Palladium-Catalyzed Synthesis of 6H-Dibenzo[c,h]chromenes and 5,6-Dihydrobenzo[c]phenanthridines: Application to the Synthesis of Dibenzo[c,h]chromene-6-ones, Benzo[c]phenanthridines, and Arnottin I

Article abstract of DOI:10.1002/adsc.201900833

6H-Dibenzo[c,h]chromenes and 5,6-dihydrobenzo[c]phenanthridines have been synthesized via Palladium (II)-catalyzed domino reactions of acetylenic substrates involving intramolecular trans-oxo/amino palladation onto the triple bond followed by nucleophilic

Full text of DOI:10.1002/adsc.201900833

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DOI: 10.1002/adsc.201900833
Palladium-Catalyzed Synthesis of 6H-Dibenzo[c,h]chromenes and
5,6-Dihydrobenzo[c]phenanthridines: Application to the Synthesis
of Dibenzo[c,h]chromene-6-ones, Benzo[c]phenanthridines, and
Arnottin I
Subhendu Pramanik,+a Moumita Jash,+a Debasmita Mondal,a and
Chinmay Chowdhurya,*
a
Organic & Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata-
700032, India
E-mail: chinmay@iicb.res.in
+
Contributed equally.
Manuscript received: July 8, 2019; Revised manuscript received: September 13, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900833
Abstract: 6H-Dibenzo[c,h]chromenes and 5,6-dihydrobenzo[c]phenanthridines have been synthesized via
Palladium (II)-catalyzed domino reactions of acetylenic substrates involving intramolecular trans-oxo/amino
palladation onto the triple bond followed by nucleophilic addition of the intermediate to a tethered cyano/
aldehyde. The scope of this reaction was extended through one step conversion of some of the products to 6H-
dibenzo[c,h]chromen-6-ones and benzo[c]phenanthridines. Utilization of this methodology led to a formal total
synthesis of the natural product Arnottin I.
Keywords: Domino reaction; Palladium catalyst; 6H-Dibenzo[c,h]chromenes; 5,6-Dihydrobenzo[c]phenanthri-
dines; Arnottin I.
1. Introduction
less explored compared to 3 in drug discovery
primarily due to the lack of straightforward and
Fused heterocycles are of great importance because of convenient synthetic methods. Scrutiny of the literature
their broad applications in different areas.[1] Among revealed a single method[3h] for a general synthesis
these compounds, the 6H-benzo[c]chromenes (1a, employing an intramolecular biaryl coupling reaction,
Figure 1) are considered as privileged scaffolds and while few other reports[10] deal with the preparation
important substructures in modern drug discovery.[2] specific molecules during the course of the synthesis
The related 6H-dibenzo[c,h]chromenes 2 also find of either 1a or related compounds. This clearly pointed
extensive use as key synthetic intermediates of medic- to the urgency of establishing a general and straightfor-
inally active compounds, besides offering easy access ward method for the synthesis of 2 starting from
to dibenzo[c,h]chromen-6-ones 3 which constitute the simple and easily accessible materials.
core structures of a broad spectrum of natural products
On the other hand, the aza-counterpart of 1a and its
and others compounds possessing bactericidal related structures such as dihydrophenanthridines (1b,
properties.[3–8] These include arnottin I[3] (5, a non- Figure 1), phenanthridinones (1c, Figure 1) and phe-
alkaloidal minor component of Xanthoxylum arnottia- nanthridines are encountered in various alkaloids and
num), defucogilvocarcins (6a–b)[4] exhibiting antimi- synthetic compounds and display a wide range of
crobial activity, and gilvocarcins (7a–b),[5] ravidomy- pharmacological effects.[11] More importantly, fusion of
cin (7c),[6] and chrysomycins (7d–e)[7] belonging to the an additional benzene ring to phenanthridines and their
class of aryl C-glycoside antibiotics.[8]
dihydro derivatives resulting in benzo[c]phenanthri-
Despite the promising biological effects[9] of 6H- dines and its 5,6-dihydro derivatives (4) lead to
dibenzo[c,h]chromenes 2, this class of compounds is products with remarkable therapeutic efficacies. For
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palladium species onto a carbon-heteroatom multiple
bond (e.g., À COÀ , À CHO, À CN) followed by proto-
nation of the resulting intermediate have proved to be
useful in the field of heterocycle synthesis after the
seminal works of Larock,[16a] Lu[16b] and Wang.[16c] In
continuation of our work on palladium-catalyzed
reactions,[17] we therefore anticipated that a general
synthesis of 6H-dibenzo[c,h]chromenes 2 and 5,6-
dihydrobenzo[c]phenanthridines 4 could be achieved
in atom economical way through one-pot domino
reactions using readily available substrates. Our con-
cept proved to be viable upon choosing appropriate
reaction conditions and catalyst. The results obtained
so far are described herein.
2. Results and Discussion
2.1. Synthesis of 6H-dibenzo[c,h]chromene deriva-
tives 2/2’
We commenced the investigation with a model study
on substrate 10a which can be easily accessed through
Sonogashira coupling between o-ethynylbenzyl alco-
hol and o-iodobenzyl cyanide (see Scheme S1 under
supporting information); selected results are presented
in Table 1. Notably, Pd(OAc)2 or its ligated complex
[i.e., Pd(OAc)2bpy] turned out to be superior to other
palladium catalysts (results not shown). Still, employ-
ment of 5 mol% of Pd(OAc)2bpy in 1,4-dioxane
furnished the desired product 2a to the extent of 38%
only along with the side product 11 resulting from
mono-cyclization (Table 1, entry 1). Even deployment
of catalyst and ligand separately in dry THF did not
quite improve the situation (Table 1, entry 2), so we
decided to test polar solvents. Indeed, carrying out this
Figure 1. Biologically active dibenzo[c,h]chromen-6-ones 5–7,
benzo[c]phenanthridines 8 and 5,6-dihydro- benzo[c]phenan-
thridines 9.
example, benzo[c]phenanthridine alkaloids 8a-c (Fig- reaction in DMA enhanced the yield of 2a to 52%
ure 1) are reported to be G-quadruplex DNA with complete suppression of the side product 11,
stabilizer,[12a] topoisomerase I/II inhibitor,[12b] and lip- though the relatively less polar DMF did not prove to
oxygenase inhibitor,[12c] respectively. The 5,6-dihydro be so efficient (Table 1, entries 3 & 4). Pleasingly,
derivatives 4 are less naturally abundant but often replacement of DMA by a still more polar solvent
exhibit distinct biological profiles. Thus 6-acetonyl (NMA) significantly improved the yield (75%) of 2a
dihydrochelerythrine (ADC) 9a (Figure 1) displays and reduced the reaction time from 6 h to 2 h (Table 1,
significant anti-HIV[13a] and anti-apoptotic[13b] effects, entry 5). But the use of Pd(OAc)2bpy or Pd(OAc)2phen
while buesgenin 9b[13c] isolated from Fagara tessman- reduced the yield of 2a marginally (Table 1, entry 6,7)
nii exhibited high anti-bacterial activity while being and required longer reaction periods (Table 1, entry 7).
non-toxic towards the normal cells. In spite of these
In order to optimize the reaction conditions further,
encouraging results, there is no general method for the we then replaced D-CSA with p-toluenesulphonic acid
synthesis of 4 to date though few specific examples (p-TsOH); to our dismay, a mixture of the desired
were reported[14] during the synthesis of other hetero- product 2a and side product 11 (~1:1) resulted[18]
cycles. This underlined the urgency for the develop- (Table 1, entry 8), establishing the superiority of D-
ment of a facile and general method for the synthesis CSA.
of 4.
On the other hand, removal of D-CSA from the
In recent times, domino reactions have emerged as reaction did not produce 2a at all, proving its necessity
efficient tools for the construction of complex mole- in this reaction (Table 1, entry 9), while carrying out
cules from the viewpoints of operational simplicity, this reaction using D-CSA alone was also unsuccessful
atom economy and assemble efficiency.[15] In partic- (Table 1, entry 10). Thus reaction conditions of entry 5
ular, reactions[16] involving 1,2-addition of a vinyl of Table 1 appeared to be optimal.
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Table 1. Optimization of the reaction conditions for 6H-
dibenzo[c,h]chromen-11-amine 2a.[a]
[a] Reaction conditions: 10a (0.2 mmol), catalyst (5 mol%,
except entry 10), bpy (6 mol%, except entries 1, 6–7 and
°
10), and additive (1.5 equiv.) in solvent (2 mL) at 100 C
under argon atmosphere.
[b] Isolated pure products.
[c] Ligand bpy (6 mol%) was used.
[d] The starting compound 10a was found to remain intact
(TLC).
Scheme 1. Palladium-catalyzed synthesis of 11-amino-6H-di-
benzo[c,h]chromenes 2.[a,b]
Abbreviations: bpy: bipyridine; phen: phenanthroline; D-CSA:
D-(+)-camphor sulfonic acid; NMA: N-methylacetamide; n.r.:
no reaction.
intact (TLC) instead. However, replacement of the aryl
ring A of 10 by a heteroaryl one (thiophene/2,4-
We next set out to explore the scope and generality dimethoxypyrimidine) worked well, affording the
of the reaction on a variety of substrates 10 as shown product (viz., 2h/2i) within 2–3.5 h with 60–74%
in Scheme 1. A series of products 2a–l could easily be yields.
prepared within 1.2–6 h with moderate to very good
Regarding the effect of substituents in the other
yields (42–78%) and a range of functional groups phenyl ring (i.e., B) of 10, introduction of electron
(viz., Me, CF3, OMe, F, Cl, NO2, CO2Me, NH2) were donating methoxy groups both at meta and para
tolerated. An electron withdrawing group (EWG) in positions reduced the reaction time (1.15 h) signifi-
phenyl ring A facilitated the reaction, affording the cantly and produced the expected product 2j in good
desired products 2b–d within 3–4 h with very good yield (66%). The reaction was facilitated further by the
yields (68–78%). In contrast, an electron donating incorporation of an additional nitro group (EWG) in
group at meta position (viz., R1 =Me) made the ring A para to the alkyne group, resulting in the
reaction somewhat sluggish with lower yield (56%) of formation of product 2k (73%). On the other hand, an
the product (2f), though the presence of two EDGs at EWG (viz., R2 =CF3 or F) at either meta or para
meta and para positions (viz., R1 =À OCH2OÀ ) deliv- position of ring B lowered the yields of the desired
ered the product 2e within 3 h. Notably, placement of products (2l or 2m) even after prolonging the reaction
a strong electron donating group (viz., OMe) at para time (2.5–3 h). These substituent effects are perhaps
position did not furnish any desired product 2g even predictable keeping in view the importance of electro-
after heating for 8 h; the starting material remained
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philicity of β-carbon (of the triple bond of 10) for the
cyclization to proceed smoothly.
Table 2. Optimization of the reaction conditions for 6H-
dibenzo[c,h]chromene 2’a.[a]
We also noted that performing this reaction with
substrates having the acetylenic carbon tethered to a
cyano group through a C3 chain (10n–o) instead of a
benzylic moiety resulted in carbonylated products 12–
13 within 2–5 h with 65–70% yield (Scheme 2) which
is in line with previous observations. [19]
Scheme 2. Synthesis of 2,3,4,6-tetrahydro-1H-benzo[c]chro-
men-1-ones 12–13.
[a] Reaction conditions: 10’a (0.2 mmol), catalyst (5 mol%,),
ligand (6 mol%), and additive (1.5 equiv.) in solvent (2 mL)
°
at 100 C under argon atmosphere.
[b] Isolated pure products.
2.2. Synthesis of 6H-dibenzo[c,h]chromenes 2’
[c] Starting material was recovered. Abbreviations: n.r.: no
reaction, bpy: bipyridine, phen: phenanthroline.
Encouraged by these results, we became interested to
apply the reaction on other substrates 10’ in which an
aldehyde functionality is used in place of a cyano
group. To our dismay, this reaction produced 2’a with
only 42% yield (Table 2, entry 1). But use of the less 10’f) is perhaps attributable to the enhanced electron
polar 1,4-dioxane instead of NMA proved beneficial, density on the β-carbon of the triple bond, involved in
delivering the expected product within 2 h with 75% the intramolecular nucleophilic attack, by the hydroxy
yield (Table 2, entry 2). Though removal of the methylgroup [see, species A (Y=O) under Scheme 10,
additive or changing the ligand to phenanthroline did vide infra]. In contrast, when the methoxy groups are
not help (Table 2, entries 3 and 4), use of a ligated placed at meta and para positions in ring B of the
catalyst [i.e., Pd(OAc)2bpy instead of Pd(OAc)2 and substrate (10’g), the expected product 2’g was indeed
bpy separately] greatly improved the yield (Table 2, formed smoothly with very good yield (75%); the high
entry 5). Replacing D-CSA by p-TsOH or decreasing reactivity of this substrate is likely due to the electron-
the polarity of the solvent further had detrimental donating effect of the methoxy group making the same
effect on the yield (Table 2, entries 6–8). Thus the carbon atom (β) of the triple bond electron deficient,
reaction conditions of entry 5 of Table 2 appeared best. thereby facilitating the cyclization through the nucleo-
To establish the generality of this methodology, the philic hydroxyl group.
optimized reaction condition was then applied to a
As anticipated, employing an electron-withdrawing
range of substrates (Scheme 3). Various substituents substituent (viz., R2 =F) at para position (substrate
(e.g. NO2, OMe, Me, F, Cl, Br etc.) in the aryl moiety 10’h) indeed produced the product 2’h, though in
of substrate 10’ were well tolerated. But a strongly reduced yield (62%) as compared to 2’c. On the other
electron-withdrawing group (R1 = NO2) in ring A para hand, the use of an electron donating methyl group at
to the alkyne moiety lowered the yield of the product meta position (10’i) led to the product 2’i with a
(2’b, 56%) considerably, while moderately active ones moderate yield (47%). Even the substrate 10’j with an
(R1 =F/Cl/Br) either at para or meta position had little alpha substituted aldehyde group reacted equally well,
impact (2’c/2’d/2’e). Of particular note, employment of showing no influence of the steric effect at this site.
an electro-donating group (viz., R1 =OMe) at para
position in the same ring (10’f) yielded no product,
2.3. Synthesis of dibenzo[c,h]chromen-6-ones 3
leaving the starting material intact (TLC); this result is
in line with our previous observation (see, product 2g After achieving a general synthesis of 6H-dibenzo[c,h]
in Scheme 1). The inertness of these substrates (10g/ chromenes 2/2', we became interested to test the
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Scheme 4. Conversion of products 2’ to 6H-dibenzo[c,h]chro-
men-6-ones 3.[a,b]
2.4. Synthesis of Pyrimidine (16) and Uracil (17)
Derivatives
In view of the immense biological activity of uracil
derivatives in cancer chemotherapy[20a–d] and our own
interest in this field,[20e] we decided to apply the
methodology for the synthesis of such molecules. The
requisite starting material 15, synthesized from pre-
cursor masked aldehyde 14a (R=H) by treating with p-
Scheme 3. Palladium-catalyzed synthesis of 6H-dibenzo[c,h]
chromenes 2’.[a,b]
applicability of this reaction through synthetic trans- TsOH, was exposed to conditions A as shown in
formation of the products prepared. Initially we Scheme 5; to our disappointment, the desired product
attempted benzylic oxidation of products 2’ which 16a (R=H) was obtained only in 20% yield. Gratify-
could provide easy access to 3. Of the various ingly, the masked aldehyde 14a, used under conditions
oxidizing agents tested, PCC appeared to be the best, B (where NMA is used instead of 1,4-dioxane),
furnishing the desired products 3a–d within few hours responded better and furnished the desired product 16a
with very good to excellent yields (79–95%, with 56% yield. Substrates 14b and 14c containing
Scheme 4). Thus synthesis of dibenzo[c,h]chromen-6- electron withdrawing (R=F) and donating (R=OMe)
ones 3 could easily be achieved in two steps starting group, respectively, also proved to be effective,
from acetylenic substrate 10 and overall yields were affording the expected products (16b and 16c) with
found to be between 48–81%.
50–65% yield (Scheme 5).
In view of the prospect of synthesizing the products
For transformation to uracil derivatives, one of the
3 directly, we carried out a reaction on substrate having products was tested for chemoselective demethylation.
ortho-carboxylic acid group in place of benzylic When 16c was treated with TMSCl/NaI at room
alcohol (of 10’a) under our optimized reaction con- temperature (Scheme 6), the desired product 17 was
ditions (entry 5 of Table 2); to our surprise, the desired formed easily albeit in moderate yield (58%). Anti-
product 3a was still found to be formed within 2 h but cancer screening of 17 in various cell lines and
only in moderate yield (42%) (See, Scheme S4 under preparation of other related uracil derivatives are
Supporting Information).
currently underway.
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Scheme 7. Palladium-catalyzed synthesis of 5,6-dihydrobenzo
[c]phenanthridin-11-amines 4.
steps (see Scheme S6 under supporting information)
was subjected to the optimized reaction conditions (see
entry 5 of Table 2), but the desired product 4’a was
formed with only 53% yield (Table 3, entry 1). Even
Table 3. Optimization of the reaction conditions for N-tosyl-
5,6-dihydrobenzo[c]phenanthridine 4’a.[a,b]
Scheme 5. Synthesis of 2,4-dimethoxy-12H-benzo[7,8]chrome-
no[3,4-d]pyrimidines 16.
Scheme 6. Conversion of 16c to uracil derivative 17.
3. Synthesis of the Aza Analogues
3.1. Synthesis of N-tosyl-5,6-dihydrobenzo[c]phe-
nanthridines 4/4’
After successful exploration of the general synthesis of
6H-dibenzo[c,h]chromenes 2/2’, we became interested
to check the feasibility of this reaction for nitrogen
heterocycles 4. Initially, the starting material 18a
(R1=R2=H) was synthesized (see Scheme S5 under
supporting information) and allowed to react under the
optimized reaction conditions (entry 5 of Table 1). To
our surprise, it merely yielded a tarry product
(Scheme 7). The situation did not improve even after
[a] In all entries, D-CSA was used as an additive.
[b] Reaction conditions: A mixture of 18’a (0.2 mmol), catalyst
(5 mol%), ligand (6 mol%), and D-CSA (1.5 equiv.) in
solvent (2 mL) was heated at the mentioned temperature
under argon atmosphere.
[c] Yield of the isolated pure products.
altering the catalyst, ligands, solvent systems, and the use of catalyst and ligand separately instead of
temperature, or through incorporation of common preformed Pd(OAc)2bpy was not helpful (Table 3,
substituents (R1=Cl/F, R2=H). Only when electron entry 2). But switching to a less polar solvent (i.e.,
donating methoxy groups were incorporated in the THF) reduced the reaction time to 2 h and improved
substrate (R1=R2=OMe; 18b), the desired product 4a the yield to 62% (Table 3, entry 3). Use of the
was formed.
preformed catalyst Pd(OAc)2bpy improved it further
We then planned to modify the structure of (Table 3, entry 4). But the reaction carried out in NMA
substrate 18 by replacing its cyano group with a formyl required (Table 3, entries 5–6) longer time (2.5–3 h)
one. Towards this, the substrate 18’a prepared in few and resulted in lower yields (38–41%), arguing against
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the use of polar solvent systems. Thus, the reaction separately under optimized reaction conditions (entry 4
conditions of entry 4 proved optimum. of Table 3); to our surprise, no trace of product
To establish the generality of the synthesis of 4’, we formation (TLC) was observed in each case even after
applied the optimized reaction conditions on substrates heating the reaction for several hours; the starting
18’ having various substitutions (Scheme 8). Initially, material was recovered instead.
3.2. Synthesis of Benzo[c]phenanthridines 19
Though some traditional[21a–d] and palladium-catalyzed
methods[21e–g] for the synthesis of 19 exist in the
literature, we felt that synthesis could easily be attained
from 4’ through a base induced elimination reaction.
Screening of a range of organic and inorganic bases
proved potassium hydroxide to be the best for this
transformation (Scheme 9). Thus the desired products
Scheme 8. Palladium-catalyzed synthesis of N-tosyl-5,6-dihy-
drobenzo[c]phenanthridines 4’.[a,b]
we used a strong electron-withdrawing group (viz.,
R1=CO2Me) in ring A para to the alkyne moiety of
substrate 18’b; indeed, it furnished the desired product
4’b in 2 h with 54% yield, while a moderately electron-
withdrawing group (i.e., R1=Cl) at meta position
afforded the desired product 4’c with very good yield
Scheme 9. Base promoted synthesis benzo[c]phenanthridines
19.[a,b]
(81%). However, attempts to prepare a substrate were synthesized conveniently within 1.5–2 h with
containing an electron-donating methoxy group moderate to very good yields (51–79%) and the
(R1=OMe) in place of the carbomethoxy (of 18’b) process was compatible with different functional
failed despite our sincere efforts.
groups (e.g., F, Cl and À OCH2OÀ ).
Regarding the effect of ring B substituents, an
The structures of all products (i.e., 2/2’, 3, 4/4’, 16–
electron-donating methylenedioxy group as in substrate 17, 19) were established firmly by spectroscopic (1H[22]
18’d resulted in product 4’d within 2 h albeit in and 13C NMR, HRMS) and analytical data. In addition,
moderate yield (42%). While the electron-withdrawing single crystal X-ray analysis[23] of 2j (Scheme 1), 2’a
fluoro group at para position (18’e) afforded the and 2’g, Scheme 3) and 4’e (Scheme 8) provided
product 4’e in 1.2 h with a good yield (67%), the less additional support to the structural conclusion.
electron-withdrawing bromo group (in 18’f) lowered
the reaction time (1 h) but also the yield (56%) palladium chemistry, a plausible reaction mechanism is
simultaneously. depicted (Scheme 10) to explain the product formation.
On the basis of our experimental results and known
Addtionally, in order to check the role of N- Thus initial activation of the triple bond of the
protecting group in substrate 18’, we deliberately acetylenic substrate by the Pd(II) catalyst leads to the
replaced the tosyl group of the same by acetyl or Boc formation of species A which may trigger heteroannu-
and the resulting substrates were allowed to react lation
through
trans-oxo/amino
palladation
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Scheme 10. Plausible mechanism for the formation of products 2/4 and 2’/4’.
pathway[17e,24] resulting in the formation of the transient that an intramolecular heteroannulation of intermediate
intermediate species B or C.[25] Next, species B and C 22, which in turn could be synthesized through a
may undergo intramolecular Grignard type nucleo- palladium-catalyzed coupling between 20[30] and 21[14b]
philic addition over a tethered cyanide/aldehyde group (see supporting information), may lead to 23 by
to produce the corresponding palladated species D[16c] adopting our newly developed method, the oxidation
and E[26a–b], respectively. While species D upon (PCC) of the benzylic hydrogens of which would
protonolysis using D-CSA followed by aromatization provide easy access to Arnottin I. It is important to
would lead to the targeted product 2/4, similar mention that the masked aldehyde precursor 22 should
protonolysis on species E[27] followed by dehydration be preferred as substrate. Indeed, the desired product
would afford the product 2’/4’.
23 was thus isolated in 58% yield within 1 h as shown
in Scheme 11.
4. Application to the Formal Total
Synthesis of Arnottin I (5)
In order to enlarge the scope of this heteroannulation
reaction further, we undertook a total synthesis of
Arnottin I (5, Figure 1) in a concise manner. This
natural product was isolated as a minor constituent
from the bark of Xanthoxylum arnottianum,[3a–b] but the
biological activities have not been explored fully
because of its low natural abundance. Nevertheless,
related natural products have aroused significant
interest in medicinal chemistry. For example, neo-
tanshinlactone displayed potent activity against human
breast cancer cell lines,[28] while chelerythrine (8a in
Figure 1) proved to be of interest in cancer chemo-
therapy due to its ability to stabilize the c-MYC and c-
KIT quadruplex DNAs[29a–b] (overexpression of which
has been associated[29c] with numerous cancers) in
addition to its role as G-quadruplex DNA stabilizer.[12a]
Scheme 11. Formal total synthesis of Arnottin I (5).
5. Conclusion
These findings provided impetus to develop various In conclusion, we have described a palladium-cata-
strategies[3b–h] in order to get easy access to 5. lyzed expeditious approach for the general synthesis of
However, some of them use long synthetic routes using dibenzo[c,h]chromen-6-ones 2/2’ and 5,6-dihydroben-
conventional reagents,[3b,f–g] while others, employing zo[c]phenanthridines 4’ through intramolecular domino
either palladium[3c–d,h] or nickel catalyst,[3e] required reactions of acetylenic substrates involving trans-oxo/
starting materials that were difficult to access. We felt aminopalladation followed by nucleophilic addition to
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was then neutralized by adjusting the pH (~7) through drop
wise addition of 20% aqueous sodium bicarbonate solution and
extracted with ethyl acetate (3×20 mL). The combined organic
extracts were washed with saturated brine (10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified through silica gel
(100–200 mesh) column chromatography using 10–40% ethyl
acetate-petroleum ether (v/v) as eluent to afford the desired
product 2.
cyanide or aldehyde group. The method is fast, atom
economical, operationally simple, and uses readily
available substrates. A range of functional groups
could easily be accommodated at different sites leaving
enough opportunity for diversification. Simple one-
step conversion of our products paved the way for
easily accessing 6H-dibenzo[c,h]chromen-6-ones 3 and
5,6-dihydrobenzo[c]phenanthridines 19 prevalent as
core structures of many medicinally active compounds.
Finally, a concise formal total synthesis of Arnottin I
was accomplished by applying the developed method.
Thus we have successfully generated rapid molecular
complexity under one pot using simple acetylenic
substrates avoiding any by-product. We believe that
this method will find applications in the total synthesis
of complex natural products and medicinally relevant
molecules as well.
6H-Dibenzo[c,h]chromen-11-amine
(2a):
Brown
gum
(37.2 mg, 75% yield), Rf =0.41 (10% ethyl acetate in petroleum
1
ether, v/v); H NMR (CDCl3, 300 MHz) δH 8.32 (d, J=7.8 Hz,
1H), 8.11 (d, J=8.4 Hz,1H), 7.54 (d, J=8.1 Hz, 1H), 7.44-7.34
(m, 2H), 7.32 (d, J=3.9 Hz, 2H), 7.24–7.19 (m, 1H), 6.78 (s,
1H), 5.12 (s, 2H), 4.20 (bs, 2H); 13C NMR (CDCl3, 150 MHz)
δC 152.8, 141.9, 134.8, 132.3, 129.9, 128.5, 127.4, 127.0, 125.3,
125.2,123.6, 122.3, 122.2, 120.0, 110.7, 104.2, 69.4; HRMS
(ESI+) m/z calculated for C17H14NO [M+H]+ 248.1075,
found 248.1083.
Experimental Section
8-Fluoro-6H-dibenzo[c,h]chromen-11-amine (2b): Brown sol-
°
id (37.1 mg, 70% yield), mp 120–122 C, Rf = 0.41 (10% ethyl
General Information
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 300 MHz) δH
8.34–8.29 (m, 1H), 8.08 (d, J=8.4 Hz, 1H),7.54 (d, J=8.1 Hz,
1H), 7.38 (t, J=7.8 Hz, 1H), 7.23–7.20 (m, 1H), 7.13–7.01 (m,
1H), 6.78 (s, 1H), 5.08 (s, 2H), 4.12 (bs, 2H); 13C NMR
(CDCl3, 150 MHz) δC 161.6 (d, J=246.6 Hz), 152.3, 141.7,
134.7, 134.6, 127.5, 126.2 (d, J=3.2 Hz), 125.5 (d, J=7.7 Hz),
125.3,122.5, 122.2, 120.1, 115.1 (d, J=21.8 Hz), 112.5 (d, J=
22.0 Hz), 110.2, 104.7, 69.0; HRMS (ESI+) m/z calculated for
C17H13FNO [M+H]+ 266.0981, found 266.0991.
All solvents were distilled prior to use. Petroleum ether refers to
fraction boiling in the range 60–80 C. Dichloromethane was
°
dried over phosphorous pentoxide, distilled, and stored over 3 Å
molecular sieves in a sealed container. 1,4-Dioxane was
distilled over sodium and benzophenone. Commercial grade dry
DMF (Dimethylformamide), DMA (Dimethylacetamide), and
NMA (N-Methylacetamide) were used as solvents. All reactions
were carried out under argon atmosphere and anhydrous
conditions unless otherwise noted. Analytical thin-layer chro-
matography (TLC) was performed on silica gel 60 F254
aluminum TLC sheets. Visualization of the developed chroma-
togram was performed by UV absorbance or iodine exposure.
For purification, column chromatography was performed using
100–200 mesh silica gel. 1H and 13C NMR spectra were
recorded on a 300, 400 or 600 MHz spectrometer using
tetramethylsilane (TMS) as internal standard. Chemical shifts
(δ) are given from TMS (δ=0.00) in parts per million (ppm)
with reference to the residual nuclei of the deuterated solvent
used [CDCl3: 1H NMR δ=7.26 ppm (s); 13C NMR δ=
77.0 ppm]. Coupling constants (J) are expressed in Hertz (Hz),
and spin multiplicities are given as s (singlet), d (doublet), dd
(double doublet), t (triplet), td (triple doublet), q (quartet), m
(multiplet), and br (broad). All 13C NMR spectra were obtained
with complete proton decoupling. Mass spectra were performed
using ESI-TOF or EI mode.
8-Nitro-6H-dibenzo[c,h]chromen-11-amine (2c): Orange solid
°
(45 mg, 78% yield), mp >230 C, Rf =0.18 (40% ethyl acetate
in petroleum ether, v/v); H NMR (CDCl3, 300 MHz) δH 8.57
1
(d, J=8.7 Hz, 1H), 8.27-8.24 (m, 1H), 8.18 (d, J=1.8 Hz, 1H),
8.11 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.45–7.41 (m,
1H), 7.28–7.23 (m, 1H), 6.80 (s, 1H), 5.20 (s, 2H), 4.14 (bs,
2H); 13C NMR (CDCl3, 150 MHz) δC 154.2, 145.9, 141.6,
136.7, 135.9, 132.6, 128.6, 125.4, 123.9, 122.9, 122.6, 120.4,
119.8, 109.4, 105.1, 68.7; HRMS (EI+) m/z calculated for
C17H12N2O3 [M]+ 292.0848, found 292.0845.
9-Chloro-6H-dibenzo[c,h]chromen-11-amine (2d): Yellow sol-
°
id (38.3 mg, 75% yield), mp 128–130 C, Rf = 0.45 (40% ethyl
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 600 MHz) δH
8.28 (d, J=8.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.54 (d, J=
7.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.30 (d, J=2.4 Hz, 1H), 7.25-
7.22 (m, 1H), 6.78 (s, 1H), 5.08 (s, 2H), 4.11 (s, 2H); 13C NMR
(CDCl3, 150 MHz) δC 152.7, 141.7, 134.9, 133.9, 132.5, 128.5,
128.4, 127.6, 125.4, 125.3, 124.9, 122.5, 122.3, 119.9, 110.0,
104.6, 68.8; HRMS (ESI+) m/z calculated for C17H13ClNO [M
+H]+ 282.0686, found 282.0691.
General Procedure for the Synthesis of 6H-dibenzo
[c,h]chromen-11-amine 2
A mixture of Pd(OAc)2 (2.2 mg, 0.01 mmol, 5 mol%), 2,2’-
bipyridine (1.9 mg, 0.012 mmol, 6 mol%) and D-CSA(69.6 mg,
6H-[1,3]Dioxolo[4’,5’:4,5]benzo[1,2-c]benzo[h]- chromen-12-
amine (2e): Pale yellow solid (36.2 mg, 62% yield), mp 184–
°
0.3 mmol, 1.5 equiv.) in dry NMA (3 mL) was stirred at 90 C
°
186 C, Rf = 0.35 (10% ethyl acetate in petroleum ether, v/v);
1H NMR (CDCl3, 400 MHz) δH 8.05 (d, J=8.4 Hz, 1H), 7.88
(s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.36–7.32 (m, 1H), 7.21–7.17
(m, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 5.99 (s, 2H), 4.98 (s, 2H),
4.08 (s, 2H); 13C NMR(CDCl3, 100 MHz) δC 152.1, 147.8,
146.5, 141.6, 134.4, 127.2, 126.2, 125.3, 123.9, 122.4, 122.2,
for 5 min under argon atmosphere. Next, the starting material
10 (0.20 mmol) dissolved in NMA (1.5 mL) was added to the
reaction mixture at the same temperature and the whole mixture
°
was allowed to stir at heating conditions (100 C) for few hours
until the completion of the reaction (TLC). The reaction mixture
Adv. Synth. Catal. 2019, 361, 1–17
9
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120.1, 110.0, 106.2, 104.8, 104.5, 101.3, 69.4; HRMS (ESI+)
m/z calculated for C18H14NO3 [M+H]+ 292.0974, found
292.1023.
(s, 1H), 5.15 (s, 2H), 4.37(s, 2H); 13C NMR(CDCl3, 150 MHz)
δC 153.4, 144.0, 135.9, 132.1, 129.3, 129.0, 128.5, 127.4, 125.8,
125.4, 123.7, 123.3, 122.8 (m), 120.4 (m), 118.6, 111.3, 103.7,
69.4; HRMS (ESI+) m/z calculated for C18H12F3O [M+H]+
301.0840, found 301.0838.
9-Methyl-6H-dibenzo[c,h]chromen-11-amine (2f): Brown sol-
°
id (29.3 mg, 56%), mp 168–170 C; Rf = 0.46 (10% ethyl
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 300 MHz) δH
8.10 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.37 (t, J=
7.4 Hz, 1H), 7.32-7.23 (m, 3H), 7.21-7.19 (m, 1H), 6.79 (s,
1H), 5.18 (d, J=12.3 Hz, 1H), 4.81 (d, J=12.3 Hz, 1H), 3.95
(s, 2H), 2.47 (s, 3H); 13C NMR(CDCl3, 150 MHz) δC 154.4,
141.7, 136.3, 134.9, 134.2, 131.9, 128.7, 127.1, 126.7, 125.2,
122.3, 122.1, 121.9, 119.4, 111.8, 102.8, 71.1, 21.7; HRMS
(ESI+) m/z calculated for C18H16NO [M+H]+ 262.1232,
found 262.1236.
2-Fluoro-6H-dibenzo[c,h]chromen-11-amine (2m) : Pale yel-
°
low solid (33.5 mg, 63% yield), mp 130–132 C, Rf =0.36 (10%
ethyl acetate in petroleum ether, v/v); 1H NMR (CDCl3,
300 MHz) δH 8.27 (d, J=7.8 Hz, 1H), 8.11-8.06 (m, 1H), 7.43–
7.38 (m, 1H), 7.31(d, J=4.2 Hz, 2H), 7.13 (dd, J=10.5,
2.1 Hz, 1H), 6.96 (td, J=8.7, 2.4 Hz, 1H), 6.69 (s, 1H), 5.11 (s,
2H), 4.25 (s, 2H); 13C NMR (CDCl3, 150 MHz) δC 162.2 (d, J=
244.6 Hz), 153.0, 143.2, 136.0 (d, J=9.9 Hz), 132.0, 129.7,
128.5, 127.0, 125.3, 125.0 (d, J=9.6 Hz), 123.4, 116.9, 112.2
(d, J=25.0 Hz), 109.8, 108.3 (d, J=21.3 Hz), 103.4 (d, J=
5.1 Hz), 69.4; HRMS (ESI+) m/z calculated for C17H13FNO
[M+H]+ 266.0981, found 266.0988.
11H-Benzo[h]thieno[2,3-c]chromen-4-amine (2h):Black gum
(37.4 mg, 74% yield), Rf =0.30 (10% ethyl acetate in petroleum
1
ether, v/v); H NMR (CDCl3, 300 MHz) δH 8.09 (d, J=8.4 Hz,
1H), 7.76 (d, J=5.1 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.37–
7.33 (m, 2H), 7.25–7.20 (m, 1H), 6.78 (s, 1H), 5.38 (s, 2H),
4.07 (brs, 2H); 13C NMR(CDCl3, 150 MHz) δC 149.5, 140.9,
134.4, 131.3, 128.9, 126.9, 125.4, 124.2, 123.9, 122.5, 122.3,
120.0, 109.7, 104.4, 64.8; HRMS (ESI+) m/z calculated for
C15H12NOS [M+H]+ 254.0640, found 254.0643.
Spectral data of Products 12–13
2,3,4,6-Tetrahydro-1H-benzo[c]chromen-1-one (12): White
solid (26 mg, 65% yield); mp 122–124 C; Rf =0.29 (10% ethyl
°
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 600 MHz) δH
8.29 (d, J=7.8 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.21 (t, J=
7.5 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 5.12 (s, 2H), 2.58–2.54
(m, 4H), 2.03–1.99 (m, 2H); 13C NMR(CDCl3, 150 MHz) δC
196.5, 174.1, 128.6, 127.8, 127.0, 126.9, 124.8, 123.7, 113.1,
69.5, 38.3, 28.9, 20.1; HRMS (EI+) m/z calculated for
C13H12O2 [M]+ 200.0837, found 200.0839.
2,4-Dimethoxy-12H-benzo[7,8]chromeno[3,4-d]pyrimidin-5-
°
amine (2i): Brown solid (37.1 mg, 60% yield), mp 112–114 C,
Rf =0.20 (30% ethyl acetate in petroleum ether, v/v); H NMR
1
(CDCl3, 300 MHz) δH 8.10 (d, J=8.4 Hz, 1H), 7.57 (d, J=
8.4 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.26–7.21 (m, 1H), 6.85
(s, 1H), 5.02 (s, 2H), 4.17 (s, 3H), 4.07 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δC 165.1, 164.9, 163.6, 152.2, 142.0, 134.7,
127.2, 125.1, 122.4, 122.1, 119.4, 106.9, 105.7, 104.6, 69.7,
55.1, 54.4; HRMS (ESI+) m/z calculated for C17H16N3O3 [M+
H]+ 310.1192, found 310.1205.
9-Chloro-2,3,4,6-tetrahydro-1H-benzo[c]chromen-1-one (13):
Pale yellow solid (32.8 mg, 70% yield), mp 164–166 C, Rf =
°
0.28 (10% ethyl acetate in petroleum ether, v/v); 1H NMR
(CDCl3, 300 MHz) δH 8.36 (t, J=1.8 Hz, 1H), 7.19–7.16 (m,
1H), 6.95 (d, J=8.1 Hz, 1H), 5.09 (s, 2H), 2.59–2.51 (m, 4H),
2.04–1.96 (m, 2H); 13C NMR (CDCl3, 75 MHz) δC 196.2,
174.9, 134.4, 129.3, 126.7, 125.0, 124.9, 124.8, 112.1, 68.9,
38.1, 28.9, 19.9; HRMS (ESI+) m/z calculated for C13H12ClO2
[M+H]+ 235.0526, found 235.0522.
2,3-Dimethoxy-6H-dibenzo[c,h]chromen-11-amine
(2j):
°
Brown solid (40.5 mg, 66% yield), mp>230 C,Rf =0.11 (10%
ethyl acetate in petroleum ether, v/v); 1H NMR (CDCl3,
600 MHz) δH 8.31 (d, J=7.8 Hz, 1H), 7.41–7.39 (m, 2H),
7.30–7.29 (m, 2H), 6.87 (s, 1H), 6.68 (s, 1H), 5.10 (s, 2H), 4.09
(s, 2H), 3.99(s, 3H), 3.98 (s, 3H); 13C NMR(CDCl3, 150 MHz)
δC 151.8, 150.8, 147.0, 140.8, 132.0, 130.8, 130.3, 128.4, 126.6,
125.1, 123.6, 114.5, 109.2, 104.4, 103.8, 101.4, 69.4, 55.9,
55.8; HRMS (EI+) m/z calculated for C19H17NO3 [M]+
307.1208, found 307.1204.
General Procedure for the Synthesis of 6H-dibenzo
[c,h]chromenes 2’
A mixture of Pd(OAc)2bpy (3.8 mg, 0.01 mmol, 5 mol%) and
D-CSA (69.6 mg, 0.3 mmol, 1.5 equiv.) in dry 1,4-dioxane
°
(2 mL) was stirred at 90 C for 5 min under argon atmosphere.
2,3-Dimethoxy-8-nitro-6H-dibenzo[c,h]chromene (2k): Red-
°
Next the starting material 10’ (0.20 mmol) dissolved in 1,4-
dioxane (1.5 mL) was added to the reaction mixture at the same
temperature and the whole mixture was allowed to stir at
dish brown solid (51.4 mg, 73% yield), mp>250 C, Rf =0.32
(10% ethyl acetate in petroleum ether, v/v); H NMR (CDCl3,
1
300 MHz) δH 8.55 (d, J=8.7 Hz, 1H), 8.24 (d, J=9.0 Hz,
1H),8.17 (s, 1H), 7.39 (s, 1H), 6.86 (s, 1H), 6.69 (s, 1H), 5.17
(s, 2H), 4.04 (s, 2H), 3.99 (s, 6H); 13C NMR (CDCl3, 150 MHz)
δC 152.9, 151.8, 147.4, 145.5, 140.6, 137.1, 132.2, 123.8, 123.7,
120.2, 114.2, 107.9, 104.6, 104.4, 101.5, 68.6, 55.9, 55.8;
HRMS (EI+) m/z calculated for C19H17N2O5 [M+H]+
353.1137, found 353.1151.
°
heating conditions (100 C) for few hours until the completion
of the reaction (TLC). Thereafter, the reaction mixture was
neutralized by adjusting the pH (~7) through drop wise addition
of 20% aqueous sodium bicarbonate solution and extracted with
ethyl acetate (3×20 mL). The combined organic extracts were
washed with saturated brine (10 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified through silica gel (100-200 mesh)
column chromatography using 0–20% ethyl acetate-petroleum
ether (v/v) as eluent to afford desired product 2’in 47–86%
yield.
3-(Trifluoromethyl)-6H-dibenzo[c,h]chromen-11-amine (2l):
Brown gum (25.2 mg, 42% yield), Rf =0.27 (10% ethyl acetate
1
in petroleum ether, v/v); H NMR (CDCl3, 300 MHz) δH 8.40
(s, 1H), 8.27 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.50
(d, J=8.7 Hz, 1H), 7.43–7.40 (m, 1H), 7.35–7.33 (m, 1H), 6.78
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6H-Dibenzo[c,h]chromene (2’a): Yellow solid (39.9 mg, 86%
68.9, 55.99, 55.91; HRMS (ESI+) m/z calculated for C19H17O3
[M+H]+ 293.1178, found 293.1174.
1
°
yield), mp 100–102 C, Rf =0.46 (petroleum ether); H NMR
(CDCl3, 600 MHz) δH 8.28-8.26 (m, 1H), 7.85 (d, J=8.4 Hz,
1H), 7.82–7.80 (m, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.55 (d, J=
8.4 Hz, 1H), 7.50–7.48 (m, 2H), 7.42 (t, J=7.8 Hz 1H), 7.31 (t,
J=7.5 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 5.32 (s, 2H); 13C
NMR (CDCl3, 150 MHz) δC 150.3, 134.4, 130.8, 130.7, 128.6,
127.6, 127.4, 126.6, 125.8, 125.3, 124.6, 122.3, 121.9, 121.6,
120.9, 117.2, 68.9; HRMS (ESI+) m/z calculated for C17H13O
[M+H]+ 233.0966, found 233.0944.
2-Fluoro-6H-dibenzo[c,h]chromene (2’h): Yellow solid
°
(31 mg, 62% yield), mp 118–120 C, Rf =0.54 (petroleum
ether); H NMR (CDCl3, 600 MHz) δH 8.29-8.26 (m, 1H), 7.86
1
(d, J=8.4 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.46 (d, J=
8.4 Hz, 1H), 7.43–7.41 (m, 2H), 7.31 (t, J=7.5 Hz 1H), 7.28–
7.24 (m, 1H), 7.22 (d, J=7.2 Hz, 1H), 5.31 (s, 2H); 13C NMR
(CDCl3, 150 MHz) δC 161.4(d, J=246 Hz), 150.5, 135.4 (d, J=
9 Hz), 130.4 (d, J=4.5 Hz), 128.6, 127.5, 125.1(d, J=
10.5 Hz), 124.7,122.4, 121.8, 120.8(d, J=4.5 Hz), 116.6 (d, J=
1.5 Hz), 115.9, 115.8, 111.0, 110.9, 68.9; HRMS (ESI+) m/z
calculated for C17H12FO [M+H]+ 251.0872, found 251.0871.
8-Nitro-6H-dibenzo[c,h]chromene
(2’b):
Yellow
solid
°
(30.0 mg, 56% yield); mp 158–160 C; Rf = 0.63 (10% ethyl
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 600 MHz) δH
8.29-8.27 (m, 2H), 8.12 (d, J=2.4 Hz, 1H), 7.85 (d, J=
8.4 Hz,1H), 7.84–7.82 (m, 2H), 7.58(d, J=8.4 Hz, 1H), 7.57-
7.53 (m, 2H), 5.40 (s, 2H); 13C NMR (CDCl3, 150 MHz) δC
151.9, 146.6, 137.3, 135.4 131.3, 127.9, 127.8, 126.4, 125.1,
124.1, 122.6, 122.5, 122.4, 120.8, 120.2, 115.3, 68.3; HRMS
(ESI+) m/z calculated for C17H12NO3 [M+H]+ 278.0817,
found 278.0814.
4-Methyl-6H-dibenzo[c,h]chromene (2’i): Yellow solid
°
(23.1 mg, 47% yield), mp 70–72 C, Rf = 0.56 (petroleum
ether); 1H NMR (CDCl3, 600 MHz) δH 7.82 (d, J=8.4 Hz, 1H),
7.74 (d, J=7.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.53 (d, J=
8.4 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.33-7.30 (m, 2H), 7.24–
7.22 (m, 2H), 5.23 (s, 2H), 2.94 (s, 3H); 13C NMR (CDCl3,
150 MHz) δC 152.8, 135.9, 135.6, 131.0, 130.8, 128.8, 128.6,
127.2, 126.4, 126.2, 125.1, 124.4, 122.6, 122.3, 121.1, 118.5,
68.2, 25.2; HRMS (ESI+) m/z calculated for C18H15O [M+
H]+ 247.1123, found 247.1122.
8-Fluoro-6H-dibenzo[c,h]chromene
(2’c): White
solid
°
(39.5 mg, 79% yield), mp 158–160 C, Rf =0.54 (petroleum
ether); 1H NMR (CDCl3, 600 MHz) δH 8.27–8.26 (m, 1H), 7.82-
7.81 (m, 1H), 7.78(d, J=8.4 Hz, 1H), 7.70-7.68 (m, 1H), 7.55
(d, J=8.4 Hz, 1H), 7.52-7.49(m, 2H), 7.11(td, J=8.55, 2.8 Hz,
1H), 6.94 (dd, J=8.4, 2.4 Hz, 1H), 5.28 (s, 2H); 13C NMR
(CDCl3, 150 MHz) δC 162.3 (d, J=246 Hz), 149.8, 134.2,
132.9 (d, J=7.5 Hz), 127.7, 126.9, 126.7, 125.9, 125.3, 123.8
(d, J=9 Hz), 122.2, 121.8, 120.7, 116.6, 115.4 (d, J=22.5 Hz),
111.9 (d, J=22.5 Hz), 68.4; HRMS (ESI+) m/z calculated for
C17H12FO [M+H]+ 251.0872, found 251.0876.
12-Methyl-6H-dibenzo[c,h]chromene (2’j): Yellow gum
(40.8 mg, 83% yield),Rf =0.44 (petroleum ether);1H NMR
(CDCl3, 600 MHz) δH 8.31 (d, J=9 Hz, 1H), 7.95 (d, J=
8.4 Hz, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.69 (s, 1H), 7.56–7.51
(m, 2H), 7.42 (t, J=7.5 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.22
(d, J=7.8 Hz, 1H), 5.30 (s, 2H), 2.71 (s, 3H); 13C NMR(CDCl3,
150 MHz) δC 148.9, 133.4, 130.9, 130.7, 128.5, 127.6, 127.3,
126.5, 125.54, 125.5, 124.6, 124.2, 122.7, 121.9, 121.3, 116.6,
68.9, 19.3; HRMS (ESI+) m/z calculated for C18H15O [M+H]
+ 247.1123, found 247.1125.
9-Chloro-6H-dibenzo[c,h]chromene (2’d): Yellow solid
°
(43.1 mg, 81% yield), mp 101–103 C, R =0.49 (petroleum
f
ether); 1H NMR (CDCl3, 400 MHz) δH 8.27-8.25 (m, 1H), 7.82-
7.78 (m, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.68 (d, J=2 Hz, 1H),
7.52–7.48 (m, 3H), 7.24 (dd, J=2 Hz,1H), 7.10 (d, J=8 Hz,
1H), 5.24 (s, 2H); 13C NMR (CDCl3, 150 MHz) δC 150.7, 134.8,
134.6, 132.6, 128.9, 127.8, 127.2, 127.1, 126.1, 125.9, 125.3,
122.4, 122.2, 121.9, 120.8, 116.1, 68.4; HRMS (ESI+) m/z
calculated for C17H12ClO [M+H]+ 267.0577, found 267.0573.
Synthesis of 6H-dibenzo[c,h]chromen-6-ones (3)
from 6H-dibenzo[c,h]chromenes 2’ by benzylic oxi-
dation
To a solution of 2’(0.086 mmol, 1 equiv.) in dry DCM was
added PCC (27.7 mg, 0.13 mmol, 1.5 equiv.) and heated at
refluxing temperature for 3–4 h until complete consumption of
the starting material (TLC).The crude product was filtered
through a plug of silicagel (100-200 mesh size) which was
washed with DCM, and the solution was concentrated in vacuo.
The crude product was purified through silica gel (100-
200 mesh) column chromatography eluting with 18–20% ethyl
acetate-petroleum ether (v/v) to furnish the pure product 3 in
64–95% yield.
8-Bromo-6H-dibenzo[c,h]chromene
(2’e):
White
solid
°
(47.1 mg, 76% yield), mp 140–142 C, Rf = 0.54 (petroleum
ether); 1H NMR (CDCl3, 600 MHz) δH 8.26-8.24 (m, 1H), 7.81–
7.79 (m, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H),
7.55–7.52 (m, 2H), 7.51–7.49 (m, 2H), 7.37 (s, 1H), 5.27 (s,
2H); 13C NMR (CDCl3, 150 MHz) δC 150.3, 134.5, 132.6,
131.6, 129.8, 127.7, 126.9, 126.0, 125.3, 123.6, 122.3, 121.8,
121.0, 120.6, 116.3, 68.2; HRMS (ESI+) m/z calculated for
C17H12BrO [M+H]+ 311.0072, found 311.0066.
6H-Dibenzo[c,h]chromen-6-one (3a): White solid (19.4 mg,
°
92% yield), mp 188–190 C, Rf = 0.53 (10% ethyl acetate in
petroleum ether, v/v); H NMR (CDCl3, 300 MHz) δH 8.59 (d,
2,3-Dimethoxy-6H-dibenzo[c,h]chromene (2’g): Yellow solid
1
°
(43.8 mg, 75% yield), mp 140–144 C, Rf = 0.55 (20% ethyl
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 600 MHz) δH
7.73–7.71 (m, 2H), 7.54 (s, 1H), 7.42–7.39 (m, 2H), 7.28 (td,
J=1.0, 7.35 Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 7.11 (s, 1H),
5.29 (s, 2H), 4.05 (s, 3H), 4.02 (s, 3H); 13C NMR (CDCl3,
150 MHz) δC 150.1, 149.44, 149.42, 130.9, 130.5, 130.4, 128.5,
127.0, 124.6, 121.8, 120.4, 120.1, 119.4, 116.1, 106.4, 101.1,
J=7.5 Hz, 1H), 8.47 (d, J=7.8 Hz, 1H), 8.19 (d, J=8.1 Hz,
1H), 8.06(d, J=9.0 Hz, 1H), 7.89–7.85 (m, 2H), 7.77 (d, J=
8.7 Hz, 1H), 7.66-7.58 (m, 3H); 13C NMR (CDCl3, 150 MHz)
δC 161.3, 147.3, 135.5, 135.0, 134.3, 130.7, 128.7, 127.9, 127.7,
127.2, 124.6, 123.9, 122.4, 122.1, 121.2, 119.2, 113.1; HRMS
(ESI+) m/z calculated for C17H11O2 [M+H]+ 247.0759, found
247.0764.
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8-Fluoro-6H-dibenzo[c,h]chromen-6-one (3b): White solid
85.9, 55.0, 54.6; HRMS (ESI+) m/z calculated for C17H15N2O3
[M+H]+ 295.1083, found 295.1086.
°
(17.9 mg, 79% yield), mp 219–221 C,Rf =0.55 (10% ethyl
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 600 MHz) δH
8.55 (d, J=8.4 Hz, 1H), 8.19.–8.17 (m, 1H), 8.10 (dd, J=3,
8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H),
7.77 (d, J=9.0 Hz, 1H), 7.65–7.56 (m, 3H); 13C NMR (CDCl3,
150 MHz) δC 162.3 (d, J= 249 Hz), 160.3 (d, J=3 Hz), 146.7,
134.1, 131.9 (d, , J=3 Hz), 127.8 (d, J=39 Hz), 127.3, 124.8,
124.6 (d, J=9 Hz), 123.8, 123.3, 123.2, 122.9 (d, J=9 Hz),
122.2, 118.9, 116.2(d, J=22.5 Hz), 112.4; HRMS (ESI+) m/z
calculated for C17H10FO2 [M+H]+ 265.0665, found 265.0644.
8-Fluoro-2,4-dimethoxy-12H-benzo[7,8]chromeno [3,4-d]pyri-
midine (16b): Pale yellow solid (61.0 mg, 65% yield), mp 158–
1
°
160 C, Rf =0.41 (20% ethyl acetate in petroleum ether, v/v); H
NMR (CDCl3, 600 MHz) δH 7.80 (d, J=1.2 Hz, 1H), 7.52 (s,
1H), 7.37–7.35 (m, 1H), 7.23 (dd, J=2.1,9.3 Hz, 1H), 6.98–
7.95 (m, 1H), 5.15 (s, 2H), 4.15 (s, 3H), 4.05 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δC 168.7, 161.8 (d, J=209.4 Hz), 151.3,
138.5(d, J=9 Hz), 136.8 (d, J= 2.2 Hz), 128.9 (d, J=1.5 Hz),
122.1, 122.0, 121.6, 113.5 (d,J=23.3 Hz), 111.4, 105.1, 104.9,
77.3, 55.1, 54.7; HRMS (ESI+) m/z calculated forC17H14FN2O3
[M+H]+ 313.0988, found 313.0991.
12-Methyl-6H-dibenzo[c,h]chromen-6-one (3c): White solid
°
(21.2 mg, 95% yield), mp 195–197 C, Rf =0.58 (10% ethyl
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 600 MHz) δH
8.63-8.61 (m, 1H), 8.47 (d, J=7.8 Hz, 1H), 8.19 (d, J=7.8 Hz,
1H), 8.01-7.99 (m, 1H), 7.88–7.85(m, 2H), 7.66–7.65 (m, 2H),
7.60 (t, J=7.5 Hz, 1H), 2.76 (s, 3H); 13C NMR (CDCl3,
150 MHz) δC 161.4, 146.0, 135.4, 134.9, 133.4, 130.8, 130.6,
128.5, 127.7, 126.8, 124.2, 123.9, 122.8, 121.9, 121.3, 119.2,
112.5, 19.5; HRMS (ESI+) m/z calculated for C18H12NaO2 [M
+Na]+ 283.0735, found 283.0740.
2,4,8,9-Tetramethoxy-12H-benzo[7,8]chromeno[3,4-d]pyrimi-
dine (16c): Pale yellow solid (53.1 mg, 50% yield), mp 212–
°
214 C, Rf = 0.19 (20% ethyl acetate in petroleum ether, v/v);
1H NMR (CDCl3, 600 MHz) δH 8.08 (d, J=9.0 Hz, 1H), 7.50
(s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 5.19 (s, 2H), 4.15
(s, 3H), 4.04 (s, 3H) 4.03 (s, 3H), 4.01(s, 3H); 13C NMR
(CDCl3, 150 MHz) δC 166.6, 163.5, 161.4, 150.1, 149.4, 148.1,
129.8, 122.5, 119.9, 119.8, 111.9, 106.1, 105.8, 100.8, 69.2,
56.0, 55.9, 54.9, 54.3; HRMS (ESI+) m/z calculated for
C19H19N2O5 [M+H]+ 355.1294, found 355.1299.
2,3-Dimethoxy-6H-dibenzo[c,h]chromen-6-one (3d): White
°
solid (16.8 mg, 64% yield), mp 176–178 C, Rf = 0.57 (10%
ethyl acetate in petroleum ether, v/v); 1H NMR (CDCl3,
300 MHz) δH 8.44 (d, J=7.8 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H),
7.91 (d, J=8.7 Hz, 1H), 7.84 (t, J=7.2 Hz, 1H), 7.79 (s, 1H),
7.61–7.54 (m, 2H), 7.14 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H); 13C
NMR (CDCl3, 150 MHz) δC 161.6, 150.9, 150.3, 146.5, 135.8,
134.9, 130.6, 130.4, 128.2, 122.9, 121.8, 120.7, 119.0, 117.6,
111.9, 106.4, 101.1, 56.4, 56.0; HRMS (ESI+) m/z calculated
for C19H15O4 [M+H]+ 307.0970, found 307.0974.
General procedure for the synthesis of
8,9-dimethoxy-1H-benzo[7,8]chromeno[3,4-d]pyri-
mi- dine-2,4(3H,12H)-dione (17)
To a well stirred and ice-cooled solution of 16c (30 mg, 0.08,
1 equiv.) in dry acetonitrile (3 mL) were added anhydrous
sodium iodide (35.7 mg, 0.24 mmol, 3 equiv.) and freshly
distilled trimethylsilylchloride (30 μL, 0.24 mmol, 3 equiv.)
successively. The reaction mixture was then stirred at room
temperature until the complete conversion of the starting
material (TLC). The solvent was removed under reduced
pressure; the crude product was filtered, and washed with ethyl
acetate several times. The resulting yellow solid was dried in
vacuo to afford the product 17.
General procedure for the synthesis of
2,4-dimethoxy-12H-benzo[7,8]chromeno[3,4-d]pyri-
mi- dine 16
A mixture of Pd(OAc)2bpy (5.7 mg, 0.015 mmol, 5 mol%), D-
CSA (139.2 mg, 0.6 mmol, 2 equiv.) in dry NMA (2 mL) was
°
stirred at 90 C for 5 min under argon atmosphere. The substrate
14 (0.3 mmol, 1 equiv.) dissolved in NMA (1.0 mL) was then
added dropwise and the whole mixture was allowed to stir at
8,9-Dimethoxy-1H-benzo[7,8]chromeno[3,4-d]pyri- midine-2,4
(3H,12H)-dione (17): Pale yellow solid (16.4 mg, 58% yield),
1
°
mp >260 C; H NMR (DMSO-d6, 600 MHz) δH 11.40 (s, 1H),
°
100 C for few hours until completion of the reaction (TLC).
11.31 (s, 1H), 8.30 (d, J=9 Hz, 1H), 7.37 (d, J=9 Hz, 1H),
7.29 (s, 1H), 7.24 (s,1H),5.03 (s, 2H), 3.85 (s, 6H); 13C NMR
(CDCl3, 150 MHz) δC 162.1, 150.7, 149.9, 149.7, 145.4,
144.9,129.2, 121.2, 119.9, 119.2, 113.2, 106.9, 101.2, 100.3,
63.9, 55.9, 55.8; HRMS (ESI+) m/z calculated for C17H15N2O5
[M+H]+ 327.0981, found 327.0990.
Thereafter, the reaction mixture was neutralized by adjusting
the pH (~7) through drop wise addition of 20% aqueous sodium
bicarbonate solution and then extracted with ethyl acetate (3×
20 mL). The combined organic extracts were washed with
saturated brine (10 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The resulting residue
was purified through silica gel (100-200 mesh) column chroma-
tography using 15–20% ethyl acetate-petroleum ether (v/v) as
eluent to afford desired product 16 in 50–65% yield.
Synthesis of 2,3-dimethoxy-5-tosyl-
5,6-dihydrobenzo[c]phenanthridin-11-amine 4a
2,4-Dimethoxy-12H-benzo[7,8]chromeno[3,4-d]pyrimidine
A
mixture of Pd(OAc)2 (2.5 mg, 0.011 mmol, 5 mol%),
°
(16a): Pale yellow solid (49.4 mg, 56% yield), mp 119–121 C,
phenanthroline (2.38 mg, 0.013 mmol, 6 mol%) and D-CSA
(76 mg, 0.33 mmol, 1.5 equiv.) in NMA(3 mL) was stirred at
reflux temperature for 5 min under argon atmosphere. Then the
starting material 18 (0.22 mmol) dissolved in NMA (1.5 mL)
was added to the reaction mixture at the same temperature and
1
Rf = 0.43 (20% ethyl acetate in petroleum ether, v/v); H NMR
(CDCl3, 600 MHz) δH7.84 (d, J=1.2 Hz, 1H), 7.57 À 7.55
(m,2H), 7.45 (d, J=7.8 Hz, 1H), 7.27–7.24 (m, 1H), 7.19 (t,
J=7.5 Hz, 1H), 5.14 (s, 2H), 4.14 (s, 3H), 4.05(s, 3H); 13C
NMR (CDCl3, 150 MHz) δC 168.7, 162.8, 160.9, 150.6, 140.7,
136.7, 129.7, 126.6, 126.3, 124.7, 121.3, 117.5, 111.4, 87.9,
°
the whole mixture was allowed to stir at 95 C for few hours
until the completion of the reaction (TLC). The reaction mixture
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was then neutralized by adjusting the pH (~7) through drop
wise addition of 20% aqueous sodium bicarbonate solution and
extracted with ethyl acetate (3×20 mL). The combined organic
extracts were washed with saturated brine (10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified through silica gel
(100–200 mesh) column chromatography using eluent 30%
ethyl acetate-petroleum ether (v/v) to afford the desired product
4a.
7.32 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 6.67 (d, J=
7.8 Hz, 2H), 5.35 (d, J=16.8 Hz, 1H), 4.58 (d, J=16.8 Hz,
1H), 3.97 (s, 3H), 2.17 (s, 3H); 13C NMR (CDCl3, 150 MHz) δC
166.5, 143.3, 136.2, 134.4, 133.6, 133.57, 132.2, 131.4, 129.2,
128.8, 128.7, 128.4, 128.1, 127.7, 127.5, 127.4, 127.3, 127.0,
126.8, 123.1, 121.3, 52.4, 50.8, 21.3; HRMS (ESI+) m/z
calculated for C26H22NO4S [M+H]+ 444.1270, found
444.1270.
9-Chloro-5-tosyl-5,6-dihydrobenzo[c]phenanthri- dine (4’c):
°
2,3-Dimethoxy-5-tosyl-5,6-dihydrobenzo[c]phenan- thridin-11-
amine (4a): Brown solid (74.9 mg, 74% yield), mp 186–
Yellow solid (67.9 mg, 81% yield), mp 140–142 C, Rf =0.46
(5% ethyl acetate in petroleum ether, v/v); H NMR (CDCl3,
1
°
188 C, Rf =0.46 (50% ethyl acetate in petroleum ether, v/v);
600 MHz) δH 8.74 (d, J=8.4 Hz, 1H), 7.89–7.86 (m, 2H), 7.67-
7.64 (m, 1H), 7.59–7.55 (m, 2H), 7.15–7.13 (m, 2H), 7.07 (d,
J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 2H), 6.75 (d, J=7.8 Hz,
2H), 5.29 (d, J=16.2 Hz, 1H), 4.48 (d, J=16.2 Hz, 1H), 2.28
(s, 3H); 13C NMR (CDCl3, 150 MHz) δC 143.6, 134.2, 133.8,
133.7, 132.9, 131.3, 130.4, 128.8, 128.3, 128.2, 127.6, 127.5,
127.4, 127.2, 126.9, 126.8, 123.4, 121.1, 50.6, 21.4; HRMS
(ESI+) m/z calculated for C24H19ClNO2S [M+H]+ 420.0825,
found 420.0823.
1H NMR (CDCl3, 600 MHz) δH 7.98 (s, 1H), 7.41 (d, J=
7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H),
7.02-6.99 (m, 2H), 6.88 (s, 1H), 6.73 (d, J=8.4 Hz, 2H), 7.68
(d, J=7.8 Hz, 2H), 5.21 (d, J=15.2 Hz, 1 Hz), 4.37 (d,J=
16.2 Hz, 1H), 4.09 (s, 3H), 4.00 (s, 3H), 2.19 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δC 150.9, 147.5, 142.3, 139.7, 133.8, 133.7,
133.5, 131.4, 130.8, 128.3, 127.2, 127.1, 126.8, 126.6, 125.3,
120.9, 119.0, 110.9, 106.1, 103.7, 56.1, 55.8, 52.1, 21.3; HRMS
(ESI+) m/z calculated for C26H25N2O4S [M+H]+ 461.1535,
found 461.1550.
12-Tosyl-12,13-dihydro-[1,3]dioxolo[4’,5’:4,5]ben-zo[1,2-c]
phenanthridine (4’d): Pale yellow solid (36.1 mg, 42% yield),
°
mp 74–78 C, Rf = 0.55 (20% ethyl acetate in petroleum ether,
v/v); H NMR (CDCl3, 600 MHz) δH 8.05 (s, 1H), 7.66 (d, J=
1
General procedure of synthesis of 5-tosyl-
5,6-dihydrobenzo[c]phenanthridine
8.4 Hz, 1H), 7.46 (d, J=8.4 Hz,1H), 7.15 (d, J=7.8 Hz, 1H),
7.11-7.10 (m, 3H), 7.05-7.03 (m, 1H), 6.81(d, J=7.8 Hz, 2H),
6.66 (d, J=7.8 Hz, 2H), 6.09 (d, J=8.4 Hz, 2H), 5.27 (d, J=
16.8 Hz, 1H), 4.50 (d, J=16.2 Hz, 1H), 2.17 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δC 148.4, 142.8, 133.4, 132.2, 131.9, 131.7,
131.4, 128.9, 128.2, 128.0, 127.6, 127.57, 127.4, 127.37, 126.1,
122.9, 119.9, 103.5, 103.3, 101.4, 51.2, 21.3; HRMS (ESI+)
m/z calculated for C25H20NO4S [M+H]+ 430.1113, found
430.1125.
A mixture of Pd(OAc)2bpy (3.8 mg, 0.01 mmol, 5 mol%), and
D-CSA (69.6 mg, 0.3 mmol, 1.5 equiv.) in dry THF (1 mL) was
°
stirred at 60 C under argon atmosphere. Then the starting
material 10’ (0.2 mmol) dissolved in dry THF (1 mL) was added
to the reaction mixture at the same temperature and the whole
mixture was allowed to stir at reflux temperature for few hours
until the completion of the reaction (TLC). Thereafter the
reaction mixture was neutralized by adjusting the pH (~7)
through drop wise addition of 20% aqueous sodium bicarbonate
solution and extracted with ethyl acetate (3×20 mL). The
combined organic extracts were washed with saturated brine
(10 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The resulting residue was
purified through silica gel (100-200 mesh) column chromatog-
raphy using eluent 10–40% ethyl acetate-petroleum ether (v/v)
to afford desired product 4’.
2-Fluoro-5-tosyl-5,6-dihydrobenzo[c]phenanthri- dine (4’e):
Yellow solid (54.0 mg, 67% yield), mp 140–142 C, Rf = 0.37
(5% ethyl acetate in petroleum ether, v/v); H NMR (CDCl3,
°
1
600 MHz) δH 8.75–8.73 (m, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.66
(d, J=8.4 Hz, 1H), 7.45 (dd, J=9.0, 2.4 Hz, 1H), 7.42–7.38
(m, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.16-7.07 (m, 3H), 6.81 (d,
J=8.4 Hz, 2H), 6.67 (d, J=7.8 Hz, 2H), 5.30 (d, J=16.8 Hz,
1H), 4.55 (d, J=16.2 Hz, 1H), 2.18 (s, 3H);13C NMR (CDCl3,
100 MHz) δC 161.4 (d, J=247 Hz), 143.1, 134.9 (d, J=10 Hz),
133.5, 132.7 (d, J=2 Hz), 131.9, 131.7, 129.9, 129.8, 128.6 (d,
J=2 Hz), 128.5 (d, J=2 Hz), 128.3, 128.1, 127.7 (d, J=5 Hz),
127.60?, 127.57, 126.3, 123.1, 122.7, 116.8 (d, J=25 Hz),
110.5 (d, J=21 Hz), 51.1, 21.4; HRMS (ESI+) m/z calculated
for C24H18FNNaO2S [M+Na]+ 426.0940, found 426.0942.
5-Tosyl-5,6-dihydrobenzo[c]phenanthridine (4’a): Yellow solid
°
(60.1 mg, 78% yield), mp 154–156 C, Rf = 0.44 (5% ethyl
acetate in petroleum ether, v/v); 1H NMR (CDCl3, 400 MHz) δH
8.72 (d, J=8.4 Hz, 1H), 7.85-7.82 (m, 2H), 7.64-7.60 (m, 2H),
7.55-7.51 (m, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.14-7.04 (m, 3H),
6.80 (d, J=8.0 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 5.29 (d, J=
16.4 Hz, 1H), 4.53 (d, J=16.4 Hz, 1H), 2.16 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δC 142.9, 133.9, 133.7, 132.5, 132.2, 132.0,
131.5, 129.3, 128.6, 128.2, 127.9, 127.6, 127.5, 127.4, 126.9,
126.8, 126.5, 126.2, 123.2, 121.4, 51.2, 21.4; HRMS (ESI+)
m/z calculated for C24H20NO2S [M+H]+ 386.1215, found
386.1201.
9-Bromo-5-tosyl-5,6-dihydrobenzo[c]phenanthri- dine (4’f):
Yellow solid (51.9 mg, 56% yield), mp 140–142 C, Rf =0.41
(5% ethyl acetate in petroleum ether, v/v); H NMR (CDCl3,
°
1
300 MHz) δH 8.60 (d, J=9.0 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H),
7.76 (d, J=8.4 Hz, 1H), 7.71–7.64 (m, 2H), 7.20 (d, J=7.5 Hz,
1H), 7.16–7.06 (m, 3H), 6.80 (d, J=8.4 Hz, 2H), 6.66 (d, J=
8.1 Hz, 2H), 5.30 (d, J=16.8 Hz, 1H), 4.54 (d, J=16.8 Hz,
1H), 2.17 (s, 3H); 13C NMR (CDCl3, 150 MHz) δC 143.0, 134.9,
133.3, 132.6, 132.1, 131.5, 130.0, 129.9, 129.5, 129.4, 128.8,
128.3, 128.2, 127.56, 127.55, 127.5, 126.3, 123.1, 122.6, 121.2,
51.0, 21.3; HRMS (ESI+) m/z calculated for C24H19BrNO2S
[M+H]+ 464.0320, found 464.0236.
Methyl 5-tosyl-5,6-dihydrobenzo[c]phenanthridine-8-carboxy-
’
°
late(4b): Brown solid (47.8 mg, 54% yield), mp 106–108 C, Rf
1
= 0.22 (5% ethyl acetate in petroleum ether, v/v); H NMR
(CDCl3, 600 MHz) δH 8.74 (d, J=9.0 Hz, 1H), 7.90-7.86 (m,
2H), 7.77–7.75 (m, 2H), 7.68–7.65 (m, 2H), 7.60–7.58 (m, 1H),
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Synthesis of Benzo[c]phenanthridine 19
Formal Synthesis of Arnottin I
To a solution of compound 4’ (0.13 mmol,1 equiv.)in dry
DMSO (3 mL)was added finely ground KOH pellets (36.4 mg,
0.65 mmol, 5 equiv.) and the reaction was allowed to stir at
room temperature for 1–2 h. After completion of the reaction
(TLC), the reaction mixture was diluted with water (8 mL) and
extracted with ethyl acetate (3×15 mL). The combined organic
layers were dried over anhydrous sodium sulphate, filtered and
concentrated under reduced pressure. The resulting crude
product was purified by silica gel (100–200 mesh) column
chromatography with 4–5%ethyl acetate-pet ether (v/v) as
eluent to afford the pure products 19 in 51–79% yield.
To a well stirred solution of PdCl2(CH3CN)2 (22.0 mg,
0.085 mmol, 0.05 equiv.) in dry acetonitrile (3 mL) were added
PPh3 (89.1 mg, 0.34 mmol, 0.2 equiv.) and Cs2CO3 (422 mg,
1.3 mmol, 4.5 equiv.) successively. After stirring the reaction
mixture at room temperature for 5 min, (6-iodo-2,3-dimethox-
yphenyl)methanol 20[30] (500 mg, 1.70 mmol, 1 equiv.) was
added and the reaction was stirred at room temperature for
20 min. Next, 5-ethynyl-6-(2-methoxyvinyl)-benzo[d][1,3]diox-
ole 21[14b] (377.7 mg, 1.87 mmol, 1.1 equiv.) was added and
°
stirring at 80 C was continued for another 6 hours until the
completion of the reaction (TLC). The reaction mixture was
quenched with water (5 mL) and extracted with ethyl acetate
(3×10 mL). The combined organic extracts were washed with
saturated brine (10 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The resulting crude
was purified by silica-gel column chromatography (100-
200 mesh)eluting with 35% petroleum ether-ethyl acetate (v/v)
to produce the desired coupling product 22 in 68% yield.
Benzo[c]phenanthridine (19a): White solid (15.2 mg, 51%
°
yield), mp 99–101 C, Rf =0.40 (5% ethyl acetate in petroleum
ether, v/v); H NMR (CDCl3, 600 MHz) δH 9.51 (s, 1H), 9.42
1
(d, J=8.4 Hz, 1H), 8.72 (d, J=8.4 Hz, 1H), 8.59 (d, J=
8.4 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H),
8.01 (d, J=7.8 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.80–7.75 (m,
2H), 7.71 (t, J=7.5 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δC
152.1, 141.5, 133.3, 132.9, 132.1, 130.9, 128.8, 127.9, 127.7,
127.4, 127.2, 127.1, 126.9, 124.7, 122.3, 121.1, 119.9; HRMS
(ESI+) m/z calculated for C17H12N [M+H]+ 230.0970, found
230.0969.
(2,3-Dimethoxy-6-((6-(2-methoxyvinyl)benzo [d][1,3]dioxol-5-
yl)ethynyl)phenyl)methanol (22) (an inseparable mixture of E/Z
isomers in the ratio 6:4): Brown gum (47.8 mg, 68% yield);
1
Rf =0.22 (50% ethyl acetate in petroleum ether, v/v); H NMR
(CDCl3, 400 MHz) δH 7.62 (s), 7.26 (s), 7.24 (m), 7.00 (d, J=
12.8 Hz), 6.90–6.89 (m), 6.84–6.80 (m), 6.28 (d, J=13.0 Hz),
6.17 (d, J=6.8 Hz), 5.93–5.92 (m), 5.78 (d, J=7.2 Hz), 4.92–
4.90 (m), 3.88-3.87 (m), 3.76 (s), 3.71 (s); 13C NMR (CDCl3,
100 MHz) δC 153.1, 149.5, 148.5, 148.1, 147.9, 147.6, 145.6,
145.2, 135.9, 135.8, 133.5, 132.7, 128.6, 115.9, 114.2, 113.6,
112.1, 111.5, 111.2, 108.8, 103.8, 103.5, 103.2, 101.4, 91.3,
91.1, 90.0, 89.8, 61.5, 60.8, 59.3, 56.6, 55.9; HRMS (ESI+)
m/z calculated for C21H21O6 [M+H]+ 369.1338 found
369.1340.
9-Chlorobenzo[c]phenanthridine (19b): White solid (21.5 mg,
°
63% yield), mp 102–104 C,Rf = 0.76 (5% ethyl acetate in
petroleum ether, v/v); H NMR (CDCl3, 600 MHz) δH 9.44 (s,
1
1H), 9.38 (d, J=8.4 Hz, 1H), 8.64 (s, 1H), 8.44 (d, J=8.4 Hz,
1H), 8.08 (d, J= 8.4 Hz, 1H), 8.05 (d, J=9 Hz, 1H), 7.99 (d,
J=7.8 Hz, 1H), 7.80–7.77 (m, 1H), 7.74–7.71 (m, 1H), 7.67
(dd, J=1.8, 9 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δC 151.3,
141.9, 137.3, 133.9, 133.5, 131.9, 130.2, 128.3, 128.0, 127.8,
127.7, 127.2, 125.1, 124.8, 121.9, 120.0, 119.6; HRMS (ESI+)
m/z calculated for C17H10ClNNa [M+Na]+ 286.0399, found
286.0402.
A mixture of Pd(OAc)2bpy (3.8 mg, 0.01 mmol, 5 mol%), and
D-CSA (125.3 mg, 0.54 mmol, 2 equiv.) in dry NMA (3 mL)
[1,3]Dioxolo[4’,5’:4,5]benzo[1,2-c]phenanthridine
(19c):
°
was stirred at 90 C for 5 min under argon atmosphere. There-
°
White solid (20.6 mg, 58% yield), mp 176–178 C, Rf =0.41
(5% ethyl acetate in petroleum ether, v/v); H NMR (CDCl3,
after compound 22 (100 mg, 0.27 mmol, 1 equiv.) dissolved in
NMA (1.5 mL) was added drop wise to the reaction mixture at
the same temperature and the whole mixture was allowed to stir
1
600 MHz) δH 9.42 (s, 1H), 8.75 (s, 1H), 8.67 (d, J=8.4 Hz,
1H), 8.45 (d, J=9.0 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.91–
7.88 (m, 2H), 7.72 (t, J=7.5 Hz, 1H), 7.30 (s, 1H), 6.15 (s,
2H); 13C NMR (CDCl3, 150 MHz) δC 151.7, 148.54, 148.52,
141.1, 132.9, 130.8, 130.2, 129.1, 128.7, 127.1, 126.9, 126.6,
122.1, 120.3, 118.4, 104.4, 102.3, 101.4; HRMS (ESI+) m/z
calculated for C18H12NO2 [M+H]+ 274.0868, found 274.0857.
°
at 100 C for few hours until the completion of the reaction
(TLC). Next, the reaction mixture was neutralized by adjusting
the pH (~7) through drop wise addition of 20% aqueous sodium
bicarbonate solution and extracted with ethyl acetate (3×
20 mL). The combined organic extracts were washed with
saturated brine (10 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The resulting residue
was purified through silica gel (100-200 mesh) column chroma-
tography using 10–40% ethyl acetate-petroleum ether (v/v) as
eluent to afford the desired product 23.
2-Fluorobenzo[c]phenanthridine (19d): White solid (25.4 mg,
°
79% yield), mp 142–143 C, Rf =0.55 (5% ethyl acetate in
petroleum ether, v/v); H NMR (CDCl3, 600 MHz) δH 9.45 (s,
1
1H), 9.41–9.38 (m, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.55 (d, J=
9.0 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.94 (d, J=9.0 Hz, 1H),
7.89 (td, J=1.2, 7.5 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.59 (dd,
J=2.4, 9.6 Hz, 1H), 7.50 (td, J=2.4, 8.7 Hz, 1H); 13C NMR
(CDCl3, 150 MHz) δC 161.9 (d, J=246 Hz), 152.4, 141.4,
134.4 (d, J=10.5 Hz), 132.8, 131.0, 128.82, 128.78, 127.6 (d,
J=9 Hz), 127.2, 127.0 (d, J=4.5 Hz), 126.7, 122.1, 121.3,
120.5, 116.4 (d, J=24 Hz), 111.3 (d, J=21 Hz); HRMS (ESI
+) m/z calculated for C17H11FN [M+H]+ 248.0876, found
263.0879.
1,2-Dimethoxy-13H-[1,3]dioxolo[4’,5’:4,5]benzo [1,2-h]benzo
[c]chromene (23): Yellow solid (50.2 mg, 55% yield), mp 284–
1
°
286 C, Rf =0.43 (10% ethyl acetate in petroleum ether, v/v); H
NMR (CDCl3, 600 MHz) δH 7.61 (d, J=8.4 Hz, 1H), 7.54 (s,
1H), 7.41 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.07 (s,
1H), 6.94 (d, J=8.7 Hz, 1H), 6.04 (s, 2H), 6.36 (s, 2H), 3.91 (s,
3H), 3.90 (s, 3H); 13C NMR (CDCl3, 150 MHz) δC 151.9, 148.8,
147.9, 147.5, 144.2, 131.1, 124.8, 124.3, 121.6, 120.5, 119.2,
117.6, 116.1, 111.7, 103.9, 101.2, 98.8, 63.6, 60.9, 55.8; HRMS
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(ESI+) m/z calculated for C20H17O5 [M+H]+ 337.1076, found
337.1074.
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[22] In H NMR, all products 2 display a singlet between
5.06-5.99 ppm for benzylic protons except compound 2f
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Palladium-Catalyzed Synthesis of 6H-Dibenzo[c,h]
chromenes and 5,6-Dihydrobenzo[c]phenanthridines: Appli-
cation to the Synthesis of Dibenzo[c,h]chromene-6-ones,
Benzo[c]phenanthridines, and Arnottin I
Adv. Synth. Catal. 2019, 361, 1–17
S. Pramanik, M. Jash, D. Mondal, C. Chowdhury*