ARTICLES
concurrent in the macroscopic sense’2. A survey of the literature
would seem to support this, as in instances where the reaction com-
position is monitored as a function of time, simultaneous processing
of the substrate and intermediates is reported (for examples see refs
3, 8, 9, 12 and 13). Conceptually, approaches to metal-catalysed,
temporally separated systems might begin by identifying pairs of
reactions that are conducted by transition-metal complexes with
similar coordination environments. These initial candidates could
be further prioritized by the presence or absence of isolable
(stable) substrate–catalyst intermediates in the first catalytic cycle.
Monitoring the composition of multistep reactions as a function
of time can provide evidence for temporal separation. This was
demonstrated herein using NMR spectroscopy, although other
common analytical methods (infrared and ultraviolet/visible spec-
troscopy, and tandem liquid chromatography–mass spectrometry)
are likely to be suitable. The experiment outlined in Fig. 2c provides
an unequivocal test for temporal separation. By adding a second
substrate to the reaction mixture after processing of the first sub-
strate is under way, one can determine if the activity of the sub-
sequent step is arrested. In this work we have used this design
strategy to develop a useful catalyst for the anti-Markovnikov reduc-
tive functionalization of alkynes. The discovery that catalyst activity
can be modulated as a function of time may create new opportu-
nities for the development of tandem reaction processes.
a
Enone
O
O
R
R
R´
R´
reduction
Wittig olefination
Alkyne
Aldehyde
O
OH
R
H
R
R
hydration
reduction
(inhibited)
Time
O
b
O
Ph
n-octyl
Ph3P
n-octyl
1l
Ph
(1.2 equiv.)
7a
6 (9 mol%), 2,2´-bipyridine (3b, 18 mol%)
or
+
HCO2H (10 equiv.)
H2O–THF, 70 °C, 48 h
O
OH
n-octyl
n-octyl
Starting material
7a/5l
4l
5l
Alkyne (1l)
7:1
2:1
Aldehyde (4l)
Figure 3 | Triple-cascade anti-Markovnikov hydration, olefination and
enone reduction. a, Temporal separation of the hydration and hydrogenation
activities was anticipated to allow for stoichiometric functionalization of the
aldehyde intermediate in situ. In this instance, we investigated in situ Wittig
olefination of the aldehyde. 1,4-Hydrogenation of the resulting enone would
provide the reductive alkylation product. b, Control experiments to probe for
an enhancement in selectivity starting from an alkyne. Reductive alkylation
of the alkyne 1l provided higher selectivity for the ketone 7a than that
beginning with aldehyde 4l. We attribute this increase in selectivity to the
delayed onset of hydrogenation activity by the catalyst, which allows for
progression of the Witting olefination.
Methods
Full experimental details and characterization data for all new compounds are
provided in the Supplementary Information.
Received 10 June 2013; accepted 11 October 2013;
published online 17 November 2013
References
1. Bornscheuer, U. T. & Kazlauskas, R. J. Catalytic promiscuity in biocatalysis:
using old enzymes to form new bonds and follow new pathways. Angew. Chem.
Int. Ed. 43, 6032–6040 (2004).
Table 3 | Hydration-olefination-1,4-reduction triple cascade.
Ph
CH3
2. Fogg, D. E. & dos Santos, E. N. Tandem catalysis: a taxonomy and illustrative
review. Coord. Chem. Rev. 248, 2365–2379 (2004).
3. Pittman, C. U. & Liang, Y. F. Sequential catalytic condensation–hydrogenation
of ketones. J. Org. Chem. 45, 5048–5052 (1980).
4. Breit, B. & Zahn, S. K. Domino hydroformylation–Wittig reactions. Angew.
Chem. Int. Ed. 38, 969–971 (1999).
Ph3P
Ph3P
or
O
O
(1.2 equiv.)
ʹ
O
2 (9 mol%), 2,2 -bipyridine (3b, 18 mol%)
R
R
HCO2H (10 equiv.)
H2O–THF, 55 °C, 48 h
ʹ
R
7a–e, 8a–e
5. Edwards, M. G. & Williams, J. M. J. Catalytic electronic activation: indirect
‘Wittig’ reaction of alcohols. Angew. Chem. Int. Ed. 41, 4740–4743 (2002).
6. Seayad, A. et al. Internal olefins to linear amines. Science 297, 1676–1678 (2002).
7. Chen, J.R. et al. Ru-catalyzed tandem cross-metathesis/intramolecular-
hydroarylation sequence. Angew. Chem. Int. Ed. 47, 2489–2492 (2008).
8. Cadierno, V. et al. Ruthenium-catalyzed redox isomerization/transfer
hydrogenation in organic and aqueous media: a one-pot tandem process for the
reduction of allylic alcohols. Green Chem. 11, 1992–2000 (2009).
9. Behr, A., Reyer, S. & Tenhumberg, N. Selective hydroformylation–
hydrogenation tandem reaction of isoprene to 3-methylpentanal. Dalton Trans
40, 11742–11747 (2011).
Yield
Yield
Entry
Substrate
Product
Rʹ = Ph Rʹ = CH3
ʹ
R
8a**, 71%
1
1c
7a, 75%
O
CH3
CH3
ʹ
R
n-octyl
2
3
1l
7b* , 72% 8b, 70%
7c†, 75% 8c, 70%
n-octyl
O
10. Kanbayashi, N., Takenaka, K., Okamura, T. & Onitsuka, K. Asymmetric auto-
tandem catalysis with a planar-chiral ruthenium complex: sequential allylic
amidation and atom-transfer radical cyclization. Angew. Chem. Int. Ed. 52,
4897–4901 (2013).
ʹ
R
1m
O
11. Fleischer, I. et al. From olefins to alcohols: efficient and regioselective
ruthenium-catalyzed domino hydroformylation/reduction sequence. Angew.
Chem. Int. Ed. 52, 2949–2953 (2013).
12. Pijnenburg, N. J., Cabon, Y. H., van Koten, G. & Klein Gebbink, R. J. Mechanistic
studies on the SCS-pincer palladium(II)-catalyzed tandem
stannylation/electrophilic allylic substitution of allyl chlorides with
hexamethylditin and benzaldehydes. Chem. Eur. J. 19, 4858–4868 (2013).
13. Yadav, A. K. et al. ‘Base effect’ in the auto-tandem palladium-catalyzed
synthesis of amino-substituted 1-methyl-1H-a-carbolines. Org. Lett. 15,
1060–1063 (2013).
O
O
O
ʹ
R
4
5
1o
1s
7d†, 81% 8d**, 76%
N
3
N
3
O
O
O
O
ʹ
R
7e, 72%
8e, 76%
CH3O
6
CH3O
6
O
14. Li, L. & Herzon, S. B. Regioselective reductive hydration of alkynes to form
branched or linear alcohols. J. Am. Chem. Soc. 134, 17376–17379 (2012).
15. Lynam, J. M. Recent mechanistic and synthetic developments in the chemistry of
transition-metal vinylidene complexes. Chem. Eur. J. 16, 8238–8247 (2010).
16. Campbell, A. N., White, P. B., Guzei, I. A. & Stahl, S. S. Allylic C–H acetoxylation
with a 4,5-diazafluorenone-ligated palladium catalyst: a ligand-based strategy to
achieve aerobic catalytic turnover. J. Am. Chem. Soc. 132, 15116–15119 (2010).
Conditions: alkyne (250 mmol), 2 (9.0 mol%), 3b (18 mol%), HCO2H (10.0 equiv.), THF–H2O (4:1
vol/vol; [alkyne] ¼ 0.4 M), 55 8C, 48 h. All yields are of spectroscopically homogeneous material,
after purification by flash-column chromatography. *Conditions: alkyne (250 mmol), 2 (9.0 mol%),
3b (18 mol%), HCO2H (10.0 equiv.), THF–H2O (4:1 vol/vol; [alkyne] ¼ 0.4 M), 55 8C, 72 h.
**Conditions: alkyne (125 mmol), 2 (9.0 mol%), 3b (18 mol%), HCO2H (15.0 equiv.), THF–H2O
(4:1 vol/vol; [alkyne] ¼ 0.4 M), 55 8C, 72 h. †Conditions: alkyne (250 mmol), 2 (9.0 mol%),
3b (18 mol%), HCO2H (5.0 equiv.), THF–H2O (4:1 vol/vol; [alkyne] ¼ 0.4 M), 55 8C, 48 h.
5
© 2013 Macmillan Publishers Limited. All rights reserved.