H2O-Regulated Chemoselectivity in Oxa- Versus Aza-Michael Reactions

Article abstract of DOI:10.1021/acs.orglett.9b01342

A H₂O-regulated chemoselective addition in oxa- and aza-Michael reactions for aminoalcohols and mixtures of structurally similar alcohols and amines was reported. The oxa-Michael reactions might be kinetically controlled, and the reactions to produce O-selective products were slowed by the addition of water. The electrophilicity of Michael acceptors and the steric hindrance of Michael donors also affect the ratios of O/N products. This method offers novel ideas over conventional metal-catalyzed or ligand-induced strategies.

Full text of DOI:10.1021/acs.orglett.9b01342

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
H O‑Regulated Chemoselectivity in Oxa- Versus Aza-Michael
2
Reactions
Rong Huang, Zhihong Li, Jianghui Yu, Hongli Chen,* and Biao Jiang*,†
†
,‡
†
†
,†
†Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai
2
‡
01210, China
University of Chinese Academy of Sciences, Beijing 100049, China
S Supporting Information
*
ABSTRACT: A H O-regulated chemoselective addition in
2
oxa- and aza-Michael reactions for aminoalcohols and
mixtures of structurally similar alcohols and amines was
reported. The oxa-Michael reactions might be kinetically
controlled, and the reactions to produce O-selective products
were slowed by the addition of water. The electrophilicity of Michael acceptors and the steric hindrance of Michael donors also
affect the ratios of O/N products. This method offers novel ideas over conventional metal-catalyzed or ligand-induced
strategies.
etero-Michael reactions are the most valuable and widely
used methods in organic chemistry for the mild
catalytic solid NaOH or KOH was used as a base (Table 1,
entries 2−4).
H
formation of C−heteroatom bonds. The oxa-Michael reac-
1
tions, which involve the use of oxygen-centered nucleophiles,
are more difficult to achieve, compared to the aza-Michael
2
reactions, which grant efficient access to nitrogen-containing
conjugation, because amines are innately more nucleophilic,
compared to alcohols. The utility of metal reagents and
catalysts to drive chemoselectivity for ambident O/N
2
,3
nucleophiles is a general methodology. Catalyst-controlled
chemoselective reactions of oxa- over aza-Michael reactions
4
have also been addressed recently (eq 1). The reversed
chemoselectivity was conducted based on a metal salt catalyst
and a strong organometallic base under anhydrous conditions.
Optimized metallic catalyst systems attract more attention, and
little is known about the effects of water and electrophiles to
the chemoselectivity of hetero-Michael reactions. Herein, we
To demonstrate the generality of this novel method, we
further evaluated the substrate scope of the chemoselective
oxa-Michael addition with a variety of aminoalcohols (Scheme
1). The result showed that many α-aminoalcohols provided the
corresponding O-adducts with excellent chemoselectivity (5−
10). The length of the alkyl chain had no impact on the
chemoselectivity (11 and 12). A change of hydrophilicity or
hydrophobicity also did not affect the chemoselectivity (13
and 14). Secondary alcohol retained the selectivity to afford O-
adduct (15).
report our findings on the H O-regulated chemoselective O-
2
and N-Michael addition reactions (eq 2). We also demon-
strated that the reactivity of electrophiles and the steric
hindrance of substrates have a great influence on the
chemoselectivity.
Our group is interested in the development of vinyl-
sulfonamides as Michael acceptors to selective probe
5
nucleophiles, and we reported that N-methyl-N-phenyl-
vinylsulfonamide (1)-based Michael addition was able to
This method was then used to modify atenolol, which is a
medication of beta blockers. After treatment with compound 1
under the standard condition, atenolol was converted to
oxygen-selective product 16 in good yield (see Scheme 2).
We further applied the method to investigate the chemo-
selectivity among the mixtures of structurally similar alcohols
5a
5c
mediate cysteine-selective or lysine-selective conjugation.
In order to expand the application of vinylsulfonamides to site-
selectively modify a nucleophile, compound 1 was further
employed to react with an ambident nucleophile 3-amino-3-
phenylpropan-1-ol (2). Preliminary experiments were per-
formed in tetrahydrofuran (THF), which was used as
commercially available grade, regarding the effect of different
bases (Table 1, entries 1−8). Interestingly, an oxygen-selective
product (3) was exclusively formed in good yield, when
(
17a−17c) and amines (18a−18c). Similarly, O-adducts (19−
Received: April 17, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Table 2. Chemoselective Addition of Alcohols (17a−17c)
over Amines (18a−18c)
b
b
entry
base
time (h)
3
(%)
0
4 (%)
1
2
3
4
5
6
7
8
LiOH (solid)
NaOH (solid)
KOH (solid)
KOH (solid)
K CO (solid)
2
2
2
0
82
0
0
0
0
0
0
0
92
98
0
overnight
2
2
2
2
2
3
Et N
0
0
0
3
DBU
DABCO (solid)
a
Reaction conditions: 1 (0.05 mol), 2 (0.06 mol), base (0.025 mol),
b
1
THF (0.5 mL), rt. Yields were determined by H NMR analysis of
crude mixture [see Figure s1 in the Supporting Information (SI)].
Scheme 1. Substrate Scope of Amino Alcohols
Figure 1. Effects of water on the chemoselectivity for 5-amino-1-
pentanol. (Yields were determined by high-performance liquid
chromatography (HPLC), and the curves were obtained using a
normalization method.)
Scheme 2. Chemoselective Modification of Atenolol
excellent yield to no product along with an increase in the
amount of water (Figure 2A). In addition, the yield
enhancement of the aza-addition product 25 was driven by
the increase of water (Figure 2B).
2
1) were obtained with a high yield rather than N-adducts
(Table 2).
On the other hand, we found that when an aqueous solution
of KOH replaced solid KOH for the reaction of compounds 1
and 2, the oxa-addition product decreased significantly. We
then paid attention to investigate the effect of water on these
reactions. The experiments that had compound 1 reacting with
5
-amino-1-pentanol, in which the alcohol and amino have
similar exposures were conducted under different quantities of
water. The result showed that the O-adduct 22 was
chemoselectively produced with no extra or a small amount
of water and decreased rapidly with the increase of water (see
Figure 1). Conversely, the yield of the aza-addition product 23
was increased along with the addition of water. A single N-
selective product 23 was obtained in good yield when the
water content was more than 14% (70 μL water in 500 μL
(
THF and H O) total solution).
We also examined the effect of water on the reaction of 1
2
Figure 2. Effects of water on the chemoselectivity for (A)
pentylalcohol and (B) pentylamine. (Yields were determined by
HPLC, and the curves were obtained using a normalization method.)
with pentylalcohol or pentylamine. Consistent with the above
results, the amount of oxa-addition product 24 decreased from
B
DOI: 10.1021/acs.orglett.9b01342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the other hand, we have observed that the reaction rates
to produce O-adducts are much faster than those of N-adducts.
The H NMR spectra showed that the reaction to produce O-
Scheme 4. Effects of Electrophiles on the Chemoselectivity
1
product 6 was completed within 20 min, whereas the reaction
to form N-product 27 lasted for 7 h (see Scheme 3, as well as
Scheme 3. Reaction Time Needed To Complete the O/N
Additions
In addition, when the electrophile 28 replaced 1 to react
1
with 26, the H NMR spectra showed that the reaction was
very fast and completed with 10 min (see Figure s6 in the
Supporting Information), which demonstrated that stronger
electrophile accelerated the reaction and facilitated to yield O-
product.
Reaction rate can also be influenced by steric hindrance. To
get a better understanding of the reaction mechanism, (1S,2R)-
Figure s5 in the Supporting Information). Based on this, we
speculated that the chemoselectivity might be determined by
competing rates and the O-selective reaction was kinetically
controlled. If that is the case, water will retard the reaction rate
to form O-adducts, which results in the change of the ratios of
O/N-products. To prove this point, we examined the effects of
water to the reaction rate in the process of forming O-adduct
(
−)-cis-1-amino-2-indanol (32), which is a sterically more
congested aminoalcohol was examined to react with electro-
philes 1 and 28. A mixture of O/N-addition products emerged
for 1 and stronger electrophile 28 retained the capability to
selectively form O-selective product. On the other hand, when
2
4.
As shown in Figure 3, the rate of oxa-Michael reaction
2
8 reacted with 32 in a solvent containing water (THF/H O =
2
decreased when the amount of water was increased. When the
4:1), N-selective product was obtained (Scheme 5). When
Scheme 5. Reaction Selectivity Influenced by Steric
Hindrance
Figure 3. Water effects on the reaction rates for O-product 24.
molar ratio of water (equivalent to 1) was within 5, a
prolonged time was required to complete the reaction with the
increase of water. Once more water was present in the reaction,
the yield of 24 obviously decreased, as shown in Figure 2A.
According to the results above, other factors that influence
the reaction rate might also affect the chemoselectivity. This
left us to consider that stronger electrophiles will promote the
oxa-Michael reaction to happen faster, whereas weaker
electrophiles might not be robust enough to make O-products
form quickly and they would be likely to weaken the
chemoselectivity. To verify this hypothesis, a series of Michael
acceptors (28−31) other than compound 1 with different
activity were set out to react with L-(+)-alaninol (26) under
the identical reaction conditions. As mentioned in the previous
section, compound 1 reacted with 26, resulting in a single O-
adduct (6 in Table 2 and Scheme 3) in high yield.
Phenylvinylsulfone 28 with high electrophilic power also led
the formation of a selective O-addition product. Reaction of 26
with (vinylsulfinyl)benzene (29), which has a reduced
electrophilicity, a mixture of O/N-addition products were
produced. When a weaker electrophile, N-phenylacrylamide
amino-2-propanol (33), in which the hydroxyl group has a
hindered environment compared to the amino group, was
employed to react with 1 or 28, only N-product was obtained
for the both electrophiles.
Given the efficient H O-regulated chemoselectivity in oxa-
2
and aza-Michael addition reactions, we continued to an
instructive case achieving high levels of chemoselectivity step
by step with no reliance on protecting groups. Under identical
conditions, as always, the O-adduct 3 and N-adduct 4 were
chemoselectively obtained in high yield when compound 1
reacted with aminoalcohol 2 on condition in THF or 20% H
solution (THF/H O = 4:1), respectively. And they further
O
2
2
reacted with compound 1 in the presence or absence of water,
respectively, producing the same product 34 bothfeyield
(Scheme 6).
Scheme 6. Application of the Method To Achieve Selective
Reaction
(30) was employed to treat with 26, the O-addition product
was not detected and an N-addition product was yielded in 18
h. No reaction occurred for the weakest electrophile,
acrylonitrile (31) (see Scheme 4).
C
DOI: 10.1021/acs.orglett.9b01342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we have developed a new protocol for
chemoselective oxa- and aza-Michael reactions of amino-
alcohols and mixtures of structurally similar alcohols and
(4) (a) Uesugi, S.; Li, Z.; Yazaki, R.; Ohshima, T. Angew. Chem., Int.
Ed. 2014, 53, 1611. (b) Li, Z.; Yazaki, R.; Ohshima, T. Org. Lett.
2
016, 18, 3350. (c) Li, Z.; Tamura, M.; Yazaki, R.; Ohshima, T. Chem.
Pharm. Bull. 2017, 65, 19.
5) (a) Huang, R.; Li, Z.; Sheng, Y.; Yu, J.; Wu, Y.; Zhan, Y.; Chen,
amines. This H O-regulated chemoselective method offers
2
(
novel ideas and potential advantages in economic cost and
environmental consideration over conventional metal-cata-
lyzed or ligand-induced strategies. We observed that the
reaction rates to produce O-adducts were much faster than
that of N-adducts; and the reactions to produce O-selective
products were slowed by the addition of water. We considered
O-selective products were kinetically controlled. Water affects
the reaction rate resulting in the influence to the chemo-
selectivity. We also demonstrated that other factors (the
electrophilicity of Michael acceptors and the steric hindrance
of Michael donors), which influence the reaction rate of oxa-
Michael addition also affect the chemoselectivity. Strong
electrophiles promote the formation of O-selective product,
and aminoalcohols having sterically less congested hydroxyl
groups are more prone to yield O-adducts. Future work will
focus on this water-regulated chemoselective addition in other
applications.
H.; Jiang, B. Org. Lett. 2018, 20, 6526. (b) Li, Z.; Huang, R.; Xu, H.;
Chen, J.; Zhan, Y.; Zhou, X.; Chen, H.; Jiang, B. Org. Lett. 2017, 19,
4972. (c) Chen, H.; Huang, R.; Li, Z.; Zhu, W.; Chen, J.; Zhan, Y.;
Jiang, B. Org. Biomol. Chem. 2017, 15, 7339. (d) Huang, R.; Li, Z. H.;
Ren, P. L.; Chen, W. Z.; Kuang, Y. Y.; Chen, J. K.; Zhan, Y. X.; Chen,
H. L.; Jiang, B. Eur. J. Org. Chem. 2018, 2018, 829.
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01342.
Experimental details, characterization data, and NMR
spectra for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*
E-mail: chenhl@shanghaitech.edu.cn.
E-mail: jiangbiao@shanghaitech.edu.cn.
*
ORCID
Hongli Chen: 0000-0002-9002-2603
Biao Jiang: 0000-0002-4292-7811
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Peixiang Ma, Dr. Wenzhang Chen, and Dr. Ke
Song (ShanghaiTech University, SIAIS, Analytical Chemistry
and Bioinformatics platform) for helpful discussions and
technical assistance with NMR experiments and mechanical
calculations.
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DOI: 10.1021/acs.orglett.9b01342
Org. Lett. XXXX, XXX, XXX−XXX