Palladium-Catalyzed Coupling of Sulfonylhydrazones with Heteroaromatic 2-Amino-Halides (Barluenga Reaction): Exploring the Electronics of the Sulfonylhydrazone

Article abstract of DOI:10.1021/acs.oprd.5b00211

This paper describes a new reactivity of the Pd-catalyzed coupling of 2-amino-3-bromo-aromatic and heteroaromatic compounds with sulfonylhydrazones (Barluenga reaction).The new catalyst system and modulation of the electronic nature of hydrazone that were needed for successful reaction are described herein.

Full text of DOI:10.1021/acs.oprd.5b00211

Communication
pubs.acs.org/OPRD
Palladium-Catalyzed Coupling of Sulfonylhydrazones with
Heteroaromatic 2‑Amino-Halides (Barluenga Reaction): Exploring the
Electronics of the Sulfonylhydrazone
Hongyu Tan,†,§ Ioannis Houpis,*,‡ Renmao Liu,§ Youchu Wang,§ Zhilong Chen,*,†
and Matthew J. Fleming∥
†Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600,
P. R. China
‡Janssen Pharmaceutica, API Development, Turnhoutseweg 30, 2340 Beerse, Belgium
§STA Pharmaceuticals, 288 Fute Zhong Rd, Shanghai 200131, P. R. China
∥Solvias AG, Romerpark 2, 4303 Kaiseraugst, Switzerland
S
* Supporting Information
RESULTS AND DISCUSSION
■
ABSTRACT: This paper describes a new reactivity of the
In our work toward the synthesis of 1, we had the need for a new
Pd-catalyzed coupling of 2-amino-3-bromo-aromatic and
approach, as the existing synthesis (Scheme 1) was rather lengthy
heteroaromatic compounds with sulfonylhydrazones (Bar-
and certainly “violated” both atom and step-economy principles.
luenga reaction).The new catalyst system and modulation
In particular, the rather expensive and difficult to purify ketone 3c
of the electronic nature of hydrazone that were needed for
had to be converted to the nonaflate 3b,14 which was converted
successful reaction are described herein.
to the vinyl boronate 3a, which could then be coupled with 2 to
form the desired product.
So, we considered the much more attractive option of reacting
a derivative of 2 (i.e., 2a or 2b) with the tosylhydrazone 4 under
INTRODUCTION
■
Hydrazones have been valuable synthetic intermediates and have
been used for such diverse purposes as identification and
purification of ketones1,2 and in enantioselective carbon−carbon
bond-forming reactions.3 In 1952 Bamford and Stevens4
discovered that sulfonylhydrazones decompose in a controlled
fashion under basic conditions to form carbon−carbon double
bonds via the diazo derivative. Shapiro et al.5 later discovered that
tosylhydrazones could be converted to a vinyl lithium species,
allowing for further functionalization. Several innovative uses of
sulfonylhydrazones as diazo precursors have been reported as
well.6 However, a more general synthetic utility of hydrazones
was not developed until 2007 when Barluenga7 discovered that
the diazo derivative resulting from the tosylhydrazone
decomposition could be converted to a Pd (II) carbene, which
in the presence of an aryl halide can lead to alkenes (eq 1). This
the Barluenga conditions. From the beginning, we were aware of
the challenges in achieving the desired transformation as there
are few examples in the literature describing successful cross
coupling of heteroaromatic halides with hydrazones.15 Even
more challenging seemed the presence of the N-heteroatom
adjacent to the reaction center.16
One could foresee that significant interference could be caused
by an unprotected nitrogen atom via coordination to the Pd.
Indeed when the unprotected 2 was reacted with 4 (Table 1
entry 1), under typical Barluenga conditions (LiOBu-t, XPhos, in
dioxane), the desired product (1, P = H) was observed as the
minor component of the reaction mixture (2%), while the
dimeric and reduced compounds 5 and 6 were the main reaction
products. In addition, 44% of the starting material 2 remained,
while less than 6% of the tosylhydrazone 4 could be detected in
the crude reaction mixture, indicating that decomposition of 4 via
unproductive pathways was faster than the desired cross-
coupling path. Also significant was the observation that
impurities 7 and 9 were formed (Scheme 2). The former
might explain the unproductive decomposition path of
hydrazone, while the latter may explain the eventual formation
of 8, as we will discuss below.
Changing the Pd source, solvent, temperature, and addition
sequence did not improve the reaction further although slow
addition of 4 afforded slightly higher yield of 1 (ca. 15%).
Therefore, a systematic examination was undertaken to study the
effect of the substrate structure, ligand, metal precursor, base,
initial discovery led to a number of useful applications: from the
synthesis of structurally diverse olefins,8 to dienes,9 enol ethers,10
and sulphones11 to cross coupling of the resulting reactive
intermediate with boronic acid derivatives12 and, recently,
nitrogen nucleophiles to prepare enamines.13
Received: June 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.5b00211
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Scheme 1. Original Approach to Key Intermediate 1
a b
,
Table 1. Evaluation of the Ligand and Base in the Coupling of 2, 2a, or 2b with Hydrazone 4
c
entry
metal prec.
Pd2(dba)3
L
base
starting material
solvent
residual 2/4 % product (yield %)
5 yield % 6 yield % 8 yield %
1
10
11
10
11
10
11
11
17
11
11
11
18
18
14
14
12
13
13
13
20
20
20
20
20
16
17
LiOBu-t
Cs2CO3
LiOBu-t
Cs2CO3
LiOBu-t
Cs2CO3
Cs2CO3
LiOBu-t
Cs2CO3
Cs2CO3
LiOBu-t
Cs2CO3
K3PO4
2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DME
44/6
21/0
24/0
8/4
1 (2)
30
22
13
10
25
20
7
19
20
12
10
24
20
7
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
15
12
2
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2-(MeCN)2
Pd(OAc)2
18
2
1 (40)
3
2a
2a
2b
2b
2a
2a
2a
2
1a (47)
1a (67)
1 (19)
1 (26)
1a (43)
1a (43)
1a (80)
1 (34)
1 (34)
1 (3)
4
5
30/2
18/22
43/0
16/7
43/0
20/2
16/6
12/0
40/8
31/15
0/0
6
7
8
16
1
16
1
9b
10
11
12
13
14b)
15 b)
16 b)
17
18
19
20
21
22
23
24b
25
26
dioxane
dioxane
dioxane
dioxane
DMA
18
27
30
10
13
17
0
20
20
50
19
20
50
25
25
19
20
13
29
42
2
2
18
2
1 (20)
1 (19)
1 (26)
1a (40)
1 (55)
1 (58)
1 (59)
1 (60)
1 (67)
1 (0)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K3PO4
2
dioxane
diglyme
dioxane
diglyme
dioxane
Me-THF
dioxane
Me-THF
Me-THF
DMA
K2CO3
Cs2CO3
K2CO3
K3PO4
2
2
0/0
2
5/0
19
10
10
10
5
2
18/0
13/2
0/13
0/3
K2CO3
K3PO4
2
2
K2CO3
K3PO4
2
2
15/7
0/0
5
K2CO3
K2CO3
K2CO3
K2CO3
2
1 (82)
1 (85)
1 (31)
1a (34)
2
DMA
0/0
2
dioxane
DMA
51/2
3/1
5
7
2a
30
31
a
All screening reactions were conducted at 110 °C with S/C ratio = 50. Pd−L ratio = 1:2. The solids were added first under an Ar blancket followed
b
c
by the solvents. All ligands and Pd precursors were handled in a glovebox as was LiOBu-t. S/C ratio = 100. Quantitative HPLC yields based on
analytically qualified standards.
Scheme 2. Barluenga Approach to 1
B
DOI: 10.1021/acs.oprd.5b00211
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Communication
solvent, and order of addition to the outcome of the reaction.
Some representative results are shown in Table 1.
In order to be able to use the effectiveness of the Barluenga
reaction for our synthesis, we had to understand the reaction
conditions that induced the formation of 8 in the hopes of
suppressing it.
First we investigated whether the formation of 8 was due to the
structures of our particular substrate or a general phenomenon of
α-amino substrates (Scheme 3). Reaction of 2-Br aniline 21 with
From these experiments the following conclusions can be
derived. (a) Protecting the nitrogen makes little difference in the
product distribution under the original reaction conditions
(Table 1, entries 1, 3, 5). (b) CataXium A (11) was at first
thought to be a better ligand when combined with carbonate
bases (Table 1, entries 2, 4, 5, 7) and Boc protection on the
nitrogen. However, (c) in order to achieve useful yields and
reduce byproducts, two equivalents of the expensive sulfonylhy-
drazone were required (Table 1, entry 9). Moreover, addition of
the latter had to be carried out over 8 h at the reaction
temperature, a tedious and hazardous process on medium- and
large-scale production.
a
Scheme 3. Coupling of 21 with 24a
a
Conditions A: [Pd2(dba)3] 1%, XPhos 4%, LiOBu-t, dioxane 110 °C.
Conditions B: Pd(OAc)2 3%, t-Bu2MeP-HBF4, (6.5%), K2CO3, DMA,
110 °C.
hydrazone 24a under the normal Barluenga conditions
(conditions A, Scheme 3) showed the same behavior as the
reaction of 2 with 4, with low yields of the desired 25a,
decomposition of 24a, and formation of 5,10-dihydrophenazine
(21c) as the byproduct. On the other hand, using the best
conditions for the preparation of 1 (conditions B, Scheme 3)
afforded 25a in good yield along with 28a, analogously to what
previously observed with 2 and 4. Clearly the formation of the
tolyl adducts (8 and 28a) is a general feature of the reaction in the
presence of the nitrogen heteroatom. In order to understand and
then prevent its formation, we decided to investigate the reaction
of the various aniline isomers, the substitution on the nitrogen
heteroatom and the electronic properties of the sulfonylhy-
drazone (Figure 2 and Table 2) under different reaction
conditions (A or B in Scheme 3).
For the coupling of ortho substituted anilines with
sulfonylhydrazones, the electronics of the aryl group of the
sulfonylhydrazone seem to be the most important factor under
our reaction conditions (condition B, Table 2, entries 1−3).
The election-rich sulfonylhydrazone 24b afforded only 65%
yield of the desired compound 25a with a significant 30% yield of
the anisole coupling product 28b. On the other hand the nitro
sulfonylhydrazone 24d gave the highest yield of 25a (95%) and
none of 28d. Interestingly, with the electron-rich sulfonylhy-
drazone 24b, even the para substituted and protected aniline
23b, normally the” best behaved” of the substrates, formed 7% of
the undesired coupling product 30a. This interesting behavior
implies that, under appropriate conditions and in the absence of
external coupling partners, electron-rich sulfonylhydrazones can
provide products resulting from an internal collapse of the
hydrazone (extruding SO2 and N2) to afford products of an
Figure 1. Ligands used in this study.
Given the observations above, we decided to focus our
attention on the free amino derivative 2, which would allow us to
avoid the two additional steps of protection and deprotection.
Our efforts were rewarded (Table 1, entries 11−24) when we
were able to achieve good yields and suppress the formation the
byproducts 5 and 6, by using di-tert-butyl methyl phosphine as
the ligand and milled K2CO3 as the base and by using 1.1−1.2
equiv of the sulfonylhydrazone. Surprisingly the reaction works
best in dimethylacetamide which is not the preferred solvent for
Barluenga reactions (Table 1, compare entries 20−23). The S/C
ratio can be improved to 100−150 without significant loss in
reaction efficiency (Table 1, entries 23, 24). It is worth noting
that the related ligand 13 gave satisfactory results, while hindered
but very electron-rich ligands (12, 14, 15, 18 or 19) gave lower
yields and poor chemoselectivity. Bidente ligands 16 and 17 with
different bite angles were also not very effective (Table 1, entries
25, 26).
When the reaction mixture from entries 23 and 24 was
examined further, we were surprised to find that, although 5 and
6 could not be detected, a new impurity (8) was formed in
substantial amounts (ca. 15%).
C
DOI: 10.1021/acs.oprd.5b00211
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Table 2. Evaluation of the Substitution of the Aniline and
Electronics of the Hydrazone
a
entry react. cond. aniline hydrazone product % yield by-pdt % yield
1
B
B
B
B
A
A
A
A
A
B
A
B
A
B
A
B
A
B
21a
21a
21a
23b
21a
21a
21a
21b
23a
23a
23b
23b
23b
23b
23b
23b
22
24b
24c
24d
24b
24b
24c
24d
24d
24d
24d
24b
24b
24d
24d
24c
24c
24d
24d
25a (65%)
25a (85%)
25a (95%)
27a (83%)
25a (35%)
25a (30%)
25a (15%)
25b (30%)
27a (92%)
27a (40%)
27b (88%)
27b (83%)
27b (71%)
27b (95%)
27b (87%)
27b (84%)
26 (95%)
28b (30%)
28c (11%)
28d (0%)
30a (7%)
21c (30%)
21c (11%)
21c (35%)
21c (0%)
30c (0%)
30c (0%)
30b (0%)
30b (0%)
30b (0%)
30b (0%)
30b (0%)
30b (0%)
29c (0%)
29c (0%)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
22
26 (38%)
a
Conditions A: [Pd2(dba)3] 1%, XPhos 4%, LiOBu-t, dioxane 110 °C.
Conditions B: Pd(OAc)2 3%, t-Bu2MeP-HBF4, (6.5%), K2CO3, DMA,
110 °C.
Scheme 4. Intermolecular vs Intramolecular Coupling of
Sulfonylhydrazones
Figure 2. Starting materials, products, and byproducts of the Barluenga
reaction of substituted anilines with hydrazone derivatives.
apparent intramolecular coupling reaction. On the other hand,
the electron poor analogues do not participate in this reaction
and so constitute the preferred starting material when the
intermolecular coupling reaction is desired with external
reagents. We have been able to demonstrate that this is a general
reaction (Scheme 4), although it appears that the intermolecular
variant requires air to achieve synthetically useful results, and will
present our results in due course.
aniline substitution patterns and that most functionality is well-
tolerated.
The original conditions (condition A, Table 2, entries 5−8) for
this coupling reaction seem to be unsuccessful with the ortho
substituted substrate even when the nitrogen is protected.
Surprisingly, for the meta and para substituted 23a, 23b, and 22,
conditions B, which were so successful with the ortho substituted
anilines, perform poorly compared to the typical Barluenga
conditions A (compare entries 9−10 and 17−18, Table 2).
Finally, the protected para substituted 23b coupled well
irrespective of the procedure used or the electronic nature of
the hydrazone coupling partner (Table 2, entries 11−16).
Having established the reactivity patterns of the aniline
regioisomeric halides and the electronic properties of the
hydrazone and derivatives, we examined the electronic properties
of various o-bromoaniline substrates in their coupling with our
best hydrazone 24d under reaction condition B (Figure 3). The
results show that there is no significant electronic effect of the
Figure 3. Scope of the coupling of o-bromoanilines with hydrazone 24d.
D
DOI: 10.1021/acs.oprd.5b00211
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Finally, we were able to complete the synthesis of our key
intermediate 1 in 85% isolated yield free from contamination by
38 as shown in eq 2:
*E-mail: zhlchen@dhu.edu.cn.
Notes
The authors declare no competing financial interest.
REFERENCES
■
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CONCLUSION
■
In conclusion, we have discovered an interesting variation of the
Barluenga reaction that is useful in the coupling of both
heterocyclic and carbocyclic ortho-halo-amino aromatics with
sulfonylhydrazones. In addition, the possibility of a very exciting
new reactivity of hydrazones has been discovered, namely, the
extrusion of N2 and SO2 from a hydrazone and the formally
intramolecular cross coupling of the two organic components.
More on this reactivity and its synthetic utility will be reported
soon.
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EXPERIMENTAL SECTION
■
A mixture of compound 2 (52.6 g, 95.2 wt %, 159.6 mmol, 1.0
equiv), t-Bu2PMeHBF4 (2.57 g, 10.37 mmol, 6.5 mol %),
Pd(OAc)2 (1.08g, 4.79 mmol, 3 mol %), K2CO3 (66.2 g, 478.9
mmol, 3.0 equiv) (Aldrich, powder), and DMA (900 mL) was
heated to 110 °C under a nitrogen atmosphere. A solution of
compound 37 (75.2 g, 231.4 mmol, 1.45 equiv) in DMA (80 mL)
was added to the mixture dropwise over 3.0 h at 110 °C. After
addition, the mixture was stirred for 3.0 h. The mixture was
cooled to 25 °C. Water (2 L) was added and the mixture was
stirred for 1.0 h. The mixture was filtered, and the cake was
washed with water (100 mL). The cake was dissolved in MTBE
(700 mL). 0.5 N HCl solution (200 mL) was added. The phase
was separated. 0.5 N HCl solution (100 mL) was added, and the
phase was separated. The combined aqueous layer was washed
with MTBE (400 mL). 5% of NaOH solution (350 mL) was
added to the aqueous layer after phase separation. The
suspension was filtered. The cake was washed with water (100
mL) and dried at 50 °C to afford compound 1 (46.3 g, 84.7%
yield). 1H NMR (400 MHz, DMSO-d6) δ 0.98 (s, 6H), 1.13 (s,
6H), 1.27 (s, 6H), 1.38 (t, J = 12.74 Hz, 2H), 1.47 (s, 2H), 1.62−
1.71 (m, 2H), 1.94−2.01 (m, 2H), 2.31−2.39 (m, 2H), 4.70 (s,
2H), 5.83−5.89 (m, 1H), 6.83 (d, J = 8.16 Hz, 1H), 6.97 (d, J =
8.16 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 25.6, 28.1,
28.5, 28.7, 34.2, 35.4, 35.8, 43.3, 71.9, 119.6, 123.0, 125.5, 135.2,
139.3, 144.6, 151.7.
Aznar, F.; Valdes
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(14) For the use of enol nonaflates, instead of the more difficult to
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.5b00211.
■
S
Spectral data for all new compounds listed in the paper
(PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: yhoupis@its.jnj.com.
■
E
DOI: 10.1021/acs.oprd.5b00211
Org. Process Res. Dev. XXXX, XXX, XXX−XXX