The GAP chemistry for chiral N-phosphonyl imine-based Strecker reaction

Article abstract of DOI:10.1039/c1gc15029d

Chiral N-phosphonyl imines were found to be efficient electrophiles for reaction with diethylaluminium cyanide, a non-volatile and inexpensive cyanide source. The reaction produced chiral Strecker adducts, α-aminonitriles, in excellent chemical yields (94-98%) and diastereoselectivities (95:5 to >99%). This synthesis was confirmed to follow the GAP chemistry (group-assistant-purification chemistry) process, which can avoid traditional chromatography and recrystallization purifications, i.e., the pure chiral α-aminonitriles bearing a chiral N-phosphonyl group can be simply obtained by washing the solid crude products with hexane. The chiral N-phosphonyl auxiliary can be easily cleaved under mildly acidic conditions and quantitatively recycled by a one-time extraction with n-butanol.

Full text of DOI:10.1039/c1gc15029d

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Green Chemistry
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PAPER
The GAP chemistry for chiral N-phosphonyl imine-based Strecker reaction
Parminder Kaur,a Walter Wever,a Suresh Pindi,a Raizada Milles,a Peng Gu,b Min Shi*b and Guigen Li*a
Received 9th January 2011, Accepted 2nd March 2011
DOI: 10.1039/c1gc15029d
Chiral N-phosphonyl imines were found to be efficient electrophiles for reaction with
diethylaluminium cyanide, a non-volatile and inexpensive cyanide source. The reaction produced
chiral Strecker adducts, a-aminonitriles, in excellent chemical yields (94–98%) and
diastereoselectivities (95 : 5 to >99%). This synthesis was confirmed to follow the GAP chemistry
(group-assistant-purification chemistry) process, which can avoid traditional chromatography and
recrystallization purifications, i.e., the pure chiral a-aminonitriles bearing a chiral N-phosphonyl
group can be simply obtained by washing the solid crude products with hexane. The chiral
N-phosphonyl auxiliary can be easily cleaved under mildly acidic conditions and quantitatively
recycled by a one-time extraction with n-butanol.
The development of efficient synthetic methods that combine
economic, environmental and green aspects constitutes a great
challenge in modern organic chemistry.1–4 It has been extremely
difficult to find general reagents, particularly chiral reagents, to
enable organic synthesis to be performed without the use of
traditional chromatography or recrystallization purifications.5
In fact, chemistry with these advantages has not been established
thus far. However, this green concept would encourage the
synthetic community to search for such reagents and related
reaction processes to better serve the academic and pharma-
ceutical industry with minimized use of energy, materials and
manpower. In the past three years, our research group has
discovered that several chiral N-phosphonyl and N-phosphinyl
imines suit the above purpose, which led to the new concept of
GAP chemistry (group-assistant-purification chemistry).5 After
this concept was generated, we examined and re-examined
previous chiral N-phosphonyl and N-phosphinyl imine-based
asymmetric reactions5–9 and found that all of these reactions can
be conducted via the GAP chemistry process.
useful synthons for the synthesis of various nitrogen- and sulfur-
containing heterocycles, such as imidazoles and thiadiazoles.12
In this regard, the asymmetric Strecker reaction has become a
very active topic in asymmetric chemistry and has been widely
used as the model reaction for organocatalysis.13 Nearly all
asymmetric catalytic Strecker reactions heavily depend on the
N-protecting groups of their imine electrophiles,10,11 such as
alkyl/aryl, RO–C( O)–, Ar2P( O)– and ArSO2 protecting
moieties. The asymmetric catalytic Strecker reaction has heavily
depended on the use of TMSCN and the in situ generation
of HCN as the cyanide nucleophile,10,11,13 two highly toxic and
volatile sources.5 In our asymmetric catalytic Strecker reaction,
Et2AlCN was employed as the cyanide source together with
the use of iso-propanol as a co-additive, which was proven
to be a crucial component for the chiral sulfinyl imine-based
asymmetric Strecker reaction.14
In our asymmetric catalytic Strecker reaction, achiral N-
phosphonyl imines were utilized as the electrophiles in the
presence of three types of catalysts: free amino alcohols,5b
primary free natural amino acids5a and BINOLs.5b This work
also represented the first use of achiral N-phosphonyl imines in
asymmetric catalysis. Excellent enantioselectivities (93–98% ee
for all cases) and chemical yields (>90% for nearly all cases) have
been achieved under convenient conditions; it was also demon-
strated that these compounds follow the GAP chemistry process,
which enables product purification simply by washing the crude
products with hexane. The achiral N-phosphonyl auxiliary was
readily cleaved under mild conditions and recycled via a one-
time extraction with n-butanol to afford a quantitative recovery
of N,N¢-bis(naphthalen-1-ylmethyl)ethane-1,2-diamine.
Two of the above syntheses involve the asymmetric catalytic
Strecker reaction.5 It is well-known that a-aminonitriles are
versatile building blocks for the synthesis of a-amino acids,
which belong to the most important building blocks in organic
and medicinal chemistry due to their use in protein, peptide and
peptidomimetic research.10,11 In addition, a-aminonitriles are
aDepartment of Chemistry and Biochemistry, Texas Tech University,
Lubbock, Texas, 79409-1061, USA. E-mail: guigen.li@ttu.edu; Fax: +1
806-742-3015
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai, 200032, P. R. China. E-mail: mshi@mail.sioc.ac.cn; Fax: +86
21-64166128
To continue the search for more practical and GAP synthesis
of a series of amino compounds, we investigated the Strecker
reaction of chiral N-phosphonyl imines with diethylaluminium
1288 | Green Chem., 2011, 13, 1288–1292
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Table 1 Results of the synthesis of N-phosphonyl substituted a-
aminonitriles 2a–2j
the imine was consumed, the reaction was quenched by adding
0.05 N HCl. The work-up and GAP purification afforded the
a-aminonitrile product in a chemical yield of 75% and with poor
diastereoselectivity (dr = 60 : 40). It was found that at least one
equiv. of i-PrOH was necessary for the complete consumption
of the chiral N-phosphonyl imine starting material. In fact, the
use of 0.3 equiv. of i-PrOH only led to 50% consumption of
chiral N,N¢-dibenzyl-N-phosphonyl imine. Furthermore, less
than 20% completion was observed when the reaction was
performed in the absence of the i-PrOH additive.
Entry
Substrate
R1
Product
Yield (%)b
drc
It was anticipated that changing the N,N¢-protecting groups
on the chiral auxiliary (Fig. 1) would improve the chemical yield
and diastereoselectivity. Various N,N¢-protecting groups, such
as iso-propyl, CH2-1-naphthyl, iso-butyl, neo-pentyl, benzyl and
cyclopentyl groups were examined for this purpose. It was
found that N,N¢-diisopropyl-N-phosphonyl imine produced the
highest yield (98%) and a diastereoselectivity of dr = 95 : 5, as
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
2a
2b
2c
2d
2e
2f
98
98
97
95
97
97
97
98
94
96
95 : 5
97 : 3
96 : 4
>99
98 : 2
>99
>99
>99
>99
98 : 2
p-methoxy
p-methyl
p-bromo
p-fluoro
p-chloro
o-chloro
o-methyl
o-bromo
o-fluoro
1g
1h
1i
2g
2h
2i
1
revealed by 31P and H-NMR analysis of the crude product.
N,N¢-dicyclopentyl-N-phosphonyl imine also generated a good
chemical yield of 88% and an acceptable diastereoselectivity
(dr = 85 : 15). The CH2-1-naphthyl group showed a lower
diastereoselectivity (dr = 70 : 30), although an excellent yield
(92%) was obtained. Surprisingly, iso-butyl and neo-pentyl
groups did not show diastereoselectivities at all. Thus, the iso-
propyl group was chosen for the chiral auxiliary, which is similar
to several of our previous asymmetric reactions using chiral
N,N¢-diisopropyl-N-phosphonyl imines.8
Various solvents, such as toluene, ether, and dichloromethane
were compared with tetrahydrofuran (THF) and it was found
that none of them afforded better outcomes than THF, which
resulted in both excellent yield (98%) and diastereoselectivity
(95 : 5), as mentioned above. However, the present asymmetric
Strecker reaction showed obvious differences from the previous
asymmetric catalytic Strecker reaction of achiral N-phosphonyl
imines.5 In the latter, toluene was proven to be superior to other
10
1j
2j
a All reactions were carried out at -78 ◦C in a 0.05 M solution of imine
in THF. b Combined yields of both isomers. c Diastereomeric ratio has
been determined by using 31P-NMR and 1H-NMR of crude products.
cyanide in the presence of i-PrOH and found that this asym-
metric reaction occurred smoothly and efficiently. Herein, we
would like to report the results of the GAP synthesis of chiral
a-aminonitriles as represented in Scheme 1 and summarized in
Table 1.
˚
solvents, including tetrahydrofuran, and 4 A molecular sieves
were needed to achieve a high yield and enantioselectivity.
After the conditions were optimized, the substrate scope of
the reaction was studied by using various chiral N-phosphonyl
imines derived from different substituted aromatic aldehydes.
As shown in Table 1, the substituents on the aromatic rings did
not show significant effects on both the chemical yields and di-
astereoselectivies. It is noteworthy that single isomeric products
were obtained in five cases, including four halogen-substituted
aromatic substrates; the resulting halogen a-aminonitriles can
be further subjected to transition metal-catalyzed coupling
reactions to give many useful building blocks (Table 1, entries
4, 6, 7, 9).15 Moreover, all products were proven to follow the
GAP chemistry process, in which pure a-aminonitrile products
were obtained simply by washing their crude products with
hexane.
Scheme 1
The chiral N,N¢-dibenzyl-N-phosphonyl imine (Fig. 1, R =
benzyl) was first employed as the electrophile to react with
diethyl aluminium cyanide. In a typical procedure, Et2AlCN
(1.5 mmol, 1.0 M solution in toluene) was added into THF,
followed by addition of i-PrOH (1.0 mmol); the solution was
stirred for 15 min at room temperature prior to being cooled
to -78 ◦C for 30 min. The chiral N-phosphonyl imine (1.0
mmol) dissolved in THF was added into the above mixture
at this temperature. The reaction mixture was stirred at -78 ◦C
for 2 h and monitored by TLC (3 : 7/hexane : EtOAc); after all
The absolute configuration of the products was determined
by converting an a-aminonitrile (2a) into an authentic sample.16
In this procedure, the N-phosphonyl group was cleaved by
treatment with 0.05 N HCl in methanol solution followed
by a one-time extraction of the cleavage mixture with n-
butanol to quantitatively recover the N,N-diisopropyl diamine
t
chiral auxiliary.17 The remaining solution was treated by Boc-
Fig. 1 Chiral N,N¢-dialkyl-N-phosphonyl imines.
protection to give a known tBoc-protected a-aminonitrile
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(Scheme 2). The optical rotation of product 3 was consistent
with that of a known sample with the S-configuration.
Experimental Section
General methods
Melting points were determined and reported uncorrected. All
commercially available solvents, unless otherwise mentioned,
were used without purification. THF was distilled over sodium
benzophenone ketyl under N2. All glassware used was dried
◦
overnight at 100 C. The NMR spectra were recorded at 500,
125 and 202 MHz for 1H, 13C and 31P, respectively. Shifts
are reported in ppm based on an internal TMS standard (for
1H/CDCl3) or on residual solvent peaks (for 13C/CDCl3). 31P
NMR spectra were referenced to external H3PO4 (0.00 ppm).
Diethylaluminium cyanide (1.0 M solution in toluene) and i-
PrOH were obtained from Aldrich and used as obtained from
commercial sources without any further purification.
Scheme 2
Based on the assignment of the absolute configuration of
the resulting a-aminonitriles, a working model for explaining
the possible asymmetric induction is suggested, as shown in
Fig. 2. In this model Et(iPrO)AlCN derived from the reaction
of Et2AlCN with iPrOH approaches the N,N¢-diiso-propyl-
N-phosphonyl imine from its re face. This observation is
consistent with our previous asymmetric reactions controlled
by (1R,2R)-N,N-diisopropyl-1,2-diaminocyclohexane-derived-
N-phosphonyl imines. Since there is no need to use an excess
amount of Et2AlCN, the six-membered transition state is not
anticipated to involve activation of the nitrogen atom of the
imine by Et2AlCN. There are two smaller steric moieties,
hydrogen and a lone pair of electrons, existing along the
CN- attacking pathway within a wide open space in the N-
phosphonimine template. This asymmetric environment ensures
the resulting S-chirality of the Strecker addition center.
Typical procedure for the synthesis of N-phosphonyl substituted
a-aminonitriles using chiral N-phosphonyl imines and
diethylaluminium cyanide
Diethylaluminium cyanide (1.0 M solution in toluene, 1.50
mmol) pre-dissolved in 3 mL THF was taken into a dry vial,
under inert gas protection. i-PrOH (1.0 mmol) was added to the
mixture and the reaction was allowed to stir for 15 min at room
temperature. After 15 min, the reaction was cooled to -78 ◦C and
stirred for 30 min at this temperature. The corresponding chiral
N-phosphonyl imine (1.0 mmol) was added to the resulting
solution dropwise. The reaction mixture was stirred for 2 h before
it was quenched by adding 0.05 M hydrochloric acid, followed by
the addition of 3 mL ethyl acetate and 3 mL water. The reaction
mixture was filtered through celite, the organic layer collected,
followed by two more extractions with ethyl acetate (2 ¥ 10 mL),
and dried over anhydrous sodium sulfate. Sodium sulfate was
filtered off and the organic layer was evaporated to obtain the
desired product as a pale yellow solid, which upon washing with
hexanes afforded the pure product as a white solid without any
further purification, in all the cases reported.
Compound 2a. White solid; yield (0.209 g, 98%); mp 110–
◦
112 C; [a]2D5 = -45.5◦ (c 0.38, CHCl3); H NMR (500 MHz,
1
Fig. 2 A working model of asymmetric induction in which the
nucleophilic species -CN attacks the N-phosphonyl imine from its re
face.
CDCl3) 7.50 (d, J = 8.0 Hz, 2H), 7.43–7.36 (m, 3H), 5.52 (t, J =
10.0 Hz, 1H), 3.63–3.55 (m, 1H), 3.48–3.34 (m, 1H), 2.99–2.91
(m, 1H), 2.78 (t, J = 9.5 Hz, 1H), 2.05–2.03 (m, 2H), 1.79–1.75
(m, 2H), 1.32 (d, J = 7.0 Hz, 6H), 1.26 (d, J = 6.5 Hz, 3H),
1.22 (d, J = 7.0 Hz, 3H), 1.13 (d, J = 7.0 Hz, 5H); 13C NMR
(125 MHz, CDCl3) 136.1 (d, J = 4.8 Hz), 129.1 (2C), 126.5 (3C),
119.6 (d, J = 3.5 Hz), 59.9 (d, J = 10.8 Hz), 59.3 (d, J = 10.3 Hz),
47.7 (d, J = 1.5 Hz, 2C), 44.0 (d, J = 2.5 Hz), 30.4 (t, J = 8.3 Hz,
2C), 24.2 (2C), 22.7 (d, J = 4.5 Hz), 22.5 (d, J = 5.8 Hz), 20.1,
20.0 (d, J = 1.5 Hz); 31P NMR (202 MHz, CDCl3) 21.22.
HRMS (ESI): m/z calcd for: C20H32N4OP, 375.2309, found:
375.2321
Conclusions
The new asymmetric GAP synthesis of chiral a-aminonitriles
has been achieved by reacting chiral N-phosphonyl imines with
diethylaluminium cyanide, together with isopropanol as a co-
additive. Excellent chemical yields (94–98%) and diastereoselec-
tivities (95 : 5 to >99%) have been achieved without the use of the
traditional purifications, chromatography and recrystallization.
The use of non-volatile diethylaluminium cyanide as the cyanide
source can make the present synthesis greener. The chiral
auxiliary was easily removed by mild acid hydrolysis and can be
recovered for re-use. More asymmetric reactions for the synthesis
of amino compounds by taking advantage of GAP chemistry
will be explored in our laboratories.
Compound 2b. White solid; yield (0.244 g, 98%); mp 124–
◦
126 C; [a]2D5 = -40.8◦ (c 0.46, CHCl3); H NMR (500 MHz,
1
CDCl3) 7.39 (d, J = 9.5 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 5.41
(t, J = 10.5 Hz, 1H), 3.77 (s, 3H), 3.55–3.52 (m, 1H), 3.42–3.34
(m, 1H), 3.09 (t, J = 9.5 Hz, 1H), 2.95 (t, J = 8.0 Hz, 1H), 2.74
(t, J = 7.5 Hz, 1H), 2.03–1.99 (m, 2H), 1.75–1.73 (m, 2H), 1.29
(d, J = 7.0 Hz, 6H), 1.23 (d, J = 6.5 Hz, 3H), 1.17–1.00 (m, 7H);
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13C NMR (125 MHz, CDCl3) 159.8, 127.9, 127.8 (2C), 119.8 (d,
J = 4.0 Hz), 114.2 (2C), 59.8 (d, J = 10.0 Hz), 59.2 (d, J = 9.3
Hz), 55.2, 47.1 (d, J = 1.5 Hz), 44.4 (d, J = 2.8 Hz), 43.9 (d, J =
4.5 Hz), 30.4 (dd, J = 9.6, 16.4 Hz, 2C), 24.1 (2C), 22.6 (d, J =
4.0 Hz), 22.5 (d, J = 3.5 Hz), 20.0, 19.9 (d, J = 1.3 Hz); 31P NMR
(202 MHz, CDCl3) 21.19.
Compound 2g. White solid; yield (0.217 g, 97%); mp 122–
124 C; [a]2D5 = 26.5◦ (c 0.68, CHCl3); H NMR (500 MHz,
CDCl3) 7.60–7.56 (m, 1H), 7.45–7.40 (m, 1H), 7.36–7.32 (m,
2H), 5.67 (t, J = 15.0 Hz 1H), 3.92–3.84 (m, 1H), 3.50–3.30 (m,
(m, 2H), 3.00–2.94 (m, 1H), 2.86–2.78 (m, 1H), 2.08–2.02 (m,
2H), 1.80–1.78 (m, 2H), 1.36–1.30 (m, 4H), 1.21 (d, J = 7.0 Hz,
6H), 1.16 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H);13C NMR
(125 MHz, CDCl3) 133.9 (d, J = 4.0 Hz), 132.6, 130.4, 130.3,
129.2, 127.7, 118.6 (d, J = 4.9 Hz), 60.1 (d, J = 5.0 Hz), 59.4 (d,
J = 5.3 Hz), 45.7 (d, J = 2.9 Hz), 44.6 (d, J = 3.0 Hz), 44.0 (d,
J = 3.9 Hz), 30.4 (d, J = 4.5 Hz), 30.3 (d, J = 3.0 Hz), 24.2 (2C),
22.4 (d, J = 4.0 Hz, 2C), 19.9, 19.8 (d, J = 2.0 Hz); 31P NMR
(202 MHz, CDCl3) 21.21.
◦
1
HRMS (ESI): m/z calcd for: C21H34N4O2P, 405.2414, found:
405.2419
Compound 2c. White solid; yield (0.174 g, 97%); mp 116–
◦
118 C; [a]2D5 = -27.5◦ (c 0.67, CHCl3); H NMR (500 MHz,
1
CDCl3) 7.37 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 5.46 (t,
J = 9.5 Hz, 1H), 3.58–3.54 (m, 1H), 3.43–3.40 (m, 1H), 2.98–2.93
(m, 1H), 2.88 (t, J = 10.5 Hz, 1H), 2.78–2.76 (m, 1H), 2.34 (s,
3H), 2.06–2.00 (m, 2H), 1.77–1.74 (m, 2H), 1.35–1.12 (m, 14H);
13C NMR (125 MHz, CDCl3) 138.9, 133.1 (d, J = 5.0 Hz), 129.7
(2C), 126.4 (2C), 119.8, 59.9 (d, J = 9.0 Hz), 59.3 (d, J = 8.3 Hz),
47.5 (d, J = 2.7 Hz), 44.5 (d, J = 3.0 Hz), 44.0 (d, J = 4.5 Hz),
31.5, 30.8, 24.2 (2C), 22.5, 21.0, 20.1 (d, J = 4.0 Hz), 19.9 (d, J =
4.5 Hz), 14.1; 31P NMR (202 MHz, CDCl3) 21.18.
HRMS (ESI): m/z calcd for: C20H31ClN4OP, 409.1919, found:
409.1916
Compound 2h. White solid; yield (0.177 g, 98%); mp 142–
◦
144 C; [a]2D5 = -34.0◦ (c 0.50, CHCl3); H NMR (500 MHz,
1
CDCl3) 7.47–7.45 (m, 1H), 7.26–7.25 (m, 2H), 7.21–7.19 (m,
1H), 5.57 (t, J = 15.5 Hz 1H), 3.62–3.56 (m, 1H), 3.42–3.32 (m,
1H), 3.14–3.06 (m, 1H), 3.0–2.92 (m, 1H), 2.82–2.74 (m, 1H),
2.48(s, 3H), 2.07–2.02 (m, 2H), 1.80–1.77 (m, 2H), 1.27–1.25 (m,
4H), 1.20 (d, J = 7.0 Hz, 6H), 1.14 (d, J = 6.9 Hz, 3H), 0.87 (d,
J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3), 135.2, 135.0,
134.5, 131.2, 129.0, 126.8, 126.7, 126.5, 119.7, 59.9 (d, J = 9.9
Hz), 59.3 (d, J = 8.9 Hz), 45.1, 44.5, 43.9, 30.5 (d, J = 3.5 Hz),
29.0 (d, J = 4.5 Hz), 24.2 (d, J = 2.5 Hz, 2C), 22.8, 22.6, 19.9 (d,
J = 4.5 Hz), 19.1, 14.1; 31P NMR (202 MHz, CDCl3) 21.15.
HRMS (ESI): m/z calcd for: C21H34N4OP, 389.2465, found:
389.2487
HRMS (ESI): m/z calcd for: C21H34N4OP, 389.2465, found:
389.2476.
Compound 2d. White solid; yield (0.220 g, 95%); mp 126–
◦
128 C; [a]2D5 = -36.4◦ (c 0.42, CHCl3); H NMR (500 MHz,
1
CDCl3) 7.53 (d, J = 8.5 Hz, 2H), 7.41 (t, J = 8.5 Hz, 2H), 5.49 (t,
J = 10.0 Hz, 1H), 3.59–3.31 (m, 2H), 3.21 (t, J = 10.5 Hz, 1H),
2.96 (t, J = 8.5 Hz, 1H), 2.79–2.75 (m, 1H), 2.04 (t, J = 10.0 Hz,
2H), 1.77 (t, J = 8.0 Hz, 2H), 1.31 (d, J = 7.0 Hz, 6H), 1.24 (d,
J = 7.0 Hz, 3H), 1.20 (d, J = 6.5 Hz, 4H), 1.13 (d, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) 135.3 (d, J = 4.8 Hz), 132.2
(2C), 128.3 (2C), 123.1, 119.2 (d, J = 3.8 Hz), 59.9 (d, J = 10.8
Hz), 59.3 (d, J = 10.3 Hz), 47.2 (d, J = 1.7 Hz), 44.5 (d, J = 2.5
Hz), 44.0 (d, J = 4.0 Hz), 30.4 (dd, J = 11.2, 21.1 Hz, 2C), 24.1
(2C), 22.6 (t, J = 4.5 Hz, 2C), 22.08, 20.04; 31P NMR (202 MHz,
CDCl3) 21.29.
Compound 2i. White solid; yield (0.242 g, 94%); mp 134–
◦
136 C; [a]2D5 = -40.5◦ (c 0.46, CHCl3); H NMR (500 MHz,
1
CDCl3) 7.42 (t, J = 9.0 Hz, 1H), 7.13 (t, J = 6.5 Hz, 1H), 7.02 (t,
J = 8.0 Hz, 2H), 5.19–5.10 (m, 1H), 4.04–3.98 (m, 2H), 3.77–3.71
(m, 1H), 3.41–3.28 (m, 2H), 3.30–3.21 (m, 1H), 3.09–3.02 (m,
1H), 2.97–2.90 (m, 1H), 2.74–2.66 (m, 1H), 2.42 (s, 3H), 2.06
(t, J = 13.5 Hz, 2H), 1.78 (d, J = 7.5 Hz, 2H), 1.30–1.16 (m,
8H), 1.13 (d, J = 7.0 Hz, 2H), 1.04–0.90 (m, 12H); 13C NMR
(125 MHz, CDCl3) 154.3, 135.7, 135.1, 131.1, 129.5, 128.0, 65.2
(d, J = 7.0 Hz), 63.4 (d, J = 7.3 Hz), 58.9 (d, J = 11.3 Hz), 58.2
(t, J = 9.8 Hz), 45.2 (dd, J = 3.8, 8.5 Hz), 31.1 (d, J = 11.8 Hz),
29.4 (t, J = 9.3 Hz), 23.3 (d, J = 8.3 Hz), 21.5 (d, J = 7.8 Hz),
21.0 (d, J = 3.3 Hz), 19.2, 19.1, 18.9, 16.0 (d, J = 6.0 Hz), 15.8
(d, J = 5.3 Hz); 31P NMR (202 MHz, CDCl3) 21.04
Compound 2e. White solid; yield (0.192 g, 97%); mp 122–
◦
124 C; [a]2D5 = -40.5◦ (c 0.50, CHCl3); H NMR (500 MHz,
1
CDCl3) 7.50 (t, J = 5.0 Hz, 2H), 7.07 (t, J = 8.5 Hz, 2H), 5.48 (t,
J = 10.0 Hz, 1H), 3.58–3.51 (m, 1H), 3.48–3.35 (m, 1H), 3.26 (t,
J = 9.0 Hz, 1H), 2.94 (t, J = 9.5 Hz, 1H), 2.79–2.71 (m, 1H), 2.03
(t, J = 6.5 Hz, 2H), 1.76 (t, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz,
6H), 1.23 (d, J = 7.0 Hz, 3H), 1.18 (d, J = 6.5 Hz, 2H), 1.16–1.13
(m, 2H), 1.12 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
163.7, 161.8, 128.6, 128.5 (d, J = 8.3 Hz), 119.5 (d, J = 3.5 Hz),
116.1, 115.9, 59.9 (d, J = 10.8 Hz), 59.3 (d, J = 10.3 Hz), 47.0 (d,
J = 1.5 Hz), 44.5 (d, J = 2.5 Hz), 44.0 (d, J = 4.0 Hz), 30.4 (dd,
J = 3.4, 8.3 Hz, 2C), 24.1 (2C), 22.6 (dd, J = 2.1, 4.5 Hz), 20.1,
20.0, 19.9 (d, J = 1.5 Hz); 31P NMR (202 MHz, CDCl3) 21.26.
HRMS (ESI): m/z calcd for: C20H31BrN4OP, 453.1414, found:
453.1420
Compound 2j. White solid; yield (0.226 g, 96%); mp 114–
◦
116 C; [a]2D5 = -35.5◦ (c 0.64, CHCl3); H NMR (500 MHz,
1
Compound 2f. White solid; yield (0.184 g, 97%); mp 108–
CDCl3) 7.49 (t, J = 7.0 Hz, 1H), 7.36 (t, J = 6.5 Hz, 1H), 7.18
(t, J = 7.0 Hz, 1H), 7.12 (t, J = 6.0 Hz, 1H), 5.59 (t, J = 9.0 Hz,
1H), 3.52–3.37 (m, 2H), 3.31–3.22 (m, 1H), 2.94 (t, J = 7.5 Hz,
1H), 2.82–2.75 (m, 1H), 2.03 (t, J = 10.0 Hz, 2H), 1.78 (t, J =
8.0 Hz, 2H), 1.31–1.06 (m, 16H); 13C NMR (125 MHz, CDCl3)
161.0, 159.1, 131.1 (d, J = 5.0 Hz), 128.8 (d, J = 5.0 Hz), 124.8
(d, J = 3.5 Hz), 118.7 (t, J = 4.8 Hz), 116.2 (d, J = 20.6 Hz), 59.9
(d, J = 10.8 Hz), 59.3 (d, J = 9.8 Hz), 44.5 (d, J = 3.0 Hz), 44.5
(d, J = 3.8 Hz), 44.0 (d, J = 4.0 Hz), 42.9 (t, J = 2.5 Hz), 42.7 (t,
J = 2.0 Hz), 30.3 (m, 2C), 24.1 (2C), 22.4 (d, J = 4.0 Hz), 22.2
◦
110 C; [a]2D5 = -48.0◦ (c 0.42, CHCl3); H NMR (500 MHz,
1
CDCl3) 7.48 (d, J = 8.5 Hz, 2H), 7.40 (t, J = 8.5 Hz, 2H), 5.56
(t, J = 10.0 Hz, 1H), 3.62–3.32 (m, 2H), 3.00–2.79 (m, 3H),
2.09–2.02 (m, 2H), 1.80–177 (m, 3H), 1.35 (d, J = 7.0 Hz, 6H),
1.24 (dd, J = 3.0, 7.0 Hz, 6H), 1.14 (d, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) 135.1, 129.3 (3C), 128.0 (2C), 119.2,
59.7 (d, J = 9.3 Hz), 59.4 (d, J = 9.3 Hz), 47.2, 44.8, 44.1, 30.4
(d, J = 9.3 Hz, 2C), 24.2 (2C), 22.7, 22.5, 20.0 (2C); 31P NMR
(202 MHz, CDCl3) 21.07.
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(d, J = 3.5 Hz), 20.2, 19.9 (d, J = 2.0 Hz); 31P NMR (202 MHz,
CDCl3) 21.12
HRMS (ESI): m/z calcd for: C20H31FN4OP, 393.2215, found:
393.2216
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Acknowledgements
Financial support by Robert A. Welch Foundation (D-1361) and
NSFC (20928001) is gratefully acknowledged. We would also
like to thank NIH (R03DA026960) for partial financial support.
We want to thank our co-workers Venkatesh Kattamuri, Trideep
Rajale and Jianbin Wu for their helpful discussions and David
W. Purkiss for assistance in NMR.
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1292 | Green Chem., 2011, 13, 1288–1292
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