Transition-Metal-Free [4+3]-Cycloaddition of ortho-Quinone Methides and Isomünchnones: Catalytic and Diastereoselective Assembly of Oxa-bridged Oxazocine Scaffolds

Article abstract of DOI:10.1002/anie.201810760

Cycloadditions are powerful processes to synthesize complex polycyclic scaffolds. Herein, we disclose a [4+3]-cycloaddition between an in situ generated ortho-quinone methide and an isomünchnone to yield oxa-bridged oxazocine cores, generating N₂ and H₂O as the sole by-products. Using only catalytic amounts of camphorsulfonic acid, it is possible to generate both reactive intermediates in one step, eliminating the need for rhodium catalysts generally employed for isomünchnone formation. Spectroscopic data and X-ray crystallography indicate the formation of the syn diastereomer, with the main side-product arising from a hydrate participating in a competing [4+2]-cycloaddition pathway.

Full text of DOI:10.1002/anie.201810760

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Transition Metal-Free [4+3]-Cycloaddition of ortho-Quinone
Methides and Isomünchnones: Catalytic and Diastereoselective
Assembly of Oxa-bridged Oxazocine Scaffolds
Authors: Heather Lam, Zafar Qureshi, Marcus Wegmann, and Mark
Lautens
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810760
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10.1002/anie.201810760
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Transition Metal-Free [4+3]-Cycloaddition of ortho-Quinone Methides
and Isomünchnones: Catalytic and Diastereoselective Assembly of Oxa-
bridged Oxazocine Scaffolds
Heather Lam, Zafar Qureshi, Marcus Wegmann, and Mark Lautens*
Abstract: Cycloadditions are powerful processes to synthesize complex
polycyclic scaffolds. Herein, we disclose a [4+3]-cycloaddition between
an in situ generated ortho-quinone methide and an isomünchnone to yield
oxa-bridged oxazocine cores, generating N2 and H2O as the sole by-
product. Using only catalytic amounts of camphorsulfonic acid, it is
possible to generate both reactive intermediates in one step, eliminating
the need for rhodium catalysts generally employed for isomünchnone
formation. Spectroscopic data and X-ray crystallography indicate the
formation of the syn diastereomer, with the main side-product arising
from a hydrate participating in a competing [4+2]-cycloaddition
pathway.
Scheme 1. General [4+3]-cycloaddition reaction between in situ generated
isomünchnone with an ortho-quinone methide.
Highly-functionalized polycyclic oxazocines are known
to have a range of biologically relevant functions.[1] However,
bridged oxazocines have not been well documented in the
literature.[2] Herein, we report a facile method towards novel oxa-
Table 1: [4+3]-cycloaddition between 1a with a stable o-QM 2a.[a]
bridged oxazocine scaffolds through the acid-catalyzed in situ
formation of ortho-quinone methides (o-QM) and isomünchones.
Although [4+2]-cycloadditions of o-QMs and [3+2]-cycloadditions
of isomünchnones are well documented in the synthesis of common
heterocycles, [4+3]-cycloadditions of o-QM and isomünchnones
have yet to be explored.[3] We envisioned that with mild conditions,
either a rhodium- or acid catalyzed formation of isomünchnone int-
1 from diazoimide 1 could occur alongside the acid-catalyzed
formation of the o-QM int-2 generating only N2 and H2O as by-
products. The reactive intermediates int-1 and int-2 would
subsequently react in a [4+3]-cycloaddition to form a complex
polycyclic scaffold (Scheme 1).
Entry
Catalyst
Rh2(OAc)4
(+)-CSA
none
x mol%
3a [%][b]
28
37
-
1a [%][b]
5
-
99
2a [%][b]
1
2
3
1
5
-
-
-
24[c]
[a] Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.2 mmol, 1.0 equiv),
Rh2(OAc)4 (x mol%) or (+)-CSA (x mol%), PhH (5 mL), 20 h. [b] 1H NMR
yields shown using 1,3,5-trimethoxybenzene as an internal standard. [c] 2a
in solution forms dimers over time.
We commenced our studies by investigating the reactivity
with a stable o-QM. Though the isomünchnones formed from 1a are
not isolable, some electron-rich o-QMs such as 2a can be isolated as
an orange solid at room temperature. As a proof of concept for the
[4+3]-cycloaddition, we applied the standard Rh2(OAc)4 catalyzed
diazo decomposition conditions to a mixture of 1a with a stable o-
QM 2a (Table 1). Under these conditions, the reaction proceeded to
give the desired cycloadduct product 3a in 28% isolated yield (entry
1). Using 5 mol% (+)-camphorsulfonic acid (CSA) allowed us to
obtain a similar result with a slightly elevated yield of 3a (entry 2).
In the absence of catalyst, 1a could be recovered near quantitatively,
whilst 2a had mostly decomposed (entry 3). The relative
[*]
H. Lam, Dr. Z. Qureshi, Dr. M. Wegmann, Prof. Dr. M. Lautens*
Davenport Laboratories, Department of Chemistry
University of Toronto
Figure 1. X-ray crystal structure of 3a.
80 St. George St. Toronto, Ontario, M5S 3H6
E-mail: mlautens@chem.utoronto.ca
stereochemistry of 3a was determined by X-ray crystallography,
which indicated the syn diastereomer had formed, wherein the
bridging oxygen atom is on the same face as the aryl group
(Figure 1).[4]
Supporting information for this article is given via a link at the end of
the document
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Table 2: Optimization of acid-catalyzed [4+3] cycloaddition between in situ
generated isomünchnones with ortho-quinone methides.[a]
Entry
Cat.
x mol% 1a:2b
solvent
3b[%][b] 3b’[%][b]
1
2
3
4
5
(+)-CSA
A1
A2
A3
A4
p-TsOH
MsOH
none
(+)-CSA
(+)-CSA
(+)-CSA
(+)-CSA
(+)-CSA
5
5
5
5
5
5
5
-
5
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
2:1
2:1
2:1
2:1
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
60(58)
20(18)
35(31)[f]
40(38) [g]
15(12) [h]
45(41)
56(50)
n.r.
24
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.r.
19
0
17
21
21
Scheme 2. Literature precedent for the [4+3]-cycloaddition
6
It is known that the transition-metal catalyzed decomposition
of diazo compounds generates a metal carbenoid, which can undergo
diverse chemical reactions.[5] Specifically, reactions between metal
carbenes and 2π-systems have been thoroughly studied, often serving
as a facile method to access bridged polycyclic scaffolds through
[3+2]-cycloadditions.[6] In the past two decades, Padwa and co-
workers have extensively explored the utility of in situ generated
isomünchnones made by diazoimide decomposition through the
formation of a rhodium-carbene species (Scheme 2a).[7] The
neighboring carbonyl oxygen cyclizes onto the rhodium-carbene to
7
8[c]
9
69(64)
<5
50
10[d]
11[d]
12
13[e]
5
20
20
20
67(60)
1,2-DCE 74(78)
[a] 1a, 2b, catalyst (x mol%) were added to a 2 dram vial equipped with a
stir bar and dissolved in solvent, which was dried over 4Å MS (5 ml). The
mixture was stirred for 10 h. 1,3,5-trimethoxybenzene was added as an
internal standard for 1H NMR yield. [b] 1H NMR yields shown using 1,3,5-
trimethoxybenzene as an internal standard. Isolated yields in brackets.
Racemic mixtures were obtained unless otherwise stated. [c] Starting
materials isolated. [d] Powdered 4Å MS (5 mg) added. [e] Same result
achieved with (±)-CSA or (-)-CSA. [f] 4% ee. [g] 14% ee. [h] 15% ee. n.r., no
reaction; n.d., not determined.
form
a five- or six-membered isomünchnone. The resulting
isomünchnone often undergoes [3+2]-cycloadditions with
dipolarophiles, in either an inter- or intramolecular fashion, to form
complex polycyclic structures.
There are also reactions between metal-carbenes generated
from vinyldiazoacetates and 4π-systems, exemplified by the work of
Davies and co-workers. They have applied [4+3]-cycloadditions to
the synthesis of tropanes, and the total synthesis of (-)-5-epi-vibsanin
E, (+)-barekoxide and (−)-barekol (Scheme 2b).[8]
We tested conditions for the combination of 1a and 2b, a
naphthyl-based o-QM precursor (Table 2). Aside from the desired
product 3b, we also observed the formation of an unprecedented
cycloadduct 3b’, a hydrate of the isomünchnone formed from a
competing formal [4+2]-cycloaddition, in the presence of the H2O
generated
from
the
o-QM
decomposition.[14]
Though
Though alkenes are the most commonly encountered
dipolarophiles for isomünchnones, 4π-systems have yet to be
explored including o-QMs. o-QMs are useful building blocks in
organic synthesis, and can be made through various methods.[9] Since
the diazo-decomposition reactions are generally performed at room
or below-room temperature, we were interested in using mild
conditions for the in situ generation of o-QMs. Schneider and
Rueping demonstrated that chalcones could be synthesized from a
[4+2]-cycloaddition between an o-QM and a 1,3-diketone.[10]
Additionally, Schneider established that it is possible to react in
situ-generated o-QM with oxonium ylides to synthesize highly
functionalized chromans.[11] This sequence involved the phosphoric
acid-catalyzed generation of the o-QM and the Rh-catalyzed
decomposition of a diazoketone (Scheme 2c).
With the large body of work pertaining to transition metal-
catalyzed decompositions of diazoalkanes, acid-catalyzed methods
offer an inexpensive alternative.[12] Johnston and co-workers
demonstrated that the decomposition of diazoalkanes can be acheived
using Brønsted acids to yield similar products as their metal-
catalyzed counterparts. [13] The full potential of this approach has yet
to be delineated. We now report that Brønsted acid-catalysis can
serve as an alternate route to accessing the desired isomünchnones
formed from diazoimides, without the need for rhodium catalysts.
enantiomerically pure (+)-CSA was used, only racemic products
were obtained. Attempts to transfer chirality from chiral phosphoric
acids, A1-4, significantly lowered the yield of the desired product,
but revealed that up to 15% enantiomeric excess could be achieved
100
1a
2b
3b
3b'
90
80
70
60
50
40
30
20
10
0
0
5
10
t/h
15
20
Figure 2. 1H NMR monitoring of the reaction. Reaction conditions: 1a (1.0
equiv), 2b (1.0 equiv), (+)-CSA (5 mol%) and 1,3,5-trimethoxybenzene
(3 mg) was added to a 2 dram vial equipped with a stir bar, dissolved in
CD2Cl2 (0.05 M) and stirred 1 min. 1 mL of the mixture was used for study.
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10.1002/anie.201810760
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COMMUNICATION
forming faster than 3b’. Taking into account the relative rates of
decomposition of the starting materials, we concluded that increasing
the ratio of 1a to 2b would improve the overall yield of the reaction.
Consequently, the use of two equivalents of 1a resulted in an increase
in yield of 3b (entry 9). Our attempts to suppress the formation of 3b’
through the addition of 4Å MS lowered the yield of 3b even when
higher loadings of catalyst were used (entry 8-12). The use of drying
agents such as MgSO4 or Na2SO4 did not affect the yield of either
product. After a screen of various solvents, we found that using 1,2-
DCE further improved the yield of 3b to 78% (entry 13).
The substrate scope of the reaction was investigated with
various diazoimides 1 and o-QM precursors 2 leading to products in
generally good yields as single diastereomers (Scheme 2). Electron-
donating groups were well tolerated on the aryl ring furnishing
products 3c–3e in good yields. Electron-withdrawing halogen groups
or a CF3-group at the para- position were tolerated and gave 3f–3h.
When the halogen was located at the meta- position, there was a
significant decrease in yield (3i). ortho-Substituents inhibited the
reaction. The aryl group could be replaced by a heteroaromatic ring
such as thiophene to give 3j. However, when the aryl group was
replaced by a pyridyl ring, the reaction failed. A seven-membered
lactam-based diazoimide could be incorporated to afford 3k in
excellent yields, the structure of which was confirmed by X-ray
crystallography. Using an acyclic diazoimide, it was possible to
obtain the desired cycloadduct 3l.
We also explored the phenol-based o-QM precursors. The
yields were generally lower than the naphthol analogues. This
outcome may be due to faster decomposition of the o-QM precursor
or the o-QM, in comparison to the diazoimide. The parent
unsubstituted o-QM precursor reacted to afford a good yield of the
desired cycloadduct 3m. Electron-donating and withdrawing groups
were tolerated at the para position of the aryl ring and the quinone
ring (3n–r, u) with decreased yields. Interestingly, placing an ortho-
methoxy group on the quinone ring gave good yields of the
cycloadduct 3s. Using the seven-membered diazoimide, we could
obtain 3t and was able to confirm the structure of the side-product 3t’
through X-ray crystallography (Figure 6).
Based on the stereochemistry of the isolated diastereomer,
possible transition states are shown in Figure 3. We cannot say if the
reaction is stepwise or concerted. If the reaction is concerted, the
product could arise from a compact transition state between the E-
o-QM and the isomünchnone or through an extended transition state
between the Z-o-QM and the isomünchnone.
Scheme 2. Substrate scope of the acid-catalyzed cycloaddition of diazomide
1 and naphthol o-QM precursors 2. Reaction conditions: 0.4 mmol (2.0 equiv)
diazoimide 1, 0.2 mmol (1.0 equiv) ortho-hydroxybenzhydryl alcohol 2, and
(+)-CSA (5 mol%), DCE (4 mL), RT, 10h. Isolated yields shown. Yield of
byproduct shown in brackets. [a] Heated to 40 °C. [b] Run at 0.2 M.
using catalyst A4 (entries 2-5). Other sulfonic acids, such as p-TsOH
and MsOH, did not improve the yield of the reaction (entries 6-7).
1
To further our understanding of the decomposition pathway, a H
NMR study under standard reaction conditions was undertaken
(Table 2, entry 1, Figure 2). Our observations revealed that during
the reaction, 1a was converted to the isomünchnone faster than 2b
converted to the o-QM. Both products formed at the outset, with 3b
Figure 3. Possible transition states between the reactive intermediates
of [4+3]-cycloaddition for the formation of syn product 3b.
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COMMUNICATION
In summary, we have developed a reaction between two
non-isolable reactive intermediates, o-QMs and isomünchnones,
using a simple and economical acid catalyst under mild conditions to
generate new oxa-bridged oxazocine scaffolds. The results of the 1H
NMR study highlight the importance of the relative rates of
decomposition of the starting materials. Both naphthol and phenol
based o-QMs could participate in the reaction. The products are
obtained as a single diastereomer and arise from a formal [4+3]-
cycloaddition with good yields. Efforts to understand the reaction
mechanism using DFT calculations and studies toward the
enantioselective version of the reaction are underway.
53, 2768-2771. c) J. Xu, S. Yuan, J. Peng, M. Miao, Z. Chen,
H. Ren. Org. Biomol. Chem., 2017, 15, 7513-7517. d) L. Villar,
U. Uria, J. I. Martinez, L. Prieto, E. Reyes, L. Carrillo, J. L. Vicario.
For enantioselective NHC-catalyzed [4+3]-cycloadditions of
o-QM with α,β-unsaturated aldehydes: e) J. Izquierdo, A. Orue, K.
A. Scheidt. J. Am. Chem. Soc. 2013, 135, 10634-10637. f) H. Lv,
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[4] CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke,
2009 (http://www.cylview.org)
[5] a) M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds, Wiley,
New York, 1998. b) Q. Q. Cheng, Y. Deng, M. Lankelma, M.
P. Doyle, Chem. Soc. Rev., 2017, 46, 5425-5443. c) A. Ford,
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Candeias, R. Paterna, P. M. P. Gois, Chem. Rev., 2016, 116,
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H. Arman, M. P. Doyle, Angew. Chem. Int. Ed. 2017, 56,
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[6] a) A. G. Smith; H. M. L. Davies, J. Am. Chem. Soc. 2012, 134,
18241 b) Q. Q. Cheng; M. Lankelma; D. Wherritt; H. Arman;
M. P. Doyle, J. Am. Chem. Soc. 2017, 139, 9839. Prein, J. Org.
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Acknowledgements
The authors would like to thank the Natural Science Research
Council (NSERC), Alphora Inc., and the University of Toronto for
funding. We thank Prof. Dr. C. Schneider for the donation of chiral
phosphoric acid catalysts. We thank Dr. A. J. Lough for the single
crystal X-ray diffraction analyses. We also thank Dr. I. Franzoni and
the Centre for Advanced Computing for preliminary DFT studies. H.
Lam thanks NSERC for a PGSD and the CREATE program for
funding. Dr. Z. Qureshi thanks the Ontario government for a
Graduate Scholarship (OGS). Dr. M. Wegmann thanks the Deutsche
Forschungsgemeinschaft (DFG) for funding.
[7] a) A. Padwa, J. Org. Chem. 1989, 54, 817-824 b) M. P. Doyle;
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Conflict of interest
[8] a) B. D. Schwartz; J. R. Denton; Y. Lian; H. M. L. Davies; C.
M. Williams, J. Am. Chem. Soc. 2009, 131, 832; b) R. P. Reddy;
H. M. L. Davies, J. Am. Chem. Soc. 2007, 129, 10312; c) M.
Harmata, S. K. Ghosh, X. Hong, S. Wacharasindhu, P.
Kirchhoefer, J. Am. Chem. Soc. 2003, 125, 2058 – 2059.
[9] W. J. Bai; J. G. David; Z. G. Feng; M. G. Weaver; K. L. Wu;
T. R. R. Pettus, Acc. Chem. Res. 2014, 47, 3655–3664.
[10] a) O. El-Sepelgy, S. Haseloff, S. K. Alamsetti, C. Schneider,
Angew. Chem. Int. Ed. 2014, 53, 7923-7927, Angew. Chem.
2014, 126, 8057-8061 b) C. C. Hsiao, H. H. Liao, M. Rueping,
Angew. Chem. Int. Ed. 2014, 53, 13258-13263, Angew. Chem.
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[11] S. K. Alamsetti, M. Spanka, C. Schneider, Angew. Chem. Int.
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[12] For the review, see: J. N. Johnston; H. Muchalski; T, L. Troyer,
Angew. Chem. Int. Ed. 2010, 49, 2290-2298.
[13] For Brønsted acid catalysis to decompose diazoalkanes, see: a)
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[14] S. Muthusamy, C. Gunanathan, Chem. Commun. 2003, 0,
440-44
The authors declare no conflict of interest.
Keywords: acid catalysis • cycloaddition • diastereoselective
• diazo compounds • ortho-quinone methide • ylides
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Title
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Heather Lam, Zafar Qureshi, Marcus
Wegmann, Ivan Franzoni, Mark
Lautens*
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Transition-Metal Free [4+3]-
Text for Table of Contents
Cycloaddition of ortho-Quinone
Methides and Carbonyl Ylides: Catalytic
and Diastereoselective Assembly of
Novel Oxazocine Scaffolds
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