The one-pot synthesis of amidonapthoquinones from aminonaphthoquinones

Article abstract of DOI:10.1016/j.tetlet.2020.151800

Described here is a one-pot method of synthesizing amidonaphthoquinones from the corresponding aminonaphthoquinones. The scope of amides that can be synthesized using this methodology is relatively broad and the yield of product is higher than the traditional methods of synthesizing these substrates. 2009 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2020.151800

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The one-pot synthesis of amidonapthoquinones from aminonaphthoquinones
Jinya Yin, Jon.D. Rainier
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S0040-4039(20)30235-5
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https://doi.org/10.1016/j.tetlet.2020.151800
TETL 151800
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Tetrahedron Letters
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26 February 2020
2 March 2020
Please cite this article as: Yin, J., Rainier, Jon.D., The one-pot synthesis of amidonapthoquinones from
aminonaphthoquinones, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151800
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The One-Pot Synthesis of
Amidonapthoquinones from
Aminonaphthoquinones
Leave this area blank for abstract info.
Jinya Yin
Jon D. Rainier*

1
Tetrahedron Letters
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The one-pot synthesis of amidonapthoquinones from aminonaphthoquinones
Jinya Yina , Jon D. Rainiera, 
aDepartment of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT, 84112, USA
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu
Article history:
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Described here is a one-pot method of synthesizing amidonaphthoquinones from the
corresponding aminonaphthoquinones. The scope of amides that can be synthesized using this
methodology is relatively broad and the yield of product is higher than the traditional methods of
synthesizing these substrates.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
amidoquinone
synthesis
reduction
tandem reaction
Scheme 1 Synthesis of amidoquinone through aminohydroquinone.4
1. Introduction
2. Results and discussion
Amidonaphthoquinones are found in a number of natural
products and biologically relevant molecular targets.1 However,
their synthesis from the corresponding aminonaphthoquinones
has generally been problematic. That the nitrogen atom is part of
a vinylogous amide is undoubtedly responsible for this lack of
In an effort to improve upon this multistep protocol, we
considered whether a one-pot aminonaphthoquinone reduction,
amide formation, and aerobic oxidation sequence might be more
successful and were encouraged that Corey and Clark had
previously communicated a related approach during their
generation of the rifamycin ansa-lactam. As outlined in Scheme
2, they reduced the rifamycin aminonaphthoquinone using
Pd/CaCO3 and H2, filtered the catalyst away from the resulting
hydroquinone, and then converted it into the desired rifamycin
ansa-lactam by heating the reaction mixture to 50 °C. Oxidation
of the hydroquinone using potassium ferricyanide enabled them
to convert it to naphthoquinone 5.5 In light of the importance of
amidonaphthoquinones, it was surprising to us that in the years
subsequent to the Corey work that the in situ reduction protocol
has not been examined in any significant detail.
reactivity.1 As
a consequence, amidonaphthoquinones are
commonly generated from the corresponding protected
aminohydroquinones followed by deprotection and oxidation
(Scheme 1). As an example of such a strategy, DeBrabander and
co-workers recently synthesized the amidonaphthoquinone of
salinisporamycin by generating the amide from the
hydronaphthoquinone and subsequently oxidizing the
hydroquinone.2 They turned to this indirect strategy only after
struggling to couple the aminonapthoquinone with the requisite
carboxylic acid. While they do not explicitly state their
examination of the necessary aminonaphthoquinone, Lang and
Groth applied
a
similarly circuitous synthesis of the
amidonaphthoquinone marcanine A.3 Finally, during our recent
study of naphthoquinone acrylamide photoelectrocyclization
reactions we suffered through low yielding amide formation from
the coupling of 2-aminonaphthoquinone with acids or acid
chlorides and were forced to adopt the more roundabout
DeBrabander route to provide the desired substrates (Scheme 1).4
Scheme 2. Corey and Clark’s Reductive Macrocyclization to the Rifamycin
Ansalactam.5
To get a sense of whether the one-pot process could be used to
generate the amidonaphthoquinones of interest to us, we initially
examined whether a modified Corey/Clark protocol could be
applied to 2-aminonaphthoquinone 7 to give acrylamide 10
(Scheme 3). We synthesized aminoquinone 7, the starting
compound for the one-pot protocol, in 83% overall yield from

2
Tetrahedron Letters
1,4-naphthoquinone using Fieser’s conditions.6 From 7, we
Entry
Product
1-pot yielda,b
77%
6-step yield
-----d
10
found that the in situ reduction, coupling, oxidation sequence
worked well. Our optimized conditions involved the sequential
hydrogenation of the quinone using 10% Pd/C and H2 (1 atm), a
N2 purge to replace the remaining H2, the rapid addition of
crotonyl chloride and NaHCO3, filtration to remove the Pd/C and
NaHCO3, and exposure of the reaction mixture to the
atmosphere.14 This sequence gave amidonaphthoquinone 10 in
69% yield. To put this result into perspective, the synthesis of 10
using the 6-step approach that was outlined in Scheme 1 required
5 chromatographic purifications and gave 10 in 29% overall
yield.
51%
-----d
11
aIsolated yield from compound 7. bYields in parentheses are calculated from 1,4-
naphthoquinone. cUsed 2 equivalent of acid chloride. dNot determined.
We next explored the scope of the sequence (Table 1). As
illustrated, a range of acid chlorides were amenable to the
protocol giving overall yields that were significantly higher than
the multi-step approach.7 Of note was that the reactions were
relatively simple to perform, they did not require the purification
of the intermediates, they generally did not result in alkene
reduction, that sensitive substrates like dienamide 16 could be
generated,10 and that -unsaturated amidonaphthoquinone 17
did not undergo isomerization using this protocol.11 Limiting at
this stage was that these conditions appear to be restricted to the
use of acid chlorides; the use of EDC in the coupling of 8 with
crotonic acid resulted in a 19% yield of 10. Also limiting in
instances where the acid chloride might be valuable was that
substrates having an α-substituent required the use of 2
equivalents of the acid chlorides to obtain yields that were
acceptable (entries 5-7).
Scheme 3. One-Pot Synthesis of Acrylamide 10 via the in situ Reduction of
Aminonaphthoquinone 7.
Table 1. One-Post Amide Couplings-Substrate Scope.
Entry
Product
1-pot yielda,b
69%
6-step yield
1
29%
(57%)
We also were able to convert napthoquinones having
substitution at the 3-position into the corresponding acrylamides.
2
3
4
5
70%
(58%)
30%
41%
33%
23%
Specifically,
2-amino-3-methoxy
and
2-amino-3-
chloronaphthaquinones were converted into acrylamides 19 and
20,8,9 respectively, in good overall yields thus demonstrating
some of the scope for this methodology (entries 10 and 11).12,13
66%
(55%)
To summarize, we have optimized and examined the scope of
a
one-pot method of synthesizing 2-amidonaphthoquinone
72%
(60%)
derivatives from aminonapthoquinones. This method was shown
to be generally superior when compared to stepwise approaches
to this family of substrates. We will continue to utilize and
optimize this protocol.
71% c
(59%)
6
7
8
71%c
(59%)
39%
-----d
32%
41%
40%c,
(33%)
73%
(61%)
79%
9
(66%)
and Dr. Peter Flynn (University of Utah) and Dr. Hsiaonung
Chen (University of Utah) for their help with NMR and Mass
Spectrometry, respectively.
Acknowledgments
Support from the National Science Foundation (CHE
1465113) and the National Institutes of Health (GM132531-
01) is gratefully acknowledged. The authors are thankful to
Mr. Minh Nguyen for carrying out preliminary experiments
References and notes
1.
Qiu, H.-Y.; Wang, P.-F.; Lin, H.-Y.; Tang, C.-Y.; Zhu, H.-L.; Yang, Y.-
H. Napthoquinones: A continuing source for discovery of

3
therapeutic antineoplastic agents. Chem. Biol. Drug Des. 2018,
91, 681-690.
2944, 1673, 1589, 1433, 1360, 1274, 1255, 1158, 1058, 990 cm–
1; HRMS (ESI) calcd. for C14H12NO3 [M+H]+ 242.0817, found
242.0824.
2.
3.
Yu Feng, Jun Liu, Yazmin P. Carrasco, John B. MacMillan, and Jef
K. De Brabander. Rifamycin Biosynthetic Congeners: Isolation and
Total Synthesis of Rifsaliniketal and Total Synthesis of
Salinisporamycin and Saliniketals A and B. J. Am. Chem. Soc. 2016,
138, 7130−7142.
Steffen Lang, Ulrich Groth. Total Syntheses of Cytotoxic, Naturally
Occurring Kalasinamide, Geovanine, and MarcanineꢀA. Angew.
Chem. Int. Ed. 2009, 48, 911-913.
12. (E)-N-(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)but-2-
enamide (19). 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.3 Hz, 1H),
8.04 (d, J = 7.2 Hz, 1H), 7.72 (dd, J = 7.1, 7.1 Hz, 1H), 7.69 (dd, J =
7.4, 7.4 Hz, 1H), 7.39 (broad s, 1H), 7.00 (dq, J = 15.2, 6.9 Hz, 1H),
6.07 (d, J = 15.3 Hz, 1H), 4.18 (s, 3H), 1.93 (d, J = 6.9 Hz, 3H); 13
C
NMR (126 MHz, CDCl3) δ 182.4, 181.4, 163.5, 150.3, 143.2, 134.2,
133.9, 131.6, 130.5, 127.0, 126.7, 126.4, 124.7, 60.6, 18.1. IR
(neat) 3243, 3015, 1669, 1640, 1620, 1593, 1582, 1525, 1445,
1336, 1317, 1300, 1264, 1213, 1193, 1041, 1010, 966 cm–1; HRMS
(ESI) calcd. for C15H14NO4 [M+H]+ 272.0923, found 272.0925.
13. (E)-N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)but-2-
enamide (20). mp 116-117 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.20
(dd, J = 7.0, 1.2 Hz, 1H), 8.12 (dd, J = 7.3, 1.1 Hz, 1H), 7.79 (ddd, J
= 7.3, 7.3, 1.2 Hz, 1H), 7.76 (ddd, J = 7.4, 7.4, 1.3 Hz, 1H), 7.71
(broad s, 1H), 7.08 (dq, J = 15.2, 6.9 Hz, 1H), 6.09 (dd, J = 15.2, 1.5
Hz, 1H), 1.97 (dd, J = 6.9, 1.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
180.1, 177.8, 162.2, 145.0, 139.4, 135.0, 134.2, 132.8, 131.8,
130.4, 127.7, 127.2, 124.4, 18.3; IR (neat) 3247, 1687, 1669, 1647,
1616, 1591, 1515, 1334, 1308, 1288, 1249, 1206, 1101, 977 cm–1;
HRMS (ESI) calcd. for C14H10NO3Na35Cl [M+Na]+ 298.0247, found
298.0252; calcd. for C14H10NO3Na37Cl [M+Na]+ 300.0217, found
300.0232.
14. General procedure for the hydrogenation coupling oxidation
protocol: To a solution of 2-amino-1,4-naphthaquinone (87 mg,
0.5 mmol) in THF (6 mL) at rt was added 10% Pd/C (9 mg). The
resulting mixture was charged with H2 gas (1 atm) and allowed to
stir overnight. After this time period the H2 balloon was removed
and the reaction mixture was purged with N2 for 5 min. To the
resulting reaction mixture was added a solution of the acid
chloride (0.55 or 1.00 mmol) in CH2Cl2 (2 mL) via syringe. The
resulting mixture was stirred at rt for 10 min and NaHCO3 (46 mg,
0.55 mmol or 84 mg, 1 mmol) was added. After stirring for an
additional 10 min the reaction mixture was passed through a
short pad of Celite using EtOAc (20 mL). The filtrate was then
exposed to the atmosphere at rt for 1 day. The reaction mixture
was concentrated and the resulting residue was purified using
flash column chromatography (hexanes:ethyl acetate).
4. Yin, J.; Landward, M.B.; Rainier, J. D. Photoelectrocyclization
Reactions of Amidonaphthoquinones. J. Org. Chem. 2020, 85, In
Press.
5.
E. J. Corey, David A. Clark. Studies on the total synthesis of
rifamycin. A method for the closure of the macrocyclic unit.
Tetrahedron. Lett. 1980, 21, 2045–2048.
6. Fieser, L.F.; Hartwell, J.L. The Reaction of Hydrazoic Acid with the
Naphthoquinones. J. Am. Chem. Soc. 1935, 57, 1482-1484.
7. Compound 18 is known, see: Zhang, C.; Chou, J.C. Metal-Free
Direct Amidation of Naphthoquinones Using Hydroxamic Acids as
an Amide Source: Application in the Synthesis of an HDAC6
Inhibitor. Org. Lett. 2016, 18, 5512-5515.
8. For the synthesis of the aminoquinone that leads to 19 see: (a)
Brandy, Y.; Brandy, N.; Akinboye, E.; Lewis, M.; Mouamba, C.;
Mack, S.; Butcher, R.; Anderson, A.J.; Bakare, O. Synthesis and
Characterization of Novel Unsymmetrical and Symmetrical 3-
Halo- or 3-Methoxy-substituted 2-Dibenzoylamino-1,4-
naphthoquinone Derivatives. Molecules 2013, 18, 1973-1984. (b)
Bakare, O.; Ashendel, C.L.; Peng, H.; Zalkow, L.H.; Burgess, E.M.
Synthesis and MEK1 inhibitory activities of imido-substituted 2-
Chloro-1,4-naphthoquinone. Bioorg. Med. Chem. 2003, 11, 3165-
3170.
9. For the synthesis of the aminoquinone that leads to 20 see: Diaz,
R.; Reyes, O.; Francois, A.; Leiva, A.M.; Loeb, B. Synthesis of a new
polypyridinic highly conjugated ligand with electron-acceptor
properties. Tetrahedron Lett. 2001, 43, 5353-6467.
10. (E)-N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2,5-dimethylhexa-
2,4-dienamide (16). mp 169-173 ˚C; 1H NMR (500 MHz, CDCl3) δ
8.85 (broad s, 1H), 8.10 (dd, J = 7.8, 1.1 Hz, 2H), 7.91 (s, 1H), 7.77
(ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 7.71 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H),
7.36 (d, J = 11.6 Hz, 1H), 6.16 (d, J = 11.6 Hz, 1H), 2.07 (s, 3H),
1.94 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 185.4, 181.6, 168.0,
146.3, 140.4, 135.1, 133.4, 133.3, 132.4, 130.1, 126.7, 126.5,
126.3, 120.9, 116.8, 27.2, 19.2, 12.6; IR (neat) 3370, 2916, 2861,
1665, 1641, 1628, 1590, 1578, 1503, 1477, 1446, 1380, 1333,
1297, 1226, 1199, 1157, 1095 cm–1; HRMS (ESI) calcd. for
C18H18NO3 [M+H]+ 296.1287, found 296.1293.
11. N-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)but-3-enamide (17). mp
158-160 ˚C; 1H NMR (500 MHz, CDCl3) δ 8.55 (broad s, 1H), 8.10
(partially obscured dd, J = 7.7, 0.9 Hz, 1H), 8.09 (partially
obscured dd, J = 7.7, 1.2 Hz, 1H), 7.85 (s, 1H), 7.78 (ddd, J = 7.5,
7.5, 1.3 Hz, 1H), 7.71 (ddd, J = 7.6, 7.6, 1.3 Hz, 1H), 6.02 (ddt, J =
17.2, 10.1, 7.1 Hz, 1H), 5.40 (dd, J = 10.4, 1.0 Hz, 1H), 5.37 (dd, J =
17.2, 1.3 Hz, 1H) 3.27 (d, J = 7.1 Hz, 2H); 13C NMR (126 MHz,
CDCl3) δ 185.3, 181.2, 170.0, 139.9, 135.1, 133.4, 132.3, 130.1,
129.8, 126.8, 126.6, 121.5, 117.4, 43.1; IR (neat) 3202, 3069,
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4
Tetrahedron
Highlights



The efficient synthesis of
amidonapthoquinones from
aminoquinones.
Coupling the one-pot reduction of
quinones with amide formation and
atmospheric re-oxidation.
The incorporation of unsaturated amides
into aminoquinones.