Kinetic study of the 7- endo selective radical cyclization of N-tert-butyl-o-bromobenzylmethacryl amides: Kinetic investigation of the cyclization and 1,7-hydrogen transfer of aromatic radicals

Article abstract of DOI:10.1021/jo400326b

A kinetic investigation of the radical cyclization of N-tert-butyl-o- bromobenzylmethacryl amides to give 2-benzazepines via 7-endo selective cyclization was undertaken. The aryl radical generated from the amide precursor by treatment with Bu₃SnH gave the three compounds, which are a 7-endo cyclized adduct, a 6-exocyclized adduct, and a reduced product. The cyclization reactions under various Bu₃SnH concentrations were traced by GC analysis. The 7-endo/6-exo selectivity was constant irrespective of variation in Bu₃SnH concentration. These results revealed that regioselectivity is controlled in a kinetic manner and that there is no possibility of a neophyl rearrangement. The use of Bu₃SnD revealed that 1,7-hydrogen transfer, in which an aryl radical abstracts a hydrogen atom from the methallylic methyl group, occurs during the reaction. Hydrogen abstraction from toluene, the reaction solvent, was also observed. The 1,7-transfer rate depended on the Bu₃SnX (X = H or D), and the reaction kinetics was examined. The k_H/k_D value for the hydrogen abstraction of aryl radical from Bu₃SnX (X = H or D) was estimated using 4-bromoanisol. The utilization of these values revealed the overall reaction kinetics and relative rates for the cyclization and reduction by Bu₃SnX (X = H or D). Kinetic parameters for hydrogen abstraction from toluene by aryl radicals were also estimated.

Full text of DOI:10.1021/jo400326b

Article
pubs.acs.org/joc
Kinetic Study of the 7-endo Selective Radical Cyclization of N-tert-
Butyl‑o‑bromobenzylmethacryl Amides: Kinetic Investigation of the
Cyclization and 1,7-Hydrogen Transfer of Aromatic Radicals
Akio Kamimura,* Tomoko Kotake, Yuriko Ishihara, Masahiro So, and Takahiro Hayashi
Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan
S
* Supporting Information
ABSTRACT: A kinetic investigation of the radical cyclization of N-tert-butyl-o-bromobenzylmethacryl amides to give 2-
benzazepines via 7-endo selective cyclization was undertaken. The aryl radical generated from the amide precursor by treatment
with Bu3SnH gave the three compounds, which are a 7-endo cyclized adduct, a 6-exocyclized adduct, and a reduced product. The
cyclization reactions under various Bu3SnH concentrations were traced by GC analysis. The 7-endo/6-exo selectivity was constant
irrespective of variation in Bu3SnH concentration. These results revealed that regioselectivity is controlled in a kinetic manner
and that there is no possibility of a neophyl rearrangement. The use of Bu3SnD revealed that 1,7-hydrogen transfer, in which an
aryl radical abstracts a hydrogen atom from the methallylic methyl group, occurs during the reaction. Hydrogen abstraction from
toluene, the reaction solvent, was also observed. The 1,7-transfer rate depended on the Bu3SnX (X = H or D), and the reaction
kinetics was examined. The kH/kD value for the hydrogen abstraction of aryl radical from Bu3SnX (X = H or D) was estimated
using 4-bromoanisol. The utilization of these values revealed the overall reaction kinetics and relative rates for the cyclization and
reduction by Bu3SnX (X = H or D). Kinetic parameters for hydrogen abstraction from toluene by aryl radicals were also
estimated.
this ambiguity and establish the reaction mechanism, we
attempted to use N-tert-butylamide instead of N-methyl amide.
Because of the steric bulkiness of the tert-butyl group, this new
precursor contains only one rotational isomer that is favorable
for radical cyclization. With this precursor, we assumed that a
kinetic study of the cyclization would afford unambiguous
results in terms of the reaction mechanism. In this study, we
report the kinetic study of 7-endo selective radical cyclization
and estimated the kinetic parameters. We also identified a novel
1,7-hydrogen transfer7,8 during the reaction.9 Hydrogen
transfer from toluene as the reaction solvent is also discussed.
INTRODUCTION
■
The radical cyclization is recognized as a useful methodology in
organic synthesis.1 In particular, the formation of a five- or six-
membered ring is effectively achieved through the reaction, and
many useful molecules have been constructed via radical
cyclization. Recently, we established the straightforward
preparation of 2-benzazepines,2 which have been of interest
because of their potentially unique biological activity.3 Our
synthesis progressed smoothly via the 7-endo selective radical
cyclization of the aryl radical. We successfully identified
interesting biological activity in these molecules, in which cell
migration was stimulated, but cell proliferation was not
accelerated.4 The reagents appear to have potential as a new
drug candidate for skin wound healing; therefore, we examined
their structure−activity relationship.4,2b We also reported a
mechanistic study of the 7-endo selective radical cyclization and
estimated kinetic parameters for 7-endo and 6-exo cyclization.5
Although the kinetics was well established, there remains some
ambiguity because the cyclization precursor contains rotational
isomers due to the presence of a tertiary amide, requiring
careful consideration of its conformational analysis.6 To remove
RESULTS AND DISCUSSION
■
Preparation of Starting Materials and Products. The
preparation of the cyclization precursor 1, 7-endo product 2, 6-
exo product 3, and reduced product 4 was carried out in the
following manner (Scheme 1). The exposure of 1-bromo-2-
(bromomethyl)-4-methoxybenzene 5 to tert-butylamine gave
Received: February 12, 2013
© XXXX American Chemical Society
A
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a
trations. Three equivalents of Bu3SnH was used for each
reaction, and all products were monitored by GC or GC-MS
analyses. The product yields were estimated by a curve-fitting
method in the presence of anthracene as an internal standard.
Table 1 shows GC yields after 15−120 min of reaction time.
Scheme 1
Table 1. Yields of 2, 3, and 4 from 1 under the Various
a
Conditions
2;
3;
4;
sum of
the
yields
time
temp
(°C)
yield
yield
yield
b
b
b
entry [Bu3SnH] (min)
(%)
(%)
(%)
1
2
0.05
0.05
0.05
0.10
0.10
0.10
0.15
0.15
0.15
0.20
0.20
0.20
60
120
15
70
78
90
70
78
90
70
78
90
70
78
90
74
78
71
77
81
77
70
78
68
70
77
71
9
7
8
6
91
91
86
96
98
94
91
94
87
90
93
90
3
9
6
4
60
9
10
7
5
60
10
7
6
17
7
a
7
20
8
13
7
Reagents and conditions: (i) tBuNH2, CH2Cl2, rt, 98%; (ii) CH2
8
120
9
C(CH3)COCl, DMAP, Et3N, CH2Cl2, 78%; (iii) Bu3SnH, AIBN,
toluene, 110 °C, 3 h, 62%; (iv) CH2CHCOCl, DMAP, Et3N,
CH2Cl2, 77%; (v) Bu3SnH, AIBN, toluene, 110 °C, 3 h, 67%; (vi)
BuLi, THF, −50 °C, then MeI, 80%; (vii) tBuNH2, CH2Cl2, rt, 92%;
(viii) CH2CH(CH3)COCl, DMAP, Et3N, CH2Cl2, 89%.
9
6.5
9
10
12
7
c
c
c
10
11
12
36
120
10
8
9
9
10
a
Reagents and conditions: (i) Bu3SnH (3 equiv), AIBN, benzene or,
b
c
N-(2-bromo-5-methoxybenzyl)-2-methylpropan-2-amine 6 in
98% yield. The methacroylation of 6 proceeded smoothly by
treatment with methacryloyl chloride in the presence of DMAP
under standard amidation conditions, and the desired precursor
tert-butylbenzene. GC yields. tert-Butylbenzene was used as the
reaction solvent.
1
1 was obtained in 78% yield. H NMR spectrum of compound
1 showed sharp signals, suggesting that compound 1 contains
only one rotational isomer. Variable-temperature NMR showed
no coalescence in any signals. The desired 7-endo adduct 2 was
prepared by the radical cyclization of 1 to give a mixture of 2, 3,
and 4, following flash chromatography separation afforded
compound 2 in 62% yield. The yield of 2 was very high
compared with the cyclization from N-methyl amide.5 These
results clearly indicated that the free rotation around the C−N
bond in 1 was fixed, and thus compound 1 contained only one
rotamer that is favorable to the radical cyclization. Although the
separation of the minor product 3 from the reaction mixture
was possible using a recycle GPC apparatus, compound 3 was
separately prepared via 6-exo selective cyclization followed by
methylation reaction. Thus, tert-butylamine 6 was acrylated
with acryloyl chloride to give 7 in 77% yield, which underwent
radical cyclization by treatment with Bu3SnH to give
dihydroisoquinolin-3-one 8 in 67% yield.10 The methylation
of 8 was carried out by treatment with BuLi followed by MeI to
give 3 in 80% yield. The reduce product 4 was prepared in a
manner similar to the preparation of 1.
The reaction was carried out at three temperatures, 70, 78, and
90 °C. tert-Butylbenzene was used as the reaction solvent at 90
°C instead of benzene. As the sum of the yields always
exceeded 85%, we anticipated that most of the reaction
products were traced by this method.
We next investigated the changes in the yields of 2, 3, and 4
according to reaction time. Figure 1 shows a typical curve for
the reaction at 78 °C, and Figure 2 shows an expansion of the
first 15 min of this experiment.
The reaction was completed after approximately 20 min, and
from then, the yields of 2 and 3 remained unchanged. The
yields of 4 slightly decreased as the reaction time increased,
probably due to further polymerization that consumed
compound 4. We investigated the early stage of the reaction
and found that the yields of 2, 3, and 4 increased in proportion
to the reaction time after a short induction period. Yields and
time were found to fit to a linear relationship, with correlation
factors of greater than 0.99. The calculated slopes represent
relative rates for the formation of each product. Their values,
k
7obs, k6obs, and kredobs, are presented in Table 2 after
Investigation of the Products Distribution of the
Reaction. With all of the materials in the reaction in hand, we
examined radical cyclization using various Bu3SnH concen-
normalization (see footnote in Table 2). These values also
represent the yield of 2, 3, and 4 based on the relative reaction
rate.
B
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Figure 1. Typical time course for the reaction of 1 with Bu3SnH (0.1 M), 78 °C. Red: compound 2; Blue: compound 3; Green: compound 4.
Figure 2. Expansion of Figure 1 for the first 15 min. Red: compound 2. Blue: compound 3. Green: compound 4.
a
Table 2. Normalized kobs Data and k7/k6 Values for the Reaction
entry
[Bu3SnH] (M)
temp (°C)
k7obs (2; yield)
k6obs (3; yield)
kredobs (4; yield)
k7/k6
1
2
0.05
0.10
0.15
0.20
0.05
0.10
0.15
0.20
0.05
0.10
0.15
0.20
70
70
70
70
78
78
78
78
90
90
90
90
79.88 0.44
77.83 0.63
75.45 0.41
74.84 0.50
81.20 0.48
78.45 0.62
77.58 0.42
75.67 0.43
80.37 1.47
78.61 0.20
76.78 1.22
76.13 0.82
9.68 0.15
9.90 0.27
8.73 0.07
9.02 0.11
9.39 0.22
9.43 0.43
9.42 0.28
9.10 0.14
9.34 1.04
10.91 0.17
9.93 0.42
9.62 0.19
10.44 0.50
12.26 0.53
15.55 0.04
16.14 0.40
9.41 0.26
12.12 0.19
13.00 0.14
15.23 0.29
10.29 0.43
11.20 0.37
13.29 0.92
14.25 0.64
8.25
7.86
8.64
8.30
8.65
8.32
8.24
8.31
8.61
7.71
7.74
7.91
3
4
5
6
7
8
9
10
11
12
a
All kobs values were normalized to k7obs + k6obs + kredobs = 100 for each entry.
C
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Scheme 2
The experiments were performed at least three times for each
entry, and the average values are shown in Table 2. These
values reflect how fast each product forms, and their ratios
represent the selectivity of the reaction under given conditions.
As the Bu3SnH concentration increased, k7obs and k6obs
decreased, while kredobs increased. This means that reduction
was preferred with increasing Bu3SnH concentration. The
reaction temperature appeared to have no significant influence
on these values. The ratio between k7obs and k6obs, k7/k6,
represents the relative rate for 7-endo/6-exo cyclization. The
calculated k7/k6 ratio was 8.26 0.40 at 70 °C, 8.38 0.27 at
78 °C, and 7.99 0.62 at 90 °C. Thus, the k7/k6 ratios were
almost constant across these three temperatures. This finding
clearly suggests that no rearrangement occurs between 7-endo
adduct and 6-exo adduct radicals and that the 7-endo/6-exo
selectivity of aryl radical cyclization is determined kinetically.
This is consistent with our previous reported results.5 Before
discussing these data further, we examined the reaction rate
using Bu3SnD.
to our surprise, 4D contained two products, depending on the
Bu3SnD concentration. Thus, the mass patterns, particularly
around m/z = 69 (allylic cation fragment) and m/z 121 (5-
methoxybenzyl cation fragment), varied with the Bu3SnD
concentration. One isomer 4Da contains a deuterium atom at
the aromatic carbon, while the other isomer 4Db contains a
deuterium atom at the allylic methyl group. NMR spectra of
4Db, isolated from the reaction, and 4Da, prepared separately,
were consistent with this assumption. Thus, these data strongly
suggest that there is a pathway in which the aryl radical
abstracts the allylic hydrogen in an intramolecular manner to
give an allylic radical, which then abstracts deuterium from
Bu3SnD giving 4Db. In other words, a 1,7-hydrogen shift
should be included as an alternative route for the formation of
reduced product 4. Scheme 4 shows our revised reaction
process. Reduction to 4 has two routes: the direct reduction of
an aryl radical by tin deuteride, and reduction via 1,7-hydrogen
transfer. Note that these two routes cannot be distinguished by
product distribution analysis when Bu3SnH is used as the
reducing reagent.
The estimation of 4Da and 4Db ratios by mass fragment
patterns was performed. The ratios were estimated by mass
fragment pattern simulation. We consulted tables for the
fragment at around 69 and 121 and estimated the D contents of
these fragments. On the basis of these values, we determined
the product ratios of 4Da and 4Db. The results are summarized
in Table 3. Plots of 4Da/4Db versus the Bu3SnD concentration
in the reaction carried out at 78 °C are depicted in Figure 3.
GC yields revealed that compounds 2D, 3D, and 4D were
obtained in yields similar to those obtained by the reaction
using Bu3SnH (entries 1−12). Plots of 4Da/4Db ratios
obtained in the reaction at 78 °C versus Bu3SnD concentration
indicated a linear relationship, as shown in Figure 3. Plots from
other reaction temperature conditions also showed a clear
linear relationship passing through the zero point. The slope
was calculated by the least-squares method to be 3.33 for 70 °C,
3.42 for 78 °C, and 3.62 for 90 °C. The correlation coefficients
were greater than 0.99 in all cases. Thus, the D distribution
ratios in 4D depended on the Bu3SnD concentration. As the
Bu3SnD concentration increased, 4Da, the direct reduction
product, became the major product. Based on these plots, the
present 1,7-hydrogen transfer should be irreversible because all
of the plots pass through zero intercepts. The D content of all
compound 4 derivatives was almost 100% as long as the
reaction was performed in benzene or tert-butylbenzene
because we used Bu3SnD for 97% D content. On the other
hand, the reaction performed in toluene produced no D
containing 4 in approximately 20% yield (entries 13−16).
These results strongly suggest that the aryl radical intermediate
1,7-Hydrogen Transfer of the Aryl Radical. Treatment
of 1 with Bu3SnD under the same reaction conditions in
benzene gave deuterated products 2D, 3D, and 4D (Scheme
2). Other deuterated products (4Da and 3D) were separately
prepared (Scheme 3).
a
Scheme 3
a
Reagents and conditions: (i) Bu3SnD, AIBN, benzene 80 °C, 2.5 h,
87%; (ii) CH2C(CH3)COCl, DMAP, Et3N, CH2Cl2, 44%; (iii)
Bu3SnD AIBN, benzene 70 °C, 3 h, 44%; (iv) BuLi, THF, −78 °C,
then MeI, 97%.
GC-MS data showed that all products had a parent mass
peak at m/z = 262; thus, complete D introduction was
achieved. 2D and 3D showed a single mass pattern indicating
that a deuterium atom was introduced at the α-carbon to the
carbonyl group in 2 and the terminal methyl group of 3,
respectively. These findings were also confirmed by the 1H and
13C NMR spectra, which clearly indicated the disappearance of
the corresponding protons and 13C−2D coupling at the
corresponding carbons, respectively. On the other hand, and
D
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Article
Scheme 4
a
Table 3. Contents of Deuterium Ratios
estimation of the hydrogen abstraction from toluene will be
discussed in a later section.
2D;
3D;
4D;
Estimation of kH/kD Using 4-Bromoanisole. These data
are useful in the investigation of kinetics of the entire reaction,
particularly for the reaction rates of the direct reduction of an
aryl radical and 1,7-hydrogen transfer. The former rate should
be dependent on the type of reducing reagent (Bu3SnX, X = H
or D), while the latter rate was independent of reagent. Thus,
we need to calculate the rate difference of the hydrogen or
deuterium abstraction of the aryl radical (kH/kD). However, this
is not easy to estimate using compound 1. Therefore, we used
4-bromoanisole as the model of compound 1 to estimate kH/
kD. Fortunately, the aryl radical is a σ-radical that should not be
affected by the aromatic ring substituents.11 Thus, the reduction
of 4-bromoanisol with a 1:1 mixture of Bu3SnH and Bu3SnD
was performed at 70, 78, and 90 °C (Scheme 5). The results are
summarized in Table 4. The kH/kD values were estimated from
the product ratio of 11-H and 11-D obtained by the m/z peak
table at 108 and 109.
temp [Bu3SnD]
yield
yield
yield
4Da/
b
4; D
a
a
a
entry (°C)
(M)
(%)
(%)
(%)
4Db
contents
1
2
3
4
5
6
7
70
70
70
70
78
78
78
78
90
90
90
90
70
70
70
70
0.05
0.10
0.15
0.20
0.05
0.10
0.15
0.20
0.05
0.10
0.15
0.20
0.05
0.10
0.15
0.20
73
72
70
68
74
75
75
75
68
67
69
67
65
73
71
62
7
8
8
8
7
8
8
8
7
8
8
8
6
8
8
7
7
8
15/82
26/71
33/64
38/60
16/80
23/74
34/63
39/58
17/75
24/69
34/61
39/55
12/65
25/54
28/55
34/50
97
97
97
98
96
97
97
97
92
93
95
94
77
79
83
84
9
9
5
6
7
8
7
c
9
5
c
c
c
10
11
12
6
6
6
d
d
d
d
13
14
15
16
7
9
10
10
a
GC yield. Yields of 4D are combined yield of 4Da and 4Db.
Scheme 5
b
c
Estimated by m/z table around 69 and 121. Reaction was carried out
d
in tert-butylbenzene. Reaction was carried out in toluene.
Table 4. Estimation of kH/kD Values in the Reduction of 4-
Bromoanisole
11-D
temp 11; yield
contents
Bu3SnD/
11-H/11-D Bu3SnH
a
b
entry (°C)
(%)
(%)
kH/kD
1
2
3
70
78
90
75
86
71
36.8 1.1
36.0 1.5
38.7 0.8
1.717
1.778
1.584
0.944
0.901
0.936
1.622
1.601
1.483
a
b
GC yield. Estimated by m/z table at 108 and 109.
The estimated kH/kD values were approximately 1.57 0.09
Figure 3. 4Da/4Db ratio plots versus [Bu3SnD] in the reaction at 78
°C.
at the temperature range of 70−90 °C. The values depended on
the reaction temperature, gradually decreasing with increasing
reaction temperature. The kH/kD values obtained are reasonably
consistent with reported results.11,12 For example, Ingold and
Lusztyk reported that the kH/kD value for the aryl radical at 25
°C is 1.6.
abstracts hydrogen from toluene to give the nondeuterated
product 4 and a benzyl radical. Thus, toluene works as an
effective hydrogen donor for the reaction of aryl radicals, even
though the hydrogen abstraction ratio was small. A kinetic
Kinetic Estimation for the Whole Reaction Pathways.
Whole reaction pathways are depicted in Scheme 6. The aryl
E
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Scheme 6
radical intermediate A, which was generated from bromine
abstraction using a tin radical, has a two-reaction route; one is
the intramolecular reaction of a radical to generate relocated
radicals, and the other is the direct hydrogen abstraction from
Bu3SnX (X = H or D) to give compound 4. The former route
includes 7-endo and 6-exo radical cyclization to give the
relocated radicals B and C as well as 1,7-hydrogen abstraction
to give radical D. We assume that the reaction rate for the latter
reaction, direct hydrogen abstraction, should depend on
whether Bu3SnH or Bu3SnD is used, while the former reaction
rate should not change. Fortunately, the subsequent reactions,
such as B to 2, C to 3, and D to 4, are irreversible, and their
reaction rates (kRX[Bu3SnX], X = H or D) should be much
slower than the reaction rates such as k7, k6, k1,7, and kArX (X =
H or D). This is supported by the fact that kRX values are the
rate constants for hydrogen abstraction from tin hydride by
alkyl radicals, and these values are estimated to be on the order
of 106 M−1 s−1,13 while kArX is the rate constant for the
hydrogen abstraction reaction of an aryl radical and should be
on the order of 108 or 109 M−1 s−1 at 80 °C.11,14 Hence, the key
parameters for the consideration of the entire reaction process
no contribution from Bu3SnX (X = H or D) to 1,7-hydrogen
transfer.
[4Ha]/[4Hb] = kArH[Bu3SnH]/k1,7 = kArH/k1,7[Bu3SnH]
The kArD/k1,7 values were estimated from the kinetic plots such
as Figure 3 by calculating the slope. To estimate kArH/k1,7, we
needed to convert kArD to kArH. These values are the rate
constants for the hydrogen abstraction of the aryl radical A
from Bu3SnX (X = H or D). We can apply the kH/kD values
estimated from the reduction of 4-bromoanisole. Thus, the
k
ArH/k1,7 values should be calculated as follows:
kArH/k1,7 = kH/kD × kArD/k1,7
Thus, we were now able to estimate the ratio of 4Ha and 4Hb,
and the values obtained are summarized in Table 5.
Table 5. Kinetic Estimation of the Product Ratio for 4Ha/
4Hb
[Bu3SnH]
(M)
temp
(°C)
entry
kArD/k1,7 kH/kD kArH/k1,7 4Ha/4Hb
are k7, k6, k1,7, and kArX
.
1
2
0.05
0.1
70
70
70
70
78
78
78
78
90
90
90
90
3.330
3.330
3.330
3.330
3.420
3.420
3.420
3.420
3.621
3.621
3.621
3.621
1.622
1.622
1.622
1.622
1.601
1.601
1.601
1.601
1.483
1.483
1.483
1.483
5.401
5.401
5.401
5.401
5.475
5.475
5.475
5.475
5.370
5.370
5.370
5.370
0.270
0.540
0.810
1.080
0.274
0.548
0.821
1.095
0.268
0.537
0.805
1.074
There are two types of compound 4 in this scheme; one is a
directed reduced product (A to 4), and the other is compound
4 produced via a 1,7-hydrogen transfer (A to D to 4). We next
attempted to estimate the ratio between the two processes. We
considered the product ratios of 4Da and 4Db again. Both
products were kinetically produced and had no equilibrium
between them. This was clearly supported by the kinetic plots
shown in Figure 3, in which the graph showed a zero intercept.
Thus, the reaction rates for producing these compounds are
shown in following equations:
3
0.15
0.2
4
5
0.05
0.1
6
7
0.15
0.2
8
9
0.05
0.1
10
11
12
0.15
0.2
d[4Da]/dt = kArD[Bu3SnD][A]
d[4Db]/dt = k1,7[A]
The 4Ha/4Hb ratios obtained were useful for the estimation
of the origin of compound 4 in the actual reactions. The kredobs
values in Table 2 were divided into [4Ha] (kArH) and [4Hb]
(k1,7). The results are summarized in Table 6. [4Ha]/([2] +
[3] + [4Hb]) (kArH/(k7obs + k6obs + k1,7)) plots for the reaction
at 78 °C are depicted in Figure 4.
[4Da]/[4Db] = kArD[Bu3SnD]/k1,7 = kArD/k1,7[Bu3SnD]
This assumption is applicable for the virtual product
distribution for 4Ha and 4Hb (both of which are the same
compound 4, but formed via different process). Here k1,7 is
constant regardless the reducing reagent used because there is
The plots in Figure 4 showed a good linear relationship, with
a correlation factor of 0.996. Other plots for the reaction at 70
F
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Table 6. Kinetic Distribution of the Products of the Reaction (Normalized)
entry [Bu3SnH] (M) temp (°C)
[2] (k7obs
)
[3] (k6obs
)
[4Hb] (k1,7
)
[4Ha] (kArH
)
[4Ha]/([2] + [3] + [4Hb]) (kArH/(k1,7 + k7 + k6))
1
2
0.05
0.1
70
70
70
70
78
78
78
78
90
90
90
90
79.88 0.44
77.83 0.63
75.45 0.41
74.84 0.50
81.20 0.48
78.45 0.62
77.58 0.42
75.67 0.43
80.37 1.47
78.61 0.20
76.78 1.22
76.13 0.82
9.68 0.63
9.90 0.27
8.73 0.07
9.02 0.11
9.39 0.22
9.43 0.43
9.42 0.28
9.10 0.14
9.34 1.04
10.19 0.17
9.93 0.42
9.62 0.19
8.22 0.39
7.96 0.35
8.59 0.02
7.76 0.19
7.39 0.21
7.83 0.12
7.14 0.08
7.27 0.14
8.11 0.34
7.29 0.24
7.36 0.51
6.87 0.31
2.22 0.11
4.30 0.19
6.96 0.02
8.38 0.21
2.02 0.06
4.29 0.07
5.86 0.07
7.96 0.15
2.18 0.09
3.91 0.13
5.93 0.41
7.38 0.33
0.02270 0.00108
0.04494 0.00195
0.07503 0.00018
0.09150 0.00227
0.02064 0.00057
0.04479 0.00069
0.06229 0.00068
0.08649 0.00166
0.02227 0.00093
0.04072 0.00135
0.06303 0.00436
0.07967 0.00356
3
0.15
0.2
4
5
0.05
0.1
6
7
0.15
0.2
8
9
0.05
0.1
10
11
12
0.15
0.2
sufficiently low Bu3SnH concentration conditions. On the other
hand, under such conditions, intramolecular hydrogen
abstraction (the 1,7-hydrogen transfer) becomes a significant
process, giving the reduced product 4, and it is not possible to
suppress this side product completely.
The reaction using Bu3SnD strongly suggested that the aryl
radical intermediate A is very reactive and abstracts hydrogen
from a solvent such as toluene to give compound 4. To
estimate the hydrogen abstraction from toluene, similar kinetic
plots, which is shown in Figure 5, were examined (Scheme 7).
Figure 4. [4Ha]/([2] + [3] + [4Hb]) plots versus [Bu3SnH] in the
reaction at 78 °C.
and 90 °C also showed a good linear relationship, with
correlation factors of 0.989 and 0.994, respectively. These
results clearly suggest that radical rearrangements, including 7-
endo/6-exo cyclization and 1,7-hydrogen transfer, are irrever-
sible. Thus, the product distribution was decided kinetically.
The slopes were estimated to be 0.469 at 70 °C, 0.429 at 78 °C,
and 0.408 at 90 °C. The values slightly decreased with
increasing reaction temperature. The slope values allowed us to
estimate actual kinetic values. Unfortunately, no definitive rate
constant for the hydrogen abstraction of the 4-methoxy-2-
methylphenyl radical from Bu3SnH is available. However, we
can estimate the desired kinetic parameters using the data for
the phenyl radical because aryl radicals are σ-radicals and their
absolute rate constants are not significantly influenced by the
substituents.11,13,15
Figure 5. 4Da/4H plots versus [Bu3SnD] in the reaction at 70 °C in
toluene.
The plots clearly suggest that the hydrogen abstraction from
toluene is irreversible. The good linear relationship to the
Bu3SnD concentration allowed us to estimate the relative rate.
The relative kinetic parameters obtained on the basis of kArH
(=1) are as follows: k7 = 1.74 (70 °C), 1.92 (78 °C), and 2.01
(90 °C), k6 = 0.21 (70 °C), 0.23 (78 °C), and 0.25 (90 °C), k1,7
= 0.18 (70 °C), 0.18 (78 °C), and 0.19 (90 °C). If the kArH
value is postulated to be the same as the rate constant of a
phenyl radical abstracting hydrogen from Bu3SnH (k = 1 × 109
M−1 s−1 at 80 °C), the kinetic parameters for the reaction at 78
°C would be k7 = 1.92 × 109 s−1, k6 = 2.3 × 108 s−1, k1,7 = 1.8 ×
108 s−1. In the overall reaction conditions, 6-exo cyclization
appears as a minor process and 7-endo selectivity is decided
kinetically. The 7-endo cyclization reaction is relatively rapid,
and the process becomes faster than the direct reduction of the
aryl radical by Bu3SnH if the reaction was performed under
Scheme 7
G
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Article
C16H23O2NBr 340.0912. Anal. Calcd for C16H22BrNO2: C, 56.48; H,
6.52; N, 4.12. Found: C, 56.53; H, 6.56; N, 4.22.
The relative rate constant of ktol should be obtained by the
following calculation:
Preparation of 2-(tert-Butyl)-8-methoxy-4-methyl-4,5-dihy-
dro-1H-benzo[c]azepin-3(2H)-one (2). A solution of AIBN
(0.0639 g, 0.389 mmol) in benzene (50 mL) was added to a solution
of Bu3SnH (2.34 mL, 8.83 mmol) and compound 1 (1.3598 g, 3.996
mmol) in benzene (150 mL) at 80 °C over 15 min. The reaction
mixture was refluxed for an additional 3 h. Then the reaction pot was
cooled, and the reaction solution was concentrated by a rotary
evaporator. The residue was subjected to flash chromatography (silica
gel/hexane−EtOAc 15:0 then 10:1 v/v) to give crude compound 2,
which was purified by recrystallization from hexane/EtOAc, giving
compound 2 in 62% yield (0.6472 g, 2.476 mmol): white solid; mp
105.5−105.8 °C; 1H NMR (500 MHz, CDCl3) δ 7.00 (d, J = 8.4 Hz, 1
H), 6.74 (dd, J = 8.4, 2.7 Hz, 1 H), 6.58 (d, J = 2.7 Hz, 1 H), 4.90 (d, J
= 17.1 Hz, 1 H), 4.17 (d, J = 17.2 Hz, 1 H), 3.78 (s, 3H), 3.48−3.40
(m, 1 H), 2.89 (dd, J = 17.1, 4.6 Hz, 1 H), 2.83 (dd, J = 17.2, 12.6 Hz,
1H), 1.41 (s, 9 H), 1.19 (d, J = 6.5 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 176.8, 157.3, 137.1, 131.5, 129.9, 113.8, 112.5, 57.8, 55.4,
47.9, 37.5, 36.6, 29.3, 18.0; HRMS (FAB M + H) m/z 262.1805, calcd
for C16H24O2N 262.1807.
ktol = 1/slope × kD/kH × kArH
Thus, the value was estimated to be approximately 0.0756
compared with kArH. This value clearly suggests that the
hydrogen abstraction from toluene is not particularly slow and
should not be an ignorable process if the reaction is performed
under very low Bu3SnH concentration conditions. Thus, we
conclude that toluene is not a good solvent for a radical
reaction that involves some rearrangement of the initial radical
and toluene should likely be a hydrogen donor that prevents
radical rearrangement including radical cyclization.
CONCLUSIONS
■
We have performed careful product distribution analyses of 7-
endo/6-exo radical cyclization by an aryl radical to give 2-
benzazepines in good yields. The investigation of the product
distribution study clearly indicated that the regioselectivity of
cyclization was determined kinetically. The use of Bu3SnD
enabled us to show that 1,7-hydrogen transfer is included in the
reaction pathway. A reduction study using 4-bromoanisole
revealed the kH/kD value for the aryl radical. These kinetic
parameters allowed investigation of the entire reaction process
and real product distribution. Furthermore, we have demon-
strated the importance of a solvent as a hydrogen donor. These
data will be useful for further kinetic studies into radical
reaction and improvement of efficiency and/or selectivity of the
radical reaction.
Deuterated 2D was isolated from kinetic samples. Combined
samples after four kinetic experiments, starting from 1 (0.274 g of 0.81
mmol) treated with Bu3SnD (0.6978 g, 2.39 mmol) under 0.15 M
conditions in benzene at 78 °C were concentrated, and the residue was
subjected to flash chromatography (silica gel/hexane then hexane−
EtOAc 1:1 v/v) to give crude 2D which was purified through
preparative GPC apparatus three times to give 2D in 59% yield
1
(0.1249 g, 0.477 mmol): white solid; mp 106−106.2 °C; H NMR
(500 MHz, CDCl3) δ 7.00 (d, J = 8.4 Hz, 1H), 6.73 (dd, J = 8.4, 2.7
Hz, 1H), 6.57 (d, J = 2.7 Hz, 1H), 4.89 (d, J = 17.1 Hz, 1H), 4.16 (d, J
= 17.2 Hz, 1H), 3.78 (s, 3H), 2.88 (d, J = 17.1 Hz, 1H), 2.82 (d, J =
17.2 Hz, 1H), 1.39 (s, 9H), 1.18 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 176.7, 157.3, 137.1, 131.5, 129.9, 113.8, 112.5, 57.8, 55.4,
47.9, 37.4, 36.2 (weak t, J2H−13C = 19.1 Hz), 29.2, 17.8; HRMS (ESI
M + H) m/z 263.1887, calcd for C16H23DO2N 263.1870.
EXPERIMENTAL SECTION
■
Preparation of N-(2-Bromo-5-methoxybenzyl)-2-methyl-
propan-2-amine (6). 1-Bromo-2-(bromomethyl)-4-methoxybenzene
5 (4.2382 g, 15.14 mmol) was dissolved in DMF (30 mL), and tert-
butylamine (1.9747 g, 27 mmol) and K2CO3 (2.6951 g, 19.5 mmol)
were added. The reaction mixture was stirred at room temperature for
3 h. Water (150 mL) was added the mixture, and the resulting mixture
was extracted with ether (30 mL × 4). The organic phase was
combined, washed with brine (30 mL × 1), and dried over Na2SO4.
Filtration and concentration gave crude 6 in 98% yield (4.0306 g, 14.9
mmol) which was used next step without further purification: pale
Preparation of N-(2-Bromo-5-methoxybenzyl)-N-(tert-
butyl)acrylamide (7). Under nitrogen atmosphere, a solution 6
(3.7494 g, 13.78 mmol) in CH2Cl2 (60 mL) was cooled at −50 °C,
and DMAP (0.5083 g, 4.16 mmol) and Et3N (2.7860 g, 27.56 mmol)
were added. A solution of acryloyl chloride (1.8708 g, 20.67 mmol) in
CH2Cl2 (40 mL) was added to the solution over 30 min. The reaction
mixture was allowed to warm to room temperature and stirred for 3.5
h. Then, 1 M aqueous HCl (50 mL) was added to the reaction
mixture, and the resulting biphasic mixture was extracted with CH2Cl2
(4 × 30 mL). The organic phase was washed with aqueous K2CO3 (30
mL) and dried over Na2SO4. Filtration and concentration gave crude 7
which was purified by flash chromatography (silica gel/hexane−EtOAc
20:1 then 10:1 v/v) to give 7 in 77% yield (3.442 g): white solid; mp
1
yellow oil; H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 8.7 Hz, 1H),
7.03 (d, J = 3.1 Hz, 1H), 6.66 (dd, J = 8.7, 3.1 Hz, 1H), 3.79 (s, 3H),
3.74 (s, 2H), 1.19 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 159.2,
141.4, 133.3, 116.2, 114.3, 114.2, 55.6, 51.0, 47.5, 29.3; HRMS (FAB
M + H) m/z 272.0641, calcd for C12H18ONBr 272.0650.
1
99.0−99.8 °C; H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz,
1H), 6.89 (d, J = 3.0 Hz, 1H), 6.70 (dd, J = 8.8, 3.0 Hz, 1H), 6.32 (dd,
J = 16.6, 2.3 Hz, 1H), 6.22 (dd, J = 16.6, 10.2 Hz, 1H), 5.54 (dd, J =
10.2, 2.2 Hz, 1H), 4.51 (s, 2H), 3.75 (s, 3H), 1.46 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 168.6, 159.5, 139.3, 133.5, 131.1, 127.8, 114.2,
113.9, 111.6, 57.7, 55.4, 49.8, 28.3; HRMS (FAB M + Na) m/z
348.0573, calcd for C15H20O2NNaBr 348.0575.
Preparation of 2-(tert-Butyl)-7-methoxy-4-methyl-1,2-
dihydroisoquinolin-3(4H)- one (8). A solution of Bu3SnH
(5.9607 g, 20.48 mmol) and AIBN (0.4036 g, 2.46 mmol) in benzene
(50 mL) was added dropwise to a solution of 7 (3.3405 g, 10.24
mmol) in benzene (250 mL) at 78 °C over 1 h. After additional
heating at 78 °C for 4 h, the reaction mixture was cooled and
concentrated in vacuo. The residue was subjected to flash
chromatography (silica gel/hexane−EtOAc 100:1, 50:1, 30:1, then
10;1 v/v) to give 8 in 67% yield (1.6886 g): pale yellow solid; mp
52.5−53 °C; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 1H),
7.06 (dd, J = 8.5, 2.5 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 4.73 (d, J =
15.7 Hz, 1H), 4.62 (d, J = 15.3 Hz, 1H), 4.04 (s, 3H), 3.63 (q, J = 7.1
Hz, 1H), 1.74 (s, 9H), 1.67 (d, J = 7.3 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 173.6, 158.2, 134.3, 130.8, 126.2, 113.1, 110.8, 57.4, 55.4,
Preparation of N-(2-Bromo-5-methoxybenzyl)-N-(tert-
butyl)methacrylamide (1). Compound 6 (3.8670 g, 14.21 mmol)
was dissolved in CH2Cl2 (120 mL) and Et3N (4.8 mL, 34.15 mmol),
and DMAP (0.4376 g, 3.58 mmol) was added. The reaction mixture
was cooled at −50 °C, and methacroyl chloride (2.1 mL, 21.5 mmol)
in CH2Cl2 (40 mL) was added. The reaction mixture was allowed to
warm to room temperature for 1 h. The reaction mixture was stirred
for a additional 2 h. Then, 1 M aqueous HCl (50 mL) was added to
the reaction mixture, and the resulting biphasic mixture was extracted
with CH2Cl2 (30 mL × 3). The organic phase was combined, washed
with saturated NaHCO3 (40 mL), and dried over Na2SO4. Filtration
and concentration in vacuo gave crude 1, which was purified through
flash chromatography (silica gel/hexane−EtOAc 15:1 v/v) to give
methacrylamide 1 in 78% yield (3.777 g, 11.10 mmol): white solid; mp
1
47.2−47.5 °C; H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 8.7 Hz, 1
H), 6.94 (d, J = 3.1 Hz, 1 H), 6.68 (dd, J = 8.7, 3.1 Hz, 1 H), 4.93 (t, J
= 1.0 Hz, 1 H), 4.88 (p, J = 1.3 Hz, 1 H), 4.58 (s, 2 H), 3.78 (s, 3 H),
1.92 (t, J = 1.3 Hz, 3 H), 1.45 (s, 9 H); 13C NMR (126 MHz, CDCl3)
δ 174.8, 159.1, 142.7, 140.1, 133.5, 114.3, 114.0, 113.2, 111.7, 57.9,
55.5, 51.3, 28.6, 20.9; HRMS (FAB M + H) m/z 340.0916, calcd for
H
dx.doi.org/10.1021/jo400326b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
46.6, 43.0, 28.5, 16.1; HRMS (FAB M + H) m/z 248.1640, calcd for
C15H22NO2 248.1651.
20.7 (weak, t, J2H−13C = 19.5 Hz); HRMS (ESI M + H) m/z
263.1872, calcd for C16H23DO2N 263.1870.
Preparation of N-(3-Methoxy-5-deuteriobenzyl)-2-methyl-
propan-2-amine (10D). A solution of AIBN (0.025 g, 0.15 mmol),
compound 6 (0.206 g, 0.755 mmol), and Bu3SnD (0.41 mL, 1.5
mmol) in benzene (8 mL) was heated at 80 °C, and the reaction
mixture was heated at refluxing temperature for 2 h. AIBN (0.036 g,
0.22 mmol) wad added to the reaction mixture and heated at the same
temperature for 30 min. The reaction mixture was poured into
concentrated HCl (10 mL), and the resulting biphasic mixture was
washed with EtOAc (3 × 20 mL). The water layer was then basified by
adding 6 M aqueous NaOH (30 mL). The resulting basic aqueous
solution was extracted with CH2Cl2 (3 × 20 mL). The organic phase
was combined and dried with Na2SO4. After filtration, the filtrate was
concentrated in vacuo to give 10D in 87% yield (0.127 g, 0.654
mmol): yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 8.2 Hz,
1H), 6.90 (d, J = 2.7 Hz, 1H), 6.77 (dd, J = 8.2, 2.6 Hz, 1H), 3.80 (s,
3H), 3.70 (s, 2H), 1.40−1.20 (br, 1H), 1.17 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 159.8, 143.2, 129.4, 120.3 (weak, t, J2H−13C = 24.2
Hz), 113.8, 112.3, 55.3, 50.8, 47.3, 29.3; HRMS (ESI M + H) m/z
195.1616, calcd for C12H19DNO 195.1608.
Preparation of 2-(tert-Butyl)-7-methoxy-4,4-dimethyl-1,2-
dihydroisoquinolin-3(4H)-one (3). Under nitrogen atmosphere,
BuLi (1.6 M, 2.44 mL, 3.9 mmol) was added to a solution of 8 (0.7514
g, 3.04 mmol) in THF (5 mL) at −50 °C. MeI (1.12 mL, 18 mmol)
was added immediately, and the reaction mixture was stirred for 20
min at the same temperature and for 1 h with warming to room
temperature. Aqueous NH4Cl (20 mL) was added to the reaction
mixture, and THF was removed by a rotary evaporator. The resulting
aqueous mixture was extracted with EtOAc (4 × 20 mL). The organic
phase was washed with aqueous Na2S2O3 (2 × 10 mL) and dried over
Na2SO4. After filtration, the filtrate was concentrated and the residue
was purified by flash chromatography (silica gel/hexane−EtOAc 20:1
v/v) to give 3 in 80% yield (0.6315 g, 2.42 mmol): white solid; mp
1
69.0−69.2 °C; H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 8.7 Hz,
1H), 6.77 (dd, J = 8.6, 2.7 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 4.42 (s,
2H), 3.74 (s, 3H), 1.45 (s, 9H), 1.35 (s, 6H); 13C NMR (126 MHz,
CDCl3) δ 175.4, 158.1, 134.4, 133.2, 125.7, 113.5, 110.9, 57.6, 55.4,
46.6, 43.3, 28.4, 25.8; HRMS (FAB M + H) m/z 262.1812, calcd for
C16H24O2N 262.1807.
Preparation of N-(tert-Butyl)-N-(3-methoxy-5-deuterio-
benzyl)methacrylamide (4Da). Methacroyl chloride (0.07 mL,
0.72 mmol) was added slowly to a solution of 10D (0.0839 g, 0.432
mmol), Et3N (0.12 mL, 0.83 mmol), and DMAP (0.0175 g, 0.14
mmol) in CH2Cl2 (10 mL) at −50 °C, and the reaction mixture was
gradually warmed to room temperature for 9 h. Aqueous 1 M HCl (5
mL) was added to the reaction mixture, and the resulting biphasic
mixture was extracted with CH2Cl2 (3 × 20 mL). The organic phase
was combined, washed with aqueous NaHCO3 (1 × 20 mL), and dried
over Na2SO4. After filtration, the filtrate was concentrated in vacuo
and the residue was subjected to flash chromatography (silica gel/
hexane−EtOAc 9:1 then 3:1) to give 4Da in 44% yield (0.0494 g,
Preparation of N-(3-Methoxybenzyl)-2-methylpropan-2-
amine (10). NaI (0.7495 g, 5 mmol) and tBuNH2 (2.9225 g, 39.97
mmol) were added to a solution of m-methoxybenzylchloride (1.5661
g, 10 mmol) in THF (20 mL), and the reaction mixture was stirred at
room temperature for 140 h. THF was removed in vacuo, and aqueous
NaHCO3 (30 mL) was added to the residue. The resulting aqueous
mixture was extracted with EtOAc (4 × 20 mL). The organic phase
was combined and dried over Na2SO4. After filtration, crude product
was isolated by concentration to give compound 10 in 92% yield
(1.7859 g, 9.24 mmol), which was used for the next stage without
1
further purification: pale yellow oil; H NMR (500 MHz, CDCl3) δ
7.22 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.90 (s, 1H), 6.77
(dd, J = 8.2, 2.6 Hz, 1H), 3.80 (s, 3H), 3.70 (s, 2H), 1.20−1.40 (br,
1H), 1.17 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 159.8, 143.3,
129.5, 120.6, 113.9, 112.3, 55.3, 50.8, 47.4, 29.3; HRMS (ESI M + H)
m/z 194.1554, calcd for C12H20NO 194.1545.
1
0.188 mmol): pale yellow oil; H NMR (500 MHz, CDCl3) δ 7.32−
7.20 (m, 1H), 6.82−6.73 (m, 2H), 5.01 (s, 1H), 4.92 (s, 1H), 4.64 (s,
2H), 3.78 (s, 3H), 1.92 (s, 3H), 1.42 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 174.7, 159.9, 143.2, 142.0, 129.6, 118.4 (weak, m), 113.5,
112.2, 111.9, 111.8, 57.8, 55.3, 50.8, 28.7, 20.9; HRMS (ESI M + H)
m/z 263.1884, calcd for C16H23DO2N 263.1870.
Preparation of N-(tert-Butyl)-N-(3-methoxybenzyl)meth-
acrylamide (4). Compound 10 (1.6446 g, 8.51 mmol) was dissolved
in CH2Cl2 (80 mL), and Et3N (2.36 mL, 17.02 mmol) and DMAP
(0.3115 g, 2.55 mmol) were added. Under nitrogen atmosphere, the
reaction mixture was cooled at −50 °C and a solution of methacroyl
chloride (1.25 mL, 12.77 mmol) in CH2Cl2 (40 mL) was added. The
reaction mixture was allowed to warm to room temperature for 20 h.
Aqueous HCl (1 M, 50 mL) was added to the reaction mixture, and
the resulting biphasic mixture was extracted with CH2Cl2 (40 mL × 3).
The organic phase was washed with aqueous NaHCO3 (20 mL) and
dried over Na2SO4. Filtration and concentration in vacuo gave crude 4,
which was purified through flash chromatography (silica gel/hexane−
EtOAc 100:1 then 10:1 v/v) to give methacrylamide 4 in 89% yield
(1.9869 g): white solid; mp 34−35 °C, 1H NMR (500 MHz, CDCl3) δ
7.24 (d, J = 7.6 Hz, 1 H), 6.85−6.75 (m, 3 H), 5.02 (s, 1 H), 4.93 (s, 1
H), 4.65 (s, 2 H), 3.80 (s, 3 H), 1.93 (s, 3 H), 1.44 (s, 9 H); 13C NMR
(126 MHz, CDCl3) δ 174.8, 159.9, 143.1, 142.1, 129.7, 118.4, 113.5,
112.2, 111.9, 57.8, 55.3, 50.9, 28.7, 21.0; HRMS (FAB M + H) m/z
262.1809, calcd for C16H24O2N 262.1807.
Preparation of 2-(tert-Butyl)-7-methoxy-4-deuteriomethyl-
1,2-dihydroisoquinolin-3(4H)-one (8D). A solution of Bu3SnD
(0.34 mL, 1.26 mmol) and AIBN (0.0202 g, 0.12 mmol) in benzene (5
mL) was added to a solution of 7 (0.2012 g, 0.62 mmol) in benzene
(20 mL) at 78 °C over 90 min using a syringe pump. After additional
heating at 78 °C for 90 min, the reaction mixture was cooled and
concentrated in vacuo. The residue was subjected to flash
chromatography (silica gel/hexane−EtOAc 15:1, 12:1, 10:1, then 8:1
v/v) to give crude 8D (0.092 g, 0.35 mmol), which was purified again
using flash chromatography (silica gel/hexane−EtOAc 12:1 then 8:1
v/v) to give 8D in 44% yield (0.0666 g, 0.268 mmol): pale yellow
1
solid; mp 50.5−51.0 °C; H NMR (500 MHz, CDCl3) δ 7.10 (d, J =
8.4 Hz, 1H), 6.82 (dd, J = 8.3, 2.3 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H),
4.48 (d, J = 15.4 Hz, 1H), 4.37 (d, J = 15.4 Hz, 1H), 3.80 (s, 3H), 3.38
(t, J = 7.1 Hz, 1H), 1.50 (s, 9H), 1.41 (d, J = 7.1 Hz, 2H); 13C NMR
(126 MHz, CDCl3) δ 173.6, 158.2, 134.4, 130.9, 126.2, 113.10, 110.8,
57.5, 55.5, 46.8, 43.0, 28.7, 16.0 (weak, t, J2H−13C = 20.8 Hz); HRMS
(ESI M + H) m/z 249.1688, calcd for C15H21DO2N 249.1713.
Preparation of 2-(tert-Butyl)-7-methoxy-4-deuteriomethyl-
4-methyl-1,2-dihydroisoquinolin-3(4H)-one (3D). Under nitro-
gen atmosphere, BuLi (1.6 M, 0.1 mL, 0.16 mmol) was added to a
solution of 8D (0.0312 g, 0.126 mmol) in THF (5 mL) at −50 °C.
MeI (0.05 mL, 0.8 mmol) was added after 20 min, and the reaction
mixture was stirred for 2 h with warming up to room temperature.
Aqueous NH4Cl (20 mL) was added to the reaction mixture, and THF
was removed by an evaporator. The resulting aqueous mixture was
extracted with EtOAc (3 × 20 mL). The organic phase was washed
with aqueous Na2S2O3 (2 × 10 mL) and dried over Na2SO4. After
filtration, the filtrate was concentrated and the residue was purified by
flash chromatography (silica gel/hexane−EtOAc 12:1 then 6:1) to give
3D in 97% yield (0.0319 g, 0.122 mmol): white solid, mp 63.0−63.5
Allylic deuterated 4Db was isolated from kinetic samples. A
combined five times samples, containing the reaction mixture starting
from 1 (0.342 g of 1 mmol) treated with Bu3SnD (0.9196 g, 3.15
mmol) under 0.025 M conditions in benzene at 78 °C, was
concentrated, and the residue was subjected to flash chromatography
(silica gel/hexane then hexane/EtOAc 1:1 v/v) to give crude 4Db
which was purified through preparative GPC apparatus three times to
give 4Db in 2% yield (0.0042 g, 0.016 mmol). GC-MS peak showed
1
that the 4Db/4 Da ratio was 96/4: yellow oil; H NMR (500 MHz,
CDCl3) δ 7.23 (d, J = 7.9 Hz, 1H), 6.82−6.74 (m, 3H), 5.01 (d, J = 1.0
Hz, 1H), 4.92 (d, J = 1.3 Hz, 1H), 4.64 (s, 2H), 3.79 (s, 3H), 1.91 (s,
2H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 174.7, 159.9,
143.1, 142.1, 129.7, 118.5, 113.5, 112.3, 111.9, 57.8, 55.3, 50.8, 28.7,
I
dx.doi.org/10.1021/jo400326b | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
°C; 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 8.6 Hz, 1H), 6.83 (dd,
J = 8.6, 2.7 Hz, 1H), 6.68 (d, J = 2.6 Hz, 1H), 4.48 (s, 2H), 3.80 (s,
3H), 1.51 (s, 9H), 1.41 (s, 3H), 1.40 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 175.3, 158.0, 134.3, 133.1, 125.6, 113.5, 110.8, 57.6, 55.4,
46.7, 43.3, 28.4, 25.8, 25.5 (t, J2H−13C = 19.4 Hz); HRMS (ESI M +
H) m/z 263.1859, calcd for C16H23DO2N 263.1870.
Erhard, K. F.; Heerding, D. A.; Keenan, R. M.; Kwon, C.; Manley, P. J.;
Newlander, K. A.; Ross, S. T.; Samanen, J. M.; Uzinskas, I. N.;
Venslavsky, J. W.; Yuan, C. C.-K.; Haltiwanger, R. C.; Gowen, M.;
Hwang, S.-M.; James, I. E.; Lark, M. W.; Rieman, D. J.; Stroup, G. B.;
Azzarano, L. M.; Salyers, K. L.; Smith, B. R.; Ward, K. W.; Johanson,
K. O.; Huffman, W. F. J. Med. Chem. 2000, 43, 22. (b) Kawase, M.;
Saito, S.; Motohashi, N. Int. J. Antimicrob. Agents 2000, 14, 193.
(c) Feuston, B. P.; Culberson, J. C.; Duggan, M. E.; Harman, G. D.;
Leu, C.-T.; Rodan, S. B. J. Med. Chem. 2002, 45, 5640. (d) Kondo, K.;
Kan, K.; Tanada, Y.; Bando, M.; Shinohara, T.; Kurimura, M.; Ogawa,
H.; Nakamura, S.; Hirano, T.; Yamamura, Y.; Kido, M.; Mori, T.;
Tominaga, M. J. Med. Chem. 2002, 45, 3805. (e) Seto, M.; Miyamoto,
N.; Aikawa, K.; Aramaki, Y.; Kanzaki, N.; Iizawa, Y.; Baba, M.;
Shiraishi, M. Bioorg. Med. Chem. 2004, 13, 365. (f) Seto, M.; Aramaki,
Y.; Okawa, T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.-i.;
Iizawa, Y.; Baba, M.; Shiraishi, M. Chem. Pharm. Bull. 2004, 52, 577.
(g) Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.;
Estrada, S. A.; Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.;
Sengupta, D.; Thomsen, W. J.; Saldana, H. R.; Whelan, K. T.;
Menzaghi, F.; Webb, R. R.; Beeley, N. R. A. Bioorg. Med. Chem. Lett.
2005, 15, 1467. (h) Hoyt, S. B.; London, C.; Gorin, D.; Wyvratt, M. J.;
Fisher, M. H.; Abbadie, C.; Felix, J. P.; Garcia, M. L.; Li, X.; Lyons, K.
A.; McGowan, E.; MacIntyre, D. E.; Martin, W. J.; Priest, B. T.; Ritter,
A.; Smith, M. M.; Warren, V. A.; Williams, B. S.; Kaczorowski, G. J.;
Parsons, W. H. Bioorg. Med. Chem. Lett. 2007, 17, 4630.
General Procedure for Kinetic Estimation: Typical Proce-
dure. A solution of compound 1 (0.3425 g, 1.006 mmol, 0.1 M) and
anthracene (5.08 mg, 0.285 mmol) in benzene (10 mL) was prepared
using a 10 mL measuring flask. A solution of Bu3SnH (0.8690 g, 2.99
mmol) in benzene (5 mL) was prepared using a 5 mL measuring flask.
AIBN (0.0398 g) was added to a 30 mL test tube, and 2 mL of the
former solution and 1 mL of the latter solution were mixed. The
resulting 3 mL solution (0.20 M for Bu3SnH) was used directly or
diluted with benzene to adjust its concentration to be 0.15 M (add 1
mL of benzene), 0.10 M (add 3 mL of benzene), and 0.05 M (add 9
mL of benzene). The reaction solution was then purged by N2 gas for
5 min and sealed. The test tube was placed into a preheated oil bath
(70 °C). 10 μL of the reaction mixture was taken as a sample for every
4 min, and the sample was analyzed and quantified by GC-MS using a
Cap-5 capillary column. The amounts of compounds 2, 3, and 4 were
estimated using a curve-fitting method with anthracene as an internal
standard. The reaction was carried out at least three times for each
concentration and temperature.
ASSOCIATED CONTENT
* Supporting Information
■
(4) (a) Matsuura, K.; Kuratani, T.; Gondo, T.; Kamimura, A.; Inui,
M. Eur. J. Pharmacol. 2007, 563, 83−3195. (b) Kamimura, A.; So, M.;
Kuratani, T.; Matsuura, K.; Inui, M. Bioorg. Med. Chem. Lett. 2009, 19,
3193.
(5) Kamimura, A.; Ishihara, Y.; So, M.; Hayashi, T. Tetrahedron Lett.
2009, 50, 1727.
S
Spectroscopic charts for compounds 1, 2, 2D, 3, 3D, 4, 4Da,
4Db, 6, 7, 8, 8D, 10, and 10D. This material is available free of
charge via the Internet at http://pubs.acs.org.
(6) (a) Stork, G.; Mah, R. Heterocycles 1989, 28, 723. (b) Curran, D.
P.; Tamine, J. J. Org. Chem. 1991, 56, 2746. (c) Curran, D. P.;
DeMello, N. C. J. Chem. Soc., Chem. Commun. 1993, 1314. (d) Curran,
D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc. 1994, 116,
3131. (e) Curran, D. P.; Liu, H. T. J. Chem. Soc., Perkin Trans. 1 1994,
1377. (f) Bremner, J. B.; Sengpracha, W. Tetrahedron 2005, 61, 941.
(g) Curran, D. P.; Guthrie, D. B.; Geib, S. J. J. Am. Chem. Soc. 2008,
130, 8437.
(7) 1,n-Hydrogen transfer for synthesis: (a) Curran, D. P.; Kim, D.;
Liu, H. T.; Shen, W. J. Am. Chem. Soc. 1988, 110, 5900. (b) Snieckus,
V.; Cuevas, J.-C.; Sloan, C. P.; Liu, H.; Curran, D. P. J. Am. Chem. Soc.
1990, 112, 896. (c) Imboden, C.; Villar, F.; Renaud, P. Org. Lett. 1999,
1, 873. (d) Cummins, J. M.; Dolling, U.-H.; Douglas, A. W.; Karady,
S.; Leonard, W. R., Jr.; Marcune, B. F. Tetrahedron Lett. 1999, 40,
6153. (e) Gosain, R.; Norrish, A. M.; Wood, M. E. Tetrahedron Lett.
1999, 40, 6673. (f) Karady, S.; Cummins, J. M.; Dannenberg, J. J.; del
Rio, E.; Dormer, P. G.; Marcune, B. F.; Reamer, R. A.; Sordo, T. L.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ak10@yamaguchi-u.ac.jp.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to a financial aid from Yamaguchi University
based on The YU Strategic Program for Fostering Research
Activities (2010-2011). We thank Dr. Kaiso, Ube Industries for
helpful discussion.
REFERENCES
■
(1) Recent reviews, see: (a) Zimmerman, J.; Halloway, A.; Sibi, M. P.
In Handbook of Cyclization Reactions; Ma, S., Ed.; Wiley-VCH:
Weinheim, Germany, 2010; Vol. 2, pp 1099−1148. (b) Majumdar, K.
C.; Mukhopadhyay, P. P.; Basu, P. K. Heterocycles 2004, 63, 1903.
(c) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Tetrahedron
2004, 60, 6239. (d) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P.
P. Tetrahedron 2005, 61, 10603. (e) Ishibashi, H. Chem. Rec. 2006, 6,
Org. Lett. 2003, 5, 1175. (g) Beaufils, F.; Den
Lett. 2004, 6, 2563. (h) Martín, A.; Perez-Martín, I.; Suar
Lett. 2005, 7, 2027. (i) Lachia, M.; Denes, F.; Beaufils, F.; Renaud, P.
Org. Lett. 2005, 7, 4103. (j) Denes, F.; Beaufils, F.; Renaud, P. Org.
Lett. 2007, 9, 4375. (k) Francisco, C. G.; Herrera, A. J.; Martín, A.;
Perez-Martín, I.; Suarez, E. Tetrahedron Lett. 2007, 48, 6384.
(l) Martín, A.; Perez-Martín, I.; Quintanal, L. M.; Suarez, E. J. Org.
Chem. 2008, 73, 7710. (m) Martín, A.; Perez-Martín, I.; Suarez, E.
Tetrahedron 2009, 65, 6147. (n) Rey, V.; Pierini, A. B.; Penenory, A. B.
J. Org. Chem. 2009, 74, 1223.
́
es
̀
, F.; Renaud, P. Org.
́
́
ez, E. Org.
́
̀
́
̀
́
́
́
23−31. (f) Barrero, A. F.; Quílez del Moral, J. F.; Sanchez, E. M.;
́
́
́
Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627. (g) Majumdar, K. C.;
Basuy, P. K.; Chattopadhyay, S. K. Tetrahedron 2007, 63, 793.
(h) Yoshioka, E.; Kohtani, S.; Miyabe, H. Heterocycles 2009, 79, 229.
(i) Rowlands, G. J. Tetrahedron 2010, 66, 1593. (j) Galli, C. Chem. Rev.
1988, 88, 765.
́
́
̌
́
̌
(8) Mechanistic studies on 1,n-hydrogen transfer: (a) Curran, D. P.;
Shen, W. J. Am. Chem. Soc. 1993, 115, 6051. (b) Viskolcz, B.; Lendvay,
G.; Ko1rtvelyesi, T.; Seres, L. J. Am. Chem. Soc. 1996, 118, 3006.
́
(2) (a) Preparation with Bu3SnH: Kamimura, A.; Taguchi, Y.;
Omata, Y.; Hagihara, M. J. Org. Chem. 2003, 68, 4996. Some greener
modifications such as using (Me3Si)3SiH or catalytic amounts of
Bu3SnH were examined but did not work well and desired 7-endo
product 2 was obtained in 3 and 16% under the same conditions,
respectively. (b) Preparation by intramolecular Friedel−Crafts
reaction: So, M.; Kotake, T.; Matsuura, K.; Inui, M.; Kamimura, A.
J. Org. Chem. 2012, 77, 4017.
(c) Chandler, S. A.; Hanson, P.; Taylor, A. B.; Walton, P. H.; Timms,
A. W. J. Chem. Soc., Perkin Trans. 2 2001, 214. (d) Zeng, L.; Kaoudia,
T.; Schiesser, C. H. Tetrahedron Lett. 2006, 47, 7911. (e) DeZutter, C.
B.; Horner, J. H.; Newcomb, M. J. Phys. Chem. A 2008, 112, 1891.
(9) Newcomb, M. Tetrahedron 1993, 49, 1151.
(10) Kamimura, A.; Taguchi, Y. Tetrahedron Lett. 2004, 45, 2335.
(11) Garden, S. J.; Avila, D. V.; Beckwith, A. L. J.; Bowry, V. W.;
Ingold, K. U.; Lusztyk, J. J. Org. Chem. 1996, 61, 805.
(3) Recent examples: (a) Miller, W. H.; Alberts, D. P.; Bhatnagar, P.
K.; Bondinell, W. E.; Callahan, J. F.; Calvo, R. R.; Cousins, R. D.;
J
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The Journal of Organic Chemistry
Article
(12) (a) Strong, H. L.; Brownawell, M. L.; San Filippo, J., Jr. J. Am.
Chem. Soc. 1983, 105, 6526. (b) Abeywickrema, A. N.; Beckwith, A. L.
J. J. Chem. Soc., Chem. Commun. 1986, 464.
(13) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc.
1981, 103, 7139.
(14) Johnston, L. J.; Lusztyk, J.; Wayner, D. D. M.; Abeywickreyma,
A. N.; Beckwith, A. L. J.; Scaiano, J. C.; Ingold, K. U. J. Am. Chem. Soc.
1985, 107, 4594.
(15) Presence of an ortho-substituent in an aryl radical essentially
does not affect the rate constant for an external hydrogen abstraction.
See: Chandler, S. A.; Hanson, P.; Taylor, A. B.; Walton, P. H.; Timms,
A. W. J. Chem. Soc., Perkin Trans. 2 2001, 214.
K
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