Enantioselective hydroformylation of aniline derivatives

Article abstract of DOI:10.1021/jo201328d

We have developed a ligand that reversibly binds to aniline substrates, allowing for the control of regioselectivity and enantioselectivity in hydroformylation. In this paper we address how the electronics of the aniline ring affect both the binding of the substrate to the ligand and the enantioselectivity in this reaction.

Full text of DOI:10.1021/jo201328d

NOTE
pubs.acs.org/joc
Enantioselective Hydroformylation of Aniline Derivatives
Candice L. Joe and Kian L. Tan*
Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467-3860, United States
S Supporting Information
b
ABSTRACT: We have developed a ligand that reversibly binds to aniline substrates,
allowing for the control of regioselectivity and enantioselectivity in hydroformylation. In
this paper we address how the electronics of the aniline ring affect both the binding of the
substrate to the ligand and the enantioselectivity in this reaction.
symmetric hydroformylation (AHF) is an efficient and
practical means of producing chiral aldehyde products.
A
The challenges in AHF are controlling both the enantioselec-
tivity and the regioselectivity of the reaction.1 Hydroformylation
of terminal olefins generally has the tendency to form the achiral
linear isomers, whereas 1,2-disubstituted olefins show poor
regiocontrol. Therefore, the majority of AHF has been per-
formed on symmetrical substrates or olefins with an electronic
preference to form the branched isomers (such as styrene).
These classes of substrates have been found to be receptive to
AHF, and a variety of ligands have been developed that promote
the reaction with high enantioselectivity.2À14 Most recently,
Zhang15 and Landis16 have also demonstrated success in the
AHF of substrates that contain an internal directing group. Our
research group has tried to diversify the substrate scope of AHF
by expanding to substrates that are not electronically activated
and do not have a directing group as part of the molecule. This is
achieved by having a phosphorus-based ligand that reversibly and
covalently binds to common organic functionalities.17À29 Upon
binding the substrate, the phosphine ligand serves as the directing
group controlling the regioselectivity. Importantly, the reversi-
bility of the bonding between the substrate and ligand allows the
ligand to be employed catalytically.30À34 We recently applied this
concept to the AHF of p-methoxyphenyl (PMP)-protected
amines toward the synthesis of β-amino alcohols.35 Although
the PMP group is a useful protecting group, aniline derivatives are
an important class of molecules found broadly in biologically
active compounds. In this paper we explore how the electronics of
the nitrogen affects both binding of the substrate to the ligand and
the enantioselectivity of the hydroformylation reaction.
Table 1. Electronic Effects on Binding to (()-1
a
entry
R
Keq
1
2
3
4
5
6
OMe (2a)
Me (2b)
H (2c)
2.9 ( 0.7
1.3 ( 0.5
1.2 ( 0.3
Cl (2d)
1.2 ( 0.2
0.64 ( 0.03
0.43 ( 0.07
CN (2e)
NO2 (2f)
a Keq values were determined by 1H NMR in triplicate.
within 1 order of magnitude of each other (Table 1). To gain
further insight into the factors that affect binding, the equilibrium
data were plotted versus both σp and σ+ Hammett parameters.
The data correlate slightly better to the σ+ values than the σp
values, consistent with there being a minor resonance compo-
nent to the binding affinity (Figure 1). The F value is small and
negative (À0.47), suggesting only a modest favorability for
binding of electron-rich rings. One interpretation of these data
is that the nitrogen lone pair is conjugated to the aromatic ring in
We initiated our investigation by studying the exchange
reaction of a variety of electronically modified anilines with
ligand 1.36 The electronics of the aniline affect the affinity of
the substrate for the ligand but do not prevent binding in any of
the tested substrates. Electron-poor anilines have a lower binding
affinity than electron-rich rings, with all of the Keq values being
Received: June 29, 2011
Published: August 15, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201328d J. Org. Chem. 2011, 76, 7590–7596
|

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NOTE
Table 2. Electronic Effects on Hydroformylation of Aniline
Substrates
Figure 1. Hammett plots.
the secondary anilines, but upon binding to the ligand the steric
repulsion between the aromatic ring and ligand rotates the lone
pair out of conjugation. Since resonance-stabilizing electron-
withdrawing groups are in direct conjugation with the nitrogen
lone pair, the equilibrium shifts toward the starting materials as
compared to donating groups. Alternatively, when the aniline is
bound to the ligand, the aniline nitrogen lone pair can participate
in donation into σ* of either the CÀN or CÀP bonds of the
heterocyclic ring.37,38 In this case donating groups would enhance
this interaction while withdrawing groups would mitigate it.
Having investigated the effects of electronics on binding
affinity to the ligand, we probed the consequences on hydro-
formylation. For the hydroformylation studies the benzyl ethers
were used as substrates, because these compounds are readily
accessible in large quantities as geometrically pure compounds
from commercially available cis-1,4-butenediol (note that hydro-
formylation of (Z)-N-(but-2-en-1-yl)aniline (2c) afforded the
desired product in 74% 1H NMR yield and 90% ee). As
previously reported using ligand 3, p-methoxyphenyl (PMP)
substrates give the product in high enantioselectivity (92% ee)
and good yield (70%; Table 2, entry 1).39 Unsubstituted and
electronically neutral aromatics form the product in comparable
levels of enantioselectivity and slightly elevated isolated yields
(Table 2, entries 2À4). When an electron-withdrawing substi-
tuent is in the para position of the aromatic ring, both the yield
and enantioselectivities decrease (Table 2, entries 5 and 6). On
the basis of gas uptake curves, these reactions stall before
reaching 100% conversion, consistent with the active catalyst
decomposing during the reaction. The exchange data show that
the ligands bound to electron-deficient aniline derivatives are
a Unless otherwise noted, the following reaction conditions were used:
(1) 15 mol % 3, 0.05 mol % p-TsOH, 45 °C, C6D6; (2) 1.75 mol %
Rh(acac)(CO)2, 35 °C, 50 psi of H2/CO, benzene; (3) NaBH4, MeOH.
c
b Isolated yield. Enantiomeric excess was determined by HPLC anal-
ysis. d Standard conditions, except 0.03 mol % p-TsOH was used for the
pre-exchange.
thermodynamically less stable, which may be leading to a more
rapid decomposition of the ligand. Analysis of the pre-exchange
reaction prior to hydroformylation by 31P NMR indicates con-
siderable decomposition of ligand 3 to a variety of unidentifiable
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The Journal of Organic Chemistry
NOTE
phosphorus compounds in the presence of compounds 4e,f.
The Hammett data suggest that electron-withdrawing groups
not directly in conjugation with the aniline lone pair would be
thermodynamically more stable. Using a substrate with a m-NO2
group gives the alcohol product in improved enantioselectivity
and yield (Table 2, entry 8), consistent with this prediction.
Similarly, a substrate with an electron-deficient pyridine ring
affords the desired product in moderate yield (64%) and good
enantioselectivity (87% ee). We also attempted to perform
hydroformylations with substitution, such as Cl and CH3, at
the ortho position of the aromatic ring. These provided low
conversion to product; we believe this is a result of difficulties in
binding sterically large substrates to the ligand.
(Z)-N-(But-2-en-1-yl)-4-methylaniline (2b). General Procedure 2
was used, giving an orange oil (1.02 g, 82%). H NMR (CDCl3, 500
1
MHz): δ 6.99 (d, 2H, J = 7.8), 6.55À6.58 (m, 2H), 5.63À5.67 (m, 1H),
5.55À5.59 (m, 1H), 3.74 (d, 2H, J = 6.6), 3.50 (br s, 1H), 2.23 (s, 3H),
1.71À1.73 (m, 3H). 13C NMR (CDCl3, 125 MHz): δ 146.3, 129.9,
128.1, 127.2, 127.0, 113.3, 41.4, 20.6, 13.3; IR: 1616, 1517, 1313, 1256,
805 cmÀ1. HRMS (DART-TOF): calcd for C11H16N [M + H]+
162.1283, found 162.1277.
N-(But-2-yn-1-yl)aniline. General Procedure 1 with aniline (7.73 mL,
84.8 mmol) was used. Column chromatography (5% EtOAc/Hex) gave
a yellow oil (1.9 g, 78%). 1H NMR (CDCl3, 500 MHz): δ 7.20À7.24 (m,
2H), 6.77À6.80 (m, 1H), 6.67À6.70 (m, 2H), 3.88 (s, 2H), 3.85 (br s,
1H), 1.81À1.82 (m, 3H). 13C NMR (CDCl3, 125 MHz): δ 147.5, 129.4,
118.4, 113.6, 79.2, 76.3, 34.2, 3.7. IR: 1601, 1502, 1313, 747, 690 cmÀ1
.
HRMS (DART-TOF): calcd for C10H12N [M + H]+ 146.0970, found
146.0967.
’ CONCLUSIONS
(Z)-N-(But-2-en-1-yl)aniline (2c, 7% E Isomer). General Procedure 2
with N-(but-2-yn-1-yl)aniline (1.01 g, 7.02 mmol) was used, affording
an orange oil (720 mg, 73%). 1H NMR (CDCl3, 500 MHz): δ
7.17À7.21 (m, 2H), 6.71À6.74 (t, 1H, J = 7.3), 6.62À6.64 (m, 2H),
5.65À5.68 (m, 1H), 5.54À5.59 (m, 1H), 3.78 (d, 2H, J = 6.6), 3.69 (d,
2HE isomer, J = 6.1), 3.63 (br s, 1H), 1.71À1.72 (m, 3H). 13C NMR
(CDCl3, 125 MHz): δ 148.5, 129.4, 127.8, 127.4, 117.6, 113.1, 41.0,
13.3. IR: 1601, 1503, 1312, 1260, 747, 690, 507 cmÀ1. HRMS (DART-
TOF): calcd for C10H14N [M + H]+ 148.1126, found 148.1119.
N-(But-2-yn-1-yl)-4-chloroaniline. General Procedure 1 with 4-chlor-
oaniline (1.88 g, 14.7 mmol) was used. Column chromatography (20%
EtOAc/Hex) yielded a light red oil (331 mg, 66%). 1H NMR (CDCl3,
500 MHz): δ 7.15À7.17 (m, 2H), 6.59À6.61 (m, 2H), 3.86 (s, 2H),
1.81 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 146.0, 129.2, 123.1,
114.7, 79.5, 75.9, 34.3, 3.7. IR: 1599, 1496, 1312, 814, 500 cmÀ1. HRMS
(DART-TOF): calcd for C10H11ClN [M + H]+ 180.0580, found
180.0581.
(Z)-N-(But-2-en-1-yl)-4-chloroaniline (2d). General Procedure 2
with N-(but-2-yn-1-yl)-4-chloroaniline (1.02 g, 5.68 mmol) was used,
affording an orange oil (814 mg, 81%). 1H NMR (CDCl3, 500 MHz): δ
7.11À7.13 (m, 2H), 6.52À6.55 (app dd, 2H, J = 6.6, 2.2), 5.65À5.68 (m,
1H), 5.51À5.54 (m, 1H), 3.73 (d, 2H, J = 6.6), 3.64 (br s, 1H),
1.70À1.72 (m, 3H). 13C NMR (CDCl3, 125 MHz): δ 147.0, 129.2,
127.7, 127.4, 122.1, 114.1, 41.1, 13.3. IR: 1599, 1496, 1311, 1176, 812,
503 cmÀ1. HRMS (DART-TOF): calcd for C10H13ClN [M + H]+
182.0737, found 182.0739.
The asymmetric hydroformylation of aniline derivatives has
been achieved using a chiral scaffolding ligand. By studying the
substrate/ligand exchange and hydroformylation reactions, we
found a correlation between binding affinity and the yield and
enantioselectivity of the hydroformylation reaction. Substrates
with high affinity for the ligand generally afford improved
enantioselectivity. Substrates with a low affinity for ligand
give lower enantioselecitvity and yield, which is potentially
a result of decomposition of the ligand during the reaction.
With this information, we are currently developing ligands
with improved stability, with the aim of improving yields and
selectivities.
’ EXPERIMENTAL SECTION
All general considerations are the same as those previously reported.35
The following compounds were made according to literature procedures
and matched reported spectra: ligand 1,26 ligand 3(OMe),35 and ligand
3(OiPr),35 N-(but-2-yn-1-yl)-4-methoxyaniline,35 (Z)-N-(but-2-en-1-
yl)-4-methoxyaniline (2a),35 2-(but-2-yn-1-yl)isoindoline-1,3-dione,40
but-2-yn-1-amine,41 (Z)-4-(benzyloxy)but-2-en-1-ol, (Z)-N-(4-(benzy-
loxy)but-2-en-1-yl)-4-methoxyaniline (4a),35 (Z)-(7((4-chlorobut-2-en-
1-yl)oxy)methyl)benzene,35 2-isobutyrylcyclohexanone,42 1-iodo-3-nitro-
benzene,43 3-iodopyridine,44 (S)-4-(benzyloxy)-2-(((4-methoxyphenyl)-
amino)methyl)butan-1-ol (5a).35
4-(But-2-yn-1-ylamino)benzonitrile. A flame-dried flask was charged
with K2CO3 (6.00 g, 45.4 mmol), 4-aminobenzonitrile (7.00 g, 56.7
mmol), DMF (140 mL), and 1-bromo-2-butyne (2.51 g, 18.9 mmol).
The reaction mixture was stirred overnight at 80 °C. The reaction
mixture was diluted with EtOAc (200 mL) and washed with water
(2 Â 100 mL). The aqueous layer was washed with EtOAc (200 mL),
and the organics were dried over MgSO4, filtered, and concentrated.
Column chromatography (20% EtOAc/Hex) afforded an orange oil
Equilibrium Substrates. General Procedure 1. To a flame-dried
flask was added p-toluidine (3.36 g, 31.4 mmol), CH3CN (30 mL), and
1-bromo-2-butyne (0.55 mL, 6.3 mmol). The reaction mixture was
stirred overnight, diluted with Et2O (100 mL), and washed with water
(2 Â 40 mL) and saturated NH4Cl (3 Â 25 mL). The organic phase was
dried over MgSO4, filtered, and concentrated.
General Procedure 2. A flame-dried flask was charged with Lindlar’s
catalyst (172 mg) and purged with nitrogen. N-(But-2-yn-1-yl)-4-
methylaniline (1.23 g, 7.74 mmol) in EtOH (15 mL) was added,
followed by quinoline (82 μL, 0.70 mmol). The flask was purged with
H2 (4Â), fitted with a H2 balloon, and stirred at room temperature for
40 min. The reaction mixture was filtered through a plug of silica and
concentrated. Column chromatography (10% EtOAc/Hex) afforded
the title compound.
1
(1.32 g, 16%). H NMR (CDCl3, 500 MHz): δ 7.42À7.44 (m, 2H),
6.60À6.62 (m, 2H), 4.47 (br s, 1H), 3.87À3.90 (m, 2H), 1.78À1.79
(app t, 3H, J = 2.4). 13C NMR (CDCl3, 125 MHz): δ 150.6, 133.7, 120.4,
112.9, 99.7, 80.0, 74.8, 33.4, 3.6. IR: 3371, 2212, 1604, 1522, 1324, 1174,
824, 543 cmÀ1. HRMS (DART-TOF): calcd for C11H11N2 [M + H]+
171.0922, found 171.0923.
N-(But-2-yn-1-yl)-4-methylaniline. General Procedure 1 was used.
Column chromatography (5% EtOAc/Hex) gave an orange oil (781 mg,
78%). 1H NMR (CDCl3, 500 MHz): δ 7.01À7.04 (m, 2H), 6.60À6.62
(m, 2H), 3.85 (s, 2H), 3.71 (br s, 1H), 2.26 (app d, 3H, J = 4.2),
1.80À1.81 (m, 3H). 13C NMR (CDCl3, 125 MHz): δ 145.2, 129.9,
127.7, 113.8, 79.1, 76.5, 34.5, 20.6, 3.5. IR: 1616, 1517, 1249, 806,
502 cmÀ1. HRMS (DART-TOF): calcd for C11H14N [M + H]+
160.1126, found 160.1119.
(Z)-4-(But-2-en-1-ylamino)benzonitrile (2e, 5% E Isomer). General
Procedure 2 with 4-(but-2-yn-1-ylamino)benzonitrile (800 mg, 4.70 mmol)
was used, affording an orange oil (622 mg, 77%). 1H NMR (CDCl3, 500
MHz): δ 7.38À7.42 (m, 2H), 6.54À6.56 (m, 2H), 5.67À5.74 (m, 1H),
5.47À5.53 (m, 1H), 4.27 (br s, 1H) 3.78À3.81 (t, 2H, J = 5.6),
3.70À3.72 (m, 2HE isomer), 1.71À1.73 (m, 3H), 1.69À1.70 (m,
2HE isomer). 13C NMR (CDCl3, 125 MHz): δ 151.4, 133.8, 128.5,
126.3, 120.7, 112.4, 98.8, 40.2, 13.3. IR: 3367, 2209, 1602, 1521, 1171,
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820, 542 cmÀ1. HRMS (DART-TOF): calcd for C11H13N2 [M + H]+
173.1079, found 173.1080.
anhydrous MgSO4, filtered, and concentrated. Column chromatography
(15% EtOAc/Hex) afforded an orange oil (748 mg, 46%). H NMR
1
N-(But-2-yn-1-yl)-4-nitroaniline. In a flame-dried flask were added
KF (426 mg, 6.17 mmol), K2CO3 (853 mg, 6.17 mmol), and 1-fluoro-4-
nitrobenzene (871 mg, 6.17 mmol). But-2-yn-1-amine (426 mg, 6.17
mmol) was added to the flask as a solution in DMSO (20 mL). The
reaction mixture was stirred at room temperature overnight. Water
(5 mL) was added, and the mixture was extracted with Et2O (150 mL).
The organic layer was dried over MgSO4, filtered, and concentrated.
Column chromatography (15% EtOAc/Hex) afforded a yellow oil
(CDCl3, 500 MHz): δ 7.28À7.36 (m, 5H), 7.00 (d, 2H, J = 8.1), 6.54
(d, 2H, J = 8.6), 5.74À5.82 (m, 2H), 4.54 (s, 2H), 4.15 (d, 2H, J = 4.9),
3.75 (d, 2H, J = 4.5), 3.55 (br s, 1H), 2.25 (s, 3H). 13C NMR (CDCl3, 125
MHz): δ 145.9, 138.3, 131.0, 129.9, 129.0, 128.6, 128.0, 127.9, 127.2,
113.4, 72.7, 65.9, 41.9, 20.6. IR: 1616, 1518, 1252, 1070, 806, 734,
696 cmÀ1. HRMS (DART-TOF): calcd for C18H22NO [M + H]+
268.1701, found 268.1698.
(Z)-2-(4-(Benzyloxy)but-2-en-1-yl)isoindoline-1,3-dione. A flame-
dried flask was charged with (Z)-4-(benzyloxy)but-2-en-1-ol (3.74 g,
21.0 mmol), triphenylphosphine (3.74 g, 21.0 mmol), phthalimide
(3.09 g, 21.0 mmol), tetrahydrofuran (105 mL), and diisopropyl
azodicarboxylate (4.13 mL, 21.0 mmol). The reaction mixture was
stirred at room temperature overnight. The mixture was concentrated.
Column chromatography (20% EtOAc/Hex) gave a colorless oil (4.23 g,
65%). 1H NMR (CDCl3, 400 MHz): δ 7.81À7.85 (m, 2H), 7.69À7.72
(m, 2H), 7.28À7.39 (m, 5H), 5.78À5.84 (m, 1H), 5.62À5.68 (m, 1H),
4.58 (s, 2H), 4.32À4.34 (m, 2H), 4.30À4.32 (m, 2H). 13C NMR
(CDCl3, 100 MHz): δ 168.1, 138.4, 134.2, 132.4, 131.0, 128.6, 128.1,
127.9, 126.4, 123.5, 72.7, 65.9, 35.2. IR: 1709, 1390, 1088, 1072, 735,
715, 698 cmÀ1. HRMS (DART-TOF): calcd for C19H18NO3 [M + H]+
308.1287, found 308.1284.
(Z)-4-(Benzyloxy)but-2-en-1-amine. A 100 mL flask was charged
with (Z)-2-(4-(benzyloxy)but-2-en-1-yl)isoindoline-1,3-dione (4.23 g,
13.7 mmol), hydrazine hydrate (1.6 mL, 25.7 mmol), and ethanol
(10 mL). The mixture was heated to 70 °C overnight. The solid was
filtered and washed with water (100 mL). The aqueous solution was
acidified to pH ∼2 with concentrated HCl and was washed with Et2O
(120 mL). The aqueous layer was then basified to pH ∼13 by solid KOH
pellets. The solution was washed with Et2O (200 mL). The organic layer
was dried over anhydrous MgSO4, filtered, and concentrated to obtain
the title compound as a pale yellow oil (1.92 g, 79%). 1H NMR (CDCl3,
500 MHz): δ 7.27À7.36 (m, 5H), 5.61À5.71 (m, 2H), 4.51 (s, 2H),
4.07 (d, 2H, J = 6.0), 3.31 (d, 2H, J = 6.1), 1.13 (br s, 2H). 13C NMR
(CDCl3, 125 MHz): δ 138.3, 134.9, 128.6, 128.0, 127.8, 126.7, 72.5,
65.7, 39.3. IR: 3067, 2854, 1453, 1088, 734, 696 cmÀ1. HRMS (DART-
TOF): calcd for C11H16NO [M + H]+ 178.1232, found 178.1240.
(Z)-N-(4-(Benzyloxy)but-2-en-1-yl)aniline (4c). General Procedure 3
was used. Column chromatography (20% EtOAc/Hex) gave a pale
orange oil (301 mg, 42%). 1H NMR (CDCl3, 500 MHz): δ 7.28À7.37
(m, 5H), 7.16À7.21 (m, 2H), 6.75 (app t, 1H, J = 7.3), 6.61 (d, 2H, J =
7.6), 5.74À5.83 (m, 2H), 4.55 (s, 2H), 4.15 (d, 2H, J = 5.4), 3.78 (d, 2H,
J = 5.6), 3.68 (br s, 1H). 13C NMR (CDCl3, 125 MHz): δ 148.2, 138.3,
130.8, 129.5, 129.1, 128.6, 128.0, 127.9, 117.9, 113.2, 72.7, 65.9, 41.6. IR:
3027, 2856, 1603, 1504, 1094, 1071, 749, 695 cmÀ1. HRMS (DART-
TOF): calcd for C17H20NO [M + H]+ 254.1545, found 254.1555.
(Z)-N-(4-(Benzyloxy)but-2-en-1-yl)-4-chloroaniline (4d). General
Procedure 3 with 1-bromo-4-chlorobenzene (540 mg, 2.82 mmol)
was used. Column chromatography (20% EtOAc/Hex) gave an orange
oil (358 mg, 44%). 1H NMR (CDCl3, 500 MHz): δ 7.28À7.37 (m, 5H),
7.10À7.13 (m, 2H), 6.49À6.51 (m, 2H), 5.79À5.84 (m, 1H),
5.70À5.75 (m, 1H), 4.54 (s, 2H), 4.14 (d, 2H, J = 6.4), 3.74 (d, 2H,
J = 6.6), 3.71 (br s, 1H). 13C NMR (CDCl3, 125 MHz): δ 146.7, 138.2,
130.4, 129.4, 129.3, 128.7, 128.0, 127.9, 122.5, 114.2, 72.8, 65.8, 41.7.
IR: 2854, 1598, 1496, 1357, 1070, 814, 735, 696, 504 cmÀ1. HRMS
(DART-TOF): calcd for C17H19ClNO [M + H]+ 288.1155, found
288.1145.
1
(660 mg, 56%). H NMR (CDCl3, 500 MHz): δ 8.11 (d, 2H, J =
9.3), 6.59À6.62 (m, 2H), 4.69 (br s, 1H), 3.93À3.95 (m, 2H),
1.79À1.80 (m, 3H). 13C NMR (CDCl3, 125 MHz): δ 152.5, 138.9,
126.4, 111.9, 80.5, 74.4, 33.7, 3.7. IR: 1616, 1515, 1231, 805, 512 cmÀ1
.
HRMS (DART-TOF): calcd for C10H11N2O2 [M + H]+ 191.0821,
found 191.0819.
(Z)-N-(But-2-en-1-yl)-4-nitroaniline (2f, 14% E Isomer). General
Procedure 2 with N-(but-2-yn-1-yl)-4-nitroaniline (66 mg, 0.35 mmol)
was used, affording a yellow oil (60 mg, 90%). 1H NMR (CDCl3, 500
MHz): δ 8.07À8.11 (m, 2H), 6.52À6.55 (m, 2H), 5.71À5.77 (m, 1H),
5.46À5.49 (m, 1H), 3.85À3.87 (m, 2H), 3.77À3.79 (m, 2HE isomer),
1.73À1.75 (m, 3H), 1.71À1.72 (m, 3HE isomer). 13C NMR (CDCl3, 125
MHz): δ 153.4, 138.3, 129.0, 126.6, 125.9, 111.4, 40.5, 13.4. IR: 3378,
1600, 1503, 1471, 1318, 1302, 1283, 1111 cmÀ1. HRMS (DART-TOF):
calcd for C10H13N2O2 [M + H]+ 193.0977, found 193.0985.
Equilibrium Experiments. In a drybox, a solution of isopropyl
alcohol (100 μL, 1.31 mmol) in benzene-d6 (1.63 M) was prepared. The
solution was dispensed into three NMR tubes. A second solution of
(Z)-N-(but-2-enyl)-4-methoxyaniline (70 mg, 0.43 mmol), ligand
(25 mg, 0.086 mmol), and p-TsOH (298 μL, 7.2 Â 10À4 M in C6H6;
note that C6H6 was removed prior to mixing with substrate and ligand)
in C6D6 (1.5 mL) was made. The solution was dispensed into three
NMR tubes. The total volume of each tube was brought to 0.7 mL. Each
reaction was allowed to equilibrate overnight at 45 °C.
Hydroformylation Substrates. General Procedure 3.45 To a
flame-dried flask was added L-proline (325 mg, 2.82 mmol), CuI (537
mg, 2.82 mmol), and K2CO3 (1.17 g, 8.46 mmol). (Z)-4-(Benzyloxy)-
but-2-en-1-amine (500 mg, 2.82 mmol) was added to the flask as a
solution in DMSO (5 mL), followed by iodobenzene (314 μL, 2.82 mmol).
The reaction mixture was heated to 60 °C for 8 h. The mixture
was diluted with EtOAc (100 mL) and washed with water (70 mL).
The organic layer was dried over anhydrous MgSO4, filtered, and
concentrated.
General Procedure 4. To a flame-dried flask was added K2CO3
(420 mg, 3.04 mmol), 4-fluorobenzonitrile (368 mg, 3.04 mmol),
(Z)-4-(benzyloxy)but-2-en-1-amine (700 mg, 3.94 mmol), and DMSO
(10 mL), which was heated to 90 °C overnight. The reaction was
quenched by the addition of water (25 mL) and was diluted with Et2O
(70 mL). The organic layer was dried over anhydrous MgSO4, filtered,
and concentrated.
General Procedure 5.42 To an oven-dried flask was added CuI
(232 mg, 1.22 mmol) and Cs2CO3 (2.00 g, 6.10 mmol). (Z)-4-(Benzyloxy)-
but-2-en-1-amine (600 mg, 3.05 mmol), 1-iodo-3-methylbenzene
(392 μL, 3.05 mmol), DMF (1.5 mL), and 2-isobutyrylcyclohexanone
(410 mg, 2.44 mmol) were added. The reaction mixture was stirred
for 12 h. The mixture was filtered through a pad of Celite, washed with
EtOAc (100 mL), and extracted with water (2 Â 25 mL). The organic
layer was dried over MgSO4, filtered, and concentrated.
(Z)-N-(4-(Benzyloxy)but-2-en-1-yl)-4-methylaniline (4b). To a flame-
dried flask was added p-toluidine (3.26 g, 30.5 mmol), (Z)-(((4-chlor-
obut-2-en-1-yl)oxy)methyl)benzene (1.20 g, 6.10 mmol), and acetonitrile
(30 mL). The reaction mixture was stirred for 12 h. The mixture was
diluted with Et2O (100 mL) and was washed with H2O (3 Â 50 mL) and
saturated aqueous NH4Cl (3 Â 50 mL). The organics were dried over
(Z)-4-((4-(Benzyloxy)but-2-en-1-yl)amino)benzonitrile (4e). General
Procedure 4 was used. Column chromatography (20% EtOAc/Hex)
afforded an orange oil (201 mg, 37%). 1H NMR (CDCl3, 500 MHz):
δ 7.39À7.42 (m, 2H), 7.29À7.37 (m, 5H), 6.51À6.53 (m, 2H),
5.82À5.87 (m, 1H), 5.67À5.71 (m, 1H), 4.55 (s, 2H), 4.26 (br s, 1H),
4.12À4.13 (m, 2H), 3.81 (br m, 2H). 13C NMR (CDCl3, 125 MHz):
7593
dx.doi.org/10.1021/jo201328d |J. Org. Chem. 2011, 76, 7590–7596

The Journal of Organic Chemistry
NOTE
δ 151.2, 138.0, 133.9, 130.0, 129.4, 128.7, 128.1, 128.0, 120.6, 112.5,
99.2, 72.9, 65.8, 40.8; IR: 3367, 1606, 1525, 1207 cmÀ1. HRMS
(DART-TOF): calcd for C18H19N2O [M + H]+ 279.1497, found
279.1498.
flask containing NaBH4 (23.0 mg, 0.600 mmol). The reaction mixture
was stirred at room temperature for 1.5 h. The reaction mixture was
quenched with water (5 mL) and extracted with CH2Cl2 (3 Â 15 mL).
The organics were dried over Na2SO4, filtered, and concentrated. The
crude reaction mixture was chromatographed (1% MeOH/DCM) to
yield the title compound.
(S)-4-(Benzyloxy)-2-((p-tolylamino)methyl)butan-1-ol (5b). Yellow
oil (47.4 mg, 79%). HPLC (OD-H, 1.0 mL/min, 23% iPrOH/77%
Hexanes, 240 nm): tr(major) = 11.9 min and tr(minor) = 20.6 min, 92% ee.
1H NMR (CDCl3, 500 MHz): δ 7.29À7.37 (m, 5H), 6.98 (d, 2H, J =
8.6), 6.54 (d, 2H, J = 8.3), 4.54 (s, 2H), 3.69 (d, 2H, J = 5.1), 3.55À3.64
(m, 2H), 3.11À3.18 (m, 2H), 2.24 (s, 3H), 2.00À2.02 (m, 1H),
1.72À1.76 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 146.1, 138.1,
129.9, 128.7, 128.0, 127.9, 127.1, 113.6, 73.5, 68.7, 65.4, 47.5, 38.8, 30.3,
20.6. IR: 3380, 2923, 2854, 1521, 1260, 1095, 807 cmÀ1. HRMS
(DART-TOF): calcd for C19H26NO2 [M + H]+ 300.1964, found
300.1977. [R]D20 = +21.8° (c = 0.330, CHCl3, l = 50 mm).
(Z)-N-(4-(Benzyloxy)but-2-en-1-yl)-4-nitroaniline (4f). General Pro-
cedure 4 with 1-fluoro-4-nitrobenzene (429 mg, 3.04 mmol) was used.
Column chromatography (20% EtOAc/Hex) gave a bright yellow oil
(457 mg, 50%). 1H NMR (CDCl3, 500 MHz): δ 8.07 (d, 2H, J = 9.3),
7.31À7.37 (m, 5H), 6.49 (d, 2H, J = 9.3), 5.86À5.90 (m, 1H),
5.69À5.74 (m, 1H), 4.63 (br s, 1H), 4.56 (s, 2H), 4.15 (d, 2H, J =
6.4), 3.86À3.89 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 153.2, 138.4,
138.0, 130.3, 128.9, 128.7, 128.1, 128.0, 126.5, 111.4, 72.9, 65.8, 40.9. IR:
3372, 1595, 1299, 1278, 1107, 830, 694 cmÀ1. HRMS (DART-TOF):
calcd for C17H19N2O3 [M + H]+ 299.1396, found 299.1407.
(Z)-N-(4-(Benzyloxy)but-2-en-1-yl)-3-methylaniline (4g). General
Procedure 5 was used. Column chromatography (10% EtOAc/Hex)
afforded an orange oil (653 mg, 80%). 1H NMR (CDCl3, 500 MHz): δ
7.30À7.37 (m, 5H), 7.08 (t, 1H, J = 7.3), 6.56 (d, 1H, J = 7.1), 6.43À6.42
(m, 2H), 5.76À5.81 (m, 2H), 4.55 (s, 2H), 4.16 (d, 2H, J = 5.4), 3.76 (d,
2H, J = 5.6), 3.63 (br s, 1H), 2.29 (s, 3H). 13C NMR (CDCl3, 125 MHz):
δ 148.2, 139.2, 138.3, 130.9, 129.3, 129.0, 128.6, 128.0, 127.9, 118.8,
114.0, 110.4, 72.7, 65.9, 41.6, 21.8. IR: 1604, 1491, 1089, 1070, 769, 735,
692 cmÀ1. HRMS (DART-TOF): calcd for C18H22NO [M + H]+
268.1701, found 268.1702.
(S)-4-(Benzyloxy)-2-((phenylamino)methyl)butan-1-ol (5c). Yellow
oil (43.9 mg, 77%). HPLC (OD-H, 1.0 mL/min, 15% iPrOH/85%
Hexanes, 240 nm): tr(major) = 15.5 min and tr(minor) = 20.4 min, 91% ee.
1H NMR (CDCl3, 500 MHz): δ 7.29À7.38 (m, 5H), 7.15À7.18 (m,
2H), 6.69À6.72 (app t, 1H, J = 7.3), 6.60 (d, 2H, J = 7.8), 4.54 (s, 2H),
3.70 (d, 2H, J = 5.1), 3.55À3.65 (m, 2H), 3.13À3.21 (m, 2H),
1.99À2.02 (m, 1H), 1.74À1.78 (m, 2H). 13C NMR (CDCl3, 125
MHz): δ 148.6, 138.0, 129.4, 128.7, 128.0, 117.6, 113.2, 73.5, 68.8,
(Z)-N-(4-(Benzyloxy)but-2-en-1-yl)-3-nitroaniline (4h). General
Procedure 3 with 1-iodo-3-nitrobenzene (886 mg, 3.56 mmol) was
used. Column chromatography (15% EtOAc/Hex) afforded a bright
orange oil (561 mg, 53%). 1H NMR (DMSO, 500 MHz): δ 7.31À7.36
(m, 5H), 7.27À7.29 (m, 2H), 6.95À6.97 (m, 1H), 6.52À6.55 (m, 1H),
5.69À5.74 (m, 1H), 5.58À5.62 (m, 1H), 4.50 (s, 2H), 4.16À4.17 (m,
2H), 3.76À3.78 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 149.6, 148.9,
138.1, 130.1, 129.9, 129.5, 128.7, 128.1, 128.0, 119.1, 112.4, 106.6, 72.9,
65.2, 46.8 38.9, 30.3. IR: 2924, 2862, 1602, 1092, 1025, 748, 610 cmÀ1
.
HRMS (DART-TOF): calcd for C18H24NO2 [M + H]+ 286.1807,
found 286.1806. [R]D20 = +19.6° (c = 0.310, CHCl3, l = 50 mm).
(S)-4-(Benzyloxy)-2-(((4-chlorophenyl)amino)methyl)butan-1-ol (5d).
Orange oil (45.9 mg, 72%). HPLC (OD-H, 1.0 mL/min, 15% iPrOH/85%
Hexanes, 240 nm): tr(major) = 13.5 min and tr(minor) = 18.5 min, 88% ee.
1H NMR (CDCl3, 500 MHz): δ 7.29À7.38 (m, 5H), 7.07À7.10 (m, 2H),
6.47À6.50 (m, 2H), 4.53 (s, 2H), 3.68 (d, 2H, J = 4.9), 3.55À3.62 (m, 2H),
3.07À3.17 (m, 2H), 1.96À2.01 (m, 1H), 1.72À1.76 (m, 2H). 13C NMR
(CDCl3, 125 MHz): δ 147.2, 138.0, 129.2, 128.7, 128.1, 128.0, 122.0, 114.1,
73.5, 68.7, 65.0, 46.8, 38.8, 30.2. IR: 3378, 2924, 2860, 1600, 1500, 1093,
816 cmÀ1. HRMS (DART-TOF): calcd for C18H23ClNO2 [M + H]
320.1417, found 320.1425. [R]D20 = +20.3° (c = 0.325, CHCl3, l = 50 mm).
(S)-4-((4-(Benzyloxy)-2-(hydroxymethyl)butyl)amino)benzonitrile
(5e). Orange oil (30.3 mg, 49%). HPLC (OD-H, 1.0 mL/min, 15%
iPrOH/85% Hexanes, 220 nm): tr(major) = 17.3 min and tr(minor) =
20.3 min, 65% ee. 1H NMR (CDCl3, 500 MHz): δ 7.30À7.38 (m, 7H),
6.44À6.47 (m, 2H), 4.90 (br s, 1H), 4.53 (s, 2H), 3.70 (d, 2H, J = 4.7),
3.56À3.63 (m, 2H), 3.12À3.25 (m, 2H), 2.25 (br s, 1H), 1.98À2.02 (m,
1H), 1.70À1.81 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 151.8, 137.9,
133.7, 128.8, 128.2, 128.1, 120.8, 112.3, 98.5, 73.7, 68.7, 64.8, 45.9, 38.8,
30.1. IR: 3373, 2922, 2867, 2211, 1606, 1528, 1173 cmÀ1. HRMS
(DART-TOF): calcd for C19H23N2O2 [M + H] 311.1760, found
311.1756. [R]D20 = +34.2° (c = 0.090, CHCl3, l = 50 mm).
65.9, 41.3. IR: 2857, 1621, 1581, 1344, 1089, 1070, 734, 689, 672 cmÀ1
.
HRMS (DART-TOF): calcd for C17H19N2O3 [M + H]+ 299.1396,
found 299.1400.
(Z)-N-(4-(Benzyloxy)but-2-en-1-yl)pyridin-3-amine (4i). General
Procedure 5 with 3-iodopyridine (833 mg, 4.06 mmol) was used. Column
chromatography (50% EtOAc/Hex) afforded an orange oil (366 mg,
1
37%). H NMR (CDCl3, 500 MHz): δ 8.00À8.01 (d, 1H, J = 3.0),
7.97À7.99 (dd, 1H, J = 4.6, 1.0), 7.29À7.35 (m, 5H), 7.06À7.08 (m,
1H), 6.83À6.86 (m, 1H), 5.81À5.86 (m, 1H), 5.72 À5.76 (m, 1H), 4.54
(s, 2H), 4.13 (d, 2H, J = 6.1), 3.78 (d, 2H, J = 5.1), 3.78 (br s, 1H). 13C
NMR (CDCl3, 125 MHz): δ 144.1, 139.3, 128.1, 136.5, 130.0, 129.7,
128.7, 128.1, 128.0, 123.8, 118.8, 72.8, 65.8, 41.1. IR: 2861, 1519, 1092,
808, 736, 697 cmÀ1. HRMS (DART-TOF): calcd for C16H19N2O
[M + H]+ 255.1497, found 255.1484.
Hydroformylation Products. General Hydroformylation Pro-
cedure. (Z)-N-(4-(Benzyloxy)but-2-en-1-yl)-4-methylaniline (53.4 mg,
0.200 mmol), (iPrO)-2 (205 μL, 0.146 M solution in C6D6), 0.05%
p-toluenesulfonic acid in benzene (175 μL, 1 Â 10À4 mmol), and C6D6
(0.4 mL) were mixed and heated to 45 °C in a sealed NMR tube. The
solution was concentrated in a dry glovebox and then was redissolved in
C6D6. The solution was heated to 45 °C for 4 h before being
concentrated again in a glovebox. The resulting residue was dissolved
in benzene (1.5 mL), mixed with 1.75% Rh(acac)(CO)2 (0.9 mg, 0.0035
mmol), and injected into the Endeavor, followed by 0.5 mL of benzene
to wash the injection port. The Endeavor was purged with nitrogen
(4 Â 100 psi). The temperature was held at 35 °C for 10 min, and the
Endeavor was pressurized to 50 psi with H2/CO. The hydroformylation
was carried out at 35 °C and 50 psi H2/CO for 14 h with stirring
at 700 rpm. The Endeavor was depressurized and cooled to ambient
temperature. A solution of 1,3,5-trimethoxybenzene in CHCl3 (100 μL,
0.1863 M) was added, and the sample was concentrated. The resulting
residue was added, as a solution in MeOH (3 mL), to a flame-dried
(S)-4-(Benzyloxy)-2-(((4-nitrophenyl)amino)methyl)butan-1-ol (5f).
Yellow oil (27.2 mg, 41%). HPLC (AS-H, 1.0 mL/min, 15% iPrOH/85%
Hexanes, 220 nm): tr(major) = 53.9 min and tr(minor) = 46.6 min, 52% ee.
1H NMR (CDCl3, 500 MHz): δ 8.01À8.04 (m, 2H), 7.32À7.38 (5H,
m), 6.37À6.39 (m, 2H), 5.36 (br s, 1H), 4.54 (s, 2H), 3.71 (br s, 2H),
3.60À3.62 (t, 2H, J = 5.5), 3.17À3.31 (m, 2H), 2.28 (br s, 1H), 2.00À2.05
(m, 1H), 1.71À1.81 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 153.9,
137.8, 137.7, 128.8, 128.3, 128.2, 126.6, 111.0, 73.7, 68.8, 64.9, 46.2,
38.8, 30.0. IR: 3370, 2922, 2855, 1598, 1308, 1279, 1108, 697 cmÀ1
.
HRMS (DART-TOF): calcd for C18H23N2O4 [M + H] 331.1658, found
331.1657. [R]D20 = +28.7° (c = 0.060, CHCl3, l = 50 mm).
(S)-4-(Benzyloxy)-2-((m-tolylamino)methyl)butan-1-ol (5g). Yel-
low oil (35.8 mg, 60%). HPLC (OD-H, 1.0 mL/min, 23% iPrOH/
77% Hexanes, 240 nm): tr(major) = 10.3 min and tr(minor) = 12.3 min,
89% ee. 1H NMR (CDCl3, 500 MHz): δ 7.29À7.38 (m, 5H), 7.04À7.07
7594
dx.doi.org/10.1021/jo201328d |J. Org. Chem. 2011, 76, 7590–7596

The Journal of Organic Chemistry
NOTE
(m, 1H), 6.53 (d, 1H, J = 7.3), 6.41À6.42 (m, 2H), 4.54 (s, 2H), 3.69 (d,
2H, J = 5.3), 3.55À3.63 (m, 2H), 3.11À3.19 (m, 2H), 2.27 (s, 3H),
2.00À2.02 (m, 1H), 1.73À1.77 (m, 2H). 13C NMR (CDCl3, 125 MHz):
δ 148.6, 139.2, 138.1, 129.3, 128.7, 128.0, 127.8, 118.6, 114.0, 110.3,
73.5, 68.8, 65.3, 46.9, 39.0, 30.3, 21.8. IR: 3378, 2919, 2858, 1604, 1092,
1028, 769, 737, 695 cmÀ1. HRMS (DART-TOF): calcd for C19H26NO2
[M + H] 300.1964, found 300.1958. [R]D20 = +28.2° (c = 0.160, CHCl3,
l = 50 mm).
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29, 2767–2776.
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2010, 352, 637–643.
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2010, 16, 871–877.
(S)-4-(Benzyloxy)-2-(((3-nitrophenyl)amino)methyl)butan-1-ol (5h).
Orange oil (40.4 mg, 61%). HPLC (OD-H, 1.0 mL/min, 7% iPrOH/93%
Hexanes, 240 nm): tr(major) = 55.9 min and tr(minor) = 37.8 min, 84%
ee. 1H NMR (CDCl3, 500 MHz): δ 7.45À7.47 (app dd, 1H, J = 8.1, 1.5),
7.28À7.37 (m, 6H), 7.19À7.22 (t, 1H, J = 8.1), 6.75À6.77 (m, 1H), 4.65
(br s, 1H), 4.53 (s, 2H), 3.70 (d, 2H, J = 4.4), 3.56À3.64 (m, 2H),
3.14À3.24 (m, 2H), 2.48 (br s, 1H), 1.99À2.04 (m, 1H), 1.71À1.82 (m,
2H). 13C NMR (CDCl3, 125 MHz): δ 149.7, 149.5, 137.9, 129.8, 128.8,
128.2, 128.1, 119.0, 111.8, 106.2, 73.6, 68.7, 65.0, 46.5, 38.8, 30.1. IR: 3386,
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2010, 49, 4047–4050.
2923, 2859, 1527, 1454, 1092, 733, 698 cmÀ1. HRMS (DART-TOF):
20
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Landis, C. R. J. Am. Chem. Soc. 2010, 132, 14027–14029.
(17) For early examples of reversible covalent bonding with ligands
for metal catalysts, see refs 17À20: Lewis, L. N.; Smith, J. F. J. Am. Chem.
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calcd for C18H23N2O4 [M + H] 331.1658, found 331.1662. [R]D
+19.8° (c = 0.200, CHCl3, l = 50 mm).
=
(S)-4-(Benzyloxy)-2-((pyridin-3-ylamino)methyl)butan-1-ol (5i).
Orange oil (36.5 mg, 64%). HPLC (OD-H, 1.0 mL/min, 21%
iPrOH/79% Hexanes, 240 nm): tr(major) = 17.2 min and tr(minor) =
1
27.6 min, 87% ee. H NMR (CDCl3, 500 MHz): δ 7.93 (br s, 2H),
7.28À7.36 (m, 5H), 7.05 (br s, 1H), 6.82 (d, 1H, J = 5.0), 4.52 (s, 2H),
4.26 (br s, 1H), 3.70 (d, 2H, J = 4.7), 3.55À3.63 (m, 2H), 3.11À3.21 (m,
2H), 1.98À2.02 (m, 1H), 1.73À1.77 (m, 2H). 13C NMR (CDCl3, 125
MHz): δ 144.8, 138.4, 138.0, 136.0, 128.7, 128.1, 128.0, 123.9, 118.7,
73.5, 68.7, 64.8, 46.3, 38.7, 30.1. IR: 2858, 1589, 1091, 794, 734,
632 cmÀ1. HRMS (DART-TOF): calcd for C17H23N2O2 [M + H]
287.1760, found 287.1759. [R]D20 = +3.5° (c = 0.465, CHCl3, l = 50 mm).
(22) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450–
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and ligands in hydroformylation see refs 23À29: Lightburn, T. E.; de
Paolis, O. A.; Cheng, K. H.; Tan, K. L. Org. Lett. 2011, 13, 2686–2689.
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132, 11841–11843.
’ ASSOCIATED CONTENT
S
Supporting Information. Figures and tables giving NMR
b
spectra for all compounds, HPLC traces, and equilibrium data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(25) Worthy, A. D.; Gagnon, M. M.; Dombrowski, M. T.; Tan, K. L.
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: kian.tan.1@bc.edu.
967–970.
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’ ACKNOWLEDGMENT
We thank the ACS-PRF (DNI-5001400) and NIGMS
(RO1GM087581) for funding this project. Mass spectrometry
instrumentation at Boston College is supported by funding from
the NSF (DBI-0619576).
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NOTE
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1
conditions. Crude H NMR analysis of the p-chloro substrate shows
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