N-alkylation of lactams with secondary heterobenzylic bromides

Article abstract of DOI:10.1016/j.tetlet.2014.08.060

We herein report a general N-alkylation reaction of lactams with secondary heterobenzylic bromides. This methodology features mild reaction condition, moderate to high product isolation yield, and broad substrate scope. Good chemical and structural tolerance has also been demonstrated by both the secondary heterobenzylic bromides and lactam substrates.

Full text of DOI:10.1016/j.tetlet.2014.08.060

Tetrahedron Letters 55 (2014) 5591–5594
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Digest Paper
N-alkylation of lactams with secondary heterobenzylic bromides
⇑
Ming Yu , Karis Stevenson, Gene Zhou
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report a general N-alkylation reaction of lactams with secondary heterobenzylic bromides.
This methodology features mild reaction condition, moderate to high product isolation yield, and broad
substrate scope. Good chemical and structural tolerance has also been demonstrated by both the second-
ary heterobenzylic bromides and lactam substrates.
Received 16 July 2014
Revised 8 August 2014
Accepted 13 August 2014
Available online 19 August 2014
Ó 2014 Published by Elsevier Ltd.
Keywords:
Lactam
N-alkylation
Sodium hydride
Secondary heterobenzylic bromide
Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5591
Results and discussions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5592
Acknowledgment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5594
Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5594
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5594
Introduction
Y
Ar
O
Ar
Y
O
Base
Lactam is a chemical structure frequently encountered in
organic chemistry. It is prevalent in naturally occurring products1
and widely applied in the design and synthesis of bioactive
compounds, including b-lactam antibiotics.2 While N-alkylation
of lactams or amides has been well documented with primary ben-
zylic halides 2a (Ar = Ph; Y = H; R = H; X = Cl, Br, or I, Scheme 1),3
secondary benzylic halides 2b (Ar = Ph; R = alkyl; X = Cl, Br, or I),
however, are less reported. A successful secondary benzylic halide
is usually boosted by an electronic withdrawing group at either the
benzylic position (e.g., R = –CO2Et)4 or the phenyl ring (e.g., Y =
4-fluoro or 3,4,5-trifluoro).5,6 We postulated that the electronic
synergy from these substituents is important for the halides to
reach the desired reactivity. Heteroaromatic cycles are generally
believed to be more electron deficient than benzene rings (notable
exceptions include pyran, thiophene, pyrrole, etc.); therefore
the corresponding secondary heterobenzylic halides may be
+
HN
R
N
R
X
1a
2a-c
3a-c
Scheme 1. N-alkylation of lactams with benzylic halides.
N
N
2d
O
O
Br
*
HN
N
Me
Cl
Me
Cl
NaH, DMF, 0 °C- rt
82%
Cl
Cl
4
5 (S/R: 1:2)
⇑
Corresponding author. Tel.: +1 650 244 2050; fax: +1 650 837 9369.
E-mail address: yum@amgen.com (M. Yu).
Scheme 2. A recent discovery.
http://dx.doi.org/10.1016/j.tetlet.2014.08.060
0040-4039/Ó 2014 Published by Elsevier Ltd.

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M. Yu et al. / Tetrahedron Letters 55 (2014) 5591–5594
Table 2
considered more reactive than secondary benzylic halides for this
reaction. But given the fact that plain secondary benzylic halides
(2c, Ar = Ph; Y = H; R = alkyl; X = Cl, Br, or I) were reported only
sporadically for amide or lactam N-alkylation,7 the real reactivity
of secondary heterobenzylic halides, especially in plain form, is
not necessarily certain for this reaction.8 In this Letter, we report
the general observations we made with a large variety of second-
ary heterobenzylic bromides and lactams for this transformation.
Scope on the aromatic component of bromides
O
Ar
O
Ar
NaH (1.5 equiv)
DMF, rt, 3.0 hr
H
N
N
Br
+
1b
2d-l
3d-l
a
Entry
1
Heterobenzylic bromide
Ar
Product/yield (%)
Results and discussions
2d
N
N
3d/85
Our MDM2/P53 inhibitor program recently needed the
synthesis of intermediate 5 (Scheme 2). While substrate 49 had
been previously N-alkylated with small alkyl halides (e.g., with
2-iodopropane or 3-bromopentane as the solvent in the presence
of NaH, 120 °C, 3–6 h, 46–58%),9–11 reaction of 4 with solid 1-(2-
pyridyl)-propyl bromide 2d, under the compelling steric hindrance
from both components, was not necessarily a warranted success.
As a matter of fact, the bromide 2d proved to barely survive harsh
reaction conditions. We envisioned that polar aprotic solvents such
as N,N-dimethylformamide (DMF) would benefit this transforma-
tion through better solvolysis of the transitional 2-oxopiperidin-
1-ide salt upon deprotonation of 4. Sodium hydride (NaH) could
serve as the base for a complete and irreversible deprotonation
of 4, thus driving the reaction to completion. From the first attempt
we were pleased to find that the reaction of 4 and 2d (1.3 equiv)
promoted by NaH in DMF at ambient temperature, provided the
desired product 5 in 82% isolated yield (a 1:2 mixture of two dia-
stereoisomers).12 The efficiency observed herein was in contrast
to what we previously experienced with many other electrophiles
2
3
2e
2f
3e/84
3f/87
N
4
5
2g
2h
N
N
N
N
3g/83
3h/84
6
7
8
2i
2j
3i/61
3j/88
3k/79
N
N
S
(except
a
-bromo ester).9 Encouraged by this result, we set out to
study this reaction in general chemical settings to contribute to
public chemical community as reference for the scope and
limitations of lactam N-alkylation with secondary heterobenzylic
bromides.
S
2k
O
In experiments designed for reaction condition perfection,
piperidin-2-one 1b was selected as a model substrate for 2-(1-bro-
mopropyl)pyridine 2d (1.3 equiv) (Table 1). Among the solvents
examined, DMF proved to be the most efficient, and facilitated
complete consumption of 1b within one hour at room tempera-
ture. Purification of the crude product by flash chromatography
on silica gel column provided the desired product 3d in 85% yield.
The reaction was less satisfactory in solvents of decreased polarity
N
9
2l
3l/73
a
Isolated yield.
(55% and 51% in toluene and THF, respectively), possibly due to
weak solvolysis of the intermediate sodium 2-oxopiperidin-1-ide
salt. Of note is that there was no O-alkylation product obtained
from this reaction. In addition to NaH, other common bases were
also screened in an attempt to find a more manageable surrogate.
Neither lithium, sodium, or potassium hexamethyldisilazane
(LiHMDS, NaHMDS, KHMDS) showed acceptable levels of reaction
yield (17%, 28%, and 21%, respectively), although they are usually
effective for similar reactions with simple electrophiles. Potassium
tert-butoxide (KOtBu) led to poor results (11%), even after pro-
longed reaction times (15 h) at raised temperatures (100 °C).
Cesium and potassium carbonate (Cs2CO3 and K2CO3) led to very
low product yield but recovery of the starting material 1b.
With reaction conditions finalized, we first investigated the
scope of the bromide component. As illustrated in Table 2, a large
variety of secondary heterobenzylic bromides were tested for
model substrate 1b. Compared to the 2-pyridylic bromide 2d, the
3- and 4-pyridylic counterparts (2e and 2f) were equally reactive
and resulted in the corresponding products in 84% and 87% yields,
respectively. Similar levels of efficiency were also observed with
the 2-pyrimidine- and pyrazine-derived bromides (2g and 2h).
The secondary benzylic bromide 2i was less effective but still
provided the desired product in 61% yield. As represented by
2j–l, five-membered heterocycles were also investigated for this
reaction. Overall a trend of good efficiency was observed across
Table 1
Optimization of reaction condition
O
N
H
N
NaH
O
N
+
N
Br
1b
2d
3d
Entry Base
Solvent
DMF
Toluene 23
THF
Temperature
(°C)
Time
(h)
Isolated yield
(%)
1
2
NaH
NaH
NaH
23
1.0
3.0
4.0
85
55
51
3
23
4
LiHMDS
DMF
23
2.5
17
5
NaHMDS DMF
23
4.0
28
6
7
8
9
10
11
KHMDS
tBuOK
tBuOK
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
23
23
100
23
100
23
4.0
15.0
2.0
15.0
5.5
15.0
21
<5a
11
<3a
<5a
<3a
a
Yields based on GC–MS analysis of crude reaction mixture.

M. Yu et al. / Tetrahedron Letters 55 (2014) 5591–5594
5593
Table 3
Table 4
Scope of heterocyclic ring substitution pattern
Scope on the alkyl groups at the arylic position
O
Ar
O
Ar
NaH (1.5 equiv)
DMF, rt, 3.0 hr
O
H
N
R
N
N
NaH (1.5 equiv)
DMF, rt, 3.0 hr
O
N
R
H
Br
2d, 2m-s
+
N
N
Br
1b
3d, 3m-s
1b
2d, t-x
3d, t-x
Entry
1
Heterobenzylic Bromide
Ar
Product/yielda (%)
a
Entry
Heterobenzylic bromide
R
Product/yield (%)
2d
N
3d/85
1
2
3
4
5
2t
2d
2u
2v
–Me
–Et
3t/89
3d/85
3u/69
3v/<2b
3w/37
–nPr
–iPr
–Ph
H3C
N
2
3
4
2m
2n
2o
3m/82
2w
F3C
N
N c
Br
6
2x
3x/62
3n/78
3o/87
a
b
c
Br
N
Isolated yield.
Yield based on GC–MS analysis of crude reaction mixture.
The complete structure (instead of R) of 2x is as shown.
CF3
Table 4 summarizes the effects from the alkyl groups (–R) at the
benzylic position of the heterobenzylic bromides. It had been clear
that the reaction efficiency gradually declined with increased steric
bulkiness of these groups (2t < 2d < 2u < 2v). Reactions with the
bromide bearing isopropyl group at this position (2v) led only to
a trace amount of 3v. The phenyl substituted bromide 2w provided
the desired product 3w in 37% yield. Also interesting is the fact that
the constrained 8-bromo-5,6,7,8-tetrahydroquinoline bromide 2x
was fairly effective as well (62%).
The scope of lactam is illustrated by commercially available
substrates 1a–g as listed in Table 5. Lactams in 5- to 7-member
ring size (1a, 1b, and 1c) demonstrated equally strong reactivity
toward 2d. Azetidin-2-one, however, has not been successful for
5
2p
3p/77
N
N
6
7
2q
2r
3q/31
3r/22
CH3
N
Br
iPr
8
2s
3s/84
N
S
2d so far under the established conditions. The
v-lactam substrate
was also tested in multiple substitution contexts. Introducing a
methyl group immediately next to the amide motif at either side
(1d and 1e) did not markedly impair the reactivity. Moreover, as
indicated by the high yields from 1d and 1e (82% and 85%, respec-
tively), increased steric bulkiness adjacent to the carbonyl element
did not result in a negative impact on the reaction either. These
data therefore forecast that a comprehensive collection of lactams
would be suitable for the discussed transformation.
a
Isolated yield.
these species as well. These results suggested that electron defi-
ciency on the aromatic ring benefits the electrophilicity of the bro-
mides in general, and that there is no obvious correlation of
reactivity versus heteroatom position.
Studies on the bromides were extended to the substitution
pattern around the heterocycles (Table 3). As exemplified by
2m–p, small alkyl (e.g., –CH3) and electron withdrawing groups
(e.g., –CF3, and –Br) were introduced at multiple positions around
the 2-pyridyl ring. These modifications demonstrated good com-
patibility (71–87%) to the reaction. Electron donating groups
(e.g., –OMe) at the 5- or 6-position of the 2-pyridyl ring were also
tolerated in reaction with 4 (data not included). Ring substitution
adjacent to the alkylation site, as illustrated by 2q and 2r, was,
however, significantly unfavorable. We attribute it to the excessive
steric congestion that resulted from these ortho-modifications. It is
noteworthy that the methoxy group at these positions led to no
desired product but complete decomposition of the bromides
under the reaction condition. It is likely that the methoxy group
under this setting engages in a neighboring group participation
effect on the benzylic position, thus disrupting the N-alkylation
process. Finally, reaction of 1b with 2-(4-isopropyl-2-thiazol-
yl)propyl bromide 2s resulted in 84% yield. This result, compared
to the data on 2j in Table 2, predicts good toleration of ring mod-
ifications for secondary five-membered heterobenzylic bromides
as well.
The secondary heterobenzylic bromides in this Letter were syn-
thesized following either of the two general procedures as outlined
in Scheme 3. The bromides 2d, 2i, and 2j (Table 2) were prepared
through direct bromination of the commercially available ArCH2Et
with N-bromosuccinimide (NBS) in the presence of azobisisobuty-
ronitrile (AIBN). Similarly, reactions of 5,6,7,8-tetrahydroquinoline
provided 2x. Bromides 2e–h and 2k–w (Tables 2–4) were synthe-
sized from the appropriate heterobenzylic carboxaldehydes via
Grignard reaction, followed by bromination of the resulting alco-
hols with CBr4 and PPh3.
A general experimental procedure for this reaction is as follows:
To an oven dried 25 mL round flask charged with stir bar under N2
atmosphere was added 1b (3.0 mmol, 1.0 equiv) followed by DMF
(6.0 mL). The reaction flask was placed into a 0 °C ice bath. To the
solution under N2 was added NaH (3.9 mmol, 1.3 equiv, 60%
dispersed in mineral oil). After 20 min, to the solution was added
2d (3.6 equiv, 1.2 equiv). The reaction flask was then removed from
the ice bath and allowed to stir at ambient temperature for
1.0–15.0 h. Reaction aliquot samples were taken for LCMS analysis
to monitor the reaction to completion. The reaction mixture was
slowly poured into a saturated aqueous NH4Cl solution (5 mL)

5594
M. Yu et al. / Tetrahedron Letters 55 (2014) 5591–5594
Table 5
Acknowledgment
Generality of the lactam substrates
The authors thank Dr. Daqing Sun, Dr. Zhihong Li, and Dr. Xiaoqi
Chen for discussions during the manuscript preparation.
O
N
O
NaH (1.5 equiv)
DMF, rt, 3.0 hr
N
HN
R
( )n
N
Supplementary data
Br
R
( )n
Supplementary data (representative experimental procedures,
characterization data, and copies of NMR) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.08.060.
1a-g
2d
3d, 6a, 6c-g
Entry
1
Lactam Substrate
Product/yielda (%)
O
1b
3d/85
6a/83
HN
References and notes
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1e
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6e/78
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67–88%; (b) RMgBr (1.5–2.5 equiv), THF, 0 °C, 44–84%; (c) CBr4 (1.3–2.0 equiv), Ph3P
(2.2 equiv), THF, 34–88%.
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McMinn, D.; Oliner, J. D.; Osgood, T.; Rew, Y.; Saiki, A. Y.; Shaffer, P.; Yan, X.; Ye,
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Gonzalez Lopez de Turiso, F.; Gribble, M. W. Jr.; Gustin, D. J.; Heath, J. A.;
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under N2, diluted with water (10 mL), and extracted with EtOAc
(15 mL Â 2). The organic layers were combined, washed with
water (10 mL), brine (5 mL), and dried over MgSO4. After the
removal of the organic solvents under reduced pressure, the result-
ing residue was purified by flash chromatography on 24 g silica gel
column using 0–60% EtOAc/hexanes as eluent to provide the
desired product 3d.
In conclusion, we have reported a conventional N-alkylation
reaction of lactams with secondary heterobenzylic bromides. This
reaction features mild reaction conditions, moderate to high prod-
uct isolation yields, and broad substrate scope on both of the reac-
tion components. High compatibility of substrate diversity has also
been demonstrated with secondary heterobenzylic bromides and
lactam substrates in diverse chemical settings.