Enhancing the scope of the Diels-Alder reaction through isonitrile chemistry: Emergence of a new class of acyl-activated dienophiles

Article abstract of DOI:10.1021/ja303876e

α,β-Unsaturated imides, formylated at the nitrogen atom, comprise a new and valuable family of dienophiles for servicing Diels-Alder reactions. These systems are assembled through extension of recently discovered isonitrile chemistry to the domain of α,β-unsaturated acids. Cycloadditions are facilitated by Et₂AlCl, presumably via chelation between the two carbonyl groups of the N-formyl amide. Applications of the isonitrile/Diels-Alder logic to the IMDA reaction, as well as methodologies to modify the N-formyl amide of the resultant cycloaddition product, are described. It is expected that this easily executed chemistry will provide a significant enhancement for application of Diels-Alder reactions to many synthetic targets.

Full text of DOI:10.1021/ja303876e

Article
pubs.acs.org/JACS
Enhancing the Scope of the Diels−Alder Reaction through Isonitrile
Chemistry: Emergence of a New Class of Acyl-Activated Dienophiles
Steven D. Townsend,† Xiangyang Wu,† and Samuel J. Danishefsky*,†,‡
†Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York,
New York 10065, United States
‡Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, New York 10027, United States
S
* Supporting Information
ABSTRACT: α,β-Unsaturated imides, formylated at the nitrogen atom,
comprise a new and valuable family of dienophiles for servicing Diels−
Alder reactions. These systems are assembled through extension of recently
discovered isonitrile chemistry to the domain of α,β-unsaturated acids.
Cycloadditions are facilitated by Et2AlCl, presumably via chelation
between the two carbonyl groups of the N-formyl amide. Applications
of the isonitrile/Diels−Alder logic to the IMDA reaction, as well as methodologies to modify the N-formyl amide of the resultant
cycloaddition product, are described. It is expected that this easily executed chemistry will provide a significant enhancement for
application of Diels−Alder reactions to many synthetic targets.
During the course of those explorations, we discovered a
rather general process, which we have termed two-component
coupling (2CC), wherein carboxylic acids 4 react with isonitriles
5, generally under microwave activation, to afford N-formyl
amides corresponding to 7, presumably via 1,3-O→N acyl
shift of the intermediate formimidate−carboxylate mixed
anhydride (FCMA, eq 2). In this connection, we wondered
INTRODUCTION
■
Powerful as the Diels−Alder (DA) reaction is as a resource in
chemical synthesis,1−4 it is certainly not without its limitations.
Our laboratory, at various levels over the years, has been involved
in addressing some of these limitations in an attempt to raise the
overall applicability of DA logic. Our earliest works focused on
the synthesis of, then-novel, dienes which would impart to their
cycloaddition products easily exploitable, complexity-enhancing
access points.5 More recently, through the use of appropriate
dienophiles, we have been able to encompass trans junctions
within the scope of DA logic.6,7 We have also shown how to use
Diels−Alder-initiated schemes to gain entry to double bond pat-
terns, isomeric with those available from the DA reaction, itself.
The limitation that we address in this contribution has to do
with well-established (though not fully appreciated) erosion of
dienophilic activity with even, seemingly, modest levels of steric
hindrance, particularly at the β-carbon of the dienophile (eq 1).
whether an α,β-unsaturated acid 8, upon reaction with
an isonitrile (5), would give rise to 10 via the corresponding
α,β-unsaturated FCMA, 9. Not unnoticed was the possibility that
9 would not advance to 10, but might instead undergo a formal
[3,3] sigmatropic shift, leading to a ketene-bearing structure
(eq 3).
The results of early probing of this question are shown in Table 1,
wherein a range of α,β-unsaturated carboxylic acid substrates readily
were converted to the corresponding acrylic N-formyl amides in
high yield.14 At least at present, we have not seen any positive
evidence of products arising from [3,3] sigmatropic shift, although
For instance, α,β-unsaturated acyl-activated dienophiles (1, A =
acid, ester, or amide) are relatively weakly reactive to thermally
induced cycloaddition. When the acyl group is bound to a tri-
substituted double bond, contained in a cyclene motif, DA
reactivity can be quite sluggish (cf. 2→3).8−10 This is a trou-
blesome limitation because it complicates the use of DA logic to
synthesize angularly substituted cis-fused bicyclic motifs (cf. 3) in
a facile way.
In a totally unrelated vein, we had been investigating some
Received: April 23, 2012
Published: June 18, 2012
important, but hitherto overlooked, chemistry of isonitriles.11−13
© 2012 American Chemical Society
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Happily, cycloaddition was nicely promoted by Et2AlCl.20
Thus, treatment of 1,3-cyclohexadiene and dienophile 10a with
2.5 equiv of Et2AlCl at room temperature afforded the DA
adduct, 12a in 70% yield and greater than 30:1 endo selectivity
(entry 3).21 An excess of Lewis acid was used in these reactions in
order to ensure bidentate coordination of the imide. As found by
the Evans laboratory in their investigations of the oxazolidi-
nones,22 we observed prohibitively slow reaction when sub-
stoichiometric amounts of Lewis acid were used. The efficiency
of this transformation is of particular note, as both cinnamates
and 1,3-cyclohexadiene are generally relatively unreactive part-
ners in DA reactions.23 In order to confirm that the high reac-
tivity, in this case, arose from the presence of the imide func-
tionality, a control experiment was performed. Thus, 10a was
deformylated, in the presence of ammonia, to generate amide 11.
As expected,24 11 did not undergo DA cycloaddition with 1,3-
cyclohexadiene under Lewis acid conditions (entry 4).
a
Table 1. Synthesis of Acrylic N-Formyl Amides
a
Key: Cyc = cyclohexyl.
Having defined effective conditions to achieve DA reaction
in the cinnamate case, we next examined their applicability to
other cases. As outlined in Table 3, dienophile 10a undergoes
the mode of progression of the hypothetical ketene, were it formed,
is unclear.
We were now in a position to evaluate whether α,β-unsaturated
N-formylamides, of the type 10, might serve as useful new versions
of α,β-acyl-activated dienophiles. In this discussion we distinguish
between acyl (A, in structures 1 and 2) and aldehydo-activated
dienophiles (i.e., A = formyl). The unique opportunities in
aldehyde activation, pioneered by the MacMillan school,15−17
will be discussed below. In particular, we were hoping that the
N-formylamide motif might enhance dienophilicity, thereby over-
coming the type of steric hindrance problems described
above. It was hoped that the electron withdrawing effect of
the formyl group would enhance the dienophilicity of 10
relative to that of a simple amide. Moreover, obvious
possibilities for chelation-based Lewis acid promotion
presented themselves.
Table 3. Scope studies
We began by exploring strictly thermal conditions to imple-
ment cycloaddition of 10a with 1,3-cyclohexadiene (Table 2).18
a
Table 2. Diels-Alder Reactions
entry
dienophile
catalyst
temp.
time (h) yield (%)
b
1
2
3
4
10a, R = CHO none
reflux
12
24
4
30
0
a
b
Three equivalents of diene was used in these reactions. endo:exo
11, R = H
none
120 °C
c
12e = 4:1; 12d = 25:1, 12g = 20:1, 12i = 20:1.
10a, R = CHO Et2AlCl (2.5 equiv) 23 °C
70
0
c
11, R = H
Et2AlCl (2.5 equiv) 23 °C
24
a
b
c
CF3CH2OH, rt→reflux. toluene, 120 °C. CH2Cl2, o→23 °C 3 eq.
cycloaddition with a range of diene coupling partners to pro-
duce adducts 12b−12d in high yield. Notably, the α-substituted
methacryl N-formyl amide, 10b, also served as a productive
coupling partner, providing cycloadducts 12e and 12f in high
yield and generally high stereoselectivity. The relatively modest
endo selectivity (4:1) observed in the particular case of the for-
mation of 12e is not surprising, given the known propensity of
methacryl dienophiles to undergo competitive exo cyclo-
addition.25 Happily, a β-substituent is nicely tolerated (see for-
mation of 12g). Not surprisingly, the challenging β,β-disub-
stituted dienophile, 10d, failed to provide DA adduct after 12 h at
room temperature.26 Upon warming to 40 °C and stirring for an
of cyclohexadience were used in these studies.
For these thermal runs, we used trifluoroethanol as the solvent.
In recent work in our laboratory, use of this solvent served to
lower the temperature requirement for uncatalyzed cyclo-
addition, possibly due to reactivity enhancing interactions with
the dienophile activators.6 After 12 h at reflux, ∼30% of 10a had
undergone cycloaddition.19 While this is far from impressive, we
noted that the corresponding N-deformylated compound, 11,
upon attempted cycloaddition with the same diene, gave no
observable Diels−Alder product (entry 2).
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a
additional 6 h, ∼10% of product 12h was detected. Finally,
we examined the reactivity of 1-cyclohexene-1-N-formyl
amide 10e. In the context of DA chemistry, the analogous
1-cyclohexenecarboxylate is a highly sluggish dienophile.27 In
contrast, the N-formyl amide-activated dienophile, 10e,
smoothly undergoes Et2AlCl-mediated cycloaddition with both
cyclohexadiene and 2,3-dimethyl-1,3-butadiene to generate
adducts 12i and 12j, respectively.28
Scheme 1. Functionalization of N-Formyl Amides Adducts
Having demonstrated that α,β-unsaturated N-formyl amides,
under Lewis acid promotion, provide exploitable reactivity in DA
chemistry, we thought it of interest to compare the dienophilicity
of systems such as 10 with conventional dienophilic activators
that have enjoyed long-term usage. For this purpose, we con-
ducted a series of experiments, wherein an N-formyl amide-
activated dienophile competes with conventional acyl activators
in the same reaction flask. We also compared the N-formyl amide
with its corresponding aldehyde.
a
Key: (a) (i) NaBH4, MeOH (ii) Et3SiH, TFA, CH2Cl2 (iii) LDA,
BH3NH3, THF. 74% over three steps (b) NH3, MeOH, >95%.
(c) LAH, Et2O, 90%.
As seen in Table 4, the dienophilicity of the N-formyl amide 10
totally dominated the course of the cycloaddition relative to
Table 4. Diels-Alder Competition Studies
Figure 1. IMDA.
tested the possibility that the acyl group could be attached to
the diene (cf. 21), while the isonitrile moiety might bear the
dienophilic element (22). In this setting, the N-formyl amide
would serve to activate the diene of 23, thereby promoting an
inverse-demand type IMDA cycloaddition to yield a comple-
mentary set of cycloadducts (cf. 24).31−33
a
2.5 equiv of Et2AlCl; 1 equiv of cyclohexadiene, CH2Cl2; 3 h; 0 °C→rt.
We first examined the feasibility of the normal demand IMDA.
Thus, compound 25 was prepared from the commercially
available primary amine.34 Subsequent 2CC with 26 provided
IMDA substrate, 27 (Scheme 2). Notably, formation of small
potential competition from ester-, acid-, and amide-activated
cinnamates (entries 1−3). In the monocarbonyl series, the only
discernible competition (∼1:13) arose from trans-cinnamalde-
hyde (entry 4). We also note that, in contrast to the aldehyde,
which provides an endo:exo mixture, the corresponding reaction
with 10a appears to afford only the endo diastereomer. In a direct
competition experiment, the N-formyl amide 10a was found to
possess levels of reactivity equivalent to the well-established
oxazolidinone-activated dienophile (entry 5).29
Scheme 2. IMDA with Acrylic N-Formyl Amides
It was important to address questions as to the manipulability
of the N-formyl amide in the DA product. The N-formyl amide
motif may be readily converted to a range of traditional func-
tional groups. For example, the facile three-step conversion
of cycloadduct 12a to alcohol 14 and amide 15 is shown in
Scheme 1.30 The amide can be further reduced to amine 16.
We next envisioned expanding this technology to enable the
rapid synthesis of complex polycyclic systems (cf. 20 and 24,
Figure 1). This would be accomplished by coupling of “value
added” isonitrile and carboxylic acid substrates, followed by intra-
molecular Diels−Alder (IMDA) cycloaddition. In one potential
application, installation of the diene coupling partner on the
isonitrile functionality (17) would serve to generate, following
2CC with an α,β-unsaturated acid, a potential IMDA substrate,
19. Subsequent Lewis acid-mediated cyclization would provide
access to bicyclic systems of the type 20. Alternatively, we field
amounts of IMDA cyclization adduct was already observed
following the microwave irradiation of the 2CC reaction. Upon
treatment with Et2AlCl, the substrate readily underwent cycliza-
tion to furnish tricyclic adduct 28 as a single diastereomer. We next
investigated the feasibility of the proposed inverse demand IMDA
sequence. Intermediate 31 was thus readily prepared through
2CC of acid 29 and isonitrile 30.35 Subsequent Et2AlCl-mediated
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cyclization delivered 32 as the main product in good yield as a
single observable diastereomer.
spectroscopic assistance, to Rebecca Wilson for preparation of
the manuscript, and to Dr. Suwei Dong for helpful discussions.
During the course of these studies we were certainly sen-
sitive to the opportunities offered by the oxazolidinone type of
dienophilic activation pioneered by Evans and associates.22
Inherent in Evans’ results was the recognition that activation by
imide-based dienophiles surpasses that of the usual acyl type
activators. Moreover, the very elegant adaption of such auxiliaries
to the attainment of high levels of diastereo- and enantioselection
has been of great utility. Also compelling has been the applica-
tion of organocatalysis, resulting in major enhancement of the
dienophilic propensities of α,β-unsaturated aldehydes and
ketones, described by MacMillan.15−17 Here also, high levels of
enantioselection, arising via diastereo-differentiated transition
states, magnified the power of the catalysis. While one can imagine
corresponding opportunities for high enantioselection with type 10
dienophiles, we have, presently, not achieved acceptable levels of
induction. Rather, the value of the chemistry described above lies in
its ability to merge complex functionalities in putative diene and
dienophile sectors, by the 2CC reaction, thereby enhancing the level
of molecular complexity available by this logic, while providing
ample “machinery” for conducting the projected DA cyclo-
addition. The critical part of the DA-enabling machinery is the
N-formyl group. Following DA cycloaddition (either inter- or
intramolecular see Table 3 and Scheme 2, respectively), the
N-formyl group, if extraneous to the target, is quickly discharged,
leaving the rest of the complexity-enhancing functionality
in place. Ongoing research is directed to building upon the
paradigm, captured in Figure 2, while also seeking to gain high
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Figure 2.
enantiocontrol through appropriate catalytic guidance via
diastereo-differentiating transition states. Results will be reported
in due course.
ASSOCIATED CONTENT
* Supporting Information
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Wiley: New York, 1990.
■
S
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AUTHOR INFORMATION
Corresponding Author
s-danishefsky@ski.mskcc.org
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10a with cyclohexadiene to afford a 72% yield of 12a. The isolated yield
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH Grant HL25848 (S.J.D.).
S.D.T. is grateful to Weill Cornell for an NIH Postdoctoral
Fellowship (CA062948). Special thanks to Dr. George Sukenick,
Hui Fang, and Sylvi Rusli of SKI’s NMR core facility for
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of this large-scale reaction is similar to that obtained on 0.1 mmol scale
(see Table 2). See Supporting Information for details.
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