N-heterocycles from chromium aminocarbenes

Article abstract of DOI:10.1021/acs.orglett.5b00313

The initial [2 + 2]-cycloadduct between a chromium aminocarbene and a tethered alkene undergoes a β-hydrogen elimination very efficiently when triphenylphosphine is added as a ligand. The reaction gives cyclic enamines or homoenamines depending on the sub

Full text of DOI:10.1021/acs.orglett.5b00313

Letter
pubs.acs.org/OrgLett
N‑Heterocycles from Chromium Aminocarbenes
Martin Dery, Kevin Assouvie, Nora Heinrich, Isabelle Rajotte, Louis-Philippe D. Lefebvre,
́
Marc-Andre Legault, and Claude Spino*
́
́ ́ ́
Universite de Sherbrooke, Departement de Chimie, 2500 boul. Universite, Sherbrooke, QC J1K 2R1, Canada
S
* Supporting Information
ABSTRACT: The initial [2 + 2]-cycloadduct between a
chromium aminocarbene and a tethered alkene undergoes a β-
hydrogen elimination very efficiently when triphenylphosphine is
added as a ligand. The reaction gives cyclic enamines or
homoenamines depending on the substitution on the alkene.
Scheme 2. Main Methods of Preparation of CAMC
hromium alkoxycarbenes 1 (CALC) and chromium
Caminocarbenes 2 (CAMC) are useful reactive intermedi-
ates and have been used to make a wide variety of organic
compounds.1,2 Both undergo a photochemically initiated formal
[2 + 2]-cycloaddition with imines to give β-lactams,
respectively.3,4 Although both CALC and CAMC resemble
each other by their structures and reactions, there are marked
differences between these two Fisher carbenes: CAMC tend to
be less reactive and are more stable than CALC; cyclo-
propanation is a main reaction pathway for CALC, not so for
CAMC (e.g., 1 → 5 or 6 versus 2 → 7 or 8 Scheme 1).5
Scheme 1. Reactions of CALC 1 and CAMC 2
known; thus formamides (9, R = H) are, in effect, the only
available source of CAMC 10 with R = H.
We have shown that the latter can undergo a formal
intramolecular [4 + 1]-cycloaddition when tethered to a diene,
as in 13a, to give N-heterobicyclic product 14a in good yields
(Scheme 3).10 Dienamine 15a often accompanied adduct 14a
as a byproduct and is the result of a β-hydride elimination on
Scheme 3. Formal [4 + 1]-Cycloaddition and β-Hydride
Elimination of CAMC 13a−c Tethered to a Diene
Chromium aminocarbenes have been generally less exploited
than their chromium alkoxycarbenes counterpart.1b,6,7 Reac-
tions involving CAMC where the carbene carbon bears a
hydrogen have been even less frequently described.1d,3d,8 This
may stem in part from the availability of methods for their
preparation. A general method for CAMC synthesis involves
the addition of pentacarbonylchromate (M2Cr(CO)5) to an
amide 9 to give CAMC 10 (Scheme 2)8b,9 Aminolysis of CALC
is possible with primary or unhindered secondary amines (11
→ 12). However, CALC 11 (Z = OR′) where R = H are not
Received: January 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the purported [2 + 2]-metallocyclobutane intermediate (cf.
Scheme 6). We have found that when 1 equiv of
triphenylphosphine is added as a ligand to chromium,
dienamine 15a becomes the sole product of the reaction. We
wondered if this reaction was general and could be performed
on simple or substituted alkenes as opposed to dienes. We
herein report that this reaction is indeed of wide scope and
proceeds with electron-rich, electron-deficient, or unactivated
alkenes and dienes, giving rise to a wide range of interesting N-
heterocyclic structures.
Table 1. Results of the Thermal Reaction of CAMC
Tethered to Different Alkenes and Dienes
yield
a
entry
R1
R2
R3
n
13
(%)
prd
CAMC are stable species that can often be purified by
chromatography on normal silica gel. They can tolerate the
presence of many functional groups and reagents, with the
exception of some oxidants.1 In many ways, CAMC are amide
surrogates and have a similar reactivity pattern.11 Scheme 4
depicts syntheses of CAMC 13i−j by the Semmelhack−
Hegedus method.8b The tolerance of the chromium amino-
carbene 13f to alkene metathesis is remarkable and useful.12
b
c
1
2
Bn
CH2(c-
C6H11)
CHCH2
CHCH2
H
H
1
1
13a
13b
−
−
15a
15b
b
c
b
c
3
4
5
c-C6H11
c-C6H11
c-C6H11
t-Bu
CHCH2
H
H
H
H
H
H
H
H
H
1
1
0
1
1
1
1
1
1
1
13c
13d
13e
13g
13h
13i
−
15c
19d
19e
19g
19h
15i
15j
15j
15k
−
H
69
42
90
72
H
d
6
H
e
7
t-Bu
Me (E,Z-mix)
Ph
f
b
8
i-Bu
33
b
Scheme 4. Synthesis of CAMC 13f and 13i−j
9
i-Bu
CO2Me
CO2Me
CC−SiMe3
Me
13j
−
f
b
b
10
i-Bu
13j
24
34
0
f
11
i-Bu
13k
13l
12
c-C6H11
Me
b
a
Isolated yield of pure compound. Complete conversion to 15 as
monitored by NMR, product unstable to chromatography. See
c
Scheme 3 for the correct structure (double bond has moved into
d
e
conjugation). No Ph3P was added. 70% yield with PPh3 added. E-
f
geometry determined from NOE experiments. Polymer-bound
ArPh2P was used.
reaction.13 For example, we could not purify 15j properly when
using the usual reaction conditions (Table 1, entry 9), but
could achieve a 24% isolated yield of pure 15j using the
polymer-bound triarylphosphine (Table 1, entry 10).
More complex polycyclic structures are accessible. CAMC-
diene 20 gave the bicyclic dienamine 21 while the analogous
CAMC-alkene 22 gave the expected exocyclic double bond in
bicyclic amine 23a along with the unexpected cyclopropane
23b (Scheme 5). As we alluded to earlier, cyclopropanation is
Heating CAMC 13a−c, tethered to a diene, in the absence of
triphenylphosphine, gave N-heterobicyclic products 14a−c,
respectively (Scheme 3).10a Heating CAMC 13a−c in the
presence of triphenylphosphine led to the formation of
dienamines 15a, 15b, and 15c as the sole products, respectively
(Table 1, entries 1−3). Complete conversion of the CAMC
13a−c to dienamines 15a−c was monitored by NMR, but the
latter are unstable to silica gel (even impregnated with Et3N),
and they could not be purified. Heating CAMC 13d, tethered
to an isolated alkene (as opposed to a diene), gave a surprising
result: 3-methylenepiperidine 19d was isolated in 69% yield as
the only product, instead of the expected tetrahydropyridine
15d (Table 1, entry 4). Using a shorter tether between the
carbene and the alkene, the more volatile pyrrolidine 19e was
formed in 42% yield (Table 1, entry 5). Bulky groups on
nitrogen are tolerated. Pyrrolidine 19g was isolated in excellent
yield (Table 1, entry 6). In this particular case, we did not add
triphenylphosphine, and though the reaction is slower, the
product can be easier to purify (2 h, 90% yield versus 1 h 70%
yield with PPh3). Therefore, the use of triphenylphosphine is
not mandatory in the case of isolated alkenes. Substitution on
the alkene as in 13h is tolerated (Table 1, entry 7). However,
trisubstituted alkenes were unreactive under these reaction
conditions (Table 1, entry 12). Conjugating substituents on the
alkene (13i−k) (Table 1, entries 8−11) led to the formation of
the corresponding unstable enamines 15i−k. These results are
perplexing, but we offer a rationale for their occurrence (vide
infra). We found that the use of polymer-bound triarylphos-
phine in these cases helps in the purification of these rather
unstable products by sequestering chromium species after the
Scheme 5. Reactions of CAMC 20, 22, 24, and 25
B
DOI: 10.1021/acs.orglett.5b00313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
not a frequently encountered reaction with CAMC and the
formation of 23b is both rare and surprising. We do not know
exactly why its formation is preferred in this case, but we
suspect that a conformational preference in the corresponding
metallacyclobutane 28 (Scheme 6) imposes a fast reductive
elimination to the cyclopropane 23b.
Scheme 7. Reaction of CAMC 32 and 34
Scheme 6. Plausible Mechanism for the Formation of
Products 15 and 19
Scheme 8. Alkaloid-like Structures via Reaction of CAMC 37
When there is no available hydrogen (CAMC 24) to allow
formation of the β-H elimination intermediates, then no
reaction occurs at 110 °C and higher temperatures lead to
decomposition. However, hydrogens at other positions may
participate (25 → 26, Scheme 5).
Scheme 6 summarizes our proposed mechanistic steps that
lead to product 15 or 19.10b All intermediates depicted in
Scheme 6 are probably under equilibrium. The scrambling of
double bond geometry is good evidence for this (cf. Table 1,
entry 7). The dependence on conjugation of the selectivity of
formation of enamine 15 or compound 19 is difficult to explain.
Based on the stability of the double bonds in the intermediate
29a or 29b, we could expect the selective formation of 19 when
R2 is conjugating and of the enamine 15 when R2 is not
conjugating. However, we observed the exact opposite. One
possible explanation implies a π-allyl complex 29c, where the
hydride might be delivered at the position with the highest
positive charge density, away from nitrogen. The cases of
dienes 13a−c and 20 are special because the corresponding
stable dienamine intermediates 30 become available via allylic
transposition.
The β-H elimination pathway works well even in the cases of
CAMC where the carbene carbon is substituted by a carbon
atom (as opposed to a hydrogen). CAMC 31 was converted
quantitatively to dienamine 32 while CAMC 33 gave a 69%
isolated yield of perhydroquinolizine 34 (Scheme 7). One
could imagine using such core structures to make natural
alkaloids, and we tested this idea with a yet more complex
substrate.
be obtained in 58% isolated yield simply by omitting to add
triphenylphosphine to the reaction flask. Both compounds are
advanced intermediates in the synthesis of cylindrocarine
alkaloids14 or members of the corynanthe group of alkaloids,15
respectively, which are underway in our laboratories.
Although the role of triphenylphosphine has not been
unambiguously ascertained, we believe that it simply makes the
metal more electron-rich. This would slow the reductive
elimination step to the [4 + 1]-adduct, allowing for the β-H
elimination to occur (Scheme 6). Initial results obtained with
the use of other ligands (e.g., isonitriles and other phosphines)
as well as other experiments support this view. A more
complete mechanistic study will be reported in due course in a
subsequent article.
From the point of view of the structural transformation, this
reaction is related to the nucleophilic addition on activated
amides.16 However, the latter reaction requires electron-rich
alkenes (enol ethers and allylsilanes for examples) whereas this
new reaction of chromium aminocarbenes, involving a β-H
elimination pathway, works well with electron-deficient,
electron-rich, or unactivated alkenes. We have shown its
scope to be wide, and we have presented examples of its
synthetic potential. Control over two competing pathways (β-H
elimination versus [4 + 1]-cycloaddition) is also possible for
CAMCs tethered to a diene. A full report will be submitted in
due course.
Scheme 8 shows the potential of this strategy in alkaloid
synthesis. Tryptamine 35 was alkylated, acylated, and then
protected to give formamide 36. Heating its chromium carbene
derivative 37 in the presence of triphenylphosphine gave a
quantitative conversion to dienamine 38. As alluded to earlier,
we can control the outcome of the reaction by adding or
omitting triphenylphosphine. For example, compound 39 could
C
DOI: 10.1021/acs.orglett.5b00313
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad, D. C.
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ASSOCIATED CONTENT
* Supporting Information
Characterization data and copies of H and 13C NMR for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
1
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Claude.Spino@USherbrooke.ca.
Notes
́
(10) (a) Dery, M.; D. Lefebvre, L.-P.; Aissa, K.; Spino, C. Org. Lett.
2013, 15, 5456−5459. (b) Sierra, M. A.; Soderberg, B.; Lander, P. A.;
Hegedus, L. S. Organometallics 1993, 12, 3769−3771.
(11) See ref 1c and 1e.
(12) To the best of our knowledge, there are no other examples of an
RCM or CM involving a molecule containing a spectator CAMC. For
examples of metathesis reactions where a CALC is present elsewhere
in the molecule, see: (a) Zhang, L.; Herndon, J. W. Tetrahedron Lett.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thanks the Natural Sciences and Engineering Council of
Canada (NSERC) and the Universite
funding.
́
de Sherbrooke for
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̈
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Nieger, M. J. Organomet. Chem. 2000, 202, 26−36.
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DOI: 10.1021/acs.orglett.5b00313
Org. Lett. XXXX, XXX, XXX−XXX