Bohlmann-Rahtz cyclodehydration of aminodienones to pyridines using N-iodosuccinimide

Article abstract of DOI:10.3390/molecules15053211

Cyclodehydration of Bohlmann-Rahtz aminodienone intermediates using N-iodosuccinimide as a Lewis acid proceeds at low temperature under very mild conditions to give the corresponding 2, 3,6-trisubstituted pyridines in high yield and with total regiocontrol.

Full text of DOI:10.3390/molecules15053211

Molecules 2010, 15, 3211-3227; doi:10.3390/molecules15053211
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Bohlmann-Rahtz Cyclodehydration of Aminodienones to
Pyridines Using N-Iodosuccinimide
Mark C. Bagley * and Christian Glover
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Author to whom correspondence should be addressed; E-Mail: Bagleymc@cardiff.ac.uk.
Received: 22 March 2010 / Accepted: 20 April 2010 / Published: 30 April 2010
Abstract: Cyclodehydration of Bohlmann-Rahtz aminodienone intermediates using
N-iodosuccinimide as a Lewis acid proceeds at low temperature under very mild conditions
to give the corresponding 2,3,6-trisubstituted pyridines in high yield and with total
regiocontrol.
Keywords: Bohlmann-Rahtz synthesis; cyclization reactions; heterocycles; Lewis acids;
pyridines
1. Introduction
The synthesis, reactions and properties of pyridine-containing derivatives is an important
component of modern heterocyclic chemistry. This heterocyclic motif is found in a large number of
pharmaceutical agents [1], as a pharmacophore of considerable importance, and a valuable synthetic
building block in drug discovery, heterocyclic chemistry and natural product synthesis [2]. Thus, new
and facile methods for the synthesis of polysubstituted pyridines are of considerable current interest, in
particular if they have a predictable and reliable regiochemical outcome and provide the heterocycle in
high yield from readily-available precursors. The Bohlmann-Rahtz pyridine synthesis bears close
relation to many well-established approaches to pyridines based upon heterocyclocondensation
processes, such as the Hantzsch dihydropyridine synthesis [3], and was first reported back in 1957 [4].
This robust two-step method provides an efficient route to 2,3,6-trisubstituted pyridines 4 from
stabilized enamines 1 and ethynyl ketones 2. It proceeds by an initial Michael addition to give an
aminodienone intermediate 3, which is isolated and purified, and subsequent cyclodehydration under
forcing conditions (up to 200 ºC) in order to facilitate E/Z-isomerization and subsequent spontaneous

Molecules 2010, 15
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heterocyclization to the pyridine product
4
(Scheme 1). Since its discovery, this
heterocyclocondensation reaction has received very little attention until recently [5], when it has found
application in the synthesis of pyridine libraries [6,7], pyrido[2,3-d]pyrimidines [8–11], α-helix
mimetics [12], nicotinonitrile-derived chromophores with tunable photophysical properties [13,14],
heterocyclic amino acids [15–17], and in the preparation of pyridine-containing natural products such
as the thiopeptide antibiotics [18–22] and chemical derivatives thereof [5,23–27].
Scheme 1. Two-step Bohlmann-Rahtz synthesis of 2,3,6-trisubstituted pyridines 4.
OR3
OR3
O
E
EtOH
50 °C
R2
+
O
O
Z
O
R2
H2N
R1
H2N
R1
2
3
1
O
O
Z
R3O
-H2O

R3O
E
R1
O
R2
H+
N
R1
N
R2
H
H
4
Given its wide range of potential applications, many efforts have been made to improve the
Bohlmann-Rahtz pyridine synthesis, with particular emphasis on catalyzing the E/Z-isomerization and
subsequent cyclodehydration in order to avoid the use of very high temperatures and broaden its
substrate specificity. Recent findings have shown that the heterocyclization can be accelerated through
the use of a Brønsted or Lewis acid [5,9,28,29] and can be carried out in just one operation through the
use of a protic solvent [30] or at high temperature under microwave dielectric heating [31]. Alternative
processing methods have also been reported for the cyclodehydration reaction, such the use of
continuous flow reactors [32,33], and this transformation can be incorporated into a one-pot multistep
process by combining with reactions such as tandem oxidation [34] or enamine formation [35] which
improves the overall chemical yield. However, despite the synthetic utility of Bohlmann-Rahtz
aminodienones 3, as evidenced by their widespread application [5–27], no studies had been undertaken
to divert these intermediates down an alternative reaction path in order to expand the scope of possible
products.
In 2002, Dechoux and co-workers described that the δ-dienaminoester 5 reacted with
N-iodosuccinimide (NIS) in methanol in the presence of sodium methoxide to give the corresponding
3-iodo-2(1H)-pyridinone 6 in 84% yield (Scheme 2) [36].
Scheme 2. Synthesis of 3-iodo-2(1H)-pyridinone 6 from δ-dienaminoester 5 by Dechoux
and co-workers [36].
MeO2C
Me
I
MeO2C
CO2Me
NIS
MeOH, NaOMe
N
O
reflux, 4 h
(84%)
Ph
N
H
Me
Ph
5
6

Molecules 2010, 15
3213
The reaction was found to be highly chemoselective and yet could be diverted to provide the
polysubstituted pyrrole as an alternative product simply by changing the reagent and altering the
conditions [37]. The use of NIS as an electrophilic iodinating agent for aldehydes, ketones and alkenes
is well reported but recent developments have seen a host of further applications, such as the use of
Brønsted or Lewis acids to improve its reactivity in electrophilic aromatic substitution reactions
[38–40], asymmetric iodination of aldehydes using an axially chiral catalyst [41] and 1,3-dicarbonyl
compounds under mild conditions [42], synthesis of haloalkenes and haloalkynes by catalytic
Hunsdiecker reaction [43], the reaction of alkynes and NIS/water to give α-diketones [44], highly
enantioselective iodocyclization of polyprenoids [45] and Au-catalyzed formation of 2-iodoenones
from propargylic alcohol derivatives [46,47], amongst others. Interestingly, there have also been a few
reports on the use of NIS as a mild and selective Lewis acid, such as in the catalytic deprotection of
TBDMS ethers to alcohols in methanol under ambient conditions [48] and the N-debenzylation of
benzylamino alcohols [49]. Given this spectrum of reactivity and the precedent offered by Dechoux
[36,37], we set out to examine the reaction of the Bohlmann-Rahtz aminodienone intermediate 3 with
NIS to establish the mechanistic course (Scheme 3). It was anticipated that reaction could proceed by
iodination followed by heteroannulation to give the 5-iodopyridine 7 in a similar fashion to Dechoux’s
pyridinone synthesis [36] (path a), iodination followed by displacement of iodide to give the
acylpyrrole 8 following Dechoux’s pyrrole-5-carboxylate synthesis [37] (path b), or whether it would
follow a new reaction course as a Lewis acid to give the Bohlmann-Rahtz pyridine 4 (path c).
Scheme 3. Possible mechanistic course (path a, b or c) of the reaction between Bohlmann-
Rahtz aminodienones 3 and NIS.
OR3
O
O
R2
H2N
R1
NIS
NIS
path a and b
path c
3
R3O2C
R1
OR3
O
O
R2
N
R2
I
4
H2N
path a
R1
path b
R3O2C
R1
R3O2C
R1
I
R2
R2
N
H
N
O
7
8
2. Results and Discussion
In order to test the behaviour of the Bohlmann-Rahtz intermediates on treatment with NIS, a sample
library of aminodienones 3 was prepared from the corresponding enamines 1 and ethynyl ketones 2.
The enamine subset 1a-c was generated according to our previously reported procedure (Scheme 4)

Molecules 2010, 15
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[29] whereas the ethynyl ketone subset employed 4-(trimethylsilyl)but-3-yn-2-one 2a as a but-3-yn-2-
one surrogate [29] and was complemented by additional aryl ethynyl ketone subset members 2b-d
prepared by the o-iodoxybenzoic acid (IBX)-mediated oxidation [51] of propargylic alcohols 9b-d,
which in turn could be generated by addition of ethynylmagnesium bromide to the corresponding
benzaldehyde 10c,d [13,29,50] (Figure 4). This small library of ethynyl ketones 2a-d was chosen to
probe if electronic effects had a major influence upon the mechanistic course and, while certainly not
exhaustive in scope, was felt to be representative.
Scheme 4. Enamine and aryl ethynyl ketone subsets, 1a-c and 2b-d, respectively.
OR3
OR3
1a R1 = Me, R3 = Et
1b R1 = Ph, R3 = Et (60%)
1c R1 = Me, R3 = tBu (98%)
NH3
O
O
[ref. 29]
O
R1
H2N
R1
O
I
HO
MgBr
O
O
O
H
HO
O
then aq.
NH4Cl
(IBX)
DMSO, 5 h
R
R
R
9b R = H
2b R = H [ref. 29]
2c R = Cl (93%)
2d R = OMe (89%)
10c R = Cl
10d R = OMe
9c R = Cl (76%)
9d R = OMe (63%)
The Michael addition of the enamine subset 1a-c and ethynyl ketones 2a-d was carried out under
traditional Bohlmann-Rahtz conditions in ethanol at 50 ºC to give pure aminodienones 3 after
purification by column chromatography on silica, in order to ensure no contamination from the
corresponding pyridines 4 was evident prior to treatment with NIS. For the most part, the Michael
addition reactions were highly efficient, apart from the synthesis of phenyldienone 3ba, which was
prepared in low yield as significant cyclodehydration to 4ba (which was removed on purification)
occurred spontaneously under the reaction conditions (Table 1).
With pure samples of the Bohlmann-Rahtz aminodienone intermediates 3 in hand, each was treated
in turn with a stoichiometric quantity of NIS in ethanol at 0 ºC. In all cases, including both electron-
poor and electron-rich aryldienones, only one reaction course was seen to operate: NIS was found to
behave as a Lewis acid under these conditions, promoting spontaneous cyclodehydration of the
normally kinetically-stable aminodienones to give the corresponding pyridine 4 in excellent yield
(Table 1). In all cases only a single pyridine regioisomer was obtained, in accordance with the course
of a Bohlmann-Rahtz cyclodehydration reaction [4,5]. The only substrate that was not efficient in this
process was aminoheptadienone 3aa (entry 1), but by extending the reaction time to 4 h, pyridine 4aa
was isolated in an acceptable 84% yield. All of the other substrates gave a near quantitative yield of the
corresponding pyridine products 4. Furthermore, in order to establish the role of the NIS, one of these
cyclodehydration reactions were carried out in the presence of a catalytic quantity (20 mol % NIS) of
reagent (entry 3) and, for this substrate, the final yield of pyridine 4ab was found to be unchanged
(>98% isolated yield).

Molecules 2010, 15
Table 1. Synthesis of aminodienones 3 and their cyclodehydration to pyridines 4 mediated by NIS.
3215
Yield% a
Entry
3
4
Yield% b
1
2
OEt
O
EtO2C
O
1
1a 2a
1b 2a
1a 2b
3aa (82)
4aa (66 or 84c)
N
N
H2N
OEt
O
EtO2C
Ph
O
2
3
3ba (23)
3ab (85)
4ba (>98)
4ab (>98)d
H2N
Ph
OEt
O
EtO2C
O
Ph
N
Ph
H2N
OEt
EtO2C
O
O
O
4
1a 2c
3ac (86)
4ac (97)
N
H2N
OEt
Cl
Cl
EtO2C
O
5
6
1a 2d
3ad (95)
3ca (68)
4ad (>98)
4ca (>98)e
N
H2N
O
O
OtBu
O
tBuO2C
O
1c 2a
N
H2N
a Isolated yield of 3, obtained after heating a solution of the corresponding subset members 1 and 2
in EtOH at 50 ºC followed by chromatographic purification on silica gel, is given in parentheses;
b
Isolated yield of 4, obtained after treatment with NIS (1 equiv.) in EtOH at 0 ºC followed by
chromatographic purification on silica gel, is given in parentheses; c Reaction with NIS was carried
out over 4 h at 0 ºC; d Isolated yield of 4ab was unchanged using either a stoichiometric (1 equiv.)
e
or catalytic (20 mol%) amount of NIS; Isolated yield of 4ca was unchanged if the reaction was
carried out in the presence of NaHCO3.
The reaction course followed by Bohlmann-Rahtz intermediates on treatment with NIS (Scheme 3,
path c) is in contrast to the behaviour of aminodienoates such as 5 as reported by Dechoux, which give
the corresponding pyrrole derivatives under comparable reaction conditions (in analogy to Scheme 3,
path b). This contrasting behaviour could be attributed to the increased reactivity of the ketone towards
cyclodehydration but nonetheless is a remarkable switch in mechanism. The surprising facility of this
process is also worthy of note. Typically, the Bohlmann-Rahtz cyclodehydration requires high
temperatures (up to 200 ºC) or the action of a Brønsted or Lewis acid under heating (microwave or
conventional), but, for most of the substrates examined, a near quantitative yield was obtained after
only 1 h at 0 ºC. In order to establish if traces of a Brønsted acid (such as HI) had been responsible for

Molecules 2010, 15
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the extremely facile cyclodehydration, the reaction of aminodienone 3ca with NIS (1 equiv.) was
repeated in the presence of NaHCO3 base (Table 1, entry 6), but the yield of pyridine 4ca was found to
be unchanged (>98% isolated yield). Purification of the NIS by recrystallization immediately prior to
use was also found to have no effect upon the reaction course or efficiency. Furthermore, in the
absence of NIS, when aminodienone 3aa was stirred in EtOH at 0 ºC, no cyclodehydration occurred at
all and only unreacted starting material was obtained, as identified by 1H-NMR spectroscopic analysis,
confirming a catalytic role for the reagent in the Z/E isomerisation and subsequent spontaneous
cyclodehydration.
3. Experimental Section
3.1. General
Commercially available reagents were used without further purification; solvents were dried by
standard procedures. Light petroleum refers to the fraction with bp 40–60 ºC, ether (Et2O) refers to
diethyl ether and EtOAc refers to ethyl acetate. Column chromatography was carried out using Merck
Kieselgel 60 H silica or Matrex silica 60. Analytical thin layer chromatography was carried out using
aluminium-backed plates coated with Merck Kieselgel 60 GF254 that were visualised under UV light
(at 254 and/or 360 nm). Melting points (mp) were determined on a Kofler hot stage apparatus and are
uncorrected. Infra–red (IR) spectra were recorded in the range 4,000–600 cm–1 on a Perkin-Elmer 1600
series FTIR spectrometer using KBr disks for solid samples and thin films between NaCl plates for
liquid samples or as a nujol mull and are reported in cm–1. Nuclear magnetic resonance (NMR) spectra
were recorded in CDCl3 at 25 ºC unless stated otherwise using a Bruker DPX 400 or 500 Avance
instrument operating at 400 or 500 MHz for 1H spectra and 100 or 125 MHz for 13C spectra and were
reported in ppm; J values were recorded in Hz and multiplicities were expressed by the usual
conventions (s = singlet, d = doublet, t = triplet, app = apparent, m = multiplet). Low-resolution mass
spectra (MS) were determined using a Fisons VG Platform II Quadrupole instrument using
atmospheric pressure chemical ionization (APcI) unless stated otherwise. ES refers to electrospray
ionization, CI refers to chemical ionization (ammonia) and EI refers to electron impact. High-
resolution mass spectra were obtained courtesy of the EPSRC Mass Spectrometry Service at Swansea,
UK using the ionisation methods specified. Microanalyses were recorded using a Perkin-Elmer 240C
Elemental Analyzer. In vacuo refers to evaporation at reduced pressure using a rotary evaporator and
diaphragm pump, followed by the removal of trace volatiles using a vacuum (oil) pump.
3.2. Typical experimental procedures
3.2.1. Typical procedure for Michael addition of an enamine 1 and ethynyl ketone 2
A solution of the enamine 1 (0.36 mmol, 1 equiv.) and alkynone 2 (0.56 mmol, 1.5 equiv.) in EtOH
(5 mL) was stirred at 50 ºC for 1–7 h, cooled and evaporated in vacuo to give the crude product.
Purification by column chromatography on silica gel, eluting with EtOAc–light petroleum, gave the
aminodienone 3.

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3.2.2. Typical procedure for cyclodehydration of a Bohlmann-Rahtz aminodienone 3 using NIS
A solution of the aminodienone 3 (0.2 mmol, 1 equiv.) and N-iodosuccinimide (NIS) (0.25 mmol,
1.2 equiv.) in EtOH (4 mL) was stirred at 0 ºC for 1 h and then evaporated in vacuo to give the crude
product. Purification by column chromatography on silica gel, eluting with EtOAc–light petroleum,
gave the pyridine 4.
3.2.3. Typical procedure for the synthesis of propargylic alcohols 9 from aldehydes 10
A solution of the aldehyde 10 (5.0 mmol) in dry THF (10 mL) was added to a stirred solution of
ethynylmagnesium bromide in THF (0.5 M; 15 mL, 7.5 mmol) at 0 ºC. The mixture was stirred at 0 ºC
for 2 h, warmed to room temperature and stirred overnight. Saturated aqueous NH4Cl solution (2 mL)
was added. The mixture was evaporated in vacuo and partitioned between ether (30 mL) and saturated
aqueous ammonium chloride solution (30 mL). The ethereal layer was washed with brine (30 mL),
dried (Na2SO4) and evaporated in vacuo.
3.3. Experimental procedures
3.3.1. Ethyl 3-amino-3-phenylpropenoate (1b)
Ammonium acetate (13.4 g, 0.17 mol) was added to a solution of ethyl benzoylacetate (5 mL,
29.0 mmol) and the mixture was heated at reflux in toluene–glacial acetic acid (5:1; 40 mL) for 20 h.
After partitioning between H2O (100 mL) and ether (60 mL), the aqueous layer was further extracted
with ether (2 × 25 mL) and the combined organic extracts were washed sequentially with saturated
aqueous NaHCO3 solution (50 mL) and brine (25 mL), dried (MgSO4) and evaporated in vacuo.
Purification by column chromatography on SiO2 gel, eluting with light petroleum–EtOAc (3:1)
+
(Rf = 0.11), gave the title compound [29] as a pale yellow oil (3.32 g, 60%) (Found: MNH4 , 209.1289.
C11H17N2O2 [MNH4 ] requires 209.1285); IR (film)/cm-1 max 3,441, 3,326, 2,979, 2,936, 1,663, 1,617,
+
1,555, 1,492, 1,364, 1,176, 1,095, 1,025, 796, 772, 699; 1H-NMR (400 MHz; CDCl3) H 8.35 (1H, bs,
NH), 7.33–7.12 (5H), 7.00 (1H, bs, NH), 4.75 (1H, s, CH), 3.95 (2H, q, J = 7.1 Hz, OCH2Me), 1.05
13
(3H, t, J = 7.1 Hz, CH2Me); C-NMR (100 MHz, CDCl3) C 170.5 (C), 160.5 (C), 137.7 (C), 130.3
(CH), 128.9 (CH), 126.2 (CH), 84.7 (CH), 59.0 (CH2), 14.6 (Me); m/z (APcI) 192 (MH+, 100%) and
146 (13).
3.3.2. tert-Butyl β-aminocrotonate (1c)
Ammonium hydroxide solution (35%, 40 mL) was added to tert-butyl acetoacetate (4 mL,
24.2 mmol) in MeOH (40 mL) and the mixture was stirred at 50 ºC for 18 h. After cooling, the solution
was evaporated in vacuo and partitioned between H2O (40 mL) and ether (40 mL). The aqueous layer
was further extracted with EtOAc (2 × 35 mL) and the combined organic extracts were washed with
brine (25 mL), dried (Na2SO4) and evaporated in vacuo to give the title compound [52] as a colourless
oil (3.72 g, 98%) (Found: MH+, 158.1178. C8H16NO2 [MH+] requires 158.1176); IR (film)/cm-1 max
1
3,554, 3,341, 2,980, 2,919, 1,666, 1,622, 1,567, 1,454, 1,390, 1,366, 1,296, 1,150, 983, 790; H-NMR
(400 MHz; CDCl3) H 8.20 (1H, bs, NH), 4.20 (1H, bs, NH), 4.35 (1H, s, CH), 1.80 (3H, s, Me), 1.38

Molecules 2010, 15
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(9H, s, CMe3); 13C-NMR (100 MHz, CDCl3) C 170.3 (C), 158.8 (C), 85.9 (CH), 78.2 (C), 28.6 (Me),
22.4 (Me); m/z (APcI) 158 (MH+, 77%).
3.3.3. 1-Phenylprop-2-yn-1-one (2b)
A solution of o-iodoxybenzoic acid (IBX) [51] (3.65 g, 13.0 mmol) in DMSO (110 mL) was stirred
for 15 min at room temperature until homogeneous. A solution of 1-phenyl-2-propyn-1-ol 9b (1.32 g,
10.0 mmol) in DMSO (10 mL) was added and the mixture was stirred for 5 h. H2O (30 mL) was added
and the mixture was stirred at room temperature for 10 min, cooled in ice and partitioned between H2O
(120 mL) and ether (90 mL). The mixture was filtered through Celite® and the aqueous layer was
further extracted with ether (50 mL). The organic extracts were combined, washed sequentially with
H2O (3 × 50 mL), saturated aqueous NaHCO3 solution (70 mL) and brine (70 mL), dried (Na2SO4) and
evaporated in vacuo to give the title compound as a pale yellow solid (1.0 g, 77%), m.p.
49–50 ºC (MeOH) (literature [29] m.p. 47–48 ºC) (Found: M+, 130.0414. C9H6O [M+] requires
130.0413); IR (KBr)/cm-1 max 3,231, 2,094, 1,645, 1,593, 1,578, 1,452, 1,317, 1,261, 1,173, 1,005,
1
695; H-NMR (400 MHz; CDCl3) H 8.12 (2H, m, o-PhH), 7.55 (1H, m, p-PhH), 7.45 (2H, m, m-
PhH), 3.36 (1H, s, CH); 13C-NMR (100 MHz; CDCl3) C 177.5 (C), 136.1 (C), 134.6 (CH), 129.7
(CH), 128.7 (CH), 80.9 (C), 80.3 (CH); m/z (EI) 130 (M•+, 16%), 77 (32), 53 (100).
3.3.4. 1-(4-Chlorophenyl)prop-2-yn-1-one (2c)
Propargylic alcohol 9c was prepared using aldehyde 10c according to the general procedure 3.2.3.
Purification by column chromatography on SiO2 gel, eluting with CH2Cl2 (Rf 0.27), gave 1-(4-
chlorophenyl)prop-2-yn-1-ol (9c) [50] as a pale yellow oil (635 mg, 76%) (Found: M+, 166.0181.
C9H7ClO [M+] requires 166.0180); IR (film)/cm–1 max 3418, 3296, 2884, 2119, 1904, 1645, 1597,
1
1490, 1406, 1257, 1192, 1092, 1015, 950, 909, 835, 791, 734, 650; H NMR (400 MHz; CDCl3) H
7.48 (2H, app d, J = 8.4 Hz, 2’,6’-PhH), 7.33 (2H, app d, J = 8.4 Hz, 3’,5’-PhH), 5.45 (1H, s, 1-H),
2.68 (1H, s, 3-H), 2.28 (1H, s, OH); 13C NMR (100 MHz; CDCl3) C 138.4 (C), 134.4 (C), 128.8 (CH),
128.0 (CH), 83.1 (CH), 75.3 (C), 63.7 (CH); m/z (EI) 166 (M•+, 9%), 164 (27), 113 (5), 111 (14), 53
(100). A solution of IBX (5.84 g, 20.8 mmol) in DMSO (120 mL) was stirred for 15 min at room
temperature until homogeneous. A solution of 1-(4-chlorophenyl)prop-2-yn-1-ol (9c) (2.72 g, 16.3
mmol) in DMSO (20 mL) was added and the mixture was stirred for 5 h. H2O (40 mL) was added and
the mixture was stirred at room temperature for 10 min, cooled in ice and partitioned between H2O
(120 mL) and ether (90 mL). The mixture was filtered through Celite® and the aqueous layer was
further extracted with ether (50 mL). The organic extracts were combined, washed sequentially with
H2O (3 × 50 mL), saturated aqueous NaHCO3 solution (70 mL) and brine (70 mL), dried (Na2SO4) and
evaporated in vacuo. Purification by column chromatography on SiO2 gel, eluting with CHCl3
(Rf = 0.45), gave the title compound as a pale yellow solid (2.50 g, 93%), m.p. 68–69 ºC (MeOH)
(literature [6] m.p. 68–69 ºC) (Found: M+, 165.9991. C9H5Cl37O [M+] requires 165.9994); IR
1
(KBr)/cm-1 max 2,921, 2,853, 2,360, 1,662, 1,462, 1,377, 1,248, 1,094, 1,003, 722; H-NMR (400
MHz; CDCl3) H 7.98 (2H, app d, J = 8.6 Hz, 2’,6’-PhH), 7.41 (2H, app d, J = 8.6 Hz, 3’,5’-PhH),
3.38 (1H, s, CH); 13C-NMR (100 MHz; CDCl3) C 176.1 (C), 141.3 (C), 134.5 (C), 131.0 (CH), 129.1

Molecules 2010, 15
3219
(CH), 81.4 (C), 79.9 (CH); m/z (EI) 166 (M•+, 7%), 164 (M•+, 21), 138 (11), 136 (33), 113 (3), 111
(12), 53 (100).
3.3.5. 1-(4-Methoxyphenyl)prop-2-yn-1-one (2d)
Propargylic alcohol 9d was prepared using aldehyde 10d according to the general procedure 3.2.3.
Purification by column chromatography on SiO2 gel, eluting with CH2Cl2 (Rf 0.10), gave 1-(4-
methoxyphenyl)prop-2-yn-1-ol (9c) [6,53] as a pale yellow oil (513 mg, 63%) (Found: MH+, 161.0596.
C10H10O2 [MH+] requires 161.0597); IR (film)/cm-1 max 3,438, 3,284, 3,003, 2,935, 2,837, 1,892,
1
1,611, 1,512, 1,464, 1,442, 1,304, 1,249, 1,174, 1,112, 1,032, 948, 833, 768; H-NMR (400 MHz;
CDCl3) H 7.50 (2H, app d, J 8.6, 2’,6’-PhH), 6.90 (2H, app d, J 8.6, 3’,5’-PhH), 5.42 (1H, s, 1-H),
13
3.85 (3H, s, OMe), 2.65 (1H, s, 3-H); C-NMR (100 MHz; CDCl3) C 159.8 (C), 132.4 (C), 128.1
(CH), 114.0 (CH), 83.7 (CH), 74.7 (C), 64.0 (CH), 55.4 (Me); m/z (EI) 162 (M•+, 100%), 161 (54), 145
(35), 131 (38), 89 (57), 53 (43). A solution of IBX (5.14 g, 18.3 mmol) in DMSO (120 mL) was stirred
for 15 min at room temperature until homogeneous. A solution of 1-(4-methoxyphenyl)prop-2-yn-1-ol
(9d) (2.27 g, 14.0 mmol) in DMSO (20 mL) was added and the mixture was stirred for 5 h. H2O
(40 mL) was added and the mixture was stirred at room temperature for 10 min, cooled in ice and
partitioned between H2O (120 mL) and ether (90 mL). The mixture was filtered through Celite® and
the aqueous layer was further extracted with ether (80 mL). The organic extracts were combined,
washed sequentially with H2O (3 × 50 mL), saturated aqueous NaHCO3 solution (70 mL) and brine
(70 mL), dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on SiO2
gel, eluting with CHCl3 (Rf = 0.29), gave the title compound as a pale yellow solid (2.50 g, 93%), m.p.
86–87 ºC (MeOH) (literature [6] m.p. 85–87 ºC) (Found: MH+, 161.0597. C10H9O2 [MH+] requires
161.0597); IR (KBr)/cm-1 max 3,297, 2,092, 1,641, 1,597, 1,572, 1,511, 1,423, 1,252, 1,170, 1,116,
1
1,023, 841, 758, 710, 685; H-NMR (400 MHz; CDCl3) H 8.05 (2H, app d, J = 8.7 Hz, 2’,6-PhH),
13
6.88 (2H, app d, J = 8.7 Hz, 3’,5’-PhH), 3.88 (3H, s, OMe), 3.29 (1H, s, CH); C-NMR (100 MHz;
CDCl3) C 176.0 (C), 164.8 (C), 132.2 (CH), 129.2 (CH), 113.9 (CH), 80.4 (C), 80.1 (C), 55.6 (Me);
m/z (APcI) 161 (MH+, 100%).
3.3.6. (2Z,4E)-2-Amino-3-ethoxycarbonylheptadien-6-one (3aa)
Aminodienone 3aa was prepared according to the general procedure 3.2.1 using ethyl -
aminocrotonate (1a) and 4-(trimethylsilyl)but-3-yn-2-one (2a). Purification by column
chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf 0.23), gave the title
compound as a yellow solid (58 mg, 82%), m.p. 125–126 ºC(light petroleum–EtOAc) (literature [29]
m.p. 125.5–126.4 ºC) (Found: C, 60.6; H, 7.7; N, 7.0. Calc. for C10H15NO3: C, 60.1; H, 7.7; N, 7.1%)
(Found: MH+, 198.1125. C10H16NO3 [MH+] requires 198.1125); IR (KBr)/cm-1 max 3,334, 3,193,
1
2,977, 1,647, 1,546, 1,488, 1,459, 1,362, 1,319, 1,286, 1,205, 1,180, 1,112, 1,024, 970, 950, 844; H-
NMR (400 MHz; CDCl3) H 9.65 (1H, bs, NH), 7.55 (1H, d, J = 15.6 Hz, 4-H), 6.50 (1H, d,
J = 15.6 Hz, 5-H), 5.5 (1H, bs, NH), 4.22 (2H, q, J = 7.1 Hz, OCH2Me), 2.22 (3H, s, Me), 2.15 (3H, s,
13
Me), 1.28 (3H, t, J = 7.1 Hz, CH2Me); C-NMR (100 MHz; CDCl3) C 199.0 (C), 169.7 (C), 165.7
(C), 139.5 (CH), 121.1 (CH), 94.4 (C), 60.0 (CH2), 28.4 (Me), 22.6 (Me), 14.4 (Me); m/z (APcI) 198
(MH+, 100%), 181 (48).

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3.3.7. (2Z,4E)-2-Amino-3-ethoxycarbonyl-1-phenylhexadien-6-one (3ba)
Aminodienone 3ba was prepared according to the general procedure 3.2.1 using ethyl 3-amino-3-
phenylpropenoate (1b) and 4-(trimethylsilyl)but-3-yn-2-one (2a). Purification by column
chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf 0.24), gave the title
compound as a yellow solid (22 mg, 23%), m.p. 104–105 ºC (light petroleum–EtOAc) (Found: C,
69.2; H, 6.6; N, 5.2. Calc. for C15H17NO3: C, 69.5; H, 6.6; N, 5.4%); IR (KBr)/cm-1 max 3,317, 3,120,
2,980, 1,654, 1,586, 1,507, 1,461, 1,345, 1,285, 1,257, 1,210, 1,119, 1,023, 1,002, 979, 927, 852, 768,
1
702, 632, 358; H-NMR (400 MHz; CDCl3) H 9.40 (1H, bs, NH), 7.50–7.30 (5H), 7.08 (1H, d,
J = 15.9 Hz, 4-H), 6.45 (1H, d, J = 15.9 Hz, 5-H), 5.45 (1H, bs, NH), 4.25 (2H, q, J = 7.1 Hz,
OCH2Me), 1.88 (3H, s, Me), 1.35 (3H, t, J = 7.1 Hz, CH2Me); 13C-NMR (100 MHz; CDCl3) C
(C), 169.8 (C), 167.4 (C), 142.1 (CH), 136.8 (CH), 130.5 (CH), 128.9 (CH), 128.4 (CH), 122.6
(CH), 95.5 (C), 60.3 (CH2), 26.8 (Me), 14.5 (CH2); m/z (APcI) 260 (MH+, 100%), 243 (12).
3.3.8. (2Z,4E)-2-Amino-3-ethoxycarbonyl-6-phenylhexadien-6-one (3ab)
Aminodienone 3ab was prepared according to the general procedure 3.2.1 using ethyl -
aminocrotonate (1a) and 1-phenylprop-2-yn-1-one (2b). Purification by column chromatography on
SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf 0.24), gave the title compound as a yellow
solid (79 mg, 85%), mp 156–157 ºC (light petroleum–EtOAc) (lit. [4] mp 164 °C) (Found: C, 69.4; H,
6.6; N, 5.2. Calc. for C15H18NO3: C, 69.5; H, 6.6; N, 5.4%) (Found: MH+, 260.1282. C15H17NO3
[MH+] requires 260.1281); IR (KBr)/cm-1 max 3,342, 3,203, 2,976, 1,623, 1,580, 1,539, 1,497, 1,378,
1,354, 1,320, 1,286, 1,223, 1,205, 1,178, 1,110, 1,055, 1,036, 1,023, 976, 847, 705, 626; 1H-NMR (400
MHz; CDCl3) H 9.67 (1H, bs, NH), 7.94 (2H, m, o-PhH), 7.86 (1H, d, J = 15.0 Hz, 4-H), 7.43 (3H,
m,p-PhH), 7.39 (1H, d, J = 15.0 Hz, 5-H), 5.70 (1H, bs, NH), 4.24 (2H, q, J = 7.1 Hz, OCH2Me), 2.33
13
(3H, s, Me), 1.35 (3H, t, J = 7.1 Hz, CH2Me); C-NMR (100 MHz; CDCl3) C 190.9 (C), 169.8 (C),
166.7 (C), 141.1 (CH), 139.7 (C), 131.8 (CH), 128.4 (CH), 128.1 (CH), 115.8 (CH), 95.6 (C), 60.0
(CH2), 22.6 (Me), 14.5 (Me); m/z (APcI) 260 (MH+, 100%).
3.3.9. (2Z,4E)-2-Amino-3-ethoxycarbonyl-6-(4-chlorophenyl)hexadien-6-one (3ac)
Aminodienone 3ac was prepared according to the general procedure 3.2.1 using ethyl -
aminocrotonate (1a) and 1-(4-chlorophenyl)prop-2-yn-1-one (2c). Purification by column
chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf 0.18), gave the title
compound as a yellow solid (91 mg, 86%), m.p. 163–164 ºC (light petroleum–EtOAc) (literature [14]
m.p. 164–165 ºC) (Found: MH+, 294.0893. C15H1735ClNO3 [MH+] requires 294.0891); IR (KBr)/cm-1
max 3,315, 3,168, 2,964, 1,653, 1,630, 1,591, 1,571, 1,539, 1,485, 1,350, 1,323, 1,288, 1,224, 1,177,
1
1,120, 1,089, 1,057, 1,037, 1,012, 975, 856, 824, 743, 713, 642, 589, 538, 502; H-NMR (400 MHz;
CDCl3) H 9.71 (1H, bs, NH), 7.88 (1H, d, J = 15.0 Hz, 4-H), 7.84 (2H, app d, J = 8.5 Hz, 2’,6’-PhH),
7.36 (2H, app d, J = 8.5 Hz, 3’,5’-PhH), 7.33 (1H, d, J = 15.0 Hz, 5-H), 5.78 (1H, bs, NH), 4.20 (2H,
13
q, J = 7.1 Hz, OCH2Me), 2.27 (3H, s Me), 1.35 (3H, t, J = 7.1 Hz, CH2Me); C-NMR (100 MHz;
CDCl3) C 189.5 (C), 169.7 (C), 167.0 (C), 141.6 (CH), 138.0 (C), 138.0 (C), 129.5 (CH), 128.6 (CH),
115.1 (CH), 95.7 (C), 60.1 (CH2), 22.6 (Me), 14.5 (Me); m/z (APcI) 296 (MH+, 32%), 294 (MH+, 100).

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3.3.10. (2Z,4E)-2-Amino-3-ethoxycarbonyl-6-(4-methoxyphenyl)hexadien-6-one (3ad)
Aminodienone 3ad was prepared according to the general procedure 3.2.1 using ethyl -
aminocrotonate (1a) and 1-(4-methoxyphenyl)prop-2-yn-1-one (2d). Purification by column
chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf 0.50), gave the title
compound as a yellow solid (99 mg, 95%), mp 155–156 ºC (light petroleum–EtOAc) (literature [54]
m.p. 159 ºC) (Found: MH+, 290.1386. C16H20NO4 [MH+] requires 290.1387); IR (KBr)/cm-1 max
3,297, 3,145, 2,974, 1,717, 1,627, 1,598, 1,576, 1,539, 1,511, 1,475, 1,362, 1,321, 1,300, 1,263, 1,231,
1
1,168, 1,126 1,021, 834, 586; H-NMR (400 MHz; CDCl3) H 9.63 (1H, bs, NH), 7.91 (2H, app d,
J = 8.8 Hz, 2’,6’-PhH), 7.82 (1H, d, J = 15.0 Hz, 4-H), 7.38 (1H, d, J = 15.0 Hz, 5-H), 6.85 (1H, app d,
J = 8.8 Hz, 3’,5’-PhH), 5.63 (1H, bs, NH), 4.23 (2H, q, J = 7.2 Hz, OCH2Me), 3.83 (3H, s, OMe), 2.25
13
(3H, s Me), 1.35 (3H, t, J = 7.2 Hz, CH2Me); C-NMR (100 MHz; CDCl3) C 189.3 (C), 169.9 (C),
166.3 (C), 162.7 (C), 140.2 (CH), 132.4 (C), 130.2 (CH), 115.7 (CH), 113.6 (CH), 95.5 (C), 60.0
(CH2), 55.4 (Me), 22.6 (Me), 14.5 (Me); m/z (APcI) 290 (MH+, 100%).
3.3.11. (2Z,4E)-2-Amino-3-tert-butoxycarbonylheptadien-6-one (3ca)
Aminodienone 3ca was prepared according to the general procedure 3.2.1 using tert-butyl -
aminocrotonate (1c) and 4-(trimethylsilyl)but-3-yn-2-one (2a). Purification by column
chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf 0.26), gave the title
compound as a yellow solid (55 mg, 68%), m.p. 142–143 ºC(light petroleum–EtOAc) (literature [14]
m.p. 142–144 ºC) (Found: C, 63.8; H, 8.5; N, 6.1. Calc. for C12H19NO3: C, 64.0; H, 8.5; N, 6.2%)
(Found: MH+, 226.1437. C12H20NO3 [MH+] requires 226.1438); IR (KBr)/cm-1 max 3,341, 3,198,
2,975, 1,654, 1,539, 1,485, 1,454, 1,362, 1,323, 1,295, 1,218, 1,160, 1,111, 1,034, 970, 840, 692, 572;
1H-NMR (400 MHz; CDCl3) H 9.60 (1H, bs, NH), 7.48 (1H, d, J = 15.4 Hz, 4-H), 6.45 (1H, d,
13
J = 15.4 Hz, 5-H), 5.39 (1H, bs, NH), 2.20 (3H, s, Me), 2.18 (3H, s, Me), 1.48 (9H, s, CMe3); C-
NMR (100 MHz; CDCl3) C 198.8 (C), 169.1 (C), 165.2 (C), 139.9 (CH), 120.8 (CH), 95.7 (C), 80.8
(C), 28.5 (Me), 28.4 (Me), 22.7 (Me); m/z (APcI) 226 (MH+, 98%), 208 (54), and 152 (100).
3.3.12. Ethyl 2,6-dimethylpyridine-3-carboxylate (4aa)
Pyridine 4aa was prepared according to the general procedure 3.2.2 using aminodienone 3aa.
Purification by column chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1)
(Rf 0.44), gave the title compound as a pale yellow oil (24 mg, 66%) (Found: MH+, 180.1017.
C10H14NO2 [MH+] requires 180.1019); IR (film)/cm-1 max 2,924, 2,825, 1,730, 1,593, 1,462, 1,377,
1
1,272, 1,236, 1,148, 1,079, 770, 722; H-NMR (400 MHz; CDCl3) H 8.03 (1H, d, J = 8.0 Hz, 4-H),
7.00 (1H, d, J = 8.0 Hz, 5-H), 4.27 (2H, q, J = 7.2 Hz, OCH2Me), 2.75 (3H, s, Me), 2.50 (3H, s, Me),
13
1.33 (3H, t, J = 7.2 Hz, CH2Me); C-NMR (100 MHz; CDCl3) C 166.7 (C), 161.1 (C), 159.4 (C),
138.9 (CH), 122.8 (C), 120.5 (CH), 61.1 (CH2), 24.8 (Me), 24.6 (Me), 13.7 (Me); m/z (APcI) 180
(MH+, 100%).

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3.3.13. Ethyl 6-methyl-2-phenylpyridine-3-carboxylate (4ba)
Pyridine 4ba was prepared according to the general procedure 3.2.2 using aminodienone 3ba.
Purification by column chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf
0.56), gave the title compound as a pale yellow solid (47 mg, 98%), m.p. 45–46 ºC (EtOH) (literature
[55] m.p. 46 ºC) (Found: MH+, 242.1175. C15H16NO2 [MH+] requires 242.1176); IR (film)/cm-1 max
3,056, 2,963, 2,915, 2,855, 2,363, 1,715, 1,589, 1,440, 1,356, 1,278 1,211, 1,137, 1,106, 1,053, 797,
1
767, 740, 699, 650; H-NMR (400 MHz; CDCl3) H 7.95 (1H, d, J = 8.0 Hz, 4-H), 7.33–7.25 (5H,
PhH), 7.12 (1H, d, J = 8.0 Hz, 5-H), 4.05 (2H, q, J = 7.1 Hz, OCH2Me), 2.55 (3H, s, Me), 0.94 (3H, t,
J = 7.1 Hz, CH2Me); 13C-NMR (100 MHz; CDCl3) C 168.2 (C), 160.8 (C), 158.7 (C), 140.5 (C),
138.4 (CH), 128.5 (CH), 128.4 (CH), 128.1 (CH), 124.4 (C), 121.3 (CH), 61.3 (CH2), 24.8 (Me), 13.6
(Me); m/z (APcI) 242 (MH+, 100%).
3.3.14. Ethyl 2-methyl-6-phenylpyridine-3-carboxylate (4ab)
Pyridine 4ab was prepared according to the general procedure 3.2.2 using aminodienone 3ab.
Purification by column chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf
0.62), gave the title compound as a pale yellow solid (47 mg, 98%), m.p. 44–45 ºC (EtOH) (literature
[4] m.p. 44 ºC) (Found: MH+, 242.1176. C15H16NO2 [MH+] requires 242.1179); IR (KBr)/cm-1 max
2,981, 1,715, 1,582, 1,496, 1,455, 1,382, 1,264, 1,185, 1,154, 1,091, 1,026, 922, 848, 798, 757, 692;
1H-NMR (400 MHz; CDCl3) H 8.21 (1H, d, J = 8.2 Hz, 4-H), 8.02 (2H, m, o-PhH), 7.60 (1H, d,
J = 8.2 Hz, 5-H), 7.42 (3H, m,p-PhH) 4.32 (2H, q, J = 7.2 Hz, OCH2Me), 2.85 (3H, s, Me), 2.45 (3H, t,
13
J = 7.2 Hz, CH2Me); C- NMR (100 MHz; CDCl3) C 166.9 (C), 160.0 (C), 159.1 (C), 139.3 (CH),
138.5 (C), 129.7 (CH), 128.8 (CH), 127.3 (CH), 123.7 (C), 117.4 (CH), 61.2 (CH2), 25.3 (Me), 14.3
(Me); m/z (APcI) 242 (MH+, 100%).
3.3.15. Ethyl 2-methyl-6-(4-chlorophenyl)pyridine-3-carboxylate (4ac)
Pyridine 4ac was prepared according to the general procedure 3.2.2 using aminodienone 3ac.
Purification by column chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf
0.68), gave the title compound as a pale yellow solid (59 mg, 97%), m.p. 48–49 ºC (aqueous EtOH)
(literaute [6] m.p. 47–48 ºC) (Found: MH+, 276.0784. C15H1535ClNO2 [MH+] requires 276.0786); IR
(KBr)/cm-1 max 2,985, 1,720, 1,585, 1,492, 1,455, 1,372, 1,265, 1,180, 1,155, 1,096, 1,013, 896, 833,
1
786, 742, 705; H-NMR (400 MHz; CDCl3) H 8.23 (1H, d, J = 8.2 Hz, 4-H), 7.95 (2H, app d,
J = 8.5 Hz, 2’,6’-PhH), 7.54 (1H, d, J = 8.2 Hz, 5-H), 7.40 (2H, app d, J = 8.5 Hz, 3’,5’-PhH), 4.38
13
(2H, q, J = 7.1 Hz, OCH2Me), 1.60 (3H, s, Me), 1.35 (3H, t, J = 7.1 Hz, CH2Me); C-NMR (100
MHz; CDCl3) C 166.5 (C), 160.1 (C), 157.7 (C), 139.4 (CH), 136.9 (C), 135.9 (C), 129.0 (CH), 128.6
(CH), 123.9 (C), 117.4 (CH), 61.2 (CH2), 25.3 (Me), 14.3 (Me); m/z (APcI) 278 (MH+, 33%), 276
(MH+, 100).
3.3.16. Ethyl 2-methyl-6-(4-methoxyphenyl)pyridine-3-carboxylate (4ad)
Pyridine 4ad was prepared according to the general procedure 3.2.2 using aminodienone 3ad.
Purification by column chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf

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0.63), gave the title compound as a pale yellow solid (53 mg, 98%), m.p. 68–69 ºC (aqueous EtOH)
(literature [6] m.p. 68–69 ºC) (Found: MH+, 272.1284. C16H18NO3 [MH+] requires 272.1281); IR
(KBr)/cm-1 max 2,989, 2,895, 1,717, 1,605, 1,579, 1,509, 1,452, 1,439, 1,389, 1,362, 1,311, 1,264,
1
1,172, 1,112, 1,088, 1,071, 1,031, 832, 785; H-NMR (500 MHz; CDCl3) H 8.20 (1H, d, J = 8.2 Hz,
4-H), 7.95 (2H, app d, J = 8.7 Hz, 2’,6’-PhH), 7.53 (1H, d, J = 8.2 Hz, 5-H), 7.37 (2H, app d,
J = 8.7 Hz, 3’,5’-PhH), 4.34 (2H, q, J = 7.1 Hz, OCH2Me), 3.82 (3H, s, OMe), 2.85 (3H, s, Me), 1.36
13
(3H, t, J = 7.1 Hz, CH2Me); C-NMR (125 MHz; CDCl3) C 166.8 (C), 161.0 (C), 160.0 (C), 158.7
(C), 139.3 (CH), 131.7 (C), 128.7 (CH), 122.8 (C), 116.5 (CH), 114.2 (CH), 61.1 (CH2), 55.4 (Me),
25.4 (Me), 14.4 (Me); m/z (APcI) 272 (MH+, 100%).
3.3.17. tert-Butyl 2,6-dimethylpyridine-3-carboxylate (4ca)
Pyridine 4ca was prepared according to the general procedure 3.2.2 using aminodienone 3ca.
Purification by column chromatography on SiO2 gel, eluting with light petroleum–EtOAc (1:1) (Rf
0.59), gave the title compound [29] as a pale yellow oil (41 mg, 98%) (Found: MH+, 208.1329.
C12H18NO2 [MH+] requires 208.1332); IR (film)/cm-1 max 2,921, 2,852, 1,724, 1,592, 1,462, 1,377,
1
1,284, 1,175, 1,144, 1,080, 771, 722; H-NMR (400 MHz; CDCl3) H 7.95 (1H, d, J = 8.0 Hz, 4-H),
6.95 (1H, d, J = 8.0 Hz, 5-H), 2.68 (3H, s, Me), 2.45 (3H, s, Me), 1.50 (9H, s, CMe3); 13C-NMR (100
MHz; CDCl3) C 166.1 (C), 160.6 (C), 158.7 (C), 138.8 (CH), 124.5 (C), 120.5 (CH), 81.7 (C), 28.2
(Me), 24.8 (Me), 24.6 (Me); m/z (APcI) 208 (MH+, 100%).
4. Conclusions
The use of NIS in EtOH represents a new and rapid mild method for the low temperature
cyclodehydration of Bohlmann-Rahtz aminodienone intermediates 3 to give the corresponding 2,3,6-
trisubstituted pyridines 4 in excellent yield and with total regiocontrol. In this process, the NIS appears
to be behaving as a remarkable Lewis acid, that catalyzes E/Z isomerisation and spontaneous
cyclodehydration at 0 ºC, rather than an iodinating agent. This method for mild and efficient
cyclodehydration is likely to find application, in particular for the synthesis of pyridines from acid-
sensitive substrates, and will be reported [23] in due course.
Acknowledgements
We thank the EPSRC Mass Spectrometry Service, Swansea for high resolution spectra and the
EPSRC for funding (studentship award to CG).
References and Notes
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2. Henkel, T.; Brunne, R.M.; Müller, H.; Reichel, F. Statistical investigation into the structural
complexity of natural products and synthetic compounds. Angew. Chem. Int. Ed. Engl. 1999, 38,
643–647.

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3. Hantzsch, A. Condensationprodukte aus Aldehydammoniak und Ketoniartigen Verbindungen.
Berichte 1881, 14, 1637–1638.
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