Computational and 13C investigations of the diazadienes and oxazadienes formed via the rearrangement of methylenecyclopropyl hydrazones and oximes

Article abstract of DOI:10.1021/ol501710m

Computational and further experimental investigations of the previously reported diazadienes, obtained via the rearrangement of methylenecyclopropyl hydrazone 1 are reported. Calculations at the CCSD(T)/cc-pVTZ//B3LYP/6-31G(d) level of theory indicate tha

Full text of DOI:10.1021/ol501710m

Letter
pubs.acs.org/OrgLett
13
Computational and C Investigations of the Diazadienes and
Oxazadienes Formed via the Rearrangement of
Methylenecyclopropyl Hydrazones and Oximes
Bo Chen,† Mark E. Scott,‡ Bruce A. Adams,‡ David A. Hrovat,† Weston Thatcher Borden,*,†
and Mark Lautens*,§
†Department of Chemistry and Center for Advanced Scientific Computing and Modeling (CASCaM), University of North Texas,
1155 Union Circle, #305070, Denton, Texas 76203-5070, United States
‡Merck Research Laboratories, Boston, Massachusetts 02115, United States
§Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario Canada, M5S 3H6
S
* Supporting Information
ABSTRACT: Computational and further experimental investiga-
tions of the previously reported diazadienes, obtained via the
rearrangement of methylenecyclopropyl hydrazone 1 are reported.
Calculations at the CCSD(T)/cc-pVTZ//B3LYP/6-31G(d) level of
theory indicate that the initially reported product 3 would, if formed,
undergo rapid electrocyclic ring opening and, hence, would be
unstable under the reaction conditions. Based on this computational
prediction, further analysis of the 13C NMR spectrum, previously
attributed to 3, led to the revision of structure 3 to that of its N-
tosylaminopyrrole constitutional isomer 11. Similarly, structure 8,
formed in the rearrangement of oxime 6, was revised to that of N-
hydroxypyrrole 12.
azadiene 2 in good yield, while reaction of 1 at high
temperature with MgCl2/TMEDA was reported to yield the
constitutional isomer 3.
wing to their strained cyclopropane rings and alkene
Ofunctionality, methylenecyclopropanes (MCPs) and their
analogues represent versatile synthetic building blocks for a
wide range of Lewis and Brønsted acid catalyzed, as well as
transition-metal-mediated transformations.1 One of the syn-
thetically beneficial properties of these strained carbocycles is
the ability of a common MCP building block to undergo
reactions by different pathways, depending on the reaction
conditions used.2 This type of reaction path control enables
access to a range of different products from a common
precursor.
In 2007, two of us (M.E.S. and M.L.) reported the utilization
of this type of product control in the rearrangement of activated
MCP hydrazones, catalyzed by different Lewis acids under
different reaction conditions (Scheme 1).3 In the presence of
MgI2, rearragement of 1 was found to furnish the cyclic
More recently, as part of a study of reactions that might
involve heavy-atom tunneling,4 three of us (B.C., D.A.H., and
W.T.B.) investigated computationally the electrocyclic ring
opening reactions of heterocyclic analogs of 1,3-cyclohexadiene,
in which a weak bond between two heteroatoms cleaves. Such
reactions would be expected to have low barriers and to involve
only minimal amounts of motion of the two heteroatoms,
conditions that should be conducive to tunneling.
In the course of this study, we carried out calculations on the
electrocyclic ring opening reactions of hydrazone 4 and
hydrazine 5, in which the tosyl and two methyl groups of 2
and 3 are replaced by hydrogens (Figure 1). We also performed
calculations on the analogous reactions of oxime 9 and
alkoxyamine 10 (Figure 2).
Geometries were optimized and vibrational analyses and
tunneling calculations were performed with the B3LYP
functional5 and the 6-31G* basis set.6 Single-point energies
were obtained at the CCSD(T) level of theory,7 using the cc-
pVTZ basis set.8 Small curvature tunneling calculations were
carried out using POLYRATE.9 All of the other calculations
were performed with Gaussian 09.10
Scheme 1. Divergent Rearrangements of MCP Hydrazone 1
Received: June 12, 2014
Published: July 22, 2014
© 2014 American Chemical Society
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Letter
10 is much lower than the barrier to the 1,5-hydrogen shift that
would convert 10 to 9.
The very low barrier to electrocyclic ring opening of 10 and
the small amount of heavy-atom motion that is required in this
reaction suggested that tunneling could make this reaction very
fast, even at cryogenic temperatures. In fact, below 30 K the
temperature-independent rate constant for ring opening by
tunneling from the lowest vibrational level of 10 was computed
to be 4.4 × 104 s−1. The calculated half-time of ca. 10−5 s for the
disappearance of 10 at cryogenic temperatures rules out the
possibility of isolation of 8 via rearrangement of 6 at 120 °C
(Scheme 2).
Based on the results of these calculations, we revisited the
structural assignment of compounds 2, 3, 7, and 8. Further
analysis of the spectroscopic data for 2, which involved
Figure 1. CCSD(T)/cc-pVTZ//B3LYP/6-31G(d) relative enthalpies
and enthalpies of activation, both in kcal/mol.
1
comparison between both expected and predicted H and 13C
NMR, confirmed the initially reported structure.3 Further
confirmation of this assignment was obtained by single crystal
X-ray analysis.11 However, upon re-examination of 3, slight
discrepancies were evident between the observed and predicted
13C NMR spectra (Table 1). While the majority of the
a
b
Table 1. Experimental versus Predicted 13C NMR
Chemical Shifts (ppm) for 3 and 11
Figure 2. CCSD(T)/cc-pVTZ//B3LYP/6-31G(d) relative enthalpies
and enthalpies of activation, both in kcal/mol.
Our computational results for 4 and 5 are summarized in
Figure 1. Hydrazone 4 is calculated to be thermodynamically
stable to both electrocyclic ring opening and to the 1,5-
hydrogen shift that would convert it to 5. Hydrazine 5 could
rearrange to 4 by the latter pathway, but the barrier to this
reaction is calculated to be 20.4 kcal/mol higher than the
barrier to electrocyclic ring opening of 5.
The low calculated barrier to electrocyclic ring opening of 5
should make this reaction very fast at 120 °C, the temperature
of the reaction from which 3 was purportedly isolated. The
calculated rate constant for electrocyclic ring opening at this
temperature is k = 6.3 × 102 s−1, giving 5 a lifetime on the order
of 10−3 s at 120 °C. Thus, our calculations rule out the
possibility that a derivative of 3, such as 5, could have been
isolated from a reaction conducted at this temperature.
In a reaction, analogous to the rearrangement in Scheme 1,
treatment of MCP-oxime 6 with MgCl2/TMEDA was reported
to give rise to oxime 7 and hydroxylamine 8 (Scheme 2).3 In
Scheme 2. Rearrangement of MCP Oxime 6
a
b
In CDCl3 at 600 MHz. 13C NMR predictions obtained using ACD
Laboratories Prediction + DB Version 12.5.12
experimentally observed values closely matched the predicted
13C shifts, small but significant differences between the
predicted and observed 13C shifts for methyl groups a and e
were found (Table 1).
order to assess the thermodynamic and kinetic stabilities of 7
and 8, we performed calculations on the unsubstituted
compounds 9 and 10. The results of our calculations are
summarized in Figure 2.
Oxime 9 is calculated to be thermodynamically stable to both
electrocyclic ring opening and to rearrangement to 10. In
contrast to 9, 10 can undergo two thermodynamically favorable
reactions. However, the barrier to electrocyclic ring opening of
Using the experimentally observed 13C shifts, we then
reconsidered other related constitutional isomers of 3 and
found that the 2,4-dimethyl pyrrole isomer 11 provides a better
fit to the 13C NMR data. We note that, following our initial
publication in this area, a subsequent report by Shi and co-
workers proposed similar analogues of 11 to be formed via an
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Letter
analogous rearrangement of methylene substituted MCP
hydrazones.13 In these examples, the related methyl-substituted
analogues showed chemical shifts (12 ppm) that are close to
what we also predict and observe for 11.
nitrogen would afford the five-membered ring in D. Proton
transfer would then give 11.
In summary, based upon our computational results and 13C
NMR analyses, we revise the originally assigned structure of the
second product of the rearrangement of 1 in Scheme 1, from 3
to 11 (Table 1), and the originally assigned structure of the
second product of the rearrangement of 6 in Scheme 2, from 8
to 12 (Table 2). These revisions illustrate that calculated
energies can play an important role in assessing the viability of
possible structures that are provisionally assigned to the
products of organic reactions.
1
Similarly, while re-examinination of the H and 13C NMR
data for 7 was found to be consistent with the initially proposed
structure,3 comparison of the experimentally observed 13C
chemical shifts for 8 with the predicted values revealed even
larger differences than those between the observed and
predicted chemical shifts for the methyl groups in 3. Especially
large deviations were found between the observed and
predicted 13C chemical shifts for sp2 hybridized carbons b, d,
and f, leading us to revise the structure, originally assigned to 8,
to that of the N-hydroxypyrrole derivative 12 (Table 2).
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra, CIF file for compound 2, calculated rate
constants and geometries, and absolute energies of calculated
structures. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
b
Table 2. Experimental versus Predicted 13C NMR
Chemical Shifts (ppm) for 8 and 12
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: borden@unt.edu.
*E-mail: mlautens@chem.utoronto.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The calculations at UNT were supported by Grant CHE-
0910527 from the National Science Foundation and Grant
B0027 from the Robert A. Welch Foundation. We thank Dr.
Alan Lough (University of Toronto) for help in determining
the X-ray structure for compound 2.
a
b
In CDCl3 at 600 MHz at −40 °C. 13C NMR predictions obtained
using ACD Laboratories Prediction + DB Version 12.5.12
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