Based on our previous studies of Heck-Matsuda reaction using pre-generated arenediazonium

salts,1,2 we started our investigation by targeting an experimental procedure for the

desymmetrization of cyclopentenol (2) applying the in situ generated arenediazonium salts
strategy. Thus, 4-Br-aniline (1a) and tert-butyl nitrite were selected as substrate and
diazotation agent, respectively, to perform a reaction test, in which Pd(TFA) 2 was chosen as the
palladium source in order to evaluate a selection of N,N ligands with established capability to
perform such transformation (Table 1).

For our delight, our first tests employing a stoichiometric ratio of 2 : 1 : 1.5 equivalents of 2, 1a
and tert-butyl nitrite, respectively, 80:20 Ph/MeOH solution as solvent and 10 mol% of the
catalyst system (1:1 Pd/ ligand ratio), L1 was able to furnish the desired 4-(4-
bromophenyl)cyclopent-2-en-1-ol 3a in a moderate yield of 42% with an excellent
enantiomeric ratio of 98:2 after 4h at 40 °C (Table 1 – entry 1). Interestingly, addition of
DTBMP (Table 1 -entry 2) as base or catalytic amount of acid methane sulfonic (5 mol%) (table
I- entry 3, see more details in ESI) did not provide any improvement in both yield and
enantiomeric ratio (Table 1- entry 2), suggesting that the present one-pot HM reaction takes
place under an almost neutral conditions in a fully self-sustainable protocol. We also observed
that addition of anisole in 0.5 eq. allowed an increasing of yield to 56% (Table 1- entry 4).

Having regard to these findings, we started the optimization process of the reaction in order
to discover the best conditions. We evaluated the concentration of methanol and found that
using 98:2 Ph/MeOH solution (Table 2-entry 1, see more details in ESI). Protection from light
exposure (in order to prevent the formation and interference of radical species in toluene) and
the presence of anisole as additive allowed to achieve the HM product in 70% and 98:2 e.r.
(Table 2 - entry 2). However, reproducibility issues were observed at 40 °C, mainly due to the
formation of triazene and a complexe mixture of bisaryl byproducts (observed in 1H-NMR
spectrum of the reactional mixture). Likewise, the same issue was observed at 60 °C and a
room temperature (Table 2-Entries 3-4) with less efficiency. In this regard, all our efforts were
conducted to find a condition which allows obtain better yields and high enantiomeric ration.
Thus, at 0 °C the triazene formation was significantly suppressed, and thereby it was possible
to stablish a reliability for the synthetic protocol, achieving 75% of yield and >99:1 of e.r. after
24 hours of reaction time (Table 1 – entry 5). Stoichiometric variations in the reagent ratio
proved to be detrimental for the overall yield (Table 1 – entries 6 – 9). The ligands L2 and L3
have proven useful in a range of HM reactions and displayed competence in our evaluations,
but yet slightly lower than L1 for this transformation (Table 1 – entries 9 – 10). Further
evaluations regarding solvent ratio were also performed, but again lower yields were observed
(Table 1 – Entries 10 – 16). Collectively, the evaluations lead us to determine the optimum
condition as being 2 equivalents of the olefin, one equivalent of the aniline and 1.5 equivalents
of the t-BuONO at 0°C for 12 hours, using 10 mol% of Pd(TFA) 2 and 10 mol% of L1 as catalyst
system. This protocol was able to provide the desired Heck product in 77% yield and >99:1 e.r.
(Table 2 – entry 11). It is relevant to emphasize that triazene byproducts were observed only in
trace amounts with this protocol (<5%, determined by 1H-NMR), and thereby the rigorous
controlled addition of aniline to the reaction mixture was dismissed
Table 1. First evaluation of the desymmetrization of 3-cyclopentenol 1 via HM reaction using in situ
generation of arenediazonium salt method
 Entry 1 2a Ligand t-BuONO Temp. (°C) Time Yield (%)a e.r.b
(equiv.) (equiv.) (mol%) (equiv.) (h)
1 2 1.0 L1 (10) 1.5 40 o.n 42 98:2
2 2 1.0 L1(10) 1.5 40 o.n 41 98:2
3 2 1.0 L1(10) 1.5 40 o.n 44 98:2
4c 2 1.0 L1(10) 1.5 40 o.n 56 98:2

All the reactions were performed in a 0.1 mmol scale | a determined by quantitative 1H-NMR analysis | b
determined by chiral HPLC analysis | c Reaction protected from light and using 0.5 equiv. of anisole as additive

Table 2 Optimization data for the desymmetrization of cyclopentenol 1 via HM reaction

Entry 1 2a [Pd] Ligand t- Temp. Time Yield e.r.b

(eq.) (eq.) (mol%) (mol%) BuONO (°C) (h) (%)a
(eq.)
1 2 1.0 Pd(TFA)2 L1(10) 1.5 40 4 62 98:2
2c 2 1.0 Pd(TFA)2 L1 (10) 1.5 40 4 22-70 98:2
3 2 1.0 Pd(TFA)2 L1 (10) 1.5 60 4 26 98:2
4 2 1.0 Pd(TFA)2 L1 (10) 1.5 r.t 12 56 98:2
5 2 1.0 Pd(TFA)2 L1 (10) 1.5 0 24 75 >99:1
6 3 1.0 Pd(TFA)2 L1 (10) 1.5 0 12 72 >99:1
7 1 1.5 Pd(TFA)2 L1 (10) 1.5 0 24 49 >99:1
8 2 1.0 Pd(TFA)2 L1 (10) 2.0 0 24 30 >99:1
9 2 1.0 Pd(TFA)2 L2 (10) 1.5 0 24 62 99:1
10 2 1.0 Pd(TFA)2 L3 (10) 1.5 0 24 54 97:3
11 2 1.0 Pd(TFA)2 L1 (10) 1.5 0 12 75 >99:1
12 2 1.0 Pd(TFA)2 L1 (6.5) 1.5 0
13 2 1.0 Pd(OAc)2 L1 (10) 1.5 0
14 2 1.0 Pd2dba3 L1 (10) 1.5 0
15d 2 1.0 Pd(TFA)2 L1 (10) 1.5 0 12 53 99:1
16e 2 1.0 Pd(TFA)2 L1 (10) 1.5 0 12 32 99:1
17f 2 1.0 Pd(TFA)2 L1 (10) 1.5 0 12 51 98:2
18g 2 1.0 Pd(TFA)2 L1 (10) 1.5 0 12 56 99:1
19h 2 1.0 Pd(TFA)2 L1 (10) 1.5 0 12 56 99:1

All the reactions were performed in a 0.1 mmol scale | a determined by quantitative 1H-NMR
analysis | b determined by chiral HPLC analysis | c Reaction protected from light and using 0.5
equiv. of anisole as additive| d PhMe/MeOH 4:1 | e PhMe/MeOH 9:1. | f 5 mol% of HFP as
additive | g acetic acid (30 mol%) as additive | h controlled addition of the aniline (2 hours) at 0
°C