Catalytic intermolecular hydroamination of vinyl ethers

Article abstract of DOI:10.1055/s-0029-1218293

This manuscript details the development of a palladium-catalyzed hydroamination of vinyl ethers. It is proposed that palladium catalyzes the hydroamination via Bronsted base catalysis, where palladium is protonated by the relatively acidic sulfonamide to

Full text of DOI:10.1055/s-0029-1218293

LETTER
3135
Catalytic Intermolecular Hydroamination of Vinyl Ethers
H
ydroamination of
i
Vinyl
rEthers mal K. Pahadi,* Jon A. Tunge*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
Fax +1(785)8645396; E-mail: tunge@ku.edu
Received 30 July 2009
the concentration of vinyl ether to 1.6 M (4 equiv) slightly
lowers the yield (entry 5), while using just 2 equivalents
considerably lowered the yield of aminol (entry 6) and in-
creased the time necessary for reaction completion. More-
Abstract: This manuscript details the development of a palladium-
catalyzed hydroamination of vinyl ethers. It is proposed that palla-
dium catalyzes the hydroamination via Brønsted base catalysis,
where palladium is protonated by the relatively acidic sulfonamide
to generate a palladium hydride as well as the active anionic sul- over, substantial quantities of enamine 4a were formed.
fonamide nucleophile. Thus, this process is distinct from known
palladium-catalyzed hydroaminations of styrene derivatives that
utilize less acidic amines.
Further lowering the concentration of 2 to 0.5 M dramati-
cally decreased the yield of 3, and only a trace amount of
enamine 4 was observed. Dioxane, MeCN, DCE, and
THF were also tested as potential solvents; only dioxane
Key words: hydroamination, vinyl ether, palladium, sulfonamide
provided any product. However, when 1,4-dioxane was
used as solvent, a 1:1 mixture of 3a and 4a was obtained
Transition-metal-catalyzed intermolecular hydroamina-
Table 1 Conditions for Hydroaminationa
tion of alkenes has attracted a great attention in recent
years.1 Much research in this line has centered on the in-
PG
tramolecular hydroamination of simple alkyl-substituted
N
OBu
Ph
a-olefins.2,3 The analogous intermolecular hydroamina-
tion of alkenes has been most successful with electron-
deficient alkenes,4 dienes,5 and vinlyarenes.6 In contrast to
these reactions, the related transition-metal-catalyzed
hydroaminations of vinyl ethers have not been extensively
investigated. Electron-rich olefins, such as vinyl ethers,
undergo palladium-catalyzed intramolecular hydroamina-
tion;7 intermolecular hydroaminations are catalyzed by
acid8 or bifunctional rhenium-oxo catalysts.9
PG
N
3a
catalyst
100 °C
+
+
OBu
Ph
H
PG
1
2a
N
Ph
4a
Entry Catalyst
PG Time Yield of Yieldof
(h)
3a (%) 4a (%)
1b Pd(PPh3)4
2b Pd(PPh3)4
3b Pd(PPh3)4
Ac
24
<5
<5
<5
94
82
50
10
80
72
75
<5
<5
<5
85
<5
<5
<5
<5
<5
25
<5
<5
<5
<5
<5
<5
<5
<5
At the outset of our investigations, it was known that pal-
ladium can catalyze the hydroamination of olefins by sev-
eral mechanisms. For instance, palladium(II) catalyzes
the intramolecular hydroamination of vinyl ethers.7 This
reaction is thought to occur via Lewis acid catalysis where
palladium coordinates the olefin, thus polarizing it toward
nucleophilic attack by the amine.7c,10 In addition, Hartwig
has developed a hydroamination of styrenes that is pro-
posed to go via acid-induced formation of p-benzyl com-
plexes.6 Herein we report a catalytic intermolecular
hydroamination of vinyl ethers that we propose utilizes
low-valent palladium as a specialized Brønsted base cata-
lyst.
Me 24
Bn
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
24
15
12
24
24
24
24
24
17
12
12
41
4
Pd(PPh3)4
5c Pd(PPh3)4
6d Pd(PPh3)4
7
8
9
PdCl2(PhCN)2
Pd2dba3/BINAP
Pd2dba3/dppb
We began investigating the potential for hydroamination
of 1-(vinyloxy)butane 2a with a variety of aniline deriva-
tives. Heating N-alkyl or N-acyl anilines in the presence of
5 mol% Pd(PPh3)4 at 100 °C resulted in no product forma-
tion. However, the more acidic N-tosyl aniline produced
the corresponding addition product 3a, which was ob-
tained in excellent yield (Table 1, entry 4) when the reac-
tion was performed in excess, neat vinyl ether. Lowering
10 Pd2dba3/dppf
11 none
12 TfOH (5 mol%)
13 TfOH/Pd(PPh3)4 (5 mol%)
14 PhCO2H/Pd(PPh3)4 (10 mol%) Ts
a Isolated yields of reactions carried out in a sealed vial with 1a (0.2
mmol) and neat 2a at 100 °C.
b Starting material was recovered.
c 1.6 M olefin in toluene.
SYNLETT 2009, No. 19, pp 3135–3138
x
x
.x
x
.2
0
0
9
Advanced online publication: 21.10.2009
DOI: 10.1055/s-0029-1218293; Art ID: S08709ST
© Georg Thieme Verlag Stuttgart · New York
d Conditions: 2 equiv 2a.

3136
N. K. Pahadi, J. A. Tunge
LETTER
as judged by 1H NMR spectroscopy. In addition, a variety
of other palladium catalysts were screened, but none was
as effective at promoting the hydroamination as Pd(PPh3)4
(entries 7–10). Thus, reactions could be run in neat vinyl
ether or in concentrated toluene solutions. For conve-
nience, we chose to run reactions in neat vinyl ether for
examination of the scope of the hydroamination.
Table 2 Scope of Hydroaminationa
Ts
N
OBu
R1
Ts
3
Pd(PPh3)4 (5 mol%)
100 °C
N
+
OBu
R1
H
+
1
2
Ts
N
Importantly, attempting to perform the same transforma-
tion without the addition of Pd(PPh3)4 produced <5%
yield of 3a over 17 hours at 100 °C (entry 11). Further-
more, since such a transformation could potentially be
catalyzed by simple Brønsted acids,3,8 the reaction was
run with 5 mol% TfOH with or without Pd(PPh3)4 and
<5% product was observed (entries 12 and 13). Instead,
TfOH promoted the decomposition of the butyl vinyl
ether to acetaldehyde dibutyl acetal.11 The reaction did
proceed with Pd(PPh3)4 and 10 mol% benzoic acid (entry
14), however, the acid additive inhibited the reaction, and
longer times were required for completion of the reaction.
Importantly, the observed inhibition by acid contrasts
with the Pd(PPh3)4-catalyzed hydroamination of vinylar-
enes which requires strong acid additives.6 Thus, we pro-
pose that the mechanism of the palladium-catalyzed
hydroamination of vinyl ethers differs from that of vinyl
arenes.
R1
4
Entry R1
2
Time
Yield of 3 Yield of 4
(equiv) (h)
(%)b
3b 67
3c 92
–
(%)b
1
2
4-BrC6H4
19
19
19
19
19
14
12
20
20
25
25
24
24
15
26
15
15
24
–
3-MeC6H4
–
3
2-MeC6H4
4d 90
4
2-Me2C6H3
4-MeOC6H4
4-MeOC6H4
3-MeOC6H4
3-MeOC6H4
4-O2N-C6H4
4-NCC6H4
–
4e 45
5
3f 80
3f 70
3g 80
3g 60
3h 60
3i 93
3j 93
3j 50
3k 40
–
6
4b
19
4b
4b
19
19
4b
19
–
7
–
8
–
9
–
Given the inhibition of the reaction by added acid, we hy-
pothesized that the Pd catalyst was behaving as a Brønsted
base to facilitate the hydroamination. If this is the case,
then the triphenylphosphine that accompanies the palladi-
um may also be capable of acting as a base and catalyzing
the reaction.8 Indeed, the reaction also proceeded in the
presence of 20 mol% Ph3P as a Lewis base, however, the
conversion was only 25% after extended reaction time.
Thus, phosphine catalysis does not account for our ob-
served results.
10
11
12
13
–
4-EtO2CC6H4
4- EtO2CC6H4
CH2(CH2)3Me
–
4j 50
4k <20
a All reactions were carried out in a sealed vial with 1 (0.2 mmol) and
2 in the presence of 5 mol% Pd(PPh3)4 at 100 °C unless otherwise in-
dicated.
b In toluene solvent.
Having the optimized conditions in hand, the scope and
limitations of the hydroamination of butyl vinyl ether with
a variety tosyl-protected amines was explored (Table 2).
Both electron-rich and electron-poor anilines are good
substrates for the reaction and groups like esters, nitro
groups, and nitriles are compatible with the reaction con-
ditions.
Table 3 Scope of Vinyl Ethersa
Ts
N
Ts
N
Pd(PPh3)4 (5 mol%)
100 °C
+
OR2
OR2
R1
H
R1
1
2
3
Entry R1
R2
2 (equiv) Time (h) Yield of 3 (%)b
Interestingly, ortho substitution of the aniline lead to ex-
clusive formation of the enamine product (entries 3 and 4,
Table 2) in good to moderate yield. Unfortunately, high
concentrations of the vinyl ether were often necessary to
promote formation of the aminol over the enamine. Last-
ly, when an aliphatic amine was exposed, the anticipated
addition product 3k was isolated in moderate yield along
with enamine 4k.
1
2
3
4
5
6
7
Ph
n-Pr
19
8b
4b
19
19
8b
19
36
14
14
26
26
14
25
3l 75
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-F3CC6H4
4-NCC6H4
n-Bu
n-Pr
Et
3m 92
3n 87
3o 89
3p 82
3q 82
3r 30
t-Bu
n-Bu
Cy
Next we turned our attention to investigating the vinyl
ethers that were compatible reaction partners in the hy-
droamination. Simple aliphatic vinyl ethers react smooth-
ly to afford the desired aminols except in the case of vinyl
cyclohexyl ether, which gives only a low yield of aminol
(Table 3, entry 7). Interestingly, the bulkier tert-butyl
ether forms the aminol in good yield (Table 3, entry 5).
a All reactions were carried out in a sealed vial with 1 (0.2 mmol) in
the presence of 5 mol% Pd(PPh3)4 at 100 °C.
b In toluene.
Synlett 2009, No. 19, 3135–3138 © Thieme Stuttgart · New York

LETTER
Hydroamination of Vinyl Ethers
3137
General Procedure for the Hydroamination of Vinyl Ethers
Representative Synthesis of Compound 3a
Cyclic vinyl ethers undergo the palladium-catalyzed hy-
droamination as well. Both five- and six-membered vinyl
ethers undergo hydroamination to provide the cyclic amin-
ols (Equation 1). An aliphatic amine also participates in
this transformation, however, the product 3u is formed in
rather low yield.
To butyl vinyl ether (2a, 0.49 mL, 3.8 mmol) and Pd(PPh3)4 (11.55
mg, 0.01 mmol), was added N-tosylaniline (49.41 mg, 0.2 mmol) in
a well-sealed pressure vial and heated to 100 °C in an aluminum
block for the designated time. The completion of reaction was mon-
itored via TLC, and the reaction stopped when amine was complete-
ly consumed. The reaction mixture was passed through a short pad
of silica gel, and the product was isolated by flash column chroma-
tography using silica gel as the stationary phase and hexane–EtOAc
(4:1) as the eluent; 66 mg (94%) of the product N-(1-butoxyethyl)-
4-methyl-N-phenylbenzenesulfonamide (3a) was obtained as a
slightly yellow oil.
1H NMR (400 MHz, CDCl3): d = 7.56 (d, J = 8.0 Hz, 2 H), 7.37–
7.28 (m, 3 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.05–7.01 (m, 2 H), 5.69
(q, J = 6.0 Hz, 1 H), 3.77 (dt, J = 9.3, 6.7 Hz, diastereotopic 1 H),
3.56 (dt, J = 9.3, 6.7 Hz, diastereotopic 1 H), 2.43 (s, Ts CH3), 1.58
(tt, J = 13.5, 4.0 Hz, 2 H), 1.37 (dq, J = 14.9, 7.3 Hz, 2 H), 1.14 (d,
J = 6.0 Hz, 3 H), 0.94 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): d = 143.17, 137.67, 134.44, 131.96, 129.18, 128.60,
128.54, 127.52, 85.06, 68.05, 31.51, 21.46, 20.62, 19.31, 13.88
ppm. IR (CH2Cl2): n = 3259, 2931, 1598, 1494, 1338, 1091, 919,
813, 754 cm–1. HRMS: m/z calcd for C19H25NO3SNa [M + Na]:
370.1453; found: 370.1450.
Ts
n
n
Pd(PPh3)4 (5 mol%)
100 °C
N
R1
+
R1
H
N
O
O
1
2
Ts
4-FC6H4
n = 0
n = 1
n = 1
3s: 95%, 26 h
3t: 85%, 15 h
3u: 40%, 18 h
4-FC6H4
Me(CH2)4CH2
Equation 1
A plausible mechanism for this transformation is outlined
in Scheme 1. Protonation of Pd(0) with the tosyl aniline
(pKa ca. 11.5 in DMSO) produces a palladium hydride
species12,13 which can undergo coordination of the vinyl
ether followed by insertion to form an alkylpalladium in-
termediate B. Related carbopalladations of vinyl ethers
have been proposed by Jordan.14 This intermediate can
undergo nucleophilic substitution by the tosyl amide,
probably via an SN1 mechanism, to produce the observed
product. The proposed intermediacy of the tosyl amide
anion is supported by the fact that we observe acid inhibi-
tion. In addition, we observed near-quantitative formation
of TsNHCH2CH2Cl when reactions were attempted in
dichloroethane. Finally, the enamine byproduct may arise
from elimination of alcohol from the aminol product,
which is promoted by sterically bulky ortho-substituted
anilines.
Acknowledgment
We thank the National Institute of General Medical Sciences
(1R01GM079644).
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Ts
N
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Ts
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N
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R2O
Pd(0)
Ts
R1
H
Ts
R1
Pd
N
Pd-H
+
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B
R2O
Scheme 1
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