Synthesis of PO(OR)2- and PR3+-disubstituted pyridines via N- (trifluoromethylsulfonyl)pyridinium triflates

Article abstract of DOI:10.1055/s-1998-2012

The efficient synthesis of dialkoxyphophoryl- and phosphonio-substituted pyridines is reported. The cationic heterocycle of N- (trifluoromethylsulfonyl)pyridinium triflate (3), or of analogous N- (trifluoromethylsulfonyl) compounds prepared from pyridine-4-phosphonium salts 5, turns out to be sufficiently activated to allow attack of P(OR)₃ and PR₃ nucleophiles to give the novel compounds bis(dialkoxyphosphoryl)pyridines 11 phosphonio(dialkoxyphosphoryl)pyridines 13. For example, 13a-d, with PO(OR)₂ at the C2 and PR₃⁺ at the C4 position, represent the first examples of an N-heteroaromatic ring substituted by both dialkoxyphosphoryl and phosphonio moieties. The structure of 13b [PPh₃⁺/PO(O-i-Pr)₂] was confirmed by X-ray analysis. In most cases, the intermediate 1-(trifluoromethylsulfonyl)dihydropyridines, such as 7, 8 (monosubstituted) or 10a and b and 12a-d (disubstituted), are sufficiently stable for isolation.

Full text of DOI:10.1055/s-1998-2012

February 1998
SYNTHESIS
195
+
Synthesis of PO(OR) - and PR -Disubstituted Pyridines via N-(Trifluoromethyl-
2
3
sulfonyl)pyridinium Triflates
a
b
a
Mirko Haase, Helmar Goerls, Ernst Anders*
Institut für Organische Chemie und Makromolekulare Chemie der Universität Jena, Humboldtstraße 10, D-07743 Jena, Germany
Tel +49(3641)948210; Fax +49(3641)948212; E-mail: c5eran@rz.uni-jena.de
a
b
Institut für Anorganische und Analytische Chemie der Universität Jena, Lessingstraße 8, D-07743 Jena, Germany
Received 8 April 1997; revised 1 August 1997
Dedicated to Professor Welzel on the occasion of his 60th birthday
Abstract: The efficient synthesis of dialkoxyphosphoryl- and phos- synthesized the pure diisopropyl 1-(ethoxycarbonyl)-1,4-di-
7
phonio-substituted pyridines is reported. The cationic heterocycle of
hydropyridine-4-phosphonate, while in the case of other
phosphites, unpredictable molar ratios of isomeric C2/C4 di-
N-(trifluoromethylsulfonyl)pyridinium triflate (3), or of analogous N-
(trifluoromethylsulfonyl) compounds prepared from pyridine-4-
hydropyridines were also observed. Katritzky, too, used the
phosphonium salts 5, turns out to be sufficiently activated to allow
9
+
steric demands of C2 and C6 substituents. A 2,6-bis(di-
attack of P(OR) and PR3 nucleophiles to give the novel compounds
3
bis(dialkoxyphosphoryl)pyridines 11 and phosphonio(dialkoxyphos- alkoxyphosphoryl)pyridine has been synthesized from 2,6-1.
phoryl)pyridines 13. For example, 13a–d, with PO(OR) at the C2 dichloropyridine N-oxide and sodium diethyl phosphite,
2
+
and PR3 at the C4 position, represent the first examples of an N-
and 3,5,6-trichloro-2,4-bis(diethoxyphosphoryl)pyridine
heteroaromatic ring substituted by both dialkoxyphosphoryl and
11
from 2,3,4,5,6-pentachloropyridine and triethyl phosphite.
+
3
phosphonio moieties. The structure of 13b [PPh /PO(O-i-Pr) ] was
2
confirmed by X-ray analysis. In most cases, the intermediate 1-
trifluoromethylsulfonyl)dihydropyridines, such as 7, 8 (monosubsti-
tuted) or 10a and b and 12a–d (disubstituted), are sufficiently stable
AmethodfortheregiospecificintroductionofthePR group
3
(
intotheC4positionoftheunsubstitutedpyridineringsystem
12, 13
was described by our group some years ago (Scheme 1).
for isolation.
This procedure takes advantage of the quantitative in situ for-
mationofN-(trifluoromethylsulfonyl)pyridiniumtriflate(N-
triflylpyridinium triflate, 3), which reacted with phosphanes
Key words: N-(trifluromethylsulfonyl)pyridinium triflates, regiose-
lective nucleophilic substitution, C2- and C4-disubstituted pyridines,
phosphites, phosphonium triflates
viadihydropyridines4andadditionofNEt togivethephos-
3
phonium salts 5. The isomeric C2-substituted products have
not been observed. Interestingly, this procedure can be re-
peated with the salts 5 to give the bisphosphonium salts 6.
Forsyntheticapplications, saltssuchas5and6deserveinter-
est as they allow a variety of pathways to further classes of
The number of synthetic procedures yielding phosphorus-
substituted aromatic ring systems has significantly in-
creased during the last decade. Nevertheless, there is a
dearth of uncomplicated methods which allow the regio-
selective introduction of, in particular, the phosphonate
13
substituted heterocyclic compounds.
[
PO(OR) ] moiety at several positions in heteroaromatic
2
ring systems. In the pyridine series, this substituent de-
1
serves attention. As demonstrated by Paine et al., 2,6-
bis(diethoxyphosphoryl)pyridineisausefulligandforrela-
tively “hard” cations such as UO22+. Furthermore, this sub-
stituent can easily be reduced to give pyridylphosphanes.
The latter serve as important ligands for relatively “soft”
2
metal cations such as Ni, Co, Zn, Cu, Pd, Pt, etc. Further,
the importance of the aryl-bonded dialkoxyphosphoryl
3
group in photostimulated SRN1 reactions and its transfor-
mations have been recently investigated.4 In particular,
theselectivedealkylationofdiisopropylphosphonateswith
TMSBr in the presence of other functional groups appears
,5
6
to be of some importance for future applications.
The C2 and the C4 ring positions of a variety of N-alkyl-
pyridinium cations can be attacked by several nucleo-
philes to give, in the first step, the corresponding
dihydropyridines. Unfortunately, in most cases these re-
actions rarely proceed with acceptable regioselectivity.
Mixtures of isomeric substitution products are the typical
result. For example, exclusive C4 attack requires bulky
substituents at the C2 and C6 positions.7 Redmore re-
ported methods, which were very useful in the case of C2
substitution, but needed 2,6-dialkyl-substituted N-alkoxy-
pyridinium or N-tritylpyridinium salts to protect both the
–9
C2 and C6 positions in order to synthesize the 4-isomer,
using sodium phosphonates as nucleophiles.8 Akiba Scheme 1
,10

1
96
Papers
SYNTHESIS
For reasons which are obvious from the introductory part, Table 1. Products 7, 8 and 9
in the present paper we summarize our efforts which final-
Prod-
uct
R
Yield
(%)
bp (°C/mbar)
or mp (°C)
Ratioa
(7/8)
ly led to C2/C4-bis[PO(OR) ]- and C2/C4-PO(OR) /
2
2
+
PR -disubstituted pyridines. The investigation presented
3
here takes advantage of the observation that, obviously, 7a, 8a
Me
Et
i-Pr
Me
Et
85
65
67
100/0.39
115/0.66
120/0.44
65/0.15
100/0.4
43–44
95:5
100:0
60:40
–
the N-SO CF substituent plays an exceptional role (vide 7b, 8b
2
3
7
9a
c, 8c
supra), which can be understood on the basis of ab initio
76 (30)b
and semiempirical MO calculations.14
80 (20)b
4
9b
c
–
9
i-Pr 5
PO(OR) -Monosubstituted 1,4- and 1,2-Dihydro-
pyridines 7 and 8, Synthesis of the C4-PO(OR)2
a
1
2
Determined by H NMR.
b
Deprotonation with HN-i-Pr in CH Cl , values in brackets: with
2
2
2
Compounds 9
NEt in CH CN.
3 3
The procedure applied (Scheme 2) reflects our efforts to
extend the previously described method to phosphites un-
der special consideration of a procedure described by
Akiba.15 From the investigations presented here, we have
drawn to the conclusion that the degree of the regioselective
C4 attack depends to a significant extent on small changes
The mixtures from 7 and 8 were dissolved in CH CN (or
3
18
CH Cl ) and deprotonated with NEt (or HN-i-Pr ). Sur-
2
2
3
2
prisingly, and fortunately, the C2-substituted dihydropy-
ridines 8 remain unaffected and, therefore, the C4-
substituted pyridines 9 can be isolated without contamina-
tion with C2 isomers (Table 1).
in the P(OR) reactant. The extremely high C4 regioselec-
3
tivity of the basic reaction (Scheme 1) was conserved in the
case of the P(OEt) nucleophile, resulting in the exclusive
3
2
1
,4-Bis[PO(OR) ]-Disubstituted 1,2-Dihydropyridines
0a and b and the Corresponding Pyridines 11a and b
formation of 7b (Table 1). Both the sterically less demand-
ing methyl, as well as the “larger” isopropyl phosphites,
yielded an excess of the corresponding C4 phosphonates
2
The monosubstituted C4 (dialkoxyphosphoryl)pyridines
exhibit sufficient N-nucleophilicity to act as acceptor for
(
7a and c, respectively) with varying amounts of the C2-
substitutedisomers8aandc. Furthermore, whileinthecase
of PR nucleophiles the isolation of intermediate dihydro-
9
the triflyl group of 2 to yield the intermediate N-triflyl
salts. These salts were reacted with P(OEt) to give the
1,2-dihydropyridines 10a (R = Et, Scheme 3). The depro-
tonation of the latter seems to be the limiting factor;
3
3
pyridines was impossible, their PO(OR) analogs 7 and 8
2
16
turned out to be sufficiently stable. Nevertheless, at room
temperature, compounds 7 slowly decompose to give prod-
uct mixtures already containing 9.
though under the influence of the base (HN-i-Pr ), the tar-
2
get compound 11a was synthesized and isolated (50%),
unfortunately the re-formation of 9 competes with the for-
mation of 11. After addition of the base, the crude reaction
mixture consists of 11a (ca. 63%) and 9a (ca. 37%), (11b,
9
b: 10%, 90%).
Scheme 2
This synthesis does not afford the isolation of the salt 3;
pyridine was reacted with trifluoromethanesulfonic anhy-
Scheme 3
dride (2), after 30 minutes (0 °C, CH CN) the trialkyl
phosphites were added. To increase the yields of 7 and 8,
+
3
C2-PO(OR) /C4-PR -Disubstituted 1,2-Dihydropy-
2
3
ridines 12a–d and the Corresponding Pyridines 13a–d
these reactions were performed in the presence of an
17
Comparable to the preceding procedure, the phosphonium
salts 5 allow (after their transformation with 2 into the cor-
equimolar amount of NaI. The resulting 7/8 molar ratios
are summarized in Table 1.

February 1998
SYNTHESIS
197
+
responding N -triflyl biscations) the regiospecific C2 at-
tack of trialkyl phosphites giving the appropriate 1,2-
dihydropyridines 12a–d (Scheme 4). Again, this reaction
was performed under very mild conditions. The instability
of 12a–d is not expressed to the extent as observed for di-
hydropyridines 10. Deprotonation of compounds 12 with
NEt yielded the disubstituted pyridines 13. The yields
3
turn out to be superior to those obtained for the bis(di-
alkoxyphosphoryl)-substituted derivatives 11. Minor
amounts of the starting material 5a were formed in the
course of the deprotonation of the 1,2-dihydropyridines
1
2a and b.
Interestingly, the phosphonium group of compound 13a
can be exchanged by deuterium under very mild condi-
tions, e.g. if the salt was reacted with BuLi/TMEDA in
THF at –78°C, followed by addition of D O (Scheme 5).
2
Under these conditions, the (diethoxyphosphoryl) group
remains unaffected and 4-deutero-2-(diethoxyphosphor-
yl)pyridine (14) was obtained in acceptable yield.
Figure. X-ray structure of 13b. Hydrogen atoms are omitted. The Ol
atom turns out to be almost orthogonal to the ring system. Selected
bond lengths (Å) and angles (°): P2-C41.809(2), P1-C1 1.813(2), N-
C41.337(3), N-C31.335(3), P1-C61.791(2), P2-O1 1.454(2), P2-O2
1
.562(2), P1 C1 C2 C3 178.2, P2 C4 C5 C1 174.9.
formation with the P=O bond orthogonal to the pyridine
ring plane turns out to be the preferred conformer. It is
noteworthy that the semiempirically (PM3) calculated
structure agrees acceptably well with the X-ray data.
The novel method presented here allows access to new
bis[PO(OR) ]-, as well as (for the first time), mixed di-
2
+
(
PO(OR) /PR )-substituted pyridines without the pre-
2
3
ceding introduction of other functional groups.
NMR spectra were recorded on a Bruker AC250 spectrometer. Chem-
ical shifts (d) are given in ppm downfield from TMS. Coupling con-
stants are given in Hz. The degree of substitution of C atoms was
determined from DEPT-135 spectra. Structure determinations were
made with the aid of CH-COSY experiments. IR spectra were record-
ed on a BIO-RAD FTS-25 spectrometer. EI Mass spectra (70 eV) were
recorded using a FisonsTrio 2000 spectrometer (cations were detected
with FAB). Microanalyses were obtained with a LECO CHNS-932 el-
ement analyzer. Analytical TLC silica gel 60 F254 plates were pur-
chased from Merck, Darmstadt. The mps are uncorrected. All solvents
used were purified by distillation and dried by standard methods. Tri-
fluoromethanesulfonic anhydride (2) was purchased from Merck, the
phosphites from Aldrich. All operations were carried out under Ar or
Scheme 4
N atmosphere. Specific details are described in the text.
2
4
-(Dialkoxyphosphoryl)-1-(trifluoromethylsulfonyl)-1,4-dihy-
dropyridines 7; General Procedure:
To a stirred solution of pyridine (0.79 g, 10 mmol) in CH CN (50 mL)
Scheme 5
3
was added trifluoromethanesulfonic anhydride (2) (2.82 g, 10 mmol)
dropwise. The solution was kept at 0°C for 0.5 h. The trialkyl phos-
phite (11 mmol) and NaI (1.5 g, 10 mmol) were added over 0.5 h at
0°C. The mixture was allowed to warm to r.t. and then heated to 50°C
+
Attempts to synthesize related compounds from C2-PR -
3
8,19
or C2-PO(OR) -substituted pyridine precursors,
and
2
P(OR) via the corresponding N-trifylpyridinium salts for 10 min. The solvent was evaporated in vacuo to dryness. The res-
3
idue was treated with CH Cl (30 mL). The suspension was filtered,
the solvent was evaporated from the filtrate, and the resulting crude
have not been successful.
2
2
As compounds 13a–d represent the first examples of an product mixture (7 and 8) was purified by bulb tube distillation, which
yielded 7.
N-heteroaromatic ring substituted by both (dialkoxyphos-
phoryl) and phosphonio moieties, the structure of [2-(di-
isopropoxyphosphoryl)-4-pyridyl]triphenylphosphonium
trifluoromethanesulfonate (13b, Figure) was determined
4
-(Dialkoxyphosphoryl)pyridines 9; General Procedure:
Method A: The first part of the procedure is analogous to the proce-
dure for 7. Specific details: after addition of the trialkyl phosphite
by X-ray single crystal diffraction. In the crystal, the con- (11 mmol) and NaI (1.5 g, 10 mmol), the solution was stirred for 1 h

1
98
Papers
SYNTHESIS
Table 2. Spectroscopic Data of the Compounds 7a–c and 9a–ca
Prod- IR
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
EI MS
(70 eV)
m/z (%)
–1
uct
n (cm )
1
+
7
7
7
9
9
9
a
b
c
2146, 1635, 1407, 1231,
3.45 (d, 1 H, 2JPH = 30, Py H-4),
33.9 (d, 1 C, J = 148, Py C-4), 53.46 (d, 2 C,
321 (M , 2.5)
CP
2
3
1198, 1043, 604, 589
3.75 (d, 6 H, J = 11, CH ), 5.15
JCP = 7.4, CH ), 105.35 (d, 2 C, J = 10, Py C-
3
3 CP
(m, 2 H, Py H-3/5), 6.47 (q, 2 H,
2/6), 119.455 (q, 1 C, J = 324.7, CF ), 123.47
CF 3
2
Py H-2/6)
(d, 2 C, J = 10, Py C-3/5)
CP
1
+
1636, 1412, 1233, 1199,
023, 603, 589
1.2 (t, 6 H, J = 7, CH ), 3.32 (d,
15.98 (s, 2 C, CH ), 33.96 (d, 1 C, J = 148, Py 349 (M , 24)
C-4), 62.22 (s, 2 C, CH ), 105.58 (d, 2 C, J
H, CH ), 5.07 (m, 2 H, Py H-3/5), 9.6, Py C-2/6), 123.03 (d, 2 C, J = 11, Py C-
3
3
CP
2
3
1
1 H, J = 20, Py H-4), 4.02 (m,
=
PH
2
CP
2
4
6
2
CP
.35 (m, 2 H, Py H-2/6)
3/5), 119.3 (q, 1 C, JCF = 323.71, CF3)
2
1
+
2153, 1633, 1410, 1231,
193, 994, 602, 565
1.29 (m, 12 H, CH ), 3.36 (d, J
23.78 (m, 4 C, CH ), 34.45 (d, 1 C, J = 2.4, Py 377 (M , 22)
3
PH
3
CP
2
1
= 30, Py H-4), 4.70 (m, 2 H, CH),
.15 (m, 2 H, Py H-3/5), 6.42
m, 2 H, Py H-2/6)
C-4), 71.28 (d, 2 C, J = 7.4, CH), 105.87 (d, 2
CP
3 2
5
(
C, J = 9.6, Py C-2/6), 122.88 (d, 1 C, J
=
CP
CP
10.6, Py C-3/5), 119.40 (q, 1 C, JCF = 324, CF3)
2
+
a
b
c
1637, 1567, 1461, 1409,
3.75 (d, 6 H, J = 11, CH ), 7.59
53.00 (d, 2 C, J = 5.7, CH ), 125.26 (d, 2 C,
188 (M , 100)
3
CP
3
3
2
1
1
5
232, 1196, 1043, 783,
30
(dd, 2 H, J = 4.3, J = 14.3, Py
JCP = 8.2, Py C-3/5), 135.99 (d, J = 186.61,
CP
3
PH
H-3/5), 8.73 (t, 2 H, J = 6.2, Py
H-2/6)
Py C-4), 150.12 (d, 2 C, J = 14.7, Py C-2/6)
C,P
3
+
1654, 1589, 1478, 1403,
1.09 (t, 6 H, J = 1 Hz, CH ), 3.89
15.66 (d, 2 C, J = 6, CH -C), 62.16 (d, 2 C,
215 (M , 57)
3
CP
3
2
2
1
5
253, 1142, 1020, 794,
36
(m, 4H, CH ), 7.39 (dd, 2H, J = 4.3, JCP = 6, CH -C), 124.67, (d, 2C, J = 8, Py
2
2
CP
3
1
JPH = 13, Py H-3/5), 8.49 (t, 2 H,
C-3/5), 137.45 (d, 1 C, J = 185.73, Py C-
4), 149.98 (d, 2 C, J = 12, Py C-2/6)
CP
3
J = 6, Py H-2/6)
CP
3
+
1713, 1588, 1467, 1403,
1.22 (dd, 12 H, J = 5, 4J
=
23.88 (d, 2 C, J = 13.4, CH -C), 71.68 (d, 1 C, 243 (M , 5)
PH
CP
3
2
2
1
5
258, 1142, 983, 773,
45
33.5, CH ), 4.74 (m, 2 H, CH),
JCP = 6, CH-C), 125.23 (d, 2 C, J = 8, Py
CP
1
3
3
7.63 (dd, 2 H, J = 4.3, J = 13.3,
C-3/5), 139.08 (d, 1 C, J = 186, Py C-4),
PH
CP
3
Py H-3/5), 8.73 (t, 2 H, J = 6,
149.83 (d, 2 C, J = 12,3 Py C-2/6)
CP
Py H-2/6)
a
Satisfactory microanalyses obtained: C ± 0.38, H ± 0,47, N ± 0. 18; 9a, 9b as picrates.
Table 3. Spectroscopic Data of the Compounds 10a and 12a–da
Prod-
uct
Yield
(%)
IR
n (cm )
1H NMR (CDCl3)
d, J (Hz)
MS
(70 eV)
m/z (%)
–
1
2
1
0a
2a
85
66
1719, 1410, 1249, 1168,
1.33 (m, 12 H, CH ), 4. 16 (m, 8 H, CH ), 5.18 (dm, 1 H, J = 25, Py
(EI) 486
(M , 12)
3
2
PH
3
+
1
034, 766, 638, 588
3067, 1726, 1626, 1587,
440, 1414, 1230, 1159,
108, 1028, 634, 524
3066, 1719, 1627, 1587,
440, 1415, 1286, 1231,
170, 1110, 1029, 635,
24
2967, 2939, 2877, 1723,
H-2), 5.96 (t, 1 H, J = 7.5, Py H-5), 6.50 (m, 2 H, Py H-3/6)
PH
1
1.34 (t, 6 H, J = 7, CH ), 4.14 (m, 4 H, CH ), 5.48 (dd, 1 H, J = 6.7,
JPH = 22, Py H-2), 5.73 (t, 1 H, J = 7, Py H-5), 6.41 (dm, 1 H, J
20, Py H-3), 6.78 (d, 1 H, J = 6.7, Py H-6), 7.70 (m, 15 H, Ph H) (
1.28 (dd, 6 H, J = 6.4, 4JPH = 19, CH ), 4.81 (m, 2 H, CH), 5.35 (m, 1 H,
Py H-2), 5.82 (dd, 1 H, J = 7.5, J = 15, Py H-5), 6.37 (m, 1 H, Py
H-3), 6.77 (d, 1 H, J = 6.5, Py H-6), 7.55 (m, 15 H, Ph H) (
(FAB)
610
M-I, 15)
3
2
2
3
1
1
=
PH
1
2b
78
(FAB)
638
M-I, 14)
3
3
1
1
5
PH
1
1
2c
77
82
0.90 (t, 9 H, J = 7, CH ), 1.31 (m, 18 H, Bu CH Et CH ), 2.34 (m, 6 H,
(FAB)
550
(M-I, 100)
3
2
3
2
1
1
618, 1463, 1414, 1283,
230, 1029, 804, 638
P-CH ), 4.13 (m, 4 H, Et CH ), 5.34 (dd, 1 H, J = 6.5, J = 22, Py
2 2 PH
H-2), 6.15 (t, 1 H, J = 7, H-5), 6.59 (m, 2 H, Py H-3/6)
4
2d
2967, 2939, 2877, 1722,
0.89 (t, 9 H, J = 6.6, Bu CH ), 1.25 (dd, 6 H, J = 4.5, J = 31, i-Pr
(FAB)
578
(M-I, 14)
3
PH
1
1
631, 1463, 1411, 1282,
230, 1028, 805, 638
CH ), 1.34 (m, 12 H, Bu CH ), 2.33 (m, 6 H, P-CH ), 4.76 (m, 2 H,
3 2 2
2
CH), 5.25 (dd, 1 H, J = 8, J = 25, Py H-2), 6.08 (m, 1 H, Py H-5),
PH
6
.73 (m, 2 H, Py H-3/6)
a
+
1
0b: Yield 20%, decomposition at 160°C, MS (EI) 542 (M , 4).
at 0°C and NEt (1.0 g, 10 mmol) was added. After another 0.5 h, the
Method B: This method does not afford the N atmosphere. The result-
3
2
mixture was allowed to warm to r.t. The solvent was evaporated in
ing mixture of the dihydropyridines 7 and 8 (10 mmol) was dissolved
in CH Cl (50 mL), and HN-i-Pr (1.0 g, 10 mmol) was added. The
vacuo and the residue was treated with 5% aq NaHCO (25 mL). Ex-
3
2
2
2
traction with CH Cl , drying (MgSO ) and evaporation of the solvent
yielded the crude product (brown oil) of compounds 9, which were
purified by bulb tube distillation.
mixture was stirred for 2 h, and the solvent was evaporated under re-
duced pressure. The residue was allowed to stand for 8 h (at ca. 6°C).
Then, the solution was decanted from the precipitated ammonium salt.
2
2
4

February 1998
SYNTHESIS
199
Table 4. Spectroscopic and Physical Data of the Compounds 11a and b, and 13a–da
Prod- Yield mp (°C)
uct (%) or bp
IR
n (cm )
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
MS
(70 eV)
m/z (%)
–
1
(°C)/mbar
2
1
1a 50
175/0.05
1727, 1642, 1.32 (m, 12 H, CH ), 4.15 (m, 16.25, 16.35 (s, 2 C, CH ), 62.99 (d, 1 C, J = 6,
(EI) 352
(M , 4)
3
3
CP
2
+
1
1
1
9
7
582, 1446, 8H, CH ), 7.77 (dm, 1 H,
CH ), 63.24 (d, 1 C, J = 6, CH ), 127.51 (dd, 1
2
2
CP
2
3
2
392, 1366,
256, 1022, (dd, 1 H, J = 6.5, J = 13,
JPH = 12.5, Py H-3), 8.22
C, J = 8.5, Py C-3), 128.97 (dd, 1 C,
CP
4 2
3
JCP = 8.5, J = 26, Py C-5), 138.22 (dd, 1 C,
CP
1
PH
3
72, 828,
94, 555
Py H-5), 8.90 (t, 1 H, J = 4.8,
Py H-6)
JCP = 12, J = 186, Py C-4), 150.17 (dd, 1 C,
CP
3 3
3J = 12, J = 22, Py C-6), 152.4 (dd, 1 C, J
CP CP CP
1
=
12, J = 228, Py C-2)
CP
1712, 1652, 1.38 (dd, 12 H, J = 7.5, 4JPH
23.81, 24.03 (t, 2 C, J = 3.7, CH ), 71.84 (d, 2
C, J = 6, CH), 127.12 (dd, 1 C, J = 3.8, J
386, 1255, CH), 4.89 (m, 2 H, CH), 7.73 = 8.4, Py C-3), 128.49 (dd, 1 C, J = 8.5, J
3
(FAB) +
408 (M ,
100)
1
1
1
1b 10
155–l70/
CP
3
2
2
2
0
.05
1581, 1466, = 42.5, CH ), 4.67 (m, 2 H,
3
CP
CP
CP
=
4
2
1
9
8
5
CP
CP
3
3
1
89, 888,
17, 769,
56
(dm, 1 H, J = 12.5, Py H-3), 25, Py C-5), 139.41 (dd, 1 C, J = 11, J = 187,
PH CP CP
3 3
8.18 (dd, 1 H, J = 6.4,
JPH – 13, Py H-5), 8.86 (t,
Py C-4), 150.35 (dd, 1 C, J = 12, J = 22, Py
CP CP
3 1
3
C-6), 153.76 (dd, 1 C, J = 12, J = 228, Py C-2)
CP CP
1
H, J = 4.8, Py H-6)
3
3a 50
128
3062, 1585, 1.31 (t, 6 H, J = 7, CH ), 4.23 16.23 (d, 2 C, J = 6.25, CH ), 64.03 (d, 2 C,
482, 1438, (m, 4 H, CH ), 7.77 (m, 16 H, JCP = 6.4, CH ), 115.31 (d, 3 C, J = 90, Ph C-
(FAB)
476 (M-I,
3
CP
3
2
1
1
1
2
2
CP
270, 1225, Ph, H-3), 7.96 (dd, 1 H, J =
1), 120.47 (q, 1 C, JCF = 320, CF ), 130.25 (m, 3 C, 85)
Py C-3/5/4), 131.10 (d, 6 C, J = 13, Ph C-3/5),
134.63 (d, 6 C, J = 10.5, Ph C-2/6), 137.33 (d, 3
3
3
3
1152, 1109, 6.5, J = 13, H-5), 9.23 (t,
PH
CP
2
1
5
032, 638,
24
1 H, J = 5, H-6)
CP
4
3
C, J = 3, Ph C-4), 153.60 (dd, 1 C, J = 12,
CP
CP
3
JCP = 21.5, Py C-6)
1585, 1569, 1.29 (dd, 6 H, J = 6, 4JPH
1
=
23.80 (dd, 2 C, J = 5, J = 12.4, CH ), 73.13 (d,
440, 1260, 20, CH ), 4.84 (m, 2 H, CH), 2 C, J = 6.4, CH), 115.40 (d, 3 C, J = 89, Ph
3
(FAB)
504 (M-I,
12)
3b 55
114–118
CP
3
2
1
3
CP
CP
1
225, 1153, 7.7 (m, 17 H, Ph, H-3/5),
C-1), 122.39 (q, 1 C, J = 320.79, CF ), 129.32
CF 3
3 1
1108, 1034, 9.22 (t, 1 H, J = 5, H-6)
(dd, 1 C, J = 12.5, J = 83, Py C-4), 129.44
CP CP
4 2
6
38, 525
(dd, 1 C, J = 8.5, J = 26, Py C-5), 129.94
CP
CP
2
2
(
dd, 1 C, J = 3.5, J = 8. 1, Py C-3), 131.1 (d,
CP CP
3 2
6
1
1
1
C, J = 13, Ph C-3/5), 134.61 (d, 6 C, J
=
CP
CP
4
0.5, Ph C-2/6), 136.39 (d, 3 C, J = 3, Ph C-4),
52.73 (dd, 1 C, J = 12, J = 21.5, Py C-6),
55.81 (dd, 1 C, J = 9, J = 228, Py C-2)
CP
3
3
CP
CP
3
1
CP
CP
3
1
3c 30
oily
product
2964, 2936, 0.89 (t, 9 H, J = 5.5, Bu
2874, 1742, CH ), 1.29 (t, 6 H, J = 7, Et
13.27 (s, 3 C, Bu CH ), 16.32 (d, 2 C, J = 6, Et
(FAB)
3
CP
1
CH ), 18.83 (d, 3 C, J = 47.5, Bu P-CH ), 23.72 417 (M-
3 CP 2
2
3
1
1
1
1
5
635, 1575, CH ), 1.45 (m, 12 H, Bu
(m, 8 C, Bu CH ), 63.96 (d, 2 C, J = 6.3, Et
I+1, 100)
3
2
CP
467, 1371, CH ), 2.60 (m, 6 H, Bu CH ), CH ); 123.83 (q, 1 C, J = 318, CF ), 127.99 (dd,
2
2
2
CF
3
4
2
261, 1156, 4.24 (m, 4 H, Et CH ), 8.04
1 C, J = 6.4, J = 26, Py C-5), 128.52 (dd,
CP CP
2 2
2
3
029, 638,
73
(dd, 1 H, J = 6, J = 11, Py 1 C, J = 3.3, J = 7. 1, Py C-3), 129. 17 (dd, 1 C,
PH
CP
CP
3
3
1
1
H-3), 8.24 (dd, 1 H, J = 5,
JPH = 12, Py H-5), 9.13 (t, 1
JCP = 12.4, J = 72.1, Py C-4), 152.45 (dd, 1 C,
JCP = 8.8, J = 21.5, Py C-6), 154.24 (dd, 1 C,
CP
3
3
CP
H, J = 4.5, Py H-6)
JCP = 7.9, JCP = 226, Py C-2)
1
1
3d 29
oily
product
2965, 2936, 0.89 (t, 9 H, J = 7, Bu CH ),
13.24 (s, 3C, Bu CH ), 18.63 (d, 3 C, J = 47,
(FAB)
444 (M-I,
9)
3
3
CP
4
2874, 1725, 1.30 (dd, 12 H, J = 6, J
=
Bu P-CH ), 23.63 (m, 10 C, i-Pr CH , Bu CH ),
2 3 2
2
PH
1
1
1
633, 1575, 22.5, i-Pr CH ), 1.46 (m, 12
72.97 (d, 2 C, J = 6.5, CH), 129.7 (q, 1 C, J
=
3
CP
CF
4
2
467, 1379, H, Bu CH ), 2.63 (m, 6 H, Bu 320, CF ), 127.72 (dd, 1 C, J = 8.5, J = 26,
2
3
CP
CP
2
2
260, 1224, CH ), 4.81 (m, 2 H, i-Pr CH), Py C-5), 128.34 (dd, J = 4, J = 7, Py C-3),
2
CP
CP
3
3
1
1154, 998,
8.02 (dd, 1 H, J = 6.5, J
=
128.96 (dd, 1 C, J = 12.5, J = 72.5, Py C-4),
CP
3 3
PH
6
38, 573
12, Py H-3), 8.21 (dm, 1 H,
152.41 (dd, 1 C, J = 9, J = 22, Py C-6),
CP CP
3 1
3
JPH = 12, Py H-5), 9.11 (t, 1 155.30 (dd, 1 C, J = 8, J = 227, Py C-2)
CP
CP
H, J = 4.5, Py H-6)
Satisfactory microanalyses obtained: C ± 0.32, H ± 0.31, N ± 0.29, S ± 0.16.
a
To separate minor amounts of impurities to get analytical purity, it is 2,4-Bis(dialkoxyphosphoryl)pyridines 11:
useful to perform a bulb tube distillation, or TLC (silica gel, EtOAc). Under Et O, the residue was cooled (6 °C) for 8 h. Then, the precipi-
2
tated ammonium salt was filtered off and the solvent was evaporated.
Disubstituted Pyridines 11a and b, and 13a–d; General Procedure: The residue (a yellow-brown oil) was purified by TLC (silica gel,
5
To a stirred solution of 9 or 5 (5 mmol) in CH Cl (50 mL), 2 (1.4 g, EtOAc/MeOH 10:1).
2
2
5
mmol) was added dropwise at r.t. A clouding of the solution was ob-
served in the case of 11, and 13c and d. After 0.5 h the trialkyl phos-
phite (6 mmol) was added. The solution became transparent after a [2-(Dialkoxyphosphoryl)-4-pyridyl]triphenylphosphonium Tri-
few minutes, then NEt (0.6 g, 6 mmol) was added. The mixture was fluoromethanesulfonates 13a and b:
3
stirred for 2 h, and the solvent was evaporated in vacuo. Specific de- The residue was treated with 5% aq NaHCO (25 mL), extracted with
3
tails for the synthesis of compounds 11a and b, 13a–d are given below. CH Cl (3 x 30 mL), dried (MgSO ), and evaporated to give the crude
2
2
4

2
00
Papers
SYNTHESIS
Table 5. 31P NMR Spectral Data for Selected Compoundsa
Structure Solution andRefinement: The structure was solved by direct
21
methods (SHELXS ) and refined by full-matrix least squares tech-
niques against F2 (SHELXL-93 ). The hydrogen atoms were in-
cluded at calculated positions with fixed thermal parameters; all
nonhydrogen atoms were refined anisotropically. The refinement
22
3
1
Prod-
uct
P NMR (CDCl ) d, J (Hz)
3
P-2
P-4
2
converged for 388 parameters at R = 0.043, wR = 0.117 and GOOF
7
b
–
q, 20.5, JPF = 2.8
d, 14.49, JPP = 11.2
d, 23.82, Jpp = 9.2
23.81
33.45
–
=
1.13. The difference Fourier synthesis on the basis of the final struc-
1
1a
d, 10.62, JPP = 11.2
d, 8.17, JPP = 9.3
qui, 6. 19, J = 7.4
qui, 8.72, J = 7.6
12.04
23 –3
tural model showed a maximum of 0.88 e Å and a minimum of
–
1
1
1
1
3a
3b
3c
4
–3
0.45 e Å . XP (SIEMENS Analytical X-ray Instruments, Inc.) was
used for structure representation.
a
This work was financially supported by the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie (Germany). We
thank Prof. Dr. K. Akiba (Hiroshima, Japan) and Prof. Dr. A. R.
Katritzky (Gainesville, Florida, USA) for useful discussions.
Shifts downfield of 85% H PO are reported as positive.
3
4
product (white-brown solid). Unreacted 5a was separated by fraction-
al crystallization from EtOAc.
Tributyl[2-(dialkoxyphosphoryl)-4-pyridyl]phosphouium
fluoromethanesulfonates 13c and d:
Similar to the procedure for 13a and b, but it was necessary to trans-
form the resulting oil to the corresponding pyridinium triflate, which
separated from the solution. This material was treated with 5% aq
Tri-
(
1) Russel, A. A.; Meline, R. L.; Duestler, E. N.; Paine, R. T. Inorg.
Chim. Acta 1995, 231, 1.
2) For reviews on Pyridylphosphines: Newcome, G. R. Chem. Rev.
(
1
993, 93, 2067.
NaHCO (25 mL). Repeating the above procedure (extraction with
3
Spiegel, G. U.; Stelzer, O. Chem. Ber. 1990, 123, 989.
CH Cl , drying with MgSO ) a brown oil was separated after addition
2
2
4
(
3) Beugelmans, R.; Chbani, M. Bull. Soc. Chim. Fr. 1995, 132,
of Et O. The dihydropyridines 10 and 12 were isolated after comple-
2
2
90.
tion of the addition of trialkyl phosphites. After addition of Et O a
2
(
(
4) Desos, P.; Lestage, P.; Cordi, A. A. J. Med. Chem. 1996, 1, 197.
5) Schull, T. L.; Fettinger, J. C.; Knight, D. A. J. Chem. Soc.,
Chem. Commun. 1995, 1487.
6) Salomon, C. J.; Breuer, E. Tetrahedron Lett. 1995, 36, 6759.
7) Akiba, K.; Matsuoka, H.; Wada, M. Tetrahedron Lett. 1981, 22,
brown oil separated. After concentration in vacuo, the residue 12a
and b was dissolved in EtOAc. The solution was filtered off from the
precipitated solid.
(
(
4
-Deuterio-2-(diethoxyphosphoryl) pyridine (14):
4
093.
To a stirred solution of13a (0.16 mmol) in THF (10mL) at –78 °C was
added a cooled mixture (–78 °C) of 1.6 M BuLi in hexane (0.3mL)
and TMEDA (0.48 mmol) in THF (5 mL). After 20 min, the solution
(
(
8) Redmore, D. J. Org. Chem. 1970, 35, 4114.
9) Katritzky, A. R.; Keay, J. G.; Sammes, M. P. J. Chem. Soc., Per-
kin Trans 1 1981, 668.
was warmed to –50°C, D O (0.8 mmol) was added, and the mixture
2
(
(
10) Redmore, D. J. Org. Chem. 1976, 41, 2148.
11) Moshchitskii, S. D.; Sologub, L. S.; Pavlenko, A. F.; Kukhar, V.
P. Zh. Obshch. Khim. 1977, 47, 1263.
12) Anders, E.; Markus, F. Chem. Ber. 1989, 122, 113.
13) Anders, E.; Markus, F. Chem. Ber. 1989, 122, 119.
14) The results of a detailed mechanistic and structural study based
on ab initio and semiempirical calculations will be published
separately.
stirred for 30 min at this temperature. The mixture was allowed to
warm to r.t. slowly before the THF was evaporated under reduced
pressure. The residue was treated with 5% aq NaHCO (10mL). Ex-
3
(
(
(
traction with CH Cl , drying (MgSO ) and evaporation of the solvent
2
2
4
yielded the crude product 14, which was purified by TLC (silica gel,
EtOAc); oily product; yield: 75%.
1
H NMR (CDCl ): d = 1.35 (t, 6 H, J =7.1 Hz, CH ), 4.21 (m, 4H,
3
3
3
CH ), 7.42 (m, 1 H, Py H-5), 7.98 (d, 1 H, J = 6.7 Hz, Py H-3),
2
P,H
(15) Akiba, K.; Negishi, Y.; Inamoto, N. Synthesis 1979, 55.
(16) After isolation, the compounds 7 and 8 are stable at ca. 5 –10°C
for several days.
3
8
.85 (d, 1 H, J = 4.8 Hz, Py H-6). 3
P,H
13
C NMR (CDCl ): d = 16.27 (d, 2 C, J = 6.0 Hz, CH ), 63.03 (d,
3
C,P
3
2
4
2
1
C, J = 5.8 Hz, CH ), 125.95 (d, 1C, J = 4.0 Hz, Py C-5),
C,P 2 C,P
2
(17) By addition of NaI the presumably reversible reaction 3 +
28.06 (d, 1C, J = 25.25 Hz, Py C-3), 135.85 (dt, 1 C, J = 25.35
C,P
C,D
P(OR) ® 7 + 8 becomes irreversible.
3
3
3
2
Hz, J = 12.37 Hz, Py C-4), 150.47 (d, 1 C, J = 22.9 Hz, Py C-
6
C.P
C,P
(18) The variant CH Cl /HN-i-Pr gives slightly better results.
(19) Synthesis of the C2-PPh -substituted bromide from 2-bromopy-
2
2
1
), 150.47 (d, 1 C, J = 227.25 Hz, Py C-2).
C,P
3
–1.
IR (film): n = 1637, 1567, 1461, 1409, 1232, 1196, 1043, 783, 530 cm
ridine: Zhmurova, I. N.; Kosinskaya, A. M.; Pinchuk, A. M. Zh.
Obshch. Khim. 1981, 51, 1538.
+
MS (EI): m/z (%) = 217 (M , 100).
The triflate was obtained from that bromide by anion exchange
with CF SO H. Neither the bromide nor the triflate reacts with
phosphites.
X-ray Crystallographic Data of 13b:
3
3
+
–
–1,
[
0
1
C H NO P ] CF SO Mr = 653.6 g mol colorless quader, size
29 32 3 2 3 3 ,
3
¯
.40 ´ 0.40 ´ 0.38 mm , triclinic, space group P1, a = 9.810(1), b =
0.849(1), c = 14.943(2) Å, a = 81.76(1), b = 83.48(1), g = 88.61(1)°,
(
20) MOLEN, An Interactive Structure Solution Procedure, Enraf–
Nonius, Delft, The Netherlands, 1990.
(21) Sheldrick G. M. Acta Crystallogr., Sect. A 1990, 46, 467.
3
–3
–1
V = 1563.7 (3) Å , Z = 2, p
F(000) = 680.
= 1.388 g cm , m(Mo-Ka) = 2.67 cm ,
calcd.
(
22) Sheldrick G. M., SHELXL-93, University of Göttingen, Germa-
Data collection: The intensity data for the compound were collected
on an Enraf–Nonius CAD4 diffractometer, using graphite-monochro-
mated Mo-Ka radiation and w-2Q scan technique at –90°C. 6606 re-
flections in ±h, ±k, +l were measured in the range 2.38 ≤ Q ≤ 26.30,
ny, 1993.
(23) Further details of the crystal structure investigations are avail-
able on request from the Fachinformationszentrum Karlsruhe,
Gesellschaft für wissenschaftlich-technische Information mbH,
D-76344 Eggenstein-Leopoldshafen (Germany), on quoting the
depository number CSD-406873, the names of the authors, and
the journal citation.
of which 6352 were independent reflections (R = 0.015). 5647 re-
int
flections having I > 2s (I). Data were corrected for Lorentz and po-
larization effects, but not for absorption.20