Mitsunobu Reaction Using Basic Amines as Pronucleophiles

Article abstract of DOI:10.1021/acs.joc.7b00622

A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C-N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C-N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43-93% yields. Importantly, C-N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system.

Full text of DOI:10.1021/acs.joc.7b00622

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Article
Mitsunobu Reaction Using Basic Amines as Pronucleophiles
Hai Huang, and Jun Yong Kang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 May 2017
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Mitsunobu Reaction Using Basic Amines as Pronucleophiles
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Hai Huang, Jun Yong Kang*
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Department of Chemistry and Biochemistry, University of Nevada Las Vegas, 4505 S.
Maryland Parkway, Las Vegas, Nevada, 89154ꢀ4003, United States
Eꢀmail: junyong.kang@unlv.edu
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Mitsunobu reaction
+
Nu
R
OH
R
Nu
Nu = NH2R, NHR1R2, RCOOH, RSH, ROH
(Amine nucleophiles allowed in this system)
R=alkyl, aryl
Azo-compound:
Application:
P-reagent:
O
O
Ph
N
O
n-Bu
N
N
N
N
N
P
N
N
N
N
O
Ph
Piribedil
(anti-Parkinsonian agent)
NHP-butane
ADDP
Abstract
A novel protocol for extending the scope of the Mitsunobu reaction to include amine
nucleophiles to form C–N bonds through the utilization of heterocyclic phosphine butane
N
ꢀ
ꢀ
(NHP–butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable
substrates for C–N bond construction. Various acidic nucleophiles such as benzoic acids, phenols,
thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers,
thioether, and tertiary sulfonamide with 43% to 93% yields. Importantly, C–N bondꢀcontaining
pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the
commercial amines under this Mitsunobu reaction system.
Introduction
Owing to the mild reaction conditions and broad substrate scope, the Mitsunobu reaction has
been widely recognized as an essential tool in organic synthesis for the substitution of primary or
secondary alcohols with acidic pronucleophiles since its discovery in 1967.1 This method has been
broadly adopted in the synthesis of a majority of functional groups from alcohols and used in a
key step of biologically active natural product synthesis to invert the stereochemistry of alcohols
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with various nucleophiles.2 Mitsunobu reaction enables the formation of C–O, C–N, C–S, and C–
C bonds in presence of phosphines and azocompounds.2a, b, 3 Despite these advantages, synthetic
applications of Mitsunobu reaction still face two major hurdles: (1. Catalytic Process) the use of
stoichiometric amount of phosphines and azocompounds as well as the generation of phosphine
oxide and hydrazine byꢀproducts, (2. Expansion of Scope) the requirement of acidic
pronucleophiles with the pKa below 11 for a successful transformation. Thus, numerous efforts
have been continuously devoted to address these hurdles. For the hurdle (1), the use of a catalytic
amount of phosphine reagents and azocompounds is a potential solution to reduce the generation
of toxic wastes in the Mitsunobu reaction. Toy and coꢀworkers reported the first hydrazineꢀbased
redox catalytic protocol of Mitsunobu reaction.4 However, a limited substrate scope of only acidic
pronucleophiles has remained unresolved. As an alternative strategy, Taniguchi group
demonstrated azocarboxylate catalytic Mitsunobu reaction based on Fe(Pc) oxidation system in
2013.5 Recently, the Aldrich group showcased a fully catalytic protocol using a catalytic loading
of both phosphine oxides and arylhydrazinecarboxamides, but showed only one working example
(with the highly acidic 4ꢀnitrobenzoic acid nucleophile).6 The scope of these catalytic Mitsunobu
reactions continues to be limited to only highly acidic pronucleophiles. These catalytic protocols
provide a foundation for potential solutions to overcome the use of stoichiometric amount of
Pꢀreagents and azocompounds; however, the expansion of the nucleophile scope to include
nonacidic or basic nucleophiles still remains a key, unresolved challenge in Mitsunobu reaction.
Novel Pꢀreagents and azocompounds have been developed to improve the efficiency of
Mitsunobu reaction over the past decades. Selected examples7 include a multipolymer system,8
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ADDP
the pKa restriction of pronucleophiles using a stable P
non aromatic nitrogen heterocycles. It is important to note that the stability of P
due to the potential application toward a phosphine catalyzed Mitsunobu reaction.
–
TBP,9 CMBP,10 CMMP11 and Ishikawa phosphorane.12 Despite these important advances,
reagent has not been realized with
reagents is key
ꢀ
ꢀ
ꢀ
ꢀ
Compounds containing nitrogen heterocycles such as piperazine, morpholine, and piperidine are
significant building blocks because of their both unique biological properties and broad
pharmaceutical applications.13 A large number of medicines containing nitrogen heterocycles such
as cinnarizine,14 flunarizine,15 piribedil,16 moclobemide,17 oxatomide,18 and fentanyl19 have been
synthesized (Fig 1). Thus, various synthetic methods have been established for C–N bond
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formation to construct the nitrogenꢀcontaining heterocycles.20 For example, multiple groups have
employed a borrowing hydrogen strategy for the Nꢀalkylation of amines using alcohols to
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introduce the C
–
N bond. While this approach has advantages over the traditional halogenated
–
alkylating reagents,21 complex transition metal
ꢀ
ligand systems (e.g., Ru,22 Ir,23 Ni,24 Pd,25 and
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others26) are required. In addition, this approach often requires harsh reaction conditions (high
reaction temperatures) and extra purification for the removal of metal impurities in final
pharmaceuticals.27 Thus, a mild, metal
ꢀfree amination reaction of alcohols is an important,
attractive transformation especially for
a
rapid synthesis of
C
–
N
bond containing
pharmaceuticals.28
R
O
O
N
N
R
N
N
N
Piribedil
N
Ph
Ph
N
O
R = Ph; Cinnarizine
R = 4-FPh; Flunarizine
N
N
O
HN
O
O
N
Ph
Oxatomide
N
N
H
N
Cl
Fentanyl
moclobemide
Fig 1. C-N bond containing pharmaceuticals
Our group has actively studied the reactivity of Nꢀheterocyclic phosphine (NHP)ꢀthioureas as
bifunctional phosphonylation reagents.29 With the strong nucleophilicity and versatile application
of the NHP units in organic synthesis,30 we turned our attention to explore their reactivity toward
oxidationꢀreduction condensation reaction. Recently, we successfully demonstrated the utility of
strongly nucleophilic diazaphosphites toward the redox condensation for carbonꢀheteroatom bond
construction (Scheme 1, eq a).31 However, this redox reaction of diazaphosphites needs
preꢀactivation of alcohols and exhibits moderate overall yields from alcohol. Hence, to advance
this methodology, we further explored the redox condensation reaction for C–N bond construction
directly from alcohols and nonꢀacidic amine proꢀnucleophiles. The construction of CꢀN bonds
using weakly acidic amines in the Mitsunobu reaction has remained underdeveloped due to the
limitation of currently working pKa below 11. In addition to the pKa restriction of the
pronucleophiles, the high nucleophilicity of amines can prohibit a successful CꢀN bond formation,
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in which the undesired azaꢀMichael reaction competes with the desired phosphaꢀMichael reaction.
Therefore, amines can directly undergo azaꢀMichael reaction with azoꢀcompound to form a
triazine byꢀproduct,32 preventing the desired phosphaꢀMichael addition reaction between
phosphines and azoꢀcompounds. Identifying the potential problems with amine nucleophiles in the
Mitsunobu reaction, we hypothesized that the highly nucleophilic phosphines would promote the
desired phosphaꢀMichael reaction. Hence, this limitation could be addressed by employing a
highly nucleophilic NHP A to preferentially form the desired betaine intermediate C, which
deprotonates pronucleophile D to generate an azoꢀphosphonium intermediate E. The alcohol F
attacks the intermediate E to produce alkoxyphosphonium G, which undergoes nucleophilic
substitution reaction with the pronucleophile D to afford the target product H (Scheme 1, eq b).
Alternatively, amine proꢀnucleophiles D could directly attack the alkoxyphosphonium
intermediate G to form the CꢀN bond. Herein, we report that the highly nucleophilic NHPs allow a
significant expansion of the scope of the Mitsunobu reaction to include previously restricted
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nitrogen nucleophiles in C–N bond formation with aliphatic alcohols.
Scheme 1. Exploration of NHPs for the Mitsunobu reaction
Our previous work:
H
Ph
O
N
N
P
DIAD
NHP-Cl
Requirement:
pre-activation of alcohols
Ar
N
a)
Ar
OH
N
Ar
+
redox condensation
Ph
This work:
O
R2
R3 Nu
N
R1
N
R2
N
B
NHP
A
H
O
P
phospha-Michael
addition reaction
N
R1
R
NHP
NHP[O]
b)
A
R1
N
Nu
NHP
R2
O
NuH
D
R3 OH
NHP
R2
O
F
N
R2
P
N
N
R3
O
N
H
R2
N
R1
R
O
2H-azo
C
G
O
E
Results and discussion
Table 1. Optimized reaction conditionsa
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P-reagent
azo-compound
N
OH
+
HN
O
solvent, t (°C)
O
1a
3a
2a
P-reagent
Ph
R
P-1: R, R1 = Ph
P-2: R, R1 = n-Bu
P-3: R = Ph, R1 = n-Bu
P-4: R, R1 = 4-MeOPh
Ph
P-7: R = t-Bu, R1 = n-Bu
P-8: R = Ph, R1 = n-Bu
P-9: R, R1 = Ph
R
R
R
N
N
P R1
P-5: R = Et
P-6: R = t-Bu
P O
P R1
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N
N
Ph
R
N
Ph
Ph
P N
N
P N
P-10
Ph
P-11
azo-compound
O
X
O
Azo-3: R = Et
Azo-4: R = i-Pr
Azo-5: R = t-Bu
N
N
Azo-1: X = CH2
Azo-2: X = O
R
O
N
O
N
N
N
R
X
O
O
entry
1
P-reagent
P-1
azo-compound
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-2
Azo-3
Azo-4
Azo-5
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
Azo-1
solvent
THF
t (°C)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
40
80
80
60
80
40
rt
yield (%)b
7
2
P-2
THF
8
3
P-3
THF
7
4
P-4
THF
8
5
P-5
THF
44
6
P-6
THF
trace
7
P-7
THF
9
8
P-8
THF
99
9
P-9
THF
18
10
11
12
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17
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20
21
22
23d
24e
P-10
P-11
P-8
THF
<5
THF
21
17
THF
P-8
THF
39
P-8
THF
50
P-8
THF
58
P-8
DCM
toluene
CH3CN
CHCl3
DCE
DCE
DCE
DCE
DCE
92
P-8
96
P-8
74
P-8
50
P-8
>99 (94)c
>99 (91)c
90 (85)c
93
P-8
P-8
P-8
40
40
P-8
>99 (92)c
aReaction condition: benzyl alcohol 1a (0.1 mmol), morpholine 2a (1.5 equiv), p-reagent
b
(1.5 equiv) and azo-compound (1.5 equiv) in solvent (0.5 mL) for 24 h. yield was
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c
determined by crude H NMR using 1,3,5ꢀtrimethylbenzene as internal standard. Isolated
yield. d1.2 equiv of P-8. e1.2 equiv of Azo-1
.
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9
To test our hypothesis, benzyl alcohol 1a and morpholine 2a were chosen as model substrates to
exam the feasibility of C–N bond formation and the results are described in Table 1. Azo-1
(1,1'ꢀ(Azodicarbonyl)dipiperidine) was first employed to screen Pꢀreagents. Although TPP (P-1)
and TBP (P-2) are common Pꢀreagents in Mitsunobu reaction, they generated the corresponding
product 3a in only 7–8% yield by NMR (entries 1 and 2). The modification of P-1 with stronger
electron donating properties did not help to improve the reactivity, providing again 7–8% yield by
NMR of 3a (entries 3 and 4). Utilization of 2ꢀethoxyꢀ1,3ꢀdiphenylꢀ1,3,2ꢀdiazaphospholidine P-5
(originally developed for a phosphonylation reagent29a in our group) produced 3a in an improved
44% NMR yield. Further modifications of P-5 to P-6 to improve the reactivity were unsuccessful
due to the decomposition of the NHP–OtBu P-6 to NHPꢀoxide via the C–O bond cleavage. To
prevent the decomposition process while maintaining the strong nucleophilicity of the NHP motif,
we synthesized C–P bonded NHPs P-7, P-8 and P-9. Among them, the NHP–butane P-8 provided
the desired product 3a in 99% yield by NMR (entries 7–9). Both aminodiphenylphosphine P-10
and phosphorus triamide P-11 were inferior to the NHPꢀbutane P-8, affording 3a in 5% and 21%
NMR yields, respectively (entries 10 and 11). With the optimized Pꢀreagent P-8 in hand, we
screened other azocompounds Azo-2–5, but they were less effective (entries 12–15). Solvent study
revealed that DCE is superior to DCM, toluene, CH3CN, and CHCl3. It is noteworthy that this
reaction performs well at room temperature, providing the desired product 3a with 85% yield
(entry 22). Finally, the optimum reaction conditions were achieved with a slight excess of P-8 (1.5
equiv) and Azo-1 ADDP (1.2 equiv), furnishing the target product 3a in 92% yield (entry 24).
With the optimum reaction conditions, we first explored the scope of amine nucleophiles
(Scheme 2). Thioꢀmorpoline provided the corresponding substitution product 3b with 71% yield.
Piperidine and an 4ꢀethyl esterꢀsubstituted piperidine afforded the desired products 3c and 3d in
66% and 80% yields, respectively. Various 4ꢀsubstituted piperazines were also successfully
employed in this reaction to give the corresponding products 3eꢀ3g in good yields.
1ꢀMethylpiperazine derivatives are important scaffolds of biologically active compounds and they
proved to be viable substrates, affording the desired products 3h and 3i in 86% and 56% yields,
respectively. Moreover, noncyclic secondary amines such as dibenzyl amine 2j and
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Nꢀbenzylaniline 2k were also successful in affording the desired products 3j and 3k in 71% and 67%
yields, respectively. Interestingly, diethyl amine 2l was not effective under the standard reaction
conditions probably due to its higher basicity and unreacted 1a was recovered. Finally, we
demonstrated that this Mitsunobu reaction protocol is a useful alternative route for a direct
synthesis of secondary amines from various primary amines (2m and 2n), providing the
corresponding secondary amine products 3m and 3n in 43% and 34% yields, respectively (with
2.7:1–1:1.7 ratio of secondary amines and tertiary amines).
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Scheme 2. Scope of aminesa
P-8 (1.5 equiv)
Azo-1 (1.2 equiv)
H
N
R2
Ph
N
R1
R2
Ph
OH
+
DCE, 40 °C, 24-36 h
R1
1a
2
3
Ph
N
Ph
N
Ph
N
Ph
N
X
N
N
R
R
R
3a, X = O, 92%b
3b, X= S, 71%
3e, R = Boc, 85%
3f, R = t-Bu, 83%
3g, R = cyclohexyl, 80%
3c, R = H, 66%
R
3d, R = COOEt, 80%
3h, R = Ph, 86%
3i, R = 4-FPh, 56%
R1
Ph
N
Ph
Ph
N
H
Ph
N
R2
H
3j, R1 = R2 = Bn, 71%
3k, R1 = Ph, R2 = Bn, 67%
3l, R1 = R2 = Et, NDc
3m, 43%
3m/3j = 2.7:1d
3n, 34%
3n/3k = 1:1.7d
aReaction conditions: 1a (0.1 mmol), 2 (1.5 equiv), P-8 (1.5 equiv) and Azo-1 (1.2 equiv) in DCE
b
c
d
1
at 40 °C for 24–36 h. Isolated yield (%). Reaction run for 36 h. Ratio assigned by using H
NMR of crude reaction mixture. ND = not determined.
Next, acidic nucleophiles were evaluated in this Mitsunobu reaction system (Scheme 3).
Benzoic acids with various substituents 4a–4h were proceeded smoothly to provide the desired
products in good yields (5a–5h). Aliphatic acids such as cyclohexanecarboxylic acid 4i also
proved to be a useful substrate to furnish an ester product 5i under the standard reaction conditions.
A conjugated acid 4j was also successful in producing the desired product 5j in 88% yield.
2,2ꢀDiphenylacetic acid 4k provided the corresponding ester 5k in 83% yield. The reaction of the
benzyl alcohol 1a with phenol 4l gave the corresponding ether product 5l in 66% yield. While a
disulfide is a major product with thiol nucleophiles in conventional Mitsunobu reaction,33
a
thioether 5m was obtained as a major product (43% yield) from thiophenol 4m. A weakly acidic
sulfonamide 4n also furnished the desired product 5n in 81% yield.
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Scheme 3. Scope of acidic nucleophilesa
5
6
7
8
P-8 (1.5 equiv)
Azo-1 (1.2 equiv)
Acidic Nu
Ph
OH
Ph
Nu
+
DCE, 40 °C, 24-36 h
1a
4
5
9
O
O
O
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Ph
Ph
O
Ph
O
Ph
Ph
5a, R = Ph, 91%b ,
O
R
Ph
5f, R = 2,4-Cl2Ph, 91%
5j, 88%
5k, 83%
Ts
5b, R = 4-MePh, 89%, 5g, R = 4-CF3Ph, 89%
5c, R = 4-FPh, 83%, 5h, R = 4-NO2Ph, 93%
5d, R = 4-ClPh, 85%, 5i, R = Cyclohexyl, 78%
5e, R = 4-BrPh, 91%
Ph
Ph
5l, X = O, 66%
5m, X = S, 43%c
X
Ph
N
Ph
5n, 81%
aReaction conditions: 1a (0.1 mmol), 4 (1.5 equiv), P-8 (1.5 equiv) and Azo-1 (1.2 equiv) in DCE
at 40 °C for 24–36 h. bIsolated yield (%). cReaction run for 36 h.
Finally, the scope of alcohols was investigated and the results are summarized in Scheme 4.
Various substituted benzyl alcohols 1bꢀ1i were wellꢀtolerated and afforded the corresponding
products 6aꢀ6h in moderate to good yields. Benzyl alcohols containing electronꢀwithdrawing
groups provided lower yields than more electron rich alcohols. Polycyclic aromatic alcohols such
as quinolinꢀ6ꢀylꢀmethanol 1j and naphthalenꢀ1ꢀylꢀmethanol 1k also turned out to be suitable
substrates in this system and furnished the desired products 6i and 6j in 77% and 84% yields,
respectively. Cinnamyl alcohol 1m produced the allylamine product 6l in 79% yield with complete
αꢀregioselectivity.34 The substitution product of an ester 6m from 2,2ꢀdiphenylethanol 1n was
isolated in 86% yield without any appreciable elimination byꢀproducts. Secondary alcohols (1o,
1p) were also suitable substrates for this reaction – providing the desired products 6n and 6o in 82%
and 68% yields, respectively. Furthermore, aliphatic alcohols such as 3ꢀphenylpropanꢀ1ꢀol 1p
were also suitable coupling partners in this Mitsunobu reaction system – yielding the
corresponding amine products 6p and 6q in 59% and 73% yields, respectively. This successful C–
N bond formation between aliphatic alcohol and amines may rule out the possibility of formation
of a carbocation intermediate, which is a suspected intermediate in Mitsunobu reaction employing
allylic or benzylic alcohols.35 Finally, we applied this Mitsunobu reaction to the synthesis of two
C–N bondꢀcontaining pharmaceuticals Piribedil 6r and Cinnarizine 6s, which were successfully
isolated in 83% and 74% yields, respectively.
Scheme 4. Scope of alcoholsa
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P-8 (1.5 equiv)
Azo-1 (1.2 equiv)
R2
R2
+
Nu
R1
1b-1t
OH
R1
Nu
DCE, 40 oC, 24-36 h
6
N
R
N
R
N
Ph
O
O
N
N
Ph
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6a, R = 4-MePh, 89%b
6b, R = 4-MeOPh, 88%
6c, R = 4-ClPh, 85%
6d, R = 4-BrPh, 82%
6e, R = 2,4-Cl2Ph, 83%
6f, R = 4-NO2Ph, 68%c
6i, 77%
O
6g, R = 4-FPh, 88%
6h, R = 4-CF3Ph, 53%c
6j, 84%
O
Ph
O
O
N
N
O
O
O
Ph
Ph
6l, 79%
6m, 86%
6k, 73%
O
O
N
N
O
Ph
N
Ph
O
Ph
O
Ph
Ph
6q, 73%
6p, 59%
6n, 82%
6o, 68%
Ph
O
O
N
N
N
N
N
Ph
N
Cinnarizine 6s, 74%
Ph
Piribedil 6r, 83%
aReaction conditions: 1 (0.1 mmol), Nu (1.5 equiv), P-8 (1.5 equiv) and Azo-1 (1.2 equiv) in DCE
at 40 °C for 24–36 h. bIsolated yield (%). cReaction run for 36 h.
To gain insights into the mechanism for this transformation, an exhaustive
isolationꢀcharacterization process of all products and byꢀproducts from the standard reaction was
performed (Scheme 5). Along with the desired substitution product 3a, we isolated Nꢀheterocyclic
phosphine oxide P-8-[O] and hydrazine Azo-1-[R] byꢀproducts in 71% and 83% yields,
respectively (eq 1). In addition, there was no coupling product generated in the absence of
azocompound Azo-1, confirming the requirement of azocompound (eq 2) for a successful
coupling reaction. Furthermore, we demonstrated that this reaction maintains its high efficiency
even at room temperature reaction conditions (eq 3). Finally, we evaluated the stereochemical
outcome employing a chiral alcohol (S)ꢀ1o under our Mitsunobu reaction conditions. A complete
inversion of configuration at the reaction center was observed when (S)ꢀ1ꢀphenylethanꢀ1ꢀol 1o
was treated with benzoic acid 4a (eq 4). All the outcomes above suggest that this transformation
follows the known Mitsunobu reaction mechanism.36
Scheme 5. Control experiments for mechanism study.
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Ph
P-8 (1.5 equiv)
Azo-1 (1.2 equiv)
H
N
O
O
N
H
OH
N
N
N
P
n-Bu
+
+
+
(1)
N
N
O
DCE, 40 °C, 24 h
N
H
O
2a
O
Ph
P-8-[O], 71%
1a
3a, 92%
Azo-1-[R], 83%
H
N
P-8 (1.5 equiv)
OH
OH
no reaction
(2)
(3)
+
+
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DCE, 40 °C, 24 h
O
2a
1a
1a
P-8 (1.5 equiv)
Azo-1 (1.2 equiv)
H
N
N
O
DCE, rt, 24 h
O
2a
3a, 85%
O
OH
O
Ph
P-8 (1.5 equiv)
Azo-1 (1.2 equiv)
+ PhCOOH
(4)
DCE, 40 °C, 24 h
(S)-1o
4a
(R)-6m
78%, er = 97:3
Conclusion
In summary, a NHPꢀbutane (1,3,2ꢀDiazaphospholidine) P-8 has been rationally developed for
the expansion of the substrate scope to include previously restricted nitrogen nucleophiles in
Mitsunobu reaction. With the strong nucleophilicity of the NHPꢀbutane P-8, nonꢀacidic amine
nucleophiles can undergo substitution reaction with aliphatic alcohols in the presence of ADDP.
This transformation also provides an alternative entry to the synthesis of secondary amines. In
addition, this reaction takes place under mild conditions and exhibits broad functional group
tolerance. A practical application of this Mitsunobu reaction system for the synthesis of the C–N
bondꢀcontaining pharmaceuticals Cinnarizine and Piribedil (anti–Parkinson agent) was also
successfully demonstrated. Further studies on the catalytic Mitsunobu reaction employing the
NHPs are underway in our Laboratory and will be reported in due course.
Experimental Section
General Information
All reactions were carried out under atmospheric conditions in ovenꢀdried glassware with
magnetic stirring bar. Dry solvents (THF, toluene, and DCM) were obtained by solvent
purification system under argon. All commercially available reagents were used as received
without further purification. Purification of reaction products was carried out by flash column
chromatography using silica gel 60 (230–400 mesh). Analytical thin layer chromatography was
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performed on 0.25 mm aluminumꢀbacked silica gel 60ꢀF plates. Visualization was accompanied
with UV light and KMnO4 solution. Concentration under reduced pressure refers to the removal of
volatiles using a rotary evaporator attached to a dry diaphragm pump (10–15 mm Hg) followed by
pumping to a constant weight with an oil pump (<300 mTorr). Infrared (IR) spectra were recorded
on an IR spectrometer with KBr wafers or a film on KBr plate. Highꢀresolution mass spectra
(HRMS) were recorded on LCMSꢀITꢀTOF mass spectrometer using ESI (electrospray ionization).
1H NMR spectra were recorded in CDCl3 on 400 MHz NMR spectrometer. The 1H chemical shifts
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1
are referenced to residual solvent signals at δ 7.26 (CHCl3) or δ 0.00 (TMS). H NMR coupling
constants (J) are reported in Hertz (Hz) and multiplicities are indicated as follows: s (singlet), bs
(broad singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublets), dt (doublet of
triplets). 13C NMR spectra were proton decoupled and recorded in CDCl3 on 100.5 MHz NMR
spectrometer. The 13C chemical shifts are referenced to solvent signals at δ 77.16 (CDCl3). 31
NMR spectra were proton decoupled and recorded in CDCl3 on 162 MHz NMR spectrometer. 31
chemical shifts are reported relative to 85% H3PO4 (0.00 ppm) as an external standard.
The procedure for the synthesis of P-reagents
P
P
Triphenylphosphine (P-1): commercial; 1H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.27 (m, 15 H).
1
Tributylphosphine (P-2): commercial; H NMR (400 MHz, CDCl3) δ 1.46ꢀ1.34 (m, 18 H),
0.95ꢀ0.88 (m, 9 H).
Butyldiphenylphosphine (P-3)37: To a solution of diphenylphosphine (177 ꢁL, 1.02 mmol),
1ꢀbromobutane (107 ꢁL, 1.0 mmol) in THF (15 mL) was added tꢀBuOK (301.4 mg, 2.69 mmol) at
0 °C under argon atmosphere. The resulting reaction mixture was refluxed for 22 h. After
refluxing for 22 h, the reaction mixture was diluted with Et2O (15 mL) and then washed with
water (15 mL) and brine (15 mL). The organic phase was dried over Na2SO4 and Na2SO4 was
filtered off. The organic solvent was evaporated under reduced pressure to give pure product P-3
as a colorless oil; 181.6 mg, 75%; 1H NMR (400 MHz, CDCl3) δ 7.48ꢀ7.36 (m, 4H), 7.35ꢀ7.28 (m,
6H), 2.07ꢀ2.01 (m, 2H), 1.49ꢀ1.36 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100.5 MHz,
CDCl3) δ 139.0 (d, J = 12.7 Hz), 132.7 (d, J = 17.8 Hz), 128.3 (d, J = 9.7 Hz), 128.4, 28.1 (d, J =
15.7 Hz), 27.8 (d, J = 11.2 Hz), 24.3 (d, J = 13.4 Hz), 13.8.
1
tris-(4-Methoxyphenyl)phosphine (P-4): commercial; H NMR (400 MHz, CDCl3) δ 7.26ꢀ7.19
(m, 6 H), 6.87 (d, J = 8.0 Hz, 6 H), 3.79 (d, J = Hz, 9 H).
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2-chloro-1,3-diphenyl-1,3,2-diazaphospholidine
(NHPꢀCl):29d
To
a
solution
of
5
6
7
8
N,N’ꢀdiphenylethylenediamine (2.12 g, 10 mmol) in DCM (40 mL ) was added anhydrous
triethylamine (2.8 mL, 20 mmol). The resulting solution was cooled to 0 °C and phosphorus
trichloride (0.86 mL, 10 mmol) was added dropwise over a period of 10 min giving a brown
solution with a small amount of white precipitate. The reaction mixture continued to stir at 0 °C
for 30 min and then 2 h at room temperature. After stirring for 2 h at room temperature, the
solvent was evaporated under reduced pressure to give orangeꢀbrown solid. The orangeꢀbrown
solid was extracted with THF (3 × 20 mL). The combined organic solutions were evaporated
under reduced pressure to give a brown freeꢀflowing solid.
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2-Ethoxy-1,3-diphenyl-1,3,2-diazaphospholidine (P-5):29a To a solution of NHPꢀCl (549.2 mg,
2.0 mmol), Et3N (0.42 mL, 3.0 mmol) in DCM (20 mL) was added ethanol (0.2 mL, 3.0 mmol) at
0 °C under argon atmosphere. The resulting reaction mixture was stirred at 0 °C for 30 min. After
stirring for 30 min at 0 °C, it was allowed to warm up to room temperature and stirred for 2 h at
room temperature. The reaction mixture was diluted with DCM (20 mL) and the resulting solution
was washed with aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and Na2SO4
was filtered off. After removal of the solvent under reduced pressure, the residue was purified by
flash column chromatography on basic alumina (Hexane/EA = 5:1) to give corresponding product
1
P-5 as white solid; 181.1 mg, 32 %; H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 8.4 Hz, 4H),
7.17ꢀ7.15 (m, 4H), 6.92 (t, J = 7.3 Hz, 2H), 3.89ꢀ3.77 (m, 4H), 3.64 (q, J = 7.0 Hz, 2H), 1.05 (t, J
= 6.9 Hz, 3H); 13C NMR (100.5 MHz, CDCl3) δ 145.2 (d, J = 17.2 Hz), 129.3, 119.9 (d, J = 1.5
Hz), 115.3 (d, J = 14.2 Hz), 59.2, 47.3 (d, J = 9.7 Hz), 16.6 (d, J = 2.9 Hz).
2-(tert-Butoxy)-1,3-diphenyl-1,3,2-diazaphospholidine (P-6): To a solution of NHPꢀCl (530.8
mg, 1.92 mmol) and Et3N (0.4 mL, 2.88 mmol) in DCM (20 mL) was added 2ꢀmethylpropanꢀ2ꢀol
(0.26 mL, 2.88 mmol) at 0 °C under argon atmosphere. The resulting reaction mixture was stirred
at 0 °C for 30 min. After stirring for 30 min at 0 °C, it was allowed to warm up to room
temperature and stirred for 2 h at room temperature. The reaction mixture was diluted with DCM
(20 mL) and the resulting solution was washed with aq. NaHCO3 and brine. The organic phase
was dried over Na2SO4 and Na2SO4 was filtered off. After removal of the solvent under reduced
pressure, the residue was purified by flash column chromatography on basic alumina (Hexane/EA
= 5:1) to give corresponding product P-6 as white solid; 236.7 mg, 39 %; mp 111ꢀ112 °C
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(decomp.); IR
ν
(KBr, cm−1) 3038, 2954, 2895, 1600, 1502, 1491, 1476, 1302, 1287, 1224, 1133,
1036, 981, 784; 1H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.30 (m, 4H), 7.30ꢀ7.24 (m, 4H), 7.08 (ddd, J
= 8.2, 3.0, 1.2 Hz, 2H), 6.88 (t, J = 7.2 Hz, 2H), 3.92ꢀ3.82 (m, 2H), 3.68ꢀ3.56 (m, 2H), 1.19 (d, J =
0.8 Hz, 9H); 13C NMR (100.5 MHz, CDCl3) δ 145.4 (d, J = 17.1 Hz), 129.1, 119.5 (d, J = 1.5 Hz),
116.0 (d, J = 13.4 Hz), 74.7 (d, J = 7.4 Hz), 46.4 (d, J = 8.2 Hz), 31.0 (d, J = 7.5 Hz); 31P NMR
(162 MHz, CDCl3): δ 106.0 ppm. HRMS (ESIꢀTOF) m/z: found [M + H]+ values corresponding to
N1,N2ꢀdiphenylethaneꢀ1,2ꢀdiamine; [M + H]+ Calcd for C14H17N2: 213.1386; found: 213.1378.
1,3-di-tert-Butyl-2-butyl-1,3,2-diazaphospholidine (P-7): To a solution of NHPꢀCl (142.2 mg,
0.6 mmol) in Et2O (4 mL) was added nꢀBuLi (1.24 M in hexane, 0.49 mL) at –78 °C under argon
atmosphere. The resulting reaction mixture was allowed to warm up slowly to room temperature.
After stirring for 15 h at room temperature, the reaction mixture was diluted with Et2O (10 mL)
and the resulting solution was washed with aq. NaHCO3 and brine. The organic phase was dried
over Na2SO4 and Na2SO4 was filtered off. The organic solvent was evaporated under reduced
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pressure to give crude product P-7 as colorless oil; 95.7 mg, 64%; IR
ν
(KBr, cm−1) 2963, 2933,
2873, 1465, 1392, 1378, 1363, 1272, 1248, 1220, 1209, 1059, 978; 1H NMR (400 MHz, CDCl3) δ
3.16ꢀ3.08 (m, 2H), 3.07ꢀ2.99 (m, 2H), 1.40ꢀ1.20 (m, 6H), 1.18 (s, 18H), 0.89 (t, J = 6.8 Hz, 3H);
13C NMR (100.5 MHz, CDCl3) δ 53.0 (d, J = 17.8 Hz), 46.9 (d, J = 7.4 Hz), 35.5 (d, J = 21.6 Hz),
29.8 (d, J = 9.7 Hz), 26.7 (d, J = 15.7 Hz), 24.3 (d, J = 11.9 Hz), 14.0; 31P NMR (162 MHz,
CDCl3): δ 94.8 ppm; HRMS (ESIꢀTOF): found [M + H]+ values corresponding to
1,3ꢀdiꢀtertꢀbutylꢀ2ꢀbutylꢀ1,3,2ꢀdiazaphospholidine 2ꢀoxide; [M + H]+ Calcd for C14H32N2OP:
275.2247; Found: 275.2253.
2-Butyl-1,3-diphenyl-1,3,2-diazaphospholidine (P-8): To a solution of NHPꢀCl (828 mg, 3.0
mmol) in Et2O (15 mL) was added nꢀBuLi (1.3 M in hexane, 2.3 mL) at –78 °C under argon
atmosphere. The resulting reaction mixture was allowed to warm up slowly to room temperature.
After stirring for 5 h at room temperature, the reaction mixture was diluted with Et2O (20 mL) and
the resulting solution was washed with aq. NaHCO3 and brine. The organic phase was dried over
Na2SO4 and Na2SO4 was filtered off. The organic solvent was evaporated under reduced pressure
to give crude product P-8 as white solid; 712.3 mg, 81%; IR
ν
(KBr, cm–1) 3059, 2958, 2870,
1597, 1496, 1298, 1284, 1112, 1091, 991, 925; mp 201ꢀ202 °C; 1H NMR (400 MHz, CDCl3) δ
7.28ꢀ7.22 (m, 4H), 7.02ꢀ6.97 (m, 4H), 6.81 (tt, J = 7.6, 0.8 Hz, 2H), 3.77 (t, J = 2.4 Hz, 4H),
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1.62ꢀ1.56 (m, 2H), 1.42ꢀ1.26 (m, 4H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR (100.5 MHz, CDCl3) δ
146.6 (d, J = 17.1 Hz), 129.2 (d, J = 1.5 Hz), 118.4 (d, J = 2.2 Hz), 115.3 (d, J = 14.9 Hz), 46.9 (d,
J = 8.9 Hz), 31.6 (d, J = 32.7 Hz), 25.8 (d, J = 14.1 Hz), 24.3 (d, J = 9.7 Hz), 13.8; 31P NMR (162
MHz, CDCl3): δ 95.6 ppm; HRMS (ESIꢀTOF) m/z: [M+K]+ Calcd for C18H23N2PK: 337.1230;
Found: 337.1235.
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1,2,3-Triphenyl-1,3,2-diazaphospholidine (P-9): To a solution of diamine (424.5 mg, 2.0 mmol)
and Et3N (0.56 mL, 4.0 mmol) in DCM (10 mL) was added dichloro(phenyl)phosphine (0.27 mL,
2.0 mmol) at –78 °C under argon atmosphere. The resulting reaction mixture was allowed to warm
up slowly to room temperature and it was stirred for 2 h at room temperature. After stirring for 2 h
at room temperature, the reaction mixture was diluted with DCM (20 mL) and the resulting
solution was washed with aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and
Na2SO4 was filtered off. After removal of the solvent under reduced pressure, the residue was
purified by flash column chromatography on basic alumina (Hexane/EA = 3:1) to give
corresponding product P-9 as white solid; 236 mg, 37%; mp 233ꢀ235 °C; IR
ν
(KBr, cm−1) 3066,
3023, 2862, 1596, 1496, 1296, 1288, 1185, 1115, 1088, 937, 740; 1H NMR (400 MHz, CDCl3) δ
7.36ꢀ7.30 (m, 2H), 7.29ꢀ7.22 (m, 7H), 7.06ꢀ7.01 (m, 4H), 6.84 (tt, J = 7.2, 0.8 Hz, 2H), 3.84ꢀ3.74
(m, 2H), 3.68ꢀ3.58 (m, 2H); 13C NMR (100.5 MHz, CDCl3) δ 146.2 (d, J = 17.1 Hz), 140.7 (d, J =
39.5 Hz), 129.6, 129.5 (d, J = 7.5 Hz), 129.3, 128.2 (d, J = 4.5 Hz), 119.1 (d, J = 2.2 Hz), 115.8 (d,
J = 14.1 Hz), 46.8 (d, J = 8.2 Hz); 31P NMR (162 MHz, CDCl3): δ 82.8 ppm; HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C20H20N2P: 319.1359; Found: 319.1357.
N,N-Diethyl-1,1-diphenylphosphinamine (P-10):38 To a solution of diphenylphosphine (180 ꢁL,
1.0 mmol) and Et3N (155ꢁL, 1.1 mmol) in Et2O (2.0 mL) was added diethylamine (115 ꢁL, 1.1
mmol) at 0 °C under argon atmosphere. The resulting reaction mixture was stirred for 10 min at 0
°C. After stirring for 10 min at 0 °C, it was allowed to warm up to room temperature and stirred
for 14 h at room temperature. The reaction mixture was diluted with Et2O (10 mL) and then it was
filtered to give crude product P-10 as white solid; 212.3 mg, 82%; 1H NMR (400 MHz, CDCl3) δ
7.44ꢀ7.38 (m, 4H), 7.36ꢀ7.28 (m, 6H), 3.12ꢀ3.02 (m, 4H), 0.95 (t, J = 6.8 Hz, 6H); 13C NMR
(100.5 MHz, CDCl3) δ 140.4 (d, J = 14.1 Hz), 131.9 (d, J = 19.4 Hz), 128.1 (d, J = 13.4 Hz),
128.0, 44.3 (d, J = 15.6 Hz), 14.5 (d, J = 3.0 Hz); 31P NMR (162 MHz, CDCl3): δ 61.7 ppm.
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N,N-Diethyl-1,3-diphenyl-1,3,2-diazaphospholidin-2-amine (P-11): To a solution of NHPꢀCl
(276.1 mg, 1.0 mmol) and Et3N (155ꢁL, 1.1 mmol) in DCM (10 mL) was added diethylamine
(115 ꢁL, 1.1 mmol) at 0 °C under argon atmosphere. The resulting reaction mixture was stirred for
10 min at 0 °C. After stirring for 10 min at 0 °C, it was allowed to warm up to room temperature
and stirred for 20 h at room temperature. After stirring for 20 h at room temperature, the reaction
mixture was diluted with Et2O (10 mL) and then it was filtered. The filtrate was concentrated to
give crude product P-11 as white solid; 103.1 mg, 33%; 1H NMR (400 MHz, CDCl3) δ 7.29ꢀ7.24
(m, 4H), 7.07ꢀ7.02 (m, 4H), 6.84 (tt, J = 7.2, 1.2 Hz, 2H), 3.96ꢀ3.78 (m, 2H), 3.71ꢀ3.59 (m, 2H),
3.07ꢀ2.98 (m, 4H), 0.89 (t, J = 7.2 Hz, 6H); 13C NMR (100.5 MHz, CDCl3) δ 146.1 (d, J = 16.4
Hz), 129.0, 118.5 (d, J = 1.5 Hz), 115.1 (d, J = 14.2 Hz), 46.2 (d, J = 9.7 Hz), 39.7 (d, J = 19.4
Hz), 14.2 (d, J = 2.9 Hz); 31P NMR (162 MHz, CDCl3): δ 95.6 ppm. Note: This compound should
be used immediately due to its air sensitivity. HRMS (ESIꢀTOF) m/z: found [M + H]+ values
corresponding to 2ꢀ(diethylamino)ꢀ1,3ꢀdiphenylꢀ1,3,2ꢀdiazaphospholidine 2ꢀoxide; [M + H]+
Calcd for C18H25N3OP: 330.1730; found: 330.1740.
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The procedure for the Mitsunobu reaction
A mixture of alcohols (0.1 mmol), Nu (0.15 mmol), P-8 (0.15 mmol), Azoꢀ1 (0.12 mmol) and
DCE (0.5 mL) in a 2 dram vial with a PTFE cap was stirred for 24ꢀ48 h at 40 °C while being
monitored with TLC analysis. Upon completion, the reaction mixture was concentrated under
reduced pressure. The residue was subjected to flash column chromatography on silica gel to give
corresponding products 3, 5, and 6.
4-Benzylmorpholine (3a):22c Pale yellow oil; 16.2 mg, 92%; Rf 0.10 (vHexane/vEA= 4:1), vHexane/vEA
(5/1, with 1% Et3N) for column; 1H NMR (400 MHz, CDCl3) δ 7.34ꢀ7.29 (m, 4H), 7.29ꢀ7.23 (m,
1H), 3.71 (t, J = 4.8 Hz, 4H), 3.50 (s, 2H), 2.44 (t, J = 4.4 Hz, 4H); 13C NMR (100.5 MHz,
CDCl3) δ 137.7, 129.2, 128.2, 127.1, 67.0, 63.5, 53.6.
4-Benzylthiomorpholine (3b):39 Pale yellow oil; 13.7 mg, 71%; Rf 0.40 (vHexane/vEA= 3:1),
1
vHexane/vEA (10/1) for column; H NMR (400 MHz, CDCl3) δ 7.34ꢀ7.28 (m, 4H), 7.26ꢀ7.24 (m,
1H), 3.51 (s, 2H), 2.72ꢀ2.65 (m, 8H); 13C NMR (100.5 MHz, CDCl3) δ 138.1, 129.0, 128.2, 127.1,
63.7, 54.9, 28.0.
1-Benzylpiperidine (3c):22c Pale yellow oil; 11.5 mg, 66%; Rf 0.20 (vHexane/vEA= 3:1), vHexane/vEA
(5/1, with 2% Et3N) for column; 1H NMR (400 MHz, CDCl3) δ 7.33ꢀ7.28 (m, 4H), 7.27ꢀ7.21 (m,
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1H), 3.47 (s, 2H), 2.37 (s, 4H), 1.61ꢀ1.53 (m, 4H), 1.46ꢀ1.39 (m, 2H); 13C NMR (100.5 MHz,
CDCl3) δ 138.6, 129.2, 128.1, 126.8, 63.9, 54.5, 25.9, 24.4.
Ethyl 1-benzylpiperidine-4-carboxylate (3d):40 Pale yellow oil; 21.2 mg, 80%; Rf 0.30
(vHexane/vEA= 3:1), vHexane/vEA (6/1, with 1% Et3N) for column; 1H NMR (400 MHz, CDCl3) δ 7.31
(d, J = 4.4 Hz, 4H), 7.28ꢀ7.23 (m, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.48 (s, 2H), 2.85 (td, J = 12.0,
3.2 Hz, 2H), 2.31ꢀ2.23 (m, 1H), 2.02 (dt, J = 11.2, 4.0 Hz, 2H), 1.91ꢀ1.83 (m, 2H), 1.82ꢀ1.70 (m,
2H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (100.5 MHz, CDCl3) δ 175.2, 138.4, 129.0, 128.2, 126.9,
63.2, 60.2, 52.9, 41.2, 28.3, 14.2.
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tert-Butyl 4-benzylpiperazine-1-carboxylate (3e):41 Pale yellow oil; 23.5 mg, 85%; Rf 0.20
(vHexane/vEA= 3:1), vHexane/vEA (6/1, with 1% Et3N) for column; 1H NMR (400 MHz, CDCl3) δ 7.31
(d, J = 4.4 Hz, 4H), 7.29ꢀ7.23 (m, 1H), 3.51 (s, 2H), 3.42 (t, J = 4.8 Hz, 4H), 2.38 (t, J = 4.8 Hz,
4H), 1.46 (s, 9H); 13C NMR (100.5 MHz, CDCl3) δ 154.8, 137.9, 129.1, 128.2, 127.1, 79.5, 63.0,
52.8, 28.4, 28.3.
1-Benzyl-4-(tert-butyl)piperazine (3f):42 Pale yellow oil; 19.2 mg, 83%; Rf 0.10 (vEA/vMeOH
=
1
95:5), vEA/vMeOH (95/5) for column; H NMR (400 MHz, CDCl3) δ 7.34ꢀ7.27 (m, 4H), 7.27ꢀ7.21
(m, 1H), 3.51 (s, 2H), 2.60 (bs, 4H), 2.50 (bs, 4H), 1.46 (s, 9H); 13C NMR (100.5 MHz, CDCl3) δ
138.1, 129.3, 128.1, 126.9, 63.1, 53.8, 45.6, 25.9, 21.9.
1-Benzyl-4-cyclohexylpiperazine (3g):28a Pale yellow oil; 20.6 mg, 80%; Rf 0.10 (vEA/vMeOH
=
1
98:2), vEA/vMeOH (98/2) for column; H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 4.4 Hz, 4H),
7.28ꢀ7.22 (m, 1H), 3.51 (s, 2H), 2.63 (bs, 4H), 2.53 (bs, 4H), 2.27 (br, 1H), 1.94ꢀ1.76 (m, 4H),
1.65ꢀ1.58 (m, 1H), 1.30ꢀ1.05 (m, 5H); 13C NMR (100.5 MHz, CDCl3) δ 138.0, 129.3, 128.2,
127.0, 63.6, 63.1, 53.3, 48.8, 28.8, 26.2, 25.8.
1-Benzhydryl-4-benzylpiperazine (3h):43 White solid; 29.4 mg, 86%; Rf 0.40 (vHexane/vEA= 3:1),
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vHexane/vEA (9/1 to 4/1) for column; H NMR (400 MHz, CDCl3) δ 7.43ꢀ7.37 (m, 4H), 7.30ꢀ7.20
(m, 9H), 7.15 (tt, J = 7.2, 2.0 Hz, 2H), 4.22 (s, 1H), 3.51 (s, 2H), 2.47 (bs, 4H), 2.42 (bs, 4H); 13
C
NMR (100.5 MHz, CDCl3) δ 142.8, 138.1, 129.2, 128.4, 128.1, 128.0, 126.9, 126.8, 76.2, 63.1,
53.3, 51.9.
1-Benzyl-4-(bis(4-fluorophenyl)methyl)piperazine (3i):44 White solid; 21.0 mg, 56%; Rf 0.20
1
(vHexane/vEA/vDCM= 8:1:4), vHexane/vEA/vDCM (8/1/4) for column; H NMR (400 MHz, CDCl3) δ
7.36ꢀ7.26 (m, 8H), 7.26ꢀ7.20 (m, 1H), 6.95 (tt, J = 8.4, 2.0 Hz, 4H), 4.21 (s, 1H), 3.51 (s, 2H),
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2.46 (bs, 4H), 2.38 (bs, 4H); 13C NMR (100.5 MHz, CDCl3) δ 161.8 (d, J = 244.1 Hz), 138.3 (d, J
= 2.9 Hz), 140.0, 129.3, 129.2, 128.1, 127.0, 115.3 (d, J = 21.6 Hz), 74.5, 63.0, 53.4, 51.7.
Tribenzylamine (3j):22c Pale yellow oil; 20.3 mg, 71%; Rf 0.50 (vHexane/vEA= 8:1), vHexane/vEA
(10/1) for column; 1H NMR (400 MHz, CDCl3) δ 7.44ꢀ7.36 (m, 6H), 7.36ꢀ7.28 (m, 6H), 7.22 (tt,
J = 7.2, 1.2 Hz, 3H), 3.55 (s, 6H); 13C NMR (100.5 MHz, CDCl3) δ 139.6, 128.7, 128.2, 126.8,
57.9.
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N,N-Dibenzylaniline (3k):28a Pale yellow oil; 18.3 mg, 67%; Rf 0.05 (vHexane/vEA= 100:1),
1
vHexane/vDCM (20/1) for column; H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.29 (m, 4H), 7.27ꢀ7.22 (m,
6H), 7.19ꢀ7.17 (m, 2H), 6.74 (d, J = 8.0 Hz, 2H), 6.70 (t, J = 7.2 Hz, 1 H), 4.65 (s, 4H); 13C NMR
(100.5 MHz, CDCl3) δ 149.2, 138.6, 129.2, 128.6, 126.8, 126.6, 116.7, 112.4, 54.2.
Dibenzylamine (3m):28a Pale yellow oil; 8.5 mg, 43%; Rf 0.20 (vHexane/vEA= 4:1), vHexane/vEA (5/1)
1
for column; H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.30 (m, 8H), 7.27ꢀ7.23 (m, 2H), 3.81 (s, 4H),
1.61 (s, 1H); 13C NMR (100.5 MHz, CDCl3) δ 140.4, 128.4, 128.1, 126.9, 53.2.
N-Benzylaniline (3n):28a Pale yellow oil; 6.3 mg, 34%; Rf 0.40 (vHexane/vEA= 16:1), vHexane/vEA
1
(100/1) for column; H NMR (400 MHz, CDCl3) δ 7.39ꢀ7.31 (m, 4H), 7.30ꢀ7.29 (m, 1H),
7.20ꢀ7.19 (m, 2H), 6.71 (tt, J = 7.2, 1.2 Hz, 1H), 6.66ꢀ6.61 (m, 2H), 4.33 (s, 2H), 4.01 (s, 1H); 13C
NMR (100.5 MHz, CDCl3) δ 148.1, 139.4, 129.3, 128.6, 127.5, 127.2, 117.5, 112.8, 48.3.
Benzyl benzoate (5a):45 Pale yellow oil; 19.3 mg, 91%; Rf 0.30 (vHexane/vEA= 16:1), vHexane/vEA
1
(100/1) for column; H NMR (400 MHz, CDCl3) δ 8.10ꢀ8.06 (m, 2H), 7.58ꢀ7.53 (m, 1H),
7.47ꢀ7.31 (m, 7H), 5.37 (s, 2H); 13C NMR (100.5 MHz, CDCl3) δ 166.4, 136.0, 133.0, 129.7,
128.6, 128.4, 128.2, 128.1, 66.7.
Benzyl 4-methylbenzoate (5b):45 Pale yellow oil; 20.1 mg, 89%; Rf 0.30 (vHexane/vEA= 16:1),
vHexane/vEA (100/1) for column; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.44 (d, J
= 7.2 Hz, 2H), 7.41ꢀ7.30 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 5.35 (s, 2H), 2.40 (s, 3H); 13C NMR
(100.5 MHz, CDCl3) δ 166.5, 143.7, 136.2, 129.7, 129.1, 128.6, 128.2, 128.1, 127.4, 66.5, 21.6.
Benzyl 4-fluorobenzoate (5c):46 Pale yellow oil; 19.1 mg, 83%; Rf 0.30 (vHexane/vEA= 16:1),
1
vHexane/vEA (100/1) for column; H NMR (400 MHz, CDCl3) δ 8.12ꢀ8.06 (m, 2H), 7.46ꢀ7.32 (m,
5H), 7.14ꢀ7.07 (m, 2H), 5.35 (s, 2H); 13C NMR (100.5 MHz, CDCl3) δ 165.8 (d, J = 253.0 Hz),
165.4, 135.9, 132.2 (d, J = 9.7 Hz), 128.6, 128.3, 128.2, 126.4 (d, J = 3.0 Hz), 115.5 (d, J = 22.3
Hz), 66.8.
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Benzyl 4-chlorobenzoate (5d):45 Pale yellow oil; 20.9 mg, 85%; Rf 0.30 (vHexane/vEA= 16:1),
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vHexane/vEA (100/1) for column; H NMR (400 MHz, CDCl3) δ 8.00 (dt, J = 8.8, 2.0 Hz, 2H),
7.46ꢀ7.32 (m, 7H), 5.35 (s, 2H); 13C NMR (100.5 MHz, CDCl3) δ 165.6, 139.5, 135.8, 131.1,
128.7, 128.6, 128.5, 128.4, 128.2, 66.9.
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Benzyl 4-bromobenzoate (5e):45 Pale yellow oil; 26.4 mg, 91%; Rf 0.30 (vHexane/vEA= 16:1),
vHexane/vEA (100/1) for column; 1H NMR (400 MHz, CDCl3) δ 8.93 (dt, J = 8.8, 2.0 Hz, 2H), 7.57
(dt, J = 8.4, 2.0 Hz, 2H), 7.45ꢀ7.32 (m, 5H), 5.35 (s, 2H); 13C NMR (100.5 MHz, CDCl3) δ 165.7,
135.8, 131.7, 131.2, 129.0, 128.6, 128.4, 128.2, 128.1, 66.9.
Benzyl 2,4-dichlorobenzoate (5f):46 Pale yellow oil; 25.5 mg, 91%; Rf 0.30 (vHexane/vEA= 16:1),
v
Hexane/vEA (100/1) for column; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 1H), 7.47 (d, J
= 2.0 Hz, 1H), 7.46ꢀ7.42 (m, 2H), 7.41ꢀ7.32 (m, 3H), 7.28 (dd, J = 8.8, 2.0 Hz, 1H), 5.36 (s, 2H);
13C NMR (100.5 MHz, CDCl3) δ 164.5, 138.4, 135.3, 135.1, 132.6, 131.0, 128.6, 128.5, 128.4,
128.1, 127.0, 67.4.
Benzyl 4-(trifluoromethyl)benzoate (5g):45 Pale yellow oil; 24.9 mg, 89%; Rf 0.30 (vHexane/vEA
=
16:1), vHexane/vEA (100/1) for column; 1H NMR (400 MHz, CDCl3) δ 8.20ꢀ8.16 (m, 2H), 7.72ꢀ7.68
(m, 2H), 7.47ꢀ7.33 (m, 5H), 5.39 (s, 2H); 13C NMR (100.5 MHz, CDCl3) δ 165.2, 135.5, 134.5 (d,
J = 32.7 Hz), 133.3 (d, J = 1.5 Hz), 130.1, 128.7, 128.5, 128.3 (d, J = 1.5 Hz), 125.4 (q, J = 3.7
Hz), 123.6 (d, J = 271.6 Hz), 67.2.
Benzyl 4-nitrobenzoate (5h):45 White solid; 24.0 mg, 93%; Rf 0.30 (vHexane/vEA= 16:1), vHexane/vEA
(100/1) for column; 1H NMR (400 MHz, CDCl3) δ 8.30ꢀ8.22 (m, 4H), 7.48ꢀ7.34 (m, 5H), 5.41 (s,
2H); 13C NMR (100.5 MHz, CDCl3) δ 164.5, 135.5, 135.2, 130.8, 128.7, 128.6, 128.4, 123.53,
123.52, 67.6.
Benzyl cyclohexanecarboxylate (5i):46 Pale yellow oil; 16.9 mg, 78%; Rf 0.30 (vHexane/vEA
=
1
16:1), vHexane/vEA (100/1) for column; H NMR (400 MHz, CDCl3) δ 7.39ꢀ7.28 (m, 5H), 5.11 (s,
2H), 2.40ꢀ2.30 (m, 1H), 1.97ꢀ1.89 (m, 2H), 1.79ꢀ1.71 (m, 2H), 1.67ꢀ1.60 (m, 1H), 1.52ꢀ1.41 (m,
2H), 1.34ꢀ1.16 (m, 3H); 13C NMR (100.5 MHz, CDCl3) δ 175.9, 136.3, 128.5, 128.0, 127.9, 65.9,
43.2, 29.0, 25.7, 25.4.
Benzyl cinnamate (5j):46 Pale yellow oil; 20.9 mg, 88%; Rf 0.30 (vHexane/vEA= 16:1), vHexane/vEA
(100/1) for column; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 16.0 Hz, 1H), 7.53ꢀ7.49 (m, 2H),
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7.44ꢀ7.31 (m, 8H), 6.49 (d, J = 16.0 Hz, 1H), 5.25 (s, 2H); 13C NMR (100.5 MHz, CDCl3) δ 166.8,
145.2, 136.1, 134.4, 130.3, 128.9, 128.6, 128.3, 128.2, 128.1, 117.9, 66.4.
Benzyl 2,2-diphenylacetate (5k):47 White solid; 25.0 mg, 83%; Rf 0.30 (vHexane/vEA= 16:1),
1
vHexane/vEA (100/1) for column; H NMR (400 MHz, CDCl3) δ 7.34ꢀ7.23 (m, 15H), 5.18 (s, 2H),
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5.07 (s, 1H); 13C NMR (100.5 MHz, CDCl3) δ 172.3, 138.6, 135.7, 128.6, 128.5, 128.4, 128.2,
128.1, 127.3, 66.9, 57.0.
(Benzyloxy)benzene (5l):39 Pale yellow oil; 12.2 mg, 66%; Rf 0.10 (vHexane/vEA= 100:0),
vHexane/vEA (100/1) for column; 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.2 Hz, 2H), 7.41ꢀ7.36
(m, 2H), 7.34ꢀ7.26 (m, 3H), 7.00ꢀ6.94 (m, 3H), 5.07 (s, 2H); 13C NMR (100.5 MHz, CDCl3) δ
158.8, 137.1, 129.5, 128.6, 127.9, 127.5, 120.9, 114.8, 69.9.
Benzyl(phenyl)sulfane (5m):48 Pale yellow oil; 8.6 mg, 43%; Rf 0.10 (vHexane/vEA= 100:0),
vHexane/vEA (100/1) for column; 1H NMR (400 MHz, CDCl3) δ 7.32ꢀ7.20 (m, 9H), 7.17 (tt, J = 7.6,
1.2 Hz, 1H), 4.12 (s, 2H); 13C NMR (100.5 MHz, CDCl3) δ 137.4, 136.3, 129.8, 128.8, 128.7,
128.5, 127.1, 126.3, 39.0.
N,N-dibenzylaniline (5n):49 White solid; 28.4 mg, 81%; Rf 0.20 (vHexane/vEA= 10:1), vHexane/vEA
1
(15/1) for column; H NMR (400 MHz, CDCl3) δ 7.73 (dt, J = 8.0, 1.6 Hz, 2H), 7.29 (d, J = 7.6
Hz, 2H), 7.23ꢀ7.18 (m, 6H), 7.08ꢀ7.03 (m, 4H), 4.31 (s, 4H), 2.44 (s, 3H); 13C NMR (100.5 MHz,
CDCl3) δ 143.2, 137.7, 135.7, 129.7, 128.6, 128.4, 127.6, 127.2, 50.5, 21.5.
4-(4-Methylbenzyl)morpholine (6a):50 Pale yellow oil; 17.0 mg, 89%; Rf 0.10 (vHexane/vEA= 4:1),
1
vHexane/vEA (5/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.0 Hz,
2H), 7.12 (d, J = 8.0 Hz, 2H), 3.70 (t, J = 4.8 Hz, 4H), 3.46 (s, 2H), 2.43 (t, J = 4.8 Hz, 4H), 2.33
(s, 3H); 13C NMR (100.5 MHz, CDCl3) δ 136.7, 134.6, 129.2, 128.9, 67.0, 63.2, 53.6, 21.1.
4-(4-methoxybenzyl)morpholine (6b):50 White solid; 19.2 mg, 88%; Rf 0.10 (vHexane/vEA= 4:1),
1
vHexane/vEA (5/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ 7.23 (dt, J = 8.8, 2.4
Hz, 2H), 6.85 (dt, J = 8.4, 2.0 Hz, 2H), 3.80 (s, 3H), 3.70 (t, J = 4.8 Hz, 4H), 3.44 (s, 2H), 2.42 (t,
J = 4.8 Hz, 4H); 13C NMR (100.5 MHz, CDCl3) δ 158.8, 130.3, 129.7, 113.6, 67.0, 62.8, 55.2,
53.5.
4-(4-Chlorobenzyl)morpholine (6c):50 Pale yellow oil; 17.7 mg, 85%; Rf 0.10 (vHexane/vEA= 4:1),
1
vHexane/vEA (5/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ 7.33ꢀ7.24 (m, 4H),
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3.70 (t, J = 4.4 Hz, 4H), 3.45 (s, 2H), 2.42 (t, J = 4.8 Hz, 4H); 13C NMR (100.5 MHz, CDCl3) δ
136.4, 132.8, 130.4, 128.4, 67.0, 62.6, 53.5.
4-(4-Bromobenzyl)morpholine (6d):39 Pale yellow oil; 21.0 mg, 82%; Rf 0.10 (vHexane/vEA= 4:1),
1
vHexane/vEA (5/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ 7.44 (dt, J = 8.4, 2.0
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Hz, 2H), 7.23ꢀ7.19 (m, 2H), 3.70 (t, J = 4.8 Hz, 4H), 3.44 (s, 2H), 2.42 (t, J = 4.8 Hz, 4H); 13C
NMR (100.5 MHz, CDCl3) δ 136.9, 131.3, 130.8, 120.9, 66.9, 62.7, 53.5.
4-(2,4-Dichlorobenzyl)morpholine (6e):51 Pale yellow oil; 20.4 mg, 83%; Rf 0.10 (vHexane/vEA
=
1
4:1), vHexane/vEA (5/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.4
Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 3.72 (t, J = 4.4 Hz, 4H), 3.57 (s,
2H), 2.50 (t, J = 4.4 Hz, 4H); 13C NMR (100.5 MHz, CDCl3) δ 134.9, 134.3, 133.2, 131.5, 129.2,
126.9, 67.0, 59.1, 53.6.
4-(4-Nitrobenzyl)morpholine (6f):39 Pale yellow oil; 14.9 mg, 68%; Rf 0.10 (vHexane/vEA= 4:1),
1
v
Hexane/vEA (5/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 8.8, 1.2
Hz, 2H), 7.53 (dd, J = 8.0, 0.8 Hz, 2H), 3.73 (t, J = 6.0 Hz, 4H), 3.60 (s, 2H), 2.47 (t, J = 4.4 Hz,
4H); 13C NMR (100.5 MHz, CDCl3) δ 174.2, 145.9, 129.5, 123.5, 66.9, 62.5, 53.6.
N,N-Dibenzyl-1-(4-fluorophenyl)methanamine (6g):28a Pale yellow oil; 26.8 mg, 88%; Rf 0.50
1
(vHexane/vEA= 8:1), vHexane/vEA (10/1) for column; H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.28 (m,
10H), 7.22 (tt, J = 7.2, 2.4 Hz, 2H), 6.99 (t, J = 8.8 Hz, 2H), 3.53 (s, 4H), 3.50 (s, 2H); 13C NMR
(100.5 MHz, CDCl3) δ 161.9 (d, J = 243.3 Hz), 139.5, 135.3 (d, J = 3.0 Hz), 130.1 (d, J = 7.4 Hz),
128.7, 128.2, 126.9, 115.0 (d, J = 20.9 Hz), 57.9, 57.1.
N,N-Dibenzyl-1-(4-(trifluoromethyl)phenyl)methanamine (6h):52 Pale yellow oil; 18.8 mg,
53%; Rf 0.50 (vHexane/vEA= 8:1), vHexane/vEA (10/1) for column; 1H NMR (400 MHz, CDCl3) δ 7.54
(dd, J = 19.2, 8.4 Hz, 4H), 7.39 (d, J = 6.8 Hz, 4H), 7.32 (t, J = 7.2 Hz, 4H), 7.26ꢀ7.21 (m, 2H),
3.59 (s, 2H), 3.56 (s, 4H); 13C NMR (100.5 MHz, CDCl3) δ 144.0, 139.1, 129.2 (d, J = 32.0 Hz),
128.8, 128.7, 128.3, 127.0, 125.1 (q, J = 3.7 Hz), 124.3 (d, J = 270.2 Hz), 58.1, 57.4.
4-(Quinolin-6-ylmethyl)morpholine (6i):53 Pale yellow oil; 17.6 mg, 77%; Rf 0.20 (vHexane/vEA
=
1:2), vHexane/vEA (1/1, with 1% Et3N) for column; 1H NMR (400 MHz, CDCl3) δ 8.90 (dd, J = 4.0,
1.6 Hz, 1H), 8.14 (dq, J = 8.0, 0.8 Hz, 1H), 8.09ꢀ8.05 (m, 1H), 7.75 (dd, J = 6.4, 2.0 Hz, 2H), 7.40
(dd, J = 8.0, 4.0 Hz, 1H), 3.74 (t, J = 4.8 Hz, 4H), 3.70 (s, 2H), 2.51 (t, J = 4.8 Hz, 4H); 13C NMR
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(100.5 MHz, CDCl3) δ 150.2, 147.8, 136.2, 135.8, 130.9, 129.4, 128.0, 127.4, 121.2, 66.9, 63.1,
53.6.
4-(Naphthalen-1-ylmethyl)morpholine (6j):54 Pale yellow oil; 19.1 mg, 84%; Rf 0.40
(vHexane/vEA= 3:1), vHexane/vEA (8/1, with 1% Et3N) for column; 1H NMR (400 MHz, CDCl3) δ 8.31
(dd, J = 7.6, 0.8 Hz, 1H), 7.82 (dd, J = 8.8, 1.6 Hz, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.54ꢀ7.46
(m, 2H), 7.44ꢀ7.36 (m, 2H), 3.90 (s, 2H), 3.69 (t, J = 4.8 Hz, 4H), 2.50 (t, J = 4.8 Hz, 4H); 13C
NMR (100.5 MHz, CDCl3) δ 133.8, 133.6, 132.5, 128.4, 128.0, 127.5, 125.7, 125.6, 125.0, 124.8,
67.1, 61.6, 53.8.
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4-(Benzo[d][1,3]dioxol-5-ylmethyl)morpholine (6k):22c Pale yellow oil; 16.1 mg, 73%; Rf 0.30
1
(vHexane/vEA= 1:1), vHexane/vEA (3/1, with 0.5% Et3N) for column; H NMR (400 MHz, CDCl3) δ
6.86 (s, 1H), 6.74 (d, J = 0.8 Hz, 2H), 5.94 (s, 2H), 3.70 (t, J = 4.8 Hz, 4H), 3.40 (s, 2H), 2.42 (t, J
= 4.4 Hz, 4H); 13C NMR (100.5 MHz, CDCl3) δ 147.6, 146.6, 131.7, 122.2, 109.4, 107.8, 100.9,
67.0, 63.1, 53.5.
4-Cinnamylmorpholine (6l):55 Pale yellow oil; 16.0 mg, 79%; Rf 0.15 (vHexane/vEA= 3:1),
1
vHexane/vEA (5/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ 7.40ꢀ7.36 (m, 2H),
7.34ꢀ7.28 (m, 2H), 7.23 (tt, J = 6.8, 1.6 Hz, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.26 (dt, J = 15.6, 7.2
Hz, 1H), 3.74 (t, J = 4.4 Hz, 4H), 3.16 (dd, J = 6.8, 1.2 Hz, 2H), 2.51 (t, J = 4.4 Hz, 4H); 13C
NMR (100.5 MHz, CDCl3) δ 136.8, 133.4, 128.6, 127.6, 126.3, 126.0, 67.0, 61.5, 53.7.
2,2-Diphenylethyl benzoate (6m):56 Pale yellow oil; 26.2 mg, 86%; Rf 0.30 (vHexane/vEA= 16:1),
vHexane/vEA (100/1) for column; 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 8.0, 1.2 Hz, 2H), 7.52
(tt, J = 7.6, 1.2 Hz, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.35ꢀ7.28 (m, 8H), 7.26ꢀ7.21 (m, 2H), 4.86 (d, J
= 7.6 Hz, 2H), 4.52 (t, J = 7.6 Hz, 1H); 13C NMR (100.5 MHz, CDCl3) δ 166.4, 141.2, 132.9,
130.1, 129.5, 128.6, 128.3, 128.2, 126.8, 67.2, 49.9.
1-Phenylethyl benzoate (6n):57 Pale yellow oil; 20.0 mg, 82%; Rf 0.30 (vHexane/vEA= 16:1),
1
vHexane/vEA (100/1) for column; H NMR (400 MHz, CDCl3) δ 8.10ꢀ8.08 (m, 2H), 7.58ꢀ7.52 (m,
1H), 7.47ꢀ7.40 (m, 4H), 7.39ꢀ7.33 (m, 2H), 7.32ꢀ7.24 (m, 1H), 6.14 (q, J = 6.4 Hz, 1H), 1.67 (dd,
J = 6.8, 1.6 Hz, 3H); 13C NMR (100.5 MHz, CDCl3) δ 165.8, 141.8, 132.9, 130.5, 129.6, 128.5,
128.3, 127.9, 126.0, 72.9, 22.4.
(E)-4-phenylbut-3-en-2-yl benzoate (6o):58 Colourless oil; 17.1 mg, 68%; Rf 0.30 (vHexane/vEA
=
50:1), vHexane/vEA (100/1) for column; 1H NMR (400 MHz, CDCl3) δ 8.10ꢀ8.06 (m, 2H), 7.58ꢀ7.52
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(m, 1H), 7.46ꢀ7.37 (m, 4H), 7.31 (t, J = 7.6 Hz, 2H), 7.26ꢀ7.21 (m, 1H), 6.70 (d, J = 16.0 Hz, 1H),
6.31 (dd, J = 16.0, 6.4 Hz, 1H), 5.83ꢀ5.75 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H); 13C NMR (100.5
MHz, CDCl3) δ 165.8, 136.4, 132.8, 131.7, 130.7, 129.6, 128.9, 128.6, 128.3, 127.9, 126.6, 71.6,
20.5.
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4-(3-Phenylpropyl)morpholine (6p):59 a threefold scaleꢀup reaction, pale yellow oil; 36.2 mg,
59%; Rf 0.28 (vEA/vMeOH = 98:2), vEA/vMeOH (98/2, with 1% Et3N) for column; 1H NMR (400 MHz,
CDCl3) δ 7.30ꢀ7.24 (m, 2H), 7.21ꢀ7.14 (m, 3H), 3.74ꢀ3.67 (m, 4H), 2.67ꢀ2.60 (m, 2H), 2.46ꢀ2.30
(m, 6H), 1.87ꢀ1.76 (m, 2H); 13C NMR (100.5 MHz, CDCl3) δ 142.0, 128.4, 128.3, 125.8, 67.0,
58.3, 53.7, 33.6, 28.2.
1-Benzhydryl-4-(3-phenylpropyl)piperazine (6q):60 Pale yellow oil; 27.0 mg, 73%; Rf 0.34
1
(vHexane/vEA= 3:1), vHexane/vEA (3/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ
7.43ꢀ7.37 (m, 4H), 7.29ꢀ7.21 (m, 6H), 7.19ꢀ7.13 (m, 5H), 4.21 (d, J = 3.2 Hz, 1H), 2.64ꢀ2.57 (m,
2H), 2.53ꢀ2.30 (m, 10H), 1.83ꢀ1.75 (m, 2H); 13C NMR (100.5 MHz, CDCl3) δ 142.8, 142.2, 128.4,
128.3, 127.9, 126.9, 125.7, 58.1, 53.5, 51.9, 33.8, 28.6.
2-(4-(Benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)pyrimidine (6r):22c White solid; 24.7 mg,
1
83%; Rf 0.15 (vHexane/vEA= 2:1), vHexane/vEA (5/1, with 1% Et3N) for column; H NMR (400 MHz,
CDCl3) δ 8.29 (d, J = 4.4 Hz, 2H), 6.89 (s, 1H), 6.76 (d, J = 0.4 Hz, 2H), 6.46 (t, J = 4.8 Hz, 1H),
5.95 (s, 2H), 3.82 (t, J = 4.8 Hz, 4H), 3.45 (s, 2H), 2.48 (t, J = 5.2 Hz, 4H); 13C NMR (100.5
MHz, CDCl3) δ 161.6, 157.7, 157.6, 147.6, 146.6, 131.9, 122.2, 109.7, 109.5, 107.9, 100.9, 62.8,
52.8, 43.7.
1-Benzhydryl-4-cinnamylpiperazine (6s):43 White solid; 27.2 mg, 74%; Rf 0.25 (vHexane/vEA
=
1
3:1), vHexane/vEA (6/1, with 1% Et3N) for column; H NMR (400 MHz, CDCl3) δ 7.43ꢀ7.38 (m,
4H), 7.37ꢀ7.33 (m, 2H), 7.31ꢀ7.17 (m, 7H), 7.16 (tt, J = 7.6, 1.2 Hz, 2H), 6.50 (d, J = 15.6 Hz, 1H),
6.26 (dt, J = 15.6, 6.8 Hz, 1H), 4.23 (s, 1H), 3.16 (dd, J = 6.8, 1.2 Hz, 2H), 2.54 (bs, 4H), 2.45 (bs,
4H); 13C NMR (100.5 MHz, CDCl3) δ 142.7, 136.9, 133.1, 128.5, 128.4, 127.9, 127.4, 126.9,
126.3, 76.1, 61.0, 53.4, 51.8, 45.8.
Control experiments
Isolation of by-products and characterization
A mixture of benzyl alcohol 1a (10.5 µL, 0.1 mmol), morpholine 2a (13.0 µL, 0.15 mmol), P-8
(44.8 mg, 0.15 mmol), Azo-1 (30.0 mg, 0.12 mmol) and DCE (0.5 mL) in a 2 dram vial with a
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PTFE cap was stirred for 24 h at 40 °C. After stirring for 24 h at 40 °C, the reaction mixture was
concentrated under reduced pressure. The residue was subjected to flash column chromatography
on silica gel to give corresponding products 3a (16.3 mg, 92%), P-8-[O] (21.1 mg, 71%), and
Azo-1-[R] (21.0 mg, 83%).
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2-Butyl-1,3-diphenyl-1,3,2-diazaphospholidine-2-oxide (P-8-[O]): mp 197ꢀ198 °C; IR
ν (KBr,
1
cm−1) 2957, 2928, 2864, 1600, 1500, 1489, 1280, 1232, 1188, 1122, 958, 754; H NMR (400
MHz, CDCl3) δ 7.37ꢀ7.32 (m, 4H), 7.31ꢀ7.26 (m, 4H), 7.03 (tt, J = 7.2, 1.2 Hz, 2H), 3.88ꢀ3.77 (m,
4H), 2.30ꢀ2.20 (m, 2H), 1.28ꢀ1.12 (m, 4H), 0.70 (t, J = 6.8 Hz, 3H); 13C NMR (100.5 MHz,
CDCl3) δ 141.8 (d, J = 7.5 Hz), 129.5, 121.8, 116.5 (d, J = 4.5 Hz), 43.7 (d, J = 8.2 Hz), 27.7 (d, J
= 111.6 Hz), 24.7 (d, J = 4.4 Hz), 23.2 (d, J = 18.6 Hz), 13.8; 31P NMR (162 MHz, CDCl3): δ
33.9 ppm; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C18H24N2OP: 315.1621; Found: 315.1620.
N'-(Piperidine-1-carbonyl)piperidine-1-carbohydrazide (Azo-1-[R]):61 1H NMR (400 MHz,
CDCl3) δ 7.09 (s, 2H), 3.40 (t, J = 5.6 Hz, 8H), 1.65ꢀ1.52 (m, 12H); 13C NMR (100.5 MHz,
CDCl3) δ 158.4, 44.9, 25.5, 24.4.
Asymmetric synthesis of (R)-1-phenylethyl benzoate, (R)-6m
A mixture of (S)ꢀ1ꢀphenylethanol (0.1 mmol) (S)ꢀ1o, benzoic acid (0.15 mmol) 4a, P-8 (0.15
mmol), Azo-1 (0.12 mmol) and DCE (0.5 mL) in a 2 dram vial with a PTFE cap was stirred for 24
h at 40 °C. After stirring for 24 h at 40 °C, the reaction mixture was concentrated under reduced
pressure. The residue was subjected to flash column chromatography on silica gel to give
corresponding (R)ꢀ1ꢀphenylethyl benzoate (R)ꢀ6m in 78% yield. HPLC: Chiral Luxcelluloseꢀ1
column, 100% hexane, 1.0 mL/min, 254 nm: tR (major) = 4.476 min; tR (minor) = 4.958, 94% ee.
Acknowledgment
This work was financially supported by University of Nevada Las Vegas. Dr. Katarzyna
LorencꢀKukula at SCAAC is acknowledged for mass spectra data. Subir Goswami (OSU) is
acknowledged for HPLC analysis of a chiral compound of (R)ꢀ6m. We also thank Prof. Rich G.
Carter (OSU) for helpful discussion. The reviewers are thanked for helpful commentary.
Supporting Information
Spectral data of all new products. This material is available free of charge via the Internet at
http://pubs.acs.org.
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