Lithiation and electrophilic substitution of dimethyl triazones

Article abstract of DOI:10.1016/j.tetlet.2012.04.121

The lithiation and electrophilic substitution of dimethyl triazones is described. Directed lithiation or tin-lithium exchange of dimethyl triazones afforded the corresponding dipole stabilized nucleophiles that were trapped with various electrophiles. Keto-triazone derivatives accessed by acylation of such nucleophiles were readily converted into the corresponding imidazolone heterocycles.

Full text of DOI:10.1016/j.tetlet.2012.04.121

Tetrahedron Letters 53 (2012) 3722–3726
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Tetrahedron Letters
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Lithiation and electrophilic substitution of dimethyl triazones
⇑
Sunkyu Han, Dustin S. Siegel, Mohammad Movassaghi
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The lithiation and electrophilic substitution of dimethyl triazones is described. Directed lithiation or tin–
lithium exchange of dimethyl triazones afforded the corresponding dipole stabilized nucleophiles that
were trapped with various electrophiles. Keto-triazone derivatives accessed by acylation of such nucle-
ophiles were readily converted to the corresponding imidazolone heterocycles.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 16 April 2012
Accepted 23 April 2012
Available online 2 May 2012
Keywords:
Triazone
Lithiation
Urea
Imidazolone
Synthesis
Complex-induced proximity effects have been utilized exten-
sively to functionalize otherwise unactivated sites of a molecule.1
In particular, the metalation and electrophilic substitution of
carbon centers adjacent to a nitrogen bearing an electron with-
drawing group has been studied extensively,2 and several exam-
ples of the directed lithiation of alkyl urea derivatives have been
reported.3 However, there have been no previous reports of the
lithiation of alkyl triazone derivatives. While triazones have found
great utility in protection of primary amines,4 their potential use to
mask urea functional groupings has received far less attention.5 In
the context of our studies concerning the total synthesis of the age-
lastatin alkaloids,6 we employed metalated triazone 1 as a syn-
thetic equivalent of metalated urea 2 to access functionalized
urea derivative 3 (Scheme 1). Herein, we report our observation
on the directed lithiation and electrophilic substitution of 1,3-di-
methyl triazones in addition to derivatization of related keto-triaz-
ones to the corresponding imidazolone heterocycles.
For these studies, we prepared several 1,3-dimethyl triazones
by direct condensation of dimethyl urea (4), formalin, and various
primary amines (Table 1).4a,4b Trimethyl triazone 6a was prepared
in 42% yield after purification by vacuum distillation (Table 1, entry
1). The isopropyl and mesityl triazones (6b and 6c) were obtained
in 20% and 21% yields, respectively (Table 1, entries 2 and 3). Nota-
bly, the benzyl and p-toluene triazones 6d and 6e were both read-
ily prepared on greater than 30 gram scale in 91% and 71% yield,
respectively (Table 1, entries 4 and 5), and could be efficiently puri-
fied by recrystallization from hexanes, rendering them particularly
attractive urea surrogates from a preparative standpoint.
We next examined the directed lithiation of 1,3-dimethyl triaz-
ones. Treatment of the 1,3-dimethyl triazone derivatives with one
equivalent of s-butyllithium at À78 °C in THF followed by quench-
ing with deuterium oxide afforded the corresponding triazone
products with complete deuterium incorporation at the methyl
group
a to the nitrogen (Table 2). Under optimal conditions the
lithiation of the methyl and benzyl triazones 6a and 6d, respec-
tively, with s-butyllithium followed by quenching with deuterium
oxide afforded the corresponding monodeuterated products in
moderate yields (41% and 50%, respectively; Table 2, entries 1
and 3). Unfortunately, these reactions were plagued by the rapid
formation of self-condensation byproducts via addition of the lith-
iated triazone to the C2-carbonyl of another triazone. The yields for
the formation of the deuterated benzyl triazone were identical
when quenched after 10, 30, or 60 min periods, which suggests
that once formed, the lithiated triazone intermediates were stable
at À78 °C for up to 1 h (Table 2, entries 3–5). Interestingly, the
mesityl and toluyl triazones 6c and 6e, respectively, underwent
the lithiation and deuteration sequence with greater efficiency to
afford the monodeuterated products 7c and 7e in 95% and 85%
yield, respectively (Table 2, entries 2 and 6). Importantly, we
observed that the formation of undesired self-condensation
O
M
E+;
Me
O
E
O
M
E+
N
N
Me
Me
N
N
N
N
hydrolysis
N
H
H
H
H
C6H4-p-Me
1
3
2
⇑
Corresponding author. Tel.: +1 617 253 3986.
E-mail address: movassag@mit.edu (M. Movassaghi).
Scheme 1. Use of the metalated triazone 1 as a synthetic equivalent of a metalated
urea 2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.121

S. Han et al. / Tetrahedron Letters 53 (2012) 3722–3726
3723
Table 1
Synthesis of triazones
optimal for the lithiation of dimethyl triazones. Attempted use of
n-butyllithium as the base additive predominantly led to undesired
addition of the butyl group to the C2 carbonyl group of the urea.
Alternatively, the use of t-butyllithium as the base additive re-
sulted in formation of a complex mixture of products consistent
with indiscriminate lithiation of the triazone substrates at unde-
sired positions. Furthermore, metal amides were ineffective as
the base additive at À78 °C and their use at higher temperatures
was complicated by decomposition of lithiated triazone intermedi-
ates. Finally, inclusion of other common additives such as tetra-
methylethylenediamine (TMEDA) or hexamethylphosphoramide
(HMPA) in combination with s-butyllithium gave no clear
advantage.
O
Me
Me
O
formalin
N
N
R
NH2
+
Me
Me
N
H
N
H
N
R
6a−f
H2O, time
100 ºC
5a−f
4
Entry
Amine
Time (h)
Yield of 6 (%)
1
2
3
4
5
5a
5b
5c
5d
5e
R = Me
24
24
48
17
19
42a
20b
21b
91c
71c
R = iPr
R = Mesityl
R = Bn
R = C6H4-p-Me
We then evaluated the reactivity of various electrophiles with
the lithiated triazones (Table 3). The lithiated triazones underwent
nucleophilic addition to a,b-unsaturated aldehydes (Table 3, entry
a
b
c
Purified by distillation.
Purified by silica gel flash column chromatography.
Purified by recrystallization from hexanes.
1–3) and benzaldehyde (Table 3, entry 4) in moderate yields (47–
70%). Methyl ester derivatives were suitable electrophiles for this
chemistry and afforded the corresponding keto-triazone products
(Table 3, entries 5–13). The use of 2.5 equivalents of the triazone
nucleophile resulted in full and efficient conversion of methyl ben-
zoate (12) to ketone 22 (Table 3, entry 5). In more challenging
cases, an increase in the equivalents of the nucleophile led to an in-
crease in the yield of the desired adduct (Table 3, entries 6–8, and
11–12). The use of excess lithiated triazone allowed for the gener-
ation of the desired keto-triazones 25c and 25e from methyl ester
15, which contains an acidic lactam N–H proton (Table 3, entry 11–
13). However, when a large excess of lithiated triazone was used,
we sometimes observed the formation of minor double-addition
byproducts. The lithiated triazone could also be trapped with trial-
Table 2
Directed lithiation and deuterium incorporation of 1,3-dimethyl triazone
O
O
7
1
N
Me
Me
Me
s-BuLi (1 equiv)
2
N
N
N
D
THF, −78 °C
time; D2O
N
R
N
R
5
6a, 6c−e
7a, 7c−e
Entry
Substrate
Time (min)
Yield of 7a (%)
kyltin chlorides to afford versatile and stable
a-stannylated triaz-
1
2
3
4
5
6
6a
6c
6d
6d
6d
6e
R = Me
R = Mes
R = Bn
R = Bn
R = Bn
10
15
10
30
60
15
41
95
50
50
50
85
ones 26d–e and 27d–e (Table 3, entries 14–17)—substrates that
allowed for a more practical C–C bond formation (vide infra).7,8
Despite the successful direct lithiation of 1,3-dimethyl triazones
described above, the formation of triazone self-condensation
byproducts complicated the reaction, and an excess of the triazone
was needed to form the desired products efficiently (Table 3, entries
8 and 10). In order to address this issue, we evaluated whether tin–
lithium exchange could generate the lithiated triazones with great-
er efficiency.9 When stannyl triazone 26d was treated with one
R = C6H4-p-Me
a
Products showed complete monodeuterium incorporation at C7.
byproducts was significantly suppressed with these substrates. It
should be noted that the use of s-butyllithium was found to be
Table 3
Triazone addition to various electrophiles
O
O
Me
Me
Me
s-BuLi, THF, −78 °C;
N
N
E
N
N
electrophile
N
R
N
R
6a,c,d,e
18−27
Entry
1b
Substrate
Electrophile
Triazone (equiv)
Product
Yielda (%)
O
TBSO
CHO
Me
8
TBSO
TBSO
N
O
N
6d
2
70
OH
N
Bn
18
CHO
HO
Me
TBSO
N
N
2b
6d
2
57
9
N
19
Bn
(continued on next page)

3724
S. Han et al. / Tetrahedron Letters 53 (2012) 3722–3726
Table 3 (continued)
Entry
Substrate
Electrophile
Triazone (equiv)
Product
Yielda (%)
O
TBSO
TBSO
Me
CHO
N
N
3b
4b
5
6d
1.7
47
10
OH
O
N
Bn
20
Me
Me
N
N
CHO
6d
6a
1.7
2.5
65
91
OH
11
N
Bn
21
O
N
N
CO2Me
12
O
N
22
Me
Bn
N
6b
7b
6d
6d
6d
2
4
6
21
49
70
O
N
O
N
O
8b
OMe
OMe
O
N
N
N
Me
OMe O
Bn
N
N
N
O
O
O
N
O
N
O
13
23d
Bn
O
O
O
9
6a
6d
2
6
37
80
R
N
10b
OMe
OMe
N
N
N
N
Me
OMe O
OMe
24a, R = Me
24d, R = Bn
14
OMe
11
12
6c
6c
6e
3.5
4
4
50
72
65
R
N
13c
OMe
OMe
N
N
Me
NH
15
OMe O
25c, R = Mes
NH
25e, R = C6H4-p-Me
14d
15e
6d
6e
Bu3SnCl 16
Bu3SnCl 16
1
1
45
64
O
Me
Bu3Sn
N
N
N
R
26d, R = Bn
26e, R = C6H4-p-Me
16
6d
6e
Cy3SnCl 17
Cy3SnCl 17
2
1
90
45
O
17e
Me
Cy3Sn
N
N
N
R
27d, R = Bn
27e, R = C6H4-p-Me 10g scale
Mes: mesityl.
a
Isolated yield after purification.
b
c
TMEDA (2 equiv) was used as an additive.
HMPA (2 equiv) was used as an additive.
1.5 equiv of trialkyltin chloride was used.
1.1 equiv of trialkyltin chloride was used.
d
e

S. Han et al. / Tetrahedron Letters 53 (2012) 3722–3726
3725
Table 4
Nucleophilic addition of the lithiated triazone obtained by tin–lithium exchange
O
O
Me
Me
n-BuLi, THF, −78 ºC;
Bu3Sn
N
N
E
N
N
electrophile
N
R
N
R
26a, 26d−e
24d, 25a, 25d−e
Entry
Substrate
Electrophile
Stannane (equiv)
Product
Yielda (%)
O
Bn
N
OMe
OMe
O
N
N
N
N
N
Me
Me
1
26d
R = Bn
2
24d
74
N
OMe O
OMe
OMe
N
N
O
O
N
O
14
O
O
O
R
N
2
3
26a
26d
R = Me
R = Bn
3
25a
25d
62
83
3.5
OMe
OMe
N
4
26e
R = C6H4-p-Me
3.5
25e
80
OMe O
NH
NH
15
a
Isolated yield after purification.
Bn
N
O
Me
O
H
H
N
O
N
N
N
Me
N
N
N
H
a
Me
OMe O
N
OMe O
OMe
83%
N
N
N
PMB
N
PMB
PMB
30
O
O
O
28
29
Scheme 2. Formation of imidazolone 30 from keto-triazone 28. Reagents and conditions: (a) 0.5 N HCl (2 equiv), MeOH, 23 °C, 83%. PMB: p-methoxybenzyl.
C6H4-p-Me
N
C6H4-p-Me
N
O
N
Me
b
N
a
O
O
H
N
N
N
N
100%
91%
Me
Me
Me
Me
32
O
O
31
33
Scheme 3. Formation of trisubstituted imidazolone 33. Reagents and conditions: (a) NaH (1.2 equiv), MeI (2 equiv), DMF, 0?23 °C, 91%; (b) 0.5 N HCl (2 equiv), MeOH, 63 °C,
100%.
equivalent of n-butyllithium at À78 °C in THF, the desired lithiated
triazone intermediate was obtained quantitatively. Importantly, the
rapid rate of tin–lithium exchange completely suppressed the forma-
tion of self-condensation byproducts. This method required only
two equivalents of lithiated triazone (via tin–lithium exchange) to
convert methyl ester 14 to ketone 24d in 74% yield (Table 4, entry
1) as compared to the six equivalents required using the direct lith-
iation route (Table 3, entry 10). Additionally, conversion of methyl
ester 15 to the corresponding keto-triazone 25 using reagents
generated through tin–lithium exchange afforded the desired
keto-triazone products in higher yields than the direct lithiation
protocol previously described (Table 4, entries 2–4).
Finally, we investigated the synthesis of imidazolones from
keto-triazones.6,10 To our delight, the triazone moiety in 28 could
be readily hydrolyzed in the presence of aqueous hydrochloric acid
in methanol at 23 °C. The 2,3-disubstituted imidazolone 30 was
obtained in 83% yield through a condensative cyclization of a puta-
tive keto-urea intermediate 29 (Scheme 2).6,11
The alkylation of these versatile keto-triazones provides an
expedient route to trisubstituted imidazolones. For example, the

3726
S. Han et al. / Tetrahedron Letters 53 (2012) 3722–3726
4. (a) Knapp, S.; Hale, J. J.; Bastos, M.; Gibson, B. F. Tetrahedron Lett. 1990, 31,
2109; (b) Knapp, S.; Hale, J. J.; Bastos, M.; Moline, A.; Chen, K. Y. J. Org. Chem.
1992, 57, 6239; (c) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.
1993, 115, 9293; (d) Pearson, W. H.; Lee, I. Y.; Mi, Y.; Stoy, P. J. Org. Chem. 2004,
69, 9109.
5. (a) Shimizu, L. S.; Smith, M. D.; Hughes, A. D.; Shimizu, K. D. Chem. Commun.
2001, 1592; (b) Xu, Y.; Smith, M. D.; Krause, J. A.; Shimizu, L. S. J. Org. Chem.
2009, 74, 4874; (c) Tian, L.; Wnag, C.; Dawn, S.; Smith, M. D.; Krause, J. A.;
Shimizu, L. S. J. Am. Chem. Soc. 2009, 131, 17620.
methylation of keto-triazone 31 occurred efficiently via its depro-
tonation with sodium hydride followed by treatment of the corre-
sponding enolate with methyl iodide to afford keto-triazone 32 in
91% yield (Scheme 3). When the methylated keto-triazone 32 was
treated with aqueous hydrochloric acid in methanol at 63 °C, 2,4-
dimethyl-3-phenyl imidazolone 33 was obtained in 100% yield.
In summary, we have described the utility of 1,3-dimethyl triaz-
ones in the introduction of a urea functional grouping through di-
rected lithiation to afford dipole-stabilized lithiated triazone
intermediates that can be trapped with various electrophiles (Ta-
ble 3). We have also shown that stannylated triazones prepared
from such lithiated triazones provide a highly efficient source of
the desired lithiated triazones and can lead to significant improve-
ment in more complex unions (Table 4). The resulting keto-triaz-
ones not only provide further opportunity for introduction of
additional substituents but they also serve as excellent precursors
for the corresponding imidazolone heterocycles.
6. Movassaghi, M.; Siegel, D. S.; Han, S. Chem. Sci. 2010, 1, 561.
7. For the use of 27e in the copper mediated cross-coupling reaction with a
thioester, see: Ref. 6.
8. Representative experimental procedure for lithiation and electrophilic trapping
of a dimethyl triazone–synthesis of stannyltriazone 27e: To a solution of
triazone 6e (10.0 g, 46.0 mmol, 1 equiv) in tetrahydrofuran (400 mL) at À78 °C
under an argon atmosphere was added s-butyllithium (1.4 M in cyclohexane,
34.5 mL, 48.0 mmol, 1.05 equiv) rapidly via cannula. After 10 min, the resulting
bright orange mixture was transferred via cannula over a 15 min period to a
solution of tricyclohexyltin chloride (20.3 g, 50.0 mmol, 1.10 equiv) in
tetrahydrofuran (400 mL) at À78 °C. After 1.5 h, saturated aqueous
ammonium chloride solution (100 mL) was added via syringe, and
approximately 80% of the volatiles were removed by concentration of the
mixture under reduced pressure. The residue was partitioned between
dichloromethane (800 mL) and water (800 mL). The layers were separated,
and the organic layer was washed with brine (800 mL), was dried over
anhydrous sodium sulfate, and was concentrated under reduced pressure. The
crude residue absorbed onto silica gel was loaded as a solid, and was purified
by flash column chromatography (silica gel: diam. 6 cm, ht. 15 cm; eluent:
hexanes then 10% ethyl acetate in hexanes) to afford stannyltriazone 27e
(12.1 g, 45%) as a white solid. 1H NMR (500 MHz, CDCl3, 20 °C): d 7.07 (app-dd,
J = 8.7, 0.7 Hz, 2H), 6.89 (app-d, J = 8.5 Hz, 2H,), 4.60 (s, 2H), 4.58 (s, 2H), 2.85 (s,
3H), 2.78 (t, J = 12.2 Hz, 2H), 2.27 (s, 3H), 1.82–1.74 (m, 6H), 1.65–1.56 (m, 9H),
1.52–1.13 (m, 18H). 13C NMR (125.8 MHz, CDCl3, 20 °C): d 156.3, 146.1, 132.2,
Acknowledgments
We acknowledge financial support by NIH-NIGMS (GM074825).
M.M. is a Camille Dreyfus Teacher-Scholar.
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