Parallel synthesis of an indole-based library via an iterative Mannich reaction sequence

Article abstract of DOI:10.1016/j.tet.2006.01.047

A library of 1,3-disubstituted indoles has been prepared via an iterative Mannich reaction sequence. The first Mannich reaction with secondary amines and formaldehyde preferentially yields 3-aminomethyl indoles, while the second Mannich reaction introduce

Full text of DOI:10.1016/j.tet.2006.01.047

Tetrahedron 62 (2006) 3439–3445
Parallel synthesis of an indole-based library via an iterative
Mannich reaction sequence
a,
Charlotta Lindquist,a,b Oguz Ersoyb, and Peter Somfai
*
*
aOrganic Chemistry, Department of Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden
bAmersham Biosciences, S-751 84 Uppsala, Sweden
Received 12 January 2005; revised 12 December 2005; accepted 12 January 2006
Available online 8 February 2006
Abstract—A library of 1,3-disubstituted indoles has been prepared via an iterative Mannich reaction sequence. The first Mannich reaction
with secondary amines and formaldehyde preferentially yields 3-aminomethyl indoles, while the second Mannich reaction introduces an
additional aminomethyl group at the N1-position of the indole ring. A library of 25 substituted indoles has thus been prepared in moderate to
good yields with purity.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
reaction proceeded efficiently, we were surprised to observe
a bis-Mannich product when extended reaction times and
excess reagents were applied. More surprisingly, this bis-
Mannich product was quite stable under conditions typical
to affinity chromatography. A review of the literature
revealed only two accounts where similar bis-Mannich
products had been observed, in both occasions as
byproducts.6 However, there were no accounts of the use
on this dual reactivity to build compounds employing two
different Mannich reactions.
Affinity chromatography is a powerful technique where a
ligand with specific affinity for a biological substance,
usually a protein, is used for the purification of this
substance.1 Combinatorial synthesis2 presents itself as a
useful tool for the development of new affinity ligands. One
such recent campaign has focused on the use of 1,3-
substituted indoles as affinity chromatography ligands.
Indoles and related heterocyclic structures are found in
numerous natural products with interesting biological
activities, and several combinatorial synthesis studies have
used the indole heterocycle as a core-function.3 The N1- and
C3-positions of the indole nucleus are relatively electron-
rich and react with various types of electrophiles.4 In the
present study, the aim was to introduce functionality in the
N1- and C3-positions while leaving the C2-position
unsubstituted. For the N1-position, alkylation with an
alkyl halide is a plausible option, but controlling the
regioselectivity in such reaction can be difficult.5 For
derivatization at the C3-position, a Mannich-type addition
was chosen as the lone pair of the resultant amine moiety
was expected to participate in the binding interactions of the
projected affinity ligands. Due to the known difficulty of
selective alkylation at the N1-position, the Mannich
reaction at the C3-position with a secondary amine and
formaldehyde was chosen as the first step. Although this
Intrigued by this finding, we undertook the synthesis of an
1,3-aminomethyl indole library where two different
Mannich reactions with secondary amines and formal-
dehyde were used in sequence to produce differentially
substituted indole scaffolds. Methyl indole-5-carboxylate
(1) was selected as the starting material, with the aim of
using the carboxylic acid functionality as an attachment
point to the chromatography matrix. Herein we describe the
synthesis of 25 1,3-aminomethyl indole compounds.
2. Results and discussion
Mannich reactions between indole and secondary imines in
water at low temperature are known to substitute the N1
position of indoles.7 The products, N-aminal indoles, are
relatively stable but convert to the thermodynamically more
stable C3-substituted aminomethyl indoles upon heating at
neutral pH or acid treatment at room temperature.4
Accordingly, we devised a synthetic strategy where the
C3-position of 1 was first substituted under standard
Keywords: Library synthesis; Mannich reaction; Affinity ligands.
*
Corresponding authors. Tel.: C46 18 6121162; fax: C46 18 6121837
(O.E.); tel.: 46 8 7906960; fax: 46 8 7912333 (P.S.); e-mail
addresses: ersoy@amersham.com; somfai@kth.se
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.047

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C. Lindquist et al. / Tetrahedron 62 (2006) 3439–3445
R1
N''
R2
R1
N''
R2
O
O
O
MeO
MeO
MeO
a
b
N
N
N
H
H
R3
N'
R4
1
2 R1R2N''H=pyrrolidine, 77%
3 R1R2N''H=4-methylpiperidine, 93%
4 R1R2N''H=diethylamine, 78%
8–31
5 R1R2N''H=4-methylpiperazine, 45%
6 R1R2N''H=morpholine, 57%
7 R1R2N''H=benzylmethylamine, 66%
Scheme 1. (a) R1R2N00H (1.2 equiv), HCHO (1.2 equiv), room temperature, 18 h; (b) R3R4N0H (1.5 equiv), HCHO (1.5 equiv), room temperature, 48 h.
Mannich conditions to yield the corresponding thermo-
dynamically stable products, 3-aminomethyl indoles 2–7
(Scheme 1).
excess amine was removed using a polymer bound electro-
philic scavanger, methylisocyanate polystyrene.11 As can be
seen from the data in Table 1, the yields vary from good to
moderate, the reason probably being that some product was
lost during purification, and that the purities of the library
compounds were generally high. However, when Et2NH was
used in the second Mannich reaction, that is, formation of
compounds 9, 14, 19, 24 and 29, products with lower purities
were obtained, which might be due to the more sterically
hindered amine moiety.
Compounds 3–7 were then selected for further library
synthesis. The combination of these compounds with five
different secondary amines then gave a library of 25 novel
compounds, 8–32 (Tables 1 and 2). The second Mannich
reaction required prolonged reaction times to reach com-
pletion and all attempts with elevated reaction temperatures
resulted in complicated reaction mixtures, perhaps due to
scrambling of the secondary amine moieties on the indole
scaffold. To simplify the purification of the library members
In order to exclude the possibility of scrambling of the N1-
and C3-substituents during the second Mannich reaction,
Table 1. Yields and purity of library compoundsa
Yield
Purity
100
90
80
70
7
60
%
50
40
30
20
10
0
6
5
4
H
Compound
Et2NH
N
H
N
3
H
N
BnMeNH
N
Amines
O
a Purity was determined from relative peaks areas of HPLC chromatogram (runs with gradient of 0–100% acetonitrile in water (0.05% TFA) for 10 min at lZ
214 nm). Yield was calculated from weight after removal of excess amine by scavanger resin. Reaction conditions: substrate (1 equiv), R3R4NH (1.5 equiv),
HCHO (1.5 equiv), dioxane:HOAc, room temperature, 48 h.
Table 2. Compound numbering
Compound
4-Methylpiperidine
Diethylamine
1-Methylpiperazine
Morpholine
Benzylmethylamine
3
4
5
6
7
8
9
10
15
20
25
30
11
16
21
26
31
12
17
22
27
32
13
18
23
28
14
19
24
29

C. Lindquist et al. / Tetrahedron 62 (2006) 3439–3445
3441
compounds 33 and 34 were prepared from 2 (64%) and 3
(62%), respectively, by using the same reaction conditions
as those employed for the library synthesis. Each reaction
yielded a single detectable Mannich product. To confirm the
structures of 33 and 34, 1D 1H and 13C NMR spectra
together with 2D 1H,1H-COSY, 1H,13C-HMQC8 and
1H,13C-HMBC9,10 spectra were recorded and interpreted.
First, assignments of all proton and carbon signals in 33 and
34 were made with assistance of the 2D COSY and HMQC
Evaporation of solvents was done parallel in a centrifugal
evaporator (Speed Vac SC201A, Savant). Scavanger
reactions were performed in individual polypropylene
tubes (PD-10 columns, Amersham Biosciences). All
chemicals and solvents were obtained from commercial
sources and were used as received. NMR spectra were
obtained on a Bruker Avance 300 in using CDCl3 as solvent
and shifts are reported downfield from (CH3)4Si (d 0). LS-
MS were obtained on a Hewlett Packard HP1100 MSD
(ESI, positive mode) using an YMC C18-hydrosphere
column (flow rate: 0.5 mL/min, gradient: 0–100% aceto-
nitrile in water (0.05% TFA) for 10 min, lZ214 nm). The
purity of all compounds were analyzed by analytic RP-
HPLC on a Shimadzu 10A system using an ACE C18-
column (flow rate: 2 mL/min, gradient: 0–100% acetonitrile
in water (0.05% TFA) for 10 min, lZ214 nm).
1
spectra. Secondly, information about long-range H, 13C
couplings extracted from the HMBC spectra was used to
determine the linkage position of the piperidine and
pyrrolidine groups on the indole ring. For both compounds
the identity of the methylene group C15 was determined by
3
the JHC coupling between H15 and C16/C20. In a similar
way, the identity of the C10 methylene moiety
3
was determined by the JHC coupling between H10 and
4.2. General procedures and spectral data
C11/C14. In compound 33, the position of the piperidine
group was deduced by the 3JHC couplings between H15 and
C2/C9 and the position of the pyrrolidine group was
deduced by the 2JHC coupling between H10 and C3 together
4.2.1. Typical procedure for the first Mannich reaction.
Methyl 3-((pyrrolidin-1-yl)methyl)-1H-indole-5-car-
boxylate (2). To a solution of 1 (300 mg, 1.71 mmol) in
dioxane–HOAc (4/1, 2.0 mL) was added a mixture of
pyrrolidine (170 mL, 2.06 mmol) and formaldehyde
(154 mL, 2.06 mmol, 37 wt% solution in water) in
dioxane–HOAc (4/1, 2.0 mL). The resultant mixture was
agitated at room temperature overnight. Evaporation of the
solvents and flash chromatography (CH2Cl2/MeOH/Et3N,
v/v/v 90:10:1) gave 2$HOAc (419 mg, 77%). HPLC-MS
(ESIC): tRZ4.34 min, m/z 259 (MCHC, 50%), 188 (100);
dH (300 MHz, CDCl3) 2.03 (m, 4H, CHHCH2N0CH2CHH),
2.30 (m, 4H, CH2N0CH2), 3.92 (s, 3H, OMe), 4.52 (s, 2H,
CH2N0), 7.49 (d, 1H, JZ8.7 Hz, H8), 7.61 (s, 1H, H2), 7.88
(dd, 1H, JZ8.7, 1.5 Hz, H7), 8.52 (d, 1H, JZ1.5 Hz, H5);
dC (75 MHz, CDCl3) 23.0, 47.9, 51.9, 52.0, 105.7, 111.8,
120.5, 122.2, 123.4, 126.9, 129.4, 138.8, 168.0; IR (film)
3
with the JHC couplings between H10 and C2/C4. In
compound 34 the situation was reversed, H15 now showed a
3
2JHC coupling to C3 and a JHC couplings to C2 and C4
3
while H10 showed JHC couplings to C2 and C9, thus
confirming the postulated structures and verifying that no
scrambling of the N1- and C3-substituents occur during the
second Mannich reaction (Fig. 1).
16
11
17
O
O
10
15
12
13
5
8
5
8
6
6
N''
N''
21
4
9
4
MeO
MeO
18
3
3
14
20
19
7
2
7
2
9
N 1
N1
16
11
15
10
17
N'
N'
12
20
14
21
18
13
2953, 1709, 1621 cmK1
.
19
33
34
4.2.2. Methyl 3-((4-methylpiperidin-1-yl)methyl)-1H-
indole-5-carboxylate (3). Prepared from 1 (200 mg,
1.14 mmol), 4-methylpiperidine (162 mL, 1.37 mmol) and
formaldehyde (103 mL, 1.37 mmol, 37 wt% solution in
water) as described for compound 2 to give 3 (304 mg,
93%). HPLC-MS (ESIC): tRZ4.81 min, m/z 287 (MCHC,
100%), 188 (58); dH (300 MHz, CDCl3) 0.96 (d, 3H, JZ
5.7 Hz, CHCH3), 1.51 (m, 3H, CHHCH2N0CH2CHH), 1.71
(m, 2H, CHHCH2N0CH2CHH), 2.42 (m, 2H, CHHN0CHH),
3.27 (m, 2H, CHHN0CHH), 3.94 (s, 3H, OMe), 4.09 (s, 2H,
CH2N0), 7.43 (d, 1H, JZ8.7 Hz, H8), 7.57 (s, 1H, H2), 7.91
(dd, 1H, JZ8.7, 1.5 Hz, H7), 8.35 (d, 1H, JZ1.5 Hz, H5);
dC (75 MHz, CDCl3) 20.8, 30.8, 33.8, 51.0, 51.9, 52.0,
104.6, 111.8, 120.6, 122.2, 123.4, 127.4, 130.0, 138.8,
Figure 1. Structure and numbering of compounds 33 and 34.
3. Conclusions
A library of 25 novel bis-1,3-aminomethyl indole com-
pounds has been prepared in moderate to good yields by
sequential use of two Mannich reactions. The average purity
of the library is greater than 70%. It have also been shown
that no scrambling of the amino substituents between the
N1- and C3-positions occurs during the second Mannich
reaction. Despite the modest library size, these results show
that iterative Mannich reactions with different secondary
amines and formaldehyde, is a useful method to build
libraries of 1,3-aminomethyl indoles. The mild reaction
conditions that are employed make this a particularly
attractive reaction sequence.
168.1; IR (film) 2956, 1697, 1621 cmK1
.
4.2.3. Methyl 3-((diethylamino)methyl)-1H-indole-5-
carboxylate (4). Prepared from 1 (300 mg, 1.71 mmol),
diethylamine (212 mL, 2.06 mmol) and formaldehyde
(154 mL, 2.06 mmol, 37 wt% solution in water) as
described for compound 2 to give 4 (349 mg, 78%).
HPLC-MS (ESIC): tRZ4.30 min, m/z 261 (MCHC,
23%), 188 (100); dH (300 MHz, CDCl3) 1.25 (m, 6H,
JZ7.5 Hz, N0CH2CH3), 2.94 (m, 4H, JZ7.5 Hz, N0CH2-
CH3), 3.92 (s, 3H, OMe), 4.20 (s, 2H, CCH2N0), 7.42 (d,
4. Experimental
4.1. Material and methods
Reactions were performed in individual glass tubes placed
in IKA-VIBRAX-VXR parallel agitation equipment.

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C. Lindquist et al. / Tetrahedron 62 (2006) 3439–3445
1H, JZ8.7 Hz, H8), 7.58 (s, 1H, H2), 7.88 (dd, 1H, JZ
8.7, 1.5 Hz, H7), 8.34 (d, 1H, JZ1.5 Hz, H5); dC
(75 MHz, CDCl3) 8.6, 44.9, 46.4, 52.0, 104, 6, 111.8,
120.3, 122.2, 123.4, 127.2, 129.9, 138.8, 168.0; IR (film)
(13), 202 (7), 194 (34), 188 (100), 150 (11), 130 (6); dH
(300 MHz, CDCl3) 0.88 (d, 3H, JZ5.7 Hz, CHCH3), 1.22
(m, 3H, CHHCH(CH3)CHH), 1.60 (m, 2H, CHHCH(CH3)-
CHH), 2.12 (m, 2H, CHHN00CHH), 2.55 (m, 4H, CH2-
N0CH2), 2.88 (m, 2H, CHHN00CHH), 3.75 (m, 4H,
CH2OCH2), 3.79 (s, 2H, CH2N0), 3.95 (s, 3H, OMe), 4.82
(s, 2H, CH2N0), 7.22 (s, 1H, H2), 7.44 (d, 1H, JZ8.7 Hz,
H8), 7.92 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.46 (d, 1H, JZ
1.5 Hz, H5); dH (75 MHz, CDCl3) 22.2, 30.7, 34.5, 51.6,
52.3, 53.7, 53.8, 67.0, 68.9, 110.3, 121.9, 122.7, 123.6,
128.4, 130.5, 140.3, 168.5; HRMS (FABC) calculated for
C22H32N3O3 (MCH): 386.2444, found: 386.2428.
2952, 1704, 1622 cmK1
.
4.2.4. Methyl 3-((4-methylpiperazin-1-yl)methyl)-1H-
indole-5-carboxylate (5). Prepared from 1 (300 mg,
1.71 mmol), 1-methylpiperazine (228 mL, 2.06 mmol) and
formaldehyde (154 mL, 2.06 mmol, 37 wt% solution in
water) as described for compound 2 to give 5 (231 mg,
45%). HPLC-MS (ESIC): tRZ3.74 min, m/z 288 (MCHC,
100%), 188 (87), 130 (8); dH (300 MHz, CDCl3) 2.52 (s, 3H,
NCH3), 2.75–3.00 (m, 8H, CH2CH2N0CH2CH2), 3.94 (s,
3H, OMe), 3.98 (s, 2H, CCH2N0), 7.46 (s, 1H, H2), 7.47 (d,
1H, JZ8.7 Hz, H8), 7.91 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.40
(d, 1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 43.8, 50.0,
51.9, 52.0, 52.7, 109.9, 111.2, 121.8, 121.9, 123.5, 127.0,
4.2.8. Compound 8. Prepared as outlined for compound 23
in 45% yield. HPLC-MS (ESIC): tRZ4.76 min, m/z 398
(MCHC, 38%), 456 (10), 359 (7), 299 (16), 287 (39), 199
(48), 188 (23), 150 (11), 142 (100), 128 (84); dH (300 MHz,
CDCl3) 0.87 (d, 3H, JZ5.7 Hz, CHCH3), 0.98 (d, 3H, JZ
6.3 Hz, CHCH3), 1.60 (m, 6H, CHHCH(CH3)CHH), 1.75
(m, 4H, HHCCH(CH3)CHH), 2.12 (m, 2H, H2CCH2N0CH2-
CH2), 2.58 (m, 2H, CHHN0CHH), 2.87 (m, 2H,
CHHN00CHH), 3.38 (m, 2H, CHHN00CHH), 3.95 (s, 3H,
OMe), 4.21 (s, 2H, CH2N0), 4.86 (s, 2H, CH2N00), 7.51 (d,
1H, JZ8.7 Hz, H8), 7.64 (s, 1H, H2), 7.85 (dd, 1H, JZ8.7,
1.5 Hz, H7), 8.32 (d, JZ1.5 Hz, 1H, H5); dC (75 MHz,
DMSO) 21.0, 21.7, 29.8, 30.3, 33.5, 33.7, 45.9, 50.3, 51.7,
67.4, 111.6, 120.6, 121.4, 121.5, 122.3, 127.1, 138.7, 167.3;
IR (film) 2974, 1711, 1614 cmK1; HRMS (FABC)
calculated for C24H36N3O2 (MCH): 398.2808, found:
398.2808.
127.2, 139.0, 168.2; IR (film) 2954, 1706, 1619 cmK1
.
4.2.5. Methyl 3-(morpholinomethyl)-1H-indole-5-
carboxylate (6). Prepared from 1 (300 mg, 1.71 mmol),
morpholine (179 mL, 2.06 mmol) and formaldehyde
(154 mL, 2.06 mmol, 37 wt% solution in water) as described
for compound 2 to give 6 (324 mg, 57%). HPLC-MS
(ESIC): tRZ4.20 min, m/z 275 (MCHC, 10%), 188 (100);
dH (300 MHz, CDCl3) 2.73 (m, 4H, CH2N0CH2), 3.73 (m,
4H, CH2OCH2), 3.92 (s, 3H, OMe), 3.96 (s, 2H, CH2N0),
7.41 (d, 1H, JZ8.7 Hz, H8), 7.45 (s, 1H, H2), 7.84 (dd, 1H,
JZ8.7, 1.5 Hz, H7), 8.47 (d, 1H, JZ1.5 Hz, H5); dC
(75 MHz, CDCl3) 43.3, 51.9, 52.0, 64.4, 108.8, 111.3,
121.5, 122.0, 123.5, 127.5, 127.6, 138.8, 168.1; IR (film)
2948, 1696, 1566, 1112 cmK1
.
4.2.9. Compound 9. Prepared as outlined for compound 23
in 66% yield. HPLC-MS (ESIC): tRZ3.99 min, m/z 372
(MCHC, 19%), 430 (15), 404 (38), 348 (24), 299 (23), 287
(100), 202 (16), 188 (46), 150 (32), 122 (10); dH (300 MHz,
CDCl3) 0.97 (d, 3H, JZ5.7 Hz, CHCH3), 1.30 (t, 6H, JZ
7.5 Hz, N00CH2CH3), 1.40–1.83 (m, 5H, H2CCH(CH3)CH2),
2.60 (m, 2H, H2CCHN0CH2CH2), 3.05 (q, 4H, JZ7.5 Hz,
NCH2CH3), 3.39 (m, 2H, CHHN00CHH), 3.93 (s, 3H, OMe),
4.24 (s, 2H, CH2N0), 4.82 (s, 2H, CH2N00), 7.47 (d, 1H, JZ
8.7 Hz, H8), 7.63 (s, 1H, H2), 7.85 (dd, 1H, JZ8.7, 1.5 Hz,
H7), 8.28 (d, 1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3)
21.3, 23.7, 29.5, 31.5, 51.3, 52.1, 52.4, 107.0, 112.3, 121.0,
122.6, 123.7, 127.9, 130.2, 139.2, 168.5; IR (film) 2956,
4.2.6. Methyl 3-((N-benzyl-N-methylamino)methyl)-1H-
indole-5-carboxylate (7). Prepared from 1 (50 mg,
285 mmol), N-benzylmethylamine (44 mL, 343 mmol) and
formaldehyde (26 mL, 343 mmol, 37 wt% solution in water)
as described for compound 2 to give 7 (58 mg, 66%).
HPLC-MS (ESIC): tRZ5.47 min, m/z 309 (MCHC, 10%),
188 (27), 122 (100); dH (300 MHz, CDCl3) 2.22 (s, 3H,
N0CH3), 3.57 (s, 2H, N0CH2Ph), 3.74 (s, 2H, CH2N0), 3.94
(s, 3H, OMe), 7.12–7.43 (m, 7H, H2, H8, Ar), 7.88 (dd, 1H,
JZ8.7, 1.5 Hz, H7), 8.50 (d, 1H, JZ1.5 Hz, H5); dC
(75 MHz, CDCl3) 38.5, 50.2, 52.0, 59.1, 106.4, 111.6,
121.0, 122.2, 123.5, 127.3, 129.0, 129.1, 129.2, 130.7,
1702, 1660 cmK1
.
131.4, 138.9, 168.1; IR (film) 2950, 1698, 1622 cmK1
.
4.2.10. Compound 10. Prepared as outlined for compound
23 in 51% yield. HPLC-MS (ESIC): tRZ4.27 min, m/z 399
(MCHC, 100%), 457 (14), 287 (17), 212 (13), 200 (37),
188 (83), 142 (8); dH (300 MHz, CDCl3) 0.96 (d, 3H, JZ
5.7 Hz, CHCH3), 1.52 (m, 3H, CHHCH(CH3)CHH), 1.71
(m, 2H, CHHCH(CH3)CHH), 2.25 (s, 3H, NCH3), 2.40 (m,
2H, CH2N(CH2C)CH2), 2.45 (m, 4H, CH2N(CH3)CH2),
2.58 (m, 4H, CH2N00CH2), 3.28 (m, 2H, CHHN0CHH), 3.95
(s, 3H, OMe), 4.09 (s, 2H, CH2N0), 4.85 (s, 2H, CH2N00),
7.48 (d, 1H, JZ8.7 Hz, H8), 7.54 (s, 1H, H2), 7.93 (dd, 1H,
JZ8.7, 1.5 Hz, H7), 8.32 (d, 1H, JZ1.5 Hz, H5); dC
(75 MHz, CDCl3) 21.6, 30.2, 32.6, 46.1, 50.5, 51.9, 52.4,
52.8, 54.9, 68.5, 110.7, 121.7, 122.6, 123.8, 128.7, 132.6,
139.8, 168.3; IR (film) 2949, 1708, 1620 cmK1; HRMS
(FABC) calculated for C23H35N4O2 (MCH): 399.2760,
found: 399.2757.
4.2.7. Typical procedure for the second Mannich
reaction. Compound 23. To a solution of compound 6
(40.0 mg, 145.8 mmol) in dioxane–HOAc (4/1 v/v, 0.5 mL)
was added a mixture of 4-methylpiperidine (25.9 mL,
218.7 mmol) and formaldehyde (24.3 mL, 218.7 mmol,
37 wt% solution in water) in dioxane–HOAc (4/1,
0.5 mL). The resultant mixture was agitated for 48 h. The
solvents were removed and the residue dissolved in CH2Cl2
(1 mL) and added to a slurry of methyl isocyanate
polystyrene HL (99 mg, 219 mmol, prewashed and pre-
swollen) in CH2Cl2 (1 mL). The resultant slurry was
agitated for 2 h. Filtration, washing of the resin and removal
of the solvents gave compound 23 that was characterized
by 1H NMR and LC-MS. HPLC-MS (ESIC): tRZ3.91 min,
m/z 408 (MCNaC, 61%), 444 (12), 424 (7), 297 (8), 287

C. Lindquist et al. / Tetrahedron 62 (2006) 3439–3445
3443
4.2.11. Compound 11. Prepared as outlined for compound
23 in 95% yield. HPLC-MS (ESI): tRZ4.61 min, m/z 386
(MCHC, 100%); dH (300 MHz, CDCl3) 0.98 (d, 3H, JZ
5.7 Hz, CHCH3), 1.25 (m, 2H, CH2N CH3), 1.48–1.82 (m,
5H, H2CCH(CH3)CH2), 2.36 (m, 2H, CH2N00CH2), 2.40 (m,
2H, CH2N(CH2C)CH2), 2.45 (m, 4H, CH2N(CH3)CH2),
2.54 (m, 4H, CH2N0CH2), 2.58 (m, 4H, CH2N00CH2), 2.69
(m, 4H, CH2OCH2), 3.95 (s, 3H, OMe), 4.20 (s, 2H,
CH2N0), 4.83 (s, 2H, CH2N00), 7.50 (d, 1H, JZ8.7 Hz, H8),
7.70 (s, 1H, H2), 7.94 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.32 (d,
1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 21.4, 30.1, 31.8,
51.1, 51.3, 52.5, 67.0, 69.0, 106.2, 110.9, 121.3, 123.0,
124.0, 128.7, 133.8, 139.7, 168.2; IR (film) 2953, 1711,
1615, 1115 cmK1; HRMS (FABC) calculated for
C22H32N3O3 (MCH): 386.2444, found: 386.2448.
CH2CH2N00CH2CH2), 3.02 (q, 4H, JZ7.5 Hz, N0CH2CH3),
3.94 (s, 3H, OMe), 4.29 (s, 2H, CH2N0), 4.82 (s, 2H,
CH2N00), 7.48 (d, 1H, JZ8.7 Hz, H8), 7.65 (s, 1H, H2), 7.94
(dd, 1H, JZ8.7, 1.5 Hz, H7), 8.33 (d, 1H, JZ1.5 Hz, H5);
dC (75 MHz, CDCl3) 10.0, 45.6, 45.8, 46.7, 50.2, 52.4, 54.7,
68.4, 108.2, 110.7, 121.6, 122.6, 128.5, 123.9, 132.5, 139.7,
168.3; IR (film) 2951, 1704, 1616 cmK1; HRMS (FABC)
calculated for C21H33N4O2 (MCH): 373.2604, found:
373.2610.
4.2.16. Compound 16. Prepared as outlined for compound
23 in 74% yield. dH (300 MHz, CDCl3) 1.28 (t, 6H, JZ
7.2 Hz, N0CH2CH3), 2.55 (t, 4H, JZ4.5 Hz, CH2N00CH2),
2.95 (q, 4H, JZ7.2 Hz, N0CH2CH3), 3.69 (t, 4H, JZ4.5 Hz,
CH2OCH2), 3.94 (s, 3H, OMe), 4.22 (s, 2H, CH2N0), 4.82 (s,
2H, CH2N00), 7.48 (d, 1H, JZ8.7 Hz, H8), 7.59 (s, 1H, H2),
7.94 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.36 (d, 1H, JZ1.5 Hz,
H5); dC (75 MHz, CDCl3) 10.5, 46.0, 47.1, 51.1, 52.4, 67.0,
68.8, 109.9, 110.5, 121.9, 122.5, 123.8, 128.6, 131.7, 139.8,
168.3; IR (film) 2967, 1709, 1614, 1116 cmK1; HRMS
(FABC) calculated for C20H30N3O3 (MCH): 360.2287,
found: 360.2289.
4.2.12. Compound 12. Prepared as outlined for compound
23 in 52% yield. HPLC-MS (ESIC): tRZ4.94 min, m/z 420
(MCHC, 19%), 287 (13), 233 (7), 188 (42), 134 (100); dH
(300 MHz, CDCl3) 0.93 (d, 3H, JZ5.7 Hz, CHCH3), 1.58
(m, 2H, CHHCH(CH3)CHH), 1.68 (m, 3H, CHHCH(CH3)-
CHH), 2.25 (s, 3H, N00CH3), 2.50 (m, 2H, CHHN0CHH),
3.33 (m, 2H, CHHN0CHH), 3.62 (s, 2H, N00CH2Ph), 3.95 (s,
3H, OMe), 4.18 (s, 2H, CH2N0), 4.90 (s, 2H, CH2N00), 7.25–
7.35 (m, 5H, Ar), 7.40 (d, 1H, JZ8.7 Hz, H8), 7.64 (s, 1H,
H2), 7.93 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.33 (d, 1H, JZ
1.5 Hz, H5); dC (75 MHz, CDCl3) 20.9, 29.7, 31.1, 40.2,
51.1, 51.8, 52.0, 59.0, 67.6, 104.9, 110.7, 120.4, 122.4,
123.5, 127.4, 128.4, 128.5, 133.2, 137.9, 139.3, 168.0; IR
(film) 2951, 1716, 1617, 1251 cmK1; HRMS (FABC)
calculated for C26H34N3O2 (MCH): 420.2651, found:
420.2652.
4.2.17. Compound 17. Prepared as outlined for compound
23 in 71% yield. dH (300 MHz, CDCl3) 1.29 (t, 6H, JZ
7.5 Hz, N0CH2CH3), 2.27 (s, 3H, N00CH3), 2.95 (q, 4H, JZ
7.5 Hz, N0CH2CH3), 3.62 (s, 2H, N00CH2Ph), 3.92 (s, 3H,
OMe), 4.24 (s, 2H, CH2N0), 4.90 (s, 2H, CH2N00), 7.22–7.38
(m, 5H, Ar), 7.40 (d, 1H, JZ8.7 Hz, H8), 7.62 (s, 1H, H2),
7.92 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.35 (d, 1H, JZ1.5 Hz,
H5); dC (75 MHz, CDCl3) 10.7, 40.6, 46.1, 47.2, 52.4, 59.4,
67.8, 109.8, 110.7, 121.9, 122.3, 123.7, 127.8, 128.6, 128.7,
128.9, 129.1, 131.7, 138.4, 139.9, 168.4; IR (film) 2950,
1709, 1614, 1247 cmK1; HRMS (FABC) calculated for
C24H32N3O2 (MCH): 394.2495, found: 394.2494.
4.2.13. Compound 13. Prepared as outlined for compound
23 in 67% yield. dH (300 MHz, CDCl3) 0.87 (d, 3H, JZ
5.7 Hz, CHCH3), 1.25 (m, 3H, CHHCH(CH3)CHH), 1.30
(tr, 6H, JZ7.5 Hz, N0CH2CH3), 20.12 (m, 2H,
CHHCH(CH3)CHH), 2.85 (m, 2H, CHHN CHH), 3.05 (q,
4H, JZ7.5 Hz, N0CH2CH3), 3.95 (s, 3H, OMe), 4.29 (s, 2H,
CH2N0), 4.88 (s, 2H, CH2N00), 7.52 (d, 1H, JZ8.7 Hz, H8),
7.62 (s, 1H, H2), 7.93 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.33 (d,
1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 10.7, 22.2, 30.7,
34.4, 46.1, 47.1, 51.6, 52.3, 69.0, 109.6, 110.6, 121.8, 122.2,
123.6, 128.4, 131.9, 140.0, 168.4; IR (film) 2949, 1716,
1614 cmK1; HRMS (FABC) calculated for C22H34N3O2
(MCH): 372.2651, found: 372.2662.
4.2.18. Compound 18. Prepared as outlined for compound
23 in 71% yield. HPLC-MS (ESI): tRZ3.62 min, m/z 421
(MCNaC, 13%), 202 (34), 150 (100), 128 (6); dH
(300 MHz, CDCl3) 0.89 (d, 3H, JZ5.7 Hz, CHCH3), 1.62
(m, 3H, H2CCH(CH3)CH2), 2.19 (m, 2H, H2CCH(CH3)-
CH2), 00 2.62 (s, 3H, NCH3), 2.88–3.18 (m, 10H,
CHHN CHH, CH2CH2N0CH2CH2), 3.94 (s, 2H, CH2N0),
3.95 (s, 3H, OMe), 4.89 (s, 2H, CH2N00), 7.39 (d, 1H, JZ
8.7 Hz, H8), 7.61 (s, 1H, H2), 7.92 (dd, 1H, JZ8.7, 1.5 Hz,
H7), 8.37 (d, 1H, JZ1.5 Hz, H5); IR (film) 2951, 1708,
1617 cmK1; HRMS (FABC) calculated for C23H35N4O2
(MCH): 399.2760, found: 399.2762.
4.2.14. Compound 14. Prepared as outlined for compound
23 in 47% yield. dH (300 MHz, CDCl3) 1.06 (t, 6H, JZ
7.2 Hz, NCH2NCH2CH3), 1.30 (tr, 6H, JZ7.5 Hz, N0CH2-
CH3), 2.62 (q, 4H, JZ7.2 Hz, N00CH2CH3), 3.00 (q, 4H, JZ
7.5 Hz, N0CH2CH3), 3.93 (s, 3H, OMe), 3.94 (s, 2H,
CH2N0), 4.30 (s, 2H, CH2N00), 7.39 (d, 1H, JZ8.7 Hz, H8),
7.65 (s, 1H, H2), 7.89 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.45 (d,
1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 9.1, 12.4, 45.2,
45.3, 46.6, 46.8, 52.2, 70.2, 105.7, 112.1, 120.6, 122.4,
123.6, 127.5, 132.6, 139.0, 168.2; IR (film) 2950, 1709,
1263 cmK1; HRMS (FABC) calculated for C20H32N3O2
(MCH): 346.2495, found: 346.2483.
4.2.19. Compound 19. Prepared as outlined for compound
23 in 46% yield. HPLC-MS (ESI): tRZ3.43 min, m/z 395
(MCNaC, 31%), 431 (21), 348 (13), 288 (20), 217 (6), 202
(78), 150 (100), 130 (15), 120 (5); dH (300 MHz, CDCl3)
1.40 (tr, 6H, JZ7.2 Hz, N0CH2CH3), 2.56 (s, 3H, NCH3),
3.10 (q, 4H, JZ7.2 Hz, NCH2CH3), 2.80–3.20 (m, 8H,
CH2CH2N00CH2CH2), 3.92 (s, 2H, CH2N0), 3.93 (s, 3H,
OMe), 4.06 (s, 2H, CH2N00), 7.28 (s, 1H, H2), 7.52 (d, 1H,
JZ8.7 Hz, H8), 7.88 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.35 (d,
1H, JZ1.5 Hz, H5); IR (film) 2717, 1697, 1621 cmK1
.
4.2.15. Compound 15. Prepared as outlined for compound
23 in 70% yield. dH (300 MHz, CDCl3) 1.30 (tr, 6H, JZ
7.5 Hz, N0CH2CH3), 2.36 (s, 3H, NCH3), 2.61 (m, 8H,
4.2.20. Compound 20. Prepared as outlined for compound
23 in 73% yield. HPLC-MS (ESI): tRZ3.52 min, m/z 422
(MCNaC, 31%), 458 (15), 438 (8), 400 (8), 348 (6), 288

3444
C. Lindquist et al. / Tetrahedron 62 (2006) 3439–3445
(30), 200 (8), 188 (100), 130 (12); dH (300 MHz, CDCl3)
1.42 (s, 3H, N00CH2CH2NCH3), 2.59 (s, 3H, N0CH2CH2-
NCH3), 2.70 (m, 8H, CH2CH2N00CH2CH2), 2.82–3.02 (m,
8H, CH2CH2N0CH2CH2), 3.91 (s, 2H, CH2N0), 3.95 (s, 3H,
OMe), 4.82 (s, 2H, CH2N00), 7.32 (s, 1H, H2), 7.43 (d, 1H,
JZ8.7 Hz, H8), 7.92 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.49 (d,
;
HRMS (FABC) calculated for C22H34N5O2 (MCH):
400.2713, found: 400.2712.
4.2.25. Compound 26. Prepared as outlined for compound
23 in 51% yield. HPLC-MS (ESI): tRZ3.90 min, m/z 396
(MCNaC, 100%), 432 (17), 412 (8), 287 (14), 188 (11),
144 (18); dH (300 MHz, CDCl3) 2.53 (m, 4H, CH2N00CH2),
2.60 (m, 4H, CH2N0CH2), 3.68 (m, 4H, CH2CH2N00CH2-
CH2), 3.76 (m, 4H, CH2CH2N0CH2CH2), 3.80 (s, 2H,
CH2N0), 3.95 (s, 3H, OMe), 4.79 (s, 2H, CH2N00), 7.27 (s,
1H, H2), 7.45 (d, 1H, JZ8.7 Hz, H8), 7.93 (dd, 1H, JZ8.7,
1.5 Hz, H7), 8.45 (d, 1H, JZ1.5 Hz, H5); dC (75 MHz,
CDCl3) 50.8, 52.0, 53.2, 66.7, 68.4, 109.9, 122.0, 122.3,
123.5, 128.2, 130.5, 139.6, 168.0; IR (film) 2923, 1710,
1614, 1115 cmK1; HRMS (FABC) calculated for
C20H28N3O4 (MCH): 374.2080, found: 374.2081.
1H, JZ1.5 Hz, H5); IR (film) 2953, 1701, 1615 cmK1
4.2.21. Compound 21. Prepared as outlined for compound
23 in 85% yield. HPLC-MS (ESIC): tRZ3.71 min, m/z 387
(MCHC, 55%), 445 (12), 425 (8), 409 (29), 300 (6), 288
(24), 202 (78), 188 (18), 150 (100), 130 (7); dH (300 MHz,
CDCl3) 2.55 (t, 4H, JZ4.2 Hz, CH2N00CH2), 2.66 (s, 3H,
NCH3), 2.85–3.25 (m, 8H, CH2CH2N0CH2CH2), 3.69
(t, 4H, JZ4.2 Hz, CH2OCH2), 3.92 (s, 2H, CH2N0), 3.95
(s, 3H, OMe), 4.81 (s, 2H, CH2N00), 7.29 (s, 1H, H2), 7.47
(d, 1H, JZ8.7 Hz, H8), 7.93 (dd, 1H, JZ8.7, 1.5 Hz, H7),
8.40 (d, 1H, JZ1.5 Hz, H5); IR (film) 2951, 1707, 1614,
1115 cmK1; HRMS (FABC) calculated for C21H31N4O3
(MCH): 387.2396, found: 387.2392.
4.2.26. Compound 27. Prepared as outlined for compound
23 in 60% yield. HPLC-MS (ESIC): tRZ4.52 min, m/z 430
(MCNaC, 100%), 466 (13), 446 (9), 188 (940)0, 134 (74),
122 (8); dH (300 MHz, CDCl3) 2.27 (s, 3H, N CH3), 2.61
(m, 4H, CH2N0CH2), 3.61 (s, 2H, N0CH2Ph), 3.77 (m, 4H,
CH2OCH2), 3.83 (s, 2H, CH2N0), 3.94 (s, 3H, OMe), 4.86 (s,
2H, CH2N00), 7.24–7.35 (m, 6H, H2, Ar), 7.38 (d, 1H, JZ
8.7 Hz, H8), 7.91 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.45 (d, 1H,
JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 40.6, 52.3, 53.5, 53.7,
59.4, 66.9, 67.7, 110.5, 122.2, 122.6, 123.7, 127.8, 128.5,
128.9, 129.1, 138.4, 140.1, 168.5; IR (film) 2923, 1709,
1614, 1254, 1116 cmK1; HRMS (FABC) calculated for
C24H30N3O3 (MCH): 408.2287, found: 408.2300.
4.2.22. Compound 22. Prepared as outlined for compound
23 in 68% yield. HPLC-MS (ESIC): tRZ4.32 min, m/z 443
(MCNaC, 39%), 479 (7), 231 (6), 202 (77), 188 (100), 150
(52), 134 (100), 122 (36); dH (300 MHz, CDCl3) 2.28 (s, 3H,
N00CH3), 2.65 (s, 3H, NCH3), 2.85–3.25 (m, 8H, CH2CH2-
N0CH2CH2), 3.62 (s, 2H, N00CH2Ph), 3.92 (s, 2H, CH2N0),
3.95 (s, 3H, OMe), 4.88 (s, 2H, CH2N00), 7.22–7.36 (m, 6H,
H2, Ar), 7.39 (d, 1H, JZ8.7 Hz, H8), 7.92 (dd, 1H, JZ8.7,
1.5 Hz, H7), 8.37 (d, 1H, JZ1.5 Hz, H5); IR (film) 2950,
1709, 1616, 1248 cmK1; HRMS (FABC) calculated for
C25H33N4O2 (MCH): 421.2604, found: 421.2613.
4.2.27. Compound 28. Prepared as outlined for compound
23 in 72% yield. HPLC-MS (ESIC): tRZ4.65 min, m/z 442
(MCNaC, 44%), 231 (100), 188 (7), 142 (20), 122 (13); dH
(300 MHz, CDCl3) 0.88 (d, 3H, JZ5.7 Hz, CHCH3), 1.23
(m, 3H, CHHCH(CH3)CHH), 1.59 (m, 2H, CHHCH(CH3)-
CHH), 2.13 (m, 2H, CHHN00CHH), 2.24 (s, 3H, N0CH3),
2.88 (m, 2H, CHHN00CHH), 3.60 (s, 2H, N0CH2Ph), 3.77 (s,
2H, CH2N0), 3.95 (s, 3H, OMe), 4.83 (s, 2H, CH2N00), 7.15–
7.47 (m, 7H, H2, H8, Ar), 7.90 (dd, 1H, JZ8.7, 1.5 Hz, H7),
8.46 (d, 1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 22.2,
30.7, 34.5, 51.6, 52.2, 52.7, 62.2, 68.8, 110.2, 121.7, 123.0,
123.6, 127.6, 128.3, 128.7, 129.6, 140.4, 168.6; IR (film)
2924, 1716, 1614, 1245 cmK1; HRMS (FABC) calculated
for C26H34N3O2 (MCH): 420.2651, found: 420.2640.
4.2.23. Compound 24. Prepared as outlined for compound
23 in 57% yield. HPLC-MS (ESIC): tRZ3.56 min, m/z 382
(MCNaC, 100%), 418 (14), 404 (11), 297 (16), 287 (29),
202 (18), 188 (27), 158 (6), 144 (10), 137 (9), 120 (10); dH
(300 MHz, CDCl3) 1.08 (t, 6H, JZ7.2 Hz, N00CH2CH3),
2.58 (m, 4H, CH2N0CH2), 2.61 (q, 4H, JZ7.2 Hz, N00CH2-
CH3), 3.75 (m, 4H, CH2OCH2), 3.80 (s, 2H, CH2N0), 3.95
(s, 3H, OMe), 4.87 (s, 2H, CH2N00), 7.27 (s, 1H, H2), 7.48
(d, 1H, JZ8.7 Hz, H8), 7.89 (dd, 1H, JZ8.7, 1.5 Hz, H7),
8.48 (d, 1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 12.6,
45.4, 51.2, 52.3, 53.6, 53.8, 67.0, 68.7, 110.0, 111.4, 122.1,
122.6, 122.9, 123.9, 127.9, 128.6, 139.3, 168.7; IR (film)
2951, 1709, 1619, 1115 cmK1; HRMS (FABC) calculated
for C20H30N3O3 (MCH): 360.2287, found: 360.2282.
4.2.28. Compound 29. Prepared as outlined for compound
23 in 55% yield. HPLC-MS (ESIC): tRZ4.42 min, m/z 416
(MCNaC, 14%), 309 (8), 231 (28), 188 (40), 122 (100); dH
(300 MHz, CDCl3) 1.06 (t, 6H, JZ7.2 Hz, N00CH2CH3),
2.24 (s, 3H, N0CH3), 2.61 (q, 4H, JZ7.2 Hz, N00CH2CH3),
3.61 (s, 2H, N0CH2Ph), 3.79 (d, 2H, JZ4.2 Hz, CH2N0),
3.95 (s, 3H, OMe), 4.86 (s, 2H, CH2N0), 7.18–7.44 (m, 7H,
H2, H8, Ar), 7.90 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.46 (d, 1H,
JZ1.5 Hz, H5); dC (75 MHz, DMSO) 21.0, 41.7, 51.6, 51.7,
58.3, 61.0, 66.8, 111.3, 122.4, 127.0, 127.4, 128.2, 128.5,
128.7, 136.1, 138.5, 139.7, 149.6, 167.3; IR (film) 2947,
1709, 1614, 1251 cmK1; HRMS (FABC) calculated for
C24H32N3O2 (MCH): 394.2495, found: 394.2487.
4.2.24. Compound 25. Prepared as outlined for compound
23 in 55% yield. HPLC-MS (ESIC): tRZ3.79 min, m/z 409
(MCNaC, 100%), 445 (20), 425 (6), 348 (7), 288 (8), 188
(100), 122 (7); dH (300 MHz, CDCl3) 2.30 (s, 3H, NCH3),
2.40–2.68 (m, 12H, CH2N0CH2, CH2CH2N00CH2CH2), 3.73
(m, 4H, CH2OCH2), 3.75 (s, 2H, CH2N0), 3.94 (s, 3H,
OMe), 4.80 (s, 2H, CH2N00) 7.17 (s, 1H, H2), 7.43 (d, 1H,
JZ8.7 Hz, H8), 7.91 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.46 (d,
1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 46.0, 50.4, 52.3,
53.8, 53.9, 55.0, 67.3, 68.4, 110.2, 122.0, 122.9, 123.7,
128.6, 129.9, 140.1, 168.5; IR (film) 2952, 1698, 1615,
1113 cmK1; HRMS (FABC) calculated for C21H31N4O3
(MCH): 387.2396, found: 387.2281.
4.2.29. Compound 30. Prepared as outlined for compound
23 in 63% yield. HPLC-MS (ESIC): tRZ4.46 min, m/z 443
(MCNaC, 67%), 459 (8), 277 (7), 188 (71), 180 (28), 134
(13), 122 (100); dH (300 MHz, CDCl3) 2.24 (s, 3H, N0CH3),
2.28 (s, 3H, NCH3), 2.35–2.72 (m, 8H, CH2CH2N00CH2-
CH2), 3.60 (s, 2H, N0CH2Ph), 3.76 (s, 2H, CH2N0), 3.95

C. Lindquist et al. / Tetrahedron 62 (2006) 3439–3445
3445
(s, 3H, OMe), 4.79 (s, 2H, CH2N00), 7.14–7.45 (m, 7H, H2,
H8, Ar), 7.91 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.46 (d, 1H, JZ
1.5 Hz, H5); dC (75 MHz, CDCl3) 46.1, 50.5, 52.3, 52.6,
55.0, 62.1, 68.4, 110.2, 121.9, 123.0, 123.7, 127.5, 128.5,
128.7, 129.6, 140.2, 168.6; IR (film) 2947, 1709, 1614,
1251 cmK1; HRMS (FABC) calculated for C25H33N4O2
(MCH): 421.2604, found: 421.2609.
additional 18 h at the solvents were removed and the residue
was flash chromatographed (CH2Cl2/MeOH/Et3N, v/v/v
90:10:1) to give 34 (83 mg, 62%). dH (300 MHz, CDCl3)
0.91 (d, 3H, JZ5.7 Hz, H21), 1.30 (m, 3H, H19, H18, H17),
1.60 (m, 2H, H19, H17), 1.75 (m, 4H, H13, H12), 2.03 (m,
2H, H20, H16), 2.64 (m, 4H, H14, H11), 2.96 (m, 2H, H20,
H16), 3.75 (s, 2H, H15), 3.93 (s, 3H, OMe), 4.96 (s, 2H,
H10), 7.23 (s, 1H, H2), 7.44 (d, 1H, JZ8.7 Hz, H8), 7.91
(dd, 1H, JZ8.7, 1.5 Hz, H7), 8.43 (d, 1H, JZ1.5 Hz, H5);
dC (75 MHz, CDCl3) 22.2 (C21), 24.0 (C12, C13), 31.0
(C18), 34.4 (C17, C19), 51.4 (C14, C11), 52.2 (MeO), 53.4
(C15), 54.0 (C20, C16), 64.9 (C10), 110.0 (C8), 112.7 (C3),
121.8 (C6), 122.6 (C5), 123.4 (C7), 128.7 (C4), 130.3 (C2),
139.9 (C9), 168.6 (CO).
4.2.30. Compound 31. Prepared as outlined for compound
23 in 64% yield. HPLC-MS (ESIC): tRZ4.60 min, m/z 430
(MCNaC, 74%), 446 (10), 362 (20), 231 (100), 180 (8),
134 (6), 122 (14); dH (300 MHz, CDCl3) 2.25 (s, 3H,
N0CH3), 2.52 (t, 4H, JZ4.5 Hz, CH2N00CH2), 3.62 (s, 2H,
N0CH2Ph), 3.69 (t, 4H, JZ4.5 Hz, CH2OCH2), 3.78 (s, 2H,
CH2N0), 3.95 (s, 3H, OMe), 4.78 (s, 2H, CH2N00), 7.18–7.45
(m, 7H, H2, H8, Ar), 7.91 (dd, 1H, JZ8.7, 1.5 Hz, H7), 8.46
(d, 1H, JZ1.5 Hz, H5); dC (75 MHz, CDCl3) 40.6, 52.3,
52.5, 59.4, 62.3, 67.6, 110.3, 121.8, 123.1, 123.7, 127.8,
128.5, 128.8, 128.9, 129.2, 138.4, 140.2, 168.6; IR (film)
Acknowledgements
2947, 1716, 1614, 1247 cmK1
.
This work was supported financially by Amersham
Biosciences and the Royal Institute of Technology. We
also wish to thank Dr. Herbert Baumann, Amersham
Biosciences, for assistance with the NMR experiments.
4.2.31. Compound 32. Prepared as outlined for compound
23 in 56% yield. HPLC-MS (ESIC): tRZ5.10 min, m/z 464
(MCNaC, 56%), 480 (7), 231 (8), 188 (100), 134 (65), 122
(52); dH (300 MHz, CDCl3) 2.26 (s, 6H, NCH3), 3.61 (m,
4H, NCH2Ph), 3.79 (s, 2H, CH2N0), 3.95 (s, 3H, OMe), 4.86
(s, 2H, CH2N00), 7.15–7.43 (m, 7H, H2, H8, Ar), 7.90 (dd,
1H, JZ8.7, 1.5 Hz, H7), 8.47 (d, 1H, JZ1.5 Hz, H5); dC
(75 MHz, CDCl3) 51.2, 52.3, 52.5, 67.1, 68.7, 110.2, 121.8,
123.0, 123.8, 128.5, 128.8, 129.7, 140.1, 168.5; IR (film)
2920, 1710, 1614, 1247, 1115 cmK1; HRMS (FABC)
calculated for C28H32N3O2 (MCH): 444.2495, found:
444.2495.
References and notes
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4.2.32. Compound 33. To compound 2 (50.0 mg,
193.5 mmol) in dioxane–HOAc (4/1, 1.0 mL) was added a
mixture of 4-methylpiperidine (34.3 mL, 290.2 mmol) and
formaldehyde (21.7 mL, 290.2 mmol, 37 wt% solution in
water) in dioxane–HOAc (4/1, 1.0 mL). The resultant
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64%). HPLC-MS (ESIC): tRZ4.12 min, m/z 370 (MCHC);
dH (300 MHz, CDCl3) 0.87 (d, 3H, JZ5.4 Hz, H-21), 1.21
(m, 3H, H-19, H18, H17), 1.60 (m, 2H, H19, H17), 1.88 (m,
4H, H13, H12), 2.13 (m, 2H, H20, H16), 2.81 (m, 4H, H14,
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JZ8.7 Hz, H8), 7.91 (dd, 1H, JZ8.7, 1.6 Hz, H7), 8.39 (d,
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(C16), 52.3 (C10), 54.1 (C11, C14), 68.9 (C15), 110.5 (C8),
111.8 (C3), 121.8 (C6), 122.1 (C5), 123.6 (C7), 128.1 (C4),
130.9 (C2), 140.0 (C9), 168.5 (CO).
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pyrrolidine (45 mL, 543 mmol) and formaldehyde (41 mL,
543 mmmol, 37 wt% solution in water) in dioxane–HOAc
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