Rhodium-catalyzed coupling of α-lactams with indole derivatives

Article abstract of DOI:10.1016/j.tet.2014.10.049

We report herein a method that allows for the formation of a C-N bond between the C-3 carbon of α-lactams and the nitrogen atom of indoles. A general procedure for the coupling of indoles and α-lactams in only 25 min with high yield is reported. The scope of the reaction was extended by the development of a method for the in situ generation of less stable phenyl-substituted α-lactams. The developed method provides an atom-economical method for the formation of substituted α-amino amides that are found in a variety of biologically-active compounds.

Full text of DOI:10.1016/j.tet.2014.10.049

Tetrahedron 70 (2014) 9709e9717
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rhodium-catalyzed coupling of
a-lactams with indole derivatives
,
,
Hannah K. Box a y, K.G. Upul Kumarasinghe a y, Radhika R. Nareddy a,
Gopalakrishna Akurathi a, Amarraj Chakraborty a, Babatunde Raji a,
Gerald B. Rowland a
,b,
*
a Department of Chemistry, Mississippi State University, MS 39762, USA
b Department of Chemistry and Biochemistry, The University of Mississippi, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2014
Received in revised form 22 October 2014
Accepted 23 October 2014
Available online 7 November 2014
We report herein a method that allows for the formation of a CeN bond between the Ce3 carbon of a-
lactams and the nitrogen atom of indoles. A general procedure for the coupling of indoles and
in only 25 min with high yield is reported. The scope of the reaction was extended by the development of
a method for the in situ generation of less stable phenyl-substituted -lactams. The developed method
-amino amides that are found in
a-lactams
a
provides an atom-economical method for the formation of substituted
a variety of biologically-active compounds.
a
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
a
-Lactams
CeN bond formation
Indole
1. Introduction
bearing amino acid derivatives would provide a new class of
compounds to screen for their biologically-active properties. While
the majority of reactions are Ce3 functionalization, several
methods have been developed for the N-functionalization of the
indole ring.18e20 The formation of CeN bonds has played an in-
creasing role in the development of new pharmaceutical com-
pounds over the last 15 years.21,22 Since initial reports of practical
methods for CeN bond formation by Buchwald and Hartwig, this
process has been one of the most utilized transformations in or-
ganic synthesis.23e27 Herein we report a Rh-catalyzed Ce3-Ne1
Recent reaction development has focused on methods devoted
to either the synthesis or utilization of strained heterocycles, such
as, epoxides and aziridines.1 Aziridinones (
a-lactams) are another
class of strained heterocycles that were first reported as in-
termediates in the reaction of diazomethane with isocyanates in
1949 by Sheehan.2 Since their initial discovery, limited research has
been performed on this class of compounds. The presence of
a carbonyl group adds additional strain to the molecule as com-
pared to epoxides or aziridines, making them highly reactive.3 The
ring opening reaction of
with indoles.
a-lactams in the formation of a CeN bond
nucleophilic ring opening of
a-lactams with strong nucleophiles
results in the product formation from nucleophilic Ce2 addition,
while the addition of weak nucleophiles results in Ce3 addition.4,5
In 1984, Alper and co-workers reported the ring-expansion of a-
2. Results/discussion
lactams in the presence of Rh and Co catalysts yielding azetidine-
A variety of transition metal catalysts were screened and gave
<5% of the product (Entries 1e4), however, the reaction proceeded
smoothly in the presence of either [Rh(COD)Cl]2 or [Ir(COD)Cl]2
(Entries 5e6). Product formation occurs in both non-polar (Entries
5, 7, 9, 10) and polar aprotic (Entry 8) organic solvents. The desired
product was obtained in 88% yield using [Rh(COD)Cl]2, benzene as
the solvent, and a microwave reactor as the heat source (Table 1,
Entry 5). While a traditional heat source provides the desired
product in high yield, the reaction time increases from 25 min to
48 h (Entry 11). The reaction did not proceed in the absence of
[Rh(COD)Cl]2 (Entry 12). To exclude the possibility of a nucleophilic
2,4-diones.6 More recently, Jeffrey and co-workers were able to
provide the first example of [4þ3] cycloaddition involving
lactams.7e9 To our knowledge, these are the only two examples in
the literature of the ring-expansion of -lactams.
a-
a
The indole framework is found in a variety of biologically active
compounds and natural products.10e14 For this reason, the de-
velopment of catalytic methods for selective functionalization of
indole has drawn much attention.15e17 The preparation of indoles
substitution mechanism,
ion generated by potassium tert-butoxide. The reaction resulted in
a-lactam was reacted with an indole an-
* Corresponding author. E-mail address: rowland@olemiss.edu (G.B. Rowland).
Both authors contributed equally.
y
http://dx.doi.org/10.1016/j.tet.2014.10.049
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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H.K. Box et al. / Tetrahedron 70 (2014) 9709e9717
Table 2 (continued)
Table 1
Optimization of N-functionalization of indolea
Entry
Indole derivative
R3
Product
Yield (%)a
5
6
t-Bu
1e
1f
70
68
Tr
1a
Entry
Cat.
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
Cu(OTf)2
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
THF
1,4-Dioxane
Chlorobenzene
Toluene
<5
<5
<5
<5
88
30
83
81
80
70
81c
0
[RuCl2(dmso)4]
[Ir(acac) (COD)]
[Rh(nbd)2]BF4
[Rh(COD)Cl]2
[Ir(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
d
7
t-Bu
Tr
1g
1h
1i
66
63
50
46
64
59
64
61
8
9
t-Bu
Tr
9
10
11
12
Benzene
Benzene
10
11
12
13
14
1j
a
Indole (0.250 mmol),
a-lactam (0.280 mmol), cat. (0.0100 mmol), solvent
t-Bu
Tr
1k
1l
(1.5 mL).
b
Yields calculated by GC against an internal standard.
Traditional heating source.
c
the addition of the indole nucleophile to the carbonyl group of the
a
-lactam and no desired product was observed.
t-Bu
Tr
1m
1n
The scope of the indole nucleophile was studied under the op-
timal conditions (Table 1, Entry 5). Additionally,
a-lactams with
both tert-butyl and trityl groups on the nitrogen atom were eval-
uated. The reaction proved to be general in terms of the structure
and electronics of the indole derivative (Table 2). The use of both
electron-deficient and electron-rich indole derivatives resulted in
the formation of the desired product in good to excellent yields. The
15
16
t-Bu
1o
1p
67
54
reaction of 5-iodoindole with a-lactams resulted in the formation
of the desired product with the iodide bond intact in good yield
(Entries 13e14). The resulting product provides a reactive handle
that could be further functionalized by transition metal-mediated
coupling methods. The use of an indole derivative with a nucleo-
philic carboxylic acid group also provided the desired product in
good yield (Entries 11e12). The reaction proceeded with indoles
substituted at the hindered Ce2 and Ce7 positions in moderate
yield (Entries 3,4,9,10,17e20). In all case the use of a trityl-
protecting group resulted in the formation of the desired product
in a lower yield than the reactions employing tert-butyl protected
Tr
17
t-Bu
1q
82
18
19
Tr
1r
1s
62
83
t-Bu
a
-lactams, which was attributed to the increased steric
interactions.
20
Tr
1t
80
a
Isolated yields.
Table 2
N-functionalization of substituted indoles with tert-butyl substituted
a
-lactams
Most reported cross-coupling procedures that result in the a-
functionalization of amides require the use of an amide, that is,
substituted with two carbon-protecting groups that are not as
readily removed as a trityl group.28 A trityl-protected indole pro-
vides a product that can easily be deprotected to yield the amide
product in 80% yield as presented in Scheme 1. This results in the
formation of a product, that is, more readily transformed into other
Entry
Indole derivative
R3
Product
Yield (%)a
1
2
3
4
t-Bu
Tr
1a
1b
1c
1d
88
73
88
75
highly functionalized organic molecules such as analogues of
amino acids.
a-
Using the previously established method for the coupling of
tert-butyl substituted -lactams to indole derivatives as a starting
point, a method for the in situ generation of the less stable phenyl
substituted -lactams and subsequent reaction with indole was
optimized (Table 3). Several bases were screened for the generation
t-Bu
Tr
a
a

H.K. Box et al. / Tetrahedron 70 (2014) 9709e9717
9711
Varying the transition metal used to catalyze the reaction from
[Rh(COD)Cl]2 to [Ir(COD)Cl]2 or Pd2dba3 provided only trace
amounts of the desired product (Entries 4e5) similar to the absence
of a transition metal catalyst (Entry 10). Increasing the mol % of
[Rh(COD)Cl]2 gave only a slight increase in yield (Entry 3 vs 6).
Lastly, the reaction was run in nonpolar (Entries 6e8) and polar
aprotic (Entry 9) solvents with the reaction proceeding well in
benzene and toluene (Entries 6e7).
While increasing the mol % of catalyst gave a slight increase in
product formation, it was not significant enough to justify the ad-
ditional catalyst. For this reason, 10 mol % was used over 20 mol %
for the remaining reactions. The optimized conditions were applied
to the coupling of a variety of substituted indoles (Table 4). Mod-
erate to high yields were achieved in all reactions, even with sub-
stituents at the hindered 2- and 7-position of the indole ring
Scheme 1. Deprotection of trityl-protected product.
of the
a
-lactam (Entries 1e3), with the highest conversion resulting
KOtBu. The reaction provided the desired product in 100 min at
room temperature. This is presumably due to a decrease in the CeN
bond strength in the phenyl substituted a-lactams. This allows for
a more rapid oxidative addition of the transition metal catalyst.
Table 3
Optimization for the in situ generation of phenyl substituted a
-lactamsa
Entry
Cat. (mol %)
Solvent
Base
Yield (%)b
1
2
3
4
5
6
7
8
9
[Rh(COD)Cl]2 (10)
[Rh(COD)Cl]2 (10)
[Rh(COD)Cl2 (10)
Pd(dba)2 (10)
[Ir(COD)Cl]2 (10)
[Rh(COD)Cl]2 (20)
[Rh(COD)Cl]2 (20)
[Rh(COD)Cl]2 (20)
[Rh(COD)Cl]2 (20)
d
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Toluene
1,4-Dioxane
THF
NaH
<5
72
90
<5
<5
93
NaOtBuc
KOtBuc
KOtBu
KOtBu
KOtBuc
KOtBuc
KOtBu
KOtBu
KOtBu
86
<5
<5
<5
10
Benzene
a
a
-bromoamide (0.190 mmol), indole (0.0950 mmol), and Solvent (1.5 mL).
b
c
Isolated yields.
Additional 0.4 equiv of base added after 90 min.
Table 4
N-functionalization of indole derivatives with phenyl substituted a-lactams
Entry
1
Indole derivative
Product
Yield (%)a
90
2a
2
3
2b
2c
67
80
(continued on next page)

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H.K. Box et al. / Tetrahedron 70 (2014) 9709e9717
Table 4 (continued )
Entry
Indole derivative
Product
Yield (%)a
4
5
2d
77
2e
2f
93
98
H
6
7
8
2g
2h
70
63
a
Isolated yields.
(Entries 2, 5). The reaction also provided the desired product in
good yield for both electron-rich indole derivatives as well as
electron deficient ones (Entries 7,8).
The next focus was to determine the reaction scope in terms of
the a-lactam. A series of functionalized a-lactams were generated
approach (Table 5). The in situ generation of the
a
-lactam was
monitored and confirmed via 1H NMR. The reaction proved to be
general in terms of the structure and electronics of the substituent
connected to the phenyl ring and proceeded in moderate to high
yield with substitution at the ortho- (Entry 7), meta- (Entries 4 and
6), or para-position (Entries 1e3, 5).
in situ, and then reacted with indole to assess the viability of this
Table 5
Scope of in situ generated functionalized a-lactams
Entry
1
a
-bromo amide
Product
Yield (%)a
90
3a
2
3
4
3b
3c
3d
81
71
70

H.K. Box et al. / Tetrahedron 70 (2014) 9709e9717
9713
Table 5 (continued )
Entry
a
-bromo amide
Product
Yield (%)a
5
3e
60
6
7
3f
63
75
3g
a
Isolated yields.
3. Conclusions
solid was washed with pentane and dried under high vacuum. With
no further purification, a white solid was recovered (2.50 g, 68%). The
spectroscopic data matches previously reported literature.29,30,33
We report a novel Rh-mediated method for the coupling of in-
doles with -lactams. The developed method results in the for-
a
mation of the desired product in good to excellent yield. The
reaction was found to be tolerant of functional groups around the
indole ring. The use of trityl protecting groups results in a slight
decrease in the yield of the desired product but can easily be
4.3. General procedure for 1aet
In a glove box, a microwave vial was charged with
a-lactam
(0.250 mmol), indole (0.280 mmol), and [RhCODCl]2 (0.0100 mmol).
The vial was closed with a cap fitted with a septum and benzene
(1.5 mL) was added via syringe. The reaction was removed from the
glove box and heated in the microwave reactor for 25 min at 160 ꢀC.
The reaction mixture cooled to room temperature and was removed
from reactor. The mixture was exposed to air, filtered through a bed
of silica, and washed with CH2Cl2. Compounds were purified using
flash column chromatography (hexanes/CH2Cl2).
deprotected to provide an
this methodology was extended to include the less stable phenyl
substituted -lactams by in situ generation. Future work will focus
on the development of a more general reaction in terms of both
a-amino amide analogue. The scope of
a
nucleophiles and a-lactams.
4. Experimental
4.1. General methods
4.3.1. N-(tert-Butyl)-2-(1H-indol-1-yl)-3,3-dimethylbutanamide
(1a). The compound was obtained as a white solid, 62.6 mg, 88%
The following reagents were purchased and used as received:
indole derivatives (Sigma Aldrich), benzene (Sigma Aldrich; anhy-
drous), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (Strem).
Unless otherwise noted, reactions were conducted with stirring in
oven-dried glassware under an inert atmosphere. Reactions were
performed in the Biotage Initiatorþ microwave reactor and flash
column chromatography was performed on a Biotage Isolera One
system using silica gel. Mass spectrometry was performed on
a Bruker UHPLC-Micro-Q/T ESI-MS in positive mode. All NMR
spectra were taken on a Bruker ADVANCE III 600 MHz spectrometer.
yield, mp 58e60 ꢀC; 1H NMR (CDCl3, 600 MHz)
d 7.68e7.65 (m, 2H),
7.36 (d, 1H, J¼8.2 Hz), 7.23 (t, 1H, J¼15.1 Hz), 7.13 (t, 1H, J¼14.8 Hz),
6.57 (d, 1H, J¼3.3 Hz), 5.36 (s, 1H), 4.49 (s, 1H), 1.30 (s, 9H), 1.13 (s,
9H); 13C NMR (CDCl3, 125 MHz)
d 166.2, 131.9, 131.1, 130.6, 129.7,
124.0, 122.2, 112.0, 104.6, 69.8, 54.3, 39.7, 31.2, 30.3; HRMS (ESI) m/z
calculated for C18H26N2NaO [MþNa]þ: 309.1943, found 309.1953.
4.3.2. 2-(1H-Indol-1-yl)-3,3-dimethyl-N-tritylbutanamide (1b). The
compound was obtained as a white solid, 87.0 mg, 73% yield, mp
56e59 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.68 (d, 1H, J¼7.8 Hz), 7.45 (s,
1H), 7.42 (d, 1H, J¼8.2 Hz), 7.32 (t, 1H, J¼14.9 Hz), 7.24e7.22 (m,
10H), 7.16 (t, 1H, J¼14.7 Hz), 7.07e7.06 (m, 5H), 6.68 (s, 1H), 6.59 (d,
1H, J¼3.1 Hz), 4.70 (s, 1H), 1.09 (s, 9H); 13C NMR (CDCl3, 125 MHz)
4.2. Synthesis of a-lactams
4.2.1. 1,3-Di-tert-butylaziridin-2-one. 2-Bromo-N-(tert-butyl)-3,3-
dimethylbutanamide (0.0600 mol) was dissolved in anhydrous
Et2O (60 mL), cooled to 0 ꢀC, and KOtBu (0.0900 mol) was added to
the reaction. The reaction stirred for 10 min at 0 ꢀC. The mixture
was then filtered through a bed of Celite and concentrated under
reduced pressure. With no further purification, an oil was re-
covered (8.00 g 78%). The spectroscopic data matches previously
reported literature.29e32
d 160.8, 146.7, 131.2, 131.1, 130.7, 130.6, 129.8, 129.7, 124.4, 123.7,
122.4, 105.1, 73.2, 39.7, 30.3, 29.8, 21.1; HRMS (ESI) m/z calculated
for C33H32N2NaO [MþNa]þ: 495.2412, found 495.2368.
4.3.3. N-(tert-Butyl)-3,3-dimethyl-2-(2-methyl-1H-indol-1-yl) buta-
namide (1c). The compound was obtained as a white solid, 66.2 mg,
88% yield, mp 100e102 ꢀC; 1H NMR (CDCl3, 600 MHz)
d 7.51 (d, 1H,
J¼7.3 Hz), 7.45 (d, 1H, J¼7.8 Hz), 7.10e7.06 (m, 2H), 6.34 (s, 1H), 5.20
(s, 1H), 4.52 (s, 1H), 2.47 (s, 3H), 1.19 (s, 9H), 1.17 (s, 9H); 13C NMR
4.2.2. 3-(tert-Butyl)-1-tritylaziridin-2-one. 2-Bromo-3,3-dimethyl-
N-tritylbutanamide (0.0110 mol) was dissolved in Et2O (80 mL),
cooled to 0 ꢀC, and NaOtBu (0.0210 mol) was added to the reaction.
The reaction warmed to room temperature and proceeded 2 h. The
reaction was washed with water (1 x 80 mL) and brine (1ꢁ80 mL),
dried with Na2SO4, and concentrated under reduced pressure. The
(CDCl3, 125 MHz) d 168.3, 137.5, 135.7, 128.8, 120.4, 119.9, 119.6,
113.9, 102.2, 65.7, 51.2, 38.3, 29.2, 28.4, 14.2; HRMS (ESI) m/z cal-
culated for C19H28N2NaO [MþNa]þ: 323.2099, found 323.2116.
4.3.4. 3,3-Dimethyl-2-(2-methyl-1H-indol-1-yl)-N-trityl butanamide
(1d). The compound was obtained as a white solid, 91.4 mg, 75%

9714
H.K. Box et al. / Tetrahedron 70 (2014) 9709e9717
yield, mp 60e64 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.51 (d, 1H,
(ESI) m/z calculated for C34H34N2NaO [MþNa]þ: 509.2569, found
J¼7.9 Hz), 7.46 (d, 1H, J¼8.4 Hz), 7.33e7.16 (m, 10H), 7.11e7.06 (m,
509.2504.
2H), 7.01e6.98 (m, 5H), 6.62 (s, 1H), 6.35 (s, 1H), 4.60 (s, 1H), 2.49 (s,
3H), 1.16 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d
170.2, 146.9, 139.7,
4.3.11. 1-(1-(tert-Butylamino)-3,3-dimethyl-1-oxobutan-2-yl)-1H-
indole-6-carboxylic acid (1k). The compound was obtained as
a white solid, 53.1 mg, 64% yield, mp 226e227 ꢀC; 1H NMR (CD3OD,
131.1, 131.0, 130.6, 130.5, 129.5, 123.5, 122.6, 122.2, 117.0, 105.2, 69.6,
40.7, 31.7, 29.8, 17.1; HRMS (ESI) m/z calculated for C34H34N2NaO
[MþNa]þ: 509.2569, found 509.2525.
600 MHz)
7.48e7.47 (m, 2H), 6.56e6.55 (m, 1H), 4.80 (s, 1H), 1.38 (s, 9H), 1.17
(s, 9H); 13C NMR (CD3OD,125 MHz)
169.1, 167.3,135.4,132.1, 128.3,
d
8.22 (s, 1H), 7.77e7.76 (m, 1H), 7.64 (d, 1H, J¼8.1 Hz),
4.3.5. N-(tert-Butyl)-3,3-dimethyl-2-(3-methyl-1H-indol-1-yl) buta-
d
namide (1e). The compound was obtained as a white solid, 52.8 mg,
122.0, 119.6, 119.5, 113.4, 101.5, 80.9, 51.0, 33.6, 27.48, 25.5; HRMS
(ESI) m/z calculated for C19H26N2NaO3 [MþNa]þ: 353.1841, found
353.1892.
70% yield, mp 125e127 ꢀC; 1H NMR (CDCl3, 600 MHz)
d 7.59 (d, 1H,
J¼7.8 Hz), 7.42 (s, 1H), 7.31 (d, 1H, J¼8.2 Hz), 7.22 (t, 1H, J¼15.0 Hz),
7.13 (t, 1H, J¼14.7 Hz), 5.37 (s, 1H), 4.44 (s, 1H), 2.35 (s, 3H), 1.30 (s,
9H), 1.12 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d
168.5, 137.7, 128.4,
4.3.12. 1-(3,3-Dimethyl-1-oxo-1-(tritylamino)butan-2-yl)-1H-in-
dole-6-carboxylic acid (1l). The compound was obtained as a white
solid, 76.5 mg, 59% yield, mp 119e121 ꢀC; 1H NMR (CDCl3,
125.1, 121.3, 119.0, 118.8, 111.0, 109.1, 67.1, 51.6, 37.0, 28.6, 27.7, 9.7;
HRMS (ESI) m/z calculated for C19H28N2NaO [MþNa]þ: 323.2099,
found 323.2096.
600 MHz)
J¼8.2 Hz), 7.38e7.37 (m,1H), 7.33 (s,1H), 7.22e7.19 (m,15H), 6.63 (s,
1H), 5.19 (s, 1H), 1.09 (s, 9H); 13C NMR (CDCl3, 125 MHz)
167.6,
d 8.65 (s, 1H), 8.23 (s, 1H), 7.86e7.85 (m, 1H), 7.68 (d, 1H,
4.3.6. 3,3-Dimethyl-2-(3-methyl-1H-indol-1-yl)-N-trity
mide (1f). The compound was obtained as a white solid, 84.0 mg,
68% yield, mp 53e56 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.61 (d, 1H,
l
butana-
d
166.5, 144.4, 135.1, 132.1, 128.5, 128.1, 127.9, 126.9, 122.5, 120.6,
120.5, 113.9, 103.0, 81.3, 70.1, 34.8, 26.5; HRMS (ESI) m/z calculated
for C34H32N2NaO3 [MþNa]þ: 539.2311, found 539.2243.
d
J¼7.8 Hz), 7.38 (d, 1H, J¼8.2 Hz), 7.34e7.15 (m, 11H), 7.06e7.05 (m,
5H), 6.66 (s, 1H), 4.66 (s, 1H), 2.35 (s, 3H), 1.12 (s, 9H); 13C NMR
(CDCl3, 125 MHz)
d
170.9, 146.7, 131.3, 131.1, 130.7, 130.5, 129.8,
4.3.13. N-(tert-Butyl)-2-(5-iodo-1H-indol-1-yl)-3,3-dimethyl buta-
namide (1m). The compound was obtained as a white solid,
65.9 mg, 64% yield, mp 142e144 ꢀC; 1H NMR (CDCl3, 600 MHz)
129.6, 124.4, 121.9, 121.8, 114.3, 105.2, 73.1, 39.4, 30.4, 29.8, 12.3;
HRMS (ESI) m/z calculated for C34H34N2NaO [MþNa]þ: 509.2569,
found 509.2503.
d
7.98 (s, 1H), 7.68 (s, 1H), 7.46 (d, 1H, J¼8.4 Hz), 7.14 (d, 1H,
J¼8.4 Hz), 6.48 (s, 1H), 5.35 (s, 1H), 4.39 (s, 1H), 1.31 (s, 9H), 1.10 (s,
9H); 13C NMR (CDCl3, 125 MHz)
170.4, 139.1, 133.3, 132.4, 132.3,
4.3.7. N-(tert-Butyl)-3,3-dimethyl-2-(5-methyl-1H-indol-1-yl) buta-
namide (1g). The compound was obtained as a white solid,
49.8 mg, 66% yield, mp 143e147 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
131.3, 114.0, 103.8, 85.4, 70.0, 54.5, 39.7, 31.2, 30.2; HRMS (ESI) m/z
calculated for C18H25IN2NaO [MþNa]þ: 435.0909, found 435.0870.
d
7.61 (d, 1H, J¼3.0 Hz), 7.45 (s, 1H), 7.25 (d, 1H, J¼8.4 Hz), 7.06
(d, 1H, J¼8.4 Hz), 6.49 (d, 1H, J¼2.7 Hz), 6.49 (d, 1H, J¼2.7 Hz),
4.3.14. 2-(5-Iodo-1H-indol-1-yl)-3,3-dimethyl-N-tritylbutanamide
6.06 (s, 1H), 4.46 (s, 1H), 2.48 (s, 3H), 1.30 (s, 9H), 1.13 (s, 9H);
(1n). The compound was obtained as a white solid, 90.9 mg, 61%
13C NMR (CDCl3, 125 MHz)
d
171.0, 138.5, 131.4, 131.0, 130.2,
yield, mp 69e73 ꢀC; 1H NMR (CDCl3, 600 MHz)
d 8.01 (m, 1H), 7.49
125.6, 123.3, 111.7, 104.2, 69.9, 54.3, 39.7, 31.2, 30.3, 23.9; HRMS
(ESI) m/z calculated for C19H28N2NaO [MþNa]þ: 323.2099, found
323.2124.
(d,1H, J¼9.3 Hz), 7.42 (s, 1H), 7.34e7.23 (m, 11H), 7.07e7.06 (m, 5H),
6.66 (s, 1H), 6.50 (d, 1H, J¼3.2 Hz), 4.60 (s, 1H), 1.07 (s, 9H); 13C NMR
(CDCl3, 125 MHz) d 170.2146.9, 146.6, 132.6, 132.5, 131.2, 131.1, 130.7,
130.6, 129.8, 123.2, 104.1, 85.7, 73.4, 39.7, 30.1, 29.8; HRMS (ESI) m/z
4.3.8. 3,3-Dimethyl-2-(5-methyl-1H-indol-1-yl)-N-trityl butanamide
calculated for C33H31IN2NaO [MþNa]þ: 621.1379, found 621.1311.
(1h). The compound was obtained as a white solid, 77.4 mg, 63%
yield, mp 52e55 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.47 (s, 1H), 7.40
4.3.15. Methyl 1-(1-(tert-butylamino)-3,3-dimethyl-1-oxobutan-2-
yl)-1H-indole-5-carboxylate (1o). The compound was obtained as
a white solid, 57.4 mg, 67% yield, mp 188e189 ꢀC; 1H NMR (CDCl3,
(m, 1H), 7.34e7.23 (m, 11H), 7.09e7.07 (m, 6H), 6.70 (s, 1H), 6.51 (d,
1 Hz, J¼3.0 Hz), 4.66 (s, 1H), 2.49 (s, 3H), 1.09 (s, 9H); 13C NMR
(CDCl3, 125 MHz)
d
170.7, 146.7, 131.6, 131.3, 131.1,130.7, 130.6,129.8,
600 MHz)
d
8.41 (s, 1H), 7.92 (d, 1H, J¼8.7 Hz), 7.83 (d, 1H, J¼3.1 Hz),
129.6, 125.9, 123.4, 104.6, 73.2, 39.7, 30.3, 29.8, 23.9, 16.7; HRMS
(ESI) m/z calculated for C34H34N2NaO [MþNa]þ: 509.2569, found
509.2516.
7.36 (d,1H, J¼8.7 Hz), 6.65 (d,1H, J¼3.1 Hz), 5.47 (s, 1H), 4.49 (s, 1H),
3.95 (s, 3H), 1.32 (s, 9H), 1.11 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d
168.1, 167.7, 139.8, 129.5, 127.6, 123.91, 123.90, 122.7, 121.5, 109.1,
103.1, 67.3, 51.8, 37.1, 28.5, 27.5; HRMS (ESI) m/z calculated for
4.3.9. N-(tert-Butyl)-3,3-dimethyl-2-(7-methyl-1H-indol-1-yl) buta-
C
20H28N2NaO3 [MþNa]þ: 367.1998, found 367.1985.
namide (1i). The compound was obtained as a white solid, 37.6 mg,
50% yield, mp 53e54 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.53 (d, 1H,
4.3.16. Methyl-1-(3,3-dimethyl-1-oxo-1-(tritylamino)butan-2-yl)-
1H-indole-5-carboxylate (1p). The compound was obtained as
a white solid, 71.5 mg, 54% yield, mp 231e233 ꢀC; 1H NMR (CDCl3,
J¼7.7 Hz), 7.49 (d, 1H, J¼3.3 Hz), 7.04 (t, 1H, J¼14.9 Hz), 6.97 (d, 1H,
J¼7.0 Hz), 6.60 (d, 1H, J¼3.3 Hz), 5.41 (s, 1H), 5.21 (s, 1H), 2.75 (s,
3H), 1.30 (s, 9H), 1.12 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d
171.8,
600 MHz)
d
8.44 (s, 1H), 7.95 (d, 1H, J¼8.2 Hz), 7.54 (s, 1H), 7.43 (d,
138.9, 131.4, 130.1, 128.6, 123.0, 122.5, 122.2, 106.0, 70.4, 54.2, 39.7,
31.3, 30.7, 24.5; HRMS (ESI) m/z calculated for C19H28N2NaO
[MþNa]þ: 323.2099, found 323.2113.
1H, J¼8.5 Hz), 7.23e7.14 (m, 10H), 7.07e7.06 (m, 5H), 6.72 (s, 1H),
6.66 (s, 1H), 4.70 (s, 1H), 3.95 (s, 3H), 1.09 (s, 9H); 13C NMR (CDCl3,
125 MHz) d 168.0,167.5,144.0,143.9,128.6,128.4,128.0,127.8,127.2,
127.1, 124.0, 123.1, 121.9, 109.1, 103.6, 70.7, 51.9, 51.8, 37.0, 27.4;
HRMS (ESI) m/z calculated for C35H34N2NaO3 [MþNa]þ: 553.2467,
found 553.2388.
4.3.10. 3,3-Dimethyl-2-(7-methyl-1H-indol-1-yl)-N-trityl
mide (1j). The compound was obtained as a white solid, 56.2 mg,
46% yield, mp 112e115 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.54e7.50
butana-
d
(m, 1H), 7.44 (m, 1H), 7.32e7.22 (m,10H), 7.07e6.99 (m, 7H), 6.77 (s,
4.3.17. N-(tert-Butyl)-2-(5-methoxy-2-methyl-1H-indol-1-yl)-3,3-
dimethylbutanamide (1q). The compound was obtained as a white
solid, 67.5 mg, 82% yield, mp 101e104 ꢀC; 1H NMR (CDCl3, 600 MHz)
1H), 6.63 (m, 1H), 4.11 (s, 1H), 2.75 (s, 3H), 1.11 (s, 9H); 13C NMR
(CDCl3, 125 MHz)
d 171.4, 146.9, 131.2, 131.0, 130.6, 129.8, 129.6,
128.9, 122.8, 122.4, 106.7, 70.9, 39.6, 38.5, 30.8, 29.5, 24.5; HRMS
d
7.33 (d, 1H, J¼9.0 Hz), 6.98 (d, 1H, J¼2.4 Hz), 6.75 (dd, 1H,

H.K. Box et al. / Tetrahedron 70 (2014) 9709e9717
9715
J1¼9.0 Hz, J2¼2.5 Hz), 5.23 (s, 1H), 4.47 (s, 1H), 3.86 (s, 3H), 2.44 (s,
3H), 1.19 (s, 9H), 1.15 (s, 9H); 13C NMR (CDCl3, 125 MHz)
168.4,
154.0, 138.2, 130.7, 129.4, 114.6, 110.1, 102.0, 101.5, 65.8, 55.6, 51.2,
38.3, 29.1, 28.4, 14.2; HRMS (ESI) m/z calculated for C20H30N2NaO2
[MþNa]þ: 353.2205, found 353.2188.
removed under reduced pressure. The crude bromo(phenyl)acetyl
chloride was used directly for the next step.
d
N,N0-Diisopropylethylamine or triethylamine (1.0e2.0 equiv)
was charged to a solution of tert-butylamine (1.0e1.1 eq) in CH2Cl2.
The reaction mixture was cooled to 0 ꢀC and the crude bromo(-
phenyl)acetyl chloride was added slowly via syringe over
45e60 min. The reaction warmed to room temperature and stirred
for 3e5 h. Products were purified by flash column chromatography
(hexanes/CH2Cl2).
4.3.18. 2-(5-Methoxy-2-methyl-1H-indol-1-yl)-3,3-dimethyl-N-tri-
tylbutanamide (1r). The compound was obtained as a white solid,
81.1 mg, 62% yield, mp 63e66 ꢀC; 1H NMR (CDCl3, 600 MHz)
d 7.31
(d, 1H, J¼9.0 Hz), 7.27e7.17 (m, 10H), 7.10 (d, 1H, J¼6.9 Hz),
7.01e6.99 (m, 5H), 6.98 (d, 1H, J¼2.0 Hz), 6.65e6.63 (m, 1H), 6.27 (s,
1H), 4.56 (s, 1H), 3.86 (s, 3H), 2.47 (s, 3H), 1.14 (s, 9H); 13C NMR
4.5.1. 2-Bromo-N-(tert-butyl)-2-phenylacetamide. Phenyl
acetic
acid (15.0 mmol), phosphorous trichloride (15.0 mmol), bromine
(30.0 mmol, excess 9.00 mmol), tert-butylamine (15.0 mmol), N,N0-
diisopropylethylamine (30.0 mmol), CH2Cl2 (75 mL). The com-
pound was obtained as a white solid, 3.30 g, 81% yield, mp
(CDCl3, 125 MHz)
d 172.6, 159.9, 146.9, 138.6, 135.8, 132.1, 131.0,
130.5,129.5,125.3,117.7,113.0,105.0, 73.0, 69.5, 58.4, 40.6, 31.6,17.1;
HRMS (ESI) m/z calculated for C35H36N2NaO2 [MþNa]þ: 539.2674,
found 539.2619.
134e136 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.43 (d, 2H, J¼7.2 Hz),
7.34e7.29 (m, 3H), 6.56 (s, 1H), 5.33 (s, 1H), 1.37 (s, 9H); 13C NMR
4.3.19. N-(tert-Butyl)-3,3-dimethyl-2-(2-methyl-5-nitro-1H-indol-1-
yl)butanamide (1s). The compound was obtained as a yellow solid,
71.5 mg, 83% yield, mp 176e178 ꢀC; 1H NMR (CDCl3, 600 MHz)
(CDCl3, 125 MHz) d 166.1, 137.8, 128.9, 128.8, 128.2, 52.1, 51.9, 28.4;
HRMS (ESI) m/z calculated for C12H17BrNO [MþH]þ: 270.0494;
found: 270.0495.
d
8.44 (s, 1H), 8.00 (d, 1H, J¼9.1 Hz), 7.61 (d, 1H, J¼9.1 Hz), 6.53 (s,
1H), 4.98 (s, 1H), 4.48 (s, 1H), 2.52 (s, 3H), 1.20 (s, 9H), 1.17 (s, 9H);
13C NMR (CDCl3, 125 MHz)
167.1, 141.8, 141.0, 139.1, 127.9, 116.4,
4.5.2. 2-Bromo-N-(tert-butyl)-2-(4-fluorophenyl)acetamide. 2-Bro
d
mo-N-(tert-butyl)-2-(4-fluorophenyl)acetamide
(4-Fluorophe
116.1, 113.7, 104.4, 66.2, 51.6, 38.3, 28.8, 28.4, 14.4; HRMS (ESI) m/z
calculated for C19H27N3NaO3 [MþNa]þ: 368.1950, found 368.1926.
nyl) acetic acid (18.0 mmol), phosphorous trichloride
(18.0 mmol), bromine (36.0 mmol, excess 11 mmol), tert-butyl-
amine (18.0 mmol), N,N0-diisopropylethylamine (36.0 mmol),
CH2Cl2 (75 mL). The compound was obtained as a white solid,
4.3.20. 3,3-Dimethyl-2-(2-methyl-5-nitro-1H-indol-1-yl)-N-trityl
butanamide (1t). The compound was obtained as a yellow solid,
106 mg, 80% yield, mp 249e250 ꢀC (decomposed); 1H NMR (CDCl3,
2.90 g, 56% yield, mp 133e135 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.41
(dd, 2H, J¼5.4, 8.4 Hz), 7.02 (t, 2H, J¼8.4 Hz), 5.32 (s, 1H), 1.39 (s,
9H); 13C NMR (CDCl3, 125 MHz)
600 MHz)
7.21e7.15 (m, 10H), 7.01e6.99 (m, 5H), 6.54 (s, 1H), 6.41 (s, 1H), 4.60
(s, 1H), 2.56 (s, 3H), 1.16 (s, 9H); 13C NMR (CDCl3, 125 MHz)
169.0,
d
8.42 (m, 1H), 7.80e7.78 (m, 1H), 7.44 (d, 1H, J¼9.2 Hz),
d
165.9, 163.6 (d, J¼990 Hz), 133.8
(d, J¼12 Hz), 130.2 (d, J¼36 Hz), 115.9 (d, J¼84 Hz), 52.2, 50.8, 28.4;
HRMS (ESI) m/z calculated for C12H16BrFNO [MþH]þ: 288.0399;
found: 288.0407.
d
146.5,144.3, 143.0,142.4,130.8,130.6,130.5,129.8,118.9, 118.7, 117.1,
107.3, 73.3, 69.9, 40.7, 31.1, 17.3; HRMS (ESI) m/z calculated for
C
34H33N3NaO3 [MþNa]þ: 554.2420, found 554.2370.
4.5.3. 2-Bromo-N-(tert-butyl)-2-(4-chlorophenyl)acetamide. 2-Bro
mo-N-(tert-butyl)-2-(4-chlorophenyl)acetamide (4-chlorophenyl)
acetic acid (30.0 mmol), phosphorous trichloride (30.0 mmol),
bromine (60.0 mmol, excess 11 mmol), tert-butylamine
(68.0 mmol), N,N0-diisopropylethylamine (77.0 mmol), CH2Cl2
(50 mL). The compound was obtained as a white solid, 6.60 g, 72%
4.4. Deprotection
4.4.1. 3,3-Dimethyl-2-(2-methyl-5-nitro-1H-indol-1-yl)
butanamide. 3,3-Dimethyl-2-(2-methyl-5-nitro-1H-indol-1-yl)-N-
trityl butanamide (0.0280 mmol) was dissolved in CH2Cl2 (0.5 mL)
and cooled to 10 ꢀC followed by the slow addition of TFA
(1.30 mmol). The reaction stirred for 3 h. The solution was con-
centrated and the crude residue was dissolved in methyl-t-butyl
ether followed by concentration. The crude product was again
dissolved in methyl-tert-butyl ether followed by the addition of
hexanes. The compound was obtained as a white solid, 11.0 mg, 80%
yield, mp 156e158 ꢀC; 1H NMR (CDCl3, 600 MHz)
J¼8.4 Hz), 7.32 (d, 2H, J¼8.4 Hz), 6.48 (s, 1H), 5.28 (s, 1H), 1.39 (s,
9H); 13C NMR (CDCl3, 125 MHz)
165.6, 136.5, 134.9, 129.7, 129.1,
d 7.37 (d, 2H,
d
52.3, 50.9, 28.4; HRMS (ESI) m/z calculated for C12H15BrClNNaO
[MþNa]þ: 327.9897; found: 327.9901.
4.5.4. 2-Bromo-2-(4-bromophenyl)-N-(tert-butyl)acetamide. 2-Bro
mo-2-(4-bromophenyl)-N-(tert-butyl)acetamide (4-bromophenyl)
acetic acid (4.90 mmol), phosphorous trichloride (4.90 mmol),
bromine (9.80 mmol, excess 2.50 mmol), tert-butylamine
(5.10 mmol), triethylamine (7.00 mmol), CH2Cl2 (50 mL). The
compound was obtained as a white solid, 0.500 g, 30% yield, mp
yield, mp 153.2e155.6 ꢀC; 1H NMR (CDCl3, 600 MHz)
d 8.45 (s, 1H),
8.01 (d,1H, J¼9.0 Hz), 7.55 (d,1H, J¼9.1 Hz), 6.54 (s,1H), 5.25 (s, 2H),
4.63 (s, 1H), 2.54 (s, 3H), 1.19 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d
172.7, 143.6, 141.7, 130.7, 130.5, 119.2, 119.0, 116.0, 107.1, 67.9, 40.8,
31.4, 17.0; HRMS (ESI) m/z calculated for C19H26N2NaO3 [MþNa]þ:
312.1324, found 312.1342.
177e179 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.49 (d, 2H, J¼8.4 Hz), 7.31
(d, 2H, J¼8.4 Hz), 6.48 (s, 1H), 5.27 (s, 1H), 1.39 (s, 9H); 13C NMR
4.5. General procedure for the synthesis of
a-bromoamides
(CDCl3, 125 MHz) d 165.5, 137.0, 132.1, 129.9, 123.1, 52.3, 50.9, 28.39;
HRMS (ESI) m/z calculated for C12H15Br2NNaO [MþNa]þ: 371.9393;
In air, a two neck oven dried round bottom flask equipped with
a reflux condenser capped with a calcium chloride drying tube was
charged with the substituted phenyl acetic acid (1.0 equiv) and
phosphorous trichloride (1.0 equiv). Bromine (2.0 equiv) was added
via syringe and the reaction mixture was heated for 1.5 h at
70e90 ꢀC. After 1.5 h, excess bromine (0.4e0.6 equiv) was added
and reaction was stirred for another 18 h at 70e90 ꢀC. The mixture
was cooled to room temperature and poured into 150 mL of ice
water. The mixture was extracted using toluene (2ꢁ150 mL), dried
over anhydrous Na2SO4, and the residual bromine and toluene were
found: 371.9394.
4.5.5. 2-bromo-N-(tert-butyl)-2-(3-chlorophenyl)acetamide. 2-bro
mo-N-(tert-butyl)-2-(3-chlorophenyl)acetamide (3-chlorophenyl)
acetic acid (18.0 mmol), phosphorous trichloride (18.0 mmol),
bromine (36.0 mmol, excess 11.0 mmol), tert-butylamine
(18.0 mmol), N,N0-diisopropylethylamine (36.0 mmol), CH2Cl2
(75 mL). The compound was obtained as a white solid, 3.10 g, 56%
yield, mp 124e127 ꢀC; 1H NMR (CDCl3, 600 MHz)
(m, 3H), 6.56 (s, 1H), 5.26 (s, 1H), 1.40 (s, 9H); 13C NMR (CDCl3,
d 7.41 (s, 1H), 7.30

9716
H.K. Box et al. / Tetrahedron 70 (2014) 9709e9717
125 MHz)
d
165.4, 139.7, 134.6, 130.2, 129.1, 128.5, 126.5, 52.3, 50.6,
with dichloromethane and filtered through plug of silica. The crude
reaction mixture was concentrated under reduced pressure and
purified by flash column chromatography (hexanes/CH2Cl2).
28.4; HRMS (ESI) m/z calculated for C12H15BrClNNaO [MþNa]þ:
327.9897; found: 327.9910.
4.5.6. 2-Bromo-N-(tert-butyl)-2-(4-methylphenyl)
acetamide. -
4.6.1. N-(tert-butyl)-2-(1H-indol-1-yl)-2-phenylacetamide (2a). The
Under the general procedure, (4-methylphenyl) acetic acid
(12.0 mmol), dimethylformamide (2 drops), chloroform (15 mL),
phosphorous trichloride (12.0 mmol) were reacted. The mixture was
cooled to 0 ꢀC and thionyl chloride (18.0 mmol) was added via sy-
ringe. The mixture warmed to room temperature and stirred for 2 h,
bromine (14.4 mmol, excess 11.0 mmol) was added, and stirred for
16 h at 80 ꢀC. N,N0-diisopropylethylamine/triethylamine (24.0 mmol)
was charged to a solution of tert-butylamine (18.0 mmol) in CH2Cl2
(50 mL). The reaction mixture was cooled to 0 ꢀC and the crude
bromo(phenyl)acetyl chloride was added slowly via syringe over
45e60 min. The reaction warmed to room temperature and stirred
for 3e5 h. Product purified by flash column chromatography (hex-
anes/EtOAc). The compound was obtained as a white solid 0.800 g,
compound was obtained as a white solid, 26.2 mg, 90% yield, mp
174e177 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.64 (d, 1H, J¼7.8 Hz),
7.39e7.33 (m, 6H), 7.23 (t, 1H, J¼7.8 Hz), 7.15 (t, 1H, J¼7.8 Hz), 6.86 (d,
1H, J¼3.0 Hz), 6.52 (d, 1H, J¼3.0 Hz), 6.01 (s, 1H), 5.35 (s, 1H), 1.25 (s,
9H); 13C NMR (CDCl3,125 MHz)
d 168.2,136.6,135.6,129.0,128.9,128.8,
128.7,126.0,122.3,121.3,120.5,109.6,103.1, 64.7, 51.8, 28.5; HRMS (ESI)
m/z calculated for C20H22N2NaO [MþNa]þ: 329.1624; found: 329.1623.
4.6.2. N-(tert-butyl)-2-(2-methyl-1H-indol-1-yl)-2-phenyl
amide (2b). The compound was obtained as a white solid, 20.5 mg,
67% yield, mp 161e164 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.53 (d, 1H,
acet-
d
J¼7.2 Hz), 7.31e7.25 (m, 3H), 7.22 (d, 2H, J¼7.2 Hz), 7.06 (dd, 1H,
J¼7.8, 6.6 Hz), 6.99 (dd, 1H, J¼8.4, 6.6 Hz), 6.96 (d, 1H, J¼7.8 Hz), 6.37
(s, 1H), 6.10 (s, 1H), 5.48 (s, 1H), 2.35 (s, 3H), 1.26 (s, 9H); 13C NMR
24% yield, mp 135e138 ꢀC; 1H NMR (CDCl3, 600 MHz)
J¼7.8 Hz), 7.17 (d, 2H, J¼7.8 Hz), 6.53 (s, 1H), 5.33 (s, 1H), 2.33 (s, 3H),
1.39 (s, 9H); 13C NMR (CDCl3, 125 MHz)
166.1, 139.0, 134.9, 129.6,
d 7.32 (d, 2H,
(CDCl3, 125 MHz) d 167.4, 137.1, 136.3, 135.5, 128.8, 128.6, 128.0, 127.9,
d
121.2, 120.2, 120.0, 111.0, 102.7, 62.5, 51.8, 28.5, 13.7; HRMS (ESI) m/z
128.1, 52.2, 52.1, 28.4, 21.2; HRMS (ESI) m/z calculated for
calculated for C21H25N2O [MþH]þ: 321.1967; found: 321.1966.
C
13H18BrNNaO [MþNa]þ: 306.0464; found: 306.0457.
4.6.3. N-(tert-butyl)-2-(3-methyl-1H-indol-1-yl)-2-phenyl
amide (2c). The compound was obtained as a white solid, 24.3 mg,
80% yield, mp 186e189 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.57 (d, 1H,
acet-
4.5.7. 2-Bromo-N-(tert-butyl)-2-(3-(trifluoromethyl)phenyl)
amide. 2-Bromo-N-(tert-butyl)-2-(3-(trifluoromethyl)phenyl)
acet-
d
acetamide [3-(trifluoromethyl) phenyl] acetic acid (44.1 mmol),
phosphorous trichloride (44.1 mmol), bromine (88.2 mmol, excess
44.1 mmol), tert-butylamine (48.5 mmol), triethylamine
(66.2 mmol), CH2Cl2 (250 mL). The compound was obtained as
a white solid, 12.7 g, 85% yield, mp 97e100 ꢀC; 1H NMR (CDCl3,
J¼7.8 Hz), 7.40e7.36 (m, 3H), 7.34e7.30 (m, 3H), 7.23 (t, 1H,
J¼7.8 Hz), 7.16 (t, 1H, J¼7.8 Hz), 6.61 (s, 1H), 5.96 (s, 1H), 5.39 (s, 1H),
2.26 (s, 3H), 1.25 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d 168.5, 137.0,
135.9, 129.3, 129.0, 128.7, 128.6, 123.3, 122.3, 119.8, 119.3, 112.3,
109.5, 64.5, 51.7, 28.5, 9.7; HRMS (ESI) m/z calculated for C21H25N2O
[MþH]þ: 321.1961; found: 321.1964.
600 MHz)
d
7.67 (s, 1H), 7.64 (d, 1H, J¼7.8 Hz), 7.59 (d, 1H, J¼7.8 Hz),
7.50 (t, 1H, J¼7.8 Hz), 6.55 (s, 1H), 5.33 (s, 1H), 1.40 (s, 9H); 13C NMR
(CDCl3, 125 MHz)
d
165.3, 139.0, 131.8, 131.3 (q, J¼132 Hz), 129.5,
4.6.4. N-(tert-butyl)-2-(5-methyl-1H-indol-1-yl)-2-phenyl
amide (2d). The compound was obtained as a white solid, 23.4 mg,
77% yield, mp 187e189 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.42 (s, 1H),
acet-
125.7 (q, J¼12.0 Hz), 125.1 (q, J¼18.0 Hz), 124.6 (q, J¼1086.0 Hz),
52.4, 50.3, 28.4; HRMS (ESI) m/z calculated for C13H15BrF3NNaO
[MþNa]þ: 360.0181; found: 360.018.
d
7.39e7.32 (m, 5H), 7.24 (dd, 1H, J¼9.6, 1.2 Hz), 7.06 (dd, 1H, J¼8.4,
1.2 Hz), 6.81 (d, 1H, J¼3.6 Hz), 6.43 (d, 1H, J¼3.0 Hz), 5.98 (s, 1H),
5.37 (s, 1H), 2.44 (s, 3H), 1.25 (s, 9H); 13C NMR (CDCl3, 125 MHz)
4.5.8. 2-Bromo-N-(tert-butyl)-2-(2-iodophenyl)acetamide. 2-Bro
mo-N-(tert-butyl)-2-(2-iodophenyl)acetamide
(2-iodophenyl)
d 168.3, 135.7, 135.0, 129.7, 129.2, 129.0, 128.7, 128.7, 126.0, 123.9,
acetic acid (10.0 mmol), phosphorous trichloride (10.0 mmol),
bromine (20.0 mmol, excess 8.00 mmol), tert-butylamine
(10.0 mmol), N,N0-diisopropylethylamine (20.0 mmol), CH2Cl2
(50 mL). The compound was obtained as a white solid, 2.60 g, 64%
120.9, 109.3, 102.6, 64.8, 51.7, 28.5, 21.4; HRMS (ESI) m/z calculated
for C21H24N2NaO [MþNa]þ: 343.1781; found: 343.1763.
4.6.5. N-(tert-butyl)-2-(7-methyl-1H-indol-1-yl)-2-phenyl
amide (2e). The compound was obtained as a white solid, 28.2 mg,
93% yield, mp 170e173 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.47 (d, 1H,
acet-
yield, mp 118e120 ꢀC; 1H NMR (CDCl3, 600 MHz)
d 7.83 (d, 1H,
J¼8.4 Hz), 7.55 (d, 1H, J¼7.8 Hz), 7.35 (t, 1H, J¼7.8 Hz), 6.97 (t, 1H,
d
J¼7.8 Hz), 6.58 (s, 1H), 5.65 (s, 1H), 1.40 (s, 9H); 13C NMR (CDCl3,
J¼7.8 Hz), 7.40e7.36 (m, 3H), 7.32 (d, 2H, J¼7.2 Hz), 7.03 (t, 1H,
J¼7.2 Hz), 6.97 (d, 1H, J¼7.2 Hz), 6.73 (s, 1H), 6.56 (s, 1H), 6.49 (s,
1H), 5.19 (s, 1H), 2.75 (s, 3H), 1.25 (s, 9H); 13C NMR (CDCl3, 125 MHz)
125 MHz)
d 165.2, 140.6, 139.8, 130.3, 129.1, 129.1, 100.7, 56.0, 52.3,
28.3; HRMS (ESI) m/z calculated for C12H15BrINNaO [MþNa]þ:
417.9297; found: 417.9279.
d 169.2, 136.6, 135.8, 129.9, 129.0, 128.9, 128.6, 126.6, 125.7, 121.2,
120.6, 119.5, 103.6, 66.3, 51.7, 28.4, 20.3; HRMS (ESI) m/z calculated
4.6. General procedure for 2aeh and 3aeg
for C21H25N2O [MþH]þ: 321.1967; found: 321.1973.
In a glove box,
a
-bromoamide (0.190 mmol) and KOt-Bu
4.6.6. N-(tert-butyl)-2-(5-iodo-1H-indol-1-yl)-2-phenylacetamide
(2f). The compound was obtained as a white solid, 40.2 mg, 98%
yield, mp 206e208 ꢀC; 1H NMR (CDCl3, 600 MHz) 7.96 (s, 1H), 7.46
(d, 1H, J¼8.4 Hz), 7.39 (d, 3H, J¼5.4 Hz), 7.29 (d, 2H, J¼6.0 Hz), 7.11
(d, 1H, J¼8.4 Hz), 6.86 (d, 1H, J¼3.0 Hz), 6.44 (d, 1H, J¼3.0 Hz), 5.94
(0.230 mmol) were weighed to an oven dried vial while indole
derivatives (0.0950 mmol) and [Rh(COD)Cl]2 (0.00950 mmol) were
measured into a separate vial. Benzene (0.7 mL) was then added via
syringe to the mixture of a-bromoamide and KOt-Bu and stirred for
20e25 min at room temperature. Benzene (0.50 mL) was added via
syringe to mixture of indole derivative and [Rh(COD)Cl]2 and then
transferred via syringe to the vial containing the in situ generated
aziridinone. Another portion of benzene (0.30 mL) was used to
rinse the vial and added to the reaction vial. The reaction mixture
was stirred for 70 min at room temperature and excess KOtBu
(0.4e0.5 equiv) was added. The reaction mixture stirred for another
30 min at room temperature. The reaction mixture was diluted
(s, 1H), 5.36 (s, 1H), 1.27 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d 167.6,
135.6, 135.2, 131.4, 130.5, 130.1, 129.1, 128.9, 128.5, 127.0, 111.5, 102.2,
84.0, 64.7, 51.9, 28.5; HRMS (ESI) m/z calculated for C20H21IN2NaO
[MþNa]þ: 455.0596 found: 455.0558.
4.6.7. N-(tert-butyl)-2-(2-methyl-5-methoxy-1H-indol-1-yl)-2-
phenylacetamide (2g). The compound was obtained as a white
solid, 23.2 mg, 70% yield, mp 131e133 ꢀC; 1H NMR (CDCl3,

H.K. Box et al. / Tetrahedron 70 (2014) 9709e9717
9717
600 MHz)
d
7.31e7.29 (m, 3H), 7.22 (d, 2H, J¼7.2 Hz), 6.99 (s, 1H),
60% yield, mp 162e165 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.65 (d, 1H,
6.79 (d, 1H, J¼9.0 Hz), 6.64 (dd, 1H, J¼7.2, 1.8 Hz), 6.29 (s, 1H), 6.04
J¼7.8 Hz), 7.37 (d, 1H, J¼7.8 Hz), 7.26 (d, 3H, J¼8.4 Hz), 7.21 (d, 2H,
7.8 Hz), 7.16 (t, 1H, J¼7.8 Hz), 6.86 (d, 1H, J¼3.0 Hz), 6.52 (d, 1H,
J¼3.0 Hz), 5.98 (s,1H), 5.33 (s,1H), 2.36 (s, 3H),1.25 (s, 9H); 13C NMR
(s, 1H), 5.47 (s, 1H), 3.81 (s, 3H), 2.34 (s, 3H), 1.26 (s, 9H); 13C NMR
(CDCl3, 125 MHz)
d 167.4, 154.3, 137.8, 135.6, 131.3, 129.4, 128.6,
128.0, 127.9, 111.8, 110.8, 102.4, 102.2, 62.6, 55.7, 51.7, 28.6, 13.7;
HRMS (ESI) m/z calculated for C22H26N2NaO2 [MþNa]þ: 373.1886;
found: 373.1877.
(CDCl3, 125 MHz) d 168.4, 138.7, 136.4, 132.4, 129.7, 128.8, 128.6,
125.9, 122.2, 121.2, 120.4, 109.6, 102.9, 64.4, 51.7, 28.4, 21.2; HRMS
(ESI) m/z calculated for C21H24N2NaO [MþNa]þ: 343.1781; found:
343.1794.
4.6.8. N-(tert-Butyl)-2-(2-methyl-5-nitro-1H-indol-1-yl)-2-pheny
acetamide (2h). The compound was obtained as a yellow solid,
22.0 mg, 63% yield, mp 73e75 ꢀC; 1H NMR (CDCl3, 600 MHz)
8.45
(d, 1H, J¼1.8 Hz), 7.91 (dd, 1H, J¼9.0, 1.8 Hz), 7.35 (d, 3H, J¼4.8 Hz),
7.18 (d, 2H, J¼4.8 Hz), 7.04 (d, 1H, J¼9.0 Hz), 6.54 (s, 1H), 6.10 (s, 1H),
5.50 (s, 1H), 2.41 (s, 3H), 1.32 (s, 9H); 13C NMR (CDCl3, 125 MHz)
l
4.6.14. N-(tert-Butyl)-2-(1H-indol-1-yl)-2-[4-(trifluoromethyl) phe-
nyl]acetamide (3f). The compound was obtained as a white solid,
22.4 mg, 63% yield, mp 188e191 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
d
7.66 (d, 1H, J¼7.8 Hz), 7.63 (d, 2H, J¼5.4 Hz), 7.52e7.49 (m, 2H),
7.34 (d, 1H, J¼7.8 Hz), 7.27 (d, 1H, J¼7.2 Hz), 7.18 (t, 1H, J¼7.8 Hz),
6.86 (d, 1H, J¼3.0 Hz), 6.58 (d, 1H, J¼3.0 Hz), 6.06 (s, 1H), 5.37 (s,
d
166.3, 141.9, 140.8, 139.5, 134.7, 129.1, 128.7, 128.0, 127.7, 116.9,
116.8, 110.9, 104.4, 63.2, 52.3, 28.5, 13.8; HRMS (ESI) m/z calculated
1H), 1.26 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d 167.3, 136.7, 136.5,
for C21H23N3NaO3 [MþNa]þ: 388.1632; found: 388.1623.
132.0, 131.3 (q, J¼132.0 Hz), 129.5, 128.9, 125.6, 125.5, 124.7, 122.9,
122.7, 121.5, 120.8, 109.5, 103.9, 64.0, 52.0, 28.5; HRMS (ESI) m/z
calculated for C21H21F3N2NaO [MþNa]þ: 397.1498; found: 397.1474.
4.6.9. N-(tert-Butyl)-2-(4-fluorophenyl)-2-(1H-indol-1-yl)
amide (3a). The compound was obtained as a white solid, 27.6 mg,
90% yield, mp 174e177 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.65 (d, 1H,
acet-
d
4.6.15. N-(tert-Butyl)-2-(1H-indol-1-yl)-2-(2-iodophenyl) acetamide
J¼7.8 Hz), 7.34e7.30 (m, 3H), 7.24 (t, 1H, J¼7.8 Hz), 7.17 (t, 1H,
J¼7.8 Hz), 7.07 (t, 2H, J¼8.4 Hz), 6.86 (d, 1H, J¼3.0 Hz), 6.54 (d, 1H,
J¼3.0 Hz), 5.99 (s, 1H), 5.35 (s, 1H), 1.25 (s, 9H); 13C NMR (CDCl3,
(3g). The compound was obtained as a white solid, 30.7 mg, 75%
yield, mp 189e191 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
7.90 (d, 1H, J¼7.8
Hz), 7.66 (d, 1H, J¼7.8 Hz), 7.39e7.37 (m, 2H), 7.23 (t, 2H, J¼7.8 Hz),
7.22 (d, 1H, J¼7.8 Hz), 7.17 (t, 1H, J¼7.8 Hz), 7.06 (t, 1H, J¼7.8 Hz),
6.84 (d, 1H, J 3.0 Hz), 6.57 (d, 1H, J¼3.0 Hz), 6.17 (s, 1H), 5.39 (s, 1H),
125 MHz)
d
168.0, 163.6 (d, J¼990 Hz), 136.5, 131.5 (d, J¼12 Hz),
130.5 (d, J¼36 Hz), 129.0, 125.8, 122.5, 121.4, 120.6, 116.1 (d,
J¼84 Hz), 109.6, 103.4, 63.9, 51.9, 28.5; HRMS (ESI) m/z calculated
for C20H21FN2NaO [MþNa]þ: 347.1530; found 347.1514.
1.28 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d 167.4, 140.1, 138.6, 136.5,
130.3, 129.0, 128.8, 128.6, 125.4, 122.4, 121.2, 120.5, 109.7, 103.3,
101.4, 68.5, 51.9, 28.4; HRMS (ESI) m/z calculated for C20H21IN2NaO
[MþNa]þ: 455.0596; found: 455.0588.
4.6.10. N-(tert-Butyl)-2-(4-chlorophenyl)-2-(1H-indol-1-yl)
amide (3b). The compound was obtained as a white solid, 26.1 mg,
81% yield, mp 143e146 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.65 (d, 1H,
acet-
d
References and notes
J¼7.8 Hz), 7.35 (d, 2H, J¼8.4 Hz), 7.32 (d,1H, J¼7.8 Hz), 7.24e7.20 (m,
3H), 7.16 (t, 1H, J¼7.2 Hz), 6.87 (d, 1H, J¼3.0 Hz), 6.55 (d, 1H,
J¼3.0 Hz), 5.98 (s, 1H), 5.35 (s, 1H), 1.25 (s, 9H); 13C NMR (CDCl3,
1. Aziridines and Epoxides in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
2. Sheehan, J. C.; Izzo, P. T. J. Am. Chem. Soc. 1949, 71, 4059.
3. Bach, R. D.; Dmitrenko, O. J. Am. Chem. Soc. 2006, 128, 4598.
4. Tantillo, D. J.; Houk, K. N.; Hoffman, R. V.; Tao, J. J. Org. Chem. 1999, 64, 3830.
5. Hoffman, R. V.; Nayyar, N. K.; Klinekole, B. W. J. Am. Chem. Soc. 1992, 114, 6262.
6. Roberto, D.; Alper, H. Organometallics 1984, 3, 1767.
7. Acharya, A.; Eickhoff, J. A.; Jeffery, C. S. Synthesis 2013, 45, 1825.
8. Jeffrey, C. S. A. D.; Carson, C. R. Org. Lett. 2012, 14, 5764.
9. Jeffrey, C. S.; Barnes, K. L. E. J. A.; Carson, C. R. J. Am. Chem. Soc. 2011, 133, 7688.
10. de Sa Alves, F. R.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med. Chem. 2009, 9,
782.
11. Fu, L. Top. Heterocycl. Chem. 2010, 26, 433.
12. Kaushik, N.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.; Verma, A.; Choi, E. Mol-
ecules 2013, 18, 6620.
13. Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010, 47, 491.
14. Wu, Y.-J. Top. Heterocycl. Chem. 2010, 26, 1.
15. Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
16. Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199.
17. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550.
18. Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C. Angew. Chem., Int. Ed.
2009, 48, 5737.
19. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684.
20. Sevov, C. S.; Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 3200.
21. Carey, J. S.; Laffan, D.; Thomson, C. W. . ,M. T. Org. Biomol. Chem. 2006, 4, 2337.
22. Bariwal, J.; Van der Eycken, E. Chem. Soc. Rev. 2013, 42, 9283.
23. Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
125 MHz) d 167.7,136.5,134.7,134.2,130.0,129.2,129.0,125.8,122.5,
121.4, 120.7, 109.6, 103.6, 63.9, 51.9, 28.5; HRMS (ESI) m/z calculated
for C20H21ClN2NaO [MþNa]þ: 363.1235; found: 363.1228.
4.6.11. 2-(4-Bromophenyl)-N-(tert-butyl)-2-(1H-indol-1-yl)
amide (3c). The compound was obtained as a white solid, 26.1 mg,
71% yield, mp 159e161 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.65 (d, 1H,
acet-
d
J¼7.8 Hz), 7.51 (d, 2H, J¼7.8 Hz), 7.32 (d, 1H, J¼8.4 Hz), 7.24 (d, 1H,
J¼7.8 Hz), 7.20e7.15 (m, 3H), 6.87 (s, 1H), 6.55 (s, 1H), 5.96 (s, 1H),
5.34 (s, 1H), 1.25 (s, 9H); 13C NMR (CDCl3, 125 MHz)
d
167.6, 136.4,
134.7, 132.2, 130.3, 128.9, 125.8, 122.9, 122.5, 121.4, 120.7, 109.6,
103.6, 64.0, 51.9, 28.5; HRMS (ESI) m/z calculated for C20H21BrKN2O
[MþK]þ: 423.0469; found: 423.0453.
4.6.12. N-(tert-Butyl)-2-(3-chlorophenyl)-2-(1H-indol-1-yl)
amide (3d). The compound was obtained as a white solid, 22.8 mg,
70% yield, mp 195e198 ꢀC; 1H NMR (CDCl3, 600 MHz)
7.65 (d, 1H,
acet-
d
J¼8.4 Hz), 7.35e7.30 (m, 4H), 7.25 (t, 1H, J¼7.2 Hz), 7.21 (d, 1H,
J¼7.2 Hz), 7.17 (t, 1H, J¼7.2 Hz), 6.89 (d, 1H, J¼3.0 Hz), 6.57 (d, 1H,
J¼3.0 Hz), 5.98 (s, 1H), 5.35 (s, 1H), 1.26 (s, 9H); 13C NMR (CDCl3,
24. Hartwig, J. F. Nature 2008, 455, 314.
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31. Yu, H. Chirality 2008, 20, 69.
125 MHz) d 167.4, 137.6, 136.5, 134.9, 130.2, 129.0, 128.9, 128.8, 126.8,
125.8,122.6,121.4,120.7,109.5,103.6, 64.0, 51.9, 28.5; HRMS (ESI) m/z
calculated for C20H21ClN2NaO [MþNa]þ: 363.1235; found: 363.1236.
4.6.13. N-(tert-Butyl)-2-(1H-indol-1-yl)-2-(4-methylphenyl)
acet-
32. Sheehan, J. C.; Beeson, J. H. J. Am. Chem. Soc. 1967, 89, 362.
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amide (3e). The compound was obtained as a white solid, 18.2 mg,