Synthesis of cyclopropanated [2.2.1] heterobicycloalkenes: An improved procedure

Article abstract of DOI:10.1080/00397911.2015.1118124

A safer and improved method to our previous report on palladium-catalyzed cyclopropanation of heterobicyclic alkenes has been developed. By using tetrahydrofuran as the solvent and a more dilute aqueous NaOH solution for the generation of diazomethane fro

Full text of DOI:10.1080/00397911.2015.1118124

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Synthesis of cyclopropanated [2.2.1]
heterobicycloalkenes: An improved procedure
Emily Carlson, Guillaume Duret, Nicolas Blanchard & William Tam
To cite this article: Emily Carlson, Guillaume Duret, Nicolas Blanchard & William Tam (2016)
Synthesis of cyclopropanated [2.2.1] heterobicycloalkenes: An improved procedure, Synthetic
Communications, 46:1, 55-62, DOI: 10.1080/00397911.2015.1118124
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Date: 23 January 2016, At: 23:04

SYNTHETIC COMMUNICATIONS®
2016, VOL. 46, NO. 1, 55–62
http://dx.doi.org/10.1080/00397911.2015.1118124
Synthesis of cyclopropanated [2.2.1] heterobicycloalkenes: An
improved procedure
Emily Carlsona, Guillaume Duretb, Nicolas Blanchardb, and William Tama
aGuelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry,
b
University of Guelph, Guelph, Ontario, Canada; Université de Strasbourg, Laboratoire de Chimie Moléculaire,
CNRS UMR 7509, Strasbourg, France
ABSTRACT
ARTICLE HISTORY
Received 21 October 2015
A safer and improved method to our previous report on palladium-
catalyzed cyclopropanation of heterobicyclic alkenes has been
developed. By using tetrahydrofuran as the solvent and a more dilute
aqueous NaOH solution for the generation of diazomethane from
Diazald, cyclopropanation could be achieved smoothly with minimal
adjustment over the course of reaction. 7-Oxabicyclic substrates with
bulky C1 or C2 groups, as well as 2,3-diazabicyclic substrates with
various N-substituents, effectively underwent cyclopropanation. Using
this methodology, yields to previously reported products were
markedly increased, and 10 new cyclopropanated [2.2.1] heterobicyc-
lic products were prepared. In addition, this work accounts for the first
reported cyclopropanation of 2,3-diazabicyclic alkenes, which all gave
excellent yields of >90%.
KEYWORDS Bicycloalkene;
cyclopropane; diazo
compounds; palladium
GRAPHICAL ABSTRACT
Introduction
Cyclopropanes are present in a variety of natural products of plant, fungal, and bacterial
origin,[1] and recently their stereoselective synthesis has received much attention in the
context of biological activity studies.[2,3] The high ring strain and reactivity of cyclopro-
panes makes them key intermediates for further transformations and appealing building
blocks to more complex structures.[4,5] Numerous methodologies exist for the preparation
of cyclopropanated carbobicycloalkenes,[6–11] while the cyclopropanation of heterobicy-
cloalkenes has proved more challenging, with only a limited number of publications to
date.[12–14] Inspired by the work of Miller and Ji,[13] our group has recently succeeded in
the first Pd(OAc)2-catalyzed cyclopropanation of 7-oxabenzonorbornadienes, demonstrating
CONTACT William Tam
wtam@uoguelph.ca
Guelph-Waterloo Centre for Graduate Work in Chemistry and Bio-
chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher's website.
© 2016 Taylor & Francis

56
E. CARLSON ET AL.
Scheme 1. Previously reported cyclopropanations of 7-oxabenzonorbornadienes.
steadfast exo stereocontrol of cyclopropanation and broad applicability to variously substi-
tuted aromatic and C1-substituted oxabenzonorbornadiene derivatives (Scheme 1).[15] In
addition, we have reported on several transformations which these novel systems can
undergo.[16,17]
In our previous report on cyclopropanation, however, we were faced with some pro-
cedural challenges: namely, the need to supply additional solvent to the reaction vessel dur-
ing reaction; incomplete consumption of starting material, potentially due to low solubility
of the substrate in Et2O; and minor complications with the addition of a viscous 50% w/v
NaOH solution over time. The current work documents a safer and improved procedure to
our former cyclopropanation methodology, where the two principle modifications
described in this paper are (1) change in reaction solvent and (2) dilution of the aqueous
NaOH solution used. In addition, the present work expands the scope of the reaction and
introduces the first examples of the palladium-catalyzed cyclopropanation of other [2.2.1]
heterobicycles, including 2,3-diazabicyclo-5-heptenes, as well as a hetarene-containing 7-
oxabicyclic alkene. The precursor bicycloalkenes that were cyclopropanated in this study
were prepared following literature procedures of [4 þ 2] cycloadditions between either fur-
ans or cyclopentadiene with the appropriate dienophile.[18–23]
Discussion
Upon our attempt to cyclopropanate compound 1d (Z ¼ tetramethylsilane [TMS],
Scheme 2) we found that the substrate did not dissolve well in Et2O, which was the solvent
previously employed for these reactions. Probing the literature, it appeared that the use of
other solvents was not uncommon in reactions employing diazomethane.[24,25] After
screening the solubilities of substrates in some of these solvents, it appeared that tetrahy-
drofuran (THF) in fact did a better job of solubilizing several of the alkenes. Use of THF
suggested another potential benefit: Because it is higher boiling than Et2O, evaporation
could be minimized and thus periodic addition of solvent by syringe, which could poten-
tially scratch the glassware or expose the chemist to small amounts of gas generated, could
be avoided. We also found that by using a more dilute 25% w/v solution and increasing the
dropping rate, the addition was smoother and could be left to be monitored less frequently.
Accordingly, the glassware dimensions were modified slightly, as well (Figure 3).
These modifications led to improved yields in compounds 2a–c, which were presented
in our former report,[15] as well as successful production of seven new cyclopropanated
oxabicycloalkenes 2d–j, each giving good to excellent yields. The substrates bearing bulky
C1-substituents including tert-butyl and trimethylsilyl underwent cyclopropanation, pro-
viding appreciable yields of 85% and 75% of cyclopropane 2c and 2d, respectively. Cyclo-
propane 2e with both bridgehead and arene substitution also gave a good yield (82%), as
did cyclopropane 2f with a long-chain bridgehead ethyl ester substituent (81%). Unlike all

SYNTHETIC COMMUNICATIONS
57
a
Scheme 2. Cyclopropanation of C1-, C2-, and arene-substituted 7-oxabicycloalkenes 1a–j. Isolated
b
yields after column chromatography. Isolated yields reported in former study (Et2O solvent).
other cyclopropanes, which showed a singlet for bridgehead proton Ha, cyclopropane 2f
1
showed a doublet at 5.04 ppm with J ¼ 2.3 Hz. H NMR coupling constants of bridgehead
proton Ha to cyclopropyl proton Hb allowed us to deduce the dihedral angle of Ha-C-C-Hb,
and the stereochemistry for each cyclopropane (Fig. 1). For the exo isomer, J values of 0–
2 Hz are expected, whereas for the endo isomer a dihedral angle of ∼42° and a coupling
constant of ∼5 Hz is expected.[26–28] The coupling seen in the present study for 2f is suffi-
ciently close to J ¼ 2 Hz that the cyclopropane was concluded to be exo with respect to the
[2.2.1] bicyclic framework, and this was even more obvious with all other cyclopropanated

58
E. CARLSON ET AL.
Figure 1. Dihedral angle analysis of exo and endo cyclopropanes 2a–j.
oxabicyclics, which showed no observable splitting for the peak of Ha. In addition, tetra-
deuterated cyclopropane 2 g was obtained in good yield of 85%, comparable to the undeut-
erated parent compound 2a.
Next, cyclopropanations on substituents at the C2-position were attempted, to examine
the effect of substituent proximity to the cyclopropanation site. Although both C2-elec-
tron-donating and electron-withdrawing substrates 1h and 1i required a larger amount
of diazomethane for cyclopropanation (6 equivalents for 1h and 8 equivalents for 1i), each
alkene underwent cyclopropanation to afford the corresponding exo cyclopropanated pro-
duct in desirable yields (94% and 72%, respectively). The yield observed for product 2i
was in good agreement with a known cyclopropanation of a similar C2-substituted 7-oxa-
norbornene (lit. 70% for two steps).[14] Finally, substrate 1j with a fused pyridyl ring also
underwent cyclopropanation successfully, suggesting that the scope of this work could be
further broadened to other hetarene-containing bicyclic substrates.
By repeating Miller and Ji’s cyclopropanation using the current modified conditions on
2-oxa-3-azabicyclic alkene 3,[13] we were able to reduce both the quantity of diazomethane
(from 8 equivalents to 2.6 equivalents) and catalyst loading (from 5 mol% to 1 mol%).
Furthermore, we showed that the reaction proceeded equally well in THF as in Et2O
(Scheme 3), giving an isolated yield of 97% relative to the previously reported 96%.
As there was no precedent of 2,3-diazabicyclic alkene cyclopropanation, we decided to
examine these substrates, as well.
Not surprisingly, cyclopropanation of bicyclic hydrazines 5a–c bearing various N-sub-
stituents all gave excellent yields of cyclopropanes 6a–c (Table 1). Because of the highly
fluxional nature of the nitrogen-containing framework of 6a–c, peaks were broadened
1
with lower intensity in H and 13C NMR experiments. Thus, although the presence of
4J-coupling (W-coupling) between Ha and Hb could not be verified, irradiation of Hc in
a selective gradient nuclear Overhauser effect spectroscopy (NOESY) experiment on 6a
unambiguously showed positive enhancement for the peak belonging to Haʹ(as well as
for the peak of Hcʹ), proving exo stereochemistry of the cyclopropane ring (Fig. 2).[29]
As with compound 4, it is conceivable that the products 6a–c obtained in this work could
be ring opened to afford nucleoside derivatives, which are key intermediates for the devel-
opment of antiviral and antitumor agents.[13]
Scheme 3. Cyclopropanation of 2-oxa-3-azabicycloalkene 3.

SYNTHETIC COMMUNICATIONS
59
Table 1. Cyclopropanation of N-substituted bicyclic [2.2.1] hydrazenes 5a–c.
Alkene
R
Product
Yield (%)a
1
2
3
5a
5b
5c
COOtBu
COOiPr
COOCH2Ph
6a
6b
6c
95
94
98
aIsolated yield after column chromatography.
The mechanism of palladium-catalyzed cyclopropanation of alkenes is believed to occur
in a stepwise manner,[30] which is consistent with computational work at the B3LYP level
of theory.[31] The Pd(OAc)2 precatalyst is reduced to its active Pd(0) state (A, Scheme 4)
which then coordinates to the reactant alkene in a bridged η2 fashion. This initial palladium
complex is in equilibrium with the diazomethane-bound intermediate 7, which releases
dinitrogen in a rate-determining step (B). Interaction of a second equivalent of alkene with
carbene complex 8 promotes rearrangement to palladacyclobutane 9, which undergoes
reductive elimination (C) to afford the cyclopropane product. In reality, the coordination
modes to palladium are thought to be more complex with reversible ligand exchange and
largely depend on alkene structure and reaction temperature. Based on Straub’s work,[31] it
is quite possible that the strained heterobicyclic alkenes in this study react via dialkene car-
bene complexes (initially coordinated to 2 equivalents of alkene), which later intramolecu-
larly rearrange to palladacyclobutanes 9.
In conclusion, the present revision of our cyclopropanation methodology was used
to create 14 cyclopropanated [2.2.1] heterobicycloalkenes, ten of which were novel
compounds and four showing equivalent or improved yields to previous preparations.
All cyclopropanes were obtained in good to excellent yields (65–98%) and the exo
stereoselectivity for each cyclopropane was confirmed through NMR experiments.
The current approach offers a safer reaction setup and is applicable to a broad class
of heterobicycles, including hetaryne-containing substrates and 2,3-diazenes. Sub-
sequent transformations of the cyclopropanes and expansion of the reaction scope will
continue in our laboratories.
Figure 2. Observed NOE correlation for cyclopropane 6a.

60
E. CARLSON ET AL.
Scheme 4. General mechanism of palladium-catalyzed cyclopropanation of alkenes.
Experimental
All reactions were carried out using a continuous flow apparatus under an inert atmos-
phere. Commercial reagents and catalysts were used without further purification. Column
chromatography was performed on 230- to 400-mesh silica gel following standard flash
column chromatography techniques,[32] and analytical thin-layer chromatography (TLC)
was performed on precoated silica gel 250 µm 60 F254 aluminum plates, visualized by
ultraviolet (UV) light and p-anisaldehyde stain. Infrared (IR) spectra were obtained as
NaCl or KBr discs on a Nicolet 380-FTIR spectrophotometer. 1H, 2H, and 13C NMR spec-
tra were recorded on Avance 400 MHz or 600 MHz spectrometers equipped with cryop-
robes and are reported in parts per million (ppm) from the solvent as internal standard
[CDCl3: δ 7.24 ppm (1H at 400/600 MHz) or δ 77.0 ppm (13C at 100/125 MHz)]. HRMS
samples were ionized by electron impact (EI) or electrospray ionization (ESI) as specified
and detection of the ions was performed by time of flight (TOF).
Cyclopropanated heterobicycloalkenes 1a–j, 4, 6a–c: General procedure
Hazard alert! Diazomethane can be fatal if inhaled and capable of detonation if appreciably
concentrated. Refer to Fig. 3: Reactor [C], equipped with a small stir bar; was charged with
alkene (1.2–17.7 mmol), Pd(OAc)2 (1 mol% of alkene), and tetrahydrofuran (40 mL); and
was capped with septum [E]. To the outlet of reactor [C] was connected in series with
Tygon tubing [I] an empty bubbler [J] to serve as a suck-back trap and a glass inlet tube
[K] inserted into filter flask [L]. Bubbler [L] was filled prior to setup with a glacial acetic
acid–water mixture (1:1). The outlet of bubbler [L] was connected to a piece of Tygon tub-
ing [Ic] directed to the back of the fumehood. Reactor [C] was then securely fitted to the
end of tube [Hb] while cooling its contents in an ice bath. Funnel [A] was filled with 25%
(12.5 M) aqueous sodium hydroxide (100–150 equivalents to alkene) ensuring that stopper
[D] was tightly shut, and the funnel was capped with septum [E]. Flask [B], equipped with
an extralarge stir bar, was charged with Diazald (2.6–8 equivalents to alkene) and 95%

SYNTHETIC COMMUNICATIONS
61
Figure 3. Experimental apparatus for the cyclopropanation of heterobicycloalkenes 1a–j, 3, and 5a–c.
(A) Custom-made dropping funnel (150 mL or 300 mL). (B) 500-mL round-bottom flask with side arm
and wide neck equipped with extra-large stir bar. (C) Reactor vessel (50 mL) with small hole at end
of inlet tube for bubbles. (D) Stopcock. (E) Tightly fitted 24/40 rubber septum wired in place. (F) Glass
nitrogen/argon inlet (9 mm OD). (G) No. 12 rubber stopper with two 9-mm bored holes. (H) High density
polyethylene tubing (7 mm ID) with any cut sharp edges smoothed with a heat gun. (I) Tygon tubing. (J)
Empty bubbler as suck-back trap for AcOH bubbler. (K) Glass inlet tube. (L) Filter flask with AcOH:H2O
(1:1) (CH2N2 trap and bubbler). (M) Room temperature water bath. (N) 0 °C ice-water bath. Note. OD,
outer diameter; ID, inner diameter.
EtOH (50 mL), and the solution was stirred. Flask [B] was then fitted with a stopper [G]
containing the inert gas inlet [F], tubing [Ha], and addition funnel [A] assembly. The
apparatus was securely clamped at both funnel [A] and flask [B] and a slow stream of argon
was passed through the system such that ∼3 bubbles per second (bps) were observed from
tube [Ha]. Once a constant flow rate of 3–5 bps was established, 25% sodium hydroxide
solution was added from funnel [A] into flask [B] at a rate of 1–2 mL/min, maintaining
efficient stirring and bubbling. Formation of the light yellow CH2N2 gas was observed with
the dissolution of Diazald. Upon complete dissipation of any yellow color (4–8 h), the reac-
tion was assessed by TLC for completion. Once the reaction was seen to be complete by
TLC, both septa [E] were removed and the apparatus was left to vent any trace CH2N2
(8–16 h). Reactor [C] was removed and its contents were poured over Celite. The filter cake
was washed with several portions (4 � 10-20 mL) of Et2O, and then concentrated and pur-
ified by column chromatography (hexanes/ethyl acetate mixture).
Representative analytical data
Exo-6-oxa-7-N-butoxycarbonyltricyclo[3.2.1.02,4]hydrazine (6a)
Yield 516 mg (95%); white solid; Rf ¼ 0.08 (EtOAc/hexanes ¼ 1:9); mp ¼ 117–119 °C. FTIR
(KBr, ν, cmÀ 1): 2977, 2932, 1737, 1694 (C O), 1367, 1339, 1164, 1111; 1H NMR
(400 MHz, CDCl3): 4.68 (br s, 1H), 4.42 (br s, 1H), 1.59 (m, 1H), 1.43 (s, 18H), 1.31 (d, J¼11.3
Hz, 1H), 1.20–1.06 (m, 2H), 0.42–0.39 (m, 1H), 0.33–0.28 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ [156.9, 156.3, 155.3] (C O; peaks appear split due to relative orientation about
nitrogen in different invertomers),[33] [80.2, 80.0], [61.3, 60.4, 59.6], 27.1, 25.8, [13.4, 13.0,
11.6, 11.1], 3.6. HRMS: Calculated for C16H26N2O4 [M]þ: 310.1893. Found: 310.1890.

62
E. CARLSON ET AL.
Funding
This work was supported by the Natural Sciences and Engineering Research Council of Canada
(NSERC).
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