Development of a General Protocol to Prepare 2H-1,3-Benzoxazine Derivatives

Article abstract of DOI:10.1021/acs.oprd.7b00209

A practical synthesis and detailed development process of 2H-1,3-benzoxazine derivatives catalyzed by aldimine and trifluoromethanesulfonic acid is described. A broad range of substrates with diverse steric and electronic properties were explored. Aliphatic/aromatic/heteroaromatic substrates all proceed well under conditions which have been optimized into a robust, scalable process.

Full text of DOI:10.1021/acs.oprd.7b00209

Subscriber access provided by UNIVERSITY OF ADELAIDE LIBRARIES
Full Paper
Development of a General Protocol to Prepare 2H-1, 3-Benzoxazine Derivatives
Ji Qi, Steven F. Oliver, Wensong Xiao, Licheng Song, and Karel M. Jos Brands
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00209 • Publication Date (Web): 23 Aug 2017
Downloaded from http://pubs.acs.org on August 23, 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.
Organic Process Research & Development 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 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Development of a General Protocol to Prepare 2Hꢀ1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀBenzoxazine Derivatives
Ji Qi,*,†, ǁ Steven F. Oliver,‡, ǁ Wensong Xiao,§ Licheng Song,§ Karel M. J. Brandsǁ
†
Department of Process Research and Development, MSD R&D (China) Co., Ltd,. Building 21
Rongda Road, Wangjing R&D Base, Zhongguancun Electronic Zone West Zone, Beijing
100012, China
‡ Department of Process Research and Development, Merck Sharp & Dohme, Hertford Road,
Hoddesdon, Hertfordshire EN11 9BU, United Kingdom
§ Department of Synthetic Chemistry, Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing,
100176, China
ǁ Department of Process Research and Development, Merck Research Laboratories, P.O. Box
2000, Rahway, New Jersey 07065, USA
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 31
1
2
3
4
5
6
7
8
9
ABSTRACT: A practical synthesis and detailed development process of 2Hꢀ1, 3ꢀbenzoxazine
derivatives catalyzed by aldimine and trifluoromethanesulfonic acid is described. A broad range
of substrates with diverse steric and electronic properties were explored.
Aliphatic/aromatic/heteroaromatic substrates all proceed well under conditions which have been
optimized into a robust, scalable process.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Keywords: 2Hꢀ1,3ꢀbenzoxazine, Aldimine, Acid catalysis, Hemiaminal
ꢀ INTRODUCTION
2Hꢀ1,3ꢀbenzoxazine and derivatives are interesting structural motifs present in natural
products1, agricultural bactericides2 and pharmaceuticals3. As shown in Figure 1, a 2Hꢀ1,3ꢀ
benzoxazine substructure is present in the key precursor for the enantioselective Pdꢀcatalyzed Cꢀ
N coupling4 to the benzoxazinoꢀindole chiral hemiaminal core of elbasvir 5, a potent inhibitor of
the HCV NS5A protein which is currently undergoing lateꢀstage clinical trials. With only a
handful of syntheses of this structural motif reported in the literature,6 an efficient and general
synthesis of 2Hꢀ1,3ꢀbenzoxazines was desired. Herein, we present the development of a practical
methodology with broad substrate scope and scalability.
ACS Paragon Plus Environment

Page 3 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. 2Hꢀ1,3ꢀbenzoxazine natural products and related bioactive molecules.
ꢀ Results and discussion
Our preliminary attempts to use 1 and benzaldehyde to form 2Hꢀ1,3ꢀbenzoxazine 2 under
standard acidꢀcatalyzed conditions (Figure 2) gave an unsatisfactory reaction profile. The desired
product 2 was generated in only 20% yield with formation of a significant amount overꢀreacted
aldol product 3. On a structurallyꢀrelated project within Merck, we had successfully used pꢀOMe
aldimine and TFA for hemiaminal formation and in that case, the reaction was driven to
completion by the crystallization of the aniline TFA salt. While this same aldimine method did
not translate directly to compound 2 (Figure 2), it did provide us with a lead for development.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 31
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Early attempts of 2Hꢀ1,3ꢀbenzoxazines formation
Our investigations into aldimineꢀmediated 2Hꢀ1,3ꢀbenzoxazines formation started with
the evaluation of several additives7 from which triflic acid (TfOH) and triflic anhydride (Tf2O)
appeared the most promising. The reactions were driven to completion by removal of water with
molecular sieves. Six aldimines, differing in their paraꢀsubstituents were prepared (4a-4f, R =
OMe, H, Me, Cl, F, CF3) and screened (Table 1). The 4ꢀFꢀaldimine 4e gave high product ratios;
78% and 73% (LC area %) with Tf2O and TfOH, respectively (entry 7 and entry 8).
Interestingly however, the 4ꢀOMe aldimine 4a led to the highest conversions (Entry 11 and 12),
albeit with significant formation of imine byꢀproduct 5a. This observation led to the hypothesis
that the presence of excess benzaldehyde could suppress the formation of imine byꢀproduct 5a.
Gratifyingly, the addition of 0.5 equiv. benzaldehyde to the 4ꢀOMe aldimine reactions yielded
>95 LC area% of desired product (Entry 13 and 14). In conclusion, both 4ꢀF and 4ꢀOMe
aldimines (4e and 4a) performed well as did both triflate sources. 8 However, for further
development we decided to focus only on the less expensive triflic acid.
Table 1. Initial screening with different aldimines
ACS Paragon Plus Environment

Page 5 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
Catalyst
Result (LC area %)
4a-4f
R=
1
10
11
15
5
2
3
7
5a-5e
15(5b)
26(5b)
20 (5c)
51 (5c)
ꢀꢀ
1
2
3
4
5
6
7
H (4b)
H (4b)
Tf2O
TfOH
Tf2O
TfOH
Tf2O
TfOH
Tf2O
56
45
59
44
87
50
78
9
CH3 (4c)
CH3 (4c)
Cl (4d)
Cl (4d)
F (4e)
10
8
ꢀꢀ
8
16
12
ꢀꢀ
3
ꢀꢀ
ꢀꢀ
8
9
F (4e)
TfOH
Tf2O
23
2
73
62
ꢀꢀ
ꢀꢀ
ꢀꢀ
CF3 (4f)
23
10
11
CF3 (4f)
TfOH
Tf2O
30
1
40
69
14
2
ꢀꢀ
OMe(4a)
24(5a)
12
OMe(4a)
OMe(4a)
TfOH
Tf2O
3
1
49
95
ꢀꢀꢀ
3
48(5a)
13 a
ꢀꢀ
14 a
OMe(4a)
TfOH
ꢀꢀ
96
2
2 (5a)
a Reactions were carried out with 0.5 equiv. of benzaldehyde
Since the 4ꢀOMe and 4ꢀF aldimines (4a and 4e) appeared the most promising, we decided to
study only these two more extensively. Solvent, equivalents of triflic acid and aldimine were
evaluated. Table 2 shows that this screening provided a distinct pattern. While both 4a and 4e
performed similarly in chlorinated solvents (CH2Cl2 and 1, 2ꢀDichloroethane) in the presence of
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 31
1
2
3
4
5
6
7
8
9
excess aldimine, 4a was significantly better at subꢀstoichiometric levels of aldimine (entries 4 vs.
9). Likewise, when the triflic acid charge was lowered from 0.3 to 0.05 equivalents, 4a (4ꢀOMe)
again outperformed 4e (4ꢀF, entries 5 vs. 10). Higher level of overꢀreacted Aldol by product 3
was observed in reactions with 4e (entry 9 and 10 vs. Entry 4 and 5). This could be due to the
higher reactivity of electron deficient aldimine 4e (4ꢀF) towards Aldol addition.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Comparison of 4ꢀF aldimine vs 4ꢀOMe aldimine a
Result（LC area%）
Aldimine
4a, 4e
Equiv.
aldimine
Equiv.
TfOH
Entry
Solvent
1
1
2
3
8
5a, 5e
1
2
3
4
5
6
7
8
ClCH2CH2Cl
CH2Cl2
1.2
1.2
1.2
0.6
1.2
1.2
1.2
1.2
0.3
0.3
0.3
0.3
0.05
0.3
0.3
0.3
86
91
68
94
94
91
90
73
ꢀꢀ
4a
4a
4a
4a
4a
4e
4e
4e
1
4
0.5 (5a)
18
1
2
1.3 (5a)
Toluene
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
2
1.0 (5a)
0.5
0.8
0.9
7
4
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
7
5
6
Toluene
9
ClCH2CH2Cl
ClCH2CH2Cl
0.3
3
1
77
75
13
4e
4e
0.6
10
1.2
18 0.2 (5e)
0.05
a Reactions were carried out with 1 (1 equiv.), benzaldehyde (1.1 equiv.), aldimine, TfOH and
4Å MS (100 wt/wt %) in solvent (0.14 M of 1) at room temperature for 18h.
All previous experiments had been run in the presence of 100 wt% of 4A molecular sieves
relative to the substrate and at relatively low concentration (0.14 M of 1). With conditions in
hand to form the desired product cleanly and in high yield, we decided to make the process more
practical by minimizing the quantities of molecular sieves and solvent. The results are shown in
Table 3. We first looked at different loadings (100, 50 and 0 wt/wt%) of molecular sieves at 0.14
M of 1 (entry 1 to 3). It was discovered that there was no significant impact on reaction
performance when the molecular sieves were reduced to as low as 50 wt/wt%. A similar trend
ACS Paragon Plus Environment

Page 7 of 31
Organic Process Research & Development
1
2
3
4
5
6
was also observed with reactions conducted at higher concentration (entry 4 to 7). In all cases the
reaction mixture remained a mobile slurry.
7
8
9
Table 3. Optimization of molecular sieves loading and reaction concentration a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4A
MS
(wt %)
Conc.
of 1
(M)
Result（LC area %）
Entry
1
3
2
3
2
5a
2
1
2
3
4
5
0.14
0.14
0.14
0.28
0.28
93
89
16
94
86
100
50
4
2
6
15
2
0.8
2
22
2
0
100
50
2
2
7
6
7
10
2
67
90
2
3
21
6
0
0.28
0.4
50
a
Reactions were carried out with 1 (1 equiv.), benzaldehyde (1.1 equiv.), aldimine 4a (1.2
equiv.), TfOH (0.3 equiv) and 4Å .MS in CH2Cl2 at room temperature for 18h.
As noted previously, the use of subꢀstoichiometric quantities of aldimine was well tolerated
and the reaction profile appeared to become cleaner at lower equivalents (Table 4), although the
reaction was significantly slower when only 0.1 equivalent 4a was used (entries 2 vs. 5 and 6).
TfOH could also be used at lower concentrations (entry 2 vs. 3), but at less than 5 mol%, there
was an adverse impact on the rate of reaction (entries 3 vs. 4). Our primary goal was to minimize
the waste generated in the process, and we ultimately found that the optimal balance to achieve a
high conversion, a clean profile and an acceptable reaction rate was the use of 0.1 equiv.
aldimine 4a and 0.2 equiv. TfOH.
Table 4. Optimization of equiv. of Acid and equiv. of Aldimine 4aa
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 31
1
2
3
4
5
6
7
8
9
Result（LC area%）
Equiv. Equiv.
1
2
3
5a
Entry
1
TfOH
4a
1.2
0.3
2
2
90
95
95
83
3
2
3
2
6
2
3
4
0.3
0.9
0.6
0.5
0.5
0.5
0.5
1
0.05
0.01
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5b
0.3
0.2
5
9
93
88
2
2
0.7
0.7
0.1
0.1
(48h)
6b
(48h)
a Reactions were carried out with 1 (1 equiv), benzaldehyde (1.1 equiv), aldimine, TfOH and 4Å
b
MS (50 wt/wt %) in CH2Cl2 (0.4 M of 1) at room temperature for 18h.
Slow reaction,
incomplete conversion at 18h. The 48h data point is reported.
Considering one of the key principles of green chemistry, we sought to move away from
chlorinated solvents to develop a more environmentally acceptable process. 9 Table 5 shows the
impact of a range of common solvents at ambient temperature in comparison with the previously
used CH2Cl2 (entry 1 to 5). Gratifyingly, both 2ꢀMeTHF and IPAc showed a significantly
improved reaction rate and profile.
Table 5. Development of an environmental friendly process with greener solvents a
Result (LC area %)
Entry
Solvent
Temp
1
26
88
2
2
3
1
ꢀꢀ
5
3
3
5a
ꢀꢀ
1
2
3
4
5
CH2Cl2
Toluene
2-MeTHF
IPAc
rt
rt
rt
rt
rt
72
12
91
92
70
ꢀꢀ
0.5
0.2
1
3
26
MeCN
a Reactions were carried out with imine 1 (1 equiv), benzaldehyde (1.1 equiv), aldimine 4a (0.1
equiv), TfOH (0.2 equiv) and 4Å MS (50 wt/wt%) in solvent (0.4 M of 1) for 18h.
With the knowledge that product 2 could be crystallized from MeOH with high purity and
recovery, the 2ꢀMeTHF system was further optimized due to its highly efficient binary azeotrope
ACS Paragon Plus Environment

Page 9 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
with MeOH that could potentially be exploited to avoid an aqueous workꢀup. All reaction
parameters with this solvent system (including alternative dehydrating agents) were evaluated
again.10 But the previous optimal conditions (0.1 equiv. aldimine, 0.2 equiv. TfOH) still gave the
best overall profile. The concentration could be increased to 0.46 M and the loading of molecular
sieves was increased to 60wt% to achieve a more robust process for scaleꢀup. In the final
optimized process (demonstrated at 500 g scale, Figure 3) the molecular sieves were filtered at
the end of reaction. After an aqueous wash to remove TfOH, the solvent is then switched from 2ꢀ
MeTHF to MeOH. This led to the crystallization of the product which can be isolated in 83%
yield with 97% LC purity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. 500g Demonstration of 2Hꢀ1,3ꢀbenzoxazine 2 formation
With these optimized conditions in hand, we then looked at the scope of this new 2Hꢀ1,3ꢀ
benzoxazine formation methodology. First, a number of aromatic aldehydes/aldimines with
different electronic and steric effects were evaluated (Table 6, 2, 8a to 8g). Under the standard
conditions (method a11), all reactions proceeded smoothly and generated the desired product in
moderate to good yields (60ꢀ80%). We then studied a heteroaromatic system (8h) and three
different aliphatic aldehydes/aldimines (8i to 8k). The performance of the standard protocol was
inferior in these cases. However, a change in reaction solvent and catalytic additives (method b:
with TFA in CH2Cl2 and method c: with TfOH in CH2Cl2) gave the desired products in more
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 31
1
2
3
4
5
6
7
8
9
acceptable yields. Finally, several substitution patterns on the left aromatic ring were studied (8l
and 8m). In general, without any further attempts to optimize yield our general 2Hꢀ1,3ꢀ
benzoxazine methodology worked well for these substrates.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 6. 2Hꢀ1, 3ꢀBenzoxazine formation with different phenol imines and aldehydes
a Method a: reactions were carried out with 1 (1 equiv), aldehyde (1.1 equiv), aldimine (0.1
b
equiv), TfOH (0.2 equiv) and 4Å MS (50 wt/wt %) in MeTHF (0.4 M of 1) at rt for 18h.
ACS Paragon Plus Environment

Page 11 of 31
Organic Process Research & Development
1
2
3
4
5
6
Method b: reactions were carried out with 1 (1 equiv), aldehyde (1.1 equiv), aldimine (1 equiv),
2,2,2ꢀtrifluoroacetic acid (0.2 equiv) and 4Å MS (100 wt/wt %) in CH2Cl2 (0.28 M of 1) at rt for
7
8
c
18h. Method c: reactions were carried out with 1 (1 equiv), aldehyde (1.1 equiv), aldimine (1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
equiv or 0.2 equiv), TfOH (0.2 equiv) and 4Å MS (100 wt/wt %) in CH2Cl2 (0.28 M of 1) at rt
for 18h.
While we developed our general protocol with isolated aldimine for convenience, we were
eager to demonstrate that the 4ꢀmethoxyaniline could also be used in a catalytic process, thus
hopefully also providing more insight to the reaction mechanism. Four experiments were carried
out as shown in Table 7. Experiment 4 showed the exact same reaction profile as our standard
conditions (experiment 1). Experiment 2 and 3 showed slightly lower conversion and more
formation of byꢀproduct 5a, which indicated that a certain amount of mixing time of aniline and
aldehyde is required to achieve a good reaction profile.
Table 7. Studies of using of aniline instead of aldimine
Result (LC area percent %)
Exp
Conditions
1
2
8
2
3
2
1
5a
2
1
2
Aldimine preꢀformed (standard condition)
All reagents added at same time
84
68
9
Benzaldehyde，aniline and 4Å MS stirred
for 30min before addition of other reagents
3
4
4
2
76
84
2
2
8
2
Benzaldehyde，aniline and 4Å MS stirred
for 60min before addition of other reagents
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 31
1
2
3
4
5
6
7
8
9
Based on these observations a plausible mechanism is proposed in Figure 4. The reaction of
aniline and benzaldehyde appeared to be relatively slow under the reaction conditions and more
than 30 min were required to achieve high conversion to aldimine, and minimization of
formation of 5a. Under acidic conditions, the activated aldimine could presumably be attacked
by 1 to form a hemiꢀaminal Int 1. Instead of releasing free aniline which would lead to more
formation of byꢀproduct 5a, we propose that Int 1 in the presence of the excess of benzaldehyde
will form benzyl iminium Int 2. In the next step Int 2 will regenerate the catalytic aldimine
shuttle as well as oxonium Int 3 which will collapse into the desired product 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Proposed mechanism for 2Hꢀ1, 3ꢀbenzoxazine formation
ꢀ Conclusion
In this study, we report the details behind the development of a general set of conditions
for the formation of 2Hꢀ1, 3ꢀbenzoxazines, which are important intermediates for a class of
ACS Paragon Plus Environment

Page 13 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Merck HCV drug candidates and precursors for a novel enantioselective Pdꢀcatalyzed CꢀN
coupling.4 A broad range of substrates with diverse steric and electronic properties, including
aliphatic/aromatic/heteroaromatic ones, were evaluated under the developed conditions.
Furthermore, we have optimized conditions for the key intermediate of elbasvir into a robust and
scalable process which was demonstrated on 500 g scale.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ Experimental section
General information. All experiments described were carried out under nitrogen atmosphere.
All reagents were stored under nitrogen atmosphere prior to use in experiments. Powdered 4Å
molecular sieves (MS) was purchased from Beijing Innochem Science & Technology Co. Ltd.
and preꢀactivated in heating oven at 300°C for 20 h prior to experiments. IR spectra were
1
measured on NEXUS 670 FTꢀIR. H, and 13C NMR spectra were recorded on Bruker DPXꢀ500
NMR Spectrometers. Chemical shifts are reported in ppm relative to the residual deuterated
solvent. Reactions were monitored by reverseꢀphase HPLC on Agilent 1260 HPLC instrument
and LCMS on Agilent 1260 HPLC with 6120 Mass Spec system. High resolution mass spectra
were recorded on a Xevo G2 QTof (Waters MS Technologies) mass spectrometer by
electrospray ionization.
Synthesis
of
2-(2-(2-bromo-5-chlorophenyl)-1-iminoethyl)-5-chlorophenol
(1)
(synthetic scheme in SI): Into a 2000 mL flask was charged 2ꢀ(2ꢀbromoꢀ5ꢀchlorophenyl)
acetic acid 9 (60.4 g, 242 mmol) and trifluoromethanesulfonic acid (1.10 kg). A solution was
formed after stirring the mixture for 10 min, and then 3ꢀchlorophenol (27.1 g, 211 mmol) was
added. The solution was heated to 55 °C overnight. LCMS showed complete conversion. The
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 31
1
2
3
4
5
6
7
8
9
mixture was cooled to rt and poured into 3 kg of iceꢀwater. The suspension was stirred for 30
min and then filtered. The solid was washed with water (300 mL x 3) and then dissolved in ethyl
acetate (1000 mL). The organic layer was dried with Na2SO4, filtered and concentrated under
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
reduced
pressure.
This
resulted
in
2ꢀ(2ꢀbromoꢀ5ꢀchlorophenyl)ꢀ1ꢀ(4ꢀchloroꢀ2ꢀ
hydroxyphenyl)ethanone 10 (82.0 g, crude) as a white solid. It was used directly in the next step.
¹H NMR (500 MHz, CDCl3): δ (ppm) 12.10 (s, 1H), 7.81 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J =
8.5 Hz), 7.26 (d, 1H, J = 3.5 Hz), 7.20 (dd, 1H, J = 8.5 Hz, 2.5 Hz), 7.05 (d, 1H, J = 2.5 Hz),
6.95 (dd, 1H, J = 8.5Hz, 2.0 Hz), 4.42 (s, 2H). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 200.8,
163.3, 142.7, 135.6, 133.9, 133.6, 131.6, 130.8, 129.3, 122.9, 119.9, 118.8, 117.6, 45.2. HRMS
TOF MS (m / z): [M + H]+ calcd for [C14H9BrCl2O2 H] 358.9241; found 358.9240. FTIR(neat):
3074 (br), 1627, 1605, 1567, 1461, 1410, 1352, 1260 cmꢀ1. Spectroscopic data for 2ꢀ(2ꢀbromoꢀ5ꢀ
chlorophenyl)ꢀ1ꢀ(4ꢀchloroꢀ2ꢀhydroxyphenyl)ethanone were identical to those reported in the
literature.4 Into a 1000ml round bottom flask was placed 2ꢀ(2ꢀbromoꢀ5ꢀchlorophenyl)ꢀ1ꢀ(4ꢀ
chloroꢀ2ꢀhydroxyphenyl)ethanone 10 (82.0 g, crude), ammonia in MeOH (400 ml, ca.9 N). The
resulting mixture was stirred at room temperature overnight. The solid was filtered and washed
with MeOH (60 ml x 2), and then dried under reduced pressure to give 2ꢀ(2ꢀ(2ꢀbromoꢀ5ꢀ
chlorophenyl)ꢀ1ꢀiminoethyl)ꢀ5ꢀchlorophenol (1, 67.1 g, 187 mmol, 77 % yield). ¹H NMR (500
MHz, CDCl3): δ (ppm) 15.23 (br, 1H), 8.85 (br, 1H), 7.62 (d, 1H, J = 8.0 Hz), 7.55 (d, 1H, J =
8.5 Hz), 7.28ꢀ7.25 (m, 2H), 7.04 (d, 1H, J = 2.0 Hz), 6.85 ( dd, 1H, J = 9.0, 2.5 Hz), 4.22 (s,
2H).¹³C NMR (125 MHz, CDCl3): δ (ppm) 175.8, 164.3, 139.2, 135.0, 134.6, 134.3, 132.2,
130.1, 128.8, 123.6, 118.8, 118.3, 116.6, 42.7. HRMS TOF MS (m / z): [M + H]+ calcd for
[C14H10BrCl(37Cl)NO H] 359.9372; found 359.9377. FTIR (neat): 2597 (br), 1594, 1491, 1461,
1366 cmꢀ1. Spectroscopic data for 1 were identical to those reported in the literature.4
ACS Paragon Plus Environment

Page 15 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
General Method A for 2H-1, 3-Benzoxazine derivative synthesis: A suspension of 2.5 g of
preꢀactivated powdered 4Å MS (50 wt/wt%) in 2ꢀMethylꢀTHF (30 ml) was cooled to 0°C, and
stirred for 10min. Phenol (1, 5.00 g, 13.9 mmol), aldehyde (15.3 mmol) and the corresponding
aldimine (1.39 or 13.9 mmol) were added, and the resulting mixture was stirred for 2min
maintaining 0ꢀ5oC. Trifluoromethanesulfonic acid (0.418 g, 2.79 mmol) was added. The ice bath
was removed and reaction mixture was warmed to rt and stirred overnight. The reaction was
monitored by LCMS. The molecular sieves were filtered and washed with 2ꢀMeTHF(5 mL). The
combined organic phases were washed with 5 wt% NaHCO3 solution (25 mL), water (25 mL) ,
dried over Na2SO4 and concentrated under reduced pressure to give the crude product. Target
compounds were purified by different purification methods.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Method B for 2Hꢀ1,3ꢀBenzoxazine derivative synthesis: A suspension of 4 g of preꢀ
activated powdered 4Å MS (100 wt/wt%) and aldehyde (12.3 mmol) in CH2Cl2 (40 ml) was
stirred for 30min at rt . Phenol (1, 4.00 g, 11.1 mmol), corresponding aldimine (11.1 mmol) and
2,2,2ꢀtrifluoroacetic acid (0.254 g, 2.23 mmol) were added and the resulting mixture was stirred
at rt for 18 h. LCMS analysis showed completion of reaction. The reaction mixture was
quenched with 5 wt% NaHCO3 solution (30 mL) and then extracted with ethyl acetate (100
mL×2 ). The combined organic phases were washed with brine, dried over Na2SO4, filtered and
concentrated to obtain the crude product, which was purified by reverse phase combiꢀflash
chromatography.
General Method C for 2H-1, 3-Benzoxazine derivative synthesis: A suspension of 6 g of
preꢀactivated powdered 4Å MS (100 wt/wt%) and aldehyde (18.4 mmol) in CH2Cl2 (60 ml) was
stirred for 30 min at rt. Phenol (1, 6.00 g, 16.7 mmol), corresponding aldimine (16.7 or 3.34
mmol) and trifluoromethanesulfonic acid (0.501 g, 3.34 mmol) were added and the resulting
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 31
1
2
3
4
5
6
7
8
9
mixture was stirred at rt for 18 h. LCMS analysis showed completion of reaction. The reaction
was quenched with 5 wt% NaHCO3 solution (30 mL), and extracted with ethyl acetate (100
mL×2 ). The combined organic phases were washed with brine, dried over Na2SO4, filtered and
concentrated to obtain the crude product, which was purified by reverse phase combiꢀflash
chromatography.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of aldimine 4a-4f: Into a round bottom flask were placed
aldehyde (1 eq), aniline (0.95 eq) and toluene (10 vol). The mixture was stirred at rt overnight.
The reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated
to dryness. Then toluene (10 vol) was added and the resulting mixture was concentrated to
dryness. This process was repeated twice. The crude aldimine was used directly in the next step
without further purification.
Reaction to prepare 4-(2-Bromo-5-chlorobenzyl)-7-chloro-
2-phenyl-2H-benzo[e][1,3]oxazine 2: The reaction was carried out using general method A
with 60 wt/wt% of powdered 4Å MS and 0.1 equiv. of corresponding aldimine. The crude
product was recrystallized from MeOH (5vol) to yield 2 as a lightꢀyellow solid (82% yield). ¹H
NMR (500 MHz, CDCl3): δ (ppm) 7.55ꢀ7.52 (m, 3H), 7.42ꢀ7.34 (m, 3H), 7.30 (d, 1H, J = 3.5
Hz,) 7.29 (s, 1H), 7.12 (dd, 1H, J = 8.5Hz, 2.5 Hz), 6.95ꢀ6.91 (m, 2H), 6.57 (1H, s), 4.16 (ABq,
2H, ꢁδAB = 0.05, JAB = 16.5 Hz). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 161.5, 155.8, 139.2,
138.9, 138.1, 133.8, 133.5, 130.6, 128.8, 128.7, 128.5, 127.0, 126.3, 122.6, 121.9, 117.3, 116.2,
88.9, 40.8. HRMS TOF MS (m / z): [M + H]+ calcd for [C21H14BrCl2NO H] 445.9709; found
445.9713. FTIR(neat): 3060, 1633, 1596, 1454, 1364, 1344 cmꢀ1. Spectroscopic data for 2 were
identical to those reported in the literature.4
4-(1-(2-bromo-5-chlorophenyl)-2-phenylvinyl)-7-chloro-2-phenyl-2H-
benzo[e][1,3]oxazine 3: ¹H NMR (300 MHz, CDCl3): δ (ppm) 7.65 (d, 1H, J = 8.2 Hz), 7.62 – 7.53
ACS Paragon Plus Environment

Page 17 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(m, 2H), 7.53 – 7.43 (m, 2H), 7.41 – 7.27 (m, 5H), 7.24 – 7.10 (m, 4H), 7.08 – 7.01 (m, 2H),
7.00 – 6.89 (m, 1H), 6.67 – 6.53 (m, 1H, weak). ¹³C NMR (75 MHz, CDCl3): δ (ppm) 164.0
(weak), 155.5 (weak) 141.5, 138.7, 138.0, 137.7, 136.4, 134.7, 133.9, 133.5, 132.5, 131.7,
129.6, 129.1, 129.0, 128.7, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 127.7, 127.4, 127.1, 121.8,
117.3, 89.0. HRMS TOF MS (m / z): [M + H]+ calcd for [C28H18BrCl2NO H] 534.0022; found 534.0027.
FTIR(neat): 3434(br), 3062, 3029, 1600, 1475, 1293, 1218, 1026 cmꢀ1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(2-(2-bromo-5-chlorophenyl)-1-((4-methoxyphenyl)imino)ethyl)-5-chlorophenol
5a:
¹H NMR (500 MHz, CDCl3): δ (ppm) 15.15 (s, 1H), 7.53 (d, 1H, J = 8.5 Hz), 7.14 (d, 1H, J =
8.6 Hz), 7.13 ꢀ 7.09 (m, 1H), 7.06 (d, 1H, J = 2.0 Hz), 7.00 (d, 1H, J = 2.0 Hz), 6.88 (m, 4H),
6.73 (dd, 1H, J = 8.6, 2.1 Hz), 4.16 (s, 2H), 3.82 (s, 3H). ¹³C NMR (125 MHz, CDCl3): δ (ppm)
170.0, 163.5, 157.7, 138.7, 138.6, 138.0, 134.1, 134.0, 130.3, 129.2, 128.7, 122.1, 121.9, 118.9,
118.6, 116.9, 114.6, 55.5, 36.2. HRMS TOF MS (m / z): [M + H]+ calcd for [C21H16BrCl2NO2 H]
463.9814; found 463.9814. FTIR (neat): 3451(br), 2950, 2837, 1610, 1562, 1506, 1246, 1200
cmꢀ1.
500g scale up procedure for the synthesis of 4-(2-Bromo-5-chlorobenzyl)-7-chloro-2-
phenyl-2H-benzo[e][1,3]oxazine 2: A suspension of 320 g of preꢀactivated powdered 4Å MS
(60 wt/wt%) in 2ꢀMethylꢀTHF (3060 ml) was cooled to 0°C, and stirred for 10min. Phenol (1,
510 g, 1.42 mol), benzaldehyde (166g, 1.56 mol) and the aldimine 4a (30.0g, 142 mmol) were
added, and the resulting mixture was stirred for 2min maintaining 0ꢀ5oC.
Trifluoromethanesulfonic acid (42.6 g, 284 mmol) was added in 10 min. The ice bath was
removed and reaction mixture was warmed to room temperature and stirred for 19h. The reaction
was monitored by LCMS. Upon completion, the molecular sieves were filtered and washed with
2ꢀMeTHF (500 mL). The combined organic phases were washed with 5 wt% NaHCO3 solution
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 31
1
2
3
4
5
6
7
8
9
(2500 mL), water (2500 mL) and concentrated to 1.2kg under reduced pressure (batch
temperature was controlled below 30°C). MeOH (5000 mL) was added and followed by addition
of seed (100 mg). The slurry was stirred at rt for 5h. The product was collected by filtration,
washed by MeOH (1000mL) and dried at 30°C under reduced pressure to yield 524g 2 as yield
yellow solid (83% yield, 97% LC purity).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(2-(2-Chlorophenyl)-1-iminoethyl) phenol 6 (synthetic scheme in SI): 2ꢀ(2ꢀChloroꢀ
phenyl)acetic acid 11 (100 g, 586 mmol), acetonitrile (500 mL) and 1 mL of DMF were charged
into a 1 L flask. Oxalyl dichloride (96.7 g, 762 mmol) was added drop wise at 25 °C over 20
min. The resulting solution was stirred for 2h. HPLC analysis showed complete conversion. The
solution was concentrated under reduced pressure to give crude 2ꢀ(2ꢀchlorophenyl)acetyl
chloride. The crude product was dissolved in acetonitrile (500 mL) and phenol (57.9 g, 616
mmol) was added. The solution was cooled to 5°C. N, NꢀDiisopropylethylamine (90.9 g, 703
mmol) was added drop wise over 30min at 5ꢀ10°C. The reaction mixture was stirred at rt
overnight. Upon completion, the reaction mixture was poured into a mixture of ethyl acetate/H2O
(1000 mL/1000 mL). The organic layer was separated. The aqueous layer was extracted with
ethyl acetate (200 mL×2). The combined organic layers were dried over Na2SO4, filtered and
concentrated. This resulted in phenyl 2ꢀ(2ꢀchloroꢀphenyl) acetate 12 as a black oil which was
used directly in the next step.
Crude phenyl 2ꢀ(2ꢀchloroꢀphenyl) acetate 12 and aluminum trichloride (104 g, 780 mmol)
were charged into a 500 mL flask. The resulting suspension was stirred for 2h at 100°C and
turned into a brown syrup. LCMS analysis showed complete conversion. The mixture was
cooled to rt which produced a solid. The solid was isolated, crushed and then added to a 1 L ice
cold solution of 3N HCl (prepared from 500 mL 6N HCl and 500 mL ice water). The resulting
ACS Paragon Plus Environment

Page 19 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
aqueous solution was extracted with ethyl acetate (500 mL×2). The combined organic layers
were dried over Na2SO4, filtered and concentrated to obtain the crude product, which was
purified via silica gel chromatography eluting with a gradient of ethyl acetate in petroleum ether
ranging from 0 to 2% to yield 56.9 g of 2ꢀ(2ꢀchlorophenyl)ꢀ1ꢀ(2ꢀhydroxyphenyl)ethanone 13 as a
white solid (39 % yield over three steps). ¹H NMR (500 MHz, CDCl3): δ (ppm) 12.08 (s, 1H),
7.91 (dd, 1H, J = 8.0 Hz, 1.5 Hz), 7.51 (td, 1H, J = 7.5 Hz, 1.5 Hz), 7.45ꢀ7.43 (m, 1H), 7.29ꢀ7.26
(m, 3H), 7.02 (dd, 1H, J = 8.5 Hz, 1.0 Hz), 6.95 (td, 1H, J = 7.0 Hz, 1.0 Hz), 4.48 (s, 2H). ¹³C
NMR (125 MHz, CDCl3): δ (ppm) 202.5, 162.6, 136.6, 134.5, 132.3, 131.6, 129.9, 129.5, 128.8,
127.0, 119.1 (2 C), 118.6, 42.8. LRMS ESI MS (m / z): [M + H]+ calcd for [C14H11ClO2 H] 247;
found 247. FTIR (neat): 1643, 1612, 1572, 1475, 1444, 1408, 1333 cmꢀ1. Spectroscopic data for
2ꢀ(2ꢀchlorophenyl)ꢀ1ꢀ(2ꢀhydroxyphenyl)ethanone 13 were identical to those reported in the
literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ(2ꢀChloroꢀphenyl)ꢀ1ꢀ(2ꢀhydroxyphenyl)ethanone 13 (17.0 g, 68.9 mmol) and ammonia in
methanol (170 mL, ca. 9N) were charged into a 500 mL flask. The color of the solution changed
to yellow and a precipitate was formed. The mixture was stirred overnight at rt. TLC analysis
showed complete conversion. The yellow solid was collected by filtration, washed with methanol
and dried to yield 8.47g of 6 (50 % yield). ¹H NMR (500 MHz, CDCl3): δ (ppm)15.05 (s, 1H),
9.03 (s, br, 1H), 7.69 (dd, 1H, J = 8.0 Hz, 1.5 Hz), 7.52ꢀ7.50 (m, 1H), 7.41ꢀ7.32 (m, 3H), 7.28ꢀ
7.24 (m, 1H), 7.04 (dd, 1H, J = 8.5 Hz, 1.0 Hz), 6.89 (td, 1H, J = 8.0 Hz, 1.0 Hz), 4.28 (d, 1H, J
= 1.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 177.1, 162.9, 135.3, 133.2, 132.4, 131.6, 130.1,
129.6, 127.9, 127.5, 118.5, 118.4, 117.8, 40.4. HRMS TOF MS (m / z): [M + H]+ calcd for
[C14H12ClNO H] 246.0685; found 246.0688. FTIR (neat): 2605 (br), 1599, 1515, 1472, 1434,
1250 cmꢀ1. Spectroscopic data for 6 were identical to those reported in the literature.4
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 31
1
2
3
4
5
6
7
8
9
2-(1-imino-2-(2-iodophenyl)ethyl)phenol 7 (synthetic scheme in SI): 2ꢀ(2ꢀBromoꢀ
phenyl)acetic acid 14 (126 g, 586 mmol), acetonitrile (500 mL) and 1 mL of DMF were charged
into a 1 L flask. Oxalyl dichloride (96.5 g, 762 mmol) was added drop wise at 25°C over 20min.
The resulting solution was stirred for 2h. HPLC analysis showed complete conversion. The
solution was concentrated under reduced pressure to give crude 2ꢀ(2ꢀbromophenyl)acetyl
chloride. The crude product was dissolved in acetonitrile (500 mL) and phenol (57.9 g, 616
mmol) was added. The solution was cooled to 5 °C. N, NꢀDiisopropylethylamine (90.9 g, 703
mmol) was added drop wise over 30 min at 5ꢀ10 °C. The reaction mixture was stirred at rt
overnight. Upon completion, the reaction mixture was poured into a biphasic mixture of ethyl
acetate/H2O(1000 mL /1000 mL). The organic layer was separated. The aqueous layer was
extracted with ethyl acetate (200 mL×2). The combined organic layers were dried over Na2SO4,
filtered and concentrated. This resulted in phenyl 2ꢀ(2ꢀbromoꢀphenyl) acetate 15 as a black oil
which was used directly in the next step.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Crude phenyl 2ꢀ(2ꢀBromoꢀphenyl) acetate 15 and aluminum trichloride (104 g, 780 mmol)
were charged into a 500 mL flask. The suspension was stirred for 2h at 100°C and a brown syrup
was formed. LCMS analysis showed complete conversion. The mixture was cooled to rt and a
solid was produced. The solid was isolated, crushed and added to a 1.26 L ice cold solution of
3N HCl (prepared from 630 mL 6N HCl and 630 mL ice water). The resulting aqueous layer was
extracted with ethyl acetate (500 mL×2). The combined organic layers were dried over Na2SO4,
filtered and concentrated to obtain the crude product, which was purified via silica gel
chromatography eluting with gradient of ethyl acetate in petroleum ether ranging from 0 to 2% to
yield 25.6 g of 2ꢀ(2ꢀbromophenyl)ꢀ1ꢀ(2ꢀhydroxyphenyl)ethanone 16 as a white solid (15 % yield
over three steps).¹H NMR (500 MHz, CDCl3): δ (ppm) 12.09 (s, 1H), 7.92 (dd, 1H, J = 8.0 Hz,
ACS Paragon Plus Environment

Page 21 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
1.5 Hz), 7.64 (dd, 1H, J = 8.0 Hz, 1.5 Hz), 7.54ꢀ7.51 (m, 1H), 7.35ꢀ7.32 (m, 1H), 7.28ꢀ7.26 (m,
1H), 7.22ꢀ7.19 (m, 1H), 7.03 (dd, 1H, J = 8.5Hz, 1.0Hz), 6.98ꢀ6.95 (m, 1H), 4.51 (s, 2H). ¹³C
NMR (125 MHz, CDCl3): δ (ppm) 202.4, 162.6, 136.6, 134.2, 132.8, 131.7, 129.9, 129.0, 127.6,
125.1, 119.12, 119.08, 118.6, 45.3. HRMS TOF MS (m / z): [M + H]+ calcd for [C14H11BrO2 H]
291.0020; found 291.0018. FTIR (neat): 2915, 1638, 1610, 1577, 1469, 1438, 1407, 1335, 1270
cmꢀ1. Spectroscopic data for 2ꢀ(2ꢀbromophenyl)ꢀ1ꢀ(2ꢀhydroxyphenyl)ethanone 16 were identical
to those reported in the literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ(2ꢀBromophenyl)ꢀ1ꢀ(2ꢀhydroxyphenyl)ethanone 16 (1.50 g, 5.2 mmol), NaI (2.32 g, 15.5
mmol), CuI (196 mg, 1 mmol), transꢀdimethylcyclohexaneꢀ1,2ꢀdiamine (293 mg, 2 mmol) and
dioxane (15 ml, degassed) were charged into a 20 mL sealed tube. The tube was sealed and
o
heated under microwave conditions at 130 C for 12h. Seven reactions were conducted in
parallel and combined for the workup. Water (200 mL) was added to the combined reaction
solutions and the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined
organic layers were dried over Na2SO4, filtered and concentrated to obtain the crude product,
which was purified via silica gel chromatography eluting with ethyl acetate in petroleum ether
(gradient from 0ꢀ2%) to yield 1ꢀ(2ꢀhydroxyphenyl)ꢀ2ꢀ(2ꢀiodophenyl)ethanone 17 (5.00 g, 14.8
mmol, 41%) as white solid. ¹H NMR (500 MHz, CDCl3): δ (ppm) 12.08 (s, 1H), 7.93ꢀ7.90 (m,
2H), 7.54ꢀ7.51 (m, 1H), 7.36 (td, 1H, J = 7.5 Hz, 1.0 Hz), 7.26 (dd, 1H, J = 8.0 Hz, 2.0 Hz),
7.05ꢀ7.01 (m, 2H), 6.99ꢀ6.95 (m, 1H), 4.52 (s, 2H). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 202.5,
162.6, 139.5, 137.8, 136.6, 130.9, 129.9, 129.0, 128.5, 119.2, 119.1, 118.7, 101.4, 50.0. HRMS
TOF MS (m / z): [M + H]+ calcd for [C14H11IO2 H] 338.9882; found 338.9888. FTIR (neat):
2906, 1633, 1609, 1577, 1405, 1333, 1265 cmꢀ1. Spectroscopic data for 1ꢀ(2ꢀhydroxyphenyl)ꢀ2ꢀ
(2ꢀiodophenyl)ethanone 17 were identical to those reported in the literature.4
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 31
1
2
3
4
5
6
7
8
9
2ꢀ(2ꢀIodoꢀphenyl)ꢀ1ꢀ(2ꢀhydroxyphenyl)ethanone 17 (5.00 g, 14.8 mmol) and ammonia in
methanol (50 ml, ca 9N) were charged in a 100 mL flask. The color of the solution changed to
yellow, and a precipitate was formed. The resulting mixture was stirred overnight. TLC analysis
showed complete conversion. The solid was collected by filtration, washed with methanol and
dried to yield 4.5 g 2ꢀ(2ꢀ(2ꢀiodophenyl)ꢀ1ꢀiminoethyl) phenol (7) as a yellow solid in 90% yield.
¹H NMR (500 MHz, CDCl3): δ (ppm) 15.03 (s, br, 1H), 8.99 (s, br, 1H), 7.96 (dd, 1H, J = 8.0
Hz, 1.0 Hz), 7.69 (dd, 1H, J = 8.0 Hz, 1.5 Hz), 7.44ꢀ7.38 (m, 2H), 7.25 (dd, 1H, J = 7.5 Hz, 1.5
Hz), 7.08 (td, 1H, J = 8.0 Hz, 1.5 Hz), 7.04 (dd, 1H, J = 8.5 Hz, 1.0 Hz), 6.90 (td, 1H, J = 7.0 Hz,
1.0 Hz), 4.30 (s, 2H). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 177.1, 162.9, 140.2, 137.0, 133.2,
131.6, 129.7, 129.0, 127.8, 118.49, 118.46, 117.8, 102.0, 47.6. HRMS TOF MS (m / z): [M + H]+
calcd for [C14H12INO H] 338.0042; found 338.0050. FTIR (neat): 2596 (br), 1598, 1515, 1472,
1426, 1331, 1248 cmꢀ1. Spectroscopic data for 10 were identical to those reported in the
literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(2-Bromo-5-chlorobenzyl)-7-chloro-2-(o-tolyl)-2H-benzo[e][1,3]oxazine 8a (Table 6):
8a was synthesized using general method A with 100 wt/wt% of powdered 4Å MS and 1.0
equiv. of the corresponding aldimine. The crude product was purified by slurrying in MeOH to
produce 8a as an off white solid (80 % yield). ¹H NMR (500 MHz, CDCl3): δ (ppm) 7.52ꢀ7.49
(m, 2H), 7.34 (d, 1H, J = 8.0 Hz), 7.30ꢀ7.22 (m, 4H), 7.11 (dd, 1H, J = 8.5, 2.5 Hz), 6.96ꢀ6.92
(m, 2H), 6.61(br, 1H), 4.18 (ABqd, 2H, ꢁδAB = 0.03, J = 16.0, 1.5 Hz), 2.48 (s, 3H). ¹³C NMR
(125 MHz, CDCl3): δ (ppm) 162.0, 156.2, 139.1, 138.1, 136.6, 136.5, 133.8, 133.5, 130.8, 130.7,
128.9, 128.6, 127.5, 126.3, 126.0, 122.7, 122.0, 117.1, 116.2, 87.5, 40.8, 19.2. HRMS TOF MS
(m / z): [M + H]+ calcd for [C22H16BrCl2NO H] 459.9865; found 459.9886. FTIR (neat): 3065,
ACS Paragon Plus Environment

Page 23 of 31
Organic Process Research & Development
1
2
1638, 1597, 1457, 1360, 1343 cmꢀ1. Spectroscopic data for 8a were identical to those reported in
3
4
5
6
the literature.4
7
8
9
4-(2-Bromo-5-chlorobenzyl)-7-chloro-2-(2-methoxyphenyl)-2H-benzo[e][1,3]oxazine
8b (Table 6): 8b was synthesized using general method A with 100 wt/wt% of powdered 4Å
MS and 1.0 equiv. of the corresponding aldimine. The crude product was purified by slurrying it
in methanol (3 vol) to produce 8b as an offꢀwhite solid (80 % yield). ¹H NMR (500 MHz,
CDCl3): δ (ppm) 7.51 (d, 1H, J = 8.5 Hz), 7.48 (dd, 1H, J = 12.0, 1.5 Hz), 7.38ꢀ7.35 (m, 1H),
7.32 (d, 1H, J = 2.5 Hz), 7.29ꢀ7.27 (m, 1H), 7.09 (dd, 1H, J = 8.0, 3.0 Hz), 7.02ꢀ6.97 (m, 2H),
6.91ꢀ6.89 (m, 3H), 4.23 (d, 1H, J = 16.0 Hz), 4.12 (d, 1H, J = 16.0 Hz), 3.88 (3H, s). ¹³C NMR
(125 MHz, CDCl3): δ (ppm) 161.7, 157.2, 156.4, 139.0, 138.2, 133.8, 133.5, 130.42, 130.36,
128.6, 128.57, 127.0, 126.3, 122.6, 121.6, 120.6, 117.1, 115.8, 111.2, 85.1, 55.7, 40.9. HRMS
TOF MS (m / z): [M + H]+ calcd for [C22H16BrCl2NO2 H] 475.9814; found 475.9836. FTIR
(neat): 3066, 1634, 1591, 1458, 1283, 1240 cmꢀ1. Spectroscopic data for 8b were identical to
those reported in the literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 2-(4-(2-bromo-5-chlorobenzyl)-7-chloro-2H-benzo[e][1,3]oxazin-2-yl)benzoate
8c (Table 6): 8c was synthesized using general method A with 50 wt/wt% of powdered 4Å MS
and 0.1 equiv. of the corresponding aldimine. The crude product was purified by reverse phase
combiꢀflash chromatography (mobile phase A: water (0.1%NH4HCO3), mobile phase B:
acetonitrile, 80%ꢀ90%, 16min) to yield 8c as a white solid (57 % yield). ¹H NMR (500 MHz,
CDCl3): δ (ppm) 7.92 (dd, 1H, J = 8.0, 1.5 Hz), 7.76 (dd, 1H, J = 8.0, 1.0 Hz), 7.56ꢀ7.51 (m,
2H), 7.43 (td, 1H, J = 8.5, 1.0 Hz), 7.32ꢀ7.29 (m ,3H), 7.11 (dd, 1H, J =8.5, 2.5 Hz), 6.95ꢀ6.92
(m, 2H), 4.36 (qd, 2H, J = 8.0, 1.0 Hz), 4.15 (ABqd, 2H, ꢁδAB = 0.03, J = 16.5, 1.5 Hz), 1.38 (t,
3H, J = 8.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 167.5, 161.7, 156.2, 139.2, 139.1, 138.1,
ACS Paragon Plus Environment

Organic Process Research & Development
Page 24 of 31
1
2
3
4
5
6
7
8
9
133.8, 133.5, 131.8, 130.7, 130.3, 130.2, 128.6, 128.5, 128.1, 126.3, 122.6, 122.0, 117.1, 116.3,
85.9, 61.2, 40.8, 14.2. HRMS TOF MS (m / z): [M + H]+ calcd for [C24H18BrCl2NO3 H]
517.9920; found 517.9930. FTIR (neat): 2974, 1707, 1634, 1596, 1460 cmꢀ1. Spectroscopic data
for 8c were identical to those reported in the literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(4-(2-bromo-5-chlorobenzyl)-7-chloro-2H-benzo[e][1,3]oxazin-2-yl)benzonitrile
8d
(Table 6): 8d was synthesized using general method A with 50 wt/wt% of powdered 4Å MS and
0.1 equiv. of the corresponding aldimine. The crude product was purified by reverse phase
combiꢀflash chromatography (mobile phase A: water (0.1% NH4HCO3), mobile phase B:
acetonitrile, 80%ꢀ90%, 16 min) to yield 8d as an offꢀwhite solid in 70 % yield. ¹H NMR (500
MHz, CDCl3): δ (ppm) 7.85 (d, 1H, J = 1.0 Hz), 7.79 (d, 1H, J = 8.0 Hz), 7.66ꢀ7.64 (m, 1H),
7.54 (d, 1H, J = 9.0 Hz), 7.51 (t, 1H, J = 7.5 Hz), 7.37ꢀ7.35 (m, 1H), 7.26 (d, 1H, J = 7.5 Hz),
7.14 (dd, 1H, J = 8.5 Hz, 2.5 Hz), 7.00ꢀ6.97 (m, 2H), 6.52 (s, 1H), 4.17 (ABqd, 2H, ꢁδAB = 0.06,
J = 16.5 Hz, 1.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 162.4, 155.2, 140.5, 139.6, 137.8,
133.8, 133.5, 132.2, 131.5, 130.9, 130.8, 129.3, 128.8, 126.3, 122.7, 122.5, 118.5, 117.3, 116.1,
112.6, 87.4, 40.7. HRMS TOF MS (m / z): [M + H]+ calcd for [C22H13BrCl2N2O H] 470.9666;
found 470.9666. FTIR (neat): 3061, 2225, 1637, 1597, 1461, 1361, 1343 cmꢀ1. Spectroscopic
data for 8d were identical to those reported in the literature.4
Ethyl 4-(4-(2-bromo-5-chlorobenzyl)-7-chloro-2H-benzo[e][1,3]oxazin-2-yl)benzoate
8e (Table 6): 8e was synthesized using general method A with 50 wt/wt% of powdered 4Å MS
and 0.1 equiv. of the corresponding aldimine. The crude product was purified by reverse phase
combiꢀflash chromatography (mobile phase A: water (0.1% NH4HCO3), mobile phase B:
acetonitrile, 80%ꢀ90%, 16min) to yield 8e as a yellow solid in 62 % yield. ¹H NMR (500 MHz,
CDCl3): δ (ppm) 8.06 (d, 2H, J = 6.5 Hz), 7.61 (d, 2H, J = 8.5 Hz), 7.52 (d, 1H, J = 8.5 Hz), 7.32
ACS Paragon Plus Environment

Page 25 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(d, 1H, J = 8.0 Hz), 7.27 (s, 1H), 7.12 (dd, 1H, J = 8.5, 2.0 Hz), 6.97 (d, 1H, J = 2.0 Hz), 6.95
(dd, 1H, J = 8.0, 2.0 Hz), 6.59 (s, 1H), 4.38 (q, 2H, J = 7.0 Hz), 4.16 (ABq, 2H, ꢁδAB = 0.05, JAB
= 16.5 Hz), 1.40 (t, 3H, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 166.2, 161.8, 155.5,
143.5, 139.4, 137.9, 133.8, 133.5, 130.8, 130.7, 129.7, 128.7, 127.0, 126.3, 122.7, 122.2, 117.3,
116.2, 88.2, 61.0, 40.7, 14.3. HRMS TOF MS (m / z): [M + H]+ calcd for [C24H18BrCl2NO3 H]
517.9920; found 517.9924. FTIR (neat): 3064, 1702, 1629, 1599, 1579, 1458 cmꢀ1.
Spectroscopic data for 8e were identical to those reported in the literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(2-bromo-5-chlorobenzyl)-7-chloro-2-(4-methoxyphenyl)-2H-benzo[e][1,3]oxazine 8f
(Table 6): 8f was synthesized using general method A with 50 wt/wt% of powdered 4Å MS and
0.1 equiv. of the corresponding aldimine. The crude product was purified by reverse phase
combiꢀflash chromatography (mobile phase A: water (0.1% NH4HCO3), mobile phase B:
acetonitrile, 80%ꢀ90%, 16 min). This resulted in 8f as a white solid in 60 % yield. ¹H NMR (500
MHz, CDCl3): δ (ppm)7.52 (d, 1H, J = 8.5 Hz), 7.46 (dt, 2H, J = 10.0, 2.5 Hz), 7.30ꢀ7.27 (m,
2H), 7.11 (dd, 1H, J = 8.5, 2.5 Hz), 6.94ꢀ6.90 (m, 4H), 6.52 (s, 1H), 4.18 (ABq, 2H, ꢁδAB = 0.05,
JAB = 15.0 Hz), 3.82 (s, 3H). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 161.5, 159.9, 155.8, 139.1,
138.1, 133.8, 133.5, 131.1, 130.6, 128.6, 128.4, 126.2, 122.7, 121.8, 117.3, 116.2, 113.8, 88.7,
55.3, 40.8. HRMS TOF MS (m / z): [M + H]+ calcd for [C22H16BrCl2NO2 H] 475.9814; found
475.9830. FTIR(neat): 2974, 1704, 1634, 1598, 1460, 1418, 1341 cmꢀ1. Spectroscopic data for 8f
were identical to those reported in the literature.4
4-(2-Bromo-5-chlorobenzyl)-7-chloro-2-(4-nitrophenyl)-2H-benzo[e][1,3]oxazine
8g
(Table 6): 8g was synthesized using general method A with 50 wt/wt% of powdered 4Å MS and
0.1 equiv. of the corresponding aldimine. The crude product was slurried in acetonitrile (5vol) to
yield 8g as a yellow solid in 63% yield. ¹H NMR (500 MHz, CDCl3): δ (ppm) 8.24 (dt, 2H, J =
ACS Paragon Plus Environment

Organic Process Research & Development
Page 26 of 31
1
2
3
4
5
6
7
8
9
9.0, 2.0 Hz), 7.73 (d, 2H, J = 8.5 Hz), 7.53 (d, 1H, J = 8.5 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.25 (d,
1H, J = 2.5 Hz), 7.14 (dd, 1H, J = 8.5, 2.5 Hz), 7.00ꢀ6.98 (m, 2H), 6.58 (s, 1H), 4.17 (ABqd, 2H,
ꢁδAB = 0.04, J = 16.5, 1.0 Hz).¹³C NMR (125 MHz, CDCl3): δ (ppm) 162.3, 155.2, 148.0, 145.7,
139.6, 137.8, 133.8, 133.5, 130.9, 128.8, 128.0, 126.4, 123.6, 122.8, 122.5, 117.3, 116.2, 87.5,
40.7. HRMS TOF MS (m / z): [M + H]+ calcd for [C21H13BrCl2N2O3 H] 490.9559; found
490.9552. FTIR (neat): 3077, 1635, 1599, 1512, 1464, 1345 cmꢀ1. Spectroscopic data for 8g were
identical to those reported in the literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(2-Bromo-5-chlorobenzyl)-7-chloro-2-(pyridin-4-yl)-2H-benzo[e] [1,3]oxazine 8h
(Table 6): 8h was synthesized using general method B. The crude was purified by reverse phase
combiꢀflash (Mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, 80%ꢀ90%,
16min) to yield 11h as a yellow syrup in 54% yield. ¹H NMR (500 MHz, CD3CN): δ (ppm)
8.56 (m, 2H), 7.57(d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8.0 Hz), 7.40ꢀ7.39 (m, 2H), 7.36 (d, 1H, J
= 2.5 Hz), 7.20 (dd, 1H, J = 8.5, 2.5 Hz), 7.08ꢀ7.04 (m, 2H), 6.47 (s, 1H), 4.21 (s, 2H). ¹³C NMR
(125 MHz, CD3CN): δ (ppm) 163.9, 156.8, 151.6, 149.0, 140.4, 135.5, 134.4, 133.1, 130.2,
128.5, 124.8, 123.9, 123.3, 118.5, 118.3, 88.7, 41.9. HRMS TOF MS (m / z): [M + H]+ calcd for
[C20H13BrCl(37Cl)N2O H] 448.9639; found 448.9657. FTIR (neat): 2918, 1713, 1630, 1597,
1451, 1347 cmꢀ1. Spectroscopic data for 8h were identical to those reported in the literature.4
4-(2-Bromo-5-chlorobenzyl)-7-chloro-2-cyclohexyl-2H-benzo[e][1,3]oxazine 8i (Table
6): 8i was synthesized using general method C with 100 wt/wt% of powdered 4Å MS and 1.0
equiv. of the corresponding aldimine. The crude product was purified by reverse phase combiꢀ
flash chromatography (mobile phase: 100% acetonitrile, 16 min). This resulted in an oil, which
solidified upon storing overnight. The solid was slurried in acetonitrile to yield 8i as a white
solid in 54 % yield. ¹H NMR (500 MHz, CDCl3): δ (ppm)7.50 (d, 1H, J = 8.5 Hz), 7.23 (d, 1H, J
ACS Paragon Plus Environment

Page 27 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
= 2.5 Hz), 7.21ꢀ7.19 (m, 1H), 7.09 (dd, 1H, J = 8.5, 2.5 Hz), 6.87ꢀ6.85 (m, 2H), 5.30 (d, 1H, J =
5.0 Hz), 4.11 (d, 1H, J = 7.0 Hz), 3.99 (d, 1H, J = 7.0 Hz), 1.90ꢀ1.68 (m, 6H), 1.30ꢀ1.15 (m,
5H). ¹³C NMR (125 MHz, CDCl3): δ (ppm) 160.3, 156.5, 138.7, 138.3, 133.7, 133.4, 130.5,
128.5, 126.1, 122.6, 121.3, 116.8, 116.0, 92.6, 43.4, 40.7, 27.8, 27.3, 26.4, 25.93, 25.89. HRMS
TOF MS (m / z): [M + H]+ calcd for [C21H20BrCl2NO H] 452.0178; found 452.0196. FTIR(neat):
2905, 2848, 1637, 1595, 1559, 1414, 1340 cmꢀ1. Spectroscopic data for 8i were identical to those
reported in the literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(2-Bromo-5-chlorobenzyl)-7-chloro-2-phenethyl-2Hbenzo[e][1,3]oxazine 8j (Table
6): 8j was synthesized using general method C with 100 wt/wt% of powdered 4Å MS and 1.0
equiv. of the corresponding aldimine. The crude product was purified by reverse phase combiꢀ
flash chromatography (mobile phase: 100% acetonitrile, 16min) to yield 8j as a yellow oil in 42
% yield. ¹H NMR (500 MHz, CD3CN): δ (ppm) 7.56 (d, 1H, 8.5 Hz), 7.45 (d, 1H, 8.5 Hz), 7.31
(d, 1H, J = 2.5 Hz), 7.26ꢀ7.23 (m, 2H), 7.19ꢀ7.15 (m, 4H), 6.99 (dd, 1H, J = 8.5, 2.0 Ha), 6.90 (d,
1H, J = 2.0 Hz), 5.44ꢀ5.41 (m, 1H), 4.10 (ABq, 2H, ꢁδAB = 0.03, JAB = 15.0 Hz), 2.78ꢀ2.68 (m,
2H), 2.09ꢀ2.05 (m, 2H). ¹³C NMR (125 MHz, CD3CN): δ (ppm) 161.3, 156.8, 142.7, 140.2,
139.3, 134.9, 133.8, 132.5, 129.50, 129.47, 129.43, 127.6, 126.9, 124.3, 122.6, 117.6, 117.5,
89.5, 41.2, 37.7, 31.1. HRMS TOF MS (m / z): [M + H]+ calcd for [C23H18BrCl(37Cl)NO H]
476.0000; found 476.0021. FTIR (neat): 3024, 2919, 1628, 1597, 1451, 1346 cmꢀ1.
Spectroscopic data for 8j were identical to those reported in the literature.4
4-(2-Bromo-5-chlorobenzyl)-7-chloro-2-isopropyl-2H-benzo[e][1,3]oxazine 8k (Table
6): 8k was synthesized using general method C with 100 wt/wt% of powdered 4Å MS and 0.2
equiv. of the corresponding aldimine. The crude product was purified by reverse phase combiꢀ
flash chromatography (mobile phase: 100% acetonitrile, 16min) to yield 8k as a yellow oil in 65
ACS Paragon Plus Environment

Organic Process Research & Development
Page 28 of 31
1
2
3
4
5
6
7
8
9
% yield. ¹H NMR (500 MHz, CD3CN): δ (ppm) 7.55 (d, 1H, J = 8.5 Hz), 7.44 (d, 1H, J = 8.5
Hz). 7.31 (d, 1H, J = 2.5 Hz), 7.17 (dd, 1H, J = 8.5, 2.5 Hz), 6.98 (dd, 1H, J = 8.5, 2.5 Hz), 6.90
(d, 1H, J = 2.0 Hz), 5.19 (dt, 1H, J = 5.0, 2.0 Hz), 4.09 (ABq, 2H, ꢁδAB = 0.05, JAB = 15.0 Hz),
2.06ꢀ2.00 (m, 1H), 0.93 (d, 6H, J = 5.0 Hz) ). ¹³C NMR (125 MHz, CD3CN): δ (ppm) 161.4,
157.4, 140.2, 139.2, 134.8, 133.8, 132.4, 129.4, 127.5, 124.2, 122.3, 117.5, 117.3, 94.1, 41.2,
34.6, 17.5. HRMS TOF MS (m / z): [M + H]+ calcd for [C18H16BrCl2NO H] 411.9865; found
411.9877. FTIR (neat): 3024, 1628, 1596, 1451, 1440, 1347 cmꢀ1. Spectroscopic data for 8k were
identical to those reported in the literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(2-Chlorobenzyl)-2-phenyl-2H-benzo[e][1,3]oxazine 8l (Table 6): 8l was synthesized
using general method A with 100 wt/wt% of powdered 4Å MS and 0.1 equiv. of the
corresponding aldimine. The crude product was purified by reverse phase combiꢀflash
chromatography (mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, 80%ꢀ
90%, 16min) to yield 8l as a white solid in 42 % yield. ¹H NMR (500 MHz, CDCl3): δ (ppm)
7.62ꢀ7.59 (m, 2H), 7.43ꢀ7.31 (m, 7H), 7.21ꢀ7.17 (m, 2H), 6.94ꢀ6.91 (m, 2H), 6.50 (s, 1H), 4.29
(d, 1H, J = 15.0 Hz), 4.20 (d, 1H, J = 20.0 Hz).¹³C NMR (125 MHz, CDCl3): δ (ppm) 163.3,
155.2, 139.6, 134.9, 134.0, 133.7, 130.4, 129.5, 128.5, 128.4, 128.1, 127.1, 126.9, 125.5, 121.5,
118.1, 116.8, 88.5, 38.4. HRMS TOF MS (m / z): [M + H]+ calcd for [C21H16ClNO H] 334.0993;
found 334.0992. FTIR (neat): 3024, 1628, 1596, 1451, 1440, 1347 cmꢀ1. Spectroscopic data for
8l were identical to those reported in the literature.4
4-(2-Iodobenzyl)-2-phenyl-2H-benzo[e][1,3]oxazine 8m (Table 6): 8m was synthesized
using general method A with 60 wt/wt% of powdered 4Å MS and 0.1 equiv. of the
corresponding aldimine. The crude product was purified by reverse phase combiꢀflash
chromatography (mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, 80%ꢀ
ACS Paragon Plus Environment

Page 29 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
90%, 16min) to yield 8m as a white solid in 60 % yield. ¹H NMR (500 MHz, CD3CN): δ (ppm)
7.89 (d, J = 7.5 Ha, 1H), 7.63ꢀ7.60 (m, 2H), 7.43ꢀ7.40 (m, 2H), 7.38ꢀ7.33 (m, 3H), 7.28ꢀ7.25 (m,
2H), 6.96ꢀ6.92 (m, 3H), 6.51 (s, 1H), 4.23 (ABqd, 2H, ꢁδAB = 0.04, J = 16.0, 25.5 Hz). ¹³C NMR
(125 MHz, CD3CN): δ (ppm) 163.4, 155.2, 140.1, 139.54, 139.46, 133.7, 129.7, 128.5, 128.40,
128.36, 128.34, 127.2, 125.7, 121.5, 118.1, 116.8, 101.4, 88.5, 46.3. HRMS TOF MS (m / z): [M
+ H]+ calcd for [C21H16INO H] 426.0355; found 426.0356. FTIR (neat): 3030, 1630, 1604, 1451,
1336, 1224 cmꢀ1. Spectroscopic data for 8m were identical to those reported in the literature.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ ASSOCIATED CONTENT
Supporting Information
1
13
Synthetic schemes for the preparation of compound 1, 6 and 7, copies of selective H and C
NMR spectra. The Supporting Information is available free of charge on the ACS Publications
website at DOI:
ꢀ AUTHORS INFORMATION
Corresponding Author
*Eꢀmail: ji_qi@merck.com
Notes
The authors declare no competing financial interest.
ꢀ ACKNOWLEDGMENTS
We thank Dr. Hongming Li (Merck Research Laboratories) for help with compound
characterization, Dr. Aaron Dumas (Merck Sharp & Dohme, UK) for developing the original
ACS Paragon Plus Environment