N -heteropolycyclic compounds from the formal intramolecular (4 + 1)-cycloaddition of chromium aminocarbenes

Article abstract of DOI:10.1021/ol4025887

Chromium aminocarbenes tethered to dienes of all three electronic natures undergo an efficient intramolecular (4 + 1)-cycloaddition to give N-heteropolycyclic compounds. Ligands on chromium had a profound effect on the course of the reaction.

Full text of DOI:10.1021/ol4025887

ORGANIC
LETTERS
2013
Vol. 15, No. 21
5456–5459
N‑Heteropolycyclic Compounds
from the Formal Intramolecular
(4 þ 1)-Cycloaddition of Chromium
Aminocarbenes
ꢀ
Martin Dery, Louis-Philippe D. Lefebvre, Kevin Aissa, and Claude Spino*
ꢀ
Universite de Sherbooke, Departement de Chimie, 2500 Boul. Universite, Sherbrooke,
QC, Canada, J1K 2R1
ꢀ
ꢀ
Claude.Spino@USherbrooke.ca
Received September 9, 2013
ABSTRACT
Chromium aminocarbenes tethered to dienes of all three electronic natures undergo an efficient intramolecular (4 þ 1)-cycloaddition to give
N-heteropolycyclic compounds. Ligands on chromium had a profound effect on the course of the reaction.
We have been interested in the (4 þ 1)-cycloaddition as a
way to synthesize five-membered carbocyclic compounds
for some time.1 We have used dialkoxyoxadiazolines (1,
X = O) as precursors of free dialkoxycarbenes,2 which
undergo formal (4 þ 1)-cycloadditions with electron-poor
dienes to give adducts such as 2 (X = O, Scheme 1).
However, while aminoalkoxyoxadiazolines (1, X = NR)
can be prepared this way, they usually give unstable
aminal-containing carbopentacycles 2 (X = NR).3 More-
over, free alkoxycarbenes, bearing only one heteroatom,
react with dienes to give only cyclopropanation products,
thus limiting the scope of this methodology.4 We there-
fore sought alternatives to making such compounds, and
chromium alkoxy- and aminocarbenes5 caught our atten-
tion. Chromium alkoxycarbenes (CALC) and chromium
aminocarbenes (CAMC) are important reactiveintermedi-
ates that undergo a plethora of reactions with alkenes,
alkynes, and dienes.6 Yet, they are often stable to air and
to chromatographic purification. CALC complexes have
beenthe subject ofmorestudies and applications thantheir
amino counterpart since the first report by Fischer on the
synthesis of alkoxychromium complexes.7 These species
can undergo formal cycloaddition reactions with 1,3-
dienes including (2 þ 1)-,8,9b (3 þ 2)-,9,10a,10b and (4 þ 1)-
cycloadditions10 depending on the nature of the carbene
and of the diene.6c However, the (4 þ 1)-cycloaddition
observed only in cases involving alkoxy(alkenyl)carbene
ꢀ
(1) (a) Spino, C.; Rezaei, H.; Dupont-Gaudet, K.; Belanger, F. J. Am.
Chem. Soc. 2004, 126, 9936–9927. (b) Boisvert, L.; Beaumier, F.; Spino,
C. Org. Lett. 2007, 9, 5361–5363. (c) Beaumier, F.; Dupuis, M.; Spino,
C.; Legault, C. Y. J. Am. Chem. Soc. 2012, 134, 5938–5953.
(2) For a review on 2,2-dialkoxy-Δ3-1,3,4-oxadiazolines and the
reactivity of bis(heteroatom-substituted)carbenes, see: Warkentin, J.
Acc. Chem. Res. 2009, 42, 205–212and references cited therein.
(3) Dupont-Gaudet, K. M.Sc. Thesis, University of Sherbrooke,
Sherbrooke, QC, Canada, 2006.
(6) For reviews of both chromium alkoxy- and aminocarbenes, see:
(a) Schwindt, M. A.; Miller, J. A.; Hegedus, L. S. J. Organomet. Chem.
1991, 413, 143–153. (b) Bernasconi, C. F. Chem. Soc. Rev. 1997, 26, 299–
ꢀ
307. (c) Barluenga, J.; Santamarıa, J.; Tomas, M. Chem. Rev. 2004, 104,
´
€
2259–2283. (d) Dotz, K. H.; Stendel, J., Jr. Chem. Rev. 2009, 109, 3227–
ꢀ
3274. (e) Fernandez-Rodrı
Chem. Commun. 2010, 46, 7670–7687. (f) Fernandez, I.; Cossı
Sierra, M. A. Acc. Chem. Res. 2010, 44, 479–490.
´
guez, M. A.; Garcı
´
a-Garcı
´
a, P.; Aguilar, E.
´
o, F. P.;
€
(7) (a) Fischer, E. O.; Maasbol, A. Angew. Chem., Int. Ed. Engl. 1964,
3, 580–581. (b) Fischer, E. O.; Aumann, R. Chem. Ber. 1968, 101, 954–
962.
ꢀ
(4) Belanger, F. M.Sc. Thesis, University of Sherbrooke, Sherbrooke,
QC, Canada, 2006.
(5) The first chromium aminocarbenes were synthesized by the group
of E. O. Fischer: (a) Klabunde, U.; Fischer, E. O. J. Am. Chem. Soc.
1967, 89, 7141–7142. (b) Baikie, P. E.; Fischer, E. O.; Mills, O. S. Chem.
Commun. 1967, 1199–1200. (c) Connor, J. A.; Fischer, E. O. Chem.
Commun. 1967, 1024.
(8) Buchert, M.; Reissig, H.-U. Liebigs Ann. 1996, 2007–2013.
(9) For lead references, see: (a) Kagoshima, H.; Fuchibe, K.; Akiyama,
T. Chem. Record 2007, 7, 104–114. (b) Hoffmann, M.; Buchert, M.;
Reissig, H.-U. Chem.;Eur. J. 1999, 5, 876–882.
r
10.1021/ol4025887
Published on Web 10/11/2013
2013 American Chemical Society

complexes. It is often a minor pathway in competition with
the more prominent (3 þ 2)-cycloaddition pathway.10,11
Five-membered carbocycles12 have been prepared by
the (3 þ 2)-cycloaddition of alkynes with β-amino-R,β-
unsaturated carbene complexes,13 alkoxycarbenes,10,11
and cyclopropyl alkoxycarbenes.14 With some notable
exceptions,10d alkenes and dienes react with CALC to give
cyclopropane products.15
Scheme 2. Intramolecular Cyclopropanation of a Chromium
Carboxyaminocarbene
Scheme 1. Oxadiazolines and Chromium Carbenes
Scheme 3. Formal (4 þ 1)-Cycloaddition of Chromium
Dimethylaminocarbene and (E)-Methyl Penta-2,4-dienoate
CAMCs are less reactive than their alkoxy counterpart
toward alkenes and have thus seen fewer applications.
Examples of cyclopropanations with CAMCs are scarcer
than ones involving CALCs. One example is shown in
Scheme 2.16 It is believed that the ester substituent on
aminocarbene 5 increases its reactivity by depleting the
electron density on chromium. There is one example of an
intermolecular (4 þ 1)-cycloaddition between a dimethyla-
minocarbene complex and (E)-methyl penta-2,4-dienoate
giving the cyclopentene product in 34% yield (Scheme 3).17
This is, in fact, the first and only example of a formal (4 þ 1)-
cycloaddition involving a CAMC and a diene.
Our initial foray into using CALCs to effect formal (4 þ 1)-
cycloadditions with dienes met with failure, not unexpect-
edly. The former gave exclusively cyclopropanation pro-
ducts while chromium dimethoxycarbene18 was completely
unreactive. We decided to explore the potential of CAMCs
to give (4 þ 1)-cycloadducts, cognizant of their lower
propensity to undergo cyclopropanation reactions. How-
ever, we were unable to improve on the results obtained by
Hegedus and his co-workers for the intermolecular reaction
of 9 to give 10 (Scheme 3). On the other hand, when we
heated a series of CAMC tethered to a diene (11), we were
delighted to find that the intramolecular version of this
reaction proceeds quite efficiently to give the corresponding
(4 þ 1)-cycloadducts (Table 1). The first striking observa-
tion from the results listed in Table 1 is that the reaction
proceeds whether electron-deficient (entries 1 and 5), elec-
tron-rich (entry 4), or unactivated dienes (entries 2 and 3)
are involved. No other (4 þ 1)-cycloaddition methodology
we know of, formal or not, displays this highly desirable
feature. Esters, ethers, and silyl ethers were compatible with
the reaction. The nitro derivative 11f decomposed upon
heating, perhaps owing to the increased acidity of the allylic
protons. The cis ring junction was obtained in all cycload-
ducts 12 and 13, and the major product 12 has the syn
stereochemistry relative to the other chiral carbons.
ꢀ
ꢀ
(10) (a) Barluenga, J.; Lopez, S.; Florez, J. Angew. Chem., Int. Ed.
€
2003, 42, 231–233. (b) Zaragoza Dorwald, F. Angew. Chem., Int. Ed.
2003, 42, 1332–1334. (c) Barluenga, J.; Fanlo, H.; Lopez, S.; Florez, J.
Angew. Chem., Int. Ed. 2007, 46, 4136–4140. (d) Barluenga, J.; Aznar, F.;
Fernandez, M. Chem.;Eur. J. 1997, 3, 1629–1637. (e) Barluenga, J.;
Tomas, M.; Ballesteros, A.; Santamarı
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a, J.; Suarez-Sobrino, A. J. Org.
Chem. 1997, 62, 9229–9235. (f) Barluenga, J.; Ballesteros, A.; Santamarı
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(11) Hoffmann, M.; Buchert, M.; Reissig, H.-U. Angew. Chem., Int.
Ed. 1997, 36, 283–285.
(12) For reviews on the use of Fisher carbenes to make five-mem-
bered carbocycles, see: (a) Herndon, J. W. Tetrahedron 2000, 56, 1257–
1280. (b) Harvey, D. F.; Sigano, D. M. Chem. Rev. 1996, 96, 271–288. (c)
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Barluenga, J.; Fernandez-Rodrıguez, M. A.; Aguilar, E. J. Organomet.
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Chem. 2005, 690, 539–587.
(13) (a) de Meijere, A. Pure Appl. Chem. 1996, 68, 61–72. (b) Flynn,
B. L.; Funke, F. J.; Silveira, C. C.; de Meijere, A. Synlett 1995, 1007–
1010. (c) Flynn, B. L.; Silveira, C. C.; de Meijere, A. Synlett 1995, 812–
814. (d) Duetsch, M.; Vidini, S.; Stein, F.; Funke, F.; Noltemeyer, M.; de
Meijere, A. J. Chem. Soc., Chem. Commun. 1994, 1679–1680.
(14) (a) Tumer, S. U.; Herndon, J. W.; McMullen, L. A. J. Am. Chem.
Soc. 1992, 114, 8394–8404. (b) Herndon, J. W.; Patel, P. P. Tetrahedron
Lett. 1997, 38, 59–62. (c) Herndon, J. W.; Matasi, J. J. J. Org. Chem.
1990, 55, 786–788. (d) Herndon, J. W.; Yan, J. J. J. Org. Chem. 1998, 63,
2325–2331.
Yields were evenhigher withunactivateddienes, ranging
between 60% and 85% (Table 2). Fused 5ꢀ5 (15a) and
5ꢀ6 bicyclic compounds (15b) could be prepared
(15) (a) Buchert, M.; Reissig, H.-U. Chem. Ber. 1992, 125, 2723–
2729. (b) Buchert, M.; Reissig, H.-U. Tetrahedron Lett. 1988, 29, 2319–
2320. (c) Buchert, M.; Reissig, H.-U. Chem. Ber. 1995, 128, 605–614.
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(16) Barluenga, J.; Aznar, F.; Gutierrez, I.; Garcıa-Granda, S.;
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Llorca-Baragano, M. A. Org. Lett. 2002, 4, 4273–4276.
(17) Sierra, M. A.; Soderberg, B.; Lander, P. A.; Hegedus, L. S.
(18) Imwinkelried, R.; Hegedus, L. S. Organometallics 1988, 7, 702–
Organometallics 1993, 12, 3769–3771.
706.
Org. Lett., Vol. 15, No. 21, 2013
5457

Table 1. Effect of Substituent R2
Scheme 4. Mechanistic Portrait of the Reaction
yield
(%)a
ratio
entry
R1
R2
CO2Me
11
12:13
1
2
3
4
5
6
Bn
a
b
c
d
e
f
43b
58
62
61
59
0
3:1c
2:1d
3:2d
3:2d
3:2d
ꢀ
Bn
CH2OTBDPS
Ph
i-Bu
i-Bu
i-Bu
i-Bu
p-MeOPh
p-(MeO2C)Ph
p-(O2N)Ph
We have observed that, with most substrates, the addi-
tion of PPh3 had a major influence on reaction rate and
the nature of the final product. In most cases, an enamine
was observed as the major or only product in the crude
reaction mixture, though it proved unstable to purifica-
tion. This enamine (19) could come from a β-elimination
pathway (Scheme 4). Even though the details of the
mechanism are not known, we believe that it should start
in a similar fashion to the one proposed for the cyclopro-
panation of olefins by chromium alkoxycarbenes:17 after
the departure of one carbon monoxide ligand, the alkene
nearest to the carbene coordinates the chromium (16) and
undergoes a (2 þ 2)-cycloaddition to form the metallacy-
clobutane 17. This species is also an allyl chromium that
will be in equilibrium with 18 from which a reductive
coupling leads to the desired (4 þ 1)-cycloaddition product
22. However, either intermediate 17 or 18 can undergo
β-elimination with one of the hydrogens at the ring
fusion to give 21 and 20, respectively. The two species are
likely in equilibrium. Reductive coupling from species 20
gives the observed conjugated enamine 19. It is not yet
clear why triphenylphosphine favors the β-elimination
process.
a Isolated yield. b Includes 21% of the product, in which the double
bond has migrated in conjugation with the ester (see Supporting
Information). c Determined by 1H NMR. d Determined by GC.
Table 2. (4 þ 1)-Cycloaddition with Nonactivated Dienes
a Determined by 1H NMR. b Reaction in refluxing m-xylene; cis/
trans ratio was measured at 13:1. c 1.05 equiv of PPh3 added. d dr =
60:40. e dr = 70:30.
Triphenylphosphine increases the overall reaction rate
and yield of the (4 þ 1)-cycloaddition when a hydrogen at
the ring fusion is absent (entry 4). However, in cases where
the steric encumbrance is too high, β-elimination at other
sites becomes competitive. The reaction of compound 23
illustrates this point (Scheme 5). While the reaction with-
out PPh3 in refluxing xylene gave 10% of the (4 þ 1)-
cycloaddition product 24, in this particular case, the addi-
tion of PPh3 led to a very clean and rapid reaction in
refluxingtoluene givingdiene25asthe soleproductin60%
yield. Presumably, intermediate 27 undergoes β-elimination
faster than reductive coupling because of steric hindrance
and strain in (4 þ 1)-cycloadduct 24. Also, preliminary
investigations of CAMCs that possess a carbon atom
attached to the carbene instead of hydrogen show that they
require high temperature and/or the addition of triphenyl-
phosphine in order to react and only the dienamine, the
product of a β-elimination, was isolated (see Supporting
Information, CAMC 76).
(entries 1 and 2) although the corresponding fused 5ꢀ7
system could not be made in this way. Steric hindrance is
well tolerated on the nitrogen atom (entries 5 and 6).
Asymmetric induction was low in these two cases (60:40
and 70:30 d.r., respectively) but wehave not yetstudied this
aspect in any depth. More importantly, the formation of
a quaternary carbon was possible (15c) in 72% yield in
xylene at 139 °C (entry 3). At that temperature, a small
amount of the cycloadduct having the trans ring junction
was observed (<8%). Interestingly, the addition of 1.05
equiv of PPh3 substantially increased the reactivity of the
carbene and the cycloadduct 15c could now be obtained in
85% yield at 111 °C. The significant effect of ligands such
as phophines or amines on the reactivity of chromium
carbene has already been observed in other reactions.19
(19) (a) Flynn, B. L.; Schirmer, H.; Duetsch, M.; de Meijere, A.
J. Org. Chem. 2001, 66, 1747–1754. (b) Giese, M. W.; Hoser, W. H.
J. Org. Chem. 2005, 70, 6222–6229.
5458
Org. Lett., Vol. 15, No. 21, 2013

Scheme 5. Effect of the Addition of PPh3
Scheme 7. Mechanistic Approach for the Two CAMC Rotamers
Scheme 6. Heating CAMC Rotamers 28a and 28b
As is the case for formamides, CAMCs have a strong
rotation barrier for the NꢀC bond, estimated to be greater
than 25 kcal/mol.20 The two rotamers do not equilibrate at
room temperature and can be separated by chromatogra-
phy and isolated without any subsequent equilibration.
A fully saturated homologue of substrate 14d was synthe-
sized, and the rotamers 28a and 28b were separated by flash
chromatography. Heating the major rotamer (we believe
it to be 28a) to 111 °C for 30 min showed no equilibration
(1H NMR) (Scheme 6). A mixture of the two rotamers was
also heated, and their ratio was shown to be constant over
time.
The stereoisomeric ratio ofthe cycloadducts12, 13, or 15
do not reflect the starting ratio of the corresponding
CAMC rotamers. This implies that both CAMC rotamers
react independently to give the same final products. By
admitting that the first step of the mechanism is a (2 þ 2)-
cycloaddition, both CAMC rotamers could react with
the internal double bound with the linker chain being in
a boat conformation. For reasons of orbital alignment,
both reactions would result in the formation of 17 with the
same relative stereochemistry (Scheme 7).
Figure 1. Complex natural products embedding the structural
motif from the formal (4 þ 1)-cycloadditions of CAMCs.
compounds. The reaction proceeds well with dienes of all
electronic natures and more so with unactivated ones. The
formation of quaternarycenters demonstrates the potential
of this reaction for target oriented synthesis. The structural
motifs generated by the intramolecular (4 þ 1)-cycloaddi-
tion of CAMCs is embedded in a large number of natural
alkaloids (Figure 1), but it can also be used to construct
other motifs thanks to the versatility of the alkene function-
ality. The addition of PPh3 was shown to have a strong
influence on the rate and outcome of the reaction, and
studies are being conducted to better understand the me-
chanistic details of the reaction.
Acknowledgment. We wish to thank the Natural
Sciences and Engineering Research Council of Canada, the
ꢀ ꢀ
Fonds Quebecois de Recherche ꢀ Nature et Technologie,
ꢀ
and the Universite de Sherbrooke for financial support.
Supporting Information Available. Experimental and
characterization data for all new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
Our preliminary investigation shows that CAMCs teth-
ered to a diene undergo efficient formal intramolecular
(4 þ 1)-cycloadditions to give bicyclic N-hetereocyclic
(20) Moser, E.; Fischer, E. O. J. Organomet. Chem. 1968, 13, 387–
398.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 21, 2013
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