Exploiting Alkylquinone Tautomerization for the Total Synthesis of Calothrixin A and B

Article abstract of DOI:10.1021/acs.joc.7b02101

The pentacyclic alkaloid calothrixin B (1) has been synthesized in 5 steps from murrayaquinone A (9). The key step involved the union of boryl aniline 31 with brominated murrayaquinone A (26). In this transformation, alkylquinone 26 undergoes tautomerization to a quinone methide, which is intercepted by boryl aniline 31 to forge a new C-N bond. An intramolecular Suzuki coupling, followed by dehydrogenative aromatization, completed the synthesis of calothrixin B. Subsequent N-oxidation of calothrixin B delivered calothrixin A. The successful synthesis of these alkaloids and the challenges that led to the development of the final synthesis plan are reported herein.

Full text of DOI:10.1021/acs.joc.7b02101

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Article
Total Synthesis of Calothrixin A & B by
Exploiting Alkylquinone Tautomerization
Luis M. Mori-Quiroz, Madeline M. Dekarske, Austin B. Prinkki, and Michael D. Clift
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 31 Oct 2017
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Total Synthesis of Calothrixin A & B by Exploiting Alkylquinone Tautomerization
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Luis M. MoriꢀQuiroz, Madeline M. Dekarske, Austin B. Prinkki and Michael D. Clift*
Department of Chemistry, The University of Kansas, Lawrence, KS, 66045
mclift@ku.edu
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ABSTRACT: The pentacyclic alkaloid calothrixin B (1) has been synthesized in 5 steps from
murrayaquinone A (9). The key step involved the union of boryl aniline 31 with brominated
murrayaquinone A (26). In this transformation, alkylquinone 26 undergoes tautomerization to a quinone
methide which is intercepted by boryl aniline 31 to forge a new C–N bond. An intramolecular Suzuki
coupling, followed by dehydrogenative aromatization, completed the synthesis of calothrixin B.
Subsequent Nꢀoxidation of calothrixin B delivered calothrixin A. The successful synthesis of these
alkaloids and the challenges that led to the development of the final synthesis plan are reported herein.
INTRODUCTION
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Calothrixin B (1) and its Nꢀoxide, calothrixin A (2), are pentacyclic alkaloids first isolated from calothrix cyanobacteria in
1999 by Rickards, Smith and coworkers.1 Their structure comprises a 1,4ꢀbenzoquinone flanked by indole and quinoline
scaffolds, making them unique among related phenanthridine alkaloids (Figure 1). Their interesting biological activities,
including potent antimalarial and anticancer activities,1, 2 have attracted the attention of synthetic chemists, resulting in several
total and formal syntheses.3 Although a few of these are rather concise and efficient, we believed that application of
methodology developed in our lab would not only allow for a comparably short and scalable synthesis of calothrixin B, but also
validate this method as a useful tool to efficiently access related phenanthridineꢀcontaining natural products and analogues
possessing interesting biological activities.
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Figure 1. Representative phenanthridineꢀcontaining alkaloids.
We recently reported a robust protocol to access benzylic amines from alkylquinones and primary or secondary amines.4 The
reaction proceeds by tautomerization of the alkylquinone to generate an orthoꢀquinone methide intermediate that is subsequently
trapped by the amine, delivering an aminated dihydroquinone. Reactions involving alkylquinone tautomerization were first
reported nearly a century ago,5ꢀ7 but only recently has this type of reactivity been exploited to develop efficient transformations,
including cycloadditions8 and electrocyclizations (see below). Relative to other methods to generate quinone methides,9 such as
thermolysis, photolysis and elimination reactions of phenol derivatives, alkylquinone tautomerization offers several advantages:
1) it avoids the need for prior functionalization (e.g. the installation of a leaving group), effectively leading to full atom
economy, 2) tautomerization typically proceeds under very mild conditions and therefore has great potential for application in
complex molecule synthesis.
In the context of natural product total synthesis, alkylquinone tautomerization has been applied in a few cases involving
intramolecular C–C and C–O bond forming processes. Pettus applied an alkylquinone tautomerization / intramolecular arylation
sequence to the total synthesis of (±)ꢀbrazilin,10 whereas Trauner devised ingenious alkylquinone tautomerization /
electrocyclization cascades to complete the total syntheses of mollugin, microphyllaquinone, and exiguamines A and B.11
Trauner also applied alkylquinone tautomerization in the total synthesis of rubioncolin B involving an intramolecular Dielsꢀ
Alder reaction of the generated quinone methide intermediate.12 Despite these successful examples, the amination of quinone
methide intermediates has remained largely ignored and has not been applied in natural product total synthesis. We therefore set
out to demonstrate the utility of alkylquinone amination as a tool for the concise and efficient assembly of alkaloid natural
products by targeting calothrixin B for total synthesis.
RESULTS AND DISCUSSION
Initial synthetic plan
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Our initial retrosynthetic analysis of calothrixin B involved disconnection of 2 C–C bonds and 2 C–N bonds, thus revealing
three simple building blocks: methylꢀpꢀbenzoquinone and 2 molecules of aniline (Scheme 1). In the forward sense, the known
quinone 5 is obtained by a selective conjugate addition of aniline to methylꢀpꢀbenzoquinone. Next, we envisioned that
alkylquinone 5 would undergo tautomerization to give its corresponding quinone methide 6 followed by nucleophilic trapping
with a second molecule of aniline, delivering 7 after oxidation of the dihydroquinone (not shown). A double, intramolecular
dehydrogenative coupling involving intermediate 7 would complete the synthesis of calothrixin B.
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Scheme 1. Retrosynthetic analysis for calothrixin B.
To test this strategy, we prepared alkylquinone 5 and explored its amination with aniline (Scheme 2); however, under a
variety of reactions conditions, including those we had previously developed,4 we were unable to detect any of the amination
product 8, or its oxidized derivative 7. It is important to mention that 5 does undergoes amination with secondary alkylamines in
modest yields, which suggested the failure to form any detectable amount of 7 or 8 is related to the attenuated nucleophilicity of
aniline.
Scheme 2. Attempted amination of alkylquinone 5 with aniline.
Alternative synthetic approach
Given that amination of 5 with aniline was not possible, our original retrosynthesis was revised to focus on two key
disconnections of 1, leading back to murrayaquinone A and aniline as potential precursors (Scheme 3). In the forward sense,
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amination of alkylquinone 9 would deliver, after oxidation of the dihydroquinone (not shown), tetracyclic quinone 11.
Intermediate 11 would then undergo a metalꢀcatalyzed intramolecular cyclization and subsequent dehydrogenation, leading to
calothrixin B. Murrayaquinone A, itself a natural product isolated from the root bark of Murraya euchrestifolia Hayata,13 is
commercially available or prepared in two steps from aniline and methylꢀpꢀbenzoquinone.14
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Scheme 3. Alternative retrosynthesis for calothrixin B leading to murrayaquinone A and aniline as building blocks.
Amination of murrayaquinone A: Preliminary experiments
We first attempted the amination of murrayaquinone A (9) with aniline under conditions previously optimized in our group,4
using iso-propanol as a solvent and triethylamine as a base. However, the limited solubility of 9 in isoꢀpropanol forced us to
examine other more polar (co)solvents. Unfortunately, these experiments were unsuccessful and none of the desired aminated
product (12) was ever observed (Scheme 4, eq. 1). Increased temperature and use of different bases led to extensive
decomposition. We attributed the failure of the reaction to two factors: 1) the low nucleophilicity of aniline, and 2) slow
tautomerization of 9 made other side reactions competitive, particularly electronꢀtransfer processes that eventually led to
reduction and/or decomposition of the alkylquinone 9.
Scheme 4. Preliminary studies.
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In order to test these hypotheses, we independently subjected both reactants, aniline and murrayaquinone, to the optimal
amination reaction conditions with competent reaction partners (scheme 4, eq. 2 and 3). We assessed the capability of aniline as
a reaction partner by testing its ability to react with 2,6ꢀdimethylbenzoquinone (13), an alkylquinone that reacted cleanly with a
wide range of substrates in our prior work.4 Reaction of alkylquinone 13 with aniline led to the amination product 14 in only
23% NMR yield, together with 38% of 2,6ꢀdimethylhydroquinone and decomposition products (scheme 4, eq. 2). In a similar
way, we evaluated the competency of 9 to undergo amination with dibenzylamine, an amine that had previously reacted
efficiently with a variety of alkylquinones. Reaction of 9 with dibenzylamine afforded, after oxidation upon exposure to air, 46%
yield of aminated quinone 15 and 15% of recovered murrayaquinone A. These experiments illustrate the modest reactivity of 9
towards amination and the poor performance of aniline as a reaction partner for this amination reaction.
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1st Generation approach: Amination of (NꢀBoc) murrayaquinone A (19) with Nꢀalkyl anilines
To address these reactivity issues, we first tested the amination of murrayaquinone A (9) using a more nucleophilic 2º NꢀPMB
aniline. Indeed this allowed the desired amination of 9 to proceed, affording a mixture of dihydroquinone 16 and quinone 17.
After exposure of the crude reaction mixture to air for 3 h, 17 was isolated in 36% yield (Scheme 5). Careful analysis of the
reaction mixture before aerobic oxidation also revealed the presence of reduced 9 (not shown). Since the reaction is run in the
absence of oxygen, the formation of reduced 9 and product 17 is likely a consequence of a redox reaction between 9 (oxidant)
and the initial aminated product 16 (reductant), which unproductively consumes 9. We reasoned that using a sacrificial oxidant
might oxidize the initial hydroquinone 16 to final product 17, effectively mitigating the undesired reduction of 9. Unfortunately,
addition of organic or inorganic oxidants led to lower yields or only marginal improvement, and other attempts to improve the
efficiency of the reaction were unsuccessful. Finally, we attempted the oxidative cyclization of 17 employing catalytic or
stoichiometric Pd(II) salts, in the presence of different bases and oxidants; however, we only observed decomposition of 17.
Scheme 5. Successful amination of murrayaquinone A (9) with NꢀPMB aniline and failed dehydrogenative coupling.
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We recognized that the electronꢀrich indole of 9 may be attenuating the electrophilicity of the corresponding quinone methide
and subsequently increasing the likelihood that the desired amination product 16 engages in redox reactions with the remaining
starting material 9. To address these issues, we installed a tertꢀbutoxycarbonyl (Boc) group on nitrogen to reduce the electronꢀ
donating capacity of the indole (table 1). Protection of the indole under standard conditions took place efficiently (96% yield).
Under optimized conditions, employing excess iꢀPr2NEt in THF, reaction of Boc protected murrayaquinone A (19) with Nꢀalkyl
aniline derivatives provided the corresponding aminated products 20aꢀc in good yields (Table 1). Compound 20a could be
isolated in 79% yield (entry 1), however compounds 20b and 20c underwent partial oxidation to 21b and 21c (entries 2 and 3)
during the isolation procedure and could not be purified. Complete oxidation of 20aꢀc with FeCl3 afforded the quinones 21aꢀc in
good yields (table 1).
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Entry
R2
PMB
allyl
Me
Product 20 Yield 20 (%) Product 21 Yield 21 (%)
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a Boc2O (1.5 equiv), DMAP (0.1 equiv), CH2Cl2, 96%. b FeCl3, MeCN, rt, or Ag2O, MeCN, rt. c NMR yield, 10:1 mixture of
20b / 21b. d NMR yield, 7:1 mixture of 20c / 21c.
Table 1. Amination of NꢀBoc murrayaquinone with different Nꢀalkyl aniline derivatives and oxidation to the corresponding
quinones 21aꢀc.
Attempted dehydrogenative cyclization of aminated quinones
Having optimized the amination step, we then focused on the oxidative C–C bond formation (Scheme 6). Treatment of
compounds 21aꢀc with catalytic or stoichiometric Pd(II) salts under conditions developed for related dehydrogenative
cyclizations,15 led mostly to decomposition of the starting material. The only products that could be identified in reactions of 21a
and 21b were NꢀPMB aniline and Nꢀallyl aniline, suggesting C–N bond cleavage as a competitive side reaction. We wondered
whether the Nꢀalkyl groups were detrimental for the desired cyclization and therefore attempted removing them under standard
oxidative (Table 1, 21a, R2=PMB) or reductive (20a and 20b, R2=PMB and allyl, respectively) conditions but this led to
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complete decomposition. Given that the dehydrogenative cyclization of compounds 21 did not take place at all, we decided to
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once again modify our synthetic strategy.
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Scheme 6. Attempted dehydrogenative cyclization of aminated murrayaquinone A derivatives 21a−c.
2nd Generation approach: synthesis of brominated precursors to avoid unsuccessful dehydrogenative coupling
Although we were able to establish optimal conditions for the amination of NꢀBoc murrayaquinone (9), the final
dehydrogenative cyclization proved to be more challenging than expected. We sought to solve this problem by introducing a
bromo substituent either at the ortho position of the aniline (as in 24, Figure 2), or at the quinone ring (as in 28). We expected
that clean oxidative addition of a Pd(0) catalyst to the C–Br bond in either 24 or 28 would lead to an organopalladium (II)
species capable of undergoing intramolecular C–H activation and subsequent reductive elimination to forge the final pyridyl ring
of calothrixin B.16
Figure 2. Brominated derivatives 24 and 28 as potential precursors to enable formation of the pyridyl ring.
In order to access 24, we first subjected 19 to amination with NꢀPMBꢀ2ꢀbromoaniline under previously optimized conditions
(scheme 7). Unfortunately the amination proceeded sluggishly to give 23 in only 22% yield, presumably due to both decreased
nucleophilicity of the amine and steric hindrance introduced by the 2ꢀbromo substituent. Modification of the reaction conditions
did not improve the yield of the reaction; for instance, running the reaction at higher temperature (dioxane, 80 ºC) led to
significant unproductive dimerization of the alkylquinone (D1, Figure 3).17 The dimerization of alkylquinones by [4+2]
cycloaddition under basic conditions has been previously observed.18
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Scheme 7. Synthesis of aminated quinones 24 and 28 and attempted cyclization.
Figure 3. Competitive cycloaddition of quinone methide derived from 19 led to D1.
Despite the low yields, we isolated compound 23 and oxidized it to the corresponding quinone 24 in 97% yield. Treatment of
24 with Pd(PPh3)4 led to regioselective 5ꢀexoꢀtrig cyclization to give the spirocyclic product 25. Given that the inherent
regioselectivity of the carbopalladation event would likely be difficult to overcome,19 we decided to pursue the alternative route
by targeting quinone 28.
Towards that end, bromination of NꢀBoc murrayaquinone A proceeded efficiently to give 26 in 94% yield (Scheme 7). In
stark contrast to reactions of 9 and 19, the more electron deficient alkylquinone derivative 26 underwent efficient
tautomerization / amination with PMBꢀaniline at room temperature while employing a catalytic amount of iꢀPr2NEt, affording
hydroquinone 27 in 90% yield. Oxidation led to quinone 28 in 88% yield. We initially tested the cyclization of 28 by employing
catalytic Pd(PPh3)4 under different conditions, however no cyclization was observed. Under stoichiometric conditions, oxidative
addition of Pd(PPh3)4 to 28 took place cleanly (scheme 7) and we were able to isolate the Pd(II) complex 29 and confirm its
structure by xꢀray crystallographic analysis. Unfortunately, attempts at promoting intramolecular C–H palladation of the pendant
aniline, and subsequent reductive elimination to 22a were not successful (Scheme 8).
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Scheme 8. Attempts at cyclizing the oxidative addition product 29.
Although our second generation approach was not successful, we learned that brominated substrates 24 and 28 underwent
efficient oxidative addition with Pd(0); however, intramolecular palladation was unsuccessful. Further, we learned that bromoꢀ
murrayaquinone A (26) undergoes highly efficient amination. This led as to consider a double functionalization strategy to
complete the cyclization step.
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3rd Generation approach: synthesis of Suzuki reaction precursors using 2ꢀborylanilines
Given that the cyclization did not take place with our previous approaches, we decided to target doubly functionalized
substrates capable of undergoing an intramolecular Suzuki reaction. Towards this end, we performed the amination of
brominated alkylquinone 26 with 2ꢀborylated anilines 30 and 31 (Scheme 9). Aniline 30 is accessible in one step from
commercially available 31 by standard reductive amination with pꢀanisaldehyde. Amination of 26 with NꢀPMB 2ꢀboryl aniline
30 proceeded in good yield (93%) using catalytic iꢀPr2NEt (20 mol%). Product 32 and its oxidized derivative 34 proved to be
difficult to purify, apparently due to instability in silica or alumina. Attempts to purify 32 and 34 by recrystallization also failed.
Inability to purify 32 and 34 forced us to turn to aniline 31 as a potential reaction partner and quite surprisingly, amination of
26 took place efficiently to give compound 33 in 67% yield. The observed reactivity of 31 in the amination reaction is
particularly interesting when compared with the poor reactivity of aniline and 2ꢀbromoaniline. We suspect that resonance
delocalization of the nitrogen lone pair into the aryl ring is decreased due to difficulty in attaining an optimal, parallel orientation
with the π system because of the steric demand created by the adjacent BPin group; this effectively increases the nucleophilicity
of nitrogen and facilitates productive amination. Hydroquinone 33 was more stable than its PMB analogue 32, and could be
purified without significant decomposition and subsequently oxidized to quinone 35 in good yield.
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Scheme 9. Amination of 26 with orthoꢀboryl anilines 30 and 31 and completion of calothrixin B and A. a NMR yield.
Finally, treatment of 35 with catalytic (dppf)PdCl2 in the presence of potassium carbonate afforded calothrixin B (1) in 79%
overall yield (>1 g scale). The reaction conditions not only led to the desired cyclization, but also concomitant dehydrogenation
of the C–N bond and Boc deprotection to afford 1.20 Treatment of calothrixin B with mꢀCPBA in refluxing dichloromethane
afforded calothrixin A (2).3a
CONCLUSIONS
In conclusion, we have synthesized calothrixin B in 5 steps and 45% overall yield from readily available murrayaquinone A
(9). The key step involved an efficient, iꢀPr2NEt catalyzed, amination of NꢀBocꢀ2ꢀbromo murrayaquinone A (26) with 2ꢀ
borylaniline 31. An intramolecular Suzuki reaction, which proceeded with concomitant Boc deprotection and dehydrogenation
completed the synthesis of calothrixin B. Calothrixin A was subsequently accessed using an established protocol for Nꢀ
oxidation. This work has demonstrated that amination via alkylquinone tautomerization is a useful tool to the total synthesis of
phenanthridineꢀcontaining natural products and we are currently pursuing the total synthesis of related alkaloids.
EXPERIMENTAL SECTION
General Information.
All moisture sensitive reactions were performed in ovenꢀdried glassware with Teflonꢀcoated magnetic stirring bars under Ar
atmosphere. Toluene, THF, dioxane, triethylamine and dichloromethane were purified by passing the solvent through activated
alumina using a solvent purification system. Commercial anhydrous diisopropylethylamine and isoꢀpropanol were used as
received. Column chromatography was performed using silica gel (230ꢀ400 mesh, grade 60) or activated neutral alumina (150
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mesh, Brockmann I). Reactions were monitored by Thin Layer Chromatography (silica gel 60 F254) and visualized using UV, or
KMnO4 or PMA stain solutions. 1H NMR, 13C NMR, 11B and 31P NMR spectra were recorded at room temperature on 400 and
500 MHz spectrometers. Chemical shifts are reported in ppm and referenced with respect to residual protic solvent as internal
reference. Infrared spectra was recorded using a iS5 FTIR spectrometer. Mass spectra were obtained on a Micromass LCT
Premier quadrupole and timeꢀofꢀflight tandem mass analyzer.
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2ꢀmethylꢀ5ꢀ(phenylamino)cyclohexaꢀ2,5ꢀdieneꢀ1,4ꢀdione (5).14a Compound 5 was prepared following a reported procedure.14a
A 1 L round bottom flask was charged with a magnetic stirring bar, 2ꢀmethylꢀ1,4ꢀbenzoquinone (6 g, 49.1 mmol, 2 equiv) and
water (600 mL). The suspension was heated to ~60 ºC until most quinone dissolved and then it was cooled down for about 30
min. A solution of aniline (2.29 g, 24.6 mmol, 1 equiv) and acetic acid (2 mL) in water (20 mL) was added the mixture was
vigorously stirred for 6 h. The suspension was extracted with CH2Cl2 (3 x 200 mL). Combined organic extracts were washed
with water (100 mL), NaHCO3 (sat) (2 x 100 mL), dried over MgSO4 and concentrated in vacuo. Flash silica gel chromatography
(3:7 hexanes / CH2Cl2) and recrystallization from warm EtOAc afforded 5 (2.5 g, 48%) as a dark violet solid: mp = 153ꢀ154 ºC;
1H NMR (500 MHz, CDCl3) δ 7.39 (m, 2H), 7.26 (s, 1H), 7.22 – 7.16 (m, 3H), 6.57 (q, J = 1.6 Hz, 1H), 6.18 (s, 1H), 2.10 (d, J
= 1.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 186.7, 183.8, 149.7, 142.9, 137.5, 129.6, 129.3, 125.3, 122.0, 100.9, 16.5. The
spectral data is in accordance with published values.
3ꢀmethylꢀ1Hꢀcarbazoleꢀ1,4(9H)ꢀdione (9, Murrayaquinone A).14b Murrayaquinone A (9) was prepared by a slight
modification of a reported procedure.14b A 100 mL round bottom flask was charged with a magnetic stirbar, quinone 5 (544 mg,
2.55 mmol, 1 equiv), Pd(OAc)2 (85.0 mg, 0.383 mmol. 0.15 equiv), Sn(OAc)2 (90.6 mg, 0.383 mmol, 0.15 equiv) and acetic
acid (51 mL). The flask was capped with a septum and flushed with O2 using a balloon. The reaction mixture was heated in an
oil bath at 90 ºC with vigorous stirring, attached to a O2 balloon. After 9 h the reaction was cooled at room temperature, diluted
with EtOAc (~20 mL) and filtered through celite, rinsing with EtOAc. If precipitation of the product occurred, THF was used to
wash the celite. The filtrate was fully concentrated, the black residue dissolved in THF and loaded into a neutral alumina
column packed with 30% EtOAc in hexanes. The column was run with 30% EtOAc in hexanes to remove the less polar
impurities and then with 30ꢀ50% THF in hexanes. The impure fractions were concentrated and recrystallized from hot EtOAc.
Compound 9 (299.7 mg, 56%) was obtained as a red solid: mp = 241ꢀ242 ºC; 1H NMR (500 MHz, DMSOꢀd6) δ 12.82 (s, 1H),
8.05 (dt, J = 7.9, 1.1 Hz, 1H), 7.57 – 7.51 (m, 1H), 7.38 (m, 1H), 7.31 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 6.62 (q, J = 1.7 Hz, 1H)
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2.07 (d, J = 1.7 Hz, 3H); 13C NMR (126 MHz, DMSO) δ 183.1, 180.1, 148.0, 137.4, 135.9, 131.6, 126.2, 123.8, 123.6, 121.6,
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2ꢀmethylꢀ6ꢀ((phenylamino)methyl)benzeneꢀ1,4ꢀdiol
(14)
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product
2ꢀmethylꢀ6ꢀ
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((phenylimino)methyl)benzeneꢀ1,4ꢀdiol (14ꢀox). A dry 7 mL vial was charged with a magnetic stirbar and 2,6ꢀdimethylꢀ1,4ꢀ
benzoquinone (100 mg, 0.735 mmol, 1 equiv). The vial was capped and evacuated / backfilled with Ar (3 cycles). iꢀPrOH (2.5
mL) was added, followed by aniline (67 ꢀL, 0.735 mmol, 1 equiv) and Et3N (0.1 mL, 0.735 mmol, 1 equiv). The vial was
heated in an aluminum block at 70 ºC for 2 h. The reaction was cooled at room temperature, opened to air and diluted with
EtOAc (2 mL). 1,3,5ꢀtrimethoxybenzene (123.5 mg, 0.735 mmol, 1 equiv) was added and the mixture concentrated in vacuo.
1H NMR analysis of the crude reaction showed 23% yield of benzylic amine product 14, whose mass spectra matched the
expected values. Flash silica gel chromatography (3% MeCN in hexanes) afforded it oxidized derivative, imine 14ꢀox (23.4 mg,
14%) as a red oil. Spectroscopic data for 14ꢀox: 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.41 (m, 2H), 7.30 – 7.24 (m, 3H),
6.82 (dd, J = 2.9, 0.9 Hz, 2H), 6.75 (d, J = 3.0 Hz, 2H), 2.28 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.2, 153.6, 148.1, 147.4,
129.4, 127.6, 126.9, 122.5, 121.1, 118.1, 114.7, 15.65; IR (cmꢀ1) 3361, 2920, 1622, 1601, 1488; HRMS (ESIꢀTOF) m/z [M+H]+
calcd for C14H14NO2+ 228.1025, found 228.1036.
3ꢀ((dibenzylamino)methyl)ꢀ1Hꢀcarbazoleꢀ1,4(9H)ꢀdione (15). A dry 7 mL vial was charged with a magnetic stirbar and
quinone 9 (22 mg, 0.104 mmol, 1 equiv). The vial was capped and evacuated / backfilled with Ar (3 cycles). iꢀPrOH (0.7 mL)
was added, followed by dibenzylamine (21 ꢀL, 0.104 mmol, 1 equiv) and Et3N (15 ꢀL, 0.104 mmol, 1 equiv). The vial was
heated in an aluminum block at 70 ºC for 2 h. The reaction was cooled at room temperature, opened to air, diluted with EtOAc
(2 mL) and stirred for 12 h. 1,3,5ꢀtrimethoxybenzene (17.5 mg, 0.104 mmol, 1 equiv) was added and the mixture concentrated
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in vacuo. H NMR analysis showed 38% yield of quinone 15. Flash silica gel chromatography (18% EtOAc in hexanes)
afforded 15 (19.4 mg, 46%) as a red solid: mp = 90 ºC (decomposition); 1H NMR (500 MHz, CDCl3) δ 9.34 (s, 1H), 8.19 (d, J
= 8.0 Hz, 1H), 7.48 (m, 1H), 7.44 – 7.37 (m, 5H), 7.35 – 7.28 (m, 5H), 7.23 (t, J = 7.4 Hz, 2H), 6.98 (m, 1H), 3.67 (s, 4H), 3.63
– 3.59 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 183.4, 180.5, 149.7, 138.8, 136.9, 135.3, 131.1, 130.3, 129.1, 128.7, 128.5,
127.2, 127.1, 124.3, 122.9, 112.9, 58.9, 51.0; IR (cmꢀ1) 3252, 3027, 2924, 1652, 1636, 1326; HRMS (ESIꢀTOF) m/z [M+H]+
calcd for C27H23N2O2+ 407.1760, found 407.1753.
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3ꢀ(((4ꢀmethoxybenzyl)(phenyl)amino)methyl)ꢀ1Hꢀcarbazoleꢀ1,4(9H)ꢀdione (17). A 7 mL vial was charged with a magnetic
stirring bar, quinone 9 (15 mg, 0.071 mmol, 1 equiv), NꢀPMB aniline (30.3 mg, 0.142 mmol, 2 equiv), closed and evacuated /
backfilled with N2 (3 cycles), then THF (0.75 mL), iꢀPrOH (0.25 mL) and Et3N (99 ꢀL, 0.71 mmol, 10 equiv) were added
consecutively by syrinte. The reaction was stirred at rt for 8 h, then opened to air and stirred for an additional 3 h. The reaction
was then concentrated in vacuo and flash silica gel chromatography (20% THF in hexanes) afforded 17 (10.8 mg, 36%) as a red
solid: mp = 195ꢀ196 ºC; 1H NMR (500 MHz, DMSOꢀ d6) δ 8.06 (dddd, J = 32.4, 8.0, 7.0, 1.2 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H),
7.40 (m, 1H), 7.33 (m, 1H), 7.19 (m, 2H), 7.12 (m, 2H), 6.89 (m, 2H), 6.62 (m, 1 H), 6.16 (t, J = 2.0 Hz, 1H), 4.60 (s, 2H), 4.54
(d, J = 2.0 Hz, 2H) 3.71 (s, 3H); 13C NMR (126 MHz, DMSOꢀ d6) δ 183.2, 179.8, 158.2, 147.7, 146.8, 137.6, 135.9, 130.5,
129.4, 129.2, 128.0, 126.5, 124.1, 123.5, 121.7, 121.6, 116.4, 116.0, 114.0, 112.1, 55.1, 53.0, 49.3; IR (cmꢀ1) 3256, 2929, 1635,
1614, 1505, 1468; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C27H23N2O3+ 423.1709, found 423.1703.
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tertꢀbutyl 3ꢀmethylꢀ1,4ꢀdioxoꢀ1,4ꢀdihydroꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (19). A 200 mL round bottom flask was charged
with a magnetic stibar, quinone 9 (1 g, 4.73 mmol. 1 equiv), THF (80 mL), diꢀtertꢀbutyl dicarbonate (1.34 g, 6.15 mmol, 1.3
equiv) and DMAP (57.8 mg, 0.472 mmol, 0.1 equiv) under air. The reaction mixture was stirred at room temperature and
monitored by TLC. After 2 h the reaction was concentrated to about 20 mL and loaded into a neutral alumina column packed
with 5% EtOAc in hexanes. The product was eluted with 5ꢀ10% EtOAc in hexanes. Compound 19 (1.41 g, 96%) was obtained
as an orange solid: mp = 153–154 ºC (decomposition); 1H NMR (400 MHz, CDCl3) δ 8.31 (dt, J = 7.9, 1.1 Hz, 1H), 8.01 (dt, J
= 8.5, 1.0 Hz, 1H), 7.50 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.41 (ddd, J = 8.0, 7.2, 1.1 Hz, 1H), 6.54 (q, J = 1.6 Hz, 1H), 2.14 (d, J
= 1.6 Hz, 3H), 1.67 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 184.5, 177.7, 148.6, 145.5, 138.32 135.4, 133.6, 128.5, 125.4,
123.6, 123.1, 121.6, 114.3, 86.0, 27.6, 15.4; IR (cmꢀ1) 2979, 1747, 1656, 1534, 1310, 1110; HRMS (ESIꢀTOF) m/z [2M+Na]+
calcd for C36H34N2O8Na+ 645.2213, found 645.2245.
tertꢀbutyl 1,4ꢀdihydroxyꢀ3ꢀ(((4ꢀmethoxybenzyl)(phenyl)amino)methyl)ꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (20a). A dry 7 mL
vial was charged with a magnetic stirbar, quinone 19 (104 mg, 0.334 mmol, 1 equiv) and NꢀPMB aniline (142 mg, 0.668 mmol,
2 equiv). The vial was capped and evacuated / backfilled with Ar (3 cycles). THF (0.7 mL) was added, followed by iꢀPr2NEt
(0.7 mL). The vial was heated in an aluminum block at 65 ºC for 24 h. The reaction was cooled at room temperature, opened to
air and concentrated in vacuo. Flash silica gel chromatography (10–15% EtOAc in hexanes) afforded 20a (139.1 mg, 79%) as a
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light green solid. mp = 145 ºC (decomposition); H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 9.94 (s, 1H), 8.43 (m, 1H), 8.04
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(m, 1H), 7.44 – 7.34 (m, 2H), 7.29 (m, 2H), 7.14 (m, 2H), 7.05 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.79 (m, 3H), 4.35 (s, 2H),
4.31 (s, 2H), 3.77 (s, 3H), 1.77 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 159.0, 154.2, 149.0, 146.1, 137.5, 137.4, 130.6, 129.1,
127.3, 126.4, 126.1, 125.8, 123.9, 123.50, 123.47, 122.0, 118.1, 116.6, 116.4, 116.0, 113.6, 86.5, 58.0, 55.1, 54.3, 28.3; IR (cmꢀ
1) 3137, 2977, 1683, 1511, 1442; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C32H33N2O5+ 525.2384, found 525.2386.
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tertꢀbutyl 3ꢀ((allyl(phenyl)amino)methyl)ꢀ1,4ꢀdihydroxyꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (20b). A dry 7 mL vial was charged
with a magnetic stirbar, quinone 19 (150 mg, 0.482 mmol, 1 equiv) and Nꢀallyl aniline (0.13 mL, 0.964 mmol, 2 equiv). The
vial was capped and evacuated / backfilled with Ar (3 cycles). THF (1 mL) was added, followed by iꢀPr2NEt (1 mL). The vial
was heated in an aluminum block at 65 ºC for 12 h. The reaction was cooled at room temperature, opened to air and
concentrated in vacuo. Flash silica gel chromatography (30–40% CH2Cl2 in hexanes) afforded 20b (139.2 mg, 65%) containing
~9% of quinone 21b as a yellowish foam. The mixture was submitted to the following step without further purification.
Spectral data for 20b: 1H NMR (500 MHz, CDCl3) δ 10.41 (s, 1H), 9.64 (s, 1H), 8.39 (d, J = 7.5 Hz, 1H), 8.06 – 7.99 (m, 1H),
7.42 – 7.27 (m, 4H), 7.20 (m, 2H), 7.03 (m, 1H), 6.77 (s, 1H), 5.83 (m, 1H), 5.25 – 5.12 (m, 2H), 4.46 (s, 2H), 3.87 (d, J = 6.5
Hz, 2H), 1.76 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 154.2, 149.0, 146.0, 137.6, 137.6, 132.0, 129.2, 126.4, 126.2, 123.9,
123.6, 123.0, 120.6, 119.8, 118.2, 116.5, 116.0, 86.65, 56.3, 55.0, 28.3 (two carbon signals are missing due to overlap); IR (cmꢀ
1) 3400, 3026, 2977, 1683, 1442, 1365; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C27H29N2O4+ 445.2127, found 445.2119.
tertꢀbutyl 1,4ꢀdihydroxyꢀ3ꢀ((methyl(phenyl)amino)methyl)ꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (20c). A dry 7 mL vial was
charged with a magnetic stirbar, quinone 19 (150 mg, 0.482 mmol, 1 equiv) and Nꢀmethyl aniline (0.104 mL, 0.964 mmol, 2
equiv). The vial was capped and evacuated / backfilled with Ar (3 cycles). THF (1 mL) was added, followed by iꢀPr2NEt (1
mL). The vial was heated in an aluminum block at 65 ºC for 12 h. The reaction was cooled at room temperature, opened to air
and 1,3,5ꢀtrimethoxybenzene (81.1 mg, 0.482 mmol, 1 equiv) was added, volatiles were removed in vacuo and the residue
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immediately analyzed by H NMR. The crude reaction mixture contained 73% of hydroquinone 20c and 10% of quinone 21c.
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The mixture was submitted to oxidation without further purification. Selected signals from crude H NMR (400 MHz, CDCl3)
10.42 (s, 1H), 8.40 (m, 1H), 8.03 (m, 1H), 7.06 (m, 1H), 4.45 (s, 2H), 2.87 (s, 3H), 1.76 (s, 9H).
tertꢀbutyl 3ꢀ(((4ꢀmethoxybenzyl)(phenyl)amino)methyl)ꢀ1,4ꢀdioxoꢀ1,4ꢀdihydroꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (21a). A 20
mL vial was charged with a magnetic stirbar, hydroquinone 20a (286 mg, 0.545 mmol, 1 equiv) and MeCN (10 mL) and THF
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(2 mL). Under air, a solution of FeCl3 (884 mg, 3.27 mmol, 6 equiv) in 0.1 M HCl (6 mL) was added dropwise with vigorous
stirring. The reaction was monitored by TLC. After ~15 min the reaction mixture was transferred to a separatory funnel rinsing
with CH2Cl2 (15 mL) and washed with NaHCO3 (aq) (5 mL). The aqueous phase was extracted with CH2Cl2 (3 x 5 mL).
Combined organic extracts were washed with water (5 mL), brine (5 mL), dried over MgSO4, filtered through a short pad of
silica gel and concentrated in vacuo. Compound 21a (267 mg, 94%) was obtained as a brown foam: mp = 131 ºC
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(decomposition); H NMR (400 MHz, CDCl3) δ 8.30 (m, 1H), 8.02 (dt, J = 8.5, 1.0 Hz, 1H), 7.51 (ddd, J = 8.5, 7.2, 1.3 Hz,
1H), 7.42 (ddd, J = 8.1, 7.2, 1.0 Hz, 1H), 7.23 – 7.14 (m, 3H), 6.86 (m, 2H), 6.77 – 6.67 (m, 3H), 6.49 (m, 1H), 4.60 (s, 2H),
4.53 (d, J = 2.1 Hz, 2H), 3.78 (s, 3H), 1.66 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 184.6, 177.5, 158.8, 148.5, 148.0, 143.9,
138.4, 135.3, 132.3, 129.7, 129.4, 128.7, 127.9, 125.5, 123.4, 123.0, 121.9, 117.3, 114.4, 114.2, 112.3, 86.2, 55.3, 53.9, 48.9,
27.6; IR (cmꢀ1) 2979, 1747, 1653, 1506, 1102; HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C32H30N2O5Na+ 545.2052, found
545.2042.
tertꢀbutyl 3ꢀ((allyl(phenyl)amino)methyl)ꢀ1,4ꢀdioxoꢀ1,4ꢀdihydroꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (21b). A 20 mL vial was
charged with a magnetic stirbar, a 10:1 mixture of 20b / 21b (102 mg, ca. 0.229 mmol, 1 equiv) and MeCN (6 mL). Under air,
Ag2O (106 mg, 0.459 mmol, 2 equiv) was added with vigorous stirring. The reaction was monitored by 1H NMR. After 90 min
the reaction mixture was diluted with EtOAc, filtered through celite and concentrated in vacuo to afford 21b (99 mg, 98%) as a
light brown solid: mp = 105 ºC (decomposition); 1H NMR (500 MHz, CDCl3) δ 8.32 (dt, J = 8.0, 1.1 Hz, 1H), 8.03 (dt, J = 8.5,
0.9 Hz, 1H), 7.52 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.43 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.21 (m, 2H), 6.74 (m, 1H), 6.67 (m, 2H),
6.49 (t, J = 2.1 Hz, 1H), 5.97 – 5.85 (m, 1H), 5.28 – 5.17 (m, 2H), 4.47 (d, J = 2.1 Hz, 2H), 4.02 (dt, J = 5.0, 1.7 Hz, 2H), 1.66
(s, 9H); 13C NMR (126 MHz, CDCl3) δ 184.7, 177.5, 148.5, 147.7, 144.2, 138.4, 135.4, 132.9, 132.3, 129.3, 128.7, 125.5,
123.4, 123.0, 121.9, 117.3, 117.1, 114.4, 112.3, 86.2, 53.4, 48.9, 27.6. IR (cmꢀ1) 3960, 2979, 1747, 1653, 1504, 1109; HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C27H27N2O4+ 443.1971, found 443.1982.
tertꢀbutyl 3ꢀ((methyl(phenyl)amino)methyl)ꢀ1,4ꢀdioxoꢀ1,4ꢀdihydroꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (21c). A 20 mL vial was
charged with a magnetic stirbar, a 7:1 mixture of 20c / 21c (268.7 mg, ca. 0.642 mmol, 1 equiv) and MeCN (10 mL). Under air,
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Ag2O (297.8 mg, 1.285 mmol, 2 equiv) was added with vigorous stirring. The reaction was monitored by H NMR. After 30
min the reaction mixture was diluted with EtOAc, filtered through celite and concentrated in vacuo. Flash silica gel
chromatography (5% THF in hexanes) afforded 21c (247 mg, 92%) as an orange solid: mp = 55 ºC (decomposition); 1H NMR
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(500 MHz, CDCl3) δ 8.32 (dt, J = 7.9, 1.1 Hz, 1H), 8.02 (dt, J = 8.5, 1.0 Hz, 1H), 7.52 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.43
(ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.25 (m, 2H), 6.79 – 6.69 (m, 3H), 6.46 (t, J = 2.1 Hz, 1H), 4.47 (d, J = 2.1 Hz, 2H), 3.09 (s,
3H), 1.66 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 184.7, 177.4, 148.4, 148.4, 144.1, 138.4, 135.3, 132.3, 129.3, 128.7, 125.5,
123.4, 123.0, 121.8, 117.3, 114.4, 112.1, 86.2, 51.3, 39.0, 27.5; IR (cmꢀ1) 2979, 1747, 1653, 1348, 1209, 1151; HRMS (ESIꢀ
TOF) m/z [M+H]+ calcd for C25H25N2O4+ 417.1814, found 417.1799.
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tertꢀbutyl 3ꢀ(((2ꢀbromophenyl)(4ꢀmethoxybenzyl)amino)methyl)ꢀ1,4ꢀdihydroxyꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (23). A dry 7
mL vial was charged with a magnetic stirbar, quinone 19 (60 mg, 0.1927 mmol, 1 equiv) and 2ꢀbromoꢀNꢀPMB aniline (112.6
mg, 0.3854 mmol, 2 equiv). The vial was capped and evacuated / backfilled with Ar (3 cycles). THF (0.4 mL) was added,
followed by iꢀPr2NEt (0.4 mL). The vial was heated in an aluminum block at 65 ºC for 21 h. The reaction was cooled at room
temperature, opened to air and 1,3,5ꢀtrimethoxybenzene (32.4, 0.1927 mmol, 1 equiv) was added. The mixture was
concentrated in vacuo and analyzed by 1H NMR. The crude contained 22% NMR yield of 23. Flash silica gel chromatography
(first column: 1:1 CH2Cl2 / hexanes, second column: 10% EtOAC in hexanes) afforded 23 (15 mg) as a tan solid: mp = 71 ºC
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(decomposition); H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 9.88 (s, 1H), 8.53 (m, 1H), 8.04 (m, 1H), 7.64 (dd, J = 7.9, 1.5
Hz, 1H), 7.40 (m, 2H), 7.20 (m, 1H), 7.02 (td, J = 7.6, 1.5 Hz, 1H), 6.95 – 6.83 (m, 2H), 6.80 (m, 3H), 4.25 (s, 2H), 4.19 (s,
2H), 3.79 (s, 3H), 1.77 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 159.1, 154.2, 146.9, 146.2, 137.5, 137.3, 133.7, 131.5, 127.8,
126.5, 126.4, 126.10, 126.01, 125.9, 125.1, 123.9, 123.8, 121.2, 117.3, 117.0, 116.5, 115.9, 113.4, 86.5, 56.0, 55.1, 54.1, 28.3;
IR (cmꢀ1) 3143, 2979, 1683, 1440, 1364, 1208, 1146; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C32H32BrN2O5+ 603.1495, found
603.1484.
diꢀtertꢀbutyl
6ꢀhydroxyꢀ15aꢀmethylꢀ9,15ꢀdioxoꢀ8a,9,15,15aꢀtetrahydroꢀ5Hꢀpyrano[3,2ꢀb:5,6ꢀc']dicarbazoleꢀ5,10(8H)ꢀ
dicarboxylate (D1). A dry 7 mL vial was charged with a magnetic stirbar, quinone 19 (227 mg, 0.729 mmol, 1 equiv) and 2ꢀ
bromoꢀNꢀPMB aniline (234 mg, 0.892 mmol, 1.1 equiv). The vial was capped and evacuated / backfilled with Ar (3 cycles).
Dioxane (2.5 mL) was added, followed by iꢀPr2NEt (0.6 mL). The vial was heated in an aluminum block at 80 ºC for 12 h. The
reaction was cooled at room temperature, opened to air and 1,3,5ꢀtrimethoxybenzene (40.8, 0.243 mmol, 0.33 equiv) was
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added. The mixture was concentrated in vacuo and immediately analyzed by H NMR. The crude contained hydroquinone 23
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(20%), dimer D1 (18%) and unreacted 19 (9%) and undetermined byproducts. After exposure to air for 5 h, H NMR analysis
of this mixture showed a higher amount of unreacted 19 (39%). Flash silica gel chromatography (20ꢀ25% EtOAC in hexanes)
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and trituration with MeCN afforded analytically pure D1 (11 mg) as a yellow solid: mp = 160 ºC (decomposition); H NMR
(500 MHz, CDCl3) δ 10.51 (s, 1H), 8.37 (m, 1H), 8.29 (dt, J = 8.0, 1.1 Hz, 1H), 8.07 (dt, J = 8.5, 0.9 Hz, 1H), 8.03 (dt, J = 8.6,
0.9 Hz, 1H), 7.54 (dddd, J = 20.0, 8.5, 7.2, 1.3 Hz, 1H), 7.44 – 7.32 (m, 3H), 6.72 (s, 1H), 3.61 (dd, J = 8.5, 6.6 Hz, 1H), 3.41
(ddd, J = 16.9, 8.6, 1.1 Hz, 1H), 3.18 (ddd, J = 16.8, 6.6, 0.9 Hz, 1H), 1.86 (s, 3H), 1.75 (s, 9H), 1.67 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 192.5, 187.8, 154.1, 148.1, 141.1, 139.1, 138.9, 138.4, 137.6, 129.1, 126.5, 125.7, 125.7, 125.4, 124.1, 123.7,
123.6, 123.6, 121.7, 116.9, 116.0, 115.7, 115.0, 114.5, 86.7, 86.3, 82.4, 54.7, 28.3, 27.5, 25.2, 23.9; IR (cmꢀ1) 3140, 2979, 2933,
1732, 1688, 1445, 1079; HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C36H34N2O8Na+ 645.2213, found 645.2241.
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tertꢀbutyl 3ꢀ(((2ꢀbromophenyl)(4ꢀmethoxybenzyl)amino)methyl)ꢀ1,4ꢀdioxoꢀ1,4ꢀdihydroꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (24).
A 7 mL vial was charged with a magnetic stirring bar, 23 (27 mg, 0.0448 mmol, 1 equiv), MeCN (1.5 mL) and Ag2O (20.7 mg,
0.0895 mmol, 2 equiv). The resulting suspension was stirred vigorously and the reaction monitored by TLC. After 1.5 h the
mixture was diluted with CH2Cl2 (2 mL) and filtered through a short pad of celite / silica gel, rinsing with CH2Cl2. The filtrate
was concentrated in vacuo to afford 24 (26 mg, 97%) as an orange oil: 1H NMR (400 MHz, CDCl3) δ 8.31 – 8.23 (m, 1H), 7.98
(dt, J = 8.5, 1.0 Hz, 1H), 7.62 (dd, J = 7.9, 1.5 Hz, 1H), 7.48 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.39 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H),
7.29 (m, 2H), 7.18 (ddd, J = 8.0, 7.2, 1.5 Hz, 1H), 7.06 (dd, J = 8.1, 1.6 Hz, 1H), 6.94 (ddd, J = 7.9, 7.2, 1.6 Hz, 1H), 6.84 –
6.79 (m, 3H), 4.19 (s, 2H), 4.16 (d, J = 2.4 Hz, 1H), 3.75 (s, 3H), 1.66 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 184.2, 177.7,
158.9, 148.5, 148.3, 144.8, 138.3, 135.2, 134.1, 134.0, 129.9, 129.4, 128.5, 128.0, 125.5, 125.4, 123.9, 123.5, 123.0, 121.7,
121.5, 114.3, 113.8, 86.1, 58.3, 55.2, 48.5, 27.6; IR (cmꢀ1) 2978, 2931, 1747, 1652, 1511, 1098; HRMS (ESIꢀTOF) m/z
[M+Na]+ calcd for C32H29BrN2O5Na+ 623.1158, found 623.1161.
tertꢀbutyl 1'ꢀ(4ꢀmethoxybenzyl)ꢀ1,4ꢀdioxoꢀ1,4ꢀdihydrospiro[carbazoleꢀ3,3'ꢀindoline]ꢀ9(2H)ꢀcarboxylate (25). A 7 mL vial
was charged with a magnetic stirring bar, 24 (10 mg, 0.01663 mmol, 1 equiv), K2CO3 (9.2 mg, 0.665 mmol. 4 equiv) and
Pd(PPh3)4 (19.2 mg, 0.01663 mmol, 1 equiv). The vial was closed and evacuated / backfilled with Ar (3 cycles), then dioxane
(0.5 mL) was added by syringe. The reaction mixture was heated in an aluminum block at 80 ºC for 4 h. The reaction was then
cooled at rt, opened to air and filtered through celite, rinsing with EtOAc. Flash silica gel chromatography (10ꢀ30% EtOAc in
hexanes) afforded 25 (5.2 mg, 60%) as a yellowish film: 1H NMR (500 MHz, CDCl3) δ 8.35 (dt, J = 8.0, 1.1 Hz, 1H), 8.07 (dt,
J = 8.6, 0.9 Hz, 1H), 7.55 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.42 (ddd, J = 8.1, 7.2, 1.0 Hz, 1H), 7.33 – 7.28 (m, 2H), 7.10 (td, J =
7.7, 1.3 Hz, 1H), 6.92 – 6.87 (m, 2H), 6.75 (dd, J = 7.4, 1.2 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.54 (td, J = 7.5, 1.0 Hz, 1H),
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4.39 (d, J = 14.6 Hz, 1H), 4.24 (d, J = 14.6 Hz, 1H), 4.10 (d, J = 9.4 Hz, 1H), 3.81 (s, 3H), 3.34 – 3.20 (m, 3H), 1.66 (s, 9H);
13C NMR (126 MHz, CDCl3) δ 193.1, 186.6, 158.7, 151.3, 148.3, 139.5, 138.6, 130.0, 129.5, 129.4, 129.1, 129.0, 125.4, 125.3,
123.9, 123.7, 123.4, 117.9, 114.3, 114.0, 108.0, 86.2, 60.8, 59.6, 55.3, 52.0, 51.2, 27.6; IR (cmꢀ1) 2924, 1750, 1683, 1511, 1370;
HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C32H31N2O5+ 523.2233, found 523.2227.
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tertꢀbutyl 2ꢀbromoꢀ3ꢀmethylꢀ1,4ꢀdioxoꢀ1,4ꢀdihydroꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (26). A dry 100 mL round bottom flask
was charged with a magnetic stirring bar, quinone 19 (1.4 g, 4.5 mmol, 1 equiv) and dichloromethane (40 mL) under air, the
solution was cooled in an ice bath and bromine (0.25 mL, 4.95 mmol, 1.1 equiv) was added drowpise. The cold bath was
removed and the reaction stirred at room temperature. After 1 h full conversion of 19 was determined by 1H NMR analysis of
an aliquot. Then sodium acetate (1.1 g, 13.5 mmol. 3 equiv) was added, followed by dry DMSO (5 mL). The suspension was
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stirred at room temperature overnight (~18 h). H NMR analysis of the reaction mixture indicated complete conversion of the
intermediate bromide to 26. The reaction was diluted with dichloromethane (50 mL) and washed with water (2 x 20 mL), brine
(20 mL), dried over MgSO4 and concentrated. Column chromatography on silica (10% EtOAc in hexanes, then EtOAc / CH2Cl2
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/ hexanes 1:4:5) afforded 1.65 g (94%) of 26 as an orange solid: mp = 198 ºC (decomposition); H NMR (500 MHz, CDCl3) δ
8.30 (dt, J = 8.0, 1.1 Hz, 1H), 8.02 (dt, J = 8.5, 0.9 Hz, 1H), 7.53 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.43 (ddd, J = 8.1, 7.2, 1.0 Hz,
1H), 2.32 (s, 3H), 1.68 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 180.6, 170.5, 148.3, 145.3, 138.8, 135.9, 134.1, 129.1, 125.7,
123.4, 123.3, 121.6, 114.4, 86.5, 27.5, 16.9; IR (cmꢀ1) 2978, 2933, 1750, 1677, 1656, 1259, 1112; HRMS (ESIꢀTOF) m/z [Mꢀ
ꢀ
BocꢀH]ꢀ calcd for C13H7BrNO2 287.9660, found 287.9677.
tertꢀbutyl 2ꢀbromoꢀ1,4ꢀdihydroxyꢀ3ꢀ(((4ꢀmethoxybenzyl)(phenyl)amino)methyl)ꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (27). A 7
mL vial was charged with a magnetic stirring bar, quinone 26 (40 mg, 0.1025 mmol, 1 equiv), NꢀPMB aniline (32.8 mg, 0.1538
mmol, 1.5 equiv) and CH2Cl2 (0.4 mL). The vial was capped, flushed with Ar (balloon), and iꢀPr2Net (3.6 ꢀL, 0.0205 mmol,
0.2 equiv) was added. The reaction was stirred at room temperature. After 4.5 h the reaction was concentrated in vacuo. Flash
silica gel chromatography (10ꢀ15% THF in hexanes) afforded 27 (55.4 mg, 90%) as a light yellow foam: mp = 86 ºC
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(decomposition); H NMR (500 MHz, CDCl3) δ 11.30 (s, 1H), 11.26 (d, J = 0.8 Hz, 1H), 8.41 (m, 1H), 7.99 (m, 1H), 7.44 –
7.31 (m, 2H), 7.31 – 7.26 (m, 3H), 7.18 (m, 2H), 7.08 – 7.02 (m, 3H), 6.83 – 6.79 (m, 2H), 4.67 (s, 2H), 4.29 (s, 2H), 3.77 (s,
3H), 1.74 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 159.2, 154.3, 148.5, 146.4, 137.5, 135.1, 130.8, 129.2, 127.3, 126.4, 126.0,
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125.8, 124.3, 124.1, 123.7, 122.4, 117.0, 116.0, 115.5, 113.8, 112.0, 87.1, 59.7, 55.2, 55.1, 28.2; IR (cmꢀ1) 3350, 3057, 2977,
1680, 1610, 1435, 1150; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C32H32BrN2O5+ 603.1495, found 603.1497.
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2ꢀbromoꢀ3ꢀ(((4ꢀmethoxybenzyl)(phenyl)amino)methyl)ꢀ1,4ꢀdioxoꢀ1,4ꢀdihydroꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate
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(28). A 20 mL vial was charged with a magnetic stirbar, hydroquinone 27 (688 mg, 1.14 mmol, 1 equiv) and MeCN (25 mL).
Under air, a solution of FeCl3 (924 mg, 3.42, 3 equiv) in 0.1 M HCl (10 mL) was added dropwise with vigorous stirring. The
reaction was monitored by TLC. After ~30 min the reaction mixture was transferred to a separatory funnel rinsing with CH2Cl2
(50 mL) and washed with NaHCO3 (aq) (10 mL). The aqueous phase was extracted with CH2Cl2 (3 x 5 mL). Combined organic
extracts were washed with water (10 mL), brine (10 mL), dried over MgSO4 and concentrated in vacuo. The crude product was
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recrystallized from dry THF to give 28 (604 mg, 88%) as a dark green solid: mp = 156 ºC (decomposition); H NMR (500
MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 1H), 8.01 (dt, J = 8.5, 0.9 Hz, 1H), 7.51 (ddd, J = 8.5, 7.1, 1.3 Hz, 1H), 7.41 (td, J = 7.6,
7.1, 1.0 Hz, 1H), 7.26 (m, 2H), 7.06 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 8.2, 2H) 6.81 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 8.3 Hz, 2H),
4.65 (s, 2H), 4.56 (s, 2H), 3.41 (s, 3H), 1.68 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 180.1, 170.1, 158.3, 149.9, 148.1, 144.5,
138.8, 137.7, 133.8, 131.3, 129.2, 129.1, 128.3, 125.6, 123.3, 121.8, 118.3, 114.6, 114.4, 113.7, 86.3, 55.5, 54.8, 49.9, 27.5; IR
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(cmꢀ1) 3058, 2980, 2932, 1748, 1676, 1536, 1108; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C32H30BrN2O5 601.1338, found
601.1349.
(9ꢀ(tertꢀbutoxycarbonyl)ꢀ3ꢀ(((4ꢀmethoxybenzyl)(phenyl)amino)methyl)ꢀ1,4ꢀdioxoꢀ4,9ꢀdihydroꢀ1Hꢀcarbazolꢀ2ꢀ
yl)bis(triphenylphosphane)palladium(II) bromide (29): A 7 mL vial was charged with a magnetic stirring bar, 28 (35 mg,
0.0582 mmol, 1 equiv), Pd(PPh3)4 (67.2 mg, 0.0582 mmol, 1 equiv). The vial was sealed and evacuated / backfilled with Ar (3
cycles), then toluene (1.5 mL) was added by syringe. The reaction was heated in an aluminum block at 80 ºC. After 3 h the
reaction was cooled to room temperature, opened to air and concentrated in vacuo. Flash silica gel chromatography (25ꢀ30%
EtOAc in hexanes) afforded 28 (68 mg, 95%) as a dark brown solid. Xꢀray quality crystals were grown from a MeCN solution
at room temperature overnight. mp = 153 ºC (decomposition); Note: two species are observed in solution by 1H NMR and 31P
NMR, whose ratio is concentration dependent. Major species: 1H NMR (500 MHz, CDCl3) δ 8.09 (dt, J = 8.0, 1.1 Hz, 1H), 7.80
(m, 1H), 7.90 – 7.51 (m, 12H), 7.40 (ddd, J = 8.5, 7.1, 1.3 Hz, 1H), 7.30 (m, 1H), 7.20 (m, 18H), 7.09 (dd, J = 8.8, 7.2 Hz, 2H),
6.80 (d, J = 8.7 Hz, 2H), 6.72 – 6.65 (m, 3H), 6.59 (m, 2H), 4.57 (s, 2H), 4.49 (s, 2H), 3.74 (s, 3H), 1.51 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 185.1 (t, J = 2.7 Hz), 180.4, 179.9, 158.0, 149.1, 148.9, 145.3 (t, J = 4.2 Hz), 137.4, 135.0, 134.4, 130.9 (t, J =
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23.7 Hz), 130.7, 130.3, 128.8, 128.0 (t, J = 5.2 Hz), 127.8, 127.6, 124.4, 123.3, 123.1, 120.6, 116.8, 114.2, 113.64, 113.61,
85.1, 55.2, 54.6, 53.5, 27.4; 31P{1H} NMR (162 MHz, CDCl3) δ 20.9 (major species), 21.2 (minor species); IR (cmꢀ1) 3054,
1742, 1635, 1505, 1368, 1349, 1100; HRMS (ESIꢀTOF) m/z [M+MeCN–Br]+ calcd for C70H62N3O5P2Pd+ 1192.3199, found
1192.3157.
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tertꢀbutyl
2ꢀbromoꢀ1,4ꢀdihydroxyꢀ3ꢀ(((2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)amino)methyl)ꢀ9Hꢀ
carbazoleꢀ9ꢀcarboxylate (33). A dry 50 mL round bottom flask was charged with a magnetic stirbar, quinone 26 (1.28 g, 3.278
mmol, 1 equiv), aniline 31 (790 mg, 3.605 mmol, 1.1 equiv) and CH2Cl2 (11 mL). The flask was capped and flushed with Ar
(balloon). Then, iꢀPr2NEt (114 ꢀL, 0.656, 0.2 equiv) was added by syringe. After 9 h, the flask was opened to air, diluted with
CH2Cl2 (60 mL) and washed with 0.1 M HCl(aq) (5 mL). The organic phase was washed NaHCO3 (aq), dried over MgSO4 and
concentrated. The mixture was triturated with EtOAc / hexanes to afford 1.288 g of 33 as a tan solid. The remaining solution
was concentrated, triturated again with EtOAc / hexanes to afford 59 mg of 33. Overall yield: 67%. mp = 150 ºC
(decomposition); 1H NMR (500 MHz, CDCl3) δ 11.32 (s, 1H), 10.64 (s, 1H), 8.39 (d, J = 7.7 Hz, 1H), 8.02 (dt, J = 8.4, 0.9 Hz,
1H), 7.74 (dd, J = 7.4, 1.7 Hz, 1H), 7.39 (m, 1H), 7.33 (m, 2H), 6.93 (m, 1H), 6.87 (s, 1H), 4.87 (s, 2H), 1.77 (s, 9H), 1.37 (s,
12H); 13C NMR (126 MHz, CDCl3) δ 154.3, 154.0, 146.4, 137.5, 136.8, 135.3, 133.3, 126.4, 126.1, 125.6, 124.1, 123.7, 120.1,
117.7, 116.0, 115.9, 114.2, 111.1, 87.2, 84.1, 50.8, 28.2, 24.9; 11B (128 MHz, CDCl3) δ 32.1; IR (cmꢀ1) 3351, 2976, 1681, 1371,
1207, 1150, 913, 747; HRMS (ESIꢀTOF) m/z [M+H+ calcd for C30H35BBrN2O6+ 609.1772, found 609.1767.
tertꢀbutyl
2ꢀbromoꢀ1,4ꢀdihydroxyꢀ3ꢀ(((4ꢀmethoxybenzyl)(2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)phenyl)amino)methyl)ꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate (32) and oxidation to tertꢀbutyl 2ꢀbromoꢀ3ꢀ(((4ꢀmethoxybenzyl)(2ꢀ
(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)amino)methyl)ꢀ1,4ꢀdioxoꢀ1,4ꢀdihydroꢀ9Hꢀcarbazoleꢀ9ꢀcarboxylate
(34). A dry 7 mL vial was charged with a magnetic stirbar, quinone 26 (100 mg, 0.256 mmol, 1 equiv), aniline 30 (95.6 mg,
0.282 mmol, 1.1 equiv) and CH2Cl2 (0.85 mL). The vial was capped and flushed with Ar (balloon). Then, iꢀPr2NEt (9 ꢀL,
0.0513, 0.2 equiv) was added by syringe. After 5 h, the vial was opened to air and CH2Cl2 (2 mL) was added, followed by
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1,3,5ꢀtrimethoxybenzene (43.1 mg, 0.256 mmol, 1 equiv). H NMR analysis indicated 72% NMR yield of 32. Attempts to
purify it were unsuccessful, but its structure was partially supported by the following data: 1H NMR (400 MHz, CDCl3) δ 11.2
(s, 1H), 10.99 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.99 (m, overlapped, 1H), 7.84 (m, 1H), 6.99 (m, 2H), 6.77 (m, overlapped,
2H), 4.53 (s, 2H), 4.24 (s, 2H), 1.73 (s, 9H), 1.47(s, 12H); The crude was submitted to oxidation: the crude was concentrated in
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vacuo and dissolved in MeCN (3 mL) and EtOAc (4 mL). Ag2O (118.8 mg, 0.513 mmol, 2 equiv based on initial 26) was added
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concentrated in vacuo. H NMR analysis indicated 27% NMR yield of 34. Attempts to purify 34 by conventional means were
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not successful, however, product 34 estimated to be >70% pure was obtained by slow precipitation at 0º C (2 weeks) from the
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crude reaction mixture dissolved in EtOAc / hexanes. A black solid that was collected by filtration, washed with hexanes and
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dried: mp = 127–128 ºC (decomposition); H NMR (400 MHz, CDCl3) δ 8.24 (dt, J = 7.9, 1.2 Hz, 1H ), 8.02 (dt, J = 8.5, 0.9
Hz, 1H), 7.71 (dd, J = 7.4, 1.8 Hz, 1H), 7.51 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.41 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.35 (ddd, J =
8.1, 7.2, 1.8 Hz, 1H), 7.29 (m, 2H), 7.19 (dd, J = 8.2, 1.0 Hz, 1H), 7.02 (td, J = 7.3, 1.0 Hz, 1H), 6.60 (m, J = 8.6 Hz, 2H), 4.48
(s, 2H), 4.33 (s, 2H), 3.51 (s, 3H), 1.68 (s, 9H), 1.29 (s, 12H); 13C NMR (126 MHz, CDCl3) δ 180.3, 170.8, 158.5, 157.5, 148.3,
144.5, 138.8, 137.0, 136.6, 134.0, 131.5, 131.4, 130.1, 128.9, 125.4, 123.5, 123.4, 123.2, 122.2, 121.8, 114.3, 113.2, 86.2, 83.5,
59.3, 54.9, 51.5, 27.5, 24.9; 11B (128 MHz, CDCl3) δ 33.3; IR (cmꢀ1) 2977, 2932, 1749, 1675, 1608, 1350; HRMS (ESIꢀTOF)
m/z [M+H]+ calcd for C38H41BBrN2O7+ 727.2190, found 727.2209.
tertꢀbutyl 2ꢀbromoꢀ1,4ꢀdioxoꢀ3ꢀ(((2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)amino)methyl)ꢀ1,4ꢀdihydroꢀ9Hꢀ
carbazoleꢀ9ꢀcarboxylate (35). A 7 mL vial was charged with a magnetic stirring bar, 33 (78 mg, 0.128 mmol, 1 equiv),
acetonitrile (3 mL) and EtOAc (2 mL). Under vigorous stirring, Ag2O (59 mg, 0.256 mmol, 2 equiv) was added and the
reaction monitored by TLC. After 15 min the reaction was filtered through a short plug a celite and silica gel, rinsing with THF,
1
to afford 35 (74 mg, 95%) as a dark green solid: mp = 161–162 ºC; H NMR (500 MHz, CDCl3) δ 8.30 (dt, J = 8.0, 1.1 Hz,
1H), 8.01 (dt, J = 8.5, 0.9 Hz, 1H), 7.60 (dd, J = 7.3, 1.8 Hz, 1H), 7.52 (ddd, J = 8.5, 7.1, 1.3 Hz, 1H), 7.42 (ddd, J = 8.1, 7.1,
1.0 Hz, 1H), 7.31 (ddd, J = 8.7, 7.2, 1.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.70 – 6.58 (m, 2H), 4.58 (d, J = 7.1 Hz, 2H), 1.67 (s,
9H), 1.34 (s, 12H); 13C NMR (126 MHz, CDCl3) δ 180.5, 170.5, 153.3, 148.2, 145.1, 139.0, 137.5, 137.2, 134.0, 133.2, 129.3,
125.7, 123.4, 123.3, 121.7, 116.4, 114.5, 110.4, 86.5, 83.7, 41.8, 27.6, 24.9; 11B (128 MHz, CDCl3) δ 31.7; IR (cmꢀ1) 3350,
2977, 1653, 1636, 1435, 1354; HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C30H33BBrN2O6+ 607.1615, found 607.1615.
Calothrixin B (1).
A Schlenk flask was charged with a magnetic stirring bar, 35 (1.02 g, 1.68 mmol, 1 equiv),
.
(dppf)PdCl2 CH2Cl2 (68.6 mg, 0.084 mmol, 0.05 equiv) and K2CO3 (1.16 g, 8.4 mmol, 5 equiv). The flask was closed with
septum and evacuated / backfilled with Ar (4 cycles), then dioxane (50 mL) and degassed H2O (10 mL) were added by syringe.
The reaction was heated in an oil bath at 100 ºC with vigorous stirring. After 5.5 h the reaction was cooled to room temperature,
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opened to air and transferred to a separatory funnel, rinsing with THF (200 mL), EtOAc (110 mL) and H2O (50 mL). The
aqueous phase was extracted with ~1:1 THF/EtOAc (2 x 50). The combined organic extracts were washed with H2O (2 x 50
mL), brine, dried over Na2SO4 and concentrated in vacuo. Flash silica gel chromatography (10ꢀ20% THF in hexanes) afforded
1 (397.3 mg, 79%) as a red solid: mp > 300 ºC; 1H NMR (400 MHz, DMSOꢀd6) δ 13.11 (s, 1H), 9.57 (s, 1H), 9.53 (dd, J = 8.6,
1.5 Hz, 1H), 8.13 (d, J = 7.9 Hz, 2H), 7.91 (ddd, J = 8.4, 6.7, 1.5 Hz, 1H), 7.85 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.58 (d, J = 8.2
Hz, 1H), 7.42 (m, 1H), 7.35 (t, J = 7.5 Hz, 1H); 13C NMR (126 MHz, DMSO) δ 180.9, 180.3, 151.2, 147.5, 138.5, 138.1, 132.6,
131.6, 130.2, 129.8, 127.20, 127.12, 124.9, 124.3, 123.4, 122.6, 122.3, 115.5, 114.0; HRMS (ESIꢀTOF) m/z [MꢀH]ꢀ calcd for
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C19H9N2O2 297.0664, found 297.0662. The spectral data is in accordance with published values.1
Calothrixin A (2). Compound 2 was prepared according to a published procedure.3a 20 mL round bottom flask was charged
with a magnetic stirring bar, compound 1 (4 mg, 0.013 mmol, 1 equiv) and mꢀCPBA (~77% w/w, 17 mg, 0.0671, ~5 equiv) and
CH2Cl2 (6 mL). A reflux condenser was attached, the system was flushed with Ar and the reaction refluxed for 4 h. The
reaction was then cooled at room temperature, diluted with CH2Cl2 (50 mL) and extracted with NaHCO3 (sat) (3 x 10 mL) and
water, until pH was neutral. The solution was dried over Na2SO4, and concentrated in vacuo. Flash silica gel chromatography
(1% Et3N in CH2Cl2) afforded 2 (2.4 mg, 57%) as an orange solid: mp = 288–290 ºC; 1H NMR (400 MHz, DMSOꢀd6) δ 13.2 (s,
2H), 9.67 (m, 1H), 8.87 (s, 1H), 8.60 (m, 1H), 8.11 (d, J = 7.9 Hz, 2H), 8.03 – 7.93 (m, 2H), 7.59 (dt, J = 8.3, 1.0 Hz, 2H), 7.44
(ddd, J = 8.3, 7.1, 1.3 Hz, 2H), 7.37 (ddd, J = 8.0, 7.0, 1.1 Hz, 2H); 13C NMR (126 MHz, DMSO) δ 178.3, 177.8, 143.1, 138.7,
138.1, 132.0, 131.9, 131.8, 129.9, 128.2, 127.0, 126.9, 124.5, 123.4, 122.0, 121.9, 119.1, 115.1, 114.0; HRMS (ESIꢀTOF) m/z
ꢀ
[MꢀH]ꢀ calcd for C19H9N2O3 313.0613, found 313.0610. The spectral data is in accordance with published values.1
ASSOCIATED CONTENT
Supporting Information
1
The supporting information if available free of charge on the ACS Publications website. Copies of H, 13C, 11B and 31P NMR
spectra of isolated compounds and crystallographic data for compounds 28 and 29.
AUTHOR INFORMATION
Corresponding Author
*email: mclift@ku.edu
ORCID
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Michael D. Clift: 0000ꢀ0001ꢀ6441ꢀ9802
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Luis M. MoriꢀQuiroz: 0000ꢀ0001ꢀ8546ꢀ7264
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ACKNOWLEDGMENTS
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We thank Prof. Mercy Anyika and Mr. Andrew Rider (Metropolitan Community College – Penn Valley, MO) for the
preparation of compound 5; and Dr. Victor Day (KU) for crystallographic analysis. Financial support from the University of
Kansas and is gratefully acknowledged. Support for NMR instrumentation used in this study was provided by NIH Shared
Instrumentation Grants # S10RR024664 and # S10OD016360, and NSF Major Instrumentation Grant # 0320648.
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