Transition metal-catalyzed hetero-[5 + 2] cycloadditions of cyclopropyl imines and alkynes: Dihydroazepines from simple, readily available starting materials

Article abstract of DOI:10.1021/ja0285013

The first example of a transition metal-catalyzed hetero-[5 + 2] cycloaddition reaction is described. Use of cyclopropyl imines as five-atom components, an alkyne as a two-carbon component, and a Rh(I) catalyst enables a new route to dihydroazepines. This

Full text of DOI:10.1021/ja0285013

Published on Web 11/23/2002
Transition Metal-Catalyzed Hetero-[5 + 2] Cycloadditions of Cyclopropyl
Imines and Alkynes: Dihydroazepines from Simple, Readily Available Starting
Materials
Paul A. Wender,* Torben M. Pedersen, and Marc J. C. Scanio
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received September 10, 2002
Scheme 1. Initial Exploration of the Aza-[5 + 2] Cycloaddition
Previous studies in our laboratory on new transition metal-
catalyzed [m + n] cycloadditions have produced the first [5 + 2]
and [6 + 2] cycloadditions of vinylcyclopropanes (VCPs) and
vinylcyclobutanes with π-systems.1-3 More recently, we have
explored the extension of these concepts for two-component [m +
n] cycloadditions to three-component [m + n + o] cycloadditions,2d
leading thus far to the first [5 + 2 + 1] cycloadditions of VCPs,
π-systems, and CO. To further enlarge this body of new reactions
and expand their synthetic utility, we have started to investigate
whether one or more heteroatoms could be introduced into any or
all of the [m + n (+ o)] components and report herein the first
transition metal-catalyzed hetero-[5 + 2] cycloadditions, leading
to a new route to dihydroazepines.4
Scheme 2. Proposed Mechanisms for the Formation of 3 and 4
Drawing a connection to our work on VCPs as 5C cycloaddition
partners, Murai et al. have recently shown that cyclopropyl imines
can be used in a Ru3(CO)12-catalyzed carbonylative cycloaddition
to provide a novel [5 + 1] cycloaddition route to six-membered
unsaturated lactams.5 The proposed intermediate in this process,
azaruthenacycle A (Scheme 2), is analogous to a rhodacyclohexene
which we proposed and have identified (NMR) as a possible
intermediate or resting state in one mechanism for the [5 + 2]
cycloaddition of VCPs.2a,b These observations led us to explore
whether cyclopropyl imines could be used as hetero five-atom
components in metal-catalyzed [5 + 2] cycloadditions.6
Our initial attempt at achieving an aza-[5 + 2] cycloaddition
involved reaction of 1 and 2 with [Rh(CO)2Cl]2 as catalyst in
dichloroethane (DCE) at 60 °C (Scheme 1). Gratifyingly, the
dihydroazepine 3 was obtained, albeit in low yield. Subsequent
control experiments demonstrated this cycloaddition did not occur
in the absence of a catalyst or with simple Lewis acids.7 The
isolation of dihydropyridine 4, the product of a [2 + 2 + 2]
cycloaddition of alkyne 2 and imine 1, was key to controlling the
selectivity of this process.8
As a working hypothesis, dihydroazepine 3 could arise from the
initial formation of metallacycle A (Scheme 2). Migratory insertion
of dimethyl acetylenedicarboxylate (DMAD) 2 into A would
generate metallacycle B. As we previously proposed for [5 + 2]
cycloadditions of VCPs, an alternative path would entail formation
of an azametallacyclopentene followed by ring expansion to B.2a
In either case, B upon reductive elimination would yield 3 and
catalyst. At higher concentrations of DMAD, the formation of C
would be favored, giving rise to 4 via D.
On the basis of this analysis and certain rate assumptions, the
formation of 3 would be favored by a low concentration of 2, which
in turn could be achieved by slow addition. This procedural change
proved to be highly successful. When DMAD was added over 12.5
h to a solution of imine 1 in toluene,9 the dihydroazepine 3 was
formed in 85% yield (GC) and isolated in 83% yield.10 Several
other imines were also examined (Table 1) and found to react with
similar efficiency. The modest yield variation as a function of
N-alkyl group is thought to be a function of product hydrolysis
during purification. Entry 5 is of mechanistic interest, as the imine
is flanked by two cyclopropyl rings and therefore could react to
give product 8 or a 2H-5,6-dihydro regioisomer.11 Only 8 is
observed. In general, dihydroazepines are formed in good to
excellent yields.
With the initial success of this hetero-[5 + 2] cycloaddition, we
sought to determine whether this new route to dihydroazepines
could be further simplified through in situ imine formation,
providing effectively a three-component process. Toward this end,
the aldehyde and amine were combined in toluene and water was
removed azeotropically using a Dean-Stark trap. The reaction
temperature was then lowered to 60 °C, after which the catalyst
was added. Slow addition of the alkyne in toluene afforded the
desired dihydroazepines in good to excellent yields (Table 2). This
serial imine formation/aza-[5 + 2] cycloaddition enables a dihy-
droazepine synthesis from three commercially available starting
materials. Attempts at simultaneous imine formation/aza-[5 + 2]
cycloaddition with either MgSO4 or molecular sieves were unsuc-
cessful.
To explore the scope and synthetic utility of this reaction, the
effect of substituents on the cyclopropane ring was investigated.
2-Methylcyclopropanecarboxaldehyde 11 (Scheme 3) was selected
to examine the regiochemical outcome of the cyclopropane cleav-
age. As observed in our work on [5 + 2] cycloadditions of VCPs,
cleavage of the less substituted cyclopropyl bond is observed,
leading to dihydroazepine 12 as a single regioisomer.12,13 Substitu-
tion at the 1-position of the cyclopropane is also tolerated, even
* Corresponding author. E-mail: wenderp@stanford.edu.
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C O M M U N I C A T I O N S
Scheme 4. Preparative Scale Aza-[5 + 2] Cycloaddition
Table 1. Aza-[5 + 2] Cycloadditions with Various Imines
described. This new cycloaddition works well with a Rh(I) catalyst
(other catalysts are being screened). The dihydroazepine cycload-
ducts are readily derived from either preformed or in situ generated
cyclopropyl imines. The serial imine formation/aza-[5 + 2]
cycloaddition enables dihydroazepine synthesis from three com-
mercially available starting materials in one operation, effectively
a three-component cycloaddition. This reaction works with aldi-
mines, ketimines, and substituted cyclopropanes. Single regioiso-
mers are obtained. These reactions are also readily scaled,
generating multigram quantities of the substituted dihydroazepines,
compounds of use as synthetic building blocks and as scaffolds
for combinatorial synthesis. Further studies are in progress.
a GC yield (isolated yield).
Table 2. Serial Imine Formation/Aza-[5 + 2] Cycloadditions
Acknowledgment. This research was supported by a grant
(CHE-0131944) from the National Science Foundation. Fellowship
support from the Carlsberg Foundation (T.M.P.), the Danish
Technical Research Council (T.M.P.), and a Stanford Graduate
Fellowship (M.J.C.S.) is gratefully acknowledged.
Supporting Information Available: Spectroscopic data and ex-
perimental details for cycloadducts 3-10, 12, 14, 16, and 18 (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
a GC yield (isolated yield).
References
Scheme 3. Aza-[5 + 2] Cycloadditions with Substituted
Substrates
(1) For a general review, see: Wender, P. A.; Bi, F. C.; Gamber, G. G.;
Gosselin, F.; Hubbard, R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.;
Zhang, L. Pure Appl. Chem. 2002, 74, 25-31.
(2) For the initial examples, see the following. Intramolecular [5 + 2]
cycloadditions: (a) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am.
Chem. Soc. 1995, 117, 4720-4721. Intermolecular [5 + 2] cycloaddi-
tions: (b) Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc. 1998,
120, 10976-10977. [6 + 2] cycloadditions: (c) Wender, P. A.; Correa,
A. G.; Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000, 122, 7815-7816. [5 +
2 + 1] cycloadditions: (d) Wender, P. A.; Gamber G. G.; Hubbard, R.
D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 2876-2877.
(3) For recent examples, see the following. Intramolecular [5 + 2] cycload-
ditions: (a) Wender, P. A.; Zhang, L. Org. Lett. 2000, 2, 2323-2326.
Intermolecular [5 + 2] cycloadditions: (b) Wender, P. A.; Gamber G.
G.; Scanio, M. J. C. Angew. Chem., Int. Ed. 2001, 40, 3895-3897.
(4) For a review of azepine natural products, see: O’Hagan, D. Nat. Prod.
Rep. 1997, 14, 637-651.
(5) (a) Kamitani, A.; Chatani, N.; Morimoto, T.; Murai, S. J. Org. Chem.
2000, 65, 9230-9233. For a review of carbonylative cycloadditions, see:
(b) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414-422.
(6) Examples of heteroatom variants of the five-carbon VCP include viny-
laziridines, vinyl epoxides, C-cyclopropyl imines, N-cyclopropyl imines,
and cyclopropanecarboxaldehydes.
(7) In a limited screening of catalysts, [Rh(CO)2Cl]2 gave the best results in
the unoptimized cyclization of 1 and 2 to 3. Ir(Cl)(CO)(PPh3)2 and RhCl-
(PPh3)3 gave 6% and 5% isolated yields of 3, respectively, and >50%
isolated yield of 4. Ru3(CO)12 or MgSO4 was ineffective as a catalyst.
(8) (a) Yamamoto, Y.; Takagishi, H.; Itoh, K. J. Am. Chem. Soc. 2002, 124,
6844-6845 and references therein. (b) For a review of [2 + 2 + 2]
cycloadditions, see: Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100,
2901-2915.
though such systems are sterically encumbered. For example,
1-isopropylcyclopropanecarboxaldehyde 13 is smoothly converted
to dihydroazepine 14, albeit at a slightly higher temperature (100
°C). Of further note is the finding that the reaction also works for
ketimines, with 15 and 17 reacting to provide the highly function-
alized dihydroazepines 16 and 18. It is interesting that the VCP
subunit of 16 does not engage in a second [5 + 2] cycloaddition
under these conditions.
Aza-[5 + 2] cycloadditions enable rapid assembly of dihy-
droazepine building blocks useful in the synthesis of more complex
molecules. To explore the preparative potential of this process, an
N-benzyl imine was selected for study since the benzyl group could
be removed in the dihydroazepine cycloadduct. Gratifyingly, we
were able to conduct the aza-[5 + 2] cycloaddition on a 15 mmol
scale, generating 4.07 g (89% isolated yield) of the expected
dihydroazepine 10 (Scheme 4).
(9) Toluene proved to give the highest yields. Other solvents (e.g., THF,
EtOAc, Et2O, acetone) gave yields which were generally lower.
(10) The current reaction conditions work best with acetylene diesters.
Acetylene monoesters, phenyl acetylene, and propargyl alcohol derivatives
were unreactive. Further studies on alkyne variations are in progress.
(11) A previous attempt on use of N-cyclopropyl benzaldimine as substrate
for a hetero-[5 + 2] cycloaddition was unsuccessful.
(12) (a) Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.; Love,
J. A.; Rieck, H. J. Am. Chem. Soc. 1999, 121, 10442-10443. (b) Wender,
P. A.; Dyckman, A. J. Org. Lett. 1999, 1, 2089-2092.
(13) The regiochemical outcome was determined by decoupling NMR experi-
ments detailed in the Supporting Information.
In summary, the first transition metal-catalyzed hetero-[5 + 2]
cycloadditions and a new method for dihydroazepine synthesis are
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