Synthesis of azepine derivatives by rhodium-catalyzed tandem 2,3-rearrangement/heterocyclization

Article abstract of DOI:10.1002/anie.201205285

Easy to N-cycle: The efficient synthesis of azepine derivatives was achieved by Rh-catalyzed tandem 2,3-rearrangement involving the heterocyclization of N-allenylnitrone intermediates (see scheme; cod=1,5-cyclooctadiene, tppms=sodium diphenylphosphinobenz

Full text of DOI:10.1002/anie.201205285

Angewandte
Chemie
DOI: 10.1002/anie.201205285
Heterocycles
Synthesis of Azepine Derivatives by Rhodium-Catalyzed Tandem 2,3-
Rearrangement/Heterocyclization**
Itaru Nakamura,* Masashi Okamoto, Yoshinori Sato, and Masahiro Terada
Catalytic carbocyclization through metallacyclic intermedi-
ates has served as one of the most powerful tools in the
construction of highly elaborate cyclic compounds in organic
synthesis.[1] In particular, vinylallenes have been extensively
utilized as the four-carbon unit in this method (Scheme 1a).[2]
which result in the corresponding azepine oxide derivatives 2
in good to high yields through a tandem 2,3-rearrangement/
heterocyclization [Eq. (1)].[8,9]
Initially, the reaction conditions were investigated using
substrate (Z)-1a, as summarized in Table 1. Although the
reaction involving [{RhCl(cod)}2] and triphenylphosphine
afforded 2a in an excellent yield (entry 1), the product
could not be separated from triphenylphosphine oxide that
was formed during the work-up process.[10–12] Consequently,
we examined the use of polymer-bound and water-soluble
Scheme 1. Cyclizations through metallacycle intermediates. a) From
a vinylallene and b) from an N-allenylnitrone intermediate (this work).
Table 1: Optimization of the reaction with (Z)-1a.[a]
To the best of our knowledge, however, syntheses of hetero-
cycles using N-allenylimine derivatives through the formation
of aza-metallacycles have yet to be investigated, presumably
because of the inherent instability of N-allenylimines.[3–5]
Recently, we demonstrated that N-allenylnitrone species
can be transiently generated during the metal-catalyzed 2,3-
rearrangement of O-propargylic oximes.[6] This may allow for
tandem 2,3-rearrangement and aza-metallacyclization reac-
tions in the construction of heterocyclic skeletons, as shown in
Scheme 1b. The use of rhodium complexes, which serve
a dual role as both p-acidic and redox catalysts, is especially
promising according to the recent reports by Tang et al.[2g–i,7]
Herein, we report on the reactions of O-propargylic cyclo-
propylcarbaldoximes 1 in the presence of rhodium catalysts,
Ligand
Solvent
t [h]
Yield of
Yield of
(mol%)[b]
2a [%][c]
3a [%][c]
1
2
3
4
5
6
7
8
PPh3 (10)
toluene[d]
THF[d]
DMF
16
24
16
24
24
24
4
24
8
12
12
16
96
36
59
67
81
77
39
76
60
85
85
(92)
3
50
18
5
3
4
51
10
23
8
3
5
PPh3[e] (15)
tppts (18)
tppms (18)
tppms (18)
tppms (12)
tppms (6)
tppms (18)
tppms (18)
tppms (18)
tppms (18)
tppms (18)
DMF
DMF[f]
DMF[f]
DMF[f]
DMSO[f]
DMA[f]
[*] Prof. Dr. I. Nakamura, Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Sendai, 980-8578 (Japan)
9
10
11
12
1,4-dioxane[f]
1,4-dioxane
1,4-dioxane[d]
E-mail: itaru-n@m.tohoku.ac.jp
Homepage: http://www.orgreact.sakura.ne.jp/en-index.html
[a] Reactions with (Z)-1a (0.4 mmol) were carried out at 808C in the
presence of [{RhCl(cod)}2] (2.5 mol%) and ligand in solvent (0.5m).
[b] Loading of phosphine ligand (mol%) shown in parentheses. [c] The
yield was determined by 1H NMR spectroscopy using 1,2-dichloroethane
as an internal standard; yield of isolated product shown in parentheses.
[d] 0.2m. [e] Polymer-bound triphenylphosphine was used. [f] 4ꢀ
molecular sieves (100 mg) were used. cod=1,5-cyclooctadiene,
DMA=dimethylacetamide, DMF=dimethylformamide, tppms=
sodium diphenylphosphinobenzene-3-sulfonate, tppts=tris(3-sulfona-
tophenyl)phosphine.
M. Okamoto, Y. Sato
Department of Chemistry, Graduate School of Science
Tohoku University (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Molecular Activation Directed toward Straight-
forward Synthesis” from the Ministry of Education, Culture, Sports,
Science and Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205285.
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phosphine ligands (entries 2–5), and decided on the use of
tppms (sodium diphenylphosphinobenzene-3-sulfonate)[13]
for our reactions. When the loading of tppms was reduced
to 6 mol%, the formation of a significant amount of 3a was
observed (entry 7). With regards to solvents, although DMF,
DMSO, and DMA in the presence of 4ꢀ molecular sieves
(MS) were effective, 1,4-dioxane gave the best result, even in
the absence of 4ꢀ MS (entry 11). The yield was further
improved by reducing the concentration (entry 12). It should
be noted that, in the absence of Rh catalysts, the reaction at
808C afforded only a small amount of 3a (11%); the desired
product, 2a, was not detected.[14]
noteworthy that the reactions selectively afforded the product
with a Z configuration at the alkylidene moiety.
Moreover, the reaction of (Z)-1j,[15] which has a methyl
group at the cyclopropane ring, afforded 2,3,5-trisubstituted
azepine derivative 2j in good yield, along with a considerable
amount of the four-membered cyclic nitrone 3j [Eq. (2)]; the
reaction did not afford the regioisomer 2j’.[2g,9e]
Next, as summarized in Table 2, the reactions were carried
out under the optimal reaction conditions (Table 1, entry 12)
using various substrates to investigate the scope of (Z)-1.
Table 2: Rh-catalyzed reactions of (Z)-1.[a]
The E isomer of the substrate, (E)-1a, which results in the
formation of the same product (2a), reacted under the same
conditions (as the Z isomer) to give the product in poor yield
(Table 3, entry 1). Therefore, the reaction conditions were
1
R1
R2
t [h]
2
Yield
[%][b]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
p-ClC6H4
p-MeOC6H4
Ph
Ph
Ph
Ph
24
12
20
16
28
36
12
120
2b
2c
2d
2e
2 f
2g
2h
2i
84
67[c]
36
nPr
Cy
Ph
Ph
Ph
Ph
67
79
76
Table 3: Optimization of the reaction with (E)-1a.
p-MeC6H4
p-MeOC6H4
p-F3CC6H4
nPr
78
45[d]
[a] Reactions with (Z)-1 (0.4 mmol) were carried out in the presence of
[{RhCl(cod)}2] (2.5 mol%) and tppms (18 mol%) in 1,4-dioxane (2 mL)
at 808C. [b] Yield of isolated product. [c] 20% of the four-membered
cyclic nitrone 3c was obtained. [d] A trace amount of the E-isomer of 2i
was detected using 1H NMR spectroscopy. Cy=cyclohexyl, tppms=
sodium diphenylphosphinobenzene-3-sulfonate.
tppms [mol%]
Solvent
2a
3a
1a
[%][a]
[%][a]
[%][a]
1
2
3
4
5
6
18
18
18
18
13
10
1,4-dioxane[b]
DMSO
DMA
16
41
31
39
(73)
40
8
5
3
3
6
54
40
45
42
4
DMF
Substrate (Z)-1b, which possesses an electron-deficient
aromatic ring at the alkyne terminus, was successfully
converted into product 2b (Table 2, entry 1), whereas sub-
strate (Z)-1c, which bears an electron-rich p-anisyl group,
gave the product in a lower yield, along with a considerable
amount (20%) of the corresponding four-membered cyclic
nitrone 3c as a by-product (entry 2). Substrate (Z)-1e, which
possesses a cyclohexyl group at the alkyne terminus, was
efficiently converted into the desired product, 2e, in good
yield (entry 4), whereas (Z)-1d, which bears an n-propyl
group at the alkyne terminus, resulted in a low yield of 2d
owing to the instability of this product (entry 3). Substrates
(Z)-1 f, (Z)-1g, and (Z)-1h, all of which possess an aryl group
at the propargyl position, were converted into products 2 f,
2g, and 2h (entries 5–7), respectively, in good yields, regard-
less of their electronic nature. In contrast, an alkyl substituent
at the propargylic position (entry 8) decreased the efficiency
of the reaction (longer reaction time and lower yield). It is
DMF
DMF[c]
43
0
[a] The yield was determined using 1H NMR spectroscopy with 1,2-
dichloroethane as an internal standard; yield of isolated product shown
in parentheses. [b] 0.2m, without 4ꢀ molecular sieves. [c] 12 h.
cod=1,5-cyclooctadiene.
reoptimized for (E)-1a, as summarized in Table 3. This time,
the amount of tppms significantly affected the yield of 2a
(entries 4–6); the best result was obtained with tppms
(13 mol%) in DMF in the presence of 4ꢀ MS (entry 5).
The use of 10 mol% of tppms resulted in the unfavorable
formation of the four-membered cyclic nitrone 3a (entry 6),
whereas the use of 18 mol% of tppms resulted in a slow
reaction (entry 4).
Substrates (E)-1 were effectively converted into products
2 by carefully adjusting the amount of tppms, as summarized
2
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Table 4: Rh-catalyzed reactions with the E isomer of 1.[a]
(E)-1 R1
R2
tppms
[mol%]
t [h]
2
Yield
[%][b]
1
2
3
4
5
6
1b
1c
1e
1 f
1h
1i
p-ClC6H4
p-MeOC6H4 Ph
Cy
Ph
Ph
Ph
Ph
13
17
15
16
9
72
24
120
48
28
120
2b 62
2c
2e
2 f
67[c]
Ph
49[d]
p-MeC6H4
p-F3CC6H4
nPr
75[e]
2h 49
11
2i
20[f]
[a] Reactions with (E)-1 (0.4 mmol) were carried out in the presence of
[{RhCl(cod)}2] (2.5 mol%), tppms (as indicated), and 4ꢀ MS (100 mg)
in DMF (0.8 mL) at 808C. [b] Yield of isolated product. [c] 3c was
obtained in 22% yield. [d] 6% of 1e was recovered. [e] 3 f was obtained in
12% yield. [f] 3i was obtained in 39% yield. A trace amount of the
E isomer of 2i was observed in the 1H NMR spectrum. cod=1,5-
cyclooctadiene, Cy=cyclohexyl, DMF=dimethylformamide,
Scheme 2. Possible reaction mechanism.
tppms=sodium diphenylphosphinobenzene-3-sulfonate.
the Rh catalyst produces 2. It should be noted that the
reactions of the E substrate were extremely sensitive to the
amount of phosphine ligand present. For reactions involving
18 mol% of tppms (Table 3, entries 1–4), the high recovery of
unreacted (E)-1a can be attributed to the decreased Lewis
acidity of the Rh catalyst as well as competitive coordination
between the substrate and tppms to the rhodium center,
which would decelerate the cyclization process from 1 to 5. In
contrast, for the reaction involving 10 mol% of tppms
(Table 3, entry 6), the increased formation of the four-
membered cyclic nitrone 3a can be explained by the
reduction of the electron-donating phosphine ligand, which
would decelerate the formation of cyclic Rh-complexed
intermediate 8 from intermediate 6. Therefore, the amount
of the phosphine ligand had to be adjusted for each substrate,
according to its p-coordination ability, rate of metallacycliza-
tion, and rate of 4p-electrocyclization. Moreover, the mass
balance for the reaction of (E)-1 was lower than that of (Z)-1,
which can be attributed to the decomposition of the substrate
by coordination between the Rh catalyst and the oxime
nitrogen atom followed by oxidative addition to the cyclo-
propane ring.[4d,e] Further mechanistic studies are currently
underway in our laboratory.
in Table 4. The reactions of substrates (E)-1c and (E)-1 f,
which both have an electron-donating substituent, required
higher amounts of tppms because of the competitive forma-
tion of four-membered cyclic nitrone 3 (entries 2 and 4,
respectively). In contrast, the reactions of (E)-1b and (E)-1h,
which both bear an electron-deficient aromatic group, gave
2b and 2h, respectively, in good to moderate yields, (entries 1
and 5) because of the partial decomposition of the starting
materials.
As 3a was not converted to 2a under the reaction
conditions, the possibility of the presence of four-membered
cyclic nitrone 3 as a reactive intermediate, as shown in
Equation (3), can be eliminated.[8a,b]
A plausible mechanism for the reaction of 1 is shown in
Scheme 2. First, the Rh catalyst coordinates to the alkyne
moiety of 1 to form p-complex 4. Nucleophilic attack by the
oxime nitrogen atom at the electrophilically activated triple
bond would lead to five-membered cyclic vinylrhodium
intermediate 5. Subsequent cleavage of the carbon–oxygen
bond and elimination of the Rh catalyst gives N-allenylni-
trone intermediate 6. The s-cis form of N-allenylnitrone 6ꢁ
allows h4-coordination to the Rh catalyst from the opposite
side of R2, as shown in intermediate 7. The formation of aza-
rhodacycle 8 and ring expansion involving selective cleavage
of the less-hindered carbon–carbon bond would lead to eight-
membered aza-rhodacycle 9. Finally, reductive elimination of
In conclusion, we have developed a new approach to the
synthesis of seven-membered aza-heterocycles under mild
reaction conditions. The present method can be employed to
synthesize azepine derivatives, which are an important class
of biologically active molecules, in an efficient manner.[16,17]
Experimental Section
Standard reaction conditions: 1,4-dioxane (0.2 mL) was added to
a mixture of [{RhCl(cod)}2] (4.9 mg, 0.01 mmol) and tppms (26.2 mg,
0.072 mmol) in a vial under an argon atmosphere and then stirred at
1008C for 1.5 h. (Z)-1a (0.4 mmol) in 1,4-dioxane (1.8 mL) was then
added to this solution. The resulting mixture was stirred at 808C for
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16 h, and then extracted using ether and water. The combined ether
layers were evaporated in vacuo to afford the crude product, which
was purified by flash column chromatography using hexane/ethyl
acetate (5:1) and ethyl acetate/methanol (50:1) as eluents to give pure
2a (101.1 mg, 92%).
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Received: July 5, 2012
Published online: && &&, &&&&
Keywords: alkynes · nitrogen heterocycles · rearrangement ·
.
rhodium · ring expansion
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4
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Heterocycles
I. Nakamura,* M. Okamoto, Y. Sato,
M. Terada
&&&& — &&&&
Synthesis of Azepine Derivatives by
Rhodium-Catalyzed Tandem 2,3-
Rearrangement/Heterocyclization
Easy to N-cycle: The efficient synthesis of
azepine derivatives was achieved by Rh-
catalyzed tandem 2,3-rearrangement
involving the heterocyclization ofN-alle-
nylnitrone intermediates.
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