Asymmetric [3 + 2] Cycloaddition of Chiral N-Phosphonyl Imines with Methyl Isocyanoacetate for Accessing 2-Imidazolines with Switchable Stereoselectivity

Article abstract of DOI:10.1021/acs.joc.6b03068

Asymmetric [3 + 2] cycloaddition of chiral N-phosphonyl imines with methyl isocyanoacetate has been established, enabling controllable/switchable stereoselectivity access to 21 examples of cycloadducts with good to excellent chemical yields (up to 92%) an

Full text of DOI:10.1021/acs.joc.6b03068

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Article
Asymmetric [3 + 2] Cycloaddition of Chiral N-Phosphonyl
Imines with Methyl Isocyanoacetate for Accessing
to 2-Imidazolines with Switchable Stereoselectivity
Shuo Qiao, Cody B. Wilcox, Daniel K. Unruh, Bo Jiang, and Guigen Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03068 • Publication Date (Web): 02 Mar 2017
Downloaded from http://pubs.acs.org on March 3, 2017
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The Journal of Organic Chemistry
Asymmetric [3 + 2] Cycloaddition of Chiral NꢀPhosphonyl Imines with Methyl
Isocyanoacetate for Accessing 2ꢀImidazolines with Switchable Stereoselectivity
Shuo Qiao,a Cody B. Wilcox,a Daniel K. Unruh,a Bo Jiang,*,a,c and Guigen Li*,a,b
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aDepartment of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409ꢀ1061,
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United States; Institute of Chemistry and BioMedical Sciences and School of Chemistry and
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Chemical Engineering, Nanjing University, Nanjing, 210093. School of Chemistry and Materials
Science, Jiangsu Normal University, Xuzhou, 221116, P. R. China
E-mail: jiangchem@jsnu.edu.cn (BJ); guigen.li@ttu.edu(GL)
RECEIVED DATE
ABSTRACT. Asymmetric [3 + 2] cycloaddition of chiral Nꢀphosphonyl imines with methyl
isocyanoacetate have been established, enabling controllable/switchable stereoselectivity accessing
to 21 examples of cycloadducts with good to excellent chemical yields (up to 92%) and high
diastereoselectivity (up to 99:1 dr). The cycloaddition reaction promoted by Cs2CO3 resulted in
diastereoenriched (4R,5S)ꢀproducts, with dr >99:1. However, it showed the reverse stereoselectivity
as diastereoenriched (4S,5R)ꢀproducts when AgF was employed as the catalyst. The synthesis
followed the groupꢀassisted purification (GAP) chemistry/technology, in which the pure
2ꢀimidazoline products were readily provided by washing the crude products with coꢀsolvents of
hexane and ethyl acetate.
Introduction
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2ꢀImidazolines represent a highly valuable class of fiveꢀmembered heterocycles and can often
serve as ‘‘privileged motifs’’ in medical and pharmaceutical chemistry owing to their significant
biological activities such as analgesic and antiꢀinflammatory activity,1 cardiovascular activity,2
antiꢀneoplastic activity,3 antiꢀfungal activity4, etc. Besides, the stereochemistry of this privileged
scaffold has been found to display diverse biological characteristics, represented by NFꢀκB
inhibitory skeleton I5 and p53 activator framework II (Figure 1).6 Specifically, stereospecific
2ꢀimidazolines are also extensively utilized as chiral auxiliaries,7 chiral catalysts,8 and ligands for
asymmetric catalysis.9 Therefore, many efforts have been made to develop various methodologies
for the stereoselective synthesis of 2ꢀimidazolines, which made them more powerful and applicable.
The great majority of these approaches involved multiꢀstep cyclization of chiral 1,2ꢀdiamines10a or
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β
ꢀhydroxy amides,10b transannulation of chiral aziridines,11 metalꢀcatalyzed asymmetric [3 + 2]
cycloaddition of isocyanoacetates with Nꢀsulfonylimines (Scheme 1a)12 and Tf2O/Ph3POꢀmediated
intramolecular cyclization of chiral Nꢀacyl diamines.13 However, these methods suffered from
multiꢀsteps, the use of noble metal catalysts like Au, and limited substrate scopes as well as inferior
enantioselective control when the transformation were enlarged, thereby limiting their potential
industrial applications. Therefore, many chemists focused these efforts on the development of chiral
auxiliaryꢀcontrolled asymmetric reactions due to its potential application of largeꢀscale
transformations. An extensive survey revealed that chiral auxiliaries mainly involve include
Nꢀtosyl,14 Nꢀtertꢀbutylsulfonyl15 and Nꢀthiophosphoryl,16 but frequently give poor
diastereoselectivity. Over the years, we have designed new chiral Nꢀphosphonyl auxiliary imines,
enabling their asymmetric additions with nucleophiles to synthesize diverse chiral amines with high
stereoselectivity (Scheme 1b).17 During this project, we conceived that under suitable reaction
conditions, asymmetric [3 + 2] cycloaddition of isocyanoacetates with Nꢀphosphonyl auxiliary
imines could proceed readily, efficiently affording 2ꢀimidazolines with high diastereoselectivity.
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The Journal of Organic Chemistry
Herein, we would like to report this special Nꢀphosphonyl 2ꢀimidazoline synthesis by using readily
available isocyanoacetates and the preformed chiral Nꢀphosphonyl auxiliary imines 1 (Schemes 1c
and 1d). Interestingly, switchable stereoselectivity was realized in this transformation when bases
and Agꢀcatalyst were employed, respectively. By using Cs2CO3 as a base promoter, the reaction
resulted in diastereoenriched (4R,5S)ꢀproducts 3, often with final dr >99:1 (Scheme 1c) whereas the
reverse stereoselectivity was observed in Agꢀcatalysis as diastereoenriched (4S,5R)ꢀproducts 4 were
provided (Scheme 1d). Notably, Nꢀphosphonyl 2ꢀimidazolines 3 and 4 could be obtained simply by
washing the crude mixture with common hexane and ether, thereby simplifying the purification
process while avoiding the use of traditional purification methods (column chromatography,
recrystallization, etc.). This convenient workup for obtaining pure products directly by introducing
wellꢀfunctionalized groups in starting materials or newly generated functionalities in target
molecules belongs to a concept called groupꢀassisted purification (GAP) chemistry/technology.
Besides, Nꢀphosphonyl auxiliary can be easily recovered and recycled though the cleavage of PꢀN
bond of Nꢀphosphorylated products under the mild conditions, which makes this strategy highly
attractive.
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Figure 1. Anti and synꢀ2ꢀimidazolines
Scheme 1. Asymmetric Synthesis of 2-Imidazolines
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Results and discussion
Our initial investigation began with the asymmetric [3 + 2] cycloaddition of the preformed
phosphonyl imine (1a) with methyl isocyanoacetate (2). The reaction in tetrahydrofuran (THF) was
carried out at room temperature using LiOH as a base promoter, giving access to 95% yield of
product 3a, but with moderate diastereoselectivity (dr = 73:27, Table 1, entry 1). Exchanging THF
for MeOH lowered the conversion (66%) and diastereoselectivity (dr = 57:43, entry 2). Using NaOH
as a base promoter, a very lower yield (25%) and poor diastereoselectivity (dr = 51:49) were
observed (entry 3). Organic bases such as 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) and
1,4ꢀdiazabicyclo[2.2.2]octane (DABCO) completely suppressed the reaction process (entries 4ꢀ5).
The use of Cs2CO3 resulted in high diastereoselectivity (dr = 96:4) albeit with a moderate yield (49%,
entry 6). Lowering temperature is adverse to the reaction process and led to a complex mixture
(entry 7). To our delight, 4Å molecular sieves as additive facilitated the transformation, affording the
expected product 3a with 99% yield (an isolated 92% yield) and high stereoselectivity (96:4 dr, entry
8). Since silver catalyst has generally showed a highly catalytic activity in [3 + 2] cycloaddition of
isocyanoacetates,18 we decided to utilize silver catalyst to investigate this transformation.
Surprisingly, Ag2O as a catalyst drive the reaction to the opposite diastereoselectivity, and the
(4S,5R)ꢀproduct 4a was obtained with 91% yield and 78:22 dr (entry 9). The investigation of solvent
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revealed that dichloromethane (DCM) exhibited the best performance, affording the desired product
3a with 97% yield and 84:16 dr (entry S10) whereas both THF and toluene gave inferior
diastereoselectivity compared with dichloromethane (entries 9 and 11). Afterward, we attempted to
employ other silver catalysts such as AgOTf and AgF to improve the reaction efficiency (entries
12ꢀ13). AgF was proven to be the most efficient, delivering 99% yield (an isolated 87% yield) and
88:12 dr (entry 12). In particular, the reverse diastereoselectivity was observed and diastereoenriched
product 3a with 91:9 dr was detected when LiCl as additives was added in this Agꢀcatalysis (entry
13). These results suggested that the baseꢀpromoted asymmetric [3 + 2] cycloaddition underwent a
different mechanism pathways compared with Agꢀcatalyzed version.
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Table 1. Screening of the Reaction Conditions
entry
1
base (or cat.) solvent
conversiona
95%
3a/4a (dr)b
73:27
57:43
51:49
ꢀ
LiOH
THF
2
LiOH
MeOH
THF
66%
3
NaOH
DBU
25%
4
THF
trace
5
DABCO
Cs2CO3
Cs2CO3
Cs2CO3
Ag2O
THF
trace
ꢀ
6
THF
49%
96:4
7c
8d
9
THF
47%
messy
96:4
THF
99% (92%)e
91%
THF
22:78
16:84
42:58
10
11
Ag2O
DCM
toluene
97%
Ag2O
99%
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12
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14f
AgOTf
AgF
DCM
DCM
DCM
trace
ꢀ
1
2
3
4
5
6
99% (87%)e
88%
12:88
91:9
AgF
7
a The conversions were determined by 31P NMR after 16 hours at room temperature. The diastereoisomer ratio were
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c
o
d
e
f
determined by 31P NMR. Reaction at ꢀ41 C; Use of activated 4Å MS (50 mg); Isolated yield based on 1a; LiCl as
additive.
With the optimized reaction conditions for selectively forming products 3a (Table 1, entry 8) and
4a (entry 12) in hand, we then set out to investigate the scope of asymmetric [3 + 2] cycloaddition
toward Nꢀphosphonyl 2ꢀimidazolines 3 and 4 by examining chiral Nꢀphosphonyl auxiliary imines 1
with methyl isocyanoacetate (2). First, a wide range of chiral Nꢀphosphonyl imines 1 were subjected
to the reaction with methyl isocyanoacetate (2) under Cs2CO3ꢀpromoted conditions, and the
corresponding densely functionalized 2ꢀimidazolines 3a-3n with generally excellent yields and high
diastereoselectivity (Scheme 2a). Chiral Nꢀphosphonyl imines 1 possessing both electronꢀdonating
and electronꢀwithdrawing groups directly bounded phenyl ring did not hamper the reaction process.
A large variety of diverse functional groups, including methyl, methoxy, fluoro, chloro, bromo,
cyano, and nitro, were well tolerated under this system. Among them, the sterically encumbered
oꢀmethylphenyl, counterparts (1d and 1e) were appropriate imine partners, enabling their
asymmetric [3 + 2] cycloaddition to access the desired products 3d and 3e with 72% and 77% yields
and >99:1 dr, respectively. Alternatively, 1ꢀnaphthyl (1ꢀNp, 1l) and nꢀbutyl (1n) analogues proved to
be effective, giving access to the corresponding products 3l and 3n in 88% and 93% yield,
respectively, albeit with poor diastereoselectivity whereas 2ꢀpyridinyl counterpart (1m) seemed very
reluctant to undergo the reaction, in which 3m was generated in a relatively low 52% yield, but with
high 96:4 dr. Next, we turned our attention to evaluating the scope of AgFꢀcatalyzed asymmetric [3
+ 2] cycloaddition toward diastereoenriched products 4 under the standard conditions (Table 1, entry
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The Journal of Organic Chemistry
Scheme 2. The Scope of Asymmetric [3 + 2] Cycloaddition
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3
4
i-Pr
i-Pr
N
N
N
R
N
Cs2CO3
C
P
N
P
GAP
+
N
CO2Me
N
O
(a)
N
CO2Me
THF, rt, 4 Å MS
O
i-Pr
i-Pr
5
R
2
1
3
6
7
8
9
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
N
N
N
N
N
N
N
N
N
N
N
N
N
P
N
P
P
N
P
P
N
N
N
N
N
CO2Me
CO2Me
4-MeC6H4
(91%)
CO2Me
CO2Me
CO2Me
O
O
O
O
O
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
2-MeC6H4
4-MeOC6H4
2-Me-4-MeOC6H3
3e
(77%)
dr > 99:1 (99:1)
Ph
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a
3a
3d
(92%)
(72%)
dr > 99:1 (96:4)
3c
3b
(92%)
dr > 99:1 (99:1)
dr > 99:1b (96:4)c
dr > 99:1 (99:1)
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
N
N
N
N
N
N
N
N
N
N
N
P
N
P
N
P
N
P
N
P
N
O
N
O
N
O
N
O
N
O
CO2Me
4-FC6H4
(87%)
CO2Me
CO2Me
CO2Me
CO2Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
3,4-(MeO)2C6H3
3-ClC6H4
4-BrC6H4
4-CNC6H4
3f
(92%)
dr > 99:1 (99:1)
3h
(86%)
dr > 99:1 (99:1)
3g
3i
(85%)
3j
(88%)
dr > 99:1 (99:1)
dr > 99:1 (99:1)
dr > 99:1 (99:1)
i-Pr
i-Pr
i-Pr
i-Pr
N
N
N
N
N
N
N
N
N
P
N
P
N
P
N
P
N
N
N
N
CO2Me
CO2Me
O
CO2Me
O
CO2Me
O
O
i-Pr
i-Pr
i-Pr
i-Pr
4-NO2C6H4
1-Np
2-Py
n-Bu
d
3l
(88%)
dr = 56:44 (56:44)
3k
(90%)
dr > 99:1 (99:1)
3n
(93%)
3m
(52%)
dr = 96:4 (96:4)
dr = 51:49 (51:49)
i-Pr
i-Pr
N
N
N
N
R
C
AgF
P
N
P
GAP
+
N
CO2Me
(b)
N
O
N
CO2Me
O
DCM, rt
i-Pr
i-Pr
R
2
4
1
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
N
N
N
N
N
N
N
N
N
N
N
N
P
P
N
N
P
P
N
P
N
N
N
N
O
N
CO2Me
CO2Me
CO2Me
4-MeC6H4
O
O
CO2Me
CO2Me
O
O
i-Pr
i-Pr
i-Pr
i-Pr
3,4-(MeO)2C6H3
i-Pr
4-MeOC6H4
(71%)
dr = 94:4 (95:5)
3-ClC6H4
(80%)
dr = 61:39 (60:40)
Ph
4d
(88%)
dr = 96:4 (90:10)
4c
4a
4e
(87%)
dr =86:14 (86:14)
4b
(66%)
dr = 95:5 (81:19)
i-Pr
i-Pr
N
N
N
N
N
P
N
P
N
N
CO2Me
4-CNC6H4
(80%)
dr = 58:42 (58:42)
CO2Me
4-BrC6H4
O
O
i-Pr
i-Pr
4g
4f
(55%)
dr = 59:41 (59:41)
(i) Reactions condition A: Nꢀphosphonyl imines, (0.5 mmol, 1 equiv) 4Å activated molecular sieves (50 mg), methyl isocyanide (3.0 equiv) and
Cs2CO3 (2.2 equiv) was reacted in THF (5 mL) at room temperature for 16 h; (ii) Reactions condition B: Nꢀphosphonyl imine (0.5 mmol, 1 equiv),
methyl isocyanide (1.2 equiv) and AgF (5 mol %) in DCM (5 mL), at room temperature for 16 h. a Yield based on GAP technology. b The
diastereoisomer ratio was determined by 31P NMR of the reaction mixture. c The diastereoisomer ratio in brackets before GAP procedure. d Isolated
yield by chromatography as product 3n is oil.
12). As shown in Scheme 2b, this protocol can tolerate structurally diverse chiral Nꢀphosphonyl
imines 1 carrying either electronically neutral, rich, or poor groups attached by phenyl moiety,
paving the way of the collection of richly decorated Nꢀphosphonyl 2ꢀimidazolines 4a-4g in
55%ꢀ88% yields. The presence of electronꢀdonating functionality on the phenyl ring gave high
diastereoselectivity (4b-4d) whereas the poor diastereoselectivity was observed with use of
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electronꢀwithdrawing substituents (4e-4g). In all cases, the pure cycloadducts 3 and 4 with generally
high diasyereoselectivity were obtained simply by washing the crude products with hexane/ether
without use of traditional chromatography and recrystallization.17 Note that this is the first reported
procedure for the synthesis of these new Nꢀphosphonyl 2ꢀimidazolines with switchable
diastereoselectivity through baseꢀpromoted or Agꢀcatalyzed asymmetric [3 + 2] cycloaddition of
chiral Nꢀphosphonyl auxiliary imines with methyl isocyanoacetate. The structures of these products
were confirmed by their NMR and HRMS spectra. In the cases of 3a and 4a, the stereoꢀstructures
were unequivocally determined by Xꢀray analysis (See Supporting Information).19
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Scheme 3. Cleavage of auxiliary of Cycloadducts
To investigate the synthetic utility of the resulting 2ꢀimidazolines, the cleavage reaction of resulting
cycloadduct 3a was conducted in the presence of KOH in mixed solvent of water and MeOH,
affording 2,3ꢀdiamino acid 5a in 80% yield.20 2,3ꢀDiamino acid 5a was converted into
imidazolidineꢀ1,3,4ꢀtricarboxylates 6a in 45% yield through Boc protection (Scheme 3). This
method could be used for the synthesis of various substituted 2,3ꢀdiamino acids or diamino alcohols
which are crucial fragment of biologically active peptides and other industrially useful molecules.
Scheme 4. Proposed Mechanism of [3 + 2] Cycloaddition Reaction
Based on above observation and analysis, the mechanisms for selectively forming products 3 and 4
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may involve two different transition states in [3 + 2] cycloaddition reactions with chiral
Nꢀphosphonyl imines, which are depicted in Scheme 4. Under basic conditions (Scheme 2a), similar
to our previous reports,20 the diastereoselectivity could be explained by Newman project transition
state 1 (TS1, route i); it is controlled well by the attack of deprotonated isocyanoacetates as a
nucleophile on the favorable siꢀface of the auxiliary group, giving a nearly diastereopure
intermediates followed by intramolecular nucleophilic addition to products 3. Importantly, the less
selectivity of using aliphatic substrate 1n as an electrophile could be explained by equal E/Z
configuration of Nꢀphosphonyl imines derived from hemiaminal under basic condition, and this
observation is consistent with the proposed transition state.21 On the other hand, a tentative transition
state 2 (TS2) accounts for the opposite selectivity can be proposed: during Ag catalysis (Scheme 2b),
the stereoꢀoriented carbonꢀcarbon forming step is supposed to be consistent with cyclization through
a sixꢀmember ring consisting of the nitrogen atom on the imine substrate, the carbon atom of
isocyanide group, and the coordinated silver ion which is stabilized by oxygen on the phosphonyl
group. The remarkable decrease of diastereoselectivity of the electronꢀwithdrawing substrates might
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be ascribed to their relatively less stability of such a transition state
.
In summary, we have established baseꢀpromoted or Agꢀcatalyzed asymmetric [3 + 2] cycloaddition
reactions with chiral Nꢀphosphonyl imines and methyl isocyanoacetate, allowing facile and efficient
synthesis of Nꢀphosphonyl 2ꢀimidazolines with switchable stereoselectivity. During the reaction
process, the use of Cs2CO3 as a base promoter led to diastereoenriched (4R,5S)ꢀproducts, often with
final dr >99:1 whereas (4S,5R)ꢀproducts with reverse stereoselectivity were provided in Agꢀcatalysis.
These products of this reaction can be further transformed into other valuable and highly
functionalized entities. Our further studies will focus on the discovery of new asymmetric reactions
of Nꢀphosphonyl functionality with other nucleophiles.
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Experimental Section
General Information
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All commercially available chemicals were used as received without further purification. Solvents
were obtained as follows: Ether, dichloromethane, tetrahydrofuran and toluene are delivered from
Innovation Technology solvent system. All reactions were carried out in flame dried flask under
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nitrogen atmosphere. The H and 13C NMR spectra were recorded in CDCl3 on a 400 MHz
instrument with TMS as internal standard. Chemical shifts (δ) were reported in ppm with respect to
TMS. Data are represented as follows: chemical shift, mutiplicity (s = singlet, d = doublet, t = triplet,
31
m = multiplet), coupling constant (J, Hz) and integration. P NMR spectra were referenced to
external H3PO4 (0.00 ppm). Shifts in 19F NMR spectra were reported based on an external
hexafluorobenzene reference. HRMS analyses were carried out using a TOFꢀMS instrument with an
ESI source.
General synthesis of Nꢀphosphonyl imine with GAP technique
To a 100 mL oven dried flask with a Teflonꢀcoated magnetic stir bar was added (S,
S)ꢀphosphonylamide (1.0 g, 3.86 mmol). 5.0 mL of toluene was added under argon atmosphere.
Aldehyde (2 equiv, 7.72 mmol) and Ti(OiPr)4 (1.0 equiv, 1.2 mL, 3.86 mmol) were added
subsequently. The suspension was stirred at 80 °C for 24 hours. The reaction was monitored by
31PNMR of the reaction mixture. When complete, the clear solution was concentrated under vacuum,
and 50 mL of dry hexane was added and the result solution was slurry for 6 h until a precipitation
formed (GAP). After filtration, the Nꢀphosphonyl imine was isolated as a pale yellow solid.
General Procedure for the Synthesis of Products 3
A 10 mL flameꢀdried roundꢀbottomed flask was charged under argon with Nꢀphosphonylimine (0.5
mmol, 1 equiv) and freshly distilled THF (5.0 mL). At room temperature, 4 Å activated molecular
sieves (50 mg) and Cs2CO3 (2.2 equiv) were added to this solution in one portion followed by the
addition of methyl isocyanide (3.0 equiv) dropwise through a syringe. Completion of the starting
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material was monitored by thin layer chromatography and 31PNMR of the reaction mixture (The
reaction could be completed in 16 hours). At this stage, 10 mL of water was added to the reaction
mixture and extracted with 2 × 5 mL of ethyl acetate. The combined organic layers were washed
with water (1 × 5 mL) and brine solution (1 × 10 mL) and dried over anhydrous Na2SO4. The solvent
was evaporated after filtration, and the crude mixture was coꢀconcentrated with hexanes. The
products were dried under high vacuum. The solid products were dissolved with ether and treated
dry hexane to afford a pure product without column chromatography (GAP). In the case of
compound 3n, it was purified with column chromatography which is soluble in hexane.
Data for pure compounds 3a-3n:
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Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate (3a)
White solid, 205 mg, 92% yield; mp 148−151 °C; [α]25 D =ꢀ119 (c = 3.8, CHCl3); 1HNMR (CDCl3,
1
400 MHz) δ = 7.38 (s, 1H), 7.30ꢀ7.20 (m, 5H), 5.08ꢀ5.06 (m, 1H), 4.75ꢀ4.71 (m, 1H), 3.71 (s, 3H),
3.18ꢀ3.13 (m, 1H), 2.88ꢀ2.86 (m, 2H), 2.80ꢀ2.79 (m, 1H), 2.02ꢀ2.00 (m, 1H), 1.98 (m, 1H),
1.78ꢀ1.75 (m, 2H), 1.56ꢀ0.88 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.6, 155.1, 128.8, 128.9,
128.3, 128.2, 127.6, 127.3, 78.7, 63.9, 60.2, 52.6, 44.9, 43.5, 30.8, 29.9, 29.8, 24.3, 24.2, 22.4, 21.5,
20.3, 20.1; 31P NMR (CDCl3 162 MHz): δ 14.4; HRMS (TOF ES+) m/z calcd for C23H36N4O3P [(M
+ H)+], 447.2520; found, 447.2538.
Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(p-tolyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3b)
1
White solid, 209 mg, 91%; mp 49−51 °C; [α]25 D =ꢀ132 (c = 2.2, CHCl3); HNMR (CDCl3, 400
1
MHz) δ = 7.43 (s, 1H), 7.22ꢀ7.09 (m, 4H), 5.08ꢀ5.05 (m, 1H), 4.67ꢀ4.62 (m, 1H), 3.73 (s, 3H),
3.21ꢀ3.19 (m, 2H), 2.91ꢀ2.88 (m, 1H), 2.46ꢀ2.44 (m, 1H), 2.30ꢀ2.25 (m, 3H), 2.05ꢀ2.01 (m, 1H),
13
1.88ꢀ1.82 (m, 1H), 1.73ꢀ1.69 (m ,2H), 1.55ꢀ0.88 (m, 16H); CNMR (CDCl3, 100 MHz) δ = 171.6,
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155.3, 139.8, 138.1, 129.5, 129.3, 127.8, 127.2,79.4, 64.1, 64.0,60.1, 59.9, 52.6, 44.4, 31.0, 30.2,
24.4, 24.3, 22.9, 22.8, 22.7, 21.2, 19.8; 31P NMR (CDCl3 162 MHz): δ 14.5; HRMS (TOF ES+) m/z
calcd for C24H38N4O3P [(M + H)+], 461.2676; found, 461.2662.
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Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
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-5-(4-methoxyphenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3c)
White solid; 219 mg, 92%, mp 112−114 °C; [α]25 D =ꢀ144 (c = 2.9, CHCl3); HNMR (CDCl3, 400
1
1
MHz) δ = 7.39 (s, 1H), 7.18ꢀ7.15 (m, 2H), 6.84ꢀ6.82 (m, 2H), 5.06ꢀ5.02 (m, 1H), 4.66ꢀ4.62 (m, 1H),
3.75 (s, 3H), 3.73 (s, 3H), 3.23ꢀ3.21 (m, 2H), 2.90ꢀ2.88 (m, 1H), 2.48ꢀ2.45 (m, 1H), 2.02ꢀ2.00 (m,
13
1H), 1.98ꢀ1.97 (m, 1H), 1.77ꢀ1.74 (m, 2H), 1.44ꢀ0.98 (m, 16H); CNMR (CDCl3, 100 MHz) δ =
171.6, 159.6, 155.1, 134.9, 128.5, 128.4, 114.1, 114.0,79.2, 63.8, 60.1, 60.0, 55.4, 52.5, 44.4, 30.7,
30.1, 24.4, 24.2, 22.7, 21.7, 21.2, 19.7; 31P NMR (CDCl3 162 MHz): δ 13.7; HRMS (TOF ES+) m/z
calcd for C24H38N4O4P [(M + H)+], 477.2625; found, 477.2627.
Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(o-tolyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3d)
White solid; 165 mg, 72%; mp 108−109 °C; [α]25 D =ꢀ89 (c = 2.8, CHCl3); HNMR (CDCl3, 400
1
1
MHz) δ = 7.55 (s, 1H), 7.14ꢀ6.94 (m, 4H), 5.48 (s, 1H), 4.59 (s, 1H), 3.75 (s, 3H), 3.28ꢀ3.26 (m, 2H),
2.91ꢀ2.89 (m, 1H), 2.45ꢀ2.41 (m, 4H), 2.06ꢀ2.02 (m, 1H), 1.98ꢀ1.90 (m, 1H) 1.66ꢀ1.59 (m, 2H),
1.26ꢀ0.97(m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.7, 155.2, 141.3, 135.1, 130.5, 127.7, 126.6,
31
125.8, 79.2, 59.9, 59.8, 59.4, 52.5, 44.3, 30.9, 30.7, 30.3, 30.2,24.4, 24.3, 22.9, 20.9, 19.7, 19.5; P
NMR (CDCl3 162 MHz): δ 14.6; HRMS (TOF ES+) m/z calcd for C24H38N4O3P [(M + H)+],
461.2676; found, 461.2668.
Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(4-methoxy-2-methylphenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3e)
White solid; 188mg, 77%; mp 83−84 °C; [α]25 D =ꢀ73 (c = 3.6, CHCl3); 1HNMR (CDCl3, 400 MHz)
1
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δ = 7.44 (s, 1H), 7.11 (m, 1H), 6.66ꢀ6.56 (m, 2H), 5.47 (s, 1H), 4.54ꢀ4.42 (m, 1H), 3.79 (s, 3H),
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3.26ꢀ3.33 (m, 2H), 2.88 (t, J = 2.5 Hz, 1H), 2.48 (t, J = 3 Hz, 1H), 2.39 (s, 3H), 2.06ꢀ2.02 (m, 1H),
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6
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1.98ꢀ1.96 (m, 1H), 1.69ꢀ1.67 (m, 2H), 1.23ꢀ0.97 (m, 17H); CNMR (CDCl3, 100 MHz) δ = 171.9,
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158.9, 155.2, 136.5, 133.8, 127.2, 115.3, 112.5,79.7, 60.2, 59.9, 59.1, 55.3, 52.6, 44.3, 30.9, 30.8,
30.3, 30.2, 24.4, 24.3, 22.9,21.0, 20.2, 19.8; 31P NMR (CDCl3 162 MHz): δ 14.5; HRMS (TOF ES+)
m/z calcd for C25H40N4O4P [(M + H)+], 491.2782; found, 491.2776.
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Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3f)
1
White solid; 233 mg ,92%; mp 97−98 °C; [α]25 D =ꢀ161 (c = 1.8, CHCl3); HNMR (CDCl3, 400
1
MHz) δ = 7.34 (s, 1H), 6.81ꢀ6.73 (m, 3H), 5.05ꢀ5.02 (m, 1H), 4.67ꢀ4.62 (m, 1H), 3.80 (s, 3H), 3.79
(s, 3H), 3.69ꢀ3.66 (m, 3H), 3.22ꢀ3.20 (m, 2H), 2.88ꢀ2.85 (m, 1H), 2.50ꢀ2.47 (m, 1H), 1.97ꢀ1.95 (m,
13
1H), 1.85ꢀ1.82 (m, 1H), 1.70ꢀ1.66 (m, 2H), 1.35ꢀ0.99 (m, 15H); CNMR (CDCl3, 100 MHz) δ =
171.5, 155.0, 149.3, 149.0, 135.2, 135.1, 119.7, 111.0, 109.8, 79.1, 64.1, 60.1, 60.0, 56.1, 55.9, 52.5,
44.4, 30.7, 30.3,24.4, 24.2, 22.9, 22.7,21.2, 19.7; 31P NMR (CDCl3 162 MHz): δ 15.4; HRMS (TOF
ES+) m/z calcd for C25H40N4O5P [(M + H)+], 507.2731; found, 507.2725.
Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(4-fluorophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3g)
1
White solid; 202 mg, 87%; mp 138−139 °C; [α]25 D =ꢀ155 (c = 1.1, CHCl3); HNMR (CDCl3, 400
1
MHz) δ = 7.35 (s, 1H), 7.23ꢀ6.95 (m, 4H), 5.11 (s, 1H), 4.64 (s, 1H), 3.72 (s, 3H), 3.27ꢀ3.25 (m, 1H),
3.07ꢀ3.03 (m, 1H), 2.89ꢀ2.87 (m, 1H), 2.55 (t, J = 10 Hz, 1H), 2.03ꢀ2.00 (m, 2H), 1.74ꢀ1.72 (m, 2H),
1.45ꢀ0.98 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.3, 163.8, 161.3, 154.7, 138.7, 128.9, 115.7,
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79.1, 63.6, 60.2, 59.8, 52.6,44.4, 44.2, 30.8, 30.1,24.3, 24.2, 23.8, 22.7, 22.6, 21.1, 19.7; P NMR
(CDCl3 162 MHz): δ 14.2; HRMS (TOF ES+) m/z calcd for C23H35FN4O3P [(M + H)+], 465.2425;
found, 465.2428.
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Methyl (4R,5S)-5-(3-chlorophenyl)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]
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diazaphosphol-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (3h)
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6
1
White solid; 208 mg, 86%; mp 64−65 °C; [α]25 D =ꢀ107 (c = 1.5, CHCl3); HNMR (CDCl3, 400
1
7
8
9
MHz) δ = 7.41 (s, 1H), 7.27ꢀ7.19 (m, 4H), 5.12 (s, 1H), 4.65 (s, 1H), 3.76 (s, 3H), 3.28ꢀ3.26 (m, 2H),
2.93ꢀ2.90 (m, 1H), 2.55 (t, J = 8 Hz, 1H), 2.07ꢀ2.04 (m, 1H), 1.92ꢀ1.89 (m, 1H), 1.78 (s, 2H),
1.43ꢀ1.06 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.2, 154.9, 144.7, 134.7, 130.2, 128.4, 127.1,
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125.3, 78.9, 63.8, 60.2, 60.1,52.7,44.4, 43.8, 30.9,24.4, 24.2, 22.9, 22.8, 22.7, 21.2, 19.7; P NMR
(CDCl3 162 MHz): δ 13.7; HRMS (TOF ES+) m/z calcd for C23H35ClN4O3P [(M + H)+], 481.2130;
found, 481.2140.
Methyl (4R,5S)-5-(4-bromophenyl)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]
diazaphosphol-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (3i)
1
White solid; 223 mg, 85%; mp 48−50 °C; [α]25 D =ꢀ127 (c = 1.5, CHCl3); HNMR (CDCl3, 400
1
MHz) δ = 7.49ꢀ7.46 (m, 2H), 7.37 (s, 1H), 7.18ꢀ7.12 (m, 2H), 5.13 (s, 1H), 4.63 (s, 1H), 3.74 (s, 3H),
3.33ꢀ3.30 (m, 1H), 3.20ꢀ3.17 (m, 1H), 2.93ꢀ2.90 (m, 1H), 2.62 (t, J = 8 Hz, 1H), 2.18ꢀ2.14 (m, 2H),
1.72ꢀ1.68 (m, 2H), 1.55ꢀ1.08 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.3, 154.7, 141.8, 131.9,
131.8, 128.8, 128.7, 122.2, 78.9, 63.7, 60.3, 60.2, 52.7,44.4, 31.2, 30.1,24.3, 24.2, 23.8, 22.9, 22.8,
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21.1, 19.8; P NMR (CDCl3 162 MHz): δ 13.3; HRMS (TOF ES+) m/z calcd for C23H35BrN4O3P
[(M + H)+], 525.1625; found, 525.1633.
Methyl (4R,5S)-5-(4-cyanophenyl)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]d
iazaphosphol-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (3j)
1
White solid; 207 mg, 88%; mp 158−160 °C; [α]25 D =ꢀ152 (c = 1.1, CHCl3); HNMR (CDCl3, 400
1
MHz) δ = 7.62ꢀ7.41 (d, 4H), 7.34 (s, 1H), 5.27ꢀ5.22 (m, 1H), 4.63ꢀ4.59 (m, 1H), 3.76 (s, 3H),
3.35ꢀ3.28 (m, 1H), 3.05ꢀ3.01 (m, 1H), 2.92ꢀ2.88 (m, 1H), 2.68 (t, J = 9.6Hz, 1H), 2.07ꢀ2.00 (m, 2H),
1.79ꢀ1.71 (m, 2H), 1.45ꢀ1.01 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 170.9, 154.2, 147.8, 132.6,
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127.8, 118.6, 112.1, 78.5, 63.9, 60.2, 59.6, 52.8, 44.3, 44.2, 31.2, 30.8,24.3, 24.2, 23.1, 23.0,
22.8,22.7, 20.8, 19.8; 31P NMR (CDCl3 162 MHz): δ 14.1; HRMS (TOF ES+) m/z calcd for
C24H35N5O3P [(M + H)+], 472.2472; found, 472.2466.
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Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
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-5-(4-nitrophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3k)
White solid; 221 mg, 90%; mp57−58 °C; [α]25 D =ꢀ236 (c = 0.8, CHCl3); HNMR (CDCl3, 400
1
1
MHz) δ = 7.91 (d, J = 14 Hz, 1H), 7.51ꢀ7.42 (m, 4H), 5.87 (s, 1H), 4.62 (s, 1H), 3.81 (s, 3H),
3.32ꢀ3.31 (m, 1H), 3.30ꢀ3.25 (m, 1H), 2.95ꢀ2.88 (m, 1H), 2.67ꢀ2.59 (m, 1H), 2.02ꢀ1.91 (m, 2H),
1.78ꢀ1.71 (m, 2H), 1.43ꢀ1.07 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 170.7, 154.8, 147.9, 133.4,
128.7, 124.8, 124.7, 79.2, 60.1,59.7, 59.6, 52.7,44.4, 44.2, 30.3, 30.2,24.3, 24.2, 23.6, 23.2, 23.1,
20.7, 19.6; 31P NMR (CDCl3 162 MHz): δ 14.7; HRMS (TOF ES+) m/z calcd for C23H35N5O5P [(M
+ H)+], 492.2370; found, 492.2472.
Methyl (4R,5S)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(naphthalen-1-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (3l)
White solid; 218 mg, 88%; mp 78−79 °C; [α]25 D =ꢀ89 (c = 1.3, CHCl3); 1HNMR (CDCl3, 400 MHz)
1
δ = 8.31 (d,J =8 Hz, 1H), 7.83ꢀ7.30 (m, 7H), 6.20ꢀ5.13 (m, 1H), 5.03ꢀ4.64 (m, 1H), 3.73ꢀ3.63 (m,
3H), 3.33ꢀ3.23 (m, 2H), 2.90ꢀ2.85 (m, 1H), 2.66ꢀ2.59 (m, 1H), 2.02ꢀ1.89 (m, 2H), 1.77ꢀ1.70 (m, 2H),
1.47ꢀ0.88 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 172.7, 157.7, 139.2, 133.2, 129.5, 128.9, 128.7,
128.2, 126.8, 126.1, 125.6, 124.7, 123.4,80.4, 66.1, 60.1, 58.4, 52.7,44.6, 44.5, 30.4,30.2, 24.3, 24.2,
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24.1, 23.2, 21.5, 19.8; P NMR (CDCl3 162 MHz): δ 15.8, 14.8; HRMS (TOF ES+) m/z calcd for
C27H38N4O3P [(M + H)+], 497.2676; found, 497.2660.
Methyl (4R,5R)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(pyridin-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (3m)
White solid; 116 mg, 52%; mp88−90 °C; [α]25 D =ꢀ48 (c = 1.9, CHCl3); 1HNMR (CDCl3, 400 MHz)
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δ = 8.58 (d, 1H, J= 4.8 Hz), 7.64ꢀ7.25 (m, 4H), 5.29ꢀ5.19 (m, 1H), 4.97ꢀ4.88 (m, 1H), 3.75 (s, 3H),
3.31ꢀ3.23 (m, 1H), 3.09ꢀ3.02 (m, 1H), 2.92ꢀ2.87 (m, 1H), 2.59ꢀ2.44 (m, 1H), 2.02ꢀ1.95 (m, 2H),
1.74ꢀ1.66 (m, 2H), 1.12ꢀ0.98 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 160.2, 154.3, 154.2, 149.9,
136.5, 123.4, 123.1, 65.1, 60.3, 60.2, 59.9, 52.6, 44.4, 30.7, 30.1, 24.4, 24.3, 22.8, 22.6, 22.5, 21.2,
19.8; 31P NMR (CDCl3 162 MHz): δ 14.1; HRMS (TOF ES+) m/z calcd for C22H35N5O3P [(M +
H)+], 448.2472; found, 448.2477.
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Methyl (4R,5S)-5-butyl-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosph
ol-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (3n)
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clear liquid; 196 mg, 92%; [α]25 D =ꢀ32 (c = 2.6, CHCl3); HNMR (CDCl3, 400 MHz) δ = 7.13 (s,
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1H), 4.38ꢀ4.32 (m, 1H), 4.12ꢀ4.05 (m, 1H), 3.67 (s, 3H), 3.38ꢀ3.26 (m, 2H), 2.97ꢀ2.92 (m, 1H),
2.74ꢀ2.69 (m, 1H), 2.02ꢀ1.88 (m, 3H), 1.76ꢀ1.62 (m, 2H), 1.45ꢀ0.88 (m, 24H); 13CNMR (CDCl3, 100
MHz) δ = 171.3, 154.7, 141.8, 131.9, 131.8, 128.8, 128.7, 122.2, 78.9, 63.7, 60.3, 60.2, 52.7,44.4,
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31.2, 30.1,24.3, 24.2, 23.8, 22.9, 22.8, 22.8, 21.1, 19.8; P NMR (CDCl3 162 MHz): δ 14.2, 14.1;
HRMS (TOF ES+) m/z calcd for C21H40N4O3P [(M + H)+], 427.2833; found, 427.2867.
General Procedure for the Synthesis of Products 4
At room temperature, AgF (5% mol) was added to a solution of Nꢀphosphonylimine (0.5 mmol, 1
equiv.) in dry DCM (5 mL), followed by the addition of methyl isocyanide (1.2 equiv.) dropwise
through a syringe. Completion of the starting material was monitored by thin layer chromatography
and 31PNMR of the reaction mixture (The reaction could be completed in 16 h). At this stage, 10 mL
of water was added to the reaction mixture and extracted with 2 × 5 mL of dichloromethane. The
combined organic layers were washed with water (1 × 5 mL) and brine solution (1 × 10 mL) and
dried over anhydrous Na2SO4. The solvent was evaporated after filtration, and the crude mixture was
coꢀconcentrated with hexanes. The products were dried under high vacuum. The solid products were
dissolved with ether and treated dry hexane to afford a pure product without column chromatography
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(GAP).
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Methyl (4S,5R)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate (4a)
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White solid; 194 mg, 87%; mp 48−49 °C; [α]25 D =31 (c = 3.6, CHCl3); 1HNMR (CDCl3, 400 MHz)
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δ = 7.41 (s, 1H), 7.27ꢀ7.22 (m, 5H), 5.04 (s, 1H), 4.72ꢀ4.66 (m, 1H), 3.69 (s, 3H), 3.18ꢀ3.05 (m, 1H),
2.91ꢀ2.83 (m, 2H), 2.82ꢀ2.71 (m, 1H), 2.01ꢀ1.95 (m, 1H), 1.89ꢀ1.82 (m, 1H), 1.71ꢀ1.69 (m, 2H),
1.56ꢀ0.88 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.5, 155.2, 142.6, 128.8, 128.5, 128.3, 127.8,
127.3, 77.5, 63.9, 60.3, 59.9, 52.5, 44.9, 43.4, 30.8, 29.8, 24.3, 24.2, 23.9, 23.2, 21.9, 20.1; 31P NMR
(CDCl3 162 MHz): δ 14.9; HRMS (TOF ES+) m/z calcd for C23H36N4O3P [(M + H)+], 447.2520;
found, 447.2530.
Methyl (4S,5R)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(p-tolyl)-4,5-dihydro-1H-imidazole-4-carboxylate (4b)
White solid; 152 mg, 66%; mp 60−61 °C; [α]25 D =39 (c = 2.2, CHCl3); 1HNMR (CDCl3, 400 MHz)
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δ = 7.44 (s, 1H), 7.37ꢀ7.03 (m, 4H), 5.14ꢀ5.07 (m, 1H), 4.72ꢀ4.66 (m, 1H), 3.67 (s, 3H), 3.20ꢀ3.15
(m, 1H), 2.91ꢀ2.88 (m, 3H), 2.30ꢀ2.25 (m, 3H), 2.01ꢀ1.95 (m, 1H), 1.82ꢀ1.76 (m, 1H), 1.74ꢀ1.65
(m ,2H), 1.55ꢀ0.88 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.6, 155.1, 139.6, 138.0, 129.4,
129.3, 127.8, 127.1, 78.6, 68.1, 63.7, 60.2, 59.9, 52.5, 44.9, 43.5, 31.1, 30.8, 25.6, 24.3, 24.2, 21.2,
21.1, 20.1; 31P NMR (CDCl3 162 MHz): δ 15.1; HRMS (TOF ES+) m/z calcd for C24H38N4O3P [(M
+ H)+], 461.2676; found, 461.2688.
Methyl (4S,5R)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(4-methoxyphenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (4c)
White solid; 169 mg, 71%; mp55−58 °C; [α]25 D =9.6 (c = 2.0, CHCl3); 1HNMR (CDCl3, 400 MHz)
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δ = 7.33 (s, 1H), 7.20ꢀ7.12 (m, 2H), 6.81ꢀ6.65 (m, 2H), 5.04ꢀ4.98 (m, 1H), 4.71ꢀ4.66 (m, 1H), 3.74
(s, 3H), 3.69 (s, 3H), 3.23ꢀ3.28 (m, 1H), 2.90ꢀ2.81 (m, 2H), 2.87ꢀ2.79 (m, 1H), 2.01ꢀ1.91 (m, 1H),
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1.89ꢀ1.82 (m, 1H) 1.73ꢀ1.69 (m, 2H), 1.43ꢀ0.79 (m, 16H); CNMR (CDCl3, 100 MHz) δ = 171.6,
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159.5, 154.8, 134.8, 128.9, 128.8, 114.1, 113.9, 78.4, 63.5, 60.1, 59.9, 55.4, 52.5, 43.5, 43.3,
30.8,29.7, 24.4, 24.3, 24.2, 23.4, 23.3, 21.4, 21.3, 21.2, 19.7; 31P NMR (CDCl3 162 MHz): δ
15.3HRMS (TOF ES+) m/z calcd for C24H38N4O4P [(M + H)+], 477.2625; found, 477.2619.
Methyl (4S,5R)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]diazaphosphol-2-yl)
-5-(2,4-dimethoxyphenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (4d)
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White solid; 222 mg, 88%; mp 58−59 °C; [α]25 D =117 (c = 2.3, CHCl3); 1HNMR (CDCl3, 400 MHz)
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δ = 7.28 (s, 1H), 6.81ꢀ6.70 (m, 3H), 5.01ꢀ4.88 (m, 1H), 4.69ꢀ4.63 (m, 1H), 3.77 (s, 3H), 3.79 (s, 3H),
3.69 (s, 3H), 3.21ꢀ3.18 (m, 1H), 2.86ꢀ2.81 (m, 2H), 2.69ꢀ2.62 (m, 1H), 1.95ꢀ1.91 (m, 2H), 1.68ꢀ1.59
(m, 1H), 1.39ꢀ0.88 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.4, 154.7, 149.1, 149.0, 135.1,
120.1, 111.0, 110.5, 78.1, 63.8, 59.9, 59.8, 56.1, 52.5, 44.8, 43.4, 30.8, 29.9,24.2, 24.1, 23.3, 23.2,
21.3,21.2, 20.1, 19.7; 31P NMR (CDCl3 162 MHz): δ 15.4; HRMS (TOF ES+) m/z calcd for
C25H40N4O5P [(M + H)+], 507.2731; found, 507.2760.
Methyl (4S,5R)-5-(3-chlorophenyl)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]
diazaphosphol-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (4e)
White solid; 192 mg, 80%; mp 77−78 °C; [α]25 D =ꢀ23 (c = 1.8, CHCl3); 1HNMR (CDCl3, 400 MHz)
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δ = 7.38 (d, J = 8 Hz, 1H), 7.36ꢀ7.21 (m, 4H), 5.10 (s, 1H), 4.68 (s, 1H), 3.74 (s, 3H), 3.24ꢀ3.19 (m,
1H), 2.89ꢀ2.22 (m, 2H), 2.03ꢀ1.95 (m, 1H), 1.90ꢀ1.88 (m, 1H), 1.73 (s, 2H), 1.55ꢀ0.73 (m, 16H);
13CNMR (CDCl3, 100 MHz) δ = 171.2, 154.9, 144.7, 134.7, 130.1, 128.4, 127.5, 125.9, 78.9, 63.5,
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60.2, 60.1,52.6,44.9, 43.5, 30.1,24.2, 24.1, 23.3, 23.1, 20.1, 19.8; P NMR (CDCl3 162 MHz): δ
15.2, 14.2; HRMS (TOF ES+) m/z calcd for C23H35ClN4O3P [(M + H)+], 481.2130; found, 481.2131.
Methyl (4S,5R)-5-(4-bromophenyl)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]
diazaphosphol-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (4f)
White solid; 145 mg, 55%; mp 66−67 °C; [α]25 D =ꢀ39 (c = 2.5, CHCl3); 1HNMR (CDCl3, 400 MHz)
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δ = 7.45ꢀ7.38 (m, 2H), 7.34 (d, J = 10 Hz, 1H), 7.15ꢀ7.03 (m, 2H), 5.11 (s, 1H), 4.68 (s, 1H), 3.74 (s,
3H), 3.25ꢀ3.22 (m, 1H), 2.89ꢀ2.82 (m, 2H), 2.58ꢀ2.52 (m, 1H), 2.03ꢀ1.95 (m, 2H), 1.88ꢀ1.82 (m, 2H),
1.47ꢀ0.81 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 171.3, 154.9, 141.8, 131.9, 131.8, 129.3, 128.9,
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122.2, 78.9, 63.5, 60.2, 59.9, 52.6,44.9, 43.5, 30.9, 29.9,24.3, 24.2, 23.2, 23.1, 20.2,19.8; P NMR
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(CDCl3 162 MHz): δ 15.4, 14.3; HRMS (TOF ES+) m/z calcd for C23H35BrN4O3P [(M + H)+],
525.1625; found, 525.1623.
Methyl (4S,5R)-5-(4-cyanophenyl)-1-((3aR,7aR)-1,3-diisopropyl-2-oxidooctahydrobenzo[d][1,3,2]d
iazaphosphol-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate (4g)
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White solid; 188 mg, 80%; mp147−148 °C; [α]25 D =ꢀ59 (c = 1.7, CHCl3); HNMR (CDCl3, 400
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MHz) δ = 7.63ꢀ7.44 (m, 4H), 7.23 (s, 1H), 5.23ꢀ5.20 (m, 1H), 4.67ꢀ4.61 (m, 1H), 3.75ꢀ3.70 (m, 3H),
3.25ꢀ3.18 (m, 1H), 2.91ꢀ2.87 (m, 2H), 2.66ꢀ2.59 (m, 1H), 2.05ꢀ2.01 (m, 2H), 1.77ꢀ1.72 (m, 2H),
1.57ꢀ0.88 (m, 16H); 13CNMR (CDCl3, 100 MHz) δ = 170.9, 154.7, 147.8, 132.6, 132.5,128.4, 127.8,
118.6, 112.2, 78.5, 63.8, 60.4, 60.3, 52.8,45.0, 44.3, 43.6, 30.7,29.9, 24.3, 24.2, 23.1, 22.2, 21.9, 20.1;
31P NMR (CDCl3 162 MHz): δ 15.3, 14.1; HRMS (TOF ES+) m/z calcd for C24H35N5O3P [(M +
H)+], 472.2472; found, 472.2482.
1,3-Di-tert-butyl 4-methyl (4R,5S)-2-oxo-5-phenylimidazolidine-1,3,4-tricarboxylate (6a)10c
The resulting imidazoline 3a (60 mg, 0.134 mmol) was dissolved in a 50% KOH solution in water (2
mL), and the solution was refluxed for 10 hours. Then, the reaction was cooled to 0 ºC and
neutralized with a 1.0 M HCl solution (until pH 6.7). The solvents were removed in vacuo and the
remaining residue was loaded onto a Amberlite H+ ion exchange resin. The column was flushed with
water, dioxane, more water and eluted with 2.0 M aqueous ammonia. The ammoniacal fraction was
reduced in vacuo to afford the crude diaminoacid 5a as a white solid in 80% yield (20 mg). The
diamino acid 5a (20 mg, 0.111 mmol) was dissolved in methanol (0.5 mL), and the solution was
cooled to 0 ºC, then SOCl2 (0.2 mL) was added dropwise and the reaction mixture was stirred under
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reflux for 12 hours. After evaporation of solvents under vacuum, the crude diaminoester was
dissolved in dry acetonitrile (5 mL), followed by addition of DMAP and (Boc)2O at 0 ºC. The
reaction mixture was stirred at room temperature for 12 hours. Evaporation of acetonitrile under
vacuum gave a solid, which was purified by column chromatography on silica gel, affording the
compound 6a as a pale yellow liquid in 47% yield (21 mg).
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1HNMR (CDCl3, 400 MHz) δ = 7.80ꢀ7.77 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.54ꢀ7.47 (m, 3H), 4.26
(s, 1H), 3.90 (s, 3H), 3.74 (s, 1H), 1.47ꢀ1.30 (m, 18H); 13CNMR (CDCl3, 100 MHz) δ = 166.1, 164.7,
148.9, 141.6, 135.3, 132.4, 128.2, 125.6, 124.5, 120.2, 114.9, 84.7, 82.2, 71.8, 59.1, 28.1; HRMS
(TOF ES+) m/z calcd for C21H29N2O7 [(M + H)+], 421.1969; found, 421.1948.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra for all pure products, and Xꢀray crystal data (CIF) for 3a and 4a. This
material is available free of charge via the Internet at http//pubs.acs.org.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We would like to acknowledge the financial support from National Natural Science Foundation of
China (No. 21332005), Robert A. Welch Foundation (Dꢀ1361, USA) and NIH (R33DA031860,
USA).
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