Regioselective catalytic hydroboration of propargylic species using Cu(I)-NHC complexes

Article abstract of DOI:10.1021/ol302086v

The catalytic regioselective hydroboration of propargylic alcohols and ethers was investigated using NHC-CuCl. We observe that different NHCCuCl complexes catalyze hydroborations of propargylic substrates with opposite regioselectivity. A 6-NHC-CuCl complex provides R-selectivity whereas β-selectivity is achieved using a 5-NHC-CuCl complex. The reaction tolerates a wide range of functional groups.

Full text of DOI:10.1021/ol302086v

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4790–4793
Regioselective Catalytic Hydroboration of
Propargylic Species Using Cu(I)-NHC
Complexes
Jin Kyoon Park,† Brian A. Ondrusek,‡ and D. Tyler McQuade*,‡
Pusan National University, Department of Chemistry, Pusan 609-735, Korea,
Florida State University, Department of Chemistry and Biochemistry,
Tallahassee, Florida 32306-4390, United States
mcquade@chem.fsu.edu
Received July 27, 2012
ABSTRACT
The catalytic regioselective hydroboration of propargylic alcohols and ethers was investigated using NHC-CuCl. We observe that different NHC-
CuCl complexes catalyze hydroborations of propargylic substrates with opposite regioselectivity. A 6-NHC-CuCl complex provides R-selectivity
whereas β-selectivity is achieved using a 5-NHC-CuCl complex. The reaction tolerates a wide range of functional groups.
New methods yielding multifunctional intermediates
are needed to aid the synthesis of complex molecules.1
Well-defined multifunctional compounds containing ver-
satile CÀB bonds are an example of intermediates that
have received significant attention recently.2 In particular,
vinyl boronates are both useful and easily produced via
addition of alkenyl heterobimetallics to electrophiles3 or
transition-metal-catalyzed hydroboration.4À6 However,
synthetic routes into all the desired regioisomers remain
a challenge.6l
Renewed interest in this area has been spurred on by
Cu(I)-catalyzed hydroboration of both internal and termi-
nal alkynes using bis(pinacolato)diboron or HBpin.6
† Pusan National University.
‡ Florida State University.
(1) Zweifel, G. S.; Nantz, M. H. Modern Organic Synthesis; W. H.
Freeman: 2006.
(2) (a) Roush, W. R.; Grover, P. T. Tetrahedron Lett. 1990, 31, 7567–
7570. (b) Barrett, A. G. M.; Malecha, J. W. J. Org. Chem. 1991, 56, 5243–
5245. (c) Roush, W. R.; Grover, P. T. Tetrahedron 1992, 48, 1981–1998.
(d) Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112–1124. (e)
Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C. Tetrahedron Lett. 2000,
41, 9413–9417. (f) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002,
124, 13644–13645. (g) Barrett, A. G. M.; Braddock, D. C.; de Koning,
P. D.; White, A. J. P.; Williams, D. J. J. Org. Chem. 2000, 65, 375–380.
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Peng, F.; Hall, D. G. J. Am. Chem. Soc. 2007, 129, 3070–3071.
This second generation of alkyne hydroboration was
pioneered by the Miyaura group,6a and catalytic alkyne
ꢀ
(3) (a) Hernandez-Toribio, J.; Hussain, M. M.; Cheng, K.; Carroll,
P. J.; Walsh, P. J. Org. Lett. 2011, 13, 6094–6097. (b) Hussain, M. M.;
Hernandez Toribio, J.; Carroll, P. J.; Walsh, P. J. Angew. Chem., Int. Ed.
ꢀ
(4) Examples are shown using borane (BÀH). For review on hydro-
metalation, see: (a) Trost, B. M.; Ball, Z. T. Synthesis 2005, 853–887.
For a review on transition-metal-catalyzed hydroboration, see: (b)
Beletskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957–5026. For hydro-
boration not using a metal catalyst, see: (c) Tucker, C. E.; Davidson, J.;
Knochel, P. J. Org. Chem. 1992, 57, 3482–3485. (d) Clay, J. M.; Vedejs,
E. J. Am. Chem. Soc. 2005, 127, 5766–5767.
2011, 50, 6337–6340. (c) Hussain, M. M.; Walsh, P. J. Angew. Chem., Int.
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Ed. 2010, 49, 1834–1837. (d) Hussain, M. M.; Li, H.; Hussain, N.; Urena,
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(e) Li, H.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 3521–
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r
10.1021/ol302086v
Published on Web 09/04/2012
2012 American Chemical Society

hydroboration was first reported by the Yun group, where
they demonstrated that acetylenic esters and phenyl-
acetylene could be regioselectively hydroborated using
Xantphos.6b Later, the Yun and Son groups showed that
internal aryl-alkynes undergo regioselective hydrobora-
tion when catalyzed by copper(I) ligated to 1,3-dimethyl-
imidazoline-2-thione or monophosphines.6c,f The Hovey-
da group demonstrated regioselective hydroborations of
terminal alkynes using 5-NHC-Cu(I) complexes to give R-
and β-selective vinylboronates.6d,e The Carretero group
developed regiocontrolled borylation of propargylic func-
tionalized dialkylalkynes catalyzed by Cu(I)-phosphine
complexes yielding β-B(Pin)-substituted (Z)-allylic alcohol.6i
The Lipshutz group introduced Cu(I) catalyzed R-selective
hydroborations of acetylenic ester using HB(Pin),6k and
the Tsuji group has generalized this synthetic method to
have a R and β product by the choice of borylating
reagents, HB(Pin) and B2Pin2, respectively.6l As an alter-
native method, herein, we present regioselective and
stereoselective Cu(I)-NHC catalyzed hydroboration of
propargylic ethers and alcohols yielding either the R-addi-
tion product, 2, or β-addition product, 3, by matching the
substrate and catalyst.
Our group recently reported the synthesis and unique
activity and reactivity of complex 4.7 Inspired by Ito and
Sawamura’s Cu(I) catalyzed formation of allenes from
propargylic species,6c,m,n we measured the product distri-
bution when similar substrates were reacted with complex
4. Instead of allene formation, we observed regio- and syn-
selective hydroboration, and as described in more detail
below, the regioselectivity is controlled by catalyst choice
(eq 1).8
Table 1. Protection Group Screening for Hydroboration of
Internal Alkynes
(5) Examples are shown using boronic ester reagent (BÀB or MÀB).
For a Pt-catalyzed reaction, see: (a) Ishiyama, T.; Matsuda, N.;
Miyaura, N.; Suzuki, A. J. Am. Chem. Soc. 1993, 115, 11018–11019.
(b) Lesley, G.; Nguyen, P.; Taylor, N. J.; Marder, T. B.; Scott, A. J.;
Clegg, W.; Norman, N. C. Organometallics 1996, 15, 5137–5154. (c)
Thomas, R. L.; Souza, F. E. S.; Marder, T. B. J. Chem. Soc., Dalton
4
5
entry
P
conva
R:βa
conva
R:βa
1
H
64%
55%
58:42
65:35
53:47
69:31
71:29
88:12
85:15b
96:4e
100%
78%
4:96
19:81
11:89
33:67
39:61
79:21
75:25c
95:5
2
TBDMS
Bn
Trans. 2001, 1650–1656. (d) Lillo, V.; Mata, J.; Ramı
Fernandez, E. Organometallics 2006, 25, 5829–5831. (e) Prokopcova, H.;
´
rez, J.; Peris, E.;
ꢀ
3
100%
100%
6%
100%
100%
76%
ꢀ
Ramırez, J.; Fernandez, E.; Kappe, C. O. Tetrahedron Lett. 2008, 49,
´
4
Ph
4831–4835. (f) Carson, M. W.; Giese, M. W.; Coghlan, M. J. Org. Lett.
2008, 10, 2701–2704. For a Rh- or Ir-catalyzed reaction, see: (g)
Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000,
122, 4990–4991. (h) Miura, T.; Takahashi, Y.; Murakami, M. Org. Lett.
2008, 10, 1743–1745. (i) Mkhalid, I. A. I.; Coapes, R. B.; Edes, S. N.;
Coventry, D. N.; Souza, F. E. S.; Thomas, R. L.; Hall, J. J.; Bi, S.-W.;
Lin, Z.; Marder, T. B. Dalton Trans. 2008, 1055–1064. For a Ni-
catalyzed reaction, see: (j) Mannathan, S.; Jeganmohan, M.; Cheng,
C. Angew. Chem., Int. Ed. 2009, 48, 2192–2195. For Pd-catalyzed
5
p-MeOC6H4
m-NO2C6H4
p-NO2C6H4
p-NO2C6H4
6
100%
100%
100%
100%
100%
87%
7
8d
a Determined by 1H NMR analysis of crude reaction mixtures.
b Reaction contains 8.6% allene product. c Reaction contains
9.8% allene product. d All reactions carried out at 0 °C except for
entry 8, which was carried out at À55 °C for 14 h. e Racemic product
was obtained using 0.5 equiv of B2Pin2 (no kinetic resolution
observed).
ꢀ
~
reactions, see: (k) Marco-Martı
´
nez, J.; Lopez-Carrillo, V.; Bunuel, E.;
ꢀ
Simancas, R.; Cardenas, D. J. J. Am. Chem. Soc. 2007, 129, 1874–1875.
~ ~ ꢀ
(l) Marco-Martınez, J.; Bunuel, E.; Munoz-Rodrıguez, R.; Cardenas,
´ ´
D. J. Org. Lett. 2008, 10, 3619–3621. (k) Ohmura, T.; Oshima, K.;
Taniguchi, H.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 12194–
12196.
To further clarify the regioselectivity observed when
using catalyst 4, we screened ester protecting groups such
as acetate, carbonate, and benzoate and observed the
formation of R-, β-addition and allene products.6c By
changing to fewer electron-withdrawing groups than esters
(shown in Table 1), we observed that hydroboration was
dominant. In most cases, the R-addition product was the
major product compared to the β-addition species. Sub-
strates containing a p-nitrophenyl ether afforded the
R-addition product in high yield and with excellent selectivity
(6) For Cu-catalyzed reactions with diboron reagents, see: (a)
Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001,
625, 47–53. (b) Lee, J.-E.; Kwon, J.; Yun, J. Chem. Commun. 2008, 733–
734. (c) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130,
15774–15775. (d) Lee, Y.; Jang, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 18234–18235. (e) Jang, H.; Zhugralin, A. R.; Lee, Y.;
Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 7859–7871. (f) Kim,
H. R.; Jung, I. G.; Yoo, K.; Jang, K.; Lee, E. S.; Yun, J.; Son, S. U.
Chem. Commun. 2010, 46, 758–760. (g) Kim, H. R.; Yun, J. Chem.
Commun. 2011, 47, 2943–2945. (h) Sasaki, Y.; Horita, Y.; Zhong, C.;
Sawamura, M.; Ito, H. Angew. Chem., Int. Ed. 2011, 50, 2778–2782. (i)
ꢀ
ꢀ
ꢀ
Moure, A. L.; Gomez Arrayas, R.; Cardenas, D. J.; Alonso, I.;
Carretero, J. C. J. Am. Chem. Soc. 2012, 134, 7219–7222. For Cu-
catalyzed diboration, see: (j) Lillo, V.; Fructos, M. R.; Ramı
´
rez, J.;
az-Requejo, M. M.; Perez, P. J.;
Fernandez, E. Chem.;Eur. J. 2007, 13, 2614–2621. For Cu-catalyzed
ꢀ
Braga, A. A. C.; Maseras, F.; Dı
´
ꢀ
ꢁ
ꢀ
(7) (a) Park, J. K.; Lackey, H. H.; Rexford, M. D.; Kovnir, K.;
Shatruk, M.; McQuade, D. T. Org. Lett. 2010, 12, 5008–5011. (b) Park,
J. K.; Lackey, H. H.; Ondrusek, B. A.; McQuade, D. T. J. Am. Chem.
Soc. 2011, 133, 2410–2413. (c) Park, J. K.; McQuade, D. T. Angew.
Chem., Int. Ed. 2012, 51, 2717–2721. (d) Park, J. K.; McQuade, D. T.
Synthesis 2012, 1485–1490.
ꢁ
reactions with borane, see: (k) Lipshutz, B. H.; Boskovic, Z. V.; Aue,
D. H. Angew. Chem., Int. Ed. 2008, 47, 10183–10186. For the control of
regioselectivity in Cu-catalyzed reactions by borylating reagents, see: (l)
Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Chem.;Eur. J. 2012, 18,
4179–4184. For Cu-catalyzed substitution reactions of nucleophilic
silicone to propargylic species in order to compare ref 6c, see: (m) Hazra,
C. K.; Oestreich, M. Org. Lett. 2012, 14, 4010–4013. (n) Vyas, D. J.;
Hazra, C. K.; Oestreich, M. Org. Lett. 2011, 13, 4362–4265.
(8) We found ref 6i about the β-selective hydroboration reaction
while we were preparing this manuscript.
Org. Lett., Vol. 14, No. 18, 2012
4791

(entry 8, Table 1). No kinetic resolution was observed
when 0.5 equiv of B2Pin2 was used.
Scheme 1. Regioselectivities Using 4a
We then measured the selectivity observed when catalyst
5 was used. Complex 5 yielded the β-addition product
(entry 1À5, Table 1) except where substrates contained
nitrophenyl ethers (entry 8, Table 1). The β-addition
selectivity was highest for alcoholic substrates (entry 1,
Table 1).8 With these results in hand, we assessed the
substrate scope by matching catalyst 4 with the p-nitro-
phenyl ether substrates to obtain the R-addition product
and catalyst 5 with alcohol substrates to yield the
β-addition product.
We examined the scope using a systematic approach
where branching and distal functional groups were con-
sidered. In most cases, catalyst 4 provided high R-selectivities
with secondary ethers (Scheme 1), delivered the B(Pin)
group to the more hindered site, and tolerated all distal
functional groups well.9 Primary ether 7a gave slightly
lower selectivity (85:15). The halide, protected amine and
silyl protected alcohol not only are compatible with reac-
tion conditions but also gave high R-selectivities (7e, 7f,
and 7g).
Matching catalyst5 and alcoholic substrates (Scheme 2),
we observed more striking substituent effects. The extent
of β-selectivity was influenced by the electronic properties
of the substrates (9b, 9d, 9e, 9f, and 9g) consistent with
literature precedent.9 Substrates containing smaller linear
aliphatic chains on the side opposite the secondary alcohol
also yielded a bias toward the β-addition product. A
reversal of selectivity was observed when aryl-substituted
internal alkynes (9h)6i or bulky substituents were proximal
to the β-carbon (9i).
a Isolated yields were shown in the parentheses. b Selectivity data
obtained by 1H NMR analysis of the crude product. c Isolated with
unknown product.
The observations gathered in Table 1 enabled us to
define optimum catalyst and substrate matches, and the
data collected in Schemes 1 and 2 indicate that the opti-
mized matches and conditions provide a wide substrate
scope. Moving forward, we had two objectives: (1)
obtain data to help explain why the functional group of
the substrate switches regiochemical preference and (2)
illustrate the potential synthetic utility of both the R- and
β-products.
Scheme 2. Regioselectivities Using 5a
From the standpoint of explaining regiochemical pre-
ferences, we compared entries 1À5 vs 6À8 in Table 1.
When complex 5 is used, we observe a gradient of selectiv-
ity where the unprotected alcohol substrates provide very
high selectivity for borylating the β-position. Substrates
containing neutral or electron releasing protecting
groups (entries 1À5) yield a modest preference for the
β-position, and electron-withdrawing groups such as ni-
trophenyl ethers exhibit reversal of selectivity yielding the
R-product (entries 6À8). From these data we propose that
the alcohol and p-nitrophenyl define a range of electronic
properties.
With this hypothesis in mind, we prepared substrates
10aÀ10d to measure the competition between steric and
(9) The Hoveyda group recently showed that distal functional groups
have a significant impact on alkyne hydroboration in ref 6e. And also
similar behavior was observed in ref 6i.
a 1H NMR yields are shown in the parentheses.
4792
Org. Lett., Vol. 14, No. 18, 2012

Scheme 3. Electronic and Steric Effects of Substrates on
Regioselectivity Using 5-NHC-CuCl, 5a
Scheme 4. Regioselectivity Observed with 6-NHC-CuCl, 4
We also developed a one-pot process to protect the
β-addition product, as isolation of the desired alcohol
was confounded by a mixture of alcohol and borate ester
(Scheme 5). We found triethanolamine completely hydro-
lyzes the borate intermediate with no transesterification of
B(Pin); however, the β-B(Pin)-substituted allylic alcohols
decompose when placed onto silica gel. The acetate pro-
tected alcohol was stable, enabling flash chromatography.12
a Reaction was carried out at À55 °C.
electronic effects (Scheme 3). Compounds 10a and 10b
represent the unencumbered and encumbered alcoholic
substrates, respectively, and 10c and 10d are similarly
representative but with the p-nitrophenyl ether group.
With 5, we observed that both 10a and 10b yielded a high
preference for the β-position, 6:94 and 4:96, respectively.
We infer from these data that sterics play very little role
when the catalyst orients to deliver the boron to the
β-position and that the electronic influence of the alcohol
polarizes the alkyne.10
Scheme 5. Protection of β-Addition Product for Isolation12
We found that the linear p-nitrophenyl ether provides no
site specific bias (52:48) whereas the branched p-nitrophenyl
ether induces high R-selectivity (up to 95:5 at À55 °C). These
results indicate that when the boron is delivered to the
R-position, selectivity is dominated by steric effects in order
to place the branched side of the alkyne proximal to the
B(Pin) and away from the bulkier NHC. When using 4, we
obtained consistent R preferences (Scheme 4), indicating that
the catalyst dominates the regioselective preference.
Next, we sought a simple strategy to deprotect the p-
nitrophenyl ether. We modified Fukase’s two-step approach
(i. H2 with Pd; ii. CAN)11a by using an indium-mediated
reduction of the nitro group11b to avoid Pd-catalyzed hydro-
genation of the double bond, followed by CAN oxidative
cleavage (eq 2). The method provided 11c in 71% yield.
In summary, we have shown a highly regioselective
R- and β-boron addition reaction to acetylenic ether and
alcohol catalyzed by 4 and 5, respectively. The R-product,
p-nitrophenyl ether, was successfully deprotected by mod-
ifying Fukase’s approach, and the unstable β-products,
hydroxy boronates, were easily isolated after protec-
tion with acetic anhydride. We are currently investigating
the synthetically useful applications of the R- and β-
products.
Acknowledgment. The authors thank the NSF (CHE-
0809261, 1152020), Pfizer, Corning Glass, and FSU for
support and FSU VP of Research and Dean of A&S for
NMR upgrades.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data of the reaction products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) It is worth noting that when substituents on the either side of the
alkyne are too large, the steric influence becomes the dominant factor
(9i, Scheme 2). We do not favor a model that invokes hydrogen bonding
because 5 reacts with benzylic ethers to provide high β-position selectiv-
ity as well.
(11) (a) Fukase, K.; Yasukochi, T.; Nakai, Y.; Kusumoto, S. Tetra-
hedron Lett. 1996, 37, 3343–3343. (b) Kim, B. H.; Han, R.; Piao, F.; Jun,
Y. M.; Baik, W.; Lee, B. M. Tetrahedron Lett. 2003, 44, 77–79.
(12) Synthetic details are shown in the Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
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