl-3-oxopenta-
noate (8f; 2.0 mL) was stirred at 130 °C for 5 h. The reaction mixture
was cooled to r.t. and the crude product was purified by flash chroma-
tography (silica gel, hexane/EtOAc 9:1 to 5:2, v/v), affording 9f (129
mg, 0.29 mmol, 60%) as a light brown solid; mp 68–69 °C; Rf = 0.38
(hexane/EtOAc, 1:1).
A solution of 7 (150 mg, 0.66 mmol) in ethyl 2-benzyl-3-oxobuta-
noate 8i (2.0 mL) was stirred at 170 °C for 1 h. The reaction mixture
was cooled to r.t. and the crude product was purified by flash chroma-
tography (silica gel, hexane/EtOAc 9:1 to 1:1, v/v), affording 9i (90 mg,
0.16 mmol, 24%) as a brown oil as a mixture of enantiomers (R,R and
S,S) and meso form (S,R = R,S); Rf = 0.47 (hexane/EtOAc, 1:1).
HPLC purity: 99.3% (254 nm), 99.0% (220 nm); tR = 6.49 min.
HPLC purity: 99.9% (254 nm), 98.9% (220 nm); tR = 7.07 min.
1H NMR (400 MHz, CDCl3): δ = 9.44 (br s, 2 H), 7.80 (s, 2 H), 5.15 (s, 2
H), 5.08 (s, 2 H), 3.67 (s, 3 H), 3.61 (s, 4 H), 3.47 (s, 3 H), 2.70–2.82 (m,
2 H), 1.17 (d, J = 7.09 Hz, 12 H).
1H NMR (400 MHz, CDCl3): δ = 8.81 (s, 4 H), 7.78 (s, 4 H), 7.17–7.32
(m, 20 H), 5.16 (s, 4 H), 4.81 (d, J = 5.87 Hz, 1 H), 4.73 (s, 2 H), 4.66 (d,
J = 5.87 Hz, 1 H), 3.74–3.80 (m, 4 H), 3.56 (s, 3 H), 3.55 (s, 3 H), 3.49 (s,
6 H), 3.18–3.34 (m, 8 H), 2.18 (s, 6 H), 2.17 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 210.2, 163.9, 154.1, 132.4, 131.9,
104.9, 101.3, 95.0, 58.5, 56.4, 48.4, 42.3, 18.0.
13C NMR (100 MHz, CDCl3): δ = 206.6, 166.2, 154.3, 137.7, 132.5,
131.6, 129.0, 127.2, 104.93, 104.90, 101.24, 101.18, 95.0, 64.4, 64.3,
58.2, 56.5, 36.9, 36.8, 30.4, 30.3.
HRMS (ESI): m/z [M + H]+ calcd for C32H37N2O8+: 577.2544; found:
577.2523; m/z [M + Na]+ calcd for C32H36N2O8Na+: 599.2364; found:
599.2342.
HRMS (ESI): m/z [M + H]+ calcd for C22H33N2O8+: 453.2231; found:
453.2231; m/z [M + Na]+ calcd for C22H32N2O8Na+: 475.2051; found:
475.2047.
N,N′-[2,5-Bis(methoxymethoxy)-1,3-phenylene]bis(2-acetyl-3-
methylbutanamide) (9g)
A solution of 7 (100 mg, 0.44 mmol) in ethyl 2-acetyl-3-methylbuta-
noate (8g; 2.0 mL) was stirred at 160 °C for 5 h. The reaction mixture
was cooled to r.t. and the crude product was purified by flash chroma-
tography (silica gel, hexane/EtOAc 9:1 to 3:2, v/v), affording 9g (150
mg, 0.31 mmol, 71%) as a light brown solid as a mixture of enantio-
mers (R,R and S,S) and meso form (S,R = R,S); mp 125–126 °C; Rf = 0.37
(hexane/EtOAc, 1:1).
N-[2,5-Bis(methoxymethoxy)-3-(3-oxobutanamido)phenyl]-2-
methyl-3-oxohexanamide (9j)
EDC·HCl (108 mg, 0.56 mmol) was added to a stirred solution of 7a
(100 mg, 0.28 mmol), 3-oxobutanoic acid (8j; 58 mg, 0.56 mmol), and
DMAP (6.8 mg, 0.056 mmol) in CH2Cl2 (5 mL). The solution was
stirred at r.t. for 30 min. The reaction mixture was diluted with CH2Cl2
(50 mL) and the organic layer was washed with H2O (2 × 25 mL). The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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A. M. Prior, D. Sun
Paper
Synthesis
organic layer was dried (anhyd Na2SO4), filtered, and concentrated to
yield an oil that was purified by flash chromatography (silica gel, hex-
ane/EtOAc 9:1 to 3:2, v/v), affording 9j (105 mg, 0.24 mmol, 86%) as a
light brown solid as a pair of enantiomers; mp 80–81 °C; Rf = 0.25
(hexane/EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): δ = 8.81 (br s, 2 H), 8.59 (br s, 1 H), 7.13 (s,
2 H), 7.05 (s, 1 H), 3.58 (q, J = 7.09 Hz, 2 H), 2.57 (t, J = 7.18 Hz, 4 H),
1.53–1.65 (m, 4 H), 1.45 (d, J = 7.09 Hz, 6 H), 0.88 (t, J = 7.28 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 210.5, 210.4, 169.12, 169.08, 158.0,
138.9, 104.2, 103.5, 54.8, 43.8, 17.0, 15.7, 15.6, 13.7.
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.34 min.
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O5+: 377.2071; found:
377.2075; m/z [M + Na]+ calcd for C20H28N2O5Na+: 399.1890; found:
399.1889.
1H NMR (400 MHz, CDCl3): δ = 9.47 (s, 1 H), 8.92 (s, 1 H), 7.82 (d, J =
2.93 Hz, 1 H), 7.78 (d, J = 2.93 Hz, 1 H), 5.15 (s, 2 H), 5.08 (d, J = 5.87
Hz, 1 H), 5.01 (d, J = 5.87 Hz, 1 H), 3.67 (s, 3 H), 3.60 (s, 2 H), 3.55 (q, J
= 7.09 Hz, 1 H), 3.47 (s, 3 H), 2.52–2.66 (m, 2 H), 2.33 (s, 3 H), 1.57–
1.68 (m, 2 H), 1.48 (d, J = 7.09 Hz, 3 H), 0.91 (t, J = 7.34 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 209.2, 204.7, 167.8, 163.6, 154.2,
132.4, 131.9, 131.8, 104.9, 104.7, 101.4, 94.9, 58.4, 56.4, 56.0, 50.8,
43.5, 31.3, 17.1, 15.0, 13.8.
N,N′-(2-Hydroxy-1,3-phenylene)bis(2-methyl-3-oxohexanamide) (11)
Yield: 325 mg (53%) (1.63 mmol scale); H2O/1 M HCl (5:1) was used
as the solvent to give 11 as a light brown oil as a mixture of enantio-
mers (R,R and S,S) and meso form (S,R = R,S) after flash column chro-
matography (hexane/EtOAc 9:1 to 2:1, v/v); Rf = 0.57 (hexane/EtOAc,
1:1).
HRMS (ESI): m/z [M + H]+ calcd for C21H31N2O8+: 439.2075; found:
439.2071; m/z [M + Na]+ calcd for C21H30N2O8Na+: 461.1894; found:
461.1891.
HPLC purity: 97.8% (254 nm), 97.5% (220 nm); tR = 6.72 min.
1H NMR (400 MHz, CDCl3): δ = 9.58 (s, 1 H), 9.07 (br s, 2 H), 7.45 (d, J =
8.07 Hz, 2 H), 6.86 (t, J = 8.07 Hz, 1 H), 3.62 (q, J = 7.34 Hz, 2 H), 2.61 (t,
J = 7.21 Hz, 4 H), 1.60–1.71 (m, 4 H), 1.53 (d, J = 7.34 Hz, 6 H), 0.93 (t,
J = 7.46 Hz, 6 H).
N-[2,5-Bis(methoxymethoxy)-3-(2-methyl-3-oxobutanamido)-
phenyl]-2-methyl-3-oxohexanamide (9k)
EDC·HCl (65 mg, 0.34 mmol) was added to a stirred solution of 7a (60
mg, 0.17 mmol), 2-methyl-3-oxobutanoic acid (8k; 39 mg, 0.34
mmol), and DMAP (4.0 mg, 0.034 mmol) in CH2Cl2 (2 mL). The solu-
tion was stirred at r.t. for 30 min. The reaction mixture was diluted
with CH2Cl2 (30 mL) and the organic layer was washed with H2O (2 ×
15 mL). The organic layer was dried (anhyd Na2SO4), filtered, and con-
centrated to yield an oil that was purified by flash chromatography
(silica gel, hexane/EtOAc 9:1 to 3:2, v/v), affording 9k (60 mg, 0.13
mmol, 78%) as a light brown solid as a mixture of two pairs of enantio-
mers (R,R; S,S and S,R; R,S); mp 82–83 °C; Rf = 0.29 (hexane/EtOAc, 1:1).
13C NMR (100 MHz, CDCl3): δ = 210.2, 169.3, 138.5, 127.5, 120.7,
117.7, 54.2, 44.0, 17.0, 16.2, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O5+: 377.2071; found:
377.2072; m/z [M + Na]+ calcd for C20H28N2O5Na+: 399.1890; found:
399.1898.
N,N′-(1,3-Phenylene)bis(2-methyl-3-oxohexanamide) (12)
Yield: 247 mg (75%) (0.92 mmol scale); CH2Cl2 was used as the sol-
vent to give 12 as a viscous light brown oil as a mixture of enantio-
mers (R,R and S,S) and meso form (S,R = R,S) after flash column chro-
matography (hexane/EtOAc 9:1 to 2:1, v/v); Rf = 0.50 (hexane/EtOAc,
1:1).
HPLC purity: 100.0% (254 nm), 100.0% (220 nm); tR = 6.52 min.
1H NMR (400 MHz, CDCl3): δ = 8.94 (s, 2 H), 8.89 (br s, 2 H), 7.80 (s, 4
H), 5.15 (s, 4 H), 5.07 (d, J = 5.62 Hz, 1 H), 5.04 (d, J = 5.62 Hz, 1 H),
4.99 (d, J = 5.62 Hz, 1 H), 4.95 (d, J = 5.62 Hz, 1 H), 3.67 (s, 6 H), 3.50–
3.60 (m, 4 H), 3.47 (s, 6 H), 2.59 (t, J = 7.15 Hz, 2 H), 2.59 (t, J = 7.15 Hz,
2 H), 2.30 (s, 6 H), 1.57–1.68 (m, 4 H), 1.50 (d, J = 7.30 Hz, 6 H), 1.49 (d,
J = 7.30 Hz, 6 H), 0.92 (t, J = 7.46 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 209.9, 207.3, 167.7, 167.6, 167.5,
154.3, 132.4, 131.9, 131.8, 104.73, 104.67, 101.4, 94.9, 58.3, 56.41,
56.36, 55.7, 43.8, 43.7, 28.84, 28.76, 17.1, 15.5, 15.4, 14.9, 14.8, 13.7.
HPLC purity: 96.2% (254 nm), 97.5% (220 nm), tR = 6.62 min.
1H NMR (400 MHz, CDCl3): δ = 8.57 (s, 2 H), 7.75–7.79 (m, 1 H), 7.29–
7.33 (m, 2 H), 7.21–7.26 (m, 1 H), 3.56 (q, J = 7.25 Hz, 2 H), 2.58 (t, J =
7.28 Hz, 4 H), 1.56–1.68 (m, 4 H), 1.47 (d, J = 7.34 Hz, 6 H), 0.91 (t, J =
7.46 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 210.5, 168.2, 138.4, 129.7, 116.2,
111.7, 55.0, 43.8, 17.0, 15.7, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C22H33N2O8+: 453.2231; found:
453.2234; m/z [M + Na]+ calcd for C22H32N2O8Na+: 475.2051; found:
475.2050.
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O4+: 361.2122; found:
361.2117; m/z [M + Na]+ calcd for C20H28N2O4Na+: 383.1941; found:
383.1934.
Substrates 10–16; General Procedure
N,N′-(2-Hydroxy-1,4-phenylene)bis(2-methyl-3-oxohexanamide) (13)
The di-β-ketoanilides 10–16 were prepared from their corresponding
diamines via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
coupling with 2-methyl-3-oxohexanoic acid in H2O or CH2Cl2
(Schemes S1–S7, Supporting Information).
Yield: 55 mg (96%) (0.15 mmol scale); CH2Cl2 was used as the solvent
to give 13 as an off-white solid as a mixture of enantiomers (R,R and
S,S) and meso form (S,R = R,S); mp 143–144 °C; Rf = 0.34 (hexane/EtOAc,
1:1).
HPLC purity: 96.8% (254 nm), 98.1% (220 nm); tR = 6.37 min.
N,N′-(5-Hydroxy-1,3-phenylene)bis(2-methyl-3-oxohexanamide) (10)
1H NMR (400 MHz, CDCl3): δ = 9.17 (br s, 1 H), 8.83 (s, 1 H), 8.69 (s, 1
H), 7.48–7.54 (m, 2 H), 6.84 (dd, J = 8.68, 2.32 Hz, 1 H), 3.54–3.65 (m, 2
H), 2.57–2.65 (m, 4 H), 1.58–1.70 (m, 4 H), 1.52 (d, J = 7.34 Hz, 3 H),
1.51 (d, J = 7.34 Hz, 3 H), 0.93 (t, J = 7.46 Hz, 3 H), 0.92 (t, J = 7.46 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O5+: 377.2071; found:
377.2088; m/z [M + Na]+ calcd for C20H28N2O5Na+: 399.1890; found:
399.1913.
Yield: 350 mg (57%) (1.63 mmol scale); CH2Cl2 was used as the sol-
vent to give 10 as an off-white solid as a mixture of enantiomers (R,R
and S,S) and meso form (S,R = R,S) after flash column chromatography
(hexane/EtOAc 9:1 to 2:1, v/v); mp 62–63 °C; Rf = 0.25 (hexane/EtOAc,
1:1).
HPLC purity: 100.0% (254 nm), 95.8% (220 nm); tR = 6.25 min.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

M
A. M. Prior, D. Sun
Paper
Synthesis
N,N′-(2-Methyl-1,3-phenylene)bis(2-methyl-3-oxohexanamide) (14)
Funding Information
Yield: 230 mg (75%) (0.82 mmol scale); H2O/1 M HCl (5:1) used as the
solvent to give 14 as an off-white solid as a mixture of enantiomers
(R,R and S,S) and meso form (S,R = R,S) after filtration and washing
with H2O; mp 232–233 °C; Rf = 0.30 (hexane/EtOAc, 1:1).
This work was supported by Hawaii Community Foundation grant
(15ADVC-74422 and 16ADVC-78728) and UHH DKICP RTRF fund.
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HPLC purity: 96.3% (254 nm), 98.9% (220 nm); tR = 6.45 min.
Acknowledgment
1H NMR (400 MHz, DMSO-d6): δ = 9.73 (s, 2 H), 7.16 (s, 3 H), 3.73 (q,
J = 6.91 Hz, 2 H), 2.56 (t, J = 7.09 Hz, 2 H), 2.56 (t, J = 7.09 Hz, 2 H), 2.04
(s, 3 H), 1.46–1.57 (m, 4 H), 1.24 (d, J = 6.85 Hz, 6 H), 0.85 (t, J = 7.46
Hz, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 206.4, 168.9, 136.5, 128.3, 125.4,
123.5, 53.3, 42.1, 16.6, 13.5, 13.1, 12.8.
HRMS (ESI): m/z [M + H]+ calcd for C21H31N2O4+: 375.2278; found:
375.2231; m/z [M + Na]+ calcd for C21H30N2O4Na+: 397.2098; found:
397.2047.
We thank Dr. Mingming Zhang and Mr. Duk Kim for their early explor-
atory work and Mr. Justin Reinicke for technical assistance with HRMS
data. We also thank the chiral screening team at Phenomenex for as-
sisting us with chiral HPLC method development. We are grateful to
Prof. T. Ross Kelly at Boston College for providing valuable feedback
and sending us their original lab notes related to the synthesis of 9d.
Supporting Information
Supporting information for this article is available online at
N,N′-(2,5-Dihydroxy-1,4-phenylene)bis(2-methyl-3-oxohexan-
amide) (15)
https://doi.org/10.1055/s-0036-1589134.
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Yield: 143 mg (78%) (0.47 mmol scale); H2O was used as the solvent
to give 15 as a grey solid as a mixture of enantiomers (R,R and S,S) and
meso form (S,R = R,S) after filtration and washing with H2O; mp 186–
187 °C; Rf = 0.25 (hexane/EtOAc, 1:1).
References
(1) http://www.who.int/mediacentre/factsheets/fs104/en/.
(2) Martens, E.; Demain, A. L. J. Antibiot. 2017, 70, 520.
(3) Hoagland, D. T.; Liu, J.; Lee, R. B.; Lee, R. E. Adv. Drug Deliv. Rev.
2016, 102, 55.
(4) Mullowney, M. W.; Hwang, C. H.; Newsome, A. G.; Wei, X.;
Tanouye, U.; Wan, B.; Carlson, S.; Barranis, N. J.; Ainmhire, E. Ó.;
Chen, W.-L.; Krishnamoorthy, K.; White, J.; Blair, R.; Lee, H.;
Burdette, J. E.; Rathod, P. K.; Parish, T.; Cho, S.; Franzblau, S. G.;
Murphy, B. T. ACS Infect. Dis. 2015, 1, 168.
HPLC purity: 97.6% (254 nm), 98.2% (220 nm); tR = 6.24 min.
1H NMR (400 MHz, DMSO-d6): δ = 9.39 (s, 2 H), 9.24 (s, 2 H), 7.50 (s, 2
H), 3.89 (q, J = 6.85 Hz, 2 H), 2.49–2.55 (m, 4 H), 1.43–1.52 (m, 4 H),
1.19 (d, J = 6.85 Hz, 6 H), 0.82 (t, J = 7.34 Hz, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 206.8, 168.7, 139.7, 122.0, 109.1,
53.5, 42.1, 16.6, 13.5, 13.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O6+: 393.2020; found:
393.2038; m/z [M + Na]+ calcd for C20H28N2O6Na+: 415.1840; found:
415.1859.
(5) Kelly, T. R.; Field, J. A.; Li, Q. Tetrahedron Lett. 1988, 29, 3545.
(6) Bair, J. S.; Palchaudhuri, R.; Hergenrother, P. J. J. Am. Chem. Soc.
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(7) Perez, J. M.; Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C.
Tetrahedron Lett. 1998, 39, 673.
N,N′-(2,5-Dioxocyclohexa-3,6-diene-1,3-diyl)bis(2-methyl-3-oxo-
hexanamide) (16)
(8) Lee, H.; Anderson, W. K. Tetrahedron Lett. 1990, 31, 4405.
(9) Perez, J. M.; Lopez-Alvarado, P.; Pascual-Alfonso, E.; Avendano,
C.; Menendez, J. C. Tetrahedron 2000, 56, 4575.
(10) Forbis, R. M.; Rinehart, K. L. Jr. J. Am. Chem. Soc. 1973, 95, 5003.
(11) Nesterenko, V. Ph.D. Thesis; University of Illinois at Urbana-
Champaign: USA, 2006.
DDQ (11 mg, 0.048 mmol) was added to a solution of 1d (19 mg,
0.048 mmol) in CH2Cl2 (2 mL) and stirred at r.t. for 30 min. The reac-
tion mixture was filtered and the filtrate was concentrated in vacuo
to yield an oil that was purified by flash chromatography (silica gel,
hexane/EtOAc 9:1 to 3:2, v/v) affording 16 (15 mg, 0.038 mmol, 80%)
as an orange oil as a mixture of enantiomers (R,R and S,S) and meso
form (S,R = R,S); Rf = 0.57 (hexane/EtOAc, 1:1).
(12) Bair, J. S. Ph.D. Thesis; University of Illinois at Urbana-Cham-
paign: USA, 2012.
HPLC purity: 91.4% (254 nm), 100.0% (220 nm); tR = 6.80 min.
(13) Nissen, F.; Detert, H. Eur. J. Org. Chem. 2011, 15, 2845.
(14) Burger, A.; Fitchett, G. T. J. Am. Chem. Soc. 1953, 75, 1359.
(15) Ghorai, D.; Kumar, S.; Mani, G. Dalton Trans. 2012, 41, 9503.
(16) Sai, K. K.; Gilbert, T. M.; Klumpp, D. A. J. Org. Chem. 2007, 72,
9761.
(17) Staskun, B. J. Org. Chem. 1964, 29, 1153.
(18) Ōmura, S.; Iwai, Y.; Hinotozawa, K.; Tanaka, H.; Takahashi, Y.;
Nakagawa, A. J. Antibiot. 1982, 35, 1425.
1H NMR (400 MHz, CDCl3): δ = 9.39 (s, 2 H), 9.38 (s, 2 H), 7.48 (s, 4 H),
3.62 (q, J = 7.34 Hz, 4 H), 2.58 (t, J = 7.21 Hz, 8 H), 1.58–1.69 (m, 8 H),
1.50 (d, J = 7.34 Hz, 12 H), 0.92 (t, J = 7.46 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 209.72, 209.69, 188.7, 179.2, 169.11,
169.09, 136.5, 116.4, 54.7, 44.2, 44.1, 16.9, 16.02, 15.96, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H27N2O6+: 391.1864; found:
391.1866; m/z [M + Na]+ calcd for C20H26N2O6Na+: 413.1683; found:
413.1690.
(19) Ōmura, S.; Nakagawa, A.; Aoyama, H.; Hinotozawa, K.; Sano, H.
Tetrahedron Lett. 1983, 24, 3643.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M