Synthesis of 4-trifluoromethylpyridines by [5+1] cyclization of 3-hydroxy-pent-4-yn-1-ones with urea

Article abstract of DOI:10.1002/adsc.201200687

Trifluoromethyl-substituted 1,3-diketones can undergo direct alkynylation reactions which are not possible for alkyl- or aryl-substituted derivatives. The products can be easily transformed into 2,6-diaryl-4-trifluoromethylpyridines by acid-mediated [5+1] cyclization with urea. The reaction was thoroughly optimized by variation of the conditions and the scope was studied in detail. The products are not readily available by other methods. A plausible mechanism was suggested based on DFT calculations.

Full text of DOI:10.1002/adsc.201200687

UPDATES
DOI: 10.1002/adsc.201200687
Synthesis of 4-Trifluoromethylpyridines by [5+1] Cyclization of
3-Hydroxy-pent-4-yn-1-ones with Urea
Viktor O. Iaroshenko,a,b,* Dmytro Ostrovskyi,a Khurshid Ayub,c
Anke Spannenberg,d and Peter Langera,d,*
a
Institute of Chemistry, University of Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax : (+49)-381-498-6410; e-mail: peter.langer@uni-rostock.de
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
b
E-mail: iva108@googlemail.com
Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
Leibniz Institute of Catalysis at the University of Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
c
d
Received: August 2, 2012; Revised: October 24, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200687.
Abstract: Trifluoromethyl-substituted 1,3-diketones
can undergo direct alkynylation reactions which are
not possible for alkyl- or aryl-substituted deriva-
tives. The products can be easily transformed into
2,6-diaryl-4-trifluoromethylpyridines by acid-medi-
ated [5+1]cyclization with urea. The reaction was
thoroughly optimized by variation of the conditions
and the scope was studied in detail. The products
are not readily available by other methods. A plau-
sible mechanism was suggested based on DFT cal-
culations.
logically very important) trifluoromethyl group to
pyridines remains a challenging goal. A number of tri-
fluoromethylated pyridines have been reported to
show remarkable pharmacological properties. For ex-
ample, pyridine-derived scaffolds 1a and 1b are con-
sidered as efficient mGluR2 antagonists;[8] bis-
AHCTUNGTREG(NNNU indolyl)-4-trifluoromethylpyridines 2 are promising
anti-cancer agents (Figure 1).[9]
Moreover, trifluoromethylated pyridines have been
applied in the field of agrochemistry. For example, pi-
coxystrobinꢀ, containing a 2-trifluoromethylpyridine
fragment, is a widely used fungicide, which is pro-
duced by DuPont.
In many cases, a Pd- or Cu-catalyzed trifluorome-
thylation of a heterocyclic moiety using TMSCF3 can
be carried out,[10] however, these methods require
Keywords: alkynes; cyclization; fluorine; pyridines;
urea
Despite the numerous approaches to the synthesis of
pyridines that have been developed throughout de-
cades, alternative pathways continue to emerge be-
cause pyridines are very important lead structures in
medicinal chemistry and material science. Classical
methods for the synthesis of pyridines include the
formal [5+1]cyclocondensation of 1,5-dicarbonyl spe-
cies or their analogues with ammonia or related com-
pounds,[1] the Diels–Alder reaction of dienophiles
with azines,[2] and the condensation of enamine deriv-
atives with dielectrophiles.[3] Much attention is being
paid nowadays to the synthesis of pyridines by transi-
tion metal-catalyzed reactions. This includes gold-cat-
alyzed reactions of propargyl vinyl ethers,[4] b-keto
esters and propargylic amines,[5] [4+2] or [2+2+
2]cycloadditions of alkynes, dienes or nitriles,[6] and
Suzuki or Sonogashira reactions.[7] Despite recent ad-
Figure 1. Pharmacologically relevant 4-trifluoromethylpyri-
vances in the field, the introduction of the (pharmaco- dines.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Viktor O. Iaroshenko et al.
UPDATES
Scheme 1. Reaction of lithiated phenylacetylene with 3-benzoyl-1,1,1-trifluoroacetone.
comparatively complicated catalytic systems and are the reaction of lithiated alkynes with 1,3-diketones
rather expensive. In recent times, a number of elegant can result in a competing deprotonation of the CH-
methods for the trifluoromethylation of pyridines acidic methylene group. We supposed, that the pres-
À
have been developed. This includes oxidative C H ence of a highly electron-withdrawing substituent,
trifluoromethylation,[11] implementation of photore- such as a trifluoromethyl group, and the use of an
dox catalysis,[12] and rhenium-catalyzed trifluorome- excess of the lithiated alkyne could result in the for-
thylation by hypervalent iodine derivatives[13]. Anoth- mation of the desired monoalkynylated product. With
er remarkable possibility is based on the multistep this concept in mind, we started our investigations.
synthesis of 4-trifluoromethylpyridines, developed by
To our delight, the reaction of 2 equiv. of lithiated
Jiang and co-workers, starting from ethyl trifluoroace- phenylacetylene, generated by LDA, with 3-benzoyl-
tate and allyl bromide. However, this protocol suffers 1,1,1-trifluoroacetone, proceeded smoothly and af-
from low overall yields.[14] Herein, we report an un- forded
3-hydroxy-1,5-diphenyl-3-(trifluoromethyl)-
precedented two-step procedure which relies on the pent-4-yn-1-one (3a) in 76% yield (Scheme 1). The
reaction of trifluoromethyl-substituted 1,3-diketones formation of the product can be explained by depro-
with lithiated alkynes and subsequent formal [5+ tonation of the substrate by the first equivalent of the
1]cyclocondensation with urea.
acetylide and subsequent attack of the second equiva-
It occurred to us that 3-hydroxypent-4-yn-1-ones, lent of the acetylide to the carbonyl group. The bis-
containing a carbonyl group and a propargylic alcohol adduct 2 was isolated as a side-product in 9% yield.
fragment, might be attractive 1,5-dielectrophilic syn- The reaction of the monoadduct with 2 equiv. of lithi-
thons which could form pyridines upon reaction with ated phenylacetylene resulted in the formation of bis-
a nitrogen source. This type of formal [5+1]cyclocon- adduct 4 in 30% yield (Scheme 1). We tried to use dif-
densation has, to the best of our knowledge, not been ferent bases (NaH, LDA) to replace the lithiated
previously studied.
alkyne in the first deprotonation step, in order to
Thus, our first task was to develop a straightforward avoid the use of 2 equiv of the alkyne. These experi-
route to the corresponding starting materials. Obvi- ments proved to be unsuccessful (formation of a com-
ously, the direct alkynylation of 1,3-diketones, which plex mixture). All attempts to use non-fluorinated
leads to monoaddition products, would be the easiest 1,3-diketones, such as dibenzoylmethane (Scheme 2)
method. However, to the best of our knowledge, only under identical conditions, failed which supports our
very few examples of such transformations have been initial concept. Moreover, initial alkynylation of cy-
previously reported in the literature and all of them clopropanated dibenzoylmenthane (which was pre-
include reactions of 2,2-disubstituted 1,3-diketones, pared to avoid enolization of the corresponding dike-
such as dialkylated ninhydrins, and products are bis- tone) did not result in formation of the desired prod-
adducts.[15] For 1,3-diketones containing an unsubsti- uct, most probably due to decomposition of the start-
tuted CH2 group, one-step double additions are im- ing material through a retro-Claisen reaction.
possible, due to the highly prevailing enol form (in
Inspired by our first successful experiment, we stud-
most organic solvents). The electrophilic nature of the ied the alkynylation of a number of 1,3-diketones
enol is very low and the electrophilicity of the re- using different acetylene derivatives (Figure 2).
maining carbonyl group is also highly reduced be- Most of the products 3a–t were isolated in good
cause of the conjugated enol fragment. In addition, yields. The synthesis of products 3s and 3t, derived
2
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 4-Trifluoromethylpyridines by [5+1] Cyclization of 3-Hydroxy-pent-4-yn-1-ones
from 1,1,1-trifluoroacetylacetone, required the use of
10 mol% of Zn(OTf)2. All products 3 were stable,
AHCTUNGTRENNUNG
except from derivatives 3s and 3t which easily decom-
posed and, thus, had to be used without purification.
With these results in hand, we studied next the
transformation of 3-hydroxy-1,5-diaryl-3-(trifluorome-
thyl)pent-4-yn-1-ones into pyridines. The first and
main problem was to identify a suitable nitrogen
source. In comparison to 1,5-dicarbonyl compounds,
which are used in cyclocondensations with ammo-
nia,[1] 3-hydroxy-pent-4-yn-1-ones are reactive only in
acidic media, because a propargyl cation must be
formed. Therefore, the use of ammonia is not suita-
ble, because of its lack of acidity. On the other hand,
the employment of ammonium acetate is also not pos-
Scheme 2. Unsuccessful alkynylation of dibenzoylmethanes.
Figure 2. Structures of 3a–t.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Viktor O. Iaroshenko et al.
UPDATES
Table 1. Optimization of the reaction conditions.
electron-rich alkynes were used and when the p-do-
nating properties of the substituent located at the
keto group are comparatively weak. Obviously, this
might be explained by carbocation stabilization in the
case of a p-donating group located at the triple bond
and the higher reactivity of the carbonyl group at-
tached to an electron-withdrawing substituent. This is
illustrated by the observation that pyridine 5n is ob-
tained in 85% yield after 2 h, starting from 3n, while,
starting from 3q, the same product was formed in
only 24% yield and required prolonged heating up to
14 h. Starting with 3s and 3t, unfortunately, no prod-
uct could be isolated under various conditions.
To extend the scope of our method, we attempted
to synthesize 2-aryl-4-trifluoromethylpyridines as well
as 4-carboxymethylpyridines, starting from appropri-
ate building blocks (Scheme 4). The use of 4-ethoxy-
1,1,1-trifluorobut-3-en-2-one (6) proved to be unsuc-
cessful, presumably because of the decreased electro-
philicity of the carbonyl group (due to the electronic
influence of the ethoxy group). Therefore, we pre-
Entry
Acid
Solvent
Time
[h][a]
Yield
of
5a [%]
1
2
3
4
PTSA (2.0 equiv.)
TfOH (2.0 equiv.)
TFA (2.0 equiv.)
MsOH
toluene
toluene
toluene
toluene
20
7
12
7
6
39
47
34
(2.0 equiv.)
5
AcOH
toluene
24
18
(2.0 equiv.)
6
7
TFA (3.5 equiv.)
TFA
toluene
toluene
12
12
68
68
(3.5 equiv.)[b]
TFA (3.5 equiv.)
TFA (3.5 equiv.)
8
9
DCE
MeNO2
15
5
41
9
[a]
The reaction was stopped after complete conversion of
the starting material.
4 ꢂ MS was used.
[b]
sible, because of its low nucleophilicity. As an alterna- pared the corresponding acetal 7,[17] which should
tive, we turned our attention to urea, which has allow for the synthesis of 6-unsubstituted 4-trifluoro-
a number of advantages in comparison to ammonia. methylpyridines. Despite the fact, that alkynylation of
On the one hand, urea is much less basic than ammo- 7 proceeded smoothly, the following cyclization was
nia. On the other hand, it is quite nucleophilic in its unsuccessful under various conditions. Unfortunately,
electroneutral form and also keeps some nucleophilic- alkynylation of benzoylpyruvate 9 also failed.
ity in the presence of acid (as it is protonated at the
The structure of product 5q was independently con-
oxygen atom). At the same time, its amide residue firmed by X-ray crystal structure analysis (Figure 4).
can be cleaved during the cyclization process under The pyridine ring and the phenyl groups are in one
acidic conditions.
plane.
To gain mechanistic insight for the acid-catalyzed
As a starting point, we have tested the use of tolu-
ene and p-toluenesulfonic acid (PTSA) as solvent and formation of pyridine 5a (Scheme 3), DFT calcula-
catalyst, respectively. The acid was used in excess tions have been performed (for details, see the Sup-
(2 equiv.). Besides its catalytic role, it also serves as porting Information). The starting material 3a has
a proton donor in the cyclization process, because it two sites available for protonation, namely, the keto
protonates the nitrogen source. However, reflux (up and alcohol oxygen atoms. Preferential protonation of
to 20 h) of a mixture of 3a, urea (1.2 equiv.) and the keto group would result in Schiff base formation
PTSA (2 equiv.) resulted in a poor yield of the de- prior to nucleophilic attack on the propargylic alcohol
sired pyridine (Table 1). Screening of a number of moiety. However, the latter would be expected in the
Brønsted acids revealed that trifluoroacetic acid was case that the alcohol oxygen atom is protonated first.
most efficient. Increasing the amount of acid Dehydration of the propargylic alcohol generates an
(3.5 equiv.) also resulted in better yields (entry 6). allene cation which can be attacked by nucleophiles
Employment of other solvents, such as DCE or nitro- and eventually would deliver scrambled products sim-
methane, resulted in a drastic decrease of the yield.
ilar to Meyer–Schuster[18] and Rupe[19] rearrange-
It is important to mention that our attempts to pre- ments. However, in our experiments, no such rear-
pare the target molecules by a one-pot procedure ranged products have been observed which indicates
were unsuccessful (formation of complex mixtures). that dehydration of the propargylic alcohol is not the
This might be explained by the fact that the acetylene, first step. This is supported by the fact that keto-pro-
which is used in excess, can react with the propargylic tonated isomer Int1A is 2.85 kcalmolÀ1 more stable
alcohol under acidic conditions to give 1,4-diynes. than the hydroxy-protonated isomer Int1B. Nucleophil-
This type of process has been previously reported.[16]
ic attack of urea on Int1A, followed by proton shift of
The preparative scope of the cyclization was next Int2A and subsequent dehydration, generates the
studied. The electronic properties of the substituents Schiff base intermediate Int3A via Int2A. The overall
attached to the keto group and to the triple bond process is thermodynamically favourable by 6.74 kcal
show a remarkable influence on the reaction time and molÀ1. A proton shift from the imine nitrogen to the
À
yield (Figure 3). The best results were obtained when alcohol oxygen generates Int4A in which the O C
4
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 4-Trifluoromethylpyridines by [5+1] Cyclization of 3-Hydroxy-pent-4-yn-1-ones
Figure 3. Scope of trifluoromethyl-substituted pyridines.
bond is considerably weak (3.11 ꢂ) which indicates
that the actual species participating in the next cycli-
zation step is the dehydrated species Int5A (Figur 5)
A transition state for the cyclization has been locat-
ed at a barrier of 7.6 kcalmolÀ1. Although the product
of cyclization is a constrained molecule with an
allene-like structure, the cyclization is thermodynami-
cally favourable by 1.2 kcalmolÀ1. A reason for the
low barrier may be the instability of the bis-allene
Scheme 3. Synthesis of pyridine 5a.
Scheme 4. Unsuccessful experiments.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Viktor O. Iaroshenko et al.
UPDATES
pathway inaccessible under the experimental condi-
tions (refluxing toluene). Therefore, the more logical
pathway follows a deprotonation/protonation mecha-
nism which was previously demonstrated by theoreti-
cal and labelling studies.[20] The weak base (trifluoro-
AHCTUNGTREGaNNUN cetate) abstracts a proton and transfers it to the cen-
tral atom of the allene moiety.[21] The resulting inter-
mediate undergoes hydrolysis to afford the pyridine
(Figure 6). The water formed during the generation of
Int5A may participate in the hydrolysis. Adduct Int8A,
which is generated by addition of water to Int7A, is
thermodynamically less stable than its precursor (by
14.93 kcalmolÀ1). A transition state (TS8A) has been
located for the dissociation of carbamic acid from the
pyridine moiety. The barrier is low (0.3 kcalmolÀ1)
and the cleavage is thermodynamically favourable (by
1.4 kcalmolÀ1).
Figure 4. X-Ray structure of compound 5q.
In conclusion, we have developed a new and con-
venient two-step procedure for the synthesis of 4-tri-
starting material Int5A. The cyclized product can un- fluoromethyl-substituted pyridines starting from 1,3-
dergo either an intramolecular 1,5 hydrogen shift or diketones, terminal alkynes and urea. A computation-
a deprotonation/protonation sequence to yield inter- al study on the mechanism was performed. The trans-
mediate Int7A. The kinetic barrier for the sigmatropic formations are easy to handle and do not require
1,5 shift is more than 50 kcalmolÀ1 which renders this costly reagents or catalysts.
Figure 5. Energy profile for the acid-catalyzed pyridine formation. All values are in kcalmolÀ1 and include unscaled zero
point energy correction.
6
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 4-Trifluoromethylpyridines by [5+1] Cyclization of 3-Hydroxy-pent-4-yn-1-ones
General Procedure for Preparation of 4-Trifluoro-
methylpyridine Compounds 5a–q
The 3-hydroxypent-4-yn-1-one (1.0 mmol) was dissolved in
toluene (3.5 mL) and, subsequently, urea (72 mg, 1.2 mmol)
and TFA (400 mg, 3.5 mmol) were added. The mixture was
heated under reflux until full conversion of the starting ma-
terial (monitored by TLC). Afterwards, triethylamine
(0.404 mg, 0.004 mol) was added and the solution was con-
centrated under vacuum. The residue was purified by
column chromatography to give the desired pyridines.
3-Hydroxy-1,5-diphenyl-3-(trifluoromethyl)pent-4-yn-1-
one (3a): Starting from 3-benzoyl-1,1,1-trifluoroacetone
(540 mg,
2.5 mmol)
and
phenylacetylene
(561 mg,
5.5 mmol); 3a was isolated as light-yellow powder; yield:
1
604 mg (76%); H NMR (300.13 MHz, CDCl3): d=3.34 (d,
1H, H-2a, 2J=16.8 Hz), 3.70 (d, 1H, H-2b, 2J=16.8 Hz),
5.35 (s, 1H, OH), 7.17 (br. m, 5H, Ph), 7.43 (m, 2H, H-3’,
3
Figure 6. Hydrolysis of Int7A, All values are in kcalmolÀ1
and include unscaled zero point energy correction.
H-5’), 7.55 (d, 1H, H-4’, J=7.5 Hz), 7.91 (dd, 2H, H-2’, H-
3
3
6’, J1 =7.2 Hz, J2 =1.2 Hz); 13C NMR (62.90 MHz, DMSO-
2
d6): d=43.0 (C-2), 68.8 (q, C-3, JC,F =31.5 Hz), 84.3 (C-4),
86.7 (C-5), 120.1 (C-4’), 124.1 (q, CF3, JC,F =286.2 Hz), 128.5
1
(C-2’, C-6’), 128.6 (C-3’’, C-5’’), 128.7 (C-3’, C-5’), 129.4 (C-
1’), 131.4 (C-2’’, C-6’’), 133.2 (C-4’’), 137.2 (C-1’’), 194.5 (C-
1); GC-MS (EI, 70 eV): m/z (%)=318 (14) [M+], 300 (15),
249 (48), 207 (41), 178 (25), 129 (76), 105 (100), 77 (68);
HR-MS (ESI): m/z=319.0945, [M+H]+, calcd. for
Experimental Section
General
˜
C18H14F3O2: 319.0940; IR (ATR): n=3398, 2955, 2222, 1622,
1599, 1575, 1512, 1453, 1403, 1167, 1045, 996, 832, 633 cmÀ1.
5-(4-tert-Butylphenyl)-3-hydroxy-1-phenyl-3-(trifluorome-
thyl)pent-4-yn-1-one (3b): Starting from 3-benzoyl-1,1,1-tri-
fluoroacetone (540 mg, 2.5 mmol) and 4-tert-butylphenylace-
tylene (869 mg, 5.5 mmol); 3b was isolated as light-yellow
All solvents were purified and dried by standard methods.
NMR spectra were recorded on Brucker AVANCE 250 II
and Brucker DPX 300 spectrometers. The following abbrevi-
ations are used to designate chemical shift multiplicities: s=
singlet, d=doublet, t=triplet, q=quartet, m=multiplet,
br=broad. IR spectra were recorded on a Perkin–Elmer
FT-IR 1600 spectrometer (ATR). Mass spectra were ob-
tained on a Hewlett–Packard HP GC/MS 5890/5972 instru-
ment (EI, 70 eV) by GC inlet or on a MX-1321 instrument
(EI, 70 eV) by direct inlet. Column chromatography was
performed on silica gel (63–200 mesh, Merck). Silica gel
Merck 60F254 plates were used for TLC. The X-ray crystal
structure analyses were deposited at the CCDC.[22]
1
liquid; yield: 776 mg (83%); H NMR (300.13 MHz, CDCl3):
2
d=1.19 (s, 9H, t-Bu), 3.34 (d, 1H, H-2a, J=16.8 Hz), 3.73
(d, 1H, H-2b, 2J=16.8 Hz), 5.37 (s, 1H, OH), 7.21 (br. s,
4H, H-2’, H-3’, H-5’, H-6’), 7.44 (m, 2H, H-3’’, H-5’’), 7.57
(m, 1H, H-4’’), 7.92 (m, 2H, H-2’’, H-6’’); 13C NMR
(62.90 MHz, CDCl3): d=31.1 (CH3), 34.8 [(CH3)3C], 41.7
(C-2), 70.6 (q, C-3, 2JC,F =32.6 Hz), 82.7 (C-4), 87.0 (C-5),
1
118.0 (C-4’), 123.3 (q, CF3, JC,F =284.3 Hz), 125.3 (C-2’, C-
6’), 128.4 (C-3’, C-5’), 128.9 (C-3’’, C-5’’), 131.7 (C-2’’, C-6’’),
134.4 (C-4’’), 136.3 (C-1’), 152.6 (C-1’’), 198.6 (C-1); GC-MS
(EI, 70 eV): m/z (%)=359 (49), 341 (60), 254 (21), 239
(100), 185 (35), 105 (76), 77 (56); HR-MS (ESI): m/z=
375.1563 [M+H]+, calcd. for C22H22F3O2: 375.1566; IR
General Procedure for the Synthesis of 3-Hydroxy-
pent-4-yn-1-ones 3a–r
˜
(ATR): n=3327, 2983, 2230, 1670, 1578, 1576, 1497, 1469,
1447, 1211, 1039, 843, 779, 765 cmÀ1.
A Schlenk flask, containing a solution of terminal alkyne
(0.0055 mol) in 6 mL of dry THF was cooled down to
À788C and an equimolar amount of n-BuLi was added
dropwise. After addition, the reaction mixture was allowed
to warm up to room temperature during 1.5 h and was then
cooled down again. The CF3-derived diketone (0.0025 mol),
dissolved in 2.5 mL of dry THF, was added dropwise to the
mixture and the solution was warmed to 208C during 3 h.
Afterwards, a solution of 0.0075 mol of NH4Cl in 5 mL of
water was added and the mixture was stirred during 15 min.
The organic layer was extracted with EtOAc (3ꢃ50 mL).
The organic layers were combined, washed with water and
dried over Na2SO4. The solvent was evaporated under
vacuum and the residue was purified by column chromatog-
raphy to give compounds 2.
3-Hydroxy-1-phenyl-3-(trifluoromethyl)non-4-yn-1-one
(3c): Starting from 3-benzoyl-1,1,1-trifluoroacetone (540 mg,
2.5 mmol) and 1-hexyne (451 mg, 5.5 mmol); 3c was isolated
as colorless liquid; yield: 529 mg (71%); 1H NMR
3
(300.13 MHz, CDCl3): d=0.76 (t, 3H, CH3, J=7.2 Hz), 1.30
3
(m, 4H, CH2), 2.08 (t, 2H, CH2, J=7.2 Hz), 3.30 (d, 1H, H-
2a, 2J=16.2 Hz), 3.60 (d, 1H, H-2b, 2J=16.2 Hz), 5.20 (s,
1H, OH), 7.55 (br. m, 3H, H-2’, H-4’, H-6’), 7.90 (dd, 2H,
3
3
H-3’, H-5’, J1 =5.1 Hz, J2 =0.9 Hz); 13C NMR (62.90 MHz,
CDCl3): d=13.4 (C-9), 18.2 (C-8), 21.7 (C-7), 30.0 (C-6),
2
41.7 (C-2), 70.2 (q, C-3, JC,F =32.1 Hz), 75.0 (C-4), 88.3 (C-
1
5), 123.3 (q, CF3, JC,F =283.7 Hz), 128.4 (C-3’, C-5’), 128.9
(C-2’, C-6’), 134.3 (C-4’), 136.4 (C-1’), 198.7 (C-1); GC-MS
(EI, 70 eV): m/z (%)=256 (10), 187 (10), 105 (100), 77 (46);
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

Viktor O. Iaroshenko et al.
UPDATES
HR-MS (ESI): m/z=299.1247 [M+H]+, calcd. for
(61%); 1H NMR (300.13 MHz, CDCl3): d=0.83 (t, 3H,
3
˜
C16H18F3O2: 299.1253; IR (ATR): n=3217, 2219, 1658, 1529,
CH3, J=2.4 Hz), 1.17 (br. m, 6H, CH2), 2.08 (t, 2H, CH2,
1456, 1389, 1286, 1214, 1000, 922, 866, 786, 619 cmÀ1.
3J=6.9 Hz), 3.18 (d, 1H, H-2a, J=15.9 Hz), 3.48 (d, 1H, H-
2
2
3-Hydroxy-1-phenyl-3-(trifluoromethyl)tridec-4-yn-1-one
(3d): Starting from 3-benzoyl-1,1,1-trifluoroacetone (540 mg,
2.5 mmol) and 1-decyne (759 mg, 5.5 mmol); 3d was isolated
as a colourless liquid; yield: 593 mg (67%); 1H NMR
2b, J=15.9 Hz), 5.17 (s, 1H, OH), 7.13 (m, 1H, H-4’), 7.71
(m, 2H, H-3’, H-5’); 13C NMR (62.90 MHz, CDCl3): d=13.8
(C-10), 18.4 (C-9), 22.0 (C-8), 27.6 (C-7), 30.7 (C-6), 42.4 (C-
2
2), 70.1 (q, C-3, JC,F =32.1 Hz), 74.7 (C-4), 88.6 (C-5), 123.2
3
1
(250.13 MHz, CDCl3): d=0.76 (t, 3H, CH3, J=7.5 Hz), 1.29
(q, CF3, JC,F =283.7 Hz), 128.6 (C-4’), 133.9 (C-3’), 135.9 (C-
3
(m, 12H, CH2), 2.07 (t, 2H, CH2, J=7.0 Hz), 3.23 (d, 1H,
5’), 143.4 (C-2’), 191.0 (C-1); GC-MS (EI, 70 eV): m/z
(%)=257 (31), 244 (100), 231 (24), 216 (12), 189 (10), 147
(13), 111 (21). HRMS (ESI): m/z=319.0972 [M+H]+, calcd.
2
2
H-2a, J=16.8 Hz), 3.60 (d, 1H, H-2b, J=16.8 Hz), 5.21 (s,
1H, -OH), 7.47 (br. m, 3H, H-2’, H-4’, H-6’), 7.91 (dd, 2H,
H-3’, H-5’, J1 =1.5 Hz, J2 =1.0 Hz); 13C NMR (62.90 MHz,
CDCl3): d=14.0 (C-13), 18.5 (C-12), 22.6 (C-11), 27.9 (C-
10), 28.6 (C-9), 28.9 (C-8), 29.0 (C-7), 31.8 (C-6), 41.7 (C-2),
70.1 (q, C-3, JC,F =32.7 Hz), 75.0 (C-4), 88.3 (C-5), 123.3 (q,
CF3, JC,F =283.1 Hz), 128.4 (C-3’, C-5’), 128.9 (C-2’, C-6’),
for C15H18F3O2S: 319.0974; IR (ATR): n=3405, 2840, 2233,
3
3
˜
1645, 1605, 1509, 1411, 1243, 1168, 1072, 831, 726, 628 cmÀ1.
3-Hydroxy-1-(thiophen-2-yl)-3-(trifluoromethyl)undeca-
4,10-diyn-1-one (3h): Starting from 4,4,4-trifluoro-1-(thio-
phen-2-yl)butane-1,3-dione (555 mg, 2.5 mmol) and 1,7-octa-
diyne (583 mg, 5.5 mmol); 3h was isolated as a yellow
2
1
134.3 (C-4’), 136.6 (C-1’), 198.7 (C-1); GC-MS (EI, 70 eV):
m/z (%)=285 (10), 238 (10), 105 (100), 77 (44); HR-MS
(ESI): m/z=355.1880 [M+H]+, calcd. for C20H26F3O2:
1
liquid; yield: 0.517 g (63%); H NMR (250.13 MHz, CDCl3):
3
d=1.46 (m, 4H, CH2), 1.85 (t, 1H, H-11, J=3.0 Hz), 2.06
2
˜
355.1879; IR (ATR): n=3437, 2925, 2855, 2240, 1674, 1597,
(m, 4H, CH2), 3.19 (d, 1H, H-2a, J=19.2 Hz), 3.48 (d, 1H,
1450, 1348, 1173, 1002, 755, 686, 624 cmÀ1.
H-2b, 2J=19.2 Hz), 5.20 (s, 1H, OH), 7.13 (dd, 1H, H-4’,
3
3-Hydroxy-5-phenyl-1-(thiophen-2-yl)-3-(trifluoromethyl)-
pent-4-yn-1-one (3e): Starting from 4,4,4-trifluoro-1-(thio-
phen-2-yl)butane-1,3-dione (555 mg, 2.5 mmol) and phenyla-
cetylene (561 mg, 5.5 mmol); 3e was isolated as light-grey
powder; yield: 656 mg (81%); 1H NMR (300.13 MHz,
3J1 =3.6 Hz, J2 =1.2 Hz), 7.20 (m, 2H, H-3’, H-5’); 13C NMR
(75.47 MHz, CDCl3): d=17.8 (C-8), 18.0 (C-7), 26.8 (C-9),
2
27.2 (C-6), 42.4 (C-2), 68.6 (C-11), 70.1 (q, C-3, JC,F
=
32.5 Hz), 75.2 (C-10), 83.9 (C-4), 88.0 (C-5), 123.2 (q, CF3,
1JC,F =283.8 Hz), 128.6 (C-4’), 133.9 (C-3’), 136.0 (C-5’),
143.4 (C-2’), 190.9 (C-1); GC-MS (EI, 70 eV): m/z (%)=302
(14), 243 (43), 202 (28), 144 (100), 128 (19); HR-MS (ESI):
m/z=329.0782 [M+H]+, calcd. for C16H16F3O2S: 329.0786;
2
CDCl3): d=3.32 (d, 1H, H-2a, J=16.5 Hz), 3.61 (d, 1H, H-
2
2b, J=16.5 Hz), 5.34 (s, 1H, -OH), 7.26 (br. m, 6H, H-2’,
H-4’, H-6’, H-3’’, H-4’’, H-5’’), 7.75 (m, 2H, H-3’, H-5’);
13C NMR (62.90 MHz, CDCl3): d=42.4 (C-2), 70.6 (q, C-3,
IR (ATR): n=3369, 3288, 2237, 2196, 1629, 1587, 1506,
˜
1
2JC,F =32.7 Hz), 83.1 (C-4), 87.1 (C-5), 123.2 (q, CF3, JC,F
=
1468, 1387, 1241, 1176, 1033, 954, 814, 682 cmÀ1.
283.7 Hz), 128.3 (C-2’, C-6’), 128.6 (C-4’), 129.3 (C-4’’), 131.8
(C-1’), 132.0 (C-3’, C-5’), 134.0 (C-3’’), 136.1 (C-5’’), 143.3
(C-2’’), 190.7 (C-1); GC-MS (EI, 70 eV): m/z (%)=323 (21)
[MÀH+], 255 (23), 237 (18), 184 (43), 129 (99), 111 (100);
HR-MS (ESI): m/z=325.0508 [M+H]+, calcd. for
1-(Furan-2-yl)-3-hydroxy-5-(4-methoxyphenyl)-3-(trifluor-
omethyl)pent-4-yn-1-one (3i): Starting from 4,4,4-trifluoro-1-
(furan-2-yl)butane-1,3-dione (515 mg, 2.5 mmol) and 4-me-
thoxyphenylacetylene (726 mg, 5.5 mmol); 3i was isolated as
light-yellow flakes; yield: 566 mg (67%); 1H NMR
2
˜
C16H12F3O2S: 325.0505; IR (ATR): n=3297, 2918, 2229,
(300.13 MHz, CDCl3): d=3.23 (d, 1H, H-2a, J=16.2 Hz),
2
1661, 1587, 1522, 1496, 1423, 1398, 1233, 1098, 1010, 954,
3.56 (d, 1H, H-2b, J=16.2 Hz), 3.71 (s, 3H, OCH3), 5.17 (s,
812 cmÀ1.
1H, OH), 6.54 (dd, 1H, H-4’’, J1 =1.8 Hz, J2 =1.8 Hz), 6.72
(m, 2H, H-2’, H-6’), 7.24 (m, 3H, H-3’, H-5’, H-3’’), 7.60 (d,
3
3
3-Hydroxy-5-(4-methoxyphenyl)-1-(thiophen-2-yl)-3-(tri-
fluoromethyl)pent-4-yn-1-one (3f): Starting from 4,4,4-tri-
fluoro-1-(thiophen-2-yl)butane-1,3-dione (555 mg, 2.5 mmol)
and 4-methoxyphenylacetylene (726 mg, 5.5 mmol); 3f was
isolated as light-yellow powder; yield: 708 mg (80%);
3
1H, H-5’’, J=0.9 Hz); 13C NMR (75.47 MHz, CDCl3): d=
2
41.7 (OCH3), 55.3 (C-2), 70.6 (q, C-3, JC,F =32.5 Hz), 81.8
(C-4), 87.2 (C-5), 113.1 (C-4’’), 113.9 (C-2’, C-6’), 119.5 (C-
1
3’’), 123.3 (q, CF3, JC,F =284.5 Hz), 133.1 (C-3’, C-5’), 148.0
2
1H NMR (300.13 MHz, CDCl3): d=3.30 (d, 1H, H-2a, J=
(C-4’), 152.1 (C-1’’), 160.3 (C-1’), 186.4 (C-1); GC-MS (EI,
70 eV): m/z (%)=338 (18) [M+], 228 (15), 198 (11), 159
(100), 144 (17), 95 (52); HR-MS (ESI): m/z=338.0761 [M]+,
16.5 Hz), 3.58 (d, 1H, H-2b, 2J=16.5 Hz), 3.71 (s, 3H,
OCH3), 5.29 (s, 1H, OH), 6.71 (d, 2H, H-2’, H-6’, 3J=
4.8 Hz), 7.19 (m, 3H, H-3’, H-5’, H-4), 7.47 (m, 2H, H-3’’,
H-5’’); 13C NMR (75.47 MHz, CDCl3): d=42.5 (OCH3), 55.3
˜
calcd. for C17H13F3O4: 338.0760; IR (ATR): n=3386, 2964,
2198, 1673, 1575, 1524, 1497, 1446, 1389, 1221, 1075, 849,
(C-2), 70.7 (q, C-3, 2JC,F =32.5 Hz), 81.9 (C-4), 87.3 (C-5),
712 cmÀ1.
1
113.0 (C-4”), 113.9 (C-2’, C-6’), 122.9 (q, CF3, JC,F
=
1-(Furan-2-yl)-3-hydroxy-3-(trifluoromethyl)dec-4-yn-1-
one (3j): Starting from 4,4,4-trifluoro-1-(furan-2-yl)butane-
1,3-dione (515 mg, 2.5 mmol) and 1-heptyne (528 mg,
5.5 mmol); 3j was isolated as an orange liquid; yield: 461 mg
(61%); 1H NMR (300.13 MHz, CDCl3): d=0.78 (t, 3H,
283.7 Hz), 128.9 (C-3’’), 133.1 (C-3’, C-5’), 134.0 (C-4’’),
136.0 (C-5’’), 143.4 (C-2’’), 160.3 (C-1’), 190.8 (C-1); GC-MS
(EI, 70 eV): m/z (%)=428 (93), 409 (11), 228 (100), 214
(23), 200 (71); HR-MS (ESI): m/z=355.0163 [M+H]+,
3
˜
calcd for C17H14F3O3S: 355.0160; IR (ATR): n=3350, 3018,
CH3, J=2.1 Hz), 1.21 (br. m, 6H, CH2), 2.08 (t, 2H, CH2,
2
2897, 1653, 1598, 1524, 1447, 1229, 1210, 1143, 1018, 859,
3J=6.6 Hz), 3.11 (d, 1H, H-2a, J=16.2 Hz), 3.45 (d, 1H, H-
687 cmÀ1.
2b, J=16.2 Hz), 5.05 (s, 1H, OH), 6.55 (dd, 1H, H-4’, J1 =
2.1 Hz, 3J2 =2.1 Hz), 7.27 (dd, 1H, H-3’, 3J1 =3.3 Hz, 3J2 =
0.4 Hz), 7.60 (t, 1H, H-5’, 3J=0.6 Hz); 13C NMR
2
3
3-Hydroxy-1-(thiophen-2-yl)-3-(trifluoromethyl)dec-4-yn-
1-one (3g): Starting from 4,4,4-trifluoro-1-(thiophen-2-yl)bu-
tane-1,3-dione (555 mg, 2.5 mmol) and 1-heptyne (528 mg,
5.5 mmol); 3g was isolated as a yellow liquid; yield: 485 mg
(75.47 MHz, CDCl3): d=13.8 (C-10), 18.4 (C-9), 22.0 (C-8),
2
27.6 (C-7), 30.7 (C-6), 41.6 (C-2), 70.0 (q, C-3, JC,F
=
8
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 4-Trifluoromethylpyridines by [5+1] Cyclization of 3-Hydroxy-pent-4-yn-1-ones
2
32.5 Hz), 74.5 (C-4), 88.6 (C-5), 113.0 (C-4’), 119.4 (C-3’),
123.2 (q, CF3, 1JC,F =284.5 Hz), 147.9 (C-5’), 152.1 (C-1’),
186.6 (C-1); GC-MS (EI, 70 eV): m/z (%)=274 (100), 144
(11), 44 (14); HR-MS (ESI): m/z=303.1198 [M+H]+, calcd.
(q, C-3, JC,F =32.7 Hz), 75.0 (C-4), 88.4 (C-5), 123.3 (q, CF3,
1JC,F =283.7 Hz), 123.4 (C-5’), 127.2 (C-7’), 127.9 (C-8’),
128.8 (C-6’), 129.2 (C-4’), 129.8 (C-3’), 130.1 (C-1’), 132.3 (C-
8a’), 133.7 (C-4a’), 136.1 (C-2’), 198.6 (C-1); GC-MS (EI,
70 eV): m/z (%)=345 (15), 288 (12), 170 (32), 155 (100),
127 (94); HR-MS (ESI): m/z=362.1483 [M]+, calcd. for
˜
for C15H18F3O3: 303.1203; IR (ATR): n=3424, 2933, 2242,
1658, 1569, 1465, 1175, 1100, 1004, 883, 765, 653 cmÀ1.
3-Hydroxy-1-(naphthalen-2-yl)-5-phenyl-3-(trifluorome-
thyl)pent-4-yn-1-one (3k): Starting from 4,4,4-trifluoro-1-
(naphthalen-2-yl)butane-1,3-dione (665 mg, 2.5 mmol) and
phenylacetylene (561 mg, 5.5 mmol); 3k was isolated as
˜
C21H21F3O2: 362.1488; IR (ATR): n=3437, 2930, 2238, 1667,
1469, 1356, 1242, 1171, 1100, 822, 746, 671 cmÀ1.
3-Hydroxy-5-phenyl-1-(pyridin-2-yl)-3-(trifluoromethyl)-
pent-4-yn-1-one (3n): Starting from 4,4,4-trifluoro-1-(pyri-
din-2-yl)butane-1,3-dione (543 mg, 2.5 mmol) and phenyl-
AHCTUNGTERGaNNUN cetylene (561 mg, 5.5 mmol); 3n was isolated as a violet
liquid; yield: 502 mg (63%); H NMR (300.13 MHz, CDCl3):
a
light-yellow powder; yield: 0.681 g (74%); 1H NMR
2
(300.13 MHz, CDCl3): d=3.48 (d, 1H, H-2a, J=16.5 Hz),
3.87 (d, 1H, H-2b, J=16.5 Hz), 5.49 (s, 1H, OH), 7.18 (br.
2
1
2
2
m, 5H, Ph), 7.55 (m, 2H, H-5’, H-7’), 7.91 (br. m, 4H, H-3’,
d=3.61 (d, 1H, H-2a, J=14.4 Hz), 3.71 (d, 1H, H-2b, J=
14.4 Hz), 7.23 (br. m, 5H, Ph), 7.53 (m, 1H, H-5’), 7.90 (m,
H-4’, H-6’, H-8’), 8.43 (s, 1H, H-1’); 13C NMR (75.47 MHz,
2
1H, H-3’’), 8.10 (m, 1H, H-4’), 8.63 (s, 1H, H-6’); 13C NMR
CDCl3): d=41.7 (C-2), 70.7 (q, C-3, JC,F =32.5 Hz), 83.4 (C-
1
2
4), 86.9 (C-5), 123.4 (q, CF3, JC,F =284.5 Hz), 123.4 (C-5’’),
(62.90 MHz, CDCl3): d=46.5 (C-2), 69.7 (q, C-3, JC,F
=
127.2 (C-7’’), 127.9 (C-8’’), 128.3 (C-3’, C-5’), 129.0 (C-6’’),
129.2 (C-4’’), 129.3 (C-3’’), 129.8 (C-1’’), 130.9 (C-4’), 131.9
(C-1’), 132.0 (C-2’, C-6’), 132.4 (C-8a’’), 133.6 (C-4a’’), 136.2
(C-2’’), 198.4 (C-1); GC-MS (EI, 70 eV): m/z (%)=368 (55)
[M+], 350 (20), 299 (24), 281 (26), 228 (56), 170 (36), 155
32.7 Hz), 83.4 (C-4), 87.3 (C-5), 121.2 (C-1’), 123.2 (C-5’’)
123.7 (q, CF3, JC,F =284.9 Hz), 128.0 (C-4’), 128.2 (C-2’, C-
6’), 129.1 (C-3’’), 132.0 (C-3’, C-5’), 138.3 (C-4’’), 148.2 (C-
6’’), 152.1 (C-2’’), 196.0 (C-1); GC-MS (EI, 70 eV): m/z
(%)=319 (11) [M+], 250 (18), 222 (17), 198 (11), 129 (100),
121 (21), 78 (29); HR-MS (ESI): m/z=319.0816 [M]+, calcd,
1
(98), 127 (100), 101 (15); HR-MS (ESI): m/z=368.1019
+
˜
[M] , calcd. for C22H15F3O2: 368.1019; IR (ATR): n=3399,
˜
for C17H12F3NO2: 319.0815; IR (ATR): n=3414, 2876, 2234,
3077, 2223, 1678, 1597, 1464, 1431, 1229, 1163, 1055, 987,
1700, 1596, 1579, 1512, 1498, 1287, 1153, 1012, 913, 846,
963, 879, 787, 679 cmÀ1.
655 cmÀ1.
5-(3-Fluorophenyl)-3-hydroxy-1-(naphthalen-2-yl)-3-(tri-
fluoromethyl)pent-4-yn-1-one (3lL): Starting from 4,4,4-tri-
3-Hydroxy-5-(4-methoxyphenyl)-1-(pyridin-2-yl)-3-(tri-
fluoromethyl)pent-4-yn-1-one (3o): Starting from 4,4,4-tri-
fluoro-1-(furan-2-yl)butane-1,3-dione (543 mg, 2.5 mmol)
and 4-methoxyphenylacetylene (726 mg, 5.5 mmol); 3o was
fluoro-1-(naphthalen-2-yl)butane-1,3-dione
(665 mg,
2.5 mmol) and 3-fluorophenylacetylene (660 mg, 5.5 mmol);
3l was isolated as a light-yellow powder; yield: 676 mg
isolated as
a light-green liquid; yield: 497 mg (59%);
1
(70%); H NMR (500.13 MHz, CD2Cl2): d=3.47 (d, 1H, H-
2
1H NMR (300.13 MHz, CDCl3): d=3.54 (d, 1H, H-2a, J=
14.1 Hz), 3.66 (d, 1H, H-2b, 2J=14.1 Hz), 3.69 (s, 3H,
OCH3), 6.72 (m, 2H, H-2’, H-6’), 7.20 (m, 2H, H-3’, H-5’),
7.53 (m,1H, H-5’’), 7.89 (m, 2H, H-3’’, OH), 8.06 (m, 1H,
H-4’’), 8.61 (m, 1H, H-6’’); 13C NMR (62.90 MHz, CD2Cl2):
d=47.0 (C-2), 55.7 (-OCH3), 70.0 (q, C-3, 2JC,F =32.7 Hz),
82.7 (C-4), 87.6 (C-5), 113.4 (C-4’), 114.3 (C-2’, C-6’), 123.4
(C-5’’), 124.2 (q, CF3, 1JC,F =284.9 Hz), 128.5 (C-3’’), 133.7
(C-3’, C-5’), 138.8 (C-4’’), 148.7 (C-6’’), 152.6 (C-2’’), 160.8
(C-1’), 196.4 (C-1); GC-MS (EI, 70 eV): m/z (%)=228 (28),
159 (100), 144 (20), 116 (18), 88 (14); HR-MS (ESI): m/z=
350.0993 [M+H]+, calcd. for C18H15F3NO3: 350.0999; IR
2a, 2J=16.5 Hz), 3.87 (d, 1H, H-2b, 2J=16.5 Hz), 5.46 (s,
1H, OH), 6.94 (m, 2H, H-2’, H-4’), 7.05 (m, 1H, H-6’), 7.13
3
3
(dd, 1H, H-5’, J1 =5.5 Hz, J2 =1.0 Hz), 7.49 (dd, 1H, H-6’’,
3J1 =7.0 Hz, 3J2 =1.0 Hz), 7.55 (dd, 1H, H-7’’, 3J1 =7.0 Hz,
3J2 =1.0 Hz), 7.85 (br. m, 4H, H-3’’, H-4’’, H-5’’, H-8’’), 8.42
3
(d, 1H, H-1’’, J=1.0 Hz); 13C NMR (125.76 MHz, CD2Cl2):
2
d=42.1 (C-2), 71.0 (q, C-3, JC,F =32.7 Hz), 84.8 (C-4), 85.7
4
2
(d, C-5, JC,F =3.8 Hz), 117.0 (d, C-2’, JC,F =23.9 Hz), 119.0
(d, C-4’, 2JC,F =23.9 Hz), 123.2 (q, CF3, 1JC,F =284.1 Hz),
123.7 (C-6’), 127.7 (C-5’’), 128.3 (d, 1H, C-4’, JC,F =7.6 Hz),
3
129.0 (C-7’’), 129.3 (C-6’’), 129.6 (C-8’’), 130.2 (C-4’’), 130.5
(C-3’’), 131.0 (C-4a’’, C-8a’’), 131.3 (C-1’’), 132.8 (d, C-1’,
1
3JC,F =8.8 Hz), 136.6 (C-2’’), 162.5 (d, C-3’, JC,F =246.9 Hz),
˜
(ATR): n=3391, 2935, 2840, 2232, 1698, 1605, 1509, 1247,
1169, 1107, 1027, 832, 617 cmÀ1.
198.7 (C-1); GC-MS (EI, 70 eV): m/z (%)=368 (100), 299
(38), 270 (59), 246 (21), 220 (22), 152 (53), 144 (25), 127
(66); HRMS (ESI): m/z=386.0927 [M]+, calcd. for
6-Cyclohexyl-3-hydroxy-1-(pyridin-2-yl)-3-(trifluorome-
thyl)hex-4-yn-1-one (3p): Starting from 4,4,4-trifluoro-1-
(furan-2-yl)butane-1,3-dione (543 mg, 2.5 mmol) and 3-cy-
clohexyl-prop-1-yne (671 mg, 5.5 mmol); 3p was isolated as
˜
C22H14F4O2: 386.0924; IR (ATR): n=3457, 3077, 2229, 2201,
1674, 1580, 1485, 1470, 1435, 1367, 1339, 1233, 1163, 1070,
a
light-violet liquid; yield: 483 mg (57%); 1H NMR
955, 933, 860, 832, 777, 741, 673, 561 cmÀ1.
(300.13 MHz, CDCl3): d=0.81 (br.m, 6H, Cy), 1.04 (m, 5H,
3-Hydroxy-1-(naphthalen-2-yl)-3-(trifluoromethyl)dec-4-
yn-1-one (3m): Starting from 4,4,4-trifluoro-1-(naphthalen-2-
yl)butane-1,3-dione (665 mg, 2.5 mmol) and 1-heptyne
(528 mg, 5.5 mmol); 3m was isolated as a colorless liquid;
yield: 579 mg (64%); 1H NMR (300.13 MHz, CDCl3): d=
3
2
Cy), 1.95 (d, 2H, H-6, J=5.4 Hz), 3.51 (d, 1H, H-2a, J=
2
15.3 Hz), 3.55 (d, 1H, H-2b, J=15.3 Hz), 7.52 (m, 1H, H-
5’), 7.90 (m, 1H, H-3’’), 8.08 (m, 1H, H-4’), 8.62 (m, 1H, H-
6’); 13C NMR (62.90 MHz, CDCl3): d=26.1 (CH2), 26.2
2
3
(CH2), 32.3 (CH2), 36.8 (CH), 46.6 (C-6), 68.8 (q, C-3, JC,F
=
0.70 (t, 3H, CH3, J=2.4 Hz), 1.16 (br. m, 6H, CH2), 2.06 (t,
3
2
32.7 Hz), 75.8 (C-4), 87.7 (C-5), 123.3 (C-3’), 124.6 (q, CF3,
1JC,F =284.3 Hz), 127.3 (C-5’), 138.2 (C-4’), 148.2 (C-6’),
152.2 (C-2’), 196.3 (C-1); GC-MS (EI, 70 eV): m/z (%)=338
(14) [MÀH+], 310 (16), 256 (46), 188 (35), 149 (29), 121
(80), 83 (100); HR-MS (ESI): m/z=340.1524, [M+H]+,
2H, CH2, J=6.9 Hz), 3.35 (d, 1H, H-2a, J=16.5 Hz), 3.75
2
(d, 1H, H-2b, J=16.5 Hz), 5.30 (s, 1H, OH), 7.55 (m, 2H,
H-5’, H-7’), 7.88 (br. m, 4H, H-3’, H-4’, H-6’, H-8’), 8.41 (s,
1H, H-1’); 13C NMR (62.90 MHz, CDCl3): d=13.8 (C-10),
18.5 (C-9), 22.0 (C-8), 27.6 (C-7), 30.7 (C-6), 41.7 (C-2), 70.3
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!

Viktor O. Iaroshenko et al.
UPDATES
˜
calcd. for C18H21F3NO2: 340.1519; IR (ATR): n=2923, 2851,
13C NMR (62.90 MHz, CDCl3): d=31.3 (CH3), 34.8
3
3
2240, 1699, 1587, 1449, 1262, 1173, 1104, 617 cmÀ1.
[(CH3)3C], 113.6 (d, C-5, JC,F =3.8 Hz), 113.8 (d, C-3, JC,F
3.8 Hz), 122.9 (q, CF3, JC,F =273.2 Hz), 125.9 (C-3’’, C-5’’),
=
1
3-Hydroxy-1-phenyl-5-(pyridin-2-yl)-3-(trifluoromethyl)-
pent-4-yn-1-one (3q): Starting from 3-benzoyl-1,1,1-trifluor-
oacetone (540 mg, 2.5 mmol) and 2-ethynylpyridine (567 mg,
5.5 mmol); 3q was isolated as a dark-green powder; yield:
126.9 (C-2’, C-6’), 127.1 (C-3’, C-5’), 128.9 (C-2’’, C-6’’),
2
129.8 (C-4’’), 135.5 (C-1’), 138.3 (C-1’’), 139.9 (q, C-4, JC,F
=
34.0 Hz), 153.1 (C-4’), 158.1 (C-6), 158.3 (C-2); GC-MS (EI,
70 eV): m/z (%)=355 (42) [M+], 340 (100), 312 (14), 156
(20); HR-MS (ESI): m/z=355.1537 [M]+, calcd. for
1
383 mg (48%); H NMR (300.13 MHz, CD2Cl2): d=3.57 (d,
1H, H-2a, 2J=18.0 Hz), 3.87 (d, 1H, H-2b, 2J=18.0 Hz),
5.78 (s, 1H, OH), 7.59 (br. m, 6H, H-3’, H-4’, H-5’, H-2’’, H-
4’’, H-6’’), 8.04 (dd, 2H, H-3’’, H-5’’, 3J1 =3.6 Hz, 3J2 =
3.0 Hz), 8.58 (m, 1H, H-6’); 13C NMR (62.90 MHz, CD2Cl2):
˜
C20H20F3N: 355.1542; IR (ATR): n=2962, 1611, 1574, 1562,
1412, 1371, 1263, 1168, 1132, 1106, 877, 840, 772, 687 cmÀ1.
2-Butyl-6-phenyl-4-(trifluoromethyl)pyridine (5c): Starting
from 3-hydroxy-1-phenyl-3-(trifluoromethyl)non-4-yn-1-one
(298 mg, 1 mmol) (3c) and urea (72 mg, 1.2 mmol); 5c was
isolated as a light-orange liquid; yield: 145 mg (52%);
1H NMR (300.13 MHz, CDCl3): d=0.90 (t, 3H, CH3, 3J=
7.2 Hz), 1.39 (m, 2H, CH2), 1.73 (m, 2H, CH2), 2.86 (t, 2H,
CH2, 3J=7.8 Hz), 7.18 (d, 1H, H-4ꢄ, 3J=8.4 Hz), 7.39 (m,
3H, H-3, H-3’, H-5’), 7.65 (s, 1H, H-5), 7.95 (m, 2H, H-2’,
H-6’); 13C NMR (62.90 MHz, CDCl3): d=13.9 (CH3), 22.5
2
d=42.3 (C-2), 70.7 (q, C-3, JC,F =32.7 Hz), 83.3 (C-4), 86.1
(C-5), 123.8 (q, CF3, JC,F =284.3 Hz), 123.9 (C-3’), 124.2 (C-
1
5’), 128.0 (C-4’’), 128.8 (C-2’’, C-6’’), 129.3 (C-3’’, C-5’’),
134.7 (C-4’), 136.6 (C-6’), 141.8 (C-1’’), 150.4 (C-1’’), 198.2
(C-1); GC-MS (EI, 70 eV): m/z (%)=318 (46) [MÀH+], 250
(14), 222 (18), 180 (51), 130 (44), 105 (100), 77 (69); HRMS
(ESI): m/z=320.0890, [M+H]+, calcd. for C17H13F3NO2:
˜
320.0893; IR (ATR): n=3086, 2790, 2239, 1689, 1586, 1470,
3
1430, 1371, 1268, 1167, 1114, 1084, 976, 763, 688, 623 cmÀ1.
3-Hydroxy-5-(4-methoxyphenyl)-1-(4-nitrophenyl)-3-(tri-
fluoromethyl)pent-4-yn-1-one (3r): Starting from 3-(4-nitro-
benzoyl)-1,1,1-trifluoroacetone (653 mg, 2.5 mmol) and 4-
methoxyphenylacetylene (726 mg, 5.5 mmol); 3r was isolat-
(CH2), 31.7 (CH2), 38.3 (CH2), 113.2 (q, C-3, JC,F =3.8 Hz),
3
1
116.4 (q, C-5, JC,F =3.8 Hz), 123.2 (q, CF3, JC,F =273.6 Hz),
127.1 (C-3’, C-5’), 128.8 (C-2’, C-6’), 129.5 (C-4’), 138.5 (C-
2
1’), 139.2 (q, C-4, JC,F =33.3 Hz), 158.1 (C-6), 164.0 (C-2);
GC-MS (EI, 70 eV): m/z (%)=250 (21), 237 (100); HRMS
ed as
a
yellow gum; yield: 609 mg (62%); 1H NMR
(ESI): m/z=280.1310 [M+H]+, calcd. for C16H17F3N:
2
˜
(300.13 MHz, CD2Cl2): d=3.46 (d, 1H, H-2a, J=15.2 Hz),
280.1308; IR (ATR): n=2958, 2930, 1573, 1459, 1412, 1372,
2
3.70 (s, 3H, OCH3), 3.73 (d, 1H, H-2b, J=15.2 Hz), 4.66 (s,
1261, 1166, 1131, 1103, 867, 773, 691, 639 cmÀ1.
1H, OH), 6.74 (dd, 2H, H-2’, H-6’’, 3J1 =4.5 Hz, 3J2 =
2-Octyl-6-phenyl-4-(trifluoromethyl)pyridine (5d): Start-
ing from 3-hydroxy-1-phenyl-3-(trifluoromethyl)tridec-4-yn-
1-one (354 mg, 1 mmol) (3d) and urea (72 mg, 1.2 mmol); 5d
was isolated as a light-orange liquid; yield: 188 mg (56%);
3
3
2.1 Hz), 7.22 (dd, 2H, H-3’, H-5’, J1 =4.5 Hz, J2 =2.1 Hz),
3
3
8.08 (dd, 2H, H-3’’, H-5’’, J1 =4.8 Hz, J2 =2.1 Hz), 8.27 (dd,
2H, H-2’’, H-6’’, 3J1 =4.8 Hz, 3J2 =2.1 Hz); 13C NMR
(62.90 MHz, CD2Cl2): d=43.2 (C-2), 55.6 (OCH3), 70.5 (q,
C-3, JC,F =32.7 Hz), 81.8 (C-4), 87.8 (C-5), 114.3 (C-2’, C-
6’), 123.4 (q, CF3, JC,F =284.9 Hz), 124.1 (C-3’, C-5’), 129.8
(C-3’’, C-5’’), 133.7 (C-2’’, C-6’’), 135.8 (C-1’), 141.0 (C-4’’),
151.2 (C-1’), 160.9 (C-1’’), 196.8 (C-1); GC-MS (EI, 70 eV):
m/z (%)=281 (78), 253 (20), 159 (100); HR-MS (ESI): m/
z=394.0892 [M+H]+, calcd. for C19H15F3NO5: 394.0897; IR
3
1H NMR (300.13 MHz, CD2Cl2): d=0.79 (t, 3H, CH3, J=
6.0 Hz), 1.27 (m, 10H, CH2), 1.72 (dd, 2H, CH2, 3J1 =
2
1
3
3
10.5 Hz, J2 =7.8 Hz), 2.84 (t, 2H, CH2, J=7.8 Hz), 7.23 (s,
1H, H-3), 7.41 (m, 3H, H-3’, H-4’, H-5’), 7.68 (s, 1H, H-5),
7.98 (m, 2H, H-2’, H-6’); 13C NMR (75.47 MHz, CD2Cl2):
d=13.3 (CH3), 22.2 (CH2), 28.7 (CH2), 28.8 (CH2), 28.9
(CH2), 29.0 (CH2), 31.4 (CH2), 37.9 (CH2), 112.4 (q, C-3,
3JC,F =3.8 Hz), 115.9 (q, C-5, 3JC,F =3.8 Hz), 122.9 (q, CF3,
1JC,F =273.2 Hz), 126.4 (C-3’, C-5’), 128.3 (C-2’, C-6’), 129.1
˜
(ATR): n=3489, 3110, 2912, 2235, 1683, 1603, 1511, 1401,
1344, 1230, 1178, 1077, 1030, 947, 840, 747, 688, 639 cmÀ1.
2,6-Diphenyl-4-(trifluoromethyl)pyridine (5a): Starting
from 3-hydroxy-1,5-diphenyl-3-(trifluoromethyl)pent-4-yn-1-
one (318 mg, 1 mmol) (3a) and urea (72 mg, 1.2 mmol); 5a
was isolated as a light-yellow powder; yield: 203 mg (68%);
mp 62–648C; 1H NMR (250.13 MHz, DMSO-d6): d=7.49
(m, 6H, H-3’, H-4’, H-5’, H-3’’, H-4’’, H-5’’), 8.25 (m, 6H, H-
3, H-5, H-2’, H-6’, H-2’’, H-6’’); 13C NMR (62.90 MHz,
DMSO-d6): d=112.6 (q, C-3, C-5, 3JC,F =3.1 Hz), 121.6 (q,
CF3, 1JC,F =274.2 Hz), 125.5 (C-3’, C-5’, C-3’’, C-5’’), 127.4
(C-2’, C-6’, C-2’’, C-6’’), 128.5 (C-4’, C-4’’), 135.8 (C-1’, C-1’’),
2
(C-4’), 137.8 (C-1’), 138.5 (q, C-4, JC,F =33.2 Hz), 157.2 (C-
2), 163.6 (C-6); GC-MS (EI, 70 eV): m/z=(%): 264 (10),
250 (19), 237 (100); HR-MS (ESI): m/z=335.1847 [M]+,
˜
calcd. for C20H24F3N: 335.1855; IR (ATR): n=2925, 1573,
1412, 1372, 1261, 1134, 879, 773, 691, 639 cmÀ1.
2-Phenyl-6-(thiophen-2-yl)-4-(trifluoromethyl)pyridine
(5e): Starting from 3-hydroxy-5-phenyl-1-(thiophen-2-yl)-3-
(trifluoromethyl)pent-4-yn-1-one (324 mg, 1 mmol) (3e) and
urea (72 mg, 1.2 mmol); 5e was isolated as light-orange crys-
tals; yield: 220 mg (72%); mp 104–1078C; 1H NMR
(300.13 MHz, CDCl3): d=7.08 (dd, 1H, H-4’’, 3J1 =3.6 Hz,
3J2 =1.5 Hz), 7.45 (br. m, 4H, H-3’, H-4’, H-5’, H-3’’), 7.66
(m, 3H, H-2’, H-6’, H-5’’), 8.06 (m, 2H, H-3, H-5); 13C NMR
2
137.7 (q, C-4, JC,F =33.3 Hz), 155.8 (C-2, C-6); GC-MS (EI,
70 eV): m/z (%)=299 (100) [M+], 230 (11), HR-MS (ESI):
m/z=300.0992 [M+H]+, calcd. for C18H13F3N: 300.0995; IR
3
˜
(ATR): n=2890, 1589, 1566, 1518, 1466, 1376, 1255, 1180,
(75.47 MHz, CDCl3): d=112.4 (q, C-5, JC,F =3.8 Hz), 113.5
3
1
1162, 1084, 877, 696 cmÀ1.
(q, C-3, JC,F =3.8 Hz), 123.0 (q, CF3, JC,F =273.9 Hz), 125.7
(C-4’’), 127.1 (C-3’, C-5’), 128.2 (C-3’’), 128.9 (C-2’, C-4’, C-
2-(4-tert-Butylphenyl)-6-phenyl-4-(trifluoromethyl)pyri-
dine (5b). Starting from 5-(4-tert-butylphenyl)-3-hydroxy-1-
phenyl-3-(trifluoromethyl)pent-4-yn-1-one (374 mg, 1 mmol)
(3b) and urea (72 mg, 1.2 mmol); 5b was isolated as a light-
2
6’), 130.0 (C-5’’), 137.7 (C-1’), 140.0 (q, C-4, JC,F =33.2 Hz),
144.0 (C-1’’), 153.5 (C-2), 158.1 (C-6); GC-MS (EI, 70 eV):
m/z (%)=305 (100) [M+]; HR-MS (ESI): m/z=306.0558
1
+
˜
yellow liquid; yield: 216 mg (61%); H NMR (300.13 MHz,
[M+H] , calcd. for C16H10F3NS: 306.0559; IR (ATR): n=
CDCl3): d=1.30 (s, 9H, t-Bu), 7.46 (br. m, 5H, Ph), 7.77 (s,
2H, H-3, H-5), 8.08 (br, m, 4H, H-2’’, H-3’’, H-5’’, H-6’’);
3068, 1568, 1436, 1403, 1373, 1337, 1264, 1167, 1126, 870,
833, 773, 714, 689, 633 cmÀ1.
10
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 4-Trifluoromethylpyridines by [5+1] Cyclization of 3-Hydroxy-pent-4-yn-1-ones
3
3
2-(4-Methoxyphenyl)-6-(thiophen-2-yl)-4-(trifluorome-
thyl)pyridine (5f): Starting from 3-hydroxy-5-(4-methoxy-
phenyl)-1-(thiophen-2-yl)-3-(trifluoromethyl)pent-4-yn-1-
one (354 mg, 1 mmol) (3f) and urea (72 mg, 1.2 mmol); 5f
was isolated as white crystals; yield: 298 mg (89%); mp 69–
718C; 1H NMR (300.13 MHz, CDCl3): d=3.81 (s, 3H,
OCH3), 6.49 (dd, 1H, H-4’’, J1 =1.8 Hz, J2 =1.8 Hz), 6.93
3 3
(m, 2H, H-3’, H-5’), 7.17 (dd, 1H, H-3’’, J1 =1.8 Hz, J2 =
3
3
0.6 Hz), 7.49 (dd, 1H, H-5’’, J1 =1.8 Hz, J2 =0.6 Hz), 7.62
(s, 1H, H-3), 7.67 (s, 1H, H-5), 7.96 (m, 2H, H-2’, H-6’);
13C NMR (62.90 MHz, CDCl3): d=55.4 (OCH3), 110.0 (C-
3
4’’), 111.4 (q, C-3, JC,F =3.8 Hz), 112.3 (C-3’’), 112.9 (q, C-3,
3
1
OCH3), 6.95 (m, 2H, H-2’, H-6’), 7.07 (dd, 1H, H-4’’, J1 =
3JC,F =3.8 Hz), 114.2 (C-2’, C-6’), 123.1 (q, CF3, JC,F
=
4
2.4 Hz, 3J2 =1.2 Hz), 7.38 (dd, 1H, H-3’’, 3J1 =4.2 Hz, J2 =
273.2 Hz), 128.4 (C-3’, C-5’), 130.5 (C-4’), 139.8 (q, C-4,
2JC,F =33.7 Hz), 143.9 (C-5’’), 150.1 (C-2’’), 153.2 (C-2), 157.9
(C-6), 161.2 (C-1’); GC-MS (EI, 70 eV): m/z (%)=319
(100) [M+], 276 (16), 246 (12); HR-MS (ESI): m/z=
319.0819, [M]+, calcd. for C17H12F3NO2: 319.0815; IR
0.9 Hz), 7.62 (m, 3H, H-5, H-3’, H-5’), 8.03 (m, 2H, H-3, H-
5’’); 13C NMR (62.90 MHz, CDCl3): d=55.4 (OCH3), 111.5
(q, C-3, 3JC,F =3.8 Hz), 112.6 (q, C-5, 3JC,F =3.8 Hz), 114.2
(C-2’, C-6’), 123.1 (q, CF3, 1JC,F =273.2 Hz), 125.5 (C-4’’),
128.1 (C-3’’), 128.4 (C-3’, C-5’), 128.7 (C-5’’), 130.3 (C-4’),
139.8 (q, C-4, 2JC,F =33.2 Hz), 144.2 (C-2’’), 153.3 (C-2),
157.7 (C-6), 161.2 (C-1’); GC-MS (EI, 70 eV): m/z (%)=335
(100) [M+], 320 (12), 292 (35), 223 (11); HR-MS (ESI):
m/z=336.0663 [M+H]+, calcd. for C17H13F3NOS: 336.0665;
˜
(ATR): n=3101, 1608, 1564, 1400, 1379, 1361, 1246, 1131,
1105, 1016, 874, 837, 753, 690, 586 cmÀ1.
2-(Furan-2-yl)-6-pentyl-4-(trifluoromethyl)pyridine (5j):
Starting from 1-(furan-2-yl)-3-hydroxy-3-(trifluoromethyl)-
dec-4-yn-1-one (302 mg, 1 mmol) (3j) and urea (72 mg,
1.2 mmol); 5j was isolated as a red liquid; yield: 144 mg
(51%); 1H NMR (300.13 MHz, CDCl3): d=0.94 (t, 3H,
CH3, 3J=1.8 Hz), 1.38 (m, 4H, CH2), 1.78 (m, 2H, CH2),
2.88 (t, 2H, CH2, 3J=7.8 Hz), 6.55 (dd, 1H, H-4’, 3J1 =
˜
IR (ATR): n=3093, 3015, 2968, 2840, 1608, 1562, 1516,
1435, 1411, 1371, 1337, 1265, 1162, 1127, 1105, 1025, 870,
831. 713, 690, 581 cmÀ1.
2-Pentyl-6-(thiophen-2-yl)-4-(trifluoromethyl)pyridine
(5g): Starting from 3-hydroxy-1-(thiophen-2-yl)-3-(trifluoro-
methyl)dec-4-yn-1-one (318 mg, 1 mmol) (3g) and urea
(72 mg, 1.2 mmol); 5g was isolated as a light-red powder;
3
1.8 Hz, J2 =0.6 Hz), 7.20 (m, 2H, H-3’, H-5’), 7.25 (s, 1H,
H-5), 7.70 (s, 1H, H-3); 13C NMR (62.90 MHz, CDCl3): d=
14.0 (CH3), 22.4 (CH2), 29.2 (CH2), 31.5 (CH2), 38.3 (CH2),
110.0 (C-4’), 111.4 (d, C-5, JC,F =3.8 Hz), 112.7 (C-3’), 116.1
(d, C-3, JC,F =3.8 Hz), 122.9 (q, CF3, JC,F =273.6 Hz), 139.2
(q, C-4, JC,F =33.7 Hz), 143.9 (C-5’), 149.8 (C-2’), 152.8 (C-
1
3
yield: 173 mg (58%); mp 47–498C; H NMR (300.13 MHz,
CDCl3): d=0.84 (t, 3H, CH3, 3J=6.9 Hz), 1.31 (m, 4H,
3
1
3
2
CH2), 1.72 (m, 2H, CH2), 2.79 (t, 2H, CH2, J=7.8 Hz), 7.06
(m, 2H, H-3’, H-4’), 7.33 (s, 1H, H-3), 7.56 (m, 2H, H-5, H-
5’); 13C NMR (75.47 MHz, CDCl3): d=14.0 (CH3), 22.5
(CH2), 29.0 (CH2), 31.5 (CH2), 38.2 (CH2), 111.4 (q, C-3,
3JC,F =3.8 Hz), 116.1 (q, C-5, 3JC,F =3.8 Hz), 121.8 (q, CF3,
1JC,F =273.2 Hz), 125.4 (C-4’), 128.4 (C-3’), 128.5 (C-5’),
2), 164.0 (C-6); GC-MS (EI, 70 eV): m/z (%)=254 (11), 240
(19), 227 (100), 198 (10); HR-MS (ESI): m/z=283.1175
+
˜
[M] , calcd. for C15H16F3NO: 283.1179; IR (ATR): n=2930,
2860, 1575, 1494, 1382, 1361, 1260, 1134, 1008, 884, 740,
695 cmÀ1.
2
139.6 (q, C-4, JC,F =33.2 Hz), 144.1 (C-1’), 153.1 (C-6), 164.0
2-(Naphthalen-2-yl)-6-phenyl-4-(trifluoromethyl)pyridine
(5k): Starting from 3-hydroxy-1-(naphthalen-2-yl)-5-phenyl-
3-(trifluoromethyl)pent-4-yn-1-one (368 mg, 1 mmol) (3k)
and urea (72 mg, 1.2 mmol); 5k was isolated as a light-
(C-2); GC-MS (EI, 70 eV): m/z (%)=270 (28), 256 (42),
243 (100); HR-MS (ESI): m/z=300.1025 [M+H]+, calcd.
˜
for C15H17F3NS: 300.1028; IR (ATR): n=2963, 2930, 1608,
1
1569, 1440, 1410, 1375, 1335, 1256, 1164, 1123, 870, 833, 794,
yellow powder; yield: 185 mg (53%); mp 97–998C; H NMR
709, 694 cmÀ1.
(300.13 MHz, CDCl3): d=7.44 (m, 5H, H-3’, H-4’, H-5’, H-
6’’, H-7’’), 7.88 (br. m, 5H, H-1’’, H-4’’, H-5’’, H-8’’, H-5),
2-(Hex-5-ynyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)pyri-
dine (5h): Starting from 3-hydroxy-1-(thiophen-2-yl)-3-(tri-
fluoromethyl)undeca-4,10-diyn-1-one (328 mg) (3h) and
urea (72 mg, 1.2 mmol); 5h was isolated as a yellow liquid;
yield: 148 mg (48%); 1H NMR (300.13 MHz, CDCl3): d=
3
8.13 (m, 2H, H-2’, H-6’), 8.23 (dd, 1H, H-3’’, J1 =6.9 Hz,
3J2 =1.8 Hz), 8.54 (s, 1H, H-3’); 13C NMR (75.47 MHz,
CDCl3): d=113.0 (q, C-3, 3JC,F =3.8 Hz), 113.2 (q, C-5,
1
3JC,F =3.8 Hz), 122.2 (q, CF3, JC,F =273.2 Hz), 123.4 (C-7’’),
3
1.59 (t, 2H, CH2, J=6.9 Hz), 1.88 (m, 3H, CH2, H-6ꢄ), 2.20
125.5 (C-5’’), 125.8 (C-6’’), 125.9 (C-3’, C-5’), 126.1 (C-8’’),
126.7 (C-4’), 127.6 (C-2’, C-6’), 127.8 (C-1’’, C-4’’), 128.8 (C-
3’’), 132.3 (C-8a’’), 133.0 (C-4a’’), 134.4 (C-1’), 137.2 (C-2’’),
3
(m, 2H, CH2), 2.82 (t, 2H, CH2, J=7.5 Hz), 7.18 (m, 2H,
H-4’’, H-3’’), 7.35 (s, 1H, H-3), 7.56 (m, 2H, H-5, H-5’’);
13C NMR (75.47 MHz, CDCl3): d=18.3 (C-3’), 27.9 (C-2’),
28.1 (C-4’), 37.5 (C-1’), 68.5 (C-6’), 84.2 (C-5’), 111.6 (q, C-3,
3JC,F =3.8 Hz), 116.1 (q, C-5, 3JC,F =3.8 Hz), 123.0 (q, CF3,
1JC,F =273.2 Hz), 125.5 (C-4’’), 128.4 (C-3’’), 128.6 (C-5’’),
139.2 (q, C-4, 2JC,F =33.2 Hz), 144.0 (C-2’’), 153.2 (C-2),
163.3 (C-6); GC-MS (EI, 70 eV): m/z (%)=308 (20), 280
2
139.0 (q, C-4, JC,F =33.2 Hz), 157.0 (C-6), 157.3 (C-2); GC-
MS (EI, 70 eV): m/z (%)=349 (100) [M+]; HR-MS (ESI):
m/z=349.1066 [M]+, calcd. for C22H14F3N: 349.1073; IR
˜
(ATR): n=2962, 1598, 1412, 1373, 1260, 1175, 1125, 1104,
1015, 796, 768, 755, 690 ,cmÀ1.
2-(3-Fluorophenyl)-6-(naphthalen-2-yl)-4-(trifluorome-
thyl)pyridine (5l): Starting from 5-(3-fluorophenyl)-3-hy-
droxy-1-(naphthalen-2-yl)-3-(trifluoromethyl)pent-4-yn-1-
one (386 mg, 1 mmol) (3l) and urea (72 mg, 1.2 mmol); 5l
was isolated as a light-yellow powder; yield: 242 mg (66%);
(19), 256 (25), 243 (100); HR-MS (ESI): m/z=310.0867
+
˜
[M+H] , calcd. for C16H15F3NS: 310.0872; IR (ATR): n=
3305, 2937, 2117, 1610, 1572, 1439, 1410, 1375, 1336, 1256,
1167, 1130, 873, 695, 629 cmÀ1.
1
2-(Furan-2-yl)-6-(4-methoxyphenyl)-4-(trifluoromethyl)-
pyridine (5i): Starting from 1-(furan-2-yl)-3-hydroxy-5-(4-
methoxyphenyl)-3-(trifluoromethyl)pent-4-yn-1-one
(338 mg, 1 mmol) (3i) and urea (72 mg, 1.2 mmol); 5i was
isolated as a yellow powder; yield: 239 mg (75%); mp 89–
928C; 1H NMR (300.13 MHz, CDCl3): d=3.80 (s, 3H,
mp 84–868C; H NMR (300.13 MHz, CD2Cl2): d=7.13 (m,
1H, H-4’), 7.47 (m, 3H, H-2ꢄ, H-5’, H-6’), 7.90 (m, 6H, H-
1’’, H-4’’, H-5’’, H-6’’, H-7’’, H-8’’), 7.96 (s, 1H, H-3), 8.24 (d,
1H, H-3’’, 3J=6.0 Hz), 8.56 (s, 1H, H-5); 13C NMR
(62.90 MHz, CD2Cl2): d=114.4 (d, C-2’, 2JC,F =23.3 Hz),
114.5 (d, C-5, 3JC,F =3.8 Hz), 115.3 (d, C-3, 3JC,F =3.8 Hz),
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
11
ÞÞ
These are not the final page numbers!

Viktor O. Iaroshenko et al.
UPDATES
2
3
119.0 (d, C-4’, JC,F =21.4 Hz), 123.0 (d, C-5’, JC,F =3.1 Hz),
123.6 (q, CF3, 1JC,F =273.6 Hz), 124.7 (C-6’’), 127.0 (C-5’’),
127.2 (C-7’’), 127.5 (C-8’’), 128.0 (C-6’’), 129.0 (C-4’’), 129.2
34.0 Hz), 149.2 (C-2”), 155.0 (C-6), 156.9 (C-2), 161.2 (C-1’).
GC-MS (EI, 70 eV): m/z (%)=330 (100) [M+], 315 (12),
287 (12); HR-MS (ESI): m/z=330.0975 [M]+, calcd. for
˜
C18H13F3N2O: 330.0975; IR (ATR): n=2962, 1607, 1585,
(C-1’’), 130.8 (C-3’’), 133.8 (C-8a’’), 134.5 (C-4a’’), 135.5 (C-
2
2’’), 140.8 (d, C-1’, 3JC,F =4.9 Hz), 141.0 (q, C-4, JC,F
=
1562, 1515, 1408, 1372, 1262, 1245, 1121, 1029, 837, 793,
660 cmÀ1.
4
34.0 Hz), 157.1 (d, C-2, JC,F =1.9 Hz), 158.5 (C-6), 163.7 (d,
C-3’, 1JC,F =245.3 Hz); GC-MS (EI, 70 eV): m/z (%)=367
(100) [M+]; HR-MS (ESI): m/z=367.0974 [M]+, calcd. for
6-(Cyclohexylmethyl)-4-(trifluoromethyl)-2,2’-bipyridine
(5p): Starting from 6-cyclohexyl-3-hydroxy-1-(pyridin-2-yl)-
3-(trifluoromethyl)hex-4-yn-1-one (339 mg, 1 mmol) (3p)
and urea (72 mg, 1.2 mmol); 5p was isolated as a greenish
˜
C22H13F4N: 367.0979; IR (ATR): n=3065, 1565, 1459, 1410,
1370, 1270, 1126, 861, 822, 782, 756, 694, 680 cmÀ1.
1
liquid; yield: 224 mg (70%); H NMR (300.13 MHz, CDCl3):
2-(Naphthalen-2-yl)-6-pentyl-4-(trifluoromethyl)pyridine
(5m): Starting from 3-hydroxy-1-(naphthalen-2-yl)-3-(tri-
fluoromethyl)dec-4-yn-1-one (362 mg, 1 mmol) (3m) and
urea (72 mg, 1.2 mmol); 5m was isolated as a light-yellow
d=1.15 (m, 5H, Cy), 1.79 (m, 6H, Cy), 2.74 (d, 2H, CH2,
3J=6.0 Hz), 7.24 (s, 1H, H-5), 7.27 (m, 1H, H-5’), 7.77 (m,
1H, H-3’), 8.42 (m, 2H, H-3, H-6’), 8.63 (m, 1H, H-4’);
13C NMR (75.47 MHz, CDCl3): d=26.2 (CH2), 26.4 (CH2),
1
liquid; yield: 173 mg (50%); H NMR (300.13 MHz, CDCl3):
3
33.1 (CH2), 38.4 (CH), 46.2 (CH2), 114.0 (d, C-3, JC,F
3.1 Hz), 118.8 (d, C-5, JC,F =3.1 Hz), 121.4 (C-5’), 123.2 (q,
=
d=0.86 (m, 3H, CH3), 1.36 (m, 4H, CH2), 1.80 (m, 2H,
3
3
CH2), 2.89 (t, 2H, CH2, J=7.8 Hz), 7.24 (s, 1H, H-5’), 7.47
1
CF3, JC,F =270.9 Hz), 124.2 (C-3’), 137.0 (C-4’), 139.2 (q, C-
(m, 2H, H-1’, H-4’), 7.86 (m, 4H, H-5’, H-6’, H-7’, H-8’),
4, 2JC,F =34.0 Hz), 149.2 (C-6’), 155.2 (C-2’’), 156.8 (C-6),
162.3 (C-2); GC-MS (EI, 70 eV): m/z (%)=238 (100); HR-
MS (ESI): m/z=321.1570 [M+H]+, calcd. for C18H20F3N2:
3
3
8.11 (dd, 1H, H-3’, J1 =6.9 Hz, J2 =1.8 Hz), 8.43 (s, 1H, H-
3); 13C NMR (62.90 MHz, CDCl3): d=14.0 (CH3), 25.5
(CH2), 29.3 (CH2), 31.6 (CH2), 38.6 (CH2), 113.4 (q, C-3,
3JC,F =3.8 Hz), 116.4 (q, C-5, 3JC,F =3.8 Hz), 123.2 (q, CF3,
1JC,F =273.6 Hz), 124.5 (C-5’), 126.4 (C-7’), 126.8 (C-8’, C-6’),
127.7 (C-4’), 128.6 (C-1’), 128.8 (C-3’), 133.4 (C-8a’), 133.9
˜
321.1570; IR (ATR): n=2922, 2850, 1586, 1568, 1449, 1408,
1372, 1263, 1165, 1131, 793, 661 cmÀ1.
2-(4-Methoxyphenyl)-6-(4-nitrophenyl)-4-(trifluorome-
thyl)pyridine (5q): Starting from 3-hydroxy-5-(4-methoxy-
phenyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)pent-4-yn-1-
one (393 mg, 1 mmol) (3r) and urea (72 mg, 1.2 mmol); 5q
was isolated as brown crystals; yield: 292 mg (78%); mp
2
(C-4a’), 135.8 (C-2’), 139.3 (q, C-4, JC,F =34.0 Hz), 157.9 (C-
6), 164.1 (C-2); GC-MS (EI, 70 eV): m/z (%)=343 (14)
[M+], 314 (33), 300 (50), 287 (100); HR-MS (ESI): m/z=
343.1540 [M]+, calcd. for C21H20F3N: 343.1542; IR (ATR):
1
136–1398C; H NMR (300.13 MHz, CDCl3): d=3.83 (s, 3H,
OCH3), 6.99 (d, 2H, H-2’, H-6’, J=6.0 Hz), 7.80 (s, 1H, H-
˜
n=3059, 2928, 2858, 1573, 1413, 1375, 1261, 1166, 1130, 857,
3
815, 740, 698 cmÀ1.
3
3), 7.84 (s, 1H, H-5), 8.06 (d, 2H, H-3’, H-5’, J=6.0 Hz),
6-Phenyl-4-(trifluoromethyl)-2,2’-bipyridine (5n): Starting
from 3-hydroxy-5-phenyl-1-(pyridin-2-yl)-3-(trifluoro-meth-
yl)pent-4-yn-1-one (319 mg, 1 mmol) (3n) or 3-hydroxy-1-
phenyl-5-(pyridin-2-yl)-3-(trifluoromethyl)pent-4-yn-1-one
(319 mg, 1 mmol) (3q) and urea (72 mg, 1.2 mmol); 5n was
isolated as a grey powder; yield: 255 mg (85% from 3n);
yield: 72 mg (24% from 3q); mp 76–788C; 1H NMR
(300.13 MHz, CD2Cl2): d=7.32 (m, 1H, H-5’’), 7.43 (m, 3H,
H-3’, H-4’, H-5’), 7.81 (m, 1H, H-3’’), 7.90 (s, 1H, H-5), 8.10
8.28 (m, 4H, H-2’’, H-3’’, H-5’’, H-6’’); 13C NMR
3
(62.90 MHz, CDCl3): d=55.4 (OCH3), 113.9 (q, C-5, JC,F
3.1 Hz), 114.3 (C-2’, C-6’), 114.6 (q, C-3, JC,F =3.1 Hz), 123.3
(q, CF3, JC,F =273.6 Hz), 124.1 (C-3’’, C-5’’), 127.9 (C-3’, C-
5’), 128.5 (C-2’’, C-6’’), 130.1 (C-4’), 140.3 (q, C-4, JC,F
34.0 Hz), 144.0 (C-4’’), 148.6 (C-1’’), 155.5 (C-2), 158.4 (C-6),
161.5 (C-1’); GC-MS (EI, 70 eV): m/z (%)=374 (100) [M+],
328 (17), 284 (13); HR-MS (ESI): m/z=375.0954 [M+H]+,
calcd. for C19H14F3N2O3:375.0951; IR (ATR): n=2845, 1682,
1607, 1563, 1525, 1368, 1348, 1246, 1162, 1128, 1028, 861,
=
3
1
2
=
˜
(m, 2H, H-2’, H-6’), 8.58 (m, 3H, H-3, H-4’’, H-6’’);
3
13C NMR (62.90 MHz, CD2Cl2): d=115.3 (d, C-3, JC,F
=
827, 696 cmÀ1.
3
3.8 Hz), 116.0 (d, C-5, JC,F =3.1 Hz), 121.7 (C-5’’), 123.7 (q,
CF3, JC,F =266.1 Hz), 125.0 (C-3’’), 127.4 (C-3’, C-5’), 129.3
1
(C-2’, C-6’), 130.3 (C-4’), 137.5 (C-4’’), 138.4 (C-4’), 140.4 (q,
2
C-4, JC,F =34.0 Hz), 149.6 (C-2’’), 155.2 (C-2’’), 157.6 (C-6),
158.1 (C-2); GC-MS (EI, 70 eV): m/z (%)=300 (100) [M+],
Acknowledgements
231 (18); HR-MS (ESI): m/z=330.0866 [M]+, calcd. for
Financial support by the State of Mecklenburg-Vorpommern
(scholarship for D. O.) is gratefully acknowledged
˜
C17H11F3N2: 300.0869; IR (ATR): n=3060, 1585, 1567, 1405,
1370, 1263, 1120, 1059, 879, 772, 688, 661 cmÀ1.
6-(4-Methoxyphenyl)-4-(trifluoromethyl)-2,2’-bipyridine
(5o): Starting from 3-hydroxy-5-(4-methoxyphenyl)-1-(pyri-
din-2-yl)-3-(trifluoromethyl)pent-4-yn-1-one
1 mmol) (3o) and urea (72 mg, 1.2 mmol); 5o was isolated as
white crystals; yield: 300 mg (91%); mp 66–698C; H NMR
(349 mg,
References
1
[1] a) N. S. Gill, K. B. James, F. Lions, K. T. Potts, J. Am.
Chem. Soc. 1952, 74, 4923–4928; b) V. I. Vysotskii,
M. N. Tilichenko, Khim. Geterotsikl. Soedin. 1976, 3,
383–385; c) A. R. Katritzky, F. Al-Omran, R. C. Patel,
S. S. Thind, J. Chem. Soc. Perkin Trans. 1 1980, 1890–
1894; d) V. G. Kharchenko, V. K. Promonenkov, S. N.
Chalaya, S. N. Lisina, Khim. Geterotsikl. Soedin. 1983,
12, 1691–1692; e) T. R. Kelly, R. L. Lebedev, J. Org.
Chem. 2002, 67, 2197–2205; f) S. Ko, C.-F. Tao, Tetrahe-
(300.13 MHz, CDCl3): d=3.82 (s, 3H, OCH3), 6.97 (m, 2H,
H-2’, H-6’), 7.30 (m, 1H, H-5’’), 7.80 (m, 2H, H-5, H-3’’),
8.06 (m, 2H, H-3’, H-5’), 8.50 (s, 1H, H-3), 8.56 (d, 1H, H-
6’’, 3J=9.0 Hz), 8.65 (dd, 1H, H-4’’, 3J1 =3.0 Hz, 3J2 =
3.0 Hz); 13C NMR (62.90 MHz, CDCl3): d=55.4 (OCH3),
114.3 (C-2’, C-6’), 114.8 (d, C-3, C-5, 3JC,F =3.8 Hz), 121.4
(C-3’’), 123.2 (q, CF3, 1JC,F =273.6 Hz), 124.4 (C-5’’), 128.4
2
(C-3’, C-5’), 130.7 (C-4’), 137.0 (C-4’’), 140.1 (q, C-4, JC,F
=
12
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of 4-Trifluoromethylpyridines by [5+1] Cyclization of 3-Hydroxy-pent-4-yn-1-ones
dron 2006, 62, 7293–7299; g) D. Craig, G. D. Henry, Tet-
rahedron Lett. 2005, 46, 2559–2562.
Vicic, J. Am. Chem. Soc. 2008, 130, 8600–8601; d) G. G.
Dubinina, J. Ogikubo, D. A. Vicic, Organometallics
[2] a) O. C. Pfꢅller, J. Sauer, Tetrahedron Lett. 1998, 39,
8821–8824; b) B. R. Lahue, S.-M. Lo, Z.-K. Wan,
G. H. C. Woo, J. K. Snyder, J. Org. Chem. 2004, 69,
7171–7182; c) D. L. Boger, L. S. Panek, J. Org. Chem.
1981, 46, 2179–2182.
[3] a) F. Lions, W. H. Perkin Jr, R. Robinson, J. Chem.
Soc. Trans. 1925, 127, 1158–1169; b) Y. Oka, K. Omura,
A. Miyake, K. Itoh, M. Tomimoto, N. Tada, S. Yurugi,
Chem. Pharm. Bull. 1975, 23, 2239–2250; c) E. Eichler,
C. S. Rooney, H. W. R. Williams, J. Heterocycl. Chem.
1976, 13, 41–42; d) B. M. Lynch, M. A. Khan, H. C.
Teo, F. Pedrotti, Can. J. Chem. 1988, 66, 420–428; e) Y.
Yamaguchi, I. Katsuyama, K. Funabiki, M. Matsui, K.
Shibata, J. Heterocycl. Chem. 1998, 35, 805–810; f) A. S.
Plaskon, S. V. Ryabukhin, D. M. Volochnyuk, K. S.
Gavrilenko, A. N. Shivanyuk, A. A. Tolmachev, J. Org.
Chem. 2008, 73, 6010–6013.
2008, 27, 6233–6235.
[11] a) Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B.
Seiple, S. Su, D. G. Blackmond, P. S. Baran, Proc. Natl.
Acad. Sci. USA 2011, 108, 14411–14415; b) T. Kino, Y.
Nagase, Y. Ohtsuka, K. Yamamoto, D. Uraguchi, K.
Tokuhisa, T. Yamakawa, J. Fluorine Chem. 2010, 131,
98–105.
[12] a) D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480,
224–228; b) Y. Ye, M. S. Sanford, J. Am. Chem. Soc.
2012, 134, 9034–9037.
[13] E. Mejia, A. Togni, ACS Catal. 2012, 2, 521–527.
[14] a) B. Jiang, X.-N. Xiong, C.-G. Yang, Bioorg. Med.
Chem. Lett. 2001, 11, 475–477; b) B. Jiang, W. Xiong,
X. Zhang, F. Zhang, Org. Process Res. Dev. 2001, 5,
531–534.
[15] X. Han, Y. Zhang, K. K. Wang, J. Org. Chem. 2005, 70,
2406–2408.
[16] T. Wang, X.-L. Chen, L. Chen, Z.-P. Zhan, Org. Lett.
2011, 13, 3324–3327.
[17] I. S. Kondratov, I. I. Gerus, A. D. Kacharov, M. G. Gor-
bunova, V. P. Kukhar, R. Froehlich, J. Fluorine Chem.
2005, 126, 543–550.
[18] K. H. Meyer, K. Schuster, Ber. Dtsch. Chem. Ges. 1922,
55, 819–823.
[4] T. Harschneck, S. F. Kirsch, J. Org. Chem. 2004, 69,
7171–7182.
´
[5] F. J. Fananas, T. Arto, A. Mendoza, F. Rodriguez, Org.
Lett. 2011, 13, 4184–4187.
[6] a) G. Chelucci, M. Falorni, G. Giacomelli, Synthesis
1990, 1121–1122; b) P. R. Chopade, J. Louie, Adv.
Synth. Catal. 2006, 348, 2307–2327; c) M. Ohashi, I.
Takeda, M. Ikawa, S. Ogosji, J. Am. Chem. Soc. 2011,
133, 18018–18021; d) I. Nakamura, Y. Yamamoto,
Chem. Rev. 2004, 104, 2127–2198.
[7] a) P. Ehlers, S. Reinmann, S. Erfle, A. Villinger, P.
Langer, Synlett 2010, 1528–1532; b) P. Ehlers, A. Neu-
bauer, S. Lochbrunner, A. Villinger, P. Langer, Org.
Lett. 2011, 13, 1618–1621.
[19] H. Rupe, E. Kambli, Helv. Chim. Acta 1926, 9, 672.
[20] R. Rodriguez, A. Navarro-Vazquez, L. Castedo, D.
Dominguez, C. Saa, J. Am. Chem. Soc. 2001, 123, 9178–
9179.
[21] S. Gronert, J. R. Keeffe, J. Org. Chem, 2007, 72, 6343–
6352.
[22] CCDC 905465 contains all crystallographic details of
this publication. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif or can
be ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB21EZ, U.K.; Fax: (+44)-1223-336-033 or de-
posit@ccdc.cam.ac.uk.
[8] S. G. Mcarthur, E. Goetschi, J. Wichmann, T. J. Wolter-
ing, PCT Int. Appl. WO 2007110337A1 20071004, 2007.
[9] W.-N. Xiong, C.-G. Yang, B. Jiang, Bioorg. Med. Chem.
2001, 9, 1773–1780.
[10] a) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A.
Watson, S. L. Buchwald, Science 2010, 328, 1679–1681;
b) X. Jiang, L. Chu, F.-L. Qing, J. Org. Chem. 2012, 77,
1251–1257; c) G. G. Dubinina, H. Furutachi, D. A.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
13
ÞÞ
These are not the final page numbers!

UPDATES
14 Synthesis of 4-Trifluoromethylpyridines by [5+1]
Cyclization of 3-Hydroxy-pent-4-yn-1-ones with Urea
Adv. Synth. Catal. 2013, 355, 1 – 14
Viktor O. Iaroshenko,* Dmytro Ostrovskyi, Khurshid Ayub,
Anke Spannenberg, Peter Langer*
14
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!