Palladium-catalyzed aerobic oxidative coupling of enantioenriched primary allylic amines with sulfonyl hydrazides leading to optically active allylic sulfones

Article abstract of DOI:10.1039/c4cc00275j

A range of highly enantioenriched primary allylic amines underwent palladium-catalyzed oxidative coupling with sulfonyl hydrazides open to air at room temperature to give structurally diverse allylic sulfones in moderate to excellent yields with excellent retention of ee. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00275j

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Palladium-catalyzed aerobic oxidative coupling of
enantioenriched primary allylic amines with
sulfonyl hydrazides leading to optically active
allylic sulfones†
Cite this: Chem. Commun., 2014,
50, 3802
Received 13th January 2014,
Accepted 13th February 2014
Ting-Ting Wang, Fu-Xiang Wang, Fu-Lai Yang and Shi-Kai Tian*
DOI: 10.1039/c4cc00275j
www.rsc.org/chemcomm
A range of highly enantioenriched primary allylic amines underwent allylic substitution via p-allylpalladium intermediates,5 we further
palladium-catalyzed oxidative coupling with sulfonyl hydrazides open envisioned that a single Pd source would catalyze the oxidative
to air at room temperature to give structurally diverse allylic sulfones coupling of allylic electrophiles with simple sulfonyl hydrazides
in moderate to excellent yields with excellent retention of ee.
yielding allylic sulfones. In connection with our recent studies on
the substitution of primary allylic amines,6b,13–15 we planned to
The allyl sulfone moiety is not only present in some biologically develop an oxidative coupling reaction of sulfonyl hydrazides with
relevant compounds such as anticancer agents1a and antibacterials,1b enantioenriched primary allylic amines. Reasoning that H2O, N2, and
but also serves as a versatile building block in chemical synthesis.2 To NH3 would be generated as small-molecule byproducts, we expected
gain direct access to allylic sulfones in a convergent fashion, much that the reaction would proceed at much lower temperature than that
attention has been paid to the coupling of allylic electrophiles with for the reaction with sulfinate salts (100 1C),6b and consequently, the
sulfonyl nucleophiles.3 In this regard, sulfinate salts have been widely erosion of ee would be significantly minimized through selective
employed as sulfonyl nucleophiles to couple with symmetrical attack of sulfonyl nucleophiles on p-allylpalladium intermedi-
(a-substituent = g-substituent) or a-unbranched allylic esters, carbo- ates, which, ideally, would be racemization-free under certain
nates, and chlorides in the presence of chiral transition metal conditions.5,6b
complexes.4,5 Complementarily, transition metal-catalyzed allylation
To our delight, a variety of sulfonyl hydrazides underwent
of sulfinate salts with enantioenriched allylic carbonates or amines Pd(OAc)2–BINAP-catalyzed oxidative coupling with amine 1a open
has been developed for the asymmetric synthesis of unsymmetrical to air at room temperature and the reaction proceeded in an
(a-substituent a g-substituent) allylic sulfones, which, however, a-selective fashion with retention of configuration and alkene geometry
requires high temperature and excess additives and in most cases to give structurally diverse allylic sulfones in moderate to excellent
exhibits significant erosion of ee.6 In addition, a single example has yields with excellent retention of ee (Table 1, entries 1–13).16 This
been disclosed for the asymmetric sulfonylation of an enantio- chemistry was successfully extended to a range of enantioenriched
enriched allylic carbonate with 1-phenyl-3-(phenylsulfonyl)-pyrrolidine- primary allylic amines, wherein the a-substituents were alkyl groups
2,5-dione.7 To our knowledge, no other type of sulfonyl nucleophile and the g-substituents were aryl, bulkier alkyl, or ester groups
has previously been reported to couple with allylic electrophiles for (entries 14–19). To avoid significant erosion of ee in some cases,
the asymmetric synthesis of allylic sulfones.
In the course of exploring new chemistry of hydrazine derivatives,8 oxygen (entries 5, 6, 9, and 16) or at a lower concentration (entry 8).
we found that the NHNH2 group and the SO2 group of an arylsulfonyl
In line with typical allylic substitution,5 the regioselectivity was
the reaction was carried out with a lower catalyst loading under
hydrazide were removed successively by Pd under oxygen at 70 1C.8a,9 determined by the steric and electronic properties of the a- and
This result prompted us to envision that milder conditions would just g-substituents in the allylic amines. In sharp contrast to the examples
remove the NHNH2 group from a simple sulfonyl hydrazide shown in entries 1–19 of Table 1, the reaction proceeded in a
(RSO2NHNH2) and the remaining part (RSO2) could serve as a g-selective fashion when the a-substituent was an aryl group and
sulfonyl source.10–12 On the basis of the ability of Pd to catalyze the g-substituent was an alkyl group (entry 20). The g-selectivity was
speculated to arise from both maximizing conjugation and minimiz-
ing steric hindrance prior to the formation of the C–S bond between
the p-allylpalladium intermediate and the sulfonyl nucleophile
(see below). As expected, effective chirality transfer was not applicable
to a symmetrical allylic amine because of the symmetry of the p-allyl
unit in the resulting p-allylpalladium intermediate (entry 21).
Department of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, China. E-mail: tiansk@ustc.edu.cn; Tel: +86 551-6360-0871
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and copies of 1H NMR and 13C NMR spectra and
HPLC traces. See DOI: 10.1039/c4cc00275j
3802 | Chem. Commun., 2014, 50, 3802--3805
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Table 1 Oxidative coupling of allylic amines with sulfonyl hydrazidesa
Table 2 Reactions of sulfonyl hydrazide 8aa
Isolated yield (%)
Yieldb eec (%)
Entry 1, R1, R2, R3, R4
2, R
3
(%)
1 (3)
Entry
Pd(OAc)2
PhSO2R
rac-3a
rac-3b
1
2
3
4
Yes
No
Yes
Yes
None
None
PhSO2H (7b)
PhSO2NHNH2 (2b)
24
0
3
—
—
30
57
1
2
3
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1a, Ph, H, Me, H
1b, Ph, Me, Me, H
2a, 4-Me-Ph
2b, Ph
2c, 4-MeO-Ph 3c
3a
3b
79
80
72
66
77
72
54
80
71
90
91
62
74
51
75
80
57
68
58
95 (95)
95 (95)
95 (94)
95 (92)
95 (95)
95 (93)
95 (93)
95 (93)
95 (94)
95 (95)
95 (94)
95 (95)
95 (94)
97 (96)
98 (96)
90 (89)
97 (95)
99 (98)
99 (99)
95 (95)
96 (0)
17
4
2d, 4-AcNH-Ph 3d
5d
6d
7
2e, 4-Cl-Ph
2f, 4-F-Ph
2g, mesityl
2h, 2-Np
2i, 2-thienyl
2j, Me
2k, Me(CH2)7
2l, Me(CH2)15 3l
2m, PhCH2
2a, 4-Me-Ph
3e
3f
3g
3h
3i
3j
3k
a
Conditions: 8a (0.20 mmol), PhSO2R (0.30 mmol), Pd(OAc)2
(10 mol%), BINAP (20 mol%), dioxane (1.2 mL), air, rt and 24 h.
8e
9d
10
11
12
13
14
15
16d
17
18
19
20 f
21
generated from 9a and Pd(0) could be active enough to couple with
the sulfinate anion to give 3a.
While 8a could not be isolated from the reaction mixture by silica
gel chromatography because of decomposition, it was successfully
prepared by condensation of (E)-4-phenylbut-3-en-2-one with 2a
followed by reduction, and purified by recrystallization.18 8a was
treated with Pd(OAc)2–BINAP open to air to give rac-3a in 24% yield,
but this product was not detected in the reaction without Pd(OAc)2
(Table 2, entries 1 and 2). Interestingly, addition of 7b to the mixture
gave rac-3a and rac-3b in 3% and 30% yields, respectively (entry 3).
Moreover, alternative addition of 2b gave the same two sulfones but
in much higher yields probably due to the ability of the sulfonyl
hydrazide to reduce Pd(II) to Pd(0) (entry 4). Clearly, these results are
not in accord with Yamamoto’s proposal that Pd(0) would convert
N0-allyl sulfonyl hydrazides to p-allylpalladium(II)-S-sulfinate inter-
mediates (with release of N2 and H2) and subsequent reductive
elimination would give sulfones.10 Instead, they suggest that sulfinate
anions would most likely be kicked off from the initially-generated
p-allylpalladium intermediates prior to their attack on the allylic
carbons (see below).
The chirality of the phosphine ligand affected both the yield
and the stereochemical outcome via formation of diastereomeric
p-allylpalladium intermediates. When compared to racemic BINAP,
the use of (R)-BINAP in the reaction of 1a (95% ee) with 2a gave 3a in
a higher yield (87%) with higher ee (97%), and the use of (S)-BINAP
gave a lower yield (59%) and lower ee (92%). Moreover, the reaction
with racemic amine rac-1a in the presence of (R)-BINAP gave 3a in
65% yield with 30% ee and the remaining ent-1a was recovered in
25% yield with 6% ee, and similar results were obtained from the
reaction with (S)-BINAP (ent-3a: 60%, 30% ee; the remaining 1a: 26%,
6% ee). These results suggest that the C–N bond cleavage is much
less affected by chiral BINAP than the C–S bond formation, which
might be responsible for the slight erosion of ee in some cases, as
shown in Table 1 (entries 4, 6–8, 15, and 17).
3m
3n
3o
3p
3q
3r
1c, 2-Cl-Ph, H, Me, H 2a, 4-Me-Ph
1d, 2-Np, H, Me, H
1e, Cy, H, Me, H
2a, 4-Me-Ph
2a, 4-Me-Ph
2a, 4-Me-Ph
1f, Ph, H, Et, H
i
1g, CO2Et, H, Pr, Me 2a, 4-Me-Ph
3s
1h, Me, H, Ph, H
1i, Ph, H, Ph, H
2a, 4-Me-Ph
2a, 4-Me-Ph
ent-3a 75
3t
65
22
23
1j, X = NHCH2Ph
1k, X = N(CH2CH2)2O 2a, 4-Me-Ph
2a, 4-Me-Ph
3a
3a
88
80
95 (92)
95 (87)
a
Conditions: 1 (0.20 mmol), 2 (0.30 mmol), Pd(OAc)2 (10 mol%), BINAP
b
c
(20 mol%), dioxane (1.2 mL), air, rt and 24 h. Isolated yield. Deter-
mined by chiral HPLC analysis. Run with 5 mol% Pd(OAc)2 and
10 mol% BINAP under oxygen. 2.0 mL of dioxane was used. ent-3a =
enantiomer of 3a.
d
e
f
Moreover, replacement of the NH2 group in the amine with a bulkier
amino group was found to decrease the efficiency of chirality transfer
(entries 22 and 23).
The aerobic oxidative coupling reaction failed to occur with
N0-substituted sulfonyl hydrazides, such as TsNHNHCH2Ph (4a)
and TsNHNHBoc (4b), and these results indicate that the NHNH2
group is essential for the reaction to take place. To gain more insights
into the reaction mechanism, we carried out electrospray ionization
mass spectrometric analysis of the Pd(OAc)2–BINAP-catalyzed reac-
tion mixture of 1a with 2a. Gratifyingly, p-allylpalladiums 5a and 6a,
sulfinic acid 7a, sulfonyl hydrazide 8a, and diazene 9a were success-
fully assigned (Fig. 1).17
7a failed to couple with 1a to give 3a under the standard reaction
conditions, and it suggests that neither 5a nor 6a, generated from 1a
and Pd(0),13b is active enough to couple with the sulfinate anion
generated from 7a and 1a. Instead, the p-allylpalladium intermediate
could be attacked by 2a, a more active N-nucleophile, to give 8a,
which was subjected to Pd(II)-catalyzed aerobic oxidation to yield
9a. We further speculated that the p-allylpalladium intermediate
There could be two possible pathways to account for the erosion
of ee: (1) partial racemization of the p-allylpalladium intermediate
and (2) attack of the sulfinate anion on the Pd atom. To our delight,
the latter pathway was demonstrated to be responsible for the erosion
of ee by the experiments shown in eqn (1). Malononitrile (10) was
selected to trap the p-allylpalladium intermediate because of the
extremely high selectivity in its attack on the allylic carbon at room
temperature.13b While the substitution of 1a with 10 did not occur
under the standard reaction conditions, addition of a sulfonyl
Fig. 1 Intermediates 5a–9a.
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some cases originates from the attack of the sulfinate anion on the Pd
atom of 16 to form 18,6b,20 which undergoes reductive elimination to
give ent-3.
In summary, a variety of highly enantioenriched primary
allylic amines underwent Pd(OAc)2–BINAP-catalyzed oxidative
coupling with sulfonyl hydrazides open to air at room tempera-
ture and the reaction proceeded in a highly regioselective
fashion with retention of configuration to give allylic sulfones
in moderate to excellent yields with excellent retention of ee.
We are grateful for the financial support from NNSFC
(21232007 and 21172206) and NBRPC (2010CB833300).
Notes and references
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Scheme 1 Proposed reaction pathways.
hydrazide gave 11a as a major product with complete retention of ee.
In contrast, the sulfone was obtained as a minor product with the
same ee as that shown in Table 1 (entries 1 and 4). The use of 2d
decreased the ee from 95% to 92%. These results substantially permit
us to conclude that the erosion of ee is attributed to the attack of the
sulfinate anion on the Pd atom of the p-allylpalladium intermediate.
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On the basis of the above experimental results and previous
relevant mechanistic studies,5,6b,8a we propose the reaction pathways
depicted in Scheme 1. Displacement of Pd(OAc)2 by 2 gives 12, which
undergoes b-hydride elimination to give 13 and releases HPdOAc.8a 10 For the reaction of allenes with tosylhydrazine, see: S. Kamijo,
Extrusion of N2 from 13 gives 7,19 which reacts with a base (1 or 2) to
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yield a sulfinate anion. Reductive elimination of HPdOAc gives HOAc
11 For acting as sulfonyl sources to substitute organic halides, see:
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the other hand, Pd(0) cleaves the C–N bond in 1, activated by an acid,
with inversion of configuration to give 5, which releases NH3 to yield
6.13b Regioselective attack of 2 on the allylic carbon of 6 proceeds with
inversion of configuration to give 8 and regenerate Pd(0) and an acid.
8 is subjected to Pd(II)-catalyzed aerobic oxidation to give 9, which
undergoes oxidative addition with Pd(0) to give 16 with inversion of
configuration. The allylic carbon of 16 is attacked regioselectively by a
sulfinate anion with inversion of configuration to give 3 and regen-
erate Pd(0).6b The configuration of 1 has been inverted four times
in the whole process and 3 is produced with net stereoretention.
The standard reaction conditions do not allow 16 to undergo
racemization via Pd–Pd-exchange,5 and the slight erosion of ee in
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3804 | Chem. Commun., 2014, 50, 3802--3805
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This journal is ©The Royal Society of Chemistry 2014
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