One-pot synthesis of 2,5-disubstituted pyrimidines from nitriles

Article abstract of DOI:10.1021/jo400720p

A practical, one-step process for the synthesis of 2,5-disubstituted pyrimidines is presented. The protocol proved to be general for the synthesis of a variety of pyrimidine-containing compounds bearing an assortment of functional groups.

Full text of DOI:10.1021/jo400720p

Subscriber access provided by MONASH UNIVERSITY
Note
One-Pot Synthesis of 2,5-Disubstituted Pyrimidines from Nitriles
Rogelio P Frutos, Xudong Wei, Nitinchandra Dahyabhai Patel, Thomas G
Tampone, Jason Alan Mulder, Carl A. Busacca, and Chris H. Senanayake
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400720p • Publication Date (Web): 08 May 2013
Downloaded from http://pubs.acs.org on May 10, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 13
The Journal of Organic Chemistry
1
2
3
4
One-Pot Synthesis of 2,5-Disubstituted Pyrimidines from Nitriles
5
6
7
8
9
Rogelio P. Frutos,* Xudong Wei,* Nitinchandra D. Patel, Thomas G. Tampone, Jason A.
Mulder, Carl A. Busacca and Chris H. Senanayake
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Chemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury
Rd./P.O. Box 368, Ridgefield, Connecticut 06877-0368 USA
rogelio.frutos@boehringerꢀingelheim.com
Table of Contents Graphic:
MeO
NH
H2N
NH
CN
MeOH,
HCl
NH3
- HCl
MeONa
2b
3b
1b
Ph
NaOMe
N
N+
-
PF6
N
N
Ph
5b
ABSTRACT: A practical oneꢀstep process for the synthesis of 2,5ꢀdisubstituted pyrimidines is
presented. The protocol proved to be general for the synthesis of a variety of pyrimidine
containing compounds bearing an assortment of functional groups.
Substituted pyrimidines1 are a diverse class of heterocycles found not only in a wide variety of
natural products,2 but also as building blocks for a number of Active Pharmaceutical Ingredients
(APIs) present in prominent commercial drugs such as Crestor®, Gleevec® and Aggrenox®. Not
surprisingly, our own interest in the development of 2,5ꢀdisubstituted pyrimidineꢀcontaining
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 13
1
2
3
4
5
6
7
8
9
small molecules as possible therapeutic agents prompted our investigation towards a
straightforward and scalable methodology for the synthesis of these compounds. A review of
current literature procedures for the synthesis of pyrimidines yielded a vast number of existing
methodologies,3,4,5,6 and although some were very elegant and efficient, few were both amenable
to the largeꢀscale synthesis of 2,5ꢀdisubstituted pyrimidines and compatible with an assortment
of functional groups.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
An attractive and well known approach to access 2,5ꢀdisubstituted pyrimidines involves the
condensation of malondialdehydes or their equivalents, such as vinamidinium salts, with
amidines.7 In particular, the condensation of thermally stable vinamidinium hexafluorophosphate
salts8,9 with amidines promised to be an efficient and versatile strategy since a variety of these
species are now commercially available, even in bulk. Accordingly, amidines10 are usually made
by adding ammonia to imidates (imino esters),11 which in turn are usually synthesized from
nitriles by means of a Pinner reaction under acidic12 or basic reaction conditions.13 In the
majority of literature procedures utilizing the Pinner reaction, nitriles are treated with anhydrous
hydrochloric acid and an alcohol in ethereal solvents and allowed to stand over a prolonged
period of time until the product precipitates and is collected by filtration.14 Yields are often
modest for many substrates and the resulting imidate hydrochloride salts tend to be highly
hygroscopic. Amidines can also be obtained with a modified Pinner reaction, in which nitriles
are treated with thiols to give thioꢀimido intermediates which are then treated with ammonia.15
Alternatively, amidines can be obtained by direct amination of nitriles with reagents like
alkylchloroaluminum amides or CuCl.16
Although widely used, the existing protocols for the synthesis of pyrimidines were labor
intensive, oftentimes impractical, inefficient or incompatible with a number of functional groups.
ACS Paragon Plus Environment

Page 3 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Therefore, the possibility of synthesizing 2,5ꢀdisubstituted pyrimidines from nitriles without
isolation of the intermediate imidates and amidines, by reacting them directly with vinamidinium
salts, was investigated (Scheme 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
X
NH
- HCl
OCH3
NH
N
R
R CN
R
NH2
R
N
5
3
2
1
X
-
PF6
4
N
N+
Scheme 1. Oneꢀpot synthesis ofpyrimidines from nitriles
Oneꢀpot processes for the direct synthesis of pyrimidines from nitriles, to the best of our
knowledge, have not been reported.17 This is likely because the multiꢀstep transformations
involved are often performed under quite different reaction conditions (acidic vs. basic), and
telescoping them in a compatible fashion is challenging. Reagents and impurities carried through
from one transformation to the next can either lead to side reactions or even completely divert
the reaction pathway. Nucleophilic functional groups, such as amines and alcohols, present in the
substrates, could represent competing reactive sites, which may further complicate the chemistry
and limit the scope of reaction.
To develop a streamlined and practical process, the synthesis of amidine 3a from nitrile 1a was
first explored (Scheme 2). Accordingly, a methoxideꢀcatalyzed imidate formation was first
investigated, but it was found to be very slow even at 55 °C and no significant product was
observed after 24 h. This was most likely associated with the steric hindrance and the electronꢀ
donating effect of the branched alkyl substituent. Alternatively, the reaction of 1a with N-acetyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 13
1
2
3
4
5
6
7
8
9
cysteine led to the formation of the corresponding thioꢀimidate intermediate 2k in moderate (30ꢀ
40%) yield. Reaction with ammonium chloride, however, failed to give the desired amidine 3a
even under reflux in methanol. Attention thus was turned to an HClꢀcatalyzed reaction. While
reaction of 1a with 1.25 M HCl in methanol gave a low conversion to the imidate, reactions with
both methanol and 4.0 M HCl in dioxane and 6.0 M HCl in i-PrOH, led to very clean formation
of the imidates 2a and 2j, which could be subsequently converted to the amidines by the addition
of ammonia with or without prior evaporation of the remaining HCl. It is likely that formation of
the imidates is facilitated by the precipitation of the imidate salts from the reaction mixture in
less polar solvents or solvent mixtures. The alkylaluminum catalyzed direct ammonia addition to
1a was not pursued due to economics and concerns about the generation of aluminum salts.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Optimization studies revealed that treatment of nitrile 1a with three equivalents of methanol and
three equivalents of HCl in dioxane (4M solution) for 16 hours at room temperature resulted in
complete conversion to the imidate. In order to minimize the use of ammonia, 1 equiv of
NaOMe was added to quench the excess amount of HCl. In this case, 2.2 equiv. of ammonia18
ACS Paragon Plus Environment

Page 5 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
were found to be sufficient to effect the full conversion from the imidate to the amidine. Several
methods such as RAMAN, ReactIR and LC/MS were evaluated as tools to monitor the formation
of the imidates and subsequent conversion to their corresponding amidines, but it was ultimately
found that analyzing aliquots by NMR was the most general and straightforward method.
Having optimized the amidine synthesis, attention was focused on obtaining general conditions
for the in-situ condensation of the amidine with a malondialdehyde or a vinamidinium salt
equivalent. To accomplish this, once formation of the amidine 3a was deemed complete,19 an
additional 1.2 equiv of NaOMe was added followed by addition of vinamidinium salt 4a. The
desired pyrimidine product 5a was obtained after one hour in 78% yield (Scheme 3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The scope of the oneꢀpot process and its suitability for the synthesis of pyrimidine bearing
compounds containing other functional groups was then investigated. The synthesis of
additional pyrimidineꢀcontaining compounds that incorporated a basic amine as described above
was a challenge for three different reasons. First, the hydrochloride salt of the amine formed
under the acidic conditions necessary for the initial formation of the imidate had to be at least
partially soluble in the reaction medium to be able to react with methanol and give rise to the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 13
1
2
3
4
5
6
7
8
9
imidate (2, Scheme 1). Moreover, the additional amine functionality could in principle compete
with ammonia during the formation of the amidine (3) from the imidate (2), and finally, the
amine could potentially interfere in a competitive way with the reaction of the amidine (3) with
the vinamidinium salt (4) in the last stage of the process. Fortunately, as shown in Table 1, a
number of nitriles containing amine functionalities (1a, 1c, 1e and 1g) proved to be adequate
substrates for the process and gave the corresponding pyrimidines (5a, 5c, 5e and 5g) when
submitted to the new oneꢀpot protocol. Similarly, the process was found to be suitable for the
synthesis of pyrimidine compounds containing phenol (1i), nitro (1d), 2ꢀchloropyridine (1e) and
ether functional groups (1f and 1h) as shown in Table 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Direct synthesis of pyrimidines from nitriles.
Entry
Nitrile
X (4)
Product
Yield
1
85%
Ph
2
3
86%
66%
Cl
Cl
4
77%
Cl
ACS Paragon Plus Environment

Page 7 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
5
6
7
85%
Cl
Cl
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
84%`
72%
Cl
N
8
9
Cl
Cl
68%
84%
N
5h
O
In conclusion, a practical, robust and general oneꢀpot process for the direct synthesis of
pyrimidines from nitriles was demonstrated. The protocol proved to be general for the synthesis
of 2,5ꢀdisubstituted pyrimidine compounds bearing a variety of functional groups in good yields
using common, inexpensive reagents.
EXPERIMENTAL SECTION
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 13
1
2
3
4
5
6
7
8
9
Unless otherwise specified, all reactions were carried out in ovenꢀdried glassware under an
atmosphere of nitrogen. NMR spectra were recorded on a 400 NMR spectrometer. Shifts are
reported in ppm relative to trimethylsilane; coupling constants (J) are reported in hertz, referred
to as apparent peak multiplicities, and may not necessarily reflect true coupling constants. High
resolution mass spectral data were acquired using a LC/MSD TOF (timeꢀofꢀflight) mass
spectrometer in an electrospray positive ionization mode via flow injection. The commercially
available starting materials were used as received without further purification and all solvents
were dried by standard methods prior to use.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General experimental procedure for the synthesis of pyrimidines 5a-i. Synthesis of 5-chloro-
2-cyclohexylpyrimidine (5b). 4M HCl in dioxane (75.0 mmol) was charged to a round bottom
flask equipped with a temperature probe, stirrer and nitrogen line. The solution was cooled to 0
°C and cyclohexane carbonitrile 1b (2.73g, 25.0 mmol) was charged as a solution in MeOH
(3.04 mL, 75 mmol) over 30 min while keeping the temperature below 10 °C. The temperature
was then adjusted to 22 °C and mixture was stirred for 6ꢀ8 h at ambient temperature. The
mixture was cooled to 5 °C and 25 wt% NaOMe in MeOH (11.4 mL, 50 mmol) was charged
while maintaining the temperature below 15 °C. The mixture was then stirred for 10ꢀ15 min at
15 °C. 7.0 N ammonia in MeOH (5.36 mL, 37.5 mmol) was charged and the resulting mixture
was stirred for 2 h at ambient temperature. The mixture was concentrated under reduced pressure
at 50 °C (approx. 130 Torr) to a volume of approximately 25 mL (to remove excess ammonia).
The resulting heterogeneous mixture containing the crude amidine (3b) was cooled to 20 °C and
25 wt% NaOMe in MeOH (14.3 mL, 63.5 mmol) was charged. The mixture was then stirred for
30
min
and
(Z)ꢀNꢀ(2ꢀchloroꢀ3ꢀ(dimethylamino)allylidene)ꢀNꢀmethylmethanaminium
ACS Paragon Plus Environment

Page 9 of 13
The Journal of Organic Chemistry
1
2
3
4
w
hexafluorophosphate (V),8
,
20 (8.09 g, 90% /w, 23.8 mmol) was charged to the above mixture in
5
6
7
8
two portions at ambient temperature over approximately 30 min. The mixture was stirred for 3 h
at ambient temperature and then concentrated under reduced pressure at 60 °C to a minimum
stirrable volume (approx. 20 mL). 2ꢀMethyltetrahydrofuran (40.7 mL) was charged and the
mixture was concentrated further to a volume of approx. 20 mL under reduced pressure at 60 °C.
2ꢀMethyltetrahydrofuran (41 mL) was charged, the mixture was cooled to ~20 °C, water (20.4
ml) was charged and the mixture was stirred for 5 min. The layers were separated and the
organic layer was collected. The aqueous layer was extracted with MeꢀTHF (20.4 ml). The
combined organic layers were washed with 30 % aq. NaOH (3 equiv NaOH) and the layers were
separated. The organic layer was dried with MgSO4 and concentrated under reduced pressure.
Flash chromatography (hexane/ethyl acetate, 9:1 to 3:1 gradient) afforded 4.21 g (86% yield) of
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
product 5b as a colorless oil that solidified upon standing: H NMR (400 MHz, CDCl3) δ 1.21ꢀ
1.34 (m,1H), 1,35ꢀ1.47 (m, 2H), 1.59 (dddd, J = 3.2, 12.4, 12.4, 12.4 Hz, 2H), 1.75 (br d, J =
12.4 Hz, 1H), 1.86 (ddd, J = 3.2, 3.2, 12.4 Hz, 2H), 1.98 (br d, J = 12.4 Hz, 2H), 2.87 (m, 1H),
13
8.62 (s, 2H); C NMR (100 MHz, CDCl3) δ 25.8, 26.1, 31.8, 46.8, 128.5, 155.3, 172.6; HRMS
calculated for [C10H14ClN2]+ 197.0840, found 197.0827.
5-Phenyl-2-(piperidin-4-yl)pyrimidine (5a): 1H NMR (400 MHz, CDCl3) δ 1.84 (dddd, J = 4.0,
12.4, 12.4, 12.4 Hz, 2H), 2.06 (br d, J = 12.4 Hz, 2H), 2.81 (dt, J = 2.4, 12.4 Hz, 2H), 3.08 (m,
13
1H), 3.24 (br d, J = 12.4 Hz, 2H), 7.44ꢀ7.58 (m, 5H), 8.89 (s, 2H); C NMR (100 MHz, CDCl3)
δ 32.3, 45.5, 46.7, 126.9, 128.6, 129.4, 131.4, 134.7, 155.1, 172.2; HRMS calculated for
[C15H18N3]+ 240.1495, observed 240.1486.
5-Chloro-2-(pyridin-4-yl)pyrimidine (5c): 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J = 1.6, 4.4
Hz, 2H), 8.78 (dd, J = 1.6, 4.4 Hz, 2H), 8.81 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 121.9,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 13
1
2
131.0, 143.6, 150.7, 156.0, 160.6; HRMS calculated for [C9H7ClN3]+ 192.0323, observed
192.0318.
3
4
5
6
7
8
9
1
5-chloro-2-(4-nitrophenyl)pyrimidine (5d): H NMR (400 MHz, CDCl3) δ 8.391 (d, J = 8.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
Hz, 2H), 8.59 (d, J = 8.2 Hz, 2H), 9.13 (2, 2H); C NMR (100 MHz, CDCl3) δ 124.1, 129.0,
130.3, 141.8, 149.0, 156.5, 159.6; HRMS calculated for [C10H7ClN3O2]+ 236.0221, found
236.0218.
1
5-chloro-2-((6-chloropyridin-3-yl)methyl)pyrimidine (5e): H NMR (400 MHz, CDCl3) δ
4.25 (s, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 2, 8.4 Hz, 1H), 8.39 (d, J = 2 Hz, 1H), 8.63
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 41.4, 124.0, 129.6, 132.1, 139.5, 150.0, 150.1, 155.9,
166.2; HRMS calculated for [C10H8Cl2N3]+ 240.0090, observed 240.0077.
1
5-Chloro-2-(2-methoxybenzyl)pyrimidine (5f): H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H),
4.30 (s, 2H), 6.86 (d, J = 8.0 Hz, 1H), 6,91 (ddd, J = 0.8, 7.6, 7.6 Hz, 1H), 7.19ꢀ7.25 (m, 2H),
8.59 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 39.3, 55.3, 110.5, 120.4, 126.3, 128.1, 128.6, 130.7,
155.4, 157.3, 168.1; HRMS calculated for [C12H12ClN2O]+ 235.0633, observed 235.0627.
1
2-(1-benzylpiperidin-4-yl)-5-chloropyrimidine (5g): H NMR (400 MHz, CDCl3) δ 1.93ꢀ1.98
(m, 4H), 2.05ꢀ2.16 (m, 2H), 2.82ꢀ2.92 (m, 1H), 3.00 (m, 2H), 3.54 (s, 2H) 7.22ꢀ7.37 (m, 5H),
13
8.61 (s, 2H); C NMR (100 MHz, CDCl3) δ 31.0, 44.7, 53.5, 63.3, 126.9, 128.1, 128.8, 129.0,
138.7, 155.4, 171.5; HRMS calculated for [C16H19ClN3]+ 288.1262, observed 288.1248.
1
5-chloro-2-(2-ethoxyethyl)pyrimidine (5h): H NMR (400 MHz, CDCl3) δ 1.17 (t, J = 7.2 Hz,
3H), 3.23 (t, J = 6.8 Hz, 2H), 3.52 (q, J = 7.2 Hz, 2H), 3.91 (t, J = 6.8 Hz, 2H), 8.63 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 15.0, 39.0, 66.2, 68.4, 129.0, 155.4, 166.8; HRMS calculated for
[C8H12ClN2O]+ 187.0633, observed 187.0626.
ACS Paragon Plus Environment

Page 11 of 13
The Journal of Organic Chemistry
1
2
3-(5-Chloropyrimidn-2-yl)phenol (5i): 1H NMR (400 MHz, CDCl3) δ 5.21 (br, 1H), 7.00 (dd, J
= 2.8, 8.4 Hz, 1H), 7.37 (dd, J = 8.0, 8.0 Hz, 1H), 7.88 (m, 1H), 7.99 (d, 8.0 Hz), 8.74 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 114.9, 118.3, 120.8, 129.5, 130.1, 138.0, 155.7, 156.0, 162.2;
HRMS calculated for [C10H8ClN2O]+ 207.0320, observed 207.0322.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Supporting information. H and 13C NMR spectral data for compounds 5aꢀi is provided. This
material is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
1.
For a review on pyrimidine chemistry see: Brown, D. J.; Evans, R. F.; Cowden, W. B.;
Fenn, M. D. The Pyrimidines; John Wiley & Sons; Montreal, 1994.
Lagoja, I. M. Chemistry & Biodiversity, 2005, 2, 1
2.
3.
4.
5.
6.
Sasada, T.; Kobayashi, F. Sakai, N. Konokahara, T. Org. Lett. 2009, 11, 2161.
Zhichkin, P.; Fairfax, D. J.; Eisenbeis, S. A. Synthesis. 2002, 720.
Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 14254
Dousson, C. B.; Heon, N. M.; Hill, G. B.; Synthesis, 2005, 11, 1817.
7 . (a) Reichardt, C.; Ferwanah, A.ꢀR.; Pressler, W.; Yun, K.ꢀY. Liebigs Ann. Chem., 1984, 4,
649 ꢀ 679 (b) Stolle, W. A. W.; Marcelis, A. T. M.; Koetsier, A.; van der Plas, H. C.;
Tetrahedron, 1989, 45, 6511 (c) Frissen, A. E.; Marcelis, A. T. M.; Melger, W. C.; van der
Plas, H. C. Tetrahedron 1989, 45, 6891; (d) Reichardt, C.; Halbritter, K. Angew. Chem.,
Int. Ed. Engl. 1975, 14, 86.
8 . Davies, I. W.; Marcoux, J.ꢀF.; Xu, J.; Paluci, M.; Corley, E. G.; Robbins, M. A.; Tsou, N.;
Ball, R. G.; Dormer, P. ; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2000, 65, 4571.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 13
1
2
3
4
5
9.
Davies, I. W.; Taylor, M.; Marcoux, J.ꢀF.; Wu, J.; Dormer, P. G.; Hughes, D.; Reider, P. J.
6
J. Org. Chem. 2001, 66, 251.
7
8
9
10. For a review: Aly, A. A.; NourꢀElꢀDin, A. M. ARKIVOC, 2008 (i) 153ꢀ194.
11. For a review: Roger, R.; Nelson, D. G. Chem. Review, 1961, 61, 179.
12. Roger, R.; Neilson, D. G.; Chem. Rev. 1961, 61, 179
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13. Shaefer, F. C.; Peters, G. A.; J. Org. Chem. 1961, 26, 412.
14. (a) Barker, P. L.; Gendler, P. L.; Rapoport, H.; J. Org. Chem. 1981, 46, 2455. (b) Ueno, H.;
Maruyama, A.; Miyake, M.; Nakao E.; Nakao, K.; Umezu, K.; Nitta, I.; J. Med Chem.
1991, 34, 2468 and references cited therein. (c) Chiba, T.; Takahashi, T.; Sakaki, J.ꢀi.;
Kaneko, C.; Chem. Pharm. Bull. 1985, 33, 3046.
15. (a) Schnur, R. C. J. Org. Chem. 1979, 44, 3726. (b) Lange, U. E. W.; Schaefer, B.; Baucke,
D.; Buschmann, E.; Mack, H. Tetrahedron Lett. 1999, 40, 7067.
16. (a) Garigipati, R. S.; Tetrahedron Lett. 1990, 31, 1969. (b) Rousselet, G.; Capdevielle, P.;
Maumy, M.; Tetrahedron Lett. 1993, 34, 6395. (c) Frutos, R. P; Gallou, I.; Reeves, D.; Xu,
Y.; Krishnamurthy, D.; Senanayake, C. H. Tetrahedron Lett. 2005, 46, 8369.
17. For early examples of the synthesis of pyrimidines from preꢀformed, isolated amidines see
references 7c and 7d.
18. For some substrates, 1.5 equiv. of ammonia was enough to complete imidine formation.
19. At this stage the reaction mixture is at nearly neutral pH.
20 In their report on the "Preparation of 2ꢀchloroꢀ1,3ꢀbis(dimethylamino)trimethinium
hexafluorophosphate", I.W. Davies et al. [Organic Syntheses, Vol. 80, p. 200 (2003)]
include the following comment: "Caution: The salt is a skin and eye irritant and was
ACS Paragon Plus Environment

Page 13 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
positive in the Ames mutagenesis assay. It should be handled in a hood with adequate
personal protective equipment."
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment