Synthesis of [N,P] ligands based on pyrrole. Application to the total synthesis of arnottin i

Article abstract of DOI:10.1016/j.tet.2014.01.002

This paper describes the synthesis of a new class of [N,P] ligands based on pyrrole with a dimethylamino group as hard donor and a phosphine moiety as soft base. We have also modified the phosphine fragment to change the electronic and steric properties of these ligands. Palladium complex 3a proved to be very efficient in Heck cross-coupling reactions and in intramolecular aryl-aryl couplings of esters and amides. We have demonstrated the applicability and efficiency of this novel catalyst in the total synthesis of the natural product arnottin I.

Full text of DOI:10.1016/j.tet.2014.01.002

Tetrahedron 70 (2014) 1422e1430
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of [N,P] ligands based on pyrrole. Application to the total
synthesis of arnottin I
a
a
a
ꢀ
ꢀ
ꢀ
ꢀ
Jesus V. Suarez-Meneses , Edgar Bonilla-Reyes , Ever A. Ble-Gonzalez ,
b
a
a,
*
ꢀ
M. Carmen Ortega-Alfaro , Ruben Alfredo Toscano , Alejandro Cordero-Vargas
,
a,
*
ꢀ
ꢀ
ꢀ
Jose G. Lopez-Cortes
a
ꢀ
ꢀ
ꢀ
ꢀ
Instituto de Química, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, Coyoacan, C.P. 04510 Mexico, D.F. Mexico
Instituto de Ciencias Nucleares, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, Coyoacan, C.P. 04510 Mexico, D.F.
b
ꢀ
ꢀ
ꢀ
ꢀ
Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes the synthesis of a new class of [N,P] ligands based on pyrrole with a dimethylamino
group as hard donor and a phosphine moiety as soft base. We have also modified the phosphine frag-
ment to change the electronic and steric properties of these ligands. Palladium complex 3a proved to be
very efficient in Heck cross-coupling reactions and in intramolecular arylearyl couplings of esters and
amides. We have demonstrated the applicability and efficiency of this novel catalyst in the total synthesis
of the natural product arnottin I.
Received 28 October 2013
Received in revised form 21 December 2013
Accepted 2 January 2014
Available online 8 January 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
[N,P] ligands
Pd coupling
Total synthesis
Arnottin I
1. Introduction
arylpyrrole ligands (PAP ligands), which have demonstrated
a broad range of catalytic applications, and are commercially
The structural diversity of natural products has been driven by
imagination and creativity in organic synthesis, and has achieved
extraordinary progress in the development of procedures for
obtaining complex molecules.1 In this context, the development of
novel strategies to achieve coupling reactions promoted by a tran-
sition metal has made possible to obtain structurally complex
molecules, forming extremely selective bonds despite the presence
of a wide variety of reactive functional groups.2 Therefore, the de-
velopment of new bidentate ligands has acquired great significance
and currently a large number of ligands with wide-ranging struc-
tural motifs are known.3 Mixed donor ligands [N,P]4 have been
successfully used in a large number of catalytic processes such as
polymerization and oligomerization of olefins,5 CeC coupling re-
actions,6 hydrogenation, and hydroformylation reactions,7 among
others.
available as CataCXium-PÒ.8 In all cases, the substituents connected
to the pyrrole nitrogen atom are based on aryl substituents forming
an NeC bond. More recently, Enthaler and co-workers9a described
a new class of PAP ligands, in which the carbon group was replaced
by an amine functionality to generate an NeN bond. Thus, the
amine-based group can be an additional donor, which can be co-
ordinated to the metal center. However, their coordination behav-
ior continues to be that of a monodentate ligand in the presence of
iron (0) carbonyl precursors, a fact, which can be attributed to the
steric hindrance of introduced diphenylamino groups. Inspired by
this concept, we have envisaged introducing a dimethylamino
group at 1-position of the pyrrole backbone with the idea of re-
ducing the steric hindrance of this amino group and increasing the
s-donor character, to allow its coordination as a bidentate ligand.
We report below an efficient synthesis of new [N,P] ligands based
on pyrrole, with a combination of hard and soft donor atoms
(Fig. 1).
We have applied variations of the phosphine fragment in order
to modify the electronic and steric properties of these ligands. The
Pd complexes derived from these ligands are very efficient in inter-
and intramolecular coupling reactions, and the applicability of
these couplings became evident with the total synthesis of arnottin
I, a coumarin-based natural product.
However, despite the variety of frameworks used to obtain
bidentate ligands, only a few examples contain pyrrole as the main
structural motif.8,9 Some of them are based on 2-phosphanyl-1-
* Corresponding authors. Tel.: þ52 55 56224464; fax: þ52 55 56162203; e-mail
addresses: acordero@unam.mx (A. Cordero-Vargas), jglcvdw@unam.mx
ꢀ
ꢀ
(J.G. Lopez-Cortes).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.002

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J.V. Suarez-Meneses et al. / Tetrahedron 70 (2014) 1422e1430
1423
Fig. 1. Features of [N,P] ligands based on pyrrole.
2. Results and discussion
2.1. Synthesis of [N,P] ligands based on pyrrole and their
palladium (II) complexes
The synthesis of bifunctional ligands 2 was made taking ad-
vantage of the regioselective lithiation of 1-(dimethylamino)pyr-
role 1.10 This metalation was easily accomplished using n-BuLi at
ꢀ78 ꢁC in anhydrous THF. Thus, the 2-lithiopyrrole obtained was
Fig. 2. ORTEP representation of ligand 2a. Ellipsoids are shown at 30% probability
ꢁ
ꢁ
level. Selected bond length (A) and bond angles ( ): P(1)eC(14B), 1.776(19); P(1)eC(2),
1.815(2); P(1)eC(8), 1.839(2); P(1)eC(14), 1.879(12); N(1)eC(5), 1.362(3); N(1)eC(2),
1.370(3); N(1)eN(2), 1.411(3); N(2)eC(7), 1.460(4); N(2)eC(6), 1.462(3); C(14B)e
C(15B), 1.377 (12); C(14B)eC(19B), 1.393(12); C(15B)eC(16B), 1.401(12); C(16B)eC(17B),
1.376(11); C(17B)eC(18B), 1.374(11); C(18B)eC(19B), 1.372(11); C(14B)eP(1)eC(2),
104.5(8); C(14B)eP(1)eC(8), 103.0(12); C(2)eP(1)eC(8), 97.60(10); C(2)eP(1)eC(14),
99.7(5); C(8)eP(1)eC(14), 101.3(8); C(5)eN(1)eC(2), 109.6(2); C(5)eN(1)eN(2),
128.65(19); C(2)eN(1)eN(2), 121.76(18); N(1)eN(2)eC(7), 110.9(2); N(1)eN(2)eC(6),
109.90(19); C(7)eN(2)eC(6), 111.3(2); C(15B)eC(14B)eC(19B), 117.0 (13); C(15B)e
C(14B)eP(1), 125.5(15); C(19B)eC(14B)eP(1), 117.4(14); C(19)eC(14)eP(1), 118.3(9);
N(1)eC(2)eC(3), 106.7(2); N(1)eC(2)eP(1), 120.70(16); C(3)eC(2)eP(1), 132.45(19);
C(13)eC(8)eC(9), 117.2(2); C(13)eC(8)eP(1), 124.62(19); C(9)eC(8)eP(1), 118.13(18);
C(15)eC(14)eP(1), 123.0(9).
quenched with the corresponding chlorophosphine at
0
ꢁC,
making possible to obtain good yields of bidentate ligands 2aec
(Scheme 1).
Scheme 1. Preparative route to of [N,P] ligands based on pyrrole.
The [N,P] ligands based on pyrrole 2aec were characterized by
spectroscopic techniques and obtained data were consistent with
the literature for this kind of compounds; 31P NMR spectra reveal
interesting properties for these ligands, showing that the signals for
the phosphanyl pyrrole 2aec are shifted to lower frequencies in
comparison to phenyl phosphines (Table 1),11 as a result of the
electron-releasing effect of the pyrrole ring.
Scheme 2. Coordination of [N,P] ligands 2aec with Pd(MeCN)2Cl2.
comparison to 2aec. This behavior has also been observed in 13C
NMR (Ddz9 ppm). These spectroscopic data lead us to suggest that
these ligands behave as bidentate donors.
Table 1
31P NMR chemical shift for [N,P] ligands based on pyrrole and their phosphine
analogues
R
PyrrolePR2 (2)
PhPR2
Dd
2.2. Catalytic evaluation of complexes 3aec in coupling
reactions
Ph
o-Tolyl
t-Bu
ꢀ29.2
ꢀ45.7
ꢀ1.2
ꢀ6
23.2
24
41.7
ꢀ21.7
40.5
To evaluate the potential of complexes 3aec as catalyst precursors
in the MizorokieHeck reaction, we performed a series of experiments
using cross-coupling between methyl acrylate and 4-iodotoluene as
a model reaction. To determine optimal conditions, the reaction was
performed under different conditions, screening parameters such as
base, reaction time, and catalyst loading under conventional heating
at 140 ꢁC. The results are summarized in Table 2.
The structural arrangement for 2a was unequivocally estab-
lished by X-ray diffraction analysis; one phenyl ring in this struc-
ture is in disorder generating two orientations in 78:22 ratio. Only
the major contributor is shown in Fig. 2.
Once ligands 2aec were obtained, we studied their coordination
ability to Pd (II). We prepared complexes 3aec by treating 2aec
with Pd(CH3CN)2Cl2 in CHCl3, obtaining, in all cases, a yellow
powder, after recrystallization from hexaneeCH2Cl2 (Scheme 2).
As expected, the 31P NMR spectra showed that the coordinated
phosphine signals are shifted to higher frequencies regarding the
free ligands, due to coordination with the Pd atom. Likewise, in 1H
NMR the signal assigned to the dimethylamine moiety coordinated
to Pd (II) is shifted by approximately 1 ppm to a higher frequency in
Our initial exploration of reaction conditions focused on catalyst
loading using complex 3a as a catalyst, DMF as a solvent, and Et3N
as a base. As shown in Table 2, it is evident that the highest TON
value (entry 6) was achieved with low catalyst loading (0.01 mol %)
after 2 h of reaction time. When we used higher catalyst loading
under the same conditions (entries 2 and 3), the reaction produced
high conversions of the coupled product but the isolated yield was
slightly decreased. Naturally, no reaction took place in the absence
of the catalyst (entry 1).

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J.V. Suarez-Meneses et al. / Tetrahedron 70 (2014) 1422e1430
1424
Table 2
more slowly at lower temperatures, but remains effective toward
the formation of coupling product, in good yields. As a further step,
we also compared these findings with known related catalysts in
order to make evident the performance of these new complexes.
Thus, two experiments were carried out using as commercial pal-
ladium complexes, (dppe)PdCl2 and (rac-BINAP)PdCl2 in the same
reaction conditions (Table 2, entries 19 and 20). The results ob-
tained indicate that complex 3a is more active and efficient in this
coupling reaction than commercial palladium catalyst at these re-
action conditions.
Having established an effective catalytic system for this cross-
coupling reaction, we next examined the scope of this procedure.
As shown in Table 3, treatment of various aryl iodides with olefins,
under optimized conditions as described above, was efficiently
carried out in moderate to good yields of the corresponding cross-
coupled products. The results indicated that catalyst 3a is active
and tolerant for a range of functionalities.
Evaluation of catalytic conditions for MizorokieHeck cross-coupling of 4-
iodotoluene with methyl acrylatea
Entry Catalyst
Time (h) [Pd]
(mol %)
Base
Yieldb (%) TON
0
TOF
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3a
3b
3c
2
2
2
0.5
1
2
3
1
1
1
1
1
1
1
1
1
0
0.5
0.1
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K3PO4
K2CO3
0
0
90
90
97
31
95
99
90c
91
97
180
970
485
6200
9500
4950
3000
9100
9700
6100
5500
9700
7200
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.005
0.005
0.005
0.005
0.005
0.005
0.005
3100
9500
9900
9000
9100
9700
6100
5500
9700
7200
9
10
11
12
13
14
15
16
17
18
19
20
Na3PO4 61
Na2CO3 55
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
97
72
99
99
77
90
93
43
79
Table 3
Scope of MizorokieHeck cross-coupling using 3aa
19,800 19,800
19,800 19,800
15,400 15,400
3a
3a
12d
18,000
18,600
8600
1500
517
8600
36e
1
(dppe)PdCl2
(BINAP)PdCl2
1
15,800 15,800
a
All reactions were performed with 5.0 mmol of the 4-iodotoulene, 6.0 mmol of
the alkene, 5 mL of DMF, and 5.6 mmol of base at reflux conditions.
b
Isolated yields.
c
The formation of side-products is observed.
d
Temperature: 120 ꢁC.
Entry
R1
R2
Time (h)
Yieldb
TON
TOF
e
Temperature: 100 ꢁC.
A
B
1
2
3
4
5
6
7
8
4-OMe
4-NH2
4-Me
2-Me
3-Me
4-H
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
Ph
Ph
Ph
Ph
Ph
Ph
Fc
4-Py
1
2
2
2
1
2
4
4
48
21
24
21
29
7
23
2
24
98
90
99
76
90
90
66
95
26
88
87
72
69
21
86
32
46
d
d
d
d
d
d
d
d
d
11
7
4
0
1
11
16
7
19,600
18,000
19,800
15,200
18,000
18,000
13,200
19,000
26
20,000
18,800
15,200
13,800
4400
19,600
9000
19,800
7600
18,000
9000
3300
The results listed in Table 2 clearly show that optimal reaction
time was 2 h of heating in DMF at 140 ꢁC. After 3 h of reaction time
(entry 7), the expected methyl cinnamate was obtained in only 90%
yield. We then examined the effect of the base on the Mizor-
okieHeck coupling reactions yield using 0.01 mol % catalyst loading
of 3a. After screening a variety of inorganic bases, K2CO3 was found
to be the most effective base (entry 9), while K3PO4 also provided
good results (entry 8). In contrast, low conversions were achieved
when the counter-ion of the base was changed (entries 10 and 11),
probably due to the poor solubility of Na2CO3 and Na3PO4. When we
used an organic base, high yields were also obtained when the re-
action was carried out with Et3N (entry 5). Based on these results,
Et3N, an inexpensive and effective base, was selected as the best base
for the Heck reaction using the mixed [N,P] bidentate ligand 3a.
We carried out optimization studies testing the same model
reaction (entries 12e16) using some precatalyst with different
substituents on the phosphine moiety, in an effort to select the
most effective precatalyst for the Heck reaction. Based on results in
Table 2, it can be seen that the activity of the precatalyst bearing an
o-tolyl phosphine group (3b) resulted in an identical yield of the
desired product (entry 15) in comparison with complex 3a, which
contains a diphenyl phosphine group. However, when the coupling
reaction was performed employing complex 3c, there was a signif-
icantly lower yield (entry 16). This behavior could be explained
4-Br
4-CF3
4-OMec
4-Me
2-Me
3-Me
4-OMe
4-NH2
4-H
4750
9
0.54
10
11
12
13
14
15
16
17
952
783
723
476
629
844
457
442
19,400
9600
10,600
4-Me
4-Me
a
All reactions were performed with 5.0 mmol of the aryl iodide, 6.0 mmol of the
alkene, 5 mL of DMF, 0.005 mol % 3a, and 5.6 mmol of Et3N at reflux conditions.
b
Isolated yields.
c
5.0 mmol 4-Bromoanisole as aryl halide, 6.0 mmol of the alkene, 5 mL of DMF,
and 5.6 mmol of Et3N, 20 mol % of TBAB, 1 mol % [Pd] at reflux conditions.
The effect of the substituent on the aromatic ring of the iodo-
benzene was examined. For this purpose, we performed a reaction
between activated and deactivated aryl iodides with methyl acry-
late (Table 3, entries 1e9). In every case, the substrate was con-
verted to the desired methyl cinnamate with isolated yields ranging
from 66 to 99%. From the results, it is evident that the more
electron-rich aryl iodides induce faster reactions, obtaining excel-
lent yields of the coupling products (entries 1e3). In the case of 4-
bromo iodobenzene, we observed the formation of other by-
products in trace amount (entry 7). To probe the effectiveness of
this catalytic system in the case of other aryl halides, we also tested
4-bromoanisole as substrate (entry 9), obtaining the corresponding
cinnamate in 26% yield after 48 h, although 20 mol % of TBAB as
additive and 1 mol % of catalyst loading were required. This result
considering that aliphatic phosphines have a strong
s-donor be-
havior, thereby increasing the electron density on the palladium
atom, unfavorable to the reductive elimination in the Heck catalytic
cycle. The steric effect of the phosphine moiety could also play an
important role in the catalytic cycle, disfavoring the olefin co-
ordination to palladium atom, and in consequence providing a poor
yield of coupling product.
Additionally, two experiments at different temperatures were
carried out (entries 17 and 18). As expected, the reaction proceeds

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J.V. Suarez-Meneses et al. / Tetrahedron 70 (2014) 1422e1430
1425
showed a poor activity of this catalytic system during the oxidative
addition into the above mentioned aryl bromide.
a catalyst loading of 5 mol % of 3a (entry 3) affords 50% yield of the
expected compound. The yield of 5a was increased to 80% when the
reaction was carried out with 1 mol % of 3a (entry 4). We found that
0.5 mol % of complex 3a provides the best results, with an optimum
yield of the coupled product (entry 5). Optimized conditions for
arylearyl coupling involved the use of AcONa as a base and
0.5 mol % of 3a in DMF at 140 ꢁC. As a further step, we evaluated the
scope of this reaction toward the arylation of amide 4b (entry 6),
obtaining 5b in moderate yield.
Substrate scope of the reaction could be extended to non-
activated olefins (entries 10e15). Thus, we decided to perform
the MizorokieHeck reaction with some iodobenzenes and styrene.
We observed a significant electronic effect of the para-substituents
on the aryl iodide on the yield of the reaction. For example, when
0.005 mol % 3a was used in presence of iodotoluene, iodoanisole, or
iodoaniline (entries 10, 13, and 14), we obtained the corresponding
stilbene in 88, 69, and 21% yields, respectively. These results show
that strong releasing groups caused a decrease in reaction yield
while a weak electron-donor group or iodobenzene (entries 10 and
15) makes possible to achieve good stilbene yields. The position of
the substituent on aryl iodide causes a slightly positive effect on the
regioselectivity of this reaction (entries 11 and 12), thus ortho or
meta groups on the aryl iodide favor the formation of the corre-
sponding stilbene product.
The MizorokieHeck reaction of 4-iodotoluene was also ex-
tended to 4-vinylpyridine and vinylferrocene in the presence of 3a
as catalysts (entries 16 and 17). In both cases, the corresponding
coupling products were obtained in moderate yields. In every case,
moderate regioselectivity toward internal olefins was observed
with a small amount of terminal olefins.
Before testing our catalyst in the total synthesis of arnottin I, we
investigated a biaryl cyclization reaction of ester 4a and amide 4b,12
with an iodine atom as a leaving group in order to demonstrate the
viability of our catalyst to generate the chromone 5a or the phe-
nanthridinone 5b, respectively (Table 4).
2.3. Total synthesis of arnottin I
Encouraged by our results, and in order to demonstrate the
applicability of the catalysts reported in this paper, we decided to
carry out the total synthesis of a pharmacologically significant
natural product. Arnottin I (6) is a coumarin-based natural product
isolated from Xanthoxylum arnottuanum as a non-alkaloid minor
component.13 Its close structural relationship to the aglycon of
gilvocarcins (defucogilvocarcins) and its pharmacological proper-
ties make it a very interesting synthetic target (Fig. 3).14 Recently,
our group reported a formal total synthesis of defucogilvocarcin M
7, which consisted in the first place in the preparation of a key a-
tetralone by a free radical additionecyclization sequence. In one of
the final steps, an intramolecular Pd(0)-catalyzed arylearyl cou-
pling was performed, providing compound 7 product after a final
deprotection step.15
Table 4
Evaluation of catalytic conditions for biaryl cyclization reactiona
Fig. 3. Arnottin I (6) and defucogilvocarcin M (7).
Thus, we decided to perform total synthesis of arnottin I using
a similar strategy as that for defucogilvocarcin M (7). As shown in
the retrosynthetic analysis (Scheme 3), arnottin I (6) would be
obtained from ester 8 through an arylearyl coupling catalyzed by
complex 3a. Ester 8 would be assembled by esterification of
naphthol 9 with acid 10,16 the latter being prepared from known
alcohol 11. Although naphthol 9 had been prepared by other
means,14d,17 we chose to prepare it by aromatization of compound
Entry AreI Product Catalyst
Base
[Pd] (mol %) Time (h) Yieldb (%)
1
2
3
4
5
6
4a
4a
4a
4a
4a
4b
5a
5a
5a
5a
5a
5b
Pd(PPh3)2Cl2 AcONa 20
21
5
79
0
3a
3a
3a
3a
3a
Et3N
AcONa
AcONa
AcONa 0.5
AcONa 0.5
1
5
1
2
1.5
50c
80
92
60c
2
10
a
All reactions were performed with 1.0 mmol of the aryl iodide, 6 mL of DMF and
1.2 mmol of base at 160 ꢁC.
12 because, as demonstrated by Zard,18
a-tetralones like 12 are
b
Isolated yields.
easily accessible through a free radical additionecyclization se-
quence between acetophenone xanthates and an appropriate rad-
ical acceptor. Moreover, 12 is a very valuable synthetic intermediate
that could serve to prepare a variety of naphthalene derivatives,19
such as naphthylamines, allowing the synthesis of other similar
natural products like nitidine16,20 or chelerythrine.21 In this way,
c
A complex mixture of side-products is observed by TLC, decreasing the yield of
desired product.
Initially, we performed arylearyl coupling of ester 4a using
a commercially available palladium catalyst. When the reaction was
carried out with Pd(PPh3)Cl2, AcONa as a base in DMF at 160 ꢁC
(entry 1), a catalyst loading of 20 mol % was needed to achieve, after
21 h of reaction, a good yield (79%) of the corresponding chromone.
With the expectation that our catalyst could provide better results,
we applied our findings in the MizorokieHeck reaction on this
arylearyl coupling. Unfortunately, when Et3N was used as a base
(entry 2), the desired product was not obtained. In the presence of
AcONa as a base, better results were accomplished and moderate to
good yields of chromone 5a were obtained (entries 3e5).
the required
a-tetralone would be obtained from a free radical
additionecyclization sequence between xanthate 13 and vinyl
pivalate.
Based on this plan, the first part of the synthesis consisted in the
preparation of tetralone 12. Thus, as shown in Scheme 4, reaction of
compound 1422 with potassium O-ethylxantogenate yielded the
desired radical precursor 13 (68% yield). When the latter reacted
with vinyl pivalate in the presence of 0.4 equiv of dilauroyl peroxide
(DLP, added portionwise), a 73% yield of adduct 15 was isolated. The
next step consisted in the radical cyclization onto the aromatic ring,
which was expected to furnish the two possible regioisomers. In
The effect of catalyst loading on arylearyl coupling reactions
using catalyst 3a was then examined. Thus, the reaction of 4a using

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J.V. Suarez-Meneses et al. / Tetrahedron 70 (2014) 1422e1430
1426
Scheme 5. Aromatization of tetralone 12.
Scheme 3. Retrosynthetic analysis for arnottin I (6).
practice, when we performed the reaction with 1.4 equiv of DLP
(added portionwise) in refluxing 1,2-dichloroethane, a separable
mixture of desired tetralone 12 and undesired product 120 was
obtained in a 7:3 ratio in favor of 12 in 60% combined yield, prob-
ably due to a steric repulsion between the OPiv group and the 3,4-
ethylendioxy moiety.
Scheme 6. Reagents and conditions: (a) Jones reagent, acetone, rt; (b) (COCl)2, NEt3,
DMF cat., CH2Cl2, 0 ꢁC to rt; (c) 8, NEt3, DMAP cat., CH2Cl2, 0 ꢁC to rt.
At this stage, we proceeded to carry out final cyclization for the
synthesis of arnottin I. In order to compare the efficiency of our
catalyst with a commercially available one, we first repeated Har-
ayama’s work,14a treating ester 8 with different sources of Pd(0),
obtaining arnottin I in moderate to good yields. Thus, we decided to
repeat the reaction with substrate 8 and Pd(PPh3)2Cl2, which was
reported to produce a 52% yield of arnottin I. Disappointingly, in our
hands, the expected compound 6 could only be observed as a minor
product and isolated at a very low yield (5%) even with a large load
(20%) of catalyst. Next, our catalyst (3a) was tested with the same
substrate and under the same conditions (sodium acetate in
refluxing DMF). Unlike Pd(PPh3)2Cl2, only a 0.5 mol % charge of
complex 3a was needed for the complete conversion of 8 into
arnottin I (6) in 35% yield, recovering a small amount of the starting
material. Even if the yield remained low due to the presence of
some traces amount of unidentified by-products, the reaction was
cleaner and easier to purify than when a commercially available
palladium complex was used (Scheme 7).
Scheme 4. Reagents and conditions: (a) KSC(S)OEt, acetone, rt; (b) vinyl pivalate, DLP
(0.4 equiv), 1,2-dichloroethane, reflux; (c) DLP (1.4 equiv), 1,2-dichloromethane, reflux.
With the desired key tetralone in hand, we proceeded to
transform it into the key naphthol 9. We found that when a solution
of 12 in toluene was treated with 3 equiv of PTSA, aromatization
took place, albeit providing a low yield (38%, Scheme 5). Attempts
to optimize the reaction by varying the acids, solvents, and reaction
times were unsuccessful, leading to incomplete reactions and/or
even lower yields.
Scheme 7. Reagents and conditions: (a) Pd(PPh3)2Cl2 (20 mol %), AcONa, DMF, 140 ꢁC;
(b) 3a (0.5 mol %), AcONa, DMF, reflux.
On the other hand, the required acid chloride 16 was prepared in
two steps from known alcohol 1016 by Jones oxidation and treat-
ment with oxalyl chloride. Once formed, the acid chloride was
immediately subjected to esterification with naphthol 9 under
standard conditions yielding 80% compound 8 (Scheme 6).
3. Conclusions
We have developed efficient bidentate [N,P] ligands based
on pyrrole, with a combination of hard and soft donor atoms.

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J.V. Suarez-Meneses et al. / Tetrahedron 70 (2014) 1422e1430
1427
Palladium complex 3a proved to be a very efficient precursor cat-
H, 6.50; N, 9.51. IR (KBr, cmꢀ1
)
nmax: 3090, 3059, 2960, 2000e1600,
alyst in Heck cross-coupling reactions and in intramolecular
arylearyl couplings of esters and amides. In order to demonstrate
the applicability and efficiency of this catalyst, we completed a total
synthesis of arnottin I. To obtain the key naphthalene derivative we
applied a free radical strategy during the first stage of synthesis. In
the crucial final step of synthesis, an arylearyl coupling promoted
by catalyst 3a was used, giving the desired product in better yields
and in cleaner reaction conditions than commercial sources of
Pd(II), and also remarkably reducing the load of palladium catalyst.
748e696. 31P NMR (50 MHz, CDCl3):
d
¼ꢀ29.2 ppm. 1H NMR
(300.53 MHz, CDCl3, ppm): 7.32 (m, 10H), 7.07 (m, 1H), 6.18 (t,
J¼3.3 Hz, 1H), 5.51 (dd, J¼1.8, 1.7 Hz, 1H),
d
2.57 (s, 6H). 13C NMR
(75.58 MHz, CDCl3, ppm): 137.7 (d, J¼8.6 Hz), 132.8 (d, J¼18.9 Hz),
133.5 (d, J¼20.0 Hz), 128.4 (dd, J¼6.9 Hz); 128.6, 116.5, 113.3, 108.4,
47.9. MS (EI) m/z (%): 294 [Mþ] (22), 251 [MþꢀC16H14NP] (100), 250
[MþꢀC16H13NP] (62), 174 [MþꢀC10H9NP] (37), 143 [MþꢀC10H9N]
(31), 77 [MþꢀC6H5] (5).
Compound (2b): White powder, mp 86e88 ꢁC (0.76 g, 56%).
Elemental analysis: found C, 76.85; H, 7.10; N, 8.80; calcd C, 74.51;
4. Experimental section
H, 7.19; N, 8.69. IR (KBr, cmꢀ1
) nmax: 3048, 2957, 2000e1600,
752e709. 31P NMR (50 MHz, CDCl3):
d
¼ꢀ45.7 ppm. 1H NMR
4.1. General considerations
(300.53 MHz, CDCl3, ppm): 7.22 (d, J¼1.5 Hz, 1H), 7.19 (m, 4H), 7.07
(m, 2H); 6.80 (dd, J¼1.5 Hz, 2H), 6.18 (ddd, J¼0.6 Hz, 1H), 5.48 (dd,
J¼1.8 Hz, 1H), 2.74 (s, 6H), 2.40 (d, J¼1.56 Hz, 6H). 13C NMR
(75.58 MHz, CDCl3, ppm): 142 (d, J¼26.2 Hz), 135.8 (d, J¼8.7 Hz),
132.9, 129.9 (d, J¼4.7 Hz), 128.3, 125.8, 116.6,114.3, 108.4, 48, 21.1 (d,
J¼21.5 Hz). MS (EI) m/z (%): 322 [Mþ] (34), 279 [MþꢀC18H18NP]
(100), 264 [MþꢀC17H15NP] (31), 197 [MþꢀC13H10P] (42).
All operations were carried out under an inert atmosphere of
nitrogen or argon gas using standard Schlenk techniques. Anhy-
drous THF was obtained by distillation under an inert atmosphere
over sodium and benzophenone. Column chromatography was
performed using 70e230 mesh silica gel. All reagents and solvents
were obtained from commercial suppliers and used without further
purification. All compounds were characterized by IR spectra,
recorded on a PerkineElmer 283B or 1420 spectrophotometer, by
means of film and KBr techniques, and all data are expressed in
wave numbers (cmꢀ1). Melting points were obtained on a Melt-
Temp II apparatus and are uncorrected. NMR spectra were mea-
sured with a Bruker Avanceþ300 and a Varian Unity (300 MHz),
using CDCl3 and C2D6SO as solvents. Chemical shifts are in parts per
Compound (2c): White powder, mp 48e50 ꢁC (1.7 g, 82%). Ele-
mental analysis: found C, 67.25; H, 10.95; N, 10.75; calcd C, 66.11; H,
10.70; N, 11.01. IR (KBr, cmꢀ1
)
nmax: 3104, 2957, 2000e1600,
31
1390e1359. P NMR (50 MHz, CDCl3, 25 ꢁC):
d
¼1.9 ppm. 1H NMR
(300.53 MHz, CDCl3, ppm): 7.16 (m,1H), 6.37 (dd, J¼1.6 Hz,1H), 6.24
(dd, J¼2.9, 3.1 Hz, 1H), 2.83 (s, 6H), 1.18 (d, J¼12.1 Hz, 18H). 13C NMR
(75.58 MHz, CDCl3, ppm): 127.1, 115.5, 113.3 (d, J¼5.2 Hz), 107.4,
48.4, 32.4 (d, J¼17.2 Hz), 30.4 (d, J¼14.9 Hz). MS (EI) m/z (%): 255
[Mþ] (47), 211 [MþꢀC12H21NP] (100), 155 [MþꢀC8H13NP] (17), 99
[MþꢀC4H5NP] (50).
million (ppm) (d
), relative to TMS. The MS-FABþ and MS-EI spectra
were obtained on a JEOL SX 102A, the values of the signals are
expressed in mass/charge units (m/z), followed by the relative in-
tensity with reference to a 100% base peak.
4.2.2. General synthesis of palladium complexes. A solution of the
corresponding ligand (0.68 mmol) and Pd(CH3CN)2Cl2 (0.68 mmol)
in chloroform (30 mL) was heated at reflux for 2 h. The solution was
allowed to cool to room temperature. The solvent was removed
under vacuum, leaving a yellow residue, which was dissolved in the
minimum amount of dichloromethane. The resulting solution was
filtered through Celite, and then the slow addition of hexane in-
duced the formation of a yellow solid, which was filtered, washed
with hexane, and dried under vacuum to give the corresponding
complexes 3aec.
4.2. Structure determination by X-ray crystallography
Suitable X-ray quality crystals of 2a were grown through slow
evaporation of a dichloromethane/n-hexane solvent mixture at
ꢀ5 ꢁC. Single white crystals of compounds 2a were mounted on
a glass fiber at room temperature. The crystals were then placed on
a Bruker SMART APEX CCD diffractometer, equipped with Mo-K
a
radiation; decay was negligible in both cases. Details of crystallo-
graphic data collected on compound 2a are provided in
Supplementary data of this article.23 Systematic absences and in-
tensity statistics were used in space group determinations. The
structures were determined using direct methods.24 Anisotropic
structure refinements were achieved using full-matrix, least-
squares techniques on all non-hydrogen atoms. All hydrogen atoms
were placed in idealized positions, based on hybridization, with
isotropic thermal parameters fixed at 1.2 times the value of the
attached atom. Structure solutions and refinements were per-
formed using SHELXTL v 6.10.25
Compound (3a): Yellow powder, mp 280 ꢁC (0.29 g, 88%). Ele-
mental analysis: found C, 43.39; H, 4.01; N, 5.63; calcd C, 45.83; H,
4.06; N, 5.93. IR (KBr, cmꢀ1
) nmax: 3105, 2928, 2000e1600,
748e693. 31P NMR (50 MHz, CDCl3):
d
¼16.7 ppm. 1H NMR
(300.53 MHz, CDCl3, ppm): 7.85 (4H, J¼2.2 Hz), 7.5 (ddd, J¼4.5 Hz,
6H), 7.39 (d, J¼1.2 Hz, 1H), 6.67 (d, J¼1.2 Hz, 1H), 6.32 (t, J¼1.6 Hz,
1H), 3.71 (s, 6H). 13C NMR (75.58 MHz, CDCl3, ppm): 133.6 (d,
J¼12.0 Hz), 132.5 (d, J¼3.0 Hz), 129.2 (d, J¼12.7 Hz), 127.9 (d,
J¼68.2 Hz), 121.9 (d, J¼73.5 Hz), 117.5 (d, J¼8.0 Hz), 117.1 (d,
J¼8.0 Hz), 113.2, 57.3. MS (FABþ) m/z (%): 472 [Mþ] (2), 437
[MþꢀC18H19ClN2PPd] (2), 294 [MþꢀC18H19N2P] (15), 251
[MþꢀC16H14NP] (100), 174 [MþꢀC10H9NP] (37), 143 [MþꢀC10H9N]
(32), 77 [MþꢀC6H5] (5).
4.2.1. General synthesis of N,N-dimethyl-1H-pyrrol-1-amine-2-
dialkylphosphine (2aec). A solution of N,N-dimethyl-1H-pyrrol-1-
amine (8.3 mmol) in anhydrous THF (30 mL) under nitrogen at-
mosphere, was cooled at ꢀ78 ꢁC and then n-butyl lithium
(9.9 mmol, 1.2 equiv, Sol. 2.5 M in n-hexane) was added dropwise
by syringe. The mixture was gradually warmed to room tempera-
ture. After reaching this temperature, the reaction mixture was
Compound (3b): Yellow powder, mp 280 ꢁC (0.12 g, 67%). Ele-
mental analysis: found C, 47.85; H, 4.84; N, 5.45; calcd C, 48.06; H,
4.60; N, 5.60. IR (KBr, cmꢀ1
) nmax: 3101, 2930, 2000e1600, 756e716.
31P NMR (50 MHz, CDCl3):
d
¼15.4 ppm. 1H NMR (300.53 MHz,
CDCl3, ppm): 7.20e7.35 (m, 9H), 6.57 (dd, J¼1.5 Hz, 1H), 6.26 (dd,
J¼1.5 Hz, 1H), 3.68 (d, J¼6 Hz, 6H), 2.57 (d, J¼21.9 Hz, 6H). 13C NMR
(75.58 MHz, CDCl3, ppm): 141.9 (d, J¼8.2 Hz), 136.9 (d, J¼17.0 Hz),
134 (d, J¼12.7 Hz), 132.6 (dd, J¼22.6 Hz), 126.6 (d, J¼12.1 Hz), 123,
116.4 (dd, J¼7.7 Hz), 113.3 (d, J¼2.2 Hz), 57.0 (d, J¼76.3 Hz), 23.5 (d,
J¼24.2 Hz).
cooled at
0
ꢁC, followed by the addition of chlor-
odiphenylphosphine (8.3 mmol) and stirring at room temperature
for 2 h. The solvent was evaporated at reduced pressure and the
crude was purified by column chromatography. Elution with hex-
ane/ethyl acetate.
Compound (2a): White powder, mp 106e108 ꢁC (2.2 g, 90%).
Elemental analysis: found C, 73.70; H, 6.69; N, 9.56; calcd C, 73.45;
Compound (3c): Yellow powder, mp 300 ꢁC (0.13 g, 88%). Ele-
mental analysis: found C, 39.35; H, 6.54; N, 6.10; calcd C, 38.95; H,

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J.V. Suarez-Meneses et al. / Tetrahedron 70 (2014) 1422e1430
1428
6.30; N, 6.49. IR (KBr, cmꢀ1
)
nmax: 3112, 2960, 1396e1366, 743. 31
P
consumed, the mixture was cooled to room temperature, concen-
NMR (50 MHz, CDCl3):
d
¼60.5 ppm. 1H NMR (300.53 MHz, CDCl3,
trated under reduced pressure, and purified by flash column
chromatography (silica gel, hexane/dichloromethane, 1:1) to afford
the title compound in 73% yield as a yellow oil. 1H NMR (CDCl3,
ppm): 7.26 (m, 1H), 6.65 (dd, J¼1.1 Hz, 1H), 6.42 (dd, J¼1.4 Hz, 1H),
3.69 (s, 6H), 1.56 (s, 9H), 1.51 (s, 9H). 13C NMR (75.58 MHz, CDCl3,
ppm): 127.1, 115.7, 113.6, 108.0, 57.3, 39.5 (d, J¼21.8 Hz), 29.3.
300 MHz)
d
¼7.53 (dd, J¼8.2, 1.8 Hz, 1H), 7.41 (d, J¼1.8 Hz, 1H), 6.84
(d, J¼8.1 Hz, 1H), 6.70 (t, J¼6.0 Hz, 1H), 6.04 (s, 2H), 4.63 (qd, J¼1.2,
4.2.3. General procedure for MizorokieHeck coupling reactions. In
a 25-mL round-bottomed flask, a mixture of aryl iodide (5 mmol),
alkene (6 mmol), and base (5.6 mmol) was placed in 4 mL of DMF,
then a solution of the complex 3 (0.005 mol %) in 1 mL of DMF was
added. The reaction mixture was refluxed for the time stated in
Tables 3 and 4 at 140 ꢁC. The reaction mixture was poured into
water (20 mL) and extracted with ether or hexane (2ꢂ30 mL). The
combined organic layers were dried over anhydrous sodium sul-
fate. After the removal of the solvent in vacuo, the resulting crude
was purified by column chromatography on silica gel (hexane/ethyl
acetate) to give the corresponding cross-coupling product (the
purified product was identified by means of determination of mp
and by 1H and 13C NMR, the data obtained are consistent with lit-
erature).26 The entire flasks used in the each coupling reaction were
meticulously cleaned with aqua regia to avoid the presence of
unseen palladium catalyst.
7.2 Hz, 2H), 3.04 (td, J¼2.1, 7.2 Hz, 2H), 2.42e2.34 (m, 2H), 1.41 (t,
J¼7.2 Hz, 3H), 1.19 (s, 9H). 13C NMR:
¼210.1, 195.8, 176.6, 151.8,
d
148.2, 131.4, 124.2, 107.8, 107.8, 101.8, 80.2, 70.1, 38.8, 33.9, 28.7,
26.9, 13.6.
4.3.3. 8-Oxo-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxol-5-yl piv-
alate (12). A solution of 15 (1.859 g, 4.669 mmol) in 1,2-
dichloroethane (47 mL) was refluxed for 15 min under N2.
Lauroyl peroxide (DLP) was then added portionwise (0.372 g,
0.933 mmol, 20 mol % per hour) to the refluxing solution. When the
starting material was completely consumed (after addition of
1.6 equiv of DLP), the crude mixture was cooled to room temper-
ature, concentrated under reduced pressure, and purified by flash
column chromatography (silica gel, hexane/dichloromethane, 3:7,
a small pad of basic alumina was packed on the top of the column to
eliminate the lauric acid generated during the reaction) and
recrystallized with hexane/dichloromethane to give a mixture of
tetralones 12 and 120 (7:3, 60% combined yield). The mixture was
separated by crystallization from hexane/dichloromethane (95:5),
to isolate tetralone 12 as a brown solid (mp 105 ꢁC). 1H NMR (CDCl3,
4.2.4. General procedure for arylearyl coupling reaction. In a 25-mL
round-bottomed flask, compound
4 (1.0 mmol) and base
(1.2 mmol) were placed in 4 mL of DMF, then a solution of the
complex 3a (0.5 mol %) in 1 mL of DMF was added. The reaction
mixture was refluxed for the time stated in Table 4 at 140 ꢁC. The
reaction mixture was poured into water (20 mL) and extracted with
ether or hexane (2ꢂ30 mL). The combined organic layers were
dried over anhydrous sodium sulfate. After the removal of the
solvent in vacuo, the resulting crude was purified by column
chromatography on silica gel (hexane/ethyl acetate) to give chro-
mone 5a or phenanthridinone 5b (the purified product was iden-
tified by determination of mp and by 1H and 13C NMR, the data
obtained are consistent with literature).27 The entire flasks used in
the each coupling reaction were meticulously cleaned with aqua
regia to avoid the presence of unseen palladium catalyst.
300 MHz)
d
¼7.47 (s, 1H), 6.83 (s, 1H), 6.04 (s, 2H), 5.98 (dd, J¼6.3,
3.9 Hz, 1H), 2.84 (ddd, J¼17.4, 9.4, 5.3 Hz, 1H), 2.61 (ddd, J¼17.4, 7.2,
4.8 Hz,1H), 2.41e2.18 (m, 2H),1.21 (s, 9H). 13C NMR (75 MHz, CDCl3)
d
¼195.2, 177.8, 152.2, 148.4, 137.8, 127.4, 107.5, 106.3, 101.9, 68.9,
38.9, 34.0, 28.6, 27.0. HRMS (FABþ) calcd for C16H18O5 290.1154,
found 290.1152. Spectral data for tetralone 120 (white solid, mp
122e123 ꢁC): 1H NMR (CDCl3, 300 MHz)
d
¼7.65 (d, J¼8.4 Hz, 1H),
6.85 (d, J¼8.4 Hz, 1H), 6.19 (t, J¼4.2 Hz, 1H), 6.15 (d, J¼7.5 Hz, 2H),
2.77 (ddd, J¼16.9, 9.7, 6.9 Hz, 1H), 2.55 (dt, J¼17.1, 4.9 Hz, 1H),
2.24e2.30 (m, 2H), 1.16 (s, 9H). 13C NMR (75 MHz, CDCl3)
d¼195.3,
177.6, 152.2, 145.3, 126.9, 123.2, 121.5, 109.0, 102.5, 63.8, 39.0, 33.82,
28.0, 27.1.
4.3. Total synthesis of arnottin I (6)
4.3.4. Naphtho[2,3-d][1,3]dioxol-5-ol (9). A solution of tetralone 12
(0.050 g, 0.172 mmol) and 0.098 g (0.515 mmol) of PTSA in 5.8 mL of
dry toluene was refluxed for 45 min with a DeaneStark apparatus.
The reaction mixture was allowed to cool at room temperature and
neutralized with a saturated solution of Na2CO3. The aqueous phase
was extracted with CH2Cl2, the combined organic extracts were
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica gel,
hexane/dichloromethane, 3:7) to give naphthol 9 (38% yield) as
4.3.1. S-2-(Benzo[d][1,3]dioxol-5-yl)-2-oxoethyl O-ethyl carbon-
odithioate (13). To a solution of 2-bromo-30,40-methylenediox-
iacetophenone (5.930 g, 24.3 mmol) in 60 mL of acetone at 0 ꢁC was
added portionwise 3.91 g (24.3 mmol) of potassium O-ethyl xan-
thogenate. The resulting mixture was stirred at room temperature
for 2 h, the solvent was evaporated, and the resulting mixture
partitioned between water and CH2Cl2. The aqueous phase was
extracted with CH2Cl2, the combined organic extracts were dried
over Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by flash column chromatography (silica gel, hex-
ane/AcOEt, 8:2) to give xanthate 13 (68% yield) as a white solid (mp
a brown solid (mp 120 ꢁC). 1H NMR (CDCl3, 300 MHz)
d
¼7.48 (s,1H),
7.27e7.24 (m, 1H), 7.14 (t, J¼7.5 Hz, 1H), 7.08 (s, 1H), 6.67 (dd, J¼9.0,
3.0 Hz, 1H), 6.02 (s, 2H), 5.15 (s, 1H). 13C NMR (75 MHz, CDCl3)
d
¼150.8, 148.0, 147.2, 132.0, 124.3, 120.7, 119.8, 107.7, 103.7, 100.9,
50 ꢁC). 1H NMR (CDCl3, 300 MHz)
d
¼7.64 (dd, J¼8.1, 1.8 Hz, 1H), 7.47
98.4. HRMS (FABþ) calcd for C11H8O3 188.0473, found 188.0472.
(d, J¼1.8 Hz, 1H), 6.88 (d, J¼8.1 Hz, 1H), 6.06 (s, 2H), 4.64 (q,
J¼7.2 Hz, 2H), 4.59 (s, 2H), 1.40 (t, J¼7.1 Hz, 3H). 13C NMR (75 MHz,
4.3.5. 6-Iodo-2,3-dimethoxybenzoic acid (10). To a cold (0 ꢁC), stir-
red solution of 2-iodo-5,6-dimethoxybenzylalcohol (0.5 g,
1.70 mmol) in acetone (8.6) was added dropwise 3.3 mL
(0.51 mmol) of Jones reagent. The reaction was stirred for a further
hour at room temperature, the acetone was evaporated at reduced
pressure, and then the residue partitioned between saturated
aqueous K2CO3 solution and CH2Cl2. After separation of the organic
layer, the aqueous phase was acidified with concentrated HCl
(pH¼2). The mixture was then extracted with dichloromethane;
the combined organic extracts were dried over Na2SO4 and con-
centrated under reduced pressure. The residue was purified by
recrystallization from hexane/dichloromethane (95:5) to give 10 in
CDCl3)
d
¼213.3, 190.3, 152.3, 148.3, 130.5, 124.9, 108.1, 108.0, 102.0,
70.6, 43.4, 13.7. HRMS (FABþ) calcd for C12H13O4S2 285.0255, found
285.0255.
4.3.2. 4-(Benzo[d][1,3]dioxol-5-yl)-1-(ethoxycarbonothioylthio)-4-
oxobutyl pivalate (15). A solution of xanthate 13 (2.0 g, 7.03 mmol)
and vinyl pivalate (1.802 g, 14.05 mmol) in
dichloroethane (DCE) was refluxed for 15 min under N2. Lauroyl
peroxide (DLP) (0.14 g, 0.087 mmol) was then added to the
refluxing solution, followed by additional portions (0.056 g,
0.35 mmol every 90 min). When starting material was completely
8 mL of 1,2-

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J.V. Suarez-Meneses et al. / Tetrahedron 70 (2014) 1422e1430
1429
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103, 2945.
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2010, 352, 2341; (b) Gillespie, J. A.; Dodds, D. L.; Kamer, P. C. J. Dalton Trans.
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53% yield. All spectroscopic and physical data matched with those
reported in the literature.16
4.3.6. 6-Iodo-2,3-dimethoxybenzoyl chloride (16). To a suspension
of acid 10 (0.195 g, 0.632 mmol) and one drop of DMF in CH2Cl2
(21 mL) at 0 ꢁC was slowly added oxalyl chloride (0.401 g,
3.159 mmol) under N2. The ice bath was removed, and the reaction
mixture was stirred at room temperature for 1 h. The resulting clear
pale yellow solution was concentrated in vacuo to afford crude 16 as
a pale yellow solid, which was used immediately for the next re-
action without further purification.
4. (a) Lundgren, R. J.; Hesp, K. D.; Stradiotto, M. Synlett 2011, 2443; (b) Wassenaar,
J.; Reek, J. N. H. Org. Biomol. Chem. 2011, 9, 1704; (c) Hargaden, G. C.; Guiry, P. J.
Chem. Rev. 2009, 109, 2505; (d) Kostas, I. D. In Phosphorous Ligands in Asym-
metric Catalysis; Bӧrner, A., Ed.; Wiley-VCH: Weinheim, Germany, 2008; Vol.
IeIII, p 596; (e) Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346, 497,; (f)
McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151; (g) Dai, L.-X.; Tu, T.; You,
4.3.7. Naphtho[2,3-d][1,3]dioxol-5-yl 6-iodo-2,3-dimethoxybenzoate
(8). To a solution of naphthol 9 (0.092 g, 0.489 mmol), triethyl-
amine (0.148 g, 1.462 mmol), and a catalytic amount of 4-DMAP in
dry CH2Cl2 (21 mL) at 0 ꢁC was slowly transferred a solution of
freshly prepared acid chloride 16 (0.207 g, 0.634 mmol) in anhy-
drous CH2Cl2 (5 mL). The reaction mixture was allowed to warm to
room temperature and stirred for 2.5 h. The mixture was extracted
with CH2Cl2, the organic phase was washed with saturated aqueous
NaHCO3, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica
gel, hexane/dichloromethane 3:7) to give ester 7 (79% yield) as
ꢂ
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a white solid (mp 162 ꢁC). 1H NMR (300 MHz, CDCl3)
d¼7.60e7.56
(m, 2H), 7.54 (s, 1H), 7.39e7.32 (m, 2H), 7.15 (s, 1H), 6.79 (d,
J¼8.7 Hz, 1H), 6.04 (s, 2H), 4.00 (s, 3H), 3.91 (s, 3H). 13C NMR
8. Selected references for anionic ligands based on pyrrole: (a) Mirebeau, J.-H.; Le
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Bideau, F.; Marrot, J.; Jaouen, G. Organometallics 2008, 27, 2911; (b) Perez-
(75 MHz, CDCl3)
134.5, 132.1, 125.3, 124.0, 116.7, 115.6, 103.8, 101.1, 98.5, 79.3, 61.7,
d
¼165.7, 153.0, 148.4, 148.1, 147.1, 146.3, 134.9,
ꢀ
ꢀ
Puente, P.; de Jesus, E.; Flores, J. C.; Gomez-Sal, P. J. Organomet. Chem. 2008, 693,
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56.1. HRMS (FABþ) calcd for C20H15O6 477.9913, found 477.9909.
4.3.8. Arnottin
I (6). Following the general method for the
€
E.; Kudrevich, S. V. Inorg. Chim. Acta 2003, 349, 58; (g) Broring, M.; Pfister, A.;
arylearyl coupling, the title compound was obtained from ester 8
(0.230 g, 0.481 mmol), sodium acetate (0.094 g, 1.145 mmol), and
complex 3a (0.001 g, 0.002 mmol) in 5 mL of DMF. After 8 h of
reaction, the compound was purified by flash chromatography
(silica gel, dichloromethane/methanol 98:2) to give ester arnottin I
1 in 35% yield as a white solid (mp 260 ꢁC). 1H NMR (300 MHz,
Ilg, K. Chem. Commun. 2000, 1407.
9. For neutral ligands based on pyrrole, see: (a) Haberberger, M.; Irran, E.; En-
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dissen, U.; Beller, M. Chem. Commun. 2004, 38; (d) Rataboul, F.; Zapf, A.; Jack-
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dEur. J. 2004, 10, 2983; (e) Harkal, S.; Kumar, K.; Michalik, D.; Zapf, A.; Jackstell,
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Tillack, A.; Ortinau, S.; Rolfs, A.; Beller, M. Org. Biomol. Chem. 2008, 6, 992; (k)
Schwarz, N.; Pews-Davtyan, A.; Alex, K.; Tillack, A.; Beller, M. Synthesis 2008,
CDCl3)
d
¼7.90 (d, J¼8.7 Hz, 1H), 7.85 (d, J¼8.4 Hz, 1H), 7.83 (s, 1H),
7.54 (d, J¼9.0 Hz, 1H), 7.46 (d, J¼9.0 Hz, 1H), 7.15 (s, 1H), 6.11 (s, 2H),
4.03 (s, 3H), 3.99 (s, 3H). MS (EI) m/z (rel intensity): 350 (65), 335
(25), 279 (25), 167 (65), 149 (100). Spectroscopic data fully matched
with those reported in the literature.13
Acknowledgements
€
3722; (l) Schwarz, N.; Pews-Davtyan, A.; Michalik, D.; Tillack, A.; Kruger, K.;
Torrens, A.; Diaz, J. L.; Beller, M. Eur. J. Org. Chem. 2008, 32, 5425 for other
applications of the cataCXium-P ligands see: (m) Hollmann, D.; Tillack, A.;
Michalik, D.; Jackstell, R.; Beller, M. Chem. Asian J. 2007, 3, 403; (n) Junge, H.;
Beller, M. Tetrahedron Lett. 2005, 46, 1031; (o) Schulz, T.; Torborg, C.; Enthaler,
S.; Schaffner, B.; Dumrath, A.; Spannenberg, A.; Neumann, H.; Bc¸ rner, A.; Beller,
M. Chem.dEur. J. 2009, 15, 4528; (p) Choi, Y. L.; Yu, C.-M.; Kim, B. T.; Heo, J.-N. J.
Org. Chem. 2009, 74, 3948.
The authors would like to acknowledge the technical assistance
ꢀ
~
ꢀ
provided by Nayeli Lopez, Rocío Patino, Erendira García, Carmen
ꢀ
€
ꢀ
ꢀ
~
Marquez, Isabel Chavez, María de los Angeles Pena, Luis Velasco,
ꢀ
and Javier Perez. They would also like to thank the DGAPA-PAPIIT
IB200912-2 and DGAPA-PAPIIT IN201411 and CONACYT 153310
10. (a) Pinnick, H. W.; Brown, S. P.; McLean, E. A.; Zoller, L. W., III. J. Org. Chem. 1981,
46, 3760; (b) Clayden, J. In Organolithiums: Selectivity for Synthesis; Elsevier
Science Ltd: Oxford, UK, 2002; p 70.
ꢀ
projects and CONACYT for the PhD grants extended to J.V. Suarez-
ꢀ
ꢀ
Meneses, E. Bonilla-Reyes, and E.A. Ble-Gonzalez.
€
11. For NMR data of PPh3, see: (a) Pretsch, E.; Buhlmann, P.; Badertscher, M.
Structure Determination of Organic Compounds; Springer: Berlin, Heidelberg,
2009; p 261; For NMR data of PPh(o-Tolyl)2, see: (b) Joshaghani, M.; Faramarzi,
E.; Rafiee, E.; Daryanavard, M.; Xiao, J.; Baillie, C. J. Mol. Catal. A Chem. 2007, 273,
310 For NMR data of PPh(t-Bu)2, see: (c) Kermagoret, A.; Braunstein, P. Dalton
Trans. 2008, 822.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.01.002.
12. Compounds 4aeb were prepared as reported in: Yao, B.; Wang, Q.; Zhu, J.
Angew. Chem., Int. Ed. 2012, 51, 5170 All spectroscopic data are consistent with
the literature, 4a: Perry, R. J.; Wilson, B. D.; Turner, S. R.; Blevins, R. W. Mac-
romolecules 1995, 28, 3509; 4b: Yao, B.; Jaccoud, C.; Wang, Q.; Zhu, J. Chem.
dEur. J. 2012, 18, 5864.
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