Chiral aminophosphines as catalysts for enantioselective double-michael indoline syntheses

Article abstract of DOI:10.3390/molecules17055626

The bisphosphine-catalyzed double-Michael addition of dinucleophiles to electron-deficient acetylenes is an efficient process for the synthesis of many nitrogencontaining heterocycles. Because the resulting heterocycles contain at least one stereogenic center, this double-Michael reaction would be even more useful if an asymmetric variant of the reaction were to be developed. Aminophosphines can also facilitate the double-Michael reaction and chiral amines are more readily available in Nature and synthetically; therefore, in this study we prepared several new chiral aminophosphines. When employed in the asymmetric double-Michael reaction between ortho-tosylamidophenyl malonate and 3-butyn-2-one, the chiral aminophosphines produced indolines in excellent yields with moderate asymmetric induction.

Full text of DOI:10.3390/molecules17055626

Molecules 2012, 17, 5626-5650; doi:10.3390/molecules17055626
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Chiral Aminophosphines as Catalysts for Enantioselective
Double-Michael Indoline Syntheses
San N. Khong and Ohyun Kwon *
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA
* Author to whom correspondence should be addressed; E-Mail: ohyun@chem.ucla.edu.
Received: 23 March 2012; in revised form: 19 April 2012 / Accepted: 23 April 2012 /
Published: 11 May 2012
Abstract: The bisphosphine-catalyzed double-Michael addition of dinucleophiles to
electron-deficient acetylenes is an efficient process for the synthesis of many nitrogen-
containing heterocycles. Because the resulting heterocycles contain at least one stereogenic
center, this double-Michael reaction would be even more useful if an asymmetric variant of
the reaction were to be developed. Aminophosphines can also facilitate the double-Michael
reaction and chiral amines are more readily available in Nature and synthetically; therefore,
in this study we prepared several new chiral aminophosphines. When employed in the
asymmetric double-Michael reaction between ortho-tosylamidophenyl malonate and
3-butyn-2-one, the chiral aminophosphines produced indolines in excellent yields with
moderate asymmetric induction.
Keywords: double-Michael reaction; chiral aminophosphines; anchimeric assistance;
indoline
1. Introduction
Most chiral natural products exist in enantiomerically pure forms, synthesized in Nature mostly
through enzyme-mediated catalysis [1]. Not surprisingly, enantioselective catalysis processes were
long believed, up until the early 1900s, to be accessible using only natural enzymes, until Bredig’s
attempts at (i) kinetic resolution of racemic camphorcarboxylic acid through selective decarboxylation
in a chiral medium (e.g., L- or D-limonene) or in the presence of a chiral alkaloid catalyst (e.g.,
nicotine or quinidine) [2–5] and (ii) asymmetric synthesis of mandelonitrile through the addition of
HCN to benzaldehyde in the presence of a cinchona alkaloid catalyst (e.g., quinidine or quinine) [2,3,6].

Molecules 2012, 17
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Although these effortful studies were conceptually groundbreaking, the enantioselectivity achieved
was synthetically impractical (<10% ee). A synthetically useful enantiomeric excess of 74% was first
achieved by Pracejus in the synthesis of (–)-methyl α-phenylpropionate from methyl phenyl ketene and
methanol with O-acetylquinine as the catalyst [7]. Catalytic asymmetric synthesis was established as a
reliable and practical approach when Knowles reported, in the late 1960s and early 1970s, the first
asymmetric hydrogenations catalyzed by transition metals bearing chiral phosphine ligands [8–13].
Shortly afterward, a great number of chiral phosphine ligands were developed to provide excellent
enantioselectivity in transition metal-catalyzed hydrogenations [14,15]. The major disadvantage of
transition metal catalysis, however, is that traces of toxic heavy metals can be left behind in the
final products.
In the early 1970s, L-proline-mediated asymmetric Robinson annulation was first reported [16–19],
although the synthesis community paid very little attention to it because the reaction was considered a
novelty. Since the concept of organocatalysis—the utilization of metal-free small organic molecules as
catalysts for organic transformations—was developed and recognized in the late 1990s, there has been an
explosion of research in the field of organocatalysis [20–22], which is now widely considered as a third
main branch of research in asymmetric synthesis, beside enzymatic catalysis and organometallic catalysis.
A chiral organocatalyst can render enantioinduction (asymmetric induction) through a few modes,
including covalent bonding, ionic bonding, and hydrogen bonding (Figure 1a–c) [21]. In 2007, we
reported a phosphine-catalyzed double-Michael addition in which a bisphosphine was the best
catalyst [23–25]. We suggested that anchimeric assistance by the other tethered phosphino group
stabilized the resultant phosphonium cation in the transitional intermediates, leading to a higher yield
of the double-Michael adduct. Because of the rigid architecture provided by intramolecular anchimeric
assistance, we suspected that a chiral element at the terminus of the non-reactive phosphino group
would be likely to endow the reactive phosphonium center with steric bias, potentially leading to a new
mode of enantioinduction (Figure 1d). Practically, the synthesis of chiral bisphosphines is often
challenging because it requires careful handling of pyrophoric and air-sensitive phosphorus-containing
intermediates.
As a variant of the bisphosphine catalyst, we sought an equivalent to a phosphino group that would
be easy to handle yet stabilize the tethered phosphonium cation through anchimeric assistance. In
Verkade’s proazaphosphatrane [26–28], the nitrogen atom could efficiently stabilize the resultant
protonated phosphonium center, making it a super base (Figure 2a). Therefore, we expected an
aminophosphine—with an amino group replacing a tethered phosphino group in the bisphosphine—To
function much like a bisphosphine when catalyzing double-Michael additions (Figure 2b). Less-toxic
and more air-stable than phosphines, amines also have advantages in terms of their synthesis and
storage. Furthermore, many diverse chiral amines are readily available commercially from natural
sources. Appending a customized chiral element to an achiral amine is also easy to achieve through
simple alkylation, imine reduction, or peptide coupling/reduction. Therefore, we proceeded to synthesize
a variety of chiral aminophosphines to determine if they could result in enantioinduction via anchimeric
assistance and concurrently to develop an asymmetric variant of the double-Michael reaction.

Molecules 2012, 17
Figure 1. Modes of enantioselective induction provided by organocatalysts through
5628
(a) covalent bonding; (b) ionic bonding; (c) hydrogen bonding; and (d) intramolecular
anchimeric assistance.
Figure 2. Possible intramolecular anchimeric assistance. (a) Verkade’s protonated
proazaphosphatrane; (b) Utilization of a chiral aminophosphine instead of a chiral
bisphosphine.

Molecules 2012, 17
5629
We propose a reaction mechanism for the double-Michael reaction that occurs via pathway A, in
which the cyclization is accomplished through direct intramolecular SN2 displacement of the
phosphonium cation (Scheme 1). Alternatively, the reaction could possibly follow mechanistic
pathway B, in which the intermediate phosphonium zwitterions serve as a Brønsted base and the
resulting phosphonium species as a counter cation of the reactive intermediate anions (Scheme 1).
In either case, the most important factor affecting the success of cyclization would be the stability of
the phosphonium species generated along the pathway [23]. If the reaction employed a chiral
aminophosphine catalyst, the enantioselectivity would probably be induced via anchimeric assistance
of the amine in stabilizing the quaternary phosphonium center.
Scheme 1. Possible mechanistic pathways for the double-Michael reaction.
2. Results and Discussion
Chiral bisphosphines featuring C2- or local C2-symmetry, obtained directly from commercial
sources, were tested in the double-Michael reaction between o-(p-tosylamido)phenylmalonate (1a) and
3-butyn-2-one (2a) to form the indoline product 3aa (Table 1) [29]. The optimal conditions for the
reaction catalyzed by diphenylphosphinopropane (DPPP) required an elevated temperature (entry 1).
Employing chiral bisphosphines as catalysts, the double-Michael reaction at elevated temperature
exhibited no enantioinduction (entries 2, 4, and 6). At room temperature, however, the reactions
exhibited low levels of enantioselectivity (entries 3, 5, 7, and 8). Employing (S,S)-DIOP as a chiral
catalyst resulted in no desired product (entry 9). Use of the chiral bisamine (DHQ)2PHAL provided a
lower yield, with no improvement in enantioselectivity (entry 10). Catalysis by the (R,R)-DACH-
napthyl Trost ligand, a chiral bisamidophosphine, resulted in a much inferior yield, with no
enantioselectivity (entry 11). Surprisingly, the aminophosphine 42, which has the same rigid carbon
framework and distance between the two functional groups as that in DIOP, catalyzed the reaction
successfully, providing a good yield and a slightly improved enantioselectivity (entries 9 and 12). This
result offered us hope that we could develop an asymmetric variant of the double-Michael addition
using a chiral aminophosphine as the catalyst.

Molecules 2012, 17
5630
Table 1. Preliminary screening with commercially available chiral bisphosphines [29].
Temp
(°C)
Time
(h)
Yield
(%) a
ee
(%)
Entry
Catalyst
1
2
DPPP
80
80
9
7
81
80
0
0
(S,S)-
DIPAMP
3
4
rt b
80
48
9
87
51
5
0
(R,R)-Et-
DuPHOS
5
6
rt
9
7
58
72
5
0
80
(S,S)-Me-BPE
7
8
rt
rt
9
9
78
66
5
5
(R)-BINAP
(S,S)-DIOP
9
rt
rt
24
9
n/r c
46
n/a d
10
(DHQ)2PHAL
5
(R,R)-DACH-
napthyl
11
rt
rt
16
24
21
86
0
6
Trost ligand
12 e
(4S,5R)-42
a Isolated yield. b rt = Room temperature. c n/r = No reaction. d n/a = Not applicable. e Synthetically
prepared phosphine.

Molecules 2012, 17
5631
2.1. Synthesis of Aminophosphines
Scheme 2 outlines our approach for the syntheses of three-carbon-tethered aminophosphines. It
starts with acylation of a primary or secondary amine with acryloyl chloride to form the corresponding
acrylamide, followed by Michael addition of diphenylphosphine to generate an amidophosphine [30],
which would eventually be converted to the aminophosphine through LiAlH4-mediated reduction.
Because the chirality of the amine would be endowed to the reactive phosphonium center, our goal was
to identify potential chiral amines from either commercial or synthetic sources. Notably, we could also
test the amidophosphine, an immediate precursor of the aminophosphine, for its enantioinduction
ability in double-Michael reactions.
Scheme 2. General route toward a 3-amino-1-phosphinopropane.
2.2. Syntheses of Chiral Aminophosphines from a Commercially Available Chiral Amine
To test the viability of the proposed synthetic route, we employed an inexpensive chiral amine 1 to
synthesize the chiral aminophosphine 5 (Scheme 3). The chiral amine 1 was first N-methylated via
formylation followed by LiAlH4-mediated reduction to furnish the chiral amine 2, which we then
treated with acryloyl chloride to prepare the acrylamide substrate 3 for subsequent Michael addition of
diphenylphosphine. We obtained our target aminophosphine 5 after LiAlH4-mediated reduction of the
Michael adduct amidophosphine 4. This synthetic route was reliable and the purification of the
products was straightforward. When testing the chiral aminophosphine 5 in the double-Michael
addition, we detected an enantioselectivity of 5% ee. The reaction yield was, however, low, due to our
early termination of the reaction to determine the enantioselectivity (Table 2, entry 1).
Shortening the tether length in the aminophosphine would bring the two functional groups in closer
proximity, potentially enhancing the interaction between amino and phosphino centers and forming
more-rigid reaction intermediates. Accordingly, we synthesized the aminophosphine 7 from the amine
2 through coupling with bromoacetyl bromide, substitution with potassium diphenylphosphide, and
LiAlH4-mediated reduction of the amidophosphine 6. To our dismay, when we employed this chiral
aminophosphine 7 in the double-Michael reaction, the enantioselectivity of the reaction was barely
detectable (Table 2, entry 2). We surmised that it might be more advantageous to feature a free N–H
group in the aminophosphine to provide a site for hydrogen bonding to the C=O oxygen atom of the
alkynone substrate [31–35]; such hydrogen bonding would bring the two functional groups closer
together in the transition intermediate (Figure 3). Thus, we treated the chiral amine 1 with acryloyl
chloride to prepare the acrylamide 8; Michael addition with diphenylphosphine under basic conditions
furnished the amidophosphine 9, which underwent LiAlH4-mediated reduction to generate the target
chiral aminophosphine 10. The enantioinduction in the double-Michael reaction catalyzed by the
aminophosphine 10 was similarly low to that induced by the aminophosphine catalyst 5, which
features no N–H bond (Table 2, entry 3). Interestingly, the amidophosphines 4, 6, and 9 also catalyzed

Molecules 2012, 17
5632
the double-Michael reaction, with yields and enantioselectivities comparable to those of their
corresponding aminophosphines (Table 2, cf. entries 1–3 and 14–16).
Scheme 3. Syntheses of two- and three-carbon-tethered aminophosphines.
Table 2. Screening with synthetic chiral aminophosphines and amidophosphines.
Yield
ee
Yield
(%) a
ee
Entry
Aminophosphine
Entry
Amidophosphine
(%) a (%) b
(%) b
1 b
2
46
86
5
0
14
15
39
95
5
0
3
4
84
83
4
3
16
17
85
91
4
0

Molecules 2012, 17
5633
Table 2. Cont.
Yield
ee
Yield
(%) a
ee
Entry
Aminophosphine
Entry
Amidophosphine
(%) a (%) b
(%) b
5
89
74
73
6
2
2
18
19
20
94
86
9
0
6
7
n/a c
n/a d
n/a d
8
9
84
91
83
–9
–2
0
21
22
23
n/a c
n/a c
n/a c
n/a d
n/a d
n/a d
n/a d
n/a d
n/a d
10
11
12
86
69
–6
10
24
25
n/a c
n/a d
n/a d
81
0
13
90
3
26
88
3
a Isolated yield. b Reaction time was 6 h. c n/a = Not available. d n/a = Not applicable.
Figure 3. Transition intermediate featuring intramolecular hydrogen bonding.

Molecules 2012, 17
5634
2.3. Syntheses of L-Proline-Derived Chiral Aminophosphines
Because our simple versions of aminophosphines with acyclic chiral amine motifs did not work
well as catalysts for the asymmetric double-Michael additions, we decided to insert a more-rigid chiral
amine motif derived from L-proline, which has been employed frequently in asymmetric reactions [36,37].
O-Benzyl aminophosphine 17 became our first synthetic target (Scheme 4). After a simple sequence of
LiAlH4-mediated reduction, N-Boc protection, and O-benzylation, we obtained the globally protected
L-prolinol 14. The Boc group of 14 was released under acidic conditions and the resulting free amine
converted to the acrylamide 15 upon treatment with acryloyl chloride. Michael addition of
diphenylphosphine to the acrylamide 15 under basic conditions cleanly afforded the amidophosphine
16, which underwent LiAlH4-mediated reduction to yield the target aminophosphine 17. Unfortunately,
we detected only 3% ee when applying the aminophosphine 17 to catalyze the double-Michael
reaction. The corresponding amidophosphine 16 provided undetectable enantioselectivity, although the
product yield was higher than that obtained with the aminophosphine 17 (Table 2, entries 4 and 17).
Scheme 4. L-Proline-derived chiral aminophosphines.

Molecules 2012, 17
5635
We suspected that unmasking the OH group in the aminophosphine 17 might potentially provide
hydrogen bonding to the C=O oxygen atom in the alkynone substrate, possibly helping to lock the
reaction intermediates into a more-rigid conformation and, hopefully, create a more-asymmetric
environment in the subsequent steps toward the final product (Figure 4) [31–35]. The hydroxymethyl
aminophosphine 19 was quickly accessible from the unprotected L-prolinol 12 through the sequence
of N-acryloylation, Michael addition of diphenylphosphine, and LiAlH4-mediated reduction. The
resulting enantioselectivities were slightly increased and encouraging: 6% ee for the aminophosphine
19 and 9% ee for the corresponding amidophosphine 18 (Table 2, entries 5 and 18). Notably, the yield
and enantioselectivity provided by the amidophosphine 18 were superior to those induced by the
aminophosphine 19 in the double-Michael addition.
Figure 4. Proposed conformation of an intermediate stabilized through intramolecular
hydrogen bonding and intramolecular anchimeric assistance.
Another scaffold, based on amino acid-derived phosphines, has recently been employed in
asymmetric nucleophilic catalysis [33–35]. In this scaffold, the two functional groups are tethered
through two carbon atoms, with the chiral element residing on the tether bridge. The aminophosphines
21 and 23–25 are derived accordingly from L-proline. The N-Tosyl aminophosphine 21 was quickly
prepared from L-prolinol 12 after global tosylation and subsequent direct displacement of the tosylate
group with potassium diphenylphosphide. The aminophosphines 24 and 25 were both obtained from
the aminophosphine 23, through LiAlH4-mediated reduction and acidic Boc-deprotection, respectively;
the aminophosphine 23 itself was quickly accessible through tosylation of N-Boc-L-prolinol 13 and
subsequent substitution with potassium diphenylphosphide. To our dismay, these L-proline-derived
aminophosphines provided generally unsatisfactory levels of enantioselectivity in the double-Michael
reaction, with the exception of 23 (Table 2, entries 8–11).
Introduction of the more substituents to the chiral element in L-proline-derived aminophosphine
could possibly enhance the catalyst enantioinduction. Aminophosphine 31 and 32 were thus
synthesized as illustrated in Scheme 5. α,α-Diphenyl L-prolinol trimethylsilyl ether 28, which was
easily prepared from L-proline (11) using a reported procedure, was subjected to the aforementioned
route of phosphine synthesis including acryloylation and Michael-addition of diphenylphosphine.
Unexpectedly, TMS protecting group was cleaved under basic Michael-addition condition to yield the
hydroxy amidophosphine 30. The reintroduction of the silyl protecting group to amidophosphine 30
was not achievable due to the hydrolysis of the product during chromatography. Amidophosphine 30
was then set forward to LAH reduction to provide aminophosphine 31 which could be silylated to
furnish O-TMS aminophosphine 32. Yet, the application of aminophosphine 31 and 32 to the double-
Michael reaction only provided lower reaction yield and enantioselectivity (Table 2, entries 6 and 7).

Molecules 2012, 17
5636
Likewise, amidophosphine 30 resulted in no enantioinduction despite higher yield than the
corresponding aminophosphine 31 in the double-Michael reaction (Table 2, entry 19).
Scheme 5. Elaboration of an L-proline-derived aminophosphine.
2.4. Syntheses of Binol-Derived Chiral Aminophosphines
Because the L-proline-derived aminophosphines were not satisfactory sources of asymmetric
induction in the double-Michael reaction, we sought to prepare binol-derived aminophosphines
featuring local C2 symmetry on the amino moiety. Chiral binol and its derivatives have been used as
sources of asymmetry in several chiral catalysts [38–41]; therefore, we selected binol as our first
choice for the preparation of C2-symmetric amine-containing aminophosphines. Scheme 6 outlines our
synthesis of the aminophosphine 41. Within five steps, using a known procedure, we obtained the local
C2-symmetric amine 38 from commercially available (S)-binol (33). We subjected the crude product of
the amine 38 directly to acryloylation to cleanly yield the acrylamide 39. Subsequent Michael addition
of diphenylphosphine and LiAlH4-mediated reduction afforded the amidophosphine 40 and the
aminophosphine 41, respectively. Our earlier version of the binol-derived aminophosphine 42 (Table 1,
entry 18) is distinct from aminophosphine 41 in that the latter possesses a shorter, more-flexible
tethering carbon atom chain. The aminophosphine 41 provided better enantioselectivity toward the
double-Michael reaction, albeit with lower yield, than the aminophosphine 42 (cf. Table 1, entry 12
with Table 2, entry 12). The amidophosphine 40, however, provided undetectable enantioselectivity in
the double-Michael reaction, even though its reaction yield was higher than that of the aminophosphine
41 (Table 2, entry 25).

Molecules 2012, 17
5637
Scheme 6. Synthesis of a binol-derived aminophosphine.
Tf2O (2.2 eq)
MeMgBr (3.0 eq)
NiCl2(dppp) (3.0 mol%)
TEA (3.0 eq)
OTf
OTf
OH
OH
DCM, 78oC
quant. yield
rt, 2 h
dry Et2O
reflux, overnight
97%
33
34
35
NBS (2.2 eq)
AIBN (10 mol%)
Br
Br
(2.2 eq)
NH2
N
MeCN, 55 oC, 8 h
99%
dry cyclohexane
reflux, overnight
68%
36
37
O
N
N
Acryloyl chloride (1.2 eq)
TEA (1.5 eq)
(3.0 eq)
O
O
O
N
NH
DCM, 0 oC
overnight, 75% (2 steps)
rt
Pd(OAc)2 (2.0 mol%), PPh3 (0.5 eq)
degassed DCM, 35 oC, 19 h
38
39
PPh2
PPh2
Ph2PH (1.2 eq), few drops
of Et4NOH (35% H2O)
LAH (5.0 eq)
N
N
MeCN, rt, overnight
85%
O
THF, 0 oC
83%
rt, 5 h
40
41
Encouraged by a slight improvement in enantioselectivity, we considered modifying the
aminophosphine 41 to hopefully further enhance the enantioselectivity of the double-Michael addition.
The introduction of an aryl group to binaphthyl systems at the 3 and 3' positions is commonly applied
to enhance the steric bias of the molecule and increase the reaction’s enantioselectivity (Figure 5) [42,43].
We decided to install naphthyl groups on the binaphthyl framework because of the ready availability of
the requisite reagent and the medium size of the naphthyl group.
Figure 5. Elaboration of the C2-symmetric element in the aminophosphine.
Using a reported multistep synthesis, we installed naphthyl substituents at the desired 3,3'-positions
to obtain the intermediate amine 55. Subjecting the crude amine 55 to the aforementioned conditions
for aminophosphine synthesis, we eventually isolated the amidophosphine 57 and the aminophosphine
58 (Scheme 7). Surprisingly, the aminophosphine 58 provided only 3% ee, lower than the

Molecules 2012, 17
5638
enantioselectivity obtained when using the unmodified aminophosphine 41 (Table 2, entries 12 and 13).
Similarly, application of the amidophosphine 57 to the double-Michael reaction gave a yield of 88%
and an enantioselectivity of only 3% ee (Table 2, entry 26).
Scheme 7. Synthesis of a modified binol-derived aminophosphine.

Molecules 2012, 17
5639
3. Experimental
3.1. General
All reactions were performed in flamed-dried round-bottom flasks under an atmosphere of Ar with
dry solvents, unless otherwise noted. A glass water condenser, fitted with a rubber septum, was
attached to each flask in the cases of reactions performed under reflux. A syringe pump and
stainless-steel needles were used for slow addition of reagents into the reaction mixtures. Reactions
were monitored through thin-layer chromatography (TLC) on 0.25-mm SiliCycle silica gel plates,
visualizing under UV light or staining with iodine, p-anisaldehyde, or potassium permanganate. Flash
column chromatography (FCC) was performed using SiliCycle Silica-P Flash silica gel (60 Å pore
size, 40–63 μm) and compressed air. Purification of phosphines was performed through quick FCC;
phosphine-containing fractions were collected immediately into a flask secured under Ar. Organic
solvents were evaporated in rotary evaporators under reduced pressure; the flasks were refilled with Ar
when isolating phosphines. Phosphine products were stored under Ar at all times.
3.2. Materials and Reagents
Reagents were used as received from commercial sources, unless otherwise noted. Acryloyl
chloride and potassium phosphate tribasic n-hydrate were purchased from Fluka. Tetraethylammonium
hydroxide (37% w/w, aqueous solution), trifluoroacetic anhydride, N,N-dimethylbarbituric acid,
methyl iodide, and (R)-(+)-1-phenylethylamine 1 were purchased from Alfa Aesar. Bromoacetyl
bromide, lithium aluminum hydride (LAH), potassium diphenylphosphide (0.5 M in THF),
methylmagnesium bromide (3.0 M in diethyl ether), hydrogen peroxide (30–32 wt %, solution in
water), n-butyllithium (1.6 M in hexanes), sodium hydride (60% dispersion in mineral oil),
methoxymethyl chloride, methyl magnesium iodide (3.0 M in diethyl ether), azobisisobutyronitrile
(AIBN), boron tribromide, allylamine, and L-proline (11) were purchased from Aldrich. Trimethyl
borate, ethyl formate, and NiCl2(dppp) were purchased from Acros Organics. Palladium(II) acetate
was purchased from Strem Chemicals. 2-Naphthaleneboronic acid and (S)-(–)-1,1'-bi-2-naphthol (33)
were purchased from Combi-Blocks. Trifluoromethanesulfonic anhydride was purchased from
Oakwood. Phenylmagnesium bromide was freshly prepared before use. N-Bromosuccinimide was
recrystallized from distilled water. TMSOTf was prepared using a published procedure [44,45].
Diphenylphosphine was prepared and purified using published procedures [46,47]. Allylamine was
redistilled prior to use. Acetonitrile (MeCN), dichloromethane (DCM), and triethylamine (TEA) were
distilled from CaH2 under Ar atmosphere. Tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled from Na and benzophenone under Ar atmosphere. Dry MeCN and dry DCM were
deoxygenated using three freeze/pump/thaw degassing cycles.
3.3. Instrumentation
IR spectra were recorded using a Perkin–Elmer Paragon 1000 FTIR spectrometer. NMR spectra
were recorded using Bruker Avance-500, ARX-500, or Avance-300 instruments, calibrated to signals
from the solvent as an internal reference [7.26 (residual CHCl3) and 77.00 (CDCl3) ppm for ¹H and

Molecules 2012, 17
5640
1
¹³C-NMR spectra, respectively]. Data for H-NMR spectra are reported in terms of chemical shift
(δ, ppm), multiplicity, coupling constant (Hz), and integration. Data for 13C-NMR spectra are reported
in terms of chemical shift (δ, ppm), multiplicity, and coupling constants (Hz) in the case of JCP
coupling. The following abbreviations are used to denote multiplicities: s = singlet; d = doublet;
t = triplet; q = quartet; qi = quintet; m = multiplet; br = broad; app = apparent. Mass spectra were
analyzed using instrument-supplied software. Gas chromatography/mass spectrometry (GC–MS) data
were obtained using an Agilent 6890–5975 GC–MS system equipped with an autosampler and an HP5
column; samples were dissolved in DCM.
3.4. Procedures for Syntheses of Amidophosphines and Aminophosphines
The amine 2 [48] and the acrylamide 8 [49] in Scheme 3 were prepared following reported
procedures. Compounds 12 [50], 13 [51], 14 [52], 20 [53], 21 [54], 22, 23, 25 [55], and 24 [56] in
Scheme 4 provided spectral data matching those reported in the literature. Compounds 26, 27 [57], and
28 [58] in Scheme 5 were prepared following reported procedures. Compounds 34–38 and 43–55 were
prepared following published procedures [43].
(R)-N-Methyl-N-(1-phenylethyl)acrylamide (3). The amine 2 (676 mg, 5 mmol) and dry DCM (20 mL)
were placed in a flame-dried flask containing a stirrer bar. Et3N (1.5 equiv.) was added to the solution
and then the reaction mixture was cooled to 0 °C. Acryloyl chloride (1.2 equiv.) was added and then
the mixture was stirred at room temperature overnight under Ar. The reaction was quenched through
the addition of aqueous ammonium chloride; the mixture was extracted with DCM (2 × 10 mL) and
the organic phases combined, dried (Na2SO4), and concentrated. The residue was purified through
column chromatography (SiO2; 30% EtOAc/Hex) to afford a pale yellow oil 3 (842.1 mg, 89%).
1H-NMR (300 MHz, CDCl3) δ (both rotamers) 7.28 (br s, 5H), 6.71–6.52 (m, 1H), 6.39–6.28 (m, 1H),
6.09 (q, J = 6.9 Hz, 0.6H), 5.69 (app d, J = 8.7 Hz, 1H), 5.23 (q, J = 6.0 Hz, 0.4H), 2.69 (s, 1H), 1.58
13
(d, J = 6.0 Hz, 1H), 1.48 (d, J = 6.9 Hz, 2H); C-NMR (75 MHz, CDCl3) δ (both rotamers) 167.2,
166.4, 140.4, 140.2, 128.7, 128.5, 128.2, 128.1, 127.6, 127.3, 126.5, 54.9, 50.6, 29.6, 28.1, 17.6, 15.5.
(R)-3-(Diphenylphosphino)-N-methyl-N-(1-phenylethyl)propanamide (4). The acrylamide 3 (568 mg,
3 mmol) and Ph2PH (783 L, 4.5 mmol) were placed in a flask containing deoxygenated MeCN
(15 mL). Aqueous 1 N NaOH (13 drops) was added and then the mixture was heated under reflux
overnight. After cooling, the reaction mixture was washed with water, dried (Na2SO4), and
concentrated. The residue was purified through column chromatography (SiO2; 30% EtOAc/Hex) to
1
afford a colorless oil 4 (788.4 mg, 70%). H-NMR (500 MHz, CDCl3) δ (both rotamers) 7.52 (br s,
5H), 7.38 (br s, 9H), 7.3 (br s, 4H), 7.18 (br s, 0.8H), 6.13 (q, J = 7.3 Hz, 0.7H), 4.99 (q, J = 7.3 Hz,
0.3H), 2.73 (br s, 1H), 2.57 (br s, 3H), 2.53–2.48 (m, 4H), 1.56 (d, J = 7.2 Hz, 1H), 1.51 (d, J = 7.2 Hz,
3H); 13C-NMR (125 MHz, CDCl3) δ 172.1 (d, J = 14.4 Hz), 140.5, 138.2, 138.1, 138.05, 138.00, 132.7
(d, J = 6.5 Hz), 132.6 (d, J = 6.5 Hz), 128.60, 128.58, 128.4, 128.35, 128.3, 127.2, 127.1, 50.3, 30.2 (d,
J = 20.5 Hz), 29.2, 23.0 (d, J = 10.9 Hz), 15.5 (rotamer) 172.1 (d, J = 14.4 Hz), 140.1, 138.3, 138.2,
138.0, 137.9, 132.6, 132.5, 127.3, 126.2, 54.4, 29.6 (d, J = 20.5 Hz), 28.0, 23.4 (d, J = 10.9 Hz), 17.6 ;
31P-NMR (202 MHz, CDCl3) δ −14.0, (rotamer) −14.2.

Molecules 2012, 17
5641
(R)-3-(Diphenylphosphino)-N-methyl-N-(1-phenylethyl)propan-1-amine (5). A solution of the
amidophosphine 4 (750.8 mg, 2 mmol) in dry THF (10 mL) was cannulated into a slurry of LAH
(379.5 mg, 10 mmol) in dry THF (10 mL) at 0 °C. The mixture was then stirred at room temperature
overnight before being cooled at 0 °C and having the reaction quenched through slow addition of 1 N
NaOH (5 mL, 5 mmol). The reaction mixture was dried with Na2SO4 (vigorous stirring for 20 min),
then filtered through Celite and washed with Et2O (3 × 10 mL). After concentrating the filtrate, the
residue was purified through column chromatography (SiO2; 3% Et3N in 10% EtOAc/Hex) to afford a
1
colorless oil 5 (585.5 mg, 81%). H-NMR (500 MHz, CDCl3) δ 7.46–7.42 (m, 5H), 7.36–7.32 (m,
10H), 3.57 (q, J = 6.7 Hz, 1H), 2.56–2.50 (m, 1H), 2.42–2.37 (m, 1H), 2.17 (s, 3H), 2.10–1.98 (m,
13
2H), 1.66–1.58 (m, 2H), 1.37 (d, J = 6.7 Hz, 3H); C-NMR (125 MHz, CDCl3) δ 143.9, 138.93 (d,
J = 13.3 Hz), 138.87 (d, J = 13.3 Hz), 132.7 (d, J = 4.4 Hz), 132.6 (d, J = 4.4 Hz), 128.4, 128.3, 128.2,
128.0, 127.6, 126.6, 63.1, 55.2 (d, J = 13.5 Hz), 38.3, 25.5 (d, J = 11.0 Hz), 23.5 (d, J = 16.0 Hz), 18.3;
31P-NMR (202 MHz, CDCl3) δ −15.1; GCMS (EI+) calcd for [C9H4Cl2O]: m/z 361.2, found 361.3.
(R)-2-(Diphenylphosphino)-N-methyl-N-(1-phenylethyl)acetamide (6). The amine 2 (676 mg, 5 mmol)
was added to a solution of DMAP (733 mg, 6 mmol) in dry THF (50 mL). The mixture was cooled to
0 °C and then bromoacetyl bromide (1.21 g, 6 mmol) in dry THF (20 mL) was added slowly. After
stirring at room temperature for 2 h, the mixture was filtered through a short pad of silica gel, which
was washed with Et2O until the product had completely eluted out. The filtrate was concentrated and
then replenished with dry THF (50 mL). The mixture was cooled to –78 °C and then Ph2PK (0.5 N in
THF, 7.5 mmol, 15 mL) was added slowly. The mixture was stirred overnight at room temperature and
then it was quenched (saturated NH4Cl), washed (water), dried (Na2SO4), and concentrated. The
residue was purified through column chromatography (SiO2; gradient 20–50% EtOAc/Hex) to afford a
1
colorless oil 6 (513 mg, 40%). H-NMR (300 MHz, CDCl3) δ (both rotamers) 7.54–7.47 (m, 6H),
7.35–7.19 (m, 15H), 6.03 (q, J = 7.1 Hz, 1H), 5.33 (q, J = 7.1 Hz, 0.4H), 3.32 (s, 0.8H), 3.23 (s, 2H),
13
2.67 (s, 1.2H), 2.65 (s, 3H), 1.56 (d, J = 7.0 Hz, 1.2H), 1.42 (d, J = 7.0 Hz, 3H); C-NMR (75 MHz,
CDCl3) δ (both rotamers) 169.84 (d, J = 7.8 Hz), 169.8 (d, J = 7.8 Hz), 140.6, 140.3, 138.2 (d, J = 14.3 Hz),
138.0 (d, J = 14.3 Hz), 133.0, 132.7, 128.9, 128.7, 128.6, 128.5, 128.4, 127.5, 127.3, 127.2, 126.5,
50.5, 35.7, 35.4, 30.4, 30.3, 28.2, 17.9, 15.5; 31P-NMR (121 MHz, CDCl3) δ −18.8, (rotamer) −18.7.
(R)-2-(Diphenylphosphino)-N-methyl-N-(1-phenylethyl)ethanamine (7). Using the procedure described
for the synthesis of the aminophosphine 5, the aminophosphine 7 (67%) was obtained as a colorless
1
oil. H-NMR (300 MHz, CDCl3) δ (both rotamers) 7.40–7.34 (m, 4H), 7.33–7.19 (m, 11H), 3.56 (q,
J = 6.8 Hz, 1H), 2.67–2.43 (m, 2H), 2.31–2.16 (m, 5H), 1.30 (d, J = 6.8 Hz, 3H); 13C-NMR (75 MHz,
CDCl3) δ 144.0, 138.7 (d, J = 12.6 Hz), 138.6 (d, J = 12.6 Hz), 132.8 (d, J = 1.9 Hz), 132.5 (d,
J = 1.9 Hz), 128.5, 128.48, 128.44, 128.35, 128.2, 127.6, 126.8, 63.1, 51.0 (d, J = 22.9 Hz), 38.5, 25.9
(d, J = 12.0 Hz), 18.9; 31P-NMR (121 MHz, CDCl3) δ −19.9.
(R)-3-(Diphenylphosphino)-N-(1-phenylethyl)propanamide (9). Using the procedure described for the
synthesis of the aminophosphine 10, but stopping at the first step, the amidophosphine 9 was obtained
1
as a colorless oil. H-NMR (300 MHz, CDCl3) δ 7.45–7.39 (m, 4H), 7.36–7.27 (m, 11H), 5.64 (d,
J = 7.3 Hz, 1H), 5.10 (app qi, J = 7.3 Hz, 1H), 2.43–2.36 (m, 2H), 2.29–2.19 (m, 2H), 1.46 (d,

Molecules 2012, 17
5642
13
J = 6.9 Hz, 3H); C-NMR (75 MHz, CDCl3) δ 171.2 (d, J = 12.8 Hz), 143.1, 137.9 (d, J = 12.6 Hz),
132.9, 132.6, 128.7 (d, J = 7.1 Hz), 128.5 (d, J = 6.6 Hz), 127.4, 126.2, 48.9, 32.9 (d, J = 18.3 Hz),
23.4 (d, J = 12.1 Hz), 21.7; 31P-NMR (121 MHz, CDCl3) δ −15.4.
(R)-3-(Diphenylphosphino)-N-(1-phenylethyl)propan-1-amine (10). Ph2PH (0.7 mL, 4 mmol) was
added to a solution of the acrylamide 8 (350 mg, 2 mmol) in dry MeCN (10 mL). Et4NOH·H2O (37%
aqueous solution, 0.5 mL) was added and then the mixture was stirred at room temperature overnight
before being concentrated. The residue was dissolved in DCM (20 mL), washed with water (5 mL),
dried (Na2SO4), and concentrated. The residue was dissolved in dry THF (5 mL) and then cannulated
into a flask containing a slurry of LAH (380 mg, 10 mmol) in dry THF (10 mL) under Argon. After
overnight stirring at room temperature, the reaction mixture was cooled to 0 °C and 1N NaOH (4 mL,
4 mmol) was added to quench the reaction. Na2SO4 was added and the mixture was stirred vigorously
for 20 min, then filtered through Celite and washed with Et2O (3 × 10 mL). The filtrate was
concentrated under vacuo and the residue was purified through column chromatography (SiO2; 5%
1
Et3N in 30% EtOAc/Hex) to afford a colorless oil 10 (569.8 mg, 82%). H-NMR (500 MHz, CDCl3)
δ 7.48–7.44 (m, 4H), 7.39–7.27 (m, 11H), 3.77 (q, J = 6.5 Hz, 1H), 2.67–2.55 (m, 2H), 2.15–2.03 (m,
13
2H), 1.72–1.57 (m, 2H), 1.38 (d, J = 6.5 Hz, 3H); C-NMR (125 MHz, CDCl3) δ 145.6, 138.7 (d,
J = 12.3 Hz), 138.6 (d, J = 12.3 Hz), 132.7 (d, J = 4.2 Hz), 132.5 (d, J = 4.2 Hz), 128.4, 128.3, 128.2,
126.7, 126.4, 58.0, 48.7 (d, J = 13.6 Hz), 26.5 (d, J = 16.0 Hz), 25.6 (d, J = 11.5 Hz), 24.2; 31P-NMR
(202 MHz, CDCl3) δ −14.6.
(S)-1-(2-((Benzyloxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one (15). TFA (25 mL) was added to a
solution of 14 (1.19 g, 6.6 mmol) in DCM (25 mL) and then the mixture was stirred for 5 h at room
temperature. The solution was concentrated and the residue poured into a premixed solid comprising
NaHCO3 and a few pieces of ice; the aqueous phase was extracted with DCM, dried (Na2SO4), and
concentrated. The residue was dissolved in dry DCM (50 mL); TEA (1.4 mL, 10 mmol) was added to
the solution, which was then cooled to 0 °C. Acryloyl chloride (0.66 mL, 8.2 mmol) was added and
then the mixture was stirred at room temperature overnight before being filtered through a short pad of
silica gel and washed with DCM (4×) until the product had eluted completely. The filtrate was
concentrated and the residue purified through column chromatography (SiO2; 30% EtOAc/Hex) to
afford 15 (1.44 g, 89%) as a pale yellow oil. 1H-NMR (300 MHz, CDCl3) δ (both rotamers) 7.37–7.28
(m, 5H), 6.56–6.32 (m, 2H), 5.68–5.59 (m, 1H), 4.53 (s, 0.5H), 4.51 (s, 1.5H), 4.42–4.36 (m, 0.5H),
4.18–4.11 (m, 0.5H), 3.70 (dd, J = 9.4, 3.1 Hz, 0.5H), 3.61–3.32 (m, 3.5H), 2.12–1.97 (m, 2H),
13
1.94–1.84 (m, 2H); C-NMR (75 MHz, CDCl3) δ (both rotamers) 164.9, 164.7, 138.6, 137.8, 129.1,
128.8, 128.5, 128.3, 127.8, 127.6, 127.5, 127.4, 73.4, 73.2, 71.7, 70.1, 56.9, 56.8, 47.4, 46.0, 29.0,
27.5, 24.2, 21.9.
(S)-1-(2-((Benzyloxy)methyl)pyrrolidin-1-yl)-3-(diphenylphosphino)propan-1-one (16). Ph2PH (1.2 mL,
6.9 mmol) and 1 M NaOH (10–15 drops) were added to a solution of 15 (1.35 g, 5.5 mmol) in dry
MeCN (10 mL) and dry DCM (10 mL). The mixture was stirred at room temperature overnight before
being concentrated and purified through column chromatography (SiO2; 50% EtOAc/Hex) to afford 16
1
(1.42 g, 60%) as a colorless oil. H-NMR (300 MHz, CDCl3) δ (both rotamers) 7.47–7.40 (m, 4H),

Molecules 2012, 17
5643
7.36–7.23 (m, 11H), 4.54 (d, J = 12.0 Hz, 0.7H), 4.47 (d, J = 12.0 Hz, 0.7H), 4.41 (d, J = 12.0 Hz,
0.3H), 4.35 (d, J = 12.0 Hz, 0.3H), 4.30–4.23 (m, 0.7H), 3.93–3.85 (m, 0.3H), 3.65 (d, J = 3.3 Hz,
0.3H), 3.62 (d, J = 3.3 Hz, 0.7H), 3.50 (d, J = 6.88 Hz, 0.6H), 3.47 (d, J = 6.88 Hz, 0.4H), 3.31–3.18
13
(m, 2H), 2.52–2.27 (m, 4H), 2.05–1.82 (m, 4H); C-NMR (75 MHz, CDCl3) δ (both rotamers) 171.1
(d, J = 14.5 Hz), 138.6, 138.4 (d, J = 16.7), 138.2 (d, J = 16.7 Hz), 132.9, 132.9 (d, J = 3.8 Hz), 132.7,
132.6 (d, J = 3.8 Hz), 128.72, 128.70, 128.53, 128.5, 128.4, 128.3, 127.54, 127.5, 73.3, 73.2, 71.4,
31
70.1, 56.9, 56.7, 47.2, 47.8, 31.4, 31.2, 28.8, 27.6, 24.1, 23.4, 22.8, 22.7, 21.9; P-NMR (121 MHz,
CDCl3) δ −15.2, (rotamer) −15.3.
(S)-2-((Benzyloxy)methyl)-1-(3-(diphenylphosphino)propyl)pyrrolidine (17). Using the procedure
described for the synthesis of the aminophosphine 5, the aminophosphine 17 (76%) was obtained as a
1
colorless oil. H-NMR (300 MHz, CDCl3) δ 7.44–7.40 (m, 4H), 7.33 (br s, 11H), 4.52 (s, 2H),
3.50–3.46 (m, 1H), 3.37–3.13 (m, 1H), 3.05–3.03 (m, 1H), 2.97–2.91 (m, 1H), 2.64–2.62 (m, 1H),
2.41–2.35 (m, 1H), 2.14–2.09 (m, 2H), 2.05–1.98 (m, 1H), 1.95–1.84 (m, 1H), 1.72–1.60 (m, 5H);
13C-NMR (75 MHz, CDCl3) δ 139.1 (d, J = 20.1 Hz), 138.9 (d, J = 19.9 Hz), 138.6, 132.9 (d, J = 15.8 Hz),
132.6 (d, J = 15.5 Hz), 128.5, 128.4, 128.3, 127.7, 127.5, 74.0, 73.3, 63.6, 56.8 (d, J = 13.8 Hz), 54.4,
28.6, 25.9 (d, J = 11.3 Hz), 25.4 (d, J = 16.1 Hz), 23.0; 31P-NMR (121 MHz, CDCl3) δ −15.9.
(S)-3-(Diphenylphosphino)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)propan-1-one (18). Using the
procedures described for the syntheses of 3 and 4, 18 was obtained as a colorless oil. IR (film) max
3385, 3051, 2951, 2875, 1621, 1434, 1313, 1188, 1052 cm–1; 1H-NMR (500 MHz, CDCl3) δ 7.46–7.42
(m, 4H), 7.35–7.32 (m, 6H), 4.97 (br s, 1H), 4.19–4.14 (m, 1H), 3.65–3.64 (m, 1H), 3.55–3.51 (m,
1H), 3.37–3.28 (m, 2H), 2.42–2.35 (m, 4H), 2.01–1.95 (m, 1H), 1.91–1.83 (m, 1H), 1.83–1.75 (m,
1H), 1.59–1.52 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ 173.4 (d, J = 14.3 Hz), 137.8 (d, J = 12.1 Hz),
137.8 (d, J = 12.1 Hz), 132.7, 132.5, 128.7, 128.4 (d, J = 6.5 Hz), 67.2, 61.2, 47.8, 31.3 (d, J = 20.3 Hz),
28.1, 24.2, 22.7 (d, J = 10.6 Hz); 31P-NMR (202 MHz, CDCl3) δ −14.3.
(S)-(1-(3-(Diphenylphosphino)propyl)pyrrolidin-2-yl)methanol (19). Using the procedure described for
the synthesis of the aminophosphine 5, the aminophosphine 19 (76%) was obtained as a colorless oil.
1H-NMR (500 MHz, CDCl3) δ 7.44–7.39 (m, 4H), 7.32 (br s, 6H), 3.62 (dd, J = 10.5, 3.2 Hz, 1H),
3.37 (d, J = 10.5 Hz, 1H), 3.05–3.01 (m, 1H), 2.85–2.79 (m, 1H), 2.54–2.51 (m, 1H), 2.36–2.31 (m,
1H), 2.17–2.11 (m, 2H), 2.05–1.99 (m, 1H), 1.88–1.81 (m, 1H), 1.79–1.73 (m, 1H), 1.71–1.66 (m,
2H), 1.64–1.58 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 138.6 (d, J = 21.5 Hz), 138.5 (d, J = 21.5 Hz),
132.7, 132.6, 132.4, 128.5, 128.4, 128.3 (d, J = 6.9 Hz), 128.27 (d, J = 6.9 Hz), 64.6, 61.7, 55.0 (d,
J = 13.1 Hz), 53.8, 27.4, 25.6 (d, J = 11.1 Hz), 25.1 (d, J = 15.6 Hz), 23.4; 31P-NMR (202 MHz,
CDCl3) δ −15.4.
(S)-1-(2-(Diphenyl((trimethylsilyl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one (29). Using the
procedure described for the synthesis of the acrylamide 15, the acrylamide 29 (81%) was obtained as a
1
colorless oil. H-NMR (500 MHz, CDCl3) δ (both rotamers) 7.47–7.25 (m, 10H), 6.81 (dd, J = 16.8,
12.3 Hz, 0.7H), 6.29 (dd, J = 16.8, 2.0 Hz, 0.7H), 6.25 (dd, J = 16.8, 12.3 Hz, 0.3H), 6.12 (dd,
J = 16.8, 2.0 Hz, 0.3H), 5.63–5.52 (m, 1H), 5.39 (dd, J = 12.3, 2.0 Hz, 0.7H), 5.10 (dd, J = 12.3,
2.0 Hz, 0.3H), 3.77–3.76 (m, 0.7H), 3.42–3.39 (m, 0.3H), 3.89–3.87 (m, 0.3H), 2.19–2.15 (m, 0.7H),

Molecules 2012, 17
5644
2.09–2.07 (m, 0.7H), 1.92–1.88 (m, 0.3H), 1.86 (br s, 1H), 1.62–1.58 (m, 0.3H), 1.51–1.46 (m, 0.7H),
1.35–1.29 (m, 0.3H), 1.20–1.14 (m, 0.7H), −0.13 (s, 2.7H), −0.25 (s, 6.3H); 13C-NMR (125 MHz,
CDCl3) δ (both rotamers) 166.01, 166.00, 144.3, 144.2, 142.3, 141.0, 130.4, 129.6, 129.3, 129.2,
128.8, 128.1, 127.6, 127.4, 127.3, 127.2, 127.0, 126.4, 125.7, 84.4, 65.9, 62.4, 48.2, 46.3, 28.3, 27.1,
23.8, 21.8, 1.8.
(S)-3-(Diphenylphosphino)-1-(2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)propan-1-one (30). Using the
procedure described for the synthesis of the amidophosphine 18, the amidophosphine 30 (94%) was
obtained as a colorless oil. 1H-NMR (500 MHz, CDCl3) δ 7.43–7.25 (m, 20H), 6.92 (s, 1H), 5.16–5.13
(m, 1H), 3.19–3.17 (m, 1H), 2.78–2.77 (m, 1H), 2.34–2.30 (m, 3H), 2.23–2.21 (m, 1H), 2.04–2.02 (m,
1H), 1.93–1.92 (m, 1H), 1.50–1.43 (m, 1H), 0.94–0.91 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ 174.8
(d, J = 15.0 Hz), 146.0, 143.3, 137.8 (d, J = 12.6 Hz), 132.7 (d, J = 11.9 Hz), 132.5 (d, J = 11.8 Hz),
128.74, 128.71, 128.5, 128.4, 128.0, 127.8, 127.6, 127.3, 127.14, 127.12, 81.9, 66.8, 48.4, 31.5 (d,
J = 19.9 Hz), 29.4, 23.1, 22.9 (d, J = 11.3 Hz); 31P-NMR (202 MHz, CDCl3) δ −14.3.
(S)-(1-(3-(Diphenylphosphino)propyl)pyrrolidin-2-yl)diphenylmethanol (31). Using the procedure
described for the synthesis of the aminophosphine 19, the aminophosphine 31 (85%) was obtained as a
white crystalline solid. 1H-NMR (500 MHz, CDCl3) δ 7.63 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 7.9 Hz,
2H), 7.42–7.30 (m, 12H), 7.26 (t, J = 7.9 Hz, 2H), 7.21–7.16 (m, 2H), 4.85 (s, 1H), 3.85–3.83 (m, 1H),
3.13–3.10 (m, 1H), 2.34–2.29 (m, 1H), 2.26–2.21 (m, 1H), 2.00–1.87 (m, 2H), 1.82–1.60 (m, 5H),
1.56–1.50 (m, 1H), 1.39–1.31 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 148.0, 146.4, 138.7 (d,
J = 16.7 Hz), 138.6 (d, J = 16.7 Hz), 132.7, 132.5 (d, J = 5.0 Hz), 132.3, 128.4, 128.29, 128.27,
128.22, 128.18, 127.9 (d, J = 4.4 Hz), 126.0, 125.6, 125.5, 77.8, 71.0, 57.4 (d, J = 14.2 Hz), 55.1, 29.4,
25.2 (d, J = 10.7 Hz), 24.9 (d, J = 15.6 Hz), 24.4; 31P-NMR (202 MHz, CDCl3) δ −14.6.
(S)-2-(Diphenyl((trimethylsilyl)oxy)methyl)-1-(3-(diphenylphosphino)propyl)pyrrolidine (32). TMSOTf
(255 L, 1.4 mmol) was added to a solution of the aminophosphine 31 (335.7 mg, 0.7 mmol) and TEA
(0.3 mL, 2.1 mmol) in dry DCM (5 mL) at 0 °C. The mixture was stirred overnight and then
concentrated. The residue was purified through column chromatography (SiO2; 15% EtOAc/Hex) to
1
afford 32 (266.5 mg, 69%) as a colorless oil. H-NMR (500 MHz, CDCl3) δ 7.61–7.58 (m, 2H),
7.53–7.50 (m, 2H), 7.46–7.42 (m, 4H), 7.41–7.37 (m, 6H), 7.34–7.31 (m, 3H), 7.29–7.27 (m, 3H), 3.75
(dd, J = 9.7, 3.2 Hz, 1H), 2.95 (q, J = 9.7 Hz, 1H), 2.66 (dt, J = 8.9, 2.2 Hz, 1H), 2.52 (dt, J = 11.3,
5.6 Hz, 1H), 2.13–2.08 (m, 2H), 1.94–1.86 (m, 1H), 1.79–1.70 (m, 2H), 1.52–1.44 (m, 2H), 1.36–1.30
13
(m, 1H), 0.67–0.57 (m, 1H), −0.12 (s, 9H); C-NMR (125 MHz, CDCl3) δ 144.4, 143.7, 139.2 (d,
J = 13.6 Hz), 139.0 (d, J = 13.6 Hz), 132.7, 132.6, 132.4, 129.6 (d, J = 4.8 Hz), 128.3, 128.2, 128.16,
126.74, 126.71, 84.5, 72.1, 59.0 (d, J = 14.5 Hz), 54.5, 28.7, 25.5, 25.5, 25.3, 23.7, 2.0; 31P-NMR (202
MHz, CDCl3) δ −14.4.
1-(3H-Dinaphtho[2,1-c:1´,2´-e]azepin-4(5H)-yl)prop-2-en-1-one (39). Using the procedure described
for the synthesis of the acrylamide 29, the acrylamide 39 (75%) was obtained as a light-yellow foam.
1H-NMR (500 MHz, CDCl3) δ 8.00–7.95 (m, 4H), 7.65 (d, J = 8.4 Hz, 1H), 7.52–7.44 (m, 5H), 7.30
(q, J = 7.0 Hz, 2H), 6.71 (dd, J = 16.9, 10.6 Hz, 1H), 6.35 (dd, J = 16.9, 1.4 Hz, 1H), 5.77 (dd,
J = 10.6, 1.4 Hz, 1H), 5.45 (d, J = 13.7 Hz, 1H), 4.79 (d, J = 12.8 Hz, 1H), 4.01 (d, J = 12.8 Hz, 1H),

Molecules 2012, 17
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13
3.60 (d, J = 13.7 Hz, 1H); C-NMR (125 MHz, CDCl3) δ 164.9, 135.2, 134.9, 133.3, 133.2, 132.8,
132.0, 131.3, 131.2, 129.2, 128.6, 128.3, 128.2, 127.9, 127.7, 127.4, 127.2, 126.7, 126.1, 126.0, 125.8,
49.7, 46.5.
1-(3H-Dinaphtho[2,1-c:1',2'-e]azepin-4(5H)-yl)-3-(diphenylphosphino)propan-1-one (40). Using the
procedure described for the synthesis of the amidophosphine 30, the amidophosphine 40 (85%) was
obtained as a white solid. 1H-NMR (500 MHz, CDCl3) δ 8.00 (t, J = 9.2 Hz, 4H), 7.68 (d, J = 8.4 Hz, 1H),
7.56–7.52 (m, 7H), 7.50–7.47 (m, 1H), 7.43–7.39 (m, 7H), 7.35–7.31 (m, 2H), 5.53 (d, J = 13.5 Hz,
1H), 4.51 (d, J = 12.9 Hz, 1H), 3.88 (d, J = 12.9 Hz, 1H), 3.56 (d, J = 13.5 Hz, 1H), 2.73–2.66 (m,
1H), 2.57–2.47 (m, 3H); 13C-NMR (125 MHz, CDCl3) δ 170.3 (d, J = 15.1 Hz), 138.1 (d, J = 18.7 Hz),
137.9 (d, J = 18.7 Hz), 135.2, 134.8, 133.3, 133.2, 133.0, 132.7 (d, J = 6.4 Hz), 132.6 (d, J = 6.4 Hz),
132.0, 131.3, 131.2, 129.2 (d, J = 6.4 Hz), 128.7 (d, J = 3.6 Hz), 128.5 (d, J = 6.6 Hz), 128.2 (d,
J = 4.3 Hz), 127.7, 127.4, 127.2, 126.7, 126.2, 126.0, 125.8, 49.1, 46.3, 30.6 (d, J = 19.9 Hz), 23.2 (d,
J = 11.0 Hz); 31P-NMR (202 MHz, CDCl3) δ −14.1.
(S)-4-(3-(Diphenylphosphino)propyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1´,2´-e]azepine (41). Using the
procedure described for the synthesis of the aminophosphine 31, the aminophosphine 41 (83%) was
obtained as a white solid. 1H-NMR (500 MHz, CDCl3) δ 7.99 (t, J = 8.0 Hz, 4H), 7.51 (q, J = 8.0 Hz,
10H), 7.39 (t, J = 6.2 Hz, 6H), 7.31 (t, J = 7.6 Hz, 2H), 3.67 (d, J = 12.4 Hz, 2H), 3.19 (d, J = 12.4 Hz,
13
2H), 2.76–2.70 (m, 1H), 2.56–2.50 (m, 1H), 2.18 (t, J = 7.7 Hz, 2H), 1.83–1.76 (m, 2H); C-NMR
(125 MHz, CDCl3) δ 138.7 (d, J = 22.4 Hz), 138.6 (d, J = 22.4 Hz), 134.8, 133.5, 133.0, 132.7 (d,
J = 4.5 Hz), 132.6 (d, J = 4.5 Hz), 131.3, 128.4, 128.32, 128.27, 128.15, 128.11, 127.6, 127.3, 125.6,
31
125.2, 56.3 (d, J = 13.9 Hz), 55.2, 25.7 (d, J = 11.5 Hz), 24.4 (d, J = 16.5 Hz); P-NMR (202 MHz,
CDCl3) δ −14.7.
1-(2,6-Di(naphthalen-2-yl)-3H-dinaphtho[2,1-c:1',2'-e]azepin-4(5H)-yl)-3-(diphenylphosphino)propan-
1-one (57). Using the procedure described for the synthesis of the amidophosphine 40, the
amidophosphine 57 was obtained as a light-yellow foam (63%). 1H-NMR (500 MHz, CDCl3) δ 8.06 (s,
1H), 8.03–8.01 (m, 4H), 7.98–7.89 (m, 10H), 7.68 (app t, J = 7.7 Hz, 2H), 7.60–7.55 (m, 6H),
7.43–7.38 (m, 3H), 7.35–7.31 (m, 6H), 7.28–7.25 (m, 2H), 7.15 (d, J = 8.5 Hz, 1H), 5.00 (app t,
J = 4.6 Hz, 1H), 4.50 (app dd, J = 13.9, 5.6 Hz, 1H), 4.17 (app dd, J = 14.1, 3.9 Hz, 1H), 183–1.77 (m,
13
2H), 1.62–1.53 (m, 2H); C-NMR (125 MHz, CDCl3) δ 170.4 (d, J = 15.3 Hz), 141.3, 140.8, 139.4,
138.4 (d, J = 10.0 Hz), 134.8, 133.23, 133.16, 133.1, 132.9, 132.6 (d, J = 4.5 Hz), 132.5 (d, J = 4.5 Hz),
132.4, 132.3, 131.9, 131.8, 129.7, 129.0, 128.54, 128.52, 128.33, 128.31, 128.25, 127.98, 127.96,
127.88, 127.7, 127.6, 127.5, 127.3, 126.7, 126.6, 126.42, 126.39, 126.2, 126.13, 126.07, 125.9, 125.5,
125.0, 40.2, 31.9 (d, J = 18.1 Hz), 22.8 (d, J = 12.0 Hz); 31P-NMR (202 MHz, CDCl3) δ −14.2.
4-(3-(Diphenylphosphino)propyl)-2,6-di(naphthalen-2-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine
(58). Using the procedure described for the synthesis of the aminophosphine 41, the aminophosphine
58 (55%) was obtained as a light-yellow foam. 1H-NMR (500 MHz, CDCl3) δ 8.11 (br s, 2H), 8.08 (s,
2H), 8.01 (d, J = 8.1 Hz, 2H), 7.90–7.82 (m, 7H), 7.58 (d, J = 8.6 Hz, 2H), 7.56–7.49 (m, 7H), 7.34
(app t, J = 7.4 Hz, 2H), 7.31–7.27 (m, 3H), 7.22 (app t, J = 7.3 Hz, 5H), 7.14 (app t, J = 7.1 Hz, 2H),
3.99 (d, J = 12.4 Hz, 2H), 3.15 (d, J = 11.8 Hz, 2H), 2.19–2.15 (m, 1H), 2.07–2.01 (m, 1H), 1.67 (br s,

Molecules 2012, 17
5646
1H); 13C-NMR (125 MHz, CDCl3) δ 140.3, 138.9, 136.2, 133.2, 132.6, 132.5, 132.4, 132.3, 131.9,
130.8, 129.3, 128.6, 128.4, 128.3, 128.1, 128.09, 128.08, 128.0, 127.7, 127.5, 126.2, 125.9, 125.8,
31
125.7, 55.0 (d, J = 13.2 Hz), 50.6, 25.2 (d, J = 11.4 Hz), 23.5 (d, J = 15.6 Hz); P-NMR (202 MHz,
CDCl3) δ −14.3.
4. Conclusion
Because the bisphosphine-catalyzed double-Michael reaction is an efficient methodology for
synthesizing 5- and 6-membered heterocycles, we sought an asymmetric variant of the reaction,
employing a chiral bisphosphine catalyst. Several common and commercially available bisphosphines
were only marginally successful at catalyzing a double-Michael indoline synthesis. After establishing
that the aminophosphine 42 was as efficient as bisphosphine at facilitating the double-Michael
reaction, we prepared a series of chiral aminophosphines.
The synthesis of a chiral aminophosphine is simpler than that of a chiral bisphosphine because of
the availability of a wide variety of chiral amines found in Nature and the ease of preparing and
handling chiral amines. We prepared a series of aminophosphines featuring tethers of two or three
carbon atoms, derived from an acyclic chiral amine, L-proline, and (S)-binol, and employed them as
catalysts in the double-Michael indoline synthesis. Despite the impractical enantioselectivities
provided by these aminophosphines, we are encouraged by some slight improvements in
enantioinduction relative to those of bisphosphines. Notably, however, we obtained these poor levels
of enantioinduction using only one type of substrate under one specific set of conditions; therefore, we
should not dismiss the use of chiral aminophosphines in double-Michael indoline syntheses until we
have subjected the systems to further investigation. To the best of our knowledge, no literature
precedent exists for chiral induction through intramolecular anchimeric assistance. Therefore, it
remains a novel and a very challenging task to discover an appropriate aminophosphine for the
asymmetric variant of the double-Michael addition and to verify the feasibility of chiral induction
through intramolecular anchimeric assistance.
Acknowledgments
Financial support was provided by the NIH (R01GM071779 and P41GM081282).
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© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).