Formal aza-Michael additions to tropone: Addition of diverse aryl- and alkylamines to tricarbonyl(tropone)iron and [(C7H7O)Fe(CO)3]BF4

Article abstract of DOI:10.1016/j.tetlet.2018.08.006

A formal aza-Michael addition to tropone by way of tricarbonyl(tropone)iron and/or the tetrafluoroborate salt formed via protonation of the complex is reported. Tricarbonyl(tropone)iron smoothly undergoes the direct aza-Michael reaction with unhindered aliphatic amines under solvent free conditions in good yields. Meanwhile, the known cationic complex [(C₇H₇O)Fe(CO)₃]BF₄ (whose reaction with a small number of nucleophiles was previously reported) undergoes addition with an even broader array of amine nucleophiles. Finally, it was discovered that protecting the aza-Michael adduct as a carbamate was necessary for oxidative demetallation of the complex.

Full text of DOI:10.1016/j.tetlet.2018.08.006

Accepted Manuscript
Formal aza-Michael additions to tropone: addition of diverse aryl- and alkyla-
mines to tricarbonyl(tropone)iron and [(C7H7O)Fe(CO)3]BF4
Zhiyuan Huang, Zaki K. Phelan, Rachel L. Tritt, Shelby D. Valent, Daniel R.
Griffith
PII:
S0040-4039(18)30978-X
https://doi.org/10.1016/j.tetlet.2018.08.006
TETL 50181
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 July 2018
28 July 2018
3 August 2018
Please cite this article as: Huang, Z., Phelan, Z.K., Tritt, R.L., Valent, S.D., Griffith, D.R., Formal aza-Michael
additions to tropone: addition of diverse aryl- and alkylamines to tricarbonyl(tropone)iron and
[(C7H7O)Fe(CO)3]BF4, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.08.006
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Tetrahedron Letters
journal homepage: www.elsevier.com
Formal aza-Michael additions to tropone: addition of diverse aryl- and
alkylamines to tricarbonyl(tropone)iron and [(C7H7O)Fe(CO)3]BF4
Zhiyuan Huang, Zaki K. Phelan, Rachel L. Tritt, Shelby D. Valent, and Daniel R. Griffith
Department of Chemistry, Lafayette College, 701 Sullivan Road, Easton, PA 18042, USA
ABSTRACT: A formal aza-Michael addition to tropone by way of tricarbonyl(tropone)iron and/or the tetrafluoroborate salt formed
via protonation of the complex is reported. Tricarbonyl(tropone)iron smoothly undergoes the direct aza-Michael reaction with
unhindered aliphatic amines under solvent free conditions in good yields. Meanwhile, the known cationic complex
[(C7H7O)Fe(CO)3]BF4 (whose reaction with a small number of nucleophiles was previously reported) undergoes addition with an even
broader array of amine nucleophiles. Finally, it was discovered that protecting the aza-Michael adduct as a carbamate was necessary for
oxidative demetallation of the complex.
Keywords: iron diene complexes, aza-Michael reaction, tropone, solvent free
Tropone and its 4 complex with an iron tricarbonyl fragment (tricarbonyl(tropone)iron (1) – readily synthesized from
tropone1) are versatile synthetic building blocks that can be elaborated to a variety of complex scaffolds containing seven-
membered rings. Whereas tropone typically reacts with nucleophiles at the 2- and 7-positions2,3 and also participates in
cycloaddition reactions4–6 at those positions, forming an -diene complex with iron(0) fundamentally alters the reactivity
of tropone. A notable illustration of the synthetic utility of 1 is Pearson and co-worker’s stereocontrolled synthesis of
heptitols7 from 1, which was adapted by Soulié and co-workers in the synthesis of a polyhydroxylated nortropane
skeleton.8,9 Furthermore, the uncomplexed double bond of 1 has been shown to act as an enone equivalent in reactions
with, for example, dienes,10,11 tetrazines,12 nitrile oxides,13 diazoalkanes,14,15 and organozinc reagents.16 A similar addition
of amine nucleophiles would furnish adducts containing several functional handles for further synthetic elaboration,
whether in the form of the -complexed diene or the corresponding free conjugated diene (Scheme 1). Thus, a formal
aza-Michael addition to tropone and/or 1 serves as a potential starting point for the synthesis of complex amines
containing a seven-membered carbocyclic ring common to a number of biologically active alkaloids (including several
monoterpenoid indole alkaloids17 and some Daphniphyllum alkaloids18).
Scheme 1. Aza-Michael adducts of tricarbonyl(tropone)iron: potential precursors for complex amines
Eisenstadt reported that the cationic complex 3 (synthesized from 1 in two steps19,20) could react with aniline or tert-
butylamine to give formal aza-Michael adducts of 1.21 However, no other amine nucleophiles were investigated and
demetallation of the products was also not reported. In addition to further exploring this chemistry, we were interested in
developing a novel, direct aza-Michael addition of 1 without the need for pre-forming the cationic complex 3. Herein, we
describe our thorough exploration of the scope and reactivity of 3 toward various amine nucleophiles. In addition, we
report the first direct aza-Michael addition of unhindered aliphatic amines to 1 as well as conditions for demetallation to
reveal the dienone functionality.
 Corresponding author. Tel.: +1-610-330-5221; fax: +1-610-330-5714; e-mail: griffitd@lafayette.edu

We began by exploring the reactivity of the dienyl tetrafluoroborate salt (3, Table 1) towards the sterically hindered
nucleophile o-toluidine. We found that, in the presence of five equivalents of o-toluidine, such a reaction cleanly gave the
desired formal aza-Michael adduct in moderate yield. We then proceeded to examine the effect of changing various
reaction parameters (Table 1). We found that reducing the amount of toluidine to two equivalents resulted in no loss in
yield and also facilitated chromatographic purification of the product. In addition, screening various aprotic solvents
showed little impact on the isolated yield, and that anhydrous conditions appeared to decrease the yield. Thus, all
subsequent reactions were carried out open to the atmosphere and no effort was made to exclude moisture. Finally,
extending the reaction time resulted in enhanced yields.
Table 1. Optimization of nucleophilic addition to cationic complex 3.
Entry
4 (equiv.)
Solvent
diethyl ether
diethyl ether
CH2Cl2
Time
30 min
30 min
30 min
30 min
30 min
30 min
30 min
24 h
Yield 2a (%)b
1
2
3
4
5
6
7
8
2
5
2
2
2
2
2
2
46
43
45
29
52
41
43
63
c
CH2Cl2
THF
toluene
EtOAc
diethyl ether
aReactions were conducted on a 0.1 mmol scale
bProducts were purified by column chromatography
cReaction performed under an argon atmosphere with anhydrous solvent
We next sought to more broadly explore the scope of this formal aza-Michael reaction (see Table 2). Compound 3 was
found to react cleanly with a wide variety of aryl and aliphatic amines, including reasonably hindered amines, in good
yields. Particularly notable is the reactivity towards o-mono- and o-disubstituted aniline derivatives. Only with 2,6-
diisopropylaniline (2e) (and, to a lesser extent, o-bromoaniline 2f) was a significant reduction in yield observed. In line
with Eisenstadt’s findings, tert-butylamine was found to cleanly react, providing the corresponding adduct in 53% yield.
Electron-withdrawal from the aniline derivative appears to be reasonably well-tolerated, with p-fluoroaniline reacting in
72% yield. On the other hand, electron-deficient aminopyridines undergo the reaction in low yields. We also found that
carbamates such as BocNH2 completely failed to react with 3.22 In each case, only a single diastereomer was obtained,
with the Fe(CO)3 fragment providing exceptional stereocontrol, as is well known with such diene complexes.23 Indeed, we
confirmed the stereochemical outcome of these additions via X-ray crystallographic analysis of the adduct of morpholine
(2l; see ESI, CCDC No. 1853243).

Table 2. Scope of nucleophilic addition to cationic complex 3.
Interestingly, we found that allowing 2,6-diisopropylaniline to react with 3 for 24 h gave an inseparable mixture of 1
and what was tentatively assigned as the product of a Friedel-Crafts type alkylation, with electrophilic attack occurring
para to the aniline nitrogen (6, Scheme 2, right side). Shortening the reaction time to 30 min resulted in the formation of
2e in low yield (see Scheme 2, left side, and Table 2). Thus, it appears that, at least with especially hindered nucleophiles,
the addition to 3 is reversible under the reaction conditions and that the Friedel-Crafts product (6) is the thermodynamic
product. This result is consistent with previous investigations into kinetic and thermodynamic additions of arylamines to
tricarbonyliron-coordinated cyclohexadienyl cations.24–26
Scheme 2. Formation of N-alkylation product 2e (left) and Friedel-Crafts product 6 (right) from 3 and 2,6-
diisopropylaniline
While we were pleased with the broad substrate scope of the
Table 3. Direct aza-Michael reactions of 1
addition to 3, we hoped to develop a more streamlined route to these
formal aza-Michael adducts, since the synthesis of 3 from 1 requires
multiple synthetic operations (typically proceeding in 40-60% overall
yield), where we found that variable (though relatively small) amounts
of 1 were recovered alongside the desired tetrafluoroborate salt. Thus,
to improve the overall yields of the adducts, we sought to explore a
direct aza-Michael reaction of 1. We were pleased to find that certain
aliphatic amines rapidly underwent the desired reaction when mixed
with 1 under solvent-free conditions at room temperature. Exploration
of the scope of this direct aza-Michael addition (Table 3) revealed that
only relatively unhindered primary amines and secondary cyclic amines
underwent the desired reaction. Acyclic secondary amines and tert-
butylamine did not react with 1 at room temperature and heating these
reactions resulted in complex product mixtures. Presumably, the

secondary cyclic amines are locked in a favorable conformation in which the nitrogen is less crowded than in the acyclic
cases. Anilines also did not undergo the desired direct addition to 1, likely because they are not sufficiently nucleophilic.
Although the direct addition does not enjoy the same broad substrate scope as the addition to 3, it is the preferred method
for preparing adducts such as 2k due to the higher yields and more direct route from 1.
The aza-Michael adducts contain a number of functional handles to further build up molecular complexity. However,
the two olefins of the dienone moiety are masked by their complexation to the iron atom. Thus, exploiting these functional
handles would be facilitated by demetallation of the complex to give the free ligand. A number of methods have been
reported for the demetallation of (-diene)tricarbonyliron(0) complexes, most of which involve oxidizing agents (e.g.
Me3NO,27 cerium ammonium nitrate (CAN),28 CuCl2,29 basic H2O2,30 FeCl331), though photochemical methods32,33 have
also been reported. Despite a few examples of successful demetallations of amine-containing (4-diene)Fe(CO)3
complexes,34–36 none of these methods proved successful with our adducts. We reasoned that oxidation of the nitrogen may
be competitive with the desired demetallation. In a few cases we isolated tropone itself, resulting from oxidative
elimination of the amino group in addition to demetallation. Therefore, we protected 2k as a tert-butyl carbamate (Scheme
3) to prevent oxidation of the amino group. This compound reacted as expected with CAN to give compound 7. We also
attempted to demetallate the unprotected adducts under acidic conditions, whereby protonation of the nitrogen would serve
as temporary protection from oxidation. However, none of these efforts proved fruitful.
In conclusion, we have developed a straightforward route to a diverse
array of formal aza-Michael adducts of tropone. Key discoveries
include: 1) thoroughly exploring and extending the scope of the reaction
between dienyl tetrafluoroborate salt 3 and nitrogen-based nucleophiles
as previously reported by Eisenstadt to include both electron-deficient
and sterically hindered nucleophiles; 2) the development of a more
Scheme 3. Demetallation of aza-Michael
efficient, direct aza-Michael reaction of 1 with unhindered aliphatic
adduct. Reagents and conditions: a) Boc2O,
amines; 3) oxidative demetallation of Boc-protected adducts by CAN
NaHCO3, EtOH, 64%; b) CAN, MeOH, 0
ºC, 94%
which required extensive exploration of known demetallation protocols.
Notably, the demetallated products contain a number of functional
groups (at minimum, a ketone and two olefins) which could serve as
handles for elaboration to more complex seven-membered ring-containing scaffolds which may be otherwise difficult to
access. A complementary suite of potential reactions involving the iron-complexed diene16 could further enhance the
versatility of these aza-Michael adducts as platforms for synthesizing complex alkaloid-like scaffolds. Efforts towards
such scaffolds are underway in our laboratory and will be reported in due course.
Acknowledgements
We thank Mr. Hayato Nakanishi for preliminary experiments exploring the reactivity of 1 towards amine nucleophiles. We
thank the Lafayette College Academic Research Committee for support through the EXCEL Scholars program. We thank
Prof. Dasan Thamattoor (Colby College) for X-ray analysis of compound 2l. High resolution mass spectra were obtained
by the Mass Spectrometry Lab at the University of Illinois (the Q-Tof Ultima mass spectrometer was purchased in part
with a grant from the National Science Foundation, Division of Biological Infrastructure (DBI-010085)).
Supplementary Material
Supplementary data associated with this article (experimental procedures, spectroscopic data for new compounds, and X-
ray crystallographic data for compound 2l) can be found, in the online version, at
https://doi.org/10.1016/j.tetlet.xxxx.xx.xxx
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 aza-Michael addition to tricarbonyl(tropone)iron under solvent-free conditions
 Addition to the corresponding cationic dienyl complex has a broader substrate scope
 Carbamates derived from aza-Michael adducts undergo smooth oxidative demetallation