Formal Carbene Insertion into C?O or C?N Bond: An Efficient Strategy for the Synthesis of 2-Substituted 2H-Chromene Derivatives from Chromene Acetals or Hemiaminal Ethers

Article abstract of DOI:10.1002/adsc.201800179

We report the palladium/Br?nsted acid co-catalyzed formal insertion of carbene into the C?O or C?N bond of 2H-chromene acetals or hemiaminal ethers. This transformation was initiated by the Br?nsted acid-promoted cleavage of the C?O or C?N bond, followed by modification of the leaving alcohol or amino fragments with palladium carbenes, and reassembly of the modified fragments. A variety of C-2 functionalized 2H-chromene derivatives were obtained in moderate yield (43～75%) with good to excellent diastereoselectivities (up to >95:5 dr) under mild conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201800179

Title: Formal Carbene Insertion into C-O or C-N Bond: an Efficient
Strategy for Synthesis of 2-Substituted 2H-Chromene Derivatives
from Chromene Acetals or Hemiaminal Ethers
Authors: Dan Zhang and Wenhao Hu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800179
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10.1002/adsc.201800179
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Formal Carbene Insertion into C-O or C-N Bond: An Efficient
Strategy for the Synthesis of 2-Substituted 2H-Chromene
Derivatives from Chromene Acetals or Hemiaminal Ethers
Dan Zhanga and Wenhao Hua,*
a
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
E-mail: huwh9@mail.sysu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
treatment of acute bacterial skin and skin structure
infections, both in phase III clinical trials.
Additionally, 2H-chromene analogs are also
employed as photochromic materials and precursors
to flavylium dyes for solar cells and optical memories.
[6] Therefore, a facile synthetic method to access these
privileged structures would be attractive.
Abstract: We report the palladium/Brønsted acid co-
catalyzed formal insertion of carbene into the C-O or C-
N bond of 2H-chromene acetals or hemiaminal ethers.
This transformation was initiated by the Brønsted acid-
promoted cleavage of the C-O or C-N bond, followed by
modification of the leaving alcohol or amino fragments
with palladium carbenes, and reassembly of the
modified fragments. A variety of C-2 functionalized 2H-
chromene derivatives were obtained in moderate yield
(43~73%) with good to excellent diastereoselectivities
(up to >95:5 dr) under mild conditions.
Considerable efforts have been made to provide 2-
substituted 2H-chromenes over the past decades
(Scheme 1). The traditional protocols involve
construction of benzopyran structure from phenol or
salicylaldehyde derivatives by annulations (Scheme 1,
a).[7] These synthetic methods typically require
Keywords: Metal carbenes; Formal insertions;
Multicomponent reactions; Synergistic catalysis; 2H-
Chromenes
multistep
manipulations
of
complicated
prefunctionalized substrates, and thus lack the
flexibility for the synthesis of C-2 derivatives. As an
alternative strategy towards late-stage C-2
modification, nucleophilic substitution of chromene
acetals, prepared from readily available coumarins,
allows for the facile synthesis of C-2 functionalized
2-Substituted
2H-chromenes
(2H-1-benzopyran
derivatives) are among the most prevalent structural
moieties present in a vast number of natural products,
pharmaceuticals, and materials.[1] For example,
natural products gaudichaudianic acid[2] and (+)-
myristinin A[3] indicated antifungal activities and
inhibition of DNA polymerase B, respectively; while
drug candidate acolbifene[4] is a nonsteroidal selective
estrogen receptor modulator (SERM) for the
treatment of breast cancer, and iclaprim[5] is an
investigational broad-spectrum antibiotic for the
2H-chromenes
(Scheme
1,
b).[8-10]
These
transformations generally proceed through in situ
generation of oxocarbenium ion by elimination of an
alkoxyl fragment under the promotion of Lewis
acids[8] or Brønsted acids,[9] or through a transition-
metal catalyzed process.[10] The nucleophilic species
include enamines,[7a] organoboron reagents,[8b-c]
organoindium
reagents,[8e]
alkynyl
copper
intermediates,[8f-h] and Grignard reagents.11 However,
many of reported examples need harsh conditions,
and for all of these methods, the leaving alkoxyl
fragment is abandoned as waste. Therefore, the
development of more efficient and green solution to
offer structurally diverse C-2 functionalized 2H-
chromenes would be certainly in demand.
Recently, we reported a novel co-catalyzed
process[12] that proceeded through the C-N bond
cleavage of β-arylamino iminium promoted by
Brønsted acid, subsequent modification of the leaving
amino fragment with metal carbene[13] to form a
transient ammonium ylide intermediate, and selective
reunion of two reactive intermediates to give trapping
products (Scheme 1, c).[14-15] Huang et al also
developed a similarly efficient process involving
Figure 1. Selected examples of naturally occurring,
biologically active, and photochromic 2H-chromene
derivatives.
1
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10.1002/adsc.201800179
Advanced Synthesis & Catalysis
result from the low stability of the resulting 1-
benzopyrylium ion. To facilitate the formation of 1-
benzopyrylium ion, an electron-donating p-
methoxyphenyl (PMP) was introduced at C-4
position of the chromene acetal (2b) to stabilize the
cation. As a result, the reaction provided desired 3b
in a yield of 49% with 55:45 dr (entry 3). To enhance
the diastereoselectivity, a bulky 9-anthryl was set to
the chromene acetal (2c), and a remarkably improved
dr (>95:5) was obtained along with moderate yield of
58% (entry 4). In this reaction, a competing O-H
insertion of alcohol and 1a is the major side reaction,
leading to the O-H insertion side product 4 and the
decrease in the yield. Screening of solvents (entries 5-
9) found that CHCl3 increased the yield to 66% and
kept dr value excellent. Another Brønsted acid, p-
toluenesulfonic acid monohydrate (p-TsOH·H2O),
was also effective, but resulted in a decreased yield of
55% (entry 10). Additionally, in the absence of
Brønsted acid, 2c was recovered, indicating the key
role of Brønsted acid in the cleavage of C-O bond
(entry 11).
Scheme 1. Synthetic strategy for the synthesis of 2H-
chromene
the palladium-catalyzed formal C-N insertion of
carbenes into aminals.[16] In this unique process, metal
carbenes were successfully incorporated into C-N
bond via a sequence of bond cleavage/fragment
modifications/reassembly. Encouraged by this
success, we expected to apply this strategy to the
Table 1. Optimization of reaction conditions for the
reaction of chromene acetal and diazo compounds.a
reaction
of
diazo
esters
and
chromene
acetals/hemiaminal ethers for the synthesis of 2-
substitued 2H-chromenes (Scheme 1, d). It was
envisioned that Brønsted acid-induced reversible
cleavage of C-O or C-N bond of chromene
acetals/hemiaminal ethers could lead to electrophilic
1-benzopyrylium ions as well as free alcohols/
amines. Subsequent modification of the alcohols/
amines with diazo compounds would form
nucleophilic oxonium or ammonium ylide
intermediates, which were trapped by the pre-formed
1-benzopyrylium intermediates to afford 2-
substituted 2H-chromenes. Herein, we report the
couplings of diazo compounds and 2H-chromene ace-
tals/hemiaminal ethers under palladium/Brønsted acid
co-catalysis for the synthesis of valuable 2-
substituted 2H-chromene derivatives. Notably,
compared with traditional nucleophilic substitution of
chromene acetals,[8-10] in this transformation, alcohol
or amine fragments serve not only as a leaving group
but also a serviceable component to generate ylide
nucleophiles, greatly improving the atom economy.
In initial efforts to implement this proposed C-X
bond cleavage/fragment modification/reassembly
sequence in the reaction of chromene derivatives and
diazo compounds, 2-benzyl-2H-coumarin (2a) was
treated with methyl α-diazo phenylacetate (1a) in the
presence of [PdCl(η3-C3H5)]2 and Brønsted acid PA-a.
entry
1
solvent
DCM
DCM
DCM
DCM
(CH2Cl)2
CHCl3
toluene
THF
Yield of 3/% b drc of 3
2
0d
/
/
2a
2a
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
2e
3
0d
49
58
52
66
43
36
31
55
0d
55:45
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
/
4
5
6
7
8
9
Et2O
10f
11g
CHCl3
CHCl3
CHCl3
12h
0i
/
a)
[PdCl(η3-C3H5)]2/PA-a/1/2 = 0.05:0.1:1.5:1.0. b) Isolated
yield. c) Determined by H MMR. d) Acetal 2a recovered.
1
e)
f)
TfOH was used instead of PA-a. p-TsOH·H2O was used
instead of PA-a. g) In the absence of PA-a. h) In the absence
of [PdCl(η3-C3H5)]2. i) 2a didn’t decompose.
Having established the optimal reaction conditions
for the formal C-O insertion, we then evaluated the
substrate scope of this transformation (Table 2).
Diazo compounds with less bulky substituents, such
as H, F, Cl, Br and Me, at para-position of phenyl
ring, provided desired products 3c–3g in moderate
yields with excellent diastereoselectivies (> 95:5 dr),
while those with a MeO at para or meta-position of
phenyl ring were also tolerated and provided 3g and
3i in the yield of 69% and 73%, respectively, but
[12,14f]
Unfortunately, the acetal 2a was not able to be
activated under this condition and therefore no
desired product was detected (table 1, entry 1).
Similar results were observed even with
trifluoromethanesulfonic acid (TfOH), a stronger
Brønsted acid (entry 2). The failure of reaction may
2
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10.1002/adsc.201800179
Advanced Synthesis & Catalysis
resulted in dramatically decreased dr. Replacing the
meta-MeO with a less bulky Br improved the dr to
85:15 (3j), while an ortho-Me would again result in
significant decrease of dr value (3k). The decrease of
dr value may result from the steric hindrance between
bulky substituent on aryl groups of diazo compounds
and extremely bulky 9-anthryl, although the bulky 9-
anthryl was the key to improving dr in condition
optimizations. In the case of Ph on C-4 of chromene
ring, no desired 3l was obtained, with the
corresponding acetal recovered. The structures of
products were confirmed and the relative
configuration was determined to be anti on the basis
of X-ray single-crystal analysis of syn-3c’,[17] the
diastereoisomer of free hydroxyl derivative of 3c.[18]
by the use of corresponding aniline (1.0 equivalent)
as an extra reaction component. Finally, X-ray single-
crystal analysis of 6a confirmed the structure and
revealed the relative configuration as syn,[17] which
was opposite to that of alkoxy counterparts 3.[19]
Table 3. Substrate Scope for the reaction of chromene
hemiaminal ethers with diazo compounds.a,b,c
Table 2. Substrate Scope for the reaction of chromene
acetals and diazo compounds a,b,c
a)
[PdCl(η3-C3H5)]2/PA-a/1/5 = 0.05:0.1:1.5:1.0. b) Isolated
yields. c) dr was determined by 1H MMR.
We also investigated the asymmetric fashion of
this reaction by chiral phosphoric acids (R)-PA-b~d.
For the reaction of 1a and acetal 2c, the bulky chiral
catalysts were not effective to promote the cleavage
of C-O (Scheme 3, eq 1). On the other hand, when
using 5a as substrate, the desired product 6a was
obtained in 38-54% yield, with a highest ee of 30%
(Scheme 3, eq 2). Asymmetric addition to
oxocarbenium ion by chiral anionic catalysis remains
a great challenge to explore.
a)
[PdCl(η3-C3H5)]2/PA-a/1/2 = 0.05:0.1:1.5:1.0. b) Isolated
yields. c) Dr was determined by 1H MMR.
We then extended the substrates to include
chromene hemiaminal ethers under the conditions
used for chromene acetals (Table 3). With respect to
diazo compounds, a halogen atom, Me, or MeO on
para-position of phenyl ring are tolerated and the
desired products 6a-6f were obtained in yield of 40-
68% with excellent diastereoselectivities (>95:5 dr).
As for the arylamino moieties in hemiaminal ethers,
for, a CO2Me, CN, or t-Bu on ortho- position of
phenyl rings is essential for high diastereoselectivities,
while an ortho-Br led to a dramatic drop in dr value.
For the chromene ring, substrate with a p-CF3C6H4
rather than PMP on C-4 position only gave trace of
product. Similarly, the major side reaction was [1,2]-
H shift of ammonium ylides, which would diminish
the yield of desired process. In view of this, the yields
of products (6b, 6c, 6e, 6g, and 6i) could be enhanced
Scheme 2. Preliminary studies of asymmetric reactions.
3
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10.1002/adsc.201800179
Advanced Synthesis & Catalysis
To get insight into the reaction pathways, we
According to the experimental results, we proposed
a C-X bond cleavage/fragment modification/
designed the following control reactions (Scheme 4).
First, treating 2c or 5a with corresponding X-H
insertion product under the standard conditions gave
no detectable desired products 3c or 6a, ruling out the
pathway via O-H or N-H insertion products (Scheme
3a). Subsequently, to understand the role of Brønsted
acid in the progress of reaction, we carried out
control reactions in absence of Brønsted acid
(Scheme 3b). For the chromene acetal, 2c was not
activated (Table 1, entry 11), demonstrating the
decisive role of PA-a in the cleavage of C-O bond.
This observation as well as the formation of O-H
insertion side product 4 under standard conditions
ruled out the Stevens [1,2]-carbon shift[20] process.
On the other hand, chromene hemiaminal ether 5a
offered 6a in 51% yield, along with N-H insertion
product 7 in yield of 39% in the absence of PA-a,
suggesting that hemiaminal ether substrates could
directly react with carbenes to give the formal C-N
insertion product and a stepwise C-N bond cleavage
before the C-C bond formation. Considering the fact
that chromene hemiaminal ether could rapid
decompose in minutes under the standard conditions,
the designed C-N bond cleavage/arylamino fragment
modification/ reassembly sequence is still reasonable.
reassembly mechanism (Scheme 4). For chromene
acetals and hemiaminal ethers, the C-X bond
cleavage/fragment modification/reassembly sequence
(path a), the C-O was cleaved under the activation of
phosphoric acid to form a 1-benzopyrylium ion A and
a leaving alcohol species, which reacted with
palladium carbene B generated from palladium-
catalyzed decomposition of diazo compound 1 to give
an active oxonium ylide C. The coupling of the two
reactive intermediates, 1-benzopyrylium ion A and
ylide C, provided the assembled products 3. On the
other hand, chromene hemiaminal ethers 5 could
undergo a reaction pathway similar to that of 2 (path
a). However, an alternative process was also possible
based on the phenomenon that 5 could also directly
react with carbene B without Brønsted acid. This
pathway proceeded through the formation of
ammonium ylide D from palladium B and substrate 5,
followed by cleavage of C-N bond of ylide D, and
reunion of the two fragments (path b).
In conclusion, we have developed an efficient
strategy involving C-X (X
=
O, N) bond
cleavage/fragment modification/reassembly sequence
for the reaction of diazo compounds with chromene
acetals/hemiaminal ethers to achieve selective formal
C-X insertions. This reaction delivers valuable
chromene derivatives in moderate yields with
moderate to excellent diastereoselectivities in a single
step under mind reaction conditions. This cleavage-
modification-reassembly process also provides a new
strategy for highly selective C-X (X = O, N)
insertions.
Experimental Section
Experimental Details: to an oven-dried test tube with a
stirring bar were added chromene acetal or hemiaminal
ethers (0.2 mmol, 1.0 equiv.), [PdCl(η3-C3H5)]2 (0.01 mol,
3.7 mg, 5.0 mol%), racemic Brønsted acid PA-a (0.02
mmol, 7.0 mg, 10 mol%) and 4Å molecular sieve (300 mg),
and then the vessel was capped by a septum for injection.
Anhydrous CHCl3 (1.5 mL) was added, and the mixture
was stirred at 25 oC. Subsequently, diazoester 1 (0.3 mmol,
53 mg, 1.5 equiv) in 1 mL CHCl3 was added during 1 h via
a syringe pump. Upon completion of the addition, the
mixture was stirred in another 5 min. The reaction mixture
was filtered and the filtrate was concentrated to give a
residue which was subjected to 1H NMR spectroscopy
analysis for the determination of dr value. Purification of
the crude products by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether/DCM = 1:50:1~1:10:1)
afforded pure products anti-3 or syn-6, in the yields shown
in Table 2 and Table 3.
Scheme 3. Control reactions.
Acknowledgements
This research was supported by the Program for Guangdong
Introducing Innovative and Entrepreneurial Teams (No.
2016ZT06Y337) and NSFC (No. 21332003).
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Scheme 4. Proposed mechanisms of the title reactions.
4
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800179
Advanced Synthesis & Catalysis
COMMUNICATION
Formal Carbene Insertion into C-O or C-N Bond:
an Efficient Strategy for Synthesis of 2-Substituted
2H-Chromene Derivatives from Chromene Acetals
or Hemiaminal Ethers
Adv. Synth. Catal. Year, Volume, Page – Page
Dan Zhang, Wenhao Hu*
6
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