Reaction of Phospholes with Aldimines: A One-Step Synthesis of Chelating, Alpha-C2-Bridged Biphospholes

Article abstract of DOI:10.1021/acs.orglett.5b01604

Phospholes react with aldimines at 170°C in the presence of mild Lewis acids to give C₂-bridged biphospholes in good yields. The mechanism includes a series of [1,5] shifts of the P-substituents around the phosphole ring, a P-H + aldimine condensation, and the formation of a transient three-membered ring that dimerizes.

Full text of DOI:10.1021/acs.orglett.5b01604

Letter
pubs.acs.org/OrgLett
Reaction of Phospholes with Aldimines: A One-Step Synthesis of
Chelating, Alpha‑C2‑Bridged Biphospholes
Zhengsong Hu,† Zongyang Li,† Kang Zhao,† Rongqiang Tian,*,† Zheng Duan,*,†
and Franco̧
is Mathey*,†,‡
†College of Chemistry and Molecular Engineering, International Phosphorus Laboratory, Joint Research Laboratory for Functional
Organophosphorus Materials of Henan Province, Zhengzhou University, Zhengzhou 450001, P. R. China
‡Division of Chemistry & Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, 637371, Singapore
S
* Supporting Information
ABSTRACT: Phospholes react with aldimines at 170 °C in the
presence of mild Lewis acids to give C2-bridged biphospholes in good
yields. The mechanism includes a series of [1,5] shifts of the P-
substituents around the phosphole ring, a P−H + aldimine
condensation, and the formation of a transient three-membered ring
that dimerizes.
rom a practical standpoint, the easy interconversion
1
Fbetween 1H- and 2H-phospholes offers a straightforward
access to bicyclic phosphines by Diels−Alder cycloaddition
between the 1-phosphadienic system of 2H-phospholes and a
variety of unsaturated systems. The resulting bicyclic phosphines
are characterized by a chiral nonracemizable bridgehead
phosphorus atom of special interest for applications in
asymmetric catalysis. A certain number of bicyclic phosphines
have already been prepared with these ideas in mind.2 In this
context, the synthesis of α-C2-bridged biphospholes is obviously
interesting because it can offer an access to chelating
biphosphines with two nonracemizable chiral phosphorus
centers. Unfortunately, until now, only one such biphosphole
has been described3 and its lengthy multistep synthesis precludes
its use for further developments. In this report, we wish to
describe an extremely simple, one step synthesis of such species
by reaction of phospholes with aldimines.
We had previously described the cycloaddition between 2H-
phospholes and aldehydes.4 Therefore, it was logical to
investigate the reaction with aldimines. Since the Diels−Alder
Figure 1. X-ray crystal structure of (2a) (R = Ph). The level set for
thermal ellipsoids of all atoms is 30%. Main distances (Å) and angles
(deg): P1−P2 2.1957(8), P1−C4 1.8019(19), C4−C5 1.511(2), C5−
C6 1.579(2), C6−C7 1.513(2), C7−P2 1.8024(17), P1−C1
1.8097(18), C1−C2 1.361(3), C2−C3 1.463(3), C3−C4 1.362(3),
P2−C10 1.8055(18), C10−C9 1.357(2), C9−C8 1.470(3), C8−C7
1.361(2), C1−P1−P2 101.24(6), C4−P1−P2 89.04(6), C1−P1−C4
90.96(9), C7−P2−P10 91.15(8), C7−P2−P1 90.10(6), C10−P2−P1
102.99(6), C1−P1−P2−C10 112.59(9), C4−P1−P2−C7 65.42(8).
reactions of imines are known to be catalyzed by mild Lewis
acids,5 we decided to investigate the reaction of the prototypical
1-phenyl-3,4-dimethylphosphole 16 with a variety of aldimines in
the presence of Lewis acids. The results were completely
unexpected. The end-products were the α-bridged biphospholes
2 (Scheme 1). In one case, the primary amine that is formed as a
Scheme 1. Reaction of Phosphole 1 with Aldimines
stoichiometric byproduct has been isolated and characterized for
R1 = Ph. It must be also noted that ketimines do not react with
Received: June 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01604
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions
Scheme 3. Trapping Intermediates 5
entry
cat. (20 mol %)
none
t = 170 °C time (h)
R = Ph R1
yield (%)
1
2
3
4
5
6
7
8
72
72
72
24
24
24
16
16
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cy
8
a
ZnCl2
10
49
trace
14
60
58
93
ZnCl2
BF3·Et2O
AlCl3
FeCl2
FeCl2
FeCl2
a
With 5 mol % ZnCl2
Table 2. Variation on the Substituents
product
P−Ar
Ph
R
R1
yield (%)
2b
2b
2c
2-thienyl
2-thienyl
p-MeO-C6H4
p-NO2-C6H4
o-Br-C6H4
p-CN-C6H4
i-Pr
Ph
Cy
Cy
Cy
Cy
Cy
Cy
Cy
44
88
91
NR
62
22
86
75
Ph
Ph
Ph
2d
2e
2f
Ph
Ph
Ph
2g
2-thienyl
Ph
Figure 3. X-ray crystal structure of (6c). The level set for thermal
ellipsoids of all atoms is 30%. Main distances (Å) and angles (deg): P1−
P2 2.2393(7), P2−C1 61.8031(18), C16−C25 1.509(3), C25−C3
1.607(2), C3−C4 1.538(3), C4−P1 1.846(2), P1−C1 1.837(2), C1−
C2 1.345(3), C2−C3 1.527(3), P2−C1 31.8048(19), C13−C14
1.356(3), C14−C15 1.468(3), C15−C16 1.359(3), C1−P1−C4
88.74(9), C13−P2−C16 91.10(9), C3−C4−P1 107.23(13).
Scheme 2. Mechanism of the Reaction
Scheme 4. Synthesis a Diphosphaferrocenophane
temperature was set a 170 °C. We also noticed that a cyclohexyl
substituent at nitrogen is more favorable than a phenyl.
We then investigated the range of aldimines that can be used
with the optimized conditions (170 °C, 16 h, FeCl2). The
reaction appears to be quite general. The electron-withdrawing
substituents disfavor the reaction (Table 2). It is also possible to
replace the phenyl group at P by another aryl or heteroaryl
substituent.
On the basis of what is known on the chemistry of 2H-
phospholes,1 we propose the following mechanism (Scheme 2).
One critical point of this mechanism involves the [1,5]
sigmatropic shift of the α-aminobenzyl substituent from P to
Cα. It is known that sp3 carbon substituents do not normally
migrate,1 and, thus, we needed to check this point. The DFT
computations7 were carried out at the B3LYP/6-311+G(d,p)
level. The transition state is shown in Figure 2.
Figure 2. Computed transition state (one negative frequency) of the
reaction:
Main distances (Å) and angles (deg): C9−P 3.04, C9−C4 2.45,
C9−N 1.34, C4−C9−P 36.5.
The computed barrier is very low at only 17.4 kcal mol−1
(zero-point energy included). It is quite clear that the amino
substituent favors the ionization of the P−C bond and weakens
it, thus favoring the migration of the sp3 carbon group. The
conversion of 4 into 5 implies a deprotonation of the phosphole
phosphole 1 under the same conditions. The X-ray crystal
structure analysis of 2a (R = Ph) is reported in Figure 1.
We screened a variety of Lewis acids as shown in Table 1. This
led us to select FeCl2 as the catalyst of choice while the
B
DOI: 10.1021/acs.orglett.5b01604
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman,
J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision D.01;
Gaussian, Inc.: Wallingford, CT, 2013.
ring at P by the nitrogen lone pair. This explains why a higher
basicity of the amino group favors the reaction. While trying to
characterize some intermediates in the reaction, we were able to
separate polycyclic derivatives 6 of the bicyclic phosphiranes 5
(Scheme 3). The products result from the [4 + 3] cycloaddition
of the 2H-phosphole 3 with 5. The formula of 6c was confirmed
by X-ray crystal structure analysis (Figure 3). Its formation fully
demonstrates the proposed mechanism.
The ready availability of biphospholes such as 2 offers a lot of
synthetic possibilities using the chemistry of the P−P bond. The
synthesis of a 1,1′-diphosphaferroceneophane is given as an
example (Scheme 4).
Many more applications of these new products can be
envisaged.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental section, NMR data for 2−7, and X-ray data for 2a
and 6c The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01604.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tianrq@zzu.edu.cn.
*E-mail: duanzheng@zzu.edu.cn.
*E-mail: fmathey@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation (21272218, 21302174), Specialized Research Fund
for the Doctoral Program of Higher Education
(20134101110004), and Zhengzhou Science and Technology
Department (131PYSGZ204) of China.
REFERENCES
(1) Mathey, F. Acc. Chem. Res. 2004, 37, 954.
(2) Robin, F.; Mercier, F.; Ricard, L.; Mathey, F.; Spagnol, M. Chem. -
Eur. J. 1997, 3, 1365. Siutkowski, M.; Mercier, F.; Ricard, L.; Mathey, F.
Organometallics 2006, 25, 2585. Gilbertson, S.; Genov, D.; Rheingold, A.
Org. Lett. 2000, 2, 2885. Mercier, F.; Brebion, F.; Dupont, R.; Mathey, F.
■
Tetrahedron: Asymmetry 2003, 14, 3137. Moller, T.; Sar
Hawkins, E. Chem. - Eur. J. 2012, 18, 16604.
́
osi, M. B.; Hey-
̈
(3) Deschamps, E.; Ricard, L.; Mathey, F. Organometallics 2001, 20,
1499.
(4) Toullec, P.; Ricard, L.; Mathey, F. J. Org. Chem. 2003, 68, 2803.
(5) Yao, S. L.; Saaby, S.; Hazell, R. G.; Jorgensen, K. A. Chem. - Eur. J.
2000, 6, 2435. Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156.
(6) Breque, A.; Mathey, F.; Savignac, P. Synthesis 1981, 1981, 983.
(7) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;
Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador,
C
DOI: 10.1021/acs.orglett.5b01604
Org. Lett. XXXX, XXX, XXX−XXX