Studying competitive lithiations at alpha-, ortho-, and benzylic positions in various N-protected aniline derivatives

Article abstract of DOI:10.1016/j.tet.2011.02.056

The directing effects of the t-BuOCONH- (NHBoc) and the t-BuCONH- (NH-pivaloyl) groups have been investigated on a series of differently substituted anilines. Depending on the nature of the directing group and the substrate, lithiation either occurred in

Full text of DOI:10.1016/j.tet.2011.02.056

Tetrahedron 67 (2011) 2895e2904
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studying competitive lithiations at alpha-, ortho-, and benzylic positions in
various N-protected aniline derivatives
*
€
Martin Schmid, Birgit Waldner, Michael Schnurch , Marko D. Mihovilovic, Peter Stanetty
Institute for Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC 1060 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 January 2011
Received in revised form 18 February 2011
Accepted 21 February 2011
Available online 26 February 2011
The directing effects of the t-BuOCONHe (NHBoc) and the t-BuCONHe (NHepivaloyl) groups have been
investigated on a series of differently substituted anilines. Depending on the nature of the directing
group and the substrate, lithiation either occurred in the ortho-, benzylic-, or alpha-position. In general, it
was observed that ortho-lithiation is the least facile process and alpha-lithiation slightly favored com-
pared to lithiation in the benzylic position. However, it was found that minor changes in the starting
materials led to different regioselectivity in the metalation process. For example, changing substituents
from methyl to ethyl can result in completely different regioselectivity. As final conclusion, a graphical
guideline for lithiation experiments is presented.
Dedicated to Professor Carmen Najera on
the occasion of her 60th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Directed metalation
Directing metalation group
Ortho-lithiation
Regioselectivity
Protecting group
1. Introduction
such as the t-BuCONH (NHepivaloyl) group have been applied as
ortho-directing groups since 1979.3,11 Despite the broad spectrum
The methodology of directed or heteroatom-facilitated metal-
ation, most importantly lithiation reactions, is a powerful and
versatile tool in organic synthesis since many years.1,2 It is essential
for achieving regioselectivity in the synthesis of complex mole-
cules. The use of substrates bearing suitable directing metalation
groups (DMGs) offers a clean and fast way for the regioselective
synthesis of polysubstituted aromatics or heteroaromatics that
would be difficult to obtain through other substitution methods.3,4
In the last decades, many examples of directed lithiation strategies
(with subsequent introduction of an electrophile) have been
reported and the subject was repeatedly reviewed.3,4 Directed or-
tho-metalation (DOM) and directed remote metalation (DRM) are
now widely applied methods in the synthesis of complex mole-
cules, such as pharmaceuticals or natural products.5e7 Therefore,
systematic investigations toward the selectivity and substrate
scope of directed metalation reactions are important since these
methods can considerably facilitate complex synthesis. The syn-
thetic chemist can nowadays choose from numerous groups pro-
moting ortho-, alpha- or remote directed lithiation.8e10
Carbamates, such as the t-BuOCONH (NHBoc) group and amides,
of available directing groups, the NHBoce and the NHepivaloyl-
group still are of special value, because the free amino group can be
regenerated during the course of a multistep reaction. While the
Boc-group can be removed under relatively mild conditions12 or
reduced to the N-methyl-group by powerful reducing agents,13 the
pivaloyl-group requires forced hydrolyzing conditions.14 This can
lead to problems, especially when there are other hydrolytically
unstable groups present in the molecule. The ortho-directing
properties of the NHBoce and the NHepivaloyl-group have already
been studied on a series of different substrates.15 However, sys-
tematic studies on compounds bearing different types of protons
(such as benzylic, aromatic, and N-alkyl hydrogens) simultaneously
available for lithiation in a single molecule are not available to the
best of our knowledge. Within this contribution we conducted such
a comparative study on a series of aniline derivatives to elaborate
how directing effects can be influenced by alkyl-substituents on the
amino group or in ortho-position in order to be able to predict the
products of lithiation reactions on higher substituted substrates
(Fig.1). Such investigations are potentially useful for a large number
of synthetic chemists taking into account that many compounds,
(e.g., natural products or pharmaceuticals) contain substituted
anilines16e20 and facile ways of accessing these compounds alter-
native to established routes are highly welcome.
* Corresponding author. Fax: þ43 158801915440; e-mail address: mschnuerch@
€
ioc.tuwien.ac.at (M. Schnurch).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.056

2896
M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
benzylic
The influence of the aliphatic residue was investigated sub-
sequently, exchanging the methyl for an ethyl group. First, the Boc-
protected substrate 6 was lithiated using 1.2 equiv t-BuLi in Et2O at
ꢀ70 ꢁC. Subsequent quenching with Me2S2 at ꢀ75 ꢁC and warming
the reaction mixture to ꢀ30 ꢁC for 2 h gave product 7 in 95% yield,
derived again from ortho-lithiation as could be expected (Scheme 2).
Interestingly, the reaction could not be driven to completion when
carrying out the lithiation at ꢀ60 ꢁC. Switching from methyl to ethyl
had no influence on the direction of lithiation when the Boc-pro-
tecting group was used. However, a different result was obtained
when N-pivaloylethylaniline 8 was investigated in a directed lith-
iation reaction. For the lithiation of 8 2.5 equiv of t-BuLi in Et2O were
used, because the first equivalent would very likely induce a migra-
tion of the pivaloyl-group (either into the alpha-position, as shown
in the literature21 or into the ortho-position if the nature of the side
chain has an influence on the position of the lithiation). The
remaining amount of t-BuLi would then attack the ketone formed in
the rearrangement process. No reaction was observed at ꢀ70 ꢁC.
Only after elevating the temperature to ꢀ20 ꢁC could the lithiation
be driven to completion within 3 h. In this, case compound 10 was
isolated after aqueous workup and precipitation as hydrochloride.
The product was formed via ortho-lithiation, and not by alpha-
lithiation as it was the case for the corresponding methyl-substrate
3. Rearrangement of the pivaloyl-group and addition of t-BuLi to the
resulting aromatic ketone (Scheme 2) then leads to compound 10.
Reactionwith an electrophile is therefore not possible whenpivaloyl
is used as N-protecting group. Hence, a slight change from the
methyl-group to an ethyl-substituent also changes the direction of
the lithiation from the alpha- to the ortho-position.
alpha
R
R
N
PG
ortho
PG = BOC, Piv
R = H, CH3
Fig. 1. Possible positions for lithiation.
2. Results and discussion
N-Protected N-methylaniline was used as the first model-sub-
strate for investigating the directed lithiation. In this compound
either deprotonation at the N-methyl-group (alpha-lithiation) or at
the benzene ring (ortho-lithiation) is possible. Lithiation of piv-
aloylmethylaniline
€
3
was described by Hellwinkel and
21
Lammerzahl: reaction with 1.1 equiv of t-BuLi in THF at ꢀ80 ꢁC
was complete after 2 h and after hydrolysis 3,3-dimethyl-1-(phe-
nylamino)-2-butanone 5 could be isolated in 63% yield. This
product was formed through alpha-lithiation and subsequent mi-
gration of the pivaloyl-group (Scheme 1). Using this study as
starting point, we investigated if switching from the pivaloyl to the
Boc-group has an influence on the selectivity of the reaction.
Lithiation of 1 with 1.2 equiv of t-BuLi in Et2O at ꢀ10 ꢁC led to
decomposition of the starting material. At ꢀ60 ꢁC, the lithiation
reaction was complete after 30 min and quenching with Me2S2 as
a fast reacting electrophile gave the ortho-lithiated product 2 in
67% yield. This shows that the lithiation was now directed into the
ortho- rather than the alpha-position. Through lithiation with
LICKOR (t-BuLi, KOtBu) in THF at ꢀ70 ꢁC the yield could be im-
proved to 92%. This already demonstrates that the nature of the
directing group has a significant influence on the position of the
lithiation. On N-protected-N-methylaniline, the Boc-group directs
preferably into the ortho-position, whereas the pivaloyl-group ac-
tivates the alpha-position.
N
PG
1) t-BuLi/Et2O,
t-BuLi/Et2O
-70°C
6: PG = Boc
8: PG = Piv
2) Me2S2, -75°C
S
N
Li
N
O
O
O
7 95%
9
N
PG
1a) t-BuLi/Et2O, -60°C
1b) LICKOR/THF, -70°C
2) Me2S2
t-BuLi/THF
1: PG = Boc
3: PG = Piv
-80°C
1. t-BuLi
2. H2O
HO
O
N
O
Li
10
S
N
N
Li
N
H
4
Scheme 2. Influence of the N-alkyl group on the lithiation position.
O
O
H2O
O
To determine the influence of an ortho-alkyl-group on the di-
rection of the lithiation, experiments on derivatives of 2-methyl-
aniline were carried out. The lithiation of Boc-protected o-toluidine
11 was first described by Clark et al.22a Reaction with 2.0 equiv of s-
or t-BuLi in THF at ꢀ40 ꢁC occurred spontaneously at the benzylic
position and was finished shortly after completing the addition of
the second equivalent.
2
conditions 1a: 67%
conditions 1b: 92%
5
63%
N
H
Scheme 1. Lithiation studies on 1 and 3.

M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
2897
Hence, electrophiles can be introduced in this position pro-
viding access to compounds 12. Reaction with DMF led to indoline
derivative 13 via attack of the negatively charged nitrogen on the
initially introduced benzylic aldehyde group. After treatment with
aqueous HCl 13 was converted to the Boc-protected indole 14 in
90% yield (Scheme 3). Cervantes et al.22b optimized the reaction
conditions described by Clark et al.22a in order to enable in-
troduction of substituents into the benzylic position in the first step
followed by cyclization to the indole ring in a second step.22b
NH
O
O
1) t-BuLi/TMEDA
2) CO2
1) t-BuLi/TMEDA
2) DMF
IV
E
COOH
NH
1a) s-BuLi/THF
NH
1b) t-BuLi/THF
OH
N
NH
2
) E+
O
O
O
O
O
O
O
O
1) s-BuLi/THF
2) DMF
12
11
VII
V
OH
HCl
N
N
O
O
O
HCl
O
HCl
80%
13
Scheme 3. Benzylic lithiation and indole formation of 11.
14 90%
O
N
N
The lithiation of N-pivaloyl-o-toluidine I was described by Fuhrer
and Gschwend and electrophiles (CO2 or TMSCl) were introduced in
the phenylmethyl-group (II).23 Stirring the reaction mixture at room
temperature for 16 h gave 2-(1,1-dimethylethyl)-indole III as
a product of a modified Madelung-synthesis (Scheme 4).24
O
O
O
O
VIII
VI
Scheme 5. Lithiations of VI.
E
1) n-BuLi/THF
2) E+
reacted again with 2.5 equiv of t-BuLi in Et2O at ꢀ10 ꢁC for 3 h and
quenched with Me2S2. Via this method 88% of 16 could be isolated
(Scheme 6). Here, both the Boc- and pivaloyl-group direct into the
CH2-position of the ethyl-group; ortho-lithiation products could
not be observed. Therefore, it can be concluded that benzylic po-
sitions are more readily lithiated compared to the ortho-position. It
is also noteworthy that no migration of the pivaloyl-group was
observed as it was the case for previous substrates.
NH
NH
O
O
n-BuLi/THF
II
I
E=TMS, CO2
N
H
1) t-BuLi/Et2O
2) Me2S2
S
III
NH
NH
88%
Scheme 4. Benzylic lithiation of I.
O
O
Lithiation of N-Boc-2-ethylaniline IV was also described by Clark
et al.,22a however, the publication fails to give the exact reaction
conditions. It rather states that t-BuLi/TMEDA gave best results,
since lithiation seemed to be much more difficult compared to
N-Boc-2-methylaniline. No ortho-lithiation products could be ob-
served. Using DMF as the electrophile, N-Boc-protected 3-methyl-
indole VI could be obtained in 80% yield after treatment with
aqueous HCl. When using CO2 as the electrophile, N-Boc-protected
3-methylindole-2(3H)-one VIII was obtained through acidic ring-
formation. Consequently, lithiation was reported at the benzylic
position only in all previous reports (Scheme 5).
15
16
Scheme 6. Benzylic lithiation of 15.
However, changing from ethyl to isopropyl as in Boc-protected
substrate 17 led to ortho-direction when lithiating with the improved
lithiation conditions established in our group (Scheme 7).25 After 2 h
of stirring with 2.5 equiv of t-BuLi in Et2O at ꢀ10 ꢁC, there was still
starting material present; addition of another equivalent of t-BuLi
could also not drive the reaction to completion. In the crude NMR
25e30% of thioether 18 could be identified, next to starting material
17. Again this indicates that lithiation in ortho-position is more slug-
gish than in the benzylic position. When the benzylic position is not
Since the regioselectivity of lithiation of N-Boc-2-ethylaniline
was established, we now investigated the regioselectivity of the
metalation of N-pivaloly-2-ethylaniline 15. This substrate was

2898
M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
1a) t-BuLi/Et2O
S
1b)LICKOR/THF
N
2 ) Me2S2
1) t-BuLi/Et2O
N
N
S
+
2) Me2S2
O
O
O
O
O
O
NH
PG
NH
PG
1) t-BuLi/Et2O
2) TMSCl
S
21
23
22
17: PG = Boc
19: PG = Piv
18: PG = Boc
20: PG = Piv
Si
Scheme 7. Ortho-lithiation of 17 and 19.
N
N
Si
+
O
O
O
O
available for lithiation due to steric reasons, metalation can be forced
into the ortho-position; however, the efficiency is low.
25
24
31%
52%
Lithiation of pivaloyl-protected 19 turned out to be a rather
difficult task. Problems occurred already when trying to dissolve 19
in Et2O. When trying to carry out the lithiation reaction in a het-
erogeneous mixture with 2.5 equiv of t-BuLi at ꢀ20 ꢁC for 4 h and
subsequent quenching with Me2S2 only 30% conversion to the
thioether 20 could be observed. Changing the solvent from Et2O to
THF led to an even decreased conversion of 5%. The lithiation re-
action was also carried out according to Fuhrer and Gschwend23
using a mixture of Et2O and THF in a ratio of 4:3. Upon cooling
the reaction mixture, parts of starting material 19 precipitated and
a maximum conversion of 20% could be obtained after several ex-
periments. The best yield of 35% could be obtained when starting
with 3.0 equiv of t-BuLi in Et2O at ꢀ10 ꢁC and addition of another
equivalent of t-BuLi after 3 h of stirring (Scheme 7). This demon-
strates again the preferred lithiation in the benzylic position. Only if
lithiation at the benzylic position is blocked, ortho-lithiation can
take place. The low yields can be attributed to solubility problems.
Again, a migration of the pivaloyl-group was not observed.
Scheme 8. Alpha- and benzylic-lithiation of 21.
The pivaloyl-protected analog 26 was first lithiated again with t-
BuLi in Et2O at ꢀ70 ꢁC for 3 h. Subsequent quenching with Me2S2
gave 65% of 27a. Quenching with tert-butylisocyanate under the
same reaction conditions gave 72% of 27b. Both products originate
from an alpha-lithiated intermediate. In contrast to findings of
21
€
Hellwinkel and Lammerzahl the pivaloyl-group did not migrate
into the alpha-position under these conditions. Interestingly,
compound 28 was obtained without addition of an electrophile
(although in low yields), which stems from a Madelung-type re-
action.24 After carrying out the reaction at ꢀ10 ꢁC for 2 h 28 was
isolated from a complex mixture in 26% yield (Scheme 9). This in-
dicates that the initial attack of the lithiating agent occurs at the
alpha-position and that the lithiation position changes to the
benzylic position when applying higher reaction temperatures.
After determining the directing effect of the individual groups
for ortho-, alpha-, and benzylic lithiation, it was interesting to ex-
plore the lithiation of substances where all these three positions are
available for lithiation simultaneously. As a first model compound
Boc-protected compound 21 was used; lithiation with 1.2 equiv of
t-BuLi in Et2O at ꢀ70 ꢁC and quenching with Me2S2 after 3 h led to
the formation of two regioisomers. Alpha-lithiated product 22
(53%) was isolated as main fraction accompanied by 15% of com-
pound 23 lithiated in the benzylic position (besides 11% of starting
material 21). Consequently, lithiation in alpha-position is slightly
favored over lithiation in the benzylic position. No ortho-lithiated
product was detected, indicating again that this is the least favor-
able position. Repeating the reaction at ꢀ30 ꢁC led to full conver-
sion and 60% of 22 and 27% of 23 could be obtained. Hence,
elevation of the temperature also changed the ratio of the two
regioisomers 22/23 from w3.5:1 to w2:1. When changing the
electrophile from Me2S2 to TMSCl, another fast reacting electro-
phile, the corresponding regioisomers 24 (52%) and 25 (31%) were
obtained which corresponds to a still lower selectivity (24/
25e1.7:1). To determine the effect of the base, the reaction was also
carried out with LICKOR. Starting material 21 was stirred with
LICKOR in THF at ꢀ70 ꢁC for 2 h and quenched with Me2S2. In this
experiment 18% of 22 and 50% of 23 could be isolated (Scheme 8).
Interestingly, changing the base caused inversion of the isomeric
ratio of 22/23 to w1:2.8. This can be interpreted in a way that the
phenylmethyl-group is the more acidic group, because of the pre-
ferred deprotonation by LICKOR, but the complexing effect of the
Boc-group in this position is inhibited for steric reasons. The
complexation affects only the N-methyl-group, which leads to
preferred deprotonation with t-BuLi in this position. No ortho-
substituted product could be observed, which can be explained by
the minor acidification by the Boc-group and steric factors.
N
1) t-BuLi/Et2O
O
1) t-BuLi/Et2O
-70°C
-10°C
26
Li
N
N
Li
O
O
E+
N
N
E
28
26%
O
27a
(
E = SCH3
, 65%),
CONHt-Bu (27b, 72)
Scheme 9. Alpha- and benzylic-lithiation of 26.
Since the N-methyl-position was preferred in both protected
N,2-dimethylanilines, it was now investigated in which direction
the reaction proceeds when switching to the corresponding N-ethyl
starting materials 29 and 31. Since the N-methyl substrates 1 and 3

M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
2899
gave lithiation in alpha-position (Scheme 1), whereas N-ethyl
substrates 6 and 8 led to ortho-lithiation (Scheme 2), we were in-
terested if a similar change in selectivity could be observed also in
this case. Lithiation of 29 was carried out with t-BuLi under the
same reaction conditions as used for the lithiation of 21 (Scheme 8).
Product 30, derived from lithiation in the benzylic position, could
be isolated in 83% yield. So again changing to an ethyl-group
switched the selectivity, now from the alpha- to the benzylic po-
sition. Keeping in mind the previous results, this was expected,
since no lithiation in the alpha-position was observed also in 6 and
8. Moreover, the observed lithiation at the benzylic position is
a logical result since it proved to be more reactive than the ortho-
position and consequently no ortho-lithiation products were ob-
served. Lithiation of the pivaloyl-protected analog 31 with 2.5 equiv
of t-BuLi in Et2O for 2 h and quenching with Me2S2 gave 80% of 32
again derived from lithiation in the benzylic position. So changing
to the ethyl-group also increased the yield of the indole product
significantly. Just like 21 (Scheme 8), 32 was formed via the attack
of the species lithiated in the benzylic position at the carbonyl-
group. The elimination of water to form the aromatic ring occurred
by acid catalysis with SiO2 during column chromatography
(Scheme 10).
lithiation will take place in the alpha-position. The same reaction
conditions were chosen as for substrate 21. The expected com-
pound 38 derived from lithiation in alpha-position was obtained in
69% yield. In contrast to starting material 21 no product derived
from lithiation in the benzylic position was observed. However, 1H
NMR analysis revealed that also ortho-substituted product 39 had
been formed in approximately 20% yield (Scheme 10). So again
a slight change in the substrate had a significant influence on the
outcome of the lithiation reaction.
3. Conclusion
Fig. 2 summarizes the results of the previously described di-
rected lithiation studies. The black wedges point to the lithiation
position in case of pivaloyl as protecting group and the plain
wedges in case of the Boc-protecting group. Directed lithiations
previously reported in the literature are also included to provide
a more comprehensive overview. Numbers in italics describe
compounds with Boc as protecting group, the numbers in normal
style point to compounds with the pivaloyl protecting group.
NH
PG
N
PG
N
PG
1) t-BuLi/Et2O
-85°C
2) Me2S2
3) SiO2
N
PG
1) t-BuLi/Et2O, -80°C
3
8
1 and
6 and
2) Me2S2, -20°C
29: PG = Boc
31:
S
PG = Piv
N
O
N
NH
PG
NH
PG
NH
PG
O
32 80%
30 82%
11
15
17
19
and
Scheme 10. Benzylic lithiation of 29 and indole formation from 31.
Since no ortho-lithiations could be observed with N,2-dime-
thylanilines (21 and 26) and N-ethyl-2-methylaniline derivatives 29
and 31 it was investigated if longer alkyl-chains could direct the
lithiation into the ortho-position. Lithiation of 33 was carried out
with t-BuLi in Et2O at ꢀ70 ꢁC for 2 h followed by quenching with
Me2S2. Indeed, 85% of ortho-substituted thioether 34 could be
isolated in accordance with our rational. Also, lithiation of N-piv-
aloyl-protected N-ethyl-2-ethylaniline 35 with 1.2 equiv of t-BuLi in
Et2O at ꢀ20 ꢁC led to compound 36 (compare to Scheme 3) derived
from ortho-lithiation, however, in only 20% yield. Carrying out the
experiment with 2.5 equiv t-BuLi improved the yield to 52%
(Scheme 11). So in this case again a migration of the pivaloyl-group
is induced and the initially formed ketone is attacked by t-BuLi also
explaining the necessity for excess lithiating reagent.
N
PG
N
PG
N
PG
21
26
29
31
33
35
and
and
and
PG = Piv
PG = Boc
N
PG
37
1) t-BuLi/Et2O
2) Me2S2
Fig. 2. Summary of directed lithiation reactions.
t-BuLi/Et2O
N
N
N
H
While unsubstituted Boc- and pivaloyl-protected anilines were
selectively lithiated in ortho-position (Fig. 2 top left),15 the in-
troduction of an N-alkyl-group led to different results. Boc-protected
1 still gave ortho-lithiation, whereas pivaloyl-protected 3 was lithi-
ated exclusively inthealpha-position. Elongating the N-alkyl chain to
ethyl gave ortho-lithiation for both protecting groups (compounds 6
and 8). Introduction of an ortho-alkyl-group (11 or 15), changed the
direction of the lithiation to the benzylic position (Schemes 3 and 6).
The introduction of an ortho-i-propyl-group (starting materials 17
and 19) again led to ortho-lithiation products exclusively due to
sterical reasons, however, in poor yields (Scheme 7).
S
PG
-20°C
-70°C
O
O
O
H
33:
PG = Boc
PG = Piv
36
20%
34
85%
35:
Scheme 11. Ortho-lithiation of 33 and 35.
Since the lithiation of 21 led to a mixture of products 22 and 23
(Scheme 8), one last experiment was carried out on the corre-
sponding ethyl-substrate 37. It was expected that no lithiation in
the benzylic position would occur on this substrate and preferred

2900
M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
The pivaloyl-group also directed the lithiation exclusively into
chloride dissolved in dry Et2O was added slowly at 0 ꢁC. The re-
action mixture was then stirred at room temperature until the re-
action was complete. Water was added and the layers were
separated. The aqueous layer was extracted twice with Et2O. The
combined organic layers were washed twice with water, 2 N HCl,
and saturated NaHCO3 solution, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
recrystallization.
the alpha-position in the N,2-dimethyl-derivative 26 (Scheme 9).
With the Boc-group (21, Scheme 8) a mixture of alpha- and ben-
zylic-substituted products 22 and 23 (Scheme 8) was obtained, the
alpha-lithiation products being preferred. It was found that the
ratio of the two products was also dependent on the temperature.
Although still the major product, compound 22 was less favored at
higher temperature. This could be explained by the fact that the
ortho-methyl-group causes the Boc-group to rotate out of the ring-
plane so that complexation into the ring is no longer favored. In-
stead, the two methyl groups are the preferred sites of attack of the
lithiating agent. The ratio of the two products could be influenced
by variation of the base and electrophile.
N-Protected N-ethyl-2-methyl derivatives 29 and 31 both gave
lithiation in the benzylic position and again no lithiation on the N-
ethyl-group (Scheme 10) was observed. On the N-pivaloyl starting
material 31, an intramolecular attack of the initially formed lithi-
ated species led to the formation of indole derivative 32 (Scheme
10).
4.2.3. General procedure C: lithiation with LICKOR. The substrate
(1.0 equiv) and 1.0e1.2 equiv of t-BuOK were dissolved in dry THF
and cooled. Then t-BuLi solution was added and the reaction mix-
ture was warmed and stirred until the lithiation was complete. The
reaction mixture was then cooled again and quenched with the
desired electrophile. After warming to room temperature and
stirring for 16 h, hydrolysis was either carried out with water or
saturated NH4Cl solution. The layers were separated and the
aqueous layer was extracted twice with Et2O. The combined or-
ganic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The product was either purified by column
chromatography, vacuum distillation or Kugelrohr distillation.
Exact temperatures, reaction times, and amounts of reagents are
specified separately for each specific compound.
N,2-Diethyl starting materials 33 and 35 both gave lithiation in
ortho-position since the lithiations of the ethyl groups are more
sluggish than lithiation in ortho-position. 2-Ethyl-N-methyl sub-
strate 37 gave then again preferred lithiation in the alpha-position
although also ortho-substituted product 39 (Scheme 12) was
obtained as by-product.
4.2.4. General procedure D: lithiation with t-BuLi. Substrate
(1.0 equiv) was dissolved in dry Et2O or dry THF and cooled. Then t-
BuLi solution was added dropwise and the reaction mixture was
warmed and stirred until the lithiation was complete. Workup and
purification were carried out as described in general procedure C.
Exact temperatures, reaction times, and amounts of reagents are
specified separately for each specific compound.
1) t-BuLi/Et2O
2) Me2S2
N
S
N
N
+
S
O
O
O
O
O
O
37
38
39
4.3. Products protected by the Boc-group
Scheme 12. Alpha- and ortho-lithiation of 37.
4.3.1. 1,1-Dimethyethyl
N-methyl-N-[2-(methylthio)phenyl]carba-
mate (2). Prepared according to general procedure C starting from
1 (0.50 g, 2.4 mmol, 1.0 equiv) and t-BuOK (0.27 g, 2.4 mmol,
1.0 equiv) dissolved in 6 mL of dry THF. t-BuLi (1.4 mL, 1.7 M so-
lution in heptane, 2.4 mmol, 1.0 equiv) was added at ꢀ80 ꢁC. The
reaction mixture was warmed to ꢀ70 ꢁC and stirred for 1.5 h.
Subsequent quenching was carried out with Me2S2 (0.25 g,
2.6 mmol, 1.1 equiv), dissolved in 3 mL of dry THF. Hydrolysis with
saturated NH4Cl solution and purification by column chromatog-
raphy (PE/EtOAc 15:1) gave 2 (0.56 g, 92%) as colorless oil as
a mixture of rotamers. Anal. Calcd for C13H19NO2S: C, 61.63; H,
7.56; N, 5.53. Found: C, 61.82; H, 7.56; N, 5.54; Rf (PE/EtOAc 5:1)
4. Experimental
4.1. General
Melting points were measured on a KOFLER hot stage micro-
scope and are uncorrected. Combustion analyses were performed
in the microanalytical laboratory at the Institute for Physical
Chemistry at the University of Vienna under the supervision of
Mag. J. Theiner. Thin layer chromatography was performed with
Merck silica gel 60 F245 plates. Column chromatography was per-
formed using silica gel Merck 60. NMR spectra were recorded on
a BRUKER AC 200 FT-NMR-spectrometer with TMS as an internal
standard. Solvents and lithiation reagents were obtained from
commercial sources. Solvents were distilled prior to use and dried if
necessary.
0.35; 1H NMR (200 MHz CDC13):
d
¼1.37 and 1.53 (2br s, 9H), 2.45
(s, 3H), 3.16 (s, 3H), 7.04e7.31 (m, 4H); 13C NMR (50 MHz, CDCl3):
d
¼14.8 (q), 15.1 (q), 28.0 (q), 35.8 (q), 36.8 (q), 79.5 (s), 79.9 (s),
125.1 (d), 125.5 (d), 127.5 (d), 127.7 (d), 128.2 (d), 137.6 (s), 140.9 (s),
154.7 (s).
4.2. General procedures
4.3.2. 1,1-Dimethyethyl N-ethyl-N-[2-(methylthio)phenyl]carbamate
(7). Prepared according to general procedure D starting from 6
(0.50 g, 2.3 mmol, 1.0 equiv) dissolved in 7 mL of dry Et2O. t-BuLi
(1.6 mL, 1.7 M solution in heptane, 2.7 mmol, 1.2 equiv) was added
at ꢀ80 ꢁC. The reaction mixture was warmed to ꢀ30 ꢁC and stirred
for 2 h. Me2S2 (0.26 g, 2.7 mmol, 1.2 equiv) dissolved in 3 mL of dry
Et2O was added at ꢀ75 ꢁC. Hydrolysis was carried out with H2O.
4.2.1. General procedure A: protection with the Boc-group. The un-
protected amine (1.0 equiv) and bis(1,1-dimethylethyl) dicarbonate
(1.0 equiv) were dissolved in dry THF and stirred under reflux for
16 h. The reaction mixture was extracted twice with 2 N HCl and
the aqueous layer was re-extracted once with Et2O. The combined
organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by Kugelrohr
distillation or vacuum distillation.
Title compound
7 was obtained via Kugelrohr distillation
(80e90 ꢁC, 0.05 mbar) as colorless oil as a mixture of rotamers
(0.57 g, 95%). Anal. Calcd for C14H21NO2S: C, 62.89; H, 7.92; N, 5.24.
Found: C, 63.03; H, 8.16; N, 5.27; Rf (PE/EtOAc 5:1) 0.50; 1H NMR
4.2.2. General procedure B: protection with the pivaloyl-group. The
unprotected amine (1.0 equiv) and 1.0 equiv of triethylamine were
dissolved in dry Et2O. Then 1.0 equiv of 2,2-dimethylpropionic acid
(200 MHz CDC13):
3.20e3.49 (m, 1H), 3.68e3.95 (m, 1H), 6.98e7.35 (m, 4H); 13C NMR
(50 MHz, CDCl3):
¼13.4 (q), 14.8 (q), 28.1 (q), 43.1 (t), 44.4 (t),
d
¼1.12 (t, 3H), 1.22e1.61 (m, 9H), 2.41 (s, 3H),
d

M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
2901
79.4 (s), 124.7 (d), 125.4 (d), 127.4 (d), 129.0 (d), 138.2 (s), 139.2 (s),
154.3 (s).
28.2 (q), 41.3 (t), 79.1 (s), 126.1 (d), 126.6 (d), 127.7 (d), 130.5 (d),
135.2 (s), 143.0 (s), 155.0 (s).
4.3.3. 1,1-Dimethylethyl N-[2-(methylethyl)-6-(methylthio)phenyl]
carbamate (18). Prepared according to general procedure D starting
from 17 (0.50 g, 2.1 mmol, 1.0 equiv) dissolved in 7 mL of dry Et2O.
t-BuLi (3.2 mL, 1.7 M solution in heptane, 5.4 mmol, 2.6 equiv) was
added at ꢀ85 ꢁC. The reaction mixture was warmed to ꢀ10 ꢁC and
stirred for 2 h. Additional t-BuLi (1.6 mL, 1. 7 M solution in heptane,
2.7 mmol, 1.3 equiv) was added. The reaction mixture was stirred at
ꢀ10 ꢁC for additional 2 h. Me2S2 (0.45 g, 4.8 mmol, 2.3 equiv) dis-
solved in 3 mL of dry Et2O was added. Hydrolysis was carried out
with water and the title compound 18 submitted to column chro-
matography (PE/EtOAc 10:1).26 Rf (PE/EtOAc 5:1) 0.55; 1H NMR
4.3.7. 1,1-Dimethylethyl N-methyl-N-[2-[(trimethylsilyl)methyl]phe-
nyl]carbamate (25). Preparation see section 4.3.6. Colorless liquid;
31% yield (0.21 g). Rf (PE/EtOAc 5:1) 0.60; 1H NMR (200 MHz
CDC13):
d
¼0.02 (s, 9H), 1.25e1.56 (m, 9H), 2.05 (s, 2H), 3.13 (s, 3H),
6.98e7.20 (m, 4H); 13C NMR (50 MHz, CDCl3):
d
¼ꢀ1.1 (q), 21.2 (t),
28.1 (q), 37.3 (q), 79.5 (s), 124.7 (d), 126.5 (d), 127.6 (d), 129.6 (d),
137.7 (s), 141.3 (s), 155.6 (s).
4.3.8. 1,1-Dimethylethyl
N-ethyl-N-(2-methylphenyl)carbamate
(29). Starting material 6 (3.00 g, 13.6 mmol, 1.0 equiv) was dis-
solved in 30 mL of dry THF and cooled to ꢀ75 ꢁC before t-BuLi so-
lution (9.6 mL, 1.7 M solution in heptane, 16.3 mmol, 1.2 equiv) was
added dropwise. The reaction mixture was warmed to ꢀ30 ꢁC and
stirred for 2 h. After cooling to ꢀ80 ꢁC methyliodide (4.0 mL,
64 mmol, 9.4 equiv) was added. The reaction mixture was warmed
to room temperature and stirred for 16 h. Hydrolysis was carried
out with 30 mL of water. The layers were separated and the aque-
ous phase was extracted twice with Et2O. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification by Kugelrohr distillation (90e100 ꢁC,
0.04 mbar) gave 29 (2.81 g, 88%) as colorless crystals. Anal. Calcd for
C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C, 71.75; H, 8.72; N,
6.00; Mp: 28e30 ꢁC; Rf (PE/EtOAc 5:1) 0.40; 1H NMR (200 MHz
(200 MHz CDC13):
3.15e3.35 (m, 1H), 5.90 (br s, 1H), 7.01e7.35 (m, 3H); 13C NMR
(50 MHz, CDCl3):
d
¼1.22 (d, J¼7 Hz, 6H), 1.52 (s, 9H), 2.42 (s, 3H),
d
¼15.2 (q), 23.3 (q), 27.5 (d), 28.1 (q), 79.9 (s),
122.4 (d), 122.6 (d), 126.2 (d), 131.3 (s), 138.1 (s), 147.4 (s), 154.1 (s).
4.3.4. 1,1-Dimethylethyl N-(2-ethylphenyl)-N-[(methylthio)methyl]
carbamate (22). Prepared according to general procedure D start-
ing from 21 (0.50 g, 2.3 mmol, 1.0 equiv) dissolved in 6 mL of dry
Et2O. t-BuLi (1.6 mL, 1.7 M solution in heptane, 2.7 mmol, 1.2 equiv)
was added at ꢀ80 ꢁC. The reaction mixture was warmed to ꢀ30 ꢁC
and stirred for 1 h. Me2S2 (0.26 g, 2.8 mmol, 1.3 equiv) dissolved in
3 mL of dry Et2O was added at ꢀ80 ꢁC. Hydrolysis was carried out
with water. The title compound 22 was purified by column chro-
matography (PE/EtOAc 20:1) and obtained in 60% yield (0.36 g) as
colorless oil as a mixture of rotamers. Anal. Calcd for C14H21NO2S: C,
62.89; H, 7.92; N, 5.24. Found: C, 62.61; H, 8.01; N, 5.04; Rf (PE/
CDC13):
3.35e3.58 (m, 1H), 3.60e3.82 (m, 1H), 6.97e7.25 (m, 4H); 13C NMR
(50 MHz, CDCl3):
d
¼1.00e1.25 (m, 3H), 1.25e1.62 (m, 9H), 2.20 (s, 3H),
d
¼13.3 (q), 13.9 (q), 17.6 (q), 28.2 (q), 44.0 (t), 45.1
(t), 79.2 (s), 126.2 (d), 126.8 (d), 128.2 (d), 130.4 (d), 135.9 (s), 140.8
(s), 154.5 (s).
EtOAc 5:1) 0.70; 1H NMR (200 MHz CDC13):
9H), 2.19 (s, 3H), 2.25 (s, 3H), 4.50 (d, J¼14 Hz, 1H), 4.95 (d, J¼14 Hz,
1H), 7.13e7.31 (m, 4H); 13C NMR (50 MHz, CDCl3):
d¼1.33 and 1.52 (2br s,
d
¼15.3 (q), 17.5
4.3.9. 1,1-Dimethylethyl N-ethyl-N-[2-[(methylthio)methyl]phenyl]
carbamate (30). Prepared according to general procedure D start-
ing from 29 (0.50 g, 2.1 mmol, 1.0 equiv) dissolved in 7 mL of dry
Et2O. t-BuLi (1.7 mL, 1. 7 M solution in heptane, 2.6 mmol, 1.2 equiv)
was added at ꢀ85 ꢁC. The reaction mixture was warmed to ꢀ30 ꢁC
and stirred for 2 h. Me2S2 (0.24 g, 2.6 mmol, 1.2 equiv) dissolved in
2 mL of dry Et2O was added at ꢀ80 ꢁC. Hydrolysis was carried out
with H2O. Purification by column chromatography (PE/EtOAc 20:1)
gave 30 (0.50 g, 83%) as colorless oil. For combustion analysis the
substance was further purified by Kugelrohr distillation (90e100 ꢁC,
0.05 mbar). Anal. Calcd for C15H23NO2S: C, 64.02; H, 8.24; N, 4.98.
Found: C, 64.26; H, 8.51; N, 5.00; Rf (PE/EtOAc 10:1) 0.35; 1H NMR
(q), 17.6 (q), 28.0 (q), 28.2 (q), 54.0 (t), 54.8 (t), 80.2 (s), 120.8 (d),
123.5 (d), 126.3 (d), 126.6 (d), 127.4 (d), 128.5 (d), 130.1 (d), 130.4 (d),
135.5 (s), 136.2 (s), 140.0 (s), 152.9 (s), 154.8 (2s). As by-product 23
was obtained (0.16 g, 27%).
4.3.5. 1,1-Dimethylethyl N-methyl-N-[2-[(methylthio)methyl]phenyl]
carbamate (23). Prepared according to general procedure C starting
from 21 (0.50 g, 2.3 mmol, 1.0 equiv) and t-BuOK (0.30 g, 2.7 mmol,
1.2 equiv) dissolved in 7 mL of dry THF. t-BuLi (1.6 mL, 1. 7 M so-
lution in heptane, 2.7 mmol, 1.2 equiv) was added at ꢀ75 ꢁC. The
reaction mixture was warmed to ꢀ70 ꢁC and stirred for 2 h. Me2S2
(0.26 g, 2.8 mmol, 1.2 equiv) dissolved in 2.5 mL of dry THF was
added. Hydrolysis and purification by column chromatography (PE/
EtOAc 20:1) gave 23 (0.30 g, 50%) as colorless oil as a mixture of
rotamers. Anal. Calcd. For C14H21NO2S: C, 62.89; H, 7.92; N, 5.24.
Found: C, 62.77; H, 7.79; N, 5.18; Rf (PE/EtOAc 5:1) 0.55; 1H NMR
(200 MHz CDC13):
d
¼1.08e1.23 (m, 3H),1.23e1.70 (m, 9H),1.98 and
2.04 (s, 3H), 3.23e3.45 (m, 1H), 3.63 (s, 2H), 3.70e3.95 (m, 1H),
6.97e7.35 (m, 3H), 7.45e7.53 and 7.62e7.70 (2 m, 1H); 13C NMR
(50 MHz, CDCl3):
(t), 79.2 (s), 126.2 (d), 126.8 (d), 128.2 (d), 130.4 (d), 135.9 (s), 140.8
(s), 154.5 (s).
d
¼13.3 (q), 13.9 (q), 17.6 (q), 28.2 (q), 44.0 (t), 45.1
(200 MHz CDC13):
3H), 3.57 (d, J¼14 Hz) and 3.69 (d, J¼14 Hz) in total 2H, 7.03e7.30
(m, 3H), 7.36e7.50 (m, 1H); 13C NMR (50 MHz, CDCl3):
d
¼1.31 and 1.52 (2br s, 9H), 2.00 (s, 3H), 3.20 (s,
d¼15.4 (q),
4.3.10. 1,1-Dimethylethyl N-ethyl-N-(2-ethylphenyl)carbamate (33).
Prepared according to general procedure A starting from N,2-
diethylbenzolamine (0.89 g, 6.0 mmol, 1.0 equiv). Compound 33
was purified by distillation under reduced pressure (85e95 ꢁC,
0.01 mbar) to give 90% (1.34 g) yield as colorless liquid. Anal. Calcd
for C15H23NO2: C, 72.25; H, 9.30; N, 5.62. Found: C, 72.52; H, 9.33;
28.1 (q), 33.7 (t), 37.4 (q), 79.7 (s), 127.1 (d), 127.6 (d), 127.7 (d), 129.0
(d), 135.4 (s), 142.4 (s), 154.8 (s). As by-product 22 (0.11 g, 18%) was
obtained.
4.3.6. 1,1-Dimethylethyl
N-(2-methylphenyl)-N-[(trimethylsilyl)
methyl]carbamate (24). Prepared according to general procedure D
starting from 12 (0.50 g, 2.3 mmol, 1.0 equiv). TMSCl (0.30 g,
2.8 mmol, 1.2 equiv) was used as the electrophile. Compound 24
was purified by column chromatography (PE/EtOAc 20:1) and
obtained as colorless liquid in 52% yield (0.34 g) Rf (PE/EtOAc 5:1)
0.65; As by-product 25 was obtained also as colorless liquid in 31%
N, 5.72; Rf (PE/EtOAc 4:1) 0.70; 1H NMR (200 MHz CDC13):
d¼1.15
(t, J¼7 Hz, 3H), 1.23 (t, J¼7 Hz, 3H), 1.45 (s, 9H), 2.65 (q, J¼7 Hz,
2H), 3.68 (q, J¼7 Hz, 2H), 6.96e7.07 (m, 3H), 7.18e7.29 (m, 1H); 13C
NMR (50 MHz, CDCl3):
(t), 79.6 (s), 124.0 (d), 125.3 (d), 126.5 (d), 128.3 (d), 142.3 (s), 144.6
(s), 154.5 (s).
d
¼13.7 (q), 15.3 (q), 28.2 (q), 28.5 (t), 44.8
yield (0.21 g). 1H NMR (200 MHz CDC13):
(m, 9H), 2.22 (s, 3H), 2.88 (d, J¼16 Hz, 1H), 3.27 (br d, J¼16 Hz, 1H),
6.96e7.22 (m, 4H); 13C NMR (50 MHz, CDCl3):
¼ꢀ1.5 (q), 17.7 (q),
d
¼0.02 (s, 9H), 1.25e1.59
4.3.11. 1,1-Dimethylethyl
N-ethyl-[2-ethyl-6-(methylthio)-phenyl]
d
carbamate (34). Prepared according to general procedure
D

2902
M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
starting from 33 (0.50 g, 2.0 mmol, 1.0 equiv) dissolved in 6 mL of
dry Et2O. t-BuLi (1.5 mL, 1. 7 M solution in heptane, 2.4 mmol,
1.2 equiv) was added at ꢀ80 ꢁC. The reaction mixture was warmed
to ꢀ70 ꢁC and stirred for 3 h. Me2S2 (0.23 g, 2.4 mmol, 1.2 equiv)
dissolved in 3 mL of dry Et2O was added. Hydrolysis was carried out
with saturated NH4Cl. Purification by column chromatography (PE/
EtOAc 10:1) gave 34 (0.51 g, 85%) as colorless crystals. Anal. Calcd
for C16H25NO2: C, 65.05; H, 8.53; N, 4.74. Found: C, 65.08; H, 8.53; N,
4.74; Mp: 53e55 ꢁC; Rf (PE/EtOAc 10:1) 0.40; 1H NMR (200 MHz
10.08; N, 4.67. Found: C, 67.88; H, 10.29; N, 4.62; Mp: 221e223 ꢁC;
Rf (PE/EtOAc 5:1) 0.8; 1H NMR (200 MHz CDC13):
d
¼1.11 (s, 18H),
1.23 (t, J¼7 Hz, 3H), 3.06 (q, J¼7 Hz, 2H), 6.73e6.88 (m, 2H),
7.06e7.18 (m,1H), 7.44 (dd, J¼10 Hz, J¼2 Hz,1H); 13C NMR (50 MHz,
CDCl3):
d
¼15.0 (q), 29.7 (q), 42.1 (s), 43.4 (t), 88.5 (s), 117.9 (d), 119.3
(d), 126.6 (d), 130.3 (d), 132.9 (s), 147.7 (s).
4.4.2. 2,2-Dimethyl-N-[2-[(1-methylthio)ethyl]phenyl]-propanamide
(16). Prepared according to general procedure D starting from 15
(0.50 g, 2.4 mmol, 1.0 equiv) dissolved in 7 mL of dry Et2O. t-BuLi
(3.8 mL, 1. 7 M solution in heptane, 6.1 mmol, 2.5 equiv) was added
at ꢀ80 ꢁC. The reaction mixture was warmed to ꢀ30 ꢁC and stirred
for 2 h. Me2S2 (0.24 g, 2.4 mmol, 1.2 equiv) dissolved in 3 mL of dry
Et2O was added and the reaction mixture was warmed to room
temperature and stirred over night. Hydrolysis was carried out with
H2O. Purification by Kugelrohr distillation (90e100 ꢁC, 0.01 mbar)
gave 16 (0.54 g, 88%) as colorless crystals. For combustion analysis
the product was further purified by recrystallization from PE. Anal.
Calcd for C14H21NOS: C, 66.89; H, 8.42; N, 5.57. Found: C, 66.93; H,
8.40; N, 5.53; Mp: 58e61 ꢁC; Rf (PE/EtOAc 5:1) 0.40; 1H NMR
CDC13):
9H), 2.40 (s, 3H), 2.62 (q, J¼7 Hz, 2H), 3.18e3.50 (m, 1H), 3.70e3.95
(m, 1H), 6.85e7.21 (m, 3H); 13C NMR (50 MHz, CDCl3):
d
¼1.07e1.20 (m, 3H), 1.21 (t, J¼7 Hz, 3H), 1.28e1.63 (m,
d¼13.4 (q),
14.0 (q), 15.4 (q), 27.9 (q), 28.1 (t), 43.2 (t), 44.6 (t), 79.3 (s), 79.8 (s),
126.2 (d), 126.9 (d), 128.6 (d), 134.5 (s), 139.5 (s), 141.4 (s), 154.4 (s).
4.3.12. 1,1-Dimethylethyl
N-(2-ethylphenyl)-N-methyl-carbamate
(37). NaH (0.20 g, 8.1 mmol, 1.2 equiv) was suspended in 7 mL of
dry DMF. Then 15 (1.50 g, 6.8 mmol,1.0 equiv), dissolved in 15 mL of
dry DMF was added dropwise. The reaction mixture was stirred at
room temperature for 2 h. Subsequently, methyliodide (1.92 g,
13.6 mmol, 2.0 equiv) was added quickly and the reaction mixture
was stirred for 1 h at room temperature. DMF was removed under
reduced pressure. The residue was taken up in 10 mL of water and
extracted with Et2O. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. After
distillation under reduced pressure (60e70 ꢁC, 0.015 mbar), 27 was
obtained in 92% (1.47 g) yield as colorless oil as a mixture of
rotamers. Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N, 5.95.
Found: C, 71.49; H, 9.21; N, 6.06; Rf (PE/EtOAc 10:1) 0.60; 1H NMR
(200 MHz CDC13):
3.97 (q, 1H), 7.01e7.39 (m, 3H), 7.95 (dd, J¼8 Hz, J¼1 Hz, 1H), 8.78
(br s, 1H); 13C NMR (50 MHz, CDCl3):
d¼1.35 (s, 9H), 1.68 (d, J¼7 Hz, 3H), 1.93 (s, 3H),
d
¼13.2 (q), 19.1 (q), 27.6 (q),
39.5 (s), 42.2 (d), 124.2 (d), 124.3 (d), 127.8 (d), 127.9 (d), 131.4 (s),
136.0 (s), 176.6 (s).
4.4.3. 2,2-Dimethyl-N-[2-(1-methylethyl)-6-(methylthio)phenyl]-
propanamide (20). Prepared according to general procedure D
starting from 19 (0.50 g, 2.4 mmol, 1.0 equiv) suspended in 11 mL of
dry Et2O. t-BuLi (4.0 mL, 1. 7 M solution in heptane, 6.8 mmol,
3.0 equiv) was added at ꢀ40 ꢁC. The reaction mixture was warmed
to ꢀ10 ꢁC and stirred for 3 h. Additional 1.4 mL of t-BuLi solution
(2.3 mmol, 1.0 equiv) were added and the reaction mixture was
stirred for another 1.5 h at ꢀ10 ꢁC. Me2S2 (0.64 g, 6.8 mmol,
3.0 equiv), dissolved in 3 mL of dry Et2O was added at ꢀ75 ꢁC.
Hydrolysis was carried out with saturated NH4Cl. Recrystallization
from DIPE gave 20 in 35% (0.21 g) yield as colorless crystals. Anal.
Calcd for C15H23NOS: C, 67.88; H, 8.73; N, 5.28. Found: C, 67.61; H,
8.48; N, 5.29; mp: 220e221 ꢁC; Rf (PE/EtOAc 3:1) 0.50; 1H NMR
(200 MHz CDC13):
d
¼1.22 (t, 3H, J¼7 Hz), 1.31 and 1.51 (2br s, 9H),
2.59 (q, 2H, J¼7 Hz), 3.15 (s, 3H), 7.01e7.32 (m, 4H); 13C NMR
(50 MHz, CDCl3):
d
¼14.4 (q), 23.6 (t), 28.1 (q), 37.2 (q), 79.4 (s),
126.3 (d), 127.2 (d), 127.4 (d), 128.7 (d), 141.0 (s), 141.8 (2s), 155.1 (s).
4.3.13. 1,1-Dimethylethyl N-(2-ethylphenyl)-N-[(methylthio)methyl]
carbamate (38). Prepared according to general procedure D start-
ing from 37 (0.50 g, 2.1 mmol, 1.0 equiv) dissolved in 7 mL of dry
Et2O. t-BuLi (1.5 mL, 1.7 M solution in heptane, 2.4 mmol, 1.2 equiv)
was added at ꢀ80 ꢁC. The reaction mixture was warmed to ꢀ30 ꢁC
and stirred for 2 h. Me2S2 (0.24 g, 2.4 mmol, 1.2 equiv) dissolved in
3 mL of dry Et2O was added. Hydrolysis was carried out with H2O.
Purification by column chromatography (PE/EtOAc 15:1) gave 38
(0.42 g, 70%) as colorless oil as a mixture of rotamers. For com-
bustion analysis, the product was further purified by Kugelrohr
distillation (80e90 ꢁC, 0.04 mbar). Anal. Calcd for C15H23NO2S: re-
quires C, 64.02; H, 8.24; N, 4.98. Found: C, 64.32; H, 8.01; N, 4.95; Rf
(200 MHz CDC13):
d
¼1.20 (d, J¼7 Hz, 6H), 1.38 (s, 9H), 2.40 (s, 3H),
2.91e3.12 (m, 1H), 6.94 (br s, 1H), 7.04 (dd, J¼8 Hz, J¼2 Hz, 1H), 7.12
(dd, J¼6 Hz, J¼2 Hz, 1H), 7.28 (dd, J¼8, 6 Hz, 1H); 13C NMR (50 MHz,
CDCl3):
d
¼15.0 (q), 23.2 (q), 27.5 (q), 28.4 (d), 39.2 (s), 122.3 (d),
122.4 (d), 128.0 (d), 131.1 (s), 137.1 (s), 147.0 (s), 177.1 (s).
4.4.4. N,2,2-Trimethyl-N-(2-methylphenyl)propanamide
(26). Prepared according to general procedure B starting from N,2-
dimethylbenzolamine (5.00 g, 41.3 mmol) with the slight change
that all the steps were carried out at room temperature. The
product was purified by recrystallization from PE to give a yield of
93% (7.88 g) of 26 as colorless crystals. Anal. Calcd for C13H19NO: C,
76.06; H, 9.33; N, 6.82. Found: C, 76.28; H, 9.59; N, 6.83; mp:
67e69 ꢁC; Rf (PE/EtOAc 4:1) 0.60; 1H NMR (200 MHz CDC13):
(PE/EtOAc 15:1) 0.45; 1H NMR (200 MHz CDC13):
d
¼1.25 (t, J¼7 Hz,
3H), 1.35 and 1.52 (2br s, 9H), 2.19 (s, 3H), 2.60 (q, J¼7 Hz, 2H), 4.35
(d, J¼14 Hz, 1H), 5.09 (d, J¼14 Hz, 1H), 7.15e7.35 (m, 4H); 13C NMR
(50 MHz, CDCl3):
(s), 126.1 (d), 127.7 (d), 128.6 (d), 129.0 (d), 139.2 (s), 141.2 (s), 154.9
(s).
d
¼14.3 (q), 15.4 (q), 23.4 (t), 28.0 (q), 54.3 (t), 80.1
4.4. Products protected by the piv-group
d
¼1.02 (s, 9H), 2.26 (s, 3H), 3.12 (s, 3H), 7.09e7.30 (m, 4H); 13C NMR
(50 MHz, CDCl3):
128.8 (d), 131.1 (d), 135.7 (s), 143.7 (s), 177.9 (s).
d
¼28.8 (q), 39.4 (q), 40.5 (s), 126.4 (d), 128.0 (d),
4.4.1. 3-(2-(Ethylamino)phenyl)-2,2,4,4-tetramethylpentan-3-ol hy-
drochloride (10). Prepared according to general procedure
D
starting from 8 (0.50 g, 2.4 mmol, 1.0 equiv) dissolved in 10 mL of
dry Et2O. t-BuLi (3.4 mL, 1.7 M solution in heptane, 5.4 mmol,
2.2 equiv) was added at ꢀ80 ꢁC. The reaction mixture was warmed
to ꢀ20 ꢁC and stirred for 3 h before 10 mL of H2O were added. After
extraction and concentration, the residue was taken up in 20 mL of
dry Et2O and precipitated as hydrochloride with gaseous HCl. The
colorless crystals of the title compound 10 (0.35 g, 55%) were fil-
tered and dried. For combustion analysis, the product was recrys-
tallized from dry THF. Anal. Calcd for C17H29NO.HCl: C, 68.09; H,
4.4.5. 2,2-Dimethyl-N-(2-methylphenyl)-N-[(methylthio)methyl]-
propanamide (27a). Prepared according to general procedure D
starting from 26 (0.50 g, 2.4 mmol, 1.0 equiv) dissolved in 10 mL of
dry Et2O. t-BuLi (1.7 mL, 1.7 M solution in heptane, 2.9 mmol,
1.2 equiv) was added at ꢀ40 ꢁC. The reaction mixture was warmed
to ꢀ70 ꢁC and stirred for 3 h. Me2S2 (0.28 g, 2.9 mmol, 1.2 equiv)
dissolved in 3 mL of dry Et2O was added at ꢀ70 ꢁC. Hydrolysis was
carried out with H2O. Purification 27a by column chromatography
(PE/EtOAc 20:1) gave 27a (0.40 g, 65%) as colorless oil. For

M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
2903
combustion analysis the product was further purified by Kugelrohr
distillation (80e90 ꢁC, 0.01 mbar). Anal. Calcd for C14H21NOS: C,
66.89; H, 8.42; N, 5.57. Found: C, 66.62; H, 8.28; N, 5.51; Rf (PE/
11.16; N, 5.01; mp: 74.5e75.5 ꢁC; Rf (PE/EtOAc 5:1) 0.55; 1H NMR
(200 MHz CDC13):
¼1.13 (s, 18H), 1.23 (t, J¼7 Hz, 3H), 1.25 (t,
d
J¼7 Hz, 3H), 2.59 (q, J¼7 Hz, 2H), 3.08 (q, 2H), 6.61e6.72 (m, 2H),
EtOAc 5:1) 0.60; 1H NMR (200 MHz CDC13):
d
¼1.02 (s, 9H), 2.16 (s,
3H), 2.28 (s, 3H), 3.77 (d, J¼13 Hz, 1H), 5.60 (d, J¼13 Hz, 1H),
7.17e7.38 (m, 4H); 13C NMR (50 MHz, CDCl3):
7.35 (dd, J¼10, 1 Hz, 1H); 13C NMR (50 MHz, CDCl3):
¼14.9 (q), 15.0
d
(q), 27.9 (t), 29.7 (q), 42.7 (s), 43.4 (t), 88.2 (s), 118.3 (d), 119.7 (d),
130.2 (d), 131.2 (s), 142.3 (s), 147.2 (s).
d¼15.9 (q), 17.8 (q),
28.7 (q), 40.1 (s), 55.0 (t), 126.0 (d), 128.5 (d), 131.1 (d), 135.8 (s),
140.7 (s), 178.2 (s). One signal (d) overlaps with another signal.
Supplementary data
4.4.6. 2,2-Dimethyl N-(2,2-dimethylaminocarbonylmethylen)-N-(2-
methylphenyl)propanamide (27b). Prepared according to general
procedure D starting from 26 (2.00 g, 9.7 mmol,1.0 equiv) dissolved
in 40 mL of dry Et2O. t-BuLi (6.9 mL, 1. 7 M solution in heptane,
11.7 mmol, 1.2 equiv) was added at ꢀ80 ꢁC. The reaction mixture
was warmed to ꢀ70 ꢁC and stirred for 2 h. Subsequently, tert-
butylisocyanate (1.1 g, 11.7 mmol, 1.2 equiv), dissolved in 5 mL of
dry Et2O was added at ꢀ70 ꢁC. Hydrolysis was carried out with
saturated NH4Cl solution. Recrystallization from DIPE gave 27b
(2.13 g, 72%) as colorless crystals. Anal. Calcd for C18H28N2O2: C,
71.02; H, 9.27; N, 9.20. Found: C, 70.87; H, 9.13; N, 9.14; mp:
128e131 ꢁC; Rf (PE/EtOAc 5:1) 0.20; 1H NMR (200 MHz CDC13):
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.02.056. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
1. (a) Clayden, J. Organolithiums: Selectivity for Synthesis; Vol. 23; Tetrahedron
Organic Chemistry Series; Pergamon: Oxford, UK, 2002 (b) Schlosser, M. Or-
ganometallics in Synthesis, 2nd ed.; Wiley: Chichester, UK, 2002.
2. See for example (a) Fitt, J. J.; Gschwend, H. W. J. Org. Chem. 1976, 41, 4029; (b)
Gschwend, H. W.; Rodriguez, H. R. Org. React.1979, 26,1; (c) Beak, P.; Snieckus, V.
ꢀ
Acc. Chem. Res. 1982, 15, 306; (d) Najera, C.; Sansano, J. M.; Yus, M. Tetrahedron
d
¼1.01 (s, 9H), 1.35 (s, 9H), 2.24 (s, 3H), 3.36 (d, J¼16 Hz, 1H), 4.64
2003, 59, 9255; (e) Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376; (f) Chadwick,
S. T.; Ramirez, A.; Gupta, L.; Collum, D. B. J. Am. Chem. Soc. 2007, 129, 2259.
3. Klis, T.; Lulinski, S.; Serwatowski, J. Curr. Org. Chem. 2008, 12, 1479.
4. Snieckus, V.; Macklin, T. Handbook of CeH Transformations; 2005; Vol. 1, pp
106e118 and 262e264.
(d, J¼16 Hz, 1H), 6.60 (br s, 1H), 7.17e7.30 (m, 4H); 13C NMR
(50 MHz, CDCl3):
d¼17.7 (q), 28.5 (2q), 40.6 (s), 50.7 (s), 57.0 (t),
126.4 (d), 128.6 (d), 129.5 (d), 131.2 (d), 135.4 (s), 142.1 (s), 168.2 (s),
178.8 (s).
5. Bolitt, V.; Mioskowski, C.; Reddy, S. P.; Falck, J. R. Synthesis 1988, 388.
6. Iwao, M.; Kuraishi, T. Org. Synth. 1996, 73, 85.
7. El-Hiti, G. A. Heterocycles 2000, 53, 1839.
8. Recent examples for substituted benzenes: (a) Clayden, J.; Turner, H.; Pickworth,
M.; Adler, T. Org. Lett. 2005, 7, 3147; (b) Chodakowski, J.; Klis, T.; Serwatowski, J.
4.4.7. 2-(1,1-Dimethylethyl)-1-ethylindole (32). Prepared according
to general procedure
D starting from 31 (0.50 g, 2.3 mmol,
ꢀ
1.0 equiv) dissolved in 7 mL of dry Et2O. t-BuLi (3.4 mL, 1.7 M so-
lution in heptane, 5.7 mmol, 2.5 equiv) was added at ꢀ80 ꢁC. The
reaction mixture was warmed to ꢀ20 ꢁC and stirred for 2 h. 10 mL
of H2O were added. Purification by column chromatography (PE/
EtOAc 50:1) gave 32 (0.37 g, 80%) as pale yellow liquid. For com-
bustion analysis the product was further purified by Kugelrohr
distillation (100e110 ꢁC, 0.04 mbar). Anal. Calcd for C14H19N: C,
83.53; H, 9.51; N, 6.96. Found: C, 83.35; H, 9.78; N, 6.83; mp:
128e131 ꢁC; Rf (PE/EtOAc 15:1) 0.60; 1H NMR (200 MHz CDC13):
Tetrahedron Lett. 2005, 46, 1963; (c) Clayden, J.; Dufour, J. Tetrahedron Lett. 2006,
47, 6945; (d) Burgos, P. O.; Fernandez, I.; Iglesias, M. J.; García-Granda, S.; Ortiz, F.
L. Org. Lett. 2008, 10, 537; (e) Wilkinson, J. A.; Raiber, E.-A.; Ducki, S. Tetrahedron
ꢀ
ꢀ
ꢀ
2008, 64, 6329; (f) Porcs-Makkay, M.; Komaromi, A.; Lukacs, G.; Simig, G. Tetra-
ꢀ
hedron 2008, 64, 1029; (g) Castanet, A.-S.; Tilly, D.; Veron, J.-B.; Samanta, S. S.;
Ganguly, T.; Mortier, J. Tetrahedron 2008, 64, 3331; (h) Michon, C.; Murai, M.;
Nakatsu, M.; Uenishi, J.; Uemura, M. Tetrahedron 2009, 65, 752; (i) Cuevas, J.-C.;
Snieckus, V. Tetrahedron Lett.1989, 30, 5837; (j) Metallinos, C.; Zaifman, J.; Dodge,
L. Org. Lett. 2008,10, 3527; (k) Metallinos, C.; Zaifman, J.; Dudding, T.; Van Belle, L.;
Taban, K. Adv. Synth. Catal. 2010, 352, 1967.
9. Recent examples for substituted heterocycles: (a) Philipova, I.; Dobrikov, G.;
Krumova, K.; Kaneti, J. J. Heterocycl. Chem. 2006, 43, 1057; (b) Robert, N.;
Bonneau, A.-L.; Hoarau, C.; Marsais, F. Org. Lett. 2006, 8, 6071; (c) Aliyenne, A.
O.; Khiari, J. E.; Kraïem, J.; Kacem, Y.; Hassine, B. B. Tetrahedron Lett. 2006, 47,
6405; (d) Comoy, C.; Banaszak, E.; Fort, Y. Tetrahedron 2006, 62, 6036; (e) Luisi,
R.; Capriati, V.; Florio, S.; Musio, B. Org. Lett. 2007, 9, 1263; (f) Clayden, J.;
Hennecke, U. Org. Lett. 2008, 10, 3567; (g) McLaughlin, M.; Marcantonio, K.;
Chen, C.; Davies, I. W. J. Org. Chem. 2008, 73, 4309; (h) Capriati, V.; Florio, S.;
Luisi, R.; Mazzanti, A.; Musio, B. J. Org. Chem. 2008, 73, 3197; (i) Affortunato, F.;
Florio, S.; Luisi, R.; Musio, B. J. Org. Chem. 2008, 73, 9214; (j) Cuevas, J.-C.; Patil,
P.; Snieckus, V. Tetrahedron Lett. 1989, 30, 5841.
d
¼1.41 (t, J¼7 Hz, 3H), 1.47 (s, 9H), 4.38 (q, J¼7 Hz), 6.38 (d, J¼1 Hz,
1H), 7.01e7.21 (m, 2H), 7.28 (dd, J¼8 Hz, J¼1 Hz, 1H), 7.54 (dd,
J¼8 Hz, J¼1 Hz, 1H); 13C NMR (50 MHz, CDCl3):
¼14.9 (q), 30.5 (q),
d
32.4 (s), 39.6 (t), 98.0 (d), 109.2 (d), 119.1 (d), 120.1 (d), 120.7 (d),
127.5 (s), 137.3 (s), 148.4 (s).
4.4.8. N-Ethyl-N-(2-ethylphenyl)-2,2-dimethylpropanamide
(35). Prepared according to general procedure B starting from N,2-
diethylbenzolamine (1.40 g, 9.4 mmol). Purification by Kugelrohr
distillation (90e100 ꢁC, 0.03 mbar) gave 35 (1.70 g, 78%) as colorless
liquid. Anal. Calcd for C15H23NO: C, 77.21; H, 9.93; N, 6.00 Found: C,
77.04; H, 10.13; N, 6.05; Rf (PE/EtOAc 5:1) 0.50; 1H NMR (200 MHz
ꢀ
10. Recent examples for directed ortho-lithiation (a) Gomez, A. M.; Casillas, M.;
ꢀ
Rodríguez, B.; Valverde, S.; Lopez, J. C. Arkivoc 2010, iii, 288; (b) Stavrakov, G.;
Simova, S.; Dimitrov, V. Tetrahedron: Asymmetry 2008, 19, 2119; (c) Kessar, S. V.;
Singh, P.; Singh, K. N.; Bharatam, P. V.; Sharma, A. K.; Lata, S.; Kaur, A. Angew.
Chem., Int. Ed. 2008, 47, 4703; (d) Flemming, J. P.; Berry, M. B.; Brown, J. M. Org.
Biomol. Chem. 2008, 6, 1215; (e) Kauch, M.; Snieckus, M.; Hoppe, D. J. Org. Chem.
2005, 70, 7149; (f) Tofi, M.; Georgiou, T.; Montagnon, T.; Vassilikogiannakis, G.
Org. Lett. 2005, 7, 3347.
CDC13):
(q, J¼7 Hz, 2H), 3.65 (q, J¼7 Hz, 2H), 6.95e7.01 (m, 2H), 7.10e7.18
(m, 1H), 7.24e7.30 (m, 1H); 13C NMR (50 MHz, CDCl3):
d
¼1.02 (s, 9H), 1.13 (t, J¼7 Hz, 3H), 1.25 (t, J¼7 Hz, 3H), 2.66
11. Recent examples for
a-lithiation: (a) Musio, B.; Clarkson, G. J.; Shipman, M.;
d
¼12.6 (q),
Florio, S.; Luisi, R. Org. Lett. 2009, 11, 325; (b) Strohmann, C.; Gessner, V. H.
Angew. Chem., Int. Ed. 2007, 46, 8281; (c) Eisch, J. J.; Adeosun, A. A. Eur. J. Org.
Chem. 2005, 993; (d) Berkheij, M.; van der Sluis, L.; Sewing, C.; den Boer, D. J.;
Terpstra, J. W.; Hiemstra, H.; Iwema, B.; Wouter, I.; van den Hoogenband, A.; van
Maarseveen, J. H. Tetrahedron Lett. 2005, 46, 2369.
15.4 (q), 28.5 (t), 29.4 (q), 40.8 (s), 47.6 (t), 126.8 (d), 127.2 (d), 128.7
(d), 129.2 (d), 143.2 (s), 145.2 (s), 177.2 (s).
12. For example: Dharanipragada, R.; Ferguson, S. B.; Diederich, F. J. Am. Chem. Soc.
4.4.9. 3-(3-Ethyl-2-(ethylamino)phenyl)-2,2,4,4-tetramethylpentan-
3-ol (36). Prepared according to general procedure D starting from
35 (0.50 g, 2.3 mmol, 1.0 equiv) dissolved in 7 mL of dry Et2O. Then
t-BuLi (3.3 mL, 1.7 M solution in heptane, 5.4 mmol, 2.6 equiv) was
added at ꢀ70 ꢁC. The reaction mixture was warmed to ꢀ20 ꢁC and
stirred for 4 h. Subsequently 10 mL of saturated NH4Cl were added.
Purification by column chromatography (PE/EtOAc 30:1) gave 36
(0.33 g, 52%) as colorless crystals. For combustion analysis the
product was further purified by recrystallization from PE. Anal.
Calcd for C19H33NO: C, 78.29; H, 11.41; N, 4.81. Found: C, 78.29; H,
1988, 110, 1679.
13. (a) Hayashi, Y.; Tamura, T.; Shoji, M. Adv. Synth. Catal. 2004, 346, 1106; (b)
Solladie-Cavallo, A.; Lupattelli, P.; Bonini, C.; Ostuni, V.; Di Blasio, N. J. Org.
Chem. 2006, 71, 9891.
14. (a) Mahboobi, S.; Pongratz, H. Synth. Commun. 1999, 29, 1645; (b) Csanyi, D.;
Timari, G.; Hajos, G. Synth. Commun. 1999, 29, 3959; (c) Soll, R. M.; Guinosso, C.;
Asselin, A. J. Org. Chem. 1988, 53, 2844.
15. (a) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798; (b) Reed, J. N.;
Rotchford, J.; Strickland, D. Tetrahedron Lett. 1988, 29, 5725; (c) Cho, I. S.; Gong,
L.; Muchowski, J. M. J. Org. Chem. 1991, 56, 7288; (d) Wender, P. A.; White, A. W.
Tetrahedron Lett. 1981, 22, 1475.
16. Su, G.-F.; Huo, L.-N.; Chen, R.; Zhao, F.-L.; Guan, Y.-F. Huaxue Xuebao 2008, 66, 2717.

2904
M. Schmid et al. / Tetrahedron 67 (2011) 2895e2904
17. Carr, A. D.; Neuss, J. C.; Orchard, M. G.; Porter, D. W. PCT Int. Appl., WO
2008012524 A1 20080131, 2008; Chem. Abstr. 2008, 148, 191838.
18. Pang, Y. -P.; Tumer, N. E.; Millard, C. B. PCT Int. Appl., WO 2010053606 A2
20100514, 2010; Chem. Abstr. 2010, 152, 542889.
22. (a) Clark, R. D.; Muchowski, J. M.; Flippin, L. A.; Repke, D. B.; Souchet, M.
Synthesis 1991, 871; (b) Cervantes, A.; Contreras, C. A.; Guzman, A.; Vale, E. E.;
Velarde, E.; Berthiaume, S. L.; Muchowski, J. M. Can. J. Chem. 1995, 73, 336.
23. Fuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44, 1133.
19. Schroeder, W., Jr.; Smart, R. P.; Morgan, R. M.; Walker, A. J. PCT Int. Appl., WO
2009100323 A2 20090813, 2009; Chem. Abstr. 2009, 151, 236681.
20. Desai, V.; Patel, D.; Desai, C. M.; Desai, J. M.; Mehta, A. G. J. Inst. Chem. (India)
2005, 77, 58.
24. Houlihan, W. J.; Parrino, V. A.; Uike, Y. J. Org. Chem. 1981, 46, 4511.
25. Stanetty, P.; Koller, H.; Mihovilovic, M. D. J. Org. Chem. 1992, 57, 6833.
26. The product 18 could not be separated from the substrate 17 due to identical Rf
values and hence a mixture of these two compounds was isolated. According to
integration of the 1H NMR spectrum, 0.17 g (28%) of 18 was obtained.
€
21. Hellwinkel, D.; Lammerzahl, F.; Hofmann, G. Chem. Ber. 1983, 116, 3378.