Metal-free tandem carbene N-H insertions and C-C bond cleavages

Article abstract of DOI:10.1039/d0sc05763k

A metal-free C-H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C-C cleavage. Compared to the simple N-H insertion manipulation of diazo, this method elegantly accomplishes a tandem N-H insertion/SEAr/C-C cleavage/aromatization reaction, and the synthetic utility of this new transformation is exemplified by the succinct syntheses of trisphaeridine and bicolorine alkaloids. This journal is

Full text of DOI:10.1039/d0sc05763k

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ARTICLE
Metal-free tandem carbene NH insertions and CC bond
cleavages†
Pu Chen,a Jiang Nan,*a Yan Hu,a Yifan Kang,a Bo Wang,a Yangmin Ma,*a Michal Szostak*ab
Received 00th January 20xx,
Accepted 00th January 20xx
A metal-free CH [5+1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two
types of prevalent phenanthridings via highly selective CC cleavage. Compared to the simple NH insertion manipulation
of diazo, this method elegantly accomplishes a tandem NH insertion/ SEAr/ CC cleavage/ aromatization reaction, and the
synthetic ultility of this new transformation is exeamplied by the succinct syntheses of trisphaeridine and bicolorine alkaloids.
DOI: 10.1039/x0xx00000x
cleavage/ oxidative aromatization four-fold domino reaction in
a single chemical operation.
Introduction
(a) Chemical transformation of diazo compounds
Carbene conversion represents one of the most fundamental
and synthetically useful reactions in modern organic syntheses.1
Of particular interest are diazo compounds, a class of “smart”
carbene precursors that are being extensively utilized as
versatile synthetic feedstock in chemical as well as biological
arena.2 A myriad of synthetically significant applications of diazo
compounds have been realized in Wolff rearrangements,3
cyclopropanations,4 ylide formations,5 XH insertions,6 CH
functionalizations7 and so forth (Scheme 1a). Regarding these
examples, it is well known that metal-carbenes play a pivotal
role; namely, diazo chemistry mainly relies on metal catalysts
(e.g. Rh, Ru, Pd, Ir, Ag, Cu and Co) for arriving at the carbenoid
reactivity. On the account of strict constraints imposed by trace
levels of metals in pharmaceuticals and also reaction economy,8
however, this “metal-engaged” mode of reactivity dramatically
overshadows the prospective applications of diazo chemistry. In
striking contrast, the evolvement of metal-free technologies
heavily lags behind, albeit several elegant yet sporadic reactions
have emerged in recent years.9 Moreover, these studies
commonly refer to a “one-fold” operation forming only a single
chemical bond within the entire process.10 Against this
background, the exploration of more synthetically innovative
streamlined approaches and strategies through multiple bond
breaking/forming events in the absence of transition-metals,
such as domino and cascade reactions of diazo compounds
would be a desirable goal. In this paper, we report a new
platform for upgrading a transform of model diazo compounds
through Brønsted acid-promoted NH insertion/ SEAr/ CC
underdeveloped
Wolff rearrangement
cyclopropanation
well-developed
Wolff rearrangement;
cyclopropanation;
or
or
[M]
R1
no [M]
R
C-H functionalization
ylide formation;
X-H insertion;
N2
N-H insertion
SEAr
C-C cleavage
oxidative aromatization
cascade transformation
&
&
&
no [M]
C-H functionalization;
this work
(b) Metal-free-catalyzed N-H insertion of diazo compounds
CO2R3
CO2R3
Ar
R1
Ar
CO2R3
metal
NH2
Ar
NH
R1
H insersion and no further transformation
limited to donor/acceptor diazo compounds;
N2
heat or blue LEDs
tuneless
very few examples;
N
(c) Metal-free-catalyzed divergent C-H [5+1] annulation (this work)
Ar/Het
Ar/Het
Ar/Het
R4
H
O
H
metal
R4
+
+
NH2
N
N
R3
H+
N2
acceptor/acceptor diazo compounds
C(O)
C
C
R4, C(O)
C
N
H insersion/
SEAr/
C
C cleavage/ aromatization relay reaction
cleavage forging structurely diverse phenanthridine
C
highly controllable
C
(d) Metal-catalyzed C-H functionlization of 2-arylanilines with diazo compounds (previous work)
CO2R3
Ar/Het
CO2R3
CO2R3
Ar/Het
Het
CO2R3
R3O2C
O
H
Rh
Ru
+
NH2
NH
NH
N2
acceptor/acceptor diazo
Scheme 1 Chemical reactivity of diazo and this work.
It is worthwhile to note that NH insertion/conversion is
among the most promising platforms for constructing the
ubiquitous CN bonds widely encountered in an enormous
number of bioactive molecules and countless top-selling
marketed drugs, and this mode of reactivity has attracted
significant endeavors in recent years and has been used to build
numerous natural products.11 To date, while impressive
progress has been garnered in the systems capitalizing on metal
catalysts,12 there is only a handful of metal-free transformations
between amines and diazo compounds13 (Scheme 1b).
Pertinent work was described by Davies14 in 2012, wherein
thermolysis strategy enabled donor/acceptor carbenes to
a. Shaanxi Key Laboratory of Chemical Additives for Industry, College of Chemistry
and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an
710021, China.
b. Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New
Jersey 07102, United States
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/x0xx00000x
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couple with amines. More recently, the groups of Davies15 and
Jurberg16 demonstrated the blue LED-triggered NH insertion
reaction with amines and carbazoles, respectively.
Notwithstanding the fundamental challenges in metal-free
carbene insertions, these cases simply operated by NH
insertion and no further derivatization took place, which sharply
hampered the formation of highly functionalized, structurally
complex nitrogen-containing molecules, such as N-
heterocycles. Indeed, these examples could be merely applied
to more active, more nucleophilic, donor/acceptor carbenes.
Within our recent strong interest in aniline chemistry,17 herein,
we report an unprecedented Brønsted acid-promoted
divergent [5+1] annulation between 2-arylanilines and
acceptor/acceptor diazo carbenes in the absence of transition-
metal catalysts (Scheme 1c), which fully differs from the
precedent reaction versions between 2-arylanilines and diazo
compounds mediated by metal-catalysts (Scheme 1d). This
newly established methodology performs a highly selective CC
bond cleavage with diazo compounds in a divergent, substrate-
controlled mode, thus rapidly building two types of prevalent
phenanthridine cores that are persistent in natural products
and functional materials,18 but their de novo synthesis often
requires intricate metal-catalyzed or light-promoted systems 19
(Scheme 2).
phenyl-substituted substrate 2b, gratifyingly, the efficacy of the
title transformation improved and yielded the target 3a in 65%
View Article Online
DOI: 10.1039/D0SC05763K
yield (entry 12). Motivated by the above structure-activity
relationship, we investigated the ester-modified diazo
compound 2c in an attempt to further the optimization;
unexpectedly, this procedure delivered exclusively another type
of phenanthridine 4a in 37% yield (entry 13). In this method,
phenyl-ester diazo compound 2d also behaved more efficiently
and led to 76% yield (entry 14). Interestingly, persistency with
diketo-derived diazo compound 2e failed to generate the
corresponding 3a and 4aII; however, the third chemoselective
product 5 was furnished in 18% yield (entry 15). Apparently, this
divergent outcome hinges upon the exact structure of the diazo
precursor to construct structurally distinct phenanthridines.
Table 1 Optimization of reaction conditions.
O
R4
H
TFA
+
3a
4aI / 4a / 4aII
5
6
+
+
+
R
NH2
100 C, O2, 15 h
N2
1a
2a-e
O
R4
R
H
R
N
4aI
R4 = SO2Ph
R4 = CO2Et
R4 = COMe
H
R4
Ph
N
6
N
N
4a
4aII
R1
OMe
RO
MeO
R2
H
H
3a
5
Wolff rearrangement product
O
O
H
H
Me
N
N
O
O
Variation from the
assigned conditions
Yieldb (%)
Me
N
N
Entry
3a
50
n.d
n.d
5
4
5
6
O
O
1a
2
None
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4aI/n.d
4a /37
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
18
n.d
14
O
NK109
O
R1 = OH, R2 = H,
Bicolorin
Trisphaeridine
e
DMF+ TFA(10.0 equiv)
THF+ TFA(10.0 equiv)
HFIP+ TFA(10.0 equiv)
toluene+ TFA(10.0 equiv)
dioxane+ TFA(10.0 equiv)
R = H, Decarine
R = CH3, Norchelerythrine
R1 = H, R2 = OCH3, Nitidine
3
33
6
Prepare phenanthridine from 2-arylaniline via C-C cleavage
4
5
5
35
CO2nBu
Pd + Cu
CN
H
H
H
6
n.d
n.d
46
Ru + Ag +Cu
NH2
N
NHTs
7
AcOH+ TFA(10.0 equiv)
Air instead of O2
20
reported method 2
relying on metal system
reported method 1
8
43
13
33
26
65
n.d
4
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
X
9
N2 instead of O2
Scheme 2 Biologically active phenanthridine derivatives and
existing synthetic methods.
10
11
12
13
14
15
80 °C instead of 100 °C
120 °C instead of 100 °C
2b instead of 2a
Results and discussion
2c instead of 2a
4a /76
4all/n.d
2d instead of 2a
At the outset, we executed this study by reacting 2-
phenylaniline 1a with diazo compound 2a (Table 1). After
investigating several reaction parameters, the desired
phenanthridine 3a was obtained in 50% isolated yield in
trifluoroacetic acid (TFA) at 100 °C under O2 for 15 h (entry 1).
Experimental results showed that employing TFA as the
reaction solvent was vital, and other common solvents such as
DMF, THF, HFIP, toluene, dioxane, and acetic acid were all
absolutely futile, wherein only a certain amount of Wolff
rearrangement product 6 was formed (entries 27). A
decreased yield occurred when the reaction proceeded under
air atmosphere; especially nonaerobic system just resulted in
13% yield of 3a (entries 89), which undoubtedly clarified the
significance of aerobic environment. Changing the reaction
temperature to either lower or higher levels diminished the
efficiency (entries 1011). When we turned our attention to
2e instead of 2a
n.d
O
O
S
O
O
O
C
O
C
O
O
O
C
O
Ph
Ph
S
Me
Ph
Me
Me
Me
Ph
OEt
OEt
O
O
N2
2a
N2
N2
N2
2c
N2
2d
2b
2e
aAssigned conditions: 1a (0.20 mmol), 2a (0.30 mmol), TFA (1.6 mL), 100
°C, 15 h, O2 atmosphere. bIsolated yields (n.d: not detected).
Having identified the optimal reaction conditions, we firstly
strived to test substrate scope of this acid-induced [5+1]
annulation reaction by choosing benzoyl-phenylsulfonyl diazo
compound 2b as a synthetic partner. Overall, an extensive range
of 2-arylanilines (1a-1q) participated in this predicted
transformation quite well, furnishing the homologous
phenanthridine products 3a-3q in 51-83% yields. With respect to
2 | J. Name., 2012, 00, 1-3
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annulation, this deacylative protocol generally showed slightly
either ortho-arene system or aniline segment, the substituted
functionalities with different electronic bouquet including methyl
(3b, 3k), methoxy (3c, 3e), phenyl (3d), methylenedioxy (3f),
fluoro (3g), bromo (3h), chloro (3l), and trifluoromethyl (3m)
were all compatible to undergo this protocol efficiently. As
expected, the electron-deficient substrates behaved slightly less
expediently. Gratifyingly, heterocyclic substrates such as thienyl
(2i) and furyl (2j) were also efficient in this [5+1] annulation
procedure. Notably, 2-arylanilines 2f-2i, possessing two potential
CH cyclization sites, preferentially operated at the least sterically
congested position with excellent regioselectivity, except for the
less selective performance with substrate 2e. More strikingly, the
very useful π-extended phenanthridines widely found in
functional materials, such as tetracycles (3n, 3p) and pentacycles
(3o, 3q) were also efficiently obtained according to this highly
selective [5+1] annulation in good yields.
inferior results with electron-deficient substrateVsi,ewaAlbrteiclietOintlinies
DOI: 10.1039/D0SC05763K
worth nothing that the appendage of bromo (4f) and ester (4g)
groups could be valuable in downstream chemical
transformations. Heterocyclic substrates 1v and 1i also allowed
to forge the corresponding products with excellent
regioselectivity (>20:1). Meanwhile, the structure of 4m was
unambiguously assigned by x-ray crystallographic analysis. It is
noteworthy that the unprotected indole substrate 1w remained
intact to produce the anticipated phenanthridine 4n in 55%
yield. Further experimental results also showed that
introducing other ester-carrying diazo compounds, such as 2f
was well supported, giving rise to the expected product 4o in
67% yield.
R2
R2
O
CO2R3
H
CO2R3
TFA
N
NH2
+
Ph
100 C, O2, 15 h
R1
R1
N2
2d, f
R2
R2
1
4a-o
SCH3
H
O
H
CH3
OCH3
TFA
SO2Ph
NH2
N
+
Ph
100 C, O2, 15 h
R1
R1
N2
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
1a-q
2b
3a-q
N
N
N
N
N
N
Ph
R
MeO
4a
4b
4c
4d
53%
76%
72%
67%
CO2Et
H
H
H
H
Br
F
N
N
N
N
H3CO
CO2Et
CO2Et
CO2Et
3a
3e
65%
O
3c
3d
51%
72% (2:1 r.r)
S
3b
: R=OMe 66%
: R=Me 71%,
F
N
N
N
O
Br
H
H
H
H
4e
4f
4g
4h
46%
33%
41%
57% (5:1 r.r)
N
O
N
N
N
O
S
CO2Et
CO2Et
N
CO2Et
3g
3h
3i
62% (7:1 r.r)
51% (5:1 r.r)
76% (>20:1 r.r)
3f
83% (>20:1 r.r)
Me
Me
Me
N
N
O
H
H
H
H
4i
4j
4k
4l
50% (10:1 r.r)
73%
66%
42%
N
N
N
N
H
S
N
Cl
F3C
CO2Et
Me
CO2
CO2Et
3j
3k
3l
3m
50%
47%
81%
66%
N
N
N
H
H
H
H
4n
4m
CCDC:1954135
55%
4o
60% (>19:1 r.r)
67%
N
N
N
N
Scheme 4 Substrate scope of deacylative [5+1] annulation.
3n
3o
3p
3q
79%
75%
62%
73%
NH2
O
Trisphaeridine
Scheme 3 Substrate scope of [5+1] annulation.
I
SO2Ph
H
O
O
Ph
B(OH)2
O
O
2b
N2
Considering the distinct chemoselective behaviour with
ester-derived diazo compound 2d (entry 14, Table 1), building
highly functionalized 6-phenanthridines, we attempted to
assess the generality of the deacylative [5+1] annulation
process. Under the identified reaction conditions, reacting diazo
2d or 2f with a series of 2-arylanilines generated 6-carboalkoxy-
phenanthridines (4a-o) in generally good yields. Notably, all the
vacant carbons around the ortho-phenyl ring were applicable to
introduce either electron-donating groups (4b-d, 4h-i),
electron-withdrawing groups (4e-4g), or sterically encumbered
phenanthrene scaffold (4j). The naphthylamine substrate 1n
was amenable to this programed synthesis smoothly as well.
Similar to the preceding desulfonylative/deacylative [5+1]
O
O
Pd(PPh3)4
TFA
N
NH2
gram-scale: 75% yield (2.0 mmol)
1f
H
3f
O
O
O
MeI
AgCl
O
O
O
O
reference
81% yield
N
N
N
N
3f1
Bicolorine Me Cl
3f2
3f
Me
I
O
O
O
KOtBu
NaBH4
78% yield
80% yield
N
3f3
Dihydrobicolorine
Me
3f4
Me
O
N-Methylcrisanidine
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Scheme 5 Synthetic application of established [5+1] annulation. imine intermediate containing electron-deficient both R1 and R2
View Article Online
might enable this [5+1] protocol smoothly.
DOI: 10.1039/D0SC05763K
In consideration of the capacity of this newly established
method to rapidly assemble phenanthridines, we embarked on
According to our mechanistic findings and literature
building trisphaeridine and other value-added derivatives precedents,21 the tentative reaction pathway for assembling
constituting the core components of Amaryllideceae alkaloids.20 the two classes of phenanthridines by divergent [5+1]
Much to our delight, 2-arylaniline 1f, which was derived directly annulation is proposed (Scheme 7). Under acidic conditions, the
from commercially available reagents via Suzuki-coupling, protonation of diazo compound initially takes place to deliver
strongly performed in the scaled-up transformation, yielding species A, followed by N2 extrusion21a-c to produce secondary
trisphaeridine molecule 3f in 75% isolated yield on gram scale. amine B via nucleophilic attack of NH2. This key intermediate as
More importantly, N-methylation of 3f produced verified undergoes oxidation and subsequently performs SEAr
phenanthridine salt 3f1 and the subsequent anion exchange process, which is supported by the superior result of electron-
gave rise to bicolorine 3f2, a natural product which was isolated
from Narcissus bicolor and shows promising anticancer activity.
Additionally, after reduction and carbonyl derivatization, two
other alkaloids, dihydrobicolorine 3f3 and N-methylcrisanidine
3f4 were also prepared in good yields.
rich 2-arylanilines in Schemes 3 and 4, to generate CH
functionalization product D. At this point, when R unit consists
of an ester group, selective C–C bond cleavage occurs via
deacylation of the more electrophilic acyl group21d-e and
concomitant release of benzoic acid that was identified by NMR
spectroscopy, followed by oxidative aromatization21f-g to give
product 4a. Comparatively, adjusting R to the more active
H4/D4
H4/D4
CO2Et
H5
O
D5
O
H
CO2Et
SO2Ph
SO2Ph group prompts
a successive de-sulfonylation/de-
Ph
+
Ph
+
N
NH2
N
1 h
1 h
acylation/oxidative
aromatization
to
finally
furnish
N2
2d
N2
2b
a)
phenanthridine 3a.
d5-1p :1p (1:1)
3a/d4-3a
4aI/d4-4aI
20%, KH/KD = 1.1:1
41%, KH/KD = 1.3:1
Ph
O
H2N
Ph
H
N
H2
O
R
R
H
COPh
N
R
Ph
H+
[O]
H+
O
R
H (D)
H
Ph
N
N
H
D-TFA
D-TFA
SO2Ph
COPh
+
H
N2
Ph
N
1
NH2
N
100 C, 15 h, O2
100 C, 15 h,O2
C
A
B
N2
2b
SEAr
2
b)
D
80%
D
< 1%
1p
3a/D-3a
3a
CO2Et
H
R
CO2Et
[O]
1
2
3
4
N-H insertion
SEAr
R = CO2Et
H2O
COPh
NH
O
H
N
NH
H
H
H
TFA
TFA
4
3
PhCOOH
NMR detected
C-C cleavage
100 C, 15 h, O2
100 C, 15 h, O2
Ph
4a
D
N
E
NH
NH
c)
oxidative aromatization
0% yield
25% yield
3a
8
7
R1 R2
NH
inferior to
R1 and R2 of EWG facilitate
<< R1 = H, R2 = EWG
R1, R2 = H
<<
R = SO2Ph
H
H
3
H
[O]
via
H
COPh
NH
H2O
H2O
N
NH
PhCOOH
G NMR detected
4
H
7
CO2Et
CO2Et
TFA
F
PhSO3H
3a
NH
N
O
100 C, 15 h,
2
d)
Scheme 7 Proposed reaction pathway.
9
23% yield
4a
Scheme 6 Mechanism studies.
Conclusions
To investigate the reaction pathway, a set of preliminary
experiments was conducted. As shown in Scheme 6, the values
(KH/KD = 1.3:1 and 1.1:1) of kinetic isotope effect implied the
SEAr was not involved in rate-determining step during this
divergent [5+1] annulation processes (Scheme 6a). Upon
treatment with deuterated TFA, the experiment outcome
suggested that the hydrogen from TFA participated in the
product formation (Scheme 6b). With respect to the formation
of phenanthridine 3a, the hypothetical electronically-neutral
secondary amine intermediate 7 was synthesized but failed to
execute the envisioned cyclization. On the contrary, the
electron-deficient amine 8 delivered the product 3a, albeit in
lower yield of 25% (Scheme 6c), which revealed that an imine
species might be engaged in the title transform and that the
In conclusion, we have demonstrated a substrate-controlled
selective [5+1] annulation reaction of 2-arylanilines with diazo
compounds by
a tandem NH insertion/ SEAr/ CC
cleavage/aromatization under metal-free conditions. Using
sulfonyl-derived diazo compounds as the coupling partners, the
substituent-free phenanthridines are prepared by a dual
desulfonylation and deacylation process. Alternatively,
introducing ester-derived diazo compounds into the system
divergently leads to the exclusive assembly of C6-carboalkoxy-
substituted phenanthridines. Remarkably, the methodology has
also been applied to a concise assembly of biologically active
trisphaeridine and bicolorine Amaryllidaceae alkaloids as well
more electron-withdrawing substrate nature favors the as their derivatives. This study to the best our knowledge
reaction. Indeed, the prepared secondary ester-carrying amine
9 also led to the construction of phenanthridine 4a in 23% yield
(Scheme 6d). Although our persistent attempts to synthesize
other potential intermediates were frustrated, the above-
outlined set of uniform experimental results indicated that an
represents the first example of Brønsted acid-promoted metal-
free NH insertion/multifold bond reorganization of diazo
compounds. Metal-free domino transformations of diazo
compounds will greatly expand the synthesis of omnipresent
synthetic motifs.
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(a) D. Nair, J. Scarpello, L. White, L. Freista dos Santos, I.
Conflicts of interest
There are no conflicts to declare.
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Vankelecom and A. Livingston, TetraDhOedI:r1o0n.10L3e9tt/D.,02S0C0015,76432K,
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Acknowledgements
This work was financially supported by the NSFC (21801159),
the China Post-doctoral Science Foundation (2018M640944),
the Natural Science Basic Research Plan in Shaanxi Province of
China (2020JQ-705), and the Education Department of Shaanxi
Province (18JK0110).
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