Rhodium(ii) catalyzed synthesis of macrocycles incorporating oxindole via O-H/N-H insertion reactions

Article abstract of DOI:10.1039/c4ob01671h

A wide variety of 10- to 29-membered oxaza-macrocycles incorporating an oxindole unit were synthesized in good yield via rhodium(ii) acetate dimer catalyzed intramolecular O-H/N-H insertion reactions. Interestingly, synthesis of C₂-symmetric macrocycles in moderate yield was also demonstrated via head to tail dimerization involving double intermolecular O-H insertion when the spacer length was decreased. The synthesis of chiral macrocycles was also delineated. This study reveals the effect of spacer length on inter- or intramolecular insertion reactions with the remotely placed hydroxyl/amino group.

Full text of DOI:10.1039/c4ob01671h

Organic &
Biomolecular Chemistry
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Rhodium(II) catalyzed synthesis of macrocycles
incorporating oxindole via O–H/N–H insertion
reactions†
Cite this: Org. Biomol. Chem., 2014,
12, 9243
Sengodagounder Muthusamy* and Thangaraju Karikalan
A wide variety of 10- to 29-membered oxaza-macrocycles incorporating an oxindole unit were
synthesized in good yield via rhodium(II) acetate dimer catalyzed intramolecular O–H/N–H insertion
reactions. Interestingly, synthesis of C2-symmetric macrocycles in moderate yield was also demonstrated
via head to tail dimerization involving double intermolecular O–H insertion when the spacer length was
decreased. The synthesis of chiral macrocycles was also delineated. This study reveals the effect of spacer
length on inter- or intramolecular insertion reactions with the remotely placed hydroxyl/amino group.
Received 6th August 2014,
Accepted 16th September 2014
DOI: 10.1039/c4ob01671h
www.rsc.org/obc
usually synthesized using high dilution techniques9/templates10
and received a great deal of attention due to their large
Introduction
The chemistry of diazocarbonyl compounds has shown, over number of applications.11 Construction of macrocycles
the years, a multitude of applications in the field of organic through the metallo-carbenoid transformation12 with diazo
synthesis. Rhodium carbenoids, generated from diazocarbonyl compounds has not received significant attention compared to
compounds, have been useful in studying an array of reac- the medium ring systems. In addition, synthesis of macro-
tions1 such as cyclopropanation, insertion and ylide for- cycles via intramolecular X–H (X = N, O, S, etc.) insertion reac-
mation. The catalytic insertion of α-diazocarbonyl compounds tions has not been noted. In particular, the oxindole moiety
into X–H (X = C, N, O, S, etc.) bonds was widely utilized in constitutes a key structural unit in several natural products.13
organic synthesis.2 Inter- and intramolecular C–H insertion Hence, the development of novel synthetic strategies leading
reactions3 employing metallo-carbenoids have been investi- to the synthesis of oxindole derivatives14 is essential. In con-
gated for the cyclic as well as acyclic compounds. However, tinuation of our interest in developing a new synthetic strategy
only limited reports are available toward the synthesis of the towards the macrocyclic15 ring systems, we herein demonstrate
medium-sized ring systems4 and macrocycles5 via the metallo- 10- to 29-membered oxaza-macrocycles incorporating the
carbenoid mediated C–H insertion reaction. The X–H bonds oxindole unit via intramolecular O–H/N–H insertion or inter-
(when X = N, O, S, etc.) are generally more reactive than the molecular head to tail dimerization reactions using 1 mol% of
corresponding C–H bond toward metallo-carbenoids.
A
a rhodium(II) acetate dimer as a catalyst. A systematic study on
number of examples exist in the chemical literature describing the metallo-carbenoid mediated formation of macrocycles
typically the intramolecular insertion of metal-stabilized carbe- based on the spacer length between diazo and alcohol/amine
noid into the X–H bond for the construction6 of five/six-mem- functionality was also delineated.
bered carbo- and heterocyclic ring systems. Moody7 and co-
workers have explained the formation of seven- to eight-mem-
bered-ring heterocyclic systems via intramolecular X–H inser-
tion reactions. Sugimura and co-workers have reported the
Results and discussion
stereoselective synthesis of ten-membered8 cyclic ethers via Initially, synthesis of substrates having an alcohol functional-
intramolecular O–H insertion reaction. Macrocycles were ity tethered on diazo compounds was planned. Towards this,
O-alkylation of 2-hydroxybenzaldehyde with 1,3-dibromo-
propane was performed to furnish the corresponding bromo-
School of Chemistry, Bharathidasan University, Tiruchirappalli 620 024, India.
benzaldehyde 1a. Subsequent reduction of 1a in the presence
of NaBH4 in methanol afforded the corresponding alcohol16 2a
E-mail: muthu@bdu.ac.in; Fax: +91-431-2407045; Tel: +91-431-2407053
†Electronic supplementary information (ESI) available: Copies of 1H NMR and
in very good yield. Successive N-alkylation of 3-diazooxindole17
13C NMR spectra of all the isolated new compounds; X-ray crystal packing of 12a
3a with 2a in the presence of potassium carbonate afforded
the corresponding cyclic diazoamide 4a in 88% yield.
and 19a. CCDC 1005105 and 1005106. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4ob01671h
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Our aim is to demonstrate the synthesis of macrocycles via yield. Next, a reaction of diazoamides 4h,i having an electron-
intramolecular insertion reactions with the remotely placed donating or -withdrawing substituent was also performed
hydroxyl group of diazoamide 415c in the presence of a metal under similar reaction conditions to obtain the corresponding
catalyst. Toward this, reaction of diazoamide 4a in the pres- macrocycles 5h,i. Reaction of diazoamides having m- or p-sub-
ence of a rhodium(II) acetate dimer in dry dichloromethane stituted alcohol 4j–n furnished the corresponding products
under an argon atmosphere smoothly afforded the corres- 5j–n in good yield.
ponding macrocycle 5a with an oxindole unit in 66% yield
After demonstrating the synthesis of 11- to 22-membered
(Scheme 1, entry 1, Table 1). Completion of the reaction took dioxaza-macrocycles incorporating an oxindole unit via an
place within 20 min and no other byproducts were observed intramolecular O–H insertion process, the trioxaza-macro-
based on the NMR spectrum of the crude reaction mixture. cycles having more than 22-membered systems were planned.
The above reaction was carried out using different solvents Thus, the required substituted cyclic diazoamides 11 were
and then optimized using dry dichloromethane at room temp- assembled via DCC coupling of salicylic acid 6 using 1,8-octane-
erature to afford macrocycle 5a. Stimulated by this result, diol 7a to afford the corresponding hydroxyl compound16 8a.
spacer length modifications between diazo and alcohol func- Subsequent O-alkylation of compound 8a using dibromo-
tionalities were planned. Thus, compounds 2 having an appro- hexane 9a in the presence of potassium carbonate afforded the
priate spacer length (n = 1, 3, 4, 7–10) underwent N-alkylation corresponding bromohydroxy compound15 10a in good yield.
of 3-diazooxindole 3a to yield the corresponding diazoamides N-alkylation of 3-diazooxindole 3a using compound 10a in the
4b–g in good yields. Reactions of diazoamides 4b–g in the presence of potassium carbonate afforded an alcohol tethered
presence of the rhodium(II) acetate dimer catalyst as described to diazoamide 11a in 81% yield (Table 2). In line with the
above afforded the corresponding macrocycles 5b–g in good above study described in Scheme 1, the rhodium(II) catalyzed
synthesis of trioxaza-macrocycles from diazoamides 11 was
planned. In this direction, the substituted diazoamide 11a in
the presence of the rhodium(II) acetate dimer under an argon
atmosphere afforded 23-membered trioxaza-macrocycle 12a
incorporating the oxindole unit in 70% yield. Representatively,
the structure of trioxa-macrocyclic compound 12a was con-
firmed by single crystal X-ray analysis (Fig. 1).
The solid-state packing arrangement of 12a showed the
presence of C–H⋯π and five intermolecular C–H⋯O hydrogen
bonding interactions.16 Subsequently, reactions of cyclic diazo-
amides 11b–d were carried out under similar conditions by
changing the spacer length (n,m) to generate the corres-
ponding 27- and 29-membered trioxaza-macrocycles 12b–d
(Table 2). After successful demonstration of the trioxaza-
macrocyclic core via intramolecular O–H insertion reaction,
the intramolecular S–H insertion reaction was further
planned. But, S–H insertion was not facile to yield a macro-
cycle from 11e because the nucleophilicity of the sulphur atom
might6a,18 quench the rhodium catalyst. The diazoamide 11e
was completely recovered from the above reaction mixture.
Next, the investigation of intramolecular N–H insertion
reaction was designed as there is no literature for the synthesis
of macrocyles via N–H insertion reaction. The required starting
precursor 15 was prepared from aniline and bromobenz-
aldehyde 1 to furnish the corresponding Schiff base 13 in
good yield. Followed by the reduction of Schiff base 13a (n = 5)
in the presence of NaBH4 in methanol afforded the corres-
ponding bromoamine16 14a in good yield. Subsequent N-alkyl-
ation of 3-diazooxindole 3a with 14a afforded the
corresponding amine tethered on diazoamide 15a in 78%
yield. Reaction of diazoamide 15a in the presence of the
Rh2(OAc)4 dimer was carried out to furnish the corresponding
17-membered oxadiaza-macrocycle 16a possessing an oxindole
unit in 68% yield (Table 3). Reactions of cyclic diazoamides
15b,c were also carried out under similar reaction conditions to
yield the corresponding 18- and 19-membered oxadiaza-
Scheme 1 Synthesis of dioxaza-macrocycles
reaction.
5 via O–H insertion
Table 1 Synthesis of macrocycles 5 via intramolecular O–H insertion
reaction
Diazo-amides 4 Macrocycles 5 Macrocyclic
Entry Aldehyde
n
(yield %)a
(yield %)a
core
1
2
3
4
5
6
7
8
2-OHC6H5CHO
1
3
4
7
8
9
4a (88)
4b (87)
4c (89)
4d (84)
4e (86)
4f (82)
5a (66)
5b (68)
5c (67)
5d (69)
5e (72)
5f (70)
5g (65)
5h (75)
5i (70)
5j (63)
5k (64)
5l (61)
5m (60)
5n (62)
11
13
14
17
18
19
20
18
18
15
19
16
20
22
2-OHC6H5CHO
2-OHC6H5CHO
2-OHC6H5CHO
2-OHC6H5CHO
2-OHC6H5CHO
2-OHC6H5CHO 10 4g (86)
Aldehydeb
8
8
4
8
4
8
4h (89)
4i (86)
4j (85)
4k (82)
4l (82)
4m (80)
9
Aldehydec
10
11
12
13
14
3-OHC6H5CHO
3-OHC6H5CHO
4-OHC6H5CHO
4-OHC6H5CHO
4-OHC6H5CHO 10 4n (81)
a Isolated yield. b 2-OH(4-OMe)C6H4CHO. c 2-OH(4-NO2)C6H4CHO.
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Table 2 Synthesis of macrocycles 12 via intramolecular O–H insertion reaction
Diazoamides 11
Macrocycles 12
Size of the
macrocycle
Entry
n
m
X
(yield %)a
(yield %)a
1
2
3
4
5
7
7
5
7
7
3
9
9
7
3
O
O
O
O
S
11a (81)
11b (78)
11c (80)
11d (76)
11e (70)
12a (70)
12b (78)
12c (72)
12d (68)
—
23
29
27
27
—
a Isolated yield.
1H NMR spectrum of 19a revealed the presence of a singlet at
δ = 4.93 ppm for the oxindole (*CH) proton. 13C and DEPT-135
experiments disclosed the presence of a characteristic *CH
signal at 76.1 ppm, three CH2 carbons and four CH carbons
(due to symmetry). The observation indicates the formation of
seven-membered-ring product 20 via an intramolecular inser-
1
tion process based on H and 13C NMR spectra. However, the
high resolution mass spectrum clearly disclosed that the
product has twice the molecular weight of 20a as 379.1669
([M + H]+). The product structure was finally confirmed as a
14-membered C2-symmetric macrocycle 19a with the additional
support of single crystal X-ray analysis (Fig. 2). Interstingly, the
formation of macrocycle 19a infers that the reaction under-
went head to tail dimerization via a double intermolecular
O–H insertion process. The solid-state packing arrangement of
19a showed the presence of C–H⋯π and three intermolecular
C–H⋯O hydrogen bonding interactions.16 In order to avoid
the above dimerization process, the above reaction was per-
formed in high dilution to yield the intramolecular O–H inser-
tion product 20a but in vain.
Fig. 1 ORTEP view of macrocycle 12a.
macrocycles via intramolecular N–H insertion. A few carbon
signals were missing in 13C spectra due to the presence of sym-
metry in products.
Encouraged by this result, the above reaction was general-
ized under similar reaction conditions using 4-bromo-1-
butanol (17b) instead of 17a as the spacer to furnish the
corresponding C2-symmetric macrocycle 19b via intermole-
cular dimerization in 50% yield. Synthesis of chiral macrocycles
was further planned. Thus, N-alkylation reaction of 3-diazo-
oxindole 3a was performed using (R)-(−)-3-bromo-2-methyl-
1-propanol (17c) under similar reaction conditions to furnish the
corresponding chiral diazoamide 18c in 65% yield. Subsequent
reaction of chiral diazoamide 18c in the presence of the
Rh2(OAc)4 dimer under an argon atmosphere furnished the
Based on the above study involving the synthesis of 11-
to 29-membered macrocycles having an oxindole unit via
intramolecular O–H/N–H insertion reactions, our aim is next
to synthesize less than 11-membered ring systems. Thus,
3-diazooxindole 3a was reacted with 3-bromo-1-propanol (17a)
in the presence of potassium carbonate to afford the corres-
ponding cyclic diazoamide 18a in 75% yield.
Subsequent reaction of diazoamide 18a in the presence of
the Rh2(OAc)4 dimer in dry dichloromethane under an argon
atmosphere afforded an interesting dimer 19a having two oxi-
ndole units in a diastereoselective manner (Table 4). The
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Table 3 Synthesis of macrocycles 16 via N–H insertion reaction
Diazoamide 15
Macrocycle 16
Macrocyclic
core
Entry
Aldehyde
n
(yield %)a
(yield %)a
1
2
3
2-OHC6H5CHO
2-OHC6H5CHO
3-OHC6H5CHO
5
6
6
15a (78)
15b (75)
15c (73)
16a (68)
16b (72)
16c (64)
17
18
19
a Isolated yield.
Table 4 Synthesis of symmetric macrocycles 19 via the head to tail dimerization process
Diazoamide 18
Macrocycle 19
Size of the
macrocycle
Entry
Bromoalcohol 17
n
R1
R2
(yield %)a
(yield %)a
1
2
3
4
5
6
3-Bromopropanol (17a)
4-Bromobutanol (17b)
(R)-(−)-3-Bromo-2-methyl-1-propanol (17c)
3-Bromopropanol (17a)
(R)-(−)-3-Bromo-2-methyl-1-propanol (17c)
2-Bromoethanol (17d)
1
2
1
1
1
0
H
H
Me
H
Me
H
H
H
H
Cl
Cl
H
18a (75)
18b (73)
18c (65)
18d (68)
18e (60)
18f (78)
19a (52)
19b (50)
19c (45)
19d (44)
19e (40)
19fb
14
16
14
14
14
—
a Isolated yield. b No product formed.
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(overall yield 32%) as a mixture of diastereomers in moderate
yield and a trace amount of 10-membered oxaza-macrocyle 20g
(4%) via intramolecular O–H insertion reaction (Scheme 2).
The diastereomers 21a,b were present in the ratio of 58 : 42
and could be separable by column chromatography (Fig. 3).
1
The H NMR spectra of 21a (isolated yield 20%) and 21b (iso-
lated yield 11%) exhibited a characteristic singlet resonance at
δ 4.885 and δ 4.897 for two *CH protons, respectively. The
intramolecular insertion product 20g exhibited a characteristic
singlet resonance at δ 4.92 for a *CH proton. Furthermore,
these compounds exhibited consistent 13C NMR and
DEPT-135 spectral data. The yield of products may vary based
on the concentration of the reaction. The reaction of cyclic
diazoamides 18a–e proceeded in an intermolecular manner to
produce the head to tail dimerization for macrocycles as a
single diastereomer. However, reaction of diazoamide 18g
afforded the intramolecular product 20 as well as the intermo-
lecular product 21 as a mixture of diastereomers.
Fig. 2 ORTEP view of C2-symmetric macrocycle 19a. There are two
molecules in the asymmetric unit; only one is shown for better clarity.
chiral macrocycle 19c in 45% yield. N-alkylation of substituted
3-diazooxindole 3b with 3-bromo-1-propanol (17a) in the pres-
ence of potassium carbonate furnished cyclic diazoamide 18d
in 68% yield. Subsequent reaction under similar reaction con-
ditions afforded the corresponding C2-symmetric macrocycle
19d in 44% yield. The above reaction was repeated under
similar reaction conditions using (R)-(−)-3-bromo-2-methyl-1-
propanol (17c) instead of 17a as the spacer to furnish the
corresponding chiral macrocycle 19e in 40% yield. However,
reaction of substrate 18f having a carbon less in spacer length,
prepared from 2-bromoethanol, did not yield the expected
product 19f which may be due to the higher strain energy19
involved in the product.
The above head to tail dimerization reaction yielded sym-
metric macrocycles having two oxindole units in a diastereose-
lective manner. Similar reaction of 3-diazooxindole 3a with
6-bromo-1-hexanol (17e) afforded the corresponding cyclic
diazoamide 18g in 70% yield. Subsequent reaction of diazoamide
18g in the presence of the Rh2(OAc)4 dimer in dichloro-
methane under an argon atmosphere for 20 min and sub-
sequent chromatography purification of the reaction mixture
afforded 20-membered oxaza-macrocyclic compounds 21a,b
Conclusions
In conclusion, a facile, mild and convenient method to syn-
thesize oxaza-macrocycles incorporating an oxindole unit via
intramolecular O–H/N–H insertion reactions in the presence
of the Rh2(OAc)4 catalyst is demonstrated. Interestingly, syn-
thesis of C2-symmetric or chiral oxaza-macrocycles in moderate
yield was delineated via head to tail dimerization involving
double intermolecular O–H insertion when the spacer length
was decreased. This catalytic method afforded 10- to 29-mem-
bered oxaza-macrocycles incorporating the oxindole unit in
good yield without using high dilution/template techniques.
This study reveals the effect of spacer length based on inter- or
intramolecular O–H/N–H insertion processes.
Experimental section
General
Melting points were determined on capillary melting point
apparatus and are uncorrected. IR spectra were recorded using
Scheme 2 Study of the double O–H insertion reaction of 18g.
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Fig. 3 NMR spectra of diastereomers 21a,b.
the ATR technique on a Bruker Alpha FT-IR spectrophoto- stirred at room temperature for 15–20 min. The progress of the
meter. Proton nuclear magnetic resonance (1H NMR) spectra reaction was monitored by TLC. After completion of the reac-
were recorded on a Bruker Avance at 400 MHz using CDCl3 in tion, the reaction mixture was concentrated under reduced
ppm (δ) related to tetramethylsilane (δ = 0.00) as an internal pressure and purified by column chromatography (SiO2,
standard and are reported as follows: chemical shift (ppm), hexane–ethyl acetate 75 : 25) to afford the respective macro-
multiplicity (br = broad, s = singlet, d = doublet, m = multi- cycles 5.
plet), coupling constant (Hz) and integration. Carbon-13
nuclear magnetic resonance (13C NMR) spectra were recorded mp 165–167 °C; IR (neat): νmax 2929, 2855, 1726, 1682, 1605,
at 100 MHz in CDCl3. Chemical shifts are reported in delta (δ) 1496, 1487, 1445, 1297, 1123, 758 cm−1
1H NMR (400 MHz,
Synthesis of macrocycle 5a. Colorless solid (90 mg, 66%);
;
CDCl3) δ = 1.76–1.80 (m, 1H), 2.30–2.41 (m, 1H), 3.47–3.51 (m,
1H), 4.06–4.18 (m, 3H), 4.31–4.38 (m, 1H), 4.48 (d, 1H, J = 12.8
Hz), 4.97 (s, 1H), 6.60 (d, 1H, J = 8 Hz), 6.81–6.86 (m, 2H), 7.05
(t, 1H, J = 7.6 Hz), 7.16 (td, 1H, J1 = 7.2 Hz, J2 = 1.6 Hz), 7.26
(dd, 1H, J1 = 7.2 Hz, J2 = 1.6 Hz), 7.31 (t, 1H, J = 7.6 Hz), 7.40
(d, 1H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 25.16 (CH2),
39.06 (CH2), 62.52 (CH2), 68.46 (CH2), 75.57 (CH, observed in
DEPT-90 NMR), 108.62 (vCH), 110.59 (vCH), 120.83 (vCH),
122.65 (vCH), 124.84 (quat-C), 125.94 (vCH), 125.95 (quat-C),
129.96 (vCH), 130.05 (vCH), 132.58 (vCH), 144.22 (quat-C),
156.51 (quat-C), 174.42 (quat-C); HRMS (ESI) Calcd for
C18H17NO3 [M + H]+ 296.1287; found, 296.1292.
units, parts per million (ppm) relative to the center of the
triplet at 77.7 ppm for CDCl3. Carbon types were determined
from 13C NMR and DEPT experiments. High resolution mass
spectra (HRMS-ESI) were obtained on a Bruker APEX 47e
FT-ICR mass spectrometer or Waters QTof-micromass spectro-
meter. Optical rotations were taken on a Jasco P-2000 polari-
meter. All solvents were purified by distillation following the
standard procedure. Thin layer chromatography was per-
formed on silica or alumina plates and components visualized
under iodine/UV light at 254 nm. Column chromatography
was performed on silica gel (100–200 mesh). All the reactions
were conducted in oven-dried glassware under a positive
pressure of argon with magnetic stirring. Reagents were added
via a syringe through septa.
Synthesis of macrocycle 5b. Colorless solid (94 mg, 68%);
mp 152–154 °C; IR (neat): νmax 2922, 2853, 1713, 1613, 1603,
1494, 1468, 1360, 1256, 1167, 752 cm−1 1H NMR (400 MHz,
;
General procedure for macrocycles 5
CDCl3) δ = 1.31–1.36 (m, 1H), 1.45–1.57 (m, 3H), 1.98–2.08 (m,
2H), 3.29 (ddd, 1H, J1 = 14.4 Hz, J2 = 4.8 Hz, J3 = 1.2 Hz),
3.56–3.62 (m, 1H), 3.92 (dt, 1H, J1 = 8.4 Hz, J2 = 3.2 Hz), 4.36
A solution of diazoamide 4 (150 mg, 1.0 mmol) and rhodium(II)
acetate dimer (1.0 mol%) in dichloromethane (15 mL) was
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(td, 1H, J1 = 13.8 Hz, J2 = 3.2 Hz), 4.38 (d, 1H, J = 10.4 Hz), 4.76 1H, J1 = 8.0 Hz, J2 = 2.0 Hz), 7.22–7.29 (m, 2H), 7.50 (dd, 1H,
(s, 1H), 5.59 (d, 1H, J = 10.4 Hz), 6.56 (d, 1H, J = 8 Hz), 6.70 (d, J1 = 7.4 Hz, J2 = 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ 25.09
1H, J = 8 Hz), 6.76 (td, 1H, J1 = 7.6 Hz, J2 = 0.8 Hz), 6.86 (td, (CH2), 25.81 (CH2), 26.56 (CH2), 26.58 (CH2), 26.71 (CH2),
1H, J1 = 7.6 Hz, J2 = 0.8 Hz), 7.10 (td, 1H, J1 = 8.0 Hz, J2 = 1.6 26.96 (CH2), 27.02 (CH2), 28.60 (CH2), 39.47 (CH2), 62.88
Hz), 7.15 (td, 1H, J1 = 7.8 Hz, J2 = 0.4 Hz), 7.21–7.26 (m, 2H); (CH2), 67.90 (CH2), 75.70 (CH, observed in DEPT-90 NMR),
13C NMR (100 MHz, CDCl3) δ 20.47 (CH2), 23.41 (CH2), 26.59 108.78 (vCH), 110.75 (vCH), 120.22 (vCH), 122.62 (vCH),
(CH2), 36.52 (CH2), 65.47 (CH2), 66.06 (CH2), 74.29 (CH, 124.82 (quat-C), 125.37 (vCH), 126.47 (quat-C), 128.46 (vCH),
observed in DEPT-90 NMR), 108.89 (vCH), 110.41 (vCH), 128.61 (vCH), 129.76 (vCH), 143.80 (quat-C), 156.29 (quat-C),
119.75 (vCH), 122.50 (vCH), 125.64 (quat-C), 125.94 (vCH), 174.19 (quat-C); HRMS (ESI) Calcd for C25H31NO3 [M + Na]+
126.31 (quat-C), 129.62 (vCH), 131.09 (vCH), 143.42 (quat-C), 416.2202; found, 416.2211.
157.83 (quat-C), 174.09 (quat-C); HRMS (ESI) Calcd for
Synthesis of macrocycle 5f. Colorless solid (98 mg, 70%);
mp 170–172 °C; IR (neat): νmax 2942, 2892, 1765, 1623, 1413,
C20H21NO3 [M + Na]+ 346.1419; found, 346.1410.
Synthesis of macrocycle 5c. Colorless solid (93 mg, 67%); 1446, 1219, 1067, 912, 738 cm−1 1H NMR (400 MHz, CDCl3)
;
mp 157–159 °C; IR (neat): νmax 2927, 2856, 1710, 1613, 1488, δ = 1.25–1.39 (m, 12H), 1.40–1.49 (m, 4H), 1.59–1.64 (m, 2H),
1467, 1466, 1367, 1263, 1163, 751 cm−1 1H NMR (400 MHz, 3.65–3.72 (m, 2H), 3.84–3.92 (m, 2H), 4.06 (d, 1H, J = 11.6 Hz),
;
CDCl3) δ = 1.21–1.40 (m, 1H), 1.48–1.58 (m, 4H), 1.67–1.72 (m, 4.12 (d, 1H, J = 11.6 Hz), 4.72 (s, 1H), 6.68 (d, 1H, J = 7.2 Hz),
3H), 3.32 (dt, 1H, J1 = 14.4 Hz, J2 = 4.0 Hz), 3.63–3.68 (m, 1H), 6.79 (t, 1H, J = 8.0 Hz), 6.85–6.92 (m, 1H), 7.13 (d, 1H, J = 8.0
3.7–4.01 (m, 1H), 4.13–4.20 (m, 1H), 4.31 (d, 1H, J = 10.0 Hz), Hz), 7.22 (dt, 1H, J1 = 7. 6 Hz, J2 = 2.0 Hz), 7.27–7.36 (m, 2H),
4.75 (s, 1H), 5.37 (d, 1H, J = 10.0 Hz), 6.68 (d, 1H, J = 8.0 Hz), 7.40–7.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.09 (CH2),
6.71 (d, 1H, J = 7.6 Hz), 6.82 (td, 1H, J1 = 8.0 Hz, J2 = 0.8 Hz), 26.46 (CH2), 26.79 (CH2), 27.23 (CH2), 27.56 (CH2), 27.89
6.91 (td, 1H, J1 = 7.6 Hz, J2 = 0.8 Hz), 7.12 (td, 1H, J1 = 7.6 Hz, (CH2), 28.12 (CH2), 28.45 (CH2), 29.63 (CH2), 39.78 (CH2),
J2 = 0.8 Hz), 7.19 (td, 1H, J1 = 8.0 Hz, J2 = 0.8 Hz), 7.28 (d, 1H, 64.12 (CH2), 67.56 (CH2), 74.38 (CH, observed in DEPT-90
J = 7.2 Hz), 7.31 (dd, 1H, J1 = 7.6 Hz, J2 = 1.6 Hz); 13C NMR NMR), 107.67 (vCH), 109.23 (vCH), 118.91 (vCH), 119.18
(100 MHz, CDCl3) δ 26.15 (CH2), 26.61 (CH2), 28.25 (CH2), (vCH), 122.76 (quat-C), 124.17 (vCH), 125.67 (quat-C), 127.67
29.38 (CH2), 40.09 (CH2), 65.74 (CH2), 67.84 (CH2), 75.11 (CH, (vCH), 128.12 (vCH), 129.89 (vCH), 140.24 (quat-C), 155.34
observed in DEPT-90 NMR), 108.50 (vCH), 111.39 (vCH), (quat-C), 176.12 (quat-C); Anal. Calcd for C26H33NO3 (407.55):
120.17 (vCH), 122.59 (vCH), 125.58 (quat-C), 126.32 (vCH), C, 76.62; H, 8.16; N, 3.44. Found: C, 76.51; H, 8.14; N, 3.41.
126.44 (quat-C), 129.30 (vCH), 129.87 (vCH), 130.57 (vCH),
Synthesis of macrocycle 5g. Colorless solid (91 mg, 65%);
144.15 (quat-C), 157.19 (quat-C), 174.09 (quat-C); Anal. Calcd mp 162–164 °C; IR (neat): νmax 2922, 2853, 1713, 1614, 1489,
1
for C21H23NO3 (337.41): C, 74.75; H, 6.87; N, 4.15. Found: C, 1464, 1455, 1235, 1105, 747 cm−1; H NMR (400 MHz, CDCl3)
74.63; H, 6.83; N, 4.18.
δ = 1.18–1.38 (m, 16H), 1.64–1.69 (m, 4H), 3.57–3.62 (m, 1H),
Synthesis of macrocycle 5d. Colorless solid (96 mg, 69%); 3.77–3.81 (m, 1H), 3.87–3.90 (m, 2H), 4.64 (d, 1H, J = 11.6 Hz),
mp 167–169 °C; IR (neat): νmax 2932, 2862, 1718, 1601, 1472, 4.80 (d, 1H, J = 11.6 Hz), 5.00 (s, 1H), 6.72–6.77 (m, 2H), 6.89
1492, 1210, 1015, 743 cm−1 1H NMR (400 MHz, CDCl3) δ = (t, 1H, J = 7.6 Hz), 6.95 (t, 1H, J = 7.6 Hz), 7.15–7.26 (m, 3H),
;
1.21–1.35 (m, 10H), 1.42–1.56 (m, 2H), 1.63–1.74 (m, 2H), 7.40 (dd, 1H, J1 = 7.4 Hz, J2 = 1.2 Hz); 13C NMR (100 MHz,
3.74–3.89 (m, 2H), 3.93–4.03 (m, 2H), 4.26 (d, 1H, J = 11.6 Hz), CDCl3) δ 25.49 (CH2), 26.07 (CH2), 26.15 (CH2), 27.04 (CH2),
4.41 (d, 1H, J = 11.6 Hz), 4.98 (s, 1H), 6.62 (d, 1H, J = 7.6 Hz), 27.14 (CH2), 27.23 (CH2), 27.38 (CH2), 27.82 (CH2), 28.35
6.85 (t, 1H, J = 7.6 Hz), 6.92–6.98 (m, 1H), 7.03 (dt, 1H, J1 = 8.0 (CH2), 29.21 (CH2), 39.42 (CH2), 64.57 (CH2), 68.20 (CH2),
Hz, J2 = 1.6 Hz), 7.18 (dt, 1H, J1 = 7.6 Hz, J2 = 2.0 Hz), 7.24–7.33 75.43 (CH, observed in DEPT-90 NMR), 108.52 (vCH), 111.16
(m, 2H), 7.42–7.53 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.12 (vCH), 120.27 (vCH), 122.50 (vCH), 125.37 (quat-C), 125.47
(CH2), 26.78 (CH2), 27.12 (CH2), 27.49 (CH2), 27.79 (CH2), (vCH), 126.54 (quat-C), 128.79 (vCH), 129.26 (vCH), 129.68
28.32 (CH2), 29.85 (CH2), 40.12 (CH2), 63.33 (CH2), 66.73 (vCH), 143.78 (quat-C), 156.73 (quat-C), 174.45 (quat-C); HRMS
(CH2), 75.12 (CH, observed in DEPT-90 NMR), 108.12 (vCH), (ESI) Calcd for C27H35NO3 [M + H]+ 422.2695; found, 422.2703.
109.43 (vCH), 119.21 (vCH), 120.78 (vCH), 123.14 (quat-C),
125.76 (vCH), 126.12 (quat-C), 128.04 (vCH), 128.86 (vCH), mp 178–180 °C; IR (neat): νmax 2927, 2855, 1718, 1612, 1589,
129.12 (vCH), 142.92 (quat-C), 156.19 (quat-C), 175.23 (quat- 1508, 1488, 1466, 1287, 1162, 732 cm−1 1H NMR (400 MHz,
C); HRMS (ESI) Calcd for C24H29NO3 [M + Na]+ 402.2045; CDCl3) δ = 1.19–1.32 (m, 12H), 1.59–1.68 (m, 4H), 3.37–3.42
found, 402.2038. (m, 1H), 3.72 (s, 3H, OCH3), 3.77–3.82 (m, 1H), 3.85–3.89 (m,
Synthesis of macrocycle 5h. Colorless solid (105 mg, 75%);
;
Synthesis of macrocycle 5e. Colorless solid (101 mg, 72%); 1H), 3.96–4.03 (m, 1H), 4.35 (d, 1H, J = 11.2 Hz), 4.64 (d, 1H,
mp 174–176 °C; IR (neat): νmax 2921, 2857, 1715, 1599, 1489, J = 11.2 Hz), 5.08 (s, 1H), 6.32 (d, 1H, J = 2.0 Hz), 6.42 (dd, 1H,
1447, 1283, 1148, 751 cm−1 1H NMR (400 MHz, CDCl3) δ = J1 = 8.4 Hz, J2 = 2.4 Hz), 6.76 (d, 1H, J = 7.6 Hz), 6.96 (t, 1H, J =
;
1.19–1.30 (m, 12H), 1.60–1.63 (m, 4H), 3.36 (dt, 1H, J1 = 14.0 7.6 Hz), 7.19–7.27 (m, 2H), 7.35 (d, 1H, J = 8.4 Hz); 13C NMR
Hz, J2 = 5.6 Hz), 3.39–4.06 (m, 1H), 3.80–3.89 (m, 2H), 4.33 (d, (100 MHz, CDCl3) δ 25.18 (CH2), 25.62 (CH2), 26.42 (CH2),
1H, J = 11.6 Hz), 4.68 (d, 1H, J = 11.6 Hz), 5.14 (s, 1H), 6.72 (d, 26.67 (CH2), 26.79 (CH2), 26.97 (CH2), 27.08 (CH2), 28.55
1H, J = 8.0 Hz), 6.77 (d, 1H, J = 7.6 Hz), 6.90 (td, 1H, J1 = 7.6 (CH2), 39.31 (CH2), 55.35 (OCH3), 63.30 (CH2), 68.06 (CH2),
Hz, J2 = 0.8 Hz), 6.96 (td, 1H, J1 = 7.6 Hz, J2 = 0.8 Hz), 7.15 (td, 75.54 (CH, observed in DEPT-90 NMR), 98.85 (vCH), 104.08
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(vCH), 108.71 (vCH), 119.02 (quat-C), 122.54 (vCH), 125.11
Synthesis of macrocycle 5l. Colorless solid (84 mg, 61%,);
(quat-C), 125.35 (vCH), 129.66 (vCH), 130.07 (vCH), 143.75 mp 161–163 °C; IR (neat): νmax 2926, 2855, 1718, 1611, 1605,
(quat-C), 157.73 (quat-C), 160.46 (quat-C), 174.39 (quat-C); 1512, 1488, 1467, 1366, 1264, 1164, 731 cm−1 1H NMR
HRMS (ESI) Calcd for C26H33NO4 [M + H]+ 424.2488; found, (400 MHz, CDCl3) δ = 1.32–1.41 (m, 4H), 1.57–1.65 (m, 4H),
424.2495. 3.45–3.55 (m, 1H), 3.78 (t, 3H, J = 6.4 Hz), 4.53 (d, 1H, J = 6
;
Synthesis of macrocycle 5i. Colorless solid (99 mg, 70%); Hz), 4.59 (s, 1H), 4.81 (d, 1H, J = 6 Hz), 6.07–6.64 (m, 2H), 6.73
mp 175–177 °C; IR (neat): νmax 2924, 2853, 1714, 1610, 1590, (d, 1H, J = 8 Hz), 6.95–7.00 (m, 1H), 7.11 (t, 2H, J = 7.6 Hz),
1510, 1485, 1336, 1263, 1108, 750 cm−1 1H NMR (400 MHz, 7.20–7.27 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 25.51 (CH2),
;
CDCl3) δ = 1.24–1.32 (m, 11H), 1.59–1.71 (m, 5H), 3.34 (td, 1H, 26.31 (CH2), 27.17 (CH2), 28.59 (CH2), 39.56 (CH2), 67.39
J1 = 14 Hz, J2 = 6 Hz), 3.92–3.97 (m, 2H), 4.05–4.13 (m, 1H), (CH2), 69.80 (CH2), 74.08 (CH, observed in DEPT-90 NMR),
4.26 (d, 1H, J = 12.8 Hz), 4.58 (d, 1H, J = 12.8 Hz), 5.21 (s, 1H), 108.59 (vCH), 114.46 (vCH), 122.62 (vCH), 125.30 (quat-C),
6.76 (d, 1H, J = 9.2 Hz), 6.81 (d, 1H, J = 8.0 Hz), 7.01 (t, 1H, J = 125.39 (vCH), 125.51 (quat-C), 125.55 (vCH), 129.16 (vCH),
7.6 Hz), 7.28 (t, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 7.2 Hz), 8.08 129.76 (vCH), 130.00 (vCH), 143.70 (quat-C), 158.71 (quat-C),
(dd, 1H, J1 = 8.8 Hz, J2 = 2.8 Hz), 8.47 (d, 1H, J = 2.8 Hz); 13C 174.84 (quat-C); HRMS (ESI) Calcd for C21H23NO3 [M + Na]+
NMR (100 MHz, CDCl3) δ 23.81 (CH2), 25.12 (CH2), 25.41 360.1576; found, 360.1568.
(CH2), 25.52 (CH2), 25.65 (CH2), 25.81 (CH2), 26.02 (CH2),
Synthesis of macrocycle 5m. Colorless solid (84 mg, 60%);
27.24 (CH2), 38.70 (CH2), 60.32 (CH2), 68.10 (CH2), 74.69 (CH, mp 163–165 °C; IR (neat): νmax 2927, 2855, 1720, 1611, 1510,
observed in DEPT-90 NMR), 107.98 (vCH), 109.11 (vCH), 1488, 1467, 1263, 1173, 733 cm−1; 1H NMR (400 MHz, CDCl3) δ
121.87 (vCH), 122.86 (vCH), 123.02 (quat-C), 123.75 (vCH), = 1.10–1.23 (m, 12H), 1.25–1.38 (m, 2H), 1.62–1.65 (m, 2H),
124.41 (quat-C), 126.80 (vCH), 129.12 (vCH), 140.32 (quat-C), 3.10–3.14 (m, 1H), 3.25–3.32 (m, 1H), 3.96 (t, 2H, J = 5.6 Hz),
142.86 (quat-C), 159.83 (quat-C), 172.56 (quat-C); HRMS (ESI) 4.50 (d, 1H, J = 12.0 Hz), 4.77 (d, 1H, J = 12.0 Hz), 4.85 (s, 1H),
Calcd for C25H30N2O5 [M + H]+ 439.2233; found, 439.2237.
6.62 (d, 1H, J = 7.6 Hz), 6.65–6.69 (m, 2H), 6.92 (d, 2H, J = 8.8
Synthesis of macrocycle 5j. Colorless solid (87 mg, 63%); Hz), 7.03 (t, 1H, J = 7.6 Hz), 7.25 (t, 1H, J = 7.6 Hz), 7.38 (d, 1H,
mp 170–172 °C; IR (neat): νmax 2926, 2855, 1714, 1611, 1488, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 23.75 (CH2), 26.04
1
1467, 1367, 1263, 1163, 731 cm−1; H NMR (400 MHz, CDCl3) (CH2), 26.39 (CH2), 26.86 (CH2), 27.05 (CH2), 27.52 (CH2),
δ = 1.35–1.55 (m, 4H), 1.61–1.68 (m, 4H), 3.26 (dt, 1H, J1 = 14 Hz, 27.63 (CH2), 27.87 (CH2), 39.80 (CH2), 66.49 (CH2), 69.31
J2 = 4.4 Hz), 3.97–4.15 (m, 3H), 4.72 (d, 1H, J = 11.6 Hz), 4.80 (CH2), 73.85 (CH, observed in DEPT-90 NMR), 108.68 (vCH),
(s, 1H), 5.38 (d, 1H, J = 11.6 Hz), 6.68 (dd, 1H, J1 = 8.2 Hz, J2 = 114.41 (vCH), 122.13 (vCH), 124.02 (quat-C), 125.85 (vCH),
2.0 Hz), 6.73 (d, 1H, J = 8.0 Hz), 6.78–6.81 (m, 2H), 6.99 (td, 128.51 (quat-C), 129.84 (vCH), 131.03 (vCH), 143.94 (quat-C),
1H, J1 = 7.2 Hz, J2 = 0.8 Hz), 7.10 (t, 1H, J = 7.6 Hz), 7.24 (td, 158.77 (quat-C), 174.46 (quat-C); HRMS (ESI) Calcd for
1H, J1 = 7.2 Hz, J2 = 0.8 Hz), 7.36 (d, 1H, J = 7.6 Hz); 13C NMR C25H31NO3 [M + Na]+ 416.2202; found, 416.2211.
(100 MHz, CDCl3) δ 24.70 (CH2), 26.55 (CH2), 26.92 (CH2),
27.17 (CH2), 39.05 (CH2), 66.78 (CH2), 70.45 (CH2), 74.41 (CH, mp 181–183 °C; IR (neat): νmax 2926, 2854, 1715, 1610, 1510,
observed in DEPT-90 NMR), 108.83 (vCH), 113.73 (vCH), 1486, 1487, 1336, 1299, 1093, 1016, 750 cm−1 1H NMR
Synthesis of macrocycle 5n. Colorless solid (87 mg, 62%);
;
116.24 (vCH), 120.15 (vCH), 122.72 (vCH), 125.14 (quat-C), (400 MHz, CDCl3) δ = 1.14–1.35 (m, 12H), 1.45–1.59 (m, 8H),
126.22 (vCH), 129.25 (vCH), 130.06 (vCH), 139.85 quat-C), 3.33–3.36 (m, 1H), 3.69–3.74 (m, 1H), 3.98–4.04 (m, 2H), 4.57
143.89 (quat-C), 157.93 (quat-C), 175.05 (quat-C); HRMS (ESI) (d, 1H, J = 11.2 Hz), 4.81 (s, 1H), 4.88 (d, 1H, J = 11.2 Hz), 6.69
Calcd for C21H23NO3 [M + Na]+ 360.1576; found, 360.1584.
(d, 1H, J = 8.0 Hz), 6.73–6.75 (m, 2H), 7.00 (t, 1H, J = 7.2 Hz),
Synthesis of macrocycle 5k. Colorless solid (90 mg, 64%); 7.15 (d, 2H, J = 8.4 Hz), 7.23 (t, 1H, J = 7.2 Hz), 7.36 (d, 1H, J =
mp 159–161 °C; IR (neat): νmax 2922, 2856, 1709, 1613, 1601, 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 25.28 (CH2), 26.17 (CH2),
1488, 1465, 1454, 1240, 1074, 752 cm−1 1H NMR (400 MHz, 26.19 (CH2), 27.24 (CH2), 27.34 (CH2), 27.63 (CH2), 27.78
;
CDCl3) δ = 1.21–1.34 (m, 10H), 1.34–1.37 (m, 2H), 1.57–1.65 (CH2), 28.12 (CH2), 28.45 (CH2), 29.15 (CH2), 39.22 (CH2),
(m, 4H), 3.44–3.50 (m, 1H), 3.80–3.87 (m, 1H), 3.97 (dt, 2H, 64.23 (CH2), 68.74 (CH2), 75.11 (CH, observed in DEPT-90
J1 = 6.8 Hz, J2 = 1.2 Hz), 4.75 (d, 1H, J = 11.2 Hz), 4.79 (s, 1H), NMR), 108.32 (vCH), 111.54 (vCH), 120.05 (vCH), 122.32
5.02 (d, 1H, J = 11.2 Hz), 6.72 (d, 1H, J = 7.6 Hz), 6.75 (dd, 1H, (vCH), 125.51 (quat-C), 125.87 (vCH), 126.24 (quat-C), 127.76
J1 = 2.0 Hz, J2 = 0.8 Hz), 6.90 (d, 1H, J = 7.6 Hz), 6.94–6.98 (m, (vCH), 128.16 (vCH), 129.28 (vCH), 145.18 (quat-C), 156.33
2H), 7.16 (d, 1H, J = 8.0 Hz), 7.19–7.23 (m, 1H), 7.29 (d, 1H, J = (quat-C), 175.15 (quat-C); HRMS (ESI) Calcd for C27H35NO3
7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 24.45 (CH2), 26.06 (CH2), [M + Na]+ 444.2515; found, 444.2509.
27.02 (CH2), 27.70 (CH2), 27.94 (CH2), 28.49 (CH2), 28.69
(CH2), 39.14 (CH2), 68.16 (CH2), 71.33 (CH2), 74.13 (CH,
General procedure for diazoamides 11
observed in DEPT-90 NMR), 108.63 (vCH), 115.03 (vCH), To an oven-dried flask, a solution containing 3-diazooxindole
115.87 (vCH), 120.39 (vCH), 122.56 (vCH), 125.61 (vCH), 3a (200 mg, 1.25 mmol) and potassium carbonate (434 mg,
125.66 (quat-C), 129.46 (vCH), 129.79 (vCH), 138.84 (quat-C), 3.14 mmol) in dry DMF was taken under an argon atmosphere.
143.69 (quat-C), 159.01 (quat-C), 174.90 (quat-C); Anal. Calcd To this reaction mixture, a solution of an appropriate aliphatic
for C25H31NO3 (393.52): C, 76.30; H, 7.94; N, 3.56. Found: C, bromoalcohol 10 (1.35 mmol) in dry DMF was slowly added
76.43; H, 7.90; N, 3.59.
over a period of 30 min and then a catalytic amount of
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tetrabutylammonium iodide was added. The progress of the (CH2), 64.82 (CH2), 68.88 (CH2), 108.94 (vCH), 113.10 (vCH),
reaction was monitored by TLC. The mixture was extracted 116.86 (quat-C), 118.33 (vCH), 119.94 (vCH), 120.81 (quat-C),
with dichloromethane (3 × 25 mL) and the combined organic 121.88 (vCH), 125.38 (vCH), 131.51 (vCH), 133.17 (vCH),
layers were washed with water (3 × 25 mL), brine (2 × 25 mL) 133.89 (quat-C), 158.53 (quat-C), 166.78 (quat-C), 166.84 (quat-
and dried (anhydrous Na2SO4). The solvent was removed C); Anal. Calcd for C33H45N3O5 (563.73): C, 70.31; H, 8.05; N,
under reduced pressure and the resulting residue was purified 7.45. Found: C, 70.44; H, 8.09; N, 7.51.
by column chromatography (SiO2, hexane–ethyl acetate 80 : 20)
to afford the respective diazoamides 11.
Synthesis of diazoamide 11d. Red viscous liquid (538 mg,
76%); IR (neat): νmax 3439, 2934, 2823, 2091, 1673, 1612, 1423,
Synthesis of diazoamide 11a. Red viscous liquid (516 mg, 1315, 1223, 1146, 1039, 746 cm−1; 1H NMR (400 MHz, CDCl3) δ
81%); IR (neat): νmax 3445, 2930, 2858, 2096, 1721, 1605, 1460, = 1.21–1.36 (m, 16H), 1.45–1.49 (m, 6H), 1.56–1.68 (m, 6H),
1
1359, 1300, 1246, 1084, 753 cm−1; H NMR (400 MHz, CDCl3) 3.58 (t, 2H, J = 7.2 Hz), 3.78 (t, 2H, J = 7.6 Hz), 3.96 (t, 2H, J =
δ = 1.71–1.27 (m, 3H), 1.33–1.38 (m, 3H), 1.46–1.49 (m, 4H), 6.8 Hz), 4.53 (t, 2H, J = 7.2 Hz), 6.78–6.83 (m, 2H), 6.94 (t, 2H,
1.63–1.69 (m, 5H), 1.73–1.98 (m, 3H), 3.56 (t, 2H, J = 6.4 Hz), J = 7.2 Hz), 7.02–7.12 (m, 2H), 7.25 (d, 1H, J = 7.6 Hz), 7.41 (d,
3.77 (t, 2H, J = 7.2 Hz), 3.94 (t, 2H, J = 6.4 Hz), 4.05 (q, 2H, J = 1H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 24.45 (CH2),
7.6 Hz), 4.18 (t, 2H, J = 7.2 Hz), 6.84–6.90 (m, 3H), 7.01 (td, 1H, 25.45 (CH2), 26.12 (CH2), 27.23 (CH2), 28.12 (CH2), 28.76
J1 = 7.8 Hz, J2 = 0.8 Hz), 7.09–7.14 (m, 2H), 7.33–7.35 (m, 1H), (CH2), 29.46 (CH2), 29.54 (CH2), 29.78 (CH2), 32.29 (CH2),
7.69 (dd, 1H, J1 = 7.6 Hz, J2 = 2.0 Hz); 13C NMR (100 MHz, 41.23 (CH2), 62.97 (CH2), 65.12 (CH2), 66.83 (CH2), 109.48
CDCl3) δ 25.70 (CH2), 26.00 (CH2), 26.60 (CH2), 28.04 (CH2), (vCH), 112.76 (vCH), 117.59 (quat-C), 118.31 (vCH), 119.90
28.41 (CH2), 28.75 (CH2), 29.08 (CH2), 29.26 (CH2), 29.32 (vCH), 121.23 (quat-C), 121.75 (vCH), 126.49 (vCH), 132.12
(CH2), 32.73 (CH2), 40.65 (CH2), 41.39 (CH2), 62.90 (CH2), (vCH), 134.34 (vCH), 134.74 (quat-C), 159.12 (quat-C), 167.46
64.93 (CH2), 68.61 (CH2), 108.95 (vCH), 113.11 (vCH), 116.86 (quat-C), 167.76 (quat-C); Anal. Calcd for C33H45N3O5 (563.73):
(quat-C), 118.35 (vCH), 120.02 (vCH), 120.82 (quat-C), 121.95 C, 70.31; H, 8.05; N, 7.45. Found: C, 70.19; H, 8.00; N, 7.38.
(vCH), 125.42 (vCH), 131.53 (vCH), 133.19 (vCH), 133.82
General procedure for synthesis of macrocycles 12
(quat-C), 158.45 (quat-C), 166.71 (quat-C), 166.74 (quat-C); Anal.
Calcd for C29H37N3O5 (507.62): C, 68.62; H, 7.35; N, 8.28. A solution of diazoamide 11 (150 mg, 1.0 mmol) and rhodium(II)
Found: C, 68.71; H, 7.30; N, 8.21.
acetate dimer (1.0 mol%) in dichloromethane (15 mL) was
Synthesis of diazoamide 11b. Red viscous liquid (580 mg, stirred at room temperature for 15–20 min. The progress of the
78%); IR (neat): νmax 3445, 2924, 2854, 2094, 1688, 1604, 1460, reaction was monitored by TLC. After completion of the reac-
1
1300, 1246, 1134, 1082, 751 cm−1; H NMR (400 MHz, CDCl3) tion, the reaction mixture was concentrated under reduced
δ = 1.26 (br, m, 9H), 1.35 (br, m, 9H), 1.42–1.47 (m, 4H), pressure and purified by column chromatography (SiO2,
1.55–1.58 (m, 2H), 1.66–1.83 (m, 8H), 3.63 (t, 2H, J = 6.8 Hz), hexane–ethyl acetate 75 : 25) to afford the respective macro-
3.81 (t, 1H, J = 7.6 Hz), 4.01 (t, 2H, J = 6.4 Hz), 4.28 (t, 2H, J = cycle 12.
6.4 Hz), 6.92–6.97 (m, 3H), 7.07 (t, 1H, J = 7.6 Hz), 7.16–7.21
(m, 2H), 7.42 (td, 1H, J1 = 7.6 Hz, J2 = 1.6 Hz), 7.76 (dd, 1H, J1 = mp 198–200 °C; IR (neat): νmax 2923, 2852, 1713, 1694, 1598,
8.0 Hz, J2 = 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ 25.73 (CH2), 1449, 1352, 1303, 1230, 1048, 757 cm−1 1H NMR (400 MHz,
Synthesis of macrocycle 12a. Colorless solid (99 mg, 70%);
;
26.01 (CH2), 26.89 (CH2), 28.07 (CH2), 28.76 (CH2), 29.25 CDCl3) δ = 1.13–1.32 (m, 5H), 1.33–1.38 (m, 6H), 1.52–1.62 (m,
(CH2), 29.30 (CH2), 29.35 (CH2), 29.41 (CH2), 29.50 (CH2), 6H), 1.68–1.73 (m, 3H), 3.25–3.34 (m, 2H), 3.45–3.51 (m, 1H),
29.58 (CH2), 32.78 (CH2), 40.79 (CH2), 62.97 (CH2), 64.96 3.85–3.93 (m, 2H), 4.05–4.12 (m, 1H), 4.16–4.24 (m, 2H), 4.86
(CH2), 68.90 (CH2), 108.92 (vCH), 113.11 (vCH), 116.89 (quat- (s, 1H), 6.76 (d, 1H, J = 7.6 Hz), 6.83 (d, 1H, J = 8.4 Hz), 6.87
C), 118.32 (vCH), 119.94 (vCH), 120.89 (quat-C), 121.86 (td, 1H, J1 = 7.6 Hz, J2 = 1.6 Hz), 7.01 (t, 1H, J = 7.6 Hz), 7.25 (t,
(vCH), 125.37 (vCH), 131.52 (vCH), 133.13 (vCH), 133.94 1H, J = 7.6 Hz), 7.03–7.35 (m, 2H), 7.66 (dd, 1H, J1 = 8.0 Hz,
(quat-C), 158.53 (quat-C), 166.76 (quat-C), 166.86 (quat-C); Anal. J2 = 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ 25.44 (CH2), 25.74
Calcd for C35H49N3O5 (591.78): C, 71.04; H, 8.35; N, 7.10. (CH2), 26.19 (CH2), 26.60 (CH2), 27.05 (CH2), 28.45 (CH2),
Found: C, 71.19; H, 8.40; N, 7.16.
28.86 (CH2), 29.26 (CH2), 29.31 (CH2), 29.37 (CH2), 39.32
Synthesis of diazoamide 11c. Red viscous liquid (566 mg, (CH2), 65.33 (CH2), 66.55 (CH2), 68.65 (CH2), 75.56 (CH,
80%); IR (neat): νmax 3449, 2925, 2855, 2092, 1683, 1694, 1603, observed in DEPT-90 NMR), 108.67 (vCH), 112.69 (vCH),
1460, 1300, 1245, 1135, 1080, 749 cm−1 1H NMR (400 MHz, 120.06 (vCH), 121.26 (quat-C), 122.68 (vCH), 125.01 (quat-C),
;
CDCl3) δ = 1.26–1.33 (m, 14H), 1.39–1.50 (m, 6H), 1.55–1.62 125.69 (vCH), 129.84 (vCH), 131.66 (vCH), 132.93 (vCH),
(m, 2H), 1.67–1.85 (m, 6H), 2.04 (br, s, 1H), 3.63 (t, 2H, J = 6.4 143.60 (quat-C), 157.88 (quat-C), 167.94 (quat-C), 174.40 (quat-
Hz), 3.80 (t, 2H, J = 7.6 Hz), 4.01 (t, 2H, J = 6.4 Hz), 4.29 (t, 2H, C); HRMS (ESI) Calcd for C29H37NO5 [M + H]+ 480.2750; found,
J = 7.2 Hz), 6.92–6.96 (m, 3H), 7.06 (t, 1H, J = 7.6 Hz), 7.18 (t, 480.2760.
2H, J = 7.6 Hz), 7.41 (td, 1H, J1 = 8.0 Hz, J2 = 1.6 Hz), 7.76 (dd,
Crystal data for compound 12a. (CCDC 1005105)
1H, J1 = 8.0 Hz, J2 = 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ C29H37NO5, M = 479.60, 0.1 × 0.1 × 0.09 mm, monoclinic,
25.49 (CH2), 25.88 (CH2), 26.00 (CH2), 26.86 (CH2), 28.06 space group p121/c1 with a = 8.8916(3) Å, b = 34.6623(15) Å, c =
(CH2), 28.77 (CH2), 29.23 (CH2), 29.28 (CH2), 29.39 (CH2), 8.5392(3) Å, α = 90.00, β = 96.831(2), γ = 90.00, V = 2613.13(17)
29.48 (CH2), 29.56 (CH2), 32.66 (CH2), 40.77 (CH2), 62.71 Å3, T = 296.15 K, R1 = 0.0848, wR2 = 0.2800 on observed data,
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z = 4, Dcalcd = 1.219 mg cm−3, F(000) = 1032, absorption coeffi- (CH2), 65.27 (CH2), 66.78 (CH2), 68.34 (CH2), 75.54 (CH,
cient = 0.082 mm−1, λ = 0.71073 Å, 6948 reflections were col- observed in DEPT-90 NMR), 109.12 (vCH), 111.96 (vCH),
lected on a smart apex CCD single crystal diffractometer, 4125 118.89 (vCH), 120.19 (quat-C), 121.34 (vCH), 124.12 (quat-C),
observed reflections (I ≥ 2σ(I)). The largest difference peak and 125.24 (vCH), 128.72 (vCH), 131.24 (vCH), 132.12 (vCH),
hole = 1.2580 and −0.5915 e Å−3, respectively. The structure 142.45 (quat-C), 156.67 (quat-C), 166.56 (quat-C), 175.25 (quat-
was solved by direct methods and refined by full-matrix least C); HRMS (ESI) Calcd for C33H45NO5 [M + Na]+ 558.3195;
squares on F2 using the SHELXL-97 software.
found, 558.3190.
Synthesis of macrocycle 12b. Colorless solid (111 mg, 78%);
mp 208–210 °C; IR (neat): νmax 2924, 2853, 1714, 1695, 1608,
General procedure for diazoamides 15
;
1598, 1486, 1466, 1365, 1215, 1190, 745 cm−1 1H NMR To an oven-dried flask, a solution containing 3-diazooxindole
(400 MHz, CDCl3) δ = 1.20–1.48 (m, 24H), 1.60–1.69 (m, 3H), 3 (200 mg, 1.25 mmol) and potassium carbonate (434 mg,
1.71–1.81 (m, 5H), 3.36–3.44 (m, 2H), 3.54–3.58 (m, 1H), 4.00 3.14 mmol) in dry DMF was taken under an argon atmosphere.
(t, 2H, J = 6.0 Hz), 4.09–4.13 (m, 1H), 4.29 (td, 2H, J1 = 6.8 Hz, To this reaction mixture, a solution of appropriate bromo-
J2 = 1.2 Hz), 4.91 (s, 1H), 6.83 (d, 1H, J = 8.0 Hz), 6.91–6.97 (m, amine 14 (1.35 mmol) in dry DMF was slowly added over a
2H), 7.08 (t, 1H, J = 7.6 Hz), 7.32 (t, 1H, J = 8.0 Hz), 7.38–7.43 period of 30 min and then a catalytic amount of tetrabutyl-
(m, 2H), 7.75 (dd, 1H, J1 = 7.6 Hz, J2 = 1.6 Hz); 13C NMR ammonium iodide was added. The progress of the reaction
(100 MHz, CDCl3) δ 25.85 (CH2), 25.98 (CH2), 26.38 (CH2), was monitored by TLC. The mixture was extracted with dichloro-
26.55 (CH2), 27.01 (CH2), 28.84 (CH2), 29.22 (CH2), 29.31 methane (3 × 25 mL) and the combined organic layers were
(CH2), 29.37 (CH2), 29.54 (CH2), 29.60 (CH2), 29.62 (CH2), washed with water (3 × 25 mL), brine (2 × 25 mL) and dried
29.83 (CH2), 29.84 (CH2), 29.88 (CH2), 39.43 (CH2), 65.16 (anhydrous Na2SO4). The solvent was removed under reduced
(CH2), 67.32 (CH2), 68.77 (CH2), 75.66 (CH, observed in pressure and the resulting residue was purified by column
DEPT-90 NMR), 108.83 (vCH), 112.83 (vCH), 119.97 (vCH), chromatography (SiO2, hexane–ethyl acetate 85 : 15) to afford
121.11 (quat-C), 122.64 (vCH), 125.05 (quat-C), 125.55 (vCH), the respective diazoamides 15.
129.81 (vCH), 131.64 (vCH), 133.02 (vCH), 143.76 (quat-C),
158.14 (quat-C), 167.77 (quat-C), 174.38 (quat-C); HRMS (ESI) 78%); IR (neat): νmax 3396, 2929, 2845, 2091, 1731, 1678, 1469,
Calcd for C35H49NO5 [M + H]+ 564.3689; found, 564.3681. 1352, 1242, 729 cm−1; 1H NMR (400 MHz, CDCl3) δ = 1.24–1.28
Synthesis of diazoamide 15a. Red viscous liquid (473 mg,
Synthesis of macrocycle 12c. Colorless solid (103 mg, 72%); (m, 7H), 1.32–1.39 (m, 2H), 1.58–1.65 (m, 3H), 1.67–1.74 (m,
mp 201–203 °C; IR (neat): νmax 2922, 2856, 1714, 1665, 1565, 2H), 3.73 (t, 2H, J = 7.6 Hz), 3.91 (t, 2H, J = 6.4 Hz), 4.26 (s,
1
1456, 1336, 1263, 1081, 751 cm−1; H NMR (400 MHz, CDCl3) 2H), 6.60–6.65 (m, 3H), 6.79 (t, 2H, J = 7.8 Hz), 6.82–6.86 (m,
δ = 1.29–1.20 (m, 11H), 1.32–1.39 (m, 7H), 1.55–1.70 (m, 10H), 1H), 7.00 (td, 1H, J1 = 7.8 Hz, J2 = 0.8 Hz), 7.06–7.16 (m, 5H),
3.28–3.36 (m, 2H), 3.38–3.42 (m, 1H), 3.92 (t, 2H, J = 6 Hz), 7.23 (dd, 1H, J1 = 7.6 Hz, J2 = 1.6 Hz); 13C NMR (100 MHz,
4.04–4.11 (m, 1H), 4.18–4.22 (m, 2H), 4.88 (s, 1H), 6.76 (d, 1H, CDCl3) δ 26.15 (CH2), 26.85 (CH2), 28.05 (CH2), 29.21 (CH2),
J = 8.0 Hz), 6.83–6.89 (m, 2H), 7.01 (t, 1H, J = 7.6 Hz), 7.25 (t, 29.27 (CH2), 29.40 (CH2), 40.75 (CH2), 44.06 (CH2), 67.90
1H, J = 7.6 Hz), 7.31–7.35 (m, 2H), 7.67 (dd, 1H, J1 = 7.6 Hz, (CH2), 108.90 (vCH), 111.09 (vCH), 113.63 (vCH), 116.88
J2 = 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 24.42 (CH2), 25.24 (quat-C), 117.91 (vCH), 118.32 (vCH), 120.33 (vCH), 121.85
(CH2), 25.48 (CH2), 26.10 (CH2), 26.48 (CH2), 26.78 (CH2), (vCH), 125.37 (vCH), 126.96 (quat-C), 128.36 (vCH), 129.07
27.10 (CH2), 27.68 (CH2), 27.97 (CH2), 28.25 (CH2), 28.75 (vCH), 129.16 (vCH), 133.93 (quat-C), 156.92 (quat-C), 166.73
(CH2), 29.36 (CH2), 29.48 (CH2), 29.78 (CH2), 39.43 (CH2), (quat-C); HRMS (ESI) Calcd for C30H34N4O2 [M
65.15 (CH2), 66.45 (CH2), 68.66 (CH2), 75.51 (CH, observed in 505.2579; found, 505.2586.
+
Na]+
DEPT-90 NMR), 108.62 (vCH), 112.49 (vCH), 120.16 (vCH),
Synthesis of diazoamide 15b. Red viscous liquid (468 mg,
121.46 (quat-C), 122.38 (vCH), 125.11 (quat-C), 125.73 (vCH), 75%); IR (neat): νmax 3393, 2926, 2854, 2094, 1720, 1603, 1461,
129.80 (vCH), 131.46 (vCH), 132.18 (vCH), 143.30 (quat-C), 1358, 1240, 750 cm−1; 1H NMR (400 MHz, CDCl3) δ = 1.18–1.36
157.18 (quat-C), 167.14 (quat-C), 174.20 (quat-C); HRMS (ESI) (m, 12H), 1.58–1.71 (m, 4H), 3.74 (t, 2H, J = 7.6 Hz), 3.85 (t,
Calcd for C33H45NO5 [M + H]+ 536.3376; found, 536.3384.
2H, J = 6.8 Hz), 4.22 (s, 2H), 6.61 (d, 2H, J = 8.0 Hz), 6.66–6.73
Synthesis of macrocycle 12d. Colorless solid (97 mg, 68%); (m, 2H), 6.86 (d, 3H, J = 7.6 Hz), 7.00 (t, 1H, J = 7.6 Hz),
mp 212–214 °C; IR (neat): νmax 2956, 2845, 1709, 1682, 1612, 7.08–7.18 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 26.30 (CH2),
1592, 1483, 1478, 1334, 1210, 1171, 752 cm−1 1H NMR 26.75 (CH2), 28.15 (CH2), 28.33 (CH2), 29.14 (CH2), 29.64
;
(400 MHz, CDCl3) δ = 1.23–1.41 (m, 20H), 1.48–1.61 (m, 4H), (CH2), 29.89 (CH2), 40.24 (CH2), 44.16 (CH2), 66.98 (CH2),
1.67–1.78 (m, 4H), 3.56–3.68 (m, 2H), 3.72–3.81 (m, 1H), 3.92 108.96 (vCH), 111.43 (vCH), 113.80 (vCH), 116.15 (quat-C),
(t, 2H, J = 7.2 Hz), 4.02–4.13 (m, 1H), 4.20 (t, 2H, J = 7.6 Hz), 117.89 (vCH), 118.10 (vCH), 120.67 (vCH), 121.15 (vCH),
4.87 (s, 1H), 6.76 (d, 1H, J = 7.6 Hz), 6.82–6.91 (m, 2H), 7.10 (t, 125.77 (vCH), 126.46 (quat-C), 128.16 (vCH), 128.87 (vCH),
1H, J = 7.2 Hz), 7.31 (t, 1H, J = 7.2 Hz), 7.36–7.42 (m, 2H), 7.61 129.26 (vCH), 133.43 (quat-C), 156.12 (quat-C), 166.43 (quat-
(d, 1H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 25.63 (CH2), C); Anal. Calcd for C31H36N4O2 (496.64): C, 74.97; H, 7.31; N,
25.76 (CH2), 26.18 (CH2), 26.35 (CH2), 26.89 (CH2), 28.56 11.28. Found: C, 74.86; H, 7.29; N, 11.23.
(CH2), 28.92 (CH2), 29.12 (CH2), 29.23 (CH2), 29.52 (CH2),
Synthesis of diazoamide 15c. Red viscous liquid (455 mg,
29.68 (CH2), 29.82 (CH2), 29.88 (CH2), 29.90 (CH2), 38.29 73%); IR (neat): νmax 3392, 2927, 2855, 2093, 1722, 1681, 1461,
9252 | Org. Biomol. Chem., 2014, 12, 9243–9256
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1356, 1238, 726 cm−1; 1H NMR (400 MHz, CDCl3) δ = 1.21–1.27 (vCH), 129.18 (vCH), 143.59 (quat-C), 148.75 (quat-C), 155.98
(m, 10H), 1.34–1.37 (m, 2H), 1.58–1.63 (m, 2H), 1.68–1.73 (m, (quat-C), 174.67 (quat-C); HRMS (ESI) Calcd for C31H36N2O2 [M
2H), 3.73 (t, 2H, J = 7.2 Hz), 3.91 (t, 2H, J = 6.4 Hz), 4.27 (s, + H]+ 469.2855; found, 469.2858.
2H), 6.63–6.67 (m, 3H), 6.79 (t, 2H, J = 8.0 Hz), 6.83–6.87 (m,
1H), 6.98–7.02 (m, 1H), 7.07–7.16 (m, 5H), 7.24 (d, 1H, J = 7.2 mp 203–205 °C; IR (neat): νmax 2928, 2853, 1720, 1608, 1503,
Hz); 13C NMR (100 MHz, CDCl3) δ 26.34 (CH2), 26.85 (CH2), 1462, 1344, 1230, 746 cm−1 1H NMR (400 MHz, CDCl3) δ =
Synthesis of macrocycle 16c. Colorless solid (90 mg, 64%);
;
28.10 (CH2), 28.12 (CH2), 28.67 (CH2), 29.12 (CH2), 29.96 1.62–1.69 (m, 8H), 1.73–1.81 (m, 4H), 1.99–2.05 (m, 4H), 3.76
(CH2), 40.14 (CH2), 44.56 (CH2), 66.78 (CH2), 108.66 (vCH), (d, 1H, J = 17.6 Hz), 3.82–3.89 (m, 2H), 4.12–4.23 (m, 2H), 4.42
111.23 (vCH), 113.64 (vCH), 116.80 (quat-C), 117.45 (vCH), (d, 1H, J = 17.6 Hz), 5.58 (s, 1H), 6.67–6.78 (m, 2H), 6.81–6.89
118.73 (vCH), 120.43 (vCH), 124.76 (vCH), 126.26 (quat-C), (m, 4H), 6.92 (d, 1H, J = 7.2 Hz), 7.02–7.12 (m, 2H), 7.31 (t, 2H,
128.86 (vCH), 129.17 (vCH), 129.56 (vCH), 133.23 (quat-C), J = 7.6 Hz), 7.36 (t, 1H, J = 7.6 Hz), 7.42 (d, 1H, J = 7.2 Hz); 13C
156.42 (quat-C), 166.73 (quat-C); Anal. Calcd for C31H36N4O2 NMR (100 MHz, CDCl3) δ 25.92 (CH2), 26.08 (CH2), 26.12
(496.64): C, 74.97; H, 7.31; N, 11.28. Found: C, 75.10; H, 7.35; (CH2), 26.36 (CH2), 26.78 (CH2), 26.90 (CH2), 27.16 (CH2),
N, 11.32.
28.89 (CH2), 39.92 (CH2), 40.61 (CH2), 62.86 (CH, observed in
DEPT-90 NMR), 67.12 (CH2), 109.34 (vCH), 110.12 (vCH),
113.65 (vCH), 116.75 (vCH), 121.46 (vCH), 124.64 (vCH),
General procedure for macrocycles 16
A solution of diazoamide 15 (150 mg, 1.0 mmol) and rhodium(II) 125.17 (quat-C), 126.31 (quat-C), 127.40 (vCH), 128.02 (vCH),
acetate dimer (1.0 mol%) in dichloromethane (15 mL) was 129.10 (vCH), 129.28 (vCH), 144.67 (quat-C), 149.64 (quat-C),
stirred at room temperature for 15–20 min. The progress of the 156.12 (quat-C), 176.23 (quat-C); HRMS (ESI) Calcd for
reaction was monitored by TLC. After completing the reaction, C31H36N2O2 [M + Na]+ 491.2674; found, 491.2668.
the reaction mixture was concentrated under reduced pressure
General procedure for diazoamides 18
and purified by column chromatography (SiO2, hexane–ethyl
acetate 75 : 25) to afford the respective macrocycle 16.
To an oven-dried flask, a solution containing 3-diazooxindole
Synthesis of macrocycle 16a. Colorless solid (96 mg, 68%); 3 (200 mg, 1.25 mmol) and potassium carbonate (434 mg,
mp 215–217 °C; IR (neat): νmax 2923, 2851, 1715, 1598, 1504, 3.14 mmol) in dry DMF was taken under an argon atmosphere.
1487, 1463, 1346, 1227, 1152, 751 cm−1 1H NMR (400 MHz, To this reaction mixture, a solution of appropriate bromoalco-
;
CDCl3) δ = 1.18–1.35 (m, 10H), 1.59–1.71 (m, 4H), 3.38 (d, 1H, hol 17 (1.35 mmol) in dry DMF was slowly added over a period
J = 13.6 Hz), 3.65 (d, 1H, J = 16.8 Hz), 3.77–3.83 (m, 1H), of 30 min and then a catalytic amount of tetrabutylammonium
3.97–4.07 (m, 2H), 4.67 (d, 1H, J = 17.2 Hz), 5.53 (s, 1H), iodide was added. The progress of the reaction was monitored
6.66–6.71 (m, 2H), 6.74–6.78 (m, 2H), 6.84 (d, 2H, J = 8.4 Hz), by TLC. The mixture was extracted with dichloromethane (3 ×
6.91 (t, 1H, J = 7.6 Hz), 7.03–7.12 (m, 3H), 7.18 (t, 1H, J = 8.4 25 mL) and the combined organic layers were washed with
Hz), 7.36 (d, 2H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ water (3 × 25 mL), brine (2 × 25 mL) and dried (anhydrous
24.79 (CH2), 26.545 (CH2), 26.548 (CH2), 26.99 (CH2), 27.52 Na2SO4). The solvent was removed under reduced pressure and
(CH2), 27.88 (CH2), 27.95 (CH2), 38.66 (CH2), 45.50 (CH2), the resulting residue was purified by column chromatography
62.05 (CH, observed in DEPT-90 NMR), 67.23 (CH2), 107.80 (SiO2, hexane–ethyl acetate 85 : 15) to afford diazoamides 18.
(vCH), 109.14 (vCH), 114.25 (vCH), 117.52 (vCH), 119.02
(vCH), 121.49 (vCH), 124.12 (quat-C), 125.05 (vCH), 125.34 75%); IR (neat): νmax 3420, 2921, 2851, 2093, 1653, 1612, 1454,
(vCH), 126.40 (vCH), 126.86 (quat-C), 127.99 (vCH), 128.12 1390, 1165, 1070, 738 cm−1 1H NMR (400 MHz, CDCl3) δ =
Synthesis of diazoamide 18a. Red viscous liquid (205 mg,
;
(vCH), 142.31 (quat-C), 147.94 (quat-C), 154.87 (quat-C), 1.86–1.92 (m, 2H), 3.33 (s, 1H), 3.58 (s, 2H), 4.01 (t, 2H, J = 6.4
173.38 (quat-C); HRMS (ESI) Calcd for C30H34N2O2 [M + H]+ Hz), 6.99 (d, 1H, J = 8 Hz), 7.11 (td, 1H, J1 = 7.6 Hz, J2 = 0.8
455.2699; found, 455.2707.
Hz), 7.19–7.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 30.36
Synthesis of macrocycle 16b. Colorless solid (102 mg, 72%); (CH2), 36.82 (CH2), 58.29 (CH2), 108.95 (vCH), 116.94 (quat-
mp 216–218 °C; IR (neat): νmax 2923, 2854, 1714, 1609, 1597, C), 118.44 (vCH), 122.35 (vCH), 125.63 (vCH), 133.40 (quat-
1503, 1487, 1465, 1277, 1222, 1047, 742 cm−1 1H NMR C), 167.84 (quat-C); Anal. Calcd for C11H11N3O2 (217.22): C,
;
(400 MHz, CDCl3) δ = 1.28–1.41 (m, 12H), 1.69–1.74 (m, 4H), 60.82; H, 5.10; N, 19.34. Found: C, 60.98; H, 5.15; N, 19.39.
3.41–3.47 (m, 1H), 3.85 (d, 1H, J = 17.6 Hz, CH2), 3.90–4.01 (m, Synthesis of diazoamide 18b. Red viscous liquid (212 mg,
2H), 4.09–4.16 (m, 1H), 4.60 (d, 1H, J = 17.6 Hz), 5.67 (s, 1H), 73%); IR (neat): νmax 3425, 2929, 2858, 2091, 1659, 1610, 1462,
6.78–6.81 (m, 2H), 6.87–6.94 (m, 4H), 6.98 (t, 1H, J = 7.6 Hz), 1395, 1187, 1089, 745 cm−1 1H NMR (400 MHz, CDCl3) δ =
;
7.14–7.22 (m, 3H), 7.29 (t, 1H, J = 8.4 Hz), 7.40 (d, 1H, J = 7.2 1.76–1.84 (m, 2H), 1.88–1.95 (m, 2H), 3.65 (s, 1H), 3.72 (s, 2H),
Hz), 7.50 (d, 1H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 3.98 (t, 2H, J = 7.2 Hz), 6.78 (d, 1H, J = 7.6 Hz), 7.17 (td, 1H,
24.73 (CH2), 26.02 (CH2), 26.14 (CH2), 26.43 (CH2), 26.64 J1 = 7.2 Hz, J2 = 1.2 Hz), 7.23–7.28 (m, 2H); 13C NMR (100 MHz,
(CH2), 26.93 (CH2), 27.11 (CH2), 28.55 (CH2), 39.80 (CH2), CDCl3) δ 27.46 (CH2), 30.28 (CH2), 36.43 (CH2), 58.02 (CH2),
46.60 (CH2), 62.44 (CH, observed in DEPT-90 NMR), 67.39 108.19 (vCH), 116.46 (quat-C), 118.38 (vCH), 122.24 (vCH),
(CH2), 108.77 (vCH), 110.29 (vCH), 115.24 (vCH), 118.50 125.81 (vCH), 133.29 (quat-C), 167.89 (quat-C); Anal. Calcd for
(vCH), 120.12 (vCH), 122.51 (vCH), 125.11 (vCH), 125.88 C12H13N3O2 (231.25): C, 62.33; H, 5.67; N, 18.17. Found: C,
(quat-C), 126.32 (quat-C), 127.42 (vCH), 128.08 (vCH), 129.01 62.39; H, 5.64; N, 18.20.
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Synthesis of diazoamide 18c. Red viscous liquid (189 mg, General procedure for macrocycles 19
65%); IR (neat): νmax 3422, 2924, 2857, 2094, 1665, 1608, 1464,
A solution of diazoamide 18 (100 mg, 1.0 mmol) and a rhodium(II)
acetate dimer (1.0 mol%) in dichloromethane (15 mL) was
stirred at room temperature for 15–20 min. The progress of the
reaction was monitored by TLC. After completion of the reac-
tion, the reaction mixture was concentrated under reduced
pressure and purified by column chromatography (SiO2,
hexane–ethyl acetate 75 : 25) to afford the macrocycles 19.
Synthesis of macrocycle 19a. Colorless solid (45 mg, 52%);
mp 211–213 °C; IR (neat): νmax 2932, 2856, 1721, 1609, 1513,
1
1398, 1184, 1040, 747 cm−1; [α]26 δ = −12.20 (c 0.1, MeOH); H
NMR (400 MHz, CDCl3) δ = 1.04 (d, 3H, J = 7.2 Hz), 1.23–1.33
(m, 1H), 2.06 (br, s, 1H), 3.38 (dd, 1H, J1 = 11.6 Hz, J2 = 5.2
Hz), 3.51 (dd, 1H, J1 = 11.6 Hz, J2 = 5.2 Hz), 3.73 (dd, 1H, J1 =
14.4 Hz, J2 = 5.2 Hz), 3.93 (dd, 1H, J1 = 14.4 Hz, J2 = 8.4 Hz),
7.00 (d, 1H, J = 7.6 Hz), 7.11 (t, 1H, J = 7.6 Hz), 7.19–7.26 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 14.98 (CH3), 35.08 (CH),
42.83 (CH2), 63.62 (CH2), 109.31 (vCH), 116.85 (quat-C),
118.35 (vCH), 122.36 (vCH), 125.60 (vCH), 134.00 (quat-C),
168.11 (quat-C); Anal. Calcd for C12H13N3O2 (231.25): C, 62.33;
H, 5.67; N, 18.17. Found: C, 62.25; H, 5.72; N, 18.11.
1478, 1340, 1234, 754 cm−1 1H NMR (400 MHz, CDCl3) δ =
;
1.98–2.02 (m, 1H), 2.11–2.20 (m, 1H), 2.69–2.75 (m, 1H), 3.36
(dt, 1H, J1 = 14.8 Hz, J2 = 3.2 Hz), 3.46–3.50 (m, 1H), 3.93–4.01
(m, 1H), 4.93 (s, 1H), 6.84 (d, 1H, J = 8 Hz), 7.12 (td, 1H, J1 =
7.6 Hz, J2 = 0.4 Hz), 7.36 (t, 1H, J = 7.6 Hz), 7.40 (d, 1H, J = 7.2
Hz); 13C NMR (100 MHz, CDCl3) δ 27.75 (CH2), 35.76 (CH2),
64.46 (CH2), 76.08 (CH), 109.07 (vCH), 123.29 (vCH), 123.90
(quat-C), 125.83 (vCH), 130.45 (vCH), 142.80 (quat-C), 174.49
(quat-C); HRMS (ESI) Calcd for C22H22N2O4 [M + H]+ 379.1658;
found, 379.1664.
Synthesis of diazoamide 18d. Red viscous liquid (201 mg,
68%); IR (neat): νmax 3424, 2943, 2845, 2098, 1650, 1613, 1459,
1389, 1174, 1075, 731 cm−1 1H NMR (400 MHz, CDCl3) δ =
;
1.74–1.87 (m, 2H), 3.67 (br, s, 1H), 3.89 (s, 2H), 4.13 (t, 2H, J =
7.0 Hz), 6.78 (d, 1H, J = 8 Hz), 7.11–7.18 (m, 1H), 7.24–7.29 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 28.96 (CH2), 37.82 (CH2),
56.29 (CH2), 107.45 (vCH), 117.78 (quat-C), 118.89 (quat-C),
121.45 (vCH), 126.78 (vCH), 134.78 (quat-C), 168.90 (quat-C);
Anal. Calcd for C11H10ClN3O2 (251.67): C, 52.50; H, 4.01; N,
16.70. Found: C, 52.67; H, 4.07; N, 16.64.
Crystal data for compound 19a. (CCDC 1005106)
C22H22N2O4, M = 378.42, 0.09 × 0.08 × 0.04 mm, triclinic, space
ˉ
group p1 with a = 7.9479(2) Å, b = 9.0065(2) Å, c = 14.4450(3) Å,
α = 75.800(10), β = 77.803(10), γ = 72.644(10), V = 946.06(4) Å3,
T = 296(2) K, R1 = 0.0528, wR2 = 0.1785 on observed data, z = 2,
Dcalcd = 1.328 mg cm−3, F(000) = 400, absorption coefficient =
0.092 mm−1, λ = 0.71073 Å, 5847 reflections were collected on
a smart apex CCD single crystal diffractometer, 3812 observed
reflections (I ≥ 2σ(I)). The largest difference peak and hole =
0.258 and −0.214 e Å−3, respectively. The structure was solved
by direct methods and refined by full-matrix least squares on
F2 using the SHELXL-97 software.
Synthesis of diazoamide 18e. Red viscous liquid (180 mg,
60%); IR (neat): νmax 3424, 2920, 2850, 2089, 1661, 1603, 1465,
1
1389, 1134, 1024, 735 cm−1; [α]26 δ = −16.34 (c 0.1, MeOH); H
NMR (400 MHz, CDCl3) δ = 1.15 (d, 3H, J = 7.6 Hz), 1.27–1.35 (m,
1H), 2.12 (br, s, 1H), 3.48 (dd, 1H, J1 = 11.6 Hz, J2 = 5.2 Hz), 3.57
(dd, 1H, J1 = 11.6 Hz, J2 = 5.2 Hz), 3.86 (dd, 1H, J1 = 14.6 Hz, J2 =
5.2 Hz), 3.98 (dd, 1H, J1 = 14.6 Hz, J2 = 8.4 Hz), 7.14 (d, 1H, J = 8.0
Hz), 7.31–7.37 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.97 (CH3),
35.34 (CH), 42.67 (CH2), 63.67 (CH2), 108.23 (vCH), 117.89 (quat-
C), 117.34 (vCH), 124.67 (vCH), 126.30 (vCH), 133.23 (quat-C),
169.23 (quat-C); Anal. Calcd for C12H12ClN3O2 (265.70): C, 54.25;
H, 4.55; N, 15.82. Found: C, 54.31; H, 4.52; N, 15.79.
Synthesis of macrocycle 19b. Colorless solid (44 mg, 50%);
mp 198–200 °C; IR (neat): νmax 2929, 2852, 1725, 1613, 1510,
1468, 1331, 1230, 764 cm−1 1H NMR (400 MHz, CDCl3) δ =
;
Synthesis of diazoamide 18f. Red viscous liquid (199 mg,
78%); IR (neat): νmax 3421, 2924, 2854, 2090, 1657, 1608, 1466,
1.67–1.77 (m, 1H), 1.79–1.85 (m, 1H), 1.89–2.07 (m, 1H),
2.19–2.32 (m, 1H), 2.81–2.92 (m, 1H), 3.42–3.49 (m 1H),
3.68–3.75 (m, 1H), 3.98–4.12 (m, 1H), 5.03 (s, 1H), 6.78 (d, 1H,
J = 7.2 Hz), 7.35 (t, 1H, J = 7.2 Hz), 7.42 (t, 1H, J = 8.0 Hz), 7.47
(d, 1H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 27.25 (CH2),
27.86 (CH2), 35.24 (CH2), 64.37 (CH2), 76.12 (CH), 109.23
(vCH), 123.32 (vCH), 123.98 (quat-C), 125.87 (vCH), 130.41
(vCH), 142.86 (quat-C), 174.67 (quat-C); HRMS (ESI) Calcd for
C24H26N2O4 [M + H]+ 407.1971; found, 407.1967.
1398, 1177, 1078, 733 cm−1 1H NMR (400 MHz, CDCl3) δ =
;
2.84 (s, 1H), 3.91 (t, 2H, J = 5.2 Hz), 3.98 (t, 2H, J = 5.2 Hz),
7.03 (d, 1H, J = 7.6 Hz), 7.09 (t, 1H, J = 7.2 Hz), 7.17–7.21 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 43.80 (CH2), 60.99 (CH2),
109.20 (vCH), 116.78 (quat-C), 118.31 (vCH), 122.27 (vCH),
125.56 (vCH), 133.98 (quat-C), 167.77 (quat-C); Anal. Calcd for
C10H9N3O2 (203.20): C, 59.11; H, 4.46; N, 20.68. Found: C,
59.27; H, 4.52; N, 20.73.
Synthesis of macrocycle 19c. Colorless solid (39 mg, 45%);
mp 210–212 °C; IR (neat): νmax 2921, 2847, 1729, 1617, 1515,
Synthesis of diazoamide 18g. Red viscous liquid (265 mg,
70%); IR (neat): νmax 3456, 2989, 2856, 2095, 1634, 1615, 1423,
1
1460, 1325, 1256, 753 cm−1; [α]31 δ = 46.36 (c 0.05, MeOH); H
1390, 1134, 1078, 740 cm−1 1H NMR (400 MHz, CDCl3) δ =
;
NMR (400 MHz, CDCl3) δ = 1.07 (d, 3H, J = 6.8 Hz), 2.22–2.31
(m, 1H), 3.10 (dd, 1H, J1 = 14.4 Hz, J2 = 4.0 Hz), 3.43–3.47 (m,
1H), 3.84–3.98 (m, 2H), 4.53 (s, 1H), 6.44 (d, 1H, J = 7.6 Hz),
6.80 (t, 1H, J = 7.2 Hz), 6.91 (d, 1H, J = 7.2 Hz), 7.07 (t, 1H, J = 8
Hz); 13C NMR (100 MHz, CDCl3) δ 15.24 (CH3), 31.73 (CH),
43.65 (CH2), 73.33 (CH2), 75.95 (CH), 108.62 (vCH), 121.94
1.62–1.87 (m, 2H), 1.89–1.97 (m, 4H), 3.65–3.75 (m, 2H), 3.79
(br, s, 2H), 3.96 (t, 2H, J = 7.2 Hz), 6.74 (d, 1H, J = 7.6 Hz), 7.45
(td, 1H, J1 = 7.2 Hz, J2 = 1.2 Hz), 7.55–7.67 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 26.46 (CH2), 26.67 (CH2), 30.20 (CH2),
36.34 (CH2), 38.78 (CH2), 58.78 (CH2), 108.34 (vCH), 116.67
(quat-C), 117.45 (vCH), 121.67 (vCH), 124.23 (vCH), 132.45 (vCH), 124.85 (vCH), 125.29 (quat-C), 129.25 (vCH), 143.40
(quat-C), 168.81 (quat-C); Anal. Calcd for C14H17N3O2 (259.30): (quat-C), 174.43 (quat-C); HRMS (ESI) Calcd for C24H26N2O4 [M
+ H]+ 407.1971; found, 407.1976.
C, 64.85; H, 6.61; N, 16.20. Found: C, 64.71; H, 6.54; N, 16.13.
9254 | Org. Biomol. Chem., 2014, 12, 9243–9256
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Paper
Synthesis of macrocycle 19d. Colorless solid (39 mg, 44%);
mp 211–213 °C; IR (neat): νmax 2932, 2856, 1721, 1609, 1513,
Acknowledgements
1478, 1340, 1234, 754 cm−1 1H NMR (400 MHz, CDCl3) δ = This research was supported by the Department of Science
;
1.86–1.91 (m, 1H), 2.17–2.23 (m, 1H), 3.27–3.32 (m, 1H), and Technology (DST), India. T. K. thanks the Council of
3.65–3.69 (m, 1H), 4.24–4.35 (m, 2H), 4.37 (s, 1H), 6.55 (d, 1H, Scientific and Industrial Research, India for a research fellow-
J = 8.4 Hz), 6.82 (d, 1H, J = 1.2 Hz), 7.17 (dd, 1H, J1 = 8.0 Hz, ship. We thank the DST, India for providing 400 MHz NMR
J2 = 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 26.89 (CH2), 37.65 and X-ray facilities under the FIST program.
(CH2), 68.55 (CH2), 75.43 (CH), 109.73 (vCH), 125.19 (vCH),
126.87 (quat-C), 127.44 (quat-C), 128.97 (vCH), 142.09 (quat-
C), 174.78 (CvO); HRMS (ESI) Calcd for C22H20Cl2N2O4
References
[M + H]+ 447.0878; found, 447.0890.
Synthesis of macrocycle 19e. Colorless solid (36 mg, 40%);
mp 220–222 °C; IR (neat): νmax 2931, 2887, 1745, 1667, 1556,
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1
1423, 1390, 1222, 750 cm−1; [α]31 δ = 42.56 (c 0.05, MeOH); H
NMR (400 MHz, CDCl3) δ = 1.06 (d, 3H, J = 6.8 Hz), 2.29–2.37
(m, 1H), 3.17 (dd, 1H, J1 = 14.4 Hz, J2 = 4.0 Hz), 3.42–3.46 (m,
1H), 3.98–4.04 (m, 2H), 4.41 (s, 1H), 6.51 (d, 1H, J = 8.4 Hz),
6.81 (s, 1H), 7.17 (d, 1H, J = 2.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 15.46 (CH3), 32.98 (CH), 44.23 (CH2), 72.67 (CH2),
75.34 (CH), 107.34 (vCH), 122.45 (quat-C), 123.35 (vCH),
126.09 (quat-C), 130.85 (vCH), 142.67 (quat-C), 173.83 (quat-
C); HRMS (ESI) Calcd for C24H24Cl2N2O4 [M + H]+ 475.1191;
found, 475.1176.
Synthesis of macrocycle 20g. Colorless liquid (3.5 mg, 4%);
IR (neat): νmax 2931, 2799, 1721, 1512, 1480, 1310, 1223,
709 cm−1 1H NMR (400 MHz, CDCl3) δ = 1.41–1.73 (m, 6H),
;
3.28–3.38 (m, 4H), 3.40–3.53 (m, 2H), 4.92 (s, 1H), 6.83 (d, 1H,
J = 7.6 Hz), 7.08 (t, 1H, J = 7.6 Hz), 7.06–7.34 (m, 1H), 7.40 (d,
1H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 26.12 (CH2),
27.43 (CH2), 28.16 (CH2), 28.78 (CH2), 33.61 (CH2), 64.12
(CH2), 76.12 (CH), 105.12 (vCH), 122.13 (vCH), 124.56 (quat-
C), 126.07 (vCH), 132.34 (vCH), 142.23 (quat-C), 172.98 (quat-
C); HRMS (ESI) Calcd for C14H17NO2 [M + H]+ 232.1338; found,
232.1329.
Synthesis of macrocycle 21a. Colorless solid (17 mg, 20%);
mp 230–232 °C; IR (neat): νmax 2944, 2860, 1726, 1619, 1545,
1487, 1311, 1230, 748 cm−1 1H NMR (400 MHz, CDCl3) δ =
;
1.54–1.65 (m, 8H), 3.29–3.43 (m, 3H), 3.99–4.06 (m, 1H), 4.88
(s, 1H), 6.81 (d, 1H, J = 7.8 Hz), 7.07 (t, 1H, J = 7.4 Hz),
7.29–7.35 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 26.89 (CH2),
27.34 (CH2), 28.06 (CH2), 29.86 (CH2), 35.67 (CH2), 63.75
(CH2), 77.43 (CH), 108.67 (vCH), 123.78 (vCH), 123.81 (quat-
C), 126.47 (vCH), 133.11 (vCH), 143.56 (quat-C), 173.67 (quat-
C); HRMS (ESI) Calcd for C28H34N2O4 [M + H]+ 463.2597;
found, 463.2578.
Synthesis of macrocycle 21b. Colorless liquid (10 mg, 11%);
IR (neat): νmax 2932, 2862, 1725, 1610, 1543, 1486, 1343, 1256,
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740 cm−1
;
1H NMR (400 MHz, CDCl3) δ = 1.31–1.38 (m, 2H),
1.52–1.67 (m, 6H), 3.32–3.41 (m, 3H), 4.01–4.08 (m, 1H), 4.89
(s, 1H), 6.74 (d, 1H, J = 7.8 Hz), 6.98 (t, 1H, J = 7.4 Hz), 7.21 (t,
1H, J = 7.6 Hz), 7.31 (d, 1H, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 26.87 (CH2), 27.36 (CH2), 28.11 (CH2), 29.98 (CH2),
35.69 (CH2), 63.78 (CH2), 77.46 (CH), 108.70 (vCH), 123.82
(vCH), 123.86 (quat-C), 126.51 (vCH), 133.13 (vCH), 143.57
(quat-C), 173.75 (quat-C); HRMS (ESI) Calcd for C28H34N2O4
[M + H]+ 463.2597; found, 463.2586.
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9256 | Org. Biomol. Chem., 2014, 12, 9243–9256
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