Regioselective Synthesis of α- And γ-Amino Quinolinyl Phosphonamides Using N-Heterocyclic Phosphines (NHPs)

Article abstract of DOI:10.1021/acs.orglett.7b03829

A regioselective phosphonylation of quinolines for the synthesis of α-amino quinolinyl phosphonamides and γ-amino quinolinyl phosphonamides has been developed under mild reaction conditions. An NHP-thiourea enables selective synthesis of α-amino quinolinyl phosphonamides by a Reissert-type reaction, and an NHP-tosylamide affords γ-amino quinolinyl phosphonamides via a 1,4-conjugate addition reaction. The corresponding amino quinolinyl phosphonate adducts were obtained in moderate to excellent yields (up to 99% yield) and regioselectivities (up to 99:1) with good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.7b03829

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Synthesis of α- and γ-Amino Quinolinyl
Phosphonamides Using N‑Heterocyclic Phosphines (NHPs)
Manasa Shetty,‡ Hai Huang,‡ and Jun Yong Kang*
Department of Chemistry and Biochemistry, University of Nevada Las Vegas, 4505 South Maryland Parkway, Las Vegas, Nevada
89154-4003, United States
S
* Supporting Information
ABSTRACT: A regioselective phosphonylation of quinolines
for the synthesis of α-amino quinolinyl phosphonamides and
γ-amino quinolinyl phosphonamides has been developed
under mild reaction conditions. An NHP-thiourea enables
selective synthesis of α-amino quinolinyl phosphonamides by a
Reissert-type reaction, and an NHP-tosylamide affords γ-
amino quinolinyl phosphonamides via a 1,4-conjugate addition
reaction. The corresponding amino quinolinyl phosphonate adducts were obtained in moderate to excellent yields (up to 99%
yield) and regioselectivities (up to 99:1) with good functional group tolerance.
ver the past five decades, amino phosphonates have
utilized for a direct phosphonylation of quinolines to construct
amino quinolinyl phosphonate derivatives.
O
received much attention due to their diverse biological
activities.1 They are defined as phosphorus analogues of naturally
occurring amino acids a1a,2 (Figure 1), comprised of a
For example, the Hamada group reported a base-promoted
phosphonylation reaction of quaternary quinolinium salts with
dialkyl or trialkyl phosphites in which a regioisomeric mixture of
α-amino phosphonate and γ-amino phosphonate was generated
(Scheme 1a).14 An acid-promoted dearomatization of quinolines
using a silylated dimethyl phosphite via a tandem 1,4−1,2-
addition reaction was disclosed by the Stevens group (Scheme
1b).15 Recently, asymmetric organocatalyzed dearomatizations
of quinolines and isoquinolines for the synthesis of chiral
heterocyclic α-amino phosphonates were released by the
Mancheno group (Scheme 1c) and the Mukherjee group,
̃
Scheme 1. Synthetic Routes toward Amino Quinolinyl
Phosphonates
Figure 1. Several amino phosphonate derivatives.
biologically, pharmaceutically important N−C−P bond unit.
Compounds with this scaffold offer broad applications in
pharmacological activities such as enzyme activators3 or
inhibitors4 and also physiological and pathological processes in
biological systems.1a,5 In particular, amino phosphonate
derivatives bearing a quinoline moiety play a vital role in
medicinal chemistry as antitumor agents b,6 antimicrobial agents
c,7 antioxidants,8 and protease inhibitors d9 (Figure 1). Also,
transition metal complexes of quinoline phosphonates have
demonstrated antitumor activities in vitro studies e10 (Figure 1).
Multicomponent reaction (MCR) has emerged as an efficient
synthetic tool for the synthesis of α-aminophosphonates
employing amines, aldehydes, and dialkyl or trialkyl phosphites
since its discovery by Kabachnick and Fields in 1952.11 This
reaction proceeds via the formation of an imine intermediate in
situ followed by a phospha-Mannich reaction,12 affording a N−
C−P bond scaffold.13 Yet, the Reissert-type reaction has been
Received: December 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03829
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Organic Letters
Letter
respectively.16 Despite the recent advances in phosphonylation
of quinolines by the dearomatization strategy, there are
limitations such as the use of bases, strong acids, additives,
special silylated phosphites, and more importantly the lack of
regioselective phosphonylation of quinolines. Therefore, the
development of a general, regioselective method of phosphony-
lation reaction to access amino quinolinyl phosphonates under
mild reaction conditions is highly desirable in synthetic organic
as well as medicinal chemistry.
Recently, our study on N-heterocyclic phosphines (NHPs)
demonstrated a strong nucleophilicity and bifunctionality of the
NHPs toward various electrophile systems17 including iminium
electrophiles17a generated in situ without the use of base and
additives. Despite the many phospha-Mannich reactions of
iminium electrophiles, a regioselective addition of phosphorus
nucleophiles to quinolinium electrophiles to offer both α- and γ-
amino quinolinyl phosphonates has not been previously
developed. With the unique bifunctionality of the NHPs, we
hypothesized that different Brønsted acid motifs on the NHPs
may activate the quinolinium electrophiles through a different
mode of ion-paring capability,18 leading to a regioselective
phosphorus addition to the quinolinium salts. Herein, we report
an NHP-promoted regioselective synthesis of α-amino quino-
linyl phosphonates (α-AQPs) and γ-amino quinolinyl phospho-
nates (γ-AQPs) without the use of acids, bases, and additives
under mild reaction conditions.
different Brønsted acids and the tether length between the NHP
and Brønsted acid motif on this ion-paring event. Interestingly,
NHP-thioureas 3b and 3c having three and four carbon-chain
linkages (Table 1, entries 2−3), respectively, provided γ-AQP 5a
as a major product. We attribute this selectivity reversal to the
proximity interruption between the electrophilic α-position of
the quinolinium and nucleophile of the NHP, resulting in the
nucleophilic attack of the NHP favorably at the electrophilic γ-
position of the quinolinium. Modification of thiourea acidity
using 3d and 3e has a similar effect on the selectivity, but they are
inferior to the parent NHP-thiourea 3a (Table 1, entries 4−5).
Both the one methyl-substituted thiourea 3f and an amide group
3g on the NHP have proven to form α-AQP 4a as a major
product (Table 1, entries 6−7). To further study the role of
Brønsted acids on the regioselectivity, NHP-ethanol 3h and
NHP-tosylamide 3i were employed under the standard reaction
conditions. However, without the H-bonding moiety, 3h
provided 5a as a major product (Table 1, entry 8), showing
the selectivity reversal. When the thiourea motif on the NHP was
replaced with a tosylamide group 3i, we observed complete
reversal in regioselectivity in the phosphonylation of quinoli-
niums, providing only γ-AQP 5a in 70% yield (Table 1, entry 9).
Next, we sought to further optimize the reaction conditions for
both 4a and 5a construction (Table 2). For the 4a formation, we
Table 2. Optimization of Reaction Conditions for α-AQP and
a
γ-AQP
To test our hypothesis, we first performed a one-pot reaction
using equimolar amounts of NHP-thiourea 3a (1.0 equiv) and
quinoline 1a (1.0 equiv) with ethyl chloroformate 2a (1.1 equiv)
in CH2Cl2 at room temperature (Table 1). The reaction
proceeds efficiently to afford 4a (α-AQPs) and 5a (γ-AQPs) in
83% yield with an 8:1 ratio (Table 1, entry 1). This high
regioselectivity of the 1,2-addition over the potential competition
of the 1,4-addition reaction is presumably associated with the H-
bonding between the chloride anion and thiourea motif through
an ion-paring process.16b,18 We next exploited the effects of
b
c
entry
solvent
NHP
4a:5a
yield (%)
1
2
3
4
5
6
7
CH2Cl2
CHCl3
DCE
3a
3a
3a
3a
3a
3a
3a
3a
3a
3i
8:1
6:1
8:1
14:1
7:1
5:1
6:1
7:1
8:1
83
69
70
54
74
62
59
89
95
87
THF
Et2O
a
Table 1. Screening of Different NHPs
toluene
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
d
8
e
9
e
10
1:99
a
Reaction conditions: 1a (0.1 mmol), 2a ( 0.11 mmol), 3a (0.1
b
mmol), and solvent (0.5 mL) at rt for 24 h. Ratio was determined by
c
1H NMR on the crude reaction mixture. Total isolated yield.
d
e
Reaction was carried out at 40 °C for 6 h. Reaction was carried out
at 40 °C for 6 h using 1a (0.2 mmol), 2a (0.22 mmol), 3a (0.1 mmol)
or 3i (0.1 mmol), and solvent (0.5 mL).
b
c
entry
NHP
4a:5a
yield (%)
found that a subsequent screening of polar and nonpolar solvents
did not improve the product yield (Table 2, entries 1−7) but
improved regioselectivity was observed with THF solvent with a
moderate yield (Table 2, entry 4). When the reaction was run at
40 °C in CH2Cl2, it was completed in 6 h with an 89% yield of 4a
(Table 2, entry 8). Further improvement of the product yield was
achieved with a slight excess of 1a and 2a without affecting the
regioselectivity, providing a 95% yield of 4a with an 8:1 ratio of
the regioisomers (Table 2, entry 9). For the optimization of 5a
formation, NHP-tosylamide 3i was employed under the same
reaction conditions of 4a construction, and this reaction
provided exclusively γ-AQP 5a in 87% yield with excellent
regioselectivity (Table 2, entry 10). Further screening of different
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
8:1
1:4
1:3
6:1
4:1
6:1
6:1
1:3
1:99
83
74
83
67
30
86
86
58
70
3g
3h
3i
a
Reaction conditions: 1a (0.1 mmol), 2a (0.11 mmol), 3a (0.1 mmol),
and solvent (0.5 mL) at rt for 24 h. Ratio was determined by H
NMR on the crude reaction mixture. Total isolated yield.
b
1
c
B
DOI: 10.1021/acs.orglett.7b03829
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Organic Letters
Letter
solvents did not increase the product yield and the selectivity of
5a (see Supporting Information, Table S1).
Having the optimized reaction conditions in hand, we
explored the scope of the reaction with different quinoline
derivatives and chloroformates using the NHP-thiourea 3a
(Scheme 2). Various chloroformates 2a−2c delivered the desired
electron-withdrawing groups (Ph, F, Cl, Br) (1f−1i) on the
quinoline moiety yielded the γ-AQPs as major products (5d−5i).
In general, quinolines with electron-donating groups exhibited
higher regioselectivity than those of electron-withdrawing
groups. We also witnessed the same dual functionalization of 6-
hydroxy quinoline 1j to yield 6-ethylcarbonate γ-AQP 5j in 62%
yield with excellent regioselectivity. Additionally, other func-
tional groups such as aldehyde 1k, methyl acrylate 1l, and
phenylacetylene 1m on the quinoline moiety afforded the
desired 1,4-adducts (5k−5m) in 55−73% yields with high
regioselectivity.
Scheme 2. Scope of Quinolines and Chloroformates Using
a
NHP-Thiourea 3a
To develop an alternative mild procedure to an existing
phosphonylation reaction of isoquinolines,16b NHP 3a was
chosen as a phosphonylation reagent for the phosphonylation of
isoquinoline 1n, and this reaction provided α-AQP 6 in 96% yield
in an atropisomeric 1:1 mixture (Scheme 4, eq a). We further
Scheme 4. Phosphonylation of Other Substrates
a
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), 3a (0.1 mmol),
b
c
and CH2Cl2 (0.5 mL) at 40 °C for 6 h. Total isolated yield. Ratio
was determined by H NMR on the crude reaction mixture. 2a (0.4
d
1
mmol) was used.
α-AQPs (4a−4c) in 95−99% yields with good regioselectivity.
Not only the quinoline derivatives containing electron-donating
groups (Me, MeO) (1d, 1e) but also those with electron-
withdrawing groups (Ph, F, Cl, Br) (1f−1i) efficiently afforded
the corresponding α-AQPs (4d−4i) with moderate to excellent
yields and high regioselectiviy. Interestingly, when 6-hydroxy
substituted quinoline 1j was employed, a dual functionalization
occurred, affording 6-ethylcarbonate α-AQP 4j instead of 6-
hydroxy α-AQP. Other functional groups such as aldehyde,
methyl acrylate, and phenylacetylene on quinoline derivatives
(1k−1m) were also well tolerated and yielded the target
products (4k−4m) with high regioselectivity.
explored this synthetic protocol to synthesize a diphosphony-
lated adduct of the quinoline substrate under mild reaction
conditions.15,19 We were delighted to see that our NHP-thiourea
3a could also function as a diphosphonylation reagent (Scheme
4, eq b), in which the 1-methylquinolin-1-ium iodide 1o was used
as an electrophile to give a double addition product 7 in 46%
yield.
To demonstrate synthetic transformation of the phosphony-
lation products, 4a and 5a were subjected to an oxidation
reaction (Scheme 5). For example, an epoxidation reaction of 4a
Next, the reactivity of the NHP-tosylamide 3i was studied
(Scheme 3). Screening of various chloroformates (2a−2c)
afforded the corresponding γ-AQPs as major products (5a−5c)
in 73−98% yields with moderate to excellent regioselectivity.
Both electron-donating groups (Me, MeO) (1d, 1e) and
Scheme 5. Synthetic Transformations
Scheme 3. Scope of Quinolines and Chloroformates Using
a
NHP-Tosylamide 3i
and 5a proceeded smoothly with m-chloroperbenzoic acid20 in
the presence of NaHCO3, providing 8a (Scheme 5, eq a) and 8b
(Scheme 5, eq b) in 88% and 97% yields, respectively.
With the experimental results and previous reports,17b,c
a
plausible reaction mechanism for the formation of α-AQP and γ-
AQP is depicted in Scheme 6. A mixture of quinoline 1a and
chloroformate 2a generates a quinolinium salt I, which promptly
reacts with the NHP-thiourea 3a to furnish diazaphosphonium
intermediate IIIa via the Reissert-type reaction probably due to a
preferred ion-paring capability16b,18,21 between the chloride
anion and thiourea moiety IIa. Then, the intermediate IIIa
undergoes an intramolecular nucleophilic substitution reaction
initiated by the anionic thiourea moiety17a to provide the desired
α-AQP 4a and a thiazolidine byproduct IVa22 (Scheme 6,
a
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), 3i (0.1 mmol),
b
c
and CH2Cl2 (0.5 mL) at 40 °C for 6 h. Total isolated yield. Ratio
was determined by H NMR on the crude reaction mixture. 2a (0.4
mmol) was used.
d
1
C
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Letter
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wide array of quinolines and chloroformates, delivering the target
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03829.
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J. 2017, 23, 5983. (b) Ray Choudhury, A.; Mukherjee, S. Chem. Sci.
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Experimental details (PDF)
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N.; Kang, J. Y. Org. Lett. 2017, 19, 958. (c) Molleti, N.; Bjornberg, C.;
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Spectral data of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: junyong.kang@unlv.edu.
ORCID
Jun Yong Kang: 0000-0002-7178-2981
Author Contributions
‡M.S. and H.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(21) (a) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J.
Am. Chem. Soc. 2007, 129, 13404. (b) Wasa, M.; Liu, R. Y.; Roche, S. P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2014, 136, 12872.
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2005, 2005, 3128.
This work was supported by University of Nevada Las Vegas
(Doctoral Graduate Research Assistant Award). Maciej Kukula
at SCAAC is acknowledged for mass spectra data.
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