Rhodium catalyzed arylation of diazo compounds with aryl boronic acids

Article abstract of DOI:10.1021/jo502922r

A general and efficient synthesis of diarylacetate, a diarylmethine derivative, was accomplished through rhodium catalyzed direct arylation of diazo compounds with arylboronic acids. The reaction tolerates various boronic acid derivatives and functional groups. Notably, chemoselective arylation of diazo compounds over other electrophiles were demonstrated. The efficacy of the developed methodology is shown by the expeditious synthesis of the core structure of diclofensine.

Full text of DOI:10.1021/jo502922r

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES
Article
Rhodium Catalyzed Arylation of Diazo Compounds with Aryl Boronic Acids
Jayanta Ghorai, and Pazhamalai Anbarasan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502922r • Publication Date (Web): 11 Mar 2015
Downloaded from http://pubs.acs.org on March 12, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 21
The Journal of Organic Chemistry
1
2
3
Rhodium Catalyzed Arylation of Diazo Compounds
4
5
6
7
with Aryl Boronic Acids
8
9
Jayanta Ghorai and Pazhamalai Anbarasan*
10
11
12
13
Department of Chemistry, Indian Institute of Technology Madras, Chennai - 600036, India
E-mail: anbarasansp@iitm.ac.in
FAX: +91-44-22574202
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
Abstract: A general and efficient synthesis of diarylacetate, a diarylmethine derivatives were
accomplished through rhodium catalyzed direct arylation of diazo compounds with arylboronic acids.
The reaction tolerates various boronic acid derivatives and functional groups. Notably, chemoselective
arylation of diazo compounds over other electrophiles were demonstrated. The efficacy of the developed
methodology is shown by the expeditious synthesis of core structure of diclofensine.
Introduction
Diarylmethines are ubiquitous subunits found in wide range of natural products and therapeutically
important molecules, such as cherylline and diclofensine (Figure 1).1 These molecules were shown to
have potent bioactivity such as antiviral, antirheumatic, antitumor and central nervous system activity as
well as inhibitor of serotonin dopamine uptake.2 Due to these potential, the synthesis of diarylmethine
derivatives, particularly, (di)arylacetic acid derivatives, the most obvious synthetic equivalent, is the
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
topic of interest to many synthetic chemist over the past few decades.3
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: Representative examples of diarylmethine containing therapeutically important molecules.
Typical synthesis of arylacetic acid derivatives from simple aromatic compounds suffers from the use
of toxic reagents, harsh reaction conditions and multistep sequence.4 These traditional methods were
subsequently replaced by transition metal (Pd or Ni) catalyzed direct arylation of either acetic acid
derivatives or α-halo acetic acid derivatives (Scheme 1a).5 However, these transformations suffers from
limited functional group tolerance and substrates scope due to the need of strong base, additionally,
most of these strategies are mainly focused on the synthesis of arylacetic acid derivatives.
Scheme 1: Synthesis of diarylacetic acid derivatives.
Most recently, an alternative synthesis of diarylacetates was accomplished from diazo carbonyl
compounds and ester of arylboronic acids employing strong base6 or expensive CF3TMS7 as an additive
(Scheme 1b). Instead of protonation as termination step, tandem alkylation was also achieved with
benzyl halide and KOtBu to afford the α,α-diaryl carboxylic esters.8 Thus, development of alternative
and general strategy for the synthesis of diarylacetic acid derivatives employing simple arylboronic acid
is highly warranted.9 Inspired by the recent development in transition metal catalyzed cross coupling of
diazo compounds10 with organoboron reagents11 and our interest in the functionalization of diazo
2
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
compounds,12 we herein disclose the rhodium-catalyzed synthesis of diarylacetic acid derivatives
through direct arylation of diazocarbonyl compounds with readily accessible arylboronic acids under
mild conditions (Scheme 1c).
1
2
3
4
5
6
7
8
Results and Discussion
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
To test our hypothesis, we chose the direct arylation of diazo compound 1a with phenylboronic acid
2a as model reaction. Initial study on the reaction of 1a (1 equiv) and 2a (1 equiv) in the presence of
metal catalysts (in toluene at 80°C) led to the rapid decomposition of diazo compound 1a. To avoid the
decomposition, solution of 1a was introduced slowly through syringe pump over the period of 30 min;
to our delight we observed the formation of expected product 3aa. Screening of various metal catalysts,
such as palladium and rhodium, revealed that rhodium based catalyst is superior than the palladium
based catalyst and afforded the product in 31% yield (Table 1, entry 1 and see Supporting information).
Table 1. Rhodium catalyzed arylation of diazo compounds: Optimization[a]
Entry [Rh]-cat.
Additive Solvent
Yield (%)[b]
1
[RhCl(COD)]2
-
-
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
31
0
2
-
3
[RhCl(COD)]2 K3PO4
K3PO4
[RhCl(COD)]2 K3PO4
91
0
4
5[c]
-
60
18
33
55
38
29
6
Rh2(OAc)4
K3PO4
K3PO4
7
8[d]
[Cp*RhCl2]2
[RhCl(COD)]2 K3PO4
[RhCl(COD)]2 K2CO3
[RhCl(COD)]2 CsF
9
10[e]
11
12
[RhCl(COD)]2 K3PO4
[RhCl(COD)]2 K3PO4
1,4-Dioxane 14
DCE 37
[a] Reaction conditions: Diazo compound 1a (0.28 mmol, 1 equiv), Phenylboronic acid 2a (0.28
mmol, 1 equiv), Rh-cat. (1 mol%), Additive (0.28 mmol, 1 equiv), 80 °C, 10 h; [b] All are isolated
yield; [c] 70 °C; [d] 0.14 mmol of K3PO4 is used; [e] 7 h.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
Interestingly, introduction of one equivalent of additive, K3PO4, to promote the transmetalation gave
the product 3aa in 91% isolated yield (Table 1, entry 3). In the absence of rhodium catalyst (with or
without additive) the expected reaction didn’t occur, which proves that the present reaction is indeed
catalyzed by rhodium catalyst (Table 1, entries 2 and 4). Next, we examined the other critical
parameters like additive, solvent and temperature. Noticeable decrease in the yield of the isolated
product 3aa was observed, when the reaction temperature was reduced to 70 °C as well as with 0.5
equivalents of additive (Table 1, entries 5 and 8). Furthermore, changing additive, solvent or metal
catalyst did not afford the expected product in comparable yield (Table 1, entries 6-12). From these
studies, we chose the following optimized conditions for investigating the generality of the
methodology: Diazo compound (1 equiv), arylboronic acid (1 equiv), [RhCl(COD)]2 (1 mol%), K3PO4
(1 equiv), Toluene, 80 °C, 10 h.
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
After identifying the best reaction conditions for direct arylation of diazo compounds with
phenylboronic acid, we subjected other phenylboron reagents under the optimized conditions to
demonstrate the generality of the present method. As can be seen in Scheme 2, reaction of diazo
compound 1a with neopentylglycol and pinacol ester of phenylboronic acid (3 and 4) in the presence of
rhodium catalyst afforded the expected arylated product 3aa in 68% and 65% yield, respectively.
Interestingly, use of triphenylboroxin 5 also furnished the product 3aa in comparable yield, with only
0.66 equivalents of 5. Although, all the boron reagents examined gave the product 3aa in good to
moderate yield, arylboronic acid was found to be superior.
Scheme 2: Rhodium catalyzed arylation of 1a with various phenylboron reagents (3-5). †0.66 equiv of
4
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
triphenylboroxin.
1
2
3
Subsequently, we investigated the scope and limitation of substituted arylboronic acid (Scheme 3).
Simple aryl and alkyl substituted diarylacetic acid derivatives (3ab, 3ac and 3ad) were achieved in
excellent yield from corresponding arylboronic acids. It is important to note that, both electron donating
as well as withdrawing substitution containing arylboronic acids gave the corresponding diarylacetic
acid derivatives (3af, 3ag and 3am) in very good yield. Sterically hindered ortho substituted arylboronic
acids (o-methyl and o-methoxy arylboronic acids) gave the corresponding arylated products (3ae and
3ah) in moderate yield. Arylation using the chlorinated arylboronic acids afforded the synthetically
useful and readily modifiable chlorinated diarylacetic acid derivatives 3aj and 3ak in 77 and 79% yield,
respectively. Furthermore, medicinally important fluorinated and trifluoromethylated diarylacetic acid
derivatives (3ai and 3al) were readily accessible under the present methodology.
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
Scheme 3. Rhodium catalyzed synthesis of diarylacetic acid derivatives 3: Scope and limitation of
arylboronic acids.
Having demonstrated the generality of substituted arylboronic acids; next, we moved on to study the
scope and limitation of substituted diazo compounds (Scheme 4). Gratifyingly, changing the bulkiness
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 21
of the ester group from methyl to ethyl, isopropyl and tert-butyl were tolerated in the present conditions
and furnished the corresponding diarylacetic acid derivatives (3ba, 3ca and 3da) in excellent yield.
Next, arylation of simple alkyl, chloro and electron donating methoxy group substituted diazo
compounds also furnished the corresponding arylated product in comparable yield. Sterically
demanding aryl-containing diazo compounds gave the arylated products 3ha and 3ka in only moderate
yield.
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
Scheme 4: Rhodium catalyzed synthesis of diarylacetic acid derivatives 3: Scope and limitation of diazo
compounds.
Interestingly, the present methodology also tolerates various functional groups, like tosyloxy, nitro and
ester, and led to the formation of corresponding products (3la, 3na and 3oa) in 69, 88 and 83% yield,
respectively. Reaction of strongly chelating cyano and secondary amide substituted diazo compounds
afforded the arylated products (3ma and 3pa) in low yield. In addition to the arylation of diazo
6
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
compounds derived from arylacetic acids, we also examined the rhodium-catalyzed arylation of the
diazocompound derived from malonic acid diester, which led the formation of arylated product 3ea in
63% yield. However, replacing aryl moiety in diazo compounds with benzyl group (PhCH2), derived
from methyl phenylpropionate did not afford the expected product 3ra. Furthermore, to understand the
chemoselectivity of the present reaction, we examine the arylation of diazo compound containing α,β-
unsaturated ester group13 that are reactive under the present conditions. Remarkably, exclusive
formation of diazo carbon arylated product 3qa was observed in 64% yield (Scheme 4).
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
Next, we were interested in extending to other electrophiles,14 like aldehyde, ketone and nitrile (Scheme
5). Reaction of equimolar mixture of diazo compound 1a and nitrile 10 with phenylboronic acid 2a
afforded the exclusive formation of arylated product 3aa along with the 78% recovery of nitrile 10
(Scheme 5c). However, the reaction of equimolar mixture of 1a and ketone 8 (or aldehyde 6) with 2a
furnished the mixture of arylated product 3aa and 9 (or 7) with 2.1:1 (or 1:1) ratio favoring the arylation
of diazo compound (Scheme 5b and 5a). Thus, the present rhodium catalyzed arylation condition is
highly selective towards the diazo compounds compared to α,β-unsaturated ester, nitriles and ketones.
Scheme 5: Chemoselectivity in rhodium catalyzed arylation of 1a with 2a.
Subsequently, effect of substituents on the phenyl ring of diazo compounds and arylboronic acids was
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
also examined. Arylation of equimolar mixture of methoxy- and methoxycarbonyl-substituted diazo
compounds, 1i and 1o, respectively, with phenylboronic acid gave the mixture of 3ia and 3oa in 1:1.5
ratio (Scheme 6a). In contrast, arylated products 3af and 3am were isolated in 1.4:1 ratio from the
rhodium catalyzed reaction of methoxy and methoxycarbonyl substituted arylboronic acids, 2f and 2m,
respectively, with diazo compound 1a (Scheme 6b). The ratio of the product revealed that the presence
of electron withdrawing group (methoxycarbonyl) in the diazo compounds 1 and electron-donating
group in the arylboronic acid 2 slightly favors the arylation over the corresponding counter part. Thus,
the present methodology complements the base mediated arylation reaction (Scheme 1b), where the
electron-withdrawing arylboronic acids gave moderately high reactivity.
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
Scheme 6: Rhodium catalyzed direct arylation: Effect of the substituents.
Next, we envisaged the synthesis of amine 12, the core structure present in the diclofensine 13, to
demonstrate the efficiency and applicability of the present methodology in organic synthesis (Scheme
7). Diclofensine is a stimulant drug having 4-aryltetrahydroisoquinoline framework and shown to have
both antidepressant and monoamines reuptake inhibitor activity.15 Synthesis began with the rhodium-
catalyzed arylation of diazo compound 1j with p-anisylboronic acid 2f under the optimized condition to
lead to the formation of 3jf in 59% yield (Scheme 7). Hydrolysis of ester followed by reduction with the
combination of sodium borohydride and iodine gave the alcohol 11 in 65% for two steps. Finally, the
key intermediate amine 12 was achieved from alcohol 11 through Mitsunobu reaction with phthalimide
followed by hydrolysis with hydrazine hydrate. Thus, the present method could be readily integrated in
8
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
the synthesis of various diarylmethine containing natural products.
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
Scheme 7: Synthesis of core structure of diclofensine 13.
On the basis of previous report on the rhodium-catalyzed arylation of various electrophiles14,16 and from
the present studies, we postulate the following mechanism for the rhodium-catalyzed arylation of diazo
compounds (Scheme 8). The catalytic reaction began with the generation of reactive arylrhodium(I)
species A from rhodium precursor and 2, through base assisted transmetallation of aryl group. Reaction
of A with diazo compounds 1 furnished the rhodium species B with extrusion of nitrogen. 1,2-Aryl
migration in rhodium species B could result to a rhodium complex C, which might exist in equilibrium
with its tautomer C’. Finally, proto-demetallation of rhodium species C could afford the arylated
product 3 along with the active rhodium species to complete the catalytic cycle.
Scheme 8: Plausible mechanism.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
1
2
3
4
5
Conclusion
6
7
8
9
We accomplished a general and direct rhodium catalyzed arylation of diazo carbonyl compounds with
arylboronic acids. The present strategy allows the synthesis of various diarylacetic acid derivatives in
good to excellent yield under operationally simple and mild reaction conditions. Importantly, the
optimized condition tolerates various functional groups like nitro, amide, ester, nitrile, trifluoromethyl
and etc. In addition, the excellent chemoselectivity was observed for arylation of diazo compounds over
α,β-unsaturated ester, nitrile and ketone. Study on the effect of substitution disclosed the better
reactivity of electron rich arylboronic acids and electron deficient diazo compounds, which is
complementary to the base mediated arylation of diazo compound. Furthermore, the potential of the
developed methodology was demonstrated by the synthesis of core structure of an antidepressant agent,
diclofensine.
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 procedure for the synthesis of substituted diarylacetic acid 3 from diazo compounds 1
and arylboronic acids 2: In a dry reaction tube, arylboronic acid 2 (0.28 mmol, 1 equiv), K3PO4 (59
mg, 0.28 mmol, 1 equiv), Rh catalyst (1.38 mg, 1 mol%), and dry toluene (0.5 mL) were added under
nitrogen atmosphere and the reaction tube was sealed with septa and kept in a preheated oil bath at 80
℃. Diazo compound 1a (50 mg, 0.28 mmol, 1 equiv) was dissolved in 0.5 mL of dry toluene and slowly
added to the reaction mixture over a period of half an hour and stirred at same temperature till the time
mentioned in the table below. The reaction mixture was cooled to room temperature and dissolved in 15
mL DCM. The DCM layer was washed with water (10 mL × 2) and brine (10 mL × 2). The combined
organic layer was dried over anhydrous Na2SO4 and concentrated to get the crude product. The crude
product was purified by column chromatography to afford the arylated product 3.
10
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
3aa:6 58 mg, 91% yield; colorless liquid; Rf = 0.55 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2961, 2933,
1739, 1443, 1381, 1273, 912, 658; 1H NMR (500 MHz, CDCl3, 24 °C): δ 7.31-7.24 (m, 10H), 5.03 (s,
1
2
3
4
5
6
13
1H), 3.74 (s, 3H); C{1H} NMR (125 MHz, CDCl3, 24 °C): δ 173.1, 138.7, 128.7, 128.7, 127.4, 57.1,
7
8
52.4; HRMS: m/z: [M+H]+ Calcd. for C15H15O2, 227.1072, found 227.1066.
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
3ab:17 68 mg, 81% yield; white solid; Rf = 0.33 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 3028, 1729,
1
2487, 1434, 1200, 1163, 1011, 760, 698; H NMR (400 MHz, CDCl3, 24 °C): δ 7.58-7.55 (m, 4H),
7.45-7.39 (m, 4H), 7.37-7.29 (m, 6H), 5.09 (s, 1H), 3.78 (s, 3H); 13C{1H} NMR (100 MHz CDCl3, , 24
°C): δ 173.0, 140.8, 140.3, 138.7, 137.8, 129.1, 128.8, 128.8, 128.8, 128.7, 127.4, 127.4, 127.2,, 56.8,
52.5; HRMS: m/z: [M+Na]+ Calcd. for C21H18O2Na, 325.1204, found 325.1190.
3ac (3ga):18 60 mg, 89% yield (59 mg, 88% yield); colorless liquid; Rf = 0.37 in 1:9 EtOAc/Hexane; IR
1
(νmax, cm-1): 3026, 2947, 1732, 1442, 1445, 1156, 1014, 700; H NMR (500 MHz, CDCl3, 24 °C): δ
7.34-7.07 (m, 9H), 5.00 (s, 1H), 3.74 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, 24 °C): δ
173.2, 138.8, 138.6, 136.4, 129.4, 128.7, 128.6, 128.2, 127.3, 125.7, 57.1, 52.4, 21.6; HRMS: m/z:
[M+H]+ Calcd. for C16H17O2, 241.1229, found 241.1233.
3ad: 59 mg, 83% yield; colorless liquid; Rf = 0.44 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2948, 2084,
1
1955, 1889, 1737, 1604, 1498, 1447, 1315, 1156, 1013, 727; H NMR (400 MHz, CDCl3, 24 °C): δ
7.32-7.28 (m, 4H), 7.27-7.23 (m, 1H), 7.10-7.03 (m, 3H), 4.97 (s, 1H), 3.74 (s, 3H), 2.23 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 173.3, 139.0, 136.9, 136.1, 135.8, 130.0, 129.9, 128.6,
127.2, 126.0, 56.8, 52.3, 19.9, 19.4; HRMS: m/z: [M+Na]+ Calcd. for C17H18O2Na, 277.1204, found
277.1205.
3ae (3ha):19 45 mg, 67% yield (44 mg, 66% yield); pale yellow liquid; Rf = 0.40 in 1:9 EtOAc/Hexane;
IR (νmax, cm-1): 3029, 2952, 2104, 1736, 1603, 1494, 1454, 1434, 1245, 1153, 1007, 735; 1H NMR (500
MHz, CDCl3, 24 °C): δ 7.33-7.31 (m, 2H), 7.28-7.23 (m, 4H), 7.20-7.18 (m, 3H), 5.22 (s, 1H), 3.75(s,
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
3H), 2.29(s, 3H); 13C{1H} NMR (125 MHz, CDCl3, 24 °C): δ 173.3, 137.9, 137.0, 136.5, 130.8, 129.0,
128.6, 127.5, 127.3, 126.3, 53.8, 52.4, 19.9; HRMS: m/z: [M+H]+ Calcd. for C16H17O2, 241.1229, found
241.1236.
1
2
3
4
5
6
7
8
9
3af (3ia):6 60 mg, 84% yield (58 mg, 81% yield); colorless liquid; Rf = 0.28 in 1:9 EtOAc/Hexane; IR
(νmax, cm-1): 2947, 1735, 1602, 1511, 1249, 1158, 1022, 815, 703; 1H NMR (400 MHz, CDCl3, 24 °C):
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
13
δ 7.34-7.24 (m, 7H), 6.86 (d, J = 8.0 Hz, 2H), 4.99 (s, 1H), 3.78 (s, 3H), 3.74 (s, 3H); C{1H} NMR
(CDCl3, 100 MHz, 24 °C): δ 173.3, 158.9, 139.0, 130.8, 129.7, 128.7, 128.5, 127.3, 114.1, 56.3, 55.3,
52.4; HRMS: m/z: [M+Na]+ Calcd. for C16H16O3Na, 279.0997, found 279.0994.
3ag:18 63 mg, 88% yield; colorless liquid; Rf = 0.37 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2947, 2835,
1
1742, 1585, 1491, 1431, 1265, 1155, 1051, 772; H NMR (CDCl3, 500 MHz, 24 °C): δ 7.32-7.22 (m,
6H), 6.91-6.79 (m, 3H), 5.00 (s, 1H), 3.77 (s, 3H), 3.74 (s, 3H); C{1H} NMR (CDCl3, 125 MHz, 24
13
°C): δ 172.9, 159.8, 140.1, 138.5, 129.7, 128.7, 128.7, 127.4, 121.1, 114.7, 112.6, 57.0, 55.3, 52.4;
HRMS: m/z: [M+H]+ Calcd. for C16H17O3, 257.1178, found 257.1166.
3ah: 46 mg, 57% yield; pale yellow liquid; Rf = 0.24 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2948, 2834,
1
1742, 1591, 1499, 1430, 1228, 1054, 805, 703; H NMR (400 MHz, CDCl3, 24 °C): δ 7.36-7.26 (m,
5H), 6.82-6.74 (m, 2H), 6.64 (d, J = 4.0 Hz, 1H), 5.29 (s, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.69 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 173.4, 153.6, 151.3, 137.6, 129.1, 129.0, 128.7, 127.4,
116.2, 112.3, 111.5, 56.2, 55.7, 52.3, 51.0; HRMS: m/z: [M+Na]+ Calcd. for C17H18O4Na, 309.1103,
found 309.1110.
3ai: 65 mg, 81% yield; colorless liquid; Rf =0.37 in1:9 EtOAc/Hexane; IR (νmax, cm-1): 3654, 3454,
2979, 2940, 1959, 1736, 1591, 1511, 1277, 1130, 916, 721, 647; 1H NMR (500 MHz, CDCl3, 24 °C): δ
7.35-6.84 (m, 8H), 4.95 (s, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.74 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3, 24 °C): δ 172.8, 152.6 (d, J = 246.0 Hz), 146.2 (d, J = 10.7 Hz), 138.5, 131.6
12
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
(d, J = 5.7 Hz), 128.8, 128.5, 127.5, 124.4 (d, J = 3.4 Hz), 116.7 (d, J = 19.5 Hz), 114.8, 65.1, 56.1,
1
2
3
52.5, 14.9; HRMS: m/z: [M+Na]+ Calcd. for C17H17O3NaF, 311.1059, found 311.1072.
4
5
6
7
3aj: 58 mg, 80% yield; colorless liquid; Rf = 0.53 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2923, 2851,
8
9
1
1740, 1594, 1433, 1198, 1154, 1013, 755, 702; H NMR (400 MHz, CDCl3, 24 °C): δ 7.36-7.18 (m,
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
13
9H), 4.99 (s, 1H), 3.75 (s, 3H); C{1H} NMR (125 MHz, CDCl3, 24 °C): δ 172.5, 140.6, 138.0, 134.5,
129.9, 128.9, 128.6, 127.7, 127.6, 126.9, 56.7, 52.5; HRMS: m/z: [M+H]+ Calcd. for C15H14O2Cl,
261.0682, found 261.0685.
3ak: 66 mg, 80% yield; colorless liquid; Rf = 0.44 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 3460, 3073,
1
2949, 1957, 1739, 1575, 1435, 1160, 1013, 856, 702; H NMR (400 MHz, CDCl3, 24 °C): δ 7.37-7.25
(m, 6H), 7.20 (d, J = 1.8 Hz, 2H), 4.94 (s, 1H), 3.75 (s, 3H); C{1H} NMR (100 MHz, CDCl3, 24 °C):
13
δ 171.9, 141.9, 137.3, 135.2, 129.1, 128.5, 128.0, 127.7, 127.3, 56.4, 52.7; HRMS: m/z: [M+Na]+
Calcd. for C15H12O2NaCl2, 317.0112, found 317.0101.
3al: 62 mg, 75% yield; colorless liquid; Rf = 0.44 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 3052, 2953,
2480, 2426, 2308, 1738, 1601, 1504, 1442, 1011, 733; 1H NMR (400 MHz, CDCl3, 24 °C): δ 7.34-7.15
(m, 9H), 5.03 (s, 1H), 3.75 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, 24 °C): 172.7, 148.5, 138.2,
137.4, 130.1, 128.9, 128.5, 127.7, 121.1, 120.5 (q, J = 257 Hz, CF3), 56.4, 52.6; HRMS: m/z: [M+K]+
Calcd. for C16H13O2F3K, 333.0505, found 333.0512.
3am: 58 mg, 73% yield; white solid; Rf = 0.45 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2952, 1732, 1433,
1286, 1198, 1152, 1104, 1017, 964, 813; 1H NMR (400 MHz, CDCl3, 24 °C): δ 7.97 (d, J = 8.0 Hz, 2H),
7.36 (d, J = 8.0 Hz, 2H), 7.33-7.23 (m, 5H), 5.05 (s, 1H), 3.87 (s, 3H), 3.73 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3, 24 °C): δ 172.4, 166.9, 143.7, 138.0, 130.0, 129.3, 128.9, 128.8, 128.6, 127.7, 57.0, 52.6,
52.2; HRMS: m/z: [M+H]+ Calcd. for C17H17O4, 285.1127, found 285.1122.
3ba:20 57 mg, 85% yield; colorless liquid; Rf = 0.37 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 1729, 1490,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
1451, 1367, 1346, 1309, 1277, 1189, 1153, 1020, 743, 705, 628; 1H NMR (500 MHz, CDCl3, 24 °C): δ
7.34-7.25 (m, 10H), 5.03 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3, 24 °C): δ 172.6, 138.9, 128.7, 128.6, 127.3, 61.3, 57.2, 14.2; HRMS: m/z: [M+H]+ Calcd
for C16H17O2, 241.1229, found 241.1237.
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
3ca:21 59 mg, 83% yield; colorless liquid; Rf = 0.39 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2982, 1725,
1
1603, 1497, 1451, 1374, 1308, 1266, 1192, 1164, 1106, 971, 743, 700; H NMR (400 MHz, CDCl3, 24
°C): δ 7.31-7.21 (m, 10H), 5.07 (sep, J = 6.2 Hz, 1H), 4.96 (s, 1H), 1.21 (d, J = 6.2 Hz, 6H, 2CH3);
13C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 172.0, 139.0, 128.7, 128.6, 127.2, 68.7, 57.4, 21.8; HRMS:
m/z: [M+H]+ Calcd. for C17H19O2, 255.1385, found 255.1380.
3da:22 64 mg, 85% yield; colorless liquid; Rf = 0.38 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 1729 1490,
1
1448, 1364, 1206, 1144, 758, 746, 701; H NMR (500 MHz, CDCl3, 24 °C): δ 7.32-7.23 (m, 10H), 4.92
13
(s, 1H), 1.45 (s, 9H); C{1H} NMR (125 MHz, CDCl3, 24 °C): δ 171.8, 139.3, 128.7, 128.6, 127.1,
81.4, 58.2, 28.1; HRMS: m/z: [M+Na]+ Calcd. for C18H20O2Na, 291.1361, found 291.1370.
3ea:23 42 mg, 63% yield; colorless liquid; Rf = 0.38 in 1:4 EtOAc/Hexane; IR (νmax, cm-1): 2982, 2306,
1
1735, 1602, 1498, 1453, 1368, 1307, 1266, 1221, 1152, 1031, 729, 607, 582, 491, 468; H NMR (400
MHz, CDCl3, 24 °C): δ 7.41-7.30 (m, 5H), 4.60 (s, 1H), 4.27-4.15 (m, 4H), 1.26 (t, J = 7.1 Hz, 6H);
13C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 168.3, 132.9, 129.4, 128.7, 128.3, 61.9, 58.1, 14.1; HRMS:
m/z: [M+H]+ Calcd. for C13H17O4, 237.1127, found 237.1127.
3fa:24 58 mg, 86% yield; colorless liquid; Rf = 0.41 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2952, 1735,
1600, 1517, 1496, 1456, 1436, 1308, 1011, 808, 732, 701; 1H NMR (400 MHz, CDCl3, 24 °C): δ 7.32-
7.31 (m, 4H), 7.27-7.24 (m, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 5.01 (s, 1H), 3.74 (s,
13
3H) 2.33 (s, 3H); C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 173.2, 139.0, 137.1, 135.8, 129.4, 128.6,
128.6, 127.3, 56.8, 52.3, 21.1; HRMS: m/z: [M+H]+ Calcd. for C16H17O2, 241.1229, found 241.1217.
14
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
3ja: 71 mg, 86% yield; colorless liquid; Rf = 0.40 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 1735, 1630,
1
2
3
1
1469, 1266, 1199, 1153, 1030, 132, 700; H NMR (500 MHz, CDCl3, 24 °C): δ 7.41-7.26 (m, 7H), 7.15
4
5
6
13
(dd, J = 8.3, 2.2 Hz, 1H), 4.96 (s, 1H), 3.75(s, 3H); C{1H} NMR (125 MHz, CDCl3, 24 °C): δ 172.2,
7
8
9
138.8, 137.6, 132.7, 131.6, 130.7, 130.6, 129.0, 128.5, 128.1, 127.8, 56.1, 52.7; HRMS: m/z: [M+Na]+
Calcd. for C15H12Cl2O2Na, 317.0112, found 317.0101.
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
3ka: 47 mg, 65% yield; colorless liquid; Rf = 0.44 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2093, 1735,
1
1630, 1469, 1433, 1266, 1199, 1030, 893, 816; H NMR (500 MHz, CDCl3, 24 °C): δ 7.37-7.19 (m,
13
9H), 5.49 (s, 1H), 3.76 (s, 3H); C{1H} NMR (125 MHz, CDCl3, 24 °C): δ 172.5, 137.2, 136.7, 134.3,
130.2, 129.7, 129.0, 128.9, 128.7, 127.6, 127.0, 53.8, 52.6; HRMS: m/z: [M+H]+ Calcd. for C15H14O2Cl,
261.0682, found 261.0677.
3la: 79 mg, 71% yield; white solid; Rf = 0.32 in 1:4 EtOAc/Hexane; IR (νmax, cm-1): 2365, 2344, 2090,
1
1739, 1648, 1375, 1154, 1110, 863; H NMR (400 MHz, CDCl3, 24 °C): δ 7.72 (d, J = 8.0 Hz, 2H),
7.36-7.23 (m, 9H), 6.95 (d, J = 8.0 Hz, 2H), 4.99 (s, 1H), 3.75 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3, 24 °C): δ 172.6, 148.8, 145.4, 138.2, 137.6, 132.6, 130.0, 129.9, 128.8, 128.6, 127.6,
122.5, 56.3, 52.5, 21.8; HRMS: m/z: [M+Na]+ Calcd for C22H20O5SNa, 419.0929, found 419.0927.
3ma: 15 mg, 21% yield; pale yellow solid; Rf = 0.34 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2225, 1735,
1
1603, 1506, 1371, 1338, 1241, 1164, 1038, 551; H NMR (400 MHz, CDCl3, 24 °C): δ 7.64 (d, J = 8.0
Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.40-7.29 (m, 5H), 5.07 (s, 1H), 4.26 (q, J = 7.0 Hz, 2H), 1.29 (t, J =
7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 171.5, 144.2, 137.5, 132.4, 129.6, 129.0,
128.6, 127.9, 118.7, 61.7, 57.1, 14.2; HRMS: m/z: [M+Na]+ Calcd. for C17H15NNaO2, 288.1000, found
288.0995.
3na:25 67 mg, 88% yield; white solid; Rf = 0.51 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 1734, 1525,
1346, 1206, 1164, 705; 1H NMR (500 MHz, CDCl3, 24 °C): δ 8.10 ( t, J = 2 Hz, 1H), 8.13 (ddd, J = 8.0,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
2.2, 1.0 Hz, 1H), 7.67-7.65 (m, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.38-7.29 (m, 4H), 5.12 (s, 1H), 3.77 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3, 24 °C): δ 172.1, 148.4, 140.8, 137.4, 134.9, 129.6, 129.1, 128.5,
128.0, 123.8, 122.5, 56.5, 52.8; HRMS: m/z: [M+Na]+ Calcd. for C15H13NNaO4, 294.0742, found
294.0737.
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
3oa: 66 mg, 83% yield; white solid; Rf = 0.45 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 2952, 1732, 1433,
1286, 1198, 1152, 1104, 1017, 964, 813; 1H NMR (400 MHz, CDCl3, 24 °C): δ 7.97 (d, J = 8.0 Hz, 2H),
7.36 (d, J = 8.0 Hz, 2H), 7.33-7.23 (m, 5H), 5.05 (s, 1H), 3.87 (s, 3H), 3.73 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3, 24 °C): δ 172.4, 166.9, 143.7, 138.0, 130.0, 129.3, 128.9, 128.8, 128.6, 127.7, 57.0, 52.6,
52.2; HRMS: m/z: [M+H]+ Calcd. for C17H17O4, 285.1127, found 285.1122.
3pa:17 28 mg, 29% yield; white solid; Rf = 0.40 in 1:9 EtOAc/Hexane; IR (νmax, cm-1): 1729, 1655,
1
1596, 1522, 1420, 1318, 1257, 1164, 712; H NMR (400 MHz, CDCl3, 24 °C): δ 7.88-7.83 (m, 3H),
7.61-7.58 (m, 2H), 7.54-7.52 (m, 1H), 7.48-7.45 (m, 2H), 7.34-7.31 (m, 6H), 5.02 (s, 2H), 3.74 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 173.0, 165.8, 138.7, 137.2, 135.0, 134.9, 132.0, 129.4,
128.9, 128.7, 128.6, 127.4, 127.1, 120.4, 56.6, 52.5; HRMS: m/z: [M+H]+ Calcd for C22H20O3N,
346.1443, found 346.1436.
3qa: 62 mg, 71% yield; white solid; Rf = 0.32 in 1:4 EtOAc/Hexane; IR (νmax, cm-1): 2365, 2344, 2090,
1
1648, 1375, 1154, 1110, 863; H NMR (400 MHz, CDCl3, 24 °C): δ 7.66 (d, J = 16.0 Hz, 1H), 7.47 (d,
J = 8.0 Hz, 2H), 7.35-7.33 (m, 2H), 7.32-7.27 (m, 4H), 7.22-7.14 (m, 1H), 6.41 (d, J = 16.0 Hz, 1H),
5.04 (s, 1H), 3.79 (s, 3H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 172.6, 167.5, 144.4,
141.1, 138.3, 133.6, 129.3, 128.9,128.6, 128.4, 127.6, 118.1, 57.0, 52.5, 51.8; HRMS: m/z: [M+H]+
Calcd for C19H19O4, 311.1283, found 311.1276.
Synthesis of 3jf: In a dry reaction tube, p-methoxyphenylboronic acid (2f) (100 mg, 0.66 mmol, 1
equiv), K3PO4 (140 mg, 0.66 mmol, 1 equiv), Rh catalyst (3.2 mg, 1 mol%), and dry toluene (1.5 mL)
were added under nitrogen atmosphere and the reaction tube was sealed with septa and kept in a
16
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
preheated oil bath at 80 °C. Diazo compound 1j (161 mg, 0.66 mmol, 1 equiv) was dissolved in 1.0 mL
of dry toluene and slowly added to the reaction mixture over a period of half an hour and stirred at same
temperature till the time mentioned in the table below. The reaction mixture was cooled to room
temperature and dissolved in 15 mL DCM. The DCM layer was washed with water (10 mL × 2) and
brine (10 mL × 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to
get the crude product. The crude product was purified by column chromatography to afford the arylated
product 3jf. 130 mg, 61% yield; Rf = 0.54 in 1:4 EtOAc/Hexane; 1H NMR (400 MHz, CDCl3, 24 °C): δ
7.38-7.36 (m, 2H), 7.21-7.17 (m, 2H), 7.13 (dd, J = 8.3, 2.1 Hz, 1H), 6.89-6.85 (m, 2H), 4.91 (s, 1H),
3.79 (s, 3H), 3.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, 24 °C): δ 172.5, 159.2, 139.3, 132.7,
131.5, 130.6, 130.5, 129.7, 129.6, 128.0, 114.4, 55.4, 55.3, 52.6; HRMS: m/z: [M+Na]+ Calcd. for
C16H14Cl2NaO3, 347.0217, found 347.0208.
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
Synthesis of 11: In an oven dried round bottomed flask equipped with a magnetic stir bar, compound
3jf (744 mg, 2.29 mmol) was taken and 2.5 M aq. KOH (2.0 mL) and THF (5 mL) were added. The
round bottom flask was kept in pre-heated oil bath at 60 °C. After completion of the reaction (monitored
by TLC), the reaction mixture was washed DCM (15 mL × 2) and made acidic by drop wise addition of
1N HCl. The aqueous layer was extracted with ethyl acetate (15 mL × 3). Combined organic layer was
washed with brine (20 mL) and dried over anhydrous sodium sulphate. Evaporation of the solvent gave
the corresponding acid, which was directly subjected to next step without further purification. 84%
1
yield; Rf = 0.24 in 2:3 EtOAc/Hexane; H NMR (400 MHz, CDCl3, 24 °C): δ 7.41-7.37 (m, 2H), 7.24-
13
7.20 (m, 2H), 7.15 (dd, J = 8.41, 1.94 Hz, 1H), 6.90-6.86 (m, 2H), 4.93 (s, 1H), 3.79 (s, 3H); C{1H}
NMR (100 MHz, CDCl3, 24 °C): δ 177.7, 159.4, 138.5, 132.8, 131.8, 130.7, 130.6, 129.7, 129.0, 128.1,
114.4, 55.4, 55.3.
In an oven dried round bottom flask equipped with a magnetic stir bar, acid (597 mg, 1.92 mmol)
obtained above was dissolved in dry THF (5 mL) and cooled to 0 °C. Sodium borohydride (290 mg,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
7.66 mmol, 4 equiv) was added portion wise with the interval of 1 min. Subsequently, solution of
elemental iodine (485 mg, 1.92 mmol, 1 equiv) in dry THF (1.0 mL) was introduced to the reaction
mixture drop wise over the period of 10 mins at 0 °C. The reaction mixture was warmed to room
temperature and stirred at room temperature for 24 hours. After completion of the reaction (monitored
by TLC), the reaction mixture was cooled to 0 °C and quenched by addition of 1N HCl. The aqueous
layer was extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine
(10 mL) and dried over anhydrous sodium sulphate. The organic layer was concentrated by evaporation
of the solvent and purified by column chromatography to yield the corresponding alcohol 11. 462 mg,
81% yield; Rf = 0.33 in 3:7 EtOAc/Hexane; IR (νmax, cm-1): 3443, 3201, 3054, 1734, 1374, 1298, 1046,
713; 1H NMR (400 MHz, CDCl3, 24 °C): δ 7.37-7.34 (m, 2H), 7.12 (d, J = 8 Hz, 2H), 7.08 (d, J = 8 Hz,
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
13
1H), 7.86 (d, J = 8 Hz, 2H), 4.10-4.07 (m, 3H), 3.78 (s, 3H), 1.95 (br, 1H); C{1H} NMR (100 MHz,
CDCl3, 24 °C): δ 158.7, 142.5, 134.3, 132.5, 130.6, 130.5, 130.2, 129.2, 127.7, 114.3, 65.7, 55.3, 51.8;
HRMS: m/z: [M+H]+ Calcd for C15H15O2Cl2, 297.0449, found 297.0440.
Synthesis of 12: In an oven dried round bottom flask equipped with a magnetic stir bar, compound 11
(462 mg, 1.55 mmol), triphenylphosphine (1.01 gm, 3.87 mmol) and phthalimide (568 mg, 3.87 mmol)
were added and flask was purged with argon. Dry THF (10 mL) was added at room temperature and the
flask was cooled to 0 °C using ice bath. After 10 mins, DIAD (0.8 mL, 3.87 mmol) was added to the
reaction mixture over the period of 10 minutes. The reaction mixture was warmed to room temperature
and stirred for 6 hours. After completion of the reaction monitored by (TLC), water (25 mL) was added
and extracted with diethyl ether (10 mL × 3). Combined organic layer was washed with brine (10 mL)
and dried over anhydrous sodium sulphate. Evaporation of the solvent followed by purification using
column chromatography afforded the imide.
In an oven dried round bottomed flask, imide (362 mg, 0.85 mmol) obtained above was added and
dissolved in methanol (8 mL). Aqueous solution of hydrazine (0.31 mL, 25 % in water) was added to
18
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
the reaction mixture and heated at 70 °C for 2 hours. After completion the reaction (monitored by TLC),
the compound was extracted with ethyl acetate (10 mL × 3) and dried over anhydrous sodium sulphate.
After evaporation of the solvent, the crude product was purified by column chromatography to yield the
primary amine 12. 160 mg, 35% yield for two steps; Rf = 0.2 in EtOAc; IR (νmax, cm-1): 3379, 2933,
2840, 1630, 1252, 1084, 1027, 803; 1H NMR (400 MHz, CDCl3, 24 °C): δ 7.34 (d, J = 8.2 Hz, 1H), 7.33
(d, J = 2.0 Hz, 1H), 7.1 (d, J = 8.6 Hz, 2H), 7.08 (dd, J = 8.3, 2.1 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 3.88
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
13
(t, J = 7.6 Hz, 1H), 3.77 (s, 3H), 3.24 (d, J = 6.8 Hz, 2H), 1.70(brs, 2H); C{1H} NMR (100 MHz,
CDCl3, 24 °C): δ 158.6, 143.7, 133.5, 132.6, 130.5, 130.5, 130.0, 129.0, 127.5, 114.3, 55.3, 53.2, 46.8;
HRMS: m/z: [M+H]+ Calcd for C15H16NOCl2, 296.0609, found 296.0620.
Supporting information: General experimental, reaction optimization data, and spectral copies of all
the new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgments: We thank the Department of Science and Technology (Project No. SR/S1/OC-
48/2012), and Board of Research in Nuclear Sciences (BRNS) through DAE Young Scientist Award
(Project No. 2012/20/37C/14/BRNS) for financial support. J.G. thanks University Grants Commission
(UGC) for a fellowship.
References:
(1)
a) Shamma, M.; Moniot, J. L. Isoquinoline Alkaloids Research 1972–1977; Plenum
Press: New York, 1978; b) Kametani, T. The Chemistry of the Isoquinoline Alkaloids; The Sendai
Institute of Heterocyclic Chemistry: Sendai, 1974; Vol. 2.
(2)
a) Xu, H.; Lv, M.; Tian, X. Curr. Med. Chem. 2009, 16, 327; b) Keller, H. H.; Schaffner,
R.; Carruba, M. O.; Burkard, W. P.; Pieri, M.; Bonetti, E. P.; Scherschlicht, R.; Prada, M. D.; Haefely,
W. E. Adv. Biochem. Psychopharmacol. 1982, 31, 249; c) Jacob, J. N.; Nichols, D. E.; Kohli, J. D.;
Glock, D. J. Med. Chem. 1981, 24, 1013.
(3)
Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
(4)
a) Heckmann, J. Justus Liebigs Ann. Chem. 1883, 220, 128; b) Rieke, R. D.; Zoltewicz,
1
2
3
J. A.; Aurich, H. G.; Weiss, W.; Vollhardt, K. P. C. Organic Syntheses; Springer Berlin Heidelberg,
4
5
6
1975; Vol. 59.
7
8
(5)
a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234; b) Johansson, C. C. C.;
9
Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49, 676; c) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110,
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
1082.
(6)
(7)
Peng, C.; Zhang, W.; Yan, G.; Wang, J. Org. Lett. 2009, 11, 1667.
Elkin, P. K.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.; Arkhipov,
D. E.; Korlyukov, A. A.; Tartakovsky, V. A. Tetrahedron Lett. 2011, 52, 5259.
(8)
(9)
Tsoi, Y.-T.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2011, 13, 5370.
Wu, G.; Deng, Y.; Wu, C.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2014, 53, 10510.
(10) For selected referece on rhodium catalyzed diazo insertion to aryl C-H bonds see: a)
Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364; b) Ye, B.; Cramer, N. Angew.
Chem., Int. Ed. 2014, 53, 7896; c) Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y. J. Am. Chem. Soc.
2012, 134, 13565; d) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.; Zhang, Y.; Wang, J. Angew. Chem., Int.
Ed. 2014, 53, 1364.
(11) a) Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2011, 1015; b) Li, H.; Zhang, Y.; Wang, J.
Synthesis 2013, 45, 3090; c) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236.
(12) a) Yadagiri, D.; Anbarasan, P. Chem. –Eur. J. 2013, 19, 15115; b) Yadagiri, D.;
Anbarasan, P. Org. Lett. 2014, 16, 2510; c) Rajasekar, S.; Anbarasan, P. J. Org. Chem. 2014, 79, 8428.
(13) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
(14) Ramadhar, T. R.; Batey, R. A. In Boronic Acids; Wiley-VCH Verlag GmbH & Co.
KGaA: 2011, p 427.
(15) Nakachi, N.; Kiuchi, Y.; Inagaki, M.; Inazu, M.; Yamazaki, Y.; Oguchi, K. Eur. J.
Pharmacol. 1995, 281, 195.
20
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
(16) Berthon-Gelloz, G.; Hayashi, T. In Boronic Acids; Wiley-VCH Verlag GmbH & Co.
1
2
3
KGaA: 2011, p 263.
4
5
6
(17) Yu, Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu, L.; Zhang, J. J. Am. Chem. Soc. 2014, 136,
7
8
6904.
9
(18) Owens, C. P.; Varela-Alvarez, A.; Boyarskikh, V.; Musaev, D. G.; Davies, H. M. L.;
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
Blakey, S. B. Chemical Science 2013, 4, 2590.
(19) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron 1999, 55, 1017.
(20) Kothapalli, R. B.; Niddana, R.; Balamurugan, R. Org. Lett. 2014, 16, 1278.
(21) Kim, S.; Lee, J. I.; Kim, Y. C. J. Org. Chem. 1985, 50, 560.
(22) Nagasawa, K.; Ohhashi, K.; Yamashita, A.; Ito, K. Chem. Lett. 1994, 23, 209.
(23) Behera, M.; Venkat Ragavan, R.; Sambaiah, M.; Erugu, B.; Rama Krishna Reddy, J.;
Mukkanti, K.; Yennam, S. Tetrahedron Lett. 2012, 53, 1060.
(24) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.
(25) Sojak, L.; Perjessy, A.; Kubinec, R.; Giumanini, A. G. Chem. papers 1998, 52, 34.
21
ACS Paragon Plus Environment