Curtius-like Rearrangement of an Iron-Nitrenoid Complex and Application in Biomimetic Synthesis of Bisindolylmethanes

Article abstract of DOI:10.1021/acs.orglett.6b00864

A Curtius-like rearrangement of hydroxamates to isocyanates was discovered. This reaction was initiated from an iron(II)-nitrenoid complex, which was generated by the iron(II)-catalyzed cleavage of N-O bonds of functionalized hydroxamates. To demonstrate the efficiency of this new Curtius-like rearrangement in synthetic chemistry, a biomimetic strategy for the one-pot preparation of bisindolylmethanes was developed.

Full text of DOI:10.1021/acs.orglett.6b00864

Letter
pubs.acs.org/OrgLett
Curtius-like Rearrangement of an Iron−Nitrenoid Complex and
Application in Biomimetic Synthesis of Bisindolylmethanes
Dashan Li,†,§ Ting Wu,†,§ Kangjiang Liang,†,§ and Chengfeng Xia*,†,‡
†State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of
Sciences, Kunming 650201, China
‡Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education, Yunnan University, Kunming 650091, China
§University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A Curtius-like rearrangement of hydroxamates to isocyanates
was discovered. This reaction was initiated from an iron(II)−nitrenoid
complex, which was generated by the iron(II)-catalyzed cleavage of N−O
bonds of functionalized hydroxamates. To demonstrate the efficiency of this
new Curtius-like rearrangement in synthetic chemistry, a biomimetic
strategy for the one-pot preparation of bisindolylmethanes was developed.
signal transducer and activator of transcription 37 and induces
hermal or photochemical decomposition of acyl azides to
apoptosis in prostate cancer.8 Arundine 1 was also found to
Tcorresponding isocyanates is known as the Curtius
promote plant growth.9 Synthetic BIM analogues, such as
bis(5-methylindol-3-yl)methane (3), bis(5-bromoindol-3-yl)
methane (4), and bis(6-chloroindol-3-yl) methane (5), have
been shown to be inhibitors of the estrogen-induced growth
of mammary tumors.10
rearrangement.1 Although nitrene intermediates are formed in
the pyrolysis of most azido compounds, the mechanism of the
Curtius rearrangement under thermal conditions most likely
occurs via a concerted process.2 In contrast, the photo-
chemical Curtius rearrangement proceeds through the
formation of nitrenes because the N−N2 bond is easily
broken by an energetic photon without alkyl or aryl
participation.3
BIMs are biosynthesized from glucobrassicin 6, which has
side chains derived from tryptophan and is among the most
widely distributed glucosinolates in nature. After being
hydrolyzed by myrosinase, 6 is converted to thiohydroximate
7 (Figure 1).11 With some specific proteins (e.g., the
epithiospecifier protein), the thiohydroxamate intermediate 7
is further converted to isothiocyanate 8 as the major
product.12 Isothiocyanate 8 is volatile and decomposes to
the indolyl-3-methylene carbocation by losing one SCN.13 In
plants, the carbocation reacts with various nucleophiles, such
as indoles, to yield BIMs. The activated acyl hydroxamates are
known to undergo Lossen rearrangement under basic
conditions to generate isocyanates.14 A Lossen-like rearrange-
ment was proposed to occur during the conversion of
thiohydroximate to isothiocyanate in the presence of
enzymes.12 Herein, we report the Curtius-like rearrangement
of iron−nitrenoid complexes via iron-catalyzed cleavage of the
N−O bonds of functionalized heteroauxin hydroxamates and
the biomimetic synthesis of BIMs.
Bisindolylmethanes (BIMs), which have a basic skeleton
consisting of two indole groups bridged by a single carbon at
the 3 and 3′ positions, have been isolated from marine and
terrestrial natural sources.4 BIMs and their analogues exhibit a
broad range of distinct biological activities.5 Arundine 1,
which was isolated from the roots of Arundo donax,4c has
been widely studied in cancer chemotherapy (Figure 1).6
Arundine 1 suppresses ovarian cancer growth and potentiates
the effect of cisplatin in tumor mouse models by targeting the
Iron(II) was reported to be involved in the conversion of
thiohydroximate to isothiocyanate with the epithiospecifier
protein.15 Iron(II) was also reported to cleave the N−O bond
Received: March 24, 2016
Figure 1. Examples of BIMs and biogenous intermediates.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00864
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of functionalized hydroxamates or the N−N bond of acyl
azides and generate an iron−nitrenoid complex for the
aminohydroxylation or aminohalolation of olefins.16 We
proposed that the iron−nitrenoid complex could also undergo
a Curtius-like rearrangement to generate the isocyanate.
To verify this hypothesis, the functionalized heteroauxin
hydroxamates 9 were subjected to the proposed rearrange-
ment with Fe(OTf)2 as the catalyst. Aniline was added as a
nucleophile to capture the unstable isocyanate intermediate
and give the corresponding urea. In the presence of 1,10-
phenanthroline (L1) as the ligand, we observed that substrate
9a was consumed and that the urea 10 was generated in
moderate yield (Table 1, entry 1, and Table S1 in the
optimized conditions and gave the corresponding ureas in
good yields (entries 8−15). In contrast, alkylamines removed
the functionalized Bz groups by aminolysis and resulted in no
reaction.
To investigate if other acyl hydroxamates can also undergo
the Curtius-like rearrangement, phenylacetyl hydroxamate 18
was subjected to the optimized reaction conditions with
Fe(OTf)2 as catalyst and L1 as ligand. As shown in Scheme 1,
urea 20 was isolated in 51% yield. Urea 20 was apparently
generated from the isocyanate intermediate 19, which was also
formed by a Curtius-like rearrangement.
Scheme 1. Curtius-like Rearrangement of Phenylacetyl
Hydroxamate by an Iron(II) Catalyst
Table 1. Optimization of the Reaction Conditions
a
b
entry substrate
ArNH2
ligand product yield (%)
1
2
9a
9b
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
aniline
aniline
aniline
aniline
aniline
aniline
aniline
L1
L1
L1
L1
10
10
10
10
10
10
10
11
12
13
14
15
16
17
63
72
85
0
Using the established iron(II)-catalyzed Curtius-like rear-
rangement, we attempted the biomimetic synthesis of BIMs.
First, we demonstrated the method for the one-pot
preparation of symmetric BIMs. A series of differently
substituted heteroauxin hydroxamates with 3,5-(CF3)2-Bz as
the functional group were used as substrates. The
correspondingly substituted indoles were used as nucleophiles.
As shown in Scheme 2, when unsubstituted heteroauxin
hydroxamate and indole were subjected to the reaction,
natural arundine 1 was obtained in 72% yield. For the
synthesis of BIMs 3, 4, and 5, which inhibit the estrogen-
induced growth of mammary tumors, the methyl-, bromo-, or
chloro-substituted substrates were used in the reactions, and
the BIMs were obtained in 71, 73, and 75% yields,
respectively. Since the heteroauxin also serves as a competitive
nucleophile during the reaction, 2 equiv of indole was added
to depress the side reaction.
3
c
4
5
6
5
L2
L3
L1
L1
L1
L1
L1
L1
L1
50
0
7
8
p-toluidine
84
78
87
81
80
77
79
9
mesitylamine
10
11
12
13
14
p-anisidine
p-chloroaniline
o-bromoaniline
o-iodoaniline
p-carbomethoxy aniline
a
The reaction was conducted with 15 mol % of iron(II) as a catalyst at
room temperature. Isolated yield. No iron(II) catalyst was added.
b
c
Supporting Information). Changing the functionalized group
by incorporating electron-withdrawing substituents, such as
2,4-Cl2 (9b) or 3,5-(CF3)2 (9c), distinctly improved the yield
to 85% (entries 2 and 3). However, no reaction occurred in
the absence of the catalyst Fe(OTf)2 (entry 4). To verify
whether the reaction proceeded through a Lewis acid
promoted Lossen process,17 both of the non-redox-active
controls (Zn(OTf)2 and Sc(OTf)3) were performed and no
rearrangements were observed (Table S2). These experimen-
tal results suggested that the formation of the iron−nitrenoid
complex was necessary for the rearrangement. Therefore, this
rearrangement proceeds as a Curtius-like rearrangement rather
than a Lossen rearrangement. Other iron(II) catalysts, such as
FeCl2, FeBr2, Fe(OAc)2, and FeSO4, also catalyzed the
rearrangement, albeit in lower yields. However, trace amount
of products were detected when Fe(NTf2)2 or K4Fe(CN)6
was used as the catalyst (Table S2). The ligand played an
important role in the reaction. When no ligand was added,
only a trace amount of urea was isolated. Changing the ligand
to 2,2′-bipyridine (L2) resulted in a lower yield, whereas the
reaction failed to proceed with 2,2′:6′,2″-terpyridine (L3)
(entries 5−7). A variety of arylamines were evaluated under
This method also provides an efficient strategy for the
preparation of unsymmetrical BIMs, which are reported less
frequently than the symmetric BIMs.18 After the N−O bond
of the 3,5-(CF3)2-Bz-functionalized heteroauxin hydroxamate
was cleaved by Fe(OTf)2 and the indolyl iminium was
formed, different indole derivatives coupled with the iminium
to give BIMs. In addition to the electron-donating indole
nucleophiles (23 and 24), the various halo-substituted indole
nucleophiles also afforded good yields of compounds 25−29.
It should be noted that the electron-deficient indole
derivatives, such as nitro or methyl carbonate, also smoothly
produced the corresponding BIMs with acceptable yields (30
and 31). Moreover, when the N-methyl or N-benzyl indoles
were subjected to this synthesis strategy, mono-N-substituted
arundines 35 and 36 were obtained in good yield (75 and
73%).
The proposed iron(II)-catalyzed Curtius-like rearrangement
mechanism is outlined in Scheme 3. The heteroauxin
hydroxamate reacted with the iron(II) catalyst to give the
iron−nitrenoid complex through cleavage of the N−O bond.
Then, a Curtius-like rearrangement was triggered to afford the
isocyanate intermediate. When there was an electron-with-
B
DOI: 10.1021/acs.orglett.6b00864
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Biomimetic One-Pot Synthesis of BIMs via Curtius-like Rearrangement
the corresponding indolyl iminium reacted with indoles to
afford BIMs in a one-pot manner.
Scheme 3. Proposed Mechanism of Biomimetic Synthesis
of BIMs with Iron(II)-Catalyzed Curtius-like
Rearrangement
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00864.
Experimental procedures and compound character-
ization (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xiachengfeng@mail.kib.ac.cn.
Notes
The authors declare no competing financial interest.
drawing group, such as a Boc protecting group, located on the
N1 position, the nitrogen of the indole was electron-deficient
and the isocyanate intermediate was stable enough and was
added by aniline. If the indole was unprotected or protected
with an electron-donating alkyl group, the lone pair electrons
of nitrogen facilitate the quick loss of one OCN anion and
biomimetically generate the indolyl iminium. Finally, an indole
nucleophilic addition of the indolyl iminium affords the
corresponding BIM.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21302193 and 21572236), the
Natural Science Foundation of Yunnan Province (2014FA008
and 2015FB167), the Yunnan High-End Technology Pro-
fessionals Introduction Program (2010CI117), and the
program for changjiang scholars and innovative research
team in university (IRT13095).
In conclusion, an iron(II)-catalyzed Curtius-like rearrange-
ment was discovered. The reaction proceeded via the
decomposition of an iron−nitrenoid complex formed by
cleavage of the N−O bonds of functionalized heteroauxin
hydroxamates. The generated isocyanates were verified
through capture by arylamines. This rearrangement reaction
was successfully employed to biomimetically synthesize BIMs.
The synthetic strategy featured an iron(II)-catalyzed cleavage
of the N−O bonds of functionalized hydroxamates to form an
iron−nitrenoid complex and the subsequent generation of
indolyl isocyanate through Curtius-like rearrangement. After
the spontaneously biomimetic loss of the isocyanate anion,
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