One-pot reduction of aryl iodides using 4-DMAP methiodide salt

Article abstract of DOI:10.1055/s-2008-1078242

An efficient one-pot procedure is described for the reduction of aryl iodides to aryl anions using a structurally simple bis-pyridinylidene electron donor, prepared in situ by treating 4-DMAP methiodide salt with base. The results show (i) that pyridinylidene carbenes can be easily used for intermolecular C-C bond formation, (ii) that bis-pyridinylidenes demonstrate superior robustness compared to electron-donor systems based on bis-imidazolylidenes, and (iii) that electron-donor strength is enhanced in the simplified DMAP-based donor. Deuterated analogues of this donor also provide mechanistic information on the source of protons when the aryl anions are quenched in situ. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078242

LETTER
2127
One-Pot Reduction of Aryl Iodides Using 4-DMAP Methiodide Salt
a
a
a
b
O
J
ne-Pot
R
e
eduction
o
a
A
ryl Iodid
n
es Garnier, John A. Murphy,* Sheng-Ze Zhou, Andrew T. Turner
a
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK
UM4 Main Lb Block Process R&D, AstraZeneca, Hurdsfield Industrial Estate, Macclesfield, SK10 2NA, UK
Fax +44(141)5484822; E-mail: John.Murphy@strath.ac.uk
b
Received 2 June 2008
Dedicated to Sir Jack Baldwin on the occasion of his 70 birthday
th
efficiently converts aryl iodides into the corresponding
aryl radicals, while 5 was used both to convert aryl ha-
Abstract: An efficient one-pot procedure is described for the re-
duction of aryl iodides to aryl anions using a structurally simple bis-
pyridinylidene electron donor, prepared in situ by treating 4-DMAP
methiodide salt with base. The results show (i) that pyridinylidene
2
lides into the corresponding aryl anions in a two-electron
3
a
transfer process, and to reductively cleave selected sul-
carbenes can be easily used for intermolecular C–C bond formation, fones and sulfonamides.4
(
ii) that bis-pyridinylidenes demonstrate superior robustness com-
pared to electron-donor systems based on bis-imidazolylidenes, and
iii) that electron-donor strength is enhanced in the simplified
DMAP-based donor. Deuterated analogues of this donor also pro-
Earlier this year, we disclosed the preparation of a new
5
class of neutral organic electron donors, based on the
(
conversion of a readily available 4-dimethylaminopyri-
vide mechanistic information on the source of protons when the aryl dinium disalt 8 into the corresponding bis-pyridinylidene
anions are quenched in situ.
6 by base treatment. The mechanism for this reaction
Key words: electron donor, pyridinylidene, reduction, 4-DMAP
(Scheme 2) is presumed to follow that proposed by Alder
et al. for ‘dimerisation’ of other N-heterocyclic carbenes.
6
The intramolecular reaction of the pyridinylidene with a
Electron-rich alkenes are easily oxidised. Baldwin and pyridinium salt was a novel finding, and proceeded with
1
a
Walker observed the spontaneous oxidation in air of di- surprising efficiency in view of the perceived instability
7
azadithiafulvalene 1 to urea 2 (Scheme 1), during an ex- of pyridinylidenes. The new donor 6 efficiently reduced
tensive study focused on sigmatropic rearrangements.1b aryl iodides and bromides to the corresponding anions,
The reactivity of bis-benzothiazolylidene 1 arises from its and constituted the most powerful neutral organic electron
easy conversion to its radical cation, and contrasts with donor known, being slightly more powerful than the bis-
5
the air-stable and commercially available tetrathiaful- imidazolylidene 5. An advantage of 6 was its ease of
valene 3. This shows the great ability of nitrogen atoms to preparation through deprotonation of the trimethylene-
stabilise radical cation intermediates that result from elec- bridged 8. Attempts to prepare a similar monobridged bis-
imidazolylidene 7 had not been successful,3b ultimately
requiring us to use doubly bridged 5 in its place; however,
compound 14, the macrocyclic precursor to 5, was incon-
venient to prepare, and hence 6 was an important discov-
ery. In this Letter, we now extend our study to
intermolecular reactions of pyridinylidene carbenes and
tron loss in such heterofulvalenes.
Recently, knowledge of the properties of electron-rich
alkenes has advanced considerably. Extremely reactive
neutral organic electron donors containing electron-rich
alkenes are now known, and constitute a promising new
class of selective and metal-free reducing agents. Thus 4
Me
S
S
S
N
S
S
S
S
O2
CH2Cl2, 0 °C
N
S
NMe MeN
O
Me
1
O
2
3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me2N
NMe2
Me
Me
Me
Me
4
5
6
7
Scheme 1
SYNLETT 2008, No. 14, pp 2127–2131
2
2
.0
8
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078242; Art ID: D19708ST
Georg Thieme Verlag Stuttgart · New York
©

2
128
J. Garnier et al.
LETTER
yields of the desired reduced product 13 were obtained
I–
I–
I–
(
Scheme 4) [a blank reaction (in the presence of NaH and
+N
N+
N+
NaH, NH3
N
DMF, but with no pyridinium salt) provided quantitative
recovery of 12].
•
•
Me2N
NMe2
When used with 9 (1.5 equiv, 16 h), the one-pot procedure
also gave 13 in 84% yield (Scheme 4). A second experi-
ment was carried out using only enough monosalt 9 to
produce 0.5 equivalents of donor 10 relative to substrate
Me2N
NMe2
8
I–
1
2. Reduction of half of the substrate was observed, as
would be expected for clean formation of 10, and subse-
quent reaction of 10 as a two-electron donor.
N
N
+N
N
H
Me2N
NMe2
To obtain spectroscopic information on 10, salt 9 was
treated with base for 16 hours in perdeuterated dimethyl-
formamide, followed by precipitation of the remaining
salts using diethyl ether, filtration, and evaporation of the
Me2N
NMe2
•
B•
6
83%
Scheme 2
1
13
nondeuterated solvent. Both H NMR and C NMR spec-
tra of 10 in DMF-d showed it to be a single isomer, al-
develop a convenient one-pot, in situ reduction of the aryl
iodide moiety, without any need to isolate the highly reac-
tive bis-pyridinylidene electron donor.
7
though the stereochemistry of the central alkene could not
be assigned. The clean formation of 10 shows that bis-
pyridinylidenes can be prepared by intermolecular reac-
tion and that, unlike the case for the bis-imidazolylidene
The pyridinium salt selected for this study was 4-DMAP
methiodide 9, which should lead to the formation of elec-
tron donor 10 (Scheme 3). Initial trials on this reaction
showed that it was significantly retarded relative to the in-
tramolecular formation of 6 from 8. Since a slow genera-
tion of a very reactive donor like 10 could lead to its
decomposition before an aryl iodide substrate would be
added, this led us to ask whether donors like 10 could be
formed in the presence of aryl iodide substrates. This
would have the advantage that 10 would undergo reaction
with the substrate as soon as it had formed. It would also
simplify the protocols for reduction of aryl halides, as it
would avoid the need to isolate the very reactive electron
donors. However, the product arising from 10 following
transfer of two electrons, namely the disalt 11, might in-
terfere with the ongoing formation of 10, and so this
would need to be tested.
5
, no trimethylene bridge is needed to hold the reacting
partners together. The oxidation potential of donor 10 was
determined to be E1/2 = –1.72 V vs. Fc/Fc , some 30 mV
+
more negative than for 6, making 10 the strongest neutral
organic electron donor known.8
In our initial research,4,5 substrates such as 15 were used
to prove the presence of anionic intermediates through the
reaction shown in Scheme 5. Formation of ketone 17 sig-
nalled the presence of aryl anions and its yield indicted a
minimum estimate of the amount of aryl anion produced
during the reaction; on the other hand, the mechanistic or-
igin of product 19 was ambiguous, since it might arise ei-
ther from protonation of the anionic intermediate 16, or
from a hydrogen transfer to the possible radical interme-
diate 18 formed after a single-electron transfer.
Later, the more efficient substrate 20 was designed, allow-
ing the derived aryl anion to undergo more rapid cyclisa-
tion, and hence providing a more accurate picture of the
The idea of generating the reactive donor in the presence
of aryl iodide substrate 12 was now firstly tried with salts
8
and 14, precursors of the known donors 6 and 5. Good
Me
Me
N+
Me Me
Me Me
I–
I–
I–
I–
+N
+N
N+
N
N
base
ArI
Ar
+
−
−
Me2N
NMe2
Me2N
NMe2
Me2N
NMe2
9
10
11
Scheme 3
I
H
I–
I–
+N
N
N+
N
i, ii, iii, or iv
O(CH2)3Ph
O(CH2)3Ph
12
13
1
4
Scheme 4 Reagents and conditions: (i) 8 (1.5 equiv), NaH, DMF, 3 h (78%); (ii) 14 (1.5 equiv), NaH, DMF, 3 h (84%); (iii) 9 (1.5 equiv),
NaH, DMF, 16 h (84%); (iv) 9 (0.5 equiv), NaH, DMF, 16 h (13, 52%; recovered 12, 39%).
Synlett 2008, No. 14, 2127–2131 © Thieme Stuttgart · New York

LETTER
One-Pot Reduction of Aryl Iodides
2129
O
O
OEt
Me
cyclisation
Me
Me
–
Me
+
2 e–
1
6
17 24%
O
OEt
Me
I–
–
i
– I–
Me
I
O
OEt
Me
e–
O
OEt
Me
+
15
hydrogen
abstraction
.
Me
Me
H
(
i) 3 (1.5 equiv), DMF, r.t.
1
8
19 54%
O
1
) donor 6
DMF, r.t.
O
O
OEt
Me
O
OH
Me
Me
+
2
) KOH, H2O
MeOH, 12 h
O
O
Me
Me
Me
I
H
20
21 8%
22 83%
Scheme 5
I–
N
N
+N
N+
I
DMF
r.t.
–
OR
OR
Me2N
NMe2
Me2N
NMe2
23
6
24
25
Scheme 6
Me Me
N
N
O
O
OEt
Me
O
OEt
Me
Me
Me2N
26
NMe2
Me
Me
DMF
Me
I
H
15
Using 2b:
Using 6:
17 27%
7 24%
19 51%
19 54%
1
Scheme 7
extent of aryl anion formation. This substrate provided 22 This provided very similar results to those obtained with
in 83% yield showing that aryl anion formation is efficient donor 6, showing that this type of elimination was not a
with these electron donors. In both byproducts 19 and 21, major source of the circled protons in Scheme 5. To study
knowledge of the origin of the circled proton is a prereq- the lability of the pyridine ring a-hydrogens towards ab-
uisite for optimisation of the design of electron donors in straction, we studied isotopic exchange in pyridinium
9
these reactions. The reduction of an aryl halide 23 produc- salts to form a-deuterated derivatives (Scheme 8) using
es two intermediates in close vicinity: the aryl anion 24 D O and Et N. N-Methylpyridinium iodide (27) showed
2
3
and the dication 25 arising from the oxidation of the donor close to quantitative exchange in the ortho position, 30%
(Scheme 6). Dication 25 is a most likely source of pro- deuteration on the N-methyl group and trace deuteration
6
2
tons in the mixture, and features a number of candidate on the para position, observed by H NMR spectroscopy.
sites for deprotonation, identified in Figure 1.
Interestingly, identical conditions applied to 9 only
showed 60% exchange, with labelling occurring exclu-
sively in the ortho position.
The possibility of a b-elimination featuring deprotonation
of the central methylene of the trimethylene bridge (ali-
phatic b-CH protons) was addressed through reaction of Ultimately, optimised conditions for exchange on disalt 8
substrate 15 with the gem-dimethyl donor 26 (Scheme 7). provided 30 cleanly (Scheme 8), with above 98% deuter-
Synlett 2008, No. 14, 2127–2131 © Thieme Stuttgart · New York

2
130
J. Garnier et al.
LETTER
I–
I–
N+
Me I–
N+
I–
I
Me
N+
Me
N+
H/D
H/D
D2O, Et3N
2 °C, 24 h
D2O, Et3N
II
7
72 °C, 24 h
III
NMe2
NMe2
27
28 >98%
9
29 >98%
ortho position:
60% deuterated
I: 30% D, II: 98% D,
III: trace D in H-NMR
2
I–
I–
I–
+N
I–
D
N+
D
+N
N+
D2O, Et3N
0 °C, 72 h
D
D
8
Me2N
NMe2
Me2N
NMe2
8
30 >98%
I–
I–
D
D
+N
N+
D
D
I
Me2N
NMe2
3
0
D/H
KHMDS, DMF
O(CH2)3Ph
O(CH2)3Ph
1
1
2
2
(I) 30 (1.5 equiv), KHMDS, DMF
(II) 30 (1.5 equiv), NaH, DMF
13 89%, 40% D
13 83%, 33% D
Scheme 8
CD3
H
H
PF6–
N+
H
H
N+
+N
N+
+N
I
N
D/H
D3C
CD3
3
1
NMe2
Me2N
NMe2
Me2N
O(CH2)3Ph
O(CH ) Ph
2
3
NaH, DMF
aliphatic β-CH
pyridinium ring
+
+
12
13 75%
5% D
protons (N CCH)
α-protons (N CH)
~
H
H
Scheme 9
+N
N+
N+
N
the exchange reaction that forms 30 and from the conver-
sions of 8 to 6 and of 9 to 10, pyridinium a-CH protons are
a major source of proton abstraction in the reaction that
quenches aryl anions.
H
+N
Me2N
NMe2
NMe2
H
H
H
H
H
To test the remaining positions, the aliphatic NCH a-pro-
tons, the synthesis of pyridinium hexafluorophosphate
+
aliphatic α-protons (N CH)
(
31) was chosen as the most suitable precursor. Using the
Figure 1
one-pot method described in the first part of this Letter,
the reduction of 12 by 31 provided 13 with low-level deu-
ation of the ortho position and no deuteration of the alkyl terium incorporation (5%), showing that the N-alkyl posi-
chain. Preparation of 30 therefore provided a convenient tions of the donor, and its corresponding dication are not
way to test the capacity of pyridine ring a-CH protons for major sources of proton for the aryl anion intermediate
the quenching of aryl anions.
This compound was reacted using the one-pot conditions In conclusion, we have developed a one-pot procedure for
Scheme 8). Optimised reaction using KHMDS showed a convenient single-step reduction of the aryl iodide moi-
(Scheme 9).
(
exclusive deuteration of the para position (40%) of 12, ety, avoiding the isolation of very reactive neutral organic
while reaction with the alternative base, NaH, led to 33% electron donors and allowing the use of slow-forming do-
labelling of the same position. As might be expected from
Synlett 2008, No. 14, 2127–2131 © Thieme Stuttgart · New York

LETTER
One-Pot Reduction of Aryl Iodides
2131
–
1 1
nor 10 starting from a precursor as simple as the 4-DMAP 1221, 1185, 1043, 901 cm . H NMR (400 MHz, DMSO-d
): d =
6
2
.36 (2 H, quin, J = 7.3 Hz, CH ), 3.20 [12 H, s, 2 N(CH ) ], 4.26 (4
salt 9.
2
3
2
H, t, J = 7.3 Hz, NCH ), 7.05 (4 H, s, meta ArH), 8.28–8.30 (int:
2
In a mechanistic study, deuterium-labelling studies show
13
0
.0761 H, m, ortho ArH). C NMR (100 MHz, DMSO-d ): d = 31.0
6
that the pyridinium ring a-protons contribute strongly to (CH ), 39.8 (CH ), 53.5 (CH ), 107.6 (CH), 141.5 (CD), 155.8 (C).
2
3
2
2
the quenching of aryl anions. Blocking of such positions,
H NMR (61 MHz, DMSO): d = 8.25 (br s, ortho ArD); calculations
1 2
based on H NMR and H NMR showed: ortho ArH only place deu-
for example, in donor 6 should significantly decrease pre-
+
+
mature quenching of aryl anions in these reactions.9
terated (>98% D). MS (ESI ): m/z (%) = 417 (13) [M – I] , 145
100).
(
Compound 31
General One-Pot Reduction Procedure
To a solution of 4-aminopyridine (471 mg, 5 mmol, 1.0 equiv) and
trideuteromethyl iodide (1.25 mL, 2.9 g, 40 mmol, 4.0 equiv) in
Under inert atmosphere, anhyd DMF (5 mL) was added to a mixture
of the aryl iodide (0.3 mmol, 1.0 equiv), donor precursor (0.45
mmol, 1.5 equiv of disalt or 0.9 mmol, 3 equiv of monosalt) and
washed NaH (108 mg, 15 mmol). Overnight stirring at r.t. followed
by filtration, extraction (H O–Et O) and purification by column
MeCN (25 mL) was added K CO (1.73 g, 12.5 mmol, 2.5 equiv).
2 3
After stirring at r.t. for 24 h the solution was brought to reflux over
12 h and left refluxing over 48 h. The solvent was evaporated and
the remaining solid dissolved in de-ionised H
O (10 mL). Upon ad-
2
2
2
chromatography provided the reduced products as reported.
dition of NaPF (1.7 g, 10 mmol, 2 equiv) in aqueous solution (5
mL) and reflux for 2 h, the solution was left to cool down slowly,
providing crystals of N-(trideuteromethyl)-4-bis(trideuterometh-
6
Measurements of deuterium incorporation in compound 13 were
1
performed using H NMR spectra (400 MHz, acetone-d ) by com-
6
yl)amino pyridinium iodide (31) as long colourless needles (1.16 g,
parative integration between the 7 H multiplet (d = 7.15–7.30 ppm)
+
4
.0 mmol, 80%); mp 182–184 °C. HRMS (ESI ): m/z calcd for
and the 3 H multiplet (d = 6.90–6.95 ppm) in which the residual pro-
+
C H D F N P: 146.1638 [M – PF ]; found: 146.1633 [M - PF ] . IR
2
8
4
9
6
2
6
6
ton signal was incorporated. Sites of labelling were verified by H
(
5
KBr): n = 3165, 3115, 3080, 1649, 1558, 1429, 1361, 1207, 838,
max
NMR spectroscopy.
–
1 1
58 cm . H NMR (400 MHz, DMSO-d ): d = 6.99–7.02 (2 H, m,
2
6
ArH), 8.18–8.21 (2 H, m, ArH). H NMR (61.4 MHz, DMSO): d =
3
DMSO-d ): d = 107.4 (CH), 142.8 (CH), 155.7 (C). MS (ESI ):
m/z (%) = 146 [M ].
Compound 10
1
3
.09 [6 D, s, N(CD ) ], 3.82 (3 D, s, NCD ). C NMR (100 MHz,
3 2 3
Under an inert atmosphere, NaH (24 mg, 1 mmol, 5.0 equiv) was
added to a stirring solution of N-methyl-4-(dimethylamino)pyridin-
ium iodide (9, 53 mg, 0.2 mmol, 1.0 equiv) in deuterated DMF (0.75
+
6
+
mL). After stirring 16 h at r.t., degassed Et O (10 mL) was added,
2
and the solution filtered. Evaporation of the nondeuterated solvent
Acknowledgment
4
4
4¢ 4¢
provided
a solution of 1,1¢,N ,N ,N ,N -hexamethyl-1H,1¢H-
1
[
2,2¢]bis-pyridinylidene-4,4¢-diamine (10). H NMR (400 MHz,
We thank the EPRSC, AstraZeneca, and the University of Strath-
clyde for funding and the EPRSC National Mass Spectrometry Ser-
vice Centre, Swansea for mass spectra.
DMF-d ): d = 2.60 [12 H, s, N(CH ) ], 2.61 (6 H, s, NCH ), 4.94 (2
7
3
2
3
H, d, J = 2.4 Hz, CH), 5.12 (2H, dd, J = 2.4, 7.2 Hz, CH), 6.23 (2 H,
d, J = 7.2 Hz, CH). 13C NMR (100 MHz, DMF-d ): d = 38.2 (CH ),
7
3
4
0.9 (CH ), 94.6 (CH), 100.2 (CH), 119.15 (C), 140.3 (CH), 143.2
3
References
(
C).
(
1) (a) Baldwin, J. E.; Walker, J. A. J. Am. Chem. Soc. 1974, 96,
96. (b) Baldwin, J. E.; Branz, S. E.; Walker, J. A. J. Org.
Compound 26
5
Starting from 1,3-bis(N¢,N¢-dimethyl-4-aminopyridinium)-2,2-di-
methylpropane dimesylate (3.53 g, 7 mmol, 1 equiv) and following
the previously published method for the synthesis of N,N,N¢,N¢-tet-
ramethyl-7,8-dihydro-6H-dipyrido[1,2-a;2¢,1¢-c][1,4] diazepine-
Chem. 1977, 42, 4142.
(
2) Murphy, J. A.; Khan, T. A.; Zhou, S. Z.; Thomson, D. W.;
Mahesh, M. Angew. Chem. Int. Ed. 2005, 44, 1356.
3) (a) Murphy, J. A.; Zhou, S. Z.; Thomson, D. W.;
Schoenebeck, F.; Mahesh, M.; Park, S. R.; Tuttle, T.;
Berlouis, L. E. A. Angew. Chem. Int. Ed. 2007, 46, 5178.
5
(
2
,12-diamine (6), 7,7, N,N,N¢,N¢-hexamethyl-7,8-dihydro-6H-di-
pyrido[1,2-a;2¢,1¢-c][1,4] diazepine-2,12-diamine (26, 1.57 g, 71%)
was obtained as a black, oxygen-sensitive solid. H NMR (400
1
(
b) Taton, T. A.; Chen, P. Angew. Chem., Int. Ed. Engl.
MHz, benzene-d ): d = 0.52 [6 H, s, C(CH ) ], 2.46 [12 H, br s,
6
3 2
1996, 35, 1011.
N(CH ) ], 2.81 (4 H, br s, CH ), 4.85 (2 H, br s, CH), 5.15 (2 H, br
3
2
2
3
(
(
(
(
(
4) Schoenebeck, F.; Murphy, J. A.; Zhou, S. Z.; Uenoyama, Y.;
Miclo, Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368.
5) Murphy, J. A.; Garnier, J.; Park, S. R.; Schoenebeck, F.;
Zhou, S.-Z.; Turner, A. T. Org. Lett. 2008, 10, 1227.
6) Alder, R. W.; Blake, M. E.; Chaker, L.; Harvey, J. N.;
Paolini, F.; Schutz, J. Angew. Chem. Int. Ed. 2004, 43, 5896.
7) Owen, J. S.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc.
1
s, CH), 5.66 (2 H, br s, CH). C NMR (100 MHz, benzene-d ): d =
6
2
1
3.8 (CH ), 30.1 (C), 40.7 (CH ), 64.4 (CH ), 95.8 (CH), 96.2 (CH),
15.9 (C), 140.1 (CH), 143.1 (C).
3 3 2
Compound 30
To a solution of 1,3-bis(N¢,N¢-dimethyl-4-aminopyridinium)pro-
pane diiodide (8, 1.68 g, 3.1 mmol, 1 equiv) in deuterated H O (15
mL) was added Et N (15 mL). The solution was stirred at 80 °C
over 3 d, evaporated, and the residual solid dried at high tempera-
ture under vacuum, providing 1,1¢-(1,3-propanediyl)bis[2,6-dideu-
tero-4(dimethylamino)pyridinium]diiodide (30) (1.68 g, >98%);
2
2004, 126, 8247.
3
8) For discussion of very strong organic electron donors, see:
Porter, W. W. III.; Vaid, T. P.; Rheingold, A. L. J. Am.
Chem. Soc. 2005, 127, 16659.
(
9) Obaid, A. Y.; Soliman, M. S. Spectrochim. Acta, Part A
+
mp (dec.) 250–270 °C. HRMS (ESI ): m/z calcd for C H D I N :
1
7
22 4 2
4
1990, 46, 1779.
+
4
2
17.1448 [M – I]; found: 417.1448 [M – I] . IR (KBr): nmax = 3053,
958, 2952, 2885, 2814, 2262, 1630, 1561, 1525, 1462, 1431, 1368,
Synlett 2008, No. 14, 2127–2131 © Thieme Stuttgart · New York

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