The Synthesis of Functionalized 3-Aryl- And 3-Heteroaryloxazolidin-2-ones and Tetrahydro-3-aryl-1,3-oxazin-2-ones via the Iodocyclocarbamation Reaction: Access to Privileged Chemical Structures and Scope and Limitations of the Method

Article abstract of DOI:10.1021/acs.joc.9b03400

3-Aryl- and 3-heteroaryloxazolidin-2-ones, by virtue of the diverse pharmacologic activities exhibited by them after subtle changes to their appended substituents, are becoming increasingly important and should be considered privileged chemical structures

Full text of DOI:10.1021/acs.joc.9b03400

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Article
The Synthesis of Functionalized 3-Aryl- and 3-Heteroaryloxazolidin-2-
ones and Tetrahydro-3-Aryl-1,3-oxazin-2-ones via the
Iodocyclocarbamation Reaction. Access to Privileged
Chemical Structures and Scope and Limitations of the Method.
Abbegail C. Bell, Alex B. Boomsma, Niecia E. Flikweert, Robert M. Hohlman, Shiyuan Zhang, Ronald L.
Blankespoor, Shannon M. Biros, Richard J. Staples, Steven J. Brickner, and Michael Robert Barbachyn
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03400 • Publication Date (Web): 21 Apr 2020
Downloaded from pubs.acs.org on April 29, 2020
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The Synthesis of Functionalized 3-Aryl- and 3-Heteroaryloxazolidin-2-ones and Tetrahydro-3-
Aryl-1,3-oxazin-2-ones via the Iodocyclocarbamation Reaction. Access to Privileged Chemical
Structures and Scope and Limitations of the Method.
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†
†
†
†
†
Abbegail C. Bell, Alex B. Boomsma, Niecia E. Flikweert, Robert M. Hohlman, Shiyuan Zhang,
†
‡
§
∥
Ronald L. Blankespoor, Shannon M. Biros, Richard J. Staples, Steven J. Brickner, and Michael R.
Barbachyn* †
†Department of Chemistry and Biochemistry, Calvin University, 1726 Knollcrest Circle SE, Grand
Rapids, MI 49546
‡Department of Chemistry, Grand Valley State University, 1 Campus Dr., Allendale, MI 49401
§Center for Crystallographic Research, Department of Chemistry, Michigan State University, 578 S.
Shaw Lane, East Lansing, MI 48824
∥SJ Brickner Consulting, LLC, 9 Fargo Dr., Ledyard, CT 06339
*E-mail: mrb43@calvin.edu
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ABSTRACT
-Aryl- and 3-heteroaryloxazolidin-2-ones, by virtue of the diverse pharmacologic activities
3
exhibited by them after subtle changes to their appended substituents, are becoming increasingly
important and should be considered privileged chemical structures. The iodocyclocarbamation reaction
has been extensively used to make many 3-alkyl-5-(halomethyl)oxazolidin-2-ones, but the
corresponding aromatic congeners have been relatively underexplored. We suggest that racemic 3-aryl-
and 3-heteroaryl-5-(iodomethyl)oxazolidin-2-ones, readily prepared by the iodocyclocarbamation
reaction of N-allylated N-aryl or N-heteroaryl carbamates, may be useful intermediates for the rapid
preparation of potential lead compounds with biological activity. We exemplify this point by using this
approach to prepare racemic linezolid, an antibacterial agent. Herein, we report results of our systematic
investigation into the scope and limitations of this process and have identified some distinguishing
characteristics within the aryl/heteroaryl series. We also describe the first preparation of 3-
aryloxazolidin-2-ones bearing new functionalized C-5 substituents derived from conjugated 1,3-dienyl
and cumulated 1,2-dienyl carbamate precursors. Finally, we describe the utility of the
iodocyclocarbamation reaction for making six-membered tetrahydro-3-aryl-1,3-oxazin-2-ones.
INTRODUCTION
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The iodocyclocarbamation reaction of allylic and homoallylic N-alkylcarbamates is an effective
means of constructing both 3-alkyloxazolidin-2-ones and their 6-membered congeners, the tetrahydro-3-
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alkyl-1,3-oxazin-2-ones. The utility of this approach was first demonstrated by Pauls and Fraser-Reid
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as part of their elegant synthesis of the amino sugar garosamine. Subsequent reports continued to
expand the usefulness of this type of transformation, but with an almost exclusive focus on
iodocyclocarbamation reactions employing N-alkyl or N-benzyl allylic carbamate substrates (Scheme
1).3
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Scheme 1. The Iodocyclocarbamation Reaction of Allylated N-Alkyl Carbamates1,2,3
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Interestingly, allylic carbamate substrates bearing aryl or heteroaryl nitrogen substituents have
been largely overlooked. Presumably, this emphasis on iodocyclocarbamation reactions leading to 3-
alkyl-5-(iodomethyl)oxazolidin-2-one products reflects a primary focus on chemical intermediates
useful for making amino alcohols, via subsequent degradation of the oxazolidinone’s carbamate linkage.
The first example of an iodocyclocarbamation reaction involving an allylated N-arylcarbamate
was reported by Brickner and co-workers and involved the iodine-mediated conversion of N-indolinyl
allylic carbamate 1 to the corresponding racemic 3-(indolin-5-yl)-5-(iodomethyl)oxazolidin-2-one 2 in
4
77% isolated yield (Scheme 2). In two subsequent papers, focused on the regioselective metalation of
stabase-protected anilines and palladium-mediated cross-coupling reactions with
trimethylstannyltropones, the iodocyclocarbamation reaction was briefly described.5a,b A few more
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recent papers describing N-4-pyridyl, N-3-thienyl, and N-1-quinolin-4-yl allylic carbamates as
substrates in the iodocyclocarbamation reaction have appeared but, again, generally not as the primary
emphasis of the described research. There remains a real need for a more comprehensive examination
of N-aryl and N-heteroaryl carbamates as substrates in the iodocyclocarbamation reaction, with the goal
of further defining and expanding the scope and limitations of this important cyclization process.
Scheme 2. Iodocyclocarbamation Reaction of N-Allyl N-(5-Indolinyl)carbamate 1
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Our interest in further exploring the iodocyclocarbamation reaction was also driven by a
recognition of the potential importance of 3-aryl- and 3-heteroaryl-5-(iodomethyl)oxazolidin-2-one
products as useful intermediates for the synthesis of a variety of therapeutically useful racemic
substances. In fact, the 5-substituted 3-aryl- and 3-heteroaryloxazolidin-2-one motif could be formally
considered as a “privileged chemical structure,” a term first coined by Evans and co-workers to describe
molecular scaffolds that, with slight changes in appended substituents, can express a wide range of
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discrete therapeutic activities. As exemplars, the marketed pharmaceutical agents linezolid,
rivaroxaban, and toloxatone, each incorporating a substituted 3-phenyloxazolidin-2-one core with
distinct C-5 side chains, exhibit antibacterial, anticoagulant, and antidepressant activities, respectively
(
Figure 1).10,11,12 Additional 3-aryl- and 3-heteroaryloxazolidin-2-ones with substitution at the 5-position
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have been reported to inhibit or bind HIV-1 protease, glycoprotein (GP-IIb/IIIa), metabotropic
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glutamate receptor (mGluR), and various calcium channel receptors.
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Figure 1. Examples of phenyloxazolidinone “privileged chemical structures.”
Taken together, the structural breadth of the therapeutic examples described above suggests a
possible synthetic role for the 3-aryl- and 3-heteroaryl-5-(iodomethyl)oxazolidin-2-one products of the
iodocyclocarbamation reaction. The primary iodide moiety would certainly be amenable to further
synthetic elaboration to provide access to a number of relevant C-5 side chain substituents. The use of
allylic carbamate starting materials with an array of aromatic and heteroaromatic appendages on their
nitrogen would provide additional structural diversity. Overall, exploitation of the iodocyclocarbamation
reaction could enable the rapid synthesis of racemic intermediates with potential to facilitate the
identification of new lead compounds. The eventual identification of any interesting compounds would
then require a subsequent developmental effort in order to generate these substances in enantiomerically
enriched form.
As described herein, while the iodocyclocarbamation reaction generally proceeds in useful yields
for a wide variety of 3-aryloxazolidin-2-ones, there was no guarantee of success a priori for an
expanded survey of the reaction, given the presence of a variety of highly electrophilic species during
the course of the reaction (Scheme 1). Iodine and other electrophilic species, such as an iodonium ion
intermediate, presented some potential for electrophilic aromatic substitution side reactions, especially
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in the presence of a very electron-rich aromatic ring (e.g. di- or trimethoxyphenyl or aminophenyl). In
addition, given the generation of benzyl iodide from the Cbz carbamates used in the cyclization process,
extension of this chemistry to the synthesis of various nitrogen-containing 3-heteroaryloxazolidin-2-ones
could potentially be thwarted by untoward alkylation of any basic nitrogen atom(s), both in the case of
the starting N-allylcarbamate as well as the cyclized product. Indeed, the development of modified
reaction conditions to circumvent this problem became crucial for salvaging the applicability of the
iodocyclocarbamation reaction to the synthesis of various 3-heteroaryloxazolidin-2-ones, for example
the pyridyl derivatives (vide infra). Finally, we also share the results of our successful attempts to extend
this cyclization chemistry beyond simple allylic carbamate substrates to encompass conjugated N-(1,3-
pentadien-5-yl) and cumulated N-(1,2-butadien-4-yl) carbamate starting materials, affording synthetic
entry to oxazolidinones bearing interesting functionalized C-5 side chains poised for further
modification. The use of a homoallylic carbamate is also described, providing entry to the
corresponding tetrahydro-3-aryl-6-(iodomethyl)-1,3-oxazin-2-one six-membered ring congeners.
RESULTS AND DISCUSSION
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Synthesis of N-Allyl N-carbobenzyloxy Anilines and Heteroarylamines 5. The N-aryl and N-
heteroaryl O-benzyl carbamates 4, required for synthesis of the N-allyl carbamate substrates 5, were
prepared in excellent yields via treatment of the requisite commercially available anilines or
heteroarylamines 3 with benzyloxy chloroformate (CbzCl), using either Schotten-Baumann conditions
with sodium bicarbonate (NaHCO ) in aqueous acetone, or anhydrous conditions with potassium
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carbonate (K CO ) in THF (Scheme 3). The N-allyl N-Cbz aromatic amine starting materials 5 for the
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planned iodocyclocarbamation reactions were most conveniently prepared in our hands by allylation of
the N-aryl- or N-heteroarylcarbamates 4. This involved deprotonation of 4 with either NaH in THF or
cesium carbonate (Cs CO ) in DMF, followed by alkylation with allyl bromide, typically at room
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temperature. In most instances, catalytic tetrabutylammonium iodide [(n-Bu) NI] was added to further
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facilitate the allylation reaction. In general, the allylated carbamates 5 were isolated as oils or gums in
good, sometimes excellent yield after chromatographic purification (Table 1). In some instances, the
allylated products 5 were difficult to separate by chromatography from any residual starting material 4.
In these cases, it was critical that the allylation reaction went to completion.
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One limitation of this method of allylation became apparent in the attempted alkylation of the 2-
aminothiazole-derived Cbz carbamate 7 (Scheme 4). In the event, the allylation reaction afforded a 3:1
ratio of the desired N-allyl carbamate 8, isolated in 72% yield, along with the thiazolylidene side product
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, resulting from allylation of the thiazole ring nitrogen, in 25% yield. The observed regioselectivity in
the allylation of 7 is very similar to the alkylation results reported in the literature for a Boc derivative of
-aminothiazole.17
2
Scheme 3. Preparation of 3-Aryl- and 3-Heteroaryl-5-(iodomethyl)oxazolidin-2-ones 6
Table 1. Synthesis of Intermediates 5 via Allylation of N-Aryl- and N-Heteroarylcarbamates 4
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entry
R
conditionsa
yield (%)b
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C H (5a)
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2,6-Me C H (5c)
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4-BrC H (5d)
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4-IC H (5e)
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3,4,5-F C H (5f)
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2,3,4-F C H (5g)
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3,5-(CF ) C H (5h)
3 2 6 3
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3-F-4-(NO )C H (5i)
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4-Br-3-MeOC H (5j)
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4-MeO-3-(CF )C H (5k)
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3,4-(MeO) C H (5l)
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3-fluoro-4-(morpholin-4-yl)C H (5m)
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pyridin-2-yl (5n)
pyridin-3-yl (5o)
pyridin-4-yl (5p)
quinolin-2-yl (5q)
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quinolin-3-yl (5r)
quinolin-6-yl (5s)
quinolin-8-yl (5t)
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A: 1) NaH, THF, 0 ºC to rt, 2) allyl bromide, (n-Bu) NI, rt; B: Cs CO , allyl bromide, (n-Bu) NI, rt.
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bIsolated yield.
Scheme 4. Allylation of Cbz Carbamate 7 derived from 2-Aminothiazole.
The Iodocyclocarbamation Reaction of N-Allylated N-Arylcarbamates 5a-m. For our initial
investigations into the iodocyclocarbamation reaction of aryl N-allyl O-benzyl carbamates 5a-m, we
used conditions similar to those utilized by Takano and Ohno for the corresponding alkyl N-allyl
subtrates.3d,f This involved treatment of 5 with 2 equivalents of I in CHCl at room temperature
2
3
(
Scheme 3). We also examined CH Cl and CH CN as alternative solvents and found that they typically
2 2 3
provided comparable results. Most of the reactions reported herein were conducted in CH Cl2
2
(
“standard conditions,” Table 2). For N-aryl substrates 5a-m, all examples underwent clean
iodocyclocarbamation under the standard conditions, providing the targeted racemic 3-aryl-5-
iodomethyl)oxazolidin-2-ones 6a-m in generally high yield, after purification by chromatography or
(
recrystallization. There was no obvious evidence of any untoward reaction in the synthesis of these
substituted 3-aryloxazolidinones. This was somewhat surprising, as we had speculated that very
electron-rich aromatic rings, such as the 3,4-dimethoxyphenyl moiety of 5l (Table 2, entry 12), might be
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susceptible to some level of an electrophilic aromatic substitution side reaction due to the presence of
the various electrophilic species noted in Scheme 1. This undesired reaction manifold was not observed
for any of the aryl systems investigated (5a-m).
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9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Iodocyclocarbamation of Allylated N-Aryl Intermediates to Provide Substituted 3-
Phenyl-5-(iodomethyl)oxazolidin-2-ones 6a-m
entry
Ar
Yield (%)a,b
1
C H (6a)
97
6
5
2
3
4
5
6
7
8
9
2-MeC H (6b)
70
86
95
94
89
92
78
74
70
73
94
6
4
2,6-Me C H (6c)
2
6
3
4-BrC H (6d)
6
4
4-IC H (6e)
6
4
3,4,5-F C H (6f)
3
6
2
2,3,4-F C H (6g)
3
6
2
3,5-(CF ) C H (6h)
3
2
6
3
3-F-4-(NO )C H (6i)
2
6
3
1
1
1
0
1
2
4-Br-3-MeOC H (6j)
6 3
4-MeO-3-(CF )C H (6k)
3
6
3
3,4-(MeO) C H (6l)
2
6
3
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13
3-fluoro-4-(morpholin-4-yl)C H (6m)
85
6
3
5
a
b
Standard conditions: 2 equivalents I , CH Cl , rt. Isolated yield.
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
2
2
2
The iodocyclocarbamation reaction of N-allyl N-[3-fluoro-4-(morpholin-4-yl)phenyl]carbamate
m was found to proceed uneventfully, despite the presence of a weakly basic tertiary amine nitrogen,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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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
5
pK = ~8) in its appended morpholine ring, to give the 5-(iodomethyl)oxazolidin-2-one 6m in 85%
b
isolated yield (Table 2, entry 13). There was no evidence of any alkylation of this nitrogen with benzyl
iodide generated during the course of the reaction. Compound 6m is amenable to further synthetic
elaboration (Scheme 5). Nucleophilic displacement of the primary iodide proceeded uneventfully with
sodium azide (DMF, 65 °C) to give the 5-(azidomethyl)oxazolidin-2-one 10 in 95% yield after
chromatography. A Staudinger reaction, followed by hydrolysis and then acetylation, afforded an 83%
isolated yield of (±)-linezolid (11), an antibiotic with potent activity against pathogenic Gram-positive
bacteria.10,18
Scheme 5. Application of the Iodocyclocarbamation Reaction to a Synthesis of the Antibiotic
Linezolid in Racemic Form
The Iodocyclocarbamation Reaction of N-Allylated N-Heteroarylcarbamates 5n-t.
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5
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5
5
5
5
5
6
The mechanism of the iodocyclocarbamation of allylic O-benzylcarbamates, as depicted in Scheme 1,
involves an intramolecular attack of the carbamate’s carbonyl oxygen atom on a cyclic iodonium ion,
leading to the intermediacy of a benzyl-substituted oxonium ion-iodide ion pair. This presumably
collapses via benzylic cleavage by iodide ion, to give one equivalent each of benzyl iodide and the 5-
0
1
2
3
4
5
6
7
8
9
0
1
2
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9
0
1
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3
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5
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7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(iodomethyl)oxazolidin-2-one. As noted above, these electrophilic species did not undergo untoward
electrophilic aromatic substitution reactions on the aryl rings examined (5a-m). However, co-generation
of these reactive intermediate alkylating species, along with the by-product benzyl iodide itself, might be
expected to represent a serious limitation with various heterocyclic substrates, in particular, N-allyl N-
heteroarylcarbamates bearing a basic nitrogen atom. Indeed, an early application of
iodocyclocarbamation reaction conditions to allylated pyridin-3-yl- and pyridin-4-ylphenyl carbamates
was reported to completely fail because of significant N-benzylation of the basic nitrogen atom in these
5
systems. A measure of success was ultimately achieved in this prior work through the introduction of
excess pyridine into the CHCl -based reaction medium to serve as an effective benzyl iodide scavenger.
3
There remained a need to systematically explore the scope and limitations of this approach, as well as
potential alternatives, in the context of the series of N-allylated N-pyridyl- and N-quinolinylcarbamates
5
n-t described herein (Table 1, entries 14-20).
We initially investigated the iodocyclocarbamation reaction of selected N-allylated N-
heteroarylcarbamate congeners 5o, 5p, 5r and 5s in CHCl (or CH Cl ) at rt or reflux temperature in the
3
2
2
presence of 2 equivalents of I (“standard conditions,” Scheme 3) and found that, in general, only trace
2
amounts of the desired products, 6o, 6p, 6r and 6s were formed. Some starting material was recovered
but the major product was presumably the corresponding N-benzyl pyridinium or quinolinium salts. A
summary of selected reaction conditions explored and iodocyclocarbamation results obtained is shown
in Table 3. The addition of 10 equivalents of pyridine to the standard reaction conditions, in an attempt
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to trap the nascent benzyl iodide, generally did not appreciably improve the reaction outcome in either
the pyridin-3-yl or quinolin-6-yl series. For example, 5o afforded only a trace of the cyclized product 6o
(Table 3, entry 1. Similarly, the quinolin-6-yl substrate 5s provided only a 23% yield of the desired
product 6s (Table 3, entry 8), along with 41% recovered starting material. What did facilitate conversion
to the targeted 5-(iodomethyl)oxazolidin-2-one products was the replacement of CHCl with CH CN in
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
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
the presence of the same pyridine additive. In this way, a 48% isolated yield of the 5-
(iodomethyl)oxazolidin-2-one product 6s was obtained from 5s after chromatographic purification
(
Table 3, entry 9), along with 23% of recovered 5s. The reason for the potentiating role of CH CN in
3
these reactions is not entirely clear but a contributing factor appears to involve some degree of trapping
of the generated benzyl iodide by-product, as varying amounts of N-benzylacetamide, presumably
resulting from a Ritter-like reaction process, are often isolated. Adding a third equivalent of I to the
2
CH CN/pyridine system provided a further enhancement, with only a trace of 5s observed and a 60%
3
yield of the targeted 3-(quinolin-6-yl)oxazolidin-2-one product 6s now realized (Table 3, entry 10).
Application of these optimized conditions to the pyridin-3yl starting material 5o afforded a 57% isolated
yield of the 3-(pyridin-3-yl)oxazolidin-2-one product 6o (Table 3, entry 2). The introduction of
additional I (up to 10 equivalents) led to reduced yields of 6o. The allylated quinolin-3-yl carbamate 5r,
2
isoelectronic with the pyridin-3-yl system, also underwent smooth cyclization to the corresponding 5-
(iodomethyl)-3-(quinolin-3-yl)oxazolidin-2-one product 6r in 64% yield (Table 3, entry 7). Application
of the optimized CH CN/pyridine-based conditions to the pyridin-4-yl substrate 5p afforded the desired
3
product 6p, but in a more modest yield of only 38% (Table 3, entry 6). It should be noted that Chung
and co-workers previously reported the iodocyclocarbamation of 5p in CHCl /pyridine but obtained
3
only a 19% yield of 6p.6
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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
Table 3. Iodocyclocarbamation of Allylated N-Heteroaryl Intermediates 5o-p, r-s to Provide
Substituted 3-Heteroaryl-5-(iodomethyl)oxazolidin-2-ones 6o-p, r-s
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
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6
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9
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9
0
Entry
HetAr
Solvent Temp (°C) Time (h) Equiv. I2 Equiv. Py Yield (%)a
1
pyridin-3-yl (6o)
CHCl3
25
81
60
24
24
48
48
24
27
15
17
22
2
3
2
2
2
3
3
2
2
3
10
10
10
10
10
10
10
10
10
10
trace
57
2
3
4
5
6
7
8
9
pyridin-3-yl (6o) CH CN
3
pyridin-4-yl (6p)
CHCl3
25/61
25
trace
trace
24
pyridin-4-yl (6p) CH Cl
2
2
pyridin-4-yl (6p) CH CN
70
3
pyridin-4-yl (6p) CH CN
81
38
3
quinolin-3-yl (6r) CH CN
81
64
3
quinolin-6-yl (6s) CHCl3
60
23
quinolin-6-yl (6s) CH CN
81
48
3
1
0
quinolin-6-yl (6s) CH CN
81
60
3
aIsolated yield.
Based on the mechanism of the iodocyclocarbamation reaction, we anticipated some challenges
in translating the N-allylated N-pyridin-2-yl carbamate 5n to the targeted 5-(iodomethyl)oxazolidin-2-
one product 6n because of the close proximity of its basic pyridine nitrogen atom to the nascent
iodonium ion intermediate (Scheme 6). Indeed, reaction of 5n with I under a variety of conditions led
2
exclusively to a new, much more polar UV-active product which was not 6n but rather, as subsequent
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analysis would reveal, the cyclized pyridinium salt 12. Remarkably, 12 survived an extractive workup
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
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2
2
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3
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3
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4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
with aqueous sodium thiosulfate to provide, after precipitation from the partially concentrated CH Cl
2
2
organic phase, a reasonably clean solid. Recrystallization from toluene/methanol afforded a 69%
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
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
isolated yield of 12 as a white crystalline solid. The NMR spectral data for 12 was consistent with the
assigned structure and this finding was unequivocally confirmed by a single-crystal X-ray structure
determination (Figure S1 in the Supporting Information).
Scheme 6. Attempted Preparation of 5-(Iodomethyl)oxazolidin-2-one 6n via Iodocyclocarbamation
Reaction of 5n
By analogy to the results obtained for 5n, the N-allyl N-quinolin-2-yl and N-allyl N-quinolin-8-yl
carbamates 5q and 5t, respectively, would also be expected to form cyclic quinolinium salts upon
treatment with I under the usual iodocyclocarbamation conditions (Scheme 7). In the event, carbamate
2
5
q afforded, after recrystallization, a 72% isolated yield of tricyclic quinolinium salt 13. Similarly, the
tricyclic quinolinium salt 14 was efficiently obtained in 87% recrystallized yield via a 6-exo cyclization
process from precursor 5t.
Scheme 7. Formation of Cyclic Quinolinium Salts 13 and 14 from Precursors 5q and 5t,
Respectively
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0
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8
9
0
Attempted Iodocyclocarbamation Reaction of N-Allylated N-Thiazolylcarbamate 8.
We subjected the aforementioned N-allyl-N-(benzyloxycarbonyl)-2-aminothiazole (8, Scheme 4) to the
optimized iodocyclocarbamation reaction conditions used in the above-described pyridyl and quinolyl
series in an attempt to generate a 3-thiazolyl-oxazolidin-2-one product (Scheme 8). While 8 was
consumed, there was no evidence for any oxazolidinone ring formation; presence of an oxazolidinone is
1
easily determined via the consistency of oxazolidinone C-4 and C-5 H NMR signals and their
associated multiplicities. There was also no formation of the other possible predicted product, a cyclic
thiazolium salt analogous to what we obtained previously in the 2-aminopyridine, 2-aminoquinoline and
8
-aminoquinoline series (see Schemes 6 and 7). In short, the thiazole ring system does not appear to be a
good substrate for the iodocyclocarbamation reaction.
Scheme 8. Attempted Iodocyclocarbamation of 8
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5
Extension of the Iodocyclocarbamation Reaction to a Conjugated N-1,3-Pentadien-5-yl
Carbamate System. Conceptually, extension of the N-allyl iodocyclocarbamation reaction to an
extended conjugated diene system would be desirable. In the parallel N-alkyl series, Takemoto and co-
workers previously described the iodocyclocarbamation reaction of, for example, N-1,3-pentadien-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
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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
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
benzyl-5-yl N-benzyl carbamate 15 (Scheme 9). Conversion of 15 to 4,5-disubstituted oxazolidin-2-
one isomers 16 and 17, in a combined yield of 64%, proceeded with good regioselectivity and a measure
of stereoselectivity (63:37, respectively). Notably, no N-aryl or N-heteroaryl carbamates were reported.
In addition, their carbamate substrates were made via a multi-step synthesis involving, as starting
materials, (tricarbonyl)iron complexes of various dienes.
Scheme 9. Iodocyclocarbamation of Substituted N-(1,3-Butadienyl)methyl Carbamate 1519
Returning to N-aryl substrates, the principal focus of this research, we envisioned a simple
alkylation strategy to construct the initial N-1,3-pentadien-5-yl carbamate substrate 18 (Scheme 10). To
20
that end, aniline-derived carbamate 4a was reacted with easily prepared 5-bromo-1,3-pentadiene in the
presence of (n-Bu) NI and Cs CO in DMF to give the desired dienyl carbamate 18 in 80% isolated
4
2
3
yield. When substrate 18 was treated under the “standard” iodocyclocarbamation conditions (2 equiv. I2,
CH Cl , rt) we were pleased to see that the 5-exo cyclization product 19 was formed in 87% yield after
2
2
chromatographic purification. The double bond of 19 was assigned the trans configuration based on the
1
observed coupling constant of 15.1 Hz in its H NMR spectrum. The functionalized 3-iodopropen-1-yl
C-5 side chain of 19 should be a useful synthetic “handle” for rapidly integrating additional structural
diversity into this privileged 3-aryloxazolidin-2-one structure. Extending this chemistry to heteroaryl
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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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
systems containing a basic nitrogen atom may be a challenge because of the intrinsic reactivity of the C-
allylic iodide moiety.
5
Scheme 10. Preparation and Iodocyclocarbamation Reaction of N-1,3-Pentadien-5-yl N-Phenyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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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
Carbamate 18 to Give 5-(3-iodoprop-1-en-1-yl)oxazolidin-2-one 19
Extension of the Iodocyclocarbamation Reaction to a Cumulated N-1,2-Butadien-4-yl
Carbamate Substrate. We were also interested in exploring the possibility of using a cumulated diene
appendage on the starting carbamate nitrogen in order to access alternative functionality, namely a vinyl
iodide, on the C-5 side chain of the oxazolidinone product. As shown in Scheme 11, we approached the
synthesis of the key N-1,2-butadien-4-yl carbamate 20 via two different routes. In the first of these, N-
alkylation of carbamate 4a with 4-bromo-1,2-butadiene21,22 was achieved with Cs CO and (n-Bu) NI in
2
3
4
DMF to afford 20 in 77% yield. A second and preferable approach involved deprotonation of 4a with
NaH in THF or DMF, followed by alkylation with propargyl bromide, to provide the N-propargyl
carbamate derivative 21 in 96% yield. Compound 21 was then subjected to a Crabbé homologation with
paraformaldehyde in the presence of CuI, (C H ) NH and 1,4-dioxane, with heating, to give the same
6
11 2
2
3
13
N-allenylmethyl derivative 20 in 75% isolated yield. Compound 20 exhibited a signal in its C NMR
2
4
spectrum at 208.9 ppm, characteristic of the central carbon of an allene moiety. Intermediate 20 was
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treated with two equivalents of I in CH Cl at rt to give, after workup and chromatographic purification,
2
2
2
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
2% of the desired 5-(1-iodoethen-1-yl)-3-phenyloxazolidin-2-one 22 along with 13% of recovered 20.
Attempts to increase the conversion by adding a third equivalent of I led to a somewhat lower yield
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
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5
6
7
8
9
0
1
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(63%) of the desired product. The H NMR spectrum of 22, which shows two alkene protons at 6.6 and
6
.0 ppm, each with small 2 Hz germinal coupling constants, is consistent with the assigned structure.
Further, signals for the individual protons at C-4 and C-5 all appear as inter-related doublets of doublets,
consistent with formation of the oxazolidinone ring system. This approach should be fully compatible
with heteroaryl-substituted starting materials. In addition, the C-5 vinyl iodide side chain of 22 should
be amenable to further synthetic manipulation, for example Suzuki-Miyaura cross-coupling reactions.
Scheme 11. Preparation and Iodocyclocarbamation Reaction of N-1,2-Butadien-4-yl N-Phenyl
Carbamate 20 to Give 5-(1-Iodoethen-1-yl)oxazolidin-2-one 22
Access to Six-membered Tetrahydro-3-aryl-6-(iodomethyl)-1,3-oxazin-2-ones via the
Iodocyclocarbamation Reaction. While the previously described chemistry permits rapid access to
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5
5
5
5
5
6
five-membered ring oxazolidinones, it would be desirable to gain entry to the corresponding six-
membered ring system, the tetrahydro-3-aryl-6-(iodomethyl)-1,3-oxazin-2-ones (Scheme 12). As a
preliminary test case, the starting N-(1-buten-4-yl)aniline 23, obtained by alkylation of aniline with 4-
0
1
2
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25
bromo-1-butene, was converted to the Cbz derivative 24 with CbzCl and K CO in anhydrous THF in
2
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2% yield. Treatment of the unsaturated carbamate 24 with I (CHCl , rt) initiated a facile 6-exo
2 3
cyclization to give the racemic tetrahydro-6-(iodomethyl)-3-phenyl-1,3-oxazin-2-one 25 in 93% isolated
yield. While not yet explored, the iodocyclocarbamation reaction of heteroaryl versions of 24 to give 3-
heteroaryl-1,3-oxazin-2ones should be possible by applying optimized conditions developed for the
pyridyl and quinolyl oxazolidinone series described above. Attempts to extend this chemistry further, to
enable the synthesis of seven-membered cyclic carbamates, were unsuccessful, as complex mixtures of
products were obtained (data not shown).
Scheme 12. Preparation of Tetrahydro-6-(Iodomethyl)-3-phenyl-1,3-oxazin-2-one 25 via an
Iodocyclocarbamation Reaction
CONCLUSIONS
In summary, the iodocyclocarbamation reaction of N-allylated N-aryl- and N-heteroarylcarbamates is an
efficient, versatile and useful method for the synthesis of racemic 3-aryl- and 3-heteroaryl-5-
(iodomethyl)oxazolidin-2-ones. The electron-rich aromatic rings examined, such as the 3,4-
dimethoxyphenyl or 4-morpholinylphenyl moieties, did not produce any by-products resulting from an
electrophilic aromatic substitution reaction with any of the various electrophilic species present in the
iodocyclocarbamation reaction mixture. Heteroaryl systems incorporating a basic nitrogen required
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modified conditions involving the use of additional I and an acetonitrile/pyridine co-solvent system to
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avoid untoward alkylation of the reactive nitrogen. When a heteroaryl basic nitrogen is present in an
orientation favoring attack on the intermediate iodonium ion, a different reaction pathway is followed
wherein cyclic ammonium salts are generated (e.g. 12, 13 and 14). Also, when the allylated thiazole-
derived carbamate 8 was subjected to the iodocyclocarbamation reaction conditions, it did not afford
predicted or well-characterized reaction products and further investigation is needed to clarify its
chemistry. The successfully synthesized 5-(iodomethyl)oxazolidin-2-one products bear useful
functionality for making a variety of pharmacologically active substances, as exemplified by the
synthesis of the antibacterial agent linezolid in racemic form. Access to alternative oxazolidinone C-5
side chains, such as the 3-iodoprop-1-en-1-yl and 1-iodoethen-1-yl groups, prepared from N-1,3-
pentadien-5-yl and N-1,2-butadien-4-yl carbamates, respectively, are also within scope of this approach.
These functionalized side chains should facilitate the incorporation of additional diversity elements into
the C-5 position of these privileged chemical structures. We also found that N-aryl-N-(1-buten-4-yl)
carbamates react under standard cyclocarbamation conditions to form the interesting racemic six-
membered tetrahydro-3-aryl-6-(iodomethyl)-1,3-oxazin-2-ones. Overall, we envision the N-aryl- and N-
heteroaryl variation of the iodocyclocarbamation reaction as having great potential to expeditiously
construct a variety of racemic compounds which could facilitate the identification of new lead
substances in various bioactivity screens. Upon such identification, subsequent development activities
would then address their preparation in enantiomerically enriched form. The most promising path to
enantiomerically enriched iodocyclocarbamation products would seem to be through an eventual
application of methodology involving chiral hypervalent iodine catalysts. The pioneering and ongoing
work in this area by Denmark, Wirth and Muñiz, amongst others, would seem to have considerable
potential as a solution to this problem.26
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EXPERIMENTAL SECTION
General Considerations. All commercially available solvents and reagents were used without further
purification, unless otherwise noted. Starting N-aryl and N-heteroaryl O-benzylcarbamates 4a-t were
commercially available, synthesized from commercially available anilines (4f, 4h), or prepared via
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Schotten-Baumann reactions as previously described: 4j, 4k, 4n, 4o, 4p, 4q, 4r, and 4s. All
moisture-sensitive reactions were conducted under a nitrogen atmosphere in oven- or flame-dried
glassware. All reactions requiring heating were conducted with a temperature-controlled oil bath.
1
Melting points were determined on a Thomas-Hoover capillary apparatus and are uncorrected. H and
13C NMR spectra were obtained on 400 or 500 MHz NMR spectrometers. Multiplicity is indicated as
follows: s (singlet); d (doublet); t (triplet); q (quartet); m (multiplet); dd (doublet of doublets); dt
(doublet of triplets); ddd (doublet of doublet of doublets); qt (quartet of triplets); app (apparent).
Chemical shifts () are reported in ppm relative to CDCl or TMS. Coupling constants (J) are reported in
3
Hz. IR spectra were obtained on a FT-IR spectrometer. High-resolution mass spectra (HRMS) were
obtained on a mass spectrometer operating in ESI (positive or negative) or APCI (positive) modes (TOF
mass analysis). Data are reported in the form m/z (relative intensity). Analytical TLC was performed on
silica gel plates with visualization generally accomplished by UV light (254 nm). Flash chromatography
was performed on silica gel (230-400 mesh). Organic solutions were concentrated using a rotary
evaporator under reduced pressure unless otherwise stated. For the single crystal X-ray crystallographic
3
study, a colorless needle-shaped crystal of compound 12 with dimensions 0.35×0.06×0.06 mm was
mounted on a nylon loop with paratone oil. Data were collected using a Bruker APEX-II CCD
diffractometer equipped with an Oxford Cryosystems low-temperature device, operating at T =
°
1
73(2) K. Data were measured using  of -0.50 per frame for 25.09 s using MoK radiation (sealed

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tube, 50 kV, 40 mA). The total number of runs and images was based on the strategy calculation from
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the program COSMO (BRUKER, V1.61, 2009). The actually achieved resolution was  = 25.374.
Cell parameters were retrieved using the SAINT (Bruker, V8.34A, 2013) software and refined using
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35
SAINT (Bruker, V8.34A, 2013) on 9540 reflections, 20 % of the observed reflections. Data reduction
was performed using the SAINT (Bruker, V8.34A, 2013) software, which corrects for Lorentz
polarization. The final completeness is 100.00 out to 25.374 in . The absorption coefficient  of this
material is 3.113 at this wavelength ( = 0.71073) and the minimum and maximum transmissions are
0.4921 and 0.9478. The structure was solved in the space group Pca2 (# 29) by Intrinsic Phasing with
1
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the ShelXT structure solution program. The structure was refined by Least Squares using version
3
7
38
2
014/6 of XL incorporated in Olex2. All non-hydrogen atoms were refined anisotropically.
Hydrogen atom positions were calculated geometrically and refined using the riding model.
General Procedure for the Preparation of O-Benzyl Carbamates 4. Method A. A mixture of the aryl
amine (60.00 mmol) and NaHCO (10.08 g, 120.00 mmol) in water (125 mL) and acetone (250 mL) was
3
cooled to 0 °C, and then treated with benzyl chloroformate (12.28 g, 10.28 mL, 72.00 mmol) over 10
min. The mixture was stirred for 1 h at 0 °C and then the cooling bath was removed. Stirring was
continued at ambient temperature overnight. Most of the acetone was then removed by rotary
evaporation under reduced pressure and the remaining mixture poured into water (200 mL) and
extracted with either EtOAc or CH Cl . The combined organic extracts were washed with saturated aq.
2
2
NaHCO , followed by brine, dried (Na SO ), filtered and concentrated under reduced pressure. The
3
2
4
crude residue was then purified by recrystallization or silica gel chromatography to provide the title
carbamate in excellent yield.
Method B. To dry THF (40 mL) under argon or nitrogen was added the aryl amine (6.65 mmol),
powdered K CO (1.06 g, 7.68 mmol), and, dropwise, benzyl chloroformate (1.19 g, 1.00 mL, 6.98
2
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mmol). After stirring overnight at ambient temperature, the bulk of the solvent was removed by rotary
evaporation under reduced pressure. The resulting paste or solid residue was combined with toluene (50
mL) and the mixture heated to boiling and then filtered gravitationally while hot. Upon cooling, the
desired title carbamate typically crystallized from the solution, was isolated by vacuum filtration, and
dried under reduced pressure to give good yields of the desired material. In some cases, a second crop
was pursued or, alternatively, the filtrate was concentrated under reduced pressure and purified by
chromatography over silica gel to provide additional title compound.
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Benzyl N-(3,4,5-trifluorophenyl)carbamate (4f). Prepared using Method A. White solid (1.125 g,
1
9
8%): mp 93-96 C; H NMR (400 MHz, CDCl )  7.38 (s, 5H), 7.07-7.10 (m, 2H), 6.71 (s, 1H), 5.19
3
13
1
(
s, 2H); C{ H} NMR (100 MHz, CDCl )  152.9, 152.5, 152.5, 152.4, 152.4, 150.1, 150.0, 150.0,
3
1
49.9,137.3, 137.2, 137.0, 135.4, 134.9, 134.7, 134.6, 133.6, 133.6, 133.5, 133.5, 133.4, 133.4, 128.7,
-
1
128.6, 128.4, 103.1, 102.8, 67.5; IR (neat) 3323, 3067, 2959, 1706, 1627, 1544, 1433, 1249, 1042 cm ;
+
HRMS (ESI) m/z: [M – H] Calcd for C H F NO 280.0585; Found 280.0593.
1
4
9
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2
Benzyl N-[3,5-bis-(trifluoromethyl)phenyl]carbamate (4h). Prepared using Method A. White solid
1
(1.144 g, 75%): mp 92-93 C; H NMR (400 MHz, CDCl )  7.89 (s, 2H), 7.56 (s, 1H), 7.37-7.41 (m,
3
13
1
5
1
H), 6.96 (s, 1H), 5.24 (s, 2H); C{ H} NMR (100 MHz, CDCl )  152.9, 139.3, 135.3, 132.8, 132.6,
3
32.3, 132.0, 128.7, 128.7, 128.6, 128.4, 127.7, 127.0, 126.3, 124.1, 122.0, 118.3, 116.8, 67.7; IR (neat)
-1
+
3318, 3108, 1710, 1553, 1388, 1280, 1223, 1179, 1134 cm ; HRMS (ESI) m/z: [M – H] Calcd for
C H F NO 362.0616; Found 362.0618.
1
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10
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2
General Procedure for the Synthesis of N-Allyl Carbamates 5. Method A. To a cooled (0 C)
solution of the aryl or heteroaryl carbamate (5.00 mmol) in dry THF (50 mL) under N was added NaH
2
(60% dispersion in mineral oil, 0.220 g, 5.50 mmol) in small portions. After stirring for 30-60 min under
N the reaction mixture was first treated with n-Bu NI (0.185 g, 0.50 mmol) and then with allyl bromide
2
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(0.617 g, 0.441 mL, 5.10 mmol). The cooling bath was then removed and the reaction mixture stirred at
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ambient temperature until TLC analysis (hexane/EtOAc) revealed the reaction to be complete. The
reaction mixture was then cooled (0 C) and carefully treated with H O (2 mL) to quench any unreacted
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NaH. The mixture was transferred to a separatory funnel with CH Cl (100 mL) and washed with H O
2
2
2
(
2 x 50 mL) and brine (50 mL). The organic layer was dried (Na SO ), filtered and concentrated under
2 4
reduced pressure to give the crude allylated product. Chromatography on silica gel, eluting with
hexane/EtOAc, afforded, after combining appropriate fractions and concentration under reduced
pressure, generally high yields of the targeted allylated product.
Method B. To a solution of the aryl or heteroaryl carbamate (1.37 mmol) in dry DMF (20 mL)
under N was added CsCO (1.341 g, 4.11 mmol), n-Bu NI (0.051 g, 0.14 mmol) and then allyl bromide
2
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(
0.498 g, 0.356 mL, 4.11 mmol). The resultant mixture was warmed to 40 C and stirred under N until
2
TLC analysis (hexane/EtOAc) revealed the reaction to be complete. The reaction mixture was cooled to
ambient temperature, treated with H O (44 mL), and then extracted with 1:1 hexane/Et O (3 x 100 mL).
2
2
The combined organic extracts were washed once with H O and brine, dried (Na SO ), filtered and
2
2
4
concentrated under reduced pressure to give the crude allylated product. Chromatography on` silica gel,
eluting with hexane/EtOAc, afforded, after combining appropriate fractions and concentration under
reduced pressure, generally high yields of the targeted allylated product.
1
N-Allyl-N-(benzyloxycarbonyl)aniline (5a) (Method A): oil (1.332 g, 97%); H NMR (400 MHz,
CDCl )  7.20-7.35 (m, 10H), 5.85-5.95 (m, 1H), 5.16 (s, 2H), 5.11-5.16 (m, 2H), 4.27 (d, J = 5.8 Hz,
3
1
3
1
2
H); C{ H} NMR (100 MHz, CDCl )  155.2, 136.6, 133.7, 128.8, 128.4, 127.8, 127.6, 126.8, 126.5,
3
-
1
117.1, 67.2, 53.3; IR (neat) 3064, 3033, 2952, 1706, 1598, 1496, 1398, 1275, 1230, 1145, 1019 cm ;
+
HRMS (ESI) m/z: [M + H] Calcd for C H NO 268.1338; Found 268.1344.
1
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N-Allyl-N-(benzyloxycarbonyl)-2-methylaniline (5b) (Method A): oil (mixture of rotamers, 0.645 g,
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9%); H NMR (400 MHz, CDCl )  7.08-7.42 (m, 9H), 5.87-5.97, (m, 1H), 5.05-5.23, (m, 4H), 4.40
3
1
3
1
(dd, J = 6.0 and 7.1 Hz, 1H), 3.94 (dd, J = 6.7 and 6.8 Hz, 1H), 2.14, 2.22 (s, s, 3H); C{ H} NMR
0
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2
3
4
5
6
7
8
9
0
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2
3
4
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7
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9
0
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4
5
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3
4
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9
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(
100 MHz, CDCl )  155.4. 140.1, 136.8, 136.0, 133.2, 130.8, 128.4, 128.3, 127.7, 127.6, 127.4, 126.5,
3
1
1
2
18.1, 67.0, 53.1, 31.0, 17.7; IR (neat) 3067, 3032, 2952, 2925, 2853, 1705, 1602, 1583, 1494, 1399,
-1
+
297, 1276, 1148, 1017 cm ; HMRS (ESI) m/z: [M + H] Calcd for C H NO 282.1494; Found
1
8
20
2
82.1497.
N-Allyl-N-(benzyloxycarbonyl)-2,6-dimethylaniline (5c) (Method B): oil (mixture of rotamers, 0.320
1
g, 73%); H NMR (400 MHz, CDCl )  7.03 – 7.43 (m, 8H), 5.89 – 6.00 (m, 1H), 5.02 – 5.23 (m, 4H),
3
1
3
1
4
.09 (dd, J = 7.8 and 7.8 Hz, 2H), 2.13, 2.19 (ss, 6H); C{ H} NMR (100 MHz, CDCl )  155.4, 139.1,
3
136.8, 136.2, 136.1, 133.6, 133.2, 128.6, 128.5, 128.3, 128.2, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4,
1
1
18.3, 118.1, 67.3, 66.9, 53.0, 52.8, 29.7, 18.4; IR (neat) 3067, 3032, 2956, 2925, 1704, 1396, 1295,
-1
+
280, 1145, 1011 cm ; HRMS (ESI) m/z: [M + H] Calcd for C H NO 296.1650; Found 296.1657.
1
9
22
2
1
N-Allyl-N-(benzyloxycarbonyl)-4-bromoaniline (5d) (Method B): oil (0.190 g, 83%); H NMR (400
MHz, CDCl )  7.44 (d, J = 7.8 Hz, 2H) 7.25 – 7.35 (m, 5H), 7.11 (d, J = 7.8 Hz, 2H) 5.83 – 5.92 (m,
3
1
3
1
1
H), 5.10 – 5.16 (m, 4H), 4.09 (d, J = 5.8 Hz, 2H); C{ H} NMR (100 MHz, CDCl )  154.9, 136.3,
3
133.4, 131.9, 128.4, 128.0, 127.8, 125.5, 117.4, 105.0, 67.5, 53.1; IR (neat) 3087, 3067, 3033, 1710,
-1
+
1
643, 1587, 1491, 1392, 1282, 1231, 1147, 1009 cm ; HRMS (ESI) m/z: [M + H] Calcd for
C H BrNO 346.0443; Found 346.0449.
1
7
17
2
1
N-Allyl-N-(benzyloxycarbonyl)-4-iodoaniline (5e) (Method A): oil (0.267 g, 96%); H NMR (400
MHz, CDCl )  7.62 -7.65 (m, 2H), 7.25 – 7.35 (m, 5H), 6.99 (d, J = 8.1 Hz, 2H), 5.82 – 5.92 (m, 1H),
3
1
3
1
5
.10 – 5.16 (m, 4H), 4.25 (d, J = 4.8 Hz, 2H); C{ H} NMR (100 MHz, CDCl )  154.9, 141.8, 137.9,
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36.3, 133.4, 128.5, 128.0, 127.8, 117.4, 67.5 53.1, IR (neat) 3063, 3032, 2922, 2849, 1706, 1584, 1487,
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
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2
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5
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-
1
+
1
407, 1388, 1280, 1229, 1146, 1005 cm ; HRMS (ESI) m/z: [M + H] Calcd for C H INO 394.0304;
17 17 2
Found 394.0310.
0
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N-Allyl-N-(benzyloxycarbonyl)-3,4,5-trifluoroaniline (5f) (Method B): oil (0.475 g, 83%); H NMR
(
400 MHz, CDCl )  7.32 -7.36 (m, 5H), 6.93 (br s, 2H), 5.82 – 5.91 (m, 1H), 5.12 - 5.19 (m, 4H), 4.24
3
1
3
1
(d, J = 5.6 Hz, 2H); C{ H} NMR (100 MHz, CDCl )  154.6, 152.1, 152.0, 151.9, 151.8, 149.6,
3
1
3
49.5, 149.4, 149.4, 135.9, 132.9, 128.5, 128.2, 127.9, 117.7, 111.0, 67.9, 53.0; IR (neat) 3087, 3068,
-1
+
036, 2952, 1712, 1622, 1529, 1449, 1409, 1326, 1234, 1143, 1046 cm ; HRMS (ESI) m/z: [M + H]
Calcd for C H F NO 322.1055; Found 322.1059.
1
7
15
3
2
1
N-Allyl-N-(benzyloxycarbonyl)-2,3,4-trifluoroaniline (5g) (Method A): oil (0.954 g, 89%); H NMR
(
400 MHz, CDCl )  7.23 - 7.40 (m, 5H), 6.90 - 6.96 (m, 2H), 5.82 – 5.92 (m, 1H), 5.10 - 5.15 (m, 4H),
3
13
1
4
1
3
.25 (d, J = 5.8 Hz, 2H); C{ H} NMR (100 MHz, CDCl )  154.8, 151.6, 151.5, 149.1, 148.9, 136.1,
3
32.7, 128.5, 128.1, 127.5, 123.4, 123.4, 123.3, 123.3, 118.5, 118.4, 111.5, 67.8, 53.0; IR (neat) 3087,
-1
067, 3036, 2956, 2925, 2853, 1714, 1614, 1514, 1498, 1402, 1306, 1242, 1149, 1021 cm ; HRMS
+
(
ESI) m/z: [M + H] Calcd for C H F NO 322.1055; Found 322.1060.
1
7
15
3
2
N-Allyl-N-(benzyloxycarbonyl)-3,5-bis(trifluoromethyl)aniline (5h) (Method A): oil (1.106 g, 85%);
1
H NMR (400 MHz, CDCl )  7.79 (s, 2H) 7.72 (s, 1H), 7.30 – 7.38 (m, 5H), 5.89 – 5.99 (m, 1H), 5.18
3
13
1
-
5.24 (m, 4H), 4.38 (d, J = 5.6 Hz, 2H); C{ H} NMR (100 MHz, CDCl )  154.4, 146.9, 143.7,
3
1
35.7, 132.9, 132.6, 132.3, 131.9, 131.6, 128.5, 128.3, 128.0, 126.0, 124.4, 121.7, 119.4, 117.8, 68.1,
52.7; IR (neat) 3091, 3069, 3035, 2956, 1716, 1618, 1472, 1398, 1342, 1278, 1261, 1182, 1137, 1045
-1
+
cm ; HRMS (ESI) m/z: [M + H] Calcd for C H F NO 404.1085; Found 404.1093.
1
9
16
6
2
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N-Allyl-N-(benzyloxycarbonyl)-3-fluoro-4-nitroaniline (5i) (Method A): oil (0.284 g, 71%); H NMR
(
500 MHz, CDCl )  8.01 (t, J = 8.7 Hz, 1H) 7.33 (s, 6H), 7.23 (d, J = 9.0 Hz, 1H), 5.83 – 5.92 (m, 1H),
3
13
1
5
1
3
.13 - 5.21 (m, 4H), 4.36 (br s, 2H); C{ H} NMR (125 MHz, CDCl )  156.8, 154.7, 154.1, 149.0,
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0
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0
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35.4, 132.6, 128.7, 128.5, 128.2, 126.4, 119.7, 119.7, 117.5, 113.9, 113.7, 68.4, 52.3; IR (neat) 3087,
-1
+
066, 3032, 2954, 1714, 1609, 1521, 1496, 1392, 1342, 1228, 1144 cm ; HRMS (ESI) m/z: [M + H]
Calcd for C H FN O 331.1094; Found 331.1100.
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4
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N-Allyl-N-(benzyloxycarbonyl)-4-bromo-3-methoxyaniline (5j) (Method A): oil (0.237 g, 48%); H
NMR (400 MHz, CDCl )  7.46 (d, J = 8.4 Hz, 1H) 7.26 – 7.38 (m, 5H), 6.79 (br s, 1H), 6.72 (d, J =
3
13
1
8
.4 Hz, 1H), 5.85 – 5.95 (m, 1H), 5.12 - 5.17 (m, 4H), 4.26 (d, J = 4.5 Hz, 2H), 3.78 (s, 3H); C{ H}
NMR (125 MHz, CDCl )  155.9, 154.9, 136.3, 133.6, 133.0, 128.5, 128.1, 127.9, 119.6, 117.4, 111.1,
3
109.2, 67.5, 56.2, 53.3; IR (neat) 3087, 3067, 3032, 3008, 2939, 1706, 1587, 1488, 1449, 1392, 1244,
-1
+
1
3
211, 1145, 1056, 1024 cm ; HRMS (ESI) m/z: [M + H] Calcd for C H BrNO 376.0549; Found,
18 19 3
76.0557.
N-Allyl-N-(benzyloxycarbonyl)-3-trifluoromethyl-4-methoxyaniline (5k) (Method A): oil (0.280 g,
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6
5
9%); H NMR (400 MHz, CDCl )  7.25 - 7.43 (m, 7H), 6.94 (d, J = 8.9 Hz, 1H) 5.83 - 5.91 (m, 1H),
3
1
3
1
.10 - 5.19 (m, 4H), 4.23 (d, J = 5.8 Hz, 2H), 3.38 (s, 3H); C{ H} NMR (125 MHz, CDCl )  155.9,
3
155.2, 136.3, 133.3, 131.8, 128.4, 128.0, 127.7, 124.4, 122.1, 120.0, 119.3, 119.1, 118.8, 118.5, 117.8,
1
12.3, 105.0, 67.5, 56.1, 53.4; IR (neat) 3087, 3067, 3036, 3012, 2956, 2936, 2845, 1708, 1621, 1589,
-1
+
1
508, 1435, 1322, 1279, 1259, 1134, 1057 cm ; HRMS (ESI) m/z: [M + H] Calcd for C H F NO
19 19 3 3
366.1317; Found 366.1324.
1
N-Allyl-N-(benzyloxycarbonyl)-3,4-dimethoxyaniline (5l) (Method B): oil (0.473 g, 96%); H NMR
(
400 MHz, CDCl )  7.26 - 7.39 (m, 5H), 6.72 -7.82 (m, 3H), 5.87 - 5.97 (m, 1H), 5.12 - 5.19 (m, 4H),
3
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The Journal of Organic Chemistry
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.24 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.80 (s,3H); C{ H} NMR (125 MHz, CDCl )  155.4, 148.8,
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9
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47.6, 136.7, 133.8, 128.4, 127.9, 127.6, 119.0, 117.3, 118.8, 67.2, 55.9, 55.8, 53.7; IR (neat) 3063,
-1
3032, 3000, 2956, 2935, 2834, 1702, 1594, 1514, 1451, 1399, 1261, 1234, 1135, 1027 cm ; HRMS
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+
(
ESI) m/z: [M + H] Calcd for C H NO 328.1549; Found 328.1555.
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N-Allyl-N-(benzyloxycarbonyl)-3-fluoro-4-(4-morpholinyl)aniline (5m) (Method A): gum (1.382 g,
1
95%); H NMR (400 MHz, CDCl )  7.32 (br s, 5H), 6.95 (br s 2H), 6.86 (t, J = 9.1 Hz, 1H), 5.84 -
3
5
.92 (m, 1H), 5.16 (br s, 3H), 5.12 (d, J = 7.8 Hz, 1H), 4.23 (d, J = 5.5 Hz, 2H), 3.87 (s, 4H) 3.08 (s,4H);
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3
1
C{ H} NMR (125 MHz, CDCl )  155.9, 155.2, 154.0, 138.4, 136.4, 133.4, 128.4, 128.0,
3
1
1
27.7,118.2, 117.4, 67.4, 67.0, 53.3, 50.9; IR (neat) 3034, 3068, 2960, 2895, 2856, 2828, 1708, 1573,
-1
+
514, 1449, 1398, 1301, 1253, 1119, 1052, 923 cm ; HRMS (ESI) m/z: [M + H] Calcd for
C H FN O 371.1771; Found 371.1779.
21 24
2
3
1
N-Allyl-N-(benzyloxycarbonyl)-2-aminopyridine (5n) (Method A): oil (0.561 g, 95%); H NMR (400
MHz, CDCl )  8.37 (d, J = 4.7 Hz, 1H), 7.59 – 7.68 (m, 2H), 7.29 - 7.35 (m, 5H), 6.99 – 7.02 (m, 1H),
3
5
.94 (tdd, J = 5.4, 10.5, 17.0 Hz, 1H), 5.22 (s, 2H), 5.05 – 5.15 (m, 2H), 4.63 (d, J = 5.4Hz, 2H).
13
1
C{ H} NMR (100 MHz, CDCl )  154.9, 153.8, 147.7, 137.2, 136.1, 134.1, 128.4, 128.1, 127.9, 119.9,
3
1
19.4, 116.3, 67.6, 49.1; IR (neat) 3067, 3032, 2954, 2927, 2857, 1714, 1646, 1587, 1466, 1395, 1362,
-1
+
1303, 1232, 1147, 1062, 1033, 993, 920, 782 cm ; HRMS (ESI) m/z: [M + H] Calcd for C H N O
2
1
6
17
2
2
69.1290; Found 269.1288.
1
N-Allyl-N-(benzyloxycarbonyl)-3-aminopyridine (5o) (Method A): oil (0.441 g, 75%); H NMR (400
MHz, CDCl )  8.54 (s, 1H), 8.44 (d, J = 3.4 Hz, 1H), 7.21 - 7.32 (m, 1H), 7.21 - 7.32 (m, 6H), 5.84 -
3
.94 (m, 1H), 5.12 - 5.17 (m, 4H), 4.29 (d, J = 5.5 Hz, 2H); 13C{ H} NMR (100 MHz, CDCl )  154.8,
1
5
3
1
47.8, 147.2, 138.5, 136.0, 133.8, 133.0, 128.4, 128.1, 127.8, 123.4, 117.7, 67.7, 53.0; IR (neat) 3036,
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