Palladium-catalyzed, chelation-assisted stereo- and regioselective synthesis of tetrasubstituted olefins by oxidative heck arylation

Article abstract of DOI:10.1002/adsc.201200306

An efficient synthesis of tetrasubstituted olefins was achieved via a palladium-catalyzed, chelation-assisted oxidative Heck arylation protocol from trisubstituted olefins bearing a tether with a directing group in a completely stereo- and regioselective manner. The stereo- and regioselectivity as well as excellent yields of tetrasubstituted olefins originated from the stabilization of a palladium intermediate by chelation between the palladium center and a directing group. Copyright

Full text of DOI:10.1002/adsc.201200306

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DOI: 10.1002/adsc.201200306
Palladium-Catalyzed, Chelation-Assisted Stereo- and
Regioselective Synthesis of Tetrasubstituted Olefins by
Oxidative Heck Arylation
Hyun Seung Lee,a Ko Hoon Kim,a Sung Hwan Kim,a and Jae Nyoung Kima,*
a
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of
Korea
Fax : (+82)-62-530-3389; e-mail: kimjn@chonnam.ac.kr
Received: April 12, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200306.
Abstract: An efficient synthesis of tetrasubstituted
olefins was achieved via a palladium-catalyzed, che-
lation-assisted oxidative Heck arylation protocol
from trisubstituted olefins bearing a tether with a di-
recting group in a completely stereo- and regiose-
lective manner. The stereo- and regioselectivity as
well as excellent yields of tetrasubstituted olefins
originated from the stabilization of a palladium in-
termediate by chelation between the palladium
center and a directing group.
ticipate in the carbopalladation process.[1] Increased
steric crowdedness during the insertion of the ArPdL
species to the hindered olefin might be an important
reason for the failure. As a powerful variant of the
normal Heck reaction, the Pd(II)-catalyzed oxidative
arylation of olefins with arenes has attracted much at-
tention.[2] The oxidative cross-coupling between ole-
fins and arenes, commonly known as the Fujiwara–
Moritani reaction or simply dehydrogenative Heck re-
action, circumvents the use of preformed or less read-
ily accessible aryl halides. However, the reaction also
did not work well for the synthesis of highly-substitut-
ed olefins.[2] Thus, the stereo- and regioselective syn-
thesis of highly-substituted olefins is still very chal-
lenging, and a very limited number of papers has
been published.[3]
Keywords: chelation; Morita–Baylis–Hillman ad-
ducts; oxidative Heck arylation; palladium
In this report, we describe an effective stereo- and
The Pd-catalyzed Mizoroki–Heck arylation of olefins regioselective synthesis of tetrasubstituted olefins by
with aryl halides has become a well-established syn- a Pd(II)-catalyzed oxidative cross-coupling reaction
[1]
À
thetic method for C C bond formation. However, between an arene and a trisubstituted olefin bearing
the normal intermolecular Heck reaction did not a tether with a directing group (DG), as shown in
work well for the synthesis of tetrasubstituted olefins Scheme 1, conceptually [Eq. (1)] and with an example
due to the reluctance of trisubstituted olefins to par- [Eq. (2)]. The DG can assist the carbopalladation of
Scheme 1. Eq. (1): Basic concept of arylation: a) C-H activation; b) rotation; c) b-H elimination. Eq. (2): Arylation example:
d) benzene, Pd
N
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Table 1. Optimization of reaction conditions for the conver-
sion of 1a to 2a.[a]
ArPdL species to the C=C double bond and control
the regiochemistry of the b-H elimination. Although
such a chelation-assisted reaction has been studied ex-
tensively for the purpose of stereo- and regiocontrol,
and multiple arylations;[4,5] however, most of the reac-
tions involved the use of aryl halides or arylboronic
acids instead of arenes.[4,5] Very recently, Pd-catalyzed
oxidative Heck reactions of allyl esters have been re-
ported with arenes and heteroarenes.[5d–g]
Entry Catalyst[b] Oxidant[c] Additive[d] Time
[h]
Yield
[%]
1
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
PivOH
PivOH
none
AcOH
TFA
20
32
24
24
24
32
32
32
92
78
75
81
<5[e]
32[e]
6[e]
68
During our recent studies on Pd(II)-catalyzed oxi-
ACHTUNGTRENNUNG
À
dative couplings, we found that a C H bond activa-
tion of an arene occurs very effectively under the in-
PivOH
fluence of PivOH and AgOAc.[6] The conditions em-
[a]
[b]
[c]
[d]
[e]
Conditions: benzene (100 equiv.), reflux.
5 mol%.
3.0 equiv.
6.0 equiv.
À
ploying PivOH as a proton shuttle during the aryl C
H bond activation were originally developed by Fag-
nou[7a] and applied extensively for the C H bond acti-
À
vation of arenes.[7b–j] Moreover, a carbopalladation of
ArPdOPiv species onto the C=C double bond would
occur readily by a chelation-assisted stabilization of
the palladium center with a suitable DG.[4,5] With
these points in mind, the reaction of methyl cinna-
mate derivative 1a (DG=carbonyl group of a uracil
moiety) and benzene was examined in the presence of
Starting material 1a was recovered in 62–87%.
PdACHTUNGTRENNUNG(TFA)2, AgOAc, and PivOH. As shown in
Scheme 1, tetrasubstituted olefin 2a was obtained in
an excellent yield (92%). The reaction of 1a and
PhPdOPiv gave the palladium intermediate I, and the
palladium center of I was stabilized by the oxygen
atom at the 2-position of a uracil moiety. The forma-
tion of this stabilized intermediate made the b-Hb
a readily removable elimination partner among the
three b-hydrogen atoms. The two remaining b-hydro-
gens inside the cycle are somewhat difficult to adapt
the required syn-relationships with the palladium
center.
Although the initial result was quite satisfactory we
examined the other reaction conditions including the
use of other oxidants, and the results are summarized
Scheme 2. Preparation of starting materials: a) 6-methylura-
cil, K2CO3, TBAB, DMF, 508C, 4 h, 56%; uracil, K2CO3,
DMF, room temperature, 3 h, 81%; b) PhCH2Br, K2CO3,
DMF, room temperature, 3 h; c) potassium phthalimide,
DMF, room temperature, 4 h; d) isatin, K2CO3, CH3CN,
room temperature, 24 h; e) benzene, H2SO4, reflux, 5 h.
in Table 1. The use of Pd
ACHTUNGRTEN(NUNG OAc)2 was less efficient
(entry 2) than Pd(TFA)2. The reaction without PivOH
ACHTUNGTRENNUNG
(entry 3) and the use of AcOH (entry 4) or
CF3COOH (entry 5) were not better. Replacement of
AgOAc with other oxidants such as Cu
ACHTUNGRTEN(NUNG OAc)2 or
K2S2O8 decreased the yield of 2a (entries 6 and 7).
Ag2CO3 was less efficient than AgOAc (entry 8). 1e was prepared by a Friedel–Crafts reaction with
Based on the screening results, the original conditions benzene from MBH adduct as reported.[9f]
(entry 1) were selected as an optimum ones.
With these starting materials, we examined the pal-
The required starting materials 1a–e, a-substituted ladium-catalyzed oxidative arylations under the opti-
methyl cinnamates, could be prepared readily from mized reaction conditions, and the results are sum-
Morita–Baylis–Hillman (MBH) adducts.[8,9] Com- marized in Figure 1, Scheme 3 and Scheme 4. Figure 1
pounds 1a and 1b were prepared from the MBH ace- shows the results obtained from the reactions of 1a,
tate and 6-methyluracil or uracil, by an SN2ꢁ type dis- 1c and 1d. Scheme 3 demonstrates the results ob-
placement reaction and a subsequent protection of tained from the reaction of 1e, and Scheme 4 de-
NH with a benzyl group, as shown in Scheme 2.[9a,b] scribes the reaction of a uracil derivative 1b. As
Phthalimide and isatin-bearing starting materials 1c shown in Figure 1, arylations of 6-methyluracil deriva-
and 1d were prepared similarly from the MBH bro- tive 1a with ortho-xylene and meta-xylene afforded 2b
mide and acetate, respectively.[9b–e] Phenyl derivative and 2c in good yields. It is interesting to note that the
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Palladium-Catalyzed, Chelation-Assisted Stereo- and Regioselective Synthesis
Figure 1. Palladium-catalyzed oxidative arylation. Conditions: substrate 1 (0.5 mmol), arene (30–100 equiv.), PdACHTUNGTRENNUNG(TFA)2
(5 mol%), AgOAc (3.0 equiv.), PivOH (6.0 equiv.).
Scheme 3. Conditions: benzene, PdACHTNUTRGNENG(U TFA)2, AgOAc, PivOH, reflux, 20 h.
action of 1a and ortho-dichlorobenzene afforded 2d in
moderate yield (47%). During the synthesis of 2b–d
we did not observe the formation of any regioisomers.
The reactions of phthalimide derivative 1c with ben-
zene, methyl benzoate, and anisole produced corre-
sponding products 2e–g in moderate to good yields
(63–85%). The meta-isomer was formed as a major
product (54%) along with a minor para-isomer (23%)
with methyl benzoate, while para-isomer was formed
as a major product with anisole. The observed regio-
Scheme 4. Conditions: benzene, PdACTHNUTRGNEUNG(TFA)2, AgOAc, PivOH,
reflux, 20 h.
reaction of 1a and para-xylene failed presumably due selectivity with methyl benzoate and anisole suggest-
À
to the steric hindrance of the methyl group of para- ed that aryl C H activation might involve an electro-
xylene. A trace amount of the product was observed philic palladation (SEAr) mechanism (vide infra).[2f–i,5d]
on TLC at the right position; however, we failed to The reaction of isatin derivative 1d and benzene gave
isolate the compound in appreciable amounts. The re- 2h in good yield (81%).
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In order to clarify the chelation effect of a DG in
1a, 1c and 1d, we examined the reaction of phenyl de-
rivative 1e which does not have such a DG. As ex-
pected, three types of products were formed together,
as shown in Scheme 3, due to three possible b-H elim-
inations. Actually, compound 3a-E (22%) and a mix-
ture of 2i/3a-Z (42%, 1:5) were isolated. In addition,
the combined yields (64%) of all products were lower
than the case of 2a (92%). The results stated that the
formation of a stabilized palladium intermediate I
(Scheme 1, vide supra) certainly controls the regio-
chemistry of the b-H elimination and facilitates the
carbopalladation step of an arylpalladium intermedi-
ate at the same time.
When we used uracil derivative 1b as a starting ma-
terial (Scheme 4), the phenylation occurred in moder-
ate yield (68%, 2j+4) at the benzylic position; how-
ever, further arylation at the 6-position of a uracil
moiety occurred to some extent to give compound 4
(13%), as in our previous paper.[6a]
Scheme 6. Catalytic cycle of oxidative arylation.
À
In order to check the possibility of a direct C H ac-
tivation of the vinyl hydrogen,[10] benzazepine deriva-
tive 5 was prepared as in our previous paper[9a] and
examined in the reaction with benzene under the
same reaction conditions, as shown in Scheme 5. No
arylation product 6 was observed, and the result
Scheme 7. Competitive arylation of 1c with benzene and
strongly suggested that the arylation of substituted benzene-d6.
methyl cinnamates might involve a typical oxidative
Heck-type reaction involving a carbopalladation, rota-
À
tion around C C bond, and a b-H elimination pro- tation is observed, and the stereochemistry of the
cess.
product obeyed that of the typical syn elimination
Thus, a plausible reaction mechanism could be sug- process. As an example, the stereochemistry of 2c was
gested as shown in Scheme 6. An arylpalladium inter- unequivocally confirmed with NOE experiments, as
mediate could be generated from arene and shown in Figure 1 (vide supra).
Pd
G
In order to understand the mechanism more clearly,
(SEAr) process.[2f–i,5d] However, a partial contribution we carried out the reaction of 1c in a mixed solvent
of a concerted metalation-deprotonation (CMD) pro- of benzene/benzene-d6 (1:1), as shown in Scheme 7.
cess cannot be ruled out completely at this stage The reaction of 1c and benzene showed a primary ki-
based on the formations of 2c and meta-2g.[2e,11]
subsequent carbopalladation of the arylpalladium in- C H (or C D) bond cleavage of benzene is involved
termediate to 1a might produce the stabilized palladi- in the rate-limiting step.
netic isotope effect, kH/kD =6.0, which stated that the
À
À
um intermediate I. As described above (Scheme 1,
In order to show the effect of a chelation for the
vide supra), selective b-Hb elimination would produce rate increase in the reaction, we examined the reac-
2a–d. The reduced Pd(0) was oxidized to Pd(II) by tion with a mixture of 1c (with DG) and 1e (without
AgOAc and the Pd(II) carry out the catalytic cycle. DG) in the presence of a limited amount of AgOAc
Under the reaction conditions, no stereochemical mu- (1.8 equiv.) under the same reaction conditions, as
Scheme 5. Attempted arylation of benzazepine 5.
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Palladium-Catalyzed, Chelation-Assisted Stereo- and Regioselective Synthesis
a cationic palladium intermediate and form a tightly-
chelated palladium intermediate (III and/or IV). Thus
we used AgOAc as a base in order to strengthen the
chelation by exchanging the iodide to acetate (condi-
tions b).[1b] As expected, compound 2e was obtained
in moderate yield (51%). However, the yield was
lower than our optimized yield of 2e (85%) using
benzene as an arene source.
Scheme 8. The effect of DG in arylation rate.
The other stereoisomers of 2b–d, 2f and 2g could
shown in Scheme 8. As expected, 1c was converted to also be prepared by simply altering the reaction se-
2e in 62% conversion yield while 1e led to a mixture quence. As an example, compound 2g-Z (a stereoiso-
of arylated products in 21% yield. The results showed mer of 2g) was prepared from the MBH bromide of
that the rate of arylation of 1c is faster than that of 1e p-anisaldehyde by introduction of phthalimide to
by about three times, presumably due to a favorable
chelation effect.
Table 2. Chelation-assisted phenylation of various alkenes.[a]
In order to check the scope of arylation, we exam-
ined the reactions with similar substrates 1f–l (see the
Supporting Information), as shown in Table 2. The re-
action of acetyl derivative 1f afforded 2k (entry 1) in
a moderate yield (72%); however, the reaction of ni-
trile derivative 1g failed completely (entry 2) presum-
ably due to the strong coordination of nitrile moiety
to the electrophilic palladium species, Pd
ACHTUNGRTEN(NUNG TFA)2 or
Pd
ACHTUNGTRENNUNG
1h afforded 2l (entry 3) in good yield (93%). When
we used N-phenyl-N-tosyl derivative 1i (entry 4), the
reaction was sluggish, and 1i was recovered in appre-
ciable amounts (27%) along with N-tosylaniline
(63%) and a mixture of 3a-Z/3a-E (60%). Thus, we
prepared N-methyl-N-methanesulfonyl derivative 1j
in order to reduce the unfavorable steric factors and
examined the reaction; however, the result was
almost same as that of 1i, and the formation of 3a-Z/
3a-E (64%) was observed again (entry 5). The reac-
À
tion mechanism for the C N bond cleavage of 1i and
1j is not clear at this stage. No reaction was observed
with 1i either without AgOAc or benzene. It is inter-
esting to note that the reaction of phosphonate 1k af-
forded alkenylphosphonate 3b-Z (entry 6),[13] presum-
ably due to the stabilizing conjugation effect between
C=C and P=O bonds. As a last entry, the reaction of
phthalimide derivative 1l was examined (entry 7). The
phenylation occurred at either site of the C=C double
bond of 1l, and 2ma and 2mb were obtained as a mix-
ture (4:3) in 69% yield, along with some diphenyl
compound 2mc (16%).
In order to compare the reactivity of arylation
using a typical Mizoroki–Heck reaction, the reaction
of 1c and iodobenzene was examined, as shown in
Scheme 9. The reaction under the typical conditions
(conditions a)[1g] did not produce 2e in any trace
amounts. The reason for the failure might be due to
inefficient carbopalladation of PhPdI, because the
palladium intermediate II bearing an iodide ligand is
less stabilized by loose chelation. As reported in the
literature,[1b,14] palladium intermediates bearing a piva-
late or acetate ligand could dissociate readily to form
[a]
[b]
Conditions: substrate (0.5 mmol), PdACTHNURTGNENG(U TFA)2 (5 mol%),
AgOAc (3.0 equiv.), PivOH (6.0 equiv.), benzene
(100 equiv.), 24 h.
Reaction time was 7 h, and 2ma and 2mb were separated
as a mixture (69%, 2ma:2mb=4:3).
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Scheme 9. Arylation of 1c with iodobenzene. Conditions a: PdCAHUTNGTRENUNG(OAc)2 (10 mol%), PAHCTUNGTRNEN(UNG o-tol)3 (20 mol%), NaHCO3 (2.5 equiv.),
TBAB (1.1 equiv.), DMF, 1308C, 30 h. Conditions b: Pd(OAc)2 (5 mol%), AgOAc (2.0 equiv.), HOAc, 1108C, 6 h.
AHCTUNGTRENNUNG
Scheme 10. Synthesis of 2g-Z: a) potassium phthalimide, DMF, room temperature, 12 h, 88%; b) benzene, Pd
AgOAc, PivOH, reflux, 12 h.
ACHTUNGTRENNUNG(TFA)2,
make 1m and a subsequent phenylation, as shown in (20 mLꢂ3), and the organic layer was dried over MgSO4.
After removal of solvent and a column chromatographic pu-
rification process (hexanes/Et2O, 1:2) compound 2a was iso-
lated as a white solid; yield: 214 mg (92%). No special
equipment and precautions were required throughout the
whole experiments.
Scheme 10.
In summary, we have documented the synthesis of
fully-substituted methyl cinnamate derivatives via
a Pd(II)-catalyzed, chelation-assisted oxidative Heck
arylation protocol in a completely stereo- and regiose-
lective manner. The stereo- and regioselective out-
come as well as excellent yields of products were ori-
ginated from the stabilization of a palladium inter-
mediate by a chelation between the palladium center
and a directing group.
Acknowledgements
This research was supported by Basic Science Research Pro-
gram through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2012R1A1B3000541).
Experimental Section
Typical Procedure for the Synthesis of 2a
References
A stirred mixture of 1a (195 mg, 0.5 mmol), PdACTHUNRGTNEUNG(TFA)2
(8 mg, 0.025 mmol), AgOAc (250 mg, 1.5 mmol) and PivOH
(306 mg, 3.0 mmol) in benzene (3.9 g, 50 mmol) was heated
to reflux under nitrogen atmosphere for 20 h. After cooling
to room temperature, the reaction mixture was filtered over
a pad of Celite and washed with CH2Cl2 (100 mL). The fil-
trates were washed with a saturated solution of NaHCO3
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Palladium-Catalyzed, Chelation-Assisted Stereo- and
Regioselective Synthesis of Tetrasubstituted Olefins by
Oxidative Heck Arylation
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Adv. Synth. Catal. 2012, 354, 1 – 9
Hyun Seung Lee, Ko Hoon Kim, Sung Hwan Kim,
Jae Nyoung Kim*
Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!