An efficient route to 5-iodo-1-methylimidazole: Synthesis of xestomanzamine A

Article abstract of DOI:10.1139/v01-092

An efficient and practical route to C-5 functionalized N-methylated imidazoles is reported. 5-Iodo-1-methylimidazole was synthesized in four steps from imidazole, with complete regiospecificity, in 73% overall yield. The synthesis of xestomanzamine A, a marine natural product isolated in 1995 from an Okinawan sponge of Xestospongia sp., has been achieved using 5-iodo-1-methylimidazole in a modified Grignard reaction with a β-carboline ester moiety, in an overall yield of 59% based upon imidazole and 53% based upon tryptamine.

Full text of DOI:10.1139/v01-092

1110
An efficient route to 5-iodo-1-methylimidazole:
synthesis of xestomanzamine A
Francis B. Panosyan and Ian W.J. Still
Abstract: An efficient and practical route to C-5 functionalized N-methylated imidazoles is reported. 5-Iodo-1-
methylimidazole was synthesized in four steps from imidazole, with complete regiospecificity, in 73% overall yield.
The synthesis of xestomanzamine A, a marine natural product isolated in 1995 from an Okinawan sponge of
Xestospongia sp., has been achieved using 5-iodo-1-methylimidazole in a modified Grignard reaction with a β-carboline
ester moiety, in an overall yield of 59% based upon imidazole and 53% based upon tryptamine.
Key words: xestomanzamine A, 5-iodo-1-methylimidazole, methyl β-carboline-1-carboxylate.
Résumé : On propose une méthode efficace et pratique de préparer des imidazoles N-méthylés et fonctionnalisés en
C-5. On a synthétisé le 5-iodo-1-méthylimidazole en quatre étapes à partir de l’imidazole, avec une régiospécificité
complète et un rendement global de 73%. Faisant appel à une réaction de Grignard modifiée entre le 5-iodo-1-
méthylimidazole et un ester de la β-carboline, on a réalisé la synthèse de la xestomanzamine A, un produit naturel ma-
rin isolé en 1995 à partir de l’éponge d’Okinawa Xestospongia sp.; le rendement global est de 59% à partir de
l’imidazole et de 53% sur la base de la tryptamine.
Mots clés : xestomanzamine A, 5-iodo-1-méthylimidazole, β-carboline-1-carboxylate de méthyle.
[Traduit par la Rédaction] Panosyan and Still 1114
Introduction
tetrahydro-β-carboline2 intermediate 5. Decarboxylation, and
a series of oxidative steps would then lead to 2 and finally to
1, Scheme 1. We decided to adopt a similar strategy in our
approach but with the initial construction of the β-carboline
unit in the form of the 1-carboxylate ester 6. We then
planned to carry out a modified Grignard reaction, using a 5-
There has recently been intensive interest in the biological
activity of naturally occurring marine alkaloids (for a recent
review of marine natural products, see ref. 1). The very pro-
lific β-carboline class of alkaloids has been the focus of par-
ticular attention (2, 3). Many of these alkaloids are isolated
from sponges and two such compounds are xestomanzamine
A (1) and its 3,4-dihydro analogue xestomanzamine B (2).
These cytotoxic constituents of an Okinawan sponge
(Xestospongia sp.) were first isolated in 1995 (4), and one
synthesis of xestomanzamine A has been reported (5). This
synthesis required at least eight steps from indole-3-
carboxaldehyde, as well as a key coupling reaction with a 5-
lithiated 1-methylimidazole, itself requiring three steps for
its preparation, which proceeds in a yield of less than 50%.
We have developed a considerably shorter, more efficient
route to xestomanzamine A, which we now describe.
halo-1-methylimidazole
7,
to
lead
directly
to
xestomanzamine A, Scheme 2.
Before we began our approach to 7b and 7c we attempted,
without success, to form the Grignard reagent from the com-
mercially available 5-chloro-1-methylimidazole 7a. While
the analogous 5-bromo- and 5-iodoimidazoles are not, at
first sight, difficult synthetic targets, one well documented
complication in imidazole chemistry is the rapid equilibra-
tion of 4- and 5-imidazolyl anions to their much more stable
2-imidazolyl anion counterpart (6, 7). Thus, lithiation of N-
methylimidazole, followed by bromination or iodination,
was ruled out. Attempts to carry out regioselective
bromination of N-methylimidazole with a variety of re-
agents, including NBS, pyridinium tribromide, 2,4,4,6-
tetrabromo-2,5-cyclohexadienone, and dibromotriphenyl-
phosphorane were also unsuccessful. Some conversion
(20%) of N-methylimidazole to 7b was achieved using 2,3-
dibromo-5,5-dimethylhydantoin (DBDMH) in THF at 0°C
(8). The low yield obtained, however, combined with a re-
port (9) of the low reactivity of 5- and 4-bromo-1-
methylimidazoles towards magnesium, convinced us to turn
our attention to the synthesis of the iodo compound 7c.
The synthesis of 5-iodo-1-methylimidazole was attempted
by the strategy used by Balaban and Pyman (10) and, more
recently, by Garegg and Samuelsson (11). We planned to
carry out iodination of imidazole at all three carbons, selec-
tive deiodination and then regiospecific methylation to af-
ford 5-iodo-1-methylimidazole 7c, Scheme 3.
Results and discussion
A likely biosynthetic route to xestomanzamine A would
probably involve condensation of tryptophan 3 with the N-
methylated histidine-derived aldehyde 4 to produce the
Received February 22, 2001. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on July 27, 2001.
F.B. Panosyan and I.W.J. Still.1 Department of Chemistry,
University of Toronto at Mississauga, Mississauga, ON
L5L 1C6, Canada.
1Corresponding author (telephone: (905) 828-5354; fax: (905)
828-5425; e-mail: istill@utm.utoronto.ca).
2IUPAC name is 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole.
Can. J. Chem. 79: 1110–1114 (2001)
DOI: 10.1139/cjc-79-7-1110
© 2001 NRC Canada

Panosyan and Still
1111
Scheme 1.
Scheme 4.
I
CH3
I
N
-
(CH3)3O+BF4
N
7c
CO2H
N
Ts
N
S
+MeOTs
N
N
NH
N
H
N
H
N
H
10
O
O
O
O
MeOH
C7H7
N
CH3N
N
CH3N
CH3N
N
11
1
2
5
Scheme 5.
N
.
NH2 HCl
CO2H
.
HO2C CHO
+
N
NH2
NH
pH = 4
N
H
N
H
N
H
CHO CH3
CO2H
4
3
12
13
MeOH, HCl
∆
S8, xylene
6
∆
Scheme 2.
NH
N
H
CO2Me
N
1
+
14
N
N
H
N
X
CO2CH3
6
CH3
Scheme 6.
7a, X = Cl
b, X = Br
c, X = I
N
N
N
EtMgBr
+
N
OCH3
I
CH2Cl2
LiCl, rt
N
N
H
N
H
Scheme 3.
O
O
CH3N
CH3
6
1
7c
I
I
N
N
N
N
N
76%
99%
98%
99%
I
I
I
N
H
N
H
N
I
N
H
N
tetrafluoroborate, followed by a methanol quench, in a mod-
ification of a recent report by Lindel and Hochgürtel (15).
This reaction afforded 7c in 99% yield. The H NMR spec-
Ts
CH3
1
10
9
8
7c
trum had three singlet peaks at δ 3.62, 7.13, and 7.62, for the
methyl, H(4), and H(2) protons, respectively. These values
were in excellent agreement with the reported literature val-
ues (12) for 5-iodo-1-methylimidazole.
This very successful, regioselective methylation at N(3) of
10 using trimethyloxonium tetrafluoroborate presumably
proceeds via the 5-iodo-1-methyl-3-tosylimidazolium salt
11, which is not isolated, Scheme 4.
The sequence of reactions leading to 7c from imidazole
(Scheme 3) does not carry the disadvantages associated with
many earlier methods for the synthesis of 5-iodo-1-
methylimidazole; namely, low yields, poor reproducibility,
and tedious purification methods. The overall yield for the
four-step synthesis of 7c from imidazole was 73%.
In our hands, the conversion of imidazole to the
triiodiomidazole 8 was best achieved with iodine in an aque-
ous solution of sodium hydroxide, in the presence of potas-
sium iodide (12). 2,4,5-Triiodoimidazole 8 separated from
the solution upon neutralization with acetic acid, in 76%
yield.
The next step was the selective deiodination of 8 to 4(5)-
iodoimidazole 9. The use of sodium sulfite by Balaban and
Pyman (10) for the analogous bromo-series has been ex-
tended to the selective deiodination reaction of 8 (13). This
reaction, in our hands, afforded 9 in 99% yield, by using
30% ethanol in water as the refluxing solvent, instead of wa-
1
ter, to avoid complete deiodination. The H NMR spectrum
The synthesis of the β-carboline ester 6 was much more
straightforward, Scheme 5. The initial 1,2,3,4-tetrahydro-β-
carboline derivative 13 was obtained through a Pictet–
Spengler condensation of tryptamine hydrochloride 12 with
glyoxylic acid, forming 13 as a white solid, in 80% yield.
The Pictet–Spengler reaction is known to proceed under
mildly acidic conditions. This reaction was initiated by the
addition of a concentrated solution of potassium hydroxide
to solubilize the reagents, and then the pH was adjusted to
about 4 with glacial acetic acid. Purification of 13 was
readily achieved by simply stirring the product briefly in
methanol at 0°C and then filtering. The acid showed the IR
bands at ν 3343 (NH) and 1616 (bonded C=O) cmG1, as ex-
pected for this compound (16).
of the reduction product 9 showed the expected signals at δ
7.62 and 7.18, indicative of H(2) and H(4)-(5), respectively.
Numerous attempts to regioselectively methylate 9 to pro-
duce the desired 7c were to no avail, under a variety of pH
conditions and using both methyl iodide and dimethyl sul-
fate as methylating agents. Finally, we were able to take ad-
vantage of a highly selective two-step procedure that
involves the initial, regioselective tosylation (14) of 9 to pro-
duce 4-iodo-1-tosylimidazole 10 in 98% yield. This selectiv-
ity may be rationalized on steric grounds, although the
formation of 10 as a result of a thermodynamic equilibration
of two initially formed regioisomers cannot be ruled out.
The final conversion of 10 into the desired 5-iodo-1-
methylimidazole 7c was achieved using trimethyloxonium
© 2001 NRC Canada

1112
Can. J. Chem. Vol. 79, 2001
Fischer esterification of 13 with methanol gave methyl
a capillary melting point apparatus and are uncorrected. IR
spectra reported were recorded on a Nicolet FT-IR
1,2,3,4-tetrahydro-β-carboline-1-carboxylate 14, as its hydro-
chloride salt (17). The synthesis of 6 was completed by
dehydrogenation of 14, after careful neutralization of the salt
with 2,2,6,6-tetramethylpiperidine, using sulfur in refluxing
xylene, in 87% yield. The ester showed a carbonyl band in
the IR at ν 1678 cmG1, which is attributed to strong
intramolecular hydrogen bonding with the indole NH.
Our initial attempt to complete the synthesis of
xestomanzamine A was carried out by addition of a solution
of EtMgBr and 5-iodo-1-methylimidazole 7c in THF to a so-
lution of the β-carboline methyl ester 6 in THF, in the pres-
ence of excess lithium chloride (17). The indole NH present
in 6 was first deprotonated with the addition of one equiva-
lent of EtMgBr, prior to the addition of 7c. Xestomanzamine
A was obtained, but in very low yield. A mild procedure has
been reported for metal–halogen exchange with N-protected
4-iodoimidazoles (18), using EtMgBr in CH2Cl2. Repeating
the reaction in CH2Cl2 again afforded xestomanzamine A,
this time in greatly improved yield. We speculate that the
use of dichloromethane may give the Grignard
organomagnesium intermediate greater covalent character,
thus making the imidazol-5-yl carbanionoid less sensitive to
equilibration with its imidazol-2-yl counterpart, Scheme 6.
It was noticed during these initial attempts that the addi-
tion of EtMgBr to 7c produced a white precipitate prior to
addition to the β-carboline ester. Grignard reagents are
known to exist in equilibrium with the corresponding binary
organomagnesium compounds. At low temperatures, and
when there is a solvent-induced precipitation of the magne-
sium salt, there is a shift of the equilibrium towards the
organomagnesium species MgAr2. We, thus, decided to di-
rect the equilibrium towards the Grignard reagent ArMgX
by warming the solution of EtMgBr and 7c briefly, prior to
addition to the β-carboline methyl ester 6. In this way the
yield of xestomanzamine A was increased finally to 81%.
spectrophotometer in the form of KBr disks, unless specified
1
otherwise. The H NMR spectra (200 MHz) and 13C NMR
spectra (125 MHz), unless specified otherwise, were ob-
tained in CDCl3 with an internal standard of TMS.
2,4,5 Triiodoimidazole (8)
Modification of a described procedure (11): a solution of
iodine (45.0 g, 0.18 mol) in 20% aqueous potassium iodide
(300 mL) was added dropwise to a stirred solution of
imidazole (7.06 g, 0.1 mol) in 2 M sodium hydroxide
(600 mL) at room temperature and the resulting mixture was
stirred overnight. Addition of acetic acid until the mixture
was neutral gave a white precipitate, which was filtered off,
washed with water, and air dried to give a product suffi-
ciently pure to continue in the next step: (35.4 g, 76%): mp
186–190°C, lit. (11) mp 190–192°C.
4(5)-Iodoimidazole (9)
Modification
of
a
described
procedure
(13):
triiodoimidazole (1.0 g, 2.24 mmol) and sodium sulfite
(4.2 g, 33.3 mol) were heated at reflux in 30% ethanol in
water solution (50 mL) for 24 h. The ethanol was removed
under reduced pressure. The remaining solution was filtered
and the filtrate extracted with diethyl ether (3 × 15 mL). The
organic extracts were combined, dried (Na2SO4), and con-
centrated under reduced pressure to afford the pure product
9 as a white solid (0.43 g, 99%): mp 136 to 137°C, lit. (13)
1
1
mp 137 to 138°C. H NMR δ: 7.18 (s, 1H), 7.62 (s, 1H). H
NMR (DMSO-d6) δ: 7.31 (s, 1H), 7.65 (s, 1H).
4-Iodo-1-p-toluenesulfonylimidazole (10)
Compound 10 was prepared from 9 based upon the proce-
dure of Cliff and Pyne (14). White solid (98%): mp 146 to
1
147°C (EtOH), lit. (14) mp 146 to 147°C; H NMR δ: 2.46
1
The physical data (mp, IR, H and 13C NMR), which we
(s, 3H), 7.37 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.83 (d, J =
obtained for xestomanzamine A, are in excellent agreement
with those reported for the natural product (4).
8.5 Hz, 2H), 7.88 (s, 1H).
Our four-step preparation of 5-iodo-1-methylimidazole in
excellent overall yield provides ready access to a synthetic
intermediate with the potential to facilitate the synthesis of
other natural products with the N-substituted, C-5
functionalized imidazole substructure (19). The efficient to-
tal synthesis of xestomanzamine A (1) has been achieved
through a modified Grignard reaction of 7c with the β-
carboline ester 6, involving a total of four steps from
tryptamine (53% overall yield) and five steps from imidazole
(59% overall yield).
5-Iodo-1-methylimidazole (7c)
To a solution of 10 (0.94 g, 2.81 mmol) in dry CH2Cl2
(30 mL) was added trimethyloxonium tetrafluoroborate
(0.46 g, 3.11 mmol). After the mixture was stirred at room
temperature for 24 h, methanol (15 mL) was added. The sol-
vent was removed under reduced pressure and the residue
was acidified with 1% HCl and extracted with CH2Cl2 (2 ×
15 mL). The aqueous solution was then basified with 5%
NaHCO3 solution and extracted with CH2Cl2 (3 × 15 mL).
The organic extracts from the basified solution were com-
bined, dried (Na2SO4), and the solvent removed under re-
duced pressure to afford the white product 7c (0.58 g, 99%):
Experimental
1
mp 106 to 107°C, lit. (12) mp 102 to 103°C. H NMR δ:
3.62 (s, 3H), 7.13 (s, 1H), 7.62 (s, 1H).
Methanol was dried over magnesium. Xylenes and di-
chloromethane were distilled over calcium hydride.
Tetrahydrofuran and diethyl ether were dried over sodium
benzophenone ketyl. Molecular sieves (3 Å) were activated
by heating in a furnace to 500°C for 3 h. All glassware for
anhydrous reactions was dried overnight prior to use and
these reactions were carried out under argon. TLC were run
on Merck silica gel 60 F254 plates, with detection by means
of a 254 nm UV visualizer. Melting points were recorded on
1,2,3,4-Tetrahydro-β-carboline-1-carboxylic acid (13)
Tryptamine hydrochloride 12 (1.95 g, 9.91 mmol) was
dissolved in water (30 mL) while heating. Glyoxylic acid
monohydrate (1.10 g, 11.95 mmol) in water (10 mL) was
added to this solution, followed by the dropwise addition of
potassium hydroxide (0.65 g, 11.58 mmol) in water (10 mL).
The pH was adjusted to 4.0 with HOAc and the mixture al-
© 2001 NRC Canada

Panosyan and Still
1113
lowed to stir at room temperature for 2 h. The solution was
then chilled and vacuum filtered, giving an impure yellow
solid. The solid was dried under vacuum and suspended in
methanol at 0°C, then quickly filtered by suction to afford
the pure white product (1.99 g, 80%): mp 210 to 211°C, lit.
(20) mp 205–208°C. IR (cmG1): 3343 (NH), 1616 (C=O).
was stirred for 24 h. The mixture was quenched (5%
NaHCO3) and extracted with dichloromethane (3 × 25 mL).
The organic extracts were combined and dried (Na2SO4).
The dichloromethane was removed under reduced pressure
and the resulting solid was purified by column chromatogra-
phy (ethyl acetate–methanol, 95:5) to give the final product
1 as a yellow solid (0.103 g, 81%): mp 184 to185°C, lit. (4)
mp 185 to 186°C. IR (Nujol) (cmG1): 3419, 1606, 1214,
1127 (lit. (4) IR (KBr pellet) (cmG1): 3427, 1612, 1211,
Methyl 1,2,3,4-tetrahydro-β-carboline-1-carboxylate
(hydrochloride salt) (14)
1
1128). H NMR δ: 4.11 (s, 3H), 7.35 (dd, J = 7.9, 6.4 Hz,
The carboxylic acid 13 (4.50 g, 20.80 mmol) was stirred
in dry methanol (100 mL), while dry HCl gas was bubbled
through the mixture for approximately 2 min. The solid dis-
solved giving a golden yellow solution. The mixture was
then brought to reflux through 3 Å sieves in a Soxhlet appa-
ratus for 3 h under argon. Most of the methanol (70 mL) was
removed under reduced pressure. The precipitate formed was
collected by suction filtration, washed with cold toluene
(30 mL), and dried under vacuum, giving the ester hydro-
chloride as yellow crystals (5.23 g, 94%): mp 205–208°C,
lit. (21) mp 212–214°C. IR (cmG1): 3384 (NH), 1757 (C=O).
1H NMR (DMSO-d6) δ: 3.00 (t, J = 6.0 Hz, 2H), 3.54 (t, J =
6.2 Hz, 2H), 3.88 (s, 3H), 5.70 (s, 1H), 7.05–7.20 (m, 2H),
7.44–7.52 (m, 2H), 10.30 (s, 2H), 11.17 (s, 1H).
1H), 7.55 (dd, J = 7.5, 6.4 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H),
7.69 (s, 1H), 8.17 (d, J = 4.9 Hz, 1H), 8.20 (d, J = 7.9 Hz,
1
1H), 8.60 (d, J = 4.9 Hz, 1H), 8.94 (s, 1H) (lit. (4) H NMR
(CDCl3) δ: 4.05 (s, 3H), 7.30 (dd, J = 8.2, 6.2 Hz, 1H), 7.55
(dd, J = 7.3, 6.2 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.66 (s,
1H), 8.09 (d, J = 5.0 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.55
(d, J = 5.0 Hz, 1H), 8.93 (s, 1H)). 13C NMR δ: 184.4, 143.8,
143.4, 141.0, 138.2, 136.7, 136.6, 131.7, 129.8, 129.3,
121.8, 120.9, 120.7, 118.6, 111.9, 35.3 (lit.(4) 13C NMR
(CDCl3) δ: 184.2, 143.6, 143.3, 140.8, 137.9, 136.5, 136.4,
131.5, 129.7, 129.6, 121.7, 120.6, 120.5, 118.4, 111.8, 35.2.
Note added in proof: After this work had been accepted
for publication we became aware of a related report on the
synthesis of xestomanzamines A and B: B.E.A. Burm, P.
Blokker, E. Jongmans, E. van Kampen, M.J. Wanner, and
G.-J. Koomen. Heterocycles, 55, 495 (2001).
Methyl β-carboline-1-carboxylate (6)
The ester hydrochloride 14 (4.00 g, 15.02 mmol), precipi-
tated sulfur (1.13 g, 35.15 mmol), and 2,2,6,6-
tetramethylpiperidine (2.40 g, 17.03 mmol) were heated at
reflux in dry xylenes (200 mL) for 5 h giving a brown solu-
tion. Evolution of H2S could be detected with lead acetate
paper. The solution was allowed to cool slowly overnight,
forming brown needles. The xylene was removed under re-
duced pressure and the residual solids were placed in a
Soxhlet thimble and extracted with acetone (100 mL) for
3 h. The acetone extracted the ester 6 from the reaction mix-
Acknowledgment
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) for partial support of this re-
search.
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while
leaving
the
insoluble
2,2,6,6-
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3378 (NH), 1678 (C=O). 1H NMR δ: 4.14 (s, 3H), 7.35–7.63
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Xestomanzamine A (1)
Ethylmagnesium bromide (1 M in hexane) (0.5 mL,
0.50 mmol) was added dropwise to a solution of 5-iodo-1-
methylimidazole 7c (0.104 g, 0.50 mmol) in dichloro-
methane (15 mL) under argon at 0°C. After completing the
addition, the mixture was warmed briefly with a heat gun to
complete the dissolution and then allowed to stir for 1 h at
room temperature. In another flask, to a stirring solution of
β-carboline ester 6 (0.104 g, 0.46 mmol) and lithium chlo-
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gon at 0°C, ethylmagnesium bromide (1 M in hexane)
(0.5 mL, 0.50 mmol) was added dropwise with a syringe.
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