Chemoselective Reduction of Sterically Demanding N,N-Diisopropylamides to Aldehydes

Article abstract of DOI:10.1021/acs.joc.7b02868

A sequential one-pot process for chemoselectively reducing sterically demanding N,N-diisopropylamides to aldehydes has been developed. In this reaction, amides are activated with EtOTf to form imidates, which are reduced with LiAlH(OR)₃ [R = t-Bu, Et] to give aldehydes by hydrolysis of the resulting hemiaminals. The non-nucleophilic base 2,6-DTBMP remarkably improves reaction efficiency. The combination of EtOTf/2,6-DTBMP and LiAlH(O-t-Bu)₃ was found to be optimal for reducing alkyl, alkenyl, alkynyl, and 2-monosubstituted aryl N,N-diisopropylamides. In contrast, EtOTf and LiAlH(OEt)₃ in the absence of base were found to be optimal for reducing extremely sterically demanding 2,6-disubstituted N,N-diisopropylbenzamides. The reaction tolerates various reducible functional groups, including aldehyde and ketone. ¹H NMR studies confirmed the formation of imidates stable in water. The synthetic usefulness of this methodology was demonstrated with N,N-diisopropylamide-directed ortho-metalation and C-H bond activation.

Full text of DOI:10.1021/acs.joc.7b02868

Subscriber access provided by University of Florida | Smathers Libraries
Featured Article
Chemoselective Reduction of Sterically Demanding
N,N-di(iso-propyl) Amides to Aldehydes
Peihong Xiao, Zhixing Tang, Kai Wang, Hua Chen, Qianyou Guo, Yang Chu, Lu Gao, and Zhenlei Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02868 • Publication Date (Web): 14 Dec 2017
Downloaded from http://pubs.acs.org on December 15, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Chemoselective
Reduction
of
Sterically
Demanding
N,N-di(iso-propyl) Amides to Aldehydes
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
a
a
a
a
a
a
Peihong Xiao, Zhixing Tang, Kai Wang, Hua Chen, Qianyou Guo, Yang Chu, Lu Gao * and
a, b
Zhenlei Song *
a
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School
b
of Pharmacy, Sichuan University, Chengdu, 610064, P. R. China. State Key Laboratory of Elemento-organic
Chemistry, Nankai University, Tianjin, 300071, P. R. China.
KEYWORDS: amides, aldehydes, reduction, imidate, steric effect
ABSTRACT: A sequential one-pot process for chemoselectively reducing sterically demanding
N,N-di(iso-propyl) amides to aldehydes has been developed. In this reaction, amides are activated
with EtOTf to form imidates, which are reduced with LiAlH(OR) [R = t-Bu, Et] to give aldehydes
3
by hydrolysis of the resulting hemiaminals. The non-nucleophilic base 2,6-DTBMP remarkably
improves reaction efficiency. The combination of EtOTf/2,6-DTBMP and LiAlH(Ot-Bu) was
3
found to be optimal for reducing alkyl, alkenyl, alkynyl and 2-monosubstituted aryl
N,N-di(iso-propyl) amides. In contrast, EtOTf and LiAlH(OEt) in the absence of base were found
3
to be optimal for reducing extremely sterically demanding 2,6-disubstituted N,N-di(iso-propyl)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
benzamides. The reaction tolerates various reducible functional groups, including aldehyde and
1
ketone. H NMR studies confirmed the formation of imidates stable in water. The synthetic
usefulness of this methodology was demonstrated with N,N-di(iso-propyl) amide-directed
ortho-metalation and C−H bond activation.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
INTRODUCTION
1
Amide reduction is among the most important transformations in organic synthesis, and it poses
a particular challenge because the orbital overlap between the nitrogen lone pair and the
2
anti-bonding orbital of the carbonyl group reduces the electrophilicity of the carbonyl carbon. Most
3
investigations in this field have focused on reduction of amides to amines. Much more difficult is
chemoselective reduction of amides to aldehydes, because the corresponding amines and alcohol
by-products form easily.
Two approaches have been reported so far for reducing amides to aldehydes, and the approaches
differ in hydride source (Scheme 1a). Approach a relies on metal hydride reagents to reduce amide
directly. Early protocols were typically suitable for amides with specialized N-substituents that
4
either decrease the delocalization of the nitrogen lone pair or, in the case of Weinreb amides,
5
chelate with metal to form a stable complex that prevents further reduction. One of the most
6
efficient aluminum hydride-based reagents is LiAlH(OEt) , invented by Brown and co-workers,
3
which reduces N,N-dimethyl and N,N-diethyl amides to the corresponding aldehydes. Georg and
co-workers succeeded in reducing tertiary amides to aldehydes using Schwartz’s reagent
7
(
Cp ZrHCl). Snieckus and co-workers later modified this procedure to form Schwartz’s reagent in
2
ACS Paragon Plus Environment

Page 3 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8
9a,9b
situ from Cp ZrCl and LiAlH(Ot-Bu) . Recently, some unique boranehydride reagents
and a
2
2
3
9
c
modified Red-Al reagent have been developed for reduction of tertiary amides to aldehydes.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 1. (a) Previous methods are limited to reduce non- or less sterically demanding amides.
b) Reduction of sterically demanding N,N-di(iso-propyl)amides by a sequential one-pot
(
imidate formation/reduction process.
Recent progresses on improving functional-group tolerance have been achieved using much
milder reducing reagents hydrosilanes (Scheme 1a, approach b). Buchwald and co-workers made
the first breakthrough by using stoichiometric amounts of Ti(Oi-Pr) in combination with
4
1
0a
Ph SiH . Only α-enolizable secondary and tertiary amides can be reduced into aldehydes upon
2
2
hydrolysis of the initially formed enamines. Charette and co-workers later succeeded in reducing
11
amides in the absence of metals, though the method was limited to secondary amides. They used
1
2
13
triflic anhydride and 2-F-pyridine to transform amides into triflicamidates, which were reduced
with Et SiH to generate an iminium species that hydrolyzed to give the desired aldehydes. Using
3
Mo(CO) as catalyst and 1,1,3,3-tetramethyldisiloxane (TMDS) as the hydride source, Adolfsson
6
and co-workers reduced various tertiary amides to aldehydes chemoselectively at temperatures
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
4
below 80 °C. The Charette and Adolfsson protocols tolerated various reducible functionalities,
including aldehydes and ketones.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N,N-di(iso-propyl) amide is a unique bulky functionality. It has shown wide utility in organic
15
16
synthesis, particularly as a good directing group in ortho-metalation and C−H bond activation
(
Scheme 1a). Due to its steric bulkiness, N,N-di(iso-propyl) amide is more robust than N,
N-dimethyl and N, N-diethyl amides under some harsh reaction conditions. But, the bulkiness
makes this group much more difficult to be reduced into aldehyde. The bulkiness of the
1
7
N,N-di(iso-propyl) group appears not hindered enough to distort the N−CO bond, leading a more
18
reducible “ketonic” C=O bond. In fact, it sterically inhibits the nucleophilic attack of the hydride
towards the carbonyl carbon. For example, LiAlH(OEt) can reduce N,N-dimethyl and diethyl
3
6
amides, but it is inert towards bulkier N,N-di(iso-propyl) amides. Schwartz’s reagent can reduce
2
-mono-substituted N, N-diethyl benzamides, but it is much less effective to reduce the
corresponding N, N-di(iso-propyl) analogues, and nearly inert towards bulkier 2,6-disubstituted
7, 8
benzamides.
Although steric limitations of the approach using hydrosilanes have not been
reported in detail, only a few published reactions have involved amides containing an
1
0, 11, 14
N,N-di(iso-propyl) group or sterically demanding carbonyl substituents.
The inability to
efficiently reduce such tertiary amides to aldehydes limits the usefulness of numerous building
1
5, 16
blocks that can be generated from N,N-di(iso-propyl) amide
.
Here we report a general methodology for reducing N,N-di(iso-propyl) amides 1 to aldehydes 2
(
Scheme 1b). Key to this method is activating amides to more electrophilic imidates, which are
reduced with LiAlH(OR) to give hemiaminals that hydrolyze into aldehydes. Hwu and co-workers
3
1
9
first tested the preliminary version of the reaction with N,N-dimethyl amides in 1990. However,
ACS Paragon Plus Environment

Page 5 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the protocol suffered from the inconvenient operation, narrow substrate scope, and low to moderate
conversion together with substantial amounts of ester by-products in some cases, and therefore has
been barely used in organic synthesis. Here we substantially improve on this method by developing
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
0
a more convenient sequential one-pot operation in which the non-nucleophilic base 2,6-DTBMP
remarkably improves efficiency. Extensive studies indicate that a wide range of N,N-di(iso-propyl)
amides, including extremely sterically demanding 2,6-disubstituted benzamides, can be reduced to
aldehydes in excellent yields. The reaction also shows unprecedented tolerance of functional
RESULTS AND DISCUSSION
TABLE 1. Screening of Reaction Conditions.
−
o
b
c
Entry Activating Reagent Additive (equiv)
(equiv)
[H ] (equiv)
T ( C)
2a:3:1a
Yield (2a)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
EtOTf (1.5)
EtOTf (1.5)
EtOTf (1.5)
EtOTf (1.1)
EtOTf (1.5)
EtOTf (1.5)
EtOTf (1.5)
EtOTf (1.5)
EtOTf (1.5)
EtOTf (1.5)
EtOTf (1.5)
EtOTf (1.5)
/
/
LiAlH(Ot-Bu) (2.0)
-78
-78
-78
-78
0
-78
-78
-78
-78
-78
-78
rt to 45
-78
-78
-78
100:0:0
100:0:0
100:0:0
78:2:20
49:35:16
48:0:52
N. D.
100:0:0
N. D.
24:76:0
0:100:0
N. D.
67%
72%
92%
74%
45%
44%
N. R.
70%
complex
22%
0%
3
LiAlH(Ot-Bu) (3.5)
3
a
2, 6-DTBMP (3.0)
2, 6-DTBMP (2.0)
2, 6-DTBMP (3.0)
2, 6-lutidine (3.0)
4-TBP (3.0)
2-F-pyridine (3.0)
2, 6-DTBMP (3.0)
2, 6-DTBMP (3.0)
2, 6-DTBMP (3.0)
2, 6-DTBMP (3.0)
2, 6-DTBMP (3.0)
2, 6-DTBMP (3.0)
Na HPO (1.5)
LiAlH(Ot-Bu) (2.0)
3
LiAlH(Ot-Bu) (2.0)
3
LiAlH(Ot-Bu) (2.0)
3
LiAlH(Ot-Bu) (2.0)
3
LiAlH(Ot-Bu) (2.0)
3
LiAlH(Ot-Bu) (2.0)
3
L-Selectride (2.0)
DIBAL-H (2.0)
0
1
2
3
4
5
NaBH (2.0)
4
Et SiH (2.0)
N. R.
90%
70%
65%
3
Tf O(1.5)
LiAlH(Ot-Bu) (2.0)
100:0:0
76:24:0
70:12:18
2
3
MeOTf (1.5)
LiAlH(Ot-Bu) (2.0)
3
Me OBF (3.0)
LiAlH(Ot-Bu) (2.0)
3
4
2
4
3
a
Reaction conditions: 1a (0.1 mmol), EtOTf (0.15 mmol), 2, 6-DTBMP (0.3 mmol) in CH Cl (2 mL) at rt for 2 h,
2
2
b
1
thenTHF (4 mL) and LiAlH(Ot-Bu) (0.2 mL, 1.1M in THF) at -78 °C for 4 h. The ratios were determined by H NMR
3
c
spectroscopy of the crude products. Yields after purification by silica gel column chromatography.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
groups: diverse reducible functionalities survive, including aldehydes and ketones. These attractive
properties of this methodology should substantially expand the synthetic potentials of
N,N-di(iso-propyl) amide as a masked aldehyde group, because it is typically inert in a number of
transformations due to its stetic bulkiness.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Screening of reaction conditions. The reaction was examined using 2-methyl N,N-di(iso-propyl)
benzamide 1a as a model scaffold. Initial attempts to directly reduce 1a proved ineffective with
either metal hydride regents or hydrosilanes because of the steric hinderance created by the
2
1
2-methyl and bulky nitrogen moieties. We reasoned that converting the amide to the more reactive
imidate might promote subsequent reduction. Indeed, reaction of 1a with EtOTf at room
temperature for 2 h followed by sequential one-pot reduction of the resulting imidate with
LiAlH(Ot-Bu) at -78 °C for 4 h provided the desired aldehyde 2a in 67% yield (entry 1, Table 1).
3
We did not observe over-reduction to amine 3 and ethyl ether, or formation of ester by-product, and
2
2
we did not recover any 1a. Increasing the loading of LiAlH(Ot-Bu) to 3.0 equiv improved yield
3
slightly to 72% (entry 2). Adding 3.0 equiv of 2,6-DTBMP as a non-nucleophilic base did not
2
3
obviously promote imidate formation, but it improved the overall efficiency, affording 2a in 92%
yield (entry 3). Decreasing the loading of both EtOTf and 2,6-DTBMP reduced yield to 80% (entry
4
). Performing the reduction at 0 °C led to amine by-product 3 as the sole product (entry 5). Using
less hindered 2,6-lutidine or non-sterically demanding 4-TBP dramatically inhibited imidate
formation (entries 6 and 7). Using 2-halogenated pyridines such as 2-F-pyridine as additives
decreased yield to 70% (entry 8). LiAlH(Ot-Bu) was far more effective than other metal hydride
3
reagents: L-selectride caused complex reactions (entry 9), while DIBAL-H or NaBH gave the
4
undesired amine 3 as the major product (entries 10 and 11). As expected, hydrosilane was too weak
ACS Paragon Plus Environment

Page 7 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
to reduce the imidate (entry 12). Tf O showed similar activation ability as EtOTf, giving aldehyde
2
2
a in 90% yield (entry 13). MeOTf and Me OBF were much less effective, leading to formation of
3 4
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
amine 3 and recovery of amide 1a (entries 14 and 15).
TABLE 2. Scope of N,N-di(iso-propyl) Benzamides.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
a
Reaction conditions: 1 (0.3 mmol), EtOTf (0.45 mmol), 2, 6-DTBMP (0.9 mmol) in CH Cl (2 mL), thenTHF (4
2
2
b
mL) and LiAlH(Ot-Bu) (0.55 mL, 1.1M in THF) at -78 °C for 4 h. Yields after purification by silica gel column
3
c
d
chromatography. Reaction temperature and time in the first step to form imidate. The yield was obtained in
gram-scale reaction using 12.0 mmol of 1j.
Scope of N,N-di(iso-propyl) benzamides. The reaction proved useful for reducing a wide range of
2
- substituted N,N-di(iso-propyl) benzamides, giving the corresponding aldehydes in yields >90%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
in most cases (Table 2). The reaction tolerated such substituents as bulky iso-propyl (2b) and phenyl
groups (2c), as well as terminal silyl-substituted alkenyl (2d) and alkynyl groups (2e), which could
be further functionalized in various ways. Although the electron-withdrawing CF lowered yield,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aldehyde 2f was still obtained in 62% yield. Notably, benzamides possessing various silyl groups at
the 2-position served as good substrates, affording aldehydes 2g-2i in high yields. Traditionally
these substrates are considered particularly difficult to reduce because of the bulky silyl groups.
Only one successful example has been reported, in which the reaction tolerated only furanamide
8
containing less sterically demanding N, N-diethyl and 2-trimethylsilylmoieties. The reaction even
tolerated the geminal bis(silyl) group, which exerts a much stronger sterical shielding effect than
24
silyl groups; the corresponding aldehyde 2j was produced in 89% yield. The reaction was also
suitable for synthesizing 2-halogenated and -oxygenated benzaldehydes 2k-2p; for reducing 2-PPh2
benzamide to 2q, which is useful in the synthesis of phosphine ligands; and for converting
2
,3-disubstituted benzamides into the corresponding benzaldehydes 2r-2t in yields >90%. In
addition to benzamides, we were able to reduce alkyl, alkenyl, alkynyl, naphthalene-, and
heterocycle-substituted amides to the corresponding aldehydes 2u-2aa. However, reaction failed to
generate the aldehyde 2ab containing a pyridine ring. We suspect that formation of the pyridine salt
out-competes formation of the desired imidate intermediate in the presence of EtOTf.
Scope of 2,6-disubstituted N,N-di(iso-propyl) benzamides.The successes shown in Table 2 led us
to examine the more challenging substrates 2,6-disubstituted N,N-di(iso-propyl) benzamides. In
these compounds, not only does the nitrogen moiety create steric hinderance, but substituents at the
2
- and 6-positions sterically shield both sides of the amide, making imidate formation and
subsequent reduction extremely difficult. To the best of our knowledge, only one previous report
ACS Paragon Plus Environment

Page 9 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
involved such a substrate: in that example, 2,6-dichloro-N,N-diethyl benzamide was reduced using
a
TABLE 3. Scope of 2,6-Disubstituted N,N-di(iso-propyl) Benzamides.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1 (0.3 mmol), EtOTf (0.6 mmol) in CH Cl (2 mL), thenTHF (4 mL) and LiAlH(OEt) (1.2 mL,
2
2
3
b
1.0M in THF) for 8 h. Yields after purification by silica gel column chromatography.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
b
Schwartz’s reagent (Cp ZrHCl) to give the aldehyde in 17% yield. When we conducted our
2
reaction under standard conditions, we failed to reduce amide 1ac to aldehyde 2ac (not shown).
6
b,25
Switching the reducing reagent from LiAlH(Ot-Bu) to the less bulky LiAlH(OEt)3
and
increasing its loading to 4.0 equiv improved yield to 67% (Table 3, entry 1). Interestingly, omitting
,6-DTBMP further increased yield to 79% (entry 2). The reaction efficiently reduced
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2,6-disubstituted amides 1ad-1ag to aldehydes 2ad-2ag in good yields (entries 3-6). No reduction
of SiMe /Me-substituted amide 1ah occurred at -78 °C (entry 7), but increasing the reduction
3
temperature to -20 °C afforded the desired aldehyde 2ah in 75% yield (entry 8). The imidate of
SiMe /SiMe -substituted amide 1ai formed readily at 45 °C, but this substrate was too bulky to
3
3
undergo reduction even at -20 °C. Thus, its N,N-diethyl analogue 1ai' was reduced instead, giving
aldehyde 2ai in 64% yield.
Functional group tolerance. We envisioned that converting amides to imidates would allow
subsequent reduction with LiAlH(Ot-Bu) without altering other reducible functional groups, which
3
is the primarily limitation when reducing amides with metal hydride reagents. To test the functional
group tolerance of our method, N,N-di(iso-propyl) benzamides containing a range of substituents at
the 4-position were examined under standard reaction conditions. The amide moiety was reduced
chemoselectively to give aldehydes 2aj-2al in high yields, while leaving NO , CN and CO Me
2
2
groups untouched (Table 4). We were pleasantly surprised to find that the reaction even tolerated
much more reducible ketone and aldehyde functionalities (2am and 2an). Such group tolerance has
been a long-standing challenge in the reduction of amides with metal hydride reagents. We are
aware of only two previous reports of amide reductions that preserve ketone and aldehyde groups;
1
1, 14
both use hydrosilane as the reducing agent.
ACS Paragon Plus Environment

Page 11 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
a
TABLE 4. Functional Group Tolerance.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1 (0.3 mmol), EtOTf (0.45 mmol), 2, 6-DTBMP (0.9 mmol) in CH Cl (2 mL), then THF (4
2
2
b
mL) and LiAlH(Ot-Bu) (0.55 mL, 1.1M in THF) at -78 °C for 4 h. Yields after purification by silica gel column
3
c
chromatography. Reaction temperature and time in the first step to form imidate.
Scope of N,N-disubstituents. We found that the steric characteristics of N-substituents
generally did not harm the high yields of aldehyde 2a (Table 5). Suitable substituents included the
liner n-Bu group (1ao) and the more sterically demanding Bn and Cy groups (1ap and 1aq). The
reaction also tolerated tertiary amides with cyclized nitrogen moieties, such as pyrrolidine (1ar),
piperidine (1as) and morpholine (1at). In contrast to steric characteristics, the electronic
characteristics of the N-substituent strongly affected reaction yield. For example, the presence of
one or two phenyl groups on the nitrogen (1au and 1av) completely blocked imidate formation. We
speculate that the phenyl ring delocalizes the lone electron pair on nitrogen, making the carbonyl
oxygen less basic than the oxygen of N,N-alkyl amides.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
TABLE 5. Scope of N,N-disubstituents.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1 (0.3 mmol), EtOTf (0.45 mmol), 2, 6-DTBMP (0.9 mmol) in CH Cl (2 mL), then THF (4
2
2
b
mL) and LiAlH(Ot-Bu) (0.55 mL, 1.1M in THF) at -78 °C for 4 h. Yields of 2a after purification by silica gel column
3
c
chromatography. Reaction temperature and time in the first step to form imidate.
Chemoselectivity in 4-amide- or –carbamate-substituted N,N-di(iso-propyl) benzamides. We
next examined whether our sequential one-pot process could chemoselectively reduce one of two
different amides in a given substrate. Reduction of 1aw using DIBAL-H afforded aldehyde 2ao, in
which the Weinreb amide was reduced, while the N,N-di(iso-propyl) amide was unaffected (Scheme
2a). Conversely, only the N,N-di(iso-propyl) amide in 1ax was reduced and the N-phenyl amide
moiety was untouched, giving amido aldehyde 2ap in 82% yield. The N,N-di(iso-propyl) amide in
1
ay was selectively reduced while the carbamate group NHBoc survived, giving aldehyde 2aq in 94%
yield. This indicates that the proton in the NHBoc group did not interfere with reduction. These
results suggest that our method can be tailored to retain or reduce N,N-di(iso-propyl) amide
ACS Paragon Plus Environment

Page 13 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
depending on downstream requirements. This may substantially expand the synthetic possibilities of
this traditionally inert functionality.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Chemoselectivity in 4-amide- or –carbamate-substituted N,N-di(iso-propyl)
benzamides.
Mechanistic studies. A feasible reaction mechanism was outlined in Scheme 3. Tertiary amide 1
reacts with EtOTf to give imidate 4. The non-nucleophilic base 2,6-DTBMP promotes this step
1
3g
probably by forming the reactive pyridinium intermediate with EtOTf. Imidate 4 is reduced by
LiAlH(OR) to give hemiaminal 5, which in turn hydrolyzes during work-up to afford aldehyde 2.
3
Scheme 3. Proposed reaction mechanism.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Figure 1. H NMR studies of imidate formation from amide 1a and EtOTf in the presence of
2
,6-DTBMP.
1
To verify this mechanism and gain additional insights, we used H NMR to analyze formation of
imidate from amide 1a and EtOTf in the presence of additive 2,6-DTBMP. Signals for 1a
disappeared completely after the reaction had proceeded for 2 h in CD Cl at room temperature.
2
2
Signals for the two methenyl protons on the nitrogen shifted downfield (0.3-0.5 ppm;), consistent
with formation of the imidate salt 6. Quenching the reaction with D O did not lead to regeneration
2
of amide 1a or formation of the corresponding ethyl ester. These results strongly suggest that the
1
imidate salt 6 is stable in the aqueous phase. Consistent with this, the H NMR spectrum of the D O
2
phase clearly shows signals for 6. Imidate stability in water may make our sequential one-pot
26
reduction process useful for developing aqueous-phase organic syntheses.
Synthetic applications. This methodology allowed us to rapidly synthesize diverse benzaldehyde
derivatives useful in downstream transformations. Amide-directed ortho-metalation (DoM) of
4-MeO benzamide 7 occurred regioselectively with s-BuLi/TMEDA (Scheme 4a). Trapping the
ACS Paragon Plus Environment

Page 15 of 51
The Journal of Organic Chemistry
1
2
3
1
5a
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
resulting phenyl lithium with Me SiCl afforded 2-SiMe benzamide 8 in 60% yield, which was
3 3
reduced to aldehyde 9 in 92% yield. This two-step process provides an efficient alternative to
traditional methods for synthesizing 2-SiMe benzaldehydes via metal-halogen exchange with the
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
7
28
corresponding bromobenzene. Benzaldehyde 9 is a useful scaffold in the anion relay-mediated,
multi-component cross-coupling with nucleophilic n-BuLi and electrophilic allylbromide, leading to
benzyl alcohol 10 in 65% yield.
Scheme 4. Synthetic applications.
N,N-di(iso-propyl) amide has been used widely as a powerful directing group in transition
metal-catalyzed activation of the ortho C−H bond in phenyl rings. However, functionalization of
these reaction products has been limited by the inability to reduce the bulky amide group. Our
method provides an efficient way to solve this problem by reducing the amide group to aldehyde
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(Scheme 4b). Benzamide 11 underwent Pd(II)-catalyzed ortho C−H bond functionalization with
1
6i
toluene to provide diaryl product 12 in 50% yield. Reducing the amide moiety in 12 under
standard conditions furnished aldehyde 13 in 86% yield, which underwent TBHP-mediated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
29
oxidative cyclization to give lactone 14 in 46% yield.
CONCLUSION
In summary, we have described an efficient method for reducing sterically demanding
N,N-di(iso-propyl) amides to aldehydes. This sequential one-pot protocol features activation of
amides with EtOTf to form imidates, which can be reduced with LiAlH(OR) to give aldehydes
3
chemoselectively. A wide range of alkyl, alkenyl, alkynyl, and aryl tertiary amides, as well as
extremely sterically demanding 2,6-disubstituted N,N-di(iso-propyl) benzamides, can function as
good substrates to afford aldehydes in generally excellent yields. Various reducible functional
1
groups, including aldehydes and ketones, are tolerated in this reaction. H NMR studies confirmed
the formation of imidate and suggest that it is stable in water. The synthetic utility of this
methodology has been demonstrated for N,N-di(iso-propyl) amide-directed ortho-metalation and
C−H bond activation. Further applications of this methodology in organic synthesis are being
explored.
EXPERIMENTAL SECTION
Commercial reagents were used without any purification. All reactions were performed using
common anhydrous, inert atmosphere techniques. Reactions were monitored by TLC which was
performed on glass-backed silica plates and visualized using UV, KMnO4 stains,
H PO ·12MoO /EtOH stains, H SO (conc.)/anisaldehyde/EtOH stains. Column chromatography
3
4
3
2
4
ACS Paragon Plus Environment

Page 17 of 51
The Journal of Organic Chemistry
1
2
3
1
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was performed using silica gel (200-300mesh) eluting with EtOAc/petroleum ether. HNMR spectra
1
3
1
were recorded at 400 MHz (Varian) and 600 MHz (Agilent), C{ H}NMR spectra were recorded at
1
00 MHz (Varian) and 150 MHz (Agilent) using CDCl (except where noted) with TMS as standard.
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Infrared spectra were obtained using KCl plates on a VECTOR22. High-resolution mass spectral
analyses performed on Waters Q-TOF. CH Cl , TMEDA, DMF, (i-Pr) NH and Et N were distilled
2
2
2
3
from CaH . THF and PhMe were distilled from sodium. All spectral data obtained for new
2
compounds are reported here.
General Procedures for Preparation of Amides
Method A: To a solution of amine (1.0 equiv) and Et N (1.2 equiv) in CH Cl was added
3
2
2
commercially available acid chloride (1.0 equiv) slowly at room temperature. The reaction mixture
was stirred for 30 min to 3 h at room temperature and then was diluted with CH Cl . The resulting
2
2
solution was washed with 1 N HCl. The organic layer was dried over Na SO , filtered and
2
4
concentrated under reduced pressure. The residue was purified by via silica gel flash column
chromatography (eluent: petroleum ether/EtOAc) to yield the target amides.
Method B: To a solution of a carboxylic acids (1 equiv) in CH Cl or toluene was added SOCl (2-4
2
2
2
equiv) slowly. Then DMF (0.05 equiv) was added at room temperature. The mixture was stirred at
room temperature or 45 °C for 1-4 h. After concentration in vacuo, the residue was dissolved in
CH Cl and cooled to 0 °C. To the solution was added Et N (1.3 equiv) and diisopropylamine (1.2
2
2
3
equiv) dropwise at 0 °C. The resulting mixture was warmed to room temperature and stirred for
additional 0.5 h. Reaction was quenched with H O and extracted with EtOAc or ether. The
2
combined organic extract was washed with sat. aq.NaCl, dried over MgSO and concentrated in
4
vacuo. The residue was purified by via silica gel flash column chromatography (eluent: petroleum
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ether/EtOAc) to yield the target amides.
Method C: To a solution of a carboxylic acid substrate (1 equiv) in CH Cl at room temperature
2
2
was added (COCl) (2 equiv) slowly. Then DMF (0.05 equiv) was added at room temperature. The
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mixture was stirred for 2 h. After concentration in vacuo, the residue was dissolved in CH Cl and
2
2
cooled to 0 °C. To the solution was added Et N (1.3 equiv) and diisopropylamine (1.2 equiv)
3
dropwise at 0 °C. The resulting mixture was warmed to room temperature and stirred for additional
2
h. Reaction was quenched with H O and extracted with EtOAc or ether. The combined organic
2
extract was washed with sat. aq.NaCl, dried over MgSO and concentrated in vacuo. The residue
4
was purified by via silica gel flash column chromatography (eluent: petroleum ether/EtOAc) to
yield the target amides.
Method D: To a solution of TMEDA (1.1 equiv) in anhydrous THF (15 mL) was added s-BuLi (1.0
M in pentane, 1.2 equiv) at -78 °C under Ar atmosphere. The reaction was stirred for 10 min before
adding the solution of benzamide (1.0 equiv) in anhydrous THF (5 mL) via cannula. After stirring
for 2 h at -78 °C, the electrophile (1.3 equiv) was added dropwise. The resulted mixture was
allowed to warm to room temperature with stirring for additional 2 h. The solvent was removed
under reduced pressure. The residue was diluted with water (10 mL), extracted with ether (2 × 15
ml), and washed with sat.aq.NaCl (15 ml). The combined organic layers were dried over Na SO ,
2
4
filtered and concentrated under reduced pressure. The residue was purified by silica gel flash
column chromatography (eluent: petroleum ether/EtOAc) to afford the target amides.
N,N-diisopropyl-2-(trifluoromethyl)benzamide (1f): Method A: 2-(trifluoromethyl)benzoyl chloride
(
1.0 g, 4.80 mmol), diisopropylamine (485 mg, 4.80 mmol), and Et N (582 mg, 5.76 mmol) in
3
CH Cl (20 mL) at room temperature for 3 h afforded 1f (1.23 g, 93% yield; mp 112-114 °C) as a
2
2
ACS Paragon Plus Environment

Page 19 of 51
The Journal of Organic Chemistry
1
2
3
1
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
white solid. H NMR (400 MHz, CDCl ) δ 7.65 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.45 (t,
3
J = 7.6 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 3.45-3.56 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.52 (d, J =
13
1
6
.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H); C{ H}NMR (150 MHz, CDCl ) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
2
167.7, 136.8 (q, J = 2.3 Hz), 131.9, 128.3, 126.6 (q, J = 4.5 Hz), 126.3, 126.1(q, J = 31.7
C-F
C-F
C-F
1
-1
Hz), 123.8 (q, J = 272.6 Hz), 50.9, 45.8, 20.5, 20.4, 19.7, 19.5; IR (cm ) 2974, 1628, 1441,
C-F
1373, 1343, 1315, 1163, 1117, 1032, 774; HRMS (ESI-TOF, m/z) calcd for C H F NNaO
1
4
18 3
+
(
M+Na) : 296.1238, found 296.1235.
2
-fluoro-N,N-diisopropylbenzamide (1k): Method A: 2-fluorobenzoyl chloride (1.0 g, 6.30 mmol),
diisopropylamine (697 mg, 6.90 mmol), and Et N (798 mg, 7.90 mmol) in CH Cl (20 mL) at room
3
2
2
1
temperature for 3 h afforded 1k (1.33 g, 94% yield; mp 100-102 °C) as a pink solid. H NMR (400
MHz, CDCl ) δ 7.24-7.29 (m, 1H), 7.21 (t, J = 6.4 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 7.01 (t, J = 8.8
3
Hz, 1H), 3.64-3.72 (m, 1H), 3.43-3.53 (m, 1H), 1.50 (d, J = 6.8 Hz, 6H), 1.13 (s, 3H), 1.03 (d, J =
13
1
1
3
4
.4 Hz, 3H); C{ H}NMR (100 MHz, CDCl ) δ 165.6, 157.7 (d, J = 244.7 Hz), 129.9 (d, J
=
3
C-F
C-F
4
2
3
7.6 Hz), 127.6 (d, J = 4.2 Hz), 126.6 (d, J = 19.2 Hz), 124.3 (d, J = 3.4 Hz), 115.0 (d,
C-F
C-F
C-F
2
-1
JC-F = 21.3 Hz), 50.9, 45.8, 20.6, 20.4, 20.3, 20.1; IR (cm ) 2970, 1632, 1453, 1341, 1212, 764;
+
HRMS (ESI-TOF, m/z) calcd for C H FNNaO (M+Na) : 246.1270, found 246.1270.
1
3
18
2
,6-dichloro-N,N-diisopropylbenzamide (1ad): Method A: 2,6-dichlorobenzoyl chloride (1.0 g, 4.77
mmol), diisopropylamine (483 mg, 4.77 mmol), and Et N (579 mg, 5.72 mmol) in CH Cl (20 mL)
3
2
2
1
at room temperature for 3 h afforded 1ad (0.43 g, 33% yield; mp 141-146 °C) as a white solid. H
NMR (400 MHz, CDCl ) δ 7.29 (d, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 3.51-3.60 (m, 2H),
3
1
3
1
1.59 (d, J = 6.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 6H); C{ H}NMR (150 MHz, CDCl ) δ 164.0, 136.8,
3
-1
1
31.6, 129.4, 128.0, 51.6, 46.3, 20.9, 20.2; IR (cm ) 2980, 1633, 1425, 1335,
793, 753;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
HRMS (ESI-TOF, m/z) calcd for C H Cl NO (M+H) : 274.0765, found 274.0769.
1
3
18
2
4
-acetyl-N,N-diisopropylbenzamide (1am): Method B: 4-acetylbenzoic acid (2.0 g, 12.2 mmol) and
SOCl (48.8 mmol, 5.8 g) in CH Cl (40 mL) at 45 °C for 4 h, then diisopropylamine (18.3 mmol,
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.85 g) and Et N (15.3 mmol, 1.54 g) in CH Cl (40 mL) at room temperature for 2 h afforded 1am
3
2
2
1
(
1.03 g, 34% yield; mp 104-108 °C) as a white solid. H NMR (400 MHz, CDCl ) δ 7.97 (d, J = 8.0
3
Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 3.66-3.72 (brs, 1H), 3.52-3.61 (brs, 1H), 2.61 (s, 3H), 1.53-1.58
1
3
1
(
m, 6H), 1.13-1.18 (m, 6H); C{ H}NMR (150 MHz, CDCl ) δ 197.4, 169.8, 143.2, 137.0, 128.6,
3
-1
1
25.7, 50.9, 46.0, 26.6, 20.6; IR (cm ) 2969, 1681, 1626, 1440, 1340, 1264, 835, 733; HRMS
+
(ESI-TOF, m/z) calcd for C H NNaO (M+Na) : 270.1470, found 270.1469.
15
21
2
4
-formyl-N,N-diisopropylbenzamide (1an): Method B: 4-formylbenzoic acid (1.0 g, 6.6 mmol) and
SOCl (26.4 mmol, 3.14 g) in CH Cl (20 mL) at 45 °C for 4 h, then diisopropylamine (7.92 mmol,
2
2
2
0
.8 g) and Et N (8.58 mmol, 0.86 g) in CH Cl (20 mL) at room temperature for 2 h afforded 1an
3 2 2
1
(
0.6 g, 40% yield; mp 97-100 °C) as a white solid. H NMR (400 MHz, CDCl ) δ 10.01 (s, 1H),
3
7.90(d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 3.70 (brs, 1H), 3.52 (brs, 1H), 1.40-1.76 (m, 6H),
13
1
0
.95-1.23 (m, 6H); C{ H}NMR (150 MHz, CDCl ) δ 191.5, 169.5, 144.4, 136.1, 130.0, 126.1,
3
-1
51.0, 46.0, 20.6; IR (cm ) 2969, 1701, 1625, 1371, 1339, 1206, 1167, 812, 759; HRMS
+
(
ESI-TOF, m/z) calcd for C H NNaO (M+Na) : 256.1313, found 256.1309.
14
19
2
N,N-diisopropyl-3-methylthiophene-2-carboxamide
(1v)
:
Method
B:
3-methylthiophene-2-carboxylic acid (0.65 g, 4.5 mmol), SOCl (9.0 mmol, 1.10 g) and DMF (0.23
2
mmol, 16.50 mg) in toluene (15 mL) at 45 °C for 1 h, then diisopropylamine (5.40 mmol, 0.55 g)
and Et N (5.70 mmol, 0.58 g) in CH Cl (20 mL) at room temperature for 2 h afforded 1v (0.69 g,
3
2
2
1
6
5% yield; mp 66-70 °C) as a white solid. H NMR (400 MHz, CDCl ) δ 7.15 (d, J = 4.8 Hz, 1H),
3
ACS Paragon Plus Environment

Page 21 of 51
The Journal of Organic Chemistry
1
2
3
1
3
1
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6.79 (d, J = 4.8 Hz, 1H), 3.51-3.95 (m, 2H), 2.22 (s, 3H), 1.24-1.59 (m, 12H); C{ H}NMR (100
-
1
MHz, CDCl ) δ 164.8, 135.2, 132.5, 129.3, 123.8, 48.9, 20.8, 14.1; IR (cm ) 2967, 1617, 1446,
3
+
1
371, 1328, 1210, 1095, 1029, 811, 708; HRMS (ESI-TOF, m/z) calcd for C H NNaOS (M+Na) :
1
2
19
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
248.1085, found 248.1082.
N,N-diisopropyl-1-methyl-1H-indole-3-carboxamide (1w): Method B: 1-methylindole-3-carboxylic
acid (0.80 g, 4.5 mmol), SOCl (9.0 mmol, 1.10 g) and DMF (0.23 mmol, 16.50 mg) in toluene (15
2
mL) at 45 °C for 1 h, then diisopropylamine (5.40 mmol, 0.55 g) and Et N (5.70 mmol, 0.58 g) in
3
CH Cl (20 mL) at room temperature for 2 h afforded 1w (0.66 g, 60% yield; mp 156-160 °C) as a
2
2
1
yellow solid. H NMR (400 MHz, CDCl ) δ 7.50 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26
3
(
t, J = 6.0 Hz, 1H), 7.17 (t, J = 6.0 Hz, 1H), 3.97 (brs, 2H), 3.80 (s, 3H), 1.39 (d, J = 6.0 Hz, 12H);
1
3
1
C{ H}NMR (100 MHz, CDCl ) δ 166.4, 136.2, 127.9, 126.7, 122.1, 120.5, 120.1, 112.9, 109.2,
3
-
1
4
8.0, 32.8, 21.2; IR (cm ) 2965, 1610, 1532, 1471, 1438, 1368, 1301, 1244, 815, 741; HRMS
+
(
ESI-TOF, m/z) calcd for C H N NaO (M+Na) : 281.1630, found 281.1631.
16
22
2
3-chloro-N,N-diisopropyl-2-methylbenzamide (1r) : Method C: 3-chloro-2-methylbenzoic acid (0.85
g, 5.0 mmol), (COCl) (10.0 mmol, 1.27 g) and DMF (0.25 mmol, 20.0 mg) in CH Cl (25 mL) at
2
2
2
room temperature for 2 h, then diisopropylamine (6.0 mmol, 0.61 g) and Et N (6.50 mmol, 0.66 g)
3
in CH Cl (25 mL) at room temperature for 2 h afforded 1r (0.90 g, 71% yield; mp 106-108 °C) as a
2
2
1
white solid. H NMR (400 MHz, CDCl ) δ 7.26 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.95 (d,
3
J = 7.2 Hz, 1H), 3.53-3.59 (m, 1H), 3.42-3.50 (m, 1H), 2.28 (s, 3H), 1.08 (d, J = 2.8 Hz, 3H), 1.06
13
1
(
d, J = 2.8 Hz, 3H), 1.02 (d, J = 2.8Hz, 3H), 1.01 (d, J = 2.8 Hz, 3H); C{ H}NMR (100 MHz,
CDCl ) δ 169.2, 140.2, 135.1, 131.6, 128.6, 126.9, 123.0, 50.7, 45.6, 20.6, 20.4 (2C), 20.2, 16.5; IR
3
-1
(
cm ) 2969, 1629, 1437, 1370, 1336,736; HRMS (ESI-TOF, m/z) calcd for C H ClNO
14 21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(M+H) : 254.1312, found 254.1306.
N,N-diisopropyl-3-methoxy-2-methylbenzamide (1s) : Method C: 3-methoxy-2-methylbenzoic acid
0.83 g, 5.0 mmol), (COCl) (10.0 mmol, 1.27 g) and DMF (0.25 mmol, 20.0 mg) in CH Cl (25 mL)
(
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
at room temperature for 2 h, then diisopropylamine (6.0 mmol, 0.61 g) and Et N (6.50 mmol, 0.66 g)
3
in CH Cl (25 mL) at room temperature for 2 h afforded 1s (0.70 g, 56% yield; mp 174-179°C) as a
2
2
1
white solid. H NMR (600 MHz, CDCl ) δ 7.15 (t, J = 5.2 Hz, 1H), 6.78 (d, J = 5.6 Hz, 1H), 6.70 (d,
3
J = 5.2 Hz, 1H), 3.82 (s, 3H), 3.64-3.68 (m, 1H), 3.46-3.52 (m, 1H), 2.16 (s, 3H), 1.57 (d, J = 3.2
13
1
Hz, 3H), 1.56 (d, J = 3.2 Hz, 3H), 1.10 (d, J = 4.4 Hz, 3H), 1.05 (d, J = 4.4 Hz, 3H); C{ H}NMR
(100 MHz, CDCl ) δ 170.3, 157.8, 139.8, 126.8, 122.2, 116.8, 109.4, 55.3, 50.7, 45.6, 20.8, 20.6
3
-1
(
2C), 20.4, 12.5; IR (cm ) 2966, 1623, 1464, 1439, 1340, 1261, 1131, 1035,749; HRMS (ESI-TOF,
+
m/z) calcd for C H NNaO (M+Na) : 272.1626, found 272.1622.
1
5
23
2
4
-chloro-N,N-diisopropyl-2-methoxybenzamide (1t) : Method C: 4-chloro-2-methoxybenzoic acid
(
0.93 g, 5.0 mmol), (COCl) (10.0 mmol, 1.27 g) and DMF (0.25 mmol, 20.0 mg) in CH Cl (30 mL)
2
2
2
at room temperature for 2 h, then diisopropylamine (6.0 mmol, 0.61 g) and Et N (6.50 mmol, 0.66 g)
3
in CH Cl (30mL) at room temperature for 2 h afforded 1t (1.11 g, 82% yield; mp 127-129°C) as a
2
2
1
white solid. H NMR (400 MHz, CDCl ) δ 7.06 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.86
3
(
s, 1H), 3.79 (s, 3H), 3.58-3.64 (m, 1H), 3.43-3.52 (m, 1H), 1.50-1.53 (m, 6H), 1.13 (d, J = 6.4 Hz,
1
3
1
3
H), 1.02 (d, J = 6.4 Hz, 3H); C{ H}NMR (150 MHz, CDCl ) δ 167.4, 155.7, 134.7, 127.6, 127.0,
3
-
1
120.9, 111.5, 55.6, 50.9, 45.7, 20.7, 20.6, 20.4, 20.3; IR (cm ) 2967, 1630, 1592, 1439, 1336, 1250,
+
1
033, 878, 764; HRMS (ESI-TOF, m/z) calcd for C H ClNNaO (M+Na) : 292.1080, found
1
4
20
2
292.1075.
N,N-diisopropyl-2-(triethylsilyl)benzamide (1h) : Method D: N,N-diisopropylbenzamide (0.40 g,
ACS Paragon Plus Environment

Page 23 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1.95 mmol), s-BuLi (1.0 M in pentane, 2.40mL, 2.40 mmol), TMEDA (0.25 g, 2.15 mmol) and
TESCl (0.39 g, 2.53 mmol) in THF (15 mL) at -78 °C to room temperature for 3 h afforded 1h as a
o
1
white solid (0.46 g, 74% yield; mp 56-59 C). H NMR (600 MHz, CDCl ) δ 7.56 (d, J = 5.6 Hz,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1H), 7.29-7.31 (m, 2H), 7.15 (m, 1H), 3.76-3.78 (m, 1H), 3.48-3.50 (m, 1H), 1.46-1.72 (m, 6H),
13
1
1
.14-1.24 (m, 6H), 0.67-0.93 (m, 15H); C{ H}NMR (150 MHz, CDCl ) δ 172.1, 144.7, 136.0,
3
-1
135.0, 128.0, 127.3, 125.3, 50.7, 45.7, 20.5, 7.5, 3.6; IR (cm ) 2955, 1630, 1424, 1369, 1331, 724;
+
HRMS (ESI-TOF, m/z) calcd for C H NNaOSi (M+Na) : 342.2229, found 342.2228.
1
9
33
N,N-diisopropyl-2-(triphenylsilyl)benzamide (1i) : Method D: N,N-diisopropylbenzamide (0.40 g,
.95 mmol), s-BuLi (1.0 M in pentane, 2.40 mL, 2.40 mmol), TMEDA (0.25 g, 2.15 mmol) and
triphenylsilyl chloride(0.75 g, 2.53 mmol) in THF (15 mL) at -78 °C to room temperature for 3 h
1
o
1
afforded 1i as a white solid (0.65 g, 72% yield; mp 129-134 C). H NMR (400 MHz, CDCl ) δ
3
7
.62 (d, J = 6.4 Hz, 6H), 7.56 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.30-7.39 (m, 11H), 3.88
13
1
(brs, 1H), 3.16 (brs, 1H), 0.99 (d, J = 6.0 Hz, 12H); C{ H}NMR (150 MHz, CDCl ) δ 170.8,
3
-1
1
3
45.5, 139.4, 136.8, 135.2, 133.3, 129.0, 128.9, 127.6, 127.5, 126.2, 50.6, 45.4, 20.7, 20.2; IR (cm )
376, 2973, 1621, 1427, 1332, 1103, 716, 697; HRMS (ESI-TOF, m/z) calcd for C H NNaOSi
3
1
33
+
(
M+Na) : 486.2229, found 486.2230.
N,N-diisopropyl-2-methoxy-6-methylbenzamide
(1af)
:
Method
D:
N,N-diisopropyl-2-methoxybenzamide (0.47 g, 2.0 mmol), s-BuLi (1.0 M in pentane, 2.40 mL, 2.40
mmol), TMEDA (0.25 g, 2.15 mmol) and MeI (0.85 g, 6.0 mmol) in THF (10 mL) at -78 °C to
o
room temperature for 3 h afforded 1af as a pale yellow solid (0.40 g, 80% yield; mp 138-142 C).
1
H NMR (600 MHz, CDCl ) δ 7.15 (t, J = 5.2Hz, 1H), 6.78 (d, J = 4.8 Hz, 1H), 6.69 (d, J = 5.6 Hz,
3
1
H), 3.77 (s, 3H), 3.61-3.67 (m, 1H), 3.46-3.51 (m, 1H), 2.27 (s, 3H), 1.59 (d, J = 4.8 Hz, 3H), 1.55
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
(d, J = 4.4 Hz, 3H), 1.10 (d, J = 4.4 Hz, 3H), 1.07 (d, J = 4.4 Hz, 3H); C{ H}NMR (150 MHz,
CDCl ) δ 168.1, 155.2, 135.4, 128.4, 127.9, 122.5, 107.8, 55.4, 50.9, 45.7, 21.0, 20.7, 20.6, 20.5,
3
-1
1
8.6; IR (cm ) 2997, 1619, 1466, 1434, 1334, 1257, 1092, 784, 764; HRMS (ESI-TOF, m/z)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
calcd for C H NNaO (M+Na) : 272.1626, found 272.1627.
1
5
23
2
N,N-diisopropyl-2-methoxy-6-(trimethylsilyl)benzamide
N,N-diisopropyl-2-methoxybenzamide (0.58 g, 2.44 mmol), s-BuLi (1.0 M in pentane, 2.90 mL,
.90 mmol), TMEDA (0.31 g, 2.68 mmol) and TMSCl (0.34 g, 3.17 mmol) in THF (10 mL) at
-78 °C to room temperature for 3 h afforded 1ag as a white solid (0.60 g, 80% yield; mp 134-137
(1ag)
:
Method
D:
2
o
1
C). H NMR (400 MHz, CDCl ) δ 7.26 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.84 (d, J =
3
8
.0 Hz, 1H), 3.75 (s, 3H), 3.59-3.69 (m, 1H), 3.44-3.53 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.54 (d, J
1
3
1
=
6.8 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H); C{ H}NMR (100 MHz, CDCl )
3
δ 169.1, 155.0, 139.0, 133.1, 128.4, 127.0, 111.1, 55.0, 50.6, 45.9, 21.0, 20.9, 20.1, 19.9, 0.4; IR
-1
(cm ) 2935, 1612, 1329, 1265, 1152, 1035, 872, 839, 758; HRMS (ESI-TOF, m/z) calcd for
+
C H NNaO Si (M+Na) : 330.1865, found 330.1865.
17
29
2
N,N-diisopropyl-2-methyl-6-(trimethylsilyl)benzamide
(1ah)
:
Method
D:
N,N-diisopropyl-2-(trimethylsilyl)benzamide (1.50 g, 5.41mmol), s-BuLi (1.0 M in pentane,
8.12mL, 8.12mmol), TMEDA (0.94 g, 8.12 mmol) and MeI (7.68 g, 54.1 mmol) in THF (40 mL) at
o
-
78 °C to room temperature for 3 h afforded 1ah as a yellow solid (1.07 g, 68% yield; mp 58-64 C).
1
H NMR (400 MHz, CDCl ) δ 7.38 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz,
3
1
6
H), 3.50-3.63 (m, 2H), 2.31 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.10 (d, J =
13
1
.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H); C{ H}NMR (100 MHz, CDCl ) δ 171.4, 143.0, 136.2,
3
-
1
133.0, 132.6, 130.9, 127.0, 50.4, 46.0, 21.1, 21.0, 20.4, 20.0, 19.4, 0.7; IR (cm ) 2964, 1626, 1439,
ACS Paragon Plus Environment

Page 25 of 51
The Journal of Organic Chemistry
1
2
3
+
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1321, 1031, 878, 837, 773; HRMS (ESI-TOF, m/z) calcd for C H NNaOSi (M+Na) : 314.1916,
17 29
found 314.1913.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N,N-diisopropyl-2,6-bis(trimethylsilyl)benzamide
(1ai)
:
Method
D:
N,N-diisopropyl-2-(trimethylsilyl)benzamide (0.56 g, 2.0 mmol), s-BuLi (1.0 M in pentane, 2.40
mL, 2.40 mmol), TMEDA (0.26 g, 2.20 mmol) and TMSCl (0.28 g, 2.60 mmol) in THF (10 mL) at
1
-78 °C to room temperature for 3 h afforded 1ai (0.60 g, 86% yield) as a colorless oil liquid. H
NMR (400 MHz, CDCl ) δ 7.56 (d, J = 7.6 Hz, 2H), 7.27(t, J = 7.6 Hz, 1H), 4.08-4.18 (m, 1H),
3
1
3
1
3.49-3.59 (m, 1H), 1.53 (d, J = 7.2 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H), 0.31 (s, 18H); C{ H}NMR
-1
(150 MHz, CDCl ) δ 172.5, 148.6, 135.9, 135.8, 125.7, 49.8, 46.1, 22.0, 21.5, 1.1; IR (cm ) 2960,
3
+
1
629, 1285, 1101, 843, 786; HRMS(ESI-TOF, m/z) calcd for C H NNaOSi (M+Na) :
19
35
2
3
72.2155, found 372.2160.
N,N-diethyl-2,6-bis(trimethylsilyl)benzamide
(1ai')
:
Method
D:
N,N-diethyl-2-(trimethylsilyl)benzamide (0.50 g, 2.0 mmol), s-BuLi (1.0 M in pentane, 2.40 mL,
2
.40 mmol), TMEDA (0.26 g, 2.20 mmol) and TMSCl (0.28 g, 2.60 mmol) in THF (10 mL) at
1
-78 °C to room temperature for 3 h afforded 1ai' (0.32 g, 50% yield) as a colorless oil liquid. H
NMR (600 MHz, CDCl ) δ 7.56 (d, J = 4.8 Hz, 2H), 7.30 (t, J = 4.8 Hz, 1H), 3.56 (q, J = 4.8 Hz,
3
2H), 3.06 (q, J = 4.8 Hz, 2H), 1.28 (t, J = 4.8 Hz, 3H), 0.97 (t, J = 4.8 Hz, 3H), 0.27 (s, 18H);
1
3
1
C{ H}NMR (150 MHz, CDCl ) δ 172.2, 147.6, 135.8, 135.5, 126.4, 43.2, 38.5, 13.2, 12.8, 0.4; IR
3
-1
(
cm ) 2956, 1631, 1245, 1095, 835, 775; HRMS (ESI-TOF, m/z) calcd for C H NNaOSi
1
7
31
2
+
(
M+Na) : 344.1842, found 344.1842.
30
Preparation of
(E)-N,N-diisopropyl-2-(2-(trimethylsilyl)vinyl)benzamide (1d) : To a
well-stirred suspension of (n-Bu) NOAc (545 mg, 1.81 mmol) and 4Å molecularsieves in dry DMF
4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(5 mL) were successively added 2-iodo-N,N-diisopropylbenzamide (300 mg, 0.91 mmol),
vinyltrimethylsilane (277 mg, 2.72 mmol) and palladium acetate (25 mg, 0.09 mmol). The reaction
o
mixture was then stirred overnight at 50 C. The mixture was diluted with Et O and filtered over
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
celite. The combined organic layers were concentrated under reduced pressure. The residue was
purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc =
1
200:1→20:1) to afford 1d (0.15 g, 55% yield; mp 97-101 °C) as a yellow solid. H NMR (400 MHz,
CDCl ) δ 7.62 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.2
3
Hz, 1H), 6.95 (d, J = 19.2 Hz, 1H), 6.50 (d, J = 19.2 Hz, 1H), 3.46-3.61 (m, 2H), 1.57-1.60 (t, J =
13
1
5.6 Hz, 6H), 1.07 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.12 (s, 9H); C{ H}NMR (150
MHz, CDCl ) δ 170.1, 140.2, 137.7, 134.2, 131.8, 128.1, 127.9, 125.1, 125.0, 50.9, 45.8, 20.7, 20.6,
3
-1
20.5, 20.3, 1.3; IR (cm ) 2959, 1629, 1336, 1032, 865, 755; HRMS (ESI-TOF, m/z) calcd for
+
C H NNaOSi (M+Na) : 326.1916, found 326.1913.
18
29
3
1
Preparation of N,N-diisopropyl-2-((trimethylsilyl)ethynyl)benzamide (1e) : To a solution of 1n
(400 mg, 1.21 mmol) in Et N (10 mL) was added DMF (5 mL),
3
bis(triphenylphosphine)palladium(II) dichloride (26 mg, 0.04 mmol), copper iodide (12 mg, 0.06
mmol) and trimethylsilylacetylene (119 mg, 1.21 mmol) at room temperature consecutively, the
reaction mixture was stirred for 6 h at room temperature and then diluted with water and extracted
with Et O (3 × 20 mL). The combined organic layer was washed with 1 N HCl (2 × 10 mL), dried
2
over Na SO , filtered and concentrated under reduced pressure. The residue was purified by silica
2
4
gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 200:1→10:1) to afford
1
1e (0.23 g, 52% yield; mp 77-79 °C) as a pale yellow solid. H NMR (400 MHz, CDCl ) δ 7.47 (d,
3
J = 7.6 Hz, 1H), 7.24-7.33 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 3.56-3.66 (m, 1H), 3.47-3.54 (m, 1H),
ACS Paragon Plus Environment

Page 27 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1.58 (t, J = 6.8 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.20 (s, 9H);
1
3
1
C{ H}NMR (150 MHz, CDCl ) δ 169.0, 141.6, 132.9, 128.7, 127.7, 124.9, 119.3, 102.4, 97.4,
3
-1
5
1.2, 45.7, 20.8, 20.7, 20.6, 20.3, 0.2; IR (cm ) 2964, 1633, 1337, 1135, 865, 757; HRMS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(ESI-TOF, m/z) calcd for C H NNaOSi(M+Na) : 324.1760, found 324.1759.
18
27
3
2
Preparation of 2-((tert-butyldimethylsilyl)oxy)-N,N-diisopropylbenzamide (1p) : To a solution
of 2-hydroxy-N,N-diiso-propylbenzamide (0.44 g, 2.0 mmol), DMAP (30 mg, 0.20mmol) and
imidazole (0.22 g, 3.2 mmol) in CH Cl (10 mL) was added tert-butyldimethylsilyl chloride (0.35 g,
2
2
2.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The solution was
filtered and the filtrate was evaporated under reduced pressure. The yellow oil was redissolved in
ether and acidified to a pH value of 1.0 with 2% hydrochloric acid. The organic layer was separated
and washed with sat. aq. NaCl (3 × 10 mL), dried over Na SO , filtered and concentrated under
2
4
reduced pressure. The residue was purified by silica gel flash column chromatography (gradient
eluent: petroleum ether/EtOAc = 200:1→20:1) to afford 1p (0.52 g, 77% yield; mp 81-83 °C) as a
1
white solid. H NMR (400 MHz, CDCl ) δ 7.17 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.92 (t,
3
J = 7.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.64-3.70 (m, 1H), 3.43-3.49 (m, 1H), 1.52 (t, J = 6.4 Hz,
1
3
6
{
H), 1.14 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 0.97 (s, 9H), 0.22 (s, 3H), 0.21 (s, 3H); C
1
H}NMR (150 MHz, CDCl ) δ 168.6, 151.2, 131.3, 128.8, 126.7, 121.1, 119.5, 50.6, 45.5, 25.8,
3
-1
20.8 (2C), 20.5, 20.4, 18.2; IR (cm ) 2961, 1636, 1472, 1338, 1252, 907, 837,783; HRMS
+
(
ESI-TOF, m/z) calcd for C H NO Si (M+H) : 336.2359, found 336.2354.
19
34
2
3
3
Preparation of 2-bromo-N,N-diisopropyl-6-methylbenzamide (1ae) : To a solution of 1ah (438
mg, 1.50 mmol) in CH Cl (5.0 mL) was added bromine (360 mg, 2.25 mmol) at 0 °C dropwise.
2
2
The reaction was stirred at 40 °C for 6 h, then diluted with sat. aq. Na SO (5 mL) and extracted
2
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 51
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with CH Cl (3 × 5 mL). The combined organic layer was dried over Na SO , filtered and
2
2
2
4
concentrated under reduced pressure. The residue was purified by silica gel flash column
chromatography (gradient eluent: petroleum ether/EtOAc = 100:1→10:1) to afford 1ae (0.41 g, 92%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yield; mp 156-162 °C) as a white solid. H NMR (400 MHz, CDCl ) δ 7.34 (d, J = 7.6 Hz, 1H),
3
7
.11 (d, J = 7.2 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 3.48-3.61 (m, 2H), 2.32 (s, 3H), 1.60 (d, J = 7.2
13
1
Hz, 3H), 1.57 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H); C{ H}NMR
(
150 MHz, CDCl ) δ 167.7, 139.2, 136.1, 130.0, 129.1, 128.9, 119.2, 51.2, 46.1, 21.2, 20.9, 20.5,
3
-1
2
0.1, 19.4; IR (cm ) 3354, 2932, 1625, 1440, 1369, 1335, 785, 736; HRMS (ESI-TOF, m/z) calcd
+
for C H BrNNaO (M+Na) : 320.0626, found 320.0627.
1
4
20
1
1
4
4
34
Preparation of
N ,N -diisopropyl-N -methoxy-N -methylterephthalamide (1aw) : To a
solution of methyl 4-(diisopropylcarbamoyl)benzoate (263 mg, 1.0 mmol) and
N-methoxymethylamine (151 mg, 1.55 mmol) in THF (2 mL) was added iso-propylmagnesium
chloride solution (2.0 M in THF, 1.5 ml, 3.0 mmol) at -20 °C. The reaction was stirred for 30 min
before quenching with sat.aq.NaHCO (2 mL) and extracted with Et O (3×5 mL). The combined
3
2
organic layers were then dried over Na SO , filtered and concentrated under reduced pressure. The
2
4
residue was purified by silica gel flash column chromatography (gradient eluent: petroleum
ether/EtOAc = 50:1→5:1) to afford 1aw (265 mg, 81% yield; mp 130-136°C) as a white solid.
1
HNMR (400 MHz, CDCl ) δ 7.64 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 3.67-3.91 (m, 1H),
3
13
1
3
1
1
.49 (brs, 4H), 3.31 (s, 3H), 1.49 (brs, 6H), 1.08 (brs, 6H); C{ H}NMR (150 MHz, CDCl ) δ
3
-1
70.2, 169.2, 140.8, 134.3, 128.4, 125.2, 61.2, 50.9, 45.8, 33.6, 20.6; IR (cm ) 2969, 1621, 1440,
+
342, 1261, 764; HRMS (ESI-TOF, m/z) calcd for C H N O (M+H) :293.1865, found 293.1862.
16 25
2
3
1
1
4
4
34
Preparation of N ,N -diisopropyl-N -methyl-N -phenylterephthalamide (1ax) : To a solution
ACS Paragon Plus Environment

Page 29 of 51
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of N-Methylaniline (81 mg, 0.75 mmol) in THF (1 mL) was added a solution of
isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.1 mL, 1.5 mmol) at room
temperature under Ar. After the mixture was stirred for 2 h at room temperature, a solution of
methyl 4-(diisopropylcarbamoyl)benzoate (132 mg, 0.5 mmol) in THF (1 mL) was added. The
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reaction was stirred for 1 h before quenching with 1 N HCl (2 mL) and extraction with Et O (3 ×5
2
mL). The combined organic layers were then dried over Na SO , filtered and concentrated under
2
4
reduced pressure. The residue was purified by silica gel flash column chromatography (gradient
eluent: petroleum ether/EtOAc = 50:1→5:1) to afford 1ax (163 mg, 96% yield; mp 140-145 °C) as
1
a white solid. H NMR (400 MHz, CDCl ) δ 7.22 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 7.6 Hz, 2H),
3
7
.00-7.04 (m, 3H), 6.93(d, J = 7.6 Hz, 2H), 3.53 (brs, 1H), 3.39 (brs, 4H), 1.38 (brs, 6H), 0.96 (brs,
1
3
1
6H); C{ H}NMR (150 MHz, CDCl ) δ 169.8, 169.6, 144.1, 139.4, 135.9, 128.9, 128.5, 126.5,
3
-1
1
26.4, 124.6, 50.5, 45.5, 38.0, 20.2; IR (cm ) 2967, 1629, 1495, 1369, 1339, 766, 699; HRMS
+
(
ESI-TOF, m/z) calcd for C H N O (M+H) : 339.2073, found 339.2073.
21
27
2
2
3
5,36
Preparation of tert-butyl (4-(diisopropylcarbamoyl)phenyl)carbamate (1ay)
: Hydrogen gas
was bubbled through the solution of 1aj (1.02 g, 4.6 mmol) and 10% Pd/C (0.20 g, 53% moisture)
in ethyl acetate (35 mL) at room temperature. After stirring for 9 h, the mixture was filtered, and the
filtrate
was
concentrated
under
reduced
pressure
to
give
compound
4
-amino-N,N-diisopropylbenzamide 1az (0.78 g, 89%) as a white solid without further purification.
To a solution of 1az (0.33 g, 1.5 mmol) in dioxane (6 mL) was added (Boc) O (0.43 g, 1.95 mmol)
2
at room temperature. After stirring at 105 °C for 3 h, the reaction mixture was poured into water
and extracted with CH Cl (3 × 10 mL). The combined organic layers were then dried over Na SO ,
2
2
2
4
filtered and concentrated under reduced pressure. The residue was purified by silica gel flash
ACS Paragon Plus Environment