Synthesis of substituted 2-phenylhistamines via a microwave promoted Suzuki coupling

Article abstract of DOI:10.1016/j.tetlet.2007.10.119

Substitutions on the 2-position of the imidazole ring of histamine have proven useful in a number of biochemical settings. Current art for the synthesis of these constructs relies upon a cumbersome and low-yielding condensation reaction. Here-in we report a new procedure for the synthesis of a series of substituted 2-phenylhistamines utilizing a microwave-promoted Suzuki coupling.

Full text of DOI:10.1016/j.tetlet.2007.10.119

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9140–9143
Synthesis of substituted 2-phenylhistamines via a
microwave promoted Suzuki coupling
Amanda P. Skoumbourdis, Susanna Moore, Marc Landsman and Craig J. Thomas*
NIH Chemical Genomics Center, National Human Genome Research Institute, NIH 9800 Medical Center Drive,
MSC 3370, Bethesda, MD 20892-3370, USA
Received 5 June 2007; revised 23 October 2007; accepted 24 October 2007
Available online 19 November 2007
Abstract—Substitutions on the 2-position of the imidazole ring of histamine have proven useful in a number of biochemical settings.
Current art for the synthesis of these constructs relies upon a cumbersome and low-yielding condensation reaction. Here-in we
report a new procedure for the synthesis of a series of substituted 2-phenylhistamines utilizing a microwave-promoted Suzuki
coupling.
Published by Elsevier Ltd.
The utility of histamine analogues in various biochemi-
cal settings is firmly established. Derivatives of hista-
mine based upon alterations to the 2-aminoethyl side
chain have been employed as substrates for histamine
N-methyltransferase and as antagonists of the H1-recep-
tor.1,2 Methyl substitution at the 4-position of histamine
generates a potent agonist of the histamine H4-recep-
tor.3 Substitutions at the 2-position of histamine have
been widely explored both synthetically and biochemi-
cally, primarily as pharmacological tools for the hista-
mine receptors. Of particular interest has been the use
of 2-phenylhistamines as potent agonists of the
H1-receptor.4,5 Recent efforts by Leurs and co-workers
have identified 2-(3-trifluoromethyl)phenylhistamine
(3a) as the sole agonist of a mutant form of the hista-
mine H1-receptor.6 This combination of a synthetic
ligand and mutant receptor provides researchers with a
tool to study the relationship between function and
phenotype of a cellular target free of the selectivity
issues which plague studies utilizing the native ligand
and unaltered protein.
strategy is the ability to quickly explore numerous alter-
ations and structural sub-types to ascertain the effective-
ness of these constructs in a variety of biochemical
settings. It is imperative that the strategies employed
to construct these compounds are appropriately conver-
gent to maximize synthetic efficiency. The full under-
standing of the biochemical utility of substituted
2-phenylhistamine analogues is likely unknown given
the limited number of analogues explored to date. The
synthesis of substituted 2-phenylhistamines has relied
upon a condensation between amidines/imidates and
2-oxo-4-phthalimido-1-butyl acetate to afford phthali-
mide protected histamine analogues.5,7 Thus, a separate
syntheses of substituted amidines or imidates are
required for individual substituted 2-phenylhistamine
analogues. Recognizing the biochemical utility of these
constructs and the need for efficient methods to generate
larger numbers of related analogues, we sought out
alternate synthetic methods.
The utility of palladium-catalyzed cross-coupling reac-
tions has evolved to become a major foundation by
which new carbon-carbon bonds are formed.8 The inclu-
sion of microwave heating has aided the speed and
efficiency of these transformations, particularly in the
case of aryl–aryl Suzuki couplings.9 It was our goal to
develop a synthetic method for the formation of substi-
tuted 2-phenylhistamines utilizing a microwave-pro-
moted Suzuki coupling between substituted phenyl
boronic acids and a common 2-halohistamine deriva-
tive. Suzuki couplings between halo-heteroaromatic
Modified native ligands such as the aforementioned his-
tamine analogues have proven to be among the most
frequently explored pharmacological tools. A key to this
Keywords: Heteroaromatic Suzuki coupling; Microwave promoted
Suzuki coupling; 2-Phenylhistamine.
*
Corresponding author. Tel.: +1 301 217 4079; fax: +1 301 217
5736; e-mail: craigt@nhgri.nih.gov
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.10.119

A. P. Skoumbourdis et al. / Tetrahedron Letters 48 (2007) 9140–9143
9141
NHBoc
N
NHBoc
NH2
N
N
a
b
I
I
see ref. 14
HN
R
HN
HN
3a -n
I
1
2
Scheme 1. Reagents and conditions: (a) 1 N HCl, reflux 72 h; then (Boc)2O, 4 M NaOH, dioxane/H2O (50% over two steps); (b) PdCl2(PPh3)2
5 mol %, DME, 30 min; then 4a–n (3 equiv), aq Na2CO3, microwave irradiation (110 °C, 2 h); then 4 N HCl microwave irradiation (110 °C, 30 min).
constructs and aryl-boronic acids are frequently
reported and successful examples include couplings
between aryl-boronic acids and benzimidazoles,10
imidazoles,11 pyrimidines,12 and oxazoles.13 A method
for the construction of substituted 2-phenylhistamines
using this approach would allow for the rapid advance-
ment of numerous analogues via a final stage coupling
from a common precursor.
product. The resulting products (3a–n) were purified
immediately (failure to immediately purify the final
products was consistently detrimental to the overall
yield). Table 1 describes the scope and generality of
the procedure utilizing variously substituted phenyl
boronic acids to yield numerous substituted 2-phenylhis-
tamine analogues.16 Yields were consistently greater
than 60% for the two step, one-pot synthetic procedure.
Our method relies upon the facile synthesis of a 2-halo-
histamine derivative for the implementation of the final
Suzuki reaction (Scheme 1). To achieve this a protocol
from Cohen and co-workers14 was utilized whereby
Boc protected (a-nitrogen) histamine was iodinated with
2.2 equiv of N-iodosuccinimide to achieve Na-Boc-2,
4-diiodohistamine (1) in quantitative yield. Monoiodi-
nations utilizing stoichiometric quantities of N-iodosuc-
cinimide resulted in complex mixtures of the mono and
diiodinated products. Treatment of 1 in refluxing 1 N
HCl for 72 h followed by replacement of the Boc pro-
tecting group effectively yielded the necessary Na-Boc-
2-iodohistamine (2) in modest yields over two steps.
This key intermediate was then subjected to Suzuki type
conditions {PdCl2(PPh3)2 [5 mol %] in DME for 30 min
followed by 3 equiv of boronic acids 4a–n in aqueous
sodium bicarbonate}.15 The mixture was heated via
microwave irradiation to 110 °C for 2 h at which time
a 4 N solution of HCl in DME was added to the reac-
tion mixture and microwave irradiation was continued
for an additional 0.5 h. Higher temperatures with short-
er reaction times resulted in decomposition of the iodo-
histamine and an inability to recover the coupled biaryl
Various catalysts were explored, as well as surveys of the
inorganic base, solvent combinations and temperature
ranges. While the results from these appraisals were
not universal, the end choice of 5 mol % PdCl2(PPh3)2
and aqueous sodium bicarbonate consistently gave the
best results. Further, we considered the need for protec-
tion of the s-nitrogen and found that such attempts were
detrimental to the Suzuki coupling. Protection of the
a-nitrogen was essential for the reaction to progress.
Use of alternate protecting groups for the a-nitrogen
was also noted to confer unfavorable results on the
procedure.
In summary, we have developed a concise, efficient,
and general method for the synthesis of substituted 2-
phenylhistamine analogues from a common precursor.
Acknowledgments
We thank J. Lloyd for HRMS data. The authors would
like to thank the Intramural Research Programs of the
NHGRI and the NIDDK, NIH for supporting this
research.
Table 1.
NH2
N
B(OH)2
References and notes
R
R
HN
3a -n
4a -n
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31, 2297–2300.
Reactant
Product
R
Yielda (%)
2. Govoni, M.; Bakker, R. A.; van de Wetering, I.; Smit, M.
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4a
4b
4c
4d
4e
4f
3a
3b
3c
3d
3e
3f
m-CF3
H
62
66
69
67
61
64
60
66
42
66
51
58
59
59
o-OCH3
p-OCH3
p-CH3
p-tbutyl
o-F
4g
4h
4i
3g
3h
3i
p-F
3,5-CF3
o-OCH3, 5-F
3,5-F
m-NO2
m-NO2, p-CH3
o-Cl
4j
3j
4k
4l
3k
3l
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Leurs, R. J. Biol. Chem. 2005, 280, 34741–34746.
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a Yields calculated from intermediate 2 following the one-pot Suzuki
1071–1084.
coupling and Boc deprotection.
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A. P. Skoumbourdis et al. / Tetrahedron Letters 48 (2007) 9140–9143
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300 MHz) d 8.00 (dd, J = 1.7, 7.7 Hz, 1H), 7.34 (ddd,
J = 1.7, 7.3, 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.03
(ddd, J = 1.0, 7.4, 7.7 Hz, 1H), 7.07 (s, 1H), 4.08 (s, 3H),
3.15 (t, J = 6.9 Hz, 2H), 2.95 (t, J = 6.9 Hz, 2H); HRMS
calcd for C12H16N3O (M+H) 218.1215, found 218.1296. 2-
(4-Methoxyphenyl)-histamine (3d): Using the general
procedure and starting with 0.027 g (0.082 mmol) of N-
tertbutylcarbonyl-2-iodohistamine, 0.012 g (67%) of 3d
´
´
10. Ezquerra, J.; Lamas, C.; Pastor, A.; Garcıa-Navıo, J. L.;
Vaquero, J. J. Tetrahedron 1997, 37, 12755–12764.
11. Langhammer, I.; Erker, T. Heterocycles 2005, 65, 2721–
2728.
12. Ceide, S. C.; Montalban, A. G. Tetrahedron Lett. 2006, 47,
4415–4418.
13. Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett.
2006, 8, 2495–2498.
1
was obtained; H NMR (CD3OD, 300 MHz) d 7.88–7.85
(m, 2H), 7.11–7.07 (m, 3H), 6.97 (s, 1H), 3.93 (s, 3H), 3.05
(t, J = 6.9 Hz, 2H), 2.88 (t, J = 6.9 Hz, 2H); HRMS calcd
for C12H16N3O (M+H) 218.1215, found 218.1292. 2-(4-
methylphenyl)-histamine (3e): Using the general procedure
and starting with 0.030 g (0.090 mmol) of N-tertbutylcar-
bonyl-2-iodohistamine, 0.011 g (61%) of 3e was obtained;
1H NMR (CD3OD, 300 MHz) d 7.82 (d, J = 8.1 Hz, 2H),
7.35 (d, J = 7.8 Hz, 2H), 7.00 (s, 1H), 3.06 (t, J = 6.9 Hz,
2H), 2.95 (t, J = 6.9 Hz, 2H), 2.47 (s, 3H); HRMS calcd
for C12H16N3 (M+H) 202.1266, found 202.1342. 2-(4-tert-
Butylphenyl)-histamine (3f): Using the general procedure
and starting with 0.028 g (0.083 mmol) of N-tertbutylcar-
bonyl-2-iodohistamine, 0.013 g (64%) of 3f was obtained;
1H NMR (CD3OD, 300 MHz) d 7.76 (d, J = 8.4 Hz, 2H),
7.47 (d, J = 8.7 Hz, 2H), 6.91 (s, 1H), 2.99 (t, J = 6.9 Hz,
2H), 2.81 (t, J = 6.9 Hz, 2H), 1.42 (s, 9H); HRMS calcd
for C15H22N3 (M+H) 244.1735, found 244.1823. 2-(2-
fluorophenyl)-histamine (3g): Using the general procedure
and starting with 0.030 g (0.089 mmol) of N-tertbutylcar-
bonyl-2-iodohistamine, 0.011 g (60%) of 3g was obtained;
1H NMR (CD3OD, 300 MHz) d 7.53 (ddd, J = 1.5, 7.5,
9.3 Hz, 1H), 7.55–7.47 (m, 1H), 7.40–7.30 (m, 2H), 7.09 (s,
1H), 3.07 (t, J = 6.9 Hz, 2H), 2.92 (t, J = 6.9 Hz, 2H);
HRMS calcd for C11H13N3F (M+H) 206.1015, found
206.1098. 2-(4-Fluorophenyl)-histamine (3h): Using the
general procedure and starting with 0.029 g (0.088 mmol)
of N-tertbutylcarbonyl-2-iodohistamine, 0.012 g (66%) of
14. Jain, R.; Avramovitch, B.; Cohen, L. A. Tetrahedron 1998,
54, 3235–3242.
15. General experimental: All microwave reactions were per-
formed in a Biotage 0.5–2.0 mL vessel with a crimped top.
1,2-Dimethoxyethane (DME) was used as purchased. The
4 M hydrochloric acid in dimethoxyethane (HCl in DME)
solution was used as purchased. The 2 M aqueous sodium
carbonate solution was freshly prepared for each iteration.
All organic reagents were used as purchased. The cata-
lyst, trans-dichlorobis(triphenylphosphine) palladium(II)
[Pd(PPh3)2Cl2] was purchased from Strem Chemicals and
stored in a desiccator. The products were purified via flash
chromatography, using 32–63 lm silica gel. Methylene
chloride for chromatography (CH2Cl2) was used as
purchased. Saturated ammonia/methanol (CH3OH/
(NH3)) was prepared by sparging methanol with ammonia
gas for approx. 1 h. A Biotage Initiator 1.2 microwave was
utilized for the Suzuki coupling reactions. HRMS were
obtained by The Proteomics and Mass Spectrometry
Facility at NIDDK/NIH/DHHS on a Waters LCT
Premier time-of-flight (TOF) mass spectrometer, using
the internal reference standard method. General procedure
for Suzuki coupling: To a solution of N-tertbutylcarbonyl-
2-iodohistamine (1 equiv) in dimethoxyethane (0.04 M)
was added PdCl2(PPh3)2 (5 mol %). The solution was
sparged with nitrogen and stirred at room temperature for
0.5 h, at which time the boronic acid (3 equiv) and aq
sodium carbonate (2 M) were added. The reaction solu-
tion was sparged again with nitrogen and then placed in
the microwave and heated for 2 h at 110 °C. When TLC
and LC–MS showed full consumption of starting materi-
als, HCl/dioxane (4 M) was added and the reaction tube
was again placed in the microwave and heated for 0.5 h.
The crude product was directly purified by column
chromatography (without additional work-up; 0–20%
CH3OH(NH3)/CH2Cl2) to isolate the histamines as free
bases. All products showed greater than 95% purity by
LCMS analysis, however, it should be noted that each
product eluted in the void volume of a 100% buffered
aqueous gradient.
1
3h was obtained; H NMR (CD3OD, 300 MHz) d 7.98–
7.93 (m, 2H), 7.31–7.26 (m, 2H), 7.04 (s, 1H), 3.11 (t,
J = 6.9 Hz, 2H), 2.92 (t, J = 6.9 Hz, 2H); HRMS calcd for
C11H13N3F (M+H) 206.1015, found 206.1101. 2-(3,5-bis-
Trifluoromethylphenyl)-histamine (3i): Using the general
procedure and starting with 0.030 g (0.088 mmol) of N-
tertbutylcarbonyl-2-iodohistamine, 0.012 g (42%) of 3i
was obtained; 1H NMR (CD3OD, 300 MHz) d 8.58 (s,
1H), 8.05 (app. s, 2H), 7.18 (s, 1H), 3.15 (t, J = 6.9 Hz,
2H), 2.97 (t, J = 6.9 Hz, 2H); HRMS calcd for
C13H12N3F6 (M+H) 324.0857, found 324.0932. 2-(2-
Methoxy-5-fluorophenyl)-histamine (3j): Using the general
procedure and starting with 0.028 g (0.084 mmol) of N-
tertbutylcarbonyl-2-iodohistamine, 0.013 g (66%) of 3j
1
16. 2-(3-Trifluoromethylphenyl)-histamine (3a): Using the
general procedure and starting with 0.10 g (0.297 mmol)
of N-tertbutylcarbonyl-2-iodohistamine, 0.047 g (62%) of
was obtained; H NMR (CD3OD, 300 MHz) d 7.75 (dd,
J = 2.7, 9.6 Hz, 1H), 7.14–7.03 (m, 2H), 6.98 (s, 1H), 3.98
(s, 3H), 3.03 (t, J = 6.9 Hz, 2H), 2.84 (t, J = 6.9 Hz, 2H);
HRMS calcd for C12H15N3OF (M+H) 236.1121, found
236.1207. 2-(3,5-Difluorophenyl)-histamine (3k): Using the
general procedure and starting with 0.030 g (0.088 mmol)
of N-tertbutylcarbonyl-2-iodohistamine, 0.010 g (51%) of
1
3a was obtained; H NMR (CD3OD, 300 MHz) d 8.29 (s,
1H) 8.21–8.17 (m, 1H), 7.78–7.72 (m, 2H), 7.10 (s, 1H),
3.09 (t, J = 6.9 Hz, 2H), 2.92 (t, J = 6.9 Hz, 2H); 13C
NMR (CD3OD, 150 MHz) d 144.8, 131.1, 130.8, 129.4,
128.1, 125.0, 124.6, 124.5, 123.2, 121.4 40.7, 28.9; HRMS
calcd for C12H13N3F3 (M+H) 256.0983, found 256.1060.
2-(Phenyl)-histamine (3b): Using the general procedure
and starting with 0.030 g (0.089 mmol) of N-tertbutylcar-
bonyl-2-iodohistamine, 0011 g (66%) of 3b was obtained;
1H NMR (CD3OD, 300 MHz) d 7.86–7.81 (m, 2H), 7.47–
7.32 (m, 3H), 6.94 (s, 1H), 2.98 (t, J = 6.9 Hz, 2H), 2.80 (t,
J = 6.9 Hz, 2H); HRMS calcd for C11H14N3 (M+H)
188.1109, found 188.1185. 2-(2-Methoxyphenyl)-histamine
(3c): Using the general procedure and starting with 0.031 g
(0.093 mmol) of N-tertbutylcarbonyl-2-iodohistamine,
0.014 g (69%) of 3c was obtained; 1H NMR (CD3OD,
1
3k was obtained; H NMR (CD3OD, 300 MHz) d 7.49–
7.44 (m, 2H) 7.04 (s, 1H), 7.0–6.92 (m, 1H), 3.10 (t,
J = 6.9 Hz, 2H), 2.88 (t, J = 6.9 Hz,2H); HRMS calcd for
C11H12N3F2 (M+H) 224.0921, found 224.1007. 2-(3-
Nitrophenyl)-histamine (3l): Using the general procedure
and starting with 0.030 g (0.089 mmol) of N-tertbutylcar-
bonyl-2-iodohistamine, 0.012 g (58%) of 3l was obtained;
1H NMR (CD3OD, 300 MHz) d 8.77–8.76 (m, 1H), 8.32–
8.22 (m, 2H), 7.84–7.78 (m, 1H), 7.10 (s, 1H), 3.17
(t, J = 6.9 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H); HRMS calcd
for C11H13N4O2 (M+H) 233.0906, found 233.1038.
2-(3-Nitro-4-methylphenyl)-histamine (3m): Using the gen-

A. P. Skoumbourdis et al. / Tetrahedron Letters 48 (2007) 9140–9143
9143
eral procedure and starting with 0.028 g (0.083 mmol) of
N-tertbutylcarbonyl-2-iodohistamine, 0.012 g (59%) of 3m
was obtained; 1H NMR (CD3OD, 300 MHz) d 8.57 (d,
J = 1.8, 1H), 8.15–8.09 (m, 1H), 7.67–7.62 (m, 1H), 7.13
(s, 1H), 3.15 (t, J = 6.9 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H),
2.69 (s, 3H); HRMS calcd for C12H15N4O2 (M+H)
247.1117, found 247.1201. 2-(2-Chlorophenyl)-histamine
(3n): Using the general procedure and starting with 0.031 g
(0.092 mmol) of N-tertbutylcarbonyl-2-iodohistamine,
0.012 g (59%) of 3n was obtained; 1H NMR (CD3OD,
300 MHz) d 7.71–7.68 (m, 1H), 7.53–7.50 (m, 1H), 7.42–
7.38 (m, 2H), 6.99 (s, 1H), 2.98 (t, J = 6.9 Hz, 2H), 2.81 (t,
J = 6.9 Hz, 2H); HRMS calcd for C11H13ClN3 (M+H)
222.0720, found 222.0797.