Intramolecular Aza-Piancatelli Rearrangement of Alkyl- or Arylamines Promoted by PPh3/Diethyl Azodicarboxylate

Article abstract of DOI:10.1021/acs.orglett.6b03853

A novel method for the construction of 1-azaspirocycles from 5-alkyl-/-arylamine furylcarbinols though intramolecular aza-Piancatelli rearrangement was developed. By using PPh₃/diethyl azodicarboxylate instead of a Lewis acid, 1-azaspirocyclic compounds were obtained in good yields and the reaction temperature was reduced to room temperature. In addition, substrates with groups that are sensitive to high temperatures or Lewis acids are tolerated under these reaction conditions. This is the first method that is applicable not only to 5-(N-arylaminoalkyl)furylcarbinols with better yields but also to 5-(N-alkylaminoalkyl)furylcarbinols.

Full text of DOI:10.1021/acs.orglett.6b03853

Letter
pubs.acs.org/OrgLett
Intramolecular Aza-Piancatelli Rearrangement of Alkyl- or
Arylamines Promoted by PPh3/Diethyl Azodicarboxylate
Zhong-Li Xu, Ping Xing,* and Biao Jiang*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A novel method for the construction of 1-azaspirocycles from 5-alkyl-/-arylamine furylcarbinols though
intramolecular aza-Piancatelli rearrangement was developed. By using PPh3/diethyl azodicarboxylate instead of a Lewis acid, 1-
azaspirocyclic compounds were obtained in good yields and the reaction temperature was reduced to room temperature. In
addition, substrates with groups that are sensitive to high temperatures or Lewis acids are tolerated under these reaction
conditions. This is the first method that is applicable not only to 5-(N-arylaminoalkyl)furylcarbinols with better yields but also to
5-(N-alkylaminoalkyl)furylcarbinols.
Scheme 1. Intramolecular Aza-Piancatelli Rearrangement
he 1-azaspirocycle ring system is widely observed in
1
2
Tnatural products, such as histrionicotoxin, cephalotaxine,
halichlorine,3 stemonamine,4 and erysotramidine5 (Figure 1).
Many reactions have been developed to build this structural
motif, and most of the synthetic strategies require two steps to
separately build the tertiary carbon center and the spirocycle,6
although few methods are able to construct this challenging
framework via one-step routes. In 2011, Alaniz presented a
novel cascade strategy for the formation of 1-azaspirocycles by
applying the aza-Piancatelli rearrangement. This reaction is
simple and inexpensive and can be applied to many different
arylamines with high yields; however, no alkylamines have been
used.7 In the following years, Alaniz reported similar reactions,
including intramolecular Piancatelli rearrangement of alcohols
and donor−acceptor cyclopropanes.8,9 When substrates with
hydroxylamine were attempted, the structural motif was
obtained in high yields, but the cleavage of N−O bonds failed
using the traditional methods.10 Here, we present the first
intramolecular aza-Piancatelli rearrangement of alkylamines,
and this protocol can also be applied to arylamines with better
yields (Scheme 1). Thus, we can avoid the cleavage of C−N or
Received: January 3, 2017
Figure 1. Natural products with 1-azaspirocycle ring systems.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03853
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthetic Routes of Furylcarbinols
Table 2. Studies on Intramolecular Aza-Piancatelli
Rearrangement
Table 1. Studies of the Intramolecular Aza-Piancatelli
Rearrangement Reaction Conditions
a
temp
(°C)
time
(h)
yield
entry
promoter (equiv)
Dy(OTf)3 (0.05)
solvent
(%)
1
2
CH3CN
CH3CN
80
80
36
36
nr
nr
Dy(OTf)3 (0.05),
TsOH•H2O (1.00)
3
4
ZnCl2 (0.05)
DME/H2O
(1:1)
100
2
nr
PPh3 (1.20)
THF
0 to rt 24
50
28
DEAD (1.20)
b
5
6
ADDP (1.50)
benzene
DMF
8
nr
nr
Bu3P (1.50)
PPh3 (1.20)
CCl4 (1.20)
TEA (1.20)
PPh3 (1.30)
NBS (1.20)
TEA (1.20)
PPh3 (1.50)
0 to rt 12
0 to rt 12
7
DCM
nr
8
DMF
0 to rt
3
48
70
40
24
20
78
c
DEAD (1.50)
9
PPh3 (1.50)
DEAD (1.50)
PPh3 (1.50)
DEAD (1.50)
PPh3 (1.50)
DEAD (1.50)
PPh3 (1.50.)
DEAD (1.50)
PPh3 (1.50)
DEAD (1.50)
DMAc
CH3CN
DCM
0 to rt
2
10
11
12
13
rt
rt
rt
rt
3
3
DMSO
DMAc
3
0.5
d
PPTS (0.20)
a
b
c
Isolated yield. ADDP = 1,1′-(azodicarbonyl)dipiperidine. DEAD =
d
diethyl azodicarboxylate. PPTS = pyridinium toluene-4-sulfonate.
O−N bonds by introducing the group we need to connect with
the N atom first, simplifying the synthetic route.
All of the furylcarbinols were synthesized using standard
synthetic procedures (Scheme 2): methyl 5-bromo-2-furoate
was used as the starting material, and one Heck reaction step
then provided the aldehyde 3. After condensation with amine 4
a
b
Added when R is an alkyl group. Isolated yield.
B
DOI: 10.1021/acs.orglett.6b03853
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Studies of the Chiral Aza-Piancatelli
Rearrangement
Scheme 4. Proposed Mechanism for Intramolecular Aza-
Piancatelli Rearrangement
and a Borch reaction, we obtained amine 5, which was then
reduced by LiAlH4 to yield furylcarbinol 2.
Furylcarbinol 2a was selected as a model substrate. Because
no aza-Piancatelli rearrangement of alkylamine furylcarbinols
have been reported, we first tried the Lewis acid Dy(OTf)3,
Dy(OTf)3/TsOH, or ZnCl2 as the catalyst, but no product was
detected (Table 1, entries 1−3). Perhaps the strong Lewis
basicity of the alkylamines could poison the Lewis acids. We
turned our attention to nonacidic conditions to promote
leaving of the hydroxyl group, which is considered to be the
start of the aza-Piancatelli rearrangement. After attempting
several conditions, such as PPh3/DEAD,11 n-Bu3P/ADDP,12
PPh3/CCl4/TEA, and PPh3/NBS/TEA (Table 1, entries 4−
7),13,14 we successfully isolated the aza-Piancatelli rearrange-
ment product in 28% yield using the PPh3/DEAD/THF
system. We then screened several solvents, including DMF,
DMAc, CH3CN, DCM, and DMSO (Table 1, entries 8−12).
DMAc was found to be the best, possibly because DMAc is
favorable for proton migration, which is very important in the
rearrangement process. When a catalytic amount of PPTS was
added for the alkylamine substrates, the yield could be further
improved (Table 1, entry 13).
The scope of the aza-Piancatelli rearrangement was
investigated. For the synthesis of 1-azaspiro[4.4]nonanes
from alkylamines, we chose several R groups, such as
phenylethyl, n-butyl, or benzyl. The yields ranged from 71 to
78% (Table 2, entries 1−4). For the synthesis of 1-
azaspiro[4.4]nonanes from arylamines, the yields were much
better, regardless of whether the substituent was electron-
withdrawing or electron-donating (Table 2, entries 5−8).
Moving the methoxyl group from the para position to the ortho
position had little influence on the yields (Table 2, entries 7
and 8). When we applied this method to construction of the 6-
azaspiro[4.5]decane ring system, the yields decreased sub-
stantially for both the alkylamine substrates and the aromatic
amine substrates. We suggest that the large ring strain of the
six-membered heterocycle restricted the aza-Piancatelli arrange-
ment. For the alkylamine substrates, the yields were
approximately 45% (Table 2, entries 9 and 10), and for
aromatic amine substrates, the yields ranged from 28 to 42%
(Table 2, entries 11−13). The yields of the alkylamine
substrates were higher than those of the aromatic amine
substrates, which was opposite the result for the 1-
azaspiro[4.4]nonanes. When there were substituents in the
benzene ring of the arylamine substrates, the yields were higher,
which was consistent with the results for the 1-azaspiro[4.4]-
nonanes.
Furylcarbinol 2a was chosen as model to study the chiral aza-
Piancatelli rearrangement (Scheme 3y clearan). We tried to
replace the PPTS with chiral acid catalysts, such as catalyst (R)-
(−)-1,1′-Binaphthyl-2,2′-diylhydrogen phosphate A or catalyst
(S)-2′-Ethoxy-1,1′-binaphthalen-2-ol B. Only racemic product
was obtained. The rearrangement of furylcarbinol 6 using (R)-
(−)-α-methylbenzylamine as chiral auxiliary occurred with little
control of stereoselectivity.
The proposed mechanism is analogous to the intramolecular
aza-Piancatelli rearrangement catalyzed by a Lewis acid,7 except
for the leaving method of the hydroxyl group. The proposed
C
DOI: 10.1021/acs.orglett.6b03853
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) (a) Iizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Uyeo, S. J. Chem.
Soc., Chem. Commun. 1973, 125−126. (b) Ye, Y.; Qin, G.-W.; Xu, R.-S.
J. Nat. Prod. 1994, 57, 665−669.
mechanism is described in Scheme 4: PPh3 reacts with DEAD
to form intermediate I, which is consistent with the Mitsunobu
reaction. Intermediate I acquires a proton from PPTS to form
intermediate II, which is then attracted by substrate 2 to form
intermediate III. Intermediate III undergoes molecular
rearrangement to form intermediate IV, which then converts
to V. Intermediate V undergoes Nazarov rearrangement,
yielding intermediate VI, which produces the desired product
1 after deprotonation. Without PPTS, intermediate I obtained a
proton from compound 2, formed intermediate VII, and
rearranged to intermediate VIII, after ring open and ring close,
to yield the product 1. The byproduct is formed though the
leaving the OPPh3 of intermediate VII. PPTS can transform a
proton to intermeditate I and, thus, form intermediate III
instead of intermediate VII. In this way, the byproduct route is
depressed. What’s more, the transformation from intermediate
IV to intermediate V is easier than the transformation from
intermediate VIII to intermediate IX, and the rate of aza-
Piancatelli rearrangement is increased.
(5) Ito, K.; Suzuki, F.; Haruna, M. J. Chem. Soc., Chem. Commun.
1978, 733−734.
(6) Dake, G. Tetrahedron 2006, 62, 3467−3492.
(7) Palmer, L. I.; Alaniz, J. R. Angew. Chem., Int. Ed. 2011, 50, 7167−
7170.
(8) Palmer, L. I.; Read de Alaniz, J. R. Org. Lett. 2013, 15, 476−479.
(9) Wenz, D. R.; Read de Alaniz, J. R. Org. Lett. 2013, 15, 3250−
3253.
(10) Veits, G. K.; Wenz, D. R.; Palmer, L. I.; Amant, A. S.; Hein, J. E.;
Alaniz, J. R. Org. Biomol. Chem. 2015, 13, 8465−8469.
(11) Mitsunobu, O. Synthesis 1981, 1981, 1−28.
(12) Boger, D. L.; Mckie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc.
1996, 118, 2301−2302.
(13) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801−811.
(14) Schmida, R.; Antoulas, S.; Ruttimann, A.; Schmid, M.; Vecchi,
̈
M.; Weiserb, H. Helv. Chim. Acta 1990, 73, 1276−1299.
In conclusion, we have developed an intramolecular aza-
Piancatelli rearrangement that is suitable for both alkyl- and
arylamine furylcarbinols. This is the first report of the aza-
Piancatelli rearrangement of alkylamines; thus, the cleaving of
C−N bonds for arylamines or N−O bonds for hydroxylamine
can be avoided. The reaction is promoted by PPh3/DEAD for
arylamine furylcarbinols and PPh3/DEAD/PPTS for alkylamine
furylcarbinols at room temperature. Because it proceeds
without Lewis acids or high temperatures, this reaction is
expected to be tolerant to acid-sensitive substrates or substrates
that decompose at high temperatures.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03853.
Full experimental details, spectroscopic data, and 1H and
13C NMR spectra for the compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xingping@sioc.ac.cn.
*E-mail: jiangb@mail.sioc.ac.cn.
ORCID
Biao Jiang: 0000-0002-4292-7811
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Science and Technology
Commission of Shanghai Municipality (15DZ2281500,
NSFC2167020782) and the Knowledge Innovation Program
of the Chinese Academy of Sciences (KGCX2-YW-202-2).
REFERENCES
■
(1) Daly, J. W.; Karle, I.; Myers, C. W.; Tokuyama, T.; Waters, J. A.;
Witkop, B. Proc. Natl. Acad. Sci. U. S. A. 1971, 68, 1870−1875.
(2) Paudler, W. W.; Kerley, G. I.; McKay, J. J. Org. Chem. 1963, 28,
2194−2197.
(3) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi, Y.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3867−3870.
D
DOI: 10.1021/acs.orglett.6b03853
Org. Lett. XXXX, XXX, XXX−XXX