A novel triphosphoramidite ligand for highly regioselective linear hydroformylation of terminal and internal olefins

Article abstract of DOI:10.1021/ol400033k

The first triphosphorus ligand has been designed and synthesized for highly regioselective linear hydroformylations. A very high l/b ratio (up to 471, 99.8% linear selectivity) was obtained in the linear hydroformylation of representative terminal and internal olefins. For the range of substrates tested, the regioselectivities achieved utilizing the novel triphosphoramidite ligand were much better than those of the bisphosphoramidite ligand and close to those of the tetraphosphoramidite ligand.

Full text of DOI:10.1021/ol400033k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Novel Triphosphoramidite Ligand for Highly
Regioselective Linear Hydroformylation
of Terminal and Internal Olefins
Caiyou Chen,† Yu Qiao,† Huiling Geng,‡ and Xumu Zhang*,†
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan,
Hubei, 430072, China, and Northwest Agriculture and Forestry University, Yangling,
Shaanxi, 712100, China
xumu@rci.rutgers.edu; xumu@whu.edu.cn
Received January 5, 2013
ABSTRACT
The first triphosphorus ligand has been designed and synthesized for highly regioselective linear hydroformylations. A very high l/b ratio
(up to 471, 99.8% linear selectivity) was obtained in the linear hydroformylation of representative terminal and internal olefins. For the range
of substrates tested, the regioselectivities achieved utilizing the novel triphosphoramidite ligand were much better than those of the
bisphosphoramidite ligand and close to those of the tetraphosphoramidite ligand.
Regioselective hydroformylation represents a powerful
CꢀC bond forming reaction converting alkenes and syn-
gas into synthetically useful aldehydes in a perfect atom
economic way.1 Due to the great importance of aldehydes
as versatile intermediates and building blocks, hydrofor-
mylation has been intensively applied in industry since its
first discovery by Otto Roelen in 1938.2,3 Oxo products
produced via a hydroformylation process are estimated at
over 10 million tons per year now.2c
In order to achieve high regioselectivities, efforts have
been made in designing new types of phosphorus ligands
for rhodium-catalyzed hydroformylation processes. As
one of the key factors determining the regioselectivity,
bisphosphorus ligands with a much stronger chelating
ability afford higher regioselectivities in the hydroformyla-
tion of simple olefins compared with the corresponding
monophosphorus ligands. Numerouscatalysts and ligands
have been developed based on bisphosphorus ligands,
which were heavily patented by companies in Oxo Chemi-
cals in the past decades (Scheme 1). As elegant examples,
Bisbi type ligands,4 Xantphos,5 Biphephos,6 Naphos,7
calix[4]arene bisphosphite,8 and self-assembled bispho-
sphane9 showed very good regioselectivities. Extraordinarily,
(4) (a) Devon, T. J.; Phillips, G. W.; Puckette, T. A.; Stavinoha, J. L.;
Vanderbilt, J. J. U.S. Patent 4694109, 1987. (b) Herrmann, W. A.; Kohlpaintner,
C. W.; Herdtweck, E.; Kiprof, P. Inorg. Chem. 1991, 30, 4271. (c) Casey, C. P.;
Whiteker, G. T.; Melville, M. G.; Lori, L. M.; Gavney, J. A.; Powell, D. R.,
Jr. J. Am. Chem. Soc. 1992, 114, 5535. (d) Herrmann, W. A.; Schmid, R.;
Kohlpaintner, C. W.; Priermeier, T. Organometallics 1995, 14, 1961. (e)
Casey, C. P.; Paulsen, E. L.; Beuttenmueller, E. W.; Proft, B. R.; Petrovich,
L. M.; Matter, B. A.; Powell, D. R. J. Am. Chem. Soc. 1997, 119, 11817.
(5) (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Organometallics 1995, 14, 3081. (b) Vander Veen,
L. A.; Boele, M. D.; Bregman, F. R.; Paul, P. C.; van Leeuwen, P. W. N.
M.; Goubitz, K.; Fraanje, J.; Schenk, H.; Bo, C. J. Am. Chem. Soc. 1998,
120, 11616. (c) Carb, J. J.; Maseras, F.; Bo, C.; van Leeuwen, P. W. N.
M. J. Am. Chem. Soc. 2001, 123, 7630.
† Wuhan University.
‡ Northwest Agriculture and Forestry University.
(1) Breit, B. Top. Curr. Chem. 2007, 279, 139.
(6) (a) Billig, E.; Abatjoglou, A. G.; Bryant, D. R. (UCC) U.S. Patent
4769498, 1988. (b) Cuny, G. D.; Buchwald, S. J. Am. Chem. Soc. 1993, 115,
2066.
(7) Klein, H.; Jackstell, R.; Wiese, K. D.; Borgmann, C.; Beller, M.
Angew. Chem., Int. Ed. 2001, 40, 3408.
(2) (a) Weissermel, K.; Arpe, H. J. Industrial Organic Chemistry;
Wiley-VCH: Weinheim, 2003; p 127. (b) Breit, B.; Seiche, W. Synthesis
€
2001, 1. (c) Franke, R.; Selent, D.; Borner, A. Chem. Rev. 2012, 112, 5675.
(3) Roelen, O. (to Chemische Verwertungsgesellschaft Oberhausen
m.b.H.) German Patent DE 849548, 1938/1952; U.S. Patent 2327066,
1943; Chem. Abstr. 1944, 38, 3631.
(8) Paciello, R.; Siggel, L.; Rc-per, M. Angew. Chem., Int. Ed. 1999, 38,
1920.
r
10.1021/ol400033k
XXXX American Chemical Society

van Leeuwen’s pyrrole-based bisphosphoramidite ligand
exhibited excellent activity and regioselectivity due to the
strong electron-withdrawing ability of the pyrrole moiety.10
Furthermore, the spiroketal-based bisphosphorus ligands
developed recently by Ding also afforded very good regio-
selectivities.11 Besides bisphosphorus ligands, by incorpor-
ating four chelating sites our group developed two classes of
tetraphosphorus ligands with a new motif which achieved
unprecedented regioselectivities (Scheme 1).12
Scheme 1. Ligands Developed for Regioselective
Hydroformylation
Figure 1. Triphosphoramidite and the corresponding bis- and
tetra-phosphoramidite ligands.
Scheme 2. Coordination Modes of the Triphosphorus Ligand
and the Corresponding Bisphosphorus Ligands
Although a number of ligands were developed, high
catalyst loadings, low reaction rates, poor selectivity, and a
narrow substrate scope are still challenging problems in the
hydroformylation process. Further development of new
efficient ligands for highly regioselective hydroformylation
is still highly desirable. Although bis- and tetra-phosphorus
ligands have been well developed for regioselective hydro-
formylation, as a missing motif, a triphosphorus ligand has
never been developed (Scheme 1). We herein report the
synthesis and application of a novel triphosphoramidite
ligand 1 (Figure 1) for highly regioselective hydroformyla-
tion of terminal and internal olefins. To the best of our
knowledge, this is the first example of triphosphorus ligands
developed for highly regioselective linear hydroformylation.
Generally, the nine-membered ring chelations of the bis-
phosphorus ligands are much weaker than the corresponding
five- or six- membered ring chelations. Thus dissociation
of the chelating phosphorus atom from the metal center
by replacement of carbon monoxide at a relatively high
temperature is possible, resulting in the formation of the
less selective catalytic species which leads to worse linear
selectivity (Scheme 2). One of the keygoals of designing the
novel triphosphoramidite ligand 1 is to enhance the chelat-
ing ability to form more selective catalytic species. As we
rationalized, there are two identical chelating modes in the
complex of ligand 1 with rhodium (Scheme 2). Dissocia-
tion of one phosphorus atom from the rhodium center is
readily accompanied by the other free one; thus the local
phosphorus concentration of rhodium center is increased
and the chelating ability is greatly enhanced compared
with the corresponding bisphosphorus ligand. In this case,
more selective catalytic species will be generated and better
linear selectivity will be obtained.
(9) (a) Breit, B.; Seiche, W. J. Am. Chem. Soc. 2003, 125, 6608. (b)
Slagt, V. F.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Angew. Chem., Int. Ed. 2001, 40, 4271. (c) Slagt, V. F.; van Leeuwen, P.
W. N. M.; Reek, J. N. H. Angew. Chem., Int. Ed. 2003, 42, 5619. (d) Slagt,
V. F.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. J. Am.
Chem. Soc. 2004, 126, 1526. (e) Breit, B.; Seiche, W. Angew. Chem., Int.
Ed. 2005, 44, 1640.
(10) van der Slot, S. C.; Duran, J.; Luten, J.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M. Organometallics 2002, 21, 3873.
(11) Jia, X.; Wang, Z.; Xia, C.; Ding, K. Chem.;Eur. J. 2012, 18,
15288.
(12) (a) Yan, Y.; Zhang, X.; Zhang, X. J. Am. Chem. Soc. 2006, 128,
16058. (b) Yan, Y.; Zhang, X.; Zhang, X. Adv. Synth. Catal. 2007, 349,
1582. (c) Yu, S.; Chie, Y.; Zhang, X. Adv. Synth. Catal. 2009, 351, 537.
(d) Yu, S.; Zhang, X.; Yan, Y.; Cai, C.; Dai, L.; Zhang, X. Chem.;Eur.
J. 2010, 16, 4938.
This novel triphosphorus ligand 1 can be easily synthe-
sized in three steps (Figure 2). Using a known procedure, a
ligand skeleton 2,6,20-trimethoxybenzene 6 can be synthe-
sized in one step from readily available materials 4 and 5.13
Reduction of the methoxy group of 6 gave 7 as a white
solid. The air stable ligand 1 was obtained by treating 7
(13) Becht, J. M.; Gissot, A.; Wagner, A.; Mioskowski, C. Chem.;
Eur. J. 2003, 9, 3209.
B
Org. Lett., Vol. XX, No. XX, XXXX

with dipyrrolylchlorophophine 8 in 62% unoptimized yield
which is much higher than that of the tetraphosphorus
ligand 3 (36% yield). The corresponding bis- and tetra-
phosphorus ligands 2 and 3 (Figure 1) were synthesized
simultaneously following literature procedures in order to
compare the regioselectivities of ligands 1, 2, and 3.10,12a
Table 1. Hydroformylation Results of 1-Octene with Ligand 1
under Different Reaction Conditionsa
T
CO/H2
linear isomerization
entry L1/Rh (°C) (atm) l/bb (%)c
(%)d
TONe
1
1:1
2:1
3:1
4:1
8:1
3:1
3:1
3:1
3:1
3:1
80
80
80
80
80
60
10/10
4
80.3
17.7
16.8
17.7
18.0
18.2
6.8
9.5 ꢁ 103
9.4 ꢁ 103
9.3 ꢁ 103
9.3 ꢁ 103
9.1 ꢁ 103
4.0 ꢁ 103
9.4 ꢁ 103
5.3 ꢁ 103
6.8 ꢁ 103
9.2 ꢁ 103
2
10/10 280 99.7
10/10 289 99.7
10/10 297 99.7
10/10 298 99.7
10/10 321 99.7
3
4
5
6
7
100 10/10 247 99.6
18.6
12.1
8.3
8
80
80
80
5/5
20/20 235 99.6
5/5 394 99.8
399 99.8
9
10f
20.6
a S/C = 10 000, [Rh] = 0.2 mM, reaction time = 1 h, toluene as
solvent, decane as internal standard. b Linear/branched ratio, deter-
mined by GC analysis. c Percentage of linear aldehyde. d Percentage of the
isomerized alkene. e Turnover number, determined on the basis of the
alkene conversion by GC analysis. f Reaction time was prolonged to 2 h.
value were observed when the syngas pressure was increased
to 20:20 bar (Table 1, entries 8ꢀ9). In order to improve the
TON value, the reaction time was prolonged to 2 h, afford-
ing a higher TON value of 9200 while maintaining the l/b
ratio to as high as 394 (Table 1, entry 10).
Figure 2. Synthesis of the triphosphoramidite ligand 1.
Utilizing the newly synthesized triphosphoramidite li-
gand 1, rhodium-catalyzed regioselective linear hydrofor-
mylations of terminal and internal olefins were explored.
Screening of the reaction conditions was conducted by
varying the ligand/metal ratio, temperature, syngas pres-
sure, and reaction time using 1-octene as the standard
substrate. The hydroformylation catalyst was prepared
in situ by mixing Rh(acac)(CO)2 with ligand 1 while the
reaction was performed utilizing 1:1 CO/H2 syngas and a
typical substrate/catalyst loading of 10000. Not surpris-
ingly, the results fluctuated dramatically under different
reaction conditions as summarized in Table 1. The ligand/
metal ratio plays a key role in determining the regioselec-
tivity (Table 1, entries 1ꢀ5). Only an l/b ratio of 4 was ob-
served when the ligand/metal ratio was 1 (Table 1, entry 1).
The minimum ligand/metal ratio was 2 to ensure high
regioselectivity (Table 1, entry 2). A very high l/b ratio of
289 was achieved when the ligand/metal ratio was 3; how-
ever, increasing the ligand/metal ratio further did not
distinctly improve the regioselectivity (Table 1, entries
4ꢀ5). As shown in Table 1, a high ligand/metal ratio gave
a smaller TON value and resulted in a higher isomerization
percentage of the alkene substrate. Temperature is also
momentous in determining the regioselectivity and isomer-
ization percentage of the alkene substrate. High tempera-
tures generally facilitate the reaction rate at the cost of
selectivity; as a result, increasing the reaction temperature
to 100 °C reduced the regioselectivity distinctly (Table 1,
entry 7). In contrast, an improved l/b ratio of 321 and a
much smaller isomerization percentage were observed
when lowering the reaction temperature to 60 °C (Table 1,
entry 6). The syngas pressure also influences the regioselec-
tivity significantly. Lowering the syngas pressure to 5:5 bar
distinctly improved the l/b ratio to 399 albeit with a smaller
TON value; in contrast, both a smaller l/b ratio and TON
In an effort to compare the regioselectivities of ligands
1ꢀ3, ligands 2 and 3 were also tested in the hydroformyla-
tion of alkenes under the optimized reaction conditions of
ligand 1 (80 °C, CO/H2 = 5/5 bar, ligand/metal ratio = 3,
reaction time = 2 h, Table 1, entry 10). Using 1-octene as a
substrate, ligand 2 afforded an l/b ratio of only 117 albeit
with a slightly higher TON value of 9400 while ligand 3
gave a higher l/b ratio of 559 but a lower TON value of
9200 (Table 2, entries 2ꢀ3), respectively. Regioselective
linear hydroformylation of other terminal alkenes was
also conducted under the optimized reaction conditions.
As listed in Table 2, a very high l/b ratio of 471 accom-
panied by a high TON value of 7400 was achieved utilizing
ligand 1 in the hydroformylation of 1-hexene (Table 2,
entry 4). In contrast, an l/b ratio of only 125 was obtained
using ligand 2 while ligand 3 afforded a higher l/b ratio of
618 (Table 2, entries 5ꢀ6). Ligand 1was also subjected to the
regioselective isomerization/hydroformylation of 2-octene.
A high l/b ratio of 47 was achieved utilizing ligand 1 (Table 2,
entry 7). Due to the much lower reactivity compared to the
corresponding terminal alkene, the TON value achieved
employing ligand 1 in the isomerization/hydroformylation
of 2-octene was much smaller (TON = 2400, Table 2,
entry 7). With ligand 2, only an l/b ratio of 16 was obtained
although the TON value is higher (Table 2, entry 8). Ligand
3 afforded a slightly higher regioselectivity (l/b ratio = 59,
Table 2, entry 9) but a lower TON value compared with
ligand 1. As can be concluded from the above results, the
regioselectivities achieved utilizing the novel triphosphora-
midite ligand 1 are much better than those of ligand 2 and
close to those of ligand 3.
In order to further explore the substrate scope, the
novel triphosphoramidite ligand 1 was also subjected to
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Hydroformylation of 1-Octene, 1-Hexene, and
2-Octene with Ligands 1ꢀ3a
Table 3. Hydroformylation Results of Styrene with Ligands
1ꢀ3a
T
time
linear isomerization
linear
(%)d
TOFe
(hꢀ1
entry substrate Lb (°C) (h) l/bc (%)d
(%)d
TONe
entry
Lb/Rh
l/bc
)
1
2
3
4
5
6
7
8
9
1-octene L1 80
1-octene L2 80
1-octene L3 80
1-hexene L1 80
1-hexene L2 80
1-hexene L3 80
2-octene L1 100
2-octene L2 100
2-octene L3 100
2
2
2
2
2
2
1
1
1
415 99.8
117 99.2
559 99.8
471 99.8
125 99.2
618 99.8
47 98.0
16 94.0
59 98.3
20.6
12.2
22.2
22.3
14.2
24.5
n.d.
n.d.
n.d.
9.2 ꢁ 103
9.4 ꢁ 103
9.2 ꢁ 103
7.4 ꢁ 103
9.0 ꢁ 103
7.5 ꢁ 103
2.4 ꢁ 103
2.8 ꢁ 103
2.0 ꢁ 103
1
2
3
4
5
6
7
8
9
L1/Rh = 1:1
L1/Rh = 2:1
L1/Rh = 3:1
L1/Rh = 4:1
L1/Rh = 5:1
L1/Rh = 6:1
L1/Rh = 8:1
L2/Rh = 4:1
L3/Rh = 4:1
2.5
3.3
3.2
3.2
3.2
3.2
3.1
1.1
5.0
71.7
76.6
76.4
76.2
76.2
76.0
75.8
52.3
83.4
840
570
430
360
280
270
200
680
470
a S/C = 10 000, [Rh] = 0.2 mM, toluene as solvent, decane as inter-
a S/C = 1000, [Rh] = 0.1 mM, toluene as solvent, decane as internal
standard, CO/H2 = 5:5 bar, reaction time = 30 min. b L1 = ligand 1,
L2 = ligand 2, L3 = ligand 3. c Linear/branched ratio, determined by
GC analysis. d Percentage of linear aldehyde. e Turnover frequency,
determined on the basis of the alkene conversion by GC analysis.
nal standard, ligand/metal ratio = 3, CO/H2 = 5:5 bar. b L1 = ligand 1,
L2 = ligand 2, L3 = ligand 3. c Linear/branched ratio, determined by
GC analysis. d Percentage of linear aldehyde. e Turnover number, de-
termined on the basis of the alkene conversion by GC analysis.
ligand 1 also exhibited excellent regioselectivities in the
isomerization/hydroformylation of an internal alkene. As
an example, ligand 1 afforded a typical l/b ratio of 47 in the
isomerization/hydroformylation of 2-octene, giving 98.0%
synthetically useful terminal aldehyde. It is noteworthy that
ligand 1 also exhibited good regioselectivities in the linear
hydroformylation of styrene which is generally considered
as a standard substrate for asymmetric hydroformylation,
affording 76.7% phenylpropanal. For the range of sub-
strates listed above, the novel triphosphoramidite ligand 1
always displayed much better regioselectivities than those of
the corresponding bisphosphoramidite ligand 2 and af-
forded comparable regioselectivities to those of the tetra-
phosphoramidite ligand 3.
the regioselective hydroformylation of styrene which is
prevalently considered as a standard substrate for asym-
metric hydroformylation due to its inherent preference to
generate branched aldehyde. Ligand 1 also exhibited good
regioselectivity affording a linear product percentage of
76.6% (Table 3, entry 2) while employing a ligand/metal
ratio of only 2. A further increase in the ligand/metal ratio
led to a slight drop in the regioselectivity and dramatic
decline in the TON value (Table 3, entries 2ꢀ7). For
comparison, the hydroformylation of styrene was also
conducted with ligand 2 and 3 under the identical reac-
tion conditions reported in the literature.12a As shown in
Table 3, ligand 2 furnished an l/b ratio of only 1.1 even
when employing a high ligand/metal ratio of 4 while ligand
3 afforded a higher l/b ratio of 5.0 (Table 3, entries 8ꢀ9).
In conclusion, a novel triphosphoramidite ligand 1 has
been developed, which is the first example of a tripho-
sphorus ligand for highly regioselective linear hydrofor-
mylation. Very high l/b ratios and TON values were ob-
tained in the linear hydroformylation of simple terminal
olefins (for 1-octene, l/b = 415, TON = 9200; for 1-hexene,
l/b = 471, TON = 7400). The novel triphosphoramidite
Acknowledgment. We are grateful for the financial
support by a grant from Wuhan University (203273463).
Supporting Information Available. Experimental proce-
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX