Reductive cyclization of bromoenynamides with alcohols as hydride source: Synthesis and reactions of 2-amidodienes

Article abstract of DOI:10.1002/adsc.201200703

Under basic conditions in alcoholic solvents, bromoenynamides undergo palladium-catalyzed cyclization to cyclic 2-amidodienes in good to excellent yields. This process represents the first use of an alcohol as a hydride source in an alkyne carbopalladation/termination sequence, with the site selectivity of the reduction showing a strong dependence on the tethering ring size (5-8), and the nature of the alcohol and base. Reaction of the dienes with a range of dienophiles (including alkenes, alkynes and arynes) under various conditions gives bi- and tricyclic azacycles, which can be further oxidized to the aromatic azacycles. Copyright

Full text of DOI:10.1002/adsc.201200703

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DOI: 10.1002/adsc.201200703
Reductive Cyclization of Bromoenynamides with Alcohols as
Hydride Source: Synthesis and Reactions of 2-Amidodienes
Rebecca L. Greenaway,a Craig D. Campbell,a Helen A. Chapman,b
and Edward A. Andersona,*
a
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX13TA, U.K.
Fax : (+44)-1865-285-002; phone: (+44)-1865-285-037; e-mail: edward.anderson@chem.ox.ac.uk
Syngenta Ltd., Jealottꢀs Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, U.K.
b
Received: August 8, 2012; Published online: November 8, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200703.
Abstract: Under basic conditions in alcoholic sol-
vents, bromoenynamides undergo palladium-cata-
lyzed cyclization to cyclic 2-amidodienes in good to
excellent yields. This process represents the first use
of an alcohol as a hydride source in an alkyne car-
bopalladation/termination sequence, with the site
selectivity of the reduction showing a strong de-
pendence on the tethering ring size (5–8), and the
nature of the alcohol and base. Reaction of the
dienes with a range of dienophiles (including al-
kenes, alkynes and arynes) under various conditions
gives bi- and tricyclic azacycles, which can be fur-
ther oxidized to the aromatic azacycles.
venient reductant in an alkyne carbopalladation se-
quence.[4] Cycloadditions of the resultant cyclic dienes
lead to bi- or tricyclic products 5 that are difficult to
access using other methods.
We began our studies with bromoenynamide 1a
(Table 1).[5] Our selection of ethanol as a cheap stoi-
chiometric reductant arose from observations made in
our previous work, where variable amounts of diene
4a had been isolated from attempted carbopallada-
tion/Suzuki cross-coupling reactions in hydroxylic sol-
vents.[2a] Initial investigations using ethanol as solvent,
Cs2CO3 as base, and 2.5 mol% PdACTHNUTRGNE(UNG PPh3)4 as catalyst,
delivered 4a in excellent yield as a single stereoiso-
mer, as evidenced by 1H NMR nOe experiments
(83%).[6] These conditions were superior to the use
Keywords: carbopalladation; homogeneous cataly-
sis; nitrogen heterocycles; reduction; ynamides
of other catalysts [e.g., PdCl
2ACHTUNGTRNE(UNNG PPh3)2, PdCl2dppf,
Pd(OAc)2/2PPh3], or triethylsilane as reducing agent,
AHCTUNGTRENNUNG
and indeed on larger scales a lower catalyst loading of
1 mol% proved viable (entry 2). Although other inor-
ganic bases were less effective (entries 3–5), increas-
Alkyne carbopalladation is a powerful tool for cas-
ꢀ
cade C C bond formation, owing to its broad sub-
strate scope and functional group tolerance, and abili-
ty to be coupled with a range of other palladium-
mediated processes.[1] One notable absence from this
field is ynamide carbopalladation, where few studies
have been described,[2] despite the recognized value
of ynamides in organic synthesis.[3] In previous work,
we showed that bromoenynamides 1 undergo efficient
carbopalladative cyclization to azabicycles 2 via cross-
coupling
of
dienylpalladium(II)
complex
3
(Scheme 1).[2a] We recognized that a reductive termi-
nation step from 3 would afford monocyclic amido-
dienes 4, which could engage in Diels–Alder cycload-
dition reactions to afford complementary aza-bicyclic
or tricyclic products. Here we describe the application
of this process and its application to a wide range of
bromoenynamides using ethanol as a hydride source,
Scheme 1. Cyclization by carbopalladation/reduction: plan-
which represents the first use of an alcohol as a con- ned synthesis of nitrogen heterocycles from ynamides.
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Table 1. Reductive cyclization of bromoenynamides 1a–c.
Entry
SM
Cat. mol%
Base
Solvent,[a] time [h]
4:6
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
1c
1c
2.5
1
Cs2CO3
Cs2CO3
NaOH
K3PO4
EtOH, 0.5
EtOH, 1
EtOH, 1
EtOH, 18
EtOH, 1
EtOH, 0.25
EtOH, 0.5
EtOH, 1
PhMe/EtOH (10:1), 2
PhMe/iPrOH (10:1), 2
PhMe/MeOH (10:1), 1
EtOH, 1.75
EtOH, 4
PhMe/EtOH (1:1), 3.5
1:0
1:0
1:0
1:0
1:0
1:0
6:1
1:3.3
1:0.4
1:0.2
1:1
1:0.15
1:0
83
84[c]
62
2.5
2.5
2.5
2.5
2.5
2.5
10
10
10
10
10
62
62
84
71
59
45
68
52
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NaHCO3
K2CO3
9
10
11
12
13
14
68
40[d]
69
2.5
1:0
[a]
Entries 1–5 at 0.02M, entries 6–14 at 0.045M.
Isolated yield.
[b]
[c]
[d]
Performed on a 2.42 mmol (1 g) scale.
1
Conversion as monitored by H NMR spectroscopy.
ing the reaction concentration enabled the isolation dienes 4f and 4g were prone to isomerization during
of 4a in an optimized 84% yield (entry 6). Notably, in purification, or on standing in CDCl3. The introduc-
none of the reactions of 1a did we observe direct re- tion of a substituent adjacent to the sulfonamide ena-
duction of the bromoalkene to alkene 6a, which re- bled the synthesis of a-branched cyclic dienamides 4h
flects the rapid nature of 5-exo-dig carbopalladation.
and 4i (entries 5 and 6). The synthesis of larger rings
In contrast, application of these conditions to the could also be demonstrated using the modified
homologous substrates 1b and 1c led to significant, or (K2CO3) cyclization conditions, which gave piperidine
even predominant, reduction of the bromoalkene to 4b and azepanes 4j and 4k (entries 7–9). Excitingly,
6b and 6c (entries 7 and 8). Attempts to retard the ynamide 1l (entry 10), which features two heteroa-
rate of hydride transfer through the use of mixed sol- toms in the ynamide/bromoalkene tether, delivered
vent systems (entries 9–11) revealed a dependence on diazepane 4l in high yield (85%). Given the particular
the nature of the alcohol cosolvent, but did not elimi- challenge of alkyne carbopalladation to form 8-mem-
nate the problem. Pleasingly, the use of different bered rings,[7] competing direct reduction (~20%) in
bases led to greater success, with K2CO3 reducing the the cyclization of bromoenynamide 1m was not unex-
extent of direct reduction, and NaHCO3 effecting ex- pected (using K2CO3 as base). However, by employ-
clusive carbopalladation, albeit with incomplete reac- ing NaHCO3 in EtOH we were delighted to be able
tion (entries 12 and 13). A compromise to these con- to effect the desired 8-membered ring formation to
ditions was found using K2CO3 in 1:1 toluene/ethanol diazocane 4m (73%, entry 12), albeit with increased
(entry 14), which gave full conversion of 1c to aze- catalyst loading and reaction time.[8]
pane diene 4c with no undesired direct reduction
(69%).
The formation of these exocyclic amidodienes can
be rationalized mechanistically (Scheme 2) by initial
With optimized sets of conditions in hand, we ex- oxidative addition of the bromoalkene, followed by
plored the scope of the cyclization (Table 2). The in- syn-carbopalladation of the ynamide to give dienyl-
fluence of the substituent at the ynamide terminus palladium intermediate 7. Coordination of ethoxide
was first investigated (entries 1–4), with alkyl and aryl to palladium enables hydride transfer via b-hydride
substituents both affording the corresponding amido- elimination, with subsequent reductive elimination af-
dienes 4d–g in good yields, although electron-rich fording diene product and regenerating Pd(0) cata-
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Reductive Cyclization of Bromoenynamides with Alcohols as Hydride Source
Table 2. Reductive cyclization of bromoenynamides to cyclic dienamides.
Entry
1
Substrate
Conditions[a]
A
Product
Yield [%][b]
83
1d
4d
2
3
1e
1f
A
A
4e
4f
65, 65[c]
61
4
1g
A
4g
66[d]
5
6
1h
1i
A
A
4h
4i
68
75
7
8
1b
1j
B
B
4b
4j
73
65
9
1k
1l
C
B
4k
4l
61
85
10
11
1m
D
4m
73
[a]
Conditions A: 2.5 mol% Pd
N
ACHTUNGTRENNUNG
ditions C: 10 mol% Pd
Isolated yield.
Performed on 1.24 mmol (0.5 g) scale with 1 mol% catalyst.
Isolated as a 1:4.2 E:Z mixture.
G
ACHTUNGTRENNUNG
[b]
[c]
[d]
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Rebecca L. Greenaway et al.
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Scheme 2. Proposed mechanism for the reductive cyclization, and deuterium-labelling studies.
lyst.[4f,9] This mechanism is supported by the use of was not successful, but could be realized using
octanol as hydride source, which led to the formation BF3·OEt2 as a Lewis acid catalyst,[13] which also gave
of octanal and octyl octanoate (implying the hemiace- cycloadduct 9f as a single isomer (entry 4).[6] Interest-
tal to be a superior hydride donor),[10] and deuterium ingly, the regioselectivity of these processes implies
labelling studies, in which >95% deuterium incorpo- the sulfonamide nitrogen atom to have a negligible
ration was observed using d2-octanol. The variation in electronic directing effect, with the diene alkyl
product ratio with inorganic base and alcohol presum- groups, or steric effects, playing a more important
ably relates to the rate of hydride transfer to palladi- role. PTAD (10d) proved a particularly good dieno-
um, which itself likely depends on both the extent of phile, affording the diazepane tricycle 9g in excellent
dissociation of the metal cation from the alkoxide yield at room temperature (84%, entry 5).
(and the resulting effect on alkoxide nucleophilicity),
To extend these Diels–Alder processes, we were at-
and the influence of the degree of branching of the al- tracted to the idea of using arynes, as these would de-
cohol on its propensity to undergo b-hydride elimina- liver tricyclic products which would not be readily ac-
tion.[9d]
cessible through other means, including our own pre-
With access to a range of cyclic dienamides now se- vious work. We found that the benzyne precursor 11a
cured, we chose to demonstrate their utility in a varie- underwent smooth reaction with 4a in 2 h at 608C
ty of cycloaddition processes (Table 3).[11] The Diels– (entry 6, Conditions D), conditions which are typical
Alder reaction of dienes 4a–c with dimethylacetylene for aryne formation,[14] but also that this reaction pro-
dicarboxylate 8 (DMAD, entry 1) revealed the reac- ceeded with equal efficiency but extended reaction
tivity of the diene to be highly dependent on the teth- time at room temperature (entry 6, Conditions E).[15]
ering ring size: all three dienes successfully gave the Evaluation of other arynes supported our view that
corresponding bicyclic cycloadducts 9a–c, but with the sulfonamide nitrogen does not act as a significant
varying reaction times. This reactivity difference activator, due to the mixture of regioisomers observed
likely reflects the influence of ring flexibility on the with arynes derived from 11b and 11c (entries 7 and
diene torsion angle, and of ring size on the bond 8).[16] The complementary regioselectivity of these two
angles of the diene. N-Phenylmaleimide 10a also per- reactions likely reflects a balance of steric and elec-
formed well under thermal conditions,[11a,b,12] as did tronic factors; addition of 11b positions the methyl
acrolein 10b, which provided cycloadduct 9e as substituent distal to the hexyl sidechain of the diene
a single regio- and diastereoisomer (entries 2 and 3).[6] to minimize steric interactions, whereas the electronic
The equivalent reaction of methacrolein 10c with 4a influence of the methoxy group in 11c favors ad-
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Reductive Cyclization of Bromoenynamides with Alcohols as Hydride Source
vanced bond formation at the exo-methylene termi- cloaddition. To our delight, diazepane diene 4l also
nus of the diene in the transition state, mirroring the underwent smooth cycloaddition with benzyne, deliv-
cycloadditions with acrolein and methacrolein. The ering dihydrobenzodiazepine 9m in excellent yield
reaction of diene 4h delivered cycloadduct 9l as (80%, entry 10).
a single diastereomer (entry 9),[17] reflecting the con-
Finally, we recognized that the products of cycload-
formational effect of the sulfonamide and arene sub- dition with alkynes and arynes could represent precur-
stituents in controlling the facial selectivity of the cy- sors to useful bi- and tricyclic heteroaromatic scaf-
Table 3. Diels–Alder reactions of cyclic dienamides.
Entry
1
Diene
Dienophile
Conditions, time [h][a]
Product
Yield [%][b]
dr/rr[c]
4a
4b
4c
8
9a
9b
9c
78
60
61
–
2
4a
10a
10b
A (1)
9d
72
1:0
A (5)
B (1)
69
65
3
4
4a
4a
9e
9f
1:0
1:0
10c
B (2)
C (2)
71
84
5
6
7
8
4l
10d
11a
9g
–
4a
4a
4c
D (2)
E (19)
D (16)
9h
9h
9i
63
81
85
–
4a
4a
11b
11c
E (21)
9j
65
2:1
D (2)
E (23)
71
76
4.4:1
3.1:1
9k
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Table 3. (Continued)
Entry
Diene
Dienophile
Conditions, time [h][a]
D (1.5)
Product
Yield [%][b]
72
dr/rr[c]
9
4h
11a
9l
1:0
10
4l
11a
D (16)
9m
80
–
[a]
Conditions A: PhMe, 808C. Conditions B: BF3·OEt2 (0.55 equiv.), CH2Cl2, ꢀ788C. Conditions C: CH2Cl2, room tempera-
ture. Conditions D: CsF (4.0 equiv), MeCN/PhMe (1:1), 608C. Conditions E: CsF (4.0 equiv), MeCN/PhMe (1:1), room
temperature.
Isolated yield.
[b]
[c]
1
Ratio indicates ratio of diastereomers (dr) or regioisomers (rr) in the crude reaction mixture as determined by H NMR
spectroscopic analysis; major isomer shown.
1.5 equiv.). The reaction mixture was heated to 808C for 1 h
(until judged complete by TLC), then it was cooled to room
temperature and filtered through a Celiteꢂ plug (EtOAc
eluent). The filtrate was concentrated under vacuum, and
the residue purified via flash chromatography (SiO2, petrole-
um ether!petroleum ether/EtOAc, 95:5) to give diene 4a
1
as a yellow oil; yield: 673 mg (2.02 mmol, 84%). H NMR
(500 MHz, CDCl3): d=7.68 (d, J=8.0 Hz, 2H), 7.23 (d, J=
8.0 Hz, 2H), 5.87 (t, J=7.5 Hz, 1H), 5.20 (t, J=2.0 Hz, 1H),
4.64 (t, J=2.0 Hz, 1H), 3.53 (t, J=7.5 Hz, 2H), 2.53 (q, J=
7.5 Hz, 2H), 2.41 (s, 3H), 1.84 (tt, J=7.5, 2.0 Hz, 2H), 1.45
(app. quintet, J=7.5 Hz, 2H), 1.39–1.29 (m, 6H), 0.89 (t, J=
7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=143.8, 143.3,
136.5, 136.0, 129.5, 127.8, 122.1, 103.5, 48.5, 31.8, 29.7, 29.5,
29.1, 29.0, 22.7, 21.6, 14.1; IR (thin film): n=2925, 1166,
1091, 801, 415 cmꢀ1; HR-MS: m/z=356.1656, calcd. for
C19H27NO2S [M+Na]+: 356.1660; Rf =0.33 (petroleum
ether/EtOAc, 10:1).
Scheme 3. Oxidation of Diels–Alder products.
folds. Pleasingly, we found that a number of cycload-
ducts could be oxidized to the corresponding arenes
in a straightforward manner using DDQ (Scheme 3),
providing indoline 12, benzoindoline 13, and naph-
thoazepine 14 in good yields (69–84%).
Typical Procedure for Cycloaddition of 4 with
Benzyne [Table 3, Entry 6 (9i)]
To CsF (50 mg, 0.33 mmol, 4.0 equiv., weighed in a glovebox)
in an oven-dried vial sealed with a rubber septum under an
argon atmosphere was added a solution of 4c (30 mg,
0.083 mmol, 1.0 equiv.) in anhydrous toluene (0.33 mL), an-
hydrous acetonitrile (0.33 mL), and 11a (40 mL, 0.165 mmol,
2.0 equiv.). The reaction mixture was heated to 608C for
16 h (until judged complete by TLC), then it was cooled to
room temperature and concentrated under vacuum. Purifi-
cation of the residue by flash chromatography (petroleum
In conclusion, we have developed the first example
of a carbopalladation/reduction cyclization process
which employs a simple alcohol as a hydride source,
via b-hydride elimination from a palladium alkoxide.
The reaction converts a wide range of bromoenyn-
ACHTUNGTRENNUNGamides to cyclic 2-amidodienes, which are substrates
for Diels–Alder reactions with electron-deficient al-
kenes and alkynes including arynes, and as such offer
a straightforward route into bi- and tricyclic azacycles. ether!petroleum ether/EtOAc, 20:1) gave 9i as a colourless
1
oil; yield: 31 mg (0.0708 mmol, 85%). H NMR (500 MHz,
CDCl3): d=7.73 (d, J=8.5 Hz, 2H), 7.25 (d, J=7.0 Hz, 2H),
7.20–7.05 (m, 4H), 4.20 (d, J=14.5 Hz, 1H), 3.97 (br s, 1H),
3.65 (dd, J=21.0, 4.0 Hz, 1H), 3.21 (dd, J=21.0, 2.0 Hz,
1H), 2.88 (t, J=12.5 Hz, 1H), 2.42 (s, 3H), 1.98 (t, J=
Experimental Section
13.5 Hz, 1H), 1.84–1.75 (m, 2H), 1.73–1.61 (m, 4H), 1.61–
Typical Procedure for the Reductive Cyclization of
1 [Table 1, entry 2 (4a)]
1.54 (m, 1H), 1.31–1.07 (m, 7H), 0.91–0.86 (m, 1H), 0.81 (t,
J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=143.1,
To a solution of ynamide 1a (1.00 g, 2.42 mmol, 1.0 equiv.)
in EtOH (54 mL, 0.045M) was added Pd(PPh3)4 (28 mg,
24.2 mmol, 1 mol%) and Cs2CO3 (1.18 g, 3.63 mmol,
139.1, 138.6, 137.1, 135.2, 134.0, 129.6, 128.1, 127.4, 127.3,
126.1, 125.9, 50.65, 44.52, 37.81, 35.02, 33.21, 31.93, 29.81,
29.61, 25.01, 23.93, 22.74, 21.66, 14.16; IR (thin film): n=
AHCTUNGTRENNUNG
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Reductive Cyclization of Bromoenynamides with Alcohols as Hydride Source
2928, 2856, 1598, 1494, 1454, 1341, 1156, 1091, 1026,
909 cmꢀ1; HR-MS: m/z=460.2264, calcd. for C27H35NNaO2S
[M+Na]+ 460.2281; Rf =0.56 (petroleum ether/EtOAc, 4:1).
4091. For the use of formate in carbopalladation/reduc-
tion, see: h) R. Grigg, V. Loganathan, V. Sridharan, P.
Stevenson, S. Sukirthalingum, T. Worakun, Tetrahedron
1996, 52, 11479–11502,. For the use of triethylsilane in
carbopalladation/reduction, see: i) C. H. Oh, S. J. Park,
Tetrahedron Lett. 2003, 44, 3785; see also refs.[3b,3c]
[5] See the Supporting Information for details of substrate
preparation.
Acknowledgements
We thank Syngenta for a studentship (to R.L.G.), and the
EPSRC (EP/H025839/1 to C.D.C.) and (EP/E055273/1 Ad-
vanced Research Fellowship to E.A.A.).
[6] See the Supporting Information for details of structural
assignment.
[7] For rare examples, see: a) S. Schweizer, W. M. Tokan,
P. J. Parsons, A. de Meijere, Eur. J. Org. Chem. 2010,
4687–4699; b) S. B. J. Kan, E. A. Anderson, Org. Lett.
2008, 10, 2323–2326.
[8] Other bases (Li2CO3, Na2CO3, Cs2CO3) and solvent
mixtures led to appreciable amounts of direct reduction
and/or incomplete conversion after prolonged reaction
times (20 h).
[9] For palladium(II)-catalyzed oxidation of alcohols, see:
a) J. A. Mueller, C. P. Goller, M. S. Sigman, J. Am.
Chem. Soc. 2004, 126, 9724–9734; b) M. J. Schultz, S. S.
Hamilton, D. R. Jensen, M. S. Sigman, J. Org. Chem.
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rahedron 2003, 59, 5789–5816; d) S. S. Stahl, Angew.
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A. Lei, Angew. Chem. 2011, 123, 5250–5254; Angew.
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805; b) M. Mori, H. Wakamatsu, N. Saito, Y. Sato, R.
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Hsung, C. Rameshkumar, J. A. Mulder, T. P. Grebe,
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R. P. Hsung, J. Antoline, H. A. Coverdale, K. C. M.
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L. Diab, P. Cordier, C. Ollivier, V. Gandon, M. Malac-
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[16] A small amount of an ene product was also detected in
the reaction of 11c; see the Supporting Information for
Adv. Synth. Catal. 2012, 354, 3187 – 3194
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Rebecca L. Greenaway et al.
COMMUNICATIONS
details. Ene reactions of benzynes are well-known; for
a recent example and leading references, see: D. A.
Candito, J. Panteleev, M. Lautens, J. Am. Chem. Soc.
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[17] The stereochemistry of this cycloadduct could not be
assigned by NMR spectroscopy; an arbitrary assign-
ment has been made based on our consideration of
possible conformations of the diene starting material;
see the Supporting Information for a brief discussion.
3194
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3187 – 3194