Synthesis of α-Aminophosphines by Copper-Catalyzed Regioselective Hydroamination of Vinylphosphines

Article abstract of DOI:10.1002/chem.201802491

A copper-catalyzed net hydroamination of vinylphosphine boranes with hydrosilanes and O-benzoylhydroxylamines has been developed. The reaction proceeds regioselectively to form the corresponding α-aminophosphine boranes of potent interest in medicinal and pharmaceutical chemistry. This copper catalysis is based on an umpolung, electrophilic amination strategy and provides a new electrophilic amination approach to α-aminophosphine derivatives. Additionally, although still preliminary, asymmetric synthesis has also been achieved by judicious choice of a chiral bisphosphine-ligated copper complex.

Full text of DOI:10.1002/chem.201802491

A Journal of
Accepted Article
Title: Synthesis of alpha-Aminophosphines by Copper-Catalyzed
Regioselective Hydroamination of Vinylphosphines
Authors: Masahiro Miura, Tatsuaki Takata, Daiki Nishikawa, and Koji
Hirano
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10.1002/chem.201802491
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COMMUNICATION
a
Synthesis of -Aminophosphines by Copper-Catalyzed
Regioselective Hydroamination of Vinylphosphines
Tatsuaki Takata,[a] Daiki Nishikawa,[a] Koji Hirano,*[a] and Masahiro Miura*[a]
Dedication
Abstract: A copper-catalyzed net hydroamination of vinylphosphine
boranes with hydrosilanes and O-benzoylhydroxylamines has been
developed. The reaction proceeds regioselectively to form the
corresponding a-aminophosphine boranes of potent interest in
medicinal and pharmaceutical chemistry. This copper catalysis is
based on an umpolung, electrophilic amination strategy and provides
regioselectivity (the copper moiety was introduced at the position
a to phosphorus), subsequent electrophilic amination[10] could
deliver the a-aminophosphines. Here, we report a copper-
catalyzed regioselective hydroamination of vinylphosphine
boranes with polymethylhydrosiloxane (PMHS) and O-
benzoylhydroxylamines (Scheme 1c). The copper catalysis can
provide new and complementary access to the a-
aminophosphines, of potent interest in medicinal and
a
new electrophilic amination approach to a-aminophosphine
derivatives. Additionally, while still preliminary, asymmetric
synthesis is also achieved by judicious choice of chiral
bisphosphine-ligated copper complex.
pharmaceutical
chemistry,
without
any
stoichiometric
preparation of organometallic reagents and/or intermediates.
Additionally, while preliminary, asymmetric synthesis is achieved
by using a chiral bisphosphine-ligated copper catalyst.
a-Aminophosphine derivatives are phosphorus analogues of a-
aminoacids and thus show some unique biological activities
such as antitumor, antibacterial, and enzyme inhibiting nature.[1]
The Mannich-type three-component coupling of aldehyde, amine,
and phosphorus nucleophile, that is, Kabachnik-Fields reaction
is the classical but most reliable approach to the above a-
aminophosphines.[2] On the other hand, a good alternative can
be an electrophilic amination[3] of alkylphosphines at the position
a to phosphorus (Scheme 1). The conventional strategies relied
on the azo and azido compounds as the electrophilic amination
reagents and thus suffer from tedious and additional N–N
reductive cleavage process for obtaining the desired a-
aminophosphines (Scheme 1a).[4] In 2014, the research group
of Wang reported the copper-catalyzed electrophilic amination
with the O-benzoylhydroxylamine derivative[5] to form the a-
a) Electrophilic amination with azo or azido compounds then reductive cleavage of N–N bonds
CO2R
O
O
N
N
O
R1 PR2
O
2
R1 PR2
[H]
RO2C
R1 PR2
2
2
R1 PR2
or
2
N
or
ArSO2 N3
RO2C
NH
CO2R
NH2
N3
b) Electrophilic amination of phosphorus α-zincates with hydroxylamines
cat. Cu
O
O
PR2
O
BzO NR2
R1 PR2
Zn(TMP)2
R1
2
R1 PR2
2
2
2
NR2
Zn
c) Hydroamination of vinylphosphines with hydrosilanes and hydroxylamines (this work)
Me
TMSO Si
H
O
TMS
cat. Cu
cat. (chiral) ligand
H
BH3
PR2
BH3
PR2
n
*
2
R1
+
(PMHS)
2
R1
NR2
BzO NR2
aminophosphines directly (Scheme 1b).[6]
However, the
working hypothesis
R
preactivation step, namely stoichiometric zincation of starting
phosphorus compounds with organozinc reagents, is inevitable.
Thus, there still remains a demand for further development of a-
aminophosphine synthesis based on electrophilic amination
strategy.
H
R
H
P
BzO NR’2
P
P
+
LnCu
H
LnCu OBz
PMHS
R
1) insertion
2) electrophilic
amination
Cu
regioselecive
NR’2
Meanwhile, in recent years, our group[7] and Buchwald’s
group[8] independently developed the copper-catalyzed net
hydroamination of various alkenes with hydrosilanes and
hydroxylamines. The reaction proceeds via 1) insertion of
alkene to an in-situ generated Cu-H and 2) electrophilic trapping
of catalytically formed alkylcopper intermediate with the
hydroxylamine, which is completely different mechanism from
the traditional hydroamination.[9] During our continuous interest
in this chemistry, we envisioned if a vinylphosphine worked as a
suitable acceptor toward the Cu-H with preferable
Scheme 1. Electrophilic amination approaches to a-aminophosphines and
working hypothesis of c). TMP
= 2,2,6,6-tetramethylpiperidinyl, TMS =
trimethylsilyl, L = ligand.
Our optimization studies commenced with identification of a
suitable phosphino group attached to the vinyl moiety (Scheme
2). With PMHS and O-benzoyl-N,N-dibenzylhydroxylamine (2a)
as the hydrosilane and electrophilic amination reagent,
respectively, we tested several vinylphosphine derivatives in the
presence of a Cu(OAc)2/CF3-dppbz catalyst and LiOtBu base,
which is among representative efficient achiral catalytic system
in our previous work.[7] Whereas free trivalent phosphine (1a),
phosphine sulfide (1a-S), and phosphonate (1a-OEt) gave no
detectable amount of hydroaminated products, phosphine oxide
(1a-O) and phosphine borane (1a-BH3) were successfully
converted to the desired a-aminophosphines 3aa-O and 3aa-
[a]
T. Takata, D. Nishikawa, Prof. Dr. K. Hirano, Prof. Dr. M. Miura
Department of Applied Chemistry
Graduate School of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Fax: (+81) 6-6879-7362
E-mail: k_hirano@chem.eng.osaka-u.ac.jp;
miura@chem.eng.osaka-u.ac.jp
1
BH3 in 31% and 61% H NMR yields, respectively (Scheme 2a).
Notably, the other regioisomer (b-aminophosphine) was not
formed at all, thus suggesting the regioselective insertion of
alkene moiety to the Cu–H (Scheme 1c, insertion step).[11]
Supporting information for this article is available on the WWW
under http://www.xxx.
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10.1002/chem.201802491
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Given the easily removable nature of BH3 protecting group, we
performed further optimization studies with the phosphine
afford piperidine- (3ad-BH3), morpholine- (3ae-BH3), N-Boc
piperazine-
(3af-BH3),
and
thiomorpholine
(3ag-BH3)-
borane 1a-BH3.
Extensive ligand screening revealed that
incorporated a-aminophosphines in 56–91% yields. Additionally,
the reaction was tolerated with the acetal-protected piperidone
(3ah-BH3), which can be deprotected to primary amine under
suitable conditions.[14]
monodentate PPh3 and P(4-MeOC6H4)3 showed better
performance to afford 75% and 73% isolated yields of 3aa-BH3,
respectively (Scheme 2b). Additional investigations of base,
hydride source, and solvent were also implemented, but further
improvements were not observed.[12]
Cu(OAc)2 (10 mol%)
PAr3 (20 mol%)
H
BH3
PR2
BH3
PR2
2
+
+
BzO NBn2
PMHS
2
R1
R1
LiOtBu
THF, RT, 4 h
NBn2
1-BH3
3-BH3
2a
a) Identification of phosphino group
PAr2
PAr2
PMHS
(0.75 mmol)
Cu(OAc)2 (10 mol%)
CF3-dppbz (10 mol%)
H
H
BH3
H
BH3
H
BH3
P
P
PPh2
PPh2
PPh2
+
C6H13
C6H13
C6H13
Ph
LiOtBu
THF, RT, 4 h
BzO NBn2
1
(0.25 mmol)
NBn2 Ar = 3,5-(CF3)2C6H3
CF3-dppbz
NBn2
NBn2
NBn2
3
2a
(0.75 mmol)
3aa-BH3 76%
(PPh3)
3ba-BH3 62%
(P(4-MeOC6H4)3)
3ca-BH3 44%
(P(4-MeOC6H4)3)
(1H NMR yield)
crystal structure of 3ca-BH3
S
BH3
O
O
PPh2
PPh2
PPh2
P(OEt)2
PPh
2 C6H13
H
BH3
C6H13
C6H13
C6H13
C6H13
H
BH3
H
BH3
H
BH3
PPh2
PPh2
1a
3aa: 0%
1a-S
1a-BH3
3aa-BH3: 61%
1a-OEt
1a-O
3aa-O: 31%
Cl
PPh2
PPh2
NC
TBSO
3aa-S: 0%
3aa-OEt: 0%
NBn2
NBn2
NBn2
NBn2
3fa-BH3 81%
(P(4-MeOC6H4)3)
b) Optimal conditions
3da-BH3 60%
(PPh3)
3ga-BH3 70%
(PPh3)
3ea-BH3 74%
(PPh3)
PMHS
(0.75 mmol)
H
BH3
PPh2 PPh3: 75%
P(4-MeOC6H4)3: 73%
Cu(OAc)2 (10 mol%)
PAr3 (20 mol%)
BH3
H
BH3
PPh2
+
H
BH3
PPh2
H
BH3
H
BH3
PCy2
C6H13
C6H13
LiOtBu
THF, RT, 4h
PPh2
BzO NBn2
PPh2
NBn2
1a-BH3
(0.25 mmol)
PivO
2a
(0.38 mmol)
3aa-BH3
NBn2
NBn2
NBn2
NBn2
3ha-BH3 78%
3ka-BH3 6%
3ia-BH3 66%
3ja-BH3 55%
(PPh3)
(PPh3)
(PPh3)
(PPh3)
Scheme 2. Representative optimization studies for copper-catalyzed
H
O
H
O
regioselective hydroamination of vinylphosphines
benzoyl-N,N-dibenzylhydroxylamine (2a).
1 with PMHS and O-
PPh2
PPh2
3aa-O 84%
(CF3-dppbz)[a]
3ka-O 57%
(CF3-dppbz)[a]
C6H13
NBn2
NBn2
With the conditions in Scheme 2b, we first examined the
scope of vinylphosphines 1-BH3. The representative
Scheme 3. Copper-catalyzed regioselective hydroamination of various
vinylphosphine boranes 1-BH3 with PMHS and O-benzoyl-N,N-
dibenzylhydroxylamine (2a). Conditions: 1-BH3 (0.25 mmol), 2a (0.38 mmol),
PMHS (0.75 mmol, based on Si-H), Cu(OAc)2 (0.025 mmol), PAr3 (0.050
mmol), LiOtBu (0.75 mmol), THF (1.5 mL), RT, 4 h, N2. Yields of the isolated
products are given. The ligand employed in parentheses. Enantiomeric ratio
(e.r.) was determined by HPLC analysis on a chiral stationary phase. [a] With
phosphine oxide 1-O (0.38 mmol), 2a (0.25 mmol), and CF3-dppbz ligand
(0.025 mmol) at 60 ˚C. Piv = tert-butylcarbonyl. TBS = tert-butyldimethylsilyl.
hydroaminated products are illustrated in Scheme 3. In addition
to 3aa-BH3, the copper catalysis accommodated several alkyl
chains including phenylethyl, cyclopropyl, and isobutyl groups at
the b position, and corresponding a-aminophosphines 3ba-BH3–
3da-BH3 were obtained in synthetically acceptable yields. The
structure of 3ca-BH3 was unambiguously confirmed by X-ray
analysis.[13]
The hydroamination reaction conditions were
H
BH3
H
BH3
H
BH3
H
BH3
compatible with common functional groups such as alkylchloride
(3ea-BH3), nitrile (3fa-BH3), silyl ether (3ga-BH3), and pivaloyl
PPh2
PPh2
PPh2
PPh2
C6H13
C6H13
C6H13
C6H13
N
N
O
N
N
Me
Bn
ester (3ha-BH3).
Additionally, the terminal vinylphosphine
3ab-BH3 91%
3ac-BH3 51%
borane and its dicyclohexylphosphine analogue were also viable
substrates to form the desired products 3ia-BH3 and 3ja-BH3 in
66% and 55% yields, respectively. On the other hand, the
bulkier b-cyclohexylvinylphosphine sluggishly reacted with 2a
under the standard conditions (3ka-BH3, 6%); however, the use
of corresponding phosphine oxide as well as modified catalyst
system (CF3-dppbz ligand, 60 ˚C) greatly improved the reaction
efficiency to deliver the a-aminophosphine oxide 3ka-O in 57%
yield. Not surprisingly, the same modified conditions could be
applicable to more sterically accessible vinylphosphine oxide
(3aa-O).
Several hydroxylamines 2 other than the dibenzylamine 2a
could be employed (Figure 1). In these cases, the P(4-
MeOC6H4)3 ligand uniformly gave better results. Acyclic N-
benzyl-N-methyl and N,N-diallyl amines were coupled with 1a-
BH3 to form the corresponding hydroaminated products 3ab-BH3
and 3ac-BH3 in 91% and 51% yields, respectively. In the latter
case, the vinylphosphine moiety was selectively hydroaminated,
and the isolated terminal olefin remained intact. Some 6-
membered cyclic amines also reacted with 1a-BH3 smoothly to
3ae-BH3 91%
3ad-BH3 68%
H
O
BH3
H
BH3
H
BH3
PPh2
PPh2
C6H13
PPh2
C6H13
C6H13
N
N
N
S
N
O
Boc
3ag-BH3 66%
3af-BH3 56%
3ah-BH3 75%
Figure 1. Products of copper-catalyzed regioselective hydroamination of 1a-
BH3 with PMHS and various hydroxylamines 2. Conditions: 1a-BH3 (0.25
mmol), 2 (0.38 mmol), PMHS (0.75 mmol, based on Si-H), Cu(OAc)2 (0.025
mmol), P(4-MeOC6H4)3 (0.050 mmol), LiOtBu (0.75 mmol), THF (1.5 mL), RT,
4 h, N2. Yields of the isolated products are given. Boc = tert-butoxycarbonyl.
We next turned our attention to development of
enantioselective copper catalysts because asymmetric synthesis
of
derivatives, is still limited in scope and selectivity and thus
remains After survey of chiral
synthetic challenge.[15]
bisphosphine ligands, we were pleased to find that the regio-
a-aminophosphines,
particularly
a-alkyl-substituted
a
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10.1002/chem.201802491
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COMMUNICATION
and enantioselective hydroamination of 1a-BH3 with the
dibenzylhydroxylamine 2a proceeded in the presence of a chiral
Cu(OAc)2•OH2/(R)-DTBM-SEGPHOS catalyst in CPME to form
the optically active 3aa-BH3 in 45% yield with 84:16 e.r.[16] While
electrophiles, respectively. The copper catalysis can provide a
new repertoire of umpolung, electrophilic amination approach to
a-aminophosphines, which are phosphorus analogues of a-
aminoacids and thus of high potential in medicinal and
pharmaceutical chemistry. Additionally, asymmetric induction is
also possible by using a chiral bisphosphine-ligated copper
catalyst. Ongoing work seeks to improve the catalytic activity
and enantioselectivity and to develop related C–N bond-forming
catalysis based on the electrophilic amination.
still
moderate
enantioselectivity,
subsequent
single
recrystallization from hexane increased the enantiomeric ratio to
99:1 e.r. Its absolute configuration was assigned to be R by the
single X-ray crystallographic analysis (Cu-Ka radiation, Flack
parameter
=
–0.002(11)).[13]
Some other vinylphosphine
boranes also underwent the asymmetric hydroamination with
similar enantioselectivity (3da-BH3, 3ga-BH3, 3ha-BH3), but a
[8e,f]
Me2N-modified hydroxylamine 2a-NMe2
was essential for
Acknowledgements
acceptable conversion. On the other hand, the piperidine
derivative 2d somewhat decreased the enantioselectivity (3ad-
BH3).
This work was supported by JSPS KAKENHI Grant Nos. JP
15H05485 (Grant-in-Aid for Young Scientists (A)) to K.H. and JP
17H06092 (Grant-in-Aid for Specially Promoted Research) to
M.M. We thank Dr. Yuji Nishii for his assistance with X-ray
analysis.
O
O
NR2
BH3
PPh2
2
O
+
+
PMHS
O
O
R1
PAr2
PAr2
R = H: 2
R = Me2N: 2-NMe2
R
1-BH3
Cu(OAc)2•OH2 (10 mol%)
(R)-DTBM-SEGPHOS (10 mol%)
H
BH3
PPh2
O
Conflict of interest
Ar = 3,5-tBu2-4-MeOC6H2
(R)-DTBM-SEGPHOS
R1
LiOtBu, CPME, RT, 4 h
NR2
3-BH3
2
The authors declare no conflict of interest.
H
BH3
H
BH3
PPh2
PPh2
C6H13
crystal structure of
(R)-3aa-BH3
NBn2
Keywords: a-aminophosphines • copper • electrophilic
NBn2
3aa-BH3 45% (2a)
84:16 e.r.
3da-BH3 53% (2a-NMe2)
87:13 e.r.
amination • hydroamination • synthetic method
recrystallization, 47%
99:1 e.r.
H
BH3
[1]
a) J. G. Allen, F. R. Atherton, M. J. Hall, C. H. Hassall, S. W. Holmes, R.
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ChemMedChem 2012, 7, 1601.
PPh2
H
BH3
H
BH3
C6H13
PPh2
PPh2
PivO
N
TBSO
NBn2
NBn2
3ga-BH3 30% (2a-NMe2)
89:11 e.r.
3ha-BH3 50% (2a-NMe2)
85:15 e.r.
3ad-BH3 47% (2d)
75:25 e.r.
Scheme 4. Regio- and enantioselective copper-catalyzed hydroamination of
1-BH3 with PMHS and 2 for synthesis of optically active a-aminophosphines 3-
BH3. The hydroxylamine used is in parentheses. Yields of the isolated
product are given. The enantiomeric ratio (e.r.) was determined by HPLC
analysis on a chiral stationary phase.
[2]
[3]
For seminal work and review, see: a) E. K. Fields, J. Am. Chem. Soc.
1952, 74, 1528; b) M. I. Kabachbik, T. Y. Medved, Bull. Acad. Sci.
USSR Div. Chem. Sci. (Engl. Transl.) 1953, 2, 769; c) G. Keglevich, E.
Balint, Molecules 2012, 17, 12821.
Finally, we conducted derivatization of (R)-3aa-BH3 (Scheme
5). The deprotection with DABCO at room temperature was
followed by oxidation with atmospheric oxygen to deliver the
optically active a-aminophosphine oxide (R)-3aa-O in 59% yield
For representative reviews on the electrophilic amination, see: a) E.
Erdik, M. Ay, Chem. Rev. 1989, 89, 1947; b) K. Narasaka, M. Kitamura,
Eur. J. Org. Chem. 2005, 21, 4505; c) E. Ciganek, Org. React. 2009, 72,
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248.
with only negligible erosion of enantiomeric ratio.[17]
The
obtained chiral a-aminophosphine oxide can be
a
useful
enantioselective
hemilabile
chiral
ligand
in
the
hydroformylation[18] as well as of potent interest in medicinal
application.[1]
[4]
[5]
a) S. E. Denmark, N. Chatani, S. V. Pansare, Tetrahedron 1992, 48,
2191; b) G. Jommi, G. Miglierini, R. Pagliarni, G. Sello, M. Sisti,
Tetrahedron 1992, 48, 7275; c) S. Hanessian, Y. L. Bennani, Synthesis
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Tetrahedron 1996, 52, 13783; e) L. Bernardi, W. Ahuang, K. A.
Jørgensen, J. Am. Chem. Soc. 2005, 127, 5772.
H
O
H
BH3
air
DABCO
PPh2
PPh2
C6H13
C6H13
toluene, RT, 8 h
NBn2
NBn2
For pioneering work on the electrophilic amination using the
hydroxylamines, see: a) H. Tsutsui, Y. Hayashi, K. Narasaka, Chem.
Lett. 1997, 26, 317; b) A. M. Berman, J. S. Johnson, J. Am. Chem. Soc.
2004, 126, 5680; c) S. Liu, L. S. Liebeskind, J. Am. Chem. Soc. 2008,
(R)-3aa-O 59% (76% brsm)
(R)-3aa-BH3 99:1 e.r.
96:4 e.r.
Scheme 5. Conversion of (R)-3aa-BH3 to (R)-3aa-O.
130, 6918.
For a unique organocatalytic approach with the
hydroxylamine, see: d) M. J. MacDonald, C. R. Hesp, D. J. Schipper, M.
Pesant, A. M. Beauchemin, Chem. Eur. J. 2013, 19, 2597.
S. L. McDonald, Q. Wang, Angew. Chem. Int. Ed. 2014, 53, 1867;
Angew. Chem. 2014, 126, 1898.
In conclusion, we have developed
a
copper-catalyzed
vinylphosphines with
hydrosilanes and hydroxylamines as hydrides and amine
regioselective
hydroamination
of
[6]
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10.1002/chem.201802491
Chemistry - A European Journal
COMMUNICATION
[7]
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Chem. Eur. J. 2017, 23, 17800.
[11] The observed regioselectivity can be attributed to the electron-
withdrawing nature of phosphine oxide and phosphine borane groups.
[12] See the Supporting Information for more detailed optimization studies.
[13] CCDC 1840666 (3ca-BH3) and 1840667 ((R)-3aa-BH3) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
[8]
[14] P. Aschwanden, C. R. J. Stephenson, E. M. Carreira, Org. Lett. 2006, 8,
2437.
[9]
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[16] See the Supporting Information for optimization studies on asymmetric
catalysis.
[17] The Cu(OAc)2/(R)-DTBM-SEGPHOS catalyst also promoted the
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50:50 e.r. See the Supporting Information for details.
[18] C. Abu-Gnim, I. Aner, J. Organomet. Chem. 1996, 516, 235.
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Synthesis of -Aminophosphines by
a
Copper-Catalyzed Regioselective
Hydroamination of Vinylphosphines
Between P and N: A copper-catalyzed net hydroamination of vinylphosphine
boranes with hydrosilanes and O-benzoylhydroxylamines has been developed.
The reaction proceeds regioselectively to form the corresponding a-
aminophosphine boranes of potent interest in medicinal and pharmaceutical
chemistry. Additionally, while still preliminary, asymmetric synthesis is also
achieved by judicious choice of chiral bisphosphine-ligated copper complex.
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