Bi(OTf)3-Catalyzed One-Step Catalytic Synthesis of N-Boc or N-Cbz Protected α-Branched Amines

Article abstract of DOI:10.1021/jo502540k

In this paper, N-Boc and N-Cbz protected α-branched amines are synthesized directly from commercially available aromatic/heteroaromatic compounds, aldehydes, and tert-butyl or benzyl carbamate bearing a variety of substituents. Bismuth(III) triflate is found to be a highly effective catalyst for this one-pot, three-component coupling reaction. In addition, the use of mild reaction conditions, low catalytic loading, easy removal of the N-protective group, and one-step synthesis under "open-flask" are advantages of the present procedure.

Full text of DOI:10.1021/jo502540k

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Article
Bi(OTf)3-Catalyzed One-Step Catalytic Synthesis of
N-Boc or N-Cbz Protected alpha-Branched Amines
Jaray Jaratjaroonphong, Surisa Tuengpanya, and Sureeporn Ruengsangtongkul
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502540k • Publication Date (Web): 05 Dec 2014
Downloaded from http://pubs.acs.org on December 8, 2014
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Bi(OTf)3ꢀCatalyzed OneꢀStep Catalytic Synthesis of NꢀBoc or NꢀCbz
Protected αꢀBranched Amines
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Jaray Jaratjaroonphong,∗ Surisa Tuengpanya, and Sureeporn Ruengsangtongkul
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science,
Burapha University, Chonburi 20131, Thailand
∗Eꢀmail: jaray@buu.ac.th
ABSTRACT
In this paper, NꢀBoc and NꢀCbz protected α−branched amines are synthesized directly from
commercially available aromatic/heteroaromatic compounds, aldehydes, and tertꢀbutyl or benzyl
carbamate bearing a variety of substituents. Bismuth(III) triflate is found to be a highly effective
catalyst for this, oneꢀpot, threeꢀcomponent coupling reaction. In addition, the use of mild reaction
conditions, low catalytic loading, easy removal of the Nꢀprotective group and oneꢀstep synthesis under
“open−flask” are advantages of the present procedure.
H
H
mild condition
N
Boc/Cbz
HN Boc/Cbz
R1
5 mol% Bi(OTf)3
Het/Ar
H
Het/Ar
O
toluene, air
room temperature
H
R1
30 examples
up to 97% yield
"one-pot synthesis"
KEYWORDS: Bi(OTf)3, Threeꢀcomponent reaction, AzaꢀFriedelꢀCrafts, α−Branched amines
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ꢀ INTRODUCTION
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The αꢀbranched amine skeleton represents a significant class of biologically active nitrogen
compounds that are found in various natural products and drugs with wellꢀrecognized pharmacological
properties (Fig. 1).1 In particular, they are the most promising therapeutic agents for neurological
disorders like Alzheimers and Parkinson disease. As a consequence, the synthesis of αꢀbranched amine
derivatives has attracted comprehensive and continuous interest from synthetic organic chemists.
Among a myriad of methods to approach functionalized αꢀbranched amine, the azaꢀFriedelꢀCrafts
reaction (AFCR) between electronꢀrich arenes and imine derivatives represents one of the most
straightforward and atomꢀeconomic strategies to access a variety of corresponding αꢀbranched
amines.2,3 Although great success has been achieved in such processes, the methods are multiꢀstep
processes and require highly electrophilic imine acceptors such as ethyl glyoxylate imines,4 and αꢀ
trifluoromethyl imines.5 In contrast, the functionalized imines of aromatic aldehydes generally proceed
to afford symmetrical triarylmethanes via a double FriedelꢀCrafts process due to the intrinsic instability
of the intermediate benzylamine under the acidic reaction conditions.6,7 Recently, several groups have
reported a multicomponent azaꢀFriedelꢀCrafts reaction for the synthesis of αꢀbranched amines in a oneꢀ
step process without isolation of the imine intermediate under standard reaction conditions.8−12 The
reaction is wellꢀestablished and practical, but the substrate scope is strictly limited to the indoles or 2ꢀ
naphthols, amides or urea and nonꢀenolizable, most notably, aryl aldehydes.8ꢀ11 Moreover, there are
disadvantages such as the use of expensive and corrosive reagents, high catalyst loading, long reaction
times, strongly acidic conditions, low yields of products and the use of microwave or ultrasonic
irradiation.8 Therefore, the development of a mild and efficient method utilizing aromatic and
heteroaromatic systems, an amine source which easily removes the nitrogenꢀprotecting group, a variety
of aldehydes including both aromatic and aliphatic aldehydes and easily available catalysts with high
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catalytic activity and short reaction times for the direct construction of αꢀbranched amine scaffolds with
multiple functional groups is still highly desirable.
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O
O
O
NHMe HCl
O
N
OH
Me2N
O
N
NO2
Cetitizine
(anti-histamine agent)
acetylcholinesterase (AChE) and
serotonin transporter (SERT) dual inhibitor
Cl
H
N
H
H
N
F3C
N
Cinacalcet
Selegiline
(treatment for Parkinson's disease)
Rasagiline
(treatment for Alzheimer's disease)
Figure 1. Representative examples of biologically active αꢀbranched amines.
Recently, Bi(OTf)3ꢀcatalyzed reactions have emerged as a versatile tool for developing syntheses
due to their numerous advantages, namely, their relatively high efficiency, low toxicity, water
compatibility, mild reaction conditions, and on ecoꢀfriendly catalytic reaction which is commercially
available or can be easily prepared from commercially available starting materials.13 Bi(OTf)3 has been
reported as catalyst for threeꢀcomponent Mannich−type reaction of a variety of in situ generated
aldimines using aldehydes, anilines, and silyl enol ethers leading to corresponding αꢀbranched
amines.14 To the best of our knowledge, however, there is no report using Bi(OTf)3 as catalyst to
promote the azaꢀFriedelꢀCrafts reaction. In continuation of the development of useful synthetic
methodologies for CꢀC and CꢀN bondꢀforming reactions,12,15 here we report an efficient Bi(OTf)3ꢀ
catalyzed oneꢀpot, three component azaꢀFriedelꢀCrafts reaction of aromatic/heteroaromatic compounds
with tertꢀbutyl or benzyl carbamates in combination with a wide variety of aldehydes under “openꢀ
flask” and mild conditions.
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ꢀ RESULTS AND DISCUSSION
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Our initial investigations employing 1,3,5ꢀtrimethoxybenzene (1a), benzaldehyde (2a), and tertꢀbutyl
carbamate (3a) as model substrates in combination with 5 mol % Bi(OTf)3 as catalyst focused on the
evaluation of the efficiency of various solvents under “open−flask” conditions (Table 1, entries 1−6).
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Among solvents tested, toluene seemed to be the most effective for this one−pot, three component azaꢀ
FriedelꢀCrafts reaction (entry 6). A slightly lower yield was obtained when using CH2Cl2,
ClCH2CH2Cl, and THF as a solvent. Encouraged by this result, we subsequently examined catalyst
loading and reaction under N2 atmosphere. Regarding the quantity of the catalyst, we found that 5 mol
% Bi(OTf)3 resulted in a high yield, contrary to the use of 10 mol % or 1 mol % Bi(OTf)3 (entries 7−8).
By comparison to the reaction in N2, the reaction in air also produced the desired products (4a) with
comparable yield (entries 6 and 9). These led to the confirmation that Bi(OTf)3 is a highly efficient
catalyst and highly tolerant of air as well as moisture. Under the reaction conditions, no sideꢀproduct 5a
was observed. A control reaction in the absence of Bi(OTf)3 gave no products and starting materials
were recovered (entry 10).
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Table 1. Optimization of the Reaction Conditionsa
4
OMe
5
6
7
8
CHO
MeO
NHBoc
Ph
MeO
Ph OMe
H2NBoc (3a)
+
+
Bi(OTf)3 (x mol%)
solvent, air, rt
MeO
OMe
MeO
OMe
MeO
OMe
MeO OMe
5a (not observed)
1a
2a
4a
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Entry
Bi(OTf)3 (mol%)
Solvent
Time (h)
4a, yieldb (%)
1
5
CH2Cl2
ClCH2CH2Cl
MeOH
2
2
88
88
72
89
75
91
84
77
93c
2
5
3
5
2
4
5
THF
2
5
5
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
2
6
5
2
7
10
1
2
8
2
9
5
2
d
10
0
48
−
a Reaction conditions: 1a (1 mmol), 2a (1.1 mmol), 3a (1 mmol), Bi(OTf)3, solvent (1 mL), room temperature.
b Isolated yields.
c The reaction was conducted under N2 atmosphere.
d No reaction based on TLC analysis.
e No sideꢀproduct 5a was observed.
To evaluate the scope of this novel strategy for the synthesis of αꢀbranched amines, a wide variety of
aldehydes were reacted with 1,3,5ꢀtrimethoxybenzene (1a) and tert−butyl or benzyl carbamates in the
presence of Bi(OTf)3 (5 mol %) at room temperature using toluene as the reaction media. The
experimental results are summarized in Table 2. In all cases, both aromatic aldehydes substituted with
electron−donating or electron−withdrawing groups and enolizable aliphatic aldehydes underwent the
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multicomponent reaction smoothly to provide the desired products 4a−o with good to excellent yields.
Even isobutyraldehyde and cyclohexanecarbaldehyde as sterically fairly demanding precursors
furnished α−branched amines 4l and 4o, respectively, in excellent yields. Compared to long chain
aliphatic aldehydes, αꢀbranched aliphatic aldehyde afforded higher yields of the desired products,
probably due to the higher electrophilicity of the carbonyl group. We also used benzyl carbamate,
serving as a nitrogen source, which cleanly provided the desired product 4a′ and 4l′ in excellent
yields.
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Scheme 1. Scope with Respect to the Aldehyde Compoundsa
OMe
MeO
NHP
R
H2NBoc (3a) or
H2NCbz (3b)
+
RCHO
Bi(OTf)3 (5 mol%)
toluene, air
rt, 2h
MeO
OMe
MeO
OMe
1a
2
4a-o (P = Boc)b
4a', 4l' (P = Cbz)b
MeO
NHBoc
OMe
MeO
NHCbz
MeO
NHBoc
n
R
MeO
MeO
OMe
MeO
OMe
4a'
4h: n = 1 (71%)
4i: n = 3 (76%)
(96%)
4a: R = H
4b: R = 2-F
(91%)
(89%)
(93%)
4c
: R = 4-F
MeO
NHBoc
MeO
NHBoc
4d: R = 4-Cl (82%)
4e
: R = 4-Br (85%)
4f: R = 4-NO2 (88%)
4g: R = OMe (81%)
MeO
OMe
MeO
OMe
4j (84%)
4k (61%)
MeO
NHBoc
OMe
MeO
NHBoc
MeO
NHCbz
OMe
n
MeO
4m
: n = 1 (85%)
MeO
OMe
4l (93%)
MeO
4n
4o
: n = 3 (91%)
: n = 4 (94%)
4l' (97%)
a Reaction conditions: 1 (1 mmol), 2 (1.1 mmol), 3 (1 mmol),
Bi(OTf)3 (5 mol%), toluene (1 mL), room temperature.
b Isolated yields.
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Encouraged by these results, the scope and generality of the reaction was further investigated with an
array of electronꢀrich aromatic/heteroaromatic compounds, aldehydes, and tertꢀbutyl or benzyl
carbamates. The experimental results are summarized in Table 2. In all cases, both electron−rich
aromatic and heteroaromatic compounds, except for pyrrole and indole proved to be very effective,
leading to the selective formation of α−branched amine adducts in moderate to good yields. Compared
to 1,3,5ꢀtrimethoxybenzene (1a), the less sterically electronꢀrich arene, 1,2,4ꢀtrimethoxybenzene (1b)
gave slightly lower yield of the azaꢀFriedelꢀCrafts products and triarylmethane 5q was obtained as a
minor product via a double FriedelꢀCrafts reaction (entries 1−2). Not only aromatic nucleophiles, but
heteroaromatic nucleophiles like 2ꢀmethylfuran (1c) or 2ꢀethylfuran (1d) were equally good to
satisfactory in affording α−branched amine derivatives 4q and 4r in modest yields (entries 3−4). 2ꢀ
Methylthiophene (1e) and 2ꢀethylthiophene (1f), which is known to be a poorly reactive substrate,16
gave satisfactory product yields, although an excess of the thiophene substrate was employed to
accomplish the reaction (entries 5−6). In constrast, heteroaromatic compounds containing nitrogen
atoms such as 2ꢀethylpyrrole (1g) and indole (1h) evolve according to a double FriedelꢀCrafts reaction
to give triarylmethane as a major product. These might be due to the intrinsic instability of α−branched
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amine derivative under our conditions (entries 7−8).6 We then tested the efficiency of this reaction with
the enolizable aldehydes, isobutyraldehyde (entry 9) and cyclohexanecarbaldehyde (entry 10).
Gratifyingly, the reactions with 2ꢀmethylfuran and tertꢀbutyl carbamate were converted into the desired
products in moderate yields. Finally, the reaction employing benzyl cabamate with heteroaromatic
compounds and benzaldehyde also afforded NꢀCbz protected α−branched amines in good yields but
with an increase in triarylmethane formation (entries 11ꢀ14).
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Table 2. Scope with Respect to the ElectronꢀRich Arenes and Carbamatesa
7
8
9
NHP
Ar
Bi(OTf)3 (5 mol%)
+
RCHO
+
Ar
H
NH2P
+
Ar
R
Ar
R
toluene, air
rt
4 (P = Boc)b
4' (P = Cbz)b
5b
3a
: P = Boc
1
2
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3b: P = Cbz
Entry Arenes Time (h)
Yield
(%)b
91
Triarylmethane 5
Yield
(%)b
α−Branched amines 4
OMe NHBoc
1
2
2
2
1a
1b
4a
4p
5a
5p
−
MeO
OMe
MeO
OMe
MeO
OMe
MeO OMe
OMe NHBoc
73
8
MeO
MeO
OMe
OMe
MeO
OMe
MeO
OMe
NHBoc
3
4
5
6
7
1
79
2
1c
1d
1e
1f
4q
4r
4s
4t
5q
5r
5s
5t
O
O
CH3
H3C
O
H3C
NHBoc
O
1
73
−
O
CH2CH3
H3CH2C
O
H3CH2C
53c
49c
7c
NHBoc
24
24
1 min
S
S
CH3
H3C
S
H3C
9c
NHBoc
S
S
CH2CH3
H3CH2C
S
H3CH2C
65d
d
NHBoc
NH
1g
4u
5u
−
H
N
CH2CH3
H3CH2C
NH
H3CH2C
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Table 2. Continueda
Entry Arenes Time (h)
Yield (%)b Triarylmethane 5
Yield (%)b
55d
α−Branched amines 4
6
7
8
NHBoc
8
10 min
32d
1h
4v
5v
9
N
H
10
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NH
N
H
NHBoc
9
12
12
74
14
12
1c
1c
4w
4x
5w
5x
O
CH3
O
O
O
H3C
H3C
NHBoc
NHCbz
NHCbz
10
70
O
CH3
H3C
O
H3C
11
12
1
1
83
16
1c
1e
5q
5s
4q′
4s′
O
O
CH3
H3C
O
H3C
72e
22e
S
S
CH3
H3C
S
H3C
NHCbz
NHCbz
13
14
12
12
58
38
32
1c
1c
5w
5x
4w′
4x′
O
CH3
O
O
O
H3C
H3C
55
O
CH3
H3C
O
H3C
a
Reaction conditions: 1 (1 mmol), 2 (1.1 mmol), 3 (1 mmol), Bi(OTf)3 (5 mol%), toluene (1 mL), room
temperature.
b Isolated yields.
c The reaction was carried out using Bi(OTf)3 (5 mol%) and arenes (1 mL) without solvent at room tempature.
d The reaction was carried out using Bi(OTf)3 (5 mol%) in toluene (15 mL) at 0 °C, dropwise.
e The reaction was carried out using Bi(OTf)3 (20 mol%) in toluene (1 mL) at room tempature.
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In order to aid our interpretation of the mechanism, a series of experiments were performed as
outlined in Scheme 2. Initially, we found that α−branched amine 4q′ and triarylmethane 5q were found
in the reaction of 2ꢀmethylfuran with N−Cbz imine 6 in the presence of 5 mol% Bi(OTf)3, strongly
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indicating that the threeꢀcomponent coupling reaction proceeded via N−Boc or N−Cbz imine
intermediates, which generated in situ under the reaction conditions (Scheme 2a). To gain a more
thorough understanding of triarylmethane formation under our condition, the reaction of 2ꢀmethylfuran
with benzaldehyde (Scheme 2b) and with desired product 4q′ (Scheme 1c) were also carried out. The
compound 5q was obtained in both cases, indicating that aldehyde and diarylmethyl carbamate act as
good alkylating agents of FriedelꢀCrafts reaction.
Scheme 2. Mechanistic Experiments
NHCbz
Ph
Ph
O
NCbz
H
Bi(OTf)3 (5 mol%)
CH3
+
(2a)
+
H3C
O
O
O
Ph
Ph
toluene, air
rt, 2h
H3C
H3C
4q'
(81%)
Ph
5q (12%)
1c
6
O
O
Bi(OTf)3 (5 mol%)
CH3
+
+
(2b)
H3C
O
O
H
toluene, air
rt, 2h
H3C
5q
(92%)
Ph
1c
2a
NHCbz
O
Bi(OTf)3 (5 mol%)
CH3
Ph
+
4q' (42%)
(2c)
H3C
O
O
O
toluene, air
rt, 2h
H3C
H3C
5q
(56%)
1c
4q'
On the basis of literature information7,11−12 and our experimental results, a plausible explanation of
the mechanism is depicted in Scheme 3. The first step is the formation of I, which is formed by
coordination of the aldehyde to Bi(OTf)3. Condensation of I with benzyl carbamate gives the resulting
activated NꢀCbz imine II. The nucleophilic addition of 2ꢀmethylfuran (1c) attacks the resulting imine II
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leading to the formation of the desired amine 4. Further, the formation of triarylmethane 5 could be
explained by addition of a second 2ꢀmethylfuran to the reactive intermediate V, which is generated by
Bi(III)) ion catalyzed carbamate elimination of 4 and/or by dehydration of IV. A structure like
intermediate V is proposed by other researchers for the reaction of indole with aldehydes17 and
imines6b,e,11
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Scheme 3. Plausible Reaction Mechanism
BiIII
O
BiIII
O
Bi(OTf)3
O
NH2Cbz
N
OR
R
H
R
H
R
H
I
II
H3C
H3C
O
O
BiIII
O
H
N
OR
BiIII
H3C
H3C
O
O
H
R
R
O
III
IV
H3C
-H2O, BiIII
- BiIII
O
BiIII
H3C
H
N
O
H3C
OR
H3C
R
O
O
O
R
R
O
V
H3C
4
5
The synthetic utility of this transformation was demonstrated by derivation of the corresponding
diarylmethyl carbamate to unsymmetrical triarylmethane (Scheme 4). FriedelꢀCrafts type substitution
reactions of 4p and 4p′ occurred cleanly by treatment with 2ꢀmethylfuran in the present of 10 mol%
Bi(OTf)3 in toluene at room temperature to afford unsymmetrical triarylmethane 7 in 69% and 82%
yields, respectively.
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Scheme 4. Synthesis of an Unsymmetrical Triarylmethane
CH3
5
6
7
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9
O
MeO
NHP
MeO
H3C
1c
O
Bi(OTf)3 (10 mol%)
MeO
MeO
toluene, air
rt, 24h
OMe
OMe
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7
4p
4p'
(P = Boc)
(P = Cbz)
(69% from 4p;
82% from 4p')
ꢀ CONCLUSIONS
In summary, we have successfully developed a oneꢀpot, threeꢀcomponent azaꢀFriedelꢀCrafts reaction
of electronꢀrich arenes with a variety of aldehydes and tertꢀbutyl or benzyl carbamate, providing an
efficient approach for the direct construction of the corresponding NꢀBoc and NꢀCbz protected
α−branched amines in the presence of a catalytic amount of Bi(OTf)3. The reactions were also
applicable to enolizable aliphatic aldehydes as well as to various heteroaromatic compounds. In
addition, the use of mild reaction conditions, low catalytic loading, easy removal of the Nꢀprotective
group18,19 and oneꢀstep synthesis are advantages of the present procedure. The further development of
asymmetric reaction is ongoing and will be reported in due course.
ꢀ EXPERIMENTAL SECTION
General Procedure. All isolated compound were characterized on the basis of H NMR and 13C
1
NMR spectroscopic data, IR spectra, and HRMS data. H NMR and 13C NMR chemical shifts are
1
reported in ppm using tetramethylsilane (TMS) as an internal standard or residual nondeuterated
solvent peak as an internal standard.
General procedure for the synthesis of α−branched amines 4. To a toluene solution (1 mL) of
electronꢀrich arene (1.0 mmol), freshly distilled aldehyde (1.1 mmol), and tertꢀbutyl or benzyl
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carbamate (1.0 mmol) in a testꢀtube open to air at room temperature was added Bi(OTf)3 (0.05 mmol).
After the reaction was stirred until completion (TLC analysis), the reaction mixture was quenched with
aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10 mL). The combined organic layer was
washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated
(aspirator then vacuo) to give a crude product, which was purified by radial chromatography (SiO2,
100% hexane to 30% EtOAc/hexane as eluent) to give the corresponding αꢀbranched amines 4 and/or
triarylmethane 5 as a byꢀproduct.
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tert-Butyl phenyl(2,4,6-trimethoxyphenyl)methylcarbamate (4a). White solid; m.p. 132ꢀ133 oC; yield
338.7 mg (91%). 1H NMR (400 MHz, CDCl3): δ 7.26ꢀ7.24 (m, 4H), 7.17ꢀ7.16 (m, 1H), 6.60 (d, J =
10.2 Hz, 1H), 6.27 (d, J = 10.2 Hz, 1H), 6.17 (s, 2H), 3.83 (s, 3H), 3.79 (s, 6H), 1.48 (s, 9H); 13C NMR
(100 MHz, CDCl3): δ 160.6, 158.6, 155.7, 143.6, 127.9, 126.1, 125.9, 111.2, 91.2, 79.0, 55.9, 55.4,
48.2, 28.6; IR (film): νmax 3456 (NꢀH), 1713, 1593, 1494, 1455, 1419, 1365, 1234, 1205, 1154, 1127,
1042, 1017, 951 cmꢀ1; HRMS (EIꢀTOF) calcd for C21H27NO5Na [M+Na]+ 396.1787, found 396.1782.
Benzyl[(2,4,6-trimethoxyphenyl)phenylmethyl]carbamate (4a′): Pale yellow oil; yield 390.8 mg
(96%). 1H NMR (400 MHz, CDCl3): δ 7.42ꢀ7.17 (m, 10H), 6.68 (d, J = 10.1 Hz, 1H), 6.52 (d, J = 10.1
Hz, 1H), 6.17 (s, 2H), 5.18 (q, J = 12.1 Hz, 1H), 5.12 (q, J = 12.1 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 6H);
13C NMR (100 MHz, CDCl3): δ 160.7, 158.5, 156.2, 142.9, 136.8, 128.5, 128.3, 128.1, 127.9, 126.0,
126.0, 110.7, 91.2, 66.7, 55.9, 55.3, 48.9; IR (film): νmax 3444 (NꢀH), 1722, 1609, 1593, 1497, 1455,
1332, 1230, 1205, 1152, 1127, 1036, 1027, 951 cmꢀ1; HRMS (EIꢀTOF) calcd for C24H25NO5 [M]+
407.1733, found 407.1727.
tert-Butyl[(2,4,6-trimethoxyphenyl)-2-fluorophenylmethyl]carbamate (4b): White solid; m.p. 128ꢀ
129 oC; yield 348.4 mg (89%). 1H NMR (400 MHz, CDCl3): δ 7.33 (t, J = 7.7 Hz, 1H), 7.15 (q, J = 6.1
Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.93 (t, J = 9.4 Hz, 1H), 6.77 (d, J = 9.9 Hz, 1H), 6.14 (s, 2H), 6.07
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(d, J = 9.9 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 6H), 1.46 (s, 9H); C NMR (100 MHz, CDCl3): δ 160.7,
160.5 (1JC-F = 247.0 Hz), 158.7, 155.1, 130.0 (2JC-F = 14.0 Hz), 128.2 (3JC-F = 4.0 Hz), 127.9 (3JC-F = 8.0
Hz), 123.1 (4JC-F = 2.0 Hz), 115.4 (2JC-F = 22.0 Hz), 110.0, 91.2, 79.2, 55.9, 55.3, 44.0, 28.5 (CH3); IR
(film): νmax 3457 (NꢀH), 1717, 1609, 1593, 1492, 1457, 1229, 1205, 1154, 1130, 1041 cmꢀ1; HRMS
(EIꢀTOF) calcd for C21H26FNO5 Na [M+Na]+ 414.1693, found 414.1687.
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tert-Butyl[(2,4,6-trimethoxyphenyl)-4-fluorophenylmethyl]carbamate (4c): White solid; m.p. 119ꢀ
121 oC; yiled 364.0 mg (93%). 1H NMR (400 MHz, CDCl3): δ 7.21 (dd, J = 8.1, 5.7 Hz, 2H), 6.92 (t, J
= 8.7 Hz, 2H), 6.55 (d, J = 10.0 Hz), 6.25 (d, J = 10.0 Hz, 1H), 6.17 (s, 2H), 3.83 (s, 3H), 3.79 (s, 6H),
1.48 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 161.7 (1JC-F = 242.0 Hz), 161.0, 158.7, 155.9, 139.6 (4JC-F
= 2.0 Hz), 127.8 (3JC-F = 8.0 Hz), 114.8 (2JC-F = 21.0 Hz), 111.2, 91.5, 79.4, 56.2, 55.6, 48.0, 28.8
(CH3); IR (film): νmax 3455 (NꢀH), 1712, 1609, 1493, 1457, 1366, 1221, 1205, 1155, 1126, 1042, 1016,
952 cmꢀ1; HRMS (EIꢀTOF) calcd for C21H26FNO5Na [M+Na]+ 414.1693, found 414.1687.
tert-Butyl[(2,4,6-trimethoxyphenyl)-4-chlorophenylmethyl]carbamate (4d): White solid; m.p. 114ꢀ
115 oC; yield 334.5 mg (82%). 1H NMR (400 MHz, CDCl3): δ 7.22ꢀ7.17 (m, 4H), 6.55 (d, J = 10.0 Hz,
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1H), 6.22 (d, J = 10.0 Hz, 1H), 6.16 (s, 2H), 3.82 (s, 3H), 3.79 (s, 6H), 1.48 (s, 9H); C NMR (100
MHz, CDCl3): δ 160.7, 158.4, 155.5, 142.2, 131.7, 127.9, 127.4, 110.5, 91.1, 79.2, 55.8, 55.3, 47.7,
28.5; IR (film): νmax 3455 (NꢀH), 1713, 1609, 1594, 1491, 1456, 1205, 1154, 1128, 1014 cmꢀ1; HRMS
(EIꢀTOF) calcd for C21H27ClNO5 [M+H]+ 408.1578, found 408.1572.
tert-Butyl[(2,4,6-trimethoxyphenyl)-4-bromophenylmethyl]carbamate (4e): White solid; m.p. 133ꢀ
135 oC; yield 384.4 mg (85%). 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4
Hz, 2H), 6.53 (d, J = 9.9 Hz, 1H), 6.21 (d, J = 9.9 Hz, 1H), 6.16 (s, 2H), 3.83 (s, 3H), 3.79 (s, 6H), 1.48
(s, 9H); 13C NMR (100 MHz, CDCl3): δ 160.7, 158.4, 155.6, 142.8, 130.9, 127.9, 119.9, 110.5, 91.1,
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79.3, 55.9, 55.4, 47.80, 28.5; IR (film): νmax 3453 (NꢀH), 1713, 1610, 1493, 1205, 1154, 1128, 1010
cmꢀ1; HRMS (EIꢀTOF) calcd for C21H26BrNO5Na [M+Na]+ 474.0892, found 474.0887.
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tert-Butyl[(2,4,6-trimethoxyphenyl)-4-nitrophenylmethyl]carbamate (4f): Yellow solid; m.p. 161ꢀ
163 oC; yield 368.2 mg (88%). 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7
Hz, 2H), 6.64 (d, J = 9.7 Hz, 1H), 6.20 (d, J = 9.7 Hz, 1H), 6.16 (s, 2H), 3.83 (s, 6H), 3.80 (s, 3H), 1.49
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(s, 9H); C NMR (100 MHz, CDCl3): δ 161.1, 158.3, 155.5, 151.6, 146.4, 126.6, 123.1, 109.7, 91.1,
79.6, 55.8, 55.3, 48.0, 28.4; IR (film): νmax 3450 (NꢀH), 1712, 1607, 1492, 1347, 1205, 1154, 1120,
1043 cmꢀ1; HRMS (EIꢀTOF) calcd for C21H27N2O7 [M+H]+ 419.1818, found 419.1815.
tert-Butyl[(2,4,6-trimethoxyphenyl)-4-methoxyphenylmethyl]carbamate (4g): White solid; m.p. 112ꢀ
113 oC; yield 327.9 mg (81%). 1H NMR (400 MHz, CDCl3): δ 7.17 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6
Hz, 2H), 6.55 (d, J = 10.2 Hz, 1H), 6.27 (d, J =10.2 Hz, 1H), 6.17 (s, 2H), 3.82 (s, 3H), 3.79 (s, 6H),
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3.77 (s, 3H), 1.48 (s, 9H); C NMR (100 MHz, CDCl3): δ 160.4, 158.5, 158.0, 155.6, 135.7, 127.1,
113.3, 111.1, 91.2, 78.9, 55.9, 55.3, 55.1, 47.8, 28.5; IR (film): νmax 3456 (NꢀH), 1712, 1609, 1593,
1510, 1495, 1465, 1365, 1246, 1205, 1154, 1126, 1038 cmꢀ1; HRMS (EIꢀTOF) calcd for C22H29NO6Na
[M+Na]+ 426.1893, found 426.1887.
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tert-Butyl[(2,4,6-trimethoxyphenyl)propyl]carbamate (4h): White solid; m.p. 85ꢀ87 C; yield 230.9
mg (71%). 1H NMR (400 MHz, CDCl3): δ 6.14 (s, 2H), 5.81 (d, J = 10.1 Hz, 1H), 5.23 (q, J = 7.7 Hz,
1H), 3.83 (s, 6H), 3.81 (s, 3H), 1.82ꢀ1.68 (m, 2H), 1.45 (s, 9H), 0.83 (t, J = 7.4 Hz, 3H); 13CꢀNMR (100
MHz, CDCl3): δ 160.0, 158.7, 155.6, 111.2, 91.0, 78.5, 55.8, 55.3, 47.2, 28.7, 28.5, 11.0; IR (film): νmax
3458 (NꢀH), 1713, 1610, 1592, 1497, 1456, 1364, 1230, 1205, 1171, 1155, 1138, 1060, 1042 cmꢀ1;
HRMS (EIꢀTOF) calcd for C17H28NO5 [M+H]+ 326.1967, found 326.1971.
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tert-Butyl[(2,4,6-trimethoxyphenyl)pentyl]carbamate (4i): White solid; m.p. 74ꢀ76 C; yield 267.2
mg (76%). 1H NMR (400 MHz, CDCl3): δ 6.13 (2H, s), 5.79 (1H, d, J = 10.2 Hz), 5.30 (1H, q, J = 8.5
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Hz), 3.83 (s, 6H), 3.81 (s, 3H), 1.76ꢀ1.64 (2H, m), 1.44 (9H, s), 1.30ꢀ1.25 (3H, m), 1.15ꢀ1.13 (1H, m),
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0.85 (3H, t, J = 7.0 Hz); C NMR (100 MHz, CDCl3): δ 159.9, 158.5, 155.4, 111.4, 90.9, 78.4, 55.7,
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55.2, 45.7, 35.5, 28.5, 28.4, 22.5, 14.0; IR (film): νmax 3458 (NꢀH), 1713, 1610, 1593, 1496, 1456,
1365, 1205, 1172, 1154, 1138, 1041 cmꢀ1; HRMS (EIꢀTOF) calcd for C19H32NO5 [M+H]+ 354.2280,
found 354.2275.
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tert-Butyl[(2,4,6-trimethoxyphenyl)-3-phenylpropyl]carbamate (4j): Colorless oil; yield 338.8 mg
(84%). 1H NMR (400 MHz, CDCl3): δ 7.28ꢀ7.23 (m, 2H), 7.17ꢀ7.13 (m, 3H), 6.14 (s, 2H), 5.86 (d, J =
10.2 Hz, 1H), 5.42 (q, J = 7.6 Hz, 1H), 3.83 (s, 6H), 3.82 (s, 3H), 2.73ꢀ2.65 (m, 1H), 2.51ꢀ2.43 (m,
1H), 2.14ꢀ2.07 (m, 1H), 2.02ꢀ1.94 (m, 1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 160.4, 158.8,
155.8, 143.0, 136.4, 128.6, 128.4, 125.7, 111.2, 91.2, 79.0, 56.1, 55.6, 46.2, 37.8, 33.2, 28.8; IR (film):
νmax 3454 (NꢀH), 1172, 1609, 1592, 1495, 1455, 1365, 1260, 1204, 1151, 1119, 1043 cmꢀ1; HRMS (EIꢀ
TOF) calcd for C23H32NO5 [M+H]+ 402.2280, found 402.2275.
tert-Butyl[(2,4,6-trimethoxyphenyl)-3-methylbutyl]carbamate (4k): White solid; m.p. 91ꢀ93 oC; yield
1
215.4 mg (61%). H NMR (400 MHz, CDCl3): δ 6.13 (s, 2H), 5.72 (d, J = 10.2 Hz, 1H), 5.41 (q, J =
7.7 Hz, 1H), 3.83 (s, 6H), 3.80 (s, 3H), 1.70ꢀ1.63 (m, 1H), 1.57ꢀ1.48 (m, 1H), 1.44 (m, 10H), 0.95 (d, J
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= 6.5 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H); C NMR (100 MHz, CDCl3): δ 159.7, 158.4, 155.3, 111.8,
90.9, 78.4, 55.7, 55.2, 45.0, 44.1, 28.5, 25.3, 22.7; IR (film): νmax 3458 (NꢀH), 1712, 1610, 1593, 1496,
1456, 1365, 1219, 1205, 1155, 1110, 1042 cmꢀ1; HRMS (EIꢀTOF) calcd for C19H32NO5 [M+H]+
354.2280, found 354.2275.
o
tert-Butyl[(2,4,6-trimethoxyphenyl)-2-methylpropyl]carbamate (4l): White solid; m.p. 127ꢀ129 C;
yield 316.6 mg (93%). 1H NMR (400 MHz, CDCl3): δ 6.12 (s, 2H), 5.75 (d, J = 10.4 Hz, 1H), 4.97 (t,
J = 10.2 Hz, 1H), 3.81 (s, 6H), 3.80 (s, 3H), 2.05ꢀ1.98 (m, 1H), 1.42 (s, 9H), 1.00 (d, J = 6.6 Hz, 3H),
13
0.69 (d, J = 6.6 Hz, 3H); C NMR (100 MHz, CDCl3): δ 159.9, 158.7, 155.8, 111.3, 91.0, 78.4, 55.8,
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55.3, 51.8, 33.3, 28.5, 19.8; IR (film): νmax 3458 (NꢀH), 1714, 1609, 1592, 1497, 1456, 1365, 1230,
1205, 1154, 1101, 1040, 1009 cmꢀ1; HRMS (EIꢀTOF) calcd for C18H30NO5 [M+H]+ 340.2124, found
340.2118.
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Benzyl[(2,4,6-trimethoxyphenyl)-2-methylpropyl]carbamate (4l′): Colorless oil; yield 363.5 mg
(97%). 1H NMR (400 MHz, CDCl3): δ 7.38ꢀ7.31 (m, 5H), 6.14 (s, 2H), 6.03 (d, J = 10.4 Hz, 1H), 5.16
(d, J = 12.2 Hz, 1H), 5.05 (q, J = 11.3 Hz, 2H), 3.82 (s, 9H), 2.11ꢀ2.07 (m, 1H), 1.04 (d, J = 6.6 Hz,
3H), 0.73 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 160.0, 158.6, 156.3, 137.0, 128.4, 128.2,
127.9, 110.8, 91.0, 66.4, 55.7, 55.3, 52.6, 33.0, 19.9, 19.6; IR (film): νmax 3448 (NꢀH), 1723, 1609,
1592, 1502, 1455, 1227, 1205, 1143, 1102 cmꢀ1; HRMS (EIꢀTOF) calcd for C21H27NO5Na [M+Na]+
396.1787, found 396.1768.
tert-Butyl[(2,4,6-trimethoxyphenyl)cyclopropylmethyl]carbamate (4m): White solid; m.p. 105ꢀ107
oC; yield 287.5 mg (85%). 1H NMR (400 MHz, CDCl3): δ 6.16 (s, 2H), 5.95 (d, J = 10.2 Hz, 1H), 4.68
(t, J = 9.7 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 6H), 1.44 (s, 9H), 1.37ꢀ1.33 (m ,1H), 0.56ꢀ0.52 (m, 1H), 0.44ꢀ
0.41 (m, 1H), 0.35ꢀ0.33 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 160.0, 158.3, 155.6, 111.6, 91.0,
78.5, 55.8, 55.3, 49.9, 28.5, 17.0, 3.7, 3.1; IR (film): νmax 3460 (NꢀH), 1712, 1610, 1593, 1495, 1456,
1205, 1154, 1111, 1041, 1017 cmꢀ1; HRMS (EIꢀTOF) calcd for C18H27NO5Na [M+Na]+ 360.1787,
found 360.1787.
tert-Butyl[(2,4,6-trimethoxyphenyl)cyclopentylmethyl]carbamate (4n): White solid; m.p. 116ꢀ118
oC; yield 333.1 mg (91%). 1H NMR (400 MHz, CDCl3): δ 6.13 (s, 2H), 5.79 (d, J = 10.4 Hz, 1H), 5.12
(t, J = 10.4 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 6H), 2.38ꢀ2.32 (m, 1H), 1.76ꢀ1.68 (m, 2H), 1.61ꢀ1.56 (m,
1H), 1.54ꢀ1.43 (m, 12H), 1.27ꢀ1.20 (m, 1H), 1.17ꢀ1.12 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 160.1,
158.8, 155.9, 112.2, 91.3, 78.6, 56.0, 55.5, 50.0, 45.8, 30.4, 29.8, 28.8, 26.9, 23.9; IR (Nujolꢀmull): νmax
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3458 (NꢀH), 1712, 1609, 1592, 1497, 1455, 1365, 1230, 1204, 1163, 1152, 1117, 1040, 1011 cmꢀ1;
HRMS (EIꢀTOF) calcd for C20H32NO5 [M+H]+ 366.2280, found 366.2275.
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tert-Butyl[(2,4,6-trimethoxyphenyl)cyclohexylmethyl]carbamate (4o): White solid; m.p. 138ꢀ140 C;
yield 357.8 mg (94%). 1H NMR (400 MHz, CDCl3): δ 6.12 (s, 2H), 5.74 (d, J = 10.3 Hz, 1H), 5.03 (t, J
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= 10.0 Hz, 1H), 3.81 (s, 6H), 3.80 (s, 3H), 1.94ꢀ1.91 (br m, 1H), 1.75ꢀ1.59 (br m, 4H), 1.43 (s, 9H),
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1.26ꢀ1.04 (br m, 5H), 0.97ꢀ0.91 (br m, 1H; C NMR (100 MHz, CDCl3): δ 159.8, 158.6, 155.7, 110.7,
90.8, 78.3, 55.7, 55.2, 50.6, 42.5, 30.0, 29.8, 28.5, 26.4, 26.2; IR (film): νmax 3458 (NꢀH), 1713, 1609,
1592, 1496, 1454, 1364, 1204, 1172, 1143, 1112, 1039, 1009 cmꢀ1; HRMS (EIꢀTOF) calcd for
C21H34NO5 [M+H]+ 380.2437, found 380.2431.
o
tert-Butyl[(2,4,5-trimethoxyphenyl)phenylmethyl]carbamate (4p): White solid; m.p. 91ꢀ93 C; yield
272.6 mg (73 %). 1H NMR (400 MHz, CDCl3): δ 7.29ꢀ7.18 (m, 5H), 6.82 (s, 1H), 6.53 (s, 1H), 6.00 (br
d, J = 8.0 Hz, 1H), 5.67 (br d, J = 5.8 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.70 (s, 3H), 1.46 (s, 9H); 13C
NMR (100 MHz, CDCl3): δ 155.7, 151.6, 149.3, 143.3, 142.8, 128.5, 127.0, 126.8, 122.0, 113.4, 98.8,
79.8, 57.0, 56.7, 56.5, 55.3, 28.5; IR (film): νmax 3368 (NꢀH), 1710, 1510, 1455, 1366, 1275, 1260,
1206, 1168, 1034 cmꢀ1; HRMS (EIꢀTOF) calcd for C21H27NO5Na [M+Na]+ 396.1787, found 396.1781.
o
tert-Butyl[2-(5-methylfuryl)phenylmethyl]carbamate (4q): White solid; m.p. 73ꢀ75 C; yield 227.5
mg (79%). 1H NMR (400 MHz, CDCl3): 7.38ꢀ7.28 (m ,5H), 5.99 (br s, 1H), 5.90 (br s, 2H), 5.30 (br s,
13
1H), 2.27 (s, 3H), 1.46 (br s, 9H); CꢀNMR (100 MHz, CDCl3): δ 155.2, 152.5, 152.4, 140.7, 128.8,
127.8, 127.2, 108.4, 106.4, 80.2, 53.0, 28.7, 13.9; IR (film): νmax 3338 (NꢀH), 1706, 1496, 1455, 1367,
1243, 1168, 1046, 1021, 964, 879, 784, 700 cmꢀ1; HRMS (ESIꢀTOF) calcd for C17H21NO3Na [M+Na]+
310.1419, found 310.1418.
tert-Butyl[2-(5-ethylfuryl)phenylmethyl]carbamate (4r): Yellow solid; m.p. 75ꢀ77 oC; yield 220.0 mg
(73%). 1H NMR (400 MHz, CDCl3): δ 7.36ꢀ7.26 (m, 5H), 5.98 (br s, 1H), 5.89 (br d, J = 3.1 Hz, 2H),
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5.28 (br s, 1H). 2.61 (q, J = 7.5 Hz, 2H), 1.45 (br s, 9H), 1.20 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 157.8, 154.9, 152.0, 140.4, 128.5, 127.5, 126.9, 107.9, 104.4, 79.9, 52.8, 28.4 (3xCH3), 21.4,
12.0; IR (film): νmax 3338 (NꢀH), 1705, 1496, 1455, 1367, 1246, 1168, 1046, 1013 cmꢀ1: HRMS (ESIꢀ
TOF) calcd for C18H23NO3Na [M+Na]+ 324.1576, found 324.1579.
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tert-Butyl[2-(5-methylthienyl)phenylmethyl]carbamate (4s): Pale yellow solid; m.p. 105ꢀ109 C;
yield 160,8 mg (53%). 1H NMR (400 MHz, CDCl3): δ 7.37ꢀ7.27 (m, 5H), 6.57ꢀ6.55 (m, 2H), 6.02 (br s,
1H), 5.21 (br s, 1H), 2.42 (s, 3H), 1.44 (br s, 9H); 13C NMR (100 MHz, CDCl3): δ 154.7, 143.8, 141.9,
139.7, 128.6, 127.6, 126.8, 125.3, 124.7, 80.0, 54.6, 28.4 (3xCH3), 15.3; IR (film): νmax 3357 (NꢀH),
1691, 1515, 1367, 1173, 1019 cmꢀ1; HRMS (ESIꢀTOF) calcd for C17H21NO2SNa [M+Na]+ 326.1191,
found 326.1190.
o
tert-Butyl[3-(5-ethylthienyl)phenylmethyl]carbamate (4t): White solid; m.p. 77ꢀ81 C; yield 154.2
mg (49%). 1H NMR (400 MHz, CDCl3): δ 7.40ꢀ7.30 (m, 5H), 6.60 (s, 2H), 6.05 (br s, 1H), 5.26 (br s,
1H), 2.80 (q, J = 7.5 Hz, 2H), 1.46 (br s, 9H), 1.29 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
154.4, 146.9, 143.0, 141.4, 128.1, 127.2, 126.4, 124.7, 122.4, 79.5, 54.2, 27.9 (3xCH3), 23.1, 15.4; IR
(film): νmax 3332 (NꢀH), 1702, 1494, 1455, 1366, 1246, 1166, 1016 cmꢀ1: HRMS (ESIꢀTOF) calcd for
C18H23NO2SNa [M+Na]+ 340.1347, found 340.1346.
o
tert-Butyl[(3-indolyl)phenylmethyl]carbamate (4v): Orange solid; m.p. 131ꢀ135 C; yield 101.9 mg
1
(32%). HꢀNMR (400 MHz, CDCI3): δ 8.08 (br s, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.43ꢀ7.35 (m, 5H),
7.31ꢀ7.28 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.77 (br s, 1H),), 6.24 (br d, J = 7.2
13
Hz, 1H), 5.25 (br s, 1H), 1.48 (br s, 9H); C NMR (100 MHz, CDCI3): δ 155.2, 142.0, 136.7, 128.4,
127.1, 126.8, 125.9, 123.2, 122.4, 119.8, 119.5, 118.0, 111.3, 79.6, 51.7, 28.4 (3xCH3); IR (film): νmax
3407, 3327, 1693, 1495, 1455, 1367, 1244, 1166, 1017 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C20H22N2O2Na [M+Na]+ 345.1579, found 345.1577.
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tert-Butyl[2-(5-methylfuryl)-2-methylpropyl]carbamate (4w): Yellow oil; yield 209.7 mg (74%). H
NMR (400 MHz, CDCl3): δ 6.01 (br d, J = 2.1 Hz, 1H), 5.88 (br d, J = 2.1 Hz, 1H), 4.89 (br d , J = 7.9
Hz, 1H), 4.49 (br t, J = 7.9 Hz, 1H), 2.27 (s, 3H), 2.10ꢀ2.05 (m, 1H), 1.46 (s, 9H), 0.94 (d, J = 6.8 Hz,
3H), 0.88 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 155.4, 152.6, 151.0, 106.9, 105.8, 79.3,
54.4, 32.3, 28.4, 19.1, 18.4, 13.5; IR (film): νmax 3347 (NꢀH), 1705, 1499, 1390, 1366, 1240, 1171,
1020 cmꢀ1; HRMS (ESIꢀTOF) calcd for C14H24NO3 [M+H]+ 254.1756, found 254.1751.
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tert-Butyl[2-(5-methylfuryl)cyclohexylmethyl]carbamate (4x): Yellow solid; m.p. 89ꢀ91 C; yield
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205.4 mg (70%). H NMR (400 MHz, CDCl3): δ 6.00 (br d, J = 1.6 Hz, 1H), 5.87 (br d, J = 1.6 Hz,
1H), 4.89 (br d, J = 8.7 Hz), 4.49 (br t, J = 8.3 Hz), 2.27 (s, 3H), 1.81ꢀ1.64 (m, 5H), 1.53ꢀ1.51 (m, 1H),
1.45 (s, 9H), 1.29ꢀ1.11 (m, 3H), 1.04ꢀ0.95 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 155.4, 152.4,
151.0, 106.9, 105.7, 79.3, 53.7, 42.0, 29.7, 29.0, 28.4, 26.3, 26.0, 13.5; IR (film): νmax 3350 (NꢀH),
1702, 1499, 1451, 1366, 1245, 1171, 1054, 1019 cmꢀ1; HRMS (ESIꢀTOF) calcd for C17H28NO3 [M+H]+
294.2069, found 294.2066.
Benzyl[2-(5-methylfuryl)phenylmethyl]carbamate (4q′
): Yellow solid; m.p. 83ꢀ87 oC; yield 265.5 mg
(83%). 1H NMR (400 MHz, CDCl3): 7.38ꢀ7.28 (m, 10H), 6.00ꢀ5.90 (br m, 3H), 5.56 (br s, 1H), 5.15 (q,
J = 12.2 Hz, 2H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 155.1, 152.0, 151.3, 139.5, 136.0,
128.2, 127.4, 126.6, 108.1, 105.8, 66.7, 52.9, 13.2: IR (film): νmax 3321 (NꢀH), 1702, 1498, 1455, 1220,
1404, 1026 cmꢀ1; HRMS (ESIꢀTOF) calcd for C20H19NO3Na [M+Na]+ 344.1263, found 344.1258.
o
Benzyl[2-(5-methylthienyl)phenylmethyl]carbamate (4s
′
): Pale yellow solid; m.p. 99ꢀ103 C; yield
242.9 mg (72%). 1H NMR (400 MHz, CDCl3): δ 7.36ꢀ7.34 (brm, 10H), 6.60 (d, J = 7.1 Hz, 2H), 6.11
13
(br d, J = 6.7 Hz, 1H), 5.49 (br s, 1H), 5.14 (q, J = 12.3 Hz, 2H), 2.43 (s, 3H); CꢀNMR (100 MHz,
CDCl3): δ 155.3, 143.1, 141.3, 139.9, 136.3, 128.6, 128.5, 128.1, 127.8, 126.8, 125.5, 124.8, 67.0, 55.1,
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15.3; IR (film): νmax 3308 (NꢀH), 1690, 1533, 1242, 1028 cmꢀ1; HRMS (ESIꢀTOF) calcd for
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C20H19NO2SNa [M+Na]+ 360.1034, found 360.1032.
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Benzyl[2-(5-methylfyryl)-2-methylpropyl]carbamate (4w
′
): Yellow oil; yield 167.0 mg (58%). H
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NMR (400 MHz, CDCl3): δ 7.39ꢀ7.34 (m, 5H), 6.04 (br d , J = 1.7 Hz, 1H), 5.89 (br d , J = 1.7 Hz,
1H), 5.16ꢀ5.13 (m, 3H), 4.56 (t, J = 8.2 Hz, 1H), 2.27 (s, 3H), 2.13ꢀ2.08 (m, 1H), 0.96 (d, J = 6.7 Hz,
3H), 0.90 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 155.9, 152.0, 152.0, 136.5, 128.5, 128.3,
128.1, 107.2, 105.8, 66.8, 55.1, 32.2, 19.1, 18.5, 13.5; IR (film): νmax 3347 (NꢀH), 1705, 1499, 1390,
1366, 1240, 1171, 1020 cmꢀ1; HRMS (ESIꢀTOF) calcd for C17H22NO3 [M+H]+ 288.1600, found
288.1605.
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Benzyl[2-(5-methylfyryl)cyclohexylmethyl]carbamate (4x
′
): Yellow oil; yield 180.1 mg (55%). H
NMR (400 MHz, CDCl3): δ 7.37 (brm, 5H), 6.03 (br s, 1H), 5.88 (br s, 1H), 5.15ꢀ5.11 (m, 3H), 4.56
(br t, J = 8.0 Hz, 1H), 2.27 (s, 3H), 1.84ꢀ1.64 (m, 5H), 1.60ꢀ1.45 (m, 1H), 1.28ꢀ1.12 (m, 3H), 1.06ꢀ0.96
(m, 2H); 13CꢀNMR (100 MHz, CDCl3): δ 156.4, 152.4, 151.7, 137.0, 129.0, 128.62, 128.58, 107.7,
106.3, 67.3, 54.8, 42.3, 30.1, 29.6, 26.7, 26.4, 14.0; IR (film): νmax 3328 (NꢀH), 1702, 1507, 1451,
1240, 1215, 1055, 1022 cmꢀ1; HRMS (ESIꢀTOF) calcd for C20H26NO3 [M+H]+ 328.1913, found
328.1907.
o
Bis(2,4,5-trimethoxyphenyl)phenylmethane (5p):15a White solid; m.p. 129ꢀ133 C; yield 17.0 mg (8
%). 1H NMR (400 MHz, CDCl3): δ 7.28ꢀ7.24 (m, 2H), 7.18 (m, 1H), 7.07 (d, J = 7.6 Hz, 2H), 6.56 (s,
2H), 6.44 (s, 2H), 6.10 (s, 1H), 3.90 (s, 6H), 3.68 (s, 6H), 3.65 (s, 6H); 13C NMR (100 MHz, CDCl3): δ
151.9, 148.4, 144.6, 143.1, 129.3, 128.3, 126.1, 124.9, 115.0, 98.8, 57.4, 57.0, 56.4, 42.9; IR (Nujolꢀ
mull): νmax 1729, 1509, 1464, 1394, 1317, 1275, 1259, 1206, 1178, 1035, 764, 750 cmꢀ1; HRMS (ESIꢀ
TOF) calcd for C25H28O6Na [M+Na]+ 447.1784, found: 447.1760.
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Bis[(5-methyl)-2-furyl]phenyl methane (5q):15b,20 Yellow oil; yield 3.0 mg (2%). H NMR (400
MHz, CDCl3): δ 7.35ꢀ7.28 (br m, 5H), 5.91 (br d, J = 4.3 Hz, 4H), 5.37 (s, 1H), 2.28 (s, 6H); 13C NMR
(100 MHz, CDCl3): δ 152.8, 151.4, 140.0, 128.39, 128.36, 126.9, 108.1, 106.0, 45.1, 13.6; IR (film):
νmax 1603, 1561, 1494, 1452, 1218, 1022, 778 cmꢀ1; HRMS (ESIꢀTOF) calcd for C17H17O2 [M+H]+
253.1229, found 253.1223.
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Bis[(5-methyl)-2-thienyl]phenyl methane (5s):15,20a,c Pale yellow oil; yield 10.0 mg, (7%). H NMR
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(400 MHz, CDCl3): δ 7.36ꢀ7.27 (m, 5H), 6.64 (br d, J = 3.3 Hz, 2H), 6.61 (br d, J = 3.3 Hz, 2H), 5.70
13
(s, 1H), 2.46 (s, 3H); C NMR (100 MHz, CDCl3): δ 145.3, 143.9, 139.1, 128.5, 128.4, 127.0, 125.7,
124.6, 47.9, 15.4; IR (film): νmax 1600, 1493, 1451, 1404, 1228, 1167, 1029, 796 cmꢀ1.
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Bis[(5-ethyl)-2-thienyl]phenyl methane (5t): Pale yellow oil; yield 14.0 mg (9%). H NMR (400
MHz, CDCl3): δ 7.39ꢀ7.31 (br m, 5H), 6.68 (br d, 4H), 5.76 (s, 1H), 2.84 (q, J = 7.5 Hz, 4H), 1.33 (t, J
= 7.5 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 146.3, 144.4, 143.5, 128.03, 127.95, 126.6, 125.1,
122.2, 47.5, 23.1, 15.4; IR (film): νmax 1600, 1493, 1452, 1377, 1316, 1260, 1220, 1074, 1015, 945,
802, 737, 699 cmꢀ1; HRMS (ESIꢀTOF) calcd for C19H20S2Na [M+Na]+ 335.0904, found 335.0901.
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Bis[(5-ethyl)-2-pyrrolyl]phenyl methane (5u): Brown oil; yield 91 mg (65%). H NMR (400 MHz,
CDCl3): δ 7.72 (br s, 1H), 7.37ꢀ7.26 (m, 5H), 5.86 (br s, 2H), 5.79 (br s, 2H), 5.40 (s, 1H), 2.59 (q, J =
7.5 Hz, 4H), 1.24 (t, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 142.7, 134.2, 131.4, 128.8,
128.7, 127.1, 107.4, 104.3, 44.5, 21.1, 13.8; IR (film): νmax 3164 (NꢀH), 1688, 1584, 1495, 1404, 1329,
1275, 1228, 1035, 958, 764 cmꢀ1; HRMS (ESIꢀTOF) calcd for C19H22N2 [M]+ 278.1783, found
278.1785.
Bis[(1H-indol-3-yl]phenyl methane (5v):20d Orange solid; m.p. 93ꢀ97 C; yield 88.4 mg (55%). H
o
1
NMR (400 MHz, CDCl3): δ 7.96 (br s, 2H), 7.42ꢀ7.36 (m, 6H), 7.32ꢀ7.30 (m, 2H), 7.23ꢀ7.17 (m, 3H),
13
7.02 (t, J = 7.5 Hz, 2H), 6.69 (br d, J = 1.5 Hz), 5.91 (s, 1H); C NMR (100 MHz, CDCl3): δ 144.3,
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136.9, 129.0, 128.5, 127.3, 126.5, 123.9, 122.2, 120.2, 119.8, 119.5, 111.4, 40.5; IR (Nujolꢀmull): νmax
3414 (NꢀH), 1601, 1492, 1456, 1417, 1337, 1265, 1217, 1152, 1093, 1010, 793, 743 cmꢀ1; HRMS (ESIꢀ
TOF) calcd for C23H18N2Na [M+Na]+ 345.1368, found 345.1360.
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Bis-1,1-[(5-methyl)-2-furyl]-2-methylpropane (5w):20c Colorless oil; yield 15.3 mg (14%). H NMR
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(400 MHz, CDCl3): δ 6.00 (br s, 2H), 5.89 (br s, 2H), 3.70 (d, J = 7.8 Hz, 1H), 2.34ꢀ2.28 (m, 7H), 0.92
13
(d, J = 6.5 Hz); C NMR (100 MHz, CDCl3): δ 154.0, 151.0, 107.5, 106.5, 47.0, 32.5, 21.4, 14.3; IR
(film): νmax 1614, 1563, 1451, 1387, 1369, 1220, 1022, 1000, 966, 782 cmꢀ1.
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Bis[(5-methyl)-2-furyl]cyclohexylmethane: (5x): Pale yellow oil; yield 15.5 mg (12%). H NMR
(400 MHz, CDCl3): δ 5.99 (d, J = 2.4 Hz, 2H), 5.88 (br d, J = 2.4 Hz, 2H), 3.71 (d, J = 8.7 Hz, 1H),
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2.29 (s, 6H), 1.98ꢀ1.94 (m, 1H), 1.73ꢀ1.60 (m, 5H), 1.30ꢀ1.12 (m, 3H), 1.01ꢀ0.91 (m, 2H); C NMR
(100 MHz, CDCl3): 153.2, 150.3, 106.7, 105.8, 45.5, 41.4, 31.2, 26.4, 26.3, 13.6; IR (film): νmax 1615,
1561, 1449, 1400, 1220, 1021, 1000, 772 cmꢀ1; HRMS (EIꢀTOF) calcd for C17H22O2Na [M+Na]+
281.1517, found 281.1504.
The reaction of 2ꢀmethylfuran (1c) with NꢀCbz imine 6. To a toluene solution (1 mL) of 2ꢀ
methylfuran (1.0 mmol,) and NꢀCbzꢀimine 6 (1.0 mmol) in a testꢀtube open to air at room temperature
was added Bi(OTf)3 (0.05 mmol). After the reaction was stirred until completion (TLC analysis), the
reaction mixture was quenched with aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10
mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and
filtered. The filtrate was evaporated (aspirator then vacuo) to give a crude product, which was purified
by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent) to give the
corresponding αꢀbranched amines 4q′ (260.3 mg, 81%) and triarylmethane 5q (15.1 mg, 12%).
The reaction of 2ꢀmethylfuran (1c) with benzaldehyde (2a). To a toluene solution (1 mL) of 2ꢀ
methylfuran (2.0 mmol,) and benzaldehyde (1.0 mmol) in a testꢀtube open to air at room temperature
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was added Bi(OTf)3 (0.05 mmol). After the reaction was stirred until completion (TLC analysis), the
reaction mixture was quenched with aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10
mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and
filtered. The filtrate was evaporated (aspirator then vacuo) to give a crude product, which was purified
by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent) to give triarylmethane
5q (232.0 mg, 92% yield).
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The reaction of 2ꢀmethylfuran (1c) with αꢀbranched amine 4q′. To a toluene solution (1 mL) of
2ꢀmethylfuran (1.0 mmol,) and αꢀbranched amine 4q′ (1.0 mmol) in a testꢀtube open to air at room
temperature was added Bi(OTf)3 (0.05 mmol). After the reaction was stirred until completion (TLC
analysis), the reaction mixture was quenched with aqueous NaHCO3 (10 mL) and extracted with
CH2Cl2 (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over
anhydrous Na2SO4 and filtered. The filtrate was evaporated (aspirator then vacuo) to give a crude
product, which was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give triarylmethane 5q (141.3 mg, 56% yield) and αꢀbranched amine 4q′ (106.0 mg. 42%)
was recovered.
General procedure for the synthesis of unsymmetrical triarylmethane 7. To a toluene solution (1
mL) of αꢀbranched amines 4p or 4p′ (0.4 mmol) and 2ꢀmethylfuran (0.4 mmol) in a testꢀtube open to
air at room temperature was added Bi(OTf)3 (0.04 mmol). After the reaction was stirred until
completion (TLC analysis), the reaction mixture was quenched with aqueous NaHCO3 (10 mL) and
extracted with CH2Cl2 (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried
over anhydrous Na2SO4 and filtered. The filtrate was evaporated (aspirator then vacuo) to give a crude
product, which was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
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eluent) to give the corresponding unsymmetrical triarylmethane 7 (93.4 mg, 69% from 4p and 111.0
mg, 82% from 4p′).
1
2-Methyl-5-[phenyl(2,4,5-trimethoxyphenyl)methyl]furan (7): Pale yellow oil. H NMR (400 MHz,
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CDCl3): δ 7.31ꢀ7.17 (m, 5H), 6.62 (s, 1H), 6.56 (s, 1H), 5.88 (br d, J = 2.0 Hz, 1H), 5.79 (s, 1H) 5.74
(br d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.73 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz,
CDCl3): 155.1, 151.2, 148.5, 143.1, 142.3, 128.6, 128.2, 126.3, 122.4, 114.1, 108.8, 105.9, 98.1, 56.8,
56.7, 56.1, 43.1, 13.6; IR (film): νmax 3104.1, 3026, 3001, 2936, 2832, 1610, 1561, 1509, 1464, 1453,
1438, 1397, 1316, 1210, 1036, 701 cmꢀ1;; HRMS (EIꢀTOF) calcd for C21H22O4Na [M+Na]+ 361.1416,
found 361.1412.
ꢀ
ACKNOWLEDGMENTS
Financial supports from the Center of Excellence for Innovation in Chemistry (PERCHꢀCIC), Office
of the Higher Education Commission, Ministry of Education and by the Research Grant of Burapha
University through National Research Council of Thailand (Grant no. 54/2554) are gratefully
acknowledged. Special thanks to Mr. Narman Mangnall, Faculty of Agriculture, Ubon Ratchathani
University for kindly proofꢀreading the English manuscript.
ꢀ
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra of all prepared products. This material is available free of charge via the
Internet at http://pubs.acs.org/.
ꢀ
AUTHOR INFORMATION
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Corresponding Author
∗Email: jaray@buu.ac.th
Notes
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The authors declare no competing financial interest.
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