Control of site of lithiation of 3-(Aminomethyl)pyridine derivatives

Article abstract of DOI:10.1055/s-0033-1338547

Lithiation of N-(pyridin-3-ylmethyl)pivalamide, tert-butyl N-(pyridin-3-ylmethyl)carbamate, and N,N-dimethyl-N′-(pyridin-3-ylmethyl) urea with tert-butyllithium (3 equiv) in anhydrous tetrahydrofuran at -78 °C takes place on the nitrogen and on the ring at the 4-position. The dilithium reagents thus obtained react with various electrophiles to give the corresponding substituted derivatives in high yields. On the other hand, regioselective side-chain lithiation occurs with lithium diisopropylamide (3.3 equiv) at -20 to 0 °C. A mixture of ring and side-chain substitution products is obtained with n-butyllithium as the lithium reagent. Treatment of one of the ring-substituted products with trifluoroacetic anhydride in dichloromethane under reflux conditions led to formation of the corresponding 1H-pyrrolo[3,4-c]pyridine in high yield. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0033-1338547

3426▌
PAPER
paper
Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives
Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives
Keith Smith,*a Gamal A. El-Hiti,*b Mohammed B. Alshammari,a,1 Ahmed Fekria,2
a
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20870600; E-mail: smithk13@cardiff.ac.uk
b
Department of Optometry, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia
E-mail: gelhiti@ksu.edu.sa
Received: 16.07.2013; Accepted after revision: 13.09.2013
with various lithium reagents invariably takes place at C3
Abstract: Lithiation of N-(pyridin-3-ylmethyl)pivalamide, tert-bu-
to give the corresponding 3-substituted derivatives after
tyl N-(pyridin-3-ylmethyl)carbamate, and N,N-dimethyl-N′-(pyri-
reactions of the lithium reagents produced with electro-
din-3-ylmethyl)urea with tert-butyllithium (3 equiv) in anhydrous
tetrahydrofuran at –78 °C takes place on the nitrogen and on the ring
philes.29,30
at the 4-position. The dilithium reagents thus obtained react with
various electrophiles to give the corresponding substituted deriva-
CH2 group between the DMG and the pyridine ring.33 It
tives in high yields. On the other hand, regioselective side-chain
Very recently, we have investigated the effect of an extra
was found that lithiation and substitution of derivatives of
lithiation occurs with lithium diisopropylamide (3.3 equiv) at –20 to
N-(pyridin-2-ylmethyl)amine 1 (Z = N, Y = CH2) or N-
(pyridin-4-ylmethyl)amine 1 (Z = CH2, Y = N) provided
easy access to various side chain (methylene) substituted
derivatives 2 in high yields (Scheme 1).33
0 °C. A mixture of ring and side-chain substitution products is ob-
tained with n-butyllithium as the lithium reagent. Treatment of one
of the ring-substituted products with trifluoroacetic anhydride in di-
chloromethane under reflux conditions led to formation of the cor-
responding 1H-pyrrolo[3,4-c]pyridine in high yield.
Key words: directed lithiation, side-chain lithiation, N-(pyridin-3-
ylmethyl)pivalamide, N,N-dimethyl-N′-(pyridin-3-ylmethyl)urea,
tert-butyl N-(pyridin-3-ylmethyl)carbamate
1) t-BuLi (2.2 equiv)
Y
Y
–78 °C, 2 h
2) electrophile
–78 °C, 2 h
H
H
N
R
N
R
Z
Z
O
E
O
3) aq NH4Cl
1
2 (71–99%)
Lithiation of aromatic compounds is an important ap-
proach for modification of such systems.3–5 In our own
studies6 we have investigated selective lithiation of vari-
ous benzyl- and phenylethylamine derivatives and shown
that the site of lithiation depends on any substituent
groups, the nature of the lithium reagent, and the reaction
conditions.7–12 We have applied such processes in the
preparation of substituted heterocycles.13–15
Z = N, Y = CH; Z = CH, Y = N; R = t-Bu, t-BuO, NMe2
Scheme 1 Lithiation of substituted N-(pyridinylmethyl)amines 1
The high selectivity in the lithiation of compounds 1 is
helped by the significant acidity of the CH2 protons as a
result of the ring nitrogen, which enhances side-chain
lithiation over ring lithiation to a greater extent than for
the simple benzyl analogues.33 However, the acidity of the
CH2 group would not be enhanced to the same extent for
the pyridin-3-ylmethylamine derivatives. Therefore, it
was of interest to investigate lithiation of N-(pyridin-3-yl-
methyl)pivalamide, N,N-dimethyl-N′-(pyridin-3-ylmeth-
yl)urea, and tert-butyl N-(pyridin-3-ylmethyl)carbamate.
We now report that lithiation can be controlled to give ei-
ther ring or side-chain substitution, depending on the pro-
tocol used.
Heterocyclic compounds are of great importance since
they represent the core unit of numerous important prod-
ucts.16 However, regioselective lithiation of substituted
pyridines is not always practical due to nucleophilic addi-
tion of alkyllithiums to the azomethine bond, although
success has sometimes been achieved by the use of less
nucleophilic lithium reagents such as lithium
diisopropylamide17–22 and lithium 2,2,6,6-tetramethylpi-
peridide.23–27
The literature records several protocols for α-lithiation
and directed ortho-metalation (DoM) of pyridines and re-
lated heterocycles, depending on the solvent, temperature,
or lithium reagent,28–30 or by the use of additives31 to con-
trol the level of aggregation of the organolithium re-
agent.32 Regioselective lithiation of pyridines containing
directing metalating groups (DMGs) mostly relies on the
position of the DMG. Pyridines containing various DMGs
directly attached to the ring at the C228 or C429 position,
3-Substituted pyridines 4–6 were synthesized, based on a
literature procedure for analogous compounds,9,10 by reac-
tion of 3-(aminomethyl)pyridine (3) with pivaloyl chlo-
O
RCOCl or (RCO)2O
N
R
NH2
H
N
N
3
4 R = t-Bu (94%)
5 R = t-BuO (92%)
6 R = NMe2 (61%)
SYNTHESIS 2013, 45, 3426–3434
Advanced online publication: 09.10.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Scheme 2 Synthesis of N-(pyridin-3-ylmethyl) derivatives 4–6
DOI: 10.1055/s-0033-1338547; Art ID: SS-2013-Z0478-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives
3427
O
OLi
1) n-BuLi
N
H
tBu
N
tBu
n-BuLi, THF
2) Ph2CO, 2 h
3) aq NH4Cl
N
N
4
7
OH
OH
Ph
Ph
O
Ph
Ph
O
Bu
N
O
tBu
tBu
N
H
tBu
N
N
H
H
+
+
N
10
N
9
8
Scheme 3 Lithiation of 4 followed by reaction with benzophenone
ride, di-tert-butyl dicarbonate or dimethylcarbamoyl respectively. The modest selectivity for the ring-substitut-
chloride, respectively (Scheme 2).
ed product, arising from dilithium reagent 13, can be com-
pared with the previously reported highly selective
lithiation of N-(pyridin-3-yl)pivalamide at C4 using n-bu-
tyllithium/N,N,N′,N′-tetramethylethylenediamine.28a
Initially, N-(pyridin-3-ylmethyl)pivalamide (4) was treat-
ed with n-butyllithium (2.2 equiv) in anhydrous tetrahy-
drofuran at –78 °C for two hours to form first the
monolithium compound 7 (Scheme 3) and then perhaps
one or more dilithium species. The mixture was then treat-
ed with benzophenone (2.2 equiv) at –78 °C for two
hours. The crude product was separated by column chro-
matography to give 8 (6%), 9 (27%), and 10 (44%) along
with residual starting material 4 (10%, Scheme 3).
Li
OLi
tBu
Li
OLi
tBu
O
H
Bu
Li
N
tBu
N
N
H
N
N
N
11
12
13
Figure 1 Structures of lithium intermediates 11–13
N-[(4-Butylpyridin-3-yl)methyl]pivalamide (8) presum-
ably results from nucleophilic addition of n-butyllithium
at the 4-position of the pyridine ring to give reagent 11
(Figure 1), followed by aromatization. Substitution prod-
ucts 9 and 10 are produced from reaction of benzophe-
none with dilithium intermediates 12 and 13 (Figure 1),
Several experiments were conducted in which alkyllithi-
um, temperature, and reaction time were varied in an at-
tempt to optimize the yield of 10 (Table 1). The use of n-
butyllithium invariably provided a mixture of 9 (30–9%)
Table 1 Yields of Compounds 8–10 and 14 Formed by Lithiation of 4 under Different Reaction Conditions (Scheme 3)
Entry
RLi (equiv)
Temp (°C)
Time (h)
Yielda (%)
4
8 or 14
9
10
1
2
n-BuLi (2.2)
n-BuLi (3.3)
n-BuLi (3.3)
n-BuLi (3.3)
t-BuLi (3.3)
t-BuLi (3.3)
t-BuLi (3.3)
LDA(3.3)
–78
2
2
2
2
2
2
2
2
4
4
4
6
4
13 (10)b
8 (6)b
30 (27)b
49 (44)b
–78
–
–
59
48
37
–
41
3
–50
–
24
25
4
–20 to 0
–78
–
36
22
5
– (8)b
–
–
96 (88)b
6
–50
22 (20)b
–
64 (63)b
7
–20 to 0
–78
–
53
–
–
32
–
8
96
86
61
28
21
31
–
9
LDA (3.3)
LDA (3.3)
LDA (3.3)
LDA (3.3)
LDA (3.3)
–78
–
11b
34
68
72
63
–
10
11
12
13
–78 to 0
–20 to 0
–20 to 0
0
–
–
–
–
–
–
–
–
a Yield by 1H NMR unless otherwise indicated.
b Yield of isolated material after purification by column chromatography.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3426–3434

3428
K. Smith et al.
PAPER
and 10 (22–49%) along with 8 (0–36%) in most cases (Ta-
ble 1, entries 1–4), based on the H NMR spectra of the
Table 2 Synthesis of Substituted N-(Pyridin-3-ylmethyl)pival-
amides 10 and 15–18
1
crude product mixtures. At higher temperatures nucleo-
philic addition of n-butyllithium competed with lithiation
to a greater extent, but lithiation remained relatively un-
selective, giving both side-chain substitution product 9
(37–48%) and ring-substitution product 10 (22–25%) in
significant amounts.
E
O
O
1) t-BuLi (3.3 equiv)
THF, –78 °C, 2 h
2) electrophile (E+)
THF, r.t., 2 h
tBu
N
tBu
N
H
H
N
N
3) aq NH4Cl
4
10 and 15–18
Entry Product Electrophile
E
Yielda
The more hindered and less aggregated tert-butyllithium
was more selective than n-butyllithium, resulting in prod-
uct mixtures containing only the addition–aromatization
product 14 (Figure 2) and the ring-substituted product 10
(Table 1, entries 5–7). As with n-butyllithium, nucleophil-
ic addition competed more effectively at higher tempera-
tures, but at –78 °C the only product was 10, which could
be isolated in 88% yield (entry 5). Presumably, dilithium
reagent 13 (Figure 1) is the kinetic product at low temper-
ature because the aromatic proton is more appropriately
positioned for directed metalation than those of the CH2
group. If so, use of a reagent that does not lend itself so
readily to complexation by the pivaloylamino group
might favour side-chain lithiation to a greater extent. In-
deed, reaction with lithium diisopropylamide (entries 8–
13) was highly regioselective towards formation of side-
chain substitution product 9, with no evidence for the for-
mation of any other products, and a reasonable yield up to
72% could be obtained following lithiation at –20 to 0 °C
for a relatively long time.
(%)
1
2
3
4
5
10
15
16
17
18
Ph2CO
Ph2C(OH)
Me2C(OH)
88
91
Me2CO
4-MeOC6H4CHO 4-MeOC6H4CH(OH) 89
4-Me2NC6H4CHO 4-Me2NC6H4CH(OH) 85
EtI
Et
90
a Yield of the pure isolated product.
the same way the two phenyl groups of compound 9
showed separated signals.
O
E
O
1) LDA (3.3 equiv)
THF, –20 to 0 °C, 6 h
2) electrophile
N
H
R
N
R
H
THF, r.t., 2 h
3) aq NH4Cl
N
N
4 R = t-Bu
5 R = t-BuO
6 R = NMe2
19 R = t-Bu, E = (CH2)5C(OH) (75%)
26 R = t-BuO, E = Ph2C(OH) (70%)
27 R = NMe2, E = Ph2C(OH) (52%)
tBu
O
tBu
O
Me
tBu
N
N
Scheme 4 Lithiation of 4–6 using lithium diisopropylamide fol-
lowed by reaction with cyclohexanone or benzophenone
N
H
H
Me
N
N
25
14
In the light of the success at controlling lithiation of 4 to
give either ring or side-chain substituted products, atten-
tion was turned to lithiation of tert-butyl N-(pyridin-3-yl-
methyl)carbamate (5) and N,N-dimethyl-N′-(pyridin-3-
ylmethyl)urea (6). Lithiations of both 5 and 6 with tert-bu-
tyllithium (3.3 equiv) under identical conditions to those
used for the ring substitution of 4 (entry 5) also gave main-
ly ring-substituted products. Reactions with several elec-
trophiles (benzophenone, acetophenone, cyclohexanone,
and benzaldehyde) were carried out and the products were
purified by column chromatography (silica gel, EtOAc–
hexane, 1:3) to give the corresponding substituted deriva-
tives 20–24 (Table 3). Yields were very high with the car-
bamate 5, but the yield of product from the single reaction
conducted with the urea 6 was significantly lower (66% of
compound 24, Table 3), at least in part because of compe-
tition from nucleophilic addition, since around 5% of
compound 25 (Figure 2) was isolated from the reaction
mixture. The reason for the increased proportion of side
product with the urea is not clear, but it is likely that the
urea is better at complexing tert-butyllithium than either
the pivalamide or the carbamate.
Figure 2 Structures of compounds 14 and 25
It was of interest to see if the reactions of the dilithium in-
termediates 13 (prepared as in entry 5) and 12 (entry 12)
with other electrophiles would be useful and general. Re-
actions with various electrophiles [acetone, 4-methoxy-
benzaldehyde, 4-(dimethylamino)benzaldehyde, and
iodoethane] were carried out (Table 2) under conditions
identical to those in Table 1, entry 5 and the products were
purified by column chromatography (silica gel, EtOAc–
hexane, 1:3) to give the corresponding substituted deriva-
1
tives 15–18 in excellent yields (Table 2). The H NMR
spectra of compounds 16 and 17 showed that the signals
of the CH2 protons appeared separately, verifying that the
protons are diastereotopic.
To test the generality of the side-chain substitution pro-
cess, cyclohexanone was used as an electrophile. It was
found that lithiation of 4 with lithium diisopropylamide
under the conditions used with benzophenone (Table 1,
entry 12) followed by reaction with cyclohexanone gave
19 (Scheme 4) in 75% yield. The two sides of the cyclo-
hexane ring appeared as separated signals in the 13C NMR
spectrum confirming that they are diastereotopic, and in
Finally, lithiations of 5 and 6 were attempted with lithium
diisopropylamide as the lithium reagent under similar
Synthesis 2013, 45, 3426–3434
© Georg Thieme Verlag Stuttgart · New York

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Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives
3429
OtBu
Table 3 Synthesis of 20–24 via Lithiation and Substitution of 5 and 6
O
E
O
N
N
O
N
TFAA, CH2Cl2
reflux, 12 h
NH
Ph
H
1) t-BuLi (3.3 equiv)
THF, –78 °C, 2 h
2) electrophile,
THF, r.t., 2 h
OH
N
R
N
R
H
H
Ph
Ph
Ph
N
N
20
28 (60%)
20–24
5 R = t-BuO
6 R = NMe2
3) aq NH4Cl
Scheme 5 Synthesis of 1,1-diphenyl-2,3-dihydro-1H-pyrrolo[3,4-
c]pyridine (28)
Entry Products
R
Electrophile
E
Yielda
(%)
the corresponding 4-substituted products in high yields.
On the other hand, the reaction was regioselective towards
the side-chin when lithium diisopropylamide (3.3 equiv)
was used as the lithium reagent at –20 to 0 °C. A mixture
of ring and side-chain substitution products, and also
some product resulting from addition–oxidation, was ob-
tained when n-butyllithium was the lithium reagent.
1
2
3
4
5
20
21
22
23
24
t-BuO
t-BuO
t-BuO
t-BuO
NMe2
Ph2CO
Ph2C(OH)
PhC(OH)Me
88
81
PhCOMe
(CH2)5CO
PhCHO
Ph2CO
(CH2)5C(OH) 80
PhCH(OH)
Ph2C(OH)
84
66b
In one case a product involving a hydroxyalkyl group on
a ring position adjacent to the acylaminomethyl group has
been shown to cyclize to a pyrrolopyridine derivative un-
der the influence of trifluoroacetic anhydride.
a Yield of the pure isolated product.
b Compound 25 (Figure 2), due to the addition of t-BuLi at C4 of 6
followed by aromatization, was isolated in 5% yield.
conditions to those used for the side-chain lithiation of 4
(Table 1, entry 12) in an attempt to produce analogous
side-chain substitution products. Indeed, lithiations of 5
and 6 with lithium diisopropylamide followed by reac-
tions with benzophenone as a representative electrophile
gave the corresponding side-chain substitution products
Melting point determinations were performed by the open capillary
method using a Gallenkamp melting point apparatus and are report-
ed uncorrected. 1H and 13C NMR spectra were recorded on a Bruker
AV500 spectrometer operating at 500 MHz (1H) and 125 MHz (13C)
relative to TMS; 13C multiplicities were revealed by DEPT signals.
Assignments of signals are based on integration values, coupling
patterns and expected chemical shift values and have not been rig-
26 and 27 in 70% and 52% yields, respectively (Scheme orously confirmed. Signals with similar characteristics might be in-
terchanged. LR-MS were recorded on a Waters GCT Premier
spectrometer and accurate mass data were recorded on a Waters
LCT Premier XE instrument. IR spectra were recorded on a Perkin
Elmer Spectrum One FT-IR spectrophotometer as thin films (liq-
4) along with recovered starting materials 5 (23%) and 6
(38%). There was no evidence for the production of a sig-
nificant amount of ring-substituted product and the mod-
est yields of side-chain substituted products, particularly
uids) or KBr discs (solids). Microanalysis was performed by War-
from the urea, presumably reflect either slow deproton-
ation or less favourable equilibrium concentrations of the
corresponding organolithium species. Among the piva-
lamide, carbamate, and urea derivatives, it would be ex-
pected that the urea would provide least stabilization of a
negative charge on the side chain.
wick analytical service at the University of Warwick. Column
chromatography was carried out using Fischer Scientific silica 60A
(35–70 μm). Alkyllithiums were obtained from Aldrich Chemical
Company and were estimated prior to use by the method of Watson
and Eastham.34 Other chemicals were obtained from Aldrich Chem-
ical Company and used without further purification.
N-(Pyridin-3-ylmethyl)pivalamide (4)
We have previously shown that ortho-(hydroxyalkyl)ben-
zylamine derivatives can be cyclized to isoindolines on
treatment with trifluoroacetic anhydride13and it was of in-
terest to know whether the same reaction would be effec-
tive with these aza analogues. Therefore, 20 was treated
with trifluoroacetic anhydride under reflux for 12 hours
and gave 28 in 60% yield (Scheme 5) after purification by
column chromatography. Clearly, cyclization of 20 via
dehydration had taken place, along with hydrolysis of the
carbamate group, to produce 1,1-diphenyl-2,3-dihydro-
1H-pyrrolo[3,4-c]pyridine (28).
To a cooled solution (0 °C) of 3-(aminomethyl)pyridine (3, 4.32 g,
40.0 mmol) and Et3N (6.10 g, 60.0 mmol) in CH2Cl2 (50 mL), piv-
aloyl chloride (5.80 g, 48.0 mmol) was slowly added in a dropwise
manner over 30 min. The mixture was stirred at 0 °C for 1 h and
poured into H2O (50 mL). The organic layer was separated, washed
with H2O (2 × 50 mL), and dried (MgSO4), and the solvent was re-
moved under reduced pressure. The crude product was separated by
column chromatography (silica gel, EtOAc–hexane; 1:3) to give
pure 4; (7.22 g, 37.6 mmol, 94%) as a colourless oil.
FT-IR: 3340, 2966, 1651, 1593, 1481, 1324, 1259, 1207, 1121 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.41–8.39 (m, 2 H, H2, H6), 7.52
(d, J = 8 Hz, 1 H, H4), 7.17 (dd, J = 5, 8 Hz, 1 H, H5), 6.37 (br,
exch., 1 H, NH), 4.36 (d, J = 6 Hz, 2 H, CH2), 1.15 [s, 9 H,
C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 178.6 (s, C=O), 148.9 (d, C2),
148.7 (d, C6), 135.3 (s, C3), 134.5 (d, C4), 123.6 (d, C5), 40.9 (t,
CH2), 38.7 [s, C(CH3)3], 27.6 [q, C(CH3)3].
In conclusion, two independent, convenient, and simple
experimental procedures have been developed for the pro-
duction of ring and side-chain substitution products of
various 3-(acylaminomethyl)pyridines. Ring lithiation
has been achieved by the use of tert-butyllithium (3.3
equiv) at –78 °C. The dilithium reagents produced in situ
MS (APCI): m/z (%) = 193 (100, [M + H]+).
were allowed to react with various electrophiles to give HRMS (APCI): m/z [M + H]+ calcd for C11H17N2O: 193.1341;
found: 193.1332.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3426–3434

3430
K. Smith et al.
PAPER
tert-Butyl N-(Pyridin-3-ylmethyl)carbamate (5)
1H NMR (500 MHz, CDCl3): δ = 8.37 (d, J = 5 Hz, 1 H, H6), 8.36
(s, 1 H, H2), 7.06 (d, J = 5 Hz, 1 H, H5), 5.72 (br, exch., 1 H, NH),
4.42 (d, J = 5 Hz, 2 H, CH2NH), 2.56 (t, J = 7 Hz, 2 H,
CH3CH2CH2CH2), 1.51 (m, 2 H, CH3CH2CH2), 1.33 (m, 2 H,
CH3CH2), 1.15 [s, 9 H, C(CH3)3], 0.87 (t, J = 7 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): δ = 178.0 (s, C=O), 149.6 (d, C2),
148.9 (d, C6), 140.6 (s, C4), 131.8 (s, C3), 124.2 (d, C5), 38.8 (t,
CH2NH), 38.7 [s, C(CH3)3], 32.3 [t, CH3CH2CH2], 31.5 (t,
CH3CH2CH2CH2), 27.6 [q, C(CH3)3], 22.6 (t, CH3CH2), 13.8 (q,
CH3).
MS (EI): m/z (%) = 248 (53, [M]+), 206 (25), 149 (29), 106 (23), 85
(100), 57 (24).
HRMS (EI): m/z [M]+ calcd for C15H24N2O: 248.1889; found:
248.1894.
To a cooled solution (0 °C) of 3-(aminomethyl)pyridine (3, 4.32 g,
40.0 mmol) and Et3N (6.10 g, 60.0 mmol) in CH2Cl2 (50 mL),
(Boc)2O (10.50 g, 48.0 mmol) was slowly added in a dropwise man-
ner over 30 min. The mixture was stirred at 0 °C for 1 h and poured
into H2O (100 mL). The organic layer was separated, washed with
H2O (2 × 50 mL), and dried (MgSO4), and the solvent was removed
under reduced pressure. The crude product was separated by col-
umn chromatography (silica gel, EtOAc–hexane; 1:3) to give pure
5 (7.70 g, 37.0 mmol, 92%) as a colourless oil.
FT-IR: 3352, 2980, 1707, 1579, 1431, 1367, 1249, 1218, 1165 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.19 (s, 1 H, H2), 8.13 (d, J = 5
Hz, 1 H, H6), 7.34 (d, J = 8 Hz, 1 H, H4), 6.93 (dd, J = 5, 8 Hz, 1
H, H5), 6.45 (br, exch., 1 H, NH), 4.01 (d, J = 6 Hz, 2 H, CH2), 1.16
[s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 156.2 (s, C=O), 148.5 (d, C2),
148.0 (d, C6), 135.0 (s, C3), 134.9 (d, C4), 123.2 (d, C5), 79.0 [s,
C(CH3)3], 41.8 (t, CH2), 28.2 [q, C(CH3)3].
MS (EI): m/z (%) = 208 (5, [M]+), 152 (30), 135 (20), 107 (68), 80
(100).
N-[2-Hydroxy-2,2-diphenyl-1-(pyridine-3-yl)ethyl]pivalamide
(9)
Table 1, entry 12; reagents: LDA, benzophenone; white solid; yield:
0.54 g (1.44 mmol, 72%); mp 222–224 °C.
FT-IR: 3434, 2932, 1652, 1558, 1423, 1336, 1213, 1025 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.47 (s, 1 H, H2), 7.88 (d, J = 5
Hz, 1 H, H6), 7.57 (d, J = 8 Hz, 1 H, H4), 7.38–6.99 (m, 10 H, 10
HPh), 6.90 (dd, J = 5, 8 Hz, 1 H, H5), 5.96 (d, J = 6 Hz, 1 H, CH),
5.22 (br, exch., 1 H, OH), 4.43 (d, J = 6 Hz, 1 H, NH), 0.99 [s, 9 H,
C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 177.7 (s, C=O), 149.4 (d, C2),
147.4 (d, C6), 144.6, 144.1 (2 s, C1Ph), 137.2 (d, C4), 135.0 (s, C3),
128.4, 128.1 (2 d, C3Ph/C5Ph), 127.4, 127.2 (2 d, C4Ph), 126.2, 125.9
(2 d, C2Ph/C6Ph), 122.5 (d, C5), 80.8 (s, COH), 57.7 (d, CH), 38.6
[s, C(CH3)3], 27.2 [q, C(CH3)3].
HRMS (EI): m/z [M]+ calcd for C11H16N2O2: 208.1212; found:
208.1207.
N,N-Dimethyl-N′-(pyridin-3-ylmethyl)urea (6)
To a cooled solution (0 °C) of 3-(aminomethyl)pyridine (3, 4.32 g,
40.0 mmol) and Et3N (6.10 g, 60.0 mmol) in CH2Cl2 (50 mL), di-
methylcarbamoyl chloride (5.20 g, 48.0 mmol) was slowly added in
a dropwise manner over 30 min. The mixture was stirred at r.t. for
1 h and poured into H2O (100 mL). The organic layer was separated,
washed with H2O (2 × 50 mL), and dried (MgSO4), and the solvent
was removed under reduced pressure. The crude product was sepa-
rated by column chromatography (silica gel, EtOAc–hexane; 1:3) to
give 6 (4.37 g, 24.4 mmol, 61%) as a reddish oil.
MS (APCI): m/z (%) = 416 (40, [M + MeCN + H]+), 375 (100, [M
+ H]+), 234 (30), 193 (35), 126 (30).
HRMS (APCI): m/z [M + H]+ calcd for C24H27N2O2: 375.2073;
found: 375.2079.
FT-IR: 3335, 2929, 1633, 1537, 1427, 1378, 1234, 1033 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.48–8.42 (m, 2 H, H2, H6), 7.70
(d, J = 8 Hz, 1 H, H4), 7.21 (dd, J = 5, 8 Hz, 1 H, H5), 5.07 (br,
exch., 1 H, NH), 4.36 (d, J = 6 Hz, 2 H, CH2), 2.85 [s, 6 H,
N(CH3)2].
13C NMR (125 MHz, CDCl3): δ = 158.3 (s, C=O), 148.7 (d, C2),
148.0 (d, C6), 136.1 (s, C3), 136.0 (d, C4), 123.7 (d, C5), 42.4 (t,
CH2), 36.3 [q, N(CH3)2].
Anal. Calcd for C24H26N2O2: C, 76.98; H, 7.00. Found: C, 76.8; H,
7.0.
N-{[4-(Hydroxydiphenylmethyl)pyridin-3-yl]methyl}pival-
amide (10)
Table 1, entry 5; reagents: t-BuLi, benzophenone; white solid;
yield: 0.72 g (1.92 mmol, 96%); mp 211–213 °C.
MS (EI): m/z (%) = 179 (100, [M]+), 135 (40), 107 (45).
FT-IR: 3381, 2984, 1640, 1546, 1425, 1240, 1017 cm–1.
HRMS (EI): m/z [M]+ calcd for C9H13N3O: 179.1059; found:
179.1057.
1H NMR (500 MHz, CDCl3): δ = 8.68 (s, 1 H, H2), 8.32 (d, J = 5
Hz, 1 H, H6), 7.38–7.28 (m, 11 H, 10 HPh, OH), 6.72 (br t, J = 6 Hz,
exch., 1 H, NH), 6.68 (d, J = 5 Hz, 1 H, H5), 4.20 (d, J = 6 Hz, 2 H,
CH2), 1.13 [s, 9 H, C(CH3)3].
Lithiation and Substitution of 4–6; General Procedure
A 1.6 M solution of n-BuLi in hexane (2.75 mL, 4.4 mmol), 1.9 M
t-BuLi in pentane (3.47 mL, 6.6 mmol), or 2.0 M LDA in a mixture
of THF, heptane, and ethylbenzene (3.30 mL, 6.6 mmol) was added
to a cold (–78 °C), stirred solution of 4, 5, or 6 (2.0 mmol) in anhyd
THF (15 mL) under N2. The mixture was stirred at –78 °C for 2 h
with n-BuLi or t-BuLi, or at –20 to 0 °C for 6 h with LDA, to ensure
the complete formation of the appropriate dilithium reagent(s) after
which an electrophile (4.4 mmol) [in anhyd THF (3 mL) if solid,
otherwise neat] was added. The mixture was stirred for 2 h and al-
lowed to warm up to r.t. It was then quenched with sat. aq NH4Cl
(10 mL). The organic layer was separated, washed with H2O (2 × 10
mL), dried (MgSO4), and evaporated under reduced pressure. The
crude mixture obtained was separated by column chromatography
(silica gel, EtOAc–hexane, 1:3) to give pure products.
13C NMR (125 MHz, CDCl3): δ = 179.0 (s, C=O), 151.2 (d, C2),
147.1 (d, C6), 146.8 (s, C4), 146.0 (s, 2 C1Ph), 134.4 (s, C3), 128.3
(d, 2 C3Ph/C5Ph), 127.6 (d, 2 C4Ph), 127.5 (d, 2 C2Ph/C6Ph), 124.1 (d,
C5), 81.7 (s, COH), 39.9 (t, CH2), 38.5 [s, C(CH3)3], 27.4 [q,
C(CH3)3].
MS (EI): m/z (%) = 374 (10, [M]+), 358 (50), 255 (100), 179 (95).
HRMS (EI): m/z [M]+ calcd for C24H26N2O2: 374.1994; found:
374.1989.
N-[(4-tert-Butylpyridin-3-yl)methyl]pivalamide (14)
Table 1, entry 6; colourless oil; yield: 0.10 g (0.40 mmol, 20%).
FT-IR: 3337, 2988, 1639, 1539, 1419, 1239, 1013 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.43 (s, 1 H, H2), 8.36 (d, J = 5
Hz, 1 H, H6), 7.25 (d, J = 5 Hz, 1 H, H5), 5.91 (br, exch., 1 H, NH),
4.61 (d, J = 5 Hz, 2 H, CH2), 1.36 [s, 9 H, C(CH3)3], 1.09 [s, 9 H,
C(CH3)3].
N-[(4-Butylpyridin-3-yl)methyl]pivalamide (8)
Table 1, entry 1; colourless oil; yield: 0.030 g (0.12 mmol, 6%).
FT-IR: 3339, 2958, 1642, 1597, 1412, 1208, 1010 cm–1.
Synthesis 2013, 45, 3426–3434
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Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives
3431
13C NMR (125 MHz, CDCl3): δ = 178.2 (s, C=O), 158.0 (s, C4),
151.0 (d, C2), 148.2 (d, C6), 132.6 (s, C3), 121.2 (d, C5), 40.5 (t,
CH2), 38.7 [s, C(CH3)3], 35.9 [s, C(CH3)], 30.7 [q, C(CH3)3], 27.5
[q, C(CH3)3].
MS (ES+): m/z (%) = 341 (100, [M]+), 329 (58), 193 (10).
HRMS (ES+): m/z [M]+ calcd for C20H27N3O2: 341.2103; found:
341.2107.
MS (EI): m/z (%) = 248 (25, [M]+), 191 (33), 148 (15), 117 (15),
101 (84), 83 (100), 68 (68), 57 (96).
HRMS (EI): m/z [M]+ calcd for C15H24N2O: 248.1889; found:
N-[(4-Ethylpyridin-3-yl)methyl]pivalamide (18)
Reagents: t-BuLi, EtI; colourless oil; yield: 0.40 g (1.8 mmol, 90%).
FT-IR: 3338, 2967, 1642, 1529, 1208, 1010 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.38–8.28 (m, 2 H, H2, H6), 7.11
(d, J = 5 Hz, 1 H, H5), 5.86 (br, exch., 1 H, NH), 4.43 (d, J = 6 Hz,
2 H, CH2), 2.62 (q, J = 7 Hz, 2 H, CH3CH2), 1.18 (t, J = 7 Hz, 3 H,
CH3CH2), 1.15 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 178.1 (s, C=O), 152.1 (s, C4),
149.2 (d, C2), 148.8 (d, C6), 131.9 (s, C3), 123.5 (d, C5), 38.79 [s,
C(CH3)3], 38.77 (t, CH2), 27.6 [q, C(CH3)3], 24.7 (t, CH3CH2), 14.0
(q, CH3CH2).
MS (EI): m/z (%) = 220 (42, [M]+), 163 (14), 135 (15), 120 (59),
107 (20), 83 (100), 77 (10), 57 (41).
HRMS (EI): m/z [M]+ calcd for C13H20N2O: 220.1576; found:
220.1574.
248.1891.
N-{[4-(2-Hydroxypropan-2-yl)pyridin-3-yl]methyl}pivalamide
(15)
Reagents: t-BuLi, acetone; colourless oil; yield: 0.45 g (1.8 mmol,
91%).
FT-IR: 3351, 2989, 1648, 1542, 1427, 1233, 1018 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.47 (s, 1 H, H2), 8.37 (d, J = 5
Hz, 1 H, H6), 7.10 (d, J = 5 Hz, 1 H, H5), 6.48 (br, exch., 1 H, NH),
4.69 (d, J = 5 Hz, 2 H, CH2), 3.36 (s, exch., 1 H, OH), 1.59 [s, 6 H,
C(CH3)2], 1.09 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 177.8 (s, C=O), 152.9 (s, C4),
150.6 (d, C2), 148.9 (d, C6), 136.4 (s, C3), 125.1 (d, C5), 73.9 (s,
C–OH), 40.3 (t, CH2), 38.6 [s, C(CH3)3], 32.1 [q, C(CH3)2], 27.5 [q,
C(CH3)3].
MS (EI): m/z (%) = 232 (50, [M – H2O]+), 217 (73), 192 (100), 174
(94), 147 (97), 118 (99), 107 (88), 92 (98), 83 (65), 65 (67).
HRMS (EI): m/z [M – H2O]+ calcd for C14H20N2O: 232.1576;
found: 232.1581.
N-[(1-Hydroxycyclohexyl)(pyridin-3-yl)methyl]pivalamide (19)
Reagents: LDA, cyclohexanone; colourless oil; yield: 0.44 g (1.5
mmol, 75%).
FT-IR: 3351, 2962, 1642, 1560, 1421, 1333, 1209, 1019 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.55 (s, 1 H, H2), 8.40 (br, 1 H,
H6), 7.60 (d, J = 8 Hz, 1 H, H4), 7.21 (br, exch., 1 H, OH), 6.75 (d,
J = 8 Hz, 1 H, H5), 6.58 (br, exch., 1 H, NH), 4.77 (d, J = 8 Hz, 1
H, CH), 1.80–1.50 (m, 10 H, 10 HCy), 1.14 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 177.5 (s, C=O), 149.2 (d, C2),
148.3 (d, C6), 136.3 (s, C3), 133.1 (d, C4), 123.3 (d, C5), 73.2 (s,
C1Cy), 63.4 (d, CH), 40.8 [s, C(CH3)3], 35.9, 35.4 (2 t, C2Cy/C6Cy),
27.5 [q, C(CH3)3], 25.3 (t, C4Cy), 21.9, 21.5 (2 t, C3Cy/C5Cy).
N-({4-[Hydroxy(4-methoxyphenyl)methyl]pyridin-3-yl}meth-
yl)pivalamide (16)
Reagents: t-BuLi, 4-methoxybenzaldehyde; colourless oil; yield:
0.58 g (1.8 mmol, 89%).
FT-IR: 3331, 2986, 1644, 1542, 1424, 1243, 1011 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.45–8.41 (m, 2 H, H2, H6), 7.40
(d, J = 5 Hz, 1 H, H5), 7.17 (d, J = 9 Hz, 2 H, H2Ar, H6Ar), 6.81 (d,
J = 9 Hz, 2 H, H3Ar, H5Ar), 7.87 (app. t, exch., J = 6 Hz, 1 H, NH),
5.96 (br, 1 H, CHOH), 4.48 (dd, J = 6, 15 Hz, 1 H, CH2), 4.38 (d,
J = 6 Hz, 1 H, OH), 4.13 (dd, J = 6, 15 Hz, 1 H, CH2), 3.73 (s, 3 H,
OCH3), 1.03 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 178.5 (s, C=O), 159.6 (s, C4Ar),
150.0 (d, C2), 147.6 (d, C6), 146.0 (s, C4), 133.8 (s, C1Ar), 131.6 (s,
C3), 128.4 (d, C2Ar/C6Ar), 122.4 (d, C5), 114.3 (d, C2Ar/C6Ar), 72.1
(d, CHOH), 55.3 (q, OCH3), 38.6 [s, C(CH3)3], 38.4 (t, CH2), 27.4
[q, C(CH3)3].
MS (EI): m/z (%) = 327 (10, [M – H]+), 267 (7), 223 (100), 118 (98),
77 (94).
HRMS (EI): m/z [M – H]+ calcd for C19H23N2O3: 327.1709; found:
327.1707.
MS (EI): m/z (%) = 290 (33, [M]+), 217 (55), 192 (100), 171 (91),
150 (55), 107 (99), 93 (96), 83 (98).
HRMS (EI): m/z [M]+ calcd for C17H26N2O2: 290.1994; found:
290.1993.
tert-Butyl N-{[4-(Hydroxydiphenylmethyl)pyridin-3-yl]meth-
yl}carbamate (20)
Reagents: t-BuLi, benzophenone; white solid; yield: 0.69 g (1.77
mmol, 88%); mp 215–217 °C.
FT-IR: 3447, 2980, 1692, 1591, 1445, 1369, 1214, 1076 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 8.45 (s, 1 H, H2), 8.34 (d, J = 5
Hz, 1 H, H6), 7.38 (s, exch., 1 H, OH), 7.36 (app. t, J = 8 Hz, 4 H,
H3Ph/H5Ph), 7.31 (t, J = 8 Hz, 2 H, H4Ph), 7.19 (d, J = 8 Hz, 4 H,
H2Ph/H6Ph), 6.89 (br, exch., 1 H, NH), 6.54 (d, J = 5 Hz, 1 H, H5),
4.07 (d, J = 6 Hz, 2 H, CH2), 1.38 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, DMSO-d6): δ = 156.2 (s, C=O), 152.9 (s,
C1Ph), 150.0 (d, C2), 148.1 (d, C6), 146.2 (s, C4), 134.4 (s, C3),
128.4 (d, 2 C3Ph/C5Ph), 127.9 (d, 2 C2Ph/C6Ph), 127.7 (d, 2 C4Ph),
123.4 (d, C5), 81.7 (s, COH), 78.5 [s, C(CH3)3], 40.6 (t, CH2), 28.7
[q, C(CH3)3].
N-[(4-{[4-(Dimethylamino)phenyl](hydroxy)methyl}pyridin-3-
yl)methyl]pivalamide (17)
Reagents: t-BuLi, 4-(dimethylamino)benzaldehyde; colourless oil;
yield: 0.58 g (1.7 mmol, 85%).
FT-IR: 3328, 2977, 1640, 1589, 1429, 1248, 1015 cm–1.
MS (APCI): m/z (%) = 432 (5, [M + MeCN + H]+), 391 (100, [M +
1H NMR (500 MHz, CDCl3): δ = 8.37 (d, J = 5 Hz, 1 H, H6), 8.31
(s, 1 H, H2), 7.43 (d, J = 5 Hz, 1 H, H5), 7.06 (d, J = 9 Hz, 2 H,
H2Ar, H6Ar), 6.59 (d, J = 9 Hz, 2 H, H3Ar, H5Ar), 5.84 (app. t, exch.,
J = 6 Hz, 1 H, NH), 5.83 (s, 1 H, CHOH), 4.45 (dd, J = 6, 15 Hz, 1
H, CH2), 4.37 (br, 1 H, OH), 4.02 (dd, J = 6, 15 Hz, 1 H, CH2), 2.84
[s, 6 H, N(CH3)2], 0.95 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 178.2 (s, C=O), 150.6 (d, C2),
150.4 (s, C4Ar), 149.0 (d, C6), 135.5 (s, C3), 131.2 (s, C1Ar), 128.2
(d, C2Ar/C6Ar), 121.5 (d, C5), 112.6 (d, C3Ar/C5Ar), 72.2 (d, CHOH),
40.4 [q, N(CH3)2], 38.5 [s, C(CH3)3], 38.4 (t, CH2), 27.4 [q,
C(CH3)3].
H]+), 115 (8).
HRMS (APCI): m/z [M + H]+ calcd for C24H27N2O3: 391.2022;
found: 391.2017.
Anal. Calcd for C24H26N2O3: C, 73.82; H, 6.71. Found: C, 73.7; H,
6.8.
tert-Butyl N-{[4-(1-Hydroxy-1-phenylethyl)pyridin-3-yl]meth-
yl}carbamate (21)
Reagents: t-BuLi, acetophenone; colourless oil; yield: 0.53 g (1.62
mmol, 81%).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3426–3434

3432
K. Smith et al.
PAPER
FT-IR: 3352, 2979, 1686, 1581, 1449, 1391, 1267, 1166 cm–1.
C3Ph/C5Ph), 127.6 (d, C2Ph/C6Ph), 127.2 (d, C4Ph), 124.0 (d, C5),
81.3 (s, COH), 41.1 (t, CH2), 36.2 [q, N(CH3)2].
MS (EI): m/z (%) = 361 (10, [M]+), 343 (70).
HRMS (EI): m/z [M]+ calcd for C22H23N3O2: 361.1790; found:
361.1790.
1H NMR (500 MHz, CDCl3): δ = 8.36 (s, 1 H, H2), 8.30 (d, J = 5
Hz, 1 H, H6), 7.79 (d, J = 8 Hz, 2 H, H2Ph/H6Ph), 7.49–7.27 (m, 4
H, H3Ph/H5Ph/H4Ph, OH), 7.07 (d, J = 5 Hz, 1 H, H5), 6.20 (br,
exch., 1 H, NH), 4.17 (app. d, J = 6 Hz, 2 H, CH2), 2.42 (s, 3 H,
CH3), 1.31 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 156.1 (s, C=O), 148.7 (d, C2),
148.1 (d, C6), 136.9 (s, C4), 135.1 (s, C1Ph), 134.9 (s, C3), 132.9 (d,
C4Ph), 128.4 (d, C3Ph/C5Ph), 128.1 (d, C2Ph/C6Ph), 123.3 (d, C5),
79.1 (s, COH), 77.4 [s, C(CH3)3], 41.9 (t, CH2), 28.2 [q, C(CH3)3],
26.3 (q, CH3).
MS (EI): m/z (%) = 313 (5, [M – CH3]+), 271 (10), 210 (60), 195
(100), 180 (60), 133 (85), 83 (95).
N′-[(4-tert-Butylpyridin-3-yl)methyl]-N,N-dimethylurea (25)
Byproduct from the preparation of 24; colourless oil; yield: 0.024 g
(0.10 mmol, 5%).
FT-IR: 3341, 2972, 1632, 1521, 1469, 1230, 1023 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.56 (s, 1 H, H2), 8.33 (d, J = 5
Hz, 1 H, H6), 7.28 (d, J = 5 Hz, 1 H, H5), 4.85 (br, exch., 1 H, NH),
4.62 (d, J = 5 Hz, 2 H, CH2), 2.85 [s, 6 H, N(CH3)2] 1.38 [s, 9 H,
C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 158.4 (s, C4), 156.7 (s, C=O),
150.2 (d, C2), 147.0 (d, C6), 128.5 (s, C3), 121.4 (d, C5), 41.7 (t,
CH2), 36.5 [q, N(CH3)2], 36.1 [s, C(CH3)3], 30.7 [q, C(CH3)3].
HRMS: m/z [M – CH3]+ calcd for C18H21N2O3: 313.1552; found:
313.1555.
tert-Butyl N-{[4-(1-Hydroxycyclohexyl)pyridin-3-yl]meth-
yl}carbamate (22)
Reagents: t-BuLi, cyclohexanone; colourless oil; yield: 0.49 g (1.6
mmol, 80%).
MS (ES+): m/z (%) = 493 (21, [2 M + Na]+), 299 (49, [M + MeCN
+ Na]+), 236 (100, [M + H]+), 191 (5).
HRMS (ES+): m/z [M + H]+ calcd for C13H22N3O: 236.1763; found:
236.1765.
FT-IR: 3347, 2979, 1700, 1579, 1449, 1367, 1280, 1252, 1167 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.36 (s, 1 H, H2), 8.32 (d, J = 5
Hz, 1 H, H6), 7.50 (d, J = 5 Hz, 1 H, H5), 7.11 (br, exch., 1 H, OH),
5.98 (br, exch., 1 H, NH), 4.18 (d, J = 6 Hz, 2 H, CH2), 2.25–1.44
(m, 10 H, 10 HCy), 1.32 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 156.1 (s, C=O), 148.7 (d, C2),
148.2 (d, C6), 135.2 (s, C4), 134.9 (s, C3), 123.4 (d, C5), 79.4 [s,
C(CH3)3], 71.9 (s, C1Cy), 43.7 (t, CH2), 38.0 (t, C2Cy/C6Cy), 28.2 [q,
C(CH3)3], 25.8 (t, C4Cy), 21.5 (t, C3Cy/C5Cy).
MS (ES): m/z (%) = 307 (100, [M + H]+), 250 (43), 209 (68), 194
(35), 153 (20).
HRMS: m/z [M + H]+ calcd for C17H27N2O3: 307.2022; found:
tert-Butyl N-[2-Hydroxy-2,2-diphenyl-1-(pyridin-3-yl)eth-
yl]carbamate (26)
Reagents: LDA, benzophenone; colourless oil; yield: 0.55 g (1.4
mmol, 70%).
FT-IR: 3357, 2931, 1693, 1541, 1423, 1374, 1224, 1061 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.21 (br, 2 H, H2/H6), 7.48 (d,
J = 8 Hz, 2 H, H2Ph/H6Ph), 7.30 (t, J = 8 Hz, 2 H, H3Ph/H5Ph), 7.26–
7.20 (m, 3 H, H4, H2Ph/H6Ph), 7.07–7.00 (m, 5 H, H5, H3Ph/H5Ph, 2
H4Ph), 6.94 (br, exch., 1 H, OH), 5.66 (d, J = 8 Hz, 1 H, CH), 5.59
(br, exch., 1 H, NH), 1.27 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 159.9 (s, C=O), 149.9 (d, C2),
148.1 (d, C6), 144.3, 144.0 (2 s, 2 C1Ph), 141.3 (s, C3), 138.0 (d,
C4), 128.5, 128.1 (2 d, 2 C3Ph/C5Ph), 127.5, 127.2 (2 d, 2 C4Ph),
126.3, 125.7 (2 d, 2 C2Ph/C6Ph), 122.0 (d, C5), 90.4 (s, COH), 81.4
[s, C(CH3)3], 58.5 (d, CH), 28.3 [q, C(CH3)3].
MS (APCI): m/z (%) = 391 (8, [M + H]+), 193 (8), 124 (28), 83
(100).
307.2014.
tert-Butyl N-({4-[Hydroxy(phenyl)methyl]pyridin-3-yl)meth-
yl}carbamate (23)
Reagents: t-BuLi, benzaldehyde; colourless oil; yield: 0.53 g (1.69
mmol, 84%).
FT-IR: 3344, 2969, 1688, 1580, 1454, 1388, 1265, 1161 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.36 (d, J = 5 Hz, 1 H, H6), 8.33
(s, 1 H, H2), 7.29–7.19 (m, 7 H, H5, HPh, OH), 5.96 (s, 1 H, CHOH),
4.97 (br, exch., 1 H, NH), 4.27 (br d, J = 14 Hz, 1 H, CH2), 4.06 (dd,
J = 5, 14 Hz, 1 H, CH2), 1.33 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): δ = 155.8 (s, C=O), 150.5 (d, C2),
149.1 (d, C6), 150.3 (s, C4), 141.7 (s, C1Ph), 131.6 (s, C3), 128.8 (d,
C3Ph/C5Ph), 128.0 (d, C4Ph), 127.0 (d, C2Ph/C6Ph), 122.0 (d, C5),
80.0 [s, C(CH3)3], 72.2 (d, CHOH), 39.6 (t, CH2), 28.4 [q, C(CH3)3].
HRMS (APCI): m/z [M + H]+ calcd for C24H27N2O3: 391.2022;
found: 391.2016.
N′-[2-Hydroxy-2,2-diphenyl-1-(pyridin-3-yl)ethyl]-N,N-di-
methylurea (27)
Reagents: LDA, benzophenone; white solid; yield: 0.38 g (1.05
mmol, 52%); mp 203–205 °C.
FT-IR: 3366, 2927, 1623, 1522, 1448, 1380, 1214, 1064 cm–1.
MS (APCI): m/z (%) = 315 (100, [M + H]+), 259 (22), 209 (9), 153
(7).
HRMS (APCI): m/z [M + H]+ calcd for C18H23N2O3: 315.1709;
found: 315.1702.
1H NMR (500 MHz, CDCl3): δ = 8.54 (s, 1 H, H2), 7.96 (d, J = 5
Hz, 1 H, H6), 7.52 (d, J = 8 Hz, 1 H, H4), 7.31–6.86 (m, 11 H, 10
HPh, OH), 7.01 (dd, J = 5, 8 Hz, 1 H, H5), 5.82 (br, exch., 1 H, NH),
5.76 (d, J = 6 Hz, 1 H, CH), 2.64 [s, 6 H, N(CH3)2].
13C NMR (125 MHz, CDCl3): δ = 157.4 (s, C=O), 149.2 (d, C2),
146.6 (d, C6), 144.7, 144.4 (2 s, 2 C1Ph), 137.8 (s, C3), 136.4 (d,
C4), 128.5, 128.0 (2 d, 2 C3Ph/C5Ph), 127.3, 127.1 (2 d, 2 C4Ph),
126.5, 125.8 (2 d, 2 C2Ph/C6Ph), 122.6 (d, C5), 80.9 (s, COH), 59.4
(d, CH), 36.1 [q, N(CH3)2].
MS (APCI): m/z (%) = 362 (100, [M + H]+), 120 (65).
HRMS (APCI): m/z [M + H]+ calcd for C22H24N3O2: 362.1869;
N′-{[4-(Hydroxydiphenylmethyl)pyridin-3-yl]methyl}-N,N-di-
methylurea (24)
Reagents: t-BuLi, benzophenone; white solid; yield: 0.48 g (1.32
mmol, 66%); mp 219–221 °C.
FT-IR: 3583, 2965, 1638, 1524, 1476, 1376, 1218, 1028 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.58 (s, 1 H, H2), 8.26 (d, J = 5
Hz, 1 H, H6), 7.33–7.28 (m, 11 H, 10 HPh, OH), 6.59 (d, J = 5 Hz,
1 H, H5), 5.38 (t, J = 6 Hz, exch., 1 H, NH), 4.12 (d, J = 6 Hz, 2 H,
CH2), 2.82 [s, 6 H, N(CH3)2].
13C NMR (125 MHz, CDCl3): δ = 158.6 (s, C=O), 153.6 (s, C4),
152.1 (d, C2), 147.8 (d, C6), 146.7 (s, C1Ph), 134.6 (s, C3), 128.1 (d,
found: 362.1874.
1,1-Diphenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (28)
A mixture of TFAA (0.50 mL, 3.60 mmol), 20 (0.50 g, 1.28 mmol),
and CH2Cl2 (10 mL) was heated under reflux for 12 h. The mixture
was quenched with H2O (10 mL). The organic layer was separated,
Synthesis 2013, 45, 3426–3434
© Georg Thieme Verlag Stuttgart · New York

PAPER
Control of Site of Lithiation of 3-(Aminomethyl)pyridine Derivatives
3433
washed with aq sat. NaHCO3 (10 mL) and H2O (2 × 10 mL), dried
(MgSO4), and evaporated under reduced pressure. The crude prod-
uct was purified by flash column chromatography (silica gel,
EtOAc–hexane, 1:3) to give 28 (0.21 g, 0.77 mmol, 60%) as a white
solid; mp 206–208 °C.
Nakatsu, M.; Uenishi, J.; Uemura, M. Tetrahedron 2009, 65,
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Belding, L.; Katz, M. J.; Dudding, T.; Britton, R. Beilstein J.
Org. Chem. 2011, 7, 1315. (i) Schmid, M.; Waldner, B.;
Schnürch, M.; Mihovilovic, M. D.; Stanetty, P. Tetrahedron
2011, 67, 2895. (j) Page, A.; Clayden, J. Beilstein J. Org.
Chem. 2011, 7, 1327. (k) Coppi, D. I.; Salomone, A.; Perna,
F. M.; Capriati, V. Angew. Chem. Int. Ed. 2012, 51, 7532.
(5) Recent examples for substituted heterocycles: (a) Robert,
N.; Bonneau, A.-L.; Hoarau, C.; Marsais, F. Org. Lett. 2006,
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Org. Lett. 2008, 10, 3567. (e) McLaughlin, M.;
FT-IR: 3054, 2985, 1589, 1422, 1265 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 8.48 (s, 1 H, H4), 8.39 (d, J = 5
Hz, 1 H, H6), 7.36–7.18 (m, 10 H, 10 HPh), 6.47 (d, J = 5 Hz, 1 H,
H7), 5.25 (br, exch., 1 H, NH), 3.43 (d, J = 6 Hz, 2 H, CH2).
13C NMR (125 MHz, DMSO-d6): δ = 156.1 (s, C7a), 152.7 (d, C4),
149.5 (d, C6), 146.7 (s, C3a), 134.2 (s, 2 C1Ph), 128.4 (d, 2
C3Ph/C5Ph), 127.8 (d, 2 C2Ph/C6Ph), 127.5 (d, 2 C4Ph), 123.7 (d, C7),
81.5 (s, C1), 41.9 (t, CH2).
MS (APCI): m/z (%) = 314 (25, [M + MeCN + H]+), 273 (100, [M
+ H]+), 256 (13).
HRMS (APCI): m/z [M + H]+ calcd for C19H17N2: 273.1392; found:
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2008, 73, 4309. (f) Capriati, V.; Florio, S.; Luisi, R.;
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Chem. 2008, 73, 9214. (h) Musio, B.; Clarkson, G. J.;
Shipman, M.; Florio, S.; Luisi, R. Org. Lett. 2009, 11, 325.
(i) Capriati, V.; Florio, S.; Perna, F. M.; Salomone, A. Chem.
Eur. J. 2010, 16, 9778. (j) Perna, F. M.; Salomone, A.;
Dammacco, M.; Florio, S.; Capriati, V. Chem. Eur. J. 2011,
17, 8216. (k) Coppi, D. I.; Salomone, A.; Perna, F. M.;
Capriati, V. Chem. Commun. 2011, 47, 9918. (l) Clayton, J.;
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273.1393.
Acknowledgment
We thank the Egyptian and the Saudi Governments for financial
support. G. A. El-Hiti would like to extend his appreciation to the
Deanship of Scientific Research at King Saud University for its fun-
ding for this research through the research group project RGP-VPP-
239.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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Synthesis 2013, 45, 3426–3434
© Georg Thieme Verlag Stuttgart · New York