Base-assisted intramolecular c-n coupling reaction from nh2-bound cyclopalladated l -phenylalanine to indoline-2-carboxylic acid

astien Coufourier, Rodolphe Tamion, Alexandra Le Foll,

Article

Base-Assisted Intramolecular C−N Coupling Reaction from

NH ‑Bound Cyclopalladated L‑Phenylalanine to Indoline-2-

carboxylic Acid

⊥

Aurel

ien Jacquin-Labarre, Seb

is Briere,*

Vincent Levacher, Carlos Afonso, Vincent Gandon, Guillaume Journot,* Jean-Franco

and Christophe Hoarau*

Cite This: https://dx.doi.org/10.1021/acs.organomet.0c00030

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sı Supporting Information

ABSTRACT: The deprotonative intramolecular-amination reaction

of phenylalanine-derived palladacycles has been investigated to

highlight a facile carbonate-assisted N−H activation before the C−N

bond formation. A major counterion eﬀect led to divergent pathways

whereby the SPhos-Pd complexes with iodine, triﬂate, or

triﬂuoroacetate anions were key intermediates to aﬀord access to

(S)-2-indolinecarboxylic acid derivatives.

INTRODUCTION

(R = EWG = COR, SO R, Y = H) have been mostly used

■

under palladium catalysis. These intramolecular C−N bond-

Due to the prevalence of nitrogen-containing heterocycles in

pharmaceutical compounds and materials, transition-metal-

catalyzed C−N bond formation is currently of high importance

forming processes involve a Pd -catalyzed N−H activation,

followed by a directed C(sp )−H intramolecular activation

ended by the reductive elimination step of the transient

palladacycle A. However, a similar palladium-promoted N−H/

C−H deshydrogenative amination sequence from a free and

in organic synthesis. In this ﬁeld of research, the intra-

molecular N−H/C−H cross-coupling approach stands as an

ideal situation among step-economy strategies. Arylalkylamine

precursors (Scheme 1a) with an activated amine NH (EWG)

less acidic primary amine platform (R = H, Y = H) remains

unsolved. This strategy is often hampered by the strong

complexation ability of RNH precursors to Pd complexes,

preventing further C(sp )−H activation events. Nevertheless,

the ortho palladation of arylalkyl(primary)amines by a

stoichiometric amount of Pd species (R = H) has been

known for decades, even for the more challenging six-

membered-ring NH -bound palladacycle B. As a matter of

fact, the so-called Buchwald−Hartwig Pd -catalyzed intra-

molecular amination of ortho-halogenated phenethylamines

Scheme 1. Intramolecular Pd-Catalyzed Amination from

Primary Amine: Context and Issues

was also applied to NH derivatives (R = H, Y = halide or

pseudo)halide). The sequence was described through the

(

proposed NH -palladacycle intermediates B (ligated by Y after

the oxidative addition event) before the ﬁnal base-promoted

amination process. Importantly, these types of palladacycles

were isolated and employed as a source of active Pd catalysts

Received: January 15, 2020

XXXX American Chemical Society

Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

under basic conditions (Scheme 1b), as demonstrated by

Table 1. Optimization of the Deprotonative Amination

Buchwald. During this intramolecular C−N coupling reaction,

Reaction of Complexes 3

the putative formation of an indoline side product was

proposed but the exact mechanism remains unclear. Most

recent mechanistic studies have provided insight into the

intermolecular Buchwald−Hartwig amination, although a focus

on intramolecular amination processes, especially with primary

amines, remains to be achieved.

entry

3-X

base/solvent

T (°C)/t (h) 4/5 yield (%)

We recently became interested in opening a straightforward

route to (S)-methyl indoline-2-carboxylate, a synthetic

intermediate used in the pharmaceutical industry (Scheme

3a-Cl

3a-I

3a-Cl

3b-I

3b-Cl

/t-BuOH

/MeCN

/toluene

100/14

100/4

100/24

100/14

130/14

0/20

48/0

77/c

c).

The C−H/N−H disconnection provoked by a

palladium-promoted dehydrogenative amination would aﬀord

a step-economical approach from the L-phenylalanine deriva-

tive 1a. This novel sequence also aﬀords a great opportunity to

tackle a mechanistic and reactivity investigation.Thanks to the

insightful investigations of Vicente and Saura-Llamas, the

isolable palladacycle intermediates 2a-X (X = Cl, I) were

readily accessible from the ammonium triﬂate salts 1a-OTf via

a C−H-directed palladation followed by ion metathesis

26/0

K CO /toluene

Na CO /toluene

Cs CO /toluene

CsF/toluene

K PO /toluene

DBU/toluene

K CO /toluene

45/33

16/10

20/25

63/37

74/26

99 (61)/c

0/46 (46)

63(50)/28

0/41 (38)

processes with NaX. In that context, we embarked on a

reactivity study of the deprotonative intramolecular-amination

event of palladium complexes of type 2 and found a marked

K CO /toluene

counterion eﬀect leading to divergent pathways. We are

pleased to report on this intramolecular C−N bond

investigation, encompassing a mechanistic insight by DFT

and mass analyses, which led to primary investigations toward

a racemization-free synthesis of indoline-2-carboxylic acid

derivatives via the palladium-promoted N−H/C−H cross-

coupling of a primary amine starting material.

Unless stated otherwise, the reaction was carried out with 0.1 mmol

of palladacycle and 0.3 mmol of base (3 equiv) in 1 mL of solvent.

Yield determined by H NMR spectroscopy with Bn O as an internal

standard. Traces of product (<10% by H NMR). The reaction was

carried out with 0.3 mmol of palladacycle. Isolated yields are given in

parentheses.

RESULTS AND DISCUSSION

At the onset, a series of phosphino-palladacycles 3a-X and 3b-

X (X = Cl, I) was prepared from the dimeric palladacycles 2-X

■

base (entry 11). Finally, these reaction conditions executed

at 130 °C led to an excellent conversion into the indoline

product 4a (99% NMR yield) and gave an isolated yield of

61% after column chromatography (entry 12). For comparison

purposes, under these optimal reaction conditions, the

chlorinated palladacycle 3a-Cl was transformed into the indole

5a in 46% yield (entry 13). A similar trend was observed with

complexes 3b-I and 3b-Cl (R = H, entries 14 and 15),

prepared from phenethylamine derivatives 1b and 2b (Scheme

1 and Table 1). Nevertheless, the isolated yields of the

corresponding indoline 4b (50%) and indole 5b (38%) were

lower than those obtained from phenylalanine-derived pallada-

cycles 3a-Cl and 3a-I, suggesting that the ester group slightly

facilitates the base-assisted N−H activation step probably by

reinforcing the N−H acidity. In any case, we could devise an

overall counterion-directed synthesis of either indole 4 or

indoline 5 thanks to this carbonate-assisted C−N bond

forming reaction.

It is worth noting that, during silica-gel column chromatog-

raphy, coelution between indoline 4a and a moderately stable

Pd complex impurity was observed, which could explain the

diﬀerence between the estimated NMR yield (up to 99% under

optimal conditions) and the isolated yield of pure product.

Among the crude reaction mixture (see the Supporting

Information), this side product was identiﬁed by electrospray

ionization Fourier transform ion cyclotron resonance mass

spectrometry (ESI-FT-ICR, Figure 1). Thus, the cationic

palladium complex with an exact m/z value of 925.3700 was

detected and features one palladium atom. Accordingly, the

(

Scheme 1c and Table 1), according to a literature protocol.

After an extensive investigation of the reaction conditions with

various complexes, we successfully performed the deprotona-

tive amination reaction (see the Supporting Information). We

found that the L-phenylalanine-derived palladium complex 3a-

Cl, ligated by the Buchwald SPhos phosphine and a chloride,

cyclized in the presence of K CO (3 equiv) in t-BuOH at 100

C (entry 1). Unfortunately, the aromatic indole product 5a

was formed in a moderate 20% NMR yield (estimated by H

NMR with an internal standard). To our delight, we observed

a major counterion eﬀect of this carbonate-assisted C−N

bond-forming step (entry 2), as iodide complex 3a-I furnished

exclusively the indoline product 4a with an improved 48%

NMR yield under similar conditions. In spite of the reaction

remaining e ﬀ ective both in polar and apolar solvents (see the

Supporting Information ), the best results were obtained in

acetonitrile and toluene, both aﬀording 4a in 77% yield

(

entries 3 and 4) in 14 h, along with the concomitant

formation of trace amounts of indole 5a. A higher proportion

of indole 5a (4a/5a = 45/33) was observed by carrying out the

reaction for 24 h (entry 6). Additionally, sodium and cesium

carbonates turned out to be less eﬀective bases for the

construction of the indoline product 4a (16−20% yields,

entries 7 and 8). Among noncarbonated bases, cesium ﬂuoride

and potassium phosphate provided indoline 4a in 63% and

4% yields, respectively (entries 9 and 10), which is in line

with the result obtained with K CO (entry 4), even though a

C H O P Pd molecular formula may account for the

52 69

4 2

signiﬁcant amount of indole 5a was detected (26−37%). In

contrast, the reaction failed when DBU was used as an organic

palladacycle depicted in Figure 1 (the palladium atom is

arbitrarily located) ﬂanked by another SPhos ligand, which

Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

ligands, and the SPhos provides the best balance between steric

and electronic eﬀects. Finally, by heating the reaction mixture

at 130 °C in the presence of SPhos ligand, the indoline 4a was

obtained in a high 95% NMR yield.

Having these conditions in hand, the investigation of the free

energy proﬁle was undertaken by DFT calculations, as depicted

in Figure 2 (see the Supporting Information for computational

details). The amine-(SPhos)Pd complex A (X = Cl, I) and

2−

CO₃were taken as energy references. The geometry of this

complex when X = I is in good agreement with that

characterized by Vicente and Saura-Llamas et al. by X-ray

crystallography. The dissociation of the halide was achieved

through TS_A_Bto give the cationic Pd complex B. With X = Cl,

I, the free energy of activation is ∼11 kcal/mol. At 373 K in

MeCN, this dissociation was found to be exergonic by 4.2 and

.9 kcal/mol, respectively. This is notably due to the well-

known ability of the SPhos moiety to act as a bidentate ligand,

involving the electron-rich carbon of the biaryl core. One of

the two nitrogen protons of B is sterically shielded by the

Figure 1. (a) Enlargement of the ESI(+)-FTICR mass spectrum of

the crude reaction mixture showing the m/z 925.370 cationic

palladium complex. (b) Theoretical isotopic pattern of the

dimethoxybenzene ring, while the other is electronically

C H O P Pd ion with a resolution of 60000.

2−

4 2

protected from the approach of CO₃

by the ester

functionality. Thus, no direct deprotonation of B into the

corresponding neutral complex E could be modeled. The

formation of E could instead derive from the direct attack of

could be formed from complex 3a through an intramolecular

C−H activation process.

In order to evaluate the inﬂuence of the phosphine ligand on

the C−N bond formation, the in situ formation of palladacycles

2−

CO₃to B to give the palladium carbonate C lying at −13.7/

2−

−

18.5 kcal/mol. Yet, the approach of CO toward B did not

a-I was undertaken by mixing the dimeric palladacycle 2a-I

yield a transition state. The intramolecular deprotonation

could then be computed through TS_C_Dlying at −10.6/−15.4

kcal/mol: i.e., only ∼3 kcal/mol above C. The resulting H-

bonded complex D is formed in a slightly endergonic fashion

with various Buchwald phosphine ligands (Scheme 2).

Scheme 2. Screening of Phosphine Ligands

(

1.7 kcal/mol above C for the two halides). The C−N bond-

forming reductive elimination toward the Pd complex F is

markedly exergonic by ∼13 kcal/mol from E, but the

corresponding transition state lies quite high relative to D

(

∼22 kcal/mol of free energy of activation). A better option is

−

to ﬁrst dissociate HCO from D to give the chelate E, which

liberates ∼10 kcal/mol of free energy. The reductive

elimination of E requires only ∼14 kcal/mol of free energy

of activation to reach TS . We also explored the direct

2−

deprotonation of A by CO₃to give G. No transition state

could be found for what seems to be a barrierless process

according to the scan of the surface. The resulting negatively

charged amido-Pd complex G is more stable than A by 7.7/

Reaction caried out with 0.1 mmol of palladacycle in 1 mL of

9.9 kcal/mol. Reductive elimination yields the H-bonded

toluene. Yield determined by H NMR with Bn O as an internal

standard.

complex H at the expense of 16.8/14.0 kcal/mol of free energy

of activation to reach TS_G_H. Alternatively, the dissociation of X

to give E requires a lower free energy of activation 10.9/8.1

kcal/mol through TSGE. Thus, the best pathway for both

halides appears to be A → G → E → F. However, this proposal

does not take the cation eﬀect into account and does not

rationalize the ion-dependence observed.

Although no indoline 4a formation was observed either from

the dimeric Pd complex 2a-I or in the presence of

triphenylphosphine ligand, the model SPhos ligand furnished

the indoline product 4a in 46% NMR yield. This

straightforward approach gave promising results in comparison

to the 77% yield obtained from the phosphine-Pd complex 3a-I

Since a clear-cut explanation accounting for a divergent

route toward the formation of the aromatic indole product 5a

from one of the chlorinated palladacycles was not found,

further experiments were carried out (see the Supporting

Information for further details). Heating the indoline products

4a in the presence of the chlorinated SPhos-palladacycle 3a-Cl

led essentially to the formation of indole 5a (Table 2, entry 1),

especially in the absence of base (entry 2). In contrast , in the

presence of the iodide palladacycle 3a-I and K CO the

(

the putative intermediate obtained from 2a-I; see Table 1,

entry 4).

Similar results were obtained with the analogous but more

sterically hindered RuPhos ligand, giving a 45% yield.

However, in this series, XPhos and the more electron rich

DavePhos and less sterically hindered JohnPhos and

CyJohnPhos were revealed to be slightly less eﬀective than

SPhos under these conditions (yields <38%). These observa-

tions suggest that the decomplexation/N−H activation/

reductive elimination sequence is optimal with Buchwald

deprotonated-amination process was the favored pathway

(entry 3, only 17% of 5a), although a mixture of products

was obtained.

Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

Figure 2. Free energy proﬁle to form the dihydroindole product 4a (ΔG in kcal/mol, geometries of TS_G_E(X = Cl) and TS_E_Fwith selected

distances in Å).

Table 2. Shedding Light on the Formation of the Indole

Side Product 5a

N−H or a C−H insertion reaction, leading eventually to indole

5a (and phenylalanine 1c) after the subsequent β-H

elimination process. The electronic or kinetic issues underlying

these counterion-divergent processes deserve further inves-

tigations, but already they show the key role of the iodide-

based complexes to secure a base-promoted amination reaction

instead of an oxidative pathway.

These results prompted us to investigate other complexes

with weakly coordinated counterions in order to investigate

their inﬂuence on these possibly divergent pathways. Thanks

to the adaptation of the Vicente and Saura-Llamas protocol,

the palladacycle 2a-OTf was synthesized and isolated as a solid

from the corresponding ammonium triﬂate salts 1a-OTf of L-

entry

X (3-X)

K CO

4a (%)

5a (%)

1c (%)

Cl (3a-Cl)

I (3a-I)

yes

traces

107

100

I (3a-I)

Reaction carried out with palladacycle 3a (0.05 mmol), the indoline

phenylalanine in the presence of Pd(OAc) (Scheme 3a).

a (1 equiv), and K CO (3 equiv) in toluene at 130 °C for 14 h.

Gratifyingly, making use of the previously optimized

conditions, we smoothly transformed the palladium complex

Yield determined by H NMR spectroscopy with Bn O as an internal

standard after ﬁltration on a pad of Celite. Precipitation of palladium

a-OTf in the presence of SPhos and K CO into the

was observed.

2 3

corresponding indoline 4a in 77% NMR yield as the major

product along with a smaller amount of indole 5a (23%). More

importantly, a similar directed C−H activation process took

place directly from the more challenging free amine 1c as

The main product 4a was apparently obtained in more than

00% yield due to the remaining starting material 4a. Without

any base, a small amount of indole 5a (12%) was still observed

but with no extra formation of indoline 4a (entry 4). It is

worth noting that, although a clear quantiﬁcation of the other

minor side products within the reaction mixture was not trivial,

an estimated amount of methyl ester phenylalanine 1b of

around 30% was measured. With these observations in hand,

we propose that a complexation event between indoline 4a

starting material by means of the electrophilic Pd(TFA) , to

furnish the more stable palladacycle 2a-TFA (Scheme 3b).

According to the H NMR and IR spectra and mass analysis,

the dimeric complexes 2a-X (X = OTf, TFA) were likely

formed. In line with the palladium complex 2a-OTf, the

homologous 2a-TFA underwent the amination sequence to

lead to indoline 4a in 73% yield, along with only 11% of indole

5a. It is worth noting that no racemization took place under

(

product of the reaction) and the chlorinated SPhos-pallada-

cycle 3a-Cl, or Pd species derived thereof, might initiate an

Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

Triﬂuoroacetate-Bridged Ortho-Palladated L-Phenylalanine

Methyl Ester (2a-TFA). N.B.: for this speciﬁc experimental

procedure, no precautions were taken against moisture or oxygen.

To a mixture of the L-phenylalanine methyl ester 1c (250 mg, 1.39

Scheme 3. Investigation toward a Palladium-Promoted N−

H/C−H Cross-Coupling

mmol) and Pd(TFA) (464 mg, 1.39 mmol) in a sealed tube was

added acetonitrile (0.1 M). The solution was stirred at 80 °C for 4 h.

The reaction mixture was ﬁltered through a pad of Celite/Na CO

washed with MeCN. The ﬁltrate was concentrated under reduced

pressure, and a mixture of Et O and n-pentane was added. The

precipitate was vigorously stirred for 10 min, and the suspension was

ﬁltered under vacuum. The solid was washed with n-pentane and then

air-dried to furnish the corresponding complex 2a-TFA as a yellow

solid (525 mg, 95%). Remark: a similar process could be achieved

from L-phenylalanine methyl ester ammonium triﬂuoroacetate salt 1a-

TFA and Pd(OAc) to give the dimer 2a-TFA. Mp: 132−134 °C. IR

(

neat): ν 3268, 2954, 1740, 1659, 1554, 1435, 1202, 850, 749, 730,

max

(

a) Reaction conditions: (a) Pd(OAc) (1 equiv), MeCN, 80 °C, 4

−1

452, 406 cm . δ (300 MHz, CD CN): 7.16 (d, J = 7.7 Hz, 1H),

7.95−6.80 (m, 3H), 5.32 (s, 1H), 4.49 (s, 1H), 3.58 (s, 3H), 3.55−

3.49 (m, 1H), 3.30 (dd, J = 14.1, 4.3 Hz, 1H), 3.11 (dd, J = 14.1, 5.8

h; (b) Pd(TFA) (1 equiv), MeCN, 80 °C, 4 h; (c) SPhos (1 equiv/

Pd), K CO (3 equiv/Pd), MeCN, 100 °C, 14 h.

Hz, 1H) ppm. δ_C(75 MHz, CD CN): 173.0, 136.9, 136.5, 128.1,

25.9, 125.7, 53.4, 50.5, 45.5 ppm (C−Pd and TFA carbons missing).

^δF (282 MHz, CD CN): −75.8 ppm. HRMS (ESI ): calcd for

C H F N O

these conditions. On the basis of these important observations,

a ﬁrst screening of conditions eventually highlighted that

methyl ester phenylalanine 1c could be transformed into the

corresponding indoline 4a in a moderate, albeit signiﬁcant,

−

Pd [M + TFA] , 904.9389; found, 904.9424.

General Procedure A for Preparation of Phosphino-

Palladacycles 3. To a solution of the corresponding dimeric

palladacycle 2a (1 equiv) in CH Cl (0.05 M) was added SPhos (1

5% yield in the presence of Pd(TFA) , SPhos, K CO , and

2 2 3

equiv/Pd) in one portion. The resulting solution was stirred at rt for

30 min and concentrated under vacuum, and n-pentane was added in

one portion. The precipitate was vigorously stirred for 10 min, and the

suspension was ﬁltered under vacuum. The solid was washed with n-

pentane and then air-dried to provide the corresponding phosphino

complex 3 as a beige solid.

AgOTf as additive (Scheme 3c). These results under

stoichiometric conditions demonstrate that complexes directly

accessible from a NH -directed C−H amination reaction could

be engaged in the subsequent deprotonated-amination

reaction.

SPhos-Chloro-Ortho-Palladated L-Phenylalanine Methyl Ester

(

3a-Cl). Following the general procedure A starting from palladacycle

CONCLUSION

In summary, this reactivity and DFT investigations of the

■

a-Cl (286 mg, 0.45 mmol), the title palladacycle 3a-Cl was

obtained as a beige solid (564 mg, 87%). Mp: 162−165 °C. IR (neat)

−

phenylalanine-derived palladacycles, obtained by NH -directed

3052, 2923, 2849, 1738, 1587, 1471, 1248, 1109, 728 cm . δ

C(sp )−H activation, sheds light on (1) a major anion eﬀect to

(300 MHz, CDCl ): 7.35 (1H, t, J = 8.4 Hz), 7.25 (1H, t, J = 7.5 Hz),

achieve the intramolecular C−N bond formation toward the

construction of the corresponding indoline product and (2) a

facile carbonate-assisted N−H activation prior to the events

leading to a reductive elimination step. We believe this study

highlights key features which will be useful for further

developments toward highly valuable catalytic dehydrogenative

amination processes, via a C−H/N−H activation process from

primary amines.

7.22−7.14 (1H, m), 7.00 (1H, ddd, J = 7.7, 3.1, 1.0 Hz), 6.92 (1H, t, J

(

7.7 Hz), 6.81 (1H, dd, J = 7.7, 4.8 Hz), 6.72−6.68 (2H, m), 6.64

2H, dd, J = 8.4, 2.7 Hz), 6.46−6.39 (1H, m), 3.82 (2H, br s), 3.69

3H, s), 3.65 (3H, s), 3.62 (3H, s), 3.22 (1H, dd, J = 13.0, 2.0 Hz),

.42 (1H, br s), 2.31−2.13 (3H, m), 1.81−1.44 (12H, m), 1.34−1.14

(

3H, m), 1.11−0.87 (5H, m) ppm. δ (75 MHz, CDCl ): 179.5,

72.8, 158.1, 139.8, 138.0, 136.5, 135.4, 133.0, 129.4, 128.9, 126.7,

24.7, 124.0, 123.3, 118.9, 103.8, 103.6, 103.1, 55.4, 55.2, 52.8, 52.4,

9.9, 48.9, 47.1, 46.8, 36.5, 36.1, 34.0, 33.9, 32.2, 31.7, 31.3, 30.5,

9.1, 28.4, 27.5, 27.2, 26.9, 26.2, 26.1, 25.6 ppm (observed complexity

EXPERIMENTAL SECTION

results from C−P coupling). δ (121 MHz, CDCl ): 46.21 ppm.

■

104

Triﬂate-Bridged Ortho-Palladated L-Phenylalanine Methyl

Ester (2a-OTf). N.B.: for this speciﬁc experimental procedure, no

precautions were taken against moisture or oxygen. To a mixture of

the L-phenylalanine methyl ester ammonium triﬂate salt 1a-OTf (1.0

HRMS (ESI ): calcd for C36

47NO P Pd [M − Cl] , 692.2285;

found, 692.2283.

SPhos-Iodo-Ortho-Palladated L-Phenylalanine Methyl Ester (3a-

I). Following the general procedure A starting from palladacycle 2a-I

(529 mg, 0.64 mmol), the title palladacycle 3a-I was obtained as a

g, 3.04 mmol) and Pd(OAc) (682 mg, 3.04 mmol) in a sealed tube

was added acetonitrile (0.1 M). The solution was stirred at 80 °C for

beige solid (970 mg, 92%). Mp: 186−188 °C. δ (300 MHz, CDCl ):

H 3

h. The reaction mixture was ﬁltered through a pad of Celite/

7.37 (1H, t, J = 8.3 Hz), 7.23−7.07 (2H, m), 6.92 (1H, dd, J = 7.4, 2.4

Hz), 6.85 (1H, br s), 6.75−6.60 (5H, m), 6.44 (1H, m), 3.99−3.75

(3H, m), 3.70 (3H, s), 3.69 (3H, s), 3.67 (3H, s), 3.55 (1H, br s) 3.21

(1H, d, J = 13.3 Hz), 2.52−2.13 (4H, m), 2.05−1.38 (12H, m), 1.37−

1.13 (3H, m), 1.08−0.92 (3H, m) ppm. δ (75 MHz, CDCl ) 173.1,

Na CO washed with MeCN. The ﬁltrate was concentrated under

reduced pressure, and a mixture of Et O and n-pentane was added.

The precipitate was vigorously stirred for 10 min, and the suspension

was ﬁltered under vacuum. The solid was washed with n-pentane and

then air-dried to furnish the corresponding complex 2a-OTf as a

158.2, 139.3, 137.0, 134.7, 133.0, 132.9, 129.6, 128.7, 127.0, 125.0,

125.0, 124.7, 123.6, 119.4, 103.9, 55.4, 53.0, 49.8, 45.6, 32.2, 30.9,

30.4, 29.1, 27.7, 27.6, 27.5, 27.4, 27.2, 27.0, 26.2, 26.0 ppm (observed

yellow solid (1.28 g, 97%). Mp: 117−118 °C. IR (neat): ν 3229,

max

−

976, 1736, 1553, 1439, 1241, 1167, 1028, 751, 638, 517, 457 cm .

δ_H(300 MHz, CD CN): 7.19 (d, J = 7.5 Hz, 1H), 7.02−6.87 (m,

complexity results from C−P coupling). HRMS (ESI ): calcd for

H), 4.31 (s, 1H), 3.64 (s, 3H), 3.64−3.57 (m, 1H), 3.33 (dd, J =

C H NO P Pd [M − I] , 692.2285; found, 692.2283. Data are in

4.1, 4.5 Hz, 1H), 3.17 (dd, J = 14.1, 5.6 Hz, 1H) ppm (one NH

accordance with THE literature.

signal missing). δ_C(75 MHz, CD CN): 172.8, 136.4, 136.1, 128.4,

General Procedure B for the Deprotonative Amination

from SPhos-Halogeno Palladacycle 3. To a mixture of SPhos-

phosphino-complex 3a (1 equiv) and K CO (3 equiv) in a ﬂame-

26.2, 126.1, 53.5, 50.4, 45.2 ppm. δ (282 MHz, CD CN): −79.3

+ 106

ppm. HRMS (ESI ): calcd for C H N O Pd [(M/2) −

(

CF SO ) + (1 × ACN)] , 325.01629; found, 325.01620.

dried sealed tube was added toluene (0.1 M). The resulting solution

Organometallics XXXX, XXX, XXX−XXX

Organometallics

orcid.org/0000-0003-1108-9410

Article

was stirred at 130 °C for 14 h under a nitrogen atmosphere and then

cooled to rt. The solution was diluted with CH Cl and ﬁltered

0000-0001-9668-9970; Email: christophe.hoarau@insa-

rouen.fr

through a pad of Celite. Bn O (0.25 equiv) was added, and the ﬁltrate

was concentrated under reduced pressure to provide a crude residue.

The conversion and NMR yield were monitored by H NMR

spectroscopy. When needed, the crude reaction mixture, after

evaporation under reduced pressure, was puriﬁed by ﬂash column

chromatography on silica gel.

Authors

Aurelien Jacquin-Labarre − Normandie Univ, UNIROUEN,

INSA Rouen, CNRS, COBRA, 76000 Rouen, France

Seb

astien Coufourier − Normandie Univ, UNIROUEN, INSA

Rouen, CNRS, COBRA, 76000 Rouen, France

Rodolphe Tamion − Industrial Research Centre-Oril Industrie,

76210 Bolbec, France

General Procedure C for Deprotonative Amination from

Dimeric Complex 2. To a mixture of dimeric complex 2 (1 equiv),

SPhos (1 equiv/Pd), and K CO (3 equiv/Pd) in a ﬂame-dried sealed

tube was added the corresponding solvent (0.1 M) under a nitrogen

atmosphere. The resulting solution was stirred at 100 °C for 14 h and

then cooled to rt. The solution was diluted with CH Cl and ﬁltered

Alexandra Le Foll − Normandie Univ, UNIROUEN, INSA

Rouen, CNRS, COBRA, 76000 Rouen, France

Vincent Levacher − Normandie Univ, UNIROUEN, INSA

Rouen, CNRS, COBRA, 76000 Rouen, France; orcid.org/

through a pad of Celite. Bn O (0.25 equiv) was added, and the ﬁltrate

was concentrated under reduced pressure to provide a crude residue.

000-0002-6429-1965

The conversion and NMR yield were monitored by H NMR

Carlos Afonso − Normandie Univ, UNIROUEN, INSA

Rouen, CNRS, COBRA, 76000 Rouen, France; orcid.org/

0000-0002-2406-5664

spectroscopy.

General Procedure D for One-Pot Synthesis of Indoline

4a). To a mixture of L-phenylalanine methyl ester 1c (18 mg, 0.1

(

mmol), Pd(TFA) (33 mg, 0.1 mmol), SPhos (41 mg, 0.1 mmol),

Vincent Gandon − Institut de Chimie Mole′culaire et des

K CO (69 mg, 0.5 mmol), and AgTFA (44 mg, 0.2 mmol) in a

Mate′riaux d’Orsay, CNRS UMR 8182, Universite

Paris-

ﬂame-dried sealed tube was added 1,4-dioxane (0.05 M) under a

nitrogen atmosphere. The resulting solution was stirred at 100 °C for

Saclay, 91405 Orsay cedex, France; Ecole Polytechnique,

Institut Polytechnique de Paris, 91128 Palaiseau cedex, France;

4 h and then cooled to rt. The solution was diluted with CH Cl and

2 2

ﬁltered through a pad of Celite. Bn O (0.25 equiv) was added, and

the ﬁltrate was concentrated under reduced pressure to provide a

crude residue. The conversion was monitored by H NMR

spectroscopy.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.organomet.0c00030

Methyl (S)-Indoline-2-carboxylate (4a). Following the general

procedure B starting from palladacycle 3a-I (247 mg, 0.3 mmol), the

title indoline 4a was obtained a yellow oil (32 mg, 61%) after

puriﬁcation by ﬂash column chromatography on silica gel (eluent

Author Contributions

A.J.-L. and S.C. contributed equally to this work.

⊥

Notes

petroleum ether/acetone [90/10]). δ_H(300 MHz, CDCl ): 7.13−

The authors declare no competing ﬁnancial interest.

.01 (2H, m), 6.79−6.69 (2H, m), 4.39 (1H, dd, J = 9.9, 5.7 Hz), 3.76

From the mass spectroscopy department.

(

3H, s), 3.47−3.25 (2H, m) (NH signal not observed). Data are in

accordance with the literature.

ACKNOWLEDGMENTS

■

Methyl 1H-Indole-2-carboxylate (5a). Following the general

procedure B starting from palladacycle 3a-Cl (219 mg, 0.3 mmol),

the title indole 5a was obtained a white solid (24 mg, 46%) after

puriﬁcation by ﬂash column chromatography on silica gel (eluent

This work has been partially supported by INSA Rouen, Rouen

University, the Centre National de la Recherche Scientiﬁque

(CNRS), EFRD, Labex SynOrg (ANR-11-LABX-0029), the

Region Normandie (CRUNCh network), and Oril Industrie,

aﬃliated with “Les laboratoires Servier”. This work has been

realized under the aegis of the joint laboratory Cobra−Oril

Industrie “IDECHEM”. V.G. thanks UPSaclay, CNRS, and

Ecole Polytechnique for ﬁnancial support. We thank Dr.

petroleum ether/acetone [95/5]). δ_H(300 MHz, CDCl ): 8.90 (s,

H), 7.70 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.33 (t, J = 7.3

Hz, 1H), 7.23 (d, J = 1.2 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.95 (s,

H) ppm. Data are in accordance with the literature.

ASSOCIATED CONTENT

sı Supporting Information

■

Fournier Jean and Dr. Verrier Cecile at Oril Industrie for

helpful discussions and for setting up this fruitful collaboration.

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.organomet.0c00030.

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Guillaume Journot − Industrial Research Centre-Oril Industrie,

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6210 Bolbec, France; Email: guillaume.journot@servier.com

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