A tunable route for the synthesis of azomethine imines and β-aminocarbonyl compounds from alkenes

Article abstract of DOI:10.1021/ja305491t

Cyclic azomethine imines possessing a β-aminocarbonyl motif are accessed from simple alkene and hydrazone starting materials. A thermal, concerted alkene aminocarbonylation pathway involving an imino-isocyanate intermediate is proposed and supported by DF

Full text of DOI:10.1021/ja305491t

Communication
pubs.acs.org/JACS
A Tunable Route for the Synthesis of Azomethine Imines
and β‑Aminocarbonyl Compounds from Alkenes
Christian Clavette, Wei Gan, Amanda Bongers, Thomas Markiewicz, Amy B. Toderian, Serge I. Gorelsky,
and Andre M. Beauchemin*
́
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario,
Canada, K1N 6N5
S
* Supporting Information
concerted mechanism involving an amino-isocyanate intermediate.9
ABSTRACT: Cyclic azomethine imines possessing a
β-aminocarbonyl motif are accessed from simple alkene
and hydrazone starting materials. A thermal, concerted alkene
aminocarbonylation pathway involving an imino-isocyanate
intermediate is proposed and supported by DFT calcu-
lations. A notable feature of the process is the steric shield-
ing present in the dipoles formed, which allows for facile
purification of the products by chromatography or crystalli-
zation. In addition, a fluorenone-derived reagent is reported,
which provides reactivity with several alkene classes and allows
for mild derivatization of the dipoles into β-aminoamides,
β-aminoesters, and β-amino acids.
To achieve an intermolecular variant, we became interested in
the analogous reactivity of imino-isocyanates.10 While pioneering
work from Jones showed that C−C π-bonds provide the desired
β-aminocarbonyl motif embedded in a cyclic azomethine imine
product,11 the efficiency of this approach or the likelihood of gen-
erating imino-isocyanates upon thermolysis of simple hydrazone
precursors remained speculative. Thus, we embarked on the
evaluation of this reactivity using an excess of a reactive alkene
(norbornene) and various hydrazones. Gratifyingly, we observed
the formation of the desired product upon thermolysis and
therefore systematically surveyed the reactivity profile of several
hydrazones (Table 1).
Table 1. Survey of Leaving Groups for an
Aminocarbonylation Reagent
a
β-Aminocarbonyl motifs are privileged structures in medicinal
chemistry,1 peptidomimetics,2 molecular recognition,3 and
natural products.4 In many pharmaceuticals (e.g., β-lactam anti-
biotics) and synthetic peptides (e.g., β-peptides) this functionality
is intimately associated with desired therapeutic properties, for
example by allowing enzyme inhibition or leading to improved
pharmacokinetic properties.5 While the importance of this struc-
ture has led to many synthetic developments, a general amino-
carbonylation route to convert readily available alkenes into
β-aminocarbonyl compounds has yet to emerge. Currently,
mild but specific intramolecular variants have been developed
using transition metal catalysis,7 and intermolecular variants rely
on the use of chlorosulfonyl isocyanate to afford β-lactams.8 The
latter approach is limited by the reactive nature of the reagent,
which operates via an ionic [2 + 2] mechanism and displays poor
functional group compatibility. To address current limita-
tions, we initiated efforts toward novel intermolecular alkene
aminocarbonylation reactivity. Herein, we report a straight-
forward synthesis of azomethine imines possessing β-amino-
carbonyl motifs from hydrazones and alkenes (eq 1) and the
derivatization of these adducts into β-aminocarbonyl com-
pounds.
b
Yields (%)
Entry
X
150 °C
120 °C
100 °C
80 °C
1
2
3
4
5
6
7
Ot-Bu (1a)
OEt (1b)
99
99
82
92
98
90
90
69
8
23
0
7
0
OCH2CF3 (1c)
OPh (1d)
55
85
64
69
69
30
84
46
60
46
9
38
11
31
13
SEt (1e)
SPh (1f)
N(i-Pr)2 (1g)
a
Conditions: hydrazone (1 equiv), alkene (10 equiv) in PhCF3 (0.05 M)
b
heated in a sealed vial (microwave reactor). NMR yield using 1,3,5-
trimethoxybenzene as an internal standard.
Selected bis-isopropyl hydrazones were evaluated at temper-
atures ranging from 80 to 150 °C, to probe the effect of the
leaving group on imino-isocyanate generation and overall reaction
efficiency (Table 1). We were delighted to observe high yields with
all hydrazones at 150 °C and that some leaving groups led to
encouraging unoptimized reactivity at or below 100 °C. As
expected, the use of better oxygen and sulfur leaving groups led
to increased yields at lower temperature [entries 2−3 (OEt vs
OCH2CF3) and entries 5−6 (SEt vs SPh)]. In agreement with
In 2009, we reported intramolecular aminocarbonylation
reactions using hydrazine derivatives and provided evidence for a
Received: June 12, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja305491t | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
recent work by Booker−Milburn, Lloyd−Jones et al.,12 we ob-
served that sterically hindered hydrazone leaving group 1g also
led to mild generation of the desired isocyanate and allowed the
use of diisopropyl amine as a leaving group. Given their excellent
level of reactivity at 150 (Ot-Bu, 1a, entry 1) and 100 °C (OPh,
1d, entry 4), these leaving groups were selected for investi-
gating the impact of hydrazone structure (Table 2).
Figure 1. X-ray crystal structure of azomethine imine 3g.
from the least hindered dipoles 3a−3c are minor byproducts
(Table 2, entries 1−3).
Table 2. Hydrazone Scope of Aminocarbonylation
After exploring the impact of hydrazone structure on inter-
molecular aminocarbonylation reactivity, we surveyed the syn-
thetic scope of the reaction with various alkene classes (Table 3).
Special emphasis was placed on fluorenone-derived hydrazone
2h, since it affords dipoles that can be transformed into several
β-aminocarbonyl compounds (vide infra). Using this versatile
reagent,16 we were pleased to observe that simple terminal alkenes
such as 1-hexene and allyltrimethylsilane reacted in good yields
(Table 3, entries 1−3). Cyclohexene (entry 4) and several dienes
provided the desired adducts in yields ranging from modest to
very good, in a trend suggesting that conjugated and strained
dienes are more reactive (entries 5−8). We were also en-
couraged by the yields obtained for vinylarenes (entries 9−11)
and related cyclic derivatives (entries 12−13). In contrast,
electron-rich alkenes such as vinylferrocene, enamine 5m, and
vinyl ethers proved to be more reactive substrates and afforded
cycloadducts at 80 °C (entries 14−25). Using hindered
diisopropyl hydrazone 1d (X = OPh), vinyl pyrrolidinone
(entry 16) as well as linear and cyclic vinyl ethers (entries 17−25)
provided the corresponding adducts efficiently, and slightly
lower yields were observed with hydrazone 2h. As previously,
the identity of the azomethine imines formed using electron-
rich alkenes was secured through X-ray crystallography of
dihydrofuran cycloadduct 5w (see Supporting Information for
details). Finally, an important trend present in Table 3 is the
high Markovnikov regioselectivity observed with all substrates.
To obtain additional insight on the mechanism of this trans-
formation, DFT calculations at the B3LYP/TZVP level17 were
performed to probe the pathway involving an imino-isocyanate
presented in eq 1.
a
Reactivity
a
Conditions: hydrazone (1 equiv), alkene (10 equiv) in PhCF3 (0.05 M)
b
heated in a sealed vial (microwave reactor, 150 °C, 3 h). Isolated yield.
c
d
e
f
Reaction at 120 °C. 15 equiv of C7H10. Reaction at 100 °C. Solvent-
free reaction; 2 equiv of C7H10.
Subsequently, we tested the reactivity of various hydrazones
toward norbornene (Table 2). Smaller hydrazone reagents
(2a−2d) provided the norbornene-derived azomethine imines
in good yields, but complete consumption of starting material
suggested the presence of competing side reactions.13 Thus, we
explored more hindered reagents and were pleased that hydra-
zones derived from adamantanone, diisopropyl ketone, and
fluorenone (Table 2, entries 7−10) resulted in excellent yields
of the aminocarbonylation products. While all entries were
performed in a microwave reactor to allow for somewhat shorter
reaction times, several gram-scale reactions were also performed
under thermal conditions with excellent efficiency (see Supporting
Information for details).
Figure 2. Transition state structure for the intermolecular amino-
carbonylation of ethylene (A) and norbornene (B) using dimethyl imino-
isocyanate. Relevant bond distances (Å) are shown. Red arrows indicate
the atomic movements which correspond to the imaginary normal mode.
The potential energy surface has been calculated for the
reaction of norbornene (see Figure S2, Supporting Information).
Figure 2 presents the transition state structure determined for the
reaction between dimethyl imino-isocyanate and both ethylene
and norbornene. Gibbs free energies of activation (ΔG‡298K) for
concerted processes in the gas phase were calculated to be 36.1
and 35.5 kcal/mol for C2H4 and C7H10 respectively, which is
consistent with a reaction requiring heat to proceed. These
barriers remain fairly unchanged when concerted amino-
Despite their dipolar nature, these useful14 azomethine imine
products are bench-stable.15 In addition, the majority of adducts
reported herein are crystalline and are readily isolated by chromato-
graphy (except 3b and 3c). Analysis of the crystal structure of
adduct 3g (Figure 1) suggests that steric shielding is responsible for
this stability, and this likely also prevents competing [3 + 2]
side reactions that could occur with the excess alkene present
under the reaction conditions. Indeed, [3 + 2]-adducts derived
carbonylation occurs in solvent (ΔG‡
is 36.3 kcal/mol for
the reaction with C7H10 in MeOH). The asynchronous transition
298K
B
dx.doi.org/10.1021/ja305491t | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Alkene Scope of Aminocarbonylation Reactivity
a
b
c
Conditions: hydrazone (1.0 equiv.), alkene (10 equiv.), heated in a sealed vial (80−150 °C, see SI) in PhCF3 at 0.05 M. Isolated yield. Isolated
d
e
f
as a mixture of regioisomers [14:1 (5e), 7:1 (5f), 6:1 (5l), 3:2 (5m)]. Solvent-free reaction. Cyclohexene as solvent. Conditions: hydrazone
(1.0 equiv), alkene (1.0 to 12 equiv), heated in a sealed vial (80−100 °C; see SI). Using 2 equiv of alkene with reagent 2h and 10 equiv with 1d and
2e, except for 5n (1), 5o (5), and 5p (12).
g
exploratory studies building on the [3 + 2] reactivity of closely
related azomethine imines22 suggest the reactivity described
herein holds potential for multicomponent reactions (eq 2).
state is also in line with the high Markovnikov selectivity observed
experimentally. Overall, these results support the pathway
presented in eq 1, and efforts are ongoing to secure conclusive
experimental evidence.
Subsequent efforts focused on the derivatization of the
azomethine imine adducts derived from hydrazone 2h into
several β-aminocarbonyl compounds (Scheme 1). Reagent 2h
was developed to allow subsequent N−N bond cleavage under
mild reducing and basic conditions, in an analogy to the Fmoc
protecting group.18 Gratifyingly, we observed that various amino-
carbonylation products provided fluorenyl-protected19 β-amino-
amides upon treatment with KBH4 and Raney Nickel in MeOH.20
β-Aminoesters and β-amino acids could also be obtained
from the β-aminoamides using literature procedures.21 The
fluorenyl protecting group could also be removed under
standard conditions.19 Overall, these derivatization procedures
establish that hydrazone 2h provides access to several types
of β-aminocarbonyl compounds from simple alkenes. Finally,
In summary, we have developed a modular route for the syn-
thesis of valuable azomethine imines from simple alkene and
hydrazone starting materials. This reactivity allows the func-
tionalization of alkenes into β-aminocarbonyl motifs, which
are embedded in the structure of stable and crystalline cyclic
dipole products. The results are consistent with a concerted
aminocarbonylation event between an alkene and an in situ
C
dx.doi.org/10.1021/ja305491t | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(5) For selected reviews, see: (a) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. Rev. 2001, 101, 3219. (b) Horne, W. S.;
Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399.
Scheme 1. Derivatization of Azomethine Imines
(6) Selected reviews: (a) Juaristi, E.; ; Soloshonok, V.A. Enantioselective
Synthesis of β-Amino Acids, 2nd ed.; Wiley: New York, 2005.
(b) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117.
(7) (a) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am. Chem. Soc.
1980, 102, 3583. (b) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc.
1982, 104, 2444. (c) Tamura, Y.; Hojo, M.; Higashimura, H.; Yoshida,
Z. J. Am. Chem. Soc. 1988, 110, 3994. (d) Cernak, T. A.; Lambert,
T. H. J. Am. Chem. Soc. 2009, 131, 3124. (e) Ambrosini, L. M.; Cernak,
T. A.; Lambert, T. H. Synthesis 2010, 870. (f) Ambrosini, L. M.;
Cernak, T. A.; Lambert, T. H. Tetrahedron 2010, 66, 4882. (g) For a
review, see: Beccalli, E. D.; Broggini, G.; Martinelli, M.; Sottocornola,
S. Chem. Rev. 2007, 107, 5318.
(8) For reviews, see: (a) Rasmussen, J. K.; Hassner, A. Chem. Rev.
1976, 76, 389. (b) Dhar, D. N.; Murthy, K. S. K. Synthesis 1986, 437.
(c) Furman, B.; Borsuk, K.; Kaluza, Z.; Lysek, R.; Chmielewski, M.
Curr. Org. Chem. 2004, 8, 463.
(9) (a) Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Gorelsky, S. I.;
Whipp, C. J.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 8740.
(b) For a seminal review, see: Reichen, W. Chem. Rev. 1978, 78, 569.
(10) For a recent review, see: Wentrup, C.; Finnerty, J. J.; Koch, R.
Curr. Org. Chem 2011, 15, 1745.
a
b
Conditions: KBH4, Ra-Ni, MeOH, 60 °C, 3 h. SOCl2, MeOH,
60 °C, 12 h. c SOCl2, MeOH, 60 °C, 12 h; then 10 M NaOH, rt. d DDQ,
THF, 0 °C, 2 h; HCl (1 M).
(11) Jones, D. W. J. Chem. Soc., Chem. Commun. 1982, 766.
(12) Hutchby, M.; Houlden, C. E.; Ford, J. G.; Tyler, S. N. G.;
Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem.,
́
Int. Ed. 2009, 48, 8721.
(13) In addition to a competing [3 + 2] with C7H10, a plausible
decomposition pathway involves dimerization of the imino-isocyanate
intermediate: for related reactivity, see: Lockley, W. J. S.;
Ramakrishnan, V. T.; Lwowski, W. Tetrahedron Lett. 1974, 2621.
(14) Recent exemples: (a) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.;
Shi, J.; Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard,
W. A., III; Guo, H.; Kwon, O. J. Am. Chem. Soc. 2011, 133, 13337 (and
cited references). (b) Hashimoto, T.; Kimura, H.; Kawamata, Y.;
Maruoka, K. Nat. Chem. 2011, 3, 642. (c) Shintani, R.; Fu, G. C. J. Am.
generated imino-isocyanate intermediate. In addition, a simple
fluorenone-derived reagent (2h) yields azomethine imine adducts
that can be converted into β-aminoamides and other derivatives
after mild reductive cleavage of the N−N bond. Improvements
and applications of this reactivity are under active investigation
and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures and characterization, revers-
ibility studies, computational details, X-ray crystal structures, and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
́
Chem. Soc. 2003, 125, 10778. (d) Suarez, A.; Downey, C. W.; Fu, G. C.
J. Am. Chem. Soc. 2005, 127, 11244. (e) Shintani, R.; Hayashi, T. J. Am.
Chem. Soc. 2006, 128, 6330. (f) Chen, W.; Yuan, X.-H.; Li, R.; Du, W.;
Wu, Y.; Ding, L.-S.; Chen, Y.-C. Adv. Synth. Catal. 2006, 348, 1818.
(g) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334.
(h) Shapiro, N. D.; Shi, Y.; Toste, F. D. J. Am. Chem. Soc. 2009, 131,
11654.
AUTHOR INFORMATION
Corresponding Author
andre.beauchemin@uottawa.ca
■
Notes
(15) For reviews, see: (a) Struckwisch, C. G. Synthesis 1973, 469.
(b) Rodina, L. L.; Kolberg, A.; Schulze, B. Heterocycles 1998, 49, 587.
(c) Schantl, J. G. In Science of Synthesis; Padwa, A., Bellus, D., Eds.;
Thieme Verlag: Stuttgart, 2004; Vol. 27, pp 731−824.
(16) Preliminary investigations with reagents 1a and 1d showed
reduced aminocarbonylation reactivity in comparison with reagent 2h.
Typically the use of solvent-free conditions and excess alkene with
reagents 1a and 1d provides higher yields of the azomethine imines.
(17) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C. T.;
Yang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (c) Schafer, A.;
Huber, C.; Ahlrichs, R. J. Chem. Phys. 1994, 100, 5829.
(18) For related reactivity, see: Magnus, P.; Garizi, N.; Seibert, K. A.;
Ornholt, A. Org. Lett. 2009, 11, 5646.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Ottawa, CCRI, CFI, the Ontario MRI,
NSERC (Discovery Grant and Discovery Accelerator Supplement
to A.M.B.) and AstraZeneca Canada for partial support of this
work. Support of related work by GreenCentre Canada is also
gratefully acknowledged. C.C. is thankful to NSERC (CREATE
on medicinal chemistry and biopharmaceutical development)
and OGS for scholarships and to AstraZeneca Canada for an
internship. W.G. thanks the University of Ottawa (Vision 2020
Postdoctoral fellowship). A.B. is thankful to NSERC (CGS-M).
We also thank Dr. Korobkov for X-ray crystallographic analyses.
(19) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki,
M. Angew. Chem., Int. Ed. 2000, 39, 1650.
(20) Alexakis, A.; Lensen, N.; Mangeney, P. Synlett 1991, 625.
(21) Li, L.-C.; Ren, J.; Liao, T.-G.; Jiang, J.-X.; Zhu, H.-J. Eur. J. Org.
Chem. 2007, 1026.
REFERENCES
■
(1) For a review, see: Kuhl, A.; Hahnl, M. G.; Dumic, M.; Mittendorf,
J. Amino Acids 2005, 29, 89.
(22) (a) Dorn, H.; Otto, A. Chem. Ber. 1968, 101, 3287. (b) Pezdirc,
L.; Glose
2008, 45, 181.
̌
lj, U.; Meden, A.; Stanovnik, B.; Svete, J. J. Heterocycl. Chem.
(2) For selected reviews, see: (a) Steer, D. L.; Lew, R. A.; Perlmutter,
P.; Smith, A. I.; Aguilar, M.-I. Curr. Med. Chem. 2002, 9, 811.
(b) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366.
(3) Disney, M. D.; Hook, D. F.; Namoto, K.; Seeberger, P. H.;
Seebach, D. Chem. Biodiversity 2005, 2, 1624.
(4) Review: Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206.
D
dx.doi.org/10.1021/ja305491t | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX