Zwitterionic Ring-Opened Oxyphosphonium Species from the Ph3P-I2 Mediated Reactions of Benzo[ d]oxazol-2(3 H)-ones with Secondary Amines

Article abstract of DOI:10.1021/acs.joc.0c00211

Instead of the expected substituted 2-aminobenzo[d]oxazoles, relatively stable ring-opened oxyphosphonium betaines were isolated for the first time from the Ph₃P-I₂-mediated reactions of benzo[d]oxazol-2(3H)-ones with acyclic seconda

Full text of DOI:10.1021/acs.joc.0c00211

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Note
Zwitterionic ring-opened oxyphosphonium species from the Ph3P-I2
mediated reactions of benzo[d]oxazol-2(3H)-ones with secondary amines
Mookda Pattarawarapan, Nittaya Wiriya, Saranphong Yimklan, Sirilak Wangngae, and Wong Phakhodee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00211 • Publication Date (Web): 03 Apr 2020
Downloaded from pubs.acs.org on April 9, 2020
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Zwitterionic ring-opened oxyphosphonium species from the Ph
3
P-I
2
mediated reactions
of benzo[d]oxazol-2(3H)-ones with secondary amines
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a,b
a
a
a
Mookda Pattarawarapan, Nittaya Wiriya, Saranphong Yimklan, Sirilak Wangngae, and
Wong Phakhodee*a, b
aDepartment of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200,
Thailand
bResearch Center on Chemistry for Development of Health Promoting Products from Northern
Resources, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
Abstract
Instead of the expected substituted 2-aminobenzo[d]oxazoles, relatively stable ring-opened
oxyphosphonium betaines were isolated for the first time from the Ph
3
P-I mediated reactions
2
of benzo[d]oxazol-2(3H)-ones with acyclic secondary amines. The structure of one of these
compounds was unambiguously confirmed by single crystal X-ray analysis. Thermolysis of the
betaines gave rise to 2-dialkylaminobenzoxazoles with concomitant loss of triphenylphosphine
oxide suggesting their possible role as intermediates in an alternative reaction path.
Keywords
Benzoxazolones;
2-Aminobenzoxazoles;
Phosphonium
betaines;
Triphenylphosphine; Iodine, Aminolysis
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Phosphonium-mediated synthesis has been a powerful tool for structure modification of
a variety of organic compounds as well as for building up molecularly complex
1
structures. As a consequence, tremendous effort has been devoted to identifying the
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key phosphonium intermediates in order to better understand the mechanistic aspect of
these reactions.
In a number of well-known organophosphorus synthetic methods, including the
2
3
4
Mitsunobu, Appel, and Michaelis-Arbuzov reactions, oxyphosphonium species have
been proposed as key intermediates. However, these phosphorous species are often
difficult to characterize due to their highly reactive nature and moisture sensitivity.5
In recent years, we have demonstrated the synthetic utility of the phosphonium
coupling strategy with several substrates using a combination of inexpensive and
commercially available Ph
3
P and I
as the key reagent.6 However, despite several
2
attempts we have been unable to isolate and identify any intermediate phosphine-
containing species.
Remarkably, in our ongoing work involving Ph
amination of benzo[d]oxazol-2(3H)-ones , instead of the expected substituted 2-
aminobenzoxazoles , we have isolated novel aryloxyphosphonium betaines from the
3
P-I
2
-mediated deoxygenative
1
2
3
reaction using relatively hindered amines as nucleophiles. Herein, we wish to report our
preliminary results emphasizing the first isolation and structural characterization of
these molecules as well as their possible role as the reaction intermediates toward
2.
When benzo[d]oxazol-2(3H)-one (1a) was treated with non-hindered cyclic
6
a
amines under our previously described conditions, the expected aminobenzoxazoles
2aa 2ae were obtained in high yields within 30 min (Scheme 1). In contrast, the
-
reactions of 1a with more sterically demanding acyclic amines including diethylamine,
dibutylamine, dibenzylamine, and cyclohexylamine were sluggish giving only trace
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amounts of the corresponding 2-dialkylaminobenzoxazoles
2 along with the betaine
products 3af-3ai in significantly higher yields (Scheme 1).
1
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Scheme 1. Reaction conditions: (i) 1a (0.74 mmol), PPh
3
(1.11 mmol), I (1.11 mmol), amine
2
o
(0.89 mmol), Et
3
N (2.22 mmol), CH
2
Cl
2
(5 mL), 0 – 25 C , 30 min.
A single-crystal X-ray structural analysis of 3ah unambiguously confirmed the
proposed ring-opened salt free betaine structure. As shown in Figure 1(a), phosphorus
arranges in a four-coordinated tetrahedral geometry with C–P–C angles in the range of
104.3(1) – 108.0(2)° and O–P–C angles in the range of 105.6(1)–116.9 (1)°. The O1–
P1–C1' angle [116.9(1)°] and O1–P1–C1″ [114.9(1)°] are larger than that of O1–P1–
C1''' [105.6(1)°], presumably due to steric repulsion involving the bulky aminophenol
fragment. The P1–O1 distance [1.578(3) Å], is virtually similar to previous studies
involving quasiphosphonium cations,5c,5e,8 indicates a single P-O bond rather than a
double bond P=O which should be in the range of 1.46(1)–1.484(1) Å.9
(
a)
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(
b)
Figure 1. (a) Asymmetric unit of 3ah. Hydrogen atoms were omitted for clarity. (b)
Weak C–H…π hydrogen bonds (green dashed line) in crystal structure viewed along a-
axis of the unit cell.
Since there is no counter anion observed in the X-ray structure, the
deprotonation of the urea N–H reasonably occurred to compensate the charge of the
1
0
quaternary phosphonium cation leading to a stable zwitterionic form. The short C1C–
O2 bond distance [1.203(4)Å] and C1C–N1–C2 bond angle [119.0(3)°] also indicates
no significant delocalozation of the negative charge over the C=O π system.8
Interestingly, two independent C–H…π hydrogen bonds important for conformation of
the molecule and supramolecular packing were also observed (see Figure 1(b)).11 The
C3'–H3'…π hydrogen bond [2.6995(1)Å] presumably forced the benzyl group
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(
involving C3B–C4B–C5B–C6B–C7B–C8B) to rotate about C2B–C3B bond with
torsion angle (N2–C2B–C3B–C4B) of 154.9(4)° to align the phenyl ring as the
hydrogen bond acceptor, whereas another benzyl group (involving C3A-C4A–C5A–
C6A–C7A–C8A) rotated in the opposite direction with torsion angle (N2–C2A–C3A–
C4A) of 134.6(4)° as C4A–H4A…π hydrogen bond donor [2.9066(1) Å] (see Figures
S2 and S3).
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The NMR spectroscopic data of 3af-3ai were similar and were all consistent
31
1
with their indicated betaine structures. The P{ H} NMR spectroscopic data of these
compounds ( 3.24-6.34 ppm) indicated that they were tetracoordinate phosphorus

p
species rather than pentacoordinate phosphoranes which should exhibit characteristic
7
phosphorus signals in the negative chemical shift region. Long range phosphorus-
carbon couplings observed in compounds 3ag and 3ah as well as no JP,C correlation with
the N-alkyl urea fragment further suggested that the phosphorus atom is directly attached
to the former ring oxygen (O-1) of 1a instead of the urea oxygen (Figure 2). Since the
3
1
6h
expected P chemical shifts of aryloxyphosphonium iodide should be at ca. 60 ppm,
3
1
the significant upfield shift of the P signals of
3
strongly implied that the phosphorus
atom is in close proximity to or under influence of the nearby negatively charged atom
1
which is in consistent with the missing resonance of the NH proton in the H NMR
+
–
spectrum. It should be noted that although the interionic [P1 …N1 ] distance measured
from the X-ray structure of a well-ordered crystalline solid 3ah is rather long (ca. 4.297
Å). In solution-state, it could become shorter depending on molecular conformations
per free rotations about C1–O1 and/or C1c–N1 single bonds.
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Figure 2. Key HMBC correlations and P-C NMR coupling constants (JPC) observed in
compounds 3ag and 3ah.
To examine possible electronic factors governing the formation of the zwitterion
3
in preference to the expected product
2
, the scope of the reaction was further
. According to Scheme
, the presence of substituent at the C6 position did not significantly affect the yield or
investigated with other substituted benzoxazolone derivatives
1
2
stability of 3. However, when a strong electron-withdrawing nitro group was located on
the para position of the ring oxygen (at C5), 2fg was rapidly formed without detectable
amount of the expected betaine 3fg. On contrary, 3gg derived from the substrate bearing
a strong electron-donating -OMe group at C5 position was obtained in high yield. This
observation is not surprising since 3fg would be destabilized preventing its formation
and/or leading to rapid conversion to 2fg
.
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Scheme 2. Formation of oxyphosphonium betaines
3
. Reaction conditions:
1
(0.74
mmol), PPh
3
(1.11 mmol), I
2
(1.11 mmol), dibutylamine (0.89 mmol), Et
3
N (2.22
o
mmol), CH Cl
2
2
(5 mL), 0 C-RT, 30 min. ND = not detected.
With these results in hand, the possible synthesis of 2-dialkylaminobenzoxazoles 2
from 3 was investigated. According to Scheme 3, upon subject to heating in toluene in a
pressure tube, all betaines
3
were converted into the corresponding 2-
dialkylaminobenzoxazoles 2 in satisfactory yields although hydrolyzed products 1 could be
observed in small amounts.
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Scheme 3. Thermal decomposition of oxyphosphonium betaines 3. Reaction conditions:
o
3
(0.50 mmol), toluene (2 mL), 120 C in 10 mL pressure tube.
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To gain insight into the mechanism for the formation of 2 and 3, a series of control
experiments were carried out. As shown in Scheme 4(a), no conversion was observed when
a was treated with dibenzylamine in the absence of Ph P-I indicating that the ring opening
process requires activation by a Ph P-derived species. This result is consistent with other
studies where aminolysis of unactivated cyclic carbamates generally requires more forcing
1
3
2
3
1
2
conditions. Additionally, no trace of 3ah was detected in the absence of Et
formation of 3 is base-mediated (Scheme 4(b)). Moreover, when 2ah was subjected to the
Ph P-I conditions, no conversion to 3ah was observed implying that 2ah is not a precursor
toward this betaine (Scheme 4(c)).
Surprisingly, the reaction of 2-hydroxyphenylurea 4 without adding external
dibenzylamine did not lead to the expected product 3ah (Scheme 4(d)). Instead, 2ah formed in
3
N suggesting the
3
2
3
1
1
high yield within 30 min at room temperature. Monitoring this reaction by P{ H} NMR
revealed a strong phosphorus resonance at 64.35 ppm which could presumably be attributed to
the presence of the unisolable intermediate I (see Figure S4).5a,6h,13 The fact that this
phosphonium species reacts rapidly in contrast to 3ah indicates that zwitterionic 3ah is
thermodynamically more stable.
To determine the possible role of 3ah as the reaction intermediate, a direct one-pot
synthesis of 2ah from 1a was carried out by initial formation of 3ah, followed by subjected to
heating (Scheme 4(e)). Indeed, 2ah was obtained in satisfactory yield even from gram scale
synthesis. 31P{ H} NMR monitoring of the reaction before heating not only showed a
resonance peak at 3.62 ppm corresponding to the betaine 3ah but also the signal of I at ca. 64
1
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ppm (see Figure S5) suggesting that the formation of 2ah involves ring opening and ring
closing mechanism.
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Scheme 4. Control experiments
Due to the limited data, it is not conclusive at this point on how the ring opening
and ring-closer proceed. Nevertheless, these observations implied that the reaction
involved more complicated processes rather than a commonly proposed C=O bond
activation-nucleophilic substitution sequence. Especially when the incoming
nucleophile with sterically bulky group(s) is sufficiently reactive, the ring-opening
toward the intermediates I and 3 is highly likely a more favourable pathway due to the
release of the ring strain of the initially formed heavily substituted benzofused five-
membered ring intermediate. It is also noteworthy that although similar ring-opened
1
4
intermediates have been proposed in several studies, such species have never been
isolated or characterized.
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In summary, we have identified stable isolable oxyphosphonium betaines from the
phosphonium mediated reaction of benzo[d]oxazol-2(3H)-ones with certain amines.
These compounds could undergo elimination of triphenylphosphine oxide giving rise to
substituted 2-aminobenzoxazoles suggesting their roles as the intermediates in an
alternative reaction pathway. This discovery not only provided strong evidence for a
new mechanism for the deoxygenative amination of cyclic carbamates, but also
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suggested the possibility of stepwise mechanism in aminolysis of activated esters, a
fundamental model for peptide bond formation in biomolecules, in which no
intermediate has yet to be determined experimentally. Further expansion of the
substrate scope and investigation of the detailed reaction mechanism are ongoing.
EXPERIMENTAL SECTION
General information
All reagents including most of the benzo[d]oxazol-2(3H)-one precursors 1 (1a-1e) were
purchased from Sigma-Aldrich or TCI and used without further purification. Compound 1f16
17
and 1g were synthesized according to the reported procedures. All reactions were run in
flame- or oven-dried glassware under N gas. The reaction was monitored by thin-layer
2
chromatography carried out on silica gel plates (60F254, MERCK, Germany) and visualized
under UV light (254 nm). Column chromatography was performed over silica gel 60 (70–230
mesh, MERCK, Germany). Melting points were determined using Mettler Toledo DSC
o
equipment at a heating rate of 6 C/min and are uncorrected. NMR spectra were recorded using
a Bruker AVANCETM (400 and 500 MHz for H). Chemical shifts were reported in parts per
million (ppm, δ) downfield from tetramethylsilane (TMS). Splitting patterns are described as
singlet (s), doublet (d), triplet (t), quartet (q), quintet (qui), sextet (sex), multiplet (m), broad
1
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(
br), doublet of doublets (dd(, triplet of doublets )td( and doublet of doublet of doublets (ddd).
High-resolution mass spectra (HRMS) were recorded using time-of-flight (TOF) via the
atmospheric pressure chemical ionization (APCI) or electrospray ionization (ESI).
1
1
1
1
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General procedure for the reaction of benzo[d]oxazol-2(3H)-ones 1 with amine.
To a solution of iodine (281 mg, 1.11 mmol) in freshly distilled dichloromethane (5
o
mL) was added triphenylphosphine (291 mg, 1.11 mmol) at 0 C under N
2
. After that, amine
(0.89 mmol) was added, followed by treatment with benzoxazolone 1 (0.74 mmol).
Triethylamine (0.31 mL, 2.22 mmol) was added before warming the solution to room
temperature. After stirring for 30 min the crude mixture was concentrated under reduced
pressure before purification by column chromatography (CC) using ethyl acetate/hexanes as
the eluent. It is noted that some compounds such as 3af and 3ai are relatively unstable and
partially decompose during the NMR study.
2-(Pyrrolidin-1-yl)benzo[d]oxazole (Scheme 1, 2aa).18 White solid; (0.1130 g, 81% yield);
o
3
o
1
mp 135-137 C (lit. mp 136-137 C); R
CDCl ) δ 7.35 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.99 (t, J
= 8.0 Hz, 1H), 3.65 (s, 4H), 2.03 (s, 4H); C{ H} NMR (125 MHz, CDCl
43.4, 123.9, 120.2, 115.8, 108.7, 47.4, 25.6.
2-(Piperidin-1-yl)benzo[d]oxazole (Scheme 1, 2ab).19 Pale yellow solid; (0.1274 g, 85%
f
0.30 (30% EtOAc/hexanes); H NMR (500 MHz,
3
1
3
1
3
) δ 161.0, 148.9,
1
o
4
o
1
yield); mp 70-73 C (lit. mp 72-75 C); R
CDCl ) δ 7.34 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.98 (td,
J = 7.5 Hz, 1H), 3.66 (s, 4H), 1.68 (s, 6H); C{ H} NMR (125 MHz, CDCl
43.4, 123.8, 120.3, 116.0, 108.6, 46.6, 25.3, 24.1.
2-Morpholinobenzo[d]oxazole (Scheme 1, 2ac).19 White solid; (0.1252 g, 83% yield); mp
f
0.35 (10% EtOAc/hexanes); H NMR (500 MHz,
3
1
3
1
3
) δ 162.5, 148.7,
1
18
o
1
9
0-92 °C (lit. mp 90-94 C); R
f
0.20 (50% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
) δ
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
7
.37 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz,
1
3
1
1
H), 3.82 (t, J = 4.5 Hz, 4H), 3.69 (t, J = 4.5 Hz, 4H); C{ H} NMR (125 MHz, CDCl ) δ
3
162.1, 148.8, 142.9, 124.1, 121.0, 116.5, 108.9, 66.2, 45.7.
2-(4-Methylpiperazin-1-yl)benzo[d]oxazole (Scheme 1, 2ad).19 White solid; (0.1287 g, 80%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
18
o
1
yield); mp 36-38 C (lit. mp 36-38 C); R
CDCl ) δ 7.36 (dd, J = 8.0, 1.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.16 (td, J = 8.0, 1.0 Hz, 1H),
.02 (td, J = 8.0, 1.5 Hz, 1H), 3.74 (t, J = 5.0 Hz, 4H), 2.54 (t, J = 5.0 Hz, 4H), 2.36 (s, 3H);
f
0.26 (10% MeOH/EtOAc); H NMR (500 MHz,
3
7
1
3
1
C{ H} NMR (125 MHz, CDCl
3
) δ 162.2, 148.8, 143.1, 124.0, 120.7, 116.3, 108.7, 54.2,
4
6.2, 45.5.
2
-(1H-Imidazol-1-yl)benzo[d]oxazole (Scheme 1, 2ae).6a Yellow solid; (0.1028 g, 75%
1
yield); mp 110-112 °C; R
f
0.26 (30% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
) δ 8.40 (s,
1H), 7.73 (t, J = 1.5 Hz, 1H), 7.69 (dd, J = 7.5, 2.0 Hz, 1H), 7.55 (dd, J = 7.5, 2.0 Hz, 2H), 7.39
13
1
(
td, J = 7.5, 2.0 Hz, 1H), 7.36 (td, J = 7.5, 2.0 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H); C{ H} NMR
125 MHz, CDCl ) δ 152.0, 149.0, 140.5, 135.9, 131.4, 125.5, 125.1, 119.7, 116.8, 110.5.
Diethylcarbamoyl)(2-((triphenylphosphonio)oxy)phenyl)amide (Scheme 1, 3af). Brown
(
3
(
1
oil; (0.1636 g, 47% yield); R
7.73 (m, 6H), 7.48 – 7.45 (m, 3H), 7.41 -7.37 (m, 6H), 7.00 (ddd, J = 7.8, 2.6, 1.5 Hz, 1H),
.69 (td, J = 7.8, 1.5 Hz, 1H), 6.60 (td, J = 7.8, 1.5 Hz, 1H), 6.46 (dt, J = 7.8, 1.5 Hz, 1H), 3.52
(q, J = 7.0 Hz, 2H), 3.32 (q, J = 7.0 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H);
f
0.43 (20% EtOAc/hexanes); H NMR (500 MHz, CDCl ) δ 7.7-
3
-
6
13
1
3
C{ H} NMR (125 MHz, CDCl
3
) δ 154.8, 146.5, 146.3 (d, Jcp = 21.8 Hz), 143.9, 132.8,
2
4
1
1
32.7 (d, Jcp = 10.0 Hz), 131.61, 131.59 (d, Jcp = 2.9 Hz), 130.8 (d, Jcp = 95.8 Hz), 128.55,
3
3
128.45 (d, Jcp = 11.9 Hz), 125.30 , 122.61, 122.55, 122.46 (d, Jcp = 10.6 Hz), 117.4, 53.5,
31
1
+
1
4.3, 13.6; P{ H} NMR (202 MHz, CDCl
3
) δ 5.14; HRMS (ESI) m/z: [M + H] Calcd for
C
29
H
30
N
2
O
2
P 469.2039; Found 469.2040.
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(
Dibutylcarbamoyl)(2-((triphenylphosphonio)oxy)phenyl)amide (Scheme 1, 3ag). Brown
1
oil; (0.2888 g, 74% yield); R
f
0.17 (20% EtOAc/hexanes); H NMR (400 MHz, CDCl
3
) δ 7.78
– 7.72 (m, 6H), 7.51 – 7.47 (m, 3H), 7.44 – 7.38 (m, 6H), 6.98 (td, J = 8.0, 1.6 Hz 1H), 6.69
td, J = 8.0, 1.6 Hz, 1H), 6.61 (td, J = 8.0, 1.6 Hz, 1H), 6.44 (d, J = 8.0, 1H), 3.43 (t, J = 7.6
Hz, 2H), 3.25 (t, J = 7.6 Hz, 2H), 1.65 (qui, J = 7.6 Hz, 2H), 1.47 (qui, J = 7.2 Hz, 2H), 1.35 –
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1
3
1
1
.20 (m, 4H), 0.87 (t, J = 7.6 Hz, 3H), 0.78 (t, J = 7.6 Hz, 3H); C{ H} NMR (100 MHz,
3
2
CDCl ) δ 155.1, 146.5, 146.3 (d, Jcp = 21.7 Hz), 143.8, 132.8, 132.7 (d, Jcp = 9.8 Hz), 131.9,
3
4
1
3
1
1
31.48, 131.47 (d, Jcp = 2.9 Hz), 130.9 (d, Jcp = 99.2 Hz), 128.5, 128.4 (d, Jcp = 12.0 Hz),
3
25.2, 122.7, 122.4, 122.3 (d, Jcp = 10.1 Hz), 117.3, 47.5, 31.0, 30.3, 20.17, 20.10, 13.92,
3
1
1
+
13.85; P{ H} NMR (162 MHz, CDCl
3
) δ 3.24; HRMS (ESI) m/z: [M + H] Calcd for
C
33
H
38
N
2
O
2
P 525.2665; Found 525.2659.
(Dibenzylcarbamoyl)(2-((triphenylphosphonio)oxy)phenyl)amide (Scheme 1, 3ah).
1
White solid; (0.3340 g, 76% yield); mp 180 - 181 °C; R
500 MHz, CDCl
7.37 -7.34 (m, 6H), 7.24 (br s, 5H), 7.11 (t, J = 7.5 Hz, 1H ), 7.07 (dt, J = 8.0, 2.0 Hz, 1H),
.03 (t, J = 7.5 Hz, 2H), 6.73 (td, J = 8.0, 2.0 Hz, 1H), 6.65 (t, J = 8.0 Hz, 1H), 6.46 (d, J = 8.0
f
0.47 (20% EtOAc/hexanes); H NMR
(
3
) δ 7.77 – 7.73 (m, 6H), 7.47 (t, J = 7.5 Hz, 3H), 7.38 (t, J = 7.5 Hz, 2H),
7
1
3
1
Hz, 1H), 4.67 (s, 2H), 4.46 (s, 2H); C{ H} NMR (125 MHz, CDCl
3
) δ 155.9, 146.2 146.1 (d,
3
2
4
Jcp = 21.7 Hz), 143.9, 137.6, 132.8, 132.7 (d, Jcp = 10.0 Hz), 131.64, 131.61 (d, Jcp = 3.0
1
3
Hz), 131.4, 131.7 (d, Jcp = 99.5 Hz), 128. 7, 128.6, 128.5 (d, Jcp = 12.4 Hz), 128.4, 127.3,
3
31
1
1
27.2, 125.6, 122.8, 122.35, 122.27 (d, Jcp = 10.4 Hz), 117.4, 49.4, 49.3; P{ H} NMR (202
+
MHz, CDCl
3
) δ 3.39; HRMS (ESI) m/z: [M + H] Calcd for C39
H
34
N
2
2
O P 593.2352; Found
5
93.2349.
(Cyclohexylcarbamoyl)(2-((triphenylphosphonio)oxy)phenyl)amide (Scheme 1, 3ai).
1
White solid; (0.1991 g, 54% yield); mp 168 - 170 °C; R
f
0.40 )20% EtOAc/hexanes); H NMR
(500 MHz, CDCl
3
) δ 7.79 – 7.75 (m, 6H), 7.53 – 7.50 (m, 3H), 7.45 – 7.41 (m, 6H), 7.02 (d, J
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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6
=
7.5 Hz 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.63 (t, J = 7.5, 1H), 6.45 (d, J = 7.5 Hz 1H), 5. 14 (d,
J = 8.0 Hz, 1H), 3.51 - 3.48 (m, 1H), 1.93 (d, J = 9.0 Hz, 2H), 1.69 – 1.56 (m, 3H), 1.36 -1.27
1
3
1
(m, , 2H), 1.19 – 1.09 (m, 3H); C{ H} NMR (125 MHz, CDCl
3
) δ 154.8, 146.6, 146.4 (d,
3
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Jcp = 21.8 Hz), 143.9, 132.8, 132.7 (d, Jcp = 9.9 Hz), 131.78, 131.76 (d, Jcp = 2.8 Hz),
1
3
1
31.0, 130.2 (d, Jcp = 99.4 Hz), 128.7, 128.6 (d, Jcp = 11.9 Hz), 125.5, 122.7, 122.6, 122.5
3
31
1
(d, Jcp = 11.0 Hz), 117.5, 49.8, 33.4, 25.6, 24.8; P{ H} NMR (202 MHz, CDCl ) δ 3.84;
3
+
HRMS (ESI) m/z: [M + H] Calcd for C31
H
32
N
2
2
O P 495.2196; Found 495.2207.
(4-Bromo-2-((triphenylphosphonio)oxy)phenyl)(dibutylcarbamoyl)amide (Scheme 2,
1
3
bg). Brown oil ; (0.3234 g, 72% yield); R
CDCl
H), 6.77 (dd, J = 8.4, 2.4 Hz, 1H), 6.27 (dd, J = 8.4, 1.2 Hz, 1H), 3.41 (t, J = 7.6 Hz, 2H), 3.24
t, J = 7.6 Hz, 2H), 1.68 – 1.60 (m, 2H), 1.45 (qui, J = 7.6 Hz, 2H), 1.38 – 1.19 (m, 4H), 0.87
f
0.4 (20% EtOAc/hexanes); H NMR (400 MHz,
3
) δ 7.76 – 7.71 (m, 6H), 7.53 – 7.49 (m, 3H), 7.45 – 7.40 (m, 6H), 7.12 (t, J = 2.4 Hz,
1
(
1
3
1
(t, J = 7.6 Hz, 3H), 0.78 (t, J = 7.6 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 154.6, 146.9,
3
2
4
1
46.7 (d, Jcp = 21.6 Hz), 143.4, 132.7, 132.7, 131.6 (d, Jcp = 9.7 Hz), 131.68, 131.65 (d, Jcp
1
3
=
2.8 Hz), 131.4, 130.4 (d, Jcp = 99.6 Hz), 128.6, 128.5 (d, Jcp = 12.0 Hz), 128.0, 125.7,
3
31
1
1
23.0, 122.9 (d, Jcp = 10.2 Hz), 107.9, 47.5, 31.0, 30.3, 20.2, 20.1, 13.9, 13.8; P{ H} NMR
+
3781BrN
(162 MHz, CDCl
3
) δ 4.05; HRMS (ESI) m/z: [M + H] Calcd for C33
H
2
2
O P 605.1751;
Found 605.1741, for C33
H
3779BrN
2
2
O P 603.1771; Found 603.1776.
(4-Chloro-2-((triphenylphosphonio)oxy)phenyl)(dibutylcarbamoyl)amide (Scheme 2,
1
3
cg). Brown oil; (0.3198 g, 77% yield); R
CDCl
H), 6.65 (dd, J = 8.4, 2.4 Hz, 1H), 6.31 (dd, J = 8.4, 1.2 Hz, 1H), 3.42 (t, J = 7.6 Hz, 2H), 3.24
t, J = 7.6 Hz, 2H), 1.64 (qui, J = 7.6 Hz, 2H), 1.45 (qui, J = 7.6 Hz, 2H), 1.34 – 1.99 (m, 4H),
f
0.4 (20% EtOAc/hexanes); H NMR (400 MHz,
3
) δ 7.76 – 7.71 (m, 6H), 7.53 – 7.49 (m, 3H), 7.48 – 7.40 (m, 6H), 6.99 (t, J = 2.4 Hz,
1
(
1
3
1
0
.87 (t, J = 7.6 Hz, 3H), 0.78 (t, J = 7.6 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 154.6,
3
2
4
146.6, 146.4 (d, Jcp = 21.6 Hz), 142.9, 132.7, 132.6 (d, Jcp = 9.7 Hz), 131.7, 131.6 (d, Jcp
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1
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=
2.9 Hz), 131.4, 130.4 (d, Jcp = 99.5 Hz), 128.6, 128.5 (d, Jcp = 12.0 Hz), 125.1, 123.0,
3
31
1
1
22.5, 122.4 (d, Jcp = 10.1 Hz), 121.1, 47.5, 31.0, 30.3, 20.2, 20.1, 13.9, 13.8; P{ H} NMR
+
3737ClN
(162 MHz, CDCl
3
) δ 3.95; HRMS (ESI) m/z: [M + H] Calcd for C33
H
2
2
O P 561.2246;
3735ClN
O P 559.2276, Found 559.2285.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Found 561.2255, for C33
H
2
2
(Dibutylcarbamoyl)(4-nitro-2-((triphenylphosphonio)oxy)phenyl)amide (Scheme 2, 3dg).
1
Yellow oil; (0.2996 g, 71% yield); R
f
0.27 (20% EtOAc/hexanes); H NMR (400 MHz, CDCl
3
)
δ 7.93 (t, J = 2.8 Hz, 1H), 7.77 – 7.72 (m, 6H), 7.64 (dd, J = 9.0, 2.8 Hz, 1H), 7.59 – 7.55 (m,
3H), 7.50 – 7.45 (m, 6H), 6.26 (dd, J = 9.0, 1.0 Hz, 1H), 3.47 (t, J = 7.6 Hz, 2H), 3.26 (t, J =
7
2
1
1
1
.6 Hz, 2H), 1.72 – 1.62 (m, 2H), 1.49 – 1.38 (m, 2H), 1.39 – 1.31 (m, 2H), 1.28 – 1.19 (m,
1
3
1
H), 0.90 (t, J = 7.6 Hz, 3H), 0.77 (t, J = 7.6 Hz, 3H).; C{ H} NMR (100 MHz, CDCl
3
) δ
3
2
54.3, 153.2, 145.2, 145.0 (d, Jcp = 23.2 Hz), 137.2, 132.7, 132.6 (d, Jcp = 9.9 Hz), 132.33,
4
3
1
32.30 (d, Jcp = 2.9 Hz), 129.7, 128.9, 128.8 (d, Jcp = 12.2 Hz), 128.7 (d, Jcp = 100.3 Hz),
3
31
1
22.4, 119.8, 1197 (d, Jcp = 11.6 Hz), 119.1, 47.6, 31.0, 30.2, 20.2, 20.0, 13.9, 13.8; P{ H}
+
NMR (162 MHz, CDCl
3
) δ 8.35; HRMS (ESI) m/z: [M + H] Calcd for C33
H
37
N
3
O P
4
570.2517; Found 570.2520.
(
5-Chloro-2-((triphenylphosphonio)oxy)phenyl)(dibutylcarbamoyl)amide (Scheme 2,
1
3
eg). Brown oil; (0.3444 g, 83% yield); R
f
0.38 (20% EtOAc/hexanes); H NMR (500 MHz,
CDCl
3
) δ 7.77 – 7.73 (m, 6H), 7.53 – 7.50 (m, 3H), 7.45 – 7.42 (m, 6H), 6.89 (d, J = 8.5 Hz,
1
H), 6.55 (d, J = 8.5 Hz, 1H), 6.35 (s, 1H), 3.43 (t, J = 7.5 Hz, 2H), 3.25 (t, J = 7.5 Hz, 2H),
.64 (qui, J = 7.5 Hz, 2H), 1.45 (qui, J = 7.5 Hz, 2H), 1.29 (hex, J = 7.5 Hz, 2H), 1.21 (hex, J
1
1
3
1
=
7.5 Hz, 2H), 0.87 (t, J = 7.5 Hz, 3H), 0.76 (t, J = 7.5 Hz, 3H); C{ H} NMR (125 MHz,
3
2
CDCl ) δ 154.9, 145.3, 145.2, 145.0 (d, Jcp = 21.0 Hz), 132.7, 132.6 (d, Jcp = 9.4 Hz), 131.9,
3
4
1
3
1
31.8 (d, Jcp = 3.0 Hz), 130.9, 130.1 (d, Jcp = 99.8 Hz), 129.9, 128.7, 128.6 (d, Jcp = 12.4
3
Hz), 123.3, 121.7, 121.6 (d, Jcp = 10.4 Hz), 116.9, 47.5, 31.0, 30.3, 20.2, 20.1, 14.0, 13.9;
3
1
1
+
P{ H} NMR (202 MHz, CDCl ) δ 4.46; HRMS (ESI) m/z: [M + H] Calcd for
3
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5
5
5
5
5
5
6
C
33
H
3737ClN
2
O
2
P 561.2246; Found 561.2254, for C33
H
3735ClN
2
O P 559.2276; Found
2
5
59.2285.
N,N-dibutyl-5-nitrobenzo[d]isoxazol-3-amine (Scheme 2, 2fg).20 Yellow solid; (0.1690 g,
o
5
o
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
8% yield); mp 84-87 C (lit. mp 85-86 C); R
f
0.41 (10% EtOAc/hexanes); H NMR (500
MHz, CDCl
3
) δ 8.16 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 3.53 (t, J = 7.5
1
3
1
Hz, 4H), 1.68 (qui, J = 7.5 Hz, 4H), 1.40 (sex, J = 7.5 Hz, 4H), 0.98 (t, J = 7.5 Hz, 6H); C{ H}
NMR (125 MHz, CDCl ) δ 164.1, 152.8, 145.0, 144.7, 116.6, 111.2, 108.1, 48.6, 30.0, 20.0,
3.9.
3
1
(Dibutylcarbamoyl)(5-methoxy-2-((triphenylphosphonio)oxy)phenyl)amide (Scheme 2,
1
3
gg). Brown oil; (0.3862 g, 94% yield); R
CDCl
Hz, 1H), 6.16 (dd, J = 8.5, 2.5 Hz, 1H), 5.98 (d, J = 2.5 Hz, 1H), 3.43 (t, J = 7.5 Hz, 2H), 3.42
f
0.31 (20% EtOAc/hexanes); H NMR (500 MHz,
3
) δ 7.78 – 7.74 (m, 6H), 7.50 – 7.47 (m, 3H), 7.43 – 7.40 (m, 6H), 6.87 (dd, J = 8.5, 2.5
(
s, 3H), 3.25 (t, J = 7.5 Hz, 2H), 1.64 (qui, J = 7.5 Hz, 2H), 1.45 (qui, J = 7.5 Hz, 2H), 1.31
hex, J = 7.5 Hz, 2H), 1.22 (hex, J = 7.5 Hz, 2H), 0.86 (t, J = 7.5 Hz, 3H), 0.76 (t, J = 7.5 Hz,
(
1
3
1
3
3H); C{ H} NMR (100 MHz, CDCl ) δ 156.9, 155.6, 144.6, 140.7, 140.5 (d, Jcp = 21.8 Hz),
3
2
4
1
1
32.8, 132.7 (d, Jcp = 9.4 Hz), 131.7, 131.6, (d, Jcp = 2.8 Hz), 131.5, 130.7 (d, Jcp = 99.4
3
3
Hz), 128.6, 128.5 (d, Jcp = 11.9 Hz), 125.2, 122.5, 108.1, 108.0 (d, Jcp = 10.9 Hz), 102.0,
31
1
55.1, 47.4, 31.0, 30.4, 20.2, 20.1, 14.0, 13.9; P{ H} NMR (202 MHz, CDCl ) δ 3.17; HRMS
3
+
(ESI) m/z: [M + H] Calcd for C34
H
40
N
2
3
O P 555.2771; Found 555.2779.
Thermolysis of Betaines 3.
In 10 mL pressure tube, betaine 3 (0.50 mmol) was added with dry toluene (4 mL). The
o
tightly capped vessel then subjected to heating in a pre-set oil bath at 120 C until reaction
completion. After cooling down, the mixture was concentrated under reduced pressure before
column chromatography using ethyl acetate/hexanes as the eluent to afford the product 2.
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N,N-Diethylbenzo[d]isoxazol-3-amine (Scheme 3, 2af). Yellow oil; (0.0845 g, 89% yield);
1
R
f
0.35 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl
3
) δ 7.37 (d, J = 7.6 Hz, 1H), 7.26
(d, J = 7.6 Hz, 1H), 7.16 (td, J = 7.6, 1.2 Hz, 1H), 7.00 (td, J = 7.6, 1.2 Hz, 1H), 3.61 (q, J =
1
3
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.2 Hz, 4H), 1.30 (t, J = 7.2 Hz, 6H). C{ H} NMR (100 MHz, CDCl ) δ 162.3, 148.9, 143.7,
3
1
23.8, 120.0, 115.8, 108.5, 43.0, 13.5.
N,N-Dibutylbenzo[d]isoxazol-3-amine (Scheme 3, 2ag).19
Yellow oil; (0.1035 g, 84%
) δ 7.36 (dd, J = 7.6, 1.2 Hz,
1
yield); R
f
0.36 (5% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
1H), 7.25 (dd, J = 7.6, 1.2 Hz, 1H), 7.15 (td, J = 7.6, 1.2 Hz, 1H), 6.99 (td, J = 7.6, 1.2 Hz, 1H),
.53 (t, J = 7.6 Hz, 4H), 1.68 (qui, J = 7.6 Hz, 4H), 1.40 (sex, J = 7.6 Hz, 4H), 0.98 (t, J = 7.6
3
1
3
1
Hz, 6H); C{ H} NMR (125 MHz, CDCl ) δ 162.6, 148.7, 143.7, 123.6, 119.8, 115.7, 108.4,
3
4
8.3, 30.1, 19.9, 13.8.
5
-Bromo-N,N-dibutylbenzo[d]isoxazol-3-amine (Scheme 3, 2bg). Colorless oil; (0.1318 g,
1
81% yield); R
f
0.50 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl
3
) δ 7.39 (d, J = 2.0 Hz,
1
H), 7.26 (dd, J = 8.4, 1.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 3.50 (t, J = 7.6 Hz, 4H), 1.66 (qui,
1
3
1
J = 7.6 Hz, 4H), 1.39 (sex, J = 7.6 Hz, 4H), 0.97 (t, J = 7.6 Hz, 6H); C{ H} NMR (100 MHz,
CDCl
3
) δ 162.8, 149.2, 143.1, 126.8, 116.6, 112.0, 111.7, 48.4, 30.1, 20.0, 13.9; HRMS (ESI)
+
2281BrN
2279BrN
O
m/z: [M + H] Calcd for C15
H
2
O 327.0895; Found 327.0930, for C15
H
2
3
25.0915; Found 325.0915.
N,N-Dibutyl-5-chlorobenzo[d]isoxazol-3-amine (Scheme 3, 2cg). Yellow oil; (0.1192 g,
1
8
1
5% yield); R
f
0.30 (5% EtOAc/hexanes); H NMR (400 MHz, CDCl
3
) δ 7.25 (d, J = 2.0 Hz,
H), 7.24 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.0, 2.0 Hz, 1H), 3.50 (t, J = 7.6 Hz, 4H), 1.67 (qui,
1
3
1
J = 7.6 Hz, 4H), 1.40 (sex, J = 7.6 Hz, 4H), 0.98 (t, J = 7.6 Hz, 6H); C{ H} NMR (100 MHz,
CDCl
3
) δ 163.0, 148.9, 142.6, 124.8, 124.0, 116.0, 109.3, 48.4, 30.1, 20.0, 13.9; HRMS (ESI)
+
2237ClN
2235ClN
O
m/z: [M + H] Calcd for C15
281.1421; Found 281.1433.
H
2
O 283.1391; Found 283.1408, for C15
H
2
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N,N-Dibutyl-5-nitrobenzo[d]isoxazol-3-amine (Scheme 3, 2dg).20 Yellow oil; (0.1266 g,
1
8
7% yield); R
f
0.35 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
) δ 8.17 (dd, J = 8.8,
2.4 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 3.56 (t, J = 7.2 Hz, 4H), 1.70
1
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
qui, J = 7.2 Hz, 4H), 1.41 (sex, J = 7.2 Hz, 4H), 0.99 (t, J = 7.2 Hz, 6H); C{ H} NMR (125
MHz, CDCl ) δ 165.4, 150.7, 147.9, 140.9, 121.5, 114.4, 104.8, 48.7, 30.0, 20.0, 13.8.
3
N,N-Dibutyl-5-chlorobenzo[d]oxazol-2-amine (Scheme 3, 2eg).21 Yellow oil; (0.1123 g,
1
8
0% yield); R
f
0.45 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
) δ 7.29 (s, 1H), 7.12
(d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.49 (t, J = 7.5 Hz, 4H), 1.65 (qui, J = 7.5 Hz,
1
3
1
5
1
H), 1.38 (sex, J = 7.5 Hz, 5H), 0.96 (t, J = 7.5 Hz, 7H); C{ H} NMR (125 MHz, CDCl ) δ
3
63.5, 147.4, 145.1, 129.0, 119.6, 115.9, 108.9, 48.4, 30.1, 20.0, 13.9.
N,N-Dibutyl-5-methoxybenzo[d]oxazol-2-amine (Scheme 3, 2gg). Yellow oil; (0.0981 g,
1
7
1% yield); R
f
0.48 (20% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
) δ 7.11 (d, J = 8.6 Hz,
1H), 6.93 (s, 1H), 6.54 (d, J = 8.6 Hz, 1H), 3.80 (s, 3H), 3.49 (t, J = 7.5 Hz, 4H), 1.65 (qui, J =
1
3
1
7
.5 Hz, 8H), 1.38 (sex, J = 7.5 Hz, 5H), 0.96 (t, J = 7.5 Hz, 6H); C{ H} NMR (125 MHz,
CDCl
3
) δ 163.4, 156.88, 156.85, 143.3, 108.3, 106.3, 100.9, 55.9, 48.4, 30.1, 20.1, 14.0. HRMS
+
(
ESI) m/z: [M + H] Calcd for C16
H
25
N
2
2
O 277.1911; Found 277.1912.
N,N-Dibenzylbenzo[d]isoxazol-3-amine (Scheme 3, 2ah).19 White solid; (0.1226 g, 78%
1
yield); mp 91-93 °C; R
f
0.44 (5% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
) δ 7.45 (d, J =
7
4
1
.6 Hz, 1H), 7.40 – 7.31 (m, 11H), 7.24 (td, J = 7.6, 1.2 Hz, 1H), 7.08 (td, J = 7.6, 1.2 Hz, 1H),
1
3
1
.75 (s, 4H); C{ H} NMR (125 MHz, CDCl
3
) δ 163.2, 148.9, 143.5, 136.3 , 128.8, 128.0,
27.8, 124.1, 120.6, 116.3, 108.9, 50.4.
N-Cyclohexylbenzo[d]isoxazol-3-amine (Scheme 3, 2ai).22 Yellow oil; (0.0831 g, 77%
1
yield); R
f
0.22 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl
3
) δ 7.38 (d, J = 7.6 Hz, 1H),
7
.25 (d, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 4.90 (br s, 1H), 3.82
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–
3.75 (m, 1H), 2.17 – 2.14 (m, 2H), 1.82 – 1.65 (m, 3H), 1.51 – 1.42 (m, 2H), 1.36 – 1.24 (m,
3
H).
Synthesis of 1,1-dibenzyl-3-(2-hydroxyphenyl)urea 4
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In 10 mL pressure tube, a solution of 1a (0.74 mmol) in 4 mL toluene was added with
dibenzylamine (0.84 mmol) and triethylamine (2.22 mmol). The tightly capped vessel was
o
then heated in a pre-set oil bath at 180 C for 4 h. After cooling down, the mixture was
concentrated under reduced pressure before column chromatography using ethyl
acetate/hexanes as the eluent to afford the product 4.
1
,1-dibenzyl-3-(2-hydroxyphenyl)urea (4). Yellow oil; (0.2211 g, 90% yield); R 0.40 (20%
f
1
EtOAc/hexanes); H NMR (500 MHz, CDCl
3
) δ 7.36 (t, J = 7.6 Hz, 4H), 7.32 (t, J = 7.6 Hz,
2
H), 7.28 (d, J = 7.6 Hz, 4H), 6.99 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.70 (t, J = 8.0
1
3
1
Hz, 1H), 6.56 (s, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.60 (s, 4H); C{ H} NMR (125 MHz, CDCl )
3
δ 157.5, 148.8, 136.4, 129.2, 128.6, 128.4, 128.1, 127.4, 126.6, 126.0, 122.1, 120.3, 119.5,
+
5
1.3; HRMS (ESI) m/z: [M + H] Calcd for C21
H
21
N
2
2
O 333.1598; Found 333.1607.
Direct synthesis of 2ah from 1a.
To a solution of iodine (281 mg, 1.11 mmol) and triphenylphosphine (291 mg, 1.11
mmol) in freshly distilled dichloromethane (5 mL), dibenzylamine (175 mg, 0.89 mmol), 1a
(0.1000 g, 0.74 mmol), and triethylamine (0.31 mL, 2.22 mmol) were sequentially added at 0
oC under N
. After stirring at 25 C for 10 min, the mixture was transferred into a pressure
o
2
tube before concentrate, followed by adding toluene (4 mL). The tightly capped vessel was
o
heated in a pre-set oil bath at 120 C until reaction completion. After cooling down, the crude
mixture was concentrated under reduced pressure before purified by CC to afford the product
2ah (0.1835 g, 79%) or 1.67 g (72%) from gram scale using 1a 1.00 g (7.40 mmol).
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
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*
E-mail: wongp2577@gmail.com. Fax: (+) 66-53-892277.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
1
13
1
31
1
DOI:
Copies of H NMR, C{ H} NMR spectra of all products, and P{ H} spectra of 3,
X-ray data of 3ah, and 2D NMR analysis of 3ag and 3ah. 31P{ H} NMR reaction monitoring
1
studies.
Acknowledgement
This work is partially supported by Chiang Mai University, Thailand and The Thailand
Research Fund through the Royal Golden Jubilee Ph.D. Program (Grant No.
PHD/0072/2559 to N.W.). Special appreciation to Chulabhorn Research Institute
(CRI), Thailand and School of Chemistry and Molecular Biosciences, University of
Wollongong, Australia for the HRMS analysis. This paper is dedicated to Prof. Dr.
Somsak Ruchirawat (CRI) for his upcoming birthday. His continuous advice, support,
and friendship over the last twenty years are gratefully acknowledged.
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