2
N.G. Paciaroni et al. / Tetrahedron Letters xxx (xxxx) xxx
resulted in a stereospecific ring-closure to yohimbine Y in 34%
yield (Scheme 3). This reaction demonstrates a unique reactivity
regarding the cyanamide functional group where the amine moiety
participated as a nucleophile to perform ring-closure. Intrigued by
these unexpected results, we were eager to explore this reaction
further by employing microwave (mw) irradiation and eliminating
zinc(0). Microwave chemistry offers several benefits to traditional
oil bath heating, which include: acceleration of reaction rate via
direct microwave absorption of organic molecules, shorter reaction
times and higher yields [15–17].
By utilizing mw irradiation, we were able to isolate yohimbine in
63% yield after five minutes at 160 °C (Table 1, Entry 3). Interest-
ingly, by decreasing the reaction time to one minute, the yield of
yohimbine improved to 74% (Table 1, Entry 4). To probe the role
microwave heating plays in this process, we ran an analogous reac-
tion using traditional oil bath heating. The oil bath heated reaction
required 17 h to complete at 100 °C and afford a lower yield of
yohimbine (56% yield; Table 1, Entry 2). This stark contrast in the
reaction outcome highlights the need of mw heating regarding
the optimization of this transformation.
Scheme 2. Synthesis of diastereomeric medium-ring ether cyanamides 6 and 7.
new compounds for biological evaluation, including major (6, aver-
age yield = 32%) and minor (7, average yield = 10%) diastereomers.
The diastereomeric cyanamide ether pairs resulting from this CAN
ring cleavage reaction were readily separated via column
chromatography.
The hydroxyl derivative, as well as both diastereomers of the
isopropyl and phenyl ethers, were treated in a similar manner
(160 °C under mw irradiation for one to five minutes) and each
derivatives produced yohimbine as the sole product in 18–62%
yield (Table 1, Entries 5–10). Moreover, the major diastereomers
of the isopropyl and phenyl ethers (Table 1, Entries 7 and 9)
resulted in higher yields of yohimbine compared to their corre-
sponding minor diastereomer ethers (Table 1, Entries 8 and 10).
This result demonstrates a preference regarding the stereochem-
istry of the starting ether cyanamide; however, each diastereomer
leads to the same product (Y) via an indole-promoted SN1 pathway.
It is interesting to note that no epi-yohimbine was observed for any
of the acid-promoted cyanamide ring-closures. This reaction
occurs through an indole-promoted expulsion of a protonated
ether, followed by nucleophilic attack by the cyanamide amine
moiety to rearomatize the indole nucleus.
With initial goals to expand the library diversity of this subset
of compounds, we sought to further modify the cyanamide using
known hydrolysis conditions to afford the secondary amine for fur-
ther modification. Cyanamide hydrolysis to the corresponding sec-
ondary amine is typically a facile conversion and often employs a
Brønsted or Lewis acid [12–14]. However, all attempts to hydrolyze
cyanamide compounds (6, 7) to the corresponding amines using
trifluoroacetic acid, zinc(II) chloride and aluminum(III) chloride
failed. Instead, we observed an unexpected and unprecedented
chemical reactivity for the cyanamide functional group, which
we report herein.
Results and discussion
Our initial experimental result came from the treatment of cya-
namide 8 with zinc(0) in acetic acid for one hour at 100 °C, which
Despite this SN1 process, this reaction is stereospecific for the
formation of yohimbine. To rationalize the observed stereospeci-
ficity, we analyzed a 2-iodobenzyl ether derivative (9) in its
ground-state orientation via X-ray crystallography (Figure 1)
[11]. In the most stable orientation of the medium-ring ether com-
pounds, the cyanamide group points away from the inner, convex
face of the central 10-membered ring of 9. Depicted in Scheme 4,
the ether oxygen of 6 is protonated and subsequently eliminated
through electron donation from the indole heterocycle to produce
Scheme 3. New acid-promoted cyanamide ring-closure to yohimbine (Y).
Table 1
Summary of microwave-enhanced, acid-promoted ring closure reactions to generate yohimbine (Y).
Entry
X
Y
Reagents
Temperature (°C)
Time (min, hr)
% Yield
1
2
3
4
5
6
7
8
9
10
OMe
OMe
OMe
OMe
OH
OH
O’Pr
H
H
H
H
H
H
H
H
O’Pr
H
AcOH
25
52 hr
17 hr
5 min
1 min
5 min
1 min
5 min
5 min
1 min
1 min
0
AcOH, oil bath
AcOH, pw
AcOH, pw
AcOH, pw
AcOH, pw
AcOH, pw
AcOH, pw
AcOH, pw
AcOH, pw
100
160
160
160
160
160
160
160
160
56
63
74
18
50
62
17
59
32
OPh
H
OPh
Please cite this article as: N. G. Paciaroni, V. M. Norwood, D. E. Garcia et al., Microwave-enhanced, stereospecific ring-closure of medium-ring cyanamide