Catalytic dicyanative 5-exo- And 6-endo-cyclization triggered by cyanopalladation of alkynes

Article abstract of DOI:10.1002/adsc.200900813

A stereoselective dicyanative 5-exo- and 6endo-cyclization using various enynes has been investigated. The mode of cyclization is critically controlled by the structure of the substrates. For example, N-allyl derivatives prefer 5-exo-cyclization, while methacryloyl amides are transformed to the corresponding lactams with tetra substituted carbons at the alpha-position via 6-endo-cyclization. Both reactions include syn-cyanopalladation to carbon≡carbon triple bonds in the initial step, and sequential cyclization followed by reductive elimination in one operation enables the construction of the highly functionalized nitrogen heterocycles. The scope of suitable substrates and a proposed mechanism are also described.

Full text of DOI:10.1002/adsc.200900813

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DOI: 10.1002/adsc.200900813
Catalytic Dicyanative 5-exo- and 6-endo-Cyclization Triggered by
Cyanopalladation of Alkynes
Shigeru Arai,a,* Yuka Koike,a and Atsushi Nishidaa
a
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Fax : (+81)-43-290-2909; e-mail: arai@p.chiba-u.ac.jp
Received: November 20, 2009; Published online: March 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900813.
Abstract: A stereoselective dicyanative 5-exo- and 6- triple bonds in the initial step, and sequential cycliza-
endo-cyclization using various enynes has been inves- tion followed by reductive elimination in one opera-
tigated. The mode of cyclization is critically con- tion enables the construction of the highly function-
trolled by the structure of the substrates. For exam- alized nitrogen heterocycles. The scope of suitable
ple, N-allyl derivatives prefer 5-exo-cyclization, while substrates and a proposed mechanism are also de-
methacryloyl amides are transformed to the corre- scribed.
sponding lactams with tetra-substituted carbons at
the alpha-position via 6-endo-cyclization. Both reac- Keywords: cyanation; cyanopalladation; cyclization;
ꢀ
tions include syn-cyanopalladation to carbon carbon oxygen; palladium
Introduction
Pd-catalysis through reductive elimination from an al-
ꢁ ꢁ
ꢁ
kenyl M CN species, which gives alkenyl CN to-
The introduction of a cyano function into simple and gether with M(0) (Scheme 1). Since a cyano function
non-activated carbon/carbon triple bonds has been on a transition metal acts as a pseudo halide (due to
one of the most significant issues in synthetic organic the lower nucleophilicity) and is unlikely to be trans-
chemistry, and nickel and palladium catalysts that ferred to carbon/carbon multiple bonds, cyanation via
enable cyanation with the introduction of H,[1] Si,[2] migratory insertion (direct CN transfer from metal to
Ge,[3] Sn,[4] S,[5] C[6,7] and B[8] functionalities have been alkynes) has not been established. On the other hand,
useful. Usually, a cyano group is installed by Ni- and we previously showed that the nucleophilic addition
Scheme 1. Different modes of cyanation mediated by metal species.
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ꢁ
of a cyano group by use of TMSCN was effectively p-complex of Pd(II). If the alkenyl PdCN intermedi-
promoted under Pd(II) catalysis in the presence of ate could react with olefins in the same molecule
oxygen, and these results are, to the best of our before reductive elimination, a new protocol for cyan-
knowledge, the first example of the cyanometallation ative cyclization could be established through the in-
of simple and non-activated alkynes.[9] In this paper, troduction of two cyano groups into different carbon/
we give a full account of a new cyanation pathway via carbon multiple bonds, as shown in Scheme 2.
cyanopalladation that enables the nucleophilic addi-
To realize our expectation, we initially investigated
tion of TMSCN (as an external cyano source) with the reaction of 1a and optimized the conditions
Pd(II) as a Lewis acid to activate alkynes, and its ap- (Table 1). The solvent effect revealed that a non-polar
plication to 5-exo- and 6-endo-cyclization to afford solvent such as toluene was ineffective for cyclization.
highly functionalized nitrogen heterocycles.
1,2-Dicyanation proceeded predominantly to give a
syn/anti mixture of 2a as the major products, which
ꢁ
means that reductive elimination from alkenyl PdCN,
rather than insertion, is preferred (entry 1). To avoid
the latter transformation before cyclization, we next
Results and Discussion
We recently developed a catalytic 1,2-dicyanation of investigated coordinative polar solvents to increase
various alkynes through the use of TMSCN with the electron density of Pd(II). As a result, this proto-
Pd(II) under aerobic conditions and proposed that col was effective for preventing the formation of 2a
both syn- and anti-cyanopalladation are key reactions and the yield of the cyclized products of syn- and
in the initial step. The former cyanation occurs at the anti-3a was increased. For example, THF gave a
terminal carbon to give syn-cyanoalkenyl-palladi- slightly better yield of 3a than 2a (entry 2). Aceto-
A
ACHTUNGTRENnNGNU itrile improved the total conversion and 3a was iso-
steric effects at the propargylic position of substrates lated in 41% yield in a stereoselective fashion
because cyanation would occur at an internal carbon (entry 3). This reaction was strongly influenced by the
by a Markovnikov process to give the corresponding concentration and temperature. When the reaction
Scheme 2. Strategy for cyclization by olefin insertion.
Table 1. Survey of conditions using 1a.
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Catalytic Dicyanative 5-exo- and 6-endo-Cyclization Triggered by Cyanopalladation
Figure 1. Substrate scope of the exo-cyclization.
was carried out in a 0.1M concentration, the forma- was easily formed exclusively in 67% yield. Substrates
tion of 2a was decreased and a higher temperature with substituents on the double bond gave 3i and 3j
promoted the cyclization with up to 57% yield of 3a in lower yield because olefin insertion was not suita-
(entries 4 and 5). Finally, propionitrile was the best ble due to the steric bulk of a methyl group. The ste-
solvent and gave 3a in 62% yield at 908C (entry 6).
reochemistry of all of the products shown below was
We next examined the substrate scope of the above determined by an NOE study (between the corre-
dicyanative exo-cyclization under the optimized con- sponding allylic and vinyl protons) and/or X-ray crys-
ditions (Figure 1). The products 3b and 3c with a tallographic analysis for 3d and 3h,[10] and these re-
phenyl group in a pyrrolidine ring were obtained in sults indicate the reaction is triggered by syn-cyano-
respective yields of 55 and 60%, although the diaste- palladation.
reoselectivity was still unsatisfactory. Interestingly, the
Next, we examined substrates bearing electron-defi-
reaction that gave 3c was much slower than those that cient olefins such as 4a and 5a. These preliminary re-
gave 3a and 3b. This result indicates that the steric sults using both amide substrates show that the reac-
bulk of a phenyl group at the propargylic position is tivity and selectivity were strongly dependent on R
important for promoting the smooth syn-cyanopalla- and the electron density of olefin, and 5-exo-cycliza-
dation in the initial step. When the substrate had a tion followed by olefin isomerization gave 7a in 23%
quaternary carbon at the a-position of nitrogen, exo- yield when 4a was used. On the other hand, the reac-
cyclization was quite slow and 3d was obtained as a tion of 5a under similar conditions promoted 6-endo-
sole product in 75% yield after 23 h. With a malonate cyclization and gave 8a, albeit in 9% yield, as shown
derivative, cyclization proceeded effectively within 2 h in Scheme 3. A conjugated double bond seems to be
to give 3e in 80% yield. Bisacetoxymethyl and 6- important for the pathway of dicyanative cyclization
membered ring products 3f and 3g were also obtained and the latter result prompted us to perform further
from the corresponding substrates under similar con- optimization of the reaction conditions because this
ditions in respective yields of 45 and 29%. When protocol is both (i) the first example of dicyanative
ortho-ethynyl-N-allyl-N-tosylanilide was examined, 3h endo-cyclization and (ii) a simple and easy way to
Scheme 3. exo- vs. endo-Cyclization using unsaturated amides.
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Table 2. Survey of conditions for 6-endo-cyclization of 5.
[a]
[b]
The product was obtained as a mixture of stereoisomers (E:Z=3:1).
Determined by H NMR analysis.
1
access functionalized lactams that contain quaternary TMSCN or HCN.[12] To obtain further information re-
carbons in a stereoselective fashion. garding mechanistic aspects, we anticipated that (i)
This reaction was shown to depend on the substitu- the oxo p-allyl intermediate 12h would be generated
ents on nitrogen. For example, when R was switched after 6-endo-cyclization to give 8h and (ii) the diaste-
from a tosyl group to a benzyl group, the yield of the reoselectivity of lactams would be influenced through
6-endo-cyclization product was increased to 23% as reductive elimination from 12h when b-substituted
inseparable stereoisomers (entry 2). A bulky substitu- unsaturated amides are used (R¼H).
ent such as a tert-butyl group gave 8c as a sole isola-
Next, we investigated the substituent effect at the
ble product, although the conversion was moderate b-position using 5i–m, as shown in Table 3. Increased
(entry 3). When the aromatic substituent was intro- steric bulk reduced 6-endo-cyclization and the reac-
duced, its steric bulk was also important for achieving tion of 5i gave 8i and 9e in respective yields of 30 and
a high yield of 8 (entry 4 vs. 5). A mesityl group pro- 52%. The stereochemistry of both methyl groups in 8i
moted the reaction smoothly within 5 h and gave the was determined to be trans by NOE (entry 1). In the
best conversion but the formation of 9 was a critical case of 5j, lower conversion similar to that with 5e
issue. Although the electronic effect with the intro- gave 8j and 9f in respective yields of 37 and 11%
duction of a methoxy or trifluoromethyl group at the (entry 2). The trans-selectivity observed for both 8i
4-position was investigated, neither the reaction rate and 8j strongly indicates that the oxo-p allyl palladi-
or the conversion was improved (entries 6 and 7). Fi- um species acts as a key intermediate and reductive
nally, 50 mol% of TMSOTf[11] as an additive was elimination would occur to avoid steric repulsion be-
found to reduce the formation of 9, and 8a was ob- tween the a- and b-substituents. As expected,
tained as a major product in 57% yield even at 508C TMSOTf decreased the reaction temperature but the
(entry 9). These results are summarized in Table 2.
yield of 8j was not successfully improved (entry 3).
To confirm the reaction pathway to 9, we next ex- When other substrates bearing an ethyl and a phenyl
amined 5h as a starting substrate and carefully investi- group at the b-position were applied to cyclization
gated all the products through 6-endo-cyclization. As conditions, their steric bulk critically affected to the
ꢁ
outlined in Scheme 4, the three products 8h, 9h and cyclization step to promote C N bond cleavage and
10h were obtained in respective yields of 10, 38 and resulted in lower yield of 8 (entries 4 and 5). These
24%. This result indicates that the endo-cyclization results are summarized in Table 3.
ꢁ
competes with C N bond cleavage to generate both
stable Pd species 13h and the cyanoallene 14h, which pose here a reaction pathway for palladium-catalyzed
Based on the above experimental results, we pro-
is converted to 10h by the conjugated addition of dicyanative 5-exo-cyclization (Scheme 5). The initial
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Catalytic Dicyanative 5-exo- and 6-endo-Cyclization Triggered by Cyanopalladation
Scheme 4. 6-endo-Cyclization of 5h.
Table 3. 6-endo-Cyclization of 5i–m.
activation of enyne substrates by Pd(II) would gener-
ate 15A and cause syn-cyanopalladation at C C triple reaction pathway in unsaturated amides can be rea-
bonds. The resulting alkenyl palladium species 15B sonably explained (Scheme 6). While the initial step
would react with C=C double bonds through insertion (syn-cyanopalladation) is similar to that in 5-exo-cycli-
to give 15C. Sequential reductive elimination gives zation, the activation mode of the substrates should
the corresponding cyclized products 3 together with be different because the side products were not the
Pd(0), which is quickly oxidized to Pd(CN)2. Since the result of reductive elimination. Thus, we propose that
On the other hand, both the stereoselectivity and
ꢀ
ꢀ
coordination of crotyl and methallyl groups to Pd(II) both C C triple bonds and carbonyl oxygen could co-
is not suitable due to their steric bulk (R=Me), re- ordinate to Pd(II) to form 16A, which is converted to
ductive elimination from 15B before cyclization to 3i 11A via syn-cyanopalladation. Moreover, TMSOTf
or 3j could be favored to give 1,2-dicyanoalkenes as would act as a Lewis acid to activate a carbonyl func-
major products.
tion as described for 16B and this activation would
enable the reaction to proceed even at 508C to give 8
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Shigeru Arai et al.
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Scheme 5. Plausible catalytic cycle for the 5-exo-cyclization of enynes.
Scheme 6. Plausible catalytic cycle for the 6-endo-cyclization of enynes.
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Catalytic Dicyanative 5-exo- and 6-endo-Cyclization Triggered by Cyanopalladation
TLC, subsequent direct column chromatography (hexane-
via 11 as described in Table 2 (entries 8 and 9). Fur-
thermore, TMSOTf reduced the formation of 9 be-
cause of smooth insertion of a C=C double bond to
AcOEt) gave the desired cyclized product 3a (yield:
91.2 mg, 62%) along with the 1,2-dicyano adducts of syn-2a
(yield: 10.5 mg, 7.1%) and anti-2a (yield: 30.0 mg, 20%).
ꢁ
an alkenyl PdOTf bond in 11B. While the driving
force for the formation of 9 along with cyanoallene
ꢁ
by C N bond cleavage is still unclear, b-nitrogen
elimination from 11 or the formation of stable species
such as 13h is one of the possibilities. When bulky
substituents on nitrogen, such as tert-butyl for benzyl
or mesityl for phenyl groups, are introduced, cycliza-
ꢁ
Acknowledgements
One of the authors (S.A.) thanks the Inohana Foundation
(Chiba University) and KAKENHI (No. 21590003) for fi-
tion rather than C N bond cleavage would be pre- nancial support. We thank Prof. Shinji Harada (Chiba Uni-
versity) for his kind support with the X-ray crystallographic
analysis.
ferred to form the corresponding oxo p-allyl palladi-
um species (12A). Due to the steric repulsion be-
tween the methyl and R groups in 12A, the stereo-
chemistry of the starting unsaturated amides does not
seem to be transferred to the corresponding lactams
when a quaternary carbon atom at the a-position is
constructed through reductive elimination, and this
could be regarded as the origin of the stereochemistry
in this reaction.
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ꢁ
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Experimental Section
All the 5-exo- and 6-endo-cyclization reactions were per-
formed on 0.3–0.5 mmol scales of starting enynes and the
product yields are given after purification by flash column
chromatography (hexane-AcOEt). The procedure for 6-
endo-cyclization is similar to the that given below even
when TMSOTf (50 mol%) was used as an additive in the re-
action (Table 3). This reagent was added at room tempera-
ture and the reaction was performed under thermal condi-
tions to give the products that were purified by flash column
chromatography (hexane-AcOEt).
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Typical Procedure for Pd-catalyzed 5-exo Cyclization
of Enynes
To a solution of enyne 1a (0.5 mmol) in EtCN (5.0 mL)
were added palladium cyanide (7.9 mg, 0.05 mmol,
10 mol%) and TMSCN (0.17 mL, 1.25 mmol) at room tem-
perature. The mixture was stirred for 5 h at 908C under
oxygen. After the reaction progress had been monitored by
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