Synthesis of Diastereoenriched α-Aminomethyl Enaminones via a Br?nsted Acid-Catalyzed Asymmetric aza-Baylis-Hillman Reaction of Chiral N-Phosphonyl Imines

Article abstract of DOI:10.1002/asia.201901734

An effective chiral GAP methodology for preparing α-aminomethyl enaminones through a (R)-CSA-catalyzed asymmetric aza-Baylis-Hillman reaction is reported. Excellent yields and high diastereoselectivity could be obtained under mild conditions and convenient GAP techniques. The confirmations of the absolute configuration of N-phosphonyl imine and chiral enaminone by X-ray diffraction provides an explicit explanation of the chirality mechanism for GAP chemistry.

Full text of DOI:10.1002/asia.201901734

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Synthesis of Diastereoenriched α-Aminomethyl Enaminones
via A Brønsted Acid-Catalyzed Asymmetric aza-Baylis-Hillman
Reaction of Chiral N-Phosphonyl Imines
Authors: Yangxue Liu, Sultan Ahmed, Xiao-Yan Qin, Hossein Rouh,
Guigen Li, Bo Jiang, and Guanzhao Wu
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10.1002/asia.201901734
Chemistry - An Asian Journal
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Synthesis of Diastereoenriched α-Aminomethyl Enaminones via
A Brønsted Acid-Catalyzed Asymmetric aza-Baylis-Hillman
Reaction of Chiral N-Phosphonyl Imines
Yangxue Liu,[a] Sultan Ahmed,[a] Xiao-Yan Qin,[c] Hossein Rouh,[a] Guanzhao Wu,[a,b] Guigen Li,*[a,b] Bo
Jiang*[c]
Dedication ((optional))
Abstract: An effective chiral GAP methodology for preparing α-
aminomethyl enaminones through a (R)-CSA-catalyzed asymmetric
aza-Baylis-Hillman reaction is reported. Excellent yields and high
diastereoselectivity could be obtained under mild conditions and
convenient GAP techniques. The confirmations of the absolute
configuration of N-phosphonyl imine and chiral enaminone by X-ray
diffraction provides an explicit explanation of the chirality mechanism
for GAP chemistry.
Figure 1. Biologically Active Enaminones.
Introduction
still highly desirable for their application in pharmaceutical
Enaminone framework widely exists in biologically active
chemistry.
substances (Figure 1) such as the anticonvulsant (type I),[1a]
Over the past several years, our efforts have made great
natural products such as the glucose-lowering (-)-multiflorine
(type II),[1b] and synthetic pharmaceutical agents such as the
progress on the design of chiral N-phosphonyl auxiliaries and
used their derived imines to develop many effective methods for
antibacterial ciprofloxacin (type III).[1c] They are also served as
the synthesis of chiral functional molecules including amides,
highly important synthons for the synthesis of heterocycles[2] and
amino acids, α-amino esters and peptides.[9] It was interesting to
note that these auxiliaries could simplify the purification progress
because the products would often be obtained simply by
washing the crude mixture with common solvents without
traditional chromatography or recrystallization, which was
defined as group-assisted purification (GAP) chemistry.[10] To
continue this project, we found that the catalytic asymmetric aza-
Baylis-Hillman reaction[11-13] of chiral N-phosphonyl imines with
pharmaceutical
compounds[3]
(anticonvulsants,[3a]
antibacterials[3b]). Besides, they also behaved as ligands for
transition metal-catalyzed transformations.[4] With these
significant contributions, the development of efficient pathways
for the synthesis of functionalized enaminones and their
derivatives from readily available starting materials has attracted
considerable attention.[5] Although enaminones could be
synthesized through traditional condensation reactions of 1,3-
dicarbonyl compounds with amines,[6] the enantioselectivity of
the chiral derivates was difficult to control.[7] Recently, Shi and
co-workers reported the enantioselective synthesis of
enaminone-containing 3-amino-2-oxindoles via
a
chiral
phosphoric acid-catalyzed asymmetric addition of enaminones
to isatin-derived N-Boc ketimines. However, the demand for
strong electron-deficient ketimines limited its application.[8]
Therefore, the continuous exploration of enantioselective
synthesis of functionalized enaminones under mild conditions is
Scheme 1. Asymmetric GAP Reaction of N-phosphonyl Imine.
[a]
Y. Liu, S. Ahmed, H. Rouh, Prof. Dr. G. Li
Department of Chemistry and Biochemistry, Texas Tech University,
Lubbock, Texas 79409-1061, USA. E-mail: guigen.li@ttu.edu
Prof. Dr. G. Li
[b]
Institute of Chemistry and BioMedical Sciences, School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing, 210093, China
E-mail: guigen.li@ttu.edu
[c]
X.-Y. Qin, Prof. Dr B. Jiang
School of Chemistry and Materials Science, Jiangsu Normal University,
Xuzhou, 221116, P. R. China
E-mail: jiangchem@jsnu.edu.cn Fax: +8651683500065; Tel:
+8651683500065
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
Scheme 2. New one pot strategy of GAP Phosphonylamide
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10.1002/asia.201901734
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cyclic enaminones in the presence of (1R)-(-)-10-
camphorsulfonic acid (CSA) as a Brønsted acid catalyst worked
and cyclic enaminone (p-methoxyphenyl = PMP) 2a to search
the optimal conditions (Table 1). The reaction did not almost
proceed in the presence of 4 Å molecular sieves (MS) in
dichloromethane (DCM) at room temperature without any
catalyst (entry 1). The presence of racemic 1,1′-binaphthyl-2,2′-
diyl hydrogen phosphate (BiNPO4H) could drive the conversion
into product 3a in 98% yield, but with poor diastereoselectivity
(73:27 dr, entry 2). The following examination on solvents
revealed that the use of either toluene, ethyl acetate (EA),
tetrahydrofuran (THF), MeOH, or N,N-dimethylformamide (DMF)
as the reaction media led to lower yields and
diastereoselectivities than that in DCM (entries 3-7 vs. entry 2),
whereas the reaction in 1,4-dioxane or MeCN delivered higher
diastereoselectivity but lower yields as compared with DCM
(entries 8-9). In view of these results, we employed DCM as the
solvent and varied Lewis acid catalysts. Exchanging BiNPO4H
(10 mol %) for PhCO2H or HOAc gave a slightly high
diastereoselectivity but with a remarkably reduced yield (entries
10-11). p-Nitrobenzoic acid was beneficial for this transformation,
furnishing 95% yield and 85:15 dr (entry 12). To our delight, an
employment of the use of (1R)-(-)-10-camphorsulfonic acid
(CSA) as a Brønsted acid catalyst gave 91% conversion and
>99:1 dr analyzed by 31P-NMR. After simply washing by hexane,
the pure product 3a could be obtained in 87% yield and >99:1 dr
(entry 13). When both TsOH and H3PO4 was used Brønsted acid
catalysts, the reaction did not provide the desired product 3a as
both acids could decompose N-phosphonyl imine 1a (entries 14-
15).
smoothly, affording
a
wide range of functionalized α-
aminomethyl enaminones in high yields (up to 94% yield) and
diastereoselectivity (up to >99:1 dr) (Scheme 1). Compared with
our previous strong base-promoted transformations, this
reaction could be well-tolerated with Brønsted acid catalytic
system, making the reaction condition milder. The synthesis also
followed the GAP chemistry/technology, in which the pure α-
aminomethyl enaminones were obtained by washing the crude
products with hexane solvent. In the meanwhile, we optimized
the procedure of synthesizing GAP amine to avoid the employ of
NaN3, which replaced phosphoryl chloride with phosphoryl
bromide followed by ammonia (Scheme 2). The overall yield of
phosphamide reached up to 95% with this strategy.
Results and Discussion
In the initial experiments, we investigated an asymmetric aza-
Baylis-Hillman reaction between chiral N-phosphonyl imine 1a
Table 1. Optimization of the Reaction Conditions.
With the optimized reaction conditions established, we then
sought to study the generality of this aza-Baylis-Hillman reaction
by examining a variety of chiral N-phosphonyl imines 1 and
cyclic enaminones. As shown in Scheme 3, cyclic enaminone 2a
was first chosen to probe the influence of the position and
electronic properties of the substituents in the phenyl of imines 1.
Various substituents did not hamper the reaction process,
delivering the corresponding α-aminomethyl enaminones 3b–3m
with 80-94% yields and 78:22 to >99:1 dr. Both electron-
donating (methyl 1b-1c and methoxy 1d, 1e) and electron-
withdrawing (chloro 1f, bromo 1g–1i, trifluoromethyl 1j, nitro 1k–
1l, and cyano 1m) groups residing in different positions of the
phenyl ring could tolerate this catalytic system well. Of these
groups, the sterically crowded o-methyl-, o-bromo-, and o-
nitrophenyl counterparts could completely orient the
diastereoselectivity to generate the corresponding products with
good yields. Alternatively, 2-naphthyl analogue 1n still showed
highly reactivity, furnishing the desired products 3n in 79% yield
and 84:16 dr. Notably, substrate 1o having a 3-furanyl group
was also proven to be suitable, providing product 3o with 73%
yield and >99:1 dr. Without methoxy group on the N-phenyl ring,
cyclic enaminone 2b led to a slightly decreased yield (70%) of
3p but retained excellent diastereoselectivity (>99:1 dr). When
two bulky isopropyl groups were installed into C2 and C6
positions of the N-phenyl ring, respectively, the reaction seemed
reluctant to undergo this catalytic process, as product 3q was
Entry
1
Catalyst (mol %)
-
Solvent[a]
DCM
yield[b] (%)
dr[c]
trace
-
2
BiNPO4H (10)
BiNPO4H (10)
BiNPO4H (10)
BiNPO4H (10)
BiNPO4H (10)
BiNPO4H (10)
BiNPO4H (10)
BiNPO4H (10)
PhCO2H
DCM
98
73:27
60:40
65:35
71:29
-
3
toluene
EA
80
4
80
5
THF
95
6
MeOH
DMF
trace
7
26
50:50
76:24
81:19
79:21
75:25
85:15
>99:1
-
8
1,4-Dioxane
MeCN
DCM
75
9
57
10
11
12
13
14
15
78
AcOH
DCM
50
p-Nitrobenzoic acid
(R)-CSA
DCM
95
DCM
91(87[d])
decomposed
decomposed
TsOH
DCM
H3PO4
DCM
-
[a] Reactions were performed on a 0.2 mmol scale in 3 mL solvent at 23 oC
with 4 Å activated molecular sieves (20 mg) for 16 h unless otherwise
mentioned. [b] The conversions were determined by 31P-NMR, in which the
reactions were not accomplished. [c] Based on analysis of 1H and 31P-NMR. [d]
Yield after GAP purification.
generated in
a
low yield of 58%, alone with poor
diastereoselectivity. 1,3-Cyclohexanedione-derived enaminone
2d was successfully engaged in this metal-free aza-Baylis-
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Figure 2. X-ray structures of 3a (CCDC number: 1970050).
Scheme 4. Proposed Mechanism of the Asymmetric aza-Baylis-Hillman
Reaction.
Conclusion
In summary, we have developed an effective chiral GAP
methodology for preparing α-aminomethyl enaminones through
a (R)-CSA-catalyzed asymmetric aza-Baylis-Hillman reaction.
Excellent yields and high diastereoselectivity could be obtained
under mild conditions and convenient GAP techniques. The
confirmation of the absolute configuration of N-phosphonyl imine
and chiral enaminone by X-ray diffraction provides an explicit
explanation of the chirality mechanism for GAP chemistry.
[a] Reactions were performed with imine (0.2 mmol, 1 equiv), enaminone (1.2
equiv), (R)-CSA (10 mol %) in 3 mL DCM at r.t. with 4 Å activated molecular
sieves (20mg) for 16 h. [b] Total yield of the isomers. [c] Based on analysis of
1H and 31P-NMR of reaction mixture.
Scheme 3. Substrate Scope of the Asymmetric aza-Baylis-Hillman Reactiona).
Hillman reaction, rendering a highly diastereoselective protocol
toward the expected α-aminomethyl enaminone 3r in 83% yield
and >99:1 dr. As expected, achiral imine reacted with 2a just
afforded 81:19 dr (3s), which proved GAP chiral auxiliary is
indispensable in this asymmetric aza-Baylis-Hillman Reaction.
The structures of these products were identified by their NMR
and HRMS spectra. In the case of 3a, the stereo-structure was
unequivocally determined by X-ray analysis (See Supporting
Information).[14]
Based on the X-ray configurations of compounds 1a & 3a, as
well as the previous literatures, a reasonable mechanism is
proposed in Scheme 4. As the configuration of imine is fixed by
the groups (iPr) on the N-atoms which are controlled by the top
chiral group, the (R)-CSA forms H-bonding with imines from the
less hindered direction. Then nucleophilic attack of enaminones
2 to imines 1 yields the intermediate Int which followed by
tautomerization to generate the final products 3.
Experimental Section
Synthetic Procedures.
One pot synthesis of chiral/achiral phosphoryl bromide
intermediate and N-Phosphonylamide. Dissolve diamine (1.1g, 5.55
mmol) into 50 mL anhydrate DCM, followed by Et3N (1.68g, 16.64 mmol)
dropwise in ice bath. POBr3 (2.23g, 7.76 mmol) was added portion wise
with stirring at 0 oC and stirred the solution mixture at r.t. for overnight.
After reaction completed, cooled reaction mixture to -78 oC, ammonia gas
condensed directly into reaction. Monitored crude reaction solution by 31P
NMR. After reaction completed, concentrated reaction mixture and
extracted with water/ DCM. Collected organic layer and dried with MgSO4.
Pure product was obtained as a pale solid. 1H and 31P NMR data of N-
Phosphonylamide obtained were consistent with the literature data.
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24.47, 24.33, 23.77, 23.70, 22.69, 22.64, 21.14, 19.89, 19.84. 31P NMR
(3aR,7aR)-2-bromo-1,3-
(162 MHz, CHLOROFORM-D)
δ = 27.45. HRMS (ESI- TOF) m/z
diisopropyloctahydrobenzo[d][1,3,2]diazaphosphole 2-oxide: light yellow
oil, 440mg, 99% yield, [α]D25 = -33.9 (c = 1.0, CHCl3). 1H NMR (400 MHz,
CHLOROFORM-D) δ 3.63 – 3.36 (m, 2H), 3.02 (td, J = 10.3, 3.0 Hz, 1H),
2.87 – 2.67 (m, 1H), 2.05 – 1.87 (m, 2H), 1.71 (t, J = 16.5 Hz, 2H), 1.29
(d, J = 6.9 Hz, 3H), 1.26 (d, J = 6.9 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.10
(d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CHLOROFORM-D) δ = 61.14,
61.04, 58.60, 58.49, 45.51, 45.47, 45.25, 45.21, 29.84, 29.70, 29.62,
24.23, 24.22, 24.07, 24.05, 21.90, 21.87, 21.73, 21.66, 20.28, 20.26,
[C35H51N4O3P + H] + calcd for 607.3777, found 607.3771.
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(o-tolyl)methyl)-
3-((4-methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one (3c): white
solid, 289 mg, 84% yield; mp 156-157 oC; [α]D25 = -315.9 (c = 1.5, CHCl3).
1H NMR (400 MHz, CHLOROFORM-D) δ 9.03 (s, 1H), 7.16 (d, J = 6.1
Hz, 1H), 6.73 (t, J = 5.7 Hz, 1H), 6.61 (dd, J = 12.2, 6.0 Hz, 4H), 6.47 (d,
J = 6.8 Hz, 2H), 5.36 (t, J = 9.0 Hz, 1H), 4.19 (dd, J = 18.0, 8.8 Hz, 1H),
4.02 (s, 3H), 3.71 (dt, J = 16.7, 5.5 Hz, 1H), 3.53 (ddd, J = 16.2, 10.7, 5.3
Hz, 1H), 3.37 (t, J = 6.9 Hz, 1H), 3.20 (t, J = 6.7 Hz, 1H), 3.09 (d, J = 13.4
Hz, 1H), 2.78 (s, 3H), 2.68 – 2.56 (m, 4H), 2.51 (d, J = 12.9 Hz, 1H), 2.39
(s, 2H), 2.03 (d, J = 5.2 Hz, 6H), 1.89 (d, J = 5.3 Hz, 3H), 1.85 (d, J = 5.4
Hz, 3H), 1.82 (d, J = 5.2 Hz, 3H), 1.73 (d, J = 10.5 Hz, 6H). 13C NMR
(101 MHz, CHLOROFORM-D) δ = 195.03, 158.12, 156.93, 141.29,
141.21, 134.38, 133.13, 129.65, 127.86, 125.80, 125.56, 124.60, 114.42,
114.05, 59.73, 58.79, 55.57, 50.93, 50.43, 44.11, 40.23, 34.74, 32.17,
31.25, 30.46, 28.59, 28.25, 25.35, 24.46, 24.30, 23.58, 22.00, 19.95,
19.66, 19.42. 31P NMR (162 MHz, CHLOROFORM-D) δ = 27.33. HRMS
(ESI- TOF) m/z [C35H51N4O3P + H] + calcd for 607.3777, found 607.3771.
18.95, 18.93. 31P NMR (162 MHz, CHLOROFORM-D) δ = 15.18. HRMS
+
(ESI- TOF) m/z [C12H24BrN2OP + H]
calcd for 323.0888, found
323.0864.
General Synthesis of N-Phosphonyl Imine with the GAP Technique.
In a 100 mL oven-dried flask, phosphonylamide (1.0g, 3.86mmol) was
dissolved in 5.0 mL of toluene under an argon atmosphere. Then
aldehyde (1.1 equiv, 4.246 mmol) and Ti(OiPr)4 (1.0 equiv, 1.2 mL, 3.86
mmol) were added subsequently. The solution mixture was stirred at 90
oC for 12h. The reaction was monitored by 31P NMR of the crude reaction
mixture. After reaction completed, the clear solution was concentrated by
vacuum; then, 50 mL of dry hexane was added, and the resulting solution
was stirred for 2h until precipitate formed (GAP). After filtration and
washes with dry hexane, N-Phosphonyl imine was isolated as a pale
yellow solid.
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(4-
methoxyphenyl)methyl)-3-((4-methoxyphenyl)amino)-5,5-
dimethylcyclohex-2-en-1-one (3d): white solid, 342 mg, 82% yield; mp
25
111-112 oC; [α]D = -268.6 (c = 1.0, CHCl3). 1H NMR (400 MHz,
CHLOROFORM-D) δ 9.74 (d, J = 44.9 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1H),
7.03 (t, J = 9.0 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H),
5.54 (dd, J = 25.5, 14.6 Hz, 1H), 3.80 (d, J = 6.7 Hz, 2H), 3.75 (s, 2H),
3.35 (qt, J = 13.4, 6.8 Hz, 1H), 3.05 – 2.90 (m, 1H), 2.78 (t, J = 9.6 Hz,
1H), 2.65 (d, J = 16.9 Hz, 1H), 2.21 – 1.82 (m, 3H), 1.73 (t, J = 11.5 Hz,
1H), 1.66 (s, 1H), 1.31 (d, J = 7.8 Hz, 1H), 1.26 (d, J = 6.9 Hz, 2H), 1.21
(d, J = 6.8 Hz, 2H), 1.14 (d, J = 6.7 Hz, 2H), 1.08 (d, J = 6.9 Hz, 2H), 1.03
(s, 2H), 0.92 (d, J = 13.2 Hz, 1H). 13C NMR (101 MHz, CHLOROFORM-D)
δ = 194.97, 158.14, 157.37, 156.81, 132.87, 126.77, 125.62, 116.15,
114.25, 112.81, 59.73, 59.63, 58.74, 58.65, 55.42, 55.03, 51.47, 50.78,
43.93, 43.89, 40.06, 31.99, 31.20, 30.49, 28.83, 27.78, 24.32, 24.18,
23.59, 23.53, 22.45, 22.41, 19.75, 19.70. 31P NMR (162 MHz,
CHLOROFORM-D) δ = 27.42. HRMS (ESI- TOF) m/z [C35H51N4O4P + H]
+ calcd for 623.3726, found 623.3721.
General Procedure for the Synthesis of Products. Dissolved N-
Phosphonyl imine (0.5 mmol, 1 equiv) and cyclic enaminone (1.2 equiv)
with freshly distilled DCM (5 mL) in a 10 mL oven-dried flask. At room
temperature, 4 Å activated molecular sieves (50 mg) was added to the
solution and stirred for 30 min, followed by adding (1R)-(-)-10-
Camphorsulfonic acid (0.1 equiv). Completion of the starting material was
monitored by both thin layer chromatography and 31P NMR of the
reaction mixture (reaction could be completed in 24h). The solvent was
evaporated under vacuum after the filtration of 4 Å activated molecular
sieves with celite; concentrate was transferred to silica column for
chromatography and eluted by mixed solvents of hexane/ ethyl acetate
(v/v, 5:1) to give pure product.
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(4-methoxy-2-
methylphenyl)methyl)-3-((4-methoxyphenyl)amino)-5,5-dimethylcyclohex-
2-en-1-one (3e): white solid, 260 mg, 89% yield; mp 112-113 oC; [α]D
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(phenyl)methyl)-
3-((4-methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one (3a): white
solid, 220 mg, 87% yield; mp 85-86 oC; [α]D = -215.7 (c = 1.0, CHCl3).
25
25
=
1H NMR (400 MHz, CHLOROFORM-D) δ 9.74 (s, 1H), 7.28 – 7.24 (m,
2H), 7.05 (dt, J = 4.8, 2.8 Hz, 4H), 6.87 – 6.82 (m, 2H), 5.54 (t, J = 10.8
Hz, 1H), 3.79 (s, 3H), 3.43 – 3.29 (m, 2H), 3.01 – 2.92 (m, 1H), 2.79 (dd,
J = 13.3, 6.0 Hz, 1H), 2.67 (d, J = 16.8 Hz, 1H), 2.27 (s, 3H), 2.01 (ddd, J
= 34.9, 30.0, 16.4 Hz, 6H), 1.75 (d, J = 6.7 Hz, 2H), 1.32 (d, J = 7.9 Hz,
2H), 1.27 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.7 Hz,
3H), 1.08 (d, J = 6.9 Hz, 3H), 1.04 (s, 3H), 0.93 (s, 3H). 13C NMR (101
MHz, CHLOROFORM-D) δ = 195.07, 158.34, 156.93, 141.43, 141.34,
134.87, 133.06, 128.33, 125.77, 125.73, 116.45, 114.39, 59.89, 58.88,
55.59, 51.86, 50.89, 43.99, 40.20, 32.11, 31.39, 30.68, 29.04, 27.88,
24.46, 23.79, 23.72, 22.68, 22.64, 21.14, 19.83. 31P NMR (162 MHz,
CHLOROFORM-D) δ = 27.53. HRMS (ESI- TOF) m/z [C34H49N4O3P + H]
+ calcd for 593.3621, found 593.3606.
-409.8 (c = 1.2, CHCl3). 1H NMR (400 MHz, CHLOROFORM-D) δ 10.00
(s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.03 (dd, J = 7.0, 5.1 Hz, 2H), 6.87 –
6.82 (m, 2H), 6.72 (dd, J = 8.6, 2.7 Hz, 1H), 6.57 (t, J = 7.9 Hz, 1H), 5.40
(t, J = 11.5 Hz, 1H), 3.97 (dd, J = 14.0, 9.4 Hz, 1H), 3.79 (s, 3H), 3.74 (s,
3H), 3.43 – 3.32 (m, 1H), 3.24 – 3.11 (m, 1H), 2.99 – 2.90 (m, 1H), 2.75
(dd, J = 13.6, 6.0 Hz, 1H), 2.61 (d, J = 16.8 Hz, 1H), 2.20 (s, 3H), 2.11 –
2.04 (m, 1H), 1.99 (d, J = 16.6 Hz, 3H), 1.89 (d, J = 16.2 Hz, 1H), 1.72 (d,
J = 11.3 Hz, 2H), 1.32 – 1.24 (m, 6H), 1.11 (d, J = 6.8 Hz, 3H), 1.07 (d, J
= 6.9 Hz, 3H), 1.02 (s, 2H), 0.94 (t, J = 3.2 Hz, 3H), 0.90 (s, 3H). 13
C
NMR (101 MHz, CHLOROFORM-D) δ = 195.23, 157.92, 157.39, 156.90,
135.64, 133.69, 133.15, 128.91, 125.55, 115.17, 114.42, 114.34, 109.66,
59.82, 58.78, 55.59, 55.05, 50.97, 49.94, 44.11, 40.21, 34.73, 32.18,
31.21, 30.42, 28.60, 28.21, 26.98, 25.35, 24.31, 23.60, 21.97, 19.94,
19.69, 19.58. 31P NMR (162 MHz, CHLOROFORM-D) δ = 27.34. HRMS
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
+
(ESI- TOF) m/z [C36H53BrN4O4P + H]
calcd for 637.3882, found
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(p-tolyl)methyl)-
3-((4-methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one (3b): white
solid, 320 mg, 87% yield; mp 108-110 oC; [α]D25 = -332.8 (c = 1.0, CHCl3).
1H NMR (400 MHz, CHLOROFORM-D) δ 9.71 (s, 1H), 7.30 – 7.23 (m,
2H), 7.10 – 7.01 (m, 4H), 6.84 (d, J = 8.8 Hz, 2H), 5.66 – 5.42 (m, 1H),
3.79 (s, 3H), 3.36 (dtt, J = 20.6, 13.6, 6.8 Hz, 2H), 3.01 – 2.92 (m, 1H),
2.79 (dd, J = 13.0, 5.9 Hz, 1H), 2.66 (d, J = 16.8 Hz, 1H), 2.27 (s, 3H),
2.15 – 1.91 (m, 6H), 1.74 (d, J = 6.8 Hz, 2H), 1.31 (d, J = 7.9 Hz, 2H),
1.27 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H),
1.08 (d, J = 6.8 Hz, 3H), 1.03 (s, 3H), 0.94 (d, J = 8.0 Hz, 3H). 13C NMR
(101 MHz, CHLOROFORM-D) δ = 195.10, 158.38, 156.95, 141.35,
134.88, 133.02, 128.34, 125.73, 116.38, 114.39, 59.78, 58.88, 55.59,
51.85, 50.89, 44.11, 44.03, 40.21, 32.12, 31.37, 30.69, 29.02, 27.89,
637.3877.
2-((R)-(3-chlorophenyl)(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)methyl)-3-((4-
methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one (3f): light yellow
solid, 310 mg, 94% yield; mp 114-115 oC; [α]D25 = -219.8 (c = 1.3, CHCl3).
1H NMR (400 MHz, CHLOROFORM-D) δ 9.82 (s, 1H), 7.42 (s, 1H), 7.23
(d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.10 – 7.02 (m, 3H), 6.88 –
6.81 (m, 2H), 5.60 (t, J = 10.9 Hz, 1H), 5.52 (t, J = 10.9 Hz, 1H), 3.78 (s,
3H), 3.46 – 3.30 (m, 2H), 3.00 – 2.92 (m, 1H), 2.80 (t, J = 8.2 Hz, 1H),
2.60 (dd, J = 60.5, 16.9 Hz, 1H), 2.15 – 1.91 (m, 5H), 1.79 – 1.69 (m, 2H),
1.34 – 1.30 (m, 2H), 1.28 – 1.21 (m, 7H), 1.19 – 1.14 (m, 4H), 1.08 (d, J
= 6.8 Hz, 2H), 1.05 (d, J = 4.5 Hz, 3H), 0.94 (dd, J = 6.1, 2.1 Hz, 3H). 13
C
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NMR (101 MHz, CHLOROFORM-D) δ = 194.92, 159.04, 157.07, 133.63,
132.76, 128.79, 126.13, 125.81, 124.01, 115.50, 114.44, 114.42, 59.78,
58.92, 55.58, 51.86, 50.77, 44.15, 44.05, 40.26, 32.34, 32.22, 31.28,
30.77, 28.89, 28.04, 24.45, 24.31, 23.83, 22.91, 19.92, 19.84. 31P NMR
(162 MHz, CHLOROFORM-D) δ = 27.47, 25.88. HRMS (ESI- TOF) m/z
[C34H48ClN4O3P + H] + calcd for 627.3231, found 627.3225.
5H), 1.75 (d, J = 6.0 Hz, 2H), 1.32 (d, J = 7.3 Hz, 2H), 1.28 (d, J = 6.8 Hz,
3H), 1.22 (d, J = 6.9 Hz, 3H), 1.20 – 1.13 (m, 5H), 1.09 (d, J = 6.8 Hz,
2H), 1.03 (d, J = 4.1 Hz, 3H), 0.95 (d, J = 5.7 Hz, 3H). 13C NMR (101
MHz, CHLOROFORM-D) δ = 194.91, 159.22, 157.17, 132.67, 127.62,
127.06, 126.14, 125.91, 125.90, 125.76, 124.53, 115.49, 114.46, 59.81,
58.84, 55.58, 52.16, 50.71, 44.11, 44.03, 40.25, 32.27, 32.12, 31.26,
30.64, 29.00, 27.85, 24.44, 24.29, 23.83, 22.64, 19.93, 19.83. 31P NMR
(162 MHz, CHLOROFORM-D) δ = 27.47, 25.82. HRMS (ESI- TOF) m/z
[C35H48F3N4O3P + H] + calcd for 661.3494, found 661.3475.
2-((R)-(4-bromophenyl)(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)methyl)-3-((4-
methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one
(3g):
pale
25
yellow solid, 330 mg, 87% yield; mp 119-120 oC; [α]D = -219.2 (c = 1.2,
CHCl3). 1H NMR (400 MHz, CHLOROFORM-D) δ 9.78 (s, 1H), 7.33 (d, J
= 8.5 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.02 (dd, J = 8.8, 5.5 Hz, 2H),
6.84 (d, J = 8.8 Hz, 2H), 5.58 (t, J = 10.9 Hz, 1H), 5.49 (t, J = 10.9 Hz,
1H), 3.77 (s, 3H), 3.43 – 3.24 (m, 2H), 2.95 (dd, J = 14.5, 5.7 Hz, 1H),
2.76 (t, J = 7.9 Hz, 1H), 2.59 (t, J = 31.1 Hz, 1H), 2.11 – 1.90 (m, 5H),
1.72 (t, J = 9.5 Hz, 2H), 1.35 – 1.28 (m, 3H), 1.25 (d, J = 6.8 Hz, 3H),
1.19 (d, J = 6.9 Hz, 3H), 1.13 (dd, J = 6.7, 3.2 Hz, 3H), 1.07 (d, J = 6.8
Hz, 3H), 1.00 (d, J = 6.1 Hz, 3H), 0.95 – 0.90 (m, 3H). 13C NMR (101
MHz, CHLOROFORM-D) δ = 194.98, 158.90, 157.64, 157.10, 143.74,
132.74, 130.72, 130.55, 127.78, 127.40, 127.05, 125.87, 119.39, 115.55,
114.42, 59.78, 58.82, 55.60, 55.57, 55.56, 44.06, 40.24, 34.73, 32.14,
31.30, 30.61, 28.93, 27.91, 25.35, 24.44, 24.29, 23.66, 22.58, 19.93,
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(4-
nitrophenyl)methyl)-3-((4-methoxyphenyl)amino)-5,5-dimethylcyclohex-2-
en-1-one (3k): yellow solid, 270 mg, 80% yield; mp 107-108 oC; [α]D = -
25
148.3 (c = 0.7, CHCl3). 1H NMR (400 MHz, CHLOROFORM-D) δ 9.98 (s,
1H), 8.16 – 8.06 (m, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.12 – 7.00 (m, 2H),
6.91 – 6.83 (m, 2H), 5.61 (t, J = 10.9 Hz, 1H), 3.80 (s, 3H), 3.45 – 3.26
(m, 2H), 3.02 – 2.93 (m, 1H), 2.81 (dd, J = 13.3, 6.0 Hz, 1H), 2.69 (d, J =
17.0 Hz, 1H), 2.06 (dd, J = 16.6, 6.9 Hz, 4H), 1.95 (d, J = 16.4 Hz, 1H),
1.82 – 1.74 (m, 2H), 1.33 (dd, J = 8.8, 4.2 Hz, 2H), 1.29 (d, J = 6.9 Hz,
3H), 1.23 (d, J = 6.9 Hz, 4H), 1.16 (d, J = 6.7 Hz, 3H), 1.10 (d, J = 6.9 Hz,
3H), 1.04 (s, 3H), 0.96
–
0.93 (m, 3H). 13C NMR (101 MHz,
CHLOROFORM-D) δ = 194.79, 159.62, 157.29, 152.83, 146.08, 132.46,
126.63, 125.88, 122.97, 115.06, 114.51, 59.85, 58.98, 55.59, 52.39,
50.61, 44.12, 40.29, 32.18, 31.65, 31.25, 30.49, 28.88, 27.92, 24.41,
24.28, 23.84, 22.66, 20.00, 19.86, 14.19. 31P NMR (162 MHz,
CHLOROFORM-D) δ = 27.39. HRMS (ESI- TOF) m/z [C35H48N5O5P + H]
+ calcd for 638.3471, found 638.3466.
19.86. 31P NMR (162 MHz, CHLOROFORM-D) δ = 27.32, 25.71. HRMS
+
(ESI- TOF) m/z [C34H48BrN4O3P + H]
calcd for 671.2725, found
671.2720.
2-((S)-(2-bromophenyl)(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)methyl)-3-((4-
methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one
(3h):
light
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
yellow solid, 305 mg, 92% yield; mp 95-96 oC; [α]D = -261.4 (c = 1.1,
CHCl3). 1H NMR (400 MHz, CHLOROFORM-D) δ 10.07 (s, 1H), 7.83 (dd,
J = 7.9, 1.1 Hz, 1H), 7.40 (dd, J = 7.9, 1.0 Hz, 1H), 7.29 – 7.24 (m, 1H),
7.09 – 7.04 (m, 2H), 6.99 (td, J = 7.8, 1.4 Hz, 1H), 6.86 – 6.82 (m, 2H),
5.49 (t, J = 11.5 Hz, 1H), 4.02 (t, J = 11.4 Hz, 1H), 3.78 (s, 3H), 3.46 –
3.33 (m, 1H), 3.23 – 3.10 (m, 1H), 2.99 – 2.90 (m, 1H), 2.74 (dd, J = 13.6,
6.1 Hz, 1H), 2.63 (d, J = 16.7 Hz, 1H), 2.16 – 1.85 (m, 6H), 1.72 (d, J =
11.0 Hz, 2H), 1.29 (d, J = 6.8 Hz, 4H), 1.12 (d, J = 6.8 Hz, 3H), 1.05 (d, J
= 6.9 Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.97 (s, 3H), 0.93 (t, J = 5.5 Hz,
1H), 0.90 (s, 3H). 13C NMR (101 MHz, CHLOROFORM-D) δ = 194.87,
159.93, 157.06, 142.44, 132.93, 132.16, 130.48, 127.50, 125.88, 125.85,
122.58, 114.39, 112.64, 59.82, 58.98, 55.58, 52.96, 50.83, 44.23, 44.05,
40.20, 34.74, 32.08, 31.09, 30.37, 28.82, 28.05, 26.98, 25.35, 24.44,
24.30, 23.45, 21.97, 19.98, 19.73. 31P NMR (162 MHz, CHLOROFORM-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(2-
nitrophenyl)methyl)-3-((4-methoxyphenyl)amino)-5,5-dimethylcyclohex-2-
en-1-one (3l): brown solid, 213 mg, 82% yield; mp 114-115 oC; [α]D = -
25
25
532.4 (c = 1.4, CHCl3). 1H NMR (400 MHz, CHLOROFORM-D) δ 10.18 (s,
1H), 7.98 (d, J = 7.9 Hz, 1H), 7.57 (dd, J = 8.0, 1.1 Hz, 1H), 7.53 – 7.47
(m, 1H), 7.25 (dd, J = 8.8, 5.8 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.86 (dd,
J = 7.0, 5.0 Hz, 2H), 6.07 (t, J = 11.2 Hz, 1H), 3.78 (s, 3H), 3.46 – 3.26
(m, 2H), 3.03 – 2.94 (m, 1H), 2.79 (t, J = 8.1 Hz, 1H), 2.51 (d, J = 16.3 Hz,
1H), 2.08 – 1.96 (m, 5H), 1.84 (d, J = 16.1 Hz, 1H), 1.74 (t, J = 9.8 Hz,
2H), 1.32 (d, J = 6.6 Hz, 2H), 1.28 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.9 Hz,
4H), 1.13 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 0.91 (s, 3H), 0.85
(d, J = 3.1 Hz, 3H). 13C NMR (101 MHz, CHLOROFORM-D) δ = 194.63,
160.80, 157.36, 148.28, 139.13, 132.50, 130.95, 129.17, 126.70, 126.31,
123.91, 114.38, 113.06, 59.98, 58.98, 55.57, 50.56, 49.28, 44.08, 40.14,
34.73, 32.43, 31.66, 31.40, 30.64, 28.95, 27.74, 25.34, 24.44, 23.88,
22.79, 20.02, 19.88. 31P NMR (162 MHz, CHLOROFORM-D) δ = 27.08.
+
D) δ = 26.88. HRMS (ESI- TOF) m/z [C34H48BrN4O3P + H] calcd for
671.2725, found 671.2720.
+
HRMS (ESI- TOF) m/z [C34H48N5O5P + H] calcd for 638.3471, found
2-((R)-(3-bromophenyl)(((3aS,7aS)-1,3-diisopropyl-2-
638.3466.
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)methyl)-3-((4-
methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one (3i): white solid,
4-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
25
120 mg, 90% yield; mp 110-111 oC; [α]D = -219.2 (c = 1.2, CHCl3). 1H
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(2-((4-
methoxyphenyl)amino)-4,4-dimethyl-6-oxocyclohex-1-en-1-
yl)methyl)benzonitrile (3m): pale yellow solid, 355 mg, 91% yield; mp
NMR (400 MHz, CHLOROFORM-D) δ 9.89 (d, J = 40.3 Hz, 1H), 7.59 (s,
1H), 7.29 – 7.22 (m, 2H), 7.13 – 7.04 (m, 3H), 6.88 – 6.83 (m, 2H), 5.56
(dt, J = 33.5, 10.9 Hz, 1H), 3.78 (d, J = 4.9 Hz, 3H), 3.43 – 3.31 (m, 2H),
3.01 – 2.93 (m, 1H), 2.81 (dd, J = 13.2, 6.1 Hz, 1H), 2.69 (d, J = 16.9 Hz,
1H), 2.53 (q, J = 7.2 Hz, 2H), 2.16 – 1.91 (m, 5H), 1.75 (d, J = 6.7 Hz,
2H), 1.32 (d, J = 7.0 Hz, 2H), 1.29 – 1.22 (m, 8H), 1.17 (d, J = 6.7 Hz,
3H), 1.08 (d, J = 6.9 Hz, 3H), 1.06 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H), 0.95
(d, J = 5.8 Hz, 3H). 13C NMR (101 MHz, CHLOROFORM-D) δ = 194.90,
159.03, 157.06, 147.10, 132.78, 129.12, 129.01, 128.69, 126.87, 125.78,
124.46, 122.04, 115.51, 114.43, 59.89, 58.92, 55.59, 51.82, 50.77, 46.31,
44.13, 44.02, 40.25, 32.23, 31.30, 30.79, 29.79, 28.90, 28.03, 24.46,
24.30, 23.78, 22.93, 19.93, 19.84, 11.59. 31P NMR (162 MHz,
CHLOROFORM-D) δ = 27.52. HRMS (ESI- TOF) m/z [C34H48BrN4O3P +
H] + calcd for 671.2725, found 671.2720.
25
128-129 oC; [α]D = -195.3 (c = 1.0, CHCl3). 1H NMR (400 MHz,
CHLOROFORM-D) δ 10.15 – 9.59 (m, 1H), 7.51 (dd, J = 18.7, 8.4 Hz,
2H), 7.26 – 7.21 (m, 1H), 7.02 (t, J = 16.4 Hz, 1H), 6.95 – 6.72 (m, 1H),
5.68 – 5.61 (m, 1H), 5.56 (t, J = 11.1 Hz, 1H), 3.78 (dd, J = 10.1, 6.6 Hz,
2H), 3.45 – 3.21 (m, 1H), 2.97 (t, J = 9.9 Hz, 1H), 2.78 (s, 1H), 2.67 (d, J
= 16.9 Hz, 1H), 2.06 (dd, J = 27.0, 11.4 Hz, 2H), 1.93 (d, J = 16.5 Hz, 1H),
1.75 (s, 1H), 1.66 (s, 1H), 1.32 (d, J = 6.5 Hz, 1H), 1.27 (d, J = 6.8 Hz,
1H), 1.21 (d, J = 6.9 Hz, 2H), 1.14 (d, J = 6.6 Hz, 2H), 1.09 (d, J = 6.8 Hz,
1H), 1.02 (s, 1H), 0.94 (d, J = 5.3 Hz, 2H). 13C NMR (101 MHz,
CHLOROFORM-D) δ = 194.72, 159.56, 157.26, 132.43, 131.36, 119.37,
114.41, 109.27, 59.73, 58.91, 55.49, 53.55, 52.25, 50.60, 44.04, 40.29,
34.67, 34.52, 32.23, 32.09, 31.59, 31.22, 30.58, 29.06, 28.79, 27.87,
25.29, 24.37, 23.65, 22.66, 20.73, 19.92, 19.81, 14.16, 11.46. 31P NMR
(162 MHz, CHLOROFORM-D) δ = 27.40, 25.96. HRMS (ESI- TOF) m/z
[C35H48N5O3P + H] + calcd for 618.3573, found 618.3557.
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(4-
(trifluoromethyl)phenyl)methyl)-3-((4-methoxyphenyl)amino)-5,5-
dimethylcyclohex-2-en-1-one (3j): pale yellow solid, 264 mg, 91% yield;
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
25
mp 121-122 oC; [α]D = -212.2 (c = 1.3, CHCl3). 1H NMR (400 MHz,
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(naphthalen-2-
yl)methyl)-3-((4-methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one
CHLOROFORM-D) δ 9.87 (s, 1H), 7.49 (s, 4H), 7.05 (t, J = 6.9 Hz, 2H),
6.86 (d, J = 8.8 Hz, 2H), 5.68 (t, J = 10.8 Hz, 1H), 5.59 (t, J = 10.7 Hz,
1H), 3.79 (s, 3H), 3.45 – 3.26 (m, 2H), 2.98 (dd, J = 14.3, 5.6 Hz, 1H),
2.79 (d, J = 9.1 Hz, 1H), 2.60 (dd, J = 62.2, 16.9 Hz, 1H), 2.11 – 1.91 (m,
(3n): light yellow solid, 212 mg, 79% yield; mp 123-124 oC; [α]D = -
25
170.1 (c = 0.9, CHCl3). 1H NMR (400 MHz, CHLOROFORM-D) δ 9.81 (s,
1H), 7.94 (s, 1H), 7.80 – 7.68 (m, 3H), 7.45 – 7.34 (m, 3H), 7.08 (t, J =
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Chemistry - An Asian Journal
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9.7 Hz, 2H), 6.89 – 6.84 (m, 2H), 5.82 (t, J = 10.9 Hz, 1H), 5.74 (t, J =
10.9 Hz, 1H), 3.97 (dt, J = 13.6, 11.3 Hz, 1H), 3.80 (s, 3H), 3.49 – 3.31
(m, 2H), 3.04 – 2.95 (m, 1H), 2.86 (dd, J = 13.2, 5.9 Hz, 1H), 2.63 (dd, J
= 64.7, 16.9 Hz, 1H), 2.03 (ddd, J = 37.4, 18.5, 12.4 Hz, 6H), 1.77 (d, J =
7.1 Hz, 2H), 1.34 (d, J = 7.4 Hz, 2H), 1.30 (d, J = 6.9 Hz, 3H), 1.26 (d, J =
6.8 Hz, 3H), 1.16 (d, J = 6.7 Hz, 3H), 1.10 (t, J = 8.6 Hz, 3H), 1.05 (d, J =
3.7 Hz, 3H), 0.97 – 0.94 (m, 3H). 13C NMR (101 MHz, CHLOROFORM-D)
δ = 195.07, 158.74, 157.02, 142.04, 133.29, 132.95, 132.13, 127.93,
127.60, 127.12, 125.84, 125.63, 125.19, 125.00, 123.91, 115.83, 114.43,
59.95, 58.85, 55.61, 52.29, 50.87, 44.11, 40.30, 32.22, 31.26, 30.72,
7.24 (dd, J = 8.7, 6.6 Hz, 2H), 7.15 – 7.04 (m, 3H), 6.86 – 6.81 (m, 2H),
5.54 (t, J = 10.6 Hz, 1H), 3.90 (dd, J = 24.8, 13.9 Hz, 1H), 3.78 (s, 3H),
3.46 – 3.31 (m, 2H), 3.00 – 2.91 (m, 1H), 2.82 (ddd, J = 24.2, 12.2, 7.3
Hz, 2H), 2.25 (dt, J = 16.5, 5.1 Hz, 1H), 2.18 – 1.72 (m, 9H), 1.32 (d, J =
7.7 Hz, 2H), 1.26 (d, J = 6.9 Hz, 6H), 1.17 (d, J = 6.7 Hz, 3H), 1.10 (d, J =
6.8 Hz, 3H). 13C NMR (101 MHz, CHLOROFORM-D) δ = 195.46, 160.63,
157.08, 144.48, 132.97, 127.59, 125.95, 125.79, 125.67, 117.49, 114.35,
59.80, 58.93, 55.59, 52.17, 44.13, 43.93, 37.32, 34.74, 31.67, 31.27,
30.68, 26.96, 24.46, 24.33, 23.57, 22.70, 22.65, 21.31, 19.90, 19.84. 31
P
NMR (162 MHz, CHLOROFORM-D) δ = 27.73. HRMS (ESI- TOF) m/z
28.91, 28.01, 26.99, 25.36, 24.49, 24.36, 23.69, 22.72, 19.97, 19.90. 31
P
[C32H45N4O3P + H] + calcd for 565.3307, found 565.3302.
NMR (162 MHz, CHLOROFORM-D) δ = 27.44, 25.82. HRMS (ESI- TOF)
m/z [C38H51N4O3P + H] + calcd for 643.3776, found 643.3771.
2-((1R)-((1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-
2-yl)amino)(phenyl)methyl)-3-((4-methoxyphenyl)amino)-5,5-
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
dimethylcyclohex-2-en-1-one (3s): light yellow solid, 142 mg, 85% yield;
25
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(furan-3-
yl)methyl)-3-((4-methoxyphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one
(3o): light yellow solid, 177 mg, 73% yield; mp 94-95 oC; [α]D = -317.7
mp 81-83 oC; [α]D = -13.6 (c = 0.9, CHCl3). 1H NMR (400 MHz,
CHLOROFORM-D) δ 9.74 (s, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.27 – 7.22
(m, 3H), 7.12 (t, J = 7.3 Hz, 1H), 7.08 – 7.01 (m, 2H), 6.88 – 6.81 (m, 2H),
5.65 (t, J = 10.8 Hz, 1H), 5.57 (t, J = 10.9 Hz, 1H), 3.80 (d, J = 4.2 Hz,
3H), 3.46 – 3.29 (m, 2H), 3.02 – 2.92 (m, 1H), 2.85 – 2.74 (m, 1H), 2.59
(dd, J = 64.6, 16.8 Hz, 1H), 2.15 – 1.91 (m, 5H), 1.81 – 1.67 (m, 3H),
1.32 (d, J = 8.1 Hz, 2H), 1.27 (d, J = 6.9 Hz, 3H), 1.23 (t, J = 4.2 Hz, 3H),
1.15 (dd, J = 6.7, 2.8 Hz, 3H), 1.08 (d, J = 6.9 Hz, 2H), 1.04 (d, J = 3.8
Hz, 3H), 0.95 (d, J = 5.4 Hz, 3H). 13C NMR (101 MHz, CHLOROFORM-D)
δ = 195.00, 158.49, 156.95, 144.46, 144.36, 133.02, 127.56, 125.87,
125.78, 125.66, 116.30, 114.40, 59.90, 58.79, 55.60, 52.10, 50.86, 44.09,
43.99, 40.21, 32.13, 31.29, 30.58, 29.04, 27.90, 24.46, 24.33, 23.75,
22.71, 22.67, 19.88, 19.84. 31P NMR (162 MHz, CHLOROFORM-D) δ =
25
(c = 0.7, CHCl3). 1H NMR (400 MHz, CHLOROFORM-D) δ 9.59 (s, 1H),
7.34 (s, 1H), 7.26 (dd, J = 5.7, 4.0 Hz, 1H), 7.03 – 6.97 (m, 2H), 6.84 –
6.80 (m, 2H), 6.34 – 6.28 (m, 1H), 5.50 – 5.35 (m, 1H), 3.77 (s, 3H), 3.44
– 3.26 (m, 2H), 2.93 (td, J = 11.0, 3.1 Hz, 1H), 2.73 (dd, J = 13.1, 6.1 Hz,
1H), 2.59 (d, J = 16.9 Hz, 1H), 2.17 (t, J = 11.8 Hz, 1H), 2.03 – 1.96 (m,
4H), 1.71 (t, J = 12.6 Hz, 2H), 1.31 – 1.27 (m, 2H), 1.24 (d, J = 3.4 Hz,
3H), 1.23 (d, J = 3.3 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H), 1.08 – 1.03 (m,
6H), 0.95 – 0.92 (m, 3H). 13C NMR (101 MHz, CHLOROFORM-D) δ =
195.20, 158.51, 157.01, 142.28, 138.77, 132.81, 129.54, 129.44, 125.84,
114.47, 114.37, 110.36, 59.69, 58.71, 55.56, 51.06, 45.90, 44.17, 44.01,
40.27, 32.15, 31.13, 30.54, 28.80, 28.03, 24.43, 24.29, 23.59, 22.35,
19.88, 19.84. 31P NMR (162 MHz, CHLOROFORM-D) δ = 26.77. HRMS
(ESI- TOF) m/z [C32H47N4O4P + H] + calcd for 583.3413, found 583.3408.
+
27.52, 25.96. HRMS (ESI- TOF) m/z [C34H49N4O3P + H] calcd for
593.3621, found 593.3602.
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(phenyl)methyl)-
5,5-dimethyl-3-(phenylamino)cyclohex-2-en-1-one (3p): grey yellow solid,
Acknowledgements
25
230 mg, 70% yield; mp 103-104 oC; [α]D = +67.4 (c = 1.5, CHCl3). 1H
We would like to acknowledge the financial support from the
National Natural Science Foundation of China (No. 21971090,
91956110, 21672100) and Robert A. Welch Foundation (D-1361,
USA).
NMR (400 MHz, CHLOROFORM-D) δ 10.04 (s, 1H), 7.38 (d, J = 7.7 Hz,
2H), 7.30 (t, J = 7.8 Hz, 2H), 7.24 (dd, J = 9.1, 6.1 Hz, 2H), 7.11 (t, J =
6.8 Hz, 3H), 5.72 – 5.49 (m, 1H), 3.85 (t, J = 10.8 Hz, 1H), 3.36 (qt, J =
13.6, 6.8 Hz, 2H), 3.03 – 2.93 (m, 1H), 2.81 (dd, J = 21.8, 14.0 Hz, 2H),
2.12 (dd, J = 16.5, 7.5 Hz, 2H), 1.99 (dd, J = 24.6, 12.5 Hz, 4H), 1.75 (d,
J = 6.5 Hz, 2H), 1.32 (d, J = 7.7 Hz, 2H), 1.26 (d, J = 6.9 Hz, 3H), 1.22 (d,
J = 6.8 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 8.7 Hz, 6H), 0.95 (s,
3H). 13C NMR (101 MHz, CHLOROFORM-D) δ = 195.52, 157.59, 144.10,
140.33, 129.19, 127.57, 125.87, 125.72, 124.03, 123.48, 117.69, 59.91,
59.81, 58.79, 52.18, 51.09, 44.15, 44.05, 40.17, 32.50, 31.28, 30.59,
28.59, 28.22, 24.46, 24.32, 23.75, 22.53, 19.95, 19.82. 31P NMR (162
Keywords: Aza-Baylis-Hillman reaction • GAP chemistry
•
•
Brønsted Acid Catalysis
• α-Aminomethyl enaminones
Asymmetric synthesis
MHz, CHLOROFORM-D)
δ
=
27.50. HRMS (ESI- TOF) m/z
[C33H47N4O2P + H] + calcd for 563.3515, found 563.3509.
References
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(phenyl)methyl)-
3-((2,6-diisopropylphenyl)amino)-5,5-dimethylcyclohex-2-en-1-one (3q):
[1]
a) K. R. Scott, G. O. Rankin, J. P. Stables, M. S. Alexander, I. O.
Edafiogho, V. A. Farrar, K. R. Kolen, J. A. Moore, L. D. Sims, A. D.
Tonnut, J. Med. Chem. 1995, 38, 4033–4043; b) H. Kubo, J. Kobayashi,
K. Higashiyama, J. Kamei, Y. Fujii, S. Ohmiya, Biol. Pharm. Bull. 2000,
23, 1114-1117; c) A. Kaushik, A. Ogbaghebriel, A. Sharma, AAA’s
Quinolones & Fluoroquinolones: Man-made Antibiotics, LAP Lambert,
Düsseldorf, 2011.
25
white solid, 176 mg, 58% yield; mp 85-86 oC; [α]D = -1055 (c = 0.4,
CHCl3). 1H NMR (400 MHz, CHLOROFORM-D) δ 8.50 – 8.02 (m, 1H),
7.51 (dd, J = 12.1, 7.7 Hz, 2H), 7.26 (ddd, J = 9.7, 5.9, 3.6 Hz, 3H), 7.16
(ddd, J = 12.1, 9.0, 5.5 Hz, 3H), 5.74 (t, J = 11.0 Hz, 1H), 5.67 (t, J = 10.8
Hz, 1H), 3.47 – 3.03 (m, 4H), 2.99 – 2.89 (m, 1H), 2.80 (dd, J = 15.8, 6.3
Hz, 1H), 2.45 (s, 1H), 2.02 (dd, J = 27.1, 21.3 Hz, 5H), 1.72 (d, J = 11.0
Hz, 2H), 1.31 – 1.23 (m, 9H), 1.22 – 1.18 (m, 6H), 1.18 – 1.13 (m, 8H),
1.10 (t, J = 6.6 Hz, 6H), 0.95 (d, J = 1.4 Hz, 1H), 0.90 (d, J = 10.2 Hz, 5H).
13C NMR (101 MHz, CHLOROFORM-D) δ = 195.17, 159.85, 147.20,
147.06, 146.61, 144.94, 133.69, 128.63, 128.20, 127.87, 127.71, 126.16,
125.93, 125.89, 123.99, 123.91, 123.55, 123.37, 114.19, 59.69, 59.01,
51.08, 50.83, 44.32, 43.99, 40.36, 34.74, 32.06, 31.57, 30.85, 28.47,
28.15, 25.36, 24.95, 24.87, 24.48, 23.97, 23.38, 22.96, 22.45, 22.32,
20.10, 19.82, 19.71. 31P NMR (162 MHz, CHLOROFORM-D) δ = 25.75,
24.41. HRMS (ESI- TOF) m/z [C39H59BrN4O2P + H] + calcd for 647.4454,
found 647.4448.
[2]
a) L. Wang, L.-X. Shi, L. Liu, Z.-X. Li, T. Xu, W.-J. Hao, G. Li, S.-J. Tu,
B. Jiang, J. Org. Chem. 2017, 82, 3605-3611; b) X.-C. Lan, T.-T. Chen,
Y. Zhao, Y. Wu, J. Wang, S.-J. Tu, B. Jiang, W.-J. Hao, Tetrahedron
Lett. 2017, 58, 1519-1522; c) W. Fan, Y.-R. Li, Q. Li, B. Jiang, G. Li,
Tetrahedron 2016, 72, 4867-4877; d) Z. Yang, W.-J. Hao, H.-W. Xu, S.-
L. Wang, B. Jiang, G. Li, S.-J. Tu, J. Org. Chem. 2015, 80, 2781-2789;
e) Q.-N. Zhu, Y.-C. Zhang, M.-M. Xu, X.-X. Sun, X. Yang, F. Shi, J. Org.
Chem. 2016, 81, 7898-7907; f) R. Yan, X. Li, X. Yang, X. Kang, L.
Xiang, G. Huang, Chem. Commun. 2015, 51, 2573-2576; g) J.-P. Wan,
S. Cao, Y. Liu, Org. Lett. 2016, 18, 6034-6037; h) F. Wang, L. Jin, L.
Kong, X. Li, Org. Lett. 2017, 19, 1812-1815; i) D. M. Patel, H. M. Patel,
ACS Sustain. Chem. Eng. 2019, 7, 18667-18676; j) D. M. Patel, M. G.
Sharma, R. M. Vala, I. Lagunes, A. Puerta, J. M. Padrón, D. P. Rajani,
2-((R)-(((3aS,7aS)-1,3-diisopropyl-2-
oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)amino)(phenyl)methyl)-
3-((4-methoxyphenyl)amino)cyclohex-2-en-1-one (3r): white solid, 184
25
mg, 83% yield; mp 93-94 oC; [α]D = -209.6 (c = 1.1, CHCl3). 1H NMR
(400 MHz, CHLOROFORM-D) δ 9.76 (s, 1H), 7.40 (d, J = 7.6 Hz, 2H),
For internal use, please do not delete. Submitted_Manuscript
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H. M. Patel, Bioorg. Chem. 2019, 86, 137-150; k) R. M. Vala, D. M.
Patel, M. G. Sharma, H. M. Patel, RSC Adv. 2019, 9, 28886-28893.
[8]
[9]
L. J. Zhou, Y. C. Zhang, F. Jiang, G. He, J. Yan, H. Lu, S. Zhang, F. Shi,
Adv. Synth. Catal. 2016, 358, 3069-3083.
[3]
a) M. S. Alexander, K. R. Scott, J. Harkless, R. J. Butcher, P. L.
Jackson-Ayotunde, Bioorg. Med. Chem. 2013, 21, 3272-3279; b) T.
Mahmud, R. Rehman, A. Gulzar, A. Khalid, J. Anwar, U. Shafique,
Waheed-uz-Zaman, M. Salman, Arab. J. Chem. 2010, 3, 219-224; c) A.
Z. El-Hashim, I. O. Edafiogho, S. M. Jaffal, M. H. Yousif, C. I.
Ezeamuzie, S. B. Kombian, Life Sci. 2011, 89, 378-387.
a) H. Zhang, Z. Yang, B. N. Zhao, G. Li, J. Org. Chem. 2018, 83, 644-
655; b) S. Qiao, C. B. Wilcox, D. K. Unruh, B. Jiang, G. Li, J. Org.
Chem. 2017, 82, 2992-2999; c) S. Qiao, S. Pindi, P. T. Spigener, B.
Jiang, G. Li, Tetrahedron Lett. 2016, 57, 619-622; d) C. W. Seifert, A.
Paniagua, G. A. White, L. Cai, G. Li, Eur. J. Org. Chem. 2016, 2016,
1714-1719; e) S. Qiao, J. Wu, J. Mo, P. T. Spigener, B. N. Zhao, B.
Jiang, G. Li, Synlett. 2017, 28, 2483-2488; f) A. Kattuboina, P. Kaur, T.
Ai, G. Li, Chem. Biol. Drug. Des. 2008, 71, 216-223.
[4]
[5]
a) J. P. Wan, C. Wang, Y. Liu, Appl. Organomet. Chem. 2012, 26, 445-
447; b) N. Chopin, M. Médebielle, G. Pilet, J. Fluor. Chem. 2013, 155,
89-96; c) Y. Liu, B. Huang, X. Cao, D. Wu, J.-P. Wan, RSC Adv. 2014,
4, 37733-37737; d) N. Chopin, G. Novitchi, M. Médebielle, G. Pilet, J.
Fluor. Chem. 2015, 179, 169-174.
[10] a) G. An, C. Seifert, G. Li, Org. Biomol. Chem. 2015, 13, 1600-1617; b)
S. Qiao, J. Mo, C. B. Wilcox, B. Jiang, G. Li, Org. Biomol. Chem. 2017,
15, 1718-1724; c) K. Chen, W.-J. Hao, S.-J. Tu, B. Jiang, Green Chem.
2019, 21, 675-683; d) H.-K. Sha, F. Liu, J. Lu, Z.-Q. Liu, W.-J. Hao, J.-L.
Tang, S.-J. Tu, B. Jiang, Green Chem. 2018, 20, 3476-3485; e) W. Fan,
K.-Y. Chen, Q.-P. Chen, G. Li, B. Jiang, Org. Biomol. Chem. 2017, 15,
6493-6499; f) D. M. Patel, R. M. Vala, M. G. Sharma, D. P. Rajani, H. M.
Patel, ChemistrySelect 2019, 4, 1031-1041.
a) J. Pérez, D. Ramón, ACS Sustain. Chem. Eng. 2015, 3, 2343-2349;
b) M. Basato, B. Corain, A. C. Veronese, F. D'Angeli, G. Valle, G.
Zanotti, J. Org. Chem. 1984, 49, 4696-4700; c) S. Ueno, R. Shimizu, R.
Kuwano, Angew. Chem. Int. Ed. 2009, 48, 4543-4545; d) B. Croxtall, E.
G. Hope, A. M. Stuart, Chem. Commun. 2003, 2430-2431; e) X. Yu, L.
Wang, X. Feng, M. Bao, Y. Yamamoto, Chem. Commun. 2013, 49,
2885-2887; f) D. Yu, Y. N. Sum, A. C. C. Ean, M. P. Chin, Y. Zhang,
Angew. Chem. Int. Ed. 2013, 52, 5125-5128; g) N.-N. Wang, L.-R.
Huang, W.-J. Hao, T.-S. Zhang, G. Li, S.-J. Tu, B. Jiang, Org. Lett.
2016, 18, 1298-1301; h) Y. Hayashi, K. Okano, A. Mori, Org. Lett. 2018,
20, 958-961; i) P. Santhini, A. Krishnan R, S. A. Babu, B. S. Simethy, G.
Das, V. K. Praveen, S. Varughese, J. John, J. Org. Chem. 2017, 82,
10537-10548; j) M. G. Sharma, J. Pandya, D. M. Patel, R. M. Vala, V.
Ramkumar, R. Subramanian, V. K. Gupta, R. L. Gardas, A.
Dhanasekaran, H. M. Patel, Polycycl. Aromat. Comp. 2019, 39, 395-
485.
[11] a) D. Basavaiah, B. S. Reddy, S. S. Badsara, Chem. Rev. 2010, 110,
5447-5674; b) G.-Q. Lin, M.-H. Xu, Y.-W. Zhong, X.-W. Sun, Acc.
Chem. Res. 2008, 41, 831-840; c) I. P. Andrews, O. Kwon, Chem. Sci.
2012, 3, 2510-2514.
[12] a) B. J. Cowen, L. B. Saunders, S. J. Miller, J. Am. Chem. Soc. 2009,
131, 6105-6107; b) G. Masson, C. Housseman, J. Zhu, Angew. Chem.,
Int. Ed. 2007, 46, 4614-4628; c) K. Hyodo, S. Nakamura, N. Shibata,
Angew. Chem. Int. Ed. 2012, 51, 10337-10487; d) G. Li, H.-X. Wei, J. J.
Gao, T. D. Caputo, Tetrahedron Lett. 2000, 41, 1-5; e) W. Pei, H.-X.
Wei, G. Li, Chem. Commun. 2002, 2412-2413.
[13] a) V. K. Aggarwal, A. M. M. Castro, A. Mereu, H. Adams, Tetrahedron
Lett. 2002, 43, 1577-1581; b) M. Shi, Y. Xu, Angew. Chem. Int. Ed.
2002, 41, 4507-4510; c) M. Shi, G. Zhao, Adv. Synth. Catal. 2004, 346,
1205-1219; d) B. Yang, M. Shen, X. Ji, Z. Xu, H. Sun, B. Jiang, G. Li, J.
Org. Chem. 2016, 81, 2488-2493; e) B. Yang, X. Ji, Y. Xue, H. Zhang,
M. Shen, B. Jiang, G. Li, Org. Biomol. Chem. 2016, 14, 6024-6035; f) Q.
Li, M. Shi, J. M. Lyte, G. Li, Tetrahedron Lett. 2006, 47, 7699-7702.
[14] CCDC 1970049 (1a) and 1970050 (3a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[6]
[7]
a) A. Arcadi, G. Bianchi, S. Di Giuseppe, F. Marinelli, Green Chem.
2003, 5, 64-67; b) Z. Zhang, L. Yin, Y. Wang, Adv. Synth. Catal. 2006,
348, 184-190; c) J. Liu, G. Cao, W. Xu, J. Cao, W. Wang, Appl.
Organomet. Chem. 2010, 24, 685-691; d) X. Cheng, S. Pei, C. Xue, K.
Cao, L. Hai, Y. Wu, RSC Adv. 2014, 4, 63897-63900.
a) Y.-N. Lu, C. Ma, J.-P. Lan, C. Zhu, Y.-J. Mao, G.-J. Mei, S. Zhang, F.
Shi, Org. Chem. Front. 2018, 5, 2657-2667; b) M.-M. Xu, H.-Q. Wang,
Y. Wan, G. He, J. Yan, S. Zhang, S.-L. Wang, F. Shi, Org. Chem. Front.
2017, 4, 358-368; c) Q.-N. Zhu, Y.-C. Zhang, M.-M. Xu, X.-X. Sun, X.
Yang, F. Shi, J. Org. Chem. 2016, 81, 7898-7907.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Yangxue Liu, Sultan Ahmed, Xiao-Yan
Qin, Hossein Rouh, Guanzhao Wu,
Guigen Li,* Bo Jiang*
Page No. – Page No.
Synthesis of Diastereoenriched α-
Aminomethyl Enaminones via
A
Text for Table of Contents
Brønsted Acid-Catalyzed Asymmetric
aza-Baylis-Hillman Reaction of Chiral
N-Phosphonyl Imines
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