Regioselective hydroformylation of sulfonamides using a scaffolding ligand

Article abstract of DOI:10.1021/ol900921e

A highly regloselectlve hydroformylatlon of allyllc sulfonamides has been developed by employing a catalytic directing group. The reaction tolerates a wide range of electronically and sterlcally modified olefins, and only 10% of the scaffolding llgand Is required to effectively control the regloselectlvlty.

Full text of DOI:10.1021/ol900921e

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2764-2767
Regioselective Hydroformylation of
Sulfonamides using a Scaffolding
Ligand
Amanda D. Worthy, Moriah M. Gagnon, Michael T. Dombrowski, and Kian L. Tan*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
kian.tan.1@bc.edu
Received April 28, 2009
ABSTRACT
A highly regioselective hydroformylation of allylic sulfonamides has been developed by employing a catalytic directing group. The reaction
tolerates a wide range of electronically and sterically modified olefins, and only 10% of the scaffolding ligand is required to effectively control
the regioselectivity.
The control of regio- and stereoselectivity is a paramount
goal in organic synthesis. Though many strategies have been
employed for this task, one of the most reliable and
predictable has been the application of directing groups.1 In
metal-based catalysis, directing groups are functionalities
within the organic substrate that can serve as a ligand for
the catalyst. The intimate association of the metal with the
substrate allows for enhanced control of the selectivity of
the transformation. A potential liability for the directing
group process is that often the ideal ligand for the metal is
not necessarily a useful functional group handle for future
synthetic transformations. This conundrum is most apparent
in hydroformylation where phosphorus-based ligands are the
ideal ligands for the reaction, yet this functionality has limited
application in organic synthesis.2 To circumvent this problem,
several groups have devised phosphorus-based directing
groups that can be cleaved easily in a subsequent step.3
Though this strategy is useful, it inherently generates a
stoichiometric amount of phosphorus-based byproduct and
requires additional synthetic steps.
Most recently our group4 as well as the Breit group5
reported catalytic directing groups6 in the regioselective
hydroformylation of homoallylic alcohols. Both groups used
the concept of reversible covalent modifications to a phos-
phorus-based ligand to allow for transient attachment of the
substrate to the ligand. The rate acceleration provided by
(3) (a) Burke, S. D.; Cobb, J. E. Tetrahedron Lett. 1986, 27, 4237. (b)
Jackson, W. R.; Perlmutter, P.; Tasdelen, E. E. Tetrahedron Lett. 1990, 31,
2461. (c) Jackson, W. R.; Perlmutter, P.; Tasdelen, E. E. J. Chem. Soc.,
Chem. Commun. 1990, 10, 763. (d) Breit, B. Angew. Chem., Int. Ed. 1996,
35, 2835. (e) Breit, B.; Zahn, S. K. J. Org. Chem. 2001, 66, 4870. (f) Breit,
B.; Demel, P.; Gebert, A. Chem. Commun. 2004, 1, 114. (g) Breit, B. Liebigs
Ann. Chem. 1997, 1841. (h) Breit, B.; Dauber, M.; Harms, K. Chem.sEur.
J. 1999, 5, 2819. (i) Krauss, I. J.; Wang, C. C. Y.; Leighton, J. L. J. Am.
Chem. Soc. 2001, 123, 11514.
(1) (a) Hoveyda, A.; Evans, D.; Fu, G. Chem. ReV. 1993, 93, 1307. (b)
Itami, K.; Yoshida, J. Synlett 2006, 2, 157. (c) Oestreich, M. Eur. J. Org.
Chem. 2005, 5, 783. (d) Kakiuchi, F.; Chatani, N. AdV. Syn. Catal. 2003,
345, 1077. (e) Dick, A.; Sanford, M. Tetrahedron 2006, 62, 2439.
(2) Breit, B. Synthesis 2001, 1, 1.
(4) Lightburn, T. E.; Dombrowski, M. T.; Tan, K. L. J. Am. Chem. Soc.
2008, 130, 9210.
(5) (a) Gru¨nanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2008, 47,
7346. (b) Smejkal, T.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 311.
10.1021/ol900921e CCC: $40.75
Published on Web 06/02/2009
 2009 American Chemical Society

the directing group allows branched selective hydroformy-
lation to proceed using only a catalytic amount of ligand.
Our bifunctional ligand incorporates two independent binding
domains: a substrate binding site and metal binding site
(Figure 1). A unique substrate binding site provides the
rate of exchange was observed (Table 1). Though the initial
exchange with ligand 1 is important, efficient catalysis cannot
be achieved without also establishing that exchange of
sulfonamide bound ligand 4 and free sulfonamide substrate
occurs. To test this important aspect, we exchanged substrate
2 onto ligand 1 then in a subsequent step added sulfonamide
3 (Scheme 1). To our surprise, we discovered that exchange
Scheme 1. Exchange Reaction with Sufonamides
Figure 1. Design of scaffolding ligand.
possibility of bonding to a variety of organic functionalities
without substantially interfering with the metal binding
domain. We have set out to expand the substrate scope so
that the most common and useful organic functional groups
can be used in the directed hydroformylation. In this report,
we discuss the application of scaffolding ligand 1 in the
synthesis of ꢀ-amino-aldehydes (Mannich product7) through
a highly regioselective hydroformylation of protected amines.
As a prerequisite to the success of our strategy, we
attempted to establish whether protected amines would
exchange rapidly with ligand 1. Preliminary studies showed
that while carbamates and amides did not exchange with 1,
sulfonamides were incorporated on to the ligand readily
(Table 1). We believe that the success of sulfonamides is
is very rapid with a 53:47 mixture of 4 and 5 forming in 1 h
at 25 °C.8
Having demonstrated that the exchange reaction occurs,
we investigated the regioselective hydroformylation of 2
(Table 2). As a control reaction, the hydroformylation was
Table 1. Relative Rates of Exchange with Sulfonamides
Table 2. Optimization of Sulfonamide Hydroformylation
R
conversion at 6 h
p-OMe-Ph
p-Me-Ph
p-NO2-Ph
(3,5-CF3)-Ph
0
0
entry pressure (psi) regioselectivity (6: 7) conversion (%)b
23%a
69%b
1a
2
200
200
200
100
300
400
50:50
60:40
90:10
88:12
95:5
>95
>95
86
83
>95
>95
a >95% conversion reached in 6 days. b >95% conversion reached in
3c
4c
5c
6c
13 h.
97:3
related to the similarity in pKa to alcohols. Indeed, we found
that as the pKa of the substrate decreased, an increase in the
a Reaction run with 4% PPh3 as the ligand. b Conversion determined
by 1H NMR. c 2 and 1 were exchanged at 55 °C prior to hydroformylation.
(6) For examples of catalytic directing group strategies in other metal
catalyzed reactions, see: (a) Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc.
1986, 108, 2728. (b) Park, Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res.
2008, 41, 222. (c) Jun, C.; Moon, C. W.; Lee, D. Chem.sEur. J. 2002, 8,
2423. (d) Bedford, R. B.; Betham, M.; Caffyn, A. J. M.; Charmant, J.; Lewis-
Alleyne, L.; Long, P.; Polo-Ceron, D.; Prashar, S. Chem. Commun. 2008,
990. (e) Bedford, R. B.; Limmert, M. E. J. Org. Chem. 2003, 68, 8669. (f)
Lewis, J. C.; Wu, J.; Bergman, R. G.; Ellman, J. A. Organometallics 2005,
24, 5737.
performed with triphenylphosphine as the ligand. The
reaction yields a 50:50 mixture of the linear and branched
products with complete conversion (Table 2, entry 1). Similar
terminal substrates have been shown to favor linear products,
suggesting that in our case there is a moderate directing group
(7) (a) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797. (b)
Cordova, A. Acc. Chem. Res. 2004, 37, 102. (c) Gnas, Y.; Glorius, F.
Synthesis 2006, 1899.
(8) At equilibrium the ratio of 4:5 is 43:57, which is expected based on
the similarity between the allyl and crotyl sulfonamides.
Org. Lett., Vol. 11, No. 13, 2009
2765

Table 3. Evaluation of Substrate Scopea
a Conditions: (a) Substrate, 10 mol % 1, 55 °C, benzene, 6 h. (b) 2 mol % Rh(acac)(CO)2, 400 psi CO/H2, 45 °C. b Regioselectivity of aldehyde:
hemiaminal determined by SFC analysis. c Regioselectivity for reactions run with 4% PPh3 instead of 1. d Hydroformylation performed at 40 °C.
e Hydroformylation performed in 5% THF/benzene. f Hydroformylation performed in 10% THF/benzene with 3 mol % Rh(acac)(CO)2 at 55 °C.
g Hydroformylation performed in 10% THF/benzene with 3 mol % Rh(acac)(CO)2 and 6 mol % PPh3 at 55 °C. h Ratio of aldehyde:hemiaminal:hydrogenated
i
product. Selectivity determined by analysis of crude H NMR. j Isolated yields of the mixture of regioisomers.
1
effect from the sulfonamide functionality.9 Hydroformylation
of 2 in the presence of 1 affords complete conversion and a
regioselectivity of 60:40 in favor of the branched isomer
(Table 2, entry 2). Because of our earlier observation that
the initial exchange between 1 and 2 is slow as compared to
hydroformylation, we decided to repeat the reaction after
preforming 4. Under the modified conditions, a significant
increase in the b:l selectivity to 90:10 is observed (Table 2,
entry 3). Optimization of the CO/H2 pressure to 400 psi
further enhances the regioselectivity to 97:3 (b:l) (Table 2,
entry 6). We believe the increased CO pressure inhibits the
background hydroformylation reaction by inhibiting olefin
coordination allowing for the directed reaction to compete
more effectively.10 Increased CO pressure may also facilitate
ligand exchange on the metal, which is important in the
turnover of the substrate.
2). Furthermore, a more sterically hindered cyclohexyl
substituted olefin provides good yield and selectivity for
the desired regioisomer (Table 2, entry 3). A Z-substituted
olefin shows enhanced reactivity, allowing the hydro-
formylation to be performed under milder reaction condi-
tions while maintaining high yields and selectivities (Table
3, entry 4). A variety of styrene derived substrates afford
the aldehyde ꢀ to the aromatic ring (Table 3, entry 5-8).
These results highlight the utility of this strategy, since
hydroformylation of styrenes usually favors the aldehyde
at the R-position. Hydroformylation of an R,ꢀ-unsaturated
ester using PPh3 as the ligand provides very high regi-
oselectivity for the hemiaminal product, presumably due
to direction from the ester functionality (Table 3, entry
9). Also a significant amount of hydrogenation of the
double bond occurs. When scaffolding ligand 1 is
employed, the regioselectivity is reversed with minimal
hydrogenation being observed (Table 3, entry 9). To
further highlight the excellent chemoselectivity of the
directed hydroformylation, reaction with a skip diene
substrate yields only one aldehyde product and leaves the
distal olefin unaffected (Table 3, entry 10).
Optimized reaction conditions in hand, we evaluated
the reaction with regards to functional group tolerance.
Application to a disubstituted olefin yields the desired
regioisomer in comparable yield to the terminal olefin with
an increase in regioselectivity to >99:1 (Table 3, entry
(9) For examples of amide directed hydroformylation see: (a) Ojima,
I.; Zhang, Z. J. Org. Chem. 1988, 53, 4422. (b) Ojima, I.; Zhang, Z. J.
Organomet. Chem. 1991, 417, 253. (c) Campi, E. M.; Chong, J. M.; Jackson,
W. R.; Van Der Schoot, M. Tetrahedron 1994, 50, 2533. (d) Dickson, R. S.;
Bowen, J.; Campi, E. M.; Jackson, W. R.; Jonasson, C. A. M.; McGrath,
F. J.; Paslow, D. J.; Polas, A.; Renton, P.; Gladiali, S. J. Mol. Cat. A. 1999,
150, 133.
(10) van Leeuwen, P. W. N. M.; Casey, C. P.; Whiteker, G. T. Rhodium
Catalyzed Hydroformylation; Leeuwen, P. W. N. M., Claver, C., Eds.;
Kluwer Academic Publishers: Norwell, MA, 2001; Chapter 4, pp 63-
106.
2766
Org. Lett., Vol. 11, No. 13, 2009

In conclusion, we have demonstrated that sulfonamides
bind to scaffolding ligand 1, and can be used in the highly
regioselective hydroformylation for the synthesis of
ꢀ-amino-aldehydes. We are currently developing enan-
tiopure scaffolding ligands so that we can perform this
reaction enantioselectively. Furthermore, we believe this
new ligand class will be useful in other metal catalyzed
reactions.
Acknowledgment. We thank Boston College for providing
funding for this research project. Mass Spectrometry at Boston
College is supported by the NSF (DBI-0619576).
Supporting Information Available: Experimental details
and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL900921E
Org. Lett., Vol. 11, No. 13, 2009
2767