Hemin-Catalyzed, Cyclodextrin-Assisted Insertion of Carbenoids into N-H Bonds

Article abstract of DOI:10.1002/adsc.201500418

An aqueous hemin-catalyzed, cyclodextrin-assisted N-H insertion reaction of α-diazo ester into aromatic amines is described here. This aqueous catalytic system showed good compatibility with various arylamines, with yields up to 96%. A size-controlled reaction phenomenon by different cyclodextrins (CDs) was also observed when ethyl diazoacetate (EDA) was used. The reaction mechanism was also preliminarily proposed on the basis of designed control experiments.

Full text of DOI:10.1002/adsc.201500418

UPDATES
DOI: 10.1002/adsc.201500418
Hemin-Catalyzed, Cyclodextrin-Assisted Insertion of Carbenoids
À
into N H Bonds
Xiaofei Xu,a Chang Li,b Zhihao Tao,a and Yuanjiang Pana,*
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, Peoples Republic of China
Fax: (+86)-571-8795-1629; phone: (+86)-571-8795-1629; e-mail: panyuanjiang@zju.edu.cn
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Peoples Republic of China
b
Received: April 29, 2015; Revised: July 6, 2015; Published online: October 14, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500418.
Abstract: An aqueous hemin-catalyzed, cyclodex-
trin-assisted N H insertion reaction of a-diazo
iridium-,[13] and palladium-based[14] catalysts have
been broadly applied to carbenoid insertion reactions.
Recently, Zhou and his co-workers demonstrated
À
ester into aromatic amines is described here. This
aqueous catalytic system showed good compatibility
with various arylamines, with yields up to 96%. A
size-controlled reaction phenomenon by different
cyclodextrins (CDs) was also observed when ethyl
diazoacetate (EDA) was used. The reaction mecha-
nism was also preliminarily proposed on the basis
of designed control experiments.
À
the enantioselective N H insertion of diazo com-
pounds.[10a,11b] Iron corroles- and iron porphyrins-cata-
À
lyzed insertions of EDA into N H bonds have also
been achieved by Gross[15] and Woo.[16] Nevertheless,
most of these established reactions were conducted in
organic solvents and required strict reaction condi-
tions, such as rigorous operation and inert atmos-
phere. On the contrary, enzymatic carbenoid transfor-
mations in aqueous media remain rare,[2b,12,17] owing to
Keywords: cyclodextrins; diazo compounds; green
À
the inclination of O H insertion by water and the
À
chemistry; hemin; N H insertion
poor water-solubility of substrates.
Such issues also hindered the use of hemin in the
catalysis of carbenoid insertions to amines. The cata-
lytic ability of hemin often decreases in aqueous
Heme is not only one of the most abundant and media owing to the hydrophobic nature of the por-
widely used metalloporphyrins in catalysis, but also phyrin ring and the absence of the peptidic microen-
the crucial cofactor in a variety of metalloenzymes. In viroment that existed in native enzymes. Complemen-
recent years, many heme-containing enzymes have re- tarily, cyclodextrins, with hydrophobic inner cavities
ceived considerable attention in biosynthetic and bio- and hydrophilic outer surfaces, can provide a favoura-
analytical chemistry,[1] such as cytochrome P450-in- ble microenvironment for hemin and increase the sol-
volved carbenoid-relevant reactions,[2] and horseradish ubility of organic substrates.[18]
peroxidase (HRP)-catalyzed oxidation of resvera-
The continuing interest in developing a sustainable
trol.[3] Possessing merits such as thermal stability and reaction system to accomplish the target transforma-
low cost, heme is considered as an ideal model com- tion under aqueous conditions by employing cheap,
pound for mechanistic study of ferriporphyrin-cata- efficient and eco-friendly catalysts has inspired the
lyzed reactions and broadening the application hori- present research. Herein, we report an efficient aque-
zon of heme enzymes.
ous hemin-catalyzed, cyclodextrin-assisted protocol
À
À
Metal-catalyzed N H insertion of a-diazo esters for the insertion of carbenoids into N H bonds.
with amines provides a facile way to prepare C N
bond-containing precursors of natural products and strate methyl phenyldiazoacetate (MPDA, 1a) and
bioactive molecules,[4] such as a-amino acids,[5] pep- aniline (2a) in the presence of 0.05 mol% heme-cen-
tides[6] and nitrogen-containing heterocycles.[7] In tered natural enzyme horseradish peroxidase (HRP)
À
Our investigations commenced with the model sub-
À
1950s, Yates reported the first example of N H inser- (entry 0 in Table 1). The reaction was carried out in
tion reaction by using copper catalysis,[8] and subse- aqueous solution at 358C for 5 days, affording the N
À
quently Paulissen and his co-workers employed the H insertion product (3a) in 9% yield determined by
catalyst Rh2(OAc)4 to achieve this reaction.[9] Since 1H NMR, in which a new one-proton singlet peak ap-
then, a variety of copper-,[10] rhodium-,[11] ruthenium-,[12] peared at 5.09 ppm for the new methane hydrogen.
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Xiaofei Xu et al.
À
Table 1. Optimization of the N H insertion reaction condi-
With the optimized conditions in hand, we next ex-
amined the substrate scope of substituted arylamines
by using MPDA as the diazocarbonyl reagent in this
hemin-catalyzed system (Table 2). The corresponding
tions.[a,b]
À
N H insertion products were obtained in moderate to
excellent yields (43–96%). Almost all of the para-sub-
stituted anilines displayed high conversions without
the side product formed through the dimerization of
À
Entry Cat. (mol%) Cyclodextrin (mol%) Yield[c] [%]
MPDA, and only a trace amount of the O H inser-
tion by-product formed by MPDA and water was de-
tected. This reaction had excellent functional group
tolerance, and both electron-withdrawing groups (3b,
3c and 3d) and electron-donating groups (3e and 3f)
remained intact in this reaction system. The compara-
ble reactivity of 4-chloroaniline (3c) and 3-chloroani-
0
1
2
3
4
5
6
7
8
9
10
11
12
13
HRP (0.05)
hemin (10)
hemin (10)
hemin (10)
hemin (10)
hemin (10)
hemin (10)
hemin (10)
hemin (10)
hemin (10)
hemin (5)
–
–
9
44
71
89
93
63
92
89
57
91
94
69
4
a-CD (16)
b-CD (16)
g-CD (16)
b-CD (100)
b-CD (50)
b-CD (20)
b-CD (10)
b-CD (20)
b-CD (20)
b-CD (20)
b-CD (20)
b-CD (100)
À
Table 2. N H insertion reactions of diverse substituted ami-
nes.[a,b]
hemin (2.5)
hemin (1)
HRP (0.05)
6
[a]
[b]
[c]
A molar ratio of 1:1.2 for MPDA:aniline was employed,
and reactions were carried out in a thermo shaker.
The results of other PTAs are shown in supporting infor-
mation.
1
Yields were determined by H NMR in CDCl3.
When 10 mol% hemin was used instead of HRP, the
reaction exhibited improved but still unsatisfactory
reactivity by giving 3a in 44% yield (entry 1 in
Table 1). We assumed that the poor reactivity was due
to the low solubility of the substrates, and then we
turned to the addition of the frequently used phase-
transfer agents (PTAs) to improve the reactivity. As
shown in Table 1, cyclodextrins (entries 2–4) dramati-
cally improved the yield of product 3a (a-CD, 71%;
b-CD, 89%; g-CD, 91%), while the other eight PTAs
(Table S1 in the Supporting Information) had no ob-
vious effect on the transformation.
Considering the comparable results in the presence
of b-CD and g-CD and the relatively low cost of the
former one, we selected b-CD as our ideal additive.
After further screening of the catalytic amounts of
hemin and CDs (entries 5–12 in Table 1), we were de-
lighted to attain the optimal conditions with 3a ob-
tained in 94% yield: 5 mol% hemin and 20 mol% b-
CD, 358C, 5 days in water (entry 10 in Table 1). How-
ever, a lower catalytic loading of hemin decreased the
yield (entries 11 and 12 in Table 1). Given that the
diazo compounds are potentially explosive, a higher
reaction temperature was not considered. When we
conducted this reaction in the catalysis of 0.05 mol%
HRP with a stoichiometric amount of b-CD, still only
a poor yield of the target product was achieved
(entry 13 in Table 1).
[a]
A molar ratio of 1:1.2 for MPDA:amine was employed,
and reactions were carried out in a thermo shaker.
[b]
1
Yields were determined by H NMR in CDCl3.
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Hemin-Catalyzed, Cyclodextrin-Assisted Insertion of Carbenoids into N H Bonds
À
Table 4. N H insertion reactions of different a-diazoacetate
line (3h) suggested that the meta- and para-substitu-
tions showed no obvious position effects. However,
the ortho-position of the substituents on the aryl
group led to a slightly reduced yield of the corre-
sponding product (3c and 3g). This result might be
due to the steric hindrance on the nucleophilic addi-
tion to the electron-deficient carbene intermediate.
As an exception, a high yield (89%) of the desired
product of 1-naphthylamine (3j) was formed in spite
of the large steric hindrance, which indicated that the
electron-donating naphthyl group could probably fa-
cilitate the reaction. Finally, the N-heterocyclic com-
substrates.[a,b]
À
pound indoline could also undergo the N H insertion
under the standard reaction conditions to afford the
corresponding product in moderate yield (3k).
However, some other amines or amides were tested
and found to be incompatible with the reaction
system, giving no N H insertion products (Table 3).
[a]
A molar ratio of 1:1.2 for a-diazoacetate:aniline was em-
ployed, and reactions were carried out in a thermo
shaker.
À
[b]
1
Yields were determined by H NMR in CDCl3.
Table 3. Investigation of unreactable amines.[a]
when benzyl phenyldiazoacetate was employed in the
À
N H insertion. Nevertheless, the reaction with ethyl
phenyldiazoacetate resulted in a low yield of the cor-
responding product (3n, 12%), which suggests that
different protecting groups of the esters could have
an immense influence on this transformation. Howev-
er, all the N H insertion products 3a–3n had almost
no enantioselectivities with ee values under 5%
(Table S3 in the Supporting Information).
When this method was applied in the reaction be-
tween EDA and aniline with a ratio of 1:1, the
double-insertion product 3p was detected in 37%
yield, along with the single-insertion product 3o in
19% yield. And only trace amount of diethyl fuma-
rate was formed. This reaction could be accomplished
in 24 h, which is much more effecient than MPDA-in-
volved reactions. After b-CD was replaced by equi-
molar a-CD or g-CD, it was discovered that the
Results Corresponding amines
OHI[b] 4-nitroaniline; 2-nitroaniline; diphenylamine;
indole; pyrrole; 2-aminophenol; guanine; uracil;
sulfanilic acid; benzamide; glucosamine; taurine;
o-phthalimide
À
NR[c]
4-aminophenol; benzylamine; dibutylamine; tert-
butylamine; iso-propylamine; piperidine
[a]
A molar ratio of 1:1.2 for MPDA:amine was employed,
and reactions were carried out in a thermo shaker.
OHI signifies O H insertion reaction between MPDA
and water.
NR signifies no reaction.
[b]
[c]
À
With the competitive hydroxy group at the para-posi- single-insertion product 3o was more favourably
tion of aniline, no reaction happened, while the pres- formed when the smaller a-CD was involved, whereas
ence of ortho-hydroxy, para-nitro or ortho-nitro group the double-insertion product 3p was preferentially
À
led to the O H insertion by-product formed by generated when the larger g-CD was used (Table 5).
MPDA and water. In addition, most of the soluble It could be inferred that the product distribution can
amines were found to give no reactions, owing to the be controlled by the hydrophobic cavity size of CDs.
protonated amines acting as bystanders in water. As This result also provides additional proof for the role
a consequence, we suppose that CD could act as a car- of CD acting as a micro-reactor.
rier enveloping the reactants within its hydrophobic
Furthermore, a mechanistic probe for carbene for-
environment, thus providing a protective sheath for mation was designed in which EDA was treated with
À
the N H insertion reactions.
The influence of the diazo ester type on this reac- After 24 h, almost complete conversion to the car-
tion was subsequently studied. Three phenyl diazoace-
5 mol% hemin and 20 mol% b-CD in water [Eq. (1)].
tate substrates were synthesized and applied in the re-
action under optimized conditions (Table 4). The de-
À
sired N H insertion product of methyl naphthyldi-
azoacetate was generated in high yield (3l, 89%). A
relatively modest reactivity (3m, 43%) was observed
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Xiaofei Xu et al.
Table 5. CD size-controlled product distribution.[a]
sive hemin in aqueous solution with the aid of b-CD.
Moderate to excellent yields of N H insertion prod-
À
ucts were obtained through a concise, green and effi-
cient strategy. This aqueous catalytic system might be
of great advantage in the transformation of carbe-
noids. The successful cooperation of hemin and cyclo-
dextrin provides a preliminary possibility for applying
heme enzymes in diazo ester-involved transforma-
tions.
Yield[b] [%]
single insertion double insertion
Experimental Section
Entry
CD
À
General Procedure for Hemin-Catalyzed N H
Insertion Reactions
1
2
3
a-CD
b-CD
g-CD
61
37
32
12
19
20
Amine (0.36 mmol) was added in 3 mL of an aqueous solu-
tion containing 0.015 mmol hemin/0.15 mmol HRP and
0.06 mmol CD, followed by addition of 0.3 mmol diazo re-
agent in one portion. The reaction vials were then placed in
a constant temperature shaker and left to shake at 200 rpm
under 358C. After 5 days, the mixture was extracted thrice
with EtOAc and water. The organic layer was further
washed with brine and then dried with Na2SO4. Finally,
hemin was filtered by using a short silica gel column with
EtOAc. The filtrate was concentrated under vacuum and
subjected to silica gel and eluted with petroleum ether-
[a]
A molar ratio of 1:1 for EDA:aniline was employed, and
reactions were carried out in a thermo shaker.
Yields were determined by H NMR in CDCl3.
[b]
1
bene dimerization product of EDA, namely, diethyl
maleate, was observed, clearly indicating that the
hemin-catalyzed N H insertion reaction proceeds
À
through a metal carbene pathway.
The proposed mechanism is depicted in Scheme 1.
At the outset, the diazo compounds undergo an elec-
trophilic addition to coordinate the unsaturated iron
center of hemin to form a hemin carbene complex, by
À
EtOAc (50:1) to give the pure N H insertion product.
1
Yields were determined by H NMR.
À
losing a molecule of nitrogen. Then, the N H inser-
tion products are generated through the nucleophilic
attack by the amines. In spite of the difficulty to cap-
ture or trap the hemin carbene intermediates due to
their rapid consumption, the disclosure of the fully
characterized iron porphyrin carbene complex pro-
vides a rational evidence for the existence of a hemin
carbene complex to a certain extent.[19]
Acknowledgements
Financial support from National Basic Research Program of
China (973 program, 2011CB710800) is gratefully acknowl-
edged.
In conclusion, the current investigation is focused
on the N H insertion reactions between aromatic
amines and diazocarbonyl reagents under the catalysis
of the commercially available and relatively inexpen-
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