Synthesis and Structure of Planar Chiral, Bifunctional Aminoboronic Acid Ferrocene Derivatives

Article abstract of DOI:10.1021/om070038l

N,N′-Diisopropylferrocenecarboxamide is utilized for an asymmetric, directed metalation approach to several planar chiral bifunctional ferrocene derivatives. Directed metalation using n-butyllithium-(-)-sparteine on N,N′-diisopropylferrocenecarboxamide can be achieved to give high yields of the corresponding boronic acid; however, it was found that a sequence involving asymmetric directed metalation-bromination, followed by lithium-halogen exchange, was more convenient to access the same derivatives since this allowed straightforward determination of the enantiomeric excess. (pR)-2-[(N,N′-Diisopropylamino)methyl]ferrocenylboronic acid and derivatives thereof could be readily accessed with high enantiomeric excess, followed by amide reduction.

Full text of DOI:10.1021/om070038l

2414
Organometallics 2007, 26, 2414-2419
Synthesis and Structure of Planar Chiral, Bifunctional
Aminoboronic Acid Ferrocene Derivatives
Andrei S. Batsanov, Damien He´rault, Judith A. K. Howard, Leonard G. F. Patrick,
Michael R. Probert, and Andrew Whiting*
Department of Chemistry, Durham UniVersity, Sciences Laboratories, South Road,
Durham DH1 3LE, United Kingdom
ReceiVed January 14, 2007
N,N′-Diisopropylferrocenecarboxamide is utilized for an asymmetric, directed metalation approach to
several planar chiral bifunctional ferrocene derivatives. Directed metalation using n-butyllithium-(-)-
sparteine on N,N′-diisopropylferrocenecarboxamide can be achieved to give high yields of the
corresponding boronic acid; however, it was found that a sequence involving asymmetric directed
metalation-bromination, followed by lithium-halogen exchange, was more convenient to access the
same derivatives since this allowed straightforward determination of the enantiomeric excess. (pR)-2-
[(N,N-Diisopropylamino)methyl]ferrocenylboronic acid and derivatives thereof could be readily accessed
with high enantiomeric excess, followed by amide reduction.
from amines and carboxylic acids.10 In this paper, we document
the synthesis and structure of planar chiral 2-N,N′-diisopropy-
laminomethyferrocenylboronate derivatives, which are direct
chiral analogues of a class of compounds that are valuable
bifunctional catalysts for direct amide formation.10
Introduction
Aminoarylboronic acids have been attracting considerable
interest for a wide variety of applications, including quantifica-
tion of enantiomeric excess,1 electrochemical,2 colorimetric, or
fluorescence saccharide sensor applications,3 selective saccharide
binding systems,4 and indicators to follow reaction kinetics.5
In addition, early studies by Letsinger et al. demonstrated the
potential for such systems as bifunctional catalysts for simple
alkylation and hydrolysis reactions.6 Indeed, there have been
many studies on the intramolecular interactions between boron
and nitrogen7 and how such interactions tune complexation
characteristics.8 However, the application of aminoarylboronic
acids as bifunctional catalysts is largely unexplored, with a noted
exception,6 and this has led us to examine the synthesis and
structure of aminoarylboronate systems9 in order to examine
their potential as catalysts for a range of organic transformations,
including the important area of in situ direct amide formation
Results and Discussion
2-N,N′-Diisopropylaminomethyphenylboronic acid is an ex-
ceptional catalyst for the direct amide formation of less reactive
amine-carboxylic acid combinations,10 which is partly ex-
plained by the effect of the hindered diisopropylamino function
that inhibits B-N chelation in both solution and solid states.9b
We therefore wanted to access a planar chiral version of this
system to examine a range of catalytic asymmetric transforma-
tions including acylation processes. Perhaps the most direct
chiral analogue of 2-N,N′-diisopropylaminomethyphenylboronic
acid would be the corresponding ferrocene-based system, i.e.,
2-N,N′-diisopropylaminomethyferrocenylboronic acid, since
the amide derivative had already been reported by Snieckus et
al.,11 and other groups had shown that ferrocenyl-based ami-
noboronate systems have interesting physical and chemical
properties.8d,12
* Corresponding author. Tel: +44 191 334 2081. Fax: +44 191 384
4737. E-mail: andy.whiting@durham.ac.uk.
(1) (a) Zhu, L.; Anslyn, E. V. J. Am. Chem. Soc. 2004, 126, 3676-
3677. (b) Zhu, L.; Zhong, Z.; Anslyn, E. V. J. Am. Chem. Soc. 2005, 127,
4260-4269.
Commercially available ferrocenecarboxaldehyde 1 was
transformed into the diisopropylamide 3 using essentially
literature methods,11a,13 as shown in Scheme 1. Diisopropylamide
3 was then subjected to asymmetric directed ortho-metalation
(2) (a) Norrild, J. C.; Søtofte, I. J. Chem. Soc., Perkin Trans. 2002, 2,
303-311. (b) Orl, A.; Shinkai, S. J. Chem. Soc., Chem. Commun. 1995,
1771-1772.
(3) (a) Ward, C. J.; Patel, P.; James, T. D. J. Chem. Soc., Perkin Trans.
2002, 1, 462-470. (b) Zhao, J.; James, T. D. Chem. Commun. 2005, 1889-
1891.
(9) (a) Giles, R. L.; Howard, J. A. K.; Patrick, L. G. F.; Probert, M. R.;
Smith, G. E.; Whiting, A. J. Organomet. Chem. 2003, 680, 257-262. (b)
Coghlan, S. W.; Giles, R. L.; Howard, J. A. K.; Probert, M. R.; Smith, G.
E.; Whiting, A. J. Organomet. Chem. 2005, 690, 4784-4793. (c) Blatch,
A. J.; Chetina, O. V.; Howard, J. A. K.; Patrick, L. G. F.; Smethurst, C.
A.; Whiting, A. Org. Biomol. Chem. 2006, 4, 3297-3302.
(10) Arnold, K.; Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.;
Whiting, A. AdV. Synth. Catal. 2006, 348, 813-820.
(11) (a) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor,
N. J.; Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685-686. (b) Metallinos,
C.; Szillat, H.; Taylor, N. J.; Snieckus, V. AdV. Synth. Catal. 2003, 345,
370-382.
(4) Dowlut, M.; Hall, D. G. J. Am. Chem. Soc. 2006, 128, 4226-4227.
(5) Nguyen, B. T.; Wiskur, S. L.; Anslyn, E. V. Org. Lett. 2004, 6, 2499-
2501.
(6) (a) Letsinger, R. L.; Dandegaonker, S. H. J. Am. Chem. Soc. 1959,
81, 498-501. (b) Letsinger, R. L.; MacLean, D. B. J. Am. Chem. Soc. 1963,
85, 2230-2236.
(7) (a) Hawkins, R. T.; Snyder, H. R. J. Org. Chem. 1960, 82, 3863-
3866. (b) Toyota, S.; Futawaka, T.; Asakura, M.; Ikeda, H.; Oki, M.
Organomet. 1998, 17, 4155-4163.
(8) (a) Wiskur, S. L.; Lavigne, J. J.; Ait-Haddou, H.; Lynch, V.; Chiu,
Y. H.; Canary, J. W.; Anslyn, E. V. Org. Lett. 2001, 3, 1311-1314. (b)
Norrild, J. C.; Søtofte, I. J. Chem. Soc., Perkin Trans. 2001, 2, 727-732.
(c) Norrild, J. C. J. Chem. Soc., Perkin Trans. 2001, 2, 719-726. (d)
Bresner, C.; Aldridge, S.; Fallis, I. A.; Jones, C.; Ooi, L.-L. Angew. Chem.,
Int. Ed. 2005, 44, 3606-3609.
(12) (a) Silva, M. E. N. P. R. A.; Pombeiro, A. J. L.; Frau´sto da Silva,
J. J. R.; Herrman, R.; Deus, N.; Bozak, R. E. J. Organomet. Chem. 1994,
480, 81-90. (b) Marr, G.; Moore, R. E.; Rockett, B. W. Tetrahedron Lett.
1968, 2521-2534.
10.1021/om070038l CCC: $37.00 © 2007 American Chemical Society
Publication on Web 03/30/2007

Aminoboronic Acid Ferrocene DeriVatiVes
Organometallics, Vol. 26, No. 9, 2007 2415
Scheme 1. Preparation of the Ferrocenecarboxylic Acid Amide 3
Scheme 2. Directed Metalation to Access Boronates 5 and 6
Scheme 3. Sparteine-Directed Metalation and Amide Reduction to Access (pR)-Bromide 8
Scheme 4. Competing Amide Reduction Providing Both
to give the crystalline pinacol derivative (pR)-5, the crystal
structure of which is shown in Figure 2. The expected11a (pR)-
absolute stereochemistry of the main component of 4 and 5 (as
shown in Figures 1 and 2) has been confirmed by anomalous
X-ray scattering (see Supporting Information).
Amine 10 and Methyl Derivatives 11
The isolation of the amide-boronic acid derivative 4 allowed
us to attempt amide reduction, as developed in the corresponding
benzene series.9b Indeed, this worked well using excess borane
at reflux to provide the desired 2-[N,N′-(diisopropylamino)-
methyl]ferrocenylboronic acid (6), which was also readily
crystallized and subjected to single-crystal X-ray structure
determination (Figure 3). It is noteworthy that the lone electron
pair of the (amino) nitrogen atom is not donated to boron; rather
it accepts an intramolecular hydrogen bond from the boronic
acid moiety. Although this bond, O(2)-H‚‚‚N, is somewhat
weaker in 6 than in the known dimethylamino analogue2a
(O‚‚‚N 2.730(3) vs 2.672(1) Å), it is preferred over B-N
chelation when there are suitably hindering substituents on
nitrogen.9b This preference is entirely as expected from our
previous observations9 and is important for the potential
application of such systems as catalysts and receptors, i.e., by
being able effectively to switch off B-N chelation. This solid-
state structure of 6 is also retained in solution, as indicated by
the 11B NMR signal at δ 32.3, characteristic of the arylboronic
acid function.
Scheme 5. Lithium-Halogen Exchange to Access Boronic
Acid 6 and Formation of the Difluoroborane‚HF Complex 12
using (-)-sparteine, as described by Snieckus,11 to give the
ortho-boronic acid 4 (Scheme 2), the 3D structure of which
was confirmed by X-ray crystallography (Figure 1). Attempts
to determine the enantiomeric excess of 4 using the methods
described11b failed to provide any separation, as did a range of
other chiral HPLC columns. It was, however, possible to verify
the clean formation of the (pR)-boronic acid 4 by esterification
Thus in 6 the boron atom maintains essentially the same
planar trigonal geometry as in 4 and 5. In all three compounds,
the boronate function is approximately coplanar with the
ferrocene ring, forming dihedral angles of 14.9° in 4, 11.9° in
5, and 18.5° in 6. In molecule 4, like in 6, this type of
conformation is stabilized by an intramolecular hydrogen bond,
(13) Neto, A. F.; Miller, J.; Faria de Andrade, V.; Fujimoto, S. Y.; Ma´ısa
de Freitas, A.; Archanjo, F. C.; Darin, V. A.; Andrade e Silva, M. L.; Borges
A. D. L.; Del Ponte, G. Z. Anorg. Allg. Chem. 2002, 628, 209-216.

2416 Organometallics, Vol. 26, No. 9, 2007
BatsanoV et al.
Figure 1. X-ray structure and hydrogen bonding of (pR)-boronic
acid 4 (50% thermal ellipsoids). Symmetry codes: (i) 1-x, (1/
2)+y, (1/2)-z; (ii) 1-x, y-(1/2), (1/2)-z.
Figure 4. X-ray structure of trifluoroborate-HF complex (pR)-
12 (50% thermal ellipsoids).
the preparation of the corresponding ferrocene bromide 7 to
enable enantiomeric excess determination, followed by an amide
reduction-boronation sequence.
Therefore, we subjected amide 3 to asymmetric directed
ortho-metalation using (-)-sparteine, as described above, fol-
lowed by bromination with 1,2-dibromotetrachloroethane to
provide ortho-bromide 7 in nearly quantitative yield (Scheme
3). It was straightforward to determine the asymmetric induction
from the directed metalation step to give 7 using a Chiralcel
OD HPLC column, which showed an excellent 96% enantio-
meric excess. The assignment of the absolute stereochemistry
of the major enantiomer of 7 as (pR) is based on the
well-precedented control by (-)-sparteine in such systems.11
Once bromide 7 had been prepared, amide reduction was
accomplished using excess borane-dimethylsulfide complex.
Not only did this produce the expected amine 8, but it was also
accompanied by the complete reduction product 914 in a crude
ratio of 83:17. After separation, the major amino product 8 was
isolated in a pure form in 54% yield (Scheme 3). There is
another report15 in the literature of this type of reduction with
borane derivatives, which shows that ferrocenyl carbonyl
compounds have this unusual ability to reduce to the methyl
derivative. However, we were intrigued to look at this process
further, and we therefore examined the reduction of the ferrocene
amide 3 under two different reduction conditions, as outlined
in Scheme 4. Generation of borane in situ from sodium
borohydride and iodine (conditions A, Scheme 4) gave reason-
able conversion and resulted in only a small amount of the
methyl derivative 11, with the amine predominating. Separation
of the mixture was not straightforward, and the major product
amine 10 was isolated in low yield. Similarly, the use of
borane-dimethyl sulfide complex as above provided a different
ratio of products; that is, at 87% conversion the amine 10 to
methyl 11 ratio was 94:6, which suggests that the amount of
complete reduction product depends more on the substrate rather
than the reagent. Confirmation of the order of events in this
reduction came from the exposure of both the ferrocene
carboxaldehyde 1 and the amine 10 to the same borane-
dimethylsulfide reaction conditions, which provided a quantita-
tive conversion to the methyl ferrocene 11 in the case of the
aldehyde 1 and no reduction in the case of amine 10. This shows
that it is the competing collapse of the tetrahedral complex after
the first B-H addition to provide the aldehyde that drives the
competing reduction to the methyl derivative. It is also
Figure 2. X-ray structure of pinacol ester of (pR)-5 (30% thermal
ellipsoids; H atoms are omitted for clarity). The tetramethyldiox-
aborolane group is disordered between two oppositely twisted
conformations with the probabilities of 45% (solid) and 55%
(dashed).
Figure 3. X-ray structure and hydrogen bonding of (pR)-ami-
noboronic acid 6 (50% thermal ellipsoids). Symmetry codes: (i)
x+(1/2), (3/2)-y, 1-z; (ii) x-(1/2), (3/2)-y, 1-z.
O(2)-H‚‚‚O(3), involving one of the boronic hydroxyl groups.
The remaining hydroxyl forms an intermolecular hydrogen bond
O(1)-H‚‚‚O(3i) in 4 and O(1)-H‚‚‚O(2i) in 6, whereby the
molecules are linked into infinite chains spiralling around the
21 screw axes [(1/2) y (1/4)] or [ x (3/4) (1/2)], respectively.
Unusually, the intermolecular hydrogen bond in 6 is directed
almost perpendicular to the plane of the acceptor oxygen atom
or the B(OH)2 group generally.
The X-ray structure again confirms the (pR)-absolute stere-
ochemistry of the main component of 6, inherited from the
parent amide 4. However, we were unable to accurately measure
the enantiopurity of this material prepared by this route using
a series of different chiral HPLC columns, and we therefore
examined an alternative route, which was expected to be more
amenable to enantiomeric excess determination. This involved
(14) Pickett, T. E.; Roca, F. X.; Richards, C. J. J. Org. Chem. 2003, 68,
2592-2599.
(15) Routaboul, L.; Chiffre, J.; Balavoine, G. G. A.; Daran, J. C.;
Manoury, E. J. Organomet. Chem. 2001, 637-639, 364-317.

Aminoboronic Acid Ferrocene DeriVatiVes
Organometallics, Vol. 26, No. 9, 2007 2417
noteworthy that the intermediate alcohol is not observed, which
presumably means the corresponding borate complex readily
undergoes rapid fragmentation and reduction. However, small
amounts of a somewhat impure compound tentatively assigned
as the corresponding primary alcohol have been observed in
reactions that did not go to completion.
Experimental Section
Ferrocenecarboxylic Acid (2). To a solution of ferrocenecar-
boxaldehyde 1 (11.24 g, 52 mmol) in acetone (500 mL) at 0 °C
was added a solution of KMnO4 (29 g, 183 mmol) in water (100
mL). After 2 h, a solution of aqueous NaOH (20% w/v) (50 mL)
was added. The reaction mixture was filtered through Celite and
washed with aqueous NaOH (10% w/v) (75 mL). The filtrate was
washed by diethyl ether (3 × 150 mL) to remove the ferrocene
carboxaldehyde, acidified to pH 4-5 with a solution of aqueous
HCl (2.4 M solution), and extracted with diethyl ether (5 × 100
mL). The combined organic phase was washed with brine (3 ×
100 mL), dried, filtered, and evaporated to give ferrocenecarboxylic
acid 2 (7.08 g, 60%) as orange needles: mp 205 °C (dec) [lit.13
210 °C (dec)]; 1H NMR (CDCl3, 400 MHz) δ 4.19 (s, 5H), 4.40 (t,
2H, J ) 2.0 Hz), 4.80 (t, 2H, J ) 2.0).
N,N-Diisopropylferrocenecarboxamide (3). To a stirred solu-
tion of 2 (12.19 g, 53 mmol) in dry toluene (90 mL) under argon
were added oxalyl chloride (9.24 mL, 106 mmol) and N,N-
dimethylformamide (0.6 mL). After 6 h, the excess oxalyl chloride
was evaporated and resuspended and re-evaporated with an equal
volume of toluene. Anhydrous diethyl ether (300 mL) was added,
and the solution was cooled to 0 °C and treated with dry
diisopropylamine (20.8 mL, 0.148 mmol). After 12 h, the mixture
was diluted with saturated aqueous NH4Cl (75 mL) and extracted
with diethyl ether (3 × 50 mL). The combined organic extract was
washed with H2O (3 × 50 mL) and brine (3 × 50 mL), dried,
filtered, and evaporated to give a brown residue, which was purified
by silica gel chromatography (9:1, hexane/ethyl acetate as eluent)
to give amide 3 as orange needles (14.7 g, 89%): mp 79-81 °C
(lit.11a 88-91 °C). All spectroscopic and analytical properties were
identical to those reported in the literature.11a
(pR)-2-(N,N-Diisopropylamido)ferroceneboronic Acid (4). A
solution of (-)-sparteine (12.9 mL, 56.0 mmol) in diethyl ether
(250 mL) was stirred at room temperature under argon for 30 min,
then cooled to -78 °C and treated with n-butyllithium (35.0 mL
of a 1.6 M solution in hexanes) over 5 min, and the resulting
solution was stirred for a further 30 min. A solution of N,N-
diisopropyl ferrocenecarboxamide 3 (8.77 g, 28.0 mmol) in diethyl
ether (250 mL) was then added dropwise via syringe pump over 9
h. After a further 10 h at -78 °C, trimethylborate (9.4 mL, 84.0
mmol) was added and the solution was stirred for a further 2 h
before warming to room temperature. After quenching with water
(200 mL), the mixture was extracted with diethyl ether (3 × 100
mL), and the combined extracts were washed with brine (3 × 100
mL) and evaporated to give a viscous, red oil. Addition of hexane
(ca. 30 mL) promoted crystallization of the desired compound 4
as small orange needles (6.0 g, 60%), which were suitable for X-ray
Isolation of (pR)-bromide 8 in high enantiomeric excess then
allowed us to prepare the (pR)-boronic acid 6 by lithium-
halogen exchange, followed by transmetalation with trimethyl
borate, which provided clean conversion to the boronic acid in
high ee (Scheme 5). Comparing the optical rotations of the
sample of 6 prepared by this route (96% ee) with that produced
by the initial route (Scheme 2) shows an optical purity of 70%
for the direct synthesis of the boronic acid 6 from Scheme 2.
This demonstrates the benefit of accessing boronic acid 6 via
initial formation of the higher ee bromide 8.
Having isolated the boronic acid 6, it was readily converted
to the corresponding trifluoroborate ammonium salt 12 with
potassium hydrogen difluoride. As in the corresponding benzene
series,9b the preferential formation of this ammonium salt rather
than formation of the potassium intramolecular B-N complex9a
is due to the more basic diisopropylamine function. The X-ray
structure of (pR)-12 (Figure 4) confirms its zwitterionic nature.
The molecular conformation is similar to that of the corre-
sponding (racemic) dimethylamino analogue,8d as well as i-Pr2-
NH-C6H4-BF3.9b In the dimethylamino analogue,8d an in-
tramolecular hydrogen bond, N-H‚‚‚F (N‚‚‚F 2.996(4) Å),
coexists with a stronger intermolecular one (N‚‚‚F 2.854(3) Å)
to the same F atom, thus forming a F2H2 parallelogram. Structure
12 contains only the intramolecular bond, N-H‚‚‚F(1), which
is consequently much stronger than in the dimethylamino
analogue8d (N‚‚‚F 2.848(2) Å), while the B-F(1) bond of 1.444-
(2) Å is substantially longer than the other two B-F bonds
(mean 1.409(2) Å). The C-B bond length in 12 (1.604(2) Å)
is intermediate between those in the dimethylamino analogue
(1.590(4) Å)8d and i-Pr2NH-C6H4-BF3 (1.618(1) Å) and
similar to those in tetrabutylammonium and potassium salts of
PhBF3 (1.600(3) and 1.61(1) Å, respectively).16 Thus, the
-
C-BF3 bond may be substantially weaker than the C-B bond
in the boronic acids 4 (1.560(2) Å) and 6 (1.563(3) Å) and the
ester 5 (1.545(4) Å).
Figure 4 also confirms the (pR)-absolute stereochemistry of
trifluoroborate 12 and the tetrahedral nature of the boron-
fluoride system, as confirmed by the 11B NMR shift of δ 4.53.
25
analysis: mp 153-154 °C (lit.11a 148-150 °C); [R]D ) -55 (c
0.006, CH2Cl2). All spectroscopic and analytical properties were
identical to those reported in the literature;11a 11B NMR (CDCl3,
128 MHz) 30.5 (br s).
(pR)-N,N-Diisopropyl-2-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboro-
lan-2-yl)ferrocenecarboxamide (5). Pinacol (0.195 g, 1.65 mmol)
and (pR)-2-(N,N-diisopropylamido)ferroceneboronic acid 4 (0.5 g,
1.40 mmol) were dissolved in diethyl ether (10 mL) and stirred
overnight. The solvent was evaporated and hexane added to
precipitate the crude product. The resulting solid was then recrystal-
lized from diethyl ether to give the ester 5 (0.5 g, 81%), crystals of
Conclusions
The synthesis of planar chiral aminoboronate systems bas-
ed on a ferrocene framework has been realized through
(-)-sparteine-directed metalation methodology, with the more
enantioselective route involving initial enantioselective bromi-
nation of amide 3, followed by amide reduction and borylation
via lithium-halogen exchange. This efficient enantioselective
process is convenient for the synthesis of systems such as 6,
and subsequent structural studies, both solid and solution state,
clearly show the general advantage of suitably hindered sub-
stituents on nitrogen for the effective prevention of boron-
nitrogen chelation, which allow these two functional groups to
act cooperatively in potential catalytic processes. Further studies
in this area will be reported in due course.
25
which were suitable for X-ray analysis: mp ) 178-179 °C; [R]D
) +15 (c 0.002, CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 0.91 and
0.99 (each d, 3H, J ) 6.4 Hz), 1.30 and 1.31 (each s, 6H), 1.49
(apparent t, 6H, J ) 6.8 Hz), 3.36 (septet, 1H, J ) 6.8 Hz), 3.54
(septet, 1H, J ) 6.8 Hz), 4.33 (s, 5H), 4.34 (t, 1H, J ) 2.4 Hz),
4.38 (q, 1H, J ) 1.2, 2.4 Hz), 4.45 (q, 1H, J ) 1.2, 2.4 Hz); 13C
NMR (CDCl3, 100 MHz) δ 19.8, 19.9, 21.1, 21.6 (CH-CH3), 25.0,
25.5, 45.7, 50.7, 70.4, 70.5, 71.9, 72.8, 83.4, 96.5, 168.1; 11B NMR
(CDCl3, 160 MHz) δ 32.6 (br s); IR (nujol, cm-1) 1634, 1487,
(16) (a) Quach, T. D.; Batey, R. A.; Lough, A. J. Acta Crystallogr. Sect.
E 2001, 57, o688-o689. (b) Conole, G.; Clough, A.; Whiting, A. Acta
Crystallogr. Sect. C 1995, 51, 1056-1059.

2418 Organometallics, Vol. 26, No. 9, 2007
BatsanoV et al.
1369, 1355, 1316, 1214, 1141, 1031, 985; MS (ES+, m/z, %) 439
(M + H, 100). Anal. Calcd for C23H44NO3B: C, 62.90; H, 7.80;
N, 3.19. Found: C, 62.71; H, 7.76; N, 3.12.
34 °C; [R]D25 ) -10 (c 0.01, CHCl3); 1H NMR (CDCl3, 400 MHz)
δ 0.93 (d, 6H, J ) 2.8 Hz), 0.95 (d, 6H, J ) 3.2 Hz), 2.85-3.10
(m, 2H), 3.45 (dd, 2H, J ) 14.4 Hz), 3.94-3.98 (br s, 1H), 4.06
(s, 5H), 4.16-4.20 (br s, 1H), 4.26-4.30 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 20.3, 21.4, 42.7, 47.2, 65.6, 68.3, 69.4, 71.0,
80.1, 87.2; IR (KBr, cm-1) 2962, 1360, 1233, 819, 488; MS (ES+,
m/z, %) 278.0 (100), 280.0 (80), 379.0 (M + H, 10), 280.0 (M +
H + 2, 8). Anal. Calcd for C17H24BrFeN: C, 54.00; H, 6.40; N,
3.70. Found: C, 53.88; H, 6.41; N, 3.33. (pR)-2-Bromomethylfer-
rocene 9 was formed as orange crystals (0.15 g, 11%): mp
(pR)-2-(N,N-Diisopropylaminomethyl)ferrocenylboronic Acid
(6). A solution of (pR)-2-(N,N-diisopropylamido)ferroceneboronic
acid 4 (0.188 g, 0.52 mmol) in THF (1.8 mL) under argon was
treated with borane dimethylsulfide (2.44 mL of a 2.0 M solution
in THF). The solution was heated at reflux for 5 days, cooled to
room temperature, and quenched with aqueous NaOH (1 mL, 5%
solution) dropwise. The resulting solution was refluxed for 1 h and
extracted with diethyl ether (3 × 1 mL), and the combined extracts
were washed with brine (3 × 1 mL), dried, and evaporated to give
a crude orange oil. The residue was purified by neutral alumina
chromatography (gradient elution, hexane, hexane/ethyl acetate,
ethyl acetate, ethyl acetate/methanol, and methanol) to give an
orange solid, which was recrystallized from acetonitrile/water
to give (pR)-6 as orange needles (0.070 g, 40%): mp )
145-148 °C; [R]D25 ) +88 (c 0.0092, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 0.91 (d, 6H, J ) 6.8 Hz), 1.05 (d, 6H, J ) 6.8 Hz),
2.95-3.10 (m, 2H), 3.35-4.00 (dd, 2H, J ) 13.0 Hz), 4.05 (s,
5H), 4.18-4.19 (m, 1H), 4.20 (s, 1H), 4.35 (s, 1H), 7.20-8.20 (br
s, 2H); 13C NMR (CDCl3, 100 MHz) δ 18.6, 20.8, 46.0, 47.3, 69.4,
69.5, 73.9, 75.1, 88.3; 11B NMR (CDCl3, 128 MHz) δ 32.3; IR
(KBr, cm-1) 3455, 2970, 1357, 1450, 1234; MS (ES+, m/z, %)
243 (100), 344 (M + H, 58), 669 (21); HRMS (ES+, m/z, %) found
(M+ + H) 344.14804, C17H27BNO254Fe requires 344.14788. Anal.
Calcd for C17H26BFeNO2: C, 59.52; H, 7.64; N, 4.08. Found: C,
59.61; H, 7.71; N, 3.97.
25
83-84 °C; [R]D ) +32.7 (c 0.0052, CH2Cl2) {lit. (opposite
enantiomer)14 mp 82-83 °C, [R]D ) -27 (c 0.11, EtOH)}; all
25
other spectroscopic and analytical properties were identical to those
reported in the literature.14
(Ferrocenylmethyl)diisopropylamine (10). Method A. To a
suspension of NaBH4 (2.9 g, 0.077 mol) in THF (60 mL) at 0 °C
under argon was added a solution of iodine (8.12 g, 0.032 mol) in
THF (40 mL) dropwise. The reaction was stirred for 0.5 h and
allowed to warm to room temperature over 1.5 h. N,N-Diisopro-
pylamidoferrocene 3 (10.0 g, 0.0319 mol) was then added portion-
wise over 0.5 h and the mixture refluxed overnight. After allowing
the solution to cool to room temperature, dilute hydrochloric acid
(200 mL of a 6 M aqueous solution) was added and the reaction
stirred until no further hydrogen was evolved. After evaporation,
solid sodium hydroxide was added until the pH became strongly
basic (pH 12) and the solution was extracted with diethyl ether.
The organic phase was then back-extracted with dilute HCl (3 ×
100 mL of a 6 M aqueous solution). The aqueous phase was then
basified with solid sodium hydroxide until the pH became strongly
basic (pH 12) and re-extracted with diethyl ether (3 × 150 mL).
The combined extracts were dried and evaporated to give a crude
red oil (6.0 g), which was purified by silica gel chromatography
(gradient elution, 1:1 hexane/ethyl acetate to ethyl acetate) to give
10 (2.50 g, 26%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ
1.03 (d, 12H, J ) 6.8), 3.08 (septet, 2H, J ) 6.6), 3.47 (s, 2H),
4.08 (s, 1H), 4.13 (s, 5H), 4.22 (s, 2H); 13C NMR (CDCl3, 100
(pR)-2-Bromo-(N,N-diisopropyl)ferrocenecarboxamide (7). To
a solution of (-)-sparteine (5.10 mL, 22.3 mmol) in diethyl ether
(80 mL) stirred under argon at -78 °C was added n-butyllithium
(14 mL of a 1.6 M solution in hexane) over 10 min. The resulting
solution was stirred for 1 h and treated with a solution of 3 (5.37
g, 17.1 mmol) in diethyl ether (60 mL) over 30 min. After 1.5 h,
a solution of 1,2-dibromotetrachloroethane (11.2 g, 34.2 mmol) in
diethyl ether (60 mL) was added over 20 min. After 1 h, the mixture
was warmed to room temperature, quenched with a saturated
aqueous solution of NH4Cl (75 mL), and extracted with diethyl
ether (3 × 40 mL). The combined organic extract was washed with
H2O (3 × 40 mL), then brine (3 × 40 mL), dried, filtered, and
evaporated to give an orange residue, which was purified by silica
gel chromatography (9:1, hexane/ethyl acetate as eluent) to give
(pR)-bromide 7 (6.7 g, >99%) as orange needles: mp ) 79-80
°C; ee ) 96%, Chiralcel OD, hexane/ether (0.5% of diethylamine),
80/20, 0.4 mL/min, 27.9 min, 33.2 min; [R]D25 +36 (c 0.1, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 0.93 (d, 3 H, J ) 5.2 Hz), 1.02 (d,
3H, J ) 6.0 Hz), 1.43 (d, 6H, J ) 6.0 Hz), 3.30-3.45 (m, 1H),
3.60-3.75 (m, 1H), 4.03 (t, 1H, J ) 2.6 Hz), 4.17 (dd, 1H, J )
1.2, 2.6 Hz), 4.32 (s, 5H), 4.35 (t, 1H, J ) 1.2, 2.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 20.9, 45.9, 50.9, 65.5, 66.3, 69.1, 72.4, 89.4,
89.6, 165.5; IR (KBr, cm-1) 2965, 1629, 1473, 1321, 816, 487;
MS (ES+, m/z, %) 393.0 (M + H, 100), 395.0 (M + H + 2, 82).
Anal. Calcd for C17H22BrFeNO: C, 52.00; H, 5.60; N, 3.60.
Found: C, 51.75; H, 5.66; N, 3.43.
MHz) δ 21.1, 44.3, 47.6, 67.5, 68.7, 69.8, 88.9; IR (neat, cm-1
)
inter alia 2963, 1685, 1459, 1361, 1165, 1105, 817; MS (ES+,
m/z, %) inter alia 300 (M+ + H, 39), 199 (100); HRMS (ES+,
m/z, %) found (M + H) 300.1395, C17H26N56Fe requires 300.1415.
Method B. To a solution of 3 (0.2 g, 0.64 mmol) in dry
tetrahydrofuran (11 mL) under argon was added borane dimethyl-
sulfide (1.3 mL, 2.6 mmol, 2 M solution in THF). The reaction
mixture was stirred at reflux for 24 h, cooled at 0 °C, and quenched
slowly with an aqueous solution of NaOH (10% w/v) until there
was no gas evolution. The mixture was heated to reflux for 2 h,
cooled to room temperature, and extracted with diethyl ether (3 ×
5 mL), and the combined organic extract was washed with brine
(3 × 5 mL), dried, filtered, and evaporated to give an orange
residue, which was purified by silica gel chromatography (gradient
elution, 9:1 hexane/ethyl acetate to ethyl acetate) to give 10 (69
mg, 36%) as a yellow oil and 11 as yellow solid (3 mg, 2%), which
was identical to that reported in the literature.17
(pR)-2-[(N,N-Diisopropylamino)methyl]ferrocenylboronic Acid
(6). To a solution of 8 (2.95 g. 7.80 mmol) in 29 mL of freshly
dried tetrahydrofuran under argon at -78 °C was added slowly
via syringe 5.85 mL (9.36 mmol) of n-butyllithium. After 45 min,
0.961 mL (8.58 mmol) of trimethylborate was added via syringe
at -78 °C. The reaction mixture was stirred for 45 min, then was
warmed to room temperature. The reaction was quenched with water
and extracted with diethyl ether (3 × 10 mL). The combined organic
phase was washed with brine (3 × 15 mL), dried, filtered, and
(pR)-2-Bromo-(N,N-diisopropylaminomethyl)ferrocene (8).
To a solution of (pR)-7 (1.92 g, 4.89 mmol) in dry tetrahydrofuran
(85 mL) under argon was added borane dimethylsulfide (10 mL,
20 mmol, 2 M solution in THF). The reaction mixture was stirred
at reflux for 24 h, cooled at 0 °C, and quenched slowly with an
aqueous solution of NaOH (10% w/v) until there was no gas
evolution. The mixture was heated to reflux for 2 h, cooled to room
temperature, and extracted with diethyl ether (3 × 50 mL), and
the combined organic extract was washed with brine (3 × 50 mL),
dried, filtered, and evaporated to give an orange residue, which
was purified by silica gel chromatography (gradient elution, 9:1
hexane/ethyl acetate to ethyl acetate) to give (pR)-8 (1.0 g, 54%)
as a yellow oil, which solidifies upon storage in the freezer: mp
(17) (a) Pickett, T. E.; Richards, C. J. Tetrahedron Lett. 1999, 40, 5251-
5254. (b) Nesmeyanov, A. N.; Kochetkova, N. S.; Leonova, E. V.; Fedin,
E. I.; Petrovskii, P. V. J. Organomet. Chem. 1972, 39, 173-177. (c) Koridze,
A. A.; Petrovskii, P. V.; Mokhov, A. I.; Lutsenko, A. I. J. Organomet.
Chem. 1977, 136, 57-63. (d) Koridze, A. A.; Petrovskii, P. V.; Gubin, S.
P.; Sokolov, V. I.; Mokhov, A. I. J. Organomet. Chem. 1977, 136, 65-71.

Aminoboronic Acid Ferrocene DeriVatiVes
Organometallics, Vol. 26, No. 9, 2007 2419
Table 1. Crystallographic Data
5
4
6
12
622151
CCDC deposit no.
622148
622149
622150
formula
fw
C17H24BFeNO3
357.03
C23H34BFeNO3
439.17
C17H26BFeNO2
343.05
C17H25BF3FeN
367.04
T (K)
120
200
120
120
cryst syst
space group (no.)
a (Å)
b (Å)
c (Å)
orthorhombic
P212121 (# 19)
8.1087(8)
12.016(1)
17.531(2)
90
1708.1(3)
4
1.388
monoclinic
P21 (# 4)
7.3099(4)
10.2092(5)
15.5910(7)
97.41(1)
1153.8(8)
2
orthorhombic
P212121 (# 19)
7.1359(4)
11.753(1)
20.110(2)
90
1686.6(2)
4
1.351
orthorhombic
P212121 (# 19)
10.842(1)
11.304(1)
13.971(1)
90
1712.3(3)
4
1.424
â (deg)
V (Å3)
Z
F
calcd (g cm-3
)
1.264
0.68
µ (mm-1
)
0.90
0.90
0.91
no. of reflns total
no. of unique reflns
Rint
18 775
16 066
23 970
18 515
3836, 3710a
0.024
6714, 5147a
0.036
4914, 3839a
0.083
6168, 5488a
0.028
R1,a,b wR2
0.021, 0.053
0.019(9)
0.043, 0.107
-0.021(15)
0.038, 0.075
-0.028(15)
0.030, 0.074
-0.003(9)
c
Flack param
b
c
2
2
2
a Reflections with I > 2σ(I). R1 ) ∑||Fo| - |Fc||/∑|Fo|. wR2 ) {∑[w(Fo - Fc )2]/∑[w(Fo )2]}1/2
.
concentrated in Vacuo. The orange residue was purified by flash
chromatography on aluminum oxide using a graduated elution
(hexane, hexane/ethyl acetate, ethyl acetate, ethyl acetate/methanol,
methanol as eluent). The fractions containing the boronic acid and
the methylboronate ester were concentrated, and the solid was
recrystallized from acetonitrile/water. Filtration gave 6 (1.50 g, 65%)
as orange needles, which were suitable for X-ray analysis: mp )
6K CCD area detector, using graphite-monochromated Mo KR
radiation (λ ) 0.71073 Å) and Cryostream (Oxford Cryosystems)
open-flow N2 cryostat and corrected for absorption by a semiem-
pirical method based on Laue equivalents.18 The structures were
solved by direct methods and refined by full-matrix least-squares
against F2 of all unique data, using SHELXTL software.19 Absolute
configurations of all compounds were determined reliably from
anomalous scattering, using the Flack method.20 On cooling,
monoclinic crystals of 5 underwent a reversible, second-order phase
transition into a triclinic (pseudomonoclinic) phase. The R and γ
angles began to deviate significantly from 90° around 145 K; at
120 K the lattice parameters are a ) 7.295(2) Å, b ) 10.163(2) Å,
c ) 15.595(3) Å, R ) 90.28(1)°, â ) 97.52(1)°, γ ) 91.88(1)°, V
) 1145.7(7) Å3. Crystal data and other experimental details are
listed in Table 1.
25
144-150 °C; [R]D ) +121 (c 0.01, CHCl3). All spectroscopic
and analytical properties were identical to those reported above.
(pR)-N-{[2-(Difluoroborylferrocenyl]methyl}-N,N-diisopropy-
lamine Hydrofluoride (12). (pR)-2-(N,N-Diisopropylaminomethyl)-
ferrocenylboronic acid 6 (1.0 g, 3.0 mmol) was dissolved in
methanol (25 mL) and treated with a solution of KHF2 (1.4 g, 17.9
mmol) in water (5 mL). After stirring the resulting suspension for
0.5 h, acetone (50 mL) was added and the resulting solution stirred
for a further 0.5 h. Evaporation gave a yellow residue, which was
extracted with DCM (ca. 30 mL), filtered, and re-evaporated to
give the HF salt 12 as a yellow powder in quantitative yield. Slow
evaporation from acetone/DCM gave crystals suitable for X-ray
Acknowledgment. We thank the EPSRC for research grants
(GR/T22759/01 and GR/R24722/01) and Professor V. Snieckus
(Queen’s University, Canada) for helpful discussions.
25
analysis: mp ) 80 °C (dec); [R]D ) +183 (c 0.0012, CH2Cl2);
1H NMR (CDCl3, 400 MHz) δ 1.15, 1.28, 1.43, and 1.57 (each d,
3H, J ) 6.8 Hz), 3.53 (septet, 1H, J ) 6.8 Hz), 3.64-3.76 (m,
2H), 4.02 (br s, 1H), 4.13 (t, 1H, J ) 2 Hz), 4.19 (s, 5H), 4.46 (s,
1H), 4.68 (dd, 1H, J ) 1.9, 12.6 Hz), 7.46 (v br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 15.9, 18.5, 18.8, 20.4, 48.7, 51.6, 52.2, 68.2,
69.1, 70.0, 74.6, 77.2; 11B NMR (CDCl3, 128 MHz) δ 4.53 (br s);
19F NMR (CDCl3, 188 MHz) δ -133.2 (br s); MS (ES+, m/z, %)
inter alia (M + H) 368 (49), 199 (100); IR (nujol, cm-1) 3121,
3077, 1400, 1343, 1310, 1277, 1228, 1188, 1151, 1134, 1119, 1103,
1067, 1036, 1012, 983, 965, 936, 897, 814; HRMS (ES+, m/z, %)
found (M + H) 368.1475, C17H26BNF356Fe requires 368.1460.
X-ray Crystallography. Single-crystal diffraction data were
collected on a Bruker three-circle diffractometer with a SMART
Supporting Information Available: General experimental
1
methods, H and 13C NMR spectra for compounds 8 and 10, and
crystallographic information (in CIF format) for 4, 5, 6, and 12 are
available free of charge via the Internet at http://pubs.acs.org.
OM070038L
(18) Sheldrick, G. M. SADABS, version 2.10; Bruker-Nonius AXS:
Madison, WI, 2003.
(19) Sheldrick, G. M. SHELXTL, version 6.14; Bruker-Nonius AXS:
Madison, WI, 2003.
(20) (a) Flack, H. D. Acta Crystallogr. Sect. A 1983, 39, 876-881. (b)
Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143-1148.