Immobilized triazine-type dehydrocondensing reagents for carboxamide formation: ROMP-Trz-Cl and ROMP(OH)-Trz-Cl

Article abstract of DOI:10.1248/cpb.55.825

New triazine-type dehydrocondensing reagents, such as ROMP-Trz-Cl and ROMP(OH)-Trz-Cl, were synthesized by a ring opening metathesis polymerization (ROMP) method, and these showed higher loading than conventional polymer-supported condensing reagents. The

Full text of DOI:10.1248/cpb.55.825

May 2007
Notes
Chem. Pharm. Bull. 55(5) 825—828 (2007)
825
Immobilized Triazine-Type Dehydrocondensing Reagents for
Carboxamide Formation: ROMP-Trz-Cl and ROMP(OH)-Trz-Cl
a,b
a
a
,a,b
Kazuhito HIOKI, Satomi KAMEYAMA, Shohei TANI, and Munetaka KUNISHIMA*
a
b
Faculty of Pharmaceutical Sciences, Kobe Gakuin University; Life Science Center, Kobe Gakuin University; Chuo-ku,
Kobe 650–8586, Japan. Received December 28, 2006; accepted February 8, 2007; published online February 9, 2007
New triazine-type dehydrocondensing reagents, such as ROMP-Trz-Cl and ROMP(OH)-Trz-Cl, were syn-
thesized by a ring opening metathesis polymerization (ROMP) method, and these showed higher loading than
conventional polymer-supported condensing reagents. These polymers effect the formation of amides in good
yields by addition of a mixture of carboxylic acid, amine and NMM. ROMP(OH)-Trz-Cl, which contains hy-
droxyl groups in the polymer chain, gave amides in good yields even in MeOH.
Key words triazine; immobilized reagent; dehydrocondensation; ring opening metathesis polymerization (ROMP); amide
The advance in combinatorial chemistry has resulted in the tion of 3—4 steps, seems not to be very easy.
development of solid-supported reagents that can be applied
Our monomer 1a was readily prepared by reacting cya-
to automated synthesis of a target molecule. As a result, nuric chloride consecutively with 5-norbornene-2-methanol
many useful reagents that are well established in the field of and MeOH (Chart 1). A CH Cl solution of the resulting
2
2
3
5)
solution-phase chemistry have been applied to immobilized monomer and cross-linker 2 in a mixing ratio of p : q, as
1—9)
reagents.
shown in Table 1, was allowed to react in the presence of
There have been some recent reports on the preparation of 0.1 mol% Grubbs’ catalyst 3 to produce four kinds of poly-
1
0—18)
immobilized reagents for dehydrocondensation.
How- mer with cross-linking percentages of 10, 30, 50 and 100%.
ever, since most of these reagents are immobilized by con- The polymer reagents exhibited condensation activity when
necting dehydrocondensing reagents to insoluble carriers treated with N-methylmorpholine (NMM). The activated
such as polystyrene and silica gel, they would be prepared by structure can be thought of that as shown in Fig. 1. Free chlo-
inefficient chemical transformation on the insoluble carrier ride ion derived from chlorotriazine was titrated to allow de-
under heterogeneous conditions. In addition, the weight pro- termination of the average molecular weight per active unit
19)
portion of the solid carrier relative to the amount of solid- (Table 1). Polymers with cross-linking at 50% or less were
supported reagent is generally high, which inevitably results found to show higher loading than that with 100% cross-link-
in the generation of large amounts of waste; this is a serious ing.
problem common to solid-supported reagents. To resolve this
issue, we developed a new immobilized triazine-type dehy-
drocondensing reagent by polymerizing the dehydrocondens-
19)
ing reagent itself. This polymer reagent is based on the
condensing agent, 4,6-dimethoxy-1,3,5-triazinyl-2-methyl-
2
0—26)
morpholinium chloride (DMT-MM)
and is a cross-
linked polymer prepared by co-polymerizing tetra(ethylene
glycol) bis(4-chloro-6-methoxy-1,3,5-triazin-2-yl) ether and
tris(2-aminoethyl)amine, which is easily substituted onto the
triazine ring under weakly basic conditions.
In this work, we developed another application for poly- Chart 1. Preparation of Monomer 1a
mer-type triazine condensing reagents: immobilization by
well-established ROMP (ring opening metathesis polymer-
ization) method, in which the reaction proceeds rapidly and
with high yield under mild neutral conditions. The dramati-
cally expanded ROMP methodology, based on the work of
Grubbs et al. in the 1990s, has been developed as an effective
method for acquiring high-loading polymer reagents by poly-
Table 1. Synthesis of ROMP-Trz -Cl
x
2
7—31)
merizing the reagent unit as a monomer.
Barrett et al.
actively developed ROMP-gel supported reagents using this
methodology, and reported many excellent immobilized
ROMP-
Degree of
cross-linking
MWaverb)
p : q
meq/g
a)
Trz -Cl
x
4
,9,32—34)
reagents.
These reagents have several advantages in
Trz10
Trz30
Trz50
Trz100
10%
30%
50%
10 : 1
10 : 3
2 : 1
2.43
2.55
2.30
1.94
412
392
436
515
addition to high-loading, e.g., high tolerance of the methathe-
sis catalysts for diverse functionalities, and readily available
monomers from inexpensive precursors. Recently, ROMP
supported coupling reagents carrying fluoroformamidinium
100%
1 : 1
11)
a) The degree of cross-linking was represented by the mole ratio of cross-linker 2 to
the monomer used in the reaction. b) Average molecular weight per active unit;
or 2-bromopyridinium were also reported. In this case,
however, preparation of the monomers, which requires opera- MWaverꢀ1000/(meq/g).
∗
To whom correspondence should be addressed. e-mail: kunisima@pharm.kobegakuin.ac.jp
© 2007 Pharmaceutical Society of Japan

8
26
Vol. 55, No. 5
A coupling reaction between phenylpropionic acid 5 and of polymer swelling; no swelling occurs in water (Table 3).
phenethylamine 6 was conducted using each polymer (2 eq) ROMP-Trz -Cl and Trz -Cl, which are cross-linked to a
1
0
30
36)
in various solvents (Table 2). The use of CH Cl and THF lesser extent than ROMP-Trz -Cl, became sticky when
2
2
50
resulted in production of the amide in high yield, while the swollen in CH Cl , and the gel particles tended to aggregate
2
2
use of MeOH resulted in a slightly lower yield. Disappoint- during shaking and thus clogged the filter, so general filtering
ingly, only small amounts of amide were obtained in water. could not be used. We employed ROMP-Trz -Cl, which has
5
0
The observed solvent effect may be correlated to the extent a lower average molecular weight than Trz100-Cl (Table 1), in
this study.
Coupling reactions between several kinds of carboxylic
acids and amines were conducted using ROMP-Trz -Cl in
5
0
CH Cl or MeOH (Table 4). The reaction can be performed
2
2
by a very simple procedure, mixing a carboxylic acid, an
amine, and NMM together with the polymer. After comple-
tion of the reaction, NMM and amine remaining in the fil-
trate were easily removed by extraction using Merck
Fig. 1. Activated Structure of the Polymer Reagent (ROMP-Trz-MM)
®
Extrelut . Amides were generally obtained in good yield in
Table 2. Amidation Activity of ROMP-Trz (xꢀ10—100) in Several Sol- CH Cl . A lower yield was obtained for 3,5-di-t-butylbenzoic
x
2
2
vents
acid (run 7), probably because diffusion of the bulky car-
boxylic acid inside the polymer was hindered, and thus de-
composition of the reagent by elimination of CH Cl from the
3
activated triazino moiety (ROMP-Trz-MM) might com-
22)
pete.
An important characteristic of the condensing reagent
DMT-MM, which is the basis of this polymer reagent, is its
a)
Yield (%)
ROMP-Trz -Cl
x
a)
CH Cl
THF
MeOH
H O
Table 3. Swelling Ratio of ROMP-Trz -Cl and ROMP(OH)-Trz -Cl
2
2
2
50
50
xꢀ10
92
96
99
97
98
93
96
97
90
84
71
73
82
90
90
2
7
15
21
2
CH Cl
THF
MeOH
H O
2
2
2
3
5
1
0
0
00
ROMP-Trz -Cl
ROMP(OH)-Trz -Cl
230%
150%
180%
150%
20%
60%
0%
0%
5
0
50
ROMP(OH)-Trz -Cl
50
a) The swelling ratios were represented by the ratio of increased volume of the poly-
a) The yield was determined by NMR.
mer by swelling to the initial volume of dried polymer.
Table 4. Dehydrocondensation Using ROMP-Trz -Cl or ROMP(OH)-Trz -Cl
5
0
50
ROMP-Trz -Cl (2 eq)
5
0
or ROMP(OH)-Trz -Cl (2 eq)
5
0
Acid (1 eq)ꢁAmine (1.1 eq)ꢁNMM (3 eq)
Amide
solvent, rt, 24 h
a)
a)
Yield (%) ROMP-Trz -Cl
Yield (%) ROMP(OH)-Trz -Cl
5
0
50
Run
Acid
Amine
CH Cl
MeOH
MeOH
2
2
1
2
3
4
5
80
95
84
91
84
90
79
71
98
96
92
87
5
5
6
5
6
6
6
95
85
74
86
80
93
CH (CH ) COOH
3
2 10
7
8
9
6
67
53
83
86
87
90
b)
CH COONa
7
—
3
b)
c)
7
—
98
a) Isolated yield. b) Not performed. c) A slight epimerization (1.3%) was observed by HPLC.

May 2007
827
Chart 2. Synthesis of ROMP(OH)-Trz -Cl
5
0
23)
methoxy-1,3,5-triazine was prepared by modification of reported proce-
high dehydrocondensing ability in water or MeOH. These
solvents are not only inexpensive and eco-friendly, but can
also suppress the aforementioned decomposition of the
reagent by solvation; thus, these solvents are the preferred
39)
dure. Other chemicals and solvents were obtained from commercial
sources and used without further purification. IR spectra were measured on a
1
Nicolet FT-IR AVATAR 360 spectrometer. H-NMR spectra were taken on a
Bruker DPX-400 spectrometer. ESI-MS and EI-MS spectra were recorded
media in which to conduct the reaction. As mentioned above, on a Waters Micromass ZQ 2000 spectrometer and JEOL JMS-700 spec-
trometer, respectively.
the observed yields for amide-formation using ROMP-Trz -
5
0
Preparation of 5-(4-Chloro-6-methoxy-1,3,5-triazin-2-yloxymethyl)-
norbornene (1a) Cyanuric chloride (21.57 g, 117.0 mmol) was added to a
mixture of 5-norbornene-2-methanol (7.26 g, 58.5 mmol) and diisopropyl-
ethylamine (9.07 g, 70.2 mmol) in dry THF (64.5 ml) at 0 °C under N2 atmos-
Cl in MeOH and water were moderate and poor, respectively.
This was probably due to the lower hydrophilicity of the
polymer, which resulted in its low swelling ratio.
In order to enhance the affinity of the polymer for protic phere. After stirring for 12 h at rt, Et
O (150 ml) was added, and the mixture
was filtered and evaporated. The residue was subjected to chromatography
hexane : AcOEtꢀ93 : 7) to give a mixture of 5-(4,6-dichloro-1,3,5-triazin-2-
2
solvents, we attempted to introduce hydroxyl groups to the
polymer chain by using monomer 1b instead of 1a (Chart 2).
The swelling ratio of the resulting polymer ROMP(OH)-
(
yloxymethyl)norbornene and by-products derived from cyanuric chloride.
The product mixture was dissolved in MeOH (100 ml) containing 10%
Trz -Cl, in CH Cl and THF decreased compared to that of water, and NaHCO (9.83 g, 117.0 mmol) was added. After stirring for 6 h at
5
0
2
2
3
®
ROMP-Trz -Cl, but tripled in MeOH (Table 3), and the 35 °C, almost all of the MeOH was removed by evaporation. Celite , MgSO
4
5
0
and CH Cl (100 ml) were added to the residue, and the mixture was filtered
through Celite and evaporated. The residue was purified by column chro-
matography (hexane : AcOEtꢀ9 : 1) to give the title compound (11.45 g,
3%, endo and exo (1.8 : 1) mixture) as a colorless oil. H-NMR (CDCl ) d:
yield of the dehydrocondensation between phenylpropionic
acid and phenethylamine in MeOH was improved. As shown
in Table 4, the yield of amides in MeOH increased for all
2
2
®
1
7
3
substrates, including 3,5-di-t-butylbenzoic acid, which had a 0.64 (endo 1H, ddd, Jꢀ11.8, 4.3, 2.7 Hz), 1.24 (exo 1H, ddd, Jꢀ11.8, 4.1,
3
1
1
1
.8 Hz), 1.30 (endo 1H, br d, Jꢀ8.3 Hz), 1.42—1.32 (exo 3H, m), 1.49 (endo
H, br d, Jꢀ8.3 Hz), 1.96—1.87 (endo 1H, exo 1H, m), 2.62—2.52 (endo
H, m), 2.90—2.82 (endo 1H, exo 2H, m), 3.01 (endo 1H, br s), 4.01 (endo
H, dd, Jꢀ10.5, 9.5 Hz), 4.07 (exo 3 H, s), 4.06 (endo 3H, s), 4.21 (endo 1H,
low yield with ROMP-Trz -Cl (run 7). N-Acetylation of
5
0
phenylalanine methyl ester hydrochloride proceeded effec-
tively using sodium acetate, which is more practical than
acetyl chloride or acetic anhydride (run 8). Reaction of Boc-
dd, Jꢀ10.5, 6.6 Hz), 4.32 (exo 1H, dd, Jꢀ10.6, 9.5 Hz), 4.51 (exo 1H, dd,
Leu-OH and H-Phe-OMe gave the corresponding dipeptide Jꢀ10.6, 6.3 Hz), 5.98 (endo 1H, dd, Jꢀ5.7, 2.9 Hz), 6.13—6.08 (exo 2H,
3
7)
m), 6.19 (endo 1H, dd, Jꢀ5.7, 3.0 Hz). Anal. Calcd for C H N ClO : C,
in 98% yield with a slight epimerization (1.3% ; run 9).
Unfortunately, ROMP(OH)-Trz -Cl did not show swelling in
12 14
3
2
5
2
2
3.84; H, 5.27; N, 15.70. Found: C, 53.58; H, 5.19; N, 15.78. MS (ESI) m/z:
5
0
ꢁ ꢁ ꢁ
14
68 (MH ), 270 (MH ). HR-MS (EI) m/z Calcd for C H N ClO (M ):
1
2
3
2
water, either, so the yield of amide in this solvent was not im-
proved.
67.0775; Found: 267.0777.
Preparation of 5-(4-Chloro-6-methoxy-1,3,5-triazin-2-yloxymethyl)-6-
In conclusion, we have succeeded in developing new tri- hydroxymethylnorbornene (1b) This compound would be undergoing
self-polymerization in a concentrated solution. It should be used immedi-
ately after concentration. To a dry THF solution (32.4 ml) of 5-norbornene-
azine-type polymers ROMP-Trz -Cl and ROMP(OH)-Trz -
Cl, synthesized by the ROMP methodology, as immobilized
dehydrocondensing reagents. These reagents work efficiently
5
0
50
2
1
,3-endo-dimethanol (5.0 g, 32.4 mmol) was added 2,4-dichloro-6-methoxy-
,3,5-triazine (7.0 g, 38.9 mmol) and diisopropylethylamine (4.19 g,
and can be prepared relatively at low cost. High-loading im- 32.4 mmol) at 0 °C. After stirring for 30 min at rt, the mixture was heated at
mobilization by ROMP results in the development of poly- 40 °C for 16 h. The resulting solution was poured into water (100 ml) and ex-
tracted with AcOEt (100 ml). The organic layer was evaporated, and the
residual oil was immediately subjected to column chromatography to give
the title compound (4.1 g, 43%) as a colorless solid. mp: 109—110 °C
mers with lower average molecular weights in comparison
with conventional solid-supported condensing reagents,
therefore, the waste arising from the immobilized reagent
1
(
dec.). H-NMR (CDCl ) d: 1.39 (1H, br d, Jꢀ8.4 Hz), 1.55 (1H, dt, Jꢀ8.4,
3
can be reduced. Since these ROMP-Trz-Cl reagents, espe- 1.8 Hz), 2.56—2.47 (1H, m), 2.76—2.67 (1H, m), 2.99 (1H, br s), 3.03 (1H,
br s), 3.39 (1H, dd, Jꢀ10.6, 7.9 Hz), 3.51 (1H, dd, Jꢀ10.6, 7.4 Hz), 4.06
cially ROMP(OH)-Trz -Cl, can be utilized in MeOH, they
5
0
(
6
4
3H, s), 4.14 (1H, dd, Jꢀ10.7, 8.9 Hz), 4.33 (1H, dd, Jꢀ10.7, 7.1 Hz),
can also be applied to the substrates which are difficult to
dissolve in the less polar solvents. Several types of nor-
bornene derivatives, which contain alcohol, aldehyde, and
1
3
.23—6.16 (2H, m). C-NMR (CDCl , 100 MHz) d: 40.9, 45.1, 45.9, 46.0,
3
9.7, 56.5, 63.2, 70.4, 135.4, 136.2, 172.3, 172.9, 173.1. Anal. Calcd for
C H N ClO : C, 52.44; H, 5.42; N, 14.11. Found: C, 52.27; H, 5.41; N,
1
3
16
3
3
ꢁ
ꢁ
amine functional groups, are available, so additional struc- 14.11. MS (ESI): m/zꢀ298 (MH ), 300 (MH ). HR-MS (EI) m/z Calcd for
ꢁ
C H N ClO (M ): 297.0880; Found: 297.0895.
tural modification should be relatively easy to achieve. Fur-
ther studies with the aim of improving the hydrophilicity of
the polymers as well as recycling the reagents according to
13 16
3
3
General Procedure for Synthesis of ROMP-Trz -Cl. ROMP-Trz -Cl
x
50
35)
To a solution of monomer 1a (5.16 g, 19.28 mmol) and cross-linker 2
1.53 g, 9.64 mmol) in dry CH Cl (96 ml) was added a solution of Grubbs’
(
2
2
our method for regeneration of 4-chloro-2,6-dimethoxy- catalyst 3 (15.9 mg, 0.019 mmol) in CH Cl (1 ml) at rt. Gelation occurred
2
2
38)
1
,3,5-triazine (CDMT) are currently underway.
within a few minutes. The gel was allowed to stand for 12 h to complete the
reaction. Ethyl vinyl ether (1 ml) and CH Cl (100 ml) were added, and the
2
2
Experimental
Dry THF and CH Cl were distilled in the usual manner. 2,4-Dichloro-6- polymer was passed through a sieve (250 mm) and washed repeatedly with
gel was crushed to small pieces (ca. 2—3 mm). After stirring for 12 h, the
2
2

8
28
Vol. 55, No. 5
2) Parlow J. J., Curr. Opin. Drug Discovery Dev., 8, 757—775 (2005).
CH Cl and Et O, and dried under reduced pressure to give ROMP-Trz -Cl
2
2
2
50
(
5.69 g, 85%, 2.30 meq/g) as colorless powder. Amount of chloride loaded
3) Gonthier E., Breinbauer R., Molecular Diversity, 9, 51—62 (2005).
4) Harned A. M., Zhang M., Vedantham P., Mukherjee S., Herpel R. H.,
Flynn D. L., Hanson P. R., Aldrichimica Acta, 38, 3—16 (2005).
5) Katritzky A. R., Suzuki K., Singh S. K., ARKIVOC, i, 12—35 (2004).
6) Barrett A. G. M., Hopkins B. T., Köbberling J., Chem. Rev., 102,
3301—3324 (2002). See also references therein.
on the polymer was determined according to our procedure previously de-
scribed. IR (ATR) cm : 1557, 1533, 1437, 1294, 1034, 814.
19)
ꢂ1
ꢂ1
ROMP-Trz(OH) -Cl: Colorless powder. IR (ATR) cm : 1558, 1534,
50
1
438, 1296, 1035, 814.
General Procedure for Amide Formation. N-Phenethyl-3-phenyl-
propanamide A solution of phenylpropionic acid (15.0 mg, 0.10 mmol),
phenethylamine (13.3 mg, 0.11 mmol), and N-methylmorpholine (30.3 mg,
7) Kirschning A., Monenschein H., Wittenberg R., Angew. Chem. Int.
Ed., 40, 650—679 (2001).
0
.30 mmol) in CH Cl2 (2.0 ml) was added to ROMP-Trz -Cl (87.2 mg,
8) Ley S. V., Baxendale I. R., Bream R. N., Jackson P. S., Leach A. G.,
Longbottom D. A., Nesi M., Scott J. S., Storer R. I., Taylor S. J., J.
Chem. Soc., Perkin Trans. 1, 2000, 3815—4195 (2000).
9) Thompson L. A., Curr. Opin. Chem. Biol., 4, 324—337 (2000).
10) Valeur E., Bradley M., Chem. Commun., 2005, 1164—1166 (2005).
11) Barrett A. G. M., Bibal B., Hopkins B. T., Köbberling J., Love A. C.,
Tedeschi L., Tetrahedron, 61, 12033—12041 (2005).
2
50
0.20 mmol). After shaken for 24 h at rt, Et O (ca. 10 ml) was added in order
2
to shrink the polymer, and then, the reaction mixture was filtered. The poly-
mer was rinsed twice with AcOEt (5 ml), and the washings and filtrates were
combined. The resulting solution was poured into the Merk Extrelut NT20
®
column containing 0.01 M HCl (10 ml). The column was eluted with AcOEt
(100 ml), and the filtrate was evaporated to give N-phenethyl-3-phenyl-
1
propanamide (25.0 mg, 99%). Colorless crystals. mp 94.5—95.5 °C. H- 12) Filip S. V., Lejeune V., Vors J.-P., Martinez J., Cavelier F., Eur. J. Org.
NMR (CDCl ) d: 2.41 (3H, t, Jꢀ7.7 Hz), 2.73 (2H, t, Jꢀ6.9 Hz), 2.94 (2H, Chem., 2004, 1936—1939 (2004).
t, Jꢀ7.7 Hz), 3.47 (2H, td, Jꢀ6.9, 6.0 Hz), 5.37 (1H, br s), 7.16—7.30 (5H, 13) Donati D., Morelli C., Porcheddu A., Taddei M., J. Org. Chem., 69,
3
ꢂ1
ꢁ
m). IR (KBr) cm : 3299, 1635, 1544. MS (ESI) m/z: 254 (MH ).
9316—9318 (2004).
N,3-Diphenylpropanamide: Colorless crystals. mp: 98—99 °C. IR (KBr)
14) Crosignani S., Gonzalez J., Swinnen D., Org. Lett., 6, 4579—4582
(2004).
15) Chinchilla R., Dodsworth D. J., Nájera C., Soriano J. M., Yus M.,
ARKIVOC, x, 41—47 (2003).
ꢂ1
1
cm : 3311, 1652, 1601, 1534, 1497, 1443, 1316, 1076, 756, 697. H-NMR
CDCl ) d: 2.65 (2H, t, Jꢀ7.6 Hz), 3.05 (2H, t, Jꢀ7.6 Hz), 7.09 (2H, t,
(
3
Jꢀ7.4 Hz), 7.19—7.33 (6H, m), 7.42 (2H, d, Jꢀ7.9 Hz). MS (ESI) m/z: 226
ꢁ
(
MH ).
16) Disadee W., Watanabe T., Ishikawa T., Synlett, 2003, 115—117 (2003).
N-(4-Chlorophenyl)-3-phenylpropanamide: Colorless crystals. mp 17) Desai M. C., Stramiello L. M. S., Tetrahedron Lett., 34, 7685—7688
ꢂ1
1
8
41.5—143 °C. IR (KBr) cm : 3294, 1658, 1590, 1519, 1488, 1310, 1093,
(1993).
1
21, 694. H-NMR (CDCl ) d: 2.65 (2H, t, Jꢀ7.5 Hz), 3.05 (2H, t,
18) Kaminski Z. J., Biopolymers, 55, 140—164 (2000).
3
Jꢀ7.5 Hz), 6.98 (1H, br s), 7.19—7.33 (7H, m), 7.37 (2H, d, Jꢀ8.7 Hz). MS 19) Kunishima M., Yamamoto K., Watanabe Y., Hioki K., Tani S., Chem.
ꢁ
(ESI) m/z: 260 (MH ).
Commun., 2005, 2698—2700 (2005).
N-(1-Phenylethyl)-3-phenylpropanamide: Colorless crystals. mp 50— 20) Hioki K., Yamamoto K., Tani S., Kunishima M., “Peptide Science
ꢂ1
1
5
1 °C. IR (KBr) cm : 3260, 1646, 1557. H-NMR (CDCl ) d: 1.40 (3H, d,
2005,” ed by Wakamiya T., The Japanese Peptide Society, Osaka,
2006, pp. 485—486.
3
Jꢀ6.9 Hz), 2.46—2.50 (2H, m), 2.97 (2H, t, Jꢀ7.5 Hz), 5.10 (1H, qd,
Jꢀ6.9, 7.2 Hz), 5.51 (1H, br s), 7.16—7.32 (10H, m). MS (ESI) m/z: 254 21) Kunishima M., Kawachi C., Iwasaki F., Terao K., Tani S., Tetrahedron
ꢁ
(
MH ).
Lett., 40, 5327—5330 (1999).
N-Phenethylcinnamamide: Colorless needles. mp 126—127 °C. IR (KBr)
22) Kunishima M., Kawachi C., Morita J., Terao K., Iwasaki F., Tani S.,
Tetrahedron, 55, 13159—13170 (1999).
ꢂ1
1
cm : 3299, 1650, 1614, 1544. H-NMR (CDCl ) d: 2.89 (2H, t, Jꢀ6.9 Hz),
3
3
.66 (2H, td, Jꢀ6.9, 6.0 Hz), 5.73 (1H, br s), 6.33 (1H, d, Jꢀ15.6 Hz), 23) Kunishima M., Kawachi C., Hioki K., Terao K., Tani S., Tetrahedron,
7
.21—7.37 (8H, m), 7.45—7.50 (2H, m), 7.62 (1H, d, Jꢀ15.6 Hz). MS (EI)
57, 1551—1558 (2001).
24) Kunishima M., Kitao A., Kawachi C., Watanabe Y., Iguchi S., Hioki
K., Tani S., Chem. Pharm. Bull., 50, 549—550 (2002).
ꢁ
m/z: 251 (M ).
-Chloro-N-phenethylbenzamide: Colorless crystals. mp 137—138 °C. IR
4
ꢂ1
1
(
KBr) cm : 3346, 1638, 1596, 1542, 1488, 1316, 1094, 844, 752, 699. H- 25) Falchi A., Giacomelli G., Porcheddu A., Taddei M., Synlett, 2000,
NMR (CDCl ) d: 2.93 (2H, t, Jꢀ6.8 Hz), 3.72 (2H, td, Jꢀ6.8, 6.0 Hz), 6.07 275—277 (2000).
1H, br s), 7.20—7.28 (3H, m), 7.30—7.40 (4H, m), 7.59—7.64 (2H, m). 26) Armitt D. J., Aust. J. Chem., 54, 469 (2001).
3
(
ꢁ
MS (ESI) m/z: 260 (MH ).
27) Fu G. C., Nguyen S. T., Grubbs R. H., J. Am. Chem. Soc., 115, 9856—
N-Phenethyldodecanamide: Colorless crystals. mp 72—73 °C. IR (KBr)
9857 (1993).
ꢂ1
1
cm : 3311, 2921, 2859, 1641, 1551, 1463, 1192, 745, 697. H-NMR 28) Schwab P., France M. B., Ziller J. W., Grubbs R. H., Angew. Chem. Int.
CDCl ) d: 0.88 (3H, t, Jꢀ7.0 Hz), 1.21—1.34 (16H, m), 1.53—1.62 (2H, Ed., 34, 2039—2041 (1995).
m), 2.11 (2H, t, Jꢀ7.6 Hz), 2.82 (2H, t, Jꢀ6.9 Hz ), 3.52 (2H, td, Jꢀ6.9, 29) Scholl M., Ding S., Lee C. W., Grubbs R. H., Org. Lett., 1, 953—956
(
3
ꢁ
6
.0 Hz), 5.39 (1H, br s), 7.16—7.35 (5H, m). MS (ESI) m/z: 304 (MH ).
(1999).
3
,5-Di-tert-butyl-N-phenethylbenzamide: Colorless crystals. mp 202—
30) Trnka T. M., Grubbs R. H., Acc. Chem. Res., 34, 18—29 (2001), and
references cited therein.
31) Grubbs R. H., Sanford M., Mathematics, Physics and Chemistry, 56,
17—21 (2002).
ꢂ1
2
7
(
(
(
03 °C. IR (KBr) cm : 3282, 2960, 1635, 1598, 1539, 1332, 1276, 1194,
42, 694. H-NMR (CDCl ) d: 1.32 (18H, s), 2.95 (2H, t, Jꢀ6.8 Hz), 3.72
2H, td, Jꢀ6.8, 6.0 Hz), 6.07 (1H, br s), 7.22—7.29 (3H, m), 7.30—7.37
2H, m), 7.49 (2H, d, Jꢀ1.8 Hz), 7.54 (1H, t, Jꢀ1.8 Hz). MS (ESI) m/z: 338 32) Fuchter M. J., Hoffman B. M., Barrett A. G. M., J. Org. Chem., 71,
MH ).
Boc-Leu-Phe-OMe: Colorless crystals. mp 83.5—84 °C. IR (KBr) cm
1
3
ꢁ
724—729 (2006).
ꢂ1
:
33) Barrett A. G. M., Hopkins B. T., Love A. C., Tedeschi L., Org. Lett., 6,
1
3
0
342, 3307, 1743, 1666, 1523. H-NMR (CDCl ) d: 0.91 (3H, d, Jꢀ6.2 Hz),
.92 (3H, d, Jꢀ6.4 Hz), 1.24—1.31 (1H, m), 1.44 (9H, s), 1.57—1.69 (2H, 34) Årstad E., Barrett A. G. M., Tedeschi L., Tetrahedron Lett., 44, 2703—
835—837 (2004).
3
m), 3.09 (1H, dd, Jꢀ5.9, 13.7 Hz), 3.14 (1H, dd, Jꢀ5.8, 13.7 Hz), 3.71 (3H,
s), 4.07 (1H, br s), 4.77 (1H, br s), 4.84 (1H, td, Jꢀ5.9, 7.8 Hz), 6.44 (1H,
2707 (2003).
35) Stille J. K., Frey D. A., J. Am. Chem. Soc., 81, 4273—4275 (1959).
br d, Jꢀ7.5 Hz), 7.08—7.13 (2H, m), 7.21—7.31 (3H, m). MS (EI) m/z: 392 36) When the reaction was conducted with 1.4 eq of ROMP-Trz -Cl in
5
0
ꢁ
(
M ).
MeOH, the yield of amide decreased to 67% presumably due to ineffi-
cient heterogeneous conditions.
IR (KBr) cm : 1752, 1648, 1537. H-NMR (CDCl ) d: 1.97 (3H, s), 3.09 37) The epimerizatoin test was performed by HPLC analysis according to
N-Acetylphenylalanine Methyl Ester: Colorless crystals. mp 89.5—90 °C.
ꢂ1
1
3
(
(
(
1H, dd, Jꢀ5.8, 13.9 Hz), 3.14 (1H, dd, Jꢀ5.9, 13.9 Hz), 3.72 (3H, s), 4.88
ref. 23.
1H, td, Jꢀ5.8, 7.9 Hz), 6.00 (1H, br s), 7.07—7.12 (2H, m), 7.22—7.32 38) Kunishima M., Hioki K., Wada A., Kobayashi H., Tani S., Tetrahedron
ꢁ
3H, m). MS (ESI) m/z: 222 (MH ).
Lett., 43, 3323—3326 (2002).
39) Dudley J. R., Thurston J. T., Schaefer F. C., Holm-Hansen D., Hull C.
References and Notes
Uozumi Y., Yamada Y., Kagaku Furontia, 16, 155—163 (2006).
J., Adams P., J. Am. Chem. Soc., 73, 2986—2990 (1951).
1)