Copper-Catalyzed Oxy-aminomethylation of Diazo Compounds with N, O-Acetals

Article abstract of DOI:10.1021/acs.orglett.9b00203

A novel oxy-aminomethylation reaction of diazo compounds has been developed, providing the α-hydroxy-β²-amino acid derivatives with quaternary carbon centers in moderate to excellent yields. Importantly, the readily available N,O-acetals have been employed as efficient bifunctionalization reagents to react with copper carbene intermediates, leading to the concurrent incorporation of an alkoxy and an iminium group into one molecule. Moreover, a water-involved three-component reaction occurs to deliver the free-hydroxy amino acid derivatives.

Full text of DOI:10.1021/acs.orglett.9b00203

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Copper-Catalyzed Oxy-aminomethylation of Diazo Compounds with
N,O‑Acetals
†
†
Jianliang Yu, Long Chen, and Jiangtao Sun*
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou
University, Changzhou 213164, P.R. China
*
S Supporting Information
ABSTRACT: A novel oxy-aminomethylation reaction of diazo
2
compounds has been developed, providing the α-hydroxy-β -amino
acid derivatives with quaternary carbon centers in moderate to
excellent yields. Importantly, the readily available N,O-acetals have
been employed as efficient bifunctionalization reagents to react with
copper carbene intermediates, leading to the concurrent incorporation of an alkoxy and an iminium group into one molecule.
Moreover, a water-involved three-component reaction occurs to deliver the free-hydroxy amino acid derivatives.
β-Amino acids are key motifs found in numerous natural
products and biologically active pharmaceuticals, and they are
Scheme 1. Previous Reports and Our Strategy
1
also key building blocks in organic synthesis, especially in
2
,3
preparing peptidic foldamers. Among various β-amino acids,
2
the α-hydroxy-β -amino acids, especially those containing a
quaternary carbon center, are very hard to achieve. Although
such types of amino acids have been widely used in drug
molecules and leading compounds with diverse pharmaceutical
4
activities (Figure 1), methods toward such compounds remain
scarce. Thus, we decided to develop a novel protocol to
accomplish their synthesis.
2
Figure 1. Examples of α-hydroxy-β -amino acid derivatives.
It is well-known that metal carbene species exhibit umpolung
reactivity on the single carbon atom through ylide formation
(
reaction with a nucleophile) followed by exposure to an
9
5
continuation with our ongoing research interest, we want to
report the development of N,O-acetals as the amphiphilic
reagents to react with diazo compounds to deliver the α-
exogenous electrophile (Scheme 1a). Typically, this amphi-
philic reactivity enables the possibility of incorporating two
functional groups into one molecule with high atom economy.
Recently, Huang and co-workers reported an elegant amino-
methylation reaction to prepare α,β-diamino acid esters via
palladium-catalyzed reaction of diazoacetates with tetrabenzyl-
methanediamine, in which the amine reagent split into both the
6
2
hydroxy-β -amino acid derivatives in good yields. It should be
noted that, just recently, Xu co-workers reported an excellent
asymmetric counteranion-directed aminomethylation to pre-
pare chiral β-diamino acid esters, in which the N,O-acetals were
employed as aminomethylation reagents in their strategy
7
nucleophilic and the electrophilic moieties in situ (Scheme 1b).
Later, our group developed a gold-catalyzed formal [4 + 1]-
cycloaddition by using hexahydro-1,3,5-triazines as the
amphiphilic reagents. Inspired by the former reports, and in
Received: January 17, 2019
8
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
0
(
Scheme 1c). Notably, different from previous reports on the
With the established optimal conditions in hand, we next
started to investigate the scope of this oxy-aminomethylation
reaction (Scheme 2). First, the scope of diazo compounds was
11
use of N,O-acetals as single aminomethylation reagents, we
herein employed these compounds as bifunctionalization
reagents to incorporate concurrently an oxygen group and an
aminomethylation group into one molecule.
Initially, N,O-acetal 1a and diazoacetate 2a were selected as
model substrates to optimize the reaction conditions (Table 1).
Scheme 2. Substrate Scope −
a c
a
Table 1. Optimization of the Reaction Conditions
b
b
time
(h)
yield of 3
yield of 4
entry
cat.
solvent
CH Cl
(%)
(%)
1
2
3
4
5
6
7
8
9
(ArO) PAuNTf
18
18
6
54
39
14
17
3
2
2
2
tBuXPhosAuCl
CH Cl
2
2
2
2
2
2
2
2
2
2
2
2
CuCl
CH Cl
2
Cu(OAc)2
Cu(MeCN) PF
CuOTf
Cu(OTf)2
Rh (OAc)4
Rh (esp)2
AgOTf
CH Cl
6
2
CH Cl
6
6
6
6
6
1
1
6
6
6
6
6
6
6
1.5
38
72
88
11
34
29
45
37
65
81
<5
61
42
<5
<5
<5
8
5
<5
<5
<5
<5
33
9
4
6
2
CH Cl
2
CH Cl
2
CH Cl
2
2
CH Cl
2
2
10
11
12
13
14
15
16
17
18
19
CH Cl
2
AgPF6
CH Cl
2
Sc(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CH Cl
2
toluene
DCE
MeCN
THF
dioxane
DMSO
DMSO
7
31
33
92
92
c
a
Unless otherwise noted, all reactions were performed with 1a (0.2
mmol), 2a (0.3 mmol), and metal catalyst (5 mol %) in solvent (4
a
Unless otherwise noted, reactions were carried out with N,O-acetal 1
b
mL) under an argon atmosphere at room temperature. Isolated
(
0.2 mmol), diazo substrate 2 (0.3 mmol), Cu(OTf) (5 mol %) in
2
b c
c
yields. The reaction was performed at 60 °C. Ar = 2,4-di-tert-
DCM (4 mL) at rt for 6 h. Isolated yields. For compounds 17−20,
butylphenyl; DCE = 1,2-dichloroethane.
the reactions were performed at 60 °C.
investigated. Generally, aryl and heterocyclic diazoacetates were
well tolerated in this transformation, affording the desired
products in good to excellent yields (5−16). For example, the
phenyl moiety of diazoacetate containing a strong electron-
withdrawing group was a good candidate and gave product 10 in
89% yield. The aryl diazoacetates bearing sensitive groups such
as carboxylate (11), amino (12), and boron ester (13) were all
applicable in this reaction to give good yields of desired
products. The alkyl diazoacetates were tolerated well to yield the
corresponding products in moderate yield (17−19). Even for
the allyl group, the reaction also proceeded well to give 67%
yield of 20. For other types of diazo compounds, the ethyl
diazoacetate (EDA) led to 67% yield of 21, and the cyclic and
acyl diazo compounds afforded the desired products in good
yields. Next, the scope of acetals was explored (26−37). For
different ether-linked acetals, the desired products were
obtained in excellent yields (26−28). With respect to the
amine moiety of the N,O-acetals, different benzyl groups bearing
either electron-donating or electron-withdrawing groups were
suitable substrates (29−32). Aside from dibenzyl-substituted
amines, methylbenzylamine and diethylamine provided 33 and
34 in 82% yield and 74% yield, respectively. Other cyclic amines,
such as piperidine, morpholine, and tetrahydroisoquinoline,
The reactions were carried out in the presence of various metal
catalysts (5 mol %) at room temperature using dichloromethane
as the solvent. First, we tried gold complexes as the catalysts in
this reaction; however, only moderate yields were obtained
(
entries 1 and 2). Then various copper salts were examined. We
observed that the reaction did not occur with CuCl and
Cu(OAc) (entries 3 and 4), whereas Cu(MeCN) PF gave
2
4
6
product 3 in 38% yield (entry 5). The yield was further increased
to 72% when CuOTf was used (entry 6). Gratifyingly, when
Cu(OTf) was employed as the catalyst, 3 was obtained in 88%
2
yield associated with a small amount of 4 (entry 7). For other
metal catalysts, rhodium and silver catalysts gave low to
moderate yields (entries 8−11). Typically, the use of Sc(OTf)
3
furnished products 3 and 4 in moderate yields (entry 12).
Finally, after screening the solvents, we found that the free
hydroxy compound 4 was isolated in 92% yield when the
reaction was performed in wet DMSO (entry 18). Furthermore,
the reaction can be finished in 1.5 h at 60 °C with the same yield
(
entry 19). It should be noted that the formation of 4 is probably
attributed to the excess of water in the solvent. If the solvents
contained more water, compound 4 was obtained the dominant
1
2
product.
B
DOI: 10.1021/acs.orglett.9b00203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
proved to be viable substrates, furnishing the desired products
Scheme 4. Control Experiments
3
5−37 in good yields.
We next used DMSO as the solvent to investigate the water-
involved three-component reaction for preparing free α-
2
hydroxy-β -amino acid derivatives (Scheme 3). As anticipated,
Scheme 3. Substrate Scope for Preparing α-hydroxy-β-amino
,
a b
acid derivatives
reaction of 1a, benzyl alcohol, and 2a led to 3/27 in a 1.8:1 ratio
Scheme 4e). Thus, we also concluded that acetal 1a can rapidly
(
split into the methoxide ion and iminium ion in the reaction
solution since the methoxide ion is a stronger nucleophile than
ethanol and benzyl alcohol. Since methanol and deuterated
methanol have the most similar reactivity and steric hindrance,
the deuterium-labeling experiments were conducted (Scheme
4
f). The ratio of 3/d-3 was almost 1:1, indicating the existence of
ion exchange between the alcohol with the methoxide ion of
N,O-acetal.
13
Upon literature reports and our experiments, the plausible
reaction mechanisms for the formation of 3 and 4 have been
proposed (Scheme 5). The reaction of diazo 2a with copper
catalyst generates copper carbene species I. Simultaneously, the
N,O-acetal 1a splits into the methoxide ion and the iminium ion
II. Then, nucleophilic addition of methoxy anion to carbene I
a
Reactions were carried out with 1 (0.2 mmol), 2 (0.3 mmol),
b
Scheme 5. Proposed Reaction Mechanisms
Cu(OTf) (5 mol %) in DMSO (4 mL) at 60 °C for 1.5 h. Isolated
yields
2
the reactions proceeded well for various aryl diazoacetates
containing both electron-donating and electron-withdrawing
groups at the para position of the phenyl moiety, providing the
desired products in excellent yields (38−44). Also, the amine
and boron ester groups were tolerated (43 and 44). The use of
cyclic diazo substrates led to 46 and 47 in 83% and 77% yield,
respectively. Alkyl diazoacetates were also tolerated, affording
the corresponding products in moderate yields (48 and 49). The
use of EDA, phenyl diazoacetamide and dihydronaphthalen-1-
one diazo led to moderate yields of target products (50−52).
For different types of N,O-acetals, the reactions also gave good
yields of desired products (54−60).
Control experiments were performed to understand the
reaction processes. First, the crossover reaction of different N,O-
acetals with diazoacetate 2a were investigated (Scheme 4a−
c).The reaction of 1a, 1b, and 2a gave mixed products of 3 and
2
6 in 1.1:1 ratio, and the ratio of 3/27 and 3/28 is 3.3:1 and
1
.4:1, respectively. These results probably indicated that (a) the
acetal 1a might split into the corresponding ions faster than
acetals 1b−d and (b) the steric hindrance of the alkoxide ion
might affect the reaction. Next, the three-component reaction of
1
a, ethanol, and 2a gave 3/26 in a 1.3:1 ratio (Scheme 4d), and
C
DOI: 10.1021/acs.orglett.9b00203
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Organic Letters
Letter
affords copper intermediates III, which would be trapped
immediately by the strong electrophilic iminium ion II to deliver
the final product 3 and regenerate the copper catalyst. As a
result, the incorporation of N,O-acetal 1a into one molecule has
been completed (catalytic cycle A). For the formation of 4, the
reaction of water with copper carbene leads to ylide intermediate
IV. This reactive intermediate would react with 1a to furnish
intermediate V, which reacts with methoxy anion to release the
final product 4 and one molecule of methanol (catalytic cycle B).
Besides the copper−carbene mechanism, another possibility is
Lewis acid catalyzed mechanism C (Table 1, entry 12). Namely,
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(
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S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00203.
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Experimental procedures along with characterization data
and copies of NMR spectra (PDF)
(
Accession Codes
(
CCDC 1890318 (41) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
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AUTHOR INFORMATION
■
*
(12) The moisture content of DMSO used here is 0.69% (w/
Corresponding Author
w);namely 1 mL of DMSO contains 0.42 mmol of H O (1.68 mmol of
2
E-mail: jtsun08@gmail.com, jtsun@cczu.edu.cn.
H O in 4 mL DMSO). However, the addition of water (5 equiv) into
2
CH Cl cannot achieve the same result with wet DMSO.
2
2
ORCID
(13) For computational studies, see: (a) Liang, Y.; Zhou, H.; Yu, Z. J.
Jiangtao Sun: 0000-0003-2516-3466
Author Contributions
Am. Chem. Soc. 2009, 131, 17783. (b) Liu, S.; Jiang, J.; Chen, J.; Wei, Q.;
Yao, W.; Xia, F.; Hu, W. Chem. Sci. 2017, 8, 4312.
†J.L. and L.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
We thank the National Natural Science Foundation of China
No. 21572024), the Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology (BM2012110), and the
Green Manufacturing Collaborative Innovation Center for their
financial support.
D
DOI: 10.1021/acs.orglett.9b00203
Org. Lett. XXXX, XXX, XXX−XXX